Synthesis of 10,11-dihydroleukotriene B4 metabolites via a nickel- catalyzed coupling reaction of cis-bromides and trans-alkenyl borates

Article abstract of DOI:10.1021/jo9913199

Synthesis of 10,11-dihydro-, 10,11,14,15-tetrahydro-, and 10,11-dihydro- 12-oxoleukotriene B₄ compounds (2, 4, 5) was accomplished stereoselectively by using the nickel-catalyzed coupling reaction illustrated in Scheme 1. The C(1)-C(7) fragments, TBS ether 10a for 2 and 4 and ethyoxyethyl (EE) ether 10b for 5, were prepared in enantiomerically pure forms (>99% ee) by a modified literature procedure (ref 11a). On the other hand, boronate esters 11a and 11b, which correspond to the C(8)-C(20) parts of 2 and 4, respectively, were synthesized from (R)-epichlorohydrin of 99% ee. Briefly, 18 was converted into acetylenes 24 and 32 through epoxide ring-opening with LiC≡CC₅H₁₁/BF₃·OEt₂ or C₇H₁₅MgBr/CuCN. Hydroboration of these acetylenes with (+)-(Ipc)₂BH followed by reaction with MeCHO afforded the corresponding diethyl boronates, which upon ligand exchange with Me₂C(CH₂OH)₂ furnished boronate esters 11a and 11b in 75% and 77% yields, respectively. In a similar manner, racemic boronate ester rac-11a, an intermediate for synthesis of 5, was prepared from racemic epichlorohydrin. For synthesis of 2, borate 25 was generated from 11a (1.5 equiv) and MeLi (1.6 equiv). Without isolation, 25 was submitted to reaction with 10a (1 equiv) in the presence of a Ni(0) species at room temperature overnight to afford 26, which upon treatment with TBAF furnished 2 in 64% yield from 10a. Similarly, 11b and 10a furnished 4 in good yield. To synthesize 5, rac-11a and EE ether 10b were joined by the coupling reaction to produce 39, which was transformed into 40 by desilylation with TBAF. After hydrolysis of 40, oxidation with PDC followed by deprotection of the EE group furnished 5 in 36% yield from 40. In addition, 2 was converted into amide 3 in 92% yield.

Full text of DOI:10.1021/jo9913199

J . Org. Chem. 2000, 65, 707-715
707
Syn th esis of 10,11-Dih yd r oleu k otr ien e B4 Meta bolites via a
Nick el-Ca ta lyzed Cou p lin g Rea ction of cis-Br om id es a n d
tr a n s-Alk en yl Bor a tes
Yuji Nakayama, G. Biju Kumar, and Yuichi Kobayashi*
Department of Biomolecular Engineering, Tokyo Institute of Technology, 4259 Nagatsuta-cho,
Midori-ku, Yokohama 226-8501, J apan
Received August 19, 1999
Synthesis of 10,11-dihydro-, 10,11,14,15-tetrahydro-, and 10,11-dihydro-12-oxoleukotriene B4
compounds (2, 4, 5) was accomplished stereoselectively by using the nickel-catalyzed coupling
reaction illustrated in Scheme 1. The C(1)-C(7) fragments, TBS ether 10a for 2 and 4 and
ethyoxyethyl (EE) ether 10b for 5, were prepared in enantiomerically pure forms (>99% ee) by a
modified literature procedure (ref 11a). On the other hand, boronate esters 11a and 11b, which
correspond to the C(8)-C(20) parts of 2 and 4, respectively, were synthesized from (R)-
epichlorohydrin (18) of 99% ee. Briefly, 18 was converted into acetylenes 24 and 32 through epoxide
ring-opening with LiCtCC5H11/BF3‚OEt2 or C7H15MgBr/CuCN. Hydroboration of these acetylenes
with (+)-(Ipc)2BH followed by reaction with MeCHO afforded the corresponding diethyl boronates,
which upon ligand exchange with Me2C(CH2OH)2 furnished boronate esters 11a and 11b in 75%
and 77% yields, respectively. In a similar manner, racemic boronate ester rac-11a , an intermediate
for synthesis of 5, was prepared from racemic epichlorohydrin. For synthesis of 2, borate 25 was
generated from 11a (1.5 equiv) and MeLi (1.6 equiv). Without isolation, 25 was submitted to reaction
with 10a (1 equiv) in the presence of a Ni(0) species at room temperature overnight to afford 26,
which upon treatment with TBAF furnished 2 in 64% yield from 10a . Similarly, 11b and 10a
furnished 4 in good yield. To synthesize 5, rac-11a and EE ether 10b were joined by the coupling
reaction to produce 39, which was transformed into 40 by desilylation with TBAF. After hydrolysis
of 40, oxidation with PDC followed by deprotection of the EE group furnished 5 in 36% yield from
40. In addition, 2 was converted into amide 3 in 92% yield.
In tr od u ction
LTB4 (4),6 10,11-dihydro-12-oxo-LTB4 (5),2a,b etc. (Figure
1). Although these products suggest a possibility that
LTB3 and LTB5 are metabolized similarly and 4 is
formally a product from LTB3, direct evidence for such a
possibility has not been reported so far. From a synthetic
point of view, establishment of a chemical method for
synthesis of these 10,11-dihydro metabolites and those
which might be produced from LTB3 and LTB5 would
facilitate greater understanding of the pathway(s), isola-
tion/determination of new metabolites, and examination
of the biological roles at several stages.
Recently, 10,11-dihydro derivatives of leukotriene B4
(LTB4) (1) have been isolated,1,2 and pathway(s) leading
to them and the specific enzymes involved in the route
have been investigated.3 On the basis of the biological
activities,2c,4 these metabolites are now recognized as
initial products of a second metabolic pathway of 1 in
addition to the ω-oxidation pathway.5 The metabolites
involve 10,11-dihydro-LTB4 (2),2,3 10,11-dihydro-12-epi-
LTB4 (structure not shown),2b,c,3d 10,11,14,15-tetrahydro-
By stimulation leukocytes produce LTB4 (1), which, in
turn, activates other leukocytes at a concentration of 10-9
M.7 Hence, 1 is believed to be a most potent mediator of
inflammation and allergic responses.8 The activation is
initiated by binding to the specific receptors, and the
sequence of amino acids of the receptor has been deter-
(1) (a) Powell, W. S. Biochem. Biophys. Res. Commun. 1987, 145,
991-998. (b) Kaever, V.; Martin, M.; Fauler, J .; Marx, K.-H.; Resch,
K. Biochim. Biophys. Acta 1987, 922, 337-344.
(2) (a) Powell, W. S.; Gravelle, F. J . Biol. Chem. 1989, 264, 5364-
5369. (b) Wainwright, S.; Falck, J . R.; Yadagiri, P.; Powell, W. S.
Biochemistry 1990, 29, 1180-1185. (c) Kumlin, M.; Falck, J . R.; Raud,
J .; Harada, Y.; Dahle´n, S.-E.; Granstro¨m, E. Biochem. Biophys. Res.
Commun. 1990, 170, 23-29.
(3) (a) Powell, W. S. Biochem. Biophys. Res. Commun. 1986, 136,
707-712. (b) Fauler, J .; Marx, K.-H.; Kaever, V.; Fro¨lich, J . C.
Prostaglandins, Leukotrienes, Essent. Fatty Acids 1989, 37, 193-196.
(c) Powell, W. S.; Gravelle, F. Biochim. Biophys. Acta 1990, 1044, 147-
157. (d) Powell, W. S.; Gravelle, F. J . Biol. Chem. 1990, 265, 9131-
9139. (e) Kasimir, S.; Scho¨nfeld, W.; Hilger, R. A.; Ko¨nig, W. Biochem.
J . 1991, 279, 283-288. (f) Scho¨nfeld, W.; Kasimir, S.; Kno¨ller, J .;
J ablonski, K.; Ko¨nig, W. J . Leukocyte Biol. 1991, 50, 303-312. (g)
Wainwright, S. L.; Powell, W. S. J . Biol. Chem. 1991, 266, 20899-
20906. (h) Yokomizo, T.; Izumi, T.; Takahashi, T.; Kasama, T.;
Kobayashi, Y.; Sato, F.; Taketani, Y.; Shimizu, T. J . Biol. Chem. 1993,
268, 18128-18135. (i) Wheelan, P.; Zirrolli, J . A.; Morelli, J . G.;
Murphy, R. C. J . Biol. Chem. 1993, 268, 25439-25448.
(5) (a) Hansson, G.; Lindgren, J . A° .; Dahle´n, S.-E.; Hedqvist, P.;
Samuelsson, B. FEBS Lett. 1981, 130, 107-112. (b) J ubiz, W.;
Rådmark, O.; Malmsten, C.; Hansson, G.; Lindgren, J . A° .; Palmblad,
J .; Ude´n, A.-M.; Samuelsson, B. J . Biol. Chem. 1982, 257, 6106-6110.
(c) Powell, W. S. J . Biol. Chem. 1984, 259, 3082-3089. (d) Shak, S.;
Goldstein, I. M. J . Biol. Chem. 1984, 259, 10181-10187.
