Diastereoselective synthesis of ω-phosphonic acid analogues of 4-arylkainoids

Article abstract of DOI:10.1039/a804666b

Radical cyclisation by the use of α,β-unsaturated phosphonate as a radical acceptor was applied to a synthesis of 7-phosphonomethylpyrrolo[1,2-c]oxazolidinones, synthetic intermediates on the route to phosphonic acid analogues of kainoids. The relative configuration at the 6;7;7a-positions was found to be highly controlled by steric effects due to the substituent at the 6-position. Thus, diethyl [{(6S*,7R*,7aS*)-6-(2-methoxyphenyl)-3-oxoperhydropyrrolo[1,2- c]-[1,3]oxazol-7-yl}methyl]phosphonate 29a and diethyl [{(6S*,7R*,7aS*)-3-oxo-6-phenylperhydropyrrolo[1,2-c][1,3]- oxazol-7-yl}methyl]phosphonate 29b were prepared with high diastereoselectivity. When the substituent at the 6-position is a 1-naphthyl group, the diethyl [{(6S*,7R*,7aS*)-6-(1-naphthyl)pyrroloxazol-7-yl}methyl] phosphonate 29c and its (6S*,7R*,7aR*)-isomer 30c were formed in the ratio 29c:30c～2:1. The stereostructure of compound 29a was determined by X-ray crystallographic analysis. The 6-o-methoxyphenyl derivative 29a was converted into the corresponding phosphonic acid analogue 33.

Full text of DOI:10.1039/a804666b

View Article Online / Journal Homepage / Table of Contents for this issue
Diastereoselective synthesis of ù-phosphonic acid analogues of
4-arylkainoids
Yoko Yuasa, Nobuko Fujimaki, Tsutomu Yokomatsu, Jun Ando and Shiroshi Shibuya*
School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi,
Hachioji Tokyo 192-0392, Japan
Received (in Cambridge) 19th June 1998, Accepted 26th August 1998
Radical cyclisation by the use of α,β-unsaturated phosphonate as a radical acceptor was applied to a synthesis of 7-
phosphonomethylpyrrolo[1,2-c]oxazolidinones, synthetic intermediates on the route to phosphonic acid analogues of
kainoids. The relative configuration at the 6;7;7a-positions was found to be highly controlled by steric effects due to
the substituent at the 6-position. Thus, diethyl [{(6S*,7R*,7aS*)-6-(2-methoxyphenyl)-3-oxoperhydropyrrolo[1,2-c]-
[1,3]oxazol-7-yl}methyl]phosphonate 29a and diethyl [{(6S*,7R*,7aS*)-3-oxo-6-phenylperhydropyrrolo[1,2-c][1,3]-
oxazol-7-yl}methyl]phosphonate 29b were prepared with high diastereoselectivity. When the substituent at the
6-position is a 1-naphthyl group, the diethyl [{(6S*,7R*,7aS*)-6-(1-naphthyl)pyrroloxazol-7-yl}methyl]phosphonate
29c and its (6S*,7R*,7aR*)-isomer 30c were formed in the ratio 29c:30c ~ 2:1. The stereostructure of compound
29a was determined by X-ray crystallographic analysis. The 6-o-methoxyphenyl derivative 29a was converted into
the corresponding phosphonic acid analogue 33.
An oxazolidinone ring can be considered as a synthon for the
synthesis of 2-amino alcohols,1 since it can be easily cleaved
under mild conditions at the two heteroatoms. It is well known
that 2-amino alcohols are preparatively useful precursors
for α-amino acids. Thus, the pyrrolooxazolidinones can be
recognized as useful synthetic intermediates for pyrrolidine-
2-carboxylic acids. The development of new methodologies for
achieving stereocontrolled construction of 6,7-disubstituted
pyrrolooxazolidinones 1 is of particular relevance to 3,4-
disubstituted pyrrolidine-2-carboxylic acids 2,2 which provide
the definitive structural feature of kainoids 3 and related
compounds. The pronounced neuroexcitatory properties of the
kainoids such as (Ϫ)-α-kainic acid 3,3 domoic acid 44 and
acromeric acid 54 have been well investigated to evaluate their
excitatory action on mammalian central neurons.5 These
excitatory amino acids interact with the kainate receptor to
cause strong depolarisation. Therefore, several kinds of
4-arylkainoids possessing strong neurophysiological activity
such as MFPA 64 and HFPA 76 have been prepared to obtain
potential agonists to the kainate receptor.
R
CO2H
R
CO2H
CO2H
CO2H
CO2H
N
N
H
N
H
O
O
2
3
1
H
CO2H
N
O
HO2C
CO2H
CO2H
N
H
CO2H
HO2C
N
H
4
5
OH
OMe
On the other hand, it is also important to find potent gluta-
mate receptor antagonists as well as agonists, since they would
be useful lead compounds to finding potent therapeutic drugs
for neuronal diseases such as epilepsy, Huntington’s chorea and
Parkinson’s disease.7 Discovery of antagonists to the N-methyl-
-aspartate (NMDA) receptor, a sub-type receptor of the
glutamate receptor, have been developed based on the struc-
tural modification of NMDA receptor agonists. A success-
ful modification for this purpose is the replacement of the
ω-carboxylic acid with a phosphonic acid group as illustrated
by compounds AP-5 8,8 AP-7 9,8 CGS 108 and CGP 11,8 which
are known potent antagonists with affinity constants in the
nanomolar range. Indeed, the structure–activity relationship9
showed that good competitive NMDA antagonists were
obtained by replacement of the distal acidic function at the
ω-position with a phosphonic acid. It is important to search
for useful probes in an analysis of physiological functions of
excitatory amino acids. Among sub-type receptor antagonists
for the glutamate receptor, NMDA receptor antagonists have
been well studied. However, kainate receptor antagonists,10
which also would be important molecules is for a study of
neuronal disease, have been relatively unexplored.
CO2H
CO2H
CO2H
N
H
CO2H
N
H
7
6
HO2C
HO2C
PO(OH)2
PO(OH)2
NH2
NH2
8
9
PO(OH)2
PO(OH)2
CO2H
N
CO2H
H
H2N
10
11
J. Chem. Soc., Perkin Trans. 1, 1998, 3577–3584
3577

View Article Online
We became interested in a synthesis of kainate receptor
antagonists by the structural modification of synthetic kainoids
having potent neurophysiological activity. Thus we planned to
prepare phosphonic acid analogues 12 in which the carboxylic
acid at the 3-position of MFPA 6 was replaced by a phosphonic
one. Herein we describe the highly diastereoselective synthesis
of phosphonic acid analogues11 of kainoids via radical cyclis-
ation which has been widely studied as an extremely elegant
method for the preparation of carbocyclic as well as hetero-
cyclic compounds.12 The key characteristic features of our
strategy for the synthesis of phosphonic acid analogues of 4-
arylkainoids is based on the following items: i. The use of
unsaturated phosphonates as a radical acceptor11 (structure 13)
for the introduction of a phosphonomethyl group at the desired
position. ii. A short-step synthesis of the (6-arylpyrrolo[1,2-c]-
OTBDMS
i
CO2CH3
CO2CH3
15
OH
OH
ii
Ar
Ar
Ar
OH
16
17
iii
OTBDMS
O
OTBDMS
O
iv
Ar
Ar
N
O
O
N
O
HO
v
18
19
oxazol-7-yl)methylphosphonate 14,
a synthon for 4-aryl-
2-carboxy-3-(phosphonomethyl)pyrrolidine 12, with high dia-
stereoselectivity (Scheme 1). The radical cyclisation was found
OTBDMS
O
OH
O
Ar
Ar
vi
PO(OEt)2
N
O
N
O
(EtO)2OP
Ar
Ar
PO(OH)2
CO2H
•
PhS
PhS
O
N
20
Ar
4
21
N
N
H
O
vii
O
O
14
12
13
PO(OEt)2
O
CHO
Scheme 1
O
Ar
viii
Ar
to give rise to the formation of allo-type kainoids, not natural-
type ones. We now describe herein the results of our studies.
N
O
N
O
PhS
PhS
22
23
Results and discussion
Synthesis of the precursors for the radical cyclisation
OMe
The synthetic utility of α-acylamino radical cyclisations for the
synthesis of heterocyclic systems has been widely reported.
