Synthesis of enantiopure bis-isoxazolines from (4R)-(+)-4-acetoxycyclopent-2-enone

Article abstract of DOI:10.1016/S0957-4166(01)00078-7

(4R)-(+)-4-Acetoxycyclopent-2-enone was used as a starting material in the stereoselective synthesis of enantiopure bis-isoxazolines.

Full text of DOI:10.1016/S0957-4166(01)00078-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 619–623
Synthesis of enantiopure bis-isoxazolines from
(4R)-(+)-4-acetoxycyclopent-2-enone
Giorgio Adembri,a M. Laura Paoli,a Patrizia Rossib and Alessandro Segaa,*
aDipartimento Farmaco Chimico Tecnologico, Via Aldo Moro, 53100 Siena, Italy
bDipartimento di Energetica, Via di Santa Marta 3, 50139 Florence, Italy
Received 9 January 2001; accepted 15 February 2001
Abstract—(4R)-(+)-4-Acetoxycyclopent-2-enone was used as a starting material in the stereoselective synthesis of enantiopure
bis-isoxazolines. © 2001 Published by Elsevier Science Ltd.
1. Introduction
2. Results and discussion
The introduction of defined stereogenic centres into
versatile molecules is of immense importance. As such,
the search for reaction pathways which stereoselectively
create multiple stereogenic centres in the minimum
number of steps is of great interest. Cycloaddition
reactions are known to be a means of introducing
stereogenic centres with defined relative stereochem-
istry. We have studied the reaction of nitrile oxides with
4-substituted cyclopent-2-enones to evaluate the influ-
ence of substituents on regio- and diastereoselectivities.1
The isoxazoline products of these reactions are impor-
tant since they can be transformed into g-amino alco-
hols or b-hydroxy ketones and, moreover, they can ex-
hibit useful pharmacological and biological activity.2–14
(4R)-(+)-4-Acetoxycyclopent-2-enone16 11 was easily
obtained from the corresponding (1R,3S)-(+)-4-
cyclopentene-1,3-diol 1-acetate 10 by a literature proce-
dure. The reaction of 11 with 2,6-dichlorobenzonitrile
oxide gave only one stereoisomer, 12, that by analogy
with racemic 9a was assigned (3aS,6R,6aR)-absolute
configuration (see Scheme 2).
Deacetylation of 12 to introduce a new a,b-unsaturated
ketone moiety for 1,3-dipolar cycloaddition with a sec-
ond molecule of nitrile oxide to form bis-isoxazolines
was then investigated. Deacetylation was easily accom-
plished by stirring the acetate in methanol at 40°C; the
enantiomerically pure (3aS,6aR)-13 was obtained in a
good 80% yield.
In the course of these studies we found that the reac-
tions of nitrile oxides with several 4-substituted-2-
cyclopentenones were completely regioselective.1
Additionally, the reaction of 2,6-dichlorobenzonitrile
oxide with 4-acetoxycyclopent-2-enone was found to be
not only completely regioselective but also completely
diastereoselective (see Scheme 1).1 Thus, the 2,6-
dichlorophenyl substituted cyclopentenone 9a was seen
as a promising molecule for the development of
homochiral functionalised structures.
The reaction of 13 with 2,6-benzonitrile oxide gave two
regioisomeric products, 14 and 15, in an 85:15 ratio (see
1
Scheme 3). While H and 13C NMR spectra and ele-
mental analysis established that compounds 14 and
15 were bis-isoxazolines, their absolute configura-
tion was determined by single-crystal X-ray diffraction.
The ORTEP plots of 14 and 15 are shown in Figs. 1
and 2.
Surprisingly, the addition of a second molecule of
nitrile oxide on 13 occurred with complete diastereo-
facial selectivity but was not completely regioselective.
The diastereofacial selectivity can be explained on the
basis of steric hindrance leading to anti-addition.
Although the major adduct 14 was that expected from
a consideration of simple molecular orbital theory, the
presence of both regioisomers is not easily explained.
It should be noted that just prior to the completion of
this study a recent paper on a closely related area was
published in the literature.15
* Corresponding author. E-mail: sega@unisi.it
0957-4166/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0957-4166(01)00078-7

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G. Adembri et al. / Tetrahedron: Asymmetry 12 (2001) 619–623
Scheme 1.
+
−
,
Scheme 2. i: C5H5NH CrO3Cl , NaOAc, 4 A sieves, CH2Cl2.

