Transcript [2+2] Photocycloaddition/ Fragmentation in the Synthesis

[2+2] Photocycloaddition/
Fragmentation in the
Synthesis of
Guanacastepenes A and E
Jennifer Chaytor
November 2, 2006
University of Ottawa
Guanacastepene A
 Isolated in 2000
 Produced by the endophytic
fungus CR115
 Fungus isolated from the branch
of a Daphnopsis americana tree
from the Guanacaste
Conservation Area in Costa Rica
 Structure determined by NMR
and X-ray crystallography
O
AcO
H
O
OH
Guanacastepene A
 Mixture of two slowly
interconverting conformers
Clardy, J.; Brady, S.F.; Singh, M.P.; Janso, J.E. J. Am. Chem. Soc. 2000, 122, 2116
Clardy, J.; Brady, S.F.; Bondi, S.M. J. Am. Chem. Soc. 2001, 123, 9900
2
Five Guanacastepene Ring
Systems
 CR115 produces a family of
related but structurally diverse
metabolites
A, B, C
O
O
15 different guanacastepenes
comprise five ring systems
 All contain the 5-7-6 tricyclic
guanacastepene skeleton
O
E, F, G, I, J, N, O
O
K
D, H
O
N
L, M
Clardy, J.; Brady, S.F.; Singh, M.P.; Janso, J.E. J. Am. Chem. Soc. 2000, 122, 2116
Clardy, J.; Brady, S.F.; Bondi, S.M. J. Am. Chem. Soc. 2001, 123, 9900
3
Potential New Antibiotics?
 Guanacastepene A showed antibiotic
activity against drug-resistant strains
of Staphylococcus aureus and
Enterococcus faecalis
 Guanacastepene I showed
antibacterial activity towards S. aureus
 C-15 aldehyde or masked aldehyde
appears to be necessary for activity
 Guanacastepene A also displays
nonselective hemolytic activity against
human blood cells
 Suggests nonspecific membrane
lysis is the mode of action
H 15
O
AcO
1
11
O
OH
3
8
18
16
Guanacastepene A
OH
O
O
OH
H3CO
Guanacastepene I
Clardy, J.; Brady, S.F.; Singh, M.P.; Janso, J.E. J. Am. Chem. Soc. 2000, 122, 2116
Clardy, J.; Brady, S.F.; Bondi, S.M. J. Am. Chem. Soc. 2001, 123, 9900
4
Clardy, J.; Singh, M.P.; Janso, J.E.; Luckman, S.W.; Brady, S.F.; Greenstein, M.; Maiese, W.M. J. Antibiot. 2002, 53, 256
Total and Formal Syntheses
H
O
O
O
OH
AcO
O
Guanacastepene A
Danishefsky 2002
O
HO
OH
Snider 2002, Hanna 2005,
Sorenson 2006
O
OH
Guanacastepene C
Mehta 2005
AcO
O
H O
OH
H3CO
Guanacastepene E
Sorenson 2006
Danishefsky et. al, Angew. Chem. Int. Ed. 2002, 41, 2185
Danishefsky et al., Angew. Chem. Int. Ed. 2002, 41, 2188
Danishefksy et al., J. Org. Chem. 2005, 70, 10619
Snider et al., J. Org. Chem. 2003, 68, 1030
O
O
O
OH
Guanacastepene N
Overman 2006
Hanna et al., Org. Lett. 2004, 6, 1817
Mehta et al., Chem. Comm. 2005, 4456
Sorenson et al., J. Am. Chem. Soc. 2006, 128, 7025
Overman et al., J. Am. Chem. Soc. 2006, ASAP 5
