Oxidative rearrangement of 2-substituted oxazolines. A novel entry to 5,6-dihydro-2H-1,4-oxazin-2-ones and morpholin-2-ones

Article abstract of DOI:10.1021/jo952144f

A novel synthesis of 5,6-dihydro-2H-1,4-oxazin-2-ones by SeO₂-promoted oxidative rearrangement of 2-alkyl- and 2-(arylmethyl)oxazolines is described. Yields are good to excellent (up to 94%) with the highest yields obtained for 2-arylmethyl- and 2-neopentyl-substituted oxazolines. This reaction provides convenient access to novel 5-aryl-substituted dihydrooxazinones in high yield. The latter compounds are important 'chiral glycine' synthons for asymmetric synthesis of α-amino acids. Since oxazolines are readily derived from carboxylic acids or their equivalents, this oxidative rearrangement constitutes an entry to synthesis of α-amino acids from carboxylic acids. A mechanism is proposed to account for the rearrangement involving a 'nitrilium to acylium' 1,2-migration.

Full text of DOI:10.1021/jo952144f

2044
J . Org. Chem. 1996, 61, 2044-2050
Oxid a tive Rea r r a n gem en t of 2-Su bstitu ted Oxa zolin es. A Novel
En tr y to 5,6-Dih yd r o-2H-1,4-oxa zin -2-on es a n d Mor p h olin -2-on es
Cynthia M. Shafer1 and Tadeusz F. Molinski*
Department of Chemistry, University of California, Davis, California 95616
Received December 4, 1995X
A novel synthesis of 5,6-dihydro-2H-1,4-oxazin-2-ones by SeO2-promoted oxidative rearrangement
of 2-alkyl- and 2-(arylmethyl)oxazolines is described. Yields are good to excellent (up to 94%) with
the highest yields obtained for 2-arylmethyl- and 2-neopentyl-substituted oxazolines. This reaction
provides convenient access to novel 5-aryl-substituted dihydrooxazinones in high yield. The latter
compounds are important “chiral glycine” synthons for asymmetric synthesis of R-amino acids.
Since oxazolines are readily derived from carboxylic acids or their equivalents, this oxidative
rearrangement constitutes an entry to synthesis of R-amino acids from carboxylic acids.
A
mechanism is proposed to account for the rearrangement involving a “nitrilium to acylium” 1,2-
migration.
In the course of preparation of intermediates for the
The IR spectrum revealed the presence of an ester
carbonyl (ν 1748 cm-1) and an imine double bond (1631
cm-1) which were further corroborated by 13C NMR (δ
synthesis of antifungal marine natural products we
discovered an unexpected oxidative rearrangement in the
SeO2-promoted oxidation of 2-substituted oxazolines, 1.
This novel reverse-Beckmann type rearrangement oc-
curred after oxidation of the R-carbon of 1 by SeO2 with
subsequent â-cleavage by 1,2-migration and concomitant
ring expansion. The molecular rearrangement was ex-
ploited for the synthesis of 3-substituted 5,6-dihydro-2H-
1,4-oxazin-2-ones (2) from oxazolines and preparation of
previously inaccessible 3-unsubstituted derivatives. The
latter are readily converted to tetrahydro-1,4-oxazin-2-
ones (4, morpholinones). Both 2 and 4 are useful chiral
glycine synthons.2-7 Since 4b has been used in efficient
syntheses of R-amino acids with high %ee2,3,7 and oxazo-
lines are readily derived from alkylimidates (carboxylic
acid equivalents), the oxidative rearrangement described
here constitutes a novel asymmetric synthesis of R-amino
acids from carboxylic acids.
1
154.5, s, CdO; 152.2, d, J CH 193 Hz, CHdN). The
exceptionally high-field 13C signal for the R,â-unsaturated
azalactone carbonyl is characteristic of dihydro-2H-1,4-
oxazin-2-ones.8 Catalytic hydrogenation of 2a (1 atm, H2,
Pd-C, Scheme 1) gave morpholin-2-one 4a ((5S)-5-iso-
propyl-3,4,5,6-tetrahydro-1,4-oxazin-2-one, m/ z 143.0944,
∆mmu 0.2) as a ninhydrin-positive secondary amine. The
spectroscopic data of 4a (1H NMR, 13C NMR) compared
well with literature values for related morpholin-2-
ones.3,5 Thus, the product of oxidation of oxazoline 1a was
shown to be the rearranged heterocycle 2a .
Resu lts
The scope of the SeO2-mediated oxidative rearrange-
ment of substituted oxazolines was investigated (Table
1). It was found that the ease of the oxidative rearrange-
ment correlated with the migratory aptitude of the R
substituent (Table 1) in the postulated 2-acyl intermedi-
ate 3 (see Discussion). The yields were highest when R
was H, aryl or tert-alkyl (e.g. 1i, entry 12, 94%, the
naphthyl isomers 1k , entry 83%, and 1l, entry 14, 93%,
respectively, and the 2-neopentyl derivative 1h , entry 10,
84%). The yield was lower for tertiary R (1g, 33%, entry
9), and 2- ethyl oxazolines (R ) Me) did not undergo the
reaction at all, but gave oxidized byproducts which were
tentatively assigned structures 5f and epi-5f (∼40%
combined, entry 8). The best yields of 2 from 2-methyl-
oxazolines were obtained for compounds substituted at
C4 with secondary alkyl or aryl groups (2a , entry 1, 75%;
2b, entry 4, 72%). The C4 oxymethylene-substituted
oxazolines 1c,d (entries 5 and 6) were also converted to
the corresponding oxazinones 2c,d , respectively, albeit
in lower yields (22% and 53%, respectively), possibly due
to competing side chain oxidation. The “parent” oxazo-
line 1e (entry 7) was oxidized with difficulty by SeO2 to
the simple, undescribed oxazinone 2e (m/ z 99) and in
Heating a solution of oxazoline 1a , C7H13NO, in diox-
ane with selenium dioxide (2.2 equiv) at reflux resulted
in efficient conversion to a single, less polar product
(TLC) which was isolated after nonaqueous workup. The
product formula, C7H11NO2 (HREIMS, m/ z 141.0785,
∆mmu 0.5) clearly showed oxidation of 1a had taken
place; however, the structure was that of dihydrooxazi-
none 2a (75% isolated yield) and not the anticipated
isomeric 2-formyloxazoline 3a . The C2 methyl signal of
1
1a had been replaced in the H NMR spectrum of 2a by
a vinyl proton signal (δ 7.87, d, J ) 2.8 Hz) which was
now allylically coupled to the N-CH (δ 3.48, 4J ) 2.8 Hz).
* To whom correspondence should be addressed.
X Abstract published in Advance ACS Abstracts, February 15, 1996.
(1) Dow Fellow, 1992-93.
(2) Dellaria, J . F.; Santarsiero, B. D. Tetrahedron Lett. 1988, 29,
6079-6082.
(3) Dellaria, J . F.; Santarsiero, B. D. J . Org. Chem. 1989, 54, 3916-
3926.
(4) Boa, A. N.; Guest, A. L.; J enkins, P. R.; Fawcett, J .; Russell, D.
R.; Waterson, D. J . Chem. Soc., Perkin Trans. 1 1993, , 478-481.
(5) Cox, G. G.; Harwood, L. M. Tetrahedron Asymmetry 1994, 5,
1669-1672.
(6) Harwood, L. M.; Macro, J .; Watkin, D.; Williams, C. E.; Wong,
L. F. Tetrahedron Asymmetry 1992, 3, 1127-1130.
(7) Williams, C. E.; Harwood, L. M. American Chemical Society
209th National Meeting, Anaheim, CA, 1995; Abstract no. 290.
(8) Berkowitz, D. B.; Schweizer, W. B. Tetrahedron 1992, 48, 1715-
1728.
