Regio- and diastereo-selectivity in 1,3-dipolar cycloadditions of nitrile oxides to 4-substituted cyclopent-2-enones

Article abstract of DOI:10.1039/b003549l

The behaviour of 4-hydroxy-4-methylcyclopent-2-enone and related 4-substituted cyclopent-2-enones towards 1,3-dipolar cycloaddition with nitrile oxides is studied.The reactions are always completely regioselective while the diastereofacial selectivity depends on the nature of the substituents. Remarkably, the reaction of 4-acetoxycyclopent2-enone shows complete regio- and diastereo-facial selectivity. The Royal Society of Chemistry 2000.

Full text of DOI:10.1039/b003549l

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Regio- and diastereo-selectivity in 1,3-dipolar cycloadditions
of nitrile oxides to 4-substituted cyclopent-2-enones
Giorgio Adembri,a Gianluca Giorgi,b Raffaella L. Lampariello,a Maria L. Paolia
and Alessandro Sega*,a
1
a Istituto di Chimica Organica, Via Aldo Moro, 53100 Siena, Italy. Fax: ϩ39-0577-234278;
E-mail: sega@unisi.it
b Centro Interdipartimentale di Analisi e Determinazioni Strutturali, Via Aldo Moro,
53100 Siena, Italy
Received (in Cambridge, UK) 3rd May 2000, Accepted 29th June 2000
Published on the Web 4th August 2000
The behaviour of 4-hydroxy-4-methylcyclopent-2-enone and related 4-substituted cyclopent-2-enones towards
1,3-dipolar cycloaddition with nitrile oxides is studied. The reactions are always completely regioselective while the
diastereofacial selectivity depends on the nature of the substituents. Remarkably, the reaction of 4-acetoxycyclopent-
2-enone shows complete regio- and diastereo-facial selectivity.
Introduction
Isoxazolines are valuable intermediates for obtaining β-hydroxy
ketones or γ-amino alcohols1 but they are also important
in their being possibly endowed with biological activity or
lending themselves to further transformations leading to
natural products or pharmacologically active compounds.2–8
The 1,3-dipolar cycloaddition of nitrile oxides to alkenes has
been one of the most general methods used for the preparation
of isoxazoline derivatives.9–12 This reaction is both regio- and
stereo-selective and the selectivity is enhanced in alkenes
Scheme 1 Reagents and conditions: i, MCPBA, CH2Cl2, Ϫ10 ЊC; ii, 1%
Na2CO3, 30 ЊC, 5 min; iii, reflux, 2 h.
bearing an allylic chiral centre. Several important studies have
been performed to determine the influence on selectivity of the
nature of the substituents at the allylic centre.13–20
Results and discussion
The reaction of 1 with nitrile oxides could give a mixture of
Considering our interest in obtaining cyclopentanes which
are polyfunctionalized in stereocontrolled way (these
a
molecules are present in many classes of natural and synthetic
compounds), we decided to study regio- and stereo-selectivity
in the 1,3-dipolar cycloaddition of nitrile oxides to several
4-substituted cyclopent-2-enones. In these molecules, regio-
selectivity is expected to be mainly determined by the α,β
unsaturated ketone moiety, and diastereoselectivity by the
nature of the substituents at the 4 position. The allylic substit-
uents in cyclopent-2-enones are part of a quite rigid structure
and this will possibly enhance facial selectivity. 4-Hydroxy-4-
methylcyclopent-2-enone, 1, is a particularly promising starting
molecule, having at its allylic centre two groups that should
exert a strong diastereofacial selectivity through hydrogen
bonding, involving the 4-OH and the oxygen of the nitrile
oxide, and through steric hindrance mainly due to the methyl.19
For the synthesis of compound 1 we followed the pathway
outlined in ref. 21, where, however, the reaction conditions and
the yield are not indicated. In Scheme 1 we report the reaction
conditions that gave the best yield according to our attempts.
Compound 1 was obtained in a good yield (80%) which was
considerably better than that given by another procedure found
in the literature.22 These conditions must be strictly followed in
order to avoid the formation of 4-hydroxy-3-methylcyclopent-
2-enone,23 2, derived from rearrangement of 1. Compound 1
is completely transformed into compound 2 when warming
is carried out for longer times or when operating in stronger
alkaline conditions (see Scheme 1).
four possible stereoisomers as shown in Scheme 2.
Scheme 2
On the basis of frontier orbital theory a preference for stereo-
isomers a and b over stereoisomers c and d is expected.13,24,25
Furthermore the discrimination exerted between the two faces
of 1 by the allylic substituents should favour the approach of
the nitrile oxide leading to a over that leading to b. In fact,
for this approach the substituents at the allylic centre are
oriented in the most favourable way: the OH group on the same
side as the oxygen of the incoming nitrile oxide and the methyl
DOI: 10.1039/b003549l
J. Chem. Soc., Perkin Trans. 1, 2000, 2649–2656
This journal is © The Royal Society of Chemistry 2000
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group antiperiplanar to it.19 The rigidity of the cyclopentenone
moiety should magnify the effect, since the two allylic substitu-
ents are held in fixed positions during the nitrile oxide attack.
The reactions of 1 with several nitrile oxides gave only two
adducts in all cases (Scheme 3).
Table 1 Yields and stereoisomers ratiosa of compounds 3a–7a, 12a–
14a and 3b–7b, 12b–15b obtained according to Scheme 3
Compound
a
b
Yield (a ϩ b) (%)
3
4
85
75
65
80
70
57
55
32
0
15
25
35
20
30
43
45
68
87
75
82
85
68
74
81
75
71
5
6
7
12
13
14
15
100
a Ratios were estimated by 1H NMR spectroscopy.
aromatic protons or the protons of the methyl group (3-CH3)
we always found a small NOE on 3a-H (2–3%) for all stereo-
isomers 3a–7a and 3b–7b (this is also a confirmation of the
previous regiochemical assignment).
In order to investigate the relative importance of steric
hindrance and hydrogen bonding in determining the ratio of
the diastereoisomers, we changed the substituents at the allylic
centre according to Fig. 1. The reactions were performed using
the same nitrile oxide (2,6-dichlorobenzonitrile oxide). This
strategy should allow at least partial separation of the two
effects, leading to the evaluation of their respective weights on
the reaction course. At the same time we can see if and to what
extent the nature of the substituents affects the regioselectivity.
Compound 7, 4-acetoxy-4-methylcyclopent-2-enone, was
prepared by acetylation of 1 with acetic anhydride, while the
other 4-substituted cyclopent-2-enones, 9–11, were prepared
according to refs. 30, 31 and 32 respectively. From the results of
the reactions shown in Scheme 3 it is immediately evident that
complete regioselectivity is retained regardless of the nature of
these substituents. This result is perhaps even more surprising
for compounds 9–11. In fact, in these compounds one of the
faces of the cyclopentenone ring presents a hydrogen atom, as
does cyclopent-2-enone itself (which gives both regioisomers).
It seems that one substituent (i.e., one of the above substitu-
ents) at the allylic position is sufficient to induce complete
regioselectivity.
The ratio of diastereoisomers is strongly affected by the sub-
stituents at the allylic centre (see Table 1). For compounds 8 and
9 the proportions of the corresponding diastereoisomers,
12a:12b = 57:43 and 13a:13b = 55:45 are almost equal. The
difference in steric hindrance between methyl and hydrogen in
compounds 1 and 9 should favour diastereoisomer 13b with
respect to 13a more than 3b with respect to 3a and indeed this
is what we found. However the fact that 13a is still formed
in comparable quantity (13a:13b = 55:45) underlines the
importance of the hydrogen bonding effect. The importance of
hydrogen bonding is also evident in comparing 1 with 8;
acetylation of the hydroxy group causes a drop in the ratio of
the diastereoisomers from 3a:3b = 85:15 to 12a:12b = 57:43.
Moreover if we consider compounds 9 and 11, the acetylation
of the hydroxy group produces a far more pronounced effect:
the attack of the nitrile oxide is only syn with the hydrogen
atom at the allylic centre. So for compound 11 the reaction
is not only completely regioselective but also completely
Scheme 3
From the chemical shifts of the protons bonded to the
bridgehead carbons (3a-H and 6a-H) we can deduce, according
to the literature,13,25,26 that the two products are type a and b
stereoisomers; in fact the difference in chemical shift between
protons 6a-H and 3a-H, ∆δ6a–3a, is obtained for all the stereo-
isomers within the following ranges: ∆δ6a–3a = 0.58–1.09 ppm
for 3a–7a and ∆δ6a–3a = 0.58–1.22 ppm for 3b–7b, while ∆δ6a–3a
is expected to be considerably lower for the other regioisomers
(c and d).
