Design, synthesis, and 1,3-dipolar cycloaddition of (5R)- [and (5S)]-5,6-dihydro-5-phenyl-2H-1,4-oxazin-2-one N-oxides as chiral (E)-geometry-fixed α-alkoxycarbonylnitrones

Article abstract of DOI:10.1021/jo000903a

Optically pure (5R)- [and (5S)]-5,6-dihydro-5-phenyl-2H-1,4-oxazin-2-one N-oxides [(5R)- and (5S)-2] were designed as chiral (E)-geometry-fixed α-alkoxycarbonylnitrones 1. The nitrones (5R)- and (5S)-2 were synthesized by three-step oxidation of (R)- and (S)-phenylglycinols [(R)- and (S)-3], condensation of the resulting (R)- and (S)-2-hydroxylamino-2-phenylethanols [(R)- and (S)-5] with glyoxylic acid, and cyclization of the intermediary nitrones (R)- and (S)-6b. The nitrone (5R)-2 reacted with olefins 7-14 under mild conditions to afford the corresponding cycloadducts 15-22 as the main products via the least sterically demanding exo modes. Cycloadduct 30 obtained from (5S)-2 and cyclopentadiene was effectively elaborated to (1S,4S,5R)-4-benzyloxycarbonylamino-2-oxabicyclo[3.3.0]oct-7-en-3-one (28), the key synthetic intermediate of carbocyclic polyoxin C.

Full text of DOI:10.1021/jo000903a

8544
J . Org. Chem. 2000, 65, 8544-8551
Design , Syn th esis, a n d 1,3-Dip ola r Cycloa d d ition of (5R)- [a n d
(5S)]-5,6-Dih yd r o-5-p h en yl-2H-1,4-oxa zin -2-on e N-Oxid es a s Ch ir a l
(E)-Geom etr y-F ixed r-Alk oxyca r bon yln itr on es
Osamu Tamura,*,† Kentoku Gotanda,‡ J un Yoshino,‡ Yasuhiro Morita,‡ Romi Terashima,‡
Mayumi Kikuchi,‡ Tsutomu Miyawaki,‡ Naka Mita,‡ Masayuki Yamashita,§
Hiroyuki Ishibashi,† and Masanori Sakamoto*,‡
Faculty of Pharmaceutical Sciences, Kanazawa University, Takaramachi, Kanazawa 920-0934, J apan,
Meiji Pharmaceutical University, Noshio, Kiyose, Tokyo 204-8588, J apan, and Kyoto Pharmaceutical
University, Misasagi, Yamashina, Kyoto 607-8414, J apan
tamura@dbs.p.kanazawa-u.ac.jp
Received J une 14, 2000
Optically pure (5R)- [and (5S)]-5,6-dihydro-5-phenyl-2H-1,4-oxazin-2-one N-oxides [(5R)- and (5S)-
2] were designed as chiral (E)-geometry-fixed R-alkoxycarbonylnitrones 1. The nitrones (5R)- and
(5S)-2 were synthesized by three-step oxidation of (R)- and (S)-phenylglycinols [(R)- and (S)-3],
condensation of the resulting (R)- and (S)-2-hydroxylamino-2-phenylethanols [(R)- and (S)-5] with
glyoxylic acid, and cyclization of the intermediary nitrones (R)- and (S)-6b. The nitrone (5R)-2
reacted with olefins 7-14 under mild conditions to afford the corresponding cycloadducts 15-22
as the main products via the least sterically demanding exo modes. Cycloadduct 30 obtained from
(5S)-2 and cyclopentadiene was effectively elaborated to (1S,4S,5R)-4-benzyloxycarbonylamino-2-
oxabicyclo[3.3.0]oct-7-en-3-one (28), the key synthetic intermediate of carbocyclic polyoxin C.
In tr od u ction
tion makes it difficult to predict the stereochemistry of
the main cycloadduct and makes analysis of the transi-
tion states complicated because a couple of transition
states give the same stereoisomer. For example, as shown
in eq 2, both the (E)-nitrone-endo and the (Z)-nitrone-
exo transition states afford the same stereochemical
outcome.5c To eliminate these ambiguities, we recently
reported the design, synthesis, and reactions of 5,6-
dihydro-5-phenyl-2H-1,4-oxazin-2-one N-oxide (2) as a
chiral (E)-geometry-fixed R-alkoxycarbonylnitrone (eq
3).7,8 We present here a full account of this work and an
application of the cycloaddition of 2 to the key synthetic
intermediate of carbocyclic polyoxin C.
Cycloadditions of nitrones with alkenes form carbon-
carbon bonds and carbon-oxygen bonds in one step to
give cycloadducts having isoxazolidine ring systems.1
Reductive cleavage of the nitrogen-oxygen bonds of the
cycloadducts provides 3-amino alcohols.2 Thus, nitrone
cycloaddition is quite a useful method for construction
of nitrogen-containing carbon frameworks. Mechanisti-
cally, the nitrone cycloaddition is a [4π + 2π]-type
concerted process similar to the Diels-Alder reaction.3
One of the problems in nitrone cycloaddition compared
to the Diels-Alder reaction is the possibility of geo-
metrical isomerization of the nitrone moiety during the
cycloaddition reaction. In particular, nitrones 1 having
electron-withdrawing groups (e.g., esters) are known to
exist as equilibrating mixtures of (E)-1 and (Z)-1 in
solution even at room temperature (eq 1).4 As a result,
cycloadditions of nitrones 1 with alkenes often give
mixtures of diastereomers, although they have been
utilized for the syntheses of natural products and com-
pounds of biological interest.5,6 Moreover, the isomeriza-
(4) (a) Inouye, Y.; Hara, J .; Kakisawa, H. Chem. Lett. 1980, 1407-
1410. (b) Inouye, Y. Bull. Chem. Soc. J pn. 1983, 56, 244-247. (c)
Inouye, Y.; Takaya, K.; Kakisawa, H. Bull. Chem. Soc. J pn. 1983, 56,
3541-3542. (d) Aurich, H. G.; Franzke, M.; Kesselheim, H. P.
Tetrahedron 1992, 48, 663-668. In general, for the case of a nitrone
having no electron-withdrawing group at the nitrone-carbon atom,
the (Z) form is sterically more stable than the corresponding (E) isomer.
For example, N-alkylation of an (E)-O-trimethylsilylated oxime initially
gives (E)-nitrone as a major isomer, which in turn isomerizes to pure
(Z) isomer during purification. See: (e) LeBel, N. A.; Balasubramaian,
N. Tetrahedron Lett. 1985, 26, 4331-4334.
(5) For recent examples, see: (a) Baumgartner, H.; O’Sullivan, A.
C.; Schneider, J . Heterocycles 1997, 45, 1537-1549. (b) Chiacchio, U.;
Rescifina, A.; Iannazzo, D.; Romeo, G. J . Org. Chem. 1999, 64, 28-36.
(c) Ondrus, V.; Orsag, M.; Fisera, L.; Pronayova, N. Tetrahedron 1999,
55, 10425-10436.
(6) For efforts to control the geometry of the nitrone 1, see: (a)
Kanemasa, S.; Tsuruoka, T. Chem. Lett. 1995, 49-50. (b) Tokunaga,
Y.; Ihara, M.; Fukumoto, K. Tetrahedron Lett. 1996, 37, 6157-6160.
(c) Tamura, O.; Mita, N.; Gotanda, K.; Yamada, K.; Nakano, T.;
Katagiri, R.; Sakamoto, M. Heterocycles 1997, 46, 95-99. Quite
recently, asymmetric reaction of nitrone 1 with vinyl ethers was
reported. Although high enantiomeric excesses were obtained in the
reactions, diastereoselectivites were not high enough. See: (d) J ensen,
K. B.; Hazell, R. G.; J ørgensen, K. A. J . Org. Chem. 1999, 64, 2353-
2360.
† Kanazawa University.
‡ Meiji Pharmaceutical University.
§ Kyoto Pharmaceutical University.
(1) For reviews of cycloadditions of nitrones, see: (a) Confalone, P.