4-(Phenylthio)oxazolidinones were shown to be useful pre-
cursors for the generation of a radical carbon at the 4-position
of oxazolidin-2-ones by homolytic cleavage of the C᎐S bond.2
Nucleophilic attack of an α-acylamino radical onto a carbon–
carbon double bond has achieved remarkable stereocontrolled
construction of polysubstituted bicyclic systems.2 In view of
the interest in the application of radical cyclisation to polysub-
stituted pyrrolooxazolidinone derivatives, the creation of two
stereogenic centres at the 7- and 7a-position of 6,7-disubstituted
pyrrolo[1,2-c]oxazolidinones via diastereoselective cyclisation
at the alkene has been studied. Radical cyclisation with olefins
are usually dominated by SOMO–LUMO† mixing;12 that is the
carbon radical acts as nucleophile and the olefin as an electro-
phile. Since the electron-withdrawing phosphonyl substituent
lowers the LUMO of the olefin and accelerates the radical
addition, radical reaction with species 13 can be expected to
proceed faster. For the synthesis of 6-aryl-7-(phosphono-
methyl)pyrrolo[1,2-c]oxazolidinone derivatives 14, the new
method for the creation of the stereogenic centre at the 7,7a-
positions has been studied.
As the first step to the N-substituted oxazolidinones 23a–c
which contain a latent radical centre, we synthesized the
3-[3-hydroxy-2-(aryl)propyl]-4-(phenylsulfanyl)-1,3-oxazolan-
2-one 21a–c through the conventional method by starting with
2-arylpropane-1,3-diols 16 as outlined in Scheme 2. Synthesis
of 3-silyloxy-2-arylpropan-1-ols 17a–c was successfully
achieved by treatment of 2-arylpropane-1,3-diols 16a and
16b,c,13 obtained by reduction of dimethyl arylmalonates 15a–c
with LiAlH4, with TBDMSCl in the presence of NaH. Coupl-
Ar =
a;
c;
b;
Scheme 2 Reagents and conditions: i) LiAlH4, Et2O; ii) NaH,
TBDMSCl, THF; iii) oxazolidine-2,4-dione, Ph3P, diisopropyl azodi-
carboxylate, THF; iv) NaBH4, MeOH; v) diphenyl disulfide, tri-n-
butylphosphine, THF; vi) Amberlyst, MeOH; vii) (COCl)2, DMSO,
Et3N, CH2Cl2; viii) CH2[P(O)(OEt)2]2, n-BuLi, THF.
ing of alcohols 17a–c with oxazolidine-2,4-dione by application
of the Mitsunobu reaction14 {Ph P, [PriOC(O)N᎐] in THF}
᎐
3
2
afforded oxazolidinediones 18a–c (70–79%). Reduction of
compounds 18a–c with NaBH4, followed by treatment of the
reduction products 19a–c with diphenyl disulfide in the
presence of tri-n-butylphosphine afforded the corresponding
4-(phenylsulfanyl)oxazolidinones 20a–c as a 1:1 mixture of
diastereomers. Upon exposure of siloxanes 20a–c to acidic
conditions (Amberlyst methanol), the silyl group could be
removed to give the desired alcohols 21a–c. For the preparation
of the 3-arylbut-1-enephosphonates 23a–c, alcohols 21a–c were
converted into the aldehydes 22a–c by Swern oxidation. Treat-
ment of aldehydes 22a–c with tetraethyl methylenediphospho-
nate afforded the desired phosphonates 23a–c in ~72% yield in
each case.
Radical cyclisation of compounds 23a–c
The radical cyclisation of 2-(α)-substituted 4-phenylsulfanyl-3-
(but-3-enyl)oxazolidines such as compounds 24 has been
thoroughly investigated.2 Radical cyclisation of compounds 24
resulted in predominant formation of products 25 with high
diastereoselectivity without formation of the alternative
diastereomer (Scheme 3). However, the diastereoselectivity in
the radical cyclisation has not been studied for those com-
† Singly occupied molecular orbital–lowest unoccupied molecular
orbital.
3578
J. Chem. Soc., Perkin Trans. 1, 1998, 3577–3584

View Article Online
H3C
H
N
O
O
N
O
R
O
R
PhS
25
24
R = CH3, CH2Ph
Scheme 3
pounds in which the substituent was located at a β-position to
the nitrogen atom. In the course of radical cyclisation, three
kinds of possible transition states 26, 27 and 28 should be
considered (Scheme 4).
(EtO)2OP
Ar
Ar
N
H
(EtO)2OP
•
O
Fig. 1 Single-crystal X-ray structure of compound 29a with crystallo-
graphic numbering scheme.
N
O
O
O
29
26
PO(OEt)2
H
(EtO)2OP
O
H
(EtO)2OP
Ar
O
O
N
N
X
O
(EtO)2OP
Ar
O
O
X
•
N
N
PhS
O
O
30
27
23 a; X = OMe, b; X = H
29
H
Ar
H
(EtO)2OP
Ar
PO(OEt)2
O
(EtO)2OP
H
(EtO)2OP
O
N
•
N
O
O
N
O
O
N
O
31
28
O
PhS
OMe
29c
23c
Ar =
a;
c;
b;
+
(EtO)2OP
H
O
N
(EtO)2OP
O
•
(EtO)2OP
N
O
O
O
•
N
O
30c
26c
27c
Scheme 5
Scheme 4 Products 29–31 are equivalent to compound 14 in Scheme 1.
in 81% yield (see Scheme 5). The reaction was, surprisingly,
found to proceed with high diastereoselectivity and the forma-
tion of either alternative diastereomer 30a or 31a was not
observed. A particularly noteworthy feature was that the rad-
ical cyclisation proceeded through the transition state 26
exclusively with complete selectivity with respect to the relative
configuration at the 6-position. The method would be widely
applicable to a synthesis of the (2S*,3R*,4S*)-isomer of
(2S,3S,4S)-MFPA 6, though it would not be applicable to a
synthesis of kainoids possessing the same stereochemistry as
that of MFPA. The stereostructure of product 29a was estab-
lished by X-ray crystallography analysis.15 A single-crystal
X-ray structure of 29a is shown in Fig. 1. A NOESY study of
compound 29a also clearly supported the correlation as shown
in Fig. 2.
The reaction proceeds via these transition states, com-
petitively. The probability of the transition states’ being formed
predominantly during the reaction course determines which
product is obtained. Taking the transition state 26, the form-
ation of product 29, thermodynamically the most stable isomer,
can be expected. The transition state 27 would form product 30.
The difference in stability of the transition states 26 and 27 is
based on the steric hindrance between the double bond and the
oxazolidinone ring, or the aryl group and the oxazolidinone
ring. The alternative transition state 28 is not favoured owing to
the significant severe allylic strain. Thus one cannot expect the
formation of products 31. The C᎐C bond-formation energy
giving the corresponding product would also be an important
factor in the reaction pathway.
At first, radical cyclisation of compound 23a was examined.
Heating of a benzene solution of compound 23a with 1.5 equiv.
of Bu3SnH in the presence of AIBN under reflux gave diethyl
[{(6S*,7R*,7aS*)-6-(2-methoxyphenyl)-3-oxoperhydropyrrolo-
[1,2-c]oxazol-7-yl}methyl]phosphonate 29a as a single product
Radical cyclisation of compound 23b in benzene solution
under reflux failed to give any cyclisation product and resulted
only in recovery of the staring material. Higher temperatures
were required to achieve the reaction. When a toluene solution
was heated, the expected product 29b was obtained in 86% yield
J. Chem. Soc., Perkin Trans. 1, 1998, 3577–3584
3579

View Article Online
OMe
N
(EtO)2OP
OMe
H
i
PO(OH)(OEt)
OH
O
N
Boc
O
29a
ii
OMe
OMe
PO(OMe)(OEt)
PO(OMe)(OEt)
OH
Fig. 2 NOESY correlation of compounds 29a, b, c and 30c.
iii
N
N
CO2H
Boc
Boc
as a single product as expected. In the case of substrate 23c, a
different mode of reaction was observed from that of analogues
23a,b. The reaction proceeded in benzene solution to give the
expected product 29c in 40% yield accompanied by the form-
ation of (6S*,7R*,7aR*)-isomer 30c, in 22% yield. In the rad-
ical cyclisation of compounds 23a,b, the reaction proceeded
through the transition states 26a,b predominantly rather than
27a,b because of the presence of steric hindrance between the
aromatic ring and the oxazolidinone in radicals 27a,b. There-
fore compounds 23a,b afforded only one kind of product, the
stereochemistry of which was shown in products 29a,b. How-
ever, in the radical cyclisation of compound 23c, the reaction
proceeds via two transition states, 26c and 27c, since the naph-
thyl ring is so bulky as to partly inhibit its free rotation. It is
easily predicted that radical 27c is less stable than radical 26c,
because of the steric hindrance produced by the aromatic ring
and the oxazolidinone, from their stereo-model study as above
(see Scheme 4). The cyclisation products 29c and 30c were easily
separated by preparative HPLC as described in the Experi-
mental section. The stereochemistry of products 29a–c and 30c
32
iv
OMe
PO(OMe)(OEt)
N
CO2Me
Boc
33
Scheme 6 Reagents and conditions: i) NaOH, Boc2O, aq. 1,4-dioxane;
ii) CH2N2, Et2O; iii) RuCl3, NaIO4, CCl4, aq. CH3CN.
and coupling constants (J) are given as δ-values (ppm) and in
Hz, respectively. The multiplicity of the signal is indicated as:
s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet,
dd = doublet of doublets, dt = doublet of triplets, br = broad
signal. 13C NMR spectra were recorded in CDCl3 on the Bruker
AM-400 (100 MHz). Chemical shifts are recorded relative to
CDCl3 (central line of triplet, δC 77.0) unless otherwise stated.
