1
Abyssomicin C
John Trant
Department of Chemistry
University of Ottawa, 2007
Abyssomicin C—From isolation to mechanism
of action
 An introduction to the tetrahydrofolate biosynthetic




3
pathway
The isolation identification of Abyssomicin C
A brief retrosynthetic overview of Abyssomicin C
K.C. Nicolaou’s synthesis: The application of Lewisacid catalysed self-assembling (LACASA) DielsAlder reaction
The mechanism of action
Folic Acid: An Introduction
O
C
O
N
HN
H2N
 Vitamin B9
N
CO2H
N
H
CO2H
N
H
N
 Needed for the catalysis of one-carbon transfer reactions
including dTMP from dUMP, and in the catalysis of glycine
synthesis.
 Not synthesised in vertebrates, but synthesised in plants,
archaea, fungi, bacteria, and some lower animals.
O
O
NH
NH
O
-O P O
O4
N
O
OH
dUMP
O
O
-O P O
O-
N
O
OH
dTMP
O
p-Aminobenzoic acid/Tetrahydrofolate pathway
Aminodeoxychorismate
Synthase
Aminodeoxychorismate
COO-
COO-
COO-
COONH3
PabA
HO
OH
O
OH
COO-
COO-
O
OH
Shikimic Acid
H2N
NH
N
N
N
O
Dihydrofolate HN
Oxidase
HO2C
O
CO2H
Folic Acid
5
N
Dihydropteroate COOH
Synthetase
Sulfa Drugs
C
O
CO2H
Dihydrofolate
NH2
p-Aminobenzoic Acid
H2O Glutamic Acid
HN
HO2C
O
HN
Trimethoprim
HN
NH
Dihydrofolate HN
Synthetase
HN
HN
C
Aminodeoxychorismate
Lyase
N
N
COO-
NH3+
H2N
N
HN
O
O
OH
Chorismate
Glutamine Glutamic Acid
H2N
PabB
COO-
Dihydropteroate
HO O
P
HO O P OH
O O
H
N
N
NH2
NH
N
O
Dihydropteridine
CO2-
-O2C
Phenylalanine
and Tyrosine
p-hydroxybenzoate
O
CO2-
Ubiquinone
(Coenzyme Q)
OH
Prephenate
2-amino-2-deoxyisochorismate
CO2NH3+
O
CO2-
Chorismate Chorismate
lyase
mutase
CO2-
Anthranilate
synthase
O
OH
4-amino-4-deoxychorismate
CO2-
CO2-
p-Aminobenzoate
Synthase
OH
O
NH3+
CO2-
Isochorismate
Synthase
CO2NH3+
O
6
CO2-
CO2OH
CO2-
Anthranilate
Isochorismate
Tryptophan
Siderophore
biosynthesis
NH3+
p-aminobenzoate
Folate
Kozlowski, M.C et al. J. Am. Chem. Soc. 1995. 117 2128-2140.
p-Aminobenzoic acid/Tetrahydrofolate pathway
Aminodeoxychorismate
synthase
Abyssomicin C
Aminodeoxychorismate
COO-
COO-
COO-
COONH3
PabA
HO
OH
O
OH
Shkimic Acid
COO-
O
C
H2N
CO2H
NH
H2N
N
Dihydrofolate
synthetase
7
HN
N
Folic Acid
HN
p-aminobenzoic acid
COOH
N
Dihydropteroate
synthetase
NH3
N
NH2
O
HN
H2O
HN
NH
N
HN
NH
O
Aminodeoxychorismate
lyase
O
HN
COO-
NH3+
Glutamic Acid
N
HN
Dihydrofolate
Oxidase
N
O
OH
Glutamine
HO2C
COO-
O
OH
Chorismate
PabB
HO2C
C
O
CO2H
Dihydrofolate
Glutamic Acid
COODihydropteroate
HO O
P
OH
HO O P
O O
H
N
N
NH2
NH
N
O
dihydropteridine
The Abyssomicins
Verrucosispora AB-18-032
HO
O
N
8
O
O
O
O
O
O
O
O
O
HO
O
O
O
O
OH
OH
OH
B
C
D
Riedlinger, J. et al. J. Antibiotics. 2004. 57, 271-279.
Bister, D. et al. Angew. Chem. Intl. Ed. 2004. 43, 2574-2576.
