Angewandte
Chemie
ˇ
[7] a) J. Pospꢁsil, I. E. Markꢂ, J. Am. Chem. Soc. 2007, 129, 3516;
[8] a) J. Cossy, S. Arseniyadis, C. Meyer, R. H. Grubbs, Metathesis in
Natural Product Synthesis: Strategies, Substrates and Catalysts,
Wiley-VCH, Weinheim, 2010; b) K. C. Nicolaou, P. G. Bulger, D.
metathesis reaction with ethylene (26; Figure 1). When using
the Grubbs II catalyst[35] without an argon purge (20 mol%
catalyst, 40 mol% 1,4-benzoquinone, toluene (1 mm), 908C,
1.5 h), we observed the desired products 24 and 26 in an
approximately 1:1 ratio. Dortaꢀs catalyst[36] (10 mol% cata-
lyst, 20 mol% tetrafluoro-1,4-benzoquinone, toluene (1 mm),
2 h, 508C), gave 26 as the major product. We speculate that
a relay-type mechanism[37] might be operative in transferring
the catalyst to the trisubstituted C18 double bond instead of
cycloreversion of the metallacyclobutane and dissociation of
the catalyst. Moreover, the truncation appears to be inter-
connected with the configuration of the double bond at C5.
Compound 26 was always isolated as a clean 5E isomer even
when 24 was a mixture of 5E and 5Z isomers.
[9] a) A. Rivkin, F. Yoshimura, A. E. Gabarda, Y. S. Sho, T.-C.
10913; b) Protodeallylation during metathesis of 1,4-dienes:
[10] a) C. Kujat, M. Bock, A. Kirschning, Synlett 2006, 419; b) C.
Kujat, PhD thesis, Universitꢄt Hannover, 2007; c) K. D.
Schleicher, PhD thesis, Massachusetts Institute of Technology,
2010.
[11] A. Kirschning, C. Kujat, S. Luiken, E. Schaumann, Eur. J. Org.
[12] A. Gansꢄuer, J. Justicia, A. Rosales, B. Rinker, Synlett 2005,
[14] C. M. Binder, D. D. Dixon, E. Almaraz, M. A. Tius, B. Singaram,
[15] a) M. Tokunaga, J. F. Larrow, F. Kakiuchi, E. N. Jacobsen,
Larrow, M. Tokunaga, K. B. Hansen, A. E. Gould, M. E. Furrow,
[17] P. Winter, C. Vaxelaire, C. Heinz, M. Christmann, Chem.
[18] P. Winter, J. Swatschek, M. Willot, L. Radtke, T. Olbrisch, A.
[19] N. Halland, A. Braunton, S. Bachmann, M. Marigo, K. A.
[20] a) M. P. Brochu, S. P. Brown, D. W. C. MacMillan, J. Am. Chem.
[21] For a recent highlight on one-pot reactions, see: C. Vaxelaire, P.
[22] a) J. Zhu, H. Bienaymꢅ, Multicomponent Reactions, Wiley-VCH,
Weinheim, 2005; b) E. Ruijter, R. Scheffelaar, R. V. A. Orru,
[23] a) M.-R. Fischer, A. Kirschning, T. Michel, E. Schaumann,
33, 217; b) T. Michel, A. Kirschning, C. Beier, N. Brꢄuer, E.
[24] L. F. Tietze, H. Geissler, J. A. Gewert, U. Jakobi, Synlett 1994,
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Khatuya, P. Bertinato, R. A. Miller, M. J. Tomaszewski, Chem.
By using Jones oxidation conditions (excess Jones-reagent
diluted in acetone, 08C)[38] the TBS ether on the primary
alcohol of 24 was cleaved and effected rapid oxidation to the
carboxylic acid in 70–85% yield, thereby avoiding double-
bond isomerization and decomposition observed upon iso-
lation of aldehyde intermediates (e.g., TEMPO-based oxida-
tions). The C11 TBS ether was removed by using HF·py
(76%), and finally selective reductive cleavage of the
propionate ester[39] in presence of the a,b-unsaturated lactone
and the carboxylic acid moiety afforded ripostatin B (1) in
42% yield (68% based on unreacted starting material). The
20
spectroscopic data including the optical rotation (½aꢁD ¼ + 26
(c = 5, MeOH), published + 35.7 (c = 1, MeOH)) was in
good[40] agreement with that reported in the literature.
In conclusion, we describe herein an efficient total
synthesis[41] of the RNA polymerase inhibitor ripostatin B.
By using a ring-closing metathesis reaction as the key step we
were able to establish the sensitive 14-membered macro-
lactone featuring the unusual doubly skipped triene moiety.
The acyclic precursors were joined in a one-pot linchpin
coupling of two terminal epoxides derived from cheap
monoterpene raw materials. Our route involves 14 steps in
the longest linear sequence (4% overall yield from geranyl
acetate) and nicely showcases the powerful interplay of
modern organocatalytic (epoxide 7) and transition metal
catalyzed transformations (Cu, Co, Pd, Ru). Future work
from our laboratories will concern the synthesis of analogues
and their biological evaluation.
Received: December 9, 2011
Published online: February 15, 2012
Keywords: antibiotics · macrocycles · metathesis ·
.
natural products · polyketides
See the Supporting Information for details.
[30] J. Inanaga, K. Hirata, H. Saeki, T. Katsuki, M. Yamaguchi, Bull.
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Antimicrob. Agents Chemother. 2000, 44, 3163.
Angew. Chem. Int. Ed. 2012, 51, 3396 –3400
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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