A desymmetrization approach toward highly oxygenated cis-decalins

Article abstract of DOI:10.1021/ol900834c

The cis-decalin core 2 of the antibiotic branimycin has been prepared by desymmetrization of diepoxynaphthalene 4. The key steps involve two successive S_N' opening of the oxa-bridges. An improved procedure for the synthesis of 4 Is also described.

Full text of DOI:10.1021/ol900834c

ORGANIC
LETTERS
2009
Vol. 11, No. 13
2884-2886
A Desymmetrization Approach toward
Highly Oxygenated cis-Decalins
Alexey Gromov,* Valentin Enev, and Johann Mulzer*
UniVersity of Vienna, Institute of Organic Chemistry, Wa¨hringerstrasse 38,
A-1090 Vienna, Austria
alexey.gromoV@uniVie.ac.at; johann.mulzer@uniVie.ac.at
Received April 19, 2009
ABSTRACT
The cis-decalin core 2 of the antibiotic branimycin has been prepared by desymmetrization of diepoxynaphthalene 4. The key steps involve
two successive SN′ opening of the oxa-bridges. An improved procedure for the synthesis of 4 is also described.
In recent years, our group became interested in the develop-
ment of various novel approaches toward the synthesis of
highly functionalized cis-decalins in the context of an
ongoing study toward the total synthesis of the highly active
antibiotic branimycin1,2 (1).
enantioselective SN′ opening of the second oxa-bridge with
a formal hydride anion.
Scheme 1. Retrosynthetic Overview of Compound 2
In our new approach, we envisioned that the construction
of the cis-decalin core 2 of branimycin (1) could be
accomplished by desymmetrization of diepoxynaphthalene
4 (Scheme 1) via two successive SN′ reactions.3
First a copper-mediated SN′ opening of one of the oxa-
bridges was performed with a Grignard reagent containing
a silyl group as a latent hydroxy group, followed by an
(1) (a) Enev, V. S.; Drescher, M.; Mulzer, J. Org. Lett. 2008, 10, 413–
416. (b) Enev, V. S.; Drescher, M.; Mulzer, J. Tetrahedron 2007, 63, 5930–
5939. (c) Marchart, S.; Mulzer, J.; Enev, V. S. Org. Lett. 2007, 9, 813–
816. (d) Felzmann, W.; Arion, V. B.; Mieusset, J. L.; Mulzer, J. Org. Lett.
2006, 8, 3849–3851. (e) Review: Mulzer, J.; Castagnolo, D.; Felzmann,
W.; Marchart, S.; Pilger, C.; Enev, V. S. Chem. Eur. J. 2006, 12, 5992–
6001
.
(2) (a) Isolation and biological activity of branimycin : Speitling, M.
Ph.D. Thesis, Universita¨t Go¨ttingen, 1998. (b) Speitling, M.; Gru¨n-Wollny,
I.; Hannske, F. G.; Laatsch, H. IRSEER Naturstofftage der DECHEMA
e.V. Irsee 2000, 2001, poster sessions 12 and 13.
(3) For similar desymmetrizations, see: (a) Lautens, M.; Fillion, E. J.
Org. Chem. 1996, 61, 7994–7995. (b) Lautens, M.; Fillion, E. J. Org. Chem.
1998, 63, 647–656. (c) Webster, R.; Bo¨ing, C.; Lautens, M. J. Am. Chem.
Soc. 2009, 131, 444–445.
The synthesis of diepoxynaphthalene 44 commenced with
the 2-fold Diels-Alder reaction between methyl propiolate
and furan (Scheme 2). When we performed this reaction at
0 °C for 4 h, both diastereomers 5a (52%) and 5b (14%)
were formed. However, on longer reaction times, the
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undesired diastereomer 5b slowly disappeared, leaving 5a
as a single diasteromer along with some decomposition
products.5 This protocol avoids the tedious chromatographic
separation of 5a and 5b and is suitable for the synthesis of
5a on a multigram scale.
Scheme 3.
Desymetrization of Compound 4a
Scheme 2.
Synthesis of Tetracycle 4a
a brsm ) based on recovered starting material.
Ni(COD)2/(R)-BINAP. Indeed, a pseudoenantiotopos-
selective hydrogen attack was achieved on both enanti-
omers of 3 to give the enantiomerically enriched regioi-
somers 119 and 12 in 91% yield, easily separable by
chromatography.10
a HPT ) 1-hydroxypyridine-2(1H)-thione.
The synthesis of 2 was continued with a Dess-Martin
oxidation of 11, followed by base-catalyzed double-bond
isomerization to provide R,ꢀ-unsaturated ketone 14 in 88%
yield. Regioselective epoxidation of diene 14 with m-CPBA
gave a 3:1 mixture of diastereomeric epoxides, easily separable
by chromatography. To avoid competitive Bayer-Villiger
oxidation, the reaction was stopped at ca. 50% conversion. The
relative configuration of the major diastereomer 2 was deter-
mined by single-crystal diffraction (see the Supporting Informa-
tion).
The four-step elaboration of ester 5a to diepoxynaph-
thalene 4 proved straightforward.4 Saponification of 5a
provided the corresponding acid, which was isolated as
the triethylammonium salt 6. Activation of the carboxylate
via the acyl tosylate and conversion to N-thionopyridyl
ester 7 was followed by reductive Barton decarboxylation
to furnish the desired tetracyclic compound 4 in 67%
overall yield from 5a.
With a reliable route to diepoxynaphthalene 4 in hand,
the selective opening of the oxa-bridges could be tested.
We were delighted to find that exposure of 4 to Me2-
PhSiCH2MgCl/CuCl/Ph3P under the conditions described
by Carretero et al.6 resulted in an anti SN′ opening of only
one of the oxa-bridges to give compound 8 in 75% yield
(82% brsm). Alcohol 8 was protected as a PMB-ether with
PMBBr (prepared in situ from PMBCl7 and NaBr in
DMF). Next, the C-Si bond was cleaved oxidatively to
deliver the corresponding primary alcohol which was
converted to methyl ether 3 in 73% yield over two steps
(Scheme 3).
To secure the absolute configuration of our products,
racemic compound 3 was separated into the enantiomers by
chiral HPLC. Under the same conditions used for the
racemate, enantiomer (+)-3 gave 11. On the other hand,
(-)-3 was converted into alcohol 15 and then into crystalline
urethane 16, the X-ray analysis of which allowed the
determination of the absolute configuration based on the
anomalous dispersion of chlorine atoms.
(8) Lautens, M.; Rovis, T. Tetrahedron 1998, 54, 1107–1116.
(9) It has to be pointed out that skipped dienes 11 and 13 (not shown,
see the Supporting Information) proved to be air sensitive to give dienyl
hydroperoxides (for a discussion, see comment 2 in the Supporting
Information).
(10) Toluene as a solvent was essential for a high yield of the desired
products. Performing the reaction in THF resulted in thformation of ca 50%
of compound 3′.
The stage was now set for the conversion of the
remaining oxa-bridge into the R,ꢀ-unsaturated ketone
moiety of 2 (Scheme 4). Following a procedure by Lautens
et al.,8 racemic compound 3 was treated with DIBAL and
(4) For preliminary studies on the synthesis of 4, see: Gromov, A.; Enev,
V.; Mulzer, J. Synth. Commun., in press.
This solvent effect might be attributed to the higher Lewis acidity of
aluminum species in the non-coordinating toluene. An increase in Lewis
acidity presumably favors coordination of Al with the oxa-bridge and
therefore facilitates the C-O bond cleavage. For other examples
of the influence of Lewis acids on oxa-bridge opening, see:
Lautens, M.; Chiu, P.; Ma, S.; Rovis, T. J. Am. Chem. Soc. 1995, 117,
532–533.
(5) For a discussion of this phenomenon, see comment 1 in the
Supporting Information.
(6) Arraya´s, R. G.; Cabrera, S.; Carretero, J. C. Org. Lett. 2003, 5, 1333–
1336.
(7) For a reliable scalable procedure for preparation of PMBCl, see:
Chaudhari, S. S.; Akamanchi, K. G. Synlett 1999, 11, 1763–1765.
Org. Lett., Vol. 11, No. 13, 2009
2885

