Asymmetric synthesis of (S)-α-methyl α-amino acids by alkylation of chiral 3,6-dihydro-2h-1,4-oxazin-2-ones using unactivated alkyl halides and organic bases

Article abstract of DOI:10.1016/S0957-4166(98)00288-2

3,6-Dihydro-2H-1,4-oxazin-2-ones 1 have been diastereoselectively (>96% de) alkylated using unactivated alkyl halides and organic bases such as 2- tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) at room temperature in the presence of LiI. Hydrolysis of the resulting alkylated systems afforded enantiomerically enriched (S)-α-methyl α-amino acids. When 1,3- diiodopropane was used, spontaneous N-alkylation also took place giving bicyclic oxazinone 6 which was hydrolyzed to (S)-α-methylproline.

Full text of DOI:10.1016/S0957-4166(98)00288-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 2769–2772
Asymmetric synthesis of (S)-α-methyl α-amino acids by
alkylation of chiral 3,6-dihydro-2H-1,4-oxazin-2-ones using
unactivated alkyl halides and organic bases
Rafael Chinchilla, Nuria Galindo and Carmen Nájera ∗
Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Alicante, Apartado 99, 03080 Alicante, Spain
Received 22 June 1998; accepted 20 July 1998
Abstract
3,6-Dihydro-2H-1,4-oxazin-2-ones1 have been diastereoselectively (>96% de) alkylated using unactivated alkyl
halides and organic bases such as 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine
(BEMP) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) at room temperature in the presence of LiI. Hydrolysis
of the resulting alkylated systems afforded enantiomerically enriched (S)-α-methyl α-amino acids. When 1,3-
diiodopropane was used, spontaneous N-alkylation also took place giving bicyclic oxazinone 6 which was
hydrolyzed to (S)-α-methylproline. © 1998 Elsevier Science Ltd. All rights reserved.
Among non-proteinogenic α-amino acids, α,α0-dialkyl derivatives, and in particular α-methyl α-
amino acids (AMAAs), have assumed an important role in bioorganic chemistry in recent years. Many
have been used as enzyme substrates or inhibitors and also as components of biologically active
peptides, increasing resistance to hydrolysis by peptidases or locking peptide conformations.1 All these
applications make the development of new methods for the preparation of enantiomerically pure AMAAs
desirable. The most direct asymmetric synthetic approach to AMAAs is the α-alkylation of chiral alanine
anion equivalents, which usually requires strong anhydrous bases (BunLi, LDA, LHMDS) and low
temperatures in order to achieve high diastereoselectivities.2
Recently we have found that new chiral 3,6-dihydro-2H-1,4-oxazin-2-ones 13 and 1,2,3,6-tetrahydro-
2-pyrazinones 24 from alanine are useful reagents for the asymmetric synthesis of (S)-α-methyl α-amino
acids 5 after highly diastereoselective alkylation under solid–liquid phase-transfer and/or palladium
catalysis at room temperature and further hydrolysis (Scheme 1). However, in spite of the synthetic
interest of phase-transfer-catalysis (PTC) conditions due to their simplicity and mildness, PTC proved
to be ineffective with 1 or 2 when using unactivated electrophiles.5 In this communication we report the
use of organic bases for the asymmetric alkylation of oxazinones 1 with representative unactivated alkyl
halides at room temperature.
∗
Corresponding author. Fax: +34-96-5903549; e-mail: cnajera@ua.es
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00288-2

