J. Am. Chem. Soc. 2007
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Chiral Allylsilanes as Enantioselective Allylation Reagents for Aldehydes Focusing on work by James S. Panek James L. Leighton R SiR3 R R and R L *L Si L* R James Bull Groupe Charette, Réunion de littérature, 4 Décembre 2007 Outline I. II. Introduction to allylation chemistry Stereocontrol features for allylsilanes Introduce SE2’ reactivity/stereospecificity Hyperconjugation, Open Transition States James S. Panek 1. Background/ Concept 2. Aldehyde Crotylation 3. Synthesis of chiral allyl silanes 4. Use in complex molecule synthesis III. James L. Leighton 1. Background/ Concept 2. Synthesis of chiral allyl silanes 3. Allylation/Crotylation 4. Imine electrophiles SiR3 R R R R L *L Si L* R The importance of allylation/crotylation chemistry O R R1 M control of chirality R2 O OH SE2' R R1 R2 O OH O R H R1 R2 Common (Excellent) Enantioselective Methods Roush Brown R1 B iPrCO2 R1 O B R2 iPrCO2 R2 R R1 L* B L* O R2 O Well defined cyclic TS’s (Type I class) OH L*2B Me R Me OH Me L*2B R Me Excellent enantio/diastereocontrol Unstable to storage Prepared in situ Used at low temperature Common (Excellent) Enantioselective Methods Keck Ti(OiPr)4 4 A MS, CH2Cl2 rt, 1h O SnBu3 R1 R OH R1 R OH OH 2 eq Lewis Base catalysed enantioselective allylation R2 R1 Ti(OiPr)4 4 A MS, CH2Cl2 O SiCl3 OH R R 5 mol % H H N O P N N Denmark, S. E.; Fu, J. Chem. Rev. 2003, 103, 2763 O 5 N R2 R1 N P N H H Allylsilanes E+ Lewis Acid E SiR3 R R1 R R R1 R SE2’ anti Stereospecific Stereocontrol?? • New Chiral Centre • Double bond geometry • When E+ = aldehyde, diastereoselectivity OH R R3 R R1 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 A N B C Inversion Stereospecific X SE2’ reactivity SN2 SN1 A N B C Inversion Stereospecific N A X Non stereospecific May be stereoselective B C* SE2’ reactivity SN2 SN1 A N B C B C* Non stereospecific May be stereoselective LG Nu A X Inversion Stereospecific SN2’ N Direct SN2 usually faster Stereospecifically Syn (depending on nucleophile) Stork: OCOAr HN OCOAr N Stork, G.; White. W. N. J. Am. Chem. Soc. 1956, 78, 4609. N SE2’ reactivity SN2 A SE2 A B C A E+ M B C M N B C stereodefined C-M bonds X A Inversion Stereospecific M E B Inversion C Retention E Grignards: non stereospecific Li, inversion or retention depending on electrophile O MeO Ph OMe MeO MeO Ph H H N tBuO O Ph BuLi sparteine tBuO tBuO H Li N CO2Me Retention O MeO O Ph CHO N tBuO Park, Y. S.; Beak. P. J. Org. Chem. 1997, 62, 1574. H N Br CHO H O Inversion SE2’ reactivity SN2 A SE2 B C E A N X Inversion Stereospecific SN2’ B Inversion C M Retention LG Nu Stereospecifically SYN Direct SN2 usually faster SE2’ E+ M M = Si, B, Mg, Sn, Ti, Cr, Zn, …. For M = Si Stereospecifically ANTI Stereocontrol for allylsilanes R2 R1 R3Si R H H R3Si ANTI R E+ R2 R1 R R3Si H < R E E H trans If there is no clearly prefered ground state conformation stereoselectivity will be reduced But reaction still occurs stereospecifically anti Hyperconjugation: s-conjugation H R2 R1 R2 R1 CH3 poor energy match poor geometry << R M > R Parallel bonds for max interaction closer in energy SiR3 Hg Hg > R Stereocontrol for allyl silanes R3Si R H H R R2 R1 ANTI R3Si R E+ R2 R1 R2 R1 H R E E H trans R2 R1 R3Si LA O H R3 SiR3 R2 R1 R OH Lewis Acid R