Enzymatic dissymmetrization of meso-2,3-dimethylbutane-1,4-diol and its diacetate. Synthesis of scalemic (-)-lasiol

Article abstract of DOI:10.1023/A:1015512419633

Acylation of meso-2,3-dimethylbutane-1,4-diol with vinyl acetate in the presence of porcine pancreatic lipase (PPL) leads to the dextrorotatory monoacetate of the above diol with enatiomeric excess (ee) 58-64 percent. Absolute configuration of this scalemic specimen was determined by its sequential transformation to levorotatory lasiol, a metabolite of the Lasius ants. Partial hydrolysis of the corresponding meso-diacetate, mediated by PPL or by the Pseudomonas sp. lipase affords the monoacetate of opposite configuration with ee 72-86 percent, a formal intermediate in the synthesis of (3S,4R)-faranal. Other microbial lipases used are distinctive in low chemoselectivity.

Full text of DOI:10.1023/A:1015512419633

Russian Chemical Bulletin, International Edition, Vol. 51, No. 3, pp. 481—487, March, 2002
481
Organic Chemistry
Enzymatic dissymmetrization of mesoꢀ2,3ꢀdimethylbutaneꢀ1,4ꢀdiol
and its diacetate. Synthesis of scalemic (−)ꢀlasiol
A. A. Vasil´ev,a O. Vielhauer,b L. Engman,c M. Pietzsch,b and E. P. Serebryakova
ꢀ
aN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (095) 135 5328
bInstitute of Biochemical Engineering, Stuttgart University,
Almandring 31, 70569 Stuttgart, Germany
cDepartment of Organic Chemistry, Institute of Chemistry, Uppsaa University,
Box 531, 751 21 Uppsala, Sweden
Acylation of mesoꢀ2,3ꢀdimethylbutaneꢀ1,4ꢀdiol with vinyl acetate in the presence of porꢀ
cine pancreatic lipase (PPL) leads to the dextrorotatory monoacetate of the above diol with
enatiomeric excess (ee) 58—64%. Absolute configuration of this scalemic specimen was deterꢀ
mined by its sequential transformation to levorotatory lasiol, a metabolite of the Lasius ants.
Partial hydrolysis of the corresponding mesoꢀdiacetate, mediated by PPL or by the Pseudomoꢀ
nas sp. lipase affords the monoacetate of opposite configuration with ee 72—86%, a formal
intermediate in the synthesis of (3S,4R)ꢀfaranal. Other microbial lipases used are distinctive in
low chemoselectivity.
Key words: mesoꢀ2,3ꢀdimethylbutaneꢀ1,4ꢀdiol; lipases; (+)ꢀ and (–)ꢀerythroꢀ4ꢀacetoxyꢀ
2,3ꢀdimethylbutanꢀ1ꢀols; selenoacetals; (2S,3S)ꢀ2,3,6ꢀtrimethylheptꢀ5ꢀenꢀ1ꢀol.
(2R*,3R*)ꢀ2,3,6ꢀTrimethylheptꢀ5ꢀenꢀ1ꢀol (lasiol, 1),
the major component of the mandibular gland secretion
produced by males of the Lasius meridionalis ants,1 has
two vicinal methyl groups in the erythro configuration.
For the introduction of this structural motif, suitably subꢀ
stituted bifunctional building blocks 21—9 as well as subꢀ
stituentꢀdirected antiꢀalkylation of 3ꢀmethylalkanolide
enolates10,11 have been employed.
Synthesis of nonꢀracemic building blocks involves teꢀ
dious application of chiral auxiliaries followed by the sepaꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 448—453, March, 2002.
1066ꢀ5285/02/5103ꢀ481 $27.00 © 2002 Plenum Publishing Corporation

482
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 3, March, 2002
Vasil´ev et al.
ration of diastereomers.2—4 Although elegant, the ring
opening of properly substituted epoxides using chiral
agents is also not unproblematic.5,6,12–14 In contrast,
asymmetric hydrolysis of diethyl 3ꢀmethylglutarate
catalysed by PLE appears to be a practical route to the
required building blocks10 if the remaining vicinal Me
group could be readily introduced.
