Asymmetric synthesis of α-Methyl α-Amino Acids through diastereoselective alkylation under mild reaction conditions of an iminic alanine template with a 1,2,3,6-Tetrahydro-2-Pyrazinone structure

Article abstract of DOI:10.1002/1099-0690(200008)2000:15<2809::AID-EJOC2809>3.0.CO;2-X

(6R)-6-Isopropyl-3-methyl-5-phenyl-1,2,3,6-tetrahydro-2-pyrazinone, obtained from (R)-valine and (S)-alanine, is highly diastereoselectively alkylated at room temperature by: a) activated alkyl halides under solid-liquid PTC conditions, b) non-activated alkyl halides with organic bases, c) electrophilic olefins employing both solid-liquid PTC conditions and organic bases, and d) allylic carbonates by means of palladium catalysis under neutral conditions. Enantiomerically pure (S)-α-methyl α-amino acids 8 are obtained by hydrolysis of the alkylated pyrazinones.

Full text of DOI:10.1002/1099-0690(200008)2000:15<2809::AID-EJOC2809>3.0.CO;2-X

FULL PAPER
Asymmetric Synthesis of α-Methyl α-Amino Acids through Diastereoselective
Alkylation under Mild Reaction Conditions of an Iminic Alanine Template with
a 1,2,3,6-Tetrahydro-2-pyrazinone Structure
[a]
[a]
[a]
´
´
´
´
Carmen Najera,* Tomas Abellan, and Jose M. Sansano
Keywords: Amino acids / Asymmetric synthesis / Pyrazinones / Phase-transfer catalysis / Palladium
(6R)-6-Isopropyl-3-methyl-5-phenyl-1,2,3,6-tetrahydro-2-py-
razinone, obtained from (R)-valine and (S)-alanine, is highly
diastereoselectively alkylated at room temperature by: a) ac-
trophilic olefins employing both solid−liquid PTC conditions
and organic bases, and d) allylic carbonates by means of pal-
ladium catalysis under neutral conditions. Enantiomerically
tivated alkyl halides under solid-liquid PTC conditions, b) pure (S)-α-methyl α-amino acids 8 are obtained by hydrolysis
non-activated alkyl halides with organic bases, c) elec- of the alkylated pyrazinones.
Introduction
economical and large-scale synthesis. Furthermore, the hy-
drolysis of the resulting α-alkylated heterocycles can also
be problematic, since harsh reaction conditions are usually
needed. Acyclic alanine aromatic aldehyde imines are very
soft nucleophiles and have recently been alkylated under
mild reaction conditions. These systems can also be hy-
Natural and unnatural modified α-amino acids in an en-
antiomerically pure form and their peptides constitute some
of the most important areas of research in the fields of me-
dicinal chemistry and protein engineering. As a con-
sequence, new and versatile synthetic methodologies have
become an important goal for organic chemists.[1] When in-
corporated into natural or synthetic peptides, and because
of the tetrasubstituted asymmetric carbon, the family of α-
methyl α-amino acids (AMAAs)[1b] result in the decrease of
both enzymatic and chemical hydrolysis[2] and also stabilize
β-turn and α-helical conformations[3] of such peptides. Nat-
ural peptides such as peptaibols,[4] TAN-1057A,[5]
MS681b,[6] etc., exhibit potent antibiotic activity and syn-
thetic peptides such as CI-998 and PD161182 are high-af-
finity ligands for CCK-B and NK3 receptors, respectively.[7]
Amongst other properties, AMAAs possess antibiotic activ-
ity,[8] they can act as enzyme and protein inhibitors,[9] they
have anti-hypertensive properties as (S)-α-methyl-DOPA
(Aldomet)[9b] and are potent antagonists of mGluR[10] and
EAA.[11] Furthermore, they are frequently used as chiral
building blocks in organic synthesis.[7,8,12]
drolyzed smoothly employing
a
combined diluted
acidicϪbasic protocol.[13] In this field, phase-transfer cata-
lysis (PTC) using TADDOL[14a] and NOBIN[14b] as chiral
ligands have been successfully applied in the alkylation re-
action of benzaldehyde alaninates with NaH, in toluene at
room temperature, with activated alkyl halides up to 82 and
68% ee, respectively. Cinchonidinium and cinchoninium
salts[15] act as phase-transfer catalysts with high enantiose-
lectivity (up to 87% ee[15g] and 50%[15h] ee, respectively) in
alkylation reactions of alanine-derived imines in the pres-
ence of activated halides. New and efficient chiral alanine
iminic derivatives should be developed for optimizing a use-
ful scalable process to synthesize AMAAs. To achieve this
goal, we have already studied the reactivity of oxazinones
1aϪb as chiral cyclic alanine templates for alkylations un-
der mild reaction conditions and these reactions show very
high levels of diastereoselectivity.[16] However, these types of
oxazinones are rather sensitive to aqueous, acidic or basic
conditions and alkylated derivatives can be obtained up to
75% yield.
Chiral cyclic enolates derived from alanine, especially
Schölkopf’s, Seebach’s and Williams’ reagents, have pro-
vided the most direct and reliable synthetic routes to
AMAAs through diastereoselective α-alkylation reac-
In order to improve the overall yields, we have designed
tions.[1a] However, the reaction normally takes place under a further template with a 1,2,3,6-tetrahydro-2-pyrazinone
anhydrous conditions and at very low temperatures because structure 2[17] that has features similar to the oxazinones 1.
very strong and sensitive bases (LDA, BuLi, KHMDS, These features include: a) a highly acidic Cα hydrogen atom,
LiHMDS, KOtBu, etc.) are required. These reaction condi- presumably as acidic as the oxazinone one because of the
tions do not allow these methodologies to be applied to presence of an electron-withdrawing group at N-1, and b)
a bulky group at C-6 able to block one of the two diastereo-
topic faces of the enolate and allow for a 1,4-transannular
[a]
asymmetric induction. The only significant difference be-
tween the two molecules is the substitution of the lactone
moiety by an imido group, which presumably would convert
2-pyrazinone 2 into a more stable compound.
Department of Organic Chemistry, Faculty of Science,
University of Alicante,
Apdo. 99, 03080 Alicante, Spain
Fax: (internat.) ϩ 34-96/590-3549
E-mail: cnajera@ua.es
Eur. J. Org. Chem. 2000, 2809Ϫ2820
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1434Ϫ193X/00/0815Ϫ2809 $ 17.50ϩ.50/0
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C. Najera, T Abellan, J. M. Sansano
FULL PAPER
which takes place under basic cyclization conditions owing
to the high acidity of the C-3 hydrogen, is not a serious
drawback for the diastereoselective alkylation of 2. It is
worth noting that no epimerization took place at C-6 dur-
ing the cyclization and N-protection steps. The use of (S)-
alanine, instead of the racemic mixture, in the synthesis of
that pyrazinone is justified because of the instability of the
cis-diastereomer during the final N-Boc protection. Similar
behaviour was observed in the case of the oxazinones,
showing that both reagents have a similar acidity.[16]
Results and Discussion
Only one example of a 1,2,3,6-tetrahydro-2-pyrazinone
has been previously described, furnishing the 2-pyrazinone
with two methyl groups at the 6-position, by reaction of
2,2-dimethyl-3-phenyl-2H-azirine with glycine ethyl ester.[18]
In this work, we report the synthesis of the chiral pyrazi-
none 2 based on the coupling of the chiral amino ketone 3,
obtained in an optically pure form, and alanine. Chiral α-
aminoisovalerophenone hydrochloride 3[19,20] was initially
prepared (Method A),[17] from -valine N,N-dimethyl-
amide, obtained by the reaction with dimethylamine hydro-
chloride in the presence of triethylamine and N,N,NЈ,NЈ-
tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluorobor-
ate (TBTU) in acetonitrile at room temperature. The crude
amide was allowed to react with phenylmagnesium bromide
(3 equiv.) in THF at room temperature giving, after hydro-
lysis with a saturated solution of hydrogen chloride in ethyl
acetate, the α-amino ketone hydrochloride 3 in 78% overall
yield [from (R)-valine] (Scheme 1).[17] Alternatively, the
chiral auxiliary 3 could be prepared (Method B) by modify-
ing the amidation step. N-Boc-(R)-valineϪpivalic acid
mixed anhydride was generated in situ and treated with ex-
cess pyrrolidine (3 equiv.) for 6 h, affording the correspond-
ing amide. This pyrrolidine amide was treated as described
in the case of the dimethylamide analogue to afford 3 in
69% overall yield [from (R)-valine] (Scheme 1). In spite of
the slightly lower yield achieved, the latter method is more
suitable for a multigram-scale preparation, since cheaper re-
agents are employed.
Scheme 2
The relative configuration of the trans-2-pyrazinone 2
was determined by NOE experiments and by comparison
of the chemical shifts of the C-3 methyl groups of trans and
cis diastereomers (δ ϭ 1.72 and 1.65, respectively) with the
analogous oxazinone 1 groups[16] (δ ϭ 1.74 and 1.70, re-
spectively). X-ray diffraction analyses could not be per-
formed, but molecular mechanics calculations[21] predict a
quasi-boat conformation where the isopropyl group adopts
an axial ‘‘flagpole’’ position (Figure 1) such as that found
in the case of oxazinone 1.[16]
The amidation reaction of compound 3 with the N-Boc-
(S)-alanine-pivalic acid mixed anhydride gave compound 4
in 95% yield. The 2-pyrazinone 5 was prepared in 86% yield
after deprotection of 4 with HCl in EtOAc, followed by
an extractive workup with a saturated aqueous solution of
potassium carbonate. Under these reaction conditions,
some epimerization took place at C-3 and pyrazinone 5 was
isolated as a 22:1 mixture of trans/cis diastereomers. Final
N-Boc protection was achieved with di-tert-butyl dicarbon-
ate [(Boc)2O] at 0 °C in THF affording, in 84% yield, a 20:1
1
mixture of trans/cis diastereomers determined by H NMR
spectroscopy and HPLC (Scheme 2). This epimerization,
Figure 1. Molecular mechanics calculations of 2-pyrazinone 2
The alkylation of compound 2 was performed under very
mild PTC reaction conditions employing potassium car-
bonate in acetonitrile and tetra-n-butylammonium bromide
(TBAB, 10 mol-%) as catalyst (Scheme 3).[16] The alkylated
product 6, whose stereochemistry was determined by NOE
experiments, was obtained in good yields (60Ϫ86%) and
Scheme 1
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Eur. J. Org. Chem. 2000, 2809Ϫ2820

Asymmetric Synthesis of α-Methyl α-Amino Acids
FULL PAPER
high diastereomeric excesses (96Ϫ98%) when very reactive
alkyl halides such as allylic bromides and iodides, propargyl
bromide, benzyl bromide, ethyl haloacetates and N-Boc-3-
bromomethylindole (entries 2Ϫ9 of Table 1) were employed.
An aldol reaction was performed with paraformaldehyde in
71% yield and 81% de (entry 10 of Table 1). Michael addi-
tions were studied using ethyl crotonate and acrylic acid
derivatives. However, the reaction only took place in good
yields (44Ϫ82%) and high de (95Ϫ96%) with monosubsti-
tuted olefins (entries 11Ϫ14 of Table 1). The observed high
diastereoselectivity could be justified by molecular mech-
anics calculations[21] of the enolate depicted in Figure 2.
The conformation of the cyclic enolate is almost planar and
its isopropyl group is orthogonally orientated, blocking the
top face of this alanine iminic derivative. Although X-ray
diffraction analyses could not be obtained, molecular mech-
anics calculations were performed for the 3-propargylic de- Figure 2. Molecular mechanics calculations of potassium enolate of 2
rivative (6R)-6c (Figure 3).These calculations show that the
pyrazinone heterocycle has a planar structure. The structure
indicated in Figure 3 shows striking similarities to the X-
ray structure determined for the analogous 3-propargylox-
azinone.[16b]
The pyrazinone 2 permitted dialkylated products to be
obtained with slightly better de and higher chemical yields
than those obtained with oxazinones 1a.[16] Heterocycles 6
are more stable under both neutral and basic aqueous con-
ditions and they could be purified by column chromato-
graphy on silica gel without any significant loss of yield.
