Phase transfer catalyzed asymmetric alkylations of imine glycinamides

Article abstract of DOI:10.1016/S0957-4166(03)00441-5

Herein we report the use of achiral imine glycinamides as substrates for asymmetric alkylations using chiral phase-transfer catalysts for the first time. Initially tried for obtaining a key intermediate for the synthesis of levobupivacaine, we expanded th

Full text of DOI:10.1016/S0957-4166(03)00441-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 2539–2545
Phase transfer catalyzed asymmetric alkylations of imine
glycinamides
Sanjeev Kumar and Uma Ramachandran*
Department of Pharmaceutical Technology, National Institute of Pharmaceutical Education & Research (NIPER) Sector-67,
Mohali, Punjab 160 062, India
Received 22 April 2003; accepted 28 May 2003
Abstract—Herein we report the use of achiral imine glycinamides as substrates for asymmetric alkylations using chiral
phase-transfer catalysts for the first time. Initially tried for obtaining a key intermediate for the synthesis of levobupivacaine, we
expanded the study to other N-mono and N,N-disubstituted imine glycinamides. A possible explanation for the lower
enantioselectivity observed in the case of alkylation of N-monosubstituted as compared to N,N-disubstituted glycinamides is also
provided.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
versions of other anesthetics like ropivacaine12 2c and
mepivacaine 2d,13 which have propyl and methyl
attached to nitrogen, respectively.
Phase transfer catalysis (PTC) is a synthetic methodol-
ogy that has gained importance due to its simplicity
and suitability for scale-up. This methodology has been
successfully employed especially in the synthesis of both
natural and unnatural a-amino acids by enantioselec-
tively alkylating the glycine and alanine Schiff bases
using chiral PTC conditions. The chiral PTCs, which
have been effectively used are the ones pioneered by
O’Donnell1 1a and later improved upon by Lygo 1b,2
Corey3 1c and more recently by Jew 1d.4 Among the
non-cinchona based PTCs, chiral spiro ammonium salts
derived from binaphthol are very promising.5
However, despite the increasing importance and useful-
ness of these PTCs in organic reactions, the utility of
these catalysts in the asymmetric alkylation of achiral
imine glycinamides remain relatively unexplored.6
There are however, examples of chiral imine glyci-
namides derived from sultams,7 ephedrine imidazolidi-
none,8 disubstituted pyrrolidines9 and dimethyloxazo-
lidines.10In our studies into the synthesis of leveobupi-
vacaine 2b which is currently being marketed as its
(S)-enantiomer, due to its less cardiotoxicity,11 we
wished to try the glycine anion equivalent methodology
for making its key amide intermediate 2a. The amide
intermediate can also be used for making the chiral
2. Results and discussion
The amide intermediate 2a can be made in different
ways;14 one route is through the pipecolic ester 5b
which in turn, can be synthesized through alkylation of
benzophenone imine tert-butylglycinate 3a as reported
by Corey et al.15 Alkylation of 3a with 1-chloro-4-
iodobutane and catalyst 1c according to the reported
procedure,15 using CsOH·H2O as the base gave the
same level of enantioselectivity (99%) but a little less
(97%) at 0°C (entry 5 and 4 in Table 1).
The other, more direct route would be the alkylation of
the imine glycinamide 3b. Besides reducing the number
* Corresponding author. Tel.: 91-172-214682-87; fax: 91-172-214692;
e-mail: umaram54@yahoo.com
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00441-5

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S. Kumar, U. Ramachandran / Tetrahedron: Asymmetry 14 (2003) 2539–2545
Table 1. Enantioselective phase-transfer-catalysed alkylation of 3a–b promoted by 1c
of steps to the final drug 2b, glycinamide 3b is a more
stable synthon than the tert-butyl ester 3a. Also, being
a sterically hindered amide it can ward off unwanted
N-alkylation. This was easily prepared16 from glycine
and 2,6-dimethylaniline in 70% yield followed by ben-
zophenone imine17 protection according to the reported
procedure.18 When we subjected glycinamide 3b to
diethyl imine glycinamide (ee 80%, entry 7, Table 2).
This significant increase in enantioselectivity in the
alkylation of N,N-disubstituted imine glycinamides
prompted us to carry out modelling studies with vari-
ous imine glycinamides and the catalysts.