Scheme 1
mesoꢀ2,3ꢀDimethylbutaneꢀ1,4ꢀdiol (3) can also be a
good source of erythro configured compounds 2. Previꢀ
ously1,9 it was used only to prepare racemic forms of such
compounds. However, the diol 3 may also be suitable for
enantiotopic discrimination of 1,4ꢀpositioned functional
groups, e.g., by enzymeꢀcatalysed partial acylation, or
by enzymatic hydrolysis of its diacetate 4. In theory,
enantiopure products of such transformations can be obꢀ
tained in quantitative yields.15—17 If so, enantiomeric
mesoꢀ4ꢀacetoxyꢀ2,3ꢀdimethylbutanꢀ1ꢀols (5 or entꢀ5)
could be processed to useful chirons in essentially the
same manner as their racemic analogue.9
Reagents and conditions: a. proꢀSꢀselective acylation,
H2C=CHOAc/toluene—PPL (or PSL), ∼20 °C;
b. proꢀSꢀselective hydrolysis, H2O (0.1 M phosphate buffer,
pH 6.8)/toluene—PPL, ∼20 °C;
c. (S)ꢀ(+)ꢀMTPAꢀCl/Py, ∼20 °C.
Results and Discussion
acetate). Similar results were obtained by enzyme mediꢀ
ated acetylation of diol 3 using PSL. When the lipase
from Humicola sp. was used as the catalyst, the yield of
monoacetate with the same 1H NMR characteristics of its
(R)ꢀMTPA derivative was as high as 65%, but at the exꢀ
pense of ee (∼20%).
In order to find the best enzyme for dissymmetrisation
of meso compounds 3 and 4, screening experiments were
performed employing the lipase from hog pancreas (PPL)
and eight microbial lipases of various origin. Unfortuꢀ
nately, the ratio of 5 and entꢀ5 (er) in the products (and
thus the enantiomeric excess, ee) could not be deterꢀ
mined by capillary gas chromatography on the available
chiral phase since their retention times coincided. Howꢀ
ever, 1H NMR analysis of the (R)ꢀMTPA esters18 derived
from the above monoacetates (5a and entꢀ5a) allowed the
determination of enantiomeric ratios, er to be made, since
the geminal protons HA(1) and HB(1) in 5a and entꢀ5a
were clearly distinguishable.*
Except for PPL and the lipase from Pseudomonas sp.
(PSL), all lipases tried showed poor chemoselectivity in
acetylation of diol 3 and in hydrolysis of diester 4 (Table 1).
Furthermore, the yields of the monoesters were less
than 50%.
After a relatively short time, smallꢀscale acetylation of
3 in the presence of PPL (Table 1) afforded a crude maꢀ
terial which, according to GC, consisted of a mixꢀ
ture of monoacetate 5 (~55%) and diacetate 4 (~45%).
This material was subjected to chromatographic separaꢀ
tion, and the monoacetate fraction was treated with
(S)ꢀ(+)ꢀMTPAꢀCl. The 1H NMR spectrum of the resultꢀ
ing pair of diastereomeric (R)ꢀMTPA esters, 5a and
entꢀ5a, displayed two groups of signals belonging to the
geminal protons HA(1) and HB(1) in each diastereomer:
δ 4.15 dd + δ 4.36 dd and δ 4.23 dd + δ 4.28 dd, in a
77:23 ratio (corresponding to 54% ee in starting monoꢀ
The PPL catalysed acetylation of diol 3 was performed
also on a 0.5 mmol scale. An aliquot of the dextrorotatory
25
monoester ([α]D +12.6 (CHCl3) at ~62% conversion
(GLC)) was isolated and transformed to diastereomeric
(R)ꢀMTPA esters, and the 1H NMR spectrum disꢀ
played the same diagnostic signals (δ 4.15 + δ 4.36 and
δ 4.23 + δ 4.28) in a 82:18 ratio. Thus, the ee of the
isolated (+)ꢀmonoacetate was 64%. In a preparative exꢀ
periment (7.2 mmol of 3) with a higher concentration of
diol and less lipase, both the yield (29% at ∼52% converꢀ
25
sion) and optical purity (58% ee, [α]D +11.0) of the
(+)ꢀmonoacetate were somewhat lower. Subsequent
transformations of this specimen (see below) showed that
its major enantiomer 5 had the 2R,3S configuration, and
hence the minor enantiomer, entꢀ5, was assigned the
2S,3R configuration.
PPL mediated hydrolysis of diacetate 4 to ∼70% conꢀ
version gave a threeꢀcomponent mixture with the monoꢀ
acetate fraction amounting to ∼55%. The latter was conꢀ
verted to a mixture of diastereomeric (R)ꢀMTPA esters.
1
Its H NMR spectrum displayed familiar diagnostic sigꢀ
nals of protons HA(1) and HB(1): (δ 4.15 + δ 4.36 and
δ 4.23 + δ 4.28), but in a 14:86 ratio. Thus, the isolated
monoester consisted mainly of entꢀ5 (ee 72%). Not surꢀ
25
prisingly, it proved to be levorotatory ([α]D –13.7 in an
experiment with 0.25 mmol of diacetate 4). In a preparaꢀ
tive experiment using less solvent and PPL the optical
* Unfortunately, the CF3 groups of MTPA esters of 5a + entꢀ5a
were indistinguishable in the 19F NMR spectra.

