A novel approach to bis-isoxazolines using a latent form of cyclopentadienone

Article abstract of DOI:10.1039/b005520o

The synthesis of a range of both racemic and homochiral 4-alkyl- and 4-aryl-8-hydroxy-2-oxa-3-azabicyclo[3.3.0]oct-3-en-6-ones (isoxazolines) from the 1,3-dipolar cycloaddition reactions between alky- and aryl-nitrile oxides and 4-alkoxycyclopent-2-enomes was described. Elimination of the 8-hydroxy group and subsequent additional cycloaddition reactions provided 5,9-disubstituted-3,11-dioxa-4,10-diazatricyclo[6.3.0^1,8.0^{2 ,6}]undeca-4,9-dien-7-ones formally derived fromcyclopentadienone. The results showed that in the structures studied the nonhydrogen atoms were included in geometric positions and given thermal parameters equivalent to 1.2 times those of the atoms to which they were attached.

Full text of DOI:10.1039/b005520o

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A novel approach to bis-isoxazolines using a latent form of
cyclopentadienone
Sanjivanjit K. Basra,a Michael G. B. Drew,a John Mann*a† and Peter D. Kaneb
1
a Department of Chemistry, Reading University, Whiteknights, Reading, UK RG6 6AD
b Novartis Ltd., Wimblehurst Road, Horsham, UK RH12 4AB
Received (in Cambridge, UK) 10th July 2000, Accepted 25th August 2000
First published as an Advance Article on the web 16th October 2000
We describe the synthesis of a range of both racemic and homochiral 4-alkyl- and 4-aryl-8-hydroxy-2-oxa-3-
azabicyclo[3.3.0]oct-3-en-6-ones (isoxazolines) from the 1,3-dipolar cycloaddition reactions between alky- and
aryl-nitrile oxides and 4-alkoxycyclopent-2-enones. Elimination of the 8-hydroxy group and subsequent additional
cycloaddition reactions provided 5,9-disubstituted-3,11-dioxa-4,10-diazatricyclo[6.3.01,8.02,6]undeca-4,9-dien-7-ones
(bis-isoxazolines) formally derived from cyclopentadienone.
The 1,3-dipolar cycloaddition of nitrile oxides to alkenes to
produce isoxazolines has become a popular route to key inter-
mediates for the construction of both natural products and
novel biologically active molecules.1 The isoxazoline ring not
only provides access to β-hydroxyketones, β-hydroxynitriles, or
γ-aminoalcohols, depending upon subsequent chemistry, but
also has biological interest in its own right. The recent syntheses
of the anti-viral nucleoside analogues 12 and the β-galactoside
as high as 2 days. This compound was obtained with an optical
rotation that was higher than others recorded in the literature.6
Reaction of 4 with nitropropane in the presence of phenyl
isocyanate and triethylamine7 (in benzene) yielded the antici-
pated isoxazoline 5 in yields ranging from 50–78%, while a simi-
lar reaction with 2-(tetrahydropyranyloxy)nitroethane provided
the adduct 6 in 46% yield. Alternatively, a variety of aryl-
isoxazolines 7 could be produced through reaction of 4 with the
oximes of aryl aldehydes in the presence of sodium hypo-
chlorite8 (in DCM). The best yield was obtained with the oxime
1
of 4-bromobenzaldehyde (typically 65%). The H NMR data
for these compounds did not allow a clear-cut decision as to
their relative stereochemistry, both in terms of J values and
after extensive NOE studies. However, an X-ray crystallo-
graphic study on both compounds 5 and 7b confirmed the anti-
stereochemistry of these adducts (Fig. 1 and Table 1).
inhibitors 2,3 are but two examples of compounds that
exemplify this fact. Our aim was to prepare a range of com-
pounds that possessed two isoxazoline rings fused to a
cyclopentanone, but which also carried a number of functional
groups that would allow the production of a ‘library’ of more
complex structures for possible biological evaluation. An over-
view of this approach is shown in Scheme 1.
Adduct 7b also provided an opportunity for further elabor-
ation, and although an attempted Heck reaction9 using Pd()
acetate and methyl acrylate failed to yield the desired product,
Suzuki reactions10 with Pd() acetate and both phenylboronic
acid and thiophene-2-boronic acid, provided the anticipated
products 8 and 9 (24% and 18% respectively, unoptimised).
The feasibility of using compound 4 as a cyclopentadienone
equivalent was then explored using adduct 7b, and to this end
the TBDMS group was first removed (5% aq. HF in MeCN,
52%) to provide alcohol 10. This was dehydrated (SOCl2,
pyridine, 47–74%) to produce the cyclopentenone 11, and
thence the bis-isoxazoline 12 through reaction with nitro-
propane in the presence of phenyl isocyanate and triethylamine
(45%). The anti-arrangement of the two isoxazoline rings was
established through an X-ray structural analysis.
This chemistry was then repeated with adduct 5 to produce
the cyclopentenone 13 which reacted with the THP-ether of
2-nitroethanol in the presence of triethylamine and phenyl iso-
cyanate to yield the bis-isoxazoline 14. Most of these reactions
were then repeated using the pure (4S)-form of compound 4.
Overall this methodology offers the possibility of preparing a
large number of stereochemically pure bis-isoxazolines where
the extent of structural variety will be limited only by the avail-
ability of the nitroalkanes or aryl oximes. We are exploring the
production of such libraries and also the subsequent chemical
transformation of these adducts.
Results and discussion
The starting material for our synthetic endeavours was the well-
known 4-hydroxycyclopent-2-enone 3, which is available on
the multigram scale from furfural using the Bac–Piancatelli
rearrangement.4 Conversion of this compound into its tert-
butyldimethylsilyl ether 4 was then achieved by standard means
(TBDMSCl, imidazole, DCM, 63%). This racemic compound
was then used for all of the initial studies, but it was also pre-
pared in homochiral form via the route shown in Scheme 2.
This uses well-established chemistry5 including a highly stereo-
selective ester hydrolysis with electric eel acetylcholine esterase
to produce (1R,3S)-1-acetoxycyclopent-4-en-3-ol. These investi-
gators went on to prepare the (4R)-enantiomer of compound 4.
We employed a novel sequence involving silyl ether protection,
acetate removal (1 M K2CO3–MeOH), and oxidation with PCC
in dichloromethane to provide the (4S)-enantiomer of 4 in an
overall yield of 54% for these three steps. The oxidation was
complete within 1.5 hours which compares very favourably with
previous efforts involving MnO2,6 where reaction times were
Experimental
† Present address: School of Chemistry, Queen’s University Belfast,
IR spectra were recorded using a Perkin-Elmer 881 series
Belfast, UK BT9 5AG.
3592
J. Chem. Soc., Perkin Trans. 1, 2000, 3592–3598
This journal is © The Royal Society of Chemistry 2000
DOI: 10.1039/b005520o

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Scheme 1
Scheme 2 (i) (Ph3P)4Pd, HOAc, THF (78%); (ii) Ac2O, py, DCM
(84%); (iii) electric eel acetylcholine esterase, NaN3, phosphate buffer
pH 6.9 (93%); (iv) TBDMSCl, imidazole, DCM (83%); (v) K2CO3,
MeOH (86%); (vi) PCC, DCM, NaOAc (89%).
at room temperature. The crystals were positioned at 70 mm
from the Image Plate. 100 Frames were measured at 2Њ intervals
with a counting time of 2 minutes. Data analysis was carried
out with the XDS programme.11 The structures were solved
using direct methods with the SHELX 86 programme.12 The
tert-butyl group was disordered in 7b and two sets of methyl
groups were redefined with occupation factors of x and 1 Ϫ x
with x refining to 0.52(2). In the three structures the non-
hydrogen atoms were included in geometric positions and given
thermal parameters equivalent to 1.2 times those of the atoms
to which they were attached. There were two molecules in the
asymmetric unit of 12. Compounds 7b and 12 were corrected
for absorption using the DIFABS programme.13 The high
R value for 7b is a consequence of the disorder of the tert-
butyl group and the poor quality of the crystal. The quality
of the crystal of 12 was also poor but in both cases the
structure determinations were of sufficient quality to identify
unequivocally the relevant stereochemistry of the molecules.
