Asymmetric aldol reaction of 2-cyanopropionates catalyzed by a trans-chelating chiral diphosphine-rhodium(I) complex: Highly enantioselective construction of quaternary chiral carbon centers at α-positions of nitriles

Article abstract of DOI:10.1016/S0022-328X(00)00049-8

The aldol reaction of 2-cyanopropionates with aldehydes proceeded under neutral conditions in the presence of a catalytic amount of the rhodium complex generated in situ from Rh(acac)(CO)₂ and triphenylphosphine, to give the corresponding β-hyd

Full text of DOI:10.1016/S0022-328X(00)00049-8

www.elsevier.nl/locate/jorganchem
Journal of Organometallic Chemistry 603 (2000) 18–29
Asymmetric aldol reaction of 2-cyanopropionates catalyzed by a
trans-chelating chiral diphosphine–rhodium(I) complex: highly
enantioselective construction of quaternary chiral carbon centers at
a-positions of nitriles
Ryoichi Kuwano *, Hiroshi Miyazaki, Yoshihiko Ito *
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto Uni6ersity, Kyoto 606-8501, Japan
Received 22 November 1999; received in revised form 18 January 2000
Abstract
The aldol reaction of 2-cyanopropionates with aldehydes proceeded under neutral conditions in the presence of a catalytic
amount of the rhodium complex generated in situ from Rh(acac)(CO)2 and triphenylphosphine, to give the corresponding
b-hydroxy-a-cyanocarboxylates bearing a quaternary chiral carbon center at the a-position of the cyano group. A high degree of
asymmetric induction for the aldol reaction was achieved by use of trans-chelating chiral diphosphine ligands, (R,R)-2,2¦-bis[(S)-
1
-(diarylphosphino)ethyl]-1,1¦-biferrocenes (TRAPs). The asymmetric aldol reactions gave optically active b-hydroxy-a-cyanocar-
boxylates with up to 94% ee. © 2000 Elsevier Science S.A. All rights reserved.
Keywords: Aldol reaction; Rhodium complex; Trans-chelating chiral ligand; Catalytic asymmetric synthesis
1
. Introduction
Recently, some low-valent transition metal complexes
were found to catalyze the Michael and the aldol
reactions of 2-cyanocarboxylates and related com-
Development of methodologies for enantioselective
3
carbon–carbon bond formation is desired in organic
synthesis [1]. In particular, catalytic asymmetric aldol
reactions provide a powerful tool for stereoselective
construction of a b-hydroxy a-substituted carbonyl unit
with vicinal chiral centers [2], which constitutes various
biologically active natural products [3]. Many efforts
have recently been made toward the development of
catalytic asymmetric aldol reactions [4]. However,
highly enantioselective synthesis of an aldol building
block bearing a quaternary chiral carbon center has
pounds under neutral conditions [14]. Coordination of
the cyano nitrogen to the transition metal atom enabled
the 2-cyanocarboxylates to generate the enolate inter-
mediate, which reacted with electrophiles [9b,15]. In the
preceding papers, we described a highly enantioselective
Michael reaction of 2-cyanopropionates with vinyl ke-
tones and acrolein catalyzed by a rhodium(I) complex
bearing a trans-chelating chiral diphosphine, (S,S)-
1
4
(R,R)-PhTRAP (1a) [16–19].
2
met with difficulty .
*
Corresponding authors. Fax: +81-75-753 5668.
E-mail address: kuwano@sbchem.kyoto-u.ac.jp (R. Kuwano)
1
For recent successful examples of catalytic asymmetric aldol
reaction using isolated metal enolate, see Ref. [5].
2
3
For a review of catalytic asymmetric construction of quaternary
For ruthenium catalyst, see Ref. [9]. For rhodium catalyst, see
chiral carbon centers, see Ref. [6]. For catalytic asymmetric aldol
reactions constructing quaternary chiral carbon centers on enolates,
see Ref. [7]. For catalytic asymmetric aldol reactions constructing
quaternary chiral carbon centers on electrophiles, see Ref. [8].
Ref. [10]. For iridium catalyst, see Ref. [11]. For rhenium catalyst, see
Ref. [12]. For palladium catalyst, see [13].
(S,S)-(R,R)-TRAP=(R,R)-2,2¦-Bis[(S)-1-(dialkylphosphino)ethyl]-
1,1¦-biferrocene: Ref. [16].
4
0022-328X/00/$ - see front matter © 2000 Elsevier Science S.A. All rights reserved.
PII: S0022-328X(00)00049-8

R. Kuwano et al. / Journal of Organometallic Chemistry 603 (2000) 18–29
19
On the other hand, the catalytic aldol reaction has
been limited to the Knoevenagel-type reaction giving
achiral a,b-unsaturated nitriles [9,11,12] except for the
aldol reaction of 2-alkoxymalononitrile catalyzed by a
palladium complex [13]. Therefore, no asymmetric aldol
reaction of 2-cyanocarboxylates has so far been re-
ported.
could be isolated without such decomposition if the
aldol product was thermodynamically stable to the
reactants. Then, we estimated theoretically the thermo-
dynamical stabilities of the aldol products 4aa–ag to
the corresponding reactants, methyl 2-cyanopropionate
(2a) and various aldehydes 3a–g, by a DFT method
(Eq. (2)).
Herein, we report a highly enantioselective aldol
reaction of 2-cyanopropionates using a chiral rhodium
catalyst, where TRAP (1) ligands are the most
5
enantioselective . The catalytic asymmetric aldol reac-
tion produces the corresponding optically active b-hy-
droxy-a-cyanocarboxylates bearing
a
quaternary
carbon center at the a-position of the cyano group with
up to 94% ee [21].
(2)
Geometry optimization and computation of energy
were performed at the B3LYP/6-31G(d) level . The
6
2. Results and discussion
starting structures of 2a and 3 for the geometry opti-
mization were searched by the semiempirical AM1
method [25]. The conformations of 4 for the calcula-
tions were chosen carefully by the consideration to the
s–s* interactions in the molecules [26], and several
possible conformations were optimized and compared
with each other in their potential energies. Vibrational
analysis was carried out for determination of zero-point
energy correction (ZPE), which was scaled with a factor
of 0.9806 [27]. For discussion of energetics, enthalpy at
2
.1. Aldol reaction of ethyl 2-cyanopropionate
2
catalyzed by Rh(acac)(CO) –2PPh3
Initially, we attempted the reaction of ethyl 2-
cyanopropionate (2b) and benzaldehyde (3e) in the
presence of the rhodium catalyst generated in situ from
Rh(acac)(CO) and 2 molar equivalents of triphenyl-
phosphine (Eq. (1)).
2
0
K was employed, which is the sum of the potential
energy and scaled ZPE.
The calculated gaps of the enthalpies between 2+3
and 4 are given in Table 1. The enthalpy change of the
aldol reaction of 2a with 3e is positive in agreement
with the result of the above experiment (entry 5). As the
size of substituent R of aldehyde decreases, the thermo-
dynamics is favorable to the formation of 4 (entries
(
1)
The reaction proceeded in 30% conversion of 2b to
give the aldol product 4be at room temperature (r.t.)
for 48 h, which was detected by the H-NMR analysis
of the reaction mixture. Any techniques of purification,
however, caused the retro-aldol reaction of 4be to give
the starting materials 2b and 3e. The result suggested to
us that an aldol product made from 2b and an aldehyde
1
–4). The results suggest that the aldol reaction of 2
1
and formaldehyde (3a) proceeds more favorably than
those of other aldehydes, and that the aldol product
can be isolated more easily than 4be. Of note is that the
formations of 4af and 4ag are thermodynamically
preferable to the decomposition into the starting mate-
rials despite the bulkiness of 3f and 3g. The results may
be caused by the instability of these aldehydes. Geome-
try optimization starting from the aldolate of 4aa gives
the two molecules, enolate of 2a and 3a, with no energy
barrier, indicating that 4 will decompose into 2 and 3
under basic conditions.