(6) (a) Wheelan, P.; Zirrolli, J . A.; Murphy, R. C. J . Am. Soc. Mass
Spectrom. 1996, 7, 129-139. (b) Wheelan, P.; Murphy, R. C.; Simon,
F. R. J . Mass Spectrom. 1996, 31, 236-246.
(7) (a) Ford-Hutchinson, A. W.; Bray, M. A.; Doig, M. V.; Shipley,
M. E.; Smith, M. J . H. Nature (London) 1980, 286, 264-265. (b)
Borgeat, P.; Sirois, P. J . Med. Chem. 1981, 24, 121-126.
(8) Reviews: (a) Samuelsson, B. Science 1983, 220, 568-575. (b)
Corey, E. J . Pure Appl. Chem. 1987, 59, 269-278. (c) Ko¨nig, W.;
Scho¨nfeld, W.; Raulf, M.; Ko¨ller, M.; Kno¨ller, J .; Scheffer, J .; Brom, J .
Eicosanoids 1990, 3, 1-22. (d) Shimizu, T.; Wolfe, L. S. J . Neurochem.
1990, 55, 1-15.
(4) (a) Kaever, V.; Damerau, B.; Wessel, K.; Resch, K. FEBS Lett.
1988, 231, 385-388. (b) Kaever, V.; Bruuns, J .; Wunder, J .; Damerau,
B.; Zimmer, G.; Fauler, J .; Wessel, K.; Floege, J .; Topley, N.; Radeke,
H.; Resch, K. Life Sci. 1990, 46, 1465-1470.
10.1021/jo9913199 CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/20/2000

708 J . Org. Chem., Vol. 65, No. 3, 2000
Nakayama et al.
F igu r e 2. Intermediates used for synthesis of 2-5: 2 and 3
from 10a + 11a ; 4 from 10a + 11b; 5 from 10b + rac-11a .
Sch em e 1
F igu r e 1. Leukotriene B4 (LTB4) (1) and dihydro-LTB4
compounds 2-5.
mined recently.9 These achievements have partially been
supported by supplying 1 and analogues synthesized by
total synthesis,10,11 and 1 is still required to further
understand the biological action and to find a new drug
against the diseases caused by leukocytes. One such
investigation probably involves installation of 1 onto
peptides and polymer supports. Unfortunately, the ex-
tremely unstable nature of 1 would certainly incur
difficulties during the installation.12 To this end, 10,11-
dihydro-LTB4 (2) is a good candidate for the following
reasons. First, 2 still retains the biological property of 1,
though 2 is less active than 1. Second, the chemical
stability of the diene system of 2 allows use of less mild
reactions which are not compatible with 1.
stereoselectivity in the formation of the cis double bond
at C(6) via Wittig reaction. Recently, we have developed
a method for synthesis of the conjugated diene unit of
type 9 as illustrated in Scheme 1.15 Reaction of boronate
esters 6 and MeLi produces lithium borates 7, which are
highly reactive species to couple with sterically hindered
cis-bromides 8 in the presence of a nickel catalyst to
afford 9 with retention of the olefin geometry. By using
this reaction as a key step, synthesis of 2, 4, and 5 was
accomplished stereoselectively, for the first time.16 In
addition, the amide of 2 (i.e., 3) was synthesized as well.
The amide might be useful as a LTB4 antagonist on the
analogy of LTB4 amide.17 Herein, we present details of
the synthesis.
Despite the importance of 10,11-dihydro metabolites
as such and as a stable substitute for 1, only two papers
accomplishing synthesis of 2, 4, and 5 have been pub-
lished so far.13,14 The synthesis, however, suffers from low
(9) Yokomizo, T.; Izumi, T.; Chang, K.; Takuwa, Y.; Shimizu, T.
Nature 1997, 387, 620-624.
(10) Reviews: (a) Corey, E. J .; Clark, D. A.; Marfat, A. In The
Leukotrienes, Chemistry and Biology; Chakrin, L. W., Bailey, D. M.,
Eds,; Academic: New York, 1984; Chapter 2. (b) Rokach, J .; Guindon,
Y.; Young, R. N.; Adams, J .; Atkinson, J . G. In The Total Synthesis of
Natural Products; ApSimon, J ., Ed.; Wiley: New York, 1988; Vol. 7, p
141. (c) Sato, F.; Kobayashi, Y. Synlett 1992, 849-857.
Resu lts a n d Discu ssion
(11) Recent syntheses: (a) Kobayashi, Y.; Shimazaki, T.; Taguchi,
H.; Sato, F. J . Org. Chem. 1990, 55, 5324-5335. (b) Avignon-Tropis,
M.; Treilhou, M.; Pougny, J . R.; Fre´chard-Ortuno, I.; Linstrumelle, G.
Tetrahedron 1991, 47, 7279-7286. (c) Avignon-Tropis, M.; Berjeaud,
J . M.; Pougny, J . R.; Fre´chard-Ortuno, I.; Guillerm, D.; Linstrumelle,
G. J . Org. Chem. 1992, 57, 651-654. (d) Treilhou, M.; Fauve, A.;
Pougny, J .-R.; Prome´, J .-C.; Veschambre, H. J . Org. Chem. 1992, 57,
3203-3208. (e) Shimazaki, T.; Kawajiri, K.; Kobayashi, Y.; Sato, F.
Prostagladins 1993, 45, 335-345. (f) Kobayashi, Y.; Shimazaki, T.;
Kawajiri, K.; Shimizu, T.; Seyama, Y.; Sato, F. Biochim. Biophys. Acta
1994, 1215, 280-284 and references therein.
Syn th etic In ter m ed ia tes. On the basis of the reac-
tion summarized in Scheme 1, the following combinations
of the boronate ester and the cis-bromide were planned
for the synthesis of 2-5: 10a and 11a for 2 and 3; 10a
and 11b for 4; 10b and rac-11a for 5 (Figure 2).
Preparation of these intermediates and synthesis of 2-5
are described below.
P r ep a r a tion of th e C(1)-C(7) Segm en ts. Two cis-
bromides (10a and 10b) were prepared according to the
(12) We had the following problems in our synthesis11a of 1 and its
analogues. (1) Treatment of an ethereal solution of 1 with diluted HCl
caused decomposition within 30 min at 0 °C. (2) Gentle bubbling of
nitrogen in an eluent for chromatography on silica gel was crucial to
prevent isomerization to the 6E isomer. (3) Use of commercial CDCl3
was responsible for the partial isomerization to the 6E isomer during
a routine 13C NMR measurement probably due to the presence of DCl.
DCl-free CDCl3 was prepared by passing CDCl3 through a pad of Al2O3
(from Merck) before use.
(14) Khanapure, S. P.; Wang, S. S.; Powell, W. S.; Rokach, J . J . Org.
Chem. 1997, 62, 325-330.
(15) Kobayashi, Y.; Nakayama, Y.; Mizojiri, R. Tetrahedron 1998,
54, 1053-1062.
(16) Preliminary communication: Kobayashi, Y.; Nakayama, Y.;
Kumar G. B. Tetrahedron Lett. 1998, 39, 6337-6340.
(17) Shimazaki, T.; Kobayashi, Y.; Sato, F.; Iwama, T.; Shikada, K.
Prostaglandins 1990, 39, 459-467.
(13) Yadagiri, P.; Lumin, S.; Falck, J . R. Tetrahedron Lett. 1989,
30, 429-432.

Synthesis of 10,11-Dihydroleukotriene B4 Metabolites
J . Org. Chem., Vol. 65, No. 3, 2000 709
Sch em e 2a
(+)-(Ipc)2BH followed by oxidation with excess MeCHO
at 40 °C and subsequent ligand exchange with the diol
furnished boronate ester 11a in 75% yield (Scheme 3).
Preparation of acetylene 24 and synthesis of 10,11-
dihydro-LTB4 (2) from boronate ester 11a were explored
by the route presented in Scheme 3. (R)-Epichlorohydrin
(18) of 99% ee was transformed into alcohol 19 by the
Yamaguchi method (LiCtCC5H11, BF3‚OEt2, -78 °C).23
Since reduction of 19 in the presence of Pd/BaSO4 and
quinoline afforded a mixture of cis-olefin 27 and its trans
isomer in varying ratios of >20 to 8:1, 19 was converted
into TBS ether 20. In contrast to 19, reduction of 20
under the same conditions afforded cis-olefin 28 exclu-
sively in 99% yield. Olefin 28 was treated with Bu4NF
and subsequently with NaOH to furnish epoxide 21 in
95% yield. Epoxide ring-opening of 21 with allenylmag-
nesium bromide (22), prepared from propargyl bromide
and Mg in the presence of HgCl2,24 afforded a mixture of
alcohol 23 and bromohydrin 29. Without separation, the
a
Reagents and conditions: (a) SOCl2, DMF (10 mol %); (b) 14a ,
PdCl2(PPh3)2 (0.4 mol %), CHCl3, 77% from 12; (c) NaBH4, 81%;
(d) t-BuOOH, Ti(OPr)4, D-(-)-DIPT; (e) Br2, -78 °C; (f) TBAF, -78
°C, THF; (g) TBSCl, imidazole; (h) CH2dCHOEt, PPTS, CH2Cl2,
86%.
literature procedure11a,18 with a modification as presented
in Scheme 2. Originally, vinylsilane rac-16 was prepared
from methyl 4-formylbutanoate and aluminate 14b,
which in turn was generated from vinylstannane 14a
mixture was treated with K2CO3 to convert 29 again to
epoxide 21, and chromatography of the resulting mixture
afforded 23 and 21 in 62% and 20% yields, respectively.