Another significant difference was found when less reactive
ethyl iodide was allowed to react with 2. In this case, 6a
was obtained in a moderate yield (entry 1 of Table 1) whilst
oxazinones 1 did not react with this electrophile under the
Scheme 3
Table 1. Diastereoselective alkylation of 2-pyrazinone 2 under solidϪliquid PTC conditions
[a]
[b]
1
Acetonitrile was used as solvent and monitored by TLC. Ϫ
Determined by H NMR (300 and 500 MHz) and HPLC analysis of
the reaction crude. Ϫ [c] Isolated yield of the major diastereomer observed after flash chromatography. Ϫ The reaction was carried out
in dichloromethane.
[d]
Eur. J. Org. Chem. 2000, 2809Ϫ2820
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C. Najera, T Abellan, J. M. Sansano
FULL PAPER
The use of strong bases (LDA, BuLi, KOtBu), even in
the presence of co-solvents (HMPA, DMPU), failed when
less reactive electrophiles were tested. In these reactions,
complex mixtures of decomposed products were obtained.
When an organic base such as Schwesinger’s base[24] [2-tert-
butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-
diazaphosphorine (BEMP)] was used, the reaction did not
give the expected results (as in the case of oxazinones
1).[16a,16c] However, the diastereoselective alkylation of 2
with unactivated alkyl halides and electrophilic olefins was
successful when employing the cheaper 1,8-diazabicy-
clo[5.4.0]undec-7-ene (DBU) at room temperature, in N-
methyl-2-pyrrolidone (NMP) as solvent and using LiI as
additive (Scheme 3 and Table 2). The amount of DBU re-
quired was 2 equiv. for alkyl halides and a catalytic amount
for electrophilic olefins (10 mol-%), instead of 5 equiv. used
for the alkylation of oxazinones 1.[16a,16c] In general, al-
kylated pyrazinones 6 were obtained from alkyl halides, in
better yields (64Ϫ84%, entries 1Ϫ6 of Table 2) than the
analogous oxazinones[16a] (28Ϫ65%) with identical diastere-
omeric ratios in both cases (Ͼ 98:2). Thus, 2-pyrazinone 2
afforded 6 in moderate yields and good de (entries 7Ϫ11 of
Table 2) when treated with electrophilic olefins under these
reaction conditions. Acrylonitrile did not react when using
DBU as base, but nevertheless a 47% yield was achieved
under PTC conditions (see entries 11 and 7 of Table 1 and
Table 2, respectively). Negligible amounts of O-alkylation
products were detected in the reaction mixture (ca. 5% be-
ing observed with ethyl iodide) whereas more significant ra-
tios were reported for oxazinones 1.[16a,16c] As in the PTC
alkylation reactions, different product 7 ratios were ob-
served. Although the formation of 7 was favoured by the
long reaction times, a radical dimerization mechanism can
be discarded since reactions carried out in the absence of
oxygen and light also gave compound 7 (entry 9 of Table
2). For electrophilic olefins, the presence of lithium iodide
was necessary to achieve good yields in spite of the iodide-
promoted generation of dimer 7. The use of lithium chlor-
ide afforded a poor yield of alkylated product without any
significant amounts of 7 (entry 10 of Table 2). On the basis
of this result, a PTC reaction was performed in the absence
of electrophilic olefin giving dimer 7 and unchanged 2, in-
dicating that the phase-transfer catalyst (TBAB) caused
dimerization of the 2-pyrazinone. However, when the reac-
tion was performed with tetraethylammonium chloride as
catalyst, no Michael adduct was detected. Using these pre-
vious results, the synthesis of dimer 7 was optimized and 7
was obtained exclusively in 87% yield using 1,2-diiodoe-
thane and DBU (2 mol-equiv.) in NMP for 24 h at room
temperature. When the same reaction was carried out under
PTC conditions (or PTC conditions using iodine), 7 was
isolated in poor yields.
Figure 3. Molecular mechanics calculations of compound (6R)-6c
same reaction conditions. In this reaction a by-product 7
was also detected and isolated in 52% yield. In accordance
with spectroscopic and analytical data, this compound
seems to be the dimer of precursor 2. The stereochemistry
(see below) could not be confirmed by X-ray analysis. Al-
though iodinated electrophiles are prone to generate this
dimer 7, very reactive brominated electrophiles did not give
significant amounts, except, as shown in entries 2 and 6,
where the bromides required longer reaction times to react
than the analogous iodides, and in entry 9 where small
amounts of bromine were present owing to the low stability
of 3-bromomethylindole.[22] The same reaction has been re-
ported by Belokon’ et al. for Schiff bases of alanine with
(S)-2-[(N-benzylpropyl)amino]benzaldehyde when alkyl
iodides were used as electrophiles.[23]
Under PTC conditions, Michael addition reactions in the
presence of electrophilic olefins also produced dimer 7. In
the case of methyl acrylate, attempts to overcome the
formation of 7 were made by changing acetonitrile with
THF, dichloromethane or dioxane, but no improvement
was achieved. Acetonitrile and dichloromethane gave sim-
ilar results in the diastereoselective alkylation, but crude
product 6/7 ratios were 3:1 and 24:1, respectively (see ent-
ries 13 and 14 of Table 1). According to the results depicted
in Table 1, nucleophilic substitution of pyrazinone 2 enolate
by activated organic halides was much faster than the
Michael addition with electrophilic olefins. This fact was
demonstrated by the bias towards alkylation shown by the
enolate when methyl 4-bromocrotonate was allowed to re-
act as an electrophile (entry 8 of Table 1). In this reaction,
the presence of the Michael adduct was not detected by 1H
NMR of the crude reaction mixture.
In spite of the similarity of structures 1 and 2, 2-pyrazi-
nones did not undergo any transformation when an activ-
ated dihalide was used in order to prepare heterocyclic α-
amino acids by subsequent C- and N-alkylation, either un-
der PTC conditions or using DBU, as occurred with oxazi-
nones 1.[16]
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Asymmetric Synthesis of α-Methyl α-Amino Acids
FULL PAPER
Table 2. Diastereoselective alkylation of 2-pyrazinone 2 with DBU as organic base in the presence of LiI
Entry
Electrophile
R
t [h][a]
Product ratio 6/7[b]
6 (%)[c]
% de[b]
1
EtI
Et
1
17:1[d]
10:1.6
10:1.5
10:0.5
5:1
(6R)-6a (84)
(6R)-6b (77)
(6R)-6l (70)
(6R)-6l (75)
(6R)-6m (64)
(6R)-6d (71)
Ϫ
(6R)-6j (69)
(6R)-6j (56)
(6R)-6j (30)
(6R)-6n (49)
97
98
98
98
98
98
Ϫ
96
96
96
95
2
CH2ϭCHCH2Cl
nBuBr
CH2CHϭCH2
nBu
20
3
24
4
nBuI
nBu
12
5
iBuI
iBu
24
6
BnCl
Bn
24
Ͼ 100:1
Ͼ 1:100
30:1
7
CH2ϭCHCN
CH2ϭCHCOMe
CH2ϭCHCO2Me
CH2ϭCHCO2Et
CH2ϭCHCO2Et
CH2CH2CN
CH2CH2COMe
CH2CH2CO2Me
CH2CH2CO2Et
CH2CH2CO2Et
24[e]
24[e]
24[e]
24[e]
24[e]
8
9
6:1[e][f]
Ͼ 100:1
10:1
10
11
[a] Monitored by TLC. Ϫ [b] Determined by 1H NMR (300 and 500 MHz) and HPLC analysis of the crude reaction mixture. Ϫ [c] Isolated
[e]
yield after flash chromatography. Ϫ [d] 5% of O-alkylation product was also detected. Ϫ The same results were obtained using 10 mol-
[f]
% or 2 mol-equiv. of DBU. Ϫ This reaction was carried out in the absence of oxygen (He) and with freshly distilled methyl acrylate.
Substrate 2 was diastereoselectively allylated by using al- 6r as the only isomer. In both examples, a regioselective
lylic carbonates and vinyloxirane[25] under mild and neutral nucleophilic addition of enolate to the less-hindered posi-
Pd0 catalysis.[16a,16b] Good yields and very good de of 2- tion of the π-allyl complex was observed.
pyrazinones 6 were achieved using Pd(PPh3)4 (2.5 mol-%)
and 1,2-(diphenylphosphanoyl)ethane (dppe, 5 mol-%) or
Pd(OAc)2 (5 mol-%) and triphenylphosphane (10 mol-%) as
catalysts, in THF at room temperature (Scheme 3 and 4 and
Table 3). Mixtures of regioisomers were obtained when un-
symmetrical allylic carbonates (entries 2 and 4 of Table 3)
were employed and were separated by flash chromato-
Scheme 4
graphy. Additives such LiI, introduced for improving the
Hydrolysis of some representative alkylated 2-pyrazi-
regioselectivity of Pd0-catalyzed allylation reaction,[26] or nones 6 was carried out with 6  aqueous hydrochloric acid
other catalysts such as [Rh(PPh3)3Cl], used for inverting the at 150 °C (pressure tube) followed by treatment with propy-
regioselectivity achieved with Pd0 catalyst,[27] did not pro- lene oxide in refluxing ethanol for 30 min. (S)-AMAAs 8
duce the expected results. The palladium(0)-catalyzed addi- were isolated by filtration in moderate to good yields and
tion of enolate of 2 onto vinyloxirane took place under sim- excellent ee (Scheme 5 and Table 4). Important (S)-AMAAs
ilar reaction conditions in good yields (77%) and excellent such as α-ethylalanine, α-methylphenylalanine, α-methylas-
de (98%) (Scheme 4 and entries 5 and 6 of Table 3). The Z/ partic acid, α-methyltryptophan, α-methylserine and α-
E ratio of final product (determined by 13C NMR and NOE methylglutamic acid were thus obtained employing this
experiments) depends on the palladium complex structure methodology. These forcing hydrolysis conditions could not
such as indicated in the literature.[25] While a complex com- be applied to α-allyllic 2-pyrazinones. However, a represent-
prised of Pd(OAc)2 (5 mol-%) and triphenylphosphane (10 ative example such as α-allylalanine 8b was obtained in 62%
mol-%) furnished a 3:1 Z/E mixture of 6r, the catalyst gen- yield after hydrolysis employing a mixture of 0.75  hydro-
erated by Pd(OAc)2 (5 mol-%) and dppe (5 mol-%) gave E- chloric acid, acetic acid containing Dowex 50X8Ϫ100 at
Table 3. Diastereoselective allylation of 2 under Pd0 catalysis
[a]
[b]
[c]
1
Monitored by TLC with Pd(OAc)2/PPh3 as catalyst. Ϫ
Isolated yield after flash chromatography. Ϫ Determined by H NMR
[d]
[e]
[f]
(300 and 500 MHz) and HPLC analysis. Ϫ
A 1:1 ratio of regioisomers was obtained. Ϫ As a 11:1 mixture of diastereomers. Ϫ
[
g
]
[
h
]
Same value of de for each regio- and diasteroisomer. Ϫ
Value for the major regio- and diastereomer. Ϫ
A 3:1 ratio of Z:E
diastereomers was detected (13C NMR). Ϫ Pd(OAc)2/dppe as catalyst. Ϫ Pure E-isomer (13C NMR).
[i]
[j]
Eur. J. Org. Chem. 2000, 2809Ϫ2820
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C. Najera, T Abellan, J. M. Sansano
FULL PAPER
100 °C for 4 d[28] (Scheme 6). Unfortunately, the chiral aux- lysis, depending on the sensitivity of the resulting amino
iliary could not be recovered at the end of the synthesis as acid.
its amino ketone hydrochloride form 3, because decomposi-
tion of this sensitive compound took place under both hy-
drolysis conditions.
Experimental Section
General: Melting points were determined with a Reichert Thermo-
var hot plate apparatus and are uncorrected. IR spectra were re-
corded with a Nicolet 510 P-FT and only the structurally important
peaks are listed. NMR spectra were measured with a Bruker AC-
300 and DRX-500 using CDCl3 as solvent and TMS as internal
standard, unless otherwise stated. Optical rotations were measured
with a Jasco DIP-1000 polarimeter. HPLC analyses were per-
formed with a Shimadzu LC-10AD equipped with an APEX-silica
5µ and DAICEL OD-H columns, eluting with mixtures acetonitr-
ile/water and n-hexane/isopropyl alcohol, respectively. Low-resolu-
tion electron impact (EI) mass spectra were obtained at 70 eV with
a Shimadzu QP-5000 and low-resolution electrospray ionization
(ESI) mass spectra were obtained with a Finnigan VG Platform.
