Intermolecular cycloaddition of N-boranonitrone with alkenes

Article abstract of DOI:10.1021/jo800878p

(Chemical Equation Presented) Ethyl glyoxylate O-tert- butyldimethylsilyloxime (8), on treatment with 2.2 equiv of BF ₃·OEt₂, generated N-boranonitrone E, which underwent intermolecular cycloaddition with alkenes 18 to afford isoxazo

Full text of DOI:10.1021/jo800878p

Intermolecular Cycloaddition of N-Boranonitrone with Alkenes
Nobuyoshi Morita,† Kenji Fukui,† Jinshi Irikuchi,† Hiroshi Sato,† Yuu Takano,†
Iwao Okamoto,† Hiroyuki Ishibashi,‡ and Osamu Tamura*,†
Showa Pharmaceutical UniVersity, Higashi-tamagawagakuen, Machida, Tokyo 194-8543, Japan, and
DiVision of Pharmaceutical Sciences, Graduate School of National Science and Technology,
Kanazawa UniVersity, Kanazawa 920-1192, Japan
tamura@ac.shoyaku.ac.jp
ReceiVed April 25, 2008
Ethyl glyoxylate O-tert-butyldimethylsilyloxime (8), on treatment with 2.2 equiv of BF3 ·OEt2, generated
N-boranonitrone E, which underwent intermolecular cycloaddition with alkenes 18 to afford isoxazolidines
19 in moderate to high yields. The cycloaddition of N-boranonitrone E with most of the alkenes gave
3,5-trans isoxazolidines as the major isomers via a concerted mechanism. However, in the case of
1-methylated cyclic alkenes (18j and 18l), the cycloaddition surprisingly furnished the 3,3a-cis-cycloadducts
(19j and 19l) as major isomers. A possible explanation is that the reaction of 1-methylated cyclic alkenes
proceeds mainly via a stepwise mechanism. This reaction of terminal alkenes is very useful for synthesis
of 1,3-anti aminoalcohol derivatives by reductive cleavage of an N-O bond.
SCHEME 1
Introduction
Nitrones are among the most useful and versatile nitrogen-
containing substrates for organic reactions such as nucleophilic
addition,1 radical addition,2 and cycloaddition.3 Among them,
intra- and intermolecular 1,3-dipolar cycloadditions of nitrones
with alkenes are powerful tools for construction of the isox-
azolidine ring system, which can be transformed into structurally
complex and biologically active nitrogen-containing compounds
through reductive cleavage of the nitrogen-oxygen bond.
Compared with nitrone-olefin cycloaddition, intramolecular
oxime-olefin cycloaddition, so-called IOOC,4,5 seems to be a
more attractive reaction, because an oxime functionality is more
readily available and is more stable than is a nitrone function.
IOOC is recognized to proceed via NH-nitrone intermediate A
generated by proton transfer from oxygen to nitrogen in the
oxime functionality, giving N-nonsubstituted cycloadduct 2
(Scheme 1).
† Showa Pharmaceutical University.
‡ Kanazawa University.
(3) For reviews, see: (a) Runa, P.; Subhash, G.; Koushik, C.; Amit, B. Synlett
2007, 2321. (b) Cardona, F.; Goti, A., Angew. Chem., Int. Ed. 2005, 44, 7832.
(c) Gothelf, K. V.; Jørgensen, K. A. Chem. Commun. 2000, 1449. (d) Gothelf,
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F.; Josep, F. Heterocycles 1999, 50, 1213. (h) Frederickson, M. Tetrahedron
1997, 53, 403. For leading references, see: (i) Partidge, K. M.; Anzovino, M. E.;
Yoon, T. P. J. Am. Chem. Soc. 2008, 130, 2920. (j) Shirahase, M.; Kanemasa,
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J. D. J. Am. Chem. Soc. 2002, 124, 4950. (l) Ishikawa, T.; Kudo, T.; Shigemori,
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Y.; Takemoto, Y. Tetrahedron Lett. 2003, 44, 2817. (h) Merino, P.; Tejero, T.
Tetrahedron 2001, 57, 8125. (i) Merino, P.; Franco, S.; Gascon, J. M.; Merchan,
F. L.; Tejero, T. Tetrahedron: Asymmetry 1999, 10, 1867.
(2) (a) Villamena, F. A.; Merle, J. K.; Hadad, C. M.; Zweier, J. L. J. Phys.
Chem. A 2007, 111, 9995. (b) Ueda, M.; Miyabe, H.; Teramachi, M.; Miyata,
O.; Naito, T. J. Org. Chem. 2005, 70, 6653. (c) Ueda, M.; Miyabe, H.; Teramachi,
M.; Miyata, O.; Naito, T. Chem. Commun. 2003, 426.
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10.1021/jo800878p CCC: $40.75 2008 American Chemical Society
Published on Web 08/23/2008

Intermolecular Cycloaddition of N-Boranonitrone with Alkenes
SCHEME 2
SCHEME 4
SCHEME 5
SCHEME 3
SCHEME 6
However, high temperature conditions are often required for
effective IOOCs because of thermodynamically unfavorable
tautomerization from oxime 1 to NH-nitrone A (Scheme 1).6
Accordingly, one of the important factors influencing the
efficiency of IOOC would be the tendency to form NH-nitrone
A from oxime 1. In fact, in the case of the intermolecular
reaction, some groups have reported that an intramolecular
hydrogen bond or metallo-nitrogen bond in the oxime moiety
makes the cycloaddition of oximes more effective. For example,
it was reported that NH-nitrone B generated from oxime 3
having an intramolecular hydrogen bond reacted with N-
phenylmaleimides to afford the corresponding product 4 (Scheme
2).7
On the other hand, palladium(II) salt has been used as a
catalyst to promote intermolecular oxime-olefin cycloaddition
(Scheme 3).8 Thus, treatment of oxime 5 with Pd(II) catalyst
generates N-metallonitrone C as an active intermediate, which
undergoes intermolecular cycloaddition with N-methylmaleim-
ide, furnishing the corresponding isoxazolidine derivatives 6 in
good to high yield.
Recently, we reported a highly efficient BF3-mediated cy-
cloaddition of O-tert-butyldimethylsilyloximes bearing an olefin
moiety, to provide N-nonsubstituted isoxazolidines 2 in good
to high yield (Scheme 4).9 Treatment of O-tert-butyldimethyl-
silyloximes 7 with BF3 ·OEt2 at room temperature smoothly gave
the corresponding isoxazolidines 2 via N-boranonitrones D as
active intermediates. This procedure effectively generates the
nitrone intermediate D by utilizing the strong N-B10 and Si-F
affinities.
More recently, the methodology has been extended to the
intermolecular cycloaddition of O-tert-butyldimethylsilyloximes
8 (O-TBS oxime) with various alkenes via N-boranonitrone E,
furnishing N-nonsubstituted isoxazolidines 9 in good yields
(Scheme 5).11 In this paper, we present a full account of this
work, including stereochemical investigation, mechanistic con-
siderations, and further transformation of cycloadducts to 1,3-
anti-aminoalcohols.
Unfortunately, both reactions are applicable only to a limited
range of activated olefins, such as N-methyl- or N-phenylma-
leimide.
(5) For recent examples, see: (a) Singh, S.; Ishar, M. P. S.; Singh, G.; Singh,
R. Can. J. Chem. 2005, 83, 260. (b) Noguchi, M.; Okada, H.; Tanaka, M.;
Matsumoto, S.; Kakehi, A.; Yamamoto, H. Bull. Chem. Soc. Jpn. 2001, 74, 917.
(c) Cheng, Q.; Zhang, W.; Tagami, Y.; Oritani, T. J. Chem. Soc., Perkin Trans.
1 2001, 452. (d) Falb, E.; Bechor, Y.; Nudelman, A.; Hassner, A.; Albeck, A.;
Gottlieb, H. E. J. Org. Chem. 1999, 64, 498. (e) Dransfield, P. J.; Moutel, S.;
Shipman, M.; Sik, V. J. Chem. Soc., Perkin Trans. 1 1999, 3349. (f) Sharma,
G. V. M.; Srinivas Reddy, I.; Goverdhan Reddy, V.; Rama Rao, A. V.
Tetrahedron: Asymmetry 1999, 10, 229. (g) Baskaran, S.; Aurich, H. G. Synlett
1998, 277. (h) Abiko, A.; Liu, J.-F.; Wang, G.; Masamune, S. Tetrahedron Lett.
1997, 38, 3261. (i) Hassner, A.; Maurya, R.; Friedman, O.; Gottlib, H. E.; Padwa,
A.; Austin, D. J. Org. Chem. 1993, 58, 4539. (j) Hassner, A.; Singh, S.; Sharma,
R.; Maurya, R. Tetrahedron 1993, 49, 2317. (k) Hassner, A.; Maurya, R.; Padwa,
A.; Bullock, W. H. J. Org. Chem. 1991, 56, 2775.
(6) Formaldehyde oxime [HO-NdCH2] was estimated to be 11.1 kcal/mol
more stable than the corresponding nitrone [-O-N+(H)dCH2] by theoretical
analysis. See: Long, J. A.; Harris, N. J.; Lammertsma, K. J. Org. Chem. 2001,
66, 6762.
(7) (a) Shirai, M.; Kuwabara, H.; Matsumoto, S.; Yamamoto, H.; Kakehi,
A.; Noguchi, M. Tetrahedron 2003, 59, 4113. (b) Grigg, R.; Thianpantagul, S.
J. Chem. Soc., Perkin Trans. 1 1984, 653.
Results and Discussion
1. Simple Extension of Cycloaddition of N-Boranonitrone
F to Intermolecular Variant. We initiated our study by
(9) (a) Tamura, O.; Mitsuya, T.; Huang, X.; Tsutsumi, Y.; Hattori, S.;
Ishibashi, H. J. Org. Chem. 2005, 70, 10720. (b) Tamura, O.; Mitsuya, T.;
Ishibashi, H. Chem. Commun. 2002, 1128.
(10) (a) Grecian, S.; Desai, P.; Mossman, C.; Poutsma, J. L.; Aube, J. J.
Org. Chem. 2007, 72, 9439. (b) Ma, Y.; Lobkovsky, E.; Collum, D. B. J. Org.
