Development of Epipolythiodiketopiperazine Syntheses and the Total Synthesis of
Diketopiperazine Alkaloids
MASSACHUSETTS INSTITUTE
OF TECHNOLOLGY
byby
Timothy C. Adams
MAY 192015
B.S., Chemistry
University of Florida, 2009
LIBRARIES
Submitted to the Department of Chemistry
In Partial Fulfillment of the Requirements for the Degree of
DOCTOR OF PHILOSOPHY
IN ORGANIC CHEMISTRY
at the
Massachusetts Institute of Technology
February 201A
@20 15 Massachusetts Institute of Technology
All right reserved
Signature of A uthor................................
.
Signature redacted
Department of Chemistry
January 5, 2014
Signature redacted
Certified by.........................................
.
Profi
o
m
A
SMoha
d Movassaghi
Prcfessor of Chemistry
Thesis Supervisor
Signature redacted
Accepted by...........................................................
Professor Robert W. Field
Chairman, Department Committee on Graduate Studies
1
This doctoral thesis has been examined by a committee in the Department of Chemistry
as follows:
Professor Mohammad Movassaghi.......
Signature redacted
S-/
Professor Rick Lane Danheiser..........
Professor Stephen L. Buchwald ..........
Th/sis Supervisor
ig nature redacted....
Signature redacted
unairman
Committee Member
2
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3
Acknowledgements
First and foremost, I would like to thank my advisor Professor Mohammad
Movassaghi for the opportunity to study organic synthesis in his lab and for carrying out
the research presented in this dissertation. I have learned a tremendous amount with
respect to chemical theory, research techniques, and chemical analysis. Mo's intuition
and insightful support has been more than helpful in determining the proper direction of
the research. Mo has also been helpful with regard to professionalism, precision, and
diligence. I hope to carry the lesson learned from him and my graduate research
experience forward in my future endeavors.
I am also thankful for Professor Gregory C. Fu for his brief time serving as a
faculty member of my thesis committee. Since taking my first chemistry course at MIT
with Professor Fu, I developed a deeper mechanistic understanding of organometallic and
physical organic chemistry. In addition, I have become more appreciative and
knowledgeable of the advanced techniques and strategies that chemists utilize to
determine reaction kinetics chemical thermodynamics.
I would like to thank Professors Rick L. Danheiser for serving as the chair of my
thesis committee and for providing guidance during my time at MIT. I am very much
appreciative of Rick for providing his support and advice to me during my time here at
MIT. I was able to work closely with Rick as a teaching assistant for his undergraduate
5.12 organic chemistry I course. His passion for instructing and nurturing undergraduate
and graduate students alike is well known to many in the department and his teaching
influence has given me a new perspective on the rewards of mentoring others.
I am thankful for Professor Buchwald joining my committee after Professor Fu's
relocation to the chemistry department at Caltech. He was great source of comfort and
reassurance as I progressed through my graduate studies. I found his class on organometallic chemistry to be quite helpful and the course was one of the most comprehensive
and informative courses on the subject of organometallic chemistry.
I would also like to thank my coworkers in the Movassaghi Lab, particularly Dr.
Nicolas Boyer, Dr. Alexis Coste, Dr. Joshua Payette, and Dr. Justin Kim. Dr. Kim's
incredible insight in physical and synthetic organic chemistry was an aspiration. His level
of knowledge of organic chemistry, his experimental technique, meticulous precision,
and dedication to the lab truly set him apart from all others. Dr. Kim was the best
example of what a hard-working chemistry graduate student should be. I'm honored to
have worked next to him in the laboratory and am thankful for his advice and council
over the years. I am sure he will go on to successfully tackle challenging problems in
chemistry and will succeed in advancing our understanding of chemical reactivity.
4
Preface
Portions of this work have been adapted from the following articles that were co-written
by the author and are reproduced in part with permission from:
Coste, A.; Kim, J.; Adams, T. C.; Movassaghi M. Chem. Sci. 2013, 4, 3191.
Copyright 2013 Royal Society of Chemistry.
5
Development of Epipolythiodiketopiperazine Syntheses and the Total Synthesis of
Diketopiperazine Alkaloids
By
Timothy Adams
Submitted to the Department of Chemistry
on February 15, 2015 in Partial Fullfillment of the
Requirements for the Degree of Doctor of Philosophy in
Organic Chemistry
ABSTRACT
I. The Development of Epipolythiodiketopiperazine (ETP) Syntheses
Epipolythiodiketopiperazine (ETP) alkaloids represent a structurally complex and
biologically potent class of secondary fungal metabolites and these molecules have been
known since the 1930s. The biological activity of these molecules is quite potent and the
modes of toxicity possessed by these agents involve the generation of reactive oxygen
species (ROS) and direct manipulation of target proteins. The biosynthesis of these
compounds has been the subject of active study and we have presented our own
hypothesis how theses molecules are synthesized by fungi. Efforts to synthesize these
alkaloids have been known since the late 1960 to early 1970s and all have highlighted the
need to install the requisite disulfide bridge at a late-stage. The ETP motif is known to be
notoriously sensitive as it is reactive towards bases and Lewis acids, and in
photochemical and redox reactions.
II. Development of ETP Syntheses for the Application of the Total Synthesis of (+)Bionectin A
The concise and efficient total synthesis of (+)-bionectin A is described. Our approach to
these natural products features a new and scalable method for erythro-hydroxytryptophan amino acid synthesis and a new mercaptan reagent for the
epipolythiodiketopiperazine (ETP) synthesis that can be unraveled under very mild
conditions. The development of this new reagent was accomplished after exploring the
acid promoted incorporation of different alkyl thiols into diketopiperazine diol substrates.
III. Concise Total Synthesis of (+)-Luteoalbusin A
The first total synthesis of (+)-luteoalbusin A is described. Our concise and
enantioselective synthesis began from the simple starting materials L-alanine and Ltryptophan. Transformations central to our route include a highly regioselective FriedelCrafts indolization that can be performed on multi-gram scale, as well as a highly
diastereoselective oxidation and thiolation. Moreover, this divergent synthesis features a
6
common aminothioisobutyryl intermediate that can be utilized to construct (+)luteoalbusin A. The spectral data obtained from the synthetic samples confirmed the
assigned structure for this natural product.
Thesis Supervisor: Professor Mohammad Movassaghi
Title: Professor of Chemistry
7
Table of Contents
I. The Development of Epipolythiodiketopiperazine (ETP) Syntheses
12
Introduction and Background
13
Biological Activity of ETPs
14
Biosynthesis of these Compounds
17
Modified Biosynthetic Hypothesis
21
Methods of Accessing ETPs
Representative Syntheses of ETP Natural Products
Conclusion
24
29
35
II. Development of ETP Syntheses for the Application of the Total Synthesis
40
of (+)-Bionectin A
Introduction and Background
Development of Alkyl Mercaptan Reagent for ETP syntheses
Results and Discussion
Development of Alkylthiol Nucleophiles
Total Synthesis of (+)-Bionectin A
41
43
45
45
48
Conclusion
52
Experimental Section
55
III. Concise Total Synthesis of (+)-Luteoalbusin A
72
Introduction and Background
Results and Discussion
Retrosynthetic Analysis
73
74
74
Synthetic Approach
75
Conclusion
Experimental Section
78
84
Appendix A: Spectra for Chapter II
Appendix B: Spectra for Chapter III
106
121
Curriculum Vitae
146
8
abbreviations
A
Ac
app
aq
atm
Boc
br
Bu
Bz,
OC
C
C
CAM
cat.
cm
cm-1
cod
d
d
d
6
DART
dba
diam.
DMA
DMAP
DMF
DMSO
DTBMP
dr
ECm
ee
El
equiv
ESI
Et
ETP
FT
g
gCOSY
h
ht
HMBC
HPLC
angstrom
specific rotation
acetyl
apparent
aqueous
atmosphere
tert-butoxycarbonyl
broad
butyl
benzoyl
degree Celsius
concentration
centi
ceric ammonium molybdate
Catalytic
centimeter
wavenumber
cyclooctadiene
days
doublet
deuterium
parts per million
direct analysis in real time
dibenylideneacetone
diameter
N,N-dimethylacetamide
4-(dimethylamino)pyridine
N,N-dimethylformamide
dimethylsulfoxide
2,6-di-tert-butyl-4-methylpyridine
diastereomeric ratio
half maximal effective concentration
enantiomeric excess
electronic ionization
equivalent
electronspray ionization
ethyl
epidithiodiketopiperazine
fourier transform
gram
gradient-selected correlation spectroscopy
hour
height
heteronuclear multiple bond correlation
high performance liquid chromatography
9
HRMS
HSQC
Hz
i
IC50
IR
J
high resolution mass spectroscopy
heternuclear single quantum correlation
Hertz
iso
half maximal inhibitory concentration
infrared
coupling constant
L
liter
m
m
m
medium
meta
meter
m
mili
M
M
mCPBA
Me
Mhz
min
mol
MOM
M.p.
MPLC
MS
m/z
N
NBS
molar
molecular mass
micro
meta-chloroperbenzoic acid
methyl
megahertz
minute
mole
methoxymethyl
melting point
medium performance liquid chromatography
mass spectrometry
mass to charge ratio
Normal
N-bromosuccinimide
NMP
N-methylpyrrolidine
NMR
nOe
NOESY
Nu
0
p
nuclear magnetic resonance
nuclear Overhauser effect
nuclear Overhauser effect spectroscopy
nucleophile
ortho
para
Ph
piv
PMA
phenyl
pivaloyl
phosphomolybdic acid
PMP
ppm
PPTS
para-methoxyphenyl
parts per million
pyridinium para-toluenesulfonate
Pr
py
propyl
pyridine
q
ref
Rf
ROESY
quartet
reference
retention factor
rotating frame nuclear Overhauser effect spectroscopy
10
rt
room temperature
s
s
s
SAR
SEM
SRB
str
t
t
TBA
sec
singlet
strong
structure activity relationship
2-(trimethylsilyl)ethoxymethyl
sulforhadoamine B
stretch
tert
triplet
tetrabutylammonium
TBS
tert-butyldimethylsilyl
Tf
TFA
THF
TLC
TMS
Ts
UV
trifluoromethanesulfonate
trifluoroacetic acid
tetrahydrofuran
thin layer chromatography
trimethylsilyl
para-toluenesulfonyl
ultraviolet
Vis
visible
w
weak
11
Chapter I.
I. The Development of Epipolythiodiketopiperazine (ETP) Syntheses
12
N0
Introduction and Background
0
H
H0M
FH N
0N
Me
gliotoxin
(1)
N
H
H
(+)-chaetocin A (2)
M
N'M
Me
N
0
4
(+)-11,11'-dideoxyverticillin A (4)
N
N(+)-chaetocin
Me
C (3)NMe
S~N'Me
H
MeMe
H
S
N
OHH
0
(+)-bionectin A (5)
0
HO
M
0
\
(+)-12,12'-dideoxychetracin A (6)
Figure 1. Representative epipolythiodiketopiperazine alkaloids.
Epipolythiodiketopiperazine (ETP) alkaloids represent a structurally complex and
biologically potent class of secondary fungal metabolites (Figure 1).I.2 This class of
compounds can be arranged in different categories, including monomeric, dimeric
C3,C3' (sp 3 -sp') linked homo- and heterodimers, as well as C3-(3'-indolyl) derivatives
(Figure 1). These molecules are all known to contain reactive bicyclic disulfide bonds
that exhibit reactivity towards oxidants, reductants, UV light, as well as strong acids and
bases. 4 Gliotoxin (1), a natural product that was first reported by Weindling in 1936 and
was later synthesized by Kishi and coworkers in 1970, represents one of the earliest
naturally occurring epidithiodiketopiperazines known. 5'6 The dimeric subset of these
alkaloids have been known since the 1970s, with the discovery of (+)-chaetocin A (2),
(+)-chaetocin C (3), and (+)-1 1,11l'-dideoxyverticillin A
(4).8'
The C3-(3'-indolyl)
alkaloids such as (+)-bionectin A (5) exhibit significant cytotoxic activity against the
murine P388 lymphocytic leukemia cell line."
13
Biological Activity of ETPs
Structure activity relationships (SAR) studies have shown the importance of the
ETP
motif in
these
molecules.'2 " There
are
several
known
ways
in which
epidithiodiketopiperazines alkaloids are known to induce cytotoxicity. These methods
include
direct sulfidation of cysteine residues of proteins
resulting in covalent
deactivation of the protein, by the evolution of reactive oxygen species through redox
cycling, and by the sequestration of zinc cations from proteins through the zinc-ejection
mechanism.
Evidence that advances the hypothesis for the deactivation of enzymes through
direct incorporation of the ETPs into proteins stems from toxicity studies of gliotoxin in
thymocyte cells.
With concentrations of gliotoxin greater than 50 [tM, calcium influx in
these cells had been observed and this was directly implicated in the toxicity of gliotoxin.
The increase in calcium flux is known to be due to the interaction of gliotoxin with a thiol
residue in the redox-sensitive plasma membrane calcium channel. The addition of
glutathione or dithiothreitol was found to inhibit this activity since the reduced ETP is
unable to oxidatively modify the thiol residues of proteins. This study provided evidence
for mixed disulfide formation as a possible means for the necrotic effects of gliotoxin.
Furthermore, gliotoxin was found to deactivate proteins such as alcohol dehydrogenase
by forming a 1:1 covalent complex with cysteine residue 281 or 282."
Redox cycling is another way in which these molecules can exhibit virulence
towards bacterial cells (Figure 1).13'5 This process was implicated as part of the toxic
biological activity of sporidesmin and of other ETPs on erythrocytes, where the toxic
14
0
SN' R1
R4
2GSH
4
02;
R3
R2
0
7
HS 0
GSSG
R
N'R1
R4
N r
R 3R'~~7R
0
R2
H
02
02
8
Scheme 1. ETP-catalyzed autoxidation of glutathione.
effects appear to be due the generation of reactive oxygen species. The process involves
the cycling between two alternative states of the ETP, from the oxidized, bicyclic form to
the reduced, dithiol state. In biological environments, the disulfide bond of ETPs such as
in 7, is known to break when exposed to cofactors such as glutathione.'" As the thiols of 8
cyclize to the closed form (7), an equivalent of the dimeric glutathione is reduced to two
equivalents of glutathione, and reactive oxygen species (ROS) such as hydrogen peroxide
and super oxide are generated by the ETP. These reactive oxygen species are thought to
promote cell death through oxidative damage or cell signaling."
Beyond the generation of harmful reactive oxygen species or the direct
incorporation of ETPs to proteins, the third known mechanism of ETP-related toxicity
has been linked to the sequestration of key cationic metals from critical proteins such as
p300 in thymocyte cells.' 5 These proteins are critical to the preservation of cells during
episodes of hypoxia-related stress. ETPs were found to reversibly bind to the CH 1
domain of these p300 proteins when reducing additives such as dithiothreitol (DDT) were
added. The CHI domain contains three key zinc cations, and when these active sites were
exposed to ETPs such as gliotoxin (1), Zn ejection from the domain was observed. This
observation suggested that the ETP can bind to the CH1 domain and coordinate to the
15
zinc cations, and in high enough concentrations, the ETP may form a stable complex with
the zinc atoms; thereby disrupting the tertiary structure of the domain. This interaction
has been found to severely impede the activity of these proteins.
Figure 2. ETP derivatives that lack cytotoxic effects.
O H
H
Ho
N,
Q
H
Me
N'MH
H
N HO
N
SO 2Ph 0
SO 2 Ph 0
SO 2 Ph
(-)-11
10
()9
Me
H 0N' Me
Boc
Me
* ~~3S'N,,OAc
Me
0
AM
0C0h
N H
SO2 Ph 0
Me
SPh
0~~N
MeOI-j
NM
'H
SO2Ph 0 0-
Me
I
~
N
PhCS
Me
S
Me
6
N H
0
SO 2Ph
Me
12
SO2Ph
N
AcO
PCMSCPh,
HS
Me
-N
(+)-13
(+)-14
Me
X
0
Me
According to our own SAR studies, the ETP motif in these molecules is
imperative for the anticancer biological activity against U-937 and HeLa cell lines.a
Based on the SAR studies of our prepared synthetic intermediates used in the preparation
of ETP alkaloids, those intermediates possessing non-oxidized u-positions such as
diketopiperazine
(+)-9,
open diketopiperazines
including
10, and ct-hydroxylated
analogues such as (-)-11 result in a complete loss of biological activity against U-937 and
Hela cell lines (Figure 2).3 Furthermore, the study demonstrated that sulfuration at only
the tryptophan C-u position is not sufficient for potent activity as in the case of Cli
monothiols 12, C 1I thioester (+)-13, and open chain polysulfane derivatives (+)-14. This
study, consistent with other reports on the activity of these compounds, suggests the need
for the disulfide bond for anticancer activity.
16
Biosynthesis of these compounds
OH
H
Me
R
N' R
Me
0
16
RN
19
0
HO(WN
me
NR
0
HS 0YN
Me,,
N'R
Me
N'R
R,N
Me
0
0
N
0H
15
17
20
HMe
Me
OH
R'N4
'Me
R'N
N'
HO
N'R
R'N
Me H
N'OH
HO'N
,,Me
R
0H
0
18
21
Scheme 2. Three common modes for the synthesis of ETPs
When considering the mechanism of the sulfidation of these diketopiperazines,
the introduction of sulfur at the C-a-positions of these diketopiperazines is believed to
proceed through the generation of reactive acyl iminiums.'" There are three pathways that
are described for the biosynthetic formation of the disulfide functional group of ETPs.
The biosynthetic routes for the incorporation of sulfur may be achieved through the
protonation of the enamide derived from 1-elimination (19), a-elimination of the ahydroxyamino acid (20), or by elimination of the N-Hydroxylated amino acid (21)
(Scheme 2)."
H HD
co2
T viride
-~
0
S
N'Me
.
H D
S
4
NH 3
OH 0 23
22
D0
C
Y. NH3
T vinrde
S NMe
oN
24OH
25
Scheme 3. Kirby's studies on the incorporation of
B-deuterated phenylalanine into gliotoxin.
17
The possibility of acyl imiunium formation resulting from protonation of the
enamide is certainly possible given the existence of these intermediates in biological
processes.'" These enamide intermediates may arise by (-elimination
of heteroatom
linked amino acid residues such as cysteine, threonine, serine, etc. Despite the existence
of these intermediates, feeding studies conducted by Kirby and coworkers suggests that
the intermediate involved in the formation of the ETP may not involve the enamine
(Scheme 3).20 Exposing monodeutero- and dideuterophenyl alanine (22 and 24) to T.
viride species of fungus
resulted
in the formation
of monodeutero-
(23)
and
dideuterogliotoxin (25) derivatives. Kirby had postulated that the benzylic proton
exchange of 23 should be faster than its rate of incorporation into gliotoxin. The cofactor,
pyridoxal, was implicated in proton/deuteron exchange at the methylene position.
Furthermore, although the exchange of the isotopic label could be enzymatically driven,
the process would not be necessary for the biosynthesis of gliotoxin. The formation of the
dideuterogliotoxin (25) derivative among the reaction products greatly diminished the
likelihood of the acyl iminium cation forming as a result of enamide protonation.
Having
considered
the enamide
alternative,
the
acyl
iminum
could
be
hypothetically generated from elimination of the C-hydroxylated species (20) or the NHydroxylated intermediate (21). Ottenheijm and coworkers championed the hypothesis
involving
the elimination
of the N-Hydroxyl
group. 8
,2'
N-Hydroxylated
natural
compounds are also known as in the case of mycelianamide2 2 and astechrome.'
Ottenheijm's biosynthetic proposal for the formation of gliotoxin begins with the
L-phenylalanine/L-serine diketopiperazine 26 (Scheme 4)." The substrate subsequently
18
H 2N
O
I
0
HN<L
O
HO 2C
NH
Q
OH
0
S-S
NH 2
-H2 0
OON fl 4
26
CO 2 H
0
N
1
OH
28
27
28
H Iju
OH 0
H,
HO 2C
S
H2N
M
HO 2C
31
0
H2N
H2 N
OH
0
OH
<NH 2
0
N
H 0
OH 29
OH
30
.1S N'Me
C02H
HO 2C
N
N
H 0
S
OH
OH
Me
eH
OH
Scheme 4. Ottenheijm's biosynthetic hypothesis for gliotoxin.
undergoes
enzymatic
oxidation
to form the bis-N,N-dihydroxylated
epoxide
27.
Dehydrative elimination of the N-Hydroxyl group, followed by cyclization generates
iminium cation 28. This electrophile is trapped by an equivalent of cystine, forming the
intermediary sulfonium 29. P-elimination from one of the cysteine residues would lead to
mixed disulfide 30. N-methylation of 30 leads to the formation of another acyl iminium
cation, 31, that undergoes nucleophilic trapping of the mixed disulfide to generate
bicyclic sulfonium 32. A final n-elimination of the sulfonium of 32 leads to the desired
product, gliotoxin 1.
Despite the precedence of N-Hydroxylated natural products, a closer examination
of the dimeric and C3-(3'-indolyl) ETP alkaloids reveals that many of these compounds
possess an N-methyl group.'" Given the widespread presence of the N-alkylated
variations of these natural products and of those which lack the disulfide bridge, it is
plausible that the installation of sulfur at the c-positions takes place after N-methylation.
19
Such a hypothesis is inconsistent with Ottenheijm's biosynthetic proposal, which would
require the involvement of non N-alkylated substrates.
Support for our proposal involving C-cx-hydroxlated intermediates (such as 20) as
biosynthetic precursors for the ETP is further substantiated by the existence of natural
products such as (+)-WIN 6482124 and (-)-ditryptophenaline.2' Although a biosynthetic
lineage of these compounds to related ETPs has yet to be proven, it is possible for the
installation of sulfur to be late stage. If indeed the ETP were formed at a late stage, such a
transformation would rely on the C-a-hydroxylated intermediate for accessing the acyl
iminium cation. Further support for the late stage installation of sulfur can be gathered
when considering
the biosynthetic
mechanism involved
in
the dimerization
of
cyclotryptamine compounds. For natural products such as (-)-chimonanthine, single
electron oxidation of the indole substructure in tryptamine is necessary for the
dimerization of these molecules; a process that may be incompatible with the presence of
the redox sensitive disulfide bond.
The C-a-hydroxylated precursor to the acyl iminium cation seemed the most
likely intermediate, and such reactive intermediates are known as in the biosynthesis of
ergotamine."s.26 We have conjectured in our biosynthetic proposal for these ETPs that the
oxidation of the C-u-centers can be accomplished by oxidative enzymes such as P450
monooxygenases. Evidence supporting this hypothesis can be found from experiments
conducted by Howlett and coworkers, whose biogenetic studies elucidated the genes
involved in the synthesis of these of sporidesmin PL and gliotoxin." In her gene
knockout and mutation studies, Howlett had identified biosynthetic gene clusters that
were critical to the production of proteins responsible for the modification of the side
20
chains in the epidithiodiketopiperazine substructure. Furthermore, he had determined that
a number of gene products involved in the biosynthetic pathways of sporidesmin PL and
gliotoxin bore sequence homology to key enzymes such as P450 monoxygenase, zinc
finger transcriptional regulator, dipeptidase, etc."-,2 7
When considering other structural elements of sporidesmin A, components such
as the sulfur bridge and the N-methyl group were found to be traced to isotopically
labeled feedstocks." The metabolic processing of S- 4 CH3 methionine by P. chartarum
led to formation of N-' 4 CH3 sporidesmin A. Furthermore, experiments conducted by
Towers and Wright suggests that the source of sulfur may be cysteine. 8 , 2 Although
isotopic labeling studies had shown inorganic sulfur and methionine to be competent
4
contributors of
S labeled sulfur atoms, L-cysteine 35 S was shown to contribute the
highest levels of
incorporated sporodesmin A (33) (Scheme 5).'8 The cofactor,
3S
pyridoxal, was implicated in the transfer of sulfur. For the formation of the disulfide
bond, the presumption is that the bond formation takes place spontaneously in the
presence of oxygen.