Published X-ray data of N-anthracenylmethyl substi-
tuted quaternary ammonium salt of cinchona alkaloids3
show that they have a single accessible binding site for
the enolates. Our modelling studies, performed using
Sybyl 6.819 along similar lines as done previously,20
showed two possible ion-pair arrangements between the
catalyst and the enolate. One ion-pair formed between
the catalyst and enolate of imine glycine tert-butyl ester
and that of the imine N,N-disubstituted glycinamides
must be mainly existing in the most favorable arrange-
ment as shown in Figure 1, which would give rise to the
observed (S)-alkylated product, but when we consider
the mono N-substituted glycinamide, like N-tert-butyl
amide 3d, there is a huge fall in stereoselectivity when
compared to that of O-tert-butyl ester 3a (53 and 95%,
respectively) even though both carry the same sterically
bulky tert-butyl group (entries 10 and 3, Table 2).
alkylation
with
1-chloro-4-iodobutane,
using
CsOH·H2O as a base with the catalyst 1c at −50°C, we
got the alkylated product 4b in only 20% ee (entry 3,
Table 1), as detected by chiral HPLC (Scheme 1). We
repeated the reaction using various conditions, but the
enantioselectivity of the alkylation did not improve
significantly (entry 1–3, Table 1).
In order to ascertain the possible reasons for the low
enantioselectivities, we repeated the reaction using ben-
zyl bromide as the alkylating agent but using sterically
more demanding groups at the amide nitrogen such as
iso-propyl and tert-butyl groups, than the planer 2,6-
dimethylbenzene. The enantioselectivity of the alkyla-
tion improved to give 6c and 6d in 42% and 53% ee,
respectively (entries 2 and 3, Table 2). At this point we
decided to see if N,N-disubstituted glycinamides would
boost the stereoselectivity. Repeating the alkylation on
N,N-disubstituted imine glycinamides 3e–h under simi-
lar conditions as given in Scheme 2, certainly showed
much higher enantioselectivity (ee 67–80%, entries 4–9,
Table 2). It should be noted however, that N,N-dicyclo
imine glycinamide did not improve the enantioselectiv-
ity (ee 75%, entry 9, Table 2) as compared to N,N-
Our modelling studies show that there is a possibility of
hydrogen bonding interaction between the amide NH
of the enolate of 3d and the quinoline nitrogen atom
when the enolate is placed in the orientation as in
Figure 2, which gives rise to the product having oppo-
site stereochemistry. Though this orientation is less
favourable due to the steric crowding, as the tert-butyl
Scheme 1. Alkylation with 1-chloro-4-iodobutane.

S. Kumar, U. Ramachandran / Tetrahedron: Asymmetry 14 (2003) 2539–2545
2541
Table 2. Enantioselective phase-transfer-catalysed benzylation of 3a–j promoted by 1b
no possibility of hydrogen bonding, whereas catalyst 1c
gave poor induction.
All the secondary amides showed low enantioselectivity
with 3b being the least. This is in agreement with the
work done earlier on various esters by the O’Donnell’s
group,1 where they observed that phenyl esters were
sterically less demanding due to their planar structure
than tert-butyl esters and hence showed worse asym-
metric induction.
Scheme 2. Alkylation with benzyl bromide.
group is placed between quinoline ring and vinyl sub-
stituent, and also due to increased charge separation
(loosening of ion-pair), it still seems to form due to the
added advantage of hydrogen bonding. This explains
the observed fall in the stereoselectivity.
3. Conclusions
We have shown for the first time that achiral benzophe-
none imine glycinamides can also be used as suitable
substrates for asymmetric alkylations using cinchona
derived catalysts under PTC conditions. We have also
tried to explain the poorer enantioselectivity of mono-
substituted glycinamides as compared to N,N-disubsti-
tuted benzophenone imine glycinamides. On reduction,
these compounds are able to yield useful chiral vicinal
diamines; work in this direction is in progress.
