Stereoselective synthesis of multiply substituted [1,2]oxazinan-3-ones via ring-closing metathesis

Article abstract of DOI:10.1139/v04-174

The title compounds are α-amino acids whose nitrogen atoms are enclosed within 4,5-disubstituted, six-membered cyclic hydroxamates and they are of interest as potential β-lactam surrogates. The compounds have been synthesized in the present work by functionalization of the double bonds of N-substituted 6H-[1,2]oxazin-3-ones, which are obtained upon successive reaction of the inflates of 5-α-hydroxy esters with O-allylhydroxylamine and acryloyl chloride, followed by cyclization of the resulting A-α-TV- acryloyl-N-allyloxyamino esters in the presence of the ring-closing metathesis (RCM) catalyst bis(tricyclohexylphosphine)benzylideneruthenium dichloride. The olefins are also accessible, but less efficiently so, by a Wittig sequence that employs bromoacetyl bromide in place of acryloyl chloride, followed successively by triphenylphosphine, silver triflate, ozonolysis, and cyclization. Asymmetric dihydroxylation of these chiral olefins affords a single diastereomer in high yield having either the αR,4S,5S- or the αR,4R,5R configuration, depending on the auxiliary. The configuration of the αR,4R,5R isomer has been confirmed by its conversion to (αR,4S,5R)-2-(α-carboxyethyl)-4- phenylacetylamino-5-hydroxy-1,2-oxazinan-3-one, whose αR,4K,5S diastereomer was previously prepared from L-ascorbic acid. With N-bromosuccinimide in aqueous dimethylformamide, a 6H-[1,2]oxazin-3-one afforded a separable 1:1 mixture of bromohydrins, which could be cyclized to epoxides or hydrogenolyzed to 5-hydroxy-1,2-oxazinan-3-ones.

Full text of DOI:10.1139/v04-174

93
Stereoselective synthesis of multiply substituted
[1,2]oxazinan-3-ones via ring-closing metathesis
Gennady V. Shustov, Melanie K. Chandler, and Saul Wolfe
Abstract: The title compounds are α-amino acids whose nitrogen atoms are enclosed within 4,5-disubstituted, six-
membered cyclic hydroxamates and they are of interest as potential β-lactam surrogates. The compounds have been
synthesized in the present work by functionalization of the double bonds of N-substituted 6H-[1,2]oxazin-3-ones, which
are obtained upon successive reaction of the triflates of S-α-hydroxy esters with O-allylhydroxylamine and acryloyl
chloride, followed by cyclization of the resulting R-α-N-acryloyl-N-allyloxyamino esters in the presence of the ring-
closing metathesis (RCM) catalyst bis(tricyclohexylphosphine)benzylideneruthenium dichloride. The olefins are also ac-
cessible, but less efficiently so, by a Wittig sequence that employs bromoacetyl bromide in place of acryloyl chloride,
followed successively by triphenylphosphine, silver triflate, ozonolysis, and cyclization. Asymmetric dihydroxylation of
these chiral olefins affords a single diastereomer in high yield having either the αR,4S,5S- or the αR,4R,5R configura-
tion, depending on the auxiliary. The configuration of the αR,4R,5R isomer has been confirmed by its conversion to
(αR,4S,5R)-2-(α-carboxyethyl)-4-phenylacetylamino-5-hydroxy-1,2-oxazinan-3-one, whose αR,4R,5S diastereomer was
previously prepared from L-ascorbic acid. With N-bromosuccinimide in aqueous dimethylformamide, a 6H-[1,2]oxazin-
3-one afforded a separable 1:1 mixture of bromohydrins, which could be cyclized to epoxides or hydrogenolyzed to 5-
hydroxy-1,2-oxazinan-3-ones.
Key words: penicillin surrogates, asymmetric dihydroxylation, bis(tricyclohexylphosphine)benzylideneruthenium
dichloride, cyclic sulfite, epoxides, azidohydrin, bromohydrin.
Résumé : Les composés mentionnés dans le titre sont des acides α-aminés dont l’atome d’azote fait partie d’hydro-
xamates cycliques à six chaînons substitués dans les positions 4 et 5 qui présentent de l’intérêt comme substituts de β-
lactames. Dans ce travail, les composés ont été synthétisés par le biais d’une fonctionnalisation de doubles liaisons de
6H-[1,2]oxazin-3-ones N-substituées qui sont obtenues par la réaction successive des triflates des esters S-α-hydroxylés
avec de la O-allylhydroxylamine et du chlorure d’acryloyle, suivie d’une cyclisation des esters R-α-N-acryloyl-N-al-
lyoxyamino en présence du catalyseur RCM, dichlorure du bis(tricyclohexylphosphine)benzylidène ruthénium. Les olé-
fines sont aussi accessibles, mais d’une façon moins efficace, par le biais d’une séquence de Wittig faisant appel au
bromure de bromoacétyle, à la place du chlorure d’acryloyle, suivie successivement d’une réaction avec le triphényl-
phosphine, le triflate d’argent, d’une ozonolyse et d’une cyclisation. La dihydroxylation asymétrique de ces oléfines
chirales conduit à un seul diastéréoisomère, avec un rendement élevé, de configuration αR,4S,5S- ou αR,4R,5R- suivant
la nature de l’auxiliaire. La configuration de l’isomère αR,4R,5R a été confirmée par sa conversion en (αR,4S,5R)-2-(α-
carboxyéthyl)-4-phénylacétylamino-5-hydroxy-1,2-oxaziran-3-one, dont le diastéréoisomère a antérieurement été préparé
à partir de l’acide L-ascorbique. La réaction du N-bromosuccinimide, dans le diméthylformamide aqueux, avec une 6H-
[1,2]oxazin-3-one conduit à la formation d’un mélange 1 : 1 de bromohydrines qui peut facilement être séparé alors
que les deux isomères peuvent être cyclisés en époxydes ou hydrogénolysés en 5-hydroxy-1,2-oxazinan-3-ones.
Mots clés : substituts de pénicilline, dihydroxylation asymétrique, dichlorure de bis(tricyclohexylphosphine)benzylidène-
ruthénium, sulfite cyclique, époxydes, azidohydrine, bromohydrine.
[Traduit par la Rédaction] Shustov et al. 103
The final stage of bacterial cell wall peptidoglycan
biosynthesis proceeds in two steps (1). The first is displace-
ment of the terminal D-alanine from an RCO-D-ala-D-ala
chain by the hydroxyl group of a serine peptidase (1 → 2).
The second is a cross-linking reaction in which the enzyme
is displaced from the depsipeptide by an amino group of an-
other chain (2 → 3). These serine peptidases, also known as
penicillin-binding proteins (PBPs) (2), are the targets of β-
lactam antibiotics (4 → 5).
It has been recognized for many years that 1 and 4 are
structural analogs (3), i.e., that β-lactam antibiotics are N-
acyl-D-ala-D-ala surrogates. Since lactivicin (6), an antibiotic
Received 9 August 2004. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on 25 February 2005.
G.V. Shustov, M.K. Chandler, and S. Wolfe.1 Department of Chemistry, Simon Fraser University, 8888 University Drive,
Burnaby, BC V5A 1S6, Canada.
1Corresponding author (e-mail: swolfe@sfu.ca).
Can. J. Chem. 83: 93–103 (2005)
doi: 10.1139/V04-174
© 2005 NRC Canada

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Can. J. Chem. Vol. 83, 2005
Scheme 1 summarizes the results obtained starting with
the α-hydroxy acids available from the nitrous acid
deaminations of L-alanine, L-valine and L-phenylglycine. In
situ reaction of allyloxyamine (8) with the triflates of 10
proceeded with inversion of configuration (6, 9) to yield the
R-α-allyloxyamino esters 11, which were converted to the
RCM precursors 12 with acryloyl chloride. With the excep-
tion of the phenyl compound (R2 = Ph), cyclization to 13
was achieved in 80%–90% yield in refluxing methylene
chloride in the presence of the first generation Grubbs catalyst
bis(tricyclohexylphosphine)benzylideneruthenium dichloride (4
to 5 mol%).
The synthetic improvement provided by the RCM ap-
proach can be seen upon comparison of the cyclizations of
12a and of the Wittig precursor 16. Thus (Scheme 2), suc-
cessive reaction of 11a with bromoacetyl bromide, triphenyl-
phosphine, and silver triflate, followed by ozonolysis and
treatment with potassium carbonate led to cyclization to 13a
in 27% yield.
Schemes 3 and 4 exemplify reaction sequences that have
been applied to the olefins 13. In Scheme 3, Sharpless asym-
metric dihydroxylation (10) leads, depending on the auxil-
iary, either to a β-diol 17 or an α-diol 19 as a single
diastereomer in each case, and these diols can be
deprotected to carboxylic acids 18 or 20, respectively. The
cyclic sulfite (11) of 19 afforded the trans-azidohydrin 22
(12),2 which was converted in 81% overall yield, into 25, the
(αR,4S,5R)-isomer of 2-(α-carboxyethyl)-4-phenylacetylamino-
5-hydroxy-1,2-oxazinan-3-one (25), which was different
from the (αR,4R,5S)-isomer (7) synthesized previously from
L-ascorbic acid.
isolated from culture filtrates of Empedobacter lactagenus
YK-258 and Lysobacter albus YK-422, also functions by
acylation of the serine hydroxyl groups of PBPs and other
penicillin-recognizing enzymes (4), it seems likely that
lactivicin is a penicillin and N-acyl-D-ala-D-ala analog, and
that an isoxazolidin-3-one ring, a five-membered cyclic
hydroxamate, is a β-lactam surrogate.
