Tetrahydro-1,3-oxazin-6-ones as templates for the stereoselective synthesis of β-substituted L-aspartic acids

Article abstract of DOI:10.1039/b004772o

Protected (4S)-4-carboxytetrahydro-1,3-oxazin-6-ones have been synthesised either by Baeyer-Villiger reaction on a 4-ketoproline derivative or, more directly, from an aspartate derivative. Two strategies have been used to develop these compounds as chiral templates in the synthesis of β-substituted aspartic acids. In the first, formation of an enaminone using Bredereck's reagent, followed by reaction with a Grignard reagent gave a series of alkylidene derivatives which could be reduced from the less hindered side by heterogeneous catalytic hydrogenation to give cis-oxazinones in a completety stereoselective manner. Alternatively, an alkylation strategy, although trans-selective, gave mixtures of isomers. The oxazinones were converted to β-substituted aspartic acids and to regioselectively protected β-substituted aspartic acids without loss of stereochemistry ar either centre.

Full text of DOI:10.1039/b004772o

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Tetrahydro-1,3-oxazin-6-ones as templates for the stereoselective
synthesis of ꢀ-substituted L-aspartic acids1
Guillaume Burtin, Pierre-Jean Corringer and Douglas W. Young*
1
Sussex Centre for Biomolecular Design and Drug Development, University of Sussex, Falmer,
Brighton, UK BN1 9QJ
Received (in Cambridge, UK) 14th June 2000, Accepted 16th August 2000
First published as an Advance Article on the web 6th October 2000
Protected (4S)-4-carboxytetrahydro-1,3-oxazin-6-ones have been synthesised either by Baeyer–Villiger reaction
on a 4-ketoproline derivative or, more directly, from an aspartate derivative. Two strategies have been used to develop
these compounds as chiral templates in the synthesis of β-substituted aspartic acids. In the first, formation of an
enaminone using Bredereck’s reagent, followed by reaction with a Grignard reagent gave a series of alkylidene
derivatives which could be reduced from the less hindered side by heterogeneous catalytic hydrogenation to give
cis-oxazinones in a completely stereoselective manner. Alternatively, an alkylation strategy, although trans-selective,
gave mixtures of isomers. The oxazinones were converted to β-substituted aspartic acids and to regioselectively
protected β-substituted aspartic acids without loss of stereochemistry at either centre.
The stereospecific synthesis of non-natural amino acids has
assumed great interest because of the use of these compounds
as synthons for a wide variety of natural products, as drug
molecules and as probes for understanding the mechanism of
biological reactions. Stereospecifically β-alkylated aspartic acids
have been of particular interest in this respect. Direct alkylation
of aspartic acid derivatives was first reported by Seebach in
1981,2 and later by Baldwin and other workers.3–12 Except for
reports of stereospecific allylation,10,11 these reactions gave
mixtures of diastereoisomers. A recent study has indicated how
the structural and experimental features in such reactions affect
the diastereoselectivity.12 Single diastereoisomeric β-alkyl-
aspartates have been synthesised indirectly using chiral β-
lactam esters as templates which are alkylated trans to the ester
group.13–16
We have developed a stereoselective method of preparing
homochiral 4-substituted glutamic acids and prolines by using
pyroglutamic acid as a chiral template.17 We have also applied
the method to the use of protected 4-ketoprolines such as 1 as
chiral templates to prepare the cis-alkyl compounds 4.18 Our
general method involved preparation of enaminones such as 2
using Bredereck’s reagent, followed by reaction with a suitable
Grignard reagent to yield enones such as 3. Catalytic hydrogen-
ation then occurred stereospecifically from the less hindered
side of 3 to give the cis-isomer 4 as the sole diastereoisomeric
product, as shown in Scheme 1.18 We reasoned that, if the
compounds 4 could be converted to oxazinones such as 5
by an appropriately regiospecific Baeyer–Villiger process, then
hydrolysis would lead to a new and stereoselective route to
Scheme 1
β-substituted aspartic acids 6. This would provide a stereo-
selective method which would give access to epimers of the
compounds prepared by alkylation of β-lactam esters.
room temperature, a 79% yield of tetrahydro-1,3-oxazin-6-one
9 was obtained. The room temperature NMR spectra of the
product were broad and difficult to interpret, but at Ϫ30 ЊC
they became clear, indicating the presence of a 7:3 mixture of
rotamers. This phenomenon is expected of acylproline deriv-
atives16,20 and so it was not surprising that it occurred with
the reduced oxazinone analogues. The regiospecificity of the
Baeyer–Villiger reaction was proved by hydrolysis of compound
9 to (S)-aspartic acid 10 and the specific rotation of this
product indicated that no racemisation had occurred at the
α-centre during the reaction. The most likely explanation for
We had prepared the substituted prolines 4 (R = Me) and 4
(R = Ph) as single diastereoisomers by the above route18 and,
although these compounds proved to be prone to epimerisation
even when subjected to chromatography on silica gel, we were in
a position to study the Baeyer–Villiger reaction. Treatment of
the unsubstituted ketone 1 with m-chloroperbenzoic acid or
with trifluoroperacetic acid failed to elicit any reaction. Bolm
et al.19 have shown that copper(II) acetate can be used to catalyse
Baeyer–Villiger oxidation of ketones with molecular oxygen
and when we used this catalyst with m-chloroperbenzoic acid at
DOI: 10.1039/b004772o
J. Chem. Soc., Perkin Trans. 1, 2000, 3451–3459
This journal is © The Royal Society of Chemistry 2000
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the regiospecificity of the Baeyer–Villiger reaction would be
that it is controlled by involvement of the nitrogen lone pair in
intermediate 7 to give the acyclic intermediate 8, as suggested in
Scheme 2.
aspartic acids. When the oxazinone 9 was reacted with
Bredereck’s reagent, the enaminone 20 was obtained in 70%
yield (Scheme 4). This was shown to be the single E-isomer by
Scheme 2 Reagents: (i) MCPBA–CuOAc2; (ii) 6 M HCl; (iii) H2CO–
Hϩ.
Since the rearrangement had given us the desired oxazine,
we now attempted to use the method to prepare oxazinones
which were stereospecifically substituted at C-5, as shown in
Scheme 3. The cis 3-ethyl derivative 4 (R = Me) was therefore
Scheme 4 Reagents and yields: (i) HC(NMe2)2OtBu; 70%; (ii) RMgBr;
R = Me, 46%; R = Ph, 88%; (iii) H2–Pd/C–EtOAc; >90%.
the NOE observed in the resonance due to the α-hydrogen, H-4,
when the NMe2 resonance was irradiated. Reaction of the
enaminone 20 with MeMgBr in THF gave the E-isomer 21
(R = Me) in 46% yield accompanied by a by-product with the
spectral characteristics of the aldehyde 22. This presumably
originated by reaction of the Grignard reagent with the oxa-
zinone or its ring opened form analogous to 8, followed by
hydrolysis of the enaminone and decarboxylation of the
resultant β-aldehydo acid in the work up. A similar by-product
was not evident when the enaminone was reacted with PhMgBr,
when an 88% yield of the E-isomer 21 (R = Ph) was obtained.
NOE studies indicated that this was the E-isomer. Hydrogen-
ation of the enones 21 in ethyl acetate using palladium on
carbon as catalyst gave single isomers 5 in nearly quantitative
yields. As the NMR spectra were complicated by rotational
isomerism, the stereochemistry of 5 (R = Me) was proved by a
single crystal X-ray structure determination1,23 which showed
the oxazine ring to be in a boat conformation and the side chain
at C-5 to be cis to the ester at C-4. The stereochemistry of 5
(R = Ph) followed from the single crystal X-ray structure1,23 of
the trans-epimer 28 whose synthesis is reported below. Interest-
ingly, when the cis isomer 5 (R = Me) was treated with LiI in
DMF at 130 ЊC, epimerisation occurred giving 55% of the
trans-epimer 12 together with 26% of the starting material 5
(R = Me).
Scheme 3 Reagents: (i) MCPBA–CuOAc2.
reacted with m-chloroperbenzoic acid and copper(II) acetate.
The expected oxazinone 5 (R = Me) was obtained in only 12%
yield at room temperature together with a 2% yield of the trans
epimer 12. The yield could be improved on heating to reflux but
epimerisation at the β-centre was exacerbated.
Although there are obvious problems in our strategy of
accessing stereospecifically alkylated aspartic acids from 3-
ketoproline derivatives via the corresponding oxazinones, the
possibility of using the oxazinones directly as chiral templates
in the synthesis of these compounds remained attractive.
We therefore examined the preparation of tetrahydro-1,3-
oxazinones by an alternative and more straightforward method
than our Baeyer–Villiger approach. We prepared the aspartate
α-ester urethanes 1121 and 1322 by literature methods and the
urethane α-ester 14 was prepared as a 3:1 mixture with the
corresponding β-ester 15 by reaction of the anhydride 16 with
benzyl alcohol. These compounds were reacted with an excess
of paraformaldehyde in refluxing toluene in the presence of
camphorsulfonic acid and 4 Å molecular sieves to yield the
corresponding oxazinones 9, 17 and 18 in good yields. The
mixture of benzyl esters 14 and 15 was resolved at this stage
by chromatographic separation of the oxazinone 18 from the
oxazolone 19.
We were now in a position to examine the use of our chiral
templates in the preparation of stereospecifically β-substituted
When we reduced the enaminone 20 directly with hydrogen
and palladium on charcoal in ethyl acetate, we obtained a
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and spectral data in accord with the literature.16 The stereo-
chemistry of the centres C-4 and C-5 of the tetrahydro-
1,3-oxazinone had therefore not been affected either during its
formation, or on alkylation or deprotection.
The synthetic utility of the alkylated oxazinones would be
enhanced if protection of the amine and α-ester groups could
be retained in the aspartate products. Use of strong base for
deprotection caused epimerisation, but when the oxazinone
23 was treated with 4:1 acetic acid:water at 45 ЊC tert-butyl
mixture of two compounds in the ratio 1.8:1 which were separ-
able chromatographically. These proved to be the trans and cis
isomers 23 and 24 respectively and so this reaction was not
stereoselective as had been the case for the alkylated products
21. In our work on the pyroglutamic acid series we had shown
that reduction of the enaminone 25 led to a single diastereo-
isomer 2624 (Scheme 5), a reaction subsequently reproduced by
(2S,3R)-N-tert-butoxycarbonyl-3-methylaspartate
31
was
obtained pure in 56% yield. Hydrolysis of the epimer 24 gave
the pure (2S,3S)-isomer 32 in 53% yield under these conditions.