0022-3263/96/1961-2044$12.00/0 © 1996 American Chemical Society

Oxidative Rearrangement of 2-Substituted Oxazolines
J . Org. Chem., Vol. 61, No. 6, 1996 2045
Ta ble 1. SeO2-P r om oted Oxid a tive Rea r r a n gem en t of 2-Su bstitu ted Oxa zolin es
Sch em e 1a
lower yield (60% by GC). Reaction of 1a in refluxing THF
(67 °C) also gave 2a ; however, the reaction proceeded
sluggishly with diminished yield (58%, entry 2). Oxida-
tion of 1a with SeO2 in refluxing pyridine (entry 3) gave
only traces of dihydrooxazinone 2a with the only other
isolable product being oxazolidinone 6,9 arising from
competitive oxidative carbon-carbon bond cleavage of the
putative formyl intermediate 3a .
6
To the best of our knowledge, 3-unsubstituted 5,6-
dihydro-2H-1,4-oxazin-2-ones are unknown in the litera-
ture so we briefly examined the chemical properties of 2
(Scheme 1). Dihydrooxazinone 2a is sensitive to water
and other hydroxylic solvents. Heating with methanol
at reflux gave a 96% yield of epimeric 3-methoxymor-
pholin-2-ones, 7 (1:1). Addition of phenyllithium to 2a
(-78 °C, THF, 20 min) gave the substituted epimeric
a
(a) MeOH, 60 °C; (b) PhMgBr, THF, -78 °C; (c) H2, Pd-C.
2-benzoyloxazolidines 8 by nucleophilic attack at the
carbonyl group and subsequent ring closure by intramo-
lecular addition of the liberated alkoxide to the 3,4-imine
(9) Evans, D. A.; Mathre, D. J .; Scott, W. L. J . Org. Chem. 1985,
50, 1830-1835.

2046 J . Org. Chem., Vol. 61, No. 6, 1996
Shafer and Molinski
Sch em e 2
ment is invoked here to account for exchange of oxidation
states between C2 and the 2-acyl substituent of the
intermediate 3 (oxazoline numbering). Because the C2
carbon of oxazoline is equivalent to a carboxamide, the
rearrangement is, formally, the reverse of the Beckmann
rearrangement in which 1,2-migration from the R-posi-
tion of activated oxime generates a iminium carbocation
(nitrilium ion).12,13 The SeO2-promoted oxidative rear-
rangement of oxazolines appears to be a rare example of
rearrangement of a nitrilium ion to give an imine. The
fission of a relatively strong sp2 carbon-carbon σ bond
in the rearrangement step i to ii may be partially
compensated by stabilization imparted to the intermedi-
ate ii by sp-sp2 rehybridization of nitrogen and oxygen.
Solvent participation appears to be important and may
contribute to stabilization of putative ionic intermediates
via covalent dioxane adducts; however, further study of
the mechanism is required to clarify the details.
SeO2-promoted oxidative rearrangement of 1 to 2 is
useful in the synthesis of optically active R-amino acids.
Although 3-substituted dihydro-2H-1,4-oxazinones are
known,14 the 3-unsubstituted analogs of 2 have not been
reported previously and represent new, potentially useful
chiral glycine synthons. The more familiar morpholin-
2-one 4b has been utilized in synthesis of R-amino acids
by stereoselective alkylation2,3 and the synthesis of
â-hydroxy-substituted amino acids via azomethine ylides,6,7
while the 6-phenyl derivative of 4b has been employed
in R-amino acid synthesis as an “electrophilic glycinate”.15
The best current preparation of 4b (condensation of
phenylglycinol with phenyl R-bromoacetate)3 is reported
to suffer from variable yields (40-83%) and is prone to
dimerization of the product. Because dihydro-2H-oxazi-
nones 2 are readily converted to 4, the SeO2 oxidative
rearrangement makes 4b conveniently accessible from
oxazolines, which in turn are easily prepared from the
corresponding 2-amino alcohols.16 Thus, oxazoline 1b
prepared by condensation of R-(-)-phenylglycinol with
ethyl acetimidate hydrochloride (Et3N, CH2Cl2, 91%), was
smoothly converted to 2b (SeO2, reflux, 1.5 h, dioxane,
72%, Table 1, entry 4). Hydrogenation of 2b (H2, 1 atm,
Pd-C, 3 h, quantitative, Scheme 1) afforded optically
pure (-)-morpholinone 4b in an overall reproducible yield
of 66% in three steps from phenylglycinol. By an
analogous sequence, 2i was hydrogenated to the known
(3S,5R)-3,5-diphenylmorpholinone 4i (91%, 60% de) in
74% overall yield from R-phenylacetimidate hydrochlo-
ride and (R)-(-)-phenylglycinol.
double bond. Brief catalytic hydrogenation of the imine
bond (1 atm, H2, Pd-C) in derivatives 2a and 2b was
quantitative and proceeded without hydrogenolysis of the
benzylic carbon in 2b. Conversion of 1i to 2i was
achieved without detectable racemization at C5 as shown
by chiral lanthanide reagent-induced shifts in the 1H
NMR spectrum of (-)-2i. Resolution of the 1H NMR
signals of (()-2i was achieved with (+)-Eu(hfc)3; however,
only one set of signals were detected in (-)-2i (>99% ee).
Ether solvents, such as dioxane, that promote Lewis
acid-catalyzed ionic mechanisms favored high yields,
possibly by stabilization of incipient cationic intermedi-
ates prior to rearrangement. Conversely, the oxidative
rearrangement of 1a fails when carried out in pyridine,
giving oxazolidinone 6 instead (entry 3). 2-Formylox-
azolines 3 could not be isolated and, in fact, appear to be
inherently unstable. Several attempts to prepare 3c by
oxidation (MnO2, Swern oxidation, TPAP or PDC) of
2-(hydroxymethyl)oxazoline 9, prepared by an indepen-
dent route (i. t-BuLi, -78 °C, THF, ii. O2, iii. (EtO)3P10 ),
were unsuccessful and returned only mixtures of prod-
1
ucts, occasionally containing 2c (∼10%, H NMR).
Discu ssion
The utility of this novel reaction was demonstrated by
a simple asymmetric synthesis of the amino acid (S) tert-
leucine (tert-butylglycine, 10, Scheme 3), a component of
natural product peptides isolated from marine sponges
of the genus Theonella.17,18 The chiral auxillary (R)-2-
phenylglycinol was readily condensed with tert-butyl-
acetyl chloride in two steps to provide oxazoline 1h .19
Oxazoline 1h was smoothly converted to 2h with SeO2
We propose a mechanism for the SeO2-promoted for-
mation of dihydrooxazinone 2 that proceeds through a
Lewis acid-catalyzed rearrangement of a 2-acyloxazoline
intermediate 3 (Scheme 2). R-Keto carbonyl compounds
are formed by SeO2 oxidation of carbonyl compounds and
their derivatives,11 and by analogy, 2-acyloxazoline 3 is
a reasonable intermediate in the oxidation of 2. In the
presence of Lewis acid, compound 3 is unstable and
undergoes rapid Lewis acid-catalyzed ring opening lead-
ing to the conjugated nitrilium ion i. The sources of
Lewis acid may be selenium-containing byproducts formed
during reduction of SeO2. Cationic i then rearranges by
a 1,2-shift to acylium ion ii followed by ring closure to
afford dihydrooxazinone 2. The nucleophilic 1,2-migra-
tion of group R (Scheme 2) in the oxidative rearrange-
(12) Beckmann, E. Chem. Ber. 1887, 20, 1507-1510.
(13) De Mayo, P. Molecular Rearrangements; Interscience: New
York, 1963; Vol. 1, pp 483-507.
(14) Biekert, E.; Sonnenbichler, J . Chem. Ber. 1961, 94, 2785-2791.
(15) Sinclair, P. J .; Zhai, D.; Reibenspies, J .; Williams, R. M. J . Am.
Chem. Soc. 1986, 108, 1103-1104.
(16) Meyers, A. I.; Knaus, G.; Kamata, K.; Ford, M. E. J . Am. Chem.
Soc. 1976, 98, 567-576.
(17) Fusetani, N.; Matsunaga, S. Chem. Rev. 1993, 93, 1793-1806.
(18) Hamada, T.; Sugawera, T.; Matsunaga, S.; Fusetani, N. Tet-
rahedron Lett. 1994, 35, 609-612.
(10) Shafer, C. M.; Molinski, T. F., unpublished results.