Table 1
Gaps of enthalpies (at 0 K) between 2a+3 and 4 (kcal mol−1)
Entry
R (3)
Product (4)
DH (anti )
DH (syn)
1
2
3
4
5
6
7
H (3a)
Me (3b)
Et (3c)
4aa
4ab
4ac
4ad
4ae
4af
4ag
−8.68
−0.79
−1.22
+1.87
+4.85
−7.13
−9.21
On the above theoretical study, we examined the
aldol reactions of 2b with 3a using a catalytic amount
(1 mol%) of various rhodium complexes (Eq. (3),
Table 2).
−1.73
−2.10
+1.09
+4.31
−8.21
−8.56
i
Pr (3d)
Ph (3e)
MeO C (3f)
2
CF3 (3g)
6
Hybrid functional B3LYP: Ref. [22]. 6-31G(d) basis set: Ref. [23].
These DFT calculations were performed with the GAUSSIAN 98
program by CRAY Origin 2000 in the Supercomputer Laboratory,
Institute for Chemical Research, Kyoto University: Ref. [24].
5
Preliminary communication: Ref. [20].

20
R. Kuwano et al. / Journal of Organometallic Chemistry 603 (2000) 18–29
Table 2
phine (entry 1). Any by-products and 2b were not
detected in the H-NMR spectra of the evaporated
a
Catalytic aldol reaction of 2b with 3a
1
b
reaction mixture and the crude product after extraction.
The aldol 4ba was isolated without decomposition in
97% yield by medium-pressure liquid chromatography
on silica gel. RhH(PPh ) and RhH(CO)(PPh ) also
promoted the aldol reaction, but the latter catalyst [10]
presented lower catalytic activity (entries 2 and 3).
Bidentate diphosphines were possible to use as a ligand
on the rhodium catalyst (entry 4). Some phosphine
ligand was indispensable to the catalytic reaction (entry
Entry
Catalyst
Yield (4ba) (%)
1
2
3
4
5
Rh(acac)(CO) –2PPh
RhH(PPh3)
97
97
49
79
18
94
41
9
2
3
4
3
4
3 3
RhH(CO)(PPh3)3
Rh(acac)(CO) –dppf
Rh(acac)(CO)2
Rh(acac)(CO) –2PPh
Rh(acac)(CO) –2PPh
RhCl(CO)(PPh3)
c
2
d
6
7
2
3
e
2
3
8
2
5
). Commercially available formalin (37%) and
a
The reactions were carried out in THF (0.5 M) at r.t. 1 h unless
otherwise noted. 2b:3a:catalyst=100:133:1. An aqueous solution of
paraformaldehyde (10% wt) was used as a source of 3a.
paraformaldehyde itself, which are convenient sources
of formaldehyde, were usable for the catalytic aldol
reaction (entries 6 and 7). The latter reaction proceeded
much slower because of the insolubility of
paraformaldehyde to THF.
b
Isolated yield by MPLC.
dppf=1,1%-bis(diphenylphosphino)ferrocene.
Formalin (37% wt) was used instead of paraformaldehyde.
Paraformaldehyde was used directly without dissolution in water.
c
d
e
The anionic ligand on the rhodium atom plays a
crucial role in the catalytic aldol reaction. RhCl(CO)-
(
PPh ) gave 4ba in only 9% yield (entry 8). The acetyl-
3
2
acetonate and hydride ligands probably deprotonate
from the a-carbon of 2b to give a zwitter ionic
rhodium–enolate complex 5, where the cyano nitrogen
of the enolate coordinates to the rhodium atom
(
Scheme 1) [15]. The enolate ligand reacts with 3a to
form a rhodium–aldolate complex 6. The aldolate lig-
and deprotonates another 2b, giving 4ba and 5.
The aldol reactions of ethyl 2-cyanopropionate (2b)
with other aldehydes 3b–g were examined in the
presence of Rh(acac)(CO) –2PPh3 catalyst (Eq. (4),
Scheme 1.
2
Table 3).
(
3)
(
4)
The reactions were carried out in THF at r.t. for 1 h.
An aqueous solution of paraformaldehyde (10% wt)
was used as a source of 3a. The aldol reaction was
completed within 1 h by the rhodium(I) complex gener-
ated in situ from Rh(acac)(CO)2 and triphenylphos-
The reactions of 2b with 3b and 3c proceeded slowly
to produce 4bb and 4bc in good yields, but the stereo-
chemistries between 2- and 3-positions were not con-
trolled at all (entries 1 and 2). A larger aldehyde 3d did
Table 3
Aldol reaction of 2b and 3 catalyzed by Rh(acac)(CO) –2PPh catalyst a
2
3
Entry
R (3)
Time (h)
Products (4)
anti/syn b
Yield (%) c
1
2
3
4
5
Me (3b)
Et (3c)
Pr (3d)
48
72
4bb
4bc
52/48
53/47
74
51
i
No reaction
1
35
d
EtO C (3f)
4bf
4bg
46/53
57/43
99
75
2
e
CF3 (3g)
a
All reactions were carried out in THF (0.5 M) at r.t. 2b:3:Rh(acac)(CO) :PPh =100:150:1:2.
2
3
b
c
Determined by 1H-NMR analysis of the crude product.
Total yield of anti and syn isomers.
d
e
Commercially available polymeric 3f (toluene solution) was used.
Commercially available hydrate of 3g was used.

R. Kuwano et al. / Journal of Organometallic Chemistry 603 (2000) 18–29
21
Table 4
Asymmetric aldol reaction of 2 with 3a
a
Entry
X (2)
Ligand b
Solvent
THF
Temperature (°C)
Time (h)
Product (4)
4ba
Yield (%) c
ee (%)
47 d
1
2
3
4
5
6
7
OEt (2b)
OEt (2b)
OEt (2b)
OEt (2b)
OEt (2b)
OEt (2b)
OEt (2b)
1a
1a
1a
1a
1a
1a
1a
0
0
0
0
0
0
0
1.5
4
72
58
90
76
87
84
87
Toluene
CH Cl
4ba
1 d
11 d
1 d
19
3
4ba
2
2
MeOH
4ba
Et O
2
3
4ba
54 d
60 d
1 d
Bu O
3
4ba
2
i
Pr O
3
4ba
2
8
9
OMe (2a)
OEt (2b)
1a
1a
Bu O
−30
−30
100
42
4aa
4ba
67
85
35 e
74
2
d
Bu O
2
i
78 d
82 d
91 f
1
0
1
O Pr (2c)
1a
1a
Bu O
−30
−30
90
70
4ca
4da
86
80
2
t
1
O Bu (2d)
Bu O
2
i
12
13
14
OCH Pr (2e)
OCH Bu2 (2f)
OCHPh2 (2g)
1a
1a
1a
Bu O
−10
−10
−10
24
24
24
4ea
4fa
4ga
82
86
96
2
2
t
g
Bu O
93
2
h
Bu O
87
2
1
5 i
N(OMe)Me (2h)
1a
Bu O
2
0
5
4ha
80
61 h
i
92 f
94 f
74 f
1
1
6
7
8
9
0
1
2
OCH Pr (2e)
1b
1b
1c
1d
Bu O
−10
−30
−10
−10
−10
−10
−10
−10
24
24
24
24
24
24
45
24
4ea
4ea
4ea
4ea
4ea
4ea
4ea
4ea
87
47
44
54
58
86
48
84
2
2
i
OCH Pr (2e)
Bu O
2
2
i
1
1
2
2
2
OCH Pr (2e)
Bu O
2
2
i
f
OCH Pr (2e)
Bu O
70
2
2
i
3 f
OCH Pr (2e)
1e
Bu O
2
2
i
22 f
OCH Pr (2e)
1f
Bu O
2
2
i
BINAP i
f
OCH Pr (2e)
Bu O
12
2
2
j
i
93 f
2
3
OCH Pr2 (2e)
1a
Bu O
2
a
b
c
d
e
f
2
(0.25 M):3a:Rh(acac)(CO) :1=100:133:1.0:1.1.