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Scheme 1.
Oxazinones 1, prepared from alanine and (S)-2-hydroxyisovalerophenone and isolated as a 1:20
cis:trans diastereomeric mixture,3 were deprotonated using organic bases such as Schwesinger’s6
2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP)7 or 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) and reacted with representative unactivated alkyl halides at room
temperature in considerably shorter reaction times and also generally with higher diastereoselectivities
1
(>96% de, 300 MHz H NMR, GLC) than when using PTC conditions,3 to afford oxazinones 38
(Scheme 2 and Table 1). Compounds 3 were obtained in diastereomerically pure form in moderate
yields after chromatographic purification (Table 1). In all cases, variable amounts of the corresponding
O-alkylated product were also detected in the reaction crude. The best yields were achieved using the
diazaphosphazine BEMP (1.1 equiv.) as base, whereas a large excess (5 equiv.) of DBU was necessary
in order to obtain full conversion of the starting material although in general with lower yields (Table 1,
entries 12–16). Polymer-bound BEMP was also investigated as the base, but the reaction was sluggish
and needed much longer reaction times. 1-Methyl-2-pyrrolidinone (NMP) was the preferred solvent
giving the best yield and C/O-alkylation ratio (Table 1, entries 4–7). When LiI was added, a significant
improvement of the C/O-alkylation ratio was observed (compare entries 1 and 2, 7 and 8, or 13 and 14
in Table 1). The strong coordination of the lithium cation with the oxygen (hard–hard interaction) could
explain the increasing C/O-alkylation ratio.9 Moreover, the addition of LiI allowed the alkylation of 1
using an alkyl bromide such as n-butyl bromide as electrophile, although with lower yield than when the
corresponding alkyl iodide was employed (compare entries 8 and 9 in Table 1).10
Scheme 2.
Hydrolysis of representative alkylated oxazinone 3d was carried out by treatment with 6 N HCl,
followed by reaction of the corresponding hydrochloride with propylene oxide affording (S)-α-
methylleucine 5d in 72% yield and >99% ee (Scheme 3),11 thus confirming the absolute configuration of
3d.
When the alkylation reaction was carried out with an unactivated alkyl diiodide such as 1,3-
diiodopropane using BEMP as base and at room temperature, not only the C-alkylation took place, but
also further N-alkylation and isomerization of the iminic double bond affording bicyclic oxazinone 612 in
55% isolated yield after flash chromatography (Scheme 4). This spontaneous cyclization reaction should
allow the preparation of precursors of interesting cyclic AMAAs13 following a more simple and direct
experimental procedure than when using other chiral templates.14 The use of DBU as base afforded lower
yields of bicyclic compound 6 due to a competing dehydrohalogenation process to a terminal olefin after
the first C-alkylation step, also giving compound 3f (R=CH2CH_CH2).3 Subsequent acid hydrolysis of

R. Chinchilla et al. / Tetrahedron: Asymmetry 9 (1998) 2769–2772
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Table 1
Alkylation of oxazinone 1 with unactivated alkyl halides
Scheme 3.
compound 6 and treatment with propylene oxide afforded enantiomerically enriched (S)-α-methylproline
(7, 81%) in 99% ee15 (Scheme 4). It is noteworthy that in this case a chromatographic enrichment in
isomer 6 after purification is impossible, the final ee only arising from a highly diastereoselective initial
C-alkylation step.
Scheme 4.
In conclusion, oxazinones 1 are proving to be versatile chiral templates which can now be highly
diastereoselectively alkylated with unactivated alkyl mono- or dihalides using organic bases at room

