EFFORTS TOWARDS THE ASYMMETRIC SYNTHESIS OF A HUMAN T-CELL LEUKEMIA VIRUS PROTEASE INHIBITOR: PILOT REACTIONS DIRECTED TOWARDS THE FORMATION OF A GAMMA-HYDROXYL-PROLINAMIDE KEY INTERMEDIATE VIA CHEMOSELECTIVE MONOSULFONYLATION AND NUCLEOPHILIC SUBSTITU

Publication Date

4-5-2019

Document Type

Poster

Degree Type

Undergraduate

Department

Chemistry

Mentor

Shawn Hitchcock

Mentor Department

Chemistry

Abstract

The first known human retrovirus to be discovered was the Human T-cell leukemia virus (HTLV-1). In contrast to other retroviruses such as HIV, HTLV-1 has only a limited number of occurrences of attempts to generate a specific HTLV-1 protease inhibitor (Akaji and Researchers in the United States and Japan isolated the virus). Since these findings and with adult T-cell leukemia/lymphoma in the 1980s, and since the discovery of HTLV-1 three more HTLV's have been identified. The HTLV-1 virus is endemic in southwestern Japan, sub-Saharan Africa, South America, parts of the Caribbean, and is seen in lower frequencies among many regions. Akaji followed up this work with the synthesis of a series of protease inhibitors. These inhibitors were synthesized by using the method of Ghosh and coworkers that involved a titanium catalyzed asymmetric aldol addition reaction using a toluenesulfonyl-2-indanyl valerate ester. The route was efficient and yielded the desired protease inhibitor target. However, it is proposed that a route employing an asymmetric glycolate aldol addition reaction would be more efficient due to the presence of the glycolate component. We became interested in developing a synthesis of the HTLV-1 protease inhibitor by a new pathway involving Crimmins' oxazolidine-2-thione chemistry using a glycolate approach. This project has involved conducting an asymmetric aldol reaction with a glycolate side chain. We have been able to demonstrate the success of this process as well as the very mild sodium borohydride cleavage of the sidechain (<30 minutes, room temperature). The cleavage process generates a 1,3-diol that has been chemoselectively substituted at the primary alcohol. Research is underway to exploit the sulfonate group in its nucleophilic substitution with a prolinamide derived from the commercially available N-tert-butoxycarbonyl-proline.

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