(S)-α-methyl,α-amino acids: A new stereocontrolled synthesis

Article abstract of DOI:10.1007/s00726-009-0289-9

A new and convenient stereocontrolled synthesis of the optically pure (S)-α-methyl,α-amino acids 6(a-d) that exploits the chiral synthon 1,4-N,N-[(S)-1-phenylethyl]-piperazine-2,5-dione (1) is described. The (S)-1-phenylethyl group, bonded to each of the N-atoms of the 2,5-diketopiperazine, acts as a chiral inductor in the first alkylation, while the steric hindrance appears to be the determining factor of stereocontrol in third and forth alkylation.

Full text of DOI:10.1007/s00726-009-0289-9

Amino Acids (2010) 38:829–837
DOI 10.1007/s00726-009-0289-9
ORIGINAL ARTICLE
(S)-a-methyl,a-amino acids: a new stereocontrolled synthesis
Daniele Balducci Æ Ilaria Lazzari Æ Magda Monari Æ
Fabio Piccinelli Æ Gianni Porzi
Received: 30 January 2009 / Accepted: 31 March 2009 / Published online: 12 April 2009
Ó Springer-Verlag 2009
Abstract A new and convenient stereocontrolled syn-
thesis of the optically pure (S)-a-methyl,a-amino acids
6(a–d) that exploits the chiral synthon 1,4-N,N-[(S)-1-
phenylethyl]-piperazine-2,5-dione (1) is described. The
(S)-1-phenylethyl group, bonded to each of the N-atoms of
the 2,5-diketopiperazine, acts as a chiral inductor in the
first alkylation, while the steric hindrance appears to be the
determining factor of stereocontrol in third and forth
alkylation.
incorporating such amino acids and then alter their bio-
logical properties (Wirth 1997; Gibson et al. 1999).
Moreover, several molecules with therapeutic effects con-
taining unnatural a-amino acids are known: a-methyl,
a-amino acids are present in natural antibiotics (Yano et al.
1997; Becker et al. 1997) and a-alkylated,a-amino acids
are useful in studies of enzyme mechanisms (Walsh et al.
1980). Furthermore, these compounds can also be used as
chiral building blocks in organic synthesis.
Various asymmetric synthetic approaches to this class of
non-proteinogenic a-amino acids have been developed, as
reported in very useful reviews by Cativiela and Diaz-
De-Villegas (1998), Xu et al. (2005), Vogt and Brase (2007),
and recently in a paper of Davies et al. (2007). However, to
the best of our knowledge, a general and efficient synthesis
of enantiomerically pure a-methyl,a-amino acids with
potential macro scale applicability has not been reported so
far. Thus, we have developed a versatile and economical
stereocontrolled synthesis which is an extension of our
original strategy accomplished for the stereoselective
approach to natural and unnatural a-amino acids. In fact,
the procedure here reported is based on our experience
acquired in many years making use of the chiral 2,5-
diketopiperazine derivative 1 (Piccinelli et al. 2003; Ferioli
et al. 2002; Paradisi et al. 2000a, b, 2002; Porzi and Sandri
1994; Orena et al. 1992, 1993) and represents an
improvement of the synthetic methodology previously
employed by us (Carloni et al. 1998; Porzi and Sandri
1998) which involves the use of an optically active mor-
pholinone derivative as chiral synthon. This procedure
provides a more convenient synthetic route as two equiv-
alents of a-methyl-a-amino acids are produced from one
equivalent of the corresponding synthon with a remarkable
improvement of atom-economy. The advantage of our
new method is the stereocontrolled alkylation of the
Keywords Diketopiperazine derivatives ꢀ
a-Methyl-a-amino acids ꢀ Asymmetric synthesis
Introduction
The stereocontrolled synthesis of optically active unnatural
a,a-dialkyl-a-amino acids containing quaternary stereo-
center, represents a very interesting goal for synthetic
chemistry (Williams 1989). The interest toward the a,a-
disubstituted a-amino acids, especially a-methyl,a-amino
acids, is due to their metabolic stability and rigidity that
may reduce the conformational freedom of peptides
D. Balducci (&) ꢀ M. Monari ꢀ G. Porzi
`
Dipartimento di Chimica ‘‘G.Ciamician’’, Universita di Bologna,
Via Selmi 2, 40126 Bologna, Italy
e-mail: daniele.balducci4@unibo.it
I. Lazzari
Dipartimento di Scienze Farmaceutiche, Universita di Ferrara,
`
Via Fossato di Mortara 17-19, 44100 Ferrara, Italy
F. Piccinelli
Laboratorio di Chimica dello stato solido DB,
`
Universita di Verona, Verona, Italy
123

830
D. Balducci et al.
Scheme 1 i Na2CO3ꢀ10H2O,
in water/acetone (Orena et al.
