Reliable assignment of absolute configuration of chiral amines based on the analysis of 1H NMR spectra of their CFTA amide diastereomers

Article abstract of DOI:10.1016/j.tetasy.2008.03.003

Applications of the CFTA method, a new and reliable procedure for the determination of the absolute configuration of chiral primary amines, are described in detail. In addition to the very high reactivity of CFTA chloride, the stable anti-periplanar conformers of CFTA amides, associated with the chiral structure of fluorine atom on a stereogenic center, are the key factors that make the technique of using ¹H NMR analysis of the CFTA diastereomers very reliable. In particular, this method is useful for the determination of the absolute stereochemistry of isotopically multi-labeled amino acid derivatives.

Full text of DOI:10.1016/j.tetasy.2008.03.003

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 847–856
Reliable assignment of absolute configuration of chiral amines
based on the analysis of H NMR spectra of their CFTA
amide diastereomers
1
Tomoya Fujiwara,a Masaru Segawa,a Hidehito Fujisawa,a Taiki Murai,a
Tamiko Takahashi,a Kenji Omata,b Kuninobu Kabuto,b Siegfried N. Lodwig,c
Clifford J. Unkeferc and Yoshio Takeuchia,*
aGraduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Sugitani 2630, Toyama 930-0194, Japan
bDepartment of Chemistry, Graduate School of Science, Tohoku University, Aramaki, Aoba-ku, Sendai 980-8578, Japan
cNational Stable Isotope Resource, Bioscience Division, MS E529, Los Alamos National Laboratory, Los Alamos, NM 87544, USA
Received 5 February 2008; accepted 3 March 2008
Available online 15 April 2008
Abstract—Applications of the CFTA method, a new and reliable procedure for the determination of the absolute configuration of chiral
primary amines, are described in detail. In addition to the very high reactivity of CFTA chloride, the stable anti-periplanar conformers of
CFTA amides, associated with the chiral structure of fluorine atom on a stereogenic center, are the key factors that make the technique of
using 1H NMR analysis of the CFTA diastereomers very reliable. In particular, this method is useful for the determination of the abso-
lute stereochemistry of isotopically multi-labeled amino acid derivatives.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
(CDAs) followed by NMR spectroscopic examination.1,2
These CDAs include a-methoxyarylacetic acid analogues
1–3 in addition to the well-known a-methoxy-a-trifluo-
romethylphenylacetic acid 4 (MTPA) (Fig. 1).3 All of these
agents, however, suffer from the problems of low reactiv-
ity4 of the corresponding acid chlorides, possible racemiza-
tion,5 and/or poor resolution ability in the NMR of their
diastereomers caused by the presence of multiple conform-
ers.6 We have recently developed a reliable method for the
determination of the absolute configuration of chiral
The determination of absolute configuration is of funda-
mental importance to various fields of organic chemistry.
Although there have been several methods1 so far reported
for this purpose, extensive research has continued for tech-
niques of more general and practical applicability. X-ray
crystallographic analysis is the most reliable method for
determining the absolute configuration. However, this is
only effective in the case where a single crystal of the sam-
ple can be obtained. Therefore, samples obtained in small
quantities from natural sources and/or those compounds
that are oils cannot be analyzed by X-ray methods. Other
procedures including the CD excitation chirality method
have been reported. However, all of these procedures also
have limitations to their practical applicability.
amines7 using a-cyano-a-fluoro-p-tolylacetic acid
5
In order to overcome the drawbacks mentioned above,
more convenient methods have been studied which involve
diastereomer formation with chiral derivatizing agents
*
Corresponding author. Tel.: +81 76 434 7555; fax: +81 76 434 5053;
e-mail: takeuchi@pha.u-toyama.ac.jp
Figure 1.
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.03.003

848
T. Fujiwara et al. / Tetrahedron: Asymmetry 19 (2008) 847–856
(CFTA). Herein we report in full the details of the CFTA
procedure.
and analysis of the AB quartet-like proton signals for the
para-substituted phenyl group is much easier than the pro-
ton signals for the other possible substitution patterns.
After the examination of several para-substituted ana-
logues of CFPA, we have settled on using CFTA 5 for
the determination of both ees and absolute configuration.11
2. Results and discussion
2.1. Molecular design of the new CDA
2.2. Application of the CFTA method to the determination of
the absolute configuration of chiral primary amines
The drawbacks of the existing CDAs seemed to be mainly
due to the inherent problems4 derived from the a-meth-
oxyacetate structure, as shown by 1–4. Upon consideration
of the necessary factors for better CDAs, especially greater
reactivity so as to allow condensation even with sterically
hindered nucleophiles, we focused on a-cyano-a-fluorophen-
ylacetic acid 6 (CFPA). This compound has a unique chiral
structure with a fluorine atom located on the stereogenic
center.8 Indeed, CFPA chloride is 500 times more reactive
than MTPA chloride, thus allowing reaction even with hin-
dered nucleophiles to give CFPA diastereomers.9 Further-
more, the 19F NMR chemical shift differences between
CFPA diastereomers are in general several times greater
than those between the well-known MTPA diastereomers.
This enables ee determination by the CFPA method for
molecules having their stereogenic centers several bonds re-
motely disposed from the derivative acid functionality.8,10
We have already reported the formation of a very stable
conformer having an all syn-periplanar (F–Ca)–(C@O)–
O–(C–H) structure in the ‘CFTA ester plane’ as the pre-
dominant rotamer of CFTA esters.12 We propose that
the formation of a very stable anti-periplanar (F–Ca)–
(C@O)–(N–H)–(C–H) conformer in the ‘CFTA amide
plane’7 is the predominant rotamer of CFTA amides, even
in CDCl3 solution. Apparently, a consistent relationship
exists between the stereochemistry of chiral amines and
the chemical shifts of the corresponding diastereomeric
CFTA amides. In order to establish this pattern, we inves-
tigated various types of chiral amines of known absolute
configurations. At first, each chiral amine 7a–y was con-
densed with both (S)- and (R)-CFTA chlorides to give
(S)- and (R)-CFTA amide diastereomers, respectively. All
proton signals for each of the (S)- and (R)-CFTA diaste-
reomers 8a–y were assigned and the Dd (=dS ꢀ dR) value
for every proton was obtained (Fig. 2).
Although CFPA was useful for the determination of the
absolute configuration of chiral molecules, this agent
proved to be rather difficult to produce as pure enantio-
mers. Moreover, the phenyl protons of the CFPA deriva-
tives appear as a complex multiplet that can often
complicate the analyses of the proton NMR spectra of a
substrate having aromatic substituents. The recognition
When the amides are depicted such that the two substitu-
ents on the stereogenic center are in the plane of the
page, and the a-protons are coming out of the plane, the
protons with positive Dd values are invariably on the right
Figure 2. Chemical shift differences (DdH) observed for CFTA amide diastereomers of chiral amines 7a–y. ui: unidentified.

T. Fujiwara et al. / Tetrahedron: Asymmetry 19 (2008) 847–856
849
Figure 3. Preferred conformations of (S)- and (R)-CFTA amides of chiral primary amines (R1R2CHNH2).
side of the CFTA amide plane while those having negative
Dd values are on the left side of the plane. We have not
found any exception to this pattern. These results can be
explained using conformational arguments, as shown in
Figure 3.
The structures illustrated show the (S)- and (R)-CFTA
amide diastereomers having an all anti-periplanar (ap) (F–
Ca)–(C@O)–(N–H)–(C–H) array. This ap conformation
was supported by X-ray crystallographic analyses of the
CFTA amide of 1-phenylethylamine13 and ab initio calcu-
lations (GAUSSIAN 98, RHF/6-31+G*) of the CFPA amide
of valine methyl ester, taken to be a closely analogous
structure.14
Figure 4. Chemical shift differences (DdH and DdD) observed for CFTA
amide diastereomers of multi-labeled amino acid methyl esters.
opportunity to look further at the scope and limitation of
the CFTA method.
The results of the CFTA derivatization are shown in Figure
4 in a manner similar to Figure 2. We found the expected
(S)-absolute configuration for both of these multi-labeled
amino acids.
In order to view the (S)-CFTA amides of chiral amines
(R1R2CHNH2) from the right side, or the (R)-CFTA
amides from the left side, via an extended Newman projec-
tion, the intervening amide linkages are omitted for conve-
nience. In the (S)-CFTA diastereomer, the shifts of the
protons of the R1 group should always be upfield, as a
result of the anisotropic shielding of the aromatic ring. In
contrast, for the (R)-diastereomer, the protons of the R2
group are shielded and therefore should appear upfield.
Thus, the Dd values for the protons on the left side of the
CFTA plane should be negative, while those on the right
side of the plane should be positive. Reinforcing these dif-
ferences, the CN group induces an anisotropic deshielding
effect15 on the proximate R1 and R2 groups in the (S)- and
(R)-CFTA diastereomers, respectively. Accordingly, the Dd
(=dS ꢀ dR) values for the protons in the R2 group, namely,
those for all the protons on the right side of the CFTA
amide plane, should be positive and those in the R1 group,
namely, those for all the protons on the left side of the
plane, should be negative (Fig. 3).
3. Conclusion
We have established that the CFTA method can be applied
not only to the determination of the absolute configuration
of chiral secondary alcohols but also to that of chiral
primary amines. Although there are other conceptually
similar procedures available, these procedures, in some
cases, cannot be applied because the chiral derivatizing
agents used for the procedures exhibit insufficient reactivi-
ties toward bulky substrates or the absolute configuration
using these procedures resulted in ambiguities. The CFTA
method has important advantages over them because of the
very high reactivity of CFTA chloride4d and because the F
atom directly connected to the stereogenic center contrib-
utes to the conformational control of the amides.7 The spe-
cific stereoelectronic environment that produces this ‘ap’
conformation is probably due to the unique F atom and
the CN group on the chiral center.16 We feel that this meth-
od should be very reliable and widely applicable. Further
clarification of the theoretical basis for the above results
We prepared isotopically multi-labeled amino acids, which
we assumed will be useful for medicinal and/or clinical
work. We needed to determine the absolute configuration
of these compounds 9a and 9b. This was also a good

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T. Fujiwara et al. / Tetrahedron: Asymmetry 19 (2008) 847–856
and the acquisition of additional data to study the general-
ity of the CFTA procedure are currently under
investigation.
d 0.87 (3H, t, J = 7.5 Hz), 1.24 (3H, d, J = 6.6 Hz), 1.50
(1H, dquint, J = 15.6, 7.4 Hz), 1.52 (1H, dqd, J = 15.6,
7.4, 7.1 Hz), 2.39 (3H, d, J = 1.5 Hz), 3.97 (1H, m), 6.22
(1H, br s), 7.27 (2H, m), 7.49 (2H, m); 19F NMR
(254 MHz, CDCl3) d ꢀ141.83 (s); MS (EI) m/z 249
(M+ + H), 248 (M+). Anal. Calcd for C14H17FN2O: C,
67.72; H, 6.90; N, 11.28. Found: C, 67.35; H, 6.93; N,
11.00.