(11) Nicolaou, K. C.; Petasis, N. A. Selenium in Organic Synthesis;
CIS: Philadelphia, 1984.
(19) Gant, T. G.; Meyers, A. I. J . Am. Chem. Soc. 1992, 114, 1010-
1015.

Oxidative Rearrangement of 2-Substituted Oxazolines
J . Org. Chem., Vol. 61, No. 6, 1996 2047
Sch em e 3a
Gen er a l P r ep a r a tion of Oxa zolin es. 2-Methyloxazoline
and ethyl acetimidate hydrochloride were purchased from the
Aldrich Chemical Co. Oxazolines were prepared according to
one of three methods. Method A: Condensation of ethyl
acetimidate hydrochloride with (S)-(+)-valinol (1a , 78%26 ) or
(R)-(-)-phenylglycinol (1b, 91%) according to Meyers.16 Method
B: Condensation of (S)-valinol or (R)-(-)-phenylglycinol with
ethyl propionimidate hydrochloride (1f),27 or ethyl R-phenyl-
acetimidate hydrochloride (1i, 87%;28 1j, 78%), or 1-naphthyl-
acetimidate (1k , 91%) or 2-naphthylacetimidate hydrochloride
(1l, 49%). Arylacetimidate hydrochlorides were prepared by
bubbling dry HCl into cold ethanolic solutions of the corre-
sponding arylacetonitriles.27 Method C: Condensation of acid
chloride with (S)-valinol or (R)-(-)-phenylglycinol followed by
dehydration of the product amide with SOCl2 and Et3N in CH2-
Cl2.19 Other oxazolines were prepared by alkylation (1c, NaH,
ArCH2Br, THF) or acylation (1d , ArCO2H, DCC, Et3N, THF)
of (R)-4-(hydroxymethyl)-2-methyloxazoline, obtained from (S)-
serine ethyl ester hydrochloride.29
a
(a) SeO2, diox, ∆; (b) H2, 1 atm, PtO2, CH2Cl2; (c) recryst, EA/
hex; (d) EtOH, HCl; (e) H2, 1 atm, Pd-C, EtOH; (f) 6 M HCl
aqueous.
(4S)-2-(2-Met h ylp r op yl)-4-isop r op yl-4,5-d ih yd r ooxa -
zole (1g). Method C: A solution of (S)-valinol (3.00 g, 29.1
mmol) in CH2Cl2 (20 mL) was added to solution of isovaleroyl
chloride (3.4 mL, 32.5 mmol) in CH2Cl2 (50 mL). Triethyl-
amine (4.6 mL, 33.0 mmol) was added, and the solution was
stirred overnight. The reaction mixture was poured into NH4-
Cl (15 mL, aqueous, saturated) and H2O (30 mL). The aqueous
layer was extracted 2 × 300 mL of Et2O. The Et2O was dried
through MgSO4 and reduced to a clear colorless oil (5.49 g)
which crystallized upon standing. The amide alcohol (5.49 g,
29.0 mmol) was then dissolved in CH2Cl2 (150 mL) to which
thionyl chloride (8.6 mL, 118 mmol) was added at 0 °C. After
3.5 h, the solvent and excess thionyl chloride was removed in
vacuo. The crude material was dissolved in Et2O (400 mL),
and 35 mL of saturated NaHCO3, 35 mL of H2O, and 23 mL
of 3 M NaOH were added. This mixture stirred for 0.5 h. Then
the layers were separated, and the aqueous layer was ex-
tracted with Et2O (400 mL). The Et2O layers were dried
through MgSO4 and reduced to a yellow oil (5.51 g) The crude
mixture was purified by bulb-to-bulb distillation (125 °C, 0.9
torr) to give 2.44 g (50%) of a clear, colorless oil. [R]D ) -56.0°
in refluxing dioxane (84%, Table 1, entry 10). Hydroge-
nation of 2h using Harwood’s conditions (PtO2, CH2Cl2,
1 atm H2),5 gave the desired (2S,4R) morpholinone
diastereomer 4h (97%, de 86%) which was improved to
de 99% (82% yield) after recrystallization from ethyl
acetate-hexane. Ethanolysis of diasteromerically pure
4h (HCl, EtOH) followed by sequential hydrogenolysis
of the phenylglycinol group3 and acid hydrolysis (6 N HCl
aqueous) provided (S)-(-)-10 (75%, from 4h ), identical
1
with an authentic sample by H NMR, [R]D, and TLC,
and optically pure as determined by Marfey’s method.20
We expect that the new 3-unsubstituted dihydro-2H-
oxazinones, in particular 2b, will find utility in R-amino
acid synthesis as electrophilic chiral glycine equivalents.21
It is noteworthy that SeO2-mediated oxidative rearrange-
ment of oxazolines provides entry to synthesis of heavily
â-branched R-amino acids in high optical purity and
complements recently reported catalytic methods, such
as the asymmetric Strecker synthesis22 and supercritical
homogeneous catalytic hydrogenation of R-enamides.23
Other potential uses of 3-unsubstituted oxazinones may
include heterocyclic synthesis via hetero-Diels-Alder
cycloaddition with suitable dienes24 or 1,3-dipolar addi-
tions of derived azamethine ylides.7 Further studies of
the mechanism of this oxidative rearrangement and its
synthetic applications are underway in our laboratory.
1
(c 5.42, CH3CN); IR (NaCl, neat) 1643 cm-1 (CdN); H NMR
(300 MHz, CDCl3) δ 0.81 (d, 3 H, J ) 6.8 Hz), 0.892 (d, 3 H, J
) 6.8 Hz), 0.895 (d, 3 H, J ) 6.6 Hz), 0.90 (d, 3 H, J ) 6.6 Hz),
1.68 (ddq, 1 H, J ) 6.8 Hz), 1.96 (dq, 1 H, J ) 6.6 Hz), 2.10 (d,
2 H, J ) 6.8 Hz), 3.84 (m, 2 H), 4.13 (m, 1 H); 13C NMR (CDCl3)
δ 18.0 (CH3), 18.6 (CH3), 22.3 (2 × CH3), 26.2 (CH), 32.4 (CH),
37.0 (CH2), 69.5 (CH2), 71.9 (CH), 166.6 (C); HREIMS found
m/ z 169.1462 (M+), C10H19NO requires 169.1467.
(4R)-2-(2,2-Dim et h ylp r op yl)-4-p h en yl-4,5-d ih yd r oox-
a zole (1h ). Method C: oil, 51%. [R]D ) +34.0° (c 4.46,
CHCl3); IR (NaCl, neat) 1661 cm-1 (CdN); 1H NMR (CDCl3) δ
1.08 (s, 9 H), 2.32 (s, 2 H), 4.05 (dd, 1 H, J ) 8.5, 8.5 Hz), 4.60
(dd, 1 H, J ) 10.2, 8.5 Hz), 5.19 (dd, 1 H, J ) 10.2, 8.5 Hz),
7.27 (m, 5 H); 13C NMR (CDCl3) δ 29.6 (CH3), 30.7 (C), 41.6
(CH2), 69.4 (CH), 74.1 (CH2), 126.4 (2 × CH), 127.2 (CH), 128.4
(2 × CH), 142.4 (C), 167.4 (C); HREIMS found m/ z 217.1464
(M+), C14H19NO requires 217.1467.
Exp er im en ta l Section
Gen er a l Exp er im en ta l. THF and 1,4-dioxane were puri-
fied by distillation from sodium-benzophenone ketyl. 1H and
13C NMR were recorded at 300 and 75 MHz, respectively.