We have recently reported that six-membered cyclic
hydroxamates of general structure 7 may also serve as
β-lactam and D-ala-D-ala surrogates. In a first synthetic
approach to such compounds (8, Z = H, Me) (5), based on
disconnection a, protected N-hydroxyglycine and N-
hydroxyalanine were coupled to racemic protected β-
hydroxy-γ-bromobutyric acid, and the cyclic hydroxamate
was generated by O1-C5 ring closure. In a second approach
(6), based on disconnection b (9), the cyclic hydroxamate
was prepared by trimethylaluminium-promoted cyclization
of an ε-aminooxyester. These initial syntheses suggested that
a stereocontrolled approach to 7, with extensive variation of
X, Y, and Z via a would be difficult, because of significant
competing O-acylation when Z ≠ H, and that syntheses via b
would also be unsatisfactory because of the large number of
steps (11 steps from L-ascorbic acid to 7, Z = Me, X = α-
hydroxy, Y = β-phenylacetamido) and low overall yield (0.9%).
This paper reports a stereocontrolled route to 7, based on
c, the functionalization of olefins 13, which are accessible in
three steps from the benzyl, benzhydryl or tert-butyl L-α-
hydroxyesters 10 by a ring-closing metathesis (RCM) strat-
egy (7).
As summarized in Scheme 4, 26, the 6H-[1,2]oxazin-3-
one prepared from benzhydryl S-lactate, reacted with N-
bromosuccinimide in aqueous dimethylformamide to give, in
addition to the dibromides 27, a separable mixture of bromo-
2 No attempt was made to improve the (nonoptimized) 18% yield of this reaction (11). Cyclic sulfates (13) are, in general, more effective sub-
strates for this reaction than cyclic sulfites, but this route was also not pursued (14).
© 2005 NRC Canada

Shustov et al.
95
Scheme 1. (i) (CF3SO2)2O, 2,6-lutidine, O-allylhydroxylamine,
CH2Cl2; (ii) CH2=CHCOCl, Et3N or 2,6-lutidine, CH2Cl2;
(iii) PhCH=RuCl2[P(Cychex)3]2 (Grubbs’catalyst), CH2Cl2 or to-
luene.
Scheme 3. (i) AD-mix-β, (DHQD)2PHAL, K2OsO4(OH)4,
MeSO2NH2, t-BuOH, H2O; (ii) AD-mix-α, (DHQ)2PHAL,
K2OsO4(OH)4, MeSO2NH2, t-BuOH, H2O; (iii) H2, Pd/C, EtOAc;
(iv) CF3CO2H, CH2Cl2; (v) SOCl2, Et3N, CH2Cl2; (vi) NaN3,
DMF; (vii) PhCH2COCl, NaHCO3, MeCN, H2O.
Scheme 2. (i) BrCH2COBr, Et3N, CH2Cl2; (ii) PPh3, toluene;
(iii) CF3SO3Ag, MeCN; (iv) O3, CH2Cl2, then Me2S, then
K2CO3, H2O.
Scheme 4. (i) NBS, DMF, H2O; (ii) K2CO3, acetone; (iii) H2,
Pd/C, Et3N, MeOH.
dried (140 °C, 24 h) glassware. The glassware was allowed
to cool in a desiccator under vacuum and assembled cold,
capped with rubber septa, and evacuated with dry nitrogen
1
gas. Both H and 13C nuclear magnetic resonance (NMR)
hydrins 28, in 26% (less polar isomer) and 20% (more polar
isomer) yields. Both bromohydrins could be cyclized to
epoxides 29, and the less polar bromohydrin could be hydro-
genolyzed in the presence of triethylamine to a single
stereoisomer of 30.
spectra were recorded on a Bruker model AMX 400 spec-
trometer operating at 400.1 and 100.6 MHz, respectively.
Chemical shifts (δ) are reported in parts per million (ppm)
relative to tetramethylsilane (TMS) in an appropriate
1
deuterated solvent. HMR data are reported in the following
manner: chemical shift, integration, peak multiplicity, cou-
pling constants, and identification. The peak multiplicities
are abbreviated as s (singlet), d (doublet), t (triplet), q (quartet),
dd (doublet of doublets), ddd (doublet of doublets of dou-
blets), m (multiplet), etc. 13CMR data are reported as δ val-
ues in ppm downfield from tetramethylsilane. Infrared (IR)
Experimental
Solvents were dried and distilled before use according to
standard literature procedures (15). Except where indicated,
chemicals were of the highest available purity from Aldrich.
All reactions were performed under dry nitrogen using oven-
© 2005 NRC Canada

96
Can. J. Chem. Vol. 83, 2005
spectra were recorded on a Bomen-Hartmann-Braun spec-
trometer (1% KBr or 1% solution). Mass spectra refer to
direct inlet EI measurements or CI measurements, using iso-
butane, or fast-atom bombardment (FAB) employing xenon
gas, on a Kratos MS50 spectrometer operated at 70 eV by G.
Owens at Simon Fraser University. Melting points (mp)
were determined on a Fisher-Johns apparatus, and are uncor-
rected. Analytical thin layer chromatography (TLC) was car-
ried out on precoated Merck silica gel 60 F-254 plates with
aluminium backing. Spots were observed under short-
wavelength UV light, or were visualized with iodine vapour,
ninhydrin, or ceric sulfate. Flash column chromatography
(16a) and dry-column flash chromatography (16b) were car-
ried out on Merck silica gel 60 (230–400 mesh), using only
distilled solvents under dry nitrogen gas. Elemental analyses
were performed by M.K. Yang on a Carlo Erba model 1106
elemental analyzer at Simon Fraser University.
the reaction mixture was stirred for 30 min at –68 to –72 °C.
A solution of allyloxyamine (4.55 g, 77 mmol) in dry
CH2Cl2 (15 mL) was then added dropwise, with cooling
(–68 to –72 °C) and stirring. The reaction mixture was
stirred for 15 min at ca. –72 °C and then was allowed to
warm to room temperature. Stirring was continued for 15 h
and the reaction mixture was then shaken with satd.
NaHCO3 (200 mL) and dried over MgSO4. After removal of
the solvent, the residue was purified by dry flash chromatog-
raphy (silica gel 60H for TLC, 10% EtOAc – hexanes) to af-
ford 8.20 g (quant) of the product as a pale yellowish oil. IR
(film, cm–1): 3264, 1740, 1456, 1208, 1170. 1H NMR
3
(100 MHz, CDCl3 + 1 drop of D2O) δ: 1.28 (3H, d, J =
3
7.1 Hz, MeCH), 3.82 (1H, q, J = 7.1 Hz, MeCH), 4.22 (2H,
3
4
dt, J = 5.7 Hz, J = 1.2 Hz, OCH2CH=CH2), 5.16–5.37
(2H, m, CH=CH2), 5.23 (2H, CH2Ph), 5.76–6.15 (1H, m,
3
3
3J = 5.7 Hz, Jcis = 9.9 Hz, Jtrans = 17.1 Hz, CH=CH2), 7.38
(5H, Ph).13C NMR (100 MHz, CDCl3) δ: 14.81, 59.09,
66.63, 75.22, 117.53, 128.06, 128.24, 128.56, 134.37,
135.84, 174.01. Anal. calcd. for C13H17NO3 (%): C 66.4, H
7.3, N 5.95; found: C 66.3, H 7.4, N 6.15.
Allyloxyamine
DBU (46.36 mL, 0.31 mol) was added in one portion,
with stirring, to a cooled solution (5–10 °C) of N-
hydroxyphthalimide (53.80 g, 0.33 mol) in DMF (120 mL).
After 10 min, allyl bromide (25.96 mL, 0.30 mol) was added
dropwise. When the addition was complete, the cooling bath
was removed and the reaction mixture was stirred at room
temperature for 1 h, until the color turned from dark bur-
gundy to yellow. Ethyl acetate (300 mL) and water (150 mL)
were added, the aqueous phase was separated, and the or-
ganic phase was washed with water (4 × 50 mL). The com-
bined aqueous extracts were back-extracted with EtOAc (3 ×
50 mL) and the combined organic layers were washed with
satd. NaHCO3 (10 × 50 mL) until the aqueous phase was
pale yellow, then with brine (2 × 75 mL), dried over anhydr.
MgSO4 and concentrated to give N-allyloxyphthalimide
58.83 g (96%), mp 59 to 60 °C (lit. value (3) mp 59 to
(R)-N-Acryloyl-N-allyloxyalanine benzyl ester (12a)
A solution of acryloyl chloride (3.26 g, 36 mmol) in dry
CH2Cl2 (20 mL) was added dropwise with cooling (–5 to
−10 °C) and stirring to a solution of (R)-N-allyloxyalanine
benzyl ester (11a) (7.06 g, 30 mmol) and Et3N (4.55 g,
45 mmol) in dry CH2Cl2 (80 mL). The reaction mixture was
stirred for 1 h at 0–5 °C and then for 4.5 h at room tempera-
ture. After dilution with CH2Cl2 (ca. 150 mL), the mixture
was washed successively with water (3 × 50 mL), 1 N HCl
(50 mL), brine (100 mL), and dried over MgSO4. Removal
of the solvent gave 9.16 g of a yellow oil, which was puri-
fied by dry flash chromatography (silica gel 60H for TLC,
3% EtOAc – hexanes to 15% EtOAc – hexanes) to afford
8.52 g (98%) of the product as a colorless oil. IR (film, cm–1):
1746, 1667, 1621, 1411. 1H NMR (100 MHz, CDCl3) δ: 1.61
60 °C) as
a white solid. A solution of the N-
allyloxyphthalimide (58.70 g, 0.289 mol) in dry ethanol
(295 mL) was treated dropwise, with stirring, with a solution
of hydrazine hydrate (14.01 mL, 0.289 mol) in EtOH
(44 mL). The reaction mixture immediately turned yellow
and a white precipitate formed. The mixture was refluxed
for 2 h, stirred at room temperature for 17 h, cooled (10–
15 °C), concentrated, and concd. HCl (30.24 mL, 0.37 mol)
was added dropwise. The white precipitate was removed by
filtration and washed with water (160 mL). The filtrate was
concentrated under reduced pressure and the residue was
maintained at 1 torr (1 torr = 133.322 4 Pa) for 3 h. Water
(100 mL) was added, the solution was filtered, and the fil-
trate was concentrated to 50 mL and added portionwise to
KOH pellets in a distillation apparatus. The product was col-
lected at 80–100 °C. A second distillation over KOH pellets
afforded 18.96 g (89%) of allyloxyamine as a colorless liq-
uid, bp 94–97 °C (lit. value (17) bp 98 to 99 °C).