Total and Formal Syntheses
H
O
O
O
OH
AcO
O
Guanacastepene A
Danishefsky 2002
O
HO
OH
Snider 2002, Hanna 2005,
Sorenson 2006
O
OH
Guanacastepene C
Mehta 2005
AcO
O
H O
OH
H3CO
Guanacastepene E
Sorenson 2006
Danishefsky et. al, Angew. Chem. Int. Ed. 2002, 41, 2185
Danishefsky et al., Angew. Chem. Int. Ed. 2002, 41, 2188
Danishefksy et al., J. Org. Chem. 2005, 70, 10619
Snider et al., J. Org. Chem. 2003, 68, 1030
O
O
O
OH
Guanacastepene N
Overman 2006
Hanna et al., Org. Lett. 2004, 6, 1817
Mehta et al., Chem. Comm. 2005, 4456
Sorenson et al., J. Am. Chem. Soc. 2006, 128, 7025
Overman et al., J. Am. Chem. Soc. 2006, ASAP 6
Snider Retrosynthesis
H
O
AcO
O
C
A
A
B
A
A
O
C
B
X = aldehyde
precursor
Methylation
and modified
Robinson annulation
OR
Ring closing
metathesis
O
X
OH
OH
O
B
A  AB  ABC approach
O
AlCl4
O
AlEt2
17 linear steps
2.6% overall yield
H
Snider, B.B.; Hawryluk, N.A. Org. Lett. 2001, 3, 569
Snider, B.B.; Shi, B. Tet. Lett. 2001, 42, 9123
Snider, B.B.; Hawryluk, N.A.; Shi, B. J. Org. Chem. 2003, 68, 1030
7
Hanna Retrosynthesis
O
AcO
A
H
B
O
O
OH
O
C
A
A  ABC approach
O
C
B
Danishefsky intermediate
17 linear steps
<1.8% overall yield
CO2Me
Tandem ring-closing
metathesis
A
MeO2C
A
B
C
8
Hanna, I.; Boyer, F-D.; Ricard, L. Org. Lett. 2004, 6, 1817
Danishefsky’s Approach
O
AcO
OHC
A
OH
OH EtO2C
AcO
C
B
A
O
C
B
Knoevenagel
cyclization
R
OH
O
A
B
EtO
AcO
O
A
O
O
B
Alkylations;
Reductive
cyclization
A  AB  ABC approach
O
A
Danishefsky, S.J.; Dudley, G.B. Org. Lett. 2001, 3, 2399
Danishefsky, S.J.; Tan, D.S.; Dudley, G.B. Angew. Chem. Int. Ed. 2002, 41, 2185
Danishefsky, S.J.; Lin, S.; Dudley, G.B.; Tan, D.S. Angew. Chem. Int. Ed. 2002, 41, 2188
9
Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619
Synthesis of Hydroazulene Core
OH
I
Ph3P, imid., I2
CH2Cl2
1) i-PrMgBr, CuBr·Me2S
Me3SiCl, THF, HMPA
2) Et3N, pentane, H2O
(94%)
O
(92%)
+
I
I
A
Me3SiO
MeLi, THF, 0 °C, 1 hr;
2.5 eq. A, HMPA
-78 °C to rt
(74-76%)
O
PCC
5.0 eq. n-BuLi
THF, 0 °C
(inverse addition)
(71-92%)
(62-65%)
OH
(plus 16-18% of
uncyclized olefin)
O
I
Danishefsky, S.J.; Dudley, G.B. Org. Lett. 2001, 3, 2399
Danishefsky, S.J.; Tan, D.S.; Dudley, G.B. Angew. Chem. Int. Ed. 2002, 41, 2185
Danishefsky, S.J.; Lin, S.; Dudley, G.B.; Tan, D.S. Angew. Chem. Int. Ed. 2002, 41, 2188
10
Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619
Successive Dialkylation Strategy
O
1) LiHMDS, THF, -78 °C
2) 3.0 eq. Me2NCH2I, THF, -78 °C  rt
3) m-CPBA, CH2Cl2/aq. NaHCO3
O
(86% overall)
MgBr
CuI, HMPA, TMSCl,
