First Total Synthesis of Gliomasolide C and Formal Total Synthesis of Sch-725674

Article abstract of DOI:10.1021/acs.joc.5b02318

Syntheses of two 14-membered macrolides Sch-725674 and Gliomasolide C are described here. The first total synthesis of Gliomasolide C, the short synthesis of Sch-725674, and regioselective Wacker oxidation of internal olefin are the highlights of this disclosure. In addition, a key macrocycle with orthogonal functionalities was designed and synthesized on a gram scale for the generation of analogues.

Full text of DOI:10.1021/acs.joc.5b02318

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First Total Synthesis of Gliomasolide C
and Formal Total Synthesis of Sch-725674
B Seetharamsingh, Pankaj V Khairnar, and D. Srinivasa Reddy
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02318 • Publication Date (Web): 03 Dec 2015
Downloaded from http://pubs.acs.org on December 3, 2015
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First Total Synthesis of Gliomasolide C and Formal
Total Synthesis of Sch-725674
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B. Seetharamsingh, Pankaj V. Khairnar and D. Srinivasa Reddy*
CSIR-National Chemical Laboratory, Division of Organic Chemistry, Dr. HomiBhabha Road,
Pune, 411008, India.
E-mail: ds.reddy@ncl.res.in
TOC Graphic
Abstract
Synthesis of two 14-membered macrolides Sch-725674 and Gliomasolide C are described here.
First total synthesis of Gliomasolide C, short synthesis of Sch-725674 and regioselective Wacker
oxidation of internal olefin are the highlights of this disclosure. In addition, a key macrocycle
with orthogonal functionalities was designed and synthesized on a gram-scale for the generation
of analogues.
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The family of 14-membered macrolides has a special attraction in the literature as they possess
excellent biological properties.1 Macrolides such as erythromycin, rustmicin, migrastatin,
clonostachydiol and sekothrixide are some of the biologically important examples of this family.1
Erythromycin2 and clarithromycin3 are the examples of US FDA approved drugs for the
treatment of bacterial infections. Therefore a lot of interest on 14-membered macrocylic lactones
was generated among the chemists as part of their medicinal chemistry and total synthesis
programs.4 Along these lines, Sch-725674 (1) and very recently isolated gliomasolides caught
our attention to start a program towards the total synthesis and screening of their various
analogues. Sch-725674 isolated by Yang and co-workers from a culture of Aspergillus sp.
showed antifungal properties and it became a popular target for total synthesis.5 The first total
synthesis of Sch-725674 and its analogues with all possible stereoisomers has been accomplished
by the Curran’s group using fluorous chemistry.6 Following Curran’s synthesis, two elegant total
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Figure 1. Structures of Sch-725674 and Gliomasolides
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syntheses of Sch-725674 by Prasad7 and Kaliappan8 groups were appeared. Very recently, five
related gliomasolides (A–E, 2-6) were isolated by Xu and co-workers from a sponge-derived
fungus Gliomastix sp. ZSDS1-F7-2 (Figure 1).9 In a limited biological screening, gliomasolide A
displayed anticancer activity against HeLa (human epithelial carcinoma cell line) cells. However,
so far no synthetic efforts were documented on gliomasolides. Our efforts towards the syntheses
of this group of natural products (Figure 1) are discussed here.
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Scheme 1. Retrosynthetic Analysis of the Target NPs
Retrosynthetically, the target molecules are envisioned from the acyclic E-olefin intermediates
which in turn could be prepared from the known building blocks 7, 8 and 9 using cross
metathesis reaction (Scheme 1). To begin with, compound 710 prepared from (R)-2-pentyloxirane
opening with 5-hexenyl Grignard reagent, was subjected to cross-metathesis11 using Grubbs’ 2nd
generation catalyst (G-II) with another olefinic partner 812 constructed from ribose using known
chemistry. The outcome from this metathesis reaction was isolation of the intermediate 10 in
82% yield with an excellent E-selectivity. After having compound 10 in hand, our next task was
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