3
3
4
(3H, d, J = 7.3 Hz, MeCH), 4.45 (2H, dq, J = 6.0 Hz, J =
3
1.1 Hz, OCH2CH=CH2), 5.09 (1H, q, J = 7.3 Hz, MeCH,),
5.21 (2H, CH2Ph), 5.25–5.47 (2H, m, CH=CH2, allyl), 5.76–
3
3
3
6.15 (1H, m, J = 6.0 Hz, Jcis = 10.0 Hz, Jtrans = 17.3 Hz,
CH=CH2, allyl), 5.83 (1H, dd, J = 2.7 Hz, Jcis = 7.6 Hz,
2
3
CH=CHAHB, acryloyl), 6.48 (1H, dd, J = 2.7 Hz, Jtrans
=
2
3
17.2 Hz, CH=CHAHB, acryloyl), 6.80 (1H, dd, 3Jcis = 7.6 Hz,
3Jtrans = 17.2 Hz, CH=CH2, acryloyl) 7.39 (5H, Ph). 13C
NMR (100 MHz, CDCl3) δ: 14.06, 56.45, 67.10, 78.27, 120.28,
126.21, 128.07, 128.21, 128.48, 130.04, 130.91, 135.47,
168.22, 170.35. MS (CI, isobutane), m/z: 290 (M+ + 1).
Anal. calcd. for C16H19NO4 (%): C 66.4, H 6.6, N 4.8;
found: C 66.4, H 6.7, N 5.1.
(R)-2-(3-Oxo-3,6-dihydro[1,2]oxazin-2-yl)-propionic acid
benzyl ester (13a)
A solution of (R)-N-acryloyl-N-allyloxyalanine benzyl
ester (12a) (7.32 g, 25.3 mmol) and bis(tricyclohexylphos-
phine)benzylideneruthenium dichloride (1.04 g, 1.26 mmol,
5 mol%) in dry CH2Cl2 (250 mL) was refluxed for 6 h under
nitrogen, with stirring. Stirring was continued for 20 h at
room temperature and the dark brown reaction mixture was
then filtered through a short pad of silica gel 60H (for TLC),
which was washed with CH2Cl2 (50 mL). After concentra-
(R)-N-Allyloxyalanine benzyl ester (11a)
A solution of triflic anhydride (10.86 g, 38.5 mmol) in dry
CH2Cl2 (20 mL) was added dropwise to a solution of benzyl
(S)-lactate (10a) (6.31 g, 35 mmol) in dry CH2Cl2 (100 mL)
with cooling (–68 to –72 °C) and stirring. After 5–7 min, a
solution of 2,6-lutidine (4.31 g, 40.3 mmol) in dry CH2Cl2
(15 mL) was added dropwise at the same temperature and
© 2005 NRC Canada

Shustov et al.
97
tion of the filrate, the dark oily residue was purified by dry
flash chromatography (silica gel 60H for TLC, 5% EtOAc –
hexanes to 15% EtOAc – hexanes) to afford 6.05 g (92%) of
1H NMR (400 MHz, CDCl3, major isomer) δ: 1.50 (3H, d,
3J = 7.4 Hz, MeCH), 4.84 (1H, dd, 2J = 11.5 Hz, 3J =
6.1 Hz, OCHACH=CH2), 4.80 (1H, q, MeCH, J = 7.4 Hz),
3
1
2
3
the product. IR (film, cm–1): 1745, 1675, 1214, 1189. H
4.84 (1H, dd, J = 11.5 Hz, J = 6.1 Hz, OCHBCH=CH2),
NMR (400 MHz, CDCl3) δ: 1.53 (3H, d, 3J = 7.3 Hz,
4.89 (1H, dd, JHH = 17.8 Hz, JHP = 12.7 Hz, CHAP), 5.06
2
2
2
3
4
2
2
MeCH), 4.46 (1H, dq, J = –15.9 Hz, J = 3.4 Hz, J =
(1H, d, J = 12.4 Hz, CHAPh), 5.10 (1H, d, J = 12.4 Hz,
2
3
3
1.8 Hz, OCHACH=CH), 4.56 (1H, dq, J = 15.9 Hz, J =
CHBPh), 5.31 (1H, br.d, Jcis = 10.4 Hz, CH=CHD), 5.35
3.4 Hz, 4J = 1.8 Hz, OCHBCH=CH), 5.15 (1H, d, 2J =
(1H, dd, JHH = 17.8 Hz, JHP = 13.8 Hz, CHBP), 5.49 (1H,
2
2
3
3
2
12.4 Hz, CHAPh), 5.19 (1H, q, MeCH, J = 7.3 Hz), 5.22
dd, Jtrans = 17.2 Hz, J = 1.2 Hz, CH=CHE), 5.92–6.02
(1H, d, J = 12.4 Hz, CHBPh), 6.04 (1H, dt, Jcis = 10.0 Hz,
(1H, m, J = 6.1 Hz, Jcis = 10.4 Hz, Jtrans = 17.2 Hz,
2
3
3
3
3
4J = 1.8 Hz, CH=CHCO), 6.72 (1H, dt, Jcis = 10.0 Hz, J =
3.4 Hz, CH2CH=CHCO), 7.27–7.40 (5H, m, Ph). 13C NMR
(100 MHz, CDCl3) δ: 13.71, 53.57, 67.08, 67.57, 122.32,
128.02, 128.26, 128.52, 135.49, 139.67, 164.64, 170.09. MS
(CI, isobutane), m/z: 262 (M+ + 1). Anal. calcd. for
C14H15NO4 (%): C 64.4, H 5.8, N 5.4; found: C 64.3, H
5.85, N 5.6.
CH=CH2), 7.4–7.8 (5H, m, PhCH2), 7.6–7.7 (15H, m, Ph3P).
3
3
Ozonolysis and cyclization of 16
A solution of 16 (6.52 g, 9.95 mmol) in CH2Cl2 (180 mL)
was cooled to –76 to –78 °C, stirred, and saturated with
ozone (moderate bubbling until a persistent blue color re-
mained). Excess ozone was removed by bubbling nitrogen
through the reaction mixture at –76 to –78 °C, and Me2S
(3.1 g, 50 mmol) was added dropwise with stirring. The re-
action mixture was allowed to warm to room temperature
and a solution of K2CO3 (6.91 g, 50 mmol) in water (20 mL)
was added with vigorous stirring. Water (100 mL) was
added and the organic layer was separated, washed with wa-
ter (2 × 30 mL), dried over MgSO4, and concentrated to a
yellow semisolid, which was purified by flash chromatogra-
phy (silica gel 60H, 20% EtOAc – hexanes) to afford 0.70 g
(27%) of 13 as a colorless oil, identical with the material
prepared previously.
(R)-N-(Bromoacetyl)-N-allyloxyalanine benzyl ester (14)
A solution of bromoacetyl bromide (2.22 g, 11 mmol) in
dry CH2Cl2 (20 mL) was added dropwise with cooling (–25 to
–30 °C) and stirring to a solution of (R)-N-allyloxyalanine
benzyl ester (11a) (2.59 g, 11 mmol) and Et3N (1.11 g,
11 mmol) in dry CH2Cl2 (30 mL). The reaction mixture was
stirred for 1 h at 0–5 °C and then allowed to warm to room
temperature. After dilution with CH2Cl2 (ca. 30 mL), the
mixture was washed successively with water (2 × 30 mL),
1 N HCl (30 mL), satd. NaHCO3 (30 mL), dried over
MgSO4, and evaporated to yield 14 as a yellowish oil. IR
1
(film, cm–1): 1746, 1678, 1455, 1214. H NMR (100 MHz,
(R)-N-Acryloyl-N-allyloxyalanine tert-butyl ester (12b)
A solution of triflic anhydride (15.52 g, 55 mmol) in dry
CH2Cl2 (25 mL) was added dropwise to a solution of tert-
butyl (S)-lactate (10b) (6.71 g, 46 mmol) in dry CH2Cl2
(130 mL) with cooling (–68 to –72 °C) and stirring. After 5–
7 min, a solution of 2,6-lutidine (6.16 g, 57.5 mmol) in dry
CH2Cl2 (20 mL) was added dropwise and stirring was
continued for 1.5 h at –68 to –72 °C. A solution of allyl-
oxyamine (6.57 g, 90 mmol) in dry CH2Cl2 (20 mL) was
then added dropwise, with continued cooling and stirring.