The structures were refined on F 2 using SHELXL.14 ‡
double beam spectrophotometer, and samples were run as thin
films or in solution using NaCl plates. Low resolution and
accurate mass data were recorded on a VG Autospec. Instru-
ment. Elemental analyses were carried out by Medac Ltd.,
Brunel University, on those compounds that were stable. All
compounds for which exact mass data are provided were
homogeneous by TLC using three different solvent systems,
3,4-Epoxycyclopent-1-ene
An ice-cooled mixture of anhydrous sodium carbonate (108.24
g, 1.02 mol), dichloromethane (450 mL), and cyclopentadiene
(70 mL, 0.85 mol) were stirred mechanically. A solution of 39%
peracetic acid (116 mL, 681 mmol) treated with anhydrous
sodium acetate (2.094 g, 26 mmol) was slowly added to the
mixture over 45 min. After stirring this solution for 2.5 h, below
25 ЊC, the solution was allowed to warm up to room temper-
ature, and stirred until starch-iodide paper indicated the
absence of oxidising agent. The white solid was filtered off and
1
and exhibited no spurious signals in their H NMR spectra at
400 MHz. NMR spectra were recorded using JEOL EX-400,
Bruker DPX 250, or Bruker WM 250 spectrometers. [α]D Values
are given in units of 10Ϫ1 deg cm2 gϪ1. Solvents were dried by
distillation from calcium hydride (DCM, dichloromethane) or
from sodium–benzophenone (diethyl ether, THF).
Crystal data for compounds 5, 7b and 12 were collected with
Mo-Kα radiation using the MARresearch Image Plate System
‡ CCDC reference number 207/479. See http://www.rsc.org/suppdata/
p1/b0/b005520o for crystallographic files in .cif format.
J. Chem. Soc., Perkin Trans. 1, 2000, 3592–3598
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Table 1 Crystal data and structure refinement for 5, 7b and 12
Identification code
5
7b
12
Empirical formula
Formula weight
Crystal system, space group
Unit cell dimensions a/Å
b/Å
C14H25NO3Si
283.44
C18H24NO3Si
410.38
C15H13BrN2O3
349.68
Monoclinic, P21
7.150(9)
9.834(11)
12.116(13)
94.66(1)
849
2, 1.109
2837/0/179
0.0645
Monoclinic, P21/n
7.091(9)
25.43(3)
11.529(14)
96.49(1)
2065
4, 1.320
2619/31/204
0.1249
Monoclinic,P21/n
5.513(8)
49.82(6)
10.840(14)
103.71(1)
2892
8, 1.604
5394/0/382
0.1080
c/Å
β/deg
Volume/Å3
Z, Calculated density/Mg mϪ3
Data/restraints/parameters
Final R indices [I > 2σ(I)] R1
wR2
0.1513
0.2598
0.2013
R indices (all data) R1
wR2
0.0964
0.1650
0.3276
0.3912
0.2553
0.2893
cis-1-Acetoxycyclopent-4-en-3-ol
Tetrakis(triphenylphosphine)palladium (0.242 g) was dissolved
in dry THF (110 mL) under an Ar atmosphere at room tem-
perature. Dry acetic acid (6.1 mL) was added to the ice-cooled
solution. A solution of 3,4-epoxycyclopentene (8.71 g, 106.1
mmol) in dry THF (35 mL) was added slowly to the catalyst
solution via a dropping funnel. After 10 min the solvent was
removed under reduced pressure and the resulting reddish-
brown oil passed through a plug of silica (50 g, 70–200 mesh)
with diethyl ether (450 mL) as eluant. The solution was dried
(MgSO4) and solvent removed under reduced pressure to yield a
pale yellow oil (6.8 g, 78% yield). νmax/cmϪ1 3400 (s) OH, 1735
(s) C᎐O; crude δ (400 MHz; CDCl3; Me4Si) 1.64 (1 H, dt,
᎐
H
J 14.5 and 3.8 Hz, H-2), 1.68 (1 H, dt, J 14.5 and 3.9 Hz, H-2),
1.9–2.1 (1 H, br s, OH), 2.06 (3 H, s, CH3), 4.70 (1H, m, H-3),
5.50 (1 H, m, H-1), 5.99 (1 H, m, HC᎐), 6.12 (1 H, m, HC᎐).
᎐
᎐
cis-1,3-Diacetoxycyclopent-4-ene
The crude monoacetate (6.338 g, 34.8 mmol) was dissolved in
DCM (75 mL) and dry pyridine (14.9 mL) was added under Ar.
Acetic anhydride (15.0 mL) was added to the ice-cooled solu-
tion and the solution left stirring for 48 hours until the reaction
had reached completion. The mixture was extracted with water
(100 mL) and diethyl ether (100 mL), then the ethereal layer was
separated, dried (MgSO4) and the solvent removed under
reduced pressure to give a dark orange–brown liquid. This mix-
ture was chromatographed (130 g flash silica, 3:1 petroleum
spirit–ethyl acetate), to give a pale yellow oil (5.3 g, 84%).
Rf = 0.4 (3:1 petroleum ether–ethyl acetate); νmax/cmϪ1 3069
(m), 2946 (m), 1735 (s) C᎐O, 733 (w), 694 (w); δ (400 MHz;
᎐
H
CDCl3; Me4Si) 1.74 (1 H, dt, J 15.0 and 3.9 Hz, H-2), 2.08 (6 H,
s, CH3), 2.89 (1 H, dt, J 15.0 and 7.5 Hz, H-2), 5.55 (2 H, dd,
J 7.5 and 3.9 Hz, H-1/3), 6.10 (2 H, s, H-4 and 5); δC (100 MHz;
CDCl3; Me4Si) 21.2 (acetate Me), 37.2 (C-2), 76.7 (C-1 and 3),
134.7 (C-4 and 5), 170.7 (2 × C᎐O); m/z (CI) 184.0744 (C H O
᎐
9
12
4
Mϩ requires 184.0736).
Fig. 1 (a) The structure of 5 with ellipsoids at 30% probability; (b) the
structure of 7b with ellipsoids at 30% probability. The tert-butyl group is
disordered and only one set of positions is shown; (c) the structure of
12 with ellipsoids at 30% probability. There are two molecules in the
asymmetric unit with similar conformations. Only one molecule is
shown.
