Synthesis of α-amino acid precursors directly from aldehydes using masked acyl cyanide reagents and N,O-dialkylated hydroxylamines

Article abstract of DOI:10.1021/jo0607515

A synthetic methodology for the synthesis of α-amino acid precursors directly from the corresponding aldehydes using N,O-dialkylated hydroxylamines and masked acyl cyanide (MAC) reagents was developed. The one-pot reaction can be carried out under mild co

Full text of DOI:10.1021/jo0607515

Synthesis of r-Amino Acid Precursors Directly from Aldehydes
Using Masked Acyl Cyanide Reagents and N,O-Dialkylated
Hydroxylamines
Hisao Nemoto,* Rujian Ma, Tomoyuki Kawamura, Masaki Kamiya, and Masayuki Shibuya
DiVision of Pharmaceutical Chemistry, Institute of Health Biosciences, Graduate School of the UniVersity
of Tokushima, 1-78, Sho-machi, Tokushima 770-8505, Japan
nem@ph.tokushima-u.ac.jp
ReceiVed April 10, 2006
A synthetic methodology for the synthesis of R-amino acid precursors directly from the corresponding
aldehydes using N,O-dialkylated hydroxylamines and masked acyl cyanide (MAC) reagents was developed.
The one-pot reaction can be carried out under mild conditions and without a separate purification step of
the imino species. The method was applied to the synthesis of optically pure (+)-4-methylphenylglycine
and the derivatives by using an Abiko-Masamune’s tricyclic 1,2-oxazolidine as the chiral auxiliary.
Introduction
purified by recrystallization prior to the nucleophilic addition
reaction of masked acyl cyanide (MAC)5 reagents 4 to afford
R-amino acid precursors 5 (Scheme 1). Similar methodology
to synthesize an optically active R-amino acid precursor 8 via
sulfinimide 7 was also reported.6 In those cases, purification of
concrete examples of imino species 3 (or 7) was fortunately
carried out by recrystallization, and the desired compound 5
(or 8) was produced in excellent yield. However, it would be
difficult to apply the synthetic methodologies if the imino
species 3 (or 7) is too oily or gummy to produce crystal. This
would be the problematic subject not only for our previous
methodologies but also for various modified Strecker-type
reactions.1
Strecker reaction is well-known as an efficient method for
the synthesis of R-amino acid.1 Recently, a number of modified
Strecker reactions that involve the preparation of imines prior
to the nucleophilic attack of hydroxycarbonyl synthons, such
as cyanide or a nitromethyl anion, have been reported.1 In
contrast, the original Strecker reaction does not require such
preparations; the aminonitriles are directly produced from
aldehydes and ammonia with cyanide anion in a one-pot
reaction. It is important to note that the aminonitrile is the major
product, and that the cyanohydrin is merely one of the minor
contaminants despite of the fact that aldehydes are generally
more reactive than the corresponding imines.2 Furthermore,
isolation of the imines requires extensive purification typically
by recrystallization or distillation, and because the imines are
usually moisture- and acid-sensitive, silica gel column chro-
matography is not viable.
For broad applicability, therefore, the synthesis of R-amino
acids that does not require a distinct step to purify the imines,7
in addition to having improved chemical yields and enantiomeric
excess,8 is highly desirable.
In our previous studies,3,4 sulfonylimine 3 was prepared from
sulfonamide 2 with the corresponding aldehyde 1 and was
(3) Nemoto, H.; Kubota, Y.; Yamamoto, Y. J. Org. Chem. 1990, 55,
4515-4516.
(4) Nemoto, H.; Kubota, Y.; Sasaki, N.; Yamamoto, Y. Synlett 1993,
465-466.
* To whom correspondence should be addressed. Telephone and Fax: 81
88-663-7284.
(1) (a) Gro¨ger, H. Chem. ReV. 2003, 103, 2795-2827. (b) Kobayashi,
S.; Ishitani, H. Chem. ReV. 1999, 99, 1069-1094. (c) Bloch, R. Chem.
ReV. 1998, 98, 1407-1438. (d) Layer, R. W. Chem. ReV. 1963, 63, 489-
510.
(2) A noteworthy exception has been reported; imines are more reactive
than aldehydes in palladium-tin-promoted systems: Nakamura, H.; Iwama,
H.; Yamamoto, Y. J. Am. Chem. Soc. 1996, 118, 6641-6647.
(5) H-C(CN)2O-R is abbreviated to H-MAC-R. Nemoto, H.; Ibaragi,
T.; Bando, M.; Kido, M.; Shibuya, M. Tetrahedron Lett. 1999, 40, 1319-
1322.
(6) Nemoto, H.; Ma, R.; Moriguchi, H.; Suzuki, I.; Shibuya, M. J.
Organomet. Chem. 2000, 611, 445-448.
(7) One-pot reaction directly from aldehydes using aminoborane reagent
was reported. Suginome, M.; Yamamoto, A.; Ito, Y. Chem. Commun. 2002,
1392-1393.
10.1021/jo0607515 CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/07/2006
6038
J. Org. Chem. 2006, 71, 6038-6043

Synthesis of R-Amino Acid Precursors
TABLE 1. Synthesis of 18 from an Aldehyde (1) with 16 and 17 in
Acetonitrile at Room Temperature
SCHEME 1
time
(h)
yield of 18
entry
R1
R6
product
(%)
1
2
3
4
5
6
7
8
4-MeC6H4-
4-MeOC6H4-
2-MeC6H4-
2-furyl
C6H5CH2CH2-
CH3(CH2)8-
4-CF3C6H4-
4-MeC6H4-
Me
Me
Me
Me
Me
Me
Me
CH2Ph
2
2
2
2
2
2
12
2
18a
18b
18c
18d
18e
18f
95
91
92
96
92
90
65
95
SCHEME 2
SCHEME 3
18g
18h
SCHEME 4
Results and Discussion
Herein, we report a method for the direct synthesis of R-amino
acid precursor 10. As shown in Scheme 2, the one-pot reaction
involves aldehyde 1 with N,O-dialkylated hydroxylamine 9 in
the presence of a MAC reagent 4.
solvent. When electron-rich aromatic aldehydes or aliphatic
aldehydes were used with 16a in the presence of pyridine,
desired adducts 18a-f were obtained within 2 h in excellent
yields (entries 1-6, respectively). In the case of an electron-
deficient aromatic aldehyde, 18g was obtained in a moderate
yield after extending the reaction time (entry 7). Additionally,
the use of 16b afforded desired adduct 18h in an excellent yield
(entry 8).
