Chiral C2-symmetric 2,5-disubstituted pyrrolidine derivatives as catalytic chiral ligands in the reactions of diethylzinc with aryl aldehydes

Article abstract of DOI:10.1039/a803336f

Two kinds of chiral C₂-symmetric 2,5-disubstituted pyrrolidlne derivatives having a β-aminoalcohol moiety have been successfully synthesized and their catalytic abilities of chiral induction have been examined in the reactions of diethylzinc wi

Full text of DOI:10.1039/a803336f

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Chiral C2-symmetric 2,5-disubstituted pyrrolidine derivatives as
catalytic chiral ligands in the reactions of diethylzinc with aryl
aldehydes
Min Shi,* Yukihiro Satoh and Yukio Masaki
Gifu Pharmaceutical University, 5-6-1 Mitahora-Higashi, Gifu 502, Japan
Two kinds of chiral C2-symmetric 2,5-disubstituted pyrrolidine derivatives having a â-aminoalcohol
moiety have been successfully synthesized and their catalytic abilities of chiral induction have been
examined in the reactions of diethylzinc with aryl aldehydes. The production of sec-alcohols having
R-absolute configuration could be achieved in very high chemical yield (85–95%) and very high
enantiomeric excess (ee) (70–96%) when N-(2Ј,2Ј-diphenyl-2Ј-hydroxyethyl)-(2R,5R)-bis(methoxymethyl)-
pyrrolidine is used as a chiral ligand. On the other hand, when an N-methyl-(2R,5R)-bis(diarylhydroxy-
methyl)pyrrolidine is used as a catalyst ligand, the ee of the corresponding sec-alcohols decreases to
20–45% and an interesting inversion of the enantioselectivity is observed in the addition reaction of m-
chloro-, p-chloro- and m-fluoro-benzaldehyde with diethylzinc under the same reaction conditions. In the
meantime, we have also synthesized some chiral C2-symmetric N-(â-hydroxyethyl)pyrrolidine derivatives
which have differently steric sized bulky substituents on the 2,5-position of the pyrrolidine ring and their
chiral induction abilities have also been examined under the same reaction conditions. Furthermore, we
have prepared a simple chiral C2-symmetric â-aminothiol pyrrolidine derivative. It has also been employed
as a chiral ligand for the same addition reaction.
C2-symmetric N-methyl-2,5-bis(diarylhydroxymethyl)pyrrol-
Introduction
idines 7a,b in the reaction of diethylzinc with arylaldehydes in
order to clearly elucidate the effect of the substituents at the
2,5- and 3,4-positions of pyrrolidine ring on the enantioselectiv-
ity. We will also disclose the catalytic abilities of some chiral
C2-symmetric N-(β-hydroxyethyl)pyrrolidine derivatives 13a–d
having bulky substituents of different steric size on the 2,5-
position of the pyrrolidine ring and a corresponding simple
β-aminothiol 14 in this addition reaction.
High efficiencies of C2-symmetric chiral reagents, including
chiral auxiliaries and catalyst ligands, in asymmetric induc-
tion have attracted much attention in asymmetric synthesis.1
Previously, we reported a short synthesis of homochiral C2-
symmetric 2,3,4,5-tetrasubstituted pyrrolidines from -manni-
tol and their use as catalytic chiral ligands in the reaction of
diethylzinc with benzaldehyde.2 A dramatic change of enan-
tioselectivity was observed between the bis(benzylideneacetal)
ligands which favoured the production of the (S)-alcohol and
the methoxylated ones which preferentially afforded the (R)-
alcohol. These results imply that the flexibility of the substitu-
ents on the pyrrolidine ring may play an important role in the
enantioselectivity for this addition reaction. In order to gain
more insight into this inversion phenomenon of enantioselec-
tivity between the two chiral pyrrolidines, recently we also
reported chiral C2-symmetric 2,5-disubstituted N-(β-hydroxy-
ethyl)pyrrolidine derivatives 4a,b and chiral C2-symmetric N-
methyl-2,5-bis(diarylhydroxymethyl)pyrrolidines 7a,b as cata-
lytic chiral ligands in the reaction of diethylzinc with arylalde-
hydes.3 We found that the chiral C2-symmetric 2,5-disubstituted
N-(β-hydroxyethyl)pyrrolidines 4a and 4b have very similar
chiral-induction abilities to those of the corresponding 2,3,4,5-
tetrasubstituted ones in the reaction of diethylzinc with benz-
aldehyde; that is, the substituents at the 3,4-position of the
pyrrolidine ring have no effect on the chiral induction for this
addition reaction.3 On the other hand, when an N-methyl-
(2R,5R)-bis(diarylhydroxymethyl)pyrrolidine 7a or 7b was used
as a catalyst ligand, inversion of the enantioselectivity was
observed in the addition reaction of m-chloro-, p-chloro- and
m-fluoro-benzaldehyde with diethylzinc under the same condi-
tions.3 In this paper we disclose full details of the catalytic
chiral-induction abilities of chiral C2-symmetric, 2,5-disubsti-
tuted N-(β-hydroxyethyl)pyrrolidine derivatives 4a,b and chiral
Results and discussion
Chiral C2-symmetric 2,5-disubstituted pyrrolidines have long
been recognized as useful chiral auxiliaries for asymmetric syn-
thesis.4 These compounds were prepared first by resolution of
trans-1-benzylpyrrolidine-2,5-dicarboxylic acid,5 and then were
synthesized from homochiral starting materials: -mannitol,6
(S)-O-benzylglycidol7 and -proline8 by means of relatively
long reaction sequences. Recently, Yamamoto reported a con-
venient and reliable synthesis of each enantiomer of the 2,5-
disubstituted pyrrolidines by the reaction of dimethyl 2,5-
dibromoadipate with (S)-(Ϫ)-1-phenylethylamine and chrom-
atographic separation.9 According to this method 1-[(S)-1Ј-
phenylethyl]-(2R,5R)-bis(methoxycarbonyl)pyrrolidine 1 and a
N-unsubstituted pyrrolidine 2 were easily obtained. Compound
2 was treated with ethyl bromoacetate to give the N-(ethoxy-
carbonylmethyl)pyrrolidine derivative 3. The N-(β-hydroxy-
ethyl)pyrrolidines 4a and 4b were then obtained from the reac-
tion of ester 3 with methylmagnesium bromide and phenyl-
magnesium bromide, respectively (Scheme 1). On the other
hand, the synthesis of chiral C2-symmetric N-methyl-(2R,5R)-
bis(diarylhydroxymethyl)pyrrolidines 7a and 7b was carried out
starting from precursor 1 through an N-unsubstituted pyrroli-
dine 5 which was obtained by removal of the N-1-phenylethyl
group by using catalytic hydrogenolysis over palladium hydrox-
ide in methanol, and successively N-methylation using form-
aldehyde to give an N-methylpyrrolidine derivative 6, followed
by treatment with the corresponding arylmagnesium bromides
(Scheme 2).
