[2+2] photocycloaddition/ fragmentation in the synthesis of guanacastepenes a and e jennifer chaytor...
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[2+2] Photocycloaddition/Fragmentation in the Synthesis of Guanacastepenes A and E
Jennifer ChaytorNovember 2, 2006
University of Ottawa
2
Guanacastepene A
OAcO OH
H O
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
Mixture of two slowly interconverting conformers
Clardy, J.; Brady, S.F.; Singh, M.P.; Janso, J.E. J. Am. Chem. Soc. 2000, 122, 2116Clardy, J.; Brady, S.F.; Bondi, S.M. J. Am. Chem. Soc. 2001, 123, 9900
3
Five Guanacastepene Ring Systems
O
O
O
N
O
O
A, B, C
E, F, G, I, J, N, O D, H
K L, M
CR115 produces a family of related but structurally diverse metabolites
15 different guanacastepenes comprise five ring systems
All contain the 5-7-6 tricyclic guanacastepene skeleton
Clardy, J.; Brady, S.F.; Singh, M.P.; Janso, J.E. J. Am. Chem. Soc. 2000, 122, 2116Clardy, J.; Brady, S.F.; Bondi, S.M. J. Am. Chem. Soc. 2001, 123, 9900
4
Potential New Antibiotics?O
AcO OHH O
Guanacastepene A
1 3
8
1618
11
15 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
OO
H3COOH
OH
Guanacastepene I
Clardy, J.; Brady, S.F.; Singh, M.P.; Janso, J.E. J. Am. Chem. Soc. 2000, 122, 2116Clardy, J.; Brady, S.F.; Bondi, S.M. J. Am. Chem. Soc. 2001, 123, 9900
Clardy, J.; Singh, M.P.; Janso, J.E.; Luckman, S.W.; Brady, S.F.; Greenstein, M.; Maiese, W.M. J. Antibiot. 2002, 53, 256
5
Total and Formal Syntheses
OAcO OH
H O
OO
AcOOH
OO
O
OOH
OHOO
H3COOH
Guanacastepene ADanishefsky 2002
Snider 2002, Hanna 2005,Sorenson 2006
HO
Guanacastepene CMehta 2005
H
Guanacastepene ESorenson 2006
O
Guanacastepene NOverman 2006
Danishefsky et. al, Angew. Chem. Int. Ed. 2002, 41, 2185Danishefsky et al., Angew. Chem. Int. Ed. 2002, 41, 2188Danishefksy et al., J. Org. Chem. 2005, 70, 10619Snider et al., J. Org. Chem. 2003, 68, 1030
Hanna et al., Org. Lett. 2004, 6, 1817Mehta et al., Chem. Comm. 2005, 4456Sorenson et al., J. Am. Chem. Soc. 2006, 128, 7025Overman et al., J. Am. Chem. Soc. 2006, ASAP
6
Total and Formal Syntheses
OAcO OH
H O
OO
AcOOH
OO
O
OOH
OHOO
H3COOH
Guanacastepene ADanishefsky 2002
Snider 2002, Hanna 2005,Sorenson 2006
HO
Guanacastepene CMehta 2005
H
Guanacastepene ESorenson 2006
O
Guanacastepene NOverman 2006
Danishefsky et. al, Angew. Chem. Int. Ed. 2002, 41, 2185Danishefsky et al., Angew. Chem. Int. Ed. 2002, 41, 2188Danishefksy et al., J. Org. Chem. 2005, 70, 10619Snider et al., J. Org. Chem. 2003, 68, 1030