IR spectra were recorded by using a Perkin-Elmer FT-IR 1710
spectrometer. Mass spectra (MS) were measured on a TSQ 700
or a VG Auto Spec instrument. Light petroleum refers to the
fraction with distillation range 30–60 ЊC.
1
was determined by H, 13C NMR and NOESY experiments as
in the case of compound 29a. All of the proton and carbon
signals of the cyclisation products 29b,c and 30c could be
assigned satisfactorily. In these radical cyclisations, the form-
ation of the all-cis product 31 was not observed.
Synthesis of 1-tert-butyl-2-methyl (2S*,3R*,4S*)-3-{[ethoxy-
(methoxy)phosphoryl]methyl}-4-(2-methoxyphenyl)tetrahydro-
pyrrole-1,2-dicarboxylate 33
2-(2-Methoxyphenyl)propane-1,3-diol 16a
To a suspension of LiAlH4 (0.76 g, 20.0 mmol) in diethyl ether
(40 cm3) was added a solution of malonate 15a (2.38 g, 10.0
mmol) in diethyl ether (20 cm3) at 0 ЊC. After being stirred for
10 h, the mixture was heated under reflux for 1.5 h. The mixture
was quenched with 20% aq. sodium hydroxide under ice-
cooling. Inorganic substances were removed by filtration. The
organic layer was dried (MgSO4), and evaporated in vacuo. The
resulting residue was chromatographed on silica gel. Elution
with hexane–ethyl acetate (4:1) gave title diol 16a (1.18 g, 65%)
as crystals, mp 75–77 ЊC; δH 7.30–7.20 (m, 1H), 7.20–7.15 (m,
1H), 6.99–6.85 (m, 2H), 4.08–3.97 (m, 2H), 3.97–3.85 (m, 2H),
3.82 (s, 3H) and 3.60–3.50 (m, 1H); δC 157.1, 128.1, 127.8,
127.6, 120.6, 110.6, 64.9 (2 carbons), 55.2 and 42.7; νmax(KBr)/
cmϪ1 3294, 1494, 1242, 965 and 758; m/z (EI) 182.1 (Mϩ)
(Found: C, 65.8; H, 7.75. C10H14O3 requires C, 65.91; H,
7.74%).
At the next stage, it is required to convert the cyclisation
product into the corresponding phosphonic acid analogue of
kainoids. Ring cleavage of the oxazolidinone ring of compound
29a was effected with aqueous base, and subsequent protection
of the nitrogen atom with a tert-butoxycarbonyl group to yield
compound 32 (Scheme 6). Oxidation of the primary hydroxy
group with RuCl3–NaIO4 followed, without purification, by
esterification with diazomethane gave fully protected ester 33
in 19.7% yield. Thus, the method of synthesis of a phosphonic
analogue of the (6S*,7R*,7aS*)-isomers of 6-arylkainoids was
established.
Experimental
All reactions requiring anhydrous conditions were conducted in
flame-dried apparatus under nitrogen. THF and diethyl ether
were distilled from sodium benzophenone ketyl; methylene
dichloride (CH2CH2) was distilled from CaH2. All reactions
were monitored by TLC using commercially available glass-
backed plates. For column chromatography, silica gel 60 (0.043–
0.063 mm) was used and the columns were eluted in the flash
mode. 1H NMR spectra were recorded on a Bruker AM 400 or
a Varian Gemini 300 spectrometer operating at 400 MHz and
300 MHz, respectively, for solution in CDCl3. The chemical
shifts, relative to tetramethylsilane (TMS) where δ(TMS) = 0,
3-(tert-Butyldimethylsilyloxy)-2-(2-methoxyphenyl)propan-1-ol
17a
To an ice-cooled, stirred suspension of 60% NaH (4.40 g, 110.0
mmol: used after removal of oil by washing with light petrol-
eum) in THF (40 cm3) was added dropwise a solution of diol 16a
(18.20 g, 100.0 mmol) in THF (40 cm3). After being stirred at rt
for 1 h, the mixture was treated with a solution of TBDMSCl
(16.58 g, 110.90 mmol) in THF (100 cm3) under ice-cooling.
3580
J. Chem. Soc., Perkin Trans. 1, 1998, 3577–3584

View Article Online
After having been stirred at rt for 8 h, the mixture was quenched
with ammonium chloride, then was extracted with ethyl acetate.
The solution was dried (MgSO4), and the solvent was removed
in vacuo. The residue was chromatographed on silica gel
[hexane–ethyl acetate (50:1)] to give title compound 17a (26.02
g, 88%) as an oil; δH 7.21–7.11 (m, 1H), 7.11–7.01 (m, 1H),
6.87–6.77 (m, 2H), 4.09–3.99 (m, 1H), 3.89–3.79 (m, 2H), 3.79
(s, 3H), 3.53–3.45 (m, 1H), 2.85–2.79 (m, 1H), 0.84 (s, 9H) and
0.00 (s, 6H); δC 157.2, 128.0, 127.9, 127.8, 120.5, 110.5, 66.6,
66.0, 55.3, 42.4, 25.8 (3 carbons), 18.1 and Ϫ5.6 (2 carbons);
νmax(neat)/cmϪ1 3446, 2954, 1494, 1243, 1103, 1055, 837 and
753; m/z (EI) 239.1 (Mϩ Ϫ Bu) (Found: C, 64.5; 9.5. C16H28O3Si
requires C, 64.82; H, 9.52%).
3-[3-(tert-Butyldimethylsilyloxy)-2-(1-naphthyl)propyl]-1,3-
oxazolane-2,4-dione 18c
This compound (3.13 g, 78%) was obtained from the alcohol 17c
(3.16 g, 100.0 mmol) as a crystalline solid according to the same
conditions as above; mp 76–79 ЊC; δH 8.18 (d, J 8.6, 1H), 7.86
(d, J 8.6, 1H), 7.78–7.75 (m, 1H), 7.57–7.45 (m, 4H), 4.48 (d,
J 15.9, 1H), 4.40 (d, J 15.9, 1H), 4.43–4.34 (m, 1H), 4.15 (dd,
J 7.5 and 13.8, 1H), 4.04 (dd, J 8.0 and 13.8, 1H), 4.02–3.92
(m, 2H), 0.88 (s, 9H), 0.01 (s, 3H) and Ϫ0.02 (s, 3H); δC 170.4,
155.9, 134.7, 133.9, 131.9, 129.0, 127.8, 126.5, 125.7, 125.3,
124.3, 122.6, 67.5, 66.3, 43.4, 39.2, 25.8 (3 carbons), 18.3, Ϫ5.5
and Ϫ5.6; νmax(KBr)/cmϪ1 2929, 1826, 1734, 1446, 1079, 837
and 780; m/z (EI) 342.1 (Mϩ Ϫ tBu) (Found: C, 66.2; H, 7.3; N,
3.5. C22H29NO4Si requires C, 66.13; H, 7.32; N, 3.50%).
3-(tert-Butyldimethylsilyloxy)-2-phenylpropan-1-ol 17b
This compound (16.40 g, 62%) was obtained as an oil from diol
16b (15.20 g, 100.0 mmol) according to the same conditions as
above; δH 7.27–7.14 (m, 5H), 4.07–3.96 (m, 1H), 3.89–3.74 (m,
2H), 3.05–2.95 (m, 1H), 2.73–2.69 (m, 1H), 0.85 (s, 9H) and
0.00 (s, 6H); δC 1138.5, 129.6 (2 carbons), 129.0 (2 carbons),
127.7, 64.9, 64.0, 43.7, 25.8 (3 carbons), 18.2 and Ϫ5.6 (2 car-
bons); νmax(neat)/cmϪ1 3393, 2929, 2360, 1472, 1255, 1094, 837
and 669; m/z (EI) 267.1 (Mϩ ϩ 1) (Found: C, 67.4; H, 9.7.
C15H26O2Si requires C, 67.61; H, 9.84%).
