A stereoselective synthesis of α-deuterium-labelled (S)-α-amino acids

Article abstract of DOI:10.1007/s00726-010-0541-3

An atom-efficient and stereoselective synthesis has been developed for the preparation of α-²H-labelled (S)-α-amino acids, starting from a novel chiral diketopi-perazine scaffold. Efficient mono-alkylation of the chiral template afforded the (S)-substituted adducts with the nature of the electrophile significantly effecting the stereochemical outcome. Subsequent alkylation was totally selective producing the 1, 4-cis adduct as the sole diastereoisomer. The deprotection was carried out using cerium ammonium nitrate followed by acid hydrolysis affording the enantipure α-amino acids. Springer-Verlag 2010.

Full text of DOI:10.1007/s00726-010-0541-3

Amino Acids (2010) 39:849–858
DOI 10.1007/s00726-010-0541-3
ORIGINAL ARTICLE
A stereoselective synthesis of a-deuterium-labelled (S)-a-amino
acids
•
Elaine O’Reilly Daniele Balducci
•
Francesca Paradisi
Received: 6 January 2010 / Accepted: 24 February 2010 / Published online: 12 March 2010
Ó Springer-Verlag 2010
Abstract An atom-efficient and stereoselective synthesis
has been developed for the preparation of a-2H-labelled
(S)-a-amino acids, starting from a novel chiral diketopi-
perazine scaffold. Efficient mono-alkylation of the chiral
template afforded the (S)-substituted adducts with the
nature of the electrophile significantly effecting the ste-
reochemical outcome. Subsequent alkylation was totally
selective producing the 1,4-cis adduct as the sole diaste-
reoisomer. The deprotection was carried out using cerium
ammonium nitrate followed by acid hydrolysis affording
the enantipure a-amino acids.
offer huge potential in the elucidation of enzymatic
mechanisms and biochemical processes (Bachmann et al.
2004; Ducho et al. 2009; Holding and Spencer 2008;
Moran et al. 2000).
There are limited examples in literature of the stereo-
selective and atom-efficient synthesis of a-2H-labelled
amino acids, which, when commercially available, are
extremely expensive. Previous approaches to their prepa-
ration include the deuterogenation of an unsaturated pre-
cursor containing a chiral auxiliary (Oba et al. 1998),
employment of a suitable deuterated reducing agent (Oba
et al. 2006; Pearce et al. 2000), rearrangement of amino
cyclopropanone hydrates (Felpin et al. 2000) and isotopic
exchange (Rose et al. 1995).
Keywords (S)-Deuterated-a-amino acids ꢀ
Diketopiperazine ꢀ Asymmetric synthesis
Diketopiperazines (DKPs) have been effectively utilised
for the synthesis of chiral amino acids because these
diverse building blocks can be easily functionalised and
hydrolysed to the corresponding amino acids. They offer a
simple and often stereoselective means of incorporating the
amino acid functionality. Orena et al. (1992) obtained both
the (S)- and the (R)-alanine, optically pure, by alkylation of
the chiral synthon (S)-3-methylpiperazine-2,5-dione, with
total diastereoselectivity, whilst a good diastereoselection
was achieved by alkylating the (R)-isomer. Porzi and
Sandri then extensively studied the stereocontrolled alkyl-
ation of chiral DKPs to obtain natural a-amino acids with
generally high diastereoselectivity (Orena et al. 1993; Porzi
and Sandri 1994; Paradisi et al. 2000a, b, 2002; Ferioli
et al. 2002; Piccinelli et al. 2003). Recently, Balducci et al.
(2009a), through an interesting application of the preceding
methodology, have achieved the synthesis of a-methyl-
amino acids with good stereoselectivity and, in particular,
a highly efficient stereocontrolled synthesis of (S)-20,60-
dimethyltyrosine (Balducci et al. 2009b), a non natural
a-amino acid that is a component of the d-opioid antagonist
Introduction
Deuterium-labelled amino acids have become valuable
biochemical tools due to their contribution to the field of
proteomics. Incorporation of these isotopically labelled and
stable amino acids into peptides can assist in protein
structure elucidation through spectroscopic methods such
as mass spectrometry (Ong et al. 2002; Veenstra et al.
2000) and NMR (Nakanishi et al. 2002; Sattler and Fesik
1996; Takeuchi et al. 2007), thus giving insight into their
secondary and tertiary structure. Labelled compounds also
E. O’Reilly ꢀ D. Balducci (&) ꢀ F. Paradisi (&)
UCD School of Chemistry and Chemical Biology,
Centre for Synthesis and Chemical Biology,
Belfield, Dublin 4, Ireland
e-mail: francesca.paradisi@ucd.ie
D. Balducci
e-mail: daniele.balducci@ucd.ie
123

850
E. O’Reilly et al.
Dmt-Tic pharmacophore present in many biologically
active compounds (d antagonists, d agonist and d antago-
nists/l agonists). Bull et al. (1998a) employed a DKP
bearing a chiral proline auxiliary for the synthesis of (R)-
alanine via C(6)-alkylation of the corresponding lithium
enolate.
Results and discussion
The chiral 1,4-bis[(S)-1-phenylethyl]piperazine-2,5-dione
1 has recently been synthesised with excellent yields under
phase transfer conditions (O’Reilly et al. 2009, 2010).
Previous work on a similar chiral synthon showed that it
directed the first alkylation with good ds, with the second
alkylation on the (S)-mono-substituted adduct being totally
selective producing solely the 1,4-cis products (Porzi and
Sandri 1994).
The synthesis of (S)-a-amino acids was achieved by
the conjugate addition of organocuprates to the related
dihydroalanine compound (Bull et al. 1998b). The same
group later reported on the use of the same chiral auxil-
iary for the preparation of quaternary a-amino acids via
alkylation a mono-lactam ether template (Davies et al.
The aim of this work was to introduce bulk on the
N-alkyl auxiliary with the aim of enhancing the selectivity
in the first alkylation. In this context, the chiral synthon 1
has been employed for the synthesis of a series of a-deu-
terium-labelled (S)-a-methyl-a-amino acids. This chiral
template was subjected to a highly efficient isotopic
exchange and after treatment with NaOH (1.0 eq) in
CH3OD, the 3,6-deuterated DKP 2 was isolated with high
isotopic purity (C95%). A comparative study was carried
out on both the labelled and non-labelled templates.
¨
2007). Schollkopf pioneered the use of a bislactim tem-
plate bearing a chiral isopropyl auxiliary for the asym-
¨
metric synthesis of chiral amino acids (Schollkopf et al.
