Diastereoselective synthesis of cyclopentanoids with hydantoin and isoxazoline substituents

Article abstract of DOI:10.1021/jo9714831

Exploiting 1,3-dipolar cycloaddition and urea → hydantoin cyclization transformations, novel spiro-[cyclopenta[d]isoxazole-4'5-imidazolindine' heterocycles of generalized structure I have been prepared. The 1-amino-3- cyclopentenecarboxylate precursor II was prepared from a suitably activated/protected derivative of glycine and the bis-alkylating agent cis- 1,4-dichloro-2-butene.

Full text of DOI:10.1021/jo9714831

J . Org. Chem. 1998, 63, 113-117
113
Dia ster eoselective Syn th esis of Cyclop en ta n oid s w ith Hyd a n toin
a n d Isoxa zolin e Su bstitu en ts
Kyung-Ho Park, Marilyn M. Olmstead, and Mark J . Kurth*
Department of Chemistry, University of California, Davis, California 95616
Received August 8, 1997X
Exploiting 1,3-dipolar cycloaddition and urea f hydantoin cyclization transformations, novel spiro-
[cyclopenta[d]isoxazole-4′,5-imidazolindine] heterocycles of generalized structure I have been
prepared. The 1-amino-3-cyclopentenecarboxylate precursor II was prepared from a suitably
activated/protected derivative of glycine and the bis-alkylating agent cis-1,4-dichloro-2-butene.
The hydantoin nucleus is an important structural
element with medicinal (cf., anticonvulsant1) as well as
agrochemical (cf., fungicidal2 and herbicidal3) activities.
Indeed a large number of hydantions adorned with
diverse substituents have been synthesized for a wide
variety of biological applications.4 These activities, coupled
with our observation that the isoxazoline heterocycle has
been used extensively to modulate various other biologi-
cally active motifs,5 led us to explore synthetic strategies
for constructing hydantoin-isoxazoline heterocycles about
a central carbocyclic core.
F igu r e 1.
of the novel spiro(cyclopenta[d]isoxazole-4′,5-imidazolin-
dine) heterocycle of generalized structure I. We envi-
sioned the 1-amino-3-cyclopentenecarboxylate precursor
(II) as deriving from a suitably activated/protected
derivative of glycine and a bis-alkylating agent such as
cis-1,4-dichloro-2-butene (Figure 1).
Drawing on the extensive glycine alkylation studies for
the synthesis of R-amino acid derivatives,10 we began our
studies with the condensation of 4-bromobenzaldehyde
with ethyl glycine hydrochloride to give Schiff base 1
(Scheme 1). Subsequent bis-alkylation of this active
methylene compound by treating a THF suspension of
sodium hydride with 1 followed by dropwise addition of
cis-1,4-dichloro-2-butene delivered cyclopentenecarboxy-
late 2 with no trace (as judged by 1H NMR) of the
potential cyclopropanecarboxylate side product. The
Schiff base moiety in 2 proved rather labile to silica gel
chromatography and therefore was most effectively used
without purification in the subsequent phenyl isocyanate-
mediated 1,3-dipolar cycloaddition reaction.
Thus, treating crude 2 with 1-nitrobutane, phenyl
isocyanate, and triethylamine (Mukaiyama method) in
dimethoxyethane (DME) at room temperature for 10 h
followed by reflux for 30 h delivered a nearly 1:1 mixture
of diastereomeric cycloaddition products (3) in 60% crude
yield. Again, the Schiff base moiety of 3 proved labile
during attempted silica gel purification so the crude
product was taken up in THF and treated with aqueous
hydrochloric acid to effect imine to amine conversion. The
resulting ammonium salts were neutralized with aqueous
sodium hydroxide and, following workup and solvent
exchange (EtOAc f CH2Cl2), the resulting primary
Isoxazoline heterocycles can be synthesized from the
1,3-dipolar cycloaddition reaction of a nitrile oxide to an
alkene using reaction protocols which perform nicely with
a variety of reaction partners.6 The requisite nitrile
oxides can be generated in situ by either (i) base-induced
dehydrohalogenation of hydroximoyl chlorides (Huisgen
methodology,7 originally reported for aromatic nitrile
oxides) or (ii) dehydration of primary nitroalkane deriva-
tives (Mukaiyama methodology, originally reported for
aliphatic nitrile oxides).8 Hydantoin heterocycles are
generally prepared by cyclization of 2-[5-aryl (or alkyl)-
ureido] acetate derivatives or carbamate derivatives in
the presence of acid or base.9
Exploiting these transformations for heterocycle con-
struction, we set out to develop a protocol for elaboration
X Abstract published in Advance ACS Abstracts, December 15, 1997.
(1) (a) Ware, E. Chem. Rev. (Washington, D.C.) 1950, 46, 403. (b)
Spinks, A.; Waring, W. S. Prog. Med. Chem. 1963, 3, 313. (c)
Karolakwojciechowska, J .; Kwiatkowski, W.; Kieckonono, K. Pharmazie
1995, 50, 114. (d) Brouillette, W. J .; J estkov, V. P.; Brown, M. L.;
Akhtar, M. S. J . Med. Chem. 1994, 37, 3289. (e) Brouillette, W. J .;
Brown, G. B.; Deloreg, T. M.; Liang, G. J . Pharm. Sci. 1990, 79, 871.
(2) Mappes, C. J .; Pommer, E. H.; Rentzea, C.; Zeeh, B. U.S. Patent.
4,198,423, 1980.
(3) Ohta, H.; J ikihara, T.; Wakabayashi, Ko.; Fujita, T. Pestic.
Biochem. Physiol. 1980, 14, 153.
(4) Avendano Lopez, C.; Gonzalez Trigo, G. Adv. Heterocycl. Chem.