* Current address and for any correspondence: Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 354 Fengline Lu,
Shanghai 200032, China.
J. Chem. Soc., Perkin Trans. 1, 1998
2547

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Table 1 Asymmetric addition reaction of diethylzinc with arylalde-
hydes in the presence of chiral pyrrolidine (4a or 4b). All products had
R-configuration.
C(O)OMe
MeO(O)C
CH2OMe
MeO(O)C
N
N
H
O
C
OH
R
R
Ph
4a or 4b (5 mol%)
1
2
*
Et
H
+
Et2Zn
C
H
8
hexane, 0 °C, 24 h
MeCN, rt; 12 h
90%
BrCH2C(O)OEt, K2CO3
R
Cat.
Yield (%)a
ee (%)
CH2OMe
MeO(O)C
H
H
p-Me
o-OMe
p-OMe
p-F
m-F
p-Cl
m-Cl
o-Cl
4a
4b
4b
4b
4b
4b
4b
4b
4b
4b
90
99
99
85
85
96
88
92
96
86
61b
91b
96b
83b
73b
70c
85d
76b
90b
92d
N
H2C
OH
MeO(O)C
0 °C to rt
CH2OMe
C
N
R
R
MeMgBr, THF
PhMgBr, THF
or
CH2C(O)OEt
4a R = Me (yield 90%)
4b R = Ph (yield 65%)
3
Scheme 1
a Isolated yields. b Determined by chiral HPLC. c Determined by
comparison of the optical rotation value with the literature value.
d Determined by 1H NMR analysis of the corresponding (ϩ)-MTPA
ester.
MeO(O)C
C(O)OMe
H2/Pd(OH)2
1
N
H
5
MeOH, rt,
30 h, 80%
HCHO, NaBH3CN
MeCN, HOAc (2 drops)
Table 2 Asymmetric addition reaction of diethylzinc with arylalde-
hydes in the presence of chiral pyrrolidine (5 mol%) (7a or 7b)
O
C
OH
R
R
7a or 7b (5 mol%)
*
Et
H
+
Et2Zn
C
H
8
MeO(O)C
C(O)OMe
hexane, 0 °C, 24 h
N
Me
6
R
Cat.
Yield (%)a
82
ee (%)
Configuration
16b
15b
53b
52b
42b
43b
16c
15d
13b
40b
38b
10d
R
R
R
R
R
R
R
S
S
S
S
R
ArMgBr, THF
R
0 °C to rt, 20 h
H
H
7a
7b
7a
7b
7a
7a
7b
7b
7a
7a
7b
7a
82
70
70
73
72
50
45
71
90
90
76
p-Me
p-Me
o-OMe
p-OMe
p-F
m-F
p-Cl
m-Cl
m-Cl
o-Cl
R
R
C
C
R
N
OH
OH
Me
7a R = H (yield: 30%)
7b R = Me (yield: 25%)
a–d As in Table 1.
Scheme 2
ligand.2 Thus the chiral-ligand characters for the C2-symmetric
2,5-disubstituted and 2,3,4,5-tetrasubstituted pyrrolidines
appear to be very similar in the reaction of diethylzinc with
benzaldehyde and, therefore, the substituents at the 3- and
4-position of the pyrrolidine ring have no effect on the enantio-
selectivity of this addition reaction. On the other hand, when
compound 7a or 7b was used as a catalyst, the ee of product 8
decreased to 20–45% and inversion of the enantioselectivity
affording the (S)-configuration preferentially was observed in
the reaction of m-chloro-, p-chloro- and m-fluoro-benzaldehyde
with diethylzinc under the same reaction conditions (Table 2).
This result is particularly interesting in view of the fact reported
by Soai13 that, when N-methyl-(2S)-(diphenylhydroxymethyl)-
pyrrolidine derived from (S)-proline was used as a chiral ligand,
no inversion phenomenon in enantioselectivity by changing
the substitution mode of the substrate arylaldehydes from
o-chloro- to m-chloro- and p-chloro-benzaldehyde could be
observed. At present the detailed mechanism of this inversion
phenomenon remains obscure and work along these lines is
in progress.
It is well known that the reaction of aldehydes with diethyl-
zinc giving sec-alcohols 8 takes place in the presence of a
catalytic amount of β-aminoalcohol.10 Excellent chiral induc-
tions including asymmetric amplifications11 by use of chiral
β-aminoalcohols in this reaction have been reported.11 Thus
we also examined this addition reaction by using the two kinds
of chiral C2-symmetric pyrrolidine derivatives 4a,b and 7a,b.
The ees of the product 8 were determined by HPLC analysis
using chiral stationary-phase column (CHIRALCEL OD) or
1H NMR analysis of the corresponding (ϩ)-methoxy(trifluoro-
methyl)phenylacetate [(ϩ)-MTPA] ester, and the absolute con-
figuration of the major enantiomer was assigned according to
the sign of its specific rotation.11,12 Their results are summarized
in Tables 1 and 2, respectively. As shown in Table 1, high yields
(85–95%) and high ees (75–95%) of the corresponding sec-
alcohols 8 were obtained by using 5 mol% of compound 4b as a
chiral catalyst ligand. The product’s configuration (R), chem-
ical yield, and ee in this addition reaction of diethylzinc with
benzaldehyde are very similar to those reported previously in
which the corresponding chiral C2-symmetric 2,3,4,5-tetra-
substituted pyrrolidine derivatives was used as a chiral catalyst
In order to elucidate the dominant factors of chiral induction
and catalytic ability in this addition reaction, we also syn-
2548
J. Chem. Soc., Perkin Trans. 1, 1998

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Table 3 Asymmetric addition reaction of diethylzinc with arylalde-
hyde in the presence of chiral pyrrolidine (5 mol%) (13a–d or 14). All
products had R-configuration.