Chem. 2005, 70, 2335. (c) Gossauer, A.; Fehr, F.; Nydegger, F.; Stockli-Evans,
H. J. Am. Chem. Soc. 1997, 119, 1599. (d) Shoemaker, J. A. W.; Hartman, J. S.
Can. J. Chem. 1999, 77, 1856. (e) Hartman, J. S.; Yuan, Z.; Fox, A.; Nguyen,
A. Can. J. Chem. 1996, 74, 2131.
(11) Tamura, O.; Morita, N.; Takano, Y.; Fukui, K.; Okamoto, I.; Haung,
X.; Tsutsumi, Y.; Ishibashi, H. Synlett 2007, 658. Quite recently, N-nonsubstituted
isoxazolidines were also obtained by cycloaddition of N-nosyl nitrones with
alkenes followed by deprotection with a thiol. See ref 3i.
(8) Frederickson, M.; Grigg, R.; Thornton-Pett, M.; Redpath, J. Tetrahedron
Lett. 1997, 38, 7777.
J. Org. Chem. Vol. 73, No. 18, 2008 7165

Morita et al.
FIGURE 2. Electronic effect of N-boranonitrone.
FIGURE 1. Selected NOEs of 12.
SCHEME 7
FIGURE 3. Frontier orbitals of F and E′.
SCHEME 8
examining the cycloaddition of benzaldehyde O-TBS oxime 1012
with styrene (18a) as a simple extension to an intermolecular
variant. Oxime 10, on treatment with styrene (18a) (10 equiv)
in the presence of 2.2 equiv of BF3 ·OEt2 in 1,2-dichloroethane
at 60 °C for 24 h,13 underwent intermolecular cycloaddition
via N-boranonitrone F to give the trans-cycloadduct 11 as a
single isomer in 40% yield (Scheme 6).
The stereochemical assignment of the product 11 was carried
out on the basis of NOE measurements of the acylated derivative
12 (Figure 1). We next attempted to improve the chemical yield
but found that reproducibility of the reaction was poor, and the
product 11 was unstable. Typically, we obtained low yield
(∼10%) with no stereoselectivity (1:1 mixture of diastereomers
of the product 11).
2. Design of N-Borano-C-ethoxycarbonyl Nitrone and
Preparation of Its Precusor. During our study on the intramo-
lecular cycloaddition of N-boranonitrone, we observed that
electron-rich carbon in the olefin tends to attack the nitrone-
carbon. For example, the reaction of oxime 13a with BF3 ·OEt2
afforded the cycloadduct 14 having a bicyclo[3.3.0] system,
whereas a similar reaction of oxime 13b afforded the cycload-
duct 15 having a bicyclo[3.2.1] system (Scheme 7).
These results show that N-boranonitrone is electrophilic in
nature. Therefore, we anticipated that replacement of the phenyl
group in N-boranonitrone F with an ester group would allow
the generation of a more electrophilic intermediary N-borano-
nitrone, which may be activated and more readily undergo the
cycloaddition (Figure 2).
MgCl2 in ethanol. Silylation of ethyl glyoxylate oxime (17)
under usual conditions afforded ethyl glyoxylate O-TBS oxime
(8) in 86% yield (2 steps).
3. Reaction of N-Borano-C-ethoxycarbonyl Nitrone with
Acyclic Alkenes. Treatment of O-TBS oxime 8 with various
alkenes 18a-h in the presence of 2.2 equiv of BF3 ·OEt2 in
1,2-dichloroethane at 60 °C under argon afforded the corre-
sponding products 19a-h in moderate to good yields (Table
1). In contrast to benzaldehyde O-TBS oxime 10, reaction of
O-TBS oxime 8 with styrene (18a) smoothly proceeded to give
the cycloadduct 19a in 71% yield as a 5:1 mixture of
diastereomers (entry 1). This result shows that the N-borano-
nitrone bearing the ester group (E) is more electrophilic and
reactive than is the N-boranonitrone having the phenyl group
(F), as expected. In addition, reaction of O-TBS oximes 8
showed good reproducibility, differing from that of benzalde-
hyde O-TBS oxime 10 with styrene (18a). In the case of
aliphatic terminal alkenes 18b and 18c, trans-cycloadducts 19b
and 19c were obtained in 78% (77:1 diastereoselectivity) and
61% (7:1 diastereoselectivity) yields, respectively, although these
reactions required prolonged reaction times (entries 2 and 3).
1,1-Disubstituted alkene 18d reacted with N-boranonitrone E,
giving rise to 5,5-disubstituted isoxazolidine 19d in rather low
yield, probably due to polymerization of the alkene 18d during
the reaction (entry 4). When O-TBS oxime 8 was treated with
ethyl methacrylate (18e) in the presence of BF3 ·OEt2 for 15 h,
cycloadduct 19e was obtained in 53% yield as a 6:1 mixture of
diastereomers (entry 5). This reaction would be applicable for
syntheses of naturally occurring 4-hydroxy-4-substituted glutam-
ic acids.15 Next, reactions of 1,2-disubstituted alkenes were
examined by using trans- and cis-3-hexene (18f and 18g)
(entries 6 and 7). Thus, trans-3-hexene (18f) furnished the
corresponding product 19f as a single isomer in 27% yield,
whereas cis-3-hexene (18g) gave 19f and 19g in 33% yield as
To estimate the difference in electrophilic nature of the
intermediary N-boranonitrones E′ and F, preliminary calcula-
tions (AM1) were conducted for the E-form of N-boranonitrone
(Figure 3). Comparison of calculated LUMOs indicates that
N-boranonitrone having the ester group (E′) is more electrophilic
than is N-boranonitrone bearing the phenyl group (F).
As shown in Scheme 8, the requisite O-TBS oxime 8 was
prepared from commercially available chloral hydrate (16).
Thus, hydrate 16 was converted into glyoxylate oxime 1714 by
treatment with hydroxyammonium sulfate in the presence of
(12) Hoffmann, R. V.; Buntain, G. A. Synthesis 1987, 831.
(13) For completion of the cycloaddition, 2 equiv of BF3 · OEt2 are essential.
See ref 9.
(15) (a) Tamura, O.; Shiro, T.; Ogasawara, M.; Toyao, A.; Ishibashi, H. J.
Org. Chem. 2005, 70, 4569. (b) Baldwin, S. W.; Long, A. Org. Lett. 2004, 6,
1653.
(14) Adachi, I.; Yamamori, T.; Hiramatsu, Y. JP 1977-50939.
7166 J. Org. Chem. Vol. 73, No. 18, 2008

Intermolecular Cycloaddition of N-Boranonitrone with Alkenes
TABLE 1. Cycloaddition of O-TBS Oxime 8 with Alkenes 18a-h
in the Presence of BF3 ·OEt2
FIGURE 4. Selected NOEs of cycloadducts 20 derived from acyclic
alkenes.
after acylation with 3,5-dinitrobenzoyl chloride under usual
conditions (Figure 4). The NOE difference spectra revealed that
major products 20a-e have 3,5-trans stereochemistry of their
isoxazolidine skeleton. The stereochemistry of the product 20f
derived from trans-3-hexene (18f) has 3,4-cis and 4,5-trans
relationships, whereas the product 20g derived from cis-3-
hexene (18g) has 3,4-trans and 4,5-cis relationships of
isoxazolidine.
4. Mechanistic Considerations. Reaction of electron-rich
styrene (18a) gave a good yield of cycloadduct, whereas
electron-poor maleimide 18h was inactive in the reaction (Table
1, entries 1 vs 8). These results strongly suggest that the
intermediary N-boranonitrone E should be electrophilic. Since
reaction of 18e afforded the cycloadduct 19e, the cycloaddition
of N-boranonitrone E with olefins 18 would proceed through a
concerted mechanism. If the reaction proceeds though a typical
stepwise mechanism, it would involve the unstable intermediate
H having a cation adjacent to the ester group (Scheme 9).
Accordingly, the reaction should proceed predominantly via the
concerted mechanism.
a Isolated yields.
a 1:2 mixture of diastereomers. Low yields of the products in
both cases may be ascribed to steric interaction and/or instability
of olefins during the reactions. The reaction of O-TBS oxime 8
with N-phenylmaleimide (18h) as an electron-poor olefin
afforded the corresponding product 19h as a single isomer in
miserable yield (entry 8).
We attempted to elucidate the stereochemistry of cycloadducts
19a-g by means of NOE measurement. However, the 1H NMR
spectra of products 19 often showed broadened signals inap-
propriate for NOE measurements, probably due to partial
coupling with NH of the isoxazolidines. Therefore, determina-
tion of the stereochemistry of cycloadducts 19 was carried out
On the other hand, the reaction of cis-3-hexene (18g) with
N-boranonitrone E gave the 4,5-cis cycloadduct 19g (22%) along
with the 4,5-trans cycloadduct 19f (11%) (Scheme 10, Table
1, entry 7). This result indicates that the cycloaddition of 18g
involves both the concerted mechanism and in part the stepwise
mechanism.
J. Org. Chem. Vol. 73, No. 18, 2008 7167

Morita et al.
SCHEME 9
FIGURE 5. Calculation of N-boranonitrone E′ by RHF/6-31G*.
SCHEME 10
For a better understanding of the cycloaddition, calculations
on the intermediary N-boranonitrone were next conducted. Four
types of geometries E′1-E′4 for nitrone E′ were computed using
the RHF/6-31G* basis set (Figure 5). The calculations indicated
that (E)-nitrone E′3 and E′4 are much more stable than (Z)-
nitrone E′1 and E′2. Optimization of the geometries of E′3 and
E′4 having the five-membered boracycles revealed that E′4 is
the most stable isomer among the four nitrones E′1-E′4.
Taking the geometry of E′4 into account, the energy levels
of the transition state (TS) models endo TS I and exo TS J
(using propene as an alkene) were calculated, using the RHF/
3-21G(*) basis set (Figure 6). Exo TS J was estimated to be
1.2 kcal/mol more stable than endo TS I, which may have steric
interaction between the methyl group of alkene and the fluorine
atom of the nitrone. Accordingly, the cycloaddition of N-
boranonitrone E with terminal alkenes 18a-c should proceed
via exo TS J, affording the 3,5-trans cycloadducts 19a-c (Table
1, entries 1-3). During the cycloaddition, a second equivalent
of BF3 might coordinate to the oxygen anion of N-boranonitrone
E.16
FIGURE 6. Calculation, using RHF/3-21G(*), of transition states for
cycloaddition of N-boranonitrone with a terminal alkene.