Enzymatic dissymmetrization
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 3, March, 2002
483
Table 1. Acetylation selectivity of diol 3 and hydrolysis selectivity of diacetate 4 in the presence of various lipases at 20—25 °C
Entry
Lipase
Acetylation of mesoꢀdiol 3
Hydrolysis of mesoꢀdiacetate 4
τ/ha
Composition of the
reaction mixture (%)b
τ/ha
Composition of the
reaction mixture (%)b
3
4
5 + entꢀ5
3
4
5 + entꢀ5
1
2
3
4
5
6
Hog pancreas (PPL)
Pseudomonas sp. (PSL)
Humicola sp. (HSL)
2
5
8
2
5
8
2
5
8
2
5
8
2
5
8
2
5
0
0
0
20
0
0
45
90
100
15
51
79
55 (er = 77 : 23)c
6
<1
15
21
0
∼34
30
24
80
34
66
10
0
22
46
6
55 (er = 14 : 86)c
55
20
65 (er = 77 : 23)c
49
21
22
7
59 (er = 27 : 73)c
Traces 35
65 (er = 60 : 40)c
6
22
46
6
22
46
2.5
8
22
6
22
46
2.5
6
<1
18
70
0
0
0
0
0
33
0
4
48
47
100
81
70
13
35
39
68
46
9
∼32
36
21
Traces
8
15
6
8
14
8
17
22
36
0
58
30
32
35
21
0
0
79
65
57
0
0
0
0
0
79
94
6
8
9
74
93
100
90
100
21
6
Rhizopus delemar (RDL)
15
27
34
26
7
0
10
0
100
92
85
94
92
53
92
79
30
17
0
34
0
55
30
40
Candida rugosa
≡ C. cylindracea
(CRL, CCL)
Candida antarctica,
type A
7
8
9
Candida antarctica,
type B
Mucor miehei
2
0
100
0
2
5
2
0
0
0
97
100
100
3
0
6
22
2.5
6
Pseudomonas cepacia
Traces
18
a
τ is time of reaction.
b Determined by capillary GLC of the reaction mixture samples.
1
с Ratios of intensities of diagnostic signals (I(δ 4.15 + δ 4.36) : I(δ 4.23 + δ 4.28)) from protons HA(1) and HB(1) in H NMR spectra of the
binary mixtures of MTPA esters. These dr values are assumed to correspond to еr in scalemic specimens 5 + entꢀ5. The first figure in
the ratio relates to the (+)ꢀmonoacetate 5.
purity of the monoacetate entꢀ5 (isolated yield 33%) was
even higher (er = 7:93, ee 86%, [α]D –15.2). Similar
result was obtained upon the hydrolysis of diacetate 4 in
the presence of PSL, but another lipases were less effecꢀ
tive (see Table 1).
The transformation of monoester 5 into scalemic lasiol
1 (Scheme 2) was performed using a methodology develꢀ
oped earlier for the synthesis of ( )ꢀfaranal.9 The preꢀ
parativeꢀscale acetylation of diol 3 in the presence of PPL
afforded monoacetate 5 with [α]D22 + 11.0 (CHCl3), which
was submitted to the Swern oxidation. The crude γꢀacetꢀ
oxyalkanal 6 without purification was converted to the
corresponding acetoxy selenoacetal using earlier described
procedure.9 Deacetylation of this material gave alcoꢀ
hol 7, the HO group of which was reprotected using
tertꢀbutyldimetylchlorosilane—imidazole. The overall
yield of Oꢀprotected selenoacetal 8 from monoacetate 5
was 47%.
25
Both the formation of the 2R,3S monoacetate 5 upon
acetylation of diol 3 and the formation of its 2S,3R counꢀ
terpart entꢀ5 upon the hydrolysis of diacetate 4 conꢀ
form to the wellꢀknown tendency of PPL to direct
the reactant towards the S configured (in the case
of meso compounds — proꢀS configured) part of the
substrate.15—17,19—21 However, numerous examples of
the PPL mediated transformations of 1,4ꢀbifunctional
meso substrates pertain only to cyclic compounds,15,19,20
and there can be exceptions to the above rule.22—24
Next, a stereocontrolled synthesis was undertaken to
correlate the absolute configuration of monoester 5 with
that of known enantiomers of compound 1.6,11
Lithiumꢀselenium exchange in selenoacetal 8, proꢀ
moted by nꢀBuLi, gave a seleniumꢀstabilised carbanion
which reacted with αꢀmethylacrolein to produce the
βꢀhydroxy selenide 9 as a mixture of four diastereomers.
