Diastereoselective Solid-Phase Synthesis of Novel Hydantoin- and Isoxazoline-Containing Heterocycles

Article abstract of DOI:10.1021/jo9807161

Exploiting 1,3-dipolar cycloaddition and carbanilide cyclization transformations, we have prepared novel spirocyclic isoxazoloimidazolidinedione heterocycles of generalized structures II and III on solid phase starting from Merrifield resin. Cyclopentanoid isoxazoloimidazolidinedione II was obtained with complete diastereoselectivity, and cyclopropanoid isoxazoloimidazolidinedione III was obtained as an ≈ 2:1 mixture of diastereomers.

Full text of DOI:10.1021/jo9807161

J . Org. Chem. 1998, 63, 6579-6585
6579
Dia ster eoselective Solid -P h a se Syn th esis of Novel Hyd a n toin - a n d
Isoxa zolin e-Con ta in in g Heter ocycles
Kyung-Ho Park, Marilyn M. Olmstead, and Mark J . Kurth*
Department of Chemistry, University of California, Davis, California 95616
Received April 17, 1998
Exploiting 1,3-dipolar cycloaddition and carbanilide cyclization transformations, we have prepared
novel spirocyclic isoxazoloimidazolidinedione heterocycles of generalized structures II and III on
solid phase starting from Merrifield resin. Cyclopentanoid isoxazoloimidazolidinedione II was
obtained with complete diastereoselectivity, and cyclopropanoid isoxazoloimidazolidinedione III
was obtained as an ≈2:1 mixture of diastereomers.
1
The hydantoin moiety has important medicinal as well
as agrochemical2 activities; a large number of hydan-
tions have been synthesized for various biological ap-
A basic tenant of combinatorial chemistry is to design
,3
analogue libraries using chemistry which allows for the
incorporation of two or more elements of diversification.
As illustrated in isoxazoloimidazolidinedione target struc-
ture I, a key synthetic questions in this study addressed
the issues of developing a solid-phase synthetic protocol
which would allow for peripheral diversification at “X”
and “Y” and core diversification at “Z”. Our initial solid-
phase target was II, where “Z” is a cyclopentyl moiety,
and from the outset, several important synthetic ques-
tions were apparent in the planning of this solid-phase
synthetic study: (i) Would it be possible to R,R-dialkylate
polymer-bound glycinate 1 with cis-1,4-dichloro-2-butene
to give the corresponding cyclopentenyl amino acid? (ii)
Would the resulting polymer-bound cyclopentenyl moiety
participate in a nitrile oxide 1,3-dipolar cycloaddition
reaction, or would we only see nitrile oxide dimerization?
(iii) As a particularly key question, would we see inter-
molecular hydrogen-bond control of alkene face selectivity
in the solid-phase cycloaddition step leading to the
diastereoselective preparation of II? (iv) Would an ester
substrate-polymer tether allow for both cyclative release
of substrate from the resin as well as traceless delivery
of cyclopentanoid isoxazoloimidazolidinedione II? Once
data addressing these synthetic questions were in hand,
the question of incorporating “X”, “Y”, and “Z” diversifica-
tion could be addressed. Clearly, the main issue here
centers on the question of whether a solid-phase synthetic
strategy can be developed to accommodate core diversi-
fication (i.e., at “Z” in I). As detailed in Scheme 1, we
planned to address this question of “Z” diversity by
targeting cyclopropanoid isoxazoloimidazolidinediones of
generalized structure III.
4
plications, and the isoxazoline heterocycle has been used
extensively to modulate various other biologically active
motifs.5 In preliminary solution studies, we developed
6
7
a novel route to cyclopentanoids adjoined to hydantoin
and isoxazoline heterocycles. The key control element
in this approach to these spiro[cyclopenta[d]isoxazole-
4
′,5-imidazoline] heterocycles was the utilization of an
intermolecular hydrogen-bond to control alkene face
selectivity in the nitrile oxide cycloaddition step.
We are interested in developing synthetic strategies8
which can be applied to combinatorial chemistry, and our
main objective in the work reported here is the develop-
ment of a stereoselective synthetic strategy for the
construction of polyfunctional heterocycles on solid-phase.
With reliable solid-phase chemistry in hand, library
preparation would set the stage for a thorough explora-
tion of the biological properties of the isoxazoloimid-
azolidinedione heterocycles targeted here.
(1) (a) Ware, E. Chem. Rev. 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
, 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.
985, 38, 177.
5) (a) Khalil, M. A.; Maponya, M. F.; Ko, D.-H.; You, Z.; Oriaku, E.
4
(
(
1
(
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.
All of our attempts at solid-phase R,R-dialkylation of
1 were unsuccessful because of ester hydrolysis with
concomitant removal of product from the resin. For
example, treating 1 with either LDA/THF or potassium
tert-butoxide/THF resulted in substantial ester hydroly-
sis. In contrast, the solution-phase alkylation of imino
ester 7 with cis-1,4-dichloro-2-butene was highly effective
(80% yield of 8) and subsequent imine hydrolysis (8 f
(
d) Simoni, D.; Manfredini, S.; Tabrizi, M. A.; Bazzanini, R.; Guarneri,
M.; Ferroni, R.; Tranielo, F.; Nastruzzi, C.; Feriotto, G.; Gambari, R.
Top. Mol. Org. Eng. 1991, 8 (Chem. Prop. Biomol. Syst.), 119.
(
6) Park, K.-H.; Olmstead, M. M.; Kurth, M. J . J . Org. Chem. 1998,
3, 113.
7) For solid-phase routes to hydantoins, see: (a) DeWitt, S. H.;
6
(
Kiely, J . S.; Stankovic, C. J .; Schroeder, M. C.; Cody, D. R.; 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.
9
), amine protection (9 f 10), and ester saponification
delivered carboxylic acid 11 (Scheme 2). O-Alkylation
of the carboxylate salt of 11 with Merrifield resin in the
(8) For recent examples, see: (a) Gong, Y.-D.; Najdi, S.; Olmstead,
M. M.; Kurth, M. J . J . Org. Chem. 1998, 63, 3081. (b) Lorsbach, B. A.;
Bagdanoff, J . T.; Miller, R. B.; Kurth, M. J . J . Org. Chem. 1998, 63,
9
presence of 18-crown-6 readily produced 2 (FTIR 1711
2
3
6
244. (c) Halm, C.; Evarts, J .; Kurth, M. J . Tetrahedron Lett. 1997,
8, 7709. (d) Kantorowski, E. J .; Kurth, M. J . J . Org. Chem. 1997, 62,
797.
(9) Roeske, R. W.; Gesellchen, P. D. Tetrahedron Lett. 1976, 38, 3369.
S0022-3263(98)00716-6 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/25/1998

6
580 J . Org. Chem., Vol. 63, No. 19, 1998
Park et al.
Sch em e 1. Cyclop en ta n oid
Isoxa zoloim id a zolid in ed ion es 6: Solid -P h a se
Rea ction s
Ta ble 1. Cyclop en ta n oid Isoxa zoloim id a zolid in ed ion e 6
P r ep a r ed by SP OS
yield (%)a
compd
-R
-R′
6
6
6
6
6
6
a
b
c
d
e
f
-Cl
-F
-H
-H
-Cl
-F
-CH3
21
27
30
21
25
26
-CH3
-CH2CH3
-CH2CH2CH3
-CH2CH2CH3
-CH2CH2CH3
a
Overall yield from PS-CH2Cl.
other diastereomer was detected. Six analogues of 6 were
prepared in this way, and these results are summarized
in Table 1.
