Total Syntheses of the Non-Peptide Bradykinin B1 Receptor Antagonist Velutinol A and Its Analogs, seco-Pregnanes with a Cage-Like Moiety

• Published in: Bulletin of the Chemical Society of Japan Vol. 92; no. 9; pp. 1474 - 1494
• Main Authors: Tamiya, Minoru, Isaka, Nobuhisa, Kitazawa, Takaaki, Hasegawa, Atsushi, Ishizawa, Kazuya, Ikeda, Mayu, Kawada, Saki, Ishiguro, Masaji
• Format: Journal Article
• Language: English
• Published: TOKYO The Chemical Society of Japan 15.09.2019; Chemical Soc Japan; Chemical Society of Japan
• Subjects: Analogs; Cages; Chemistry; Chemistry, Multidisciplinary; Cleavage; Construction; Oxidation; Physical Sciences; Reaction time; Science & Technology; Stereoselectivity; Synthesis; Bradykinin B1 receptor (B1R); Natural product syntheses; seco-Pregnane; KININ B-1 RECEPTORS; OXIDATION; HYDROXYLATION; COMPOUND; CARBONYL-COMPOUNDS; MANDEVILLA-VELUTINA; PHARMACOLOGY; 14,15-SECOPREGNANE GLYCOSIDES; STEP SYNTHESIS; DERIVATIVES
• ISSN: 0009-2673; 1348-0634
• DOI: 10.1246/bcsj.20190048

We describe here the syntheses of velutinol A (1) and the structurally similar compounds 2–4 sharing a highly oxygenated seco-pregnane cage-like structure. The synthesis of velutinol A (1, 15,16-seco-pregnane) features the highly regioselective construction of Δ14 silyl enol ether from 15-keto-21,22-diol, followed by stereoselective introduction of a sterically hindered β-hydroxy group at the C14 position by Rubottom oxidation. Prolonged reaction time and the use of an excess amount of mCPBA at this step allowed double Rubottom oxidation, enabling us to introduce the requisite hydroxy groups at the C14 and C16 positions in one pot. Subsequent oxidative cleavage of the C15–16 bond, deprotection, and intramolecular acetalization allowed the concise total synthesis of velutinol A (1). Utilization of α,α-dihydroxyketone, the double Rubottom oxidation product, for formation of the ether F-ring by 5-exo-cyclization, and subsequent C14–21 oxidative cleavage, effectively achieved the synthesis of pentalinonside-aglycon (2). Construction of the 14,15-seco-structures of two other analogs, argeloside aglycon (3) and illustrol (4), was achieved by Baeyer–Villiger oxidation of 15(21)-keto derivatives. Introduction of the 20-oxo group potentially embedded in argeloside aglycon was accomplished by Wacker oxidation of Δ20, which was constructed by Grieco–Nishizawa syn-β-elimination of the C21-primary alcohol obtained by reduction of the Baeyer–Villiger product. Intramolecular double acetalization of the 15,16-dihydroxy-14,20-oxo derivative to form the cage-like structure of the DEF-rings required a moderately weak acid. This step was the key to accessing argeloside aglycon (3), as otherwise the easily aromatized β,γ-dihydroxyketone moiety was transformed to furan. Sharpless asymmetric dihydroxylation of Δ20 to set the C20 stereocenter, followed by intramolecular double acetalization, achieved the stereoselective synthesis of illustrol With all synthesized compounds, structural requirements of steroidal bradykinine B1 receptor antagonist would be revealed.