Racemic and chiral nonracemic alpha-substituted and alpha-unsubstituted beta-fluoroalkyl beta-amino acid derivatives 6 and 9 have been synthesized in two steps starting from fluorinated imidoyl chlorides 1 and ester enolates. This approach is based on the chemical reduction of previously obtained gamma-fluorinated beta-enamino esters 4 by using ZnI(2)/NaBH(4) in a nonchelated aprotic medium (dry CH(2)Cl(2)) as the reducing agent. A metal-chelated six-membered model has been suggested to explain the stereochemical outcome of the reduction reaction. The process takes place with high yields and with moderate to good diastereoselectivity. The best results related to diastereoselective reduction of chiral beta-enamino esters 4 were provided by the use of (-)-8-phenylmenthol as a chiral auxiliary.

[reaction: see text]. Hydride reduction of C=N bonds stereocontrolled by intramolecular pi-stacking interactions of 1-naphthylsulfinyl and N-aryl groups, nonoxidative Pummerer rearrangement, and ring-closing metathesis are efficiently combined in a highly stereoselective entry to enantiomerically pure cyclic and acyclic fluorinated beta-amino alcohols and alpha-amino acid derivatives, respectively.

Reaction of fluorinated imidoyl chlorides 3 with ketimines 1a provides fluorinated 1,3-diimines, which were exclusively isolated as vinylogous amidine tautomers 2beta, with good yields. Fluorinated beta-enamino ketones 4 are obtained by regioselective hydrolysis of 2. Complementary methods for the synthesis of regioisomeric beta-enamino ketones 4 and 5 are also reported. These methods include the reaction of azaenolates of ketimines with fluorinated esters 6 and reactions of ketone enolates with fluorinated imidoyl chlorides 3. The behavior of these systems in hydrolysis reactions was also tested.

Reaction of fluorinated and nonfluorinated N-substituted imidoyl chlorides 1 with lithium derivatives of enantiopure methyl p-tolyl sulfoxide 2a (or racemic methyl phenyl sulfoxide 2b) gave a wide variety of chiral N-substituted beta-imino sulfoxides 4 in good to excellent yields. The title compounds (R)-4 were also prepared by aza-Wittig reaction of gamma-fluoro-beta-keto sulfoxides (R)-5 and N-aryl iminophosphoranes 6. The imino-enamino equilibrium was studied, showing, in all instances, the imino form as the predominant tautomer independent of the nature of the N-substituent. The configuration of the C=N double bond was found to be Z for both N-alkyl and N-aryl derivatives on the basis of (1)H NMR NOE difference experiments performed over several compounds. Ab initio calculations (HF/6-31G) carried out on several representative examples of 1 and 4 are, in general, consistent with the experimental results.

A new two-step approach for the diastereoselective synthesis of the syn α-methyl β-fluoroalkyl β-amino esters 4 has been developed. This approach is based on the chemical reduction of the fluorinated β-enamino esters 3, which have been previously obtained from imidoyl chlorides 1 and lithium ester enolates, with ZnI2/NaBH4 as the reducing agent. The process takes place with high syn diastereoselectivity and good to excellent yields. A metal-chelated six-membered model has been suggested to explain the stereochemical outcome of the reduction reaction.