4. Experimental
4.1. General
Melting points were measured with a Yanaco micro melt-
ing point apparatus and are uncorrected. Microanalyses
were performed by the Microanalysis Center of Toyama
Medical and Pharmaceutical University. Spectroscopic
measurements were carried out with the following instru-
ments: optical rotations, JASCO DIP-1000 digital polari-
meter; IR spectra, Perkin–Elmer 1600 Series FTIR; mass
spectra (MS), JEOL JMS-GCmate; high resolution mass
spectra (HRMS), JEOL JMS-AX 505 HAD or Bruker
APEX III; 1H NMR spectra, Varian Unity 500
(500 MHz) or JEOL GSX-400 (400 MHz), in CDCl3 with
4.2.2. N-[(S)-2-Butyl]-(R)-2-cyano-2-fluoro-p-tolylacetamide
[(R)-CFTA amide of 7a]. Colorless needles; mp 93–95 °C
28
(from hexane/CH2Cl2); ½aꢂD ¼ þ11:0 (c 1.0, MeOH); IR
(KBr) 3331, 2256, 1681 cmꢀ1; 1H NMR (500 MHz, CDCl3)
d 0.96 (3H, t, J = 7.5 Hz), 1.17 (3H, d, J = 6.6 Hz), 1.58
(2H, dq, J = 14.3, 7.4 Hz), 2.39 (3H, d, J = 1.5 Hz), 3.96
(1H, dqd, J = 7.4, 6.6, 1.7 Hz), 6.25 (1H, br s), 7.27 (2H,
m), 7.49 (2H, m); 19F NMR (254 MHz, CDCl3) d
ꢀ141.30 (s); MS (EI) m/z 248 (M+). Anal. Calcd for
C14H17FN2O: C, 67.72; H, 6.90; N, 11.28. Found: C,
67.89; H, 7.20; N, 11.26.
2
TMS (=0.00 ppm) as an internal standard; D NMR spec-
tra, JEOL GSX-400 (61 MHz), in CHCl3 with CDCl3
(=7.26 ppm) as an internal standard. 19F NMR spectra,
Varian Unity 500 (470 MHz), JEOL JNM-GX 270
(254 MHz) or JEOL GSX-400 (376 MHz), in CDCl3 with
CFCl3 (=0.00 ppm) as an internal standard. Column chro-
matography was performed on Fuji Silysia BW-200, Kanto
chemical Silica Gel 60N (0.040–0.050 mm), or Merck Silica
Gel 60 (0.040–0.063 mm). Thin layer chromatography was
performed on Merck 5715.
4.2.3. N-[(R)-2-(3-Methyl)butyl]-(S)-2-cyano-2-fluoro-p-tol-
ylacetamide [(S)-CFTA amide of 7b]. Colorless needles;
29
mp 100–102 °C (from hexane/CH2Cl2); ½aꢂD ¼ ꢀ2:5 (c
1
2.0, MeOH); IR (KBr) 3324, 2260, 1680 cmꢀ1; H NMR
(500 MHz, CDCl3) d 0.95 (3H, d, J = 6.8 Hz), 0.96 (3H,
d, J = 6.8 Hz), 1.13 (3H, d, J = 6.8 Hz), 1.80 (1H, quint,
J = 6.8 Hz), 2.40 (3H, br d, J = 1.7 Hz), 3.91 (1H, quintd,
J = 6.8, 1.7 Hz), 6.26 (1H, br s), 7.27 (2H, br d,
J = 8.2 Hz), 7.49 (2H, br d, J = 6.8 Hz); 19F NMR
(254 MHz, CDCl3) d ꢀ141.28 (s); MS (EI) m/z 262 (M+);
HRMS (EI) calcd for C15H19FN2O (M+): 262.1481; found:
262.1469.
4.2. Typical procedure for the condensation of a-cyano-a-
fluoro-p-tolylacetyl chloride with chiral amines
(R)-CFTA chloride (30.0 mg, 0.142 mmol) was added to a
solution of (R)-(+)-1-(p-tolyl)ethylamine 7m (20.4 lL,
0.142 mmol) and pyridine (23.0 lL, 0.284 mmol) in dry
CH2Cl2 (1 mL) at room temperature. After stirring at room
temperature for 2 h, the solvent and excess pyridine were
evaporated in vacuo. A solution of the residue in H2O
(0.2 mL) was extracted with EtOAc (3 mL ꢁ 3). The com-
bined extracts were dried over MgSO4 and the solvent
was evaporated. The residue was purified by preparative
TLC (eluent; hexane/EtOAc = 1:1) to give N-[(R)-1-(p-tol-
4.2.4. N-[(R)-2-(3-Methyl)butyl]-(R)-2-cyano-2-fluoro-p-tol-
ylacetamide [(R)-CFTA amide of 7b]. Colorless needles;
29
mp 65–67 °C (from hexane/CH2Cl2); ½aꢂD ¼ ꢀ19:6 (c 1.8,
MeOH); IR (KBr) 3668, 2254, 1678 cmꢀ1 1H NMR
;
(500 MHz, CDCl3) d 0.87 (6H, d, J = 6.8 Hz), 1.20 (3H,
d, J = 6.8 Hz), 1.73 (1H, quint, J = 6.8 Hz), 2.39 (3H, br
s), 3.92 (1H, quintd, J = 6.8, 1.7 Hz), 6.26 (1H, br s),
7.27 (2H, br d, J = 8.2 Hz), 7.49 (2H, br d, J = 7.7 Hz);
19F NMR (254 MHz, CDCl3) d ꢀ142.30 (s); MS (EI) m/z
262 (M+); HRMS (EI) calcd for C15H19FN2O (M+):
262.1481; found: 262.1480.
yl)ethyl]-(R)-a-cyano-a-fluoro-p-tolylacetamide
(44 mg,
100%) as colorless needles: Mp 80–81 °C (from hexane/
27
CH2Cl2); ½aꢂD ¼ þ110:2 (c 1.2, MeOH); IR (KBr) 3336,
4.2.5. N-[(R)-2-(3,3-Dimethyl)butyl]-(S)-2-cyano-2-fluoro-p-
tolylacetamide [(S)-CFTA amide of 7c]. Colorless needles;
2256, 1678 cmꢀ1
;
1H NMR (500 MHz, CDCl3) d 1.60
29
(3H, d, J = 7.1 Hz), 2.34 (3H, s), 2.37 (3H, s), 5.12 (1H,
dq, J = 7.4, 7.1 Hz), 6.65 (1H, br s), 7.16 (4H, s), 7.22
(2H, br d, J = 7.9 Hz), 7.41 (2H, br d, J = 8.1 Hz); 19F
NMR (254 MHz, CDCl3) d ꢀ140.99 (s); MS (EI) m/z 310
(M+). Anal. Calcd for C19H19FN2O: C, 73.53; H, 6.17;
N, 9.03. Found: C, 73.55; H, 5.92; N, 8.87.
mp 80–82 °C (from hexane/CH2Cl2); ½aꢂD ¼ ꢀ2:6 (c 1.5,
MeOH); IR (KBr) 3316, 2250, 1681 cmꢀ1 1H NMR
;
(500 MHz, CDCl3)
d 0.96 (9H, s), 1.10 (3H, d,
J = 6.8 Hz), 2.39 (3H, br s), 3.92 (1H, dqd, J = 9.8, 6.8,
1.7 Hz), 6.26 (1H, br s), 7.27 (2H, br d, J = 9.0 Hz), 7.49
(2H, d, J = 7.7 Hz); 19F NMR (254 MHz; CDCl3) d
ꢀ141.06 (s); MS (EI) m/z 276 (M+). Anal. Calcd for
C16H21FN2O: C, 69.54; H, 7.66; N, 10.14. Found: C,
69.41; H, 7.80; N, 9.85.
Other amides were prepared in the same manner in 40–
100% yields.
4.2.1. N-[(S)-2-Butyl]-(S)-2-cyano-2-fluoro-p-tolylacetamide
[(S)-CFTA amide of 7a]. Colorless needles; mp 69–70 °C
4.2.6. N-[(R)-2-(3,3-Dimethyl)butyl]-(R)-2-cyano-2-fluoro-p-
tolylacetamide [(R)-CFTA amide of 7c]. Pale yellow oil;
25
27
(from hexane/CH2Cl2); ½aꢂD ¼ þ18:0 (c 1.3, MeOH); IR
½aꢂD ¼ ꢀ21:7 (c 2.0, MeOH); IR (neat) 3337, 2253,
(KBr) 3328, 2255, 1675 cmꢀ1; 1H NMR (500 MHz, CDCl3)
1698 cmꢀ1; H NMR (500 MHz, CDCl3) d 0.86 (9H, s),
1

T. Fujiwara et al. / Tetrahedron: Asymmetry 19 (2008) 847–856
851
1.18 (3H, d, J = 6.8 Hz), 2.39 (3H, br s), 3.90 (1H, dqd,
J = 9.8, 6.8, 1.7 Hz), 6.26 (1H, br s), 7.27 (2H, br d,
J = 9.0 Hz), 7.49 (2H, d, J = 7.7 Hz); 19F NMR
(254 MHz, CDCl3) d ꢀ143.13 (s); MS (EI) m/z 276 (M+);
HRMS (EI) calcd for C16H21FN2O (M+): 276.1638; found:
276.1621.