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R. Chinchilla et al. / Tetrahedron: Asymmetry 9 (1998) 2769–2772
temperature for the asymmetric synthesis of acyclic and cyclic AMAAs under relatively mild and simple
reaction conditions. Further work to exploit the synthetic uses of these heterocycles is underway.
Acknowledgements
We thank the Dirección General de Investigación Científica y Técnica (DGICYT) of the Spanish
Ministerio de Educación y Cultura (MEC) (PB94-1515) for financial support. N.G. thanks MEC for a
grant.
References
1. Some examples: (a) Jung, M. J. In Chemistry and Biochemistry of the Amino Acids, Barrett, G. C., Ed.; Chapman and Hall:
New York, 1985; pp. 227–245. (b) Altmann, K. H.; Altmann, E.; Mutter, M. Helv. Chim. Acta 1992, 75, 1198–1210. (c)
Giannis, A.; Kolter, T. Angew. Chem. Int. Ed. Engl. 1993, 32, 1244–1267.
2. Recent reviews: (a) Williams, R. M. Synthesis of Optically Active Amino Acids, Pergamon Press: Oxford, 1989. (b)
Heimgartner, H. Angew. Chem. Int. Ed. Engl. 1991, 30, 238–264. (c) Duthaler, R. O. Tetrahedron 1994, 50, 1540–1650. (d)
Seebach, D.; Sting, A. R.; Hoffmann, M. Angew. Chem. Int. Ed. Engl. 1996, 35, 2708–2748. (e) Wirth, T. Angew. Chem.
Int. Ed. Engl. 1997, 36, 225–227.
3. Chinchilla, R.; Falvello, L. R.; Galindo, N.; Nájera, C. Angew. Chem. Int. Ed. Engl. 1997, 36, 995–997.
4. Abellán, T.; Nájera, C.; Sansano, J. M. Tetrahedron: Asymmetry, in press.
5. Attempted alkylation of 1 with alkyl iodides using strong anhydrous bases (LDA, LHMDS, KOBut, NaH) under different
reaction conditions failed.
6. Schwesinger, R.; Willaredt, J.; Schlemper, H.; Keller, M.; Schmitt, D.; Fritz, H. Chem. Ber. 1994, 127, 2435–2454, and
references cited therein.
7. The use of BEMP as base has proved to be effective in the recent alkylation of the resin-bound benzophenone imine of
glycine with unactivated alkyl halides: (a) O’Donnell, M. J.; Lugar, C. W.; Pottorf, R. S.; Zhou, C.; Scott, W. L.; Cwi,
C. L. Tetrahedron Lett. 1997, 38, 7163–7166. (b) O’Donnell, M. J.; Zhou, C.; Scott, W. L. J. Am. Chem. Soc. 1996, 118,
6070–6072.
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25
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8. Specific rotations: 3a: [α]D +26.5 (c 1.6, CH2Cl2). 3b: [α]D +42.8 (c 2, CH2Cl2). 3c: [α]D +28.5 (c 1.1, CH2Cl2).
25
25
3d: [α]D +72.7 (c 1.4, CH2Cl2). 3e: [α]D +20.7 (c 1.3, CH2Cl2).
9. For a recent discussion on lithium salt effects in organic synthesis, see: Seebach, D.; Beck, A. K.; Studer, A. In Modern
Synthetic Methods 1995, VCH Publishers: Basel, 1995; Vol. 7, pp. 1–178.
10. Typical procedure: To a solution of the oxazinone 1 (0.5 mmol, 116 mg) and LiI (see Table 1) in the appropriate solvent
(1 mL) was added the corresponding base (BEMP: 0.55 mmol, 159 µL; DBU: 2.5 mmol, 374 µL) at 0°C. The alkyl
halide (1 mmol) was added at once and the temperature was allowed to rise to rt until total consumption of the starting
material (GLC, Table 1). The mixture was diluted with EtOAc (25 mL), washed with water (3×10 mL), dried (Na2SO4),
evaporated in vacuo (15 torr) and the residue purified by flash chromatography on silica gel (Hex/EtOAc mixtures)
affording compounds 3.
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11. Specific rotation: [α]D +38.2 (c 2, H2O). Lit. [α]D +34.2 (c 3, H2O): Kruizinga, W. H.; Bolster, J.; Kellog, R. M.;
Kamphuis, J.; Boesten, W. H. J.; Meijer, E. M.; Schoemaker, H. E. J. Org. Chem. 1988, 53, 1826–1827.
25
12. Selected data for 6: [α]D −317.8 (c 1, CH2Cl2); 1H NMR (300 MHz, CDCl3) δ: 1.01 (d, J=6.7 Hz, 3H), 1.30 (d, J=7.0
Hz, 3H), 1.31 (s, 3H), 1.66–1.86 (m, 2H), 1.94 (m, 1H), 2.67–2.84 (m, 3H), 3.16 (m, 1H), 7.34 (m, 5H); 13C NMR (75
MHz, CDCl3) δ: 19.8, 21.1, 21.8, 22.9, 27.8, 35.5, 50.8, 61.2, 122.4, 128.1, 128.3, 129.2, 134.8, 139.3, 169.1.
13. For example, (S)-α-methylproline has been shown to stabilize the type-I β-turn conformations in peptides containing the
Asn-Pro-Asn-Ala (NPNA) motif of the Plasmodium falciparum circumsporozoite protein: Bisang, C.; Weber, C.; Inglis,
J.; Schiffer, C. A.; van Gunsteren, W. F.; Jelesarov, I.; Bosshard, H. R.; Robinson, J. A. J. Am. Chem. Soc. 1995, 117,
7904–7915.
14. (a) Bajgrowicz, J.; El Achquar, A.; Roumestant, M.-L.; Pigière, C.; Viallefont, P. Heterocycles 1986, 24, 2165–2167. (b)
Schöllkopf, U.; Hinrichs, R.; Lonsky, R. Angew. Chem. Int. Ed. Engl. 1987, 26, 143–144. (c) Seebach, D.; Dziadulewicz,
E.; Behrendt, L.; Cantoreggi, S.; Fitzi, R. Liebigs. Ann. Chem. 1989, 1215–1232.
25
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15. Specific rotation: [α]D −71.9 (c 1, MeOH). Lit.14b [α]D −72.1 (c 1, MeOH).