The nitrile oxide/isoxazoline approach to eleven-carbon monosaccharides: cycloaddition of D- and L-arabinonitrile oxides to 5,6-dideoxyhex-5-enofuranoses and characterisation of the resulting 2-isoxazolines

Article abstract of DOI:10.1016/S0008-6215(98)00323-1

Cycloaddition of 2,3:4,5-di-O-isopropylidene-D-arabinonitrile oxide 5, generated by base-induced dehydrochlorination of hydroximoyl chloride 10, to D-Glc-derived alkene 7 afforded an 89:11 diastereomeric mixture of (5R)- and (5S)-3-(1,2:3,4-di-O-isopropyl

Full text of DOI:10.1016/S0008-6215(98)00323-1

www.elsevier.nl/locate/carres
Carbohydrate Research 322 (1999) 1–13
The nitrile oxide/isoxazoline approach to eleven-carbon
monosaccharides: cycloaddition of
D
- and
L
-arabinonitrile oxides to 5,6-dideoxyhex-5-enofuranoses
and characterisation of the resulting 2-isoxazolinesꢀ
Robert O. Gould, Karen E. McGhie, R. Michael Paton *
Department of Chemistry, Uni6ersity of Edinburgh, West Mains Road, Edinburgh EH9 3JJ, UK
Received 6 October 1998; accepted 7 December 1998
Abstract
Cycloaddition of 2,3:4,5-di-O-isopropylidene-
tion of hydroximoyl chloride 10, to -Glc-derived alkene 7 afforded an 89:11 diastereomeric mixture of (5R)- and
(5S)-3-(1,2:3,4-di-O-isopropylidene- -arabino-tetritol-1-yl)-5-(3-O-benzyl-1,2-O-isopropylidene-a- -xylo-tetro-
furanos-4-yl)-4,5-dihydroisoxazoles 11 and 12. The corresponding reaction of nitrile oxide 5 with -Man-derived
alkene 8 proceeded similarly yielding 4,5-dihydroisoxazoles 17 and 18 (82:18). Comparable levels of p-facial
selectivity (66–76% d.e.) in favour of 5R-adducts were observed for the reactions of -Ara-derived nitrile oxide 6
D
-arabinonitrile oxide 5, generated by base-induced dehydrochlorina-
D
D
D
D
L
with alkenes 7 and 8 to form dihydroisoxazoles 23/24 and 25/26, thus demonstrating that the configuration of the
nitrile oxide component in the cycloaddition has little effect on the stereochemical outcome of the reaction. The
structure of dihydroisoxazoline 23 was determined by X-ray crystallography, and cycloadducts 11, 12, 17, 18, 23–26
were identified from their physical and spectroscopic properties by comparison with those of known analogues
prepared from the same alkenes. © 1999 Elsevier Science Ltd. All rights reserved.
Keywords: Nitrile oxide cycloadditions; 2-Isoxazolines (4,5-dihydroisoxazoles); Undecose derivatives; X-ray crystallography
the free form and as components of numerous
biopolymers, these chain-extended monosac-
charides are less abundant and are usually
found as subunits of natural products of
varied biological function.
Eleven-carbon monosaccharides are of par-
ticular interest as they have been identified in
several nucleoside antibiotics. For instance,
the anthelmintic agent hikizimycin (also
named anthelmycin) incorporates the amino-
undecose hikosamine 1 [3,4]. Other examples
include the tunicamycins [5], which exhibit
antimicrobial, antifungal and antiviral activ-
1. Introduction
Monosaccharides having a backbone of
seven or more carbon atoms, i.e., heptoses,
octoses, nonoses, etc., are collectively referred
to as higher-carbon sugars [2]. Compared with
the pentoses and hexoses which occur both in
ꢀ For a preliminary description of part of this work, see
Ref [1].
* Corresponding author. Tel.: +44-131-6504714; fax: +
44-131-6504743.
E-mail address: r.m.paton@ed.ac.uk (R.M. Paton)
0008-6215/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(98)00323-1

2
R.O. Gould et al. / Carbohydrate Research 322 (1999) 1–13
ity, and the herbicidins [6] which possess both
antibiotic and herbicidal properties. The iden-
tification of such long-chain monosaccharides
and recognition of the key roles they play
when incorporated into larger structures has
stimulated interest in developing effective
methods for their synthesis. The structural
complexity of these polyhydroxylated com-
pounds presents a synthetic challenge, particu-
larly in terms of the stereochemical control of
the required carbon–carbon bond forming re-
actions. Several approaches have been
adopted including iterative one, two, three
and four carbon extensions of aldoses, conver-
gent carbohydrate couplings and stereoselec-
Scheme 2.
for the synthesis of natural products and ana-
logues [18]. We have recently reported [19] its
application for the preparation of nonose and
decose derivatives; for example, the key car-
bon–carbon bond forming step in the synthe-
sis of nonose derivative 3 involves 1,3-dipolar
cycloaddition of a two-carbon nitrile oxide
(EtO2CCꢀN+−O−) to the 6,7-dideoxyhept-6-
enopyranoside 4 derived from -Gal. We con-
D
sidered that this methodology would also be
well suited for the construction of 11-carbon
monosaccharides. Several possible combina-
tions of 1,3-dipole (nitrile oxide) and olefinic
dipolarophile components are conceivable,
e.g., 4-carbon nitrile oxide plus 7-carbon
alkene, 5-carbon nitrile oxide plus 6-carbon
alkene, etc. For the present investigation we
chose to use five-carbon nitrile oxides with
six-carbon dipolarophiles as much of the de-
sired stereochemical features of the target un-
decoses is already present in the starting
materials, which are themselves readily acces-
sible by established literature procedures. The
approach, which is illustrated in Scheme 2,
involves chain-elongation at the non-reducing
terminus of v-unsaturated hexoses by cycload-
dition with pentose-derived nitrile oxides, fol-
lowed by hydrogenolysis of the resulting
isoxazolines. To demonstrate the feasibility of
tive
syntheses
from
non-carbohydrate
precursors. Techniques employed for the as-
sembly of undecose carbon skeletons include
Wittig-olefination/osmylation [4,7,8], radical
coupling reactions [9], aldol [10,11] and ni-
troaldol additions [12], four-carbon extensions
via butenolides [13,14], diene–aldehyde cyclo-
condensations [15], and addition reactions of
carbohydrate-based enolates [10,16]. Methods
based on 2-(trimethylsilyl)thiazole chemistry
[17] and the so-called ‘naked-sugar approach’
involving modification of 7-oxanorbornenyl
derivatives [11] have also been reported. In
this and the following paper we describe a new
route, based on nitrile oxide/isoxazoline chem-
istry [18], which provides access to 11-carbon
sugars from readily available starting
materials.
the route we selected
oxides 5 and 6 as the 1,3-dipole components
and -Glc- and -Man-derived 5,6-dideoxy-
and as the
D- and
L-arabinonitrile
D
D
hex-5-enofuranosides
dipolarophiles.
7
8
1,3-Dipolar cycloaddition of nitrile oxides
(RCꢀN+–O−) to alkenes affords 2-isoxazoli-
nes (4,5-dihydroisoxazoles, 2) from which var-
ious functionality including b-hydroxyketones
and g-aminoalcohols can be released by cleav-
age of the N–O bond (Scheme 1). In recent
years, this methodology has been widely used
2. Results and discussion
The dipolarophile components 5,6-dideoxy-
a-D
-xylo- and a- -lyxo-hex-5-enofuranosides
D
Scheme 1.

