Preparation of a-Amino Acids by Oxidative Oxazoline–Oxazinone Rearrangement–Hydrogenation
chiral nucleophilic glycine equivalents. Molecular calcula-
tions reveal a possible origin of the unusually large d.r.
values observed in the hydrogenation of certain oxazinones.
Experimental Section
For complete procedures, details of sample preparation, and spectroscop-
ic characterization (1H and 13C NMR spectra) of 11a,c–e 12a,c–e,
13a,c,d,f,g see the Supporting Information.
General Procedure for Carboxamide Preparation
Carboxylic acid was heated at reflux in a solution of SOCl2 (5–10 equiva-
lents) in benzene or CHCl3, depending on solubility, for about 3 h. Sol-
vent and excess SOCl2 were removed under vacuum and the acyl chloride
residue was dissolved in dry CH2Cl2 (to a concentration of 0.1–0.2m)
prior to the next step. Freshly prepared acyl chloride in dry CH2Cl2 was
added slowly to a solution of one equivalent of phenylglycinol [(S)-1 or
(R)-(2)] in dry CH2Cl2 (ca. 0.1m) at 08, and the reaction mixture allowed
to warm to RT Following work-up, the crude product was purified by
flash chromatography (silica) to obtain the desired carboxamide 9.
N-((R)-2-Hydroxy-1-phenylethyl)-3-methyl-3-phenylbutanamide (9b)
Colorless
solid
(89%);
m.p.:
98–998C;
AHCTUNGTERNUNNG ;
½aꢂ2D3 =ꢀ32.6
(c=
2.78 g.100 mLꢀ1,CHCl3); IR: n˜ =3318(br s), 3029, 2964, 1644, 1538 cmꢀ1
1H NMR (400 MHz, CDCl3): d=1.41 (s, 3H), 1.45 (s, 3H), 2.52 (s, 2H),
3.01 (s, OH), 3.50 (d, J=4.4 Hz, 2H), 4.79–4.82 (m, 1H), 5.68 (d, J=
4.8 Hz, 1H), 6.86–6.91 (m, 2H), 7.20–7.24 (m, 4H), 7.29–7.39 ppm (m,
4H); 13C NMR (100 MHz, CDCl3): d=29.2 (CH3), 29.3 (CH3), 37.9 (C),
51.6 (CH2), 55.9 (CH), 66.5 (CH2), 126.0 (2xCH), 126.5 (CH), 126.8
(2xCH), 127.8 (CH), 128.8 (2xCH), 128.9 (2xCH), 139.1 (C), 148.1 (C),
171.9 ppm (C); HRMS: (DCI/NH3) m/z 298.1815 [M+H]+, Calcd
C19H24NO2 298.1807.
(R)-4,5-Dihydro-2-(2-methyl-2-phenylpropyl)-4-phenyloxazole (10b)
A
solution of carboxamide 9b (75 mg, 0.25 mmol) in dry CH2Cl2
(2.5 mL) was cooled to ꢀ788C, then treated dropwise with DAST (36 mL,
0.28 mmol, 1.1 equiv).[13] After stirring at ꢀ788C for 75 min, anhydrous
potassium carbonate (52.3 mg, 0.38 mmol, 1.5 equiv) was added in one
portion, and the mixture allowed to warm to RT over 4 h. Saturated
aqueous NaHCO3 (5 mL) was added in one portion with vigorous stir-
ring, and the mixture partitioned against CH2Cl2 (3ꢁ5 mL). The com-
bined organic extracts were dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure to give the crude product
(70.0 mg), which was purified by flash chromatography on silica gel (1:4
ethyl acetate/petroleum ether), to provide the desired oxazoline 10b
(61.9 mg, 89%) as an oil which slowly crystallized into a colorless solid.
