A key intermediate towards oxylipins. A formal synthesis of (12S)-HETE and (12S)-LTB4

Article abstract of DOI:10.1039/a807074a

A key intermediate in the synthesis of various oxylipins, the optically active (3S,5Z)-3-methoxymethoxyundec-5-en-1-yne, has been obtained in 11 steps starting from propane-1,3-diol, with an overall yield of 14%.

Full text of DOI:10.1039/a807074a

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104 J. CHEM. RESEARCH (S), 1999
J. Chem. Research (S),
1999, 104±105$
A Key Intermediate towards Oxylipins. A Formal
Synthesis of (12S)-HETE and (12S)-LTB4$
Abdelhamid Benkouidera and Patrick Pale*b
aLaboratoire de Chimie Organique Physique, Associe au CNRS,
Universite de Reims-Champagne-Ardenne, BP 347, 51100 Reims, France
bLaboratoire de Synthese et Reactivite Organique, Universite L. Pasteur, 4 rue B. Pascal,
67000 Strasbourg, France
A key intermediate in the synthesis of various oxylipins, the optically active (3S,5Z)-3-methoxymethoxyundec-5-en-1-
yne, has been obtained in 11 steps starting from propane-1,3-diol, with an overall yield of 14%.
Oxidized metabolites of fatty acid, oxylipins,1 commonly
found in marine organisms,2 constitute a new, rapidly grow-
ing family of natural products. The scarcity of these com-
pounds, their almost unknown biological activity and the
fact that a large part of them also belongs to the eicosanoid
family,2 an important class of metabolites involved in
mammalian physiology and diseases, are leading to increas-
ing interest in their studies.1,2,6±8 Engaged in this area,3,4
we describe here an enantioselective synthesis of (3S,5Z)-
enzymatic resolution of the corresponding racemic acetate.9
We devised an alternative route based on asymmetric
reduction of ynones12 which allows for more ¯exibility in
the introduction of the chirality and of various substituents.
3-methoxymethoxyundec-5-en-1-yne,
towards various oxylipins.
a
key intermediate
Since several oxylipins5 share a common unit containing
Z and E double bonds as well as an allylic alcohol having
the S absolute con®guration (Scheme 1), a (3S,1E,5Z)-3-
hydroxyundeca-1,5-dienyl organometallic would be a con-
venient reagent for their synthesis. Adding this reagent to
a cyclopropyl aldehyde should give access to constano-
lactones6 and solandelactones7 or engaging it in coupling
reactions should a€ord polyenic oxylipins.8 Such an organo-
metallic compound could be obtained by hydrometallation
of the corresponding acetylene i.e. (3S,5Z)-undec-5-en-1-yn-
3-ol.
Scheme 2 Reagents: i, ClSi-ButPh2, NEt3, 4-(dimethylamino)-
pyridine (DMAP), CH2Cl2 or dihydropyran (DHP), p-TsOH,
CH2Cl2 (74±60%); ii, DMSO, (COCl)2, NEt3, THF (80±97%);
/
iii, Me3SiC CLi, THF (95±99%); iv, Na2B4O7, MeOH±H2O (90%)
Several ynones bearing di€erent protecting groups have
been prepared from propane-1,3-diol using standard chem-
istry except for the deprotection of the acetylenic function.
Carefully controlled conditions were required and sodium
borate in aqueous methanol proved to be the perfect reagent
a€ording 4a±c in excellent yields (Scheme 2). These ynones
were then submitted to Alpine-borane.12b The enantiomeric
purity of the prop-2-ynylic alcohols so obtained, 5a±b, 6a±c,
was determined after converting each one to (3S,5Z)-undec-
5-en-1-yn-3-ol and comparing each optical rotation with the
value reported for the known enantiomer.9,10 As shown
in Table 1, ee (enantiomeric excess) varied upon protection
or otherwise of the acetylenic and hydroxy functions (entry
Scheme 1
This optically active (S)-prop-2-ynylic alcohol has only
been described once in the literature but without details,9
in contrast to its (R)-enantiomer which was obtained after
opening a chiral glycidol,10 sugar modi®cations11 or from
Scheme 3 Reagents: i, ClCH2OCH3, NEtPri2, DMAP, CH2Cl2
(84%); ii, Bun4NF, THF (98%); iii, BunLi, THF then Me3SiCl
*To receive any correspondence (e-mail: ppale@chimie.u-strasbg.fr).
$This is a Short Paper as de®ned in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1999, Issue 1]; there is there-
fore no corresponding material in J. Chem. Research (M).
(74%); iv, DMSO, (COCl)2, NEt3, THF (79%); v, Ph3P(C6H11n) ,
Br , sodium hexamethyldisilazide, HMPA±THF (54%).
MOMO ˆ methoxymethoxy
‡