3-[3-(tert-Butyldimethylsilyloxy)-2-(2-methoxyphenyl)propyl]-4-
hydroxy-1,3-oxazolan-2-one 19a
To a stirred solution of dione 18a (3.79 g, 10.0 mmol) in metha-
nol (100 cm3) was added NaBH4 (0.76 g, 20.0 mmol) in small
portions at 0 ЊC. After being stirred for 30 min at the same
temperature, then for a further 2 h at rt, the mixture was
quenched with acetone. The solvent was evaporated off and the
resulting residue was diluted with water and extracted with
chloroform. The solution was dried (Na2SO4), and the solvent
was removed in vacuo. The residue was chromatographed on
silica gel with hexane–ethyl acetate (6:1) as eluant to give
title compound 19a (3.12 g, 82%) as a crystalline product; mp
92–95 ЊC; δH 7.27–7.18 (m, 2H), 6.96–6.88 (m, 2H), 5.25–5.18
(m, 0.5H), 5.08–5.01 (m, 0.5H), 4.55–4.45 (m, 1H), 4.45–4.35
(m, 1H), 3.92–3.63 (m, 5H), 3.82 (s, 3H), 0.91 (m, 4.5H), 0.90
(m, 4.5H), 0.05 (s, 3H) and 0.00 (s, 3H); νmax(KBr)/cmϪ1 3311,
2929, 1747, 1475, 1107, 1008, 937 and 776; m/z (EI) 381.1 (Mϩ)
and 324.1 (Mϩ Ϫ tBu) (Found: C, 59.7; H, 8.2; N, 3.7. C19H31-
NO5Si requires C, 59.81; H, 8.19; N, 3.67%).
3-(tert-Butyldimethylsilyloxy)-2-(1-naphthyl)propan-1-ol 17c
This compound (22.85 g, 72%) was obtained from diol 16c
(20.20 g, 100.0 mmol) as an oil [from 15c (20.20 g, 100.0
mmol)]; δH 8.11 (d, J 8.5, 1H), 7.80 (d, J 8.5, 1H), 7.69 (d, J 8.2,
1H), 7.49–7.40 (m, 2H), 7.38–7.33 (m, 1H), 7.23–7.20 (m,
1H), 4.19–4.14 (m, 1H), 4.01–3.87 (m, 3H), 2.90–2.87 (m, 1H),
0.86 (s, 9H) and 0.00 (s, 6H); δC 134.3, 133.9, 131.9, 129.0,
127.8, 126.5, 125.7, 125.3, 124.3, 122.6, 65.7, 64.9, 43.4, 25.8 (3
carbons), 18.3, Ϫ5.5 and Ϫ5.4; νmax(neat)/cmϪ1 3049, 2360,
1471, 1096, 837 and 777; m/z (EI) 259.1 (Mϩ Ϫ tBu) (Found: C,
72.0; H, 8.8. C19H28O2Si requires C, 72.10; H, 8.92%).
3-[3-(tert-Butyldimethylsilyloxy)-2-(2-methoxyphenyl)propyl]-4-
3-[3-(tert-Butyldimethylsilyloxy)-2-(2-methoxyphenyl)propyl]-
hydroxy-1,3-oxazolan-2-one 19b
1,3-oxazolane-2,4-dione 18a
This compound (2.75 g, 78%) was obtained from dione 18b (3.49
g, 10.0 mmol) as a crystalline material according to the same
conditions as above; mp 76–79 ЊC; δH 7.38–7.20 (m, 5H), 5.20–
5.16 (m, 0.5H), 4.82–4.78 (m, 0.5H), 4.24–4.12 (m, 1H), 4.09–
4.03 (m, 1H), 3.94–3.78 (m, 3H), 3.71–3.56 (m, 1H), 3.33–3.25
(m, 1H), 0.90 (s, 9H), 0.03 (s, 3H) and 0.00 (s, 3H); νmax(KBr)/
cmϪ1 3319, 2932, 1719, 1475, 1251, 1109, 839, 775 and 772; m/z
(EI) 352.2 (Mϩ ϩ 1) and 294.1 (Mϩ Ϫ tBu) (Found: C, 61.4; H,
8.3; N, 4.1. C18H29NO4Si requires C, 61.50; H, 8.32; N, 3.99%).
A solution of diisopropyl azodicarboxylate (2.17 cm3, 11.0
mmol) in THF was added dropwise to an ice-cooled, stirred
solution of the alcohol 17a (2.96 g, 10.0 mmol), oxazolidine-
2,4-dione (1.11 g, 11.0 mmol) and triphenylphosphine (2.89 g,
11.0 mmol) in THF (30 cm3). After being stirred at the same
temperature for 10 min, the stirred mixture was kept at rt for
12 h. The solvent was removed in vacuo and the residue was
chromatographed on silica gel. Elution with hexane–ethyl acet-
ate (10:1) gave title compound 18a (2.99 g, 79%); δH 7.25–7.13
(m, 2H), 6.94–6.91 (m, 2H), 4.51 (d, J 15.8, 1H), 4.45 (d, J 15.8,
1H), 4.05–3.84 (m, 3H), 3.84–3.73 (m, 2H), 3.79 (s, 3H), 0.86 (s,
9H) and 0.02 (s, 6H); δC 170.2, 157.4, 155.7, 128.7, 128.2, 126.7,
120.4, 110.5, 67.3, 64.8, 55.2, 41.7, 39.7, 25.7 (3 carbons), 18.2
and Ϫ15.7 (2 carbons); νmax(neat)/cmϪ1 2953, 2342, 1737, 1417,
1246 and 776; m/z (EI) 322.1 (Mϩ Ϫ tBu) (Found: C, 60.0; H,
7.75; N, 3.7. C19H29NO5Si requires C, 60.13; H, 7.70; N, 3.69%).
3-[3-(tert-Butyldimethylsilyloxy)-2-(1-naphthyl)propyl]-4-
hydroxy-1,3-oxazolan-2-one 19c
This compound (3.14 g, 78%) was obtained from dione 18c
(3.99 g, 10.0 mmol) as a crystalline product according to the
same conditions as above; mp 100–104 ЊC; δH 8.17 (d, J 8.4,
1H), 7.87 (d, J 7.7, 1H), 7.78–7.74 (m, 1H), 7.57–7.42 (m, 4H),
5.14–5.08 (m, 1H), 4.85–4.75 (m, 1H), 4.27–4.20 (m, 1H), 4.15–
4.08 (m, 1H), 4.08–4.01 (m, 1H), 4.01–3.93 (m, 3H), 3.88–3.79
(m, 1H), 0.87 (s, 9H), 0.04 (s, 3H) and 0.03 (s, 3H); νmax(KBr)/
cmϪ1 3348, 2958, 1742, 1475, 1241, 1115, 849 and 775; m/z (EI)
402.1 (Mϩ ϩ 1) and 344.1 (Mϩ Ϫ tBu) (Found: C, 65.8; H, 7.7;
N, 3.6. C22H31NO4Si requires C, 65.82; H, 7.78; N, 3.49%).
3-[3-(tert-Butyldimethylsilyloxy)-2-phenylpropyl]-1,3-
oxazolane-2,4-dione 18b
This compound (2.43 g, 70%) was obtained from the alcohol 17b
(2.66 g, 10.0 mmol) as a crystalline solid according to the same
conditions as above; mp 57–59 ЊC; δH 7.36–7.14 (m, 5H), 4.55–
4.38 (m, 2H), 3.98–3.88 (m, 2H), 3.90–3.80 (m, 2H), 3.50–3.55
(m, 1H), 0.87 (s, 9H) and 0.00 (s, 6H); δC 170.2, 155.7, 138.5,
128.5 (2 carbons), 128.1 (2 carbons), 127.4, 67.5, 66.1, 45.3,
42.7, 25.8 (3 carbons), 18.3 and Ϫ5.6 (2 carbons); νmax(KBr)/
cmϪ1 2926, 1808, 1703, 1456, 1423, 1255, 1156, 1050 and 790;
m/z (EI) 350.1 (Mϩ ϩ 1) and 292.1 (Mϩ Ϫ tBu) (Found: C, 61.7;
H, 7.8; N, 4.0. C18H27NO4Si requires C, 61.86; H, 7.79; N,
4.01%).