E with acyclic olefins 18a-g prompted us to examine the
reaction with cyclic olefins, such as cyclopentenes and cyclo-
hexenes (Table 2). Reactions of O-TBS oxime 8 with cyclo-
pentenes 18i and 18j in the presence of BF3 ·OEt2 afforded
bicyclic products 19i (8:1 diastereomeric ratio) and 19j (3:1
diastereomeric ratio) in 65% and 79% yields, respectively
(entries 1 and 2). In contrast, it was found that the corresponding
cyclohexenes were less reactive. Thus, cycloaddition of cyclo-
hexenes 18k and 18l gave the corresponding products in 33%
yield (19k) as a 8:1 mixture of diastereomers and in 32% yield
(19l) as a 3:1 mixture of diastereomers (entries 3 and 4).
After acylation, as described above for 19a-g (Figure 4),
the stereochemistry of the bicyclic products 19i-l was also
determined by analysis of NOE difference spectra of 20i′, 20j,
20k′, and 20l (Figure 7). Surprisingly, the reaction of cyclo-
pentene (18i) and cyclohexene (18k) provided 3,3a-trans adducts
19i and 19k, whereas 1-methylcyclopentene (18j) and 1-meth-
ylcyclohexene (18l) afforded 3,3a-cis adducts 19j and 19l,
respectively.
5. Reaction of N-Borano-C-ethoxycarbonyl Nitrone with
Cyclic Alkenes. The efficient cycloaddition of N-boranonitrone
To understand the difference in stereoselectivity of the
reactions between nonsubstituted cyclic alkene (18i and 18k)
(16) Katagiri, N.; Okada, M.; Morishita, Y.; Kaneko, C. Tetrahedron 1997,
53, 5725.
7168 J. Org. Chem. Vol. 73, No. 18, 2008

Intermolecular Cycloaddition of N-Boranonitrone with Alkenes
TABLE 2. Cycloaddition of O-TBS Oxime 8 with Cyclic Alkenes
18i-l in the Presence of BF3 ·OEt2
FIGURE 8. Calculated transition states, using RHF/3-21G(*), for
cycloaddition of N-boranonitrone with cyclopentene (18i).
and methylated cyclic alkenes (18j and 18l), the energy levels
of the transition states TS K and L for the reactions of
cyclopentene and TS M and N for the reactions of 1-methyl-
cyclopentene were calculated using the RHF/3-21G(*) basis set
(Figure 8 and 9). The results indicated that TS L is more stable
than TS K by 4.4 kcal/mol. This conclusion seems reasonable
in view of the likely steric interaction between methylenes of
cyclopentene and the boracycle of the nitrone and is consistent
with the experimental results of cycloaddition of cyclopentene
with N-boranonitrone, leading to cycloadduct 19i (Figure 8,
Table 2, entry 1). On the other hand, calculations of TSs M
and N for cycloaddition of 1-methylcyclopentene with N-
FIGURE 9. Calculated transition states, using RHF/3-21G(*), for
cycloaddition of N-boranonitrone with 1-methylcyclopentene (18j).
boranonitrone indicated that TS N leading to 19j′ (minor isomer)
was more stable than TS M by 4.2 kcal/mol. However, this
calculation is inconsistent with the fact that reaction of 1-me-
thylcyclopentene with N-boranonitrone gave the 3,3a-cis adduct
19j as the major isomer. This inconsistency may indicate that
a stepwise mechanism operates in the reaction of 1-methylcy-
clopentene. Since even the reaction of N-boranonitrone E with
cis-3-hexene (18g) proceeds via both a concerted mechanism
and a stepwise mechanism, it seems reasonable to consider a
stepwise mechanism for the reaction of 1-methylcyclopentene
with N-boranonitrone, which may generate a stable tert-
carbocation intermediate. TSs O and P are candidate transition
states of the stepwise mechanism (Figure 10). Since TS O has
severe steric interaction between the cyclopentene ring and
fluorine atom of N-boranonitrone, the reaction may proceed via
TS P. Thus, N-boranonitrone reacts with 1-methylcyclopentene
(18j) via TS P, giving the zwitterionic intermediate Q, which
undergoes C-O bond formation between the oxygen anion and
tert-carbocation after rotation of the cyclopentane ring about
the generated C-C single bond, affording the 3,3a-cis-adduct
19j. Similarly, the reaction of cyclohexene (18k) would proceed
via a concerted mechanism to give the 3,3a-trans-cycloadduct
19k, whereas the reaction of 1-methylcyclohexene (18l) afforded
the 3,3a-cis adduct 19l, probably via a stepwise mechanism.
6. Application to Synthesis of 1,3-anti Aminoalcohols. To
validate the applicability of our methodology in organic
FIGURE 7. Selected NOEs of cycloadducts derived from cyclic
alkenes.
J. Org. Chem. Vol. 73, No. 18, 2008 7169

Morita et al.
O-TBS oxime 8 by utilizing the strong N-B and Si-F affinities,
is a highly electrophilic and active intermediate. To our
knowledge, this is the first example of intermolecular cycload-
dition of oxime derivatives with various alkenes. Further
extension of the procedure is currently under investigation in
our laboratories.
Experimental Section
Ethyl Glyoxylate-O-tert-butyldimethylsilyloxime (8). To a solu-
tion of ethyl 2-hydroxyiminoacetate (17)14 (0.91 g, 7.8 mmol) in
DMF (12 mL) were added tert-butylchlorodimethylsilane (1.8 g,
12 mmol) and imidazole (1.6 g, 24 mmol) at 0 °C under argon.
The mixture was stirred for 46 h, poured into water, and extracted
with Et2O. The combined organic phases were washed with brine
and dried over Na2SO4. The solvent was removed by rotary
evaporation and the crude product was purified by column chro-
matography on silica gel with hexane-Et2O (20:1) to afford 8 (1.8
1
g, 98%) as a colorless oil. IR (KBr) 1749, 1728 cm-1; H NMR
(300 MHz, CDCl3) δ 7.62 (1H, s), 4.30 (2H, q, J ) 7.1 Hz), 1.33
(3H, t, J ) 7.1 Hz), 0.95 (9H, s), 0.23 (6H, s); 13C NMR (75 MHz,
CDCl3) δ 162.3, 146.1, 61.3, 25.7, 18.0, 14.0, -5.4; HRMS (EI)
m/z calcd for C10H21NO3Si 231.1291, found 231.1270.
General Procedure for Cycloaddition of O-TBS Oxime 8 with
Alkenes 18. To a solution of 8 in (CH2Cl)2 were added alkene 18
and BF3 ·OEt2 at room temperature, and then the reaction mixture
was stirred at 60 °C for 2-22 h under argon. After complete
consumption of 8, a saturated aqueous solution of NaHCO3 was
added to the reaction mixture at 0 °C, and the whole was extracted
with CH2Cl2. The combined organic phases were washed with brine,
dried over sodium sulfate, and concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel
with hexane-AcOEt as eluent to afford the product 19.
FIGURE 10. Proposed reaction mechanism for reaction of N-borano-
nitrone with 1-methylcyclopentene (18j).
SCHEME 11
General Procedure for the Acylation of the Cycloadducts 19.
To a solution of cycloadduct 19 in THF was added Et3N and 3,5-
dinitrobenzoyl chloride at 0 °C under argon. The mixture was stirred
for 1-24 h at room temperature, poured into water, and extracted
with CH2Cl2. The combined organic phases were washed with brine
and dried over sodium sulfate. The solvent was removed by
evaporation, and the crude product was purified by column
chromatography on silica gel with hexane-AcOEt to afford the
product 20.
(3R*,5R*)-3,5-Diphenylisoxazolidine (11). A mixture of 10 (200
mg, 0.85 mmol), 18a (0.97 mL, 8.5 mmol) and BF3 ·OEt2 (0.24
mL, 1.9 mmol) in (CH2Cl)2 (5 mL) furnished 11 (77 mg, 40%) as
1
a colorless oil. [reaction time: 24 h/hexane-AcOEt ) 10:1] H
NMR (300 MHz, CDCl3) δ 7.55-7.25 (10H, m), 5.21 (1H, dd, J
) 8.1, 6.9 Hz), 4.72-4.65 (1H, br d, J ) 7.5 Hz), 2.81-2.63 (2H,
m); 13C NMR (75 MHz, CDCl3) δ 142.5, 135.3, 129.1, 128.8, 128.1,
127.3, 126.1, 124.8, 83.3, 61.0, 41.5; HRMS (EI) m/z calcd for
C15H15NO 225.1154, found 225.1148.
synthesis, we tried the synthesis of 1,3-anti aminoalcohol
(Scheme 11). Treatment of isoxazolidines 19a-c with NaBH4
in THF followed by protection with Boc2O afforded the alcohol
derivatives 21a-c in 63-87% yields in two steps. The cleavage
of the N-O bond with molybdenum hexacarbonyl in boiling
CH3CN-H2O gave 1,3-aminoalcohols 22a-c in 58-83% yield.
This synthetic sequence demonstrates the potential utility of the
present cycloaddition for the synthesis of natural products and
related compounds of biological importance.17
7. Conclusions. We have explored a highly efficient inter-
molecular cycloaddition of N-boranonitrone E with various
alkenes to give the corresponding isoxazolidine derivatives in
moderate to high yields. N-Boranonitrone E, generated from
(3R*,5R*)-3,5-Diphenyl-2-(3,5-dinitrobenzoyl)isoxazolidine (12).
A mixture of cycloadduct 11 (17 mg, 0.075 mmol), Et3N (12 µL,
0.083 mmol) and 3,5-dinitrobenzoyl chloride (19 mg, 0.083 mmol)
in THF (3 mL) furnished 12 (24 mg, 75%) as a colorless oil.
