Diastereofacial selectivity in the cycloaddition of nitrones to (E)-γ-oxygenated α,β-unsaturated esters

Article abstract of DOI:10.1021/jo960960x

The 1,3-dipolar cycloadditions of nitrones 1 and 2 to a series of 1,2-disubstituted electron-deficient olefins bearing an allylic stereocenter, 4-8, are reported. The syn/anti stereochemistry of the major endo adducts may be rationalized through the Houk transition-state model, but the possibility of intramolecular hydrogen bonding must be taken into account. In the case of the minor exo adducts the syn stereochemistry always predominates.

Full text of DOI:10.1021/jo960960x

8578
J . Org. Chem. 1996, 61, 8578-8585
Dia ster eofa cia l Selectivity in th e Cycloa d d ition of Nitr on es to
(E)-γ-Oxygen a ted r,â-Un sa tu r a ted Ester s
Fe´lix Busque´,† Pedro de March,*,† Marta Figueredo,† J osep Font,*,† Montserrat Monsalvatje,†
Albert Virgili,† AÄ ngel AÄ lvarez-Larena,‡ and J uan F. Piniella‡
Departament de Quı´mica, Universitat Auto`noma de Barcelona, 08193 Bellaterra (Barcelona), Spain, and
Unitat de Cristal.lografia, Universitat Auto`noma de Barcelona, 08193 Bellaterra (Barcelona), Spain
Received May 24, 1996X
The 1,3-dipolar cycloadditions of nitrones 1 and 2 to a series of 1,2-disubstituted electron-deficient
olefins bearing an allylic stereocenter, 4-8, are reported. The syn/anti stereochemistry of the major
endo adducts may be rationalized through the Houk transition-state model, but the possibility of
intramolecular hydrogen bonding must be taken into account. In the case of the minor exo adducts
the syn stereochemistry always predominates.
Ch a r t 1
In tr od u ction
The synthesis of 4,5-dihydroisoxazoles (∆2-isoxazolines)
and tetrahydroisoxazoles (isoxazolidines) through intra-
and intermolecular 1,3-dipolar cycloadditions of alkenes
to nitrile oxides and nitrones, respectively, has been the
subject of much research during recent years.1 When
using olefins with a chiral center at the allylic position
as the dipolarophile component of the cycloaddition
process, one can achieve control of the relative stereo-
chemistry of the new stereogenic centers of the hetero-
cycle in relation to the original allylic atom. To ratio-
nalize the stereochemical outcome of nitrile oxide
cycloadditions to allylic ethers and alcohols, Houk et al.2
developed a transition-state model that was later ex-
tended to nitrone cycloadditions. According to this model,
the inside alkoxy and the outside alcohol effects are
responsible for the predominance of anti and syn stereo-
chemistries of the cycloadducts starting with allylic
ethers and alcohols, respectively: with the OH group in
the outside position the hydrogen bonding with the
oxygen atom of the dipole is maximized. A large number
of reported studies describe intermolecular reactions
between chiral terminal olefins bearing an electronega-
tive atom (O, N, S) at the allylic position and nitrile
oxides1c,2a,c,3 or nitrones,1c,4 but most published work
related to reactions between these dipoles and 1,2-
disubstituted olefins with an allylic stereocenter describes
intramolecular cycloadditions.2c,d,5 Published examples
dealing with intermolecular cycloaddition reactions be-
tween such olefins and nitrile oxides6-8 or nitrones6,9,10
are scarce and appeared only very recently.
The influence of allylic substituents in determining the
facial selectivity in 1,3-dipolar cycloadditions has also
been studied recently for other dipoles such as azome-
thine ylides6,11 and diazo compounds.12
(4) (a) Ito, M.; Kibayashi, C. Tetrahedron Lett. 1990, 31, 5065. (b)
Ito, M.; Kibayashi, C. Tetrahedron 1991, 47, 9329. (c) Krol, W. J .; Mao,
S.; Steele, D. L.; Townsend, C. A. J . Org. Chem. 1991, 56, 728. (d)
Annunziata, R.; Cinquini, M.; Cozzi, F.; Giaroni, P.; Raimondi, L.
Tetrahedron Lett. 1991, 32, 1659. (e) Ito, M.; Maeda, M.; Kibayashi,
C. Tetrahedron Lett. 1992, 33, 3765. (f) Shimazaki, M.; Okazaki, F.;
Nakajima, F.; Ishikawa, T.; Ohta, A. Heterocycles 1993, 36, 1823. (g)
Ina, H.; Ito, M.; Kibayashi, C. J . Org. Chem. 1996, 61, 1023.
(5) (a) Annunziata, R.; Cinquini, M.; Cozzi, F.; Gennari, C.; Rai-
mondi, L. J . Org. Chem. 1987, 52, 4674. (b) Annunziata, R.; Cinquini,
M.; Cozzi, F.; Raimondi, L. Tetrahedron 1987, 43, 4051. (c) Annun-
ziata, R.; Cinquini, M.; Cozzi, F.; Raimondi, L. J . Org. Chem. 1990,
55, 1901. (d) Collins, I.; Nadin, A.; Holmes, A. B.; Long, M. E.; Man,
J .; Baker, R. J . Chem. Soc., Perkin Trans. 1 1994, 2205.
(6) Annunziata, R.; Benaglia, M.; Cinquini, M.; Raimondi, L.
Tetrahedron 1993, 49, 8629.
† Departament de Qu´ımica.
‡ Unitat de Cristal.lografia.
X Abstract published in Advance ACS Abstracts, November 1, 1996.
(1) (a) Tufariello, J . J . 1,3-Dipolar Cycloaddition Chemistry; J ohn
Wiley and Sons, Inc.: New York, 1984. (b) Torssell, K. B. G. Nitrile
Oxides, Nitrones, and Nitronates in Organic Synthesis; VCH Verlags-
gesellschaft: Weinheim, 1988. (c) Annunziata, R.; Cinquini, M.; Cozzi,
F.; Raimondi, L. Gazz. Chim. Ital. 1989, 119, 253 and references cited
therein.
(2) (a) Houk, K. N.; Moses, S. R.; Wu, Y.-D.; Rondan, N. G.; J a¨ger,
V.; Schohe, R.; Fronczek, F. R. J . Am. Chem. Soc. 1984, 106, 3880. (b)
Houk, K. N.; Duh, H.-Y.; Wu, Y.-D.; Moses, S. R. J . Am. Chem. Soc.
1986, 108, 2754. (c) Brown, F. K.; Raimondi, L.; Wu, Y.-D.; Houk, K.
N. Tetrahedron Lett. 1992, 33, 4405. (d) Raimondi, L.; Wu, Y.-D.;
Brown, F. K.; Houk, K. N. Tetrahedron Lett. 1992, 33, 4409.
(3) (a) J a¨ger, V.; Schohe, R. Tetrahedron 1984, 40, 2199. (b) Curran,
D. P.; Gothe, S. A. Tetrahedron 1988, 44, 3945. (c) De Amici, M.; De
Micheli, C.; Misani, V. Tetrahedron 1990, 46, 1975. (d) Kanemasa,
S.; Kobayashi, S.; Nishiuchi, M.; Yamamoto, H.; Wada, E. Tetrahedron
Lett. 1991, 32, 6367. (e) Kanemasa, S.; Kobayashi, S. Bull. Chem. Soc.
J pn. 1993, 66, 2685. (f) Annunziata, R.; Benaglia, M.; Cinquini, M.;
Cozzi, F.; Raimondi, L. J . Org. Chem. 1995, 60, 4697. (g) Gravestock,
M. B.; Paton, R. M.; Todd, C. J . Tetrahedron: Asymmetry 1995, 6, 2723.
(h) Schwab, W.; Anagnostopulos, H.; Ryder, B. R.; Schleyerbach, R.;
Weithmann, K. U. Ger. Offen. DE 4,408,084; Chem. Abstr. 1996, 124,
86996t.
(7) Mancera, M.; Roffe´, I.; Galbis, J . A. Tetrahedron 1995, 51, 6349.
(8) de Blas, J .; Carretero, J . C.; Dom´ınguez, E. Tetrahedron: Asym-
metry 1995, 6, 1035.
(9) (a) Kanemasa, S.; Tsuruoka, T.; Yamamoto, H. Tetrahedron Lett.
1995, 36, 5019. (b) Baskaran, S.; Trivedi, G. K. J . Chem. Res., Synop.
1995, 308.
(10) de March, P.; Figueredo, M.; Font, J .; Monsalvatje, M. Recl.
Trav. Chim. Pays-Bas 1995, 114, 357.
(11) (a) Wee, A. G. H. J . Chem. Soc., Perkin Trans. 1 1989, 1363.
(b) Kanemasa, S.; Yamamoto, H.; Wada, E.; Sakurai, T.; Urushido, K.
Bull. Chem. Soc. J pn. 1990, 63, 2857. (c) Annunziata, R.; Cinquini,
M.; Cozzi, F.; Raimondi, L.; Pilati, T. Tetrahedron: Asymmetry 1991,
2, 1329. (d) Pa¨tzel, M.; Galley, G.; J ones, P. G.; Chrapkowsky, A.
Tetrahedron 1993, 34, 5707. (e) Galley, G.; Liebscher, J .; Pa¨tzel, M.
J . Org. Chem. 1995, 60, 5005.