35
SH
H 3N
C02
MeO
15sme
35
Na 2 SO 4
low incorporation
H3N
0
HO
high incorporation
002
P chartarum
' N-Me
MeO
N . N
MeH
Me
sporidesmln A (33)
low incorporation
Scheme 5. Kirby's studies on the incorporation of b-deuterated phenylalanine
into gliotoxin.
Our Hypothesis for ETP Biogenesis
Based on our own biosynthetic hypothesis, which was later corroborated by
Hertweck and coworkers in 2014,27, it is believed that the installation of sulfur of the
21
yroxa phosphate
ETPs involves the addition of nucleophilc sulfur onto an acyl iminum species (Scheme
6 ).3d
Diketopiperazine 34 may undergo dihydroxylation at the a-positions to form
diketopiperazine diol 35. Ionization of the a-hydroxylated species forms the acyl iminum
36, which may undergo nucleophilc attack from the thiol of glutathione to form
HO
HO
0
O
H
+ R3
O
R1N RI1N
i
4
N'R3
R2
R'
N
R4
HOR
R2
O
NR
R1N
R2
N'R3
,-LP
-i
R4
O
-
R2
R
HO
NR0P3
H21'N
ORMe
3
NH
S
NMe0
R
NR3
R1'N
R4
O
-Gly
0
-H 240 f H
R2
+PLP
N'R3
R1 N
R
HPO_-H2
/
0
HO
R2 R
s
HO 3PO
R1'N
CO2
+ GO
gluta hione
R4N
N
NC
/
N
OH
HMeRCN
-PP0
r1NN3PO~
42
00C2
002
40
f1
R
R4
Me
PL
43PO-
-8
OH
HN /
+ HNN
N
Me
R
C2
N
S
CHO
Scheme 6. Our unifying biosynthetic proposal for the incoporation of sulfur In ETP alkaloids.
the glutathione-linked intermediate 37. Subsequent hydrolysis of the L-glutamine and Lglycine residues of the glutathione-ETP intermediate leads to the formation of the
cysteine-linked diketopiperazine 38. The removal of the bound cysteine residue could be
achieved by its interaction with the cofactor, pyridoxal phosphate (PLP). The free amine
of the cysteine-bound ETP adds to the aldehyde functional group of the PLP cofactor,
resulting in condensation and formation of the corresponding imine 39. The protonated
pyridinium acts as an electron sink, which allows for the tautomerization of the imine to
generate exocyclic enamine 40. Enamine 40 can expel the bound diketopiperazine-
22
thiolate leading to form hydroxythiol 41. After a second round of these transformations at
the other a-position to produce iminothiol 42, a transient dithiol is formed and undergoes
oxidative cyclization to form epidithiodiketopiperazine 43.
HS 0H
o
R2SNR3
0f
R
O3
R2H11- N, R3
R4
HO 3PO
-
S
N
glutarhione
N
H
HO 3PO
C2
HS?
f4R
O
-S
H0 3PO
4
46
C02
Me
R2HS0 N'R3
RN
r
R4 49
45
Me
OH
C
H:
o
OH
4
N
R1'N
NC02
H
N' R3
R2H_
R1N'
:
S
H
OH
Me
o
SkN'R3
R
N
1N
H 43
R2
N'R3
R2H
R2 SN'R3
48
R1Ni"
R4
0
4
glutathione
Scheme 7. Our unifying biosynthetic proposal for the incoporation of sulfur in
higher order ETP alkaloids.
Furthermore, higher order polysulfane derivatives can be produced in a similar
fashion, starting from the epidithiodiketopiperazine (43) (Scheme 7) .d-4 Our proposed
biosynthetic pathway involves the addition of a second equivalent of a glutathione
nucleophile to the diketopiperazine disulfide bond of 43 to form intermediate thiol 44.
The epitrithiodiketopiperazine substrate (47) can be accessed in two different ways. One
of which involves the imine tautomerization of the PLP-linked thiol (46) to form the
enamine
functionality
needed
to
expel
the
disulfide
of
46
that
leads
to
epitrithiodiektopiperazine 47 after oxidation. The second mechanism can be described as
an intramolecular nucleophilic attack of the disulfide by the free C-a thiol in 45 to
23
directly lead to 47. Further sulfurations of the polysulfide bridge would be achieved
through this iterative process, thus leading to epitetrathiodiketopiperazine 49.
Methods for Accessing ETPs
Scheme 8. Prior synthetic approaches to the epidithiodiketopiperazine substructure
B5%
AcSK,
)
0
N'
Br 2, 15000
1,2-dichloroethane
70%
N
me'
50
0
Trown 1968
N'..Me
E
NaH, S2 C 2
OEt
Me'N
0 0
Br
N'Me
Me'
N
Br
51
o
Eto
N'Me
2) HCI, EtOH, 64%
3) 5,5'-dithiobis-(2nitrobenzoic acid)
72%
Me
N
S
0 52
N'Me
Me' N S4-)r OEt
dioxane, 60 *C
054
53
Hino 1971
N
1) NaNH2, NH 3 ;S13
2) NaNH 2, NH 3;
N
0 5
0
55
Schmidt 1972
N
<
N
45% (over 4 steps)
HO
N
CN DPhH,
0 H
1)
12, KI
N
_S
N
Pb(OAc) 4 ,
7000C, 32%
2) HCI aq. 65%
-
(
N
1)
N
N
0 OH 58
55
57
0
0
0SH 56
0
3) NaBH 4
H0
N
0
H S0
H0
H 2S,
ZnCI 2
CHC1n,2*C
2)H2,CI, 2306%
2) 12, KI, 66%
(two steps)
S
N
N
57
Schmidt 1973
Scheme
8
shows
representative
methods
for
accessing
the
epidithiodiketopiperazine functional group.27 c,28 One of the earliest methods for the
synthesis of ETPs originates from Trown and coworkers in 1968.29 After bromination of
the c-positions of sarcosine anhydride 50 with bromine and heating in dichloroethane to
150 'C, direct displacement of the secondary bromide of a-positions of 51 with
thioacetate led to the formation of the bis-thioacetic ester intermediate in 95% yield.
Following this step, the acetyl groups of the thioesters were cleaved with a solution of
hydrochloric acid in ethanol, and the intermediate dithiol was treated with 5,5'-dithiobis(2-nitrobenzoic acid). This oxidation led to the formation of the desired bis-sarcosine
24
ETP 52 in 72% yield. The syn substitution for these thiols is required in order for
successful oxidation to the disulfide.
Furthermore,
other
methods
for
accessing
these
ETPs
have
included
deprotonation of the C-a-positions of 53 with sodium hydride and trapping the enolate
with an electrophilic sulfur source as demonstrated by Hino in 19710.3 The intramolecular
trapping of the sulfenyl chloride to produce ETP 54 precludes the use of oxidants for
forming
the
disulfide
bond.
This
method
also
helped
to
enhance
the
syn
diastereoselectivity of the sulfidation of the C-a positions. Use of elemental/monoclinic
sulfur to synthesize ETPs was first reported by Schmidt in 1972.3' Repeated treatments to
these sulfidation conditions were necessary for the double incorporation of sulfur at the
C-a positions. A separate oxidation step, with in situ generated potassium triiodide from
iodine and potassium iodide, was necessary to form the desired bicycle 57 in 45% over 4
steps.
One of the earliest examples of forming ETPs through the use of Lewis Acids and
hydrogen sulfide was executed by Schmidt in 1973.3
Radical oxidation of the C-a
positions of 55 with lead tetraacetate in benzene at 70 'C, followed by hydrolysis of the
corresponding C-a acetate esters led to the formation of diol 58. Ionization of these
tertiary alcohols was achieved by using zinc dichloride, and the resulting acyl iminium
cations were trapped by a hydrogen sulfide. Potassium triiodide oxidation of the bisthiols
led to the formation of 57 in 66% yield. Furthermore, future advances in the synthesis of
ETPs centered on the trapping of acyl iminium cations generated by non-alcohol leaving
groups as shown by Matsunari in 1975 (Scheme
9).3
Treatment of diketopiperazine 59
with NBS and AIBN
25
Scheme 9. Prior synthetic approaches to the epidithiodiketopiperazine substructure
Me'N
'-Me
59
o
MeO
NMe
Me'N
I'
N
NHMe
Me, Me Br
Cu(OAc) 2
(TMS) 3SiH, AlBN
CH 2C 2, 80 0C, 73%
N'Me
-,'OA.
N
M N"
68
Movassaghi 2009
PivO
0
0
56%
N
MeH
4'
OAc
H "'H 0
1) BF3-OEt 2 , DTMP
Et3 SiH, DCM, 82%
2) Otera's catalyst
MeOH/PhMe
85 00,92%
Me-'
N
Me
S N
OH
N
0
H
72
0
N M
[NaHMDS-S 8 ]
THF, 23 *C
MPh
M
10
NN
,S
0
i
0
O
N
H H
HO HO SNN
71
Movassaghi 2010
NN
S
70
O
.,'N
Ph 3C
H
H0
N Me
Me'N
0
0 N'Me
69
-CPh 3
N
Ph-"
e
0 67
N,
I\oN
N~A
0O6TBS
H
N
Me'
Me
M
0 0Sme00
O HN
AcO
0
F
OH
Me"
N-
AcQ
-0
-
0
1) NaBH 4, THF/EtOH
2) K1 3 aq. (72% over
three steps)
&SN'Me
Ph
Ph
Me'N
73
S N' Me
Ph
Me N V
0 74
Ph
0 75
Nicolaou 2012
0
PMBS
0
BnNH2, DMAP
OEt
PMBSH
MeCN, reflux
68%
Bn" N 'f0AOAc
PMBS<
BBr3 , DCM
0
SN'Bn
-78CC
12, 23 00
SPMB
Bn N
76
0
Hilton 2013
0
N Bn
Bn' N
85%
77
0
78
HMe
HO
0
0
1Boc
mbutanone
5%N
OeTEMeN
NJ.
N' R5
M
N,~
-1211
-
'~'
0
O~'
H
, ______BN__02~
~1"~ Me pyrrolidine
SN' Me0
21N'
80%
N'
"--,3'5nm14-DMN
ascorbic acid,
S0Ph
(+)-79, R = Boc, R' = Piv
Movassaghi 2013
MeH
H
N
4-merapto-2-
"N
MeCN, 56%
"-.
I
80
EtSH
K1,,y
N
N
N
'
1
N
R = Ac
N
TBSO 0-H0H
N
Me
HTE NH Me ethanolamine~eNSN NM
0
N,
3) Sc(OTf) 3, H2S
4) 02, MeOH, 37%
(over two steps)
NOAC
0 66
0 65
NMe
Me Me
1) TBAF, AcOH, 96%
2) Ac 20, DMAP, 100%
N'Me
Overman 2007
2) H2S, ZnCl 2, CHCl 3
3) K1 3, CHC13 , 18%
(over three steps)
-N
Me N 7Me 61
0
OH 63
TMSORO 0
QH0
Me
-70 *CC23 00
2) 02,p37%
(over three steps)
NM
N-e
Ottenheijm 1975
1) nBu 3 SnH, AIBN
PhMe, 70 *C
1) H2S, ZnCl 2
N M
0O>M
Me
Br
OMe
0
Me Me
M eC O C OC I
0014, 2300
0
NH62
'C
N Me
Br
Matsunari 1975
Me
eJ~
H
N~
NCS
1) NBS, AIBN
CC14, 77 *C, 32%
2) NaOAc, MeOH, 66*.
NMe
.
Me
r'~ S
0
K 3 py
810
(+)-bionectin A (81)
26
led to radical bromination of the C-a centers. This was followed by exposure to sodium
acetate in methanol produced the C-a bisdimethoxy intermediate 60 in 66% yield. After
reduction
of
the
bromides
with
tributyltin
hydride
and
AIBN,
the
dimethoxydiketopiperazine was sequentially treated with zinc dichloride and hydrogen
sulfide and was followed by oxidation with potassium triiodide to afford the desired ETP
61 in 18% yield over three steps. In the same year, Ottenheijm had reported a case where
activation of the C-a centers could be achieved by the synthesis of diketopiperazine
substrates through the use of a-ketoacid chlorides." Exposure of indoline amide 62 to 2oxo-propanoyl chloride afforded chloro-hydroxy diketopiperazine 63. Treatment of 63
with zinc dichloride and hydrogen sulfide, followed by molecular oxygen generated the
desired indoline ETP 64 in 37% yield over three steps. Overman's 2007 report for the
synthesis of ETP 67 illustrates another method that involves oxidation of the a-positions
through esterification.3 4 Radical oxidation of intermediate 65 with copper diacetate and
AIBN afforded silyl ether 67 in 73% yield. After converting the TMS silyl ether to the
acetate in high yield, scandium triflate promoted ionization of the acetate groups and
trapping with hydrogen sulfide produced the corresponding bisthiol, which was exposed
to molecular oxygen to afford 67 in 37% over two steps.
Use of thiol nucleophiles to trap acyl iminium cations was shown to be possible in
more advanced systems as demonstrated by Movassaghi and coworkers in 2009. The
report had shown the utility of trithiocarbonate diketopiperazine adducts as precursors to
the ETP in the total synthesis of 11,1 '-dideoxyverticillin
A. 4 Use of this dithiol
nucleophile was intended to maximize the diastereoselectivity of the sulfidation step.
Treatment diol 68 with potassium trithiocarbonate with TFA led to the formation of the
27
bistrithiocarbonate adduct 69 in 56% yield. Mild aminolysis of the trithiocarbonates was
executed with the addition of ethanolamine, and the subsequent titration of the reaction
mixture with potassium triiodide gave (+)-11,1
'-dideoxyverticillin (70) in 62% yield.
In the synthesis of (+)-chaetocin A (72), a different set of synthetic challenges
related to differences in ionization potential of the analogous tertiary alcohols prompted
the search for other complimentary sulfidation methods. These differences in ionizing
ability of these tertiary alcohols stemmed from the presence of neighboring heteroatoms,
thus slowing the rate of ionization due to inductive effects. As a result, a new systematic
approach was developed to address the syntheses of ETPs such as (+)-chaetocin A ( 7 2 ).d
The dimeric bisdisulfide 71 was found to cyclize upon exposure to Lewis acids such as
BF 3.OEt2 with dichloromethane in 82%. Methanolysis of the alcohols was achieved using
Otera's catalyst in methanol and toluene at 85 'C, which afforded the natural product (72)
in 92% yield. The utility of this method was further revealed in its application to the
syntheses of higher order ETPs such as (+)-chaetocin C and (+)-12,12'-dideoxychetracin
A.3d
In 2012, Nicolaou had applied Schmidt's method of using monoclininc sulfur and
strong bases such as sodium bis(trimethylsilyl)amide (NaHMDS) to convert bis-Lphenylalanine diketopiperazine 73 to tetrasulfide 74.35 Reduction of this higher order
polysulfane (74) with sodium borohydride, followed by treatment with potassium
triiodide produced the desired ETP 75 in 72%. Furthermore, acyclic ETP precursors such
as 76 may undergo cyclization and thiolation in a one pot procedure as delineated by
Hilton in 2013.36 Treatment of diacetate 76 with benzylamine and 4-methoxy-atoluenethiol
(PMBSH)
and 4-N,N-dimethylaminopyridine
(DMAP)
was shown to
28
produce bis-para-methoxybenzyl
disulfide 77 in 68% yield. Cleavage of the two
thioethers with boron tribromide at -78 'C, followed by exposure to iodine at 23 *C
produced the desired ETP 78 in 85% yield.
Furthermore, Movassaghi and coworkers had developed another method of
synthesizing ETPs through a highly diastereoselective bissulfidation strategy.
In the
synthesis of (+)-bionectin A, advanced intermediate (+)-79 was found to undergo a
diastereoselective double sulfidation when treated with 4-mercapto-2-butanone and TFA,
with concomitant loss of the BOC protecting groups on the N'1 and C12 positions. This
produced the desired bisthioether major product 80 in 80% yield as a 3:1 mixture of
diastereomers. The desired adduct was isolated after the photoinduced deprotection of the
benzenesulfonyl
protecting
group,
which
afforded
the
penultimate
bisthioether
intermediate (80) in 56% yield. Mild unraveling of these thioethers with pyrrolidine in
the presence of ethanethiol produced (+)-bionectin A (81) in 81% yield.
Representative Synthesis of ETP natural products
N- CHO
e
N
H~
4
steps
N
o
HS
H'
82
N'Me
'J"~
SH
0 83
0
MeOBF'Et2
80%
H
PMP$O
H
PMP-.$
Triton B
tBu
H
N
MeN-t
-
Scheme 10. Synthesis of Gliotoxin (Kishi)
%
o
( )-84
3:1 dr
o
MeN
0
Ho
(t)-86
(:t)-85
14
7 steps
0
0
Me
'S N'M
HH0
i1
OH
OH
PMP
1,) BCI 3, 50%
2)mCPBA; HCIO 4
H
M S
MeN >-\\
C
H
OH
H
BnO
CI, PhLi
MS-1
MeN<(
OBn (t)-88
H6
(t)-87
Over the course of the early 1970s, Kishi and coworkers were able to complete
the total syntheses of a number of epidithiodiketopiperazine alkaloids.2
Example
29
syntheses include gliotoxin, sporodesmin3 7 and hyalodendrin. 38 For the total syntheses of
these natural products, Kishi's strategy involved the early installation of sulfur at the Cc-positions as a protected thiol ketal, followed by subsequent alkylation steps for further
elaboration at the bridgehead carbons. This thioketal protecting group effectively enabled
the sulfur functionality to be carried over many steps. The thiols were deprotected at a
late stage and were oxidized to form the desired dissulfide bond.
For Kishi's gliotoxin synthesis, the sarcosine-glycine derived diketopiperazine 82
was elaborated using the method first developed by Trown and coworkers (Scheme 10).2"
After accessing
the dithioacetal
( )-84
through the thioketalization
of 83 with
anisaldehyde and BF3.OEt 2, the compound was treated with Triton B and epoxide ( )-85
in DMSO, which resulted in the formation of N-alkylated intermediate ( )-86. Further
synthetic steps led to the formation of benzylic chloride ( )-87, which was cyclized via
bridgehead deprotonation with phenyl lithium, followed by intramolecular displacement
of the benzylic chloride and bridgehead alkylation with benzyl chloromethyl ether
(BOMCl) to form intermediate ( )-88 in 45% yield. Deprotection of the benzyl ether of
( )-88
with
boron
trichloride,
followed
oxidative
deprotection
of
the
para-
methoxyphenyl (PMP) group with mCPBA in perchloric acid furnished ( )-gliotoxin (1)
Scheme 11. Synthesis of Spordesmin (Kishi)
O
O
MOM'
S
Me
o
NBS, BzOOB
KSAc, 74%
MOM'
PMP
HCI, MeOH, 50 *C
(PMPCHS) 3, BF3OEtZ
80%, 2:1 dr
N'Me
AcS
N'me
N
0
90
89
H
S
N'mom
MeN,
M
o
(
nBuLi, THE, 61%
)-91
Me
HO
HO
CI
0
N'Me 1) NaOH
2) mCPBA CI
Me 3) BF3 -OEt2
NH
-5% (over MeO
three steps)
O e (:L)-95
-
MeO
OMe
0
AcO
AcQ
|
-
SN
M
'S,..
eP
4
S >-PMB
s,'
Me
N 'H
OMe me ( )-94
C
MeN
CeO
0
0
S
MeOPMB
N
()mom'
( )-93
92
-Me
Me
-meMeN
M
M
30
in 65% yield.
For the synthesis of sporodesmin, Kishi's synthesis commenced with the
thiolation of diketopiperazine 89 (Scheme 11).37 Radical bromination of the a-centers
with NBS was followed by elimination and SN 2 displacement with potassium thioacetate
to afford intermediate 90 in 74% yield. Methanolysis of the thioester with catalytic
hydrochloric acid, followed by treatment with boron trifluoride diethyletherate and
trapping of the acyl iminum with anisaldehyde dithioketal trimer led to the formation of
PMP protected disulfide ( )-91 in 80% yield as a 2:1 mixture of diastereomers. After the
installation of the C-a-sulfur groups, intermediate ( )-91 was treated with nBuLi and
acid chloride 92. This coupling reaction led to the formation of ( )-93 in 61% yield. After
further elaborations, tetracyclic diacetate ( )-94 was treated with sodium hydroxide to
hydrolyze the acetyl groups. The protected thiols were released upon addition of mCPBA
and BF3-OEt2, which ultimately afforded sporodesmin ( )-95 in 25% yield over three
steps.
Scheme 12. Synthesis of Hyalodendrin (Kishi)
O
0
-1 N'
Me
Me*'N
HS Irk N'
me tBuOK, MOMCI MOMS,''N'Me
Me' N
SH
THF, 0 *C, 80%
o0
50()-97
Me"
N t ,..
0
(over two steps)
0
MOMS
N'Me
HCIO 4 aq. (70%)
N' Me
OH THF, 23 C, 28%
()-100
.,'SMOM
LDA, BnBr
THF, -78 *C;
MOMBr, 63%
(two steps)
O
Ph
Me'N
(+70
NS,.
NHE
Me'
0
( )-99
12
OMe DCM, 230 C
0
Me
-'
Ph/_
N
OMe
5MOM
Me'
0
MO
(*)-98
In Kishi's hyalodendrin synthesis, a similar early stage installation of the sulfur
functionality at the C-a positions was adopted, with the thiols protected as bisthiolethers
(Scheme 12)."' Dithiol 96 was prepared from sarcosine anhydride 50 using Trown's
31
methodology. 2 9 The thiols of 96 were protected as the bisthioethers through treatment
with potassium tert-butoxide and chloromethyl methyl ether to form the Bis-MOM
protected dithioether ( )-97 in 80% yield. Subsequent alkylation steps were performed
with exposure of ( )-97 to 2 equivalents of LDA, which was followed by treatment with
benzyl
bromide
methyl
and bromomethyl
ether
to produce
the
syn-dialkylated
intermediate ( )-98. Deprotection of the bisthioether group of ( )-98 involved oxidative
unraveling with iodine, followed by exposure to perchloric acid to hydrolyze the methoxy
group. These steps afforded the desired natural product ( )-100 in 28% over two steps.
Scheme 13. Synthesis of Hyalodendrin (Rastetter)
N'Me
N
mN. OH
1) tBuOK, Ph2 tBuSiCI
2) LDA, BnBr
-
Ph 0N'Me
-M'
0me"
7
OTBDPS
OB
,,
Ph
LDA, S8
NaBH 4
N'Me
MN
T
OBP
WN
0
-103
MeS
%'0
o
Ph
1) MeSCI, NEt3
2) HCI, MeOH
51% (over three steps)
( )-102
101
me
'S NM
e'N OH
NaBH 4
K13, pyr
(r%
Ph
MeS.S 0
NM'
Nnp)N
Me
OH
S
(three steps)
NEt3
Ph 3 CSSCI
MS
Ph
Me'N
OH
(:t)-104
( )-105 CPh3
(t)-100
N'Me
Furthermore, Rastetter and coworkers had made contributions to ETP total
synthesis (Scheme 13). The synthesis of ( )-hyalodendrin by Rastetter in 1980, as
opposed to the syntheses conducted by Kishi and coworkers, features a late stage
installation of sulfur at the ct-positions that was followed by diketopiperazine alkylation.3 9
This total synthesis was one of the first to employ acyclic disulfides as precursors to the
ETP.