N.; Huie, E. M. Org. React. 1988, 36, 1-173. (b) Deshong, P.; Lander,
S. W., J r.; Leginus, J . M.; Dicken, C. M. In Advances in Cycloaddition;
Curran, D. P., Ed.; J AI Press: Greenwich, CT, 1988; Vol. 1, pp 87-
128. (c) Carruthers, W. Cycloaddition Reaction in Organic Synthesis;
Pergamon Press: Oxford, 1990. (d) Little, R. D. In Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press:
Oxford, 1991; Vol. 5, pp 239-270. (e) Padwa, A. Intermolecular 1,3-
dipolar cycloadditions. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Semmelhack, M. F., Eds.; Pergamon Press: Oxford,
1991; Vol. 4, Chapter 9, pp 1069-1109. (f) Gothelf, K. V.; J ørgensen,
K. A. Chem. Rev. 1998, 98, 863-909.
(2) Frederickson, M. Tetrahedron 1997, 53, 403-425.
(3) Carruthers, W. Some Modern Methods of Organic Synthesis;
Cambridge University Press: Cambridge, U.K., 1986; pp 256-262.
(7) For preliminary communication, see: Tamura, O.; Gotanda, K.;
Terashima, R.; Kikuchi, M.; Miyawaki, T.; Sakamoto, M. Chem.
Commun. 1996, 1861-1862.
10.1021/jo000903a CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/18/2000

N-Oxides as Chiral R-Alkoxycarbonylnitrones
J . Org. Chem., Vol. 65, No. 25, 2000 8545
Sch em e 1a
Resu lts a n d Discu ssion
1. Syn th esis of (5R)- [a n d (5S)]-5,6-Dih yd r o-5-
ph en yl-2H-1,4-oxazin -2-on e N-Oxides [(5R)- an d (5S)-
2]. Our synthesis of the chiral (E)-geometry-fixed nitrone
(5R)-2 began with three-step oxidation of (R)-phenylgly-
cinol [(R)-3] to the corresponding hydroxylamine [(R)-5],
as shown in Scheme 1.9-11 Thus, imine formation of (R)-3
with p-methoxybenzaldehyde and oxidation of the result-
ing imine (R)-4 with m-chloroperbenzoic acid gave the
corresponding oxaziridine,9 which was treated with hy-
droxylamine hydrochloride in methanol to furnish the
chiral hydroxylamine (R)-5 in an excellent overall yield.
Conversion of the hydroxylamine (R)-5 to the cyclic
nitrone (5R)-2 was next examined. Heating hydroxyl-
amine (R)-5 with methyl glyoxylate in boiling benzene
followed by treatment of the resulting nitrone (R)-6a with
1,3-bis(isothiocyanate)tetrabutyldistannoxane12 for intra-
molecular transesterification gave the desired nitrone
(5R)-2 as a crystalline material in 45% yield (Table 1,
entry 1). The yield was improved to 64% by the use of
anhydrous p-toluenesulfonic acid (TsOH) for the cycliza-
tion of (R)-6a instead of the tin catalyst (entry 2). The
best result was obtained by employing glyoxylic acid.
Thus, treatment of the hydroxylamine (R)-5 with a 40%
aqueous solution of glyoxylic acid in dichloromethane
a
Key: (a) p-methoxybenzaldehyde, toluene, reflux; (b) m-CPBA,
CH2Cl2; (c) NH2OH‚HCl, MeOH, 93% from (R)-3; (d) see Table 1.
Ta ble 1. P r ep a r a tion of (5R)-2 fr om (R)-5
entry
1
conditions
yield (%)
45
OHC-CO2Me, C6H6, reflux,
then [(SCN)nBu2Sn]2O, MS4A
OHC-CO2Me, C6H6, reflux,
then 1 equiv of TsOH, 70 °C
40% OHC-CO2H(aq), CH2Cl2, rt,
then 1 equiv of TsOH, reflux
2
3
64
85
followed by azeotropic removal of water afforded nitrone
carboxylic acid (R)-6b in dichloromethane, which, without
isolation, was cyclized with TsOH, giving rise to (5R)-2
in 85% yield (entry 3). In the same manner, the antipodal
(5S)-2 could be readily prepared from (S)-phenylglycinol
[(S)-3]. The structures of the nitrones (5R)- and (5S)-2
were unambiguously confirmed by an X-ray diffraction
of (5S)-2 (see the Supporting Information). To our knowl-
edge, this is the first case of syntheses of both enanti-
omers of optically pure six-membered-ring nitrone.13-15
Nitrones (5R)- and (5S)-2 can be handled under ambient
air and can be stored for several months in a refrigerator.
(8) For closely related five-membered-ring nitrones, see: (a) Kata-
giri, N.; Sato, H.; Kurimoto, A.; Okada, M.; Yamada, A.; Kaneko, C. J .
Org. Chem. 1994, 59, 8101-8106. (b) Katagiri, N.; Okada, M.; Kaneko,
C. Tetrahedron Lett. 1996, 37, 1801-1804. (c) Katagiri, N.; Okada,
M.; Morishita, Y.; Kaneko, C. Chem. Commun. 1996, 2137-2138. (d)
Katagiri, N.; Okada, M.; Morishita, Y.; Kaneko, C. Tetrahedron 1997,
53, 5725-5746.
(13) Although several types of chiral five-membered-ring nitrones
are known,14 optically pure six-membered-ring nitrone is quite rare.
See: Oppolzer, W.; Deerberg, J .; Tamura, O. Helv. Chim. Acta 1994,
77, 554-560.
(9) For the three-step oxidation of primary amine into hydroxyl-
amine, see: Poło´nski, T.; Chimiak, A. Tetrahedron Lett. 1974, 2453-
2456. Because oxidation of secondary amines leading to nitrones is
known, direct oxidation of (5R)-perhydro-5-phenyloxazin-2-one to the
nitrone (5R)-2 was also attempted. However, the oxidation with Na2-
(14) For examples of optically pure five-membered-ring nitrones,
see: (a) Bernet, B.; Krawczyk, E.; Vasella, A. Helv. Chim. Acta 1985,
68, 2299-2311. (b) Be´rranger, T.; Andre´-Barre`s, C.; Kobayakawa, M.;
Langlois, Y. Tetrahedron Lett. 1993, 34, 5079-5082. (c) Berranger, T.;
Langlois, Y. Tetrahedron Lett. 1995, 36, 5523-5526. (d) Langlois, Y.
Curr. Org. Chem. 1998, 2, 1-18 and references therein. (f) McCaig, A.
E.; Wightman, R. G. Tetrahedron Lett. 1993, 34, 3939-3942. (g) Cicchi,
S.; Ho¨ld, I.; Brandi, A. J . Org. Chem. 1993, 58, 5274-5275. (h) Cordero,
F. M.; Cicchi, S.; Goti, A.; Brandi, A. Tetrahedron Lett. 1994, 35, 949-
952. (i) Brandi, A.; Cicchi, S.; Goti, A.; Koprowski, M.; Pietrusiewicz,
K. M. J . Org. Chem. 1994, 59, 1315-1318. (j) Brandi, A.; Cicchi, S.;
Cordero, F. M.; Frignoli, R.; Goti, A.; Picasso, S.; Vogel, P. J . Org. Chem.
1995, 60, 6806-6812. (k) Anichini, B.; Goti, A.; Brandi, A.; Kozhushkov,
S. I.; de Meijere, A. Synlett 1997, 25-26. (l) Ishikawa, T.; Tajima, Y.;
Fukui, M.; Saito, S. Angew. Chem., Int. Ed. Engl. 1996, 35, 1863-
1864. (m) Hall, A.; Meldrum, K. P.; Therond, P. R.; Wightman, R. H.
Synlett 1997, 123-125. See also refs 8b-d.
10a
WO4-H2O2 or SeO2-H2O210b gave only a low yield of (5R)-2 (<10%)
probably because of its instability under the oxidation conditions. After
our communication,6 it was reported that (5R)-perhydro-5-phenyl-
oxazin-2-one can be oxidized with dimethyl dioxirane to afford (5R)-2
as an orange oil.11
(10) (a) Murahashi, S.; Shiota, T.; Imada, Y. Org. Synth. 1992, 70,
265-271. (b) Murahashi, S.; Shiota, T. Tetrahedron Lett. 1987, 28,
2382-2385. See also: (c) J oseph, R.; Sudalai, A.; Ravindranathan, T.
Synlett 1995, 1177-1178.
(11) Baldwin, S. W.; Young, B. G.; McPhail, A. T. Tetrahedron Lett.
