Organocatalytic asymmetric direct vinylogous aldol reactions of 2-furanone and application in the synthesis of (+)-L-733,060, (+)-CP-99,994, (2S,3R)-3-hydroxypipecolic acid and (+)-febrifugine

Paul, Eldho K. (2014) Organocatalytic asymmetric direct vinylogous aldol reactions of 2-furanone and application in the synthesis of (+)-L-733,060, (+)-CP-99,994, (2S,3R)-3-hydroxypipecolic acid and (+)-febrifugine. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

The organocatalytic, direct vinylogous aldol reaction (ODVA) of 2-furanone (γ-crotonolactone) is of interest because the reaction provides direct access to γ-substituted butenolides, an important structural motif in several natural products and biologically active compounds. We have observed that this reaction is catalyzed by chiral aminothioureas and aminosquaramides. A detailed investigation of this method is described in Chapter 2. The ODVA reaction of γ-crotonolactone with aldehydes can be used for the synthesis of substance P receptor antagonist piperidines (+)-L-733,060 and (+)-CP-99,994, and also for the synthesis of (2S,3R)-3-hydroxypipecolic acid, which is a component of tetrazomine, an antitumor agent and an antibiotic. These results are presented in Chapter 3. This methodology is also useful for the total synthesis of the antimalarial alkaloid (+)-febrifugine and a formal synthesis of (+)-halofuginone, an antimalarial agent. The results of this work are described in Chapter 4.

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