Baran Lab
Sir Jack Baldwin
Savvas N. Georgiades
JACK E. BALDWIN-SHORT BIO
REARRANGEMENTS
♦ Born in London in 1938.
♦ Undergraduate studies at Imperial College,
London. Obtained his B.Sc. (1st class) in 1960.
♦ Graduate studies at Imperial under the
supervision of Nobel laureate, Professor Sir
Derek Barton. Structure elucidation of
byssochalmic acid using chemical methods.
Awarded his Ph.D. in 1964.
♦ Appointed assistant lecturer at Imperial
College in 1965.
♦ 1967-Moved to the US to join Pennsylvania
State University as Assistant Professor of
Chemistry.
♦ 1969-Promoted to Associate Professor.
♦ 1970-Joined the chemistry department at
MIT.
♦ 1971-Promoted to full Professor.
♦ March 1972-Returned to the UK as the Daniel Professor of Chemistry at King's
College.
♦ November 1972-Back to MIT.
♦ 1978-Elected Fellow of the Royal Society and appointed Waynflete Professor of
Chemistry at the University of Oxford, UK.
♦ Held the Waynflete chair at Dyson Perrins Laboratory and then at the Chemistry
Research Laboratory for 27 years until his retirement in 2005.
♦ 1997. Awarded a knighthood for his contributions to organic chemistry.
♦ Still maintains an active group at Oxford University.
♦ Awarded many prestigious awards and prizes.
♦ Published more than 600 papers. Second most cited author in Chemical
Communications. Author of their most cited publication ever, "Rules for Ring
Closure".
>>> 2,3-Sigmatropic rearrangements
a
a
b
e
c
e
(concerted, favored at low T)
b
d
c
d
a
b
e
a
d
b
c
(stepwise, radical
dissocation-recombination,
favored at high T)
d
c
Sulfonium ylids, Chem. Commun. 1968 , 18, 1083-1084
1) Et3 OBF4
2) n-BuLi/THF/-70 o C
Ph
S
Ph
C
S
Ph
Ph
Sulfonium ylids, Chem. Commun. 1971 , 7, 359
OH
1)
Br
OH
n-BuLi/THF
-40 oC
2) Me3 OBF4
BF4
SH
AREAS OF INVESTIGATION
♦ Biomimetic synthesis of natural products, especially sponge alkaloids and fungal
metabolites.
♦ Development of synthetic methodology.
♦ Chemical and biological studies on the biosynthesis of beta-lactam antibiotics.
♦ Parallel synthesis methodology.
e
O
S
O
Sulfonium ylid
readily undergoes
2,3-rearrangement
S
S
1
Sir Jack Baldwin
Baran Lab
Allylic ether anions, Tetrahedr on Lett. 1970, 5, 353-356
Allylic disulfides, J. Am. Chem. Soc. 1971, 93, 6307-6308
OH
OH
O
t-BuLi/THF
-20
83/17
25 oC: 77/23
S
All carbon anionic, Chem. Commun. 1970, 3, 165-166
1) Li/THF/-70
2) -20 oC/5h
oC
Ts
+
(T dependence of
product distribution)
HN
quantitative
N
H
Br
R2
N
N
X
N
Br
Diazenes, J. Am. Chem. Soc. 1971, 93, 788-789
N
N
N
R1
H
O
O
1) Deprotonation
2) 130 o C/30 min
N
N
PPh3
S
Mechanism?
S
Br
H
N
Ts
S
SMe
KOH
N
H
N
SMe
S
1) NaH
MeS
2) 65 o C
S
Reformatsky-Claisen, Chem. Commun. 1973, 4, 117-118
1) Deprotonation
2) 35 oC/1 min
O
NH
S
S
>>> 3,3-Sigmatropic rearrangements
N-Ammonio-amidates, Chem. Commun. 1970 , 1, 31-32
N
S
Nucleophilic carbenes, Chem. Commun. 1972, 6, 354-355
Cl
Br
Benzene
rt/98%
S
+
o C:
NH2
Savvas N. Georgiades
+
N
N
R3
OZnBr
O
OZnBr
R2
O
Zn
H
R4
R1
H
R3
O
Benzene/80 o C/
H
R4
>90%
R2 R1
O
H
H
R4
R3
Enol phosphate variant, Chem. Commun. 1973 , 4, 117-118
O
O
O
O P OR
P
Cl
OR 3,3-Rearrangement
RO
OR
Cl
O
O
Cl3 C
OR
70%
Cl
Cl
O
O
P OR
OR
O
N
N
2
Sir Jack Baldwin
Baran Lab
Savvas N. Georgiades
>>> Rearrangements of strained dipolar species
BALDWIN'S RULES FOR RING CLOSURE
Episulfoxides, J. Am. Chem. Soc. 1971, 93, 2810-2812
>>> Primary literature
∆
S O
(previously observed and believed to
proceed in cheletropic concerted fashion)
+ SO
S OH
O
35 oC
S O
Mechanism?