1979, 1891). He found that a base-induced alkylation on
the bislactim template proceeded with high asymmetric
induction due to the directing effect of the auxiliary.
Although the use of the chiral isopropyl auxiliary gives
impressive stereoselection at the C(6) position in all of
the above cases, the nature of this auxiliary at C(3) means
upon hydrolysis a valine by-product is generated. This by-
product can prove very difficult to separate from the
desired amino acid and it is often necessary to convert the
amino acids mixture to the corresponding esters and
separate them by column chromatography or distillation
(Davies et al. 2007: Bull et al. 2007; Smith et al. 2006).
Herein, we report a novel, atom-efficient and stereo-
selective synthesis of a-2H-labelled a-amino acids, which
employs the chiral synthon 1 (Scheme 1), previously
developed by our group (O’Reilly et al. 2009, 2010).
Porzi and Sandri (1994) exploited a similar chiral synthon
for the synthesis of a-amino acids by alkylating on the
DKP ring and found that it promoted good diastereose-
lectivity (ds). The same chiral DKP was later exploited
for the synthesis of (S)-a-methyl amino acids (Balducci
et al. 2009a) and gave good stereoselectivity on alkyl-
ation. Initially, attempts were made to introduce the
deuterium onto the a-carbon of the disubstituted DKP by
using two equivalents of lithium bis(trimethylsilyl)amide
Mono-alkylation of templates 1 and 2
Efficient C(3)-alkylation of 1 and 2 was achieved using
1.0 eq of LHMDS, when the enolate was quenched with
1.0 eq of the appropriate electrophile, benzyl bromide,
ethyl iodide and methyl iodide, affording the (3S)-mono-
alkylated products in high yields and with good ds in most
cases. The stereochemistry of selected compounds (3b
and 4d) was determined by 1H NMR NOESY experiments.
1
A marked H NMR shielding pattern was observed for the
(3R) and (3S)-mono-alkylated derivatives and these pat-
terns were exploited to assign the stereochemistry of the
other compounds by analogy. The de of all the compounds
was determined by 1H NMR analysis of the crude mixture.
The stereochemistry of the final amino acids was then
confirmed by comparison with previously reported optical
rotation values.
There was no notable distinction in the selectivity
attained when using DKP templates 1 or 2. Efficient
C(3)-alkylation was achieved with all three electrophiles
with the selectivity strongly dependent on the steric
contribution from the alkyl halide. No selectivity was
observed on quenching the enolate of 1 or 2 with methyl
iodide. The 50:50 mixture of 3a:4a and 3d:4d isomers
obtained was easily separated by column chromatogra-
phy. Modest selectivity was observed for the C(3)-
alkylation of templates 1 and 2 with ethyl iodide,
affording the (3S) products 3b and 3e, respectively, with
a de of 20%. Alkylation of both templates with benzyl
bromide furnished the (3S)-isomers 3c and 3f in a de of
66%, an increase of 16% on the previously reported
chiral synthon 1.
2
(LHMDS) and quenching with H2O. However, as Rose
et al. (1995) found, this method resulted in low selectivity
and the formation of by-products. The procedure was then
adapted, allowing for the incorporation of deuterium
through a highly efficient isotopic exchange. The N-pro-
tecting group employed functions as a chiral auxiliary,
which can direct the stereochemistry on alkylation,
resulting in a diastereomeric excess (de) of up to 66%.
The use of this N-protecting group also allows for its
cleavage under mild conditions by employing cerium
ammonium nitrate (CAN), allowing retention of the DKP
scaffold and increasing the spectrum of amino acids
achievable using this synthetic strategy.
123

Synthesis of a-deuterium-labelled (S)-a-amino acids
851
O
O
D
OMe
OMe
N
N
D
i
D
N
N
MeO
MeO
D
O
O
1
2
O
O
O
R2
R1
OMe
OMe
N
6
N
6
3
3
R2
R1
+
R2
R2
ii
N
N
1 or 2
MeO
MeO
R2
R2
O
3a-f
4a-f
iii
O
R1
OMe
D
N
6
R1
COOH
3
R2
iv
R1
N
MeO
NH2
R2
O
5d-f
7d-f
a; R1 = CH3
b; R1 = CH3CH2 R2 = H
c; R1 = CH2Ph
v
O
d; R1 = CH3
e; R1 = CH3CH2 R2 = D
f; R1 = CH2Ph
vi
R1
HN
6
3
R2
R2
NH
R1
O
6f
Scheme 1 (i) NaOH, CH3OD, reflux; (ii) and (iii) LHMDS, anhyd. THF, R-X; (iv) HI, reflux then Dowex resin (5d and 5e) (Balducci et al.
2009b and references therein); (v) CAN, CH3Cl2/H2O (3:2) (5f). (vi) HCl, reflux then Dowex resin
Alkylation of mono-substituted templates 3a–f,
4a and 4d
in Scheme 2. This phenomenon was first observed by Porzi
and Sandri (1994). Incorporation of this isomerisation step
into the synthesis means the yield of the (3S,6S) isomers
can be dramatically increased and up to a further 25% of
the target isomer is attainable.
C(6)-alkylation of the (S)-mono-substituted adducts 3a–f
was highly selective ([98%) in each case, yielding the
(3S,6S) dialkyl derivatives 5a–f as the sole diastereoiso-
mer. In the case of the methyl derivatives, a small quantity
of tri-alkylated product had formed and was inseparable
from the 5b and 5e isomers. Consequently, full character-
isation of these two compounds and the amino acid (2S)-
[2-2H]-2-aminobutanoic acid, which resulted from the
hydrolysis of 5e, was not possible.
The diastereoisomers 5d and 8d were easily separated
by chromatography and the (3S,6S) isomer hydrolysed to
the corresponding (S)-amino acid 7d. This step compen-
sates for the relatively modest stereoselectivity in the C(3)-
alkylation. The (3R,6R) isomer 8d was also hydrolysed,
yielding the (R)-amino acid 10d.
It is worth noting that C(6)-alkylation of the (3R) mono-
substituted derivatives 4 gives a mixture of (3R,6R) and
(3R,6S) isomers, which when treated under basic condi-
tions without any purification, isomerise, yielding a 50:50
mixture of (3R,6R) and (3S,6S) products, as demonstrated
Deprotection and hydrolysis of templates 5d–f
The nature of the chiral directing group on this novel
template allows for mild deprotection using CAN and
retention of the substituted DKP scaffold or, alternatively,
123

852
E. O’Reilly et al.
Scheme 2 (i) LHMDS, anhyd.
