Enantioselective synthesis of (-)-LL-C10037α from benzoquinone

Article abstract of DOI:10.1021/ol991038n

(formula presented) The enantioselective total synthesis of the Streptomyces metabolite (-)-LL-C10037α has been accomplished in 10 steps and 20% overall yield. An early chiral intermediate was resolved with Candida rugosa lipase to provide (+)-5 with an e

Full text of DOI:10.1021/ol991038n

ORGANIC
LETTERS
1999
Vol. 1, No. 9
1483-1485
Enantioselective Synthesis of
(−)-LL-C10037r from Benzoquinone
Sean T. Murphy, Josef R. Bencsik, and Carl R. Johnson*
Department of Chemistry, Wayne State UniVersity, Detroit, Michigan 48202
crj@chem.wayne.edu
Received September 13, 1999
ABSTRACT
The enantioselective total synthesis of the Streptomyces metabolite (−)-LL-C10037r has been accomplished in 10 steps and 20% overall yield.
An early chiral intermediate was resolved with Candida rugosa lipase to provide (+)-5 with an enantiomeric excess g98%. The synthesis is
notable in that no protecting groups are required and that all carbons in the core structure of LL-C10037r are derived from the readily
available p-benzoquinone.
LL-C10037R (1) is a metabolite of Streptomyces LL-C10037
and shows antibacterial and antitumor activity.1 After the
initial report of the isolation,1 the structure was revised and
shown by an X-ray diffraction study to be the epoxyquinol
1.2 The absolute configuration was later confirmed by X-ray
analysis of an ester derivative.3 The epoxyquinol core of LL-
C10037R is found in a number of other antibiotics including
the manumycins,4 such as manumycin A (2), alisamycin,5
asukamycin,6 and nisamycin.7 The manumycins are note-
worthy because they are also potent and selective inhibitors
of Ras farnesyltransferase,8 an enzyme linked to many human
cancers.
(1) Lee, M. D.; Fantini, A. A.; Morton, G. O.; James, J. C.; Borders, D.
B.; Testa, R. T. J. Antibiot. 1984, 37, 1149-1152.
(2) Whittle, Y. G.; Gould, S. J. J. Am. Chem. Soc. 1987, 109, 5043-
5044.
(3) Shen, B.; Whittle, Y. G.; Gould, S. J.; Keszler, D. A. J. Org. Chem.
1990, 55, 4422-4426.
(4) (a) Buzzetti, F.; Gau¨mann, E.; Hu¨tter, R.; Keller-Schierlein, W.;
Neipp, L.; Prelog, V.; Za¨hner, H. Pharm. Acta HelV. 1963, 38, 871. (b)
Schro¨der, K.; Zeeck, A. Tetrahedron Lett. 1973, 4995. (c) Zeeck, A.;
Schro¨der, K.; Frobel, K.; Grote, R.; Thiericke, R. J. Antibiot. 1987, 40,
1530. (d) Zeeck, A.; Frobel, K.; Heusel, C.; Schro¨der, K.; Thiericke, R. J.
Antibiot. 1987, 40, 1541. (e) Thiericke, R.; Stellwaag, M.; Zeeck, A.;
Snatzke, G. J. Antibiot. 1987, 40, 1549. (f) Thiericke, R.; Zeeck, A.;
Nakagawa, A.; Omura, S.; Herrold, R. E.; Wu, S. T. S.; Beale, J. M.; Floss,
H. G. J. Am. Chem. Soc. 1990, 112, 3979. (g) Sattler, I.; Gro¨ne, C.; Zeeck,
A. J. Org. Chem. 1993, 58, 6583. (h) Shu, Y.-Z.; Huang, S.; Wang, R. R.;
Lam, K. S.; Klohr, S. E.; Volk, K. J.; Pirnik, D. M.; Wells, J. S.; Fernandes,
P. B.; Patel, P. S. J. Antibiot. 1994, 47, 324.
(5) (a) Franco, C. M. M.; Maurya, R.; Vijayakumar, E. K. S.; Chatterjee,
S.; Blumbach, J.; Ganguli, B. N. J. Antibiot. 1991, 44, 1289. (b) Chatterjee,
S.; Vijayakumar, E. K. S.; Franco, C. M. M.; Blumbach, J.; Ganguli, B. N.
J. Antibiot. 1993, 46, 1027. (c) Hayashi, K.; Nakagawa, M.; Fujita, T.;
Nakayama, M. Biosci. Biotech. Biochem. 1994, 58, 1332.
Racemic syntheses of LL-C10037R have been published
by the groups of both Wipf9 and Taylor.10 One enantiose-
(6) (a) Omura, S.; Kitao, C.; Tanaka, H.; Oiwa, R.; Takahashi, Y.;
Nakagawa, A.; Shimada, M.; Iwai, Y. J. Antibiot. 1976, 29, 876. (b)
Kakinuma, K.; Ikekawa, N.; Nakagawa, A.; Omura, S. J. Am. Chem. Soc.
1979, 101, 3402. (c) Cho, H. G.; Sattler, I.; Beale, J. M.; Zeeck, A.; Floss,
H. G. J. Org. Chem. 1993, 58, 7925.
(7) (a) Hayashi, K.; Nakagawa, M.; Fujita, T.; Tanimori, S.; Nakayama,
M. J. Antibiot. 1993, 46, 1904. (b) Hayashi, K.; Nakagawa, M.; Nakayama,
M. J. Antibiot. 1994, 47, 1104. (c) Hayashi, K.; Nakagawa, M.; Fujita, T.;
Tanimori, S.; Nakayama, M. J. Antibiot. 1994, 47, 1110.
10.1021/ol991038n CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/02/1999