After an additional 15 min stirring at –72 °C, the reaction
mixture was allowed to warm to room temperature, and stir-
ring was continued for 15 h. The reaction mixture was then
shaken with satd. NaHCO3 and the organic layer was dried
over magnesium sulfate and evaporated to give 14.31 g (79%
yield) of a 1.0:0.97 mixture of (R)-N-allyloxyalanine tert-
butyl ester (11b) and 2,6-lutidine. Additional 2,6-lutidine
(2.66 g, 24.8 mmol) was added to a solution of this mixture
in dry CH2Cl2 (100 mL), the solution was cooled to –15 to
−20 °C, and a solution of acryloyl chloride (5.09 g,
56.3 mmol) in dry CH2Cl2 (20 mL) was added dropwise,
with stirring. Stirring was continued for 1 h at 0–5 °C and
then 20 h at room temperature. After dilution with CH2Cl2
(ca. 150 mL), the mixture was washed successively with wa-
ter (4 × 50 mL), 1 mol L–1 citric acid (2 × 50 mL), satd.
NaHCO3 (2 × 50 mL), dried over MgSO4, and concentrated
to give 12.73 g of a red oil, which was purified by dry flash
chromatography (silica gel 60H for TLC, 1% EtOAc – hex-
anes to 7% EtOAc – hexanes) to afford 8.91 g (70% over the
two steps) of 12b as a colorless oil. IR (film, cm–1): 2981,
1738, 1667, 1622, 1411. 1H NMR (100 MHz, CDCl3) δ: 1.47
CDCl3) δ: 1.60 (3H, d, 3J = 7.3 Hz, MeCH), 4.08 (2H,
CH2Br), 4.49 (2H, dt, 3J = 6.1 Hz, 4J = 0.9 Hz,
3
OCH2CH=CH2), 4.98 (1H, q, MeCH, J = 7.3 Hz), 5.16–
5.48 (2H, m, CH=CH2), 5.20 (2H, CH2Ph), 5.76–6.15
3
3
3
(1H, m, J = 6.1 Hz, Jcis = 10.0 Hz, Jtrans = 17.3 Hz,
CH=CH2), 7.29–7.41 (5H, m, Ph). MS (CI, isobutane), m/z:
358, 356 (M+ + 1).
Conversion of 14 to 15
A solution of 14 (3.90 g, 11 mmol) in dry toluene
(10 mL) was added dropwise to a solution of triphenyl-
phosphine (2.88 g, 11 mmol) in dry toluene (20 mL), and
the reaction mixture was stirred for 24 h at room tempera-
ture. The precipitated yellow oil was separated, washed with
toluene, and dried in vacuo to give a solid yellowish hygro-
scopic foam, which was reprecipitated from a mixture of dry
CH2Cl2 (10 mL) and absolute ether (ca. 100 mL) to afford
5.16 g (76%) of 15 as a white hygroscopic foam.
Conversion of the bromide salt 15 to the triflate salt 16
A solution of silver trifluoromethanesulfonate (2.56 g,
10 mmol) in dry MeCN (20 mL) was added dropwise with
stirring to a solution of 15 (6.18 g, 10 mmol) in dry MeCN
(25 mL). The yellow precipitate was collected on a sintered
glass funnel using a short pad of Celite® 545, and washed
with MeCN (ca. 50 mL). The filtrate was concentrated under
reduced pressure and the residual yellow foam was dissolved
in CH2Cl2 (100 mL) and a small amount of MgSO4 was
added to coagulate small particles of AgBr. The solution was
filtered again and the filtrate was concentrated to provide
6.52 g (quant) of 16 as a yellow highly hygroscopic foam.
3
(9H, Me3C), 1.53 (3H, d, J = 7.3 Hz, MeCH), 4.48 (2H, dq,
© 2005 NRC Canada

98
Can. J. Chem. Vol. 83, 2005
4
3
3J = 5.9 Hz, J = 1.2 Hz, OCH2CH=CH2), 4.93 (1H, q, J =
washed successively with satd. NaHCO3 (3 × 5 mL) and
brine (2 × 5 mL), dried over anhydr. MgSO4, and concen-
trated to give 0.99 g of a yellow solid. Recrystallization
from hexanes yielded 0.82 g (80%) of 10c as white crystals,
7.3 Hz, MeCH,), 5.26–5.50 (2H, m, CH=CH2, allyl), 5.76–
3
3
3
6.18 (1H, m, J = 5.9 Hz, Jcis = 10.1 Hz, Jtrans = 15.6 Hz,
CH=CH2, allyl), 5.81 (1H, dd, J = 2.6 Hz, Jcis = 9.5 Hz,
2
3
CH=CHAHB, acryloyl), 6.46 (1H, dd, J = 2.6 Hz, Jtrans
=
mp 71 to 72 °C. H NMR (400 MHz, CDCl3) δ: 0.76 (d, 3H,
2
3
1
17.0 Hz, CH=CHAHB, acryloyl), 6.80 (1H, dd, 3Jcis = 9.5 Hz,
3Jtrans = 17.0 Hz, CH=CH2, acryloyl). 13C NMR (100 MHz,
CDCl3) δ: 14.12, 27.91, 57.28, 78.22, 81.83, 120.02, 126.42,
129.75, 131.09, 132.41, 168.34, 169.55. MS (CI, isobutane),
m/z: 256 (M+ + 1).
-CH3), 1.02 (d, 3H, -CH3), 2.12–2.23 (m, 1H, CHMe2), 2.68
(br. s, 1H, OH), 4.16 (d, 1H, CHOH), 6.96 (s, 1H, CHPh2),
7.20–7.45 (m, 10H, ArH). MS (CI, isobutane), m/z: 285 (M+
+ 1). Anal. calcd. for C18H20O3 (%): C 76.03, H 7.09; found:
C 76.13, H 7.12.
Cyclization of 12b to 13b
(R)-2-Allyloxyamino-3-methylbutryic acid benzhydryl
ester (11c)
A solution of (R)-N-acryloyl-N-allyloxyalanine tert-butyl
ester (12b) (3.39 g, 13.27 mmol) and bis(tricyclohexyl-
phosphine)benzylideneruthenium dichloride (Grubbs’ cata-
lyst) (0.48 g, 0.58 mmol, 4.4 mol%) in dry benzene (120 mL)
was refluxed with stirring under nitrogen for 6 h. Additional
amounts (0.23 g, 0.28 mmol and 0.21 g, 0.25 mmol) of the
catalyst were added and the reaction mixture was refluxed
for 8 h after each of these additions. The dark brown reac-
tion mixture was then filtered through a short pad of silica
gel 60H (for TLC), which was washed with CH2Cl2
(100 mL). The filtrate was concentrated and the dark oily
residue was purified by dry flash chromatography (silica gel
60H for TLC, 5% EtOAc – hexanes to 20% EtOAc – hex-
anes) to afford 2.45 g (81%) of 13b as an oil. IR (film, cm–1):
A solution of triflic anhydride (4.42 mL, 26.29 mmol) in
dry CH2Cl2 (12 mL) was added dropwise via syringe to a so-
lution of 10c (6.50 g, 22.86 mmol) in dry CH2Cl2 (70 mL),
with cooling (–68 to –70 °C) and stirring. After 5 min, a so-
lution of 2,6-lutidine (3.19 mL, 27.43 mmol) in dry CH2Cl2
(10 mL) was added dropwise. The pale yellow reaction mix-
ture was stirred at –68 °C for 1 h, warmed to room tempera-
ture, and stirred for an additional 17 h. The solvent was
removed under reduced pressure and the residue (in EtOAc)
was washed with 1 N citric acid (5 × 100 mL), dried over
anhydr. MgSO4, and evaporated to give 9 g of a red
semisolid. This was purified via dry flash chromatography
(silica gel 60H for TLC, 5% EtOAc – hexanes) to afford
8.04 g of the triflate as a pale yellow solid. 1H NMR
(400 MHz, CDCl3) δ: 0.89 (d, 3H, -CH3), 1.05 (d, 3H, -CH3),
2.38–2.46 (m, 1H, CHMe2), 5.04 (d, 1H, CHOSO2CF3), 7.00
(s, 1H, CHPh2), 7.20–7.42 (m, 10H, ArH). MS (CI, isobu-
tane), m/z: 417 (M+ + 1). Anal. calcd. for C19H19O5SF3 (%):
C 54.80, H 4.60; found: C 54.55, H 4.63.
A solution of allyloxylamine (5.41 g, 0.074 mol) in dry
CH3CN (35 mL) was added, with stirring, to a solution of
the above triflate (7.71 g, 0.018 mol) in dry CH3CN
(80 mL). The reaction mixture was refluxed for 3 h, cooled
to room temperature, and evaporated under reduced pres-
sure. The residue, in EtOAc (100 mL), was washed succes-
sively with satd. NaHCO3 (3 × 100 mL) and brine (2 ×
100 mL), dried over anhydr. MgSO4, and concentrated to
give 6.67 g of a pale yellow oil. Purification by dry flash
chromatography (silica gel 60H for TLC, 10% EtOAc – hex-
1
2979, 1737, 1677, 1368, 1162. H NMR (400 MHz, CDCl3)
3
δ: 1.46 (9H, Me3C), 1.53 (3H, d, J = 7.3 Hz, MeCH), 4.49
(1H, dq, 2J = 15.8 Hz, 3J = 3.4 Hz, 4J = 1.8 Hz,
2
3
OCHACH=CH), 4.64 (1H, dq, J = –15.8 Hz, J = 3.4 Hz,
4J = 1.8 Hz, OCHBCH=CH), 5.03 (1H, q, MeCH, 3J = 7.3 Hz),
3
4
6.05 (1H, dt, Jcis = 10.0 Hz, J = 1.8 Hz, CH=CHCO), 6.74
3
3
(1H, dt, Jcis = 10.0 Hz, J = 3.4 Hz, CH2CH=CHCO). 13C
NMR (100 MHz, CDCl3) δ: 13.77, 27.95, 54.16, 67.53,
81.82, 122.46, 139.47, 164.67, 169.28. MS (CI, isobutane),
m/z: 228 (M+ + 1). Anal. calcd. for C11H17NO4 (%): C 58.1,
H 7.5, N 6.2; found: C 58.4, H 7.7, N 6.3.