1992), ii NaOH, in CH3CN
(Cho et al. 2004), iii Metallation
of 1 with 1 M LHMDS in dry
THF, then R-X, iv Metallation
of 3 with 1 M LHMDS in dry
THF, then R-X; v Metallation of
4 with 1 M LHMDS in dry
THF, then CH3I, vi Refluxing in
57% HI, then treatment with
Dowex 50 WX 8 ion-exchange
resin. R = (a) CH3–CH2, (b)
CH3–CH2–CH2, (c) CH3–
O
CH3
O
CH3
O
i
iii
ii
N
Ph
6
Ph
Cl
N
H
3
Ph
N
Cl
Cl
CH3
O
1
O
O
CH3
O
CH3
O
O
CH3
6
R
H
Ph
Ph
N
Ph
N
N
3
iv
S
3
R
3
S
Ph
N
S
+
Ph
N
H
R
Ph
N
H
R
R
(CH2)2–CH2, (d) Ph–CH2
H
CH3
CH3
O
CH3
2(a-d)
3(a-d)
4(a-d)
O
O
CH3
O
H3C
R
H3C
Ph
N
R
v
vi
2
OH
N
Ph
R
CH3
NH2
CH3
6(a-d)
5(a-d)
intermediate 3 which occurs with practically total diaste-
reoselectivity furnishing only the cis derivative (3S,6S)-4,
as we have already observed in analogous cases (Piccinelli
et al. 2003; Ferioli et al. 2002; Paradisi et al. 2000a, b,
2002; Porzi and Sandri 1994; Orena et al. 1992, 1993).
Besides, by a simple one pot procedure the intermediate 5
is converted to the title products in high yield (Scheme 1).
et al. 2003; Ferioli et al. 2002; Paradisi et al. 2000a, b,
2002; Porzi and Sandri 1994; Orena et al. 1992, 1993).
Along with the intermediate 4, also the corresponding tri-
alkylderivative is recovered in about 20% of the overall
yield of the reaction except when R = CH2Ph.
The 3,6-dialkyl derivative 4 was then alkylated twice in
a one pot procedure with CH3I obtaining the tetraalkylated
2,5-diketopiperazine (3S,6S)-5 (Scheme 1). The stereo-
chemistry of compounds 5 was confirmed by X-ray crys-
tallography where possible. Otherwise, determination of
the stereochemistry was achieved by analysis of the NMR
spectra, in which half of the expected signals were present
in relation to the number of protons and carbon atoms in
the compound. This is evidently due to the magnetic
equivalence of protons and carbon atoms (Orena et al.
1992, 1993; Porzi and Sandri 1994), that is a C2 symmetry
axis, which is not present in the trans derivatives (see as
example compounds 5a and 8). In this step, the steric
interaction appears to be the determining factor of the
stereochemical control because the alkylation occurs with a
practically total stereoselectivity because the second alkyl
group, presently CH3, is introduced at C-3 in trans con-
figuration with respect to the bulkier group at C-6 position.
Thus, the stereochemical outcome of the third and fourth
alkylation is most likely controlled by the relative bulki-
ness of the R group with respect to CH3. Consequently, it
can be asserted that the first alkyl group introduced must be
bulkier than the second one in order to obtain both centres
Results and discussion
The versatile chiral synthon 1,4-N,N-[(S)-phenethyl]-
piperazine-2,5-dione (1) previously employed by us (Pic-
cinelli et al. 2003; Ferioli et al. 2002; Paradisi et al. 2000a,
b, 2002; Porzi and Sandri 1994; Orena et al. 1992, 1993),
was easily obtained in good yield by a modified procedure
(Porzi and Sandri 1994; Orena et al. 1992). In fact, the
chloroacetamide of (S)-phenylethylamine, obtained from
chloroacetyl chloride and (S)-phenyl ethylamine, was
coupled in one pot in an alkaline medium furnishing 1
(Scheme 1) in good yield (Cho et al. 2004). In the first
alkylation reaction the diastereomer (3S)-3 was obtained in
20–50% d.e. because of the presence of the chiral inductor
group (S)-1-phenylethyl bonded to each N-atom of the 2,5-
diketopiperazine. The second alkylation gave the dialkyl
derivative (3S,6S)-4 with a total 1,4-cis induction, the d.e.
1
determined by H NMR being greater than 98%, as we
have already observed for similar substrates (Piccinelli
123

(S)-a-methyl,a-amino acids
831
Scheme 2 Dimethyl-7 and
tetraalkyl-8-intermediates
O
O
O
H
CH3
Ph
H
CH3
Ph
C2H5
H3C
H3C
N
N
R
S
S
S
Ph
N
Ph
H3C
N
C2H5
CH3
CH3
H3C
H
H
O
7
8
in the S-configuration. As a matter of fact, when R = CH3,
the alkylation of 7 with C2H5I gave only the undesired
tetralkyl derivative (3S,6R)-8 as confirmed from the NMR
spectra of the product (Scheme 2). The stereochemistry of
compound 8 has been determinate by X-ray (Fig. 5).
