Lipase-mediated deracemization of secondary 1-phenyl-substituted propargylic alcohols of different topology

Article abstract of DOI:10.1023/B:RUCB.0000035659.02761.1a

Acetylation of (±)-1-phenylnon-2-yn-1-ol, (±)-1-phenylhept-1- yn-3-ol, and (±)-1-phenylundec-4-yn-3-ol ((±)-5) in the presence of lipase from Candida cylindracea (CCL) proceeds slowly to give products with ee ≤20%. The acetates of these alcohols are hydrolyzed in the presence of porcine pancreatic lipase (PPL) equally unsatisfactorily. The (η⁶-arene)tricarbonylchromium complex of alcohol (±)-5 is acetylated in the presence of CCL up to ～22% conversion to give (R)-acetate whose oxidative decomplexation followed by saponification results in alcohol (R)-(-)-5 with ee ≥95%. The configuration of alcohols (-)-5 and (+)-5 was determined by NMR spectroscopy of their esters with (R)- and (S)-Mosher's acids.

Full text of DOI:10.1023/B:RUCB.0000035659.02761.1a

Russian Chemical Bulletin, International Edition, Vol. 53, No. 3, pp. 693—702, March, 2004
693
Lipaseꢀmediated deracemization of secondary 1ꢀphenylꢀsubstituted propargylic
alcohols of different topology
A. L. Vlasyuk, G. D. Gamalevich, A. V. Ignatenko, E. P. Serebryakov,ꢀ and M. I. Struchkova
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (095) 135 5328.
Acetylation of
(
)ꢀ1ꢀphenylnonꢀ2ꢀynꢀ1ꢀol,
( )ꢀ1ꢀphenylheptꢀ1ꢀynꢀ3ꢀol, and
(
)ꢀ1ꢀphenylundecꢀ4ꢀynꢀ3ꢀol (( )ꢀ5) in the presence of lipase from Candida cylindracea
(CCL) proceeds slowly to give products with ее ≤20%. The acetates of these alcohols are
hydrolyzed in the presence of porcine pancreatic lipase (PPL) equally unsatisfactorily. The
6
(η ꢀarene)tricarbonylchromium complex of alcohol ( )ꢀ5 is acetylated in the presence of CCL
up to ~22% conversion to give (R)ꢀacetate whose oxidative decomplexation followed by saꢀ
ponification results in alcohol (R)ꢀ(–)ꢀ5 with ее ≥95%. The configuration of alcohols (–)ꢀ5
and (+)ꢀ5 was determined by NMR spectroscopy of their esters with (R)ꢀ and (S)ꢀMosher´s
acids.
Key words: 1ꢀphenylꢀsubstituted secondary propargyl alcohols and acetates, topology; the
6
efficiency of enzymatic deracemization; haptoꢀcomplexation of arenes, (η ꢀarene)triꢀ
carbonylchromium complexes, increase in the enantioselectivity; lipases.
Secondary propargylic alcohols (SPA) with high enanꢀ
failed to provide deracemization of ( )ꢀ1ꢀphenylethanol16
and its acetate.15 The dependence of the efficiency of
EKR on the distance between the η6ꢀcoordination site
(Ph) and the reaction center (HCOH) was estimated by
acetylating three different racemic SPA of the general
formula as Ph—(CH2)i(C≡C)j—CHOH—(C≡C)k—Alk,
where i = j = 0, k = 1 (1), or i = k = 0, j = 1 (3), or i = 2,
j = 0, k = 1 (5), in the presence of lipases.
tiomeric purity are valuable chiral building blocks (CBB)
for the synthesis of allenes,1 lactones,2 and heterocycles3
often encountered among natural and biologically
active compounds. These CBB are prepared by resoluꢀ
tion of racemic SPA into antipodes via diastereomeric
derivatives,2a,b,3a by reduction of α,βꢀacetylenic ketones
with chiral metal hydrides2c—h,4 or microbial oxidoreducꢀ
tases,5 by various reactions of metallated acetylene deꢀ
rivatives in the presence of homochiral catalysts,6 and
by fragmentation of homochiral βꢀchloroepoxides.7 At
present, the resolution of racemic SPA is more and more
often accomplished by enzymatic kinetic resolution
(EKR) catalyzed by porcine pancreatic lipase (PPL),2i,8
microbial lipases,9—12 and the Bacillus subtilis culture.13
Of these, PPL and lipase from the yeast Candida
cylindracea (CCL) are most available.9
Deracemization of ( )ꢀSPA by means of PPL and
CCL sometimes gives products with high ее but the rate
of this process is lower than that in the case of similar
allylic alcohols or secondary alkanols.9,10 In the present
work, we studied the dependence of the rate and stereoꢀ
selectivity of PPLꢀ and CCLꢀcatalyzed EKR of racemic
SPA on their topology and describes an attempt to inꢀ
crease the enantioselectivity of EKR of phenylꢀsubstiꢀ
tuted SPA following their conversion into (η6ꢀarene)triꢀ
carbonylchromium complexes. This approach proved to
be successful in the case of ( )ꢀ3ꢀ(4ꢀmethoxycarboꢀ
nyl)phenylꢀ2ꢀmethylpropanol and its acetate,14,15 but
An alternative version of EKR, viz., hydrolysis of the
corresponding acetates, ( )ꢀ2, ( )ꢀ4, and ( )ꢀ6 in the
presence of PPL, was also studied.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 661—669, March, 2004.
1066ꢀ5285/04/5303ꢀ0693 © 2004 Plenum Publishing Corporation

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Vlasyuk et al.
Table 1. Efficiency of deracemization of propargylic substrates
Alcohols ( )ꢀ1 and ( )ꢀ5 were prepared by the Jocic´
in the case of partial acetylation of alcoholsa
reaction from octꢀ1ꢀyne (7) and benzaldehyde or hydroꢀ
cinnamaldehyde (10), respectively. Similarly, alcohol
( )ꢀ3 was prepared from phenylacetylene (8) and pentanal
(9). The resulting alcohols were converted into acꢀ
etates ( )ꢀ2, ( )ꢀ4, and ( )ꢀ6 by a standard procedure
(Scheme 1).
Entry Subꢀ Lipase τ/h
Degree Yield
of conꢀ of the
Recovery
of the
strate
version acetateb alcoholb
(%)
1
2
3
4
5
6 c
7
(
(
(
(
(
(
(
(
)ꢀ1
)ꢀ1
)ꢀ1
)ꢀ3
)ꢀ3
)ꢀ5
)ꢀ5
)ꢀ5
PPL
60
∼0
∼0
0
∼0
∼0
∼0
0
∼0
0
5
58
∼0
98
97
100
100
100
93
CCL 48
RSL 120
CCL 84
RSL 120
PPL
CCL 144
RSL 120
Scheme 1
0
72
∼5—6
58—60
0
41d
∼100
8
a
In the vinyl acetate—Et2O system at 20—22 °C; subꢀ
strate : lipase = 1 : 1 (w/w).
b The yield of the chromatographically pure product.
c The alcohol ( )ꢀ5 to PPL ratio is 1 : 2.
d [α]D +5.3 (CHCl3).
rather rapidly and after 6 days the degree of conversion
reached ~58% (Table 1). The fraction of the unreacted
22
alcohol had [α]D +5.3 (CHCl3). This sample, (+)ꢀ5A,
Reagents and conditions: a. EtMgBr, Et2O, 20→35 °C;
b. PhCHO, 20→35 °C; c. Ac2O—DMAP (cat.), Py, ~20 °C;
d. Me(CH2)3CHO (9), 20→35 °C; e. C6H13C≡CMgBr, Et2O,
20→35 °C.
was converted according to Mosher—Lightner17,18 into
an ester of (S)ꢀMosher´s acid (αꢀmethoxyꢀαꢀtrifluoroꢀ
methylphenylacetic acid) ((S)ꢀMTPAꢀester I). Judging
by the diastereomer ratio (dr) in (S)ꢀMTPAꢀester I, the
ее value for alcohol (+)ꢀ5A was ~20%.