G. Adembri et al. / Tetrahedron: Asymmetry 12 (2001) 619–623
621
Scheme 3.
In conclusion, the stereogenic centre in 11 directly and
indirectly controls the configuration of all other stereo-
centres introduced in each reaction step. The com-
pounds obtained, 12, 13, 14 and 15, lend themselves to
further synthetic manipulation. To our knowledge, 14 is
the first reported homochiral C2 symmetric bis-isoxazo-
line with a ketone functionality. Such uncommon
molecules have important applications.17–19
3. Experimental
Figure 1. ORTEP drawing of the absolute configuration of
compound 14.
3.1. General procedure
Melting points were measured on a Kofler apparatus
and are uncorrected. Elemental analyses were per-
formed on a Perkin–Elmer 240C elemental analyser.
NMR spectra were recorded for CDCl3 solutions on a
Bruker AC 200 spectrometer (200 MHz). Chemical
shifts (l) are measured in ppm, relative to TMS as
internal standard, and coupling constants (J) are in
hertz. Optical rotations were determined with an optical
activity instrument. Crystallographic data were col-
lected on a Siemens P4 automatic diffractometer.
Silica gel plates (Merck F254) and silica gel 60 (Merck
70–230 mesh) were used for analytical TLC and column
chromatography, respectively. Extracts were dried over
anhydrous Na2SO4. Concentrations were performed on
a rotary evaporator. Petroleum spirit refers to the frac-
tion of distillation range 30–50°C.
(1R,3S)-(+)-4-Cyclopentene-1,3-diol 1-acetate, 99+%,
was purchased from Aldrich. 2,6-Dichlorobenzonitrile
oxide was prepared by dehydrohalogenation of the
corresponding hydroxamoyl chloride by treatment with
sodium hypochlorite.20–22 In order to minimise its
dimerisation
[formation
of
furazan
N-oxide
(furoxan)],23,24 the nitrile oxide was prepared directly
before use and used as a solution which was added
dropwise over a few minutes to the solution of the
Figure 2. ORTEP drawing of the absolute configuration of
compound 15.

