Total synthesis of the ramoplanin A2 and ramoplanose aglycon.
A convergent total synthesis of the ramoplanin A2 and ramoplanose aglycon is disclosed. Three key subunits composed of residues 3-9 (heptapeptide 15), pentadepsipeptide 26, 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. As such, macrocyclization at the chosen Phe(9)-D-Orn(10) site may benefit from both beta-sheet preorganization as well as closure at a D-amine terminus. 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 reported to be 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, La Jolla, California 92037, USA.
Wanner
Jutta
J
Lee
Richard J
RJ
Bounaud
Pierre-Yves
PY
Boger
Dale L
DL
D000890:Anti-Infective Agents / Q000737:chemistry*; D047630:Depsipeptides; D006023:Glycoproteins / Q000138:chemical synthesis*; D009842:Oligopeptides / Q000138:chemical synthesis; D010456:Peptides, Cyclic / Q000138:chemical synthesis*
D000890:Anti-Infective Agents; D047630:Depsipeptides; D006023:Glycoproteins; D009842:Oligopeptides; D010456:Peptides, Cyclic; C416073:ramoplanin A2