Starting
with
enol
101,
protection
of
the
enol
alcohol
with
tert-
butyldiphenylchlorosilane (TBDPSCI), followed by benzylation of the other a-center
with benzyl bromide and LDA produced silyl ether ( )-102 in 97% yeild. After sulfur
incorporation to produce thiol ( )-103 in a manner akin to Schmidt's sulfidation
32
methodology, further elaborations to construct the mixed disulfide of ( )-104 involved
treating ( )-103 with triethylamine, followed by the addition of methyl sulfenyl chloride.
Methanolysis of the silylenol ether of this intermediate afforded ( )-104 in 51% yield
over the three-step process. The formation of the mixed trityl disulfide ( )-105 was
achieved
in a similar fashion, with exposure
trityldisulfenyl
chloride.
Both disulfides
were
of ( )-104 to triethylamine
reductively cleaved
and
with sodium
borohydride to generate the in situ unprotected dithiols, which were oxidized to afford
( )-hyalodendrin (100) in 29% yield over the three steps.
Scheme 14. Synthesis of (+)-hyalodendrin (Fukuyama)
Me
EtO
R
BnS
me'
1)Os0 4 , NMO
N'me
N
SV7' H
(+)-100
acetone, 23 0C
2) BF 3*OEt 2,
00C, 49%
(over two steps)
me
N
H
Me'
108
07
107
106
Ph
H
two steps
_SBn
Me'
NHMe
0
TMSBr, MeCN
reflux, 75% over
N
P3) TMSOTf, Et3SiH, 66%
Ph 3CS 0
0
me
P
NCM
me'N
110
1) LDA, PhCHO
THF, -78 *C, 56%
2) MsC, TMEDA, 92%
LDA, THF, -78 *C;
: TrSCI, 0 "C
Ph
Nme
N
Me-,'
H
00
109
In 2014, Fukuyama and coworkers had reported a synthesis of (+)-hyalodendrin
that was similar to Kishi's total synthesis in that it relies on the incorporation of sulfur at
an early stage (Scheme 14).4 Critical to this synthesis was the polysulfane cyclization
methodology developed in our laboratory for the synthesis of more complex ETPs.3d
n
this route, L-cysteine derivative 106 was further elaborated into diketopiperazine 107.
Treatment of 107 with trimethylsilyl bromide (TMSBr) in refluxing acetonitrile generated
the cyclized, monoprotected C-u sulfide 108. Alkylation of intermediate 108 was
conducted using benzaldehyde and LDA at -78 *C in 56% yield. The resulting secondary
33
benzylic alcohol was efficiently mesylated and was reduced using trimethylsilyl triflate
(TMSOTf) and triethyl silane as the reductant, which led to the formation of bicycle 109
in 66% yield. The exocyclic olefin in 110 was produced though elimination of the sulfide
with LDA and the resulting thiolate was treated with tritylsulfenyl chloride to generate
the mixed trityldisulfide 110. This enamide double bond underwent dihydroxylation with
Upjohn's conditions and the resulting trityl disulfide was cyclized with BF 3-OEt2 at 0 'C
to afford the desired (+)-hyalodendrin (100) in 49% over two steps.
Scheme 15. Synthesis of (-)-Acetylaranotin (Reisman)
CO 2Et.
2Et
BOPCIETeoc
T
OH
TMF,
No0
111 + H02C
H
112
87%
OTBS
OH
H
TBAF*(tBuOH) 4
MeCN, 70*C
o
OH
N
N
H
H
0113
4
INaHMDS, THF
S 8;NaHMDS
40%
0
N N
0
H
opropanedithiol
N
O
(-)-117
Oft
Et3N
Oft
N
MeCN; 02
c
45%
0
NCM,
116
N
AcCl, DMAP
70%
OH
0
115
0
Reisman's synthesis of (-)-acetylaranotin represents the utility of installing sulfur
groups at the C-a positions with the use of diketopiperazine enolates and trapping with
electrophilic sulfur (Scheme 15).4' Few synthetic strategies involve late stage sulfur
incorporation with harsh basic conditions in complex molecular settings as in this case.
The synthesis involved the coupling of amine 111 and carboxylic acid 112 with N,A"-
bis(2-oxo-3-oxazolidinyl) phosphinic chloride (BOPCI) to produce amide 113 in 87%
yield. Cleavage of the TBS silyl ether and of the Teoc group with TBAF in acetonitrile,
followed by heating to 70 *C led to the formation of diketopiperazine diol 114. Exposure
of diol 114 to NaHMDS and monoclinic sulfur, followed by the addition of more
34
NaHMDS led to the formation of tetrasulfide 115 in moderate yield. The remaining steps
involved acetylation of the secondary allylic alcohols with acetyl chloride and DMAP in
70% yield, followed by sequential treatment with propanedithiol and molecular oxygen
under basic conditions. These last steps afforded the natural product (-)-117 in 45%
yield.
Conclusion
The characterization of epipolythiodiketopiperazines has had a rich history that
extends back to the early
20
century. 5 ETPs display cytotoxic activity in ways that
involve the direct sulfidation of protein residues, the formation of reactive oxygen
species, and through the sequestration of metals from enzymes. Such activity is thought
to be possessed in higher order ETP containing natural products as well. These
compounds display a wide variety of biological activity, including antibacterial,
anticancer, antiviral, and antiparasitic activity. The earliest syntheses to be completed for
these compounds were competed in the 1970s and 1980s from Kishi, Rastetter and
others. The early methods of the syntheses of ETPs involved the use of strongly basic
conditions and electrophilic sulfur sources to generate the ETP. This approach to the
synthesis of ETPs could best be achieved using simple diketopiperazine scaffolds,
although there are known syntheses that have been able to use this strategy in complex
systems, as in the case of Reisman's synthesis of (-)-Acetylaranotin. More developments
have highlighted the biomimetic approach of using acidic conditions and nucleophilic
thiols to install the sulfur functional groups that would serve as precursors to the ETP.
When addressing complex syntheses of these compounds, careful retrosynthetic planning
35
is necessary to access these molecules given their inherent sensitivity to a number of
reaction conditions.
References for the first chapter:
1. For reviews on cyclotryptophan and cyclotryptamine alkaloids, see: Anthoni, U.;
Christophersen, C.; Nielsen, P. H. in Alkaloids: Chemical and Biological Perspectives,
ed. S. W. Pelletier, Pergamon Press, London, 1999, vol. 13, ch. 2, pp. 163-236; T. Hino
and M. Nakagawa, in The Alkaloids: Chemistry and Pharmacology, ed. A. Brossi,
Academic Press, New York, 1989, vol. 34, ch. 1, pp. 1-75.
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S. J. Trends Pharmacol.Sci., 1987, 8, 144. (b) Waring, P.; Eichner, R. D.; Mullbacher,
A. Med. Res. Rev. 1988, 8,499. (c) Gardiner, D. M.; Waring, P.; Howlett, B. J.
Microbiology, 2005, 151, 1021. (d) Patron, N. J.; Waller, R. F.; Cozijnsen, A. J.;
Straney, D. C.; Gardiner, D. M.; Nierman, W. C.; Howlett, B. J. BMC Evol. Biol., 2007,
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Sci., 2013,4, 1646. (b) DeLorbe, J. E.; Home, D.; Jove, R.; Mennen, S. M.; Nam, S.;
Zhang, F.L.; Overman, L. E. J. Am. Chem. Soc. 2013, 135, 4117. (c) Kim, J.;
Ashenhurst, J. A.; Movassaghi, M. Science, 2009, 324, 238. (d) Kim, K.; Movassaghi,
M. J. Am. Chem. Soc. 2010, 132, 14376. (e) Coste, A.; Kim, J.; Adams, T. C.;
Movassaghi, M. Chem. Sci. 2013,4,3191; (f) Boyer, N.; Movassaghi, M. Chem. Sci.
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4. Kim, J.; Ashenhurst, J. A.; Movassaghi, M. Science, 2009, 324, 238.
36
5. Weindling, R.; Emerson, 0. H. Phytopathology, 1936, 26, 1068.
6. Fukuyama, T.; Kishi, Y. J. Am. Chem. Soc. 1976, 98, 6723.
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10. Dong, J. Y.; He, H. P.; Shen, Y. M.; Zhang, K. Q. J. Nat. Prod, 2005, 68, 1510.
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13. Kwon-Chung, K. J.; Sugui, J. A.; Med. Mycol. 2009, 47, S97.
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1987, 7, 17. (c) Chai, C. L. L.; Heath, G. A.; Buleatt, P. B.; O'Shea, G. A. J. Chem.
Soc. Perkin Trans. 2, 1999, 389. (d) Chai, C. L. L.; Waring, P. Redox Rep. 2000, 5,
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A.; Hertweck, C. J. Am. Chem. Soc. 2010, 132, 10136.
15. Iwasa, E.; Hamashima, Y.; Sodeoka, M. Isr. J. Chem. 2011,51,420.
16. (a) Jordan, T. W.; Pederson, J. S. J. Cell Sci. 1986, 85, 33 (b) Bernardo, P. H.;
Brasch, N.; Chai, C. L L.; Waring, P. J. Biol. Chem. 2003, 278, 46549.
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18. Kim, J.; Movassaghi, M. Chem. Soc. Rev. 2009, 38, 3035.
19. Bycroft, B. W. Nature 1969, 224, 595.
37
20. Johns, N.; Kirby, G. W.; Bu'Lock, J. D.; Ryles, A. P. J. Chem. Soc., Perkin Trans. I
1975,383.
21. Hercheid, J. D. M.; Nivad, R. J. F.; Tijhuis, M. W.; Ottenheijm, H. C. J. J. Org.
Chem. 1980, 45, 1885.
22. Oxford, A. E.; Raistrick H. Biochemical Journal 1947, 42, 323.
23. Arai, K.; Sato, S.; Shimizu, S.; Keiicki, N.; Yamamoto, Y. Chem. Pharm. Bull. 1981,
29, 1510.
24. Barrow, C. J.; Cai, P.; Snyder, J. K.; Sedlock, D. M.; Sun, H. H.; Cooper, R. J. Org.
Chem. 1993,58,6016.
25. Nakagawa, M.; Sugumi, H.; Kodato, S.; Hino, T. Tetrahedron Letters, 1981, 22,
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26. Quigley, F. R.; Floss, H. G. J. Org. Chem. 1981,46,464.
27. (a) Fox, E. M.; Howlett, B. J.; Mycol. Res. 2008, 112, 162. (b) Gardiner, D. M.;
Howlett, B. J. FEMS Microbiol. Lett. 2005, 248, 241. (c). Scharf, D. H.; Habel, A.;
Heinekamp, T.; Brakhage, A. A.; Hertweck, C. J. Am. Chem. Soc. 2014, 136, 11674.
28. Towers, N. R.; Wright, D. E. N. Z. J. Agric. Res. 1969, 12, 275.
28. Kim, J. PhD. Dissertation, Massachusetts Institute of Technology, 2013.
29. Trown, P. W. Biochem. Biophys. Res. Commun. 1968,33,402.
30. Hino, T.; Sato, T. Tetrahedron Lett. 1971, 12, 3127.
31. (a) Poisel, H.; Schmidt, U. Chem. Ber. 1972, 105, 625. (b) Ohler, E.; Tataruch, F.;
Schmidt, U. Chem. Ber. 1973, 106, 396.
32. Yoshimura, J.; Nakamura, H.; Matsunari, K.; Sugiuama Y. Chem. Lett. 1974, 559.
33. Ottenheijm, H. C. J.; Kerkoff, G. P. C.; Bijen, J. W. H. A. J. Chem. Soc. Chem.
38
Comm. 1975, 768.
34. Overman, L. E.; Sato, T. Org. Lett. 2007, 9, 5267.
35. Nicolaou, K. C.; Giguere, D.; Totokotsopoulos, S.; Sun, Y. P. Angew. Chem. Int. Ed.
2012,51,728.
36. Sil, B. C.; Hilton, S. T. Synlett, 2014,24,2563.
37. Fukuyama, T.; Kishi, Y. J. Am. Chem. Soc. 1976, 98, 6723.
38. Fukuyama T.; Nakatsuka, S.; Kishi, Y. Tetrahedron 1981, 37, 2045.
39. Williams, R. M.; Rastetter, W. H. J. Org. Chem. 1980, 45, 2625.
40. Takeuchi, R.; Shimokawa, J.; Fukuyama, T. Chem. Sci. 2014, 5, 2003.
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39
II. Development of ETP Syntheses for the Application of the Total Synthesis
of (+)-Bionectin A
40
Introduction and Background
The
development
of
more
technologies
for
the
syntheses
of
epipolythiodiketopiperazines has been an area of active research.' Beginning in the late
1970s, the early methods for synthesizing ETPs called for the use of radical intermediates
and strong bases. Although these methods can indeed produce the desired ETP moiety,
they may prove too harsh with respect to late-stage incorporation of sulfur for certain
natural products. The ETP motif is known to be quite sensitive to bases and UV light,
possess mild stability to acids, and are known to be redox active.2 Functional group
incompatibility issues may certainly arise due to the sensitivity of this group; and
therefore, we had sought to develop more robust, complimentary methods for accessing
these structures at the late stage. Preliminary studies in our group had shown the direct
conversion of the complex diketopiperazine 1-DKP (Scheme 1) to the corresponding
epidithiodiketopiperazine 1-ETP to be challenging (Scheme 1). Eventually, greater
success in accessing the ETP natural products would involve the use of acidic conditions.
Scheme 1. Previous attempts at forming EFPs through
strongly basic conditions
NHM
o
R2
LHMDS
MNe R
SN, Me
,
or
THF
HMDS
SC
3
R2
ETP 1
DKP1
(not isolated)
Reaction Byproducts
H
-
'HH
NH
0
,XA
Me
Nz
N
"3
R2
'M
N
0
epimerization
2
X = H or SH
incomplete sulfidation
Scheme 2 shows the final steps of our previous methods for the construction of
complex epidithiodiketopiperazines. Diene 2, reaction A, a model substrate used to test
41
Me
A
0
Me
A Me
~
A
TBSO
PhSS
23OC, 28 h
SO2Ph 0
52%,
SO 2 Ph 0
N "H"
SO2Ph 0
3
4
Me
S
~
B JMk NMe
eF~e
Fj
e. HN
. J0 02CN a SNMeet h a n ol a mi n e M
OH
T
C00
HOH
N
~AcH Me
~
C
HN~J~
7
F
N
Ae
2)Oth'ac stnoNan
NMeMe
M82%
~~l Me
NN So-
Me
N
2:1 dr
N
5 Me HN NMe
Kpyr MeN
0
Me
0
BF3-OEt 2
H2S
N"(
2
0HH
Me
0
Ne
C
56
MeS
Ph3C
MeS
OAc
. N
0
SN'H
N)
,HN
0
H
1) E0~ r 3NCh
2
DTMPS
MCe2%
13 ,t
0)
62%S
0
85*C,92%
~
'N
-
0
N
'HeO/he
2
H
0
8
Pr+)Scheme 2. Our group's strategies for the sulfidation of diketopiperazines.
the effectiveness of a direct sulfidation, was converted to the ETP with exposure to
hydrogen sulfide and boron trifluoride diethyl etherate (BF3
2
) inHOEt
moderate yield. 2 A
2:1 mixture of diastereomers was obtained, with the desired diasteromer 3 being the
major component. We have developed other ETP synthetic methodologies, such as the
use of a trithiocarbonate in order to maximize the diastereoselectivty of the thiolation
step. 2
Final
elaboration
to
ETP
(+)-7, reaction
B,
involved
cleavage
of
the
-
trithiocarbonate with ethanolamine and titration of the reaction mixture with a K13
pyridine solution. This produced the desired (+)-1 1,11 '-dideoxyverticillin A (+)-7 in 62%
yield. Furthermore, a robust method for accessing higher order polysulfane ETPs (such as
epitrithiodiketopiperazines
and
epitetrathiodiketopiperazines)
was
developed. 2 An
example of this methodology was delineated in the synthesis of (+)-chaetocin A (9),
reaction C, where the dimeric disulfide 8 was obtained using a highly diastereoselective
monothiolation reaction of the Cli position, followed by sulfidation of this monothiol
with trityl sulfenyl chloride. 2b,3 Ionization of the isobutyrate leaving group of 8 with
42
boron trifluoride diethyl etherate (BF3-OEt2) followed by methanolysis of the acetate
using Otera's catalyst in toluene at 90 'C led to the cyclization of the mixed disulfide to
form the (+)-chaetocin A (9).
Development of Alkyl Mercaptan Reagents for the Synthesis of ETPs
The previous ETP synthetic methods outlined above were quite successful in their
application of the total synthesis of certain natural products. However, when addressing
the syntheses of other related ETPs, such as in (+)-bionectin A, limitations to the scope of
these methods became apparent.' Differences in ionizing potential of either tertiary
alcohol of the C-a-positions resulted in either incomplete or poorly diastereoselective
sulfidations in the presence of Bronsted or Lewis acids and hydrogen sulfide. Thus, a
complementary method was sought to aid in the preparation (+)-bionectin A and of other
related systems.
Scheme 3. Synthesis of (+)-gliocladin B with alkyl thiols
H
HN
HO
o
Me
N'
H
SO 2Ph 0
10
OHN
1) MeSNa, TFA/MeNO 2 (1:1, v/v),
0 to 23 *C, 77%
2) 350 nm, 1,4-dimethoxynaphthalene,
L-ascorbic acid, sodium L-ascorbate,
MeCN/H 20, 23 *C, 88%
MeSA
N'Me
N
N'H 0
WNe
(+)-gliocladin B (11)
From our previous study of (+)-gliocladin B, we had observed that direct
conversion of diketopiperazine diol (+)-10 to (+)-gliocladin B (11) was possible with
TFA and alkyl thiols such as sodium methane thiolate (Scheme 3):? The desired benzene
sulfonyl protected natural product was obtained in 77% as a single diasteromer. The high
diastereoselectivity of this reaction prompted us to seek an analogous transformation with
other alkyl thiols to essentially serve as hydrogen sulfide surrogates, where removal of
the alkyl group could be conducted at a late stage and under mild conditions to afford the
43
ETP. We conjectured that the process by which the alkyl group could be removed would
involve a
-elimination of the thiol. After investigating different electron withdrawing
groups, we determined
that ketones
were the optimal functional
group for this
elimination. Since ETPs are known to possess sensitivity to a basic conditions, we sought
the use of milder reaction conditions such as secondary amines. Through a mechanism
analogous to our biosynthetic proposal of ETPs, we hypothesized that the secondary
amine, such as pyrrolidine, could condense with the bisketone 12 to form iminium 13
(Scheme 4). Tautomerization to form the enamine 14 and expulsion of the thiol via 3elimination would lead to intermediate 15. After a second round of this pyrrolidinecatalyzed
@-elimination
at the other sulfide, dithiol 16 would be liberated and in the
presence of molecular oxygen, would ultimately lead to the formation of ETP 17.
Ph
N+ OH
Ph
Ph
CS
0
0
P
H
N
N
20
0_
_
12 Ph
14 0o
Ph
Ph
P h
R SH
-
HS 130
0
12
[01
N0
N
0S
5
N
NN~N
o
17
N
20
H-H
H_
H
Ph
N
-H 20
16
15
Scheme 4. New biogenetically inspired route to ETPs
In the development of this chemistry, two concerns had to be addressed. One of
which involved the reversibility of the thiol expulsion. To drive the equilibrium towards
product formation, a sacrificial thiol (or excess pyrrolidine) was necessary to sequester
44
the reactive unsaturated iminium-leaving group. The second concern pertained to the
final oxidation step leading to product formation. Although molecular oxygen appeared
to be suitable for the disulfide bond formation in select model systems, the addition of
K1 3-pyridine solutions was sometimes necessary to effect the final S-S bond formation.
Results and Discussion
Development of Alkylthiol Nucleophiles
0
CI
18
1) AcSH, Et3 N, DCM
2) 6 MHCI, THF
reflux, 59%
(over two steps)
0
SH
19
Scheme 5. Synthesis of 3-mercaptopropiophenone
The thiol nucleophiles could be readily prepared from the conjugate addition of
the corresponding enone with a thioacid or through the direct displacement of the alkyl
halide, followed by hydrolysis.4 In situ generation of the enone from the alkyl halide
upon exposure to bases such as triethylamine may also be involved. For preparation of
the 3-mercapto-propiophenone, chloride 18 was exposed to thioacetic acid and triethyl
amine to produce the intermediate thioester, which was subjected to 6 N aqueous
hydrochloric acid and heated to reflux (Scheme 5). This hydrolysis produced the desired
mercaptan 19 in 59% over two steps, which was one of two main thiols that were
explored in the acid promoted thiolation and in the sulfide deprotection steps.
Table 1 (font) shows the select substrates that were utilized in the development of
this methodology. Subjection of the bisproline. diketopiperazine diol to trifluoroacetic
acid and commercially
available 4-mercapto-2-butanone
in acetonitrile
produced
diketopiperazine bissulfide 20 as a 4:1 mixture of diastereomers, where the major (syn)
product was isolated in 70% yield. Unraveling the protected thiols of 20 with pyrrolidine
45
N{,K
in acetonitrile under an oxygen atmosphere provided the desired ETP 17 in 65% yield.
Employment
of
other
thiols
for
this
substitution
was
successful,
with
3-
mercaptopropiophenone providing high levels of diastereoselectivity and comparable
yields. Treatment of the bisproline diol with 3-mercaptopropiophenone (19) and TFA in
acetonitrile produced bisthioether 12 as 9:1 mixture of diastereomers, where the desired
syn product was isolated in 78% yield. This bisthioether adduct was mildly cleaved upon
treatment with pyrrolidine while under an oxygen atmosphere and this produced ETP 17
in 60% yield. When testing this methodology on the more advanced tetracyclic model
substrates, bisthioether 21 was synthesized from its corresponding diol as an 8:1 mixture
of diasteromers, with the desired syn product being isolated in 75% yield. Cleavage of the
thioethers with pyrrolidine in acetonitrile gave the desired ETP 3 in 57% yield.
HO
R
a
N'R3
R2
0
R2
RNfR
b4
0
yielda
or
I1'N
no1'N
0
Bissulfide
N-
R1',N
R4
'R
0
yeild
ETP
0
70%
N 'ND
o
RPhs
N'R3
R2
4
0
Rme,
C
N'R3
65%
NSSND
RMe 20
0
O
17
0
N
C
N78%
o
'RPh 1
nPr,
N
CNS060%
2
nPr,
N0Me
75%
N
SO2 Ph
0
'RPh 21
17
0
S
Me
557%
S
S0 2Ph 0 3
Table 1. Stereoselective sulfidation of diketopiperazines.
Conditions: (a) 4-mercapto-2-butanone, TFA, MeCN, 23 0C; (b) 3mercaptopropiophenone, TFA, MeCN, 23 'C. (c) pyrrolidine, 02,
MeCN, 23 C.
46
One advantage of the use of the 4-mercapto-2-butanone reagent is that its
corresponding bissulfide adduct underwent the pyrrolidine-catalyzed deprotection at a
faster rate and was thus more suitable when applied to more sensitive systems.4
Scheme 6. Other explored thiols for the sulfidation diketopiperazines.
o
Me
0
K
22
SH
0
MeOK23
SH
SH
HO
24
0
0
SH
H-'
25
-
N
(C 3 H 6
OS)n
26
Me 2N
-
SH
27
As seen previously, other thiols such as hydrogen sulfide, and thiols such as 19
and 22, are able to trap the C-cx acyl iminium of the diketopiperazines under acidic
conditions. Commercially available reagent 22 was a thiol that was utilized in our total
synthesis of (+)-bionectin A and C (Scheme 6). In light of these thiols, other reagents
were found to be less applicable to ETP synthesis. After initial consideration of aldehyde
25, we decided that this thiol would not be an optimal reagent for sulfidation of
diketopiperazines due to its known propensity to spontaneously oligomerize to 26.' Other
reagents such as the methyl ester 236, the commercially available carboxylic acid 24, and
the amide 277 were found to be competent nucleophiles in the thiolation of the C-a acyl
iminium. However, the alkyl groups of these sulfides could not be removed using the
mild pyrrolidine conditions. These sulfide adducts were unreactive towards amine and
alkoxide bases in protic or aprotic solvent. Ultimately, ketone thiols were shown to be the
most reliable reagent with respect to the thiolation and removal of the ketoalkyl groups.