HRMS (EI) were recorded with a Finnigan MAT 95S. Microana-
lyses were performed by the Microanalysis Service of the University
of Alicante. Analytical TLC was performed with Schleicher &
Schuell F1400/LS silica gel plates and the spots were visualized
with UV light at 254 nm. Flash chromatography was carried out
with Merck silica gel 60 (0.040Ϫ0.063 mm).
Scheme 5
Scheme 6
Conclusions
Synthesis of (2R)-2-Amino-3-methyl-1-phenyl-1-butanone Hydro-
chloride (3)[19] ؊ Method A: Sodium bicarbonate (1.68 g, 20 mmol),
di-tert-butyl dicarbonate (2.18 g, 10 mmol) and dioxane (15 mL)
were added to a stirred suspension of (R)-valine (1.17 g, 10 mmol)
in water (15 mL). The mixture was heated at reflux for 12 h and
the solvent was then evaporated. The residue was extracted with
A new strategy for the synthesis of enantiomerically pure
3,5,6-trisubstituted 1,2,3,6-tetrahydro-2-pyrazinones has
been developed. The diastereoselective α-alkylation or α-al-
lylation under very mild conditions occurs in higher yields
(up to 86%) than those obtained from oxazinones 1, be- ethyl acetate (20 mL) and a saturated aqueous solution of potas-
sium bisulfate (20 mL) was added. The organic phase was separ-
ated, dried (Na2SO4) and concentrated in vacuo affording the pro-
tected valine (2.17 g) in a near-quantitative yield. This compound
was then dissolved in acetonitrile (30 mL) together with TBTU
(3.22 g, 10 mmol) and dimethylamine chlorohydrate (4.10 g,
50 mmol). The mixture was cooled to Ϫ20 °C, and triethylamine
(9.7 mL, 70 mmol) was added. The reaction mixture was stirred at
room temperature overnight. The solvent was evaporated and the
residue dissolved in ethyl acetate (25 mL). The organic phase was
washed with brine (20 mL), dried (Na2SO4) and concentrated in
cause pyrazinones are more stable compounds in aqueous
media and no decomposition was observed after purifica-
tion. The diastereomeric excesses are similar or even slightly
better than the reported ones for oxazinones. Another ad-
vantage of this chiral template, relative to oxazinones 1, rep-
resents the possibility of Michael additions with elec-
trophilic olefins as well as additions to reactive and unreact-
ive organic halides using catalytic or stoichiometric
amounts of DBU as base. Finally, (S)-AMAAs can be ob-
tained through two complementary procedures of hydro- vacuo giving the corresponding dimethylamide (2.44 g) in a near-
Table 4. Synthesis of (S)-AMAAs 8
[a]
[b]
[c]
Based on compound (6R)-6, after recrystallization. Ϫ
Determined by comparison with [α] values reported in the literature. Ϫ
[d]
Dowex 50X-100, AcOH, toluene, 0.75  HCl, reflux 4 d instead of 6  HCl at 150 °C was used. Ϫ
observed in the crude reaction mixture.
A partial decomposition was
2814
Eur. J. Org. Chem. 2000, 2809Ϫ2820

Asymmetric Synthesis of α-Methyl α-Amino Acids
FULL PAPER
quantitative yield. Phenylmagnesium bromide (1  solution in
3  solution of hydrogen chloride in ethyl acetate (50 mL) was
THF, 30 mL, 30 mmol) was added to a stirred solution of dimethyl-
stirred for 1 h. The solvent was evaporated, the residue dissolved
amide (2.44 g, 10 mmol) in THF (20 mL) at 0 °C and stirring was in hydrochloric acid (0.1 , 10 mL) and washed with ether (10 mL).
continued at room temperature for 1 d. A saturated solution of
ammonium chloride (100 mL) was added dropwise at 0 °C, fol-
lowed by ethyl acetate (20 mL). The organic phase was separated,
dried (Na2SO4) and concentrated. The resulting residue was treated
with a solution of hydrogen chloride in ethyl acetate (3 , 80 mL)
and stirred at room temperature for 30 min. The solvent was evap-
orated in vacuo and the remaining solid was washed with hot n-
The organic phase was discarded and the aqueous phase was
treated with a saturated solution of K2CO3 (50 mL) and extracted
with ethyl acetate (3 ϫ 15 mL). The organic phase was separated,
dried (Na2SO4) and concentrated affording pure pyrazinone 5.
When cyclization was not complete in this step (1H NMR mon-
itoring) the pure mixture was dissolved in dichloromethane (10 mL)
and triethylamine (1.5 mL, 10 mmol) and the resulting solution was
hexane to afford ketone hydrochloride 3 (2.95 g, 70% overall yield stirred overnight at room temperature. Solvents were evaporated
from valine). Ϫ Method B: Pivaloyl chloride (1.23 mL, 10 mmol)
was added dropwise to a solution of N-Boc-protected valine
and compound 5 was obtained (1.98 g, 86%) as a pale yellow oil.
Ϫ C14H18N2O (230.2): calcd. C 73.05, H 7.8, N 12.15; found C,
(2.17 g, 10 mmol) and triethylamine (2.02 g, 10 mmol) in THF 73.5, H 7.9, N 11.8. Ϫ [α]2D5 ϭ Ϫ76.5 (c ϭ 1.60, CH2Cl2). Ϫ TLC:
(60 mL) at 0 °C, and the resulting suspension was stirred for 1 h at
the same temperature. Pyrrolidine (1.40 g, 20 mmol) was added and
the resulting mixture was stirred for 6 h. The solvent was evapor-
Rf ϭ 0.51 (ethyl acetate). Ϫ IR (film): ν˜ ϭ 3500Ϫ3200, 1670Ϫ1660
cmϪ1. Ϫ 1H NMR (300 MHz): δ (major diastereomer) ϭ 0.78, 1.02
[2 d, J ϭ 6.7 Hz, 6 H, (CH3)2CH)], 1.68 [d, J ϭ 7.6 Hz, 3 H,
ated and the residue dissolved in ethyl acetate (25 mL). The organic CH3CHCO], 2.08 [m, 1 H, CH(CH3)2], 4.21 (qd, J ϭ 7.3, 2.8 Hz,
phase was washed with brine (20 mL), dried (Na2SO4) and concen-
trated in vacuo to give the corresponding amide (2.40 g) in a near-
quantitative yield. Phenylmagnesium bromide (1  solution in
THF, 30 mL, 30 mmol) was added to a stirred solution of dimethyl-
1 H, CHCO), 4.71 (m, 1 H, CHN), 7.71Ϫ7.18 (m, 5 H, ArH), 8.15
(br. s, 1 H, NH). Ϫ 13C NMR (75 MHz): δ (major diastereomer) ϭ
15.7, 19.1 [(CH3)2CH)], 19.5 [CH3CHCO], 32.5 [CH(CH3)2], 56.1
(CHN), 60.2 (CH3CHCO), 126.7, 128.5, 129.3, 136.8 (ArC), 164.1
amide (2.44 g, 10 mmol) in THF (20 mL) at 0 °C and stirring was (CϭN), 172.7 (CO). Ϫ MS (ESI); m/z (%): 231 (27) [Mϩ ϩ 1].
continued at room temperature for 1 d. A saturated solution of
Synthesis
of
(3S,6R)-N-1-Boc-6-Isopropyl-3-methyl-5-phenyl-
ammonium chloride (100 mL) was added dropwise at 0 °C, fol-
lowed by ethyl acetate (20 mL) . The organic phase was separated,
dried (Na2SO4) and concentrated. The resulting residue was treated
with a solution of hydrogen chloride in ethyl acetate (3 , 80 mL)
and stirred at room temperature for 30 min. The solvent was evap-
orated in vacuo and the remaining solid washed with hot n-hexane
to afford ketone 3 hydrochloride (2.95 g, 69% overall yield from
valine) as a colourless solid, m.p. 206Ϫ208 °C from ethyl acetate
(ref.[19] 205Ϫ207 from MeOH/EtOAc). Ϫ [α]2D5 ϭ Ϫ61.4 (c ϭ 0.65,
H2O). Ϫ IR (KBr): ν˜ ϭ 3000Ϫ2750, 1680 cmϪ1. Ϫ 1H NMR
(300 MHz): δ ϭ 0.84, 1.12 [2 d, J ϭ 7.3 Hz, 6 H, (CH3)2CH], 2.45
[m, 1 H, CH(CH3)2], 5.14 (d, J ϭ 3.7 Hz, 1 H, CHN), 7.35Ϫ8.03
(m, 5 H, ArH). Ϫ 13C NMR (75 MHz): δ ϭ 21.9, 24.9 [(CH3)2CH],
36.1 [CH(CH3)2], 67.2 (CHN), 132.1, 134.5, 135.3, 141.8 (ArC),
204.7 (CO). Ϫ MS (EI); m/z (%): 178 (0.01) [Mϩ Ϫ Cl], 105 (11),
77 (24), 72 (100), 57 (16), 56 (21), 55 (59), 51 (12), 43 (26).
1,2,3,6-tetrahydro-2-pyrazinone (2): Di-tert-butyl dicarbonate
(2.64 g, 11 mmol) dissolved in THF (6 mL) was added to a stirred
solution of 5 (2.30 g, 10 mmol) and 4-(dimethylamino)pyridine
(70 mg, 0.1 mmol) in THF (30 mL) at 0 °C and stirring continued
for 90 min at the same temperature. THF was evaporated in vacuo
and the residue purified by chromatography (SiO2) eluting with n-
hexane yielding 2 (2.77 g, 84%) as a pale yellow oil. Ϫ C19H26N2O3
(330.3): calcd. C 69.0, H 7.6, N 4.1; found C, 69.1, H 7.9, N 4.5.
Ϫ TLC: Rf ϭ 0.62 (n-hexane/ethyl acetate, 3:2). Ϫ IR (film): ν˜ ϭ
1780Ϫ1700 cmϪ1. Ϫ 1H NMR (300 MHz): δ (major diastereo-
mer) ϭ 0.85, 0.97 [2 d, J ϭ 6.7 Hz, 6 H, (CH3)2CH)], 1.59 [s, 9
H, (CH3)3C], 1.72 (d, J ϭ 7.3 Hz, 3 H, CH3CHCO), 2.21 [m, 1 H,
(CH3)2CH)], 4.33 (q, J ϭ 7.3 Hz, 1 H, CH3CHCO), 5.63 (d, J ϭ
8.5 Hz, 1 H, CHN), 7.85Ϫ7.42 (m, 5 H, ArH). Ϫ 13C NMR
(75 MHz): δ (major diastereomer) ϭ 18.3, 19.4 [(CH3)2CH)], 20.4
[CH3CHCO], 27.8 [(CH3)3C], 31.5 [(CH3)2CH)], 58.6 (CHN), 61.0
(CH3CHCO), 83.7 [(CH3)3C], 126.8, 128.6, 130.6, 137.2 (ArC),
152.1, 167.8, 170.2 (2 ϫ CϭO and CϭN). Ϫ MS (ESI); m/z (%):
331 (21) [Mϩ ϩ 1]. ϪMS (EI); m/z (%): 330 (3) [Mϩ], 230 (37), 215
(46), 91 (14), 77 (15), 44 (100). Ϫ HRMS calcd. for C19H26N2O3:
330.1943; found 330.1948.