The reactions are thus, somewhat surprisingly, completely
regioselective. Reactions of nitrile oxides with cyclopent-2-
enone itself in fact give both regioisomers.13 The reaction of
2,6-dichlorobenzonitrile oxide with cyclopent-2-enone run in
our laboratories under the same conditions as the correspond-
ing reaction of 1 gave the two regioisomers in the ratio
a:c = 85:15. Reactions of nitrile oxides with molecules that
have a certain resemblance to ours, such as 3- or 3,5-substituted
cyclopentenes and 5-substituted furan-2(5H)-ones, also give
both regioisomers.14,15,27,28 We found very few exceptions to
this behaviour; the reactions of benzonitrile oxide with (Ϫ)-5-
menthyloxyfuran-2(5H)-one29 and of acetonitrile oxide with
5-(ethylthio)furan-2(5H)-one are completely regioselective.28
On the other hand the ratios between the two diastereo-
isomers (3a–7a to the corresponding 3b–7b; see Table 1),
determined by integration of the methyl-group’s signals in the
1H NMR spectrum of the crude reaction mixtures, are in
agreement with the orienting effects of the hydroxy and methyl
groups: 3a–7a are always the major isomers even if the ratio
also depends on the nature of the nitrile oxide.
The assignment of the structure of diastereoisomers 3a–7a
and 3b–7b was made on the basis of a nuclear Overhauser effect
(NOE) study. Irradiation of the protons of the methyl group at
the allylic centre gave, in all cases, an NOE on 6a-H (5-8%)
for one stereoisomer and no NOE for the other stereoisomer
(it thus follows that the structures are 3a–7a for the former
and 3b–7b for the latter). Moreover, on presaturation of the
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Table 3 Yields and stereoisomers ratiosa of compounds 16a–19a,
16b–19b and 21a obtained according to Scheme 4
Table 2 Selected NOE effects for compounds 12a–14a and 12b–15b in
0.05 M solutions in CDCl3
Compound
Irradiated
Observed
NOE %
Compound
a
b
Yield (a ϩ b) (%)
12a
12b
13a
6-CH3
6-CH3
3a-H
6-H
6a-H
6a-H
3a-H
6-H
6a-H
6-CH3
6-CH3
6-H
6a-H
6a-H
6a-H
6a-H
3a-H
6-H
6a-H
6a-H
3a-H
6a-H
6a-H
6a-H
6.7
0
16
17
18
19
21
90
68
75
75
10
32
25
25
0
92
96
94
92
90
4.0
7.5
11.7
4.4
5.0
1.5
9.7
0
100
a Ratios were estimated by 1H NMR spectroscopy.
13b
located to maximize the difference between the two faces of the
cyclopentane ring and to give the highest diastereoisomeric
ratio. However, the methyl group bonded to C-6 could also
have an influence on the pathway chosen by the reagent. In
order to test this possibility we performed the same reaction
under identical conditions on the adduct of 2,6-dichloro-
benzonitrile oxide with cyclopent-2-enone (adduct 20a).
When this methyl group was absent, the approach of the
reagent was only from the face opposite the isoxazoline ring,
leading to compound 21a with no evidence of its diastereo-
isomer (see Table 3).
The relative stereochemistry of compounds 16a–19a, 16b–
19b and 21a was established from qualitative NOE experi-
ments. Presaturation of the methyl protons, 6-Me, gave an NOE
on the proton of the hydroxy group, 4-OH, for the minor iso-
mers (4–6%) and no NOE on 4-OH for the major isomers, while
presaturation of 3a-H gave an NOE on 4-H for the major iso-
mers (6–11%) and no NOE or far smaller NOE for the minor
isomers (0–2.5%). Thus major isomers have structures 16a–19a
and minor isomers have structures 16b–19b.
The synthesis of polyfunctionalized substrates is based on a
carefully planned protection/deprotection strategy. In our case
it may be very important to protect the hydroxy group in key
compound 1. However, attempts to acetylate 1 under various
conditions gave the corresponding 4-acetoxy-4-methylcyclo-
pent-2-enone 8 in 45–50% yield. This quite low yield is due to
the low reactivity of the tertiary hydroxy group but also to the
competing reaction leading to the rearranged product 2. If
acetylation is tried in the next stage on the adduct of 1 with 2,6-
dichlorobenzonitrile oxide, 3a, the result is even worse since the
dehydrated compound, 22, is practically the only product (see
Scheme 5). The structure of this compound is immediately
14a
14b
15b
5.8
1.2
diastereoselective. In compound 10 only steric effects can play
a role in addressing the approach of nitrile oxide and, as
expected, isomer 14b predominates over 14a.
The relative stereochemistry of the cycloadducts was deter-
mined through NOE analysis (see Table 2).
The complete regioselectivity diminishes the number of the
isomers from four to two and, in the case of compound 11, to
only one (15b). In these isomers the relative stereochemistry of
the three chiral centres is defined. We should then expect that
these centres would exert a good degree of chiral induction in
the formation of any new chiral centre. This possibility is of
particular importance given our general purpose of obtaining
cyclopentanes which are polyfunctionalized in a stereo-
controlled way. In order to have a first glimpse at the effective-
ness of this strategy we made a preliminary attempt involving
the reduction of the carbonyl group in compound 3a, which
should give cyclopentane derivatives with two hydroxy groups
in 1,3 relative positions.
The reduction was performed using NaBH4, which gives
higher (almost quantitative) yields than LiAlH4. Results are
reported in Scheme 4.
Scheme 5 Reagents and conditions: AcCl, 40 ЊC.
1
recognizable by its H NMR spectrum: disappearance of the
AB system of the methylene protons and appearance of a new
signal (br s) at δ 6.04 (H-5), while the signal of the methyl
protons shifts from δ 1.44 to δ 2.31.
The reduction of the carbonyl moiety in 3a leads to the
introduction of a secondary hydroxy group (compound 16a).
This group should react to give the monoacetylated derivative.
In fact, reaction of 16a with acetyl chloride gave only one
product in very good yield (92%). However, the NMR analysis
showed that this product was not the expected monoacetylated
derivative, but the diacetylated product 23a (see Scheme 6), as
was confirmed by X-ray crystal diffraction. The ORTEP plot is
shown in Fig. 1, where it can be seen that the two acetoxy
groups retained the same relative stereochemistry as the corre-
sponding hydroxy groups in the parent compound 16a.
Scheme 4 Reagents and conditions: i, NaBH4, MeOH, Ϫ10 ЊC.
The attack of the reagent is always predominantly from the
less hindered face opposite the isoxazoline ring and stereo-
isomers 16a–19a prevail (Table 3). This behaviour is partic-
ularly significant for compound 3a: the diastereoisomeric ratio
16a:16b is considerably greater than the ratios of 17a, 18a and
19a to the corresponding isomers 17b, 18b and 19b. Probably
the chlorine atoms on the benzene ring of 3a are strategically
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were measured with gated decoupling techniques using NOE
difference-pulse sequences.
Silica gel plates (Merck F254) and silica gel 60 (Merck 70–230
mesh) were used for analytical TLC and for column chrom-
atography, respectively. Extracts were dried over sodium sulfate.
Concentrations were performed on a rotary evaporator. Petrol-
eum spirit refers to the fraction of distillation range 30–50 ЊC.
4-Hydroxy-4-methylcyclopent-2-enone 1
1% aq. Na2CO3 (10 ml) was added to (Z)-diacetylethylene (1.5 g,
13.4 mmol). The mixture was stirred at 30 ЊC for 5 min, and
then left at room temperature without stirring. The reaction
was followed by TLC (diethyl ether–petroleum spirit 2:1). The
solution was extracted with CH2Cl2, then the extract was dried
(Na2SO4), filtered and concentrated to give 1 as a colourless oil
(1.2 g, 80%) (Found: C, 64.13; H, 7.05. Calc. for C6H8O2: C,
64.28; H, 7.14%); δH 1.39 (3 H, s, CH3), 2.32 (1 H, d, J5,5Ј 18.5,
5-H), 2.42 (1 H, d, J5,5Ј 18.5, 5Ј-H), 3.70 (1 H, br s, OH), 5.91
(1 H, d, J2,3 5.4, 2-H), 7.34 (1 H, d, J2,3 5.4, 3-H); δC 27.1 (CH3),
50.2 (C-5), 76.0 (C-4), 132.0 (C-2), 167.5 (C-3), 207.8 (C-1).
Fig. 1 X-Ray molecular structure of diacetate 23a with crystallo-
graphic numbering scheme.