lective synthesis has also been accomplished, published by
Wipf et al. in 1995.9b The synthesis relied on a chiral
auxiliary to achieve enantioselectivity in an epoxidation
reaction and was completed in an overall yield of ca. 1%
from 2,5-dimethoxyaniline. Curiously, the enantiomer of (-)-
LL-C10037R is also a natural product. The (+)-enantiomer,
named (+)-MT 35214, has been efficiently synthesized by
Taylor et al. using a phase-transfer catalyst to effect an
enantioselective epoxidation. Unfortunately, a catalyst could
not be found to produce the enantiomeric epoxide, thus
precluding a synthesis of (-)-LL-C10037R.
Continuing our program of using enzymes in the enanti-
oselective synthesis of highly functionalized, biologically
active molecules,11 we now report the synthesis of LL-
C10037R starting from readily available benzoquinone
(Scheme 1). The first part of the synthesis follows previous
the diol 4. By treating the C2-symmetrical diol 4 with base
and maintaining the temperature at 0 °C, only one of the
hydroxyl groups closes to form the monoepoxide (()-5 in
excellent yield (92%). Maintaining the temperature at 0 °C
is crucial during this step, since permitting the reaction to
warm to room temperature allows for formation of the
corresponding diepoxide.13
Racemic epoxide 5 was exposed to Candida rugosa lipase
in toluene/isopropenyl acetate; only (-)-5 was acetylated,
leaving (+)-5 untouched. Separation from the acetylated
product by flash chromatography produced (+)-5 in 47%
yield and g98% ee [[R]25D +170 (c 1.0, CHCl3) (lit.12 [R]25
D
+174 (c 1.0, CHCl3); lit.14 [R]25D +170.6 (c 0.812, CHCl3))].
Recrystallization did not result in increased optical rotation.
To introduce the nitrogen present in the natural product,
(+)-5 was treated with sodium azide in the presence of zinc
sulfate to form azide (-)-6 in 95% yield. As expected, the
epoxide was attacked at the more labile allylic position
(confirmed by X-ray analysis of (()-6). Next, the oxygen
that was to become the hydroxyl group in the final product
was introduced stereoselectively by hydroxyl-directed m-
CPBA epoxidation15 to give (-)-7 (94%). The relative
stereochemistry of the epoxidation was confirmed by X-ray
analysis on (()-7. The epoxide (-)-7 was transformed into
the diepoxide (-)-8 with potassium hydroxide in methanol
at 0 °C (86%).
Scheme 1a
We anticipated a tandem oxidation/â-elimination reaction
on amide 10 would lead directly to the final product 1. To
arrive at 10, we required chemoselective reduction of the
azide function in (-)-8, leading to 9. Our initial attempts to
reduce the azide by hydrogenation16 produced the desired
amine 9 along with an epoxide-reduced product tentatively
assigned structure 12 (Scheme 2). A variety of catalysts were
Scheme 2
a Reagents: (a) Br2, 0 °C; (b) NaBH4, 0 °C, 81% over two steps
(ref 13); (c) KOH, 0 °C, 92%; (d) (()-5 (6.8 g), Candida rugosa
lipase (Sigma) (200 wt %), 4:1 toluene/isopropenyl acetate (125
mL), 6 d, 47%, g98% ee; (e) NaN3, ZnSO4, 95%; (f) MCPBA,
94%; (g) KOH, 0 °C, 86%; (h) Pd/S, H2; (i) Ac2O, Et3N, 84%
over two steps; (j) Dess-Martin periodinane, 87%.
examined, including palladium on carbon, palladium hy-
droxide on carbon (Pearlman’s catalyst), and palladium,
sulfided, 5 wt % on carbon (Aldrich) as well as a number of
work by our group in which epoxide 5 was enzymatically
resolved and shown to react with various nucleophiles by
opening the epoxide at the allylic position.12 Following the
literature procedure from Altenbach, Stegelmeier, and Vo-
gel,13 p-benzoquinone was sequentially trans-brominated and
stereoselectively reduced with sodium borohydride to give
(8) (a) Hara, M.; Akasaka, K.; Akinaga, S.; Okabe, M.; Nakano, H.;
Gomez, R.; Wood, D.; Uh, M.; Tamanoi, F. Proc. Natl. Acad. Sci. U.S.A.
1993, 90, 2281. (b) Nagase, T.; Kawata, S.; Yamazaki, E.; Ishiguro, H.;
Matuzawa, Y. Hepatology 1993, 18, 190. (c) Hara, M.; Han. M. Proc. Natl.
Acad. Sci. U.S.A. 1995, 92, 3333.
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Org. Lett., Vol. 1, No. 9, 1999