S0022-3263(96)00960-7 CCC: $12.00 © 1996 American Chemical Society

Cycloaddition of Nitrones to R,â-Unsaturated Esters
J . Org. Chem., Vol. 61, No. 24, 1996 8579
Ta ble 1. Isola ted Yield s in th e Cycloa d d ition s of Nitr on es 1 a n d 2 to Olefin s 3-824
entry
nitrone
olefin
endo-anti (%)
endo-syn (%)
exo-anti (%)
exo-syn (%)
110
2
1
1
1
1
1
2
2
2
2
2
2
3
5
6
7
8
3
4
5
6
7
8
9a (60)
10a (59)
11a (70)
12a (34)
13a (28)
14a (52)
15a (44)
16a (48)
17a (50)
18a (35)
19a (33)
9b (22)
10b (18)
11b (14)
12b (49)
13b (57)
14b (22)
15b (23)
16b (20)
17b (26)
18b (42)
19b (37)
traces
traces
traces
traces
traces
310
4
5
610
7
14c (4)
15c (traces)
16c (8)
17c (5)
18c (4)
14d (14)
15d (10)
16d (12)
17d (12)
18d (13)
19d (19)
8
9
10
11
19c (5)
We have recently described10 the reactions of nitrones
1 and 2 (Chart 1) with methyl (E)-6-(benzyloxy)-4-
hydroxy-2-hexenoate (3) that were found to be anti
stereoselective, contrary to the prediction of Houk’s
model. To explain this unexpected result we considered
two hypotheses: the formation of an intramolecular
hydrogen bond masks the hydroxyl group in 3, and
consequently, this olefin behaves like an ether, or the
presence of a benzyl moiety in 3 gives rise to π stacking
interactions13 in the transition state controlling the steric
course of the reaction. To seek some insight into the
problem, we decided to carry out the cycloadditions of
nitrones 1 and 2 to several (E)-γ-oxygenated R,â-unsatur-
ated esters 4-8, which were chosen to evaluate the
factors influencing the steric course of the reaction. We
report herein the results of the stereochemical outcome
of these cycloaddition reactions. As shown, Houk’s
transition-state model can now be extended to the forma-
tion of adducts derived from 1,2-disubstituted olefins
through both endo and exo transition states. The decisive
influence of intramolecular hydrogen bonding in the
olefin in the steric course of the cycloaddition is also
demonstrated.
this compound through a different procedure that in-
volves reduction of the known methyl (E)-4-oxo-2-pen-
tenoate.22
The results of the cycloadditions of nitrones 1 and 2 to
olefins 3-8 are summarized in Table 1. All the cycload-
ditions were regioselective, affording cycloadducts with
the ester group attached to the 4-position of the isoxazo-
lidine (Chart 2).1,16,23 The NMR data for all the adducts
are consistent with the expected regiochemistry, since the
â-carbonylic proton H-2 resonates in all the cycloadducts
9-19 at lower fields than the R-carbonylic proton H-3.
In all the reactions of nitrone 1 we isolated only two
cycloadducts in overall yields of about 85%. Both adducts
are derived from endo transition states, although traces
1
of exo compounds were detected by H NMR analysis of
some chromatographic fractions. The cis relationship
between H-3 and H-3a for adducts 9-13 can be deduced
from the large values of J 3,3a that move in the narrow
range 7.5-8.2 Hz. The analysis of molecular models
shows that these protons are almost eclipsed in the endo
adducts but practically orthogonal in the exo derivatives.
This assignment is reinforced by NOE experiments on
compounds 9a and 11a 10 and by chemical correlation for
adduct 13a (vide infra).
Resu lts a n d Discu ssion
For the purpose of this work we decided to utilize cyclic
nitrones 114 and 2,15 which we had already used as dipoles
in front of several (Z)-R,â-unsaturated lactones.16 With
these nitrones, which are incapable of E/Z isomerization,
one can directly relate the stereochemistry of the prod-
ucts to the endo/exo selectivity of the cycloaddition
process, provided that the reaction is conducted under
conditions of kinetic control.
Olefin 4 was selected as one of the dipolarophiles to
preclude the potential π stacking effect of the aromatic
ring in alkene 3. Oxidation of methyl 6-methoxy-2-
hexenoate17 with selenium dioxide afforded the new
compound 4 in 57% yield along with the corresponding
γ-oxo derivative. To avoid the formation of intramolecu-
lar hydrogen bonding and as an ether analogue of 3, we
selected the mesylate 5.18 Olefins 619 and 711a,20 were also
included in this study because the subunit 3-butene-1,2-
diol and the corresponding ketal have been extensively
incorporated in dipolarophile structures.3a,c,4d,5b,c,6,11a Fi-
nally, methyl 4-hydroxy-2-pentenoate (8) was chosen
because it is an allylic alcohol unable to form an intramo-
lecular hydrogen bond. Although several methods have
been described in the literature for the synthesis of 821
in both racemic and enantiopure form, we have prepared
(12) (a) Galley, G.; Pa¨tzel, M.; J ones, P. G. Tetrahedron 1995, 51,
1631. (b) Baskaran, S.; Vasu, J .; Prasad, R.; Kodukulla, K.; Trivedi,
G. K. Tetrahedron 1996, 52, 4515.
(13) J ones, G. B.; Chapman, B. Synthesis 1995, 475.
(14) Murahashi, S. I.; Shiota, T. Tetrahedron Lett. 1987, 28, 2383.
(15) (a) Thesing, J .; Sirrenberg, W. Chem. Ber. 1959, 92, 1748. (b)
Sabel, W. Chem. Ind. (London) 1966, 1216. (c) Ali, Sk. A.; Wazeer, M.
I. M. J . Chem. Soc., Perkin Trans. 1 1988, 597.
(16) (a) Cid, P.; de March, P.; Figueredo, M.; Font, J .; Mila´n, S.;
Soria, A.; Virgili, A. Tetrahedron 1993, 49, 3857. (b) Alonso-Perarnau,
D.; de March, P.; Figueredo, M.; Font, J .; Soria, A. Tetrahedron 1993,
49, 4267. (c) Busque´, F.; Cid, P.; de March, P.; Figueredo, M.; Font, J .
Heterocycles 1995, 40, 387.
(17) Although this product was already known (Brown, R. T.;
Blackstock, W. P.; Wingfield, M. Tetrahedron Lett. 1984, 25, 1831),
its preparation was not described.
(18) de March, P.; Figueredo, M.; Font, J .; Monsalvatje, M. Synth.
Commun. 1995, 25, 331.
(19) (a) Mann, J .; Partlett, N. K.; Thomas, A. J . Chem. Res., Synop.
1987, 369. (b) Takano, S.; Kurotaki, A.; Takahashi, M.; Ogasawara,
K. Synthesis 1986, 403.
(20) Font, J . An. Qu´ım. 1966, 62B, 477.
(21) (a) Stotter, P. L.; Eppner, J . B. Tetrahedron Lett. 1973, 2417.
(b) Yamagiva, S.; Sato, H.; Hoshi, N.; Kosugi, H.; Uda, H. J . Chem.
Soc., Perkin Trans.
1 1979, 570. (c) Bernardi, A.; Cardani, S.;
Scolastico, C.; Villa, R. Tetrahedron 1988, 44, 491. (d) Craig, D.;
Daniels, K. Tetrahedron Lett. 1990, 31, 6441. (e) Burgess, K.; Cassidy,
J .; Henderson, I. J . Org. Chem. 1991, 56, 2050.
(22) Schuda, P. F.; Ebner, C. B.; Potlock, S. J . Synthesis 1987, 1055.
(23) (a) Olsson, T.; Stern, K.; Westman, G. Tetrahedron 1990, 46,
2473. (b) Ali, Sk. A.; Wazeer, M. I. M.; Mazhar-Ul-Haque Tetrahedron
1990, 46, 7207.

8580 J . Org. Chem., Vol. 61, No. 24, 1996
Busque´ et al.
Ch a r t 2
Ch a r t 3
they all present J 3,3a values of about 10 Hz, while the
endo adducts show J 3,3a ca. 8.4 Hz.10 This assignment is
reinforced by 13C NMR data: in the trans invertomers
the absorptions of C-3, C-3a, and C-4 are upfield shifted
in the endo with respect to the corresponding exo isomers,
as a consequence of their position relative to the pseudo-
axial carbonyl group at C-3.16a
The syn/anti assignment of the major endo adducts
could be unambiguously established for all compounds
14-19. The determination of this relative stereochem-
istry in products 14a and 14b was done by independent
chemical correlation of each isomer with the previously
reported lactones 21a and 21b (Chart 3) derived from
exo-anti and exo-syn transition states, respectively.10,16a
The great concordance of the NMR data of 14a ,b with
those of 15a ,b allowed us to assign the stereochemistry
of this last pair. The stereochemistry of the mesylates
16a ,b could be assessed preparing them individually from
each alcohol 14a ,b and that of the series 19 through
analogy with 14 and 15. The syn/anti assignment of
compounds 17a ,b and 18a ,b was based on the above-
mentioned trend of several significant NMR data. More-
over, in an analytical experiment, ketalization of 18a
gave the isomer 17a .
The elucidation of the syn/anti stereochemistry of two
of the minor adducts, luckily coming from different
cycloaddition reactions, namely compounds 15d and 16d ,
could be assured, by X-ray diffraction analyses, as exo-
syn in both cases.25 Since all alcohols 14 were indepen-
dently transformed into the corresponding mesylates 16,
the relative stereochemistry of 14d was also secured as
exo-syn. The NMR data for the ketal pair 17c,d are
consistent enough with those of closely related com-
pounds previously reported3a,c,4d,5b,c,10 and do allow the
assignment of their syn/anti stereochemistry. At this
point, we have to consider a general trend observed in
the polarity of the compounds so far assigned: the anti-
isomer is always less polar than the syn-isomer, and this
rule applies to cycloadducts derived from nitrones 1 or 2
and from both endo or exo transition states. Therefore,
among the exo adducts obtained in the reactions between
2 and alcohols 7 and 8, those more polars, namely 18d
The assignment of the relative configuration at C-2/
C-1′ of 11a and 11b was based on literature data for
24
related ketal adducts.3a,c,4d,5b,c,10 In such compounds, it
has been observed that the chemical shift value for H-2
and H-1′ always increases on passing from anti, 11a , to
syn, 11b, while the value of J 2,1′ decreases in the same
sequence. For diols 12a and 12b the chemical shift value
for H-2 increases and for H-1′ decreases on passing from
anti, 12a , to syn, 12b.4d Since in this case the observed
differences are very small, we carried out an additional
experiment, namely the acid hydrolysis of acetonide 11a ,
which gave diol 12a , validating the previous assignments.