Homonuclear J couplings were confirmed by COSY or single-
frequency decoupling experiments. 13C NMR signal chemical
shift and multiplicity assignments (CH3, methyl; CH2, meth-
ylene; CH, methine; C, quaternary) were made from DEPT,
HETCOR, and HMBC spectra. GCMS was carried out on a
capillary column (silicone coating) coupled to an ion-trap mass
detector. High resolution mass spectra were provided by the
University of Minnesota Mass Spectrometry Laboratory. Other
procedures are described elsewhere.25
(4S)-2-Ben zyl-4-isop r op yl-4,5-d ih yd r ooxa zole (1j). Me-
thod B: clear oil, 78%; Rf ) 0.26, 3:7 ethyl acetate:hexane. IR
1
(NaCl, neat) 1669 cm-1 (CdN); H NMR (CDCl3) δ 0.85 (d, 3
H, J ) 6.8 Hz), 0.94 (d, 3 H, J ) 6.8 Hz), 1.72 (dq, 1 H, J ) 6.8
Hz), 3.60 (s, 2 H), 3.87 (m, 2 H), 4.14 (m, 1 H), 7.29 (m, 5 H);
13C NMR (CDCl3) δ 17.8 (CH3), 18.4 (CH3), 32.3 (CH), 34.6
(CH2), 69.9 (CH2), 71.8 (CH), 126.6 (CH), 128.2 (2 × CH), 128.6
(2 × CH), 135.1 (C), 165.3 (C); HREIMS found m/ z 203.1311
(M+), C13H17NO requires 203.1310.
(20) Marfey, P. Carlsberg Res. Commun. 1984, 49, 591-596.
(21) Williams, R. M. Synthesis of Optically Active R-Amino Acids;
Pergamon: Oxford, 1989; p 410.
(22) Namdeve, N. D.; Gigstad, K. M.; Iyer, M. S.; Lipton, M. A. 209th
American Chemical Society Meeting, Anaheim, CA, 1995; Abstract no.
372.
(4R)-2-(1-Na p h t h ylm et h yl)-4-p h en yl-4,5-d ih yd r ooxa -
zole (1k ). Method B: Triethylamine (5.2 mL, 37.3 mmol) was
(26) Kurth, M. J .; Decker, O. H. W. J . Org. Chem. 1985, 50, 5769-
5775.
(23) Burk, M. J .; Feng, S.; Gross, M. F.; Tumas, W. J . Am. Chem.
Soc. 1995, 117, 8277-8278.
(27) McElvain, S. M.; Nelson, J . W. J . Am. Chem. Soc. 1942, 64,
1825-1827.
(28) Meyers, A. I.; Slade, J . J . Org. Chem. 1980, 45, 2785-2791.
(29) Meyers, A. I.; Smith, R. K.; Whitten, C. E. J . Org. Chem. 1979,
44, 2250-2256.
(24) Midland, M. M.; Koops, R. W. J . Org. Chem. 1992, 57, 1158-
1161.
(25) Searle, P. A.; Molinski, T. F. J . Org. Chem. 1993, 58, 7578-
7580.

2048 J . Org. Chem., Vol. 61, No. 6, 1996
Shafer and Molinski
added dropwise to a stirred mixture of (R)-(-)-2-phenylglycinol
(3.94 g, 28.7 mmol), ethyl 1-naphthylacetimidate hydrochloride
(8.60 g, 34.5 mmol), and CH2Cl2 (144 mL). After stirring at
room temperature overnight, the reaction mixture was poured
into ice-water, and the aqueous layer was extracted three
times with CH2Cl2. The organic layer was dried (MgSO4) and
reduced in vacuo to an opaque, viscous oil (8.58 g). Baseline
impurities were removed by column chromatography (silica
gel, 3:7 ethyl acetate:hexane) to give 1k as a yellow solid (5.94
g, 91%; Rf ) 0.18, 3:7 ethyl acetate:hexane). Mp 57-59 °C;
[R]D ) +62.6° (c 4.65, CHCl3); UV (acetonitrile) 225 (ꢀ 44670),
271 (5870), 281 (6970), 288 (4700), 291 (4680), 313 nm (220);
IR (NaCl, neat) 1662 cm-1 (CdN); 1H NMR (CDCl3) δ 3.93 (dd,
1 H, J ) 8.5, 8.1 Hz), 4.14 (s, 2 H), 4.43 (dd, 1 H, J ) 10.1, 8.5
Hz), 5.10 (dd, 1 H, J ) 10.1, 8.1 Hz), 7.19 (m, 5 H), 7.43 (m, 4
H), 7.74 (d, 1 H, J ) 8.1), 7.80 (dd, 1 H, J ) 7.6, 1.3 Hz), 8.22
(d, 1 H, J ) 8.6 Hz); 13C NMR (CDCl3) δ 32.6 (CH2), 69.5 (CH),
74.7 (CH2), 124.0 (CH), 125.3 (CH), 125.6 (CH), 126.0 (CH),
126.4 (CH), 127.3 (CH), 127.5 (CH), 127.8 (CH), 128.4 (2 ×
CH), 128.5 (CH), 131.2 (C), 131.9 (C), 133.7 (C), 142.1 (C), 157.2
(C), 166.9 (C); HREIMS found m/ z 287.1308 (M+), C20H17NO
requires 287.1310.
H), 7.90 (d, 1 H, J ) 2.6 Hz, H-3); 13C NMR (CDCl3) δ 56.1
(CH), 68.0 (CH2), 69.0 (CH2), 73.6 (CH2), 127.6 (CH), 127.9
1
(CH), 128.5 (CH), 137.3 (C), 153.5 (CH, J C-H ) 194 Hz, C-3),
154.3 (C); HRCIMS found m/ z 220.0982 (MH+), C12H14NO3
requires 220.0974.
(5S)-5-[(6′-Meth oxy-2′-n a p h th oyloxy)m eth yl]-5,6-d ih y-
d r o-2H-1,4-oxa zin -2-on e (2d ): colorless solid (53%); Rf ) 0.56
(ethyl acetate); 1H NMR (CDCl3) δ 3.95 (s, 3 H), 4.26 (m, 1 H),
4.50 (dd, 1 H, J ) 11.8, 8.6 Hz), 4.57 (dd, 1 H, J ) 11.6, 6.4
Hz), 4.68 (dd, 1 H, J ) 11.8, 4.4 Hz), 4.77 (dd, 1 H, J ) 11.6,
4.5 Hz), 7.15 (d, 1 H, J ) 2.5 Hz), 7.21 (dd, 1 H, J ) 8.9, 2.5
Hz), 7.76 (d, 1 H, 8.6 Hz), 7.85 (d, 1 H, 8.9 Hz), 7.97 (dd, 1 H,
J ) 8.6, 1.7 Hz), 7.98 (d, 1 H, J ) 2.8, H-3), 8.49 (bs, 1 H); 13
C
NMR (CDCl3) δ 55.3 (CH3), 55.4 (CH), 63.3 (CH2), 67.7 (CH2),
105.7 (CH), 119.8 (CH), 124.0 (C), 125.7 (CH), 127.0 (CH),
127.8 (C), 130.9 (CH), 131.2 (CH), 137.4 (C), 154.0 (CH, C-3),
159.8 (C), 166.3 (C); HREIMS found m/ z 313.0956 (M+),
C17H15NO5 requires 313.0950.
5,6-Dih yd r o-2H-1,4-oxa zin -2-on e (2e). A solution of 2-
methyloxazoline (1e, 0.1037 g, 1.22 mmol) and n-nonane (10
mol %, internal standard) in dry THF (6 mL) was heated under
reflux with SeO2 (0.2875 g, 2.59 mmol) and the reaction
monitored by GCMS. After 1.5 h, the crude mixture was
filtered through silica gel and eluted with diethyl ether.
Careful evaporation of the eluate under a stream of nitrogen
gave a yellow oil (11 mg) containing 2e that was analyzed by
NMR and GCMS. 60% yield by GC; 1H NMR (CDCl3) δ 3.87,
(m, 2H), 4.47 (t, 2H, J ) 5.5 Hz), 7.88 (t, 1H, CHdN, J ) 2.3
Hz), ; GCMS, m/ z 99 (M+), tR 7.29 min, 50-150 °C @ 4 °C/
min, 30 m × 0.32 mm, DB5.
