New ways to determine the absolute configurations of alkyl 6-R-cyclohexa-1,3-dienecarboxylates

Article abstract of DOI:10.1023/A:1023987613185

Two new methods for the determinatuion of the absolute configuration of methyl 4-methyl-6-(2-methylprop-1-enyl)cyclohexa-1,3-dienecarboxylate are proposed, and the configurations attributed previously to its (+)- and (-)-enantiometers are confirmed. Chira

Full text of DOI:10.1023/A:1023987613185

734
Russian Chemical Bulletin, International Edition, Vol. 52, No. 3, pp. 734—739, March, 2003
New ways to determine the absolute configurations
of alkyl 6ꢀRꢀcyclohexaꢀ1,3ꢀdienecarboxylates*
ꢀ
E. P. Serebryakov, M. A. Shcherbakov, G. D. Gamalevich, and M. I. Struchkova
N. D. Zelinsky Institute of Organic Chemistry of the Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (095) 135 5328.
Two new methods for the determinatuion of the absolute configuration of methyl 4ꢀmethylꢀ
6ꢀ(2ꢀmethylpropꢀ1ꢀenyl)cyclohexaꢀ1,3ꢀdienecarboxylate are proposed, and the configurations
attributed previously to its (+)ꢀ and (–)ꢀenantiometers are confirmed. Chiral methyl carboxyꢀ
late is converted into the corresponding alcohol whose configuration is deduced from either the
rate of hydrolysis of the respective racemic acetate in the presence of pancreatic lipase (method 1)
or from the difference between the Eu(fod)3ꢀinduced shifts of the MeO signals in the 1H NMR
spectra of the diastereomeric esters of Sꢀ or RꢀMosher´s acid (method 2).
Key words: [4ꢀmethylꢀ6ꢀ(2ꢀmethylpropꢀ1ꢀenyl)cyclohexaꢀ1,3ꢀdiene]methanol, synthesis
and acylation; pancreatic lipase, hydrolysis of acetates; europium(III); complexation with
esters of Mosher´s acid.
Originally, the absolute configuration of cyclohexaꢀ
Procedure 1. Determination of the configuration
using pancreatic lipase
dienecarboxylates of the type 1 was deduced from the
signs of displacement of diagnostic chemical shifts δH in
their 1H NMR spectra induced by chiral solvating agents,
(S)ꢀBINOL and (R)ꢀBINOL.1 Previously, this method
has been used to determine the absolute configurations of
chiral sulfoxides.2 The assignments made in the study
cited1 relied only on the known similarity between the
carbonyl and sulfoxide groups.3 The purpose of the present
work is to verify the validity of the absolute configurations
attributed to the (+)ꢀ and (–)ꢀenantiomers of esters 1 by
employing some other independent methods. Two ways
of determining the configuration have been tried in relaꢀ
tion to scalemic ester (+)ꢀ1a (R = Me2C=CH, Alk =
Me); specimens of this ester with different ee have been
obtained previously.1,4 Both procedures start with the hyꢀ
dride reduction of ester 1a to give the corresponding priꢀ
mary alcohol 2.
An original approach to the determination of the conꢀ
figurations of the (+)ꢀ and (–)ꢀenantiomers of alcohol 2
is based on enzymatic hydrolysis of the acetates of raceꢀ
mic alcohols mediated by porcine pancreatic lipase (PPL).
The enantioselectivity of this reaction has been studied
rather comprehensively. Several models have been proꢀ
posed to explain the enantioselectivity of ester hydrolysis
inherent in PPL.5 A general interpretation explains this
selectivity in terms of a conformational substrate model
(CSM).6 According to the CSM, hydrolysis is faster for
that component of a racemic acetate whose fixation
in a conventional mode on a conventional diastereofaceous
plane in a specific Wꢀshaped conformation (no less than
five coplanar C and O atoms in succession at the end of
the chain including the reaction center) results in a situaꢀ
tion where the bulkiest substituent at the asymmetric carꢀ
bon atom nearest to the reaction center in the alcohol
fragment falls into the sterically less hindered sector loꢀ
cated conventionally on the αꢀside of this plane. A similar
fixation of the Wꢀshaped conformation of the second
enantiomer forces this substituent into the sterically conꢀ
gested ("viscous") sector, located conventionally on the
βꢀside of the diastereodiscriminating plane, and thus reꢀ
tards the hydrolysis. The configurations of esters (+)ꢀ1a
and (–)ꢀ1a were deduced by comparing the specimens of
alcohol 2 obtained by hydride reduction of ester (+)ꢀ1a
and by partial hydrolysis of racemic acetate ( )ꢀ3 in the
presence of PPL.