2
(S,S)-(R,R)-1 was used.
Isolated yield.
Determined by HPLC analysis with CHIRALCEL OD-H.
Determined by HPLC analysis with CHIRALCEL OJ.
Determined by HPLC analysis with CHIRALCEL AD.
Determined by HPLC analysis with CHIRALCEL AS.
Determined by HPLC analysis of its N-(3,5-dintrophenyl)carbamate derivative with SUMICHIRAL OA-4500.
The reaction was carried out in 1.0 M. (R)-BINAP was used.
Formalin (37% wt) was used.
g
h
i
j
not react with 2b at all (entry 3). The aldol products 4bf
and 4bg were obtained in good yields without their
decomposition by retro-aldol reaction (entries 4 and 5).
were the most effective in related asymmetric reactions
of 2 to the best of our knowledge [17,19].
Table 4 summarized the results of the asymmetric
aldol reactions of 2 with formaldehyde (3a) using 1
2
2
.2. Catalytic asymmetric aldol reaction of
-cyanopropionates with formaldehyde
mol% of Rh(acac)(CO) –(S,S)-(R,R)-PhTRAP (1a)
catalyst under various conditions (Eq. (5)).
2
Next, we developed the asymmetric aldol reaction of
2-cyanopropionates (2) with aldehydes by use of opti-
cally active phosphine ligands instead of triphenylphos-
phine. Trans-chelating chiral ligands TRAP (1) were
chosen in this study, because the chiral diphosphines
(5)

22
R. Kuwano et al. / Journal of Organometallic Chemistry 603 (2000) 18–29
The enantiomeric excess of 4 was heavily dependent
upon the reaction solvent (entries 1–7). Only ethereal
lower enantioselectivity and catalytic activity (entry 18).
The aldol reaction using 1b proceeded at −30°C to
yield 4ea with 94% ee (entry 17). FurTRAP (1d), which
has smaller 2-furyl groups on the phosphorus atoms,
was less effective than 1a (entry 19). Probably, the
P-aromatic substituents of 1 play an important role in
the enantioface selection of the enolate of 2 coordinat-
ing to the rhodium atom, because ligands 1e and 1f
bearing P-aliphatic substituents presented low enan-
tioselectivities (entries 20 and 21). On the other hand,
cis-chelating chiral diphosphine ligands failed to give
4ea with high enantiomeric excess, indicating that the
trans-chelating property of 1 is a crucial factor of a
high degree of the asymmetric induction (entry 22). To
our surprise, commercially available formalin (37% wt
in water) gave 4ea without loss of the enantioselectivity
solvents, such as THF and Et O, produced successful
2
asymmetric induction for the asymmetric aldol reac-
tion. In particular, Bu O was the most effective for the
2
asymmetric aldol reaction of 2 using Rh(acac)(CO) –1a
2
catalyst (entry 6). Coordination of an oxygen lone pair
of the ethereal solvent to the rhodium atom is, perhaps,
important for the enantioface-selection of the enolate of
i
2
. The reaction carried out in Pr O gave the nearly
2
racemic product, because the large isopropyl groups of
the solvent molecule might shield the oxygen lone pairs
from the coordination to the rhodium atom (entry 7).
The size of the ester substituent of 2 was crucial for
the enantioselectivity of the asymmetric aldol reaction
entries 8–14). Methyl ester 2a gave 4aa with only 35%
ee. As the ester substituent of 2 was large, enantiomeric
excess of 4 was increased. 2-Cyanopropionates 2e and
(
(
93% ee) in high yield, although the selectivity was
heavily affected by the reaction solvent (entry 24).
2
f bearing a bulky secondary alkyl ester group gave
2
2
.3. Catalytic asymmetric aldol reaction of
-cyanopropionates with other aldehydes
aldol adducts 4ea and 4fa with high enantiomeric ex-
cesses, which have a quaternary chiral carbon center at
the a-position of the cyano group. Such large secondary
alkyl groups were more effective than the tert-butyl
group. Diphenylmethyl ester 2g, which is easily hy-
drolyzed with hydrogen or acid [28], also gave 4ga with
high enantiomeric excess (entry 14). N-Methoxy-N-
methylamide 2h, which is synthetically convertible to
aldehyde or ketone [29], provided 4ha with 61% ee
Other aldehydes 3b–f were subjected to the asym-
metric aldol reaction with (S,S)-(R,R)-TRAP–rhodium
catalyst (Eq. (6), Table 5).
(
entry 15).
The enantioselectivity and the rate of the aldol reac-
tion of 2e were slightly improved by electron-donating
ligand 1b (entry 16), while the electron-withdrawing
group on the P-aromatic substituents of 1c caused
(6)
Table 5
a
Asymmetric aldol reaction of 2 with 3
Entry
2
3
Time (h)
Product (4)
Yield (%) b
anti/syn c
ee (anti ) (%)
ee (syn) (%)
d
d
1
2
3
4
5
6
7
8
2b
2c
2e
2e
2e
2e
2e
2e
3b
3b
3b
3b
3b
3c
3e
3f
24
24
24
24
72
48
72
88
4bb
4cb
4eb
4eb
4eb
4ec
No reaction
4ef
63
61
67
80
80
76
45/55
47/53
81/19
77/23
84/16
75/25
31
55
23
50
33
28
43
10
e
e
f
f
86 (2S,3S)
78 (2S,3S)
78 (2S,3S)
57 (2S,3S)
g
f
f
h
f
f
i
j
j
k
91 (2S,3R) l
63 (2S,3S) l
88
68/32
a
All reactions were carried out in Bu O (0.25 M). 2:3:Rh(acac)(CO) :(S,S)-(R,R)-1a=100:750:1.0:1.1.
2
2
b
c
d
e
f
Combined yield of anti- and syn-4.
Determined by 1H-NMR analysis of the crude product.
Determined by HPLC analysis with CHIRALCEL AS.
Determined by HPLC analysis of its N-(3,5-dintrophenyl)carbamate derivative with SUMICHIRAL OA-4100.
Determined by HPLC analysis of its N-(3,5-dintrophenyl)carbamate derivative with SUMICHIRAL OA-4000.
The reaction was carried out in Bu O–H O (10:1).
g
h
i
2
2
(S,S)-(R,R)-1b was used.
Ten equivalents of 3c was used.
Determined by HPLC analysis of its N-(3,5-dintrophenyl)carbamate derivative with SUMICHIRAL OA-4500.
Two equivalents of 3f was used.
j
k
l
Determined by HPLC analysis of its N-(3,5-dintrophenyl)carbamate derivative with SUMICHIRAL OA-4400.

R. Kuwano et al. / Journal of Organometallic Chemistry 603 (2000) 18–29
23
syn-4eb was obtained from the aldol reaction of 2e and
b using Rh(acac)(CO) –2PPh catalyst. Addition of
3
2
3
water reduced the diastereo- and enantioselectivities
slightly (entry 4). Ligand 1b improved the diastereo-
selectivity, but lowered the enantiomeric excess of anti-
4
eb (entry 5). The aldol reaction of 2e with 3c pro-
ceeded, but with lower stereoselectivity (entry 6).