Conversion of R-aminonitrile or R-aminonitromethane to the
corresponding R-amino acid requires harsh acidic and aqueous
conditions.1 In contrast, the compound 10 can be transformed
under mild conditions to R-amino acid derivative 13 via 11 and
12 (Scheme 3).3-6 Furthermore, because the acyl cyanide 12
(generated in situ) is equivalent to an activated ester,3-6 the
subsequent amide bond formation can be carried out without
the use of condensation reagents, such as carbodiimides.
Appropriate selection of the R7XH (alcohols or amines) can
allow for the synthesis of R-amino acids 14 and R-amino amides
or peptides 15.
Synthesis of 18 via one-pot reaction of an aldehyde (1) with
a MAC reagent 173,9 and the hydrochloride salt of 16 is listed
in Table 1. On the basis of a previous study on the reaction
between an aldehyde and a MAC reagent to form 1,2-adduct
1910,11 (Scheme 4), acetonitrile was chosen as the reaction
Subsequently, our studies revealed that N,O-dialkylated
hydroxylamine is essential for this reaction. Reaction was not
observed when dimethylamine hydrochloride was used in place
of 16, even in the presence of bases, such as triethylamine,
pyridine, diisopropylethylamine, N,N-dimethylaniline, N-meth-
ylmorpholine, or 4-(N,N-dimethylamino)pyridine. When me-
thylamine, O-methylhydroxylamine, hydroxylamine, or hydra-
zine were used in place of 16, the formation of corresponding
N-methylimine, oximes, or hydrazone was merely observed, and
the corresponding adduct was not detected.
1
The appearance of new peaks in the H NMR spectra of a
mixture of 16a, 4-tolualdehyde, and pyridine-d5 (molar ratio )
1.2:1.0:2.0), in acetonitrile-d3 at 25 °C, indicated the formation
of 20 (R1 ) 4-CH3C6H4, R5 ) R6 ) Me) (Scheme 4). Therefore,
the reaction mechanism can be described as follows: first, the
hydrochloride salt of 9 is neutralized using pyridine. Although
the actual presence of the iminium cation 21 has yet to be
established, small amounts of 21 should exist via its equilibrium
with 20. Because of the presumably high reactivity of 21, a
nucleophile attack by the anion of 4 should afford desired adduct
10. Comparatively, the formation of 19 should occur more
(8) Example of recent asymmetric Strecker reactions. (a) Iyer, M. S.;
Gigstad, K. M.; Namdev, N. D.; Lipton, M. J. Am. Chem. Soc. 1996, 118,
4910-4911. (b) Masumoto, S.; Usuda, H.; Suzuki, M.; Kanai, M.; Shibasaki,
M. J. Am. Chem. Soc. 2003, 125, 5634-5635. (c) Cogan, D. A.; Liu, G.;
Ellman, J. Tetrahedron 1999, 55, 8883-8904 and sited in ref 1.
(9) An alternative and practical preparation of 4: Nemoto, H.; Li, X.;
Ma, R.; Suzuki, I.; Shibuya, M. Tetrahedron Lett. 2003, 44, 73-75.
(10) Nemoto, H.; Kubota, Y.; Yamamoto, Y. J. Chem. Soc., Chem.
Commun. 1994, 1665-1666.
(11) Nemoto, H.; Ma, R.; Ibaragi, T.; Suzuki, I.; Shibuya, M. Tetrahedron
2000, 56, 1463-1468.
J. Org. Chem, Vol. 71, No. 16, 2006 6039

Nemoto et al.
SCHEME 5
SCHEME 7
SCHEME 8
SCHEME 6
SCHEME 9
readily than that of 10. However, the formation of 19 is
reversible,10,11 which would continuously regenerate 1 and 4.
In contrast, 10 is relatively stable, and its reversible process
(from 10 back to 4 and 21) should be insignificant. As a result,
aldehyde 1 is converted to 10 in excellent yields.
To illustrate the unmasking and condensation step from 10
to 13, the transformation of 18a to 22-24, as shown in Scheme
5, is described. First, the 1-ethoxyethyl (EE) moiety of 18a was
deprotected using 10% trifluoroacetic acid in dichloromethane
for 10 min at 0 °C. Upon removal of excess trifluoroacetic acid
in vacuo, the unprotected compound was reacted with methanol,
butylamine, and glycine methyl ester as R7XH to afford 22
(80%), 23 (82%), and 24 (76%), respectively. On the basis of
our previous studies of MAC reagents,3-6,10-15 the reaction did
not require any condensation reagents.
The reaction of an aldehyde 25 bearing an acid-labile
protecting group was carried out, as shown in Scheme 6, to
demonstrate that the reaction conditions from 1 to 13, especially
for unmasking (from 10 to 13), are milder than those for the
conversion of nitrile to carboxylic acid. Accordingly, 26 was
successfully synthesized from 25 (80% overall yield) via
sequential reactions without the isolation of intermediate 10.
The synthesis of optically pure 4-methylphenylglycine pre-
cursor (-)-29 is shown in Scheme 7. Adduct (-)-29 was
obtained in 88% chemical yield with >99% diastereomeric
purity directly from 4-tolualdehyde using (+)-27, an optically
pure N,O-dialkylated hydroxylamine developed by Abiko and
Masamune,16,17 and silylated MAC reagent 28.3,9,18
The absolute configuration at the newly formed asymmetric
center of (-)-29 was determined by comparing the rotation of
(+)-32, which was derived from (-)-29 via (+)-30 and (+)-31
(76% overall yield), to that of (S)-(4-methylphenyl)glycine
hydrochloride ([R]25D ) +151°, c 1; 1 N HCl (aq))19 (Scheme
8).
