New chiral alanine template with a 1,2,3,6-tetrahydro-2-pyrazinone structure for the asymmetric synthesis of α-methyl α-amino acids

Article abstract of DOI:10.1016/S0957-4166(98)00208-0

(R)-6-Isopropyl-5-phenyl- 1,2,3,6-tetrahydro-2-pyrazinone, prepared from (R)-valine and (S)-alanine, reacts With activated alkyl halides and electrophilic olefins under solid-liquid PTC conditions: with K₂CO₃ as base, at room temperature and with high diastereoselectivity (>94%). The palladium-catalyzed allylation reaction of this alanine derivative under neutral conditions at room temperature also takes place with a de>96%. Final hydrolysis of alkylated pyrazinones affords enantiomerically pure α-methyl α-amino acids.

Full text of DOI:10.1016/S0957-4166(98)00208-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 2211–2214
New chiral alanine template with a 1,2,3,6-tetrahydro-
2-pyrazinone structure for the asymmetric synthesis of α-methyl
α-amino acids †
Tomás Abellán, Carmen Nájera ∗ and José M. Sansano
Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
Received 12 May 1998; accepted 21 May 1998
Abstract
(R)-6-Isopropyl-5-phenyl-1,2,3,6-tetrahydro-2-pyrazinone,prepared from (R)-valine and (S)-alanine, reacts with
activated alkyl halides and electrophilic olefins under solid–liquid PTC conditions with K2CO3 as base, at room
temperature and with high diastereoselectivity (>94%). The palladium-catalyzed allylation reaction of this alanine
derivative under neutral conditions at room temperature also takes place with a de>96%. Final hydrolysis of
alkylated pyrazinones affords enantiomerically pure α-methyl α-amino acids. © 1998 Elsevier Science Ltd. All
rights reserved.
The great importance of nonproteinogenic α,α-disubstituted α-amino acids, especially α-methyl α-
amino acids (AMAAs), is based on their remarkable influence on the conformation of peptides into which
they are incorporated, thus reducing enzymatic and chemical hydrolysis. Moreover, as free amino acids
AMAAs act also as enzyme inhibitors and starting building blocks for the synthesis of natural products.1
The α-alkylation of suitable chiral alanine enolates is one of the best strategies to create the quaternary
stereogenic center.2 Schöllkopf’s bislactim ether 1, Seebach’s oxa- and imidazolidinones 2 and Williams’
diphenyl-oxazinones 3 are representative examples of cyclic chiral templates for the asymmetric syn-
thesis of AMAAs. Usually, the enolization of alanine or glycine chiral derivatives requires the use of
very strong bases (LDA, LHMDS, nBuLi) at very low temperatures. These strict reaction conditions are
important drawbacks for the industrial use of these systems.
∗
†
Corresponding author. Fax: +34-96-5903549; e-mail: cnajera@ua.es
Dedicated to Professor Antonio González on the occasion of his 80th birthday.
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00208-0

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T. Abellán et al. / Tetrahedron: Asymmetry 9 (1998) 2211–2214
We have recently described the application of a new cyclic iminic alanine template with 3,6-dihydro-
2H-1,4-oxazin-2-one structure 4,3 prepared from α-bromoisovalerophenone and (S)-alanine, for the
asymmetric synthesis of AMAAs. It can be diastereoselectively alkylated under solid–liquid phase
transfer catalysis (PTC) with K2CO3 as base or under neutral palladium(0) catalysis at room temperature.
In this communication we report the preparation of a new related system with the tetrahydro-2-pyrazinone
structure 5, which can be used also for the asymmetric synthesis of AMAAs under similar reaction
conditions. This type of template 5 has similar structural features to oxazinones 4: (a) the phenyl group
at the 5-position should favour the formation of the imine group and the enolization process; (b) the
stereogenic center at the 6-position can produce intra-annular 1,4-asymmetric induction at C-3 during
the alkylation of the planar enolate; (c) the acidity of the alanine unit should increase with the Boc-
protection of the N-1 together with the phenylimino group; (d) it can be prepared from available starting
amino acids (R)-valine and (S)-alanine; and (e) after alkylation they can be easily hydrolyzed.4
The synthesis of the tetrahydro-2-pyrazinones 55 is based on the coupling of the α-amidoketone
6, derived from (R)-valine, and N-Boc-L-alanine in order to prepare the trans-diasteromer6 with the
appropriate configuration at the 6-position for L-AMAAs. N-Boc-D-Valine was transformed into the
N,N-dimethylamide by reaction with dimethylamine chlorohydrate in the presence of triethylamine
and N,N,N0,N0-tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate (TBTU) in acetonitrile. The
crude amide was allowed to react with phenylmagnesium bromide in THF at room temperature affording
the α-amino ketone 6 in 78% overall yield. Deprotection of the amino group and amidation with the
N-Boc-L-alanine pivalic acid mixed anhydride gave compound 7 (95% yield). The pyrazinone 8 was
obtained in 86% yield after deprotection of 7 followed by extractive work-up with aqueous K2CO3. Final
N-Boc-protection with (Boc)2O at 0°C provided product 5 in 84% yield as ca. 20:1 mixture7 of trans/cis
diastereomers8 due to the high acidity of the H-3 of the alanine unit (Scheme 1). The same behaviour
was observed in the case of oxazinone 4 but is irrelevant for the diastereoselectivity of the alkylations
(see below). The relative configuration for the trans-pyrazinone 5 was determined by NOE experiments.
Molecular mechanics calculations9 predict quasi-boat conformation with the isopropyl group in the axial
position, as in the case of oxazinone 4.3
Scheme 1.
The alkylation of 5 with a variety of activated alkyl halides and electrophilic olefins took place with
K2CO3 as base and tetra-n-butylammonium bromide (TBAB) in CH3CN or CH2Cl2 at room temperature
giving compounds 9 in good yields and high diastereoselectivities (Scheme 2 and Table 1 entries 1–8).
Pyrazinones 5 underwent highly regio- and diastereoselective allylation under neutral conditions
with allylic carbonates using Pd(PPh3)4 (5 mol%) as catalyst in THF at room temperature, the same
results have been obtained with Pd(OAc)2 (5 mol%) and PPh3 (10 mol%) to yield compounds 9a, 9i