thesized some chiral C2-symmetric N-(β-hydroxyethyl)pyrrol-
idine derivatives having bulky substituents of different steric
size on the 2,5-position of pyrrolidine ring. As shown in
Scheme 3, compound 9 can be readily obtained from 1-[(S)-1Ј-
Chiral ligand
(13a–d, or 14)
R
R
O
C
OH
C* Et
H
5 mol%)
1
H
+ Et2Zn
hexane, 0 °C
rt, 18 h
8
HOH2C
CH2OH
R
H
Chiral ligand
Yield (%)a
ee (%)
N
13a
13a
13a
13a
13a
13a
13b
13b
13b
13b
13b
13b
13c
13c
13c
13c
13c
13c
13d
13d
14
88
69
56
67
60
97
74
50
42
44
79
40
74
70
75
63
96
87
70
72
58
60b
62b
60b
63c
60d
74b
55b
63b
55b
40b
56d
48b
43b
48b
49b
54b
48b
44b
40b
42b
9b
Ph
o-OCH3
p-OCH3
p-F
m-F
m-Cl
H
p-CH3
o-OCH3
p-OCH3
m-Cl
p-Cl
9
N
XCl, (Me2CH)2NEt, DMF
X = CH2OMe (MOM)
NH, CH2Cl2
XCl,
X = SiMe2But (TBDMS)
SiPh2But (TBDPS)
CH2OCH2CH2OMe (MEM)
Pd(OH)2/H2
MeOH
H
XOH2C
CH2OX
XOH2C
CH2OX
p-CH3
o-OCH3
p-OCH3
m-Cl
p-Cl
H
p-CH3
H
N
H
N
11a–d
Ph
10a–d
MeCN, rt ,12 h BrCH2C(O)OEt, K2CO3
a–d As in Table 1.
PhMgBr, THF
0 °C to rt
XOH2C
CH2OX
XOH2C
CH2OX
N
N
The results using chiral pyrrolidines 13a–d, 14 as catalyst
ligands in the asymmetric addition reaction of diethylzinc to
aryl aldehydes are summarized in Table 3. High chemical yields
(50–90%) and moderate ees (40–70%) could be achieved by use
of the chiral ligands 13a–d. However, the enantioselectivities
apparently decrease compared with the corresponding chiral
pyrrolidine 4b. In particular, when the bulky chiral pyrrolidine
13c or 13d was employed as a chiral ligand, the ee of the formed
corresponding sec-alcohol is only 40%. Using β-aminothiol 14
as chiral ligand gave only very poor ee (9%). These results sug-
gest that the enhancement of the bulkiness of chiral ligand
does not always increase the enantioselectivity in some cases,
and that appropriate adjustment of the bulkiness of the chiral
ligand is very subtle and important.
The mechanism and nonlinear effects of enantioselective
addition of dialkylzinc to aldehydes promoted by chiral amino-
alcohols have been clearly disclosed by Noyori.11,15 The ethyl-
ation proceeds via a dinuclear zinc species A containing the
chiral C2-symmetric pyrrolidine auxiliary, an aldehyde ligand,
and three ethyl groups, where the bridging ethyl group
migrates from zinc to the aldehyde carbon. The opposite
enantioselectivity between chiral C2-symmetric N-(β-
hydroxyethyl)pyrrolidine bearing a 6-membered benzylidene
acetal functional group fused at the 2,3,4,5-position and the
methoxylated ones2 could be attributed to an additional
coordination to the zinc atom by the methoxy group on the
side chain of compound 4a or 4b which might enhance the
Lewis acidity of the β-aminoalcohol-chelated zinc complex
and influence the approach of aldehyde (complex C), whereas
the fixed structure of complex B does not have such flexibility
for this kind of coordination. At present, we postulate that
this additional coordination is responsible for the opposite
enantioselectivity. In order to verify this point, we tried to
synthesize the pyrrolidine derivative D, which does not have
an oxygen atom on the side chain, as a chiral ligand for the
reaction of aryl aldehyde with diethylzinc. Unfortunately, we
have failed in the preparation of this simple compound by
CH2C(O)OEt
H2C
OH
Ph
Ph
a: X = MOM, (yield: 30%)
b: X = MEM, (yield: 40%)
c: X = TBDMS, (yield: 30%)
d: X = TBDPS, (yield: 30%)
Scheme 3
phenylethyl]-(2R,5R)-bis(methoxycarbonyl)pyrrolidine
1
by
reduction with lithium aluminium hydride. From compound 9
according to the standard procedures for protection of hydroxy
groups, we can easily introduce a MOM, a MEM, a TBDMS
and a tert-butyldiphenylsilyl group (TBDPS) on the 2,5-
position of pyrrolidine ring, respectively. Then, in the same
reaction procedure as described above, we can successfully syn-
thesize the corresponding chiral C2-symmetric N-(β-hydroxy-
ethyl)pyrrolidine derivatives 13a–d (Scheme 3). Furthermore,
recently we have reported that a chiral C2-symmetric N-(β-
mercaptoethyl)pyrrolidine bearing a 6-membered benzylidene
acetal functional group fused at the 2,3,4,5-position was found
to exhibit very high efficiency as a chiral ligand in the asym-
metric addition reaction of aldehyde with diethylzinc to give
extremely high ee (99%) of the product 8.14 Therefore, we syn-
thesized a simple β-aminothiol 14 from the reaction of chiral
C2-symmetric pyrrolidine derivative 11c with ethylene sulfide
and expected this ligand to have very high asymmetric induction
ability as well (Scheme 4).
