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Chiral Allylsilanes as Enantioselective Allylation Reagents for Aldehydes Focusing on work by James Bull Groupe Charette, Réunion de littérature, 4 Décembre.

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Presentation on theme: "Chiral Allylsilanes as Enantioselective Allylation Reagents for Aldehydes Focusing on work by James Bull Groupe Charette, Réunion de littérature, 4 Décembre."— Presentation transcript:

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

2 Outline I.Introduction to allylation chemistry Stereocontrol features for allylsilanes Introduce S E 2’ reactivity/stereospecificity Hyperconjugation, Open Transition States II.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

3 The importance of allylation/crotylation chemistry

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

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

6 Allylsilanes S E 2’ anti Stereospecific Stereocontrol?? New Chiral Centre Double bond geometry When E + = aldehyde, diastereoselectivity

7 What is S E 2’ reactivity?? Stereospecific ≠ 100% stereoselective Defined by mechanism Determined by Structure/steric effects Conformation effects What is a stereospecific reaction??

8 S E 2’ reactivity SN2SN2 Inversion Stereospecific

9 S E 2’ reactivity SN2SN2 Inversion Stereospecific SN1SN1 Non stereospecific May be stereoselective

10 S E 2’ reactivity SN2SN2 Inversion Stereospecific SN1SN1 Non stereospecific May be stereoselective S N 2’ Direct S N 2 usually faster Stereospecifically Syn (depending on nucleophile) Stork: Stork, G.; White. W. N. J. Am. Chem. Soc. 1956, 78, 4609.

11 S E 2’ reactivity SN2SN2 Inversion Stereospecific Grignards: non stereospecific Li, inversion or retention depending on electrophile stereodefined C-M bonds SE2SE2 Park, Y. S.; Beak. P. J. Org. Chem. 1997, 62, 1574.

12 S E 2’ reactivity SN2SN2 Inversion Stereospecific S N 2’ Stereospecifically SYN Direct S N 2 usually faster SE2SE2 S E 2’ For M = Si Stereospecifically ANTI M = Si, B, Mg, Sn, Ti, Cr, Zn, ….

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

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

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

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

17 Outline I.Introduction to allylation chemistry, Stereocontrol features for allylsilanes Introduce S E 2’ reactivity/stereospecificity Hyperconjugation, Open Transition States II.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

18 James S. Panek b BSc Chemistry (SUNY Buffalo) 1984 PhD Medicinal Chemistry (Kansas) with Dale Boger Post Doc (Yale) with Danishefsky 1986 Boston University Chiral E-crotylsilane: Well behaved S E 2’ Anti addition Complete transfer of chirality Provides easily functionalised products Able to control reaction pathway by control of temperature and Lewis acid

19 Crotylation using syn-selectivity Panek, J. S.; Yang. M. J. Am. Chem. Soc. 1991, 113, Complete chirality transfer from silane, no other diastereoisomers observed Anti S E 2’ E double bond Syn Selective

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

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

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

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

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

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

26 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

27 Synthesis of chiral silanes Enolate Ireland-Claisen Sparks, M. A.; Panek, J. S. Org. Chem. 1991, 56, 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,

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

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

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

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

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

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

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

35 Outline I.Introduction to allylation chemistry, Stereocontrol features for allylsilanes Introduce S E 2’ reactivity/stereospecificity Hyperconjugation, Open Transition States II.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

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

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

38 “Strain-Release Lewis Acidity” Myers and Denmark Utimoto

39 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, Zhang, X.; Houk, K. N.; Leighton, J. L, Angew. Chem. Int. Ed. 2005, 44, 938.

40 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.

41 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.

42 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

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

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

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

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

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

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

49 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, Berger, R.; Duff, K.; Leighton, J. L, J. Am. Chem. Soc. 2004, 126, 5686.

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

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

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

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


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