This solid-phase synthesis of II from 11 accommodates
peripheral diversification at “X” and “Y” from simple
nitroalkane and isocyanate reagents, respectively. We
next turned to the question of incorporating core diver-
sification at “Z” (see I; Scheme 1) and decided to explore
routes to cyclopropanoids of general structure III.
Dialkylation of 7 with cis-1,4-dichloro-2-butene delivers
8
and what we believed to be a trace of the cyclopropanoid
analogue 12. Thus, we were delighted to find that
1
1
substituting cis-1,4-bis(methylsulfonyl)oxy)-2-butene for
cis-1,4-dichloro-2-butene resulted in formation of cyclo-
propyl imino ester 12 (Scheme 3) as the major R,R-
dialkylation product.12 This completely diastereoselective
alkylation (i.e., there was no evidence for the cyclopropyl
imino ester with trans carboethoxy and vinyl moieties)
did produce cyclopentenyl imino ester 8 as a minor side
f
product. However, the R values for these two structur-
ally isomeric products were same, so hydrolysis of those
intermediate imines gave two different values of com-
pound 9 (R
compound 13 (R
f
≈ 0.1 in 50% ethyl acetate in hexane) and
f
≈ 0.3), which were easily separated by
flash chromatography (overall yield from 7; 18%:39% )
9
:13).
Imine hydrolysis to 13 followed by addition of phenyl
isocyanate delivered urea 14. Unlike cyclopentenoid 4
where the urea moiety is ideally positioned for diaste-
reofacial selective delivery of the nitrile oxide to the
alkene, the trans configuration of the urea and vinyl
moieties precludes H-bonding delivery of the nitrile oxide.
Consequently, isoxazoline formation from 14 proceeds
with only minimal selectivity giving mixtures of C1′R-
and C1′â-isomers 15 and 16, respectively (see Table 2).
This solution-phase route to cyclopropanoid isoxazolo-
imidazolidinedione III was completed by base-mediated
cyclization of 15 to 17 and 16 to 18. Single-crystal X-ray
Sch em e 2. Syn th esis of Cyclop en ten yl Am in o
Acid
2 2 3
chrystallographic analysis of 17a (R′ ) CH CH CH ; see
Figure 1) verified the relative cyclopropane stereochem-
istries of 12-18 and established the C1′ stereochemis-
tries of 15-18.
Our solid-phase approach to cyclopropanoid isoxazolo-
imidazolidinediones III began with amino ester 13 which
was BOC-protected (f19), saponified (f20), and coupled
with Merrifield resin to give resin 21 (Scheme 4). Depro-
tection to amino ester 22 delivered the solid-phase
analogue of 13 which, upon isocyanate treatment, gave
urea 23. 1,3-Dipolar cycloaddition with a Mukaiyama-
cm-1). The BOC group in amino ester 2 was then cleaved
by 50% TFA in CH Cl and the resulting ammonium salt
was neutralized by a triethylamine/CH Cl wash to give
2
2
2
2
amino ester 3. At this point, various isocyanates were
reacted with amino ester 3 to give urea 4 (4a : R ) H,
-1
FTIR 1736, 1700, 1654 cm ). A hydrogen bond-directed
intermolecular 1,3-dipolar cycloaddition reaction (i.e.,
(
10) For reviews of nitrile oxide-isoxazoline methodology, see: (a)
6
urea NH‚‚‚OsNtCR) of the alkene in 4 with a Mu-
Curran, D. P. Adv. Cycladdit. 1988, 1, 129. (b) Torssel, K. B. G. Nitrile
Oxides, Nitrones and Nitronates in Organic Synthesis; VCH Publish-
ers: Weinheim, Germany, 1988.
kaiyama-generated nitrile oxide10 was carried out to give
intermediate 5. This transformation (4 f 5) proceeds
with complete face diastereoselective as evidenced by the
base-mediated cyclative release of only 6; no trace of the
(
(
11) Ding, Z.; Tufariello, J . J . Synth. Commun. 1990, 20, 227.
12) Nantz, M. H.; Radisson, X.; Fuchs, P. L. Synth. Commun. 1987,
17, 55.

Hydantoin- and Isoxazoline-Containing Heterocycles
J . Org. Chem., Vol. 63, No. 19, 1998 6581
Sch em e 3. Cyclop r op a n oid
Isoxa zoloim id a zolid in ed ion es 17/18;
Solu tion -P h a se Rea ction s
F igu r e 1. Computer-generated single-crystal X-ray structure
of 18a .
Sch em e 4. Cyclop r op a n oid
Isoxa zoloim id a zolid in ed ion es 17/18; Solid -P h a se
Rea ction s
Ta ble 2. Cyclop r op a n oid Isoxa zoloim id a zolid in ed ion e
P r ep a r ed by Solu tion -P h a se Rea ction s
1
5 or 16 isoxazoloimid 17 or 18
-R
isoxazoline yield (%) azolidinedione yield (%)
-
-
-
-
-
-
CH2CH2CH3
CH2CH2CH3
CH3
CH3
C6H5
15a (R1′)
16a (â1′)
15b (R1′)
16b (â1′)
15c (R1′)
16c (â1′)
12
61
9
65
33
51
17a (R1′)
18a (â1′)
17b (R1′)
18b (â1′)
17c (R1′)
18c (â1′)
82
85
78
75
81
75
C6H5
generated nitrile oxide gave an R/â-mixture of C1′
epimeric isoxazolines as evidenced by obtaining a mixture
of 17 and 18 upon cyclative release from the resin.
However, in the case of R ) Cl, the C1′-epimer of 18 (i.e.,
Ta ble 3. Cyclop r op a n oid Isoxa zoloim id a zolid in ed ion e
P r ep a r ed by SP OS
compd
7a /18a
18d
18e
8f
-R
-R′
yield (%)a
≈C1′R/â ratio
b
1
-H
-CH2CH2CH3
22
18
15
19
1/2.6
1
7) readily decomposed13 and could not be isolated in a
-Cl
-Cl
-Cl
-CH CH3
b
b
b
2
substantial amount. The overall yield of isoxazoloimid-
azolidinediones 17/18 was ≈19% (see Table 3) from
Merrifield resin which translates to an ≈76% yield per
transformation in this six step solid-phase procedure.
-CH2CH2CH3
1
-C6H5
a Overall yield from PS-CH Cl. b The C1′ epimer of 18 (i.e., 17)
2
was negligible.13
In summary, we have developed synthetic strategies
for the solid-phase preparation of novel heterocycles of
generalized structures II and III. The solid-phase meth-
ods developed provide fast, reliable access to an array of
structurally interesting isoxazoloimidazolidinediones with
a number of advantages over the corresponding solution-
phase chemistry. These include easy reaction workup
manipulations (i.e., filtration and solvent washing), ready
access to milligram quantities of isoxazoloimidazolidinedi-
ones with labor efficient procedures, overall yields com-
(13) Crude reaction mixtures of 17/18 (R ) Cl) rapidly turn deep
brown as a result of decomposition of 17. In contrast, isolated 18 is
stable when stored dark and in the cold. This decomposition explains
the lower yield for R ) Cl (< yield for R ) H; see Table 3).
