A versatile asymmetric synthesis of highly enantiomerically enriched 12(S)-HETE via a combination of enzymatic and chemical processes

Article abstract of DOI:10.1016/S0040-4039(02)00670-6

This paper describes a versatile asymmetric synthesis of highly enantiomerically enriched 12(S)-HETE via enzymatic kinetic resolution of the key allylic alcohol synthon and the facile introduction of three alkyne units which were concomitantly converted t

Full text of DOI:10.1016/S0040-4039(02)00670-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3825–3828
A versatile asymmetric synthesis of highly enantiomerically
enriched 12(S)-HETE via a combination of enzymatic and
chemical processes
Young-Ger Suh,a,* Kyung-Hoon Min,a Yong-Sil Lee,a Seung-Yong Seo,a Seok-Ho Kima and
Hyun-Ju Parkb
aCollege of Pharmacy, Seoul National University, San 56-1, Shinrim-Dong, Kwanak-Gu, Seoul 151-742, South Korea
bCollege of Pharmacy, Sungkyunkwan University, Suwon 440-746, South Korea
Received 12 December 2001; revised 6 April 2002; accepted 8 April 2002
Abstract—This paper describes a versatile asymmetric synthesis of highly enantiomerically enriched 12(S)-HETE via enzymatic
kinetic resolution of the key allylic alcohol synthon and the facile introduction of three alkyne units which were concomitantly
converted to three alkenes units. © 2002 Elsevier Science Ltd. All rights reserved.
Arachidonic acid is metabolized through the 12-lipoxy-
genase (12-LOX) and the cytochrome P-450 pathways
to produce 12(S)-hydroxyeicosatetraenoic acid (12(S)-
HETE, 1a) and 12(R)-hydroxyeicosatetraenoic acid
(12(R)-HETE, 1b), respectively. These two endogenous
substances have recently been discovered to be impli-
cated in a number of important biological activities
such as hypertension, thrombosis, metastasis of tumor
cell, angiogenesis, and inflammation.1 In particular, it
has recently been reported by us that both the capsa-
icin-activated channel of sensory neurons and the
cloned capsaicin receptor (VR1) are activated by the
eicosanoids including these metabolites.2 Accordingly,
the necessity of the extended studies on VR1 activation
by HETEs prompted us to synthesize a substantial
amount of HETEs and a variety of their structural
analogues including stereoisomer (Fig. 1).
HETE has been reported in 1978 by Corey group.3 In
particular, the enantioselective synthesis of 12-HETE
has recently been intensively investigated by a number
of research groups. However, we wished to develop a
concise and divergent synthetic route to both (R)- and
(S)-12-HETE because most of the reported syntheses
have employed the limited synthetic precursors such as
carbohydrates or glycidol as a chiral source.4 We report
herein a novel and efficient asymmetric synthesis of (S)-
and (R)-12-HETE via combination of enzymatic and
chemical processes.
Our synthetic strategy (Scheme 1) envisions (1) the
prompt access to both (S)- and (R)-allylic alcohol
synthons in a highly optically pure form utilizing enzy-
matic kinetic resolution, (2) the facile introduction of
three alkyne units as a perfect cis-olefin precursors, (3)
the single step generation of the requisite three cis-
olefins by P-2 nickel catalyzed reduction.
The synthetic approaches toward 12-HETE have been
continuously studied since the first synthesis of 12-
Our synthesis (Scheme 2) commenced with the prepara-
tion of the optically pure allylic alcohol (S)-5 as the
initial key intermediate. Monosilylation5 of the readily
available cis-1,4-butenediol followed by Swern
oxidation6 afforded the trans-olefinic aldehyde 7. Treat-
ment of the aldehyde 7 with propargylaluminium
sesquibromide provided the allylic alcohol 5 as a
racemic mixture.7 At this stage, we looked for an
enzymatic kinetic resolution of 5 for the optically active
(S)-5 because the enzymatic process turn out to be
superior to the chemical process in terms of high enan-
Figure 1. The key structure of 12-LOX metabolites and its
corresponding chiral synthon.
* Corresponding author. Tel.: +82-2-880-7875; fax: +82-2-888-0649;
e-mail: ygsuh@snu.ac.kr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00670-6