Debenzylation to remove the chiral inductor and hydrolytic
cleavage of heterocyclic ring were simply carried out in
one step by refluxing in 57% HI, according to the proce-
dure described already (Orena et al. 1992). After adsorp-
tion on an ion-exchange resin in acid form (Dowex 50WX
8, 20–50 mesh), the pure a-methyl,a-amino acids 6 were
recovered by eluting with 5 M NH4OH. The conversion of
the intermediates 5 to the (S)-a-substituted alanine deriv-
atives 6 was monitored by TLC and 1H NMR showing that
the debenzylation reaction occurs before the heterocyclic
ring opening.
stereocenters was confirmed both by single crystal X-ray
determination (see later) performed on 5(a, d) and the cis-
3,6-dibenzyl-3-methyl derivative 9 precursor of 5d (Fig. 1)
and by the coincidence of the specific rotation values of the
title a-methyl-a-amino acids 6(a–d) with those reported in
literature (see ‘‘Experimental’’).
We believe that the strategy described above is inter-
esting as the (3R)-diastereomer 2 can also be utilized. In
fact, as we have already observed (Ferioli et al. 2002;
Paradisi et al. 2002) alkylation of the isomer 2 gave a
mixture of cis and trans isomers and the latter one can be
isomerized in an alkaline solution to a 50% mixture of the
cis isomers (3R,6R) and (3S,6S). Both the cis isomers,
separable by silica gel chromatography, can be employed
to obtain the a,a0-disubstituted a-amino acids in enantio-
meric pure form.
The absolute configuration of 2 and 3 was assigned by
means of 1H-NMR spectroscopy on the basis of the
observed shielding effect (Porzi and Sandri 1994; Orena
et al. 1992) exerted by the phenyl ring on the (C-3)-H in 3
with respect to 2. Analogously, the stereochemistry of 4 and
5 was deduced taking into account such a shielding effect
suffered by (C-3)-H and (C-6)-H in 4 and by (C-3)-CH3 and
(C-6)-CH3 in 5. For instance, the (C-3)-H in 2d and 3d
resonates as dd at 4.3 ppm and at 4.1 ppm, respectively, and
the signals of (C-3)-H and (C-6)-H in 4d are overlapped
resonating at 4.0 ppm according to that previously observed
(Paradisi et al. 2002). In addition, as already registered for
analogous substrates (Porzi and Sandri 1994; Orena et al.
1992), the 1H- and 13C NMR spectra of the intermediates 4
and 5 show half signals indicating the presence of a C2
symmetry axis, typical of the cis derivative, which causes
the overlapping of the magnetically equivalent nucleus.
Furthermore, the configuration of the new C-3 and C-6
X-ray diffraction studies
The X-ray crystal structures of 5(a, d) and 9 are shown in
Fig. 2 and the ORTEP drawing of 5(a, d), 8 and 9 are
reported in Fig. 3. The absolute configuration of C(2) and
C(4) stereogenic carbons in 5(a, d), 8 and 9 was deter-
mined from the X-ray data with the help of known con-
figuration at C(5) and C(13) stereocenters fixed by the
synthetic route.
It is worth mentioning that the C(2) and C(4) carbon
stereocentres have the same (S) configuration in all mole-
cules. The diketopiperazine ring conformations, in the
three solid state structures, are different (see Fig. 4): in 5a,
the heterocyclic ring slightly deviates from planarity, 5d
has a boat conformation and 9 has five almost coplanar
atoms of the ring [C(1), C(2), C(3), N(1) and N(2)] and
Fig. 1 Tetraalkyl-5(a, d) and
trialkyl-9 intermediates
O
O
H
O
H
H
CH3
Ph
CH3
Ph
CH3
Ph
C2H5
H3C
H3C
PhH2C
H
PhH2C
Ph
N
N
N
N
N
N
Ph
Ph
H3C
CH2Ph
CH3
CH2Ph
CH3
C2H5
CH3
H3C
H
H3C
H
H
O
O
O
5d
5a
9
123

832
D. Balducci et al.
Fig. 2 X-ray crystal structures
of 5(a, d) and 9. Configurations
of the stereogenic carbons (in
the three structures): C(2) (S);
C(4) (S); C(5) (S); C(13) (S).
C(2) and C(4) atoms correspond
to C(3) and C(6) atoms in
Scheme 1
Fig. 3 ORTEP drawing of
5(a, d), 8 and 9. Thermal
ellipsoids are at 30%
probability level
Fig. 4 Conformations of
diketopiperazine rings in 5(a, d)
and 9
˚
C(4) is out of the plane of 0.317(2) A. The three molecules
differ also for the orientation of both alkyl groups and of
the (S)-phenylethyl chiral fragment. In this context, the
conformation of 5d is influenced by two weak intramo-
H(31)—p 140.2(4)°] (Fig. 2). These values are in agree-
ment with the ones reported in literature for X–H—p
interaction (Najera et al. 2000). A close inspection of the
crystal packings reveals the absence of significant inter-
molecular contacts except for an hydrogen bond interaction
between an amidic oxygen and a proton of a molecule of
˚
lecular C--H ꢀ ꢀ ꢀ pPh hydrogen bonds [H(31)—p 2.75(3) A,
˚
C(31)—p 3.52(4) A and C(31)-H(31)—p 141.3(5)° and
˚
˚
˚
methanol that crystallized in 5a [O(methanol)-H1 1.03(4) A,
H(27)—p 2.83(2) A, C(31)—p 3.59(3) A and C(31)-
123

(S)-a-methyl,a-amino acids
833
Optical rotation values were measured at 25°C on a Perkin-
Elmer 343 polarimeter. Dry THF was distilled from sodium
benzophenone ketyl. Chromatographic separations were
performed with silica gel 60 (230–400 mesh).