Hanna et al., Org. Lett. 2004, 6, 1817Mehta et al., Chem. Comm. 2005, 4456Sorenson et al., J. Am. Chem. Soc. 2006, 128, 7025Overman et al., J. Am. Chem. Soc. 2006, ASAP
7
Snider RetrosynthesisO OH
O
AcO
HOXOH
OOR
O
H
OAlEt2
AlCl4O
Methylationand modifiedRobinson annulation
AA
AA BBC
B
X = aldehydeprecursor
Ring closingmetathesis
C
Snider, B.B.; Hawryluk, N.A. Org. Lett. 2001, 3, 569Snider, B.B.; Shi, B. Tet. Lett. 2001, 42, 9123
Snider, B.B.; Hawryluk, N.A.; Shi, B. J. Org. Chem. 2003, 68, 1030
A AB ABC approach
17 linear steps2.6% overall yield
8
Hanna RetrosynthesisO OH
O
AcO
HO O
O
Danishefsky intermediate
MeO2CCO2MeTandem ring-closing
metathesisB
BC C
B
C
A A
A
A
Hanna, I.; Boyer, F-D.; Ricard, L. Org. Lett. 2004, 6, 1817
A ABC approach
17 linear steps<1.8% overall yield
9
Danishefsky’s Approach
A AB ABC approachO
RO
AcO
O OHCOH
A
A
A
B
B CAcO
OH EtO2CO
AB C
OAcO
OHO
AB
OEtO
Knoevenagelcyclization
Alkylations;
Reductivecyclization
Danishefsky, S.J.; Dudley, G.B. Org. Lett. 2001, 3, 2399Danishefsky, 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, 2188Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619
10
Synthesis of Hydroazulene Core
O Me3SiO
II
IOH
+
OIOH
Ph3P, imid., I2CH2Cl2(92%)
(94%)
MeLi, THF, 0 °C, 1 hr;2.5 eq. A, HMPA
-78 °C to rt
(74-76%)
1) i-PrMgBr, CuBr·Me2SMe3SiCl, THF, HMPA
2) Et3N, pentane, H2O
5.0 eq. n-BuLiTHF, 0 °C
(inverse addition)
(62-65%)
(plus 16-18% of uncyclized olefin)
A
O
PCC
(71-92%)
Danishefsky, S.J.; Dudley, G.B. Org. Lett. 2001, 3, 2399Danishefsky, 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, 2188Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619
11
Successive Dialkylation Strategy
O O
OSiMe3O
1) LiHMDS, THF, -78 °C2) 3.0 eq. Me2NCH2I, THF, -78 °C rt3) m-CPBA, CH2Cl2/aq. NaHCO3
MgBrCuI, HMPA, TMSCl,THF, -78 °C
(86% overall)
1) MeLi, THF, 0 °C2) MeI, HMPA, -78 °C rt
(77% over 3 steps)8
11
Danishefsky, S.J.; Tan, D.S.; Dudley, G.B. Angew. Chem. Int. Ed. 2002, 41, 2185Danishefsky, S.J.; Lin, S.; Dudley, G.B.; Tan, D.S. Angew. Chem. Int. Ed. 2002, 41, 2188
Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619
12
Hydroboration and OxidationsO ethylene glycol
TsOH, PhH, reflux
(89%)
O
O
O
O
OHH
O
1) 9-BBN, THF, 0 °C rt2) 3N NaOH, 30% H2O2, rt
(98%)
O
ODess-Martin periodinane
CH2Cl2, rt
(83%)
Danishefsky, S.J.; Tan, D.S.; Dudley, G.B. Angew. Chem. Int. Ed. 2002, 41, 2185Danishefsky, S.J.; Lin, S.; Dudley, G.B.; Tan, D.S. Angew. Chem. Int. Ed. 2002, 41, 2188
Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619
13
Epoxide-Opening β-Elimination/Knoevenagel