1985, 38, 177.
(5) (a) Khalil, M. A.; Maponya, M. F.; Ko, D.-H.; You, Z.; Oriaku, E.
T.; Lee, H. J . Med. Chem. Res. 1996, 6, 52. (b) Groutas, W. C.;
Venkataraman, R.; Chong, L. S.; Yooder, J . E.; Epp, J . B.; Stanga, M.
A.; Kim, E.-H. Bioorg. Med. Chem. 1995, 3, 125. (c) Levin, J . I.; Chan,
P. S.; Coupet, J .; Bailey, T. K.; Vice, G.; Thibault, L.; Lai, F.;
Venkatesan, A. M.; Cobuzzi, A. Bioorg. Med. Chem. Lett. 1994, 4, 1703.
(d) Simoni, D.; Manfredini, S.; Tabrizi, M. A.; Bazzanini, R.; Guarneri,
M.; Ferroni, R.; Tranielo, F.; Nastruzzi, C.; Feriotto, G.; Gambari, R.
Top. Mol. Organ. Eng. 1991, 8 (Chem. Prop. Biomol. Syst.), 119.
(6) For reviews of nitrile oxide-isoxazoline methodology, see (a)
Curran, D. P. Adv. Cycloaddit. 1988, 1, 129. (b) Torssell, K. B. G. Nitrile
Oxides, Nitrones and Nitronates in Organic Synthesis; VCH Publishers:
Weinheim, 1988.
(9) (a) DeWitt, S. H.; Kiely, J . S.; Stankovic, C. J .; Schroeder, M.
C.; Reynolds Cody, D. M.; Pavia, M. R. Proc. Natl. Acad. Sci. U.S.A.
1993, 90, 6909. (b) Dressman, B. A.; Spangle, L. A.; Kaldor, S. W.
Tetrahedron Lett. 1996, 37, 937.
(7) Christl, M.; Huisgen, R. Chem. Ber. 1973, 106, 3345.
(8) Mukaiyama, T.; Hoshino, T. J . Am. Chem. Soc. 1960, 62, 5339.
(10) (a) Bey, P.; Vevert, J . P. Tetrahedron Lett. 1977, 17, 1455. (b)
O’Donnel M. J .; Wu S.; Huffman J . C. Tetrahedron Lett. 1994, 50, 4507.
S0022-3263(97)01483-7 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/09/1998

114 J . Org. Chem., Vol. 63, No. 1, 1998
Park et al.
Sch em e 1.
Sch em e 2.
Ta ble 1. Dia ster eoselective F or m a tion of
Cyclop en ta [d ]isoxa zoles (III)
% yield % yield
compound
R′
R′′
(III)
(IV)
5 (III), 6 (IV)
13 (III)
14 (III)
15 (III), 16 (IV) CH2CH2CH3 p-ClC6H4
17 (III) CH2CH2CH3 p-FC6H4
CH2CH2CH3 C6H5
54
58
60
55
56
3
CH3
C6H5
C6H5
C6H5
amines (4) were intercepted with phenyl isocyanate to
deliver ureas 5 (16% overall yield from 1) and 6 (14%
overall yield from 1) which proved easily separable by
silica gel chromatography. Alternatively, this mixture
of ureas could be cyclized to hydantoins 7 and 8 by base
treatment; specifically, triethylamine in DME at reflux
caused 5/6 f 7/8.
5
6
Ta ble 2. Dia ster eoselective F or m a tion of
Sp ir ocyclop en ta [d ]isoxa zole-4′,5-im id a zolid in es (I)
compound
R′
R′′
C6H5
% yield (I)
7 (I)
CH2CH2CH3
CH3
82
73
60
78
80
We were unable to make unambiguous stereochemical
18 (I)
19 (I)
20 (I)
21 (I)
C6H5
1
assignments at 5/6 using H NMR experiments. Fortu-
C6H5
C6H5
nately, 5 is crystalline and single-crystal X-ray analysis
(Figure 2) established the relative stereochemistry of
urea 5 (and hence 6) and, by relating 5 f 7 and 6 f 8,
the relative stereochemistry of hydantoins 7 and 8.
Before proceeding with the preparation of R′ and R′′
analogues of I, we felt it would be advantageous to
address the Schiff base lability issue and, reflecting on
the transformations employed in Scheme 1, an attractive
alternative appeared to be imine f urea conversion
earlier in the sequence. Specifically, our idea was to react
aminocyclopentenecarboxylate II with an isocyanate to
replace the sensitive imine with a stable urea. This
change in sequence, however, introduces the question of
how the urea moiety would behave in the nitrile oxide
cycloaddition step. Intrigued by the potential, we set out
to prepare urea 10 (Scheme 2).
Treatment of cyclopentenecarboxylate 2 with aqueous
hydrochloric acid in THF followed by aqueous sodium
hydroxide delivered amino ester 9. Urea formation
followed in straightforward fashion by treatment with
phenyl isocyanate yielded 10 which, unlike imine ana-
logue 2, was easily purified by silica gel chromatography
(60% overall yield from imino ester 1). In the key step,
the urea moiety of 10 proved to be additionally advanta-
geous in that it provides facial direction in the reaction
of the in situ generated nitrile oxide with the cyclopen-
tenoid moiety. Thus, we were pleased to find that 10
gave one major cycloaddition product which, by compari-
son with the results of Scheme 1, proved to be isoxazoline
CH2CH2CH3
CH2CH2CH3
p-ClC6H4
p-FC6H4
5. One final advantage of the imine/urea switch also
surfaced in this cycloaddition step. Namely, urea 5 can
be caused to undergo cyclization to hydantoin 7 without
intermediate isolation. By treating cyclopentenecarboxy-
late 10 with the nitroalkane, isocyanate, and triethyl-
amine first at room temperature followed by warming
the reaction mixture (12 h delivers 5) to reflux without
isolation results in conversion of 5 to 7.