THF, -78 °C
O
11
8
1) MeLi, THF, 0 °C
2) MeI, HMPA, -78 °C  rt
OSiMe3
(77% over 3 steps)
Danishefsky, S.J.; Tan, D.S.; Dudley, G.B. Angew. Chem. Int. Ed. 2002, 41, 2185
Danishefsky, S.J.; Lin, S.; Dudley, G.B.; Tan, D.S. Angew. Chem. Int. Ed. 2002, 41, 2188
11
Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619
Hydroboration and Oxidations
O
ethylene glycol
TsOH, PhH, reflux
O
O
(89%)
1) 9-BBN, THF, 0 °C rt
2) 3N NaOH, 30% H2O2, rt
(98%)
O
O
O
O
H
Dess-Martin periodinane
CH2Cl2, rt
(83%)
O
OH
Danishefsky, S.J.; Tan, D.S.; Dudley, G.B. Angew. Chem. Int. Ed. 2002, 41, 2185
Danishefsky, S.J.; Lin, S.; Dudley, G.B.; Tan, D.S. Angew. Chem. Int. Ed. 2002, 41, 2188
12
Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619
Epoxide-Opening βElimination/Knoevenagel Cyclization
O
EtO
O
O
O
O
X
N2CHCO2Et
SnCl2, CH2Cl2, rt
H
TsOH
H2O in acetone (5%)
70 °C
(80% over two steps)
X = -OCH2CH2OX=O
m-CPBA
CH2Cl2, 0 °C
(89%)
EtO
OH
O
EtO
O
NaOEt
EtOH, 50 °C
O
O
O
O
(80%)
Danishefsky, S.J.; Tan, D.S.; Dudley, G.B. Angew. Chem. Int. Ed. 2002, 41, 2185
Danishefsky, S.J.; Lin, S.; Dudley, G.B.; Tan, D.S. Angew. Chem. Int. Ed. 2002, 41, 2188
13
Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619
Final Steps to Guanacastepene A
EtO
O
OR
O
DIBAL-H, CH2Cl2
-78 °C  0 °C
OSiEt3
OH
OH
5
(:80:20)
Et3SiOTf
pyridine
CH2Cl2, 0 °C
R=H
R = SiEt3
(80-85%)
1)
H3CO
2) DIBAL-H, CH2Cl2
-78 °C  0 °C
OCH3
PPTS, CH2Cl2, 0 °C
(67% over 4 steps)
O
O
1) Ph3P, benzoic acid
DIAD, THF, -78 C rt
O
2) TBAF, THF, 0 °C
OSiEt3
OH
OH
(91-98%)
3) Dess-Martin periodinane
pyridine, CH2Cl2
(90%)
Danishefsky, S.J.; Tan, D.S.; Dudley, G.B. Angew. Chem. Int. Ed. 2002, 41, 2185
Danishefsky, S.J.; Lin, S.; Dudley, G.B.; Tan, D.S. Angew. Chem. Int. Ed. 2002, 41, 2188
14
Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619
Final Steps to Guanacastepene A
O
O
O
13
1) Et3SiOTf
Et3N, CH2Cl2
2) DMDO/acetone
CH2Cl2, -78 °C
3) Me2S
O
O
O
HO
(82-90% overall)
Ac2O, pyridine
DMAP, CH2Cl2
(96%)
O
AcO
H
O
O
OH
O
1) PPTS, MeOH, 70 °C
13
O
AcO
2) PhI(OAc)2, TEMPO
CH2Cl2
Guanacastepene A
(59-65% overall)
Danishefsky, S.J.; Tan, D.S.; Dudley, G.B. Angew. Chem. Int. Ed. 2002, 41, 2185
Danishefsky, S.J.; Lin, S.; Dudley, G.B.; Tan, D.S. Angew. Chem. Int. Ed. 2002, 41, 2188
15
Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619
Danishefsky’s Total Synthesis:
Summary



17 steps to key intermediate (5.3% overall yield)
20 steps to Guanacastepene A (3.0% overall yield)
Key step: tandem epoxide-opening βelimination/Knoevenagel cyclization
O
O
O
O
H
O
