Design and synthesis of useful intermediates for novel lipoxygenase substrates through enzymatic resolution

Article abstract of DOI:10.1016/S0957-4166(00)00495-X

Unnatural lipoxygenase substrates carrying spacing modifiers with a non-ionic hydroxy terminus and with methylene (flanked by the cis,cis diene moiety) pro-(S)-hydrogen can be synthesized from the intermediates 1a-1c. These intermediates are conveniently synthesized via enzymatic resolution with lipase in organic solvents.

Full text of DOI:10.1016/S0957-4166(00)00495-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 53–57
Design and synthesis of useful intermediates for novel
lipoxygenase substrates through enzymatic resolution
J. S. Yadav,* S. Nanda and A. Bhaskar Rao
Organic Division, Indian Institute of Chemical Technology, Hyderabad-500007, India
Received 14 September 2000; accepted 31 October 2000
Abstract—Unnatural lipoxygenase substrates carrying spacing modifiers with a non-ionic hydroxy terminus and with methylene
(flanked by the cis,cis diene moiety) pro-(S)-hydrogen can be synthesized from the intermediates 1a–1c. These intermediates are
conveniently synthesized via enzymatic resolution with lipase in organic solvents. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Here we wish to report the synthesis of 2a–2c in
enantiomerically pure form through a stereoselective
enzymatic transesterification reaction in organic solvent
medium (Scheme 2).
Lipoxygenases (linoleate: oxygen oxidoreductase) are a
group of non-heme iron containing dioxygenases which
catalyze the addition of molecular oxygen to 1(Z),4(Z)
polyunsaturated fatty acids in a regio- and stereospe-
cific way.1 The stereospecificity of lipoxygenases is char-
acterized by the stereoselective removal of one of the
two hydrogen atoms from the prochiral center.2 It was
earlier reported that lipoxygenase from soybean
stereoselectively removes pro-(S)-hydrogen from the
prochiral center.3 Previous studies of modified sub-
strates with soybean lipoxygenase reveal that the essen-
2. Results and discussion
In the first step of the synthesis 2-propyn-1-ol was
deprotonated with LiNH2 and the anion alkylated with
1-bromopentane to give 2-octyn-1-ol in 70% yield.
Swern oxidation7 of 2-octyn-1-ol then provided 2-octyn-
al, and subsequent condensation of 2-octynal with the
appropriate tetrahydropyranyl protected alkynol gave
the di-acetylenic alcohols 3a–3c. Removal of the tetra-
hydropyranyl protecting group with MeOH–PPTS8
afforded the diols 4a–4c and selective monoprotection
of the primary alcohol function of 4a–4c with TBDMS-
tial structural requirements are
a single v-6(Z),
(Z)-1,4-pentadienyl moiety and an appropriately spaced
proximal carboxyl group.4 It had long been considered
that the carboxyl groups of the fatty acid was impor-
tant for enzymatic recognition and binding.5
However, research from several groups reveals that a
carboxylic group or a charged head group in fatty acid
analogues is not an essential structural requirement for
binding and catalysis in soybean lipoxygenase catalyzed
oxidations,6 and substrates having a non-ionic hydroxy
terminus are ‘recognized’ by soybean lipoxygenase. On
the basis of this premise, we envisaged a synthetic route
to obtain the unnatural lipoxygenase substrates 1a–1c
in enantiomerically pure form (Scheme 1) where the
methylene hydrogen flanked by the (Z),(Z) diene moi-
ety is pro-(S). Retrosynthetic analysis reveals that com-
pounds 1a–1c can be synthesized from the intermediate
* Corresponding author. Fax: +91-407170512; e-mail: yadav@
iict.ap.nic.in
Scheme 1. Substrates 1a–1c having pro-(S)-hydrogen.
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00495-X

54
J. S. Yada6 et al. / Tetrahedron: Asymmetry 12 (2001) 53–57
Scheme 2. Asymmetric synthesis of 2a–2f. Reagents and conditions: (a) LiNH2, C5H11Br, THF–HMPA (10:1), 70%; (b) (COCl)2,
DMSO, Et3N, −78°C, 80%; (c) n-BuLi, THF–HMPA (6:1), −78°C, 1 h, then rt 6 h, 70%; (d) PPTS–MeOH, 80%; (e) imidazole,
TBDMS–Cl, rt, 60%; (f) imidazole, TBDPS-Cl, rt, 60%; (g) vinyl acetate, diethylether; (h) Ac2O, Et3N, DMAP.