Reaction of 5 (R = Ph) with 4:1 acetic acid:water at 45 ЊC gave
(2S,3S)-3-benzyl-N-tert-butoxycarbonylaspartic acid 6 (R = Ph)
in 51% yield. Regioselective deprotection could also be effected
using one equivalent of aqueous LiOOH in THF, as under
these conditions, the oxazinone 23 gave tert-butyl (2S,3R)-N-
tert-butoxycarbonyl-3-methylaspartate 32 in 40% yield as a
single stereoisomer.
We have developed two new strategies for the synthesis of
free β-substituted aspartic acids and their α-bis-protected
derivatives, using tetrahydro-1,3-oxazin-6-ones as chiral tem-
plates. One, the enaminone–Grignard strategy, is entirely stereo-
selective, giving the cis products. The method is therefore
complementary to the β-lactam strategy13–16 which gives the
trans aspartates. Our second strategy, involving alkylation,
gives mixtures of diastereoisomers with trans products
predominating.
Scheme 5 (i) ref. 24.
Coudert et al.25 using the corresponding methyl ester. We had
confirmed the stereochemistry of our product 26 by NOE24 and
X-ray structure analysis26 whilst Coudert et al.25 used degrad-
ative methods. As we felt that the lack of diastereoselectivity
might be due to the possibility of epimerisation at C-5 by the
dimethylamine liberated in the reaction, we conducted the
hydrogenation in the presence of acetic acid. The rate of the
reaction appeared to be accelerated but there was still a 1:1
mixture of the diastereoisomers 23 and 24.
As our Bredereck–Grignard–hydrogenation sequence had
been so successful in obtaining single stereoisomers, it was of
interest to study stereoselectivity in alkylation of the parent
oxazinone 9. Reaction with excess MeI and LHMDS at Ϫ20 ЊC
gave a 52% yield of a mixture of the diastereoisomeric mono-
methyl derivatives 23 and 24 in a 1.3:1 ratio together with a
28% yield of the dialkylated product 27. The overall stereo-
selectivity in the monoalkylation reaction proved to be trans.
Use of KHMDS at Ϫ72 ЊC increased the trans :cis ratio to
3.9:1. Benzylation, which had been shown to be entirely trans
selective in the pyroglutamic acid series,27 was achieved by react-
ing the oxazinone 9 with excess benzyl bromide and either
LHMDS or NaHMDS. In the oxazinone series, although the
trans isomer was the predominant isomer, it was not exclusively
so. The trans :cis ratio 28:5 (R = Ph) was 4:1 (LHMDS) and
4.4:1 (NaHMDS) and bisbenzylation to yield 29 was observed.
Experimental
Melting points were determined on a Kofler hot stage and
optical rotations (in units of 10Ϫ1 deg cm2 gϪ1) on a Perkin-Elmer
PE 241 polarimeter using a 1 dm path length. IR spectra were
recorded on a Perkin-Elmer 1710 Fourier transform instrument.
1H NMR spectra were determined on Bruker DPX 300 (300
MHz), WM 360 (360 MHz) or AMX 500 (500 MHz) FT
instruments and 13C NMR spectra (1H decoupled) on Bruker
AC-P 250 (62.9 MHz), DPX 300 (75.5 MHz) or AMX-500
(125.8 MHz) instruments with INEPT experiments to help
assign the spectra and residual solvent peaks as internal refer-
ences. NOE experiments were recorded by Dr A. G. Avent on a
Bruker AMX 500 FT instrument. J values are given in Hz.
Mass spectra were recorded on Kratos MF 80RF or Fisons
VG-Autospec instruments by Mr A. M. Greenway and Dr A.
Abdul-Sada (Sussex) and on Kratos MS50 and Fisons VG BIO
Q instruments by Drs D. Dell and D. Cooper at Wellcome
Research Laboratories. 3-NBA refers to 3-nitrobenzyl alcohol.
Accurate mass measurements were obtained from the EPSRC
Central Mass Spectrometry Service, Swansea or from Dr S.
Chotai (Wellcome) and microanalyses were performed by
Medac Ltd and by Miss W. C. Man and Mrs C. Lawless (Well-
come). Column chromatography was performed using Merck
Kieselgel 60 (230–400 mesh - Art 9385), Sorbsil C60 40/60 A
and Fluka Silica Gel 60 (220–440 mesh). Petroleum ether refers
throughout to a fraction of alkanes, bp 60–80 ЊC. Non aqueous
Treatment of the trans-methyloxazinone 23 with 6 M HCl at
room temperature gave (2S,3R)-3-methylaspartic acid hydro-
chloride 30 as a single isomer in 80% yield and with analytical
J. Chem. Soc., Perkin Trans. 1, 2000, 3451–3459
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reactions were conducted in oven-dried glassware under an
atmosphere of nitrogen.
dichloroethane (10 ml) followed by copper(II) acetate mono-
hydrate (70 mg, 0.35 mmol). The mixture was stirred for 40 h at
room temperature, further m-chloroperbenzoic acid (50–60%,
400 mg, 1.1–1.4 mmol) was added and the mixture was stirred
for a further 20 h. The mixture was filtered, the solvent was
removed in vacuo from the filtrate, and the residue was chrom-
atographed on silica gel, eluting with a gradient of petroleum
ether–ethyl acetate (9:1 to 8:2) to give (4S,5S)-3,4-bis(tert-
butoxycarbonyl)-5-ethyltetrahydro-1,3-oxazin-6-one 5 (R = Me)
(87 mg, 12%) together with the epimer (4S,5R)-3,4-bis(tert-
butoxycarbonyl)-5-ethyltetrahydro-1,3-oxazin-6-one 12 (12 mg,
2%) and starting material (140 mg, 21%). The new compounds
had identical spectra to those reported below for samples
prepared by independent methods.
(4S)-3,4-Bis(tert-butoxycarbonyl)tetrahydro-1,3-oxazin-6-one,
9
Method A. From tert-butyl (2S)-N-tert-butoxycarbonyl-4-
oxoproline, 1, by Baeyer–Villiger reaction. m-Chloroperbenzoic
acid (50–60%, 25 g, 72–87 mmol) followed by copper(II) acetate
monohydrate (2 g, 10 mmol) was added to a solution of tert-
butyl (2S)-N-tert-butoxycarbonyl-4-oxoproline 118 (19 g, 66.7
mmol) in 1,2-dichloroethane (110 ml). The reaction was stirred
overnight at room temperature. A further portion of m-chloro-
perbenzoic acid (50–60%, 10 g, 29–35 mmol) was added and the
mixture was stirred for a further 5 h. The white solid was filtered
off and the filtrate was concentrated, extracted with ethyl
acetate and washed with saturated aqueous NaHCO3, water
and brine and dried (Na2SO4). The solvent was removed in
vacuo and the residue was purified by chromatography on silica
gel, eluting with petroleum ether–ethyl acetate (84:16) to give
(4S)-3,4-bis(tert-butoxycarbonyl)tetrahydro-1,3-oxazin-6-one 9
as a white solid which was recrystallised from petroleum ether
(15.9 g, 79%); mp 84–85 ЊC; [α]2D5 Ϫ120.14 (c 1, CHCl3) (Found:
C, 55.9; H, 7.9; N, 4.6. C14H23NO6 requires C, 55.8; H, 7.7; N,
4.6%); m/z (CI-NH3) 319 ([M ϩ NH4]ϩ) and 302 ([M ϩ H]ϩ);
νmax (KBr)/cmϪ1 1770 (lactone), 1743 (ester) and 1710
(urethane); δH (500 MHz, C2HCl3, 2 rotational isomers at
Ϫ30 ЊC) (First rotamer, 71%) 1.44 (18H, m, C(CH3)3), 2.79 (1H,
dd, J5A,4 11.3, J5A,5B 15.7, H-5A), 3.04 (1H, dd, J5B,4 6.9, J5B,5A
15.7, H-5B), 4.40 (1H, dd, J4,5B 6.9, J4,5A 11.3, H-4), 5.19 (1H, d,
J2A,2B 10.5, H-2A) and 5.89 (1H, d, J2B,2A 10.5, H-2B) (Second
rotamer, 29%) 1.44 (18H, m, C(CH3)3), 2.80 (1H, dd, J5A,4 10.5,
J5A,5B 16.00, H-5A), 3.11 (1H, dd, J5B,4 7.6, J5B,5A 16.0, H-5B),
4.53 (1H, dd, J4,5B 7.6, J4,5A 10.5, H-4), 5.23 (1H, d, J2A,2B 10.7,
H-2A) and 5.75 (1H, d, J2B,2A 10.7, H-2B); δC (125.8 MHz,
C2HCl3, 2 rotational isomers at Ϫ30 ЊC) 27.63 and 27.67
(C(CH3)3), 27.84 and 27.87 (C(CH3)3), 31.94 (C-5), 51.42 and
52.21 (C-4) 72.32 and 73.22 (C-2), 82.50 and 82.73 (OC(CH3)3),
82.89 and 83.00 (OC(CH3)3), 152.11 and 152.26 (urethane),
168.92 and 169.08 (ester) and 169.14 (lactone).
(2S)-1-Benzyl and (2S)-4-benzyl N-benzyloxycarbonylaspartate,
14 and 15
(2S)-N-Benzyloxycarbonylaspartic acid (24.4 g, 91.1 mmol),
dimethylaminopyridine (1.1 g, 9.0 mmol) and dry benzyl
alcohol (14.2 ml, 137 mmol) were dissolved in dry dichloro-
methane (460 ml) and cooled to 0 ЊC under nitrogen. 1-(3-
Dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride
(EDCI) (17.5 g, 91.3 mmol) was added with stirring. Stirring
was continued at 0 ЊC for 2 h and at room temperature for 18 h.
The mixture was washed with 0.5 M aqueous hydrochloride
acid and water and dried (MgSO4). The solvent was removed
in vacuo to give an oil, which was purified by column chrom-
atography on silica gel using a gradient of dichloromethane–
methanol (0, 1 and 2%) as eluent to afford a 1:3 mixture of
(2S)-4-benzyl and (2S)-1-benzyl N-benzyloxycarbonylasp-
artate 14 and 15 as a white solid (25.5 g, 78%); m/z [ϩve FAB
(3-NBA)] 358 ([M ϩ H]ϩ) and 380 ([M ϩ Na]ϩ); δH (300 MHz,
C2HCl3) 9.48 (1H, br s, CO2H), 7.31 (5H, s, ArH), 7.29 (5H, s,
ArH), 5.76 (1H, d, JNH,2 8.3, NH), 5.15 (30% of 4H, s, CH2Ph),
5.09 (70% of 4H, s, CH2Ph), 4.67–4.64 (1H, m, H-2), 3.09 (1H,
dd, J3A,3B 17.7, J3A,2 4.1, H-3A) and 2.89 (1H, dd, J3B,3A 17.7,
J3B,2 4.3, H-3B); δC (75.5 MHz, C2HCl3) 175.9 (acid), 170.5
(ester), 156.1 (urethane), 135.9, 135.0, 128.6, 128.5, 128.4,
128.3, 128.2 and 128.1 (Ar), 67.7 and 67.3 (CH2Ph), 50.3 (C-2)
and 36.4 (C-3).