R.O. Gould et al. / Carbohydrate Research 322 (1999) 1–13
3
FAB mass spectrometry. Chemical formulae
7 [20] and 8 [21] were synthesised by reduction
of the corresponding 5,6-dimesylates using a
zinc–copper couple and sodium iodide as pre-
viously reported [22]. As both alkenes decom-
posed slowly on prolonged storage, they were
prepared immediately prior to use. The nitrile
oxides 5 and 6 were generated from the corre-
sponding oximes via the hydroximoyl chlo-
rides using a procedure based on that
developed by Torssell et al. [23], which in-
volves in situ chlorination with N-chlorosuc-
cinimide followed by base-induced dehydro-
were verified by elemental analysis and/or
high resolution mass spectrometry. The
D
-
Ara-derived hydroximoyl chloride 10 has been
prepared and isolated previously by Tronchet
et al. [26] via direct chlorination of the oxime,
and its conversion to nitrile oxide 5 and trap-
ping as its isoxazole cycloadduct by reaction
with phenylacetylene has also been described
[27]. The corresponding
6, however, has not been reported.
Cycloaddition of -arabinonitrile oxide 5 to
-xylo-hex-5-enofuranoside 7 afforded after
L
-arabinonitrile oxide
D
D
chlorination. The
prepared in four steps and 30% overall yield
from the parent -Ara using the approach
D
-Ara oxime precursor was
chromatography unreacted alkene (35% recov-
ered), an inseparable mixture of two oxadia-
zoles both incorporating two nitrile oxide
fragments, followed by a fraction containing
5R- and 5S-3-tetritolyl-5-tetrofuranosyl-isoxa-
zolines 11 and 12 in 71% combined yield
(Scheme 3). The main nitrile oxide dimer was
identified as the 1,2,5-oxadiazole N-oxide 13
[27] by mass spectrometry and from the char-
acteristic 13C NMR signals for the heterocyclic
ring carbons at 110 (C-3) and 156 ppm (C-4),
together with peaks for the carbons of the two
distinct tetritolyl moieties. It is well estab-
lished [25] that 1,2,5-oxadiazole N-oxides—
commonly called furoxans or furazan
N-oxides—are the principal products formed
from nitrile oxides in the absence of a dipolar-
ophile. Evidence for a second dimeric com-
pound was provided by mass spectrometry
and by the presence in the 13C NMR spectrum
of satellite peaks for the oxadiazole ring car-
bons and for the carbons of the tetritolyl
substituents, and it was thus tentatively as-
signed 1,2,4-oxadiazole structure 14. Forma-
tion of such 1,2,4-oxadiazoles accompanying
cycloadducts of nitrile oxides generated by
triethylamine-mediated dehydrochlorination
of hydroximoyl halides has been reported pre-
viously [28] and has been attributed [29] to
alternative base-induced dimerisation path-
ways. The individual isoxazolines 11 and 12
were separated by further chromatography
and the major product purified by crystallisa-
tion. The two adducts are readily identified as
isoxazolines from their NMR spectra (Tables
1–3). In each case, the heterocyclic ring pro-
tons give rise to a characteristic ABX system
with 5-H, which is adjacent to the ring oxy-
D
described by Tronchet et al. [24] involving
conversion to the 2,3:4,5-diisopropylidene
derivative via the diethyl dithioacetal, with
subsequent oximation using hydroxylamine
hydrochloride/pyridine. The -Ara oxime was
L
obtained similarly in 28% overall yield. Both
oximes were formed as approx. 5:1 mixtures
1
of E and Z isomers as judged by H NMR
spectroscopy, and were used as such for the
conversion to the nitrile oxides.
Cycloaddition reactions.—In order to min-
imise the formation of unwanted dimeric by-
products, which are a common feature of
nitrile oxide cycloaddition reactions [25], the
nitrile oxides were generated in situ in the
presence of an excess of the dipolarophile. In
a typical experiment, N-chlorosuccinimide
and a catalytic amount of pyridine were added
to a chloroform solution of the oxime (1
equiv) to generate the hydroximoyl chloride,
which was not isolated. The alkene (1.5 equiv)
was added, the mixture cooled to 0 °C, and a
chloroform solution of triethylamine (1.1
equiv) delivered over 10–12 h by means of a
motorised syringe. After removal of the tri-
ethylamine hydrochloride by washing with
water, the diastereomeric isoxazoline cycload-
ducts were separated from the excess alkene
and dimeric by-products by chromatography.
A small quantity of the adduct mixture was
1
used for isomer ratio measurement by H
NMR spectroscopy, and the remainder sub-
jected to further chromatography to afford
the individual isoxazolines. The products were
characterised by 1H and 13C NMR spec-
troscopy, optical rotation measurements and