(R)-3-Methyl-2-(3-oxo-3,6-dihydro[1,2]oxazin-2-yl)-
butyric acid (13, R1 = H, R2 = CH(Me)2)
A solution of 13c (2.00 g, 5.47 mmol) in 98% formic acid
(120 mL) was stirred vigorously at room temperature for
6 h. The solvent was then removed in vacuo, and the residue,
in dry CH2Cl2 (100 mL), was dried over anhydr. MgSO4. Re-
moval of the solvent gave 2.22 g of a yellow oil, which was
purified via dry flash chromatography (silica gel 60H for
TLC, 30% EtOAc – hexanes → 100% EtOAc) to afford
1
anes) afforded 5.62 g (89%) of 11c as a colorless oil. H
NMR (400 MHz, CDCl3) δ: 0.86 (d, 3H, -CH3), 0.92 (d, 3H,
-CH3), 1.85–1.94 (m, 1H, CHMe2), 3.57 (d, 1H, NCH),
4.17–4.19 (m, 2H, OCH2), 5.14–5.18 (m, 1H, OCH2CH=CHH),
5.22 (dd, 1H, OCH2CH=CHH), 5.83–5.93 (m, 1H, OCH2CH),
6.98 (s, 1H, CHPh2), 7.23–7.40 (m, 10H, ArH). MS (CI, iso-
butane), m/z: 340 (M+ + 1). Anal. calcd. for C21H25NO3 (%):
C 74.31, H 7.42, N 4.13; found: C 74.49, H 7.46, N 4.40.
1
0.82 g (75%) of the product as a yellow solid. H NMR
(100 MHz, CDCl3) δ: 1.10 (d, 3H, -CH3), 1.15 (d, 3H,
-CH3), 2.20–2.80 (m, 1H, CHMe2), 4.40–4.75 (m, 2H,
NOCH2), 4.90 (d, 1H, NCH), 6.15 (dt, 1H, NOCH2CH=CH),
6.81 (dt, 1H, NOCH2CH), 8.33 (br. s, 1H, CO2H). MS (CI,
isobutane), m/z: 200 (M+ + 1).
(R)-2-(N-Acryloyl, N-allyloxyamino)-3-methylbutyric
acid benzhydryl ester (12c)
A solution of 11c (5.08 g, 14.98 mmol) in dry CH2Cl2
(50 mL) was treated in one portion with triethylamine
(3.13 mL, 22.47 mmol). The solution was stirred at room
temperature for 5 min, cooled to 0 °C, and 97% acryloyl
chloride (1.50 mL, 17.98 mmol) was added dropwise via sy-
ringe. This mixture was stirred at 0 °C for 45 min, then al-
lowed to warm to room temperature, and stirring was
continued for 2.5 h. The light orange reaction mixture was
(S)-2-Hydroxy-3-methylbutyric acid benzhydryl ester (10c)
A solution of diphenyldiazomethane (0.70 g, 3.60 mmol)
in EtOAc (5 mL) was added portionwise with cooling (ice
bath) and stirring to a solution of (S)-2-hydroxy-3-methyl-
butyric acid (0.51 g, 4.36 mmol) in EtOAc (5 mL). The re-
sulting purple solution was stirred at room temperature for
6 h until the color faded to pale yellow, and then was
© 2005 NRC Canada

Shustov et al.
99
then diluted with CH2Cl2 (150 mL) and washed successively
with water (3 × 50 mL), 1 N HCl (50 mL), and brine
(100 mL), dried over anhydr. MgSO4, and evaporated to
5.67g of an orange oil. Purification by dry flash chromatog-
raphy (silica gel 60H for TLC, 3% EtOAc – hexanes → 5%
EtOAc – hexanes) gave 4.79 g (81%) of 12c as a yellow oil.
1H NMR (400 MHz, CDCl3) δ: 0.95 (d, 3H, -CH3), 0.96 (d,
3H, -CH3), 2.44–2.54 (m, 1H, CHMe2), 4.15 (dd, 1H,
OCHH), 4.32 (dd, 1H, OCHH), 4.87 (d, 1H, NCH), 5.17–
5.22 (m, 2H, OCH2CH=CH2), 5.73–5.82 (m, 2H, OCH2CH +
NC=OCH), 6.48 (dd, 1H, NC=OCH=CHH), 6.71 (dd, 1H,
NC=OCH=CHH), 6.91 (s, 1H, CHPh2), 7.20–7.40 (m, 10H,
ArH). MS (CI, isobutane), m/z: 394 (M+ + 1).
and the cooling bath was then removed and the mixture al-
lowed to warm to room temperature. Stirring was continued
at room temperature for 17 h and the dark yellow solution
was mixed in a separatory funnel with 250 mL of satd.
NaHCO3. The two layers were gently mixed by bubbling ni-
trogen for 20 min, and then shaken manually. The organic
phase was separated, washed successively with satd.
NaHCO3 (2 × 250 mL) and brine (250 mL), dried over
MgSO4, and evaporated to 24.05 g of a mixture of 11d and
2,6-lutidine (1:0.37, mol:mol), which was used in the next
step without further purification. 1H NMR (100 MHz,
CDCl3) δ: 4.28 (dt, 2H, NOCH2), 4.95 (br. d, 1H, NCH),
5.10–5.45 (m, 2H, NOCH2CH=CH2), 5.72–6.15 (m, 1H,
NOCH2CH), 6.22 (br. d, 1H, NH), 6.98 (s, 1H, CHPh2),
7.02–7.50 (m, 10H, ArH).
(R)-3-Methyl-2-(3-oxo-3,6-dihydro[1,2]oxazin-2-yl)-
butyric acid benzhydryl ester (13c)
Bis(tricyclohexylphosphine)benzylideneruthenium di-
chloride (0.34 g, 0.42 mmol) was weighed directly into a
250 mL flask, placed under a nitrogen atmosphere, and dry
CH2Cl2 (25 mL) was added, followed by a solution of 12c
(3.28 g, 8.33 mmol) in dry CH2Cl2 (60 mL). The dark purple
reaction mixture was refluxed for 4 h, cooled to room tem-
perature, filtered through a short, densely packed pad of sil-
ica gel 60H for TLC (φ - 3.8 cm, l - 2 cm), which was
washed with CH2Cl2 (5 × 20 mL). Removal of the solvent
gave 3.18 g of a brown oil, which was purified via dry flash
chromatography (silica gel 60H for TLC, 5% EtOAc –
hexanes → 20% EtOAc – hexanes) to afford 3.57 g (90%) of
(R)-(N-Acryloyl, N-␣-allyloxyamino)phenylacetic acid
benzhydryl ester (12d)
2,6-Lutidine (4.24 mL, 36.4 mmol) was added dropwise,
with stirring, to a solution of 11d (9.06 g, 24.26 mmol) in
dry CH2Cl2 (75 mL). After 5 min at room temperature, the
reaction mixture was cooled to 0 °C and a solution of 97%
acryloyl chloride (2.44 mL, 29.12 mmol) in dry CH2Cl2
(25 mL) was added dropwise with stirring. This mixture was
stirred at 0 °C for 45 min, then allowed to warm to room
temperature and stirred for 17 h. The reaction mixture was
diluted with CH2Cl2 (50 mL) and washed successively with
water (50 mL), 1 N citric acid (2 × 100 mL), satd. NaHCO3
(2 × 75 mL), and brine (100 mL), dried over anhydr.
MgSO4, and evaporated to a dark orange oil, which was pu-
rified via dry flash chromatography (silica gel 60H for TLC,
3% EtOAc – hexanes → 20% EtOAc – hexanes) to afford
1
the product as a brown oil. H NMR (400 MHz, CDCl3) δ:
0.99 (d, 3H, -CH3), 1.01 (d, 3H, -CH3), 2.44–2.53 (m, 1H,
CHMe2), 4.38 (ddd, 2H, NOCH2), 4.97 (d, 1H, NCH), 6.05
(dt, 1H, NOCH2CH=CH), 6.68 (dt, 1H, NOCH2CH), 6.92 (s,
1H, CHPh2), 7.20–7.40 (m, 10H, ArH). MS (CI, isobutane),
m/z: 366 (M+ + 1).
1
8.36 g (81%) of 12d as a yellow oil. H NMR (400 MHz,
CDCl3) δ: 3.60 (dd, 1H, NOCHH), 4.07 (dd, 1H, NOCHH),
5.04 (dd, 1H, NOCH2CH=CHH), 5.10 (dd, 1H,
NOCH2CH=CHH), 5.53–5.63 (m, 1H, NOCH2CH), 5.84
(dd, 1H, C=OCH), 6.28 (s, 1H, NCH), 6.49 (dd,
C=OCHCHH), 6.77 (dd, 1H, C=OCHCHH), 6.94 (s, 1H,
CHPh2), 7.02–7.46 (m, 15H, ArH). MS (CI, isobutane), m/z:
428 (M+ + 1).