1998, 39, 6819-6822.
(12) Otera, J .; Dan-oh, N.; Nozaki, H. J . Org. Chem. 1991, 56, 5307-
5311.

8546 J . Org. Chem., Vol. 65, No. 25, 2000
Tamura et al.
Ta ble 2. Cycloa d d ition of (5R)-2 w ith Alk en esa
2. In ter m olecu la r Cycloa d d ition of th e Cyclic
Nitr on es (5R)- a n d (5S)-2 w ith Alk en es 7-14. With
both enantiomers of the cyclic nitrones in hand, we next
examined their reactivity and stereoselectivity in cyclo-
additions, using nitrone (5R)-2. As shown in Table 2, the
nitrone (5R)-2 reacted with various alkenes 7-14 under
mild conditions from the less hindered side in an exo
mode to give cycloadducts 15-22 as the main products.
Typically, treatment of nitrone (5R)-2 with ethyl vinyl
ether (7) in benzene at room temperature gave cycload-
duct 15 along with small amounts of other stereoisomers
(entry 1). Reactions of nitrone (5R)-2 with other terminal
alkenes 8, 9, and 2,3-dihydrofuran (10) also gave products
16-18 bearing the same stereochemical sense as that of
15 accompanied by stereoisomers (entries 2-4). In con-
trast, cycloaddition with 1,1-disubstituted alkenes 11 and
12 and with cyclic alkenes 13 and 14 was much cleaner
and gave cycloadducts 19-21 and (9R)-22 as single
stereoisomers, respectively (entries 5-8). Reaction of the
antipodal nitrone (5S)-2 with cyclopentene 14, of course,
gave the enantiomeric cycloadduct (9S)-22. In sharp
contrast to the above reactions, the nitrone (5R)-2 did
not react with N-methylmaleimide at all. This fact clearly
shows that the cycloaddition of the nitrone seems to be
a LUMO-nitrone-controlled cycloaddition.1f The cycload-
ducts of the nitrone (5R)-2 are conformationally rigidified
by the six-membered rings, and their stereostructures
could therefore be readily assigned on the basis of the
NOE difference spectra of 15, 16, 19, 20, and 22 or the
NOESY spectrum of 21, as depicted in Figure 1.
The stereochemical course of the reactions of (5R)-2
may be rationalized by taking into account four possible
transition-state models A-D, as illustrated in Scheme
2. Thus, the transition states A and B reacting from the
R face would be apparently unfavorable because of the
nonbonded interactions between a dipolarophile and the
phenyl group of the nitrone. Because the â-endo transi-
tion state C would also bear steric interaction between
the R group of the dipolarophile and the ring of the
nitrone, the cycloaddition of (5R)-2 mainly proceeds via
the model D, having the least steric interaction to afford
cycloadducts 15-21 and (9R)-22.
It was recently reported that the related five-membered-
ring nitrones undergo cycloaddition with electron-rich
alkenes to give cycloadducts.8 However, the reactivities
of these nitrones are much lower than those of the six-
membered-ring nitrone (5R)-2. For example, cycloaddi-
tion of the nitrone (5R)-2 with ethyl vinyl ether (7)
smoothly proceeds at room temperature in a benzene
solution (Table 2, entry 1), whereas cycloaddition of the
five-membered-ring nitrone 23 requires high-pressure
conditions (8000 bar) even though ethyl vinyl ether (7)
is used as the solvent.8a,d This remarkable difference in
reactivity appears to be rationalized by two factors
(Figure 2). One is, of course, the number of substituents.
Each of the π faces of 23 would be shielded by the
methylene group of the cyclohexane ring, whereas the
phenyl group of nitrone (5R)-2 blocks only the R face.
Consequently, reaction of 23 with dipolarophile 7 may
suffer from severe steric interaction. The other factor
a
The nitrone (5R)-2 was treated with 10 equiv of a dipolarophile
b
except for 12 (3 equiv). The ratio was obtained from HPLC
analysis. c No other isomer was detected by 270 MHz 1H NMR.
(15) For other structurally related 1,3-dipoles, see: (a) Harwood,
L. M.; Lilley, I. A. Tetrahedron Lett. 1993, 34, 537-540. (b) Williams,
R. M.; Zhai, W.; Aldous, D. J .; Aldous, S. C. J . Org. Chem. 1992, 57,
6527-6532. (c) Roussi, F.; Bonin, M.; Chiaroni, A.; Micoin, L.; Riche,
C.; Husson, H.-P. Tetrahedron Lett. 1999, 40, 3727-3730 and refer-
ences therein.
d
The antipode (5S)-2 was used.
might arise from a difference in ring sizes. The distance
of CR-CR′ of the five-membered-ring nitrone 23 may be

N-Oxides as Chiral R-Alkoxycarbonylnitrones
J . Org. Chem., Vol. 65, No. 25, 2000 8547
F igu r e 2. Distances between R and R′ and between reaction
sites of the nitrones (5R)-2 and 23: R-R′ of (5R)-2 > R-R′ of
23; a < b.
Sch em e 3a
F igu r e 1. Selected NOEs of the cycloadducts.
Sch em e 2
a
Key: (a) 20% Pd(OH)2-C, H2 (6 atm), AcOH, rt; (b) HCl-
EtOH, 90% from (9R)-22; (c) 3,5-dinitrobenzoyl chloride, Et3N,
THF, 90%.
(for further discussion, see the Supporting Informa-
tion).16,17
3. Tr a n sfor m a tion s of th e Cycloa d d u cts: Syn th e-
sis of th e In ter m ed ia te of Ca r bocyclic P olyoxin C.
To determine both the facility of “deprotection” of the
cycloadduct and the optical purity of the products,
chemical transformations of enantiomeric cycloadducts
(9R)-22 and (9S)-22 were next examined. Hydrogenolysis
of (9R)-22 in the presence of 20% palladium hydroxide
on charcoal in acetic acid caused simultaneous reductive
cleavage of both N-O and N-CHPh bonds and lacton-
ization to give hydrochloride (4R)-24 after treatment with
ethanolic hydrogen chloride. The hydrochloride (4R)-24
was acylated with 3,5-dinitrobenzoyl chloride under the
usual conditions to afford benzamide (4R)-25. The anti-
pode (4S)-25 was produced in the same manner. Chiral
HPLC analyses of benzamides (4R)-25 and (4S)-25
revealed that both enantiomers had at least 99% ee and
that no racemization of 2 took place during both the
preparation of 2 and the cycloaddition steps (Scheme 3).
Carbocyclic polyoxin C (26) is an analogue of uracil
polyoxin C, which is known as the C-terminal amino acid
of an antibiotic nikkomycin Bz (Scheme 4). Interest has
(16) In cycloaddition chemistry, the distance of the reaction site often
plays an important role. It is known that reactivity of cyclopentadiene
with tetracyanoethene is 2600-fold higher than that of cyclohexa-1,3-
diene.17a Ali et al. reported that the reaction of tetrahydropyridine
1-oxide (six-membered-ring nitrone) with ethyl vinyl ether is 27 times
faster than that of 1-pyrroline-1-oxide.17b Kotera et al. reported that
cycloaddition of six-membered-ring carbonyl ylide with ethyl vinyl ether
gives a higher yield of cycloadduct than does that of seven-membered-
ring carbonyl ylide.17c
(17) (a) Sustmann, R.; Bo¨hm, M.; Sauer, J . Chem. Ber. 1979, 112,
883-889. See also: (a) Ru¨cker, C.; Lang, D.; Sauer, J .; Friege, H.;
Sustmann, R. Chem. Ber. 1980, 113, 1663-1690. (b) Ali, Sk. A.;
Wazeer, M. I. M. J . Chem. Soc., Perkin Trans. 2 1986, 1789-1792. (c)
Kotera, M.; Ishii, K.; Tamura, O.; Sakamoto, M. J . Chem. Soc., Perkin
Trans. 1 1998, 313-318.
shortened compared to that of the six-membered-ring
nitrone (5R)-2. This might enhance the steric repulsion
between the methene groups and dipolarophile 7. More-
over, the distance between the CR and the oxygen atom
of the nitrone 23 seems to be more expanded by the five-
membered ring than by the six-membered ring of nitrone
(5R)-2 (length a < length b). Consequently, the LUMO
orbitals of (5R)-2 may overlap more effectively with the
HOMO orbitals of the vinyl ether 7 than do those of 23

8548 J . Org. Chem., Vol. 65, No. 25, 2000
Tamura et al.