6
parable to our one-pot solution-phase protocol but with
improved product purity and much simpler product

6
582 J . Org. Chem., Vol. 63, No. 19, 1998
Park et al.
isolation/purification, and the practical ability to use
excess reagents to drive solid-phase chemical reactions
to completion. Our cyclative release strategy (i.e., 5 f 6
and 24 f 18) affords another important synthetic
advantage to this solid-phase chemistry in that products
with ≈95% purity are obtained from the resin after the
five solid-phase steps required for conversion of 11 to 6
or 20 to 18. Moreover, we have shown that 6 is obtained
with complete diastereoselectivity because the urea
moiety in solid-phase 4 is a powerful control element
which utilizes an intermolecular hydrogen-bond to control
alkene face selectivity in the nitrile oxide cycloaddition
step. The work reported here secures the first stage in
a program aimed at the solid-phase diversification of
hydantoin- and isoxazoline-based pharmocophores. By
employment of this general and expedient solid-phase
synthetic methodology, construction of a large combina-
torial library of isoxazoloimidazolidinedione derivatives
is currently in progress. The solid-phase synthesis of
other classes of biologically important organic compounds
is also under investigation and will be reported in due
course.
Resin 5 (R ) H, R′ ) Et). Following the same procedure
used for making resin 5 (R ) Cl, R′ ) Me) gave the desired
-
1
resin (300 mg). FTIR (KBr): 1737, 1697 cm
.
Resin 5 (R ) H, R′ ) P r op yl). Following the same
procedure used for making resin 5 (R ) Cl, R′ ) Me) gave the
-1
desired resin (305 mg). FTIR (KBr): 1738, 1698 cm
.
Resin 5 (R ) Cl, R′ ) P r op yl). Following the same
procedure used for making resin 5 (R ) Cl, R′ ) Me) gave the
-
1
desired resin (303 mg). FTIR (KBr): 1735, 1700 cm
.
Resin 5 (R ) F , R′ ) P r op yl). Following the same
procedure used for making resin 5 (R ) Cl, R′ ) Me) gave the
-
1
desired resin (280 mg). FTIR (KBr): 1734, 1699 cm
.
(
3aR*,5S*,6aS*)-Spiro[1′-(p-chlorophenyl)-3-methyl-4,5,6,-
6
a -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] (6a ) fr om Resin 5 (R ) Cl, R′ ) Me).
Using the same procedures described for the synthesis of resins
1-4 from Merrifield resin (300 mg, 1 mmol of Cl/g) delivered
resin 5 (340 mg; R ) Cl, R′ ) Me). This resin was treated
with Et
overnight. After filtration and washing of the resin with THF
2 × 30 mL), the solvent was removed under reduced pressure
and the residue was purified by short silica gel column to give
a (20 mg, 0.063 mmol, overall 20% yield) as a solid: Mp >260
3
N (1 mL) using a magnetic stirrer in THF at 60 °C
(
6
-1
1
°
C; FTIR (KBr) 3104, 2931, 1777, 1709 cm ; H NMR (300
MHz, CDCl ) δ 7.45-7.38 (m, 4H), 5.99 (s, 1H), 5.27 (dd, 1H,
J ) 8.3, 4.4 Hz), 3.76 (t, 1H, J ) 9.17 Hz), 2.63-2.45 (m, 3H),
.18 (d, 1H, J ) 14.14 Hz), 2.07 (s, 3H); 13C NMR (300 MHz,
DMSO-d ) δ 175.3, 157.1, 154.0, 132.1, 130.8, 128.6, 128.3,
3.8, 67.3, 54.5, 11.3. Anal. Calcd for C15 : C, 56.34;
H, 4.41; N, 13.14. Found: C, 56.40; H, 4.37; N, 13.09.
3a R*,5S*,6a S*)-Sp ir o[1′-(p -flu or op h en yl)-3-m et h yl-
,5,6,6a-tetr ah ydr o-3a H-cyclopen ta[d]isoxazole-4′,5-im id-
3
2
Exp er im en ta l Section
6
8
3 3
H14ClN O
Resin 2. Boc acid (11) (1 g, 4.40 mmol) was treated with
KOH (1.0 equiv) in EtOH/H O (10 mL/5 mL, 2:1) at ambient
2
temperature for 1 h. After removal of the solvent, the
potassium salt of 11 was dried under vacuum to give 1.15 g
(
4
a zolid in e-2′,5′-d ion e] (6b) fr om Resin 5 (R ) F , R′ ) Me).
Using the same procedures described for the synthesis of 6a ,
resin 5 (R ) F, R′ ) Me) gave 6b (35 mg, 0.083 mmol, overall
(4.33 mmol) of a solid which was dissolved in DMF (40 mL).
Merrifield resin (2.16 g, 2.16 mmol; loading ) 1 mmol of Cl/g)
and 18-crown-6 (1.136 g, 4.3 mmol) were added to this DMF
solution, and the reaction mixture was stirred with a magnetic
stir bar at 70 °C for 50 h. The resin was washed with DMF (2
2
1
2
4
7% yield) as a solid: Mp 248-249 °C; FTIR (KBr) 3208, 2962,
-1
1
774, 1714 cm ; H NMR (300 MHz, CDCl ) δ 7.43-7.38 (m,
3
H), 7.18-7.12 (m, 2H), 5.99 (s, 1H), 5.27 (dd, 1H, J ) 7.47,
×
30 mL), THF (30 mL), THF/H
and finally ether (30 mL). The resin was dried under vacuum
2
O (2 × 30 mL), THF (30 mL),
.54 Hz), 3.76 (t, 1H, J ) 9.23 Hz), 2.64-2.45 (m, 3H), 2.18
13
(
1
d, 1H, J ) 14.11), 2.07 (s, 3H); C NMR (300 MHz, CDCl ) δ
3
-
1
to give 2.4 g of the desired resin. FTIR (KBr): 1711 cm
Resin 3. Resin 2 (1.8 g) was treated with 50% TFA/CH
(30 mL) using a magnetic stirrer at ambient temperature
for 1 h. The resin was washed with CH Cl (30 mL), dioxane/
CH Cl Cl (2 × 30
(1:1, 2 × 30 mL), dioxane (30 mL), and CH
mL), followed by treatment with 10% Et N in CH Cl (30 mL)
for 1 h. The resin was washed with DMF (2 × 30 mL), CH
Cl
(2 × 30 mL) and ether (30 mL) and dried under vacuum
to give the desired resin (1.6 g). FTIR (KBr): 3459, 3380, 1726
.
73.9, 162.0 (d, J ) 249 Hz), 158.6, 154.6, 127.8 (d, J ) 8.6
2
-
Hz), 127.4, 116.1 (d, J ) 22.86 Hz), 86.0, 67.8, 55.2, 45.1, 41.2,
12.1. Anal. Calcd for C15 : C, 59.40; H, 4.65; N,
Cl
2
3 3
H14FN O
2
2
13.85. Found: C, 59.50; H, 4.67; N, 13.77.
2
2
2
2
(3a R*,5S*,6a S*)-Sp ir o[3-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] (6c) fr om Resin 5 (R ) H, R′ ) Et). Using the
same procedures described for the synthesis of 6a , resin 5 (R
) H, R′ ) Et) gave 6c (27 mg, 0.091 mmol, overall 30% yield)
as a solid: Mp 196 °C; FTIR (KBr) 3225, 2971, 1776, 1714
3
2
2
2
-
2
-
1
cm
Resin 4 (R ) H). Resin 3 (300 mg) was treated with 0.5
M phenyl isocyanate using a magnetic stirrer in CH Cl (30
mL) for 10 h at ambient temperature. The resin was washed
with DMF (2 × 30 mL), THF (2 × 30 mL), CH Cl (30 mL),
and ether (30 mL). Drying in vacuo gave the desired resin
.
