Enantioselective cyanocarbonation of ketones with chiral base

Article abstract of DOI:10.1016/j.tet.2006.06.077

A highly enantioselective cyanocarbonation of dialkyl ketones catalyzed by commercially available and easily recyclable cinchona alkaloid derivatives has been developed. The reaction provides a useful approach for the enantioselective construction of tetrasubstituted carbon stereocenters. Mechanistic studies have been carried out to shed light on the origin of the catalytic activity of the cinchona alkaloid and the asymmetric induction step.

Full text of DOI:10.1016/j.tet.2006.06.077

Tetrahedron 62 (2006) 11320–11330
Enantioselective cyanocarbonation of ketones with chiral base
y
*
Shi-Kai Tian and Li Deng
Department of Chemistry, Brandeis University, Waltham, MA 02454-9110, USA
Received 9 May 2006; revised 17 June 2006; accepted 21 June 2006
Available online 24 July 2006
Abstract—A highly enantioselective cyanocarbonation of dialkyl ketones catalyzed by commercially available and easily recyclable
cinchona alkaloid derivatives has been developed. The reaction provides a useful approach for the enantioselective construction of tetra-
substituted carbon stereocenters. Mechanistic studies have been carried out to shed light on the origin of the catalytic activity of the cinchona
alkaloid and the asymmetric induction step.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
have been made with both approaches for the highly enantio-
selective cyanation of various ketones.4,5
The asymmetric construction of molecules with tetrasubsti-
tuted carbon stereocenters is fundamentally important and
represents a great challenge in organic synthesis.1 A concep-
tually direct and attractive approach is to transform prochiral
ketones to chiral building blocks each containing an
O-substituted quaternary stereocenter by catalytic asymmet-
ric C–C bond formation. The realization of this approach
requires the development of chiral catalysts that are effective
in promoting a C–C bond forming reaction involving a
relatively weak electrophile and in discriminating the two
enantiotopic faces of the sterically hindered ketone function-
ality. Achieving synthetically useful enantioselectivity with
unconjugated aliphatic ketones is particularly challenging
since the two alkyl substituents of ketone closely resemble
each other both electronically and sterically.
LA
*
O
O
O
XCN
XCN
R1
X CN
R2
R1
R2
R1
R2
X CN
LB
*
LA
*
LB
*
+
LB
X+
O-
R2
X
*
LA
NC OX
R1 R2
NC O-
NC
R1
*
R1
R2
*
*
*
Chiral Lewis Acid Approach
Chiral Lewis Base Approach
Scheme 1. Conceptual chemical catalyst-promoted asymmetric cyanation
of ketones.
In this article we describe in detail the synthetic and mecha-
nistic studies of the first highly enantioselective cyanation of
ketones catalyzed by chiral Lewis bases.6 We embarked on
the development of a chiral amine-catalyzed cyanation of
ketone for both conceptual and practical considerations. In
light of the lack of a precedent, the successful development
of a highly enantioselective cyanation of ketone with a chiral
amine would introduce a conceptually new strategy to this
area of research. As most organic functionalities are Lewis
basic in nature, a chiral amine-catalyzed reaction may pro-
vide the advantage of excellent functional group tolerance.
Moreover, the switch of its solubility between aqueous and
organic phases corresponding to its protonated and free
base form renders a chiral amine catalyst easy to be sepa-
rated from most organic compounds and subsequently to
be recycled. Finally, a catalytic asymmetric reaction with
a chiral organic catalyst provides certain advantage in terms
of environmental friendliness as well as applicability for
pharmaceutical manufacturing.
The asymmetric cyanation of ketones, an important reaction
for the creation of chiral tetrasubstituted carbon stereo-
centers via asymmetric C–C bond formation, produces
versatile chiral cyanohydrins, which can be easily converted
to many synthetically useful building blocks such as
a-hydroxy acids, a-hydroxy aldehydes (or ketones), and
b-aminoalcohols.2 In principle, the catalytic asymmetric
cyanation of ketones can be promoted by two fundamentally
different mechanisms involving either a chiral Lewis acid
that activates the electrophilic ketone or a chiral Lewis
base that activates the nucleophilic cyanating agent
(Scheme 1),3 and in the recent years great breakthroughs
* Corresponding author. Tel.: +1 781 736 2529; fax: +1 781 736 2516;
e-mail: deng@brandeis.edu
Present address: Department of Chemistry, University of Science &
y
Technology of China, 96 Jinzhai Road, Hefei, Anhui 230026, PR China.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.06.077

S.-K. Tian, L. Deng / Tetrahedron 62 (2006) 11320–11330
11321
Table 1. Organic amine-catalyzed cyanocarbonation of 2-heptanone (1a)
2. Results and discussion
NCCO2Me (1.5 eq.)
Amine (10 mol %)
O
OCO2Me
Me
NC
n-C5H11
2.1. Tertiary amine-catalyzed cyanocarbonation of
ketones
n-C5H11
Me
THF, rt; 6 h
1a
2aa
The first obstacle to overcome in the development of a chiral
Lewis base-catalyzed cyanation was the establishment of an
efficient amine-catalyzed cyanation of ketones. In 1999,
Poirier and co-workers described the synthesis of racemic
tertiary cyanohydrin carbonate 2 in good yield by the addi-
tion of 5–10 equiv of methyl cyanoformate (4, R3¼Me) to
ketone 1 in the presence of 20 equiv of diisopropylamine
(3, R4¼iPr) (Scheme 2).7 The use of secondary amine 3
and alkyl cyanoformate 4 in a large excess amount hinted
at the existence of a decomposition reaction involving these
two reagents. We postulated that the reaction proceeded
through the mechanism outlined in Scheme 2, which pro-
vided a rational for the decomposition of the alkyl cyano-
formate 4 and the secondary amine 3. The acyl ammonium
intermediates 5 and 6, derived from amine 3 and alkyl cyano-
formate 4, could undergo deprotonation by another molecule
of 3 to irreversibly form carbamate 7. According to this
postulation, we envisaged that these two decomposition path-
ways could be eliminated by employing a tertiary amine, in
lieu of a secondary amine, to mediate the cyanocarbonation.
Additionally, if our rationale was correct, not only a catalytic
cyanocarbonation with tertiary amine could be developed,
but also such a reaction should require a drastically reduced
amount, if not 1 equiv, of alkyl cyanoformate 4.
Amine
iPr2NH Pyridine NEt3 Quinuclidine DABCO DBU
Conv. (%)a 3.0
0.0
38
37
84
98
a
Determined by GC using dodecane as an internal standard.
promoting the conversion of ketone 1 to cyanohydrin car-
bonate 2, we observed that the cyanocarbonation of 2-hepta-
none with 10 mol % of NEt3 and 1.5 equiv of methyl
cyanoformate in THF at 25 ꢀC proceeded in 38% conversion
(Table 1), thereby demonstrating that the cyanocarbonation
of a ketone with alkyl cyanoformate 4 could be realized
with a catalytic amount of a tertiary amine. It should be
noted that the same reaction with 10 mol % of diisopropyl-
amine, a secondary amine, proceeded in only 3.0% conver-
sion. While pyridine, a weaker base, failed to catalyze this
transformation, other tertiary amines, such as DABCO and
DBU, were found to give significantly higher conversion
than that by NEt3 (Table 1).8
2.2. Chiral Lewis base-catalyzed asymmetric
cyanocarbonation of ketones
Encouraged by our success in establishing a tertiary amine-
catalyzed cyanocarbonation of ketones, we next focused on
the development of an enantioselective variant with a tertiary
chiral amine. The promising catalytic activity of DABCO
and our discovery in 2000 that certain commercially avail-
able modified cinchona alkaloids (Fig. 1) are highly efficient
With these expectations we began to investigate the use of
a tertiary amine to promote the cyanocarbonation of ketones.
Although Poirier and co-workers reported that excess NEt3
was even much less effective than diisopropylamine in
NCCO2R3 (5-10 eq.)
NH(R4)2 (20 eq.)