The PPLꢀmediated hydrolysis of acetates ( )ꢀ2, ( )ꢀ4,
and ( )ꢀ6 proceeds even more slowly (Table 2). A degree
of conversion of acetates ( )ꢀ4 and ( )ꢀ6 satisfactory for
preparative purposes was attained over 15 and 7 days,
respectively.
As appears from the amplitudes of [α]D, alcohols (+)ꢀ1,
(–)ꢀ3, and sample (+)ꢀ5B with [α]D +3.8 (CHCl3) had
low ее. In the (S)ꢀMTPAꢀester I´ obtained from alcoꢀ
hol (+)ꢀ5B, the dr value corresponded to the ее of ~15%.
For alcohol (+)ꢀ1 isolated after hydrolysis of acetate
Results and Discussion
Enzymatic deracemization of propargylic alcohols.
Acetylation of alcohols ( )ꢀ1, ( )ꢀ3, and ( )ꢀ5 with viꢀ
nyl acetate was carried out in Et2O in the presence of
PPL, CCL, and lipase from Rhizopus sp. (RSL). No reacꢀ
tion of alcohols ( )ꢀ1 and ( )ꢀ3 occurred in 2—5 days.
Alcohol ( )ꢀ5 did not react in the presence of RSL and
exhibited low reactivity in the presence of PPL. Only in
the case of CCL, did the transformation of ( )ꢀ5 proceed
Table 2. Efficiency of deracemization of propargylic substrates in the enzymatic hydrolysis
of acetatesa by the PPL
Entry Substrate τ/h
Degree of
conversion
(%)
Resulting alcohol
Recovery of the
acetateb (%)
Yieldb (%) [α]D (CHCl3)c
1
2
3
4
(
(
(
(
)ꢀ2
)ꢀ4
)ꢀ6
)ꢀ6
168
360
72
16
35
11
(+)ꢀ1, 15
(–)ꢀ3, 35
(+)ꢀ5, 11d
(+)ꢀ5B, 45
+6.8
–0.77
+4.3
84
64
88
54
168
~46
+3.8
a In the phosphate buffer (рH 6.5, 20—22 °C), substrate : PPL = 1 : 2 (w/w).
b The yield of the chromatographically pure product.
c The polarimetric concentrations were 0.3—1.0.
d ee < 20%.

Lipaseꢀmediated deracemization of alcohols
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 3, March, 2004
695
( )ꢀ2, the sign of [α]D coincides with the signs of [α]D
of enantiomers with known real configurations in the
ArCH(OH)C≡CR chemotype.6a,12 Taking into account
the IUPAC seniority rules for substituents (MeC≡C >
> Ph > HC≡C),19 this attests to the (S)ꢀconfiguration of
alcohol (+)ꢀ1. Alcohol (–)ꢀ3 isolated upon hydrolysis of
acetate ( )ꢀ4 is homologous to (S)ꢀ(–)ꢀ4ꢀphenylbutꢀ3ꢀ
ynꢀ2ꢀol6a,11a and (S)ꢀ(–)ꢀ1ꢀpentꢀ1ꢀynꢀ3ꢀol.6a Apparꢀ
ently, it also has the Sꢀconfiguration but the ее value for
the sample in question is close to zero.
An attempt to prepare [η6ꢀ(3ꢀoxopropyl)benzene]triꢀ
carbonylchromium (13), an intermediate in the Jocic´ synꢀ
thesis of alcohol ( )ꢀ11, by direct heating of aldehyde 10
with Cr(CO)6 was also unsuccessful. Aldehyde 13 and
alcohol ( )ꢀ11 were synthesized in an alternative route
(Scheme 2). Dimethyl acetal 14 prepared from aldehyde
10 smoothly reacted with Cr(CO)6 to give crystalline
η6ꢀarene complex (15), whose mild hydrolysis afforded
oxo complex 13. The Jocic´ reaction of this product gave
the target alcohol ( )ꢀ11 in an overall yield of 52%.
Scheme 2
S (L = H) or R (L = Alk, Ar, SiR3)
Lit. data:6a R = H,
L = Ph, [α]D +2.26, ee 43%;
L = SiMe3, [α]D +10.3, ee 21%
Lit. data:12 L = H,
Lit. data:6a,11a Alk = Me,
[α]D –50.6, ee 95% or
[α]D –8.39, ee 40%
Alk = Et,
R = H, [α]D +20, ee 72%;
R = OMe, [α]D +5.3, ee 10%;
R = CN, [α]D +21.1, ee 96%
[α]D –13.7 (Et2O),
ee 70%
The low rates and low enantioselectivities of the EKR
of alcohols ( )ꢀ1, ( )ꢀ3, and ( )ꢀ5 and their acetates
( )ꢀ2, ( )ꢀ4, and ( )ꢀ6 in the presence of PPL, CCL,
and RSL makes this route to these propargyl CBB inefꢀ
fective. It is notable that the vicinity of the reaction site,
CHOR (R = H, Ac), and the conformationally rigid Ph
or PhC≡C groups in substrates ( )ꢀ1, ( )ꢀ3 and ( )ꢀ2,
( )ꢀ4 has an adverse influence on the rates of their EKR.
Meanwhile, substrates ( )ꢀ5 and ( )ꢀ6 in which one end
of the C≡C—CH(OR) triad is linked to a conformationꢀ
ally flexible group react relatively fast.
(η6ꢀArene)tricarbonylchromium complexes of subꢀ
strates ( )ꢀ5 and ( )ꢀ6 and their enzymatic kinetic resoluꢀ
tion. Due to the low rate of PPLꢀmediated hydrolysis of
acetates ( )ꢀ2 and ( )ꢀ4 (see Table 2) and the previously
noted14—16 decrease in the rate of enzymatic hydrolysis
and acylation of other aliphaticꢀaromatic substrates upon
transformation into (η6ꢀarene)tricarbonylchromium comꢀ
plexes, we studied the effect of η6ꢀcomplexation on the
enantioselectivity of the EKR only for alcohol 5 and acꢀ
etate 6. Attempted transformation of compounds ( )ꢀ5
and ( )ꢀ6 into the corresponding η6ꢀcomplexes ( )ꢀ11
and ( )ꢀ12 by heating the substrates with Cr(CO)6 acꢀ
cording to Pauson20 failed. Viscous polymers were formed
instead of η6ꢀcomplexes.