47
Total Synthesis of (+)-Bionectin A
(+)-Bionectins A and C belong to the subclass of P-Hydroxytryptophan derived
natural products, and they were first isolated in 2006 by Zheng et al. from the fungus
Bionectra byssicola species (Figure 1).' These compounds are known to be cytotoxic
towards
methicillin-resistant
and quinolone-resistant staphylococcus
aureus
Gram-
positive eubacteria with MICs as low as 10 pg mL. These molecules possess a C3-(3'indolyl) substructure and belong to the P-hydroxy subclass of ETP natural products
(Figure 1).
H
N
H
N
S
Hj
N'Me
(+)-bionectin A (28)
Me O
0
MeN
HO
Me'N
0
OH
S
o
Me
HO
SNMe
OH "
0
(+)-leptosin K (30)
M
N
Me
N
H
SMe
H
N
M
o
N' Me
(+)-bionectin C (29)
H
Me'N
o
N HN
H
0
H
Me
H
Me
0
(+)-verticillin A (31)
Figure 1. Representative C 12-hydroxylated ETPs
Overman has previously reported the synthesis of several bionectin natural
products and of other related derivatives such as (+)-gliocladine C (Scheme 7).' His
synthesis involved the preparation of the advanced C3-(3'-indolyl) intermediate 32,
which was oxidized using the Sharpless dihydroxylation protocol to generate the desired
diol 33 in 80% yield. The diols were acetylated with acetic anhydride and DMAP to
afford intermediate 34 in high yield. The CII tertiary alcohol and the C15 silyl ether of
34 were treated with boron trifluoride diethyl etherate and hydrogen sulfide to produce
48
bisthiol 35. The generated bisthiol 35 was oxidized in the same pot with molecular
oxygen to produce the desired ETP 36. Alternatively, iodine and triethylamine were
found to be suitable conditions for this disulfide formation and the reaction yield ranged
from 53% to 70% yield. A final methanolysis of the C12 secondary acetate with
lanthanum triflate in methanol at 45 *C was found to produce (+)-gliocladine C (37) in
75% yield.
Scheme 7. Final steps in the Total Synthesis of Gliocladin C (Overman)
Boc
N
o
N
N
Boc
O
AD-Mix a, HN/M
A-iH 2NSO 2Me
NMe tBuOH, H20, acetone
"Me
23 -C, 80%
TN
~~H
Ho HO 0
N
'H
Boc
32
Ac2 0, DMAP
NMe DCM, 2300
Me
87%
OTBS
33
NMe
MMe
H H 0OH
eOHC
MeNMe
NH1f
(+)-gliocladine C (37)
Boc
N
RO RO 0
NMe
N
N H
Boc
Me
OTBS
34, R = Ac
BF3 -OEt 2, H 2 S
DCM, -78 OC
H to 23 0C
H
H
SNMe
00A
Boc
N
M
I
C, 53-70%
23
"r S
HO0
36, R = Ac
L
N
H
35, R = Ac
The synthetic strategy used in our synthesis of (+)-bionectin A relied on our bisthiolation/deprotection methodology for the installation of the disulfide bridge (Scheme
8). Our synthesis of (+)-bionectin A and C commenced with a diastereoselective aldol
coupling of indole-3-carboxaldehyde 38 and (-)-pinanone-derived ethyl iminoglycinate
39" to produce
-hydroxytryptophan derivative 40 in 58% yield in 14:1 diastereomeric
ratio. Silyl protection of the benzylic secondary alcohol was achieved with TBSOTf and
2,6-lutidine at 0 'C. Subsequent hydrolysis of the imine with 2 N hydrochloric acid
afforded the amine (+)-41 in 75% yield over two steps. Compounds of this type were
previously accessed using methods of Feldman.
The efficient EDC promoted amino
acid coupling of amine (+)-41 with N-Boc-sarcosine afforded the intermediate peptide in
49
CHO
/
rfi'OB
TiCl(OEt) 3, NEt3
PhO2 SN
DCM,
'Me
55%
40
Me
N
\
N
SO 2 Ph HO a
Me
38
OH
39
H
PhO 2SN
(-)-42
NMe
N
I
HO
Me
Me
1) 2,6-lutidine,
TBSOTf, DCM, 0O*C
2) 2 N HCI, THF, 75%
(over two steps)
QTBS
1) N-Boc-sarcosine
EDC-HCI, HOBt
0
HO
C02Et
N
CO 2Et
DCM, 23 *C, 94%
2) TFA, DCM, 23 C;
AcOH, morpholine
tBuOH, 80 *C, 89%
PhO2SN
NH 2
(+)-41
Br2 , MeCN
0OC anisole
55%
0
H
HOQH
K
0
Br
NMe
NH
SO2 Ph
0
(+)-43
Boc
/\
Et 2
N
Si
H
Me
N'
'
N.
0
SO 2Ph
(+)-44
Scheme 8. Asymmetric synthesis of b-hydroxy intermediate (+)-46
94% yield, which was subjected to trifluoroacetic acid in dichloromethane. The reaction
was concentrated and treated with acetic acid, morpholine and tert-butanol at 80 'C to
generate diketopiperazine (-)-42 in 89% yield. Exposure of (-)-42 to bromine in
acetonitrile at 0 'C cleanly produced the desilylated tetracycle intermediate (+)-43 as a
9:1 mixture of endo:exo products, favoring the desired endo diastereomer in 55% yield.
The above synthetic sequence was contemporaneously executed and refined by Dr. Justin
Kim and Dr. Alexis Coste, my collaborators on this project.' They proceeded to advance
diketopipeazine (+)-43 to silacycle (+)-44 and verified its absolute stereochemistry.
For the remaining steps leading towards (+)-bionectin (28), Dr. Kim demonstrated
the esterification of the ClI and C15 alcohols of intermediate (-)-45 using pivaloyl
chloride and DMAP at 23 'C to produce diester (+)-46 in 83% yield (Scheme 9).
Treatment of a solution of dipivaloate (+)-46 with 4-mercapto-2-butanone with TFA in
nitromethane at 23 'C produced bisthioether 47 in 80% yield as a 3:1 diastereomeric
50
H
NN
Boc
N
~iRHO
Boc
1-N
RR'O
0
Me/
MeHO
10N'M
PivCI, DMAP
>"OH
DCM, 23C
N.1H5OH83% NH OR
'~ N
RROONM
N 'HII16
SO 2Ph 0
SO 2Ph 0
(+)-46, R = Boc, R' = Piv
(--45
o
~3:1
Me
H
Me
Me
HN -- 0
S230C,
350 nm, 1,4-DMN
acid, sodium
ascorbic
-L-ascorbae
4-merapto-2-butanone
TFA, MeNO 2, 80%
dr
H
Me
1
H
Me
/MHO SO
0 MeGN, 20
56%
117N
N
SO 2Ph 0
47
H
0
(+)-481 pyrrolidine, EtSH
THF, 23 0; K1 3
pyr, DCM, 81%
H
N
S
N
Me
N'Me
H
N
Me
N'Me
NaBH 4 , Mel, pyr
MeOH, O*C, 97%
'
S
N
Me
H
0
(+)-bionectin C (29)
H
0
(+)-bionectin A (28)
Scheme 9. Final steps for the synthesis of (+)-bionectins A and C
(Executed by Justin Kim)
mixture with concomitant loss of the tert-butoxycarbonyl groups at the NI' amine and
C12 alcohol. The major diastereomer possessed the desired CI1,C15-stereochemistry and
could be isolated in 56% yield upon photoinduced electron transfer-mediated removal of
the benzenesulfonyl group to form (+)-48." The bisthioethers were removed with a mild
enamine-mediated
transthioetherification
protocol
employing
pyrrolidine
in
tetrahydrofuran at 23 'C. As opposed to the model substrates that were explored in Table
1, a sacrificial thiol additive was found to optimize the unveiling of the C-a thiols:
exposure to an atmosphere of oxygen was insufficient in oxidizing the dithiol to the
disulfide. Mild oxidation of the generated dithiol with K1 3 in pyridine afforded the target
natural product (+)-bionectin A (28) in 81% yield over two steps. Consistent with the
biosynthesis of (+)-bionectin C, the bis-S-methyl derivative (+)-29 was produced in 97%
51
yield by reduction of disulfide (+)-28 with sodium borohydride, followed by the addition
of methyl iodide.
Conclusion
Using a biomimetic protocol for the cleavage of P-mercaptan-linked ketones, we
were able to access (+)-bionectin A and C. The use of this method was advantageous in
that the previous methods used to synthesize other complex ETPs weren't not applicable
to these natural products. This lack of applicability is due to the incomplete ionization of
the ClI alcohol and the lack of stereocontrol for the C15 sulfidation. Although different
thiols were able to diastereoselectively add to diketopiperazine substructures, only ketone
thiols were found to undergo mild cleavage to reveal the thiol. This procedure is robust
for the synthesis of ETPs and the method obviates the need for noxious hydrogen sulfide.
This method of synthesizing ETPs compliments our growing repertoire of strategies that
can be used to access a broad range of alkaloids.
52
References for chapter 2
1.
For selects methods of ETP synthesis, see (a) Trown, P. W. Biochem. Biophys.
Res. Commun. 1968, 33, 402. (b) Hino, T.; Sato, T. Tetrahedron Lett. 1971, 12,
3127. (c) Ohler, E.; Tataruch, F.; Schmidt, U. Chem. Ber. 1973, 106, 396. (d)
Yoshimura, J.; Nakamura, H.; Matsunari, K.; Sugiuama Y. Chem. Lett. 1974,559.
2. (a) Kim, J.; Ashenhurst, J. A.; Movassaghi, M. Science, 2009, 324, 238. (b). Kim,
K.; Movassaghi, M. J. Am. Chem. Soc. 2010, 132, 14376.
3. Boyer, N.; Movasaghi, M. Chem. Sci. 2012,3, 1798.
4. Coste, A.; Kim, J.; Adams, T. C.; Movassaghi, M. Chem. Sci. 2013,4,3191.
5.
Carlsen, L.; Egsgaard, H. J. Chem. Soc. Perkin Trans. II 1984,609.
6. Kumar. I.; Jolly, R. S. Org. Lett. 2001, 3, 283.
7. Casuso, P.; Loinaz, I.; Moller, M.; Carrasco, P.; Pomposo, J. A.; Grande, H. J.;
Odriozola, 1. SupramolecularChemistry, 2009, 21, 5 81.
8.
Zheng, C. J.; Kim, C. J.; Bai, Y. H.; Kim, Y. H.; Kim, W. G. J. Nat. Prod. 2006,
69, 1816.
9. Delorbe, J. E.; Horne, D.; Jove, R.; Mennen, S. M.; Nam, S.; Zhang, F. L.;
Overman, L. E.; J. Am. Chem. Soc. 2013, 135,4117.
10. see supporting information in: Coste, A.; Kim, J.; Adams, T. C.; Movassaghi, M.
Chem. Sci. 2013, 4, 3191.
11. Oguri, T.; Kawai, N.; Shiori, T.; Yamada, S. I.; Chem. Pharm. Bull. 1978, 26,
803.
12. (a) Boger, D. L.; Patane, M. A.; Zhou, J. J. Am. Chem. Soc. 1994, 116, 8544. (b)
Feldman, K. S.; Karatjas, A. G. Org. Lett. 2004, 6, 8544. (c) Feldman, K. S.;
53
Vidulova, D. B.; Karatjas A. G. J. Org. Chem. 2005, 70, 6429. (d) Koketsu, K.;
Oguri, H.; Watanabe, K.; Oikawa, H. Org. Lett. 2006, 8, 4719.
13. Hamada, T.; Nishida, A.; and Yonemitsu, 0.; J. Am. Chem. Soc. 1986, 108, 140.
54
Experimental Section
General Procedures. All reactions were performed in oven-dried or flame-dried roundbottom flasks. The flasks were fitted with rubber septa and reactions were conducted
under a positive pressure of argon. Cannulae or gas-tight syringes with stainless steel
needles were used to transfer air- or moisture-sensitive liquids. Where necessary (so
noted), solutions were deoxygenated by sparging with argon for a minimum of 10 min.
Flash column chromatography was performed as described by Still et al. using granular
silica gel (60-A pore size, 40-63 pm, 4-6% H 20 content, Zeochem).' Analytical thin
layer chromatography (TLC) was performed using glass plates pre-coated with 0.25 mm
230-400 mesh silica gel impregnated with a fluorescent indicator (254 nm). TLC plates
were visualized by exposure to short wave ultraviolet light (254 nm) and an aqueous
solution of ceric ammonium molybdate (CAM) followed by heating on a hot plate (- 250
C). Organic solutions were concentrated at 29-30 *C on rotary evaporators capable of
achieving a minimum pressure of -2 torr. The benzenesulfonyl photodeprotection was
accomplished by irradiation in a Rayonet RMR-200 photochemical reactor (Southern
New England Ultraviolet Company, Branford, CT, USA) equipped with 16 lamps (RPR3500,24 W, max= 350 nm, bandwidth ~ 20 nm).
Materials. Commercial reagents and solvents were used as received with the following
exceptions: dichloromethane, acetonitrile, tetrahydrofuran, methanol, pyridine, toluene,
and triethylamine were purchased from J.T. Baker (Cycletainer T") and were purified by
the method of Grubbs et al. under positive argon pressure. 2
Nitromethane and
nitroethane (from Sigma-Aldrich) were purified by fractional distillation over calcium
'Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923..
A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J. Organometallics1996, 15, 1518.
2 Pangborn,
55
hydride and were stored over Linde 4A molecular sieves in Schlenk flasks sealed with
septa and teflon tape under argon atmosphere.' Titanium (IV) ethoxide (99.99%-Ti)
PURATREM and bromine were purchased from Strem Chemicals, Inc.; N-Boc-Lsarcosine,
1 -ethyl-3-(3-dimethylaminopropyl)
carbodiimide
hydrochloride,
N-
Hydroxybenzotriazole, tert-butyldimethylsilyl trifluoromethanesulfonate, trifluoroacetic
acid, 4-(dimethylamino)pyridine, silver nitrate were purchased from Chem-Impex; 1,4dimethoxynaphthalene was purchased from Alfa Aesar; di-tert-butyl dicarbonate was
purchased from Oakwood Products, Inc.; 2,6-di-tert-butyl-4-methylpyridine (DTBMP)
was purchased from OChem Incorporation. All other solvents and chemicals were
purchased
from
Sigma-Aldrich.
1,4-Dimethoxynaphthalene
was
purified
by
crystallization from absolute ethanol.
Instrumentation. Proton nuclear magnetic resonance ('H NMR) spectra were recorded
with
a Bruker AVANCE-600
NMR
spectrometer
(with a Magnex
Scientific
superconducting actively-shielded magnet) or with a Varian inverse probe 500 INOVA
spectrometer, are reported in parts per million on the 6 scale, and are referenced from the
residual protium in the NMR solvent (CDCl 3 : 6 7.26 (CHCl 3 ), or acetone-d6: 6 2.05
(acetone-d6). 4 Data are reported as follows: chemical shift [multiplicity (br = broad, s =
singlet, d = doublet, t = triplet, sp = septet, m = multiplet), coupling constant(s) in Hertz,
integration, assignmentl.
Carbon-13 nuclear magnetic resonance (13C NMR) spectra
were recorded with a Bruker AVANCE-600 NMR Spectrometer (with a Magnex
Scientific superconducting actively-shielded magnet) or a Bruker AVANCE-400 NMR
3Armarego, W. L. F.; Chai, C. L. L. PurificationofLaboratory Chemicals, 5'h ed.; Butterworth-Heinemann: London,
2003.
4 Fulmer, G. R.; Miller, A. J. M.; Sherden, N. H.; Gottlieb, H. E.; Nudelman, A.; Stoltz, B. M.; Bercaw, J. E.; Goldberg,
K. I. Organometallics2010, 29, 2176.
56
Spectrometer (with a Magnex Scientific superconducting magnet) or with a Varian 500
INOVA spectrometer, are reported in parts per million on the 6 scale, and are referenced
from the carbon resonances of the solvent (CDCl 3 : 6 77.23, acetone-d6 : 29.84). Data are
reported
as follows:
assignment).
chemical
shift (multiplicity, coupling constant(s) in Hertz,
Infrared data (IR) were obtained with a Perkin-Elmer 2000 FTIR and are
reported as follows: frequency of absorption (cm'), intensity of absorption (s = strong, m
= medium, w = weak, br = broad).
Optical rotations were measured on a Jasco-1010
polarimeter with a sodium lamp and are reported as follows: [aCkT -C (c = g/100 mL,
solvent).
We are grateful to Dr. Li Li and Deborah Bass for obtaining the mass
spectrometric
data
at
the
Department
Massachusetts Institute of Technology.
of Chemistry's
Instrumentation
Facility,
High resolution mass spectra (HRMS) were
recorded on a Bruker Daltonics APEXIV 4.7 Tesla FT-ICR-MS using an electrospray
(ESI) ionization source.
Positional Numbering
System. At
least three numbering
systems
for dimeric
diketopiperazine alkaloids exist in the literature.5 In assigning the 1H and 13C NMR data
of all intermediates en route to our total syntheses of (+)-bionectins A (1) and C (2), we
wished to employ a uniform numbering scheme. For ease of direct comparison,
particularly between early intermediates, non-thiolated diketopiperazines, and advanced
compounds, the numbering system used by Barrow for (+)-WIN-64821 (using positional
numbers 1-21) is optimal and used throughout this report. In key instances, the products
are accompanied by the numbering system as shown below.
5
(a) Von Hauser, D.; Weber, H. P.; Sigg, H. P. Helv. Chim. Acta 1970, 53, 1061. (b) Barrow, C. J.; Cai, P.; Snyder, J.
K.; Sedlock, D. M.; Sun, H. H.; Cooper, R. J. Org. Chem. 1993, 58, 6016. (c) Springer, J. P.; Bluhi, G.; Kobbe, B.;
Demain, A. L.; Clardy, J. TetrahedronLett. 1977, 28, 2403. (d) Zheng, C.-J. ; Kim, C-J. ; Bae, K. S. ; Kim, Y.-H. ;
Kim, W.-G J Nat. Prod. 2006, 69, 1816. (e) DeLorbe, J. E. ; Jabri, S. Y. ; Mennen, S. M. ; Overman, L. E. ; Zhang, F.L. J. Am. Chem. Soc. 2011, 133, 6549.
57
-,N
0
H
N
Ph
S 'Me
N 'M
N
"NJ*H M
0
H
Me"
H
N
N
H
M
M
MeN
N
&"N
H
"H
Ph
0
l*-
(+)-WIN-64821
Barrow's numbering for the
simpler diketopiperazine
framework
(-)-gliocladine C
Kim's isolation report
Overman's report
H
H
H0 0
Me
HO 1~ 0
NSMe
S N
-~NN
H
0
(+)-bionectin A (1)
This document
H
0
(+)-bionectin C (2)
This document
58
1 13
6
OEt
CHO
C02Et
-
HO..
SO 2Ph
38
Me
39
TiCI(OEt) 3
Me
Me
M40
DCM, -10 C
55%
OH 0
:
P
U20I,
1 N
1
HO11)-1
7
,'Me
20
24Me
19
Me
12-Hydroxytryptophan Alcohol 40:
A solution of chlorotitanium (IV) triethoxide (11.2 g, 51.5 mmol, 1.05 equiv) in
dichloromethane (69 mL) was added via cannula to a solution of ethyl 2-((IS,2S,5S)-2hydroxypinan-3-imino)glycinate (39, 12.4 g, 48.9 mmol, 1 equiv) in dichloromethane
(300 mL) at -10 *C. A fine powder of 1-(phenylsulfonyl)-IH-indole-3-carbaldehyde(1O,
14.7 g, 51.5 mmol, 1.05 equiv) was then added to the reaction mixture. Triethylamine
(13.6 mL, 98.0 mmol, 2.00 equiv) was added dropwise via syringe and the reaction
mixture was stirred at 0 'C. After 7 h, brine (1 L) at 0 'C was added to the reaction
mixture and the resulting bilayer suspension was filtered through Celite. The organic
layer was separated, and the aqueous layer was extracted with dichloromethane (2 x 100
mL). The combined organic layers were dried with anhydrous sodium sulfate, were
filtered, and were concentrated under reduced pressure. The resulting orange foam was
purified by flash column chromatography on silica gel (eluent: gradient, 30-+50% ethyl
acetate in hexanes) to provide an inseparable mixture of diastereomeric aldol products
(15.2 g, 55%) as a foam. For the full characterization data of 40, please see Coste, A.;
Kim, J.; Adams, T. C.; Movassaghi, M. Chem. Sci. 2013,4,3191.
59
OH
-
.. 2
PhO 2SN
CO 2Et
N
HO.
Me
40
1) 2,6-lutidine,
.Me
Me
TBSOTfDCM, 0 *C
2) 2 N HCI, THF
(75% over two steps)
/
\
0
TBSO
3
1
3
OBt
I
PhO2SN,
NH 2
(+)-41
12-Hydroxytryptophan Amine (+)-41:
t-Butyldimethylsilyl trifluoromethanesulfonate (7.26 mL, 31.5 mmol, 1.20 equiv)
was added via syringe to a solution of 12-hydroxytryptophan alcohol 40 (14.1 g, 26.3
mmol, 1 equiv) and 2,6-lutidine (6.23 mL, 53.7 mmol, 2.04 equiv) in dichloromethane
(500 mL) at 0 *C. After 2 h, saturated aqueous ammonium chloride solution (750 mL)
was added to the reaction mixture and the resulting solution was allowed to warm to 23
'C. After 10 min, the layers were separated and the aqueous layer was further extracted
with dichloromethane (2 x 200 mL). The combined organic layers were dried over
anhydrous sodium sulfate, were filtered, and were concentrated under reduced pressure.
The resulting orange foam was advanced to the amine hydrolysis step. Aqueous hydrogen
chloride solution (2 N, 300 mL) was added to a solution of the crude 12-
hydroxytryptophan silyl ether in tetrahydrofuran (300 mL) at 23 'C. After 2.0 h, the
mixture was concentrated to remove the organic solvent. The resulting mixture was
extracted with ethyl acetate (3 x 300 mL). The combined organic layers were dried over
anhydrous sodium sulfate, were filtered, and were concentrated under reduced pressure.
The resulting orange foam was purified by flash column chromatography on silica gel
(30% ethyl acetate in hexanes) to provide 12-hydroxytryptophan amine (+)-41 (11.8 g,
75%) as a yellow foam. For the full characterization data of (+)-41, please see Coste, A.;
Kim, J.; Adams, T. C.; Movassaghi, M. Chem. Sci. 2013, 4, 3191.
60
OTBS
/'
QOE
PhO 2SN
C02Et
NH 2
(+)-41
1) N-Boc-sarcosine
H I, HOBt
ED
DCM, 23 C
2) TFA, DCM, 23 *C;
AcOH, morpholine
(89%
IBuOH,
over
two80
steps))C,
0
TBSO
17
: H:_11 N Me
. 3 1'2
I2
6h
PhO 2SN 1
iN
10
(-)-42
1
0
Diketopiperazine (-)-42:
A round-bottom flask was charged sequentially with 12-hydroxytryptophan amine
(+)-41 (7.05 g, 14.0 mmol, 1 equiv), N-Boc-sarcosine (2.57 g, 13.6 mmol, 1.30 equiv),
N-hydroxybenzotriazole
(2.13 g,
15.7 mmol,
1.50 equiv),
1-ethyl-3-(3dimethylaminopropyl) carbodiimide hydrogen chloride (4.03 g, 21.0 mmol, 2.00 equiv),
and powdered 4 A molecular sieves (3.00 g), and the contents were placed under an
atmosphere of argon. Dichloromethane (70 mL) was introduced via cannula and the
resulting solution was cooled to 0 *C. Triethylamine (4.40 mL, 31.5 mmol, 3.00 equiv)
was subsequently added dropwise via syringe and the reaction mixture was allowed to
warm slowly to 23 *C. After 8 h, saturated aqueous sodium bicarbonate solution (200
mL) was added, and the aqueous layer was extracted with ethyl acetate (3 x 250 mL).