Cyclization
H
OO
OX
X = -OCH2CH2O-
X = O
N2CHCO2EtSnCl2, CH2Cl2, rt
TsOHH2O in acetone (5%)
70 °C(80% over two steps)
OOO
OEtOOH
m-CPBACH2Cl2, 0 °C
(89%)
NaOEtEtOH, 50 °C
(80%)
O
OEtO
O
OEtO
Danishefsky, S.J.; Tan, D.S.; Dudley, G.B. Angew. Chem. Int. Ed. 2002, 41, 2185Danishefsky, S.J.; Lin, S.; Dudley, G.B.; Tan, D.S. Angew. Chem. Int. Ed. 2002, 41, 2188
Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619
14
Final Steps to Guanacastepene A
O
OEtOOR
OHOSiEt3
R = H
R = SiEt3
DIBAL-H, CH2Cl2 -78 °C 0 °C
(:80:20)
OH
OHOSiEt3 OH
1) Ph3P, benzoic acidDIAD, THF, -78 C rt
2) DIBAL-H, CH2Cl2 -78 °C 0 °C
(67% over 4 steps)
O O
O
OCH3H3CO
PPTS, CH2Cl2, 0 °C
1)
2) TBAF, THF, 0 °C
(91-98%)
3) Dess-Martin periodinanepyridine, CH2Cl2
(90%)
Et3SiOTfpyridine
CH2Cl2, 0 °C
(80-85%)
5
Danishefsky, S.J.; Tan, D.S.; Dudley, G.B. Angew. Chem. Int. Ed. 2002, 41, 2185Danishefsky, S.J.; Lin, S.; Dudley, G.B.; Tan, D.S. Angew. Chem. Int. Ed. 2002, 41, 2188
Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619
15
Final Steps to Guanacastepene A
O O
O
O O
O
HO
O O
O
AcO
O OH
O
AcO
H
1) Et3SiOTfEt3N, CH2Cl22) DMDO/acetoneCH2Cl2, -78 °C3) Me2S
(82-90% overall)
Ac2O, pyridineDMAP, CH2Cl2
(96%)
1) PPTS, MeOH, 70 °C
2) PhI(OAc)2, TEMPO CH2Cl2
(59-65% overall)Guanacastepene A
13
13
Danishefsky, S.J.; Tan, D.S.; Dudley, G.B. Angew. Chem. Int. Ed. 2002, 41, 2185Danishefsky, S.J.; Lin, S.; Dudley, G.B.; Tan, D.S. Angew. Chem. Int. Ed. 2002, 41, 2188
Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619
16
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
β-elimination/Knoevenagel cyclization
O O
O
Key intermediate
O OH
O
AcO
H
Guanacastepene A
17
Sorenson’s Approach
Sorenson, E.J.; Shipe, W.D. Org. Lett. 2002, 4, 2063Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025
A + C AC ABC approachO
SnMe3 AcO+
O O
OSePhO
Allyl Stillecross-coupling
Intramolecular [2+2]photocycloaddition
Fragmentation/enolate trapping
Elimination;PG Manipulation
AB C
A
A
C
CB
A C
O
O
O
O PMP
O
O PMP
O
O PMP
O
O PMP
Danishefskyintermediate
18
Reductive Opening of Cyclopropyl Ketones
O O
O
HClHOAc
LiNH3
Cl
O
1
5
10
1
5
10
Shoulders, B.A.; Kwie, W.W.; Klyne, W.; Gardner, P.D. Tetrahedron, 1965, 21, 2973
Dauben, W.G.; Deviny, E.J. J. Am. Chem. Soc. 1966, 31, 3794
19
Reductive Opening of Cyclopropyl Ketones
O OLi
NH3
(+)-carone
1
6
7
R O
R'R O
R'
2 e-
Breakage of 1,6 bond: -more stable 2º carbanion
Breakage of 1,7 bond:-Less stable 3º carbanion-Overlap with π system
Dauben, W.G.; Deviny, E.J. J. Am. Chem. Soc. 1966, 31, 3794
