cis-decalins from quinic acid: Toward a synthesis of branimycin

Article abstract of DOI:10.1021/ol0630189

(Chemical Equation Presented) Starting from (-)-quinic acid an efficient synthesis of highly functionalized cis-α,β-unsaturated ketone 3, an advanced precursor of branimycin, has been accomplished via two key step reactions: a ring closing metathesis reac

Full text of DOI:10.1021/ol0630189

ORGANIC
LETTERS
2007
Vol. 9, No. 5
813-816
cis-Decalins from Quinic Acid: Toward
a Synthesis of Branimycin
Stefan Marchart, Johann Mulzer,* and Valentin S. Enev*
Institut fu¨r Organische Chemie, Wa¨hringerstrasse 38, A-1090 Wien, Austria
Valentin.eneV@uniVie.ac.at; johann.mulzer@uniVie.ac.at
Received December 14, 2006
ABSTRACT
Starting from (−)-quinic acid an efficient synthesis of highly functionalized cis-r,â-unsaturated ketone 3, an advanced precursor of branimycin,
has been accomplished via two key step reactions: a ring closing metathesis reaction to prepare the cis-decalin system, and a highly
stereoselective epoxidation reaction.
The synthesis of highly functionalized cis-decalin systems
has been a longstanding problem. In many cases Diels-
Alder-based annulations to p-quinoids have been employed,
but despite the conceptual simplicity of this approach the
subsequent elaboration of stereogenic centers and appendages
has proved problematic. Intrigued by the low price of quinic
acid we looked for possibilities to annulate a second ring to
this template. By using a non-Diels-Alder methodology, a
richly elaborated cis-decalin system should be generated. As
a target for this strategy we chose branimycin (1),1,2 an
unusual member of the nargenicin antibiotic family,3 which
has been isolated from Streptomyces by the Laatsch group
in Go¨ttingen.4 Biological tests have shown that branimycin
is active against Escherichia coli, Bacillus subtilis, Staphylo-
coccus aureus, and in particular Streptomyces Viridochro-
mogenes. Apart form the biological activity, the complex
cis-fused decalin core, the 1,4-oxygen bridge, and the
9-membered macrolide ring make 1 an attractive target for
total synthesis.
The retrosynthetic concept is shown in Figure 1. As a key
disconnection the 1,2-addition of vinyllithium subunit 2 to
bicyclic 7,8-epoxy-12-ketone 3 was envisaged. This highly
convergent approach necessitates efficient syntheses of both
2 and 3. As outlined before, (-)-quinic acid5 7 was chosen
as a starting material for 3, to explore whether the existing
chiral centers could be used to control the synthesis of an
enantiomerically and diastereomerically pure cis-decalin
system. Ring B should be constructed by a ring closing
metathesis6 (RCM) of 4, in which the required monosubsti-
tuted double bonds were to be installed via two successive
Claisen-Ireland rearrangements,7 from protected diol precur-
(1) Enev, V. S.; Drescher, M.; Kaehlig, H.; Mulzer, J. Synlett 2005, 14,
2227-2229.
(2) Felzmann, W.; Arion, V. B.; Mieusset, J. L.; Mulzer, J. Org. Lett.
2006, 8, 3849-3851.
(5) (a) Barco, A.; Benetti, S.; De Risi, C.; Marchetti, P.; Pollini, G. P.;
Zanirato, V. Tetrahedron: Asymmetry 1997, 8, 3515-3545. (b) Usami, Y.;
Ueda, Y. Chem. Lett. 2005, 34, 1062-1063.
(3) (a) Review: Kallmerten, J. Studies in Natural Procducts Chemistry;
Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, The Netherlands, 1995; Vol.
17, pp 283-310 and references cited therein. (b) Celmer, W. D.; Chmurny,
C. N.; Moppett, C. E.; Ware, R. S.; Watts, P. C.; Whipple, E. B. J. Am.
Chem. Soc. 1980, 102, 4203-4209. (c) Tone, J.; Shibakawa, R.; Maeda,
H.; Yamauchi, Y.; Niki, K.; Saito, M.; Tsukuda, K.; Whipple, E. B.; Watts,
P. C.; Moppett, C. E.; Jefferson, M. T.; Huang, L. H.; Cullen, W. P.; Celmer,
W. D. 20th Interscience Conference on Antimicrobial Agents and Chemo-
therapy, New Orleans, LA, Abstract 62, Sep 22-24, 1980.
(4) Speitling, M.; Gru¨n-Wollny, I.; Hannske, F. G.; Laatsch, H. 12 and
13 IRSEER Naturstofftage der DECHEMA e. V. Irsee, 2000 and 2001.
(6) Fu¨rstner A. Angew. Chem., Int. Ed. 2000, 39, 3012-3043. Grubbs,
R. H.; Chang, S. Tetrahedron 1998, 54, 4413-4450. Trinka, T. M.; Grubbs,
R. H. Acc. Chem. Res. 2001, 34, 18-29. Armstrong, S. K. J. Chem. Soc.,
Perkin Trans. 1 1998, 371-388. Lee, C. W.; Grubbs, R. H. Org. Lett. 2000,
2, 2145-2147. Gaich, T.; Mulzer, J. Curr. Top. Med. Chem. 2005, 5, 1473-
1494. Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed.
2005, 44, 4490-4527.
(7) Paquette, L. A. ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon: New York, 1991; Vol. 5, pp 785-
898.
10.1021/ol0630189 CCC: $37.00
© 2007 American Chemical Society
Published on Web 02/01/2007