Abyssomicin C as a Chorismate mimic
O
C
-O
COOHO
O
-OOC
O COO-
Chorismate
OH
O
O
O
O
O
OH
9
Copley, A.D.; Knowles, J.R. J. Am. Chem. Soc. 1987. 109, 5008-5013.
Abyssomicin C
O
O
O
O
OH
10
O
A Short Retrosynthetic Overview
Snider/Sorenson/Couladaros Approach to the initial disconnection
O
O
O
O
O
O
O
O
O
OH
OH
O
MeO
O
O
O
O
O
O
O
O
Li
O
O
MeO
O
O
MeO
11
1
Snider, B.B.; Zou, Y. Org. Lett. 2005. 7, 4939-4941.
Zapf, C.W.; Harrison, B.A.; Drahl, C.; Sorenson, E.J. Angew. Chem. Int. Ed.
2005. 44, 6533-6537.
Couladouros, E.A.; Bouzas, E.A.; Magos, A.D. Tet. Lett. 2005. 62, 5272-5279.
A Short Retrosynthetic Overview
Sorenson’s Retrosynthesis of 1
O
O
O
O
OP
O
O
1
Snider’s Retrosynthesis of 1
O
O
O
OP
O
O
(MeO)2P
OP
O
1
12
O
O
A Short Retrosynthetic Overview
Maier’s and Georgiadis’ Retrosynthesis of Abyssomicin C
O
O
O
O
O
O
O
O
TBSO
O
O
O
OP
OH
X
OH
OP
OH
O
AcO
O
PO
H
O
OR
OAc
O
O
HO
TBSO
O
Rath, J.; Kinast, S.; Maier, M.E. Org. Lett. 2005. 7, 3089-3092.
Zografos, A.L.; Yiotakis, A.; Georgiadis, D. Org. Lett. 2005. 7, 4512-4518.
13
Nicolaou’s Retrosynthesis
O
O
O
O
O
O
O
O
O
O
O
O
O
OH
OH
O
OH
CH3
O O CH
3
O
AcO
O
OH
CH3
O
AcO
O
O
O
OH
OH
O
OMe
14
Nicolaou, K.C.; Harrison, S.T. Angew. Chem. Int. Ed. 2006. 45, 3256-3260.
Nicolaou, K.C.; Harrison, S.T. J. Am. Chem. Soc. 2007. 129, 429-440.
OH
O
MeO
O
O
HO
MeOH
O
O
15
O
But...
O
MeO
D
OH
A:B:C:D=1.3:1.2:1.3:1.0
OH
OMe
120º C
O
O
MeO
OCH3
OH
C
MeOH
O
Ward, D. E.; Abaee, M.S.
Org .Lett. 2000. 2, 3937-3940.
16
OH
OMe
B
OH
O
O
A
Examples from literature
OH
R1
MeO
O
OH
B(OR2)2
R1
BOR2
O
THF 16 h
25ºC
Batey, R.A.; Thadani, A.N.; Lough, A.J. J. Am. Chem. Soc. 1999. 121, 450-45.
OH
OH
OH
R 49-67%
AlMe
3
R
dr 1:1-3:1
3 eq
Bertozzi, F.; Olsson, R.; Frejd, T. Org. Lett. 2000. 2, 1283-1286.
OH
OH
MgX
O
R
O
L.A.
17
OH
OH
1)
PhCH3
2) Me3N(O)
60-80%
H2O
endo:exo 2:1-9:1
8 examples
2 examples
MeO
R1
130 ºC
3h
R
60%
dr 9:1
1 example
Stork, G.; Chan, T.Y. J. Am. Chem. Soc. 1995. 117, 6595-6596.
Ward, D. E.; Abaee, M.S.Org .Lett. 2000. 2, 3937-3940.
Ward’s Solution
OH
BrMgO
MeMgBr
Benzene
0-25ºC
18
O
O
MeO
O
O
Br Mg
O
O
95%
Ward, D.E.; Abaee, M.S. Org. Lett. 2000. 2, 3937-3940.
An Early Attempt at Olefination
O
O
KHMDS
O2, P(OEt)3
O OH
O OH
LiOH
O
LiO
HO
96%
H3O+
O OH
HO
O OH
HO
HO
O
19
O OH
O OH
O
HO
Nicolaou, K.C.; Harrison, S.T. J. Am. Chem. Soc. 2007. 129, 429-440.