Regents and conditions: a. Cr(CO)6, (Bun)2O—THF (5 : 1),
~140 °C, Ar; b. MeOH—TsOH (cat.), 20—22 °C;
c. Me2CO—H2O (4 : 1, v/v), H2C2O4 (cat.), refluxing;
d. nꢀC6H13C≡CMgBr, Et2O, 20→35 °C.
The CCLꢀcatalyzed asymmetrization of alcohol
( )ꢀ11 by acylation with vinyl acetate in Et2O (~20 °C,
Ar) proceeded very slowly (the conversion C ≈ 22% was
attained in ~21 days) but it was much more enanꢀ
tioselective than the analogous EKR of alcohol ( )ꢀ5.
The isolated acetate (+)ꢀ12 (sample A) with [α]D +31.6
(CHCl3) was subjected to oxidative decomplexation by
treatment with iodine to give acetate (+)ꢀ6 with [α]D +29.5
(CHCl3), which was further saponified to alcohol (–)ꢀ5
with [α]D –26.4 (CHCl3). In the (R)ꢀMTPAꢀester II obꢀ
tained from this alcohol, the diastereomer ratio was
1
97.5 : 2.5 (dr ≥ 95, H and 19F NMR data). Hence, in
the sample of alcohol (–)ꢀ5, the ее value was ≥95%
(Scheme 3).
The repeated acetylation of the "residual alcohol" 11
under the same conditions to a degree of conversion
of 17% gave an additional amount of acetate (+)ꢀ12
(sample В) with [α]D +31.0 (CHCl3). Alcohol 11 remainꢀ
ing after the second EKR (sample 11B) had [α]D +2.8
(CHCl3). The oxidative decomplexation of alcohol 11В

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Russ.Chem.Bull., Int.Ed., Vol. 53, No. 3, March, 2004
Vlasyuk et al.
Scheme 3
Note. The values in parentheses are [α]D for solutions in CHCl3.
Reagents and conditions: a. H2C=CHOAc—CCL, Et2O, ~20 °C; b. I2, THF, 20 °C; c. KOH—MeOH, 20 °C.
with iodine resulted in a sample of alcohol (+)ꢀ5 with
[α]D +12.8 (CHCl3). This alcohol (sample (+)ꢀ5C)
was converted into (S)ꢀMTPA and (R)ꢀMTPA esters
((S)ꢀMTPA I″ and (R)ꢀMTPA III, respectively) with
nearly equal dr values (76:24 and 77:23), which implies
that in the sample (+)ꢀ5C, ее ~52%.*
Acetylation of alcohols ( )ꢀ5 and ( )ꢀ11 in the presꢀ
ence of CCL (see Table 1 and Scheme 3) has shown that
alcohol (–)ꢀ5 and its η6ꢀcomplex (–)ꢀ11 react more rapꢀ
idly. Thus, the transformation of the starting SPA ( )ꢀ5
into η6ꢀcomplex ( )ꢀ11 does not change the sense of
enantioselectivity of the EKR, whereas the coordination
of Cr(CO)3 to a primary aliphaticꢀaromatic alcohol15 has
resulted in its reversal.
Acetate ( )ꢀ12 was hydrolyzed in the presence of PPL
in a phosphate buffer (рH 7) up to a ∼75% conversion,
which took 30 days. The isolated alcohol fraction had
[α]D –0.5 (CHCl3). The residual acetate, i.e., TLCꢀpure
complex (–)ꢀ12, was subjected to oxidative decomꢀ
plexation to give acetate (+)ꢀ6 with [α]D +4.3, which
corresponds to ее ~16%. This ее value for C = 75% imꢀ
plies a very low enantioselectivity of the hydrolysis of
η6ꢀcomplex ( )ꢀ12 in the presence of PPL.
Absolute configuration of alcohols (+)ꢀ5 and (–)ꢀ5.
The configuration of these alcohols was determined on
the basis of regular features known for the 1H 17,21,22
and 19F NMR 21,23 spectra of their esters with (S)ꢀ or
(R)ꢀMosher´s acid. The δH and δF values for the signals of
each component in the spectra of MTPA esters, which
depend on the configuration of Mosher´s acid, the
dr values, and the corresponding ее values are summaꢀ
rized in Table 3.
1
In the H NMR spectra of the (S)ꢀMTPA esters of
alcohol (+)ꢀ5, the signal for the H atom at C(1) in the
major diastereomer occurs in a higher field, while the
signals for the H atoms at C(6) are in a lower field with
respect to the corresponding signals of the minor diasteꢀ
reomer; the MeO group is less shielded in the major diaꢀ
stereomer than in the minor component. In the 19F NMR
spectrum, the signal for the CF3 group of the major diasꢀ
tereomer is located in the lower field than that for the
minor diastereomer. These data altogether correspond to
the arrangement of the PhCH2CH2 and nꢀC5H11CH2C≡C
groups in the eclipsed conformation of the MTPA ester
(Fig. 1) in which the C(1) unit is shielded by the Ph group
of the acyl fragment, the C(6) unit lies outside the shieldꢀ
ing area, the CF3 group is coplanar with the neighboring
C=O group, and the CH3O group is not shielded by the
Ph group at C(1). Since according to the IUPAC rules,19
the nꢀC5H11CH2C≡C group is senior to the PhCH2CH2
group and, in addition, it has a greater calculated van der
Waals volume,24 the (S)ꢀMTPA ester I was identified as
having the 3S,2´Sꢀconfiguration and alcohol (+)ꢀ5, as
having the Sꢀconfiguration.
6
* It is notable that the η ꢀarene complex ( )ꢀ11 is acetylated in
the presence of CCL with somewhat higher enantioselectivity
than its precursor, secondary alcohol
(
)ꢀ5, whereas similar acetylation of
6
η ꢀcomplex of the primary alcohol
)ꢀ16 in the presence of CCL proꢀ
(
ceeds with lower enantioselectivity
than acetylation of its precursor, priꢀ
mary alcohol ( )ꢀ4ꢀ[HOCH2CH(Me)CH2]C6H4CO2Me.15
The 1H and 19F NMR spectra of the (R)ꢀMTPA ester
II obtained from alcohol (–)ꢀ5 contained virtually the

Lipaseꢀmediated deracemization of alcohols
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 3, March, 2004
697
Table 3. Diagnostic δ and δ signals in the spectra of binary esters formed by alcohol (+)ꢀ5 and (S)ꢀMosher´s acid chloride
H
F
((S)ꢀMTPA I, I´, I″) and binary esters formed by alcohols (–)ꢀ5 and (+)ꢀ5 and (R)ꢀMosher´s acid chloride ((R)ꢀMTPA II and
(R)ꢀMTPA III)
20 a
c
d
Starting
alcohol
[α]D
MTPA ester
δ
δ
The ее value in the
H
F
(configuration)b
starting alcohol (%)e
С(1)Н2
С(6)Н2
С(2´)ОМе (s)
3.62 ≥ 3.58
(+)ꢀ5A
(+)ꢀ5B
(+)ꢀ5C
(+)ꢀ5C
(–)ꢀ5
+5.3f
(S)ꢀMTPA I
(3S, 2´S)
2.66 (m)
2.70 (m)
2.10 (br.m)
2.07 (m)
–71.20
–71.52
(60 : 40)
–71.19
–71.52
(57.5 : 42.5)
–71.20
–71.51
(76 : 24)
–71.48
–71.18
(76 : 24)
–71.16
∼20
+3.8
+12.8
+12.8
–26.4
(S)ꢀMTPA I´
(3S, 2´S)
Not determined
∼15
(S)ꢀMTPA I´´
(3S, 2´S)
2.66 (m)
2.70 (m)
2.10 (br.m)
2.07 (m)
3.62 (∼2.3 H)
3.58 (∼0.7 H)
∼52 (∼54)
52 (∼54)
∼95 (∼94)
(R)ꢀMTPA III
(3S,2´R)
2.70 (br.m)
2.67 (m)
2.07 (br.m)
2.10 (m)
3.58 (∼2.3 H)
3.63 (∼0.7 H)
(R)ꢀMTPA II
(3R, 2´R)
2.67 (br.m)
∼2.70 (m)g
2.10 (br.m)
2.08 (m)g
3.63 (∼2.9 H)
3.59 (∼0.1 H)
–71.50
(97.5 : 2.5)
Note. CDCl3 as the solvent; temperature for recording the spectra, 274 K.
