A non-diels-alder approach to the cis-decalin core of branimycin

Article abstract of DOI:10.1021/ol7027338

The synthesis of the highly substituted cis-decalin core of branimycin has been accomplished. A catalytic copper mediated S_N2′ opening of oxabicycle 7 with Grignard reagent and ring-closing metathesis served as key transformations.

Full text of DOI:10.1021/ol7027338

ORGANIC
LETTERS
2008
Vol. 10, No. 3
413-416
A Non-Diels−Alder Approach to the
cis-Decalin Core of Branimycin
Valentin S. Enev,* Martina Drescher, and Johann Mulzer*
Institut fu¨r Organische Chemie, Wa¨hringerstrasse 38, A-1090 Wien, Austria
Valentin.eneV@uniVie.ac.at; johann.mulzer@uniVie.ac.at
Received November 12, 2007
ABSTRACT
The synthesis of the highly substituted cis-decalin core of branimycin has been accomplished. A catalytic copper mediated SN2
′ opening of
oxabicycle 7 with Grignard reagent and ring-closing metathesis served as key transformations.
In our ongoing project toward the synthesis of the novel
antibiotic branimycin 1,1,2 we were interested in developing
a new non-Diels-Alder methodology for the synthesis of
highly substituted cis-decalin system which turned out to be
the main challenge in the synthesis of 1.
Recently,3 we have reported an efficient synthesis of
advanced precursor of branimycin, from quinic acid via a
multistep pathway including Claisen-Ireland rearrangements
and ring-closing metathesis reactions. Although the synthesis
was successful, some difficulties associated with itslengthy,
low diastereoselectivity and moderate yields in some stepss
prompted us to develop a new approach to cis-decalin
intermediate 3 which will be coupled at a late stage with 2
under concomitant epoxide opening and formation of the
C2-C7-oxygen bridge in 1.
In our retrosynthetic route to 3 (Scheme 1), we envisioned
that the construction of the decalin core could be ac-
complished by a ring closing metathesis4 (RCM) of 4, which
in turn was to be synthesized from aldehyde 5 via Hiyama-
Nozaki-Kishi5,6 reaction, followed by regio- and stereose-
lective epoxidation of the endocyclic double bond. Finally,
(4) 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.
(5) Okude, Y.; Hirano, S.; Hiyama, T.; Nozaki, H. J. Am. Chem. Soc.
1977, 99, 3179-3180. Okude, Y.; Hiyama, T.; Nozaki, H. Tetrahedron
Lett. 1977, 3829-3832.
(6) Recent reviews: (a) Takai, K.; Nozaki, H. Proc. Jpn. Acad., Ser. B
2000, 76B, 123-131. (b) Fu¨rstner, A. Chem. ReV. 1999, 99, 991-1045.
(c) Wessjohann, L. A.; Scheid, G. Synthesis 1999, 1, 1-36. (d) Avalos,
M.; Babiano, R.; Cintas, P.; Jimenez, J. L.; Palacios, J. C. Chem. Soc. ReV.
1999, 28, 169-177.
(1) Enev, V. S.; Drescher, M.; Kaehlig, H.; Mulzer, J. Synlett 2005, 14,
2227-2229.
(2) (a) Felzmann, W.; Arion, V. B.; Mieusset, J. L.; Mulzer, J. Org. Lett.
2006, 8, 3849-3851. (b) Felzmann, W.; Castagnolo, D.; Rosenbeiger, D.;
Mulzer, J. Org. Chem. 2007, 72, 2182-2186.
(3) Marchart, S.; Mulzer, J.; Enev, V. S. Org. Lett. 2007, 9, 813-816.
10.1021/ol7027338 CCC: $40.75
© 2008 American Chemical Society
Published on Web 12/28/2007