NC OCO2R3
R1 R2
2
O
R1
R2
THF, rt
1
O
(R4)2H2N+CN-
8
NH(R4)2
3
+
+
1
2 + 3
R3O
N(R4)
2
NCCO2R3
4
7
1
O
+
O
O-
R2
NC
R1
+
(R4)2HN
3
CN-
OR3
(R4)2HN
OR3
5
6
Scheme 2. Decomposition of secondary amines to carbamates 7.
OMe
DHQD
O
DHQD
N
O
DHQD
DHQD
N
H
N
Me
Cl
DHQD (dihydroquinidyl)
DHQD-PHN
DHQD-MEQ
DHQD-CLB
OMe
DHQD
Ph
O
DHQD
DHQD
O
N
N
N
N
N
H
N
DHQD
Ph
O
DHQD
(DHQD)2PHAL
DHQ (dihydroquinyl)
(DHQD)2PYR
(DHQD)2AQN
Figure 1. Structures of commercially available modified cinchona alkaloids.

11322
S.-K. Tian, L. Deng / Tetrahedron 62 (2006) 11320–11330
catalysts for enantioselective alcoholysis of cyclic anhy-
drides9 immediately attracted us to the possibility of using
cinchona alkaloid to realize a highly enantioselective cyano-
carbonation of ketones.
groups in order to achieve high enantioselectivity. We were
pleased to observe that the enantioselectivity improved
significantly with dialkyl ketones bearing two alkyl groups
that are significantly different from each other in terms of
steric bulk. As summarized in Table 3, a variety of acyclic
and cyclic dialkyl ketones, both a-substituted and a,a-di-
substituted, were transformed to the corresponding tertiary
cyanohydrin carbonates in good to excellent enantioselectiv-
ity and in synthetically useful yield with DHQD-PHN and
(DHQD)2AQN (Table 3). The enantioselective cyanation
of the sterically hindered a,a-disubstituted ketones has
been reported previously only once with pinacolone (1g)
using an enzymatic method.10 Particularly noteworthy is
that, for the first time, a catalytic asymmetric cyanation of
a cyclic ketone is realized with excellent enantioselectivity
(entries 14, 15, 19, and 20, Table 3). To our knowledge,
highly enantioselective cyanation of cyclic ketones remains
extremely rare.4g The reaction, catalyzed by a chiral base
catalyst, readily tolerated acid-sensitive functionality, which
is illustrated by the successful enantioselective cyano-
carbonation of acyclic and cyclic ketones bearing either an
acetal or ketal functionality (entries 9, 11, 12, 16–18, and
21, Table 3).
The catalyst screening studies were conducted via the asym-
metric cyanocarbonation of 2-heptanone (1a) with 1.2 equiv
of methyl cyanoformate and 10 mol % of the chiral amine
catalyst in CHCl3 at 25 ꢀC. As shown in Table 2, DHQD-
PHN and (DHQD)2AQN provided the highest ee (27%,
entries 4 and 7), and the latter gave a higher conversion.
With (DHQD)2AQN as the catalyst, the enantioselectivity
of the asymmetric cyanocarbonation of 2-heptanone (1a)
can be improved from 27 to 40% ee by employing ethyl
cyanoformate and performing the reaction at ꢁ24 ꢀC (entry
17, Table 2). The substitution of ethyl cyanoformate with
benzyl cyanoformate and the employment of other common
organic solvents such as dichloromethane, ether, toluene,
and acetonitrile resulted in deteriorated enantioselectivity
for the asymmetric cyanocarbonation of 2-heptanone (1a).
Under the optimized reaction condition, the (DHQ)2AQN-
catalyzed asymmetric cyanocarbonation of 2-heptanone
(1a) provided the corresponding tertiary cyanohydrin
carbonate in 53% yield and 64% ee (entry 3, Table 3), and
the (DHQ)2AQN-catalyzed reaction of 2-butanone provided
the product in 51% yield and 41% ee (entry 4, Table 3).
Although such enantioselectivity obtained with these
a-unbranched methyl alkyl ketones was not synthetically
useful, these results were very encouraging considering
that these ketones are especially difficult substrates for
enantioselective nucleophilic additions, as a chiral catalyst
must discriminate efficiently the methyl vs ethyl or n-pentyl
The modified cinchona alkaloid-catalyzed asymmetric
cyanocarbonation proceeded cleanly to consistently afford
the chiral tertiary cyanohydrin carbonates in greater than
95% yield based on converted ketones (Table 3). The reac-
tions were usually quenched after 2–7 days when they
reached a conversion greater than 50% to provide the desired
products in 51–99% isolated yields. It should be noted that
the catalyst loading could be reduced substantially without
any significant adverse effect on the enantioselectivity and
yield of the reaction. For example, the nearly quantitative
yield and excellent ee obtained from the cyanocarbonation
of ketone 1l (entry 17, Table 3) using 20 mol % catalyst
can also be realized by using 10 mol % catalyst (entry 18,
Table 3). These results have been successfully reproduced
in a 10 mmol scale reaction from which the catalyst,
DHQD-PHN, was recovered quantitatively using a simple
extractive procedure. Although an extended reaction time
was required with a reduced catalyst loading, the reaction
can be carried out by simply allowing the reaction mixture
in a vial to stand in a freezer without stirring and any
special precaution to exclude moisture and air. Modified
cinchona alkaloids derived from quinine and quinidine
have been shown to furnish highly enantioselective access
to both enantiomers of the tertiary cyanohydrin carbonates
(Table 3).11
Table 2. Screening studies on the catalysts, solvents, alkyl cyanoformates,
and temperaturea
NCCO2R (1.2 eq.)
Catalyst (10 mol %)
O
2aa R =Me
2ba R =Et
2ca R =Bn
NC OCO2R
n-C5H11
n-C5H11
Me
Me
1a
Entry
R
Catalyst
Solvent T (ꢀC) Conv. (%)b ee (%)c,d
1
2
3
4
5
6
7
8
Me Quinidine
CHCl3
CHCl3
CHCl3
CHCl3
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
66
63
85
83
80
86
94
96
98
95
86
54
84
95
97
97
96
2.6
17
Me DHQD-CLB
Me DHQD-MEQ
Me DHQD-PHN
Me (DHQD)2PHAL CHCl3
Me (DHQD)2PYR CHCl3
Me (DHQD)2AQN CHCl3
Me (DHQD)2AQN CH2Cl2
Me (DHQD)2AQN CCl4
Me (DHQD)2AQN PhMe
Me (DHQD)2AQN Et2O
Me (DHQD)2AQN THF
Me (DHQD)2AQN EtOAc
Me (DHQD)2AQN CH3CN
Et (DHQD)2AQN CHCl3
Bn (DHQD)2AQN CHCl3
17
27
22
11
27
23
20
14
17
9
10
11
12
13
14
15
16
17
2.3. Chemical transformations of chiral tertiary
cyanohydrin carbonates
6.9
11
22
32
26
40
Cyanohydrin carbonates are more stable than their corre-
sponding cyanohydrins toward acidic or basic conditions.
However, the two functional groups, cyano and carbonate,
of cyanohydrin carbonate can undergo useful chemical
transformations under appropriate conditions. For example,
LiAlH4 reduces the optically active cyanohydrin carbonates
(2bf and 2bk) to the synthetically and biologically important
chiral b-aminoalcohols without any deterioration in ee
(Scheme 3).
Et (DHQD)2AQN CHCl3 ꢁ24
a
The reaction was performed by treatment of 2-heptanone (0.20 mmol)
with alkyl cyanoformate (1.2 equiv) and catalyst (10 mol %) in solvent
(0.20 mL).
Determined by GC using dodecane as an internal standard.
Determined by chiral GC and HPLC analysis.
b
c
d
The absolute configuration of the major enantiomer was determined to be
R by acidic hydrolysis of the product (see Section 4 for the details).