Silylation of 23 afforded acetylene 24 in 93% yield.
Successful transformation of 24 to boronate ester 11a is
described in the above paragraph. For coupling of cis-
bromide 10a and boronate 11a , lithium borate 25 and a
Ni(0) species were generated by addition of MeLi (1.6
equiv) to a mixture of 11a (1.5 equiv) and NiCl2(PPh3)2
(10 mol %) in THF. After addition of bromide 10a (1
equiv), the reaction was carried out at room temperature
overnight to furnish diene 26 stereoselectively in 77%
yield. Finally, treatment of 26 with excess Bu4NF ensued
desilylation and hydrolysis to afford the target molecule
2 in 83% yield.
through lithiation using n-BuLi followed by Li/Al ex-
change with Et2AlCl. Although the reaction proceeded
efficiently, isolation of rac-16 from a mixture containing
a large mass of coproduced Bu4Sn by chromatography
required somewhat larger volumes of silica gel and an
eluent. To avoid the production of Bu4Sn, the Stille
reaction19 was applied to acid chloride 13 and stannane
14a . The reaction proceeded smoothly to furnish a
mixture of ketone 15 and Bu3SnCl, and the latter was
simply removed by washing with aqueous NaOH, thus
allowing easy purification of 15 by chromatography.
Reduction of ketone 15 with NaBH4 then afforded race-
mic alcohol rac-16 in 62% overall yield from the half-acid
12. Transformation of rac-16 into cis-bromide 10a exactly
followed the literature procedure,11a which involves, as
the key reaction, kinetic resolution of rac-16 using the
Sharpless reagent20 to produce (S)-16 (structure not
shown) of >99% ee (determined by 1H NMR spectroscopy
of the derived MTPA ester). On the other hand, reaction
of alcohol 17 with CH2dCHOEt furnished 10b in 86%
yield.
For conversion of acid 2 to amide 3, 2 was esterified
with CH2N2 (eq 1). The resulting methyl ester was then
(21) (a) For example, an application of the Takai reaction21b to
boronate ester i21c produced a stereoisomeric mixture of alkene iii,
though the original reaction using ii furnishes stereoselectively the
corresponding trans isomer, which is, however, marginally reactive for
the coupling with cis-bromides.15
P r ep a r a tion of th e C(8)-C(20) Segm en t 11a a n d
Syn th esis of 10,11-Dih yd r o-LTB4 (2) a n d Its Am id e
3. To secure a synthetic route eventually leading to 2 and
3, a method for obtaining the key boronate ester 11a was
explored first. Among the methods so far published,21 the
protocol developed by Suzuki and Miyaura22 was found
to be suitable. Thus, hydroboration of acetylene 24 with
(18) Kitano, Y.; Matsumoto, T.; Sato, F. Tetrahedron 1988, 44,
4073-4086.
(19) (a) Milstein, D.; Stille, J . K. J . Org. Chem. 1979, 44, 1613-
1618. (b) Labadie, J . W.; Tueting, D.; Stille, J . K. J . Org. Chem. 1983,
48, 4634-4642.
(b) Takai, K.; Shinomiya, N.; Kaihara, H.; Yoshida, N.; Moriwake, T.;
Utimoto, K. Synlett 1995, 963-964. (c) Wuts, P. G. M.; Thompson, P.
A. J . Organomet. Chem. 1982, 234, 137-141.
(22) Kamabuchi, A.; Moriya, T.; Miyaura, N.; Suzuki, A. Synth.
Commun. 1993, 23, 2851-2859.
(20) (a) Martin, V. S.; Woodard, S. S.; Katsuki, T.; Yamada, Y.;
Ikeda, M.; Sharpless, K. B. J . Am. Chem. Soc. 1981, 103, 6237-6240.
(b) Gao, Y.; Hanson, R. M.; Klunder, J . M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J . Am. Chem. Soc. 1987, 109, 5765-5780.
(23) Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391-394.
(24) Hopf, H.; Bo¨hm, I.; Kleinschroth, J . In Organic Syntheses;
Freeman, J . P., Ed.; Wiley: New York, 1990; Collect. Vol. 7, pp 485-
490.

710 J . Org. Chem., Vol. 65, No. 3, 2000
Nakayama et al.
Sch em e 3a
a
Reagents and conditions: (a) LiCtCC5H11, BF3‚OEt2, 70%; (b) TBSCl, imidazole, 99% for 20, 93% for 24; (c) H2, Pd/BaSO4, quinoline,
MeOH, 100%; (d) TBAF, THF then NaOH, THF, 95%; (e) 22 (1.5 equiv), Et2O, -30 to 0 °C, then K2CO3, MeOH, rt, 1 h, 62%; (f) (i)
(+)-(Ipc)2BH (1.2 equiv), THF, -35 to 0 °C, 2 h; (ii) MeCHO (15 equiv), 40 °C; (iii) Me2C(CH2OH)2 (1.2 equiv), rt, 1 h, 75%; (g) 11a (1.5
equiv), NiCl2(PPh3)2 (10 mol %), MeLi (1.6 equiv), THF, 0 °C, 20 min; (h) 10a (1 equiv), rt, overnight, 77% based on 10a ; (i) TBAF (10
equiv), THF, rt, overnight, 83%.
Sch em e 4a
a
Reagents and conditions: (a) C7H15MgBr, CuCN, THF, 100%; (b) NaOH, THF, rt, 3 h, 96%; (c) 22, Et2O, -50 to -10 °C, then K2CO3,
MeOH, 57%; (d) TBSCl, imidazole, 90%; (e) (i) (+)-(Ipc)2BH, THF, -35 to 0 °C, 2 h; (ii) MeCHO, 40 °C; (iii) Me2C(CH2OH)2, rt, 1 h, 77%;
(f) 11b (1.5 equiv), NiCl2(PPh3)2 (10 mol %), MeLi (1.6 equiv), THF, 0 °C, 20 min; (g) 10a (1 equiv), rt, overnight, 74% based on 10a ; (h)
TBAF (10 equiv), THF, 78%.
treated with NH3 in MeOH for several days, furnishing
amide 3 in 92% yield. During the conversion, isomeriza-
tion of the cis double bond to the trans one was not
1
observed by H NMR spectroscopy.
Syn th esis of 10,11,14,15-Tetr a h yd r o-LTB4 (4). To
prepare the key intermediate 11b, epoxide 18 of 99% ee
was converted into another epoxide (30)25 in 96% yield
by copper-catalyzed epoxide ring-opening with C7H15
-
MgBr followed by reaction with NaOH (Scheme 4). Then
30 was converted into boronate ester 11b through
acetylenes 31 and 32 with yields similar to those obtained
(25) Preparation of 30 by another method: (a) Masaoka, Y.; Saka-
kibara, M.; Mori, K. Agric. Biol. Chem. 1982, 46, 2319-2324. (b) Sugai,
T.; Mori, K. Agric. Biol. Chem. 1984, 48, 2497-2500.

Synthesis of 10,11-Dihydroleukotriene B4 Metabolites
J . Org. Chem., Vol. 65, No. 3, 2000 711
Sch em e 6a
F igu r e 3. Acetylenes 35a ,b and boronate esters 36a ,b used
as model compounds for synthesis of 5 (for results, see Schemes
5).
Sch em e 5. Resu ts of th e Mod el Stu d y for
Syn th esis of 5
a
Reagents and conditions: (a) rac-11a (1.5 equiv), NiCl2(PPh3)2
(15 mol %), MeLi (1.6 equiv), THF, 0 °C, 20 min; (b) 10b (1 equiv),
rt, overnight, 48% based on 10b; (c) TBAF (2 equiv), THF, rt,
overnight, 70%; (d) 1 N NaOH, MeOH; (e) PDC (1.5 equiv), Celite,
44% from 40; (f) PPTS, i-PrOH, rt, 8 h, 81%.
borate rac-25, and reaction with cis-bromide 10b afforded
diene 39 in 48% yield, which upon desilylation furnished
alcohol 40 in 70% yield as depicted in Scheme 6. After
hydrolysis, the crucial oxidation was successfully achieved
with PDC, furnishing ketone 41 in 44% yield. Finally,
deprotection of the EE group at C(5) completed the
synthesis of 12-oxo-LTB4 5.
Con clu sion
In summary, we have succeeded in synthesizing 10,11-
dihydro-LTB4 (2) and its amide 3 in a stereoselective
fashion, for the first time. By using the present method,
other dihydro-LTB4 compounds (4 and 5) have also been
synthesized stereoselectively. Since the double bond at
C(14) of LTB4 (1) is not responsible for the biological
property,17 4 is probably more convenient as a substitute
of 1 than 2 because synthesis of 4 is simpler than that of
2 due to the absence of the double bond. Furthermore,
the present method is definitely applicable to stereo-
selective synthesis of other 10,11-dihydro-LTB4 com-
pounds. We believe that biological research of 10,11-
dihydro-LTB4 compounds as well as LTB4 would be much
accelerated with these results.
for preparation of 11a . Coupling reaction of boronate 11b
and bromide 10a also proceeded in a stereoselective
manner to produce diene 34 in 74% yield, which upon
hydrolysis afforded tetrahydro-LTB4 (4) in 78% yield.