Resolution using electric eel acetylcholine esterase
(1R,3S)-(؉)-1-Acetoxycyclopent-4-en-3-ol. Phosphate buffer
solution, pH 6.9 (1.45 M, 215 mL), was made up to 535 mL
with water, and to this solution was added sodium azide (0.052
g, 0.80 mmol) followed by the electric eel acetylcholine esterase
(0.004 g, 2112 units), and finally 1,3-diacetoxycyclopent-4-ene
(10.84 g, 59.4 mmol). The two-phase mixture was gently stirred
for 9 h, then extracted with diethyl ether (3 × 100 mL) and a
1:1 mixture of diethyl ether–ethyl acetate (15 × 100 mL). The
organic extracts were combined, dried (MgSO4), concentrated
and the residue chromatographed to yield colourless crystals
(6.42 g, 93%). Mp 48.8–51.5 ЊC [1:1 petrol–ether (5 mL
washed thoroughly with DCM. The solvent was removed by
distillation, and the residue purified by reduced pressure distil-
lation (35–44 ЊC, 35–40 mmHg) to provide a colourless oil
(27.74 g, 50%), which was stored below Ϫ20 ЊC. Rf = 0.7 (1:1
petroleum ether (bp 40–60 ЊC)–ethyl acetate); νmax/cmϪ1 3048
(s), 2911 (s), 2819 (w), 1284 (s), 914 (s), 814 (s), 715 (s); δH (400
MHz; CDCl3; Me4Si) 2.48 (2 H, m, CH2), 3.87 (2 H, m, H-1/2),
6.05 (2 H, m, H-3/4); δC (100 MHz; CDCl3; Me4Si) 35.2 (C-5),
56.3 (C-1), 58.6 (C-2), 130.9 (C-4), 137.4 (C-3).
g
Ϫ1)] (lit.5 50.7–51.3 ЊC). Rf = 0.3 (1:1 petroleum ether–ethyl
acetate); [α]D20 ϩ65.7 (c 1.03, chloroform) (lit.5 [α]D23 ϩ73.8,
3594
J. Chem. Soc., Perkin Trans. 1, 2000, 3592–3598

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chloroform); νmax/cmϪ1 3395 (m) OH, 2924 (w) CH2, 1732 (s)
C᎐O, 1358 (w), 1257 (s), 1007 (m); δ (400 MHz; CDCl ; Me Si)
1.66 (1 H, dt, J 14.7 and 3.8 Hz, H-2), 2.06 (3 H, s, CH3 of
acetate), 2.81 (1 H, overlapping dt, J 14.7 and 7.3 Hz, H-2), 4.72
(1 H, m, H-3), 5.50 (1 H, m, H-1), 5.99 (1 H, m, H-4), 6.13 (1 H,
m, H-5); δC (100 MHz; CDCl3; Me4Si) 21.2 (CH3), 40.5 (C-2),
3905–3367 (br s) OH, 2955, 2929 and 2858 (m) CH2, CH3, 1363
(m), 1252 (s), 1070 (s), 1020 (m), 906 (m), 837 (m), 776 (m);
δH (250 MHz; CDCl3; Me4Si) 0.09 (6 H, s, Me of TBS), 0.90
(9 H, s, t-Bu of TBS), 1.52 (1 H, dt, J5,5 13.8, J5,1/4 4.5 Hz, H-5),
1.63 (1 H, br s, OH), 2.64–2.75 (1 H, dt, J5,5 13.8, J5,1/4 7.0 Hz,
H-5), 4.56–4.69 (2 H, m, H-1 and 4), 5.88–5.97 (2 H, m, H-2
and 3); δC (63 MHz; CDCl3; Me4Si) Ϫ4.3 (Me of TBS), 18.6
(t-Bu quaternary), 26.3 (t-Bu), 45.1 (C-5), 75.5 and 75.7 (C-1
and 4), 136.0 and 137.4 (C-2 and 3); m/z (CI) 214.1389
(C11H22O2Si Mϩ requires 214.1389).
᎐
H
3
4
74.8 (C-3), 77.0 (C-1), 132.6 (C-4), 138.5 (C-5), 170.8 (C᎐O of
᎐
acetate).
4-Hydroxycyclopent-2-enone (from furfuryl alcohol) (3)
Furfuryl alcohol (32.70 g, 300 mmol) was dissolved in water
(1000 mL) and the solution de-gassed prior to addition of
hydroquinone (0.35 g, 3.2 mmol) and sodium dihydrogen
orthophosphate (1.63 g, 10.5 mmol). The pH of the solution
was adjusted to 4.1 using 0.25 M orthophosphoric acid before
the reaction mixture was heated under reflux under Ar for
16.5 h. A brown oil developing in the solution after this time
was dispersed with 1,4-dioxane (200 mL). After a further 23 h
the reaction mixture was allowed to cool to room temperature
and extracted with toluene (3 × 100 mL). The remaining aque-
ous phase was concentrated to 150 mL and extracted with ethyl
acetate (6 × 100 mL), dried (MgSO4) and concentrated to give a
crude brown oil (17.258 g, 53% yield). No further purification
was undertaken. Rf = 0.28 (2:1 ethyl acetate–petroleum ether);
νmax/cmϪ1 3388 (br s) OH, 2925 (w) CH , 1713 (s) C᎐O, 1586
(4S)-(؊)-4-tert-Butyldimethylsilyloxycyclopent-2-en-1-one
(؊)-(4)
To a solution of the alcohol 3 (6.419 g, 29.9 mmol) in dry DCM
(140 mL) were added anhydrous sodium acetate (0.737 g, 9.0
mmol) and powdered 4 Å sieves (10.9 g). This mixture was
cooled prior to the portion-wise addition of PCC (9.678 g, 44.9
mmol). The mixture was allowed to warm to RT under N2 and
stirred for 10 min. The chromate salts were precipitated out
with ether (100 mL) and the mixture filtered through Celite–
silica plug and washed thoroughly with ethyl acetate. The com-
bined organic extracts were dried (brine, MgSO4), concentrated
and the residue chromatographed (1.5:8.5 ether–petrol) to
yield colourless crystals (5.661 g, 89%). Mp 29–31 ЊC; lit.,6 32–
33 ЊC; Rf = 0.31 (8.5:1.5 petroleum ether–diethyl ether); [α]D20
Ϫ72.0 (c 0.50, methanol) (lit.,6 [α]D23 Ϫ65.1, c 0.94, methanol);
δH (250 MHz; CDCl3; Me4Si) 0.13 (3 H, s, Me), 0.14 (3 H, s,
Me), 0.91 (9 H, s, t-Bu), 2.25 (1 H, dd, J5,5 18.2, J5,4 2.2 Hz,
H-5), 2.71 (1 H, dd, J5Ј,5 18.2, J5,4 6.0 Hz, H-5), 4.96–5.02 (1 H,
m, H-4), 6.18 (1 H, dd, J2,3 5.7, J2,4 1.3 Hz, H-2), 7.45 (1 H, dd,
J3,2 5.7, J3,4 2.3 Hz, H-3); m/z (CI) 212.1284 (C11H20O2Si Mϩ
requires 212.1283).
᎐
2
(w) C᎐C, 1404 (w), 1342 (m), 1190 (m), 1104 (m), 1045 (m), 947
᎐
(w), 797 (m); δH (400 MHz; CDCl3; Me4Si) 2.29 (1 H, dd, J5,5
18.7, J5,4 2.2 Hz, H-5), 2.78 (2 H, m, J5,5 18.7, J5,4 5.9 Hz, H-5
and OH), 5.06 (1 H, m, H-4), 6.23 (1 H, dd, J3,2 5.5, J2,4 1.3 Hz,
H-2), 7.59 (1 H, dd, J2,3 5.5, J3,4 2.2 Hz, H-3); δC (100 MHz;
CDCl3; Me4Si) 44.2 (CH2), 70.4 (C-4), 135.1 (C-2), 163.4 (C-3),
207.1 (C-1).
(1R,4S)-(؊)-1-Acetoxy-4-tert-butyldimethylsilyloxycyclopent-
2-ene
General procedure for formation of isoxazolines under
Mukaiyama conditions: (1S,5S,8S)-4-ethyl-8-(tert-butyl-
dimethylsiloxy)-2-oxa-3-azabicyclo[3.3.0]oct-3-en-6-one (5)
To a solution of (1R,4S)-(ϩ)-1-acetoxy-4-hydroxycyclopent-2-
ene (5.3 g, 42.0 mmol) in dry DCM (60 mL) was added imid-
azole (4.005 g, 58.8 mmol) and this solution was cooled to 0 ЊC.
A solution of tert-butyldimethylchlorosilane (7.599 g, 50.4
mmol) in dry DCM (40 mL) was added to the reaction mixture
which was allowed to warm to RT, and stirred under N2 for 1 h.