J = 11.1 Hz), 7.48 (2H, br d, J = 7.3 Hz); 19F NMR
(254 MHz, CHCl3) d ꢀ141.14 (s); MS (EI) m/z 331
(M++H). Anal. Calcd for C20H27FN2O: C, 72.70; H,
8.24; N, 8.48. Found: C, 72.62; H, 8.49; N, 8.23.
4.2.11. N-[(1R,2S,4R)-Bornyl]-(S)-2-cyano-2-fluoro-p-tolyl-
acetamide [(S)-CFTA amide of 7f]. Colorless needles;
29
4.2.7. N-[(S)-1-(Cyclohexyl)ethyl]-(S)-2-cyano-2-fluoro-p-
tolylacetamide [(S)-CFTA amide of 7d]. Colorless needles;
mp 79–80 °C (from hexane/CH2Cl2); ½aꢂD ¼ ꢀ14:8 (c 1.1,
MeOH); IR (KBr) 3351, 2253, 1682 cmꢀ1 1H NMR
;
28
mp 63–64 °C (from hexane/CH2Cl2); ½aꢂD ¼ ꢀ3:8 (c 1.1,
(500 MHz, CDCl3) d 0.73 (3H, s), 0.88 (3H, s), 0.93 (1H,
dd, J = 13.9, 4.7 Hz), 0.94 (3H, s), 1.24 (1H, m), 1.41
(1H, dt, J = 13.9, 5.8 Hz), 1.44 (1H, tdd, J = 13.7, 4.8,
1.9 Hz), 1.74 (1H, t, J = 4.5 Hz), 1.82 (1H, dddd,
J = 13.9, 8.1, 6.2, 2.8 Hz), 2.40 (3H, br d, J = 1.7 Hz),
2.43 (1H, dddd, J = 13.7, 11.2, 4.8, 3.6 Hz), 4.28 (1H,
dddd, J = 11.1, 4.2, 1.9, 1.1 Hz), 6.44 (1H, br s), 7.28
(2H, br d, J = 8.5 Hz), 7.51 (2H, br d, J = 8.3 Hz); 19F
NMR (470 MHz, CDCl3) d ꢀ141.03 (s); MS (EI) m/z 328
(M+). Anal. Calcd for C20H25FN2O: C, 73.14; H, 7.67;
N, 8.53. Found: C, 73.19; H, 7.83; N, 8.80.
MeOH); IR (KBr) 3315, 2252, 1678 cmꢀ1 1H NMR
;
(500 MHz, CDCl3) d 0.91 (1H, qd, J = 12.4, 3.4 Hz), 0.94
(1H, qd, J = 12.4, 3.4 Hz), 1.08 (1H, m), 1.19 (2H, qq,
J = 16.8, 3.8 Hz), 1.20 (3H, d, J = 6.8 Hz), 1.36 (1H,
ddq, J = 15.2, 12.4, 3.4 Hz), 1.65 (3H, m), 1.73 (2H, br d,
J = 12.5 Hz), 2.39 (3H, br d, J = 0.8 Hz), 3.90 (1H, dqd,
J = 15.4, 6.8, 1.6 Hz), 6.27 (1H, br s), 7.27 (2H, br d,
J = 7.9 Hz), 7.49 (2H, br d, J = 8.3 Hz); 19F NMR
(254 MHz, CDCl3) d ꢀ141.76 (s); MS (EI) m/z 302 (M+).
Anal. Calcd for C18H23FN2O: C, 71.50; H, 7.67; N, 9.26.
Found: C, 71.50; H, 7.62; N, 8.96.
4.2.12. N-[(1R,2S,4R)-Bornyl]-(R)-2-cyano-2-fluoro-p-tolyl-
acetamide [(R)-CFTA amide of 7f]. Colorless needles;
4.2.8. N-[(S)-1-(Cyclohexyl)ethyl]-(R)-2-cyano-2-fluoro-p-
tolylacetamide [(R)-CFTA amide of 7d]. Colorless needles;
28
mp 108–110 °C (from hexane/CH2Cl2); ½aꢂD ¼ ꢀ24:3 (c
28
1
mp 129–130 °C (from hexane/CH2Cl2); ½aꢂD ¼ ꢀ18:2 (c
1.1, MeOH); IR (KBr) 3311, 2254, 1676 cmꢀ1; H NMR
1
1.1, MeOH); IR (KBr) 3321, 2253, 1676 cmꢀ1; H NMR
(500 MHz, CDCl3) d 0.81 (1H, dd, J = 13.5, 4.5 Hz), 0.89
(3H, s), 0.90 (3H, s), 0.94 (3H, s), 1.20 (1H, ddd,
J = 13.9, 7.6, 6.1 Hz), 1.46 (1H, ddd, J = 14.1, 7.9,
6.6 Hz), 1.50 (1H, dddd, J = 14.0, 8.3, 5.8, 1.8 Hz), 1.71
(1H, t, J = 4.2 Hz), 1.82 (1H, m), 2.36 (1H, m), 2.39 (3H,
br d, J = 1.5 Hz), 4.25 (1H, m), 6.44 (1H, br s), 7.27 (2H,
br d, J = 8.6 Hz), 7.50 (2H, br d, J = 8.3 Hz); 19F NMR
(470 MHz, CDCl3) d ꢀ142.01 (s); MS (EI) m/z 328 (M+).
Anal. Calcd for C20H25FN2O: C, 73.14; H, 7.67; N, 8.53.
Found: C, 73.11; H, 7.69; N, 8.43.
(500 MHz, CDCl3) d 1.00 (1H, m), 1.04 (1H, m), 1.13
(3H, d, J = 6.8 Hz), 1.15 (1H, m), 1.26 (2H, m), 1.42
(1H, ddq, J = 15.0, 12.2, 3.2 Hz), 1.69 (1H, br d,
J = 13.2 Hz), 1.71 (1H, br d, J = 12.4 Hz), 1.77 (1H, m),
1.78 (2H, m), 2.39 (3H, br s), 3.90 (1H, sext, J = 6.6 Hz),
6.28 (1H, br s), 7.27 (2H, br d, J = 8.1 Hz), 7.49 (2H, br
d, J = 8.1 Hz); 19F NMR (254 MHz, CDCl3) d ꢀ141.18
(s); MS (EI) m/z 302 (M+). Anal. Calcd for C18H23FN2O:
C, 71.50; H, 7.67; N, 9.26. Found: C, 71.46; H, 7.56; N,
9.50.
4.2.13. N-[(1R,2S,3S)-Isopinocampheyl]-(S)-2-cyano-2-fluoro-
p-tolylacetamide [(S)-CFTA amide of 7g]. Colorless
4.2.9. N-[(1R,2S,5R)-Menthyl]-(S)-2-cyano-2-fluoro-p-tolyl-
acetamide [(S)-CFTA amide of 7e]. Colorless solid; mp
28
needles; mp 122–123 °C (from hexane/CH2Cl2); ½aꢂD ¼
29
75–77 °C (from hexane/CH2Cl2); ½aꢂD ¼ ꢀ36:7 (c 0.7,
þ24:5 (c 1.1, MeOH); IR (KBr) 3315, 2255, 1677 cmꢀ1
;
CHCl3); IR (KBr) 3323, 2255, 1677 cmꢀ1
;
1H NMR
1H NMR (500 MHz, CDCl3) d 0.89 (1H, d, J = 10.0 Hz),
1.04 (3H, s), 1.06 (3H, d, J = 7.3 Hz), 1.24 (3H, s), 1.64
(1H, ddd, J = 14.1, 6.4, 2.4 Hz), 1.84 (1H, m), 1.85 (1H,
br d, J = 6.4 Hz), 2.02 (1H, dtd, J = 8.3, 3.8, 2.4 Hz),
2.40 (3H, br d, J = 1.7 Hz), 2.46 (1H, dddd, J = 9.8, 7.2,
6.2, 2.3 Hz), 2.67 (1H, dddd, J = 13.9, 10.2, 3.7, 2.3 Hz),
4.32 (1H, m), 6.34 (1H, br d, J = 8.1 Hz), 7.28 (2H, br d,
J = 8.6 Hz), 7.50 (2H, br d, J = 8.4 Hz); 19F NMR
(470 MHz, CDCl3) d ꢀ140.73 (s); MS (EI) m/z 328 (M+).
Anal. Calcd for C20H25FN2O: C, 73.14; H, 7.67; N, 8.53.
Found: C, 73.28; H, 7.71; N, 8.58.
(500 MHz, CDCl3) d 0.84 (3H, d, J = 7.2 Hz), 0.87 (1H,
m), 0.88 (3H, d, J = 6.4 Hz), 0.91 (1H, m), 0.94 (3H, d,
J = 6.8 Hz), 1.12 (1H, qd, J = 12.4, 3.4 Hz), 1.18 (1H,
ddt, J = 12.1, 10.1, 2.6 Hz), 1.48 (1H, m), 1.72 (1H, m),
1.73 (1H, m), 1.89 (1H, m), 1.90 (1H, m), 2.39 (3H, d,
J = 1.7 Hz), 3.82 (1H, m), 6.15 (1H, br d, J = 6.0 Hz),
7.27 (2H, br d, J = 8.8 Hz), 7.48 (2H, br d, J = 8.5 Hz);
19F NMR (254 MHz, CDCl3) d ꢀ140.96 (s); MS (EI) m/z
331 (M++H). Anal. Calcd for C20H27FN2O: C, 72.70; H,
8.24; N, 8.48. Found: C, 72.90; H, 8.53; N, 8.35.
