Synthesis of α, α-dideutero-β-amino esters

Article abstract of DOI:10.1016/j.tetlet.2012.01.004

A straight forward entry to α, α-dideutero-β-amino esters starting from the corresponding imines and deuterated acetonitrile has been developed involving a two-step process.

Full text of DOI:10.1016/j.tetlet.2012.01.004

Tetrahedron Letters 53 (2012) 1292–1295
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of
a,a
-dideutero-b-amino esters
⇑
S. Chandrasekhar , Mrunal Pendke, Chandrashekar Muththe, Srirama Murthy Akondi, Prathama S. Mainkar
Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 July 2011
Revised 2 January 2012
Accepted 4 January 2012
Available online 10 January 2012
A straight forward entry to
deuterated acetonitrile has been developed involving a two-step process.
a,a-dideutero-b-amino esters starting from the corresponding imines and
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
b-Amino acids
Deuterium
Deuterated acetonitrile
Chiral induction
Imines
b-Amino acids and b-peptides have acquired a place of promi-
nence mainly because of their pharmaceutical potential. Unique
features of b-peptides when compared to their a-analogues are: in-
modified.12 However, this method has a disadvantage that amino
acids which are available commercially can only be used. The syn-
thetic scheme becomes multi-step if one chooses to synthesize
creased metabolic stability, higher structural diversity and forma-
tion of well-defined structures.1 These features make b-peptides
important peptido-mimetics with various biological activities.
b-Amino acids are also found to be the components of many natural
products such as Taxol,2 Cryptophycin 1,3 Jusplankinolide,4 Besta-
tin5 etc. b-Amino acids are also the precursors of bioactive
b-lactams.6
Deuterium is a non-radioactive labeling atom which has found
an important place in the pharmaceutical industry as a marker
atom, a tool to explore bio-availability and protein structure eluci-
dation, giving insight into their secondary and tertiary structures.
It has been explored by the pharmaceutical industry for better
binding to enzymes, better bio-availability, and slower hydrolysis
to metabolites.7 Some of the deuterated pharmaceuticals reported
are: paroxetine, reyataz, rimonabant, mosapride, venlafaxine, deu-
terated atorvastatin etc.8
a
-amino acids first and then modify them to get the deuterated
derivatives.
We envisaged the synthesis of unusual b-amino acids with
dideuteration at -position using easily accessible starting mate-
a,a
rials. Thus, CD3CN was used as the source of deuterium. Aldehydes
were converted to the corresponding imines by classical reaction
and imines were the starting materials for the two-step synthesis
for dideutero amino acids. The imines were treated with CD3CN
in the presence of LDA at ꢀ78 °C to get nitriles. Hydrolysis of the
nitrile group with sulfuric acid in methanol gave the corresponding
methyl esters of
a,a-dideutero-b-amino acids in a 55–75% yield
over 2 steps. The esters obtained were characterized using 1H
NMR, mass, IR, 13C NMR etc. Chiral induction to get the enantio-
mers was carried out by substituting benzylamine with R-or S-a-
phenylethylamine (Scheme 1).
There are limited examples in the literature for the stereo-selec-
R'
H
R'
tive and atom-efficient synthesis of a-deuterated amino acids, which
N
HN
LDA
when commercially available, are expensive.9 With this background
and in continuation of our interest in deuteration chemistry10 as well
CD3CN
CN
D
R
R
-78 °C
D
as in peptido-mimetics we conceived a program to synthesize a,a-
R'
dideutero-b-amino acids to add to the repertoire of unusual b-amino
HN
acids that are already synthesized in our group.11
H2SO4
COOCH3
D
Synthesis of
a,-a-dideuterated-b-amino acids has been
R
CH3OH
D
reported earlier where the available
a-amino acids have been
⇑
Corresponding author. Tel.: +91 040 27193210; fax: +91 040 27160512.
E-mail address: srivaric@iict.res.in (S. Chandrasekhar).