(4R)-2-(2-Na p h t h ylm et h yl)-4-p h en yl-4,5-d ih yd r ooxa -
zole (1l). Method B: Oxazoline 1l was prepared (49%) from
ethyl 2-naphthylacetimidate hydrochloride in a similar fashion
to 1k : yellow solid, Rf ) 0.14, 3:7 ethyl acetate:hexane. Mp
50-50.5 °C; [R]D ) +86.1° (c 4.92, CHCl3); UV (acetonitrile)
224 (ꢀ 111,000), 267 (6750), 276 (6970), 286 (5250), 366 nm
1
(1950); IR (NaCl, neat) 1666 cm-1 (CdN); H NMR (CDCl3) δ
3.82 (s, 2 H), 4.09 (dd, 1 H, J ) 8.5, 8.2 Hz), 4.60 (dd, 1 H, J
) 10.0, 8.5 Hz), 5.21 (dd, 1 H, J ) 10.0, 8.2 Hz), 7.28 (m, 5 H),
7.48 (m, 3 H), 7.82 (m, 4 H); 13C NMR (CDCl3) δ 34.8 (CH2),
69.4 (CH), 74.7 (CH2), 125.6 (CH), 125.9 (CH), 126.4 (3 × CH),
126.9 (CH), 127.3 (CH), 127.5 (2 × CH), 128.1 (CH), 128.5 (2
× CH), 132.3 (C), 132.5 (C), 133.3 (C), 142.1 (C), 166.9 (C);
HREIMS found m/ z 287.1308 (M+), C20H17NO requires
287.1310.
(5S)-2,5-Diisop r op yl-5,6-d ih yd r o-2H -1,4-oxa zin -2-on e
(2g): 33%; Rf ) 0.47, 3:7 ethyl acetate:hexane. [R]D ) +89.4°
(c 3.76, acetonitrile); IR (NaCl, neat) 1738 (CdO), 1637 (CdN)
1
cm-1; H NMR (CDCl3) δ 1.02 (d, 3 H, J ) 7.0 Hz), 1.05 (d, 3
H, J ) 7.0 Hz), 1.13 (d, 3 H, J ) 6.8 Hz), 1.16 (d, 3 H, J ) 6.8
Hz), 1.86 (dq, 1 H, J ) 6.8 Hz), 3.20 (dq, 1 H, J ) 7.0, 1.3 Hz),
3.40 (dddd, 1 H, J ) 9.2, 6.8, 4.1, 1.3 Hz), 4.14 (dd, 1 H, J )
11.3, 9.2 Hz), 4.39 (dd, 1 H, J ) 11.3, 4.1 Hz); 13C NMR (CDCl3)
δ 18.6 (CH3), 19.1 (CH3), 19.3 (CH3), 20.0 (CH3), 30.4 (CH),
31.8 (CH), 60.8 (CH), 68.2 (CH2), 155.6 (C), 165.6 (C); HREIMS
found m/ z 183.1255 (M+), C10H17NO2 requires 183.1259.
Gen er a l P r oced u r e for SeO2-P r om oted Oxid a tive Re-
ar r an gem en t. (5S)-5-Isopr opyl-5,6-dih ydr o-2H-1,4-oxazin -
2-on e (2a ). A solution of (4S)-oxazoline 1a (0.101 g, 0.82
mmol)26 in dry dioxane (2 mL) was added to a suspension of
selenium dioxide (0.196 g, 1.77 mmol) in dioxane (2 mL), and
the mixture was heated at reflux for 2 h. The mixture was
cooled and purified by direct application to a column of silica
gel and elution with ethyl acetate to give 2a as a light-tan oil,
essentially pure by 1H NMR (0.0849 g, 75%), Rf 0.58 (ethyl
acetate). Crystallization of 2a from n-hexane at -20 °C gave
an analytical sample as long colorless needles: mp 2-3 °C;
[R]D ) +97.4° (c 0.83, CHCl3); CD (hexane) λ 197 nm (∆ ꢀ -7.5),
243 (7.8), 291 (-0.1), 335 (0.5); UV (hexane) λ 202 nm (ꢀ 13800),
(5R)-3-ter t-Bu tyl-5-p h en yl-5,6-d ih yd r o-2H-1,4-oxa zin -
2-on e (2h ): yellow solid, 84%. Mp 63-65.5 °C; [R]D ) -191.1°
(c 5.37, CHCl3); IR (NaCl, neat) 1742 (CdO), 1628 (CdN) cm-1
;
1H NMR (CDCl3) δ 1.38 (s, 9 H), 4.00 (dd, 1 H, J ) 11.3, 11.0
Hz), 4.45 (dd, 1 H, J ) 11.3, 4.3 Hz), 4.76 (dd, 1 H, J ) 11.0,
4.3 Hz), 7.36 (m, 5 H); 13C NMR (CDCl3) δ 27.9 (CH3), 39.1
(C), 59.2 (CH), 71.0 (CH2), 126.8 (2 × CH), 127.9 (CH), 128.6
(2 × CH), 137.0 (C), 154.0 (C), 168.5 (C); HREIMS found m/ z
231.1257 (M+), C14H17NO2 requires 231.1259.
1
348 (298); IR (NaCl, neat) 1748 (CdO), 1631 (CdN) cm-1; H
(5R)-3,5-Dip h en yl-5,6-d ih yd r o-2H-1,4-oxa zin -2-on e (2i):
yellow oil (94%); Rf ) 0.68 (ethyl acetate); [R]D ) -351° (c 3.96,
CHCl3); UV (acetonitrile) λ 210 (ꢀ 20700), 265 (7500), 366 (210);
NMR (CDCl3) δ 1.04 (d, 3 H, J ) 6.8 Hz, i-Pr), 1.06 (d, 3 H, J
) 6.8 Hz, i-Pr), 1.93 (dq, 1 H, J ) 6.8, 6.8 Hz, i-Pr), 3.48 (dddd,
1 H, J ) 9.5, 6.8, 4.4, 2.8 Hz, H5), 4.24 (dd, 1 H, J ) 11.7, 9.5
Hz, H6a), 4.45 (dd, 1 H, J ) 11.7, 4.4 Hz, H6b), 7.87 (d, 1 H,
J ) 2.8 Hz, H3); 13C NMR (CDCl3) δ 18.7 (CH3), 19.2 (CH3),
IR (NaCl, neat) 1746 (CdO), 1609 (CdN) cm-1 1H NMR
;
(CDCl3) δ 4.25 (dd, 1 H, J ) 11.3, 10.8 Hz), 4.59 (dd, 1 H, J )
11.3, 4.4 Hz), 4.98 (dd, 1 H, J ) 10.8, 4.4 Hz), 7.40 (m, 8 H),
8.08 (m, 2 H); 13C NMR (CDCl3) δ 60.1 (CH), 71.2 (CH2), 127.1
(CH), 128.1 (CH), 128.2 (CH), 128.8 (2 × CH), 131.2 (CH), 133.9
(C), 136.8 (C), 154.8 (C), 158.2 (C); HREIMS found m/ z (M+)
251.0955, C16H13NO2 requires 251.0946. Lanthanide shifts
induced by titration of both (-)-2i and (()-2i (prepared from
(()-phenylglycinol) with a CDCl3 solution of (+)-Eu(hfc)3 (20
1
30.4 (CH), 61.5 (CH), 68.3 (CH2), 152.2 (CH, J C-H ) 193 Hz,
C3), 154.5 (C, C2); HREIMS found m/ z 141.0785 (M+), C7H11
-
NO2 requires 141.0790. Anal. Calcd for C7H11NO2: C, 59.56;
H, 7.85; N, 9.92. Found: C, 59.21; H, 7.89; N, 9.83.
(5R)-5-P h en yl-5,6-dih ydr o-2H-1,4-oxazin -2-on e (2b): yel-
low oil (72%); [R]D ) -252° (c 5.23, CHCl3); UV (acetonitrile)
λ 212 (ꢀ 11200), 240 (1420), 338 (150); IR (NaCl, neat) 1762
(CdO), 1631 (CdN) cm-1; 1H NMR (CDCl3) δ 4.28 (dd, 1 H, J
) 11.7, 10.8 Hz, H6a), 4.61 (dd, 1 H, J ) 11.7, 4.7 Hz, H6b),
4.91 (ddd, 1 H, J ) 10.8, 4.7, 3.1 Hz, H5), 7.37 (m, 5 H), 8.06
(d, 1 H, J ) 3.1 Hz, H-3); 13C NMR (CDCl3) δ 59.5 (CH), 70.6
(CH2), 126.8 (CH), 128.1 (CH), 128.6 (CH), 136.0 (C), 152.9
(CH, C-3), 153.8 (C); HREIMS found m/ z 175.0634 (M+), C10H9-
NO2 requires 175.0633.