The stereochemistry of 13a was unequivocally estab-
lished as endo-anti by its conversion into the known
tricyclic compound 2016b (Chart 3). This transformation
was accomplished through epimerization of the R-carbo-
nylic proton of 13a by treatment with NaH in THF at rt.
For the other hydroxylic pair (9a ,b) an identical trend is
observed as for 13a ,b on the values of δ H-2, δ H-1′, J 2,1′
,
δ C-2 and δ C-1′ on passing from the first eluted to the
more polar adduct. Finally, each alcohol 9a and 9b was
converted separately into the corresponding mesylates
10a and 10b.
The reactions of nitrone 2 with olefins 3-8 afforded
four diastereoisomers in each case. The NMR spectra of
some of these adducts at room temperature show broad
absorptions due to the slow nitrogen inversion of the
perhydroisoxazolo[2,3-a]pyridine ring.16a Therefore, some
spectra were registered at lower temperatures and the
cis and trans invertomers could be observed separately.
In all the stereoisomers of 14-19 the trans invertomer
predominates (g85%).
For each cycloaddition, we assigned the exo stereo-
chemistry to the two less polar and minor adducts, since
(24) The numbering 1′, although unsystematic for cycloadducts
containing the dioxolane ring, refers to the general formulas in Table
1, and its use assists the discussion of the results. Systematic
numbering has been utilized in the Experimental Section.
(25) The authors have deposited atomic coordinates for 15d and 16d
with the Cambridge Crystallographic Data Centre. The coordinates
can be obtained, on request, from the Director, Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.

Cycloaddition of Nitrones to R,â-Unsaturated Esters
J . Org. Chem., Vol. 61, No. 24, 1996 8581
Sch em e 1
and 19d , should be exo-syn. This stereochemical assign-
ment is reinforced considering the geometry of the
transition state (vide infra).
All the cycloadditions were run under conditions of
kinetic control, since no reequilibration was ever observed
when the isolated products were subjected to the reaction
conditions. Therefore, it is obvious that the endo transi-
tion states are favoured over the exo in all cases. This
observation is in agreement with previously reported
results on cycloadditions of nitrones to (E)-R,â-unsatur-
ated esters.10,15c,23 Now, concerning the major endo
cycloadducts, the important facts in relation to the syn/
anti selectivity are the following:
(i) For the non hydroxylic olefins 5 and 6 (Table 1,
entries 2, 3, 8, and 9) the anti approach clearly predomi-
nates, in agreement with the inside alkoxy theory (Scheme
1).
(ii) For alcohol 8 (Table 1, entries 5 and 11) a prefer-
ence for the syn approach is observed, also according with
the outside alcohol model.
(iii) On the contrary, in the cycloadditions to the allylic
alcohols 3 and 4 (Table 1, entries 1, 6, and 7) the anti
isomers again clearly predominate. We therefore con-
clude that the aromatic ring is not the cause for the
unexpected selectivity. The hypothesis that the forma-
tion of an intramolecular hydrogen bond between the
alkoxy group and the allylic alcohol in the dipolarophile
competes advantageously with the intermolecular hy-
drogen bond with the oxygen atom of the dipole seems
more plausible. Consequently, alcohols 3 and 4 would
in practice behave as ethers in the cycloaddition process.
(iv) On the other hand, the typical alcohol selectivity
shown by diol 7 (Table 1, entries 4 and 10) can be
attributed to the fact that this olefin is able simulta-
neously to form intra- and intermolecular hydrogen bonds
in the transition state.
These results indicate that the Houk transition-state
model can be extended to endo adducts of 1,2-disubsti-
tuted electron-poor substrates, but the possibility of
intramolecular hydrogen bonding must be taken into
account. Considering this, we can now explain some
results previously reported by others. For instance,
Kanemasa et al.3e found the cycloaddition of nitrile oxide
to methyl 2-(1-hydroxyalkyl)propenoates to be anti selec-
tive and, although the authors indicate this result is
opposite to the one expected, they did not give any
explanation. Also, in the recent work by Annunziata et
al.,3f dealing with analogous cycloadditions, identical
selectivity was obtained using ether derivatives or alco-
hols, but no comments were made about this result or
about hydrogen bonds. All those allylic alcohols are
substrates capable of forming an intramolecular hydro-
gen bond which would explain their behaviour as ether
derivatives.
not be neglected. Adducts derived from an exo transition
state present always syn selectivity.
Exp er im en ta l Section
Gen er a l P r oced u r es. See ref 16. CH2Cl2 free of ethanol
and stabilized with amylene was used in the mesylation
reactions. GC analyses were performed with a capillary
column (crosslinked methyl silicone gum, 12 m × 0.2 mm ×
0.3 µm), Tinj ) 180 °C, T ) 120 °C. NMR spectra were recorded
by Servei de Ressona`ncia Magne`tica Nuclear de la Universitat
Auto`noma de Barcelona. Acetone-d6 was used as solvent for
NMR experiments unless otherwise stated. The following
starting compounds were prepared according to previously
described methods: 1,14 2,15 3,18 (R)-3,18 5,18, 6,19 7.11a,20 The
reactions between nitrone 1 and olefins 3 and 6, and between
nitrone 2 and alkene 3 have been already published.10
Meth yl (E)-6-Meth oxy-2-h exen oa te. 4-Methoxybutanol
(8.02 g, 76.9 mmol) was oxidized with PCC following literature
data.26 To the concentrated solution (200 mL) containing the
crude 4-methoxybutanal (without distillation) (methoxycar-
bonyl)methylenetriphenylphosphorane (20.58 g, 61.5 mmol)
was added in small portions. After 2 h at rt the solvent was
removed and the solid residue was washed several times with
a hot mixture of ether-hexane (1:1). The solvent of the
combined extracts was removed and the crude material (7.10
g) was purified by flash chromatography using ether-hexane
(3:1) as eluent to yield pure methyl 6-methoxy-2-hexenoate as
a colorless liquid (4.80 g, 30.4 mmol, 39% overall yield): 1H
NMR (250 MHz, CDCl3) δ 6.94 (dt, J ) 15.7, 6.9 Hz, 1 H),
5.80 (dt, J ) 15.7, 1.8 Hz, 1 H), 3.69 (s, 3H), 3.35 (t, J ) 6.4
Hz, 2 H), 3.28 (s, 3 H), 2.25 (q, J ) 8.0 Hz, 2 H), 1.69
(quintuplet, J ) 6.6 Hz, 2 H); 13C NMR (62.5 MHz, CDCl3) δ
166.4, 148.3, 120.8, 71.1, 58.0, 50.8, 28.3, 27.6.
For the minor exo adducts we observed that the syn
isomers predominate over the anti in all the cases
studied. This fact is in agreement with a model in which
the most favorable transition state should have the bulky
alkyl chain in anti position and the smallest group
(proton) occupying the most steric demanding inside
position, which lies directly above or below the nitrone
skeleton (Scheme 1).
In conclusion, our studies indicate that the Houk
transition-state model may be extended to adducts
derived from an endo transition state when using 1,2-
disubstituted electron-poor olefins, but for allylic alcohols,
the possibility of intramolecular hydrogen bonding can
Meth yl (E)-4-Hyd r oxy-6-m eth oxy-2-h exen oa te (4). Se-
lenium dioxide (1.37 g, 12.3 mmol) was added to a solution of
methyl (E)-6-methoxy-2-hexenoate (1.50 g, 9.5 mmol) in diox-
ane (150 mL), and the mixture was kept at reflux for 6 h. The
cold solution was filtered, and the solvent was removed to
afford 1.82 g of a yellow oil. Flash chromatography of this
crude material afforded the following fractions: (i) 210 mg (1.3
mmol) of starting product using hexane-ethyl acetate (3:1) as
eluent; (ii) 480 mg (2.8 mmol, 34% yield) of methyl (E)-6-
methoxy-4-oxo-2-hexenoate as a pale yellow solid using the
same eluent; and (iii) 810 mg (4.7 mmol, 57% yield) of methyl
(26) Stetter, H.; Leinen, H. T. Chem. Ber. 1983, 116, 254.

8582 J . Org. Chem., Vol. 61, No. 24, 1996
Busque´ et al.
(E)-4-hydroxy-6-methoxy-2-hexenoate (4) as a pale yellow oil
using hexane-ethyl acetate (1:1) as eluent. Methyl 6-meth-
oxy-4-oxo-2-hexenoate: mp 35-7 °C (ether/hexane); IR (KBr)
1.83-1.69 (m, 2 H), 1.55 (m, 1 H); 13C-NMR (62.5 MHz) δ
171.8, 78.9, 73.1, 68.3, 64.3, 56.8, 53.3, 52.1, 27.6, 24.7; MS
m/z 231 (7), 200 (11), 86 (100). Anal. Calcd for C10H17NO5:
C, 51.94; H, 7.41; N, 6.06. Found: C, 52.07; H, 7.39; N, 6.18.
Rea ction betw een Nitr on e 1 a n d Olefin 8. A solution
of nitrone 1 (1.69 g, 19.9 mmol) and methyl (E)-4-hydroxy-2-
pentenoate (8) (800 mg, 6.15 mmol) in CHCl3 (45 mL) was
heated at reflux for 40 h under argon. Flash chromatography
of the crude material (1.74 g) using ethyl acetate as eluent
yielded two fractions. The GC-MS analysis of the less polar
fraction (437 mg, 2.03 mmol, 33% yield), a colorless oil,
revealed the presence of three compounds: t1 ) 10.0 min (81%),
t2 ) 10.9 min (10%), t3 ) 11.2 min (4%). The major product
was methyl (2RS,3RS,3aSR)-2-[(1SR)-1-hydroxyethyl]hexahy-
dropyrrolo[1,2-b]isoxazole-3-carboxylate (13a ), and the minor
components were the exo-anti, 13c, and exo-syn, 13d , adducts.