R= Ar, Alkyl; R' = Bn, R or S
Ph
Scheme 1. Synthesis of a,a-dideutero-b-amino acids via benzyl imines.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.004

S. Chandrasekhar et al. / Tetrahedron Letters 53 (2012) 1292–1295
1293
Table 1
Synthesis of a,a-dideutero-b-Amino acid esters
Entry
Imine
b-Amino acid (as methyl ester)
Yield (%)a
Bn
H
Bn
N
HN
COOCH3
1
55
D
D
1a
1b
Bn
Bn
Bn
N
N
HN
COOCH3
2
3
60
65
H
D
D
2a
2b
H3CO
H3CO
Bn
HN
COOCH3
H
D
D
H3CO
H3CO
OCH3
H3CO
H3CO
OCH3
3b
3a
Bn
N
Bn
HN
COOCH3
H
4
5
62
70
D
D
4b
OCH3
OCH3
H3CO HN
4a
Bn
N
Bn
H3CO
COOCH3
H
D
D
H3CO
OCH3
H3CO
OCH3
Bn
5b
5a
Bn
N
N
HN
COOCH3
6
7
8
9
75
70
65
70
H
D
D
Br
Cl
F
Br
Cl
F
6b
6a
Bn
Bn
HN
COOCH3
H
D
D
7b
8b
7a
Bn
Bn
N
HN
COOCH3
H
D
D
8a
Bn
Bn
HN
D
N
COOCH3
D
H
9a
9b
Bn
H
Bn
N
HN
O
O
COOCH3
10
11
60
72
10a
D
D
10b
Bn
Bn
HN
N
COOCH3
D
H
D
11a
11b
Bn
Bn
N
HN
COOCH3
D
12
70
H
D
12b
12a
a
Yield of the product after two steps (nucleophilic addition, hydrolysis/esterification).

1294
S. Chandrasekhar et al. / Tetrahedron Letters 53 (2012) 1292–1295
Table 2
Enantioselective
a
,
a-dideutero-b-Amino acid esters
Entry
Imine
b-Amino acid (as methyl ester)
Yield (%)a
60/99b
HN
Ph
N
Ph
1
COOCH3
13a
D
D
13b
HN
Ph
COOCH3
N
Ph
2
3
60/99b
70/99b
13b'
13a'
D
D
Ph
Ph
N
Ph
NH
COOCH3
D
D
14a
14b
N
Ph
NH
D
4
70/99b
COOCH3
D
14b'
14a'
a
Yield of the product after two steps (nucleophilic addition, hydrolysis/esterification).
% ee determined by Chiral HPLC using ChiralCel OD-H column.
b
O
O
S
H
O
S
Cs CO3, CH2Cl2
H
2
N
Ph
NH2
reflux, 16 h, 98%
15
O
S
NH2
MeOH.HCl
NH
D
CD3CN , LDA
COOMe
D
Ph
reflux, 12 h, 70%
CN
D
D
-78 °C, THF, 65%
Ph
17
16
Scheme 2. Synthesis of a, a-dideutero-b-amino acids via tert-butylsulfinimines.
In a typical study benzaldehyde imine 1a was alkylated with
CD3CN mediated by LDA in THF followed by sulfuric acid catalyzed
hydrolysis in methanol which furnished 1b in 55% yields. The deu-
terium enrichment was found to be over 99% based on 2H NMR
which helped us infer that during anion generation, there was no ex-
change of D with H, the reaction being carried out with care under
anhydrous conditions (anhydrous THF and nitrogen atmosphere).
To substantiate our protocol various substituted aryl imines (Table
1, entries 2–9), heteroaryl imine (entry 10) and aliphatic imine
Attempts to deprotect 6b using Pd/C-ammonium formate
resulted in an inseparable mixture of compounds.13 Similarly,
NIS-catalyzed reaction also provided the mixture of products.
Deprotection of the chiral auxiliary using Pd/C-H2 was also not
successful.
Several attempts to obtain deuterated amino esters from both
6b and 14b failed by reported deprotection protocols. A change
in the protecting group was attempted and thus the reaction of
benzaldehyde was carried out with tert-butylsulfinamide to give
imine 15. LDA-mediated reaction of deuterated acetonitrile with
15 gave dideuterated nitrile 16. Treatment of 16 with methanolic
HCl smoothly converted the nitrile group to the methyl ester and
simultaneously deprotected the chiral auxiliary. The resulting
dideutero-amino ester 17 was characterized by 1H NMR, 13C
NMR, and optical rotation (Scheme 2). The absolute stereochemis-
try of the new stereo-center generated was predicted based on the
literature.15
(entry 11) provided the corresponding a,a-dideutero-b-amino acid
methyl esters (over a 60% yield for 3 steps-alkylation, hydrolysis,
esterification). It was also observed that cinnamaldehyde imine
(entry 12) provided 12b in over a 70% yield. This indicated that sub-
stituents on the aromatic ring as well as unsaturation in conjugation
to aromatic ring do not have any effect on the synthesis of nitriles/
esters.