4.2.10. N-[(1R,2S,5R)-Menthyl]-(R)-2-cyano-2-fluoro-p-tol-
ylacetamide [(R)-CFTA amide of 7e]. Colorless needles;
4.2.14. N-[(1R,2S,3S)-Isopinocampheyl]-(R)-2-cyano-2-flu-
oro-p-tolylacetamide [(R)-CFTA amide of 7g]. Colorless
29
mp 163–165 °C (from hexane/CH2Cl2); ½aꢂD ¼ þ41:0 (c
needles; mp 111–113 °C (from hexane/CH2Cl2);
28
1
0.7, CHCl3); IR (KBr) 3318, 2257, 1674 cmꢀ1; H NMR
½aꢂD ¼ þ19:0 (c 1.0, MeOH); IR (KBr) 3276, 2253,
1
(500 MHz, CDCl3) d 0.69 (3H, d, J = 6.9 Hz), 0.86 (3H,
d, J = 6.9 Hz), 0.86 (1H, m), 0.92 (1H, m), 0.92 (3H, d,
J = 6.8 Hz), 1.08 (1H, qd, J = 12.8, 3.4 Hz), 1.17 (1H,
ddt, J = 11.9, 10.7, 3.0 Hz), 1.50 (1H, m), 1.68 (1H, m),
1.69 (1H, m), 1.74 (1H, m), 2.07 (1H, m), 2.40 (3H, d,
J = 0.9 Hz), 3.81 (1H, m), 6.14 (1H, br s), 7.28 (2H, br d,
1675 cmꢀ1; H NMR (500 MHz, CDCl3) d 0.88 (1H, d,
J = 10.0 Hz), 1.03 (3H, s), 1.18 (3H, d, J = 7.1 Hz), 1.24
(3H, s), 1.51 (1H, ddd, J = 14.1, 6.2, 2.4 Hz), 1.88 (1H,
m), 1.89 (1H, m), 1.97 (1H, dddd, J = 7.2, 6.3, 3.8,
2.4 Hz), 2.39 (3H, br d, J = 1.7 Hz), 2.45 (1H, dtd,
J = 9.8, 6.8, 2.4 Hz), 2.59 (1H, dddd, J = 13.9, 10.0, 3.7,

852
T. Fujiwara et al. / Tetrahedron: Asymmetry 19 (2008) 847–856
2.3 Hz), 4.32 (1H, dddd, J = 13.8, 11.8, 4.6, 3.4 Hz), 6.33
(1H, br s), 7.28 (2H, br d, J = 8.6 Hz), 7.50 (2H, br d,
J = 8.4 Hz); 19F NMR (470 MHz, CDCl3) d ꢀ141.67 (s);
MS (EI) m/z 328 (M+). Anal. Calcd for C20H25FN2O: C,
73.14; H, 7.67; N, 8.53. Found: C, 73.08; H, 7.45; N, 8.34.
4.2.19. N-[(S)-1-Phenylethyl]-(S)-2-cyano-2-fluoro-p-tolyl-
acetamide [(S)-CFTA amide of 7j]. Colorless needles;
27
mp 69–72 °C (from hexane/CH2Cl2); ½aꢂD ¼ ꢀ88:9 (c 1.2,
MeOH); IR (KBr) 3330, 2252, 1680 cmꢀ1 1H NMR
;
(500 MHz, CDCl3) d 1.62 (3H, d, J = 7.1 Hz), 2.37 (3H,
s), 5.16 (1H, quint, J = 7.1 Hz), 6.67 (1H, br s), 7.22 (2H,
br d, J = 7.9 Hz), 7.27 (2H, br d, J = 6.6 Hz), 7.31 (1H,
m), 7.35 (2H, m), 7.40 (2H, br d, J = 8.3 Hz); 19F NMR
(254 MHz, CDCl3) d ꢀ140.99 (s); MS (EI) m/z 297
(M++H), 296 (M+). Anal. Calcd for C18H17FN2O: C,
72.95; H, 5.78; N, 9.45. Found: C, 72.87; H, 5.52; N, 9.48.
4.2.15. N-[(2S)-1-Hydroxy-4-methylpentyl]-(S)-2-cyano-2-
fluoro-p-tolylacetamide [(S)-CFTA amide of 7h]. Colorless
26
needles; mp 77–79 °C (from hexane/CH2Cl2); ½aꢂD ¼ ꢀ14:8
1
(c 0.9, MeOH); IR (KBr) 3483, 3323, 2258, 1675 cmꢀ1; H
NMR (500 MHz, CDCl3) d 0.97 (6H, d, J = 6.6 Hz), 1.43
(1H, br ddd, J = 14.1, 8.1, 5.8 Hz), 1.53 (1H, br ddd,
J = 13.9, 9.0, 6.0 Hz), 1.68 (1H, m), 1.69–1.85 (1H, br s),
2.39 (3H, br s), 3.61 (1H, dd, J = 11.1, 5.1 Hz), 3.71 (1H,
dd, J = 11.1, 1.3 Hz), 4.14 (1H, m), 6.59 (1H, br d,
J = 6.7 Hz), 7.27 (2H, br d, J = 8.6 Hz), 7.53 (2H, br d,
J = 8.3 Hz); 19F NMR (254 MHz, CDCl3) d ꢀ140.29 (s);
MS (EI) m/z 293 (M++H), 291 (M+ꢀH), 277 (M+ꢀ15),
274 (M+ꢀ18); HRMS (EI) calcd for C16H21FN2O2 (M+):
292.1587; found: 292.1596.
4.2.20. N-[(S)-1-Phenylethyl]-(R)-2-cyano-2-fluoro-p-tolyl-
acetamide [(R)-CFTA amide of 7j]. Colorless needles;
26
mp 127–129 °C (from hexane/CH2Cl2); ½aꢂD ¼ ꢀ89:6 (c
1
1.6, MeOH); IR (KBr) 3328, 2252, 1676 cmꢀ1; H NMR
(500 MHz, CDCl3) d 1.54 (3H, d, J = 6.8 Hz), 2.40 (3H,
s), 5.16 (1H, dq, J = 7.1, 6.8 Hz), 6.68 (1H, br s), 7.29
(2H, br d, J = 7.9 Hz), 7.34 (2H, m), 7.39 (1H, m), 7.40
(2H, m), 7.51 (2H, br d, J = 8.1 Hz); 19F NMR
(254 MHz, CDCl3) d ꢀ142.27 (s); MS (EI) m/z 297
(M++H), 296 (M+). Anal. Calcd for C18H17FN2O: C,
72.95; H, 5.78; N, 9.45. Found: C, 72.97; H, 5.89; N, 9.31.
4.2.16. N-[(2S)-1-Hydroxy-4-methylpentyl]-(R)-2-cyano-2-
fluoro-p-tolylacetamide [(R)-CFTA amide of 7h]. Colorless
28
needles; mp 55–56 °C (from hexane/CH2Cl2); ½aꢂD ¼ ꢀ22:6
1
(c 0.9, MeOH); IR (KBr) 3483, 3326, 2258, 1679 cmꢀ1; H
4.2.21. N-[(S)-1-Naphthylethyl]-(S)-2-cyano-2-fluoro-p-tolyl-
acetamide [(S)-CFTA amide of 7k]. Colorless needles; mp
NMR (500 MHz, CDCl3) d 0.87 (3H, d, J = 6.4 Hz), 0.90
(3H, d, J = 6.4 Hz), 1.42 (1H, br ddd, J = 14.2, 8.1,
5.6 Hz), 1.49 (1H, br ddd, J = 14.6, 8.8, 5.6 Hz), 1.52
(1H, m), 1.76–1.96 (1H, br s), 2.40 (3H, br s), 3.68 (1H,
dd, J = 11.1, 4.3 Hz), 3.79 (1H, dd, J = 11.1, 3.8 Hz),
4.10 (1H, m), 6.64 (1H, br d, J = 7.2 Hz), 7.27 (2H, br d,
J = 7.9 Hz), 7.49 (2H, br d, J = 8.3 Hz); 19F NMR
(254 MHz, CDCl3) d ꢀ142.29 (s); MS (EI) m/z 274
(M+ꢀ18). Anal. Calcd for C16H21FN2O2: C, 65.73; H,
7.24; N, 9.58. Found: C, 65.95; H, 7.40; N, 9.33.
26
106–107 °C (from hexane/CH2Cl2); ½aꢂD ¼ þ23:6 (c 1.6,
MeOH); IR (KBr) 3303, 2250, 1679 cmꢀ1 1H NMR
;
(500 MHz, CDCl3) d 1.81 (3H, d, J = 6.8 Hz), 2.37 (3H,
d, J = 1.7 Hz), 5.94 (1H, dq, J = 7.1, 6.9 Hz), 6.69 (1H,
br s), 7.16 (2H, br d, J = 8.1 Hz), 7.37 (2H, br d,
J = 8.3 Hz), 7.39 (1H, ddd, J = 8.4, 7.0, 1.4 Hz), 7.47
(1H, dd, J = 7.6, 7.3 Hz), 7.50 (1H, ddd, J = 8.1, 6.9,
1.2 Hz), 7.52 (1H, br d, J = 8.1 Hz), 7.84 (1H, d,
J = 8.1 Hz), 7.85 (1H, d, J = 8.6 Hz), 7.88 (1H, br d,
J = 8.1 Hz); 19F NMR (254 MHz, CDCl3) d ꢀ141.19 (s);
MS (EI) m/z 346 (M+). Anal. Calcd for C22H19FN2O: C,
76.28; H, 5.53; N, 8.09. Found: C, 76.32; H, 5.26; N, 8.03.
4.2.17.
fluoro-p-tolylacetamide [(S)-CFTA amide of 7i]. Colorless
plates; mp 101–104 °C (from hexane/CH2Cl2);
½aꢂD ¼ ꢀ60:8 (c 0.8, MeOH); IR (KBr) 3393, 3327, 2266,
1689 cmꢀ1 1H NMR (500 MHz, CDCl3) d 1.79–1.99
N-[(1R)-2-Hydroxy-1-phenylethyl]-(S)-2-cyano-2-
28
4.2.22. N-[(S)-1-Naphthylethyl]-(R)-2-cyano-2-fluoro-p-tolyl-
acetamide [(R)-CFTA amide of 7k]. Colorless needles; mp
;
28
(1H, br s), 2.38 (3H, br s), 3.97 (1H, dd, J = 11.3,
4.7 Hz), 4.01 (1H, dd, J = 11.1, 4.1 Hz), 5.12 (1H, dt,
J = 7.5, 4.4 Hz), 7.24 (5H, m), 7.32 (1H, br t,
J = 6.8 Hz), 7.35 (2H, br t, J = 7.4 Hz), 7.44 (2H, br d,
J = 7.8 Hz); 19F NMR (254 MHz, CDCl3) d ꢀ142.12 (s);
MS (EI) m/z 294 (M+ꢀ18); HRMS (EI) calcd for
C18H17FN2O2 (M+): 312.1274; found: 312.1307.