OH
AcO
Key intermediate
Guanacastepene A
16
Sorenson’s Approach
O
O
Elimination;
PG Manipulation
O
A
A
C
B
O
O
PMP
O
A
SePh
PMP
O
C
B
Fragmentation/
enolate trapping
Danishefsky
intermediate
O
O
O
Intramolecular [2+2]
photocycloaddition
O
PMP
O
C
Allyl Stille
cross-coupling
O
O
A
SnMe3
+
AcO
PMP
O
A + C  AC  ABC approach
C
Sorenson, E.J.; Shipe, W.D. Org. Lett. 2002, 4, 2063
Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025
17
Reductive Opening of Cyclopropyl
Ketones
O
1
10
HCl
HOAc
O
5
Cl
Shoulders, B.A.; Kwie, W.W.; Klyne, W.; Gardner, P.D. Tetrahedron, 1965, 21, 2973
O
1
10
Li
NH3
O
5
Dauben, W.G.; Deviny, E.J. J. Am. Chem. Soc. 1966, 31, 3794
18
Reductive Opening of Cyclopropyl
Ketones
O
R
2 e-
R'
R'
O
1
O
R
7
O
Li
NH3
6
(+)-carone
Breakage of 1,6 bond:
-more stable 2º carbanion
O
7
6
Breakage of 1,7 bond:
-Less stable 3º carbanion
-Overlap with π system
1
Dauben, W.G.; Deviny, E.J. J. Am. Chem. Soc. 1966, 31, 3794
19
Favouring Cyclobutane Cleavage
OH
Bu3SnH, C6H6
TMSCl, NaI
CH3CH, 80 °C
I
80 °C
1
(±)-silphinene
Conditions
Ratio of 1:2
1.0 eq. Bu3SnH, C6H6, 80 °C, 0.01M AIBN
1:1
0.1 eq. Bu3SnCl, 1.0 eq. NaBH4, EtOH, 150 °C
>20:1
1.0 eq. Bu3SnH, AIBN (cat.), C6H6, 80 °C (syringe pump addition) 100:0
2
20
Crimmins, M.T.; Mascarella, S.W. Tet. Lett. 1987, 28, 5063
SmI2-Promoted Radical Ring
Opening
O
3
R1(H)
O
-
M (+ e )
M
R1
O
ring
opening
R2
R2(H)
SmI2
THF
DMPU
O
4
M
R2
O
39%
SmI2
THF
DMPU
O
TMS
O
79%
(mixture of geometric
isomers)
TMS
21
Motherwell, W.B.; Batey, R.A. Tetrahedron Letters, 1991, 32, 6649
Trapping of Samarium Enolates
with Electrophiles
O
1) SmI2
THF
DMPU
O
2) Br
-78° C
37%
O
1) SmI2
THF
DMPU
OTMS
2) TMSCl
-78° C
34%
O
1) SmI2
THF
DMPU
OAc
2) AcCl
-78° C
57%
22
Motherwell, W.B.; Batey, R.A. Tetrahedron Letters, 1991, 32, 6649
Synthesis of Ring A
O
1) 0.2 mol % PtO2, H2,rt
2) LDA, THF, -78 °C  rt
3) MeI, 0 °C  rt
(96%, 3 steps)
1) O3, EtOAc, -78 °C
2) H2, Pd/C, rt
H
O
O
O
(48-54%)
OH
(S)-(+)-Carvone
NaCN, p-TsOH,
THF·H2O, rt
(99%)
O
CN
OH 1) 3.0 eq. LiHMDS, THF, rt
2) 1 N aq. HCl
(50-58%)
OH
O
O
EDCI, 0 °C  rt
CH2Cl2
(79%)
Sorenson, E.J.; Shipe, W.D. Org. Lett. 2002, 4, 2063
Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025
NC
O
OH
23
Synthesis of Stille Coupling Partner
(Ring A)
O
O
OH
Et3N, NfF
CH2Cl2, rt
O
ONf Pd(dppf)Cl2, Me3SnSnMe3
(94%)
SnMe3
NMP, 60 °C
(63%)
O OF FF F
S
Nf =
F
F FF F
Sorenson, E.J.; Shipe, W.D. Org. Lett. 2002, 4, 2063
Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025
24
Synthesis of Ring C
O
O
OTMS
O
O
1)
O
O
LDA, TMSCl
