Enantioselective total synthesis of the diterpenes kempene-2, kempene-1, and 3-epi-kempene-1 from the defense secretion of higher termites

Article abstract of DOI:10.1002/anie.201007551

(Chemical Equation Presented) Two rings in one sweep: A domino metathesis of the bicyclic dienyne 4 (TBS=tertbutyldimethylsilyl) obtained from a catalytic enantioselective Diels-Alder reaction as the key process enabled the efficient preparation of the tetracyclic diterpenes kempene-2 (1), kempene-1 (2), and 3-epi-kempene-1 (3).

Full text of DOI:10.1002/anie.201007551

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
Homepage: http://www.chm.tu-dresden.de/oc1/
[**] 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
under http://dx.doi.org/10.1002/anie.201007551.
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Angew. Chem. Int. Ed. 2011, 50, 2954 –2956

Scheme 3. Catalytic enantioselective Diels–Alder route to bicyclic ketone 20. a) 9, 5 mol% 10, CH2Cl2, ꢀ788C, 98%, 94% ee; b) Zn, HOAc, reflux,
31% 11 (+68% diastereomers); c) L-selectride, THF, ꢀ788C, 90%; d) MOMCl, iPr2NEt, CH2Cl2, reflux, 96%; e) 1. 14, sBuLi, THF, ꢀ60!ꢀ238C,
2. 13, ꢀ78!ꢀ608C, 3. KH, ꢀ608C!RT; f) TFA, CH2Cl2, RT, 65% (2 steps; 79% based on recovered 13); g) 1. 16, LiHMDS, THF, 08C, 2. 15, 08C,
87%; h) TsOH, MeOH, reflux, 87%; i) TBSOTf, 2,6-lutidine, CH2Cl2, 08C, 95%; j) BH3·SMe2, THF, 08C, 83%; k) DMP, CH2Cl2, 08C!RT, 91%.
DMP=Dess–Martin periodinane, L-selectride=lithium tri-sec-butylborohydride, LiHMDS=lithium hexamethyldisilazide, MOMCl=methoxymethyl
chloride, TBSOTf=tert-butyldimethylsilyl triflate, TFA=trifluoroacetic acid, TsOH=toluenesulfonic acid.
the MOM ether 13. In analogy to the Dauben route,[6] an
efficient chain extension of 13 to give aldehyde 15 succeeded
by application of silane 14 in a Peterson olefination followed
by acidic hydrolysis. Another carbonyl olefination of 15 with
the ylide derived from 16 led to enol ether 17. Treatment of 17
with methanol and acid effected both solvolysis of the MOM
ether and formation of a dimethyl acetal to afford 18. After
silylation to give 19, ketone 20 was obtained by hydrobora-
tion/oxidation and subsequent Dess–Martin oxidation as a
mixture of two diastereomers.
Generation of the trimethylsilyl enol ether of 20 under
thermodynamic control[16] and oxidation with DDQ[7a] led to
enone 21. Cleavage of the dimethyl acetal under mild
conditions[17] gave aldehyde 22 (Scheme 4). Chemoselective
Wittig reaction of 22 with the ylide derived from 23 then
yielded the bicyclic enone 24. Conjugate addition of the
propynyl aluminate[18,19] generated from 25 led to silyl enol
ether 26 as a single diastereomer, and after mild hydrolysis
ketone 27 was isolated. A completely diastereoselective[20] a-
allylation of 27 to give the desired dienyne 29 (6 with R =
Scheme 4. Conversion of bicyclic ketone 20 into dienyne 29. a) TMSI, HMDS, THF, RT; b) DDQ, benzene, RT, 67% (2 steps); c) PPTS, acetone,
reflux, 97%; d) 1. 23, BuLi, THF, 08C, 2. 22, 08C, 90%; e) 1. 25, BuLi, THF, ꢀ788C, 2. Me3Al, ꢀ788C, 3. 24, TBSOTf, ꢀ788C, 84%; f) 2n HCl,
THF, RT, 97%; g) TMSI, HMDS, THF, RT; h) 1. MeLi, 08C, 2. 28, HMPA, ꢀ208C, 40% 29 + 52% 30 (2 steps); i) toluene, reflux, 90%.
DDQ=2,3-dichloro-5,6-dicyano-p-benzoquinone, HMDS=hexamethyldisilazane, HMPA=hexamethylphosphoramide, PPTS=pyridinium p-tolue-
nesulfonate, TMSI=trimethylsilyl iodide.
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TBS) succeeded by reaction of the lithium enolate formed
reported synthesis of rac-1[6] and can be increased further by
recycling of the undesired diastereomers of 11.
under thermodynamic control with 28. Allyl ether 30 also
generated in this reaction could be converted with complete
diastereoselectivity to 29 by means of a Claisen rearrange-
ment.
Received: December 1, 2010
Published online: February 25, 2011
Completion of the synthesis of kempenes 1–3 was initiated
by the domino metathesis reaction[11–13] of dienyne 29 using
the Grubbs II catalyst 31 (Scheme 5). This reaction furnished
Keywords: asymmetric catalysis · cycloaddition ·
domino reactions · metathesis · natural products
.
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Scheme 5. Domino metathesis of 29 and completion of the synthesis
of kempene-2 (1), kempene-1 (2), and 3-epi-kempene-1 (3). a) 5 mol%
31, CH2Cl2, reflux, 92%; b) Bu4NF, THF, reflux, 100%; c) Ac2O,
pyridine, DMAP, CH2Cl2, RT, 91% 1, 100% 2, 100% 3; d) LiAlH4, THF,
08C, 60% 34 + 26% 35. Cy=cyclohexyl, DMAP=4-dimethylamino-
pyridine, Mes=mesityl.
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the protected tetracyclic compound 32 with high efficiency as
the only cyclization product. This key step could also be
realized in good yield (82%) with 10 mol% of the Grubbs I
catalyst. Silyl ether 32 was quantitatively deprotected to
afford alcohol 33, which finally gave (+)-kempene-2 (1) after
acetylation. A circular dichroism (CD) spectrum (MeOH) of
synthetic 1 exhibited a strong positive Cotton effect at 294 nm
(De = + 1.43) as was reported for the natural product 1
(289 nm, De = + 1.46).[2,21] This confirms the absolute config-
uration assigned by Prestwich, since the stereochemical
control by catalyst 10 is well understood.[14,15] Reduction of
33 with lithium aluminum hydride led to a 2.3:1 mixture of
diols 34 and 35.[3] Acetylation of these diols to give (+)-
kempene-1 (2) and (+)-3-epi-kempene-2 (3) proceeded very
efficiently.[3]
In summary, we have accomplished the enantioselective
total synthesis of (+)-kempene-2 (1) commencing with 2,6-
dimethyl-1,4-benzoquinone (8) in only 23 steps with an
overall yield of 3.2%. The diterpenes (+)-kempene-1 (2)
and (+)-3-epi-kempene-1 (3) were obtained in 24 steps each.
Owing to the domino metathesis strategy, the efficiency of the
route developed here is considerably higher than that of the
[17] C. E. Masse, M. Yang, J. Solomon, J. S. Panek, J. Am. Chem. Soc.
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[21] Optical rotation data for the natural products 1– 3 have
obviously not been measured because of the small amounts
isolated.
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