a The specific rotations were determination for solutions in CDCl3 (c 0.3—1.0).
b Configuration of the major diastereomer.
c The signals from the predominant component are underlined.
d The values in parentheses are the intensity ratios for the CF3 peaks.
e The values in parentheses are the ее values calculated from the ratio of the integral intensities of the signals from the methoxy groups.
The values in parentheses are the multiplicity and the integral intensity; the signals from the major component are underlined.
22
f [α]D
.
g The signals from the minor MTPA ester barely differ from the base line noise in the spectrum.
same signals as those of the (S)ꢀMTPA esters I and I″ (see
Table 3 and Fig. 1); the difference was only in dr values.
This means that the (R)ꢀMTPA ester II is the antipode to
the major diastereomer in the (S)ꢀMTPA esters I and I″.
Hence, the (R)ꢀMTPA ester II has the 3R,2´Rꢀconfiguraꢀ
tion and alcohol (–)ꢀ5, Rꢀconfiguration.
minor diastereomer by 0.08 and 0.5 ppm, respectively.
The chelate formed by the Eu ion with the predominant
component of the (R)ꢀMTPA ester II is sterically less
hindered (more stable) than the chelate formed by the
minor component, and, hence, the OMе group is
deshielded more appreciably in the former case.
This is confirmed by the 19F NMR spectra of MTPA
esters. The signal of the CF3 group of the major compoꢀ
nent in the spectrum of (R)ꢀMTPA ester III occurs in the
higher field than the signals of the CF3 groups of the
major components of (S)ꢀMTPA ester I or (R)ꢀMTPA
ester II. This is typical of the 19F NMR spectra of MTPA
esters with different absolute configurations of the alꢀ
cohol and the acyl moieties,21,23 and in the case of
(R)ꢀMTPA ester III, it confirms the Sꢀconfiguration of
the alcoholic fragment.
∆δ OMe = 1.72
H
The same conclusion can be drawn from determinaꢀ
tion of the configurations of alcohols (+)ꢀ5 and (–)ꢀ5
from the Eu(fod)3ꢀinduced shifts of the signals for the
MеO group in the 1H NMR specrta.21,25 In the 1H NMR
spectra of (R)ꢀMTPA ester II recorded in the presence of
0.25—0.5 equiv. of Eu(fod)3, the downfield shifts of the
singlet for the MеO group in the major diastereomer (∆δ)
are greater than those of the corresponding signal in the
∆δ OMe = 1.22
H
The lipases CCL, PPL, and RSL proved ineffective
for the production of CBB from SPA of types ( )ꢀ1 and

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Russ.Chem.Bull., Int.Ed., Vol. 53, No. 3, March, 2004
Vlasyuk et al.
ously14—16 for the primary alcohol, occurred in this case.
Unfortunately, due to the difficulty of direct transformaꢀ
tion of propargylic substrates like ( )ꢀ5 into complexes
( )ꢀ11 and low rates of the EKR of these complexes, this
route is not attractive from the preparative standpoint.
Experimental
All boiling and melting points were not corrected. The 1H and
13C NMR spectra were recorded on a Bruker AMꢀ300 instruꢀ
ment, and 19F NMR spectra were run on a Bruker ACꢀ200
spectrometer (with FCCl3 as the standard) in CDCl3 at 20 5 °C.
IR spectra were measured for solutions in CHCl3 (unless stated
otherwise) on a Specord IRꢀ80 instrument at 20—22 °C. The
[α]D values were determined on a JASCOꢀDIP 360 polarimeter
for solutions in CHCl3. The completeness of the reactions and
the product purity were estimated by TLC on Silufol UV 254
plates, the spots being visualized by I2 vapor and/or a solution of
KMnO4. Column chromatography was carried out on a neutral
silica gel (Fluka, 0.04—0.06 mm). Powders of the PPL (Serva,
14 U mg–1), CCL (Fluka, 2.3 U mg–1), and RSL (Serva) were
stored at –16 2 °C and, prior to use, they were maintained
at a constant temperature in a vacuum block. (S)ꢀ and
(R)ꢀαꢀMethoxyꢀαꢀtrifluoromethylphenylacetyl
chlorides
(MTPAꢀCl) were prepared from (R)ꢀ and (S)ꢀMosher´s acid
(Fluka) without special purification. Liquid reagents and solꢀ
vents (including H2O) were distilled prior to use and purified by
the procedures recommended in the handbook.27
(
)ꢀ1ꢀPhenylnonꢀ2ꢀynꢀ1ꢀol (( )ꢀ1). A solution of EtBr
(8 mL, 11.4 g, 0.105 mol) in 30 mL of anhydrous Et2O was
added with stirring under argon to magnesium chips (2.42 g,
0.101 mol). Then a solution of octꢀ1ꢀyne (7) (10.4 mL, 7.72 g,
0.070 mol) in 30 mL of anhydrous Et2O was added to the resultꢀ
ing EtMgBr, and the reaction mixture was stirred until the evoꢀ
lution of ethane ceased (2 h). A solution of PhCHO (7.1 mL,
7.42 g, 0.070 mol) in 20 mL of anhydrous Et2O was added to the
resulting Jocic´ reagent over a period of 45 min, and the mixture
was refluxed for 30 min and left for 16 h. The yellowish suspenꢀ
sion was diluted with Et2O (20 mL) and mixed with a cold
solution of NH4Cl (10 g) in 100 mL of water. The colored upper
layer and the ethereal extracts from the aqueous layer (3×25 mL)
were combined, washed with saturated brine (3×25 mL), dried
(Na2SO4), and concentrated in vacuo (40 °C (bath) (35 Torr)).
The residue was fractionated in vacuo (0.5 Torr). After evaporaꢀ
tion of volatile impurities (b.p. 77—78 °C), alcohol ( )ꢀ1 was
isolated as a yellowish oil with b.p. 130—132 °C (0.5 Torr) and
Rf 0.65 (hexane—Et2O, 3 : 1). The yield was 8.18 g (54%).