Benzaldehyde (3e) did not react at all because of the
steric hindrance of TRAP ligand (entry 7). Ethyl gly-
oxylate (3f) reacted smoothly with 2e giving a mixture
of 91% ee of anti-(2S,3R)-4ef and 63% ee of syn-
(
2S,3S)-4ef in a ratio of 68:32 (entry 8).
2.4. Stereocontrol in the catalytic asymmetric aldol
reaction
The observed stereochemistry at the 2-position of the
aldol products 4 suggests that (S,S)-(R,R)-1a on the
rhodium complex differentiates the steric bulkiness be-
tween the a-methyl and alkoxycarbonyl group of 2, one
of the P-phenyl substituents blocking the approach of
an aldehyde to the si-face of the enolate coordinating
to the rhodium atom [17b].
The preferential formation of anti-4 in the aldol
reactions of 2e with 3 may suggest that this reaction
proceeded through the antiperiplanar transition state
TS1 (Fig. 1). Compared with TS2 giving syn-4, TS1
Fig. 1. Possible structures for the transition state of the aldol reaction
of 2 with 3 using the 1a–rhodium catalyst.
avoids the steric repulsion between the aldehyde sub-
i
stituent (R) and the bulky CH Pr ester. The synclinal
2
transition state TS3 giving an anti-aldol may be less
favorable than TS4 due to the steric interaction be-
tween R and one of the P-phenyl groups of 1a. An-
other type of synclinal transition states such as TS3%, in
which the carbon–oxygen double bond of 3 lies in
parallel with the carbon–anionic oxygen bond of 2, are
energetically disfavored on the basis of not only steric
factor but also electrostatic considerations (Fig. 2).
The low diastereoselectivities in the reactions of 2b
and 2c may be due to the lesser steric repulsion between
the R and ester group, which results in the low
diastereoselectivities. The aldol reaction with 3f is antic-
ipated to be affected by the electrostatic repulsion
between the ethoxycarbonyl group of 3f and the oxo
anion in the zwitter ionic (enolato)rhodium, which may
cause the deterioration of the diastereoselectivity.
Fig. 2. Synclinal transition state TS3%.
Fig. 3. The results of the 1H-NMR analysis of 7.
The ester substituent of 2 influenced heavily not only
the enantioselectivity but also the ratio of anti- to
syn-isomer. The aldol reactions of ethyl ester 2b and
isopropyl ester 2c with 3b resulted in low enantioselec-
tivities and gave a mixture of both diastereomers in ca.
2.5. Assignment of the absolute configurations of the
aldol products
The absolute configuration of 4eb was deduced by
NMR techniques as follows. First, the absolute configu-
ration on the 3-carbon atom of the major diastereomer
of 4eb obtained from the present asymmetric aldol
1:1 (entries 1 and 2). The use of large diisopropylmethyl
ester 2e improved remarkably the selectivities, giving
anti-(2S,3S)-4eb with 86% ee in good anti-selectivity
1
(
anti:syn=81:19) (entry 3). The enantioface selection of
b is controlled by the chiral ligand 1a as well as the
ester substituent, because a 1:1 mixture of anti- and
reaction was assigned by the H-NMR analysis of its
3
(R)-O-methylmandelate 7. Representative chemical
shifts of the major and minor diastereomers of 7 are

24
R. Kuwano et al. / Journal of Organometallic Chemistry 603 (2000) 18–29
shown in Fig. 3. Proton resonances belonging to the
higher priority group of the major diastereomer of 4eb
appear in a lower magnetic field than those of the
minor isomer, indicating the absolute configuration at
the 3-position to be S according to the procedure
proposed by Trost [30].
Moreover, we succeeded in a highly enantioselective
catalytic aldol reaction of 2 with formaldehyde by use
of a trans-chelating chiral diphosphine ligand, (S,S)-
(R,R)-PhTRAP (1a) or 1b. The catalytic asymmetric
aldol reaction produced quaternary chiral carbon cen-
ters at the a-position of the cyano group with high
enantiomeric excesses (up to 94% ee). The size of the
ester substituent of 2 is essential for the high enantio-
selectivity. Aldehydes 3b and 3f gave preferentially anti-
aldol products (2S,3S)-4eb and (2S,3R)-4ef with high
enantiomeric excesses. Enantiofaces of aldehydes 3 re-
acting with the nucleophile is controlled by both the
chiral ligand and ester substituent.
The relative configuration of 4eb between the 2- and
1
1
3
-positions was assigned by the H{ H}-NOE experi-
ment of acetonide 8, which was prepared from a
diastereomer of racemic 4bb (Scheme 2). The
diastereomer was separable from another isomer by
medium-pressure liquid chromatography. After the pro-
tection of the hydroxyl group of 4bb with trimethylsilyl
group, the ethoxycarbonyl group was reduced success-
fully by lithium borohydride to give 1,3-diol 9 resulting
from the treatment of the reaction mixture with acid.
The trimethylsilyl protection was needed to prevent the
retro-aldol reaction of 4bb. The reaction of 9 with
4. Experimental
4.1. General
2,2-dimethoxypropane in the presence of camphor sul-
fonic acid catalyst gave acetonide 8. The result of the
NOE experiments of 8 is shown in Fig. 4, indicating
that the relative configuration of the starting 4bb is syn.
On the other hand, the diastereomeric mixture of 4eb
obtained from the asymmetric aldol reaction was con-
Optical rotations were measured with a Perkin–
Elmer 243 polarimeter. NMR spectra were obtained
with a Varian Gemini-2000 spectrometer and a Varian
VXR-200 spectrometer equipped with 7.0 T and 4.0 T
magnets, respectively. Preparative medium-pressure liq-
uid chromatographies were performed with a C.I.G.
pre-packed column CPS-223L-1 (Kusano). Flash
column chromatographies were performed with silica
gel 60 (230–400 mesh, Merck).
1
verted into 9. The H-NMR analysis of the diastereo-
meric mixture indicates that the major diastereomer of
4eb formed in the asymmetric aldol reaction using
TRAP ligand has anti-(2S,3S) configuration. The abso-
lute configurations of 4ec and 4ef were assigned in a
similar manner.
4.2. Materials
Tetrahydrofuran (THF), dibutyl ether (Bu O), and
2
3. Conclusions
toluene were distilled from sodium-benzophenone ketyl
under nitrogen atmosphere. Dichloromethane was dis-
The aldol reaction of 2-cyanopropionates (2) with
tilled from CaH . 2b and 3b–e were commercially
2
aldehydes was promoted under neutral conditions by a
available and purified with distillation before use.
catalytic amount of the rhodium complex generated
Rh(acac)(CO) was commercially available and purified
2
from Rh(acac)(CO) and triphenylphosphine. Success-
ful isolation of the aldol products 4 depended on the
thermodynamical stability of 4 to the reactants 2+3.
with sublimation before use. 2a, 2c–g [17b], and 3f [31]
used in the asymmetric aldol reaction were prepared
according to literature procedures.
2
4.3. 2-Cyano-N-methoxy-N-methylpropionamide (2h)
A solution of trimethylaluminum (7.2 g, 100 mmol)
in toluene (50 ml) was added dropwise to a suspension
of N,O-dimethylhydroxylamine hydrochloride (9.77 g,
1
00 mmol) in toluene (50 ml) at 0°C for 30 min. The
Scheme 2.
mixture was stirred at r.t. for 1 h. The resulting solution
was added dropwise to a solution of 2b (6.37 g, 50
mmol) in THF (50 ml) at 0°C for 20 min. After stirring
at r.t. for 16 h, the mixture was diluted carefully with
5
% HCl (aq.), and extracted with EtOAc. The organic
phase was washed with brine, dried over MgSO , and
4
evaporated. The residue was purified with distillation,
giving 4.25 g (60%) of 2h: Colorless oil; bp 125°C/18
Fig. 4. The results of the 1H{ H}-NOE experiments of 8.