Cl or TBDPS-Cl under standard conditions afforded
alcohols 2a–2f. Transesterification of 2a–2f with vinyl
acetate in the presence of Candida rugosa lipase (CRL)
in diethylether provided the required (R)-alcohols 5a–5f
in 33–46% yields (Table 1), which were then acetylated
with Ac2O, Et3N to give the desired (R)-acetates 6a–6f.
The (S)-acetates 7a–7f were obtained in 35–45% yield
(Table 1). The absolute configurations of the alcohols
and acetates were assigned according to a previous
report.9 Optical purity is in the range of 60–96% in
both cases as determined by chiral HPLC analysis
(Table 1, Scheme 2).
the di-acetylenic moiety using Lindlar catalyst, removal
of the silyl protecting groups and attachment of the
appropriate prosthetic group. We have just achieved
the total synthesis of 1a–1c, and we are currently
engaged in the study of their reactivity with soybean
lipoxygenase. These results will be communicated in
due course.
3. Conclusion
The enantiomers of 1a–1c having pro-(R)-hydrogen can
be synthesized from compounds 7a–7c by following the
same sequence of reaction as described earlier. Due to
the absence of pro-(S)-hydrogen these compounds may
act as suitable substrate analog inhibitors for soybean
lipoxygenase, which are of great biological interest.
This study is currently under investigation. In conclu-
sion an efficient and convenient enzymatic resolution
has been carried out for the synthesis of a series of key
intermediates for novel lipoxygenase substrates.
Among the organic solvents used for the transesterifica-
tion, diethylether provided the best results with respect
to both yield and ee (Table 2). Porcine pancreatic lipase
(PPL) and lipase from Pseudomonas species were also
used to mediate the same transesterification reaction,
but no significant transesterification reaction occurred.
The alcohols 2a–2f have one small and one large group
attached to the hydroxymethine functionality. The large
group contains a bulky functionality (-OTBDMS,
-OTBDPS) slightly removed from the asymmetric cen-
ter. In all cases the (S)-isomer of 2a–2f undergoes rapid
transesterification compared to the corresponding (R)-
isomer which remains unreacted. These findings are in
perfect agreement with the previous work.11 The total
synthesis of lipoxygenase substrates 1a–1c can be
achieved from 5a–5f after some simple reaction
sequences which includes controlled hydrogenation of
4. Experimental
4.1. General
Unless otherwise stated, materials were obtained from
commercial suppliers and used without further purifica-
tion. THF and diethylether were distilled from sodium

J. S. Yada6 et al. / Tetrahedron: Asymmetry 12 (2001) 53–57
55
Table 1. Transesterification of compounds 2a–2f with CRL and vinyl acetate
Entry
Comp.
Time (h)
Conversion (c)
(S)-Acetate
(R)-Alcohol
Yield
Eb
a
Eep
95
96
96
94
95
95
Yield
Eesa
61
1
2
3
4
5
6
2a
2d
2b
2e
2c
2f
25
28
26
40
32
26
40
38
35
42
40
45
38
42
40
40
35
39
33
40
46
41
30
37
75
90
82
66
75
92
58
60
67
63
77
a Ees were calculated by chiral HPLC (Diacel, Chiral OD column, hexane–isopropanol, 9:1).
b Enantioselectivities of the reactions (E)10 were determined from the following equation; E=ln [1−c(1+eep)]/ln[1−c (1−eep)], where eep=pdt·ee;
c=ees/(ees+eep)%.
benzophenone ketyl. HMPA was distilled from BaO
extracted with ether. The combined organic layer was
washed with water, brine and dried (Na2SO4). The
crude product was purified by column chromatography
to give 2-octyn-1-ol (9 g 70%). IR (TF): 3400, 1090
cm−1; PMR: 0.9 (t, J=7 Hz, 3H), 1.2–1.6 (m, 6H), 2.2
(t, J=7 Hz, 2H), 4.1 (s, 2H). EIMS (m/z): 126 (M+).