The combined organic layers were dried over anhydrous sodium sulfate, were filtered,
and were concentrated under reduced pressure. The resulting orange foam was advanced
to the diketopiperazine formation stage. Trifluoroacetic acid (27 mL) was introduced
dropwise to a solution of the crude dipeptide in dichloromethane (140 mL) at 23 *C.
After 1 h, the reaction mixture was concentrated to dryness under reduced pressure. The
crude residue was dissolved in tert-butanol (210 mL). Acetic acid (32 mL) and
morpholine (32 mL) were successively added to the solution, and the resulting reaction
mixture was warmed to 80 *C. After 1.5 h, the reaction mixture was concentrated under
reduced pressure and the solids were removed by vacuum filtration over a sintered
funnel. The solids were extracted with ethyl acetate and the combined organic filtrates
were concentrated under reduced pressure. The resulting orange oil was purified by flash
column chromatography on silica gel (eluent: 50% ethyl acetate in hexanes) to provide
diketopiperazine (-)-42 (5.0 g, 89% over two steps) as a yellow foam. For the full
characterization data of (-)-42, please see Coste, A.; Kim, J.; Adams, T. C.; Movassaghi,
M. Chem. Sci. 2013,4,3191.
61
TBSO
/\
1 'H"
PhO 2SN
H
0
HN.<
O
(-)-42
M
N'Me
Br 2, MeCN
0
C, anisole
55
HQ
Br.
6
H
13
N' Me
3
8
N
SO2 Ph 0
(+)-43
Tetracyclic Bromide (+)-43:
A solution of bromine (2 M, 20.3 mL, 40.0 mmol, 4.00 equiv) in acetonitrile that
was precooled to 0 *C was poured in one portion into a solution of diketopiperazine (-)15 (5.36 g, 10.1 mmol, 1 equiv) in acetonitrile (200 mL) at 0 'C. After 10 min, anisole
(6.63 mL, 61.0 mmol, 6.00 equiv) was poured into the reaction mixture. After 10 min, a
mixture of saturated aqueous sodium thiosulfate solution and saturated aqueous sodium
bicarbonate solution (1:1, 300 mL) was added to the red solution. The reaction mixture
was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried
over anhydrous sodium sulfate, were filtered, and were concentrated under reduced
pressure. The resulting residue was purified by flash column chromatography on silica
gel (eluent: 30% acetone in dichloromethane) to afford the endo-tetracyclic bromide (+)-
(+)-43 (5.50 g, 55%) as a white foam. For the full characterization data of (+)-43, please
see Coste, A.; Kim, J.; Adams, T. C.; Movassaghi, M. Chem. Sci. 2013,4, 3191.
62
0
Ph
'-CI
1) AcSH, Et3N, CH 2C 2
2) 6 M HCI, THF, reflux
59%
0
Ph A-SH
18
3-Mercaptopropiophenone (18):
Triethylamine (1.49 mL, 10.7 mmol, 1.50 equiv) was added to a solution of 3chloropropiophenone (1.20 g, 7.12 mmol, 1 equiv) in dichloromethane (100 mL) at 23
'C. Thioacetic acid (602 pL, 8.54 mmol, 1.20 equiv) was then added dropwise to the
solution. After 1 h, the reaction mixture was concentrated in vacuo. The crude residue
was dissolved in tetrahydrofuran (50 mL) and aqueous hydrochloric acid (6 N, 50 mL)
was added to the solution. Thee reaction mixture was then heated to reflux. After 36 h,
the reaction was diluted with ethyl acetate (200 mL) and washed with saturated aqueous
sodium bicarbonate solution (400 mL). The aqueous layer was extracted with ethyl
acetate (3 x 200 mL), and the combined organic layers were dried over sodium sulfate,
were filtered, and were concentrated under reduced pressure. The crude reaction mixture
was purified by flash column chromatography on silica gel (eluent: 20% ethyl acetate in
hexanes) to afford 3-mercaptopropiophenone (18,703 mg, 59.4%) as a colorless oil.
'H NMR (500 MHz, CDC13 , 20 'C):
8 7.93 (d, J = 7.5, 2H, COPh-o-H),
7.55 (t, J = 7.5, 1H, COPh-p-H), 7.45
(app-t, J = 7.5, 2H, COPh-m-H), 3.31
(t, J = 7, 2H, CH2CH2SH, 2.89 (dt, J =
8.5, 6.0, 2H, CH2CH2SH), 1.74 (t, J =
8.5, 1H, SH).
3
6 198.2 (C=O), 136.8 (COPh-ipso-C),
133.6 (COPh-p-C), 128.9 (COPh-mC),
128.2
(COPh-o-C), 42.7
C NMR (125.8 MHz, CDCl3 , 20 "C):
(CH2CH2SH), 19.1 (CH 2CH 2SH).
FTIR (thin film) cm-':
3061 (w), 2941 (w), 1683 (s), 1597
(m), 1580 (m) 1448 (m).
HRMS (ESI) (mlz):
calc'd for C9H,,OS [M+H]: 167.0525,
found 167.0526
TLC (20% ethyl acetate in hexanes), Rf.
0.28 (UV, CAM).
63
0
0
HO
N
Me <
SH
TFA, MeCN, 23 *C
N
Me t'S
0
70%
OH S
S
9
Me
0
Bisproline Bis(ethylmethylketone thioether) (-)-19:
Trifluoroacetic acid (15 mL) was added via syringe to a solution of bisproline diol
Si (397 mg, 1.76 mmol, 1 equiv) and 3-mercaptobutan-2-one (18, 928 pL, 8.77 mmol,
5.00 equiv) in acetonitrile (15 mL) at 23 *C. The clear solution immediately turned
yellow. After 30 min, the reaction was diluted with ethyl acetate (50 mL) and washed
with saturated aqueous sodium bicarbonate solution (50 mL). The aqueous layer was
extracted with ethyl acetate (3 x 20 mL), and the combined organic layers were dried
over sodium sulfate, were filtered, and were concentrated under reduced pressure. The
crude reaction mixture was purified by flash column chromatography on silica gel
(eluent: 3% acetone in dichloromethane) to afford the bisproline bis(ethylmethylketone
thioether) (-)-19 (490 mg, 70.2%) as a white solid.
'H NMR (500 MHz, CDCl 3 , 20 *C):
6 3.68-3.62 (m, 2H, C2 H), 3.56-3.51
(m, 2H, C2 H), 2.90-2.87 (m, 4H,
CH), 2.75-2.61 (m, 4H, C7H), 2.462.42 (m, 2H, C4Ha), 2.33-2.22 (m, 2H,
'3C NMR (125.8 MHz, CDC1 3 , 20 *C):
C3Ha), 2.12-2.04 (m, 2H, C4 Hb), 2.10
(s, 6H, COCH3 ), 2.01-1.95 (m, 2H,
C3H).
6 206.4 (C9 ), 165.3 (C), 71.7 (C),
45.4 (C2),43.2 (C), 35.4 (C4), 30.0
(COCH 3), 25.2 (C8 ),20.0 (C3).
FTIR (thin film) cm~':
1715 (m), 1660 (s), 1409 (s), 1363 (w),
1158 (w)
HRMS (ESI) (mlz):
calc'd for C1 8H 3 0N 3 0 4 S 2
[M+NHj]:
416.1672, found: 416.1679.
laiD24:
TLC (10% acetone in dichloromethane), Rf.
-33 (c = 0.28, CH2 C 2 ).
0.39 (UV, CAM).
64
0
MeAK
pyrrolidine, 02
MeCN, 23 *C
1
65%
S 0
0 S
,
Me0
0
o (-)-20
Bisproline Epidithiodiketopiperazine (-)-20:
Pyrrolidine (70.0 RL, 852 pmol, 4.07 equiv) was added to a solution of
bis(ethylmethylketone thioether) (-)-19 (83.5 mg, 210 pmol, 1 equiv) in acetonitrile (250
PL) at 23 *C, and the reaction was placed under a balloon of oxygen. The clear solution
immediately turned orange. After 1 h, the reaction was diluted with dichloromethane (5
mL) and washed with saturated aqueous ammonium chloride solution (5 mL). The
aqueous layer was extracted with ethyl acetate (3 x 3 mL), and the combined organic
layers were dried over sodium sulfate, were filtered, and were concentrated under
reduced pressure. The orange residue was purified by flash column chromatography on
silica gel (eluent: 3% acetone in dichloromethane) to afford the bisproline
epidithiodiketopiperazine (-)-20 (34.8 mg, 64.8%) as a white solid.
'H NMR (500 MHz, CDCl 3 , 20 *C):
6 3.88-3.84 (m, 2H, C2 Ha), 3.58-3.52
(m, 2H, C2 H), 3.02-2.94 (m, 2H,
C4 Ha), 2.35-2.27 (m, 2H, C4 H), 2.352.27 (m, 2H, C3Ha), 2.25-2.18 (m, 2H,
13 C
NMR (125.8 MHz, CDCl 3, 20 *C):
C3 H).
6 164.1 (C6 ), 6 78.1 (C), 6 46.6 (C 2),
632.9(C 4), 624.4(C 3).
FTIR (thin film) cm-':
2921 (m), 1660 (s), 1405 (m), 1338
(w), 1097 (m)
HRMS (ESI) (mlz):
calc'd for CjOH1 2N 2 NaO 2 S 2 [M+Na]*:
279.0323, found: 279.0314.
laiD24:
-144 (c = 0.11, CH 2C 2).
0.44 (UV, CAM).
TLC (10% acetone in dichloromethane), Rf.
65
0
HO 0
N
0
Ph'<
SH
TFA, MeCN, 23 *C
PhK-
S 0
78%
0OH s1
(-)-21
OP
0
Bisproline bis(ethylphenylketone thioether) (-)-21:
Trifluoroacetic acid (1 mL) was added via syringe to a solution of bisproline diol
S1 (36.6 mg, 0.162 mmol, 1 equiv) and 3-mercaptopropiophenone (18, 76.2 pL, 801
pnol, 5.00 equiv) in acetonitrile (1 mL) at 23 'C. The clear solution immediately turned
yellow. After 30 min, the reaction was diluted with ethyl acetate (5 mL) and washed with
saturated aqueous sodium bicarbonate solution (5 mL). The aqueous layer was extracted
with ethyl acetate (3 x 5 mL), and the combined organic layers were dried over sodium
sulfate, were filtered, and were concentrated under reduced pressure. The crude reaction
mixture was purified by flash column chromatography on silica gel (eluent: 3% acetone
in dichloromethane) to afford the bisproline bis(ethylmethylketone thioether) (-)-21 (65.9
mg, 77.5%) as a white solid.
'H NMR (500 MHz, CDC 3, 20 *C):
6 7.89 (d, J = 7.5, 4H, COPh-o-H),
7.53 (t, J = 7.5, 2H, COPh-p-H), 7.42
(app-t, J = 8.0, 4H, COPh-m-H), 3.733.67 (m, 2H, C 2Ha), 3.61-3.56 (m, 2H,
C2 H), 3.33-3.27 (m, 2H, C7 Ha), 3.233.26 (m, 2H, C7Hb), 3.12-3.09 (m, 4H,
CAH), 2.55-2.51 (m, 2H, C4Ha), 2.382.28 (m, 2H, C3Ha), 2.17-2.10 (m, 2H,
'3C
NMR (125.8 MHz, CDCl 3 , 20 *C):
C4 H), 2.05-1.99 (m, 2H, C3 Hb).
6 198.7 (C9 ), 166.2 (C6), 137.2
(COPh-ipso-C), 133.6 (COPh-p-C),
128.9 (COPh-m-C), 128.2 (COPh-oC), 72.5 (C), 45.7 (C2), 38.9 (C),
35.7 (C 4), 25.7 (C8 ),20.1 (C3).
FTIR (thin film) cm-':
2956 (w), 1683 (m), 1660 (m), 1597
(w), 1448 (w), 1406 (m), 1350 (w).
HRMS (ESI) (m/z):
calc'd for C 28 H 34 N 30 4 S2
540.1925, found: 540.1925.
Ia]D24:
TLC (10% acetone in dichloromethane), Rf.
[M+NH 4 :
-54 (c = 0.17, CH 2C 2)0.43 (UV, CAM).
66
0
pyrrolidine, 02
MeCN, 23 0C
PhS
(-)-21
0
P
0
0
(-)-20
0
Bisproline Epidithiodiketopiperazine (-)-20:
Pyrrolidine (24.3 VL, 284 pmol, 3.79 equiv) was added to a solution of
bis(ethylmethylketone thioether) (-)-21 (39.2 mg, 75.0 imol, 1 equiv) in acetonitrile (250
liL) at 23 *C, and the reaction was placed under a balloon of oxygen. The clear solution
immediately turned orange. After 1 h, the reaction was diluted with dichloromethane (5
mL) and washed with saturated aqueous ammonium chloride solution (5 mL). The
aqueous layer was extracted with dichloromethane (3 x 3 mL), and the combined organic
layers were dried over sodium sulfate, were filtered, and were concentrated under
reduced pressure. The orange residue was purified by flash column chromatography on
silica gel (eluent: 3% acetone in dichloromethane) to afford the bisproline
epidithiodiketopiperazine (-)-20 (11.5 mg, 59.8%) as a white solid. Please see page 61
for the full characterization data for bisprolineepidithiodiketopiperazine (-)-20.
67
a
0
Me
HO J 0
'
I~YN' Me
NN
SO2Ph
0
Ph
SH
TFA, MeCN, 23 *C
H"eO
S2
Ph
20
M2 S
5
N.Me
(',
73%
SO 2
h
0
(+)-23
23O
0
3-Propyl Tetracyclic Bis(ethylphenylketone thioether) (+)-23:
Trifluoroacetic acid (1 mL) was added via syringe to a solution of 3-propyl
tetracyclic diol S2 (46.3 mg, 95.4 pmol, 1 equiv) and 3-mercaptopropiophenone (18,72.3
pL, 477 prmol, 5.00 equiv) in acetonitrile (1 mL) at 23 *C. The clear solution
immediately turned yellow. After 30 min, the reaction was diluted with ethyl acetate (5
mL) and washed with saturated aqueous sodium bicarbonate solution (2 mL). The
aqueous layer was extracted with ethyl acetate (3 x 5 mL), and the combined organic
layers were dried over sodium sulfate, were filtered, and were concentrated under
reduced pressure.
The crude reaction mixture was purified by flash column
chromatography on silica gel (eluent: 3% acetone in dichloromethane) to afford the 3propyl tetracyclic bis(ethylphenylketone thioether) (+)-23 (54.5 mg, 73.1%) as a white
solid.
'H NMR (500 MHz, CDC 3,20 *C):
8 8.00-7.97 (m, 4H, COPh-m-H), 7.81
(d, J = 8.5, 2H, SO2 Ph-o-H), 7.67 (d,
lH, C8H), (7.53-7.48, (m, 1H, SO 2Php-H), 7.53-7.48 (m, 2H, SO2 Ph-m-H),
7.47-7.53 (m, 4H, COPh-o-H), 7.477.35 (m, 2H, COPh-p-H), 7.53-7.48
(m, 1H, SO 2 Ph-p-H), 7.17 (app-dt, J =
1.3, 7.0, 1H, C7 H), 7.06 (d, J = 7.5,
1H, C5H), 7.00 (app-t, J = 7.5, 1H,
CH), 6.26 (s, 1H, C2H), 3.45-3.38 (m,
1H, C19Ha), 3.30-3.23 (m, IH, CI9 Hb),
3.12-3.02 (m, 2H, C 20H), 3.07 (s, 3H,
C1 8H), 2.99-2.92 (m, 2H, C22 H), 2.81
(d, J = 14, 1H, CI2 Ha), 2.61-2.68 (m,
2H, C23H), 2.30 (d, J = 14, 1H, CI 2 Hb),
1.92 (s, 3H, C1 7H), 1.44-1.37 (m, 2H,
CH2CH 2CH 3), 1.31-1.22 (m, 2H,
CH2CH2CH 3), 0.56-0.52 (m, 3H,
CH2CH2CH3).
13C NMR (125 MHz, CDCl 3 , 20 *C):
6 199.1 (C 21), 198.4 (C 24), 166.7 (C6),
164.8 (C1 3 ), 143.6 (C9 ), 138.9 (SO2Phipso-C), 137.2 (COPh-ipso-C), 137.1
(COPh-ipso-C), 136.3 (C 4 ), 133.9
(COPh-p-C),
133.9
(SO2 Ph-p-C),
133.8 (COPh-p-C), 129.9 (C 7), 129.4
68
(SO 2 Ph-o-C), 129.3 (SO 2Ph-m-C),
129.2 (COPh-o-C), 129.0 (COPh-oC), 128.8 (COPh-m-C), 128.1 (COPhm-C), 125.3 (C), 123.5 (C), 116.6
(C8 ), 83.0 (C2 ), 71.7 (C1 ,), 68.8 (C15),
50.0
(C 12),
42.5
54.1
(C3),
(CH 2CH 2CH 3), 39.6 (C 20), 38.8 (C23),
30.1 (C18), 27.1 (CI7 ), 25.9 (C19), 25.3
14.7
38.4 (CH 2CH2CH3),
(C 22 ),
(CH 2CH2CH3).
FTIR (thin film) cm-':
2924 (m), 2851 (m), 1682 (s), 1597
(w), 1448 (m), 1372 (m).
HRMS (ESI) (m/z):
calc'd for C4 2 H 4 7N 4 0 6 S 3 [M+NH4I+:
799.2652, found: 799.2658
ICID 24:
+124 (c = 0.075)
TLC (5% acetone in dichloromethane), Rf.
0.25 (UV, CAM)
69
Ph
MeM
pyrrolidine, 02
MeCN, 23 *C
N'rr
Me
Ph
Me
s2
N
SO2 Ph 0
(+)-23
13
SN'
57%
IONlt
SOPh 0
0
Me
24
3-Propyl Pentacyclic Epidithiodiketopiperazine (24):
Pyrrolidine (6.8 VL, 82.8 pmol, 4.16 equiv) was added to a solution of 3-propyl
tetracyclic bis(ethylphenylketone thioether) (+)-23 (15.6 mg, 19.9 Pmol, 1 equiv) in
acetonitrile (150 pL) at 23 *C, and the reaction was placed under a balloon of oxygen.
The clear solution immediately turned orange. After 1 h, the reaction was diluted with
dichloromethane (3 mL) and washed with saturated aqueous ammonium chloride solution
(3 mL). The aqueous layer was extracted with ethyl acetate (3 x 2 mL), and the combined
organic layers were dried over sodium sulfate, were filtered, and were concentrated under
reduced pressure. The orange residue was purified by flash column chromatography on
silica gel (eluent: 3% acetone in dichloromethane) to afford the 3-propyl pentacyclic
epidithiodiketopiperazine 24 (5.9 mg, 57.4%) as a white solid.
'H NMR (500 MHz, CDCl 3, 20 *C):
8 7.80 (d, J = 7.0, 2H, SO2 Ph-o-H),
7.53 (app-t, J = 7.0, 1H, SO 2 Ph-p-H),
7.46-7.37 (m, 1H, CH), 7.46-7.37
(m, 2H, SO 2 Ph-m-H), 7.29, (app-dt, J
= 1.1, 7.7, 1H, C7H), 7.16 (app-t, J =
7.7, 1H, CH), 7.12 (d, J = 7.6, 1H,
CH), 6.09 (s, 1H, C2H), 3.19 (d, J =
15.2, 1H, CI 2 Ha), 2.98 (s, 2H, CJ8H),
2.57 (d, J = 15.2, 1H, CI 2 Hb), 1.87 (s,
3H, C, 7H),
1.43-1.30
(m,
lH,
CH2CH2CH 3), 1.22-1.04 (m, 2H,
CH2CH 2CH 3), 0.77-0.68 (m, 2H,
CH2CH2CH3).
'3C NMR (125.8 MHz, CDCl 3 , 20 *C):
FTIR (thin film) cm-':
165.9 (C13), 161.6 (C1 6), 142.1 (C9 ),
139.8 (SO2 Ph-ipso-C), 137.6 (C4 ),
133.4 (SO2 Ph-p-C), 129.3 (C7), 129.2
(SO2 Ph-m-C), 127.4 (SO2 Ph-o-C),
125.9 (C6 ), 123.6 (C5 ), 118.4 (C),
83.7 (C 2), 73.7 (C1,), 73.5 (C 5 ), 55.9
(C3), 41.8 (C12 ), 40.0 (CH 2CH 2CH 3),
27.7 (CI8 ), 18.3 (CH 2CH 2CH 3), 18.0
(C,7), 14.3 (CH 2CH2CH3)2960 (w), 1713 (s), 1688 (s), 1478 (w),
8
1460 (w), 1341 (m), 1172 (m), 1092
(w).
70
HRMS (ESI) (mlz):
calc'd for C 24 H 2 5 NaN 3 0 4 S 3
IM+Na*:
538.0899, found: 538.0923.
TLC (1 % acetone in dichloromethane), Rf.
0.21 (UV, CAM).
71
Chapter III.
Concise Total Synthesis of (+)-Luteoalbusin A
72
Introduction and Background
Figure 1. Representative C3-(3-indolyl) Diketopiperazine
Alkaloids
H
H
NNN
S
N'MN
No
OH
N
0N
H
N
HH
(+)-T988C
H
40
S
Me
(+)-gliocladine D
H
H
s
N
H
NMe
H
0
(+)-luteoalbusin A (1)
N 'H
HHO0
OH
(+)-luteoalbusin B (2)
Marine natural products, such as epipolythiodiketopiperazine (ETP) alkaloids,
represent a structurally complex and biologically potent class of secondary fungal
metabolites.'
3
The nature of the substituent at the C3 position of these ETPs can give rise
to different varieties of these compounds.
Dimeric ETPs such as (+)-dideoxyverticllin,
(+)-chaetocin A and other structurally related derivatives have been synthesized by our
laboratory.! In addition, the C3-(3'-indolyl) substitution establishes an interesting subset
of these diketopiperazine alkaloids and representative examples are shown in Figure 1.9"Io
These
molecules possess a hexahydropyrroloindole
substructure, as
well as an
epipolythiodiketopiperazine moiety. In 2012, the synthesis of two C3-(3'-indolyl) ETPs,
(+)-12-deoxybionectin and (+)-bionectin A, were reported by our laboratory.8&.9 As part
of our expanding program to access new C3-(3'-indolyl) alkaloids, we took interest in the
synthesis of a recently discovered molecule: (+)-luteoalbusin A (1). This natural product
was first isolated from the marine fungi Acrostalagmus luteoalbus SCSIO F457 by Wang
and coworkers in 2012.10 This mycotoxin is derived from L-tryptophan and L-serine. It
has been found in related systems that these molecules possess increased virulence
73
0
H0
_O2PNO2H
OH
N
N
H
N'H
activity with an increased degree of sulfuration of the ETP moiety." The biological
targets of these natural products includes a range of ailments such as antitumor, antiviral,
antibacterial,
anti-inflammatory,
and various psychiatric disorders.'
Howlett and
coworkers had reported that the cytotoxic activity characteristic of these molecules
involves the generation of reactive oxygen species from the epipolysulfane bridge."
Given the intriguing biological activity and structural complexity of these compounds, we
sought the development of their efficient syntheses. Herein, we report the first concise
total synthesis of and the synthetic challenges associated with the preparation of (+)luteoalbusin A (1).