Stereochemistry of 9 by hydrolysis to (2S)-aspartic acid, 10.
Hydrochloric acid (6 M, 2 ml) was added to a solution of (4S)-
3,4-bis(tert-butoxycarbonyl)tetrahydro-1,3-oxazin-6-one 9 (50
mg, 0.17 mmol) in tetrahydrofuran (2 ml). After stirring over-
night at room temperature, the solvent was removed in vacuo to
(4S)-3,4-Bis(benzyloxycarbonyl)-2,3,4,5-tetrahydro-6H-1,3-
oxazin-6-one, 18
The mixture 4-benzyl and 1-benzyl (2S)-N-benzyloxycarb-
onylaspartate 14 and 15 (1 g, 2.8 mmol) was dissolved in dry
toluene (20 ml) under nitrogen. Paraformaldehyde (392 mg,
13.1 mmol), camphorsulfonic acid (130 mg, 0.56 mmol) and
4 Å activated molecular sieves (1.7 g) were successively added.
The mixture was stirred for 4 h at 90 ЊC and filtered through
Celite at room temperature. The organic layer was washed
with water and dried (MgSO4). The solvent was removed in
vacuo to give an oil, which was purified by column chrom-
atography on silica gel using a gradient of petroleum ether–
ethyl acetate (10, 15, 20%) as eluent to afford (4S)-benzyl 2-(3-
benzyloxycarbonyl-5-oxo-1,3-oxazolidin-4-yl)acetate 19 as an
oil (196 mg, 19%) which was discarded and (4S)-3,4-
bis(benzyloxycarbonyl)-2,3,4,5-tetrahydro-6H-1,3-oxazin-6-
one 18 as a colourless oil which crystallised on long standing
(633 mg, 62%); [α]2D5 Ϫ77.4 (c 1, CHCl3) (Found: C, 64.9; H, 5.2;
N, 3.75. C20H19NO6 requires C, 65.0; H, 5.2; N, 3.8%); m/z
[ϩve FAB (3-NBA)] 370 ([M ϩ H]ϩ) and 392 ([M ϩ Na]ϩ);
νmax (film)/cmϪ1 1752 (lactone/ester) and 1719 (urethane);
δH (500 MHz, C2HCl3, 2 rotamers at Ϫ15 ЊC) (First rotamer
53%) 7.48–7.22 (10H, m, ArH), 5.94 (1H, d, J2A,2B 10.5, H-2A),
5.28–5.08 (5H, m, H-2B and 2 × CH2Ph), 4.68 (1H, dd, J4,5A
10.7, J4,5B 7.2, H-4), 3.07 (1H, dd, J5A,5B 16.1, J5S,4 7.2, H-5A),
2.85 (1H, dd, J5B,5A 16.1, J5B,4 10.7, H-5B) (Second rotamer 47%)
7.48–7.22 (10H, m, ArH), 5.83 (1H, d, J2A,2B 10.9, H-2A), 5.28–
5.08 (5H, m, H-2B and 2 × CH2Ph), 4.82 (1H, dd, J4,5B 10.8,
1
give a brown solid (33 mg, quantitative) with an identical H
NMR spectrum to that of commercial L-aspartic acid hydro-
chloride; [α]2D5 ϩ13.1 (c 0.7, H2O), (commercial L-aspartic acid
hydrochloride. [α]2D5 ϩ14.2 (c 1, H2O)).
Method B. Reaction of 1-tert-butyl (2S)-N-butoxycarbonyl-
aspartate, 11, with formaldehyde. 1-tert-Butyl (2S)-N-butoxy-
carbonylaspartate 1121 (11.3 g, 39.1 mmol) was dissolved in
dry toluene (220 ml) under nitrogen. Paraformaldehyde (5.47 g,
182 mmol), camphorsulfonic acid (1.8 g, 7.82 mmol) and 4 Å
activated molecular sieves (24 g) were successively added. The
mixture was stirred for 3 h at 90 ЊC and filtered through Celite
at room temperature. The organic layer was washed with water
and dried (MgSO4). The solvent was removed in vacuo to give
an oil which was purified by column chromatography on silica
gel using a gradient of petroleum ether–ethyl acetate (10, 15,
20%) as eluent to afford (4S)-3,4-bis(tert-butoxycarbonyl)-
2,3,4,5-tetrahydro-6H-1,3-oxazin-6-one 9 as a white crystalline
solid (7.1 g, 60%); mp 72–73 ЊC, [α]2D5 Ϫ111.1 (c 1, CHCl3) with
identical spectra to the sample prepared by method A.
Baeyer–Villiger reaction on compound 4 (R ؍ Me). m-Chloro-
perbenzoic acid (50–60%, 800 mg, 2.3–2.8 mmol) was added
to a solution of crude tert-butyl (2S,3S)-N-tert-butoxycarbonyl-
3-ethyl-4-oxoproline 4 (R = Me)18 (670 mg 2.2 mmol) in 1,2-
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J4,5A 7.6, H-4), 3.15 (1H, dd, J5A,5B 16.1, J5S,4 7.6, H-5A) and
2.84 (1H, dd, J5B,5A 16.1, J5B,4 10.8, H-5B); δC (125.8 MHz,
C2HCl3, 2 rotational isomers at Ϫ34 ЊC) 169.7 and 169.5 (ester/
lactone), 168.0 and 167.9 (ester/lactone), 153.3 and 153.2
(urethane), 134.7, 134.5, 134.3, 134.2, 128.8, 128.7, 128.6, 128.5
and 128.0 (Ar), 72.7 and 72.6 (C-2), 68.6, 68.3 and 67.7
(CH2Ph), 51.6 and 51.2 (C-4), and 31.6 and 31.5 (C-5).
in the H-4 singlets and of 13.5% in the ethylenic singlets, whilst
irradiation of the ethylenic singlets resulted in a NOE of 1.3%
in the N(CH3)2 singlet; δC (125.8 MHz, C2HCl3, 2 rotational
isomers at Ϫ34 ЊC) 27.56 and 27.89 (C(CH3)3), 52.49 and 54.01
(N(CH3)2), 71.30 and 72.09 (C-2), 81.77 and 82.02 (OC(CH3)3),
82.32 and 82.47 (OC(CH3)3), 84.61 and 84.93 (C-5), 151.58 and
152.27 (HC᎐), 152.68 (urethane), 168.20 and 169.42 (ester), and
᎐
169.62 and 169.85 (lactone).
(4S)-4-Benzyloxycarbonyl-3-tert-butoxycarbonyl-2,3,4,5-tetra-
hydro-6H-1,3-oxazin-6-one, 17
(4S)-3,4-Bis(tert-butoxycarbonyl)-5-ethylidenetetrahydro-1,3-
oxazin-6-one, 21 (R = Me)
1-Benzyl (2S)-N-tert-butoxycarbonylaspartate 1322 (6.3 g,
19.5 mmol) was dissolved in dry toluene (110 ml) under nitro-
gen. Paraformaldehyde (2.8 g, 93.3 mmol), camphorsulfonic
acid (1 g, 4 mmol) and 4 Å activated molecular sieves (12 mg)
were successively added. The mixture was stirred for 4 h at
90 ЊC and filtered through Celite at room temperature. The
organic layer was washed with water and dried (MgSO4). The
solvent was removed in vacuo to give an oil which was purified
by column chromatography on silica gel using a gradient of
petroleum ether–ethyl acetate (10, 15, 20%) as eluent to afford
(4S)-4-benzyloxycarbonyl-3-tert-butoxycarbonyl-2,3,4,5-
tetrahydro-6H-1,3-oxazin-6-one 17 as a colourless oil which
crystallised on long standing (3.9 g, 60%); mp 49–50 ЊC; [α]D25
Ϫ93.0 (c 1, CHCl3) (Found: C, 60.9; H, 6.3; N, 4.1. C17H21NO6
requires C, 60.9; H, 6.3; N, 4.2%); m/z [ϩve FAB (3-NBA)]
336 ([M ϩ H]ϩ) and 358 ([M ϩ Na]ϩ); νmax (film)/cmϪ1 1773
(lactone/ester) and 1719 (urethane); δH (500 MHz, C2HCl3, 2
rotational isomers at Ϫ15 ЊC) (First rotamer 55%) 7.41–7.32
(5H, m, ArH), 5.94 (1H, d, J2A,2B 10.5, H-2A), 5.26–5.10 (3H,
m, H-2B and CH2Ph), 4.51 (1H, dd, J4,5B 11.0, J4,5A 7.1, H-4),
3.05 (1H, dd, J5A,5B 16.0, J5A,4 7.1, H-5A), 2.81 (1H, dd,
J5B,5A 16.0, J5B,4 11.0, H-5B) and 1.34 (9H, s, OC(CH3)3)
(Second rotamer 45%) 7.41–7.32 (5H, m, ArH), 5.81 (1H, d,
J2A,2B 10.8, H-2A), 5.26–5.10 (3H, m, H-2B and CH2Ph), 4.61
(1H, dd, J4,5B 10.7, J4,5A 7.5, H-4), 3.12 (1H, dd, J5A,5B 16.2,
J5A,4 7.5, H-5A), 2.83 (1H, dd, J5B,5A 16.2, J5B,4 10.7, H-5B) and
1.47 (9H, s, OC(CH3)3); δC (125.8 MHz, C2HCl3, 2 rotational
isomers at Ϫ15 ЊC) 168.8, 168.4 and 168.2 (ester/lactone), 153.4
and 153.2 (urethane), 134.7, 134.6, 128.6, 128.5, 128.4, 128.3
and 128.0 (Ar), 83.3 and 83.1 (OC(CH3)3), 72.8 and 72.7 (C-2),
68.5 and 68.3 (CH2Ph), 52.1 and 51.8 (C-4), 31.9 (C-5) and 27.7
and 27.5 (OC(CH3)3).
A solution of methylmagnesium bromide (3 M in tetrahydro-
furan, 34 ml, 102 mmol) was added dropwise to a solution of
(4S)-3,4-bis(tert-butoxycarbonyl)-5-(dimethylaminomethylene)-
tetrahydro-1,3-oxazin-6-one 20 (12 g, 33.7 mmol) in dry
ether (400 ml) cooled to Ϫ78 ЊC, under nitrogen. The mixture
was stirred for 15 min at this temperature and for 5 h at 0 ЊC.
