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[reaction: see text] An asymmetric synthesis of (S)-gamma-fluoroleucine ethyl ester 1 is described. The key transformation involves a lipase-catalyzed dynamic ring-opening of 2-(3-butenyl)azlactone 7b with EtOH to give amide ester (S)-6b in 84% enantiomeric excess. Removal of the N-pentenoyl group with N,N'-dibromodimethylhydantoin in the presence of trifluoroacetic acid afforded the titled compound, which was isolated as its hydrogen sulfate salt in 75% yield and >97% ee.

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The asymmetric alkynylation reaction catalyzed by amino alcohol derived ligands (1R,2S)-3 or (1S,2R)-4 with dimethylzinc provides a simple and practical method to make chiral propargylic alcohols, and it is complementary to the asymmetric reduction methods. In the presence of 10 mol% (1R,2S)-3 or (1S,2R)-4, a variety of aromatic aldehydes were converted to the corresponding chiral propargylic alcohols with very good enantioselectivities and yields. This one-pot asymmetric reaction is carried out under mild reaction conditions. Neither strong base nor transmetallation is required. It is an efficient reaction, greatly accelerated by the added chiral ligand. Preliminary mechanistic and NMR studies have also been carried out. Chiral propargylic alcohols are useful building blocks for the enantioselective synthesis of complex molecules. 1 A powerful approach to these compounds involves the asymmetric reduction of a,b-ynones (approach A, Scheme 1) via either the catalytic asymmetric hydroboration 2 or transition metal catalyzed transfer hydrogenation. 3 While excellent yields and enantioselectivities are obtained for the alkyl substituted propargylic alcohols (R 1 = alkyl), there has been no report of reduction of the corresponding aromatic a,b-ynones (R 1 = Ar) by these methods. A complementary approach to these compounds involves the asymmetric addition of alkynes to aromatic aldehydes (approach B, Scheme 1). Scheme 1However, unlike the catalytic enantioselective addition of dialkyl-4 and alkenylzinc 5 compounds to aldehydes where considerable progress has been made, the current methods for enantioselective alkynylation reactions are far from ideal. 6-8 Some suffer from the use of substoichiometric to stoichiometric amounts of ligands or catalysts, others from either moderate enantioselectivities or the formation of considerable amounts of byproducts (alkylated products).Our research led us to the discovery of a practical and efficient enantioselective method for the alkynylation of aromatic aldehydes with both aromatic and aliphatic acetylene substrates catalyzed by readily available chiral ligands derived from commercially available amino alcohols. We have also devised the method to suppress the alkyl addition to the aldehydes. Scheme 2A typical procedure (Scheme 2) involves the addition of dimethylzinc (1.1-1.2 equiv) in toluene to a solution of the alkyne (1.2 equiv) in THF at -20 °C. The chiral ligand (0.1 equiv) is added as a solid under nitrogen atmosphere after 15 minutes, and after another 15 minutes, the arylaldehyde (1 equiv) is added. The reactions are generally complete in 18-25 hours at -20 °C to -30 °C. An array of aromatic aldehydes has been studied under these conditions, and the representative results are summarized in Table 1. As illustrated in Table 1, the corresponding chiral propargylic alcohols 2 were formed in very good yields and good enantioselectivities. Most of the substituted arylaldehydes underwent the addition reaction with higher levels of enantioselectivity compared with the parent be...