Chemoenzymatic synthesis of (2R,6R,10R)-6,10,14-trimethylpentadecan-2-ol, sex pheromone of rice moth (Corcyra cephalonica), and of its (2S,6R,10R)-diastereomer

Article abstract of DOI:10.1134/S1070428011020217

Based on the catalyzed by lipase Amano PS kinetic separation of the two-component mixture of diastereomers of (2RS,6R,10R)-6,10,14- trimethylpentadecan-2-ol in the acylation with the succinic anhydride we obtained the (2R,6R,10R)-6,10,14-trimethylpentadec

Full text of DOI:10.1134/S1070428011020217

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2011, Vol. 47, No. 2, pp. 290294. Pleiades Publishing, Ltd., 2011.
Original Russian Text  R.V. Shafikov, A.Yu. Spivak, V.N. Odinokov, 2011, published in Zhurnal Organicheskoi Khimii, 2011, Vol. 47, No. 2, pp. 296299.
Chemoenzymatic Synthesis
of (2R,6R,10R)-6,10,14-Trimethylpentadecan-2-ol,
Sex Pheromone of Rice Moth (Corcyra cephalonica),
and of Its (2S,6R,10R)-Diastereomer
R. V. Shafikov, A. Yu. Spivak, and V. N. Odinokov
Institute of Petrochemistry and Catalysis, Russian Academy of Sciences, Ufa, 450075 Russia
e-mail: ink@anrb.ru
Received May 20, 2010
Abstract—Based on the catalyzed by lipase Amano PS kinetic separation of the two-component mixture of
diastereomers of (2RS,6R,10R)-6,10,14-trimethylpentadecan-2-ol in the acylation with the succinic anhydride we
obtained the (2R,6R,10R)-6,10,14-trimethylpentadecan-2-ol, the sex pheromone of rice moth (Corcyra cephalonica)
and its (2S,6R,10R)-diastereomer.
DOI: 10.1134/S1070428011020217
The natural pheromone of rice moth (Corcyra cephalonica
Stainton), (2R,6R,10R)-6,10,14-trimethylpentadecane-2-
ol (IIIа) and its 2S,6R,10R)-diastereomer IIIb were ob-
tained by combining chiral block-synthons in multistage
syntheses (11–12 stages) [1, 2].An attractive approach to
the synthesis of individual alcohols IIIa and IIIb consists
in a kinetic separation of the two-component mixture of
these diastereomers catalyzed by lipases. It was reported
on the enzymatic preparation of (2R,6R,10R)-alcohol
IIIa by the lipase PS catalyzed hydrolysis of acetates of
the (2RS,6R,10R)-alcohols IIIa and IIIb [3], obtained
from (R)-β-citronellol and methyl (S)-3-hydroxy-2-
methylpropionate in a 13-stage synthesis [3].
acylation with succinic anhydride or vinyl acetate in the
presence of lipases Amano PS or Candida cylindracea in
diisopropyl ether at 20°С. The unreacted alcohol IIIb and
the acyl derivatives of alcohol IIIa, hemisuccinate IV or
acetate V, were separated by column chromatography on
silica gel. The alkaline hydrolysis of compounds IV and
V yielded alcohol IIIa.
Aiming at the elucidation of the possibility of the esti-
mation of the diastereomeric excess of alcohols IIIa and
IIIb obtained by the enzymatic separation their diaste-
reomers mixture by treating with N-benzyloxycarbonyl-
L-valine (Cbz-L-valine) activated with N,N'-dicyclohex-
ylcarbodiimide (DCC) and N,N-dimethylaminopyridine
(DMAP) was converted into the corresponding mixture
of О-(2RS-acyl)derivatives VI. The assignment of the
signals in the 1Н and 13С NMR spectra of compound VI
was performed from the analysis of 1D and 2D spectra.