The above explanation also seems to fit in with the
difference in the levels of diastereoselectivities observed
by Marouka6 while benzylating the dipeptide Gly-
L-
Phe. High levels of diastereoselectivities were achieved
using chiral spiro ammonium catalysts, where there was

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S. Kumar, U. Ramachandran / Tetrahedron: Asymmetry 14 (2003) 2539–2545
4. Experimental
4.1. General
Melting points are uncorrected. 1H and 13C spectra
were recorded at 300 MHz Bruker Advance spectrome-
ter with chemical shifts in ppm and tetramethylsilane as
the internal standard. Infra-red absorption spectra were
recorded on a Nicolet Impact 410 spectrometer, the
frequencies in the IR spectra are indicated in cm−1.
Mass spectra data were recorded on a Finnigan-MAT
LCMS spectrometer with electron spray ionization and
atmospheric pressure ionization modes. Elemental
analyses were recorded on a Elementa Vario EL. HPLC
was performed on a Shimadzu SPD-10A using chiral
phase column (DIACEL Chiralcel, OD-H), with the
conditions outlined in the relevant experiment. TLC
was performed on plates pre-coated (0.25 mm) with
silica gel 60, Merck F-254. The plates were visualized
by the use of a combination of UV (254 nm) and
iodine. Column chromatography was carried out with
silica gel Merck 60 (80–230 mesh). Molecular modelling
studies were done using Sybyl 6.8 installed on an
Octane 2 SG workstation.
4.2. General procedure for the preparation of benzophe-
none imine glycinamides
Figure 1. Ion-pair between the catalyst19 and the (E)-enolate
of 3d in the conformation which will give rise to the (S)-
product.
Benzophenone imine glycinamides were synthesized
from the appropriate glycinamide hydrochloride16 and
diphenylmethyl imine17 according to the reported
procedure.18
4.2.1. N1-(2,6-Dimethylphenyl)-N2-(diphenylmethylene)-
glycinamide. Compound 3b was obtained from N1-(2,6-
dimethylphenyl)-2-aminoacetamide hydrochloride16 in
82% yield; mp 118–119°C; wmax (KBr) 3330, 3053, 2914,
1
2881, 1684, 1627, 1499, 1440, 1286, 776, 699; H NMR
l (CDCl3, 300 MHz) 2.30 (s, 6H), 4.16 (s, 2H), 7.11 (s,
3H), 7.20 (d, J=7.5 Hz, 2H), 7.34–7.52 (m, 6H), 7.67
(d, J=7.4 Hz, 2H), 8.94 (s, 1H); 13C NMR l (CDCl3,
300 MHz) 18.4, 56.6, 127.0, 127.0, 128.0, 128.1, 128.2,
128.8, 128.9, 130.7, 133.8, 135.0, 135.8, 138.4, 168.8,
170.2; MS (m/z): 344 (24%), 343 (100%). Anal. calcd
for C23H22N2O: C, 80.67; H, 6.48; N, 8.18 Found: C,
80.59; H, 6.50; N, 8.15.
4.2.2. N2-(Diphenylmethylene)-N1-isopropylglycinamide.
Compound 3c was obtained from N1-isopropyl-2-
aminoacetamide hydrochloride16 in 87% yield; mp 88–
89°C; wmax (KBr) 3345, 3054, 2964, 2871, 1646, 1528,
1
1314, 1286, 1173, 779, 698; H NMR l (CDCl3, 300
MHz) 1.25 (d, J=6.54 Hz, 6H), 3.93 (s, 2H), 4.17 (m,
1H), 7.13 (d, J=7.54 Hz, 2H), 7.2–7.4 (m, 5H), 7.62 (d,
J=7.02 Hz, 2H); 13C NMR l (CDCl3, 300 MHz) 22.7,
40.7, 56.5, 127.0, 128.1, 128.2, 128.7, 128.8, 130.5,
135.9, 138.6, 169.6, 169.9; MS (m/z): 282 (22%), 281
(100%). Anal. calcd for C18H20N2O: C, 77.11; H, 7.19;
N, 9.99 Found: C, 76.98; H, 7.28; N, 10.03.