S
♦ Rules apply to cyclic transition states leading to ring formation or intramolecular
group transfer. Nucleophilic, radical and cationic processes follow the rules, but
not electrocyclic reactions!
thiosulfoxylate
♦ Rules only apply to first row elements-"violations" reported for larger atoms (S,
Si, etc) due to larger atomic radii/orbital size/bond lengths.
S
H
Chem. Commun. 1976, 18, 734-736
Chem. Commun. 1976, 18, 736-738
Chem. Commun. 1977, 3, 77
Chem. Commun. 1977, 7, 233-235
J. Or g. Chem. 1977, 42, 3846-3852
T etrahed ron 1982, 38, 2939-2947
sulfenic acid
At high T (>150 o C) olefin products are observed. Given that mixtures of cis and
trans 2-butene are obtained, SO loss likely goes through radical pathway (Tdependent).
♦ EXO process-breaking bond positioned exocyclic to smallest formed ring.
ENDO process-breaking bond positioned endocyclic to smallest formed ring.
♦ The rationale lies in the stereochemical requirements of the transition state
(distances/ angles) and ability of the system to achieve the required trajectory.
Aziridine-N-oxides, J. Am. Chem. Soc. 1971 , 93, 4082-4084
a=180 o
H
OH
T<0 oC
N
N
O
Y
X
Y
X
X
a=109
N
TET
O
T<0
oC
N
TRIG
X
Y
Y Burgi-Dunitz
angle
(exclusively
trans)
O
Multisubstituted aziridine oxide gives rise to alternative products.
Concerted or radical?
o
X
a=120
o
DIG
Y
X
Y
3
Sir Jack Baldwin
Baran Lab
>>> Digonal Systems (DIG)
>>> Tetrahedral Systems (TET)
Y
X
X
X
X
Y
3-EXO-TET
allowed
X
4-EXO-TET
allowed
X
Y
3-ENDO-TET
???
Savvas N. Georgiades
Y
Y
5-EXO-TET
allowed
X
X
Y
X
4-ENDO-TET
???
X
6-EXO-TET
allowed
7-EXO-TET
allowed
X
Y
6-ENDO-TET
forbidden
3-EXO-DIG
forbidden
X
X
4-EXO-DIG
forbidden
X
Y
X
3-ENDO-DIG
forbidden
4-ENDO-DIG
forbidden
X
Y
Y
5-EXO-DIG
allowed
Y
Y
7-ENDO-TET
forbidden
X
Y
Y
Y
Y
5-ENDO-TET
forbidden
X
Y
6-EXO-DIG
allowed
7-EXO-DIG
allowed
Y
X
5-ENDO-DIG
allowed
Y
6-ENDO-DIG
allowed
X
Y
7-ENDO-DIG
allowed
>>> Trigonal Systems (TRIG)
>>> Example of favored vs. disfavored process
Y
X
X
X
Y
3-EXO-TRIG
allowed
4-EXO-TRIG
allowed
X
Y
5-EXO-TRIG
allowed
Y
MeO2C
Y
6-EXO-TRIG
allowed
7-EXO-TRIG
allowed
O
5-EXO-TRIG
O
X
MeO2 C
OMe
NH2
CO2 Me
X
5-ENDO-TRIG
MeO2C
X
Y
X
Y
X
Y
4-ENDO-TRIG
forbidden
5-ENDO-TRIG
forbidden
N
H
>>> Example of exception for second row element:
X
Y
X
Y
CO2Me
3-ENDO-TRIG
forbidden
N
H
6-ENDO-TRIG
allowed
7-ENDO-TRIG
allowed
SH
CO2Me
Base
5-ENDO-TRIG
S
4
Sir Jack Baldwin
Baran Lab
>>> Example of competing allowed processes
Savvas N. Georgiades
>>> Ring closures involving enolates
(predominantkinetically preferred)
6-EXO-TRIG
O
(ENOLENDO)-EXO-TET
Y
O
5-member or smaller disfavored (treat as ENDO-TRIG)
6-member or larger favored (treat as ENDO-TRIG)
Base
O
HO MeO
MO
X
CO2Me
(kinetically
disfavored)
6-ENDO-TRIG
O
Y
(ENOLEXO)-EXO-TET
All sizes favored (treat as EXO-TRIG)
♦ In cases where an EXO and an ENDO process compete, EXO appears to be
predominant for TRIG systems whereas ENDO is predominant for DIG systems.