Synthesis of N-1-[(1R)-1-Benzoyl-2-methylpropyl]-(2S)-2-(N-Boc-
amino)propanamide (4): Compound 3 (2.13 g, 10 mmol) was added
to a suspension of freshly prepared N-Boc-(S)-alanine-pivalic acid
mixed anhydride[29] (10 mmol) containing triethylamine (4.17 mL,
30 mmol) at 0 °C and the reaction mixture stirred at room temper-
ature for 3 h. Water (40 mL) and ethyl acetate (30 mL) were added,
the organic phase was separated, dried (Na2SO4) and concentrated
in vacuo. The residue was washed with hot n-hexane, yielding ke-
tone 4 (3.31 g, 95%) as colourless sticky oil. Ϫ C19H28N2O4 (348.4):
Diastereoselective Alkylation of 2 under PTC Conditions. ؊ General
Procedure: A suspension of pyrazinone 2 (0.33 g, 1 mmol), tetra-n-
butylammonium chloride (32 mg, 0.1 mmol), potassium carbonate
(0.414 g, 3 mmol) and the electrophile (1.5 mmol) in acetonitrile
(5 mL) was stirred at room temperature for times depicted in Table
1. The solvent was evaporated and the residue purified by chroma-
tography (SiO2) eluting with mixtures of n-hexane/ethyl acetate giv-
ing product 6 in yields and de’s shown in Table 1. Physical and
analytical data follow.
calcd. C 65.5, H 8.05, N 8.05; found C 65.4, H 8.0, N 7.8. Ϫ [α]2D5
ϭ
Ϫ67.4 (c ϭ 1.07, CH2Cl2). Ϫ TLC: Rf ϭ 0.43 (hexane/ethyl acetate,
1
3/2). Ϫ IR (film): ν˜ ϭ 3400Ϫ3200, 1700Ϫ1600 cmϪ1. Ϫ H NMR
(300 MHz): δ ϭ 0.78, 1.02 [2 d, J ϭ 6.7 Hz, 6 H, (CH3)2CH], 1.39
(d, J ϭ 7.3 Hz, 3 H, CH3CHN), 1.45 [s, 9 H, (CH3)3C], 2.21 [m, 1
H, CH(CH3)2], 4.34 (m, 1 H, CHCH3), 5.49 (br. s, 1 H, NHBoc),
5.59 (dd, J ϭ 8.5, 4.5 Hz, 1 H, CHCOAr), 8.02Ϫ7.01 (m, 6 H,
ArH, NHCOCH). Ϫ 13C NMR (75 MHz): δ ϭ 16.5, 18.4
[(CH3)2CH], 19.8 (CH3CH), 28.1 [(CH3)3C], 31.5 [CH(CH3)2], 57.7
(CHCH3, CHN), 81.7 [(CH3)3C], 125.5, 128.6, 133.5, 135.1 (ArC),
155.2, 172.9 (2 ϫ NCO), 198.9 (ArCO). Ϫ MS (ESI); m/z (%): 349
(34) [Mϩ ϩ 1].
(3S,6R)-N-1-(tert-Butoxycarbonyl)-3-ethyl-6-isopropyl-3-methyl-5-
phenyl-1,2,3,6-tetrahydro-2-pyrazinone (6a): Pale yellow oil.
Ϫ
[α]D25 ϭ Ϫ151.7 (c ϭ 1.03, CH2Cl2). ϪTLC: Rf ϭ 0.76 (n-hexane/ethyl
acetate, 3:2). Ϫ IR (film): ν˜ ϭ 1712Ϫ1655 cmϪ1. Ϫ 1H NMR
(300 MHz): δ ϭ 0.74 (t, J ϭ 7.6 Hz, 3 H, CH3CH2), 0.81, 0.86 [2
d, J ϭ 7.0 Hz, 6 H, (CH3)2CH)], 1.55 [s, 12 H, (CH3)3C, CH3CCO],
1.97 [m, 1 H, (CH3)2CH], 1.94, 2.12 (2 m, 2 H, CH2), 5.52 (d, J ϭ
Synthesis of (3S,6R)-6-Isopropyl-3-methyl-5-phenyl-1,2,3,6-tetrahy-
dro-2-pyrazinone (5): A solution of ketone 4 (3.84 g, 10 mmol) in a 5.5 Hz, 1 H, CHN), 7.76, 7.42 (m, 5 H, ArH). Ϫ 13C NMR
Eur. J. Org. Chem. 2000, 2809Ϫ2820
2815

´
´
C. Najera, T Abellan, J. M. Sansano
FULL PAPER
(75 MHz): δ ϭ 18.5 (CH3CH2), 18.9, 19.8 [(CH3)2CH)], 26.6 J ϭ 16.2 Hz, 2 H, CH2CO), 3.94, 4.00 (2 dq, J ϭ 10.8, 7.2 Hz, 2
(CH3CCO), 28.0 [(CH3)3C], 34.7 [(CH3)2CH)], 37.4 (CH2), 61.5 H, CH2O), 5.63 (d, J ϭ 5.8 Hz, 1 H, CHN), 7.72Ϫ7.28 (m, 5 H,
(CHN), 66.1 (CH3CCO), 83.3 [(CH3)3C], 127.1, 128.6, 130.2, 138.1 ArH). Ϫ 13C NMR (75 MHz): δ ϭ 14.0 (CH2CH3), 19.0, 20.2
(ArC), 151.8 (CϭN), 163.8 (CO2tBu), 175.7 (CH3CCON). Ϫ MS
(EI); m/z (%): 357 (1) [Mϩ Ϫ 1], 230 (1), 117 (13), 91 (70), 77 (51),
43 (100). Ϫ HRMS calcd. for C21H30N2O3: 358.2256; found
358.2255.
[(CH3)2CH)], 27.2 (CH3CCO), 27.9 [(CH3)3C], 34.8 [(CH3)2CH)],
47.8 (CH2CO), 60.2 (CH2O), 61.2 (CHN), 62.8 (CH3CCO), 83.6
[(CH3)3C], 127.0, 128.5, 130.2, 138.3 (ArC), 152.1, 164.3, 179.0,
172.6 (3 ϫ CϭO and CϭN). Ϫ MS (EI); m/z (%): 316 (5) [Mϩ
Ϫ
100], 229 (15), 213 (12), 185 (11), 104 (100), 91 (84), 77 (41), 44
(83). Ϫ HRMS calcd. for C23H32N2O5: 416.2311; found 416.2313.
(3S,6R)-3-Allyl-N-1-(tert-butoxycarbonyl)-6-isopropyl-3-methyl-5-
phenyl-1,2,3,6-tetrahydro-2-pyrazinone (6b): Pale yellow oil.
[α]D25 ϭ Ϫ88.9 (c ϭ 0.80, CH2Cl2). Ϫ TLC: Rf ϭ 0.77 (n-hexane/ethyl
acetate, 3:2). Ϫ IR (film): ν˜ ϭ 3075, 1651, 981, 1802, 1631 cmϪ1
1H NMR (300 MHz): δ ϭ 0.78, 0.86 [2 d, J ϭ 6.7 Hz, 6 H,
Ϫ
(3S,6R)-N-1-(tert-Butoxycarbonyl)-6-isopropyl-3-methyl-3-[(E)-3-
methyloxycarbonyl-2-propenyl]-5-phenyl-1,2,3,6-tetrahydro-2-pyra-
zinone (6f): Pale yellow oil. Ϫ [α]2D5 ϭ Ϫ117.2 (c ϭ 1.70, CH2Cl2).
Ϫ TLC: Rf ϭ 0.58 (n-hexane/ethyl acetate, 3:2). Ϫ IR (film): ν˜ ϭ
.
Ϫ
(CH3)2CH)], 1.54 [s, 9 H, (CH3)3C], 1.58 (s, 3 H, CH3CCO), 1.98
[m, 1 H, (CH3)2CH)], 2.64 (dd, J ϭ 13.4, 6.7 Hz, 1 H, CH2CHϭ
C), 2.73 (dd, J ϭ 13.4, 8.6 Hz, 1 H, CH2CHϭC), 4.98 (d, J ϭ
10.4 Hz, 1 H, CHϭCH2), 5.04 (d, J ϭ 17.7 Hz, 1 H, CHϭCH2),
5.55 (d, J ϭ 4.9 Hz, 1 H, CHN), 5.59 (m, 1 H, CHϭCH2),
7.76Ϫ7.20 (m, 5 H, ArH). Ϫ 13C NMR (75 MHz): δ ϭ 18.7, 19.6
[(CH3)2CH)], 26.2 [CH3CCO], 28.0 [(CH3)3C], 34.5 [(CH3)2CH)],
48.1 (CH2CHϭC), 61.5 (CHN), 66.3 (CH3CCO), 83.2 [(CH3)3C],
118.7 (CHϭCH2), 127.1, 128.6, 130.2, 132.6, 137.9 (ArC, CHϭ
CH2), 151.6, 163.3, 174.9 (2 ϫ CϭO, CϭN). Ϫ MS (EI); m/z (%):
270 (9) [Mϩ Ϫ 100], 229 (100), 213 (15), 199 (2), 91 (4), 77 (5), 44
(11). Ϫ HRMS calcd. for C22H30N2O3: 370. 2256; found 370.2260.
1
3059, 1659, 985, 1772, 1725, 1659, 1291, 1155 cmϪ1. Ϫ H NMR
(300 MHz): δ ϭ 0.81, 0.84 [2 d, J ϭ 7.0 Hz, 6 H, (CH3)2CH)], 1.53
[s, 9 H, (CH3)3C], 1.61 (s, 3 H, CH3CCO), 1.98 [m, 1 H,
(CH3)2CH)], 2.80 (ddd, J ϭ 13.3, 6.9, 1.5 Hz, 1 H, CH2), 2.87 (ddd,
J ϭ 13.3, 8.6, 1.2 Hz, 1 H, CH2), 3.66 (s, 3 H, OCH3), 5.49 (d, J ϭ
5.8 Hz,
1 H, CHN), 5.84 (dm, J ϭ 15.9 Hz, 1 H, CHϭ
CHCO2CH3), 6.74 (ddd, J ϭ 15.9, 8.6, 6.9 Hz, 1 H, CHϭ
CHCO2CH3), 7.78Ϫ7.28 (m, 5 H, ArH). Ϫ 13C NMR (75 MHz):
δ ϭ 19.0, 19.7 [(CH3)2CH)], 26.4 (CH3CCO), 27.8 [(CH3)3C], 34.4
[(CH3)2CH)], 46.1 (CH2), 51.2 (OCH3), 61.3 (CHN), 65.9
(CH3CCO), 83.4 [(CH3)3C], 124.3, 127.1, 128.5, 130.4, 137.6, 142.9
(ArC, CϭC), 151.6, 164.2, 166.2 and 174.3 (3 ϫ CϭO, CϭN). Ϫ
MS (EI); m/z (%): 328 (4) [Mϩ Ϫ 100], 313 (1), 297 (1), 229 (100),
213 (14), 185 (18), 91 (10), 77 (11), 44 (9). Ϫ HRMS calcd. for
C24H32N2O5: 428.2311; found 428.2307.
(3S,6R)-N-1-(tert-Butoxycarbonyl)-6-isopropyl-3-methyl-5-phenyl-3-
(2-propynyl)-1,2,3,6-tetrahydro-2-pyrazinone (6c): Pale yellow oil. Ϫ
[α]2D5 ϭ Ϫ194.5 (c ϭ 0.96, CH2Cl2). Ϫ TLC: Rf ϭ 0.29 (n-hexane/
1
ethyl acetate, 4:1). Ϫ IR (film): ν˜ ϭ 3250, 1716,1662 cmϪ1. Ϫ H
tert-Butyl [3-(3S,6R)-N-1-(tert-Butoxycarbonyl)-6-isopropyl-3-
methyl-2-oxo-5-phenyl-1,2,3,6-tetrahydropyrazinylmethyl]-1H-1-in-
dolecarboxylate (6g): Light brown oil. Ϫ C33H41N3O5 (559.6):
calcd. C 70.82, H 7.38, N 7.51; found C 71.00, H 7.41, N 7.80. Ϫ
[α]2D5 ϭ Ϫ43.7 (c ϭ 3.00, CH2Cl2). Ϫ TLC: Rf ϭ 0.68 (n-hexane/
NMR (300 MHz): δ ϭ 0.79, 0.88 [2 d, J ϭ 6.9 Hz, 6 H,
(CH3)2CH)], 1.56 [s, 9 H, (CH3)3C], 1.61 (s, 3 H, CH3CCO), 1.90
(t, J ϭ 2.6 Hz, 1 H, CϵCH), 1.98 [m, 1 H, (CH3)2CH)], 2.75, 2.90
(2 dd, J ϭ 16.1, 2.6 Hz, 2 H, CH2), 5.67 (d, J ϭ 4.9 Hz, 1 H,
CHN), 7.78Ϫ7.20 (m, 5 H, ArH). Ϫ 13C NMR (75 MHz): δ ϭ
18.5, 19.6 [(CH3)2CH)], 25.9 (CH3CCO), 28.0 [(CH3)3C], 34.1
(CH2), 34.3 [(CH3)2CH)], 61.6 (CHN), 65.2 (CH3CCO), 70.8
(CϵCH), 79.6 (CϵCH), 83.5 [(CH3)3C], 127.2, 128.6, 130.4, 137.8
(ArC), 151.6, 164.4, 173.5 (2 ϫ CϭO and CϭN). Ϫ MS (EI); m/z
(%): 369 (5) [Mϩ ϩ 1], 253 (13), 229 (3), 213 (6), 77 (6), 44 (100).