In the 13С NMR spectra of diastereomeric acylates VI
a double set of signals is observed from the atoms С1,
С2, С2', С3', С4', С5' contiguous to the chiral centers 2
and 2’. However we failed to distinguish in the 1Н NMR
spectra the signals suitable for the evaluation of the dia-
stereomeric excess after the enzymatic separation of the
mixture of alcohols IIIa and IIIb. Therefore the results
of the separation of the mixture of diastereomers IIIa
and IIIb cayalyzed by lipases were evaluated based on
We developed a short synthetic route to the diaste-
reomeric mixture of the (2RS,6R,10R)-alcohols IIIa
and IIIb by the hydride reduction of (6R,10R)-6,10,14-
trimethylpentadecan-2-one (II) prepared by the previ-
ously elaborated method of the chlorophyll I ozonolysis
obtained from common nettle (Urtica dioica L.) [4]. By
the subsequent kinetic separation of the alcohols IIIa and
IIIb mixture catalyzed by lipases we obtained optically
pure diastereomers (2R,6R,10R)- IIIа and (2S,6R,10R)-
IIIb.
The kinetic separation of the mixture of diastereo-
meric alcohols IIIa and IIIb was performed by their
290

CHEMOENZYMATIC SYNTHESIS OF (2R,6R,10R)-6,10,14-TRIMETHYLPENTADECAN-2-OL
291
Scheme.
HC
CH2
R
5
4
7
6
3
2
1
H3C
8
9
N
N
20
10
Mg
O3_Ba(OH)2
19 N
N
14
11
H
H
H
16
12
18
13
15
CH3
H
17
H3C
O
H3C
Me2CO
89%
II
H
H3C
CH2
O
3
O
OC
H
COCH3
O
I (R = Me, CHO)
O
OH
O
CO2
H
H
H
H
H
H
b
+
IIIb
IV
OH
a
H
H
c
O
95%
IIIа, IIIb
O
OH
H
H
H
H
d
H
H
+
IIIb
e
IIIа
V
12'
c
13'
8'
11'
10'
O
H
7'
N
2'
6'
17
18
16
1'
O
9'
3'
H
H
9
O
a, NaBH4–MeOH; b, succinic anhydride–Lipase–(i-PrO)2O; c, MeONa–MeOH; d, AcOCH=CH2–Lipase–(i-PrO)2O; e, Cbz-L-valine–
DCC–DMAP–CH2Cl2.
the optical rotation.
IV formed at the 16% conversion of the alcohols mixture
IIIa and IIIb after 2-hour reaction of the alcohols mixture
with the equimolar amount of succinic anhydride in the
diisopropyl ether in the presence of lipase Amano PS at
20°С. The hemisuccinate IV obtained in this experiment
was also optically pure.
Alcohol (2R,6R,10R)- IIIa with a specific optical ro-
tation [α]D20 –6.3° (c 1.0, pentane) identical in the sign and
the absolute value to the described in the literature opti-
cally pure (2R,6R,10R)-6,10,14-trimethylpentadecan-2-ol
[1–3] was obtained by the hydrolysis of hemisuccinate
Acylation of the mixture of (2RS,6R,10R)-diastereomeric alcohols IIIa and IIIb with succinct anhydride (А) and vinyl acetate
(B) in diisopropyl ether in the presence of lipases Amano PS (PS-C) and Candida cylindracea (CCL)а
[α]D20 in pentane (ее, %)
Lipase
Acylating agent
Reaction time, h
Conversion, %
IIIа
IIIb
PS-C
PS-C
А
А
2
3
16
19
–6.3 (99)
–5.0 (78)
+0.7 (9)
+1.2 (15)
PS-C
PS-C
PS-C
PS-Cb
CCL
А
А
А
А
А
B
4
6
22
26
48
18
51
47
–4.6 (72)
–3.7 (58)
–3.0 (47)
–3.5 (55)
+0.3
+1.6 (20)
+4.1 (51)
+8.1 (100)
+1.6 (20)
+5.0 (63)
+3.9 (49)
24
7
24
24
PS-C
–1.4 (22)
а
The ratio of IIIa and IIIb to the acylating agent was equimolar, of IIIa and IIIb to lipase, 3 : 2 by weight; reaction temperature 20°С.
b Reaction temperature 8°С.
