Total synthesis of the ramoplanin A2 and ramoplanose aglycon.
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-beta-hydroxyasparagine and the development of effective and near-racemization free conditions for esterification of its hindered alcohol (EDCI, DMAP, 0 degrees 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 beta-sheet preorganization of an acyclic macrocyclization substrate for 49-membered ring closure. By altering the order of final couplings, two macrocyclization sites, Phe(9)-d-Orn(10) and Gly(14)-Leu(15), were examined. Macrocyclization at the highly successful Phe(9)-d-Orn(10) site (89%) may benefit from both beta-sheet preorganization as well as closure at a d-amine terminus within the confines of a beta-turn at the end of the H-bonded antiparallel beta-strands. A more modest, but acceptable macrocyclization reaction at the Gly(14)-Leu(15) site (40-50%) found at the other end of the H-bonded antiparallel beta-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 Asn(1) 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.
Jiang
Wanlong
W
Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Wanner
Jutta
J
Lee
Richard J
RJ
Bounaud
Pierre-Yves
PY
Boger
Dale L
DL
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry; D047630:Depsipeptides; D006023:Glycoproteins / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry; D017433:Protein Structure, Secondary
D000900:Anti-Bacterial Agents; D047630:Depsipeptides; D006023:Glycoproteins; D009842:Oligopeptides; D010456:Peptides, Cyclic; C472958:ramoplanose aglycon; C416073:ramoplanin A2