Ϫ HRMS calcd. for C22H28N2O3: 368.2099; found 368.2101.
ethyl acetate, 3:2). Ϫ IR (film): ν˜ ϭ 3055, 1661, 1769Ϫ1721 cmϪ1
1H NMR (300 MHz): δ ϭ 0.71, 0.78 [2 d, J ϭ 7.3 Hz, 6 H,
.
Ϫ
(CH3)2CH)], 1.34, 1.56 [2 ϫ s, 18 H, (CH3)3C], 1.52 (s, 3 H,
CH3CCO), 1.88 [m, 1 H, (CH3)2CH], 3.28, 3.45 (2 ϫ d, J ϭ
14.0 Hz, 2 H, CH2), 5.16 (d, J ϭ 4.9 Hz, 1 H, CHN), 6.86 (t, J ϭ
7.6 Hz, 1 H, CϭCHN), 8.02Ϫ7.10 (m, 9 H, ArH). Ϫ 13C NMR
(75 MHz): δ ϭ 19.1, 19.5 [(CH3)2CH)], 26.9 (CH3CCO), 28.1
[(CH3)3C], 34.7 [(CH3)2CH)], 39.7 (CH2), 61.1 (CHN), 66.8
(CH3CCO), 83.2 [2 ϫ (CH3)3C], 114.6 (CHϭCN), 115.5 (CHϭ
CN), 120.8, 122.1, 123.8, 125.0, 127.0, 128.4, 130.1, 138.3 (ArC),
151.3 (CϭN), 163.4 (CO2tBu) and 173.9 (CH3CCON). Ϫ MS (EI);
m/z (%): 228 (100), 213 (30), 185 (74), 77 (25).
(3S,6R)-3-Benzyl-N-1-(tert-butoxycarbonyl)-6-isopropyl-3-methyl-5-
phenyl-1,2,3,6-tetrahydro-2-pyrazinone (6d): Pale yellow oil.
Ϫ
[α]D25 ϭ Ϫ74.2 (c ϭ 0.50, CH2Cl2). Ϫ TLC: Rf ϭ 0.56 (n-hexane/ethyl
acetate, 3/2). Ϫ IR (film): ν˜ ϭ 1772, 1661 cmϪ1. Ϫ 1H NMR
(300 MHz): δ ϭ 0.66, 0.77 [2 d, J ϭ 6.9 Hz, 6 H, (CH3)2CH)], 1.48
[s, 9 H, (CH3)3C], 1.71 (s, 3 H, CH3CCO), 1.88 [m, 1 H,
(CH3)2CH)], 3.18, 3.31 (2 d, J ϭ 12.7 Hz, 2 H, CH2), 5.04 (d, J ϭ
4.3 Hz, 1 H, CHN), 7.61Ϫ6.99 (m, 10 H, ArH). Ϫ 13C NMR
(75 MHz): δ ϭ 18.8, 19.1 [(CH3)2CH)], 26.8 (CH3CCO), 27.9
[(CH3)3C], 34.4 [(CH3)2CH)], 50.0 (CH2), 61.5 (CHN), 66.9
(CH3CCO), 83.0 [(CH3)3C], 126.5, 126.8, 127.5, 128.5, 130.0, 130.4,
136.1, 138.4 (ArC), 151.0, 162.9, 173.7 (2 ϫ CϭO and CϭN). Ϫ
MS (EI); m/z (%): 320 (7) [Mϩ Ϫ 100], 229 (100), 213 (14), 199 (2),
91 (34), 77 (9), 44 (20). Ϫ HRMS calcd. for C26H32N2O3: 420.2413;
found 420.2421.
(3S,6R)-N-1-(tert-Butoxycarbonyl)-3-hydroxymethyl-6-isopropyl-3-
methyl-5-phenyl-1,2,3,6-tetrahydro-2-pyrazinone (6h): Pale yellow
oil. Ϫ [α]2D5 ϭ Ϫ107.5 (c ϭ 2.1, CH2Cl2). Ϫ TLC: Rf ϭ 0.50 (n-
hexane/ethyl acetate, 3:2). Ϫ IR (film): ν˜ ϭ 3400, 1770, 1700 and
1600 cmϪ1. Ϫ 1H NMR (300 MHz): δ ϭ 0.83, 0.86 [2 d, J ϭ
6.7 Hz, 6 H, (CH3)2CH)], 1.52 (s, 3 H, CH3CCO), 1.55 [s, 9 H,
(CH3)3C], 1.96 [m, 1 H, (CH3)2CH], 3.78, 3.90 (2 d, J ϭ 10.4 Hz,
2 H, CH2), 5.55 (d, J ϭ 6.7 Hz, 1 H, CHN), 7.76Ϫ7.41 (m, 5 H,
ArH). Ϫ 13C NMR (75 MHz): δ ϭ 19.2, 20.2 [(CH3)2CH)], 25.9
(CH3CCO), 28.0 [(CH3)3C], 34.0 [(CH3)2CH)], 61.1 (CHN), 66.0
(CH3CCO), 71.2 (CH2), 83.7 [(CH3)3C], 127.2, 128.7, 130.7, 137.7
(ArC), 151.8 (CϭN), 166.3 (CO2tBu), 173.8 (CH3CCON). Ϫ MS
(EI); m/z (%): 260 [Mϩ Ϫ 100], 229 (100), 215 (10), 213 (17), 187
(18), 117 (8), 104 (13), 91 (11), 77 (16), 72 (20), 44 (15) and 41 (34).
Ϫ HRMS calcd. for C20H28N2O4: 360.2049; found 360.2048.
(3S,6R)-N-1-(tert-Butoxycarbonyl)-3-(ethoxycarbonyl)methyl-6-
isopropyl-3-methyl-5-phenyl-1,2,3,6-tetrahydro-2-pyrazinone
(6e):
Pale yellow oil. Ϫ [α]2D5 Ϫ124.9 (c ϭ 1.03, CH2Cl2). Ϫ TLC: Rf ϭ
0.59 (n-hexane/ethyl acetate, 3:2). Ϫ IR (film): ν˜ ϭ 1770, 1738, 1670
1
cmϪ1. Ϫ H NMR (300 MHz): δ ϭ 0.85, 0.87 [2 d, J ϭ 4.6 Hz, 6
H, (CH3)2CH)], 1.09 (t, J ϭ 7.2 Hz, 3 H, CH2CH3) 1.58 [s, 12 H, (3S,6R)-N-1-(tert-Butoxycarbonyl)-3-(2-cyanoethyl)-6-isopropyl-3-
(CH3)3C, CH3CCO], 1.97 [m, 1 H, (CH3)2CH)], 2.90, 3.33 (2 d, methyl-5-phenyl-1,2,3,6-tetrahydro-2-pyrazinone (6i): Light yellow
2816
Eur. J. Org. Chem. 2000, 2809Ϫ2820

Asymmetric Synthesis of α-Methyl α-Amino Acids
FULL PAPER
oil. Ϫ [α]2D5 ϭ Ϫ111.5 (c ϭ1.00, CH2Cl2). Ϫ TLC: Rf ϭ 0.50 (n-
lithium iodide (133 mg, 1 mmol), DBU (0.284 mL, 2 mmol or
hexane/ethyl acetate, 3:2). Ϫ IR (film): ν˜ ϭ 2247, 1731, 1715 and 0.015, 0.1 mmol, see text and Table 2) and the electrophile
1644 cmϪ1. Ϫ 1H NMR (300 MHz): δ ϭ 0.84, 0.88 [2 d, J ϭ
(1.5 mmol) in NMP (5 mL) was stirred at room temperature for
7.3 Hz, 6 H, (CH3)2CH)], 1.57 [s, 12 H, (CH3)3C, CH3CCO], 1.98 times depicted in Table 2. The solvent was evaporated and the res-
[m, 1 H, (CH3)2CH)], 2.25, 2.47 [2 m, 4 H, (CH2)2CN], 5.49 (d, idue purified by chromatography (SiO2) eluting with mixtures of n-
J ϭ 6.1 Hz, 1 H, CHN), 7.77Ϫ7.40 (m, 5 H, ArH). Ϫ 13C NMR
hexane/ethyl acetate giving product 6 in yields shown in Table 2.
(75 MHz): δ ϭ 12.7 (CH2CN), 19.3, 20.3 [(CH3)2CH)], 26.5 Physical and analytical data follow.
(CH3CCO), 28.0 [(CH3)3C], 35.2 [(CH3)2CH)], 38.8 (CH2CH2CN),
(3S,6R)-3-Butyl-N-1-(tert-butoxycarbonyl)-6-isopropyl-3-methyl-5-
phenyl-1,2,3,6-tetrahydro-2-pyrazinone (6l): Pale yellow oil.
61.3 (CHN), 64.2 (CH3CCO), 84.3 [(CH3)3C], 119.2 (CN), 127.2,
128.7, 130.8, 137.4 (ArC), 151.8, 165.8, 173.6 (2 ϫ CϭO, CϭN).
Ϫ MS (EI); m/z (%): 283 (17) [Mϩ Ϫ 100], 268 (12), 243 (6), 230
(17), 229 (100), 213 (17), 91 (9), 77 (19), 44 (13). Ϫ HRMS calcd.
for C29H29N3O3: 383.2210; found 383.2211.
Ϫ
[α]2D5 ϭ Ϫ29.0 (c ϭ 3.00, CH2Cl2). Ϫ TLC: Rf ϭ 0.69 (n-hexane/
ethyl acetate, 3:2). Ϫ IR (film): ν˜ ϭ 1800Ϫ1716. Ϫ 1H NMR
(300 MHz): δ ϭ 0.80, 0.85 [2 ϫ d, J ϭ 6.7 Hz, 6 H, (CH3)2CH)],
0.81 (t, J ϭ 6.7 Hz, 3 H, CH3CH2), 1.51 (s, 3 H, CH3CCO), 1.55 [
s, 9 H, (CH3)3C], 2.16Ϫ1.66 [m, 7 H, (CH2)3, (CH3)2CH], 5.52 (d,
J ϭ 5.5 Hz, CHN), 7.75Ϫ7.18 (m, 5 H, ArH). Ϫ 13C NMR
(75 MHz): δ ϭ 14.0 (CH3CH2), 18.9, 19.8 [(CH3)2CH)], 22.7
(CH3CH2), 26.3 (CH3CH2CH2), 26.9 (CH3CCO), 28.1 [(CH3)3C],
(3S,6R)-N-1-(tert-Butoxycarbonyl)-6-isopropyl-3-methyl-3-(3-
oxobutyl)-5-phenyl-1,2,3,6-tetrahydro-2-pyrazinone (6j): Pale yellow
oil. Ϫ [α]2D5 ϭ Ϫ137.9 (c ϭ 0.72, CH2Cl2). Ϫ TLC: Rf ϭ 0.58 (n-
hexane/ethyl acetate, 3:2). Ϫ IR (film): ν˜ ϭ 1770, 1732, 1715, 1651
cmϪ1. Ϫ 1H NMR (300 MHz): δ ϭ 0.85 [d, J ϭ 7.0 Hz, 6 H, 34.7, [(CH3)2CH)], 44.3 (CH2CCO), 61.6 (CHN), 65.8 (CH3CCO),
(CH3)2CH)], 1.57 [s, 12 H, (CH3)3C, CH3CCO], 2.02 (s, 3 H, 83.3 [(CH3)3C], 127.1, 128.6, 130.2, 138.1 (ArC), 151.9 (CϭN),
CH3CO), 2.58Ϫ1.95 [m, 5 H, (CH3)2CH, (CH2)2CO], 5.50 (d, J ϭ
163.8 (CO2tBu), 175.9 (CH3CCON). Ϫ MS (EI); m/z (%): 286 (9)
6.1 Hz, 1 H, CHN), 7.77Ϫ7.28 (m, 5 H, ArH). Ϫ 13C NMR [Mϩ Ϫ 100], 229 (100), 213 (13), 187 (7), 91 (6), 77 (6), 41 (23). Ϫ
(75 MHz): δ ϭ 19.1, 20.0 [(CH3)2CH)], 26.5 (CH3CCO), 28.0 HRMS calcd. for C23H34N2O3: 386.2570; found 386.2573.