622
G. Adembri et al. / Tetrahedron: Asymmetry 12 (2001) 619–623
appropriate reagent. The furoxan was easily separated
by column chromatography.
by flash chromatography (diethyl ether–petroleum spirit,
1:1) to give the cycloadducts 14 and 15 (0.76 g, 85%).
Compound 14. White solid (0.65 g, 85%). Mp 192–193°C
3.2. Synthesis of (4R)-(+)-4-acetoxy-cyclopent-2-enone
1
(methanol). [h]2D0=+362.3 (c=0.6, CHCl3). H NMR:
11
4.62 (2H, d, J3a,7b=J4a,7a=9.3, H3a, H4a); 5.75 (2H, d,
J
3a,7b=J4a,7a=9.3, H7a, H7b); 7.30–7.38 (6H, m, Ar). 13
C
Compound 11 was prepared from (1R,3S)-(+)-4-
cyclopentene-1,3-diol 1-acetate, 10, according to a liter-
ature procedure.16
NMR: 62.8 (C3a, C4a); 90.1 (C7a, C7b); 125.4 (2C1%);
128.2 (4C3%); 131.9 (2C4%); 135.3 (4C2%); 148.9 (C3, C5);
201.0 (C4). Anal. calcd for C19H10Cl4N2O3: C, 50.00; H,
2.19; N, 6.14. Found: C, 50.08; H, 2.24; N, 6.20%.
3.3. Synthesis of (3aS,6R,6aR)-(+)-3-(2,6-dichloro-
phenyl)-4-oxo-4,5,6,6a-tetrahydro-3aH-cyclopent[d]-
isoxazol-6-yl acetate 12
Compound 15. White solid (0.11 g, 15%). Mp 239°C,
with decomposition (CHCl3). [h]2D0=+428.6 (c=0.04,
1
CHCl3). H NMR: 4.45 (1H, d, J3a,7b=9.6, H3a); 4.86
A solution of 2,6-dichlorobenzonitrile oxide (1.68 g, 9.1
mmol) in CH2Cl2 (15 mL) was added dropwise to a
stirred solution of 11 (0.84 g, 6 mmol) in CH2Cl2 (10 mL)
at room temperature. The solution was stirred for 8 hours
at room temperature and then concentrated. The residue
was purified by flash chromatography (diethyl ether–
petroleum spirit, 1:1) to give the cycloadduct 12 as a
white solid (1.45 g, 74%). Mp 149.5–150.5°C (methanol).
(1H, d, J4a,7a=10.2, H7a); 5.42 (1H, d, J4a,7a=10.2, H4a);
5.57 (1H, d, J3a,7b=9.6, H7b); 7.35–7.49 (6H, m, Ar). 13
C
NMR: 59.8 (C7a); 62.1 (C3a); 82.7 (C4a); 83.9 (C7b);
125.5 (C1%); 126.1 (C1%); 128.5 (2C3%); 128.7 (2C3%); 132.1
(C4%); 132.2 (C4%); 135.4 (2C2%); 135.5 (2C2%); 148.7 (C3);
152.5 (C7); 205.1 (C4). Anal. calcd for C19H10Cl4N2O3:
C, 50.00; H, 2.19; N, 6.14. Found: C, 50.11; H, 2.25; N,
6.23%.
1
[h]2D0=+319.5 (c=0.3, CHCl3). H NMR: 2.02 (3H, s,
CH3); 2.44 (1H, dd, J5,5%=18.5, J5%,6=1.4, H5%); 2.93 (1H,
dd, J5,5%=18.5, J5,6=6.1, H5); 4.31 (1H, d, J3a,6a=9.4,
3.6. X-Ray structural analysis of compounds 14 and 15
H3a); 5.43 (2H, m, H-6, H6a); 7.31–7.40 (3H, m, Ar). 13
C
NMR: 20.8 (CH3); 42.1 (C5); 62.3 (C3a); 73.9 (C6a); 88.2
(C6); 126.1 (C1%); 128.3 (C3%, C5%); 131.7 (C4%); 135.3 (C2%,
C6%); 150.0 (C3); 169.7 (OCO); 205.5 (C4). Anal. calcd
for C14H11Cl2NO4: C, 51.22; H, 3.35; N, 4.27. Found: C,
51.29; H 3.40; N, 4.31%.
Compound 14: C19H10Cl4N2O3, M=456.09. Trigonal,
space group P32; a=19.580(1), b=19.580(1), c=
3
,
,
13.362(1) A; V=4436.4(5) A , Z=9, F(000)=2070,
v=5.667 mm−1,
D
calcd=1.536
g
cm−3, graphite
,
monochromated (Cu-Ka) radiation (u=1.5418 A).
Compound 15: C19H10Cl4N2O3, M=456.09. Monoclinic,
3.4. Synthesis of (3aS,6aR)-(+)-(2,6-dichlorophenyl)-
3a,6a-dihydro-4H-cyclopent[d]isoxazol-4-one 13
space group P21; a=9.364(2), b=7.978(2), c=12.649(1)
3
,
,
A, i=102.43(1)°; V=922.8(3) A , Z=2, F(000)=460,
v=6.054 mm−1,
D
calcd=1.641
g
cm−3, graphite
A solution of 12 (0.66 g, 2 mmol) in methanol (15 mL)
was stirred for 1 h at 40°C and then concentrated. The
residue was treated with warm petroleum spirit and the
solution was filtered. Compound 13 precipitated from the
solution as a white solid (0.43 g, 80%). Mp 98–99°C
,
monochromated (Cu-Ka) radiation (u=1.5418 A).
Data sets were collected consisting of 4369 and 1788
reflections (2qmax=120 and 128°) for 14 and 15, respec-
tively. Data were corrected for Lorentz and polarisation
effects and for absorption using the Walker and Stuart
method.25 The structures were solved by direct methods
of SIR-97,26 and refined using the full-matrix least-
squares on F2 provided by SHELXL-93.27 The final R
indexes were 0.0774 and 0.0746 for 14 and 15, respec-
tively, for 759 and 255 refined parameters using the 4354
and 1599 reflections having I>2|(I). Anisotropic thermal
parameters were used for all the non-hydrogen atoms.
The hydrogen atoms were introduced into calculated
positions and refined with an overall isotropic tempera-
ture parameter. The absolute configuration was deter-
mined for both structures, the Flack parameter28 for the
correct enantiomer being equal to 0.01(2) and 0.01(4) for
14 and 15, respectively.
1
(methanol). [h]2D0=+347.6 (c=0.3, CHCl3). H NMR:
4.29 (1H, d, J3a,6a=7.4, H3a); 5.91 (1H, dd, J3a,6a=7.4,
J
6,6a=2.0, H6a); 6.34 (1H, d, J5,6=5.7, H5); 7.30–7.38
(3H, m, Ar); 7.65 (1H, dd, J5,6=5.7, J6,6a=2.0, H6). 13
C
NMR: 59.6 (C3a); 83.9 (C6a); 126.6 (C1%); 128.1 (C3%,
C5%); 131.5 (C4%); 134.5 (C5); 135.1 (C2%, C6%); 150.3 (C3);
158.3 (C6); 199.9 (C4). Anal. calcd for C12H7Cl2NO2: C,
53.73; H, 2.61; N, 5.22. Found: C, 53.79; H, 2.66; N,
5.28%.
3.5. Synthesis of (3aS,4aS,7aR,7bR)-(+)-3,5-di(2,6-
dichlorophenyl)-4H-[1,2]oxazolo[5%,4%:3,4]cyclopenta[d]-
[1,2]oxazol-4-one 14 and (3aS,3bS,6aS,7aS)-(+)-3,6-
di(2,6-dichlorophenyl)-7H-[1,2]oxazolo[4%,5%:3,4]cyclo-
penta[d][1,2]oxazol-7-one 15
A solution of 2,6-dichlorobenzonitrile oxide (0.50 g, 2.7
mmol) in CH2Cl2 (5 mL) was added dropwise to a stirred
solution of 13 (0.54 g, 2 mmol) in CH2Cl2 (5 mL) at room
temperature. The solution was stirred for 8 h at room
temperature and concentrated. The residue was purified
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