1H NMR, δ: 0.91 (narrow m, 3 H, Me); 1.36—1.62 (m, 8 H);
2.03 (m, 2 H, C(4)H2); 4.28 (narrow m, 1 H, C(1)H2); 4.60
Fig. 1. Diagnostic signals δ and δ of the major isomers of
H
F
MTPA esters. The "mirror" configurations of the major diastereꢀ
omers in binary MTPA esters, (S)ꢀMTPA I and (R)ꢀMTPA II,
are manifested in the coinciding δ and δ values for the diagꢀ
H
F
nostic signals in their NMR spectra (see Table 3).
( )ꢀ3 in which the reaction center (CHOH, CHOAc)
adjoins bulky, conformationally rigid Ph or PhC≡C groups.
An increase in the distance between the Ph and CHOH
groups in alcohol ( )ꢀ5 and the higher conformational
flexibility of its molecule enhance only slightly the effiꢀ
ciency of the EKR. A multiple increase in the enantioꢀ
selectivity of the enzymatic deracemization of the secꢀ
ondary aliphaticꢀaromatic alcohol was attained for the
first time by performing the reaction for the correspondꢀ
ing (η6ꢀarene)tricarbonylchromium complex;* moreover,
no reversal of the process enantioselectivity, noted previꢀ
(br.s, 1 H, OH); 7.22—7.46 (m, 3 H and 2 H, Ph). IR, ν/cm–1
:
* Before publication of the studies of our research group,14,15 all
3340 m (OH), 355 and 3030 w (ArH), 2215 w (C≡C), 1610 m
6
examples of lipaseꢀmediated deracemization of (η ꢀarene)triꢀ
(C=C), 1040 s (C—O). The 1H NMR and IR spectra of alcohol
carbonylchromium complexes of aliphaticꢀaromatic alcohols
referred to objects with a planar asymmetry, which arises upon
haptoꢀcomplexation of orthoꢀ or metaꢀdisubstituted arenes with
(
)ꢀ1 were similar to those reported previously.6a
(
)ꢀ1ꢀPhenylheptꢀ1ꢀynꢀ3ꢀol (( )ꢀ3). A solution of phenylꢀ
acetylene (8) (3.8 mL, 3.53 g, 0.035 mol) in 10 mL of Et2O was
added to a solution of EtMgBr prepared from Mg (0.92 g,
0.038 mol) and EtBr (3.2 mL, 4.6 g, 0.042 mol) in 25 mL of
Et2O, and the reaction mixture was brought to gentle boiling,
which was maintained for 2 h. A solution of pentanal (9)
(2.47 mL, 2.07 g, 0.024 mol) in 4.5 mL Et2O was added over a
6
Cr(CO)3.26 Even in the case of η ꢀarene complex formed by
(
)ꢀ1ꢀ(2ꢀmethoxyphenyl)ethanol (a mixture of four diastereoꢀ
mers),26c the high selectivity of its EKR was due to the planar
asymmetry rather than to the presence of the asymmetric center
in the side chain.

Lipaseꢀmediated deracemization of alcohols
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 3, March, 2004
699
period of 45 min, and the mixture was refluxed for an additional
30 min, quenched with a cold solution of NH4Cl (40 mL), and
extracted with Et2O (75 mL). The ethereal extract was washed
with brine and dried (MgSO4), and the ether was evaporated
in vacuo. The residue (4.04 g) was fractionated in vacuo. The
fraction with b.p. 30—50 °C (8 Torr) contained the excess 8,
while the major fraction (b.p. 119—121 °C (1 Torr)), a yellow
( )ꢀ1ꢀPhenylnonꢀ2ꢀynꢀ1ꢀol acetate (( )ꢀ2), yield 97%,
Rf 0.74 (hexane—AcOEt, 85 : 15). 1H NMR, δ: 0.89 (narrow m,
3 H, Me); 1.35—1.70 (m, 8 H); 2.04 (s, 3 H, COMe); 2.11 (m,
2 H, C(4)H2); 5.12 (narrow m, 2 H, C(1)H2); 7.22—7.46 (m,
3 H, 2 H, Ph). IR, ν/cm–1: 3350 and 3030 w (ArH); 2235 w
(C≡C), 1742 s (C=O); 1610 m (C=C).
(
)ꢀ1ꢀPhenylheptꢀ1ꢀynꢀ3ꢀol acetate (( )ꢀ4), yield 98.5%,
20
20
20
oil with a "fat" smell (nD 1.5290) that crystallized on storage
yellowish oil, nD 1.5125 (cf. Ref. 27a: nD 1.5117), Rf 0.68
(hexane—AcOEt, 9 : 1). 1H NMR, δ: 0.91 (t, Me, 3J = 7.0 Hz);
1.35—1.67 (m, 4 H); 1.85—1.9 (m, 2 H, C(4)H2); 2.10 (s, 3 H,
COMe); 5.12 (t, C(3)H, 3J = 5.8 Hz); 7.28—7.36 and 7.45—7.48
(both m, 3 H and 2 H, Ph). IR (film), ν/cm–1: 3350 and 3040 w,
2230 (C≡C), 1742 s (C≡O); 1600 m, 1055 s.
as needles, represented pure alcohol ( )ꢀ3 with Rf 0.49
(hexane—AcOEt, 5 : 1) (cf. Ref. 28a: b.p. 144 °C (1 Torr),
20
1
nD 1.5298). The yield was 2.75 g (63%). H NMR, δ: 0.96 (t,
Me, 3J = 7.0 Hz); 1.35—1.56 (m, 4 H); 1.81—1.90 (m, 2 H,
C(4)H2); 4.61 (t, C(3)H, 3J = 5.8 Hz); 5.10 (narrow m, 1 H,
OH); 7.28—7.36 and 7.45—7.48 (both m, 3 H and 2 H, Ph). IR
(film), ν/cm–1: 3360 m (OH), 3370 and 3040 w (ArH); 2230
(C≡C), 1605 m (C=C), 1030 s (C—O). The 1H NMR and
IR spectra of alcohol ( )ꢀ3 are similar to those described
previously.28b,c
1ꢀPhenylundecꢀ4ꢀynꢀ3ꢀol acetate (( )ꢀ6), yield 94%, Rf 0.68
1
(hexane—AcOEt, 85 : 15). H NMR, δ: 0.93 (t, 3 H, Me, 3J =
6.7 Hz); 1.25—1.40 (m, 6 H, C(10)H2—C(8)H2); 1.56—1.65
(dt, 2 H, C(2)H2, 3J = 6.2 and 6.8 Hz); 2.03 (s, 3 H, COMe);
2.10 (t, 2 H, C(6)H2, 3J = 7.0 Hz); 2.20 (dt, C(2)H2, 3J =
6.4 and 5.6 Hz); 2.75 (dt, 2 H, C(1)H2, 3J = 6.4 Hz, 4J ≈
1.0 Hz); 5.35 (m, 1 H, C(3)H); 7.22—7.39 (m, 3 H and 2 H,
PhH). 13C NMR, δ: 14.15, 18.79, 22.65, 28,63, 28.73, 31.42,
31.58, 39.75, 62.15, 81.04, 86.15, 125.94, 128.44, 128.52, 141.56,
170.97. IR, ν/cm–1: 3050 and 3040, 2230, 1740, 1620.
(3,3ꢀDimethoxypropyl)benzene (14). Neat TsOH•H2O
(0.10 g) was added to a solution of hydrocinnamaldehyde 10
(2.5 g, 18.7 mmol) in 40 mL of anhydrous MеOH under argon.