The reaction was quenched by addition of saturated aqueous
NH4Cl and the ether layer was washed with water, brine and
dried (Na2SO4). The solvent was removed in vacuo. Chrom-
atography on silica gel, eluting with petroleum ether–ethyl
acetate (85:15) afforded (4S)-3,4-bis(tert-butoxycarbonyl)-
5-ethylidenetetrahydro-1,3-oxazin-6-one 21 (R = Me) as a colour-
less oil (5.33 g, 48%); [α]2D0 ϩ26.11 (c 1, CHCl3) (m/z (EI)
(M ϩ HϪBoc) 227.11428. C11H17NO4 requires 227.11569); m/z
(FAB) 328 ([M ϩ H]ϩ); νmax(film)/cmϪ1 1741 (ester/lactone) and
1713 (urethane); δH (500 MHz, C2HCl3, 2 rotational isomers at
Ϫ34 ЊC) (First rotamer, 69%) 1.42 (18H, s, C(CH3)3), 1.97 (3H,
d, J 7.4, CH3), 5.59 (1H, s, H-4), and 5.42 (1H, d, J2A,2B 10.5,
H-2A), 5.62 (1H, d, J2B,2A 10.5, H-2B) and 7.39 (1H, q, J 7.4,
HC᎐) (Second rotamer, 31%) 1.45 (18H, s, C(CH ) ), 1.97 (3H,
᎐
3
3
d, J 7.4, CH3), 5.26 (1H, s, H-4), 5.37 (1H, d, J2A,2B 10.1, H-2A),
5.55 (1H, d, J2B,2A 10.1, H-2B) and 7.23 (1H, q, J 7.4, HC᎐); the
᎐
geometry of the ethylidene group was assigned on the basis
of NOE difference spectra at 273 K, irradiation of the CH3
doublet resulting in a NOE of 10.5% in the H-4 singlets and
of 9.3% in the ethylenic multiplets, while irradiation of the
ethylenic multiplets gave a NOE of 2.5% in the CH3 doublet;
δC (125.8 MHz, C2HCl3, 2 rotational isomers at Ϫ34 ЊC) 15.18
and 15.82 (CH3), 27.62 and 27.66 (C(CH3)3), 27.88 (C(CH3)3),
53.81 and 55.81 (C-4), 71.99 and 73.08 (C-2), 82.61 and 82.77
(OC(CH3)3), 83.16 and 83.47 (OC(CH3)3), 122.05 and 122.48
(C᎐), 145.46 and 146.98 (HC᎐), 152.05 and 152.26 (urethane),
᎐
᎐
(4S)-3,4-Bis(tert-butoxycarbonyl)-5-(dimethylaminomethyl-
ene)tetrahydro-1,3-oxazin-6-one, 20
163.91 and 165.01 (ester), and 167.23 and 167.27 (lactone).
A further product, tert-butyl N-tert-butoxycarbonyl-N-ethyl-
aspart-4-al 22, was a colourless oil (1.76 g 17%); [α]2D0 Ϫ2.20 (c 1,
CHCl3) (m/z (EI) 200.12783 ([MϪBoc]ϩ). C10H18NO3 requires
200.1286); m/z (FAB) 302 ([M ϩ H]ϩ); νmax (film)/cmϪ1 1703
(urethane/aldehyde) and 1725 (ester); δH (360 MHz, C2HCl3, 2
rotational isomers) (First rotamer, 56%) 1.15 (3H, t, J 7, CH3),
1.45 (18H, s, C(CH3)3), 2.88 (1H, dd, J3A,3B 17.9, J3A,2 7, H-3A),
3.12 (1H, 2qd, JAB 14, J 7, CHA-CH3), 3.37 (1H, dd, J3B,2 7.2,
J3B,3A 17.9, H-3B), 3.45 (1H, 2qd, JAB 14, J 7, CHB-CH3), 4.31–
4.35 (1H, m, H-2), and 9.80 (1H, s, CHO) (Second rotamer,
44%) 1.15 (3H, t, J 7, CH3), 1.45 (18H, s, C(CH3)3), 2.74 (1H,
dd, J3A,3B 17.9, J3A,2 5.4, H-3A), 3.20 (1H, qd, JAB 14, J 7, CHA-
CH3), 3.53 (1H, qd, JBA 14, J 7, CHB-CH3), 4.31–4.35 (1H, m,
H-2) and 9.80 (1H, s, CHO); δC (125.8 MHz, C2HCl3,
2 rotational isomers) 13.50 and 13.85 (CH3), 27.54 and 27.71
(C(CH3)3), 28.14 (C(CH3)3), 44.19 and 45.47 (CH2-CH3), 44.40
(C-3), 79.88 and 80.65 (OC(CH3)3), 81.55 and 81.9 (OC(CH3)3),
154.02 and 154.55 (urethane), 169.62 and 169.92 (ester), and
199.89 and 200.74 (CHO).
tert-Butoxybis(dimethylamino)methane (Bredereck’s reagent)
(33 ml, 160 mmol) was added to a solution of (4S)-3,4-bis(tert-
butoxycarbonyl)tetrahydro-1,3-oxazin-6-one 9 (15.8 g, 52.5
mmol) in dry dimethoxyethane (350 ml). The solution was
heated at reflux for 1 h and the solvent was removed in vacuo.
The residue was chromatographed on silica gel, eluting with
petroleum ether–ethyl acetate (1:2). The product was recrystal-
lised from petroleum ether to give a white solid (12 g). Further
chromatography of the mother liquors afforded further
material (1.1 g) (total yield 13.1 g, 70%); mp 101–102 ЊC;
[α]2D5 ϩ79.41 (c 1, CHCl3) (Found C, 56.9; H, 7.9; N, 7.7.
C17H28N2O6requires C, 57.3; H, 7.9; N, 7.9%) (m/z (EI)
356.19379. C17H28N2O6requires 356.1946); λmax MeOH/nm 296;
νmax (KBr)/cmϪ1 1730 (ester), 1710 (urethane) and 1688 (lac-
tone); δH (500 MHz, C2HCl3, 2 rotational isomers at Ϫ34 ЊC)
(First rotamer, 70%) 7.69 (1H, s, HC᎐), 5.69 (1H, s, H-4), 5.49
᎐
(1H, d, J2A,2B 10.2, H-2A), 5.21 (1H, d, J2B,2A 10.2, H-2B), 3.16
(6H, s, N(CH3)2), 1.45 (9H, s, OC(CH3)3) and 1.42 (9H, s,
OC(CH ) ) (Second rotamer, 30%) 7.57 (1H, s, HC᎐), 5.42 (1H,
᎐
3
3
(4S,5S)-3,4-Bis(tert-butoxycarbonyl)-5-ethyltetrahydro-1,3-
oxazin-6-one, 5 (R = Me)
s, H-4), 5.40 (1H, d, J2A,2B 9.7, H-2A), 5.28 (1H, d, J2B,2A 9.7,
H-2B), 3.18 (6H, s, N(CH3)2), 1.44 (9H, s, OC(CH3)3) and 1.40
(9H, s, OC(CH3)3); the geometry of the enaminone was
assigned on the basis of NOE difference spectra at 25 ЊC as
irradiation of the N(CH3)2 singlet resulted in a NOE of 16.6%
(4S)-3,4-Bis(tert-butoxycarbonyl)-5-ethylidenetetrahydro-1,3-
oxazin-6-one 21 (R = Me) (5.33 g, 16.7 mmol) was hydro-
genated in ethyl acetate (100 ml) for 2 h in the presence of 10%
J. Chem. Soc., Perkin Trans. 1, 2000, 3451–3459
3455

View Article Online
palladium on activated carbon (1.4 g). After a filtration on
Celite, the solvent was removed from the filtrate in vacuo and
the residue was chromatographed on silica gel, eluting with
petroleum ether–ethyl acetate (8:2) to give (4S,5S)-3,4-
temperature and filtered through Celite. The solvent was
removed in vacuo to give an oil, which was purified by column
chromatography on silica gel using a gradient of petroleum
ether–ethyl acetate (5, 10, 15%) as eluent to afford (4S,5S)-3,4-
bis(tert-butoxycarbonyl)-5-benzyl-2,3,4,5-tetrahydro-6H-1,3-
oxazin-6-one 5 (R = Ph) (797 mg, 90%) as a white crystalline
solid; mp 100–101 ЊC; [α]D25 Ϫ15.8 (c 1, CHCl3) (Found: C, 64.6;
H, 7.5; N, 3.5. C21H29NO6 requires C, 64.4; H, 7.4; N, 3.6%);
m/z [ϩve FAB (3-NBA)] 392 ([M ϩ H]ϩ) and 414 ([M ϩ Na]ϩ);
νmax (film)/cmϪ1 1772 (lactone), 1740 (ester) and 1713
(urethane); δH (500 MHz, C2HCl3, 2 rotamers at Ϫ25 ЊC) (First
rotamer, 53%) 7.34–7.25 (5H, m, ArH), 5.95 (1H, d, J2A,2B 10.3,
H-2A), 5.13 (1H, d, J2B,2A 10.3, H-2B), 4.27 (1H, d, J4,5 6.7,
H-4), 3.26 (1H, dd, J7A,7B 14.4, J7A,5 5.0, H-7A), 3.18–3.14 (1H,
m, H-5), 2.64 (1H, dd, J7B,7A 14.4, J7B,5 8.7, H-7B), 1.52 (9H, s,
OC(CH3)3) and 1.43 (9H, s, OC(CH3)3) (Second rotamer, 47%)
7.34–7.25 (5H, m, ArH), 5.79 (1H, d, J2A,2B 10.3, H-2A), 5.07
(1H, d, J2B,2A 10.3, H-2B), 4.32 (1H, d, J4,5 6.8, H-4), 3.26 (1H,
dd, J7A,7B 14.4, J7A,5 5.0, H-7A), 3.18–3.14 (1H, m, H-5), 2.68
(1H, dd, J7B,7A 14.4, J7B,5 8.9, H-7B), 1.50 (9H, s, OC(CH3)3) and
1.45 (9H, s, OC(CH3)3); δC (125.8 MHz, C2HCl3, 2 rotamers at
Ϫ25 ЊC) 170.8 and 170.7 (lactone), 167.9 and 167.5 (ester),
152.2 and 152.1 (urethane), 137.3, 129.3, 129.2, 128.6, 128.5
and 126.8 (Ar), 83.3, 83.0, 82.7 and 82.5 (OC(CH3)3), 72.0, 71.4
(C-2), 57.6 and 57.2 (C-4), 43.2 (C-5), 31.1 and 31.0 (CH2Ph),
and 27.9, 27.8, 27.6 and 27.5 (OC(CH3)3).
bis(tert-butoxycarbonyl)-5-ethyltetrahydro-1,3-oxazin-6-one
5
(R = Me) as a white solid (5.06 g, 95%); mp 67–68 ЊC;
[α]2D0 ϩ107.77 (c 1, CHCl3) (Found: C, 57.9; H, 8.2; N, 4.2.