S.-K. Tian, L. Deng / Tetrahedron 62 (2006) 11320–11330
11323
Table 3. Catalytic asymmetric cyanocarbonation of dialkyl ketones with modified cinchona alkaloidsa,b
O
NC OCO2Et
NCCO2Et, Catalyst, CHCl3
R1
R2
R1
R2
*
2b(a-n)
1
Entry
Substrate
Catalyst (mol %)
Temp (ꢀC)
Time (days)
Conv.c (%)
Yieldd (%)
eee(%)
1
2
3
4
(DHQD)2AQN (20)
(DHQD)2AQN (20)
(DHQ)2AQN (15)
(DHQ)2AQN (10)
ꢁ24
ꢁ24
ꢁ24
ꢁ24
ꢁ24
ꢁ24
ꢁ24
ꢁ24
ꢁ24
0.5
2.5
6
56
96
55
54
93
53
51
59
40
64f
41
O
R
1a, R¼n-C5H11
R
R
1b, R¼Et
1c, R¼Me
1d, R¼Allyl
1e, R¼(CH2)5
1f, R¼OnPr
1g, R¼Me
1h, R¼OMe
1i, R¼OEt
5
—
5
6
7
8
9
(DHQD)2AQN (10)
(DHQ)2AQN (15)
(DHQ)2AQN (20)
(DHQ)2AQN (20)
DHQD-PHN (30)
4
6
2
2
4
—
—
57
55
90
54
51
54
52
86
59
76f
81
O
87
96g
O
10
11
12
(DHQD)2AQN (30)
DHQD-PHN (35)
DHQD-PHN (35)
ꢁ24
ꢁ24
ꢁ12
5
4
4
58
67
68
55
63
65
88
85
90
R
R
O
13
1j
(DHQD)2AQN (10)
25
3
—
66
74
14
15
16
17
18
(DHQ)2AQN (15)
(DHQD)2AQN (15)
DHQ-PHN (30)
DHQD-PHN (20)
DHQD-PHN (10)
ꢁ24
ꢁ24
ꢁ24
ꢁ24
ꢁ24
ꢁ12
ꢁ24
ꢁ12
4
2
4
3
7
79
68
83
97
76
66
80
96
99
95
97f
95
93f
94
1k, R¼Me
1l, R¼OEt
O
R
R
100
O
19
20
21
(DHQ)2AQN (30)
(DHQD)2AQN (20)
DHQD-PHN (35)
5
4
5
56
65
82
53
62
78
92
91f
96
R
1m, R¼Me
1n, R¼OEt
R
a
The reaction was performed by treatment of the ketone (0.20 mmol) with ethyl cyanoformate (1 equiv for entries 3–6, 15; 1.5 equiv for entries 1, 2, 7, 8;
2.0 equiv for entries 9, 10, 13, 20; 3.0 equiv for the other entries) and catalyst in chloroform (0.20 mL for entries 9–21; 0.30 mL for entries 1, 2, 7, 8;
0.40 mL for entries 3–6).
The catalyst was recovered in quantitative yield.
Determined by GC using dodecane as an internal standard.
Isolated yields.
The ee of the product was determined by chiral GC and HPLC analysis.
The opposite enantiomer is generated.
The absolute configuration of the major enantiomer was determined to be S (see Section 4 for the details).
b
c
d
e
f
g
NHCbz
(66% yield, 96% ee)
NC
OCO2Et
(+)-2be under the same condition was dominated by the
decomposition of the starting material to generate the corre-
sponding ketone 1e.
HO
n
Pr O
1) LiAlH4
n
Pr O
2) CbzCl, NEt3
n
OPr
(S)-2bf
n
OPr
(S)-9f
NHCOPh
(64% yield, 95% ee)
2.4. Mechanistic considerations
NC
OCO2Et
HO
1) LiAlH4
*
*
2) PhCOCl, NEt3
While the enantioselective cyanocarbonation of unconju-
gated ketones was found to proceed very cleanly, the ee of
the product (cyanohydrin carbonate 2) generated from reac-
tions with simple dialkyl ketones such as 1a started to
decrease noticeably when the conversion of the reaction pro-
ceeded over 55% (comparing entries 1 and 2 of Table 3, also
see Fig. 2). This made it necessary to stop the reactions with
simple dialkyl ketones well before they reached completion,
resulting in the generation of the optically active cyano-
carbonates 2 in modest yet still useful yield (Table 3). Inter-
estingly, this ee variation is significantly less pronounced in
a reaction employing a,a-dialkoxy cyclic and acyclic ketone
such as 1f, 1h, 1i, 1l, and 1n, and the corresponding highly
enantioenriched cyanohydrin carbonates could be isolated
in good to excellent yield. This ee variation of the product
has to be accounted for by any proposed reaction mechanism.
9k
2bk (95% ee)
Scheme 3. Conversion of chiral tertiary cyanohydrin carbonates to b-amino-
alcohol derivatives.
In the presence of a strong acid a simple cyanohydrin
carbonate such as (R)-(+)-2ba was hydrolyzed to give the
corresponding a-hydroxy acid (Scheme 4). However, the
acidic hydrolysis of b-substituted cyanohydrin carbonate
NC
n-C5H11
(R)-(+)-2ba
OCO2Et
HOOC
OH
conc. HCl, 100 °C
n-C5H11
81%
10a
O
NC
OCO2Et
conc. HCl, 100 °C
*
Illustrated in Scheme 5 is a mechanism proposed to explain
the origin of the enantioselectivity of the modified cinchona
alkaloid-catalyzed cyanocarbonation. In principle, the
(+)-2be
Scheme 4. Acidic hydrolysis of cyanohydrin carbonates.
1e

11324
100
S.-K. Tian, L. Deng / Tetrahedron 62 (2006) 11320–11330
because the rate of the interconversion between 13A and
13B, involving retrocyanation of 13 and cyanation of 1, is
not significantly faster than that of the kinetic resolution
step.13 Increasing the rate of the interconversion between
13A and 13B should lead to a reduction in the extent of
the ee drop, a phenomenon observed in the reaction with
a,a-dialkoxy ketones. The electron-withdrawing dialkoxy
group presumably activated the ketone toward nucleophilic
attack by CNꢁ, thereby increasing the rate of the intercon-
version step. This in turn lessened the decline in the ee of
the product 2 as the reaction proceeded to high conversion.
80
60
40
20
0
1a
1g
1i
We have found that certain ketone cyanohydrin such as 14 is
stable enough to be isolated. This raised the possibility of
quenching the modified cinchona alkaloid-catalyzed cyano-
carbonation with an alcohol to trap intermediates 13A and
13B by protonation of the alkoxide ions (Fig. 3). According
to the proposed mechanism outlined in Scheme 5 and assum-
ing that the protonation is much faster than the interconver-
sion between 13A and 13B, the er (enantiomer ratio) of
cyanohydrin 14 should reflect the dr (diastereomer ratio)
of intermediates 13A and 13B. Consequently, if the high
enantioselectivity is due to efficient kinetic resolution of
13A and 13B, the ee of cyanohydrin 14 should be signifi-
cantly lower than that of the cyanocarbonate 2. On the other
hand, if the asymmetric induction occurred in the step of
cyanation of ketone 1, the ee values of 14 and 2 should
closely match each other. In a modified cinchona alkaloid-
catalyzed cyanocarbonation of pinacolone (1g) in chloro-
form, the reaction mixture was treated with methanol and
the resulting mixture was then subjected to GC analysis
under conditions that allowed determination of ee values
of both 14 and 2bg. As shown by the GC chromatograms
in Figure 3, the ee of cyanohydrin 14 is much lower than
that of the cyanocarbonation product 2bg (21 vs 83% ee).
This result provided an experimental evidence to support
the mechanistic proposal that the ee determination step in
the cinchona alkaloid-catalyzed cyanocarbonation of pina-
colone (1g) is the dynamic kinetic resolution of the putative
intermediates 13Ag and 13Bg via asymmetric transfer of the
alkoxycarbonyl group.