For the spectroscopic data of compounds 2(b, d), 3(b, d)
and 4(b, d) see Porzi and Sandri (1994), while the data of
compound 7 were described by Orena et al. (1992).
The diffraction experiments for the 5(a, d), 8 and 9 were
carried out at room temperature on a Bruker APEX II
CCD-based diffractometer using graphite monochromated
˚
Mo-Ka radiation (k = 0.71073 A). Intensity data were
measured over full diffraction spheres using 0.3° wide x
scans, crystal-to-detector distance 5.0 cm. The software
SMART was used for collecting frames of data, indexing
reflections and determination of lattice parameters. The
collected frames were then processed for integration by
software SAINT and an empirical absorption correction
was applied with SADABS. The structures were solved by
direct methods (SIR 97) and subsequent Fourier syntheses,
and refined by full-matrix least-squares calculations on F2
(SHELXTL) attributing anisotropic thermal parameters to
the non-hydrogen atoms.
Fig. 5 Molecular structure of 8. Configurations of the stereogenic
carbons are: C(2) (S), C(4) (R), C(5) (S), C(13) (S)
O(methanol)-H1 ꢀ ꢀ ꢀ O(1) 167(4)°, O(methanol) ꢀ ꢀ ꢀ O(1)
˚
2.765(3) A].
The stereochemistry of 8 (Fig. 5) shows that the mole-
cule differs from 5a for the configuration of the stereogenic
carbon C(4) which is R instead of S.
The C1 molecular symmetry of 8, derived from the
rationalization of the 1H and 13C-NMR spectra in solution,
is in agreement with the observed molecular structure.
Crystallographic in CIF format for 5a (CCDC 715767),
5d (CCDC 715768), 8 (CCDC 715769) and 9 (CCDC
715770) are available free of charge via the internet at
http://pubs.acs.org.
General procedure for the conversion of 1–2 and 3
To a stirred solution of 1 (4.67 g, 14.5 mmol) in dry THF
(70 mL), cooled at -78°C, 14.5 mL (1 M solution in THF)
of LHMDS was added. After 1 h the alkyl halide
(14.5 mmol) was added dropwise to the reaction mixture
and stirred for about 1 h at -78°C. Subsequently, the
cooling bath was removed and after about 2 h the reaction
was quenched by the addition of water (70 mL) and
extracted with ethyl acetate. The organic solution was dried
and the solvent evaporated under reduced pressure. The
residue was submitted to silica gel chromatography eluting
with hexane/ethyl acetate to separate the diastereomers 2
and 3.
Conclusions
We have demonstrated that the readily available chiral
diketopiperazine 1 is a very useful synthon for the stereo-
controlled synthesis of a-substituted alanine derivatives.
Thus, we believe that it would be interesting to undertake
further work to optimize and extend the methodology to
other unnatural a-amino acids present in biologically active
compounds. Our synthetic route is suitable for macro scale
applicability. In fact, simply and well-understood reactions
are employed and all the reaction intermediates are
obtained in good yield. The procedure here described was
patented (deposition number RM2008A000118).
(3R)-1,4-N,N-[(S)-phenylethyl]-3-ethylpiperazine-2,5-
dione 2a
After chromatography (EtAc-Hex: 25/75) the product was
obtained as a white solid in 35% yield by alkylating 1 with
1
iodoethane. H NMR d: 0.61 (t,3H,J = 7.5); 1.09 (m,2H),
Experimental
1.56 (d,3H,J = 7.2); 1.60 (d,3H,J = 7.2), 3.54 (qAB,2H,
J = 17.4), 3.92 (dd, 1H,J = 4.8, 8.1), 5.85 (q,1H,J = 7.2),
5.94 (q,1H,J = 7.2), 7.31 (m,10ArH). 13C NMR d: 9.2,
15.1, 16.1, 25.8, 45.0, 50.2, 51.4, 58.5, 127.2, 127.8, 128.0,
128.1, 128.5, 128.7, 138.5, 139.4, 164.9, 166.5. [a]D -324.3
(c 1.0, CHCl3). M.p. 156–157°C. Anal. Calcd. for C22H26N2O2:
C,75.4; H,7.48; N,7.99. Found: C,75.65; H,7.50; N,7.95
(Rf = 0.60, EtAc/Hex: 35/65).
General
Melting points are uncorrected. H- and 13C-NMR spectra
1
were recorded on a Gemini spectrometer at 300 MHz using
CDCl3 as the solvent, unless otherwise stated. Chemical
shifts are reported in ppm using the residual solvent signal
as reference and the coupling constants (J) are in Hz.
123

834
D. Balducci et al.
(3R)-1,4-N,N-[(S)-phenylethyl]-3-butylpiperazine-2,5-
dione 2c
the cooling bath removed. The reaction, followed by TLC,
was quenched after 5–6 h by adding water (60 mL). The
reaction product was extracted with ethyl acetate, the
organic solution dried and the solvent evaporated under
reduced pressure. The residue was purified by silica gel
chromatography eluting with hexane/ethyl acetate.