4-Hydroxy-3-methylcyclopent-2-enone 2
1% aq. Na2CO3 (10 ml) was added to (Z)-diacetylethylene (1.5 g,
13.4 mmol). The mixture was refluxed for 2 h. The solution was
extracted with CH2Cl2, then the extract was dried, filtered and
the filtrate concentrated to give 2 as a yellow oil (1 g, 70%)
(Found: C, 64.08; H, 7.21. Calc. for C6H8O2: C, 64.28; H,
7.14%); δH 2.10 (3 H, br s, CH3), 2.24 (1 H, dd, J5,5Ј 18.4, J4,5 2.1,
5-H), 2.70 (1 H, dd, J5,5Ј 18.4, J4,5Ј 6.1, 5Ј-H), 3.55 (1 H, br s,
OH), 4.69 (1 H, dd, J4,5 2.1, J4,5Ј 6.1, 4-H), 5.86 (1 H, br s, 2-H);
δC 15.7 (CH3), 45.1 (C-5), 72.3 (C-4), 131.0 (C-2), 178.1 (C-3),
206.4 (C-1).
Scheme 6 Reagents and conditions: AcCl, 40 ЊC.
This finding could be explained by a mechanism of intra-
molecular transesterification. Similar examples can be found
in the literature; see, for instance, the rapid conversion of N-
benzoylnor-ψ-tropine into O-benzoylnor-ψ-tropine in acid
solution.33
4-Acetoxy-4-methylcyclopent-2-enone 8
A catalytic amount of 4-(dimethylamino)pyridine and then,
dropwise, triethylamine (2.49 ml) were added to a solution of
cyclopentenone 1 (2 g, 17.8 mmol) in stirred acetic anhydride.
The resulting mixture was stirred at rt for 72 h. The solution
was concentrated and the residue purified by column chrom-
atography (diethyl ether–petroleum spirit 1:1, then 2:1 and
only diethyl ether at the end) to give compound 8 (1.12 g, 45%)
as an oil (Found: C, 62.23; H, 6.15. Calc. for C8H10O3: C, 62.34;
H, 6.49%); δH 1.69 (3 H, s, 6-CH3), 2.02 (3 H, s, COCH3), 2.53
(1 H, d, J5,5Ј 18.0, 5-H), 2.83 (1 H, d, J5,5Ј 18.0, 5Ј-H), 6.18 (1 H,
d, J2,3 5.6, 2-H), 7.73 (1 H, d, J2,3 5.6, 3-H); δC 21.7 (COCH3),
24.7 (CH3), 48.5 (C-5), 83.6 (C-4), 134.1 (C-2), 163.1 (C-3),
205.0 (C-1).
In order to test this probable mechanism we tried the same
reaction on the other diastereoisomer produced in the reduc-
tion of cycloadduct 3a in which the two hydroxy groups are
in a relative trans relationship, 16b. In this case we obtained
only the monoacetylated product 24b (see Scheme 6), derived,
as expected, from the reaction of the secondary OH group.
The structure of compound 24b follows from the disappear-
ance of the broad doublet in the proton NMR spectrum due
to the proton of the secondary hydroxy group (this proton is
coupled with 4-H), while the broad singlet of the proton of the
tertiary hydroxy group is still present.
The remarkably complete regioselectivity that we found in
these reactions could thus be an interesting basis for the
stereocontrolled functionalization of 4-substituted cyclopent-
2-enones. The behaviour of 4-acetoxycyclopent-2-enone that
reacts with 2,6-dichlorobenzonitrile oxide giving only one
adduct (15b) (complete regio- and stereo-selectivity) is of
special significance. This adduct has three chiral centres with
assigned relative stereochemistry and a fourth chiral centre
can be introduced with good stereoselectivity, for instance by
reduction of the carbonyl group, as we have shown.
The other 4-substituted cyclopent-2-enones, 4-hydroxy-
cyclopent-2-enone 9, 4-methylcyclopent-2-enone 10 and 4-
acetoxycyclopent-2-enone 11 were prepared according to the
procedures cited in refs. 30, 31 and 32, respectively.
The arylnitrile oxides were prepared by dehydrohalogenation
of the corresponding hydroxamoyl chlorides with triethyl-
amine.34–36 For 2,6-dichlorobenzonitrile oxide the dehydro-
halogenation of the corresponding hydroxamoyl chloride was
performed by treatment with sodium hypochlorite.37–39 Aceto-
nitrile oxide was prepared from nitroethane according to the
Mukaiyama–Hoshino method.40 In order to minimize their
dimerization [formation of furazan N-oxides (furoxans)],10,11 all
nitrile oxides were generated just before use and their solutions
were added dropwise in a few minutes to a solution of the
respective cyclopentenone. The furoxans were easily separated
by column chromatography.
Further studies for the development of these promising
results are therefore underway.
Experimental
Mps were measured on a Kofler apparatus and are uncorrected.
Elemental analyses were performed on a Perkin-Elmer 240C
elemental analyser. NMR spectra were recorded for CDCl3
solutions (unless otherwise stated) on a Bruker AC 200 spec-
trometer (200 MHz). Chemical shifts (δ) were measured in ppm,
relative to TMS as internal standard, and coupling constants
(J) are in hertz. When necessary, NMR data were assigned
using HH- and CH-correlated spectra. Proton–proton NOEs
General method for the preparation of compounds 3a, 3b,
12a–14a and 12b–15b
A solution of 2,6-dichlorobenzonitrile oxide (1.68 g, 9.1 mmol)
in CH2Cl2 (15 ml) was added dropwise under stirring to a
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solution of the appropriate 4-substituted cyclopent-2-enone
(6.0 mmol) in CH2Cl2 (10 ml) at room temperature. The solu-
tion was stirred at room temperature for 8 h and then concen-
trated and the residue was purified by flash chromatography
(diethyl ether–petroleum spirit, 1:1) to give the corresponding
cycloadduct.
(3aRS,6RS,6aRS)-3-(2,6-Dichlorophenyl)-6-methyl-3a,5,6,-
6a-tetrahydro-4H-cyclopent[d]isoxazol-4-one 14a and (3aRS,
6SR,6aRS)-3-(2,6-dichlorophenyl)-6-methyl-3a,5,6,6a-tetra-
hydro-4H-cyclopent[d]isoxazol-4-one 14b. Compound 14a (0.42
g, 32%) (white solid), mp 115 ЊC (from cyclohexane) (Found: C,
54.72; H, 3.74; N, 4.76. Calc. for C13H11Cl2NO2: C, 54.90; H,
3.87; N, 4.93%); δH 1.18 (3 H, d, JMe,6 6.6, Me), 2.14 (1 H, m,
5Ј-H), 2.78 (1 H, m, 6-H), 2.81 (1 H, m, 5-H), 4.24 (1 H, d, J3a,6a
9.1, 3a-H), 5.21 (1 H, dd, J3a,6a 9.1, J6,6a 2.5, 6a-H), 7.25–7.50
(3 H, m, ArH); δC 19.2 (CH3), 36.2 (C-6), 43.7 (C-5), 62.3
(C-3a), 91.2 (C-6a), 126.7 (C), 128.2 (2 × CH), 131.5 (CH),
135.3 (2 × CCl), 149.7 (C-3), 208.6 (C-4).
Compound 14b (0.90 g, 68%) (white solid), mp 133–135 ЊC
(from diethyl ether) (Found: C, 55.08; H, 3.94; N, 5.06%); δH
1.39 (3 H, d, JMe,6 6.6, Me), 2.51 (2 H, m, 5-H2), 2.65 (1 H, m,
6-H), 4.20 (1 H, d, J3a,6a 8.7, 3a-H), 5.44 (1 H, dd, J3a,6a 8.7, J6,6a
4.5, 6a-H), 7.25–7.50 (3 H, m, ArH); δC 14.5 (Me), 35.9 (C-6),
42.8 (C-5), 64.3 (C-3a), 88.1 (C-6a), 126.7 (C), 128.0 (2 × CH),
131.7 (CH), 135.3 (2 × CCl), 150.1 (C-3), 208.9 (C-4).
(3aRS,6RS,6aSR)-3-(2,6-Dichlorophenyl)-6-hydroxy-6-
methyl-3a,5,6,6a-tetrahydro-4H-cyclopent[d]isoxazol-4-one 3a
and
(3aRS,6SR,6aSR)-3-(2,6-dichlorophenyl)-6-hydroxy-6-
methyl-3a,5,6,6a-tetrahydro-4H-cyclopent[d]isoxazol-4-one 3b.
Compound 3a (1.3 g, 85%) (white solid), mp 174–176 ЊC (from
cyclohexane) (Found: C, 52.31; H, 3.80; N, 4.66. Calc. for
C13H11Cl2NO3: C, 52.00; H, 3.66; N, 4.66%); δH 1.44 (3 H, s,
CH3), 2.45 (1 H, d, J5,5Ј 17.0, 5-H), 2.67 (1 H, d, J5,5Ј 17.0, 5Ј-H),
2.86 (1 H, s, OH), 4.42 (1 H, d, J3a,6a 9.8, 3a-H), 5.21 (1 H, d,
J3a,6a 9.8, 6a-H), 7.36 (3 H, m, ArH); δC 25.9 (Me), 50.0 (C-5),
63.9 (C-3a), 75.1 (C-6), 89.6 (C-6a), 125.9 (C), 128.1 (2 × CH),
131.4 (CH), 135.0 (2 × CCl), 150.7 (C-3), 204.5 (C-4).