Scheme 4.
Opening of the Second Oxa-Bridge and Synthesis of Compound 2a
a The major diastereomer is shown.
vinyllithium species to the carbonyl group led to lithium
alcoholoate 18-Li. On raising the temperature, cyclization
of the lithium alkoxide onto the epoxide was achieved to
give tricycle 19 with the desired oxa-bridge. Uncyclized 18
was isolated in trace amounts and was converted to the
desired 19 by strring with silica gel, thus giving 19 in 61%
combined yield.
Scheme 5
.
Coupling of 2 and 17 and Formation of the
Oxa-Bridge
In conclusion, we have demonstrated that organometallic
catalysis can be used for a successive desymmetrization of
diepoxynaphthalene 4. This opens a direct access to highly
functionalized cis-decalin systems as exemplified by the core
of branimycin.
Acknowledgment. We thank Dr. Hanspeter Ka¨hlig, Dr.
Lothar Brecker, and Susanne Felsinger for NMR analysis,
Prof. Vladimir Arion for X-ray analysis (all Universitiy of
Vienna, Austria), and Dr. Neil Sheddan (LOBA Feinchemie
GmbH, Vienna, Austria) for help in the preparation of the
manuscript.
Supporting Information Available: Experimental pro-
cedures and analytical data for all new compounds and crystal
data of compounds 2 and 16. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL900834C
Finally, pursuing the strategy envisioned in our group,1a,e,11
we coupled ketone 2 and the lithitiated side chain obtained
from iodide 17 (Scheme 5).12 Nucleophilic addition of the
(11) Cf. also: Plata, D. J.; Kallmerten, J. J. Am. Chem. Soc. 1998, 110,
4041–4042.
(12) Felzmann, W.; Castagnolo, D.; Rosenbeiger, D.; Mulzer, J. Org.
Chem. 2007, 72, 2182–2186.
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Org. Lett., Vol. 11, No. 13, 2009