4
R.O. Gould et al. / Carbohydrate Research 322 (1999) 1–13
Scheme 3. Reagents: (i) NCS, pyridine; (ii) Et3N.
3
gen, at highest chemical shift; the J values of
8–11 Hz for 5-H/6-Ha,b and the geminal
coupling of ꢀ17 Hz for 6-Ha/6-Hb are also
typical of 3,5-disubstituted isoxazolines
1
[18d,19]. The H NMR spectra, which for
both isomers show considerable overlap for
the protons at the 4-, 9-, 10- and 11-positions,
were interpreted using COSY spectra and se-
lective decoupling experiments; full analysis of
13
resonates at higher chemical shift for the ma-
jor isomer (Dl= +1.2 for both 11/12 and
15/16), whereas the order is reversed for C-5
(Dl= −2.5 for both 11/12 and 15/16).
Smaller but consistent shifts are observed for
2-H, 3-H, 4-H, C-1, C-7, and PhCH2. Differ-
ences in the physical properties of the indi-
vidual diastereomers are also useful in assign-
ing structure; the major adducts have the
more negative optical rotations (11 −69.5°,
12 +20.4°; 15 −99.9°, 16 −20.3°), and
have a greater Rf value for TLC on silica.
Similar spectroscopic and physical property
correlations have been used to identify dia-
stereomeric pairs of isoxazolines resulting
form nitrile oxide cycloadditions to various
carbohydrate alkenes [18e,19,30,31]. The ma-
jor isomer was therefore assigned structure 11,
which like 15, has R configuration at the
newly created asymmetric centre C-5 and an
erythro relationship between this carbon and
the adjacent carbon (C-4). It follows that the
minor isomer must have structure 12. Neither
of the other two possible cycloadducts in which
the C NMR data was accomplished with the
1
aid of H–13C correlation spectra. The isomer
1
ratio (89:11) was measured from the H NMR
spectrum of the product mixture by compari-
son of the anomeric proton signals which are
well separated (Dl 0.09 ppm) despite the re-
moteness of this nucleus from the centre of
asymmetry. The individual diastereomers were
identified by comparison of their physical and
spectroscopic properties with those of isoxazo-
lines 15 and 16, obtained from the corre-
sponding reaction of benzonitrile oxide with
the same alkene, the structures of which had
previously been established unambiguously by
X-ray crystallography [31]. The NMR data
are distinctive for each pair of adducts (see
Tables 1–3). In particular, the signals for the
anomeric proton are at lower chemical shift
for the major isomers (Dl= −0.09 for 11/12,
−0.11 for 15/16), whereas 5-H and 6a,b-H
are all at higher frequency (Dl 5-H=0.14 for
11/12, 0.11 for 15/16; Dl 6a-H=0.34 for 11/
12, 0.35 for 15/16; Dl 6b-H=0.62 for 11/12,
0.58 for 15/16). In the 13C NMR spectrum C-6

R.O. Gould et al. / Carbohydrate Research 322 (1999) 1–13
5
Table 1
1H NMR chemical shifts (lH/ppm)a
b
1-H
5.88
5.97
2-H
4.59
4.64
4.64
4.70
4.52
4.55
4.52
4.52
4.58
4.66
3-H
4.05
3.94
4.14
4.05
4.72
4.68
4.72
4.65
4.06
3.95
4-H
4.15
4.23
4.23
4.34
3.96
4.00
4.00
3.93
4.18
4.19
5-H
4.94
4.80
5.10
4.99
4.91
4.79
4.87
4.80
4.91
4.85
6-H
8-H
4.73
9-H
4.21
4.05
10-H
4.16
4.10
11-H
PhCH2
OMe
Me
11
12
3.20
3.20
2.86
3.94
4.10
3.93
4.06
4.61
4.67
4.39
4.68
4.71
4.71
4.44
1.29, 1.32, 1.38
1.42, 1.43, 1.46
1.29. 1.30, 1.32
1.35, 1.37, 1.45
1.25, 1.31
4.61
2.58
15c 5.94
16c 6.05
3.55
3.45
3.20
1.27, 1.35
2.87
4.70
4.73
3.25
17
18
23
24
25
26
4.84
4.95
4.86
4.93
5.89
5.97
3.14
3.14
3.22
2.86
3.17
3.08
3.27
2.79
3.23
3.14
3.02
2.56
4.16
4.15
4.13
4.15
3.94
4.07
3.96
4.09
3.93
1.27, 1.29, 1.37
1.40, 1.41, 1.42
1.27, 1.31, 1.38
1.40, 1.41, 1.42
1.26, 1.29, 1.36
1.39, 1.41, 1.41
1.25, 1.30, 1.36
1.37, 1.39, 1.41
1.29, 1.32, 1.38
1.40, 1.42, 1.46
1.30, 1.31, 1.35
1.36, 1.40, 1.44
4.70
4.69
4.68
4.70
4.65
3.33
3.27
3.30
4.19
4.13
4.06
d
d
d
4.19
4.15
4.09
3.95
4.07
3.91
4.63
4.66
4.42
3.91
e
e
a Recorded in CDCl3 at 360 MHz.
b Also l 7.2–7.7 (Ph).
c See Ref [31].
d 4.06–4.16 (3×H, 2nd order multiplet).
e 4.05–4.13.
the oxygen of the nitrile oxide is attached to
C-6 rather than C-5 of the dipolarophile were
detected; the reaction is therefore regiospecific
and diastereoselective (78% d.e.) in favour of
the product with
D
-arabino- -gluco configura-
D
tion, i.e., with erythro stereochemistry for
C-4–C-5.
The corresponding reaction of
D
-arabinoni-
Having established effective procedures for
the generation of the -arabinonitrile oxide
trile oxide 5 with
D-Man-derived hex-5-eno-
D
furanoside 8 under similar conditions afforded
an 41:9 mixture of isoxazolines 17 and 18 in
57% combined yield. The individual isomers
were identified by comparison of their spectro-
scopic data and physical properties with those
reported [31] for the pairs of diastereomeric
3-phenyl- and 3-ethoxycarbonyl-isoxazolines
19/20 and 21/22, formed by cycloaddition of
benzonitrile oxide and ethoxycarbonylfor-
monitrile oxide, respectively, to the same
alkene. For example, the major adduct again
has the less positive optical rotation (17 +
15.1°, 18 +64.4°), compared with literature
[33] values for 19/20 (−35.2°/+24.8°) and
21/22 (−43.8°/+90.0°). The major adduct
and characterised its isoxazoline cycloadducts
with typical hex-5-enofuranosides, the corre-
sponding reactions of the
L
-antipode 6 with
the same alkenes were examined. Of particular
interest is the effect of inverting the configura-
tion of the 1,3-dipole component on the stere-
ochemical outcome of the cycloaddition
process.
L
-Arabinonitrile oxide 6 was gener-
-ara-
ated from 2,3:4,5-di-O-isopropylidene-
L
binose oxime using the same chlorination–
dehydrochlorination protocol. Reaction with
D-lyxo-hex-5-enofuranoside 8 afforded a pair
of diastereomeric isoxazolines in the ratio
83:17 and 61% combined yield. X-ray crystal
structure analysis of the major isomer, vide
was thus assigned
D
-arabino-
D
-manno struc-
infra, showed that the adduct has
-manno-structure 23, and that the newly-cre-
ated asymmetric centre C-5 again has R
L
-arabino-
ture 17 and the minor isomer
structure 18.
D
-arabino- -gulo
L
D