Compound 3b (0.23 g, 15%) (pale yellow oil) (Found: C,
52.40; H, 3.62; N, 4.55%); δH 1.68 (3 H, s, CH3), 2.44 (1 H, d,
J5,5Ј 17.2, 5-H), 2.77 (1 H, d, J5,5Ј 17.2, 5Ј-H), 4.36 (1 H, d, J3a,6a
9.8, 3a-H), 5.18 (1 H, d, J3a,6a 9.8, 6a-H), 7.34 (3 H, m, ArH); δC
22.7 (Me), 48.8 (C-5), 63.4 (C-3a), 77.0 (C-6), 92.0 (C-6a), 126.2
(C), 128.1 (2 × CH), 131.3 (CH), 135.0 (2 × CCl), 150.3 (C-3),
206.3 (C-4).
(3aRS,6SR,6aSR)-3-(2,6-Dichlorophenyl)-4-oxo-4,5,6,6a-
tetrahydro-3aH-cyclopent[d]isoxazol-6-yl acetate 15b. Com-
pound 15b (1.0 g, 100%) (white solid), mp 127–129 ЊC (from
cyclohexane) (Found: C, 53.98; H, 3.64; N, 4.71. Calc. for
C14H11Cl2NO3: C, 53.84; H, 3.52; N, 4.48%); δH 2.18 (3 H, s,
CH3), 2.43 (1 H, dd, J5,5Ј 18.4, J3a,5Ј 1.4, 5Ј-H), 2.95 (1 H, dd, J5,5Ј
18.4, J5,6 5.2, 5-H), 4.30 (1 H, dd, J3a,6a 6.5, J3a,5Ј 1.4, 3a-H), 5.34
(1 H, br d, J5,6 5.2, 6-H), 5.60 (1 H, br d, J3a,6a 6.5, 6a-H), 7.22–
7.44 (3 H, m, ArH); δC 20.8 (Me), 42.1 (C-5), 62.3 (C-3a), 73.9
(C-6a), 88.2 (C-6), 126.1 (C), 128.3 (2 × CH), 131.7 (CH), 135.3
(2 × CCl), 150.0 (C-3), 169.7 (OCO), 205.5 (C-4).
(3aRS,6RS,6aSR)-3-(2,6-Dichlorophenyl)-6-methyl-4-oxo-
4,5,6,6a-tetrahydro-3aH-cyclopent[d]isoxazol-6-yl acetate 12a
and (3aRS,6SR,6aSR)-3-(2,6-dichlorophenyl)-6-methyl-4-oxo-
4,5,6,6a-tetrahydro-3aH-cyclopent[d]isoxazol-6-yl acetate 12b.
Compound 12a (0.56 g, 57%) (white solid), mp 161–163 ЊC
(from cyclohexane) (Found: C, 52.35; H, 3.67; N, 4.15. Calc.
for C15H13Cl2NO4: C, 52.63; H, 3.80; N, 4.09%); δH 1.61 (3 H,
s, CH3), 2.16 (3 H, s, COCH3), 2.75 (1 H, dt, J5,5Ј 16.9,
J5Ј,6a = J3a,5Ј = 1.2, 5Ј-H), 3.15 (1 H, br d, J5,5Ј 16.9, 5-H), 4.30
(1 H, br d, J3a,6a 8.7, 3a-H), 5.75 (1 H, br d, J3a,6a 8.7, 6a-H),
7.26–7.42 (3 H, m, ArH); δC 21.5 (CH3), 23.7 (COCH3), 48.3
(C-5), 64.0 (C-3a), 81.8 (C-6), 89.0 (C-6a), 126.4 (C), 128.3
(2 × CH), 131.6 (CH), 135.4 (2 × CCl), 149.6 (C-3), 170.1
(OCO), 203.5 (C-4).
Compound 12b (0.42 g, 43%) (white solid), mp 192–194 ЊC
(from cyclohexane) (Found: C, 52.85; H, 3.60; N, 4.18%);
δH 1.78 (3 H, s, CH3), 2.04 (3 H, s, COCH3), 2.70 (1 H, d, J5,5Ј
18.6, 5-H), 2.91 (1 H, dt, J5,5Ј 18.6, J5Ј,6a = J3a,5Ј = 1.0, 5-H), 4.62
(1 H, dd, J3a,6a 9.5, J3a,5Ј 1.0, 3a-H), 5.44 (1 H, dd, J3a,6a 9.5, J5Ј,6a
1.0, 6a-H), 7.40–7.52 (3 H, m, ArH); δC 21.2 (CH3), 21.3
(COCH3), 47.9 (C-5), 64.8 (C-3a), 84.6 (C-6), 90.1 (C-6a), 126.0
(C), 128.0 (2 × CH), 131.4 (CH), 135.6 (2 × CCl), 150.0 (C-3),
170.6 (OCO), 204.2 (C-4).
(3aRS,6RS,6aSR)-3-(4-Chlorophenyl)-6-hydroxy-6-methyl-
3a,5,6,6a-tetrahydro-4H-cyclopent[d]isoxazol-4-one 4a and
(3aRS,6SR,6aSR)-3-(4-chlorophenyl)-6-hydroxy-6-methyl-3a,5,
6,6a-tetrahydro-4H-cyclopent[d]isoxazol-4-one 4b. A solution
of 4-chlorobenzonitrile oxide (1.2 g, 7.8 mmol) in diethyl ether
(25 ml) was added dropwise under stirring at Ϫ5 ЊC to a solu-
tion of the cyclopentenone 1 (0.6 g, 5.3 mmol) in diethyl ether
(10 ml). The solution was stirred at room temperature for 8 h. It
was then concentrated to give a residue, which was resolved by
column chromatography (diethyl ether–petroleum spirit 2:1) to
provide cycloadducts 4a and 4b (1.1 g, 75%).
Compound 4a (0.8 g, 75%) (white needles), mp 126–129 ЊC
(from diethyl ether) (Found: C, 58.42; H, 4.51; N, 5.13. Calc.
for C13H12ClNO3: C, 58.76; H, 4.52; N, 5.27%); δH 1.44 (3 H, s,
CH3), 2.46 (1 H, d, J5,5Ј 16.9, 5-H), 2.66 (1 H, d, J5,5Ј 16.9, 5Ј-H),
2.87 (1 H, s, OH), 4.36 (1 H, d, J3a,6a 9.7, 3a-H), 5.13 (1 H, d,
J3a,6a 9.7, 6a-H), 7.38 (2 H, d, J 8.4, ArH), 7.82 (2 H, d, J 8.4,
ArH); δC 25.8 (CH3), 50.0 (C-5), 61.7 (C-3a), 74.8 (C-6), 90.4
(C-6a), 125.9 (C), 128.9 (2 × CH), 129.2 (2 × CH), 136.8
(CCl), 153.1 (C-3), 205.2 (C-4).
Compound 4b (0.27 g, 25%) (white needles), mp 149–151 ЊC
(from diethyl ether) (Found: C, 58.52; H, 4.41; N, 5.38%);
δH 1.65 (3 H, s, CH3), 2.43 (1 H, dt, J5,5Ј 16.9, J5,6a = J5,3a = 1.2,
5-H), 2.60 (1 H, d, J5,5Ј 16.9, 5Ј-H), 3.01 (1 H, s, OH), 4.34 (1 H,
dd, J3a,6a 8.3, J5,3a 1.2, 3a-H), 5.09 (1 H, dd, J3a,6a 8.3, J5,6a 1.2,
6a-H), 7.38 (2 H, d, J 8.7, ArH), 7.82 (2 H, d, J 8.7, ArH);
δC 23.1 (Me), 49.0 (C-5), 60.8 (C-3a), 76.5 (C-6), 92.8 (C-6a),
126.2 (C), 128.9 (2 × CH), 129.0 (2 × CH), 136.7 (CCl), 152.9
(C-3), 207.1 (C-4).
