Groupe Charette, Réunion de littérature, 4 Décembre 2007 Chiral Allylsilanes as Enantioselective Allylation Reagents for Aldehydes Focusing on work by James S. Panek and James L. Leighton James Bull Groupe Charette, Réunion de littérature, 4 Décembre 2007

Outline Introduction to allylation chemistry Stereocontrol features for allylsilanes Introduce SE2’ reactivity/stereospecificity Hyperconjugation, Open Transition States James S. Panek Background/ Concept Aldehyde Crotylation Synthesis of chiral allyl silanes Use in complex molecule synthesis James L. Leighton Allylation/Crotylation Imine electrophiles

The importance of allylation/crotylation chemistry

Common (Excellent) Enantioselective Methods Brown Roush Well defined cyclic TS’s (Type I class) Excellent enantio/diastereocontrol Unstable to storage Prepared in situ Used at low temperature

Common (Excellent) Enantioselective Methods Keck Lewis Base catalysed enantioselective allylation Denmark, S. E.; Fu, J. Chem. Rev. 2003, 103, 2763

Allylsilanes SE2’ anti Stereospecific Stereocontrol?? New Chiral Centre Double bond geometry When E+ = aldehyde, diastereoselectivity

What is a stereospecific reaction?? What is SE2’ reactivity?? What is a stereospecific reaction?? Stereospecific ≠ 100% stereoselective Defined by mechanism Determined by Structure/steric effects Conformation effects

SE2’ reactivity SN2 Inversion Stereospecific

SE2’ reactivity SN2 SN1 Inversion Non stereospecific Stereospecific May be stereoselective

SE2’ reactivity SN2 SN1 SN2’ Inversion Non stereospecific May be stereoselective SN2’ Direct SN2 usually faster Stereospecifically Syn (depending on nucleophile) Stork: Stork, G.; White. W. N. J. Am. Chem. Soc. 1956, 78, 4609.

SE2’ reactivity SN2 SE2 Inversion Stereospecific stereodefined C-M bonds Inversion Stereospecific Grignards: non stereospecific Li, inversion or retention depending on electrophile Park, Y. S.; Beak. P. J. Org. Chem. 1997, 62, 1574.

SE2’ reactivity SN2 SE2 SN2’ SE2’ Inversion Stereospecific Stereospecifically SYN Direct SN2 usually faster M = Si, B, Mg, Sn, Ti, Cr, Zn, …. For M = Si Stereospecifically ANTI

Stereocontrol for allylsilanes If there is no clearly prefered ground state conformation stereoselectivity will be reduced But reaction still occurs stereospecifically anti Hyperconjugation: s-conjugation Parallel bonds for max interaction

Stereocontrol for allyl silanes Open Transition State (Type II class) No preorganisation by Lewis Acid

Open TS for crotylsilane reagents TS may adopt an antiperiplanar or synclinal arrangement Relative energy differences between antiperiplanar and synclinal TS are negligible Antiperiplanar Transition States for crotyl silanes E-silane SYN diastereoselective ANTI diastereoselective Z-silane SYN diastereoselective ANTI diastereoselective SYN product preferred

Open TS for crotylsilane reagents Synclinal Transition States E-silane SYN diastereoselective ANTI diastereoselective Z-silane Both antiperiplanar and synclinal TS predict syn selectivity

Outline Introduction to allylation chemistry, Stereocontrol features for allylsilanes Introduce SE2’ reactivity/stereospecificity Hyperconjugation, Open Transition States James S. Panek Background/ Concept Aldehyde Crotylation Synthesis of chiral allyl silanes Use in complex molecule synthesis James L. Leighton Allylation/Crotylation Imine electrophiles

James S. Panek b. 1956 1979 BSc Chemistry (SUNY Buffalo) 1984 PhD Medicinal Chemistry (Kansas) with Dale Boger 1984-86 Post Doc (Yale) with Danishefsky 1986 Boston University Chiral E-crotylsilane: Well behaved SE2’ Anti addition Complete transfer of chirality Provides easily functionalised products Able to control reaction pathway by control of temperature and Lewis acid

Crotylation using syn-selectivity Complete chirality transfer from silane, no other diastereoisomers observed Anti SE2’ E double bond Syn Selective Panek, J. S.; Yang. M. J. Am. Chem. Soc. 1991, 113, 6594.

Crotylation using Syn-selectivity Panek, J. S.; Yang. M. J. Org Chem. 1991, 56, 5755.