S
XOH2C
CH2OX
XOH2C
CH2OX
N
H
N
CH2CH2SH
14
CH3CN
11c
X = SiMe2But (TBDMS)
Scheme 4
J. Chem. Soc., Perkin Trans. 1, 1998
2549

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N-Ethoxycarbonylmethyl-(2R,5R)-bis(methoxymethyl)-
pyrrolidine 3
ROH2C
CH2OR
N
O
O
C
An acetonitrile solution (20 ml) of (2R,5R)-bis(methoxy-
methyl)pyrrolidine 2 (637 mg, 4.0 mmol) and ethyl bromo-
acetate (802 mg, 4.8 mmol) was stirred at rt in the presence of
potassium carbonate (553 mg, 4.0 mmol) for 12 h. After usual
work-up, the residue was chromatographed on a flash column
(SiO2) to give title ester 3 as an oil (880 mg, 90%); [α]D ϩ43.9 (c
1.2, CHCl3); δH(270 MHz; CDCl3) 1.27 (3 H, t, J 7.3), 1.48–1.62
(2 H, m), 1.89–2.05 (2 H, m), 3.28 (6 H, s), 3.25–3.45 (4 H, m),
3.35–3.49 (2 H, m), 3.70 (2 H, d, J 1.46) and 4.16 (2 H, q, J
7.32); MS (FABϩ/Gly) m/z (%) 246 (10, Mϩ ϩ H), 216 (100,
Mϩ Ϫ 30) and 200 (60, Mϩ Ϫ 46). C12H23NO4 (245) (Found: C,
58.7; H, 9.4; N, 5.8. C12H23NO4 requires C, 58.75; H, 9.45; N,
5.71%).
Ar
Zn
Ph
Ph
Et
H
Zn Et
Et
A
Ph
Ph
O
O
H2
C
H2
C
O
MeO
N
OMe
O
N
O
Zn
Ph
Et
Zn
Ph
Ph
O
Et
Ph
Complex B
Complex C
N-(2-Hydroxy-2-methylpropyl)-(2R,5R)-bis(methoxymethyl)-
pyrrolidine 4a
RCH2
CH2R
Compound 4a was prepared from the reaction of ester 3 (245
mg, 1.0 mmol) with methylmagnesium bromide (1 ; 5 ml, 5
mmol) in THF (10 ml) at rt for 3 h. After usual work-up, the
residue was chromatographed on a flash column (SiO2) to give
title compound 4a as an oil (208 mg, 90%); [α]D ϩ57.8 (c 1.62,
CHCl3); δH(270 MHz; CDCl3) 1.14 (3 H, s), 1.18 (3 H, s), 1.60–
1.73 (2 H, m), 1.84–1.98 (2 H, m), 2.45 (1 H, d, J 14.2), 2.97
(1 H, d, J 14.16), 3.18–3.29 (2 H, m), 3.33 (6 H, s) and 3.34–3.38
(4 H, m) [Found: C, 62.3; H, 10.8; N, 6.0%; HR-MS (FABϩ/
NBA) m/z 232.1906 (Mϩ ϩ H). C12H25NO3 requires C, 62.31;
H, 10.89; N, 6.06%; M ϩ H, 232.1914].
N
H2C
OH
Ph
C
Ph
D
the usual synthetic methodology. Further work is in progress
to prepare this compound.
Experimental
N-(2-Hydroxy-2,2-diphenylethyl)-(2R,5R)-bis(methoxymethyl)-
pyrrolidine 4b
Mps were obtained with a Yanagimoto micro melting point
apparatus and are uncorrected. Optical rotations were deter-
mined in a solution of CHCl3 or EtOH at 20 ЊC by using a
JASCO DIP-360 digital polarimeter; [α]D-values are given in
Compound 4b was prepared from the reaction of compound 3
(134 mg, 0.55 mmol) with phenylmagnesium bromide (1 ; 5.5
ml, 5.5 mmol) in THF (20 ml) at rt for 20 h. After usual work-
up, the residue was chromatographed on a flash column (SiO2)
to give title alcohol 4b as a solid (127 mg, 65%); mp 78–79 ЊC;
[α]D ϩ11.7 (c 1.17, CHCl3); δH(270 MHz; CDCl3) 1.53–1.70 (2
H, m), 1.75–1.90 (2 H, m), 2.79 (2 H, br), 3.18 (2 H, dd, J 9.76
and 3.42), 3.27 (6 H, s), 3.24–3.32 (3 H, m), 3.95 (1 H, d,
J 14.16), 5.37 (1 H, br) and 7.14–7.60 (10 H, m, ArH); MS (EI)
m/z (%) 354 (8, Mϩ Ϫ 1) and 337 (100, Mϩ Ϫ 18) (Found: C,
74.1; H, 8.3; N, 3.95. C22H29NO3 requires C, 74.33; H, 8.22; N,
3.94%).
1
units of 10Ϫ1 deg cm2 gϪ1. H NMR spectra were determined
for solutions in CDCl3 with tetramethylsilane (TMS) as
internal standard on a JNM-GX270 spectrometer; J-values
are in Hz. Mass spectra were recorded with a JMS D-300
instrument. FAB Mass spectra [in m-nitrobenzyl alcohol
(NBA) or glycerine (Gly)] were recorded on a JEOL JMS-
HX100 mass spectrometer. All solid compounds reported in
this paper gave satisfactory CHN microanalyses with a Perkin-
Elmer Model 240 analyzer. Hexane was distilled from calcium
hydride under nitrogen. The preparations of compounds 1, 2,
5 and 9 were reported in a previous paper.9 All ethylation
experiments were performed under argon using standard
Schlenk techniques. The optical purities of sec-alcohols were
determined by HPLC analysis using a chiral stationary phase
column (column, Daicel Co. CHIRALCEL OD; eluent,
100:0.5–2 hexane–propan-2-ol mixture; flow rate, 1.0 ml
(2R,5R)-Bis(methoxycarbonyl)-N-methylpyrrolidine 6
Sodium cyanoborohydride (200 mg, 3.22 mmol) and two drops
of acetic acid were added to a solution of (2R,5R)-bis(methoxy-
carbonyl)pyrrolidine 5 (300 mg, 1.61 mmol) in acetonitrile (5
ml) containing aq. formaldehyde (30%; 78.3 µl) and the reac-
tion mixture was stirred for ca. 2 h at rt. After usual work-up,
the residue was chromatographed on a flash column (SiO2) to
give title compound 6 as an oil (259 mg, 80%); [α]D ϩ100.3 (c 1.0,
CHCl3); δH(270 MHz; CDCl3) 1.51–2.0 (4 H, m), 3.20 (3 H, s,
NMe), 3.64 (6 H, s, OMe) and 4.10–4.40 (2 H, m); MS (EI) m/z
(%) 201 (10, Mϩ), 142 (100, Mϩ Ϫ 59) and 59 (60, Mϩ Ϫ 142)
(Found: C, 53.5; H, 7.5; N, 6.9. C9H15NO4 requires C, 53.72; H,
7.51; N, 6.96%).
