Received October 1, 2002

Abstract:

Full details of a convergent total synthesis of the ramoplanin A2 and ramoplanose aglycon are disclosed. Three key subunits composed of residues 3-9 (heptapeptide 15), pentadepsipeptide 26 (residues 1, 2 and 15-17), and pentapeptide 34 (residues 10-14) were prepared, sequentially coupled, and cyclized to provide the 49-membered depsipeptide core of the aglycon. Key to the preparation of the pentadepsipeptide 26 incorporating the backbone ester was the asymmetric synthesis of an orthogonally protected L-threo--hydroxyasparagine and the development of effective and near-racemization free conditions for esterification of its hindered alcohol (EDCI, DMAP, 0 C). The coupling sites were chosen to maximize the convergency of the synthesis including that of the three subunits, to prevent late stage racemization of carboxylate-activated phenylglycine-derived residues, and to enlist -sheet preorganization of an acyclic macrocyclization substrate for 49-membered ring closure. By altering the order of final couplings, two macrocyclization sites, Phe⁹-D-Orn¹⁰ and Gly¹⁴-Leu¹⁵, were examined. Macrocyclization at the highly successful Phe⁹-D-Orn¹⁰ site (89%) may benefit from both -sheet preorganization as well as closure at a D-amine terminus within the confines of a -turn at the end of the H-bonded antiparallel -strands. A more modest, but acceptable macrocyclization reaction at the Gly¹⁴-Leu¹⁵ site (40-50%) found at the other end of the H-bonded antiparallel -strands within a small flexible loop may also benefit from preorganization of the cyclization substrate, is conducted on a substrate incapable of competitive racemization, and accommodates the convergent preparation of analogues bearing depsipeptide modifications. Deliberate late-stage incorporation of the subunit bearing the labile depsipeptide ester and a final stage Asn¹ side-chain introduction provides future access to analogues of the aglycons which themselves are equally potent or more potent than the natural products in antimicrobial assays.

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