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Scheme 1. Retrosynthetic analysis of 12(S)-HETE.
Scheme 2. Reagents and conditions: (a) TBDPSCl, (iPr)2NEt, CH2Cl2, rt; (b) (COCl)2, DMSO, Et3N, CH2Cl2; (c) Al, HgCl2,
CHꢀCCH2Br, THF, −78°C, 80% for three steps; (d) Amano AK (80 mg/mmol), vinyl acetate (0.55 equiv.), t-BuOMe, 20°C.
col.12 For the introduction of the third alkyne unit, the
tioselectivity and stereochemical diversity of the prod-
enyne 3 was coupled with the known propargylic bro-
mide 413 in the presence of copper to give triyne 2 in
90% yield.14,15 Finally, the requisite three cis-alkene
units of 12(S)-HETE was successfully elaborated by the
concomitant reduction of three alkynes of 2 to three
cis-alkenes. Initial attempts for the conversion of the
triyne 2 to the tetraene 10 under a variety of reduction
conditions did not provide the successful result. In most
cases, complete reduction of three alkynes to alkanes or
partial reduction of only one or two alkynes was
observed.16 However, partial hydrogenation of three
alkynes of 2 in the presence of P-2 nickel catalyst
afforded the desired tetraene 10.17 The perfectly selec-
tive partial reduction of all three alkynes to alkenes was
quite effective under these conditions. The synthesis of
12(S)-HETE was completed by the known two step
sequence (Scheme 3).4
ucts. Moreover, this procedure is capable of providing
both enantiomers in highly optically pure form through
a single step operation. The kinetic resolution of the
racemic alcohol 5 was carried out in t-BuOMe at 20°C
using P. fluorescens lipase (Amano AK) as a biocatalyst
and vinyl acetate as an acyl donor.8 As we anticipated,
the enzyme-catalyzed kinetic resolution afforded the
considerably high enantiomeric excesses (>99.5%) for
both (S)-5 and 6 as well as the high chemical yields
(>49%) in short reaction time (4.5 h).9 It is noticeable
that the multi-gram quantities of the optically pure
allylic alcohol (S)-5 and (R)-5 could be procured by
this sequence.
The carbon chain elongation of (S)-5 followed by the
introduction of additional two alkyne units for the
intermediate 2 were quite straightforward. Protection of
the alcohol (S)-5 with TBDPSCl and then alkylation of
the terminal alkyne with bromopentane gave the bissilyl
ether 8 in 90% yield for two steps. Selective TBDPS
deprotection of 8 by HF–pyridine treatment10 and
TPAP oxidation11 of the resulting alcohol afforded the
a,b-unsaturated aldehyde 9. Introduction of the second
alkyne unit to 9 was executed by a facile conversion of
aldehyde to alkyne according to Corey–Fuchs proto-
In summary, a versatile and concise synthetic route to
12(S)-HETE has been developed. The key part of this
synthesis involves the enzymatic preparation of enan-
tiomerically pure allylic alcohols as a useful chiral
synthon for the synthesis of both 12(S) and 12(R)-
HETE as well as the related eicosanoids. In addition,
the facile and concomitant conversion of three alkynes

Y.-G. Suh et al. / Tetrahedron Letters 43 (2002) 3825–3828
3827
Scheme 3. Reagents and conditions: (a) TBDPSCl, imidazole, DMF, rt, 91%; (b) n-BuLi, Br(CH2)4CH3, THF, HMPA, 0°C“rt,
,
82%; (c) HF–pyridine, THF/pyridine (2/1), 20°C, 80%; (d) TPAP, NMO, 4 A MS, CH2Cl2, rt, 89%; (e) i. CBr4, PPh3, CH2Cl2,
ii. n-BuLi, THF, 0°C, 77%; (f) 4, n-Bu4NBr, CuI, K2CO3, DMF, −20°C“rt, 90%; (g) NaBH4, Ni(OAc)2·4H2O, H2,
H2NCH2CH2NH2, EtOH, rt, 69%; (h) Ref. 4.
to three alkenes using P-2 nickel catalyst is also
involved. This unique synthetic procedure which is
capable of providing both 12(S) and 12(R)-HETE in an
efficient and versatile way offers a useful synthetic route
to the biologically important eicosanoids.
8. A mixture of ( )-5 (1.52 g, 4.17 mmol), Amano AK (333
mg) and vinyl acetate (0.21 mL, 2.29 mmol) in t-BuOMe
(20 mL) was stirred at 20°C for 4.5 h. The lipase was
filtrated off and the filtrate was concentrated in vacuo.
The residue was purified by flash column chromatogra-
phy on silica gel (15% EtOAc/hexane) to give 758 mg
(49.8%) of (S)-5 and 840 mg (49.5%) of 6. The enan-
tiomeric excesses of the products were determined by
chiral HPLC analysis (Chiralcel OD, i-PrOH:n-hexane=
99.5:0.5, 0.5 mL/min) after transformation of the remain-
ing enantiomer (S)-5 into the corresponding acetate.
(S)-5; [h]2D0 +20° (c 0.96, acetone).
9. The absolute configurations of (S)-5 and 6 were deter-
mined on the basis of the reported results: Nakamura,
K.; Takenaka, K.; Ohno, A. Tetrahedron: Asymmetry
1998, 4229–4439. However, they were finally confirmed
by comparison of the spectral data of the intermediate 9
with the reported one of its antipode: Peng, Z.; Li, Y.;
Wu, W.; Liu, C.; Wu, Y. J. Chem. Soc., Perkin Trans. 1
1996, 1057–1066.
Acknowledgements
This research was supported by grant 01-PJ1-PG3-
21500-0051 from the Ministry of Health and Welfare
and in part by the Research Institute of Pharmaceutical
Science, Seoul National University.
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Y.-G. Suh et al. / Tetrahedron Letters 43 (2002) 3825–3828
16. The conversion of single alkyne to cis-alkene by
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added NaBH4 (8 mg, 0.21 mmol) under Ar. The reac-
tion mixture was stirred for 20 min and ethylene
diamine (30 mL) and 2 (20 mg, 0.04 mmol) were added.
After exchange of the Ar for H2, the reaction mixture
was stirred at room temperature for an additional 15
min, and filtrated through a Celite pad. The filtrate was
concentrated in vacuo and the residue was purified by
flash column chromatography on silica gel (5% EtOAc/
hexane) to give 14 mg (69%) of 10. Repeated purifica-
tion of the fractions contaminated with small amount of
the isomeric products provided the higher yield (80ꢀ
85%). The tetraene 10 was identical in all aspects to the
reported intermediate.