Sch em e 4
Sch em e 6a
Sch em e 5
a
Key: (a) Mo(CO)6, CH3CN-H2O (10:1), reflux; (b) (Boc)2O, 0
°C, 68%; (c) TsOH, CH2Cl2, 40 °C, then CbzCl, NaHCO3(aq).
With cycloadduct 30 in hand and having all stereo-
centers, our attention turned to the reductive cleavage
of the N-O bond of the cycloadduct 30 with the preserv-
ing of the carbon-carbon double bond. For this aim,
molybdenum hexacarbonyl21 was employed instead of
hydrogenolysis conditions (Scheme 6). Heating the cy-
cloadduct 30 with molybdenum hexacarbonyl in boiling
acetonitrile-water (10:1) gave, to our surprise, R-hy-
droxyacetophenone (31) instead of an expected lactone
32. This unexpected reaction is interpreted as follows.
Nonreductive cleavage of the N-O bond of 30 gives cyclic
imine E, which lactonizes to afford F . The imine moiety
of F then undergoes hydrolysis under the reaction
conditions to give R-hydroxyacetophenone (31) and depro-
tected lactone 33. Although it is assumed that the lactone
33 should be produced under these conditions, it was not
isolated probably because of the high polarity of 33. We
reasoned that effective protection of the primary amino
group of 33 under the conditions employed might make
possible a straightforward synthesis of lactone 28. After
some effort, we were delighted to find such reaction
conditions. Thus, cycloadduct 30 was heated with molyb-
denum hexacarbonyl in acetonitrile-water followed by
treatment with di-tert-butyl dicarbonate at low temper-
ature to afford Boc-protected lactone 34 in 68% yield.
Finally, treatment of lactone 34 with TsOH followed by
acylation with benzyloxycarbonyl chloride afforded the
key synthetic intermediate 28 of carbocyclic polyoxin C
(26) in 86% yield.22
been shown in its structure-activity relationship, and
it has been synthesized by several groups.18 One of the
most direct syntheses of 26 was demonstrated by Aggar-
wal’s group.18a,b Palladium-catalyzed introduction of uracil
to lactone 28 followed by benzylation of the generated
carboxyl group gives cyclopentene 27, which leads to 26
by dihydroxylation of the carbon-carbon double bond and
deprotection. In the original synthesis of 26, preparation
of optically active 28 took four steps from hydroxyl
congener 29, which was synthesized by the Diels-Alder
reaction of cyclopentadiene and glyoxylic acid, separation
of the resulting diastereomeric mixture, and optical
resolution.19 Accordingly, direct access to the lactone 28
may be the key point in the efficient synthesis of
carbocyclic polyoxin C (26). We envisioned a short-step
entry to the key intermediate 28 from (5S)-2.
Our synthesis of the lactone 28 began with the cy-
cloaddition of (5S)-2 to cyclopentadiene, as shown in
Scheme 5.20 Treatment of nitrone (5S)-2 with excess
cyclopentadiene in benzene at room temperature gave an
80:16:4 mixture of diastereomers. The main product 30,
assigned by NOE, was readily isolated in 76% yield by
crystallization and chromatography.
(18) For syntheses of optically active 26, see: (a) Aggarwal, V. K.;
Monteiro, N.; Tarver, G. J .; Lindell, S. D. J . Org. Chem. 1996, 61,
1192-1193. (b) Aggarwal, V. K.; Monteiro, N. J . Chem. Soc., Perkin
Trans. 1 1997, 2531-2537. (c) Kapeller, H.; Griengl, H. Tetrahedron
1997, 43, 14635-14644. For syntheses of racemic 26, see: (d) Baum-
gartner, H.; Marschner, C.; Pucher, R.; Singer, M.; Griengl, H.
Tetrahedron Lett. 1992, 43, 6443-6444. (e) Ward, S. E.; Holmes, A.
B.; McCague, R. Chem. Commun. 1997, 2085-2086.
Although the exact mechanism for the formation of the
lactone 33 from cycloadduct 30 remains unknown, one
(19) For preparation of racemic 28, see ref 18e.
(20) A carbocyclic nucleoside, carbovir, was also synthesized by
employing cycloaddition of a chiral five-membered-ring nitrone with
cyclopentadiene. See ref 14c. For general reviews on carbocyclic
nucleosides, see: (a) Borthwick, A. D.; Biggadike, K. Tetrahedron 1992,
48, 571-623. (b) Agrofoglio, L.; Suhas, E.; Farese, A.; Condom, R.;
Challand, S. R.; Earl, R. A.; Guedj, R. Tetrahedron 1994, 50, 10611-
10669.
(21) Cicchi, S.; Goti, A.; Brandi, A.; Guarna, A. Tetrahedron Lett.
1990, 31, 3351-3354.
(22) Direct protection of 33 with a benzyloxycarbonyl group instead
of a Boc group was unsuccessful. Attempts to deprotect the Boc group
by trifluoroacetic acid, ethanolic hydrogen chloride, or trimethylsilyl
trifluoromethansulfonate particularly failed to lead only to low yields
of 34 (<30%).

N-Oxides as Chiral R-Alkoxycarbonylnitrones
J . Org. Chem., Vol. 65, No. 25, 2000 8549
(100 mL), and to the solution was added dropwise a solution
of m-chloroperbenzoic acid (75% purity, 27.3 g, 0.121 mol) in
dichloromethane (200 mL) at 0 °C over 1.5 h. After further
stirring for 30 min, precipitated m-chlorobenzoic acid was
filtered off, and the filtrate was washed with a 10% aqueous
solution of potassium carbonate and dried (MgSO4). After
filtration, the filtrate was concentrated in vacuo to give a
residue which was dissolved in methanol (160 mL). To the
solution was added hydroxylamine hydrochloride (12.0 g, 0.16
mol) in methanol at room temperature, and the mixture was
further stirred for 18 h. Concentrated hydrochloric acid (15
mL) was added to the mixture, and the mixture was concen-
trated in vacuo to give a residue, which was partitioned
between water (100 mL) and ether (200 mL). The aqueous
phase was further washed with ether until no nonpolar
materials were observed by TLC analysis. The aqueous phase
was neutralized by adding sodium carbonate and then ex-
tracted with chloroform (50 mL × 8) with salting-out. The
organic phases were combined, dried (MgSO4), filtered, and
concentrated in vacuo to afford (R)-5 (10.8 g, 94%) as a
crystalline solid. This material was pure enough for the next
step. An analytical sample was obtained by recrystallization
Sch em e 7
possible explanation may be derived from consideration
of both the rigid structure of 30 and the mechanism
proposed21 for reductive cleavage of the N-O bond by
molybdenum hexacarbonyl, as shown in Scheme 7.
Oxidative addition of molybdenum into the N-O bond
of adduct 30 followed by elimination of an oxygen atom
from the molybdenum may give molybdenum complex
G.23 The oxy anion of G might abstract the axial-oriented
R′ proton, which could overlap with the p orbital of the
nitrogen atom, giving rise to iminium complex H.24 The
complex H may then release molybdenum to afford cyclic
imine E (for further discussion, see the Supporting
Information).
(ethyl acetate-hexane): mp 67-68 °C; [R]20 -38° (c 0.99,
D
1
CHCl3); H NMR (270 MHz, CDCl3) δ 2.17 (1H, s), 3.21 (1H,
br s), 3.93 (1H, s), 3.88 (2H, d, J ) 5.9 Hz), 4.14 (1H, t, J ) 5.9
Hz), 7.27-7.39 (5H, m). HRMS calcd for C8H11NO2, 153.0790;
found, 153.0786. Anal. Calcd for C8H11NO2: C, 62.73; H, 7.24;
N, 9.14. Found: C, 62.68; H, 7.06; N, 9.06.