1
minϪ1; detection, 254 nm light) or H NMR analysis of the
corresponding (ϩ)-MTPA ester, and the absolute configur-
ation of the major enantiomer was assigned according to the
sign of the specific rotation.
Preparation of the corresponding (؉)-á-methoxy-á-(trifluoro-
methyl)phenylacetic acid ester [(؉)-MTPA ester]
Oxalyl dichloride (144.7 mg, 1.14 mmol) was added to a
hexane solution (10 ml) of (ϩ)-α-methoxy-α-(trifluoromethyl)-
phenylacetic acid (56.2 mg, 0.24 mmol) and DMF (17.5 mg,
0.24 mmol) at rt and the reaction mixture was stirred for 1 h.
After filtration, and removal of the solvent under reduced pres-
sure, the residue was added to a dichloromethane solution of
the obtained sec-alcohol (0.2 mmol), triethylamine (60.7 mg,
0.6 mmol) and DMAP (10 mg, 0.08 mmol) at rt. The reaction
mixture was also stirred at rt for 1 h. After usual work-up, the
residue was purified by TLC (20 cm × 20 cm. Developer 4:1
hexane–ethyl acetate mixture) to give the corresponding (ϩ)-
MTPA ester.
(2R,5R)-Bis(hydroxydiphenylmethyl)-N-methylpyrrolidine 7a
Compound 7a was prepared from the reaction of 6 (200 mg, 1.0
mmol) with an excess of phenylmagnesium bromide in THF (30
ml) at rt for 3 h and under reflux for 3 h. After usual work-up,
the residue was chromatographed on a flash column (SiO2) to
give title diol 7a as a solid (250 mg, 50%), mp 246–248 ЊC; [α]D
ϩ71.6 (c 0.5, CHCl3); δH(270 MHz; CDCl3) 1.51–2.0 (4 H, m),
2.84 (3 H, s, NMe), 4.10–4.40 (2 H, m) and 7.0–7.60 (20 H, m,
ArH); MS (EI) m/z (%) 449 (10, Mϩ) and 266 (100, Mϩ Ϫ 183)
(Found: C, 82.8; H, 6.9; N, 3.1. C31H31NO2 requires C, 82.82; H,
6.94; N, 3.12%).
2550
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
(2R,5R)-Bis[hydroxybis(4-methylphenyl)methyl]-N-methyl-
pyrrolidine 7b
N, 6.35%; HRMS (EI) m/z 219.1470 (Mϩ). C10H21NO4 requires
C, 54.78; H, 9.65; N, 6.39%; M, 219.1471].
Compound 7b was prepared in the same manner as that
described above, with 4-methylphenylmagnesium bromide
(152 mg, 35%), mp 195–197 ЊC; [α]D ϩ60.8 (c 0.5, CHCl3);
δH(270 MHz; CDCl3) 1.51–2.0 (4 H, m), 2.30 (12 H, s, Me), 2.84
(3 H, s, NMe), 4.10–4.40 (2 H, m) and 7.0–7.60 (16 H, m, ArH);
MS (EI) m/z (%) 505 (10, Mϩ) and 294 (100, Mϩ Ϫ 211)
(Found: C, 83.0; H, 7.78; N, 2.7. C35H39NO2 requires C, 83.13;
H, 7.77; N, 2.77%).
(2R,5R)-Bis(methoxyethoxymethyl)pyrrolidine 11b
Compound 11b was prepared in the same manner as that
described above, from compound 10b (175 mg, 92%); [α]D
Ϫ4.4 (c 1.0, CH2Cl2); δH(270 MHz; CDCl3) 1.40–1.60 (2 H,
m), 1.90–2.10 (2 H, m), 3.40 (6 H, s, CH3), 3.34–3.70 (6 H, m),
3.40–3.70 (8 H, m, OCH2CH2O) and 4.75 (4 H, s, OCH2O)
[Found: C, 54.7; H, 9.5; N, 4.5%; HRMS (EI) m/z 307.1990
(Mϩ). C14H29NO6 requires C, 54.70; H, 9.51; N, 4.56%; M,
307.1996].
(2R,5R)-Bis(methoxymethoxymethyl)-N-[(1S)-phenylethyl]-
pyrrolidine 10a
Compound 10a was prepared from the reaction of (2R,5R)-
bis(hydroxymethyl)-N-[(1S)-phenylethyl]pyrrolidine 9 (200 mg,
0.85 mmol) with methoxymethyl chloride (360 mg, 4.5 mmol) in
the presence of N,N-diisopropylethylamine (DIPEA) (1.30 g,
10 mmol) in DMF (20 ml). After usual work-up, the residue
was chromatographed on a flash column (SiO2) to give title
compound 10a as an oil (247 mg, 90%); δH(270 MHz; CDCl3)
1.49 (3 H, d, J 6.4, CH3), 1.60–1.90 (2 H, m), 1.90–2.20 (2 H,
m), 3.05 (2 H, dd, J 8.3 and 8.3, CH2), 3.27 (6 H, s, OMe), 3.10–
3.40 (4 H, m), 3.96 (1 H, q, J 6.4), 4.45 (4 H, s, OCH2O) and
7.20–7.60 (5 H, m, ArH) [Found: C, 66.8; H, 9.0; N, 4.3%;
HRMS (EI) m/z 323.2096 (Mϩ). C18H29NO4 requires C, 66.85;
H, 9.04; N, 4.33%; M, 323.2098].