Figure 2. Ion-pair between the catalyst19 and the (E)-enolate
of 3d in the conformation, which will give rise to the (R)-
product (Hydrogen bonding shown in dotted line)
4.2.3.
glycinamide. Compound 3d was obtained from N1-
N1-(tert-Butyl)-N2-(diphenylmethylene)-

S. Kumar, U. Ramachandran / Tetrahedron: Asymmetry 14 (2003) 2539–2545
2543
(tert-butyl)-2-aminoacetamide hydrochloride16 in 85%
yield; mp 108–109°C; wmax (KBr) 3374, 3080, 2966,
1672, 1623, 1526, 1449, 1286, 1223, 777, 699; H NMR
Anal. calcd for C27H34N2O: C, 80.56; H, 8.51; N, 6.96.
Found: C, 80.39; H, 8.64; N, 6.90.
1
l (CDCl3, 300 MHz) 1.44 (s, 9H), 3.85 (s, 2H), 7.13 (d,
J=7.39 Hz, 2H), 7.14–7.46 (m, 6H), 7.6 (d, J=7.64 Hz,
2H); 13C NMR l (CDCl3, 300 MHz) 28.7, 50.5, 56.9,
127.1, 128.1, 128.6, 128.8, 130.5, 135.9, 138.6, 169.4,
169.5; MS (m/z): 296 (20%), 295 (100%). Anal. calcd
for C26H28N2O: C, 81.21; H, 7.34; N, 7.29. Found: C,
80.83; H, 7.41; N, 7.24.
4.3. General procedure for the alkylation of benzophe-
none imine glycinamide and tert-butyl N-(diphenyl-
methylene)glycinate
Alkyl halide (8.4 mmol) was added to a mixture of the
appropriate benzophenone imine glycinamide 3b–h or
tert-butyl N-(diphenylmethylene)glycinate18 (3a, 1.6
mmol)
and
N-anthracenylmethyl
cinchonidium
4.2.4.
N-(Diphenylmethylene)-2-oxo-2-pyrrolidin-1-
bromide21 (0.16 mmol) in toluene/chloroform (7:3) 10
mL. The reaction mixture was cooled to the appropri-
ate temp, base (16.94 mmol) was added and the result-
ing mixture stirred vigorously until the starting material
had been consumed (4–28 h). The suspension was
diluted with diethyl ether (35 mL), washed with water
(2×10 mL), dried over Na2SO4, filtered and concen-
trated under reduced pressure to give crude products
4a–b, 6a–h. Purification of the residue by silica chro-
matography afforded the desired products in 58–85%
yield. The enantioselectivity was determined by chiral
HPLC analysis (DIACEL Chiralcel OD-H, hexane/iso-
propanol, flow rate 0.5 mL, min−1, 20°C, u 254 nm).
The absolute configuration was determined by compari-
son of the specific rotation of the hydrolyzed product(s)
ylethanamine. Compound 3e was obtained from 2-oxo-
2-pyrrolidin-1-ylethylamine hydrochloride16 in 92%
yield; mp 94–95°C; wmax (KBr): 2977, 2876, 1627, 1449,
1
1425, 1324, 793, 709; H NMR l (CDCl3, 300 MHz)
1.79–1.97 (m, 4H), 3.48 (q, J=6.61 Hz, 4H), 4.18 (s,
2H), 7.23 (d, J=6.3 Hz, 2H), 7.29–7.46 (m, 6H), 7.64
(d, J=7.79 Hz, 2H); 13C NMR l (CDCl3, 300 MHz)
24.0, 26.0, 45.8, 46.4, 57.3, 127.7, 127.9, 128.4, 128.5,
130.1, 135.9, 139.3, 168.4, 170.8; MS (m/z): 294 (18%),
293 (100%). Anal. calcd for C19H20N2O: C, 78.05; H,
6.89; N, 9.58. Found: C, 77.96; H, 6.95; N, 9.53.
4.2.5.
N-(Diphenylmethylene)-2-oxo-2-piperidin-1-
ylethanamine. Compound 3f was obtained from 2-
amino-1-piperidino-1-ethanone hydrochloride16 in 86%
yield; mp 73–74°C; wmax (KBr) 3488, 2941, 2856, 1625,
with
L
-phenylalanine.