h the desired compound 6 in a 87% yield as a single
diastereomer. Separation of racemic 6 via chiral HPLC gave
both enantiomers whose absolute stereochemistry was as-
signed using the Mosher method.11
Scheme 1. Retrosynthetic Analysis of Branimycin
The desired R-enantiomer (R refers to the absolute
configuration at C-1) was deprotected, and the resulting diol
8R was treated with p-methoxybenzaldehyde to give acetal
9 in 66% yield (Scheme 3).12 Dess-Martin oxidation of 9
furnished aldehyde 10 (89%) which was used without further
purification.
The direct conversion of aldehyde 10 to olefin 1213
proved more problematic than expected. Attempts to use
Wittig-14 or Tebbe olefination15 or a Takai16 reaction to
install the vinyl group led to inseparable mixtures of
unidentified products. Initial efforts to perform a Peterson
olefination17 using LiCH2TMS or TMSCH2MgCl also
failed. It turned out that these reagents are too basic as they
give a mixture of recovered aldehyde 10 and its con-
jugated isomer. Finally, the cerium reagent prepared from
18
LiCH2TMS and CeCl3 converted 10 into diastereomeri-
cally pure 11 as white needles in 92% yield. The configu-
ration of the new stereogenic center was assigned by
X-ray diffraction studies on single crystals of 11 (Figure 1)
we anticipated that aldehyde 5 would arise from a copper-
mediated SN2′ opening of oxabicycle7,8 7 with the Grignard
reagent containing a dimethyl(phenyl)silyl group as a masked
hydroxy group.9
The synthesis (Scheme 2) starts from the readily available
dibenzyl ether 7.10 Following the slightly modified Arrayas’
procedure, reaction of 7 with 1.6 equiv of PhMe2SiMgCl in
the presence of 10 mol % CuCl and Ph3P afforded after 24
Figure 1. ORTEP-319 projection (ellipsoid: 50% probability) of
compound 11.
Scheme 2. Synthesis of Compound 8
obtained by slow diffusion of hexane into a corresponding
ethyl acetate solution.
The exclusive formation of only one diastereomer
can be rationalized in terms of the transition state shown in
Scheme 3.
(7) Arrayas, R. G.; Cabrera, S.; Carretero, J. C. Org. Lett. 2003, 5, 1333-
1336.
(8) For other examples of transition metal-catalyzed opening of oxabi-
cyclic alkenes see: (a) Lautens, M.; Fagnou, K.; Hiebert, S. Acc. Chem.
Res. 2003, 36, 48-58. (b) Lautens, M.; Hiebert, S. J. Am. Chem. Soc. 2004,
126, 1437-1447 and references therein. (c) Nakamura, M.; Hirai, A.;
Nakamura, E. J. Am. Chem. Soc. 2000, 122, 978-979. (d) Nakamura, M.;
Matsuo, K.; Inoue, T.; Nakamura, E. Org. Lett. 2003, 5, 1373-1375.
(9) Fleming, I.; Henning, R.; Parker, D. C.; Plaut, H. E.; Sanderson, P.
E. J. J. Chem. Soc., Perkin Trans. 1995, 1, 317-337.
(10) Lautens, M.; Ma, S.; Belter, R. K.; Chiu, P.; Leschziner, A. J. Org.
Chem. 1992 57, 4065-4066.
(11) (a) Sullivan, G. R.; Dale, J. A.; Mosher, H. S. J. Org. Chem. 1973,
38, 2143-2147. (b) Seco, J. M.; Quin˜noa´, E.; Riguera, R. Tetrahedron
Asymmetry 2001 12, 2915-2925.
414
Org. Lett., Vol. 10, No. 3, 2008