(S)-␣-Hydroxyphenylacetic acid benzhydryl ester (10d)
A solution of diphenyldiazomethane (0.53 g, 2.72 mmol)
in EtOAc (5 mL) was added portionwise with cooling (ice
bath) and stirring to a solution of (S)-mandelic acid (0.50 g,
3.29 mmol) in EtOAc (5 mL). The purple reaction mixture
was stirred at room temperature for 1 h and was then washed
successively with satd. NaHCO3 (3 × 5 mL) and brine (2 ×
5 mL), dried over anhydr. MgSO4, and concentrated to
0.99 g of a yellow solid, which was recrystallized from hex-
anes to give 0.67 g (80%) of the ester, mp 87 to 88 °C (lit.
(R)-(3-Oxo-3,6-dihydro[1,2]oxazin-2-yl)-phenylacetic
acid benzhydryl ester (13d)
Bis(tricyclohexylphosphine)benzylideneruthenium di-
chloride (0.11 g, 0.13 mmol) was weighed directly into a
50 mL flask, placed under a nitrogen atmosphere, and dry
CH2Cl2 (10 mL) was added, followed by a solution of 12d
(1.10 g, 2.58 mmol) in dry CH2Cl2 (15 mL). The purple re-
action mixture was refluxed for 3 h, an additional 0.11 g of
the catalyst was added, and refluxing was continued for an-
other 2 h. The mixture was then allowed to cool to room
temperature and filtered through a short, densely packed pad
of silica gel 60H for TLC (φ - 3.8 cm, l - 2 cm), which was
washed with CH2Cl2 (5 × 20 mL). Evaporation gave a brown
oil, which was purified via column chromatography (5%
EtOAc – hexanes → 30% EtOAc – hexanes) to afford 0.50 g
1
value (18) mp 87 to 88 °C). H NMR (400 MHz, CDCl3) δ:
3.45 (d, 1H, OH), 5.28 (d, 1H, CHOH), 6.75 (s, 1H,
CHPh2), 7.20–7.45 (m, 15H, ArH).
(R)-␣-Allyloxyaminophenylacetic acid benzhydryl ester
(11d)
A solution of triflic anyhydride (10.80 mL, 64.47 mmol)
in dry CH2Cl2 (25 mL) was added dropwise via syringe to a
solution of 10d (17.85 g, 56.1 mmol) in dry CH2Cl2
(175 mL), with cooling (–68 to –70 °C) and stirring. After
5 min, a solution of 2,6-lutidine (7.80 mL, 67.28 mmol) in
dry CH2Cl2 (25 mL) was added dropwise. The pale yellow
reaction mixture was stirred at –68 °C for 1 h, and a solution
of allyloxyamine (7.29 g, 99.8 mmol) in dry CH2Cl2
(25 mL) was added dropwise with continued cooling and
stirring. The yellow reaction mixture was stirred for 30 min
1
(50%) of 13d as a brown oil. H NMR (400 MHz, CDCl3) δ:
4.34 (ddd, 1H, NOCHH), 4.61 (ddd, 1H, NOCHH), 6.04 (dt,
1H, NOCH2CH=CH), 6.37 (s, 1H, NCH), 6.70 (dt, 1H,
NOCH2CH), 6.96 (s, 1H, CHPh2), 7.10–7.40 (m, 15H, ArH).
MS (CI, isobutane), m/z: 410 (M+ + 1).
© 2005 NRC Canada

100
Can. J. Chem. Vol. 83, 2005
(␣R,4S,5S)-2-(␣-Benzoxycarbonylethyl)-4,5-dihydroxy-
1,2-oxazinan-3-one (17)
(␣R,4R,5R)-2-(␣-Carboxyethyl)-4,5-dihydroxy-1,2-
oxazinan-3-one (20)
Trifluoroacetic acid (0.9 mL) was added in one portion to
a cooled (ca. 0 °C) stirred solution of the tert-butyl ester 19
(0.0467 g, 0.179 mmol) in CH2Cl2 (0.9 mL). The reaction
mixture was maintained at room temperature for 1 h and was
concentrated under reduced pressure. The semisolid residue
was triturated with dry ether and dried in vacuo to afford
A mixture of K2OsO2(OH)4 (0.0063 g, 0.017 mmol),
(DHQD)2PHAL (0.032 g, 0.041 mmol), and AD-mix-β
(1.41 g) was dissolved in a mixture of tert-butanol (5 mL)
and water (5 mL). After dissolution of the salts,
methanesulfonamide (0.099 g, 1.04 mmol) was added and
the mixture was cooled to –2 °C. The benzyl ester 13a
(0.26 g, 1.01 mmol) was added in one portion and the heter-
ogeneous slurry was stirred vigorously for 14 h at –2 to
+2 °C. Sodium sulfite (1.5 g) was added to quench the reac-
tion and stirring was continued for 1 h at room temperature.
Methylene chloride (10 mL) was added and the organic
layer was separated. The aqueous phase was extracted with
CH2Cl2 (5 × 5 mL) and the combined organic extracts were
dried over MgSO4. After removal of the solvent, the yellow-
ish semisolid residue was purified by dry flash chromatogra-
phy (silica gel 60H for TLC, 15% EtOAc – hexanes to
EtOAc) to afford 0.158 g (81%) of the product as a white
1
0.0295 g (80%) of the product as a white solid. H NMR
3
(400 MHz, CD3CN) δ: 1.41 (3H, d, J = 7.3 Hz, α-MeCH),
3.60 (2H, br. s, OH, OH, COOH), 4.14 (1H, dd, 2J =
–11.6 Hz, 3J = 2.3 Hz, 6-HA), 4.34 (1H, d, 3J = 4.1 Hz, 4-H),
2
3
4.40 (1H, dd, J = –11.6 Hz, J = 7.4 Hz, 6-HB), 4.49–4.45
3
(2H, m, 5-H), 5.01 (1H, q, J = 7.3 Hz, α-CH), 5.31 (1H,
br. s, COOH). 13C NMR (100 MHz, CD3CN) δ: 14.45,
54.48, 70.05, 70.99, 77.77, 167.30, 171.82.
(␣R,1R,6R)-2-(␣-tert-Butoxycarbonylethyl)-8-thia-3,7,9-
trioxa-4-azabicyclo[4.3.0]nona-5,8-dione (21)
1
solid. H NMR (400 MHz, CDCl3 + 2 drops of CD3OD) δ:
A solution of thionyl chloride (1.64 g, 13.75 mmol) in dry
CH2Cl2 (15 mL) was added dropwise with cooling (–15 to
−20 °C) and stirring to a solution of the diol 19 (2.40 g,
9.17 mmol) and Et3N (3.71 g, 36.67 mmol) in dry CH2Cl2
(45 mL). After stirring for 1 h at –2 to 2 °C, the reaction
mixture was diluted with CH2Cl2 (60 mL) and washed suc-
cessively with water (20 mL), 1 mol L–1 citric acid (20 mL),
satd. NaHCO3 (20 mL), dried over MgSO4, and evaporated
to give the cyclic sulfite 21 (2.52 g, 90%) as a 1:1 mixture of
diastereomers. 1H NMR (400 MHz, CDCl3) δ: 1.45 (9H,
Me3C), 1.46 (9H, Me3′C), 1.47 (3H, d, 3J = 7.3 Hz, α-
3
2
1.53 (3H, d, J = 7.3 Hz, α-MeCH), 3.96 (1H, dd, J =
−11.8 Hz, 3J = 2.5 Hz, 6-HA), 4.41 (1H, d, 3J = 4.1 Hz, 4-H),
2
3
4.44 (1H, dd, J = –11.8 Hz, J = 6.8 Hz, 6-HB), 4.55–4.51
3
(1H, m, 5-H), 5.11 (1H, q, J = 7.3 Hz, -CH), 5.13 (1H, s,
CH2Ph), 7.34–7.24 (5H, m, Ph).
(␣R,4S,5S)-2-(␣-Carboxyethyl)-4,5-dihydroxy-1,2-
oxazinan-3-one (18)
A suspension of 5% Pd-C (0.137 g) in EtOAc (10 mL)
was stirred for 1 h in a hydrogen atmosphere and a solution
of the benzyl ester 17 (0.137 g, 0.464 mmol) in EtOAc
(15 mL) was added dropwise. The reaction mixture was
stirred for 8 h under hydrogen and filtered through a short
pad of silica gel 60H (for TLC) followed by washing with
MeOH (7 × 5 mL). After evaporation of the filtrate under re-
duced pressure, the residue was triturated with dry ether and
dried in vacuo to provide 0.093 g (98%) of the product as a
3
MeCH), 1.49 (3H, d, J = 7.3 Hz, α-Me′CH), 4.43 (1H, dd,
2J = –12.4 Hz, 3J = 5.5 Hz, 2-HA), 4.48 (1H, dd, 2J =
3
2
−11.5 Hz, J = 5.0 Hz, 2-HA′), 4.51 (1H, dd, J = –11.5 Hz,
3J = 5.0 Hz, 2-HB), 4.60 (1H, dd, 2J = –12.4 Hz, 3J = 6.5 Hz,
3
2-HB′), 5.01 (1H, q, J = 7.3 Hz, α-CH), 5.05 (1H, q, α-CH,
3J = 7.3 Hz), 5.18 (1H, d, J = 8.2 Hz, 6-H), 5.22 (1H, m,
3
3J = 8.2, 6.5, 5.5 Hz, 1-H), 5.37 (1H, d, J = 7.3 Hz, 6-H′),
3
3
5.50 (1H, m, J = 7.3, 5.0 Hz, 1-H′). The compound was
1
white solid. H NMR (400 MHz, CD3CN) δ: 1.44 (3H, d,
used in the next reaction without further purification.
