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Asymmetric synthesis
The document outlines various strategies for asymmetric synthesis involving the addition of non-chiral nucleophiles to chiral carbonyl compounds such as aldehydes and ketones. Key concepts include Cram's rule, Felkin-Anh model, chelation control, and the use of chiral auxiliaries and catalysts. The document discusses the importance of electronic interactions, stereochemical outcomes, and methodologies for achieving high enantioselectivity in these reactions.
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Asymmetric synthesis
- 1. ASYMMETRIC SYNTHESIS Additions tocarbonyl compounds
- 2. OUTLINE • Addition ofnon-chiral nucleophiles to chiral aldehydes or ketones • Cram’s rule • Felkin-Anh model • Chelation control • Chiral auxiliaries • Chiral acetals • Chiral reagents • Chiral catalysts • ‘Chiral amplification’
- 3. ACHIRAL NU +PROCHIRAL C=O A R O B C Nu A R B OH C Nu A R B Nu C HO A B OH C R Z R1 R2 A B OH C R Z R2 R1 A B R C HO Z R1 R2 A B R C HO Z R2 R1 R1 R2 Z
- 4. ADDITION TO O R Nu L SM O R L S M O R S M L Nu Cram Karabatsos
- 5. ADDITION TO R SM L Nu d.e.% H H H H Me Me Me H H H H H H H Me Et Me Me Me Me Me Ph Ph Ph Ph Ph Ph Ph MeMgI MeMgI EtMgBr PhMgBr MeMgI EtMgI PhMgI 33 43 50 >60 66 75 83 O R L S M O R S M L Nu
- 6. FAULTY ASSUMPTIONS • Groundstate and reactive conformation are wrong. • Ground state and reactive conformation (TS) cannot be assumed to be the same. • The directing influence of substituents does not only derive from their steric effects. Electronic interactions are crucial. • The C=O group assumes pyramidal state early, therefore Cram model is unfavourable.
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- 10. EXAMPLES R S LY: Nu(solvent) d.e.% Ph Ph Ph Ph Ph Ph Ph Me Me Me H Me Me Me Me Me Me Me Me Me H Me Ph Ph Ph Ph Ph Ph Ph Ph Ph C7H15 H OH OH OH OH OMe OMe OMe OH OMe OMEM OH MeLi(Et2O) Me2Mg(Et2O) MeMgBr(Et2O) MeMgBr(THF MeLi(Et2O) MeMgBr(Et2O) MeMgBr(THF) Ph2Mg(Et2O) Ph2Mg(THF) C4H9MgBr(THF) PhLi(Et2O) 84 66 50 80 34 34 84 74 86 100 46 O R L Y S Nu M
- 11. CHIRAL AUXILIARIES • Attachedto the carbonyl compound • Attached to the nucleophile • Chiral acetals and a-ketoaldehydes • Sulfoxides • Organometallics • Allylboranes, -silanes, -stannanes
- 12. AUXILIARY ATTACHED TOCARBONYL MeO O PhN N H H R1 O PhN N H H R1 OH PhN N H H R1 MgBr R2 MgBr R 2 d.e. 60-98% Ph O PhN N H H Ph OH PhN N H H R RTi(iPrO)3 d.e. > 97% Ph R PhN N H H HO RLi d.e. ~ 60% R 1 CHO R2 OH
- 13. 1,3-OXATHIANES O O S 1. BnSH, NaOH 2.Na/NH3 3. (CH2O)n, TsOH 1. BuLi 2. EtCHO 3. DMSO, TFAA, Et3N O S Et O O S Et nPrMgBr HO nPr d.e. > 92% N-CSI, AgNO3 Et OHC nPr HO O S O + O S Me O O S Me HO d.e. > 92% MgCl2; CH2=CHMgBr O O OH Me (R)-mevalolactone
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- 15. AUXILIARY ATTACHED TONUCLEOPHILE S Tol O Pri Me O S Tol O Me S Tol O CF3 OH Ph MeMgBr 1. LDA 2. PhCOCF3 d.e. ~ 50% S Tol O STol S Tol O STol R OH H CHO R OMe H BuLi; RCHO R = Ph, e.e. 70% H O S O Li Tol H STol Ph
- 16. ORGANOMETALLIC: CHIRAL LIGAND PhOH Me NH SO2Tol N Ti O Me OiPr SO2Tol Ph Me Me OH NO2 e.e. 90% 1. TiMe4 2. iPrOH o-NO2C6H4CHO OH OH O O Ti OiPr OiPr Ph C10H7 OH Ti(OiPr)3Cl 1. PhMgBr 2. C10H7CHO e.e. > 98%
