Cu(I)-catalyzed decarboxylative aldol-type and Mannich-type reactions for asymmetric construction of contiguous trisubstituted and quaternary stereocenters

Article abstract of DOI:10.1016/j.tet.2011.05.108

The catalytic asymmetric decarboxylative aldol-type reaction between aldehydes and cyanocarboxylic acids and Mannich-type reaction between aldimines and cyanocarboxylic acids were developed. α,α,β-Trisubstituted- β-hydroxy nitriles bearing contiguous all-carbon quaternary and trisubstituted stereocenters were produced with moderate enantio- and diastereoselectivity in the presence of 10 mol % CuOAc-TANIAPHOS (or DTBM-SEGPHOS) complex in the aldol-type reaction. α,α,β- Trisubstituted-β-amino nitriles containing contiguous all-carbon quaternary and trisubstituted stereocenters were produced with moderate to high enantio- and diastereoselectivity using 5 mol % CuOAc-(R)-DTBM-SEGPHOS complex in the Mannich-type reaction. These reactions proceed through Cu(I)-catalyzed decarboxylative nucleophile generation, followed by the addition of the resulting chiral Cu-ketenimide to aldehydes or imines. Because the reactions proceed under very mild conditions at nearly neutral pH, the reactions are applicable to a wide range of substrate combinations, including both aromatic and aliphatic substrates. Finally, α,α,β-trisubstituted-β- amino nitriles were converted to β^2,2,3-amino acid derivatives through simple acidic hydrolysis without any racemization and epimerization.

Full text of DOI:10.1016/j.tet.2011.05.108

Tetrahedron 68 (2012) 3497e3506
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Cu(I)-catalyzed decarboxylative aldol-type and Mannich-type reactions
for asymmetric construction of contiguous trisubstituted and quaternary
stereocenters
,
b,
Liang Yin a, Motomu Kanai a , Masakatsu Shibasaki
*
*
a Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
b Institute of Microbial Chemistry, Tokyo, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 April 2011
Received in revised form 16 May 2011
Accepted 25 May 2011
Available online 31 May 2011
The catalytic asymmetric decarboxylative aldol-type reaction between aldehydes and cyanocarboxylic
acids and Mannich-type reaction between aldimines and cyanocarboxylic acids were developed.
Trisubstituted- -hydroxy nitriles bearing contiguous all-carbon quaternary and trisubstituted stereo-
centers were produced with moderate enantio- and diastereoselectivity in the presence of 10 mol %
CuOAceTANIAPHOS (or DTBM-SEGPHOS) complex in the aldol-type reaction. -Trisubstituted-b-
a,a,b-
b
a,a
,b
amino nitriles containing contiguous all-carbon quaternary and trisubstituted stereocenters were
produced with moderate to high enantio- and diastereoselectivity using 5 mol % CuOAce(R)-DTBM-
SEGPHOS complex in the Mannich-type reaction. These reactions proceed through Cu(I)-catalyzed de-
carboxylative nucleophile generation, followed by the addition of the resulting chiral Cu-ketenimide to
aldehydes or imines. Because the reactions proceed under very mild conditions at nearly neutral pH, the
reactions are applicable to a wide range of substrate combinations, including both aromatic and aliphatic
substrates. Finally,
through simple acidic hydrolysis without any racemization and epimerization.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Decarboxylation
Quaternary stereocenters
Cu(I) catalyst
Mannich-type reaction
Aldol-type reaction
a,a,b-trisubstituted-b-amino nitriles were converted to b
2,2,3-amino acid derivatives
1. Introduction
endothermic extrusion of CO2 from arene carboxylates to generate
arylcopper species, which transferred the aryl groups to a palladium
catalyst for the cross-coupling reaction. An attractive point of this
catalysis is the use of readily available carboxylic acids as a source of
aryl nucleophiles in place of expensive organometallic compounds.6
Except for carboxylic acids, allyl esters, and carbonates were repor-
ted as substrates for decarboxylative nucleophile generation in
asymmetric allylation catalyzes.7 A recent outstanding application
of this catalytic asymmetric process is the total synthesis of
(ꢀ)-cyanthiwigin F by means of double catalytic enantioselective
The decarboxylative nucleophile generation is typically obse-
rved in the biosynthesis of fatty acids and polyketides.1 Enzymatic
activation of a malonic acid half thioester through extrusion of CO2
generates a thioester enolate. Claisen condensation between the
enolate and another thioester affords a desired elongated b-keto
thioester. Inspired by this reaction in nature, Shair and co-workers
developed a catalytic asymmetric aldol reaction between a malonic
acid half thioester and aldehydes in the presence of Cu(OTf)2 and
a chiral bisoxazoline ligand.2 Their detailed mechanistic studies,
however, later revealed that the artificial decarboxylative aldol
reaction in fact proceeded through direct addition of the malonic
acid half thioester to an aldehyde, followed by decarboxylation of
decarboxylative alkylation using a bis(allylic b
-ketoester).8
Inspired by these important previous findings, we recently de-
veloped a catalytic asymmetric decarboxylative Mannich-type re-
action involving nucleophile generation via Cu(I)-catalyzed
a
,a
-disubstituted malonic acid half thioester.3 It is evident that
extrusion of CO2 from cyanocarboxylic acids.9 A series of linear
b-
a nucleophile generation via decarboxylation was not involved in
this catalytic asymmetric process.
amino-
containing contiguous
a
,
a
-disubstituted nitriles
(b
2,2,3-amino acid derivatives)
-trisubstituted chiral
a
-quaternary10 and
b
In 2006, Goossen and co-workers reported a quite intriguing
decarboxylative cross-coupling reaction utilizing a combination of
copper and palladium catalysts.4,5 A copper catalyst mediates
carbons11 was synthesized in high yields, diastereoselectivity and
enantioselectivity. Here, we report an extension of the Cu(I)-
catalyzed decarboxylative nucleophile generation to an asymmet-
ric aldol-type reaction. Moreover, optimizations and results of the
catalytic asymmetric decarboxylative Mannich-type reaction are
described in detail.
* Corresponding authors. E-mail addresses: kanai@mol.f.u-tokyo.ac.jp (M. Kanai),
mshibasa@bikaken.or.jp (M. Shibasaki).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.108

3498
L. Yin et al. / Tetrahedron 68 (2012) 3497e3506
2. Results and discussion
JOSIPHOS and MANDYPHOS were not suitable to the reaction ei-
ther, affording both low diastereoselectivity and enantioselectivity
(entries 4 and 5). TANIAPHOS was found to be a promising ligand,
producing a 3:1 diastereo-ratio and 62% ee for the major di-
2.1. Catalytic asymmetric decarboxylative aldol-type reaction
2-Cyano-2-phenylpropionic acid (1a), which was reported to
astereoisomer (entry 6). A structurally similar ligand, Cy-
give 2-phenylpropionitrile through cinchonine-catalyzed de-
TANIAPHOS, did not give higher enantioselectivity despite the
significantly improved diastereoselectivity (entry 7). (R)-DTBM-
SEGPHOS, which was the best ligand for our previous nitrile aldol
reaction,14a afforded inferior enantioselectivity in this case (entry
9). Furthermore, monodentate phosphine ligand MONOPHOS pro-
duced unsatisfactory results with regards to both reactivity and
selectivity (entry 10).
carboxylation,12 was selected as
a nucleophile precursor for
decarboxylative aldol-type reaction.13 Reactions between 1a and
benzaldehyde (2a) in the presence of copper(I) salts and chiral li-
gands were investigated, based on our previous development of the
catalytic enantioselective nitrile aldol reaction.14 Screening of
copper(I) sources identified CuOAc or CuTC (TC¼thiophene-2-
carboxylate) as the optimal catalyst in terms of product yield and
enantioselectivity of the major diastereoisomer. Using CuOAc as the
metal source, a series of phosphine ligands was examined next
(Table 1).
A
series of TANIAPHOS derivatives was screened further
(Table 2).15 Although diastereoselectivity improved in some cases
(entries 2, 3, and 5), enantioselectivity significantly decreased.
When a bulky substituent was introduced at the phosphine part
(entry 7), yield, diastereoselectivity and enantioselectivity all de-
creased. Thus, screening of TANIAPHOS derivatives did not give any
improved results.
Table 1
Screening of chiral ligands in Cu(I)-catalyzed asymmetric decarboxylative aldol-type
reaction
O
OH
CuOAc (10 mol %)
ligand (10 mol %)
Table 2
CN
Me
Ph
COOH
H
Screening of TANIAPHOS derivatives in Cu(I)-catalyzed asymmetric decarboxylative
aldol-type reaction
Ph
THF, T oC, 36 h
Me
CN
O
OH
2a
1a (1.5 equiv)
3a
CuOAc (10 mol %)
ligand (10 mol %)
CN
Me
Ph COOH
H
_
Ph
THF (0.5 M), 30 oC, 36 h
Me
Entry
Ligand
T
Yielda
drb
eec
CN
2a
1a (1.5 equiv)
3a
R2P
1
2
3
4
5
6
7
8
9
(R)-Tol-BINAP
(R,R)-Ph-BPE
(R,R)-i-Pr-DuPHos
(R,S)-JOSIPHOS
(S,S,R,R)-MANDYPHOS
(S,S)-TANIAPHOS
(S,S)-Cy-TANIAPHOS
CTH-(R)-P-Phos
(R)-DTBM-SEGPHOS
(R)-MONOPHOS
ꢀ20
ꢀ20
ꢀ30
ꢀ30
ꢀ30
ꢀ30
ꢀ30
ꢀ20
ꢀ20
ꢀ20
67%
52%
78%
72%
51%
85%
51%
92%
95%
11%
1.4/1
8.0/1
7.0/1
3.1/1
3.0/1
3.0/1
10.0/1
3.0/1
6.5/1
2.0/1
<5%/23%
27%d/24%
12%d/13%
<5%/13%
13%d/44%
62%/47%
46%d/<5%
32%d/38%
45%/39%
<5%/<5%
R2P
Fe
N
R'
R''
Entry
Ligand
Yielda
drb
eec
1
2
3
4
5
6
7
R¼Ph, R0¼R00¼Me
85%
58%
56%
88%
68%
71%
50%
3/1
5/1
5/1
3/1
7/1
3/1
2/1
62%/47%
11%/16%
31%/32%
62%/52%
31%/11%
34%/49%
23%/44%
R¼Cy, R0¼R00¼Et
10
R¼Cy, R0¼i-Pr, R00¼Et
R¼4-CH3eC6H4, R0¼R00¼Me
R¼2-CH3eC6H4, R0¼R00¼Me
R¼Ph, R0¼R00¼Et
i
Pr
Ph
Ph
P
P
PAr2
PAr2
i
P
Pr
P
i
Pr
R¼2,4-(CH3)2eC6H4, R0¼R00¼Me
Ph
Ph
i
Determined by 1H NMR of crude mixtures in the presence of an internal
a
Pr
i
(R)-TolBINAP
(Ar = 4-CH3-C6H4)
(R,R)-Ph-BPE
(R,R)- Pr-DuPHOS
standard.