O
16
7
20
Favouring Cyclobutane Cleavage
OH ITMSCl, NaI
CH3CH, 80 °C
Bu3SnH, C6H6
80 °C
1
2
(±)-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 >20:11.0 eq. Bu3SnH, AIBN (cat.), C6H6, 80 °C (syringe pump addition) 100:0
Crimmins, M.T.; Mascarella, S.W. Tet. Lett. 1987, 28, 5063
21
SmI2-Promoted Radical Ring Opening
O OSmI2THF
DMPU
39%
O
TMS
OSmI2THF
DMPU
79%(mixture of geometric
isomers)
TMS
Motherwell, W.B.; Batey, R.A. Tetrahedron Letters, 1991, 32, 6649
OR1(H)
R2(H)
OR1
R2
M O
R2
M
M (+ e-)ring
opening
3 4
22
Trapping of Samarium Enolates with Electrophiles
O O1) SmI2
THFDMPU
37%
2) Br
O
-78° C
1) SmI2THF
DMPU
34%
2) TMSCl-78° C
OTMS
O
1) SmI2THF
DMPU
57%
2) AcCl-78° C
OAc
Motherwell, W.B.; Batey, R.A. Tetrahedron Letters, 1991, 32, 6649
23
Synthesis of Ring A
O OH
O
O
OH
NC
OH
O
OH
O
O
CNO
OH
(96%, 3 steps)
1) O3, EtOAc, -78 °C 2) H2, Pd/C, rt
(48-54%)
NaCN, p-TsOH, THF·H2O, rt
(99%)
1) 0.2 mol % PtO2, H2,rt 2) LDA, THF, -78 °C rt3) MeI, 0 °C rt
EDCI, 0 °C rtCH2Cl2
(79%)
1) 3.0 eq. LiHMDS, THF, rt2) 1 N aq. HCl
(50-58%)
(S)-(+)-Carvone
Sorenson, E.J.; Shipe, W.D. Org. Lett. 2002, 4, 2063Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025
24
Synthesis of Stille Coupling Partner (Ring A)
O
OH
O
ONf
O
SnMe3Et3N, NfFCH2Cl2, rt
Pd(dppf)Cl2, Me3SnSnMe3NMP, 60 °C
Nf = SF F
FF F
F F
F F
O O
(94%) (63%)
Sorenson, E.J.; Shipe, W.D. Org. Lett. 2002, 4, 2063Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025
25
Synthesis of Ring CO OTMS
OO
MeO
O
MeO
OOMeO
O
MeO
O
OPMB
O OMeO
MeO
O OMe
LDA, TMSClTHF, -15 °C rt
(98%)
O
OO
O
THF, 0 °C rt
(99%)
1)
2) 1 N HCl, 0 °C rt
mCPBA, NaHCO3CH2Cl2, rt
(96%)
1) 0.07 eq. CSAMeOH, reflux
Cl3CO
HN
O2)
100%
0.1 eq. CSA, CH2Cl2, rt
Sorenson, E.J.; Shipe, W.D. Org. Lett. 2002, 4, 2063Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025
26
Synthesis of Ring C
OPMB
O OMeO
MeO
O OMe
OPMB
HO
OO
PMP
OPMB
OO
PMP
HOAcO
OMe
OMe
1) LiAlH4Et2O
0 °C rt
2)
PPTSCH2Cl2, rt
(87%) (two steps)
(80%)
NO2
SeNC1)
n-Bu3PTHF
0 °C rt
2) 30% aq H2O2i-Pr2EtN
0 °C 45 °C
(71%)
1) 0.25 eq. PPTSMeOH, rt
(85%)
2) DDQCH2Cl2, rt
(69%)
Ac2ODMAP
pyridine, rt
(100%)
racemate
O
O PMP
O
O PMP
MeO
Sorenson, E.J.; Shipe, W.D. Org. Lett. 2002, 4, 2063Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025
27
Resolution of C-Ring Fragment
AcO
O
O
OAc
O
O
OAc
+
racemate separable by column chromatography
O
OHOAc
DMAP, DCCCH2Cl2, 0 °C rt
(98%)
O
O PMP
O
O PMP
O
O O
1:1
Sorenson, E.J.; Shipe, W.D. Org. Lett. 2002, 4, 2063Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025