Thus, as a result of our “early” imine to urea switch,
imino ester 2 can be converted with diastereoselectivity
to heterocycle I by an efficient three-pot sequence which
has the potential of introducing variable R′ substituents
in the selection of the nitroalkane (10 f 7) and variable
R′′ substituents in the selection of the isocyanate (9 f
10). We have established the validity of this synthetic
potential by preparing the heterocycles listed in Tables
1 and 2. Moreover, 2 f 7 can be effected as a two-pot
sequence by hydrolysis of 2 to 9 followed by a one-pot
conversion of 9 to 7; treatment of 9 with PhNdCdO (3
equiv) in DME at room temperature (0.5 h), addition of
1-nitrobutane and triethylamine at room temperature (10
h), and finally warming to reflux (3 d) delivered 7 in 30%
yield from 2.
Highly diastereoselective cycloaddition reactions of
nitrile oxides to alkenes are rare.11 We believe the facial
diastereoselectivity observed in the reaction of cyclopen-

Diastereoselective Synthesis of Cyclopentanoids
J . Org. Chem., Vol. 63, No. 1, 1998 115
3.18 (d, J ) 15.5 Hz, 2H), 2.69 (d, J ) 15.5 Hz, 2H), 1.27 (t, J
) 7.1 Hz, 3H). 13C NMR (300 MHz, CDCl3) δ 173.9, 157.6,
135.2, 131.7, 129.7, 127.9, 125.2, 74.9, 61.2, 43.9, 14.1.
E t h yl (3a R*,5S*,6a S*)-5-(3-P h en ylu r eid o)-3-p r op yl-
3a ,5,6,6a -t et r a h yd r o-4H -cyclop en t a [d ]isoxa zole-5-ca r -
boxyla te (5) a n d Eth yl (3a R*,5R*,6a S*)-5-(3-P h en ylu r e-
i d o )-3-p r o p y l-3a ,5,6,6a -t e t r a h y d r o -4H -c y c lo p e n t a -
[d ]isoxa zole-5-ca r boxyla te (6) fr om 2. A DME (30 mL)
solution of imine 2 (1.4 g, 4.3 mmol) was added to phenyl
isocyanate (1.0 g, 8.7 mmol) and 1-nitrobutane (0.45 g, 4.3
mmol) followed by triethylamine (0.043 g, 0.43 mmol) under
nitrogen. The reaction mixture was stirred for 10 h at room
temperature and then refluxed for 30 h. DME was removed
by rotary evaporation to give crude 3 which was dissolved in
THF (20 mL) and treated with aqueous HCl (1N, 5 mL). After
stirring 20 min at room temperature, the reaction mixture was
transferred to a separatory funnel, and water (30 mL) and
ethyl acetate (50 mL) were added. The water layer was
removed by separation, and aqueous NaOH (1N) was added
to adjust the pH to 9. The resulting water layer was extracted
with ethyl acetate (2 × 30 mL), and the combined organic layer
was dried (MgSO4) and filtered.
F igu r e 2. Single-Crystal X-ray Diffraction of Urea 5.
Ethyl acetate was removed (rotary evaporation), and meth-
ylene chloride (20 mL) was added to the residue followed by
phenyl isocyanate (0.52 g, 4.35 mmol). The solution was
stirred for 30 min at room temperature, the solvent removed
(rotary evaporation), and the residue purified by column
chromatography (silica gel, EtOAc:hexanes ) 1:3) to give 5
(0.28 g, 0.79 mmol, 16%) and 6 (0.25 g, 0.69 mmol, 14%) as a
white solid. 5: mp 122 °C; IR (KBr) 3379, 2961, 1733, 1676,
F igu r e 3. H-Bonding Contolled Cycloaddition.
1616, 1549 cm-1 1H NMR (300 MHz, CDCl3) δ 7.59 (bs, 1H),
.
tenyl ureas such as 10 with nitrile oxides can be
understood based on H-bonded direction of the cycload-
dition step as depicted in V (Figure 3).
7.31 (d, J ) 7.3 Hz, 2H), 7.23 (dd, J ) 7.1, 7.3 Hz, 2H), 6.98 (t,
J ) 7.1 Hz, 1H), 5.92 (bs, 1H), 5.20 (dd, J ) 9.2, 5.4 Hz, 1H),
4.27-4.15 (m, 2H), 3.80 (dd, J ) 9.2, 9.0 Hz, 1H), 2.92 (d, J )
14.4 Hz, 1H), 2.69 (dd, J ) 14.4, 9.2 Hz, 1H), 2.42-2.21 (m,
2H), 2.28 (t, J ) 7.8 Hz, 2H), 1.66-1.55 (m, 2H), 1.24 (t, J )
7.1 Hz, 3H), 0.91 (t, J ) 7.3 Hz, 3H). 13C NMR (300 MHz,
CDCl3) δ 172.9, 162.5, 154.7, 139.0, 128.4, 122.7, 119.4, 84.1,
65.3, 61.6, 54.5, 46.1, 36.9, 28.2, 19.5, 14.1, 13.8. Anal. Calcd
for C19H25N3O4: C, 63.49; H, 7.01; N, 11.69. Found: C, 63.43;
H, 6.93; N, 11.64. 6: mp 155 °C; IR (KBr) 3354, 2961, 1742,
Exp er im en ta l Section
Eth yl 2-[[(E)-1-(4-Br om op h en yl)m eth ylid en e]a m in o]-
a ceta te (1). Anhydrous magnesium sulfate (5 g) and triethyl-
amine (7.2 g, 71.6 mmol) were added to a solution of p-bro-
mobenzaldehyde (6.63 g, 35.8 mmol) and ethyl glycine
hydrochloride (5 g, 35.8 mmol) in methylene chloride (100 mL).