-
1
1
cm ; H NMR (300 MHz, CDCl
s, 1H), 5.26 (dd, 1H, J ) 8.28, 4.37 Hz), 3.79 (t, 1H, J ) 8.98
Hz), 2.64-2.46 (m, 4H), 2.39-2.27 (m, 1H), 2.17 (d, 1H, J )
4.12 Hz), 1.24 (t, 3H, J ) 7.5 Hz); 13C NMR (300 MHz, CDCl
δ 173.9, 163.2, 154.7, 131.4, 129.1, 128.3, 126.0, 86.1, 67.8, 53.8,
44.9, 41.4, 20.4, 10.78. Anal. Calcd for C H N O : C, 64.20;
3
) δ 7.50-7.35 (m, 5H), 6.02
(
2
2
1
3
)
2
2
-
1
(0.31 g). FTIR (KBr): 1736, 1700, 1654 cm
.
16 17
3
3
H, 5.72; N, 14.03. Found: C, 64.06; H, 5.71; N, 13.95.
3a R*,5S*,6a S*)-Sp ir o[1′-p h en yl-3-p r op yl-4,5,6,6a -tet-
Resin 4 (R ) Cl). Following the same procedure used for
(
making resin 4 (R ) H) but using 0.5 M 4-chlorophenyl
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] (6d ) fr om Resin 5 (R ) H, R′ ) P r op yl). Using
isocyanate gave the desired resin (320 mg). FTIR (KBr): 1737,
-
1
1
702 cm .
the same procedures described for the synthesis of 6a , resin 5
Resin 4 (R ) F ). Following the same procedure used for
6
(
2
R ) H, R′ ) propyl) gave 6d (20 mg, 0.064 mmol, overall
making resin 4 (R ) H) but using 0.5 M 4-fluorophenyl
1% yield) as a solid.
3a R*,5S*,6a S*)-Sp ir o[1′-(p -ch lor op h en yl)-3-p r op yl-
,5,6,6a-tetr ah ydr o-3a H-cyclopen ta[d]isoxazole-4′,5-im id-
isocyanate gave the desired resin (310 mg). FTIR (KBr): 1734,
(
-
1
1
654 cm
Resin 5 (R ) Cl, R′ ) Me). To a mixture of resin 4 (R )
Cl, 300 mg), 0.5 M nitroethane, and 0.5 M of phenyl isocyanate
in THF (20 mL) was added Et N (10 µL). The reaction mixture
was stirred with a magnetic stir bar at 60 °C overnight and
then washed with DMF (2 × 30 mL), THF (2 × 30 mL), CH
Cl (30 mL), and ether (30 mL). Drying in vacuo gave the
desired resin (310 mg). FTIR (KBr): 1735, 1700 cm
.
4
a zolid in e-2′,5′-d ion e] (6e) fr om R esin 5 (R ) Cl, R ′ )
P r op yl). Using the same procedures described for the syn-
6
3
thesis of 6a , resin 5 (R ) Cl, R′ ) propyl) gave 6e (26 mg,
0
.075 mmol, overall 25% yield) as a solid.
3a R*,5S*,6a S*)-Sp ir o[1′-(p -flu or op h en yl)-3-p r op yl-
,5,6,6a-tetr ah ydr o-3a H-cyclopen ta[d]isoxazole-4′,5-im id-
2
-
(
2
4
-
1
.
a zolid in e-2′,5′-d ion e] (6f) fr om R esin 5 (R ) F , R ′ )
Resin 5 (R ) F , R′ ) Me). Following the same procedure
used for making resin 5 (R ) Cl, R′ ) Me) gave the desired
P r op yl). Using the same procedures described for the syn-
6
thesis of 6a , resin 5 (R ) F, R′ ) propyl) gave 6f (26 mg,
-
1
resin (290 mg). FTIR (KBr): 1734, 1699 cm
.
0.078 mmol, overall 26% yield) as a solid.

Hydantoin- and Isoxazoline-Containing Heterocycles
J . Org. Chem., Vol. 63, No. 19, 1998 6583
E t h yl 1-((ter t-Bu t oxyca r b on yl)a m in o)cyclop en t a -3-
en e-1-ca r boxyla te (10) fr om 9. Compound 9 (4 g, 25.8
mmol) was treated with di-tert-butyl dicarbonate (5.63 g, 25.8
pressure, followed by the silica gel column chromatography
(3:7 ethyl acetate/hexane) gave 15a (25 mg, 0.07 mmol, 13%)
as a liquid and 16a (12 mg, 0.33 mmol, 62%) as a solid.
-
1
1
mmol) in CH
was removed in vacuo, and the residue was recrystallized
ethyl acetate/hexane) to give 10 (6 g, 23.5 mmol, 91%) as a
2
Cl
2
(100 mL) at reflux overnight. The solvent
15a : FTIR (neat) 3357, 2963, 1724, 1662 cm ; H NMR
(300 MHz, CDCl ) δ 7.33-7.04 (m, 5H), 6.99 (s, 1H), 5.71 (s,
3
(
1H), 4.79 (m, 1H), 4.15 (m, 2H), 3.39 (dd, 1H, J ) 17.15, 6.54
Hz), 3.0 (dd, 1H, J ) 17.15, 10.35 Hz), 2.33 (t, 2H, J ) 7.22
Hz), 1.87-1.79 (m, 1H), 1.67-1.53 (m, 3H), 1.41 (dd, 1H, J )
-
1 1
solid. Mp 82 °C; FTIR (KBr) 3279, 2981, 1735, 1701 cm ; H
NMR (300 MHz, CDCl
(
3
) δ 5.65 (s, 2H), 5.10 (s, br, 1H), 4.20
q, 2H, J ) 7.1 Hz), 3.05 (d, 2H, J ) 15.6 Hz), 2.6 (d, 2H, J )
1
3
9.27, 5.20 Hz), 1.25 (t, 3H, 7.15 Hz), 0.94 (t, 3H, 7.39 Hz);
C
1
5.6 Hz), 1.43 (s, 9H), 1.27 (t, 3H, J ) 7.1 Hz); 13C NMR (300
) δ 174.3, 154.9, 127.7, 64.3, 61.5, 44.9, 28.3, 27.4,
NMR (300 MHz, CDCl ) δ 171.8, 160.2, 156.0, 138.3, 129.2,
3
MHz, CDCl
4.2.
-((ter t-Bu toxycar bon yl)am in o)cyclopen ta-3-en e-1-car -
boxylic Acid (11) fr om 10. Compound 10 (3.5 g, 13.72 mmol)
and sodium hydroxide (1.09 g, 27.4 mmol) in EtOH/H O (20
3
124.0, 120.9, 79.2, 61.8, 42.1, 37.7, 35.5, 29.8, 23.4, 19.8, 14.3,
13.8.