[(CH3)3C], 29.7 (CH3CO), 34.9 [(CH3)2CH)], 37.9, 38.8
(3S,6R)-N-1-(tert-Butoxycarbonyl)-3-isobutyl-6-isopropyl-3-methyl-
[(CH2)2CO], 61.3 (CHN), 64.6 (CH3CCO), 83.6 [(CH3)3C], 127.1,
5-phenyl-1,2,3,6-tetrahydro-2-pyrazinone (6m): Pale yellow oil. Ϫ
128.6, 130.5, 137.7 (ArC), 151.9, 164.3, 174.9 (CON, CO2tBu,
[α]D25 ϭ Ϫ71.3 (c ϭ1.05, CH2Cl2). Ϫ TLC: Rf ϭ 0.58 (n-hexane/ethyl
acetate, 3:2). Ϫ IR (film): ν˜ ϭ 1800Ϫ1716, 1395, 1370 cmϪ1. Ϫ 1H
NMR (300 MHz): δ ϭ 0.86Ϫ0.74 (m, 12 H, 2 ϫ (CH3)2CH)], 1.51
(s, 3 H, CH3CCO), 1.54 [ s, 9 H, (CH3)3C], 1.86 (dd, J ϭ 14.0,
6.1 Hz, 1 H, CH2), 1.95 [m, 2 H, 2 ϫ (CH3)2CH], 2.08 (dd, J ϭ
14.0, 6.4 Hz, 1 H, CH2), 5.53 (d, J ϭ 6.1 Hz, 1 H, CHN),
7.75Ϫ7.19 (m, 5 H, ArH). Ϫ 13C NMR (75 MHz): δ ϭ 19.1, 20.0,
23.5, 24.8 [2 ϫ (CH3)2CH)], 27.9 (CH3CCO), 28.1 [(CH3)3C], 34.2,
ArCϭN), 207.7 (CH3CO). Ϫ MS (EI); m/z (%): 302 (3) [Mϩ ϩ 2
Ϫ 100], 284 (3), 269 (8), 229 (3), 91 (6), 77 (11), 44 (89), 43 (100).
Ϫ HRMS calcd. for C23H32N2O4: 400.2362; found 400.3366.
(3S,6R)-N-1-(tert-Butoxycarbonyl)-6-isopropyl-3-methyl-3-(2-meth-
oxycarbonyl)ethyl-5-phenyl-1,2,3,6-tetrahydro-2-pyrazinone
(6k):
Pale yellow oil. Ϫ [α]2D5 ϭ Ϫ109.2 (c ϭ 0.70, CH2Cl2). Ϫ TLC: Rf ϭ
0.29 (n-hexane/ethyl acetate, 4:1). Ϫ IR (film): ν˜ ϭ 1770, 1727,
1650 cmϪ1. Ϫ 1H NMR (300 MHz): δ ϭ 0.84 [d, J ϭ 6.7 Hz, 6 34.9 [2 ϫ (CH3)2CH)], 52.7 (CH2), 61.3 (CHN), 65.8 (CH3CCO),
H, (CH3)2CH)], 1.56 [s, 12 H, (CH3)3C, CH3CCO], 1.98 [m, 1 H,
83.4 [(CH3)3C], 126.9, 127.0, 128.7, 130.1 (ArC), 151.8 (CϭN),
H, 162.8 (CO2tBu), 175.5 (CH3CCON). Ϫ MS (EI); m/z (%): 286 (9)
[Mϩ Ϫ 100], 229 (100), 213 (12), 187 (13), 41 (28). Ϫ HRMS calcd.
(CH3)2CH)], 2.29 [m, H, (CH2)2CO2CH3], 3.48 [s,
4
3
(CH2)2CO2CH3], 5.50 (d, J ϭ 6.1 Hz, 1 H, CHN), 7.76Ϫ7.22 (m,
5 H, ArH). Ϫ 13C NMR (75 MHz): δ ϭ 19.2, 20.1 [(CH3)2CH)], for C23H34N2O3: 386.2569; found 386.2568.
26.7 (CH3CCO), 28.2 [(CH3)3C], 29.6 (CH2CH2CO2CH3), 35.1
(3S,6R)-N-1-(tert-Butoxycarbonyl)-3-(2-ethoxycarbonylethyl)-6-
[(CH3)2CH)], 39.0 (CH2CH2CO2CH3), 51.7 (OCH3), 61.7 (CHN),
65.2 (CH3CCO), 84.2 [(CH3)3C], 127.9, 129.3, 131.3, 138.6 (ArC),
152.8, 165.4, 174.4, 175.9 (3 ϫ CϭO, CϭN). Ϫ MS (EI); m/z (%):
316 (3) [Mϩ Ϫ 100], 285 (1), 229 (15), 91 (100), 77 (6), 44 (73). Ϫ
HRMS calcd. for C23H32N2O5: 416.2311; found 416.2316.
isopropyl-3-methyl-5-phenyl-1,2,3,6-tetrahydro-2-pyrazinone
(6n):
Pale yellow oil. Ϫ [α]2D5 ϭ Ϫ122.6 (c ϭ 2.80, CH2Cl2). Ϫ TLC: Rf ϭ
0.68 (n-hexane/ethyl acetate, 3:2). Ϫ IR (film): ν˜ ϭ 1765, 1719, 1640
1
cmϪ1. Ϫ H NMR (300 MHz): δ ϭ 0.83, 0.84 [2 ϫ d, J ϭ 7.0 Hz,
6 H, (CH3)2CH)], 1.13 (t, J ϭ 7.0 Hz, 3 H, OCH2CH3), 1.58 [s, 12
H, (CH3)3C, CH3CCO], 1.95 [m, 1 H, (CH3)2CH)], 2.43Ϫ2.21 (m,
4 H, 2 ϫ CH2), 3.94 (q, J ϭ 7.0 Hz, 2 H, OCH2CH3), 5.49 (d, J ϭ
C-3 Dimer of (6R)-N-1-(tert-butoxycarbonyl)-6-isopropyl-3-methyl-
5-phenyl-1,2,3,6-tetrahydro-2-pyrazinone (7): Pale yellow oil. Ϫ
C38H50N4O6 (658.6): calcd. C 69.3, H 7.6, N 8.5; found C 69.0, H 6.1 Hz, 1 H, CHN) and 7.76Ϫ7.41 (m, 5 H, ArH). Ϫ 13C NMR
7.7, N 8.9. Ϫ [α]2D5 ϭ Ϫ151.7 (c ϭ 0.50, CH2Cl2). Ϫ TLC: Rf ϭ
0.43 (n-hexane/ethyl acetate, 4:1). Ϫ IR (film): ν˜ ϭ 1800, 1714, 1645
(75 MHz): δ ϭ 14.1 (OCH2CH3), 19.1, 20.1 [(CH3)2CH)], 26.5
(CH3CCO), 28.0 [(CH3)3C], 29.7 (CH2CH2CO2Et), 35.0
cmϪ1. Ϫ 1H NMR (300 MHz): δ ϭ 0.59, 0.75 [2 d, J ϭ 7.0 Hz, 12 [(CH3)2CH)], 38.8 (CH2CH2CO2Et), 61.3 (CHN), 64.8 (CH3CCO),
H, 2 ϫ (CH3)2CH)], 1.52 [s, 18 H, 2 ϫ (CH3)3C], 1.78 (s, 6 H, 2 ϫ 83.7 [(CH3)3C], 127.2, 128.6, 130.5, 137.7 (ArC), 151.9, 165.4,
CH3CCO), 1.85 [m, 2 H, 2 ϫ (CH3)2CH)], 5.55 (d, J ϭ 3.7 Hz, 2
172.8, 176.0 (3 ϫ CϭO and CϭN). Ϫ MS (EI); m/z (%): 330 (10)
H, 2 ϫ CHN) and 7.78Ϫ7.20 (m, 10 H, 2 ϫ ArH). Ϫ 13C NMR [Mϩ Ϫ 100], 285 (7), 230 (17), 229 (100), 91 (5), 77 (5), 44 (5). Ϫ
(75 MHz): δ ϭ 18.5, 19.1 [2 ϫ (CH3)2CH)], 21.8 (2 ϫ CH3CCO),
28.1 [2 ϫ (CH3)3C], 34.1 [2 ϫ (CH3)2CH)], 61.3 (2 ϫ CHN), 71.6
(2 ϫ CH3CCO), 82.4 [2 ϫ (CH3)3C], 126.8, 128.2, 130.2, 137.7
(ArC), 151.2, 163.1, 172.3 (4 ϫ CϭO, 2 ϫ CϭN). Ϫ MS (EI); m/z
(%): 662 (0.6) [Mϩ ϩ 4], 648 (0.6), 329 (5), 274 (13), 229 (31), 187
(55), 186 (100), 158 (42), 157 (12), 117 (11), 116 (29), 104 (11), 90
(10), 89 (18), 77 (10), 57 (94), 43 (17), 41 (35).
HRMS calcd. for C24H34N2O5: 430.2468; found 430.2462.
Diastereoselective Allylation of 2 under Neutral Palladium(0)-Cata-
lyzed Conditions. ؊ General Procedure: A solution of pyrazinone 2
(0.33 g, 1 mmol), and palladium catalyst (a) triphenylphosphane
(27 mg, 0.1 mmol), palladium acetate (8 mg, 0.05 mmol) or (b)
dppe (20 mg, 0.05 mmol), palladium acetate (8 mg, 0.05 mmol) or
(c) dppe (20 mg, 0.05 mmol), Pd(PPh3)4 (29 mg, 0.025 mmol) and
the corresponding allylic carbonate or vinyloxirane (1.1 mmol) in
THF (5 mL) was stirred at room temperature for times depicted in
Diastereoselective Alkylation of 2 under Organic Base Conditions.
؊ General Procedure: A solution of pyrazinone 2 (0.33 g, 1 mmol),
Eur. J. Org. Chem. 2000, 2809Ϫ2820
2817

´
´
C. Najera, T Abellan, J. M. Sansano
FULL PAPER
Table 3. The solvent was evaporated and the residue purified by
CH3CCO), 1.97 [m, 1 H, (CH3)2CH], 2.81 (ddd, J ϭ 13.1, 6.7,
chromatography (SiO2) eluting with mixtures of n-hexane/ethyl 1.2 Hz, 1 H, CH2CHϭCH), 2.89 (ddd, J ϭ 13.1, 8.5, 0.9 Hz, 1 H,
acetate giving product 6 in yields shown in Table 3. Physical and
analytical data follow.
CH2CHϭCH), 5.47 (d, J ϭ 4.9 Hz, CHN), 5.98 (m, 1 H, CH2CHϭ
CH), 6.38 (d, J ϭ 15.8 Hz, 1 H, CH2CHϭCH), 7.75Ϫ7.13 (m, 10
H, ArH). Ϫ 13C NMR (75 MHz): δ ϭ 18.9, 19.6 [(CH3)2CH)], 26.3
(CH3CCO), 27.7 [(CH3)3C], 34.7 [(CH3)2CH)], 47.4 (CH2CHϭC),
61.6 (CHN), 66.6 (CH3CCO), 83.2 [(CH3)3C], 123.1, 124.0, 126.2,
127.1, 128.3, 128.6, 130.3, 133.8, 137.4, 138.1 (ArC, CHϭCH),
151.6, 163.6, 174.9 (2 ϫ CϭO, CϭN). Ϫ MS (EI); m/z (%): 346 (1)
[Mϩ Ϫ 100], 229 (100), 213 (11), 187 (22), 117 (16), 91 (9), 77 (5),
43 (8). Ϫ HRMS calcd. for C28H34N2O3: 446.2569; found 446.2571.