A Modified Julia-Olefination Strategy
O OH
1) NaSPh
O
2) MeOH, H2SO4
O OH
MeO
71%
20
O OH
MeO
SPh
82%
1) H2O2
2) TMSCl, NEt3,
DMAP
O OTMS
1) LiHMDS,
CH2ICI
MeO
2) Na (Hg)
3) aq HCl, MeOH
SO2Ph
72%
OH
Me2Zn
Br
O
Mg
0 ºC 5min
Zn
O O
5 min
0 ºC
MeMgBr
HO
HO
0 ºC 5min
O
MeO
S- BINOL
O
Zn
O
O
O
O
95% yield
93% ee
21
O
Mg
Br
O
Ward, D.E.; Souweha, M. S. Org. Lett. 2005. 7, 3533-3536.
The Disadvantages
 Stoichiometric amount of enantiopure BINOL and
ZnMe2 in the first step of the synthesis.
 Synthesis had become lengthy (7 steps, 38% yield).
O OH
MeO
22
Asymmetric Borane Reduction
O
MeO
N
O
1.5eq PhSCH3
1.5 eq DABCO
1.5 eq n-BuLi
Ph
S
81%
1.1 eq catecholborane
H Ph
0.1 eq
Ph
N O
B
O H
O
PhS
H
30%
23
MeMgBr
Me-(R)-CBS
OH
Methyl Acrylate
S
Ph
Toluene 55 ºC
95% yield, 90% ee
30%!!!!
 Use of “sacrificial” alcohol resulted in no increase in
yield.
 Lewis Acid scan produced no increase of the yield
(TiCl4, AlCl3, Zn(OTf)2, MgBr2•OEt2/i-Pr2NEt).
 But...Remember that the enantioselective Diels-Alder
Reaction was faster than the racemic version...
24
Bidentate Ligands
Entry
Auxiliary
1
2
None
(±)-Binol
Base/Metal
Reaction Yield (%)
Time1 (h)
MeMgBr (1.0 eq) 24
30
MeMgBr (1.0 eq) 24
<5
Me2Zn (1.0 eq)
MeMgBr (1.0 eq) 36
35
Me2Zn (1.0 eq)
3
OH
4
OH
OH
5
NH2
OH
MeMgBr (2.0 eq) 24
49
MeMgBr (2.0 eq) 48
55
MeMgBr (3.0 eq) 48
MeMgBr (4.0 eq) 12
70
6
80
N
6
7
1)
25
2eq “
3 eq “
”
”
Time required for consumption of diene as monitored by NMR.
The Proposed Transition State
OH
Ph
S
N
MeMgBr
Methyl Acrylate
Mg
Toluene 55 ºC
O
PhS
O
O
Mg
Br
O
MeOH
O H
O
PhS
26
H
80%
Julia-Type Reduction
O OH
O H
LiHMDS;
O2, P(OEt)3
O
H
PhS
H
74%
PhS
O-
O
O
O
OTES
97%
27
O
O O
2) aq NH4Cl
66 ºC 2h MeO
3) TESCl,
Imidazole
DMAP
dtBB
O
[O]
O CO
OH2Me
HO
O
0.5 eq. dtBB
9.6 eq[O]Li
MeI, K2CO3
PhO2S
H
99%
1) t-BuOOH
VO(OEt)3
2) Ac2O
O OH
O OAc
HO
1)2.5 eq LiHMDS MeO
H
1 hr -78 to 25 ºC
O
88%
O
O
O
O
OH
28
O
Synthesis of The Coupling Partner
HO
OTBS
SO3 Pyridine
DCM:DMSO (2:1)
O
OTBS
2 eq
MgBr
THF -78 ºC
O
OPMB
84%
29
1) NaH, PMBCl,
TBAI, DMF
2) HCl, MeOH
3) SO3 Pyridine,
DCM:DMSO (2:1)
OTBS
OH
74% (two steps)
O
OH
O
1) t-BuLi, THF
2)
O
O
OPMB
O
O
O
OTES
OPMB
OTES
61%
3 eq DDQ
DCM: NaHCO3
saturated (10:1)
OH
5 mol%
mol% Grubbs
Grubbs 2
2
HO
O
Various
homodimerised
and 5
polymerised by-products
O
O
OTES
30
HO
OH
O
O
O
OTES
96%
HO
HO
OH
O
1 mol% HCl
MeOH
25 ºC, 1 h
O
O
OH
O
O
O
OH
94%
OTES
5 mol% Grubbs 2
OH
O
Covers O
blue
O O
IBX
MnO2
OH
31
O
OH
HO
O
O
O O
OH
78%
Dess-Martin
PDC
Swern
O
O O
O
A New Approach
OH
AcO
O
O
O
1) 1.2 eq t-BuLi
2)
O
AcO
O
O
O
O
AcO
O
IBX
DMSO 25 ºC
45 min
O
O
OTES
OTES
90%
OTES
75%
5 eq (CH2SH)2
5 eq BF3 OEt2
DCM, 12 h
S
S
HO
O
O
O
OH
90%
32
S
S
AcO
O
3.4 eq K2CO3
MeOH 25 ºC
O
O
OH
90%
S
S
HO
O
O
O
OH
S
S
HO
1) IBX
2)
MgBr
O
5 mol% Grubbs 2
O
O
OH
65%
HO
S
S
HO
O
2.5 eq IBX
DMSO
O
H
OH
85%
S
S
O
O
HO
O
O
HO
O
O
H
H
33
3 eq PhI(OTFA)2 O
CH3CN/H2O (10:1)
25 ºC 10 min
OH
73%
OH
50%
 5.6% overall yield, 19 steps from Weinreb Amide
 The NMR did not match that of the previously
isolated natural compound.