THF, CH3I; (ii) NaOH, CH3OD;
(iii) HI, reflux then Dowex resin
(Balducci et al. 2009b and
references therein)
4d
i
O
Me
OMe
N
6
3
D
D
N
MeO
Me
O
Mixture of (3R,6R) & (3R,6S) isomers
ii
O
O
Me
D
OMe
OMe
Me
N
6
N
6
3
3
D
+
Me
D
N
N
MeO
MeO
D
Me
O
O
5d
50:50 mixture of (3S,6S) & (3R,6R)
8d
iii
iii
D
D
COOH
COOH
NH2
NH2
7d
10d
for a one-pot deprotection and hydrolysis of the substituted
DKPs to the corresponding a-amino acids (Scheme 1).
The di-substituted templates 5d and 5e were deprotected
and hydrolysed in one-pot in refluxing HI, yielding the
corresponding a-2H-labelled (S)-a-amino acids 7d and 7e
in quantitative yields after purification on Dowex resin
(Balducci et al. 2009b and references therein).
Conclusion
A short and efficient stereoselective synthesis of a-2H-
labelled (S)-a-amino acids has been developed, which can
give a de of up to 66% when a bulky electrophile is
employed. The modest selectivity in the first alkylation can
be compensated for by the isomerisation of the mixture of
(3R,6R) and (3R,6S)-substituted templates, which results
from the alkylation of the (3R)- mono-substituted deriva-
tive 4d, allowing a theoretical 25% of the (3S,6S) isomer to
be recovered. We have demonstrated that the (3R,6R)-
substituted templates can be hydrolysed to the corre-
sponding (R)-a-amino acids, which are valuable synthetic
and biologically important entities. The N-alkyl sub-
stituent, which acts as a chiral directing group, also allows
for mild deprotection with retention of the DKP scaffold
and its symmetric nature leads to a straightforward purifi-
cation of the target amino acids. This synthetic approach
can potentially be employed for the preparation of a wide
Treatment of 5f with CAN yielded deprotected DKP 6f,
which was subjected to a mild acid hydrolysis affording the
enantiopure a-2H-labelled (S)-a-amino acid 7f that was
purified on Dowex resin.
In both cases, the symmetrical nature of the template
allows for exceptional ease of purification, which is not the
case when a non-symmetrical template is used where the
directing group is present on the C(6) carbon. In these
cases, it is often necessary to convert the amino acid salts
to the corresponding methyl esters followed by distillation
or chromatography (Davies et al. 2007), where an overall
maximum yield of 50% is attainable.
123

Synthesis of a-deuterium-labelled (S)-a-amino acids
853
range of a-2H-labelled (S)-a-amino acids, giving access to
important biological tools that are often commercially
inaccessible or expensive.
HRMS (ESI): m/z calculated for C22H23D4N2O4: 387.2222,
found: 387.2222 [M?H]?.
General procedure for the synthesis of compounds 3, 4
and 5
Experimental section
LHMDS (solution in THF, 1.0 eq) was added dropwise to
a stirred solution of template 1 or 2 (1.0 eq) in anhydrous
THF at -20°C. After 1 h, the mixture was cooled to
-78°C and a solution of the alkyl halide (1.0 eq) in
anhydrous THF was added dropwise. The reaction mix-
ture was allowed to warm slowly to room temperature
and stirred for a further 1 h before being quenched by the
addition of water (2H2O in the case of the deuterated
derivatives). Ethyl acetate was added, the organic layer
was separated and the aqueous layer was extracted with
ethyl acetate (93). The organic layers were combined,
washed with brine, dried over MgSO4 and concentrated
in vacuo. The crude residue was purified by column
chromatography.
General methods
Proton and carbon nuclear magnetic resonance spectra (1H
and 13C NMR, respectively) were recorded on 300 MHz
(operating frequencies: 1H, 299.88 MHz; 13C, 75.41),
400 MHz (operating frequencies: 1H, 399.75 MHz; 13C,
101.00), 500 MHz (operating frequencies: 1H, 499.72
MHz; 13C, 125.65) and 600 MHz (operating frequencies:
1H, 599.78 MHz; 13C, 150.82) FT spectrometers. Tetra-
methylsilane was used as an internal reference in the
deuterated chloroform (CDCl3) (d = 0.00 ppm) for 1H
NMR spectra. The middle CDCl3 solvent peak was refer-
enced to 77.02 ppm for 13C NMR spectra. Dioxane was
used as an internal reference in the deuterated water (D2O)
(d = 3.75 ppm) for 1H NMR spectra and (d = 67.19 ppm)
for 13C NMR. The residual dimethyl sulfoxide peak was
referenced when applicable (d = 2.54 ppm) for the 1H
NMR spectra and (d = 40.45 ppm) for 13C NMR. The
coupling constants (J) are in Hz and the chemical shifts (d)
are given in parts per million. High-resolution mass spectra
were obtained on a Waters/Micromass instrument. Optical
rotation values were measured at 20°C on a Perkin-Elmer
241 polarimeter. Melting points are uncorrected. Evapo-
ration in vacuo refers to the removal of solvent on a
Bu¨chi rotary evaporator with an integrated vacuum pump.
Thin-layer chromatography (TLC) was carried out on
aluminium-backed 60 F254 silica gel.
(S)-1,4-Bis((S)-1-(4-methoxyphenyl)ethyl)-3-
methylpiperazine-2,5-dione 3a
After column chromatography (hexane–EtOAc, 3/1), the
product was obtained as an off-white waxy solid of 46%
yield after alkylating 1 with iodomethane. (Rf = 0.21,
EtOAc-hexane, 60/40); 1H NMR (300 MHz, CDCl3) d
7.14–7.11 (m, 4H), 6.89–6.85 (m, 4H), 5.81–5.73 (m, 2H),
3.87–3.75 (m, 8H), 3.60 (d, J = 16.9 Hz, 1H), 1.58 (d,
J = 7.2 Hz, 3H), 1.49–1.46 (m, 6H); 13C NMR (75 MHz,
CDCl3) d 167.9, 165.0, 159.2, 131.1, 130.7, 128.2, 128.2,
114.2, 114.1, 55.3, 55.3, 52.8, 51.0, 49.4, 44.2, 19.6, 17.5,
15.4; [a]2D0 = -297.5 (c = 1.5, CHCl3); HRMS (ESI): m/z
calculated for C23H29N2O4: 397.2127, found: 397.2145
[M?H]?.
For synthesis and spectroscopic data and characterisa-
tion of compound 1, see O’Reilly et al. 2009, 2010.
