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Asymmetric Synthesis. α -Substitution using chiral enolates. Outline. Requirements for stereoselective enolate alkylation Imposing facial bias on alkylation Chiral auxiliaries leading to acids or alcohols Chiral auxiliaries leading to ketones.
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Asymmetric Synthesis α-Substitution using chiral enolates
Outline • Requirements for stereoselective enolate alkylation • Imposing facial bias on alkylation • Chiral auxiliaries leading to acids or alcohols • Chiral auxiliaries leading to ketones
Requirements for stereoselective enolate alkylation • Only one geometrical isomer must be formed • Base • Solvent • Temperature • Counter-ion • Chiral auxiliary
Stereoelectronic requirements for deprotonation and alkylation • Maximum overlap of orbitals during bond-breaking and formation • Preferred conformation during deprotonation • Electrophile approach is slightly away from perpendicular, towards the auxiliary
Enolate geometry Ireland:
LDA TS with HMPA Sun & Collum, J Amer Chem Soc2000, 122, 2452-2458
Other effects • % HMPA • Substituent (R) size • [BuLi] % hexane • [LiCl] or LiBr] • Other bases
Evans Oxazolidinone Evans & Gage, Organic Syntheses 1989, 68, 77 Chemical Reviews 1996, 96, 835-875
Application: Antibiotic X-206 Evans et al., J Amer Chem Soc 1988, 110, 2506
Other electrophiles • Hydroxylation • Bromination • Amination • Acylation
Enantioselective ketone synthesis • Acyl converted to imine • Stereochemistry controlled through chelation
Chiral hydrazines SAMP RAMP Enders, In Asymmetric Synthesis (Ed. Morrison), Vol. 3, pp. 275-339.
Rationalization • Reaction with acyclic and cyclic ketones and aldehydes • Methoxy group is important for high stereoselectivity • Therefore chelation, as in oxazolines • Removal by acid hydrolysis or ozonolysis
Application Leioburnum vittatum & L. calcar Enders & Baus, Liebigs Ann Chem1983, 1439
Antibiotic X-14547A Nicolaou et al.,J Amer Chem Soc1981, 103, 6967, 6969