(3S,6R)-3-[(E)-2-Butenyl]-N-1-(tert-butoxycarbonyl)-6-isopropyl-3-
methyl-5-phenyl-1,2,3,6-tetrahydro-2-pyrazinone (6o): Pale yellow
oil. Ϫ [α]2D5 ϭ Ϫ96.6 (c ϭ 2.10, CH2Cl2). Ϫ TLC: Rf ϭ 0.53 (n-
hexane/ethyl acetate, 8:1). Ϫ IR (film): ν˜ ϭ 3028, 1658, 981, 1715
1
cmϪ1. Ϫ H NMR (300 MHz): δ ϭ 0.70, 0.78 [2 d, J ϭ 7.0 Hz, 6
H, (CH3)2CH)], 1.48 [s, 12 H, (CH3)3C, CH3CCO], 1.49 (d, J ϭ
2.8 Hz, 3 H, CH3CHϭC), 1.90 [m, 1 H, (CH3)2CH], 2.48 (dd, J ϭ
13.1, 6.7 Hz, 1 H, CH2CHϭCH), 2.59 (dd, J ϭ 13.1, 8.3 Hz, 1 H,
CH2CHϭCH), 5.14, 5.37 (2 m, 2 H, CHϭCH), 5.44 (d, J ϭ 4.9 Hz,
CHN), 7.68Ϫ7.35 (m, 5 H, ArH). Ϫ 13C NMR (75 MHz): δ ϭ
18.1 (CH3CHϭC), 18.8, 19.6 [(CH3)2CH], 26.1 (CH3CCO), 28.0
[(CH3)3C], 34.5 [(CH3)2CH)], 47.1 (CH2CHϭC), 61.6 (CHN), 66.4
(CH3CCO), 83.0 [(CH3)3C], 124.9, 129.4 (CHϭCH), 127.0, 128.6,
130.2, 138.1 (ArC), 151.7, 163.1, 175.1 (2 ϫ CϭO and CϭN). Ϫ
MS (EI); m/z (%): 284 (5) [Mϩ Ϫ 100], 229 (100), 213 (15), 185 (18),
91 (7), 77 (10), 55 (27), 44 (64). Ϫ HRMS calcd. for C23H32N2O3:
384.2413; found 384.2413.
(3S,6R)-N-1-(tert-Butoxycarbonyl)-3-[(Z)-4-hydroxy-2-butenyl]-6-
isopropyl-3-methyl-5-phenyl-1,2,3,6-tetrahydro-2-pyrazinone (Z-6r):
Pale yellow oil.Ϫ TLC: Rf ϭ 0.35 (hexane/ethyl acetate, 3:2). Ϫ IR
(film): ν˜ ϭ 3600Ϫ3200 (OH), 3020, 1650, 928, 1722 cmϪ1. Ϫ 1H
NMR (300 MHz): δ (major diastereomer) ϭ 0.83 [2 d, J ϭ 7.0 Hz,
6 H, (CH3)2CH)], 1.57 [s, 9 H, (CH3)3C], 1.60 (s, 3 H, CH3CCO),
1.95 [m, 1 H, (CH3)2CH], 2.73 (dd, J ϭ 13.1, 7.3 Hz, 1 H, CH2CN),
3.01 (dd, J ϭ 13.1, 8.9 Hz, 1 H, CH2CN), 3.98 (m, 2 H, CH2OH),
4.64 (s, 1 H, OH), 5.33 (m, 1 H, CHϭCHCH2OH), 5.51 (d, J ϭ
6.1 Hz, CHN), 5.73 (m, 1 H, CHϭCHCH2OH), 7.75Ϫ7.19 (m, 5
H, ArH). Ϫ 13C NMR (75 MHz): δ (major diastereomer) ϭ 19.1,
20.1 [(CH3)2CH)], 27.0 (CH3CCO), 28.0 [(CH3)3C], 35.1
[(CH3)2CH)], 41.6 (CH2CϭC), 57.8 (CH2OH), 61.1 (CHN), 66.4
(CH3CCO), 84.2 [(CH3)3C], 127.1, 128.8 (CHϭCH), 126.7, 128.7,
130.8, 137.5 (ArC), 151.4, 165.1, 174.7 (2 ϫ CϭO, CϭN). Ϫ MS
(EI); m/z (%): 400 (1) [Mϩ], 262 (100), 228 (4), 183 (92), 108 (46),
91 (2), 77 (6), 44 (7). Ϫ HRMS calcd. for C23H32N2O4: 400.2362;
found 400.2384.
(3S,6R)-N-1-(tert-Butoxycarbonyl)-6-isopropyl-3-methyl-3-[1-
methyl-2-propenyl)-5-phenyl-1,2,3,6-tetrahydro-2-pyrazinone (6o):
Pale yellow oil. Ϫ [α]2D5 ϭ Ϫ131.4 (c ϭ 0.85, CH2Cl2). Ϫ TLC: Rf ϭ
0.63 (n-hexane/ethyl acetate). Ϫ IR (film): ν˜ ϭ 3070, 1650, 920,
1724 cmϪ1. Ϫ 1H NMR (300 MHz): δ ϭ 0.78, 0.79 [2 d, J ϭ
6.9 Hz, 6 H, (CH3)2CH)], 1.48Ϫ1.43 [m with s at δ ϭ 1.45, 12 H,
(CH3)3C, CH3CCO], 1.89 (d, J ϭ 7.0 Hz, 3 H, CH3CH), 1.90 [m,
1 H, (CH3)2CH], 2.73 (m, 1 H, CH3CH), 4.99 (dd, J ϭ 4.7, 2.2 Hz,
1 H, CHϭCH2), 4.97Ϫ5.06 (m, 2 H, CHϭCH2), 5.43 (d, J ϭ
6.4 Hz, 1 H, CHN), 5.92 (ddd, J ϭ 19.2, 10.1, 9.2 Hz, 1 H, CHϭ
CH2), 7.74Ϫ7.35 (m, 5 H, ArH). Ϫ 13C NMR (75 MHz): δ ϭ 15.7
(CH3CH), 19.1, 20.1 [(CH3)2CH)], 25.3 (CH3CCO), 28.0
[(CH3)3C], 35.0 [(CH3)2CH)], 50.0 (CH3CH), 60.7 (CHN), 67.5
(CH3CCO), 83.3 [(CH3)3C], 116.1 (CHϭCH2), 127.1, 128.4, 130.2,
137.9 (ArC), 139.9 (CHϭCH2), 151.8, 163.4, 175.8 (2 ϫ CϭO, Cϭ
N). Ϫ MS (EI); m/z (%): 284 (4) [Mϩ Ϫ 100], 229 (100), 213 (16),
187 (32), 185 (13), 91 (6), 77 (7), 55 (13), 44 (9). Ϫ HRMS calcd.
for C23H32N2O3: 384.2413; found 384.2414.
(3S,6R)-N-1-(tert-Butoxycarbonyl)-3-[(E)-4-hydroxy-2-butenyl]-6-
isopropyl-3-methyl-5-phenyl-1,2,3,6-tetrahydro-2-pyrazinone (E-6r):
Pale yellow oil. Ϫ [α]2D5 ϭ Ϫ 43.0 (c ϭ 1.50, CH2Cl2) Ϫ TLC: Rf ϭ
0.35 (n-hexane/ethyl acetate, 3:2). Ϫ IR (film): ν˜ ϭ 3600Ϫ3200,
3020, 1670, 928, 1731 cmϪ1. Ϫ 1H NMR (300 MHz): δ ϭ 0.78,
0.84 [2 d, J ϭ 6.7 Hz, 6 H, (CH3)2CH)], 1.57 [s, 9 H, (CH3)3C],
1.60 (s, 3 H, CH3CCO), 1.95 [m, 1 H, (CH3)2CH], 2.60Ϫ2.77 (m,
2 H, CH2CϭC), 3.96Ϫ4.14 (m, 3 H, CH2OH), 5.46 (d, J ϭ 4.9 Hz,
1 H, CHN), 5.49Ϫ5.89 (m, 2 H, CHϭCH), 7.19Ϫ7.75 (m, 5 H,
ArH). Ϫ 13C NMR (75 MHz): δ ϭ 18.8, 19.7 [(CH3)2CH)], 26.1
(CH3CCO), 28.0 [(CH3)3C], 34.7 [(CH3)2CH)], 46.4 (CH2CϭC),
61.7 (CHN), 63.4 (CH2OH), 66.3 (CH3CCO), 83.6 [(CH3)3C],
123.5, 126.5, 127.1, 128.7, 130.4, 137.8 (ArC, CϭC), 151.7, 163.7,
174.8 (2 ϫ CϭO, CϭN). Ϫ MS (EI); m/z (%): 400 (1) [Mϩ], 300
(3) [Mϩ Ϫ 100], 230 (18), 229 (100), 228 (32), 213 (20), 187 (17),
185 (22), 91 (8), 77 (12), 44 (10), 41 (20). Ϫ HRMS calcd. for
C23H32N2O4: 400.2362; found 400.2357.
(3S,6R)-3-(2-Methylallyl)-N-1-(tert-butoxycarbonyl)-6-isopropyl-3-
methyl-5-phenyl-1,2,3,6-tetrahydro-2-pyrazinone (6p): Colourless
oil. Ϫ [α]2D5 ϭ Ϫ96.2 (c ϭ 1.05, CH2Cl2). Ϫ TLC: Rf ϭ 0.34 (n-
hexane/ethyl acetate, 8:1). Ϫ IR (film): ν˜ ϭ 3070, 1650, 900, 1721
1
cmϪ1. Ϫ H NMR (300 MHz): δ ϭ 0.71, 0.79 [2 d, J ϭ 7.0 Hz, 6
H, (CH3)2CH)], 1.31 (s, 3 H, CH3CCO), 1.48 [s, 12 H, (CH3)3C,
CH3CϭCH2], 1.91 [m, 1 H, (CH3)2CH], 2.53, 2.74 (2 d, J ϭ
12.8 Hz, 2 H, CH2CϭCH2), 4.61, 4.67 (2s, 2 H, CϭCH2), 5.47 (d,
J ϭ 4.9 Hz, 1 H, CHN), 7.71,7.27 (m, 5 H, ArH). Ϫ 13C NMR
(75 MHz): δ ϭ 18.9, 19.6 [(CH3)2CH)], 24.3 (CH3CϭCH2), 27.2
(CH3CCO), 28.0 [(CH3)3C], 34.6 [(CH3)2CH)], 51.1 (CH2CϭCH2),
61.2 (CHN), 66.8 (CH3CCO), 83.2 [(CH3)3C], 114.9 (CH2CϭCH2),
127.0, 128.5, 130.1, 138.1 (ArC), 141.2 (CH2CϭCH2), 151.8, 162.7,
174.4 (2 ϫ CϭO, CϭN). Ϫ MS (EI); m/z (%): 284 (6) [Mϩ Ϫ 100],
229 (100), 213 (16), 185 (17), 91 (9), 77 (9), 55 (14), 44 (10). Ϫ
HRMS calcd. for C23H32N2O3: 384.2413; found 384.2420.
General Procedure for the Synthesis of (S)-AMAAs 8 Using 6
M
HCl: A mixture of hydrochloric acid (6 , 5 mL) and 2-pyrazinone
6 (1 mmol) was placed in a sealed tube and heated at 150 °C for 3
d. The aqueous phase was extracted with ethyl acetate (10 mL),
and the water layer was separated, concentrated in vacuo and the
resulting residue dissolved in ethanol (5 mL). Propylene oxide
(2 mL) was added, and the resulting solution was heated at reflux
for 30 min. The mixture was cooled, and the precipitate was filtered
and washed with ethyl acetate and acetone, giving AMAAs 8 in
yields shown in Table 4.
