Additions to carbonyl compounds Asymmetric Synthesis Additions to carbonyl compounds

Outline Addition of non-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’

Achiral Nu + prochiral C=O

Addition to Cram Karabatsos Cram & Elhafez, J Amer Chem Soc 1952, 74, 5828.

Addition to R S M L Nu d.e.% H Me Et Ph MeMgI EtMgBr PhMgBr EtMgI PhMgI 33 43 50 >60 66 75 83 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 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.

Felkin-Anh Model

Nucleophile Approach Anh, Bürgi-Dunitz

Chelation Control J Amer Chem Soc 1990, 112, 6130.

Examples R S L Y: Nu(solvent) d.e.% Ph Me H C7H15 OH OMe OMEM MeLi(Et2O) Me2Mg(Et2O) MeMgBr(Et2O) MeMgBr(THF MeMgBr(THF) Ph2Mg(Et2O) Ph2Mg(THF) C4H9MgBr(THF) PhLi(Et2O) 84 66 50 80 34 74 86 100 46

Chiral auxiliaries Attached to the carbonyl compound Attached to the nucleophile Chiral 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 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 stereoisomer

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 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 diastereoselectivity and enantioselectivity Reagent enantioselectivity overrides intrinsic chiral aldehyde facial selectivity Consistent and predictable Also with -chiral aldehydes Diamine-based ligands

Allylsilanes and Allylstannanes Promoted by Lewis acids High diastereoselectivity ‘Cram controlled’ “Chelation 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 addition 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 90 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 Cram’s rule Felkin-Anh model Chelation control Chiral auxiliaries Chiral acetals Chiral reagents Chiral catalysts ‘Chiral amplification’

Questions ?