146–148 °C (from hexane/CH2Cl2); ½aꢂD ¼ ꢀ38:6 (c 0.5,
MeOH); IR (KBr) 3274, 2250, 1665 cmꢀ1 1H NMR
;
(500 MHz, CDCl3) d 1.71 (3H, d, J = 6.8 Hz), 2.41 (3H,
d, J = 1.1 Hz), 5.96 (1H, dq, J = 7.1, 6.8 Hz), 6.74 (1H,
br d, J = 4.7 Hz), 7.29 (2H, d, J = 7.9 Hz), 7.49 (1H, t,
J = 7.8 Hz), 7.51 (2H, d, J = 9.0 Hz), 7.52 (1H, d,
J = 8.3 Hz), 7.54 (1H, m), 7.60 (1H, ddd, J = 8.4, 6.9,
1.5 Hz), 7.86 (1H, d, J = 8.1 Hz), 7.90 (1H, dd, J = 8.1,
0.6 Hz), 8.05 (1H, d, J = 8.6 Hz); 19F NMR (254 MHz,
CDCl3) d ꢀ142.21 (s); MS (EI) m/z 346 (M+). Anal. Calcd
for C22H19FN2O: C, 76.28; H, 5.53; N, 8.09. Found: C,
76.05; H, 5.52; N, 7.83.
4.2.18. N-[(1R)-2-Hydroxy-1-phenylethyl]-(R)-2-cyano-2-
fluoro-p-tolylacetamide [(R)-CFTA amide of 7i]. Pale yel-
low solid; mp 157–158 °C (from hexane/CH2Cl2);
26
½aꢂD ¼ ꢀ98:1 (c 1.2, MeOH); IR (KBr) 3468, 3278, 2240,
1697 cmꢀ1 1H NMR (500 MHz, CDCl3) d 1.77–1.90
;
(1H, br s), 2.41 (3H, br d, J = 1.5 Hz), 3.93 (2H, br s),
5.12 (1H, dt, J = 7.5, 4.7 Hz), 7.21 (1H, br s), 7.30 (2H,
br d, J = 8.0 Hz), 7.32 (2H, br d, J = 7.6 Hz), 7.36 (1H,
tt, J = 7.4, 1.5 Hz), 7.42 (2H, tt, J = 7.5, 1.3 Hz), 7.56
(2H, br d, J = 7.8 Hz); 19F NMR (254 MHz, CDCl3) d
ꢀ141.42 (s); MS (EI) m/z 294 (M+ꢀ18); HRMS (EI) calcd
for C18H18FN2O2 (M+ + H): 313.1352; found: 313.1389.
4.2.23. N-[(S)-1-(p-Nitrophenyl)ethyl]-(S)-2-cyano-2-fluoro-
p-tolylacetamide [(S)-CFTA amide of 7l]. Pale yellow oil;
28
½aꢂD ¼ ꢀ77:5 (c 1.1, MeOH); IR (neat) 3333, 2252,
1
1692 cmꢀ1; H NMR (500 MHz, CDCl3) d 1.64 (3H, d,
J = 7.1 Hz), 2.39 (3H, br s), 5.22 (1H, quint, J = 7.1 Hz),
6.75 (1H, br s), 7.25 (2H, m), 7.38 (4H, br d, J = 9.0 Hz),
8.17 (2H, br d, J = 8.8 Hz); 19F NMR (254 MHz, CDCl3)

T. Fujiwara et al. / Tetrahedron: Asymmetry 19 (2008) 847–856
853
d ꢀ143.36 (s); MS (EI) m/z 341 (M+); HRMS (EI) calcd for
4.2.29. N-[(R)-1-Methoxycarbonylpropyl]-( )-2-cyano-2-flu-
oro-p-tolylacetamide [( )-CFTA amide of 7o]. 1H NMR
(400 MHz, CDCl3) d 0.84 (3H, t, J = 7.6 Hz), 0.99 (3H, t,
J = 7.6 Hz), 1.77 (1H, ddq, J = 13.9, 7.6, 6.4 Hz), 1.85
(1H, ddq, J = 13.9, 7.6, 6.4 Hz), 1.94 (1H, ddq, J = 13.9,
7.6, 5.4 Hz), 2.03 (1H, ddq, J = 13.9, 7.6, 5.4 Hz), 2.39
(6H, s), 3.76 (3H, s), 3.81 (3H, s), 4.59 (1H, m), 4.61 (1H,
m), 7.03 (1H, br s), 7.08 (1H, br s), 7.28 (4H, d,
J = 7.8 Hz), 7.50 (2H, dd, J = 8.6, 1.2 Hz), 7.54 (2H, dd,
J = 8.3, 1.2 Hz); 19F NMR (376 MHz, CDCl3) d ꢀ140.84
(s), ꢀ143.84 (s).
C18H16FN3O3 (M+): 341.1176; found: 341.1147.
4.2.24.
N-[(S)-1-(p-Nitrophenyl)ethyl]-(R)-2-cyano-2-
fluoro-p-tolylacetamide [(R)-CFTA amide of 7l]. Colorless
27
needles; mp 139–142 °C (from hexane/CH2Cl2); ½aꢂD
¼
ꢀ118:9 (c 1.4, MeOH); IR (KBr) 3327, 2253, 1679 cmꢀ1
;
1H NMR (500 MHz, CDCl3) d 1.59 (3H, d, J = 7.1 Hz),
2.41 (3H, br s), 5.20 (1H, quint, J = 7.1 Hz), 6.73 (1H, br
s), 7.30 (2H, br d, J = 7.9 Hz), 7.50 (4H, m), 8.25 (2H, br
d, J = 9.0 Hz); 19F NMR (254 MHz, CDCl3) d ꢀ143.36
(s); MS (EI) m/z 341 (M+). Anal. Calcd for C18H16FN3O3:
C, 63.34; H, 4.72; N, 12.31. Found: C, 63.13; H, 4.69; N,
12.30.
4.2.30. N-[(S)-1-Methoxycarbonyl-2-methylpropyl]-(R)-2-
cyano-2-fluoro-p-tolylacetamide [(R)-CFTA amide of
25
7p]. Colorless oil; ½aꢂD ¼ þ2:8 (c 1.0, CHCl3); IR (neat)
4.2.25. N-[(R)-1-(p-Tolyl)ethyl]-(S)-2-cyano-2-fluoro-p-tolyl-
acetamide [(S)-CFTA amide of 7m]. Colorless prisms; mp
3341, 2967, 1746, 1705 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 0.87 (3H, d, J = 6.9 Hz), 0.88 (3H, d, J = 7.0 Hz), 2.20
(1H, septd, J = 6.9, 4.9 Hz), 2.40 (3H, br s), 3.80 (3H, s),
4.58 (1H, ddd, J = 8.8, 4.6, 1.2 Hz), 6.99 (1H, br d,
J = 5.2 Hz), 7.29 (2H, br d, J = 8.6 Hz), 7.51 (2H, br d,
J = 7.5 Hz); 19F NMR (254 MHz, CDCl3) d ꢀ144.58 (s);
MS (EI) m/z 306 (M+); HRMS (EI) calcd for
C16H19FN2O3 (M+): 306.1380; found: 306.1407.
26
177–178 °C (from hexane/CH2Cl2); ½aꢂD ¼ þ119:3 (c 1.1,
MeOH); IR (KBr) 3328, 2257, 1676 cmꢀ1 1H NMR
;
(500 MHz, CDCl3) d 1.53 (3H, d, J = 6.8 Hz), 2.36 (3H,
s), 2.37 (3H, d, J = 0.9 Hz), 5.12 (1H, quint, J = 6.8 Hz),
6.62 (1H, br s), 7.20 (2H, d, J = 8.3 Hz), 7.24 (2H, d,
J = 8.3 Hz), 7.29 (2H, d, J = 7.9 Hz), 7.51 (2H, d,
J = 8.3 Hz); 19F NMR (254 MHz, CDCl3) d ꢀ142.15 (s);
MS (EI) m/z 310 (M+). Anal. Calcd for C19H19FN2O: C,
73.53; H, 6.17; N, 9.03. Found: C, 73.55; H, 5.92; N, 8.87.
4.2.31. N-[(S)-1-Methoxycarbonyl-2-methylpropyl]-( )-2-
cyano-2-fluoro-p-tolylacetamide [( )-CFTA amide of
7p]. 1H NMR (400 MHz, CDCl3) d 0.86 (3H, d,
J = 7.1 Hz), 0.88 (3H, d, J = 7.1 Hz), 0.98 (3H, d,
J = 6.9 Hz), 1.02 (3H, d, J = 6.9 Hz), 2.20 (1H, m), 2.31
(1H, m), 2.39 (6H, s), 3.76 (3H, s), 3.81 (3H, s), 4.57 (1H,
ddd, J = 8.9, 4.4, 1.5 Hz), 4.58 (1H, ddd, J = 8.8, 4.4,
1.2 Hz), 7.00 (2H, br s), 7.28 (4H, d, J = 7.1 Hz), 7.51
(2H, d, J = 7.6 Hz), 7.53 (2H, dd, J = 7.6, 1.5 Hz); 19F
NMR (254 MHz, CDCl3) d ꢀ140.95 (s), ꢀ144.58 (s).
4.2.26. N-[(S)-1-Methoxycarbonylethyl]-(R)-2-cyano-2-flu-
oro-p-tolylacetamide [(R)-CFTA amide of 7n]. Colorless
25
needles; mp 111 °C (from hexane/CHCl3); ½aꢂD ¼ þ1:2 (c
1.0, CHCl3); IR (KBr) 3358, 3006, 2959, 1744,
1
1684 cmꢀ1; H NMR (400 MHz, CDCl3) d 1.44 (3H, d,
J = 7.1 Hz), 2.39 (3H, d, J = 1.2 Hz), 3.82 (3H, s), 4.62
(1H, dqd, J = 7.1, 1.7, 1.0 Hz), 7.15 (1H, br s), 7.28 (2H,
br d, J = 8.1 Hz), 7.49 (2H, br d, J = 8.5 Hz); 19F NMR
(254 MHz, CDCl3) d ꢀ143.16 (s); MS (EI) m/z 278 (M+).
