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Synthesis 2021; 53(07): 1247-1261
DOI: 10.1055/s-0040-1706003
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Forskolin Editing via Radical Iodo- and Hydroalkylation

Elena Pruteanu  ‡
a   Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, Freiestrasse 3, 3012 Bern, Switzerland
b   Institute of Chemistry MECR, 3 Academiei str., MD-2028, Chișinău, Republic of Moldova
,
Nicholas D. C. Tappin  ‡
a   Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, Freiestrasse 3, 3012 Bern, Switzerland
,
Vladilena Gîrbu 
a   Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, Freiestrasse 3, 3012 Bern, Switzerland
b   Institute of Chemistry MECR, 3 Academiei str., MD-2028, Chișinău, Republic of Moldova
,
Olga Morarescu 
b   Institute of Chemistry MECR, 3 Academiei str., MD-2028, Chișinău, Republic of Moldova
,
Fabrice Dénès 
a   Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, Freiestrasse 3, 3012 Bern, Switzerland
,
Veaceslav Kulciţki  ∗
b   Institute of Chemistry MECR, 3 Academiei str., MD-2028, Chișinău, Republic of Moldova
,
Philippe Renaud  ∗
a   Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, Freiestrasse 3, 3012 Bern, Switzerland
› Author AffiliationsThis work was funded by the Swiss National Science Foundation: project IZ73Z0_152346/1 (SCOPES program involving VK and PR) and project 200020_172621 (PR). EP and VG were both partly supported by the State Secretariat for Education and Innovation (SERI) via a Swiss Government Excellence Scholarships for Foreign Scholars and Artists.
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Abstract

The modification of highly oxygenated forskolin as well as manoyl and epi-manoyl oxide, two less functionalized model substrates sharing the same polycyclic skeleton, via intermolecular carbon-centered radical addition to the vinyl moiety has been investigated. Highly regio- and reasonably stereoselective iodine atom transfer radical addition (ATRA) reactions were developed. Unprotected forskolin afforded an unexpected cyclic ether derivative. Protection of the 1,3-diol as an acetonide led the formation of the iodine ATRA product. Interestingly, by changing the mode of initiation of the radical process, in situ protection of the forskolin 1,3-diol moiety as a cyclic boronic ester took place during the iodine ATRA process without disruption of the radical chain process. This very mild radical-mediated in situ protection of 1,3-diol is expected to be of interest for a broad range of radical and non-radical transformations. Finally, by using our recently developed tert-butyl­catechol-mediated hydroalkylation procedure, highly efficient preparation of forskolin derivatives bearing an extra ester or sulfone group was achieved.

Key words

radical reaction - natural product modification - alkenes - boronic ester - 1,3-diol protecting group - triethylborane

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/s-0040-1706003.
  • Supporting Information


Publication History

Received: 01 November 2020

Accepted after revision: 30 November 2020

Article published online:
11 January 2021

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