,
and stored over 3 A molecular sieves. Dichloromethane
(DCM) was distilled from calcium hydride. Lipase
(from Candida rugosa, type VII, 1440 units/mg of
protein), lipase (from Porcine pancreas, type II, 66
units/mg of protein) and lipase (from Pseudomonas
species, type XIII, 60 units/mg of protein) were
obtained from Sigma Co. (USA) and used as obtained.
1H NMR spectra were recorded in CDCl3 on a Varian
VXR 200 (200 MHz) instrument. Chemical shifts are
reported as ppm downfield from tetramethylsilane.
Infrared spectra were recorded on a Perkin–Elmer 1420
spectrometer. For enzymatic reactions the solvents
4.3. 2-Octynal
2-Octyn-1-ol (2 g, 15 mmol) in DCM was added to
oxallyl chloride (1.44 mL, 15 mmol) and DMSO (2.3
mL, 30 mmol) in DCM (50 mL) at −78°C. The temper-
ature was maintained at −78°C for a further 1 h.
Triethylamine (10 mL, 75 mmol) was then added and
after stirring for 5 min the mixture was allowed to
warm to 25°C and stirred for a further 30 min at the
same temperature. Water was added to the solution,
and the mixture was extracted with DCM. The organic
extract was washed with water, brine and dried
(Na2SO4). The organic extract was evaporated and
purified by column chromatography to afford 2-octynal
in 80% yield. IR (TF): 2820, 1700 cm−1; PMR: 0.9 (t,
J=7 Hz, 3H), 1.2–1.5 (m, 4H), 1.6 (m, 2H), 2.4 (t, J=7
Hz, 2H), 9.1 (s, 1H). EIMS (m/z): 124 (M+).
,
employed were desiccated over 4 A molecular sieve
powder for 50 h prior to use. Optical rotations were
measured on a JASCO Dip 360 digital polarimeter. The
abbreviation TF denotes the thin film.
4.2. 2-Octyn-1-ol
2-Propyn-1-ol (7 g, 100 mmol) was added to a stirred
suspension of lithium amide (prepared from 1.4 g, 0.2 g
atom of Li in liquid ammonia, 150 ml) over 15 min and
stirred for an additional 1 h. 1-Bromopentane (15.6 g,
100 mmol) in THF–HMPA (60 mL, 10:1) was then
added and the reaction mixture allowed to stir for a
further 6 h. The reaction was quenched with solid
NH4Cl (10 g) and the excess ammonia was then allowed
to evaporate. The residue was dissolved in water and
4.4. 1-(4-Tetrahydro-2H-pyranyloxy-1-butynyl)-2-
octynyl alcohol 3a
2-(3-Butynyloxy)tetrahydro-2H-pyran (1 g, 6.6 mmol)
was dissolved in THF–HMPA (6:1, 30 mL). n-BuLi (2.5
M in hexane, 2.6 mL, 6.6 mmol) was added dropwise to
the solution at −78°C, and stirring was continued for a
further 1 h at the same temperature. 2-Octynal (0.85 g,
6.75 mmol) was added slowly and the solution allowed
to warm to room temperature. The mixture was stirred
for a further 6 h at room temperature, and saturated
NH4Cl solution was added. The mixture was extracted
with ethyl acetate and the organic extract was washed
with water, brine, dried (Na2SO4) and evaporated. The
residue was purified by column chromatography to give
3a in 60% yield. IR (TF): 3390 cm−1; PMR: 0.9 (t, J=7
Table 2. Transesterification of 2a with CRL in different
organic solvents
Entry
Solvent
Time (h)
Yield (%)
Ee
(S)-acetate
1
2
3
4
5
Diethylether
Hexane
Cyclohexane
t-Butylmethylether
Tetrahydrofuran
25
48
70
40
42
40
15
18
10
22
95
72
40
58
60

56
J. S. Yada6 et al. / Tetrahedron: Asymmetry 12 (2001) 53–57
Hz, 3H), 1.2–1.4 (m, 6H), 1.6–1.8 (m, 6H), 2.2 (t, J=7
Hz, 2H), 2.5 (t, J=7 Hz, 2H), 3.5 (m, 2H), 3.8 (m, 2H),
4.6 (t, J=4 Hz, 1H), 5.0 (s, 1H). EIMS (m/z): 278 (M+).