The reaction mixture was extracted from water (50 mL) with
DCM (3 × 25 mL). The organic extracts were combined, dried
and concentrated and the residue chromatographed to yield a
colourless oil (8.91 g, 83%). Rf = 0.3 (0.5:9.5 diethyl ether–
petroleum ether); [α]D20 Ϫ7.2 (c 0.59, chloroform) (lit.,6 [α]D20
Ϫ1.32, c 1.52, MeOH); νmax/cmϪ1 2931 and 2857 (m) CH2, CH3,
To a solution of (4S)-tert-butyldimethylsilyloxycyclopent-2-en-
1-one (0.500 g, 2.35 mmol), dry triethylamine (0.164 mL, 1.18
mmol) and nitropropane (0.53 mL, 5.94 mmol) in dry benzene
(7 mL), was added a solution of phenyl isocyanate (1.60 mL,
9.90 mmol) in dry benzene (6 mL) via a motorised syringe
pump over 6 h. The clear yellow solution became opaque and
slightly viscous during the isocyanate addition. The mixture
was stirred overnight at room temp. and quenched with water
(15 mL). The mixture was filtered through a plug of Celite and
then gravity filtered prior to extraction with benzene. The
organic extracts were combined, dried (brine, MgSO4), concen-
trated and chromatographed to yield a pale yellow crystalline
solid (0.336 g, 50%). Mp 42.0–44.0 ЊC; Rf = 0.50 (1.5:8.5 diethyl
1735 (s) C᎐O, 1369 (m), 1239 (s), 1107 (m) Si–O, 1050 (m), 1022
᎐
(m), 837 (m), 778 (m); δH (250 MHz; CDCl3; Me4Si) 0.09 (3 H, s,
Me of TBS), 0.09 (3 H, s, Me of TBS), 0.90 (9 H, s, t-Bu of
TBS), 1.56–1.66 (1 H, m, H-5), 2.05 (3 H, s, Me of acetate),
2.75–2.87 (1 H, m, H-5), 4.69–4.74 (1 H, m, H-4), 5.44–5.49
(1 H, m, H-1), 5.87–5.98 (2 H, m, H-2 and 3); δC (63 MHz;
CDCl3; Me4Si) Ϫ4.7 and Ϫ4.6 (Me of TBS), 18.2 (t-Bu
quaternary), 21.2 (Me of acetate), 25.9 (t-Bu), 41.2 (C-5), 74.9
ether–petroleum ether); [α]D20 Ϫ500.6 (c 0.54, chloroform); νmax
cmϪ1 2930 and 2857 (s) CH , CH , 1755 (s) C᎐O, 1610–1660 (br
/
᎐
2
3
w) C᎐N, 1463 (m) CH , CH , 1257.8 (m) Si–Me, 1134 (s),
᎐
2
3
1089.1 (m) Si–O, 1044 (m), 922 (m) Si–Me, 836 (s), 780 (m);
δH (250 MHz; CDCl3; Me4Si) 0.10 (3 H, s, Me of TBS), 0.12
(3 H, s, Me of TBS), 0.87 (9 H, s, t-Bu), 1.20 (3 H, t, J 7.3 Hz,
CH3 ethyl), 2.31 (2 H, m, H-7 and 1 H from ethyl CH2), 2.46
(1 H, m, 1 H from ethyl CH2), 2.60 (1 H, dd, J7,7Ј 17.4, J7,8 4.9
Hz, H-7), 3.79 (1 H, m, H-5), 4.51 (1 H, m, J8,7Ј 4.9 Hz, H-8),
5.04 (1 H, unresolved ddd, J1,8 8.6, J1,5 8.6, J1,7 1.5 Hz, H-1);
δC (63 MHz; CDCl3; Me4Si) Ϫ5.0 (Me of TBS), 10.5 (C-ethyl
CH3), 17.9 (quaternary of t-Bu), 19.8 (C-ethyl CH2), 25.6
(t-Bu), 44.8 (C-7), 61.4 (C-5), 71.8 (C-8), 89.9 (C-1), 156.4
(C-4), 208.7 (C-6); m/z (CI) 283.1603 (C14H25NO3Si Mϩ
requires 283.1604).
(C-4), 77.2 (C-1), 131.2 and 138.9 (C-2 and 3), 171.0 (C᎐O); m/z
᎐
(CI) 197.1372 (C13H24O3Si M Ϫ acetateϩ requires 197.1362).
(4S)-(؊)-1-tert-Butyldimethylsiloxycyclopent-2-en-1-ol
To a solution of (1R,4S)-(Ϫ)-1-acetoxy-4-tert-butyldimethyl-
siloxycyclopent-2-ene (8.911 g, 34.8 mmol) in AR methanol
(150 mL) was added a solution of potassium carbonate (1 M,
35.0 mL) at RT. The mixture was stirred for 1.5 h and concen-
trated. The residue was taken up into DCM (50 mL) and
extracted from brine (30 mL) with DCM (5 × 30 mL). The
organic extracts were combined, dried (MgSO4) and concen-
trated to yield a colourless oil (6.419 g, 86%) which was used
without further purification. Rf = 0.29 (3:7 diethyl ether–
petroleum ether); [α]D20 Ϫ30.4 (c 0.5, chloroform); νmax/cmϪ1
Protection of 2-nitroethanol: 2-(2Ј-nitroethoxy)tetrahydropyran
To a solution of 2-nitroethanol (0.201 g, 2.2 mmol) in dry
DCM (2.5 mL) was added PTSA (0.044 g, 0.23 mmol). This
J. Chem. Soc., Perkin Trans. 1, 2000, 3592–3598
3595

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colourless solution was cooled to 0 ЊC prior to the dropwise
addition of 3,4-dihydro-2H-pyran (0.220 mL, 2.4 mmol). The
colourless solution became opaque, and the reaction mixture
was allowed to warm to RT. The solution went through a series
of colour changes—blue, green, then brown as the solution was
stirred overnight under N2. The mixture was extracted from
water (2 mL) with DCM, the organic extracts were combined,
dried, concentrated and the residue purified by column chrom-
atography to yield a colourless oil (0.242 g, 63%). Rf = 0.27 (3:7
diethyl ether–petroleum ether); δH (250 MHz; CDCl3; Me4Si)
1.49–1.63 (4 H, m, H-4 and H-5), 1.65–1.83 (2 H, m, H-6),
3.50–3.58 (1 H, m, H-3), 3.76–3.85 (1 H, m, H-3), 3.94–4.03
(1 H, m, H-2Ј), 4.19–4.27 (1 H, m, H-2Ј), 4.55–4.59 (2 H, m,
H-1Ј), 4.66–4.68 (1 H, m, H-2).