♦ In many cases kinetics rather than thermodynamics dictate the outcome of the
cyclization reaction.
OM
5-(ENOLENDO)-EXO-TET
>>> Turning a forbidden into an allowed cyclization process
O
Br
Example:
X
O
MO
O
5-EXO-TET
5-ENDO-TRIG
X
OH
O
NaOMe/MeOH
Y
OH
H
O
OH
+
5-EXO-TRIG
(ENOLENDO)-EXO-TRIG
5-member or smaller disfavored (treat as ENDO-TRIG)
6-member or larger favored (treat as ENDO-TRIG)
MO
OH
OH
Y
(ENOLEXO)-EXO-TRIG
OH
All sizes favored (treat as EXO-TRIG)
OH
OM
OH
OH
5
Sir Jack Baldwin
Baran Lab
>>> Conversion of penicillin sulfoxides into 6,7-epi-1-oxocephams:
BETA-LACTAM TRANSFORMATIONS
T etr ahedron 1980, 36, 1628-1630
>>> Ring expansion of penicillins to cephalosporins
Chem. Commun. 1987, 2, 104-106
H
N
R
Br
S
O
Br
S
H
N
R
Ph 3SnH/AIBN/
benzene/reflux/2 h
N
H
N
R
R (40%)
S (35%)
N
CO2Me
Ph 3SnH/AIBN/
benzene/reflux/2 h
S
S
O
Br
N
O
H
N
R
H
N
R
R (49%)
S (39%)
N
O
CO2 Me
CO2 Me
O
O
27%
R
S
N
S
Cl2/93%
CO2Me
H
N
Cl
N
OH
O
CO 2Me
CO2Me
*
O
+
OH
N
O
O
30%
CO2Me
Trans:Cis=5:3
H
N
R
SnCl2
OH
O
OH
OsO4/85%
N
CO2Me
O
O
H
N
O
OH
O
O
CO2 Me
S
O
S
O
O
O
94%
CO2Me
N
H
N
O
O
CO2Me
H
N
R
S
N
N
O
R
H
N
R
Ph3 SnAllyl/AIBN/
benzene/reflux/3 h
Ac2 O/Me3 P=O/ R
toluene/reflux/
95%
O
Mechanism?
O
H
N
R
O
O
Savvas N. Georgiades
Cl
N
O
O
O
>>> Ring expansion of penicillins to 3-exomethylene cephalosporins
H
N
R
O
S
N
CO2Me
H
N
R
O
Vitamin B12
Co(I)
20-30 min/20 o C
S
N
H
N
R
O
S
30% conversion
(instability of SM)
>95:5 exo:endo
O
O
93% conversion
>98:2 exo:endo
SnCl2 or AgBF4
OH
H
N
R
O
OH
O
N
O
CO2Me
N
CO2Me
I
N
O
H
N
R
Cl
OH
O
I
O
H
N
R
T etrahed ron Lett. 1991, 32, 7093-7096
*
N
OH
CO2Me
O
OH
O
26%
CO2Me
CO2Me
6
Sir Jack Baldwin
Baran Lab
>>> Convertion of penam sulfoxides to stable azetidinone sulfenic acids
T etr ahedron Lett. 1998, 39, 6983-6986
Savvas N. Georgiades
>>> Conversion of n-membered lactams to (n+1)-membered oxonitrogen
heterocycles
Chem. Commun. 1993, 18, 1434-1435
Only this diastereomer gives
stable sulfenic acid!