To further demonstrate the utility of this strategy in synthesiz-
ing enantioselective
a
,
a
-dideutero-b-amino acids, the imines 13a,
In summary, we present here a very simple synthetic strategy
13a0, 14a, 14a0 were prepared from aldehyde and chiral amine (R
and S-phenylethylamine) (Table 2, entries 1–4). The reactions of
these imines, under described conditions, provided 13b, 13b0,
14b and 14b0, respectively, in 9:1 diastereomeric ratio.14
for the preparation of unusual a,a-dideutero-b-amino esters start-
ing from respective benzylimines and tert-butyl sulfinimines.16
Even though, products obtained from benzyl imines could not be
converted to free amino acids, the problem was circumvented by

S. Chandrasekhar et al. / Tetrahedron Letters 53 (2012) 1292–1295
1295
(10 mL) was added slowly to the mixture. The reaction mixture was then
stirred at ꢀ78 °C for about 4 h, then quenched with saturated NH4Cl solution,
and extracted with ethyl acetate (3 ꢁ 30 mL). The combined ethyl acetate
layers were dried over Na2SO4, filtered, and evaporated under reduced
pressure. Upon drying under vacuum, the resulting compound was further
subjected to purification by column chromatography. Yield 1.95 g (80%)
General procedure for b-amino esters:
In a 25 mL round bottomed flask nitrile (100 mg, 1 mmol) was dissolved in
methanol (3 mL) and cooled to 0 °C. Then 1 mL conc. H2SO4 was added
dropwise to this reaction mixture and refluxed for 4 h (or till the reaction was
complete). The reaction was quenched with sodium bicarbonate till pH neutral,
the solid was filtered under vacuum, and washed with methanol. The filtrate
was concentrated under reduced pressure and the residue was purified by
column chromatography. Yield 0.039 g (69%).
using tert-butyl sulfinimide route. Further work is in progress to
generalize the protocols.
Acknowledgments
PSM thanks DST for Woman Scientist Scheme (WOS-A, GAP-
0317), MP, CM and ASRM are grateful to CSIR, New Delhi for re-
search fellowship. The authors are grateful to heavy water board,
Department of Atomic Energy for providing CD3CN and the review-
ers for their help in improving the manuscript.
Spectral data for representative new compounds:
Methyl 3-(benzylamino)-2, 2-dideutero-3-phenylpropanoate (1b): 1H NMR
(300 MHz, CDCl3) d 7.20–7.40 (m, 10H), 3.94 (d, J = 4.5 Hz, 1H), 3.68 (dd,
J = 12.8, 27.2 Hz, 1H), 3.62 (s, 3H), 3.52 (dd, J = 12.8, 24.9 Hz, 1H), 2.18 (br, 1H);
2H NMR (CHCl3, 83.3 MHz) d 2.65 (s, 2D); 13C NMR (75 MHz, CDCl3) d 172.2,
140.4, 139.4, 129.0, 128.7, 128.6, 128.2, 127.7, 127.3, 127.2, 127.0, 126.9, 58.7,
Supplementary data
Supplementary data (1H NMR spectra for compounds 1–16 and
intermediates) associated with this article can be found, in the on-
line version, at doi:10.1016/j.tetlet.2012.01.004.
58.2, 51.3, 29.7; IR (KBr)
m ;
3614, 2923, 2853, 1645, 1453, 1219, 771, 700 cmꢀ1
MS (EI) m/z 272 [M]+. HRMS (ESI) m/z calcd for C17H17D2NO2: 272.1614, found
272.1618 [M+H]+.
Methyl 3-(benzylamino)-2, 2-dideutero-3-(4-methoxyphenyl) propanoate (2b): 1
H
References and notes
NMR (300 MHz, CDCl3) d 7.20–7.48 (m, 6H), 6.88 (d, J = 8.5 Hz, 4H), 5.12 (s, 1H),
4.15 (d, J = 7.04 Hz, 1H), 4.12 (d, J = 7.0 Hz, 1H), 3.83 (s, 6H); 13C NMR (75 MHz,
CDCl3) d 173.7, 135.7, 135.6, 133.4, 133.3, 129.8, 129.7, 127.7, 127.6, 64.2, 60.2,
1. Seebach, D.; Beck, A. K.; Bierbaum, D. J. Chem. Biodiversity 2004, 1, 1111.
2. Ojima, I.; Lin, S.; Wang, T. Curr. Med. Chem. 1999, 6, 927.
34.3, 33.5, 26.8; IR (KBr)
m
3465, 2923, 2853, 1637, 1465, 1256, 692 cmꢀ1; MS
3. Shin, C. L.; Gossett, S.; Gruber, J. M.; Grossman, C. S.; Andis, S. L.; Schultz, R. M.;
Worzalk, J. F.; Coebett, T. H.; Metz, J. T. Bioorg. Med. Chem. Lett. 1999, 9, 69.