1
1
16a : Mp 152 °C; FTIR (KBr) 3303, 2961, 2873, 1724, 1659
cm- ; H NMR (300 MHz, CDCl
) δ 7.76 (s, br, 1H), 7.6-7.0
1
1
3
2
(m, 5H), 5.63 (s, br, 1H), 4.7 (m, 1H), 4.34-4.11 (m, 2H), 3.17
(dd, 1H, J ) 17.03, 10.4 Hz), 2.83 (dd, 1H, J ) 17.03, 7.24
Hz), 2.34 (t, 3H, J ) 7.3 Hz), 1.89-1.77 (m, 2H), 1.66-1.51
mL/20 mL) were refluxed overnight. The solvent was removed
under reduced pressure, and 1 N HCl was added to the
reaction mixture until the pH reached 2-3. Ethyl acetate (40
1
3
(m, 3H), 1.22 (t, 3H, J ) 7.1 Hz), 0.95 (t, 3H, J ) 7.2 Hz);
NMR (300 MHz, CDCl ) δ 170.8, 159.5, 156.1, 139.1, 128.9,
122.9, 119.6, 79.2, 62.2, 42.3, 38.3, 35.5, 29.7, 21.6, 19.8, 14.2,
13.8. Anal. Calcd for C19 : C, 63.49; H, 7.01; N, 11.69.
C
mL × 2) extraction, drying over anhydrous MgSO
4
, and
3
removal of solvent under reduced pressure gave 11 (2.7 g, 11.8
mmol, 87%) as a solid: Mp 137 °C; FTIR (KBr) 3258, 3066,
25 3 4
H N O
2
2
)
1
5
975, 1708, 1653 cm-1; H NMR (300 MHz, CDCl
1
3
) δ 5.66 (s,
Found: C, 63.26; H, 7.05; N, 11.61.
H), 5.14 (s, br, 1H), 3.13 (d, 2H, J ) 16.3 Hz), 2.64 (d, 2H, J
16.3 Hz), 1.44 (s, 9H); C NMR (300 MHz, CDCl
27.6, 64.4, 44.8, 28.3, 27.4. Anal. Calcd for C11
8.13; H, 7.54; N, 6.16. Found: C, 57.98; H, 7.64; N, 6.12.
E t h yl (1R*,2S*,1′R*)-2-(4′-Met h yl-2′,3′-oxa zolin yl)-1-
((N-p h en ylca r ba m oyl)a m in o)cyclop r op a n eca r boxyla te
(15b) a n d Eth yl (1R*,2S*,1′S*)-2-(4′-Meth yl-2′,3′-oxa zoli-
n yl)-1-((N-p h en ylca r b a m oyl)a m in o)cyclop r op a n e ca r -
boxyla te (16b) fr om 14. Following the same procedure
described 15a and 16a , nitroethane (41 mg, 0.54 mmol) gave
15b (17 mg, 0.05 mmol, 9%) and 16b (117 mg, 0.35 mmol, 65%)
as solids.
1
3
3
) δ 155.8,
: C,
H
17NO
4
E t h yl (1R*,2S*)-1-Am in o-2-vin ylcyclop r op a n e-1-ca r -
boxyla te (13) fr om 7. Compound 7 (1.10 g, 4.09 mmol) was
treated with NaH (0.216 g, 9 mmol) in THF (30 mL) at ambient
temperature. A solution of cis-1,4-bis(methylsulfonyl)oxy)-2-
butene (1 g, 4.09 mmol) in DMF (5 mL) was added dropwise
to the solution at ambient temperature. After 12 h, ether (80
mL) and cold water (40 mL) were added to the reaction mixture
and the ether layer was separated and dried (anhydrous
15b: Mp 174-175 °C; FTIR (KBr) 3356, 2978, 1694 cm-1;
1
H NMR (300 MHz, CDCl ) δ 7.31-7.06 (m, 5H), 6.95 (s, 1H),
3
5.67 (s, 1H), 4.81 (m, 1H), 4.17 (q, 2H, J ) 7.1 Hz), 3.39 (dd,
1H, J ) 17.29, 6.64 Hz), 3.0 (dd, 1H, J ) 17.29, 10.12 Hz), 2.0
(s, 3H), 1.84 (m, 1H), 1.65 (m, 1H), 1.42 (dd, 1H, J ) 9.32,
MgSO
residue was passed through a silica gel column which was
presaturated with 10% Et N in hexane. Removal of the
4
). After removal of the ether at reduced pressure, the
5.26 Hz), 1.25 (t, 3H, J ) 7.1 Hz); 13C NMR (300 MHz, CDCl
)
3
3
δ 171.8, 157.6, 156.0, 138.2, 129.3, 124.1, 121.1, 79.5, 61.8, 43.7,
37.7, 35.5, 23.4, 14.3, 13.3. Anal. Calcd for C17 : C,
61.61; H, 6.38; N, 12.68. Found: C, 61.49; H, 6.47; N, 12.45.
solvent under reduced pressure gave compounds 8 and 12 (1
g of crude) as an inseparable mixture which was treated with
21 3 4
H N O
-
1
1
N HCl (10 mL) in THF (10 mL) for 30 min. Ethyl acetate
16b: Mp 149 °C; FTIR (KBr) 3304, 2983, 1716, 1662 cm ;
H NMR (300 MHz, CDCl ) δ 7.75 (s, br, 1H), 7.57 (m, 2H),
3
1
(40 mL) and water (30 mL) were added to the reaction mixture,
and the aqueous layer was treated with 1 N NaOH solution
until the pH reached 9-10. Extraction with ethyl acetate (30
7.31-7.28 (m, 2H), 7.02 (t, 1H, J ) 7.36 Hz), 5.47 (s, br, 1H),
4.76 (m, 1H), 4.24 (m, 2H), 3.17 (dd, 1H, J ) 17.16, 10.53 Hz),
2.85 (dd, 1H, J ) 17.16, 7.26 Hz), 2.02 (s, 3H), 1.88 (m, 1H),
1.78 (dd, 1H, J ) 7.79, 5.07 Hz), 1.53 (dd, 1H, J ) 9.55, 5.07
mL × 2), drying over anhydrous MgSO
4
, and silica gel column
chromatography (1:1 ethyl acetate/hexane) gave 9 (0.12 g, 0.77
mmol, 18%) and 13 (0.25 g, 1.61 mmol, 39%) as liquids.
6
Hz), 1.23 (t, 3H, J ) 7.1 Hz); 13C NMR (300 MHz, CDCl
) δ
171.0, 156.3, 156.0, 139.2, 128.8, 122.8, 119.5, 77.9, 62.1, 43.9,
38.3, 36.2, 21.4, 14.2, 13.3. Anal. Calcd for C17 : C,
3
1
3: FTIR (neat) 3381, 3322, 2983, 1720 cm-1; 1H NMR (300
MHz, CDCl
3
) δ 5.69 (ddd, 1H, J ) 17.41, 10.29, 10.25 Hz), 5.21
21 3 4
H N O
(
4
4
dd, 1H, J ) 17.41, 1.8 Hz), 5.03 (dd, 1H, J ) 10.29, 1.8 Hz),
61.61; H, 6.38; N, 12.68. Found: C, 61.46; H, 6.41; N, 12.57.
Eth yl (1R*,2S*,1′R*)-2-(4′-p h en yl-2′,3′-oxa zolin yl)-1-((N-
ph en ylcar bam oyl)am in o)cyclopr opan e car boxylate (15c)
a n d Eth yl (1R*,2S*,1′S*)-2-(4′-P h en yl-2′,3′-oxa zolin yl)-1-
((N-p h en ylca r ba m oyl)a m in o)cyclop r op a n eca r boxyla te
(16c) fr om 14. Following the same procedure described for
15a and 16a , R-nitrotoluene (74 mg, 0.54 mmol) gave 15c (73
mg, 0.18 mmol, 33%) and 16c (109 mg, 0.28 mmol, 51%) as
solids.
.17 (m, 2H), 2.08 (s, 2H), 2.01 (m, 1H), 1.55 (dd, 1H, J ) 7.44,
.70 Hz), 1.33 (dd, 1H, J ) 9.38, 4.70 Hz), 1.27 (t, 3H, 7.21
1
3
Hz); C NMR (300 MHz, CDCl
2.5, 35.7, 23.1, 14.4.