Me
N
b
R2P
Determined by 1H NMR of crude mixtures.
Me
c
Determined by chiral HPLC.
Ph2P
Ph
PCy2
Fe
Me
Ph
Ph2P
Fe
R2P
Fe
N
Me
H
Me
N
Me
PPh2
Using a complex of CuOAc and TANIAPHOS as the catalyst, ef-
Me
(R,S)-JOSIPHOS
(S,S,R,R)-MANDYPHOS
(S,S)-TANIAPHOS (R = Ph)
(S,S)-TANIAPHOS-Cy (R = Cy)
fects of solvents were tested next (Table 3). The reaction in EtOAc
produced high yield, but diastereoselectivity and enantioselectivity
were lower (entry 1). Acetonitrile, dichloromethane, and ethanol
were not suitable regarding reactivity (entries 2e4). Toluene, ether,
and tBuOCH3 were not competent either (entries 5e7). The reaction
in DMF afforded acceptable results (entry 8). However, using DMA
(N,N-dimethylacetamide) as solvent did not improve the results
(entry 9). Finally, the reaction in THF gave the best results in light of
the yield (85%), diastereoselectivity (3.0/1), and enantioselectivity
(62% for the major diastereoisomer; entry 10). Using chiral hydro-
gen bond donors ((R,R)- and (S,S)-TUC) as additives did not give any
improved results (entries 11 and 12).
Thus-optimized conditions were applied to a range of aldehydes
(Fig. 1). Although addition products were obtained in high yields,
both enantioselectivity and diastereoselectivity from aromatic al-
dehydes were only moderate to low (3aee). In the case of an ali-
phatic aldehyde (isobutyraldehyde), however, product 3f was
produced with 79% ee by the use of DTBM-SEGPHOS as a chiral
ligand. Using TANIAPHOS in this case, 3f was not obtained (no
addition reaction). The fact that decent enantioselectivity was
obtained from an aliphatic aldehyde is noteworthy, because the
OMe
O
N
O
O
PAr2
PAr2
MeO
MeO
PPh2
PPh2
O
O
Me
Me
P
N
N
O
(R)-DTBM-SEGPHOS
(Ar = 3,5- Bu-4-MeO-C6H2)
OMe
CTH-(R)-P-PHOS
t
(R)-MONOPHOS
a
Yields determined by 1H NMR of crude mixtures in the presence of an internal
standard.
b
Diastereo-ratios (dr) determined by 1H NMR of crude mixtures. In all entries, the
same diastereomer as shown in the scheme was obtained as the major product.
c
Enantiomeric excesses (ee) determined by chiral HPLC.
The enantiomer of 3a was produced as the major isomer.
d
(R)-Tol-BINAP did not show high asymmetric induction in the
decarboxylative aldol-type reaction (Table 1, entry 1). In the cases
of (R,R)-Ph-BPE and (R,R)-i-Pr-DuPhos, high diastereoselectivity
was observed, but enantioselectivity was low (entries 2 and 3).

L. Yin et al. / Tetrahedron 68 (2012) 3497e3506
3499
Table 3
type reaction, was employed with CuOAc in the reaction between
1a and aldimines. Our investigation began with the screening of
protecting groups on the nitrogen atom in benzaldimines (Table 4).
The reaction with N-Boc-imine afforded a complex mixture, pos-
sibly due to its lability (entry 1). Hydrazone was intact under the
reaction conditions (entry 2). Sulfonyl imines proved to be a suit-
able class of substrates, affording the corresponding products in
excellent yields (entries 3e5). However, both diastereoselectivity
and enantioselectivity were moderate to low. Finally, N-diphenyl-
phosphinoyl benzaldimine 4a was found to be the most promising
substrate, giving product 5a in 64% yield, 6.6/1 diastereoselectivity,
and 75% ee of the major diastereoisomer (entry 6). Despite in-
tensive screening of TANIAPHOS analogs, however, no further im-
proved results were obtained.
Solvent effects in Cu(I)-catalyzed asymmetric decarboxylative aldol-type reaction
O
OH
CuOAc (10 mol %)
CN
Me
TANIAPHOS (10 mol %)
Ph COOH
H
_
solvent (0.5 M), 30 oC, 36 h
Ph
3a
Me
CN
2a
1a (1.5 equiv)
Entry
Solvent
Additive
Yielda
drb
eec
1
2
3
4
5
6
7
8
EtOAc
CH3CN
CH2Cl2
C2H5OH
Toluene
Ether
d
80%
8%
2.0/1
1.8/1
2.0/1
1.6/1
2.3/1
2.5/1
2.0/1
3.0/1
3.0/1
3.0/1
3.0/1
3.0/1
53%/10%
d
d
d
18%
17%
64%
39%
66%
76%
56%
85%
77%
81%
48%/31%
41%/17%
57%/24%
52%/< 5%
51%/17%
62%/56%
58%/42%
62%/47%
61%/36%
61%/32%
d
d
d
t-BuOCH3
DMF
d
d
9
DMA
THF
THF
THF
d
10
11
12
d
(R,R)-TUCd
Table 4
(S,S)-TUCd
Screening of protecting groups in Cu(I)-catalyzed decarboxylative Mannich-type
reaction using TANIAPHOS
Me
Me
Me
Me
N
N
H
N
H
H
N
H
PG
PG
N
F3C
N
F3C
CuOAc (10 mol %)
N
HN
Ph
Ph COOH
TANIAPHOS (10 mol %)
CN
Me
S
S
H
Me
CN
THF, T (oC), 12 h
CF3
CF3
(R,R)-TUC
(S,S)-TUC
1a
(1.5 equiv)
a
Determined by 1H NMR of crude mixtures in the presence of an internal
Entry
1
Aldimine
T
Yielda
drb
eec
standard.
b
c
Determined by 1H NMR of crude mixtures.
Determined by chiral HPLC.
10 mol % was added.
Boc
N
d
0
0
d
d
d
d
Ph
H
NHBz
CuOAc (10 mol %)
OH
R2
N
O
R2 COOH
TANIAPHOS (10 mol %)
2
3
Trace
90%
d
CN
R3
R1
Ph
H
R1
H
R3
CN
THF (0.5 M), 12 h
2
1 (2.5 equiv)
3
O
O
S
S
O
N
ꢀ30
1.2/1
48%/57%
34%/45%
Ph2P
Fe
O
O
PAr2
PAr2
Ph
H
Ph2P
OH
NO2
N
Me
O
O
O
S
Me
4
5
N
0
92%
90%
64%
1.2/1
1.2/1
6.6/1
Ar = 4-CH3-C6H4
TANIAPHOS
(R)-DTBM-SEGPHOS
OH
NO2
NO2
Ph
H
OH
CN
Me
CN
Me
CN
Me
O
O
S
H
Ph
3a
Ph
3b
Ph
3c
N
0
0
37%/41%
75%/23%
Br
93% (−25 oC)
d.r. = 3.0/1, 46% ee
Ph
92% (−20 oC)
d.r. = 2.2/1, 34% ee
95% (−25 o
C)
d.r. = 3.0/1, 62% ee
O
PPh2
OH
CN
OH
CN
OH
6
N
CN
Me
Ph
Determined by 1H NMR of crude mixtures in the presence of an internal
4a
H
Ph
Ph
3f
Ph
Me
Me
F3C
a
3d
3e
96% (−25 oC)
d.r. = 3.0/1, 39% ee
58% (−15 oC)
d.r. = 2.0/1, 27% ee
82% (−15 oC)a
d.r. = 3.4/1, 79% ee
standard.
b
c
Determined by 1H NMR of crude mixtures.
Determined by chiral HPLC.
Fig. 1. Substrate scope of Cu(I)-catalyzed asymmetric decarboxylative aldol-type re-
action. a(R)-DTBM-SEGPHOS was used as a chiral ligand instead of TANIAPHOS. Ab-
solute and relative configurations of 3a were determined based on the comparison to
the reported data.11c Configurations of other products were assigned by analogy.
Because it was difficult to obtain high enantioselectivity using
TANIAPHOS derivatives, more broad screening of chiral ligands was
performed (Table 5). Biaryl-type ligands, (S)-tol-BINAP and (R)-
DIFLUORPHOS, showed certain asymmetric induction, however
both diastereoselectivity and enantioselectivity were less satisfac-
tory than TANIAPHOS (entries 1 and 2). TANIAPHOS-related ligands
containing a ferrocene core, such as (S,S)-MANDYPHOS and (R,S)-
JOSIPHOS, were not effective (entries 3 and 4). Chiral ligands
containing more than one chiral centers, such as (R,R)-BPE,
(R,R)-NORPHOS, and (S,S,R,R)-TANGPHOS were not better than
TANIAPHOS (entries 5e7). Poor yield, diastereoselectivity, and
enantioselectivity were obtained using nitrogen-containing li-
gands, such as (S)-QUINAP and Trost ligand (entries 8 and 9).
previous Denmark’s catalytic asymmetric aldol reaction of alde-
hydes and silyl ketenimide afforded 3 with excellent enantiose-
lectivity only from aromatic aldehydes.11c
2.2. Catalytic asymmetric decarboxylative Mannich-type
reaction
The Cu(I)-catalyzed decarboxylative nucleophile generation was
further extended to an asymmetric Mannich-type reaction16 using
1a. TANIAPHOS, the optimal ligand for the decarboxylative aldol-

3500
L. Yin et al. / Tetrahedron 68 (2012) 3497e3506
Table 5
(entry 1). On the other hand, slow addition of 1a proved to be the
effective method. Using 10 mol % CuOAc and 10 mol % (R)-DTBM-
SEGPHOS, slow addition (ca. 6 h) of 1.5 equiv of 1a afforded 5a in
91% yield with maintaining diastereoselectivity and enantiose-
lectivity at 0 ꢁC (entry 3). Surprisingly, at lower temperature of
ꢀ10 ꢁC, the addition did not proceed at all, and a quantitative
amount of 2-phenylpropionitrile was produced via decarboxylation
followed by protonation of the resulting ketenimide. Reducing the
catalyst to 5 mol % provided 5a in 43% yield using 1.5 equiv of 1a at
0 ꢁC (entry 5). Finally, increasing the amount of 1a to 2.5 equiv, 5a
was obtained in 98% yield, 7.0/1 dr and 87% ee (major di-
astereoisomer; entry 7) (Table 6).