Pht
O
O
N
S
S
O
O
N
O
N
N
O
1) Me 2SOCH2/DMSO/rt/97%
2) Rh 2(CF3CO2 )4/1,2-DCE/
reflux/77%
CO2Bn
O
BnO2 C
Pht
1) Me2 SOCH2/DMSO/rt
2) Rh2 (CF3 CO2)4/1,2-DCE/
reflux
Silica gel
56%
O
OH
N
S
O
N
O
CO2 CHPh2
S
N
O
N
CO 2CHPh 2
N
O
Boc
O
Boc
BnO2C
TEA (cat)/benzene
ambient T/50 min
70%
SYNTHETIC METHODOLOGY
MeO
Pht
1) LDA/THF/95 oC
2) CF3SO3Me/
-95 oC-rt/1 h/52%
S
N
>>> Synthesis of substituted pyrrolidines by SmI2-mediated ring closure
T etrahedr on 1994, 50, 9425-9438
T etrahedr on 1994, 50, 9411-9424
O
BnO2C
1) R
BnO2C
p-TSA (cat)/DMF/
100 o C/1 h/57%
N Boc
Mechanism?
Boc
CO2 Bn
Benzene/H2O/
heat/150 oC
~90%
CO2 Bn
Pht
S
Br
NH2
MeO2C
OTBDMS
N
CO2 Bn
O
Pht
S
N
O
CO2Me
DIBAL/toluene/
-78 oC
78%
R
2) PhOCOCl/NaHCO3/
H2 O/EtOAc
O
Methyl propiolate/
benzene/50 oC/
30 min/72%
N
Et3N/toluene
N
R
OHC
CO2Ph
MeO2 C
SmI 2/t BuOH/
HMPA/THF/0 oC R
OTBDMS
70-80%
CO2Ph
OTBDMS
N CO2Ph
HO
OTBDMS
(R=H, alkyl, TMS)
BnO 2C
7
Sir Jack Baldwin
Baran Lab
>>> Carbocyclic ring expansions via free radical pathways
>>> Free radical macrocyclization via propiolate esters
Tetrahedr on 1992, 48, 3413-3428
Chem. Commun. 1988 , 21, 1404-1406
T etr ahedron 1989 , 45, 909-922
T etr ahedron 1991 , 47, 6795-6812
T etr ahedron 1992 , 48, 3385-3412
O
OLi
X
O
I
LiSnBu 3
Propiolic acid/
DCC/DMAP/
OH
EtOAc
55-70%
n
HMPA
SnBu3
Br
Bu 3SnH/AIBN/
benzene/reflux
O
n
40-60%
O
O
O
NaI/acetone/rt
90-100%
n=9-11: 14-16 membered trans a,b-unsaturated lactones
n<9: Reduction at radical center prevents cyclization
75%
O
X
Ph3 SnH/AIBN/
benzene/reflux
X=SePh
X=Br
X=I
Br
SnBu3
Savv as N. Georgiades
Me
>>> C-C Coupling of terminal alkenes via sulfonylation-alkylationdesulfinylation sequence
78%
Mechanism?
Chem. Commun. 1988, 11, 702-704
1) n-BuLi/THF/0-20 oC
2) Prenyl bromide/THF/
-78-20 oC
3) AcOH quench
Further refinement to macrocyclic lactones
O
O
Me
H2/Pd-C
EtOAc
O
Me
1) MeSO2I
2) Base
O
mCPBA/DCM
Me
65-70%
85%
(R)-(+)-Limonene
52%
H SO Me
2
SO2Me
92%
(±)-Dihydrorecifeiolide
1) n-BuLi/THF/-78 oC
2) EtOAc/THF/-78-20 oC
3) AcOH quench
Another synthetically useful variant
O
I
SnBu3
Bu 3SnH (cat)/AIBN (cat)/
benzene/reflux/81%
Mechanism?
O
Al/Hg/THF/
H2O/20 oC
80%
H
Mechanism?
