A short catalytic enantioselective synthesis of the proinflammatory eicosanoid 12(R)-hydroxy-5(Z),8(Z),10(E),14(Z)-eicosatetraenoic acid (12(R)-HETE)

Article abstract of DOI:10.1021/ol0062392

(equation presented) A new and effective pathway is described for the synthesis of 12(R)-HETE and the 12(S)-enantiomer from the common intermediates 4 and 8.

Full text of DOI:10.1021/ol0062392

ORGANIC
LETTERS
2000
Vol. 2, No. 16
2543-2544
A Short Catalytic Enantioselective
Synthesis of the Proinflammatory
Eicosanoid 12(R)-Hydroxy-
5(Z),8(Z),10(E),14(Z)-eicosatetraenoic
Acid (12(R)-HETE)
Xiaojun Han and E. J. Corey*
Department of Chemistry and Chemical Biology, HarVard UniVersity,
12 Oxford Street, Cambridge, Massachusetts 02138
corey@chemistry.harVard.edu
Received June 21, 2000
ABSTRACT
A new and effective pathway is described for the synthesis of 12(R)-HETE and the 12(S)-enantiomer from the common intermediates 4 and 8.
The understanding of the cyclooxygenase (CO) pathway to
prostanoids (PG’s) and of the 5-lipoxygenase (5-LO) pathway
to leukotrienes from arachidonic acid has had profound
effects on biology and medicine and represents a major
contribution of chemistry to these fields. Recently, it has
become clear that the 12-LO pathway from arachidonic to
12-hydroxy-5(Z),8(Z),10(E),14(Z)-eicosatetraenoic acid (12-
HETE), discovered over a quarter of a century ago by
Hamberg and Samuelsson in human platelets1 and epidermis
of psoriasis,2 also plays a critical role in human health and
disease. The 12-LO pathway and 12-HETE have been
implicated, inter alia, in angiogenesis,3 the viability and
metastatic potential of tumor cells,4 atherogenesis,5 coronary
thrombosis,6 type I diabetes induction,7 inflammation and
psoriasis,2,8 and inhibition of apoptosis.9 It has been estab-
lished that 12(R)-HETE is present in psoriatic tissue rather
than the more common 12(S)-enantiomer.10 It also has been
(1) Hamberg, M.; Samuelsson, B. Proc. Natl. Acad. Sci. U.S.A. 1974,
71, 3400.
(2) Hammarstro¨m, S.; Hamberg, M.; Samuelsson, B.; Duell, E. A.;
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(3) (a) Nie, D.; Tang, K.; Diglio, C.; Honn, K. V. Blood 2000, 95, 2304.
(b) Tang, K.; Finley, R. L.; Nie, D.; Honn, K. V. Biochemistry 2000, 39,
3185. (c) Nie, D.; Hillman, G. G.; Geddes, T.; Tang, K.; Pierson, C.;
Grignon, D. J.; Honn, K. V. AdV. Exptl. Med. Biol. 1999, 469, 623.
(4) (a) Ding, X. Z.; Iversen, P.; Cluck, M. W.; Knezetic, J. A.; Adrian,
T. E. Biochem. Biophys. Res. Commun. 1999, 261, 218. (b) Chen, L. C.;
Chen, B. K.; Liu, Y. W.; Chang, W. C. FEBS Lett. 1999, 455, 105. (c)
Tang, K.; Honn, K. V. AdV. Exptl. Med. Biol. 1999, 447, 181. (d) Yamamoto,
S.; Suzuki, H.; Ueda, N. Prog. Lipid Res. 1997, 36, 23. (e) Herbertsson,
H.; Hammarstro¨m, S. AdV. Exptl. Med. Biol. 1997, 400A, 287. (f) Nie, D.;
Hillman, G. G.; Geddes, T.; Tang, K.; Pierson, C.; Grignon, D. J.; Honn,
K. V. Cancer Res. 1998, 58, 4047.
(5) Cyrus, T.; Witztum, J. L.; Rader, D. J.; Tangirala, R.; Fazio, S.;
Linton, M. F.; Funk, C. D. J. Clin. InVest. 1993, 103, 1597.
(6) Katoh, A.; Ikeda, H.; Murohara, T.; Haramaki, N.; Ito, H.; Imaizumi,
T. Circulation 1998, 98, 2891.
(7) Bleich, D.; Chen, S.; Zipser, B.; Sun, D.; Funk, C. D.; Nadler, J. L.
J. Clin. InVest. 1999, 103, 1431.
(8) (a) Ziboh, V. A. Lipids 1996, 31, S249. (b) Natarajan, R.; Pei, H.;
Gu, J. L.; Sarma, J. M.; Nadler, J. CardioVasc. Res. 1999, 41, 489.
(9) Tang, D. G.; Chen, Y. Q.; Honn, K. V. Proc. Natl. Acad. Sci. U.S.A.
1996, 93, 5241.
(10) (a) Woolard, P. M. Biochem. Biophys. Res. Commun. 1986, 136,
169. (b) Cunningham, F. M.; Woolard, P. M. Prostaglandins 1987, 34, 71.
(11) (a) Boeglin, W. E.; Kim, R. B.; Brash, A. R. Proc. Natl. Acad. Sci.
U.S.A. 1998, 95, 6744. (b) Sun, D.; McDonnell, M.; Chen, X. S.; Lakkis,
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10.1021/ol0062392 CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/08/2000