Finally, the synthesis of a protected dipeptide using (-)-29
was carried out. As shown in Scheme 9, (+)-N-Boc-(4-
methylphenyl)glycylglycine methyl ester [(+)-34] was synthe-
sized in three steps from 4-tolualdehyde in 65% overall yield.
Conclusion
In conclusion, a one-pot synthetic methodology was devel-
oped to prepare R-amino acid precursors directly from aldehydes
using MAC reagents and N,O-dialkylated hydroxylamines,
under mild conditions, and without the need to isolate and purify
the imino species. The method was applied toward the three-
step synthesis of an optically pure protected dipeptide using an
Abiko-Masamune’s tricyclic 1,2-oxazolidine16,17 as the chiral
auxiliary. Consequently, various optically active rare or un-
natural R-amino acids and peptides can be readily synthesized
using MAC reagents.
(12) Kubota, Y.; Nemoto, H.; Yamamoto, Y. J. Org. Chem. 1991, 56,
7195-7196.
(13) Nemoto, H.; Ma, R.; Suzuki, I.; Shibuya, M. Org. Lett. 2000, 2,
4245-4247.
(17) Abiko, A.; Moriya, O.; Filla, S. A.; Masamune, S. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 793-795.
(18) The tert-butyldimethylsilyl (TBS) group is used instead of EE to
avoid the influence from an asymmetric center of EE to diastereoselectivity
and to simplify the analysis of product.
(19) Hassan, N. A.; Bayer, E.; Jochims, J. C. J. Chem. Soc., Perkin Trans.
1 1998, 3747-3758.
(14) Nemoto, H.; Ma, R.; Li, X.; Suzuki, I.; Shibuya, M. Tetrahedron
Lett. 2001, 42, 2145-2147.
(15) Nemoto, H.; Kawamura, T.; Miyoshi, N. J. Am. Chem. Soc. 2005,
127, 14546-14547.
(16) Abiko, A.; Davis, W. M.; Masamune, S. Tetrahedron: Asymmetry
1995, 6, 1295-1300.
6040 J. Org. Chem., Vol. 71, No. 16, 2006

Synthesis of R-Amino Acid Precursors
(CH), 71.2 and 71.1 (CH), 68.5 and 68.4 (C), 62.2 and 62.0 (CH2),
60.2 and 60.2 (CH3), 42.2 and 42.1 (CH3), 20.2 and 19.9 (CH3),
14.7 and 14.6 (CH3); EI-HRMS calcd for C12H14N3O3 [(M -
OC2H5)+] 248.1035, found 248.1032.
Experimental Section
General Procedure for the Synthesis of 18: A mixture of
aldehyde 1 (1.0 mmol), hydrochloride salt of N,O-dimethylhy-
droxylamine (16a) (117.0 mg, 1.2 mmol), 17 (185.0 mg, 1.2 mmol),
and pyridine (158.0 mg, 2.0 mmol) in acetonitrile (3 mL) was stirred
at room temperature for 2-8 h. The resulting solution was then
filtered through an aluminum oxide 90 (activity II-III) pad (1 × 5
cm) and eluted with CH2Cl2. The filtrate was concentrated, and
the residue was purified by silica gel column chromatography,
eluted with hexane/ethyl acetate (5-20:1) to afford 18a-g. In the
case of 18h, the hydrochloride salt of N-methyl-O-benzylhydroxyl-
amine (16b) (208.3 mg, 1.2 mmol) was used in place of 16a.
2-Cyano-2-(1-ethoxy)ethoxy-3-(N-methoxy-N-methyl)amino-
3-(4-methylphenyl)propionitrile (18a): Colorless oil; IR (CHCl3)
ν 2987, 2940, 2250, 1515, 1446, 1153, 1069, 1022, 819 cm-1; 1H
NMR (CDCl3, 300 MHz) δ 7.36 (d, J ) 8.0 Hz, 2H), 7.16 (d, J )
8.0 Hz, 2H), 5.22 and 5.11 (q, J ) 5.2 Hz, 1H), 4.07 and 4.06 (s,
1H), 3.72 and 3.70 (s, 3H), 3.73-3.50 (m, 1H), 3.30-3.13 (m,
1H), 2.49 (s, 3H), 2.35 (s, 3H), 1.39 and 1.24 (d, J ) 5.2 Hz, 3H),
1.23 and 1.04 (t, J ) 7.0 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ
139.5 and 139.4 (C), 130.2 and 130.0 (two of CH), 129.6 and 129.2
(C), 129.1 and 129.1 (two of CH), 114.7 and 114.0 (C), 113.5 and
112.6 (C), 101.1 and 100.8 (CH), 78.0 and 77.8 (CH), 68.9 and
68.5 (C), 62.2 and 61.5 (CH2), 59.7 and 59.7 (CH3), 42.6 and 42.5
(CH3), 21.17 and 21.15 (CH3), 20.0 and 19.9 (CH3), 14.7 and 14.5
(CH3); EI-HRMS calcd for C15H18N3O2 [(M - OC2H5)+] 272.1399,
found 272.1365.