(3aRS,6RS,6aSR)-3-(2,6-Dichlorophenyl)-6-hydroxy-3a,5,6,-
6a-tetrahydro-4H-cyclopent[d]isoxazol-4-one 13a and (3aRS,
6SR,6aSR)-3-(2,6-dichlorophenyl)-6-hydroxy-3a,5,6,6a-tetra-
hydro-4H-cyclopent[d]isoxazol-4-one 13b. Compound 13a
(0.78 g, 55%) (white solid), mp 110–112 ЊC (from cyclohexane)
(Found: C, 50.55; H, 3.30; N, 4.98. Calc. for C12H9Cl2NO3: C,
50.35; H, 3.15; N, 4.8%); δH 2.63 (2 H, m, 5-H2), 4.40 (1 H, d,
J3a,6a 10.0, 3a-H), 4.62 (1H, dd, J6,6a 5.4, J5,6 5.9, 6-H), 5.53 (1 H,
dd, J6,6a 5.4, J3a,6a 10.0, 6a-H), 7.28–7.45 (3 H, m, ArH); δC 44.5
(C-5), 63.1 (C-3a), 69.5 (C-6), 84.9 (C-6a), 126.0 (C), 128.2
(2 × CH), 131.5 (CH), 135.2 (2 × CCl), 150.7 (C-3), 205.5
(C-4).
Compound 13b (0.63 g, 45%) (white solid), mp 142 ЊC (from
cyclohexane) (Found: C, 50.22; H, 3.04; N, 4.78%); δH 2.47
(1 H, br d, J5,5Ј 17.8, 5Ј-H), 2.91 (1 H, dd, J5,5Ј 17.8, J5,6 5.5,
5-H), 4.34 (1 H, br d, J3a,6a 8.9, 3a-H), 4.76 (1 H, br d, J5,6 5.5,
6-H), 5.41 (1 H, d, J3a,6a 8.9, 6a-H), 7.30–7.50 (3 H, m, ArH); δC
44.5 (C-5), 61.9 (C-3a), 71.9 (C-6), 90.6 (C-6a), 128.3 (2 × CH),
128.6 (C), 131.6 (CH), 135.3 (2 × CCl), 150.1 (C-3), 206.6 (C-4).
(3aRS,6RS,6aSR)-6-Hydroxy-6-methyl-3-(4-methylphenyl)-
3a,5,6,6a-tetrahydro-4H-cyclopent[d]isoxazol-4-one 5a and
(3aRS,6SR,6aSR)-6-hydroxy-6-methyl-3-(4-methylphenyl)-3a,
5,6,6a-tetrahydro-4H-cyclopent[d]isoxazol-4-one 5b. A solu-
tion of 4-methylbenzonitrile oxide (2 g, 15 mmol) in CH2Cl2
(60 ml) at Ϫ5 ЊC was added dropwise to a solution of the
cyclopentenone 1 (1 g, 8.9 mmol) in CH2Cl2 (30 ml), cooled
to Ϫ5 ЊC. The mixture was stirred at room temperature for 24 h.
J. Chem. Soc., Perkin Trans. 1, 2000, 2649–2656
2653

View Article Online
The solution was concentrated, treated with benzene, and fil-
tered. The benzene solution was concentrated and the
residue was resolved by column chromatography (diethyl
ether–petroleum spirit 2:1) to yield the cycloadducts 5a and 5b
(1.8 g, 82%).
Compound 5a (1.16 g, 65%) (white solid), mp 144–146 ЊC
(from diethyl ether) (Found: C, 68.38; H, 6.12; N, 5.71. Calc.
for C14H15NO3: C, 68.57; H, 6.12; N, 5.71%); δH 1.42 (3 H, s,
6-CH3), 2.36 (3 H, s, CH3), 2.49 (1 H, d, J5,5Ј 16.1, 5Ј-H), 2.69
(1 H, d, J5,5Ј 16.1, 5-H), 4.44 (1 H, d, J3a,6a 9.0, 3a-H), 5.02 (1 H,
d, J3a,6a 9.0, 6a-H), 7.24 (2 H, d, J 8.1, ArH), 7.77 (2 H, d, J 8.1,
ArH); δC 21.3 (Me), 25.8 (6-CH3), 49.9 (C-5), 62.0 (C-3a), 74.7
(C-6), 90.0 (C-6a), 124.3 (C), 127.8 (2 × CH), 129.3 (2 × CH),
141.0 (C), 153.8 (C-3), 205.1 (C-4).
Compound 5b (0.62 g, 35%) (colourless oil) (Found: C, 68.78;
H, 6.32; N, 5.84%); δH 1.64 (3 H, s, 6-Me), 2.38 (3 H, s, Me),
2.46 (1 H, d, J5,5Ј 16.1, 5Ј-H), 2.66 (1 H, d, J5,5Ј 16.1, 5-H), 3.90
(1 H, d, J3a,6a 9.0, 3a-H), 5.12 (1 H, d, J3a,6a 9.0, 6a-H), 7.22 (2 H,
d, J 8.1, ArH), 7.71 (2 H, d, J 8.1, ArH); δC 21.3 (Me), 23.3
(6-CH3), 48.5 (C-5), 60.4 (C-3a), 76.7 (C-6), 92.1 (C-6a), 124.2
(C), 127.6 (2 × CH), 129.4 (2 × CH), 141.0 (C), 153.6 (C-3),
206.1 (C-4).
Compound 7b (0.92 g, 30%) (pale yellow oil) (Found: C, 56.56;
H, 6.48; N, 8.20%); δH 1.54 (3 H, s, 6-Me), 2.00 (3 H, s, 3-Me),
2.10 (1 H, dd, J5,6a 1.0, J5,5Ј 19.4, 5-H), 2.35 (1 H, d, J5,5Ј 19.4,
5Ј-H), 2.44 (1 H, s, OH), 3.83 (1 H, br d, J3a,6a 8.3, 3a-H), 4.90
(1 H, dd, J5,6a 1.0, J3a,6a 8.3, 6a-H); δC 11.4 (6-CH3), 22.5
(3-CH3), 48.5 (C-5), 64.5 (C-3a), 76.5 (C-6), 90.9 (C-6a), 152.1
(C-3), 209.3 (C-4).
General method for the reduction of compounds 3a–7a and 20a
with NaBH4
NaBH4 (3 mmol for 1 mmol of cycloadduct) was slowly added
under stirring to a cooled solution (Ϫ5 ЊC) of the appropriate
cycloadduct (0.5 g) in CH3OH (26 ml). The reaction mixture
was stirred at Ϫ5 ЊC for 1 h. The solution was concentrated,
treated with dil. HCl, and extracted with CH2Cl2. The organic
layer was dried over anhydrous sodium sulfate; hence it was
filtered and concentrated to give the reduced cycloadducts.
(3aRS,4RS,6SR,6aRS)-3-(2,6-Dichlorophenyl)-6-methyl-
4,5,6,6a-tetrahydro-3aH-cyclopent[d]isoxazole-4,6-diol 16a and
(3aRS,4SR,6SR,6aRS)-3-(2,6-dichlorophenyl)-6-methyl-4,5,6,
6a-tetrahydro-3aH-cyclopent[d]isoxazole-4,6-diol 16b. The
cycloadduct mixture was resolved by column chromatography
(diethyl ether–petroleum spirit 3:1) to provide reduced
cycloadducts 16a and 16b (0.46 g, 92%).
(3aRS,6RS,6aSR)-6-Hydroxy-6-methyl-3-phenyl-3a,5,6,6a-
tetrahydro-4H-cyclopent[d]isoxazol-4-one 6a and (3aRS,6SR,
6aSR)-6-hydroxy-6-methyl-3-phenyl-3a,5,6,6a-tetrahydro-4H-
cyclopent[d]isoxazol-4-one 6b. A solution of benzonitrile oxide
(3 g, 25 mmol) in CH2Cl2 (90 ml) at Ϫ5 ЊC was added dropwise
to a solution of the cyclopentenone 1 (2 g, 17.8 mmol) in
CH2Cl2 (50 ml) cooled to Ϫ5 ЊC. The mixture was stirred at
room temperature for 8 h. The solution was concentrated,
treated with benzene, filtered, and resolved by column chrom-
atography (diethyl ether–petroleum spirit 2:1) to yield the
cycloadducts 6a and 6b (3.5 g, 85%).
Compound 6a (2.8 g, 80%) (white solid), mp 137–138 ЊC
(from cyclohexane) (Found: C, 67.21; H, 5.62; N, 5.85. Calc. for
C13H13NO3: C, 67.53; H, 5.63; N, 6.06%); δH 1.44 (3 H, s, Me),
2.46 (1 H, dd, J5,5Ј 16.8, J3a,5 1.0, 5-H), 2.68 (1 H, d, J5,5Ј 16.8,
5Ј-H), 2.82 (1 H, br s, OH), 4.40 (1 H, dd, J3a,6a 9.2, J3a,5 1.0,
3a-H), 5.12 (1 H, d, J3a,6a 9.2, 6a-H), 7.40–7.46 (3 H, m, ArH),
7.85–7.91 (2 H, m, ArH); δC 25.9 (Me), 50.0 (C-5), 62.0 (C-3a),
74.8 (C-6), 90.3 (C-6a), 127.4 (C), 127.9 (2 × CH), 128.7
(2 × CH), 130.7 (CH), 153.9 (C-3), 205.1 (C-4).