Eth yl (1R*,2S*)-1-((N-P h en ylca r ba m oyl)a m in o)-2-vi-
n ylcyclop r op a n e ca r boxyla te (14) fr om 13. Compound 13
0.2 g, 1.29 mmol) in CH Cl (20 mL) was treated with phenyl
3
) δ 173.8, 135.1, 116.3, 61.1,
4
(
2
2
isocyanate (0.153 g, 1.29 mmol) at ambient temperature for 1
h. Removal of the solvent under the reduced pressure,
followed by recrystallization (1:1 ethyl acetate/hexane) gave
15c: Mp 204 °C; FTIR (KBr) 3360, 3094, 2980, 1721, 1652
cm- ; H NMR (300 MHz, CDCl
) δ 7.69-7.04 (m, 10H), 6.94
1
1
3
1
4 (317 mg, 1.15 mmol, 90%) as a solid: Mp 150 °C; FTIR
(s, 1H), 5.72 (s, 1H), 5.00 (m, 1H), 4.16 (m, 2H), 3.80 (dd, 1H,
J ) 16.86, 6.83 Hz), 3.38 (dd, 1H, J ) 16.86, 10.51 Hz), 1.90
(m, 1H), 1.70 (dd, 1H, J ) 7.99, 5.34 Hz), 1.45 (dd, 1H, J )
-
1 1
(KBr) 3348, 3087, 2981, 1729, 1642 cm ; H NMR (300 MHz,
CDCl ) δ 7.04-7.36 (m, 5H), 6.83 (s, 1H), 5.76 (m, 1H), 5.62
3
1
3
(
s, 1H), 5.33 (d, 1H, J ) 17.16 Hz), 5.17 (d, 1H, J ) 11.61 Hz),
9.27, 5.34 Hz), 1.25 (t, 3H, J ) 7.13 Hz); C NMR (300 MHz,
CDCl ) δ 171.8, 157.6, 156.1, 138.1, 130.1, 129.6, 129.3, 128.7,
126.9, 124.2, 121.2, 80.6, 61.9, 40.0, 37.9, 35.5, 23.4, 14.3.
Anal. Calcd for C22 C, 67.16; H, 5.89; N, 10.68.
4
5
7
1
.18 (q, 2H, J ) 7.11 Hz), 2.21 (m, 1H), 1.91 (dd, 1H, J ) 7.91,
.31 Hz), 1.59 (dd, 1H, J ) 9.56, 5.31 Hz), 1.24 (t, 3H, J )
3
1
3
.11 Hz); C NMR (300 MHz, CDCl
3
) δ 171.4, 155.8, 138.3,
23 3 4
H N O :
33.4, 129.2, 123.8, 120.5, 118.4, 61.8, 40.9, 34.9, 23.4, 14.3.
Found: C, 66.99; H, 5.81; N, 10.54.
Eth yl (1R*,2S*,1′R*)-2-(4′-p r op yl-2′,3′-oxa zolin yl)-1-((N-
p h en ylca r ba m oyl)a m in o)cyclop r op a n eca r boxyla te (15a )
a n d Eth yl (1R*,2S*,1′S*)-2-(4′-P r op yl 2′,3′-oxa zolin yl)-1-
(N-p h en ylca r ba m oyl)a m in o)cyclop r op a n eca r boxyla te
16a ) fr om 14. Compound 14 (150 mg, 0.54 mmol) in DME
10 mL) was treated with 1-nitrobutane (56 mg, 0.54 mmol),
16c: Mp 199-200 °C; FTIR (KBr) 3373, 3059, 2984, 1719,
-
1 1
3
1660 cm ; H NMR (300 MHz, CDCl ) δ 7.66-7.01 (m, 11H),
5.40 (s, br, 1H), 4.95 (m, 1H), 4.36-4.15 (m, 2H), 3.60 (dd, 1H,
J ) 16.65, 10.53 Hz), 3.24 (dd, 1H, J ) 16.65, 7.08 Hz), 2.02
(m, 1H), 1.87 (dd, 1H, J ) 7.77, 5.1 Hz), 1.58 (dd, 1H, J )
(
(
(
1
3
9.51, 5.1 Hz), 1.26 (t, 3H, J ) 7.15 Hz); C NMR (300 MHz,
CDCl ) δ 171.2, 157.1, 155.8, 138.9, 130.4, 129.1, 128.9, 128.8,
126.8, 123.1, 119.8, 78.9, 62.4, 40.3, 38.4, 35.7, 21.8, 14.2.
phenyl isocyanate (130 mg, 1.09 mmol), and Et
3
N (0.01 mL)
3
at 70 °C overnight. Removal of the solvent at reduced

6
584 J . Org. Chem., Vol. 63, No. 19, 1998
1R*,3S*,1′S*)-5,7-Dia za -1-(4′-p r op yl-2′,3′-oxa zolin yl)-5-
Park et al.
(
1.55 (m, 2H); 13C NMR (300 MHz, CDCl
3
) δ 171.5, 156.4, 156.3,
132.0, 130.2, 129.7, 129.0, 128.8, 128.2, 126.8, 126.5, 77.2, 44.1,
p h en ylsp ir o[2,4]h ep ta n e-4,6-d ion e (17a ) fr om 15a . Com-
pound 15a (100 mg, 0.278 mmol) was treated with sodium (3.2
mg, 0.14 mmol) in EtOH (5 mL) for 4 h. Removal of the solvent
under the reduced pressure and silica gel column chromatog-
raphy (1:2 ethyl acetate/hexane) gave 17a (71 mg, 0.23 mmol,
40.1, 31.4, 17.4. Anal. Calcd for C20
4.93; N, 12.09. Found: C, 69.07; H, 5.03; N, 11.70.
1R*,3S*,1′R*)-5,7-Dia za -1-(4′-eth yl-2′,3′-oxa zolin yl)-5-
p-ch lor op h en yl)sp ir o[2,4]h ep ta n e-4,6-d ion e (18d ) fr om
17 3 3
H N O : C, 69.15; H,
(
(
8
2%) as a liquid: FTIR (neat) 3286, 2963, 1777, 1715 cm-1
;
Resin 24 (R ) Cl, R′ ) Eth yl). Using the same procedure
described for the preparation of 6a (DMF, 90 °C), resin 24 (R
Cl, R′ ) ethyl) gave 18d (18 mg, 0.054 mmol, 18% overall)
as a solid: Mp 215 °C; FTIR (KBr) 3317, 2976, 1783, 1713
1
H NMR (300 MHz, CDCl
.85 (m, 1H), 3.05 (dd, 1H, J ) 16.85, 10.23 Hz), 2.64 (dd, 1H,
J ) 16.85, 7.17 Hz), 2.32 (t, 2H, J ) 7.30 Hz), 1.93 (m, 1H),
3
) δ 7.51-7.37 (m, 5H), 7.23 (s, 1H),
4
)
1
7
1
1
.79-1.67(m, 2H), 1.58 (q, 2H, J ) 7.43 Hz), 0.96 (t, 3H, J )
-1
1
cm ; H NMR (300 MHz, CDCl
3
) δ 7.45-7.38 (m, 4H), 6.99
1
3
.43 Hz); C NMR (300 MHz, CDCl ) δ 171.7, 159.1, 156.1,
3
(
s, 1H), 4.93-4.85 (m, 1H), 3.15 (dd, 1H, J ) 16.92, 10.37 Hz),
31.5, 129.2, 128.5, 126.1, 77.5, 43.7, 42.5, 31.2, 29.7, 20.8, 19.7,
3.8.