Scheme 1. Synthesis of Rearrangement Precursor 5
newly formed stereocenter is planned to be inverted in a later
stage of the synthesis. Benzylation and removal of the BDA11
group furnished diol 9 in 80% yield over three steps.
Conversion of 9 to 5 was achieved in a two-step sequences
regioselective acylation of the C7-hydroxy group of 9 (p-
MeOC6H4OCH2COCl,12 2,6-di-tert-butylpyridine,13 82% yield)
followed by TES protection at the C8-hydroxy groupswhich
set the scene for the first Claisen-Ireland rearrangement.
Following Corey’s procedure14 ester 5 was converted to the
silylketene acetal under internal quench conditions (TMSCl/
LHMDS) and subsequently heated to give 10 (94% after one
recycling step) as a mixture of isomers (Scheme 2). The low
stereoselectivity for C12 was inconsequential as this stereo-
genic center becomes oxidized later in the synthesis.
Nevertheless, the diastereomers were separated to avoid
ambiguous spectra information for the proximate reaction
steps. The synthesis was carried on with pure main isomer
10, whose configuration was assigned by 2D NMR studies
of the corresponding iodolactone 10a.15
Figure 1. Retrosynthetic analysis.
sor 5. In turn, 5 would be assembled in stereoselective
fashion from enone 6.
Our synthesis started from the known compound 8,8 which
was subjected to a Mukaiyama-type condensation with
dimethoxymethane9 (Scheme 1) to afford 6 as a single
diastereomer in moderate yield (55%, 78% after recycling).
The same stereoselectivity has been observed with use of
m-CPBA and NBS as electrophiles, which is a consequence
of the conformational rigidity due to the trans-diequatorial-
protected 1,2-diol. An axial attack on the electron-rich C9
avoids a twist boat conformation.10
Acid 10 was transformed to olefin 11 in 3 steps via
reduction to the corresponding aldehyde and subsequent
(11) Ley, S. V.; Baeschlin, D. K.; Dixon, D. J.; Foster, A. C.; Ince, S.
J.; Priepke, H. W. M.; Reynolds, D. J. Chem. ReV. 2001, 101, 53-80.
(12) Piers, E.; Lemieux, R. Organometallics 1995, 14, 5011-5012.
(13) It has to be pointed out that use of pyridine or 2,6-lutidine resulted
in a 1:1 mixture of C-7/8 O-acyl regioisomers.
(14) Corey, E. J.; Gross, A. Tetrahedron Lett. 1984, 25, 495-498.
(15) Selected NOE data for 10a.
Longer reaction times improved the yield remarkably, but
with a sacrifice in diastereomeric ratio. Luche reduction of
6 occurred exclusively from the less hindered side. This
(8) Murray, L. M.; O’Brien, P.; Taylor, R. J. K. Org. Lett. 2003, 5, 1943-
1946.
(9) Murata, S.; Suzuki, M.; Noyori, R. Tetrahedron 1988, 13, 4259-
4275.
(10) (a) Murray, L. M.; O’Brien, P.; Taylor, R. J. K. Org. Lett. 2003, 5,
1943-1946. (b) Mathews, R. S.; Girgenti, S. J.; Folkers, E. A. J. Chem.
Soc., Chem. Commun. 1970, 708-709. (c) House, H. O.; Umen, M. J. J.
Org. Chem. 1973, 38, 1000-1003. (d) Skaddan, M. B.; Wu¨st, F. R.;
Katzenellenbogen, J. A. J. Org. Chem. 1999, 64, 8108-8121.
814
Org. Lett., Vol. 9, No. 5, 2007