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SHAFIKOV et al.
292
On reducing the acylation temperature to 8°С the same
ment under the action of the ethanol solution of anise
aldehyde acidified with sulfuric and acetic acids. The
specific activity of the lipase from Candida cylindra-
cea (CCL, Fluka) 3.85 units·mg–1. The lipase Amano
Lipase PS from Burkholderia cepacia was purchased
from Aldrich.
conversion of alcohols IIIa and IIIb was obtained in 7 h,
and the optical purity of alcohol IIIa reduced therewith
to 55% (see the table).
At increasing the conversion of the alcoxols mixture
IIIa and IIIb the optical purity of (2R,6R,10R)-diastereo-
meric alcohol IIIa decreased (at the conversion 19, 22,
and 26% the optical purity of obtained alcohol IIIa was
78, 72, and 58% respectively], but at the same time the
optical purity of the residual alcohol IIIb increased (ee
15, 20, and 51%) (see the table).At the conversion ~50%
attained at 20°С within 24 h alcohol (2S,6R,10R)-IIIb was
obtained with a specific optical rotation [α]D20 +8.1° (c 1.4,
pentane) identical in the sign and the absolute value to
the described in the literature optically pure (2S,6R,10R)-
6,10,14-trimethylpentadecan-2-ol [1, 2].
(2RS,6R,10R)-6,10,14-Trimethylpentadecane-2-
ols IIIа and IIIb. To a solution of 0.42 g (1.56 mmol)
of (6R,10R)-6,10,14-trimethylpentadecan-2-one (II)
([α]D25 +1.05°, prepared by procedure [4]) in 12 ml of
MeOH at 0°С while stirring was added in one portion
0.12 g (3.20 mmol) of NaBH4. The temperature was
gradually raised to the ambient, and the mixture was
stirred for 2 h. Then the reaction mixture was evaporated
in air. To the residue 25 ml EtOAc was added, the solution
was washed in succession with 3 N HCl (2 × 20 ml), with
saturated solution of NaHCO3, and with brine, and dried
with MgSO4. On evaporation of the solvent the yield
of the mixture of alcohols IIIа and IIIb 0.40 g (95%).
Colorless oily substance, Rf 0.56 (hexane–EtOAc, 3 : 1),
[α]D20 +0.8° (c 1.2, pentane), [α]D20 2.6° (c 2.0, CHCl3).
The use as catalyst lipase CCL under the same condi-
tions (20°С, 24 h, conversion ~50%) resulted in a decrease
in the optical purity of alcohol IIIb to 63%, and the use of
vinyl acetate as acylating agent (catalyst lipase Amano PS,
24 h, conversion ~50%) gave alcohol IIIb of the optical
purity of 49% (see the table).
1
IR spectrum, ν, cm–1: 3600–3300, 1100 (ОН). Н NMR
spectrum, δ, ppm: 0.85 d, 0.87 d (12Н, Mе-С6, Mе-
С10, Mе-С14, Н3С15, J 6.4 Hz), 1.06–1.57 m (24Н, СН,
СН2), 1.19 d (3Н, Н3С1, J 6.4 Hz), 3.80 br.s (1Н, ОН),
3.79, 3.82 d.d (1Н, НС2, J 6.4 Hz). 13С NMR spectrum,
δ, ppm: 19.67 and 19.74 (Mе-С6, Mе-С10), 22.62 and
22.71 (Mе-С14, С15), 23.24 (С1), 24.48 (С4), 24.46 and
24.79 (C8, C12), 27.97 (C14), 32.78 (C6, C10), 37.02 (C5),
37.28, 37.37 and 37.42 (C7, C9, C11), 39.36 (C13), 39.72
(C3), 68.22 (C2). Found, %: C 79.89; H 14.19. С18Н38О.