The reaction mixture was stirred at 20 °C, the course of the
reaction being monitored by TLC (hexane—AcOEt, 5 : 1, v/v);
after 4 h, the starting aldehyde 10 was completely converted into
acetal 14. The catalyst was neutralized by adding КOH powder
to рH 8. Methanol was evaporated in vacuo and the residue was
washed with dry Et2O (3×5 mL), the precipitate being separated
by decantation. The combined ethereal extract was concenꢀ
trated (40 °C (bath) (10 Torr)) and the residue was distilled at
96 °C (1 Torr) to give pure acetal 14 as a light oil with a sharp
1ꢀPhenylundecꢀ4ꢀynꢀ3ꢀol (( )ꢀ5) was prepared similarly to
alcohols ( )ꢀ1 and ( )ꢀ3. A solution of 14 mL of octꢀ1ꢀyne (7)
(10.47 g, 0.095 mol) in 16 mL of Et2O was added dropwise to a
solution of EtMgBr prepared from Mg (2.51 g, 0.105 mol) and
EtBr (8.8 mL, 12.55 g, 0.115 mol) in 20 mL of Et2O, and the
reaction mixture was gently refluxed for 2 h. When the mixture
was cooled to ~25 °C, a fine precipitate was formed, whose
dissolution required stirring under reflux for an additional 45 min.
Then a solution of hydrocinnamaldehyde (10) (8.50 g, 0.063 mol)
in 20 mL of Et2O was added and the mixture was stirred for
30 min at 20—25 °C and for 30 min under reflux, and was kept
for 16 h at 4—6 °C. Then ∼50 mL of crushed ice and 100 mL of a
saturated solution of NH4Cl were added. The organic layer was
separated, the aqueous layer was extracted with Et2O (4×25 mL),
and the combined organic phase was washed with a saturated
solution of NaHCO3 (2×25 mL) and brine (3×25 mL), dried
(Na2SO4), and concentrated in vacuo. The residue (oil, 10.8 g)
was fractionated on a column with SiO2 in the hexane—Et2O
system (9 : 1, v/v). The fraction with Rf 0.49 (hexane—AcOEt,
5 : 1), a colorless oil, represented alcohol ( )ꢀ5. The yield was
9.19 g (59.3%). Found (%): C, 83.27; H, 10.06. C17H24O. Calꢀ
culated (%): C, 83.55; H, 9.90. 1H NMR, δ: 0.91 (narrow m,
3 H, Me); 1.23—1.41 (m, 6 H, 3 CH2); 1.46—1.63 (m, 2 H
C(7´)H2); 2.07 (m, 2 H, C(6)H2); 2.20 (m, C(2)H2); 2.68 (dt,
2 H, C(1)H2, 3J = 6.4 Hz, 4J = 0.8 Hz); 4.25 (s, 1 H, OH); 4.40
(dt, 2 H, C(3)H2, 3J = 5.6 Hz, 5J ≈ 0.7 Hz); 7.22—7.39 (m, 5 H,
PhH). 13C NMR, δ: 14.15 (Mе), 18.79, 22.65, 28,63, 28.73,
31.42, 31.58, 39.75 (7 CH2), 62.15 (HCOH), 81.04 and 86.15
22
23
smell, nD 1.4879 (cf. Ref. 29: nD 1.4890). The yield was
2.92 g (87%). 1H NMR, δ: 1.97 (m, 2 H, C(2)H2); 2.72 (t, 2 H,
C(1)H2, 3J = 6.7 Hz); 3.37 (s, 6 H, 2 MeO); 4.42 (t, 1 H,
C(3)H, 3J = 5.7 Hz); 7.20—7.38 (m, 5 H, Ph).
6
(
)ꢀ[η ꢀ(3,3ꢀDimethoxypropyl)benzene]tricarbonylchromium
(15). Acetal 14 (0.74 g, 4.11 mmol), anhydrous diꢀnꢀbutyl ether
(10 mL), anhydrous THF (2 mL), and chromium hexacarbonyl
(1.0 g, 4.5 mmol) were placed in an argonꢀfilled flask. The
mixture was refluxed under Ar (~140 °C) for 50 h, the sublimed
Cr(CO)6 being returned periodically into the flask. The content
of the flask was cooled down to ~40 °C (bath) and concentrated
in vacuo, the greenishꢀbrown residue was triturated with Et2O
(3×10 mL), and the extract was decanted off and mixed with a
small amount of SiO2. The solvent was evaporated in vacuo and
the residue was applied onto a column with SiO2. Elution with
hexane—Et2O mixtures (5 : 1 and 4 : 1, v/v) yielded chromium
complex 15 as a brightꢀyellow oil, which rapidly crystallized
when stored under argon, m.p. 53—54 °C (hexane—Et2O, 2 : 1).
Yield 1.09 g (84%). 1H NMR, δ: 2.45 (pseudoq, 2 H, C(2)H2,
3J = 6.7 Hz); 2.88 (m, 2 H, C(1)H2); 3.35 (s, 6 H, 2 MeO); 4.42
(C≡C), 125.94, 128.44, 128.52, and 141.56 (Ph). IR, ν/cm–1
:
3590 m (OH), 3070 and 3040 w (ArH), 2230 w (C≡C), 1605
(C=C), 1050 s (C—O).
Acetylation of alcohols ( )ꢀ1, ( )ꢀ3, and ( )ꢀ5 (general proꢀ
cedure). 4ꢀDimethylaminopyridine (0.4—1 mmol) was added to
a solution of a substrate (4—10 mmol) in a mixture of anhydrous
Ac2O (8—20 mmol), anhydrous Pу (4—10 mmol), and hexane
(10—25 mL). The mixture was left for 48 h at 18—25 °C and
stirred with cold 10% HCl (3×5 min). The upper layer was
washed with a 10% solution of NaHCO3 (3 times) and water
(3 times), dried (Na2SO4), and concentrated in vacuo. Accordꢀ
ing to TLC data and 1H NMR and IR spectra, all products (pale
yellow oils) were free from the starting compounds or side prodꢀ
ucts; they were used in subsequent operations without addiꢀ
tional purification.
6
(t, 1 H, C(3)H, 3J = 5.7 Hz); 5.20 (m, 3 H, A3В2 system, η ꢀarene
6
fragment В); 5.38 (m, 2 H, A3В2 system, η ꢀarene fragment A).
6
[η ꢀ(3ꢀOxopropyl)benzene]tricarbonylchromium (13). A soꢀ
6
lution of η ꢀcomplex ( )ꢀ15 (2.0 g, 6.33 mmol) in 40 mL of
acetone was placed in an argonꢀfilled flask. Water (10 mL) and
oxalic acid (H2C2O4•2H2O) (1.0 g, 7.9 mmol) were added. The

700
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 3, March, 2004
Vlasyuk et al.
mixture was refluxed, the course of the reaction being moniꢀ
tored by TLC (hexane—AcOEt, 3 : 1, visualization by I2 vapor).
