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 throughiodine–magnesium–copper 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 α‐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). Exploiting two successive metal‐mediated transformations, the diazoketone A is efficiently converted via B into the dihydrotropolone C. While B and C did not exhibit cytotoxic properties, surprisingly, they were found to sensitize resistant tumor cells (Nalm 6) against the clinically used anticancer drug doxorubicin.