(2R,5R)-Bis(tert-butyldimethylsiloxymethyl)pyrrolidine 11c
Compound 11c was prepared in the same manner as that
described above, from compound 10c (178 mg, 80%); [α]D
ϩ10.4 (c 1.17, CH2Cl2); δH(270 MHz; CDCl3) 0.10 (12 H, s,
CH3), 0.90 [18 H, s, (CH3)3C], 1.30–1.50 (2 H, m), 1.80–1.95 (2
H, m), 1.96 (1 H, s), 3.25 (2 H, qu), 3.45 (4 H, dd, J 5.86 and
3.20) [Found: C, 60.15; H, 11.45; N, 3.9%; HRMS (EI) m/z
359.2668 (Mϩ). C18H41NO2Si2 requires C, 60.11; H, 11.49; N,
3.90%; M, 359.2677].
(2R,5R)-Bis(tert-butyldiphenylsiloxymethyl)pyrrolidine 11d
Compound 11d was prepared in the same manner as that
described above, from compound 10d (188 mg, 50%); [α]D ϩ1.5
(c 1.0, CH2Cl2); δH(270 MHz; CDCl3) 1.0 [18 H, s, (CH3)3C],
1.70–2.0 (4 H, m), 3.30–3.50 (2 H, m), 3.60–3.80 (4 H, m) and
7.30–7.80 (20 H, m, ArH) [Found: C, 75.05; H, 8.05; N, 2.3%;
HRMS (EI) m/z 607.3301 (Mϩ). C38H49NO2Si2 requires C,
75.07; H, 8.12; N, 2.30%; M, 607.3304].
(2R,5R)-Bis(methoxyethoxymethyl)-N-[(1S)-phenylethyl]-
pyrrolidine 10b
Compound 10b was prepared in the same manner as that
described above, with MEMCl, DIPEA and DMF (279 mg,
80%); δH(270 MHz; CDCl3) 1.48 (3 H, d, J 6.8, CH3), 1.70–1.90
(2 H, m), 1.90–2.10 (2 H, m), 3.06 (2 H, dd, J 8.3 and 8.3, CH2),
3.20–3.35 (4 H, m), 3.38 (6 H, s, CH3), 3.50–3.70 (8 H, m,
OCH2CH2O), 3.95 (1 H, q, J 6.8), 4.55 (4 H, s, OCH2O) and
7.20–7.50 (5 H, m, ArH) [Found: C, 64.1; H, 9.05; N, 3.4%;
HRMS (EI) m/z 411.2617 (Mϩ). C22H37NO6 requires C, 64.21;
H, 9.06; N, 3.40%; M, 411.2622].
N-Ethoxycarbonylmethyl-(2R,5R)-bis(methoxymethyl)-
pyrrolidine 12a
Compound 12a was prepared from the reaction of compound
11a (323 mg, 2.04 mmol) with ethyl bromoacetate (417 mg, 2.5
mmol) in the presence of potassium carbonate (345 mg, 2.5
mmol) in acetonitrile (20 ml) at rt for 24 h. After usual work-up,
the residue was purified by means of flash column chroma-
tography (eluent: ethyl acetate–hexane 1:4) to give title com-
pound 12a as an oil (214 mg, 35%); [α]D ϩ52.5 (c 0.5, CHCl3);
δH(270 MHz; CDCl3) 1.27 (3 H, t, J 6.4, CH3), 1.52–1.80 (2 H,
m), 2.0–2.20 (2 H, m), 3.35 (6 H, s, OCH3), 3.40–3.55 (6 H, m),
3.70 (1 H, d, J 15.2), 3.73 (1 H, d, J 15.2), 4.14 (2 H, q, J 6.8,
CH2) and 4.58 (4 H, s, OCH2O) [Found: C, 55.0; H, 8.95; N,
4.6%; HRMS (EI) m/z 305.1835 (Mϩ). C14H27NO6 requires C,
55.07; H, 8.91; N, 4.59%; M, 305.1839].
(2R,5R)-Bis(tert-butyldimethylsiloxymethyl)-N-[(1S)-phenyl-
ethyl]pyrrolidine 10c
Compound 10c was prepared in the same manner as that
described above, with TBDMSCl, DIPEA and DMF (373 mg,
95%); [α]D20 ϩ25.1 (c 1.0, CH2Cl2); δH(270 MHz; CDCl3) Ϫ0.07
(6 H, s, CH3), Ϫ0.09 (6 H, s, CH3), 0.83 [18 H, s, C(CH3)3],
1.45 (3 H, d, J 6.8, CH3), 1.60–1.70 (2 H, m), 1.80–2.0 (2 H,
m), 3.10–3.20 (4 H, m, CH2), 3.23 (2 H, dd, J 5.86 and 3.2),
4.02 (1 H, q, J 6.8) and 7.20–7.50 (5 H, m, ArH) [Found: C,
67.2; H, 10.5; N, 3.0%; HRMS (EI) m/z 463.3301 (Mϩ).
C26H49NO2Si2 requires C, 67.33; H, 10.65; N, 3.02%; M,
463.3304].
N-Ethoxycarbonylmethyl-(2R,5R)-bis(methoxyethoxymethyl)-
pyrrolidine 12b
Compound 12b was prepared in the same manner as that
described above, from compound 11b (281 mg, 35%); [α]D
ϩ60.1 (c 0.5, CHCl3); δH(270 MHz; CDCl3) 1.34 (3 H, t, J 6.4,
CH3), 1.60–1.80 (2 H, m), 2.0–2.20 (2 H, m), 3.47 (6 H, s,
OCH3), 3.50–3.80 (12 H, m), 3.70–3.85 (4 H, m), 4.23 (2 H, q, J
6.8, CH2) and 4.75 (4 H, s, OCH2O) (Found: C, 54.85; H, 8.95;
N, 3.6%; HRMS (EI) m/z 393.2360 (Mϩ). C18H35NO8 requires
C, 54.95; H, 8.97; N, 3.56%; M, 393.2364).
(2R,5R)-Bis(tert-butyldiphenylsiloxymethyl)-N-[(1S)-phenyl-
ethyl]pyrrolidine 10d
Compound 10d was prepared in the same manner as that
described above, with TBDPSCl, DIPEA and DMF (513 mg,
85%); [α]D20 ϩ13.4 (c 1, CH2Cl2); δH(270 MHz; CDCl3) 0.99
[18 H, s, (CH3)3C], 1.15 [3 H, d, J 6.8], 1.50–1.60 (2 H, m), 1.90–
2.0 (2 H, m), 3.10–3.50 (6 H, m), 3.80 (1 H, q, J 6.4) and 7.0–
7.80 (25 H, m, ArH) [Found: C, 77.5; H, 8.1; N, 1.9%; HRMS
(EI) m/z 711.3920 (Mϩ). C46H57NO2Si2 requires C, 77.59; H,
8.07; N, 1.97%; M, 711.3930].