Syn th esis of 10,11-Dih yd r o-12-oxo-LTB4 (5). The
coupling strategy was examined preliminarily with model
boronate esters 36a and 36b (Figure 3). These intermedi-
ates were prepared from acetylenes 35a and 35b in 54%
and 62% yields, respectively, by the method through
hydroboration with (Ipc)2BH.22 Attempted coupling of
bromide 10a with ketone 36a under the conditions used
in Schemes 3 and 4 (MeLi, NiCl2(PPh3)2) produced messy
products (Scheme 5). On the other hand, acetal 36b
furnished the coupling product 37 in 71% yield. Unfor-
tunately, deprotection of the ketal group in 37 under a
variety of conditions resulted in recovery or decomposi-
tion of 37.
Next, we explored another route involving oxidation
of a 12-hydroxyl compound. To differentiate the two
hydroxyl groups at C(5) and C(12), ethoxyethyl ether 10b
was chosen as the C(1)-C(7) part and the racemic
boronate ester (rac-11a ) was prepared from racemic
epichlorohydrin exactly following the route summarized
in Scheme 3. Treatment of rac-11a with MeLi produced
Exp er im en ta l Section
Gen er a l Meth od s. Infrared (IR) spectra are reported in
1
wavenumbers (cm-1). Unless otherwise noted, H NMR (300
MHz) and 13C NMR (75 MHz) spectra were measured in CDCl3
using SiMe4 (δ 0 ppm) and the center line of CDCl3 triplet (δ
77.1 ppm) as internal standards, respectively. The following
solvents were distilled before use: THF (from Na/benzophe-
none), Et2O (from Na/benzophenone), and CH2Cl2 (from CaH2).
N,N-Dimethylformamide (DMF) was dried over CaH2. Acet-
aldehyde (purity >99.5%) was purchased from Aldrich, and
(R)-epichlorohydrin (20) (99% ee) was kindly offered by Daiso,
J apan. The phosphate buffer of pH 5 was prepared by mixing
Na2HPO4‚12H2O (7.38 g), citric acid (2.04 g), and H2O (200
mL). trans-1-(Trimethylsilyl)-2-(tributylstannyl)ethylene was
prepared from trimethylsilylacetylene by the literature meth-
od.26 Routinely, an organic extract was dried over MgSO4 and
(26) Cunico, R. F.; Clayton, F. J . J . Org. Chem. 1976, 41, 1480-
1482.

712 J . Org. Chem., Vol. 65, No. 3, 2000
Nakayama et al.
concentrated by using a rotary evaporator to leave a residual
oil, which was purified by chromatography on silica gel. Some
intermediates were distilled before use, and oven temperatures
are given as boiling points.
3082, 1739, 1620 cm-1
;
1H NMR δ 1.11 and 1.15 (2t, J ) 7
and 7 Hz, 3 H), 1.21 and 1.25 (2d, J ) 5.5 and 5.5 Hz, 3 H),
1.41-1.78 (m, 4 H), 2.25-2.33 (m, 2 H), 3.60 (s, 3 H), 3.29-
3.66 (m, 2 H), 4.32-4.40 and 4.51-4.64 (2m, 2 H), 5.94-6.29
(m, 2 H); 13C NMR δ 174.1, 136.8, 136.1, 109.6, 108.1, 99.7,
98.3, 73.5, 72.9, 61.7, 61.0, 51.5, 34.04, 33.94, 33.80, 33.76,
4-Meth oxyca r bon ylbu ta n oic Acid (12).27 A solution of
glutaric anhydride (6.00 g, 52.6 mmol) and NaOMe (57 mg,
1.06 mmol) in MeOH (75 mL) was stirred at room temperature
overnight and most of the MeOH was removed by evaporation.
A residue obtained was diluted with H2O, and the resulting
mixture was extracted with EtOAc twice. The combined
extracts were dried and concentrated to give an oil, which was
purified by chromatography to furnish 12 (7.25 g, 95%): IR
20.67, 20.49, 20.47, 20.42, 15.3, 15.1. Anal. Calcd for C12H21
BrO4: C, 46.61; H, 6.85. Found: C, 46.66; H, 6.74.
-
(R)-1-Ch lor o-4-d ecyn -2-ol (19). To a solution of 1-heptyne
(2.83 mL, 21.6 mmol) in THF (20 mL) was added n-BuLi (7.0
mL, 2.31 M in hexane, 16.2 mmol) at -78 °C. After the solution
was stirred for 30 min at -78 °C, BF3‚OEt2 (2.26 mL, 18.4
mmol) and, after 10 min, (R)-epichlorohydrin (18) (99% ee, 0.99
g, 10.8 mmol) were added to the solution. The resulting
solution was stirred at -78 °C for 30 min and poured into a
mixture of EtOAc and saturated aqueous NH4Cl with vigorous
stirring. The layers were separated, and the aqueous layer was
extracted with EtOAc three times. The combined organic
layers were dried and concentrated to give an oil, which was
subjected to chromatography (hexane:Et2O ) 20:1 to 10:1)
to afford 19 (1.42 g, 70%): [R]25D -11.0 (c 0.86, CHCl3); bp 110
1
(neat) 3250, 1736, 1709 cm-1; H NMR δ 1.86 (quintet, J ) 7
Hz, 2 H), 2.29-2.39 (m, 4 H), 3.60 (s, 3 H), 11.62 (br s, 1 H);
13C NMR δ 179.1, 173.6, 51.5, 32.8, 32.7, 19.6. Anal. Calcd for
C6H10O4: C, 49.31; H, 6.90. Found: C, 49.13; H, 6.85.
Meth yl (E)-5-Oxo-7-tr im eth ylsilyl-6-h ep ten oa te (15).
To a solution of 12 (0.96 g, 6.58 mmol) and DMF (0.05 mL,
0.65 mmol) in benzene (10 mL) was added SOCl2 (0.72 mL,
9.87 mmol), and the resulting solution was heated for 2 h (bath
temperature 80 °C). After the solution was cooled to room
temperature, volatile materials were removed by using a
vacuum pump to give crude 13, which was used for the next
reaction without further purification.
°C (1 Torr); IR (neat) 3392, 1084, 1051 cm-1; H NMR δ 0.89
1
(t, J ) 7 Hz, 3 H), 1.20-1.40 (m, 4 H), 1.40-1.54 (m, 2 H),
2.15 (tt, J ) 7, 2 Hz, 2 H), 2.40 (br s, 1 H), 2.46-2.54 (m, 2 H),
3.61 (dd, J ) 11, 6 Hz, 1 H), 3.70 (dd, J ) 11, 5 Hz, 1 H),
3.86-3.98 (m, 1 H); 13C NMR δ 84.0, 74.4, 70.1, 48.3, 31.1,
28.5, 24.7, 22.2, 18.6, 13.9.
To the above acid chloride 13 dissolved in CHCl3 (10 mL)
were added PdCl2(PPh3)2 (18 mg, 0.026 mmol) and 14a (2.69
g, 6.91 mmol). The resulting solution was heated overnight
(bath temperature 65 °C), cooled to room temperature, washed
with 1 N NaOH, dried, and concentrated. The residue thus
obtained was purified by chromatography (hexane/EtOAc) to
give 15 (1.15 g, 77%): bp 125 °C (1 Torr); IR (neat) 1739, 1697,
1678, 1590 cm-1; 1H NMR δ 0.13 (s, 9 H), 1.94 (quintet, J ) 7
Hz, 2 H), 2.37 (t, J ) 7 Hz, 2 H), 2.67 (t, J ) 7 Hz, 2 H), 3.67
(R )-2-[(t er t -Bu t yld im e t h ylsilyl)oxy]-1-ch lor o-4-d e -
cyn e (20). A solution of alcohol 19 (3.12 g, 16.5 mmol), TBSCl
(3.02 g, 20.0 mmol), and imidazole (1.69 g, 24.8 mmol) in DMF
(30 mL) was stirred at room temperature overnight and poured
into a mixture of saturated NaHCO3 and hexane. The mixture
was stirred vigorously at room temperature for 1 h, the layers
were separated, and the aqueous layer was extracted with
hexane. The combined hexane solutions were dried and
concentrated to furnish an oil, which was purified by chroma-
tography (hexane) to afford 20 (4.95 g, 99%): IR (neat) 1255,
(s, 3 H), 6.46 (d, J ) 19 Hz, 1 H), 7.05 (d, J ) 19 Hz, 1 H); 13
C
NMR δ 199.1, 173.4, 146.4, 142.0, 51.1, 37.8, 32.6, 18.7, -2.3.
Anal. Calcd for C11H20O3Si: C, 57.85; H, 8.83. Found: C, 57.47;
9.07.