3J = 7.3 Hz, α-MeCH), 3.00 (2H, br. s, OH, OH), 3.90
3
(1H, m, 6-HA), 4.37 (1H, d, J = 4.4 Hz, 4-H), 4.49–4.43
3
(␣R,4S,5R)-2-(␣-tert-Butoxycarbonylethyl)-4-azido-5-
hydroxy-1,2-oxazinan-3-one (22)
(2H, m, 6-HB, 5-H), 5.01 (1H, q, J = 7.3 Hz, -CH), 5.31
(1H, br. s, COOH). 13C NMR (100 MHz, CD3CN) δ: 13.55,
Sodium azide (1.60 g, 24.6 mmol) was added in one por-
tion to a stirred solution of the cyclic sulfite (2.52 g,
8.21 mmol) in HMPA (15 mL), and the solution was stirred
for 24 h at room temperature. Then EtOAc (50 mL) was
added and the resultant mixture was washed successively
with water (2 × 15 mL) and 1 mol L–1 citric acid (15 mL).
The combined aqueous layers were extracted with EtOAc
(3 × 15 mL). The combined organic extracts were washed
successively with satd. NaHCO3 (50 mL), brine (2 × 50 mL),
dried over MgSO4, and concentrated. The dark oily residue
was purified by flash chromatography (silica gel 60H, 1%
MeCN – CH2Cl2 to 10% MeCN – CH2Cl2) to afford 0.37 g
(16%) of the product as a yellowish oil. IR (film, cm–1):
3436, 2981, 2116, 1739, 1685, 1256, 1158. 1H NMR
54.34, 70.15, 70.64, 78.41, 171.22, 172.85.
(␣R,4R,5R)-2-(␣-tert-Butoxycarbonylethyl)-4,5-
dihydroxy-1,2-oxazinan-3-one (19)
This compound was obtained in 83% yield from 13b as a
white solid (mp 93 to 94 °C) as described above, but with
1
(DHQ)2PHAL as the auxiliary. H NMR (400 MHz, CDCl3
3
+ 2 drops of CD3OD) δ: 1.44 (3H, d, J = 7.3 Hz, α-MeCH),
1.45 (9H, Me3C), 2.25 (2H, br. s, OH, OH), 4.30 (1H, dd,
3
3
2J = –11.9 Hz, J = 2.8 Hz, 6-HA), 4.37 (1H, d, J = 4.5 Hz,
2
3
4-H), 4.38 (1H, dd, J = –11.9 Hz, J = 7.3 Hz, 6-HB), 4.56–
4.52 (1H, br. m, 5-H), 4.96 (1H, q, J = 7.3 Hz, α-CH). 13C
3
NMR (100 MHz, CDCl3) δ: 13.96, 27.92, 54.89, 68.89,
69.98, 76.55, 83.01, 169.46, 169.94. IR (KBr), cm–1: 3423,
2985, 1739, 1662, 1415, 1152. MS (CI, isobutane), m/z: 262
(M+ + 1). Anal. calcd. for C11H19NO6 (%): C 50.6, H 7.3, N
5.4; found: C 50.5, H 7.4, N 5.4.
3
(400 MHz, CDCl3) δ: 1.46 (9H, Me3C), 1.48 (3H, d, J =
3
7.3 Hz, α-MeCH), 2.65 (1H, d, J = 4.5 Hz, OH), 4.08–4.02
2
3
(1H, m, 5-H), 4.08 (1H, dd, J = –11.6 Hz, J = 3.5 Hz, 6-
2
3
HA), 4.27 (1H, dd, J = –11.6 Hz, J = 6.1 Hz, 6-HB), 4.37
© 2005 NRC Canada

Shustov et al.
101
3
3
(1H, d, J = 7.6 Hz, 4-H), 4.93 (1H, q, J = 7.3 Hz, α-CH).
13C NMR (100 MHz, CDCl3) δ: 13.32, 27.98, 55.25, 64.62,
70.52, 75.25, 82.79, 167.33, 168.37. MS (CI, isobutane),
m/z: 287 (M+ + 1). Anal. calcd. for C11H18N4O5 (%): C 46.2,
H 6.3, N 19.6; found: C 46.4, H 6.3, N 19.4.
5 mL, cooled to ca. 5 °C and the pH was adjusted to 2 to 3
with 1 mol L–1 HCl (2.8 mL). The white precipitate was col-
lected, washed with water, and dried in vacuo to afford
0.364 g (91%) of 25 as a white solid, mp 194 to 195 °C
(dec.) (from isopropanol). IR (KBr, cm–1): 3361, 2913,
1
1729, 1666, 1630, 1542, 1440, 1233. H NMR (400 MHz,
3
CD3OD) δ: 1.47 (3H, d, J = 7.3 Hz, α-MeCH), 3.62 (1H, d,
(␣R,4S,5R)-2-(␣-Carboxyethyl)-4-azido-5-hydroxy-1,2-
oxazinan-3-one (23)
2J = –14.8 Hz, CHAPh), 3.67 (1H, d, 2J = –14.8 Hz, CHBPh),
2
3
4.06 (1H, dd, J = –11.4 Hz, J = 3.7 Hz, 6-HA), 4.12–4.06
Precooled (ca. 0 °C) trifluoroacetic acid (6.5 mL) was
added dropwise to a cooled (0 to –5 °C) stirred solution of
the tert-butyl ester 21 (0.469 g, 1.64 mmol) in CH2Cl2
(8 mL). The reaction mixture was maintained at room tem-
perature for 1.5 h and was then concentrated under reduced
pressure. Traces of trifluoroacetic acid were removed by re-
peated addition and evaporation of dry ether (3 × 15 mL).
After drying in vacuo, 0.373 g (99%) of the product was ob-
tained as a yellowish semisolid. IR (film, cm–1): 3456, 2959,
2125, 1746, 1654, 1284. 1H NMR (400 MHz, CDCl3) δ: 1.58
2
3
(1H, m, 5-H), 4.33 (1H, dd, J = –11.4 Hz, J = 5.6 Hz, 6-
HB), 4.66 (1H, d, 3J = 8.0 Hz, 4-H), 4.96 (1H, q, 3J =
7.3 Hz, α-CH), 7.38–7.17 (5H, m, Ph). 13C NMR (100 MHz,
CD3OD) δ: 13.71, 43.63, 55.70, 57.54, 71.84, 79.10, 127.85,
129.51, 130.37, 136.63, 169.61, 172.71, 174.89. MS (CI,
isobutane), m/z: 323 (M+ + 1). Anal. calcd. for C15H18N2O6
(%): C 55.9, H 5.6, N 8.7; found: C 55.7, H 5.7, N 8.6.
Functionalization of a 6H[1,2]oxazin-3-one with aq. N-
bromosuccinimide — Bromohydrins, epoxides, and
alcohols
3
(3H, d, J = 7.4 Hz, α-MeCH), 4.10–4.06 (1H, m, 5-H), 4.13
2
3
(1H, dd, J = –11.7 Hz, J = 4.1 Hz, 6-HA), 4.31 (1H, dd,
2J = –11.7 Hz, J = 5.9 Hz, 6-HB), 4.43 (1H, d, J = 7.4 Hz,
3
3
3
4-H), 5.12 (1H, q, J = 7.4 Hz, α-CH), 6.51 (2H, br. s, OH,
COOH). 13C NMR (100 MHz, CD3CN) δ: 13.51, 54.74,
65.75, 71.38, 78.21, 167.55, 170.91. MS (CI, isobutane),
m/z: 231 (M+ + 1). The compound was used in the next reac-
tion without further purification.
(␣R,4S,5R)-2-(␣-Carboxyethyl)-4-amino-5-hydroxy-1,2-
oxazinan-3-one (24)
A suspension of 5% Pd-C (0.175 g) in EtOAc (10 mL)
was stirred for 1.5 h under a hydrogen atmosphere and a so-
lution of the azido alcohol 23 (0.37 g, 1.62 mmol) in EtOAc
(15 mL) was added dropwise. The reaction mixture was
stirred under hydrogen for 17 h and then evaporated to dry-
ness. The residue was washed with dry ether (3 × 15 mL)
and the product was extracted from the dried residue with
hot (ca. 70 °C) water (30 mL). The aqueous solution was fil-
tered through a paper filter and the black solid was washed
with hot water (3 × 10 mL). Evaporation of the filtrate pro-
vided 0.296 g (90%) of the product 24 as a white solid, mp
200–202 °C (dec.). IR (KBr, cm–1): 3158, 1684, 1599, 1568,
The olefin 26 was prepared from the triflate of benzhydryl
S-lactate by sequential reactions with allyloxyamine,
acryloyl chloride, and bis(tricyclohexylphosphine)benzyl-
1
ideneruthenium dichloride. H NMR (100 MHz, CDCl3) δ:
1.60 (3H), 4.40 (2H), 4.57 (1H), 6.05 (1H), 6.68 (1H), 6.91
(1H) 7.35 (10H). N-Bromosuccinimide (1.06 g, 2 equiv.,
5.92 mmol) was added with rapid stirring to a solution of 26
(1.00 g, 2.96 mmol) in DMF (2.3 mL, 10 equiv., 29.6 mmol)
and H2O (110 µL, 2 equiv., 5.92 mmol). The resulting mix-
ture was stirred for 24 h at room temperature. Water (20 mL)
was then added and the mixture was extracted with Et2O
(3 × 30 mL). The combined organic extracts were dried over
MgSO4, and concentrated under reduced pressure to an oil.
Flash column chromatography (5%–30% EtOAc – hexanes,
gradient) provided, in order of elution, a mixture of
dibromides (27) (199 mg), unreacted starting material
(212 mg), and two diastereomeric bromohydrins 28 (268 and
206 mg, 26% and 20%, respectively). There was no reaction
after 48 h when the experiment was performed in aq. THF.