Calculated, %: С 79.93; H 14.16.
Thus the hydride reduction of (6R,10R)-6,10,14-
trimethylpentadecan-2-one, the product of chlorophyll
ozonolysis, made it possible to obtain by the shortest
route the mixture of diastereomeric (2RS,6R,10R)-
6,10,14-trimethylpentadecan-2-ols that at the catalysis
with lipase Amano PS was kinetically separated into
optically pure (2R,6R,10R)- and (2S,6R,10R)-6,10,14-
trimethylpentadecan-2-ols IIIa and IIIb.
EXPERIMENTAL
Hemisuccinate (2R,6R,10R)-6,10,14-trimethyl-
pentadecane-2-ol (IV). To a solution of 0.14 g (0.52
mmol) of the mixture of alcohols IIIа and IIIb in 7 ml
of diisopropyl ether was added 0.05 g (0.50 mmol) of
succinic anhydride and 0.09 g of lipase Amano PS. The
reaction mixture was stirred at 20°С monitoring the con-
version of the substrate by TLC (eluent hexane–EtOAc,
3 : 1) and GLC (samples of the reaction mixture after
treating with the ether solution of diazomethane). When
the conversion attained 16% (2 h) the reaction mixture
was filtered through a glass frit no. 3, the precipitate was
washed with diisopropyl ether (3 × 10 ml), the combined
filtrates were concentrated at the reduced pressure and
40°С. The residue was subjected to column chromatog-
raphy on SiO2 (5 g, eluent petroleum ether). We obtained
0.113 g (81%) of alcohol IIIb {Rf 0.56 (hexane–EtOAc,
3 : 1), [α]D20 +2.1° (с 4.2, pentane), [α]D20 +0.9° (c 3.1,
1Н and 13С NMR spectra were registered on a spec-
trometer Bruker Avance-400, operating frequencies
400.13 (Н1) and 100.62 (С13) MHz, solvent CDCl3.
Homo- and heteronuclear experiments COSY, HSQC,
HMBC were carried out on the spectrometer Bruker
Avance-400 applying the standard programs of Bruker
Co. The chemical shifts are reported with respect to TMS.
The specific optical rotation was measured on a polarim-
eter Perkin Elmer-141. High resolution mass spectra were
taken on an instrument MALDI TOF/TOF Autoflex-III
Bruker. IR spectra were recorded on a spectrophotom-
eter Carl Zeiss Jena Specord 75 IR from pellets with
KBr. UV spectra were obtained on spectrophotometers
Perkin Elmer Specord M-40 and Lambda-750. The TLC
was performed on plates with SiO2 (Silufol), develop-
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CHEMOENZYMATIC SYNTHESIS OF (2R,6R,10R)-6,10,14-TRIMETHYLPENTADECAN-2-OL
293
CHCl3), ее 26%} and 0.025 g (13%) of hemisuccinate
IV, Rf 0.08 (hexane–EtOAc, 3 : 1), [α]D20 –2.1° (с 1.1,
pentane), [α]D20 –1.1° (c 0.9, CHCl3). 1Н NMR spectrum,
δ, ppm: 0.85 and 0.87 d.d (12Н, Mе-С6, Mе-С10, Mе-С14,
Н3С15, J 6.8 Hz), 1.08–1.57 m (21Н, СН, СН2), 1.28 d
(3Н, Н3С1, J 6.8 Hz), 2.42 m (2Н, Н2С2'), 2.52 m (2Н,
Н2С3'), 4.84 m (1Н, НС2). 13С NMR spectrum, δ, ppm:
19.53 (С1), 19.74 (Mе-С6, Mе-С10), 22.62 and 22.72
(Mе-С14, С15), 24.51 and 24.81 (С4, C8 and C12), 27.97
(C14), 29.69 (С2' and С3'), 32.69 and 32.82 (C6, C10),
36.18 (C3), 37.01, 37.06, 37.31 and 37.50 (C5, C7, C9,
C11), 39.37 (C13), 71.38 (C2), 174.28 (С4'), 180.01 (С1').