3-[3-(tert-Butyldimethylsilyloxy)-2-(2-methoxyphenyl)propyl]-4-
phenylsulfanyl-1,3-oxazolan-2-one 20a
To a stirred solution of compound 19a (3.81 g, 10.0 mmol) and
diphenyl disulfide (2.40 g, 11.0 mmol) in THF (40 cm3) was
added dropwise tri-n-butylphosphine (2.7 cm3, 11.0 mmol) at
0 ЊC. After being stirred for 30 min at the same temperature and
then for a further 12 h at rt, the mixture was quenched with
J. Chem. Soc., Perkin Trans. 1, 1998, 3577–3584
3581

View Article Online
water and extracted with diethyl ether. The solution was dried
(MgSO4), and evaporated in vacuo. The residue was chromato-
graphed on silica gel. Elution with hexane–ethyl acetate (20:1)
gave title compound 20a (2.62 g, 55%) as an oil; δH 7.45–7.15 (m,
7H), 6.93–6.83 (m, 2H), 4.85 (dd, J 7.5 and 4.0, 0.5H), 4.50 (dd,
J 8.1 and 3.4, 0.5H), 4.31–4.14 (m, 2H), 4.08–4.00 (m, 1H),
3.96–3.82 (m, 1H), 3.89–3.70 (m, 2H), 3.85 (s, 3H), 3.79–3.51
(m, 1H), 0.88 (s, 9H) and 0.02 (s, 6H); νmax(neat)/cmϪ1 2954,
1762, 1471, 1245 and 1104; m/z (EI) 474.2 (Mϩ ϩ 1), 416.1
(Mϩ Ϫ tBu) and 364.2 (Mϩ Ϫ SPh) (Found: C, 63.5; H, 7.6; N,
3.05. C25H35NO4SSi requires C, 63.39; H, 7.45; N, 2.96%).
(0.5 carbon), 157.1 (0.5 carbon), 140.0 (0.5 carbon), 139.2
(0.5 carbon), 135.2 (0.5 carbon), 135.0 (0.5 carbon), 129.5
(2 carbon), 128.8 (2 carbon), 128.6, 128.5, 128.0, 127.8, 127.6
(0.5 carbon), 127.4 (0.5 carbon), 127.3, 68.2 (0.5 carbon), 67.9
(0.5 carbon), 65.4 (0.5 carbon), 64.7 (0.5 carbon), 64.3 (0.5
carbon), 63.3 (0.5 carbon), 46.0 (0.5 carbon), 45.9 (0.5 carbon),
43.5 (0.5 carbon) and 43.0 (0.5 carbon); νmax(neat)/cmϪ1 3451,
3060, 1752, 1418, 1217, 1070, 1039, 752 and 702; m/z (EI) 330.1
(Mϩ ϩ 1) and 220.1 (Mϩ Ϫ SPh) (HRMS, Found: Mϩ Ϫ SPh,
220.0973. C12H14NO3 m/z, requires 220.0974).
3-[3-Hydroxy-2-(1-naphthyl)propyl]-4-phenylsulfanyl-1,3-
oxazolan-2-one 21c
3-[3-(tert-Butyldimethylsilyloxy)-2-phenylpropyl]-4-phenyl-
sulfanyl-1,3-oxazolan-2-one 20b
This compound (2.80 g, 74%) was obtained from compound
20c (4.93 g, 10.0 mmol) as an oil according to the same condi-
tions as above; δH 8.09–8.00 (m, 1H), 7.85–7.80 (m, 1H), 7.80–
7.65 (m, 1H), 7.54–7.10 (m, 9H), 4.41–4.32 (m, 1H), 4.32–4.21
(m, 1H), 4.21–4.07 (m, 3H) and 4.07–3.80 (m, 3H); δC 157.9 (0.5
carbon), 157.3 (0.5 carbon), 136.1, 135.2, 134.8, 134.7, 134.0,
129.6, 129.5, 129.4, 129.2 (0.5 carbon), 129.1 (0.5 carbon),
127.9, 127.8 (0.5 carbon), 126.7 (0.5 carbon), 126.5, 125.8,
125.5 (0.5 carbon), 125.3 (0.5 carbon), 123.8, 122.5, 68.6, 68.0
(0.5 carbon), 67.9 (0.5 carbon), 64.7 (0.5 carbon), 64.4 (0.5
carbon), 46.1 and 40.0; νmax(neat)/cmϪ1 2360, 1747, 1472, 1418,
1217, 1039 and 780; m/z (EI) 380.10 (Mϩ ϩ 1) and 270.0
(Mϩ Ϫ SPh) (HRMS, Found: Mϩ Ϫ SPh, 270.1137. C16H16NO3
requires m/z, 270.1130).
This compound (2.47 g, 56%) was obtained from compound 19b
(3.51 g, 10.0 mmol) as a crystalline material according to the
same conditions as above; mp 63–65 ЊC; δH 7.48–7.21 (m, 10H),
4.86 (dd, J 7.9 and 3.4, 0.5H), 4.31–4.20 (m, 2H), 4.16 (dd, J 7.9
and 1.8, 0.5H), 4.08–4.00 (m, 1H), 3.95 (dd, J 14.0 and 6.4,
0.5H), 3.86 (d, J 5.9, 1H), 3.82 (t, J 5.1, 0.5H), 3.77–3.69 (m,
1H), 3.20–3.10 (m, 1H), 0.90 (s, 9H), 0.01 (s, 3H) and 0.00 (s,
3H); νmax(KBr)/cmϪ1 2927, 1736, 1472, 1172, 1098, 839, 752 and
697; m/z (EI) 444.1 (Mϩ ϩ 1) and 334.1 (Mϩ Ϫ SPh) (Found: C,
64.9; H, 7.3; N, 3.2. C24H33NO3SSi requires C, 64.97; H, 7.50;
N, 3.16%).
3-[3-(tert-Butyldimethylsilyloxy)-2-(1-naphthyl)propyl]-
4-phenylsulfanyl-1,3-oxazolan-2-one 20c
This compound (2.48 g, 50%) was obtained from compound 19c
(4.01 g, 10.0 mmol) as an oil according to the same conditions
as above; δH 8.11 (d, J 8.2, 0.5H), 8.00 (d, J 8.2, 0.5H), 7.88–7.85
(m, 1H), 7.76 (t, J 8.7, 1H), 7.55–7.28 (m, 9H), 4.67 (t, J 5.8,
1H), 4.30–4.20 (m, 1H), 4.20–4.15 (m, 1H), 4.15–4.06 (m, 2H),
4.06–3.78 (m, 3H), 0.90 (s, 9H), 0.04 (s, 3H) and 0.03 (s, 3H);
νmax(neat)/cmϪ1 3055, 1762, 1471, 1412, 1255, 1092, 838 and
779; m/z (EI) 494.1 (Mϩ ϩ 1) and 436.0 (Mϩ Ϫ tBu) (HRMS,
Found: Mϩ, 436.139. C28H35NO3SSi requires M, 436.1403).
3-[2-Formyl-2-(2-methoxyphenyl)propyl]-4-phenylsulfanyl-1,3-
oxazolan-2-one 22a
DMSO (1.88 cm3, 24 mmol) was added to a stirred solution of
oxalyl dichloride (1.46 cm3, 11.5 mmol) in methylene dichloride
(10 cm3) at Ϫ78 ЊC. After 15 min, a solution of the alcohol 21a
(3.59 g, 10.0 mmol) in methylene dichloride (5 cm3) was slowly
added to the mixture at Ϫ78 ЊC. After the mixture had been
stirred for 1 h at the same temperature, triethylamine (4.05 cm3,
40 mmol) was added. The mixture was warmed to rt and
kept for 2 h, and then was diluted with water (10 cm3). The
mixture was extracted with chloroform. The extract was dried
(MgSO4) and the solvent was removed in vacuo. The residue
was chromatographed on silica gel. Elution with hexane–ethyl
acetate (4:1) gave title compound 22a (3.40 g, 95%) as an oil;
δH 9.58 (s, 0.5H), 9.54 (s, 0.5H), 7.50–6.80 (m, 9H), 5.23–5.18
(m, 1H), 4.52–3.98 (m, 3H), 3.89–3.68 (m, 1H), 3.76 (s, 3H)
and 3.52–3.30 (m, 1H); νmax(neat)/cmϪ1 2360, 1757, 1494 and
1250; m/z (EI) 358.0 (Mϩ ϩ 1) and 248.1 (Mϩ Ϫ SPh)
(HRMS, Found: Mϩ Ϫ SPh, 248.0929. C13H14NO4 requires
m/z, 248.0923).
3-[3-Hydroxy-2-(2-methoxyphenyl)propyl]-4-phenylsulfanyl-1,3-
oxazolan-2-one 21a
A mixture of siloxane 20a (4.73 g, 10.0 mmol), Amberlyst (1.00
g) and methanol (75 cm3) was heated under reflux for 15 h.
After removal of Amberlyst by filtration, the solvent was evap-
orated off in vacuo. The residue was chromatographed on silica
gel. Elution with hexane–ethyl acetate (2:1) gave title compound
21a (3.13 g, 87%) as an oily diastereomeric mixture δH 7.38–7.32
(m, 5H), 7.32–7.19 (m, 1H), 7.13–7.10 (m, 1H), 6.96–6.86 (m,
2H), 4.74–4.68 (m, 0.5H), 4.48–4.39 (m, 1H), 4.36–4.29
(m, 0.5H), 4.29–4.20 (m, 1H), 4.03–3.96 (m, 1H), 3.90–3.86 (m,
2H), 3.83 (s, 3H), 3.80–3.74 (m, 1H), 3.65–3.55 (m, 0.5H) and
3.51–3.41 (m, 0.5H); δC 157.3 (0.5 carbon), 157.2 (0.5 carbon),
135.3 (0.5 carbon), 135.0 (0.5 carbon), 129.6 (0.5 carbon), 129.4
(0.5 carbon), 128.9 (0.5 carbon), 128.8 (0.5 carbon), 128.3,
127.6, 127.3, 120.9, 110.7, 68.2 (0.5 carbon), 68.0 (0.5 carbon),
65.4 (0.5 carbon), 64.4 (0.5 carbon), 63.3 (0.5 carbon), 62.6
(0.5 carbon), 55.4 (0.5 carbon), 55.3 (0.5 carbon), 42.1
(0.5 carbon), 41.4 (0.5 carbon), 39.9 (0.5 carbon) and 39.2 (0.5
carbon); νmax(KBr)/cmϪ1 3447, 2360, 1747, 1244 and 1027; m/z
(EI) 360.1 (Mϩ ϩ 1) and 250.0 (Mϩ Ϫ SPh) (HRMS, Found:
Mϩ Ϫ SPh, 250.1050. C13H16NO4 requires m/z 250.1079).