R = Ph, αꢀfuryl, PhCH=CH, Me2CH,
Me2CHCH2, Me2C=CH, Me;
Alk = Me, Et But
R1 = Me2C=CH;
R2 = H (2), Ac (3)
* Dedicated to Academician I. P. Beletskaya on the occasion of
her anniversary.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 703—708, March, 2003.
1066ꢀ5285/03/5203ꢀ734 $25.00 © 2003 Plenum Publishing Corporation

Absolute configuration of chiral cyclohexadienes
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 3, March, 2003
735
20
Specimens of ester (+)ꢀ1a with [α]D +248 or +190
Using the CSM, these data would help to determine which
of the enantiomers of acetate 3 has the Me2C=CH ligand
at C(6) in the αꢀsector.
(c 1.0, PhH) were reduced with LiAlH4 in an Et2O—THF
mixture, and specimens of alcohol (+)ꢀ2 with [α]D20 +148
and +134, respectively (c 1.0, PhH), were isolated in
66—74% yields. According to the assignment made previꢀ
ously for ester (+)ꢀ1a,1 they had to be identified as having
the Sꢀconfiguration and ee ∼84 and ∼64%, respectively.
The known racemic ester ( )ꢀ1a 7 was converted in the
same way into alcohol ( )ꢀ2, which was transformed into
acetate ( )ꢀ3 by the standard method. Hydrolysis of acꢀ
etate ( )ꢀ3 in an 0.1 M phosphate buffer (рH 6.8, 20 °C;
3 : PPL = 2 : 1 w/w), to ∼10% and 32% degrees of converꢀ
sion afforded specimens of alcohol (–)ꢀ2 with [α]D20 –41
and –27.5 (c 1.0, PhH), respectively. In conformity with
previous data,1 the Rꢀconfiguration and ee ∼14.5 and 9.3%
were ascribed to the levorotatory enantiomer of acetate 3
whose hydrolysis was faster (Scheme 1). To verify these
assignments, we calculated the G°298 values for the most
stable configuration and the Wꢀshaped conformation of
acetate 3 in order to estimate the population of the
Wꢀshaped conformer under the conditions of hydrolysis.
MNDO calculations showed that acetate 3 is most
stable in conformation A where the Me2C=CH group and
the AcO group are located on opposite sides of the ring at
a maximum distance from each other (Fig. 1, a). The
calculated ∆G°298 value for the transition of conformation
A into the Wꢀshaped conformation B, in which the
CH2OAc fragment is almost coplanar with the ring diene
system (Fig. 1, b), was 1.17 kcal mol–1. Thus, it follows
that the equilibrium constant К = [B]/[A] amounts to
∼0.14 and the [B]/[A] ratio is ∼12 : 88. Therefore, the
binding of conformation B to the active site of PPL, as on
the postulated plane, is energetically admissible. Accordꢀ
ing to the CSM, of the two enantiomers of acetate 3, the
Rꢀenantiomer is fixed on the diastereofaceous plane in a
position favorable for hydrolysis, because its Me2C=CH
group is directed toward the sterically less hindered αꢀ
side. When molecule (S)ꢀ3 in conformation B is fixed on
the diastereofaceous plane, the Me2C=CH group falls
into the sterically hindered βꢀsector and hydrolysis is deꢀ
celerated.