Met h yl (5R,6E)- a n d (5S,6E)-5-H yd r oxy-7-t r im et h yl-
silyl-6-h ep ten oa te (r a c-16). To an ice-cold solution of ketone
15 (701 mg, 3.07 mmol) in MeOH (10 mL) was added NaBH4
(58 mg, 1.53 mmol) portionwise. The mixture was stirred at 0
°C for 30 min, and most of the MeOH was removed by using
a rotary evaporator. To the residue was added brine, and the
product was extracted with EtOAc repeatedly. The combined
EtOAc solutions were dried and concentrated to afford an oil,
which was purified by chromatography (benzene/EtOAc) to
furnish rac-16 (576 mg, 81%). The IR and 13C NMR spectra of
rac-16 were identical with those reported previously.18 1H
NMR (CDCl3) of rac-16: δ 0.07 (s, 9 H), 1.50-1.84 (m, 4 H),
2.36 (t, J ) 7 Hz, 2 H), 2.6 (br s, 1 H), 3.67 (s, 3 H), 4.05-4.15
(m, 1 H), 5.87 (d, J ) 19 Hz, 1 H), 6.04 (dd, J ) 19, 5.5 Hz, 1
H).28
Meth yl (5S,6E)-5-[(ter t-Bu tyld im eth ylsilyl)oxy]-7-tr i-
m eth ylsilyl-6-h ep ten oa te (10a ). According to the literature
procedure,18 (S)-16 of >99% ee (determined by 1H NMR
spectroscopy of the MTPA ester) was prepared from rac-16 by
the kinetic resolution using t-BuOOH, D-(-)-DIPT, and Ti-
(OPr)4, and converted into TBS ether 10a by bromination with
Br2 followed by reaction with TBAF and protection with
TBSCl.11a
Meth yl (5S,6Z)-7-Br om o-5-(1-eth oxyeth oxy)-6-h ep ten -
oa te (10b). A solution of 17 (1.80 g, 7.59 mmol), ethyl vinyl
ether (2.18 mL, 22.8 mmol), and PPTS (190 mg, 0.76 mmol)
in CH2Cl2 (10 mL) was stirred at room temperature for 2 h
and poured into saturated NaHCO3 with EtOAc. The layers
were separated, and the aqueous layer was extracted with
EtOAc. The combined extracts were dried over NaHCO3 and
MgSO4, and concentrated to leave an oil, which was purified
by chromatography (hexane/EtOAc with a few drops of NEt3)
to furnish 10b (2.01 g, 86%): bp 115 °C (1 Torr); IR (neat)
1113, 837, 777 cm-1 1H NMR δ 0.10 (s, 3 H), 0.11 (s, 3 H),
;
0.89 (s, 12 H), 1.23-1.41 (m, 4 H), 1.41-1.54 (m, 2 H), 2.13
(tt, J ) 7, 2 Hz, 2 H), 2.38-2.45 (m, 2 H), 3.51 (dd, J ) 11, 6
Hz, 1 H), 3.64 (dd, J ) 11, 5 Hz, 1 H), 3.88-3.98 (m, 1 H); 13
C
NMR δ 82.4, 75.3, 71.3, 47.9, 30.6, 28.2, 25.29, 25.21, 21.8,
18.3, 17.6, 13.5, -5.2.
(2R ,4Z)-2-[(t er t -Bu t yld im e t h ylsilyl)oxy]-1-ch lor o-4-
d ecen e (28). A mixture of 5% Pd/BaSO4 (0.25 g) and quinoline
(0.25 mL) in MeOH (60 mL) was stirred at room temperature
for 30 min under argon, and argon was replaced by hydrogen.
The mixture was stirred for 30 min further at room temper-
ature, and acetylene 20 (4.95 g, 16.3 mmol) was added to it.
After hydrogen uptake reached a plateau (ca. 2 h), the mixture
was filtered through a pad of Celite by suction with Et2O, and
the filtrate was concentrated to leave an oil, which was purified
by chromatography (hexane) to afford olefin 28 (4.97 g,
100%): [R]29D -13.6 (c 1.22, CHCl3); IR (neat) 3008, 1103, 837,
775 cm-1; 1H NMR δ 0.08 (s, 3 H), 0.09 (s, 3 H), 0.88 (t, J ) 7
Hz, 3 H), 0.89 (s, 9 H), 1.20-1.40 (m, 6 H), 2.03 (q, J ) 7 Hz,
2 H), 2.29-2.37 (m, 2 H), 3.40 (dd, J ) 11, 6 Hz, 1 H), 3.45
(dd, J ) 11, 5 Hz, 1 H), 3.80-3.90 (m, 1 H), 5.37 (dtt, J ) 11,
7, 1 Hz, 1 H), 5.49 (dtt, J ) 11, 7, 1 Hz, 1 H); 13C NMR δ 133.2,
124.2, 72.6, 48.4, 32.9, 31.6, 29.3, 27.4, 25.8, 22.6, 18.1, 14.0,
-4.7.
(2R,2′Z)-2-(2′-Octen yl)oxir a n e (21). To a solution of 28
(4.97 g, 16.3 mmol) in THF (20 mL) was added TBAF (32 mL,
1.0 M in THF, 32 mmol). The resulting solution was stirred
at room temperature overnight and poured into saturated
NH4Cl. The mixture was extracted with hexane twice. The
combined extracts were rinsed with brine, dried, and concen-
trated to afford crude 27, which was used for the next reaction
without further purification. An analytically pure sample was
obtained by chromatography (hexane/Et2O): 1H NMR δ 0.88
(t, J ) 7 Hz, 1 H), 1.22-1.40 (m, 6 H), 2.03 (q, J ) 7 Hz, 2 H),
2.23 (br d, J ) 5 Hz, 1 H), 2.34 (t, J ) 7 Hz, 1 H), 3.50 (dd, J
) 11, 7 Hz, 1 H), 3.63 (dd, J ) 11, 4 Hz, 1 H), 3.77-3.90 (m,
(27) Ohta, H.; Tetsukawa, H.; Noto, N. J . Org. Chem. 1982, 47,
2400-2404.
(28) In the original paper, the 1H NMR spectrum was measured in
CCl4.

Synthesis of 10,11-Dihydroleukotriene B4 Metabolites
J . Org. Chem., Vol. 65, No. 3, 2000 713
1 H), 5.37 (dtt, J ) 11, 7, 1 Hz, 1 H), 5.57 (dtt, J ) 11, 7, 1 Hz,
1 H); 13C NMR δ 134.3, 123.6, 71.3, 49.6, 32.2, 31.5, 29.2, 27.4,
22.5, 14.0.
Acetaldehyde (1.34 mL, 24 mmol) was added to it at 0 °C, and
the resulting solution was stirred overnight at the bath
temperature of 40 °C, under which the solution refluxed gently.
The volatile material was removed under reduced pressure to
afford the corresponding diethyl boronate, which was diluted
with THF (3 mL) for the next transesterification.
To a solution of the above alcohol 27 dissolved in THF (20
mL) was added crushed NaOH (3.2 g, 80 mmol), and the
mixture was stirred vigorously at room temperature for 3 h
and poured into water. The product was extracted with Et2O
repeatedly. The combined ethereal solutions were dried and
concentrated to leave an oil, which was purified by chroma-
tography (hexane/Et2O) to afford epoxide 21 (2.38 g, 95%): bp
To the above THF solution was added 2,2-dimethy-1,3-
propanediol (200 mg, 1.92 mmol), and the resulting solution
was stirred at room temperature for 1 h. Concentration and
purification of the residue by chromatography (hexane/EtOAc)
afforded 11a (507 mg, 75%), which was distilled for the next
1
140 °C (12 Torr); IR (neat) 3045, 3010, 833 cm-1; H NMR δ
0.87 (t, J ) 7 Hz, 3 H), 1.18-1.40 (m, 6 H), 2.02 (q, J ) 7 Hz,
2 H), 2.25 (dt, J ) 15, 7 Hz, 1 H), 2.39 (dt, J ) 15, 7 Hz, 1 H),
2.50 (dd, J ) 5, 3 Hz, 1 H) 2.73 (dd, J ) 5, 4 Hz, 1 H), 2.89-
2.97 (m, 1 H), 5.33-5.45 (m, 1 H), 5.46-5.58 (m, 1 H); 13C NMR
δ 133.4, 123.1, 51.7, 46.7, 31.4, 30.1, 29.2, 27.3, 22.5, 14.0. Anal.
Calcd for C10H18O: C, 77.87; H, 11.76. Found: C, 77.50; H,
12.15.
reaction: [R]29 -10.3 (c 1.28, CHCl3); bp 210 °C (1 Torr); IR
D
(neat) 3006, 1639, 1089, 837, 775 cm-1; 1H NMR δ 0.029 (s, 3
H), 0.033 (s, 3 H), 0.87 (s, 12 H), 0.95 (s, 6 H), 1.18-1.40 (m,
6 H), 1.45-1.60 (m, 2 H), 1.93-2.04 (m, 2 H), 2.05-2.30 (m, 4
H), 3.62 (s, 4 H), 3.66-3.71 (m, 1 H), 5.34 (d, J ) 18 Hz, 1 H),
5.29-5.48 (m, 2 H), 6.54 (dt, J ) 18, 6 Hz, 2 H). Anal. Calcd
for C24H47BO3Si: C, 68.22; H, 11.21. Found: C, 67.81; H, 11.03.