1
1441, 1253, 1230, 1021, 707; H NMR l (CDCl3, 300
4.3.1.
tert-Butyl-N-(diphenylmethylene)-L-phenylalan-
MHz) 1.57–1.60 (m, 6H), 3.27–3.57 (m, 4H), 4.23 (s,
2H), 7.18–7.49 (m, 8H), 7.63 (d, J=8.05 Hz, 2H); 13C
NMR l (CDCl3, 300 MHz) 24.4, 25.4, 26.1, 26.4, 42.9,
45.0, 46.8, 56.9, 127.7, 127.9, 128.1, 128.4, 128.5, 128.5,
129.9, 130.1, 132.3, 135.9, 139.3, 168.1, 170.2; MS
(m/z): 294 (18%), 293 (100%). Anal. calcd for
C20H22N2O: C, 78.40; H, 7.24; N, 9.08. Found: C,
77.80; H, 7.32; N, 8.99.
inate. Compound 6a was obtained from 3a in 85%
1
yield; pale yellow oil; H NMR l (CDCl3, 300 MHz)
1.41 (s, 9H), 3.22–3.09 (m, 2H), 4.08 (dd, J=4.98 Hz,
J=9.08 Hz, 1H), 6.53–7.62 (m, 15H); Rt HPLC
(99.5:0.5, hexane/isopropanol, 8.1 min (S-isomer) 17.5
min (R-isomer)).
4.3.2. tert-Butyl-6-chloro-N-(diphenylmethylene)-L-nor-
4.2.6.
N2-(Diphenylmethylene)-N1,N1-diethylglyci-
leucinate. Compound 4a was obtained from 3a in 83%
namide. Compound 3g was obtained from N,N-diethyl-
2-aminoacetamide hydrochloride16 in 90% yield; mp
104–105°C; wmax (KBr) 3054, 2975, 2927, 288, 1649,
1
yield; pale yellow oil; H NMR l (CDCl3, 300 MHz)
1.30–1.44 (m, 11H), 1.71 (m, 2H), 1.80 (q, J=7.61 Hz,
2H), 3.49 (t, J=6.66 Hz, 2H), 3.92 (t, J=6.46 Hz, 1H),
7.16–7.65 (m, 9H), 7.80 (d, J=7.17 Hz, 1H); Rt HPLC
(99.5:0.5, hexane/isopropanol, 12.0 min (S-isomer) 14.9
min (R-isomer)).
1
1480, 1429, 1259, 1144, 773, 701; H NMR l (CDCl3,
300 MHz) 1.26 (t, J=7.06 Hz, 6H), 3.37 (m, 4H), 4.23
(s, 2H), 7.20–7.23 (m, 2H), 7.26–7.47 (m, 6H), 7.64–7.66
(m, 2H); 13C NMR l (CDCl3, 300 MHz) 12.8, 14.1,
40.0, 41.7, 56.4, 127.6, 127.7, 128.3, 128.4, 129.9, 135.8,
139.2, 168.7, 170.4; MS (m/z): 296 (20%), 295 (100%).
Anal. calcd for C19H22N2O: C, 77.52; H, 7.53; N, 9.52.
Found: C, 77.34; H, 7.58; N, 9.49.
4.3.3.
methylene)-
6-Chloro-N1-(2,6-dimethylphenyl)-N2-(diphenyl-
-norleucinamide. Compound 4b was
L
obtained from 3b in 58% yield; colourless oil; [h]2D5=
−5.8 (c 0.5, CH2Cl2), ee 20%; wmax (film) 3347, 3062,
2926, 2249, 1715, 1494, 1315, 908, 733; 1H NMR l
(CDCl3, 300 MHz) 1.55–1.78 (m, 6H), 2.18 (s, 6H), 3.31
(m, 1H), 3.46 (t, J=6.43 Hz), 4.93 (s, 1H), 7.06–7.46
(m, 13H), 8.53 (s, 1H); 13C NMR l (CDCl3, 300 MHz)
18.5, 23.1, 32.2, 34.7, 44.6, 66.0, 127.5, 127.7, 128.1,
128.2, 128.5, 128.8, 128.9, 130.7, 133.7, 135.6, 136.7,
138.3, 169.8, 171.4; MS (m/z): 434 (24%), 433 (100%).