[reaction time: 12 h/hexane-AcOEt ) 5:1] IR (neat) 1655 cm-1
;
1H NMR (300 MHz, CDCl3) δ 9.02 (1H, br t, J ) 2.1 Hz), 8.66
(2H, d, J ) 2.4 Hz), 7.53-7.13 (10H, m), 5.94 (1H, dd, J ) 8.7,
5.7 Hz; spin saturation at δ ) 3.21/5% NOE), 5.53 (1H, dd, J )
7.2, 4.2 Hz; spin saturation at δ ) 2.84/5% NOE), 3.21 (1H, ddd,
J ) 12.9, 8.7, 3.9 Hz), 2.84 (1H, ddd, J ) 12.9, 7.2, 5.7 Hz); 13C
NMR (75 MHz, CDCl3) δ 164.6, 148.1, 140.2, 136.4, 134.8, 129.7,
129.4, 129.1, 128.9, 128.1, 126.7, 126.2, 121.0, 85.3, 62.0, 45.6;
HRMS (EI) m/z calcd for C22H17N3O6 419.1117, found 419.1115.
(3R*,5R*)-5-Phenylisoxazolidine-3-carboxylic Acid Ethyl Ester
(19a) and (3R*,5S*)-5-Phenylisoxazolidine-3-carboxylic Acid Eth-
yl Ester (19a′). A mixture of 8 (210 mg, 0.91 mmol), 18a (1.5 mL,
13 mmol) and BF3 ·OEt2 (0.25 mL, 1.9 mmol) in (CH2Cl)2 (5 mL)
(17) (a) Stauffer, C. S.; Bhaket, P.; Fothergill, A. W.; Rinaldi, M. G.; Datta,
A. J. Org. Chem. 2007, 72, 9991. (b) Iida, H.; Kasahara, K.; Kibayashi, C. J. Am.
Chem. Soc. 1986, 108, 4647. (c) Tufariello, J. J. Acc. Chem. Res. 1979, 12, 396.
7170 J. Org. Chem. Vol. 73, No. 18, 2008

Intermolecular Cycloaddition of N-Boranonitrone with Alkenes
afforded 19a (120 mg, 59%) and 19a′ (25 mg, 12%), each as a
colorless oil. [reaction time: 2 h/hexane-AcOEt ) 2:1] 19a: IR
(KBr) 1732 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.40-7.20 (5H,
m), 6.09 (1H, br s), 5.03 (1H, br s), 4.22 (2H, q, J ) 7.2 Hz),
4.22-4.16 (1H, m), 3.02-2.93 (1H, m), 2.53-2.44 (1H, m), 1.29
(3H, t, J ) 7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 172.0, 134.4,
128.6, 128.2, 126.4, 83.0, 61.8, 61.6, 42.7, 14.1; HRMS (EI) m/z
calcd for C12H15NO3 221.1052, found 221.1054. 19a′: IR (KBr)
1734 cm-1;1H NMR (300 MHz, CDCl3) δ 7.40-7.25 (5H, m), 7.10
(1H, br s), 5.03 (1H, br s), 4.23 (2H, q, J ) 7.2 Hz), 4.20 (1H, m),
2.98 (1H, ddd, J ) 12.6, 8.7, 7.5 Hz), 2.49 (1H, m), 1.29 (3H, t,
J ) 7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 171.6, 139.0, 128.6,
128.2, 126.4, 85.0, 62.0, 61.7, 41.6, 14.1; HRMS (FAB) m/z calcd
for C12H16NO3 [M + H]+ 222.1130, found 222.1128.
NOE), 4.30 (2H, br q, J ) 7.2 Hz), 2.60 (1H, ddd, J ) 12.6, 5.4,
3.3 Hz), 2.40 (1H, ddd, J ) 12.6, 9.3, 7.8 Hz), 1.65-1.55 (2H,
m), 1.32 (3H, t, J ) 7.2 Hz), 1.31-1.28 (4H, m), 0.86 (3H, t, J )
7.5 Hz); 13C NMR (75 MHz, CDCl3) δ 169.1, 161.0, 148.1, 136.0,
129.7, 121.0, 82.0, 62.3, 58.7, 37.2, 32.0, 28.1, 22.3, 14.1, 13.8;
HRMS (EI) m/z calcd for C17H21N3O8 395.1329, found 395.1327.
(3R*,5S*)-5-(4-Methoxybutyl)isoxazolidine-3-carboxylic Acid Eth-
yl Ester (19c) and (3R*,5R*)-5-(4-Methoxybutyl)isoxazolidine-3-
carboxylic Acid Ethyl Ester (19c′). A mixture of 8 (290 mg, 1.30
mmol), 18c (1.4 mL, 12 mmol) and BF3 ·OEt2 (0.36 mL, 2.8 mmol)
in (CH2Cl)2 (5 mL) afforded 19c (150 mg, 53%) and 19c′ (24 mg,
8%), each as a colorless oil. [reaction time: 22 h/hexane-AcOEt
1
) 1:1] 19c: IR (KBr) 1732 cm-1; H NMR (300 MHz, CDCl3) δ
5.82 (1H, br s), 4.22 (2H, q, J ) 7.2 Hz), 4.02-3.97 (1H, m), 3.86
(1H, br s), 3.36 (2H, t, J ) 6.3 Hz), 3.31 (3H, s), 2.35-2.28 (1H,
m), 2.18-2.07 (1H, m), 1.75-1.43 (6H, m), 1.29 (3H, t, J ) 7.2
Hz); 13C NMR (75 MHz, CDCl3) δ 172.2, 81.6, 72.4, 61.6, 61.2,
58.5, 40.3, 32.8, 29.5, 22.9, 14.0; HRMS (EI) m/z calcd for
C11H21NO4 231.1471, found 231.1447. 19c′: IR (KBr) 1724 cm-1
1H NMR (300 MHz, CDCl3) δ 5.83 (1H, br s), 4.23 (2H, q, J )
7.2 Hz), 4.25-4.18 (1H, m), 4.01 (1H, dd, J ) 9.3, 6.0 Hz), 3.38
(2H, t, J ) 6.3 Hz), 3.33 (3H, s), 2.69-2.59 (1H, m), 2.05-1.95
(1H, m), 1.73-1.43 (6H, m), 1.30 (3H, s); 13C NMR (75 MHz,
CDCl3) δ 172.8, 80.8, 72.5, 61.6, 61.4, 58.6, 43.3, 29.7, 29.5, 22.9,
14.1; HRMS (EI) m/z calcd for C11H21NO4 231.1471, found
231.1424.
(3R*,5R*)-2-(3,5-Dinitrobenzoyl)-5-phenylisoxazolidine-3-car-
boxylic Acid Ethyl Ester (20a). A mixture of cycloadduct 19a (43
mg, 0.19 mmol), Et3N (32 µL, 0.23 mmol) and 3,5-dinitrobenzoyl
chloride (58 mg, 0.25 mmol) in THF (5 mL) furnished 20a (74
mg, 91%) as a colorless oil. [reaction time: 5 h/hexane-AcOEt )
1
2:1] IR (KBr) 1743, 1661 cm-1; H NMR (300 MHz, acetone-d6)
δ 9.01 (1H, br t, J ) 2.1 Hz), 8.74 (2H, d, J ) 2.1 Hz), 7.51-7.29
(5H, m), 5.62 (1H, br t, J ) 6.0 Hz), 5.33 (1H, dd, J ) 9.0, 4.5
Hz), 4.29 (2H, q, J ) 7.2 Hz), 3.13 (1H, ddd, J ) 12.9, 9.0, 6.0
Hz; spin saturation at δ ) 5.33/5% NOE), 3.00 (1H, ddd, J ) 12.9,
6.0, 4.5 Hz; spin saturation at δ ) 5.62/8% NOE), 1.31 (3H, t, J
) 7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 169.2, 163.6, 147.9,
136.0, 135.0, 129.6, 129.3, 128.9, 127.0, 120.7, 82.9, 62.5, 59.0,
37.3, 14.2; HRMS (EI) m/z calcd for C19H17N3O8 415.1016, found
415.1005.
(3R*,5S*)-2-(3,5-Dinitrobenzoyl)-5-(4-methoxybutyl)isoxazolidine-
3-carboxylic Acid Ethyl Ester (20c). A mixture of cycloadduct 19c
(38 mg, 0.17 mmol), Et3N (28 µL, 0.20 mmol) and 3,5-dinitroben-
zoyl chloride (47 mg, 0.20 mmol) in THF (5 mL) furnished 20c
(37 mg, 52%) as a colorless oil. [reaction time: 24 h/hexane-AcOEt
(3R*,5S*)-2-(3,5-Dinitrobenzoyl)-5-phenylisoxazolidine-3-car-
boxylic Acid Ethyl Ester (20a′). A mixture of cycloadduct 19a′ (20
mg, 0.090 mmol), Et3N (15 µL, 0.11 mmol) and 3,5-dinitrobenzoyl
chloride (31 mg, 0.13 mmol) in THF (5 mL) furnished 20a′ (26
mg, 71%) as a colorless oil. [reaction time: 2 h/hexane-AcOEt )
) 5:3] IR (KBr) 1745 cm-1 1H NMR (300 MHz, CDCl3) δ
;
9.18-9.13 (3H, m), 5.02 (1H, dd, J ) 9.6, 3.3 Hz; spin saturation
at δ ) 2.41/5% NOE), 4.56-4.47 (1H, m; spin saturation at δ )
2.61/4% NOE), 4.30 (2H, q, J ) 6.9 Hz), 3.30 (2H, t, J ) 6.0 Hz),
3.27 (3H, s), 2.61 (1H, ddd, J ) 12.6, 9.3, 5.7 Hz), 2.41 (1H, ddd,
J ) 12.6, 9.3, 7.8 Hz), 1.64-1.36 (6H, m), 1.34 (3H, t, J ) 7.2
Hz); 13C NMR (75 MHz, CDCl3) δ 169.1, 161.3, 148.1, 135.9,
129.7, 121.0, 82.0, 72.1, 62.3, 58.6, 58.5, 37.2, 32.2, 29.3, 22.9,
14.1; HRMS (EI) m/z calcd for C18H23N3O9 425.1434, found
425.1437.