(3S,6R)-N-1-(tert-Butoxycarbonyl)-6-isopropyl-3-methyl-5-phenyl-3-
[(E)-3-phenyl-2-propenyl]-1,2,3,6-tetrahydro-2-pyrazinone (6q): Pale
yellow oil. Ϫ [α]2D5 ϭ Ϫ93.3 (c ϭ 0.70, CH2Cl2). Ϫ TLC: Rf ϭ 0.65
(n-hexane/ethyl acetate, 3:2). Ϫ IR (film): ν˜ ϭ 3026, 1653, 980 and
1720 cmϪ1. Ϫ 1H NMR (300 MHz): δ ϭ 0.77, 0.85 [2 d, J ϭ
(S)-α-Ethylalanine (8a): [α]2D5 ϭ ϩ10.1 (c ϭ 1, H2O), ref.[16a] [α]2D0
Ϫ10.3 (c ϭ 1, H2O).
ϭ
(S)-α-Methylphenylalanine (8d): Ϫ [α]2D5 ϭ Ϫ22.1 (c ϭ 1, H2O),
6.9 Hz, 6 H, (CH3)2CH)], 1.37 [s, 9 H, (CH3)3C], 1.63 (s, 3 H, ref.[16a] [α]D ϭ Ϫ22.1 (c ϭ 1, H2O).
2818 Eur. J. Org. Chem. 2000, 2809Ϫ2820

Asymmetric Synthesis of α-Methyl α-Amino Acids
FULL PAPER
[6]
[7]
[8]
(S)-α-Methylaspartic acid (8e): [α]2D5 ϭ ϩ52.5 (c ϭ 1, H2O), ref.[16a]
[α]D ϭ Ϫ52.9 (c ϭ 1, H2O).
H. Yano, S. Nakanishi, Y. Ikuina, K. Ando, M. Yoshida, Y.
Saitoh, Y. Matsuda, C. Bando, J. Antibiot. 1997, 50,
992Ϫ997, 998Ϫ1008.
B. G. M. Burgand, D. C. Horwell, A. Padova, M. C. Pritchard,
Tetrahedron 1996, 52, 13035Ϫ13050, and references cited
therein.
(S)-α-Methyltryptophan (8g): [α]2D5 ϭ Ϫ11.3 (c ϭ 1.1, H2O), ref.[30]
for (R) isomer [α]2D0 ϭ ϩ11.6 (c ϭ 1.1, H2O).
Naturally occurring antibiotics such as lactacistin, conagenin,
altemicidin, myomicin and sphingofungins are structurally
(S)-α-Methylserine (8h): [α]2D5 ϭ ϩ5.1 (c ϭ 1, H2O), ref.[16a] [α]D
ϩ6.3 (c ϭ 1, H2O).
ϭ
[8a]
complex AMAAs. Ϫ
B. M. Trost, C. B. Lee, J. Am. Chem.
[8b]
Soc. 1998, 120, 6818Ϫ6819. Ϫ
N. Chida, J. Takeoka, K.
(S)-α-Methylglutamic acid (8k): [α]2D5 ϭ ϩ22.1 (c ϭ 2.6, 6  HCl),
ref.[16a] [α]D ϭ ϩ22.0 (c ϭ 2.7, 6  HCl).
Ando, N. Tsutsumi, S. Ogawa, Tetrahedron 1997, 53,
16287Ϫ16298. Ϫ [8c] A. Kovacs-Kulyassa, P. Herczegh, F. Szta-
´
ricskai, Tetrahedron 1997, 53, 13883Ϫ13896. Ϫ [8d] S. Hatakey-
ama, H. Matsumoto, H. Fukuyama, Y. Mukugi, H. Irie, J. Org.
Chem. 1997, 62, 2275Ϫ2279. Ϫ [8e] S. Kobayashi, M. Matsum-
ara, T. Furuta, T. Hayashi, S. Iwamoto, Synlett 1997, 301Ϫ303;
S. Kobayashi, T. Furuta, Tetrahedron 1998, 54, 10275Ϫ10294.
[9a] Y. Aoyagi, R. M. Williams, Synlett 1998, 1099Ϫ1100. Ϫ [9b]
J. C. Stinson, Chem. Eng. News 1992, 70(39), 46Ϫ79.
Hydrolysis of Compound (6R)-6b: A suspension of cation-exchange
resin Dowex 50X-100 (3.5 mL) and HCl (0.75 , 3 mL, prepared
in deionised water) was added to a solution of (6R)-6b (370 mg,
1 mmol) in acetic acid (0.8 mL) and toluene (1.2 mL). The resulting
mixture was heated at reflux for 4 d, and then cooled at room
temperature and transferred to a column. The resin was washed
with water until neutral pH was obtained, ethanol and finally with
10% aqueous ammonia, affording a suspension of the correspond-
ing amino acid. The solid was filtered and washed with ethyl acet-
ate and acetone, affording pure amino acid 8b (80 mg, 62%).
[9]
[10] [10a]
D. Ma, H. Tian, J. Chem. Soc., Perkin Trans. 1 1997,
[10b]
´
E. Ndzie, P. Cardinael, A. R. Schoofs, G.
3493Ϫ3496. Ϫ
Coquerel, Tetrahedron: Asymmetry 1997, 8, 2913Ϫ2920. Ϫ [10c]
D. Ma, Z. Ma, J. Jian, Z. Yang, C. Zheng, Tetrahedron: Asym-
metry 1997, 8, 889Ϫ893.
[11]
´
´
C. Cativiela, M. D. Dıaz-de Villegas, J. A. Galvez, Y. Lapen˜a,
Tetrahedron 1997, 53, 5891Ϫ5898.
(S) α-Allylalanine (8b)·HCl: [α]2D5 ϭ Ϫ14.1 (c ϭ 1.3, D2O), ref.[16a]
[α]2D0 ϭ Ϫ14.4 (c ϭ 1.3, D2O).
´
[12] [12a]
A. B. Smith III, A. B. Benowitz, M. C. Guzman, P. A.
Sprengeler, R. Hirschmann, J. Am. Chem. Soc. 1998, 120,
[12b]
12704Ϫ12705. Ϫ
P. Wipf, S. Venkatraman, Synlett 1997,
1Ϫ10. Ϫ [12c] H. Cheng, P. Keitz, J. B. Jones, J. Org. Chem.1994,
59, 7671Ϫ7676. Ϫ [12d] U. Koert, Nachr. Chem. Tech. Lab. 1995,
43, 347Ϫ354.
Acknowledgments
[13]
´
´
T. Abellan, R. Chinchilla, N. Galindo, G. Guillena, C. Najera,
J. M. Sansano, Eur. J. Org. Chem., in press.
´
This work was supported by the Direccion General de Ensen˜anza
´
´
Superior e Investigacion Cientıfica (Projects PB94Ϫ1515 and
PB97Ϫ0123). T. A. thanks E. Lilly S. A. for a grant and J. M. S.
[14] [14a]
Y. N. Belokon, K. A. Kochetkov, T. D. Churkina, N. S.
´
Ikonnikov, A. A. Chesnokov, O. V. Larionov, V. S. Parmar, R.
Kumar, H. B. Kagan, Tetrahedron: Asymmetry 1998, 9,
851Ϫ857. Ϫ [14b] Y. N. Belokon, K. A. Kochetkov, T. D. Churk-
ina, N. S. Ikonnikov, S. Vyskocyl, H. B. Kagan, Tetrahedron:
Asymmetry 1999, 10, 1723Ϫ1728.
´
thanks the Spanish Ministerio de Educacion y Cultura (MEC) for
´
a contract under the program Acciones para la Incorporacion a
´
Espan˜a de Doctores y Tecnologos.
[15] [15a]
E. J. Corey, F. Xu, M. C. Noe, J. Am. Chem. Soc. 1997,
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[1]
For reviews see: [1a] C. Cativiela, M. D. Dıaz-de Villegas, Tetra-
119, 12414Ϫ12415. Ϫ
E. J. Corey, F. Xu, M. Noe, Tetra-
´
hedron 1998, 39, 5347Ϫ5350. Ϫ [15c] B. Lygo, P. G. Wainwright,
[1b]
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Highlights of
[15d]
Tetrahedron Lett. 1997, 38, 8595Ϫ8598. Ϫ
T. Ooi, M. Ka-
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D. Seebach, A. R. Sting, M.
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[15e] E. V. Dehmlow, S. Wagner, A. Müller. Tetrahedron 1999,
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[1e]
55, 6335Ϫ6346. Ϫ
M. Horikawa, J. Busch-Petersen, E. J.
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M. North, Contemp. Org. Synth. 1996, 323Ϫ343. Ϫ
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[2]
[2a]
´
R. Chinchilla, N. Galindo, C. Najera, Synthesis 1999,
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D. C. Horwell, G. S. Ratcliffe, E.
Roberts, Bioorg. Med. Chem. Lett. 1991, 1, 169Ϫ171. Ϫ
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[2b]
704Ϫ717. Ϫ
´
R. Chinchilla, L. R. Falvello, N. Galindo, C.
W.
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H. J. Boesten, B. H. N. Dassen, J. C. S. Kleijans, B. van Agen,
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78, 757Ϫ760.
´
R. Chinchilla, N. Galindo, C. Najera, Tetrahedron: Asymmetry
1999, 9, 2769Ϫ2772.
[17]
[18]
´
´
For preliminary communication see: T. Abellan, C. Najera, J.
M. Sansano, Tetrahedron: Asymmetry 1998, 9, 2211Ϫ2214.
To our knowledge, the only reported example of these kinds
of heterocycles is the case of 1,2,3,6-tetrahydro-6,6-dimethyl-5-
phenyl-2-pyrazinone, prepared by the reaction of 2,2-dimethyl-
3-phenyl-2H-azirine with glycine ethyl ester: G. Alvernhe, A.
Laurent, A. Masroua, Tetrahedron Lett. 1983, 24, 1153Ϫ1156.
The chiral amino ketone was recently prepared from N-Cbz-
(S)-valine N-methoxy-N-methyl amide, but no experimental
yield and analytical data were reported: P. Edwards, D. J. Wol-
anin, D. W. Andisik, M. W. Davis, J. Med. Chem. 1995, 38,
76Ϫ85.
[3]
For some examples see: [3a] M. Tanaka, N. Imakawa, M. Kurih-
[3b]
ara, H. Suemune, Helv. Chim. Acta 1999, 82, 494Ϫ510. Ϫ
´
´
A. I. Jimenez, C. Cativiela, M. Parıs, J. M. Peregrina, A. Av-
enoza, A. Aubry, M. Marrand, Tetrahedron Lett. 1998, 39,
[19]
[20]
[3c]
7841Ϫ7844. Ϫ
A. Polese, F. Formaggio, M. Crisma, G.
Valle, C. Toniolo, G. M. Bonora, Q. B. Broxterman, J. Kam-
[3d]
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M. Altolfer, C. Lehmann, P. Schönholzer, K. Müller, J. Org.
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Chem. 1996, 61, 4080Ϫ4086. Ϫ
Daly, C. Lehmann, P. Schönholzer, K. Müller, Tetrahedron
D. Obrecht, U. Bohdal, J.
´
The racemic compound was also reported: A. Guzman, C.
[3f]
Quintero, J. M. Muchowski. Can. J. Chem. 1991, 69,
1995, 51, 10883Ϫ10900. Ϫ
D. Obrecht, C. Lehmann, R.
2059Ϫ2063, and references cited therein.
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[3g]
[21]
[22]
78, 1567Ϫ1587. Ϫ
C. Bisang, C. Weber, J. Inglis, C. A.
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[4]
[5]
[23]
Eur. J. Org. Chem. 2000, 2809Ϫ2820
2819

´
´
C. Najera, T Abellan, J. M. Sansano
FULL PAPER
[24] [24a]
[26]
[27]
[28]
[29]
[30]
M. J. O’Donnell, F. Delgado, C. Hostettler, R. Schwes-
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inger, Tetrahedron Lett. 1998, 39, 8775Ϫ8788. Ϫ
M. J.
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5581Ϫ5582.
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cited therein.
´
´
A. Mazon, C. Najera. Tetrahedron: Asymmetry 1997, 8,
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Received January 23, 2000
[25]
The palladium(0)-catalyzed addition of benzophenone imine of
α-aminoacetonitrile to vinyloxiranes has been previously de-
´
´
scribed: A. Mazon, C. Najera, J. Ezquerra, C. Pedregal, Tetra-
hedron Lett. 1997, 38, 2167Ϫ2170.
[O00041]
2820
Eur. J. Org. Chem. 2000, 2809Ϫ2820