(1S,5S,8S)-4-(4Ј-Bromophenyl)-8-(tert-butyldimethylsiloxy)-2-
oxa-3-azabicyclo[3.3.0]oct-3-en-6-one (7b)
Preparation as for 7a, using (4S)-4-(tert-butyldimethylsiloxy)-
cyclopent-2-enone (4) (1.003 g, 4.7 mmol) to yield a white solid
(1.295 g, 73%). Mp 88–94 ЊC; C18H24BrNO3Si requires C 52.68,
H 5.89, N 3.41%; found C 52.51, H 6.06, N 3.85%; Rf = 0.56
(1:9 diethyl ether–petroleum ether); [α]D20 Ϫ52.2 (c 0.51, chloro-
form); νmax/cmϪ1 2927 (s) CH and CH , 1752 (s) C᎐O, 1399 (m),
᎐
2
3
1257 (m), 1133 (s), 1072 (s), 918 (s), 836 (s), 470 (m); δH (250
MHz; CDCl3; Me4Si) 0.13 (3 H, s, Si–Me), 0.15 (3 H, s, Si–Me),
0.89 (9 H, s, t-Bu), 2.36 (1 H, m, J7,7 17.1 Hz, H-7), 2.65 (1 H,
dd, J7Ј,7 17.1, J7Ј,8 4.7 Hz, H-7Ј), 4.23 (1 H, m, J5,1 8.6 Hz, H-5),
4.60 (1 H, m, J8,7Ј 4.7 Hz, H-8), 5.24 (1 H, m, J1,5 8.6 Hz, H-1),
7.53 (2 H, d, J3Ј,2Ј 8.9 Hz, H-3Ј), 7.75 (2 H, d, J2Ј,3Ј 8.9 Hz, H-2Ј);
δC (100 MHz; CDCl3; Me4Si) Ϫ4.9 (2 × Si–Me), 17.9 (t-Bu
quaternary C), 25.6 (t-Bu), 45.0 (C-7), 58.7 (C-5), 71.0 (C-8),
91.6 (C-1), 125.0 and 126.7 (C-1Ј and C-4Ј), 129.2 (C-3Ј), 131.9
(C-2Ј), 152.8 (C-4), 207.9 (C-6); m/z (CI) 409.0720 (C18H24-
BrNO3Si Mϩ Ϫ H requires 409.0709).
(1S,5S,8S)-4-(Tetrahydropyran-2Ј-yloxymethyl)-8-(tert-butyl-
dimethylsilyloxy)-2-oxa-3-azabicyclo[3.3.0]oct-3-en-6-one (6)
Procedure as for 5, but using THP protected nitroethanol, and
reaction time was approximately 48 h. Reaction carried out on
0.500 g (alkene) scale, to yield a colourless oil (0.296 g, 33%).
Rf = 0.27 (3:7 diethyl ether–petroleum ether); [α]D20 Ϫ243.8
(c 0.53, chloroform); νmax/cmϪ1 2952 (s) CH2, CH3, 2858 (s)
(1S,4S,8S)-4-(4Ј-Iodophenyl)-8-(tert-butyldimethylsilyloxy)-2-
oxa-3-azabicyclo[3.3.0]oct-3-en-6-one (7c)
CH , CH , 1755 (s) C᎐O, 1616 (w) C᎐N, 1472 (m) CH , CH ,
᎐
᎐
2
3
2
3
To a solution of (4S)-(Ϫ)-4-tert-butyldimethylsiloxycyclopent-
2-en-1-one (4) (0.201 g, 0.95 mmol) and 4-iodobenzaldoxime
(0.448 g, 1.8 mmol) in DCM (10 mL) was added triethylamine
(0.014 mL, 0.1 mmol). The pale yellow solution was cooled to
0 ЊC prior to dropwise addition of NaOCl solution (5%, 15 mL)
over 1 h. The opaque mixture was allowed to warm to RT and
stirred vigorously for 43 h. The mixture was extracted with
DCM (3 × 15 mL). The organic extracts were combined, dried
(brine, MgSO4), concentrated and the residue chromatographed
(gradient elution: 100% petroleum ether to 1% diethyl ether in
petroleum ether, to 2% diethyl ether) to yield a white solid
(0.197 g, 45%). Mp 99–106 ЊC; Rf = 0.54 (1:9 diethyl ether–
petroleum ether); [α]D20 Ϫ48.0 (c 0.52, chloroform); νmax/cmϪ1
1391 (m), 1362 (m), 1301.4 (m), 1260 (s), 1202 (w), 1129 (s) Si–
Me, 1078 (s) Si–O, 1037 (s), 921 (m) Si–Me, 837 (s), 780 (m);
δH (250 MHz; CDCl3; Me4Si) 0.10 (3 H, s, Si–Me), 0.12 (3 H, s,
Si–Me), 0.87 (9 H, s, t-Bu), 1.43–1.88 (6 H, m, 3 × CH2 of
THP), 2.34 (1 H, m, J7,7 17.4 Hz, H-7), 2.55 (1 H, dd, J7,7 17.4,
J7,8 4.9 Hz, H-7), 3.46–3.61 (1 H, m, 1 H from CH2 of THP),
3.79–3.97 (1 H, m, 1 H from CH2 of THP), 4.01 (1 H, m, J5,1 8.7
Hz, H-5), 4.14–4.31 (1 H, m, CH2-OTHP), 4.38–4.50 (1 H, m,
CH2-OTHP), 4.50–4.55 (1 H, m, CH of THP), 4.68–4.76 (1 H,
m, H-8), 5.09–5.14 (1 H, m, J1,5 8.7 Hz, H-1); δC (100 MHz;
CDCl3; Me4Si) Ϫ4.9 (Si–Me), 17.9 (t-Bu quaternary), 18.8 and
18.9 (CH2 of THP), 25.2 (CH2 of THP), 25.6 (Me of t-Bu), 30.1
and 30.2 (CH2 of THP), 44.9 (C-7), 59.6 (C-5), 60.3 (CH2-
OTHP), 61.7 and 62.0 (CH2 of THP), 71.6, 71.7 and 71.9 (CH
of THP), 90.6 (C-1), 97.8 and 99.1 (C-8), 152.9 and 153.3 (C-4),
208.0 and 208.2 (C-6); m/z (CI) 369.1957 (C19H30NO5Si Mϩ
requires 369.1972).
2954, 2928 and 2857 (s) CH , CH , 1756 (s) C᎐O, 1584 (w), 1488
᎐
2
3
(w), 1472 (w), 1396 (m), 1332 (w), 1259 (m), 1156 (w), 1131
(m), 1081 (m), 1048 (m), 1006 (m), 920 (m), 836 (m) para-
disubstituted benzene, 780 (m); δH (250 MHz; CDCl3; Me4Si)
0.13 (3 H, s, Me), 0.14 (3 H, s, Me), 0.89 (9 H, s, t-Bu), 2.33–2.40
(1 H, m, J7,7 17.1 Hz, H-7), 2.65 (1 H, dd, J7,7 17.1, J7,8 4.6 Hz,
H-7), 4.21–4.25 (1 H, m, J5,1 8.5 Hz, H-5), 4.60 (1 H, d, J8,7 4.6
Hz, H-8), 5.22–5.27 (1 H, m, J1,5 8.5 Hz, H-1), 7.61 (2 H, dt,
J2Ј,3Ј 8.7, J2Ј,2Ј ≡ J2Ј,3aЈ 2.0 Hz, H-aromatic), 7.76 (2 H, dt, J3Ј,2Ј
8.7, J3Ј,3Ј ≡ J3Ј,2aЈ 2.0 Hz, H-aromatic); δC (63 MHz; CDCl3;
Me4Si) Ϫ4.4 (2 × Me), 18.4 (t-Bu quaternary), 26.1 (t-Bu), 45.4
(C-7), 59.0 (C-5), 71.4 (C-8), 92.1 (C-1), 97.5 (C-aromatic),
127.6 (C-aromatic quaternary), 129.6 (C-aromatic), 138.3
(C-aromatic), 153.4 (C-4), 208.4 (C-6); m/z (CI) 457.0570
(C18H24NO3SiI Mϩ requires 457.0570).