Scheme 3. Synthesis of Compound 14
Scheme 4. Hiyama-Nozaki-Kishi Reaction Aldehyde 14
Scheme 5. Ring-Closing Metathesis of Compounds 16-18
elimination provided the undesired conjugated diene. We
speculated that the initially formed potassium alkoxide was
responsible for this isomerization. In fact, performing the
reaction in high dilution improved the yield of 12 to 70%
together with 20% of the conjugated diene. Additionally,
replacement of KH with NaHMDS in THF/DMF fully
suppressed the side reaction and gave the desired olefin 12
in almost quantitave yield. DIBAL-H reduction of 12,
followed by oxidation, gave aldehyde 14 in 72% yield over
two steps.
Conversion of â-hydroxysilane 11 into olefin 12
again proved tricky. Under standard conditions, KH/THF,
(12) The side product of the reaction (25%) is compound 9a.
Conversion of 9a under acidic conditions improved the yield of the desired
acetal to 88%.
(13) Takeda, T., Ed. Modern Carbonyl Olefination; Wiley-VCH Verlag
GmbH & Co. KGaA: Weinheim, 2004.
(14) Wittig, G.; Scho¨llkopf, U. Chem. Ber. 1954, 87, 1318.
(15) (a) Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem. Soc.
1978, 100, 3611-3613. (b) Beadham, I.; Micklefield, J. Curr. Org. Synth.
2005, 2, 231-250.
(16) Okazoe, T.; Takai, K.; Utimoto, K. J. Am. Chem. Soc. 1987, 109,
951-953.
(17) Peterson, D. J. Org. Chem. 1968, 33, 780-784.
(18) Liu, H. J.; Shia, K. S.; Zhu, B. Y. Tetrahedron 1999, 55, 3803-
3828.
(21) It has to be pointed out that, although the RCM reaction was
quantitative, attempts to subject compounds 19 and 20 to chromatography
in the presence of air resulted in a substantial loss of the material, most
probably via oxidation of the diene system. For example, exposure of
structurally similar compound A to air gave after 20 min hydroperoxide B
in 90% yield. Gromov, A. Ph.D. Thesis in preparation.
(19) Farrugia, L. J. J. Appl. Crystallogr. 1997, 30, 565.
(20) Prepared from HOCH2CHdCH(CH2)2ODPS: Nicolaou, K. C.;
Lizos, D. E.; Kim, D. W.; Schlawe, D.; Noronha, R. G.; Longbottom, D.
A.; Rodriquez, M.; Bucci, M.; Cirino, G. J. Am. Chem. Soc. 2006, 128,
4460-4470.
Org. Lett., Vol. 10, No. 3, 2008
415

corresponding bicyclic derivatives (Scheme 5). RCM of
alcohols 16-18 in the presence of 5 mol % of Grubb’s
second-generation catalyst provided in quantitative yields
compounds 19, 20, and 21, respectively, whose relative
configurations were unambiguously elucidated by NOE
experiments.21
Scheme 6. Synthesis of Compound 24
Having proved that compounds 16 and 17 are C-12
epimers (branimycin numbering), both were oxidized (Scheme
6) to provide ketone 22 (63% yield from 14). Epoxidation
of 22 (mCPBA, 1.1 equiv) afforded epoxide 4 as a single
regio- and stereoisomer in 85% yield.
Unfortunately, at this stage we were not able to assign
the configuration of oxirane, but we hoped that the existing
stereocenters in 22 will direct epoxidation to the desired
R-epoxide. Finally, RCM of 4 in the presence of 5% Grubbs
second-generation catalyst provided epoxyketone 3 in 90%
yield. To confirm the configuration of the oxirane as well
the feasibility to use 3 in our synthetic strategy toward
branimycin, ketone 3 was reacted with 23.2b As expected,
the addition to the carbonyl group was followed by tran-
sannular epoxide opening under formation of the oxygen
bridge in 24. The structure and stereochemistry of 24 were
confirmed by two-dimensional (2D) NMR studies.
In summary, we have demonstrated the utility of SN2′
opening of oxabicyclic alkenes in combination with RCM
for a construction of highly substituted cis-decalin system
which we regard as a promising intermediate in a synthesis
of branimycin.
Acknowledgment. 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 crystal-
lography.
The stage was now set for the simultaneous introduction
of the second double bond required for a RCM reaction and
the C2-appendage (branimycin numbering). Thus, aldehyde
14 was treated with allylbromide 1520 (Scheme 4) according
to Hiyama-Nozaki-Kishi protocol (CrCl2, THF),6 to give
in 89% yield a mixture of compounds 16 (49%), 17 (21%),
and 18 (19%). The relative syn and anti configurations of
the products were established through conversion to their
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.
OL7027338
416
Org. Lett., Vol. 10, No. 3, 2008