2
1
3
1
1
.75 (dd, 1H, J ) 16.92, 6.66 Hz), 2.38 (q, 2H, J ) 7.53 Hz),
.95 (dd, 1H, J ) 18.22, 9.26 Hz), 1.61-1.53 (m, 2H), 1.18 (t,
(
1R*,3S*,1′R*)-5,7-Dia za -1-(4′-p r op yl-2′,3′-oxa zolin yl)-
13
H, J ) 7.53 Hz); C NMR (300 MHz, CDCl ) δ 171.2, 160.0,
3
5
-p h en ylsp ir o[2,4]h ep ta n e-4,6-d ion e (18a ) fr om 16a . Fol-
56.1, 134.0, 130.3, 129.3, 127.6, 75.9, 44.0, 42.0, 31.5, 21.4,
7.5, 10.9. Anal. Calcd for C16 : C, 57.57; H, 4.83;
lowing the same procedure described for making compound
7a , using compound 16a (100 mg, 0.278 mmol) gave 18a (74
mg, 0.236 mmol, 85%) as a solid: Mp 158 °C; FTIR (KBr) 3318,
H
3 3
16ClN O
1
N, 12.58. Found: C,57.63; H, 4.79; N, 12.47.
961, 1785, 1733 cm-1; H NMR (300 MHz, CDCl
.35 (m, 5H), 6.9 (s, br, 1H), 4.89 (m, 1H), 3.13 (m, 1H), 2.72
1
(1R*,3S*,1′R*)-5,7-Dia za -1-(4′-p r op yl-2′,3′-oxa zolin yl)-
-(p-ch lor op h en yl)sp ir o[2,4]h ep ta n e-4,6-d ion e (18e) fr om
Resin 24 (R ) Cl, R′ ) P r op yl). Using the same procedure
described for the preparation of 6a (DMF, 90 °C), resin 24 (R
Cl, R′ ) propyl) gave 18e (16 mg, 0.046 mmol, 15% overall)
as a solid: Mp 196 °C; FTIR (KBr) 3315, 2959, 1783, 1714
) δ 7.45-7.38 (m, 4H), 6.97
s, 1H), 4.93-4.84 (m, 1H), 3.13 (dd, 1H, J ) 16.93, 10.41 Hz),
.73 (dd, 1H, J ) 16.93, 6.69 Hz), 2.34 (t, 2H, J ) 7.72 Hz),
.93 (dd, 1H, J ) 18.19, 9.26 Hz), 1.67-1.55 (m, 4H), 0.97 (t,
) δ 171.2, 158.7,
56.1, 134.0, 130.1, 129.2, 127.6, 75.8, 43.9, 42.1, 31.5, 29.6,
9.8, 17.5, 13.8 Anal. Calcd for C17 : C, 58.70; H,
2
7
3
) δ 7.49-
5
(m, 1H), 2.34 (t, 2H, J ) 7.38 Hz), 1.93 (m, 1H), 1.64-1.56 (m,
H), 0.97 (t, 3H, J ) 7.40 Hz); 1 C NMR (300 MHz, CDCl
3
4
1
3
6
3
) δ
71.7, 158.7, 157.1, 131.7, 129.1, 128.3, 126.5, 75.9, 44.0, 42.2,
1.4, 29.7, 19.8, 17.4, 13.8. Anal. Calcd for C17 : C,
5.16; H, 6.11; N, 13.40. Found: C, 65.21; H, 6.11; N, 13.35.
7a a n d 18a (fr om Resin 24). Using the same procedure
described for the preparation of 6a (DMF, 90 °C), resin 24 (R
H, R′ ) propyl) gave 17a (5 mg, 0.017 mmol, 6% overall)
and 18a (15 mg, 0.047 mmol, 16% overall) as solids.
1R*,3S*,1′S*)-5,7-Dia za -1-(4′-m eth yl-2′,3′-oxa zolin yl)-
-p h en ylsp ir o[2,4]h ep ta n e-4,6-d ion e (17b) fr om 15b. Fol-
lowing the same procedure described for making compound
7a , using compound 15b (100 mg, 0.302 mmol) gave 17b (67
mg, 0.234 mmol, 78%) as a solid: Mp 116 °C; FTIR (KBr) 3335,
)
19 3 3
H N O
-
1
1
cm ; H NMR (300 MHz, CDCl
3
(
1
2
1
3
1
1
5
)
H, J ) 7.39 Hz); 13C NMR (300 MHz, CDCl
3
(
H
3 3
18ClN O
5
.21; N, 12.08. Found: C, 58.94; H, 5.25; N, 11.88.
1
(1R*,3S*,1′R*)-5,7-Dia za -1-(4′-p h en yl-2′,3′-oxa zolin yl)-
5-(p-ch lor op h en yl)sp ir o[2,4]h ep ta n e-4,6-d ion e (18f) fr om
Resin 24 (R ) Cl, R′ ) P h en yl). Using the same procedure
described for the preparation of 6a (DMF, 90 °C), resin 24 (R
) Cl, R′ ) phenyl) gave 18f (21 mg, 0.055 mmol, 19% overall)
as a solid: Mp 260 °C (dec); FTIR (KBr) 3353, 3109, 1784, 1715
924, 2886, 1771, 1708 cm-1; H NMR (300 MHz, CDCl
.51-7.37 (m, 5H), 6.63 (s, 1H), 4.88 (m, 1H), 3.07 (dd, 1H, J
16.98, 10.32 Hz), 2.68 (dd, 1H, J ) 16.98, 7.06 Hz), 2.00 (s,
H), 1.93 (m, 1H), 1.83 (dd, 1H, J ) 7.78, 6.11 Hz), 1.72 (dd,
) δ 171.5,
1
) δ
2
7
)
3
1
1
2
3
H, J ) 9.52, 6.11 Hz); 13C NMR (300 MHz, CDCl
55.9, 155.4, 131.5, 129.2, 128.5, 126.1, 77.7, 44.1, 43.7, 31.4,
0.8, 13.3.
-1
1
3
cm ; H NMR (300 MHz, CDCl ) δ 7.68-7.65 (m, 2H), 7.43-
3
7.39 (m, 5H), 6.83 (s, 1H), 5.15-5.06 (m, 1H), 3.56 (dd, 1H, J
) 16.62, 10.51 Hz), 3.19 (dd, 1H, J ) 16.62, 6.48 Hz), 2.02 (m,
1H), 1.67-1.57 (m, 2H); 13C NMR (300 MHz, CDCl
) δ 171.2,
156.3, 156.1, 134.0, 130.3, 130.1, 129.3, 128.8, 127.6, 126.7,
76.6, 44.0, 40.0, 31.5, 17.6. Anal. Calcd for C20 : C,
(
1R*,3S*,1′R*)-5,7-Dia za -1-(4′-m eth yl-2′,3′-oxa zolin yl)-
3
5
-p h en ylsp ir o[2,4]h ep ta n e-4,6-d ion e (18b) fr om 16b. Fol-
lowing the same procedure described for making compound
7a , using compound 16b (100 mg, 0.302 mmol) gave 18b (64
mg, 0.224 mmol, 75%) as a solid: Mp 184 °C; FTIR (KBr) 3360,
3 3
H16ClN O
1
62.91; H, 4.22 N, 11.00. Found: C,63.01; H, 4.29; N, 10.89.