 After 18 hours in CDCl3 a new set of peaks
appeared.
 The new peaks matched those of the previously
isolated abyssomicin C.
O
MeO
34
N
Generation of Possible Atropisomers
HO
H
O
LnRu
H
H
O
S
S
O
5 mol% Grubbs 2
0.002M DCM
40 ºC 1hr

N Mes
Cl
Ru
Cl
Ph
PCy3
O O
[re] O
LnRu
O
H
O O
HO
H
OH
S
S
HO
si approach
S
S
OH
re approach
O
O
S
S
O
H
O O
HO
LnRu
H
[si]
OH
35
O
Mes N
OH
HO
O
O O
H
S
S
HO
S
S
OH
OH
36
Nicolaou and Harrison J. Am. Chem. Soc. 2006, 129, 430-440.
The Differences
O
O
O
H
O O
CDCl3
O
O
O
H
O O
OH
OH
2
1
O
O
O
H
O O
OH
1
37
CDCl3
O
O
O
H
O O
OH
2
Nicolaou and Harrison J. Am. Chem. Soc. 2006, 129, 430-440.
Nicolaou’s Proposed Mechanism
O
O
O
H+ O
O
O
O
O
O
OH
H+ O
O
O

OH
38
O
O
O

O
O
O
H
O
OH
O
O
O+
O+H
O
O
O
OH
 H+O
O
O
O
O
O+
O
H
O
OH
O
OH
O
O
O
O
OH
H
O
O
O
O
O
O
OH

HO
OH
O
H+ O
O
O
O
O
OH

OH
OH
O
OH
O
O
O
O
O
O

HO
OH
O
O+H
OH
O
O
CDCl
/HCl
3O
O
O
O
O+
O
O
H+
O
O
OH
O
Biosynthetic Ramifications
O
O
O
L-selectride
O
O
O
OH
atrop-abyssomicin C
O
O
O
O
L-selectride
O
OH
abyssomicin C
39
-O
O
H
O
H3O+
HO
O
O
H
O
O
OH
OH
Abyssomicin D
Z-enolate
OO
H
O
O
H3O+
O
OH
E-enolate
O
HO
O
O
H
O
O
O
O
OH
O
H
O
O
OH
Iso-abyssomicin D
Figure modified from Nicolaou et Harrison J. Am. Chem. Soc 2007. 129, 429-440.
H H O
Biosynthetic Ramifications
NH2
N
HO
% Starting Material Remaining
O
Abyssomicin C
OH OH
NADH
EtO2C
Me
Atrop-abyssomicin C
CO2Et
N
H
Me
Time (h)
40
Figure modified from Nicolaou et Harrison J. Am. Chem. Soc. 2007. 129, 429-440.
Minimum Inhibitory Concentrations for the analogues
O
O
H
O O
O
H
O
H
O O
O
H
S
S
O
O
O
H
O O
O
H
O
H
O O
O
H
OAc
OH
OH
OH
Abyssomicin C atrop-Abyssomicin C Ac-Abyssomicin C
Dithiane
20 µM
20 µM
15 µM
atrop-Abyssomicin C
70 µM
S
O
O
S
O
O
HO
O O
H
O O
H
MeO
O O
O
H
C
OH
OH
-O
O COOOH
>500 µM
>500 µM
Dithiane-hydroxy
Abyssomicin C
>500 µM
41
OH
Proposed Mechanism of Action
42
Figure adapted from Parsons, J. F.
et. al. Biochem. 2002. 41, 2198-2208.