3-(2-Formyl-2-phenylpropyl)-4-phenylsulfanyl-1,3-oxazolan-2-
one 22b
This compound (3.01 g, 92%) was obtained from compound
21b (3.29 g, 10.0 mmol) as an oil according to the same condi-
tions as above; δH 9.64 (s, 0.5H), 9.63 (s, 0.5H), 7.42–7.01 (m,
10H), 5.15–5.05 (m, 0.5H), 4.42–4.33 (m, 0.5H), 4.24–4.16 (m,
1H), 4.16–4.01 (m, 2H), 3.96–3.89 (m, 1H), and 3.81–3.62 (m,
1H); νmax(neat)/cmϪ1 1757, 1413, 1216, 1170, 1038, 752, 701; m/z
(EI) 328.1 (Mϩ ϩ 1) and 218.1 (Mϩ Ϫ SPh) (HRMS, Found:
Mϩ Ϫ SPh, 218.0826. C12H12NO3 requires m/z, 218.0817).
3-(3-Hydroxy-2-phenylpropyl)-4-phenylsulfanyl-1,3-oxazolan-2-
one 21b
3-[2-Formyl-2-(1-naphthyl)propyl]-4-phenylsulfanyl-1,3-
oxazolan-2-one 22c
This compound (2.29 g, 72%) was obtained from compound
20b (4.43 g, 10.0 mmol) as an oil according to the same condi-
tions as above; δH 7.34–7.04 (m, 10H), 4.43–4.39 (m, 1H), 4.34–
4.26 (m, 1H), 4.17–4.11 (m, 1H), 4.10–4.00 (m, 0.5H), 3.97–3.86
(m, 1H), 3.81–3.60 (m, 3H) and 3.59–3.51 (m, 0.5H); δC 157.7
This compound (3.28 g, 87%) was obtained from compound
21c (3.79 g, 10.0 mmol) as an oil according to the same condi-
tions as above; δH 9.71 (s, 0.5H), 9.70 (s, 0.5H), 8.31 (s, 0.5H),
8.30 (s, 0.5H), 7.85–7.75 (m, 2H), 7.61–7.53 (m, 1H), 7.51–7.45
(m, 2H), 7.40–7.37 (m, 1H), 7.37–7.11 (m, 5H), 5.30 (dd, J 8.2
3582
J. Chem. Soc., Perkin Trans. 1, 1998, 3577–3584

View Article Online
and 3.2, 0.5H), 4.98 (dd, J 10.2 and 3.9, 0.5H), 4.44 (dd, J 9.8
and 8.2, 0.5H), 4.25 (dd, J 12.8 and 3.2, 0.5H), 4.06–3.95 (m,
2H), 3.92–3.82 (m, 1H), 3.72–3.67 (m, 1H); νmax(neat)/cmϪ1
2362, 1752, 1412, 1212, 1070 and 782 cmϪ1, m/z (EI) 377.0 (Mϩ)
and 268.1 (Mϩ Ϫ SPh) (HRMS, Found: Mϩ, 377.1098.
C22H19NO3S requires M, 377.1086).
Diethyl [{(6S*,7R*,7aS*)-6-(2-methoxyphenyl)-3-oxoperhydro-
pyrrolo[1,2-c][1,3]oxazol-7-yl}methyl]phosphonate 29a
A solution of tributyltin hydride (0.44 g, 1.50 mmol) in benzene
(100 cm3) and AIBN (16.4 mg, 0.1 mmol) was slowly added
to a solution of compound 23a (0.49 g, 1.0 mmol) in boiling
benzene (100 cm3). After the addition, the mixture was further
refluxed for 5 h and was then evaporated. The resulting residue
was chromatographed on silica gel. After removal of non-polar
material by elution with hexane, elution with ethyl acetate–
methanol (50:1) gave title bicycle 29a (0.33 g, 86%) as a crystal-
line product; mp 73–76 ЊC; δH 7.29–7.22 (m, 1H), 7.17–7.11 (m,
1H), 6.98–6.85 (m, 2H), 4.56 (dd, J 8.3 and 9.3, 1H), 4.49–4.41
(m, 1H), 4.31 (dd, J 6.6 and 9.3, 1H), 4.09–3.93 (m, 5H), 3.81 (s
3H), 3.28–3.14 (m, 2H), 2.91–2.80 (m, 1H), 1.80–1.72 (m, 2H),
1.28 (t, J 7.1, 3H) and 1.25 (t, J 7.1, 3H); δC 160.3, 155.2, 128.6,
127.7, 125.2, 120.8, 110.8, 65.9, 61.8 (2 carbons), 59.3, 55.2,
51.6, 46.6, 41.2, 24.1 (d, JCP 141.6 and 16.3 (2 carbons);
δP 30.18; νmax(KBr)/cmϪ1 2998, 1757, 1494, 1392, 1239, 1061,
1024, 964, 761; m/z (EI) 383.1 (Mϩ) (Found: C, 56.2; H, 6.8; N,
3.75. C18H26NO6P requires C, 56.40; H, 6.83; N, 3.65%).
Diethyl [(E)-3-(2-methoxyphenyl)-4-(2-oxo-4-phenylsulfanyl-
1,3-oxazolan-3-yl)but-1-enyl]phosphonate 23a
To a solution of tetraethyl methylenebisphosphonate in THF
n
(35 cm3) was added a solution of 1.6  BuLi in hexane (12.0
mmol) at Ϫ30 ЊC in small portions. The mixture was stirred for
0.5 h and to this solution was added a solution of aldehyde 22a
(3.57 g, 10.0 mmol) in THF (7 cm3) at Ϫ78 ЊC. After being
stirred at 10 ЊC for 5 h, the mixture was quenched with aq.
ammonium chloride (15 cm3) and extracted with ethyl acetate.
The extract was dried (MgSO4), and evaporated in vacuo. The
residue was chromatographed on silica gel [hexane–ethyl
acetate (50:1)] to give title phosphonate 23a (3.47 g, 71%) as an
oil; δH 7.44–7.33 (m, 7H), 7.27–7.24 (m, 1H), 7.16–7.13 (m, 1H),
6.97–6.87 (m, 1H), 5.85–5.63 (m, 1H), 4.90 (dd, J 8.1 and 3.2,
0.5H), 4.36–4.30 (m, 0.5H), 4.28–3.98 (m, 9H), 3.82 (s, 1.5H),
3.81 (s, 1.5H) and 1.49–1.36 (m, 6H); δC 156.7 (0.5 carbon),
156.2 (0.5 carbon), 151.2 (0.5 carbon), 150.8 (0.5 carbon), 134.9
(0.5 carbon), 134.7 (0.5 carbon), 129.2 (2 carbons), 129.1,
129.0, 128.8, 128.6, 128.4, 128.2, 128.1, 119.8 (0.5 carbon),
119.4 (0.5 carbon), 117.7 (0.5 carbon), 117.3 (0.5 carbon), 67.6
(0.5 carbon), 67.4 (0.5 carbon), 64.2 (0.5 carbon), 64.1 (0.5
carbon), 61.7, 61.4 (2 carbons), 55.0, 43.4 (0.5 carbon), 43.3 (0.5
carbon) and 16.0 (2 carbons); δP 19.02; νmax(neat)/cmϪ1 2982,
1757, 1494, 1246, 1026, 964 and 754; m/z (EI) 492.1 (Mϩ ϩ 1)
and 382.1 (Mϩ Ϫ SPh) (Found: Mϩ Ϫ SPh, 382.1410. C18H25-
NO6P requires m/z, 382.1420).