T. Abellán et al. / Tetrahedron: Asymmetry 9 (1998) 2211–2214
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Scheme 2.
Table 1
Synthesis of compounds 9
and 9j (Scheme 2 and Table 1 entries 9–11). The configuration of pyrazinones 9 was confirmed by
1
NOE experiments and diastereomeric ratios were determined by HPLC and/or H NMR (300 MHz)
spectroscopy. Final hydrolysis of representative alkylated pyrazinones 9 with 6 N aqueous HCl at 150°C
(pressure tube) and further treatment of α-amino acid hydrochlorides with propylene oxide in refluxing
ethanol for 30 min gave free AMAAs 10 with high ee according to their [α] values (Scheme 3 and
Table 2).
Scheme 3.
In conclusion, we have found that the new alanine derivative with the 1,2,3,6-tetrahydro-2-pyrazinone
structure 5 can be alkylated under very mild and simple reaction conditions, such as solid–liquid PTC and
palladium(0) catalysis at room temperature, with high diastereoselectivity. This methodology has been

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T. Abellán et al. / Tetrahedron: Asymmetry 9 (1998) 2211–2214
Table 2
Synthesis of α-methyl α-amino acids (AMAAs) 10
applied to the synthesis of optically active L-AMAAs. Further applications of these chiral heterocycles
in asymmetric synthesis of other α-amino acids are underway.12
Acknowledgements
This work was supported by the DGICYT, Spain (Project no. PB94-1515). J. M. S. thanks the Spanish
Ministerio de Educación y Cultura for financial support.
References
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2. (a) Williams, R. M. In Synthesis of Optically Active Amino Acids, Pergamon Press: Oxford, 1989. (b) Duthaler, R. O.
Tetrahedron 1994, 50, 1540–1650. (c) Seebach, D.; Sting, A. R.; Hoffmann, M. Angew. Chem. Int. Ed. Engl. 1996, 35,
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5. To our knowledge the only example of this type of heterocycle is 1,2,3,6-tetrahydro-6,6-dimethyl-5-phenylpyrazinone,
which has been prepared by reaction of 2,2-dimethyl-3-phenyl-2H-azirine with glycine ethyl ester: Alvernhe, G.; Laurent,
A.; Masroua, A. Tetrahedron Lett. 1983, 24, 1153–1156.
6. The cis-derivative of oxazinones 4 are configurationally unstable at the 3-position.3
7. Determined by HPLC and 1H NMR (300 MHz).
8. The chemical shifts for the methyl groups at 3-position of the trans and cis diastereomers (1.72 and 1.65, respectively) are
similar to those observed in the oxazinones (1.74 and 1.70, respectively).
9. PC Model for Windows from Serena Software and Hyperchem 5.0 from Hypercube were used for these calculations.
10. Cativiela, C.; Díaz-de Villegas, M. D.; Gálvez, J. A. Tetrahedron: Asymmetry 1994, 5, 261–268.
11. Dictionary of Organic Compounds, Chapman and Hall: New York, 1982.
12. We have already communicated the preparation of α,β-didehydro α-amino acid derivatives by means of the corresponding
glycine equivalent: First International Electronic Conference on Synthetic Organic Chemistry (ECSOC-1), A0007,
September 1997.