Found, %: C 71.36; H 11.37. С22Н42О4. Calculated, %:
С 71.31; H 11.42.
0.07 g of lipase Amano PS. The reaction mixture was
stirred at 20°С monitoring the conversion of the substrate
as described above in the synthesis of compound IV at
the acylation of the alcohols mixture with the succinic
anhydride. Attaining the conversion of 47% the reaction
mixture was worked up as described above. We obtained
0.053 g (53%) of alcohol IIIb {Rf 0.56 (hexane–EtOAc,
3 : 1), [α]D20 +2.9° (с 2.7, CHCl3)} and 0.039 g (34%)
of acetate V, Rf 0.76 (hexane–EtOAc, 3 : 1), [α]D20 +0.9°
(с 2.1, CHCl3). 1Н NMR spectrum, δ, ppm: 0.85 and 0.87
d.d (12Н, Mе-С6, Mе-С10, Mе-С14, Н3С15, J 6.8 Hz),
1.05–1.61 m (21Н, СН, СН2), 1.21 d (3Н, Н3С1, J 6.0 Hz)
2.03 s (3Н, MеСО), 4.90 m (1Н, НС2). 13С NMR spec-
trum, δ, ppm: 19.61 (С1), 19.72 and 19.96 (Mе-С6, Mе-
С10), 21.34 (MеСО), 22.60 and 22.69 (Mе-С14, С15),
22.85 (С4), 24.44 and 24.78 (C8, C12), 27.96 (C14), 32.66
and 32.77 (C6, C10), 36.22 (C3), 36.76 (C5), 37.27, 37.35
and 37.41 (C7, C9, C11), 39.36 (C13), 71.02 (С2), 170.72
(СО). Found, %: C 76.91; H 12.84. С20Н40О2. Calculated,
%: С 76.81; H 12.93.
(2R,6R,10R)-6,10,14-Trimethylpentadecane-2-
ol (IIIа). To a solution of 0.025 g (0.068 mmol) of
hemisuccinate IV in 3 ml of methanol was added 0.003 g
(0.13 mmol) of sodium. The reaction mixture was stirred
for 0.5 h, then 5% solution of HCl was added dropwise
(till neutral reaction), the reaction product was extracted
into EtOAc (3 × 6 ml), the extract was evaporated, the
residue was subjected to column chromatography on
SiO2 (3 g, eluent petroleum ether). Yield 0.017 g (93%),
Rf 0.56 (hexane–EtOAc, 3 : 1), [α]D20 –6.3° (с 1.0, pentane)
{[α]D18 –6.4° (c 1.1, pentane) [1, 2], [α]D20 –6.5° (с 4.9,
pentane) [3]}, [α]D20 –3.2° (с 1.2, CHCl3). IR and 1Н NMR
spectra are identical to those published in [1]. 13С NMR
spectrum was identical to the spectrum reported above
for the mixture of alcohols IIIа and IIIb.