Scheme 1
Since the sign of [α]D did not change upon the reducꢀ
tion of ester (+)ꢀ1a into alcohol 2, alcohol (–)ꢀ2 resultꢀ
ing from enzymatic hydrolysis should correspond to ester
(–)ꢀ1a, which has previously been identified1 as Rꢀenanꢀ
tiomer. Thus, within the framework of the CSM the conꢀ
figurations of (+)ꢀ2 and (–)ꢀ2 are consistent with conꢀ
figurations assigned previously for esters (S)ꢀ(+)ꢀ1a and
(R)ꢀ(–)ꢀ1a.
Procedure 2. Determination of the configuration from
the EuIIIꢀinduced shift (δH) in the 1H NMR spectra
of Mosher´s esters (MTPA esters)
Yet another way of validating the configurations asꢀ
signed to esters (+)ꢀ1a and (–)ꢀ1a involves the determiꢀ
nation of absolute configuration of the βꢀC atom in
alcohols of the type RCH(R1)CH2OH from the europium
βꢀdiketonateꢀinduced shift of the signals for the protons
1
of the CH3O group in the H NMR spectra of their
(R)ꢀ and (S)ꢀMTPA esters.8 It was important to find out
whether this method can be extended to the MTPA esters
of alcohols like 2 (esters 4) in which the asymmetric cenꢀ
ter is remote from the reaction center. We proceeded
from the premises given in the original publication,8a
namely, (1) coordination of Eu ion to two Oꢀatoms of the
MTPA moiety occurs in the most stable conformation of
the MTPA ester and from the side favorable for complexꢀ
ation; in this particular case, this is either the front or the
rear of the plane through the C(4) and C(1) atoms and the
O—C(=O)—C* group; (2) the stronger the coordination
of Eu to the MTPA ester the larger the downfield shift of
δOCH3 (Scheme 2).
Reagents: a. LiAlH4/THF—Et2O (66—74%);
b. Ac2O/Py—DMAP (71%); c. H2O (pH 6.8)/PPL
(conversion C ∼10 or 32%).

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Russ.Chem.Bull., Int.Ed., Vol. 52, No. 3, March, 2003
Serebryakov et al.
a
b
c
Fig. 1. a. Stable conformation A of acetate (S)ꢀ3. The C(1) and C(4) atoms of the ring and the 4ꢀCH3 and CH2OAc groups lie in the
plane orthogonal to the diastereofaceous plane that accommodates the substrate molecule; the Me2C=CH and CH2OAc groups are
removed as far as possible from each other. b. Wꢀconformation B. The C and O atoms of the CH2OCOCH3 group lie in the
diastereozero plane of molecule 3. c. Determination of the absolute configuration of alcohols (+)ꢀ2 and (–)ꢀ2 from the rates of
hydrolysis of their acetates in terms of the conformational substrate model with PPL. The fixation of the Wꢀconformation of molecule
(–)ꢀ3 on the diastereonought plane is consistent with a higher rate of hydrolysis for (R)ꢀ3 compared to (S)ꢀ3; α is the αꢀside (sterically
nonhindered), fast hydrolysis in the presence of PPL; β is the βꢀside (sterically hindered), slow hydrolysis in the presence of PPL.
In the case where the lanthanide approaches the less
hindered side of the S,Sꢀdiastereomer (Scheme 2), the
resulting chelate C is sterically less hindered than its diasꢀ
tereomer D. The downfield shift of the OMe signal in the
1H NMR spectrum of C is relatively large. When the
lanthanide comes from the less hindered side of the
(6R,2´S)ꢀdiastereomer (Scheme 2), the resulting chelate
D is sterically more congested than diastereomer C. The
was added to solutions of the diastereomeric MTPA esꢀ
ters (in the pair of (S)ꢀMTPA esters, [(6S,2´S)ꢀ4] >
> [(6R,2´S)ꢀ4], while in the pair of (R)ꢀMTPA esters,
[(6S,2´R)ꢀ4] > [(6R,2´R´)ꢀ4]), and the shifts of the sigꢀ
nals for the OMe groups were measured in the spectra of
binary mixtures of the chelates thus formed.