The reaction was complete in 2.5 h. The reaction mixture was
cooled and neutralized with solid NaHCO3 (1.68 g, 20 mmol)
with stirring. The precipitated salts were filtered off and washed
with acetone. The filtrate and the acetone washings were comꢀ
bined and concentrated in vacuo. The remaining aqueous
emulsion was saturated with NaCl and extracted with AcOEt
(3×25 mL). The extract was dried (Na2SO4) and concentrated
to a constant weight at 45 °C (bath) (10 Torr) to give aldehyde
13 (TLC and 1H NMR data) as a darkꢀyellow oil, which was
used in the next synthetic step without further purification. The
yield was 1.70 g (≥95%). 1H NMR, δ: 2.72 (td, 2 H, C(2)H2,
J = 6.2 and 1.1 Hz*); 2.80 (dd, 2 H, C(1)H2, J = 6.2 and
Et2O, and the mixture was stirred at 18—23 °C for 507 h (21 day),
the course of the reaction being monitored by TLC. The lipase
was separated from the liquid phase by filtering the reaction
mixture through Florisil® (4 g). The filtrate was concentrated
in vacuo (40 °C (bath) (10 Torr) and the reaction products were
separated on a column with SiO2 using a hexane—Et2O mixture
(2 : 1, v/v) as the eluent. Complex (R)ꢀ12 (sample A) was formed
as a yellow oil with Rf 0.75 (hexane—AcOEt, 2 : 1) and
[α]D25 +31.6 (c 1.0). The yield was 48.6 mg (21.9%). 1H NMR*,
δ: 0.91 (t, 3 H, Me, 3J = 6.7 Hz); 1.20—1.41 (m, 6 H, 3 CH2);
1.45—1.60 (m, 2 H, C(7)H2); 1.99 (m, 2 H, C(2)H2); 2.08 (s,
3
3 H, COMe); 2.23 (dt, 2 H, C(6)H2, J = 6.7 Hz, 5J ≈ 0.9 Hz);
2.57 (dt, 2 H, C(1)H2, 3J = 6.7 Hz, 4J = 0.7 Hz); 5.18—5.23 (m,
6
3 H, A3В2 system, η ꢀarene fragment В); 5.32—5.48 (m,
6
∼0.8 Hz); 5.23 (m, 3 H, A3В2 system η ꢀarene fragment В); 5.39
1 H + 2 H, superposition of the signal from HCOAc onto the
6
6
(m, 2 H, A3В2 system, η ꢀarene fragment A with J = 6.5 Hz);
signal of two protons of the η ꢀarene fragment A). IR, ν/cm–1
:
9.83 (br.s, 1 H, C(3)H, J = 1.1 Hz). IR (film), ν/cm–1: 1975 and
2230 w (C≡C), 1980 and 1955 m.ꢀs ((η ꢀArH)•Cr(CO)3), 1735 s
(C=O), 1600, 1235 s (C—O). Further elution gave the fraction
of recovered alcohol 11 (138 mg, 69%).
6
6
1960 [m.ꢀs, (η ꢀArH)•Cr(CO)3], 1870, 1725 (s, CH=O). The
1H NMR and IR spectral data almost coincided with those
reported previously.30
(R)ꢀ(+)ꢀ3ꢀAcetoxyꢀ1ꢀphenylundecꢀ4ꢀyn (or 1ꢀphenylundecꢀ
4ꢀynꢀ3(R)ꢀol acetate) ((R)ꢀ6). Crystalline I2 (38 mg, 0.149 mmol)
was added under Ar to a solution of acetate (R)ꢀ12A (42.2 mg,
0.10 mmol) in 1.0 mL of anhydrous THF and the mixture was
stirred for 30 min. During this period, the complex (R)ꢀ12 comꢀ
pletely disappeared (TLC data). The excess of I2 was reduced by
1.5 mL of a saturated solution of Na2S2O3 (the brown color
changed to darkꢀgreen). The reaction mixture was extracted
with Et2O (3×3 mL), the extract was washed with a saturated
solution of Na2S2O3 and brine (2×2 mL), every aqueous layer
obtained after extraction being washed once more with 1 mL of
ether. The total ethereal extract was dried (Na2SO4), the solvent
was evaporated in vacuo to give pure acetate (R)ꢀ6 as a pale
6
(
)ꢀ[η ꢀ(3ꢀHydroxyundecꢀ4ꢀynꢀ1ꢀyl)benzene]tricarbonylꢀ
chromium (( )ꢀ11). Magnesium (100 mg, 4.16 mmol), anhydrous
Et2O (10 mL), and a crystal of I2 were placed in an argonꢀfilled
flask. The mixture was stirred until the color of iodine disapꢀ
peared, EtBr (0.10 mL) was added, and, when the formation of
EtMgBr started (the mixture became turbid), an additionaol
portion of EtBr (0.24 mL) was added (total amount, 0.34 mL,
4.98 mmol). When magnesium completely dissolved, a solution
of octꢀ1ꢀyne (7) (0.56 mL, 416 mg, 3.78 mmol) in 3 mL of
anhydrous Et2O was added to the EtMgBr formed. The reaction
mixture was stirred under reflux until the evolution of ethane
ceased (2.5 h) and cooled to 20 °C, and a solution of aldehyde 13
(0.680 g, 2.52 mmol) in 5 mL of anhydrous Et2O was added. The
mixture was refluxed and stirred for an additional 0.5 h, cooled
to ~20 °C, and left for 18 h. Crushed ice (5 mL) and a saturated
aqueous solution of NH4Cl (25 mL) were added with stirring at
0—5 °C. The aqueous layer was separated and extracted with
Et2O (3×10 mL). The organic layer and the ethereal extract
were combined, washed with brine (4×15 mL), dried (Na2SO4),
and concentrated in vacuo. The residue (oil, 0.9 g) was chromatoꢀ
graphed on a column with SiO2 (40 g) in a hexane—AcOEt
gradient (95 : 5 → 75 : 25, v/v). Elution with a hexane—AcOEt
mixture (4 : 1) gave pure alcohol ( )ꢀ11 as a thick yellow oil
with Rf 0.80 (hexane—AcOEt, 1 : 1) or 0.62 (hexane—AcOEt,
2 : 1). The yield was 0.721 g (75%). 1H NMR*: 0.90 (t, 3 H, Me,
3J = 6.8 Hz); 1.31—1.43 (m, 6 H, 3 CH2); 1.54 (m, 2 H, C(7)H2);
1.95 (m+s, 3 H, overlap of C(2)H2 and OH); 2.22 (dt, 2 H,
C(6)H2, J = 6.7 Hz, J ≈ 0.8 Hz); 2.57 (dt, 2 H, C(1)H2, J =
6.7 Hz, J ≈ 0.8 Hz); 4.12 (m, 1 H, C(3)H, J = 5.7 Hz); 5.17—5.23
25
yellow oil with [α]D +29.5 (c 0.63). The yield was 36 mg
(94.8%). The Rf value and the 1H NMR spectrum of acetate
(R)ꢀ6 were virtually identical to those of acetate ( )ꢀ6 (see
above).
(R)ꢀ(–)ꢀ1ꢀPhenylundecꢀ4ꢀynꢀ3ꢀol ((R)ꢀ5). Powdered potasꢀ
sium hydroxide (10 mg, 0.178 mmol) was added to a solution of
acetate (R)ꢀ6 (50 mg, 0.175 mmol) in a mixture of anhydrous
MеOH (3 mL) and anhydrous hexane (1 mL), and the mixture
was stirred for 20 min (TLC monitoring, hexane—AcOEt, 10 : 1).