1
2:1] IR (KBr) 1745, 1658 cm-1; H NMR (300 MHz, CDCl3) δ
9.16-9.12 (3H, m), 7.42-7.35 (5H, m), 5.29 (1H, dd, J ) 9.3, 7.5
Hz), 5.05 (1H, dd, J ) 10.2, 6.0 Hz), 4.32 (2H, q, J ) 7.2 Hz),
3.16 (1H, ddd, J ) 12.6, 9.3, 6.0 Hz; spin saturation at δ ) 5.29/
16% NOE; δ ) 5.05/16% NOE), 2.63 (1H, ddd, J ) 12.6, 10.2,
7.5 Hz), 1.35 (3H, t, J ) 7.2 Hz); 13C NMR (75 MHz, CDCl3) δ
168.9, 163.6, 148.1, 135.7, 134.4, 129.7, 129.6, 129.0, 126.7, 121.2,
84.6, 62.4, 59.0, 39.7, 14.1; HRMS (EI) m/z calcd for C19H17N3O8
415.1016, found 415.1007.
5,5-Diethylisoxazolidine-3-carbozylic Acid Ethyl Ester (19d). A
mixture of 8 (300 mg, 1.3 mmol), 18d (1.5 mL, 12 mmol) and
BF3 ·OEt2 (0.36 mL, 2.8 mmol) in (CH2Cl)2 (5 mL) afforded 19d
(86 mg, 33%) as a colorless oil. [reaction time: 3 h/hexane-AcOEt
(3R*,5S*)-5-Butylisoxazolidine-3-carboxylic Acid Ethyl Ester
(19b) and (3R*,5R*)-5-Butylisoxazolidine-3-carboxylic Acid Eth-
yl Ester (19b′). A mixture of 8 (300 mg, 1.3 mmol), 18b (1.60 mL,
13 mmol) and BF3 ·OEt2 (0.35 mL, 2.9 mmol) in (CH2Cl)2 (10
mL) afforded 19b (200 mg, 77%) and 19b′ (3 mg, 1%), each as a
colorless oil. [reaction time: 18 h/hexane-AcOEt ) 2:1] 19b: IR
(KBr) 1733 cm-1; 1H NMR (300 MHz, CDCl3) δ 5.81 (1H, br s),
4.22 (2H, q, J ) 7.2 Hz), 4.00 (1H, br q, J ) 4.5 Hz), 3.87-3.83
(1H, m), 2.35-2.25 (1H, m), 2.17-2.07 (1H, m), 1.70-1.62 (1H,
m), 1.61-1.50 (1H, m), 1.48-1.30 (4H, m), 1.29 (3H, t, J ) 7.2
Hz), 0.90 (3H, t, J ) 7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 172.3,
81.8, 61.6, 61.1, 40.4, 32.7, 28.4, 22.6, 14.0, 13.9; HRMS (EI) m/z
1
) 3:1] IR (KBr) 1734 cm-1; H NMR (300 MHz, CDCl3) δ 5.89
(1H, br s), 4.23 (2H, q, J ) 7.2 Hz), 3.99 (1H, dd, J ) 9.0, 7.5
Hz), 2.32 (1H, dd, J ) 12.5, 9.2 Hz), 2.03 (1H, m), 1.59 (4H, m),
1.30 (3H, t, J ) 7.1 Hz), 0.92 (3H, t, J ) 7.5 Hz), 0.90 (3H, t, J
) 7.5 Hz); 13C NMR (75 MHz, CDCl3) δ 171.7, 88.6, 62.1, 61.4,
43.2, 28.6, 28.4, 14.1, 8.5, 8.3; HRMS (EI) m/z calcd for C10H19NO3
201.1365, found 201.1361.
(3R*,5R*)-5-Methylisoxazolidine-3,5-dicarboxylic Acid Dieth-
yl Ester (19e) and (3R*,5S*)-5-Methylisoxazolidine-3,5-dicarboxy-
lic Acid Diethyl Ester (19e′). A mixture of 8 (210 mg, 0.92 mmol),
18e (1.4 mL, 12 mmol) and BF3 ·OEt2 (0.25 mL, 1.9 mmol) in
(CH2Cl)2 (5 mL) afforded 19e (99 mg, 46%) and 19e′ (15 mg, 7%),
each as a colorless oil. [reaction time: 15 h/hexane-AcOEt ) 4:1]
1
calcd for C10H19NO3 201.1365, found 201.1382. 19b′: H NMR
(300 MHz, CDCl3) δ 4.23 (2H, q, J ) 7.2 Hz), 4.03-3.90 (2H,
m), 2.63 (1H, ddd, J ) 12.3, 9.0, 7.2 Hz), 2.00-1.95 (1H, m),
1.70-1.20 (6H, m), 1.30 (3H, t, J ) 6.9 Hz), 0.90 (3H, t, J ) 6.9
Hz); HRMS (EI) m/z calcd for C10H19NO3 201.1365, found
201.1362.
(3R*,5S*)-5-Butyl-2-(3,5-dinitrobenzoyl)isoxazolidine-3-carboxy-
lic Acid Ethyl Ester (20b). A mixture of cycloadduct 19b (7.0 mg,
0.035 mmol), Et3N (40 µL, 0.29 mmol) and 3,5-dinitrobenzoyl
chloride (41 mg, 0.18 mmol) in THF (5 mL) furnished 20b (11
mg, 83%) as a colorless oil. [reaction time: 3 h/hexane-AcOEt )
4:1] IR (KBr) 1749 cm-1; 1H NMR (300 MHz, CDCl3) δ 9.17-9.15
(3H, m), 5.01 (1H, dd, J ) 9.6, 3.3 Hz; spin saturation at δ )
2.40/6% NOE), 4.57-4.48 (1H, m; spin saturation at δ ) 2.60/6%
1
19e: IR (KBr) 1739, 1738 cm-1; H NMR (300 MHz, CDCl3) δ
6.42 (1H, br d, J ) 11.4 Hz), 4.16 (2H, dq, J ) 7.2, 1.5 Hz), 4.15
(2H, q, J ) 7.2 Hz), 4.07-3.97 (1H, m), 2.62 (1H, dd, J ) 12.9,
6.3 Hz), 2.40 (1H, dd, J ) 12.9, 9.9 Hz), 1.48 (3H, s), 1.24 (3H,
t, J ) 7.2 Hz), 1.22 (3H, t, J ) 7.2 Hz); 13C NMR (75 MHz, CDCl3)
δ 173.2, 170.6, 85.0, 61.7, 61.6, 61.4, 45.0, 21.7, 14.0, 14.0; HRMS
(EI) m/z calcd for C10H17NO5 231.1107, found 231.1093. 19e′: IR
(KBr) 1735 cm-1; 1H NMR (300 MHz, CDCl3) δ 6.44 (1H, br s),
4.17 (2H, q, J ) 7.2 Hz), 4.16 (2H, q, J ) 7.2 Hz), 4.04 (1H, dd,
J ) 8.7, 4.2 Hz), 2.78-2.74 (1H, m), 2.45-2.40 (1H, m), 1.50
(3H, s), 1.23 (3H, t, J ) 7.2 Hz), 1.22 (3H, t, J ) 7.2 Hz); 13C
J. Org. Chem. Vol. 73, No. 18, 2008 7171

Morita et al.
NMR (75 MHz, CDCl3) δ 173.5, 171.5, 85.0, 61.9, 61.7, 61.6, 43.5,
21.3, 14.1, 14.0; HRMS (EI) m/z calcd for C10H17NO5 231.1107,
found 231.1117.
4,6-Dioxo-5-phenylhexahydropyrrolo[3,4-d]isoxazole-3-carboxy-
lic Acid Ethyl Ester (19h). A mixture of 8 (410 mg, 1.8 mmol),
18h (3.0 g, 13 mmol) and BF3 ·OEt2 (0.50 mL, 3.9 mmol) in
(CH2Cl)2 (3 mL) afforded cycloadduct 19h (36 mg, 7%) as a
colorless oil. [reaction time: 6 h/hexane-AcOEt ) 2:1] IR (KBr)
1726, 1627 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.52-7.40 (3H,
m), 7.29-7.27 (2H, m), 5.95 (1H, d, J ) 13.5 Hz), 5.21 (1H, d, J
) 7.5 Hz), 4.36 (1H, d, J ) 9.0 Hz), 4.35-4.26 (2H, m), 4.02
(1H, dd, J ) 9.0, 7.5 Hz), 1.35 (3H, t, J ) 7.2 Hz); 13C NMR (75
MHz, CDCl3) δ 172.2, 171.9, 167.5, 130.8, 129.4, 129.3, 126.3,
80.9, 65.3, 62.9, 52.5, 14.0; HRMS (EI) m/z calcd for C14H14N2O5
290.0903, found 290.0895.
(3R*,5R*)-2-(3,5-Dinitrobenzoyl)-5-methylisoxazolidine-3,5-di-
carboxylic Acid Diethyl Ester (20e). A mixture of cycloadduct 19e
(40 mg, 0.17 mmol), Et3N (30 µL, 0.20 mmol) and 3,5-dinitroben-
zoyl chloride (44 mg, 0.19 mmol) in THF (4 mL) furnished 20e
(65 mg, 90%) as a colorless oil. [reaction time: 2 h/hexane-AcOEt
) 2:1] IR (KBr) 1747, 1649 cm-1; 1H NMR (300 MHz CDCl3) δ
9.34 (2H, d, J ) 1.8 Hz), 9.20-9.15 (1H, br t, J ) 2.1 Hz), 4.92
(1H, dd, J ) 10.8, 2.7 Hz), 4.35 (2H, q, J ) 7.2 Hz), 4.25 (2H, q,
J ) 7.2 Hz), 3.17 (1H, dd, J ) 13.2, 2.7 Hz; spin saturation at δ
) 1.60/6% NOE), 2.60 (1H, dd, J ) 13.2, 10.5 Hz; spin saturation
at δ ) 4.92/17% NOE), 1.60 (3H, s), 1.34 (3H, t, J ) 7.2 Hz),
1.31 (3H, t, J ) 7.2 Hz). 13C NMR (75 MHz, CDCl3) δ 171.1,
168.0, 160.7, 148.2, 135.8, 129.9, 121.1, 85.9, 62.7, 62.3, 58.4,
40.8, 21.6, 14.0, 14.0; HRMS (EI) m/z calcd for C17H19N3O10
425.1070, found 425.1076.