Scheme 2. Preparation of RCM Precursor 4
Scheme 3. Synthesis of Epoxyketone 16
subsequently oxidized (DMP)20 to give 15 in 78% yield
(Scheme 3). 2D NMR spectra confirmed that none of the
dreaded epimerization at C11 had occurred.
Stereo- and regioselective epoxidation of the C7-C8
double bond with m-CPBA furnished diastereomerically pure
crystalline epoxyketone 16 whose relative configuration was
established by single-crystal diffraction (Figure 2).
Wittig olefination16 in 84% overall yield. To initiate the
second Claisen-Ireland rearrangement 11 was desilylated
and the resulting allylic alcohol was acylated to give ester
12 via Mitsunobu inversion.17 In the course of this reaction
the C6-appendage was introduced simultaneously. The
conversion of 12 to di-olefin 4 followed the established four-
step sequence: rearrangement to 13, followed by esterifi-
cation, reduction to the corresponding aldehyde, and Wittig
olefination (dr 2:1, 56% overall yield). The RCM reaction
was carried out with either the Grubbs’ second generation
catalyst18 or Hoveyda-Grubbs’ second generation catalyst.19
Unfortunately it turned out that Grubbs’ second generation
catalyst underwent decomposition in the course of the
reaction at the required temperature (ca 75 °C), whereas
Grubbs-Hoveyda catalyst was stable enough to give 65%
of cis-decalin 14 with only starting material left, which could
be recycled (Scheme 3). After chromatographic separation
the pure isomer 14 was deprotected (DDQ/DCM/buffer) and
Figure 2. ORTEP-321 projection (ellipsoid: 50% probability) of
epoxyketone 3.
In conclusion, we have shown that quinic acid is a suitable
substrate for stereocontrolled annulations via the Claisen-
Ireland rearrangement; RCM protocol. Quite obviously the
configurations at C6 and C11 can be manipulated at will by
acylating diol 9 under retention or inversion of configuration
so that cis- and trans-decalins with either absolute config-
uration should be available under perfect stereocontrol.
Specifically, we have described an efficient route to the cis-
decalin core of branimycin, whose further synthesis is
actively pursued in our laboratory.
(16) Cadogan, J. I. G. Orgnanophosphorus Reagents in Organic Syn-
thesis; Academic Press: New York, 1979.
(17) Mitsunobu, O. Synthesis 1981, 1, 1-28.
(18) Grubbs, R. H.; Schwab, B.; Ziller, J. W. J. Am. Chem. Soc. 1996,
118, 100-110.
(19) (a) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J.
Am. Chem. Soc. 2000, 122, 8168-8179. (b) Gessler, S.; Randl, S.; Blechert,
S. Tetrahedron Lett. 2000, 41, 9973-9976.
(20) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156.
(21) Farrugia, L. J. J. Appl. Crystallogr. 1997, 30, 565.
Org. Lett., Vol. 9, No. 5, 2007
815

We thank Dr. Hans-Peter Kaehlig, Dr. Lothar Brecker,
and Susanne Felsinger for NMR analysis, M. Zinke for
performing the HPLC separations, and Prof. Vladimir Arion
(all University of Vienna) for crystallography. Moreover the
financial support from the Austrian Science Fund (FWF) is
gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures and analytical data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0630189
816
Org. Lett., Vol. 9, No. 5, 2007