The reaction mixture was stirred for 10 h at room temperature
at which time the magnesium sulfate was removed by filtra-
tion. The solvent was removed by rotary evaporation, ether
(100 mL) and brine (50 mL) were added, the ether layer was
separated, and the organic layer was dried (MgSO4). Filtration
and removal of the solvent (rotary evaporation) yielded Schiff
base 1 (9 g, 33.3 mmol, 93%) as a white liquid. 1: IR (neat)
1638, 1554 cm-1 1H NMR (300 MHz, CDCl3) δ 7.40-6.91 (m,
.
6H), 5.78 (bs, 1H), 5.12-5.05 (m, 1H), 4.14-4.07 (m, 2H), 3.63
(m, 1H), 2.54 (d, J ) 9.2 Hz, 1H), 2.50-2.15 (m, 3H), 1.59-
1.46(m, 2H), 1.16 (t, J ) 7.2 Hz, 3H), 0.89 (t, J ) 7.3 Hz, 3H).
13C NMR (300 MHz, CDCl3) δ 173.0, 161.7, 155.5, 138.5, 129.0,
123.2, 119.6, 84.5, 66.1, 61.9, 53.9, 45.1, 39.0, 28.3, 19.4, 13.9,
13.8. Anal. Calcd for C19H25N3O4: C, 63.49; H, 7.01; N, 11.69.
Found: C, 63.31; H, 7.04; N, 11.53.
2981, 1742, 1648, 1590 cm-1
.
1H NMR (300 MHz, CDCl3) δ
E t h yl (3a R*,5S*,6a S*)5-(3-P h en ylu r eid o)-3-p r op yl-
3a ,5,6,6a -t et r a h yd r o-4H -cyclop en t a [d ]isoxa zole-5-ca r -
boxyla te (5) fr om 10. To a solution of urea 10 (0.5 g, 1.8
mmol) in DME (30 mL) were added phenyl isocyanate (0.43 g,
3.6 mmol) and 1-nitrobutane (0.19 g, 1.8 mmol) followed by
the addition of triethylamine (18 mg, 0.18 mmol) under
nitrogen. The reaction mixture was stirred for 10 h at room
temperature and then refluxed for 30 h. DME was removed
(rotary evaporation) and the residue purified by column
chromatography (silica gel, EtOAc:hexanes ) 1:3) to give 5
(0.33 g, 0.93 mmol, 51%) as a white solid. 5: mp 122 °C; IR
8.23 (s, 1H), 7.64 (d, J ) 8.3 Hz, 2H), 7.55 (d, J ) 8.2 Hz, 2H),
4.38 (s, 2H), 4.23 (q, J ) 7.1 Hz, 2H), 1.29 (t, J ) 7.1 Hz, 3H).
13C NMR (300 MHz, CDCl3) δ 169.8, 164.0, 134.4, 131.7, 129.7,
125.6, 61.8, 61.0, 14.1.
Eth yl 1-[[(E)-1-(4-Br om op h en yl)m eth ylid en e]a m in o]-
cyclop en t-3-en e-1-ca r boxyla te (2). Schiff base 1 (1 g, 3.7
mmol) in THF (5 mL) was added to a reaction flask containing
sodium hydride (0.19 g, 8.1 mmol) in THF (30 mL) under
nitrogen. After 5 min, cis-1,4-dichloro-2-butene (0.46 g, 3.7
mmol) was added dropwise, and the reaction mixture was
stirred at room temperature for 2 h and refluxed for 1 h. After
cooling and solvent removal (rotary evaporation), ether (80
mL), ice (20 g), and cold water (20 mL) were added to the
reaction mixture. The layers were separated, and the organic
layer was dried (MgSO4). Filtration, removal of the solvent
(rotary evaporation), and column chromatography (silica gel,
5% triethylamine in hexane) of the residue gave cyclopentene-
carboxylate 2 (0.96 g, 2.98 mmol, 80%) as a yellow liquid. 2:
(KBr) 3379, 2961, 1733, 1676, 1616, 1549 cm-1
.
1H NMR (300
MHz, CDCl3) δ 7.59 (bs, 1H), 7.31 (d, J ) 7.3 Hz, 2H), 7.23
(dd, J ) 7.1, 7.3 Hz, 2H), 6.98 (t, J ) 7.1 Hz, 1H), 5.92 (bs,
1H), 5.20 (dd, J ) 9.2, 5.4 Hz, 1H), 4.27-4.15 (m, 2H), 3.80
(dd, J ) 9.2, 9.0 Hz, 1H), 2.92 (d, J ) 14.4 Hz, 1H), 2.69 (dd,
J ) 14.4, 9.2 Hz, 1H), 2.42-2.21 (m, 2H), 2.28 (t, J ) 7.8 Hz,
2H), 1.66-1.55 (m, 2H), 1.24 (t, J ) 7.1 Hz, 3H), 0.91 (t, J )
7.3 Hz, 3H). 13C NMR (300 MHz, CDCl3) δ 172.9, 162.5, 154.7,
139.0, 128.4, 122.7, 119.4, 84.1, 65.3, 61.6, 54.5, 46.1, 36.9, 28.2,
19.5, 14.1, 13.8. Anal. Calcd for C19H25N3O4: C, 63.49; H,
7.01; N, 11.69. Found: C, 63.43; H, 6.93; N, 11.64.
IR (neat) 3059, 2979, 2935, 1728, 1640, 1589 cm-1 1H NMR
.