1
mmHg; H-NMR (300 MHz, CDCl , TMS): l 1.54 (d,
1
3

R. Kuwano et al. / Journal of Organometallic Chemistry 603 (2000) 18–29
25
J=7.3 Hz, 3H), 3.25 (s, 3H), 3.83 (s, 3H), 3.86 (q,
(s, 3H), 2.49 (br d, 1H), 4.12 (br quintet, 1H), 4.32 (q,
1
3
1
13
1
J=7.3 Hz, 1H); C{ H}-NMR (75 MHz, CDCl ): l
J=7.1 Hz, 2H); C{ H}-NMR (75 MHz, CDCl ): l
3
3
14.4, 28.5, 32.6, 61.5, 118.2, 166.4.
13.9, 18.5, 18.9, 49.9, 63.0, 70.4, 118.4, 168.9.
4
.4. Catalytic aldol reaction of 2b with 3a
4.7. Ethyl 2-cyano-3-hydroxy-2-methylpentanoate (4bc)
Each diastereomer of 4bc was not separated by
[ethyl 2-cyano-3-hydroxy-2-methylpropionate (4ba)]
A suspension of paraformaldehyde (100 mg) in dis-
medium-pressure liquid chromatography at all. Color-
1
tilled water (1.0 ml) was stirred under reflux for 1 h,
giving a clear solution of paraformaldehyde. A solution
of Rh(acac)(CO) (2.6 mg, 10 mmol) and PPh (5.2 mg,
2
less oil; H-NMR (300 MHz, CDCl , TMS): l 1.08 (t,
3
J=7.2 Hz, 3H of a diastereomer), 1.09 (t, J=7.2 Hz,
3H of a diastereomer), 1.34 (t, J=7.2 Hz, 3H of a
2
3
0 mmol) in THF (2.0 ml) was stirred at r.t. After 10
diastereomer), 1.35 (t, J=7.1 Hz, 3H of
a
min, 2b (127 mg, 1.0 mmol) and the solution of
paraformaldehyde in water prepared freshly (0.4 ml, 1.3
mmol) were added to the solution. The mixture was
stirred at r.t. for 1 h. The mixture was diluted with
brine, and extracted with EtOAc. The organic phase
was dried over Na SO , and evaporated. The residue
diastereomer), 1.47–1.83 (m, 2H), 1.59 (s, 3H of a
diastereomer), 1.65 (s, 3H of a diastereomer), 2.42 (d,
J=6.9 Hz, 1H of a diastereomer), 2.52 (d, J=7.8 Hz,
1
H of a diastereomer), 3.74–3.90 (m, 1H), 4.22–4.37
13
1
(
m, 2H); C{ H}-NMR (75 MHz, CDCl ): l 10.3,
3
2
4
1
6
0.5, 13.82, 13.85, 18.9, 20.0, 25.2, 26.1, 49.7, 50.3, 62.9,
3.0, 75.7, 76.5, 118.56, 118.64, 168.9, 169.2.
was purified with medium-pressure liquid chromato-
graphy (EtOAc/hexane=1/1), after passing through a
short column of silica gel (EtOAc), giving 152 mg (97%)
4.8. Diethyl 2-cyano-3-hydroxy-2-methylsuccinate (4bf)
1
of 4ba: Colorless oil; H-NMR (300 MHz, CDCl3,
TMS): l 1.35 (t, J=7.1 Hz, 3H), 1.59 (s, 3H), 2.56 (t,
J=7.1 Hz, 1H), 3.87 (dd, J=7.1, 11.1 Hz, 1H), 3.95
Each diastereomer of 4bf was not separated by
medium-pressure liquid chromatography at all. Color-
(
dd, J=7.1, 11.1 Hz, 1H), 4.31 (q, J=7.1 Hz, 2H);
1
less oil; H-NMR (300 MHz, CDCl , TMS): l 1.341 (t,
1
3
1
3
C{ H}-NMR (75 MHz, CDCl ): l 13.8, 19.4, 46.1,
3
J=7.2 Hz, 3H of a diastereomer), 1.346 (t, J=7.2 Hz,
63.1, 66.7, 118.9, 168.5.
3
H of a diastereomer), 1.354 (t, J=7.2 Hz, 3H of a
diastereomer), 1.358 (t, J=7.1 Hz, 3H of
diastereomer), 1.68 (s, 3H of a diastereomer), 1.71 (s,
H of a diastereomer), 3.43 (d, J=5.9 Hz, 1H of a
diastereomer), 3.52 (d, J=7.2 Hz, 1H of
diastereomer), 4.23–4.46 (m, 4H), 4.52 (d, J=7.2 Hz,
H of a diastereomer), 4.56 (d, J=5.9 Hz, 1H of a
a
4.5. General procedure of catalytic aldol reaction
of 2b with 3
3
a
A solution of Rh(acac)(CO) (2.6 mg, 10 mmol) and
2
PPh (5.2 mg, 20 mmol) in THF (2.0 ml) was stirred at
3
1
r.t.. After 10 min, 2b (127 mg, 1.0 mmol) and 3 (1.5
mmol) were added to the solution. After stirring at r.t.
until completion of the reaction, the mixture was evap-
orated under reduced pressure. The residue was purified
with medium-pressure liquid chromatography (EtOAc/
hexane), after passing through a short column of silica
gel (EtOAc), giving 4.
13
1
diastereomer); C{ H}-NMR (75 MHz, CDCl ): l
3
1
7
3.8, 13.88, 13.93, 19.2, 19.9, 48.0, 48.3, 63.2, 63.3, 73.0,
3.4, 117.2, 117.5, 166.8, 167.2, 170.2, 170.6.
4
.9. Ethyl 2-cyano-4,4,4-trifluoro-3-hydroxy-2-
methylbutanoate (4bg)
Each diastereomer of 4bg was completely separated
by medium-pressure liquid chromatography.
4.6. Ethyl 2-cyano-3-hydroxy-2-methylbutanoate (4bb)
Each diastereomer of 4bb was partially separated by
medium-pressure liquid chromatography.
4
.9.1. anti-4bg
Yield, 43%; colorless oil; H-NMR (300 MHz,
CDCl , TMS): l 1.35 (t, J=7.1 Hz, 3H), 1.79 (s, 3H),
1
4
.6.1. anti-4bb
3
1
3
.82 (br s, 1H), 4.32 (dq, J=10.9, 7.1 Hz, 1H), 4.34
Colorless oil; H-NMR (300 MHz, CDCl , TMS): l
3
(
dq, J=10.9, 7.1 Hz, 1H), 4.44 (q, J=6.2 Hz, 1H);
1
(
.35 (t, J=7.2 Hz, 3H), 1.38 (d, J=6.3 Hz, 3H), 1.66
1
3
1
s, 3H), 2.35 (br d, 1H), 4.16 (br quintet, 1H), 4.30 (q,
C{ H}-NMR (75 MHz, CDCl ): l 13.6, 20.5, 45.3,
3
1
3
1
J=7.2 Hz, 2H); C{ H}-NMR (75 MHz, CDCl ): l
63.9, 72.6 (q, J=32 Hz), 116.1, 123.4 (q, J=282 Hz),
3
1
4
1
3.9, 18.3, 20.1, 50.9, 63.0, 71.2, 118.3, 169.1.
166.7.