THF, -15 °C rt
THF, 0 °C  rt
(98%)
2) 1 N HCl, 0 °C  rt
O
MeO
MeO
O
(99%)
mCPBA, NaHCO3
CH2Cl2, rt
(96%)
O
O
OMe
OPMB
MeO
1) 0.07 eq. CSA
MeOH, reflux
100%
2)
O
OMe
HN
Cl3C
MeO
O
O O
MeO
O
O
O
0.1 eq. CSA, CH2Cl2, rt
Sorenson, E.J.; Shipe, W.D. Org. Lett. 2002, 4, 2063
Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025
25
Synthesis of Ring C
O
O
OMe
OPMB
MeO
1) LiAlH4
Et2O
0 °C  rt
(87%) (two steps)
O
O
OPMB
OMe
2)
O
PMP
OMe
OMe
MeO
1)
HO
PPTS
CH2Cl2, rt
NO2
n-Bu3P
THF
0 °C  rt
(80%)
O
AcO
PMP
O
O
Ac2O
DMAP
pyridine, rt
HO
PMP
O
(100%)
racemate
NC
Se
PMP
1) 0.25 eq. PPTS
MeOH, rt
(85%)
O
2) 30% aq H2O2
i-Pr2EtN
0 °C  45 °C
(71%)
O
OPMB
2) DDQ
CH2Cl2, rt
(69%)
Sorenson, E.J.; Shipe, W.D. Org. Lett. 2002, 4, 2063
Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025
26
Resolution of C-Ring Fragment
O
O
O
AcO
PMP
O
O
O
O
PMP
OAc
OH
OAc
DMAP, DCC
CH2Cl2, 0 °C  rt
+
O
O
(98%)
O
O
O
OAc
1:1
racemate
separable by column chromatography
Sorenson, E.J.; Shipe, W.D. Org. Lett. 2002, 4, 2063
Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025
27
Stille Cross-Coupling
O
O
O
SnMe3
+
O
OAc
PMP
O
O
LiCl, CuCl,
Pd(PPh3)4,
DMSO,
rt  60 °C
(78%)
Sorenson, E.J.; Shipe, W.D. Org. Lett. 2002, 4, 2063
Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025
Corey, E.J.; Han, X.; Stoltz, B.M. J. Am. Chem. Soc. 1991, 121, 7600
O
PMP
O
28
Proposed Catalytic Cycle for CuClAccelerated Stille Coupling
L4Pd + LiCl
2L + Li+ L2PdClA
LiCl + L2Pd
Ar R
F
B
ArX
X
R
L2Pd
L2Pd
Ar
E
+ CuX
+ LiCl
C
RCuLiCl
D
Ar
Bu3SnCl
RSnBu3 + CuCl + LiCl
Corey, E.J.; Han, X.; Stoltz, B.M. J. Am. Chem. Soc. 1991, 121, 7600
29
Formation of Ring B
O
O
PMP
O
O
hv
0.5 eq. i-Pr2NEt
Et2O
O
PMP
O
(82%)
1) 2.5 eq. SmI2
10 eq. HMPA
THF, rt
2) PhSeBr
(50%)
O
O
PMP
O
O
O
SePh
mCPBA
CH2Cl2
-78 °C
PMP
O
(86%)
Sorenson, E.J.; Shipe, W.D. Org. Lett. 2002, 4, 2063
Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025
30
Proposed Mechanism
O
O
PMP
One-electron
reduction of keto group
O
O
I2SmO
PMP
O
Selective ring
fragmentation
O
O
SePh
PMP
O
PhSeBr
OSmI2
O
PMP
O
31
Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025
Confirmation of Stereochemistry
O
O
PMP
O
1) H2NOMe·HCl
pyridine
MeOH
2)
Cl
Br
DMAP
O
pyridine, rt
(50%, two steps)
Br
O
MeO N
O
Br
O
O
32
Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025
Synthesis of Guanacastepene E
O
PMP
O
OSiEt3
O
PMP
O
O
Et3N, Et3SiOTf
CH2Cl2, -78 °C
mCPBA
CH2Cl2
-78 °C
O
AcO
O
PMP
O
O
Ac2O, DMAP
pyridine, rt
O
HO
PMP
O
(45%, 3 steps)
33
Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025