1
mol %) gave only one set of H NMR signals for the optically
active product (ee > 99%).
(5S)-5-Isop r op yl-2-p h en yl-5,6-d ih yd r o-2H-1,4-oxa zin -2-
on e (2j): yellow oil, 74%. [R]D ) +151.3° (c 1.08, CHCl3); UV
(acetonitrile) 264 (ꢀ 6290), 328 nm (640); IR (NaCl, neat) 1738
(CdO), 1610 (CdN) cm-1; 1H NMR (CDCl3) δ 1.10 (d, 3 H, J )
6.8 Hz), 1.15 (d, 3 H, J ) 6.8 Hz), 2.01 (dq, 1 H, J ) 6.8 Hz),
3.58 (ddd, 1 H, J ) 9.7, 6.8, 4.0 Hz), 4.27 (dd, 1 H, J ) 11.2,
9.7 Hz), 4.53 (dd, 1 H, J ) 11.2, 4.0 Hz), 7.43 (m, 3 H), 8.00
(m, 2 H); 13C NMR (CDCl3) δ 19.0 (CH3), 19.5 (CH3), 30.6 (CH),
62.0 (CH), 68.5 (CH2), 128.2 (CH), 128.6 (CH), 130.9 (CH),
134.2 (C), 155.4 (C), 157.4 (C); HREIMS found m/ z 217.1103
(M+), C13H15NO2 requires 217.1103.
(5R)-5-[(Ben zyloxy)m eth yl]-5,6-d ih yd r o-2H-1,4-oxa zin -
2-on e (2c): colorless oil (22%); Rf ) 0.62 (ethyl acetate); [R]D
) -23.8° (c 0.913, CHCl3); IR (NaCl, neat) 1746 (CdO) cm-1
;
1H NMR (CDCl3) δ 3.62 (dd, 1 H, J ) 9.6, 7.3 Hz), 3.87 (dd, 1
H, J ) 9.6, 4.2 Hz), 4.00 (m, 1 H), 4.42 (dd, 1 H, J ) 11.7, 8.4
Hz), 4.57 (dd, 1 H, J ) 11.7, 4.4 Hz), 4.59 (s, 2 H), 7.35 (m, 5

Oxidative Rearrangement of 2-Substituted Oxazolines
J . Org. Chem., Vol. 61, No. 6, 1996 2049
(5R)-3-(1-Naph th yl)-5-ph en yl-5,6-dih ydr o-2H-1,4-oxazin -
127.2 (CH), 128.6 (CH), 128.8 (CH), 138.3 (C), 168.9 (C);
HREIMS found m/ z 233.1416 (M+), C14H19NO2 requires
233.1416. Anal. Calcd for C14H19NO2: C, 72.07; H, 8.21; N,
6.00. Found: C, 72.16; H, 8.22; N, 6.00.
2-on e (2k ): yellow solid (93%); mp 155.5-156 °C; [R]D
)
-276.2° (c 2.54, CHCl3); UV (acetonitrile) 220 (ꢀ 78220), 273
(5980), 278 nm (ꢀ 5840); IR (NaCl, neat) 1739 (CdO), 1610
1
(CdN) cm-1; H NMR (300 MHz, CDCl3) δ 4.48 (dd, 1 H, J )
(3S,5R)-3,5-Dip h en yl-3,4,5,6-t et r a h yd r o-1,4-oxa zin -2-
on e (4i). Compound 2i was hydrogenated as described above
for 4b to obtain a mixture of diastereoisomers 4i (4:1, 1H
NMR), oil (91%); Rf ) 0.53 (1:1 ethyl acetate:hexane); UV
(acetonitrile) 207 (ꢀ 11900), 252 (350), 257 (370), 263 (290); IR
(NaCl, neat) 3315 (NH), 1743 (CdO) cm-1; 1H NMR (CDCl3) δ
2.60 (bs, 1 H), 4.36 (m, 3 H), 4.79/4.91 (s, 1 H), 7.36 (m, 10 H);
13C NMR (CDCl3) δ 52.0/57.4 (CH), 60.3/64.0 (CH), 73.8/74.8
(CH2), 126.8/127.0 (CH), 127.2/128.1 (CH), 128.3/128.4 (CH),
128.6 (CH), 128.8 (2 × CH), 137.4/137.9 (C), 138.0/138.1 (C),
168.3/168.9 (C); 126.8-128.8 several signals; HREIMS found
m/ z (M+) 253.1109, C16H15NO2 requires 253.1103.
Dim er ic P r od u cts, 5f a n d epi-5f, fr om SeO2 Oxid a tion
of 1f. A solution of 1f (0.400 g, 2.84 mmol) in dioxane (7 mL)
was added to selenium dioxide (0.70 g, 6.3 mmol) suspended
in dioxane (7 mL). The mixture was stirred and heated under
reflux (1 h), cooled, and filtered through silica gel with 1:1 ethyl
acetate:hexane. Removal of solvent under reduced pressure
gave a reddish-brown oil (0.250 g) which was separated by
chromatography (silica gel, gradient, 1:4 to 3:1 ethyl acetate:
hexane) to afford of 5f (86.5 mg, 20%) and epi-5f (91.6 mg,
21%).
11.5, 10.6 Hz), 4.71 (dd, 1 H, J ) 11.5, 4.4 Hz), 5.14 (dd, 1 H,
J ) 10.6, 4.4 Hz), 7.36 (m, 4 H), 7.50 (m, 3 H), 7.69 (d, 1 H, J
) 7.1 Hz), 7.87 (m, 1 H), 7.93 (d, 1 H, J ) 8.2 Hz), 8.04 (m, 1
H); 13C NMR (CDCl3) δ 60.6 (CH), 71.5 (CH2), 124.6 (CH), 124.8
(CH), 126.1 (CH), 126.8 (CH), 127.1 (2 × CH), 128.1 (CH), 128.3
(CH), 128.6 (CH), 128.9 (2 × CH), 130.8 (CH), 130.9 (C), 132.0
(C), 133.6 (C), 136.4 (C), 155.2 (C), 161.1 (C); HREIMS found
m/ z 301.1105 (M+), C20H15NO2 requires 301.1103. Anal.
Calcd for C20H15NO2: C, 79.71; H, 5.02; N, 4.65. Found: C,
79.81; H, 5.06; N, 4.86.
(5R)-3-(2-Naph th yl)-5-ph en yl-5,6-dih ydr o-2H-1,4-oxazin -
2-on e (2l): yellow solid (83%; Rf ) 0.34, 3:7 ethyl acetate:
hexane); mp 108-108.5 °C; [R]D ) -336° (c 4.96, CHCl3); UV
(acetonitrile) 221 (ꢀ 61600), 261 (17200), 299 (12200), 343 nm
(3100); IR (NaCl, neat) 1739 (CdO), 1603 (CdN) cm-1 1H
;
NMR (CDCl3) δ 4.21 (dd, 1 H, J ) 11.3, 10.8 Hz), 4.55 (dd, 1
H, J ) 11.3, 4.4 Hz), 4.95 (dd, 1 H, J ) 10.8, 4.4 Hz), 7.34 (m,
5 H), 7.47 (m, 2 H), 7.84 (m, 3 H), 8.16 (dd, 1 H, J ) 8.7, 1.7
Hz), 8.68 (s, 1 H); 13C NMR (CDCl3) δ 60.2 (CH), 71.1 (CH2),
124.6 (CH), 126.4 (CH), 127.1 (2 × CH), 127.5 (CH), 127.6 (CH),
127.9 (CH), 128.1 (CH), 128.7 (2 × CH), 129.2 (CH), 130.3 (C),
131.1 (C), 132.5 (C), 134.4 (C), 136.8 (C), 154.9 (C), 157.8 (C);