On treating 9 with methanesulfonyl chloride and Et3N

484
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Vasil´ev et al.
gave (–)ꢀlasiol as the sole product. The 1H and 13C NMR
spectra of the latter displayed practically the same δC, δH
and J values as those reported in the literature for ( )ꢀ1 1
and for the two enantiomers of lasiol.5,11
Scheme 2
The alcohol (–)ꢀ1 thus obtained had [α]D22 –6.6 (hexꢀ
ane), which corresponds to about 51—52% ee. This
follows from the comparison of its specific rotation
with that reported earlier (−12.9) for practically enanꢀ
tiopure (2S,3S)ꢀlasiol5,11 and from the diastereomer ratio
of the mixture of (R)ꢀ and (S)ꢀMTPA esters prepared
from our specimen of (–)ꢀ1 and both (S)ꢀ(+)ꢀ and
1
(R)ꢀ(−)ꢀMTPAꢀCl, correspondingly. In the H NMR
spectrum of the resulting mixture of (R)ꢀMTPA esters
((–)ꢀ1a) ratio of integral intensities of signals at δH 4.18
and 4.29 (both dd) to those of at δH 4.11 and 4.37 (both dd)
(and dr value accordingly) was 79:21. The 1H NMR specꢀ
trum of (S)ꢀMTPA esters showed the opposite pattern of
intensity of the same signals. Curiously enough, this patꢀ
tern (δ 4.18 + δ 4.29) is similar to that reported for the
(S)ꢀMTPA ester of enantiopure (S,S)ꢀ(–)ꢀ1, while the
former (δ 4.11 + δ 4.37) was observed in the spectrum of
(R)ꢀMTPA ester of (−)ꢀ1.5,11 To avoid a mistake, for
more certainty we confirmed the negative rotation of
MTPAꢀCl prepared from (S)ꢀMTPA.18
Previously,11 the levorotatory lasiol was prepared from
the optically pure (S)ꢀ3ꢀmethylbutanꢀ4ꢀolide. We feel that
the agreement of [α]D signs (hexane) of enantiopure11 and
scalemic (ee > 50%, this work) lasiol is the strongest eviꢀ
dence for the absolute configuration. Moreover, a strucꢀ
tural analogue of lasiol, (2S,3S,5E,9Z)ꢀ2,3,6,10ꢀtetraꢀ
methyldodecaꢀ5,9ꢀdienꢀ1ꢀol, close precursor of "unnatuꢀ
ral" (−)ꢀentꢀfaranal, is also levorotatory.4 It appears that
the introduction of additional erythroꢀpositioned methyl
group at C(3) in the aliphatic chain would not affect the
tendency of (S)ꢀ2ꢀmethylalkanꢀ1ꢀols to be levorotatory
in aprotic nonꢀpolar solvents.25—29
The (S,S)ꢀconfiguration of scalemic (−)ꢀ1 proves that
both the PPL mediated acetylation of mesoꢀ2,3ꢀdimethylꢀ
butaneꢀ1,4ꢀdiol and the hydrolysis of its diacetate are
proꢀ(S)ꢀselective. Scalemic monoacetates thus formed
(5 and entꢀ5 correspondingly) are optical antipodes.
Sequential transformation of monoacetate 5 into aldeꢀ
hyde 6 and further into selenoacetal 8 may be repeated
starting from entꢀ5. The preparation of selenoacetal
entꢀ8 by this route is equivalent to the formal synthesis of
(+)ꢀfaranal, the trail pheromone of the Pharaoh's ant,
since the corresponding racemic seleno acetal ( )ꢀ8 has
been recently employed in the synthesis of the latter.9
Reagents and conditions: a. CH2=CHOAc/toluene—PPL,
∼22 °C, 18 h;
b. 1) (COCl)2—DMSO/CH2Cl2, –50 °C, 2) Et3N;
c. PhSeH—ZnCl2/CCl4, 0 → 20 °C;
d. MeOH/K2CO3, ~22°C; e. TBSCl—ImH/DMF;
f. 1) BuLi, THF, −78°C, 2) CH2=CH(Me)CHO;
g. MsCl—Et3N/CH2Cl2, 20 °C, 3 h; h. Bu4NF/THF;
i. Ac2O/DMAP, ∼20 °C;
6
j. H2 (50 atm.)—(η ꢀnaphthalene)⋅Cr(CO)3/THF, 50°C, 3 h;
k. (S)ꢀMTPAꢀCl/Py.