.6.2. syn-4bb
4.9.2. syn-4bg
Yield, 32%; colorless oil; H-NMR (300 MHz,
1
1
Colorless oil; H-NMR (300 MHz, CDCl , TMS): l
3
.35 (t, J=7.1 Hz, 3H), 1.40 (d, J=6.3 Hz, 3H), 1.56
CDCl , TMS): l 1.37 (t, J=7.2 Hz, 3H), 1.74 (s, 3H),
3

26
R. Kuwano et al. / Journal of Organometallic Chemistry 603 (2000) 18–29
4
.08 (br s, 1H), 4.35 (q, J=7.2 Hz, 2H), 4.44 (q, J=6.7
4.14. 2-Methyl-2-propyl (S)-2-cyano-3-hydroxy-2-
methylpropionate (4da)
1
3
1
Hz, 1H); C{ H}-NMR (75 MHz, CDCl ): l 13.6,
3
1
9.6, 46.0, 64.1, 72.7 (q, J=32 Hz), 116.5, 123.5 (q,
1
J=282 Hz), 167.5.
Colorless oil; H-NMR (300 MHz, CDCl , TMS): l
3
1
.53 (s, 9H), 1.55 (s, 3H), 2.42 (br, 1H), 3.84 (d,
13
1
4
.10. General procedure of catalytic asymmetric aldol
J=11.1 Hz, 1H), 3.89 (d, J=11.1 Hz); C{ H}-NMR
75 MHz, CDCl ): l 19.4, 27.7, 46.6, 66.7, 84.6, 119.2,
reaction of 2 with 3a
(
3
1
67.6.
A suspension of paraformaldehyde (100 mg) in dis-
tilled water (1.0 ml) was stirred under reflux for 1 h,
giving a clear solution of paraformaldehyde. A solution
4.15. 2,4-Dimethyl-3-pentyl (S)-2-cyano-3-hydroxy-2-
methylpropionate (4ea)
of Rh(acac)(CO) (1.3 mg, 5.0 mmol) and (S,S)-(R,R)-
2
1
a (4.3 mg, 5.4 mmol) in Bu O (2.0 ml) was stirred at
20
1
2
Colorless oil; [h]D −5.15 (c 0.97, CHCl ); H-NMR
3
r.t. for 10 min. After cooling to the reaction tempera-
ture, 2 (0.5 mmol) and the solution of paraformalde-
hyde in water prepared freshly (0.2 ml, 0.67 mmol) were
added to the solution. After stirring until completion of
the reaction, the mixture was diluted with brine, and
extracted with EtOAc. The organic phase was washed
with brine, dried over Na SO , and evaporated. The
residue was purified with medium-pressure liquid chro-
matography, after passing through a short column of
silica gel, giving 4.
(
300 MHz, CDCl , TMS): l 0.91 (d, J=6.9 Hz, 3H),
3
0
0
2
.92 (d, J=6.9 Hz, 3H), 0.927 (d, J=6.9 Hz, 3H),
.932 (d, J=6.9 Hz, 3H), 1.62 (s, 3H), 1.91–2.09 (m,
H), 2.46 (br s, 1H), 3.88 (d, J=11.1 Hz, 1H), 3.96 (d,
J=11.1 Hz, 1H), 4.68 (t, J=6.2 Hz, 1H); C{ H}-
NMR (75 MHz, CDCl ): l 16.8, 17.1, 19.4, 19.6, 29.4,
1
3
1
3
2
4
4
9
6.3, 66.7, 86.4, 118.9, 168.7. Anal. Found: C, 63.30; H,
.29; N, 5.95. Calc. for C H NO : C, 63.41; H, 9.31;
12 21
3
N, 6.16%.
4
.11. Methyl 2-cyano-3-hydroxy-2-methylpropionate
4.16. 2,2,4,4-Tetramethyl-3-pentyl (S)-2-cyano-3-
hydroxy-2-methylpropionate (4fa)
(
4aa)
1
20
1
Colorless oil; H-NMR (300 MHz, CDCl , TMS): l
Colorless oil; [h] −7.68 (c 1.03, CHCl ); H-NMR
D 3
3
1
.60 (s, 3H), 2.52 (br s, 1H), 3.87 (s, 3H), 3.88 (br d,
(300 MHz, CDCl , TMS): l 1.05 (s, 9H), 1.07 (s, 9H),
3
1
3
1
J=9.3 Hz, 1H), 3.95 (br d, J=9.3 Hz, 1H); C{ H}-
NMR (75 MHz, CDCl ): l 19.4, 46.0, 53.7, 66.7, 118.8,
1.63 (s, 3H), 2.45–2.60 (br m, 1H), 3.88 (dd, J=11.1,
6.6 Hz, 1H), 3.98 (dd, J=6.9, 11.1 Hz, 1H), 4.69 (s,
3
13
1
169.0. Anal. Found: C, 50.30; H, 6.35; N, 9.63. Calc.
1H); C{ H}-NMR (75 MHz, CDCl ): l 19.6, 28.4,
3
for C H NO : C, 50.35; H, 6.34; N, 9.79%.
6
9
3
28.5, 37.3, 46.4, 66.6, 89.6, 119.0, 168.3. Anal. Found:
C, 65.58; H, 9.74; N, 5.44. Calc. for C H NO : C,
14
25
3
4.12. Ethyl (S)-2-cyano-3-hydroxy-2-methylpropionate
6
5.85; H, 9.87; N, 5.49%.
(
4ba)
4
.17. Diphenylmethyl (S)-2-cyano-3-hydroxy-2-
2
0
1
Colorless oil; [h]D −7.11 (c 1.02, CHCl ); H-NMR
3
methylpropionate (4ga)
(
300 MHz, CDCl , TMS): l 1.35 (t, J=7.1 Hz, 3H),
3
1
1
.59 (s, 3H), 2.56 (t, J=7.1 Hz, 1H), 3.87 (dd, J=7.1,
1.1 Hz, 1H), 3.95 (dd, J=7.1, 11.1 Hz, 1H), 4.31 (q,
20
White solid; m.p. 77–78°C; [h]D −12.2 (c 0.98,
1
CHCl ); H-NMR (300 MHz, CDCl , TMS): l 1.57 (s,
1
3
1
3
3
J=7.1 Hz, 2H); C{ H}-NMR (75 MHz, CDCl ): l
1
C, 53.52; H, 6.99; N, 8.73. Calc. for C H NO : C,
5
3
3
3
(
4
1
H), 2.54 (br s, 1H), 3.85 (dd, J=3.0, 10.8 Hz, 1H),
.94 (dd, J=3.6, 10.8 Hz, 1H), 6.91 (s, 1H), 7.27–7.41
m, 10H); C{ H}-NMR (75 MHz, CDCl ): l 19.2,
6.3, 66.6, 79.5, 118.7, 126.8, 127.0, 128.4, 128.5,
28.76, 128.79, 139.0, 167.5.
3.8, 19.4, 46.1, 63.1, 66.7, 118.9, 168.5. Anal. Found:
7
11
3
13
1
3
3.49; H, 7.05; N, 8.91%.
4
.13. 2-Propyl (S)-2-cyano-3-hydroxy-2-
methylpropionate (4ca)
4.18. (S)-2-Cyano-3-hydroxy-N-methoxy-2,N-
2
0
1
dimethylpropionamide (4ha)
Colorless oil; [h]D −7.12 (c 0.98, CHCl ); H-NMR
3
(
300 MHz, CDCl , TMS): l 1.32 (d, J=6.3 Hz, 3H),
3
1
Colorless oil; H-NMR (200 MHz, CDCl , TMS): l
1
1
1
.33 (d, J=6.3 Hz, 3H), 1.58 (s, 3H), 2.45–2.58 (br m,
H), 3.86 (dd, J=6.6, 11.3 Hz, 1H), 3.94 (dd, J=7.2,
3
1.58 (s, 3H), 3.08 (t, J=7.5 Hz, 1H), 3.26 (s, 3H), 3.85
(dd, J=7.5, 11.3 Hz, 1H), 3.88 (s, 3H), 3.99 (dd,
J=7.5, 11.3 Hz, 1H);
1
3
1
1.3 Hz, 1H), 5.12 (septet, J=6.3 Hz, 1H); C{ H}-
13
1
NMR (75 MHz, CDCl ): l 19.3, 21.38, 21.41, 46.1,
C{ H}-NMR (50 MHz,
3
66.7, 71.3, 118.9, 168.0.
