Communication
Organic & Biomolecular Chemistry
To gain further support for this proposal two further model
unsaturated alcohols were prepared. The first, dihydroxy ester
45 lacking the second double bond, was synthesised by an ana-
logous route to that used for 40 but starting from crotonal
(Scheme 7B). Sharpless epoxidation of 45 gave a mixture of
THP and THF products 47 and 48 in 44% and 19% isolated
yield respectively, with no further products detected
(Scheme 7B). Finally, unsaturated alcohol 49 was prepared and
treated with mCPBA to give a mixture of epoxides 50 which
were not purified but on addition of CSA gave THFs 51 and 52
arising from the expected 5-exo cyclisation (Scheme 7C). These
results taken together are in accord with the proposal that
both the C-5 alcohol and 8,9-alkene of ambruticin J may play a
role in directing intramolecular epoxide ring opening to form
ambruticin F. Hence, if a non-enzymatic cyclisation of epoxide
4 occurs then, based on these simple model studies, formation
of the THP would be reasonable.
Notes and references
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Conclusions
AmbJ is a flavin-dependent monooxygenase proposed to cata-
lyse oxidation of ambruticin J to epoxide 4 (Scheme 1).14
However, as no epoxide hydrolase has been identified in the
ambruticin biosynthetic gene cluster, it is not clear if AmbJ
also catalyses a 6-endo epoxide ring opening to give ambruticin
F or if THP formation occurs spontaneously. The results of
model studies described herein on the chemical epoxidation
and cyclisation of unsaturated alcohols (40, 45 and 49) are in
accord with the proposal that both the C-5 alcohol and 8,9-
alkene of ambruticin J may play a role in directing 6-endo intra-
molecular ring opening to form ambruticin F. However,
studies with AmbJ are essential to fully understand the biosyn-
thesis of ambruticin F. To facilitate these biochemical investi-
gations, we have completed a convergent total synthesis of
ambruticin J. The approach involved construction of the
carbon framework via the synthesis of three fragments 12, 13
and 14 which were united via a thallium-accelerated Suzuki–
Miyaura cross-coupling and Julia–Kocienski olefination. A
global deprotection of 34, selective oxidation to lactone 36 and
finally hydrolysis under mild conditions gave ambruticin
J. This modular route may be readily adapted to generate
ambruticin J analogues to investigate the substrate specificity
of AmbJ and these studies are currently underway in our
laboratories.
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alcohol in which a 6-membered ring (THP) is formed, and
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formed oxygen heterocycle. In contrast, 5-exo refers to cycli-
sation of an epoxy-alcohol where the epoxide C–C bond is
outside the newly formed THF ring.
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We thank the Bristol Chemical Synthesis Centre for Doctoral 24 K. C. Nicolaou, M. E. Duggan, C.-K. Hwang and
Training, funded by EPSRC (EP/G036764/1), and the University
of Bristol, for a PhD studentship to JIB.
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6214 | Org. Biomol. Chem., 2021, 19, 6210–6215
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