R3 Open Transition State (Type II class) R2R1 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 SYN product preferred ANTI diastereoselective Open TS for crotylsilane reagents Synclinal Transition States E-silane Z-silane SYN diastereoselective ANTI diastereoselective Both antiperiplanar and synclinal TS predict syn selectivity Outline I. II. Introduction to allylation chemistry, Stereocontrol features for allylsilanes Introduce SE2’ reactivity/stereospecificity Hyperconjugation, Open Transition States James S. Panek 1. Background/ Concept 2. Aldehyde Crotylation 3. Synthesis of chiral allyl silanes 4. Use in complex molecule synthesis III. James L. Leighton 1. Background/ Concept 2. Synthesis of chiral allyl silanes 3. Allylation/Crotylation 4. Imine electrophiles SiR3 R R R R L *L Si L* R 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 R R X CO2Me SiMe2Ph 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 OMe Ar OMe OMe Me CO2Me OMe O Me CO2Me SiMe2Ph OMe Major TMSOTf –78 ºC, CH2Cl2 90%, 13:1, 95% ee OMe OMe Minor CO2Me Complete chirality transfer from silane, no other diastereoisomers observed Anti SE2’ E double bond Syn Selective OMe OMe OMe OMe Panek, J. S.; Yang. M. J. Am. Chem. Soc. 1991, 113, 6594. 92%, 40:1, 95% ee Crotylation using Syn-selectivity OMe BnO OMe Me OMe Me TMSOTf CO2Me SiMe2Ph Me BnO CO2Me –78 ºC, CH2Cl2 16 h 88%, 30:1, 96% ee OMe BnO OMe CO2Me OMe OMe BnO CO2Me 96%, 20:1, 96% ee OMe CO2Me O 86%, 30:1, 96% ee Panek, J. S.; Yang. M. J. Org Chem. 1991, 56, 5755. 70%, 30:1, 96% ee Crotylation using Syn-selectivity TMSOBn TMSOTf OAc O Me BnO CO2Me SiMe2Ph OBn BnO CO2Me –78 ºC to –35 ºC CH2Cl2 51%, 20:1 Form oxonium in situ OMe OAc OAc OAc OBn CO2Me CO2Me O 85%, 20:1 87%, 20:1 Pd catalysed allylic transposition to form 1,3-diols OBn BnO PdCl2 (20 mol%) CH2Cl2, rt OAc CO2Me OBn OAc BnO CO2Me 36 h 86% complete preservation of chirality 1,3-syn diol OMe BnO Me OMe OAc CO2Me SiMe2Ph TMSOTf –78 ºC to –70 ºC CH2Cl2 OMe OAc BnO CO2Me 54%, 20:1 Panek, J. S.; Yang. M.; Solomon J. S. J. Org. Chem. 1993, 58, 1003. PdCl2 (20 mol%) CH2Cl2, rt OMe OAc BnO CO2Me 36 h 96% Acyclic Diastereoselectivity - Reversing Syn Selectivity Me Me CO2Me SiMe2Ph O BF3.OEt2, –78 ºC BnO OH BnO CO2Me Re face attack 6.5:1 syn:anti Me Me CO2Me SiMe2Ph O BnO MgBr2.OEt2, –25 ºC OH BnO CO2Me Si face attack 1: 12.2 syn:anti Panek, J. S.; Cirillo, P. F. J. Org. Chem. 1993, 58, 999. Chiral Aldehydes - Double stereodifferentiation Syn:Anti R O Me BnO O R Me BnO O CO2Me SiMe2Ph R Me TBDPSO O TBDPSO CO2Me SiMe2Ph CO2Me SiMe2Ph R Me CO2Me SiMe2Ph TiCl4 (1.1 eq) CH2Cl2, –78 ºC TiCl4 (1.1 eq) CH2Cl2, –78 ºC OH R CO2Me OH R CO2Me BnO BnO TBDPSO R = Me, 85%, 1:30 R = Et, 69%, 1:10 OH R CO2Me R = Me,98 %, 1:8 R = Et, 79%, 1:10 OH R CO2Me R = H, 90%, >30:1 R = Me, 79%, >30:1 R = Et, 74%, 15:1 TiCl4 (1.1 eq) CH2Cl2, –78 ºC TBDPSO TiCl4 (1.1 eq) CH2Cl2, –78 ºC R = Me, 64%, 10:1 R = Et, 35%, 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 O Me TBDPSO O TBDPSO OH R CO2Me SiMe2Ph CO2Me SiMe2Ph TiCl4 (1.1 eq) CH2Cl2, –78 ºC TBDPSO Jain, N. F.; Takenaka, N.; Panek, J. S. J. Am. Chem. Soc. 1996, 118, 12475. R CO2Me BnO OH R Me TiCl4 (1.1 eq) CH2Cl2, –78 ºC R CO2Me Chiral Aldehydes - 1,3-induction? R Me CO2Me SiMe2Ph R Me CO2Me SiMe2Ph R Me CO2Me SiMe2Ph R Me CO2Me SiMe2Ph