Thiazolidine-2-thione Directed Diastereoselective Addition of Chlorotitanium Enolates to Aldimines

Abstract

Asymmetric Mannich condensations can give rise to enantiomerically pure β-amino carbonyl functionalities, which are important constituents of many biologically active natural products and therapeutics. We describe the titanium tetrachloride-mediated reaction of chiral enolates derived from thiazolidine thiones and non-enolizable imines. For example, N-(4-methoxyphenyl)benzaldimine (1) yields 2R,3S-(anti)-products with good selectivity, while N-benzyloxycarbonylbenzaldimine (2) equilibrates and subsequently eliminates benzyl alkoxide under the reaction conditions to produce 2R,3R-(syn)-isocyanates with excellent selectivity. This reversal in selectivity from anti to syn can be achieved operationally by simply changing the group Z on the nitrogen and the reaction conditions.

Key words

diastereoselectivity - enolates - titanium - aldimines - thiazolidine-2-thiones

References

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15

Enolates were generated by exposing thiazolidine thiones 3a-e to either one or two equivalents of TiCl₄ and freshly distilled (-)-sparteine. The use of diisopropylethylamine in place of (-)-sparteine resulted in similar selectivities, but with lower chemical yields.

20

For the reaction of 3a with 1i, a single crystal X-ray structure determination of the major product 4i (Figure [3] ), established its relative and absolute stereochemistry as anti-2R,3S. Stereochemical assignments for 4ii,vii, 5i,iv and 6i,ix were made by correlating ¹H and ¹³C chemical shifts with those of 4i, 5i and 6i, respectively.

23

PMP-substituted imines derived from aliphatic aldehydes (enolizable aldehydes) have also been subject to investigation. Good selectivities were obtained with i-Pr and s-Bu, but the major anti-product was formed in poor yield (< 20%). α-Deprotonation and/or imine degradation under the reaction conditions compete unproductively with enolate addition to the CN- double bond.

25

Other diastereomeric products were not detected using either ¹H NMR or HPLC.

27

This hypothesis is supported by molecular mechanics calculations.