CDCl ): l 18.4, 33.0, 43.0, 61.1, 67.0, 119.8, 168.3.
3

R. Kuwano et al. / Journal of Organometallic Chemistry 603 (2000) 18–29
27
4.19. Isopropyl 2-cyano-3-hydroxy-2-methylbutanoate
4.22. 2,4-Dimethyl-3-pentyl 2-cyano-3-ethoxycarbonyl-
(
4cb)
3-hydroxy-2-methylpropionate (4ef)
4
.19.1. anti-4cb
Colorless oil; H-NMR (300 MHz, CDCl , TMS): l
4.22.1. anti-(2S,3R)-4ef
Colorless oil; H-NMR (300 MHz, CDCl , TMS): l
1
1
3
3
1
1
.322 (d, J=6.3 Hz, 3H), 1.324 (d, J=6.3 Hz, 3H),
.37 (d, J=6.3 Hz, 3H), 1.64 (s, 3H), 2.35 (d, J=6.3
0.89–0.99 (m, 12H), 1.36 (t, J=7.1 Hz, 3H), 1.68 (s,
3H), 1.88–2.14 (m, 2H), 3.42 (d, J=5.5 Hz, 1H),
4.26–4.50 (m, 2H), 4.63–4.73 (m, 2H); C{ H}-NMR
13
1
Hz, 1H), 4.15 (quintet, J=6.3 Hz, 1H), 5.11 (septet,
J=6.3 Hz, 1H); C{ H}-NMR (75 MHz, CDCl ): l
1
3
1
(75 MHz, CDCl ): l 14.0, 16.9, 17.1, 19.1, 19.4, 19.5,
3
3
1
8.4, 18.9, 21.4, 50.0, 70.3, 71.1, 118.5, 168.4.
29.4, 29.5, 47.6, 63.4, 72.4, 86.9, 117.7, 166.9, 170.7.
Anal. Found: C, 59.89; H, 8.58; N, 4.40. Calc. for
C H NO : C, 60.18; H, 8.42; N, 4.68%.
4.19.2. syn-4cb
15
25
5
1
Colorless oil; H-NMR (300 MHz, CDCl , TMS): l
3
1
1
.326 (d, J=6.3 Hz, 3H), 1.335 (d, J=6.3 Hz, 3H),
.40 (d, J=6.3 Hz, 3H), 1.55 (s, 3H), 2.45 (d, J=6.9
4.22.2. syn-(2S,3S)-4ef
Colorless oil; H-NMR (300 MHz, CDCl , TMS): l
1
3
Hz, 1H), 4.11 (dq, J=6.9, 6.3 Hz, 1H), 5.13 (septet,
0.92 (d, J=6.9 Hz, 6H), 0.936 (d, J=6.9 Hz, 3H),
0.939 (d, J=6.6 Hz, 3H), 1.36 (t, J=7.2 Hz, 3H), 1.74
(s, 3H), 1.93–2.06 (m, 2H), 3.54 (d, J=7.1 Hz, 1H),
1
3
1
J=6.3 Hz, 1H); C{ H}-NMR (75 MHz, CDCl ): l
3
18.3, 20.0, 21.4, 21.5, 50.9, 71.2, 118.4, 168.6.
4
.28–4.44 (m, 2H), 4.47 (d, J=7.1 Hz, 1H), 4.68 (t,
13
1
4.20. 2,4-Dimethyl-3-pentyl
J=6.0 Hz, 1H); C{ H}-NMR (75 MHz, CDCl ): l
3
(
(
2S,3S)-2-cyano-3-hydroxy-2-methylbutanoate
anti-4eb)
14.0, 17.0, 19.35, 19.41, 20.5, 29.4, 29.5, 48.6, 63.1, 73.4,
87.0, 117.5, 167.3, 170.4.
Isolated as a mixture of anti- and syn-4eb: Colorless
4.23. Preparation of (R)-O-methylmandelate of 4eb (7)
1
oil; H-NMR (300 MHz, CDCl , TMS): l 0.89–0.96
3
(
2
m, 12H), 1.40 (d, J=6.3 Hz, 3H), 1.68 (s, 3H), 1.91–
.10 (m, 2H), 2.45 (d, J=6.3 Hz, 1H), 4.23 (quintet,
Oxalyl chloride (8.7 ml, 100 mmol) and a catalytic
amount of DMF (1 drop) were added to a suspension
of (R)-O-methylmandelic acid (10 mg, 60 mmol) in
CH Cl (0.1 ml) at 0°C. After stirring at r.t. for 30 min,
1
3
1
J=6.3 Hz, 1H), 4.67 (t, J=6.0 Hz, 1H); C{ H}-
NMR (75 MHz, CDCl ): l 16.9, 17.1, 18.6, 18.9, 19.40,
3
2
2
19.44, 20.5, 29.3, 29.4, 49.9, 70.0, 86.3, 118.5, 169.2.
the solvent and excess oxalyl chloride were removed in
Anal. Found: C, 64.45; H, 9.45; N, 6.09. Calc. for
C H NO : C, 64.70; H, 9.61; N, 5.80%.
vacuo. A solution of 4eb (12 mg, 50 mmol) in CH Cl
2
2
(0.2 ml) and pyridine (20 ml, 250 mmol) were added to
the residue at r.t.. After stirring for 8 h, the mixture was
diluted with 8.5% H PO (aq.) and extracted with Et O.
1
3
23
3
4
2
.21. 2,4-Dimethyl-3-pentyl
-cyano-3-hydroxy-2-methylpentanoate (4ec)
3
4
2
The organic phase was washed with 8.5% H PO (aq.),
3 4
with brine, dried over MgSO , and evaporated. The
4
4
.21.1. anti-(2S,3S)-4ec
Colorless oil; [h]D −5.39 (c 1.03, CHCl ); H-NMR
residue was purified with preparative TLC, giving 7 as
a diastereomeric mixture. The ratio of the dia-
stereomers corresponded with the enantiomeric excess
of starting anti-4eb.
2
0
1
3
(
(
300 MHz, CDCl , TMS): l 0.89–0.96 (m, 12H), 1.09
t, J=7.5 Hz, 3H), 1.51–1.83 (m, 2H), 1.67 (s,3H),
3
1.91–2.08 (m, 2H), 2.40 (d, J=6.3 Hz, 1H), 3.90 (ddd,
J=10.5, 6.3, 2.4 Hz, 1H), 4.67 (t, J=6.0 Hz, 1H);
4.24. (2S*,3S*)-2-Cyano-2-methyl-1,3-butanediol
(syn-9)
1
3
1
C{ H}-NMR (75 MHz, CDCl ): l 10.6, 17.0, 17.1,
3
1
1
8.8, 19.4, 19.5, 25.9, 29.39, 29.43, 49.6, 75.3, 86.3,
18.7, 169.2. Anal. Found: C, 66.09; H, 9.77; N, 5.62.
Trimethylsilylchloride (282 mg, 2.6 mmol) and
pyridine (256 mg, 3.2 mmol) were added to a solution
of syn-4bb (214 mg, 1.25 mmol) in THF (2.5 ml). The
mixture was stirred at r.t. for 2.5 h, diluted with water,
and extracted with EtOAc. The organic phase was
washed with brine, dried over Na SO , and evaporated.
Calc. for C H NO : C, 65.85; H, 9.87; N, 5.49%.
