9624
J . Org. Chem. 1998, 63, 9624-9625
Sch em e 1
En a n tioselective Tota l Syn th esis of
Ta u r osp on gin A
He´le`ne Lebel and Eric N. J acobsen*
Department of Chemistry and Chemical Biology, Harvard
University, Cambridge, MA 02138
Received September 29, 1998
Taurospongin A (1) is a structurally interesting fatty acid
derivative isolated recently from the Okinawan marine
sponge Hippospongia sp. and found to exhibit remarkable
dual activity as a potent inhibitor of both DNA polymerase
â and HIV reverse transcriptase.1 As a synthetic target,
taurospongin A displays several structurally interesting
elements including a stereochemically defined tertiary al-
cohol at C3 and differentially acylated secondary alcohols
at C7 and C9. We describe herein the first total synthesis
of 1 by an approach that features the use of highly effective
asymmetric catalytic reactions to set each stereocenter
independently.
The synthetic plan is outlined in Scheme 1. After discon-
nection of taurine (2) and fatty acid 3, fragment 4 remains
as the only chiral component. We envisioned tertiary alcohol
construction by alkylation of 2,2-disubstituted epoxide 5, a
substrate that would serve not only the purposes of this
synthesis but also as an interesting test for recently devel-
oped epoxide kinetic resolution protocols. To attain maxi-
mum flexibility in the synthesis of taurospongin A and its
diastereomers, we anticipated establishing the 1,3-diol
relationship at C7-C9 by means of distinct asymmetric
carbonyl reduction reactions.
Recently, our laboratories have identified highly effective
methods for the kinetic resolution of terminal epoxides
catalyzed by cobalt complex 7 and chromium complex 8.2,3
While the hydrolytic kinetic resolution (HKR) with catalyst
7 has been used with success with a wide variety of
monosubstituted terminal epoxides, 2,2-disubstituted ep-
oxide (()-54,5 failed to react under HKR conditions. In
contrast, kinetic resolution with (salen)Cr catalyst 8 and
TMSN3 proved successful, providing the desired enantioen-
riched epoxide (S)-5 with a krel > 14 (eq 1).6 Thus, by
larly notable given the small degree of steric differentiation
between the substituents in this 2,2-disubstituted epoxide.
Reaction of 5 with lithium acetylide/BF3‚OEt2 proceeded
cleanly to provide the desired tertiary alcohol, which was
next protected as a triethyl silyl ether to complete the
synthesis of chiral building block 9 (Scheme 2). â-Hydroxy
ester 6 was prepared in 99% ee by the asymmetric catalytic
hydrogenation of methyl acetoacetate as reported by Noyori
and co-workers.8 Protection as the TBS ether provided the
requisite second chiral building block, 10. The lithium
acetylide derivative of 9 was coupled with the Weinreb amide
derived from 10 to afford ynone 11 in 72% yield.9,10
With the fragment 11 in hand, only the stereocenter at
C7 remained to be set. Although a variety of methods exist
for the stereocontrolled reduction of â-alkoxy ketones, mod-
est diastereoselectivities are often observed, especially in
substrates lacking R-substituents.11 The asymmetric cata-
lytic transfer hydrogenation of ynones disclosed recently by
Noyori was considered as a particularly attractive alterna-
tive.12 In the context of our synthesis, the successful
implementation of the Noyori reduction would allow prepa-
ration of either C7 epimer by selection of the appropriate
enantiomer of the chiral catalyst. Treatment of propargylic
(3) (a) Larrow, J . F.; Schaus, S. E.; J acobsen, E. N. J . Am. Chem. Soc.
1996, 118, 7420-7421. (b) Schaus, S. E.; J acobsen, E. N. Tetrahedron Lett.
1996, 37, 7937-7940. (c) Martinez, L. E.; Leighton, J . L.; Carsten, D. H.;
J acobsen, E. N. J . Am. Chem. Soc. 1995, 117, 5897-5898.
(4) Racemic epoxide 5 was prepared in two steps and 85% yield from
commercially available 3-methyl-3-buten-1-ol (see the Supporting Informa-
tion).
(5) For selected examples of kinetic resolution of 2,2-disubstituted
epoxides, see: (a) Orru, R. V. A.; Mayer, S. F.; Kroutil, W.; Faber, K.
Tetrahedron 1998, 54, 859-874. (b) Osprian, I.; Kroutil, W.; Mischitz, M.;
Faber, K. Tetrahedron: Asymmetry 1997, 8, 65-71. (c) Lakner, F. J .; Hager,
L. P. J . Org. Chem. 1996, 61, 3923-3925.
(6) The stereochemical assignment was made by comparison with
literature data: Gill, M.; Smrdel, A. F. Tetrahedron: Asymmetry 1990, 1,
453-464.
(7) Hansen, K. B.; Leighton, J . L.; J acobsen, E. N. J . Am. Chem. Soc.
1996, 118, 10924-10925. In the kinetic resolution of terminal epoxides,
the secondary alcohol that is generated upon ring opening reacts readily
with TMSN3 to generate HN3 and the corresponding silyl ether. As a result,
only a catalytic amount of Brønsted acid is needed for the reaction, and
adventitious water is generally sufficient. In contrast, the tertiary alcohol
generated in the ring opening of 5 is unreactive toward TMSN3, so a
stoichiometric amount of Brønsted acid is needed.
employing 0.65 equiv of TMSN3 and 0.65 equiv of 2-propanol,
chiral epoxide 5 was isolated in 37% yield and 97% ee. The
use of 2-propanol was found to be essential for the attain-
ment of reasonable reaction rates in the kinetic resolution
of 5. This additive effects the stoichiometric conversion of
TMSN3 to HN3, the latter having been shown previously to
be the active reagent in the catalytic cycle.7 The good
selectivity observed in the kinetic resolution of 5 is particu-
(8) (a) Kitamura, M.; Tokunaga, M.; Ohkuma, T.; Noyori, R. Tetrahedron
Lett. 1991, 32, 4163-4166. (b) Kitamura, M.; Tokunaga, M.; Ohkuma, T.;
Noyori, R. Org. Synth. 1992, 71, 1-13.
(9) Williams, J . M.; J obson, R. B.; Yasuda, N.; Marchesini, G.; Dolling,
U. H.; Grabowski, E. J . J . Tetrahedron Lett. 1995, 36, 5461-5464.
(10) The starting terminal alkyne 9 was also recovered in 24% yield.
(11) For selected examples of diastereoselective reduction of â-alkoxy
ketones to give syn-1,3-monoprotected diols, see: (a) Mori, Y.; Kuhara, M.;
Takeuchi, A.; Suzuki, M. Tetrahedron Lett. 1988, 29, 5419-5422. (b)
Yamazaki, N.; Kibayashi, C. J . Am. Chem. Soc. 1989, 111, 1396-1408. (c)
Yoshimatsu, M.; Naito, M.; Shimizu, H.; Muraoka, O.; Tanabe, G.; Kataoka,
T. J . Org. Chem. 1996, 61, 8200-8206.
(1) Ishiyama, H.; Ishibashi, M.; Ogawa, A.; Yoshida, S.; Kobayashi, J . J .
Org. Chem. 1997, 62, 3831-3836.
(2) Tokunaga, M.; Larrow, J . F.; Kakiuchi, F.; J acobsen, E. N. Science
1997, 277, 936-938.
(12) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J . Am. Chem.
Soc. 1997, 119, 8738-8739.
10.1021/jo9819741 CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/26/1998