Silyl homoenolates, synthesis

Heteroatom-stabilized Carbanions. Heteroatom-stabilized and allylic carbanions serve as homoenolate anions and acyl anion equivalents, e.g. a-anions of protected cyanohydrins of aldehydes and Q ,/3-unsaturated aldehydes are intermediates in general syntheses of ketones and Q ,/3-unsaturated ketones (eq 36). Allylic anions of cyanohydrin ethers may be a-alkylated (eq 37) or, if warmed to —25°C, may undergo 1,3-silyl migration to cyanoenolates which may be trapped with TMSCl. Metalated Q -aminonitriles of aldehydes are used for the synthesis of ketones and enamines (eq 38). Similarly, allylic anions from 2-morpholino-3-alkenenitriles undergo predominantly a-C-alkyl-ation to give, after hydrolysis, a,/3-unsaturated ketones (eq 39). ... 

We have developed a completely new synthesis of chiral aldols 12 by formal enantioselelective connection of a C-0 and a C-C bonding at the C3-position of a homoenolate dianion synthon 11 (Scheme 1). Because the natural polarity of the reactants is reversed twice the direct approach is not possible. Therefore we used the allyl amine 1 and enamine 2 as excellent synthesis equivalents of homoenolates, which can be silylated and alkylated, respectively (Scheme 2). 

These model studies provided the impetus to extend this methodology to the preparation of monofluoro ketomethylene peptide isosteres. Monofluoro ketomethylene peptide isosteres 15 (Figure 3) could be very interesting peptide mimetics since they are true peptide isosteres whose binding region can be extended in both the P and P directions by standard methods. Moreover the ketone carbonyl group is rendered more electrophilic by the fluoro substituent but yet is only partially hydrated ( 20-50%) upon treatment with water so that interaction with several different types of proteases is possible. The first synthesis of a monofluoro ketomethylene peptide isostere utilized a homoenolate equivalent to assemble the isostere skeleton and fluorination of a silyl enol ether to introduce the C-3 fluorine substituent.(20) Overall this route was long (>10 steps) and the introduction of fluorine was completely non-stereoselective. 

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