Synthesis of Guanacastepene E
O
O
PMP
O
AcO
OH
O
0.25 eq. PPTS
MeOH, 70 °C
OH
AcO
(88%)
SiO2
CH2Cl2, rt
(78%)
O
AcO
H O
O
OH
(+)-Guanacastepene E
H
AcO
O
OH
(+)-Guanacastepene A
34
Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025
Completion of Formal Synthesis of
Guanacastepene A
O
O
PMP
O
0.2 eq. PPTS
2,2-dimethoxypropane
60 °C
O
O
O
(77%)
Danishefsky intermediate
Sorenson, E.J.; Shipe, W.D. Org. Lett. 2002, 4, 2063
Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025
35
Sorenson’s Formal Synthesis:
Summary




1.2% overall yield of Guanacastepene E
1.2% overall yield of Danishefsky’s key intermediate to
Guanacastepene A
24 steps (longest linear sequence is 17 steps)
Key steps: π-allyl Stille cross-coupling followed by a
[2+2] photocycloaddition/reductive fragmentation
O
AcO
H O
OH
(+)-Guanacastepene E
36
Comparison of Key Steps
EtO
O
OH
EtO
O
O
O
O
O
O
O
EtO
O
O
O
O
X
O
H
OH
Danishefsky:
17 steps, 5.3% yield
AcO
Sorenson:
24 steps, 1.2% yield
Danishefsky intermediate
O
O
SePh
PMP
O
Guanacastepene A
O
O
PMP
O
O
O
PMP
O
37
Acknowledgements
Dr. Robert Ben
Nick Afagh
Paul Czechura
Rachelle Denis
Elena Dimitrijevic
Hasan Khan
Caroline Proulx
Tahir Rana
Roger Tam
John Trant
Elisabeth von Moos
Former Ben Lab members
38
39
Investigation Non-Cyclizing
Reduction
 Increased dilution favours cyclization – suggests intermolecular pathway
 THF-d8 – no deuterium incorporation, no change in ratio of products
 workup with D2O – no exchange of I for D  no remaining vinyllithium
 Is enolizable cyclopentanone serving as a proton source?
I
O
5.0 eq. n-BuLi
(inverse addition)
0 °C, THF, 30 min;
then Ac2O
HO
OAc
O
+
+
Danishefsky, S.J.; Dudley, G.B. Org. Lett. 2001, 3, 2399
Danishefsky, S.J.; Mandal, M. Tet. Lett. 2004, 45, 3827
40
Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619
Isotope Labelling
1
R
R
H/D
2
R2 OH
R1
O
5.0 eq. BuLi
THF, 0 °C
(inverse
addition)
H/D
2
R
1
R
O
+
Ratio
R 1 = R2 = H
78:22
R1 = D, R2 = H
88:12
R 1 = R2 = D
91:9
 Using dideutero-cyclopropanone increased the ratio from 78:22 to 91:9
Danishefsky, S.J.; Dudley, G.B. Org. Lett. 2001, 3, 2399
Danishefsky, S.J.; Mandal, M. Tet. Lett. 2004, 45, 3827
41
Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619
Investigation Mechanism and
Proton Source
a
I
D
5.0 eq. n-BuLi
(inverse addition)
0 °C, THF, 30 min
D
O
Li
D
D
O
Path a
n-BuI
D/H
H/D
D
O
D
D
O
Two proton sources: 1) enolizable cyclopentanone, 2) iodobutane via E2 elimination
Danishefsky, S.J.; Dudley, G.B. Org. Lett. 2001, 3, 2399