6
R.O. Gould et al. / Carbohydrate Research 322 (1999) 1–13
Table 2
1H NMR couplings (Jx−y/Hz)a
1–2
3.7
2–3
B1
B1
B1
B1
3–4
3.2
3.8
3.7
3.9
3.7
3.7
3.7
3.8
3.2
4.2
4–5
7.8
7.8
8.2
7.6
5.9
8.6
6.2
8.6
8.0
7.3
5–6
6a–6b
8–9
6.5
6.9
9–10
6.7
10–11
11a–11b
8.3
PhCH2
b
11
12
15c
16c
17
18
23
24
25
26
8.8
8.8
10.9
8.9
9.8
7.5
10.9
9.8
9.1
9.1
10.5
9.0
10.7
8.1
10.5
8.7
10.5
7.5
11.0
8.4
4.6
6.1
4.7
6.1
11.8
3.9
3.7
3.9
17.4
17.2
7.0
8.9
12.0
b
16.8
11.8
b
B1
5.9
6.4
6.9
6.6
6.7
6.6
6.7
6.8
4.4
6.0
4.5
6.1
4.8
8.5
8.5
8.5
8.3
8.4
8.0
b
B1
B1
B1
5.9
5.9
5.9
17.3
17.5
17.4
17.8
17.1
6.8
6.1
b
b
b
3.7
3.9
B1
B1
6.6
4.7
6.1
11.6
12.0
b
4.5
b
a Recorded in CDCl3 at 360 MHz.
b Not determined.
c See Ref [31].
anti, the smallest (H) ‘outside’, and the alkoxy
group in the ‘inside’ position. For 5,6-
dideoxy-5-enofuranosides the anti substituent
is linked via the five-membered sugar ring to
the alkoxy in the ‘inside’ position as illustrated
in Fig. 1. There may also be a contribution to
the observed erythro-selectivity attributable to
the homoallylic alkoxy group at C-3, which in
such cyclic systems is known to reinforce the
effect of the allylic group when there is a threo
relationship between these two substituents
[31–33]. Of particular note are the near identi-
cal isomer ratios found for cycloadditions in-
configuration. The minor isomer therefore has
-arabino- -gulo structure 24. -Arabinonitrile
oxide 6 reacted similarly with -Glc-derived
L
L
L
D
alkene 7 to give a 22:3 mixture of
gluco isoxazoline 25 (59%) and
ido isomer 25 (8%).
L
-arabino-D-
L
-arabino-
L
-
y-Facial
diastereomeric isoxazolines resulting from cy-
cloaddition of the - and -arabinonitrile ox-
selecti6ity.—The
ratios
of
D
L
ides 5 and 6 to hex-5-enofuranosides 7 and 8
are compared in Table 4 with those reported
[31–33] for the corresponding reactions of
benzonitrile oxide and ethoxycarbonylfor-
monitrile oxide with the same dipolarophiles.
The isomer ratios for the series of nitrile ox-
ides are broadly similar, with typical d.e. val-
ues of 70–88% for reactions with alkene 7,
and 64–66% d.e. with alkene 8. In all cases
the major adduct has R configuration at the
newly created asymmetric centre C-5 and an
erythro relationship for C-4−C-5. The pre-
ponderance of erythro adducts is typical of
nitrile oxide cycloadditions to chiral allyl
ethers [31–35], and can be rationalised in
terms of the ‘inside alkoxy effect’ proposed by
Houk et al. [35]; the preferred transition state
is considered to have the largest substituent
volving the
D
- and -arabinonitrile oxides: 78
L
cf 76% d.e. for addition to alkene 5, and 64 cf
66% for addition to alkene 6. It is thus con-
cluded that inversion of configuration at the
asymmetric centre adjacent to the carbon of
the nitrile oxide moiety has negligible effect.
In contrast, for the addition of nitrile oxides
to chiral allyl ethers where the centre of asym-
metry is adjacent to the alkene there is a
distinct preference for erythro-adduct forma-
tion. Low diastereoselectivities have also been
observed for cycloadditions involving other
chiral nitrile oxides, e.g., in the reactions of
1,3-dioxolane-4-carbonitrile oxide [18e,36] and

Table 3
13C NMR chemical shifts (lC/ppm)a
C-1
C-2–C-4
C-5
C-6
C-7
C-8–C-10
C-11
66.5
66.4
CMe2
CMe2
CH2Ph PhC
PhCH
OMe
11
12
104.9
105.5
80.2, 81.2
82.4
81.6, 81.6
81.6
80.5, 81.4
82.8
81.6, 81.8
81.9
79.1, 79.5
84.7
80.0, 81.1
84.7
79.0, 79.1
84.7
80.0, 81.2
84.6
76.9
79.4
77.1
79.6
77.9
79.6b
78.0
74.5
77.0
79.4
37.2
36.0
38.2
37.0
36.5
36.6
36.7
36.8
37.6
36.3
156.7
156.4
156.8
156.1
157.5
156.7
157.5
156.6
157.5
156.3
74.3, 75.9
78.6
72.4, 74.2
78.4
109.5, 110.4
111.6
109.5, 110.4
111.9
24.8, 25.9, 26.2
26.4, 26.5, 26.7
24.8, 26.2, 26.4
26.4, 26.7, 26.7
26.1, 26.7
72.2
71.4
72.6
71.6
137.1
136.7
127.4, 127.7
128.2
127.9, 128.0
128.4
126.7, 127.8, 127.9
128.4, 128.6, 130.0
126.5, 127.9, 128.1
128.5, 129.9, 130.1
15c 105.1
16c 105.6
111.8
137.3
129.3
136.7
129.2
/
112.0
26.3, 26.8
17
18
23
24
25
26
107.1
107.4
107.0
107.3
105.0
105.6
74.5, 76.0
78.6
66.6
66.6
66.5
66.7
66.6
66.7
109.7, 110.6
112.5
109.7, 110.6
112.8
109.6, 110.5
112.4
109.6, 110.4
112.8
109.7, 110.6
111.8
109.7, 110.4
112.0
24.2, 25.0, 25.6
26.4, 26.5, 26.9
24.6, 24.9, 25.8
26.4, 26.5, 26.8
24.2, 24.9, 25.6
26.4, 26.4, 26.8
24.6, 24.8, 25.8
26.4. 26.4, 26.7
25.0, 26.0, 26.4
26.4, 16.6, 26.8
24.9, 26.4, 26.4
26.4, 26.8, 12.8
54.6
54.7
54.5
54.6
74.4, 74.6
78.7b
74.3, 75.9
78.6
74.5, 75.9
78.6
74.4, 75.9
78.7
74.4, 75.9
78.6
322
(
80.4, 81.3
82.6
81.7, 81.9
82.0
72.4
71.5
137.3
136.7
127.5, 127.8
128.3
127.9, 128.1
128.4
a Recorded in CDCl3 at 90 MHz.
b Alternative assignments.
c See Ref [31].