General procedure for the formation of isoxazolines using sodium
hypochlorite: rac-(1S*,5S*,8S*)-4-phenyl-8-(tert-butyldimethyl-
silyloxy)-2-oxa-3-azabicyclo[3.3.0]oct-3-en-6-one (7a)
To a solution of rac-4-(tert-butyldimethylsilyloxy)cyclopent-2-
en-1-one (4) (0.11 g, 0.52 mmol) and benzaldoxime in DCM
(8 ml) at 0 ЊC was added sodium hypochlorite solution (4%
aq., 7.5 ml) dropwise over 15 min. The reaction mixture was
allowed to warm to room temperature and stirred vigorously
for 18 h. The reaction mixture was then extracted with DCM,
the organic extracts combined, dried and concentrated prior to
chromatography that yielded a white crystalline solid. Mp 102–
104 ЊC; Rf = 0.42 (1:9 diethyl ether–petroleum ether); νmax/cmϪ1
3064 (w) aromatic C–C, 2955, 2930 and 2857 (s) CH2 and CH3,
(1S,5S,8S)-4-(4Ј,4Љ-Biphenylyl)-8-(tert-butyldimethylsilyloxy)-
2-oxa-3-azabicyclo[3.3.0]oct-3-en-6-one (8)
1758 –C᎐O, 1593 (m) aromatic C–C, 1506 (w), 1472 and 1446
To a stirred solution of the 4-(4Ј-bromophenyl)-8-(tert-butyl-
dimethylsiloxy)-2-oxa-3-azabicyclo[3.3.0]oct-3-en-6-one (7b)
(0.099 g, 0.24 mmol) and phenylboronic acid (0.031 g, 0.25
mmol) in DME (1 mL) under Ar, was added triphenylphos-
phine (0.02 g, 0.08 mmol) and palladium() acetate (0.005 g,
0.02 mmol), followed by sodium carbonate solution (2 M, 0.145
mL, 0.29 mmol) and water (0.1 mL). The reaction mixture was
heated under gentle reflux for 6.5 h, and during this time the
solution underwent colour changes from yellow to orange, and
finally brown. The reaction mixture was extracted from water
(2 mL) with ethyl acetate. The organic extracts were washed
with dilute sodium bicarbonate solution, dried (MgSO4, brine),
concentrated and chromatographed (gradient elution from
100% petroleum ether to 25% diethyl ether in petroleum ether)
to yield a colourless crystalline solid (0.018 g, 24% yield). Mp
᎐
(m) CH2 and CH3, 1392 (w), 1362 (w) CH3, 1344 (m), 1259 (s)
Si–Me, 1178 (w), 1156 (m), 1131 (s), 1080 (s), 1049 (s), 1023 (w),
100 (w), 976 (w), 920 (m), 836 (s), 780 and 691 (m) monosubsti-
tuted benzene; δH (400 MHz; CDCl3; Me4Si) 0.00 (3 H, s, Me),
0.18 (3 H, s, Me), 0.76 (9 H, s, t-Bu), 2.22 (1 H, unresolved dd,
J7,7Ј 16.9 Hz, H-7), 2.54 (1 H, dd, J7Ј,7 16.9, J7Ј,8 4.4 Hz, H-7Ј),
4.15 (1 H, d, J5,1 8.6 Hz, H-5), 4.47 (1 H, m, H-8), 5.11 (1 H,
d, J1,5 8.6 Hz, H-1), 7.28 (3 H, m, H-aromatic), 7.77 (2 H,
m, H-aromatic); δC (63 MHz; CDCl3; Me4Si) Ϫ4.9 (Si–Me),
17.9 and 18.0 (quaternary of t-Bu), 25.6 (t-Bu), 45.0 (C-7),
58.8 (C-5), 71.1 (C-8), 91.4 (C-1), 128.3 (C-aromatic), 128.7
(C-aromatic), 130.4 (C-aromatic quaternary), 153.5 (C-4),
208.0 (C-6); m/z (CI) 331.1604 (C18H25NO3Si Mϩ requires
331.1604).
3596
J. Chem. Soc., Perkin Trans. 1, 2000, 3592–3598

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135–149 ЊC; Rf = 0.68 (2.5:7.5 diethyl ether–petroleum ether);
[α]D20 Ϫ16.2 (c 1.2, chloroform); νmax/cmϪ1 2955 and 2855 (m)
run in 6:4 diethyl ether–petroleum ether) to yield a yellow oil
(0.032 g, 59% yield). Rf = 0.34 (8:4 diethyl ether–petroleum
–CH , –CH , 1753 (s) –C᎐O, 1488 (w), 1462 (w), 1408 (w), 1336
ether); νmax/cmϪ1 3388 (br s) –OH, 2977 (m) –CH2, –CH3, 1748
᎐
2
3
(w), 1260 (m), 1131 (m), 1079 and 1046 (m) Si–O, 1007 (w), 915
(s), 843 (s) p-substituted benzene, 783 (m), 764 (s) monosubsti-
tuted benzene, 728 (w), 698 (s) monosubstituted benzene;
δH (400 MHz; CDCl3; Me4Si) 0.14 (3 H, s, Si–Me), 0.16 (3 H, s,
Si–Me), 0.90 (9 H, s, t-Bu), 2.37 (1 H, unresolved m, J7,7 17.1
Hz, H-7), 2.70 (1 H, dd, J7,7 17.1, J7,8 4.7 Hz, H-7), 4.31 (1 H,
ddd, J5,1 8.5, J5,7 1.6, J5,8 0.5 Hz, H-5), 4.62 (1 H, m, J8,7 4.7 Hz,
H-8), 5.26 (1 H, m, J1,5 8.5 Hz, H-1), 7.26–7.47 (3 H, m,
H-aromatic), 7.56–7.68 (4 H, m, H-aromatic), 7.94–7.99 (2 H,
m, H-aromatic); δC (63 MHz; CDCl3; Me4Si) Ϫ4.8 (Si–Me),
18.0 (C-t-Bu), 25.7 (Me of t-Bu), 45.0 (C-7), 58.9 (C-5), 71.2
(C-8), 91.5 (C-1), 126.6 (C-aromatic quaternary), 127.1 and
127.4 (C-aromatic), 127.9, 128.2 and 128.9 (C-aromatic), 140.1
and 143.2 (C-aromatic quaternary), 153.4 (C-4), 208.2 (C-1);
m/z (CI) 407.1912 (C24H29NO3Si Mϩ requires 407.1917).
(s) –C᎐O, 1616 (w) C᎐N, 1393 (w), 1288 (w), 1135 (m), 1021 (w),
᎐ ᎐
982 (w), 892 (m); δH (400 MHz; CDCl3; Me4Si) 1.21 (3 H, t,
J 7.5 Hz, CH3 of ethyl), 2.20 (1 H, br s, OH), 2.24–2.58 (3 H, m,
CH2 of ethyl and 1 × H-7), 2.64 (1 H, dd, J7,7 17.9, J7,8 5.1 Hz,
H-7), 3.85 (1 H, d, J5,1 8.8 Hz, H-5), 4.61 (1 H, br d, J8,7 5.1 Hz,
H-8), 5.14 (1 H, unresolved dd, J1,5 8.8, J1,8 1.4 Hz, H-1); δC (63
MHz; CDCl3; Me4Si) 10.261 (CH3), 19.7 (CH2), 44.0 (C-7),
61.5 (C-5), 71.0 (C-8), 89.2 (C-1), 156.6 (C-4), 208.81 (C-6); m/z
(CI) 169.0745 (C8H11NO3 Mϩ requires 169.0739).