(5R)-5,6-Dih yd r o-5-p h en yl-1,4-oxa d in -2-on e [(5R)-2]. To
a suspension of a 40% aqueous solution of glyoxylic acid (10.0
g, 54 mmol) in dichloromethane (100 mL) was added dropwise
a solution of (R)-5 (7.50 g, 49 mmol) in dichloromethane (100
mL), and the mixture was stirred for 30 min. The water of
the mixture was removed azeotropically by using a dropping
funnel with an equalization arm. Anhydrous p-toluenesulfonic
acid (10.1 g, 54 mmol) was added to the mixture, and the
mixture was heated at reflux for 2 h. After cooling, the mixture
was washed with water, and the aqueous phase was extracted
with dichloromethane. The organic phases were combined,
washed with a saturated aqueous solution of sodium bicarbon-
ate, dried (MgSO4), and filtered. The filtrate was concentrated
in vacuo to give the residue, which was purified by column
chromatography on silica gel (ethyl acetate/hexane ) 1/1) to
afford (5R)-2 (10.6 g, 85%) as a crystalline solid: mp 67-68
°C (hexene-ethyl acetate); [R]20D +80° (c 1.03, CHCl3); 1H NMR
(270 MHz, CDCl3) δ 4.66 (1H, dd, J ) 12.5, 5.0 Hz), 4.76 (1H,
dd, J ) 12.5, 4.0 Hz), 5.02 (1H, br t, J ) 4.6 Hz), 7.28-7.40
(5H, m). HRMS m/z calcd for C10H9NO3, 191.0582; found,
191.0579.
Con clu sion
We have designed and synthesized chiral and geometry-
fixed R-alkoxycarbonylnitrones (5R)- and (5S)-2. The
cycloadditions of the nitrones proceeded under mild con-
ditions with good stereoselectivities. The stereochemis-
tries of the major cycloadducts were readily predicted and
were confirmed by NOE experiments because of the rigid
structures. Moreover, the cycloaddition of nitrone (5S)-2
could be applied to a short synthesis of the key interme-
diate of carbocyclic polyoxin C. Further applications of
the cycloaddition of 2 are currently under investigation.25
Exp er im en ta l Section
(S)-3-Hyd r oxya m in o-2-p h en yleth a n ol [(S)-5]. This was
obtained from (S)-phenylglycinol [(S)-3] by the same procedure
as that described for (R)-5: mp 66-68 °C (hexene-ethyl
Melting points are uncorrected. Mass spectra were deter-
mined at an ionizing voltage of 70 eV. Unless otherwise stated,
all reactions were performed in flame-dried glassware under
an atmosphere of dry argon. Solutions were evaporated under
reduced pressure using a rotary evaporator. HPLC analyses
were performed using a Finepack SIL-5 (column A) or a
SUMICHIRAL OA 4600 (column B).
acetate); [R]23 +38° (c 0.32, CHCl3).
D
(5S)-5,6-Dih ydr o-5-ph en yl-1,4-oxadin -2-on e [(5S)-2]. This
was obtained from (S)-5 by the same procedure as that
described for (5R)-2: mp 67-68 °C (hexene-ethyl acetate);
[R]20 -80° (c 1.03, CHCl3).
D
(1R,5R,8R)-6-Aza -8-eth oxy-3,7-d ioxa -5-p h en ylbicyclo-
[4.3.0]n on a n -2-on e (15). A solution of nitrone (5R)-2 (20.0
mg, 0.1 mmol) and ethyl vinyl ether (7; 100 µL, 1.05 mmol) in
benzene (1 mL) was stirred at room temperature for 16 h. The
mixture was concentrated in vacuo to give the residue, which
was subjected to column chromatography on silica gel (hex-
anes/ethyl acetate ) 3/2) to afford a diastereomeric mixture
of cycloadducts (83:8:9, 24.0 mg, 87%). HPLC (column A,
hexanes/ethyl acetate ) 3/1, 1.0 mL/min), retention time (min)
14.92 (83%), 18.78 (8), 27.52 (9). An analytical sample of 15
was obtained by column chromatography on silica gel (hexane/
(R)-3-Hyd r oxya m in o-2-p h en yleth a n ol [(R)-5]. A solu-
tion of (R)-phenylglycinol [(R)-3; 15.4 g, 0.11 mol] and p-
methoxybenzaldehyde (10.6 g, 0.080 mol) in benzene (150 mL)
was heated at reflux with a Dean-Stark trap for 2 h. After
cooling, the mixture was concentrated in vacuo to give crude
(R)-2-phenyl-N-(4-methoxybenzylidene)aminoethanol [(R)-4].
This was used for the next reaction without further purifica-
tion. The crude imine (R)-4 was dissolved in dichloromethane
(23) Normally, a nitrenium complex undergoes hydrolysis under the
conditions to afford a 3-amino alcohol. See ref 21.
(24) The same type of abstraction of a pseudoaxial proton was
reported in oxidative ring opening of a bicyclic isoxazolidine. See: (a)
Ali, Sk. A.; Wazeer, M. I. M. Tetrahedron Lett. 1992, 33, 3219-3222.
(b) Ali, Sk. A.; Wazeer, M. I. M. Tetrahedron Lett. 1993, 34, 137-140.
See also ref 14c.
(25) For example, see: Tamura, O.; Kuroki, T.; Sakai, Y.; Takizawa,
J .; Yoshino, J .; Morita, Y.; Mita, N.; Gotanda, K.; Sakamoto, M.
Tetrahedron Lett. 1999, 40, 895-898.
ethyl acetate ) 4/1); mp 72-73 °C (hexanes-ether); [R]25
D
-208° (c 1.05, CHCl3); 1H NMR (270 MHz, CDCl3) δ 1.19 (3H,
t, J ) 6.9 Hz), 2.68 (1H, ddd, J ) 13.2, 8.2, 1.0 Hz, spin
saturation at δ ) 4.49 f 8% NOE), 2.79 (1H, ddd, J ) 13.2,
8.9, 5.0 Hz, spin saturation at δ ) 4.12 f 2% NOE, δ ) 5.19
f 4% NOE), 3.42 (1H, dq, J ) 9.6, 6.9 Hz, spin saturation at
δ ) 5.19 f 5% NOE), 3.72 (1H, dq, J ) 9.6, 6.9 Hz, spin

8550 J . Org. Chem., Vol. 65, No. 25, 2000
Tamura et al.
saturation at δ ) 5.19 f 2% NOE), 4.12 (1H, dd, J ) 9.9, 3.6
Hz), 4.27 (1H, dd, J ) 11.9, 9.9 Hz), 4.36 (1H, dd, J ) 11.9,
3.6 Hz, spin saturation at δ ) 4.12 f 7% NOE), 4.49 (1H, br
t, J ) 8.2 Hz), 5.19 (1H, br d, J ) 5.0 Hz), 7.34-7.50 (5H, m).
HRMS calcd for C14H17NO4, 263.1158; found, 263.1161. Anal.
Calcd for C14H17NO4: C, 63.87; H, 6.51; N, 5.32. Found: C,
63.63; H, 6.55; N, 5.33.
(1R,5R)-6-Aza -8,8-d im eth yl-3,7-d ioxa -5-p h en ylbicyclo-
[4.3.0]n on a n -2-on e (19). Isobutene (11) was bubbled through
a solution of nitrone (5R)-2 (40.2 mg, 0.21 mmol) in benzene
(1 mL) at 0 °C, and then the mixture was stirred at 60 °C in
a sealed tube for 18 h. The mixture was concentrated in vacuo
to give the residue, which was subjected to column chroma-
tography on silica gel (hexane/ethyl acetate ) 1/1) to afford
19 (49.2 mg, 95%): mp 47-48 °C (hexanes-ether); [R]28
D
(1R,5R,8R)-6-Aza-8-(ter t-bu tyldim eth ylsilyloxym eth yl)-
3,7-d ioxa -5-p h en ylbicyclo[4.3.0]n on a n -2-on e (16). A solu-
tion of nitrone (5R)-2 (60.0 mg, 0.31 mmol) and 3-(tert-
butyldimethylsilyl)oxy-1-propene (8; 500 mg, 3.14 mmol) in
benzene (6 mL) was stirred at 60 °C for 12 h. The mixture
was concentrated in vacuo to give the residue, which was
subjected to column chromatography on silica gel (hexane/ethyl
acetate ) 4/1) to afford a diastereomeric mixture of cycload-
ducts (75:5:11:9, 101.8 mg, 89%). HPLC (column A, hexane/
ethyl acetate ) 4/1, 1.0 mL/min), retention time (min) 6.32
(5%), 7.78 (75), 11.28 (11), 12.72 (9). An analytical sample of
16 was obtained by recrystallization: mp 53-55 °C (hexane);
1
-104° (c 1.01, CHCl3); H NMR (500 MHz, C6D6) δ 0.55 (3H,
s), 0.57 (3H, s), 1.54 (1H, dd, J ) 12.8, 8.5 Hz, spin saturation
at δ ) 1.92 f 11% NOE), 1.92 (1 H, dd, J ) 12.8, 7.3 Hz, spin
saturation at δ ) 1.54 f 17% NOE, δ ) 3.41 f 3% NOE),
3.14 (1H, dd, J ) 11.6, 10.4 Hz), 3.29 (1H, dd, J ) 8.5, 7.3 Hz,
spin saturation at δ ) 1.54 f 10% NOE, δ ) 1.92 f 8% NOE),
3.31 (1H, dd, J ) 11.6, 3.7 Hz), 3.41 (1H, dd, J ) 10.4, 3.7 Hz,
spin saturation at δ ) 1.92 f 3% NOE), 6.55-6.74 (5H, m).
