Synthesis of L-738,372 and

The possibility of using a non-covalently bound chiral modifier to direct the steric course of a reaction represents a very appealing method for the stereoselective synthesis of enantiomerically pure drugs. The preparation of the single stereocenter-containing L-738,372 and L-743,726 illustrate this approach (Fig. 16) [57]. 

The non-nucleosidal, reverse-transcriptase inhibitor L-738,372 36 could be obtained in up to 99.5% e.e. by addition of lithium 2-pyridylacetylide to substrate 35 in the presence of quinine (Fig. 16), followed by iV-1 protecting group removal in acidic conditions. 

The structurally related product L-743,726 39 was similarly prepared by addition of lithium cyclopropylacetylide to ketone 37 in the presence of a /V,/V-disubstituted norephedrine derivative. This occurred in 98% e.e. at 0°C to give adduct 38 that was subsequently cyclized to afford 39. 

The kinetic resolution of racemic tertiary P-hydroxyamines by enantioselective /V-oxide formation was developed by the Sharpless group as a corollary of the allylic alcohol epoxida- 

For instance, (S)-propranolol can be obtained in five steps with an 11% overall yield (including the crucial resolution process) as described in Fig. 17. 

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Figure 16. Stereoselective synthesis of L-738,372 and L-743,726. Reagents a, quinine, BuLi, then lithium 2-pyridylacetylide b, camphorsulfonic acid c, trifluoroacetic acid d, lithium cyclopropylacetylide, N-pyrrolidinyl norephedrine.

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