Compound 16a (0.41 g, 90%) (white solid), mp 197–199 ЊC
(from cyclohexane) (Found: C, 51.26; H, 4.58; N, 4.56. Calc. for
C13H13Cl2NO3: C, 51.55; H, 4.30; N, 4.64%); δH (DMSO-d6)
1.12 (3 H, s, Me), 1.71 (1 H, dd, J4,5Ј 5.8, J5,5Ј 11.5, 5Ј-H), 1.84
(1 H, t, J5,5Ј 11.5, J4,5 11.5, 5-H), 4.15 (1 H, m, J4,5 11.5, J4,5Ј 5.8,
JOH,4 4.4, 4-H), 4.42 (1 H, dd, J3a,6a 9.2, J3a,4 7.4, 3a-H), 4.51 (1 H,
d, J3a,6a 9.2, 6a-H), 4.74 (1 H, d, JOH,4 4.4, 4-OH), 4.83 (1 H, s,
6-OH), 7.32–7.50 (3 H, m, ArH); δC (DMSO-d6) 24.6 (Me),
44.8 (C-5), 58.1 (C-3a), 71.8 (C-6a), 77.6 (C-6), 90.4 (C-4), 128.0
(2 × CH), 130.2 (C), 130.4 (CH), 134.1 (2 × CCl), 153.8 (C-3).
Compound 16b (0.05 g, 10%) (white solid), mp 96–98 ЊC
(from cyclohexane) (Found: C, 51.20; H, 4.25; N, 4.40%);
δH (DMSO-d6) 1.25 (3 H, s, 6-Me), 1.58 (1 H, dd, J5,5Ј 12.1, J4,5Ј
10.7, 5Ј-H), 1.81 (1 H, dd, J5,5Ј 12.1, J4,5 5.5, 5-H), 4.39–4.60
(3 H, m, 4-, 3a-, 6a-H), 4.76 (1 H, d, JOH,4 3.8, 4-OH), 4.86 (1 H,
s, 6-OH), 7.32–7.50 (3 H, m, ArH); δC (DMSO-d6): 24.2 (Me),
43.5 (C-5), 56.3 (C-3a), 70.0 (C-6a), 78.1 (C-6), 92.4 (C-4), 128.2
(2 × CH), 130.4 (C), 131.0 (CH), 135.1 (2 × CCl), 152.3 (C-3).
Compound 6b (0.7 g, 20%) (colourless oil) (Found: C, 67.81;
H, 5.82; N, 5.95%); δH 1.65 (3 H, s, Me), 2.53 (1 H, d, J5,5Ј 16.8,
5-H), 2.79 (1 H, br d, J5,5Ј 16.8, 5Ј-H), 4.43 (1 H, d, J3a,6a 9.2, 3a-
H), 5.01 (1 H, d, J3a,6a 9.2, 6a-H), 7.40–7.46 (3 H, m, ArH),
7.85–7.91 (2 H, m, ArH); δC 22.6 (Me), 49.4 (C-5), 60.8 (C-3a),
75.4 (C-6), 91.6 (C-6a), 127.5 (C), 127.9 (2 × CH), 128.8
(2 × CH), 130.9 (CH), 152.7 (C-3), 206.3 (C-4).
(3aRS,4RS,6SR,6aRS)-3-(4-Chlorophenyl)-6-methyl-4,5,6,
6a-tetrahydro-3aH-cyclopent[d]isoxazole-4,6-diol
17a
and
(3aRS,4SR,6SR,6aRS)-3-(4-chlorophenyl)-6-methyl-4,5,6,6a-
tetrahydro-3aH-cyclopent[d]isoxazole-46-diol 17b. The cyclo-
adduct mixture was resolved by column chromatography
(chloroform–methanol 95:5) to afford the reduced cyclo-
adducts 17a and 17b (0.48 g, 96%).
(3aRS,6RS,6aSR)-6-Hydroxy-3,6-dimethyl-3a,5,6,6a-tetra-
hydro-4H-cyclopent[d]isoxazol-4-one 7a and (3aRS,6SR,
6aSR)-6-hydroxy-3,6-dimethyl-3a,5,6,6a-tetrahydro-4H-cyclo-
pent[d]isoxazol-4-one 7b. An acetonitrile oxide solution (27.2
mmol in benzene) was added dropwise to a solution of the
cyclopentenone 1 (3 g, 26.8 mmol) in benzene (90 ml). The
reaction mixture was stirred overnight at room temperature,
filtered, and the resulting solution was concentrated to give a
residue. This was resolved by flash chromatography (ethyl
acetate–n-hexane 1:1) to yield compounds 7a and 7b (3.1 g,
68%).
Compound 7a (2.1 g, 70%) (white solid), mp 77 ЊC (from
cyclohexane) (Found: C, 56.46; H, 6.38; N, 8.17. Calc. for
C8H11NO3: C, 56.80; H, 6.51; N, 8.28%); δH 1.43 (3 H, s, 6-Me),
2.05 (3 H, d, J3a,3Me 1.0, 3-Me), 2.36 (1 H, d, J5,5Ј 17.2, 5Ј-H),
2.56 (1 H, d, J5,5Ј 17.2, 5-H), 2.68 (1 H, s, OH), 3.87 (1 H, br d,
J3a,6a 9.9, 3a-H), 4.96 (1 H, d, J6a,3a 9.9, 6a-H); δC 11.4 (6-CH3),
25.9 (3-CH3), 50.1 (C-5), 64.6 (C-3a), 75.1 (C-6), 87.9 (C-6a),
152.6 (C-3), 206.2 (C-4).
Compound 17a (0.32 g, 68%) (white solid), mp 158–160 ЊC
(Found: C, 58.49; H, 5.5; N, 5.3. Calc. for C13H14ClNO3: C,
58.32; H, 5.2; N, 5.2%); δH (CD3COCD3) 1.36 (3 H, s, Me), 1.89
(1 H, dd, J5,5Ј 13.2, J5,4 4.6, 5-H), 1.98 (1 H, dd, J5,5Ј 13.2, J4,5Ј
5.6, 5Ј-H), 3.98 (2 H, br s, 4-OH, 6-OH), 4.04 (1 H, dd, J3a,4 7.1,
J3a,6a 10.3, 3a-H), 4.24 (1 H, m, 4-H), 4.68 (1 H, d, J3a,6a 10.3, 6a-
H), 7.39 (2 H, d, J 8.4, ArH), 7.75 (2 H, d, J 8.4, ArH); δC
(CD3COCD3) 26.5 (Me), 47.6 (C-5), 61.7 (C-3a), 75.1 (C-4),
78.8 (C-6), 91.7 (C-6a), 127.9 (C), 129.4 (2 × CH), 129.6
(2 × CH), 135.9 (CCl), 156.6 (C-3).
Compound 17b (0.15 g, 32%) (white solid), mp 169–170 ЊC
(Found: C, 58.42; H, 5.3; N, 5.4%); δH (CD3COCD3) 1.42 (3 H,
s, Me), 1.73 (1 H, dd, J5,5Ј 13.1, J5,4 6, 5-H), 2.03 (1 H, dd, J5,5Ј
13.1, J4,5Ј 6.2, 5Ј-H), 3.63 (2 H, br s, 4-OH, 6-OH), 4.03 (1 H, dd,
J3a,4 3.5, J3a,6a 10.5, 3a-H), 4.34 (1 H, m, 4-H), 4.88 (1 H, d, J3a,6a
10.5, 6a-H), 7.46 (2 H, d, J 8.4, ArH), 7.87 (2 H, d, J 8.4, ArH);
δC (CD3COCD3) 25.9 (Me), 47.1 (C-5), 58.3 (C-3a), 73.7 (C-4),
79.6 (C-6), 93.3 (C-6a), 128.2 (C), 129.1 (2 × CH), 129.5
(2 × CH), 135.2 (CCl), 157.1 (C-3).
2654
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(3aRS,4RS,6SR,6aRS)-6-Methyl-3-phenyl-4,5,6,6a-tetra-
hydro-3aH-cyclopent[d]isoxazole-4,6-diol 18a and (3aRS,4SR,
6SR,6aRS)-6-methyl-3-phenyl-4,5,6,6a-tetrahydro-3aH-cyclo-
pent[d]isoxazole-4,6-diol 18b. The cycloadduct mixture was
resolved by column chromatography (chloroform–methanol
95:5), to afford 18a and 18b (0.47 g, 94%).