1
1400. H NMR (400 MHz, CD3OD + 1 drop of CF3CO2H)
3
2
δ: 1.52 (3H, d, J = 7.4 Hz, α-MeCH), 4.08 (1H, dd, J =
3
–11.7 Hz, J = 2.5 Hz, 6-HA), 4.18–4.16 (2H, m, 4-H, 5-H),
2
3
4.46–4.41 (1H, dd, J = –11.7 Hz, J = 6.4 Hz, 6-HB), 4.98
(1H, q, J = 7.4 Hz, α-CH). 13C NMR (100 MHz, D2O) δ:
3
17.62, 59.62, 61.42, 73.69, 82.48, 169.06, 180.86. MS (CI,
isobutane), m/z: 205 (M+
+
1). Anal. calcd. for
C7H12N2O5·0.5H2O (%): C 39.4, H 6.1, N 13.1; found: C
39.3, H 6.2, N 13.2.
Dibromides 27
1H NMR (400 MHz, CDCl3) δ: 7.33–7.34 (m, Ar-H), 6.92
(s, H-7), 6.91 (s, H-7′), 5.30 (q, J = 7.3 Hz, H-5), 5.27 (q,
J = 7.3 Hz, H-5′), 4.73 (d, J = 4.0 Hz, H-2), 4.68 (d, J =
4.1 Hz, H-2′), 4.54–4.65 (m, containing 4.63 (dd, J = 4.3,
12.6 Hz, H-4a), 4.51 (dd, J = 5.7, 12.3 Hz, H-4a′)), 4.31 (dd,
J = 12.3, 5.8 Hz, H-4b′), 4.15 (dd, J = 12.7, 4.1 Hz, H-4b),
1.58 (d, J = 7.3 Hz, H-8), 1.56 (d, J = 7.3 Hz, H-8′).13C
NMR (75 MHz, CDCl3) δ: 168.4 and 138.3 (C-6, C-6′),
163.5 and 162.5 (C-1, C-1′), 139.5 and 139.3 (Ar-a, Ar-a′),
128.6, 128.5, 128.3, 128.2, 128.1, 127.4, 127.3, 127.2,
(␣R,4S,5R)-2-(␣-Carboxyethyl)-4-phenylacetylamino-5-
hydroxy-1,2-oxazinan-3-one (25)
A solution of phenylacetyl chloride (0.191 g, 1.24 mmol)
in dry MeCN (3 mL) was added dropwise with cooling
(–5 to –6 °C) and stirring to a solution of the amino acid 24
(0.290 g, 1.36 mmol) and NaHCO3 (0.343 g, 4.08 mmol) in
water (7 mL). The reaction mixture was stirred for 2 h at
0 to −2 °C and for 1 h at room temperature and was then
concentrated under reduced pressure to a volume of ca.
© 2005 NRC Canada

102
Can. J. Chem. Vol. 83, 2005
126.9, 126.8, 126.5, 78.5 and 78.4 (C-7, C-7′), 73.5 and 72.4
(C-4, C-4′), 54.5 and 54.3 (C-5, C-5′), 46.5 and 45.6 (C-2, C-
2′), 43.5 and 43.3 (C-3, C-3′), 13.3 (C-8, C-8′).
and 10% Pd-C (10 mg) was stirred under hydrogen for 18 h
and then filtered through a pad of Celite®. The pad was
washed with ethanol and the combined filtrates were con-
centrated. The residue was partitioned between H2O (10 mL)
and Et2O (10 mL). The ether layer was dried (MgSO4) and
evaporated to a viscous yellow oil. Flash column chromatog-
28 (Less polar isomer)
1H NMR (400 MHz, CDCl3) δ (ppm): 7.29–7.34 (m, Ar-
H), 6.89 (s, H-7), 5.27 (q, J = 7.3 Hz, H-5), 4.44 (dd, J =
5.0, 11.7 Hz, H-4a), 4.42 (dd, J = 0.7, 4.6 Hz, H-2), 4.34–
4.36 (br m, H-3), 4.06 (dd, J = 11.7, 2.5 Hz, H-4b), 3.25
(br s, -OH), 1.59 (d, J = 7.3 Hz, H-8). 13C NMR (75 MHz,
CDCl3) δ (ppm): 169.3 (C-6), 167.0 (C-1), 139.2, 139.1 (Ar-
a), 128.6 (Ar-c), 128.3, 128.1 (Ar-d), 127.2, 126.8 (Ar-b),
78.8 (C-7), 73.0 (C-3), 71.6 (C-4), 54.6 (C-5), 44.7 (C-1),
13.2 (C-8). MS (CI, isobutane), m/z: 435, 433 (M+ + 1).
raphy (10%–80% EtOAc
–
hexanes) provided the
debromination product 30 (27 mg). 1H NMR (400 MHz,
CDCl3) δ (ppm): 7.31–7.37 (m, Ar-H), 6.90 (s, H7-), 5.32 (q,
J = 7.3 Hz, H-5), 4.35–4.42 (m, H-3), 4.13 (dd, J = 11.8,
5.4 Hz, H-2a), 4.01 (ddd, J = 11.8, 3.2, 1.0 Hz, H-2b), 2.77
(dd, J = 15.7, 5.0 Hz, H-4a), 2.64 (ddd, J = 15.7, 3.8,
1.0 Hz, H-4b), 1.56 (d, J = 7.3 Hz, H-8). 13C NMR
(75 MHz, CDCl3) δ (ppm): 169.9 (C-6), 169.2 (C-1), 139.4,
139.3 (Ar-a), 128.6, 128.6 (Ar-c), 128.2, 128.1 (Ar-d),
127.2, 126.8 (Ar-b), 78.5 (C-7), 76.2 (C-4), 66.2 (C-3), 53.5
(C-5), 38.6 (C-2), 13.6 (C-8).
28 (More polar isomer)
1H NMR (400 MHz, CDCl3) δ (ppm): 7.29–7.35 (m, Ar-
H), 6.89 (s, H-7), 5.23 (q, J = 7.3 Hz, H-5), 4.56 (d, J =
6.1 Hz, H-2), 4.46 (dd, J = 11.7, 5.8 Hz, H-4a), 4.28–4.35
(br m, H-3), 3.90 (dd, J = 11.7, 3.5 Hz, H-4b), 2.86 (br s,
-OH), 1.56 (d, J = 7.3 Hz, H-8). 13C NMR (75 MHz, CDCl3)
δ (ppm): 168.7 (C-6), 164.0 (C-1), 139.3 (Ar-a), 128.6 (Ar-
c), 128.3, 128.1 (Ar-d), 127.3, 126.8 (Ar-b), 78.5 (C-7), 74.4
(C-3), 73.0 (C-4), 54.6 (C-5), 49.0 (C-1), 13.7 (C-8). MS
(CI, isobutane), m/z: 435, 433 (M+ + 1).
Acknowledgements
The authors thank Sarah Chinapoo for technical assis-
tance, and the Natural Sciences and Engineering Research
Council of Canada (NSERC), the Western Technology Seed
Investment Fund, and the BC Science Council for financial
support.
Epoxides 29
Potassium carbonate (62 mg, 1.1 equiv.) was added to a
solution of 28 (171 mg, 0.41 mmol) in acetone (2 mL). The
resulting mixture was stirred at room temperature for 24 h,
concentrated under reduced pressure, and the residue shaken
with a mixture of 10% NH4Cl (50 mL) and Et2O (50 mL).
The aqueous phase was extracted with Et2O (3 × 20 mL) and
the combined ether layers were dried over MgSO4 and evap-
orated. Flash column chromatography of the residue (20%–
25% EtOAc – hexanes) afforded the appropriate epoxide
(39.6 mg, 29%).
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29 Isomer I (from the less polar 28)
1H NMR (400 MHz, CDCl3) δ (ppm): 7.31–7.37 (m, Ar-
H), 6.83 (s, H-7), 5.16 (q, J = 7.3 Hz, H-5), 4.40 (d, J =
12.5 Hz, H-4a), 4.02 (d, J = 12.5 Hz, H-4b), 3.65–3.67 (m,
H-2 and H-3), 1.50 (d, J = 7.3 Hz, H-8). 13C NMR (75 MHz,
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a), 128.5, 128.4 (Ar-c), 127.9, 127.8 (Ar-d), 127.0, 126.9
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29 Isomer II (from the more polar 28)
1H NMR (400 MHz, CDCl3) δ (ppm): 7.30–7.37 (m, Ar-
H), 6.89 (s, H-7), 5.31 (q, J = 7.3 Hz, H-5), 4.18 (d of
multiplets, J = 12.7 Hz, H-4a), 4.06 (d, J = 12.7 Hz, H-4b),
3.63 (d, J = 4.1 Hz, H-2), 3.60 (dd, J = 4.1, 1.3 Hz, H-3),
1.55 (d, J = 7.3 Hz, H-8). 13C NMR (75 MHz, CDCl3) δ
(ppm): 169.0 (C-6), 163.7 (C-1), 139.4, 139.3 (Ar-a), 128.5,
128.5 (Ar-c), 128.3, 128.1 (Ar-d), 127.3, 126.7 (Ar-b), 78.3
(C-7), 66.9 (C-4), 53.8 (C-2), 53.3 (C-5), 48.9 (C-3), 13.8
(C-8).
Debromination of 28
A solution of the less polar isomer of 28 (200 mg,
0.196 mmol) in MeOH (1.5 mL) containing Et3N (36 µL)
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© 2005 NRC Canada

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© 2005 NRC Canada