The values of the lanthanideꢀinduced downfield shifts
(LIDS) of the OMeꢀgroup signals for the major and miꢀ
nor diastereomers were used to determine the strength of
the Eu(fod)3 complexes with each of the four MTPA esꢀ
ters. This provided grounds for deducing the configuraꢀ
tions of the major and minor enantiomer in the starting
scalemic alcohol (+)ꢀ2. The results are presented in
Table 1. Tentative MNDO calculations showed that the
1
downfield shift of the OMe signal in its H NMR specꢀ
trum is relatively small.
20
Scalemic alcohol 2 with [α]D +134 (ee ∼64%) was
acylated with (R)ꢀ or (S)ꢀMTPA chloride to give a binary
mixture of diastereomeric MTPA esters (Scheme 3); their
1H NMR spectra in CDCl3 were recorded. Then Eu(fod)3

Absolute configuration of chiral cyclohexadienes
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 3, March, 2003
737
Scheme 2
stable conformation of the four MTPA esters of alcohol 2
is similar to conformation A of acetate 3 (see Fig. 1, a).
It can be seen (see Table 1 and Scheme 2) that in the
pair of diastereomeric (S)ꢀMTPA esters formed by the
major alcohol (+)ꢀ2 and by its minor (levorotatory) enanꢀ
tiomer, a larger LIDS for OCH3 belongs to the chelate of
the major diastereomer. This diastereomer is formed upon
such an approach of Eu(fod)3 to the stable conformer of
the MTPA ester where the bulky substituents in the alcoꢀ
holic (Me2C=CH) and acyl (Ph) fragments of the molꢀ
ecule occupy opposite sides of the plane passing through
the C(4) and C(1) atoms and the O—C(=O)—C* triad.
In the case of Sꢀconfiguration of the acyl fragment, this
approach is expected to be from the "rear" side of this
plane, which is possible only when the distance between
Eu(fod)3 and Me2C=CH is substantial, and this implies
Sꢀconfiguration of the C(6) center in the alcoholic fragꢀ
ment. The smaller LIDS (see Scheme 2) should refer to
the minor diastereomer (6R,2´S)ꢀ4 and its complex with
Eu(fod)3 in which both the Me2C=CH and Ph groups are
located on one side of the plane accommodating the C(4)
and C(1) atoms and the O—C(=O)—C* fragment (in this
case, the approach of Eu(fod)3 to the stable conformer of
ester (6R,2´S)ꢀ4 occurs from the "frontal" side of the
plane). In the pair of diastereomeric (R)ꢀMTPA esters,
the stereochemical situation for the major and minor comꢀ
ponents is reversed: the complex formed by the minor
(R,R)ꢀester is more stable, while the complex of the
(6S,2´R)ꢀester with Eu(fod)3 is more labile. The LIDS in
the 1H NMR spectrum change accordingly.
Scheme 3
Thus, determination of the configurations of the maꢀ
jor and minor enantiomers in scalemic alcohol (+)ꢀ2 led
to the same conclusion as the use of CSM, namely, alcoꢀ
hol (+)ꢀ2 has the Sꢀconfiguration. Since (+)ꢀ2 was preꢀ
pared by hydride reduction of ester (+)ꢀ1a, this confirms
the Sꢀconfiguration of this ester determined previously.
1
In previous studies1,4 where H NMR spectroscopy was
a. (R)ꢀ(–)ꢀМТРАꢀCl; b. (S)ꢀ(+)ꢀМТРАꢀCl
used in combination with BINOL, Sꢀconfigurations were

738
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 3, March, 2003
Serebryakov et al.
