Asymmetric Synthesis.ppt

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1、Asymmetric Synthesis,Additions to carbonyl compounds,Outline,Addition of non-chiral nucleophiles to chiral aldehydes or ketones Crams rule Felkin-Anh model Chelation control Chiral auxiliaries Chiral acetals Chiral reagents Chiral catalysts Chiral amplification,Achiral Nu + prochiral C=O,Addition to

2、,Cram & Elhafez, J Amer Chem Soc 1952, 74, 5828.,Cram,Karabatsos,Addition to,Cram & Elhafez, J Amer Chem Soc 1952, 74, 5828.,Faulty Assumptions,Ground state and reactive conformation are wrong. Ground state and reactive conformation (TS) cannot be assumed to be the same. The directing influence of s

3、ubstituents 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.,Felkin-Anh Model,Nucleophile Approach,Anh, Brgi-Dunitz,Chelation Control,J Amer Chem Soc 1990, 112, 6130.,Examples,Chiral

4、 auxiliaries,Attached to the carbonyl compound Attached to the nucleophileChiral acetals and a-ketoaldehydes Sulfoxides Organometallics Allylboranes, -silanes, -stannanes,Auxiliary attached to carbonyl,Tetrah Lett 1991, 32, 2919,1,3-Oxathianes,Transition state model,Auxiliary attached to nucleophile

5、,J C S Perkin I 1981, 1278,Organometallic: Chiral ligand,Tetrah Lett 1986, 27, 5711,Allylic nucleophiles,Alternative route 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 stereoi

6、somer,Chiral boron reagents,Examples (1),R anti:syn e.e. % n-C9H19 99:1 88 TBSOCH2CH2 97:3 85 tBu 95:5 73 n-C7H15CH=CH 99:1 74,Examples (2),R anti:syn e.e. % n-C9H19 3:97 86 TBSOCH2CH2 3:97 72 tBu 1:99 70 n-C7H15CH=CH 3:97 62,Examples (3),R e.e. % n-C4H9 95 Ph 90 tBu 98 C6H11 99,Chen, Eur J Org Chem

7、 2005, 1665-1668,Transition state,Selectivity: E anti,Double asymmetric synthesis,Iterative Asymmetric Synthesis,J Amer Chem Soc 1990, 112, 6348,Diisopinocampheylborane,Addition to aldehydes,R e.e. % Yield % Me 93 74 Et 86 71 iPr 90 86 nBu 87 72 tBu 83 88 Ph 96 81,Other allylic boranes,High diastere

8、oselectivity and enantioselectivity Reagent enantioselectivity overrides intrinsic chiral aldehyde facial selectivity Consistent and predictable Also with -chiral aldehydesDiamine-based ligands,Allylsilanes and Allylstannanes,Promoted by Lewis acids High diastereoselectivity Cram controlled “Chelati

9、on controlled,Chiral Catalysts,Organozinc catalysts Chiral amplification,Chiral ligand as catalyst,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.,Dialkylzinc additio

10、n to aldehydes,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,J Amer Chem Soc 1986, 108, 6071,Transition state model,Aminothiocyanate derivatives,R Yield, % e.e., % Ph 98 96 p-Cl-Ph 97 95 o-MeO-Ph 96 9

11、0 p-MeO-Ph 95 91 2-Naphthyl 95 93 C6H13 82 75,Tetrahedron Letters 2005, 46(15), 2695-2696,Transition state?,Tetrahedron Letters 2005, 46, 2695-2696,Chiral amplification,High catalyst optical purity is not needed!,J Amer Chem Soc 1989, 111, 4028,Why amplification?,(50%),(50%),Summary,Addition of non-chiral nucleophiles to chiral aldehydes or ketones Crams rule Felkin-Anh model Chelation control Chiral auxiliaries Chiral acetals Chiral reagents Chiral catalysts Chiral amplification,Questions ?,