Anal. calcd for C27H29ClN2O: C,74.90; H, 6.75; N,
6.47. Found: C, 74.78; H, 6.83; N, 6.43; The enan-
tiomeric excess was determined after reducing the imine
to amine; Rt HPLC (hexane/isopropanol, 15.2 min
(S-isomer), 19.8 min (R-isomer)).
4.2.7. N2-(Diphenylmethylene)-N1,N1-dicyclohexylglyci-
namide. Compound 3h was obtained from N,N-dicyclo-
hexyl-2-aminoacetamide hydrochloride16 in 80% yield;
mp 116–117°C; wmax (KBr) 3052, 2928, 2850, 1624,
1
1443, 1313, 1182, 783, 700; H NMR l (CDCl3, 300
MHz) 1.05–1.32 (m, 6H), 1.46–1.58 (m, 6H) 1.65–1.76
(m, 7H), 2.49 (bs, 1H), 2.91 (bs, 1H), 3.68 (m, 1H), 4.19
(s, 2H), 7.21 (dd, J=1.42 Hz, J=5.67 Hz, 2H), 7.30–
7.48 (m, 6H), 7.64 (d, J=6.76 Hz, 2H); 13C NMR l
(CDCl3, 300 MHz) 25.2, 25.8, 26.5, 29.7, 31.2, 55.9,
57.7, 59.1, 127.8, 127.8, 128.3, 128.5, 130.0, 135.9,
139.4, 168.8, 169.9; MS (m/z): 404 (24%), 403 (100%).

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S. Kumar, U. Ramachandran / Tetrahedron: Asymmetry 14 (2003) 2539–2545
4.3.4. N-(2,6-Dimethylphenyl)-N-(diphenylmethylene)-
L
-
(m/z): 384 (20%), 383 (100%). Anal. calcd for
C26H26N2O: C, 81.64; H, 6.85; N, 7.32. Found: C,
81.48; H, 6.93; N, 7.29. Rt HPLC (85:15, hexane/iso-
propanol, 19.0 min (S-isomer), 21.9 min (R-isomer)).
phenylalaninamide. Compound 6b was obtained from 3b
in 65% yield; Colourless oil; [h]2D5=−4.3 (c 1, CH2Cl2),
ee 16%; wmax (film) 3340, 3057, 3025, 2920, 2853, 1686,
1
1621, 1492, 1283, 771, 697; H NMR l (CDCl3, 300
MHz) 2.20 (s, 6H), 3.18 (dd, J=3.57 Hz, J=9.45 Hz,
1H), 3.33 (dd, J=2.98 Hz, J=10.07 Hz, 1H), 4.33 (dd,
J=3.07 Hz, J=6.31 Hz, 1H), 6.46 (d, J=6.98 Hz, 2H),
7.03–7.44 (m, 14H), 7.63 (d, J=7.03 Hz, 2H), 8.26 (s,
1H); 13C NMR l (CDCl3, 300 MHz) 18.4, 41.6, 68.0,
126.3, 127.1, 127.2, 128.1, 128.3, 128.5, 130.2, 130.6,
133.7, 135.0, 135.3, 137.7, 138.8, 170.2, 170.9; MS
(m/z): 434 (38%), 433 (100%). Anal. calcd for
C30H28N2O: C, 83.30; H, 6.52; N, 8.18. Found: C,
83.20; H, 6.56; N, 8.13. Rt HPLC (98:2 hexane/iso-
propanol, 25.62 min (S-isomer) 53.44 min (R-isomer)).
4.3.8.
(2S)-N-(Diphenylmethylene)-1-oxo-3-phenyl-1-
piperidin-1-ylpropan-2-amine. Compound 6f was
obtained form 3f in 76% yield; mp 120–121°C; [h]2D5=
−48.7 (c 1, CH2Cl2), ee 66%; wmax (KBr) 2925, 2858,
1624, 1496, 1443, 1219, 998, 694, 775; 1H NMR l
(CDCl3, 300 MHz) 1.10 (bs, 1H), 1.25 (bs, 1H), 1.50
(m, 4H), 3.09-3.18 (m, 2H), 3.28-3.34 (m, 2H), 3.51 (m,
2H), 4.51 (dd, J=1.44 Hz, J=6.17 Hz, 1H), 6.80 (m,
2H), 7.06–7.67 (m, 13H); 13C NMR l (CDCl3, 300
MHz) 24.5, 25.6, 26.2, 40.9, 41.9, 43.4, 46.2, 47.2, 50.4,
66.3, 126.3, 127.5, 127.7, 127.9, 128.2, 128.3, 128.4,
128.7, 129.4, 129.7, 130.1, 136.5, 138.3, 139.3, 169.0,
169.9; MS (m/z): 398 (10%), 397 (100%); Anal. calcd
for C27H28N2O: C, 81.78; H, 7.12; N, 7.06. Found: C,
81.69; H, 7.31; N, 6.99. Rt HPLC (90:10 hexane/iso-
propanol, 12.3 min (S-isomer), 14.3 min (R-isomer)).