(1S,5S,8S)-4-(4Ј-Bromophenyl)-8-hydroxy-2-oxa-3-azabicyclo-
[3.3.0]oct-3-en-6-one (10)
Procedure as for 4-ethyl-8-hydroxy-2-oxa-3-azabicyclo[3.3.0]-
oct-3-en-6-one, using 0.28 g of silyl ether to yield a white solid
(0.104 g, 52%). Mp 138–145 ЊC. Rf = 0.26 (6:4 diethyl ether–
petroleum ether; [α]D20 Ϫ74.0 (c 0.50, chloroform); νmax/cmϪ1
rac-(1S*,5S*,8S*)-4-(4Ј-Thiophen-2Љ-ylphenyl)-8-(tert-butyl-
dimethylsilyloxy)-2-oxa-3-azabicyclo[3.3.0]oct-3-en-6-one (9)
~3500 (br s) OH, 2943 (m) CH , CH , 1753 (s) C᎐O; δ (250
᎐
2
3
H
MHz; CDCl3; Me4Si) 2.18 (1 H, br s, OH), 2.43–2.52 (1 H, m
J7,7 17.7 Hz, H-7), 2.73 (1 H, dd, J7,7 17.7, J7,8 4.8 Hz, H-7), 4.27–
4.31 (1 H, m, J5,1 8.7 Hz, H-5), 4.72 (1 H, d, J8,7 4.8 Hz, H-8),
5.32–5.37 (1 H, m, J1,5 8.7 Hz, H-1), 7.53–7.57 (2 H, m, J3 8.8
Hz, H-aromatic), 7.74–7.78 (2 H, m, J 8.8 Hz, H-aromatic);
δC (63 MHz; CDCl3; Me4Si) 44.4 (C-7), 58.7 (C-5), 70.5 (C-8),
91.0 (C-1), 125.2 and 126.4 (C-aromatic quaternary), 129.2 and
132.1 (C-aromatic), 152.8 (C-4), 207.7 (C-6); m/z (CI) 294.9848
(C12H10NO3Br Mϩ requires 294.9844).
To a stirred solution of the 4-(4Ј-bromobenzyl)-8-(tert-butyl-
dimethylsiloxy)-2-oxa-3-azabicyclo[3.3.0]oct-3-en-6-one (7b)
(0.099 g, 0.24 mmol) and thiophene-2-boronic acid (0.033 g,
0.26 mmol) in DME (1 mL) under Ar, was added triphenyl-
phosphine (0.019 g, 0.07 mmol) and palladium() acetate
(0.005 g, 0.02 mmol) which gave a yellow solution. Addition of
sodium carbonate solution (2 M, 0.145 mL, 0.29 mmol) and
water (0.1 mL) led to colour changes: yellow to orange; to red–
orange; to red. The reaction mixture was heated under gentle
reflux for 5.5 h, which caused a colour change from red to
brown. The reaction mixture was cooled in air and extracted
from water (1 mL) with ethyl acetate. The organic extracts
were washed with dilute sodium bicarbonate solution, dried
(MgSO4, brine), concentrated and chromatographed (gradient
elution from 100% petroleum ether to 25% diethyl ether in
petroleum ether) to yield a colourless crystalline solid (0.012 g,
14% yield). Mp 111–120 ЊC; C22H27NO3SSi requires C 63.89, H
6.58, N 3.38%; found C 63.40, H 6.37, N 3.23%; Rf = 0.62
(2.5:7.5 diethyl ether–petroleum ether); νmax/cmϪ1 2954 (m) and
rac-(1S*,5S*)-4-Ethyl-2-oxa-3-azabicyclo[3.3.0]octa-3,7-dien-
6-one (13)
To a solution of 4-ethyl-8-hydroxy-2-oxa-3-azabicyclo[3.3.0]-
oct-3-en-6-one (0.130 g, 0.77 mmol) in dry DCM (3 mL), was
added dry pyridine (0.124 mL, 1.5 mmol). This yellow solution
was cooled to 0 ЊC under Ar, prior to the dropwise addition of
thionyl chloride (0.06 mL, 0.82 mmol). The reaction mixture
was allowed to warm to RT, and stirred for 2 h. Water (5 mL)
was added to the reaction mixture which was then extracted
with DCM. The organic extracts were combined, dried
(MgSO4, brine), concentrated and the residue chromato-
graphed to yield a pale yellow oil (0.084 g, 72%). Rf = 0.38 (7:3
diethyl ether–petroleum ether); νmax/cmϪ1 2975 and 2349 (m)
2929 (m) CH , CH , 2857 (m) CH , CH , 1756 (s) C᎐O, 1605.5
᎐
2
3
2
3
(w), 1471 (w), 1413 (w), 1339 (w), 1260 (m), 1131 (s), 1080 (m),
1048 (m), 1000 (w), 921 (m), 836 (s) para-substituted benzene,
781 (m), 696.2 (m); δH (400 MHz; CDCl3; Me4Si) 0.13 (3 H, s,
Si–Me), 0.15 (3 H, s, Si–Me), 0.90 (9 H, s, t-Bu), 2.36 (1 H,
unresolved m, J7,7 17.1 Hz, H-7), 2.68 (1 H, dd, J7,7 17.1, J7,8 4.7
Hz, H-7), 4.28 (1 H, unresolved ddd, J5,1 8.5, J5,7 1.6 Hz, H-5),
4.70 (1 H, m, J8,7 4.7 Hz, H-8), 5.25 (1 H, m, J1,5 8.5, J1,7/1,8 1.5
Hz, H-1), 7.1 (1 H, dd, J 5.1, J 3.6 Hz, H-4Љ thiophene), 7.32
(1 H, dd, J 5.1, J 1.2 Hz, H-3Љ/5Љ thiophene), 7.38 (1 H, dd,
J 3.6, J 1.2 Hz, H-3Љ/5Љ thiophene), 7.63–7.68 (2 H, d, J 8.4 Hz,
H-aromatic), 7.88–7.92 (2 H, d, J 8.4 Hz, H-aromatic); δC (63
MHz; CDCl3; Me4Si) Ϫ4.8 (2 Si–Me), 18.0 (quart. t-Bu), 25.7
(3 Me from t-Bu), 45.1 (C-7), 58.9 (C-5), 71.2 (C-8), 91.5 (C-1),
124.0 and 125.8 (C-3Љ and 5Љ thiophene), 126.0 (C-3Ј aromatic),
126.6 (C-aromatic quaternary), 128.3 (C-4Љ thiophene), 128.4
(C-2Ј aromatic), 136.4 and 143.4 (C-4Ј aromatic quaternary and
C-2Љ thiophene quaternary), 153.3 (C-4), 208.1 (C-6); m/z (CI)
413.1484 (C24H29NO3Si Mϩ requires 413.1481).
CH , CH , 1716 (s) C᎐O, 1699 (w), 1683 (w), 1652 (w), 1335 (w),
᎐
2
3
1174 (w), 965 (w), 878 (w), 671 (w); δH (400 MHz; CDCl3;
Me4Si) 1.21 (3 H, t, J 7.5 Hz, CH3 of ethyl), 2.23–2.39 (1 H, m,
CH2 of ethyl), 2.43–2.58 (1 H, m, CH2 of ethyl), 3.84 (1 H, d,
J5,1 7.4 Hz, H-5), 5.69 (1 H, dd, J1,5 7.4, J1,8 2.0 Hz, H-1), 6.26
(1 H, d, J7,8 5.7 Hz, H-7), 7.58 (1 H, dd, J8,7 5.7, J8,1 2.0 Hz,
H-8); δC (63 MHz; CDCl3; Me4Si) 10.3 (C-2Ј), 19.9 (C-1Ј), 59.6
(C-5), 82.7 and 133.8 (C-7), 156.1 (C-4), 159.3 (C-8), 201.3
(C-6); m/z (CI) 151.0638 (C8H9NO2 Mϩ requires 151.0633).