Scheme 1
discovered that humans possess genes encoding the 12(R)-
and chiral 12-HETEs have been described, none being of
the modern catalytic enantioselective type.14
LO11 as well as genes for the longer known 12(S)-LO
enzymes.4d,12 Interestingly, 12(R)-HETE (1) appears to be
an order of magnitude more proinflammatory than 12(S)-
HETE (2).10
The pathway of synthesis of 1 is summarized in Scheme
1. The allylic bromide 3, synthesized in 65% yield by
coupling of 1 equiv of 1-heptynylmagnesium bromide with
(E)-1,4-dibromo-2-butene in the presence of 10 mol % of
CuBr in THF at 0 f 50 °C15 was converted to (E)-â,γ-
unsaturated ester 4 by Pd(0)-catalyzed carbonylation in
methanol.16 Sharpless asymmetric dihydroxylation of 4 using
the dihydroquinidine-based biscinchona catalyst/reagent AD-
mix-â (Aldrich) occurred with in situ lactonization to give
the chiral â-hydroxy lactone 5, [R]2D2 +45.4 (c 0.8, Me2-
CO), of 95% ee17 as determined by HPLC analysis using a
Whelk O-1 column with 1:9 isopropyl alcohol-hexane as
eluent (retention times: 21.7 min for S,S-enantiomer of 5 and
26.1 min for 5). Selective Lindlar reduction of the triple bond
of 5 gave the corresponding Z-olefin, which was converted
to the methanesulfonate and reduced with DIBAL-H in
toluene at -78 °C to form lactol mesylate 6. Reaction of 6
with the ylide (Z)-Ph3PdCHCH2CHdCH(CH2)3COOMe
(8)18 in 1:0.3 THF-HMPA at -25 °C for 1 h produced the
methyl ester (7) of 12(R)-HETE, [R]2D2 -14.8 (c 0.9,
acetone), which was spectroscopically identical with an
authentic sample. Saponification of the methyl ester 7 with
1:1 1 N LiOH(aq)-THF affords 12(R)-HETE (1).
The growing importance of 12(S)- and 12(R)-HETE in
biological regulation and disease underscores the need for
adequate supplies of these enantiomeric substances for
fundamental studies. This paper reports an efficient and short
synthetic route to the enantiomers 1 and 2 using modern
catalytic asymmetric methodology. The route is illustrated
specifically for the 12(R)-HETE (1) but clearly can be applied
equally well to the enantiomer 2. Since the original synthesis
of 12(S)-HETE,13 a number of other syntheses of racemic
(12) (a) Izumi, T.; Hoshiko, S.; Rådmark, O.; Samuelsson, B. Proc. Natl.
Acad. Sci. U.S.A. 1990, 87, 7477. (b) Funk, C. D.; Furci, L.; Fitzgerald, G.
A. Proc. Natl. Acad. Sci. U.S.A. 1990, 87, 5638.
(13) Corey, E. J.; Niwa, H.; Knolle, J. J. Am. Chem. Soc. 1978, 100,