(2R,5R)-Bis(tert-butyldimethylsiloxymethyl)-N-(ethoxy-
carbonylmethyl)pyrrolidine 12c
Compound 12c was prepared in the same manner as that
described above, from compound 11c (318 mg, 35%); [α]D ϩ40.3
(c 0.5, CHCl3); δH(270 MHz; CDCl3) 0.08 (6 H, s, CH3), 0.085
(6 H, s, CH3), 1.24 (3 H, t, J 6.4, CH3), 1.50–1.70 (2 H, m),
1.85–2.10 (2 H, m), 3.20–3.28 (2 H, m), 3.55 (4 H, dd, J 5.6 and
3.4, CH2), 3.68 (1 H, d, J 17.8), 3.79 (1 H, d, J 17.8) and 4.14 (2
H, q, J 6.4, CH2) [Found: C, 59.25; H, 10.65; N, 3.1%; HRMS
(EI) m/z 445.3043 (Mϩ). C22H47NO4Si2 requires C, 59.28; H,
10.63; N, 3.14%; M, 445.3045].
(2R,5R)-Bis(methoxymethyl)pyrrolidine 11a
Compound 11a was prepared by catalytic hydrogenolysis of
compound 10a (200 mg, 0.62 mmol) over palladium hydroxide
in methanol (30 ml) (125 mg, 92%); [α]D Ϫ6.4 (c 1.0, CH2Cl2);
δH(270 MHz; CDCl3) 1.60–1.90 (2 H, m), 1.90–2.20 (2 H, m),
3.05 (2 H, dd, J 8.3 and 8.3, CH2), 3.27 (6 H, s, OCH3), 3.10–
3.40 (4 H, m) and 4.45 (4 H, s, OCH2O) [Found: C, 54.7; H, 9.5;
J. Chem. Soc., Perkin Trans. 1, 1998
2551

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(2R,5R)-Bis(tert-butyldiphenylsiloxymethyl)-N-ethoxycarbonyl-
methylpyrrolidine 12d
(2R,5R)-Bis(tert-butyldimethylsiloxymethyl)-N-(2-mercapto-
ethyl)pyrrolidine 14
Compound 12d was prepared in the same manner as that
described above, from compound 11d (495 mg, 35%); [α]D
ϩ43.6 (c 0.5, CHCl3); δH(270 MHz; CDCl3) 1.05 [18 H, s,
(CH3)3C], 1.14 (3 H, t, J 6.8, CH3), 1.50–1.70 (2 H, m), 1.90–
2.10 (2 H, m), 3.40–3.55 (2 H, m), 3.50–3.75 (4 H, m), 3.80–3.90
(2 H, m), 4.25 (2 H, q, J 6.4, CH2) and 7.30–7.80 (20 H, m,
ArH) [Found: C, 72.65; H, 7.95; N, 2.1%; HRMS (EI) m/z
693.3670 (Mϩ). C42H55NO4Si2 requires C, 72.68; H, 7.99; N,
2.02%; M, 693.3672].
Compound 14 was prepared from the reaction of free amine 11c
(200 mg, 0.56 mmol) with excess of ethylene sulfide in aceto-
nitrile (20 ml) at rt. After evaporation under reduced pressure,
the residue was purified by means of flash column chroma-
tography (eluent: ethyl acetate–hexane 1:4) to give title com-
pound 14 as an oil (152 mg, 65%); [α]D ϩ12.6 (c 0.5, CHCl3);
δH(270 MHz; CDCl3) 0.01 (12 H, s, CH3), 0.85 (18 H, s, CH3),
1.50–1.70 (2 H, m), 1.80–2.0 (2 H, m), 2.45–2.95 (4 H, m), 3.0–
3.20 (3 H, m), 3.42 (2 H, dd, J 10.0 and 5.37) and 3.52 (2 H, J
10.0 and 5.37) [Found: C, 57.2; H, 10.75; N, 3.4%; HRMS (EI)
m/z 419.2710 (Mϩ). C20H45NO2SSi2 requires C, 57.22; H, 10.80;
N, 3.34%; M, 419.2712].
N-(2-Hydroxy-2,2-diphenylethyl)-(2R,5R)-bis(methoxymethyl)-
pyrrolidine 13a
Compound 13a was prepared from the reaction of compound
12a (100 mg, 0.35 mmol) with phenylmagnesium bromide (1 ;
1.2 ml) in THF (15 ml) at rt for 24 h under nitrogen. After usual
work-up, the residue was purified by means of flash column
chromatography (eluent: ethyl acetate–hexane 1:4) to give title
compound 13a as an oil (51 mg, 35%); [α]D ϩ10.4 (c 0.95,
CHCl3); δH(270 MHz; CDCl3) 1.55–1.80 (2 H, m), 1.85–2.10 (2
H, m), 2.80–3.0 (2 H, m), 3.31 (1 H, d, J 13.7), 3.34 (6 H, s,
OCH3), 3.96 (1 H, d, J 13.7), 4.56 (4 H, s, OCH2O) and 7.10–
7.70 (10 H, m, ArH) [Found: C, 69.35; H, 7.95; N, 3.3%; HRMS
(EI) m/z 415.2355 (Mϩ). C24H33NO5 requires C, 69.37; H, 8.01;
N, 3.37%; M, 415.2360].
Typical reaction procedure
To a suspension of β-aminoalcohol 4b (18.0 mg, 0.050 mmol) in
hexane (2.0 ml) was added diethylzinc (2.2 mmol, 2.2 ml of 1 
hexane solution) at 0 ЊC. After stirring of the mixture for 0.5 h,
benzaldehyde (106.0 mg, 1.0 mmol) was added and the reaction
mixture was stirred for 24 h at 0 ЊC. The reaction was quenched
by 3% aq. HCl and the product was extracted with ethyl acetate.
The extract was dried over MgSO4, and then evaporated under
reduced pressure. The residue was purified by silica gel TLC to
give optically active 1-phenylpropan-1-ol 8 (134.2 mg, 99%).