C16H27NO6 requires C, 58.3; H, 8.3; N, 4.3%) (m/z (EI)
229.13051 ([MϪBoc]ϩ). C11H19NO4 requires 229.1313); νmax
(KBr)/cmϪ1 1772 (lactone), 1741 (ester) and 1713 (urethane);
δH (360 MHz, C2HCl3, 2 rotational isomers) (First rotamer,
56%) 1.07 (3H, t, J 7.5, CH3), 1.43 (18H, m, C(CH3)3), 1.6–1.9
(2H, m, CH2-CH3), 2.78 (1H, m, H-5), 4.36 (1H, d, J4,5 7.0,
H-4), 5.13 and 5.88 (2H, 2 × d, J2A,2B 10.1, H-2) (Second
rotamer) 1.07 (3H, t, J 7.5, CH3), 1.43 (18H, m, C(CH3)3), 4.39
(1H, d, J4,5 7.15, H-4), 5.17 and 5.73 (2H, 2 × d, J2A,2B 10.1,
H-2); δC (62.9 MHz, C2HCl3, 2 rotational isomers) 11.80 (CH3-
CH2), 19.47 (CH2-CH3), 27.6, 27.78 and 28.08 (C(CH3)3), 42.39
(C-5), 57.92 and 58.22 (C-4), 71.52 and 72.03 (C-2), 82.53 and
82.94 (C(CH3)3), 152.42 (urethane), 167.53 (ester) and 170.55
(lactone). The X-ray crystal structure data for this compound
have been lodged at the CCDC,23 with reference code
KAGJUX.
(4S,5S)-3,4-Bis(tert-butoxycarbonyl)-5-benzylidene-2,3,4,5-
tetrahydro-6H-1,3-oxazin-6-one, 21 (R ؍ Ph)
(4S)-3,4-Bis(tert-butoxycarbonyl)-5-(dimethylaminomethyl-
ene)-2,3,4,5-tetrahydro-6H-1,3-oxazin-6-one 20 (1.0 g, 2.81
mmol) was dissolved in diethyl ether (30 ml) and cooled to
Ϫ30 ЊC under nitrogen. Phenylmagnesium bromide (3.0 M in
diethyl ether, 2.81 ml, 8.43 mmol) was added dropwise with
stirring. The mixture was allowed to warm to room temperature
over a period of 1.5 h. After stirring at 22 ЊC for 45 min,
the mixture was quenched with excess saturated aqueous
ammonium chloride at room temperature and extracted with
ethyl acetate. The combined organic layers were washed with
water and dried (MgSO4). The solvent was removed in vacuo to
give an oil, which was purified by column chromatography on
silica gel using a gradient of petroleum ether–ethyl acetate (5,
10%) as eluent to afford (4S,5S)-3,4-bis(tert-butoxycarbonyl)-
(4S,5R)-3,4-Bis(tert-butoxycarbonyl)-5-ethyltetrahydro-1,3-
oxazin-6-one, 12
Lithium iodide (320 mg, 2.1 mmol) was added to a solution
of (4S,5S)-3,4-bis(tert-butoxycarbonyl)-5-ethyltetrahydro-1,3-
oxazin-6-one 5 (R = Me) (80 mg, 0.24 mmol) in dimethylform-
amide (8 ml) and the mixture was stirred at 130 ЊC until no
further reaction was observed by TLC (6 h). The solution was
concentrated and extracted with ethyl acetate. The extracts were
washed with water and dried (Na2SO4). The solvents were
removed in vacuo and the residue was chromatographed on
silica gel. Elution with petroleum ether–ethyl acetate (85:15)
afforded
(4S,5R)-3,4-bis(tert-butoxycarbonyl)-5-ethyltetra-
hydro-1,3-oxazin-6-one 12 as a colourless oil (44 mg, 55%); [α]D20
Ϫ113.40 (c 0.5, CHCl3); m/z (FAB-MS) 330 ([M ϩ H]ϩ); νmax
(film)/cmϪ1 1770 (lactone), 1745 (ester) and 1720 (urethane); δH
(500 MHz, C2HCl3, 2 rotational isomers) (First rotamer, 75%)
1.05 (3H, t, J 7.3, CH3), 1.44 (9H, s, C(CH3)3), 1.48 (9H, 2s,
C(CH3)3), 1.68–1.85 (2H, m, CH2-CH3), 2.77–2.85 (1H, m,
H-5), 4.01 (1H, d, J4,5 11.6, H-4), 5.18 (1H, d, J2A,2B 10.4, H-2A)
and 5.91 (1H, d, J2B,2A 10.4, H-2B) (Second rotamer, 25%) 1.05
(3H, t, J 7.3, CH3), 1.44 (9H, s, C(CH3)3), 1.47 (9H, 2s,
C(CH3)3), 1.68–1.85 (2H, m, CH2CH3), 2.77–2.85 (1H, m, H-5),
4.17 (1H, d, J4,5 11.6, H-4), 5.24 (1H, d, J2A,2B 10.6, H-2A) and
5.75 (1H, d, J2B,2A 10.6, H-2B); δC (125.8 MHz, C2HCl3, 2
rotational isomers) 10.96 and 11.38 (CH3), 19.95 and 20.13
(CH2-CH3), 27.66 and 27.71 (C(CH3)3), 27.85 and 27.91
(C(CH3)3), 42.72 and 42.85 (C-5), 55.73 and 56.80 (C-4), 71.52
and 72.49 (C-2), 82.49 and 82.56 (OC(CH3)3), 82.82 and 82.95
(OC(CH3)3), 151.96 and 152.10 (urethane), 170.09 and 170.23
(ester) and 171.05 and 171.22 (lactone). Subsequent elution
with petroleum ether–ethyl acetate (8:2) afforded starting
material (21 mg 26%).
5-benzylidene-2,3,4,5-tetrahydro-6H-1,3-oxazin-6-one
21
(R = Ph) as an oil (0.96 g, 88%); [α]2D5 ϩ77.7 (c 1, CHCl3) (m/z
(FAB) (3-NBA) Found: 390.1882. C21H28NO6 ([M ϩ H]ϩ)
requires 390.1917); m/z [ϩve FAB (3-NBA)] 390 ([M ϩ H]ϩ)
and 412 ([M ϩ Na]ϩ); νmax (film)/cmϪ1 1739 (br, ester/lactone)
and 1719 (urethane); δH (500 MHz, C2HCl3, 2 rotamers at
Ϫ20 ЊC) (First rotamer, 59%) 7.87 (1H, s, HC᎐), 7.65–7.63 (2H,
᎐
m, ArH), 7.46–7.45 (1H, m, ArH), 7.41–7.40 (2H, m, ArH),
5.70 (1H, s, H-4), 5.55 (1H, d, J2A,2B 10.3, H-2A), 5.28 (1H, d,
J2B,2A 10.3, H-2B), 1.46 (9H, s, OC(CH3)3) and 1.36 (9H, s,
OC(CH ) ) (Second rotamer, 41%) 7.78 (1H, s, HC᎐), 7.65–7.63
᎐
3
3
(2H, m, ArH), 7.46–7.45 (1H, m, ArH), 7.41–7.40 (2H, m,
ArH), 5.67 (1H, d, J2A,2B 10.1, H-2A), 5.51 (1H, s, H-4), 5.18
(1H, d, J2B,2A 10.1, H-2B), 1.42 (9H, s, OC(CH3)3) and 1.40 (9H,
s, OC(CH3)3); δC (125.8 MHz, C2HCl3, 2 rotamers at Ϫ15 ЊC)
167.2 (ester), 152.0 (urethane), 144.8 and 143.8 (HC᎐), 132.7,
᎐
132.6, 130.4, 130.3, 130.2, 129.9, 128.8 and 128.7 (Ar), 122.1
and 121.3 (C-5), 83.7, 83.5, 82.9 and 82.7 (OC(CH3)3), 72.7 and
71.9 (C-2), 56.8 and 55.7 (C-4) and 27.9, 27.8, 27.6 and 27.4
(OC(CH3)3).
(4S,5R)- and (4S,5S)-3,4-Bis(tert-butoxycarbonyl)-5-methyl-
2,3,4,5-tetrahydro-6H-1,3-oxazin-6-one, 23 and 24
(4S,5S)-3,4-Bis(tert-butoxycarbonyl)-5-benzyl-2,3,4,5-tetra-
hydro-6H-1,3-oxazin-6-one, 5 (R ؍ Ph)
Method A. By catalytic hydrogenation of the enaminone 20 in
EtOAc. (4S)-3,4-Bis(tert-butoxycarbonyl)-5-(dimethylamino-
methylene)-2,3,4,5-tetrahydro-6H-1,3-oxazin-6-one 20 (322 mg,
0.9 mmol) was dissolved in ethyl acetate (8 ml) and 10% pal-
ladium on carbon (160 mg, 50% w/w) was added. The reaction
was stirred under an atmosphere of hydrogen for 3 days at room
temperature and filtered through Celite. The solvent was
Method A. By catalytic hydrogenation of 21 (R ؍ Ph).