4. Crews, P.; Manes, L. V.; Boehler, M. Tetrahedron Lett. 1986, 27, 2797.
5. Rogers, R.; Verdine, G. L. Tetrahedron Lett. 2001, 42, 3563.
6. Abell, A. D.; Gardiner, J. J. Org. Chem. 1999, 64, 9668.
7. Patterson, B. W.; Hachey, D. L.; Cook, G. L.; Amann, J. M.; Klein, P. D. J. Lipid Res.
1991, 32, 1063.
8. Yarnell, A. Y. Chem. Eng. News 2009, 87, 36.
9. (a) O’Reilly, E.; Balducci, D.; Paradisi, F. Amino Acids 2010, 39, 849; (b) Maeda,
Y.; Tago, K.; Eguchi, T.; Kakinuma, K. Biosci. Biotech. Biochem. 1996, 60, 1248; (c)
Oba, M.; Nakajima, S.; Nishiyama, K. Chem. Commun. 1996, 1875; (d) Oba, M.;
Ohkuma, K.; Hitokawa, H.; Shirai, A.; Nishiyama, K. J. Label Compd. Radiopharm.
2006, 49, 229; (e) Sewald, N.; Hiller, K. D.; Helmreich, B. Liebigs Ann. 1995, 925;
(f) Blomquist, A. T.; Cedergren, R. J.; Hiscock, B. F. Proc. Natl. Acad. Sci. 1966, 55,
453; (g) Feeney, J.; Birdsall, B.; Ostler, G.; Carr, M. D.; Kairi, M. FEBS Lett. 1990,
272, 197.
(EI) m/z 301.5 [M]+.
Methyl 3-(benzylamino)-2,2-dideutero-3-(4-bromophenyl)propanoate (6b): 1H
NMR (300 MHz, CDCl3) d 7.20–7.50 (m, 9H), 4.01 (d, J = 9.8 Hz, 1H), 3.65 (s,
3H), 3.50 (d, J = 6.8 Hz, 2H), 2.00 (br, 1H); 13C NMR (75 MHz, CDCl3) d 171.9,
141.2, 139.7, 132.2, 131.8, 129.0, 128.5, 128.2, 127.8, 127.2, 127.1, 121.3, 58.0,
51.8, 51.2, 29.7; IR (KBr)
m 3465, 3028, 1730, 1454, 1254, 1009, 819, 734, 699,
594 cmꢀ1; MS (EI) m/z 349.9[M]+.
Methyl 3-(benzylamino)-2,2-dideutero-4-methylpentanoate (11b): 1H NMR
(300 MHz, CDCl3)
d 7.20–7.32 (m, 5H), 3.80 (d, J = 12.8 Hz, 2H), 3.65 (d,
J = 8.3 Hz, 3H), 3.42 (s, 1H), 1.0 (d, J = 6.7 Hz, 3H), 0.96 (d, J = 6.7 Hz, 3H), 13C
NMR (75 MHz, CDCl3) d 169.0, 128.5, 128.2, 127.2, 59.0, 51.5, 31.9, 31.1, 29.7,
18.6, 18.5; IR (KBr)
m
;
3348, 3062, 2957, 2853, 1602, 1454, 1250, 1155, 1104,
971, 753, 699 cmꢀ1
MS (EI) m/z 238 [M]+; HRMS (ESI) m/z calcd for
C
14H19D2NO2: 238.1771, found 238.1772 [M+H]+.