1,4-Bis[(S)-[3-2H,6-2H]-1-phenylethyl]piperazine-2,5-
dione 2
(S)-3-Ethyl-1,4-bis((S)-1-(4-
methoxyphenyl)ethyl)piperazine-2,5-dione 3b
DKP 1 (1.0 eq) and NaOH (1.0 eq) was stirred in refluxing
CH3OD for 4 h. The solvent was removed in vacuo and
water was added. The solution was extracted with ethyl
acetate (93) and the organic fractions combined, dried
over MgSO4 and concentrated. The product was isolated as
a white solid of 90% yield with no further purification.
M.p: 109.5–110.3°C; (Rf = 0.5, EtOAc/hexane, 60:40); 1H
NMR (300 MHz, CDCl3) d 7.18 (d, J = 8.7 Hz, 4H), 6.86
(d, J = 8.7 Hz, 4H), 5.90 (q, J = 7.1 Hz, 2H), 3.80 (s, 6H),
1.51 (d, J = 7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3)
d 163.7, 159.3, 130.2, 128.6, 114.1, 55.3, 49.6, 44.2 (t,
J = 20.3 Hz), 15.3; [a]2D0 = -342.2 (c = 1.1, CHCl3);
After column chromatography (hexane–EtOAc, 3/1), the
product was obtained as a thick yellow oil of 55% yield
after alkylating 1 with iodoethane. (Rf = 0.35, EtOAc–
1
hexane, 60/40); H NMR (500 MHz, CDCl3) d 7.15–7.11
(m, 4H), 6.90–6.85 (m, 4H), 5.84 (q, J = 7.1 Hz, 1H), 5.72
(q, J = 7.2 Hz, 1H), 3.89 (d, J = 17.2 Hz, 1H), 3.82 (s, 3H),
3.81 (s, 3H), 3.67–3.63 (m, 1H), 3.56 (d, J = 17.2 Hz, 1H),
1.98–1.84 (m, 1H), 1.87–1.76 (m, 1H), 1.59 (d, J = 7.2 Hz,
3H), 1.47 (d, J = 7.1 Hz, 3H), 1.01–0.96 (m, 3H); 13C
NMR (126 MHz, CDCl3) d 166.6, 165.2, 159.3, 159.3,
130.8, 130.7, 128.4, 128.4, 114.2, 114.2, 58.2, 55.3, 55.3,
51.7, 49.5, 44.3, 27.5, 17.5, 15.6, 9.4; [a]2D0 = -330.4
123

854
E. O’Reilly et al.
(c = 0.5, CHCl3); HRMS (ESI): m/z calculated for
C24H31N2O4: 411.2284, found: 411.2284 [M?H]?.
55.2, 51.5, 49.3, 44.3–43.6 (m), 27.3, 17.4, 15.5, 9.3;
[a]2D0 = 260.1 (c = 0.3, CHCl3); HRMS (ESI): m/z calcu-
lated for C24H27D3N2O4Na: 436.2292, found: 436.2294
[M?Na]?.
(S)-3-Benzyl-1,4-bis((S)-1-(4-
methoxyphenyl)ethyl)piperazine-2,5-dione 3c
(S)-[3-2H,6-2H2]-3-Benzyl-1,4-bis((S)-1-(4-
methoxyphenyl)ethyl)piperazine-2,5-dione 3f
After column chromatography (hexane–EtOAc, 3/1), the
product was obtained as a white solid of 77% yield after
alkylating 1 with benzyl bromide. Mp: 116.3–118°C;
After column chromatography (hexane–EtOAc, 5/1), the
product was obtained as a white waxy solid of 78% yield
after alkylating 2 with benzyl bromide. Mp: 195.2–
196.0°C; (Rf = 0.41, EtOAc–hexane, 60/40); 1H NMR
(300 MHz, CDCl3) d 7.37–7.18 (m, 5H), 7.17–7.12 (m,
2H), 7.02–6.96 (m, 2H), 6.92–6.85 (m, 2H), 6.83–6.77 (m,
2H), 5.85 (q, J = 7.3 Hz, 1H), 5.73 (q, J = 7.0 Hz, 1H),
3.82 (s, 3H), 3.79 (s, 3H), 3.29 (d, J = 13.9 Hz, 1H), 3.10
(d, J = 13.9 Hz, 1H), 1.79 (d, J = 7.0 Hz, 3H), 1.17 (d,
J = 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 166.1,
166.00, 159.3, 159.1, 135.1, 131.0, 130.8, 130.3, 128.7,
128.4, 128.1, 127.7, 114.2, 113.9, 57.7 (t, J = 21.8 Hz),
55.2, 55.2, 51.9, 49.2, 42.9–43.4 (m), 39.9, 18.2, 14.6;
[a]2D0 = -227.2 (c = 0.7, CHCl3); HRMS (ESI): m/z cal-
culated for C29H30D3N2O4: 476.2629, found: 476.2652
[M?H]?.
1
(Rf = 0.51, EtOAc–hexane, 60/40); H NMR (500 MHz,
CDCl3) d 7.35–7.27 (m, 3H), 7.21 (dd, J = 7.5, 1.7 Hz,
2H), 7.14 (d, J = 8.6 Hz, 2H), 6.99 (d, J = 8.6 Hz, 2H),
6.91–6.86 (m, 2H), 6.83–6.78 (m, 2H), 5.85 (q,
J = 7.3 Hz, 1H), 5.73 (q, J = 7.1 Hz, 1H), 4.05 (m, 1H),
3.83 (s, 3H), 3.78 (s, 3H), 3.30 (dd, J = 13.8, 4.2 Hz, 1H),
3.11 (dd, J = 13.8, 4.2 Hz, 1H), 3.01 (d, J = 17.0 Hz,
3H), 2.14 (d, J = 17.0 Hz, 3H), 1.79 (d, J = 7.3 Hz, 1H),
1.17 (d, J = 7.1 Hz, 1H); 13C NMR (126 MHz, CDCl3) d
166.2, 166.1, 159.4, 159.2, 135.3, 131.2, 130.9, 130.4,
128.8, 128.5, 128.1, 127.7, 114.3, 114.0, 58.1, 55.3, 55.3,
52.1, 49.3, 43.6, 40.1, 18.2, 14.7; [a]2D0 = -232.8 (c = 0.6,
CHCl3); HRMS (ESI): m/z calculated for C29H33N2O4:
473.2440, found 473.2421 [M?H]?.