The second fraction, a colorless oil, was identified as methyl
(2RS,3RS,3aSR)-2-[(1RS)-1-hydroxyethyl]hexahydropyrrolo-
[1,2-b]isoxazole-3-carboxylate (13b, 745 mg, 3.47 mmol, 57%
yield). 13a (81% stereochemical purity): IR (film) 3213, 1731
cm-1; 1H NMR (400 MHz) δ 4.15 (t, J ≈ 5.7 Hz, 1 H), 3.81 (m,
1 H), 3.80 (q, J ≈ 7.7 Hz, 1 H), 3.69 (dd, J ) 8.0, 6.0 Hz, 1 H),
3.68 (s, 3 H), 3.20 (ddd, J ) 13.0, 8.0, 4.4 Hz, 1 H), 2.95 (dt, J
) 13.0, 7.8 Hz, 1 H), 1.95 (m, 1 H), 1.80-1.63 (m, 2 H), 1.57
(m, 1 H), 1.07 (d, J ) 6.7 Hz, 3 H); 13C NMR (100 MHz) δ
170.8, 83.1, 69.1, 69.0, 56.3, 53.3, 52.1, 27.2, 24.5, 19.8; MS
m/z 215 (13), 85 (100). Anal. Calcd for C10H17NO4: C, 55.80;
H: 7.96; N, 6.51. Found: C, 55.74; H, 8.03; N, 6.44. 13b: IR
1
1731, 1699, 1636 cm-1; H NMR (250 MHz, CDCl3) δ 7.05 (d,
J ) 16.1 Hz, 1 H), 6.65 (d, J ) 16.1 Hz, 1 H), 3.77 (s, 3 H),
3.66 (t, J ) 6.2 Hz, 2 H), 3.29 (s, 3 H), 2.85 (t, J ) 6.2 Hz, 2
H); 13C NMR (62.5 MHz, CDCl3) δ 197.6, 165.6, 139.3, 130.4,
66.9, 58.6, 52.1, 41.2; MS m/z 141 (4), 113 (100). Anal. Calcd
for C8H12O4: C, 55.81; H, 7.03. Found: C, 55.85; H, 7.06. 4:
IR (KBr) 3444, 1727, 1660 cm-1; 1H NMR (250 MHz, CDCl3) δ
6.90 (dd, J ) 16.1, 4.4 Hz, 1 H), 6.07 (dd, J ) 16.1, 1.8 Hz, 1
H), 4.45 (m, 1 H), 3.69 (s, 3 H), 3.57 (ddd, J ) 9.5, 6.6, 4.4 Hz,
1 H), 3.54 (ddd, J ) 9.5, 6.6, 3.7 Hz, 1 H), 3.30 (s, 3 H), 1.86
(m, 1 H), 1.72 (m, 1 H); 13C NMR (62.5 MHz, CDCl3) δ 166.7,
150.0, 119.3, 69.8, 69.1, 58.4, 51.1, 35.2; MS m/z 175 (0.2), 143
(5), 115 (37), 45 (100). Anal. Calcd for C8H14O4: C, 55.16; H,
8.10. Found: C, 54.96; H, 8.14.
Meth yl (E)-4-Hyd r oxy-2-p en ten oa te (8). A magnetically
stirred solution of methyl (E)-4-oxo-2-pentenoate22 (2.67 g, 20.8
mmol) in anhydrous methanol (75 mL) under argon was cooled
to 0 °C. NaBH4 was slowly added and after 50 min at the
same temperature the solvent was removed. CHCl3 (20 mL)
and 1 M sulfuric acid (20 mL) were added to the residue. The
organic phase was washed with CHCl3 (2 × 20 mL), dried over
anhydrous Na2SO4, and the solvent was removed to afford 2.60
g of crude material. Purification by flash chromatography
using hexane-ethyl acetate (1:1) as eluent yielded compound
4 as a colorless oil (2.49 g, 19.2 mmol, 92% yield), whose
spectroscopic data matched with those previously published.21
Rea ction betw een Nitr on e 1 a n d Olefin (R)-3. The
reaction was run under the same conditions previously de-
(film) 3220, 1732 cm-1 1H NMR (400 MHz) δ 4.09 (dd, J )
;
7.1, 4.7 Hz, 1 H), 3.78 (q, J ≈ 7.8 Hz, 1 H), 3.67 (m, 1 H), 3.65
(s, 3 H), 3.58 (t, J ≈ 7.5 Hz, 1 H), 3.17 (ddd, J ) 13.0, 7.7, 4.7
Hz, 1 H), 2.95 (dt, J ) 13.0, 7.7 Hz, 1 H), 1.93 (m, 1 H), 1.75
(m, 1 H), 1.65 (m, 1 H), 1.53 (m, 1 H), 1.07 (d, J ) 6.6 Hz, 3
H); 13C NMR (100 MHz) δ 171.9, 82.6, 68.7, 68.2, 56.7, 53.7,
52.1, 27.5, 24.6, 19.6. MS m/z 215 (22), 86 (100). Anal. Calcd
for C10H17NO4: C, 55.80; H, 7.96; N, 6.51. Found: C, 55.80;
H, 8.05; N, 6.61.
scribed for racemic 3.10 (2S,3S,3aR,1′R)-9a : [R]20 ) 83° (c )
D
1.73 in CHCl3). (2R,3R,3aS,1′R)-9b: [R]20 ) -75° (c ) 1.22
D
in CHCl3).
Rea ction betw een Nitr on e 1 a n d Olefin 5. A solution
of nitrone 1 (914 mg, 10.7 mmol) and mesylate 5 (1.40 g, 4.3
mmol) in CHCl3 (20 mL) was heated at reflux for 48 h under
argon. Removal of the solvent gave 2.60 g of crude material.
Purification by flash chromatography using hexane-ethyl
acetate (1:4) as eluent yielded the following fractions: (i)
methyl (2RS,3RS,3aSR)-2-[(1SR)-3-(benzyloxy)-1-(mesyloxy)-
propyl]hexahydropyrrolo[1,2-b]isoxazole-3-carboxylate (10a )
(343 mg, 0.83 mmol, 19% yield) as a colorless oil; and (ii) 1.15
g (2.8 mmol, 65% yield) of a mixture of compounds 10a , 10b,
and traces of the corresponding exo adducts.
Repeated flash chromatography of the second fraction under
the same conditions gave 225 mg (0.54 mmol, 12% yield) of
product 10a and 902 mg (2.18 mmol, 51% yield) of a mixture
of all four adducts. In the last fraction the ratio 10a /10b was
1.6:1 and the endo/exo was 10:1. The overall yield was 59% of
10a and 18% of 10b. For spectroscopic data for 10a and 10b
see below.
Rea ction betw een Nitr on e 2 a n d Olefin (R)-3. The
reaction was run under the same conditions described for
racemic 3.10 (2S,3S,3aR,1′R)-14a : [R]20 ) -29° (c ) 2.30 in
D
CHCl3). (2R,3R,3aS,1′R)-14b: [R]20 ) 10.5° (c ) 2.50 in
D
CHCl3). (2R,3R,3aR,1′R)-14d : [R]20 ) -51° (c ) 3.4 in
D
CHCl3).
Rea ction betw een Nitr on e 2 a n d Olefin 4. To a solution
of nitrone 2 (prepared from 1.13 g (11.2 mmol) of N-hydroxy-
piperidine and 7.30 g (33.6 mmol) of yellow HgO) in CH2Cl2
(25 mL) was added a solution of methyl (E)-6-methoxy-4-
hydroxy-2-hexenoate (4) (1.38 g, 7.9 mmol) in CH2Cl2 (2 mL),
and the mixture was kept at rt for 2 d under nitrogen. Flash
chromatography of the crude material (2.56 g) using ether as
eluent afforded the following fractions: (i) 231 mg (0.85 mmol,
11% yield) of a 7:1 mixture of methyl (2RS,3RS,3aRS)-2-
[(1RS)-1-hydroxy-3-methoxypropyl]hexahydro-2H-isoxazolo-
[2,3-a]pyridine-3-carboxylate (15d ) and the exo-anti isomer,
15c, as an oil, from which 15d crystallized (ethyl acetate/
pentane); (ii) 960 mg (3.51 mmol, 44% yield) of the endo-anti
isomer, 15a , as a colorless oil; and (iii) 500 mg (1.85 mmol,
23% yield) of the endo-syn isomer, 15b, as a colorless oil.