Table 1. Determination of the absolute configuration of alcohols (+)ꢀ2 and (–)ꢀ2 from
the induced shift (∆δ ) of the OMeꢀgroup signals in the 1H NMR spectra of binary
H
mixtures of MTPA esters 4
MTPA
Eu(fod)3
in the sample
(mol.%)
δ
Configuration
of alcohol 2 with
ОCH
3
fragment
in the Eu
chelate
(∆δ )
H
greater ∆δ
H
major peak
minor peak
(S)ꢀMTPA
(R)ꢀMTPA
0
25
3.47
3.59
(0.12)
3.42
3.43
3.49
(0.06)
3.46
S
0
25
3.49
3.57
R
(0.07)
(0.11)
with Rf 0.69 (PhH—AcOEt 2 : 1, v/v). 1H NMR, δ: 1.60
(br.s, 1 H); 1.72 (s, 3 H); 1.75 (s, 3 H); 1.83 (s, 3 H); 1.95 (dd,
1 H, C(5)HA, JAB = 9 Hz, JAM = 12 Hz); 2.40 (dd,, 1 H, C(5)HB,
JAB = 9 Hz, JBM = 18 Hz); 3.15 (ddd, 1 H, C(6)H2, JAM = 12 Hz,
JBM = 18 Hz, Jvic = 10 Hz); 4.03 (s, 2 H, CH2OH); 5.22 (d, 1 H,
Jvic = 10 Hz); 5.65 (d, C(3)H, 1 H, J2,3 = 6 Hz); 5.85 (d, C(2)H,
1 H, J2,3 = 6 Hz). 13C NMR, δ: 18.03; 23.36; 25.84; 33.59;
35.54; 65.18; 118.25, 119.79; 125.59; 131.90; 134.32; 137.88.
IR, ν/cm–1: 3600, 1600, 1032. MS, m/z (Irel (%)): 178 [M]+
(52), 160 [M – H2O]+ (20), 147 (62), 119 (31), 105 (100), 91
assigned to all dextrorotatory cyclohexadienes (when
R = Me, this is formally the Rꢀenantiomer) and Rꢀconꢀ
figurations were found for the levorotatory compounds
(except for the case where R = Me). Moreover, the agreeꢀ
ment of the results of the determining of the absolute
configuration of ester (+)ꢀ1a by three independent methꢀ
ods validates other previous assignments of the absolute
configurations of these esters.1,4
This allows one to interpret more reliably the effects of
various factors on the stereoselectivity of the catalytic
asymmetric synthesis of cyclohexadienes.1,4
20
(54). A specimen of (+)ꢀ1a with [α]D +248 (c 1.0, PhH),
ee ∼82—84%, was converted into alcohol (+)ꢀ2 with [α]D20 + 148
(c 1.0, PhH), yield 40 mg (66%). Another specimen of (+)ꢀ1a
with [α]D20 +190 (c 1.0, PhH), ee ∼63—64%, gave a specimen of
Experimental
19
(+)ꢀ2 with [α]D + 134 (c 1.0, PhH) with a similar 1H NMR
spectrum, yield 45 mg (74%).
NMR spectra were recorded in CDCl3 at 20 °C on Bruker
AMꢀ300 (operating at 300.13 MHz, for 1H) and Bruker ACꢀ200
(operating at 50.3 MHz, for 13C) spectrometers. IR spectra were
measured for solutions in CHCl3 on a Specord IRꢀ80 instruꢀ
ment. The [α]D values were determined on a JASCO DIPꢀ360
polarimeter for solutions in C6H6 at 16—22 °C. Mass spectra
were run on a Finnigan MAT INCOSꢀ50 mass spectrometer
(EI, 70 eV, direct inlet). The completeness of the reactions and
the product purity were checked by TLC on Silufol UVꢀ254
plates. Column chromatography was carried out on neutral Silica
gel 40 (Fluka, particle size 0.04—0.06 mm). All solvents were
purified9 prior to use. Porcine pancreatic lipase with a specific
activity of 14.7 units mg–1 (Serva) or 47 units mg–1 (OlainFarm,
Latvia), LiAlH4, Eu(fod)3, and (S)ꢀ and (R)ꢀMTPA (Fluka)
were used as purchased. Specimens of ester (+)ꢀ1a were preꢀ
pared by a known procedure,1 and the specimen of ester ( )ꢀ1a