Having established the optimized reaction conditions, the sub-
strate scope was then investigated (Table 7). As for the imines, ar-
omatic imines containing both electron-donating and withdrawing
substituents at the para-position, as well as heteroaromatic imines
were tolerated (entries 1e8, 11, and 12). The reaction proceeded
with complete chemoselectivity to the imine functionality in the
presence of a ketone group (entry 7). Sterically congested ortho-
substituted aromatic imines afforded excellent enantioselectivity,
although yield and diastereoselectivity were slightly decreased
(entries 9 and 10). Unfortunately, p-nitrobenzaldehyde-derived
imine 4t did not produce the desired product under the current
reaction conditions (no reaction; entry 20). Remarkably, however,
Screening of chiral ligands in Cu(I)-catalyzed asymmetric decarboxylative Mannich-
type reaction
P(O)Ph2
P(O)Ph2
CuOAc (10 mol %)
ligand (10 mol %)
N
HN
Ph COOH
CN
Me
H
Me
CN
THF, 0 oC, 12 h
Ph
4a
1a (1.5 equiv)
5a
Entry
Ligand
Yielda
drb
eec
1
2
3
4
5
6
7
8
9
(R)-Tol-BINAP
83%
73%
70%
41%
73%
12%
30%
15%
23%
30%
3.5/1
3.9/1
2.7/1
4.1/1
5.2/1
5.3/1
2.6/1
4.0/1
4.0/1
7.0/1
37%d/47%
27%/33%
27%d/37%
31%/20%
52%d/28%
6%d/11%
25%/13%
19%/8%
(R)-DIFLUORPHOS
(S,S,R,R)-MANDYPHOS
(R,S)-JOSIPHOS
(R,R)-Ph-BPE
(R,R)-NORPHOS
(S,S,R,R)-TANGPHOS
(S)-QUINAP
(R,R)-Trost ligand
(R)-DTBM-SEGPHOS
13%/8%
10
87%/73%
O
F
F
H
PPh2
O
O
PPh2
PPh2
H
P
P
H
H
F
F
PPh2
O
(R)-DIFLUORPHOS
(S,S,R,R)-TANGPHOS
(R,R)-NORPHOS
N
aliphatic imines containing acidic a-protons and thus susceptible
O
O
NH HN
under basic conditions were competent substrates in this decar-
boxylative Mannich-type reaction due to the mild reaction condi-
tions (entries 13e17). The diastereoselectivity was moderate in
aliphatic imine cases. As for the cyanocarboxylic acids, the enantio-
and diastereoselectivity decreased slightly according to the size of
PPh2
PPh2 Ph2P
(R,R)-Ph-Trost Ligand
(S)-QUINAP
Determined by 1H NMR of crude mixtures in the presence of an internal
a
the a-substituents (entries 1e5 and 13e15). Nevertheless, products
standard.
b
Determined by 1H NMR of crude mixtures. In all entries, the same diastereomer
containing a synthetically useful allyl group at the quaternary
center were produced with meaningful efficiency (entries 3 and
15). It is also noteworthy that this method was applicable to
a cyanoacetic acid without an aromatic substituent, affording the
products with reasonable enantioselectivity (entries 18 and 19). To
our knowledge, this is the first general catalytic asymmetric
as shown in the scheme was obtained as the major product.
c
Determined by chiral HPLC.
The enantiomer of 5a was produced as the major isomer.
d
Finally, product 5a was produced in 7.0/1 dr and 87% ee (major
diastereoisomer) when (R)-DTBM-SEGPHOS was employed, al-
though the yield was low (entry 10).
method to access
and aliphatic substituents at the
b
2,2,3-amino acid derivatives with both aromatic
- and/or -position(s).
a
b
Since (R)-DTBM-SEGPHOS was identified as the most appro-
priate chiral ligand regarding enantioselectivity and diaster-
eoselectivity, further optimization of reaction conditions was
carried out to improve the yield (Table 6). The reaction temperature
was raised to room temperature, but only 23% yield of 5a was
obtained even when 3.0 equiv of cyanoacetic acid 1a was employed
2.3. Transformation of the product
After examining the substrate scope, conversion of product 5a to
b
2,2,3-amino acid derivatives was studied (Table 8). Reported con-
ditions17,18 for the cleavage of N-diphenylphosphinoyl group was
tried first. Only deprotection of the amine (6a) was observed
remaining the CN group intact (entries 1 and 2). Higher tempera-
ture and concentration of HCl did not afford any improvement
(entries 3e6). The method generating HCl in situ also did not work
well in this case (entry 7). Finally, treatment with 9 M H2SO4 was
found to be suitable for simultaneous hydrolysis of the N-diphe-
nylphosphinoyl amide and the cyano group. Enantiomerically-
Table 6
Further optimization of reaction conditions
CuOAc (X mol %)
P(O)Ph2
P(O)Ph2
(R)-DTBM-
N
HN
SEGPHOS (X mol %)
Ph COOH
CN
Me
H
Me
CN
THF, 0 oC, 12 h
Ph
enriched
b
2,2,3-amino amide 7a was produced without any
4a
1a
(Y equiv)
5a
racemization and epimerization.
Entry
T
X
Y
Yielda
drb
eec
2.4. Proposed catalytic cycle
1
2
3
4
5
6
7
rt
0
0
10
10
10
10
5
3.0
23%
30%
91%
d
7.0/1
7.0/1
7.0/1
d
87%/69%
87%/73%
87%/73%
d
1.5
1.5d
1.5
A possible catalytic cycle for the decarboxylative Mannich-type
reaction is postulated as shown in Fig. 2. First, anion exchange
between the chiral copper acetate complex and cyanoacetic acid 1
produces copper cyanoacetate 8. Then, chiral copper(I) ketenimide
9, the active nucleophile, is generated via extrusion of CO2, which is
facilitated by a softesoft interaction between Cu(I) and nitrile (8).
Copper(I) ketenimide 9 reacts with aldimine 4 to afford the corre-
sponding copper(I) amide intermediate 10, which is protonated by
ꢀ10
0
1.5d
2.0d
2.5d
43%
83%
98%
7.0/1
7.0/1
7.0/1
87%/70%
87%/70%
87%/70%
0
0
5
5
a
Determined by 1H NMR of crude mixtures in the presence of an internal
standard.
b
Determined by 1H NMR of crude mixtures.
Determined by chiral HPLC.
Slowly added over ca. 6 h.
c
d
1 to give the product
a,a-disubstituted-b-amino-nitrile 5 with

L. Yin et al. / Tetrahedron 68 (2012) 3497e3506
3501
Table 8
Hydrolysis of N-diphenylphosphinoyl amido nitrile
P(O)Ph2
Table 7
NH2
HN
NH2
O
Substrate scope of Cu(I)-catalyzed asymmetric decarboxylative Mannich-type
reaction
CN
CN
acidic conditions
T (oC), t (h)
NH2
Ph Me
6a
Ph
Ph
Me
Me
CuOAc (5 mol %)
P( )Ph
P(O)Ph2
CN
O
2
5a (d.r. >50/1, 87% ee)
7a
(R)-DTBM-
HN
R1
N
R2 COOH
SEGPHOS (5 mol %)
R1
H
R3
CN
THF, 0 oC, 12 h
R3
Entry
Acidic conditions
T
t
Results
R2
4
1
(2.5 equiv)
with slow addition
5
1
2
3
4
5
6
7
8
4 M HCl aq
4 M HCleMeOH
4 M HCl aq
6 M HCleEtOH
12 M HCl aq
12 M HCl aq
TMSCleMeOH
9 M H2SO4 aq
60
60
12
12
12
3
12
12
2
Mainly 6a
Mainly 6a
Mainly 6a
Mainly 6a
Mainly 6a
Mainly 6a
100
90
Entry
1
Product (major isomer)
Yield (%)a drb
ee (%)c
60
94
7.1:1 87
100
50
120
X = H, R = Me (5a)
6aþMany side-products
O
X = H, R = Et (5b)
1.5
7a (70%)a
PPh2
2
3
4
5
6
7
96
90
93
93
96
95
6.5:1 81
5.4:1 80d
7.4:1 97
6.0:1 80
6.4:1 82
7.4:1 80
X = H, R = allyl (5c)
X = MeO, R = Me (5d)
X = MeO, R = Et (5e)
X = Br, R = Me (5f)
X = MeCO, R = Me (5g)
HN
Ph
a
dr >50/1, 87% ee.
CN
R
X
P
P
NHP(O)Ph2
AcO Cu
(R)-DTBM-SEGPHOS
*
CN
8
9
51
63
9.1:1 84
4.0:1 90
5h
Ph
Me
5
1
1
NHP(O)Ph2
CN
5i
AcOH
O
Ph
Me
P
*
P
O
C
Cu
P(O)Ph2
Me
Cu
NHP(O)Ph2
CN
*
N
P
P
10
62
5.2:1 93
5j
R2
R3
CN
R3
N
Ph
R1
Me
8
10
R2
NHP(O)Ph2
CN
R2
11
12
13
5k
94
93
82
8.9:1 85
8.4:1 83
2.1:1 95
C
N
4
CO2
Ph
Me
O
S
R3
Cu
P
P
9
NHP(O)Ph2
CN
5l
Ph
Me
Fig. 2. Proposed catalytic cycle for the asymmetric decarboxylative Mannich-type
reaction.
NHP(O)Ph2
CN
R = Me (5m)
R = Et (5n)
R = allyl (5o)
regenerating 8. A competitive reaction is protonation of reactive
copper(I) ketenimide 9 by 1, resulting in low yield under one por-
tion addition of 1. The catalytic asymmetric decarboxylative aldol-
type reaction should proceed in a similar way.