O S
bisabolenes
71%
O
O
8
Sir Jack Baldwin
Baran Lab
>>> Synthesis of trisubstituted allenes
>>> Thermal ene reaction of aldehydes and t butyl- or phenylhydrazones
T etr ahedron Lett. 1995, 36, 7925-7928
80%
R1
R1
1) BuLi/-78 oC
2) EtOAc
R2
R3
R1
3) Al/Hg/THF/H2 O
(75-95%)
R1
C
56%
OH
N
Li
R3
E+
N
R1
Li
N
R2
R1
N
R3
N
H
X
N
N
55-60%
X
R1
Cl
O
X
R1
50-90%
1) Ph 3PBr2/DMF/0 o C
2) Ph 3P/62%
H
N
Cl
Zn/HOAc/60
Br
PPh 3 Cl
Not methyl acrylate or
acrylonitrile
R2
R2
Toluene/reflux/
24 h/argon
H
E
E+ =alkyl halides, aldehydes,
ketones, crotonates
N
1) TFA/20 o C/1-4 h/argon
2) (CO2 H)2 /H2O/Et2O/
20 oC/5-16h/argon
Chem. Commun. 1984, 3, 152-153
CuCl2/HCl (2M)
N
R2=Ph, t Bu
X=CO2Me, CN
>>> Preparation of chloro-3-cumulenes
Cl
R3
R2
R1
H
R3
R2
R2
(R1, R2 , R3=alkyl, alkenyl, benzyl, etc)
OH
N
R2
R1
SO2 Me
(80-92%)
SO2 Me
(75-85%)
R1
1) BuLi/-78 o C
2) R3 X
Chem. Commun. 1984, 16, 1095-1096
Tetr ahedr on 1986, 42, 4247-4252
o
SO2Me 1) BuLi/-78 C
2) R2X
OTs 1) NaSMe
2) Oxone
Savvas N. Georgiades
oC/1.5
h
Ph
45-52%
2)
C
O
Mechanism?
C
N
R1
H
1) LiHMDS
O
O
Cl
o
Pd/C/H2/50 C/12-24 h/50%
45-51%
88%
HN
R1
1) PtO2/H2 /20 oC/24 h
2) MeOH/HCl
NH3+ Cl R1
X
9
Sir Jack Baldwin
Baran Lab
>>> Functionalization of unactivated methyl groups through organopalladation
Chem. Commun. 1985, 3, 126-127
T etrahed ron 1985, 41, 699-711
HO
HO
N
NaPdCl4/
NaOAc
>>> Formation of 1H-pyrazolo[4,3-c]pyridines from bis-acetylenic-N-benzoylhydrazones
Tetr ahedr on 2004, 60, 933-938
R
N NH
O
Cl
1) Pyridine
HO
N
2) Pb(OAc)4 (1 eq)
2 3) NaBH4
Pd
N
Savvas N. Georgiades
85%
OCOMe
MeCOCl/AlCl 3/
CH2Cl2/0 oC/100%
TMS
NH2NHR/MeOH
(50-90%)
96%
TMS
TMS
+ (E)
R
>>> Formation of 1,2,4-triazepines and oxatriazaindenones from bisacetylenic ketones
N N
PhCOCl/AlCl 3/
CH2Cl2/reflux
O
J. Org. Chem. 2005 , 70, 3307-3308
Ph
33% aq. NH3/EtOH/85 oC
(35-70%)
Mechanism?
OH
Various solvents
R1
CO2Et
Boc
N
H
H
N
NH
Ph
F3COC N
N
H
Ph
F3 COC
N
N
N
N
N
One-pot procedures!
Org. Lett. 2005, 7, 3705-3707
Ph
CO2 Et
O
MeO
N
CO2Et
O
O
OH
MeO
OR
O2 /CDCl3/
5-35 days
Ph
MeO
O
1) TFAA/CH2 Cl 2
2) NaOH
O
1) NaH/THF/DMF
2) R-X
N
N
H
O
1) LDA/THF/0 oC
2) CO2
OH
N
O
N
Ph
R=Ph, p-NO2C6H4, m-NO2C6H4
>>> Oxidative Rearrangement of 6-Methoxypyran-2-ones
R2
THF or CH2 Cl 2/
TBAF/reflux/2 h/
87% (R1=R2 =Ph)
O
Ph
TMS
CO2Et
CH2 Cl 2/TFAA/reflux/
3 h/82% (R1 =R2=Ph)
Mechanism?
