A Bioinspired Synthesis of (±)-Rubrobramide, (±)-Flavipucine, and (±)-Isoflavipucine

• Published in: Angewandte Chemie (International ed.) Vol. 55; no. 33; pp. 9553 - 9556
• Main Authors: Mizutani, Shoma, Komori, Kenta, Taniguchi, Tohru, Monde, Kenji, Kuramochi, Kouji, Tsubaki, Kazunori
• Format: Journal Article
• Language: English
• Published: WEINHEIM Blackwell Publishing Ltd 08.08.2016; Wiley; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: Absolute configuration; Amides; biomimetic synthesis; Biomimetics; Cascade chemical reactions; Chemical synthesis; Chemistry; Chemistry, Multidisciplinary; Circular dichroism; configuration determination; Dichroism; Isomerization; lactams; Physical Sciences; Science & Technology; total synthesis; vibrational spectroscopy; ANTIBIOTICS; FLAVIPUCINE; VIBRATIONAL CIRCULAR-DICHROISM; CONFIGURATION; EXCITON CHIRALITY METHOD; configuration determination; CLADOBOTRYUM-RUBROBRUNNESCENS; (&/-)-FLAVIPUCINE; REARRANGEMENT; lactams; ISOFLAVIPUCINE; ASPERGILLUS-FLAVIPES; vibrational spectroscopy; total synthesis; biomimetic synthesis
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201602910

A biomimetic synthesis of naturally occurring lactams rubrobramide, flavipucine, and isoflavipucine is described. The key step is a regioselective Darzens reaction between isobutyl glyoxal and an α‐bromo‐β‐ketoamide. The construction of the core tricyclic ring system of rubrobramide was achieved by a cascade reaction in a single step from an α,β‐epoxy‐γ‐lactam. Furthermore, the absolute configuration of naturally occurring (+)‐rubrobramide was determined by vibrational circular dichroism. (±)‐Flavipucine and (±)‐isoflavipucine were synthesized from an epoxyimide, which was prepared by reaction of isobutyl glyoxal with a protected α‐bromo‐β‐ketoamide. Deprotection of the epoxyimide and formation of the pyridone ring gave (±)‐flavipucine, which was converted into (±)‐isoflavipucine by thermal isomerization. Three pieces: Total synthesis of (±)‐rubrobramide, (±)‐flavipucine, and (±)‐isoflavipucine was achieved by a Darzens reaction between isobutyl glyoxal and α‐bromo‐β‐ketoamides, removal of the protecting group(s), and ring formation. After optical resolution of synthetic (±)‐rubrobramide, the absolute configuration of naturally occurring (+)‐rubrobramide was determined by vibrational circular dichroism.