15a : IR (film) 3454, 1738 cm-1; 1H-NMR (400 MHz) δ 4.18 (t,
J ) 5.0 Hz, 1 H), 4.07 (d, J ) 5.0 Hz, 1 H), 3.73 (dtd, J ) 9.7,
5.0, 3.2 Hz, 1 H), 3.64 (s, 3 H), 3.52-3.40 (m, 2 H), 3.27 (m, 1
H), 3.24 (dd, J ) 8.3, 5.0 Hz, 1 H), 3.23 (s, 3 H), 2.36 (ddd, J
) 10.9, 8.3, 2.5 Hz, 1 H), 2.30 (ddd, J ) 12.4, 9.1, 3.0 Hz, 1 H),
1.87 (m, 1 H), 1.75-1.65 (m, 3 H), 1.52-1.40 (m, 2 H), 1.25-
1.10 (m, 2 H); 13C-NMR (62.5 MHz, CDCl3) δ 171.9, 81.6, 70.0,
69.3, 69.2, 58.5, 55.2, 51.5, 50.9, 32.5, 26.4, 24.0, 23.3; MS m/z
Rea ction betw een Nitr on e 1 a n d Olefin 7. A solution
of nitrone 1 (262 mg, 3.1 mmol) and methyl (E)-4,6-dihydroxy-
2-pentenoate (7, 300 mg, 2.05 mmol) in CHCl3 (10 mL) was
heated at reflux for 1 d under argon. Removal of the solvent
gave 570 mg of crude material. Purification by flash chroma-
tography on silica gel (J . T. Baker 30-60 µm) using ether-
methanol (30:1) as eluent yielded the following fractions: (i)
methyl (2RS,3RS,3aSR)-2-[(1SR)-1,2-dihydroxyethyl]hexahy-
dropyrrolo[1,2-b]isoxazole-3-carboxylate (12a ) (167 mg, 0.72
mmol, 34% yield) as a colorless oil; and (ii) 235 mg (1.02 mmol,
49% yield) of the endo-syn isomer, 12b. 12a : IR (film) 3378,
1736 cm-1 1H-NMR (400 MHz) δ 4.36 (t, J ) 6.1 Hz, 1 H),
;
3.81 (q, J ≈ 7.6 Hz, 1 H), 3.76 (dd, J ) 8.2, 6.1 Hz, 1 H), 3.68
(m, 1 H), 3.67 (s, 3 H), 3.61 (dd, J ) 11.0, 4.0 Hz, 1 H), 3.49
(dd, J ) 11.0, 5.5 Hz, 1 H), 3.20 (ddd, J ) 13.1, 7.9, 4.5 Hz, 1
H), 2.97 (dt, J ) 13.1, 7.9 Hz, 1 H), 1.95 (m, 1 H), 1.79-1.65
(m, 2 H), 1.63-1.55 (m, 1 H); 13C-NMR (100 MHz) δ 172.4,
79.5, 73.6, 68.9, 64.1, 56.3, 54.2, 52.0, 27.2, 24.6; MS m/z 231
(12), 200 (5), 86 (100). Anal. Calcd for C10H17NO5: C, 51.94;
H, 7.41; N, 6.06. Found: C, 51.92; H, 7.40; N, 6.14. 12b: IR
273 (15), 100 (91), 99 (89), 84 (100). Anal. Calcd for C13H23
-
NO5: C, 57.13; H: 8.48; N, 5.12. Found: C, 57.19; H, 8.51;
N, 5.10. 15b: IR (film) 3452, 1738 cm-1; 1H-NMR (400 MHz)
δ 4.28 (dd, J ) 5.2, 4.0 Hz, 1 H), 3.83 (d, J ) 7.1 Hz, 1 H),
3.70 (ddt, J ) 9.4, 7.1, 3.8 Hz, 1 H), 3.64 (s, 3 H), 3.52-3.40
(m, 2 H), 3.28 (m, 1 H), 3.24 (s, 3 H), 3.22 (dd, J ) 8.4, 5.2 Hz,
1 H), 2.37 (ddd, J ) 11.7, 8.4, 2.7 Hz, 1 H), 2.32 (ddd, J )
12.4, 9.2, 3.0 Hz, 1 H), 1.87 (dq, J ) 9.2, 2.5 Hz, 1 H), 1.77-
1.55 (m, 4 H), 1.45 (m, 1 H), 1.25-1.10 (m, 2 H); 13C-NMR
(62.5 MHz, CDCl3) δ 171.9, 81.2, 70.0, 69.9, 69.4, 58.6, 55.3,
(film) 3378, 1735 cm-1 1H-NMR (400 MHz) δ 4.42 (dd, J )
;
6.7, 3.4 Hz, 1 H), 3.85 (q, J ≈ 7.5 Hz, 1 H), 3.81 (t, J ) 7.6, 1
H), 3.69 (s, 3 H), 3.61-3.48 (m, 3 H), 3.20 (ddd, J ) 13.1, 7.6,
4.7 Hz, 1 H), 2.99 (dt, J ) 13.1, 7.9 Hz, 1 H), 1.95 (m, 1 H),

Cycloaddition of Nitrones to R,â-Unsaturated Esters
J . Org. Chem., Vol. 61, No. 24, 1996 8583
52.3, 51.7, 33.4, 26.5, 24.2, 23.4; MS m/z 273 (10), 100 (100),
99 (48), 84 (74). Anal. Calcd for C13H23NO5: C, 57.13; H, 8.48;
N, 5.12. Found: C, 56.97; H, 8.60; N, 5.12. 15d : mp: 51-2
°C (ethyl acetate/pentane); IR (KBr) 3462, 1738 cm-1; 1H-NMR
(250 MHz, CDCl3) δ 4.11 (t, J ≈ 4.4 Hz, 1 H), 3.72 (m, 1 H),
3.69 (s, 3 H), 3.56-3.45 (m, 2 H), 3.39 (m, 1 H), 3.31 (s, 3 H),
3.12 (dd, J ) 10.2, 5.1 Hz, 1 H), 2.48-2.36 (m, 2 H), 2.07 (br
d, J ) 12.4 Hz, 1 H), 1.90-1.65 (m, 4 H), 1.65-1.20 (m, 3 H);
13C-NMR (62.5 MHz, CDCl3) δ 172.2, 81.1, 71.6, 70.4, 69.6,
58.7, 54.9, 54.3, 52.2, 33.8, 28.6, 24.4, 23.2; MS m/z 273 (11),
100 (100), 84 (65). Anal. Calcd for C13H23NO5: C, 57.13; H,
8.48; N, 5.12. Found: C, 57.30; H, 8.50; N, 5.16.
(dd, J ) 8.5, 6.7 Hz, 1 H), 3.80 (dd, J ) 8.5, 6.1 Hz, 1 H), 3.68
(s, 3 H), 3.27 (dt, J ) 9.2, 3.4 Hz, 1 H), 2.82 (dd, J ) 9.9, 5.6
Hz, 1 H), 2.37 (ddd, J ) 12.2, 9.2, 2.9 Hz, 1 H), 2.28 (ddd, J )
11.1, 9.9, 2.5 Hz, 1 H), 2.00 (m, 1 H), 1.74 (m, 1 H), 1.68 (m, 1
H), 1.49 (m, 1 H), 1.34 (m, 1 H), 1.30 (s, 3 H), 1.23 (s, 3 H),
1.17 (m, 1 H); 13C NMR (100 MHz, 250 K) δ 172.3, 109.7, 80.1,
77.1, 71.0, 65.4, 55.3, 54.5, 52.4, 29.0, 26.5, 25.0, 24.9, 23.7;
MS m/z 285 (23), 270 (42), 100 (100), 99 (93), 84 (98); [R]20
)
D
-25.4° (c ) 1.05 in CHCl3). Anal. Calcd for C14H23NO5: C,
58.93; H, 8.12; N, 4.91. Found: C, 58.99; H, 8.32; N, 4.96.
Rea ction betw een Nitr on e 2 a n d Olefin 7. To a solution
of nitrone 2 (prepared from 630 mg (6.23 mmol) of N-
hydroxypiperidine and 4.05 g (18.7 mmol) of yellow HgO) in
CH2Cl2 (15 mL) was added a solution of methyl (E)-4,6-
dihydroxy-2-pentenoate (7) (700 mg, 4.79 mmol) in CH2Cl2 (2
mL), and the mixture was kept at rt for 3 d under nitrogen.
Flash chromatography of the crude material (1.34 g) on silica
gel (J . T. Baker 30-60 µm) using ether-methanol (30:1) as
eluent afforded the following fractions: (i) 110 mg (0.75 mmol)
of starting olefin 7; (ii) 170 mg (0.69 mmol, 17% yield) of a 1:3
mixture of methyl (2RS,3RS,3aRS)-2-[(1SR)-1,2-dihydroxy-
ethyl]hexahydro-2H-isoxazolo[2,3-a]pyridine-3-carboxylate (18c)
and the exo-syn isomer, 18d , respectively, as a colorless oil;
(iii) 350 mg (1.43 mmol, 35% yield) of the endo-anti isomer,
18a , as a colorless oil; and (iv) 420 mg (1.71 mmol, 42% yield)
of the endo-syn isomer, 18b, as a colorless oil. 18a : IR (film)
Rea ction betw een Nitr on e 2 a n d Olefin 5. To a solution
of nitrone 2 (prepared from 108 mg (1.07 mmol) of N-
hydroxypiperidine and 693 mg (3.21 mmol) of yellow HgO) in
CH2Cl2 (5 mL) was added methyl (E)-6-(benzyloxy)-4-(mesyl-
oxy)-2-hexenoate (5) (351 mg, 1.07 mmol), and the mixture was
kept at rt for 4 d under nitrogen. Flash chromatography of
the crude material using hexane-ethyl acetate (1:2) as eluent
afforded the following fractions: (i) 95 mg (0.21 mmol, 20%
yield) of a 2:3 mixture of methyl (2RS,3RS,3aRS)-2-[(1SR)-3-
(benzyloxy)-1-(mesyloxy)propyl]hexahydro-2H-isoxazolo[2,3-a]-
pyridine-3-carboxylate (16c) and the exo-syn isomer, 16d ,
respectively; and (ii) 310 mg (0.72 mmol, 68% yield) of a 2.4:1
mixture of the endo-anti, 16a , and endo-syn, 16b, adducts,
respectively. For spectroscopic data for 16a -16d see below.
Rea ction betw een Nitr on e 2 a n d Olefin 6. To a solution
of nitrone 2 (prepared from 1.09 g (10.8 mmol) of N-hydroxy-
piperidine and 6.30 g (29.2 mmol) of yellow HgO) in CH2Cl2
(50 mL) was added methyl (S,E)-3-(2,2-dimethyl-1,3-dioxolan-
4-yl)-2-propenoate (6) (1.00 g, 5.4 mmol), and the mixture was
kept at rt for 20 h under nitrogen. Flash chromatography of
the crude product using hexane-ether mixtures of increasing
polarity afforded the following fractions: (i) 77 mg (0.27 mmol,
5% yield) of methyl (2S,3S,3aS)-2-[(4R)-2,2-dimethyl-1,3-di-
oxolan-4-yl]hexahydro-2H-isoxazolo[2,3-a]pyridine-3-carboxy-
late (17c) as a colorless oil; (ii) 185 mg (0.65 mmol, 12% yield)
of the (2R,3R,3aR,4′R)-isomer, 17d , as a colorless oil; (iii) 769
mg (2.70 mmol, 50% yield) of the (2S,3S,3aR,4′R)-isomer, 17a ,
as a colorless oil; and (iv) 400 mg (1.40 mmol, 26% yield) of
the (2R,3R,3aS,4′R)-isomer, 17b, as a solid. 17a : IR (film)
1741 cm-1; 1H NMR (400 MHz, 250 K) δ 4.29 (dd, J ) 6.8, 4.9
Hz, 1 H), 4.07 (td, J ) 6.4, 4.6 Hz, 1 H), 4.03 (dd, J ) 8.2, 6.3
Hz, 1 H), 3.68 (dd, J ) 8.2, 4.6 Hz, 1 H), 3.64 (s, 3 H), 3.27 (br
dt, J ) 9.2, 3.0 Hz, 1 H), 3.21 (dd, J ) 8.2, 4.9 Hz, 1 H), 2.42
(ddd, J ) 11.0, 8.2, 2.3 Hz, 1 H), 2.28 (ddd, J ) 12.2, 9.2, 3.0
Hz, 1 H), 1.90 (m, 1 H), 1.72-1.62 (m, 2 H), 1.44 (m, 1 H),
1.28 (s, 3 H), 1.23 (s, 3 H), 1.15-1.03 (m, 2 H); 13C NMR (100
MHz, 250 K) δ 172.2, 109.5, 79.4, 76.2, 69.4, 67.1, 55.3, 52.9,
51.8, 27.3, 26.6, 25.1, 24.8, 23.9; MS m/z 285 (16), 270 (28),
100 (93), 99 (70), 84 (100); [R]20D ) -39.4° (c ) 2.33 in CHCl3).