Danishefsky, S.J.; Mandal, M. Tet. Lett. 2004, 45, 3827
42
Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619
Proposed Oxidation
Nu
Nu = solvolytic
nucleophile
AcO
[O]
O
(a)
Solvolysis
O
O
acyl
transfer
O
AcO
AcO
O
O
Expected result:
Solvolysis gives retention
Thermolysis gives inversion
O
O
O
AcO
(b)
Thermolysis
Danishefsky, S.J.; Lin, S.; Dudley, G.B.; Tan, D.S. Angew. Chem. Int. Ed. 2002, 41, 2188
43
Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619
Studies on Oxidation
 Solvolysis goes with retention
 Epoxidation must occur from β-face
(a)
Solvolysis
O
O
O
O
1) Et3N, DMAP
AcCl, Ac2O, 100 °C
2) DMDO/acetone
CH2Cl2, -78 °C to
O °C
O
O
O
O
AcO
O
AcO
O
stereochemistry
not defined
O
(b)
Thermolysis
O
AcO
1:1
Danishefsky, S.J.; Lin, S.; Dudley, G.B.; Tan, D.S. Angew. Chem. Int. Ed. 2002, 41, 2188
44
Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619
Torsional Steering
O
Me
i-Pr
O
Me
i-Pr
O
O
OAc
H
i-Pr
Staggered
H
(Favoured)
OAc
Boat
-attack
Me
i-Pr
O
OAc
Me
i-Pr
i-Pr
H
OAc
O
O
H
O
O
Eclipsed
(Disfavour
ed)
-attack
Houk, K.N.; Danishefsky, S.J.; Cheong, P.H.; Yun, H. Org. Lett. 2006, 8, 1513
Me
i-Pr
OAc
O
Chair
45
Stereoselective Epoxidation
OAc
O
O
DMDO/acetone
CH2Cl2, -50 °C
O
OAc
O
O
then Me2S
O
O
Me
i-Pr
O
OAc
O
H
Me
i-Pr
i-Pr
Staggered
H
(Favoured)
O
OAc
-epoxide
-attack
Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619
46
Houk, K.N.; Danishefsky, S.J.; Cheong, P.H.; Yun, H. Org. Lett. 2006, 8, 1513
Studies on Oxidation
(a)
Solvolysis
O
O
O
O
1) Et3N, DMAP
AcCl, Ac2O, 100 °C
2) DMDO/acetone
CH2Cl2, -78 °C to
O °C
O
O
O
O
AcO
O
AcO
O
 Thermolysis lacks stereoselectivity
 Why?
O
(b)
Thermolysis
O
AcO
1:1
Danishefsky, S.J.; Lin, S.; Dudley, G.B.; Tan, D.S. Angew. Chem. Int. Ed. 2002, 41, 2188
47
Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619
Competing Heterolytic Cleavage
O
O
O
O
O
O
DMDO/acetone
CH2Cl2, 150 °C
AcO
O
then Me2S
AcO
O
 = 40:1
O
HO
 = 90:10
Ac2O, DMAP
pyridine, CH2Cl2
O
O
O
AcO
retention
48
Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619
SmI2-Promoted Regioselective
Radical Ring-Opening
i-Pr
i-Pr
SmI2, t-BuOH
HMPA, THF, rt
O
99%
O
SmI2, t-BuOH
HMPA, THF, rt
O
99%
O
Kakiuchi, K.; Minato, K.; Tsutsumi, K.; Morimoto, T.; Kurosawa, H. Tet. Lett. 2003, 44, 1963
49
SmI2-Promoted Regioselective
Radical Ring-Opening
O
MeO2C
CO2Me
SmI2, MeOH
+
HMPA, THF, rt
O
O
OH
18% (65:35)
55%
SmI2, t-BuOH
HMPA, THF, rt
NC
CN
99%
O
SmI2, t-BuOH
+
HMPA, THF, rt
O
O
OH
2%
81%
Kakiuchi, K.; Minato, K.; Tsutsumi, K.; Morimoto, T.; Kurosawa, H. Tet. Lett. 2003, 44, 1963
50