TiCl4 (1.1 eq) CH2Cl2, –78 ºC TiCl4 (1.1 eq) CH2Cl2, –78 ºC TiCl4 (1.1 eq) CH2Cl2, –78 ºC TiCl4 (1.1 eq) CH2Cl2, –78 ºC 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 H SiPhMe2 Lipase (0.5 eq) OH vinyl acetate HO tBu3P Pt SiPhMe2 O (MeO)3CCH3 cat. propionic acid toluene reflux OAc 86% Si SiPhMe2 O 46% SiPhMe2 OH Si OH SiPhMe2 HSiPhMe2 (1.1 eq) THF, 50 ºC Me 48% CO2Me SiMe2Ph JohnsonClaisen 86% 96% ee OMe 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 HO SiPhMe2 R O R Me DCC DMAP OH SiPhMe2 1. LDA, TMSCl Me –78 ºC to rt O R 2. SOCl2/MeOH CO2Me SiMe2Ph syn:anti R = Me 1:12 81% R = OH >25:1 65% R = OMe 23:1 81% O LDA, HMPS, TMSCl Enolate R = Me 16:1 69% R Me CO2Me SiMe2Ph LDA electrophile Me CO2Me SiMe2Ph Anti:syn MeI 100:1 BnBr 75:1 . . 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 PhMe2Si OH D-(–)-DET Ti(OiPr)4,MS CH2Cl2, –20 ºC OH OTMS SiMe2Ph 91%, 97% ee O PhMe2Si OH 1. Citric acid MeOH OH 2. Ac2O, pyr DMAP, CH2Cl2 71% SiMe2Ph Huang, H.; Panek, J. S. Org. Lett. 2003, 5, 1991. OAc 1. TMSCl, Et3N DMAP, CH2Cl2, –20 ºC 2. MgBr CuI, THF –50 ºC 85% Synthesis of Oleandolide - Retrosynthesis OP PO OP 1 OP 7 H [M] OP OP 8 13 O R Me CO2Me SiMe2Ph R-2 Me CO2Me SiMe2Ph S-3, R = H S-4, R = Me 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. Me Synthesis of Oleandolide Me O TBDPSO H CO2Me OH CO2Me SiMe2Ph R-2 TBDPSO TiCl4, CH2Cl2 –78 ºC to –35 ºC 90%, >30:1 Syn:Anti Felkin approach tBu 1. 2% HCl/MeOH, 92% 2. tBuSi(OTf)2, 2,4-lutidine 3. O3, Me2S, MeOH/pyr (90%, 2 steps) tBu tBu Si O O Si Me H O S-3 CO2Me SiMe2Ph TiCl4, CH2Cl2 –78 ºC to –35 ºC 1. HF.py 2. TBDPSCl, 92% (2 steps) 3. Me2C(OMe)2, PPTS, 99% TBDPSO O O tBu CO2Me O O OH CO2Me 87%, >30:1 Anti:Syn Felkin approach 1. O3, Me2S, MeOH/pyr 2. NaBH4, MeOH,90% (2 steps) 3. I2, PPh3, Imid, 98% TBDPSO 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. O O I Synthesis of Oleandolide Me O TBSO R-2 H CO2Me SiMe2Ph OH CO2Me HO BF3.Et2O, CH2Cl2 –78 ºC to 0 ºC 82%, >20:1 Syn:Anti Me 1. TBSOTf, 2,6-lutidine 2. O3,Me2S (93% 2 steps) TBSO Me OTBS O S-3 CO2Me TBSO SiMe2Ph TBSO OH CO2Me TiCl4, CH2Cl2 –50 ºC 82%, >30:1 Anti:Syn O3, Me2S 90% TBSO TBSO OH O 1. Me4NBH(OAc)3 MeCN, AcOH, –20 ºC, 89% 2. PhCH(OMe)2, CSA, 89% 3. HF.py, py, 96% 4. Dess Martin 95% 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. Ph TBSO O O O Synthesis of Oleandolide Ph O O TBSO TBDPSO O O I O tBuLi Ph O O TBSO O O TBDPSO O 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 Me O Me BnO CO2Me SiMe2Ph BF3.OEt2, –78 ºC OH BnO CO2Me 6.5:1 syn:anti If allowed to warm.. BnO SiMe2Ph Me O Me CO2Me SiMe2Ph BF3.OEt2, –78 ºC to –30 ºC BnO O H CO2Me H 80%, 30:1 syn:anti, 96%de F3B Me O BnO Me CO2Me SiMe2Ph 1,2 silyl migration competes with elimination Panek, J. S.; Yang, M. J. Am. Chem. Soc. 1991, 113, 9868. F3B O SiR3 Me BnO CO2Me Me Same concepts apply…. O R LA OH H R CO2Me Me R'O2C N R R R LA R H NHCO2R' H Z Me R SiMe2Ph X CO2Me H CO2Me Me CO2Me SiMe2Ph O MeO2C H CHO R3Si Me E+ E CO2Me Me O R Me H MeO2C H O R H 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 I. II. Introduction to allylation chemistry, Stereocontrol features for allylsilanes Introduce SE2’ reactivity/stereospecificity Hyperconjugation, Open Transition States James S. Panek 1. Background/ Concept 2. Aldehyde Crotylation 3. Synthesis of chiral allyl