Anal. Calcd for C14H15FN2O3: C, 60.42; H, 5.43; N,
10.07. Found: C, 60.15; H, 5.52; N, 10.04.
4.2.32. N-[(S)-1-Methoxycarbonyl-2,2-dimethylpropyl]-(R)-
2-cyano-2-fluoro-p-tolylacetamide [(R)-CFTA amide of
25
7q]. Colorless oil; ½aꢂD ¼ ꢀ15:4 (c 1.0, CHCl3); IR (neat)
3422, 3353, 3100–2800, 1742, 1713 cmꢀ1
;
1H NMR
4.2.27. N-[(S)-1-Methoxycarbonylethyl]-( )-2-cyano-2-flu-
oro-p-tolylacetamide [( )-CFTA amide of 7n]. 1H NMR
(400 MHz, CDCl3) d 1.45 (3H, d, J = 7.1 Hz), 1.54 (3H,
d, J = 7.1 Hz), 2.39 (6H, d, J = 2.0 Hz), 3.77 (3H, s), 3.82
(3H, s), 4.61 (1H, ddq, J = 7.1, 1.6, 1.3 Hz), 4.63 (1H,
ddq, J = 7.1, 1.6, 1.3 Hz), 7.06 (1H, br s), 7.15 (1H, br s),
7.28 (4H, d, J = 8.1 Hz), 7.50 (2H, dd, J = 8.3, 1.0 Hz),
7.54 (2H, dd, J = 8.3, 1.5 Hz); 19F NMR (254 MHz,
CDCl3) d ꢀ140.73 (s), ꢀ143.16 (s).
(400 MHz, CDCl3) d 0.91 (9H, s), 2.39 (3H, br s), 3.79
(3H, s), 4.46 (1H, dd, J = 9.5, 1.4 Hz), 6.99 (1H, br d,
J = 5.4 Hz), 7.29 (2H, br d, J = 8.6 Hz), 7.51 (2H, br d,
J = 7.8 Hz); 19F NMR (376 MHz, CDCl3) dꢀ145.76 (s);
MS (EI) m/z 320 (M+). Anal. Calcd for C17H21FN2O3:
C, 63.74; H, 6.61; N, 8.74. Found: C, 63.47; H, 6.70; N,
8.68.
4.2.33. N-[(S)-1-Methoxycarbonyl-2,2-dimethylpropyl]-( )-
2-cyano-2-fluoro-p-tolylacetamide [( )-CFTA amide of
7q]. 1H NMR (270 MHz, CDCl3) d 0.91 (9H, s), 1.05
(9H, s), 2.39 (6H, s), 3.74 (3H, s), 3.80 (3H, s), 4.45 (1H,
dd, J = 9.2, 1.4 Hz), 4.47 (1H, dd, J = 9.2, 1.6 Hz), 7.00
(2H, br d, J = 6.2 Hz), 7.28 (4H, d, J = 8.6 Hz), 7.50
(2H, d, J = 7.8 Hz), 7.51 (2H, d, J = 8.1 Hz); 19F NMR
(376 MHz, CDCl3) d ꢀ141.68 (s), ꢀ145.75 (s).
4.2.28.
N-[(R)-1-Methoxycarbonylpropyl]-(R)-2-cyano-2-
fluoro-p-tolylacetamide [(R)-CFTA amide of 7o]. Colorless
25
needles; mp 71 °C (from hexane/Et2O); ½aꢂD ¼ þ0:8 (c 1.0,
1
CHCl3); IR (KBr) 3346, 3100–2800, 1757, 1686 cmꢀ1; H
NMR (400 MHz, CDCl3) d 0.99 (3H, t, J = 7.6 Hz), 1.86
(1H, dqd, J = 14.7, 7.6, 7.3 Hz), 2.02 (1H, dqd, J = 14.9,
7.6, 5.1 Hz), 2.39 (3H, d, J = 2.0 Hz), 3.77 (3H, s), 4.59
(1H, dddd, J = 7.8, 6.8, 5.4, 1.5 Hz), 7.01 (1H, br d,
J = 3.6 Hz), 7.28 (2H, br d, J = 8.2 Hz), 7.53 (2H, dq,
J = 8.3, 1.5 Hz); 19F NMR (376 MHz, CDCl3) d ꢀ140.84
(s); MS (EI) m/z 292 (M+). Anal. Calcd for C15H17FN2O3:
C, 61.63; H, 5.86; N, 9.58. Found: C, 61.33; H, 6.01; N,
9.57.
4.2.34. N-[(S)-1-Methoxycarbonyl-3-methylbutyl]-(R)-2-
cyano-2-fluoro-p-tolylacetamide [(R)-CFTA amide of
7r]. Colorless crystals; mp 62 °C (from hexane/Et2O);
25
½aꢂD ¼ ꢀ1:1 (c 1.0, CHCl3); IR (KBr) 3337, 2959, 1750,
1
1700 cmꢀ1; H NMR (400 MHz, CDCl3) d 0.88 (3H, d,
J = 6.1 Hz), 0.90 (3H, d, J = 6.3 Hz), 1.53 (1H, m), 1.59

854
T. Fujiwara et al. / Tetrahedron: Asymmetry 19 (2008) 847–856
(1H, ddd, J = 13.8, 8.8, 6.1 Hz), 1.70 (1H, ddd, J = 13.9,
8.3, 5.6 Hz), 2.40 (3H, d, J = 1.5 Hz), 3.80 (3H, s), 4.66
(1H, dddd, J = 8.6, 8.3, 5.6, 1.5 Hz), 6.90 (1H, br d,
J = 5.4 Hz), 7.28 (2H, br d, J = 8.6 Hz), 7.49 (2H, dq,
J = 8.6, 1.0 Hz); 19F NMR (376 MHz, CDCl3) d ꢀ143.76
(s); MS (EI) m/z 320 (M+). Anal. Calcd for C17H21FN2O3:
C, 63.74; H, 6.61; N, 8.74. Found: C, 63.58; H, 6.74; N,
8.75.
4.4, 0.7 Hz), 4.88 (1H, dtd, J = 8.7, 4.4, 1.5 Hz), 5.10
(2H, s), 5.17 (2H, s), 7.20 (2H, d, J = 8.6 Hz), 7.27–7.39
(12H, m), 7.43 (2H, dd, J = 8.6, 1.2 Hz), 7.55 (1H, br s),
7.56 (2H, dd, J = 8.3, 1.5 Hz), 7.61 (1H, br s); 19F NMR
(376 MHz, CDCl3) d ꢀ140.82 (s), ꢀ143.34 (s).
4.2.40. N-[(S)-3-Ethoxycarbonyl-1-methoxycarbonylpropyl]-
(R)-2-cyano-2-fluoro-p-tolylacetamide [(R)-CFTA amide of
25
7u]. Colorless oil; ½aꢂD ¼ þ2:7 (c 1.0, CHCl3); IR (neat)
1
4.2.35.
N-[(S)-1-Methoxycarbonyl-3-methylbutyl]-( )-2-
3337, 3100–2800, 1738, 1705 cmꢀ1; H NMR (400 MHz,
cyano-2-fluoro-p-tolylacetamide [( )-CFTA amide of
7r]. 1H NMR (400 MHz, CDCl3) d 0.88 (3H, d,
J = 6.4 Hz), 0.90 (3H, d, J = 6.4 Hz), 0.99 (3H, d,
J = 6.1 Hz), 1.00 (3H, d, J = 5.9 Hz), 1.48–1.81 (6H, m),
2.39 (6H, s), 3.74 (3H, s), 3.80 (3H, s), 4.63–4.68 (2H, m),
6.89 (2H, br s), 7.28 (4H, d, J = 8.1 Hz), 7.49 (2H, d,
J = 8.1 Hz), 7.54 (2H, d, J = 7.1 Hz); 19F NMR
(376 MHz, CDCl3) d ꢀ140.06 (s), ꢀ143.76 (s).
CDCl3) d 1.23 (3H, t, J = 6.8 Hz), 2.08 (1H, ddd,
J = 14.2, 8.3, 7.3 Hz), 2.22 (1H, m), 2.27–2.38 (2H, m),
2.40 (3H, br s), 3.80 (3H, s), 4.09 (1H, qd, J = 6.8,
3.7 Hz), 4.12 (1H, qd, J = 6.8, 3.2 Hz), 4.61 (1H, m), 7.28
(2H, br d, J = 8.0 Hz), 7.42 (1H, br d, J = 5.8 Hz), 7.51
(2H, br d, J = 7.6 Hz); 19F NMR (376 MHz, CDCl3) d
ꢀ144.77 (s); MS (EI) m/z 364 (M+). Anal. Calcd for
C18H21FN2O5: C, 59.33; H, 5.81; N, 7.69. Found: C,
59.14; H, 5.81; N, 7.69.
4.2.36. N-[(S)-1-Methoxycarbonyl-4-thiapentyl]-(R)-2-
cyano-2-fluoro-p-tolylacetamide [(R)-CFTA amide of 7s].
4.2.41. N-[(S)-3-Ethoxycarbonyl-1-methoxycarbonylpropyl]-
( )-2-cyano-2-fluoro-p-tolylacetamide [( )-CFTA amide of
25
Colorless oil; ½aꢂD ¼ þ21:7 (c 1.0, CHCl3); IR (neat) 3335,
3100–2800, 1748, 1705 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 2.01 (3H, s), 2.05 (1H, m), 2.17 (1H, m), 2.40 (3H, br s),
2.40 (2H, m), 3.82 (3H, s), 4.74 (1H, br dd, J = 6.4, 5.2 Hz),
7.28 (3H, br d, J = 8.3 Hz), 7.50 (2H, br d, J = 7.7 Hz); 19F
NMR (254 MHz, CDCl3) d ꢀ145.15 (s); MS (EI) m/z
338 (M+); HRMS (EI) calcd for C16H19FN2O3S (M+):
338.1100; found: 338.1117.