To assess the importance of the softesoft interaction between
Cu(I) catalyst and cyanocarboxylic acids involved in the decarboxy-
lative nucleophile generation step (8), reactions of aldimine 4a with
simple, unactivated cyanoacetic acid 11 and with malonic acid half
ester 12 were performed (Fig. 3). The reaction between 4a and 11
afforded product 13 in 53% yield (Eq. 1). In the reaction between 4a
and 12, however, undecarboxylated addition product 14 was
detected as the major product with a slight amount of decarbox-
ylative Mannich-type product 15 (Eq. 2). These results illustrate
Ph
14
15
72
71
2.7:1 83
1.6:1 80
R
NHP(O)Ph2
CN
16
17
75
83
2.4:1 84
2.5:1 85
5p
Ph
Me
NHP(O)Ph2
CN
5q
Ph
Ph
Me
18
19
70
73
4.5:1 70
2.1:1 80
NHP(O)Ph2
5r
R = Ph ( )
5s
CN
R
R = c-Hex (
)
Me
CuOAc (10 mol %)
P(O)Ph2
CN
P(O)Ph2
HN
Ph
rac-BINAP (10 mol %)
O
O
HN
Ph
(eq. 1)
(eq. 2)
4a
+
+
C
O
N
CN
Me
HO
HO
20
0
d
d
THF, 50 oC, 12 h
5t
11
13: 53%
O2N
P(O)Ph2
CO2Bn
CO2H
a
CuOAc (10 mol %)
rac-BINAP (10 mol %)
HN
Ph
Isolated combined yield of diastereomers.
Determined by 1H NMR.
Determined by chiral HPLC.
P(O)Ph2
CO2Bn
b
c
HN
Ph
4a
+
THF, 50 oC, 12 h
OBn
d
Absolute and relative configurations were determined by X-ray crystallography.
12
14: ca. 30%
15: <10%
Fig. 3. Control experiments to assess the importance of softesoft interaction between
Cu(I) catalyst and nitrile in decarboxylative nucleophile generation.

3502
L. Yin et al. / Tetrahedron 68 (2012) 3497e3506
that the softesoft interaction between Cu(I) catalyst and cyano
group of the nucleophile precursors plays a key role in facilitating
the decarboxylative nucleophile generation.
evaporation of the solvent afforded cyanoacetic acid 1a in a pure
form, whichwasutilizedforthecatalytic asymmetricdecarboxylative
aldol-type reaction and Mannich-type reaction without purification
(91% yield for two steps). Compound 1b and 1c were synthesized in
a similar manner using EtI and allyl bromide, respectively (yield
>80%). Cyano-methyl-vinyl-acetic acid was synthesized through
hydrolysis of the known corresponding ethyl ester.20
3. Conclusion
In summary, a catalytic asymmetric aldol-type reaction of alde-
hydes with cyanoacetic acids and Mannich-type reaction of aldi-
mines with cyanoacetic acids were developed based on the catalytic
decarboxylative nucleophile generation, which was facilitated by
thesoftesoft interaction between Cu(I)andthecyanogroup. A series
4.2.1. Cyano-methyl-phenyl-acetic acid ethyl ester. Colorless oil; 1H
NMR (500 MHz, CDCl3)
4.17e4.25 (m, 2H), 7.32e7.50 (m, 3H), 7.51 (dd, J¼7.4, 1.2 Hz, 2H);
13C NMR (126 MHz, CDCl3)
: 14.2, 25.2, 48.7, 63.6, 119.9, 126.1,
d: 1.22 (t, J¼7.0 Hz, 3H), 1.93 (s, 3H),
of
yields, moderate diastereoselectivity and enantioselectivity in the
aldol-type reaction. An array of -disubstituted- -amino acid de-
a,
a
-disubstituted-b-hydroxy nitriles was produced in excellent
d
129.2,129.5,136.2,168.3; IR (neat, cmꢀ1):
n 2244,1735; MS (ESI) m/z
a
,a
b
226 (MþNa)þ; HRMS (FAB) calcd for C12H13NNaO2 (MþNa)þ
rivatives were constructed in high to excellent yields, high diaster-
eoselectivity and high enantioselectivity in the Mannich-type
reaction. This is the first general catalytic asymmetric synthesis of
226.0844. Found 226.0850.
4.2.2. Cyano-ethyl-phenyl-acetic acid ethyl ester. Colorless oil; 1H
a
,
a
-disubstituted-
b
-amino acid derivatives. These catalytic asym-
NMR (500 MHz, CDCl3)
d
: 1.03 (t, J¼7.4 Hz, 3H), 1.20 (t, J¼7.0 Hz,
metric CeC bond-formations proceeds under very mild conditions
and neutral to weakly acidic pH. Further extension of this catalytic
nucleophile activation concept to other important asymmetric CeC
bond forming reactions are currently ongoing.
3H), 2.09e2.17 (m, 1H), 2.36e2.43 (m, 1H), 4.13e4.25 (m, 2H),
7.30e7.38 (m, 3H), 7.51 (d, J¼7.7 Hz, 2H); 13C NMR (126 MHz, CDCl3)
d
: 10.1, 14.1, 31.9, 55.4, 63.4, 118.6, 126.4, 129.1, 129.4, 134.8, 167.9; IR
(neat, cmꢀ1):
n
2243, 1743; MS (ESI) m/z 240 (MþNa)þ; HRMS (FAB)
calcd for C13H15NNaO2 (MþNa)þ 240.1000. Found 240.1010.
4. Experimental section
4.1. General
4.2.3. Cyano-allyl-phenyl-acetic acid ethyl ester. Colorless oil; 1H
NMR (500 MHz, CDCl3)
d
: 1.19 (t, J¼7.1 Hz, 3H), 2.82 (q, J¼7.0 Hz,
1H), 3.06e3.11 (m, 1H), 4.13e4.24 (m, 2H), 5.18 (d, J¼10.4 Hz, 1H),
Infrared (IR) spectra were recorded on a JASCO FT/IR 410 Fourier
transform infrared spectrophotometer. NMR spectra were recorded
on a JEOL JNM-LA500 or ECX500 spectrometer, operating at
500 MHz for 1H NMR, 125.65 MHz for 13C NMR, and 202.35 MHz for
31P NMR. Chemical shifts were reported in parts per million on the
5.22 (d, J¼17.1 Hz, 1H), 5.67e5.76 (m, 1H), 7.30e7.38 (m, 3H), 7.52
(d, J¼7.6 Hz, 2H); 13C NMR (126 MHz, CDCl3)
d: 14.1, 42.5, 54.4, 63.4,
118.2, 121.4, 126.4, 129.2, 129.4, 131.0, 134.4, 167.4; IR (neat, cmꢀ1):
n
2246, 1743; MS (ESI) m/z 252 (MþNa)þ; HRMS (FAB) calcd for
C14H15NNaO2 (MþNa)þ 252.1000. Found 252.0991.
d
scale relative to residual CHCl3 (
d
¼7.24 for 1H NMR and
¼77.0 for
d
13C NMR) as an internal reference or H3PO4 (
d
¼0 for 31P NMR) as an
4.3. Catalytic asymmetric decarboxylative aldol-type reaction
General procedure (for 3a): Cyanoacetic acid 1a (0.50 mmol in
external standard. Optical rotations were measured on a JASCO
P-1010 polarimeter. ESI mass spectra were measured on Waters-
ZQ4000. FAB mass spectra were measured on a JEOL JMS-BU20
GCmate or a JEOL JMS-700 V. Column chromatography was per-
formed with silica gel Merck 60 (230e400 mesh ASTM) or neutral
200.0
mL THF, 2.5 equiv) was added as a portion to a THF solution
(0.2 mL) of CuOAc (2.4 mg, 0.02 mmol, 10 mol %), TANIAPHOS
(13.6 mg, 0.02 mmol, 10 mol %), and aldehyde 3a (20.3
mL,
silica gel 60 N (KANTO CHEMICAL, spherical, neutral, 40e100
mm).
0.20 mmol) at ꢀ20 ꢁC under stirring. After 36 h, evaporation of the
reaction mixture afforded a crude product. The diastereomer ratio
was determined by 1H NMR at this stage to be 3.0/1 (the ratio of
The enantiomeric excesses (ee’s) were determined by HPLC. HPLC
analysis was performed on JASCO HPLC systems containing of fol-
lowing: pump, PU-980; detector, UV-970, measured at 254 nm;
column, Daicel Chiralpak AD-H, Daicel Chiralpak AS-H Daicel
Chiralcel OD-H or Daicel Chiralcel IC; mobile phase, 2-propanol/
hexane; flow rate, 1.0 mL/min. Reactions were carried out in dry
solvents under an argon atmosphere, unless otherwise stated. Dry
tetrahydrofuran (THF) was purchased from Kanto Chemical. Co.,
Inc., or freshly distilled from Ph2COeNa. CuOAc was purchased
from Aldrich, and used without any purification. (R)-DTBM-SEG-
RPHOS was purchased from Strem. N-Phosphinoyl aldimines were
synthesized according to the literature procedures.17,19
single peaks at
d 4.87 ppm (major) and 4.85 ppm (minor)). A
mixture of diastereomers was obtained through silica gel column
chromatography (acetate/hexane¼5/1) as a colorless oil (40.4 mg,
85%). Part of the major isomer was isolated with PTLC for data
collection.
4.3.1. 3-Hydroxy-2-methyl-2,3-diphenylpropionitrile (3a). Known
compound.11c MS (ESI) m/z 260 (MþNa)þ; HPLC condition: Chir-
alpak AD-H, flow rate: 1.0 mL/min, n-hexane/i-PrOH¼20/1,
t¼30.5 min (minor), 29.3 min (major). 254 nm detect.
4.2. Synthesis of CN-acetic acids
4.3.2. 3-(4-Bromophenyl)-3-hydroxy-2-methyl-2-phenylpropionitrile
(3b). Known compound.11c MS (ESI) m/z 338, 340 (MþNa)þ; HPLC
condition: Chiralpak AD-H, flow rate: 1.0 mL/min, n-hexane/i-
PrOH¼9/1, t¼12.7 min (major), 13.8 min (minor). 254 nm detect.
