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Additions to carbonyl compounds
Asymmetric Synthesis Additions to carbonyl compounds
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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’
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Achiral Nu + prochiral C=O
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Addition to Cram Karabatsos
Cram & Elhafez, J Amer Chem Soc 1952, 74, 5828.
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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.
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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.
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Felkin-Anh Model
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Nucleophile Approach Anh, Bürgi-Dunitz
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Chelation Control J Amer Chem Soc 1990, 112, 6130.
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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
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Chiral auxiliaries Attached to the carbonyl compound
Attached to the nucleophile Chiral acetals and a-ketoaldehydes Sulfoxides Organometallics Allylboranes, -silanes, -stannanes
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Auxiliary attached to carbonyl
Tetrah Lett 1991, 32, 2919
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1,3-Oxathianes
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Transition state model
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Auxiliary attached to nucleophile
J C S Perkin I 1981, 1278
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Organometallic: Chiral ligand
Tetrah Lett 1986, 27, 5711
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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
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Chiral boron reagents
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Examples (1) R anti:syn e.e. % n-C9H19 > 99:1 88
TBSOCH2CH2 > 97:3 85 tBu :5 73 n-C7H15CH=CH > 99:1 74
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Examples (2) R anti:syn e.e. % n-C9H19 3:97 86 TBSOCH2CH2 > 3:97 72
tBu > 1: n-C7H15CH=CH 3:
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Examples (3) R e.e. % n-C4H9 95 Ph 90 tBu 98 C6H11 99
Chen, Eur J Org Chem 2005,
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Transition state
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Selectivity: E → anti
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Double asymmetric synthesis
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Iterative Asymmetric Synthesis
J Amer Chem Soc 1990, 112, 6348
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Diisopinocampheylborane
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Addition to aldehydes R e.e. % Yield % Me 93 74 Et 86 71 iPr 90 86
nBu tBu Ph
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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
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Allylsilanes and Allylstannanes
Promoted by Lewis acids High diastereoselectivity ‘Cram controlled’ “Chelation controlled’
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Chiral Catalysts Organozinc catalysts Chiral amplification
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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.
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Dialkylzinc addition to aldehydes
R Nu e.e., % Ph Me Ph Et Ph Bu p-Cl-Ph Et p-MeO-Ph Et 2-Furyl C5H >95 (E)-C6H5-CH=CH Et (E)-Bu3SnCH=CH C5H PhCH2CH2 Et J Amer Chem Soc 1986, 108, 6071
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Transition state model
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Aminothiocyanate derivatives
R Yield, % e.e., % Ph p-Cl-Ph o-MeO-Ph p-MeO-Ph 2-Naphthyl C6H Tetrahedron Letters 2005, 46(15),
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Transition state? Tetrahedron Letters 2005, 46,
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Chiral amplification High catalyst optical purity is not needed!
J Amer Chem Soc 1989, 111, 4028
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Why amplification? (50%) (50%)
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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’
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Questions ?
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