solvents (EtOH, MeOH, EtOAc); all produced mixtures. In
examining other methods of azide reduction, we found that
reduction with triphenylphosphine17 proceeded smoothly to
give the desired product 9. Unfortunately, the triphenylphos-
phine oxide produced in the reaction made purification of 9
or the diacetylated product 13 extremely difficult. Finally,
in examining the Pd hydrogenation conditions further, we
found that the sulfided palladium on carbon catalyst when
run in THF gave the amine 9 as the only detectable product
by TLC and NMR. Due to the extreme polarity of the amine
9, the crude material was acetylated directly with acetic
anhydride and triethylamine to provide the penultimate
acetamide 10 (84% over two steps).
yield of 87%. The reaction appeared to be complete within
20 min, and no signs of the ketone 11 were seen by TLC.
To account for the selective formation of 1, we propose that
the periodinane reacts quickly with the hydroxyl functional-
ity, thus forming a complex and thereby sequestering all of
the reagent so that as the product 1 forms no reagent is
available for over-oxidation to an epoxyquinone. The proton
and carbon NMR spectra of the synthesized (-)-1 matched
perfectly those of the natural product.1,2 After one recrys-
tallization, the optical rotation and melting point were in
excellent agreement with the naturally obtained material: mp
149-151 °C; [R]22D -201 (c 0.34, MeOH) [lit.1 mp 153 °C;
lit.3 [R]20 -202 (c 0.334, MeOH)].
D
A potential complication in the strategy of an oxidation/
elimination sequence for conversion of 10 to 1 is that the
elimination reveals a new alcohol in the desired product 1
that could be further oxidized to an epoxyquinone. To our
delight, the Dess-Martin periodinane18 reacted quickly with
10 in acetonitrile to provide (-)-LL-C10037R in a very good
In summary, we have synthesized (-)-LL-C10037R using
an enzymatic resolution on an early intermediate. Starting
from benzoquinone, the title compound was synthesized in
10 steps and 20% overall yield.19 Notable reactions include
a chemoselective azide reduction with sulfided palladium on
carbon and a tandem oxidation/â-elimination reaction.
Although LL-C10037R is a densely functionalized small
molecule, no protecting groups were needed during the
synthesis, which contributed to the high efficiency achieved.
(9) (a) Wipf, P.; Kim, Y. J. Org. Chem. 1994, 59, 3518-3519. (b) Wipf,
P.; Kim, Y.; Jahn, H. Synthesis 1995, 1549-1561.
(10) (a) Kapfer, I.; Lewis, N. J.; Macdonald, G.; Taylor, R. J. K.
Tetrahedron Lett. 1996, 37, 2101-2104. (b) Taylor, R. J. K.; Alcaraz, L.;
Kapfer-Eyer, I.; Macdonald, G.; Wei, X.; Lewis, N. Synthesis 1998, 775-
790.
(11) (a) Johnson, C. R. Acc. Chem. Res. 1998, 31, 333-341. (b) Johnson,
C. R.; Wells, G. W. Curr. Opinion Chem. Biol. 1998, 2, 70-76.
(12) Kohrt, J. T.; Gu, J.-X.; Johnson, C. R. J. Org. Chem. 1998, 63,
5088-5093.
(13) Altenbach, H.-J.; Stegelmeier, H.; Vogel, E. Tetrahedron Lett. 1978,
3333-3336.
(14) Koreeda, M.; Yoshihara, M. J. Chem. Soc., Chem. Commun. 1981,
974-976.
Acknowledgment. We gratefully acknowledge support
of the National Science Foundation (CHE-9801679). We
thank Dr. Mary Jane Heeg for the X-ray structure determina-
tions and Dr. Lew Hryhorczuk for assistance with mass
spectroscopy analyses.
Supporting Information Available: Experimental pro-
(15) Henbest, H. B.; Wilson, R. A. L. J. Chem. Soc. 1959, 1958-1965.
(16) For a review on the chemistry of azides, including reduction, see:
Scriven, E. F. V.; Turnbull, K. Chem. ReV. 1988, 88, 297-368.
(17) Vaultier, M.; Knouzi, N.; Carrie, R. Tetrahedron Lett. 1983, 24,
763.
(18) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4156-4158.
(b) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-7287
(19) The overall yield includes the resolution step, which has a maximum
yield of only 50%.
cedures and full characterization for the optically active
compounds 6-10 and (-)-1, H NMR spectra for these
compounds, and X-ray structures for (()-6 and (()-7. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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