After chromatography (EtAc-Hex: 25/75 the product was
obtained as white solid in 25% yield by alkylating 1
with iodobutane. 1H NMR d: 0.66 (m,3H), 0.8–1.17
(m,6H), 1.58 (d,3H,J = 7.2), 1.62 (d,3H,J = 7.2), 3.57
(qAB,2H,J = 17.4), 3.97 (m,1H), 5.91 (q,1H,J = 7.2); 5.96
(q,1H,J = 7.2), 7.38 (m,10ArH). 13C NMR d: 13.6, 15.0,
16.0, 22.0, 26.7, 32.2, 45.0, 50.2, 51.2, 57.3, 127.2, 127.9,
128.0, 128.1, 128.6, 128.7, 138.6, 139.4, 164.9, 166.8. [a]D
-350.1 (c 0.4, CHCl3). M.p. 135–136°C. Anal. Calcd. for
C24H30N2O2: C,76.16; H,7.99; N,7.40. Found: C,75.98;
H,7.96; N,7.42 (Rf = 0.52, EtAc/Hex: 35/65).
(3S,6S)-1,4-N,N-[(S)-phenylethyl]-3,6-diethylpiperazine-
2,5-dione 4a
After chromatography (EtAc-Hex: 25/75) the product was
obtained as a wax in 85% yield by alkylating 3a with
iodoethane. 1H NMR d: 1.11 (t,6H,J = 7.4), 1.63
(d,6H,J = 7.2); 1.95 (m,4H), 3.58 (dd,2H,J = 5.8, 8.4),
5.84 (q,2H,J = 7.2), 7.28 (m,10ArH). 13C NMR d: 11.2,
17.2, 29.6, 51.4, 58.6, 126.8, 127.3, 127.9, 128.5, 139.2,
166.7. [a]D -136 (c 0.2, CHCl3). Anal. Calcd. for
C24H30N2O2: C,76.16; H,7.99; N,7.4. Found: C,76.76;
H,8.01; N,7.38 (Rf = 0.60, EtAc/Hex: 35/65).
(3S)-1,4-N,N-[(S)-phenylethyl]-3-ethylpiperazine-2,5-
dione 3a
After chromatography (EtAc-Hex: 25/75) the product was
obtained as a wax in 55% yield by alkylating 1 with
iodoethane. 1H NMR d: 1.03 (t,3H,J = 7.4), 1.54
(d,3H,J = 7.2), 1.65 (d,3H,J = 7.2), 1.78–2.07 (m,2H),
3.71 (dd,1H,J = 4.0, 8.4), 3.78 (qAB,2H,J = 17.4), 5.82
(q,1H,J = 7.2), 5.93 (q,1H,J = 7.2), 7.29 (m,10ArH). 13C
NMR d: 9.4, 15.4, 17.3, 27.5, 44.5, 49.8, 52.0, 58.4, 127.0,
127.1, 127.9, 128.0, 128.7, 128.8, 138.7, 139.0, 165.2,
166.5. [a]D -263.5 (c 0.3, CHCl3). Anal. Calcd. for
C22H26N2O2: C,75.40; H,7.48; N,7.99. Found: C,75.55;
H,7.45; N,8.02 (Rf = 0.50, EtAc/Hex: 35/65).
(3S,6S)-1,4-N,N-[(S)-phenylethyl]-3,6-dibutylpiperazine-
2,5-dione 4c
After chromatography (EtAc-Hex: 25/75) the product was
obtained as a wax in 90% yield by alkylating 3c with
iodobutane. The reaction was quenched after 7–8 h 1H
NMR d: 0.94 (t,6H,J = 7), 1.24–2.61 (m,8H), 1.63
(d,6H,J = 7.2), 1.89 (m,4H), 3.65 (dd,2H,J = 5.4, 8.6),
5.84 (q,2H,J = 7.2), 7.32 (m,10ArH). 13C NMR d: 13.8,
17.5, 22.5, 29.1, 36.5, 51.6, 57.5, 127.0, 127.9, 128.7,
139.5, 167.4. [a]D -103.2 (c 1.3, CHCl3). Anal. Calcd. for
C28H38N2O2: C,77.38; H,8.81; N,6.45. Found: C,77.52;
H,8.82; N,6.43 (Rf = 0.60, EtAc/Hex: 35/65).
(3S)-1,4-N,N-[(S)-phenylethyl]-3-butylpiperazine-2,5-
dione 3c
After chromatography (EtAc-Hex: 25/75 the product was
obtained as a wax in 65% yield by alkylating 1 with
1
iodobutane. H NMR d: 0.94 (m,3H), 1.39(m,4H), 1.53
General procedure to (3S,6S)-3,6-dimethyl-3,6-
dialkylderivatives 5
(d,3H,J = 7.4), 1.64(d,3H,J = 7.4), 1.84 (m,2H), 3.74
(dd, 1H,J = 4.4, 8.4), 3.78 (qAB,2H,J = 17), 5.80
(q,1H,J = 7.4), 5.90 (q,1H,J = 7.4), 7.30 (m,10ArH). 13C
NMR d: 13.8, 15.4, 17.3, 22.5, 27.1, 34.0, 44.6, 49.8, 52.0,
57.4, 127.0, 127.1, 127.9, 128.1, 128.8, 128.9, 138.8,
139.1, 165.3, 166.8. [a]D -127.9 (c 0.7, CHCl3). Anal.