(S)-[3-2H,6-2H2]-1,4-Bis((S)-1-(4-methoxyphenyl)ethyl)-3-
methylpiperazine-2,5-dione 3d
(R)-1,4-Bis((S)-1-(4-methoxyphenyl)ethyl)-3-
methylpiperazine-2,5-dione 4a
After column chromatography (hexane–EtOAc, 3/1), the
product was obtained as a clear oil of 45% yield after
alkylating 2 with methyl iodide. (Rf = 0.34, EtOAc–
hexane, 60/40); 1H NMR (300 MHz, CDCl3) d 7.29
(d, J = 8.6 Hz, 2H), 7.14 (d, J = 8.6 Hz, 2H), 6.91–6.82
(m, 4H), 5.82–5.71 (m, 2H), 3.80 (s, 3H), 3.79 (s, 3H),1.54
(d, J = 2.9 Hz, 3H), 1.51 (d, J = 2.9 Hz, 3H), 0.71 (s,
3H); 13C NMR (101 MHz, CDCl3) d 167.7, 164.7, 159.0,
130.9, 130.5, 128.0, 127.9, 113.9, 113.9, 55.1, 55.0, 52.2 (t,
J = 23.2 Hz), 50.7, 49.2, 44.0–43.4 (m), 19.3, 17.3, 15.2;
[a]2D0 = -314.2 (c = 1.6, CHCl3); HRMS (ESI): m/z cal-
culated for C23H25D3N2O4Na: 422.2135, found: 422.2147
[M?Na]?.
After column chromatography (hexane–EtOAc: 3/1), the
product was obtained as a white solid of 44% yield after
alkylating
1
with iodomethane. Mp: 134–135.3°C;
1
(Rf = 0.41, EtOAc–hexane, 60/40); H NMR (500 MHz,
CDCl3) d 7.31–7.27 (m, 2H), 7.18–7.14 (m, 2H), 6.87–6.83
(m, 4H), 5.89–5.83 (m, 2H), 3.99 (q, J = 7.0 Hz, 1H), 3.80
(s, 3H), 3.79 (s, 3H), 3.70–3.61 (d, J = 17.2 Hz, 1H), 3.32
(d, J = 17.2 Hz, 1H), 1.54–1.51 (m, 6H), 0.72 (d,
J = 7.0 Hz, 3H); 13C NMR (126 MHz, CDCl3) d 168.0,
164.7, 159.4, 159.3, 131.3, 130.6, 129.2, 129.1, 128.4,
114.2, 114.0, 55.3, 52.9, 50.3, 49.7, 45.0, 18.0, 16.3, 15.4;
[a]2D0 = -360.5 (c = 1.3, CHCl3); HRMS (ESI): m/z cal-
culated for C23H29N2O4: 397.2127, found: 397.2110
[M?H]?.
(S)-[3-2H,6-2H2]-3-Ethyl-1,4-bis((S)-1-(4-
methoxyphenyl)ethyl)piperazine-2,5-dione 3e
(R)-3-Ethyl-1,4-bis((S)-1-(4-
methoxyphenyl)ethyl)piperazine-2,5-dione 4b
After column chromatography (hexane–EtOAc, 3/1), the
product was obtained as an oil in 56% yield after alkylating
2 with ethyl iodide. (Rf = 0.33, EtOAc–hexane, 60/40); 1H
NMR (300 MHz, CDCl3) d 7.16–7.10 (m, 4H), 6.93–6.84
(m, 4H), 5.84 (q, J = 7.1 Hz, 1H), 5.72 (q, J = 7.2 Hz,
1H), 3.81 (s, 6H), 2.02–1.74 (m, 2H), 1.58 (d, J = 7.2 Hz,
3H), 1.47 (d, J = 7.1 Hz, 3H), 1.03–0.95 (m, 3H); 13C
NMR (101 MHz, CDCl3) d 166.4, 165.0, 159.2, 159.1,
130.7, 130.6, 114.1, 114.0, 57.7 (t, J = 21.8 Hz), 55.2,
After column chromatography (hexane–EtOAc, 3/1), the
product was obtained as a white solid of 37% yield after
alkylating 1 with iodoethane. Mp: 107–109.5; (Rf = 0.45,
EtOAc–hexane, 60/40); 1H NMR (500 MHz, CDCl3) d
7.30 (d, J = 8.7 Hz, 2H), 7.17 (d, J = 8.7 Hz, 2H), 6.85–
6.86 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H) 5.88
(q, J = 7.1 Hz, 1H), 5.78 (q, J = 7.1 Hz, 1H), 3.90–3.86
123

Synthesis of a-deuterium-labelled (S)-a-amino acids
855
1
(m, 1H), 3.80 (s, 3H), 3.79 (s,3H), 3.64 (d, J = 17.4 Hz, 1H),
3.38 (d, J = 17.4 Hz, 1H), 1.55 (d, J = 7.1 Hz, 3H), 1.51
(d, J = 7.1 Hz, 3H), 1.13–1.06 (m, 2H), 0.63–0.59 (m,
3H); 13C NMR (151 MHz, CDCl3) d 166.6, 164.9, 159.4,
159.3, 131.6, 130.7, 129.1, 128.5, 114.1, 113.9, 58.4, 55.3,
51.0, 49.8, 45.0, 25.9, 16.5, 15.4, 9.3; [a]2D0 = -351.5
(c = 1.0, CHCl3); HRMS (ESI): m/z calculated for
C24H31N2O4: 411.2284, found: 411.2294 [M?H]?.
(Rf = 0.33, EtOAc–hexane, 60/40); H NMR (500 MHz,
CDCl3) d 7.32–7.29 (m, 2H), 7.19–7.16 (m, 2H), 6.87–6.83
(m, 4H), 5.88 (q, J = 7.1 Hz, 1H), 5.78 (q, J = 7.1 Hz,
1H), 3.79 (s, 3H), 3.78 (s, 3H), 1.55 (d, J = 7.1 Hz, 3H),
1.50 (d, J = 7.1 Hz, 3H), 1.13–1.07 (m, 2H), 0.63–0.57
(m, 3H); 13C NMR (75 MHz, CDCl3) d 166.5, 164.8,
159.2, 159.1, 131.4, 130.6, 129.0, 128.4, 114.0, 113.8, 57.9
(t, J = 20.7 Hz), 55.1, 50.8, 49.6, 45.0–44.3 (m), 26.8,
25.7, 16.3, 15.2, 9.2; [a]2D0 = -352.2 (c = 0.6, CHCl3);
HRMS (ESI): m/z calculated for C24H28D3N2O3: 414.2472,
found: 414.2459.