Anal. Calcd for C14H23NO5: C, 58.93; H, 8.12; N, 4.91.
Found: C, 58.87; H, 8.23; N, 4.93. 17b: mp 44-5 °C; IR (KBr)
1740 cm-1; 1H NMR (400 MHz, 250 K) δ 4.37 (t, J ) 5.2 Hz, 1
H), 4.24 (ddd, J ) 7.2, 6.1, 5.2 Hz, 1 H), 4.03 (dd, J ) 8.5, 7.2
Hz, 1 H), 3.71 (dd, J ) 8.5, 6.1 Hz, 1 H), 3.64 (s, 3 H), 3.30 (br
dt, J ) 9.2, 2.8 Hz, 1 H), 3.16 (dd, J ) 8.5, 5.2 Hz, 1 H), 2.40
(ddd, J ) 11.2, 8.5, 2.4 Hz, 1 H), 2.31 (ddd, J ) 12.3, 9.2, 3.0
Hz, 1 H), 1.88 (m, 1 H), 1.72-1.62 (m, 2 H), 1.45 (m, 1 H),
1.31 (s, 3 H), 1.24 (s, 3 H), 1.30-1.05 (m, 2 H); 13C NMR (100
MHz, 250 K) δ 172.1, 109.7, 79.1, 75.8, 69.9, 65.7, 55.5, 52.1,
51.8, 27.4, 26.4, 25.1, 24.8, 24.0; MS m/z 285 (17), 270 (34),
3398, 1737 cm-1
;
1H-NMR (400 MHz, CDCl3) δ 4.33 (t, J )
5.0 Hz, 1 H), 3.72 (m, 1 H), 3.69 (s, 3 H), 3.63 (m, 1 H), 3.51
(dd, J ) 11.5, 6.0 Hz, 1 H), 3.42 (m, 1 H), 3.31 (dd, J ) 8.2, 5.0
Hz, 1 H), 2.38-2.30 (m, 2 H), 1.90 (br d, J ) 10.5 Hz, 1 H),
1.75-1.60 (m, 2 H), 1.50 (m, 1 H), 1.40-1.10 (m, 2 H); 13C-
NMR (62.5 MHz, CDCl3) δ 172.3, 79.4, 71.5, 69.2, 63.5, 55.3,
51.8, 51.7, 26.5, 24.2, 23.4; MS m/z 245 (9), 100 (62), 99 (100).
Anal. Calcd for C11H19NO5: C, 53.87; H, 7.81; N, 5.71.
Found: C, 53.73; H, 7.82; N, 5.68. 18b: IR (film) 3390, 1736
1
cm-1; H-NMR (250 MHz, CDCl3) δ 4.41 (dd, J ) 5.1, 2.2 Hz,
1 H), 3.65 (s, 3 H), 3.70-3.35 (m, 4 H), 3.30 (dd, J ) 8.5, 5.1
Hz, 1 H), 2.39-2.32 (m, 2 H), 1.88 (br d, J ) 8.8 Hz, 1 H),
1.75-1.45 (m, 3 H), 1.40-1.10 (m, 2 H); 13C-NMR (62.5 MHz,
CDCl3) δ 172.0, 79.6, 71.6, 69.3, 64.2, 55.3, 52.3, 51.8, 26.5,
24.2, 23.4; MS m/z 245 (8), 99 (100). Anal. Calcd for C11H19
-
NO5: C, 53.87; H, 7.81; N, 5.71. Found: C, 53.82; H, 7.88; N,
5.70. 18c (observable signals from the mixture 18c/18d 1:3):
1H-NMR (250 MHz, CDCl3) δ 4.34 (dd, J ) 5.3, 4.0 Hz, 1 H),
3.89 (m, 1 H), 3.20 (dd, J ) 9.9, 5.3 Hz, 1 H); 13C-NMR (62.5
MHz, CDCl3) δ 79.4, 73.7, 69.9, 62.6, 54.8, 52.6, 28.6. 18d
(from the mixture 18c/18d 1:3): 1H-NMR (250 MHz, CDCl3)
(85% trans-invertomer) δ 4.29 (dd, J ) 5.3, 2.7 Hz, 1 H), 3.72
(s, 3 H), 3.80-3.60 (m, 3 H), 3.39 (m, 1 H), 3.21 (dd, J ) 9.8,
5.3 Hz, 1 H), 2.49-2.39 (m, 2 H), 2.12 (m, 1 H), 1.85-1.75 (m,
2 H), 1.61-1.20 (m, 3 H); 13C-NMR (62.5 MHz, CDCl3) δ 171.9,
78.4, 74.2, 70.0, 64.2, 54.9, 54.0, 52.3, 28.5, 24.4, 23.1. Mixture
18c/18d 1:3: IR (film) 3397, 1737 cm-1; MS m/z 245 (10), 100
(100), 99 (83). Anal. Calcd for C11H19NO5: C, 53.87; H, 7.81;
N, 5.71. Found: C, 53.80; H, 7.85; N, 5.73.
Rea ction betw een Nitr on e 2 a n d Olefin 8. To a solution
of nitrone 2 (prepared from 931 mg (9.22 mmol) of N-
hydroxypiperidine and 5.97 g (27.7 mmol) of yellow HgO) in
CH2Cl2 (50 mL) was added methyl (E)-4-hydroxy-2-pentenoate
(8) (800 mg, 6.15 mmol), and the mixture was kept at rt for
20 h under nitrogen. Flash chromatography of the crude
product using hexane-ether mixtures of increasing polarity
afforded the following fractions: (i) 70 mg (0.30 mmol, 5%
yield) of methyl (2RS,3RS,3aRS)-2-[(1SR)-1-hydroxyethyl]-
hexahydro-2H-isoxazolo[2,3-a]pyridine-3-carboxylate (19c) as
a colorless oil; (ii) 267 mg (1.17 mmol, 19% yield) of the
(2RS,3RS,3aRS,1′RS)-isomer, 19d , as a colorless oil; (iii) 465
mg (2.03 mmol, 33% yield) of the (2RS,3RS,3aSR,1′SR)-isomer,
19a , as a solid; and (iv) 521 mg (2.28 mmol, 37% yield) of the
(2RS,3RS,3aSR,1′RS)-isomer, 19b, as a solid. 19a : mp 54-5
100 (100), 99 (76), 84 (99); [R]20 ) 23.6° (c ) 1.44 in CHCl3).
D
Anal. Calcd for C14H23NO5: C, 58.93; H, 8.12; N, 4.91.
Found: C, 58.89; H, 8.16; N, 4.86. 17c: IR (film) 1741 cm-1
;
1H NMR (400 MHz, 250 K) δ 4.09 (dd, J ) 7.9, 5.2 Hz, 1 H),
4.01 (m, 2 H), 3.88 (m, 1 H), 3.67 (s, 3 H), 3.24 (dt, J ) 9.2, 3.0
Hz, 1 H), 2.94 (dd, J ) 10.1, 5.2 Hz, 1 H), 2.35 (ddd, J ) 12.2,
9.2, 3.0 Hz, 1 H), 2.25 (ddd, J ) 11.0, 10.1, 2.4 Hz, 1 H), 2.01
(m, 1 H), 1.72 (m, 1 H), 1.67 (m, 1 H), 1.48 (m, 1 H), 1.40 (m,
1 H), 1.24 (s, 3 H), 1.20 (s, 3 H), 1.19 (m, 1 H); 13C NMR (100
MHz, 250 K) δ 172.5, 109.5, 79.3, 77.8, 71.8, 67.6, 56.7, 55.5,
52.2, 29.8, 27.1, 25.4, 25.0, 23.8. Anal. Calcd for C14H23NO5:
C, 58.93; H, 8.12; N, 4.91. Found: C, 58.90; H, 8.20; N, 4.92.
1
°C; IR (film) 3409, 1739 cm-1; H NMR (400 MHz, 250 K) δ
4.24 (d, J ) 4.6 Hz, 1 H), 4.11 (t, J ) 5.0 Hz, 1 H), 3.72 (m, 1
H), 3.63 (s, 3 H), 3.25 (m, 1 H), 3.22 (dd, J ) 8.4, 5.0 Hz, 1 H),
2.35 (ddd, J ) 10.6, 8.4, 2.5 Hz, 1 H), 2.28 (ddd, J ) 12.3, 9.2,
3.0 Hz, 1 H), 1.85 (m, 1 H), 1.70-1.60 (m, 2 H), 1.42 (m, 1 H),
1.23-1.05 (m, 2 H), 1.05 (d, J ) 6.6 Hz, 3 H); 13C NMR (100
1
17d : IR (film) 1739 cm-1; H NMR (400 MHz, 250 K) δ 4.26
(dt, J ) 7.5, 6.5 Hz, 1 H), 4.16 (dd, J ) 7.5, 5.6 Hz, 1 H), 4.02

8584 J . Org. Chem., Vol. 61, No. 24, 1996
Busque´ et al.