0
20
40
60
80
100
Conversion (%)
Figure 2. The ee of the product vs the conversion in the modified cinchona
alkaloid-catalyzed asymmetric cyanocarbonation of ketones 1a, 1g, and 1i.
asymmetric induction may arise from the enantioselective
addition of the cyanide, as part of a chiral ion complex 12,
to ketone 1. The ee deterioration of cyanocarbonate 2, how-
ever, is difficult to be accounted for by such a mechanism, as
it is highly unlikely that the ee deterioration as described
above is due to either side reactions or catalyst decomposi-
tions, given that the reaction proceeded in excellent yield
and the cinchona alkaloid catalysts could be recycled in
nearly quantitative yield at the end of the reaction. On the
other hand, the unusual ee deterioration of the cyanohydrin
carbonate 2 could be explained by an alternative mode of
asymmetric induction invoking a dynamic kinetic resolu-
tion12 of intermediates 13A and 13B. Conceivably, the two
diastereomeric complexes 13A and 13B, while undergoing
interconversion between each other through ketone 1, could
undergo transfer of the alkoxycarbonyl group from the N-
acyl ammonium to the alkoxide at different rate, thereby
generating product 2 in optically active form via a kinetic
resolution of 13A and 13B. According to this model, the sig-
nificant drop in ee observed with simple dialkyl ketones is
O
OCO2R3
R2
NCCO2R3
NR3 (chiral tertiary amine)
NC
R1
R1
R2
*
*
1
2
O
O
*
11
NR3
OR3
OR3
OR3
NC
NC
R1
O
O
4
k
fast
R2
2A
CN-
+
O
O
O
k
slow
+
CN-
.
*
OR3
NC
R1
R3N
12
R2
+
*
OR3
R3N
2B
O
O-
O
O
NC
R1
R1
+
R2
. *
OR3
OR3
R2
R3N
1
Kinetic
13A
Resolution:
ee determining
step
-O
R1
CN
R2
+
*
Interconversion (kinv
)
.
R3N
13B
Scheme 5. A proposed catalytic cycle for a tertiary chiral amine-catalyzed asymmetric cyanocarbonation of ketones.

S.-K. Tian, L. Deng / Tetrahedron 62 (2006) 11320–11330
11325
NCCO2Et (2.0 eq.)
(DHQD)2AQN (15 mol %)
O-
-O CN
O
NC
O
O
+
+
+
*
*
R3N
CHCl3, -24 °C
R3N
13Bg
OEt
OEt
1g
13Ag
NC
OCO2Et
NC OH
MeOH
*
14
*
2bg
Figure 3. Chiral GC chromatograms (the retention time was expressed in minutes): top, racemic 14; middle, racemic 2bg; bottom, reaction mixture of the
(DHQD)2AQN-catalyzed asymmetric cyanocarbonation of pinacolone (1g) quenched at 54% conversion.
3. Conclusion
VG 7070 high resolution mass spectrometer. Infrared spec-
tra were recorded on a Perkin–Elmer FTIR Spectrometer.
Specific rotations were measured on a Jasco Digital
Polarimeter.
The development of the first highly enantioselective cyano-
carbonation of prochiral ketones promoted by a chiral base
catalyst is documented.14 Importantly, the reaction comple-
ments known enzyme- and transition metal-based methods
in substrate scope via its unique ability to promote highly
enantioselective cyanocarbonation of sterically hindered
simple dialkyl ketones. Additional desirable features of the
reaction are the utilization of easily accessible and fully
recyclable cinchona alkaloid catalysts and the employment
of a simple experimental protocol that is insensitive to either
air or moisture. These features should render the reaction
a useful catalytic entry for the asymmetric synthesis of
tertiary cyanohydrin derivatives via prochiral ketones. The
reaction is conceptually interesting as the first efficient
asymmetric cyanation of simple ketones realized with a
chiral Lewis base approach. Mechanistic studies provided
experimental evidence to shed significant light on the asym-
metric induction step, in which the modified cinchona alka-
loid acts as a chiral nucleophilic catalyst. These mechanistic
studies in combination with those revealing cinchona
alkaloids as highly efficient chiral general base catalysts
underscore their remarkable ability to function as versatile
yet efficient chiral organic catalysts for a wide variety of
asymmetric transformations.5b,15
Analytical gas-liquid chromatography (GC) was performed
on a Hewlett–Packard 6890 Series instrument equipped
with a split mode capillary injection system, a flame ioniza-
tion detector, using a HP-5 GC column or a GC column with
chiral stationary phase [gamma cyclodextrin trifluoroacetyl
(30 mꢂ0.25 mm) or HP chiral (20% permethylated B-cyclo-
dextrin, 30 mꢂ0.25 mm)]. All the GC analyses of chiral
cyanohydrin carbonates were carried out with both a crude
reaction sample and a sample purified by silica gel chroma-
tography. High pressure liquid chromatography (HPLC)
analyses were performed on a Hewlett–Packard 1100 Series
instrument equipped with an isostatic pump, using a Daicel
Chiralpak AS (250ꢂ4.6 mm), AD (250ꢂ4.6 mm) or Hyper-
sil SI (200ꢂ4.6 mm) column. UV detection was monitored
at 254 or 220 nm.
Unless otherwise mentioned, ketones, alkyl cyanoformates,
and catalysts were purchased from Aldrich (Milwaukee) and
used without further purification. Ketone 1e was prepared
via oxidation of 1-cyclohexylethanol with PCC. Ketones
1d,16 1f,17 and 1i,18 were prepared according to the litera-
ture. Ketones 1l and 1n were prepared using a modified
literature procedure19 as described below. Chloroform was
distilled over K2CO3 before use.
4. Experimental
4.1. General
4.2. Preparation of 2,2-diethoxycyclopentanone (1l)
1H and 13C NMR spectra were recorded on a Varian instru-
ment (400 MHz and 100 MHz, respectively) and internally
referenced to SiMe4 signal. Low-resolution mass spectra
for all the new compounds were recorded on a Hewlett–
Packard 5989A GC–MS, and exact mass spectra on a
To a solution of p-toluenesulfonic acid (150 mg) and cyclo-
pentanone (16.8 g, 200 mmol) in ethanol (50 mL) was added
triethyl orthoformate (32.6 g, 220 mmol). A vigorous reac-
tion ensued which caused ebullition, after which the reaction
solution was heated at reflux for 15 min. Then another

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S.-K. Tian, L. Deng / Tetrahedron 62 (2006) 11320–11330
portion of p-toluenesulfonic acid (200 mg) was added,
and the reaction mixture was fractionated to give 1-ethoxy-
cyclopentene (68–70 ꢀC/80 mmHg, 14.5 g, 65%) as a color-
less oil.
4.5. Screening studies on the catalysts
To a stirred solution of 2-heptanone (1a) (23 mg,
0.20 mmol) in chloroform (0.20 mL) at room temperature
was added the modified cinchona alkaloid (10 mol %),
dodecane (2–4 mL, as the internal standard), and methyl
cyanoformate (20 mg, 0.24 mmol). The mixture was allowed
to stand for 31 h, then added aqueous HCl (1 N, 2.0 mL),
and extracted with ether (10 mL). The organic layer was
washed with brine, dried over MgSO4, and concentrated.
The residue was purified by silica gel column chromato-
graphy (acetone/hexane 1:400–1:100) to give (R)-2-meth-
oxycarboxy-2-methylheptanenitrile (2aa) as a colorless oil.
The ee was determined with chiral GC [gamma cyclodextrin
trifluoroacetyl, 80 ꢀC, 4 min, 5 ꢀC/min to 110 ꢀC, t (ma-
To a solution of 1-ethoxycyclopentene (2.24 g, 20.0 mmol)
in ethanol (40 mL) at 0 ꢀC was added dropwise a solution
of mCPBA (4.00 g, 22.0 mmol) in ethanol (40 mL) over
1 h. The mixture was allowed to warm to room temperature
and stirred for 20 min. The mixture was neutralized with
saturated aqueous NaHCO3. Ethanol was removed under
reduced pressure and the residue was extracted with ether.
The organic layer was dried over MgSO4 and concentrated
to give crude 2,2-diethoxycyclopentanol.