was prepared similarly.7
(+)ꢀ[4ꢀMethylꢀ6ꢀ(2ꢀmethylpropꢀ1ꢀenyl)cyclohexaꢀ1,3ꢀ
diene]methanol, (S)ꢀ2. A 1.4 M solution (0.5 mL) of LiAlH4
(∼27 mg, 0.7 mmol) in anhydrous THF was added at 20 °C
under argon to a solution of ester (+)ꢀ1a (70 mg, 0.34 mmol) in
5 mL of anhydrous Et2O (5 mL). The mixture was stirred for
15 min, 1 mL of water was added dropwise, and the precipitate
was filtered off and washed with Et2O (2×5 mL). The combined
organic filtrate was dried (Na2SO4) and concentrated in vacuo,
and the residue was chromatographed on a column with SiO2
(3 g). Elution with benzene gave alcohol (+)ꢀ1a as a colorless oil
Alcohol ( )ꢀ2a was prepared in a similar way in 71% yield
from 70 mg (0.34 mmol) of specimen ( )ꢀ1a; the Rf value and
the spectroscopic characteristics of the product fully coincided
with those given above. An increase in the amount of a 1.4 M
solution of LiAlH4 to 1 mL (∼54 mg, ∼1.4 mmol) or in the
reaction time (to 1 h) gave rise to a product of "overhydroꢀ
genation" of 2 containing only two double bonds, which was
difficult to separate. This impurity (colorless oil, 8.5 mg) was
isolated in a nearly pure state by repeated chromatography on
SiO2. 1H NMR, δ: 1.52 (br.s, 1 H, OH); 1.66 (s, 3 H); 1.70
(s, 3 H); 1.73 (s, 3 H); 1.86—2.21 (m, 5 H); 3.64 (d, 2 H, J = 6.8
Hz); 5.22 (d, 1 H, Jvic = 10 Hz); 5.38 (nar.m, 1 H). IR, ν/cm–1
:
3640 (s), 1650 (w), 1040 (s). On the basis of these data, the
product was identified as ( )ꢀ[4ꢀmethylꢀ2ꢀ(2ꢀmethylpropꢀ1ꢀ
enyl)cyclohexꢀ3ꢀene]methanol.
(
)ꢀ[4ꢀMethylꢀ6ꢀ(2ꢀmethylpropꢀ1ꢀenyl)cyclohexaꢀ1,3ꢀ
diene]methanol acetate, ( )ꢀ3. Pyridine (31 µL, 0.38 mmol),
Ac2O (36 µL, 0.38 mmol), and DMAP (3 mg) were added to a
solution of alcohol ( )ꢀ2 (57 mg, 0.32 mmol) in 2 mL of hexꢀ
ane. After 18 h, the solution was concentrated in vacuo, and the
residue was chromatographрed on a column with SiO2; elution
with a hexane—PhH mixture (1 : 1, v/v) gave acetate ( )ꢀ3 as a
colorless oil. Yield 50 mg (71%). 1H NMR, δ: 1.65 (s, 3 H); 1.69
(s, 3 H); 1.78 (s, 3 H); 1.97 (dd, 1 H, C(5)HA, JAB = 8 Hz, JAM
2 Hz); 2.04 (s, 3 H); 2.39 (dd, C(5)HB, 1 H, JAB = 8 Hz, JBM
9 Hz); 3.12 (ddd, C(6)H, 1 H, JAM = 2 Hz, JBM = 9 Hz, Jvic
=
=
=
10 Hz); 4.48 (dd, 2 H, CH2OAc, J = 13 Hz, J´ = 6 Hz); 5.16

Absolute configuration of chiral cyclohexadienes
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 3, March, 2003
739
(d, 1 H, Jvic = 10 Hz); 5.64 (m, 1 H, C(3)H); 5.88 (d, 1 H,
C(2)H, J2,3 = 6 Hz). IR, ν/cm–1: 1738, 1600.
(–)ꢀ[4ꢀMethylꢀ6ꢀ(2ꢀmethylpropꢀ1ꢀenyl)cyclohexaꢀ1,3ꢀ
diene]methanol, (R)ꢀ2. A. Enzymatic hydrolysis, low degree of
conversion. PPL (Serva) powder (30 mg) was added in one porꢀ
tion with vigorous stirring at 20 °C to an emulsion of acetate
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 99ꢀ03ꢀ
32992), the Program for Support of Leading Scientific
Schools of the Russian Federation (Project No. 00ꢀ15ꢀ
97347), and partially by the INTAS program (grant
96ꢀ1109).