Compound 18a (0.35 g, 75%) (white solid), mp 135–137 ЊC
(Found: C, 67.1; H, 6.7; N, 6.2. Calc. for C13H15NO3: C, 66.9;
H, 6.4; N, 6.0%); δH (CD3COCD3) 1.36 (3 H, s, Me), 1.90 (1 H,
dd, J5,5Ј 13.2, J5,4 4.4, 5-H), 1.98 (1 H, dd, J5,5Ј 13.2, J4,5Ј 4.6,
5Ј-H), 3.90 (1 H, d, JOH,4 9.2, 4-OH), 3.94 (1 H, s, 6-OH), 4.40
(1 H, dd, J3a,4 7.2, J3a,6 10.5, 3a-H), 4.59 (1 H, m, 4-H), 4.77 (1H,
d, J3a,6a 10.5, 6a-H), 7.37 (3 H, m, ArH), 7.75 (2 H, m,
ArH); δC (CD3COCD3) 25.9 (Me), 47.3 (C-5), 58.7 (C-3a), 73.9
(C-4), 79.8 (C-6), 93.0 (C-6a), 127.9 (2 × CH), 128.9 (2 × CH),
129.9 (CH), 131.7 (C), 157.9 (C-3).
Compound 18b (0.12 g, 25%) (white solid), mp 146–149 ЊC
(Found: C, 66.5; H, 6.0; N, 6.3%); δH (CD3COCD3) 1.43 (3 H, s,
Me), 1.74 (1 H, dd, J5,5Ј 13.2, J5,4 5.6, 5-H), 2.02 (1 H, dd, J5,5Ј
13.2, J4,5Ј 6.0, 5Ј-H), 3.35 (1 H, s, 6-OH), 4.04 (1 H, dd, J3a,4 3.2,
J3a,6a 10.3, 3a-H), 4.36 (1 H, m, 4-H), 4.52 (1 H, d, JOH,4 5.3,
4-OH), 4.84 (1 H, d, J3a,6a 10.3, 6a-H), 7.43 (3 H, m, ArH), 7.86
(2 H, m, ArH); δC (CD3COCD3) 26.6 (Me), 47.6 (C-5), 61.9
(C-3a), 75.0 (C-4), 83.6 (C-6), 91.4 (C-6a), 127.8 (2 × CH),
129.4 (2 × CH), 129.9 (C), 130.4 (CH), 158.4 (C-3).
δC 22.3 (C-4), 34.5 (C-5), 51.9 (C-3a), 83.1 (C-6a), 126.9 (C),
128.4 (2 × CH), 131.4 (CH), 135.3 (2 × CCl), 155.1 (C-3),
211.3 (C-6).
(3aRS,4RS,6aSR)-3-(2,6-Dichlorophenyl)-4,5,6,6a-tetra-
hydro-3aH-cyclopent[d]isoxazole-4-ol 21a. NaBH4 was slowly
added to a cooled solution (Ϫ5 ЊC) of the cycloadduct 20a
(0.5 g, 1.85 mmol) in CH3OH (15 ml). The reaction mixture
was stirred at 0 ЊC for 1 h. The solution was concentrated to
give a white solid, which was treated with dil. HCl. The solution
was extracted with CH2Cl2 and the organic layer was dried
over anhydrous sodium sulfate, filtered, and concentrated to
give 21a as a white solid (0.45 g, 90%), mp 196–198 ЊC
(from cyclohexane) (Found: C, 52.86; H, 3.95; N, 4.99. Calc.
for C12H11Cl2NO2: C, 52.94; H, 4.04; N, 5.15%); δH 1.55–2.03
(5 H, m, 3a-H, 5- and 6-H2), 4.35 (1 H, m, 4-H), 5.25 (1 H, m,
6a-H), 7.2–7.4 (3 H, m, ArH); δC 31.0 (C-6), 31.6 (C-5), 57.3
(C-3a), 77.1 (C-6a), 86.8 (C-4), 126.1 (C), 128.5 (2 × CH), 129.8
(CH), 134.8 (2 × CCl), 152.9 (C-3).
(3aRS,6aSR)-3-(2,6-Dichlorophenyl)-6-methyl-3a,6a-dihydro-
4H-cyclopent[d]isoxazol-4-one 22
Acetyl chloride was added in excess to the cycloadduct 3a (0.5
g, 1.7 mmol). The mixture was stirred and heated at 40 ЊC until
the solid dissolved. The reaction was stirred for 12 h at room
temperature and the solution was then concentrated; the result-
ing oily residue was treated with diethyl ether to provide 22 as a
white solid (0.36 g, 77%), mp 175–177 ЊC (from cyclohexane)
(Found: C, 52.99; H, 3.24; N, 4.97. Calc. for C12H9Cl2NO2: C,
53.33; H, 3.33; N, 5.20%); δH 2.31 (3 H, s, Me), 4.33 (1 H, d,
J3a,6a 7.5, 3a-H), 5.67 (1 H, br d, J3a,6a 7.5, 6a-H), 6.04 (1 H, br s,
5-H), 7.26–7.40 (3 H, m, ArH); δC 16.6 (Me), 61.1 (C-3a), 86.3
(C-6a), 128.2 (C), 130.4 (2 × CH), 131.5 (CH), 132.8 (C-5),
135.3 (2 × CCl), 151.2 (C-3), 173.1 (C-6), 199.4 (C-4).
(3aRS,4RS,6SR,6aRS)-3,6-Dimethyl-4,5,6,6a-tetrahydro-
3aH-cyclopent[d]isoxazole-4,6-diol 19a and (3aRS,4SR,6SR,
6aRS)-3,6-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopent[d]isox-
azole-4,6-diol 19b. The cycloadduct mixture was resolved by
column chromatography (n-hexane–ethyl acetate 2:1) to afford
19a and 19b (0.47 g, 92%).
Compound 19a (0.35 g, 75%) (white solid), mp 118–120 ЊC
(Found: C, 56.40; H, 7.7; N, 8.4. Calc. for C8H13NO3: C, 56.14;
H, 7.6; N, 8.2%); δH 1.36 (3 H, s, 6-Me), 1.75 (1 H, dd, J5,5Ј 14,
J5Ј,4 4.8, 5Ј-H), 2.05 (1 H, d, J5,5Ј 14, 5-H), 2.07 (3 H, s, 3-Me),
2.95 (1 H, br d, J 1.7, 6-OH), 3.61 (1 H, br d, J4,OH 11.2, 4-OH),
3.86 (1 H, dd, J3a,6a 11.3, 3a-H), 4.39 (1 H, m, 4-H), 4.63 (1 H, d,
J3a,6a 11.3, 6a-H); δC 13.1 (3-CH3), 25.6 (6-CH3), 46.3 (C-5), 62.6
(C-3a), 73.6 (C-4), 80.3 (C-6), 90.2 (C-6a), 153.4 (C-3).
Compound 19b (0.12 g, 25%) (white solid), mp 114–116 ЊC
(Found: C, 56.20; H, 7.5; N, 8.7%); δH 1.41 (3 H, s, 6-Me), 1.71
(1 H, dd, J5,5Ј 15.8, J 5,4 5.8, 5-H), 2.03 (3 H, s, 3-Me), 2.07 (1 H,
dd, J5,5Ј 15.8, J 5Ј,4 6.2, 5Ј-H), 2.52 (1 H, br s, 6-OH), 2.68 (1 H,
br s, 4-OH), 3.53 (1 H, dd, J3a,4 9.3, 3a-H), 4.39 (1 H, m, 4-H),
4.68 (1 H, d, J3a,6a 10.6, 6a-H); δC 11.2 (3-CH3), 26.4 (6-CH3),
46.9 (C-5), 64.6 (C-3a), 73.9 (C-4), 79.1 (C-6), 88.7 (C-6a), 156.7
(C-3).
(3aRS,4RS,6SR,6aRS)-3-(2,6-Dichlorophenyl)-6-methyl-
4,5,6,6a-tetrahydro-3aH-cyclopent[d]isoxazole-4,6-diyl
diacetate 23a
Acetyl chloride was added in excess to the cycloadduct 16a (0.5
g, 1.65 mmol). The mixture was stirred and heated at 40 ЊC until
the solid dissolved. The reaction was refluxed for 4 h and then
concentrated. The residue, treated with methylene dichloride
and concentrated, gave 23a as white needles (0.59 g, 92%),
mp 154–155 ЊC (from cyclohexane) (Found: C, 53.04; H, 4.25;
N, 4.05. Calc. for C17H17Cl2NO5: C, 52.9; H, 4.4; N, 3.6%);
δH 1.46 (3 H, s, Me), 1.57 (3 H, s, Me), 2.13 (3 H, s, Me), 2.27
(1 H, d, J5,5Ј 11.2, 5Ј-H), 2.42 (1 H, d, J5,5Ј 11.2, 5-H), 4.82 (1 H,
t, J3a,6a = J3a,4 = 9.3, 3a-H), 5.07 (1 H, m, 4-H), 5.33 (1 H, d, J3a,6a
9.3, 6a-H), 7.25 (1 H, m, ArH), 7.38 (2 H, m, Ar H); δC 19.6
(6-CH3), 21.5 (Me), 23.2 (Me), 39.6 (C-5), 53.7 (C-3a), 72.2
(C-4), 82.9 (C-6), 88.5 (C-6a), 128.5 (2 × CH), 128.9 (C), 130.5
(CH), 135.4 (2 × CCl), 151.9 (C-3), 169.9 (OCO), 170.1 (OCO).