(3R*,3aS*,6aS*)-Octahydrocyclopenta[c]pyrrole-1-carboxylic Acid
Ethyl Ester (19i) and (3R*,3aR*,6aR*)-Octahydrocyclopenta[c]pyr-
role-1-carboxylic Acid Ethyl Ester (19i′). A mixture of 8 (100 mg,
0.43 mmol), 18i (0.38 mL, 4.3 mmol) and BF3 ·OEt2 (0.12 mL,
0.95 mmol) in (CH2Cl)2 (3 mL) afforded 19i (46 mg, 58%) and
19i′ (6 mg, 7%) as a colorless oil. [reaction time: 2 h/hexane-AcOEt
1
) 4:1] 19i: IR (KBr) 1736 cm-1; H NMR (300 MHz, CDCl3) δ
(3R*,4R*,5S*)-4,5-Diethylisoxazolidine-3-carboxylic Acid Eth-
yl Ether (19f). A mixture of 8 (500 mg, 2.2 mmol), 18f (2.6 mL,
28 mmol) and BF3 ·OEt2 (0.57 mL, 4.5 mmol) in (CH2Cl)2 (8 mL)
afforded cycloadduct 19f (120 mg, 27%) as a colorless oil. [reaction
5.67 (1H, br s), 4.53 (1H, dd, J ) 6.9, 5.4 Hz), 4.24 (2H, dq, J )
7.2, 1.8 Hz), 3.51 (1H, br d, J ) 6.6 Hz), 2.94 (1H, br d, J ) 6.0
Hz), 1.95-1.90 (1H, m), 1.80-1.65 (4H, m), 1.54-1.45 (1H, m),
1.31 (3H, t, J ) 7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 171.2,
89.1, 69.3, 61.3, 54.1, 32.2, 31.2, 23.2, 14.0; HRMS (EI) m/z calcd
1
time: 3 h/hexane-AcOEt ) 2:1] IR (KBr) 1733 cm-1; H NMR
(300 MHz, CDCl3) δ 5.80 (1H, br s), 4.23 (2H, dq, J ) 7.2, 3.0
Hz), 4.08 (1H, br d, J ) 9.0 Hz), 3.57-3.49 (1H, m), 2.31-2.21
(1H, m), 1.75-1.65 (1H, m), 1.62-1.50 (1H, m), 1.48-1.33 (2H,
m), 1.31 (3H, t, J ) 7.2 Hz), 1.01 (3H, t, J ) 7.2 Hz), 0.95 (3H,
t, J ) 7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 170.5, 88.2, 65.6,
61.2, 52.4, 26.5, 21.6, 14.1, 12.4, 10.4; HRMS (EI) m/z calcd for
C10H19NO3 201.1365, found 201.1370.
for C9H15NO3 185.1052, found 185.1035. 19i′: IR (KBr) 1723 cm-1
;
1H NMR (300 MHz, CDCl3) δ 5.78 (1H, br s), 4.70 (1H, br s),
4.24 (2H, q, J ) 7.2 Hz), 4.07 (1H, d, J ) 7.8 Hz), 3.27-3.17
(1H, m), 1.92-1.80 (1H, m), 1.78-1.45 (5H, m), 1.31 (3H, t, J )
7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 169.7, 87.9, 66.1, 61.2,
50.7, 33.2, 27.8, 26.1, 14.2; HRMS (EI) m/z calcd for C9H15NO3
185.1052, found 185.1045.
(3R*,4R*,5S*)-2-(3,5-Dinitrobenzoyl)-4,5-diethylisoxazolidine-3-
carboxylic Acid Ethyl Ester (20f). The mixture of cycloadduct 19f
(60 mg, 0.30 mmol), NEt3 (50 µL, 0.36 mmol) and 3,5-dinitroben-
zoyl chloride (75 mg, 0.33 mmol) in THF (4 mL) furnished 20f
(87 mg, 74%) as a colorless oil. [reaction time: 1.5 h/hexane-AcOEt
) 2:1] IR (KBr) 1747, 1639 cm-1; 1H NMR (300 MHz, CDCl3) δ
9.17-9.14 (3H, m), 5.03 (1H, d, J ) 8.7 Hz), 4.31 (2H, dq, J )
7.2, 2.1 Hz), 4.19 (1H, dt, J ) 8.7, 3.3 Hz), 2.49 (1H, ddt, J )
14.4, 8.7, 5.7 Hz; spin saturation at δ ) 5.03/11% NOE), 1.83-1.71
(1H, m), 1.61-1.36 (3H, m), 1.35 (3H, t, J ) 7.2 Hz), 1.12 (3H,
t, J ) 7.2 Hz), 1.01 (3H, t, J ) 7.2 Hz); 13C NMR (75 MHz, CDCl3)
δ 168.0, 160.1, 148.1, 135.9, 129.7, 120.9, 86.3, 62.9, 61.9, 50.3,
24.7, 19.9, 14.2, 12.5, 10.2; HRMS (EI) m/z calcd for C17H21N3O8
395.1329, found 395.1325.
(3R*,4S*,5S*)-4,5-Diethylisoxazolidine-3-carboxylic Acid Eth-
yl Ether (19g). A mixture of 8 (370 mg, 1.6 mmol), 18g (2.0 mL,
16 mmol) and BF3 ·OEt2 (0.5 mL, 3.6 mmol) in (CH2Cl)2 (5 mL)
afforded 19g (72 mg, 22%) and 19f (36 mg, 11%), each as a
colorless oil. [reaction time: 3 h/hexane-AcOEt ) 5:1] 19g: IR
(KBr) 1733 cm-1; 1H NMR (300 MHz, CDCl3) δ 5.86 (1H, br s),
4.24 (2H, dq, J ) 7.2, 2.7 Hz), 3.72-3.65 (2H, m), 2.38-2.30
(1H, m), 1.65-1.45 (3H, m), 1.44-1.35 (1H, m), 1.30 (3H, t, J )
7.2 Hz), 1.00 (6H, t, J ) 7.5 Hz); 13C NMR (75 MHz, CDCl3) δ
172.7, 86.0, 66.4, 61.5, 52.9, 21.4, 21.1, 14.0, 11.9, 11.1; HRMS
(EI) m/z calcd for C10H19NO3 201.1365, found 201.1353.
(3R*,3aR*,6aR*)-2-(3,5-Dinitrobenzoyl)hexahydrocyclo-
penta[d]isoxazole-3-carboxylic Acid Ethyl Ester (20i′). A mixture
of cycloadduct 19i′ (12 mg, 0.063 mmol), Et3N (10 µL, 0.069
mmol) and 3,5-dinitrobenzoyl chloride (16 mg, 0.069 mmol) in
THF (2 mL) furnished 20i′ (24 mg, quant.) as a colorless oil.
[reaction time: 1 h/hexane-AcOEt ) 3:1] IR (KBr) 1741, 1643
cm-1; 1H NMR (300 MHz, CDCl3) δ 9.16 (1H, br t, J ) 2.1 Hz),
9.09 (2H, d, J ) 2.1 Hz), 5.25 (1H, d, J ) 9.6 Hz), 4.70-4.67
(1H, m), 4.31 (2H, q, J ) 7.2 Hz), 3.47-3.37 (1H, m; spin
saturation at δ ) 5.25/12% NOE; δ ) 4.70-4.67/11% NOE),
2.05-1.68 (6H, m), 1.35 (3H, t, J ) 7.2 Hz); 13C NMR (75 MHz,
CDCl3) δ 167.6, 162.3, 148.1, 136.0, 129.7, 121.0, 89.8, 62.5, 61.9,
48.8, 29.9, 27.7, 25.2, 14.2; HRMS (EI) m/z calcd for C16H17N3O8
379.1016, found 379.1029.
(3R*,3aR*,6aR*)-6a-Methyloctahydrocyclopenta[c]pyrrole-1-
carboxylic Acid Ethyl Ester (19j) and (3R*,3aS*,6aS*)-6a-Methy-
loctahydrocyclopenta[c]pyrrole-1-carboxylic Acid Ethyl Ester (19j′).
A mixture of 8 (300 mg, 1.3 mmol), 18j (1.4 mL, 13.0 mmol) and
BF3 ·OEt2 (0.31 mL, 2.9 mmol) in (CH2Cl)2 (10 mL) afforded 19j
(160 mg, 61%) and 19j′ (47 mg, 18%), each as a colorless oil.
[reaction time: 2 h/hexane-AcOEt ) 3:1] 19j: IR (KBr) 1733 cm-1
;
1H NMR (300 MHz, CDCl3) δ 5.93 (1H, br s), 4.22 (2H, q, J )
7.2 Hz), 4.12 (1H, d, J ) 7.5 Hz), 2.73 (1H, dd, J ) 14.4, 7.5 Hz),
1.82-1.72 (4H, m), 1.58-1.40 (2H, m), 1.40 (3H, s), 1.29 (3H, t,
J ) 7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 169.4, 95.5, 66.0, 61.1,
55.7, 39.5, 28.2, 26.4, 24.8, 14.2; HRMS (EI) m/z calcd for
(3R*,4S*,5S*)-2-(3,5-Dinitrobenzoyl)-4,5-diethylisoxazolidine-3-
carboxylic Acid Ethyl Ester (20g). A mixture of cycloadduct 19g
(10 mg, 0.050 mmol), Et3N (15 µL, 0.11 mmol) and 3,5-
dinitrobenzoyl chloride (12 mg, 0.050 mmol) in THF (2 mL)
furnished 20g (15 mg, 74%) as a colorless oil. [reaction time: 3
C10H17NO3 199.1208, found 199.1187. 19j′: IR (KBr) 1735 cm-1
;
1H NMR (300 MHz, CDCl3) δ 5.95 (1H, br s), 4.24 (2H, dq, J )
7.2, 2.1 Hz), 3.56 (1H, d, J ) 6.6 Hz), 2.49 (1H, br s), 1.98-1.90
(1H, m), 1.85-1.40 (5H, m), 1.37 (3H, s), 1.29 (3H, t, J ) 7.2
Hz); 13C NMR (75 MHz, CDCl3) δ 171.3, 96.1, 70.2, 61.4, 59.2,
38.5, 32.2, 24.4, 23.5, 14.1; HRMS (EI) m/z calcd for C10H17NO3
199.1208, found 199.1201.