General procedure: To a mixture of commercially available ethyl
2-cyano-2-phenylacetate (9.46 g, 50 mmol) and MeI (3.74 mL,
60 mmol), acetone (80 mL) and K2CO3 (7.6 g) were added. After
stirring the mixture for 3 h at room temperature, the mixture was
passed through a short pad of silica gel. The silica gel was washed
with acetone, and combined organic eluents were evaporated. The
resulting oil was dissolved in EtOH (10 mL), and 10% aqueous KOH
solution was added. The resulting mixture was stirred at room
temperature for 2 h Et2O was added, and the aqueous layer was
separated. The aqueous layer was washed twice with Et2O, and
acidified with 2 N H2SO4. Extraction with Et2O for three times, and
4.3.3. 3-Hydroxy-2-methyl-3-naphthalen-2-yl-2-phenylpropionitrile
(3c). Known compound.11c MS (ESI) m/z 310 (MþNa)þ; HPLC con-
dition: Chiralpak AY-H, flow rate: 1.0 mL/min, n-hexane/i-PrOH¼9/
1, t¼44.1 min (minor), 29.3 min (major). 254 nm detect.
4.3.4. 3-Hydroxy-2-methyl-2-phenyl-3-(4-trifluoromethylphenyl)
propionitrile (3d). Known compound.11c MS (ESI) m/z 328
(MþNa)þ; HPLC condition: Chiralpak OD-H, flow rate: 1.0 mL/min,

L. Yin et al. / Tetrahedron 68 (2012) 3497e3506
3503
n-hexane/i-PrOH¼9/1, t¼11.9 min (major), 17.3 min (minor).
t¼35.9 min (major), 85.1 min (minor). 254 nm detect; [
(c 1.7, CHCl3) (81% ee).
a]
23 ꢀ26.1
D
254 nm detect.
4.3.5. 3-Hydroxy-2-methyl-3-naphthalen-1-yl-2-phenylpropionitrile
(3e). Known compound.11c MS (ESI) m/z 310 (MþNa)þ; HPLC con-
dition: Chiralpak AD-H, flow rate: 1.0 mL/min, n-hexane/i-PrOH¼9/
1, t¼21.3 min (minor), 53.2 min (major). 254 nm detect.
4.4.3. (2R,3R)-N-Diphenylphosphinoyl-3-amino-2-allyl-2-phenyl-3-
phenylpropionitrile (5c). Colorless needles; mp 196 ꢁC; 1H NMR
(500 MHz, CDCl3)
d
: 2.46 (dd, J¼7.7, 14.4 Hz, 1H), 2.80 (dd, J¼6.7,
14.4 Hz,1H), 3.37 (dd, J¼8.0,10.6 Hz,1H), 4.48 (t like, J¼10.6 Hz,1H),
4.93 (d, J¼10.1 Hz, 1H), 5.01 (dd, J¼1.4, 17.1 Hz, 1H), 5.38 (m, 1H),
7.03 (m, 2H), 7.17e7.28 (m, 9H), 7.33e7.38 (m, 9H); 13C NMR
4.3.6. 3-Hydroxy-2,4-dimethyl-2-phenyl-pentanenitrile
(3f). Colorless oil; 1H NMR (500 MHz, CDCl3)
d
: 0.86 (d, J¼7.1 Hz,
(126 MHz, CDCl3)
d
: 41.4, 55.0 (d, J¼6.2 Hz), 62.0, 120.3, 127.8, 128.0,
3H), 0.94 (d, J¼6.7 Hz, 3H), 1.60e1.66 (m, 1H), 1.83 (s, 3H), 2.02 (d,
J¼8.0 Hz, 1H), 3.65 (dd, J¼7.6, 3.1 Hz, 1H), 7.31 (t, J¼7.0 Hz, 1H), 7.38
128.1,128.2,128.3,128.3,128.4,128.8,131.3,131.5 (d, J¼10 Hz),131.9,
132.2 (d, J¼10 Hz), 134.8, 138.4; 31P NMR (202 MHz, CDCl3)
d: 23.5;
(t, J¼7.4 Hz, 2H), 7.44 (d, J¼7.6 Hz, 2H); 13C NMR (126 MHz, CDCl3)
d:
IR (neat, cmꢀ1):
n 3201, 2238, 1187, 1105; MS (ESI) m/z 485
15.7, 22.3, 26.4, 30.5, 48.5, 81.9, 122.6, 126.4, 128.5, 129.5, 139.0; IR
(MþNa)þ; HRMS (FAB) calcd for C30H28N2OP (MþH)þ 463.1934.
(neat, cmꢀ1):
n
3476, 2241; MS (ESI) m/z 226 (MþNa)þ; HRMS (FAB)
Found 463.1935. HPLC condition: Chiralpak AD-H, flow rate: 1.0 mL/
calcd for C13H17NNaO (MþNa)þ 226.1208. Found 226.1203. HPLC
condition: Chiralpak AS-H, flow rate: 1.0 mL/min, n-hexane/i-
PrOH¼9/1, t¼7.7 min (major), 15.0 min (minor). 220 nm detect;
min, n-hexane/i-PrOH¼4/1, t¼43.1 min (major), 63.1 min (minor).
23
254 nm detect; [
a]
ꢀ29.2 (c 0.68, CHCl3) (80% ee). The relative
D
and absolute configurations were determined by X-ray crystallog-
[
a]
23 ꢀ12.3 (c 0.0144, CHCl3) (79% ee).
raphy (see Section 4).
D
4.4.4. N-Diphenylphosphinoyl-3-amino-2-methyl-2-phenyl-3-(4-
4.4. Catalytic asymmetric decarboxylative Mannich-type
reaction
methoylphenyl)propionitrile (5d). Colorless oil; 1H NMR (500 MHz,
CDCl3)
d
: 1.57 (s, 3H), 3.33 (dd, J¼6.6,10.7 Hz, 3H), 3.73 (s, 3H), 4.34 (t
like, J¼10.0 Hz,1H), 6.72 (d like, J¼11.6 Hz, 2H), 6.96 (d like, J¼11.6 Hz,
General procedure (for 5a): Cyanoacetic acid 1a (0.50 mmol in
2H), 7.20e7.30 (m, 6H), 7.33e7.38 (m, 7H), 7.40e7.45 (m, 2H); 13C
200.0
at a rate of 0.5
m
L THF, 2.5 equiv) was added slowly using a syringe pump
L/min to a THF solution (0.2 mL) of CuOAc
NMR (126 MHz, CDCl3)
d
: 25.2, 49.5 (d, J¼7.2 Hz), 55.2, 62.4, 113.6,
m
121.8,127.0,128.2,128.3,128.3,128.4,128.4,128.8,129.0,130.5,131.7
(1.2 mg, 0.01 mmol, 5 mol %), (R)-DTBM-SEGPHOS (11.8 mg,
0.01 mmol, 5 mol %), and imine 4a (61.1 mg, 0.20 mmol) at 0 ꢁC
under stirring. After 12 h (total reaction time including slow
addition), the reaction was quenched by adding 1 N HCl. Products
were extracted with AcOEt, and the combined organic layers
were washed with brine. After drying with Na2SO4, filtration, and
evaporation afforded a crude mixture. The diastereomer ratio
was determined by 1H NMR at this stage to be 7.1/1 (the ratio of
(d, J¼9 Hz), 131.8, 132.2 (d, J¼9 Hz), 137.4, 159.5; 31P NMR (202 MHz,
CDCl3) d n 3200, 2235, 1515, 1438, 1183; MS
: 23.3; IR (neat, cmꢀ1):
(ESI) m/z 489 (MþNa)þ; HRMS (FAB) calcd for C29H28N2O2P (MþH)þ
467.1883. Found 467.1878. HPLC condition: Chiralpak AD-H, flow
rate: 1.0 mL/min, n-hexane/i-PrOH¼9/1, t¼88.4 min (minor),
93.1 min (major). 254 nm detect; [
a]
23 ꢀ49.6 (c 1.0, CHCl3) (97% ee).
D
4.4.5. N-Diphenylphosphinoyl-3-amino-2-ethyl-2-phenyl-3-(4-
triple peaks at
d
4.44 ppm (major) and 4.32 ppm (minor)). A
methoxyphenyl)propionitrile (5e). Colorless oil; 1H NMR (500 MHz,
mixture of diastereomers was obtained through silica gel column
chromatography (acetate/hexane¼3/1) as a colorless oil (82.0 mg,
94%). Part of the major isomer was isolated with PTLC for data
collection.
CDCl3)
d
: 0.71 (t, J¼7.3 Hz, 3H), 1.70 (m, 1H), 2.01 (m, 1H), 3.30 (m,
1H), 3.73 (s, 3H), 4.37 (t like, J¼9.5 Hz, 1H), 6.71 (d like, J¼8.6 Hz,
1H), 6.97 (d like, J¼8.6 Hz, 2H), 7.17e7.25 (m, 6H), 7.32e7.40 (m,
9H); 13C NMR (126 MHz, CDCl3)
d: 9.6, 30.6, 55.2, 56.3 (d, J¼7 Hz),
62.1, 113.6, 120.8, 127.5, 128.2 (d, J¼12 Hz), 128.3, 128.3 (d, J¼10 Hz),
4.4.1. N-Diphenylphosphinoyl-3-amino-2-methyl-2-phenyl-3-
128.9, 129.1, 130.8, 131.6 (d, J¼9 Hz), 131.8, 132.2 (d, J¼8 Hz), 135.3,
phenylpropionitrile (5a). Colorless oil; 1H NMR (500 MHz, CDCl3)
d:
159.4; 31P NMR (202 MHz, CDCl3) : 23.2; IR (neat, cmꢀ1):
d n 2235,
1.57 (s, 3H), 3.40 (m, 1H), 4.39 (t like, J¼9.9 Hz, 1H), 7.05e7.07 (m,
1183, 1088; MS (ESI) m/z 503 (MþNa)þ; HRMS (FAB) calcd for
2H), 7.17e7.28 (m, 9H), 7.33e7.43 (m, 9H); 13C NMR (126 MHz,
C30H30N2O2P (MþH)þ 481.2039. Found 481.2041. HPLC condition:
CDCl3)
d
: 25.3, 49.3, 62.7, 121.7, 126.9, 128.1, 128.2, 128.3, 128.4,
Chiralpak AD-H, flow rate: 1.0 mL/min, n-hexane/i-PrOH¼9/1,
23
128.9, 131.6 (d, J¼9 Hz), 131.8, 132.1 (d, J¼9 Hz), 137.4, 138.4; 31P
t¼73.8 min (major), 112.5 min (minor). 254 nm detect; [
a]
D
NMR (202 MHz, CDCl3) d n 2237, 1186, 1104;
: 23.6; IR (neat, cmꢀ1):
ꢀ103.4 (c 0.24, CHCl3) (80% ee).