CO2Et
Ph
Boc
R2
(R1, R2=Ph or alkyl)
N
Various
temperatures
R
N
(50-75%)
O
R1
N
TMS
O
MeO
O
O
Mechanism?
RO
O
MeO
O
O
40-80%
Baldwin invokes a second molecule to explain product formation!
10
Sir Jack Baldwin
Baran Lab
>>> Dimerization of butenolides
O
O
Org. Lett. 2003, 5, 3049-3052
J. Or g. Chem. 2004, 69, 9100-9108
T etrahedr on Lett. 2005 , 46, 4633-4637
Et3N/TBDMSOTf/
CH2Cl2 /30 oC/18 h
OTBDMS
R
R
Tetrahedr on Lett. 2006 , 47, 39-41
O
45-55%
60-85%
>>> Formation of substituted pyrano[3,2-c]pyridines via Diels-Alder rxn of
3-methylenepyridin-4-ones:
OH
O
mCPBA/CH2 Cl 2/
rt/30 min
O
Cl
R
N
R=H:
N
OBoc
2) Boc 2O/Et3N
45% (2 steps)
O
O
O
O
O
N
R
O
O
O
n=1-2
O
O
O
O
O
O
O
O
O
n=1-2
O
H
(51%)
N
N
O
O
OMe
O
(50-55%)
O
O
O
O
(R=alkyl)
O
O
N
Boc
O
O
130 oC
R
O
O
O
N
R
O
O
N
O
O
Examples:
OMe OH
BH3.DMS
O 52% (2 steps)
1) (TMS)2S/NaOMe/
O
O
25-80%
Diastereomeric
mixtures
OMe
2) DMF
N
O
SOCl2/pyridine/
THF/-78 oC/30 min
35-70%
/ t BuLi
O
CoCl(Ph3P)3 /
benzene/rt/2 h
O
1)
Br
O
SOCl2 /CH2Cl2 /
rt/18 h or
OMe
R
R
R=Alkyl:
Savvas N. Georgiades
O
O
OMe
R1
MeO
O
(R1,R2=alkyl)
O
O
OMe
R2
n=1-2
O
O
R1
R
R2
N
R
OH
n=1-2
(50-70%)
O
O
(75-80%)
(R=alkyl, alkenyl, Ph)
N
No rxn with simple alkenes
11
Sir Jack Baldwin
Baran Lab
>>> Synthesis of oxa-tricyclo[5.3.1.01,5]undecanones
>>> Preparation of epoxyisonitriles from thiooximes
T etr ahedron 2005 , 61 , 3025-3032
T etr ahedron Lett. 1990, 31, 2051-2054
T etr ahedron Lett. 1990, 31, 2047-2050
Propargyl bromide/
Bu4NHSO 4 (cat)/
NaOH (15M)/
toluene/0 oC-rt/99%
1) TBDMSCl/imidazole/DMF/rt/91%
2) n-BuLi/DMF/THF/-78 oC-rt/98%
3) NaBH4/MeOH/0 o C-rt/98%
HO
O
TolS
O O
N
HO
or p-TSA/H2O/MeOH/0 oC/
10 min/93% (R=TMS)
R
R=H
R=TMS
(CF3SO2)2O
O
OH
R
O
DCM/0 oC-rt/
Mechanism?
O
Various ring sizes, substituents on ring
Aromatic exo-epoxide variant
TolS
O
2/
CN
DIPEA/-78 o C
n-BuLi/TMSCl/THF/
-78 oC-rt/90%
tBuOOH/VO(acac)
O
H
OAc
Mechanism?
TBAF/THF/0 oC-rt/91% (R=H)
OTBDMS
OHCHN
DCM/-40 oC
O
TBDMSO
O
NHCHO
PPh3/
propylene oxide
O
O
Savvas N. Georgiades
HO
Ac2O/DMAP/TEA/0 oC-rt AcO
O
R
O
N
NC
O
O
O
O
X
Various substituents (X),
fused aromatics
X
R
Application in the total synthesis of trichoviridin
83% (R=H)
78% (R=TMS)
86% (R=H)
68% (R=TMS)
Chem. Commun. 1996, 1, 41-42
O
OTBDMS
TEA/toluene/reflux
OTMS
O
Mechanism?