(300 MHz, CDCl3) δ 8.16 (s, 1H), 7.62 (d, J ) 8.4 Hz, 2H),
7.53 (d, J ) 8.4 Hz, 2H), 5.71 (s, 2H), 4.23 (q, J ) 7.1 Hz, 2H),
(3a R*,5S*,6a S*)-Sp ir o[3-p r op yl-1-p h en yl-4,5,6,6a -t et -
r a h yd r o-3a H-cyclop en ta [d ]isoxa zole-4′,5-im id a zolid in e-
2′,5′-d ion e] (7) fr om 5. Triethylamine (0.11 mL, 0.83 mmol)
was added to a DME (20 mL) solution of 5 (0.15 g, 0.41 mmol),
(11) (a) Kozikowski, A. P.; Ghosh, A. K. J . Am. Chem. Soc. 1982,
104, 5788. (b) De Amici, M.; De Micheli, C.; Ortisi, A.; Gatti, G.;
Gandolfi, R.; Toma, L. J . Org. Chem. 1989, 54, 793. (c) Curran, D. P.;
Choi, S.-M.; Gothe, S. A.; Lin, F. J . Org. Chem. 1990, 55, 3710.

116 J . Org. Chem., Vol. 63, No. 1, 1998
Park et al.
and the reaction mixture was refluxed for 2 d. DME was
removed (rotary evaporation), and the residue was recrystal-
lized (EtOAc:hexanes ) 1:3) to give 7 (0.106 g, 0.34 mmol, 82%)
as a white solid. 7: mp 188 °C; IR (KBr) 3223, 2957, 1778,
E t h yl (3a R*,5S*,6a S*)-5-(3-P h en ylu r eid o)-3-m et h yl-
3a ,5,6,6a -t et r a h yd r o-4H -cyclop en t a [d ]isoxa zole-5-ca r -
boxyla te (13) fr om 10. As with 5 f 10, nitroethane gave
13 (0.35 g, 1.05 mmol, 58%) as a white solid. 13: mp 145 °C.
1712, 1497, 1409 cm-1 1H NMR (300 MHz, CDCl3) δ 7.49-
.
IR (KBr) 3359, 2981, 1731, 1696, 1670 cm-1
.
1H NMR (300
7.26 (m, 5H), 6.11 (bs, 1H), 5.23 (dd, J ) 8.3, 4.5 Hz, 1H), 3.77
(dd, J ) 9.0, 9.3 Hz, 1H), 2.61-2.13 (m, 6H), 1.75-1.60 (m,
2H), 1.01 (t, J ) 7.3 Hz, 3H). 13C NMR (300 MHz, acetone-d6)
δ 173.9, 161.9, 154.6, 131.4, 129.0, 128.2, 125.9, 85.8, 67.7, 53.7,
44.8, 41.2, 28.6, 19.5, 13.8. Anal. Calcd for C17H19N3O3: C,
65.16; H, 6.11; N, 13.4. Found: C, 64.89; H, 5.99; N, 13.24.
MHz, CDCl3) δ 7.94 (bs, 1H), 7.32 (d, J ) 8.2 Hz, 2H), 7.19
(dd, J ) 8.0, 7.6 Hz, 2H), 6.94 (dd, J ) 7.4, 7.3 Hz, 1H), 6.09
(bs, 1H), 5.20 (dd, J ) 8.5, 6.0 Hz, 1H), 4.27-4.13 (m, 2H),
3.77 (dd, J ) 9.2, 8.8 Hz, 1H), 2.92 (d, J ) 14.2 Hz, 1H), 2.69
(dd, J ) 14.2, 9.2 Hz, 1H), 2.35-2.22 (m, 2H), 1.98 (s, 3H),
1.23 (t, J ) 7.0 Hz, 3H). 13C NMR (300 MHz, CDCl3) δ 173.0,
159.0, 154.7, 139.1, 128.6, 122.2, 118.8, 84.1, 65.0, 61.4, 55.7,
45.9, 36.7, 13.9, 11.4. Anal. Calcd for C17H21N3O4: C, 61.61;
H, 6.38; N, 12.68. Found: C, 61.82; H, 6.36; N, 12.62.
(3a R*,5R*,6a S*)-Sp ir o[3-p r op yl-1-p h en yl-4,5,6,6a -t et -
r a h yd r o-3a H-cyclop en ta [d ]isoxa zole-4′,5-im id a zolid in e-
2′,5′-d ion e] (8) fr om 6. As with 5 f 7, 8 (0.18 g, 0.6 mmol,
83%) was obtained as a white solid. 8: mp 166 °C; IR (KBr)
E t h yl (3a R*,5S*,6a S*)-5-(3-P h en ylu r eid o)-3-p h en yl-
3a ,5,6,6a -t et r a h yd r o-4H -cyclop en t a [d ]isoxa zole-5-ca r -
boxyla te (14) fr om 10. As with 5 f 10, phenylnitromethane
gave 14 (0.43 g, 1.09 mmol, 60%) as a white solid. 14: mp
191 °C. IR (KBr) 3396, 3367, 1731, 1699, 1674, 1596, 1536
3283, 2962, 1780, 1719, 1501, 1409 cm-1 1H NMR (300 MHz,
.
CDCl3) δ 7.82 (s, 1H), 7.48-7.34 (m, 5H), 5.10 (m, 1H), 3.60
(m, 1H), 2.42-2.13 (m, 6H), 1.87-1.52 (m, 2H), 0.96 (t, J )
7.3 Hz, 3H). 13C NMR (300 MHz, CDCl3) δ 173.3, 159.7, 155.8,
131.4, 129.1, 128.4, 126.0, 84.3, 68.5, 54.0, 45.0, 40.6, 28.4, 19.4,
13.8. Anal. Calcd for C17H19N3O3: C, 65.16; H, 6.11; N, 13.41.
Found: C, 65.31; H, 6.16; N, 13.38.
cm-1 1H NMR (300 MHz, CDCl3) δ 7.70-6.86 (m, 11H), 6.00
.