2-Cyano-2-(1-ethoxy)ethoxy-3-(N-methoxy-N-methyl)amino-
3-(4-methoxyphenyl)propionitrile (18b): Colorless oil; IR (CHCl3)
ν 2940, 2248, 1612, 1515, 1252, 1179, 1069, 1038, 838 cm-1; 1H
NMR (CDCl3, 300 MHz) δ 7.41 (d, J ) 7.9 Hz, 2H), 6.88 (d, J )
7.9 Hz, 2H), 5.23 and 5.11 (q, J ) 5.1 Hz, 1H), 4.05 and 4.04 (s,
1H), 3.81 (s, 3H), 3.72 and 3.70 (s, 3H), 3.74-3.50 (m, 1H), 3.33-
3.16 (m, 1H), 2.49 (s, 3H), 1.39 and 1.26 (d, J ) 5.1 Hz, 3H), 1.23
and 1.06 (t, J ) 7.1 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 160.5
and 160.4 (C), 131.6 and 131.4 (two of CH), 124.5 and 124.3 (C),
114.8 and 114.0 (C), 113.8 and 113.8 (two of CH), 113.6 and 112.7
(C), 101.2 and 100.9 (CH), 77.8 and 77.5 (CH), 69.0 and 68.6 (C),
62.3 and 61.6 (CH2), 59.8 and 59.8 (CH3), 55.3 and 55.2 (CH3),
42.6 and 42.5 (CH3), 20.1 and 20.0 (CH3), 14.8 and 14.6 (CH3);
EI-HRMS calcd for C16H20N3O4 [(M - CH3)+] 318.1454, found
318.1447.
2-Cyano-2-(1-ethoxy)ethoxy-3-(N-methoxy-N-methyl)amino-
5-phenylpentanenitrile (18e): Colorless oil; IR (CHCl3) ν 2988,
2939, 2243, 1450, 1388, 1154, 1034 cm-1; 1H NMR (CDCl3, 300
MHz) δ 7.36-7.14 (m, 5H), 5.26 (q, J ) 5.2 Hz, 1H), 3.85-3.71
(m, 1H), 3.70-3.58 (m, 1H), 3.57 and 3.58 (s, 3H), 3.17 and 3.15
(t, J ) 5.3 Hz, 1H), 2.96-2.73 (m, 2H), 2.70 and 2.72 (s, 3H),
2.40-2.24 (m, 1H), 2.17-1.96 (m, 1H), 1.49 (d, J ) 5.2 Hz, 3H),
1.28 (t, J ) 7.0 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 140.7 and
140.7 (C), 128.5 and 128.5 (two of CH), 128.4 and 128.4 (two of
CH), 126.3 and 126.3 (CH), 114.5 and 113.7 (C), 113.3 and 112.5
(C), 101.5 and 101.3 (CH), 71.6 and 71.3 (CH), 70.4 and 70.3 (C),
62.4 and 62.3 (CH2), 60.2 and 60.1 (CH3), 42.3 and 42.1 (CH3),
33.8 and 33.6 (CH2), 27.0 and 26.9 (CH2), 20.3 and 20.2 (CH3),
14.7 and 14.7 (CH3); EI-HRMS calcd for C18H26N3O3 (MH+)
332.1974, found 332.1991.
2-Cyano-2-(1-ethoxy)ethoxy-3-(N-methoxy-N-methyl)amin-
ododecanenitrile (18f): Colorless oil; IR (CHCl3) ν 2929, 2857,
2247, 1467, 1152, 1072, 1041 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 5.25 and 5.24 (q, J ) 5.1 Hz, 1H), 3.85-3.70 (m, 1H), 3.70-
3.57 (m, 1H), 3.56 (s, 3H), 3.14 and 3.11 (t, J ) 4.1 Hz, 1H), 2.77
and 2.76 (s, 3H), 3.22-3.03 (m, 1H), 1.80-1.15 (m, 18H), 1.48
and 1.47 (d, J ) 5.1 Hz, 3H), 0.88 (t, J ) 6.8 Hz, 3H); 13C NMR
(CDCl3, 75 MHz) δ 114.6 and 113.8 (C), 113.5 and 112.6 (C),
101.4 and 101.2 (CH), 72.8 and 72.5 (CH), 70.4 and 70.2 (C), 62.4
and 62.3 (CH2), 60.1 and 60.0 (CH3), 42.3 and 42.2 (CH3), 31.8
and 31.8 (CH2), 29.6 and 29.6 (CH2), 29.4 and 29.4 (CH2), 29.3
and 29.3 (CH2), 29.2 and 29.2 (CH2), 28.1 and 27.9 (CH2), 25.4
and 25.1 (CH2), 22.6 and 22.6 (CH2), 20.2 and 20.1 (CH3), 14.7
and 14.7 (CH3), 14.0 and 14.0 (CH3); EI-HRMS calcd for
C19H35N3O3 (MH+) 353.2678, found 353.2669.
2-Cyano-2-(1-ethoxy)ethoxy-3-(N-methoxy-N-methyl)amino-
3-(4-trifluoromethylphenyl)propionitrile (18g): Colorless oil; IR
(CHCl3) ν 2987, 2245, 1326, 1171, 1135, 1068, 848 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 7.66 (d, J ) 9.0 Hz, 2H), 7.63 (d, J ) 9.0
Hz, 2H), 5.22 and 5.11 (q, J ) 5.1 Hz, 1H), 4.19 and 4.18 (s, 1H),
3.75 and 3.73 (s, 3H), 3.73-3.49 (m, 1H), 3.23-3.10 (m, 1H),
2.51 (s, 3H), 1.38 and 1.23 (d, J ) 5.1 Hz, 3H), 1.24 and 1.02 (t,
J ) 7.0 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 136.4 and 136.2
(C), 131.8 and 131.7 (q, JC-F ) 22.7 Hz, C), 131.0 and 130.7 (two
of CH), 125.32 and 125.26 (q, J C-F ) 3.7 Hz, two of CH), 123.8
2-Cyano-2-(1-ethoxy)ethoxy-3-(N-methoxy-N-methyl)amino-
3-(2-methylphenyl)propionitrile (18c): Colorless gummy material;
IR (CHCl3) ν 2981, 2941, 2247, 1465, 1388, 1153, 1068 cm-1; 1H
NMR (CDCl3, 300 MHz) δ 7.82-7.66 (m, 1H), 7.34-7.13 (m,
3H), 5.23 and 5.07 (q, J ) 5.2 Hz, 1H), 4.56 and 4.54 (s, 1H),
3.75 and 3.73 (s, 3H), 3.73-3.49 (m, 1H), 3.23-3.03 (m, 1H),
2.48 (s, 3H), 2.37 and 2.35 (s, 3H), 1.36 and 1.18 (d, J ) 5.2 Hz,
3H), 1.22 and 1.00 (t, J ) 7.0 Hz, 3H); 13C NMR (CDCl3, 75 MHz)
δ 138.4 and 138.4 (C), 131.7 and 131.6 (C), 130.5 and 130.4 (CH),
129.0 and 128.9 (CH), 128.3 and 128.0 (CH), 126.4 and 126.3 (CH),
115.0 and 114.2 (C), 113.4 and 112.5 (C), 101.1 and 100.6 (CH),
72.9 and 72.7 (CH), 68.9 and 68.7 (C), 62.1 and 61.1 (CH2), 59.6
and 59.6 (CH3), 42.4 and 42.4 (CH3), 20.3 and 20.2 (CH3), 19.9
and 19.8 (CH3), 14.7 and 14.5 (CH3); EI-MS for C17H23N3O3 (M+)