Calcd. for C24H30N2O2: C,76.16; H,7.99; N,7.40. Found:
C,76.26; H,7.98; N,7.44 (Rf = 0.62, EtAc/Hex: 35/65).
To a stirred solution of 4 (11.26 mmol) in dry THF
(60 mL), cooled at -78°C, 11.3 mL (1 M solution in THF)
of LHMDS was added and after 1 h iodomethane
(0.71 mL, 11.26 mmol) was added dropwise to the reaction
mixture. The reaction was stirred for about 1 h at -78°C
and then the cooling bath removed. After 2 h the reaction
was cooled at -78°C and 1.5 equivalents of 1 M LHMDS
(17 mL) was added. After 1 h iodomethane (0.71 mL,
11.3 mmol) was added, then the cooling bath was removed
and the reaction mixture was stirred overnight. The reac-
tion was quenched by adding water (60 mL) and the title
product was extracted with ethyl acetate. The organic
solution was dried and the solvent evaporated under
reduced pressure. The residue was purified by silica gel
chromatography eluting with hexane/ethyl acetate.
General procedure to (3S,6S)-dialkyl derivatives 4
To a stirred solution of 3 (12.5 mmol) in dry THF (60 mL),
cooled at -78°C, 12.5 mL (1 M solution in THF) of
LHMDS was added and after 1 h the alkyl halide
(12.55 mmol) was added dropwise to the reaction mixture.
The reaction was stirred for about 1 h at -78°C and then
123

(S)-a-methyl,a-amino acids
835
3S,6S)-1,4-N,N-[(S)-phenylethyl]-3,6-diethyl-3,6-
dimethylpiperazine-2,5-dione 5a
General procedure to a-methyl-a-amino acids 6
The intermediate 5 (1 mmol) was refluxed in 57% HI
(10 mL) for 8–9 h. The reaction solution was then evapo-
rated under vacuum and the residue dissolved in water
(10 mL) and extracted with ethyl acetate. The aqueous
solution was eluted more than once on a column filled with
the acid ion-exchange resin Dowex 50 WX 8 (20–50 mesh)
carefully washed with distilled water. The resin was again
washed with distilled water until neutral pH of eluent and
then the title product was recovered eluting with 5 M
NH4OH. The aqueous solution was evaporated under
vacuum until dryness and the pure a-methyl,a-aminoacid
was obtained in practically quantitative yield.
After chromatography (EtAc-Hex: 25/75) the product was
1
obtained as a white solid in 85% yield. H NMR d: 0.52
(t,6H,J = 7); 1.68 (s,6H), 1.78 (m,2H), 1.89 (d,6H,J = 7),
2.19 (m,2H), 4.47 (q,2H,J = 7), 7.21–7.59 (m,10ArH). 13
C
NMR d: 9.2, 20.6, 27.1, 31.2, 56.8, 66.5, 126.8, 127.8,
128.0, 141.7, 168.2. [a]D ?44.9 (c 0.6, CHCl3). Anal.
Calcd. for C26H34N2O2: C,76.81; H,8.43; N,6.89. Found:
C,76.87; H,8.41; N,6.86. M.p. = 134–135°C (Rf = 0.65,
EtAc/Hex: 35/65).
(3S,6S)-1,4-N,N-[(S)-phenylethyl]-3,6-dipropyl-3,6-
dimethylpiperazine-2,5-dione 5b
(S)-2-ethylalanine 6a
After chromatography (EtAc-Hex: 25/75) the product was
1
obtained as white solid in 90% yield. H NMR d: 0.52
1H NMR (CD3OD) d: 0.99 (t,3H,J = 7.4), 1.45 (s,3H),
1.73 (m,1H), 1.93 (m,1H). 13C NMR d: 8.7, 23.5, 32.0,
63.0, 176.8. [a]D ?10.2 (c 1, H2O) [(Najera et al. 2000)
[a]D ?10.1 (c 1, H2O)].
(t,6H,J = 7), 0.63–1.11 (m,4H), 1.67 (s,6H), 1.68 (m,2H),
1.88 (d,6H,J = 7), 2.13 (m,2H), 4.47 (q,2H,J = 7), 7.27
(m,6ArH), 7.56 (m,4ArH). 13C NMR d: 13.3, 17.6, 21.1,
27.4, 40.5, 57.3, 66.1, 126.9, 128, 142.3, 168.4. [a]D ?67.1
(c 1.0, CHCl3). M.p. 169°C (dec). Anal. Calcd. for
C28H38N2O2: C,77.38; H,8.81; N,6.45. Found: C,77.67;
H,8.85; N,6.46 (Rf = 0.62, EtAc/Hex: 35/65).