Narrowing the Search
Ser266 Thr270 Thr276
Cys263
Ser256
Ser254
Ser422
Cys421
43
Active Site
OO
CC
-O
-O
Ser342
Thr343
Thr345
OO COO- COO
OH
OH
Thr408 Thr411
Ser366
Thr368
Cys391
Ser393
Identifying the nucleophile
44
Keller, H. et. al. Angew. Chem. Intl. Ed. 2007. 46, 8284-8286.
O
HO
H
O
O
O
H
O
O
Cys
O
-O
O
O
Cys
O
O
O
Cys
OH
O
OH
OH
OH
HO
O
O
Cys
SH
HO
SH
HN
O
45
CO2H
OH
O
Minimum Inhibitory Concentrations for the analogues
O
O
H
O O
O
H
O
H
O O
O
H
S
S
O
O
O
H
O O
O
H
O
H
O O
O
H
OAc
OH
OH
OH
Abyssomicin C atrop-Abyssomicin C Ac-Abyssomicin C
Dithiane
20 µM
20 µM
15 µM
atrop-Abyssomicin C
70 µM
S
O
O
S
O
O
HO
O O
H
O O
H
MeO
O O
H
OH
OH
OH
>500 µM
>500 µM
Dithiane-hydroxy
Abyssomicin C
>500 µM
46
In Conclusion
 Examined the Folate Biosynthesis pathway.
 Examined Nicolaou’s application and modification
to Ward’s LACASA approach to Diels-Alder
Reactions using an allylic alcohol diene.
 Delved into Nicolaou’s Approach for the total
synthesis of Abyssomicin C.
 Demonstrated how Nicolaou’s synthetic work
uncovered the potent inhibitor, atrop-abyssomicin
C, leading to a better understanding of the
abyssomicin mechanism of action.
47
Acknowledgements










Roger Tam
Pawel Czechura
Jennifer Chaytor
Elisabeth Von Moos
Tahir Rana
Wendy Campbell
Sandra Ferreira
Ruoying “Gloria” Gong
Jaqueline Tokarew
Ivan Petrov
Dr. Michael Souweha
Dr. Matthieu Leclere
Dr. Robert Ben
And NSERC for providing funding to make this possible
48
Couladouros’ Retrosynthesis of 2
O
O
MeO
O
O
OH
O
HOMeO
OH
O
MeO
O
O
O
2
I
3
4
AcO
O
AcO
O
O
OH
MeO
O
O
O
O
O
O
OMe
OMe
49
O
EtO2C
CO2Et
5
O
OMe
O
Synthesis of Building Block 5
(NMe2)2CHOMe MeO
MeO
O NaCNBH4
O
MeO
O
O
O
O
N
N
MeI
MeO
MeO
O
O
5
NaHCO3
O
O
NMe3
Takeda et al. J. Org. Chem. 1987, 52, 4135-4137
50
Synthesis of 4
65% total yield
CO2Et 1) NaOEt 25ºC
2) HCl, AcOH 105ºC
EtO2C
3) Ac2O, reflux
O
O
OMe
O
7
O
O
:
O
3
NEt3, THF, Reflux
AcO
O
(COCl)2, DMSO
AcO
DCM NEt3
51
OH
O
1) LiAlH4, THF 0ºC
2) AcOCHCH2,
Amino Lipase AK
THF 0ºC
Putting The Pieces Together
MeO
O
O
5
AcO
1) LDA, THF -100 C
OH
MeO
2)
O
AcO
4
O
O
45-58%
1) IBX DMSO
HO
2) Novozyme 435,
Toluene
phosphate buffer
O
IBX DMSO
MeO
HO
O
70%
MeO
O
O
O
41%
O
I
CrCl2
HO
O
MeO
O
O
52
Putting The Pieces Together Take 2
MeO
O
AcO
1) LDA, THF -100 C
O
5
OH
MeO
2)
O
O
AcO
TBSCl
Imidazole
DMF
AcO
MeO
O
O
45-58%
4
OTBS
HO
Guanidine HCl
EtOH/4M NaOH
OTBS
MeO
O
O
O
85%
78%
1) IBX DMSO
2) CrCl2, NiCl2
THF/DMSO
I
O
O
O
O
O
O
O
O
O
O
Toluene 100ºC
70%
O
O
O
53
O
O
OMe
I
O
I-
O
O
OMe
OTBS
MeO
I2
OMe
I
O
OMe
I
HO
O
MeO
1) TBAF, THF
O
O
2) IBX, DMSO
44%
O
O
O
1 eq DMDO
OMe Acetone 0º-23ºC
18 h
O
O
O
O
O
OMe
67%
O
10 eq. LiCl
DMSO
50ºC
O
O
O
O
OH
50%
54
O
1.2 eq. PTSA
5 eq. LiCl
AcN 50ºC 2h.