Results and Discussion
Retrosynthetic Analysis
Scheme 1. Retrosynthetic Analysis
H,
HeCPh
Me
Me
polysulfane
N
0H
N
(+)-H
a n d
Ni1
rd
3H
Br.
0
N
-11
Me
TIPS
N
o
172
Nw Me
Friedel-Grafts
alkylations
Me1.*1
_
=
e
5=
3
N
N,
SOPh
0
(+)-
sulfide ation
/?HO
N
N-..
selectie
OAc
O
e Me
TIPS
0N
N H H 0*
3z
SN H
H
SOPh 0'
polysulfaine
N'Me
SN
cyclizN OAc
formation N1
j
0
me dihydroxyatioantio
1
-'.
OAc
*N
SOPh
N Me
Nzz~
15s
QAc
0
The retrosynthesis of (1) involved a late stage deacetylation of the C 17 alcohol
and Lewis acid promoted cyclization of the corresponding disulfide (-)-11 (Scheme 1).
Introduction of the mixed sulfides was achieved through the formation of key
intermediate (+)-9. We envisioned that the requisite substrate for the introduction of
sulfur at the CiI position to be diol (+)-6. Diketopiperazinediol (+)-6 was readily
74
~H
74%
2
,0,IH
N
H
obtained by utilizing a highly diastereoselective double C-H oxidation at the CII and
C15 positions of (+)-5 with bispyridinesilver(I) permanganate. Diketopiperazinediol
precursor (+)-5
was produced by utilizing a highly
regioselective Friedel-Crafts
indolization of (+)-3 and C5'-bromo-N1'-TIPS indole. Tetracyclic diketopiperazine
bromide (+)-3 was quickly accessed in 3 steps according to our previously reported
procedure."
Synthetic Approach
Scheme 2. Preparation of aminothioisobutyrate (+)-9
Nr,Me
-HN
TIPSorCN' HSOH3
ANDCOAc 3OAc, MeOH A
~NHEtNO 2, DT13MP
Me
N'
DAgSbF
3
TIPS
TIPS
Br
N,, .
0
0
HC,
2'P/
H2/CM
OAc 23 -C,83%
SO 2Ph 0
SO2Ph
(+- M-4
f
N'
t
""
(+)-PY2AgMnO
H
Me
C
Me
( N_00
SO 2Ph 0
+8Me TMe7
DMAP,
DCMoC,e72%
st
.e
TPrCOCI
b
HeS
a
OAc
TIPS gMeCN, 58%4
N
h fo 0
Me
HO0
e on
N"
S02 Ph 0
N'
Mad degt
"HN ()-OAc
OH
EItN
Ne
15
2
-I
ssoPh O
SO2Ph 0(+-
Our synthesis of (+)-luteoalbusin A (+)-I began with the silver-mediated FriedelCrafts indolization of (+)-3 (Scheme 2). From our preliminary studies on the
regioselectivity
of the indolization, Friedel-Crafts reactions
involving an indole
nucleophile typically result in a mixture of constitutional isomers, with the C3-NI' linked
product as the major product. Because of this lack of selectivity, protecting groups were
required on the Ni' position, as well as the C5' position, to maximize the formation of
the desired C3-C3' regioisomer.c Therefore, we had designed the nucleophilic indole
fragment to contain a removable bromide at the C5' position and a triisopropyl silyl
(TIPS) group at the Nl' position. Treatment of (+)-3 with 5-bromo-l-(triisopropylsilyl)-
75
lH-indole and silver(I) tetrafluoroborate in nitroethane at 0 'C afforded the desired C3indolyihexacyclic bromide (+)-4 as the sole regioisomer in 74% yield. With the desired
product in hand, the C5' bromide of (+)-4 was removed through hydrogenolysis under
one atmosphere of hydrogen gas in a 2:3 mixture of ethyl acetate and methanol at 23 'C
to produce hexahydropyrroloindole
(+)-5 in 83% yield. After construction of the
hexacyclic core, further functionalization of the diketopiperazine moiety was addressed.
Oxidation of the ClI and C15 alpha centers of the diketopiperazine would be necessary
to install the requisite polysulfide bridge in both natural products. A diastereoselective
dihydroxylation of the CII and C15 alpha centers of (+)-5 with bis(pyridine)silver(I)
permanganate (Py 2AgMnO 4) in acetonitrile at 23 'C provided hexacyclic diol (+)-6 as a
single diastereomer in 58% yield, which represents an approximate yield of 80% for each
oxidation event. 3
4
The mechanism is believed to go through a stereoretentive radical
rebound mechanism with initial hydrogen atom abstraction, followed by trapping of the
generated carbon centered radical.'
The shown configurations for the CII and C15
tertiary alcohols in (+)-6 are consistent with our previous observations for this oxidation
on similar systems by NMR analysis.' For the subsequent sulfidation of the CII position,
it has been observed in our earlier studies of related systems that nonnucleophilic
solvents are necessary for the selective ionization of the CII alcohol and trapping with an
alkyl mercaptan.c,9c Furthermore, due to the inductive effect of the neighboring
heteroatom at C17, the rate of ionization at the C15 position is greatly decreased.b Thus,
exposure of diol (+)-6 to trifluoroacetic acid (TFA) in hydrogen sulfide (H 2 S) saturated
nitroethane at 0 'C produced monothiol 7 with concomitant loss of the TIPS protecting
group at the NI' position.'" After concentrating the reaction, the residue was treated with
76
4-dimethylaminopyridine (DMAP) and isobutyryl chloride in dichloromethane at 0 *C to
generate the desired isobutyrylthioester (+)-8
in 72% yield over two steps. The
isobutyrate groups at CII and C15 served two purposes. Activation of the tertiary alcohol
at C15 through esterification with isobutyryl chloride was required for the polysulfane
cyclization step. Moreover, the acylation of the CII thiol was necessary to enhance the
stability of the molecule for the photoinduced electron transfer-promoted removal of the
N1-benzenesulfonyl group.
7
Other sulfur containing functional groups at the Cl 1
position were observed to be incompatible with the photochemical reaction conditions
and would often lead to decomposition of the substrate. Thus treatment of (+)-9 with 1,4dimethoxynapthalene (1,4-DMN) in buffered aqueous ascorbic acid/acetonitrile solution
in 350 nm light produced the desired common intermediate (+)-9 in 83% yield.
Scheme 3. Final Steps Towards (+)-luteoalbusin A (1)
Me
N
PO
(
23 *C,e
Me
M()
M
'H 0 0~0A H20M,3%
S0P
(+)-
N
H
Me
1
,M
350
+A
PMeC
N"H0Ac
HN00
23 l7Oh, 8 3%-N'H
H0 0
HX J
me-1
Me+Me1Me(Me-1a
Mbyhee
it
oeee
SN
Me-1
meM
a
Me,~
N-
Me MN THMe
NE
230DDB Ne
N
_e
A
DTBMP0
a me
Me
NO Bf
ydaInein
H
M
F
Me
Me
1THF
Subsequent exposure of the regenerated hemithioaminal 9a to triphenylmethane sulfenyl
chloride (TrSCI) and triethyl amine provided the desired mixed disulfide (-)-1
in 80%
77
yield.'" 9 Ionization of the C15 isobutyrate group and subsequent cyclization of the
disulfide with concomitant loss of the triphenylmethyl cation was accomplished through
the treatment of (-)-10 with boron trifluoride diethyletherate and 2,6-di-tert-butyl-4methylpyridine
(DTBMP)
in
dichloromethane.
This
furnished
the
penultimate
luteoalbusin A acetate (+)-11 in 73% yield. Late-stage deprotection of the C17 alcohol of
(+)-11 was achieved by utilizing trimethyltin hydroxide in toluene at 90
oC.
2
This
deprotection afforded (+)-luteoalbusin A (1) in 73% yield. The data obtained from our
synthetic samples matched the known characterization data from the isolation report.'0
Furthermore, consistent with our earlier synthesis of epipolythiodiektopiperazines,
b
a
similar stategy has been applied to the first total synthesis of (+)-luteoalbusin B and
efforts towards the optimization of this synthesis are presently ongoing.
Conclusion
Epipolythiodiketopiperazine alkaloids represent a structurally fascinating and
biologically potent class of natural products. Using commercially available starting
materials, (+)-luteoalbusin A have been synthesized from the tetracyclic bromide (+)-3.
Friedel-Crafts arylation of the C3 position generated the desired hexacyclic bromide (+)3.
The
C5'-bromide
and
Ni'-TIPS
groups
were
instrumental
for maximizing
regioselectivity in the addition. Two highly diastereoselective functionalizations were
critical to the synthesis: a dihydroxylation of the C11 and C15 positions and the
sulfidation of the ClI position with hydrogen sulfide. Furthermore, studies conducted by
our laboratory and by our collaborators have provided evidence for the translational
applicability of the biological activity of these compounds in cancer cell lines.
78
References
1. For reviews on cyclotryptophan and cyclotryptamine alkaloids, see: Anthoni
U., Christophersen C. and Nielsen P. H. in Alkaloids: Chemical and Biological
Perspectives, ed. S. W. Pelletier, Pergamon Press, London, 1999, vol. 13, ch. 2,
pp. 163-236; T. Hino and M. Nakagawa, in The Alkaloids: Chemistry and
Pharmacology, ed. A. Brossi, Academic Press, New York, 1989, vol. 34, ch. 1,
pp. 1-75.
2.
For reviews on epipolythiodiketopiperazines, see: (a) Jordan, T. W.; Cordiner,
S. J. Trends Pharmacol. Sci., 1987, 8, 144. (b) Waring, P.; Eichner, R. D.;
Mullbacher, A. Med. Res. Rev. 1988, 8, 499. (c) Gardiner, D. M.; Waring, P.;
Howlett, B. J. Microbiology, 2005, 151, 1021. (d) Patron, N. J.; Waller, R. F.;
Cozijnsen, A. J.; Straney, D. C.; Gardiner, D. M.; Nierman, W. C.; Howlett, B. J.
BMC Evol. Biol., 2007, 7, 174. (e) Huang, R.; Zhou, X.; Xu, T.; Yang, X.; Liu, Y.
Chem. Biodiversity, 2010, 7,2809. (f) Iwasa, E.; Hamashima Y.; Sodeoka, M. Isr.
J. Chem., 2011, 51, 420.
3. (a) Boyer, N.; Morrison, K. C.; Kim, J.; Hergenrother, P. J.; Movassaghi M.
Chem. Sci., 2013, 4, 1646. (b) DeLorbe, J. E.; Horne, D.; Jove, R.; Mennen, S.
M.; Nam, S.; Zhang, F.L.; Overman, L. E. J. Am. Chem. Soc. 2013, 135, 4117;
and references cited in these reports.
4. For approaches to the C3sp3-C7'sp2 linkage in total synthesis, see: (a)
Steven, A.; Overman, L. E. Angew. Chem., Int. Ed. 2007, 46, 5488. (b) Overman,
L. E.; Peterson, E. A. Tetrahedron, 2003, 59, 6905. (c) Govek, S. P.; Overman, L.
79
E. Tetrahedron 2007, 63, 8499; (d) Kodanko, J. J.; Hiebert, S.; Peterson, E. A.;
Sung, L.; Overman, L. E.; de Moura Linck, V.; Goerck, G. C.; Amador, T. A.;
Leal, M. B.; Elisabetsky, E. J. Org. Chem. 2007, 72, 7909. (e) Schammel, A. W.;
Boal, B. W.; Zu, L.; Mesganaw T.; Garg, N. K. Tetrahedron 2010, 66, 4687. (f)
Snell, R. H.; Woodward, R. L.; Willis, M. C. Angew. Chem. Int. Ed. 2011, 50,
9116. (g) Zhu, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2012, 134, 10815. (h)
Kieffer, M. E.; Chuang K. V.; Reisman, S. E. Chem. Sci. 2012, 3, 3170. (i)
Kieffer, M. E.; Chuang, K. V.; Reisman, S. E. J. Am. Chem. Soc. 2013, 135,5557.
5. For approaches to the C3sp3-C3'sp3 linkage, see: (a) Hendrickson, J. B.; Rees,
R.; Goschke, R. Proc. Chem. Soc. Lond. 1962, 383. (b) Hino, T.; Yamada, S. I.
Tetrahedron Lett. 1963, 4, 1757. (c) Scott, A. I.; McCapra F.; Hall, E. S. J. Am.
Chem. Soc. 1964, 86, 302. (d) Nakagawa, M.; Sugumi, H.; Kodato S.; Hino, T.
Tetrahedron Lett., 1981, 22, 5323. (e) Fang, C. L.; Home, S.; Taylor, N.; Rodrigo,
R. J. Am. Chem. Soc. 1994, 116, 9480. (f) Link, J. T.; Overman, L. E. J. Am.
Chem. Soc. 1996, 118, 8166. (g) Overman, L. E.; Paone D.; Stearns, B. A. J. Am.
Chem. Soc. 1999, 121, 7702.
(h) Somei, M.; Oshikiri, N.; Hasegawa, M.;
Yamada, F. Heterocycles, 1999, 51, 1237. (i) Overman, L. E.; Larrow, J. F.;
Stearns, B. A.; Vance, J. M. Angew. Chem. Int. Ed. 2000, 39, 213. (j) Ishikawa,
H.; Takayama, H.; Aimi, N. Tetrahedron Lett. 2002, 43, 5637. (k) Matsuda, Y.;
Kitajima, M.; Takayama, H. Heterocycles, 2005,65, 1031.
6. For approaches to the C3sp3-N1' linkages, see: (a) Matsuda, Y.; Kitajima, M.;
Thkayama, H. Org. Lett. 2008, 10, 125. (b) Newhouse, T.; Baran, P. S. J. Am.
Chem. Soc. 2008, 130, 10886. (c) Espejo, V. R.; Rainier, J. D. J. Am. Chem. Soc.
80
2008, 130, 12894. (d) Newhouse, T.; Lewis, C. A.; Baran, P. S. J. Am. Chem. Soc.
2009, 131, 6360. (e) Espejo, V. R.; Li, X. B.; Rainier, J. D. J. Am. Chem. Soc.
2010, 132, 8282. (f) Espejo, V. R.; Rainier, J. D. Org. Lett. 2010, 12, 2154. (g)
Perez-Balado, C.; de Lera, A. R. Org. Biomol. Chem. 2010, 8, 5179. (h)
Villanueva-Margalef, I.; Thurston, D. E.; Zinzalla, G. Org. Biomol. Chem. 2010,
8, 5294. (i) Rainier, J. D.; Espejo, V. R. Isr. J. Chem. 2011, 51, 473.
7. For approaches to epipolythiodiketopiperazines,
see:
(a) Trown, P. W.
Biochem. Biophys. Res. Commun. 1968, 33, 402. (b)
Hino, T.; Sato, T.
Tetrahedron Lett. 1971, 12, 3127. (c) Poisel, H.; Schmidt, U. Chem. Ber. 1971,
104. 1714. (d) Poisel, H.; Schmidt, U. Chem. Ber. 1972, 105, 625. (e) Ohler, E.;
Tataruch, F.; Schmidt, U. Chem. Ber. 1973, 106, 396. (f) Ottenheijm, H. C. J.;
Herscheid, J. D. M.; Kerkhoff, G. P. C.; Spande, T. F. J. Org. Chem. 1976, 41,
3433. (g) Coffen, D. L.; Katonak, D. A.; Nelson, N. R.; Sancilio, F. D. J. Org.
Chem. 1977, 42, 948. (h) Herscheid, J. D. M.; Nivard, R. J. F.; Tijhuis, M. W.;
Scholten, H. P. H.; Ottenheijm, H. C. J. J. Org. Chem. 1980, 45, 1885. (i)
Williams, R. M.; Armstrong, R. W.; Maruyama, L. K.; Dung, J.-S.; Anderson, 0.
P. J. Am. Chem. Soc. 1985, 107, 3246. (j) Moody, C. J.; Slawin, A. M. Z.;
Willows, D.; Org. Biomol. Chem. 2003, 1, 2716. (k) Aliev, A. E.; Hilton, S. T.;
Motherwell, W. B.;
Selwood, D. L. Tetrahedron Lett. 2006, 47, 2387. (1)
Overman, L. E.; Sato, T. Org. Lett. 2007, 9, 5267. (m) Polaske, N. W.; Dubey, R.;
Nichol, G. S.; Olenyuk, B. Tetrahedron:Asymmetry, 2009,20, 2742. (n) Ruff, B.
M.; Zhong, S.; Nieger, M.; Brase, S. Org. Biomol. Chem. 2012, 10, 935. (o)
Nicolaou, K. C.; Giguere, D.; Totokotsopoulos, S.; Sun, Y. P. Angew. Chem., Int.
81
Ed. 2012, 51, 728. (p) Williams, R. M.; Rastetter, W. H. J. Org. Chem, 1980, 45,
2625. (q) Iwasa, E.; Hamashima, Y.; Fujishira, S.; Higuchi, E.; Ito, A.; Yoshida,
M.; Sodeoka, M. J. Am. Chem. Soc. 2010, 132,4078.
8. For our synthetic strategies relevant to epipolythiodiketopiperazines, see: (a)
Kim, J.; Ashenhurst, J. A.; Movassaghi, M. Science, 2009, 324, 238. (b) Kim, J.;
Movassaghi, M. J. Am. Chem. Soc. 2012, 132, 14376. (c) Coste, A.; Kim, J.;
Adams, T. C.; Movassaghi, M. Chem. Sci. 2012, 4, 3191.
9. (a) Feng, Y.; Blunt, J. W.; Cole, A. L. J.; Munro, M. H. G. J. Nat. Prod. 2004,67,
2090. (b) Dong, J. Y.; He, H. P.; Shen, Y-M.; Zhang, K. Q. J. Nat. Prod. 2005,
68, 1510. (c) Boyer, N.; Movassaghi, M. Chem. Sci. 2012, 3, 1789.
10. Wang, F. Z.; Huang, Z.; Shi, X. F.; Chen, Y. C.; Zhang, W. M.; Tian, X. P.; Li, J.;
Zhang, S. Bioorg. Med. Chem. Lett. 2012, 22, 7265.
11. Saito, T.; Suzuki, Y.; Koyama, K.; Natori, S.; itaka, Y.; Kinoshita, T. Chem.
Pharm. Bull. 1942, 36, 1942.
12. Gardiner, D. M.; Waring, P.; Howlett, B. J. Microbiology, 2005, 151, 1021.
13. Gardner, K.; Mayer, J. M. Science, 1995, 269, 1849.
14. Firouzabadi, H.; Vessal, B.; Naderi, M.; Tetrahedron Lett. 1978, 23, 1847.
15. Strassner, T.; Houk, K. N. J. Am. Chem. Soc. 2000, 122, 7821.
16. High degrees of diastereoselectivity was achieved in the thiolation with H 2S due
to the C3 stereocenter.
17. Hamada, T.; Nishida, A.; Yonemitsu, O. J. Am. Chem. Soc. 1986, 108, 140.
18. For
epidithiodiketopiperazine
synthesis
using
sulfenyl
chlorides
such
as
chloro(triphenylmethane)disulfane for thiol protection, see 15. For preparation of
82
this reagent, see: Williams, C. R.; Britten, J. F.; Harpp, D. N. J. Org. Chem. 1994,
59,806.
19. The efficiency of the thiol sulfenylation in the presence of the C17 alcohol was
inefficient and led to decomposition of the material.
20. Nicolaou, K. C.; Estrada, A. A.; Zak, M.; Lee, S. H.; Safina, B. S. Angew. Chem.
Int. Ed. 2005,44, 1378.
83
Experimental Section
General Procedures. All reactions were performed in oven-dried or flame-dried roundbottom flasks. The flasks were fitted with rubber septa and reactions were conducted
under a positive pressure of argon. Cannulae or gas-tight syringes with stainless steel
needles were used to transfer air- or moisture-sensitive liquids.
Where necessary (so
noted), solutions were deoxygenated by sparging with argon for a minimum of 10 min.
Flash column chromatography was performed as described by Still et al. using granular
silica gel (60-A pore size, 40-63 pm, 4-6% H20 content, Zeochem).6 Analytical thin
layer chromatography (TLC) was performed using glass plates pre-coated with 0.25 mm
230-400 mesh silica gel impregnated with a fluorescent indicator (254 nm). TLC plates
were visualized by exposure to short wave ultraviolet light (254 nm) and an aqueous
solution of ceric ammonium molybdate (CAM) followed by heating on a hot plate (~ 250
'C). Organic solutions were concentrated at 29-30 *C on rotary evaporators capable of
achieving a minimum pressure of -2 torr. The benzenesulfonyl photodeprotection was
accomplished by irradiation in a Rayonet RMR-200 photochemical reactor (Southern
New England Ultraviolet Company, Branford, CT, USA) equipped with 16 lamps (RPR-
3500,24 W,
kax =
350 nm, bandwidth ~ 20 nm).
Materials. Commercial reagents and solvents were used as received with the following
exceptions: dichloromethane, acetonitrile, tetrahydrofuran, methanol, pyridine, toluene,
and triethylamine were purchased from J.T. Baker (Cycletainer TP) and were purified by
the method of Grubbs et al. under positive argon pressure.'
Nitromethane and
nitroethane (from Sigma-Aldrich) were purified by fractional distillation over calcium
6 Still,
W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.
7 Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J. Organometallics1996, 15, 1518.
84
hydride and were stored over Linde 4A molecular sieves in Schlenk flasks sealed with
septa and teflon tape under argon atmosphere.' Titanium (IV) ethoxide (99.99%-Ti)
PURATREM and bromine were purchased from Strem Chemicals, Inc.; N-Boc-Lsarcosine,
I -ethyl-3-(3-dimethylaminopropyl)
carbodiimide
hydrochloride,
N-
Hydroxybenzotriazole, tert-butyldimethylsilyl trifluoromethanesulfonate, trifluoroacetic
acid, 4-(dimethylamino)pyridine, silver nitrate were purchased from Chem-Impex; 1,4dimethoxynaphthalene was purchased from Alfa Aesar; di-tert-butyl dicarbonate was
purchased from Oakwood Products, Inc.; 2,6-di-tert-butyl-4-methylpyridine (DTBMP)
was purchased from OChem Incorporation. All other solvents and chemicals were
purchased
from
Sigma-Aldrich.
1,4-Dimethoxynaphthalene
was
purified
by
crystallization from absolute ethanol.
Instrumentation. Proton nuclear magnetic resonance ('H NMR) spectra were recorded
with a
Bruker AVANCE-600
NMR spectrometer
(with
a Magnex
Scientific
superconducting actively-shielded magnet) or with a Varian inverse probe 500 INOVA
spectrometer, are reported in parts per million on the 6 scale, and are referenced from the
residual protium in the NMR solvent (CDCl 3 : 8 7.26 (CHCl 3), or acetone-d6: 6 2.05
(acetone-d6).' Data are reported as follows: chemical shift [multiplicity (br = broad, s =
singlet, d = doublet, t = triplet, sp = septet, m = multiplet), coupling constant(s) in Hertz,
integration, assignment].
Carbon-13 nuclear magnetic resonance ('3 C NMR) spectra
were recorded with a Bruker AVANCE-600 NMR Spectrometer (with a Magnex
Scientific superconducting actively-shielded magnet) or a Bruker AVANCE-400 NMR
8 Armarego, W. L. F.; Chai, C. L. L. Purificationof Laboratory Chemicals, 5th ed.; Butterworth-Heinemann: London,
2003.