1
4
25
3
4.21.2. syn-4ec
1
Colorless oil; H-NMR (300 MHz, CDCl , TMS): l
3
0
.88–0.96 (m, 12H), 1.10 (t, J=7.4 Hz, 3H), 1.50–1.68
2
4
(
m, 1H), 1.62 (s, 3H), 1.71–1.86 (m, 1H), 1.92–2.09 (m,
Lithium borohydride (39 mg, 1.79 mmol) was added to
2
2
H), 2.53 (d, J=7.8 Hz, 1H), 3.80 (ddd, J=10.8, 7.8,
.3 Hz, 1H), 4.68 (t, J=6.0 Hz, 1H); C{ H}-NMR
a solution of the residue (270 mg) in Et O (1.0 ml) and
toluene (2.0 ml). The mixture was stirred at r.t. for 12
h, diluted with 10% HCl (aq.), and extracted with
2
1
3
1
(
75 MHz, CDCl ): l 10.4, 16.8, 17.1, 19.38, 19.43, 20.6,
3
25.1, 29.3, 29.4, 50.6, 76.3, 86.3, 118.7, 169.5.
EtOAc. The organic phase was dried over MgSO and
4

28
R. Kuwano et al. / Journal of Organometallic Chemistry 603 (2000) 18–29
Mulzer, E. Schaumann (Eds.), Stereoselective Synthesis, vols.
2–6, Thieme, Stuttgart, 1996.
evaporated. The residue was purified with flash column
chromatography, giving 56 mg (35%) of syn-9: H-
1
[
2] For reviews, see: (a) M. Sawamura, Y. Ito, Asymmetric aldol
reaction, in: I. Ojima (Ed.), Catalytic Asymmetric Synthesis,
VCH, New York, 1993, pp. 367–388. (b) J. Seyden-Penne,
Chiral Auxiliaries and Ligands in Asymmetric Synthesis: Addi-
tion to CꢀO and CꢀN Double Bonds, Wiley, New York, 1995,
pp. 209–365. (c) H. Gr o¨ ger, E.M. Vogl, M. Shibasaki, Chem.
Eur. J. 4 (1998) 1137. (d) E.M. Carreira, Mukaiyama aldol
reaction, in: E.N. Jacobsen, A. Pfaltz, H. Yamamoto (Eds.),
Comprehensive Asymmetric Catalysis, vol. III, Springer, Berlin,
NMR (200 MHz, CDCl , TMS): l 1.24 (s, 3H), 1.37 (d,
3
J=6.3 Hz, 3H), 3.00–3.70 (br, 2H), 3.73–3.96 (m, 3H).
4
1
.24.1. (4S*, 5S*)-5-Cyano-2,2,4,5-tetramethyl-
,3-dioxane (8)
2
,2-Dimethoxypropane (85 mg, 0.81 mmol) was
added to a solution of syn-9 (40 mg, 0.31 mmol) and
-10-camphorsulfonic acid (3.9 mg, 17 mmol) in CH Cl2
1
999, pp. 997–1065.
D
2
[
3] D. Barton, K. Nakanishi, O. Meth-Cohn ((Eds.), Comprehensive
Natural Products Chemistry, Elsevier, Oxford, 1999.
[4] (a) Y. Ito, M. Sawamura, T. Hayashi, J. Am. Chem. Soc. 108
(1996) 6405. (b) T. Hayashi, M. Sawamura, Y. Ito, Tetrahedron
48 (1992) 1999. (c) H. Sasai, T. Suzuki, N. Ito, K. Tanaka, T.
Date, K. Okamura, M. Shibasaki, J. Am. Chem. Soc. 115 (1993)
(
0.6 ml). The mixture was stirred at r.t. for 16 h, diluted
with saturated Na CO (aq.), and extracted with
2
3
EtOAc. The organic phase was dried over Na SO and
2
4
evaporated. The residue was purified with flash column
1
chromatography, giving 23 mg (43%) of 8: H-NMR
1
0372. (d) T. Arai, Y.M.A. Yamada, N. Yamamoto, H. Sasai,
(
300 MHz, CDCl , TMS): l 1.19 (s, 3H), 1.35 (d,
3
M. Shibasaki, Chem. Eur. J. 2 (1996) 1368. (e) Y.M.A. Yamada,
N. Yoshikawa, H. Sasai, M. Shibasaki, Angew. Chem. Int. Ed.
Engl. 36 (1997) 1871. (f) N. Yoshikawa, Y.M.A. Yamada, J.
Das, H. Sasai, M. Shibasaki, J. Am. Chem. Soc. 121 (1999) 4168.
J=6.0 Hz, 3H), 1.45 (s, 3H), 1.48 (s, 3H), 3.67 (d,
J=11.7 Hz, 1H), 3.74 (q, J=6.0 Hz, 1H), 3.92 (d,
1
3
1
J=11.7 Hz, 1H); C{ H}-NMR (75 MHz, CDCl ): l
3
(
g) M. Horikawa, J. Busch-Petersen, E.J. Corey, Tetrahedron
1
7.0, 17.7, 18.5, 29.2, 38.5, 67.1, 71.0, 99.4, 120.9.
.25. Preparation of 9 from 4eb
Lett. 40 (1999) 3843.
[
5] (a) M. Sodeoka, K. Ohrai, M. Shibasaki, J. Org. Chem. 60
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4
Trimethylsilylchloride (51 mg, 0.473 mmol) and
pyridine (68 mg, 0.87 mmol) were added to a solution
of a diastereomeric mixture of 4eb (32.9 mg, 0.14
mmol) in THF (0.25 ml). The mixture was stirred at r.t.
for 18 h, diluted with water, and extracted with EtOAc.
The organic phase was washed with brine, dried over
[
6] E.J. Corey, A. Guzman-Perez, Angew. Chem. Int. Ed. Engl. 37
(
1988) 389.
Na SO , and evaporated. Lithium borohydride (10 mg,
2
4
[7] (a) Y. Ito, M. Sawamura, E. Shirakawa, K. Hayashizaki, T.
Hayashi, Tetrahedron Lett. 29 (1988) 235. (b) Y. Ito, M. Sawa-
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0.46 mmol) was added to a solution of the residue (26.1
mg) in Et O (0.5 ml). The mixture was stirred at r.t. for
2
4
4 (1988) 5253.
48 h, diluted with water, and extracted with EtOAc.
[
[
8] (a) Y. Ito, M. Sawamura, H. Hamashima, T. Emura, T.
Hayashi, Tetrahedron Lett. 30 (1989) 4681. (b) D.A. Evans,
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The organic phase was washed with brine, dried over
Na SO , and evaporated. A solution (1.0 M) of TBAF
2
4
in THF (0.10 ml, 0.10 mmol) was added to a solution
of the residue (8.8 mg) prepared above in THF (0.1 ml).
The mixture was stirred at r.t. for 1.5 h, diluted with 1
N HCl (aq.), and extracted with EtOAc. The organic
phase was dried over Na SO4 and evaporated. The
2
residue was purified with flash column chromatogra-
phy, giving 5.6 mg (31%) of a diastereomeric mixture of
9
4
1
.
[
.25.1. anti-9
1
H-NMR (200 MHz, CDCl , TMS): l 1.29 (s, 3H),
3
[
[
[
.36 (d, J=6.4 Hz, 3H), 2.74 (br s, 2H), 3.73 (d,
J=11.2 Hz, 1H), 3.82 (d, J=11.2 Hz, 1H), 4.13 (q,
J=6.4 Hz, 1H).
14] Y. Yamamoto, Y. Kubota, Y. Honda, H. Fukui, N. Asao, H.
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[
[
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Redon, A. Krief, Bull. Chem. Soc. Jpn. 70 (1997) 2807.
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