317. Anal. Calcd for C17H23N3O3: C, 64.33; H, 7.30; N, 13.24.
Found: C, 64.21; H, 7.32; N, 13.10.
(q, J
) 271.2 Hz, C), 114.4 and 113.6 (C), 113.1 and 112.2
C-F
(C), 101.4 and 101.2 (CH), 77.7 and 77.3 (CH), 68.5 and 68.1 (C),
62.5 and 61.7 (CH2), 60.03 and 60.01 (CH3), 42.6 and 42.5 (CH3),
20.0 and 19.8 (CH3), 14.7 and 14.5 (CH3); EI-HRMS calcd for
C15H15F3N3O2 [(M - OC2H5)+] 326.1116, found 326.1092.
2-Cyano-2-(1-ethoxy)ethoxy-3-(N-benzyloxy-N-methyl)amino-
3-(4-methylphenyl)propionitrile (18h): Colorless oil; IR (CHCl3)
ν 2988, 2926, 2260, 1604, 1515, 1455, 1153, 1069, 1021, 820 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 7.45 (d, J ) 8.1 Hz, 2H), 7.43-
7.29 (m, 5H), 7.16 (d, J ) 8.1 Hz, 2H), 5.23 and 5.13 (q, J ) 5.2
Hz, 1H), 5.00 and 4.92 (d, J ) 11.0 Hz, 1H), 4.95 and 4.94 (s,
1H), 4.14 and 4.13 (s, 1H), 3.74-3.50 (m, 1H), 3.35-3.17 (m,
1H), 2.47 (s, 3H), 2.35 (s, 3H), 1.39 and 1.27 (d, J ) 5.2 Hz, 3H),
1.23 and 1.06 (t, J ) 7.0 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ
139.5 and 139.4 (C), 136.4 and 136.3 (C), 130.4 and 130.1 (two of
CH), 129.4 and 129.1 (C), 129.1 and 129.1 (two of CH), 129.1
and 129.0 (two of CH), 128.3 and 128.3 (two of CH), 128.1 and
128.0 (CH), 114.6 and 113.7 (C), 113.7 and 112.7 (C), 101.2 and
100.9 (CH), 78.0 and 77.8 (CH), 75.3 and 75.3 (CH2), 69.1 and
68.7 (C), 62.2 and 61.6 (CH2), 43.9 and 43.8 (CH3), 21.1 and 21.1
(CH3), 20.0 and 19.9 (CH3), 14.7 and 14.5 (CH3); EI-HRMS calcd
for C23H28N3O3 (MH+) 394.2131, found 394.2108.
2-Cyano-2-(1-ethoxy)ethoxy-3-(N-methoxy-N-methyl)amino-
3-(2-furanyl)propionitrile (18d): Colorless oil; IR (CHCl3) ν 2940,
1445, 1151, 1082, 1020, 950, 930, 858 cm-1; H NMR (CDCl3,
1
300 MHz) δ 7.50-7.41 (m, 1H), 6.70-6.62 (m, 1H), 6.46-6.37
(m, 1H), 5.27 and 5.19 (q, J ) 5.2 Hz, 1H), 4.33 and 4.32 (s, 1H),
3.80-3.53 (m, 1H), 3.67 (s, 3H), 3.52-3.30 (m, 1H), 2.55 and
2.55 (s, 3H), 1.47 and 1.33 (d, J ) 5.2 Hz, 3H), 1.26 and 1.14 (t,
J ) 7.1 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 145.0 and 145.0
(C), 143.5 and 143.4 (CH), 114.2 and 113.3 (C), 113.0 and 112.1
(C), 112.6 and 112.6 (CH), 110.9 and 110.9 (CH), 101.4 and 101.3
Transformation of 18a to r-Amino Acid Derivatives 22-24:
To a solution of the crude product 18a (prepared from 1 mmol of
4-tolualdehyde) in CH2Cl2 (5 mL) was added trifluoroacetic acid
J. Org. Chem, Vol. 71, No. 16, 2006 6041

Nemoto et al.
(3.0 equiv, 0.23 mL). The mixture was stirred for 10 min at 0 °C
and then cooled to -25 °C. To the resulting solution was added a
mixture of Et3N (5 equiv) and MeOH (1 mL), or R7XH (2.0 equiv)
and Et3N (3.0 equiv). After being stirred for 1 h at -25 °C, the
mixture was concentrated in vacuo. The residue was purified with
silica gel column chromatography to give 22-24.