HRMS m/z calcd for C14H17NO3, 247.1208: found, 247.1205.
Anal. Calcd for C14H17NO3: C, 68.00; H, 6.93; N, 5.66. Found:
C, 67.75; H, 6.92; N, 5.60.
(1R,5R)-6-Aza -3,7-d ioxa -5-p h en ylsp ir o[b icyclo[4.3.0]-
n on a n e-8,1′-cyclop en ta n ]-2-on e (20). A solution of nitrone
(5R)-2 (20.0 mg, 0.10 mmol) and methylencyclopentane (12;
33 µL, 0.31 mmol) in benzene (1 mL) was stirred at 50 °C for
32 h. The mixture was concentrated in vacuo to give the
residue, which was purified by column chromatography on
silica gel (hexane/ethyl acetate ) 6/1) to afford 20 (24.4 mg,
[R]23 -92° (c 0.99, CHCl3); 1H NMR (500 MHz, CDCl3) δ 0.00
D
(3H, s), 0.02 (3H, s), 0.86 (9H, s), 2.69 (1H, ddd, J ) 12.8, 8.9,
7.9 Hz, spin saturation at δ ) 4.07 f 6% NOE), 2.73 (1H, ddd,
J ) 12.8, 8.9, 5.2 Hz), 3.57 (1H, dd, J ) 11.0, 4.9 Hz, spin
saturation at δ ) 3.64 f 11% NOE), 3.64 (1H, dd, J ) 11.0,
4.3 Hz, spin saturation at δ ) 3.57 f 13% NOE), 4.07 (1H,
dd, J ) 10.4, 3.7 Hz), 4.20 (1H, dd, J ) 11.9, 10.4 Hz), 4.25
(1H, br dd, J ) 8.2, 4.6 Hz, spin saturation at δ ) 3.57 f 7%
NOE, δ ) 3.64 f 10% NOE), 4.28 (1H, dd, J ) 11.9, 3.7 Hz,
spin saturation at δ ) 4.07 f 11% NOE), 4.34 (1H, t, J ) 8.9
Hz, spin saturation at δ ) 3.57 f 2% NOE), 7.31-7.44 (5H,
m). HRMS calcd for C19H29NO4Si, 363.1866; found, 363.1866.
Anal. Calcd for C19H29NO4Si: C, 62.78; H, 8.04; N, 3.85.
Found: C, 62.61; H, 8.06; N, 3.80.
87%): mp 99-100 °C (hexanes-ethyl acetate); [R]26 -93° (c
D
1.00, CHCl3); 1H NMR (500 MHz, C6D6) δ 0.86-0.92 (1H, m),
0.93-1.01 (2H, m), 1.07-1.19 (3H, m), 1.37 (1H, m), 1.60 (1H,
m), 1.87 (1H, dd, J ) 12.5, 8.2 Hz, spin saturation at δ ) 2.25
f 17% NOE, δ ) 3.53 f 9% NOE), 2.25 (1H, dd, J ) 12.5, 7.9
Hz, spin saturation at δ ) 1.87 f 21% NOE), 3.35 (1H, dd, J
) 11.6, 10.7 Hz, spin saturation at δ ) 1.87 f 12% NOE, δ )
3.53 f 4% NOE), 3.50 (1H, dd, J ) 11.6, 3.7 Hz), 3.53 (1H, br
t, J ) 7.9 Hz), 3.60 (1H, dd, J ) 10.7, 3.7 Hz, spin saturation
at δ ) 2.25 f 4% NOE), 6.73-6.94 (5H, m, Ar-H). HRMS
m/z calcd for C16H19NO3, 273.1365; found, 273.1363. Anal.
Calcd for C16H19NO3: C, 70.31; H, 7.01; N, 5.12. Found: C,
70.11; H, 7.01; N, 5.08.
(1R,5R,8S)-6-Aza-8-bu tyl-3,7-dioxa-5-ph en ylbicyclo[4.3.0]-
n on a n -2-on e (17). A solution of nitrone (5R)-2 (66.6 mg, 0.35
mmol) and 1-hexene (9; 436 µL, 3.48 mmol) in benzene (2 mL)
was stirred at 60 °C for 8 h. The mixture was concentrated in
vacuo to give the residue, which was subjected to column
chromatography on silica gel (hexane/ethyl acetate ) 1/1) to
afford a diastereomeric mixture of cycloadducts (85:7:8, 82 mg,
86%). HPLC (column A, hexane/ethyl acetate ) 3/1, 1.0 mL/
min), retention time (min) 6.06 (85%), 7.78 (75), 12.51 (8).
Further column chromatography on silica gel (hexane/ethyl
acetate ) 1/1) and recrystallization from hexanes-ether gave
(1R ,2S ,3R ,7R ,10S ,11R )-8-Aza -5,9-d io x a -7-p h e n y l-
tetr a cyclo[9.2.12,6.03,8]tetr a d eca n -4-on e (21). A solution of
nitrone (5R)-2 (60.0 mg, 0.31 mmol) and norbornylene (13; 295
mg, 3.14 mmol) in benzene (6 mL) was stirred at room
temperature for 9 h. The mixture was concentrated in vacuo
to give the residue, which was purified by column chromatog-
raphy on silica gel (hexane/ethyl acetate ) 3/1) to afford 21
pure 17: mp 80-81 °C (ether-hexane); [R]28 -118° (c 0.84,
D
1
CHCl3); H NMR (500 MHz, CD3CO2D) δ 0.86 (3H, t, J ) 7.0
(82.4 mg, 92%): mp 149-150 °C (ethyl acetate-hexane); [R]28
D
Hz), 1.22-1.62 (6H, m), 2.44 (1H, ddd, J ) 12.5, 9.5, 6.7 Hz),
2.84 (1H, dt, J ) 12.5, 7.6 Hz), 4.25 (1H, dd, J ) 10.7, 3.7 Hz),
4.25 (1H, m), 4.31 (1H, dd, J ) 11.6, 3.7 Hz), 4.37 (1H, dd, J
) 11.6, 10.7 Hz), 4.52 (1H, dd, J ) 9.5, 7.6 Hz), 7.32-7.49
(5H, m). HRMS m/z calcd for C16H21NO3, 275.1521; found,
275.1521. Anal. Calcd for C16H21NO3: C, 69.79; H, 7.69; N,
5.09. Found: C, 69.73; H, 7.70; N, 5.05.
-208° (c 1.02, CHCl3); 1H NMR (500 MHz, CDCl3) δ 0.97-
1.01 (1H, m), 1.12 (1H, ddd, J ) 9.5, 2.7, 1.5 Hz), 1.16 (1H, dt,
J ) 11.6, 2.4 Hz), 1.52-1.61 (2H, m), 1.67 (1H, d quin, J )
9.5, 1.5 Hz), 2.30 (1H, br d, J ) 4.3 Hz), 2.54 (1H, br d, J )
3.1 Hz), 2.70 (1H, ddd, J ) 7.9, 6.4, 1.2 Hz), 3.83 (1H, d, J )
7.9 Hz), 4.02 (1H, dd, J ) 10.4, 4.0 Hz), 4.06 (1H, br d, J ) 6.4
Hz), 4.20 (1H, dd, J ) 11.6, 10.4 Hz), 4.25 (1H, dd, J ) 11.6,
4.0 Hz), 7.34-7.45 (5H, m). HRMS m/z calcd for C17H19NO3,
285.1365; found, 285.1366. Anal. Calcd for C17H19NO3: C,
71.56; H, 6.71; N, 4.91. Found: C, 71.49; H, 6.84; N, 4.89.