O
O
O
O
OH
O
quantitative
Synthesis of Vinyl Iodide 3
O
Entry
1
1
22
33
1
I
Conditions
Solvents
E/Z
Yield (%)
CrCI2, CH3I, 0°C
CrCI2, CH3I, 0°C
Ph3P+(I-)CH2I,
NaHMDS, -78°C
THF
THF:Dioxane; 6:1
THF
2:1
2:1
1.2:1
85
75
87
Takai’s Conditions (Takai, K. et al. J. Am. Chem. Soc. 1986, 108, 7408-7410.
Evans’ Conditions (Evans, D.A. et al. J. Am. Chem. Soc.1993, 115, 4497-4513.
3
Stork’s conditions (Stork, G. et al. Tet. Lett. 1989, 30, 2173-2174.
2
55
Isomerisation Conditions
O
O
O
H
O O
CDCl3
OH
1
Entry
1
2
3
4
5
6
7
8
9
56
Conditions
Unstabalised CDCl3
Xylenes 180°C
TFA/DCM (1:1)
1 eq. BF3• OEt2 DCM
1 eq. CSA, DCM
1 M aq HCl:THF (3:1)
1M HCl in Et2O (0.2 eq.)/d6-THF
1M HCl in Et2O (0.2 eq.)/CDCl3
1 eq. p-TsOH, 5 eq. LiCl
CD3CN, 50°C
O
O
O
H
O O
OH
2
Time (h)
24
12
24
24
24
24
1
1
2
Ratio (1:2)
2:1
No isomerisation
No isomerisation
No isomerisation
No isomerisation
No isomerisation
1.0:1.6
2.5:1.0
1.0:2.0
Isolation and Identification
 Isolated in 2004 by Süssmuth from an
actinomycete of genus Verrucosipora, discovered
in a sediment sample from the Japanese Sea.
 Investigated because of pABA inhibition identified
by an agar-plate diffusion assay
 Structure determination by NMR and X-Ray
57
Whoopdeedoo
 Folic acid, Vitamin B12 is an essential vitamin.
 Not synthesised in vertebrates
 Fungi, Bacteria, Plants, Achaea, and insects and
anthropods all synthesise it.
 So it has the possibility of providing broad
spectrum antibiotics.
 Sulfonamides and Trimethoprim are existing
antibiotics that inhibit the Folate Synthesis
Pathway
58
Andrus’ Lactone
59
Agar Plate Diffusion Assay
 Screened 930 extracts.
Lives
60
No Activity
Dies
Metabolic
Activity
B. subtilis
in simple
medium
B. subtilis
in complex
medium
Dies
Lives
General
Toxin
Riedlinger, J. et al. J. Antibiotics. 2004. 57, 271-279
pAba+Trp
+Phe+Tyr
Verrucosispora AB-18-032
Phe+Tyr
B.
Subtilis in
simple
medium
pAba
Trp
61
ibid
Borane Transition State
Ph
Ph
N O
B
Me
O
L2B
H
SPh
62
A Shorter Route
AcO
O
O
1) 1.2 eq. t-BuLi
2)
O
AcO
O
AcO
OH
O
O
O
O
O
IBX
DMSO 25ºC
45 min
O
O
OTES
1.2 eq t-BuLi
1.1 eq
O
HO
O
O
OTES
63
5 eq(CH2SH)2
5 eq BF3 OEt2
DCM 12 h
O
S
S
HO
O
O
OTES
90%
OTES
75%
O
(CH2SH)2
TMSOTf
O
O
OH
76% over 2 steps
S
S
AcO
O
3.4 eq K2CO3
MeOH 25ºC
O
O
OH
90%
O
O
O
O
Kinetic Studies
O
OH
Irreversible Inhibition: KIapp=390μM;
kinact=0.8 min-1
O
O
O
O
O
OH
64
Keller, H et. al. Angew. Chem. Intl. Ed. 2007. 46, 8284-8286
Ward’s DA evidence
65