MS (ESI) m/z 459 (MþNa)þ; HRMS (FAB) calcd for C28H26NO2P
(MþH)þ 437.1777. Found 437.1805. HPLC condition: Chiralpak AD-
4.4.6. N-Diphenylphosphinoyl-3-amino-2-methyl-2-phenyl-3-(4-
H, flow rate: 1.0 mL/min, n-hexane/i-PrOH¼4/1, t¼21.4 min (ma-
bromophenyl)propionitrile (5f). Colorless oil; 1H NMR (500 MHz,
23
jor), 29.3 min (minor). 254 nm detect; [
a
]
ꢀ48.0 (c 1.1, CHCl3)
CDCl3)
d
: 1.57 (s, 3H), 3.34 (dd, J¼6.4, 10.4 Hz, 1H), 4.36 (t like
D
(87% ee).
J¼9.6 Hz, 1H), 6.94 (d like, J¼8.4 Hz, 2H), 7.2e7.28 (m, 6H), 7.33 (d
like, J¼8.4 Hz, 2H), 7.36e7.45 (m, 9H); 13C NMR (126 MHz, CDCl3)
d:
4.4.2. N-Diphenylphosphinoyl-3-amino-2-ethyl-2-phenyl-3-
25.1, 49.0 (d, J¼7 Hz), 62.3, 121.5, 122.6, 126.9, 128.3 (d, J¼13 Hz),
cyclohexanylpropionitrile (5b). Colorless oil; 1H NMR (500 MHz,
128.5 (d, J¼13 Hz), 128.6, 129.0, 129.6, 131.4, 131.4, 131.6 (d,
CDCl3)
d
: 0.71 (t, J¼7.3 Hz, 3H),1.69 (dq, J¼7.3, 14.6 Hz,1H), 2.02 (dq,
J¼10 Hz), 132.0 (m), 132.1, 137.0, 137.4; 31P NMR (202 MHz, CDCl3)
d:
J¼7.3, 14.6 Hz, 3H), 3.38 (dd, J¼7.9, 11.0 Hz, 1H), 4.45 (dd, J¼9.5,
23.4; IR (neat, cmꢀ1):
n 2236, 1185, 1088; MS (ESI) m/z 537, 539
11.0 Hz, 1H), 7.07 (dd, J¼2.2, 8.0 Hz, 2H), 7.20 (m, 9H), 7.35 (m, 9H);
(MþNa)þ; HRMS (FAB) calcd for C28H25BrN2OP (MþH)þ 515.0882.
Found 515.0879. HPLC condition: Chiralpak AD-H, flow rate:
1.0 mL/min, n-hexane/i-PrOH¼4/1, t¼34.7 min (minor), 42.4 min
13C NMR (126 MHz, CDCl3)
d: 9.6, 30.6, 56.1 (d, J¼6.2 Hz), 62.5,112.6,
120.6, 127.5, 128.0, 128.1, 128.2e128.4 (5 peaks due to 31P coupling),
128.9, 131.1, 131.6 (d, J¼10 Hz), 131.8, 132.2 (d, J¼10 Hz), 132.6, 135.3,
(major). 254 nm detect; [
a
]
D
23 ꢀ227.1 (c 0.16, CHCl3) (82% ee).
138.7; 31P NMR (202 MHz, CDCl3) : 23.4; IR (neat, cmꢀ1):
d n 2235,
1437, 1190, 1105; MS (ESI) m/z 473 (MþNa)þ; HRMS (FAB) calcd for
C29H28N2OP (MþH)þ 451.1934. Found 451.1921. HPLC condition:
Chiralpak AD-H, flow rate: 1.0 mL/min, n-hexane/i-PrOH¼4/1,
4.4.7. N-Diphenylphosphinoyl-3-amino-2-methyl-2-phenyl-3-(4-
acetylphenyl)propionitrile (5g). Colorless oil; 1H NMR (500 MHz,
CDCl3)
d
: 1.58 (s, 3H), 2.53 (s, 3H), 3.43 (m, 1H), 4.45 (dd, J¼8.8,

3504
L. Yin et al. / Tetrahedron 68 (2012) 3497e3506
10.7 Hz, 1H), 7.17e7.7.26 (m, 9H), 7.34e7.44 (m, 8H), 7.80 (d,
1194, 1107; MS (ESI) m/z 449 (MþNa)þ; HRMS (FAB) calcd for
C26H24N2O2P (MþH)þ 427.1570. Found 427.1578. HPLC condition:
Chiralpak AD-H, flow rate: 1.0 mL/min, n-hexane/i-PrOH¼4/1,
J¼8.3 Hz, 2H); 13C NMR (126 MHz, CDCl3)
d: 25.1, 26.7, 49.0 (d,
J¼7.3 Hz), 62.6, 121.4, 126.9, 128.3, 128.4, 128.4, 128.6 (d, J¼19 Hz),
129.0, 131.7 (d, J¼9 Hz), 132.0 (m), 137.0 (d, J¼5 Hz), 143.5, 197.6; 31P
t¼24.8 min (major), 28.0 min (minor). 254 nm detect; [
a
]
23 ꢀ36.4 (c
D
NMR (202 MHz, CDCl3)
d
: 23.4; IR (neat, cmꢀ1):
n
2237, 1683, 1188,
1.26, CHCl3) (85% ee).
1092; MS (ESI) m/z 501 (MþNa)þ; HRMS (FAB) calcd for
C30H28N2O2P (MþH)þ 479.1883. Found 479.1904. HPLC condition:
Chiralpak AD-H, flow rate: 1.0 mL/min, n-hexane/i-PrOH¼4/1,
4.4.12. N-Diphenylphosphinoyl-3-amino-2-methyl-2-phenyl-3-
thienylpropionitrile (5l). Colorless oil; 1H NMR (500 MHz, CDCl3)
d
:
t¼47.6 min (minor), 58.8 min (major). 254 nm detect; [
(c 0.48, CHCl3) (80% ee).
a
]
D
23 ꢀ52.3
1.63 (s, 3H), 3.30 (dd, J¼7.7, 10.6 Hz, 1H), 4.02 (t like, J¼10.6 Hz, 2H),
6.84 (dd, J¼3.7, 4.9 Hz, 1H), 6.89 (d like, J¼3.7 Hz, 1H), 7.14 (br d,
J¼5.2 Hz, 1H), 7.21e7.40 (m, 13H), 7.46 (m, 2H); 13C NMR (126 MHz,
4.4.8. N-Diphenylphosphinoyl-3-amino-2-methyl-2-phenyl-3-(2-
CDCl3)
d
: 25.1, 49.9 (d, J¼6 Hz), 58.7, 121.8, 125.2, 126.6, 126.7, 126.8,
naphthyl)propionitrile (5h). Cloudy oil; 1H NMR (500 MHz, CDCl3)
128.2, 128.3, 128.3, 128.4, 128.5, 128.8, 131.6 (d, J¼10 Hz), 131.9 (m),
d
: 1.61 (s, 3H), 3.49 (dd, J¼7.0, 11.0 Hz, 1H), 4.57 (dd, J¼9.5, 11.0 Hz,
132.0 (d, J¼10 Hz), 137.1, 142.0; 31P NMR (202 MHz, CDCl3)
d: 23.8;
1H), 7.12 (ddd, J¼3.1, 7.7, 7.7 Hz, 2H), 7.21e7.31 (m, 6H), 7.33e7.46
(m, 11H), 7.66 (dd, J¼2.2, 7.0 Hz, 1H), 7.69 (d, J¼8.6 Hz, 1H), 7.75 (dd,
IR (neat, cmꢀ1):
n
2234, 1437, 1191; MS (ESI) m/z 465 (MþNa)þ;
HRMS (FAB) calcd for C26H24N2OPS (MþH)þ 443.1341. Found
443.1326. HPLC condition: Chiralpak IC, flow rate: 1.0 mL/min, n-
hexane/i-PrOH¼4/1, t¼18.4 min (major), 26.0 min (minor). 254 nm
J¼2.1, 7.0 Hz, 1H); 13C NMR (126 MHz, CDCl3)
d: 25.4, 49.3 (d,
J¼7 Hz), 63.1, 121.8, 125.0, 126.3, 126.4, 127.0, 127.6, 127.6, 128.1,
128.2, 128.2, 128.2, 128.3, 128.4, 128.5, 128.9, 131.7 (d, J¼10 Hz),
131.8 (d, J¼6 Hz), 131.9 (d, J¼6 Hz), 132.1 (d, J¼10 Hz), 132.8, 133.2,
detect; [
a
]
D
23 ꢀ14.2 (c 0.94, CHCl3) (83% ee).
135.8, 135.8, 137.4; 31P NMR (202 MHz, CDCl3)
d: 23.5; IR (neat,
4.4.13. N-Diphenylphosphinoyl-3-amino-2-methyl-2-phenyl-3-
cmꢀ1):
n
2237, 1185, 1104; MS (ESI) m/z 509 (MþNa)þ; HRMS (FAB)
cyclohexanylpropionitrile (5m). Colorless oil; 1H NMR (500 MHz,
calcd for C32H28N2OP (MþH)þ 487.1934. Found 487.1937. HPLC
condition: Chiralpak AD-H, flow rate: 1.0 mL/min, n-hexane/
i-PrOH¼9/1, t¼38.3 min (major), 82.2 min (minor). 254 nm detect;
CDCl3) d: 0.83 (m, 1H), 1.06 (m, 3H), 1.19 (m, 3H), 1.55 (m, 4H), 1.71
(s, 3H), 2.82 (dd, J¼6.4, 12.0 Hz, 1H), 3.22 (t like, J¼12.0 Hz, 1H), 7.25
(m, 5H), 7.34 (m, 2H), 7.38 (m, 3H), 7.45 (m, 3H), 7.77 (m, 2H); 13C
[
a
]
23 ꢀ57.9 (c 0.52, CHCl3) (84% ee).