Meth yl (5S,6Z,8E,12S,14Z)-5,12-Bis[(ter t-bu tyld im eth -
ylsilyl)oxy]-6,8,14-eicosa tr ien oa te (26). To an ice-cold mix-
ture of 11a (89 mg, 0.21 mmol), NiCl2(PPh3)2 (10 mg, 0.015
mmol), and THF (0.3 mL) was added MeLi (0.20 mL, 1.12 M
in ether, 0.22 mmol). The resulting dark red solution was
stirred at 0 °C for 20 min, and bromide 10a (>99% ee, 49 mg,
0.14 mmol) (vide supra) was added to it. Stirring was continued
at room temperature overnight. A few drops of NEt3, hexane,
and saturated NH4Cl were added to the solution successively,
and the resulting mixture was stirred for 30 min vigorously.
The layers were separated, and the aqueous layer was
extracted with hexane twice. The combined extracts were dried
and concentrated to give an oil, which was purified by
chromatography (hexane:Et2O ) 50:1) to furnish 26 (63 mg,
(5S,7Z)-7-Tr id ecen -1-yn -5-ol (23). Requisite allenylmag-
nesium bromide 22 in Et2O (ca. 0.50 M) was prepared
according to the literature procedure24 from propargyl bromide
(2.3 mL, 30 mmol), magnesium (0.80 g, 33 mmol), HgCl2 (15
mg), and Et2O (13 mL), and diluted with additional Et2O (45
mL) to make a 0.5 M solution, which was used for the next
reaction without titration.
To a solution of 21 (2.30 g, 14.9 mmol) in Et2O (30 mL) was
added a freshly prepared solution of 22 (44.7 mL, 22.4 mmol)
at -30 °C dropwise. The solution was warmed to 0 °C over 2
h and poured into saturated NH4Cl. The mixture was extracted
with Et2O, dried, and concentrated to leave an oil, which was
1
a mixture of 23 and 29 by H NMR spectroscopy.
To the mixture dissolved in MeOH (15 mL) was added
K2CO3 (2.06 g, 14.9 mmol) portionwise. The resulting mixture
was stirred at room temperature for 1 h and poured into H2O.
The product was extracted with Et2O several times, and the
combined ethereal solutions were dried and concentrated. The
residue obtained was purified by chromatography (hexane/
Et2O) to afford epoxide 21 (0.46 g, 20%) first and then alcohol
23 (1.80 g, 62%). Spectral data of 23: IR (neat) 3360, 3311,
77%): [R]22 +6.7 (c 0.60, CHCl3); IR (neat) 3010, 1743, 837,
D
1
775 cm-1; H NMR δ 0.01, 0.04, 0.049, and 0.052 (4s, 12 H),
0.87 (s, 9 H), 0.88 (t, J ) 7 Hz, 3 H), 0.89 (s, 9 H), 1.20-1.80
(m, 12 H), 2.01 (q, J ) 7 Hz, 2 H), 2.07-2.25 (m, 4 H), 2.31 (t,
J ) 7 Hz, 2 H), 3.66 (s, 3 H), 3.62-3.74 (m, 1 H), 4.48-4.57
(m, 1 H), 5.23 (dd, J ) 11, 9 Hz, 1 H), 5.32-5.50 (m, 2 H),
5.68 (dt, J ) 15, 7 Hz, 1 H), 5.88 (t, J ) 11 Hz, 1 H), 6.22 (dd,
J ) 15, 11 Hz, 1 H); 13C NMR δ 174.3, 136.5, 132.9, 132.0,
128.2, 125.6, 125.4, 71.8, 68.6, 51.5, 37.8, 36.3, 35.2, 34.0, 31.6,
29.3, 28.8, 27.4, 25.91, 25.86, 22.6, 20.9, 18.15, 18.10, 14.1,
-4.27, -4.35, -4.6, -4.9. Anal. Calcd for C33H64O4Si2: C,
68.22; H, 11.10. Found: C, 68.16; H, 11.08.
3008, 2112, 1070 cm-1 1H NMR δ 0.88 (t, J ) 7 Hz, 3 H),
;
1.20-1.45 (m, 6 H), 1.58-1.74 (m, 2 H), 1.76 (d, J ) 4 Hz, 1
H), 1.96 (t, J ) 3 Hz, 1 H), 2.04 (q, J ) 7 Hz, 2 H), 2.24 (t, J
) 7 Hz, 2 H), 2.34 (dt, J ) 3, 7 Hz, 2 H), 3.71-3.83 (m, 1 H),
5.39 (dtt, J ) 11, 7, 1 Hz, 1 H), 5.57 (dtt, J ) 11, 7, 1, 1 H); 13
C
NMR δ 134.1, 124.7, 84.3, 70.3, 68.7, 35.3, 35.1, 31.5, 29.3,
10,11-Dih yd r oleu k otr ien e B4 (2). To a solution of 26 (100
mg, 0.172 mmol) in THF (7 mL) was added a solution of TBAF
(1.72 mL, 1.0 M in THF, 1.72 mmol). After the solution was
stirred at room temperature overnight, the solution was poured
into a vigorously stirred mixture of Et2O and the phosphate
buffer (pH 5). The layers were separated, and the aqueous
layer was extracted with Et2O. The combined ethereal solu-
tions were washed with brine, dried, and concentrated. The
residual oil was purified by chromatography (Et2O/MeOH) to
27.4, 22.5, 15.0, 14.0.
(5S,7Z)-5-[(ter t-Bu t yld im et h ylsilyl)oxy]-7-t r id ecen -1-
yn e (24). A solution of 23 (1.69 g, 8.70 mmol), TBSCl (1.57 g,
10.4 mmol), and imidazole (0.89 g, 13 mmol) in DMF (10 mL)
was stirred at room temperature overnight and poured into a
mixture of saturated NaHCO3 and hexane. After the solution
was stirred vigorously at room temperature for 30 min, the
layers were separated, and the aqueous layer was extracted
with hexane twice. The combined hexane solutions were dried
and concentrated to give an oil, which was purified by
chromatography to afford 24 (2.50 g, 93%): [R]25D -30.4 (c 0.93,
CHCl3); bp 160 °C (1 Torr); IR (neat) 3318, 3010, 2119, 1082,
1
afford 2 (48 mg, 83%): IR (neat) 3383, 3016, 1714 cm-1; H
NMR δ 0.87 (t, J ) 7 Hz, 3 H), 1.10-1.80 (m, 12 H), 2.03 (q,
J ) 7 Hz, 2 H), 2.12-2.29 (m, 4 H), 2.37 (t, J ) 7 Hz, 2 H),
3.57-3.69 (m, 1 H), 4.60 (dt, J ) 9, 7 Hz, 1 H), 4.66-5.20 (m,
3 H), 5.28 (dd, J ) 11, 9 Hz, 1 H), 5.32-5.44 (m, 1 H), 5.48-
5.61 (m, 1 H), 5.72 (dt, J ) 15, 7 Hz, 1 H), 6.00 (t, J ) 11 Hz,
1 H), 6.34 (dd, J ) 15, 11 Hz, 1 H); 13C NMR δ 178.7, 136.6,
133.8, 131.6, 130.4, 125.8, 124.9, 70.8, 67.5, 36.4, 35.8, 35.3,
33.7, 31.5, 29.3, 29.0, 27.4, 22.5, 20.6, 14.0.
1
837, 775 cm-1; H NMR δ 0.08 (s, 6 H), 0.89 (s, 12 H), 1.20-
1.42 (m, 6 H), 1.54-1.75 (m, 2 H), 1.93 (t, J ) 3 Hz, 1 H), 2.02
(q, J ) 7 Hz, 2 H), 2.10-2.30 (m, 4 H), 3.75-3.85 (m, 1 H),
5.32-5.52 (m, 2 H); 13C NMR δ 132.2, 125.2, 84.7, 70.8, 68.3,
35.3, 35.2, 31.6, 29.3, 27.4, 25.9, 22.6, 18.1, 14.6, 14.0, -4.4,
-4.8. Anal. Calcd for C19H36OSi: C, 73.95; H, 11.76. Found:
C, 73.87; H, 11.71.
(5S,6Z,8E,12S,14Z)-5,12-Dih yd r oxy-6,8,14-eicosa tr ien -
a m id e (Am id e of 10,11-Dih yd r oleu k otr ien e B4) (3). 10,11-
Dihydroleukotriene B4 (2) (15 mg, 0.044 mmol) was converted
to methyl ester with CH2N2 in a usual manner. A solution of
the methyl ester dissolved in MeOH (0.5 mL) which was
saturated with NH3 was placed in glass tubing. It was sealed
and left at room temperature for 5 days. The volatile material
was removed under reduced pressure, and the residue was
purified by chromatography (Et2O/MeOH) to afford amide 3
(1′E,5′S,7′Z)-2-[5′-{(ter t-Bu t yld im et h ylsilyl)oxy}-1′,7′-
tr id eca d ien yl]-5,5-d im eth yl-1,3,2-d ioxa bor in a n e (11a ). To
a solution of BH3‚SMe2 (0.96 mL, 2.0 M in THF, 1.92 mmol)
was added (-)-R-pinene (0.75 mL, 4.81 mmol) at 0 °C. After
the solution was stirred at 0 °C for 1 h, the white precipitate
of (+)-(Ipc)2BH covered the solution. The ice-water bath was
removed, and stirring was continued for 2 h further to ensure
complete formation of (+)-(Ipc)2BH. The mixture was cooled
to -35 °C, and 24 (494 mg, 1.60 mmol) was added to the flask.