(4S,5S)-3,4-Bis(tert-butoxycarbonyl)-5-benzylidene-2,3,4,5-
tetrahydro-6H-1,3-oxazin-6-one 21 (R = Ph) (880 mg, 2.26
mmol) was dissolved in ethyl acetate (25 ml) and 10% palladium
on carbon (220 mg, 25% w/w) was added. The reaction was
stirred under an atmosphere of hydrogen for 3 days at room
3456
J. Chem. Soc., Perkin Trans. 1, 2000, 3451–3459

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removed in vacuo to give an oil, which was purified by column
chromatography on silica gel using a gradient of petroleum
ether–ethyl acetate (15, 20%) as eluent to afford (4S,5R)-3,4-
bis(tert-butoxycarbonyl)-5-methyl-2,3,4,5-tetrahydro-6H-1,3-
oxazin-6-one 23 (161 mg, 57%) as a white crystalline solid; mp
47–48 ЊC; [α]2D5 Ϫ121.4 (c 1, CHCl3) (Found: C, 57.1; H, 8.1; N,
4.4. C15H25NO6 requires C, 57.1; H, 8.0; N, 4.4%); m/z [ϩve
FAB (3-NBA)] 316 ([M ϩ H]ϩ) and 338 ([M ϩ Na]ϩ); νmax
(film)/cmϪ1 1763 (lactone), 1735 (ester) and 1719 (urethane);
δH [500 MHz, (C2H3)2SO, 42 ЊC] 5.67 (1H, d, J2A,2B 9, H-2A),
5.25 (1H, d, J2B,2A 9, H-2B), 3.95 (1H, d, J4,5 11.3, H-4), 3.24–
2.99 (1H, m, H-5), 1.45 (9H, s, OC(CH3)3), 1.41 (9H, s,
OC(CH3)3) and 1.19 (1H, d, J 6.6, Me); δC [125.8 MHz,
(C2H3)2SO, 5 ЊC] 171.5 (lactone), 169.7 (ester), 151.9
(urethane), 81.7 and 81.2 (OC(CH3)3), 71.2 (C-2), 58.5 (C-4),
36.1 (C-5), 27.7 and 27.5 (OC(CH3)3) and 12.5 (CH3) and
(4S,5S)-3,4-bis(tert-butoxycarbonyl)-5-methyl-2,3,4,5-tetra-
hydro-6H-1,3-oxazin-6-one 24 (87 mg, 31%) as a white crystal-
line solid; mp 114–115 ЊC; [α]2D5 ϩ84.2 (c 1, CHCl3) (Found: C,
57.2; H, 8.0; N, 4.4. C15H25NO6 requires C, 57.1; H, 8.0; N,
4.4%); m/z [ϩve FAB (3-NBA)] 316 ([M ϩ H]ϩ) and 338
([M ϩ Na]ϩ); νmax (KBr)/cmϪ1 1763 (lactone), 1735 (ester) and
1719 (urethane); δH [500 MHz, (C2H3)2SO, 2 rotamers at 25 ЊC]
(First rotamer, 57%) 5.67 (1H, d, J2A,2B 9.9, H-2A), 5.22 (1H, d,
J2B,2A 9.9, H-2B), 4.27 (1H, d, J4,5 7.0, H-4), 3.51–3.46 (1H, m,
H-5), 1.38 (18H, s, OC(CH3)3) and 1.02 (3H, d, J 6.4, CH3)
(Second rotamer 43%) 5.60 (1H, d, J2A,2B 10.2, H-2A), 5.28 (1H,
d, J2B,2A 10.2, H-2B), 4.18 (1H, d, J4,5 7.3, H-4), 3.51–3.46 (1H,
m, H-5), 1.41 (9H, s, OC(CH3)3), 1.33 (9H, s, OC(CH3)3) and
1.02 (3H, d, J 6.4, CH3); δC [125.8 MHz, (C2H3)2SO, 2 rotamers
at 25 ЊC] (First rotamer, 57%) 171.8 and 171.7 (lactone), 168.4
and 167.9 (ester), 151.9 (urethane), 81.9, 81.3, 81.2 and 81.1
(OC(CH3)3), 71.7 and 71.2 (C-2), 59.1 and 59.0 (C-4), 34.7 and
34.4 (C-5), 27.8, 27.7, 27.5 and 27.4 (OC(CH3)3), 10.9 and 10.8
(CH3).
29%) as a colourless oil; [α]2D5 Ϫ112.8 (c 1, CHCl3) with identical
spectra to those of the sample prepared above; and (4S,5S)-
3,4-bis(tert-butoxycarbonyl)-5-methyl-2,3,4,5-tetrahydro-6H-
1,3-oxazin-6-one 24 (24 mg, 23%) as a white crystalline solid,
mp 98–99 ЊC; [α]2D5 ϩ67.8 (c 1, CHCl3) with identical spectra to
those of the sample prepared above. The column also yielded
starting material (5 mg, 5%) and the dialkylated product (4S)-
3,4-bis(tert-butoxycarbonyl)-5,5-dimethyl-2,3,4,5-tetrahydro-
6H-1,3-oxazin-6-one 27 (30 mg, 28%); mp 91–92 ЊC; [α]2D5 Ϫ65.8
(c 1, CHCl3) (Found: C, 58.3; H, 8.2; N, 4.2. C16H27NO6
requires C, 58.3; H, 8.3; N, 4.3%); m/z [ϩve FAB (3-NBA)] 330
([M ϩ H]ϩ) and 352 ([M ϩ Na]ϩ); δH (300 MHz, C2HCl3, 2
rotamers at 27 ЊC) (First rotamer, 57%) 5.88 (1H, d, J2A,2B 10.1,
H-2A), 5.40 (1H, d, J2B,2A 10.2, H-2B), 4.19 (1H, s, H-4), 1.47
(9H, s, OC(CH3)3), 1.46 (9H, s, OC(CH3)3), 1.43 (3H, s, CH3)
and 1.29 (3H, s, CH3) (Second rotamer 43%) 5.73 (1H, d, J2A,2B
10.1, H-2A), 5.31 (1H, d, J2B,2A 10.0, H-2B), 4.20 (1H, s, H-4),
1.45 (9H, s, OC(CH3)3), 1.44 (9H, s, OC(CH3)3), 1.43 (3H, s,
CH3) and 1.29 (3H, s, CH3); δC (75.5 MHz, C2HCl3, 2 rotamers
at 27 ЊC) 173.4 and 173.3 (lactone), 168.1 (ester), 152.2
(urethane), 83.1, 82.5 and 82.4 (OC(CH3)3), 73.2 and 72.3 (C-2),
62.4 and 61.4 (C-4), 40.6 and 40.1 (C-5), 28.1 and 28.0
(OC(CH3)3) and 26.6, 26.5 and 22.2 (CH3).
Method D. By alkylation using methyl iodide and KHMDS.
(4S)-3,4-Bis(tert-butoxycarbonyl)-2,3,4,5-tetrahydro-6H-1,3-
oxazin-6-one 9 (100 mg, 0.33 mmol) was dissolved in dry
tetrahydrofuran (1 ml) and cooled to Ϫ75 ЊC under nitrogen.
Potassium bis(trimethylsilyl)amide (0.5 M in toluene, 1.2 ml,
0.6 mmol) was added with stirring. Stirring was continued at
Ϫ75 ЊC for 1 h and methyl iodide (0.062 ml, 0.99 mmol) was
added. The solution was stirred 7.5 h at Ϫ75 ЊC, quenched with
excess saturated aqueous ammonium chloride at Ϫ20 ЊC and
extracted with ethyl acetate. The combined organic layers were
washed with water and dried (MgSO4). The solvent was
removed in vacuo to give an oil, which was purified by column
chromatography on silica gel using a gradient of petroleum
ether–ethyl acetate (10, 15 and 20%) as eluent to afford
(4S,5R)-3,4-bis(tert-butoxycarbonyl)-5-methyl-2,3,4,5-tetra-
hydro-6H-1,3-oxazin-6-one 23 (31 mg, 30%), (4S,5S)-3,4-
bis(tert-butoxycarbonyl)-5-methyl-2,3,4,5-tetrahydro-6H-1,3-
oxazin-6-one 24 (8 mg, 8%), (4S)-3,4-bis(tert-butoxycarbonyl)-
2,3,4,5-tetrahydro-6H-1,3-oxazin-6-one 9 (24 mg, 24%) and
(4S)-3,4-bis(tert-butoxycarbonyl)-5,5-dimethyl-2,3,4,5-tetra-
hydro-6H-1,3-oxazin-6-one 27 (18 mg, 17%), all with spectra in
keeping with those of authentic samples.
Method B. By hydrogenation of enaminone 20 in presence
of acetic acid. (4S)-3,4-Bis(tert-butoxycarbonyl)-5-(dimethyl-
aminomethylene)-2,3,4,5-tetrahydro-6H-1,3-oxazin-6-one 20
(1.5 g, 4.19 mmol) was dissolved in a mixture of ethyl acetate
(30 ml) and acetic acid (2 ml) and 10% palladium on carbon
(780 mg, 50% w/w) was added. The reaction was stirred under
an atmosphere of hydrogen for 2 days at room temperature and
filtered through Celite. The solvent was removed in vacuo to
give an oil, which was purified by column chromatography on
silica gel using a gradient of petroleum ether–ethyl acetate (15,
20%) as eluent to afford (4S,5R)-3,4-bis(tert-butoxycarbonyl)-
5-methyl-2,3,4,5-tetrahydro-6H-1,3-oxazin-6-one 23 (640 mg,
48%) and (4S,5S)-3,4-bis(tert-butoxycarbonyl)-5-methyl-
2,3,4,5-tetrahydro-6H-1,3-oxazin-6-one 24 (660 mg, 50%) as
white crystalline solids with identical spectra to those of the
samples prepared above.
(4S,5R)- and (4S,5S)-3,4-Bis(tert-butoxycarbonyl)-5-benzyl-
2,3,4,5-tetrahydro-6H-1,3-oxazin-6-one 28 and 5 (R ؍ Ph)
Method A. By alkylation using benzyl bromide LHMDS and
HMPA. (4S)-3,4-Bis(tert-butoxycarbonyl)-2,3,4,5-tetrahydro-
6H-1,3,oxazin-6-one 9 (100 mg, 0.33 mmol) was dissolved
in dry tetrahydrofuran (1 ml) with hexamethylphosphoramide
(0.2 ml) and cooled to Ϫ75 ЊC under nitrogen. Lithium
bis(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 0.73 ml,
0.73 mmol) was added with stirring. Stirring was continued at
Ϫ75 ЊC for 1 h and benzyl bromide (0.2 ml, 1.65 mmol) was
added. The resulting solution was stirred for 7 h at Ϫ75 ЊC and
allowed to warm to Ϫ40 ЊC over a period of 1 h. The mixture
was quenched by adding oxalic acid (89 mg) in diethyl ether (1
ml) at Ϫ75 ЊC and extracted with ethyl acetate. The combined
organic layers were washed with water and dried (MgSO4). The
solvent was removed in vacuo to give an oil, which was purified
by column chromatography on silica gel using a gradient of
petroleum ether–ethyl acetate (10, 15 and 20%) as eluent to
afford (4S,5R)-3,4-bis(tert-butoxycarbonyl)-5-benzyl-2,3,4,5-
tetrahydro-6H-1,3-oxazin-6-one 28 (35 mg, 27%) as a white
crystalline solid; mp 134–135 ЊC; [α]2D5 Ϫ144.0 (c 1, CHCl3)
(Found: C, 64.45; H, 7.5; N, 3.6. C21H29NO6 requires C, 64.4; H,
Method C. By alkylation of 9 using methyl iodide and
LHMDS. (4S)-3,4-Bis(tert-butoxycarbonyl)-2,3,4,5-tetrahydro-
6H-1,3-oxazin-6-one 9 (100 mg, 0.33 mmol) was dissolved in
dry tetrahydrofuran (1 ml) and cooled to Ϫ75 ЊC under nitro-
gen. Lithium bis(trimethylsilyl)amide (1.0 M in tetrahydro-
furan, 0.73 ml, 0.73 mmol) was added with stirring. Stirring was
continued at Ϫ75 ЊC for 1 h and methyl iodide (0.1 ml, 1.6
mmol) was added. The resulting solution was stirred for 1 h at
Ϫ75 ЊC and allowed to warm to Ϫ20 ЊC over a period of 4 h.