O
Precursor to tropolone
natural products
R
86% (R=H)
74% (R=TMS)
OH
OH
O
OH
O
7 steps
N STol
O
NC
(trichoviridin)
12
Sir Jack Baldwin
Baran Lab
TOTAL SYNTHESES
>>> Synthesis of tabtoxinine beta-lactam
(naturally occuring inhibitor of glutamine synthase)
Sealed tube/
90-100 oC/
24 h/85%
Cl
Cl
N
CN
Pyridine/
CN reflux/72%
Chem. Commun. 1985 , 22, 1549-1550
Et4NIO4/
DCM
O
Ph
Ph
O
O
(1.5 equiv)
N
O
Ph pyridine/DCM/25 C/57%
O
N
O
O
Ph
>>> Biomimetic synthesis of acromelic acid A
(neuroexcitatory activity)
1) BnBr/K 2CO3/DMF/91%
Br
OH 2) NBS/CCl /rt/49%
4
OBn
O
O
O
Ph
NH2
HO
CO2t Bu
MeO
BnO
CO2Me
OBn
N
OBn
OMe
OH
O
TfO
OMe
OMe
O
O
T etrahedr on 1998, 54, 7465-7484
1) n-BuLi/THF/-78
(HO)2B
2) B(OMe)3
OBn 3) NH4Cl/H2O
H
N
O
Ph
oC
Ph
10% Pd-C/EtOH/
H2/100%
O
O
(+5% diester)
O
O
N
O
O
N
H
N
Ph
KMnO4/Bu4 NHSO4/
benzene/H2 O/rt/98%
O
Ph 2) Boc-ON/DCM/83%
O
1) 98% Formic acid/99%
2) PPh3/di-2-pyridyl disulfide/ O
MeCN/80 oC/2 h/63%
HO2C
o
1) NaBH3 (OCOCF3 )/58%
O
NHBoc
Cl
NHBoc
CN
O
O
HO2C
OH
Ph
73% (single
regioisomer)
NHBoc
HO2C
O
O O
CN
N
H
N
HO
Savvas N. Georgiad es
BnO
COPh
CO2t Bu
Pd(Ph3P)4 /DME/NaCO 3 (aq)/
LiCl/heat/67%
N
PhOC
CO2 Me
MeO
HO2C
MeO
HO
CO2Me
Conc. HCl/
100 oC/100%
1) Ag 2CO3 on celite/DCM/rt
MeO2 C
2) Pb(OAc)4/MeOH/DCM/0 oC/81%
H2/Pd black/
EtOAc/rt/100% HO
Mechanism?
R/S=15:1
PhOC
CO2 tBu
N
CO2Me
N
PhOC
O
NH
NH3/rt/100%
O
CO2t Bu
CO2Me
HO2 C
O
CO2H
HN
HCl
CO2H
HN
CO2 H
CO2H
13
Sir Jack Baldwin
Baran Lab
Savvas N. Georgiades
Tetrahedr on 2004, 60, 3695-3712
>>> Synthesis of 5,5',6,6'-tetrahydroxy-3,3'-biindolyl
(antioxidant from beetroot)
Bu3Sn
"Dead-end" route
BnCl/K2CO3/acetone/
65 oC/4 days/87%
HO
HO
Reduction
(various conditions)
BnO
OBn
BnO
BnO
1) I2/HgO/CH2Cl2 /
rt/15 h/78%
BnO
I
BnO
2) HNO3 (aq.)/
AcOH/rt/2 h/94%
BnO
NO2
OBn
Pd(Ph3P)4 /CuI/CsF/
DMF/40 oC/2 h/92%
p-TSA/benzene/mol. BnO
sieves/85 oC/2 days/25%
OBn
O2N
NO2
BnO
OH
N
O2 /3 months
OBn
Mechanism?
NH2
NH2
BnO
O
Mechanism?
NO CYCLIZATION!
OBn
O
OBn
BnO
H2N
SnBu3
O
N
OBn
BnO
N
OBn
OBn
Productive route
O
HO
1) BnCl/K2 CO3/DMF/
o
H 120 C/15 h/99%
HO
2) MeNO2/NH4 OAc/
BnO
AcOH/120 oC/40 min/98%
BnO
NO2
1) Iron powder/AcOH/benzene/
cyclohexane/SiO2/120 oC/30 min/61%
BnO
NO2
Mechanism?