28
Stille Cross-Coupling
O
O
OAc
O
SnMe3+
OLiCl, CuCl,Pd(PPh3)4,
DMSO, rt 60 °C
(78%)
O
O PMP
O
O PMP
Sorenson, E.J.; Shipe, W.D. Org. Lett. 2002, 4, 2063Sorenson, 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
29
Proposed Catalytic Cycle for CuCl-Accelerated Stille Coupling
2L + Li+ L2PdCl- L4Pd + LiCl
A
LiCl + L2Pd
BAr R ArX
L2PdR
Ar
L2PdX
Ar
RCuLiCl
Bu3SnCl
RSnBu3 + CuCl + LiCl
+ CuX+ LiCl
C
D
E
F
Corey, E.J.; Han, X.; Stoltz, B.M. J. Am. Chem. Soc. 1991, 121, 7600
30
Formation of Ring BO O
OSePh
O
hv0.5 eq. i-Pr2NEt
Et2O
(82%)1) 2.5 eq. SmI210 eq. HMPA
THF, rt
(50%)
2) PhSeBr
mCPBACH2Cl2-78 °C
(86%)
O
O
O
O
O
O
O
O
PMP PMP
PMPPMP
Sorenson, E.J.; Shipe, W.D. Org. Lett. 2002, 4, 2063Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025
31
Proposed MechanismO
OSmI2
O
O
O
O
PMP
PMP
I2SmOO
O PMP
PhSeBrO
O
O PMP
SePh
One-electronreduction of keto group
Selective ringfragmentation
Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025
32
Confirmation of StereochemistryO
NMeO
O
O PMP
O
O
O
O
Br
Br
O
ClBr
1) H2NOMe·HClpyridineMeOH
2)
DMAPpyridine, rt
(50%, two steps)
Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025
33
Synthesis of Guanacastepene E
OO
OOSiEt3
O
OPMP PMP
OO
O PMPO
O
O PMP
HOAcO
Et3N, Et3SiOTfCH2Cl2, -78 °C
mCPBACH2Cl2-78 °C
Ac2O, DMAPpyridine, rt
(45%, 3 steps)
Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025
34
Synthesis of Guanacastepene EO
O
O PMP
AcOO
OH
OH
AcO
OOH
O
AcO
HOOHAcO
OH
0.25 eq. PPTSMeOH, 70 °C
(88%)
SiO2CH2Cl2, rt(78%)
(+)-Guanacastepene A(+)-Guanacastepene E
Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025
35
Completion of Formal Synthesis of Guanacastepene A
O OO
O
O
O PMP0.2 eq. PPTS
2,2-dimethoxypropane60 °C
(77%)
Danishefsky intermediate
Sorenson, E.J.; Shipe, W.D. Org. Lett. 2002, 4, 2063Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025
36
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
OOHAcO
OH
(+)-Guanacastepene E
37
Comparison of Key Steps
XOOO
OEtOOH O
OEtO
O
OEtO
O OH
O
AcO
H
Guanacastepene A
OO
O
Danishefsky intermediate
OOOSePh O
O
O
O
O
O PMPPMPPMP
Danishefsky:17 steps, 5.3% yield
Sorenson:24 steps, 1.2% yield
38
AcknowledgementsDr. Robert Ben
Nick Afagh Paul CzechuraRachelle Denis
Elena DimitrijevicHasan Khan
Caroline ProulxTahir RanaRoger TamJohn Trant
Elisabeth von Moos
Former Ben Lab members
39
40
Investigation Non-Cyclizing Reduction
O
I
OAcOHO
+ +
5.0 eq. n-BuLi (inverse addition)0 °C, THF, 30 min;
then Ac2O
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?
