The Hetero Diels-Alder-Biocatalysis Strategy

A retro-synthetic analysis of 1 as shown in Fig. 3 indicates that 3,6-dihydro-2H-pyran derivatives could serve as key intermediates in the synthesis of 1 and that hetero Diels-Alder reactions could be used to make these 3,6-dihydro-2H-pyran intermediate [3, 4]. 

Our first approach, which looked very attractive, was based on a catalytic asymmetric hetero Diels-Alder reaction between butadiene and trityloxyacetaldehyde (Fig. 3). This reaction would have been highly atom economic, and if it could be done with a chiral catalyst, would lead directly to 2-(S)-trityloxymethyl-3,6-dihydro-2H-pyran 6 (Fig. 4) that could be used to make 1. There is a precedent in the literature for such a hetero Diels-Alder reaction, where benzyloxyacetaldehyde reacts 

Since our catalytic approaches failed, we next attempted a chiral auxiliary approach. The glyoxyloyl function was incorporated into (2R)-bornane-10,2-sultam, 

Our proposed synthesis of 1 using a hetero Diels-Alder-biocatalysis approach is shown in Fig. 4. In this study, we report the details of the development of a commercially viable process to make 1 based on the enzyme resolution of (R,S) 4 [12]. 

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