4.9. 1-(4-O-tert-Butyldiphenylsilyl-1-butynyl)-1(S)-2-
octynyl acetate 7d
IR (TF): 3000, 1760 cm−1; PMR: 0.9 (t, J=7 Hz, 3H),
1.1 (s, 9H), 1.2–1.6 (m, 6H), 2.1 (s, 3H), 2.35 (t, J=7 Hz,
2H), 2.65 (t, J=7 Hz, 2H), 3.8 (t, J=7 Hz, 2H), 6.0 (s,
1H), 7.2–7.7 (m, 10H). FABMS: 475 (M+1)
4.5. 3,6-Dodecadiyne-1,5-diol 4a
A solution of 3a (0.5 g, 1.8 mmol) dissolved in methanol
(10 mL) was treated with catalytic PPTS and stirred for
45 min at room temperature. The methanol was evapo-
rated, and the crude product was dissolved in DCM,
washed with 5% NaHCO3 solution, water, brine and dried
(Na2SO4). Purification by column chromatography gave
4a in 80% yield. IR (TF): 3410 cm−1; PMR: 0.9 (t, J=7
Hz, 3H), 1.2–1.5 (m, 6H), 2.2 (t, J=7 Hz, 2H), 2.5 (t,
J=7 Hz, 2H), 3.7 (t, J=7 Hz, 2H), 5.1 (s, 1H). EIMS
(m/z): 194 (M+).
4.10. 1-(5-Tetrahydro-2H-2-pyranyloxy-1-pentyl)-2-
octynylalcohol 3b
IR (TF): 3385 cm−1; PMR: 0.85 (t, J=7 Hz, 3H), 1.2–1.4
(m, 6H), 1.6–1.8 (m, 8H), 2.15 (t, J=7 Hz, 2H), 2.3 (t,
J=7 Hz, 2H), 3.5 (m, 2H), 3.75 (m, 2H), 4.65 (t, J=4
Hz, 1H), 5.0 (s, 1H). EIMS (m/z): 292 (M+).
4.11. 1-(6-Tetrahydro-2H-2-pyranyloxy-1-hexynyl)-2-
octynylalcohol 3c
4.6. ( )-1-(4-O-tert-Butyldimethylsilyl-1-butynyl)-2-
octynyl alcohol 2a
IR (TF): 3380 cm−1 PMR: 0.9 (t, J=7 Hz, 3H), 1.2–1.9
(m, 16H), 2.2–2.4 (m, 4H), 3.45 (m, 2H), 3.75 (m, 2H),
4.65 (t, J=4 Hz, 1H), 5.1 (s, 1H). EIMS (m/z): 306 (M+).
A solution of 4a (0.3 g, 1.54 mmol) in DCM (10 mL) was
cooled to 0°C was treated with imidazole (0.16 g, 2.3
mmol) and stirred for 15 min. tert-Butyldimethylchlorosi-
lane (0.25 g, 1.7 mmol) was added and the mixture stirred
for a further 1 h at room temperature. Water was added
to the reaction mixture, and extracted with DCM.
Purification through column chromatography gave 2a in
60% yield. IR (TF): 3380 cm−1; PMR: 0.0 (s, 6H), 0.8–1.0
(brs, 12H), 1.2–1.6 (m, 6H), 2.2 (t, J=7 Hz, 2H), 2.5 (t,
J=7 Hz, 2H), 3.7 (t, J=7 Hz, 2H), 5.1 (s, 1H). FABMS:
309 (M+1).
4.12. 4,7-Tridecadiyne-1,6-diol 4b
PMR: 1.0 (t, J=7 Hz, 3H), 1.2–1.6 (m, 8H), 2.15 (t, J=7
Hz, 2H), 2.21 (t, J=7 Hz, 2H), 3.65 (t, J=7 Hz, 2H),
5.1 (s, 1H). EIMS (m/z): 208 (M+).
4.13. 5,8-Tetradecadiyne-1,7-diol 4c
PMR: 0.9 (t, J=7 Hz, 3H), 1.2–1.4 (m, 4H), 1.5–1.8 (m,
6H), 2.2–2.4 (m, 4H), 3.7 (t, J=7 Hz, 2H), 5.0 (s, 1H).
EIMS (m/z): 222 (M+).