1
To a solution of pyridine (19.0 g, 240 mmol) in dichloro-
methane (300 mL) at room temperature (cooled with water
bath) was added CrO3 (12.0 g, 120 mmol). The mixture
was stirred for 15 min and the crude 2,2-diethoxycyclo-
pentanol was added dropwise. After stirring for an additional
15 min at room temperature, ether (300 mL) was added and
the mixture was stirred vigorously for 5 min. The mixture
was filtered through a pad of silica gel and the filtrate was
concentrated. The residue was purified by silica gel column
chromatography (acetone/hexane 1:100) to give 2,2-dieth-
oxycyclopentanone (1l) (2.53 g, 74% for two steps) as a
colorless oil. 1H NMR (400 MHz, CDCl3) d 1.12 (t,
J¼7.2 Hz, 6H), 1.79–1.88 (m, 2H), 1.98 (t, J¼6.6 Hz, 2H),
2.23 (t, J¼7.3 Hz, 2H), 3.42–3.56 (m, 4H); 13C NMR
(100 MHz, CDCl3) d 15.3, 16.8, 34.2, 34.9, 58.3, 100.6,
jor)¼23.5 min, t (minor)¼26.2 min]. H NMR (400 MHz,
CDCl3) d 0.91 (t, J¼6.8 Hz, 3H), 1.29–1.39 (m, 4H),
1.44–1.62 (m, 2H), 1.78 (s, 3H), 1.85–1.94 (m, 1H), 1.98–
2.06 (m, 1H), 3.84 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 14.1, 22.5, 23.6, 24.6, 31.4, 39.8, 55.4, 74.5, 118.6, 153.4.
4.6. Screening studies on the solvents and alkyl
cyanoformates
The procedure for the screening studies on the catalysts was
used while employing a different solvent or alkyl cyanofor-
mate. The ee of (R)-2-benzyloxycarboxy-2-methylheptane-
nitrile [(R)-2ca] was determined with chiral HPLC [Daicel
Chiralpak OD, isopropanol/hexane 10:90, 0.50 mL/min,
l¼220 nm; for a (DHQD)2AQN-catalyzed reaction, t
210.2; IR (neat) n 2977, 1756, 1444, 1392, 1199 cmꢁ1
;
(major)¼13.2 min, t (minor)¼11.7 min]. Colorless oil; H
1
MS (NH3/CI) m/z 190 (M+NH+4), 173 (MH+), 144
(MꢁCO), 127 (MꢁOEt); HRMS (NH3/CI) calcd for
C9H17O3 (MH+) 173.1178, found 173.1175.
NMR (400 MHz, CDCl3) d 0.89 (t, J¼7.2 Hz, 3H), 1.27–
1.39 (m, 4H), 1.41–1.61 (m, 2H), 1.76 (s, 3H), 1.86–1.96
(m, 1H), 1.98–2.08 (m, 1H), 5.18 (s, 2H), 7.31–7.40 (m,
5H); 13C NMR (100 MHz, CDCl3) d 14.0, 22.4, 23.5, 24.5,
31.3, 39.6, 74.5, 76.9, 118.5, 128.7, 128.8, 128.9, 134.6, 152.7.
4.3. Preparation of 2,2-diethoxycyclohexanone (1n)
4.7. General procedure for the asymmetric catalytic
cyanocarbonation of ketones
This compound was prepared in 60% yield (three steps) fol-
lowing the same procedure employed for 2,2-diethoxycyclo-
pentanone. Colorless oil; 1H NMR (400 MHz, CDCl3) d 1.21
(t, J¼7.4 Hz, 6H), 1.71–1.82 (m, 4H), 1.92–1.96 (m, 2H),
2.47–2.51 (m, 2H), 3.37–3.45 (m, 2H), 3.48–3.56 (m, 2H);
13C NMR (100 MHz, CDCl3) d 15.5, 22.2, 27.7, 36.5,
40.3, 57.2, 101.0, 207.6; IR (neat) n 2976, 1736, 1446,
1390, 1159 cmꢁ1; MS (NH3/CI) m/z 204 (M+NH+4), 187
(MH+), 158 (MꢁCO), 141 (MꢁOEt); HRMS (NH3/CI)
calcd for C10H19O3 (MH+) 187.1334, found 187.1331.
To a stirred solution of ketone (0.20 mmol) in chloroform
(0.20–0.40 mL) at the temperature indicated in Table 3
was added the modified cinchona alkaloid (10–35 mol %),
dodecane (2–4 mL), and ethyl cyanoformate (1.0–3.0 equiv).
The resulting mixture was allowed to stand at that tempera-
ture in a freezer without stirring. When the reaction reached
the conversion indicated in Table 3 as determined by GC,
aqueous HCl (1 N, 2.0 mL) was added to the reaction
mixture. The mixture was extracted with ether (10 mL),
and the organic layer was washed with brine, dried over
MgSO4, and concentrated. The residue was purified by silica
gel column chromatography (acetone/hexane 1:400–1:100)
to give the chiral cyanohydrin carbonate.
4.4. General procedure for the preparation of racemic
cyanohydrin carbonates
To a stirred mixture of ketone (0.50 mmol) and alkyl cyano-
formate (1.5–3.0 equiv) at room temperature (cooled with
water bath) was slowly added DABCO or DBU (20 mol %).
The reaction was monitored by either GC or TLC. The mix-
ture was allowed to stand for 1.5–24 h and then diluted with
ether. The resulting mixture was washed successively with
1 N HCl and brine. The organic layer was dried over
MgSO4 and concentrated. The residue was purified by silica
gel column chromatography (acetone/hexane 1:400–1:100)
to give the desired racemic cyanohydrin carbonate in good
to excellent yield.
To the aqueous layer was added K2CO3 to adjust the pH
value of the solution to 9–11. The resulting mixture was ex-
tracted with ethyl acetate (10 mL), and the organic layer was
washed with brine, dried over Na2SO4, and concentrated to
1
afford the recovered catalyst, which is H NMR (CDCl3,
400 M) pure, in quantitative yield.
4.7.1. (R)-(D)-2-Ethoxycarboxy-2-methylheptanenitrile
[(R)-(D)-2ba]. The ee was determined with chiral GC

S.-K. Tian, L. Deng / Tetrahedron 62 (2006) 11320–11330
11327
[gamma cyclodextrin trifluoroacetyl, 110 ꢀC, 4 min,
0.10 ꢀC/min to 112 ꢀC; for a (DHQD)2AQN-catalyzed
reaction, t (major)¼19.8 min, t (minor)¼20.5 min]. Color-
d 1.12–1.31 (m, 5H), 1.34 (t, J¼7.2 Hz, 3H), 1.67–1.74
(m, 1H), 1.75 (s, 3H), 1.82–1.92 (m, 4H), 1.99–2.06 (m,
1H), 4.25 (q, J¼7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 14.3, 21.6, 25.9, 26.0, 27.0, 27.3, 46.0, 64.8, 77.8, 118.2,
1
less oil; 59% ee; [a]D25 +16.2 (c 0.67, CHCl3); H NMR
(400 MHz, CDCl3) d 0.91 (t, J¼7.0 Hz, 3H), 1.35 (t,
J¼7.2 Hz, 3H), 1.29–1.40 (m, 4H), 1.44–1.63 (m, 2H),
1.78 (s, 3H), 1.86–1.94 (m, 1H), 1.98–2.06 (m, 1H), 4.26
(q, J¼7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 14.0,
14.2, 22.4, 23.6, 24.5, 31.4, 39.7, 64.8, 74.3, 118.6, 152.7;
IR (neat) n 2950, 1759, 1468, 1371, 1265 cmꢁ1; MS (EI)
m/z 214 (MH+), 187 (MꢁCN); HRMS (EI) calcd for
C11H20NO3 (MH+) 214.1443, found 214.1441.
152.8; IR (neat) n 2936, 1757, 1454, 1371, 1267 cmꢁ1
;
MS (EI) m/z 226 (MH+); HRMS (EI) calcd for C12H20NO3
(MH+) 226.1443, found 226.1450.
