Studies toward the synthesis of fostriecin analogs and total synthesis and structural elucidation of coibacins A and B

Author(s)

Carolina Martins Avila

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Instituto de Química
• Defense date: 2014-11-28

Examining board members

Ronaldo Aloise Pilli; Gustavo Seoane Muniz; Paulo Roberto Ribeiro Costa; Carlos Roque Duarte Correia; Paulo Mitsuo Imamura

• Advisor: Ronaldo Aloise Pilli

Abstract

In chapter 1, a new synthetic route for fostriecin and analogues was studied with the 1,4-anti boron-mediated aldol reaction as the key step in the formation of the stereogenic center at C11. In this context, the influence of the ?-alkoxy substituent in the aldol reaction involving the boron enolate of the chiral methyl ketones with a quaternary stereogenic center at C-8 was evaluated. The reaction scope was explored by using aldehydes with different steric and electronic patterns. Products were obtained in excellent diastereoselectivity (rd 1,4-anti versus 1,4-syn > 90:10). This methodology was applied to the synthesis of C5-C13 fragment of fostriecin in 10 steps and 8.4% overall yield from commercially available (2E)-2-methyl-2-buten-1-ol. This intermediate was used by G. A. O¿Doherty and co-workers in the most recent total synthesis of fostriecin and it was prepared in 15 steps from (2E)-pent-2-en-4-yn-1-ol (Org. Lett., 12, 3752, 2010). In chapter 2, a flexible synthetic route for four stereoisomers of the natural product coibacin A was developed based on a modular approach in order to establish the absolute configuration of this natural product. This synthetic strategy possesses as key steps the Wittig and Julia olefination reactions and Charette asymmetric cyclopropanation reaction. After comparison by chiral HPLC chromatography of the retention time of the four synthetic stereoisomers with a sample of coibacin A obtained from natural sources, the absolute configuration of the natural product was unequivocally established as 5R,16S,18S. The stereochemistry of the stereogenic center at C-5 of the ?,?-unsaturated ?-lactone, that had been previously assigned as S, was corrected to R and the absolute configurations at C-16 and C-18 were assigned as S and S, respectively. Therefore, we accomplished the first total synthesis of the unsaturated polyketide coibacin A in 13 steps (longest linear sequence) and 3.4% overall yield from commercially available (S)-glycidol. Additionally, we synthesized the 5R,14S,16S isomer of coibacin B in 13 steps (longest linear sequence) and 5.7% overall yield (AU)

• FAPESP's process: 10/08673-6 - Studies toward the Synthesis of Analogues of Fostriecin and Total Synthesis and Structural Elucidation of Coibacinas A and B
• Grantee: Carolina Martins Avila de Sant'Ana
• Support Opportunities: Scholarships in Brazil - Doctorate