(1S,5S)-4-(4Ј-Bromophenyl)-2-oxa-3-azabicyclo[3.3.0]octa-3,7-
dien-6-one (11)
Procedure as for 4-ethyl-2-oxa-3-azabicyclo[3.3.0]octa-3,7-
dien-6-one using 0.098 g of alcohol to yield a white solid (0.063
g, 68%). Mp 83–86 ЊC; Rf = 0.38 (6:4 diethyl ether–petroleum
ether); [α]D20 ϩ201.3 (c 0.51, chloroform); νmax/cmϪ1 2925 (w)
rac-4-Ethyl-8-hydroxy-2-oxa-3-azabicyclo[3.3.0]oct-3-en-6-one
CH , CH , 1721 (s) C᎐O, 1590 (m) C᎐N, 1491 (m), 1398 (m),
᎐
᎐
2
3
To rac-(1R*,5R*,8R*)-4-ethyl-8-(tert-butyldimethylsilyloxy)-
2-oxa-3-azabicyclo[3.3.0]oct-3-en-6-one (0.100 g, 0.35 mmol)
was added a 5% solution of HF (40% aqueous solution, 0.5
mL) in acetonitrile (2 mL). The orange solution was stirred at
RT for 2.5 h. Water (2 mL) was added to the reaction mixture,
which was then extracted with chloroform. The organic extracts
were combined, dried, concentrated and the residue chromato-
graphed (column packed in 1:1 diethyl ether–petroleum ether,
1388 (m), 1168 (m), 1072 (m), 1009 (m), 895 (m) p-substituted
benzene, 823 (w), 785 (w); δH (250 MHz; CDCl3; Me4Si) 4.31
(1 H, m, J5,1 7.6 Hz, H-5), 5.90–5.95 (1 H, m, J1,5 7.6 Hz, H-1),
6.32 (1 H, d, J7,8 5.7 Hz, H-7), 7.52–7.58 (2 H, m, J 8.8 Hz,
H-aromatic), 7.64–7.67 (2 H, m, J8,7 5.7 Hz, H-8), 7.78–7.83
(2 H, m, J 8.8 Hz, H-aromatic); δC (63 MHz; CDCl3; Me4Si)
57.7 (C-5), 85.2 (C-1), 125.4 and 127.2 (C-aromatic quatern-
ary), 129.6 and 132.3 (C-aromatic), 134.8 (C-7), 152.5 (C-4),
J. Chem. Soc., Perkin Trans. 1, 2000, 3592–3598
3597

View Online
158.7 (C-8), 200.8 (C-6); m/z (CI) 277.9819 (C12H8NO2Br Mϩ
ture was filtered through Celite then filter paper before extract-
requires 277.9817).
ing with benzene. The organic extracts were combined, dried,
concentrated and the residue chromatographed to yield a
colourless crystalline solid (0.029 g, 44%). Mp 157–159 ЊC.
Rf = 0.22 (3:7 diethyl ether–petroleum ether); νmax/cmϪ1 2940 (s)
rac-(1S*,2S*,6R*,8R*)-5-(Tetrahydropyran-2Ј-yloxymethyl)-9-
ethyl-3,11-dioxa-4,10-diazatricyclo[6.3.01,8.02,6]undeca-4,9-dien-
7-one (14)
–CH , –CH , 1751 (s) –C᎐O, 896 (s) p-substituted benzene;
᎐
2
3
δH (400 MHz; CDCl3; Me4Si) 1.22 (3 H, t, J 7.4 Hz, Me of
ethyl), 2.34–2.45 (1 H, m, CH2 of ethyl), 2.51–2.61 (1 H, m,
CH2 of ethyl), 4.04 (1 H, d, J8,1 9.6 Hz, H-8), 4.46 (1 H, d,
J6,2 9.6 Hz, H-6), 5.47 (1 H, d, J1,8 9.6 Hz, H-1), 5.59 (1 H,
d, J2,6 9.6 Hz, H-2), 7.57 (2 H, m, J 8.9 Hz, H-3Ј aromatic),
7.71 (2 H, m, J 8.9 Hz, H-2Ј aromatic); δC (63 MHz; CDCl3;
Me4Si) 10.4 (ethyl CH3), 19.7 (ethyl CH2), 60.0 (C-6), 62.5
(C-8), 87.0 (C-1), 90.0 (C-2), 125.4 and 126.0 (C-1Ј and C-4Ј
aromatic), 129.3 and 132.0 (C-2Ј and C-3Ј aromatic), 152.0
(C-5), 155.4 (C-9), 203.4 and 203.6 (C-7); m/z (CI) 349.0186
(C14H13N2O3Br Mϩ requires 349.0188).
To a solution of rac-4-ethyl-2-oxa-3-azabicyclo[3.3.0]octa-3,7-
dien-6-one (13) (0.08 g, 0.53 mmol) in dry benzene (1.5 mL)
were added the THP protected 2-nitroethanol (0.23 g, 1.31
mmol) and dry triethylamine (0.041 mL, 0.29 mmol). A solu-
tion of phenyl isocyanate (0.40 mL, 0.29 mmol) in dry benzene
(2.5 mL) was added to this pale yellow solution over 4 h via
a motorised syringe pump. The reaction mixture was stirred
under N2 for 72 h and quenched with water (4 mL). This mix-
ture was filtered through Celite then filter paper before extract-
ing with benzene. The organic extracts were combined, dried
(brine, MgSO4), concentrated and the residue chromatographed
to yield a pale yellow oil (0.08 g, 50%). Rf = 0.21 (4:5 diethyl
ether–petroleum ether); νmax/cmϪ1 2942 (s) –CH2, –CH3, 1753
Acknowledgements
S. K. B. thanks Novartis Ltd. for financial support, and we
thank the EPSRC and the University of Reading for funds for
the Image Plate System.
(s) –C᎐O, 1596 (w) C᎐N, 1547 (w), 1500 (w), 1443 (m), 1262
᎐
᎐
(m), 1202 (m), 1123 (s), 1077 (m) C–O–C, 1036 (s), 968 (w), 885
(s); δH (400 MHz; CDCl3; Me4Si) 1.22 (3 H, t, J 7.4 Hz, Me of
ethyl), 1.43–1.83 (6 H, m, CH2 of THP), 2.28–2.42 (1 H, m, CH2
of ethyl), 2.45–2.64 (1 H, m, CH2 of ethyl), 3.44–3.78 (1 H, m,
H-3Ј of THP), 3.83–3.94 (1 H, CH2O of THP), 3.96 (1 H, app.
d, J8,1/6,2 7.5 Hz, H-6/8), 4.02 (1 H, m, H-6/8), 4.21–4.59 (2 H, m,
CH2-O-THP), 4.65–4.74 (1 H, m, H-2Ј of THP), 5.40 (2 H, app.
t, H-1 and H-2); δC (63 MHz; CDCl3; Me4Si) 10.4 (ethyl CH3),
19.1 (CH2 of THP), 19.6 (ethyl CH2), 25.2, 30.2 and 30.2 (C-6Ј/
3Ј/4Ј of THP), 59.5 and 60.2 (C-6 and C-8), 61.0 and 62.5 (CH2-
O-THP and C-3Ј of THP), 87.6 and 87.7 (C-2Ј of THP), 88.6
(C-1), 98.4 (C-2), 152.7 and 152.4 (C-5), 155.0 and 155.1 (C-8),
203.4 and 203.6 (C-7); m/z (CI) 308.1377 (C15H20N2O5 Mϩ
requires 308.1372).
References
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rac-(1S*,2S*,6R*,8R*)-5-( p-Bromophenyl)-9-ethyl-3,11-dioxa-
4,10-diazatricyclo[6.3.01,8.02,6]undeca-4,9-dien-7-one (12)
To a solution of rac-4-(4Ј-bromophenyl)-2-oxa-3-azabicyclo-
[3.3.0]octa-3,7-dien-6-one (11) (0.065 g, 0.23 mmol) in dry
benzene (1 mL) were added the nitropropane (0.052 mL, 0.58
mmol) and dry triethylamine (0.016 mL, 0.11 mmol). A solu-
tion of phenyl isocyanate (0.16 mL, 0.99 mmol) in dry benzene
(2 mL) was added to this pale yellow solution over 3 h via
a motorised syringe pump. The reaction mixture was stirred
under N2 for 45 h and quenched with water (4 mL). This mix-
3598
J. Chem. Soc., Perkin Trans. 1, 2000, 3592–3598