9 Fulmer, G. R.; Miller, A. J. M.; Sherden, N. H.; Gottlieb, H. E.; Nudelman, A.; Stoltz, B. M.; Bercaw, J. E.; Goldberg,
K. I. Organometallics2010, 29, 2176.
85
Spectrometer (with a Magnex Scientific superconducting magnet) or with a Varian 500
INOVA spectrometer, are reported in parts per million on the 6 scale, and are referenced
from the carbon resonances of the solvent (CDCI 3 : 8 77.23, acetone-d6 : 29.84). Data are
reported
as follows:
assignment).
chemical
shift (multiplicity,
coupling constant(s)
in Hertz,
Infrared data (IR) were obtained with a Perkin-Elmer 2000 FTIR and are
reported as follows: frequency of absorption (cm-'), intensity of absorption (s = strong, m
= medium, w = weak, br = broad). Optical rotations were measured on a Jasco-1010
polarimeter with a sodium lamp and are reported as follows: IacI'T *C (c = gl100 mL,
solvent).
We are grateful to Dr. Li Li and Deborah Bass for obtaining the mass
spectrometric
data
at
the
Department
Massachusetts Institute of Technology.
of
Chemistry's
Instrumentation
Facility,
High resolution mass spectra (HRMS) were
recorded on a Bruker Daltonics APEXIV 4.7 Tesla FT-ICR-MS using an electrospray
(ESI) ionization source.
Positional Numbering
System.
At least three numbering
systems for dimeric
diketopiperazine alkaloids exist in the literature.'0 In assigning the 'H and
3
C NMR data
of all intermediates en route to our total syntheses of (+)-luteoalbusin A (1) and B (2), we
wished to employ a uniform numbering scheme.
For ease of direct comparison,
particularly between early intermediates, non-thiolated diketopiperazines, and advanced
compounds, the numbering system used by Barrow for (+)-WIN-64821 (using positional
numbers 1-21) is optimal and used throughout this report. In key instances, the products
are accompanied by the numbering system as shown below.
'0 (a) Von Hauser, D.; Weber, H. P.; Sigg, H. P. HeIv. Chim. Acta 1970, 53, 1061. (b) Barrow, C. J.; Cai, P.; Snyder, J.
K.; Sedlock, D. M.; Sun, H. H.; Cooper, R. J. Org. Chem. 1993, 58, 6016. (c) Springer, J. P.; Buchi, G.; Kobbe, B.;
Demain, A. L.; Clardy, J. TetrahedronLett. 1977, 28, 2403. (d) Zheng, C.-J. ; Kim, C.-J. ; Bae, K. S. ; Kim, Y.-H. ;
Kim, W.-G J. Nat. Prod 2006, 69, 1816. (e) DeLorbe, J. E.; Jabri, S. Y. ; Mennen, S. M. ; Overman, L. E. ; Zhang, F.L. J. Am. Chem. Soc. 2011, 133, 6549.
86
O
N
/3 12 \
11
oa.
a
5
N
H
1
SN
Me
H
N
Ph1N 3
HN
Y
0
H
N'
NPh
H
8
8
-
12
' 9.N'
S
0
3",, 21S 3
SN'
3
0
H
6
(+)-luteoalbusin A (1)
This document
0
(+)-WiN-64821
Barrow's numbering for the
simpler diketopiperazine
framework
H
7
7'6
NH
12
1
3
(+)-bionectin A
Kim's isolation report
Overman's reports
8
H,
'
H1
7'
8
2
17
'Me
N
'O
H
(+)-luteoalbusin B (2)
This document
87
I'll
10'
Me
iPr
Me
0
Br,
7
H
N
0
SO 2 Ph
Me
Br
QH
)0::N
TIPS
TP
N
l,2'
AgBF 4 , DTBMP,
EtNO,, 0 -C, 2 h;
13
12c
213N16:.
N 1M6B
B
74%
Hc
3'
1
8
18
Me
OAc
NH
S02IPh 0
C3-(5-Bromo-1-TIPS-indol-3-yl)-pyrrolidinoindoline (+)-6:
A round-bottom flask was charged with endo-tetracyclic bromide (+)-3 (348 mg,
630 imol, 1 equiv), 2,6-di-tert-butyl-4-methylpyridine (DTBMP, 155 mg, 760 gmol,
1.20 equiv), and 5-bromo-1-triisopropylsilyl-1H-indole (889 mg, 2.52 mmol, 4.00 equiv),
and the mixture was dried azeotropically (concentration of a benzene solution, 2 x 15
mL) under reduced pressure and placed under an argon atmosphere. Anhydrous
nitroethane (10 mL) was introduced via syringe, and the mixture was cooled to 0 *C in an
ice-water bath. A solution of silver (I) tetrafluoroborate (491 mg, 2.52 mmol, 4.00 equiv)
in anhydrous nitroethane (5 mL) at 0 *C was introduced via cannula to the solution
containing the tetracyclic bromide (+)-17. After 5 min, a black precipitate was observed
in the clear yellow reaction solution. The reaction flask was covered in aluminum foil,
and the suspension was maintained at 0 *C. After 1 hour, saturated aqueous sodium
chloride solution (25 mL) was introduced, and the resulting biphasic mixture was
vigorously stirred for 30 min at 0 *C. The reaction mixture was diluted with ethyl acetate
(10 mL), was filtered through a Celite pad, and the solid was washed with ethyl acetate (3
x 20 mL). The combined filtrates were washed with 5% aqueous citric acid solution (2 x
50 mL), water (3 x 50 mL), and saturated aqueous sodium chloride solution (25 mL). The
organic layer was dried over anhydrous sodium sulfate, was filtered, and was
concentrated under reduced pressure. The resulting orange residue was purified by flash
column chromatography (eluent: gradient, 2 -> 10% acetone in dichloromethane) to
afford the indole adduct (+)-6 (421 mg, 81.0%) as a white solid. Structural assignments
were made with additional information from gCOSY, HSQC, and HMBC data.
'H NMR (500 MHz, CDC1 3 , 20 *C):
8 7.97 (d, J = 8.5, 2H, SO2 Ph-o-H),
7.71 (d, J = 8.5, 1H, C8H), 7.51 (t, J =
7.5, 1H, SO 2 Ph-p-H), 7.36 (t, J = 7.5,
2H, SO 2 Ph-m-H), 7.29-7.25 (m, (2H,
C7H, C8H), 7.13 (dd, J = 9.0, 2.0, 1H,
C7,H), 6.96 (apt-t, J = 7.5, 1H, CH),
6.89 (s, 1H, C2,H), 6.84 (d, J = 7.5,
1H,C 5H), 6.51, d, J= 1.8, 1H,C5 .H),
6.27 (s, 1H, C 2H), 4.86 (dd, J = 12.5,
2.5, 1H, Ci 7Ha), 4.60 (dd, J= 12.5, 2.5,
1H, C17Hb), 4.47 (dd, J= 10.5, 7.5, 1H,
C1 5H) 4.05 (app-t, J = 2.5, 1H, CI5H),
3.05 (dd, J = 14.5, 10.5, 1H, CI 2 HA),
3.03 (s, 3H, C18 H), 2.80 (dd, J = 14.5,
88
10.5, 1H, CI 2 Hb), 1.96 (s,
CH 3acete), 1.56 (app-sp, J = 7.5
3H,
3H,
CIOH), 1.37 (app-d, J = 18.0, 18H,
C1IH).
3
1
C NMR (150 MHz, CDC 3 , 20 'C):
6 170.9 (C=Oaccate), 168.5 (C13 ), 166.0
(CI), 141.3 (C,,), 139.8 (C,), 137.3
134.2
(C 4 ),
134.6
(SO2 Ph-i-C),
(SO 2Ph-p-C), 130.9 (C2 .), 130.3 (C 4.),
129.6
127.9
(C6 ),
(C,),
(C7), 129.3, (SO 2Ph-m-C
(SO 2Ph-o-C), 125.4 (CT.)
124.1, (C5), 121.8 (C5,),
115.7 (C), 115.4 (C3.),
(C),
124.7
116.1
113.6
(C6 .), 83.1, (C 2 ), 61.1 (C11), 60.8 (C1 7),
59.1 (C15), 55.0 (C 3 ), 38.5 (C12), 30.0
(C1 4 ), 20.9 (CH 3 aceate) 18.3 (C 1 ) 12.9
(CIO)
FTIR (thin film) cm-':
3061 (s), 2950 (s), 1675 (m), 1451 (m),
1385 (m).
HRMS (ESI) (m/z):
calc'd
for C4OH48BrN 4 0 6 S
IM+H]:
819.2242,
found: 819.2262.
24
[caID :
+ 139.9 (c = 0.34, CHC 3).
TLC (5% acetone in dichloromethane), Rf.
0.26 (UV, CAM, KMnO 4 ).
89
/
Br
TIPS
N
0
N
'
SO2PN
1M
Sil
Mek .iPr
M iPr
H 2 (1 atm)
Me
OAc
Pd/C (10% wt)
MeOH, EtOAc
8 h, 23 *C
83%
6'O
SO 2Ph 0
2'
H
H0
13
OAc
2.
8
SO2Ph
18
0
C3-(1-TIPS-indol-3-yl)-pyrrolidinoindoline (+)-7:
A mixture of anhydrous methanol and ethyl acetate (3:2 v/v, 5 mL) was
introduced into around-bottom flask charged with the indole adduct (+)-6 (108 mg, 130
pmol, 1 equiv) and palladium on activated charcoal (10% w/w, 27.7 mg, 301 pmol, 0.200
equiv). The flask was purged with argon for 5 minutes. The flask was then sealed under
an atmosphere of hydrogen after being purged with hydrogen gas for 10 minutes. The
solution was vigorously stirred at room temperature for 8 hours. The reaction was diluted
with saturated aqueous ammonium chloride solution and extracted with ethyl acetate (2 x
10 mL). The organic layers were combined, dried with anhydrous sodium sulfate, and
concentrated under reduced pressure. The resulting orange residue was purified by flash
column chromatography (eluent: gradient, 2 -+ 10% acetone in dichloromethane) to
afford the indole adduct (+)-7 (80.7 mg, quantitative yield) as a white solid.
'H NMR (500 MHz, CDCl3 , 20 'C):
8 8.05 (d, J = 7.0, 2H, SO 2 Ph-o-H),
7.82 (d, J = 8.5, 1H, CH), 7.57 (app-t,
J = 7.0, 1H, SO 2 Ph-p-H), 7.41-7.38
(m, 3H, C8,H, SO2 Ph-m-H), 7.25 (t, J
= 8.0, 1H, C7H), 7.01 (t, J = 7.5, 1H,
CTH), 6.97 (s, IH, C 2,H), 6.93 (t, J =
7.5, 1H, CH), 6.76 (d, J = 7.5, 1H,
CH), 6.55 (t, J = 7.5, 1H, C6,H), 6.32
(s, 1H, C 2H), 6.02 (d, 2H, J = 8.5, 1H,
C5,H), 4.90 (dd, J = 11.5, 3.0, 1H,
C17HA), 4.60 (dd, J = 11.5, 3.0, 1H,
CI 7H), 4.46 (dd, J = 10.5, 6.5, 1H,
CIH), 4.03 (app-t, J = 2.7, 1H, C1,H),
3.09 (dd, J = 14.0, 10.5, 1H, CI2 HA),
3.05 (s, 3H, C, 8H), 2.69 (dd, J = 14.5,
10.0, 1H, CI 2 H), 2.04 (s, 3H,
CH3acetate), 1.61 (app-sp, J = 7.5, 3H,
CO,,H), 1.07 (app-d, J = 18.0, 18H,
C,.H).
13C NMR (150 MHz, CDCl 3 , 20 *C):
8 171.0 (C=Oacetate),
168.9 (C,3 ), 166.5
(C1 6 ), 142.7 (C,.), 139.7 (C9), 137.0
133.7
135.0
(C4 ),
(SO 2 Ph-i-C),
129.3
129.4 (C2 .),
(SO 2Ph-p-C),
90
(SO 2 Ph-m-C), 129.1 (SO 2Ph-o-C),
128.5 (C 4.), 128.3 (C7 ), 124.6 (C 7,),
123.8 (C6 ), 122.3 (C5), 120.2 (CO.),
119.3 (C8.), 115.7 (C) 115.3 (C3.),
114.6 (C6 .), 82.9 (C 2 ), 61.1 (C1 ,), 60.9
(C 17), 59.5 (C1 5), 55.3 (C 3), 38.6 (C12 ),
29.9 (C1 7), 21.0 (CH 3 .ete), (18.4 (C 1 .),
13.0 (CIO,).
FTIR (thin film) cm-':
HRMS (ESI) (mlz):
2950 (br-s), 1734 (m), 1675 (m), 1384
(m), 1150 (m),
calc'd for C40H5 2 N 5 O6 SSi
758.3402,
found: 758.3391.
TL
n24
TLC (5% acetone in dichloromethane), Rf.
IM+NH 4
+:
+137.1 (c = 1.12, CHC 3).
0.34 (UV, CAM, KMnO 4).
91
11,
Me
Me2U ijPr
8
'-iPr
TIPS
H
N
Me
N'M
OAc
Py 2AgMnO 4
MeCN, 23 *C
2h
58%
N
312HO
65
SO 2 Ph 0
2
8
13 Ne
N 16
.
17_OAc
NNH i OH
SO 2 Ph 0
C3-(1-TIPS-indol-3-yl)-pyrrolidinoindoline diol (+)-8:
Bis(pyridine)silver permanganate (581 mg, 1.51 mmol, 5.00 equiv) was added as
a solid to a solution of C3-(1-TIPS-indol-3-yl)-pyrrolidinoindoline (+)-7 (224 mg, 303
prmol, 1 equiv) in acetonitrile (10 mL) at 23 'C. After 2 hours, the reaction mixture was
diluted with ethyl acetate (10 mL) and washed with aqueous sodium bisulfite solution (1
M, 20 mL). The resulting aqueous layer was extracted with ethyl acetate (2 x 20 mL) and
the combined organic layers were dried over anhydrous sodium sulfate, were filtered, and
were concentrated under reduced pressure. The crude reaction mixture was purified by
flash column chromatography on silica gel (eluent: 5% acetone in dichloromethane) to
afford pyrrolidinoindoline diol (+)-8 (136 mg, 58%) as a colorless solid. Structural
assignments were made using additional information from gCOSY, HSQC, and HMBC
experiments.
'H NMR (500 MHz, CDC 3 , 20 *C):
6 7.81 (d, J = 8.3, 2H, SO2 Ph-o-H),
7.68 (d, J = 8.0, 1H, CAH), 7.46 (t, J =
8.0, 1H, SO 2 Ph-p-H), 7.41 (d, J = 8.0,
1H, C8,H), 7.28-7.23 (m, 3H, SO 2Phm-H, CH), 7.05 (t, J = 8.0, 1H, C7H),
7.02 (t, J = 8.0, 1H, CH), 6.95 (d, J =
7.0, 1H, C5H), 6.92 (s, 1H, C2,H), 6.67
(t, J = 7.0, 1H, C6,H), 6.53 (br-d, J =
7.0, 1H, C5,H), 5.04 (br-s, 1H, OH),
5.02 (br-s, OH), 4.85 (d, J = 11.0, 1H,
CIHA), 4.25 (d, J = 11.0, 1H, CIHb),
3.21 (d, J= 14.5, 1H,Ci 2Ha),3.15 (d, J
= 14.5, 1H, CI 2 H), 2.98 (s, 3H, CH),
1.88 (s, 3H, CH 3 aceate), 1.59 (h, 3H,
COH), 1.05 (app-d, 18H, C11,H).
13 C
6 170.4 (C=Oacetate), 167.3 (C1 3 ), 167.0
(C1 6 ), 142.6 (C,.), 139.7 (C9), 137.5
(C 4.), 135.4 (C4 ), 133.7 (SO2 Ph-p-C),
131.0 (C6), 129.4 (C7,), 129.2 (SO 2Phm-C), 128.4 (SO 2 Ph-i-C), 128.1
NMR (150 MHz, CDCI 3 , 20 C):
(SO 2 Ph-o-C), 125.0 (C 2 .), 124.6 (C5 ),
122.3 (CT.) 120.6 (CO.), 119.4 (CO,),
116.7 (C), 115.9 (C8), 114.6 (C.),
88.3 (C1,), 86.3 (C,5 ), 83.7 (C 2), 63.8
92
(C 17), 54.3 (C 3), 46.4 (C12 ),27.7 (C18),
20.9 (CH3acete), 18.4 (C 11,), 13.0 (CIO).
FTIR (thin film) cm~':
3374 (s), 2949 (s), 2869 (m), 1749 (m),
1697 (s), 1450 (m), 1374 (s), 1229 (m),
1170 (s),
HRMS (ESI) (m/z):
calc'd for C4H 4,N 4 0 8 SSi IM+H]:
773.3035, found: 773.3016.
[CaID 24:
+9.0 (c = 0.91, CHC 3).
TLC (10% acetone in dichloromethane), Rf.
0.23 (UV, CAM).
93
~
TIPS
-HO
N.Me
TF1N818M
132S)
i-PrCOCI, pyridine
1cN,STFh 6*C, 2 h,M0A 2)-C
N
OcEtNO
N,
-
Me
MeJ
H
81
1
N
2
3
I17
NH OH
SO2Ph_
(+)-6
8
Me N~1
~H
Ac
O
N 'H
SO2Ph
0
CH2C,730 min
cHC 2 30 m_
Me
1.7 iOAc
OH
8
SO2Ph
(+)-8
7
0
MeTMe
Hexacyclic thioisobutyrate (+)-10:
A slow stream of hydrogen sulfide gas was introduced into a solution of diol (+)-8
(507 mg, 660 pmol, I equiv) in anhydrous nitroethane (10.0 mL) at 0 *C, providing a
saturated hydrogensulfide solution. After 15 min, trifluoroacetic acid (1 mL) was added
via syringe, and the slow introduction of hydrogen sulfide into the mixture was
maintained for another 10 min. The reaction mixture was left under an atmosphere of
hydrogen sulfide for an additional 2 h at 0 *C. The resulting mixture was concentrated
under reduced pressure to afford the hexacyclic aminothiol 9 that was used in the next
step without further purification. The orange residue was dissolved in anhydrous
dichloromethane (10 mL) and cooled to 0 *C in an ice-water bath. 4dimethylaminopyridine (DMAP) (802, 6.56 mmol, 10.0 equiv) was added to the solution
of the hexacyclic aminothiol 9 followed by addition of isobutyryl chloride (344 piL, 3.28
mmol, 5.00 equiv). After 30 minutes, the ice-water bath was removed, and the yellow
solution was allowed to warm to 23 *C. Methanol (1 mL) was added to the solution. After
5 min, the reaction mixture was diluted with dichloromethane (10 mL). The resulting
mixture was sequentially washed with aqueous hydrogen chloride solution (1 N, 2 x 20
mL), water (2 x 20 mL), and saturated aqueous sodium chloride solution (20 mL). The
organic layer was dried over anhydrous sodium sulfate, was filtered, and was
concentrated under reduced pressure. The yellow residue was purified by flash column
chromatography on silica gel (eluent: gradient, 15 -+ 30% acetone in hexanes) to afford
the thioisobutyrate (+)-10 (368 mg, 72.1%) as a colorless gel.
'H NMR (500 MHz, CDC1 3 , 20 *C):
8 7.88 (br-s, IH, NIH), 7.75 (d, J =
8.0, 1H, CH), 7.52 (app-d, J = 8.5,
2H, SO2 Ph-o-H), 7.35-7.26 (m, 3H,
C6.H, CH, SO 2 Ph-p-H), 7.23 (d, J =
8.5, 1H, C5H) 7.11 (app-d, J= 7.5, 1H,
C8.H), 7.07 (app-d, J = 7.5, 1H, C5,H),
7.06-7.01 (m, 3H, SO2 Ph-m-H, CAH),
6.75 (app-t, J = 7.5, 1H, C7,H), 6.74 (s,
1H, C 2H), 6.36 (d, J = 2.5, 1H, C2,H),
4.81 (d, J= 11.5, 1H,C1 7Ha),4.47 (d, J
= 11.5, 1H, CI 7H), 3.91 (d, J = 14.5,
1H, C1 2Ha), 3.50 (d, J = 14.5, 1H,
CI 2 H), 2.89 (s, 3H, C18H), 2.63 (appsp, J= 7.0, 1H,
sp, J = 7.0, 1H,
3H,
CHibosyrate),
2.18 (app-
2. (s,
1.25-1.19 (m, 6H,
0.92 (d, J = 7.5, 3H,
CHhioisobutyrate),
CH3 acetate),
CH 3 isobutyrate),
94
CH3tioisoutyrate),
0.82 (d, J = 7.5, 3H,
CH3thioisobutyrate)
13C
NMR (150 MHz, CDC1 3, 20 0C):
8
175.7
200.7 (C=Othioisobuyrate),
166.7
(C=Oacetate),
170.5
(C=Oisobutyrate),
(C 13), 161.6 (C 16), 143.1 (C,), 138.6
(SO 2 Ph-i-C), 137.6 (C,.), 136.7 (C 4),
133.7 (SO 2 Ph-p-C), 129.8 (C 7), 129.1
(SO 2 Ph-m-C), 127.8 (SO2 Ph-o-C),
125.8 (C6 ), 125.5 (C 5), 125.1 (C 4 .),
123.9 (C 2.), 122.9 (C7 .), 120.6 (C6 ),
120.2 (CS.), 117.4 (C 8), 116.7 (C3 .),
111.9 (C8 .), 87.4 (C 15 ), 85.1 (C 2), 74.8
(C 1,), 63.9 (C 17), 54.3 (C 3), 44.5 (C 12 ),
43.9 (CHthioisobutyrate), 34.5 (CHj,,utyrate),
29.1 (C 18), 21.8 (CH3 acetate), 19.8
(CH3sobutyrate), 19.6 (CH3sobutyrate), 19.6
(CH3thioisobutrate), 19.0 (CH3thiosisobutyrate)
FTIR (thin film) cm-':
3398 (s), 2974 (m), 1745 (s), 1698 (s),
1461 (m), 1448 (m), 1369 (s), 1266
(w), 1220 (m), 1171 (m), 1092 (m),
1054 (m), 950 (m).
HRMS (ESI) (m/z):
calc'd for C 3 9 H4oN4 NaO9 S 2 [M+Na]*:
795.2129,
[aID24:
TLC (5% ethyl acetate in dichloromethane), Rf.
found: 795.2161.
+31 (c = 0.45, CHC1 3 )0.26 (UV, CAM, KMnO 4).
95
OMe
Me
0
O
\/ S
'-N
N
'H
SO 2Ph
(+)-8
Me
NMe
OAc
0
Me
0
350 nm
Na-L-ascorbate
ascorbic d
OMe
1,4-dimethoxynaphtalene
H 20, MeCN, 23 *C, 6 h
83%
Me
Me
O
8
012
S1
2'
,Me
5
2
8
H'
N 1
''H N 0 0
(-9
Me
7OAc
Me
Hexacyclic aminothioisobutyrate (+)-9:
A 125-mL Pyrex round-bottom flask was sequentially charged with
hexacyclicthioisobutyrate (+)-8 (524 mg, 565 pmol, 1 equiv), L-ascorbic acid (966 mg,
5.65 mmol, 10.0 equiv), sodium L-ascorbate (1.11 g, 5.65 mmol, 10.0 equiv), and 1,4dimethoxynaphthalene (2.12 g, 11.3 mmol, 20.0 equiv), and the mixture was placed
under an argon atmosphere.A solution of water in acetonitrile (20% v/v, 20 mL) that was
purged with argon for 15 min at 23 *C was transferred to the flask via cannula. The
system was vigorously stirred under an argon atmosphere and irradiated with a Rayonet
photoreactor equipped with 16 lamps emitting at 350 nm at 23 *C. After 6 hours, the
lamps were turned off, and the reaction mixture was diluted with ethyl acetate (30 mL).
