436848-85-0Relevant articles and documents
Total synthesis of the ramoplanin A2 and ramoplanose aglycon
Jiang, Wanlong,Wanner, Jutta,Lee, Richard J.,Bounaud, Pierre-Yves,Boger, Dale L.
, p. 1877 - 1887 (2007/10/03)
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-β-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 β-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 β-sheet preorganization as well as closure at a D-amine terminus within the confines of a β-turn at the end of the H-bonded antiparallel β-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 β-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.
Total synthesis of the ramoplanin A2 and ramoplanose aglycon
Jiang, Wanlong,Wanner, Jutta,Lee, Richard J.,Bounaud, Pierre-Yves,Boger, Dale L.
, p. 5288 - 5290 (2007/10/03)
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-β-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 β-sheet preorganization of an acyclic macrocyclization substrate for 49-membered ring closure. As such, macrocyclization at the chosen Phe9-d-Orn10 site may benefit from both β-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 Asn1 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. Copyright