elimination of vicinal PhSe and OH group occurred. Subꢀ
sequent removal of the TBS group allowed us to isolate
the conjugated diene 10 as a 3:2 mixture of 4E and 4Z
stereoisomers. Mild 1,4ꢀcisꢀhydrogenation of 10 using
(η ꢀnaphthalene)chromium tricarbonyl as the catalyst folꢀ
lowed by deacetylation of the resulting acetoxy monoolefin
Experimental
NMR spectra were recorded in CDCl3 at 399.95 MHz (1H),
100.57 MHz (13C) and 57.21 MHz (77Se) using a Varian
Unityꢀ400 spectrometer. NMR 77Se spectra (working frequency
6

Enzymatic dissymmetrization
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 3, March, 2002
485
57.21 MHz) were measured using a Varian XLꢀ300 instruꢀ
ment, the chemical shifts are given in ppm relative to neat
Me2Se. GC analysis was performed using a capillary column
(15 m × 0.25 mm) with heptakis(6ꢀOꢀtertꢀbutyldimethylsilylꢀ
2,3ꢀdiꢀOꢀmethyl)ꢀβꢀcyclodextrine at 115 °C as the stationary
phase and helium (40 kPa) as the carrier gas. Optical rotations
were measured using a JASCOꢀDIP 360 instrument. Elemental
analyses were performed by Analytical Laboratories, Lindlar,
Germany. mesoꢀ2,3ꢀDimethylbutaneꢀ1,4ꢀdiol was prepared from
mesoꢀ2,3ꢀdimethylsuccinic acid (Aldrich) as described.9 Synꢀ
added and agitation was continued for 16 h at 22 °C. The reacꢀ
tion mixture was concentrated in vacuo and the remainder
was subjected to column chromatography. Elution with penꢀ
tane—AcOEt mixture (85 : 15) gave 0.233 g (16%) of diacetate 4.
Subsequent elution with pentane—AcOEt (6 : 4) afforded 0.329 g
(29%) of scalemic monoacetate (5 + entꢀ5) as a colourless oil
1
with [α]D22 +11.0 (c 2.6, CHCl3). H NMR and 13C NMR data
for the optically active monoacetate were in good agreement
with those for the racemate (see Ref. 9). Ratio of integral intenꢀ
sities of HA and HB signals in 1H NMR spectrum of its
(R)ꢀMTPA ester: I(δ 4.15 + δ 4.36) : I(δ 4.23 + δ 4.28) = 79 : 21 (ee 58%).
Finally, unconverted diol 3 (0.408 g, 48%) was eluted with penꢀ
tane—AcOEt (2 : 8 v/v) .
B. To the solution of diol 3 (59 mg, 0.5 mmol) in toluene
(10 mL) vinyl acetate (0.28 mL) and PPL (0.2 g) were added,
and stirring was continued for 8 h. A sample of monocetate
(5 + entꢀ5) with [α]D22 +12.6 (c 1.0, CHCl3) was isolated. Yield:
41 mg (52%). Ratio of integral intensities in 1H NMR spectrum
6
theses of (η ꢀnaphthalene)chromium tricarbonyl and benzeneꢀ
selenol were prepared according to known procedures cited in
Ref. 9. Column chromatography was performed using silica gel
MATREX LC 60/A/35ꢀ70 MY 80/25 85040 (GRACE Davison)
using pentane—AcOEt mixtures as eluents.
mesoꢀ1,4ꢀDiacetoxyꢀ2,3ꢀdimethylbutane (4) was prepared by
standard acetylation of diol 3 with excess Ac2O (∼20 °C) folꢀ
lowed by column chromatography (pentane—AcOEt, 85 : 15),
colourless oil. 1H NMR, δ: 0.95 (d, 6 H, CH3, J = 6.9 Hz), 1.87
(m, 2 H, CH), 2.03 (s, 6 H, CH3), 3.95 (dd, 2 H, OCHA,
J = 10.9 Hz, J = 3.9 Hz), 4.05 (dd, 2 H, OCHB, J = 10.9 Hz,
J = 4.05 Hz). 13C NMR, δ: 14.2 (CH3), 20.9 (CH3), 34.5 (CH),
67.0 (CH2), 171.1 (C=O).