Crotylation using Syn-selectivity Form oxonium in situ Pd catalysed allylic transposition to form 1,3-diols complete preservation of chirality 1,3-syn diol Panek, J. S.; Yang. M.; Solomon J. S. J. Org. Chem. 1993, 58, 1003.

Acyclic Diastereoselectivity - Reversing Syn Selectivity Re face attack Si face attack Panek, J. S.; Cirillo, P. F. J. Org. Chem. 1993, 58, 999.

Chiral Aldehydes - Double stereodifferentiation Syn:Anti R = Me, 64%, 10:1 R = Et, 35%, 15:1 R = Me, 85%, 1:30 R = Et, 69%, 1:10 R = Me,98 %, 1:8 R = Et, 79%, 1:10 R = H, 90%, >30:1 R = Me, 79%, >30:1 R = Et, 74%, 15:1 Chirality of the aldehyde controls the absolute stereochemistry of the oxygen bearing stereogenic centre. Chelation control with OBn, Felkin control with OTBDPS

Chiral Aldehydes - Double stereodifferentiation Jain, N. F.; Takenaka, N.; Panek, J. S. J. Am. Chem. Soc. 1996, 118, 12475.

Chiral Aldehydes - 1,3-induction? Silane reagents override 1,3-induction of the chiral aldehyde Predisposed to local Felkin induction to determine hydroxy stereochemistry Jain, N. F.; Takenaka, N.; Panek, J. S. J. Am. Chem. Soc. 1996, 118, 12475.

Synthesis of chiral silanes Johnson- Claisen Complete preservation of chirality Beresis, R. T.; Solomon J. S.; Yang. M.; Jain, N. F.; Panek, J. S.; Org. Synth. 1998, 75, 78. Panek, J. S.; Yang. M. J. Am. Chem. Soc. 1991, 113, 6594

Synthesis of chiral silanes Ireland-Claisen Enolate . Sparks, M. A.; Panek, J. S. Org. Chem. 1991, 56, 3431. Panek, J. S.; Yang. M.; Solomon J. S. J. Org. Chem. 1993, 58, 1003 Panek, J. S.; Beresis, R.; Xu, F.; Yang, M. Org. Chem. 1991, 56, 7341.

Synthesis of chiral silanes Huang, H.; Panek, J. S. Org. Lett. 2003, 5, 1991.

Synthesis of Oleandolide - Retrosynthesis Hu, T.; Takenada; N.; Panek, J. S. J. Am. Chem. Soc. 1999, 121, 9229. Hu, T.; Takenada; N.; Panek, J. S. J. Am. Chem. Soc. 2002, 124, 12806.

Synthesis of Oleandolide 90%, >30:1 Syn:Anti Felkin approach 87%, >30:1 Anti:Syn Felkin approach Hu, T.; Takenada; N.; Panek, J. S. J. Am. Chem. Soc. 1999, 121, 9229. Hu, T.; Takenada; N.; Panek, J. S. J. Am. Chem. Soc. 2002, 124, 12806.

Synthesis of Oleandolide 82%, >20:1 Syn:Anti 82%, >30:1 Anti:Syn Hu, T.; Takenada; N.; Panek, J. S. J. Am. Chem. Soc. 1999, 121, 9229. Hu, T.; Takenada; N.; Panek, J. S. J. Am. Chem. Soc. 2002, 124, 12806.

Synthesis of Oleandolide Hu, T.; Takenada; N.; Panek, J. S. J. Am. Chem. Soc. 1999, 121, 9229. Hu, T.; Takenada; N.; Panek, J. S. J. Am. Chem. Soc. 2002, 124, 12806.

Alternative Reaction Pathways If allowed to warm.. 1,2 silyl migration competes with elimination Panek, J. S.; Yang, M. J. Am. Chem. Soc. 1991, 113, 9868.