4.7.6. (S)-(D)-2-Ethoxycarboxy-2-methyl-3,3-diprop-
oxypropionitrile [(S)-(D)-2bf]. The ee and absolute
configuration were determined after transforming this com-
pound to its corresponding b-aminoalcohol derivative 9f
(vide infra). Colorless oil; 96% ee (DHQD-PHN-catalyzed
reaction); [a]D25 +14.6 (c 1.25, CHCl3); 1H NMR
(400 MHz, CDCl3) d 0.94 (t, J¼7.2 Hz, 3H), 0.97 (t, J¼
7.2 Hz, 3H), 1.34 (t, J¼7.0 Hz, 3H), 1.58–1.72 (m, 4H),
1.76 (s, 3H), 3.48–3.55 (m, 1H), 3.61–3.66 (m, 1H), 3.70–
3.82 (m, 2H), 4.26 (q, J¼7.2 Hz, 2H), 4.90 (s, 1H); 13C
NMR (100 MHz, CDCl3) d 10.6, 14.3, 18.5, 23.1, 23.2,
65.1, 72.4, 72.9, 75.7, 102.0, 117.5, 152.7; IR (neat)
n 2968, 1760, 1466, 1372, 1267 cmꢁ1; MS (CH4/CI) m/z
274 (MH+); HRMS (CH4/CI) calcd for C13H24NO5 (MH+)
274.1654, found 274.1659.
4.7.2. (L)-2-Ethoxycarboxy-2-methylbutanenitrile [(L)-
2bb]. The ee was determined with chiral GC [gamma cyclo-
dextrin trifluoroacetyl, 120 ꢀC, 4.0 min, 0.10 ꢀC/min to
85 ꢀC; for a (DHQ)2AQN-catalyzed reaction, t (major)¼
43.4 min, t (minor)¼42.0 min]. Colorless oil; 41% ee;
1
[a]2D5 ꢁ8.0 (c 0.70, CHCl3); H NMR (400 MHz, CDCl3)
d 1.13 (t, J¼7.2 Hz, 3H), 1.34 (t, J¼7.2 Hz, 3H), 1.77 (s,
3H), 1.97 (dt, J¼21.0, 7.2 Hz, 1H), 2.10 (dt, J¼21.0,
7.2 Hz, 1H), 4.26 (q, J¼7.2 Hz, 2H); 13C NMR (100 MHz,
CDCl3) d 8.3, 14.2, 24.0, 35.0, 64.8, 74.8, 118.5, 152.7; IR
(neat) n 2985, 1758, 1465, 1371, 1263 cmꢁ1; MS (EI) m/z
172 (MH+), 145 (MꢁCN); HRMS (CH4/CI) calcd for
C8H14NO3 (MH+) 172.0974, found 172.0975.
4.7.7. (D)-2-Ethoxycarboxy-2,3,3-trimethylbutyronitrile
[(D)-2bg]. The ee was determined with chiral GC [20%
permethylated B-cyclodextrin, 60 ꢀC, 4 min, 0.10 ꢀC/min to
75 ꢀC; for a (DHQD)2AQN-catalyzed reaction, t (major)¼
124.3 min, t (minor)¼126.6 min]. Colorless oil; 88% ee;
4.7.3. (L)-2-Ethoxycarboxy-2,3-dimethylbutanenitrile
[(L)-2bc]. The ee was determined with chiral GC [gamma
cyclodextrin trifluoroacetyl, 100 ꢀC, 25.0 min, 1.0 ꢀC/min
to 105 ꢀC; for a (DHQ)2AQN-catalyzed reaction, t (major)¼
21.1 min, t (minor)¼20.6 min]. Colorless oil; 76% ee; [a]D25
ꢁ17.6 (c 1.50, CHCl3); 1H NMR (400 MHz, CDCl3) d 1.10
(d, J¼6.8 Hz, 3H), 1.14 (d, J¼6.4 Hz, 3H), 1.34 (t, J¼
7.2 Hz, 3H), 1.75 (s, 3H), 2.19–2.29 (m, 1H), 4.25 (q,
J¼7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 14.1, 16.6,
17.0, 21.1, 36.6, 64.6, 78.0, 117.8, 152.7; IR (neat) n 2981,
1757, 1467, 1372, 1264 cmꢁ1; MS (EI) m/z 186 (MH+),
159 (MꢁCN); HRMS (EI) calcd for C9H16NO3 (MH+)
186.1130, found 186.1126.
1
[a]2D5 +36.0 (c 0.90, CHCl3); H NMR (400 MHz, CDCl3)
d 1.15 (s, 9H), 1.34 (t, J¼7.2 Hz, 3H), 1.76 (s, 3H), 4.25
(q, J¼7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 14.3,
19.1, 24.8, 38.8, 64.8, 80.5, 118.2, 153.0; IR (neat) n 2981,
1760, 1469, 1372, 1266 cmꢁ1; MS (EI) m/z 200 (MH+),
173 (MꢁCN); HRMS (EI) calcd for C10H18NO3 (MH+)
200.1287, found 200.1287.
4.7.8. (D)-3,3-Dimethoxy-2-ethoxycarboxy-2-methyl-
butyronitrile [(D)-2bh]. The ee was determined with chiral
GC [gamma cyclodextrin trifluoroacetyl, 120 ꢀC, 10.0 min,
0.1 ꢀC/min to 123 ꢀC; for a DHQD-PHN-catalyzed reaction,
t (major)¼26.0 min, t (minor)¼25.3 min]. Colorless oil;
4.7.4. (L)-2-Ethoxycarboxy-2-methyl-3-(2-propenyl)-5-
hexenenitrile [(L)-2bd]. The ee was determined with chiral
GC [gamma cyclodextrin trifluoroacetyl, 110 ꢀC, 4 min,
0.10 ꢀC/min to 114 ꢀC; for a (DHQ)2AQN-catalyzed reac-
tion, t (major)¼36.8 min, t (minor)¼38.1 min]. Colorless
oil; 81% ee; [a]D25 ꢁ25.4 (c 0.95, CHCl3); 1H NMR
(400 MHz, CDCl3) d 1.34 (t, J¼7.2 Hz, 3H), 1.79 (s, 3H),
2.18–2.29 (m, 3H), 2.32–2.41 (m, 1H), 2.44–2.54 (m, 1H),
4.25 (q, J¼7.2 Hz, 2H), 5.05–5.15 (m, 4H), 5.73–5.86 (m,
2H); 13C NMR (100 MHz, CDCl3) d 14.3, 22.3, 33.4, 34.1,
45.5, 64.9, 77.4, 117.6, 117.7, 118.3, 135.6, 135.6, 152.6;
IR (neat) n 3080, 2983, 1759, 1642, 1444, 1371,
1260 cmꢁ1; MS (CH4/CI) m/z 238 (MH+), 211 (MꢁCN);
HRMS (CH4/CI) calcd for C13H20NO3 (MH+) 238.1443,
found 238.1450.
1
[a]2D5 +41.8 (c 2.25, CHCl3); H NMR (400 MHz, CDCl3)
d 1.34 (t, J¼7.2 Hz, 3H), 1.53 (s, 3H), 1.83 (s, 3H), 3.42
(s, 3H), 3.44 (s, 3H), 4.26 (q, J¼7.2 Hz, 2H); 13C NMR
(100 MHz, CDCl3) d 14.3, 16.9, 19.8, 51.4, 65.1, 78.9,
102.0, 117.8, 152.5; IR (neat) n 2984, 1760, 1454, 1372,
1265 cmꢁ1; MS (EI) m/z 232 (MH+), 200 (MꢁOMe);
HRMS (CH4/CI) calcd for C10H18NO5 (MH+) 232.1185,
found 232.1174.