(bs, 1H), 5.39 (m, 1H), 4.38-4.30 (m, 1H), 4.27-4.15 (m, 2H),
2.94-2.75 (m, 2H), 2.50-2.36 (m, 2H), 1.23 (t, J ) 7.1 Hz, 3H).
13C NMR (300 MHz, CDCl3) δ 172.8, 160.9, 154.5, 138.4, 130.4,
128.9, 128.7, 128.0, 127.1, 122.9, 120.0, 86.3, 65.6, 61.6, 52.3,
45.5, 38.8, 14.1. Anal. Calcd for C22H23N3O4: C, 67.16; H,
5.89; N, 10.68. Found: C, 66.95; H, 5.81; N, 10.66.
Eth yl 1-Am in ocyclop en t-3-en e-1-ca r boxyla te (9). To a
solution of cyclopentenecarboxylate 2 (11 g, 34.1 mmol) in THF
(80 mL) was added aqueous HCl (1 N, 35 mL), and the reaction
mixture was stirred at room temperature for 30 min. Water
(30 mL) was added to the reaction mixture which was
extracted with ethyl acetate (2 × 50 mL). The aqueous layer
was basified with sodium hydroxide (1 N) until pH ) 9, and
the resulting solution was extracted with ethyl acetate (2 ×
50 mL). The organic layer was dried (MgSO4), filtered, and
concentrated (rotary evaporation) to afford amino ester 9 (4.39
g, 28.3 mmol, 83%) as a colorless liquid. 9: IR (neat) 3058,
Eth yl (3a R*,5S*,6a S*)-5-[3-(p-Ch lor op h en yl)u r eid o]-3-
p r op yl-3a ,5,6,6a -tetr a h yd r o-4H-cyclop en ta [d ]isoxa zole-
5-ca r boxyla te (15) a n d Eth yl (3a R*,5R*,6a S*)-5-[3-(p-
Ch lor op h en yl)u r eid o]-3-p r op yl-3a ,5,6,6a -tetr a h yd r o-4H-
cyclop en ta [d ]isoxa zole-5-ca r boxyla te (16) fr om 11. To a
solution of urea 11 (0.56 g, 1.8 mmol) in DME (30 mL) were
added phenyl isocyanate (0.434 g, 3.6 mmol) and 1-nitrobutane
(0.18 g, 1.8 mmol) followed by the addition of triethylamine
(18 mg, 0.18 mmol) under nitrogen. The reaction mixture was
stirred for 10 h at room temperature and then refluxed for 30
h. DME was removed (rotary evaporation), and the residue
was purified by column chromatography (silica gel, EtOAc:
hexane ) 1:3) to give 15 (0.394 g, 1.0 mmol, 55%) and 16 (0.038
g, 0.09 mmol, 5.3%) as white solids. 15: mp 178 °C. IR (KBr)
2925, 1727, 1207 cm-1
.
1H NMR (300 MHz, CDCl3) δ 5.67 (s,
2H), 4.19 (q, J ) 7.1 Hz, 2H), 2.97 (d, J ) 15.3 Hz, 2H), 2.31
(d, J ) 15.3 Hz, 2H), 1.80 (s, 2H), 1.28 (t, J ) 7.1 Hz, 3H). 13
C
NMR (300 MHz, CDCl3) δ 176.9, 127.3, 62.9, 60.6, 46.6, 13.7.
E t h yl 1-(3-P h en ylu r eid o)cyclop en t -3-en e-1-ca r boxy-
la te (10). Phenyl isocyanate (2.0 g, 17.0 mmol) was added to
a methylene chloride (80 mL) solution of amino ester 9 (2.6 g,
17.0 mmol) at room temperature. After 30 min, the resulting
solid was removed by filtration, and the filter cake recrystal-
lized (EtOAc:hexanes ) 1:1) to give urea 10 (4.2 g, 15.32 mmol,
90%) as a white solid. 10: mp 192 °C. IR (KBr) 3365, 3310,
3376, 2962, 1739, 1691, 1596 cm-1
.
1H NMR (300 MHz, CDCl3)
δ 7.59 (s, 1H), 7.16-7.25 (m, 4H), 5.90 (bs, 1H), 5.19 (m, 1H),
4.27-4.15 (m, 2H), 3.81 (t, J ) 9.1 Hz, 1H), 2.92 (d, J ) 14
Hz, 1H), 2.72-2.64 (dd, J ) 14.5, 9.4 Hz, 1H), 2.42-2.20 (m,
4H), 1.68-1.52 (m, 2H), 1.24 (t, J ) 7.1 Hz, 3H), 0.91 (t, J )
7.36 Hz, 3H). 13C NMR (300 MHz, CDCl3) δ 172.7, 162.6,
154.4, 137.6, 128.8, 127.8, 120.6, 84.3, 65.5, 61.7, 54.5, 46.1,
37.0, 28.3, 19.5, 14.1, 13.7. Anal. Calcd for C19H24ClN3O4: C,
57.94; H, 6.14; N, 10.67. Found: C, 58.23; H, 6.28; N, 10.76.
16: mp 209 °C. IR (KBr) 3382, 2962, 1737, 1698, 1598, 1544
1733, 1644, 1606, 1552 cm-1
.
1H NMR (300 MHz, CDCl3) δ
7.30-7.01 (m, 5H), 6.77 (s, 1H), 5.67 (s, 2H), 5.6 (bs, 1H), 4.2
(q, J ) 7.1 Hz, 2H), 3.1 (d, J ) 15.8 Hz, 2H), 2.7 (d, J ) 15.8
Hz, 2H), 1.26 (t, J ) 7.1 Hz, 3H). 13C NMR (300 MHz, CDCl3)
δ 174.2, 154.9, 140.5, 128.7, 127.7, 121.6, 118.1, 64.1, 60.6, 44.7,
13.7. Anal. Calcd for C15H18N2O3: C, 65.67; H, 6.61; N, 10.21.
Found: C, 65.46; H, 6.49; N, 10.17.
cm-1 1H NMR (300 MHz, CDCl3) δ 7.25-7.12 (m, 4H), 6.98
.