Screening of lipases efficiency. Microscale acetylation and
hydrolysis (Table 1). Acetylation of diol 3. Mixtures of a lipase
(Roche Diagnostics) (20 mg) with standard 0.01 M solution of
diol 3 (1 mL) and vinyl acetate (150 mmol L–1) in toluene were
vigorously stirred at 20—25 °C. The progress of acetylation was
monitored by GC analysis of aliquots of the reaction mixture,
which were diluted with an equal volume of toluene and centriꢀ
fuged.
Hydrolysis of diacetate 4. A lipase (25 mg) was dispersed in
0.1 M phosphate buffer (pH 6.8) (1 mL) for 5 min. Then 0.01 M
solution of diacetate 4 in toluene (0.8 mL) was added, and
stirring was continued at 20—25 °C. Aliquots of a reaction mixꢀ
ture (0.25 mL) were homogenised, shaken with AcOEt (0.2 mL)
and then centrifuged. The organic layers thus separated were
analysed by GC.
Determination of optical purity of monoacetates 5 and entꢀ5.
Diol 3 (59 mg, 0.5 mmol) and diacetate 4 (40.4 mg, 0.2 mmol)
were reacted with vinyl acetate or aqueous buffer correspondꢀ
ingly (taken proportionally along with lipase) as described
above. The reaction mixtures were treated as above and subꢀ
jected to column chromatography. Elution with pentane—AcOEt
(85 : 15, v/v) afforded diacetate 4. Subsequent elution with a
pentane—EtOAc gradient (7 : 3 → 6 : 4) gave scalemic monoꢀ
acetates (5 + entꢀ5), which on treatment with (S)ꢀ(+)ꢀMTPAꢀCl
(Aldrich) in pyridine were converted into the corresponding
mixtures of diastereomeric (R)ꢀMTPA esters (5a + entꢀ5a).
1H NMR (signals of geminal protons HA and HB of the
of corresponding (R)ꢀMTPA ester: I(δ 4.15 + δ 4.36) : I(δ 4.23 + δ 4.28)
82 : 18 (ee 64%).
=
(2S,3R)ꢀ4ꢀAcetoxyꢀ2,3ꢀdimethylbutanꢀ1ꢀol (entꢀ5). A.
A mixture of diacetate 4 (400 mg, 1.98 mmol), toluene (10 mL),
0.1 M phosphate buffer (12 mL) and PPL (200 mg) was vigorꢀ
ously stirred at 22 2 °C for 48 h with occasional addition of 2 M
aqueous NaOH solution (1 mL in total) to maintain pH at 6.8.
By that moment the concentrations of the three components
(4, 5 + entꢀ5 and 3) in homogenised aliquot related as 30 : 53 : 17
(GLC data). The organic layer was separated, the aqueous phase
was extracted with ether. The combined organic extracts were
dried (Na2SO4), concentrated in vacuo, and the remainder
was subjected to column chromatography. Elution with penꢀ
tane—AcOEt (85 : 15) gave diacetate 4 (88 mg, 22%). Subseꢀ
quent elution with pentane—AcOEt (6 : 4) afforded scalemic
25
levorotatory monoacetate (entꢀ5 + 5) with [α]D –15.2 (c 1.0,
1
CHCl3), yield 103 mg (33%). H NMR spectrum of the correꢀ
sponding (R)ꢀMTPA ester displays two groups of diagnostic sigꢀ
nals from HA and HB in the ratio I(δ 4.15 + δ 4.36) : I(δ 4.23 + δ 4.28)
=
7 : 93. This corresponds to a 86% ee of scalemic monoacetate
entꢀ5 . Elution with pentane—AcOEt mixture (2 : 8) brought
about 21 mg (9%) of diol 3.
B. A mixture of diacetate 4 (40 mg), toluene (20 mL), phosꢀ
phate buffer (pH 6.8, 26 mL) and PPL powder (625 mg) was
stirred at 22 °C for 33 h (NaOH titration was omitted). Then the
reaction mixture was treated as above to afford 14 mg (44%) of
25
monoacetate (entꢀ5 + 5) with [α]D –13.7 (c 1.0, CHCl3).
1H NMR spectrum of the corresponding (R)ꢀMTPA ester:
I(δ 4.15 + δ 4.36) : I(δ 4.23 + δ 4.28) = 14 : 86 (ee 72%).