BnO
70% HNO3/AcOH/
rt/2 h/97%
BnO
NO2
2) nBuLi/THF/-78 oC/15 min
3) TIPSCl/-78 o C/2 h
95% (2 steps)
TIPS
TIPS
I2/Hg(OAc)2/CH2Cl2 /
0 oC/2 h/100%
I
BnO
Pd(PhCN)2Cl2/TDAE/
DMF/50 oC/1.5 h/68%
N
H
N
OBn
1) TBAF/THF/
rt/10 min/82%
OBn
or NIS/THF/rt/
20 min/83%
BnO
N
BnO
2) H2/Pd black/
THF/18 h/94%
TIPS
BnO
N
N
BnO
OH
OH
HO
HO
N
H
TIPS
14
Sir Jack Baldwin
Baran Lab
Savvas N. Georgi ades
Org. Lett. 2003, 5, 2351-2354
Tetrahedron 2006, 62, 4603-4614
>>> Studies towards a biomimetic synthesis of pyridomacrolidin (protein tyrosine kinase inhibitor)
1) H 2NOBn/xylene/
CSA (cat.)/reflux/
CO 2Me
24 h/93%
Me2NH/Et2O/
CO2Me
rt/1 h/100%
2) NaCNBH3/EtOH/
HCl/rt/12 h/79%
N
OH
O
O
CO 2Me
NH
OBn
OH
Br2/CH2Cl 2/
reflux/12 h/72% Br
CO 2Me
N
O
B
OBn
O
OH
O
N
O
Pd(Ph3P)4/Na2CO3/
THF/reflux/12 h/71%
2) 10% Pd-C/dioxane/
H 2/rt/2 h/90%
O
PhI(OAc)2/CH 2Cl2/
reflux/24 h/60%
O
HO
HO
O
Pb(OAc)4/benzene/
70 oC/20 h/25%
O
H
OH
O
N
O
OH
O
N
O
O
H
B
OH
A
H
OH
O
N
O
O
C
O
O H
O
H
N
O
B
OH
O
N
O
OH
O
+
N
O
O H
O
H
OH
O
H
HO
HO
O
O
+
H
OH
N
O H
O
HO
O
HO
H
Applicable to various
unfunctionalized cyclic
enones
T etrahed ron 2005,
61, 1773-1784
O
H
(B/C/D=1:2:5)
A
OH
OBn
OBn
(A/B=1.4:1)
N
O
H
N
O
AlCl3/toluene/
95 oC/2 days/40%
H
O
OH
O
H
OH
O
HO
OH
O
2) CDI/THF/12 h
3) NaH/rt/5 h
86% (2 steps)
DMAP (cat.)/Et3N/
O
THF/0 oC/30 min/84%
O
1)
HO
N
1) LiOH/THF/H 2O/
OBn
rt/2 h/100%
H
O
Pyridomacrolidin
O
D
15
Sir Jack Baldwin
Baran Lab
Savvas N. Georgi ades
Org. Lett. 2003, 5, 2987-2988
Tetrahedron 2006, 62, 9892-9901
>>> Biomimetic synthesis of (+)-Panepophenanthrin (novel inhibitor of the ubiquitin-activating enzyme)
O
O
Br2/CHCl3/
0 oC/98%
Br
1) NaBH4 (aq.)/
Et2O/0 oC/85%
Br
2) Acetylation
O
+ent
O
Br
Pig pancreas
lipase/pH=7/
rt/3 days
Br
Kinetic
resolution
OAc
+ent
OH
m-CPBA/CH2Cl2/
0 oC/85%
OAc
Br
Br
35%, >99% ee
Br
+deacylated ent
39%, >99% ee
OH
O
Br
O
O
O
OTES
Pd2dba3/Ph3As/
toluene/110 oC/92%
OH
Br
O
OH
1) Neat/rt/overnight/>99%
2) NH 4F/MeOH/rt/89%
Bu3Sn
O
3) TESCl/2,6-lutidine/
CH2Cl2/0 oC/90%
LiOH/Et 2O/MeOH/
0 oC-rt/72%
OAc
1) DMP/CH2Cl2/0 oC
2) NaHCO3/Na2S2O3
55% (2 steps)
O
OAc
OTES
OH
O
O
O
HO
H
HO
OH
H
O
16