The mixture was quenched with excess saturated aqueous
ammonium chloride at Ϫ20 ЊC and extracted with ethyl acetate.
The combined organic layers were washed with water and dried
(MgSO4). The solvent was removed in vacuo to give an oil,
which was purified by column chromatography on silica gel
using a gradient of petroleum ether–ethyl acetate (10, 15 and
20%) as eluent to afford (4S,5R)-3,4-bis(tert-butoxycarbonyl)-
5-methyl-2,3,4,5-tetrahydro-6H-1,3-oxazin-6-one 23 (30 mg,
J. Chem. Soc., Perkin Trans. 1, 2000, 3451–3459
3457

View Article Online
7.5; N, 3.6%); m/z [ϩve FAB (3-NBA)] 392 ([M ϩ H]ϩ) and
414 ([M ϩ Na]ϩ); νmax (KBr)/cmϪ1 1772 (lactone), 1740 (ester)
and 1713 (urethane); δH [500 MHz, (C2H3)2SO, 42 ЊC] 7.31–7.12
(5H, m, ArH), 5.64 (1H, d, J2A,2B 10, H-2A), 5.34 (1H, d, J2B,2A
10, H-2B), 4.18 (1H, d, J4,5 10.8, H-4), 3.52 (1H, ddd, J5,4 10.8,
J5,7A 7.9, J5,7B 3.2, H-5), 3.12 (1H, dd, J7A,7B 14.8, J7A,5 7.9,
H-7A), 2.99 (1H, dd, J7B,7A 14.8, J7B,5 3.2, H-7B), 1.41 (9H, s,
OC(CH3)3) and 1.39 (9H, s, OC(CH3)3); δC (125.8 MHz,
C2HCl3, 2 rotamers at Ϫ25 ЊC; ratio 53:47) 170.8 and 170.7
(lactone), 170.0 and 169.9 (ester), 152.0 and 151.9 (urethane),
138.0, 137.9, 129.5, 129.4, 128.5, 128.3 and 126.8 (Ar), 83.3,
83.2, 82.7 and 82.6 (OC(CH3)3), 72.6 and 71.6 (C-2), 57.5 and
56.4 (C-4), 44.4 and 44.3 (C-5), 32.8 and 31.2 (CH2Ph), 28.0,
27.9 and 27.8 (OC(CH3)3). The X-ray crystal structure data for
this compound have been lodged with the CCDC,23 reference
code KAGNOV. (4S,5S)-3,4-Bis(tert-butoxycarbonyl)-5-
benzyl-2,3,4,5-tetrahydro-6H-1,3-oxazin-6-one 5 (R = Ph) (8 mg,
6%) was also obtained from the column as a colourless oil with
spectra identical to those from the sample from hydrogenation
of the benzylidene compound 21 (R = Ph). The column also gave
(4S)-3,4-bis(tert-butoxycarbonyl)-2,3,4,5-tetrahydro-6H-1,3-
oxazin-6-one 9 (37 mg, 37%) and the dialkylated product (4S)-
3,4-bis(tert-butoxycarbonyl)-5,5-dibenzyl-2,3,4,5-tetrahydro-
6H-1,3-oxazin-6-one 29 (17 mg, 11%); [α]2D5 Ϫ11.5 (c 1, CHCl3)
(Found 482.2576. C28H36NO6 ([M ϩ H]ϩ) requires 482.2543);
m/z [ϩve FAB (3-NBA)] 482 ([M ϩ H]ϩ) and 504 ([M ϩ Na]ϩ);
νmax (film)/cmϪ1 1749 (lactone/ester) and 1719 (urethane); δH
(500 MHz, C2HCl3, 2 rotamers at Ϫ25 ЊC) (First rotamer, 73%)
7.42–7.19 (10H, m, ArH), 5.94 (1H, d, J2A,2B 10.3, H-2A), 5.34
(1H, d, J2B,2A 10.3, H-2B), 4.82 (1H, s, H-4), 3.69 (1H, d, JAB
13.6, CH2Ph), 3.33 (1H, d, JBA 13.6, CH2Ph), 2.86 (1H, d, JAB
13.7, CH2Ph), 2.80 (1H, d, JBA 13.7, CH2Ph), 1.66 (9H, s,
OC(CH3)3) and 1.25 (9H, s, OC(CH3)3) (Second rotamer, 26%)
7.42–7.19 (10H, m, ArH), 5.76 (1H, d, J2A,2B 10.3, H-2A), 5.51
(1H, d, J2B,2A 10.3, H-2B), 4.85 (1H, s, H-4), 3.59 (1H, d, JAB
13.8, CH2Ph), 3.37 (1H, d, JA,B 13.9, CH2Ph), 2.85 (1H, d, JB,A
13.9, CH2Ph), 2.80 (1H, d, JB,A 13.8, CH2Ph), 1.62 (9H, s,
OC(CH3)3) and 1.41 (9H, s, OC(CH3)3); δC (125.8 MHz,
C2HCl3, 2 rotamers at Ϫ25 ЊC) 169.0 and 168.9 (lactone),
168.6 and 168.4 (ester), 151.6 and 151.3 (urethane), 136.2,
135.7, 133.8, 133.6, 131.5, 131.3, 130.4, 130.2, 128.3, 128.2,
127.7 and 127.0 (Ar), 83.4, 83.3, 82.4 and 81.9 (OC(CH3)3),
72.0 and 70.8 (C-2), 55.7 and 55.4 (C-4), 50.9 and 50.4 (C-5),
41.1, 40.8, 40.1 and 39.7 (CH2Ph), 28.1, 28.0, 27.9 and 27.6
(OC(CH3)3).
(2S,3R)-3-Methylaspartic acid hydrochloride 30
(4S,5R)-3,4-Bis(tert-butoxycarbonyl)-5-methyl-2,3,4,5-tetra-
hydro-6H-1,3-oxazin-6-one 23 (55 mg, 0.17 mmol) was dis-
solved in a minimum of diethyl ether and 6 M aqueous
hydrochloric acid (1.5 ml) was added. The mixture was stirred
for 15 h at room temperature and washed with diethyl ether.
The aqueous layer was lyophilised using a freeze dryer. The
residual yellow foam was recrystallised in a mixture of absolute
ethanol and diethyl ether to yield (2S,3R)-3-methylaspartic acid
hydrochloride 30 (25 g, 80%); mp 165–166 ЊC; [α]2D5 ϩ29.7 (c 1, 5
M HCl) [lit.16 [α]2D5 ϩ32.9 (c 0.8, 5 M HCl)] (Found: C, 32.7;
H, 5.5; N, 7.4, C5H10NO4Cl requires C, 32.7; H, 5.5; N, 7.6%);
m/z [ϩve FAB (glycerol)] 148 ([free amino acid ϩ H]ϩ);
2
δH (300 MHz, H2O) 4.08 (1H, d, J2,3 4.0, H-2), 3.15 (1H, dq,
J3,2 4.0, J3,Me 7.4. H-3) and 1.12 (3H, d, JMe,3 7.4, CH3); δC (75.5
2
MHz, H2O) 176.1 (acid), 170.9 (acid), 55.0 (C-2), 39.5 (C-3)
and 12.3 (CH3).
1-tert-Butyl (2S,3R)-3-methyl-N-tert-butoxycarbonylaspartate,
31
Method A. Using HOAc–H2O. (4S,5R)-3,4-Bis(tert-butoxy-
carbonyl)-5-methyl-2,3,4,5-tetrahydro-6H-1,3-oxazin-6-one
(23) (429 mg, 1.36 mmol) was dissolved in a 4:1 mixture of
acetic acid and water (16 ml). The mixture was stirred for 3 days
at 50 ЊC and the solvent was removed in vacuo. The residue was
partitioned between diethyl ether and 1 M aqueous sodium
hydroxide. The organic layer was washed with 1 M aqueous
sodium hydroxide, and the combined aqueous layers were acidi-
fied to pH 2 with 10% aqueous citric acid. The aqueous layer
was extracted with ethyl acetate. The combined organic layers
were washed with water and dried (MgSO4). The solvent was
removed in vacuo to give an oil, which was purified by column
chromatography on silica gel using a gradient of petroleum
ether–ethyl acetate (10, 15 and 20%) as eluent to afford 1-tert-
butyl (2S,3R)-3-methyl-N-tert-butoxycarbonylaspartate 31 as a
colourless oil which crystallised on standing (231 mg, 56%);
mp 89–90 ЊC; [α]2D5 Ϫ12.8 (c 1, MeOH) (Found: C, 55.6; H, 8.2;
N, 4.55. C14H25NO6 requires C, 55.4; H, 8.3; N, 4.6%); m/z
[ϩve FAB (3 NBA)] 304 ([M ϩ H]ϩ); νmax (film)/cmϪ1 3439
(br, acid) and 1719 (br ester/urethane); δH (300 MHz, C2HCl3,
25 ЊC) 10.16 (1H, br s, CO2H), 5.39 (1H, d, JNH,2 9.0, NH),
4.42 (1H, dd, J2,NH 9.0, J2,3 3.6, H-2), 3.18 (1H, dq, J2,3 3.6,
J3,Me 7.2, H-3), 1.40 (9H, s, OC(CH3)3), 1.39 (9H, s, OC(CH3)3)
and 1.18 (1H, d, JMe,3 7.2, CH3) (peaks due to second rotamer)
6.09 (1H, d, JNH,2 7.9, NH), 4.22–4.33 (1H, m, H-2) and
2.97–3.09 (1H, m, H-3); δC (75.5 MHz, C2HCl3, 25 ЊC) 179.3
(C-4), 169.7 (C-1), 156.0 (urethane), 82.5 (OC(CH3)3), 79.9
(OC(CH3)3), 55.5 (C-2), 41.4 (C-3), 28.2 and 27.7 (OC(CH3)3)
and 12.8 (CH3). Further elution gave starting material 23
(21 mg, 5%).
Method B. Alkylation using sodium bis(trimethylsilyl)amide.
(4S)-3,4-Bis(tert-butoxycarbonyl)-2,3,4,5-tetrahydro-6H-1,3-
oxazin-6-one 9 (100 mg, 0.33 mmol) was dissolved in dry
tetrahydrofuran (1 ml) and cooled to Ϫ75 ЊC under nitrogen.