7u]. 1H NMR (400 MHz, CDCl3)
d 1.23 (3H, t,
J = 7.1 Hz), 1.28 (3H, t, J = 7.1 Hz), 2.08 (1H, m), 2.17
(1H, m), 2.21 (1H, m), 2.29 (1H, m), 2.31 (1H, m), 2.35
(1H, m), 2.39 (6H, s), 2.45 (1H, m), 2.50 (1H, ddd,
J = 17.0, 7.3, 7.1 Hz), 3.75 (3H, s), 3.80 (3H, s), 4.10 (2H,
dq, J = 7.1, 2.9 Hz), 4.18 (2H, q, J = 7.1 Hz), 4.61 (1H,
m), 4.62 (1H, m), 7.28 (4H, d, J = 8.7 Hz), 7.44 (1H, br
s), 7.51 (2H, d, J = 8.1 Hz), 7.55 (2H, dd, J = 8.2,
1.2 Hz), 7.55 (1H, br s); 19F NMR (376 MHz, CDCl3) d
ꢀ140.51 (s), ꢀ144.77 (s).
4.2.37.
N-[(S)-1-Methoxycarbonyl-4-thiapentyl]-( )-2-
cyano-2-fluoro-p-tolylacetamide [( )-CFTA amide of
7s]. 1H NMR (400 MHz, CDCl3) d 2.01 (3H, s), 2.07
(1H, m), 2.13 (3H, s), 2.14 (1H, m), 2.19 (1H, m), 2.27
(1H, dtd, J = 14.4, 7.3, 5.1 Hz), 2.38 (1H, m), 2.39 (6H,
s), 2.41 (1H, m), 2.56 (1H, m), 2.60 (1H, m), 3.77 (3H, s),
3.82 (3H, s), 4.74 (1H, m), 4.76 (1H, m), 7.27–7.29 (5H,
m), 7.36 (1H, br s), 7.51 (2H, d, J = 7.6 Hz), 7.54 (2H,
dd, J = 8.3, 1.2 Hz); 19F NMR (254 MHz, CDCl3) d
ꢀ141.15 (s), ꢀ145.15 (s).
4.2.42. N-[(1S,2R)-1-Methoxycarbonyl-2-benzyloxypropyl]-
(R)-2-cyano-2-fluoro-p-tolylacetamide [(R)-CFTA amide of
25
7v]. Colorless oil; ½aꢂD ¼ þ9:3 (c 1.0, CHCl3); IR (neat)
3548, 3434, 3100–2800, 1752, 1713 cmꢀ1
;
1H NMR
(400 MHz, CDCl3) d 1.09 (3H, d, J = 6.4 Hz), 2.39 (3H,
br s), 3.71 (3H, s), 4.16 (1H, qd, J = 6.4, 1.2 Hz), 4.37
(1H, d, J = 12.0 Hz), 4.57 (1H, d, J = 11.7 Hz), 4.61 (1H,
ddd, J = 9.1, 2.2, 1.3 Hz), 7.18 (1H, br d, J = 7.1 Hz),
7.21–7.28 (4H, m), 7.29–7.38 (3H, m), 7.53 (2H, d,
J = 6.6 Hz); 19F NMR (376 MHz, CDCl3) d ꢀ144.63 (s);
MS (EI) m/z 398 (M+); HRMS (EI) calcd for
C22H23FN2O4 (M+): 398.1642; found: 398.1670.
4.2.38. N-[(S)-2-Benzyloxycarbonyl-1-methoxycarbonyleth-
yl]-(R)-2-cyano-2-fluoro-p-tolylacetamide [(R)-CFTA amide
25
of 7t]. Colorless oil; ½aꢂD ¼ þ48:1 (c 1.0, CHCl3); IR
(neat) 3350, 3100–2800, 1744, 1709 cmꢀ1
;
1H NMR
(400 MHz, CDCl3) d 2.36 (3H, d, J = 1.1 Hz), 2.88 (1H,
dd, J = 17.1, 4.7 Hz), 2.99 (1H, dd, J = 17.1, 4.2 Hz),
3.77 (3H, s), 4.83 (1H, br ddd, J = 7.8, 4.7, 4.2 Hz), 5.10
(2H, s), 7.21 (2H, d, J = 8.3 Hz), 7.31 (2H, m), 7.35 (3H,
m), 7.42 (2H, br d, J = 8.3 Hz), 7.54 (1H, br d,
J = 6.0 Hz); 19F NMR (376 MHz, CDCl3) d ꢀ143.34 (s);
MS (EI) m/z 412 (M+). Anal. Calcd for C22H21FN2O5:
C, 64.07; H, 5.13; N, 6.79. Found: C, 63.71; H, 5.40; N,
6.69.
4.2.43. N-[(1S,2R)-1-Methoxycarbonyl-2-benzyloxypropyl]-
( )-2-cyano-2-fluoro-p-tolylacetamide [( )-CFTA amide of
7v]. 1H NMR (400 MHz, CDCl3) d 1.09 (3H, d,
J = 6.4 Hz), 1.31 (3H, d, J = 6.4 Hz), 2.39 (6H, s), 3.64
(3H, s), 3.71 (3H, s), 4.16 (1H, dq, J = 6.4, 2.2 Hz), 4.23
(1H, dq, J = 6.4, 2.2 Hz), 4.37 (1H, d, J = 12.0 Hz), 4.40
(1H, d, J = 12.0 Hz), 4.56 (1H, d, J = 12.0 Hz), 4.61 (1H,
m), 4.62 (1H, m), 4.62 (1H, d, J = 12.0 Hz), 7.19 (1H, br
s), 7.22–7.37 (15H, m), 7.53 (2H, d, J = 7.6 Hz), 7.59
(2H, dd, J = 8.3, 1.5 Hz); 19F NMR (376 MHz, CDCl3) d
ꢀ138.67 (s), ꢀ144.63 (s).
4.2.39. N-[(S)-2-Benzyloxycarbonyl-1-methoxycarbonyleth-
yl]-( )-2-cyano-2-fluoro-p-tolylacetamide [( )-CFTA amide
of 7t]. 1H NMR (400 MHz, CDCl3) d 2.36 (3H, d,
J = 1.5 Hz), 2.39 (3H, d, J = 2.0 Hz), 2.88 (1H, dd,
J = 17.1, 4.4 Hz), 2.96 (1H, dd, J = 17.7, 4.4 Hz), 3.10
(1H, dd, J = 17.2, 4.4 Hz), 3.20 (1H, dd, J = 17.5,
4.4 Hz), 3.70 (3H, s), 3.77 (3H, s), 4.83 (1H, dtd, J = 7.8,
4.2.44. N-[(S)-1-Methoxycarbonyl-2-phenylethyl]-(R)-2-
cyano-2-fluoro-p-tolylacetamide [(R)-CFTA amide of
7w]. Colorless needles; mp 151 °C (from hexane/CHCl3);
25
½aꢂD ¼ ꢀ41:2 (c 1.0, CHCl3); IR (KBr) 3252, 3100–2900,

T. Fujiwara et al. / Tetrahedron: Asymmetry 19 (2008) 847–856
855
2359, 1750, 1698, 1684 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 2.41 (3H, d, J = 1.0 Hz), 3.07 (1H, dd, J = 14.2, 6.6 Hz),
3.19 (1H, dd, J = 14.0, 5.4 Hz), 3.81 (3H, s), 4.91 (1H,
dddd, J = 6.6, 6.4, 5.4, 1.0 Hz), 6.91 (3H, m), 7.17–7.27
(5H, m), 7.29 (2H, br d, J = 8.3 Hz); 19F NMR
(254 MHz, CDCl3) d ꢀ145.00 (s); MS (EI) m/z 354 (M+),
353 (M+ ꢀ 1). Anal. Calcd for C20H19FN2O3: C, 67.79;
H, 5.40; N, 7.91. Found: C, 67.56; H, 5.61; N, 7.91.
MHz, CDCl3) d ꢀ143.16 (s); MS (EI) m/z 335 (M++H),
334 (M+); HRMS (EI) calcd for C18H23FN2O3 (M+):
334.1693; found: 334.1687.
4.2.49.
N-[(S)-1-Methoxycarbonyl-4-methylpentyl]-( )-2-
cyano-2-fluoro-p-tolylacetamide [( )-CFTA amide of
7y]. 1H NMR (400 MHz, CDCl3) d 0.86 (3H, d,
J = 6.4 Hz), 0.87 (3H, d, J = 6.4 Hz), 0.94 (3H, d,
J = 6.4 Hz), 0.96 (3H, d, J = 6.4 Hz), 1.35 (1H, m), 1.38
(1H, m), 1.47 (1H, m), 1.56 (1H, m), 1.63 (2H, m), 2.39
(6H, s), 2.51 (1H, dd, J = 16.1, 5.4 Hz), 2.56 (1H, dd,
J = 16.1, 4.9 Hz), 2.59 (1H, dd, J = 16.4, 4.6 Hz), 2.68
(1H, dd, J = 16.4, 4.9 Hz), 3.64 (3H, s), 3.72 (3H, s), 4.33
(1H, m), 4.35 (1H, m), 7.09 (1H, br s), 7.21 (1H, br s),
7.25–7.28 (4H, m), 7.48–7.50 (4H, m); 19F NMR
(376 MHz, CDCl3) d ꢀ143.11 (s), ꢀ143.30 (s).
4.2.45.
N-[(S)-1-Methoxycarbonyl-2-phenylethyl]-( )-2-
cyano-2-fluoro-p-tolylacetamide [( )-CFTA amide of
7w]. 1H NMR (400 MHz, CDCl3) d 2.38 (3H, d,
J = 1.7 Hz), 2.41 (3H, d, J = 1.2 Hz), 3.07 (1H, dd,
J = 14.2, 6.6 Hz), 3.20 (1H, dd, J = 14.2, 5.4 Hz), 3.20
(1H, dd, J = 14.2, 5.6 Hz), 3.26 (1H, dd, J = 14.2,
5.9 Hz), 3.76 (3H, s), 3.81 (3H, s), 4.87 (1H, dtd, J = 8.1,
5.6, 1.5 Hz), 4.92 (1H, dddd, J = 7.8, 6.6, 5.6, 1.2 Hz),
6.91 (4H, m), 7.11 (2H, dd, J = 7.6, 1.2 Hz), 7.18–7.36
(12H, m), 7.48 (2H, dd, J = 8.3, 1.2 Hz); 19F NMR
(254 MHz, CDCl3) d ꢀ141.42 (s), ꢀ145.00 (s).