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J. CHEM. RESEARCH (S), 1999 105
Table 1
Entry
Ynone
PG'
PG
solvent±conca
alcohol
[a]D
eeb
1
2
3
4
5
6
7
3a
3a
4a
4a
3b
4b
4c
Me3Si
Me3Si
H
H
Me3Si
H
TBDPSd
TBDPS
TBDPS
TBDPS
THPd
THF 0.5 M
THF 2 M
THF 0.5 M
Neat
THF 0.5 M
THF 0.5 M
THF 0.5 M
5a
5a
6a
6a
5b
6b
6c
‡287'
‡283'
387'
283'
1383'
88
90%
76%
81%
50%
36%
21%
Ðc
TBDPS
H
H
Ðc
aYnone concentration; bsee text for ee determination; cno transformation; d TBDPS ˆ SiButPh2;
THP ˆ tetrahydropyran-2-yl; 9-BBN ˆ 9-borabicyclo[3.3.1]nonane.
(42), 91 (47), 82 (68), 68 (75), 55 (52). Found: C, 74.54; H, 10.29,
C13H22O2 requires C 74.28; H 10.47%.
1 vs. 3, 5 vs. 6), and upon the nature of the remote hydroxy
protecting group (entries 5±6 vs. 1±4). The striking e€ect%
of the remote protecting group may be due to competition
for borane coordination.
A. B. thanks the French and Algerian governments for a
doctoral fellowship.
The protected pent-4-yne-1,3-diol 5a, obtained with a
reasonable optical purity,} was further elaborated to the
required oxylipin synthon as shown in Scheme 3. Two steps
proved to be critical in this sequence: the oxidation of
the free primary alcohol 7 prone to b-elimination and the
exclusive formation of the Z double bond achieved via a
`salt free' Wittig reaction.3 Desilylation eventually gave the
required terminal acetylene 8. since its (R)-enantiomer
has been used in the synthesis of (12R)-HETE10 as well
as LTB4,8a,10,11 the present synthesis constitutes a formal
synthesis of their enantiomers, i.e. (12S)-LTB4 and (12S)-
HETE, the latter being present in marine organisms.5c,5a
Received, 10th September 1998; Accepted, 19th October 1998
Paper E/8/07074A
References
1 W. H. Gerwick, Chem. Rev., 1993, 93, 1807.
2 W. H. Gerwick and M. W. Bernart, Eicosanoids and related
compounds from marine algae, in Marine Biotechnology, Vol. I:
Pharmaceutical and bioactive natural products, ed. D. H. Attaway
and O. R. Zaborsky, Plenum, New York, 1992, p. 101.
3 D. Grandjean, P. Pale and J. Chuche, Tetrahedron, 1991, 47,
1215.
4 A. Benkouider, PhD Thesis, 1994, University of Reims-
Champagne-Ardenne, Reims; C. Barloy-Da Silva, PhD Thesis,
1998, University L. Pasteur, Strasbourg.
5 (a) Constanolactones: D. G. Nagle and W. H. Gerwick, J. Org.
Chem., 1994, 59, 7227; Tetrahedron Lett., 1989, 31, 2995; (b)
Solandelactones: Y. Seo, K. W. Cho, J.-R. Rho, J. Shin, B.-M.
Kwon, S.-H. Bok and J.-I. Song, Tetrahedron, 1996, 52, 10583;
(c) 12 S-HETE and 6E-LTB4: M. W. Bernart and W. H.
Gerwick, Phytochemistry, 1994, 36, 1233.
6 For other synthetic approaches towards these lactones, see:
S. Varadarajan, D. K. Mohapatra and A. Datta, Tetrahedron
Lett., 1998, 39, 5667; H. Miyaoka, T. Shigemoto and Y. Yamada,
Heterocycles, 1998, 47, 415; J. D. White and M. S. Jensen,
J. Am. Chem. Soc., 1995, 117, 6224; T. Nagasawa, Y. Onoguchi,
T. Matsumoto and K. Suzuki, Synlett, 1995, 1023.
