Communications
DOI: 10.1002/anie.201007551
Diterpenes
Enantioselective Total Synthesis of the Diterpenes Kempene-2,
Kempene-1, and 3-epi-Kempene-1 from the Defense Secretion of
Higher Termites**
Melanie Schubert and Peter Metz*
Dedicated to Professor Jochen Mattay on the occasion of his 65th birthday
Nasutitermes rippertii and Nasutitermes ephratae; an intra-
Soldiers of the termite subfamily Nasutitermitinae found
worldwide defend themselves against aggressors by ejecting a
secretion containing structurally unique tetracyclic diter-
penes.[1] Kempene-2 (1), kempene-1 (2), and 3-epi-kem-
pene-1 (3) are diterpenes with a kempane skeleton isolated
first from the defense secretion of termite soldiers of the
species Nasutitermes kempae[2] and Bulbitermes singaporen-
sis[3] (Scheme 1).[4,5] The synthesis of these exceptional natural
molecular Diels–Alder reaction was the key transformation in
the synthesis.[8] Recent studies[9] on the biological activity of 5
showed that this norditerpene exhibits an antibiotic activity
against B. subtilis similar to that of antimicrobial trinervi-
tanes.[10] In the course of our work[11] on the construction of
hydroazulenes through domino metathesis reactions[12,13] we
have now selected the tetracyclic kempanes 1–3 as challeng-
ing synthetic targets with seven and eight contiguous stereo-
genic centers, respectively, including two quarternary carbon
atoms.
Herein we report on the first enantioselective synthesis of
the diterpenes 1–3 by the domino metathesis reaction of a
suitably substituted dienyne 6, which in turn was obtained
from the bicyclic compound 7 generated in high enantiomeric
purity by
a catalytic asymmetric Diels–Alder reaction
(Scheme 2).[14,15]
Scheme 2. Retrosynthesis of kempanes 1–3.
Scheme 1. Tetracyclic diterpenes (1–4) from the defense secretion of
higher termites and the synthetic analogue 5.
For the enantioselective synthesis of dienyne 6 an
asymmetric [4+2] cycloaddition of 2,6-dimethyl-1,4-benzo-
quinone (8) with isoprene (9) was used, which was catalyzed
very efficiently by the oxazaborolidine aluminum tribromide
complex 10 (Scheme 3).[14,15] Under optimized reaction con-
ditions 7 was obtained in very good yield and with excellent
regioselectivity (> 99:1) and high enantiomeric excess on a
gram scale. This reaction constitutes a formal enantioselective
synthesis of kempene-2 (1), since rac-7 was already trans-
formed to rac-1. However, in contrast to the present work, a
McMurry reaction served as the key step to generate the
seven-membered ring of the target molecule in moderate
yield.[6] After reduction of the electron-deficient olefin in 7
under equilibrating conditions,[6] the pure stereoisomer 11 was
isolated in 31% yield. Three additional diastereomers of 11
were isolated (68% overall yield) and could partially be
converted to 11 by treating again with zinc and acetic acid. A
chemo- and diastereoselective reduction of diketone 11 with
l-selectride delivered alcohol 12,[6] which was converted to
products has proven to be problematic. So far, only the total
synthesis of racemic kempene-2 (rac-1) has been reported,[6]
whereas a number of other synthetic studies[7] have not yet led
to the desired kempanes. Recently, we achieved the enantio-
selective synthesis of 4-desmethyl-3a-hydroxy-15-rippertene
(5), a close analogue of rippertene 4, which was isolated from
[*] M. Schubert, Prof. Dr. P. Metz
Fachrichtung Chemie und Lebensmittelchemie
Organische Chemie I, Technische Universitꢀt Dresden
Bergstrasse 66, 01069 Dresden (Germany)
Fax: (+49)351-463-33162
E-mail: peter.metz@chemie.tu-dresden.de
[**] This work was supported by the Deutsche Forschungsgemeinschaft
(ME 776/17-1, ME 776/17-2).
Supporting information for this article is available on the WWW
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 2954 –2956