(R)-3-Benzyl-1,4-bis((S)-1-(4-
methoxyphenyl)ethyl)piperazine-2,5-dione 4c
After column chromatography (hexane–EtOAc, 3/1), the
product was obtained as a white solid of 12% yield after
alkylating 1 with benzyl bromide. Mp: 190.8–192.2°C;
(R)-[3-2H,6-2H2]-3-Benzyl-1,4-bis((S)-1-(4-
methoxyphenyl)ethyl)piperazine-2,5-dione 4f
1
(Rf = 0.42, EtOAc–hexane, 60/40); H NMR (500 MHz,
After column chromatography (hexane–EtOAc, 3/1), the
product was obtained as a white solid of 13% yield after
alkylating 2 with benzyl bromide. Mp: 195.2–196.0°C;
CDCl3) d 7.49–7.46 (m, 2H), 7.09–7.06 (m, 2H), 7.05–7.01
(m, 1H), 6.94 (dd, J = 9.3, 2.5 Hz, 2H), 6.92–6.88 (m,
2H), 6.85–6.81 (m, 2H), 6.70 (d, J = 7.4 Hz, 2H), 5.90 (q,
J = 7.1 Hz, 1H), 5.74 (q, J = 7.1 Hz, 1H), 4.28 (dd,
J = 5.9, 3.5 Hz, 1H), 3.82 (s, 3H), 3.81 (s, 3H), 3.31 (d,
J = 17.1 Hz, 1H), 2.68 (dd, J = 13.8, 3.5 Hz, 1H), 2.08–
2.02 (m, 2H), 1.58 (d, J = 7.1 Hz, 3H), 1.38 (d,
J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3) d 166.2,
165.6, 159.7, 159.3, 134.9, 131.1, 130.2, 129.9, 129.8,
129.2, 128.3, 127.0, 114.2, 113.8, 58.2, 55.4, 55.3, 51.7,
50.4, 44.7, 38.1, 17.1, 16.2; [a]2D0 = -287.0 (c = 0.5,
CHCl3); HRMS (ESI): m/z calculated for C29H31N2O4:
471.2284, found: 471.2284 [M-H]-.
1
(Rf = 0.41, EtOAc–hexane, 60/40); H NMR (300 MHz,
CDCl3) d 7.48 (d, J = 8.5 Hz, 2H), 7.13–6.79 (m, 9H),
6.69 (d, J = 7.5 Hz, 2H), 5.90 (q, J = 7.2 Hz, 1H), 5.74
(q, J = 7.2 Hz, 1H), 3.83 (s, 3H), 3.81 (s, 3H), 2.68 (d,
J = 13.5 Hz, 1H), 2.03 (d, J = 13.5 Hz, 1H), 1.58 (d,
J = 7.2 Hz, 3H), 1.38 (d, J = 7.2 Hz, 3H); 13C NMR
(151 MHz, CDCl3) d 166.3, 165.6, 159.8, 159.3, 134.9,
131.1, 130.2, 129.9, 129.8, 129.2, 128.3, 127.0, 114.3,
113.8, 57.8 (t, J = 22.3 Hz), 55.4, 55.3, 51.7, 50.3, 44.7–
44.0 (m), 38.1, 17.1, 16.2; [a]2D0 = -291.3 (c = 0.8,
CHCl3); HRMS (ESI): m/z calculated for C29H30D3N2O4:
476.2629, found: 476.2642 [M?H]?.
(R)-[3-2H,6-2H2]-1,4-Bis((S)-1-(4-methoxyphenyl)ethyl)-3-
methylpiperazine-2,5-dione 4d
(3S,6S)-1,4-Bis((S)-1-(4-methoxyphenyl)ethyl)-3,6-
dimethylpiperazine-2,5-dione 5a
After column chromatography (hexane–EtOAc, 3/1), the
product was obtained as a white solid of 45% yield after
alkylating 2 with methyl iodide. Mp. 133.7–135.4°C;
After column chromatography (hexane–EtOAc, 3/1), the
product was obtained as an oil of 91% yield after alkylating
3a with iodomethane. (Rf = 0.31, EtOAc–hexane, 60/40);
1H NMR (400 MHz, CDCl3) d 7.16–7.09 (m, 4H), 6.90–
6.85 (m, 4H), 5.75 (q, J = 7.2 Hz, 2H), 3.82 (s, 6H), 3.77
(q, J = 7.1 Hz, 2H), 1.61–1.55 (m, 12H); 13C NMR
(101 MHz, CDCl3) d 168.2, 159.3, 130.8, 128.5, 114.2,
55.3, 52.7, 51.4, 22.1, 17.7; [a]2D0 = -260.1 (c = 2.1,
CHCl3); HRMS (ESI): m/z calculated for C24H31N2O4:
411.2284, found: 411.2285 [M?H]?.
1
(Rf = 0.34, EtOAc–hexane, 60/40); H NMR (300 MHz,
CDCl3) d 7.29 (d, J = 8.6 Hz, 2H), 7.14 (d, J = 8.6 Hz,
2H), 6.90–6.82 (m, 4H), 5.91–5.80 (m, 2H), 3.80 (s, 3H),
3.79 (s, 3H),1.54 (d, J = 2.9 Hz, 3H), 1.51 (d, J = 2.9 Hz,
3H), 0.71 (s, 3H); 13C NMR (151 MHz, CDCl3) d 168.1,
164.7, 159.4, 159.3, 131.3, 130.7, 129.2, 128.4, 114.2,
114.0, 55.3, 52.5 (t, J = 22.7 Hz), 50.3, 49.7, 45.0–44.5
(m), 17.9, 16.4, 15.5; [a]2D0 = -297.6 (c = 0.7, CHCl3);
HRMS (ESI): m/z calculated for C23H26D3N2O4: 400.2316,
found: 400.2313 [M?H]?.
(3S,6S)-3,6-Diethyl-1,4-bis((S)-1-(4-
methoxyphenyl)ethyl)piperazine-2,5-dione 5b
(R)-[3-2H,6-2H2]-3-Ethyl-1,4-bis((S)-1-(4-
methoxyphenyl)ethyl)piperazine-2,5-dione 4e
After column chromatography (hexane–EtOAc, 3/1), the
product was obtained as a yellow oil after alkylating 3b
1
with iodoethane. (Rf = 0.60, EtOAc–hexane, 60/40); H
After column chromatography (hexane–EtOAc, 3/1), the
product was obtained as a white solid of 36% yield after
NMR (500 MHz, CDCl3) d 7.12–7.09 (m, 4H), 6.87–6.85
(m, 4H), 5.76 (q, J = 7.2 Hz, 2H), 3.81 (s, 6H), 3.53 (dd,
alkylating
2 with ethyl iodide. Mp: 121.9–123.4;
123

856
E. O’Reilly et al.
J = 9.7, 4.6 Hz, 2H), 1.95–1.84 (m, 4H), 1.57–1.56 (m,
6H), 1.09–1.05 (m, 6H); 13C NMR (126 MHz, CDCl3) d
167.0, 159.1, 128.8, 128.3, 114.1, 58.6, 55.2, 51.2, 29.8,
17.7, 11.4; HRMS (ESI): m/z calculated for for
C26H35N2O4 439.2597, found: 439.2597 [M?H]?; The
specific rotation and yield of this compound was not
measured, due to the compound being insufficiently pure.
and yield of this compound was not measured, due to the
compound being insufficiently pure.