8
R.O. Gould et al. / Carbohydrate Research 322 (1999) 1–13
Table 4
Selectivity of nitrile oxide cycloadditions to alkenes 7 and 8
Nitrile oxide
Erythro:threo ratio
-xylo-alkene 7
D
D-lyxo-alkene 8
PhCNO
90:10a
94:6b
82:18a
82:18a
EtO2CCNO
86:14a
85:15b
89:11
88:12
D
-Ara-CNO 5
82:18
83:17
L
-Ara-CNO 6
a Ref [31].
b Ref [32].
Fig. 1. Preferred transition state for cycloaddition of nitrile
oxides to alkenes 7 and 8.
oxazoline-4-carbonitrile oxides [37] with achi-
ral alkenes. In each case, the minimal influ-
ence of adjacent asymmetric centres in the
nitrile oxide component can be attributed to
the greater distance between the pre-existing
and newly formed stereocentres (Fig. 2).
Structure of isoxazoline 23.—For the reac-
Fig. 3. Crystal structure of isoxazoline 23 showing the two
molecular shapes 23A and 23B.
tion of
L
-Ara-derived nitrile oxide 6 with
D-
lyxo-hex-5-enofuranoside 8 the configurations
of the individual diastereomeric cycloadducts
were confirmed by obtaining a single-crystal
structure of the first-eluted isomer, which was
identified as (5R)-5-(2,3-O-isopropylidene-1-
In the crystal two similar but distinct molec-
ular shapes 23A and 23B were discernible
(Fig. 3). The Cremer and Pople puckering
parameters [38,39] for the isoxazoline, fura-
noside, and three 1,3-dioxolane rings are given
in Table 5. There are significant differences in
the shapes of the two molecules in both the
furanoside and isoxazoline regions. In 23A the
O-methyl-a-
D
-lyxo-tetrofuranos-4-yl)-3-(1,2:3,
-arabino-tetritol-1-yl)-
4-di-O-isopropylidene-
L
4,5-dihydroisoxazole (23); the slower-eluting
adduct therefore has 5S structure 24. Unam-
biguous identification of the adducts 23 and
24 allows the structures of the other isomeric
pairs of isoxazolines to be assigned with confi-
dence on the basis of TLC Rf values, and
NMR and optical rotation data [19e].
furanoside ring adopts the twist conformation
O-4
T
with ƒ=18°, whereas for 23B ƒ=12°,
C-1
indicating that its conformation is intermedi-
ate between twist (ƒ=18°) and envelope
(
O-4E, ƒ=0°). The ƒ value of 351° for the
isoxazoline in 23A shows that in this molecule
the ring adopts a conformation midway be-
tween twist (O-5TC-5, ƒ=345°) and envelope
(
O-5E, ƒ=360°). In contrast, for molecule 23B
the isoxazoline with ƒ=325° is almost com-
pletely in the envelope form EC-5 (ƒ=324°);
the torsion angle associated with the imine
Fig. 2. Proximity of asymmetric centres in the nitrile oxide
and dipolarphile components.