NMR (126 MHz, CDCl3) d: 24.9, 25.9, 26.0, 26.7, 27.2, 32.8, 40.3 (d,
D
J¼2 Hz), 48.2 (d, J¼7 Hz), 63.5 (d, J¼2 Hz), 123.1, 126.6, 128.1, 128.3,
4.4.9. N-Diphenylphosphinoyl-3-amino-2-methyl-2-phenyl-3-(1-
128.4, 128.4, 128.5, 128.8, 131.7 (d, J¼3 Hz), 132.0 (d, J¼3 Hz), 132.2
naphthyl)propionitrile (5i). Cloudy oil; 1H NMR (500 MHz, CDCl3)
(d, J¼6 Hz), 132.3 (d, J¼6 Hz), 138.2; 31P NMR (202 MHz, CDCl3)
d:
d
: 1.44 (s, 3H), 3.60 (dd, J¼6.1, 10.3 Hz, 1H), 5.39 (t like, J¼10.3 Hz,
22.7; IR (neat, cmꢀ1):
n
2231, 1108; MS (ESI) m/z 465 (MþNa)þ;
1H), 7.08 (ddd, J¼3.1, 8.0, 8.0 Hz, 2H), 7.20e7.24 (m, 4H), 7.30e7.46
(m, 10H), 7.52 (dd, J¼1.4, 8.6 Hz, 2H), 7.57 (t like, J¼8.0 Hz, 2H), 7.77
HRMS (FAB) calcd for C28H32N2OP (MþH)þ 443.2247. Found
443.2263. HPLC condition: Chiralcel OD-H, flow rate: 1.0 mL/min,
(t, J¼7.6 Hz, 2H); 13C NMR (126 MHz, CDCl3)
d
: 25.2, 50.5 (d,
n-hexane/i-PrOH¼99/1, t¼38.1 min (minor), 43.4 min (major).
23
J¼7 Hz), 55.9, 121.6, 122.2, 124.9, 125.3, 125.6, 126.3, 127.0, 128.1,
128.2, 128.3, 128.4, 128.5, 128.9, 129.0, 131.4, 131.7 (d, J¼5 Hz),
131.8 (d, J¼7 Hz), 131.8 (d, J¼10 Hz), 132.1 (d, J¼9 Hz), 133.5, 135.4,
210 nm detect; [
a
]
ꢀ22.4 (c 0.40, CHCl3) (95% ee).
D
4.4.14. N-Diphenylphosphinoyl-3-amino-2-ethyl-2-phenyl-3-
138.2; 31P NMR (202 MHz, CDCl3)
d
: 23.2; IR (neat, cmꢀ1):
n
2236,
cyclohexanylpropionitrile (5n). Colorless oil; 1H NMR (500 MHz,
1193, 1105; MS (ESI) m/z 487 (MþH)þ; HRMS (FAB) calcd for
C32H28N2OP (MþH)þ 487.1934. Found 487.1937. HPLC condition:
Chiralpak AD-H, flow rate: 1.0 mL/min, n-hexane/i-PrOH¼9/1,
CDCl3)
d
: 0.73 (t, J¼7.5 Hz, 3H), 0.98e1.07 (m, 4H), 1.18e1.24 (m,
3H), 1.32 (m, 1H), 1.44 (ddd, J¼3.4, 12.6, 25.2 Hz, 1H), 1.64 (br d,
J¼13.2 Hz,1H),1.82 (br t, J¼11.5 Hz,1H),1.95 (dq, J¼6.9,13.7 Hz,1H),
2.21 (dq, J¼6.9, 13.7 Hz, 1H), 2.79 (dd, J¼7.5, 11.6 Hz, 1H), 3.27 (t,
J¼11.6 Hz, 1H), 7.23e7.29 (m, 5H), 7.33 (dd, J¼1.2, 7.3 Hz, 2H),
t¼27.8 min (major), 51.1 min (minor). 254 nm detect; [
(c 0.35, CHCl3) (>99% ee).
a
]
23 þ36.7
D
7.36e7.46 (m, 6H), 7.71 (m, 2H); 13C NMR (126 MHz, CDCl3)
d: 9.7,
4.4.10. N-Diphenylphosphinoyl-3-amino-2-methyl-2-phenyl-3-(2-
26.0, 26.7, 30.2, 32.9, 40.8, 55.0 (d, J¼6 Hz), 63.2, 122.0, 127.2, 128.0,
128.3, 128.4, 128.4, 128.5, 128.8, 131.4, 131.7 (d, J¼4 Hz), 132.0 (d,
J¼2 Hz), 132.1 (d, J¼10 Hz), 132.2 (d, J¼10 Hz), 133.0 135.6; 31P NMR
methylphenyl)propionitrile (5j). Colorless oil; 1H NMR (500 MHz,
CDCl3)
d
: 1.66 (s, 3H),1.95 (s, 3H), 3.35 (dd, J¼7.7,11.0 Hz,1H), 4.75 (t
like, J¼11.0 Hz, 1H), 7.00 (m, 2H), 7.10 (m, 2H), 7.18 (m, 2H), 7.24
(202 MHz, CDCl3) d n 2232, 1194, 1121; MS
: 22.5; IR (neat, cmꢀ1):
(ddd, J¼3.4, 7.6, 7.6 Hz, 2H), 7.34e7.42 (m, 11H); 13C NMR (126 MHz,
(ESI) m/z 479 (MþNa)þ; HRMS (FAB) calcd for C29H34N2OP (MþH)þ
CDCl3)
d
: 19.7, 24.7, 49.2 (d, J¼6 Hz), 56.8, 121.9, 126.2, 126.4, 127.3,
457.2403. Found 457.2383. HPLC condition: Chiralpak IC, flow rate:
128.0, 128.2, 128.3, 128.4, 128.4, 128.5, 128.7, 130.5, 131.6 (d,
1.0 mL/min, n-hexane/i-PrOH¼20/1, t¼38.7 min (major), 41.5 min
23
J¼10 Hz), 131.9 (d, J¼8 Hz), 131.9 (d, J¼9 Hz), 132.2 (d, J¼10 Hz),
(minor). 210 nm detect; [
a
]
ꢀ6.4 (c 0.13, CHCl3) (83% ee).
D
135.9, 137.2, 137.5; 31P NMR (202 MHz, CDCl3)
d: 23.0; IR (neat,
cmꢀ1):
n
2234, 1195, 1123, 1108, 1074; MS (ESI) m/z 475 (MþNa)þ;
4.4.15. N-Diphenylphosphinoyl-3-amino-2-allyl-2-phenyl-3-
HRMS (FAB) calcd for C29H28N2OP (MþH)þ 451.1934. Found
cyclohexanylpropionitrile (5o). Colorless oil; 1H NMR (500 MHz,
451.1916. HPLC condition: Chiralpak AD-H, flow rate: 1.0 mL/min, n-
CDCl3) d: 0.85 (m, 1H), 0.93e1.04 (m, 4H), 1.22 (m, 2H), 1.34 (m,
hexane/i-PrOH¼9/1, t¼14.1 min (major), 16.4 min (minor). 254 nm
1H), 1.40 (m, 1H), 1.63 (br d, J¼12.5 Hz, 1H), 1.83 (m, 1H), 2.60 (dd,
J¼7.3, 14.2 Hz, 1H), 2.79 (dd, J¼7.7, 11.5 Hz, 1H), 3.02 (dd, J¼6.5,
14.2 Hz, 1H), 3.33 (t like, J¼11.5 Hz, 1H), 4.96 (d, J¼10.1 Hz, 1H),
5.04 (d, J¼17.1 Hz, 1H), 5.36 (m, 1H), 7.1e7.31 (m, 5H), 7.35e7.40
(m, 5H), 7.46e7.50 (m, 3H), 7.73 (m, 2H); 13C NMR (126 MHz,
23
detect; [
a
]
ꢀ24.0 (c 0.20, CHCl3) (70% ee).
D
4.4.11. N-Diphenylphosphinoyl-3-amino-2-methyl-2-phenyl-3-
furylpropionitrile (5k). Colorless oil; 1H NMR (500 MHz, CDCl3)
d:
1.67 (s, 3H), 3.46 (dd, J¼7.9, 11.3 Hz,1H), 4.63 (dd, J¼9.5, 11.3 Hz, 1H),
CDCl3)
d
: 26.0, 26.7, 27.2, 32.9, 40.7, 41.4, 54.0 (d, J¼5 Hz), 63.0 (d,
6.21 (br d, J¼3.4 Hz, 1H), 6.27 (dd, J¼1.9, 3.4 Hz, 1H), 7.27e7.45 (m,
J¼2 Hz), 120.0, 121.7, 127.4, 128.2, 128.4, 128.5, 128.5, 128.8, 131.7,
14H), 7.53(m, 2H);13C NMR (126MHz, CDCl3)
d
:24.4, 48.9 (d, J¼6 Hz),
131.8 (d, J¼2 Hz), 132.1 (d, J¼2 Hz), 132.1 (d, J¼9 Hz), 132.2 (d,
56.6, 109.0, 110.5, 121.7, 126.7, 128.3 (d, J¼10 Hz), 128.4 (d, J¼9 Hz),
J¼9 Hz), 135.3; 31P NMR (202 MHz, CDCl3)
d
: 22.6; IR (neat, cmꢀ1):
128.4, 128.8, 131.6 (d, J¼10 Hz), 131.9, 132.0 (d, J¼10 Hz), 137.2, 142.2,
n
2230, 1122; MS (ESI) m/z 491 (MþNa)þ; HRMS (FAB) calcd for
151.0; 31P NMR (202 MHz, CDCl3)
d
: 24.2; IR (neat, cmꢀ1):
n
2236,
C30H34N2OP (MþH)þ 469.2403. Found 469.2426. HPLC condition:

L. Yin et al. / Tetrahedron 68 (2012) 3497e3506
3505
Chiralcel OD-H, flow rate: 1.0 mL/min, n-hexane/i-PrOH¼99/1,
t¼32.2 min (minor), 34.6 min (major). 210 nm detect; [
(c 0.12, CHCl3) (97% ee).
a]
23 ꢀ135.7
D
t¼28.6 min (major), 30.5 min (minor). 210 nm detect; [
a
]
24 þ23.8
D
(c 0.11, CHCl3) (80% ee).
