Total Synthesis of the Ramoplanin A2 and Ramoplanose Aglycon
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- 作者：Wanlong Jiang ; Jutta Wanner ; Richard J. Lee ; Pierre-Yves Bounaud ; and Dale L. Boger
- 刊名：Journal of the American Chemical Society
- 出版年：2003
- 出版时间：February 19, 2003
- 年：2003
- 卷：125
- 期：7
- 页码：1877 - 1887
- 全文大小：387K
- 年卷期：v.125,no.7(February 19, 2003)
- ISSN：1520-5126
文摘
Full details of a convergent total synthesis of the ramoplanin A2 and ramoplanose aglycon aredisclosed. Three key subunits composed of residues 3-9 (heptapeptide 15), pentadepsipeptide 26 (residues1, 2 and 15-17), and pentapeptide 34 (residues 10-14) were prepared, sequentially coupled, and cyclizedto 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 protectedL-threo-
-hydroxyasparagine and the development of effective and near-racemization free conditions foresterification of its hindered alcohol (EDCI, DMAP, 0 
C). The coupling sites were chosen to maximize theconvergency of the synthesis including that of the three subunits, to prevent late stage racemization ofcarboxylate-activated phenylglycine-derived residues, and to enlist -sheet preorganization of an acyclicmacrocyclization substrate for 49-membered ring closure. By altering the order of final couplings, twomacrocyclization sites, Phe9-D-Orn10 and Gly14-Leu15, were examined. Macrocyclization at the highlysuccessful Phe9-D-Orn10 site (89%) may benefit from both -sheet preorganization as well as closure ata D-amine terminus within the confines of a -turn at the end of the H-bonded antiparallel -strands. Amore modest, but acceptable macrocyclization reaction at the Gly14-Leu15 site (40-50%) found at theother end of the H-bonded antiparallel -strands within a small flexible loop may also benefit frompreorganization of the cyclization substrate, is conducted on a substrate incapable of competitiveracemization, and accommodates the convergent preparation of analogues bearing depsipeptide modifications. Deliberate late-stage incorporation of the subunit bearing the labile depsipeptide ester and a finalstage Asn1 side-chain introduction provides future access to analogues of the aglycons which themselvesare equally potent or more potent than the natural products in antimicrobial assays.
-hydroxyasparagine and the development of effective and near-racemization free conditions foresterification of its hindered alcohol (EDCI, DMAP, 0 C). The coupling sites were chosen to maximize theconvergency of the synthesis including that of the three subunits, to prevent late stage racemization ofcarboxylate-activated phenylglycine-derived residues, and to enlist -sheet preorganization of an acyclicmacrocyclization substrate for 49-membered ring closure. By altering the order of final couplings, twomacrocyclization sites, Phe9-D-Orn10 and Gly14-Leu15, were examined. Macrocyclization at the highlysuccessful Phe9-D-Orn10 site (89%) may benefit from both -sheet preorganization as well as closure ata D-amine terminus within the confines of a -turn at the end of the H-bonded antiparallel -strands. Amore modest, but acceptable macrocyclization reaction at the Gly14-Leu15 site (40-50%) found at theother end of the H-bonded antiparallel -strands within a small flexible loop may also benefit frompreorganization of the cyclization substrate, is conducted on a substrate incapable of competitiveracemization, and accommodates the convergent preparation of analogues bearing depsipeptide modifications. Deliberate late-stage incorporation of the subunit bearing the labile depsipeptide ester and a finalstage Asn1 side-chain introduction provides future access to analogues of the aglycons which themselvesare equally potent or more potent than the natural products in antimicrobial assays.