silanes 4. Use in complex molecule synthesis III. James L. Leighton 1. Background/ Concept 2. Synthesis of chiral allyl silanes 3. Allylation/Crotylation 4. Imine electrophiles SiR3 R R R R L *L Si L* R 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 R L *L Si L* R Cyclic transition state Concept B reagents - Type I cyclic TS R2 R R1 Si Reagents - Type II open TS L* B L* O Make Si more Lewis-acidic to encourage a cyclic transition state R2 R R1 L* Si L* O “Strain-Release Lewis Acidity” Myers and Denmark Utimoto Strained Silacycles: New reagents for allylation O Si O Cl Tol O Ph H rt OH Ph 52% Uncatalysed O Si O Cl O Si O Cl Tol O Ph H Tol O Ph N. R. rt H rt N. R. 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 Ph O Si N Cl Me Ph OH NH Me DBU, CH2Cl2 SiCl3 Easily prepared Stable to storage Convenient work-up Ph O Si N Cl Me 88% 2:1 dr 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 Ph O Si N Cl Me (s,s) Toluene –10 ºC, 2h O R H OH R 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 Br N Si N Cl Best ee Br confers crystallinity Stable solid (moderate air sensitivity) Straightforward synthesis Single crystallisation to purify Br 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 pBrPh CH2Cl2 –10 ºC, 20h O N Si N Cl pBrPh R H OH R (R,R) 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 Chiral substrate: OBn OH (R,R) OBn O Ph 86%, 95:5 dr Ph CH2Cl2 –10 ºC, 20h OBn OH (S,S) 86%, 98:2 dr Ph pBrPh N Si N Cl (R,R) pBrPh Overrides 1,3 induction of chiral aldehyde Kubota, K.; Leighton, J. L, Angew. Chem. Int. Ed. 2003, 42, 946 Crotylation - Cis reagent pBrPh CH2Cl2 0 ºC, 20h O N Si N Cl pBrPh 1.1 equiv R OH H R (R,R) Syn:Anti dr >15:1 Hackman, B. M.; Lombardi, P. J.; Leighton, J. L, Org. Lett. 2004, 6, 4375 Crotylation - Trans reagent pBrPh CH2Cl2 0 ºC, 20h O N Si N Cl pBrPh R H OH R (R,R) 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 O Ph O O NH N CH2Cl2 10 ºC, 16h Si N Cl R H (s,s) Me Requires NHAc directing group 1.5 eq NH HN R 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 O Ph O Si N Cl Me (s,s) Ph NH N R1 CHCl3 40 ºC, 24h R2 Berger, R.; Duff, K.; Leighton, J. L, J. Am. Chem. Soc. 2004, 126, 5686. R2 NHNHBz R1 Imine electrophiles - Aldimine crotylation O Ph O Si N Cl Me (s,s) Trans reagent NH N R O Ph H Ph NH CH2Cl2 10 ºC, 16h HN R Me 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 HO Ph R1 O HO R R R1 R2 HO HN HN 85% 92%ee 83% 96%ee O N H N Si N Cl Me HN 80% 87%ee HN H HO HN N CH2Cl2 rt, 16h N R2 Si Cl N Me (s,s) H N HO 64% 98:2 dr 98%ee R1 Toluene 23 ºC HN H R N R N N H N N R1 N O 71% 88%ee H Me N HN N 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. 86% 91%ee Imine electrophiles - Cinnamylation HO HO Ar Ar N N Ph HN R R Ph H DCE, reflux HN O Si N Cl Me Ph Huber, J. D..; Leighton, J. L, J. Am. Chem. Soc. 2007, 129, 14552. R H DCE, reflux R Ph Imine electrophiles - Cinnamylation HO HO Ar Ar N N Ph HN R R Ph H DCE, reflux HN O Si N Cl Me Ph Huber, J. D..; Leighton, J. L, J. Am. Chem. Soc. 2007, 129, 14552. R H DCE, reflux R Ph Summary Panek: Chiral allyl silanes for acyclic stereocontrol O R Me BnO TiCl4 (1.1 eq) CH2Cl2, –78 ºC CO2Me SiMe2Ph OH R BnO 85%, dr 1:30 Leighton: Chiral allyl silanes allowing cyclic stereocontrol pBrPh Si N Cl (R,R) CH2Cl2 –10 ºC, 20h O N pBrPh TBSO H OH TBSO 61%, 98% ee CO2Me