4.7. ( )-1-(4-O-tert-Butyldiphenylsilyl-1-butynyl)-2-
octynyl alcohol 2d
A solution of 4a (0.2 g, 1 mmol) and DCM (6 mL) at
0°C was treated with imidazole (0.11 g, 1.5 mmol) and
the solution was stirred for 15 min. tert-
Butyldiphenylchlorosilane (0.31 g, 1.1 mmol) was added
and the solution was stirred for a further 2 h at room
temperature. After usual workup and purification, 2d was
obtained in 62% yield. IR (TF): 3390, 3010 cm−1; PMR:
0.85 (t, J=7 Hz, 3H), 1.0 (s, 9H), 1.2–1.5 (m, 6H), 2.25
(t, J=7 Hz, 2H), 2.5 (t, J=7 Hz, 2H), 3.7 (t, J=7 Hz,
2H), 5.0 (s, 1H), 7.35–7.7 (m, 10H). FABMS: 433 (M+1).
4.14. 1-(5-O-tert-Butyldimethylsilyl-1-pentynyl)-2-
octynylalcohol 2b
PMR: 0.1 (s, 6H), 0.9 (brs, 12H), 1.2–1.7 (m, 8H), 2.15
(t, J=7 Hz, 2H), 2.3 (t, J=7 Hz, 2H), 3.62 (t, J=7 Hz,
2H), 5.0 (s, 1H). FABMS: 323 (M+1).
4.15. 1-(6-O-tert-Butyldimethylsilyl-1-hexynyl)-2-
octynylalcohol 2c
PMR: 0.0 (s, 6H), 1.0 (brs, 12H), 1.2–1.6 (m, 10H),
2.2–2.4 (m, 4H), 3.7 (t, J=7 Hz, 2H), 5.0 (s, 1H).
FABMS: 337 (M+1).
4.8. 1-(4-O-tert-Butyldimethylsilyl-1-butynyl)-1(S)-2-
octynyl acetate 7a
In a typical resolution experiment a solution of 2a (100
mg) in dry ether (10 mL) was stirred with vinyl acetate
(3 equiv.) followed by the addition of CRL (100 mg). The
reaction mixture was stirred in an orbit shaker at 250 rpm
at room temperature for 25 h. After 50% conversion (by
GC analysis) the reaction mixture was filtered through
Celite and evaporated to dryness. Compounds 7a and 5a
were isolated after flash chromatography. The enzyme
loses virtually no catalytic activity after each transester-
ificationrunat30°C,andtherefore can be used repeatedly.
IR(TF):1765cm−1;PMR:0.0(s, 6H), 0.9 (s, 12H), 1.2–1.6
(m, 6H), 2.1 (s, 3H), 2.25 (t, J=7 Hz, 2H), 2.45 (t, J=7
Hz, 2H), 3.7 (t, J=7 Hz, 2H), 5.9 (s, 1H). FABMS: 351
(M+1).
4.16. 1-(5-O-tert-Butyldiphenylsilyl-1-pentynyl)-2-
octynylalcohol 2e
IR (TF): 3380, 3005 cm−1; PMR: 0.9 (t, J=7 Hz, 2H),
1.1 (s, 9H), 1.3–1.8 (m, 8H), 2.1 (t, J=7 Hz, 2H), 2.28
(t, J=7 Hz, 2H), 3.7 (t, J=7 Hz, 2H), 5.1 (s, 1H), 7.3–7.7
(m, 10H). FABMS: 447 (M+1).
4.17. 1-(6-O-tert-Butyldiphenylsilyl-1-hexynyl)-2-
octynylalcohol
PMR: 0.85 (t, J=7 Hz, 3H), 1.05 (s, 9H), 1.2–1.8 (m,
10H), 2.2–2.4 (m, 4H), 3.75 (t, J=7 Hz, 2H), 5.0 (s, 1H),
7.25–7.7 (m, 10H). FABMS: 460 (M+1).

J. S. Yada6 et al. / Tetrahedron: Asymmetry 12 (2001) 53–57
57
4.18. 1-(5-O-tert-Butyldimethylsilyl-1-pentynyl)-1(S)-2-
octynyl acetate 7b
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4.19. 1-(6-O-tert-Butyldimethylsilyl-1-hexynyl)-1(S)-2-
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IR (TF): 1765 cm−1; PMR: 0.1 (s, 6H), 1.0 (brs, 12H),
1.2–1.5 (m, 6H), 1.6 (m, 4H), 2.09 (s, 3H), 2.25 (m, 4H),
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research fellowship.
.
.