kendomycin and carbene

Ansa compounds are gifts from microbes with intriguing molecular structures and highly potent bioactivities. One of the ansa compounds, kendomycin, has an oxa-metacyclophane skeleton with a quinone methide core and a fully substituted tetrahydropyran ring. Beyond a common synthetic strategy for construction of the ansa skeleton (i.e., elongation of an alkyl chain from an aromatic core followed by macrocyclization), we challenged a new method for construction of the ansa skeleton via simultaneous macrocyclization and benzannulation (using an intramolecular Dötz benzannulation). Understanding the reactivity of various Fischer-type ω-alkynyloxy chromium carbene complexes with kendomycin analogue syntheses led to achievement of the total synthesis of kendomycin. Investigations of structure-activity relationships revealed the need for an ansa skeleton for antimicrobial activity. Therefore, we envisage that this intramolecular Dötz benzannulation will enable divergent syntheses of ansa compounds which have important bioactive potential.

Topics: Coordination Complexes; Macrocyclic Compounds; Methane; Quinones; Rifabutin; Structure-Activity Relationship

One-step formation of the ansa-skeleton realized the synthesis of kendomycin, an ansa-type quinone methide. The Fischer carbene complex derived from the ansa-chain portion was subjected to the intramolecular Dotz benzannulation to afford the desired oxametacyclophane with exclusive regioselectivity. Subsequent Claisen rearrangement, ortho oxidation of the resulting phenol derivative, and mild transformation from p-quinone to p-quinone methide on a silica gel plate furnished kendomycin.

Topics: Chromium; Methane; Rifabutin; Spectrophotometry, Ultraviolet