1942.
(14) (a) Corey, E. J.; Marfat, A.; Falck, J. R.; Albright, J. O. J. Am.
Chem. Soc. 1980, 102, 1433. (b) Corey, E. J.; Kyler, K.; Raju, N.
Tetrahedron Lett. 1984, 25, 5115. (c) Russell, S. W.; Pabon, H. J. J. J.
Chem. Soc., Perkin Trans. 1 1982, 545. (d) Just, G.; Wang, Z. Y.
Tetrahedron Lett. 1985, 26, 2993. (e) Just, G.; Wang, Z. Y. J. Org. Chem.
1986, 51, 4796. (f) Yadagiri, P.; Lumin, S.; Mosset, P.; Capdevila, J.; Falck,
J. R. Tetrahedron Lett. 1986, 27, 6039. (g) Shimazaki, T.; Kobayashi, Y.;
Sato, F. Chem. Lett. 1988, 1785. (h) Nagata, R.; Kawakami, M.; Matsuura,
T.; Saito, I. Tetrahedron Lett. 1989, 30, 2817. (i) Nicolaou, K. C.; Ramphal,
J. Y.; Abe, Y. Synthesis 1989, 898. (j) Mosset, P.; Pointeau, P.; Aubert, F.;
Lellouche, J. P.; Beaucourt, J. P.; Gre´e, R. Bull. Soc. Chim. Fr. 1990, 127,
298. (k) Lumin, S.; Falck, J. R.; Schwartzman, M. L. Tetrahedron Lett.
1991, 32, 2315.
(15) Nicolaou, K. C.; Ladduwahetty, T.; Elisseou, E. M. J. Chem. Soc.,
Chem. Commun. 1985, 1580.
(16) Kiji, J.; Okano, T.; Higashimae, Y.; Fukui, Y. Bull. Chem. Soc.
Jpn. 1996, 69, 1029. Increased pressure of CO minimizes methanolysis of
allylic bromide 3 to the corresponding methyl ether.
(17) (a) Sharpless, K. B.; Amberg, W.; Bennani, Y.; Crispino, G. A.;
Hartung, J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.; Xu,
D.; Zhang, X.-L. J. Org. Chem. 1992, 57, 2768. (b) Wang, Z.; Zhang, X.;
Sharpless, K. B.; Sinha, S. C.; Sinha-Bagchi, A.; Keinan, E. Tetrahedron
Lett. 1992, 33, 6407.
(18) Ylide 8 was prepared from the corresponding phosphonium salt by
reaction with sodium hexamethyldisilazide in THF at -25 °C, see: (a)
Zamboni, R.; Milette, S.; Rokach, J. Tetrahedron Lett. 1983, 24, 4899. (b)
Sandri, J.; Viala, J. J. Org. Chem. 1995, 60, 6627.
Modification of the synthesis shown in Scheme 1 by
replacing AD-mix-â by AD-mix-R in the synthesis allows
formation of ent-5 and therefore 12(S)-HETE (2).
The synthetic process described herein thus allows the
preparation of both 12(R)- and 12(S)-HETE from the
common building blocks 4 and 8 in a remarkably simple
and effective way.
Acknowledgment. This research was assisted by a grant
from the National Science Foundation. We are very grateful
to Dr. Sheldon Crane for experimental assistance.
OL0062392
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Org. Lett., Vol. 2, No. 16, 2000