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Abstract
A new, direct approach to $\beta$-lactones has been developed involving a direct, highly diastereoselective, ZnCl$\sb2$-mediated, tandem Mukaiyama aldol-lactonization (TMAL) reaction employing thiopyridylsilylketene acetals and various aldehydes. This method provided 3,4-disubstituted $\beta$-lactones with high trans diastereoselectivity and it is the first aldol-lactonization approach to $\alpha$-unsubstituted $\beta$-lactones. In addition, this method was applied to the first total synthesis of the potent pancreatic lipase inhibitor, (-)-panclicin D. The key step involved the TMAL reaction which proceeded with excellent internal stereoselectivity ($>$19:1, trans/cis) and good relative stereoselectivity (9.3:1, anti/syn) and efficiently set two of the four stereogenic centers found in (-)-panclicin D. The synthesis was completed in six steps and 20% overall yield from n-octanal and can be readily adapted to synthesize any member of this growing class of lipase inhibitors. The use of various $\alpha$- or $\beta$-substituted optically active aldehydes in the TMAL reaction gave the corresponding optically active $\beta$-lactones with less than 2% racemization with $\alpha$-epimerizable aldehydes. In light of the utility demonstrated in the course of this study, the TMAL reaction is expected to become a very useful stereoselective route to $\beta$-lactones.
In addition, titanium-based chiral Lewis acids have been studied for catalysis of the (2+2) cycloaddition of silylketenes and aldehydes. We found that the Seebach and Narasaka Ti-TADDOL catalysts provide excellent cis diastereoselectivity, The resulting $\alpha$-silylated 3,4-disubstituted $\beta$-lactones were subsequently desilylated and the $\beta$-substituted-$\beta$-lactones were obtained in low to good enantiomeric excess (9-80% ee). The stereochemistry of the cycloadditions are in accord with previous reports by Yamamoto wherein high cis diastereoselectivities were obtained with bulky Lewis acids. These results can be rationalized by the transition state models recently proposed by Cossio. The effect of tether length of benzyloxy substituted aldehydes on diastereoselectivity was also investigated. The reversed diastereoselectivities observed suggest possible bidentate chelation of the Lewis acid with the aldehydes.