was concentrated in vacuo. The residue was purified with silica
gel column chromatography using hexane/ethyl acetate (5:1) as the
eluent to give (-)-29 (174 mg, 0.37 mmol, 88% yield) as colorless
crystals: mp 80-81 °C (hexane/ethyl acetate); [R]22 -58.9° (c
D
0.54, CHCl3); IR (CHCl3) ν 2959, 2933, 1490, 1455, 1139, 846,
1
830 cm-1; H NMR (CDCl3, 300 MHz) δ 7.51 (d, J ) 7.7 Hz,
2H), 7.27 (br d, J ) 7.7 Hz, 3H), 7.13 (br t, J ) 7.6 Hz, 1H), 6.92
(br t, J ) 7.6 Hz, 1H), 6.77 (d, J ) 7.6 Hz, 1H), 4.36 (s, 1H), 4.63
(d, J ) 9.8, 8.1 Hz, 1H), 4.33-4.05 (m, 4H), 3.32-3.12 (m, 1H),
2.38 (s, 3H), 0.66 (s, 9H), 0.29 (s, 3H), 0.09 (s, 3H); 13C NMR
(CDCl3, 75 MHz) δ 155.6 (C), 140.1 (C), 130.4 (C), 129.9 (CH),
129.6 (two of CH), 129.4 (two of CH), 128.8 (CH), 121.7 (CH),
121.3 (C), 116.7 (CH), 116.3 (C), 114.0 (C), 75.3 (CH), 67.7 (CH2),
66.0 (C), 63.8 (CH2), 60.8 (CH), 39.1 (CH), 24.8 (three of CH3),
21.2 (CH3), 17.8 (C), -4.6 (CH3), -5.0 (CH3); EI-HRMS calcd
for C27H33N3O3Si (M+) 475.2291, found 475.2277. Anal. Calcd
for C27H33N3O3Si: C, 68.18; H, 6.99; N, 8.83. Found: C, 68.27;
H, 7.15; N, 8.65.
Methyl r-(N-methoxy-N-methyl)amino-2-(4-methylphenyl)-
acetate (22): Colorless oil; IR (CHCl3) ν 2958, 1743, 1441, 1171,
1
1042, 826 cm-1; H NMR (CDCl3, 300 MHz) δ 7.34 (d, J ) 7.9
Hz, 2H), 7.13 (d, J ) 7.9 Hz, 2H), 4.19 (s, 1H), 3.68 (s, 3H), 3.57
(s, 3H), 2.42 (s, 3H), 2.33 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ
171.1 (C), 138.6 (C), 131.9 (C), 129.3 (two of CH), 128.6 (two of
CH), 76.6 (CH), 60.0 (CH3), 51.9 (CH3), 42.1 (CH3), 21.1 (CH3);
EI-HRMS calcd for C12H17NO3 (M+) 223.1208, found 223.1185.
N-n-Butyl-2-(N-methoxy-N-methyl)amino-2-(4-methylpheny-
l)acetamide (23): White powder, mp 72-74 °C (hexane/ethyl
acetate); IR (CHCl3) ν 3405, 2963, 1673, 1515, 1463, 1045, 909,
1
830 cm-1; H NMR (CDCl3, 300 MHz) δ 7.25 (d, J ) 8.1 Hz,
2H), 7.12 (d, J ) 8.1 Hz, 2H), 6.59 (br, -NH, 1H), 4.06 (s, 1H),
3.52 (s, 3H), 3.34-3.23 (m, 2H), 2.46 (s, 3H), 2.32 (s, 3H), 1.61-
1.27 (m, 4H), 0.92 (t, J ) 7.3 Hz, 3H); 13C NMR (CDCl3, 75 MHz)
δ 170.6 (C), 138.1 (C), 133.1 (C), 129.2 (two of CH), 128.3 (two
of CH), 78.1 (CH), 59.5 (CH3), 41.9 (CH3), 38.9 (CH2), 31.8 (CH2),
21.1 (CH3), 20.1 (CH2), 13.7 (CH3); EI-MS for C15H24N2O2 (M+)
264. Anal. Calcd for C15H24N2O2: C, 68.15; H, 9.15; N, 10.60.
Found: C, 68.00; H, 9.17; N, 10.61.
N-Methoxycarbonylmethyl-a-(N-methoxy-N-methyl)amino-2-
(4-methylphenyl)acetamide (24): Colorless oil; IR (CHCl3) ν 3403,
2955, 1747, 1681, 1515, 1439, 1372, 1240 cm-1; 1H NMR (CDCl3,
300 MHz) δ 7.28 (d, J ) 8.1 Hz, 2H), 7.12 (d, J ) 8.1 Hz, 2H),
7.16 (br, -NH, 1H), 4.17 (dd, J ) 18.6, 5.0 Hz, 1H), 4.13 (s, 1H),
4.04 (dd, J ) 18.6, 5.0 Hz, 1H), 3.77 (s, 3H), 3.57 (s, 3H), 2.49 (s,
3H), 2.32 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 171.0 (C), 170.5
(C), 138.3 (C), 132.6 (C), 129.3 (two of CH), 128.5 (two of CH),
77.8 (CH), 59.5 (CH3), 52.3 (CH3), 41.8 (CH3), 41.0 (CH2), 21.1
(CH3); EI-HRMS calcd for C14H20N2O4 (M+) 280.1423, found
280.1425.