(S)-2-propylalanine 6b
1H NMR (D2O) d: 0.85 (t,3H,J = 7), 1.2 (m,2H), 1.38
(s,3H), 1.7 (m,2H). 13C NMR (D2O) d: 14.0, 17.5, 23.2,
40.1, 62.3, 177.7. The title compound was converted into
the hydrochloride salt: [a]D ?6.3 (c 1.0, H2O) [(Moretto
et al. 2000) [a]D ?6.5 (c 1, H2O)].
(3S,6S)-1,4-N,N-[(S)-phenylethyl]-3,6-dibutyl-3,6-
dimethylpiperazine-2,5-dione 5c
After chromatography (EtAc-Hex: 25/75) the product was
1
obtained as a wax in 80% yield. H NMR d: 0.55 (m,6H),
(S)-2-butylalanine 6c
0.65–1.18 (m,8H), 1.67 (s,6H), 1.87 (m,2H), 1.89
(d,6H,J = 7), 2.09 (m,2H), 4.47 (q,2H,J = 7), 7.19–7.61
(m,10ArH). 13C NMR d: 13.7, 21.1, 22.2, 27.0, 27.4, 38.5,
57.3, 66.2, 127.0, 127.9, 128.1, 142.2, 168.4. [a]D ?29.3
(c 0.3, CHCl3). Anal. Calcd. for C30H42N2O2: C,77.88;
H,9.15; N,6.05. Found: C,77.99; H,9.19; N,6.06 (Rf = 058,
EtAc/Hex: 35/65).
1H NMR (CD3OD) d: 0.94 (m,3H), 1.36 (m,4H), 1.44
(s,3H), 1.58–1.97 (m,2H). 13C NMR d: 14.3, 24.0, 27.2,
39.0, 62.6, 176.8. The title compound was converted into
the hydrochloride salt: [a]D ?10.1 (c 1, H2O) [(Davis et al.
2000) [a]D ?10.5 (c 1, H2O)].
(S)-2-benzylalanine 6d
(3S,6S)-1,4-N,N-[(S)-phenylethyl]-3,6-dibenzyl-3,6-
dimethylpiperazine-2,5-dione 5d
1H NMR (CD3OD) d: 1.52 (s,3H), 3.11 (qAB,2H,J = 14.2),
7.31 (m,5ArH). 13C NMR d: 23.7, 44.5, 63.0, 128.6, 129.9,
131.5, 136.3, 176.3. [a]D -21.7 (c 0.3, H2O) [(Kruizinga
et al.1988) [a]D-22.0 (c 1.0, H2O)]. The title compound
was converted into the hydrochloride salt: [a]D -5.8 (c 1,
H2O) [(Kolb and Barth 1980) [a]D-5.6 (c 1, H2O)].
After chromatography (EtAc-Hex: 25/75) the product was
1
obtained as a white solid in 90% yield. H NMR d: 1.73
(s,6H), 1.89 (d,6H,J = 7), 3.0 (qAB,4H,J = 14.2), 4.66
(q,2H,J = 7), 6.60 (m,4ArH), 6.96 (m,4ArH), 7.12
(m,2ArH), 7.30 (m,10ArH). 13C NMR d: 16.6, 26.8, 44.7,
56.8, 66.0, 126.5, 126.9, 127.7, 127.9, 128.8, 130.7, 135.8,
140.8, 167.0. [a]D ?86.2 (c 0.5, CHCl3). Anal. Calcd. for
C36H38N2O2: C,81.47; H,7.22; N,5.28. Found: C,81.60;
H,7.19; N,5.27. M.p. 134.5–135.5°C (Rf = 0.65, EtAc/
Hex: 35/65).
(3S,6R)-1,4-N,N-[(S)-phenylethyl]-3,6-diethyl-3,6-
dimethylpiperazine-2,5-dione 8
It was obtained starting from 7 and following the procedure
described for 5. The title product was isolated as a white
123

836
D. Balducci et al.
synthesis of a-alkyl a-amino acids. J Org Chem 65:8704. doi:
10.1021/jo001179z
Ferioli F, Piccinelli F, Porzi G, Sandri S (2002) Stereoselective
synthesis of bis(a-amino acid) derivatives isosteric with cysteine.
Part 4. Tetrahedron Asymmetry 13:1181. doi:10.1016/S0957-
4166(02)00262-8
Gibson SE, Guillo N, Tozer MJ (1999) Towards control of x-space:
conformationally constrained analogues of Phe, Tyr, Trp and
His. Tetrahedron 55:585. doi:10.1016/S0040-4020(98)00942-9
Kolb M, Barth J (1980) Asymmetric synthesis of amines by carbon–
carbon coupling in the a-position to nitrogen. Angew Chem Int
Ed Engl 19:725. doi:10.1002/anie.198007251
solid (M.p. 170.2–171.6°C) in about 80% yield after crystal-
lization from methanol. 1H NMR d: 0.4 (t,3H,J = 7.2), 1.02
(t,3H,J = 7.2), 1.71 (s,3H), 1.78 (s,3H), 1.92 (d,6H, J = 7),
1.8 (m,3H), 2.2 (m,1H), 4.49 (m,2H), 7.2–7.6 (m,10ArH). 13
C
NMR d: 8.5, 9.3, 17.6, 20.1, 27.2, 28.6, 32.2, 32.5, 55.0, 56.3,
66.1, 66.2, 126.8, 127.7, 127.8, 127.9, 128.2, 141.2, 141.4,
167.7, 168.0. [a]D -80.9 (c 0.7, CHCl3). Anal. Calcd. for
C26H34N2O2: C,76.81; H,8.43; N,6.89. Found: C,76.97;
H,8.40; N,6.88.