4.7.9. (D)-3,3-Diethoxy-2-ethoxycarboxy-2-methyl-
butyronitrile [(D)-2bi]. The ee was determined with chiral
GC [gamma cyclodextrin trifluoroacetyl, 100 ꢀC, 4 min,
0.10 ꢀC/min to 106 ꢀC; for a DHQD-PHN-catalyzed reac-
tion, t (major)¼48.3 min, t (minor)¼46.7 min]. Colorless
oil; 90% ee; [a]D25 +34.5 (c 2.35, CHCl3); 1H NMR
(400 MHz, CDCl3) d 1.20–1.24 (m, 6H), 1.34 (t, J¼
7.0 Hz, 3H), 1.54 (s, 3H), 1.83 (s, 3H), 3.63–3.72 (m, 4H),
4.25 (q, J¼7.0 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 14.3, 15.6, 17.9, 19.7, 59.0, 59.1, 64.9, 79.2, 101.6,
118.0, 152.6; IR (neat) n 2982, 1759, 1446, 1372,
1263 cmꢁ1; MS (CH4/CI) m/z 260 (MH+), 214 (MꢁOEt);
4.7.5. (L)-2-Cyclohexyl-2-ethoxycarboxy-propionitrile
[(L)-2be]. The ee was determined with chiral GC [gamma
cyclodextrin trifluoroacetyl, 120 ꢀC, 4 min, 0.10 ꢀC/min to
124 ꢀC; for a (DHQ)2AQN-catalyzed reaction, t (major)¼
35.1 min, t (minor)¼36.9 min]. Colorless oil; 87% ee;
1
[a]2D5 ꢁ25.5 (c 0.80, CHCl3); H NMR (400 MHz, CDCl3)

11328
S.-K. Tian, L. Deng / Tetrahedron 62 (2006) 11320–11330
HRMS (CH4/CI) calcd for C12H22NO5 (MH+) 260.1498,
found 260.1502.
(400 MHz, CDCl3) d 1.21 (t, J¼7.0 Hz, 3H), 1.25 (t, J¼
7.0 Hz, 3H), 1.34 (t, J¼7.2 Hz, 3H), 1.44–1.62 (m, 4H),
1.78–1.96 (m, 2H), 2.24–2.34 (m, 1H), 2.42–2.52 (m, 1H),
3.62 (q, J¼7.0 Hz, 2H), 3.72–3.82 (m, 2H), 4.26 (q,
J¼7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 14.3, 15.4,
15.6, 20.4, 21.4, 30.2, 32.2, 57.3, 57.9, 64.9, 99.5, 117.4,
4.7.10. 2-Ethoxycarboxy-2-(adamantan-1-yl)propio-
nitrile (2bj). The ee was determined after transforming
this compound to its corresponding b-aminoalcohol deriva-
tive 9j (vide infra). White solid; 74% ee; 1H NMR
(400 MHz, CDCl3) d 1.34 (t, J¼7.0 Hz, 3H), 1.66–1.84
(m, 15H), 2.08–2.11 (m, 3H), 4.24 (q, J¼7.0 Hz, 2H); 13C
NMR (100 MHz, CDCl3) d 14.3, 17.7, 28.2, 36.0, 36.6,
39.9, 64.7, 80.9, 117.8, 153.1.
152.4; IR (neat) n 2979, 1758, 1447, 1371, 1258 cmꢁ1
;
MS (CH4/CI) m/z 286 (MH+), 285 (M+), 240 (MꢁOEt);
HRMS (CH4/CI) calcd for C14H23NO5 (M+) 285.1576,
found 285.1564.
4.8. A 10 mmol-scale synthesis of (D)-2,2-diethoxy-1-
ethoxycarboxycyclopentanecarbonitrile [(D)-2bl]
4.7.11. (L)-1-Ethoxycarboxy-2,2-dimethylcyclopentane-
carbonitrile [(L)-2bk]. The ee was determined with chiral
GC [gamma cyclodextrin trifluoroacetyl, 90 ꢀC, 4 min,
0.10 ꢀC/min to 100 ꢀC; for a (DHQ)2AQN-catalyzed reac-
tion, t (major)¼87.5 min, t (minor)¼91.7 min]. Colorless
oil; 95% ee; [a]D25 ꢁ15.8 (c 1.90, CHCl3); 1H NMR
(400 MHz, CDCl3) d 1.16 (s, 3H), 1.21 (s, 3H), 1.34 (t, J¼
7.2 Hz, 3H), 1.63–1.92 (m, 4H), 2.33–2.42 (m, 1H), 2.51–
2.60 (m, 1H), 4.19–4.31 (m, 2H); 13C NMR (100 MHz,
CDCl3) d 14.3, 19.6, 21.5, 25.1, 35.3, 36.7, 47.6, 65.0,
84.8, 117.7, 153.3; IR (neat) n 2974, 1760, 1470, 1372,
1276 cmꢁ1; MS (EI) m/z 212 (MH+); HRMS (EI) calcd for
C11H18NO3 (MH+) 212.1287, found 212.1297.
To a stirred solution of 2,2-diethoxycyclopentanone (1.72 g,
10.0 mmol) and DHQD-PHN (502 mg, 1.00 mmol) in chlo-
roform (10 mL) at ꢁ24 ꢀC was added dropwise ethyl cyano-
formate (2.97 g, 30.0 mmol). After the mixture was allowed
to stand at ꢁ24 ꢀC in a freezer for 7 days, aqueous HCl
(1 N, 20 mL) was added. The resulting mixture was stirred
vigorously for 2 min and then extracted with ether (50 mL),
and the organic layer was washed with brine, dried over
MgSO4, and concentrated. The residue was purified by
silica gel column chromatography (acetone/hexane 1:100)
to give the cyanohydrin carbonate (2.69 g, 99%, 94% ee)
as a white solid. This compound was also obtained in
87% yield and 97% ee simply by recrystallizing the residue
in hexane.
4.7.12. (L)-2,2-Diethoxy-1-ethoxycarboxycyclopentane-
carbonitrile [(L)-2bl]. The ee was determined with chiral
GC [gamma cyclodextrin trifluoroacetyl, 95 ꢀC, 4 min,
0.05 ꢀC/min to 104 ꢀC; for a DHQ-PHN-catalyzed reaction,
t (major)¼150.6 min, t (minor)¼158.3 min]. White solid,
To the aqueous layer was added K2CO3 to adjust the pH
value of the solution to 9–11. The resulting mixture was
extracted with ethyl acetate (50 mL), and the organic layer
was washed with brine, dried over Na2SO4, and concentrated
to afford the recovered catalyst DHQD-PHN, which is H
NMR (CDCl3, 400 M) pure, in quantitative yield.
1
mp 74–75 ꢀC; 95% ee; [a]D25 ꢁ32.1 (c 2.70, CHCl3); H
NMR (400 MHz, CDCl3) d 1.20 (t, J¼7.0 Hz, 3H), 1.24 (t,
J¼7.0 Hz, 3H), 1.33 (t, J¼7.1 Hz, 3H), 1.68–1.75 (m, 2H),
1.82–1.90 (m, 1H), 2.08–2.15 (m, 1H), 2.39–2.57 (m, 2H),
3.54–3.62 (m, 2H), 3.71–3.86 (m, 2H), 4.25 (q, J¼7.1 Hz,
2H); 13C NMR (100 MHz, CDCl3) d 14.3, 15.3, 18.1, 30.5,
35.9, 57.5, 58.8, 65.1, 79.2, 109.3, 117.1, 152.7; IR
(CHCl3) n 3019, 1757, 1423, 1221 cmꢁ1; MS (CH4/CI)
m/z 271 (M+); HRMS (CH4/CI) calcd for C13H21NO5 (M+)
271.1420, found 271.1424.
