[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