4.3.5. N-Isopropyl-N-(diphenylmethylene)-L-phenylalan-
inamide. Compound 6c was obtained form 3c in 80%
yield; mp 114–115°C; [h]2D5=−41.4 (c 1, CH2Cl2), ee
42%; wmax (KBr) 3380, 3058, 2970, 2919, 1674, 1625,
1
1502, 1444, 1283, 764, 697; H NMR l (CDCl3, 300
MHz) 1.14 (dd, J=2.77 Hz, J=3.75 Hz, 6H), 2.99 (dd,
J=4.20 Hz, J=8.88 Hz, 1H), 3.15 (dd, J=3.29 Hz,
J=9.77 Hz, 1H), 4.11 (dd, J=4.68 Hz, J=5.46 Hz,
2H), 6.48 (d, J=6.82 Hz, 2H), 6.59 (d, J=7.81 Hz,
1H), 7.02–7.58 (m, 13H); 13C NMR l (CDCl3, 300
MHz) 22.3, 22.7, 22.8, 40.8, 41.5, 67.5, 126.2, 127.3,
128.0, 128.1, 128.3, 128.3, 128.5, 130.1, 130.4, 135.5,
137.8, 139.2, 169.6, 171.6; MS (m/z): 372 (26%), 371
(100%); Anal. calcd for C25H26N2O: C, 81.05; H, 7.07;
N, 7.56. Found: C, 80.95; H, 7.14; N, 7.49; Rt HPLC
(95:5 hexane/isopropanol, 9.4 min (S-isomer), 13.9 min
(R-isomer)).
4.3.9. N,N-Diethyl-N-(diphenylmethylene)-L-phenylalan-
inamide. Compound 6g was obtained form 3g in 84%
yield; mp 111–112°C; [h]2D5=−51.8 (c 1, CH2Cl2), ee
80%; wmax (KBr) 3058, 3022, 2970, 2930, 1648, 1611,
1
1446, 1260, 1078, 792, 701; H NMR l (CDCl3, 300
MHz) 0.72 (t, J=7.04 Hz, 3H) 1.04 (t, J=7.04 Hz,
3H), 2.92–3.11 (m, 3H), 3.24-3.38 (m, 3H), 4.42 (t,
J=6.72 Hz, 1H), 6.84 (d, J=4.29 Hz, 2H), 7.05–7.39
(m, 11H), 7.64 (d, J=6.91 Hz, 2H); 13C NMR l
(CDCl3, 300 MHz) 12.8, 14.2, 40.5, 41.1, 66.0, 126.2,
127.4, 127.8, 128.1, 128.2, 128.3, 128.4, 128.7, 129.6,
130.1, 136.5. 138.2, 139.3, 168.8, 170.6; MS (m/z): 386
(20%), 385 (100%). Anal. calcd for C26H28N2O: C,
81.21; H, 7.34; N, 7.29. Found: C, 81.12; 7.58; N, 7.24.
Rt HPLC (95:5, hexane/isopropanol, 21.6 min (S-iso-
mer), 27.5 min (R-isomer)).
4.3.6.