(
)ꢀ3 (76 mg, 0.34 mmol) in an 0.1 M phosphate buffer, рH 6.8
(0.5 mL). The resulting slurry was stirred for 7 h and extracted
with benzene (3×2 mL); the organic layer was washed with
saturated brine, dried (Na2SO4), and concentrated in vacuo.
The residue was chromatographed on a column with SiO2 (1 g).
Elution with a hexane—AcOEt mixture (10 : 1, v/v) yielded first
a fraction of the unchanged acetate (32 mg) and then levorotaꢀ
tory alcohol (R)ꢀ2 as a colorless oil whose Rf and IR spectrum
References
1. A. G. Nigmatov, and E. P. Serebryakov. Izv. Akad. Nauk,
Ser. Khim., 1996, 663 [Russ. Chem. Bull., 1996, 45, 623 (Engl.
Transl.)].
2. (a) F. Toda, K. Mori, and J. Okada, Chem. Lett., 1988, 131;
(b) F. Toda, K. Mori, and A. Sato, Bull. Chem. Soc. Jpn.,
1988, 61, 4167.
21
were the same as for specimens of (+)ꢀ2 but with [α]D –41
(c 0.5, PhH). Yield 6.2 mg (10%).
3. H. H. Szmant, in Sulfur in Organic and Inorganic Chemistry,
Ed. A. Senning, Marcel Dekker, New York, 1971, Vol. 1,
Chapter 5.
B. Enzymatic hydrolysis, ∼32% conversion. A heterogeneous
mixture containing acetate ( )ꢀ3 (220 mg, 1 mmol), PPL powꢀ
der (100 mg, OlainFarm), and an 0.1 M phosphate buffer, рH 6.8
(2 mL) was vigorously stirred for 3.5 h at 20 °C and worked up as
described above. Elution of the column with 11 column volumes
of a hexane—AcOEt mixture (10 : 1, v/v) gave alcohol (–)ꢀ2
with [α]D –27.5 (c 1.0, PhH) and with Rf value and H NMR
spectrum identical to those found for alcohols (+)ꢀ2 and ( )ꢀ2.
Yield 57 mg (32%).
4. E. P. Serebryakov, A. G. Nigmatov, M. A. Shcherbakov,
and M. I. Struchkova, Izv. Akad. Nauk, Ser. Khim., 1998, 84
[Russ. Chem. Bull., 1998, 47, 82 (Engl. Transl.)].
5. (a) Enzyme Catalysis in Organic Synthesis, Eds. K. Drauz and
H. Waldmann, VCH, Weinheim, Germany, 1995, Vol. 1,
pp. 178—261; (b) C. H. Wong and G. M. Whitesides, Enꢀ
zymes in Synthetic Organic Chemistry. (2nd ed.), Pergamon
Press, Throwbridge, UK, 1995, pp. 9—13, 60—130;
(c) K. Faber, Biotransformations in Organic Chemistry. A Textꢀ
book (2nd ed.), Springer, Berlin, 1995, pp. 1—144;
(d) J. Ehrler and D. Seebach, Liebigs Ann. Chem., 1990, 379;
(e) P. G. Hultin and J. B. Jones, Tetrahedron Lett., 1992, 33,
1399; (f) G. Guanti, L. Banfi, and E. Narusano, J. Org.
Chem., 1992, 57, 1540; (g) Z. Wimmer, Tetrahedron, 1992,
48, 8431.
6. E. P. Serebryakov and G. D. Gamalevich, Mendeleev
Commun., 1996, 221.
7. A. G. Nigmatov, I. N. Kornilova, and E. P. Serebryakov,
Izv. Akad. Nauk, Ser. Khim., 1996, 134 [Russ. Chem. Bull.,
1996, 45, 204 (Engl. Transl.)].
8. (a) F. Yasuhara and S. Yamaguchi, Tetrahedron Lett., 1977,
4985; (b) Y. Sugimoto, T. Tsuyuki, Y. Moriyama, and
T. Takahashi, Bull. Chem. Soc. Jpn., 1980, 53, 3723;
(c) S. Yamaguchi, in Asymmetric Synthesis, Vol. 1, Ed. J. D.