The resulting mixture was gradually warmed to 0 °C over 2
h, during which time the white precipitate disappeared.
(13 mg, 92%): IR (neat) 3348, 3192, 3008, 1668, 1614 cm-1
;
1H NMR δ 0.87 (t, J ) 7 Hz, 3 H), 1.1-2.3 (m, 22 H), 3.61
(quintet, J ) 6 Hz, 1 H), 4.59 (q, J ) 7 Hz, 1 H), 5.29 (t, J )
11 Hz, 1 H), 5.35-5.44 (m, 1 H), 5.50-5.62 (m, 1 H), 5.72 (dt,

714 J . Org. Chem., Vol. 65, No. 3, 2000
Nakayama et al.
J ) 15, 7 Hz, 1 H), 5.6-5.9 (m, 2 H), 6.00 (t, J ) 11 Hz, 1 H),
6.34 (dd, J ) 15, 11 Hz, 1 H); 13C NMR δ 175.9, 136.7, 133.7,
131.6, 130.3, 125.8, 125.1, 70.6, 67.5, 36.6, 35.9, 35.5, 35.4, 31.5,
29.3, 29.1, 27.4, 22.5, 21.2, 14.0.
the corresponding diethyl boronate, which was diluted with
THF (3 mL) for the next transesterification.
2,2-Dimethyl-1,3-propanediol (200 mg, 1.92 mmol) was
added to the THF solution prepared above. After 1 h at room
temperature, the solution was concentrated by using a rotary
evaporator to give an oily residue, which was purified by
chromatography (hexane/EtOAc) to afford 11b (523 mg, 77%),
(R)-2-Octyloxir a n e (30). To a mixture of (R)-epichlorohy-
drin (18) (99% ee, 3.00 mL, 38.3 mmol), CuCN (350 mg, 3.91
mmol), and THF (40 mL) was added heptylmagnesium bro-
mide (115 mL, 0.50 M in THF, 57.5 mmol) dropwise at -78
°C. The solution was warmed to 0 °C over 2 h and poured into
a mixture of saturated NH4Cl and Et2O with vigorous stirring.
The layers were separated, and the aqueous layer was
extracted with EtOAc. The combined extracts were dried and
concentrated to furnish a residue, which was purified by
chromatography (hexane/EtOAc) to afford (R)-1-chloro-2-
which was distilled for the next reaction: [R]29 +1.2 (c, 1.14,
D
CHCl3); bp 210 °C (1 Torr); IR (neat) 1637, 835, 773 cm-1; 1H
NMR δ 0.02 (s, 6 H), 0.87 (s, 12 H), 0.96 (s, 6 H), 1.16-1.46
(m, 14 H), 1.47-1.57 (m, 2 H), 2.04-2.28 (m, 2 H), 3.62 (s, 4
H), 3.59-3.69 (m, 1 H), 5.35 (dt, J ) 18, 1.5 Hz, 1 H), 6.55 (dt,
J ) 18, 6 Hz, 1 H). Anal. Calcd for C24H49BO3Si: C, 67.90; H,
11.63. Found: C, 67.75; H, 11.34.
decanol (7.38 g, 100%): bp 120 °C (1 Torr); IR (neat) 3379 cm-1
;
Met h yl (5S,6Z,8E,12R)-5,12-Bis[(ter t-b u t yld im et h yl-
silyl)oxy]-6,8-eicosa d ien oa te (34). According to the proce-
dure described for preparation of 26, boronate ester 11b (89
mg, 0.21 mmol), bromide 10a (>99% ee, 50 mg, 0.14 mmol),
NiCl2(PPh3)2 (10 mg, 0.015 mmol), MeLi (0.20 mL, 1.12 M in
Et2O, 0.22 mmol), and THF (0.3 mL) furnished 34 (60 mg, 74%)
1H NMR δ 0.87 (t, J ) 7 Hz, 3 H), 1.15-1.57 (m, 14 H), 2.19
(d, J ) 5 Hz, 1 H), 3.47 (dd, J ) 11, 7 Hz, 1 H), 3.63 (dd, J )
11, 3 Hz, 1 H), 3.73-3.85 (m, 1 H); 13C NMR δ 71.5, 50.6, 34.2,
31.8, 29.5, 29.4, 29.2, 25.5, 22.6, 14.1.
To a solution of the above alcohol (7.00 g, 36.3 mmol) in THF
(40 mL) was added crushed NaOH (7.28 g, 182 mmol). The
mixture was stirred vigorously at room temperature for 3 h
and poured into water. The product was extracted with Et2O
repeatedly. The combined ethereal solutions were washed with
saturated NH4Cl, dried, and concentrated to give an oil, which
was purified by chromatography (hexane/Et2O) to afford
epoxide 30 (5.45 g, 96%): [R]27D +7.2 (c 0.98, CHCl3); bp 90 °C
(12 Torr). The 1H NMR spectrum of 32 thus prepared was
coincident with that given in ref 29.
(R)-1-Tr id ecyn -5-ol (31). To a solution of 30 (3.00 g, 16.1
mmol) in THF (30 mL) was added a freshly prepared (vide
supra) solution of allenylmagnesium bromide 22 (48 mL, ca.
0.50 M in Et2O, 24 mmol) at -50 °C dropwise. The solution
was warmed over 2 h to -10 °C and poured into a mixture of
saturated NH4Cl and Et2O with vigorous stirring. The layers
were separated, and the aqueous layer was extracted with
EtOAc. The combined extracts were dried and concentrated
to give a mixture of 31 and 1-bromo-2-decanol.
after purification by chromatography (hexane/Et2O): [R]22
D
+8.3 (c 0.40, CHCl3); IR (neat) 1741, 1086, 837, 777 cm-1; H
1
NMR δ 0.04 (s, 12 H), 0.87 (s, 9 H), 0.88 (t, J ) 7 Hz, 3 H),
0.89 (s, 9 H), 1.2-1.8 (m, 20 H), 2.04-2.19 (m, 2 H), 2.31 (t, J
) 7 Hz, 2 H), 3.66 (s, 3 H), 3.60-3.69 (m, 1 H), 4.55 (dt, J )
9, 7 Hz, 1 H), 5.23 (dd, J ) 11, 9 Hz, 1 H), 5.68 (dt, J ) 15, 7
Hz, 1 H), 5.89 (t, J ) 11 Hz, 1 H), 6.22 (dd, J ) 15, 11 Hz, 1
H); 13C NMR δ 174.3, 136.6, 132.8, 128.2, 125.3, 71.9, 68.7,
51.5, 37.8, 37.1, 36.6, 34.0, 31.9, 29.9, 29.6, 29.3, 28.6, 25.92,
25.86, 25.3, 22.7, 20.9, 18.15, 18.12, 14.1, -4.3, -4.4, -4.5,
-4.9. Anal. Calcd for C33H66O4Si2: C, 67.98; H, 11.41. Found:
C, 67.95; H, 11.44.
10,11,14,15-Tetr a h yd r oleu k otr ien e B4 (4). According to
the procedure for preparation of 2, a solution of 34 (50 mg,
0.086 mmol) in THF (2 mL) was treated with TBAF (0.86 mL,
1.0 M in THF, 0.86 mmol) at room temperature overnight to
afford 4 (23 mg, 78%) after chromatography (Et2O/MeOH): IR
(neat) 3367, 1716 cm-1 1H NMR δ 0.87 (t, J ) 7 Hz, 3 H),
;
To a solution of the above mixture in MeOH (30 mL) was
added K2CO3 (2.2 g, 16 mmol) portionwise. The resulting
mixture was stirred at room temperature for 1 h and poured
into H2O. The product was extracted with EtOAc several times,
and the combined organic layers were dried and concentrated.
The residue was subjected to chromatography (hexane:EtOAc
) 30:1 to 20:1) to afford epoxide 30 (0.41 g, 16%) and 31 (1.81
g, 57%), respectively. Spectral data of 31: IR (neat) 3340, 3313,
1.1-1.8 (m, 20 H), 2.10-2.30 (m, 2 H), 2.30-2.43 (m, 2 H),
3.54-3.66 (m, 1 H), 3.80-4.70 (m, 3 H), 4.50-4.70 (m, 1 H),
5.29 (dd, J ) 11, 9 Hz, 1 H), 5.71 (dt, J ) 15, 7 Hz, 1 H), 6.00
(t, J ) 11 Hz, 1 H), 6.34 (dd, J ) 15, 11 Hz, 1 H); 13C NMR δ
178.2, 136.6, 131.6, 130.3, 125.9, 71.3, 67.5, 37.5, 36.4, 36.3,
33.6, 31.9, 29.7, 29.6, 29.3, 28.9, 25.6, 22.7, 20.6, 14.1.