R.O. Gould et al. / Carbohydrate Research 322 (1999) 1–13
9
adducts are now available for conversion to
undecose derivatives by reductive hydrolytic
ring opening.
double bond O-5–N-7=C-7–C-6 is 0.26° and
C-5 lies 0.164 A out of the best plane through
these four atoms. The CꢁN bond lengths
,
,
,
(1.282 A for 23A, 1.269 A for 23B) are typical
for the localised imino portion of 2-isoxazoli-
nes. In both 23A and 23B the three 1,3-diox-
olane rings have conformations intermediate
between twist and envelope. Selected H–C–
C–H torsion angles from the X-ray data are
compared with the observed and calculated
3. Experimental
General methods and materials.—Melting
points were measured on a Gallenkamp capil-
lary apparatus and are uncorrected. Micro-
analyses were obtained using a Perkin–Elmer
2400 instrument. Optical rotations were mea-
sured at 21 °C on a Perkin–Elmer 141 polar-
imeter using 1.8 mL of filtered solution. The
3
[40] J values in Table 6. Although satisfac-
tory correlation is found for some of the data,
e.g., J1,2, J2,3, J8,9, and J10,11a, there are signifi-
cant deviations elsewhere. As previously noted
[33,41] the relationship between the observed
and calculated J values for the isoxazoline
ring protons can be inconsistent. Another
noteworthy feature of the crystal structure is
the antiperiplanar relationship between 4-H
and 5-H at the junction of the furanoside and
isoxazoline, for which the observed torsion
angle H-4–C-4–C-5–H-5 is 178.1 and 176.9°
in the two crystalline forms. In solution the
corresponding 1H–1H coupling is 6.2 Hz,
which is significantly smaller than the calcu-
lated value (10.3 Hz). There is a similar incon-
sistency for H-9–C-9–C-10–H-10, for which
13
1H and C NMR spectra were recorded with
Brucker WP200SY, AX250 and WH360 or
Varian VXR600 spectrometers on solutions in
CDCl3 with Me4Si as internal standard.
FAB+ and high-resolution mass spectra were
obtained on a Kratos MS50TC instrument
using either glycerol or thioglycerol matrices.
Infrared spectra were recorded as films or
Nujol mulls using a Perkin–Elmer 781 spec-
trometer. Preparative TLC was carried out on
glass plates coated with a layer of Kieselgel
GF254 (0.5 mm) which contained 13% CaSO4
and a fluorescent indicator. E. Merck alu-
minium-backed plates coated with Kieselgel
GF254 (0.2 mm) were used for analytical TLC;
detection was by UV or sulfuric acid charring.
Dry flash chromatography was carried out
using Kieselgel GF254 and eluted under water
pump vacuum. 3-O-Benzyl-5,6-dideoxy-1,2-O-
3
the observed and calculated J values are 6.8
and 10.2 Hz, respectively. These deviations
suggest that where there is the possibility of
free rotation, i.e., at C-4–C-5 and C-9–C-10,
the preferred conformation in solution differs
markedly from that in the crystal.
In conclusion, the 1,3-dipolar cycloaddition
of arabinose-derived nitrile oxides to 5,6-
dideoxyhex-5-enofuranosides provides a mild
method for the regiospecific and diastereo-
selective construction of the 11-carbon frame-
work of undecoses. The isoxazoline cyclo-
isopropylidene-a-
(7) [20] (89%) and methyl 5,6-dideoxy-2,3-di-
-lyxo-hex-5-enofuran-
D
-xylo-hex-5-enofuranose
O-isopropylidene-a-
D
oside (8) [21] (96%) were prepared by reduc-
tion (Zn–Cu, NaI) of the corresponding 5,6-
dimesylates as previously reported [22,33]. The
isomer ratios of the isoxazoline cyclo-
Table 5
Cremer and Pople puckering parametersa for the two crystalline forms of isoxazoline 23
,
Ring
Atoms
Q (A)
ƒ (°)
23A
23B
23A
23B
Isoxazoline
Furanoside
Dioxolane
Dioxolane
Dioxolane
O-5–N-7–C-7–C-6–C-5
O-4–C-1–C-2–C-3–C-4
O-2–C-13–O-3–C-3–C-2
O-8–C-16–O-9–C-9–C-8
O-10–C-19–O-11–C-11–C-10
0.026
0.349
0.248
0.319
0.305
0.101
0.342
0.274
0.304
0.313
351
18
11
99
31
325
12
10
160
263
a Ref [31].

10
R.O. Gould et al. / Carbohydrate Research 322 (1999) 1–13
Table 6
Selected torsion angles involving hydrogen [H(X)–C(X)–C(Y)–H(Y)] for the two crystalline forms of isoxazoline 23 with observed
and calculateda coupling constants
HX, HY
1,2
2,3
3,4
4,5
5,6a
5,6b
8,9
9,10
10,11a
10,11b
Angle (°)
Jcalc (Hz)
Jobs (Hz)
23A −89.4
23B −89.6
−12.0
−11.4
7.7
−15.7
−18.3
7.5
178.1
176.9
10.3
10.2
6.2
121.4
113.7
4.1
3.1
8.1
−1.0
−8.6
8.1
7.9
10.7
155.1
151.1
8.8
8.3
6.6
−177.0
175.7
10.2
−3.4
−26.2
8.0
−124.3
−147.8
4.5
23A
23B
23
1.4
1.4
B1
7.8
5.9
7.4
3.7
10.2
6.8
6.7
6.1
7.9
4.8
a 7.76 cos2 q−1.1 cos q+1.4 (see Ref [40]).
1
adducts were measured from the H NMR
spectra of the crude reaction products.
oxide (13) [27] [lC (50 MHz, CDCl3) 24.9,
26.1, 26.2, 26.8 (8 CH3), 67.1, 67.2 (CH2),
71.3, 73.0 75.7, 76.5, 76.6, 79.9 (CH), 109.7,
109.9, 111.4, 111.7, 112.2 (CMe2, C-3), 156.0
(C-4); (FAB) HRMS: Calcd for C22H35N2O10
[M+H]+: m/z 487.22915. Found: m/z
487.22918] together with traces of 3,5-di-O-
2,3:4,5 - Di - O - isopropylidene -
oxime 9 [24].—This was prepared in 95% yield
from 2,3:4,5-di-O-isopropylidene- -arabinose
D
- arabinose
D
[42] by standard literature procedures [43]
using NH2OH·HCl/Na2CO3 in MeOH–water.
NMR spectroscopy indicated that the pro-
duct was a ca. 5:1 mixture of E and Z iso-
mers.
isopropylidene- -arabino-tetritol-1-yl)-1,2,4-
D
oxadiazole (14) [lC (50 MHz, CDCl3) 156.1
(C-3), 161.7 (C-5); (FAB) HRMS: Calcd for
C22H35N2O9 [M+H]+ 471.23424. Found: m/z
471.23428]; and a pair of diastereomeric isoxa-
zolines 11 and 12 in the ratio of 89:11. The
major isomer, which eluted first, was obtained
as a white solid and was identified as (5R)-5-
2,3:4,5 - Di - O - isopropylidene - - arabinose
L
oxime.—This was prepared (93%) similarly to
a ca. 5:1 mixture of E and Z isomers from
2,3:4,5-di-O-isopropylidene-
Cycloaddition of
-xylo-hex-5-enofuranoside 7.—A solution of
2,3:4,5 - di - O - isopropylidene - - arabinose
L
-arabinose [42].
D
-arabinonitrile oxide 5 to
D
(3-O-benzyl-1,2-O-isopropylidene-a-
tetrofuranos-4-yl)-3-(1,2:3,4-di-O-isopropyli-
dene- -arabino-tetritol-1-yl)-4,5-dihydroisoxa-
D
-xylo-
D
oxime 9 (1.20 g, 4.9 mmol) in dry CHCl3 (5
mL) was added to a suspension of N-chloro-
succinimide (0.65 g, 4.9 mmol) in dry CHCl3
(5 mL) and dry pyridine (0.05 mL) and the
mixture stirred at room temperature for 30
min. The alkene 7 (2.03 g, 7.3 mmol) in dry
CHCl3 (5 mL) was added and the solution
cooled in an ice–salt bath. Triethylamine
(0.54 g, 5.4 mmol) in CHCl3 (35 mL) was
added over 11 h by means of a motorised
syringe pump and the mixture stirred for a
further 10 h. The solution was washed with
water (2×20 mL), dried (MgSO4) and the
solvent evaporated in vacuo to afford a syrup.
Dry flash chromatography on silica (15–30%
Et2O in hexane, gradient elution) afforded the
following compounds in order of elution: un-
reacted 7 (0.71 g, 35%); an inseparable mix-
ture (0.20 g) of 3,4-di-(1,2:3,4-di-O-isopro-
D
zole (11) (1.60 g, 63%) [mp 74–75 °C (from
EtOH); [h]2D1 −60.5° (c 0.44 in CHCl3); Anal.
Calcd for C27H37NO9: C, 62.4; H, 7.2; N, 2.7.
Found: C, 62.4; H, 7.3; N, 2.7]. The minor
isomer, which was isolated as an oil, was
identified as (5S)-5-(3-O-benzyl-1,2-O-iso-
propylidene-a-
D
-xylo-tetrofuranos-4-yl)-3-
-arabino-tetri-
(1,2:3,4-di-O-isopropylidene-
D
tol-1-yl)-4,5-dihydroisoxazole (12) (0.20 g, 8%)
([h]2D1 +20.4° (c 1.22 in CHCl3); (FAB)
HRMS: Calcd for C27H38NO9 [M+H]+: m/z
520.25464. Found: m/z 520.25463). For NMR
data of isoxazolines 11 and 12, see Tables
1–3.
Cycloaddition of
-lyxo-hex-5-enofuranoside 8.—Using the
D
-arabinonitrile oxide 5 to
D
procedure described above, oxime 9 (0.90 g,
3.7 mmol) with alkene 8 (1.10 g, 5.5 mmol)
yielded in order of elution unreacted 8 (0.52 g,
pylidene- -arabino-tetritol-1-yl)furazan-N-
D