- 17. ALLYLIC NUCLEOPHILES • Alternativeroute to aldol-type products • Two new chiral centres introduced • Complication: reaction at C-1 • Achiral reactants: syn and anti racemates • Chiral reactants: in principle one major stereoisomer R 1 CHO R2 MLn + R 1 OH R 2 O3 Me2S R 1 OH CHO R 2
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- 19. EXAMPLES (1) R H O B O O R CO2IPr OH CO2iPr anti + Ranti:syn e.e. % n-C9H19 > 99:1 88 TBSOCH2CH2 > 97:3 85 tBu 95:5 73 n-C7H15CH=CH > 99:1 74
- 20. EXAMPLES (2) R H O B O O R CO2IPr OH CO2iPr + syn Ranti:syn e.e. % n-C9H19 3:97 86 TBSOCH2CH2 > 3:97 72 tBu > 1:99 70 n-C7H15CH=CH 3:97 62
- 21. EXAMPLES (3) R H O B O O R CONHBn OH CONHBn + Re.e. % n-C4H9 95 Ph 90 tBu 98 C6H11 99
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- 23. SELECTIVITY: E →ANTI B O O R CO2IPr OH CO2iPr anti O B O O CO2IPr CO2IPr H R RCHO
- 24. DOUBLE ASYMMETRIC SYNTHESIS B O O CO2IPr CO2iPrB O O CO2IPr CO2iPr (R,R) (S,S) OR RO CHO (R,R): matched pair: 92 : 8 (S,S): mismatched pair: 13 : 87 RO RO OH OH +
- 25. ITERATIVE ASYMMETRIC SYNTHESIS R1 CHO+ R2 MLn R 1 OH R2 R 1 OP R2 R 1 OP CHO R 2 + R3 MLn R 1 OP R 2 OH R 3 OSitBuPh2 CHO Me 24 OMe OMe OMe Me O Me OAc Me Me O Me Me 24 A B C D Order of bond formation: A, B, C, D Each with >90% stereoselectivity
- 26. DI ISO PINOCAMPHEYLBORANE Me Me Me Me Me Me B 2 (-)-a-Pinene Me Me Me H3B-SMe2 Me Me Me BH 2 MeOH Me Me Me BOMe 2 H2C=CHCH2MgBr Me Me Me B 2 (+)-a-Pinene (-)-Ipc2BH
- 27. ADDITION TO ALDEHYDES Ipc2B (-)- RCHO R OH Re.e. % Yield % Me 93 74 Et 86 71 iPr 90 86 nBu 87 72 tBu 83 88 Ph 96 81
- 28. OTHER ALLYLIC BORANES •High diastereoselectivity and enantioselectivity • Reagent enantioselectivity overrides intrinsic chiral aldehyde facial selectivity • Consistent and predictable • Also with a-chiral aldehydes • Diamine-based ligands
- 29. ALLYLSILANES AND ALLYLSTANNANES •Promoted by Lewis acids • High diastereoselectivity • ‘Cram controlled’ • “Chelation controlled’ CHIRAL CATALYSTS • Organozinc catalysts • Chiral amplification
- 30. CHIRAL LIGAND ASCATALYST • Organometallic reagent must be relatively unreactive towards C=O unless combined with the catalyst – ligand acceleration. • Catalyst must have suitable 3D structure to provide high e.e.
- 31. DIALKYLZINC ADDITION TOALDEHYDES R CHO + Nu2Zn + (-)-DAIB (~2 mol%) R Nu OH NMe2 Me Me Me OH (-)-3-exo-(dimethylamino)isoborneol (-)- DAIB R Nu e.e., % Ph Me 91 Ph Et 99 Ph Bu 98 p-Cl-Ph Et 93 p-MeO-Ph Et 93 2-Furyl C5H11 >95 (E)-C6H5-CH=CH Et 96 (E)-Bu3SnCH=CH C5H11 85 PhCH2CH2 Et 90
- 32. TRANSITION STATE MODEL N Me Me Me OZnA Me Me O Nu R ZnB Nu Nu H
- 33. AMINOTHIOCYANATE DERIVATIVES RCHO +Et2Zn R Et H OH L* (5 mol%) RT R2N SCN Me Ph L* (R) R Yield, % e.e., % Ph 98 96 p-Cl-Ph 97 95 o-MeO-Ph 96 90 p-MeO-Ph 95 91 2-Naphthyl 95 93 C6H13 82 75
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- 35. CHIRAL AMPLIFICATION • Highcatalyst optical purity is not needed!
- 36. WHY AMPLIFICATION? (-)-DAIB +(+)-DAIB (75%) (25%) (-)-DAIB/(-)-DAIB) (+)-DAIB/(+)-DAIB (-)-DAIB/(+)-DAIB dimer dimer meso-dimer Et2Zn + (50%) (50%)