(s, 1H), 5.73 (bs, 1H), 5.17(m, 1H), 4.20 (q, J ) 7.1 Hz, 2H),
3.75 (m, 1H), 2.62 (m, 2H), 2.46-2.22 (m, 4H), 1.70-1.53 (m,
2H), 1.25(t, J ) 7.1 Hz, 3H), 0.97 (t, J ) 7.4 Hz, 3H). 13C NMR
(300 MHz, CDCl3) δ 173.6, 161.4, 154.9, 137.0, 129.0, 128.5,
121.0, 84.6, 66.4, 62.2, 54.3, 45.6, 39.2, 28.4, 19.5, 13.9, 13.8.
Anal. Calcd for C19H24ClN3O4: C, 57.94; H, 6.14; N, 10.67.
Found: C, 57.89; H, 6.20; N, 10.45.
Eth yl 1-[3-(p-Ch lor op h en yl)u r eid o]cyclop en t-3-en e-1-
ca r boxyla te (11). As with 9 f 10, p-chlorophenyl isocyanate
gave 11 (0.8 g, 2.6 mmol, 88%) as a white solid. 11: mp 135
°C. IR (KBr) 3343, 2979, 1741, 1639, 1598, 1554, 1492 cm-1
.
1H NMR (300 MHz, CDCl3) δ 7.23-7.10 (m, 4H), 5.87 (bs, 1H),
5.66 (s, 2H), 4.22 (q, J ) 7.1 Hz, 2H), 3.09 (d, J ) 15.8 Hz,
2H), 2.65 (d, J ) 15.8 Hz, 2H), 1.26 (t, J ) 7.1 Hz, 3H). 13C
NMR (300 MHz, CDCl3) δ 175.3, 155.0, 137.2, 128.8, 128.2,
Eth yl (3a R*,5S*,6a S*)-5-[3-(p-F lu or op h en yl)u r eid o]-3-
p r op yl-3a ,5,6,6a -tetr a h yd r o-4H-cyclop en ta [d ]isoxa zole-
5-ca r boxyla te (17) fr om 12. As with 11 f 15, 12 gave 17
(56%) plus its inseparable diastereomer (6%) as a white solid
(0.4 g, 1.06 mmol, 62% combined yield). 17 with its diastere-
omer: mp 136-137 °C. IR (KBr) 3376, 2960, 1735, 1689, 1556,
127.7, 121.1, 64.3, 61.8, 44.9, 14.0. Anal. Calcd for C15H17
-
ClN2O3: C, 58.35; H, 5.55; N, 9.07. Found: C, 58.18; H, 5.57;
N, 9.01.
Eth yl 1-[3-(p-F lu or op h en yl)u r eid o]cyclop en t-3-en e-1-
ca r boxyla te (12). As with 9 f 10, p-fluorophenyl isocyanate
gave 12 (0.75 g, 2.56 mmol, 92%) as a white solid. 12: mp 146
1508. cm-1 1H NMR (300 MHz, CDCl3) a mixture of diaster-
.
°C. IR (KBr) 3365, 2985, 1733, 1646, 1624, 1560, 1508 cm-1
.
eomers (major) δ 7.56 (s, 1H), 7.27-7.22 (m, 2H), 6.95-6.89
(m, 2H), 5.86 (bs, 1H), 5.19 (dd, J ) 9.1, 5.7 Hz, 1H), 4.27-
4.16 (m, 2H), 3.80 (t, J ) 9.1 Hz, 1H), 2.92-2.88 (d J ) 14 Hz,
1H), 2.71-2.63 (dd, J ) 14, 9.5 Hz, 1H), 2.42-2.20 (m, 4H),
1.78-1.51(m, 2H), 1.25 (t, J ) 7.1 Hz, 3H), 0.91 (t, J ) 7.3
Hz, 3H). 13C NMR (300 MHz, CDCl3) a mixture of diastere-
omers (major) δ 172.4, 162.1, 158.3 (d, J ) 242 Hz), 154.4,
134.5, 121.1 (d, J ) 7.1 Hz), 114.9 (d, J ) 22.3 Hz), 83.8, 65.0,
61.2, 54.1, 45.7, 36.6, 27.8, 19.0, 13.7, 13.3. Anal. Calcd for
1H NMR (300 MHz, CDCl3) δ 7.25-7.18 (m, 3H), 6.89-6.84
(m, 2H), 5.89 (bs, 1H), 5.64 (s, 2H), 4.20 (q, J ) 7.1 Hz, 2H),
3.08 (d, J ) 16 Hz, 2H), 2.64 (d, J ) 16 Hz, 2H), 1.24 (t, J )
7.1 Hz, 3H). 13C NMR (300 MHz, CDCl3) δ 175.2, 159.0 (d, J
) 242.3 Hz), 155.5, 134.5 (d, J ) 2.3 Hz), 127.7, 122.1 (d, J )
7.75 Hz), 115.4 (d, J ) 22.35 Hz), 64.3, 61.7, 44.9, 14.0. Anal.
Calcd for C15H17FN2O3: C, 61.63; H, 5.86; N, 9.58. Found: C,
61.63; H, 5.95; N, 9.59.

Diastereoselective Synthesis of Cyclopentanoids
J . Org. Chem., Vol. 63, No. 1, 1998 117
C19H24FN3O4: C, 60.47; H, 6.41; N, 11.13. Found: C, 60.31;
H, 6.36; N, 11.12.