(1R,2S,6S,9R)-8-Aza-7,11-dioxa-9-ph en yltr icyclo[6.4.0.02,6]-
d od eca n -12-on e [(9R)-22]. A solution of nitrone (5R)-2 (200.0
mg, 1.05 mmol) and cyclopentene (14; 1.9 mL, 20.92 mmol) in
benzene (10 mL) was stirred at room temperature for 30 h.
The mixture was concentrated in vacuo to give the residue.
HPLC (column A, ethyl acetate/hexane ) 1/4, 1.0 mL/min),
retention time (min) 11.62 (100%). An analytical sample of
(9R)-22 (247.8 mg, 91%) was obtained by recrystallization from
(1R ,2S ,6R ,9R )-8-Aza -5,7,11-t r ioxa -9-p h e n ylt r icyclo-
[6.4.0.02,6]d od eca n -12-on e (18). A solution of nitrone (5R)-2
(20.0 mg, 0.10 mmol) and 2,3-dihydrofuran (10; 79 µL, 1.0
mmol) in benzene (1 mL) was stirred at room temperature for
18 h. The mixture was concentrated in vacuo to give the
residue, which was subjected to column chromatography on
silica gel (hexane/ethyl acetate ) 2/1) to afford a diastereomeric
mixture of cycloadducts (87:13, 22.7 mg, 83%). HPLC (column
A, hexane/ethyl acetate ) 3/1, 1.0 mL/min), retention time
(min) 21.60 (87%), 24.48 (13). Recrystallization from hexanes-
ethyl acetate gave pure 18: mp 204-205 °C (ethyl acetate-
hexane); [R]26 -100° (c 1.03, CHCl3); 1H NMR (500 MHz,
ethyl acetate-hexane: mp 206-207 °C; [R]28 -186° (c 1.03,
D
D
CHCl3); 1H NMR (270 MHz, CDCl3) δ 1.43-1.89 (5H, m), 2.02-
2.07 (1H, m), 3.35 (1H, br q, J ) 6.9 Hz, spin saturation at δ
) 4.70 f 9% NOE), 3.85 (1H, d, J ) 8.6 Hz), 4.10 (1H, dd, J
) 9.9, 4.0 Hz, spin saturation at δ ) 4.70 f 6% NOE), 4.20
(1H, dd, J ) 10.9, 9.9 Hz), 4.27 (1H, dd, J ) 10.9, 4.0 Hz),
4.70 (1H, br dd, J ) 6.9, 5.3 Hz), 7.34-7.46 (5H, m). HRMS
m/z calcd for C15H17NO3, 259.1209; found, 259.1207. Anal.
Calcd for C15H17NO3: C, 69.48; H, 6.61; N, 5.40. Found: C,
69.19; H, 6.57; N, 5.36.
CDCl3) δ 2.08 (1H, br dd, J ) 13.0, 5.5 Hz), 2.23 (1H, ddt, J )
13.0, 11.6, 8.5 Hz), 3.73 (1H, dddd, J ) 8.5, 5.2, 3.7, 1.2 Hz),
3.87 (1H, d, J ) 3.7 Hz), 4.06 (1H, td, J ) 8.5, 1.5 Hz), 4.14
(1H, ddd, J ) 11.3, 8.5, 5.5 Hz), 4.31 (1H, dd, J ) 8.2, 4.0 Hz),
4.38 (1H, dd, J ) 11.9, 8.2 Hz), 4.63 (1H, dd, J ) 11.9, 4.0
Hz), 5.83 (1H, d, J ) 5.2 Hz), 7.33-7.48 (5H, m). HRMS m/z
calcd for C14H15NO4, 261.1001; found, 261.0992. Anal. Calcd
for C14H15NO4: C, 64.35; H, 5.78; N, 5.36. Found: C, 64.09;
H, 5.80; N, 5.31.

N-Oxides as Chiral R-Alkoxycarbonylnitrones
J . Org. Chem., Vol. 65, No. 25, 2000 8551
(1S,2R,6R,9S)-8-Aza-7,11-dioxa-9-ph en yltr icyclo[6.4.0.02,6]-
d od eca n -12-on e [(9S)-22]. This was obtained from (5S)-2 and
14 by the same procedure as that described for (9R)-22: mp
for 4 h. Crystals precipitated were collected by filtration to
yield 30 (1.66 g). The filtrate was concentrated in vacuo to give
a residue, which was purified by chromatography on silica gel
(CH2Cl2/hexane ) 5/1) to afford additional 30 (398 mg, total
206-207 °C (hexane-ethyl acetate); [R]28 +183° (c 0.99,
D
CHCl3).
78%): mp 219-220 °C (hexanes-ethyl acetate); [R]20 +185°
D
1
(1S,4R,5S)-3-Oxo-2-oxa bicyclo[3.3.0]octa -4-yla m m on i-
u m Ch lor id e [(4R)-24] a n d (1S,4R,5S)-4-(3,5-Din itr oben -
zoyl)a m in o-2-oxa bicyclo[3.3.0]octa n -3-on e [(4R)-25]. A
mixture of (9R)-22 (102 mg, 0.39 mmol) and 20% palladium
hydroxide on charcoal (247 mg) in acetic acid (8 mL) was
stirred at room temperature under hydrogen (6 kg/cm2) for 6
h. The catalyst was filtered off, and the filtrate was concen-
trated in vacuo. The residue was dissolved in ethanolic
hydrogen chloride, and then the mixture was concentrated in
vacuo. The residue was dissolved in a minimum amount of
ethanol, and then slow addition of ether gave precipitates of
(c 1.01, CHCl3); H NMR (400 MHz, CDCl3) δ 2.66-2.79 (2H,
m), 3.54 (1H, dddd, J ) 8.8, 7.8, 6.8, 2.4 Hz), 3.82 (1H, d, J )
8.8 Hz), 4.12 (1H, dd, J ) 10.5, 3.7 Hz), 4.21 (1H, dd, J ) 11.5,
10.5 Hz), 4.30 (1H, dd, J ) 11.5, 3.7 Hz), 5.30 (1H, br d, J )
7.8 Hz, spin saturation at δ ) 4.12 f 4% NOE), 5.70 (1H, dq,
J ) 5.6, 2.4 Hz), 5.91 (1H, dtd, J ) 5.6, 2.2, 1.0 Hz), 7.34-
7.46 (5H, m); 13C NMR (100 MHz, CDCl3) δ 37.1, 49.5, 62.0,
70.3, 70.7, 88.1, 128.2, 129.3, 129.5, 130.0, 134.4, 135.8, 173.7.
HRMS m/z calcd for C15H15NO3, 257.1052: found, 257.1051.
Anal. Calcd for C15H15NO3: C, 70.02; H, 5.88; N, 5.44. Found:
C, 69.86; H, 5.88; N, 5.42.