7 For another approach towards these lactones, see: S. Varadarajan,
D. K. Mohapatra and A. Datta, Tetrahedron Lett., 1998, 39,
1075.
8 For related synthesis of eicosanoids, see: (a) D. Chemin and
G. Linstrumelle, Tetrahedron, 1992, 48, 1943; (b) K. C. Nicolaou,
J. Y. Ramphal, N. A. Petasis and C. N. Serhan, Angew. Chem.,
Int. Ed., 1991, 30, 1100.
9 M. Treilhou, A. Fauve, J.-R. Pougny, J. C. Prome and
H. Veschambre, J. Org. Chem., 1992, 57, 3203.
10 K. C. Nicolaou, J. Y. Ramphal and Y. Abe, Synthesis, 1989,
898.
11 P. Pianetti, P. Rollin and J.-R. Pougny, Tetrahedron Lett., 1986,
27, 5853.
Experimental
NMR spectra were recorded on a Bruker AC-250. J values are
in Hz. IR spectra were recorded on a Spectra®le IR Plus MIDAC
spectrometer. Mass spectra were measured on a Jeol D300 (70 eV)
mass spectrometer. Solvents and the usual reagents were dried and
puri®ed by conventional methods.
Desilylation. 5-tert-Butyldiphenylsilyloxypent-1-yn-3-one 4a.ÐTo a
solution of 3a (4.6 g, 11.27 mmol) in methanol (80 ml) was added
a 0.01 M aqueous borax solution (25 ml). After 30 min at room tem-
perature, the mixture was chilled to 0 8C then treated with 10%
HCl aqueous solution (20 ml). After methanol evaporation, the
mixture was extracted with diethyl ether (3 Â60 ml), the organic
phase was then dried and concentrated yielding a clear oil which
was puri®ed by ¯ash chromatography. ꢀH 1.07 (9H, s), 2.83 (2H, t,
J 6.1), 3.22 (1H, s), 4.06 (2H, t, J 6.1), 7.43 (6H, m), 7.70 (4H, m);
ꢀC 19.15 (s), 26.70 (q), 48.12 (t), 59.02 (t), 78.74 (s), 81.39 (d),
127.68 (d), 129.72 (d), 133.28 (s), 135.55 (d), 185.54 (s); ꢁ/cm
(CHCl3): 3280, 2090, 1670; m/z (%): 279 (11), 278 (63), 248 (10),
206 (100), 200 (41).
Data for (3S,5Z)-3-methoxymethoxyundec-5-en-1-yne 8.Ð[ꢂ]D
106 (c ˆ 0.85, CH2Cl2); ꢀH 0.91 (3H, t, J 7), 1.25±1.45 (6H, m),
2.07 (2H, td, J 7.0, 7.0), 2.42 (1H, d, J 1.9), 2.50 91H, dd, J 6.2,
0.5), 2.53 (1H, dd, J 6.9, J 0.5), 3.41 (3H, s), 4.33 (1H, ddd, J 6.6,
6.6, 1.9), 4.61 (1H, d, J 6.7), 4.93 (1H, d, J 6.7), 5.42 (1H, dtt,
J 10.8, 6.6, J 1.6), 5.59 (1H, dtt, J 10.8, 6.2, 1.6); ꢀC 14.02 (q), 22.50
(t), 27.41 (t), 29.16 (t), 31.45 (t), 33.52 (t), 55.59 (d), 65.22 (q), 73.49
1
20
1
(d), 82.31 (s), 94.09 (t), 123.58 (d), 133.22 (d). ꢁ/cm (CHCl3):
3290, 2080; m/z (%): 211 (M ‡1, <1), 124 (46), 99 (100), 96
‡
12 (a) H. C. Brown and P. V. Ramachandran, Acc. Chem.
Res., 1992, 25, 16; (b) M. M. Midland, A. J. Tramontano,
A. Kazubski, R. S. Graham, D. J. S. Tsai and D. B. Cardin,
Tetrahedron, 1984, 40, 1371; M. M. Midland and R. S. Graham,
Org. Synth., 1984, 63, 57; (c) C. Helal and E. J. Corey,
Tetrahedron Lett., 1995, 36, 9153; (d) C. J. Helal, P. A.
Magriotis and E. J. Corey, J. Am. Chem. Soc., 1996, 118, 10938.
±
%A remote steric e€ect across a C C triple bond was recently
observed in another enantioselective reduction: see ref. 12(d).
}The ees obtained are similar to the highest described for related
compounds.12a,b