9.1, 9.0 Hz, 1H), 2.62-2.14 (m, 6H), 1.73-1.61 (m, 2H), 1.03
(t, J ) 7.3 Hz, 3H). 13C NMR (300 MHz, CDCl3) δ 173.6, 162.0,
154.2, 133.9, 130.0, 129.2, 127.0, 85.8, 67.8, 53.8, 44.9, 41.3,
28.7, 19.6, 13.8. Anal. Calcd for C17H18ClN3O3: C, 58.71; H,
5.21; N, 12.08. Found: C, 58.77; H, 5.27; N, 12.01.
(3a R*,5S*,6a S*)-Sp ir o[3-m et h yl-1-p h en yl-4,5,6,6a -t et -
r a h yd r o-3a H-cyclop en ta [d ]isoxa zole-4′,5-im id a zolid in e-
2′,5′-d ion e] (18) fr om 13. As with 5 f 7, 18 (0.063 g, 0.22
mmol, 73%) was obtained as a white solid. 18: mp 220 °C.
(3a R *,5S *,6a S *)-Sp ir o[3-p r op yl-1-(p -flu or op h e n yl)-
4,5,6,6a -t e t r a h yd r o-3a H -cyclop e n t a [d ]isoxa zole -4′,5-
im id a zolid in e-2′,5′-d ion e] (21) fr om 17. As with 5 f 7, 21
(0.104 g, 0.314 mmol, 80%) was obtained as a white solid. 20:
IR (KBr) 3347, 2959, 1785, 1713, 1501, 1414 cm-1 1H NMR
.
(300 MHz, CDCl3) δ 7.49-7.35 (m, 5H), 6.08 (bs, 1H), 5.27 (dd,
J ) 8.3, 4.8 Hz, 1H), 3.75 (t, J ) 9.0 Hz, 1H), 2.63-2.44 (m,
3H), 2.18 (d, J ) 15.7 Hz, 1H), 2.06 (s, 3H). 13C NMR (300
MHz, CDCl3) δ 173.8, 158.6, 154.7, 131.3, 129.0, 128.3, 125.9,
86.0, 67.7, 55.1, 45.0, 41.1, 12.1. Anal. Calcd for C15H15N3O3:
C, 63.14; H, 5.29; N, 14.72. Found: C, 63.10; H, 5.32; N, 14.62.
(3aR*,5S*,6aS*)-Spir o[1,3-diph en yl-4,5,6,6a-tetr ah ydr o-
3a H -cyclop en t a [d ]isoxa zole-4′,5-im id a zolid in e-2′,5′-d i-
on e] (19) fr om 14. As with 5 f 7, 19 (0.105 g, 30 mmol, 60%)
was obtained as a white solid. 19: mp 245 °C. IR (KBr) 3265,
mp 225 °C. IR (KBr) 3199, 2977, 1774, 1714, 1513, 1415 cm-1
.
1H NMR (300 MHz, CDCl3) δ 7.43-7.38 (m, 2H), 7.18-7.12
(m, 2H), 6.06 (s, 1H), 5.25(dd, J ) 8.1, 4.5 Hz, 1H), 3.78 (t, J
) 8.6 Hz, 1H), 2.62-2.14 (m, 6H), 1.76-1.59 (m, 2H), 1.01 (t,
J ) 7.3 Hz, 3H). 13C NMR (300 MHz, CDCl3) δ 173.8, 162.0,
161.9 (d, J ) 249 Hz), 154.5, 127.7, (d, J ) 8.7 Hz), 127.5 (d,
J ) 2.5 Hz), 116.0 (d, J ) 23.1 Hz), 85.9, 67.8, 53.8, 44.9, 41.3,
28.7, 19.6, 13.8. Anal. Calcd for C17H18FN3O3: C, 61.62; H,
5.48; N, 12.68. Found: C, 61.86; H, 5.47; N, 12.62.
2972, 1780, 1710, 1500, 1412 cm-1 1H NMR (300 MHz, CDCl3)
.
δ 7.80-7.26 (m, 10H), 6.05 (bs, 1H), 5.48-5.44 (m, 1H), 4.34-
4.28 (m, 1H), 2.80 (dd, J ) 14.1, 10.4 Hz, 1H), 2.71-2.57 (m,
2H), 2.33 (dd, J ) 14.1, 1.8 Hz, 1H). 13C NMR (300 MHz,
CDCl3) δ 174.2, 160.8, 155.0, 131.7, 131.1, 129.5, 128.7, 128.2,
127.5, 127.4, 126.3, 88.1, 68.3, 51.9, 45.2, 42.8. Anal. Calcd
for C20H17N3O3: C, 69.15; H, 4.93; N, 12.09. Found: C, 69.24;
H, 4.87; N, 12.08. (3a R*,5S*,6a S*)-Sp ir o[3-p r op yl-1-(p-
ch lor op h en yl)-4,5,6,6a -tetr a h yd r o-3a H-cyclop en ta [d ]is-
oxa zole-4′,5-im id a zolid in e-2′,5′-d ion e] (20) fr om 15. As
with 5 f 7, 20 (0.205 g, 0.59 mmol, 78%) was obtained as a
white solid. 20: mp 241 °C. IR (KBr) 3210, 2965, 1778, 1716,
Ack n ow led gm en t. We are grateful to the National
Science Foundation and Novartis Crop Protection AG
for financial support of this research.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR/13C NMR
and IR spectra for compounds 1, 2, 9, and 15 (12 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
1496, 1403 cm-1
.
1H NMR (300 MHz, CDCl3) δ 7.45-7.38 (m,
4H), 6.03 (s, 1H), 5.24(dd, J ) 8.2, 4.5 Hz, 1H), 3.77 (dd, J )
J O9714831