(+)-Methyl-(2S)-[(3aS,9bR)-3H,3aH,9bH-chromano[4,3-c]1,2-
oxazolidinyl]-2-(4-methylphenyl)acetate (30): To a solution of
(-)-29 (117.8 mg, 0.248 mmol) and MeOH (23.8 mg, 30 µL, 0.743
mmol) in THF (5 mL) was added Bu4NF (1.0 M solution in THF)
(298 µL, 0.298 mmol) at -40 °C. The resulting mixture was stirred
for an additional 1 h at -40 °C, quenched with a saturated NH4Cl
solution (5 mL), and extracted with CH2Cl2 (3 × 10 mL). The
combined organic layers were dried over MgSO4 and concentrated
in vacuo. The residue was purified with silica gel column
chromatography using hexane/ethyl acetate (3:1) as the eluent to
give 30 (74.0 mg, 0.218 mmol, 88% yield) as a white crystal: mp
160-161 °C (hexane/ethyl acetate); [R]22D +17.2° (c 0.65, CHCl3);
IR (KBr) ν 2952, 2885, 1740, 1489, 1454, 1252, 1217, 1168, 756
1
cm-1; H NMR (CDCl3, 300 MHz) δ 7.56 (d, J ) 8.1 Hz, 2H),
7.24 (d, J ) 8.1 Hz, 2H), 7.09 (d, J ) 7.8 Hz, 1H), 7.07 (br t, J )
7.8 Hz, 1H), 6.87 (br t, J ) 7.8 Hz, 1H), 6.74 (br t, J ) 7.8 Hz,
1H), 4.62 (s, 1H), 4.46 (dd, J ) 10.5, 8.3 Hz, 1H), 4.25-4.03 (m,
4H), 3.72 (s, 3H), 3.29-3.16 (m, 1H), 2.38 (s, 3H); 13C NMR
(CDCl3, 75 MHz) δ 170.1 (C), 155.8 (C), 139.4 (C), 131.9 (C),
130.6 (CH), 129.8 (two of CH), 129.1 (two of CH), 128.6 (CH),
122.2 (C), 121.9 (CH), 116.7 (CH), 72.9 (CH), 68.4 (CH2), 64.9
(CH2), 59.0 (CH), 52.5 (CH3), 40.1 (CH), 21.3 (CH3); EI-MS for
C20H21NO4 (M+) 339. Anal. Calcd for C20H21NO4: C, 70.78; H,
6.24; N, 4.13. Found: C, 70.57; H, 6.60; N, 4.02.
(+)-Methyl-(2S)-3-N-(tert-butoxycarbonylamino)-2-(4-meth-
ylphenyl)acetate (31): To a solution of (+)-30 (74 mg, 0.218
mmol) and Boc2O (143 mg, 0.656 mmol) in methanol (8 mL) was
suspended Pd(OH)2 (20% on carbon, 15 mg). The resulting
suspension was stirred for 72 h at 70 psi of hydrogen. The mixture
was filtered and concentrated in vacuo. The residue was purified
with silica gel column chromatography using hexane/ethyl acetate
(3:1) as the eluent to give 31 (52.3 mg, 0.187 mmol, 86% yield) as
a white solid: 98% ee [HPLC: Daicel Chiralcel OD, hexane/EtOH
(120:1), 0.3 mL/min; Rt ) 17.2 min for (R)-31; Rt ) 19.3 min for
(S)-31]; colorless oil, [R]22D +128.9° (c 2.36, CHCl3); IR (KBr) ν
3383, 2977, 1747, 1716, 1511, 1168, 1055 cm-1; 1H NMR (CDCl3,
300 MHz) δ 7.24 (d, J ) 7.9 Hz, 2H), 7.23 (d, J ) 7.9 Hz, 2H),
5.52 (br d, J ) 7.2 Hz, 1H), 5.27 (d, J ) 7.2 Hz, 1H), 3.70 (s, 3H),
2.33 (s, 3H), 1.43 (s, 9H); 13C NMR (CDCl3, 75 MHz) δ 171.8
(C), 154.8 (C), 138.3 (C), 133.9 (C), 129.6 (two of CH), 127.0
(two of CH), 80.1 (C), 57.3 (CH), 52.6 (CH3), 28.3 (three of CH3),
21.1 (CH3); EI-HRMS calcd for C15H21NO4 (M+) 279.1471, found
279.1479.
2-(2H-Benzo[3,4-d]1,3-dioxolan-5-yl)-N-butyl-a-(N-methoxy-
N-methyl)aminoacetamide (26): A mixture of piperonal (25) (40.9
mg, 0.273 mmol), hydrochloride salt of 16a (32.0 mg, 0.328 mmol),
17 (50.0 mg, 0.324 mmol), and pyridine (65.0 mg, 0822 mmol) in
acetonitrile (1 mL) was stirred at room temperature for 2 h. The
resulting solution was filtered through an aluminum oxide 90
(activity II-III) pad (1 × 5 cm), washed with CH2Cl2, and then
concentrated. The residue was resolved in CH2Cl2 (2 mL), and
trifluoroacetic acid (93 mg, 0.815 mL) was added. The mixture
was stirred for 10 min at 0 °C and then cooled to -25 °C. To the
resulting solution was added butylamine (100 mg, 0.14 mL, 0.136
mmol). After being stirred for 1 h at -25 °C, the mixture was
concentrated in vacuo. The residue was purified with silica gel
column chromatography using chloroform/ethyl acetate (3:1) as the
eluent to give 26 (64.2 mg, 0.218 mmol, 80% yield) as a white
form: IR (KBr) ν 3299, 2962, 1651, 1533, 1487, 1442, 1257, 1042,
1
931 cm-1; H NMR (CDCl3, 300 MHz) δ 6.88 (d, J ) 1.5 Hz,
1H), 6.84 (dd, J ) 18.0, 1.5 Hz, 1H), 6.84 (d, J ) 18.0 Hz, 1H),
6.58 (br, -NH, 1H), 5.94 (br s, 2H), 4.00 (s, 1H), 3.53 (s, 3H),
3.36-3.22 (m, 2H), 2.46 (s, 3H), 1.58-1.45 (m, 2H), 1.43-1.28
(m, 2H), 0.92 (t, J ) 7.2 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ
170.5 (C), 147.7 (C), 147.6 (C), 129.6 (C), 122.3 (CH), 108.5 (CH),
108.2 (CH), 101.1 (CH2), 77.8 (CH), 59.5 (CH3), 41.7 (CH3), 38.9
(CH2), 31.7 (CH2), 20.0 (CH2), 13.7 (CH3); EI-MS for C15H22N2O4
(M+) 294. Anal. Calcd for C15H22N2O4: C, 61.21; H, 7.53; N, 9.52.
Found: C, 60.92; H, 7.52; N, 9.47.