HREIMS found m/ z 301.1103 (M+), C20H15NO2 requires
301.1103. Anal. Calcd for C20H15NO2: C, 79.71; H, 5.02; N,
4.65. Found: C, 79.60; H, 5.11; N, 4.69.
5f: solid; [R]D ) +33.0° (c 1.09, CHCl3); UV (acetonitrile) λ
286 (ꢀ 12700), 314 nm (13500); IR (NaCl, neat) 3293 (weak),
1
1742, 1685, 1616 cm-1; H NMR (CDCl3) δ 0.96 (d, 3 H, J )
6.8 Hz), 0.97 (d, 3 H, J ) 6.7 Hz), 1.12 (m (overlapped d and
t), 6 H), 1.89 (dq, 1 H, J ) 6.7 Hz), 2.34 (q, 2 H, J ) 7.5 Hz),
2.44 (septet, 1 H, J ) 6.9 Hz), 3.12 (m, 1 H), 4.08 (dd, 1 H, J
) 11.4, 7.4 Hz), 4.20 (dd, 1 H, J ) 11.4, 4.1 Hz), 4.80 (s, 2 H),
7.11 (d, 1 H, J ) 13.4 Hz), 7.99 (bt, 1 H, J ) 9.7 Hz); 13C NMR
(CDCl3) δ 9.0 (CH3), 18.1 (CH3), 19.4 (2 × CH3), 19.5 (CH3),
27.4 (CH2), 30.1 (CH), 34.0 (CH), 64.1 (CH), 65.0 (CH2), 66.8
(CH2), 104.6 (C), 152.2 (CH), 155.8 (C), 163.5 (C), 174.1 (C);
HREIMS found m/ z 310.1885 (M+), C16H26N2O4 requires
310.1893.
(5S)-5-Isopr opyl-3,4,5,6-tetr ah ydr o-1,4-oxazin -2-on e (4a).
A solution of 2a (0.100 g, 0.709 mmol) in ethyl acetate (4 mL)
was hydrogenated (Pd-C, 10% w/w, 10 mg, 1 atm H2) at room
temperature for 4 h. Additional Pd-C (32.3 mg) was added
and hydrogenation continued for another 3 h. The mixture
was filtered through diatomaceous earth and the filter pad
washed with ethyl acetate. Solvent was removed from the
combined filtrate and washings to give morpholin-2-one 4a as
a yellow oil (80.4 mg; 79%; Rf ) 0.18, ethyl acetate), pure by
1
TLC and H NMR. [R]D ) +15.5° (c 1.73, CHCl3); UV (MeOH)
epi-5f: solid; [R]D ) +6.0° (c 0.58, CHCl3); UV (acetonitrile)
λ 204 (ꢀ 3290), 252 (330); IR (NaCl, neat) 3312 (NH), 1741
(CdO) cm-1; 1H NMR (CDCl3) δ 0.90 (d, 3 H, J ) 6.8 Hz), 0.94
(d, 3 H, J ) 6.8 Hz), 1.62 (dq, 1 H, J ) 6.8, 6.8 Hz), 1.74 (bs,
1 H), 2.69 (ddd, 1 H, J ) 10.7, 6.8, 3.7 Hz), 3.56 (d, 1 H, J )
18.0 Hz), 3.72 (d, 1 H, J ) 18.0 Hz), 4.10 (dd, 1 H, J ) 11.0,
10.7 Hz), 4.36 (dd, 1 H, J ) 11.0, 3.7 Hz); 13C NMR (CDCl3) δ
18.5 (CH3), 18.6 (CH3), 29.6 (CH), 47.7 (CH2), 56.6 (CH), 72.5
λ 312 nm (ꢀ 19800); IR (NaCl, neat) 3318 (weak), 1739, 1702,
1
1621 cm-1; H NMR (CDCl3) δ 0.98 (d, 3 H, J ) 6.8 Hz), 0.99
(d, 3 H, J ) 6.8 Hz), 1.14 (m, (overlapped d and t), 6 H), 1.92
(dq, 1 H, J ) 6.7 Hz), 2.36 (q, 2 H, J ) 7.6 Hz), 2.50 (septet,
1 H, J ) 6.9 Hz), 3.26 (m , 1H), 4.18 (m, 2H), 4.83 (s, 2 H),
5.80 (bt, 1 H, J ) 11.5 Hz), 7.39 (d, 1 H, J ) 13.5 Hz); 13C
NMR (CDCl3) δ 9.0 (CH3), 18.2 (CH3), 19.4 (CH3), 19.5 (2 ×
CH3), 27.5 (CH2), 30.3 (CH), 34.0 (CH), 63.1 (CH), 65.0 (CH2),
67.2 (CH2), 104.9 (C), 144.5 (CH), 158.9 (C), 162.0 (C), 174.2
(C); HREIMS found m/ z 310.1882 (M+), C16H26N2O4 requires
310.1893.
(CH2), 168.5 (C); HREIMS found m/ z 143.0944 (M+), C7H13
-
NO2 requires 143.0946.
(5R)-5-P h en yl-3,4,5,6-tetr a h yd r o-1,4-oxa zin -2-on e (4b):3
Compound 2b was hydrogenated as above to obtain 4b as
yellow oil (quantitative); Rf ) 0.39 (ethyl acetate); [R]D
)
(4S)-4-Isop r op yl-2-oxa zolid in on e (6). A solution of 1a
(0.298 g, 2.35 mmol) in dry pyridine (6 mL) was added to SeO2
(0.576 g, 5.20 mmol) in pyridine (6 mL) and the mixture heated
at reflux (1 h), cooled, and eluted through silica gel with 1:1
ethyl acetate:hexane. The brown residue (0.1094 g) obtained
by removal of solvent under vacuum was purified by chroma-
tography (silica, gradient from 1:9 ethyl acetate:hexane to ethyl
acetate) to afford the known oxazolidinone 6 as a yellow oil
-91.6° (c 4.81, CHCl3); UV (acetonitrile) λ 205 (ꢀ 9090); IR
(NaCl, neat) 3239 (NH), 1743 (CdO) cm-1; 1H NMR (CDCl3) δ
3.83 (d, 1 H, J ) 17.8 Hz), 3.95 (d, 1 H, J ) 17.8 Hz), 4.18 (dd,
1 H, J ) 10.3, 3.7 Hz), 4.29 (dd, 1 H, J ) 10.6, 10.3 Hz), 4.40
(dd, 1 H, J ) 10.6, 3.7 Hz), 7.38 (m, 5 H); 13C NMR (CDCl3) δ
48.1 (CH2), 55.9 (CH), 74.1 (CH2), 126.7 (CH), 128.2 (CH), 128.6
(CH), 137.4 (C), 167.6 (C); HREIMS found m/ z 177.0785 (M+),
C10H11NO2 requires 177.0790. Anal. Calcd for C10H11NO2: C,
67.77; H, 6.26; N, 7.91. Found: C, 67.55; H, 6.25; N, 7.90.
(5R)-3-ter t-Bu tyl-5-ph en yl-3,4,5,6-tetr ah ydr o-1,4-oxazin -
2-on e (4h ). Compound 2h (0.0214 g, 0.093 mmol) was
dissolved in CH2Cl2 (1 mL). The flask was purged with N2,
and platinum(IV) oxide (14.7 mg) was added. The stirred
mixture was hydrogenated for 3 h. After purging with N2, the
mixture was filtered through diatomaceous earth. Removal
of the solvent gave 4h as a white solid (21.4 mg, 99%; Rf )
0.32, 3:7 ethyl acetate:hexane). 1H NMR showed a 13:1
mixture of diastereomers. Crystallization from ethyl acetate-
hexane provided a single diastereomer (82%, de >99%): mp
111-112 °C; [R]D ) -76.4° (c 2.00, CHCl3); IR (NaCl, neat)
(32.8 mg, 11%):9 IR (NaCl, neat) 3275 (NH), 1748 (CdO) cm-1
;
1H NMR (CDCl3) δ 0.88 (d, 3 H, J ) 6.8 Hz), 0.94 (d, 3 H, J )
6.8 Hz), 1.71 (dq, 1 H, J ) 6.8, 6.8 Hz), 3.59 (m, 1 H), 4.08 (dd,
1 H, J ) 8.7, 6.3 Hz), 4.42 (dd, 1 H, J ) 8.7, 8.7 Hz), 6.85 (bs,
1 H); 13C NMR (CDCl3) δ 17.6 (CH3), 17.9 (CH3), 32.6 (CH),
58.4 (CH), 68.6 (CH2), 160.5 (C).