Eth yl (1R*,2S*)-1-((ter t-Bu toxyca r bon yl)a m in o)-2-vi-
n ylcyclop r op a n e-1-ca r boxyla te (19) fr om 13. Following
the procedure described for making compound 10, using
compound 13 (4 g, 25.8 mmol) gave 19 (5.8 g, 22.7 mmol, 88%)
078, 2917, 1781, 1710 cm-1; H NMR (300 MHz, CDCl
1
) δ
3
7
)
3
3
.50-7.35 (m, 5H), 6.86 (s, 1H), 4.93 (m, 1H), 3.14 (dd, 1H, J
17.07, 9.61 Hz), 2.75 (dd, 1H, J ) 17.07, 6.77 Hz), 2.01 (s,
H), 1.94 (dd, 1H, J ) 18.23, 9.33 Hz), 1.61-1.56 (m, 2H); 13
C
-1 1
as a liquid: FTIR (neat) 3360, 3085, 2980, 1726 cm ; H NMR
300 MHz, CDCl ) δ 5.82-5.70 (m, 1H), 5.27 (dd, 1H, J ) 17.09,
.32 Hz), 5.10 (dd, 1H, J ) 10.3, 1.63 Hz), 4.18 (m, 2H), 2.13
m, 1H), 1.80 (m, 1H), 1.44 (s, 9H), 1.43 (m, 1H), 1.25 (t, 3H,
NMR (300 MHz, CDCl
1
3
) δ 171.5, 156.2, 155.1, 131.5, 129.1,
(
3
28.3, 126.5, 76.1, 43.9, 43.8, 31.4, 17.4, 13.3. Anal. Calcd
1
for C15
H, 5.32; N, 14.66.
1R*,3S*,1′S*)-5,7-Dia za -1-(4′-p h en yl-2′,3′-oxa zolin yl)-
-p h en ylsp ir o[2,4]h ep ta n e-4,6-d ion e (17c) fr om 15c. Fol-
lowing the same procedure described for making compound
7a , using compound 15c (100 mg, 0.254 mmol) gave 17c (71
mg, 0.204 mmol, 81%) as a solid: Mp 169 °C; FTIR (KBr) 3284,
15 3 3
H N O : C, 63.14; H, 5.29; N, 14.72. Found: C, 63.30;
(
13
J ) 7.08); C NMR (300 MHz, CDCl
17.6, 80.1, 61.3, 40.9, 34.2, 28.3, 23.3, 14.3.
1R*,2S*)-1-((ter t-Bu t oxyca r b on yl)a m in o)-2-vin ylcy-
3
) δ 170.9, 155.9, 133.8,
(
1
5
(
clop r op a n e-1-ca r boxylic Acid (20) fr om 19. Following the
procedure described for making compound 11, using compound
9 (3.5 g, 13.72 mmol) gave compound 20 (2.8 g, 12.33 mmol,
0%) as a solid: Mp 159 °C; FTIR (KBr) 3263, 2986, 1702,
653 cm ; H NMR (300 MHz, CDCl ) δ 9.6 (s, br, 1H), 5.78
m, 1H), 5.30 (d, 1H, J ) 16.71 Hz), 5.31 (dd, 1H, J ) 10.27,
1
1
9
1
064, 1777, 1700 cm-1; H NMR (300 MHz, CDCl
1
) δ 7.66-
3
7
1
1
6
1
4
3
.36 (m, 10H), 6.85 (s, 1H), 5.07 (m, 1H), 3.47 (dd, 1H, J )
6.54, 10.47 Hz), 3.07 (dd, 1H, J ) 16.54, 6.85 Hz), 2.01 (m,
H), 1.87 (dd, 1H, J ) 7.78, 6.19 Hz), 1.74 (dd, 1H, J ) 9.49,
-
1 1
3
(
1
1
1
.4 Hz), 2.19 (dd, 1H, J ) 17.58, 8.91 Hz), 1.81 (s, br, 1H),
.53 (s, br, 1H), 1.45 (s, 9H); 13C NMR (300 MHz, CDCl
) δ
76.5, 156.1, 133.5, 118.1, 81.6, 40.7, 35.1, 28.3, 23.5. Anal.
: C, 58.13; H, 7.54; N, 6.16. Found: C,
8.26; H, 7.64; N, 6.05.
Resin 21. Following the same procedure described for
making resin 2, 20 gave resin 21 (2.54 g): FTIR (KBr) 1725
1
3
.17 Hz); C NMR (300 MHz, CDCl ) δ 171.5, 156.6, 156.1,
3
3
38.9, 131.4, 130.4, 129.2, 128.8, 128.5, 126.7, 126.1, 78.6, 43.8,
0.4, 31.3, 20.8.
Calcd for C11H17NO
4
5
(
1R*,3S*,1′R*)-5,7-Dia za -1-(4′-p h en yl-2′,3′-oxa zolin yl)-
5
-p h en ylsp ir o[2,4]h ep ta n e-4,6-d ion e (18c) fr om 16c. Fol-
lowing the same procedure described for making compound
7a , using compound 16c (100 mg, 0.254 mmol) gave 18c (66
mg, 0.19 mmol, 75%) as a solid: Mp 235 °C (dec); FTIR (KBr)
1
-
1
cm
.
339, 3062, 1785, 1710 cm-1; H NMR (300 MHz, CDCl
1
) δ
Resin 22. Following the same procedure described for
making resin 3, 21 gave resin 22 (2.44 g): FTIR (KBr) 3473,
3
7
1
3
.68-7.28 (m, 11H), 5.08 (m, 1H), 3.48 (dd, 1H, J ) 15.32,
0.63 Hz), 3.13 (dd, 1H, J ) 15.32, 6.84), 2.00 (m, 1H), 1.65-
-
1
3385, 1719 cm
.

Hydantoin- and Isoxazoline-Containing Heterocycles
J . Org. Chem., Vol. 63, No. 19, 1998 6585
Resin 23 (R ) H). Following the same procedure described
for making resin 4, 22 gave resin 23 (300 mg): FTIR (KBr)
Resin 24 (R ) Cl, R′ ) P h en yl). Following the same
procedure described for making resin 5 (R ) Cl, R′ ) Me), 23
-
1
-1
1
727, 1658 cm
Resin 23 (R ) Cl). Following the same procedure described
for making resin 4, 22 gave resin 23 (310 mg): FTIR (KBr)
.
gave resin 24 (308 mg): FTIR (KBr) 1728 cm .
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 FTIR spectra for compounds 10, 13, 14, 15a , 16c, 17a -c,
and 19, tables of X-ray data, and ORTEP diagrams (38 pages).
This material is contained in libraries on microfiche, im-
mediately 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.
-
1
1
717, 1654 cm
Resin 24 (R ) H, R′ ) P r op yl). Following the same
procedure described for making resin 5 (R ) Cl, R′ ) Me), 23
.
-
1
gave resin 24 (305 mg): FTIR (KBr) 1727, 1699 cm
.
Resin 24 (R ) Cl, R′ ) Eth yl). Following the same
procedure described for making resin 5 (R ) Cl, R′ ) Me), 23
-
1
gave resin 24 (302 mg): FTIR (KBr) 1725 cm
.
Resin 24 (R ) Cl, R′ ) P r op yl). Following the same
procedure described for making resin 5 (R ) Cl, R′ ) Me), 23
-
1
gave resin 24 (310 mg): FTIR (KBr) 1726, 1698 cm
.
J O9807161