(3S,6S)-[3-2H,6-2H]-3,6-Dibenzyl-1,4-bis((S)-1-(4-
methoxyphenyl)ethyl)piperazine-2,5-dione 5f
After column chromatography (hexane–EtOAc, 3/1), the
product was obtained as an oil of 91% yield after alkylating
3f with benzyl bromide. (Rf = 0.58, EtOAc–hexane, 60/
(3S,6S)-3,6-Dibenzyl-1,4-bis((S)-1-(4-
methoxyphenyl)ethyl)piperazine-2,5-dione 5c
1
40); H NMR (300 MHz, CDCl3) d 7.34–7.20 (m, 6H),
7.15–7.01 (m, 8H), 6.86–6.79 (m, 4H), 5.75–5.64 (m, 2H),
3.79 (s, 6H), 2.85 (d, J = 14.5 Hz, 2H), 2.68 (d,
J = 14.5 Hz, 2H), 1.56 (d, J = 7.3 Hz, 6H); 13C NMR
(75 MHz, CDCl3) d 166.7, 159.2, 137.0, 130.6, 129.5,
128.8, 128.5, 127.0, 114.1, 58.5 (t, J = 20.7 Hz), 55.2,
52.5, 40.9, 18.1; [a]D20 = -99.0 (c = 0.3, CHCl3); HRMS
(ESI): m/z calculated for C36H37D2N2O4: 565.3035, found:
565.3027[M?H]?.
After column chromatography (hexane–EtOAc, 3/1), the
product was obtained as a white waxy solid in 90% yield
after alkylating 3c with benzyl bromide. (Rf = 0.61,
EtOAc–hexane, 60/40); 1H NMR (500 MHz, CDCl3) d
7.32–7.22 (m, 6H), 7.12–7.08 (m, 4H), 7.07–7.03 (m, 4H),
6.84–6.81 (m, 4H), 5.70 (q, J = 7.2 Hz, 2H), 3.96 (dd,
J = 7.0, 4.4 Hz, 2H), 3.81 (s, 6H), 2.82 (dd, J = 14.5,
4.4 Hz, 2H), 2.70 (dd, J = 14.5, 7.0 Hz, 2H), 1.58–1.55 (d,
J = 7.2 Hz, 6H); 13C NMR (126 MHz, CDCl3) d 166.8,
159.3, 137.1, 130.7, 129.6, 128.9, 128.6, 127.0, 114.2,
58.9, 55.3, 52.7, 41.1, 18.2; [a]2D0 = -83.1 (c = 0.8,
CHCl3); HRMS (ESI): m/z calculated for C36H39N2O4:
563.2910, found: 563.2919 [M?H]?.
(3S,6S)-[3-2H,6-2H]-3,6-Dibenzylpiperazine-2,5-dione 6f
DKP 5f (1.00 g, 1.77 mmol) was dissolved in CH3CN/H2O
(3:2) and CAN (932 mg, 7.1 mmol) was added. The solu-
tion was stirred at room temperature for 2 h. The precipitate
was filtered, washed with H2O and dried in vacuo. Off-
1
white solid; Mp: 305°C (decomp); H NMR (600 MHz,
(3S,6S)-[3-2H,6-2H]-1,4-Bis((S)-1-(4-
methoxyphenyl)ethyl)-3,6-dimethylpiperazine-2,5-dione 5d
DMSO-d6) d 7.92 (s, 2H), 7.40–7.02 (m, 10H), 2.61 (d,
J = 13.4 Hz, 2H), 2.27 (d, J = 12.9 Hz, 2H); 13C NMR
(151 MHz, DMSO-d6) d 166.1, 136.5, 129.8, 128.2, 126.5,
55.3 (t, J = 15.5 Hz), 40.1. The specific rotation of this
compound was not recorded due to solubility problems.
After column chromatography (hexane–EtOAc, 3/1), the
product was obtained as a clear oil of 90% yield after
alkylating 3d with methyl iodide. (Rf = 0.30, EtOAc–
1
hexane, 60/40); H NMR (400 MHz, CDCl3) d 7.15–7.11
General procedure for the deprotection and hydrolysis
of 7(d–f)
(m, 4H), 6.90–6.86 (m, 4H), 5.75 (q, J = 7.2 Hz, 2H), 3.82
(s, 6H), 1.61–1.55 (m, 12H); 13C NMR (101 MHz, CDCl3)
d 168.2, 159.2, 130.8, 128.4, 114.2, 55.3, 52.4 (t,
J = 21.0 Hz), 51.3, 21.9, 17.7; [a]2D0 = -260.5 (c = 1.7,
CHCl3); HRMS (ESI): m/z calculated for C24H29D2N2O4:
413.2409, found: 413.2389 [M?H]?.
Compounds 5d, e (1.2 mmol) were refluxed in 57% HI
(3 mL) for 2 h (Balducci et al. 2009b and references
therein). The crude solution was loaded directly onto a
column containing the acid ion-exchange resin Dowex 50
WX 8. The resin was washed with distilled water (95),
before eluting the amino acid with NH4OH (5 M). The
aqueous solution was concentrated in vacuo and the pure
amino acids were isolated in quantitative yields.
(3S,6S)-[3-2H,6-2H]-3,6-Diethyl-1,4-bis((S)-1-(4-
methoxyphenyl)ethyl)piperazine-2,5-dione 5e
After column chromatography (hexane–EtOAc, 3/1), the
product was obtained as an oil after alkylating 3e with
1
iodoethane. (Rf = 0.45, EtOAc–hexane, 60/40); H NMR
Hydrolysis of 6f
(500 MHz, CDCl3) d 7.13–7.08 (m, 4H), 6.88–6.84 (m,
4H), 5.76 (q, J = 7.2 Hz, 2H), 3.81 (s, 6H), 1.95–1.82 (m,
4H), 1.56 (d, J = 7.2 Hz, 6H), 1.09–1.04 (m, 6H); 13C
NMR (101 MHz, CDCl3) d 166.9, 159.0, 131.1, 128.2,
113.9, 58.1 (t, J = 21.2 Hz), 55.0, 51.0, 30.1, 29.5, 17.5,
11.2; HRMS (ESI): m/z calculated for C26H33D2N2O4:
441.2722, found: 441.2709 [M?H]?. The specific rotation
Compound 6f (1.2 mmol) was stirred in refluxing 6 M HCl
(3 mL) for 2 h. The crude solution was loaded directly onto
a column containing the acid ion-exchange resin Dowex 50
WX 8. The resin was washed with distilled water (95)
before eluting the amino acid with NH4OH (5 M). The
aqueous solution was concentrated in vacuo and the pure
amino acid 7f was isolated in quantitative yield.