4.2.50. N-[(S)-1-(Methoxycarbonyl-a-13C)ethyl-2-d3-13C2]-
(S)-2-cyano-2-fluoro-p-tolylacetamide-15N [(S)-CFTA amide
of 9a]. Colorless needles; mp 78–79 °C (from hexane/
26
CHCl3); ½aꢂD ¼ ꢀ14:6 (c 0.9, CHCl3); IR (film) 3337,
4.2.46. N-[(S)-1-Methoxycarbonyl-2-(3-indolyl)ethyl]-(R)-2-
cyano-2-fluoro-p-tolylacetamide [(R)-CFTA amide of 7x].
2228, 1701, 1655 cmꢀ1 1H NMR (500 MHz, CDCl3) d
;
2.39 (3H, s), 3.77 (3H, d, J = 3.8 Hz), 4.60 (1H, dd,
25
Colorless crystals; mp 128 °C (from hexane/CHCl3); ½aꢂD
¼
J = 144.2, 5.8 Hz), 7.06 (1H, dd, J = 93.6, 6.4 Hz), 7.28
2
þ51:8 (c 1.0, CHCl3); IR (KBr) 3397, 3316, 3100–2900,
(2H, d, J = 7.7 Hz), 7.54 (2H, d, J = 8.5 Hz); D NMR
1738, 1684 cmꢀ1 1H NMR (400 MHz, CDCl3) d 2.38
;
(61 MHz, CHCl3) d 1.51 (d, J = 19.8 Hz); 19F NMR
(254 MHz, CDCl3) d ꢀ140.69 (s); MS (EI) m/z 285 (M+);
HRMS (ESI) calcd for C1113C3H13D3FN15NO3 (M++H):
286.1404; found: 286.1399.
(3H, br s), 3.33 (2H, d, J = 5.9 Hz), 3.75 (3H, s), 4.95
(1H, br dt, J = 7.8, 5.9 Hz), 6.81 (1H, d, J = 2.5 Hz),
6.99 (1H, br d, J = 5.8 Hz), 7.06 (1H, br dd, J = 8.1,
7.1 Hz), 7.16 (2H, br d, J = 7.8 Hz), 7.20 (1H, t, J =
7.1 Hz), 7.28 (2H, br d, J = 8.3 Hz), 7.34 (1H, d, J =
8.0 Hz), 7.39 (1H, d, J = 8.1 Hz), 8.05 (1H, br s); 19F
NMR (376 MHz, CDCl3) d ꢀ144.80 (s); MS (EI) m/z 393
(M+). Anal. Calcd for C22H20FN3O3: C, 67.17; H, 5.12;
N, 10.68. Found: C, 67.21; H, 5.40; N, 10.65.
4.2.51. N-[(S)-1-(Methoxycarbonyl-a-13C)ethyl-2-d3-13C2]-
(R)-2-cyano-2-fluoro-p-tolylacetamide-15N [(R)-CFTA amide
of 9a]. Colorless needles; mp 112–113 °C (from hexane/
28
CHCl3); ½aꢂD ¼ þ0:3 (c 0.9, CHCl3); IR (film) 3348, 2257,
1700, 1647 cmꢀ1 1H NMR (500 MHz, CDCl3) d 2.40
;
(3H, s), 3.82 (3H, d, J = 3.8 Hz), 4.61 (1H, dd, J = 144.0,
4.2.47.
N-[(S)-1-Methoxycarbonyl-2-(3-indolyl)ethyl]-
5.6 Hz), 7.16 (1H, dd, J = 93.3, 5.3 Hz), 7.28 (2H, d,
2
( )-2-cyano-2-fluoro-p-tolylacetamide [( )-CFTA amide of
7x]. 1H NMR (400 MHz, CDCl3) d 2.36 (3H, d,
J = 1.5 Hz), 2.38 (3H, s), 3.33 (2H, d, J = 5.6 Hz), 3.44
(2H, d, J = 5.4 Hz), 3.71 (3H, s), 3.75 (3H, s), 4.93 (1H,
m), 4.95 (1H, m), 6.80 (1H, d, J = 2.0 Hz), 6.99 (1H, br
s), 7.02 (1H, d, J = 2.2 Hz), 7.05 (1H, br s), 7.06 (1H, dd,
J = 8.1, 7.1 Hz), 7.16 (1H, dd, J = 7.6, 7.1 Hz), 7.17 (2H,
d, J = 7.8 Hz), 7.20 (1H, dd, J = 7.8, 7.1 Hz), 7.22 (1H,
dd, J = 7.8, 7.1 Hz), 7.23 (2H, d, J = 7.6 Hz), 7.29 (2H,
d, J = 7.8 Hz), 7.35 (1H, d, J = 7.8 Hz), 7.37 (1H, d,
J = 7.8 Hz), 7.40 (1H, d, J = 8.1 Hz), 7.48 (2H, d,
J = 7.6 Hz), 7.55 (1H, d, J = 7.6 Hz), 8.04 (1H, br s),
8.16 (1H, br s); 19F NMR (376 MHz, CDCl3) d ꢀ140.40
(s), ꢀ144.80 (s).
J = 8.1 Hz), 7.50 (2H, d, J = 8.1 Hz); D NMR (61 MHz,
CHCl3) d 1.42 (d, J = 20.1 Hz); 19F NMR (254 MHz,
CDCl3) d ꢀ143.17 (s); MS (EI) m/z 285 (M+); HRMS
(ESI) calcd for C1113C3H13D3FN15NO3 (M++H):
286.1404; found: 286.1399.
4.2.52. N-[(S)-1-(Methoxycarbonyl-a-13C)2-methyl-d3-pro-
pyl-3-d3-1-13C]-(S)-2-cyano-2-fluoro-p-tolylacetamide-15N
[(S)-CFTA amide of 9b]. Colorless oil; IR (neat) 3345,
2224, 1698 cmꢀ1 1H NMR (500 MHz, CDCl3) d 2.27
;
(1H, s), 2.39 (3H, d, J = 1.3 Hz), 3.76 (3H, d,
J = 3.8 Hz), 4.56 (1H, dddddd, J = 144.0, 9.0, 6.4, 4.5,
1.7, 1.2 Hz), 7.00 (1H, ddddd, J = 92.7, 9.0, 3.0, 1.3,
1.2 Hz), 7.28 (2H, d, J = 7.7 Hz), 7.53 (2H, d,
2
J = 6.8 Hz); D NMR (61 MHz, CHCl3) d 0.99 (s); 19F
4.2.48. N-[(S)-1-Methoxycarbonyl-4-methylpentyl]-(S)-2-
cyano-2-fluoro-p-tolylacetamide [(S)-CFTA amide of 7y].
NMR (254 MHz, CDCl3) d ꢀ140.94 (s); HRMS (ESI)
calcd for C1413C2H13D6FN15NNaO3 (M+Na+): 338.1691;
found: 338.1686.
Colorless needles; mp 95–96 °C (from hexane/CHCl3);
27
½aꢂD ¼ ꢀ42:2 (c 0.91, CHCl3); IR (KBr) 3316, 3073, 2251,
1737, 1681 cmꢀ1
;
1H NMR (270 MHz, CDCl3) d 0.95
4.2.53. N-[(S)-1-(Methoxycarbonyl-a-13C)2-methyl-d3-pro-
pyl-3-d3-1-13C]-(R)-2-cyano-2-fluoro-p-tolylacetamide-15N
[(R)-CFTA amide of 9b]. Colorless oil; IR (neat) 3333,
(3H, d, J = 6.2 Hz), 0.96 (3H, d, J = 6.2 Hz), 1.38 (1H,
m), 1.55–1.69 (2H, m), 2.39 (3H, s), 2.51 (1H, dd, J =
16.2, 4.9 Hz), 2.56 (1H, dd, J = 16.2, 4.9 Hz), 3.64 (3H,
s), 4.34 (1H, m), 7.09 (1H, br d, J = 5.9 Hz), 7.26 (2H, d,
J = 7.8 Hz), 7.50 (2H, d, J = 8.1 Hz); 19F NMR (254
2224, 1698 cmꢀ1 1H NMR (500 MHz, CDCl3) d 2.16
;
(1H, s), 2.40 (3H, d, J = 0.9 Hz), 3.81 (3H, d,
J = 3.8 Hz), 4.46 (1H, ddddt, J = 144.0, 9.8, 8.5, 4.7,

856
T. Fujiwara et al. / Tetrahedron: Asymmetry 19 (2008) 847–856
´
6. Seco, J. M.; Latypov, S. K.; Quinoa, E.; Riguera, R. J. Org.
˜
1.3 Hz), 7.00 (1H, dddt, J = 92.7, 8.5, 3.4, 1.7 Hz),
7.29 (2H, d, J = 8.1 Hz), 7.51 (2H, d, J = 7.7 Hz); 2D
NMR (61 MHz, CHCl3) d 0.83 (s); 19F NMR (254 MHz,
Chem. 1997, 62, 7569–7574.
7. Takeuchi, Y.; Segawa, M.; Fujisawa, H.; Omata, K.; Lodwig,
S. N.; Unkefer, C. J. Angew. Chem., Int. Ed. 2006, 45, 4617–
4619.
8. Takeuchi, Y.; Itoh, N.; Note, H.; Koizumi, T.; Yamaguchi,
K. J. Am. Chem. Soc. 1991, 113, 6318–6320.
CDCl3)
d
ꢀ144.58 (s); HRMS (ESI) calcd for
C1413C2H13D6FN15NNaO3 (M+Na+): 338.1691; found:
338.1686.
9. Takeuchi, Y.; Itoh, N.; Koizumi, T. J. Chem. Soc.,
Chem. Commun. 1992, 1514–1515, see also: Chem. Ind.
1992, 874.
11. (a) Takeuchi, Y.; Konishi, M.; Hori, H.; Takahashi, T.; Kirk,
K. L. Enantiomer 1999, 4, 339–344; (b) Takahashi, T.;
Fukushima, A.; Taraka, Y.; Tekeuchi, Y.; Kabuto, K.;
Kabuto, C. Chem. Commun. 2000, 788–790.
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