Diethyl{(6S*,7R*,7aS*)-(3-oxo-6-phenylperhydropyrrolo[1,2-c]-
[1,3]oxazol-7-yl)methyl}phosphonate 29b
The mixture of compound 23b (0.46 g, 1.0 mmol) was treated
with tributyltin hydride (0.44 g, 1.50 mmol) in toluene in the
presence of AIBN (16 mg, 0.1 mmol) according to the same
method as above. After the addition, the mixture was further
refluxed for 5 h and was then evaporated. The resulting residue
was chromatographed on silica gel. Non-polar material was
removed by elution with hexane, and successive elution with
ethyl acetate–methanol (50:1) gave title compound 29b (0.30 g,
85%) as a solid; mp 37–39 ЊC; δH 7.32–7.13 (m, 5H), 4.50 (dd,
J 8.5 and 9.6, 1H), 4.43–4.36 (m, 1H), 4.21 (dd, J 6.3 and 9.6,
1H), 4.02–3.89 (m, 5H), 3.14 (dd, J 9.4 and 11.9, 1H), 2.87–2.82
(m, 1H), 2.67–2.56 (m, 1H), 1.73–1.66 (m, 2H) and 1.28–1.19
(m, 6H); δC 161.0, 138.0, 129.9 (2 carbons), 128.8, 127.5, 127.4,
65.6, 61.8 (2 carbons), 59.2, 52.9, 52.0, 51.9, 43.5, 23.6 (d, JCP
141.8), 16.2 and 16.1; δP 29.74; νmax(KBr)/cmϪ1 2361, 1751,
1397, 1220, 1054, 1024 and 773; m/z (EI) 353.1 (Mϩ) and 309.1
(Mϩ Ϫ OEt) (Found: C, 57.5; H, 6.9; N, 4.0. C17H24NO5P
requires C, 57.58; H, 6.85; N, 3.96%).
Diethyl [(E)-4-(2-oxo-4-phenylsulfanyl-1,3-oxazolan-3-yl)-3-
phenylbut-1-enyl]phosphonate 23b
This compound (3.31 g, 72%) was obtained from aldehyde 22b
(3.57 g, 10.0 mmol) as an oil according to the same conditions
as above; δH 7.26–6.87 (m, 10H), 6.78–6.61 (m, 1H), 5.62–5.45
(m, 1H), 4.11–4.06 (m, 1H), 3.99–3.92 (m, 1H), 3.92–3.72 (m,
6H), 3.67–3.55 (m, 1H), 3.53–3.44 (m, 1H) and 1.18–1.01 (m,
6H); δC 156.4 (0.5 carbon), 156.3 (0.5 carbon), 151.4 (0.5
carbon), 150.8 (0.5 carbon), 135.1, 129.5, 129.4, 129.0, 128.6,
128.4, 128.2, 127.9, 127.7, 127.6, 127.5, 120.5 (0.5 carbon),
120.1 (0.5 carbon), 118.7 (0.5 carbon), 118.3 (0.5 carbon),
67.8 (0.5 carbon), 67.6 0.5 carbon), 64.7, 61.8, 61.7, 48.3 (0.5
carbon), 48.0 (0.5 carbon), 45.2 (0.5 carbon), 45.0 (0.5 carbon),
16.3 and 16.2; δP 18.51; νmax(neat)/cmϪ1 1757, 1416, 1242, 1052,
1025, 965, 751 and 702; m/z (EI) 462.1 (Mϩ ϩ 1) and 352.1
(Mϩ Ϫ SPh) (HRMS, Found: Mϩ Ϫ SPh, 352.1314. C17H23-
NO5P requires m/z, 352.1314).
Radical cyclisation of compound 23c; Synthesis of diethyl [{(6S*,
7R*,7aS*)-6-(1-naphthyl)-3-oxoperhydropyrrolo[1,2-c][1,3]-
oxazol-7-yl}methyl]phosphonate 29c and (6S*,7R*,7aR*)-isomer
30c
A mixture of compound 23c (0.51 g, 10.0 mmol) and tributyltin
hydride (0.44 g, 1.50 mmol) in benzene was heated in the pres-
ence of AIBN (16 mg, 0.1 mmol) for 3 h, the solvent was
removed, and the resulting residue was chromatographed on
silica gel. Elution with ethyl acetate–methanol (50:1) afforded a
mixture of diastereomers 29c and 30c; these were separated on
a preparative packed column (Inertsil PREP-SIL, GL science)
by elution with hexane–ethyl acetate (11:89) at a flow rate of
Diethyl [(E)-3-(1-naphthyl)-4-(2-oxo-4-phenylsulfanyl-1,3-
oxazolan-3-yl)but-1-enyl]phosphonate 23c
This compound (3.68 g, 72%) was obtained from aldehyde 22c
(3.77 g, 10.0 mmol) as an oil according to the same conditions
as above; δH 8.03–7.93 (m, 1H), 7.86–7.70 (m, 2H), 7.52–7.14
(m, 9H), 7.15–6.94 (m, 1H), 5.91–5.61 (m, 1H), 4.89–4.50 (m,
2H), 4.33–3.73 (m, 8H) and 1.38–1.12 (m, 6H); δC 156.3 (0.5
carbon), 156.0 (0.5 carbon), 151.1 (0.5 carbon), 150.9 (0.5
carbon), 135.0, 129.4, 129.3, 129.2, 128.9, 128.8, 128.7, 128.2,
128.1, 128.0, 126.4, 125.8, 125.6, 125.3, 125.2, 124.3, 120.5
(0.5 carbon), 120.1 (0.5 carbon), 118.6 (0.5 carbon), 118.2
(0.5 carbon), 67.7 (0.5 carbon), 67.6 (0.5 carbon), 65.0 (0.5
carbon), 64.4 (0.5 carbon), 61.6, 61.5, 45.4, 44.6 and 16.0 (2
carbons); δP 18.58; νmax(neat)/cmϪ1 1756, 1473, 1416, 1244,
1162 and 963; m/z (EI) 511.1 (Mϩ) and 402.1 (Mϩ Ϫ SPh)
(HRMS, Found: Mϩ Ϫ SPh, 402.1470. C21H25NO5P m/z,
requires 402.1470).
1.5 cm3 minϪ1
.
Diethyl [{(6S*,7R*,7aS*)-6-(1-naphthyl)-3-oxoperhydropyrrolo-
[1,2-c][1,3]oxazol-7-yl}methyl]phosphonate 29c
Retention time tR 41.28 min; δH 8.18 (d, J 8.4, 1H), 7.86 (d,
J 8.0, 1H), 7.78 (d, J 8.0, 1H), 7.57–7.39 (m, 4H), 4.58 (dd, J 8.6
and 9.4, 1H), 4.53–4.43 (m, 1H), 4.39 (dd, J 5.6 and 9.6, 1H),
4.17 (dd, J 11.9 and 6.8, 1H), 4.14–4.00 (m, 4H), 3.95 (dd, J 14.6
and 7.3, 1H), 3.31 (dd, J 11.9 and 7.6, 1H), 2.96–2.86 (m, 1H),
1.91–1.74 (m, 2H), 1.28 (t, J 7.1, 3H) and 1.26 (t, J 7.1, 3H); δC
161.9, 134.4, 133.9, 132.1, 128.9, 128.0, 126.5, 125.9, 125.2,
122.9 (2 carbons), 65.3, 61.9 (2 carbons), 59.7, 52.5, 46.9, 41.6,
24.0 (d, JCP 143.1), 16.3 and 16.2; δP 29.88; νmax(neat)/cmϪ1
2930, 2342, 1752, 1394, 1243, 1025 and 779; m/z (EI) 403.1 (Mϩ)
J. Chem. Soc., Perkin Trans. 1, 1998, 3577–3584
3583

View Article Online
(HRMS, Found: Mϩ, 403.1547. C21H26NO5P requires M,
403.1549).
CH3) [HRMS, Found: (Mϩ Ϫ Bu Ϫ CH2OH Ϫ CH3),
340.0960. C15H19NO6P requires m/z, 340.0950].
Diethyl [{(6S*,7R*,7aR*)-6-(1-naphthyl)-3-oxoperhydropyrrolo-
[1,2-c][1,3]oxazol-7-yl}methyl]phosphonate 30c
1-tert-Butyl 2-methyl (2S*,3R*,4S*)-3-{[ethoxy(methoxy)-
phosphoryl]methyl}-4-(2-methoxyphenyl)tetrahydropyrrole-1,2-
dicarboxylate 33
Retention time tR 51.59 min; mp 117–120 ЊC; δH 8.10 (d, J 8.5,
1H), 7.88 (d, J 8.5, 1H), 7.78 (d, J 8.1, 1H), 7.59–7.33 (m, 4H),
4.57 (dd, J 8.8 and 9.3, 1H), 4.37 (dd, J 6.3 and 9.3, 1H), 4.27–
4.22 (m, 1H), 4.21–4.10 (m, 4H), 4.03–3.95 (m, 1H), 3.64–3.54
(m, 1H), 2.96 (dd, J 11.6 and 13.2, 1H), 2.49–2.40 (m, 1H),
2.25–2.04 (m, 2H) and 1.35 (t, J 7.1, 6H); δC 156.7, 136.7, 134.0,
131.2, 129.1, 127.9, 126.7, 125.9, 125.3, 122.7, 122.5, 67.5, 62.5,
62.3, 54.2, 47.1, 39.7 (d, JCP 141.8), 36.5, 31.2 (d, JCP 141.8),
16.6 and 16.5; δP 27.22; νmax(neat)/cmϪ1 2927, 1758, 1426, 1242,
1051, 965 and 781; m/z (EI) 403.1 (Mϩ) (HRMS, Found: Mϩ,
403.1550. C21H26NO5P requires C21H26NO5P, M, 403.1549).
To a solution of the alcohol 32 (44.30 mg, 0.11 mmol) in a
mixture of acetonitrile (1 cm3), carbon tetrachloride (1 cm3)
and water (1.5 cm3) was added sodium metaperiodate (93.77
mg, 0.41 mmol). Ruthenium trichloride hydrate (1.0 mg, 0.005
mmol) was added to this biphasic mixture, which was stirred
vigorously for 3.5 h at rt and then extracted with chloroform.