(4R)-24 (62.5 mg, 90%): mp 178-180 °C (ethanol-ether);
(1S ,4S ,5R )-4-(t er t -Bu t yloxyc a r b on yl)a m in o-2-oxa -
bicyclo[3.3.0]oct-7-en -3-on e (34). A mixture of 30 (200 mg,
0.77 mmol) and molybdenum hexacarbonyl (410 mg, 1.55
mmol) in acetonitrile-water (10:1, 25 mL) was heated at reflux
for 2 h. After cooling to 0 °C, di-tert-butyl dicarbonate (1.7 mL,
7.8 mmol) was added to the mixture, and the mixture was
stirred at room temperature for 10 h. The mixture was filtered
through a pad of Celite, and the filtrate was concentrated in
vacuo. The residue was purified by column chromatography
on silica gel (CH2Cl2/ether ) 20/1) to afford 34 (127 mg, 68%):
1
[R]23 -64° (c 0.98, CH3OH); H NMR (270 MHz, CD3OD) δ
D
1.49-2.02 (6H, m), 3.07 (1H, ddt, J ) 5.6, 5.3, 8.9 Hz, spin
saturation at δ ) 4.48 f 7% NOE, δ ) 5.02 f 4% NOE), 4.48
(1H, d, J ) 8.9 Hz, spin saturation at δ ) 3.07 f 6% NOE, δ
) 5.02 f 2% NOE), 5.02 (1H, ddd, J ) 5.3, 4.3, 1.7 Hz, spin
saturation at δ ) 3.07 f 4% NOE, δ ) 4.48 f 2% NOE). This
compound was used for the next step without further purifica-
tion because of its hygroscopicity. To a stirred suspension of
(4R)-24 (2.8 mg, 20 µmol) in dry THF (0.5 mL) were succes-
sively added triethylamine (24 mL, 0.17 mmol) and 3,5-
dinitrobenzoyl chloride (36.3 mg, 0.16 mmol) in dry THF (1
mL) at room temperature. After stirring for 1 h, an aqueous
saturated solution of sodium bicarbonate (1 mL) was added
to the mixture, and the mixture was vigorously stirred for 20
min. The mixture was diluted with water and extracted several
times with dichloromethane. The organic phases were com-
bined, dried (MgSO4), and filtered. The filtrate was concen-
trated in vacuo to give a residue, which was purified by column
chromatography on silica gel to afford (4R)-25 (4.7 mg, 90%):
mp 173-174 °C (ether-hexane); [R]20 +43° (c 0.97, CHCl3);
D
1H NMR (400 MHz, CDCl3) δ 1.39 (9H, s), 2.33 (1H, br d, J )
17.3 Hz), 2.43 (1H, br dd, J ) 17.3, 8.8 Hz), 3.36 (1H, br ddd,
J ) 8.8, 8.3, 6.4 Hz), 4.58 (1H, br dd, J ) 8.3, 4.0 Hz), 5.08
(1H, br s), 5.31 (1H, br d, J ) 6.4 Hz), 5.88 (1H, br dq, J ) 4.6,
2.2 Hz), 6.16 (1H, br dt, J ) 4.6, 2.2 Hz); 13C NMR (100 MHz,
CDCl3) δ 28.5, 32.3, 41.0, 53.8, 80.5, 87.4, 128.5, 141.1, 156,
174. HRMS m/z calcd for C12H17NO4, 239.1156; found, 239.1158.
Anal. Calcd for C12H17NO4: C, 60.24; H, 7.16; N, 5.85. Found:
C, 60.20; H, 7.15; N, 5.84.
mp 231-232 °C (ethyl acetate-hexane); [R]25 -152° (c 1.10,
(1S,4S,5R)-4-Ben zyloxyca r b on yla m in o-2-oxa b icyclo-
[3.3.0]oct-7-en -3-on e (28). To a stirred solution of 34 (100
mg, 0.42 mmol) in dry dichloromethane (3 mL) was added
anhydrous p-toluenesulfonic acid (159 mg, 0.84 mmol) at room
temperature, and then the mixture was stirred at 40 °C for 2
h. After cooling to 0 °C, to the mixture was successively added
a saturated aqueous solution of sodium bicarbonate (1.5 mL)
and benzyl chloroformate (123 µL, 0.84 mmol), and then the
mixture was stirred for 2 h under these conditions. The
mixture was diluted with dichloromethane, washed with
water, dried (MgSO4), and filtered. The filtrate was concen-
trated in vacuo to give a reside, which was purified by column
chromatography on silica gel (ether/hexane ) 1/1) to afford
D
CHCl3); 1H NMR (270 MHz, CDCl3) δ 0.76-2.14 (6H, m), 3.28-
3.39 (1H, m), 5.05 (1H, dd, J ) 8.6, 5.6 Hz), 5.10 (1H, dt, J )
1.3, 5.3 Hz), 7.54 (1H, br d, J ) 4.9 Hz), 8.94 (2H, d, J ) 2.0
Hz), 9.12 (1 H, br t, J ) 2.0 Hz). HRMS m/z calcd for
C
C
14H13N3O7, 335.0754; found, 335.0757. Anal. Calcd for
14H13N3O7: C, 50.15; H, 3.91; N, 12.53. Found: C, 50.01; H,
3.95; N, 12.54. The HPLC analyses using this sample and (4S)-
25 obtained below indicated that optical purity of (4R)-25 was
at least 99% ee. HPLC (column B, hexane/1,2-dichloroethane/
ethanol ) 60/30/10, 1.0 mL/min); mixture of (4R)-25 and (4S)-
25, retention time (min) 5.52, 7.00; (4R)-25, retention time
(min) 6.90 (100%).
28 (98.0 mg, 86%): mp 146-147 °C (ethyl acetate-hexane);
(1R,4S,5R)-3-Oxo-2-oxa bicyclo[3.3.0]octa -4-yla m m on i-
u m Ch lor id e [(4S)-24] a n d (1R,4S,5R)-4-(3,5-Din itr oben -
zoyl)a m in o-2-oxa bicyclo[3.3.0]octa n -3-on e [(4S)-25]. Com-
pound (4S)-24 was obtained from (9S)-22 by the same procedure
as that described for (4R)-24: mp 175-177 °C (ethanol-ether);
1
[R]20 +35° (c 0.97, CHCl3); H NMR (500 MHz, CDCl3, -53
D
°C, two broad signals at room temperature) δ 2.39 (1H, ddt, J
) 18.0, 6.4, 2.2 Hz), 2.54 (1H, ddt, J ) 18.0, 9.1, 2.2 Hz), 3.49
(1H, tt, J ) 9.1, 6.4 Hz), 4.80 (1H, dd, J ) 9.1, 4.9 Hz), 5.13
(1H, d, J ) 11.9 Hz), 5.18 (1H, d, J ) 11.9 Hz), 5.46 (1H, dd,
J ) 6.4, 2.2 Hz), 5.51 (1H, d, J ) 4.9 Hz), 6.01 (1H, dq, J )
5.5, 2.2 Hz), 6.30 (1H, dt, J ) 5.5, 2.2 Hz), 7.40-7.45 (5H, m);
13C NMR (126 MHz, CDCl3, -53 °C) δ 31.9, 40.2, 53.5, 67.3,
87.1, 127.4, 128.2, 128.4, 128.5, 135.2, 141.1, 156.0, 174.4.
HRMS m/z calcd for C15H15NO4, 273.1001; found, 273.1006.
Anal. Calcd for C15H15NO4: C, 65.93; H, 5.53; N, 5.13. Found:
C, 65.75; H, 5.56; N, 5.10. These physical data are identical to
those reported.18b
[R]23 +68° (c 0.95, CH3OH). Compound (4S)-25 was obtained
D
from (4S)-24 by the same procedure as that described for (4R)-
25: mp 231-233 °C (ethyl acetate-hexane); [R]25 -148° (c
D
1.10, CHCl3). The HPLC analyses using this sample and (4R)-
25 obtained below indicated that optical purity of (4S)-25 was
at least 99% ee. HPLC (column B, hexane/1,2-dichloroethane/
ethanol ) 60/30/10, 1.0 mL/min); mixture of (4R)-25 and (4S)-
25, retention time (min) 5.52, 7.00; (4S)-25, retention time
(min) 5.24 (100%).
(3a R,3b S,7S,8a S)-7-P h en yl-3,3a ,3b ,6,7,8a -h exa h yd r o-
5,8-d ioxa -7a -a za cyclop en ta [a ]in d en -4-on e (30). A mixture
of (5S)-2 (50.0 mg, 0.26 mmol) and cyclopentadiene (0.1 mL,
2.62 mmol) in benzene (10 mL) was stirred at room temper-
ature for 4 h. The mixture was concentrated in vacuo to give
a residue, which was subjected to column chromatography on
silica gel (hexane/ethyl acetate ) 3/1) to afford a mixture of
diastereomers. HPLC (column A, CH2Cl2/ethyl acetate ) 10/
1, 1.0 mL/min), retention time (min) 4.66 (80%), 6.38 (16), 7.76
(4). The following preparative experiment was carried out. A
mixture of (5S)-2 (2.65 g, 14 mmol) and cyclopentadiene (9 mL,
0.14 mol) in benzene (30 mL) was stirred at room temperature
Ack n ow led gm en t. This study was partially sup-
ported by a Grant-in-Aid for Scientific Research from
the Ministry of Education, Science, Sports and Culture,
J apan.
Su p p or tin g In for m a tion Ava ila ble: ORTEP diagram
and CIF file of the X-ray structure of (5S)-2, supplementary
discussions for Figure 2 and for Scheme 7. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O000903A