Morrison, Acad. Press, New York, 1983; (d) F. Yasuhara,
S. Yamaguchi, R. Kasai, and O. Tanaka, Tetrahedron Lett.,
1986, 27, 4033.
20
1
Esters of alcohol (+)ꢀ2 with (S)ꢀMosher´s acid, (6S,2´S)ꢀ4
and (6R,2´S)ꢀ4. A solution of (R)ꢀ(methoxy)(phenyl)(trifluoroꢀ
methyl)acetyl chloride ((R)ꢀMTPAꢀCl), prepared from acid
(S)ꢀMTPA (39 mg, 0.38 mmol) by a known procedure,10 in
0.5 mL of Py was added to a solution of alcohol (+)ꢀ2 (20 mg,
0.11 mmol) in CCl4 (30 µL). The reaction mixture was stirred at
20 °C for 24 h, treated with a solution of N,Nꢀdimethylethyleneꢀ
diamine (14 mg, ∼0.15 mmol) in a minimum volume of CCl4 by
a known procedure,11 and acidified with 1 M HCl (2.5 mL). The
organic layer was separated and the aqueous phase was extracted
with Et2O (2×1 mL). The combined organic phase was washed
repeatedly with 1 M HCl, a saturated solution of NaHCO3, and
water, dried (Na2SO4), and concentrated in vacuo. The thick
liquid residue was chromatographed on a column with SiO2
(2 g); elution with benzene gave a binary mixture of MTPA
esters. Yield 31.4 mg (71%). 1H NMR (CDCl3), δ: 1.48 and 1.49
(both s, 3 H); 1.58 and 1.60 (both s, 3 H); 1.86 (m, 3 H);
2.26—2.31 (m, 2 H); 3.00—3.10 (m, 1 H); 3.43 < 3.47 (both s,
3 H); 4.62 (br.s, 2 H); 5.04 (br.d, 1 H); 5.54 (d, 1 H, J = 6 Hz);
5.84 (br.d, 1 H, J = 6 Hz); 7.25—7.60 (m, 5 H).
Esters of alcohol (+)ꢀ2 and (R)ꢀMosher´s acid, (6S,2´R)ꢀ4
and (6R,2´R)ꢀ4. The reaction of 20 mg of the same specimen of
the alcohol with (S)ꢀ(methoxy)(phenyl)(trifluoromethyl)acetyl
chloride ((S)ꢀMTPAꢀCl), prepared from acid (R)ꢀMTPA
(40 mg) carried out by the same procedure gave 40 mg of a
binary mixture of (R)ꢀMTPA esters. 1H NMR (CDCl3), δ: 1.56
and 1.59 (both s, 3 H); 1.60 and 1.62 (both s, 3 H); 1.85 (m, 3 H);
2.24—2.29 (m, 2 H); 3.00—3.10 (m, 1 H); 3.42 > 3.46 (both s,
3 H); 4.69 (m, 2 H); 5.11 (br.d, 1 H); 5.54 (d, 1 H, J = 6 Hz);
5.85 (br.d, 1 H, J = 6 Hz); 7.25—7.66 (m, 5 H).
9. A. Gordon and R. Ford, The Chemist's Companion, Wiley,
New York, 1972, Chapter 7.
10. J. A. Dale and D. S. Morrison, J. Am. Chem. Soc., 1973,
95, 512.
11. N. Kalyanam and D.A. Lightner, Tetrahedron Lett.,
1979, 415.
12. G. D. Gamalevich, A. V. Ignatenko, E. P. Serebryakov, and
N. E. Voishvillo, Izv. Akad. Nauk, Ser. Khim., 1995, 761
[Russ. Chem. Bull., 1995, 44, 745 (Engl. Transl.)].
Complexation of MTPA esters 4 with Eu(fod) was carried out
by a procedure used previously.12 The results are presented in
Table 1.
Received May 7, 2002
in revised form October 12, 2002