(3R*,3aR*,6aR*)-2-(3,5-Dinitrobenzoyl)-6a-methylhexahydrocy-
clopenta[d]-isoxazole-3-carboxylic Acid Ethyl Ester (20j). A mixture
of cycloadduct 19j (72 mg, 0.36 mmol), Et3N (56 µL, 0.40 mmol)
and 3,5-dinitrobenzoyl chloride (92 mg, 0.40 mmol) in THF (3 mL)
furnished 20j (120 mg, 87%) as a colorless oil. [reaction time: 12
1
h/hexane-AcOEt ) 4:1] IR (KBr) 1755, 1739, 1641 cm-1; H
NMR (300 MHz, CDCl3) δ 9.16 (3H, s), 4.65 (1H, d, J ) 5.1 Hz),
4.46-4.40 (1H, m), 4.31 (2H, q, J ) 7.2 Hz), 2.70-2.62 (1H, m;
spin saturation at δ ) 4.46-4.40/11% NOE), 1.62-1.44 (4H, m),
1.34 (3H, t, J ) 7.2 Hz), 1.08 (3H, t, J ) 7.2 Hz), 0.88 (3H, t, J
) 7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 169.1, 160.8, 148.1,
135.9, 129.7, 121.0, 85.8, 63.2, 62.2, 50.2, 20.3, 20.3, 14.1, 12.0,
10.6; HRMS (EI) m/z calcd for C17H21N3O8 395.1329, found
395.1327.
7172 J. Org. Chem. Vol. 73, No. 18, 2008

Intermolecular Cycloaddition of N-Boranonitrone with Alkenes
h/hexane-AcOEt ) 3:1] IR (KBr) 1735, 1629 cm-1; 1H NMR (300
MHz, CDCl3) δ 9.15 (1H, br t, J ) 2.1 Hz), 9.09 (2H, d, J ) 2.1
Hz), 5.24 (1H, d, J ) 9.3 Hz), 4.31 (2H, q, J ) 7.2 Hz), 3.07-2.99
(1H, m; spin saturation at δ ) 5.24/13% NOE; δ ) 1.36/4% NOE),
2.13-2.05 (1H, m), 2.01-1.62 (5H, m), 1.36 (3H, s), 1.35 (3H, t,
J ) 7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 167.6, 162.4, 148.1,
136.0, 129.7, 120.9, 98.0, 62.8, 61.8, 53.2, 36.2, 28.7, 25.4, 22.1,
14.2; HRMS (EI) m/z calcd for C17H19N3O8 393.1172, found
393.1165.
(1H, m), 1.66-1.30 (6H, m), 1.34 (3H, t, J ) 7.2 Hz), 1.14 (3H,
s); 13C NMR (75 MHz, CDCl3) δ 167.0, 148.1, 136.1, 129.9, 129.9,
121.0, 85.7, 64.2, 61.9, 46.2, 32.5, 24.6, 24.0, 23.3, 21.0, 14.2;
HRMS (FAB) m/z calcd for C18H22N3O8 [M + H]+ 408.1407, found
1
408.1396. 20l′: IR (KBr) 1728, 1666 cm-1; H NMR (300 MHz,
CDCl3) δ 9.16-9.14 (1H, m), 9.11 (2H, br d, J ) 2.4 Hz), 4.78
(1H, d, J ) 9.9 Hz), 4.30 (2H, dq, J ) 7.5, 1.2 Hz), 2.57-2.54
(1H, m), 2.13-2.09 (1H, m), 1.79-1.50 (7H, m), 1.44 (3H, s),
1.33 (3H, t, J ) 7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 169.1,
148.1, 136.1, 129.9, 129.8, 120.9, 86.5, 62.1, 61.7, 50.0, 31.4, 23.6,
22.8, 21.3, 19.9, 14.2; HRMS (FAB) m/z calcd for C18H22N3O8
[M + H]+ 408.1407, found 408.1415.
(3R*,3aS*,7aS*)-Octahydrobenzo[d]isoxazole-3-carboxylic Acid
Ethyl Ester (19k) and (3R*,3aR*,7aR*)-Octahydrobenzo[d]isox-
azole-3-carboxylic Acid Ethyl Ester (19k′). A mixture of 8 (200
mg, 0.86 mmol), 18k (0.88 mL, 8.6 mmol) and BF3 ·OEt2 (0.24
mL, 1.9 mmol) in (CH2Cl)2 (5 mL) afforded an inseparable mixture
General Procedure for the Synthesis of 1,3-Anti Aminoalco-
hols 22. Reduction: To a solution of 19 in MeOH was added slowly
NaBH4 at 0 °C under argon. After complete consumption of 19
(the reaction was monitored by thin layer chromatograghy), the
solvent was removed by evaporation. Ethyl acetate and water were
added to the residue, and the whole was extracted with AcOEt.
The combined organic phases were washed with brine, dried over
MgSO4, and concentrated under reduced pressure to afford the crude
3-hydroxymethylisoxazolidine derivative. This material was used
for next reaction without further purification. Protection: To a
solution of the above 3-hydroxymethylisoxazolidine derivative in
CH3CN was added slowly Boc2O at 0 °C under argon, and the
mixture was stirred at room temperature (for 21b) or 60 °C (for
21a and 21c). After evaporation, the residue was purified by column
chromatography on silica gel with hexane-AcOEt to afford the
product 21 as a colorless oil. Cleavage of the N-O bond in
isoxazolizine derivatives: To a solution of 21 in CH3CN-H2O (9:
1) was added Mo(CO)6 at room temperature. The reaction mixture
was stirred at reflux and concentrated. The residue was purified by
column chromatography on silica gel with hexane-AcOEt to afford
22 as a colorless oil.
(3R*,5R*)-3-Hydroxymethyl-5-phenylisoxazolidine-2-carboxy-
lic Acid tert-Butyl Ester (21a). Reduction: A mixture of 19a (50
mg, 0.23 mmol) and NaBH4 (86 mg, 2.3 mmol) in MeOH (2 mL)
afforded crude (3R*,5R*)-3-hydroxymethyl-5-phenylisoxazolidine
[reaction time: 1 h]. Protection: A mixture of the above compound
(41 mg, 0.23 mmol) and Boc2O (82 mg, 0.34 mmol) furnished 21a
(54 mg, 86%). [reaction time: 1 h/hexane-AcOEt ) 2:1] IR (KBr)
3450, 1697 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.41-7.31 (5H,
m), 5.28 (1H, dd, J ) 7.0, 5.0 Hz), 4.30 (1H, ddt, J ) 8.5, 6.0, 3.6
Hz), 3.80 (1H, ddd, J ) 11.0, 6.6, 3.6 Hz), 3.71 (1H, ddd, J )
11.0, 6.5, 5.0 Hz), 3.05 (1H, dd, J ) 6.6, 5.0 Hz), 2.63 (1H, ddd,
J ) 12.5, 8.5, 5.0 Hz), 2.48 (1H, ddd, J ) 12.5, 7.0, 6.0 Hz), 1.40
(9H, s); 13C NMR (75 MHz, CDCl3) δ 157.3, 138.3, 128.4, 128.3,
126.6, 82.2, 81.1, 64.9, 60.8, 36.8, 28.0; HRMS (FAB) m/z calcd
for C15H22NO4 [M + H]+ 280.1549, found 280.1546.
(2R*,4R*)-2-(N-tert-Butoxycarbonyl)amino-4-phenyl-1,4-butane-
diol (22a). A mixture of 21a (27 mg, 0.10 mmol) and Mo(CO)6
(26 mg, 0.10 mmol) in CH3CN-H2O (9:1, 2 mL) afforded 22a
(16 mg, 58%). [reaction time: 1 h/hexane-AcOEt ) 2:1] IR (KBr)
3400, 1683 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.38-7.25 (5H,
m), 5.16 (1H, br d, J ) 8.1 Hz), 4.75 (1H, br d, J ) 8.7 Hz), 4.03
(1H, br s), 4.02-3.95 (1H, m), 3.80-3.70 (1H, m), 3.68-3.60 (1H,
m), 2.40 (1H, br s), 1.90-1.78 (2H, m), 1.47 (9H, s); 13C NMR
(75 MHz, CDCl3) δ 157.3, 144.1, 128.4, 127.3, 125.5, 80.2, 70.4,
65.5, 49.7, 42.3, 28.3; HRMS (FAB) m/z calcd for C15H24NO4 [M
+ H]+ 282.1705, found 282.1694.
(3R*,5S*)-5-Butyl-3-hydroxymethylisoxazolidine-2-carboxylic Acid
tert-Butyl Ester (21b). Reduction: A mixture of 19b (47 mg, 0.23
mmol) and NaBH4 (88 mg, 2.3 mmol) in MeOH (2 mL) afforded
crude (3R*,5R*)-5-butyl-3-hydroxymethylisoxazolidine [reaction
time: 2 h]. Protection: A mixture of the above compound (26 mg,
0.16 mmol) and Boc2O (35 mg, 0.16 mmol) in CH3CN (1 mL)
furnished 21b (26 mg, 63%). [reaction time: 3 h/hexane-AcOEt
) 1:2] IR (KBr) 3455, 1701 cm-1; 1H NMR (300 MHz, CDCl3) δ
4.29-4.15 (2H, m), 3.73-3.66 (1H, m), 3.62-3.55 (1H, m), 2.76
(1H, br t, J ) 4.9 Hz), 2.18-2.01 (2H, m), 1.58-1.47 (2H, m),
1
of 19k and 19k′ (57 mg, 33%, dr ) 8:1 by H NMR analysis) as
a colorless oil. [reaction time: 6 h/hexane-AcOEt ) 3:1] 19k and
19k′: IR (KBr) 1731 cm-1 1H NMR (300 MHz, CDCl3) δ
;
4.33-4.28/3.85-3.82* (1H, m), 4.23* (2H, q, J ) 7.2 Hz), 4.23/
3.70* (1H, br d, J ) 2.4 Hz), 2.56-2.52/2.51-2.43* (1H, m),
2.10-1.45 (8H, m), 1.30*/1.27 (3H, t, J ) 7.2 Hz); 13C NMR (75
MHz, CDCl3) δ 172.8*, 77.7*, 66.9*, 65.1, 61.6*, 61.3, 61.2, 47.2*,
43.9, 27.9*, 25.9, 25.4*, 23.7*, 23.5, 21.7, 20.0*, 19.9, 14.0*, 13.9;
HRMS (EI) m/z calcd for C10H17NO3 199.1208, found 199.1212.