References
N-(2-Hydroxy-2,2-diphenylethyl)-(2R,5R)-bis(methoxyethoxy-
methyl)pyrrolidine 13b
1 H. B. Kagan and T. P. Dang, J. Am. Chem. Soc., 1972, 94, 6429;
J. K. Whitesell, Chem. Rev., 1989, 89, 1581.
2 Y. Masaki, H. Oda, K. Kazuta, A. Usui, A. Itoh and F. Xu,
Tetrahedron Lett., 1992, 33, 5089.
3 M. Shi, Y. Satoh, T. Makihara and Y. Masaki, Tetrahedron:
Asymmetry, 1995, 6, 2109.
4 T. Katsuki and M. Yamaguchi, J. Synth. Org. Chem. Jpn., 1986,
44, 532; S. Ikegami, H. Uchiyama, T. Hayama, T. Katsuki and
M. Yamaguchi, Tetrahedron, 1988, 44, 5333 and references cited
therein; V. Gouverneur and L. Ghosez, Tetrahedron: Asymmetry,
1990, 1, 363; Tetrahedron Lett., 1991, 32, 5349.
5 Y. Kawanami, Y. Ito, T. Kitagawa, Y. Taniguchi, T. Katsuki and
M. Yamaguchi, Tetrahedron Lett., 1984, 25, 857.
6 M. Marzi and D. Misiti, Tetrahedron Lett., 1989, 30, 6075.
7 S. Takano, M. Moriya, Y. Iwabuchi and K. Ogasawara, Tetrahedron
Lett., 1989, 30, 3805.
8 K. Izawa, S. Nishi and S. Asada, Jpn. Kokai Tokkyo Koko, 6229, 569
[8729, 569] (Chem. Abstr., 1987, 106, 213 770v).
Compound 13b was prepared in the same manner as that
described above, from compound 12b (62 mg, 35%); [α]D ϩ6.9
(c 1.05, CHCl3); δH(270 MHz; CDCl3) 1.51–1.80 (2 H, m), 1.80–
2.0 (2 H, m), 2.80–2.95 (2 H, m), 3.31 (1 H, d, J 10.2), 3.30–3.50
(4 H, m), 3.38 (6 H, s, OCH3), 3.54–3.62 (4 H, m), 3.70–3.80
(5 H, m), 4.0 (1 H, d, J 10.2), 4.66 (4 H, s, OCH2O) and 7.15–
7.80 (10 H, m, ArH) [Found: C, 66.75; H, 8.15; N, 2.76%;
HRMS (EI) m/z 503.2881 (Mϩ). C28H41NO7 requires C, 66.78;
H, 8.21; N, 2.78%; M, 503.2884].
(2R,5R)-Bis(tert-butyldimethylsiloxymethyl)-N-(2-hydroxy-2,2-
diphenylethyl)pyrrolidine 13c
Compound 13c was prepared in the same manner as that
described above, from compound 12c (68 mg, 35%); [α]D Ϫ3.9
(c 0.87, CHCl3); δH(270 MHz; CDCl3) 0.05 (6 H, s, CH3), 0.10
(6 H, s, CH3), 0.85 [18 H, s, (CH3)3C], 1.40–1.75 (2 H, m), 1.80–
2.0 (2 H, m), 2.70–2.90 (2 H, m), 3.28 (1 H, d, J 13.2), 3.50 (2 H,
dd, J 10.3 and 3.4), 3.51 (2 H, dd, J 10.3 and 3.4), 4.0 (1 H, d, J
13.2) and 7.10–7.60 (10 H, m, ArH) [Found: C, 69.05; H, 9.65;
N, 2.5%; HRMS (EI) m/z 555.3560 (Mϩ). C32H53NO3Si2
requires C, 69.13; H, 9.61; N, 2.52%; M, 555.3566].
9 Y. Yamamoto, J. Hoshino, Y. Fujimoto, J. Ohmoto and S. Sawada,
Synthesis, 1993, 298.
10 E. J. Corey, P.-W. Yuen, F. J. Hannon and D. A. Wierda, J. Org.
Chem., 1990, 55, 784; R. Noyori and M. Kitamura, Angew. Chem.,
Int. Ed. Engl., 1991, 30, 49 and references cited therein.
11 N. Oguni, Y. Matsuda and T. Kaneko, J. Am. Chem. Soc., 1988, 110,
7877; M. Kitamura, S. Okada, S. Suga and R. Noyori, ibid., 1989,
111, 4028.
12 J. Kang, J. W. Lee and J. I. Kim, J. Chem. Soc., Chem. Commun.,
1994, 2009.
13 K. Soai, A. Ookawa, K. Ogawa and T. Kaba, J. Chem. Soc., Chem.
Commun., 1987, 467.
14 Y. Masaki, Y. Satoh, T. Makihara and M. Shi, Chem. Pharm. Bull.,
1996, 44, 454.
15 M. Kitamura, S. Suga, M. Niwa and R. Noyori, J. Am. Chem. Soc.,
1995, 117, 4832.
(2R,5R)-Bis(tert-butyldiphenylsiloxymethyl)-N-(2-hydroxy-2,2-
diphenylethyl)pyrrolidine 13d
Compound 13d was prepared in the same manner as that
described above, from compound 12d (98 mg, 35%); [α]D Ϫ6.4
(c 0.5, CHCl3); δH(270 MHz; CDCl3) 1.05 [18 H, s, (CH3)3C],
1.60–1.90 (2 H, m), 1.90–2.10 (2 H, m), 2.75–2.90 (2 H, m), 3.10
(1 H, d, J 13.7), 3.26 (2 H, dd, J 10.4 and 3.7, CH2), 3.52 (2 H,
dd, J 10.4 and 4.4, CH2), 3.74 (1 H, d, J 13.7) and 7.0–7.80 (30
H, m, ArH) [Found: C, 77.65; H, 7.6; N, 1.8%; HRMS (EI) m/z
803.4192 (Mϩ). C52H61NO3Si2 requires C, 77.66; H, 7.65; N,
1.74%; M, 803.4192].
Paper 8/03336F
Received 5th May 1998
Accepted 1st June 1998
2552
J. Chem. Soc., Perkin Trans. 1, 1998