1
4.9. Transformation of cyanohydrin carbonate (L)-2bk
to b-aminoalcohol derivative 9k
To a solution of (ꢁ)-2bk (95% ee, 20 mg, 0.095 mmol) in
ether (0.50 mL) at room temperature was added LiAlH4
(18 mg, 0.47 mmol). The mixture was stirred for 2 h, and
then added water (three drops) and ether (5.0 mL). The
resulting mixture was dried over Na2SO4, filtered, and to
the filtrate was added benzoyl chloride (25 mg, 0.18 mmol)
and triethylamine (36 mg, 0.36 mmol). After being stirred
at room temperature for 2 h, the mixture was filtered and
concentrated. The residue was purified by silica gel column
chromatography (acetone/hexane 1:20–1:10) to give amide
9k (13 mg, 63%) as a white solid. The ee of 9k was deter-
mined to be 95% with chiral HPLC [Daicel Chiralpak AS,
isopropanol/hexane 5:95, 1.0 mL/min, t (major)¼33.9 min,
4.7.13. (L)-1-Ethoxycarboxy-2,2-dimethylcyclohexane-
carbonitrile [(L)-2bm]. The ee was determined by chiral
GC [gamma cyclodextrin trifluoroacetyl, 115 ꢀC, 4 min,
0.10 ꢀC/min to 121 ꢀC; for a (DHQ)2AQN-catalyzed reac-
tion, t (major)¼51.1 min, t (minor)¼54.0 min]. Colorless
oil; 92% ee; [a]D25 ꢁ15.5 (c 2.00, CHCl3); 1H NMR
(400 MHz, CDCl3) d 1.13 (s, 3H), 1.22 (s, 3H), 1.34 (t,
J¼7.2 Hz, 3H), 1.48–1.68 (m, 6H), 2.11–2.21 (m, 1H),
2.30–2.40 (m, 1H), 4.25 (q, J¼7.2 Hz, 2H); 13C NMR
(100 MHz, CDCl3) d 14.3, 20.4, 21.6, 22.7, 25.2, 29.1,
35.7, 38.2, 64.7, 81.2, 117.7, 152.8; IR (neat) n 2939,
1755, 1458, 1371, 1261 cmꢁ1; MS (EI) m/z 226 (MH+);
HRMS (EI) calcd for C12H20NO3 (MH+) 226.1443, found
226.1448.
1
t (minor)¼43.2 min]. Mp 98–100 ꢀC; H NMR (400 MHz,
CDCl3) d 0.97 (s, 3H), 1.06 (s, 3H), 1.45–1.53 (m, 1H),
1.60–1.84 (m, 4H), 1.91–2.00 (m, 1H), 2.22 (br s, 1H),
3.44 (dd, J¼13.8, 4.4 Hz, 1H), 3.68 (dd, J¼13.8, 7.0 Hz,
1H), 6.69 (br s, 1H), 7.39–7.44 (m, 2H), 7.49 (t, J¼7.2 Hz,
1H), 7.78 (d, J¼7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 19.0, 22.3, 24.7, 36.1, 39.5, 44.8, 45.2, 84.1, 127.1,
128.7, 131.6, 134.8, 168.4; MS (NH3/CI) m/z 248 (MH+),
230 (MꢁOH); HRMS (NH3/CI) calcd for C15H22NO2
(MH+) 248.1651, found 248.1660.
4.7.14. (D)-2,2-Diethoxy-1-ethoxycarboxycyclohexane-
carbonitrile [(D)-2bn]. The ee was determined with chiral
GC [gamma cyclodextrin trifluoroacetyl, 105 ꢀC, 4 min,
0.05 ꢀC/min to 113 ꢀC; for a DHQD-PHN-catalyzed reac-
tion, t (major)¼145.9 min, t (minor)¼143.6 min]. Colorless
oil; 96% ee; [a]D25 +26.0 (c 2.50, CHCl3); 1H NMR

S.-K. Tian, L. Deng / Tetrahedron 62 (2006) 11320–11330
11329
4.10. Transformation of cyanohydrin carbonate
(S)-(D)-2bf to b-aminoalcohol derivative (S)-9f
Acknowledgements
We gratefully acknowledge the financial support of NIH
(GM-61591), Research Corporation (RI-0311), the Harcourt
General Charitable Foundation and Daiso Inc.
Cyanohydrin carbonate (S)-(+)-2bf (prepared from a
DHQD-PHN-catalyzed reaction, 14 mg, 0.050 mmol) was
reduced to its corresponding b-aminoalcohol with LiAlH4
using the same procedure as described above. To the solution
of crude b-aminoalcohol in ether (5 mL) was added benzyl
chloroformate (17 mg, 0.10 mmol) and triethylamine
(20 mg, 0.20 mmol). The mixture was stirred at room
temperature for 1 h, and then concentrated. The residue
was purified by silica gel column chromatography (acetone/
hexane 1:40) to give carbamate (S)-9f (12 mg, 66%) as a col-
orless oil. The ee of (S)-9f was determined to be 96% [HPLC
conditions: Daicel Chiralpak AD+Hypersil SI, isopropanol/
hexane 1:99, 0.5 mL/min, t (major)¼91.7 min, t (minor)¼
103.3 min]. (S)-9f can also be obtained from (S)-(+)-2-
trimethylsiloxy-2-methyl-3,3-dipropoxypropionitrile5b em-
ploying the same sequences, so the absolute configuration
was determined to be S. 1H NMR (400 MHz, CDCl3)
d 0.94 (t, J¼7.4 Hz, 6H), 1.17 (s, 3H), 1.58–1.68 (m, 4H),
2.45 (s, 1H), 3.30–3.36 (m, 2H), 3.43–3.50 (m, 2H), 3.71–
3.79 (m, 2H), 4.24 (s, 1H), 5.11 (s, 2H), 5.25–5.30 (m,
1H), 7.39–7.39 (m, 5H); 13C NMR (100 MHz, CDCl3)
d 10.8, 20.7, 23.4, 46.7, 65.6, 66.9, 72.8, 72.8, 74.1, 107.8,
127.2, 128.2, 128.7, 136.9, 157.2.
References and notes
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4.11. Transformation of cyanohydrin carbonate 2bj to
b-aminoalcohol derivative 9j
This transformation was accomplished by employing the
above sequences. The ee was determined to be 74% with
chiral HPLC [Daicel Chiralpak OD, isopropanol/hexane
20:80, 0.50 mL/min, l¼254 nm;
t
(major)¼13.4 min,
t (minor)¼12.0 min]. White solid; 1H NMR (400 MHz,
CDCl3) d 1.14 (s, 3H), 1.62–1.76 (m, 12H), 2.01–2.07 (m,
3H), 3.45 (dd, J¼13.4, 3.0 Hz, 1H), 3.67 (dd, J¼13.4,
8.0 Hz, 1H), 6.58–6.62 (m, 1H), 7.41–7.52 (m, 3H), 7.78–
7.81 (m, 2H); 13C NMR (100 MHz, CDCl3) d 19.6, 28.7,
34.6, 36.4, 37.2, 39.1, 44.7, 76.8, 127.1, 128.8, 131.6,
134.9, 168.6.
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4.12. Acidic hydrolysis of (R)-(D)-2ba
To a concentrated aqueous hydrochloric acid (5 mL) was
added (R)-(+)-2ba (59% ee, 82 mg, 0.38 mmol). The mix-
ture was stirred at room temperature overnight and then
heated under reflux for 5 h. After being cooled down to
room temperature, the mixture was extracted with ethyl
acetate (3ꢂ5 mL). The organic layer was washed with brine,
dried over Na2SO4, and concentrated. The residue was puri-
fied by flash chromatography (ether/hexane 1:1) to give
(R)-(ꢁ)-2-hydroxy-2-methylheptanoic acid (10a) (50 mg,
81%). The absolute configuration of (+)-2ba was determined
to be R by comparing the specific rotation {[a]2D5 ꢁ5.4 (c
1.60, CHCl3)} with that reported in literature {[a]2D5 ꢁ9.4
(c 0.35, CHCl3), 98% ee}.20 1H NMR (400 MHz, CDCl3)
d 0.88 (t, J¼7.2 Hz, 3H), 1.15–1.36 (m, 5H), 1.42–1.53
(m, 1H), 1.47 (s, 3H), 1.62–1.72 (m, 1H), 1.75–1.84 (m,
1H), 6.60 (br s, 2H); 13C NMR (100 MHz, CDCl3) d 14.1,
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11330
S.-K. Tian, L. Deng / Tetrahedron 62 (2006) 11320–11330
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