Synthesis of Oxa-B-Ring Analogs of Colchicine through Rh-Catalyzed Intramolecular [5+2] Cycloaddition

A synthetic approach towards (5R)-5-methyl-6-oxa-desacetamido colchicine as a conformationally defined non-natural colchicine analog with a modified B-ring was undertaken. The synthetic strategy was based on a Rh-catalyzed cascade reaction involving a [5+2] cycloaddition of a carbonyl ylide intermediate as a key step, in which both seven-membered rings of the polycyclic framework are formed in a single operation. Starting from 2-iodo-3,4,5-trimethoxy-acetophenone, an upper side-chain was constructed through enantioselective CBS reduction (up to 75?%?ee) and propargylation, while a lower succinoyl side-chain was attached either throughiodinemagnesiumcopper exchange and subsequent reaction with methyl 4-chloro-4-oxobutanoate, or by Pd-catalyzed Stille cross-coupling with 2-tributylstannyl-5-methoxyfuran followed by hydrolytic furan-opening. Treatment of an a-diazoketone intermediate with Rh2(OAc)4 (3 mol-%)initiated the diastereoselective key cyclization cascade (=97:3?dr). Treatment of the cycloadduct 3 with Et2AlCl afforded an interesting 11,12-dihydrocolchicine analog 24, which, however, could not be oxidized to the corresponding tropolone. Structural assignments were confirmed by X-ray crystallography. While compounds 3 and 24 did not exhibit noteworthy cytotoxic activity by themselves, they were found to strongly enhance the cytostatic (apoptosis-inducing) activity of doxorubicin against resistant Nalm-6 cells (i.e., in a synergy effect).