Figure 1. Minimized structures of 11b (B3LYP 6-31G(D), Spartan), rela-
tive energies (E8) and Boltzmann populations (%). (a) i, E8=
0 kcalmolꢀ1
ACHTUNGTRENNUNG(96.3%). (b) ii, E8=8.06 kcal (3.7%).
and reinforcing the directing effect of the C-5 phenyl group.
Similar conformational preferences of CH2COOMe and
indol-3-yl groups—specifically, differential rotameric prefer-
ences for gem-dimethyl and sp2 groups—led to comparable
d.r. values for the hydrogenation of 11e–g (d.r.>80:1),
much higher than those of 11a (d.r.=8.7) and other 2-tert-
alkyloxazinones (d.r.=13:1).[1a,d] The effect was diminished
in the hydrogenation of 11c (d.r.=9:1) where the 1-phenyl-
ethyl substituent is secondary, but recovered in 11d (d.r.>
80:1) where the all-sp2, conjugated substituent and planarity
m.p.: 98–998C; ½aꢂ2D3 =+11.3 (c=7.91 g.100 mLꢀ1
,
CHCl3); 1H NMR
(400 MHz, CDCl3): d=1.58 (s, 3H), 1.60 (s, 3H, CH3), 2.76 (d, J=
13.8 Hz, 1H), 2.86 (d, J=13.8 Hz, 1H), 3.88 (t, J=8.4 Hz, 1H), 4.47 (dd,
J=8.4 and 10.2 Hz, 1H), 5.12 (dd, J=8.4 and 10.2 Hz, 1H), 6.99~7.02
(m, 2H), 7.26~7.52 ppm (m, 8H); 13C NMR (100 MHz, CDCl3): d=29.2
(CH3), 29.9 (CH3), 38.0 (C), 42.8 (CH2), 69.8 (CH), 74.7 (CH2), 126.1
(2xCH), 126.3 (CH), 126.9 (2xCH), 127.6 (CH), 128.5ACTHNUTRGNE(UNG 2xCH), 128.8
(2xCH), 142.7 (C), 148.4 (C), 167.1 ppm (C); IR (film): n˜ =3060, 2964,
1658, 1602, 1496, 1446 cmꢀ1; GCMS (EI 70 eV): m/z (%) 280 [M+H]+
(100), 279 (54) [M+]; HRMS (EI): m/z calcd for C19H21NO: 279.1623
[M+]; found: 279.1619.
ꢀ
of the C2 C3(=N) para-hydroxyphenyl array exposes the
singular influence of the C-5 phenyl directing effect.[17]
In summary, an evaluation of the scope of the oxidative
oxazoline–oxazinone hydrogenation (OOOH) sequence, ex-
ploiting 5-phenyl-substitued oxazinones 11 as electrophilic
glycine equivalents, was carried out. The sequence was gen-
erally applicable, returning morpholinones 12 and their cor-
responding amino acids 13 with exceptionally high diaste-
reoselectivities. The OOOH sequence affords a practical
route to a-amino acids that are otherwise difficult to obtain
by methods involving asymmetric synthesis or catalysis with
(R)-5,6-Dihydro-5-phenyl-3-(2-phenylpropan-2-yl)-1,4-oxazin-2-one (11b)
Oxidative rearrangement of oxazoline 10a was effected with SeO2 (in re-
fluxing EtOAc, 4.5 h) using the general procedure described above.[1e,5,18]
The crude product was purified by preparative tlc (4:1 petroleum ether/
ethyl acetate) to provide dihydrooxazinone 11b as a white solid (72%).
m.p. 130–1338C; ½aꢂ2D3 =ꢀ99.5 (c=0.62 g.100 mLꢀ1
,
CHCl3); 1H NMR
(400 MHz, CDCl3): d=1.67 (s, 3H), 1.78 (s, 3H), 4.12 (t, J=11.4 Hz,
1H), 4.51 (dd, J=4.5 and 11.4 Hz, 1H), 4.92 (dd, J=4.5 and 11.4 Hz,
Chem. Asian J. 2011, 6, 2022 – 2027
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2025