(3R*,3aS*,7aS*)-2-(3,5-Dinitrobenzoyl)octahydrobenzo[d]isoxa-
zole-3-carboxylic Acid Ethyl Ester (20k) and (3R*,3aR*,7aR*)-2-
(3,5-Dinitrobenzoyl)octahydrobenzo[d]isoxazole-3-carboxylic Acid
Ethyl Ester (20k′). A mixture of cycloadduct 19k and 19k′ (70
mg, 0.35 mmol), Et3N (59 µL, 0.42 mmol) and 3,5-dinitrobenzoyl
chloride (97 mg, 0.42 mmol) in THF (3 mL) furnished 20k (71
mg, 51%) and 20k′ (7 mg, 5%), each as a colorless oil. [reaction
time: 2 h/hexane-AcOEt ) 3:1] 20k: IR (KBr) 1742, 1630 cm-1
;
1H NMR (300 MHz, CDCl3) δ 9.15-9.12 (3H, m), 4.67 (1H, br d,
J ) 3.3 Hz), 4.59 (1H, dd, J ) 8.7, 4.2 Hz), 4.29 (2H, q, J ) 7.2
Hz), 2.73-2.71 (1H, m), 1.95-1.42 (8H, m), 1.26 (3H, t, J ) 7.2
Hz); 13C NMR (75 MHz, CDCl3) δ 168.8, 161.0, 148.1, 136.1,
129.6, 120.9, 79.3, 64.3, 62.2, 44.0, 26.3, 25.4, 22.6, 20.3, 14.1;
HRMS (FAB) m/z calcd for C17H20N3O8 [M + H]+ 394.1250, found
1
394.1260. 20k′: H NMR (300 MHz, CDCl3) δ 9.18-9.13 (3H,
m), 5.02 (1H, d, J ) 6.9 Hz), 4.30 (2H, q, J ) 7.2 Hz), 4.20-4.17
(1H, m), 2.92-2.83 (1H, m; spin saturation at δ ) 5.02/9% NOE;
δ ) 4.20-4.17/12% NOE), 2.10-1.50 (8H, m), 1.33 (3H, t, J )
7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 168.7, 163.4, 148.1, 136.0,
129.9, 121.1, 81.1, 64.5, 61.9, 42.0, 25.4, 23.5, 22.7, 19.7, 14.3;
HRMS (FAB) m/z calcd for C17H20N3O8 [M + H]+ 394.1250, found
364.1242.
(3R*,3aR*,7aR*)-7a-Methyloctahydrobenzo[d]isoxazole-3-car-
boxylic Acid Ethyl Ester (19l) and (3R*,3aS*,7aS*)-7a-Methyloc-
tahydrobenzo[d]isoxazole-3-carboxylic Acid Ethyl Ester (19l′). A
mixture of 8 (200 mg, 0.86 mmol), 18l (1.0 mL, 8.6 mmol) and
BF3 ·OEt2 (0.24 mL, 1.9 mmol) in (CH2Cl)2 (5 mL) afforded an
1
inseparable mixture of 19l and 19l′ (59 mg, 32%, dr ) 3:1 by H
NMR analysis) as a colorless oil. [reaction time: 6 h/hexane-AcOEt
1
) 3:1] 19l and 19l′: H NMR (300 MHz, CD3OD) δ 4.31*/3.89
(1H, br d, J ) 7.2 Hz), 4.21 (2H, q, J ) 7.2 Hz), 2.46-2.38*/
2.30-2.26 (1H, m), 1.87-1.80 (1H, m), 1.75-1.63 (1H, m),
1.60-1.40 (6H, m), 1.28*/1.27 (3H, t, J ) 7.2 Hz), 1.26/1.24*
(3H, s).
(3R*,3aR*,7aR*)-2-(3,5-Dinitrobenzoyl)-7a-methyloctahydroben-
zo[d]isoxazole-3-carboxylicAcidEthylEster(20l)and(3R*,3aS*,7aS*)-
2-(3,5-Dinitrobenzoyl)-7a-methyloctahydrobenzo[d]-isoxazole-3-
carboxylic Acid Ethyl Ester (20l′). A mixture of cycloadduct 19l
and 19l′ (40 mg, 0.18 mmol), Et3N (28 µL, 0.20 mmol) and 3,5-
dinitrobenzoyl chloride (47 mg, 0.20 mmol) in THF (10 mL)
furnished 20l (54 mg, 72%) and 20l′ (21 mg, 28%), each as a
colorless oil. [reaction time: 2 h/hexane-AcOEt ) 3:1] 20l: IR
(KBr) 1755, 1652 cm-1; 1H NMR (300 MHz, CDCl3) δ 9.21-9.12
(3H, m), 5.08 (1H, d, J ) 7.2 Hz), 4.30 (2H, q, J ) 7.2 Hz),
2.66-2.57 (1H, m; spin saturation at δ ) 5.08/10% NOE; spin
saturation at δ ) 1.14/4% NOE), 2.08-2.03 (1H, m), 1.79-1.75
J. Org. Chem. Vol. 73, No. 18, 2008 7173

Morita et al.
1.51 (9H, s), 1.40-1.28 (4H, m), 0.91 (3H, t, J ) 7.2 Hz); 13C
NMR (75 MHz, CDCl3) δ 158.1, 82.2, 80.8, 65.1, 60.5, 36.2, 33.2,
28.3, 28.2, 22.5, 14.0. HRMS (FAB) m/z calcd for C13H26NO4 [M
+ H]+ 260.1862, found 260.1867.
33.3, 29.4, 28.2, 22.8; HRMS (FAB) m/z calcd for C14H28NO5 [M
+ H]+ 290.1967, found 290.1960.
(2R*,4S*)-8-Methoxy-2-(N-tert-butoxycarbonyl)amino-1,4-oc-
tanediol (22c). A mixture of 21c (40 mg, 0.14 mmol) and Mo(CO)6
(73 mg, 0.28 mmol) in CH3CN-H2O (9:1, 3 mL) afforded 22c
(27 mg, 66%). [reaction time: 12 h/hexane-AcOEt ) 1:3] IR (KBr)
(2R*,4S*)-2-(N-tert-Butoxycarbonyl)amino-1,4-octanediol (22b).
A mixture of 21b (13 mg, 0.051 mmol) and Mo(CO)6 (67 mg, 0.26
mmol) in CH3CN-H2O (9:1, 2 mL) afforded 22b (11 mg, 83%).
[reaction time: 2 h/hexane-AcOEt ) 2:3] IR (KBr) 3385, 1685
cm-1; 1H NMR (300 MHz, CDCl3) δ 5.01 (1H, br d, J ) 8.4 Hz),
3.94-3.86 (1H, m), 3.76-3.73 (1H, m), 3.65-3.59 (2H, m), 3.58
(1H, br s), 2.12 (1H, br s), 1.66-1.57 (2H, m), 1.54-1.46 (2H,
m), 1.45 (9H, m), 1.42-1.26 (4H, m), 0.90 (3H, t, J ) 7.3 Hz);
13C NMR (75 MHz, CDCl3) δ 157.3, 80.0, 67.9, 65.7, 49.4, 40.1,
36.9, 28.3, 28.1, 22.6, 14.1. HRMS (FAB) m/z calcd for C13H28NO4
[M + H]+ 262.2018, found 262.2006.
(3R*,5S*)-3-Hydroxymethyl-5-(4-methoxybutyl)isoxazolidine-2-
carboxylic Acid tert-Butyl Ester (21c). Reduction: A mixture of
19c (88 mg, 0.39 mmol) and NaBH4 (146 mg, 3.9 mmol) in MeOH
(3 mL) afforded crude (3R*,5S*)-3-hydroxymethyl-5-(4-methoxy-
butyl)isoxazolidine [reaction time: 1.5 h]. Protection: A mixture
of the above compound (73 mg, 0.39 mmol) and Boc2O (93 mg,
0.42 mmol) furnished 21c (97 mg, 87%). [reaction time: 2
h/hexane-AcOEt ) 1:2] IR (KBr) 3455, 1701 cm-1; 1H NMR (300
MHz, CDCl3) δ 4.29-4.16 (2H, m), 3.70 (1H, ddd, J ) 11.5, 6.9,
3.6 Hz), 3.58 (1H, ddd, J ) 11.5, 6.9, 5.0 Hz), 3.38 (2H, br t, J )
6.0 Hz), 3.33 (3H, s), 2.75 (1H, br t, J ) 6.0 Hz), 2.15 (1H, ddd,
J ) 12.5, 6.9, 6.0 Hz), 2.06 (1H, ddd, J ) 12.5, 8.7, 4.5 Hz),
1.62-1.56 (4H, m), 1.51 (9H, s), 1.46-1.37 (2H, m); 13C NMR
(75 MHz, CDCl3) δ 158.0, 82.3, 80.6, 72.5, 65.1, 60.5, 58.6, 36.1,
1
3390, 1686 cm-1; H NMR (300 MHz, CDCl3) δ 5.06 (2H, br d,
J ) 8.4 Hz), 3.90-3.82 (2H, m), 3.75-3.68 (1H, m), 3.65-3.58
(1H, m), 3.38 (2H, br t, J ) 6.0 Hz), 3.33 (3H, s), 2.55 (1H, br s),
1.66-1.40 (8H, m), 1.45 (9H, s); 13C NMR (75 MHz, CDCl3) δ
157.3, 80.0, 72.7, 67.7, 65.5, 58.5, 49.4, 40.1, 36.9, 29.5, 28.3, 22.5;
HRMS (FAB) m/z calcd for C14H30NO5 [M + H]+ 292.2124, found
292.2139.
Acknowledgment. Financial support of this study by a Grant-
in-Aid for Young Scientists (B) and a Grant-in-Aid for Scientific
Research on the Priority Area “Creation of Biologically
Functional Molecules” from the Ministry of Education, Culture,
Sports, Science, and Technology of Japan is gratefully
acknowledged.
Supporting Information Available: Preparation of com-
pounds; 1H and 13C NMR spectra for compounds; AM1
calculation of E′ and F; RHF/6-31G* calculation of E′1, E′2,
E′3, E′4; RHF/3-21G(*) calculation of TS I, TS J, TS K, TS L,
TS M, and TS N. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO800878P
7174 J. Org. Chem. Vol. 73, No. 18, 2008