Kruizinga WH, Bolster J, Kellogg RM, Kamphuis J, Boesten WHJ,
Meijer EM, Schoemaker J (1988) Synthesis of optically pure
alpha-alkylated alpha-amino acids and a single-step method for
enantiomeric excess determination. Org Chem 53:1826. doi:
10.1021/jo00243a049
(3S,6S)-1,4-N,N-[(S)-phenylethyl]-3,6-dibenzyl-3-
methylpiperazine-2,5-dione 9
The product was obtained as a white solid in 70% yield by
Moretto A, Peggion C, Formaggio F, Crisma M, Toniolo C, Piazza C,
Kaptein B, Broxterman QB, Ruiz I, Diaz-de-Villegas MD,
the monoalkylation of 4d with CH3I and following the
1
general procedure employed to synthesize 4. H NMR d:
Galvez JA, Cativiela
C (2000) (aMe)Nva: stereoselective
syntheses and preferred conformations of selected model pep-
tides. J Pept Res 56:283. doi:10.1034/j.1399-3011.2000.00768.x
Najera C, Abellan T, Sansano JM (2000) Asymmetric synthesis of
alpha-methyl alpha-amino acids through diastereoselective
alkylation under mild reaction conditions of an iminic alanine
template with a 1,2,3,6-tetrahydro-2-pyrazinone structure. Eur J
Org Chem 2809. doi:10.1002/1099-0690(200008)2000:15\
2809::AIDEJOC2809[3.0.CO;2-X
1.51 (dd,1H,J = 9.2, 14.6), 1.61 (d,3H,J = 7), 1.88
(d,3H,J = 7), 1.92 (s,3H), 2.27 (dd,1H,J = 4, 14.6); 3.14
(qAB,2H,J = 13.6), 3.68 (dd,1H,J = 4, 9.2), 4.71
(q,1H,J = 7), 5.58 (q,1HJ = 7), 6.68 (m,4ArH), 7.07–7.38
(m,14ArH), 7.62 (m,2ArH). 13C NMR d : 17.7, 21.4, 27.9,
41.3, 44.1, 55.0, 57.7, 59.0, 68.7, 126.3, 127.0, 127.1,
127.5, 128.0, 128.1, 128.2, 128.3, 128.6, 128.7, 128.8,
128.9, 129.4, 131.3, 135.8, 137.3, 138.3, 142.4, 165.8,
167.6. [a]D ?224.4 (c 0.5, CHCl3). Anal. Calcd. for
C35H36N2O2: C,81.36; H,7.02; N,5.42. Found: C,81.56;
H,6.99; N,5.40. M.p. 204–205°C.
Orena M, Porzi G, Sandri S (1992) Diastereoselective alkylation of
(3S)- and (3R)-3-methylpiperazine-2,5-dione derivatives.
A
convenient approach to both (S)- and (R)-alanine. J Org Chem
57:6532. doi:10.1021/jo00050a030
Orena M, Porzi G, Sandri S (1993) (3R)-Methylpiperazine-2 and
(3S)-methylpiperazine-2,5-dione derivatives as useful interme-
diates in the enantioselective synthesis of alpha-amino esters.
J Chem Res Synop 318
Acknowledgments Financial support was from the University of
Bologna (RFO funds, ex 60%). The authors thank Prof. S. Sandri for
the fundamental work developed in the research team for many years,
particularly in the field of the asymmetric synthesis of natural and
unnatural a-amino acids and pseudopeptides.
Paradisi F, Porzi G, Rinaldi S, Sandri S (2000a) Stereoselective
synthesis of a, a’-diamino-dicarboxylic acids part 2. Tetrahedron
Asymmetry 11:4617. doi:10.1016/S0957-4166(00)00450-X
Paradisi F, Porzi G, Rinaldi S, Sandri S (2000b) A simple asymmetric
synthesis of (?)- and (-)-2,6-diaminopimelic acids. Tetrahedron
Asymmetry 11:1259. doi:10.1016/S0957-4166(00)00050-1
Paradisi F, Piccinelli F, Porzi G, Sandri S (2002) Enantioselective
synthesis of 2,6-diaminopimelic acid derivatives. Part 3. Tetrahe-
dron Asymmetry 13:497. doi:10.1016/S0957-4166(02)00126-X
Piccinelli F, Porzi G, Sandri M, Sandri S (2003) Stereocontrolled
synthesis of enantiomerically pure unsaturated analogues of 2,6-
DAP. Part 5. Tetrahedron Asymmetry 14:393. doi:10.1016/
S0957-4166(02)00834-0
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