This thesis focuses on the asymmetric reduction of N-protected derivatives of (3S)-3-amino-1-chloro-4-phenyl-2-butanone to their corresponding diastereomeric alcohol products, which are key intermediates in the synthesis of HIV protease inhibitors. Although the stereoselective synthesis of the (S,S) alcohol product is easily achieved, preparing the (R,S) diastereomer is much more challenging. I investigated three diastereoselective reduction processes: 1) Meerwein-Ponndorf-Verley (MPV) reduction, 2) asymmetric transfer hydrogenation, and 3) boron reducing agents. The diastereoselectivity of the MPV reduction still favored the (S,S) product; however, I discovered a significant rate enhancement when the standard catalyst (aluminum isopropoxide) was replaced with aluminum tert-butoxide. Many reaction variables were investigated in the asymmetric transfer hydrogenation reaction and the diastereoselectivity was improved to give a ratio of the desired (R,S) diastereomer to the undesired (S,S) alcohol of 9.5:1. Using chiral oxazaborolidine catalysts, an unprecedented (R,S) to (S,S) ratio of 9.5:1 was achieved. Finally, I investigated the effect of the N-protecting group on the stereoselectivity of the reduction. When the original boc-protecting group was replaced with a phthalimide group, the diastereoselectivity of the MPV reduction was reversed to favor the desired (R,S) product.
| Identifer | oai:union.ndltd.org:GATECH/oai:smartech.gatech.edu:1853/39464 |
| Date | 04 January 2010 |
| Creators | Kitagawa, Kristen |
| Publisher | Georgia Institute of Technology |
| Source Sets | Georgia Tech Electronic Thesis and Dissertation Archive |
| Detected Language | English |
| Type | Dissertation |
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