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Short Paper | Special issue | Vol 99, No. 1, 2019, pp.604-613
Published online, 14th June, 2018
DOI: 10.3987/COM-18-S(F)4
Efficient Synthesis of Methyl (S)-4-(1-Methylpyrrolidin-2-yl)-3-oxobutanoate as the Key Intermediate for Tropane Alkaloid Biosynthesis with Optically Active Form

Nanda Kumar Katakam, Cole W. Seifert, John D’Auria,* and Guigen Li*

*Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409-1061, U.S.A.

Abstract

Methyl (S)-4-(1-methylpyrrolidin-2-yl)-3-oxobutanoate has been synthesized for enzymatic studies on cyclization enzymes during cocaine biosynthesis in Erythroxylum coca plants. During the present new synthesis, L-proline was first protected with Cbz group and reduced to chiral amino alcohol, which were then followed by Swern oxidation, Wittig reaction and decarboxylative condensation. At the last step, N-methylamino acid precursor was treated with 1,1’-carbonyldiimidazole followed by reacting with methyl potassium malonate to give the 3-oxobutanoate in 54% overall yield. This new strategy has proven to avoid obvious racemization of the L-proline chiral center during the synthesis. In addition, six of the eight synthesis steps were performed via GAP chemistry/technology without the use of column chromatography for purification.