(3aRS,6aRS)-3-(2,6-Dichlorophenyl)-3a,5,6,6a-tetrahydro-
4H-cyclopent[d]isoxazol-4-one 20a and (3aRS,6aSR)-3-(2,6-
dichlorophenyl)-3a,4,5,6a-tetrahydro-6H-cyclopent[d]isoxazol-
6-one 20c. A solution of 2,6-dichlorobenzonitrile oxide (1.5 g,
8.1 mmol) in CH2Cl2 (20 ml) was slowly added to a solution of
cyclopent-2-enone (0.6 g, 7.3 mmol) in CH2Cl2 (15 ml) at room
temperature. The solution was stirred at room temperature for
8 h. It was then concentrated and the residue, resolved by col-
umn chromatography (diethyl ether–petroleum spirit 2:1), gave
20a and 20c (1.44 g, 73%).
Compound 20a (1.2 g, 85%) (white solid), mp 126 ЊC (from
cyclohexane) (Found: C, 53.1; H, 3.15; N, 5.00. Calc. for
C12H9Cl2NO2: C, 53.33; H, 3.33; N, 5.20%); δH 2.40–2.85 (4 H,
m, 5- and 6-H2), 4.27 (1 H, d, J3a,6a 9.2, 3a-H), 5.72 (1 H, m,
J3a,6a 9.2, 6a-H), 7.33–7.50 (3 H, m, ArH); δC 28.6 (C-6), 35.2
(C-5), 62.6 (C-3a), 85.0 (C-6a), 126.4 (C), 127.9 (2 × CH), 131.2
(CH), 134.9 (2 × CCl), 149.3 (C-3), 209.1 (C-4).
(3aRS,4SR,6SR,6aRS)-3-(2,6-Dichlorophenyl)-6-hydroxy-6-
methyl-4,5,6,6a-tetrahydro-3aH-cyclopent[d]isoxazol-4-yl
acetate 24b
Acetyl chloride was added in excess to the cycloadduct 16b
(0.5 g, 1.65 mmol). The mixture was stirred and heated at 40 ЊC
until the solid dissolved. The reaction mixture was refluxed for
24 h and then concentrated. The resulting residue was treated
with methylene dichloride and concentrated to give 24b as white
needles (0.51 g, 90%), mp 260 ЊC (decomp.) (from cyclohexane)
(Found: C, 52.0; H, 4.2; N, 3.98. Calc. for C15H15Cl2NO4: C,
52.3; H, 4.4; N, 4.1%); δH 1.56 (3 H, s, Me), 2.11 (3 H, s,
OCOMe), 2.25 (2 H, dd, 5-H2), 4.78 (1 H, m, 3a-H), 4.88 (1 H,
s, 6-OH), 5.05 (1 H, m, 6a-H), 5.25 (1 H, d, 4-H), 7.20–7.40 (3
H, m, ArH); δC 19.6 (OCOCH3), 23.3 (6-CH3), 39.6 (C-5), 53.7
(C-3a), 72.2 (C-4), 82.0 (C-6), 88.5 (C-6a), 127.1 (C), 128.5 (2 ×
CH), 130.5 (CH), 135.5 (2 × CCl), 151.9 (C-3), 170.0 (OCO).
Compound 20c (0.22 g, 15%) (white solid), mp 119 ЊC (from
cyclohexane) (Found: C, 53.13; H, 3.20; N, 5.10%); δH 2.05–2.20
(2 H, m, 4-H2), 2.38–2.65 (2 H, m, 5-H2), 4.59 (1 H, m,
3a-H), 4.88 (1 H, d, J3a,6a 9.7, 6a-H), 7.29–7.51 (3 H, m, ArH);
J. Chem. Soc., Perkin Trans. 1, 2000, 2649–2656
2655

View Article Online
12 B. B. Shankar, D. Y. Yang, S. Girton and A. K. Ganguly,
Crystal structure determination of compound 23a†
Tetrahedron Lett., 1998, 39, 2447.
Crystal data. C17H17Cl2NO5, M = 386.22, monoclinic,
a = 17.410(3), b = 8.739(2), c = 12.188(2) Å, β = 107.29(1)Њ, V =
1770.7(5) Å3, T = 295 K, space group P2(1)/c (no. 14), Z = 4,
13 G. Bianchi, C. De Micheli, R. Gandolfi, P. Grünanger, P. Vita-Finzi
and O. V. de Pava, J. Chem. Soc., Perkin Trans. 1, 1973, 1148.
14 P. Caramella and G. Cellerino, Tetrahedron Lett., 1974, 229.
15 P. Beltrame, P. L. Beltrame, P. Caramella, G. Cellerino and
R. Fantechi, Tetrahedron Lett., 1975, 3543.
µ(Mo-Kα) = 0.04 cmϪ1, 3126 independent reflections (Rint
=
0.024), 1974 observed reflections [I > 2σ(I)], R1 [I > 2σ(I)] =
0.049, wR2 [I > 2σ(I)] = 0.093.
16 P. Caramella, N. G. Rondan, M. N. Paddon-Row and K. N. Houk,
J. Am. Chem. Soc., 1981, 103, 2438.
17 A. P. Kozikowski and A. K. Ghosh, J. Am. Chem. Soc., 1982, 104,
5788.
Structure analysis and refinement. Direct methods imple-
mented in the SHELXS-97.41 Full-matrix anisotropic least-
squares on F2 for all reflections for all non-H-atoms. The
hydrogen atoms were located on Fourier difference maps and
were included in the structure-factor calculations as riding
atoms on the appropriate atoms. Minimized function wR2 =
18 V. Jäger, R. Shohe and E. F. Paulus, Tetrahedron Lett., 1983, 24,
5501.
19 K. N. Houk, S. R. Moses, Y.-D. Wu, G. N. Rondan, V. Jäger,
R. Shohe and F. R. Fronczek, J. Am. Chem. Soc., 1984, 106, 3880.
20 A. P. Kozikowski and A. K. Ghosh, J. Org. Chem., 1984, 49, 2762.
21 T. Shono, Y. Matsumura, H. Hamaguchi and K. Nakamura, Chem.
Lett., 1976, 1249.
22 D. H. Hua, S. Venkataraman, R. Chan-Yu-Kuig and J. V. Paukstelis,
J. Am. Chem. Soc., 1988, 110, 4741.
23 A. Scettri, G. Piancatelli, M. D’Auria and G. David, Tetrahedron,
1979, 35, 135.
24 G. Bianchi, R. Gandolfi and C. De Micheli, J. Chem. Res. (S),
1981, 6.
4
[Σw(Fo2 Ϫ Fc2)2/[Σw(Fo )]1/2 with weighting scheme w = 1/
[σ2(Fo)2 ϩ 0.0356P2 ϩ 0.5238P], where P = (Fo2 ϩ 2Fc2)/3. Min.
max. height in last ∆ρ map of Ϫ0.24 and 0.22 e ÅϪ3. Atomic
scattering factors were taken from ref. 42. Structure refine-
ment and molecular graphics were performed by using
SHELXL-97,43 and SHELXTL-Plus44 package. Bond angles
and bond distances have been deposited at the Cambridge
Crystallographic Data Centre (CCDC).
25 R. Huisgen and M. Christl, Chem. Ber., 1973, 106, 3275.
26 R. Huisgen and M. Christl, Chem. Ber., 1973, 106, 3345.
27 E. Keller, B. de Lange, M. T. Rispens and B. L. Feringa,
Tetrahedron, 1993, 49, 8899.
28 R. Alguacil, F. Farina and M. V. Martin, Tetrahedron, 1996, 52,
3457.
† CCDC reference number 207/450. See http://www.rsc.org/suppdata/
p1/b0/b003549l/ for crystallographic files in .cif format.
29 B. de Lange and B. L. Feringa, Tetrahedron Lett., 1988, 29, 5317.
30 T. T. Curran, D. A. Hay and C. P. Koegel, Tetrahedron, 1997, 53,
1983.
31 G. Kjeldsen, J. S. Knudsen, L. S. Ravn-Petersen and K. B. G.
Torssell, Tetrahedron, 1983, 39, 2237.
32 S. P. Khanapure, N. Najafi, S. Manna, J. J. Yang and J. Rokach,
J. Org. Chem., 1995, 60, 7548.
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2656
J. Chem. Soc., Perkin Trans. 1, 2000, 2649–2656