(E)-methyl 3-(Benzylamino)-2,2-dideutero-5-phenylpent-4-enoate (12b): 1H
NMR (300 MHz, CDCl3) d 7.20–7.58 (m, 12H), 3.75 (d, J = 18.9 Hz, 1H), 3.35
(s, 5H,); 2H NMR (CHCl3, 83.3 MHz) d 2.65 (s, 2 D); 13C NMR (75 MHz, CDCl3) d
10. Chandrasekhar, S.; Vijaykumar, B. V. D.; Chandra, B. M.; Reddy, Ch. R.; Naresh,
P. Tetrahedron Lett. 2011, 52, 3865.
11. (a) Chandrasekhar, S.; Babu, B. N.; Prabhakar, A.; Sudhakar, A.; Reddy, M. S.;
Kiran, M. U.; Jagadeesh, B. Chem. Commun. 2006, 1548; (b) Jagadeesh, B.; Kiran,
M. U.; Sudhakar, A.; Chandrasekhar, S. Chem. Eur. J. 2009, 15, 12592.
12. (a) Caputo, R.; Longobardo, L. Amino Acids 2007, 32, 401; (b) Chen, S.-T.; Tu, C.-
C.; Wang, K.-T. Biotechnol. Lett. 1992, 14, 269; (c) Blomquist, A. T.; Cedergren, R.
J. Can. J. Chem. 1968, 46, 1053; (d) Guaragna, A.; Pedatella, S.; Pinto, V.;
Palumbo, G. Synthesis 2006, 4013.
13. (a) Leplae, P. R.; Umezawa, N.; Lee, H.-S.; Gellman, S. H. J. Org. Chem. 2001, 66,
5629; (b) The reaction of 6b under Pd/C-ammonium formate provided the
following mixture of products based on LCMS in ratio 40.77
(Phenylethylamine, C), 37.45 (amino ester, A) and 19.98 (ester without
amino group, B).
193.8, 152.9, 134.0, 131.3, 129.1, 128.6, 128.5, 37.4, 37.1, 30.0, 29.7; IR (KBr)
m
3460, 2925, 2853, 1635, 1453, 751, 698 cmꢀ1; MS (EI) m/z 336 [M]++39; HRMS
(ESI) m/z calcd for C19H19D2NO2: 298.1771, found 298.1778 [M+H]+.
4-(Methyl-2,2-dideutero-3-((R)-1-phenylethylamino)pentanenitrile): 1H NMR
(300 MHz, CDCl3) d 7.23–7.53 (m, 5H), 4.34 (q, J = 6.8, 13.2 Hz, 1H), 2.35 (m,
1H), 2.14 (m, 1H), 1.51 (d, J = 6.8 Hz, 3H), 1.28 (s, 6H); 13C NMR (75 MHz,
CDCl3) d 133.4, 129.3, 128.9, 127.6, 126.2, 125.5, 120.5, 58.8, 53.4, 36.7, 29.7,
23.8, 22.8; IR (KBr)
m ;
3321, 2924, 2969, 2851, 2195, 1598, 913, 744, 700 cmꢀ1
MS (EI) m/z 219 [M]+; ½a D25
ꢂ
+ 21.0 (c= 0.1, CHCl3); HPLC retention time for R-(+)
isomer it was found to be 5.599 (ee = 99%).
4-(Methyl-2,2-dideutero-3-((S)-1-phenylethylamino)pentanenitrile): 1H NMR
(300 MHz, CDCl3) d 7.16–7.35 (m, 5H,), 4.28 (q, J = 6.8, 12.8 Hz, 1H), 2.12 (m,
1H), 1.92 (m, 1H), 1.47 (d, J = 6.8 Hz, 3H), 0.94 (dd, J = 6.8, 10.6 Hz, 6H), 2H NMR
(CHCl3, 83.3 MHz) d 2.65 (s, 2D); 13C NMR (75 MHz, CDCl3) d 137.5, 129.1,
NH2
COOCH3
128.9, 127.6, 126.8, 125.5, 121.4, 53.4, 38.8, 29.7, 23.8, 22.7; IR (KBr)
m 3322,
COOCH3
D
2924, 2969, 2851, 2191, 1594, 913, 795, 700 cmꢀ1; MS (EI) m/z 219 [M]; ½a 2D5
ꢂ
NH2
D
D
D
ꢀ15.0 (c = 0.1, CHCl3); HPLC retention time for S-(ꢀ) isomer it was found to be
4.952 (ee = 99%).