MHz, 250 K) δ 172.7, 83.5, 69.6, 66.9, 55.4, 51.8, 51.6, 27.2,
24.8, 24.0, 20.1; MS m/z 229 (25), 100 (51), 99 (100). Anal.
Calcd for C11H19NO4: C, 57.63; H, 8.35; N, 6.11. Found: C,
57.06; H, 8.33; N, 5.87. 19b: mp 51-2 °C; IR (film) 3440, 1738
(2R,3R,3a S,1′R)-10b. The product was obtained in 84%
yield starting from (2R,3R,3aS,1′R)-9b . (2R,3R,3aS,1′R)-
10b: [R]20 ) 37° (c ) 0.85 in CHCl3).
D
Meth yl (2RS,3RS,3a SR)-2-[(1SR)-3-(Ben zyloxy)-1-(m e-
syloxy)p r op yl]h exa h yd r o-2H-isoxa zolo[2,3-a ]p yr id in e-3-
ca r boxyla t e (16a ). The same procedure described for the
preparation of mesylate 10a was used to prepare 16a starting
from alcohol 14a . Compound 16a was obtained as a colorless
oil in 95% yield after purification by flash chromatography
using hexane-ethyl acetate (2:3) as eluent. 16a : IR (film)
1
cm-1; H NMR (400 MHz, 250 K) (ca. 95% trans-invertomer)
δ 4.20 (t, J ) 5.1 Hz, 1 H), 4.18 (d, J ) 6.4 Hz, 1 H), 3.74 (m,
1 H), 3.61 (s, 3 H), 3.25 (m, 1 H), 3.16 (dd, J ) 8.4, 5.1 Hz, 1
H), 2.35 (ddd, J ) 11.3, 8.4, 2.4 Hz, 1 H), 2.28 (ddd, J ) 12.2,
9.1, 2.9 Hz, 1 H), 1.85 (m, 1 H), 1.72-1.55 (m, 2 H), 1.42 (m,
1 H), 1.30-1.10 (m, 2 H), 1.07 (d, J ) 6.5 Hz, 3 H); 13C NMR
(100 MHz, 250 K) δ 172.4, 82.6, 69.7, 67.0, 55.4, 52.1, 51.7,
27.2, 24.7, 24.0, 19.3; MS m/z 229 (24), 100 (76), 99 (100). Anal.
Calcd for C11H19NO4: C, 57.63; H, 8.35; N, 6.11. Found: C,
57.70; H, 8.30; N, 6.14. 19c: 1H NMR (400 MHz, 250 K) (ca.
95% trans-invertomer) δ 4.06 (br s, 1 H), 3.93 (dd, J ) 6.4, 5.2
Hz, 1 H), 3.76 (m, 1 H), 3.65 (s, 3 H), 3.27 (m, 1 H), 3.08 (dd,
J ) 10.1, 5.2 Hz, 1 H), 2.34 (ddd, J ) 12.2, 9.0, 2.9 Hz, 1 H),
2.28 (ddd, J ) 11.3, 10.1, 2.6 Hz, 1 H), 2.02 (m, 1 H), 1.75-
1.60 (m, 2 H), 1.49 (m, 1 H), 1.35-1.10 (m, 2 H), 1.08 (d, J )
6.7 Hz, 3 H); 13C NMR (100 MHz, 250 K) δ 172.8, 82.9, 71.6,
69.6, 55.1, 54.5, 52.0, 28.8, 24.6, 23.5, 19.9; MS m/z 229 (1),
100 (100), 99 (99). Anal. Calcd for C11H19NO4: C, 57.63; H,
8.35; N, 6.11. Found: C, 57.79; H, 8.40; N, 6.10. 19d : IR
(film) 3450, 3424, 2941, 2858, 1739 cm-1; 1H NMR (400 MHz,
250 K) (ca. 95% trans-invertomer) δ 4.13 (br s, 1 H), 3.87 (dd,
J ) 6.9, 5.5 Hz, 1 H), 3.70 (m, 1 H), 3.66 (s, 3 H), 3.30 (m, 1
H), 2.83 (dd, J ) 9.9, 5.5 Hz, 1 H), 2.38-2.28 (m, 2 H), 2.00
(m, 1 H), 1.77-1.60 (m, 2 H), 1.48 (m, 1 H), 1.32 (m, 1 H),
1.16 (m, 1 H), 1.02 (d, J ) 6.5 Hz, 3 H); 13C NMR (100 MHz,
250 K) δ 172.5, 83.7, 71.4, 69.1, 55.2, 54.9, 52.3, 28.9, 24.7,
23.7, 18.4; MS m/z 229 (16), 100 (99), 99 (100). Anal. Calcd
for C11H19NO4: C, 57.63; H, 8.35; N, 6.11. Found: C, 57.86;
H, 8.46; N, 6.11.
1738, 1359, 1196 cm-1
; 1H NMR (400 MHz, 250 K) δ 7.36 (m,
5 H), 5.01 (ddd, J ) 6.7, 4.3, 2.3 Hz, 1 H), 4.56 (dd, J ) 5.2,
2.3 Hz, 1 H), 4.49 (d, J ) 11.6 Hz, 1 H), 4.44 (d, J ) 11.6 Hz,
1 H), 3.64 (s, 3 H), 3.56 (m, 2 H), 3.36 (m, 1 H), 3.30 (dd, J )
8.3, 5.2 Hz, 1 H), 3.18 (s, 3 H), 2.52 (ddd, J ) 11.2, 8.3, 2.4 Hz,
1 H), 2.40 (ddd, J ) 12.0, 9.1, 2.7 Hz, 1 H), 1.94-1.76 (m, 2
H), 1.74-1.61 (m, 2 H), 1.51-1.38 (m, 1 H), 1.29-1.16 (m, 2
H), 1.15-1.02 (m, 1 H); 13C NMR (100 MHz, 250 K) δ 171.7,
139.2, 128.9, 128.4, 128.1, 79.9, 78.9, 73.0, 69.6, 65.8, 55.3, 52.0,
50.7, 38.7, 32.2, 27.4, 24.7, 23.7; MS m/z 427 (2), 100 (35), 99
(52), 91 (100), 84 (64). Anal. Calcd for C20H29NO7S: C, 56.19;
H, 6.84; N, 3.28; S, 7.50. Found: C, 56.13; H, 6.89; N, 3.28; S,
7.47.
(2S,3S,3a R,1′R)-16a . The product was obtained in 86%
yield starting from (2S,3S,3aR,1′R)-14a . (2S,3S,3aR,1′R)-
16a : [R]20 ) -46° (c ) 1.08 in CHCl3).
D
Meth yl (2RS,3RS,3a SR)-2-[(1RS)-3-(Ben zyloxy)-1-(m e-
syloxy)p r op yl]h exa h yd r o-2H-isoxa zolo[2,3-a ]p yr id in e-3-
ca r boxyla te (16b). The same procedure described for the
preparation of mesylate 10a was used to prepare 16b starting
from alcohol 14b. Compound 16b was obtained as a colorless
solid in 84% yield after purification by flash chromatography
using hexane-ethyl acetate (2:3) as eluent. 16b: mp 87-8
°C (ethyl acetate-hexane); IR (film) 1737, 1357, 1198 cm-1
;
Meth yl (2RS,3RS,3a SR)-2-[(1SR)-3-(Ben zyloxy)-1-(m e-
syloxy)p r op yl]h exa h yd r op yr r olo[1,2-b]isoxa zole-3-ca r -
boxyla te (10a ). A solution of alcohol 9a (74 mg, 0.22 mmol)
in CH2Cl2 (6 mL) was added to a solution of mesyl chloride
(86 µL, 1.1 mmol) in anhydrous pyridine (0.50 mL) at rt under
argon. After 80 h at the same temperature, water (2 mL) was
added, and the mixture was stirred during 2 h. The organic
phase was washed with water (3 × 2 mL) and dried over
anhydrous Na2SO4, and the solvent was removed at 0.2 Torr.
Flash chromatography of the crude material using ethyl
acetate as eluent afforded 77 mg (0.19 mmol, 85% yield) of
10a as a colorless oil. 10a : 1H NMR (400 MHz) δ 7.32 (m, 5
H), 4.97 (dt, J ) 8.8, 3.8 Hz, 1 H), 4.54 (dd, J ) 7.3, 3.8 Hz, 1
H), 4.52 (d, J ) 11.6 Hz, 1 H), 4.46 (d, J ) 11.6 Hz, 1 H), 3.88
(q, J ≈ 7.6 Hz, 1 H), 3.81 (t, J ≈ 7.5 Hz, 1 H), 3.72 (s, 3 H),
3.57 (m, 2 H), 3.23 (ddd, J ) 13.1, 7.7, 4.1 Hz, 1 H), 3.17 (s, 3
H), 2.97 (dt, J ) 13.1, 7.7 Hz, 1 H), 2.08-1.91 (m, 2 H), 1.90-
1.67 (m, 3 H), 1.54 (m, 1 H); 13C NMR (100 MHz) δ 171.6, 139.6,
128.9, 128.4, 128.1, 80.6, 79.6, 73.3, 68.9, 66.4, 56.8, 53.2, 52.4,
38.7, 32.2, 27.2, 24.5. Anal. Calcd for C19H27NO7S: C, 55.19;
H, 6.58; N, 3.39; S, 7.75. Found: C, 55.06; H, 6.66; N, 3.30; S,
7.66.