123

Synthesis of a-deuterium-labelled (S)-a-amino acids
(2S)-[2-2H]-Alanine 7d
857
Acknowledgments We express our gratitude to Sustainable Energy
Ireland, administered by the Irish Research Council for Science,
Engineering and Technology (IRCSET) for funding Elaine O’Reilly.
We would also like to acknowledge the facilities of the Centre for
Synthesis and Chemical Biology (CSCB), funded by the Higher
Education Authorities Programme for Research in Third-Level
Institutions (PRTLIs). We are grateful to Prof. Patrick Guiry for the
use of his Perkin-Elmer 241 polarimeter.
1
White solid; Mp: 285–287°C; H NMR (500 MHz, D2O)
d 1.53 (s, 3H); 13C NMR (126 MHz, D2O) d 175.7, 50.3
(t, J = 22.7 Hz), 16.1. [a]2D0 = ?13.6 (c = 0.8, 1 M HCl).
(2S)-[2-2H]-2-Aminobutanoic acid 7e
1
White solid; H NMR (400 MHz, D2O) d 1.94 – 1.83 (m,
References
2H), 1.02–0.93 (m, 3H); 13C NMR (101 MHz, D2O) d
175.5, 56.2 (t, J = 22.4 Hz), 24.2, 9.1. The MP, yield and
specific rotation values of this compound were not mea-
sured, due to the compound being insufficiently pure.
Bachmann S, Knudsen KR, Jorgensen KA (2004) Mimicking
enzymatic transaminations: attempts to understand and develop
a catalytic asymmetric approach to chiral a-amino acids. Org
Biomol Chem 2:2044–2049
Balducci D, Lazzari I, Monari M, Piccinelli F, Porzi G (2009a) (S)-a-
methyl, a-amino acids: a new stereocontrolled synthesis. Amino
Acids. doi:10.1007/s00726-009-0289-9
(2S)-[2-2H]-Phenylalanine 7f
Balducci D, Contaldi S, Lazzari I, Porzi G (2009b) A highly efficient
stereocontrolled synthesis of (S)-20,63/3/2010-dimethyltyrosine
[(S)-DMT]. Tetrahedron Asymmetr 20:1398–1401
Bull SD, Davies SG, O’Shea MD (1998a) Stereoselective conjugate
addition of organocuprates to a dehydroalanine derived diketo-
piperazine. J Chem Soc Perkin Trans 1(1):3657–3658
Bull SD, Davies, SG, Epstein SW, Ouzman VA (1998b) Chiral relay
auxiliary for the synthesis of enantiomerically pure a-amino
acids. Chem Commun 659–660
White solid; Mp: 270°C (decomp) [lit. ref. Mp: 264°C]
(Rose et al. 1995); H NMR (400 MHz, D2O) d 7.47–7.29
(m, 5H), 3.28 (d, J = 14.5 Hz, 1H), 3.11 (d, J = 14.5 Hz,
1H); 13C NMR (101 MHz, D2O) d 174.5, 135.7, 129.98,
129.7, 128.3, 56.3 (t, J = 22.5 Hz), 36.9; [a]2D0 = -32.5
(c = 0.8, H2O) [lit. ref. [a]2D0 = -32.5] (Gout et al. 1978).
1
Isomerisation of mixture of (3R,6R) and (3R,6S) isomers
yielding 5d and 8d
Bull SD, Davies SG, Garner AC, Parkes AL, Roberts PM, Sellers
TGR, Smith AD, Tamayo JA, Thomson JE, Vickers RJ (2007)
On the origins of diastereocelectivity in the alkylation of
diketopiperazine enolates. New J Chem 31:486–495
The mixture of isomers (413 mg, 1.0 mmol) was dissolved
in CH3OD (3 mL) and NaOH (40 mg, 1.0 mmol) was added.
The reaction was stirred under reflux for 2 h. D2O (5 mL)
was added and the solution was extracted with EtOAc
(5 9 5 mL). The organic layers were combined, dried over
MgSO4 and concentrated in vacuo. The isomers were purified
by column chromatography (Hexane–EtOAc, 3/1) yielding
(3S,6S)-[3-2H,6-2H]-1,4-Bis((S)-1-(4-methoxyphenyl)
ethyl)-3,6-dimethylpiperazine-2,5-dione 5d (182 mg, 44%
yield) as a clear oil and (3R,6R)-[3-2H,6-2H]-1,4-Bis((S)-1-
(4-methoxyphenyl)ethyl)-3,6-dimethylpiperazine-2,5-dione
8d (190 mg, 46% yield) as a white solid. Spectroscopic data
for compound 5d was identical to that reported previously.
8d M.p: 141.9-143.7°C; (Rf = 0.60, EtOAc–hexane, 60/40);
1H NMR (300 MHz, CDCl3) d 7.29 (m, 4H), 6.95–6.81 (m,
4H), 5.80 (q, J = 7.1 Hz, 2H), 3.80 (s, 6H), 1.55 (d,
J = 7.1 Hz, 6H), 0.88 (s, 6H); 13C NMR (75 MHz, CDCl3) d
167.9, 159.3, 131.7, 129.1, 113.9, 55.2, 52.8 (t, J = 21.5),
50.7, 20.4, 16.2; [a]D20 = -307.9 (c = 1.1, CHCl3); HRMS
(ESI): m/z calculated for C24H29D2N2O4: 413.2409, found:
413.2419 [M?H]?.
Davies SG, Garner AC, Ouzman VA, Roberts PM, Smith AD, Snow
EJ, Thomson JE, Tamayo JA, Vickers RJ (2007) Diastereose-
lective synthesis of quaternary a-amino acids from diketopiper-
azine templates. Org Biomol Chem 5:2138–2147
Ducho C, Hamed RB, Batchelar ET, Sorensen JL, Odell B, Schofield
CJ (2009) Synthesis of regio- and stereoselectively deuterium-
labelled derivatives of L-glutamate semialdehyde for studies on
carbapenem biosynthesis. Org Biomol Chem 7:2770–2779
Felpin FX, Doris E, Wagner A, Valleix A, Rousseau B, Mioskowski
C (2000) Rearrangement of a-amino cyclopropanone hydrate: a
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