R.O. Gould et al. / Carbohydrate Research 322 (1999) 1–13
11
yielded in order of elution unreacted 8 (0.69 g,
58%); an inseparable mixture (0.11 g) of nitrile
oxide dimers; (5R)-5-(2,3-O-isopropylidene-1-
47%); an inseparable mixture (0.09 g) of fura-
zan-N-oxide 13 and 1,2,4-oxadiazole 14; (5R)-
5-(2,3-O-isopropylidene-1-O-methyl-a- -lyxo-t
D
etrofuranos-4-yl)-3-(1,2:3,4-di-O-isopropyli-
dene- -arabino-tetritol-1-yl)-4,5-dihydroisoxa-
O-methyl-a-
D
-lyxo-tetrofuranos-4-yl)-3-(1,2:
-arabino-tetritol-1-
D
3,4-di-O-isopropylidene-
L
zole (17) (0.75 g, 46%) [mp 86–87 °C (from
EtOH); [h]2D1 +15.1° (c 1.45 in CHCl3); Anal.
Calcd for C21H33NO9: C, 56.9; H, 7.5; N, 3.2.
Found: C, 56.4; H, 7.7; N, 3.2; (FAB) HRMS:
Calcd for C21H34NO9 [M+H]+: m/z
444.22334. Found: m/z 444.22334]; and (5S)-
yl)-4,5-dihydroisoxazole (23) (0.78 g, 45%)
[mp 88–89 °C (from hexane); [h]1D9 −45.8° (c
0.53 in CHCl3); Anal. Calcd for C21H33NO9:
C, 56.9; H, 7.5; N, 3.2. Found: C, 56.8; H, 7.7;
N, 3.5]; and (5S)-5-(2,3-O-isopropylidene-1-
O-methyl-a-
D
-lyxo-tetrofuranos-4-yl)-3-(1,2:
-arabino-tetritol-1-
5-(2,3-O-isopropylidene-1-O-methyl-a-
tetrofuranos-4-yl)-3-(1,2:3,4-di-O-isopropyli-
dene- -arabino-tetritol-1-yl)-4,5-dihydroisoxa-
D-lyxo-
3,4-di-O-isopropylidene-
L
yl)-4,5-dihydroisoxazole (24) (0.27 g, 16%)
([h]1D9 +11.1° (c 0.61 in CHCl3); (FAB)
HRMS: Calcd for C21H34NO9 [M+H]+: m/z
444.22334. Found: m/z 444.22333); isomer ra-
tio 23:24=83:17. For NMR data of isoxazoli-
nes 23 and 24, see Tables 1–3.
Crystal structure determination of isoxazo-
line 23.—C21H33NO9, M=443.5, monoclinic,
space group P21, a=17.281(10), b=5.409(4),
D
zole (18) (0.18 g, 11%) [mp 77–79 °C (from
1:1 Me2CHOH–hexane); [h]2D0 +68.0° (c 0.93
in CHCl3); (FAB) HRMS: Calcd for
C21H34NO9 [M+H]+: m/z 444.22334. Found:
m/z 444.22333]; isomer ratio 17:18=82:18.
For NMR data of isoxazolines 17 and 18, see
Tables 1–3.
Cycloaddition of
-xylo-hex-5-enofuranoside 7.—Using the
procedure described above 2,3:4,5-di-O-iso-
propylidene- -arabinose oxime (1.00 g, 4.1
L-arabinonitrile oxide 6 to
,
c=26.437(13) A, i=107.06(4)°, V=2362.4
D
3
,
A , refined using 32 2q values, with 25B2q
,
B27°, Mo Ka radiation, u=0.71073 A, Z=
L
4, dx =1.25 g cm−3, v=0.097 mm−1, T=293
K, F(000)=952. Colourless plates, 0.80×
0.56×0.12 mm. 2499 Data collected, Stoe¨
Stadi-4 diffractometer, ꢀ/2q mode with on-
line profile fitting, 5.0B2qB40.0°, −16B
hB15, 0BkB5, 0BlB25. Three standard
reflections collected every 2 h, maximum drift
correction 2%. No absorption correction.
Structure solved by direct methods using
SHELXS [44] and refined using SHELXL [44],
using scattering factors therein. All non-hy-
drogen atoms refined anisotropically, with
loose restraints to equivalence the two inde-
mmol) with alkene 7 (1.69 g, 6.1 mmol)
yielded in order of elution unreacted 7 (0.92 g,
54%); an inseparable mixture (0.11 g) of nitrile
oxide dimers; (5R)-5-(3-O-benzyl-1,2-O-iso-
propylidene-a-
D
-xylo-tetrofuranos-4-yl)-3-
-arabino-tetri-
(1,2:3,4-di-O-isopropylidene-
L
tol-1-yl)-4,5-dihydroisoxazole (25) (1.26 g,
59%) [mp 99–100 °C (from EtOH); [h]D19
−99.9° (c 0.93 in CHCl3); Anal. Calcd for
C27H37NO9: C, 62.4; H, 7.2; N, 2.7. Found: C,
62.2; H, 7.3; N, 2.75]; and (5S)-5-(3-O-benzyl-
1,2-O-isopropylidene-a-
D
-xylo-tetrofuranos-
-arabino-
4-yl)-3-(1,2:3,4-di-O-isopropylidene-
L
pendent molecules; hydrogen atoms inserted
tetritol-1-yl)-4,5-dihydroisoxazole (26) (0.17 g,
8%) [mp 121–122 °C (from EtOH); [h]D20
−20.3° (c 0.29 in CHCl3); (FAB) HRMS:
Calcd for C27H38NO9 [M+H]+: m/z
520.25464. Found: m/z 520.25463]; isomer ra-
tio 25:26=88:12. For NMR data of isoxazoli-
nes 25 and 26, see Tables 1–3.
2
,
in calculated positions with fixed U=0.10 A .
Weighting scheme w–1 =|2(F2)+0.08P2, P=
(max(Fo2, 0)+2Fc2). At convergence (max D/
|=0.010) R1=0.053 (for 1587 data with
I\2|(I). wR2=0.120, S=1.07 for 559
parameters and 93 restraints. Final difference
synthesis gave no feature outside the range
Cycloaddition of
-lyxo-hex-5-enofuranoside 8.—Using the
procedure described above 2,3:4,5-di-O-
isopropylidene- -arabinose oxime (0.96 g, 3.9
mmol) with alkene 8 (1.18 g, 5.9 mmol)
L-arabinonitrile oxide 6 to
−0.18 to +0.18 e A−3. Atomic coordinates
,
D
and equivalent isotropic displacement parame-
ters are listed in Table 7. Tables of bond
lengths and angles, torsion angles, atomic co-
L