(3S,5S)- a n d (3R,5S)-3-Meth oxy-5-isop r op yl-3,4,5,6-tet-
r a h yd r o-1,4-oxa zin -2-on e (7). 5,6-Dihydro-2H-oxazin-2-one
2a (0.0422 g, 0.299 mmol) was heated in methanol (1.5 mL,
37.0 mmol) at reflux (6 h). Removal of the solvent under
reduced pressure afforded 7 as a 1:1 mixture of C3 epimers
(yellow oil, 0.0497 g, 96%; Rf ) 0.48, ethyl acetate): UV
(hexane) λ 202 (ꢀ 1520), 220 (540); IR (NaCl, neat) 3311 (NH),
3330 (NH), 1728 (CdO) cm-1
.
1H NMR (C6D6) δ 1.04 (s, 9 H),
1750 (CdO) cm-1 1H NMR (CDCl3) δ 0.91 (d, 3 H, J ) 6.7
;
3.13 (s, 1 H), 3.54 (dd, 1 H, J ) 10.3, 3.0 Hz), 3.72 (dd, 1 H, J
) 10.3, 3.0 Hz), 3.85 (dd, 1 H, J ) 10.3, 10.3 Hz); 13C NMR
(CDCl3) δ 26.6 (CH3), 36.3 (C), 56.6 (CH), 67.2 (CH), 74.3 (CH2),
Hz), 0.93 (d, 3 H, J ) 6.7 Hz), 1.04 (d, 3H, J ) 6.7 Hz), 1.08
(d, 3 H, J ) 6.7 Hz), 1.64 (dq, 2 × 1 H, J ) 6.7, 6.7 Hz), 2.20
(bs, 1 H), 3.00 (m, 1 H), 3.18 (ddd, 1 H, J ) 7.5, 7.5, 7.5 Hz),

2050 J . Org. Chem., Vol. 61, No. 6, 1996
Shafer and Molinski
3.32 (m, 1 H), 3.42 (t, 1 H, J ) 7.5, 7.5 Hz), 3.77 (s, 3 H), 3.80
(s, 3 H), 3.95 (m, 1 H), 4.05 (t, 1 H, J ) 7.5, 7.5 Hz), 4.87 (s, 1
H), 5.04 (s, 1 H); 13C NMR (CDCl3) δ 19.4/19.6 (CH3), 20.0/
20.3 (CH3), 31.2/31.4 (CH), 52.0/52.2 (CH3), 63.8/65.5 (CH),
69.7/69.8 (CH2), 88.0/88.2 (CH), 169.9/170.3 (C); HREIMS
found m/ z 173.1042 (M+), C8H15NO3 requires 173.1052.
were diluted with ethanol and concentrated under vacuum to
give of an off-white solid (11.7 mg). The residue was dissolved
in 6 M HCl aqueous (2 mL) and heated in a sealed tube (110
°C) for 26 h. After cooling to room temperature, the volatiles
were removed from the mixture to give a pale-yellow solid (11.2
mg) which was eluted through a short charcoal column with
water. Removal of water gave pure (S)-tert-leucine hydrochlo-
ride (10, white solid, 10.5 mg, 75% for three steps), which was
identical with an authentic sample by 1H NMR, [R]D and TLC
(Rf ) 0.43, 3:1:1 n-BuOH:AcOH:H2O). A portion of the product
(ca. 0.5 mg) was treated with 1-fluoro-2,4-dinitrophenyl-5(S)-
alaninamide (FDAA) according to Marfey20 as were authentic
(S)-(-)-10 and (()-10, and the FDAA adducts were analyzed
by diode array HPLC (4.6 mm × 150 mm RP18 column, 1.5
mL min-1, elution with a linear gradient; buffer A, 90% 0.05
M triethylamine phosphate, B, 10% acetonitrile, to 10% buffer
A over 30 min) and UV monitoring at λ 340 nm. Synthetic
(S)-tert-Leucine FDAA adduct eluted at 18.1 min, and no
adduct was detected from (R)-tert-leucine (20.1 min).
(4S)-4-Isop r op yl-2-ben zoyl-3H-1,3-oxa zolid in e (8).
A
solution of phenylmagnesium bromide in THF (1 M, 3.0 mL,
3.0 mmol) was added dropwise to a stirred solution of 2a (0.401
g, 2.85 mmol) in dry THF (15 mL) at -78 °C. The reaction
was quenched at -78 °C after 20 min by the addition of
NaHCO3 (aqueous, saturated, 2.5 mL). The reaction mixture
was diluted with ethyl acetate (50 mL) and H2O (10 mL), and
the layers were separated. The aqueous layer was extracted
with 3 × 75 mL of ethyl acetate. The combined organic layers
were dried (MgSO4), and the solvent was removed to give a
yellow oil (0.567 g) consisting of a 1:1 epimeric mixture of the
sensitive product 8 (57%, by NMR); Rf ) 0.74 (1:1 ethyl acetate:
hexane). Silica gel chromatography provided pure 8 accom-
panied by substantial loss of material through decomposi-
tion: colorless oil; UV (MeOH) λ 247 (ꢀ 8360), 287 (2170); IR
(NaCl, neat) 3305 (NH, weak), 1692 (PhCdO) cm-1; 1H NMR
(CDCl3) δ 0.91 (d, 3 H, J ) 6.7 Hz), 0.95 (d, 3 H, J ) 6.7 Hz),
1.04 (d, 3 H, J ) 6.6 Hz), 1.13 (d, 3 H, J ) 6.6 Hz), 1.68/1.70
(dq, 1 H, J ) 6.6 Hz), 2.90 (bs, 1 H), 3.13 (m, 3 H), 3.62 (dd, 1
H, J ) 7.9, 6.2 Hz), 3.92 (dd, 1 H, J ) 7.9, 6.8 Hz)/3.98 (dd, 1
H, J ) 6.8, 5.9 Hz), 5.60/5.62 (s, 1 H, H2), 7.53 (m, 3 H), 8.10
(m, 2 H); 13C NMR (CDCl3) δ 19.4/19.9(CH3), 20.0/20.6 (CH3),
31.3 /31.9 (CH), 64.1/65.8 (CH), 69.9/70.0 (CH2), 89.2/89.4 (CH),
128.5 /128.6 (2 × CH), 129.3 /129.4 (2 × CH), 133.6 /133.9 (CH),
134.2/134.3 (C), 193.6/194.3 (CdO); HREIMS found m/ z
219.1252 (M+), C13H17NO2 requires 219.1259.
(S)-ter t-Leu cin e Hyd r och lor id e (10). A solution of mor-
philinone 4h (0.0195 g) in ethanol (10 mL) was saturated with
dry HCl and then heated at reflux for 16 h, cooled, and
concentrated under vacuum to a yellow oil (35.8 mg). The
residue was dissolved in CHCl3, reevaporated, and dissolved
in ethanol (10 mL). Pd-C (10% w/w, 13.1 mg) was added and
the mixture hydrogenated (25 °C, 1 atm H2) for 5 h. After the
mixture was filtered through diatomaceous earth, the filtrate
was concentrated to an off-white solid which was dissolved in
water and extracted once with ether.3 The ether layer was
back-extracted with water, and the combined aqueous layers
Ack n ow led gm en t. We are grateful to Dr. Michael
Nantz for valuable discussions and Nicole Ortega and
Dan Morse for technical assistance. We also thank Drs.
Carlito Lebrilla and J iangyue Wu for mass spectromet-
ric measurements on 2a ,j and J eff de Ropp for assis-
tance with HMQC spectra. This research was sup-
ported in part by the NIH (AI-31660) and the UC Davis
Committee on Research. T.F.M. gratefully acknowl-
edges the receipt of an American Cyanamid Faculty
Award. The 500 MHz NMR spectrometer was partially
funded through NIH ISIO-RR04795 and NSF BBS88-
04739.
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
and 13C NMR spectra of 1h ,k -l, 2a -d ,g-l, 4a ,b,h ,i, and 6-8
1
and H NMR of (-)-2i and (()-2i (43 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of this journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
J O952144F