The resulting solution was sequentially washed with saturated aqueous sodium
bicarbonate solution (30 mL), water (2 x 30 mL), and saturated aqueous sodium chloride
solution (30 mL). The aqueous layer was extracted with ethyl acetate (2 x 20 mL). The
combined organic layers were dried over anhydrous sodium sulfate, were filtered, and
were concentrated under reduced pressure. The residue was purified by flash column
chromatography on silica gel (eluent: gradient, 5-+20% aceteone in hexanes) to afford
the aminothioisobutyrate (+)-9 (297 mg, 83.0%) as a colorless oil.
6 8.36 (br-s, 1H, N1,H), 7.82 (d, J =
8.5, 1H, C5,H), 7.30 (d, J = 8.5, 1H,
C8 ,H), 7.16-7.13 (m, 2H, CH, CH),
7.09 (app-t, J = 7.5, 1H, C7H), 7.02
(app-t, J = 7.5, 1H, C6,H), 6.82 (d, J =
2.6, 1H, C 2,H), 6.71 (app-t, J = 7.5,
1H, C6H), 6.66 (d, J = 7.5, 1H, C8H),
6.11 (s, I H, C2 H), 4.81 (d, J = 13.5,
1H, CI 7Ha), 4.46 (d, J = 13.5, 1H,
CI 2 H), 4.18 (d, J = 14.5, 1H, C12aH),
3.57 (d, J = 14.5, 1H, C1 2Hb), 2.94 (s,
3H, CI8H), 2.62 (app-sp, J = 7.0 1H,
CHisobutyrate), 2.19 (app-sp, J = 7.0 iH,
CHthioisobutyrate), 2.12 (s, 3H, CH3acetate),
1.21 (d, J = 7.0, 3H,
CH3 isobutyrate), 1.18
(d, J= 7.0, 3H, CH3 isobutyrate), 0.92 (d, J
= 7.0, 3H, CH3thioisobutyrate)9 0.83 (d, J
7.0, 3 H, CH3thiisobutryate)
-
'H NMR (500 MHz, CDC1 3 , 20 *C):
96
'3C NMR (150 MHz, CDC 3 , 20 "C):
6
201.2
(C=Othiosiobutryate),
(C=Oisobutyrate), 170.5 (C=Oacetate),
(C 13 ), 162.7 (CI), 149.5 (C,),
(C,.), 133.1 ( C4 ), 129.4 (C7 ),
(C 4.), 125.1 (Cs), 123.5 (C 2 ),
(C7 ), 120.9 (C6 ), 120.4 (CS.),
(C), 118.2 (C.), 112.2 (CO.),
175 .5
166.5
137.9
125.7
122.9
120.1
110.1
(C8),87.1 (C15),84.0 (C2),73.9 (C1 ),
63.7 (C 17), 54.7 (C 3), 44.0 (C 12), 43.8
(CHthioisobutyrate), 34.5 (CHoutyrte), 29.0
(C18 ),
21.8
(CH3soutyrate),
19.9
(CH 3acetate),
19.7 (CH3sobutryate), 19.5
(CH3thioisobutryate),
19.1 (CH3thioisobutyrate)
FTIR (thin film) cm-':
3385 (br), 2975 (m), 2360 (m), 1748
(s), 1686 (s), 1609 (w), 1484 (w), 1423
(w), 1379 (m), 1223 (m), 1067 (w),
747 (m).
HRMS (ESI) (mlz):
calc'd for C33 H3 6N4 NaO7 S [M+Na]:
655.2197, found: 655.2183.
I LID24:
+26 (c = 0.085, CHC 3).
TLC (50% ethyl acetate in hexanes), Rf.
0.38 (UV, CAM).
97
Me
'-
H2NNH 2, THF
0 *C, 10 min;
TrSCI, Et3N, THF
0 *C, 1 h
80%
QO431
N'
. 2)
-
NMe
CPh3
HI
81
(H N 'H O
0
N+-9
Me
OAc
o
M
N' H0
8
H1
H
(-)-11
Me
Me
Triphenylmethanedisulfide (-)-11:
Anhydrous hydrazine in tetrahydrofuran (1 M, 800 [tL, 800 pmol, 1.00 equiv) was
added via syringe to a solution of aminothioisobutyrate (+)-9 (50.3 mg, 800 Pmol, 1
equiv) in anhydrous tetrahydrofuran (2 mL) at 0 *C. After 10 min, the reaction mixture
was diluted sequentially with saturated aqueous ammonium chloride solution (5 mL) and
ethyl acetate (5 mL). The organic layer was sequentially washed with saturated aqueous
ammonium chloride solution (10 mL), water (2 x 10 mL), and saturated aqueous sodium
chloride solution (10 mL). The aqueous layer was extracted with ethyl acetate (2 x 10
mL). The combined organic layers were dried over anhydrous sodium sulfate, were
filtered, and were concentrated under reduced pressure to afford the hexacyclic
aminothiol that was used in the next step without further purification.Triethylamine (111
pL, 8.00 mmol, 10.0 equiv) and solid triphenylmethanesulfenyl chloride (124 mg, 4.00
mmol, 5.00 equiv) were sequentially added to a solution of aminothiol in anhydrous
tetrahydrofuran (2 mL) at 0 'C under an argon atmosphere. After 1 h, the solution was
partitioned between saturated aqueous ammonium chloride (5 mL) and ethyl acetate (5
mL). The aqueous layer was extracted with ethyl acetate (2 x 10 mL), and the combined
organic layers were washed sequentially with water (2 x 20 mL) and saturated aqueous
sodium chloride solution (20 mL), were dried over anhydrous sodium sulfate, were
filtered, and were concentrated under reduced pressure. The residue was purified by flash
column chromatography on silica gel (eluent: gradient, 10 --* 50% ethyl acetate in
hexanes) to afford triphenylmethanedisulfide (-)-11 (53.6 mg, 80.1 %)as a white solid.
8 8.01 (br-s, 1H, N,.H), 7.82 (d, J =
8.0, 1H, C5,H), 7.32 (d, J = 8.0, IH,
C8,H), 7.27-7.23 (m, 9H, C(Ph-o-H) 3
C(Ph-p-H) 3), 7.22-7.19 (m, 2H, C7H,
C 7,H), 7.17-7.14 (m, 6H, C(Ph-m-H) 3),
7.06 (app-t, J = 7.5, 1H, C6,H), 6.82 (d,
,
'H NMR (500 MHz, CDCl3 , 20 *C):
J = 7.5, 1H, CH), 6.73-6.69 (m, 3H,
C2 .H, CAH, CH), 5.93 (s, 1H, C2 H),
4.93 (s, IH, NIH), 4.66 (d, J = 12.5,
1H, CI 7 Ha), 4.40 (d, J = 12.5, 1H,
CI 7H), 3.55 (d, J = 15.0, 1H, C1 2 Ha),
2.92 (d, J = 15.0, 1H, C1 2Hb), 2.80 (s,
3H, CI 8H), 2.61 (app-sp, J = 7.5, 1H,
CHisoutyrate), 1.98 (s, 3H, CH3ace-te),
1.21-1.18 (m, 6H, CHsobutyrate)-
98
3
1C
NMR (125 MHz, CDCl 3 , 20 C):
8
170.8
175.5
(C=Oisobutyate),
(C=Oacetate), 164.7 (C 13), 163.1 (C 16),
148.7 (C9 ), 144.8 (C(Ph-i-C) 3), 137.9
(C,.), 131.9 (C 4 ), 131.4 (C(Ph-m-C) 3),
129.6 (C7 ), 128.3 (C(Ph-o-C) 3), 127.8
(C(Ph-p-C) 3), 125.9 (C 4.), 126.0 (C),
123.5 (C 2.), 122.9 (C7 .), 121.1 (C.),
120.5 (C5 .), 120.3 (C6 ), 118.3 (C 3 ,),
112.0 (C8.), 110.3 (C8 ), 87.5 (C 2 ), 84.1
(C 15 ), 73.7 (C 11), 63.4 (C 17), 54.2 (C 3),
47.2 (C 12 ), 34.4 (CHisoutyrate), 28.7
19.5
(CH 3acetate),
21.7
(C 18),
(CH3isobutyrate), 19.1 (CH3sobutyrale)FTIR (thin film) cm-':
3402 (br-m), 3056 (w), 2975 (w), 2360
(w), 1747(m), 1684 (s), 1609 (w),
1485 (w), 1459 (w), 1446 (w), 1377
(m), 1223 (w), 1067 (m)
HRMS (ESI) (mlz):
calc'd for C8H44N 4NaO 6 S 2 [M+Na+:
859.2594, found: 859.2569.
IaD 24
-50 (c = 0.38, CHCl 3).
TLC (50% ethyl acetate in hexanes), Rf
0.58 (UV, CAM).
99
H
CPh 3
Me
NH
H 1 0
Hr
8'
NMeO
Me
Me
BF3OEt 2, Et3SiH
DTBMP
CH 2CI 2 , 23 OC, 2 h
73%
(+)-2
2
8
HI
13
SN
H 1.12
8
18
Me3
N
0
(+)-12
(+)-Luteoalbusin A Acetate (12):
Dichloromethane (1 mL) was added via syringe to a flask charged with
bis(triphenylmethanedisulfide) (-)-11 (37.4 mg, 400 pmol, I equiv) and 2,6-di-tert-butyl4-methylpyridine (118 mg, 570 mmol, 15.0 equiv) under an argon atmosphere.
Triethylsilane (60.2 pL, 400 pmol, 10.0 equiv) was then added to the solution at 23 *C
via syringe followed by borontrifluoride-etherate (45.9 pL, 0.40 mmol, 10.0 equiv). After
2 hours, a saturated aqueous ammonium chloride solution (2 mL) was added to the
solution. The reaction mixture was dilutedwith dichloromethane (10 mL) and washed
with saturated aqueous ammonium chloride solution (5 mL). The aqueous layer was
extracted with dichloromethane (2 x 5 mL), and the combined organic layers were dried
over anhydrous sodium sulfate, were filtered, and were concentrated under reduced
pressure. The residue was purified by flash column chromatography on silica gel (eluent:
50% ethyl acetate in hexanes) to afford (+)-luteoalbusin A acetate (12) (14.0 mg, 73.0%)
as a white solid.
'H NMR (500 MHz, CDC 3 , 20 *C):
6 8.07 (br-s, lH, NR.H), 7.51 (d, J =
7.5, 1H, C5.H), 7.38 (d, J = 8.0, 1H,
C8 .H), 7.24-7.18 (m, 3H, CAH, C7 ,H,
CSH), 7.10 (app-t, J = 8.5, 1H, CH),
6.96 (d, J = 2.6, 1H, C 2.H), 6.88 (app-t,
J= 7.5, 1H,C6H), 6.75 (d, J= 7.5, 1H,
CH), 5.99 (s, 1H, C2H), 5.32 (s, 1H,
NIH), 4.99 (d, J = 13.5, 1H, CI7 Ha),
4.71 (d, J= 13.5, 1H, C1 7Hb),4.15 (d, J
= 15.0, 1H, Ci 2Ha), 3.14 (s, 3H, C, 8 H),
3.00 (d, J= 15.0, 1H, Ct2Hb), 2.18 (s,
3H, CH3ace,,ta)-
'3C NMR (150 MHz, CDCl 3, 20 *C):
6 170.3 (C=Oacetate), 166.6 (C1 3 ), 161.9
(C16 ), 148.7 (C9 ), 138.0 (C,.), 132.3
(C4 ), 129.9 (C7 ), 125.6 (C4 .), 124.7
(C), 123.4 (C2 .), 123.3 (CT.), 120.9
(C.), 120.6 (C.), 120.1 (C6 ), 117.0
(C.), 112.4 (C.), 110.8 (C8 ), 83.8
(C2), 75.5 (C 5 ),75.0 (C I), 60.6 (C 7),
56.2 (C 3 ), 44.3 (C,2), 28.8 (CI), 21.4
(CH3acetate).
100
FTIR (thin film) cm-':
3380 (br m), 2921 (m), 2850 (s), 1750
(m), 1689 (m), 1459 (s), 1377 (m),
1223 (w), 1048 (w), 744 (w), 666 (w).
HRMS (ESI) (m/z):
calc'd
for
507.1155,
C 25 H23N 40 4 S 2
IM+H:
found: 507.1146.
ICLID24:
+42.0 (c = 0.095, CHCl 3 ).
TLC (50% ethyl acetate in hexanes), Rf.
0.36 (UV, CAM).
101
H
OEQMe
~
N
H
1
eOAC
.
Hv
Me3SnOH_
PhMe, 90 OC
5 h, 73%
0
(+)-12
H
1
0
(+)-Luteoalbusin A (1):
Trimethyltin hydroxide (3.9 mg, 200 pmol, 1.00 equiv) was added as a solid to a
sealed tube reaction vessel containing a solution of (+)-luteoalbusin A acetate (12) (11.0
mg, 200 imol, 1 equiv) in toluene (2 mL) under an argon atmosphere. The resulting
reaction mixture was heated to 90 *C. After 5 h, the solution was diluted with
dichloromethane (10 mL) and loaded onto a silica gel column and purified by flash
column chromatography (eluent: 50% ethyl aceate in hexanes) to afford (+)-luteoalbusin
A (1, 7.4 mg, 73%) as a colorless gel.
'H NMR (500 MHz, acetone-d6 , 20 'C):
6 10.25 (br-s, 1H, NIH), 7.56 (d, J =
8.0, 1H, C5 ,H), 7.43 (d, J = 8.0, 1H,
C8,H), 7.33 (d, J = 8.0, 1H, C5H), 7.12
(dd, J = 8.0, 7.5, 1H, C7H), 7.12 (dd, J
= 8.0, 7.5 1H (C7,H) 6.99 (dd, J = 8.0,
7.5, 1H, C6,H), 6.79 (d, J = 8.0, 1H,
CH), 6.78 (dd, J= 8.0, 7.5, 1H, C6H),
6.22 (br-s, I H, NIH), 5.98 (d, J= 1.0,
IH, C2 H), 4.66 (dd, J = 7.5, 6.0, 1H,
OH), 4.34 (d, J = 12.7, 1H, CI7 Ha),
4.41 (d, J= 12.7, 1H, C, 7Hb),4.05 (d, J
= 15.0, 1H, Ct 2Ha), 3.18 (s, 3H, C, 8 H),
3.10 (d,J= 15.0, 1H, CI 2Hb).
'3C NMR (150 MHz, acetone-d6 , 20 *C):
6 168.1 (C1 3 ), 164.2 (C,6 ), 150.7 (C9 ),
139.7 (C,.), 134.4 (C4 ), 130.6 (C7 ),
127.1 (C 4.), 125.9 (C5 ), 125.0 (C2 .),
123.7 (C7 .), 121.1 (C.), 120.8 (C5 .),
120.8 (C6), 118.5 (C3 .), 113.9 (C8.),
111.6 (C8), 85.1 (C2), 79.0 (C,5), 76.1
(C,,), 61.4 (C,7 ), 57.5 (C 3), 45.5 (C, 2 ),
28.8 (C,8 ).
FTIR (thin film) cm-':
3380 (br-s), 2920 (s), 2850 (s), 1750
(m), 1689 (m), 1483 (w), 1459 (w),
1378 (w), 1223 (m), 1100 (w), 1048
(w).
HRMS (ESI) (m/z):
calc'd
for
C23H 2 ,N 4 0 3 S 2
[M+H]:
465.1050, found: 465.1045.
24
[aID :
+290 (c = 0.085, CHCl 3).
102
TLC (50% ethyl acetate in hexanes), Rf
0.36 (UV, CAM).
103
Table Si. Comparison of our data for (+)-Luteoalbusin A with literature:
This Work
Wang's Report
(+)-Luteoalbusin A
(+)-Luteoalbusin A
'H NMR, 500 MHz,
'H NMR, 500 MHz,
acetone-d6 , 20 *C
acetone-d6 , 20 *C
NI
6.22 (s)
6.22 (s)
0
C2
5.98 (d, J= 1.0)
5.98 (d, J= 0.9)
0
C4
-
C3
Ab
-
Assignment
C5
7.32 (d, J= 8.0)
7.33 (d, J= 8.0
-0.01
C6
6.77 (dd, J= 8.0,
7.5)
7.11 (dd, J= 8.0,
6.78 (dd, J= 8.0,
7.5)
7.12 (dd, J= 7.9,
-0.01
7.5)
7.6)
6.78 (d, J= 8.0)
6.79 (d, J= 8.0)
-0.01
3.09 (d, J= 15.0),
4.06 (d, J= 15.0)
3.10 (d, J= 15.0),
4.05 (d, J= 15.0)
0.01,-0.01
3.17 (s)
3.18 (s)
-0.01
C17
4.34 (d, J= 12.7),
4.41 (d, J= 12.7)
4.34 (d, J= 12.8),
4.41 (d, J= 12.8)
0
OH
-
4.67 (dd, J= 7.5,
6.0)
C8
C9
-0.01
-
C7
N1O
ClC12
C14
-
C13
C15
-
C16
10.27 (s)
10.25 (s)
C2'
7.13 (d, J= 2.5)
7.15 (d, J= 2.5)
0.02
-0.02
C3'
-
NI'
-
C4'
C5'
7.55 (d, J= 8.0)
7.56 (d, J= 7.9)
-0.01
C6'
6.99 (dd, J= 8.0,
6.99 (dd, J= 8.0,
0
7.5)
7.4)
7.11 (dd, J= 8.0,
7.12 (dd, J 8.0,
7.5)
7.5)
7.42 (d, J= 8.0)
7.43 (d, J= 8.0)
C7'
C8'
-0.01
0.01
C9'
104
Table S2. Comparison of our data for (+)-Luteoalbusin A with literature:
This Work
Wang's Report
(+)-Luteoalbusin A
(+)-Luteoalbusin A
"C NMR, 125 MHz,
"C NMR, 125 MHz,
acetone-d6 , 20 'C
acetone-d6 , 20 *C
(ppm)
C2
85.1
85.1
0
C3
57.5
57.5
0
C4
134.4
134.4
0
C5
125.9
125.9
0
C6
120.7
120.8
-0.1
C7
130.5
130.6
-0.1
C8
111.5
111.6
-0.1
C9
150.7
-
0
NIO
150.7
-
-
Assignment
C11
76.0
76.1
-0.1
C12
45.5
45.5
0
C13
168.1
168.1
0
C14
28.7
28.8
-0.1
C15
79.1
79.0
0.1
C16
164.2
164.3
-0.1
C17
61.1
-
61.4
-
-0.3
C2'
124.9
125.0
-0.1
C3'
118.4
118.5
-0.1
C4'
127.1
127.1
0
C5'
121.1
120.8
0.3
C6'
121.1
121.1
0
C7'
123.6
123.7
-0.1
C8'
113.8
113.9
-0.1
C9'
139.7
139.7
0
OH
-
NI'
-
NI
105
Appendix A.
Spectra for Chapter 2
106
SAMPLE
solvent
DEC.
CDCo3
ACQUISITION
sfrq
125.672
tn
C13
at
2.000
np
125588
sw
31397.2
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pw
6.7
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3.000
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11
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in
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-2521.0
30158.3
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60
40
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solvent
DEC. & VT
125.672
C13
dpwr
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dm
nnn
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w
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1.0
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500 400.0
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solvent
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ACQUISITION
sfrq
499.746
tn
Hi
at
3.001
np
63050
sw
10504.2
fb
not used
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3
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56
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2.000
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1519.5
nt
1000
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dmf
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125.795 dseq
tn
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1.0
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sw
37735.8 lb
0.30
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ft
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1 fn
13 L072
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n
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11
in
dp
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sp
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n
n
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499.746
sfrq
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3.001
at
63050
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10504.2
sw
fb
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4
tpwr
56
8.6
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nt
256
ct
256
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n
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n
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hs
sp
wp
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sc
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hzm
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ai
dfrq
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1.0
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wtfile
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ft
fin
26 2144
math
werr
wexp
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wnt
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nn
DISPLAY
ph
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solvent
COC13
ACQUISITION
125.795
sfrq
CIS
tn
1.736
at
131010
np
3773S.8
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not used
fb
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bs
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ss
58
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0.30
lb
wtfile
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fn
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ph
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180
160
140
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DEC. & VT
500.229
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da
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dam
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1.0
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60
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1000
500 400.0
0
SAMPLE
DEC. & VT
12 5.672
dfrq
cis
dn
dpwr
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10000
ACQUISITION
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409.746 dseq
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n
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10504.2 WtItle
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1000 wbs
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n
solvent
COCIS
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n
in
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6496.6
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SAMPLE
solvent
CDC13
file /data/export/home/movassag/NVtada/rocky/TA-VI-122-
BCarbon.fid
ACQUISITION
sfrq
125.795
tn
C13
1.736
at
np
131010
37735.8
sw
not used
fb
bs
8
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1
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0.763
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1e+09
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solvent
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200
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ACQUISITION
500.433
sfrq
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4.999
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12012.0
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fb
3
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60
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ACQUISITION
sfrq
125.795
C13
tn
at
1.736
np
131010
sw
37735.8
fb
not used
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ss
1
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58
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125.844
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Curriculum Vitae
Timothy C. Adams
88 Sumner Street, Apartment 1
Boston, MA 02125
tadams@mit.edu
Phone: 321.759.9115
Education
Massachusetts Institute of Technology, Cambridge, MA
Ph.D. in Organic Chemistry, expected Jan 2015
Graduate Research Advisor: Professor Mohammad Movassaghi
Focus: Multi-step chemical synthesis
University of Florida, Gainesville, FL
B.S. in Chemistry, 2009
Undergraduate Research Advisor: Professor Sukwon Hong
Focus: Organocopper chemistry
Professional and Research Experience
Graduate Research Assistant
MassachusettsInstitute of Technology, Mohammad Movassaghi, Cambridge, MA, 2009present
* Conducted methodology studies for the synthesis of densely functionalized sulfurcontaining diketopiperazine molecules. The project involved the design and
synthesis of a new mercaptan reagent for use as a hydrogen sulfide surrogate. This
discovery led to the completion of several natural products, including (+)bionectins A and C.
*
Conducted the first known total synthesis of (+)-luteoalbusins A. A novel,
intramolecular thiolation strategy was developed to access the higher order
polysulfane congeners for this family of alkaloids.
Undergraduate Research Assistant
University of Florida,Sukwon Hong, Gainesville, FL, 2007-2009
* Designed and synthesized chiral, acyclic diaminocarbene ligands for Cu (I)
catalyzed Michael addition reaction. Studies were also conducted to elucidate the
mechanism for this transformation.
Academic Honors and Awards
2012-2014
2010-2011
2009-2010
2008-2009
2008-2009
2007-2009
National Science Foundation Graduate Research Fellowship
Walter L. Hughes Memorial Graduate Fellowship
Graduate Institute Fellowship-MIT
REU Research Fellowship-Universityof Florida
ACS Petroleum Research Fellowship-Universityof Florida
American Chemical Society Scholar
Teaching Experience
Grader in Synthetic Organic Chemistry II (graduate)
Massachusetts Institute of Technology, Cambridge, MA, 2014
108
Teaching Assistant in Organic Chemistry I (undergraduate)
MassachusettsInstitute of Technology, Cambridge,MA, 2010
* Led multiple discussion sections centered on molecular structure and chemical
reactivity.
Teaching Assistant in Organic Chemistry II (undergraduate)
MassachusettsInstitute of Technology, Cambridge, MA, 2009
* Led multiple discussion sections focused on rudimentary organic synthesis.
Tutor in Organic Chemistry I and II (undergraduate)
Brevard Community College, Palm Bay, FL, 2007
* Held one on one tutoring sessions in basic organic chemistry.
Publications
2013
"Concise Total Synthesis of (+)-Bionectins A and C" Coste, A.; Kim, J.;
Adams, T. C.; Movassaghi, M. Chem. Sci. 2013, 4, 3191-3197.
Conferences
2013
Boston Symposium on Organic and Bioorganic Chemistry
Poster presenter: "The Concise Total Synthesis of (+)-Bionectin
A and C"
109