(2RS,6R,10R)-6,10,14-Trimethylpentadec-2-yl-
2-(N-benzyloxycarbonyl)-L-valinate (VI). To a solu-
tion of 0.06 g (0.22 mmol) of the mixture of alcohols
IIIа and IIIb in 5 ml of freshly distilled CH2Cl2 was
added at stirring 0.11 g (0.44 mmol) of Cbz-L-valine,
0.09 g (0.44 mmol) of DCC, and 0.004 g (0.03 mmol)
of DMAP (a precipitate separated), the reaction mixture
was stirred for 4 h till the complete consumption of the
initial substrate (TLC monitoring). The reaction mixture
was filtered through a folded paper filter, the filtrate was
evaporated in a vacuum, the residue was subjected to
column chromatography on SiO2 (5 г, eluent petroleum
ether). Yield 0.11 g (98%), colorless oily substance,
Rf 0.69, (hexane–EtOAc, 3 : 1), [α]D20 +5.1° (с 6.1,
CHCl3). IR spectrum, ν, cm–1: 3356 (NH), 2928 (О–СО),
1728 (С=О), 1536 and 1499 (Ph). UV spectrum (CHCl3),
λmаx., nm (ε): 258 (272). 1Н NMR spectrum, δ, ppm:
0.88 d (12Н, Mе-С6, Mе-С10, Mе-С14, Н3С15, J 6.8 Hz),
0.99 and 1.00 d (6Н, 4'-Mе, 5'-Mе, J 4.5 Hz), 1.08–1.62 m
(21Н, СН, СН2), 1.24 d, 1.27 d (3Н, Н3С1, J 4.5 Hz),
2.20 m (1Н, НС3'), 4.31 m (1Н, НС2'), 4.97 m (1Н, НС2),
5.13 s (2Н, Н2С7'), 5.35 br.s (1Н, NН), 7.27–7.38 m (5Н,
Н9'–13'). 13С NMR spectrum, δ, ppm: 17.24 and 17.40
(С5'), 18.93 and 19.10 (С4'), 19.61 and 19.75 (Mе-С6,
Mе-С10), 19.91 and 19.98 (С1), 22.64, 22.74 and 22.84
(С4, Mе-С14, С15), 24.47 and 24.81 (C8, C12), 27.98 (C14),
31.36 and 31.40 (С3'), 32.66 (C6), 32.80 (C10), 36.15 (C3),
(2S,6R,10R)-6,10,14-Trimethylpentadecane-2-ol
(IIIb). To a solution of 0.100 g (0.37 mmol) of the mix-
ture of alcohols IIIа and IIIb in 5 ml of diisopropyl ether
was added 0.037 g (0.37 mmol) of succinic anhydride
and 0.066 g of lipase Amano PS. The reaction mixture
was stirred at 20°С for 24 h (conversion 48%). Further
workup was performed as described in the synthesis of
compound IV. We obtained 0.052 g (52%) of alcohol
IIIb {Rf 0.56 (hexane–EtOAc, 3 : 1), [α]D20 +8.1° (с 1.4,
pentane) ([α]D18 +8.0° (c 1.1, pentane) [1, 2]), [α]D20 +4.4°
(с 2.2, CHCl3); IR and 1Н NMR spectra are identical to
those published in [1]} and 0.044 g (32%) of hemisuc-
cinate IV {Rf 0.08 (hexane–EtOAc, 3 : 1), [α]D20 –0.7°
(с 1.6, CHCl3)}.
(2R,6R,10R)-6,10,14-Trimethylpentadec-2-yl ac-
etate (V). To a solution of 0.10 g (0.52 mmol) of the
mixture of alcohols IIIа and IIIb in 5 ml of diisopropyl
ether was added 0.03 g (0.50 mmol) of vinyl acetate and
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 2 2011

SHAFIKOV et al.
294
36.72 (C5), 37.29, 37.39 and 37.42 (C7, C9, C11), 39.37
(C13), 58.98 and 59.10 (С2'), 66.95 (С7'), 72.42 and 72.48
(С2), 128.15 and 128.53 (С9'–С13'), 136.35 (С8'), 156.22
(С6'), 173.56 (С1'). Found M+ 526.860. C31H53NNaO4.
Calculated M 526.747.
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Lieb. Ann., 1991, p. 259.
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ACKNOWLEDGMENT
The study was carried out under a financial support
of the Russian Foundation for Basic Research (grant
no. 10-03-00105).
4. Odinokov, V.N., Mallyabaeva, M.I., Spivak, A.Yu.,
Emel’yanova, G.A., and Dzhemilev, U.M., Dokl. Akad.
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 2 2011