N-(tert-Butyl)-N-(diphenylmethylene)-L-phenyl-
alaninamide. Compound 6d was obtained form 3d in
84% yield; mp 124–125°C; [h]2D5=−7.8 (c 1, CH2Cl2), ee
53%; wmax (KBr) 3378, 3033, 2964, 2928, 2870, 1664,
1617, 1507, 1447, 1278, 1224, 755, 700; 1H NMR l
(CDCl3, 300 MHz) 1.35 (s, 9H), 2.99 (dd, J=4.22 Hz,
J=8.83 Hz, 1H), 3.14 (dd, J=3.25 Hz, J=9.80 Hz,
1H), 4.03 (dd, J=3.32 Hz, J=5.42 Hz, 1H), 6.86 (d,
J=6.86 Hz, 2H), 6.69 (s, 1H), 7.01–7.42 (m, 10H), 7.56
(d, J=6.87 Hz, 2H); 13C NMR l (CDCl3, 300 MHz)
28.7, 41.5, 50.6, 67.9, 126.1, 127.2, 127.9, 128.1, 128.2,
128.4, 130.1, 130.3, 135.4, 137.8, 139.1, 169.0, 171.6;
MS (m/z): 386 (25%), 385 (100%). Anal. calcd for
C26H28N2O: C, 81.21; H, 7.34; N, 7.29. Found: C,
80.98; H, 7.48; N, 7.23. Rt HPLC (95:5 hexane/iso-
propanol, 9.6 min (S-isomer), 20.1 min (R-isomer)).
4.3.10.
N,N-Dicyclohexyl-N-(diphenylmethylene)-L-
phenylalaninamide. Compound 6h was obtained form 3h
in 60% yield; Pale yellow oil; [h]2D5=−25.2 (c 0.5,
MeOH), ee 75%; wmax (film) 3048, 3022, 2930, 1625,
1
1446, 1319, 1260, 1098, 772, 701; H NMR l (CDCl3,
300 MHz) 1.03–1.29 (m, 6H), 1.42–1.53 (m, 6H) 1.62–
1.70 (m, 7H), 2.40 (bs, 1H), 2.91–3.0 (m, 2H), 3.24 (dd,
J=3.25 Hz, J=9.87 Hz, 1H), 3.59 (m, 1H), 4.29 (t,
J=6.92 Hz, 1H), 6.82 (d, J=3.55 Hz, 2H), 7.09–7.48
(m, 11H), 7.65 (d, J=6.76 Hz, 2H); 13C NMR l
(CDCl3, 300 MHz) 25.3, 25.7, 26.8, 29.9, 31.2, 55.2,
59.3, 67.2, 126.2, 127.3, 127.8, 128.0, 128.3, 128.4,
128.7, 129.5, 130.1, 135.9, 138.7, 169.2, 170.2; MS
(m/z): 495.3 (10%), 494 (25%), 493 (100%); Anal. calcd
for C34H40N2O: C, 82.88; H, 8.18; N, 5.69. Found: C,
82.74; H, 8.29; N, 5.63. Rt HPLC (98:2, hexane/iso-
propanol, 8.1 min (S-isomer), 17.5 (R-isomer)).
4.3.7.
(2S)-N-(Diphenylmethylene)-1-oxo-3-phenyl-1-
pyrrolidin-1-ylpropan-2-amine. Compound 6e was
obtained form 3e in 82% yield; mp 126–127°C; [h]2D5=
−55.9 (c 1, CH2Cl2), ee 67%; wmax (KBr) 2974, 2869,
1
1637, 1437, 1286, 773, 701; H NMR l (CDCl3, 300
MHz) 1.54–1.64 (m, 4H), 2.72 (t, J=5.72 Hz, 2H), 3.21
(dd, J=7.11 Hz, J=5.82 Hz, 1H), 3.29-3.44 (m, 3H),
4.33 (t, J=6.99 Hz, 1H), 6.87 (d, J=3.58 Hz, 2H),
7.07–7.38 (m, 11H), 7.65 (d, J=7.34 Hz, 2H); 13C
NMR l (CDCl3, 300 MHz) 23.7, 25.9, 40.9, 45.7, 45.9,
67.2, 126.2, 127.3, 127.8, 128.0, 128.3, 128.3, 128.7,
129.6, 130.1, 137.0, 138.1, 139.1, 169.2, 170.3; MS
Acknowledgements
We are thankful to Dr. Sophia Elizabeth for helpful
discussions and carrying out molecular modelling
studies.

S. Kumar, U. Ramachandran / Tetrahedron: Asymmetry 14 (2003) 2539–2545
2545
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