12
R.O. Gould et al. / Carbohydrate Research 322 (1999) 1–13
Table 7 (Continued)
Table 7
Atomic coordinates (×104) and equivalent isotropic displace-
2
3
a
,
ment parameters (A ×10 ) for isoxazoline 23
x
y
z
Ueq
a
x
y
z
Ueq
C-48
C-49
C-50
C-51
9089(6)
7960(20)
6223(17)
8020(20)
4630(20)
2309(4)
1088(3)
1074(4)
606(3)
121(4)
60(3)
88(3)
5456(5)
4789(5)
5288(6)
C-1
O-1
C-2
O-2
C-3
O-3
C-4
O-4
C-5
O-5
C-6
C-7
N-7
C-8
O-8
C-9
6080(5)
3860(20)
5383(16)
4920(20)
3078(15)
6594(16)
5796(12)
5909(18)
3700(12)
5366(19)
7625(15)
4672(19)
6756(18)
8359(17)
7192(17)
7892(12)
4895(16)
5389(12)
4587(17)
4018(13)
2398(18)
879(13)
4540(30)
4010(20)
5220(20)
1990(20)
6641(18)
4940(20)
8550(20)
2278(18)
3620(20)
688(19)
6012(3)
5914(3)
6467(4)
6727(2)
6209(3)
6434(2)
5624(3)
5596(2)
5351(3)
5355(2)
4768(3)
4508(3)
4834(3)
3931(3)
3718(2)
3613(3)
3117(2)
3513(3)
4013(2)
3168(3)
3490(3)
5504(4)
6838(3)
7368(3)
6767(4)
3227(3)
3288(4)
2800(3)
3917(3)
3791(3)
4390(3)
71(3)
98(2)
81(3)
89(2)
55(3)
62(2)
56(3)
67(2)
65(3)
84(2)
73(3)
48(2)
68(2)
53(2)
72(2)
48(2)
65(2)
49(2)
71(2)
62(3)
95(2)
120(5)
61(3)
94(4)
117(4)
59(3)
104(4)
95(4)
58(3)
100(4)
93(3)
80(3)
105(3)
70(3)
94(2)
58(2)
68(2)
66(3)
70(2)
63(3)
74(2)
73(3)
50(3)
60(2)
51(3)
61(2)
47(2)
72(2)
56(3)
72(2)
69(3)
68(2)
155(6)
61(3)
97(4)
103(4)
68(3)
120(5)
5421(4)
6732(5)
7292(4)
7238(5)
8039(3)
6916(5)
6435(3)
7548(5)
8002(3)
7223(5)
7525(5)
7939(4)
7360(5)
6540(3)
7449(4)
6854(3)
8251(5)
8819(3)
8303(5)
8909(4)
4758(5)
8082(5)
8377(5)
8640(6)
6216(5)
5573(5)
5879(5)
9383(5)
10054(5)
9679(5)
8763(6)
9498(4)
8187(5)
7545(4)
7750(5)
6922(3)
8037(5)
8388(4)
7378(5)
7070(3)
7663(6)
7612(5)
7295(4)
7886(4)
8735(3)
7527(4)
8175(4)
6810(5)
6202(4)
6398(5)
5562(3)
10106(6)
6822(5)
6635(6)
6163(6)
8888(5)
9547(6)
102(4)
a Ueq is defined as one-third of the trace of the orthogo-
nalised Uij tensor.
ordinates involving hydrogen, and thermal
parameters are given as supplementary tables,
which have been deposited with the Cam-
bridge Crystallographic Data Centre.
Acknowledgements
O-9
We are grateful to the SERC and DENI for
research and maintenance (K.E.McG.) grants,
and we thank Drs I.H. Sadler and D. Reed for
assistance with NMR spectra.
C-10
O-10
C-11
O-11
C-12
C-13
C-14
C-15
C-16
C-17
C-18
C-19
C-20
C-21
C-31
O-31
C-32
O-32
C-33
O-33
C-34
O-34
C-35
O-35
C-36
C-37
N-37
C-38
O-38
C-39
O-39
C-40
O-40
C-41
O-41
C-42
C-43
C-44
C-45
C-46
C-47
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8528(16)
9230(20)
7896(15)
−1045(4)
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−1758(2)
−1034(3)
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1591(3)
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