The enantioselective synthesis of phomopsin B.

A variety of natural products and synthetic molecules cause mitotic arrest by interfering with microtubule function, and a few molecules of this mechanistic class are anticancer drugs. The ustiloxin and phomopsin families of natural products (Scheme 1) are potent microtubule depolymerizers isolated from the fungus species Ustilaginoidea virens and Phomopsis leptostromiformis, respectively. Members of both families possess a similar 13-membered macrolactam. The most striking differences between the ustiloxins and the phomopsins are that the latter contain an unsaturated side chain, display dehydration of the valine residue within the macrocycle, and possess the opposite configuration at the C10 position. Competitive tubulin binding assays demonstrated that one binding site for these compounds overlaps with the binding site for vinca alkaloids. A secondary tubulin binding site for the phomopsins is as yet unidentified. Because ustiloxin D (1) is only slightly less active than phomopsin A (2), it has been suggested that the macrocycle alone may be responsible for much of the biological activity. Three total syntheses of ustiloxin D have been reported, one from this laboratory and two from the Joulligroup. We have used this knowledge, along with our previously reported progress, to synthesize the complex antimitotic phomopsin B (3). Phomopsin B is a hexapeptide although it contains none of the standard proteinogenic amino acids. Rather, there are four unsaturated residues, two oxidized residues, and an aryl alkyl ether side-chain connection. A logical initial disconnection for phomopsin B would rely on independent construction of both the macrocycle acid and side-chain amine, to be joined by peptide coupling. Unfortunately, such a strategy could not be realized, and our present synthesis necessitated incorporation of the side chain prior to macrocycle closure (Scheme 2). In spite of this accomodation, our established syntheses of both the tripeptide side-chain precursor 6 and DVal 7 could be used when these units were coupled in sequence with intermediate 5 (Scheme 2). We chose to incorporate a precursor to the last residue of the tripeptide side chain because E-DAsp isomerizes to Z-DAsp in alkaline solution. Although innovative approaches to prepare the vicinal C2,C3 stereocenters of aryl alkyl ether 5 had been reported,