(+)-(2S)-(4-Methylphenyl)glycine hydrochloride (32): The
mixture of (+)-31 (58.5 mg, 0.210 mmol) in 3 N HCl (2 mL) was
refluxed for 3 h. The resulting mixture was concentrated and dried
in vacuo to give 32 (43 mg, 0.213 mmol, 100% yield) as white
needle crystals: [R]22 +148.0° (c 1.0, 1 N HCl); {[R]22 +151°
(-)-[(tert-Butyldimethylsilyl)oxy]]{(1R){[(3aS,9bR)-3H,3aH,-
9bH-chromano[4,3-c]1,2-oxazolidinyl](4-methylphenyl)methyl}-
1,1-dicarbonitrile (29): A mixture of 4-tolualdehyde (50.1 mg, 0.42
mmol), (+)-27‚HCl (90.0 mg, 0.42 mmol), 28 (98.0 mg, 0.50
mmol), and pyridine (66.0 mg, 0.84 mmol) in acetonitrile (3 mL)
was stirred at room temperature for 12 h. Then the resulting solution
D
D
(c 1.0, 1 N HCl)};19 IR (KBr) ν 2984 (br), 1735, 1483, 1225, 1184,
884 cm-1; 1H NMR (CF3COOD, 300 MHz) δ 10.70 (s, 4 H), 7.38
(d, J ) 8.1 Hz, 2H), 7.34 (d, J ) 8.1 Hz, 2H), 5.42 (br s, 1H), 2.41
6042 J. Org. Chem., Vol. 71, No. 16, 2006

Synthesis of R-Amino Acid Precursors
(s, 3H); 13C NMR (CF3COOD, 75 MHz) δ 174.3 (C), 144.7 (C),
132.5 (two of CH), 129.9 (two of CH), 127.5 (C), 60.3 (CH), 21.6
(CH3); EI-HRMS calcd for C9H11NO2 (M+) 165.0790, found
165.0739.
(+)-N-Butyl-(2S)-3-N-(tert-butoxylcarbonylamino)-(4-meth-
ylphenyl)acetamide (34): 34 (37.3 mg, 0.111 mmol, 78% yield)
was obtained from (+)-33 (56.5 mg, 0.143 mmol) using the same
procedure as that for the transformation from 30 to 31: [R]22
D
(+)-(2R)-N-Methoxycarbonylmethyl-[(3aS,9bR)-3H,3aH,9bH-
chromano-[4,3-c]1,2-oxazolidinyl]-(4-methylphenyl)acetamide (33):
(+)-33 (95.3 mg, 0.241 mmol, 85% yield) was obtained from
(-)-29 (134.8 mg, 0.284 mmol) and H2NCH2CO2Me (2.0 M in
CH2Cl2) (0.36 mL, 0.720 mmol) using the same procedure as that
+101.4° (c 0.59, CHCl3); mp 124-125 °C (hexane/ethyl acetate);
1
IR (KBr) ν 3310, 2977, 1750, 1658, 1526, 1171 cm-1; H NMR
(CDCl3, 300 MHz) δ 7.27 (d, J ) 7.9 Hz, 2H), 7.16 (d, J ) 7.9
Hz, 2H), 6.42 (br s, 1H), 5.71 (br s, 1H), 5.18 (br s, 1H), 4.07 (dd,
J ) 18.2, 5.3 Hz, 1H), 3.95 (dd, J ) 18.2, 5.0 Hz, 1H), 3.72 (s,
3H), 2.33 (s, 3H), 1.41 (s, 9H); 13C NMR (CDCl3, 75 MHz) δ
170.6 (C), 169.9 (C), 155.7 (C), 138.3 (C), 135.0 (C), 129.7 (two
of CH), 127.2 (two of CH), 80.1 (C), 58.3 (CH), 52.4 (CH3), 41.4
(CH2), 28.3 (three of CH3), 21.1 (CH3); EI-HRMS calcd for
C17H24N2O5 (M+) 336.1685, found 336.1683.
1
for the transformation from 18a to 24. H NMR indicated 33 was
a diastereomerically pure product. [R]22 +35.9° (c 1.6, CHCl3);
D
IR (KBr) ν 3276, 3068, 2947, 1755, 1658, 1552, 1248, 1200, 1036,
1
985, 759 cm-1; H NMR (CDCl3, 300 MHz) δ 7.55 (br s, 1H,
-NH), 7.47 (d, J ) 8.0 Hz, 2H), 7.24 (br d, J ) 8.0 Hz, 3H), 7.13
(br t, J ) 7.6 Hz, 1H), 6.94 (br t, J ) 7.6 Hz, 1H), 6.78 (d, J ) 7.6
Hz, 1H), 4.47 (s, 1H), 4.44 (dd, J ) 9.5, 8.1 Hz, 1H), 4.29 (dd, J
) 18.1, 4.5 Hz, 1H), 4.26-4.00 (m, 4H), 3.89 (dd, J ) 18.1, 4.5
Hz, 1H), 3.72 (s, 3H), 3.25-3.11 (m, 1H), 2.35 (s, 3H); 13C NMR
(CDCl3, 75 MHz) δ 170.4 (C), 170.2 (C), 155.8 (C), 139.1 (C),
132.7 (C), 130.2 (two of CH), 130.0 (CH), 128.8 (two of CH),
128.3 (CH), 122.1 (C), 121.7 (CH), 116.8 (CH), 72.4 (CH), 67.5
(CH2), 64.5 (CH2), 58.2 (CH), 52.2 (CH3), 40.7 (CH2), 39.7 (CH),
21.2 (CH3); EI-MS for C22H24N2O5 (M+) 396. Anal. Calcd for
C22H24N2O5: C, 66.65; H, 6.10; N, 7.07. Found: C, 66.61; H, 6.18;
N, 7.07.
Acknowledgment. This work was partly supported by a
Grant-in-Aid for Scientific Research of the Ministry of Educa-
tion of Japan (Grant No. 15510177 in 2003-2004).
Supporting Information Available: 1H and 13C NMR spectra
of compounds 18, 22-24, 26, and 29-34. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO0607515
J. Org. Chem, Vol. 71, No. 16, 2006 6043