Meth yl (5S,6Z,8E,12S,14Z)- a n d (5S,6Z,8E,12R,14Z)-12-
[(ter t-Bu tyld im eth ylsilyl)oxy]-5-(1-eth oxyeth oxy)-6,8,14-
eicosa tr ien oa te (39). According to the procedure for prepa-
ration of 26, bromide 10b (100 mg, 0.323 mmol), racemic
boronate ester rac-11a (205 mg, 0.485 mmol), NiCl2(PPh3)2 (30
mg, 0.046 mmol), MeLi (0.41 mL, 1.24 M in Et2O, 0.51 mmol),
and THF (0.6 mL) furnished 39 (83 mg, 48% based on 10b)
after chromatography (hexane:Et2O ) 15:2 with a few drops
of NEt3): IR (neat) 1741, 835, 775 cm-1; 1H NMR δ 0.047 and
0.052 (2s, 6 H), 0.88 (br s, 12 H), 1.1-1.8 (m), 1.96-2.37 (m,
8 H), 3.65 (s, 3 H), 3.33-3.73 (m, 3 H), 4.28-4.39 and 4.50-
4.60 (2m, 1 H), 4.60-4.70 (m, 1 H), 5.05-5.50 (m, 3 H), 5.64-
5.78 (m, 1 H), 6.02 and 6.10 (2t, J ) 11 Hz, 1 H), 6.18-6.38
(m, 1 H). Anal. Calcd for C31H58O5Si: C, 69.10; H, 10.85.
Found: C, 69.06; H, 10.94.
1
2119 cm-1; H NMR δ 0.87 (t, J ) 7 Hz, 3 H), 1.17-1.75 (m,
17 H), 1.96 (t, J ) 3 Hz, 1 H), 2.32 (ddd, J ) 7.4, 6.8, 2.7 Hz,
2 H), 3.67-3.80 (m, 1 H); 13C NMR δ 84.4, 70.9, 68.7, 37.4,
35.7, 31.9, 29.6, 29.5, 29.2, 25.6, 22.6, 15.0, 14.1.
(R)-5-[(ter t-Bu tyld im eth ylsilyl)oxy]-1-tr id ecyn e (32).
According to the procedure for TBS protection of 19, alcohol
31 (1.00 g, 5.09 mmol) was treated with TBSCl (0.92 g, 6.1
mmol), imidazole (0.52 g, 7.64 mmol), and DMF (10 mL) to
afford 32 (1.43 g, 90%) after chromatography (hexane): [R]28
D
-18.4 (c 1.57, CHCl3); bp 160 °C (1 Torr); IR (neat) 3313, 2119,
837, 775 cm-1; 1H NMR δ 0.05 (s 3 H), 0.06 (s, 3 H), 0.88 (s, 12
H), 1.15-1.50 (m, 14 H), 1.54-1.72 (m, 2 H), 1.92 (t, J ) 3
Hz, 1 H), 2.23 (dt, J ) 3, 7 Hz, 2 H), 3.75 (quintet, J ) 6 Hz,
1 H); 13C NMR δ 84.8, 70.9, 68.2, 37.1, 35.6, 31.9, 29.8, 29.6,
29.3, 25.9, 25.1, 22.7, 18.1, 14.5, 14.1, -4.4, -4.6. Anal. Calcd
for C19H38OSi: C, 73.47; H, 12.33. Found: C, 73.41; H, 12.28.
(1′E,5′R)-2-[5′-{(ter t-Bu tyld im eth ylsilyl)oxy}-1′-tr id ec-
en yl]-5,5-d im eth yl-1,3,2-d ioxa bor in a n e (11b). To a white
suspension of (+)-(Ipc)2BH in THF, prepared according to the
procedure for preparation of 11a by using the same quantity
of the reagents, was added 32 (497 mg, 1.60 mmol) at -35 °C
dropwise. The resulting mixture was gradually warmed to 0
°C over 2 h, and acetaldehyde (1.34 mL, 24 mmol) was added
at 0 °C. The resulting solution was stirred overnight at 40 °C
(oil bath temperature; gentle reflux) and concentrated to leave
Meth yl (5S,6Z,8E,12S,14Z)- a n d (5S,6Z,8E,12R,14Z)-5-
(1-Eth oxyeth oxy)-12-h yd r oxy-6,8,14-eicosa tr ien oa te (40).
A solution of 39 (150 mg, 0.278 mmol) in THF (5 mL) was
treated with TBAF (0.56 mL, 1.0 M in THF, 0.56 mmol) at
room temperature overnight and poured into a mixture of
saturated NH4Cl and Et2O with vigorous stirring. The layers
were separated, and the aqueous layer was extracted with
Et2O. The combined ethereal solutions were dried and con-
centrated to afford an oil, which was purified by chromatog-
raphy (hexane:EtOAc ) 5:1 to 3:1 with a few drops of NEt3)
to afford 40 (83 mg, 70%): IR (neat) 3462, 1741, 1095 cm-1
;
1H NMR δ 0.88 (t, J ) 7 Hz, 3 H), 1.1-1.8 (m), 1.99-2.36 (m,
8 H), 3.66 (s, 3 H), 3.33-3.70 (m, 3 H), 4.30-4.40 and 4.50-
4.60 (2m, 1 H), 4.61-4.70 (m, 1 H), 5.06-5.30 (m, 1 H), 5.32-
5.46 (m, 1 H), 5.50-5.64 (m, 1 H), 5.73 (dt, J ) 15, 7 Hz, 1 H),
(29) The Aldrich Library of 13C and 1H FT NMR Spectra, 1st ed.;
Pouchert, C. J ., Behnke, J ., Eds.; Aldrich: Milwaukee, 1993; Vol. 1, p
365 C.

Synthesis of 10,11-Dihydroleukotriene B4 Metabolites
J . Org. Chem., Vol. 65, No. 3, 2000 715
5.98-6.18 (m, 1 H), 6.24-6.44 (m, 1 H). Anal. Calcd for
saturated NaHCO3. The mixture was extracted with EtOAc
twice. The combined extracts were dried and concentrated to
leave an oil, which was purified by chromatography (Et2O/
MeOH) to furnish 5 (4 mg, 81%): 1H NMR δ 0.88 (t, J ) 7 Hz,
3 H), 1.1-1.9 (m), 2.02 (q, J ) 7 Hz, 2 H), 2.34-2.42 (m, 4 H),
2.55 (t, J ) 7 Hz, 2 H), 3.16 (d, J ) 7 Hz, 2 H), 4.54-4.63 (m,
1 H), 5.31 (dd, J ) 11, 9 Hz, 1 H), 5.46-5.64 (m, 2 H), 5.71
(dt, J ) 15, 7 Hz, 1 H), 6.00 (t, J ) 11 Hz, 1 H), 6.34 (dd, J )
15, 11 Hz, 1 H).
C
25H44O5: C, 70.72; H, 10.44. Found: C, 70.56; H, 10.46.
(5S,6Z,8E,14Z)-5-(1-Eth oxyeth oxy)-12-oxo-6,8,14-eico-
sa tr ien oic Acid (41). A mixture of 40 (70 mg, 0.165 mmol)
and 1 N NaOH (1.65 mL, 1.65 mmol) in MeOH (9 mL) was
stirred at room temperature overnight, and 1 N HCl was added
carefully until the solution became slightly acidic. The product
was extracted with EtOAc twice. The combined extracts were
dried and concentrated to give the corresponding acid, which
was used for the next oxidation without further purification.
To an ice-cold solution of the acid dissolved in CH2Cl2 (1.5
mL) were added Celite (0.2 g) and PDC (93 mg, 0.25 mmol).
The resulting mixture was stirred at room temperature for 4
h and filtered through a pad of Celite with Et2O. The combined
filtrates were concentrated, and a residual oil was purified by
chromatography (hexane/Et2O) to obtain 41 (30 mg, 44% from
Ack n ow led gm en t. The support of a Grant-in-Aid
for Scientific Research from the Ministry of Education,
Science, Sports, and Culture, Government of J apan, is
gratefully acknowledged. Helpful guidance to carry out
the CrCl2-mediated reaction under Professor K. Takai
of Okayama University is very much appreciated. We
also thank Daiso Co. Ltd. for a generous supply of (R)-
18.
1
40): IR (neat) 3420, 1714, 1095 cm-1; H NMR δ 0.88 (t, J )
7 Hz, 3 H), 1.1-1.8 (m), 2.01 (q, J ) 7 Hz, 2 H), 2.31-2.43 (m,
4 H), 2.55 (t, J ) 7 Hz, 2 H), 3.16 (d, J ) 7 Hz, 2 H), 3.32-
3.72 (m, 2 H), 4.30-4.40 and 4.48-4.60 (2m, 1 H), 4.60-4.69
(m, 1 H), 5.14 and 5.28 (2t, J ) 11 Hz, 1 H), 5.44-5.76 (m, 3
H), 6.00 and 6.08 (2t, J ) 11 Hz, 1 H), 6.22-6.39 (m, 1 H).
10,11-Dih yd r o-12-oxoleu k otr ien e B4 (5). A solution of 41
(6 mg, 0.015 mmol) and PPTS (ca. 1 mg) in i-PrOH (0.1 mL)
was stirred at room temperature for 8 h and poured into
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
compounds lacking elemental analyses. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
J O9913199