Br
Br
3-(Phenyl-2,2-dideutero-3-((R)-1-phenylethylamino)propanenitrile): 1H NMR
(300 MHz, CDCl3) d 1.47 (3H, d, J = 6.7 Hz), 2.10 (1H, m), 4.28 (1H, q, J = 6.6,
13.0 Hz), 4.54 (1H, m), 7.15–7.38 (10H, m); 2H NMR (CHCl3, 83.3 MHz) d 2.48
(s, 2D); 13C NMR (75 MHz, CDCl3) d 132.9, 131.1, 128.6, 115.0, 60.3, 48.5, 29.7,
B
C
A
14. The diastereomeric ratio was determined by HPLC and enantiomeric excess by
chiral HPLC for major diastereomer.
15. (a) Tang, P. T.; Ellman, A. J. J. Org. Chem. 2002, 67, 7819–7832; (b) Davis, A. F.;
Chao, B.; Fang, T.; Szewczyk, M. J. Org. Lett. 2000, 2, 1041–1043.
24.6, 22.7; IR (KBr)
m
3434, 2189, 1669, 768 cmꢀ1; MS (EI) m/z 253 [M]+; ½a 2D5
ꢂ
+18.0 (c = 0.35, CHCl3); HPLC retention time for R-(+) isomer was found to be
9.195 (ee = 99%) dr = 9:1.
16. General procedures for the synthesis of a,a-dideuterated-b-amino acids:
3-(Phenyl-2,2-dideutero-3-((S)-1-phenylethylamino)propanenitrile): 1H NMR
(300 MHz, CDCl3) d 1.25 (3H, s), 2.14 (1H, m), 3.89 (1H, m), 4.13 (1H, m),
7.10–7.36 (10H, m); 2H NMR (CHCl3, 83.3 MHz): d 2.40 (s, 2D); 13C NMR
(75 MHz, CDCl3) d 142.6, 128.7, 128.5, 128.2, 127.3, 125.4, 117.2, 62.5, 53.2,
Preparation of imines:
A
100 mL round bottomed flask was charged with benzaldehyde (2 mL,
1 mmol) in methanol (10 mL). Benzyl amine (2.1 mL, 1 mmol) was added to it
followed by potassium carbonate (catalytic) till the reaction mixture was
alkaline. The solution was allowed to stir at room temperature overnight. After
29.5, 23.5; IR (KBr)
m
3323, 2189, 1594, 1539, 1299, 733, 698 cmꢀ1; MS (EI) m/z
253 [M]+; ½a 2D5
ꢂ
ꢀ24.0 (c = 0.35, CHCl3); HPLC retention time for S-(-) isomer
completion of the reaction, it was filtered through
a bed of celite and
concentrated on rotavapor at low temperature. This imine was then dissolved
in dry THF under nitrogen atmosphere and stored for the next step. Yield 3.31 g
(90%).
was found to be 9.023 (ee = 99%).
(S)-N-((R)-2-Cyano 2,2-dideutero-1-phenyl)-2-methylpropane-2-sulfinamide 15:
1H NMR (500 MHz, CDCl3) d 7.44–7.35 (m, 5H), 4.73 (d, J = 4.0 Hz, 1H), 3.68
(brs, 1H), 1.29 (s, 9H); 13C NMR (75 MHz, CDCl3) d 138.9, 129.2, 126.6, 116.5,
General procedure for the preparation of racemic deuterated nitriles:
56.4, 54.4, 29.6, 22.6; MS (EI) m/z 253 [M]+.+1; ½a D25
ꢂ
ꢀ60.0 (C = 0.1, CHCl3).
A
thoroughly dried flask purged with nitrogen, was charged with
(R)-Methyl 3-amino-2,2-dideutero-3-phenylpropanoate (17): 1H NMR (500 MHz,
CDCl3) d 7.41–7.30 (m, 5H), 4.34 (S, 1H), 3.49 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 172.3, 128.9, 128.6, 127.5, 126.2, 52.5, 51.7, 29.6; MS (EI) m/z 182 [M]+.+1;
diisopropylamine (1.03 mL, 1 mmol) in dry THF (3 mL) and cooled to ꢀ10 °C.
Then, n-BuLi 2.5 M (6.2 mL, 1 mmol) was added slowly to it. The reaction
mixture was allowed to stir for 20 min and then cooled to ꢀ78 °C. Deuterated
acetonitrile (0.5 mL 2 mmol) in 3 mL of dry THF was added to the solution.
After about 30 min freshly prepared imine (2 g, 1 mmol) dissolved in dry THF
½ ꢂ +16.0 (C = 0.1, CHCl3).
a 2D5