The extract was dried (Na2SO4) and the solvent was evaporated
off in vacuo. To a solution of the residue (without purification)
was added a solution of diazomethane in diethyl ether at 0 ЊC.
After 20 min the solvent was evaporated off in vacuo, and the
remaining oil was chromatographed on silica gel. Elution with
chloroform–methanol (10:1) gave title ester 33 (19.78 mg, 42%)
as an oil; δH 7.28–7.06 (m, 2H), 6.97–6.82 (m, 2H), 4.24–4.01
(m, 1H), 4.01–3.58 (m, 13H), 3.51 (d, J 11.0, 1H), 3.46 (d,
J 11.0, 1H), 2.93–2.04 (m, 2H), 1.56–1.37 (m, 9H) and 1.37–
1.13 (m, 3H); δC 172.7, 158.2, 128.5, 128.4, 125.6, 120.7, 110.7,
80.5, 66.4, 62.1, 61.6, 55.2 (3 carbons), 52.2, 51.9, 51.1, 48.3,
28.3, 28.1, 27.9 and 16.3; δP 30.92; νmax(neat)/cmϪ1 2360, 1698,
1398, 1249, 1028 and 773; m/z (EI) 471.1 (Mϩ) and 415.0
(Mϩ Ϫ tBu) (HRMS, Found: Mϩ Ϫ tBu, 415.1387. C18H25NO8P
requires m/z, 415.1396).
X-Ray crystallographic analysis on compound 29a
X-ray crystal data of compound 29a were collected by Mac-
Science MXC 18 diffractometers. The structure was solved by
direct methods using SIR 92 (Giacovazzo, 1994)15 and refined
with a full matrix least-squares method.
Crystal data of compound 29a. C18H26O6P, Mr = 383.00,
orthorhombic, space group Pca 21, a = 16.132(7), b =
14.507(7), c = 8.162(6), V = 1910(2) Å3, T = 298 K, Z = 4,
Dx = 1.331 Mg cmϪ3, (Cu-Kα) = 1.54178 Å, µ = 15.554 mmϪ1
R = 0.065 over 1833 independent reflections.‡
,
References
tert-Butyl (2S*,3R*,4S*)-3-{[ethoxy(methoxy)phosphoryl]-
methyl}-2-hydroxymethyl-4-(2-methoxyphenyl)tetrahydro-
pyrrole-1-carboxylate 32
1 S. Shibuya, T. Yokomatus and Y. Yuasa, Studies in Natural Products
Chemistry, ed. Atta-ur-Rahman, Elsevier, Amsterdam, 1993, vol.
12, p. 445, and references cited therein.
2 Y. Yuasa, J. Ando and S. Shibuya, (a) J. Chem. Soc., Chem.
Commun., 1994, 1383; (b) J. Chem. Soc., Perkin Trans. 1, 1995, 473.
3 (a) S. Murakami, T. Takmoto and Z. Shimizu, J. Pharm. Soc.
Jpn., 1953, 73, 1026; (b) J. T. Coyle, J. Neurochem., 1983, 41, 1;
(c) H. Shimazaki and S. Konishi, Brain Res., 1970, 24, 368; (d) E. G.
McGeer, J. W. Olney and P. L. MacGeer, Kainic Acid as a Tool
in Neurobiology, Rav Press, New York, 1978; (e) O. Goldberg,
A. Luni and V. Techberg, J. Med. Chem., 1983, 26, 39; ( f )
H. Shimazaki, M. Ishida, Y. Goyoh and S. Kwak, Brain Res., 1989,
503, 330.
4 K. Hashimoto, M. Horikawa and H. Shirahama, Tetrahedron Lett.,
1990, 31, 7047 and references cited therein.
5 A. D. Parsons, Tetrahedron, 1996, 52, 4149.
6 K. Hashimoto, M. Horikawa, M. Ishida and H. Shirahama, Bioorg.
Med. Chem. Lett., 1992, 12, 743.
7 W. F. Maragos, J. T. Greenamyre, J. B. Penny, Jr. and A. B. Young,
Trends Neurosci., 1987, 10, 65.
8 J. P. Whitten, B. L. Harrison, H. J. R. Weintraub and I. A.
McDonald, J. Med. Chem., 1992, 35, 1509.
9 J. P. Whitten, B. M. Baron and I. A. McDonald, Bioorg. Med. Chem.
Lett., 1992, 13, 23.
10 (a) I. Jefferies, Bioorg. Med. Chem. Lett., 1992, 2, 1519; (b)
M. Tabcheh, L. Pappalardo, M.-L. Roumestant and Ph.
Viallefont, Amino Acids, 1992, 2, 191.
11 T. Yokomatsu, T. Shimizu, Y. Yuasa and S. Shibuya, Synlett, 1995,
1280.
12 B. Giese, Radicals in Organic Synthesis: Formation of Carbon–
Carbon Bonds, Pergamon Press, Oxford, 1986, p. 41, and references
cited therein.
13 (a) G. Guanti, E. Narisano, T. Podgorski, S. Thea and A. Williams,
Tetrahedron, 1990, 46, 7081; (b) T. Bando, Y. Namba and
K. Shishido, Tetrahedron: Asymmetry, 1997, 8, 2159.
14 O. Mitsunobu, M. Wada and T. Sano, J. Am. Chem. Soc., 1972, 94,
679.
A mixture of bicycle 29a (0.38 g, 1.0 mmol) and 10% aq.
sodium hydroxide (0.5 cm3) in 1,4-dioxane (8 cm3) was heated
under reflux for 17 h. After the mixture had warmed to 0 ЊC in
an ice-bath, a solution of di-tert-butyl dicarbonate (0.52 g, 2.4
mmol) in 1,4-dioxane (8 cm3) was slowly added to the reaction
mixture and stirring was maintained for 2 h. The mixture was
then quenched with water and extracted with ethyl acetate.
The extract was acidified carefully with 5% hydrochloric acid
(0.5 cm3) and then further extracted with ethyl acetate. The
combined organic layer was dried (MgSO4), and evaporated
in vacuo. To a solution of the residue, without purification,
in methanol was slowly added a solution of diazomethane in
diethyl ether at 0 ЊC, until the yellow colour persisted. After 20
min, the solvent was evaporated off in vacuo, and the residue
was chromatographed on silica gel. Elution with chloroform–
methanol (20:1) gave title alcohol 32 (0.209 g, 47%) as an oil;
δH 7.21–7.03 (m, 2H), 6.87–6.80 (m, 2H), 4.12–4.03 (m, 1H),
3.80 (s, 3H), 3.74–3.71 (m, 1H), 3.71–3.67 (m, 2H), 3.67–3.64
(m, 1H), 3.62 (s, 3H), 3.58–3.23 (m, 2H), 3.03–2.87 (br s, 1H),
2.84 (d, J 15.6, 1H), 2.76 (d, J 15.6, 1H), 2.01–1.70 (m, 2H),
1.48–1.33 (m, 9H) and 1.28–1.10 (m, 3H); δC 170.1, 157.8,
128.5, 128.4, 125.3, 120.8, 110.8, 80.2, 66.5, 66.0, 60.3, 55.4,
54.6, 53.5, 53.1, 43.4, 43.0, 28.3 (3 carbons) and 16.2; δP 29.25;
νmax(neat)/cmϪ1 2955, 2342, 1693, 1397, 1247, 1170 and 1028;
m/z (EI) 444.1 (Mϩ ϩ 1) and 340.9 (Mϩ Ϫ But Ϫ CH2OH Ϫ
‡ Full crystallographic details, excluding structure factor tables, have
been deposited at the Cambridge Crystallographic Data Centre
(CCDC). For details of the deposition scheme, see ‘Instructions for
Authors’, J. Chem. Soc., Perkin Trans. 1, available via the RSC Web
page (http://www.rsc.org/authors). Any request to the CCDC for this
material should quote the full literature citation and the reference
number 207/255.
15 A. Altomare, M. C. Burla, G. Cascarano, C. Giacovazzo,
A. Gualiadi and G. Olidor, J. Appl. Crystallogr., 1994, 27, 435.
Paper 8/04666B
3584
J. Chem. Soc., Perkin Trans. 1, 1998, 3577–3584