4.4.20. 3-Amino-2-methyl-2,3-diphenylpropionamide (7a). Colorless
oil; 1H NMR (500 MHz, CDCl3)
: 1.45 (s, 3H), 2.14 (br, 2H), 4.77 (s,
4.4.16. N-Diphenylphosphinoyl-3-amino-2-methyl-2-phenyl-3-(2-
d
methylpropyl)propionitrile (5p). Colorless oil; 1H NMR (500 MHz,
1H), 5.80 (br, 1H), 7.28 (m, 6H), 7.33 (t, J¼7.0 Hz, 2H), 7.37 (d,
CDCl3)
d
: 0.61 (d, J¼6.8 Hz, 1H), 0.77 (d, J¼6.7 Hz, 1H), 1.18 (ddd,
J¼7.0 Hz, 2H), 7.95 (br, 1H); 13C NMR (126 MHz, CDCl3)
d: 22.1, 55.4,
J¼3.5, 10.4, 10.4 Hz, 1H), 1.50 (m, 1H), 1.76 (s, 3H), 1.84 (m, 1H), 2.43
62.3, 126.6, 127.0, 127.5, 127.8, 128.5, 140.3, 143.2, 177.5; IR (neat,
(dd, J¼7.0, 11.3 Hz, 1H), 3.43 (m, 1H), 7.21e7.45 (m, 10H), 7.55 (m,
cmꢀ1):
n
3377, 1649, 1348; MS (ESI) m/z 255 (MþH)þ, 277 (MþNa)þ;
2H), 7.74 (m, 2H); 13C NMR (126 MHz, CDCl3)
d
: 21.3, 23.8, 24.2, 24.3,
HRMS (FAB) calcd for C16H18N2OCs (MþCs)þ 387.0468. Found
387.0469; HPLC condition: Chiralpak AS-H, flow rate: 1.0 mL/min, n-
hexane/i-PrOH¼9/1, t¼57.8 min (major), 71.4 min (minor). 254 nm
detect.
44.3 (d, J¼3 Hz), 48.6 (d, J¼4 Hz), 123.0, 127.1, 128.1, 128.3, 128.5,
128.5, 128.7, 131.5, 131.8 (d, J¼2 Hz), 132.0 (d, J¼2 Hz), 132.1 (d,
J¼9 Hz), 132.2 (d, J¼9 Hz), 137.2; 31P NMR (202 MHz, CDCl3)
d: 22.4;
IR (neat, cmꢀ1):
n
2234, 1186, 1107; MS (ESI) m/z 439 (MþNa)þ;
HRMS (FAB) calcd for C26H30N2OP (MþH)þ 417.2090. Found
417.2115. HPLC condition: Chiralcel OD-H, flow rate: 1.0 mL/min,
n-hexane/i-PrOH¼99/1, t¼21.8 min (major), 35.5 min (minor).
4.5. Determination of the absolute configuration
Enantiomerically pure 4ac was isolated using preparative chiral
HPLC (Daicel Chiralpak AD-H, flow rate: 1.0 mL/min, n-hexane/i-
PrOH¼4/1). X-ray grade crystals (colorless needles) were obtained
through recrystallization from CH2Cl2/hexane.
210 nm detect; [
a
]
D
23 þ14.6 (c 0.45, CHCl3) (>99% ee).
4.4.17. N-Diphenylphosphinoyl-3-amino-2-methyl-2-phenyl-3-(2-
phenylethyl)propionitrile (5q). Colorless oil; 1H NMR (500 MHz,
CDCl3)
d
: 1.59 (m, 1H), 1.71 (s, 3H), 2.16 (m, 1H), 2.57 (ddd, J¼6.1,
10.7, 13.8 Hz, 1H), 2.65 (dd, J¼6.8, 11.6 Hz, 1H), 2.85 (ddd, J¼4.9, 10.7,
13.8 Hz, 1H), 3.50 (m, 1H), 6.99 (d, J¼7.1 Hz, 2H), 7.10 (d, J¼7.4 Hz,
1H), 7.14e7.27 (m, 7H), 7.31 (m, 2H), 7.38 (m, 3H), 7.46 (m, 3H), 7.77
(m, 2H); 13C NMR (126 MHz, CDCl3)
d
: 24.1, 32.5, 36.2 (d, J¼3 Hz),
48.4 (d, J¼6 Hz), 58.8 (d, J¼2 Hz), 122.8, 126.0, 126.9, 128.2, 128.3,
128.4, 128.4, 128.4, 128.5, 128.6, 128.8, 129.1, 131.8, 132.1 (d, J¼7 Hz),
137.3, 141.0; 31P NMR (202 MHz, CDCl3) : 22.9; IR (neat, cmꢀ1):
d n
3141, 2234, 1191, 1106; MS (ESI) m/z 489 (MþNa)þ; HRMS (FAB)
calcd for C30H30N2OP (MþH)þ 465.2090. Found 465.2119. HPLC
condition: Chiralpak AD-H, flow rate: 1.0 mL/min, n-hexane/i-
PrOH¼9/1, t¼24.4 min (major), 47.5 min (minor). 210 nm detect;
[
a]
23 ꢀ19.5 (c 0.96, CHCl3) (76% ee).
D
4.4.18. N-Diphenylphosphinoyl-3-amino-2-methyl-2-vinyl-3-
phenylpropionitrile (5r). Cloudy oil (diastereomer was not com-
Acknowledgements
pletely separable, ca. 10/1 mixture); 1H NMR (500 MHz, CDCl3)
d:
1.20 (s, 3H), 3.55 (t like, J¼10.2 Hz, 1H), 4.14 (t like, J¼10.2 Hz, 1H),
5.38 (d, J¼10.3 Hz, 1H), 5.53 (d, J¼17.2 Hz, 1H), 5.92 (dd, J¼10.3,
17.2 Hz, 1H), 7.14e7.18 (m, 4H), 7.21e7.22 (m, 3H), 7.32 (dt, J¼1.2,
7.5 Hz, 1H), 7.37 (dt, J¼2.9, 8.0 Hz, 2H), 7.46 (m, 3H), 7.67 (m, 2H);
Financial support was provided by Grant-in-Aid for Young Sci-
entists (S) from JSPS. L. Y. thanks JSPS for research fellowships.
References and notes
13C NMR (126 MHz, CDCl3)
d: 23.9, 47.8 (d, J¼5 Hz), 60.6, 118.0,
1. Staunton, J.; Weissman, K. J. Nat. Prod. Rep. 2001, 18, 380.
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Lee, H. M.; Fortner, K. C.; Aloise, A. D.; Shair, M. D. J. Am. Chem. Soc. 2005, 127,
7284.
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6. (a) Goossen, L. J.; Rodríguez, N.; Melzer, B.; Linder, C.; Deng, G.-J.; Levy, L. M. J.
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7. (a) Review: Mohr, J. T.; Stoltz, B. M. Chem.dAsian J. 2007, 2, 1476 More recent
representative publications (b) Trost, B. M.; Lehr, K.; Michaelis, D. J.; Xu, J.;
Buckl, A. K. J. Am. Chem. Soc. 2010, 132, 8915; (c) Trost, B. M.; Xu, J.; Schmidt, T. J.
Am. Chem. Soc. 2009, 131, 18343.
120.6, 127.7, 128.1, 128.2, 128.4, 128.4, 128.5, 128.6, 131.6 (d,
J¼10 Hz), 131.8 (d, J¼4 Hz), 132.2 (d, J¼4 Hz), 132.5 (d, J¼11 Hz),
137.0, 138.4 (d, J¼2 Hz); 31P NMR (202 MHz, CDCl3)
d: 24.1; IR (neat,
cmꢀ1):
n
2238, 1184, 1105; MS (ESI) m/z 409 (MþNa)þ; HRMS (FAB)
calcd for C24H24N2OP (MþH)þ 387.1621. Found 387.1625. HPLC
condition: Chiralpak IC, flow rate: 1.0 mL/min, n-hexane/i-PrOH¼9/
1, t¼20.6 min (major), 30.0 min (minor). 254 nm detect; [
a
]
25 ꢀ6.1
D
(c 0.41, CHCl3) (96% ee).
4.4.19. N-Diphenylphosphinoyl-3-amino-2-methyl-2-vinyl-3-
cyclohexanylpropionitrile (5s). Colorless oil; 1H NMR (500 MHz,
CDCl3) d: 1.05 (m, 1H), 1.17 (m, 3H), 1.29e1.34 (m, 2H), 1.38 (s, 3H),
1.52 (m, 1H), 1.62 (m, 1H), 1.69 (m, 2H), 1.80 (m, 1H), 2.89 (dd, J¼8.6,
11.6 Hz, 1H), 3.00 (t like, J¼11.6 Hz), 5.12 (d, J¼10.4 Hz, 1H), 5.39 (d,
J¼17.1 Hz, 1H), 5.60 (dd, J¼10.4, 17.1 Hz, 1H), 7.37e7.48 (m, 6H), 7.75
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Trost, B. M.; Jiang, C. Synthesis 2006, 369.
(m, 2H), 7.82 (m, 2H); 13C NMR (126 MHz, CDCl3)
d: 22.6, 24.5, 24.6,
11. Examples of catalytic asymmetric construction of contiguous quaternary-
trisubstituted carbons: (a) Lee, E. C.; Hodous, B. L.; Bergin, E.; Shih, C.; Fu, G.
C. J. Am. Chem. Soc. 2005, 127, 11586; (b) Chowdari, N. S.; Suri, J. T.; Barbas, C. F.,
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25.1, 25.7, 28.2, 31.1, 38.6, 45.1 (d, J¼5 Hz), 60.3, 115.4, 120.4, 126.9
(d, J¼13 Hz), 127.0 (d, J¼12 Hz), 130.4, 130.5 (d, J¼9 Hz), 130.6 (d,
J¼9 Hz), 130.8 (d, J¼9 Hz), 130.9 (d, J¼10 Hz), 131.6 (d, J¼57 Hz),
135.9; 31P NMR (202 MHz, CDCl3) : 22.9; IR (neat, cmꢀ1):
d n 2925,
2234, 1183, 1107; MS (ESI) m/z 415 (MþNa)þ; HRMS (FAB) calcd for
C24H30N2OP (MþH)þ 393.2090. Found 393.2103. HPLC condition:
Chiralpak IC, flow rate: 1.0 mL/min, n-hexane/i-PrOH¼20/1,

3506
L. Yin et al. / Tetrahedron 68 (2012) 3497e3506
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