Sodium bis(trimethylsilyl)amide (1.0 M in tetrahydrofuran,
0.73 ml, 0.73 mmol) was added with stirring. Stirring was con-
tinued at Ϫ75 ЊC for 1 h and benzyl bromide (0.2 ml, 1.65
mmol) was added. The resulting solution was stirred 6.5 h at
Ϫ75 ЊC. The mixture was quenched by adding oxalic acid (89
mg) in diethyl ether (1 ml) at Ϫ75 ЊC and extracted with ethyl
acetate. The combined organic layers were washed with water
and dried (MgSO4). The solvent was removed in vacuo to give
an oil, which was purified by column chromatography on silica
gel using a gradient of petroleum ether–ethyl acetate (10, 15
and 20%) as eluent to afford (4S,5R)-3,4-bis(tert-butoxy-
carbonyl)-5-benzyl-2,3,4,5-tetrahydro-6H-1,3-oxazin-6-one 28
(28 mg, 22%), (4S,5S)-3,4-bis(tert-butoxycarbonyl)-5-benzyl-
2,3,4,5-tetrahydro-6H-1,3-oxazin-6-one 5 (R = Ph) (7 mg, 5%),
(4S)-3,4-bis(tert-butoxycarbonyl)-2,3,4,5-tetrahydro-6H-1,3-
oxazin-6-one 9 (43 mg, 43%) and (4S)-3,4-bis(tert-butoxy-
carbonyl)-5,5-dibenzyl-2,3,4,5-tetrahydro-6H-1,3-oxazin-6-one
29 (16 mg, 10%) with spectra identical to those of authentic
samples.
Method B. Using LiOOH. (4S,5R)-3,4-Bis(tert-butoxycarb-
onyl)-5-methyl-2,3,4,5-tetrahydro-6H-1,3-oxazin-6-one 23 (71
mg, 0.23 mmol) was dissolved in tetrahydrofuran (3.5 ml) and
water (1 ml) and cooled to 0 ЊC. Aqueous hydrogen peroxide
(30%, 0.02 ml) and 1 M aqueous lithium hydroxide (0.27 ml,
0.27 mmol) were successively added with stirring. Stirring was
continued at 0 ЊC for 6 h. 1.5 M Aqueous sodium sulfite (0.6 ml)
was added at 0 ЊC and the mixture was diluted with water,
washed with diethyl ether and carefully acidified to pH 2 with
2 M aqueous hydrochloric acid. The solution was extracted
with ethyl acetate. The combined organic layers were washed
with water and dried (MgSO4). The solvent was removed in
vacuo to give an oil, which was purified by column chrom-
atography on silica gel using a gradient of petroleum ether–
ethyl acetate (10 and 20%) as eluent to yield 1-tert-butyl
(2S,3R)-3-methyl-N-tert-butoxycarbonylaspartate 31 (28 mg,
40%) identical to the sample prepared by method A.
3458
J. Chem. Soc., Perkin Trans. 1, 2000, 3451–3459

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1-tert-Butyl (2S,3S)-3-methyl-N-tert-butoxycarbonylaspartate,
32
Acknowledgements
We thank Conseil Régional Provence, Alpes, Côte d’Azur
(G. B.) and INSERM and the Medical Research Council
(P. J. C.) for post doctoral fellowships and Mr S. Garrett and
Mr K. Papadopoulos for preliminary experiments. We also
thank Dr A. G. Avent for variable temperature and saturation
transfer NMR experiments and the EPSRC National Mass
Spectrometry Service, Swansea for some of the accurate
mass measurements.
(4S,5S)-3,4-Bis(tert-butoxycarbonyl)-5-methyl-2,3,4,5-tetra-
hydro-6H-1,3-oxazin-6-one 24 (362 mg, 1.15 mmol) was dis-
solved in a 4:1 mixture of acetic acid and water (14 ml). The
mixture was stirred for 3 days at 50 ЊC and the solvent was
removed in vacuo. The residue was partitioned between diethyl
ether and 1 M aqueous sodium hydroxide. The organic layer
was washed with 1 M aqueous sodium hydroxide and the com-
bined aqueous layers were acidified carefully to pH 2 with 10%
aqueous citric acid. The aqueous layer was extracted with ethyl
acetate. The combined organic layers were washed with water
and dried (MgSO4). The solvent was removed in vacuo to give
an oil, which was purified by column chromatography on silica
gel using a gradient of petroleum ether–ethyl acetate (10, 15 and
20%) as eluent to afford 1-tert-butyl (2S,3S)-3-methyl-N-tert-
butoxycarbonylaspartate 32 as an oil (184 mg, 53%) (Found:
304.1760 ([M ϩ H]ϩ). C14H26NO6 requires 304.1766); m/z
[ϩve FAB (3-NBA)] 304 ([M ϩ H]ϩ) and 326 ([M ϩ Na]ϩ);
νmax (film)/cmϪ1 3341 (br, acid) and 1720 (br, ester/urethane);
δH (300 MHz, C2HCl3, 25 ЊC) 9.76 (1H, br s, CO2H), 5.33 (1H,
d, JNH,2 8.7, NH), 4.45 (1H, dd J2,NH 8.7, J2,3 4.5, H-2), 2.92 (1H,
dq, J3,2 4.5, J3,Me 7.2, H-3), 1.42 (9H, s, OC(CH3)3), 1.40 (9H, s,
OC(CH3)3) and 1.20 (1H, d, JMe,3 7.2, CH3) (peaks due to second
rotamer) 6.12–5.97 (1H, m, NH), 4.41–4.29 (1H, m, H-2) and
2.97–3.09 (1H, m, H-3); δC (75.5 MHz, C2HCl3, 25 ЊC) 178.6
(C-4), 169.6 (C-1), 155.4 (urethane), 82.6 (OC(CH3)3), 80.0
(OC(CH3)3), 55.7 (C-2), 42.4 (C-3), 28.2 and 27.8 (OC(CH3)3)
and 13.0 (CH3). Starting material 24 (33 mg, 8%) was obtained
on further elution.
References
1 Part of this work has been reported as a preliminary communication
in G. Burtin, P.-J. Corringer, P. B. Hitchcock and D. W. Young,
Tetrahedron Lett., 1999, 40, 4275.
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Godfrey, Tetrahedron, 1995, 51, 5169.
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34, 3405.
20 J. Hondrelis, G. Lonergan, S. Voliotis and J. Matsoukas,
Tetrahedron, 1990, 46, 565.
21 Using the method for the corresponding glutamate derivative by
R. K. Olsen, K. Ramasamy and T. Emery, J. Org. Chem., 1984, 49,
3527.
1-tert-Butyl (2S,3S)-3-benzyl-N-tert-butoxycarbonylaspartate, 6
(R ؍ Ph)
(4S,5S)-3,4-Bis(tert-butoxycarbonyl)-5-benzyl-2,3,4,5-tetra-
hydro-6H-1,3-oxazin-6-one 5 (R = Ph) (300 mg, 0.77 mmol) was
dissolved in a 4:1 mixture of acetic acid and water (10 ml). The
mixture was stirred for 2 days at 50 ЊC and the solvent was
removed in vacuo. The residue was partitioned between diethyl
ether and 1 M aqueous sodium hydroxide. The organic layer was
washed with 1 M aqueous sodium hydroxide and the combined
aqueous layers were acidified carefully to pH 2 with 10%
aqueous citric acid. The aqueous layer was extracted with ethyl
acetate. The combined organic layers were washed with water
and dried (MgSO4). The solvent was removed in vacuo to give
an oil, which was purified by column chromatography on silica
gel using a gradient of petroleum ether–ethyl acetate (10, 15
and 20%) as eluent to afford 1-tert-butyl (2S,3S)-3-benzyl-N-
tert-butoxycarbonylaspartate 6, (R = Ph) as a white crystalline
solid (148 mg, 51%); mp 96–97 ЊC (lit.6 mp 132–135 ЊC); [α]2D5
ϩ3.8 (c 1, MeOH), Ϫ1.3 (c 1, CHCl3) (Found: C, 63.3; H, 7.6;
N, 3.7. C20H29NO6 requires C, 63.3; H, 7.7; N, 3.7%); m/z [ϩve
FAB (3-NBA)] 380 ([M ϩ H]ϩ) and 402 ([M ϩ Na]ϩ);
νmax (KBr)/cmϪ1 3267 (br, acid/NH), 1727 and 1664 (br ester/
urethane); δH (300 MHz, C2HCl3, 25 ЊC) 9.69 (1H, br s, CO2H),
7.22–7.10 (5H, m, ArH), 5.34 (1H, d, JNH,2 8.5, NH), 4.44 (1H,
dd, J2,NH 8.5, J2,3 3.4, H-2), 3.05–2.95 (2H, m, H-3 and CH2Ph),
2.85–2.78 (1H, m, CH2Ph), 1.39 (9H, s, OC(CH3)3) and 1.35
(9H, s, OC(CH3)3) (peaks due to second rotamer) 6.18–6.04
(1H, m, NH) and 4.29–4.18 (1H, m, H-2); δC (75.5 MHz,
C2HCl3, 25 ЊC) 177.7 (C-4), 169.6 (C-1), 155.3 (urethane),
138.4, 129.0, 128.6 and 126.7 (Ar), 83.1 and 80.2 (OC(CH3)3),
54.8 (C-2), 50.3 (C-3), 34.1 (CH2Ph), 28.3 and 28.0
(OC(CH3)3.
22 H. Gregory, J. S. Morley, J. M. Smith and M. J. Smithers, J. Chem.
Soc. (C), 1968, 715.
23 The X-ray data for these compounds were reported in our
preliminary communication; (ref. 1) and the atomic coordinates
were lodged with the Cambridge Crystallography Data Centre,
University Chemical Laboratory, Lensfield Road, Cambridge, CB2
1EW. They are available on request from the Director of the CCDC
at the above address. Compound 5 (R = Me) has CCDC reference
code KAGJUX; and compound 28 has CCDC reference code
KAGNOV.
24 (a) R. A. August, J. A. Khan, C. M. Moody and D. W. Young, Tetra-
hedron Lett., 1992, 33, 4617; (b) R. A. August, J. A. Khan, C. M.
Moody and D. W. Young, J. Chem. Soc., Perkin Trans. 1, 1996, 507.
25 E. Coudert, F. Acher and R. Azerad, Synthesis, 1997, 863.
26 J.-D. Charrier, J. E. S. Duffy, P. B. Hitchcock and D. W. Young,
Tetrahedron Lett., 1998, 39, 2199.
27 J. E. Baldwin, T. Miranda, M. Moloney and T. Hokelek,
Tetrahedron, 1989, 45, 7459.
J. Chem. Soc., Perkin Trans. 1, 2000, 3451–3459
3459