(2S,3R)ꢀ2,3ꢀDimethylꢀ4,4ꢀbis(phenylseleno)butanꢀ1ꢀol (7)
was obtained from 500 mg (3.12 mmol) of dextrorotatory 2R,3S
monoester (5 : entꢀ5 = 79 : 21, ee 58%) using a three step
protocol described earlier9 for the corresponding racemic
selenoacetal. Yield: 735 mg (57%), a colourless viscous oil
CF3(Ph)(OMe)COOCH2 moiety, δ : diastereomer 1, 4.15 (dd,
H
2J = 11.1 Hz, 3J = 6.8 Hz) and 4.36 (dd, 2J = 11.1 Hz,
3J = 5.4 Hz); diastereomer 2, 4.23 (dd, 2J = 11.1 Hz, 3J = 6.8 Hz)
and 4.28 (dd, 2J = 10.9 Hz, 3J = 5.4 Hz). Ratios between integral
intensities of these signals (dr) were assumed to reflect enantioꢀ
meric ratios of 5 and entꢀ5 formed in the above experiments.
The values thus determined are shown in Table 1.
25
with [α]D +32.3 (c 1.0, CHCl3). NMR 1H and 13C spectra
of compound 7 and its racemic analogue were practically
identical.
(2R,3S)ꢀ4ꢀ(tertꢀButyldimethylsilyloxy)ꢀ2,3ꢀdimethylꢀ1,1ꢀ
bis(phenylseleno)butane (8) was prepared from selenoacetal 7
(700 mg, 1.70 mmol) as described earlier for the racemate.9
(2R,3S)ꢀ4ꢀAcetoxyꢀ2,3ꢀdimethylbutanꢀ1ꢀol (5). A. To a
stirred mixture of diol 3 (0.85 g, 7.2 mmol) and toluene (17 mL)
vinyl acetate (1 mL, ∼11 mmol) and PPL powder (0.35 g) were
27
Yield: 0.742 g (82%). Yellowish viscous oil with [α]D +20.5
(c 2.0, CHCl3).

486
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 3, March, 2002
Vasil´ev et al.
(5R,6S)ꢀ7ꢀ(tertꢀButyldimethylsilyloxy)ꢀ2,5,6ꢀtrimethylꢀ
tion of the diene was carried out for 2 h at 40 atm. After decomꢀ
pression, the solvent was removed in vacuo and the remainder
was subjected to column chromatography in pentane — AcOEt
gradient (100 : 0 → 97 : 3). Without further purification
(2S,3S)ꢀ1ꢀacetoxyꢀ2,3,6ꢀtrimethylheptꢀ5ꢀene (acetate of
(–)ꢀlasiol) thus isolated was deacylated upon stirring with K2CO3
(10 mg) in MeOH (1.5 mL) for 5 h. The solvent was evaporated,
and the residue during column chromatography was eluted with
pentane—AcOEt (4 : 1) to afford chemically pure scalemic
4ꢀphenylselenoheptꢀ1ꢀenꢀ3ꢀol (9). To a stirred solution of
selenoacetal 8 (655 mg, 1.24 mmol) in THF (7 mL) at –78 °C
nꢀBuLi (0.5 mL of a 2.5 M solution in hexane, 1.24 mmol) was
added. The mixture was stirred for 5 min, treated with a solution
of 2ꢀmethylpropenal (87 mg, 1.24 mmol) in THF (1 mL), and
the temperature was raised to 20 °C. The reaction mixture was
quenched with NaHCO3 (aq) and extracted with ether, the exꢀ
tracts were dried (MgSO4) and concentrated in vacuo. Column
chromatography (gradient pentane — AcOEt 99 : 1 → 98 : 2)
afforded 398 mg (73%) of a mixture of four diastereomers of
selenide 9 as a yellowish oil. Found (%): C, 59.79; H, 8.64.
C22H38O2SeSi. Calculated (%): C, 59.84; H, 8.67. 77Se NMR,
δ: 235.8, 254.8, 269.8, 322.5.
22
(–)ꢀlasiol ((–)ꢀ1) as a colourless oil with [α]D –6.6 (c 1.56,
1
hexane) (yield 41 mg (81%)). The H and 13C NMR data were
in good agreement with those previously reported for ( )ꢀ,
(+)ꢀ and (−)ꢀlasiol.1,5,11
(R)ꢀMTPA ester of (–)ꢀlasiol, (–)ꢀ1a, was prepared rouꢀ
tinely from scalemic alcohol (–)ꢀ1 and (S)ꢀ(+)ꢀMTPAꢀCl
in pyridine.18 NMR 1H (ratio of intensities (I) of two
groups from geminal protons HA and HB in the fragment
CF3(Ph)(OMe)CСO2CH2 and corresponding δH (ppm) are inꢀ
dicated): I(δ 4.18 + δ 4.29) : I(δ 4.11 + δ 4.36) = 79 : 21 (corresponds to
58% ee in the starting alcohol).
