Stereoselective synthesis of C12–C21 common fragment of thermolides 1–5

Article abstract of DOI:10.1016/j.tetlet.2018.06.020

A highly stereoselective synthesis of C12–C21 common fragment of thermolides 1–5 has been described. The salient features of the synthesis are the utilization of desymmetrization protocol, Barton-McCombie reaction, Brown's asymmetric allylation and Wacker oxidation.

Full text of DOI:10.1016/j.tetlet.2018.06.020

Tetrahedron Letters xxx (2018) xxx–xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereoselective synthesis of C12–C21 common fragment of thermolides
1–5
⇑
Vavilapalli Satyanarayana, Gavireddy Chaithanya Kumar, Katta Muralikrishna, Jhillu Singh Yadav
Centre for Semiochemicals, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly stereoselective synthesis of C12–C21 common fragment of thermolides 1–5 has been described.
The salient features of the synthesis are the utilization of desymmetrization protocol, Barton-McCombie
reaction, Brown’s asymmetric allylation and Wacker oxidation.
Received 18 May 2018
Accepted 6 June 2018
Available online xxxx
Ó 2018 Published by Elsevier Ltd.
Keywords:
Nematodes
Desymmetrization
Barton-McCombie reaction
Brown’s allylation
Wacker oxidation
Introduction
Thermolides are PKS-NRPS hybrid metabolites, which were iso-
lated in 2012 by Niu et al., from thermophilic fungus Thermomyces
thermophilus YM 3–4 (1–6) collected from tengchong hotspring of
Yunnan, China [1,2] (Fig. 1). Thermolides 1 and 2 exhibits potent
inhibitory activity against a wide range of nematodes including
economically destructive rootknot nematode (Meloidogyne incog-
nita) and pine-wood nematode (Bursaphelenchus xylophilus) [3].
Compounds 3 and 4 also show a moderate nematicidal activity
against above two nematodes.
From structural side, all natural products containing a common
13-membered lactam-bearing macrolactone. Thermolides 1–5
have a common C9 polypropionate side chain with three methyl
groups and three hydroxyls, in which two hydroxyls at C16 and
C18 are syn to each other and third hydroxyl at C20 is anti-relation-
ship with C16 and C18. These unusual structural features, twelve
stereogenic centers, sensitive functionalities and nematicidal activ-
ities make thermolides 1–5 attractive for synthesis [1,2].
For the last two decades, our group has explored the potential-
ity of desymmetrization strategy for the synthesis of biologically
active natural and designed molecules [4]. This strategy offers
the generation of contiguous chiral centers from a single bicyclic
precursor by using desymmetrization strategy.
Fig. 1. Structures of thermolides 1–5.
protocol, Brown’s asymmetric allylation and Wacker oxidation as
key reactions.
The retrosynthetic analysis of C12–C21 fragment of thermolides
1–5 is outlined in Scheme 1. We envisioned that fragment 2 could
be synthesized from Brown’s allylated compound 3 by using
Wacker oxidation and anti-reduction. The allyl compound 3 could
be obtained from triol 4, which in turn could be easily synthesized
from known bicyclic olefine 5 [5].
Herein, we describe stereoselective synthesis of C12–C21
common fragment of thermolides 1–5 by using desymmetrization
Results and discussion
⇑
Our synthesis was commenced from reductive cleavage of
bicyclic lactone 6, which was synthesized by desymmetrization
Corresponding author.
E-mail address: yadavpub@gmail.com (J. Singh Yadav).
https://doi.org/10.1016/j.tetlet.2018.06.020
0040-4039/Ó 2018 Published by Elsevier Ltd.
Please cite this article in press as: Satyanarayana V., et al. Tetrahedron Lett. (2018), https://doi.org/10.1016/j.tetlet.2018.06.020

2
V. Satyanarayana et al. / Tetrahedron Letters xxx (2018) xxx–xxx
Scheme 1. Retrosynthetic analysis of thermolides.
of the bicyclic olefine 5. Compound 6 was treated with LiAlH4 in
dry THF to afford the triol 4 in 90% yield [6] (Scheme 2).
The 1,3-diol group of compound 4 was protected as an ace-
tonide [6] using 2,2-dimethoxypropane (2,2-DMP) and catalytic
amount of CSA in CH2Cl2 and the free primary hydroxyl group of
acetonide was protected as its TBS ether to furnish 7. The TBS ether
7 was treated with CuCl2Á2H2O in acetonitrile followed by the
selective silylation of the primary hydroxy group as its TBDPS ether
8 was achieved in 90% yield under the classical conditions
(TBDPSCl, imidazole in CH2Cl2). The free secondary hydroxyl group
of 8 was converted into the corresponding xanthate ester 9 using
LiHMDS, CS2 and methyl iodide at À78 °C with 86% yield [6a,7].
Later the compound 9 was deoxygenated under Barton-McCombie
conditions using tri-n-butyltin hydride and catalytic amount of
Scheme 2. Synthesis of alcohol compound 10.
Scheme 3. Synthesis of C12–C21 fragment 2.
Please cite this article in press as: Satyanarayana V., et al. Tetrahedron Lett. (2018), https://doi.org/10.1016/j.tetlet.2018.06.020

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get molecule (Scheme 3). The allyl compound 3 was subjected to
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dimethyl acetal in the presence of a catalytic amount of CSA to
afford compound 2 in 89% yield (Scheme 3). The synthesis of
C12–C21 fragment of thermolides 1–5 involved 13 steps starting
from exo-methylated bicyclic lactone 6 with a 20.1% overall yield.
Further efforts towards the completion of the total synthesis of
thermolides 1–5 are currently underway.
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Conclusion
In conclusion, a concise and highly stereoselective approach for
C12–C21 fragment of thermolides 1–5 were achieved by employ-
ing desymmetrization strategy, Barton-McCombie reaction,
Brown’s asymmetric allylation, Wacker oxidation and anti-reduc-
tion as key steps. The synthesis involved 13 steps starting from
bicylic lactone 6 with a 20.1% overall yield. Further work towards
the total synthesis of thermolides 1–5 is ongoing.
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Acknowledgements
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VS, KM thanks UGC, New Delhi and GCR thanks CSIR, New Delhi
for the award of a fellowship.
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Please cite this article in press as: Satyanarayana V., et al. Tetrahedron Lett. (2018), https://doi.org/10.1016/j.tetlet.2018.06.020