C O M M U N I C A T I O N S
Table 2. Phase-Transfer-Catalyzed Asymmetric Strecker Reaction
of Aldimines 3a
3
(R1)
reaction
time (h)
entry
% yieldb
% eec
product
1
2
3
4
5
6
7
c-Oct
i-Pr
Ph(CH2)2
(CH3)2CHCH2
t-Bu
2
3
2
3
3
8
8
88
85
81
82
94
95
98
97
93
90
88
94
98
97
4b
4c
4d
4e
4f
Ph(CH3)2C
Ad
4g
4h
Figure 1. ORTEP diagrams of 1-PF6 (a) and 2a (b). Hydrogen atoms
a The reaction was conducted with 1.5 equiv of 2 M aq KCN and 2c (1
mol %) in toluene-H2O (v/v 1:3) at 0 °C. b Isolated yield. c Determined
by HPLC analysis. Absolute configuration was deduced from that of 4a.
and solvent molecules are omitted for clarity.
X-ray diffraction analysis of 1-PF6, revealing its R,R,R configu-
ration (Figure 1a). As expected, each phenyl substituent at the 3,3′-
positions of the binaphthyl unit is nearly perpendicular to the
attached naphthalene ring, extending over the central cationic
nitrogen. Further, the two pendant ortho-phenyl groups are parallel
to each other, which extends the aromatic surface in the reaction
cavity. This could position the imine functionality in an ideal
proximity to the cyanide ion in the chiral environment, enabling
an efficient and stereoselective bond formation.
aqueous KCN as a cyanide source through the development of new
chiral quaternary ammonium iodide 2c bearing a stereochemically
defined tetranaphthyl backbone. This study represents a new
approach to asymmetric Strecker-type reactions, which holds
distinctive practical advantages and should fulfill the continuing
demand for the availability of a broad range of R-amino acids in
diverse scientific disciplines.
To examine this hypothesis, we evaluated the potential of 1 as
a catalyst for the asymmetric cyanation of 3a (R2 ) p-Tol) under
the biphasic conditions. Thus, a mixture of 3a (R2 ) p-Tol) and 1
(1 mol %) in toluene-aqueous KCN (1.2 equiv) was vigorously
stirred at 0 °C. TLC monitoring indicated the complete consumption
of the substrate after 2 h, and the desired 4a (R2 ) p-Tol) was
isolated in 84% yield with 24% ee (entry 3, Table 1). The
N-mesitylenesulfonyl imine 3a (R2 ) Mes) enhanced the enantio-
selectivity to 57% ee, though longer reaction time was required
(entry 4). These promising results support the molecular design
concept used for catalyst optimization, which was further improved
by replacing the 3,3′-substituents with the 2-phenyl-1-naphthyl
group. The chiral quaternary ammonium iodide 2a with the
stereochemically homogeneous tetranaphthyl backbone was pre-
pared in a manner similar to that of 1 (Scheme 2). Subsequent
crystallographic analysis confirmed the enlarged chiral cavity, which
suggested the possibility of enhanced enantiofacial selectivity
(Figure 1b). Indeed, catalyst 2a exhibited high chiral efficiency in
the reaction of 3a (R2 ) Mes) under similar conditions to afford
4a (R2 ) Mes) with 89% ee (entry 5). Moreover, the additional
phenyl substituents at the 4-position of the outer naphthyl units
(2b) gave even better enantiocontrol (entry 6). Finally, the introduc-
tion of an electron-withdrawing trifluoromethyl group to all the
appended phenyl groups (2c) improved the enantioselectivity further
(entry 7). The phase-transfer cyanation of 3a (R2 ) Mes) with 1.5
equiv of KCN and 2c was completed in 2 h to produce 4a (R2 )
Mes) in 89% yield with 95% ee (entry 8).
Other selected examples in Table 2 demonstrate the effectiveness
of this new asymmetric Strecker protocol for a variety of aliphatic
aldimines.8 Generally, 1 mol % of 2c with 1.5 equiv of KCN was
sufficient for efficient reactions, and the corresponding protected
amino nitriles 4 were obtained in high yield with excellent
enantioselectivity. This system accommodates substrates having
R-tert-alkyl substituents, such as pivalaldimine (entries 5-7). This
enables a facile synthesis of enantiomerically enriched tert-leucine
and its various analogues, which are important chiral building blocks
not accessible by the asymmetric alkylation of glycine derivatives.4
In conclusion, we have accomplished the phase-transfer-
catalyzed, highly enantioselective cyanation of aldimines using
Acknowledgment. This work was partially supported by a
Grant-in-Aid for Scientific Research on Priority Areas “Advanced
Molecular Transformation of Carbon Resources” from the Ministry
of Education, Culture, Sports, Science and Technology, Japan.
Supporting Information Available: Representative experimental
procedures and spectroscopic characterization of new compounds
(PDF); the crystallographic data for 1-PF6 and 2a (CIF). This material
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(8) The present conditions are not effective for aromatic aldimines.
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