(2S,3R)ꢀ1ꢀAcetoxyꢀ2,3,6ꢀtrimethylheptaꢀ4,6ꢀdiene (10). To
a stirred solution of selenide 9 (360 mg, 0.815 mmol) and NEt3
(0.57 mL, 3.3 mmol) in CH2Cl2 (4.3 mL) MsCl (0.20 mL) was
added dropwise at 20 °C, and stirring was continued for 3 h. The
reaction was quenched with NaHCO3 (aq) and extracted with
ether. The extract was dried (CaCl2) and concentrated in vacuo,
and the oily residue was subjected to column chromatography.
Elution with gradient pentane — AcOEt (99 : 1 → 98 : 5) afꢀ
forded 205 mg (93%) of (2S,3R)ꢀ1ꢀ(tertꢀbutyldimethylsilyloxy)ꢀ
2,3,6ꢀtrimethylheptaꢀ4,6ꢀdiene, which was immediately deꢀ
silylated by treating its solution in THF with 1 M solution of
Bu4NF in THF (0.84 mL) for 14 h at 20—22 °C. The alcohol
thus formed was subjected to chromatography using penꢀ
tane — AcOEt (9 : 1). However, it could not be separated
from tertꢀbutyldimethylsilanol that was formed as byꢀproduct.
Therefore, the fraction containing this alcohol (along with
ButMe2SiOH) was treated with a small excess Ac2O in the presꢀ
ence of ∼10 mg of DMAP (20 °C, 2 h) and concentrated in
vacuo. Column chromatography with gradient pentane – AcOEt
(99 : 1 → 97 : 3) afforded the title acetate 10 as a 3:2 mixture of
E/Z isomers in a yield of 97 mg (64%). Found (%): C, 73.28;
H, 10.26. C12H20O2. Calculated (%): C, 73.43; H, 10.27.
1H NMR, δ: Eꢀisomer: 0.88 (d, 3 H, CH3, J = 7.0 Hz), 1.04 (d,
3 H, CH3, J = 7.0 Hz), 1.78 (m, 1 H, CH), 1.82 (s, 3 H, CH3
allylic), 2.05 (s, 3 H, CH3CO), 2.31 (sextet, 1 H, CH, J =
6.4 Hz), 3.88 (dd, 1 H, OCHA, J = 10.9 Hz, J = 6.8 Hz), 3.98
(dd, 1 H, OCHB, J = 10.9 Hz, J = 6.4 Hz), 4.88 (br. s, 2 H,
=CH2), 5.51 (dd, 1 H, C(4)H, J = 15.7 Hz, J = 8.5 Hz), 6.10 (d,
1 H, C(5)H, J = 15.7 Hz); Zꢀisomer: 0.89 (d, 3 H, CH3, J =
6.9 Hz), 1.01 (d, 3 H, CH3, J = 7.0 Hz), 1.71 (m, 1 H, CH), 1.85
(s, 3 H, allylic), 2.03 (s, 3 H, CH3CO), 2.88 (m, 1 H, CH), 3.90
(dd, 1 H, OCHA), 3.96 (dd, 1 H, OCHB), 4.82 (br. s, 1 H,
C(7)HA), 4.91 (br s, 1 H, C(7)HB), 5.23 (t, 1 H, C(4)H, J =
11.6 Hz), 5.85 (d, 1 H, C(5)H, J = 11.9 Hz). 13C NMR, δ:
Eꢀisomer: 13.3 (CH3), 18.0 (CH3), 18.7 (CH3), 20.9 (CH3),
37.6 (CH), 38.5 (CH), 67.8 (CH2), 114.9 (=CH2), 132.7 (=CH),
132.9 (=CH), 141.9 (=C), 171.2 (C=O); Zꢀisomer: 13.3 (CH3),
19.0 (CH3), 21.0 (CH3), 23.3 (CH3), 33.4 (CH), 37.8 (CH),
67.8 (CH2), 114.9 (=CH2), 130.9 (=CH), 133.8 (=CH),
141.8 (=C), 171.2 (C=O).
(S)ꢀMTPA ester of (–)ꢀlasiol, (–)ꢀ1b, was prepared from (–)ꢀ1
and (–)ꢀ(R)ꢀMTPAꢀCl. 1H NMR: I(δ 4.18 + δ 4.29) : I(δ 4.11 + δ 4.36)
=
21 : 79 (58% ee in the starting alcohol). 19F NMR, δF: –71.93 for
both diastereomers.
This work was supported by the Russian Foundation
for Basic Research (Project No. 99ꢀ03ꢀ32992) and the
Swedish Natural Research Council. Roche Diagnostics is
acknowledged for generous gift of lipases used.
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Received August 16, 2001;
in revised form November 12, 2001