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Synthesis 2022; 54(07): 1733-1744
DOI: 10.1055/s-0041-1737242
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On the Structure of Thailandene A: Synthetic Examination of the Cryptic Natural Product Aided by a Theoretical Approach

Karoline G. Primdahl
a   Department of Pharmaceutical Chemistry, University of Oslo, P.O. Box 1068, 0316 Oslo, Norway
,
Åsmund Kaupang
a   Department of Pharmaceutical Chemistry, University of Oslo, P.O. Box 1068, 0316 Oslo, Norway
,
Jong-Duk Park
b   Department of Chemistry, Princeton University, Princeton, New Jersey 08544, USA
,
Mohammad R. Seyedsayamdost
b   Department of Chemistry, Princeton University, Princeton, New Jersey 08544, USA
,
Jens M. J. Nolsøe
c   Faculty of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences, P.O. Box 5003, 1432 Ås, Norway
,
Marius Aursnes∗
a   Department of Pharmaceutical Chemistry, University of Oslo, P.O. Box 1068, 0316 Oslo, Norway
› Author AffiliationsM.A. is grateful to the Research Council of Norway (RCN, Norges Forskningsråd) for a grant (FRINATEK, 262901). A research scholarship to J. M. J. N. (FRIPRO, 287416) from the Research Council of Norway (RCN) is gratefully recognized. This work was partly supported by the Research Council of Norway through the Norwegian NMR Package in 1994 and partly supported by the Research Council of Norway through the Norwegian NMR Platform, NNP (226244/F50). Additional support by the Department of Chemistry and the Faculty of Mathematics and Natural Sciences at University of Oslo (Universitet i Oslo) is also appreciated.
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Abstract

Phenotype-guided transposon mutagenesis has emerged as a valuable tool to access cryptic metabolites encoded in bacterial genomes. Recently, the method was demonstrated by inducing silent biosynthetic gene clusters in Burkholderia thailandensis. Amongst the isolated metabolic products, thailandene A exhibited promising antibiotic activity. By assignment, the linear polyenic aldehyde contained a labile motif, where an ostensible chiral secondary alcohol was interlaced in an allylic and a homoallylic constellation. Our attention was drawn to the pseudo-symmetric relationship between the heterofunctionalities, indicating the transformation of a dodecapentaenedial scaffold. Centering on an iterative cross-coupling protocol, the assigned all-E-(12R)-hydroxydodecapentaenal moiety was assembled by combining Zincke chemistry with the MIDA-attenuated Suzuki reaction developed in the Burke laboratory. Thus, according to the devised strategy, the mixed 1,2-bisborylated vinyl linchpin was consecutively functionalized with 5-bromodienal derivatives in a doubly orthogonal fashion. However, when the synthetic material was matched against the bacterial isolate, inconsistencies were observed. A re-examination of the cryptic natural product was conducted by juxtaposing analytical data from experiment and density functional theory calculations, in which hydroperoxide was evaluated as a candidate metabolite present in the bacterial isolate.

Key words

natural products - stereoselective synthesis - total synthesis - aldol reaction - antibiotics - antifungal agents - hyperconjugation - palladium

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/s-0041-1737242.
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Publication History

Received: 10 July 2021

Accepted after revision: 19 November 2021

Article published online:
17 January 2022

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