The reaction mixture was neutralized to рH 7 with glacial AcOH.
The solvents were evaporated (50 °C (bath) (5 Torr), water
(1.5 mL) was added to the residue to dissolve the precipitated
salts, and the aqueous emulsion was extracted with Et2O
(3×5 mL). The combined extracts were dried (Na2SO4) and
concentrated in vacuo to a constant weight to give alcohol (R)ꢀ5
(TLC data and 1H NMR spectra) as a thick paleꢀyellow oil with
[α]D20 –26.4 (c 1.0). The yield was 40.1 mg (89%).
6
(m, 3 H, A3В2 system, η ꢀarene fragment В); 5.36—5.42 (m,
(S)ꢀ(+)ꢀ1ꢀPhenylundecꢀ4ꢀynꢀ3ꢀol ((S)ꢀ5). Method 1. The
fraction of scalemic alcohol 11 (138 mg) that has not entered
into the CCLꢀmediated acetylation of alcohol ( )ꢀ11 (see above)
was subjected to the repeated EKR under identical conditions.
Incubation under argon for 600 h followed by the conventioinal
workup and separation of the products on a column with
SiO2 gave additional 26.2 mg (17%) of acetate (R)ꢀ12B with
6
2 H, A3В2 system, η ꢀarene fragment A). 13C NMR, δ: 14.12,
18.74, 22.60, 28.63, 30,76, 31,36, 39.14, 61.66 (CHOH), 80.36
and 90.48 (C≡C), 92.65, 92.73, 93.82, and 112.97 (Ph), 177.02
(Cr…CO). IR, ν/cm–1: 3565 m (OH), 2230 w (C≡C), 1980 and
6
1955 m.ꢀs ((η ꢀArH)•Cr(CO)3), 1600 (C=C), 1040 s (C—O).
6
(R)ꢀ(+)ꢀ[η ꢀ(3ꢀAcetoxyundecꢀ4ꢀynꢀ1ꢀyl)benzene]tricarboꢀ
22
nylchromium ((R)ꢀ12). Freshly distilled vinyl acetate (0.146 mL,
137 mg, 1.90 mmol) and 200 mg of CCL were added under Ar to
a solution of alcohol ( )ꢀ11 (200 mg, 0.53 mmol) in 5 mL of dry
[α]D +31.0 (c 1.0) and 93 mg (81.2%) alcohol (S)ꢀ11 as a
22
bright yellow oil, [α]D +2.8 (c 0.82). Under argon, crystalꢀ
line I2 (76 mg, 0.3 mmol) was added to a solution of alcohol
(S)ꢀ11 (84 mg, 0.2 mmol) in 3 mL of anhydrous THF and the
reaction mixture was stirred until (S)ꢀ11 completely disappeared
* Apparent spinꢀspin coupling constants.

Lipaseꢀmediated deracemization of alcohols
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 3, March, 2004
701
(TLC monitoring, 25 min). The excess of I2 was reduced with a
saturated solution of Na2S2O3. The mixture was extracted with
Et2O and the extract was washed with a saturated solution of
NaHCO3 (2×2 mL) and brine (3×2 mL). The total ethereal
extract was dried (Na2SO4) and concentrated in vacuo to give
alcohol (S)ꢀ5 as a pale yellow oil, [α]D20 +12.8 (c 0.6). The yield
was 54 mg (87.5%). The Rf value and 1H NMR data for alcohol
(S)ꢀ5 were virtually identical to those of alcohols ( )ꢀ5 and
(R)ꢀ5. (see above)
and (3R,2´S)ꢀMTPA ester (minor component), designated as
(S)ꢀMTPA ester I″. The yield was 85 mg (93%).
Similarly, acylation of alcohol (R)ꢀ5 with ее ≥95% with
(R)ꢀMosher´s acid chloride ((S)ꢀMTPAꢀCl) gave a binary mixꢀ
ture of ester (3R,2´R)ꢀMTPA and ester (3R,2´S)ꢀMTPA, desigꢀ
nated as (R)ꢀMTPAꢀester II, while the reaction of alcohol (S)ꢀ5
gave a binary mixture of ester (3S,2´R)ꢀMTPA (major compoꢀ
nent) and (3S,2´R)ꢀMTPA ester (minor component), designated
as ester (R)ꢀMTPA III. Both binary esters are lightꢀyellow oils.
The 1H NMR spectra of ester (S)ꢀMTPA I, ester (R)ꢀMTPA II,
and ester (R)ꢀMTPA III are qualitatively similar to each other
Method 2. Vinyl acetate (10 mL, 95 mg, 1.11 mmol) and
90 mg of the CCL were added to a solution of alcohol ( )ꢀ5
(90 mg, 0.37 mmol) in 3 mL of anhydrous Et2O. The reaction
mixture was vigorously stirred at 20—22 °C for 144 h. The lipase
was filtered through a layer of Celiteꢀ539® (60—80 mesh), the
filtrate was concentrated in vacuo, and the resulting product
mixture was chromatographed on a column with SiO2 in the
hexane—Et2O gradient (100 : 0 → 90 : 10). The isolated fracꢀ
tions were acetate 6 (60 mg, 57%) and unconsumed alcohol
and to the spectra of acetates (R)ꢀ6 and (S)ꢀ6. The δ and
H
δ
F values essential for the determination of the absolute configuꢀ
ration of the alcohol residues in these MTPA esters are preꢀ
sented in Table 3.
Complexation with Eu(fod)3. The absolute configurations
of the major and minor components in esters (R)ꢀMTPA II
and (R)ꢀMTPA III were determined according to known
methods.21,24
20
(S)ꢀ5 with Rf 0.51 (hexane—AcOEt, 9 : 1) and [α]D +5.3
(c 1.0). The yield was 37.1 mg (41%), which corresponds to a
∼58% conversion of alcohol ( )ꢀ5.
The authors are grateful to A. A. Vasil´ev (N. D.
Zelinsky Institute of Organic Chemistry, Russian Acadꢀ
emy of Sciences) for his interest in this study and valuable
advices.
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 02ꢀ03ꢀ33348)
and by President of the Russian Federation (Program for
the Support of Leading Scientific Schools, Projects
00ꢀ15ꢀ97347 and NShꢀ1802.2003.3).
Method 3. Acetate ( )ꢀ6 (200 mg) and a PPL powder
(400 mg) were added to 5 mL of 0.1 M aqueous phosphate buffer
with рH 6.5. The mixture was vigorously stirred at 20—23 °C for
168 h. The lipase was filtered off through a layer of Celiteꢀ539®.
The filtrate, a whitish emulsion, was extracted with ether
(3×3 mL), the total extract was washed with brine, dried
(Na2SO4), and concentrated in vacuo. The residue was chroꢀ
matographed on a column with SiO2. Elution with a hexꢀ
ane—Et2O mixture (9 : 1) gave the fraction of recovered acꢀ
etate 6 (110 mg, 55%) followed by the fraction of alcohol (S)ꢀ5
20
References
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The efficiency of enzymatic kinetic resolution of alcohols into
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Received January 20, 2004;
in revised form March 10, 2004