Danishefsky, S.J.; Dudley, G.B. Org. Lett. 2001, 3, 2399Danishefsky, S.J.; Mandal, M. Tet. Lett. 2004, 45, 3827
Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619
41
Isotope Labelling
O
H/DR2
R1
R2
R1O
H/DR2
R1OH
+5.0 eq. BuLi
THF, 0 °C(inverseaddition)
R1 = R2 = H
R1 = D, R2 = H
R1 = R2 = D
Ratio
78:22
88:12
91:9
Using dideutero-cyclopropanone increased the ratio from 78:22 to 91:9
Danishefsky, S.J.; Dudley, G.B. Org. Lett. 2001, 3, 2399Danishefsky, S.J.; Mandal, M. Tet. Lett. 2004, 45, 3827
Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619
42
Investigation Mechanism and Proton Source
O
I
O O
5.0 eq. n-BuLi (inverse addition)0 °C, THF, 30 min
DD O
LiD
D
DD
DD/H
H/D
n-BuI
a
Path a
Two proton sources: 1) enolizable cyclopentanone, 2) iodobutane via E2 elimination
Danishefsky, S.J.; Dudley, G.B. Org. Lett. 2001, 3, 2399Danishefsky, S.J.; Mandal, M. Tet. Lett. 2004, 45, 3827
Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619
43
Proposed Oxidation
AcO
O O
O
[O]
O
AcO
O
O
O
O
Nu
(a)Solvolysis
(b)Thermolysis
AcO
O
AcO
acyltransfer
Nu = solvolytic nucleophile
Danishefsky, S.J.; Lin, S.; Dudley, G.B.; Tan, D.S. Angew. Chem. Int. Ed. 2002, 41, 2188Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619
Expected result:Solvolysis gives retentionThermolysis gives inversion
44
Studies on Oxidation
(a)Solvolysis
(b)Thermolysis
OO
O
OO
AcO
OO
O
OO
O
O
AcO
AcO1:1
1) Et3N, DMAPAcCl, Ac2O, 100 °C
2) DMDO/acetoneCH2Cl2, -78 °C to O °C
stereochemistrynot defined
Solvolysis goes with retention Epoxidation must occur from β-face
Danishefsky, S.J.; Lin, S.; Dudley, G.B.; Tan, D.S. Angew. Chem. Int. Ed. 2002, 41, 2188Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619
45
Torsional Steering
Mei-Pr
OAc
O
Mei-Pr
O
OAc
O
O
Mei-Pr
OAc
-attack
-attack
H
i-PrO
H
i-PrH
O
O
H
O
Staggered
Eclipsed
(Favoured)
(Disfavoured)
Mei-Pr
OAc
Mei-Pr
O
O
OAc
Boat
Chair
Houk, K.N.; Danishefsky, S.J.; Cheong, P.H.; Yun, H. Org. Lett. 2006, 8, 1513
46
Stereoselective Epoxidation
Mei-Pr
OAc
O
O
H
i-PrO
H
O
-attack
Staggered
Mei-Pr
OAc
O
-epoxide
(Favoured)
OAc
O
O OAc
O
OODMDO/acetoneCH2Cl2, -50 °C
then Me2S
Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619Houk, K.N.; Danishefsky, S.J.; Cheong, P.H.; Yun, H. Org. Lett. 2006, 8, 1513
47
Studies on Oxidation
(a)Solvolysis
(b)Thermolysis
OO
O
OO
AcO
OO
O
OO
O
O
AcO
AcO
1:1
1) Et3N, DMAPAcCl, Ac2O, 100 °C
2) DMDO/acetoneCH2Cl2, -78 °C to O °C
Thermolysis lacks stereoselectivity Why?
Danishefsky, S.J.; Lin, S.; Dudley, G.B.; Tan, D.S. Angew. Chem. Int. Ed. 2002, 41, 2188Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619
48
Competing Heterolytic CleavageOO
AcO
OO
O
O
AcO
OO
AcO
O
OO
O
DMDO/acetoneCH2Cl2, 150 °C
then Me2S
HO
= 90:10
= 40:1
Ac2O, DMAPpyridine, CH2Cl2
retention
Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619
49
SmI2-Promoted Regioselective Radical Ring-Opening
O
i-Pr
O
i-PrSmI2, t-BuOH
HMPA, THF, rt
99%
O O
SmI2, t-BuOH
HMPA, THF, rt
99%
Kakiuchi, K.; Minato, K.; Tsutsumi, K.; Morimoto, T.; Kurosawa, H. Tet. Lett. 2003, 44, 1963
50
SmI2-Promoted Regioselective Radical Ring-Opening
O
CO2MeSmI2, MeOH
HMPA, THF, rt
MeO2C
OH
O
O
+
18% (65:35) 55%
O
CNSmI2, t-BuOH
HMPA, THF, rt
NC
O
+
81%2%
O
OH
SmI2, t-BuOHHMPA, THF, rt
99%
Kakiuchi, K.; Minato, K.; Tsutsumi, K.; Morimoto, T.; Kurosawa, H. Tet. Lett. 2003, 44, 1963
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