Same concepts apply…. Masse, C. E.; Panek. J. S. Chem. Rev. 1995, 95, 1293, Fleming, I.; Barbero, A.; Walter, D. Chem. Rev. 1997, 97, 2063. Huang, H.; Panek, J. S. J. Am. Chem. Soc. 2000, 122, 9836

Outline Introduction to allylation chemistry, Stereocontrol features for allylsilanes Introduce SE2’ reactivity/stereospecificity Hyperconjugation, Open Transition States James S. Panek Background/ Concept Aldehyde Crotylation Synthesis of chiral allyl silanes Use in complex molecule synthesis James L. Leighton Allylation/Crotylation Imine electrophiles

James L. Leighton b. 1964 1987 BSc Chemistry (Yale) 1994 PhD Chemistry (Harvard) with David Evans 1994-96 Post Doc (Harvard) with Eric Jacobsen 1996 Columbia University Cyclic transition state

Concept B reagents - Type I cyclic TS Si Reagents - Type II open TS Make Si more Lewis-acidic to encourage a cyclic transition state

“Strain-Release Lewis Acidity” Myers and Denmark Utimoto

Strained Silacycles: New reagents for allylation Supports idea that ring strain is important Ring strain still exists due to long Si-O and short C-O bonds Proceeds via cyclic TS Kinnaird, J. W. A.; Ng, P. Y.; Kubota, K.; Wang, X.; Leighton, J. L, J. Am. Chem. Soc. 2002, 124, 7920. Zhang, X.; Houk, K. N.; Leighton, J. L, Angew. Chem. Int. Ed. 2005, 44, 938.

Synthesis of Chiral Allyl Silanes Screen chiral 1,2-diols, amino-alcohols and diamines Easily prepared Stable to storage Convenient work-up Mixture of diastereoisomers Interconvert? React in same way? Kinnaird, J. W. A.; Ng, P. Y.; Kubota, K.; Wang, X.; Leighton, J. L, J. Am. Chem. Soc. 2002, 124, 7920.

Scope - optimised conditions Table 1 Kinnaird, J. W. A.; Ng, P. Y.; Kubota, K.; Wang, X.; Leighton, J. L, J. Am. Chem. Soc. 2002, 124, 7920.

Diamine ligand Best ee Br confers crystallinity Stable solid (moderate air sensitivity) Straightforward synthesis Single crystallisation to purify Kubota, K.; Leighton, J. L, Angew. Chem. Int. Ed. 2003, 42, 946. Zhang, X.; Houk, K. N.; Leighton, J. L, Angew. Chem. Int. Ed. 2005, 44, 938

Scope Aliphatic Substrates Aromatic Substrates Excellent ee“among highest observed for this reaction” CH2Cl2 best solvent for allylation. Much longer reaction time 20h vs 2h Kubota, K.; Leighton, J. L, Angew. Chem. Int. Ed. 2003, 42, 946

Scope - Chiral substrate Overrides 1,3 induction of chiral aldehyde Kubota, K.; Leighton, J. L, Angew. Chem. Int. Ed. 2003, 42, 946

Crotylation - Cis reagent Syn:Anti dr >15:1 Hackman, B. M.; Lombardi, P. J.; Leighton, J. L, Org. Lett. 2004, 6, 4375

Crotylation - Trans reagent Anti:Syn dr >25:1 Reagents are crystalline solids but moisture sensitive - storable eg in glove box High MW diamine. - 90% recoverable Hackman, B. M.; Lombardi, P. J.; Leighton, J. L, Org. Lett. 2004, 6, 4375

Imine electrophiles - Aldimine allylation Requires NHAc directing group Single recrystallisation allows access to enantiopure compounds Berger, R.; Rabbat, P.M.; Leighton, J. L, J. Am. Chem. Soc. 2003, 125, 9596.

Imine electrophiles - Ketimine allylation Berger, R.; Duff, K.; Leighton, J. L, J. Am. Chem. Soc. 2004, 126, 5686.

Imine electrophiles - Aldimine crotylation Trans reagent Syn product 89%, 95:5, 97%22 Berger, R.; Rabbat, P.M.; Leighton, J. L, J. Am. Chem. Soc. 2003, 125, 9596. Berger, R.; Duff, K.; Leighton, J. L, J. Am. Chem. Soc. 2004, 126, 5686.

Imine electrophiles - directing groups Rabbat, P. M.; Valdez, S. C.; Leighton, J. L, Org. Lett. 2006, 8, 6119. Perl, N. R.; Leighton, J. L, Org. Lett. 2007, 9, 3699.

Imine electrophiles - Cinnamylation Huber, J. D..; Leighton, J. L, J. Am. Chem. Soc. 2007, 129, 14552.

Imine electrophiles - Cinnamylation Huber, J. D..; Leighton, J. L, J. Am. Chem. Soc. 2007, 129, 14552.

Summary Panek: Chiral allyl silanes for acyclic stereocontrol Leighton: Chiral allyl silanes allowing cyclic stereocontrol