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[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

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2 2 photocycloaddition fragmentation in the synthesis of guanacastepenes a and e

[2+2] Photocycloaddition/Fragmentation in the Synthesis of Guanacastepenes A and E

Jennifer Chaytor

November 2, 2006

University of Ottawa

guanacastepene a
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, 2116

Clardy, J.; Brady, S.F.; Bondi, S.M. J. Am. Chem. Soc. 2001, 123, 9900

five guanacastepene ring systems
Five Guanacastepene Ring Systems
  • 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, 2116

Clardy, J.; Brady, S.F.; Bondi, S.M. J. Am. Chem. Soc. 2001, 123, 9900

potential new antibiotics
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

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

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
Total and Formal Syntheses

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

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

total and formal syntheses1
Total and Formal Syntheses

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

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

snider retrosynthesis
Snider Retrosynthesis

A  AB  ABC approach

17 linear steps

2.6% overall yield

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

hanna retrosynthesis
Hanna Retrosynthesis

A  ABC approach

17 linear steps

<1.8% overall yield

Hanna, I.; Boyer, F-D.; Ricard, L. Org. Lett. 2004, 6, 1817

danishefsky s approach
Danishefsky’s Approach

A  AB  ABC approach

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

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
Synthesis of Hydroazulene Core

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

Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619

successive dialkylation strategy
Successive Dialkylation Strategy

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

Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619

hydroboration and oxidations
Hydroboration and Oxidations

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

Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619

epoxide opening elimination knoevenagel cyclization
Epoxide-Opening β-Elimination/Knoevenagel Cyclization

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

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
Final Steps to Guanacastepene A

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

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 a1
Final Steps to Guanacastepene A

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

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
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
sorenson s approach
Sorenson’s Approach

A + C  AC  ABC approach

Sorenson, E.J.; Shipe, W.D. Org. Lett. 2002, 4, 2063

Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025

reductive opening of cyclopropyl ketones
Reductive Opening of Cyclopropyl Ketones

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

reductive opening of cyclopropyl ketones1
Reductive Opening of Cyclopropyl Ketones

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

favouring cyclobutane cleavage
Favouring Cyclobutane Cleavage

Crimmins, M.T.; Mascarella, S.W. Tet. Lett. 1987, 28, 5063

smi 2 promoted radical ring opening
SmI2-Promoted Radical Ring Opening

Motherwell, W.B.; Batey, R.A. Tetrahedron Letters, 1991, 32, 6649

trapping of samarium enolates with electrophiles
Trapping of Samarium Enolates with Electrophiles

Motherwell, W.B.; Batey, R.A. Tetrahedron Letters, 1991, 32, 6649

synthesis of ring a
Synthesis of Ring A

Sorenson, E.J.; Shipe, W.D. Org. Lett. 2002, 4, 2063

Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025

synthesis of stille coupling partner ring a
Synthesis of Stille Coupling Partner (Ring A)

Sorenson, E.J.; Shipe, W.D. Org. Lett. 2002, 4, 2063

Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025

synthesis of ring c
Synthesis of Ring 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

synthesis of ring c1
Synthesis of Ring 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

resolution of c ring fragment
Resolution of C-Ring Fragment

Sorenson, E.J.; Shipe, W.D. Org. Lett. 2002, 4, 2063

Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025

stille cross coupling
Stille Cross-Coupling

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

proposed catalytic cycle for cucl accelerated stille coupling
Proposed Catalytic Cycle for CuCl-Accelerated Stille Coupling

Corey, E.J.; Han, X.; Stoltz, B.M. J. Am. Chem. Soc. 1991, 121, 7600

formation of ring b
Formation of Ring B

Sorenson, E.J.; Shipe, W.D. Org. Lett. 2002, 4, 2063

Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025

proposed mechanism
Proposed Mechanism

Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025

confirmation of stereochemistry
Confirmation of Stereochemistry

Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025

synthesis of guanacastepene e
Synthesis of Guanacastepene E

Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025

synthesis of guanacastepene e1
Synthesis of Guanacastepene E

Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025

completion of formal synthesis of guanacastepene a
Completion of Formal Synthesis of Guanacastepene A

Sorenson, E.J.; Shipe, W.D. Org. Lett. 2002, 4, 2063

Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025

sorenson s formal synthesis summary
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
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

Acknowledgements
investigation non cyclizing reduction
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?

Danishefsky, S.J.; Dudley, G.B. Org. Lett. 2001, 3, 2399

Danishefsky, 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

isotope labelling
Isotope Labelling
  • 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

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
Investigation Mechanism and Proton Source
  • 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

Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619

proposed oxidation
Proposed Oxidation

Expected result:

Solvolysis gives retention

Thermolysis gives inversion

Danishefsky, 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

studies on oxidation
Studies on Oxidation
  • 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, 2188

Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619

torsional steering
Torsional Steering

Houk, K.N.; Danishefsky, S.J.; Cheong, P.H.; Yun, H. Org. Lett. 2006, 8, 1513

stereoselective epoxidation
Stereoselective Epoxidation

Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619

Houk, K.N.; Danishefsky, S.J.; Cheong, P.H.; Yun, H. Org. Lett. 2006, 8, 1513

studies on oxidation1
Studies on Oxidation
  • Thermolysis lacks stereoselectivity
  • Why?

Danishefsky, 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

competing heterolytic cleavage
Competing Heterolytic Cleavage

Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619

smi 2 promoted regioselective radical ring opening
SmI2-Promoted Regioselective Radical Ring-Opening

Kakiuchi, K.; Minato, K.; Tsutsumi, K.; Morimoto, T.; Kurosawa, H. Tet. Lett. 2003, 44, 1963

smi 2 promoted regioselective radical ring opening1
SmI2-Promoted Regioselective Radical Ring-Opening

Kakiuchi, K.; Minato, K.; Tsutsumi, K.; Morimoto, T.; Kurosawa, H. Tet. Lett. 2003, 44, 1963