1H NMR (400 MHz, 250 K) δ 7.36 (m, 5 H), 4.92 (q, J ) 5.3
Hz, 1 H), 4.57 (t, J ) 5.3 Hz, 1 H), 4.49 (d, J ) 11.7 Hz, 1 H),
4.44 (d, J ) 11.7 Hz, 1 H), 3.65 (s, 3 H), 3.57 (t, J ) 6.0 Hz, 2
H), 3.33 (dd, J ) 8.2, 5.3 Hz, 1 H), 3.31 (m, 1 H), 3.18 (s, 3 H),
2.47 (ddd, J ) 11.3, 8.2, 2.4 Hz, 1 H), 2.35 (ddd, J ) 12.1, 9.1,
2.7 Hz, 1 H), 1.98 (q, J ≈ 6.1 Hz, 2 H), 1.89 (br d, J ) 12.2 Hz,
1 H), 1.73-1.61 (m, 2 H), 1.51-1.38 (m, 1 H), 1.27-1.04 (m, 2
H); 13C NMR (100 MHz, 250 K) δ 171.8, 139.1, 128.9, 128.4,
128.1, 79.8, 79.0, 73.0, 69.5, 65.5, 55.4, 52.3, 52.0, 38.1, 32.0,
27.3, 24.7, 23.8; MS m/z 427 (1), 100 (30), 99 (37), 91 (100), 84
(96). Anal. Calcd for C20H29NO7S: C, 56.19; H, 6.84; N, 3.28;
S, 7.50. Found: C, 56.32; H, 6.99; N, 3.39; S, 7.55.
(2R,3R,3a S,1′R)-16b. The product was obtained in 90%
yield starting from (2R,3R,3aS,1′R)-14b. (2R,3R,3aS,1′R)-
16b: [R]20 ) 19° (c ) 1.07 in CHCl3).
D
Meth yl (2RS,3RS,3a RS)-2-[(1SR)-3-(Ben zyloxy)-1-(m e-
syloxy)p r op yl]h exa h yd r o-2H-isoxa zolo[2,3-a ]p yr id in e-3-
ca r boxyla te (16c). The same procedure described for the
preparation of mesylate 10a was used to prepare 16c starting
from alcohol 14c. Compound 16c was obtained as a colorless
oil in 84% yield after purification by flash chromatography
using hexane-ethyl acetate (1:1) as eluent. 16c: IR (film)
1737, 1358, 1195 cm-1; 1H NMR (400 MHz, 250 K) δ 7.36 (m,
5 H), 4.93 (ddd, J ) 8.1, 4.5, 3.5 Hz, 1 H), 4.51 (d, J ) 11.5
Hz, 1 H), 4.40 (d, J ) 11.5 Hz, 1 H), 4.40 (dd, J ) 6.3, 4.5 Hz,
1 H), 3.69 (s, 3 H), 3.63-3.54 (m, 2 H), 3.28 (m, 1 H), 3.18 (dd,
J ) 10.1, 6.3 Hz, 1 H), 3.17 (s, 3 H), 2.41-2.31 (m, 2 H), 2.09-
2.00 (m, 2 H), 1.89-1.79 (m, 1 H), 1.78-1.61 (m, 2 H), 1.58-
1.33 (m, 2 H), 1.26-1.11 (m, 1 H); 13C NMR (100 MHz, 250 K)
δ 172.0, 139.3, 128.9, 128.5, 128.1, 81.0, 79.5, 73.1, 71.2, 65.9,
55.4, 54.3, 52.5, 38.2, 31.8, 28.9, 24.8, 23.5. Anal. Calcd for
C20H29NO7S: C, 56.19; H, 6.84; N, 3.28; S, 7.50. Found: C,
55.96; H, 6.90; N, 3.32; S, 7.39.
(2S,3S,3a R,1′R)-10a . The product was obtained in 82%
yield starting with (2S,3S,3aR,1′R)-9a . (2S,3S,3aR,1′R)-10a :
[R]20 ) -20.0° (c ) 0.90 in CHCl3).
D
Meth yl (2RS,3RS,3a SR)-2-[(1RS)-3-(Ben zyloxy)-1-(m e-
syloxy)p r op yl]h exa h yd r op yr r olo[1,2-b]isoxa zole-3-ca r -
boxyla te (10b). The same procedure described for the
preparation of mesylate 10a was used to prepare 10b starting
from alcohol 9b. Compound 10b was obtained as a colorless
oil in 82% yield. 10b: 1H NMR (400 MHz) δ 7.33 (m, 5 H),
4.88 (br td, J ) 7.8, 3.7 Hz, 1 H), 4.51 (d, J ) 11.6 Hz, 1 H),
4.46 (t, J ≈ 7.0 Hz, 1 H), 4.45 (d, J ) 11.6 Hz, 1 H), 3.85 (q, J
≈ 7.9 Hz, 1 H), 3.70 (s, 3 H), 3.68 (dd, J ) 7.6, 6.1 Hz, 1 H),
3.60 (dd, J ) 6.7, 5.5 Hz, 2 H), 3.21 (ddd, J ) 13.4, 7.9, 4.0
Hz, 1 H), 3.12 (s, 3 H), 2.95 (dt, J ) 13.4, 7.9 Hz, 1 H), 2.10-
1.66 (m, 5 H), 1.54 (m, 1 H); 13C NMR (100 MHz) δ 171.3, 139.5,
128.9, 128.4, 128.1, 80.2, 79.1, 73.3, 68.9, 66.2, 56.5, 54.0, 52.3,
38.3, 32.0, 27.5, 24.7. Anal. Calcd for C19H27NO7S: C, 55.19;
H, 6.58; N, 3.39; S, 7.75. Found: C, 55.18; H, 6.62; N, 3.33; S,
7.58.
Meth yl (2RS,3RS,3a RS)-2-[(1RS)-3-(Ben zyloxy)-1-(m e-
syloxy)p r op yl]h exa h yd r o-2H-isoxa zolo[2,3-a ]p yr id in e-3-
ca r boxyla te (16d ). The same procedure described for the
preparation of mesylate 10a was used to prepare 16d starting
from alcohol 14d . Compound 16d was obtained as a colorless
solid in 84% yield after purification by flash chromatography
using hexane-ethyl acetate (1:1) as eluent. 16d : mp 63-5
°C (ethyl acetate-hexane); IR (film) 1736, 1356, 1200 cm-1
;

Cycloaddition of Nitrones to R,â-Unsaturated Esters
J . Org. Chem., Vol. 61, No. 24, 1996 8585
1H NMR (400 MHz, 250 K) δ 7.36 (m, 5 H), 4.77 (td, J ) 9.3,
2.7 Hz, 1 H), 4.49 (d, J ) 11.8 Hz, 1 H), 4.43 (d, J ) 11.8 Hz,
1 H), 4.32 (dd, J ) 9.3, 5.1 Hz, 1 H), 3.66 (s, 3 H), 3.61-3.50
(m, 2 H), 3.30 (m, 1 H), 3.11 (s, 3 H), 2.91 (dd, J ) 9.7, 5.1 Hz,
1 H), 2.43 (ddd, J ) 12.2, 9.1, 2.9 Hz, 1 H), 2.36 (ddd, J )
12.0, 9.7, 2.5 Hz, 1 H), 2.07-1.92 (m, 2 H), 1.85-1.63 (m, 3
H), 1.60-1.46 (m, 1 H), 1.46-1.34 (m, 1 H), 1.26-1.13 (m, 1
H); 13C NMR (100 MHz, 250 K) δ 171.9, 139.2, 128.9, 128.4,
128.1, 81.4, 79.7, 73.1, 71.6, 65.6, 55.2, 55.0, 52.5, 38.1, 31.1,
28.9, 24.8, 23.6. Anal. Calcd for C20H29NO7S: C, 56.19; H,
6.84; N, 3.28; S, 7.50. Found: C, 56.07; H, 6.79; N, 3.24; S,
7.40.
Cl2 (4 mL), and the solution was washed with water (3 × 4
mL) and dried over anhydrous Na2SO4. Flash chromatography
of the crude material using hexane-ethyl acetate (1:1) as
eluent yielded the following fractions: (i) 21b16a (6 mg, 0.02
mmol, 5.5% yield, 24% yield based on unrecovered 14b); and
(ii) 14b (101 mg, 0.29 mmol).
Ack n ow led gm en t. We gratefully acknowledge the
Ministerio de Educacio´n y Ciencia for financial support
through Direccio´n General de Investigacio´n Cient´ıfica
y Te´cnica (project PB92-0605) and Comissio´ Interde-
partamental de Recerca i Innovacio´ Tecnolo´gica for a
grant to F.B.
(2R,3R,3a R,1′R)-16d . The product was obtained in 83%
yield starting from (2R,3R,3aR,1′R)-14d . (2R,3R,3aR,1′R)-
16d : [R]20 ) -29° (c ) 1.10 in CHCl3).
D
Ch em ica l Cor r ela tion of 13a w ith 20. A mixture of NaH
(10 mg of a 50% dispersion in mineral oil, 0.21 mmol) and
adduct 13a (140 mg, 0.65 mmol) in THF (6 mL) was stirred at
rt for 7 h. The solvent was exchanged by CH2Cl2 (4 mL), and
the solution was washed with water (3 × 4 mL) and dried over
anhydrous Na2SO4. Flash chromatography of the crude mate-
rial using ethyl acetate as eluent yielded the following frac-
tions: (i) 2016b (8 mg, 0.04 mmol, 7% yield, 49% yield based
on unrecovered 13a ); and (ii) 13a (121 mg, 0.56 mmol).
Ch em ica l Cor r ela tion of 14b w ith 21b. A mixture of
NaH (15 mg of a 50% dispersion in mineral oil, 0.31 mmol)
and adduct 14b (129 mg, 0.37 mmol) in THF (4 mL) was
heated at reflux for 8 h. The solvent was exchanged by CH2-
Su p p or tin g In for m a tion Ava ila ble: Full assignment of
1H and 13C NMR peaks of methyl (E)-6-methoxy-2-hexenoate,
methyl (E)-6-methoxy-4-oxo-2-hexenoate, and compounds 4,
10a ,b, 12a ,b, 13a ,b, 15a ,b,d , 16a -d , 17a -d , 18a -d , and
19a -d . Tables containing the most significant NMR data for
adducts 9-13 and 14-19. ORTEP drawing and details for
the X-ray data acquisition for 15d and 16d (15 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.
J O960960X