Synthesis and intramolecular nitrile oxide cycloaddition of 3,5′-ether-linked pseudooligosaccharide derivatives: An approach to chiral macrooxacycles

Article abstract of DOI:10.1021/jo050689w

3,5′-Ether-linked pseudooligopentose derivatives were synthesized for the first time from readily available carbohydrate precursors. The 1,2-isopropylidene-protected ether-linked oligopentoses are potentially important as precursors of novel RNA analogues

Full text of DOI:10.1021/jo050689w

preparation of medium rings become a simpler task.5
However, apart from their operational simplicity the
nitrile oxide and the related nitrone cycloaddition reac-
tions are more atom-economic, and the products are
amenable to transformations that can lead to the intro-
duction of extra functionalities. While chiral benzo-fused
eight- to 12-membered medium-sized cyclic ethers fused
to isoxazoline rings have been obtained by cycloaddition
of nitrile oxides having 1,2-disubstituted phenyl rings as
structural constraints,6 a remaining challenge in this
area is the utilization of a chiral nonaromatic alkene-
bearing carbohydrate ring as a structural constraint. In
this way, the nitrile oxide cycloaddition would provide
macrocyclic compounds devoid of any benzo fusion and
allow for the introduction of additional chiral centers
present in the carbohydrate ring. An ether-linked pseudo-
oligosaccharide 1 appeared to be an attractive scaffold
for performing the aforementioned nitrile oxide cyclo-
addition, because the anomeric sites of the carbohydrate
units in the resulting cycloadducts would be available for
further elaborations including conjugation with other
bioactive units such as peptides as well as conversion to
nucleosides. Another important aspect of this reaction
is that it might allow for the preparation of medium-sized
rings from substrates of suitable sizes. Ether-linked
pseudooligosaccharide derivatives have received little
attention, and only a few 2,6′-, 3,6′-, and 6,6′-ether-linked
dihexoses are known.7 A 3,5′-ether-linked oligopentose
molecule is of particular interest due to its close similar-
ity to the nucleic acid backbone. We describe herein the
synthesis of hitherto unreported 3,5′-ether-linked pseudo-
oligopentose derivatives and their intramolecular nitrile
oxide cycloaddition leading to the synthesis of isoxazo-
lines fused to 10-16-membered oxacycles.
Synthesis and Intramolecular Nitrile Oxide
Cycloaddition of 3,5′-Ether-Linked
Pseudooligosaccharide Derivatives: An
Approach to Chiral Macrooxacycles
Jhimli Sengupta,† Ranjan Mukhopadhyay,†
Anup Bhattacharjya,*,† Mohan M. Bhadbhade,‡ and
Gaurav V. Bhosekar‡
Indian Institute of Chemical Biology, 4, Raja S. C. Mullick
Road, Kolkata 700032, India, and National Chemical
Laboratory, Pune 411008, India
anupbhattacharjya@iicb.res.in
Received April 7, 2005
3,5′-Ether-linked pseudooligopentose derivatives were syn-
thesized for the first time from readily available carbohy-
drate precursors. The 1,2-isopropylidene-protected ether-
linked oligopentoses are potentially important as precursors
of novel RNA analogues. Intramolecular cycloaddition of the
nitrile oxides prepared from these derivatives led to the
diastereoselective formation of chiral isoxazolines fused to
10-16-membered oxacycles. The stereochemistry of some of
these isoxazolines was established by X-ray diffraction and
NOESY analysis.
Intramolecular 1,3-dipolar nitrile oxide cycloaddition
is one of the most important methods for the synthesis
of cyclic compounds.1 The application of this and the
related nitrone cycloaddition in O- and N-alkenylcarbo-
hydrate derivatives is an emerging area devoted to the
synthesis of a variety of enantiopure cyclic compounds
including cyclic ethers and amines.2 The synthesis of
macrocyclic rings by the application of intramolecular
nitrile oxide cycloaddition has been reported,3 although
the synthesis of medium-ring compounds has rarely been
accomplished using this method.3d,4 In general, the
synthesis of medium rings by conventional cyclization
methods is difficult, and only recently with the introduc-
tion of efficient ring-closing metathesis catalysts has the
The attempted synthesis of a 3,5′-linked pseudodisac-
charide 4 by alkylation of commercially available 1,2:5,6-
diisopropylideneglucofuranose (3) with the known mesyl
derivative 28 in the presence of NaH in THF or DMF was
unsuccessful. The adoption of a reported9 procedure for
the synthesis of ethers involving extended heating of a
mixture of 2 and 3 in aqueous NaOH in the presence of
† Indian Institute of Chemical Biology.
‡ National Chemical Laboratory.
(1) (a) Padwa, A. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 4, pp 1069. (b)
Wade, P. A. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 4, pp 1111.
(2) (a) Gothelf, K. V.; Jorgensen, K. A. Chem. Rev. 1998, 98, 863.
(b) Frederickson, M. Tetrahedron 1997, 53, 403. (c) Osborn, H. M. I.;
Gemmell, N.; Harwood, L. M. J. Chem. Soc., Perkin Trans. 1 2002,
2419.
(3) (a) Ko, S. S.; Confalone, P. N. Tetrahedron 1985, 41, 3511. (b)
Kim, B. H.; Jeong, E. J.; Jung, W. H. J. Am. Chem. Soc. 1995, 117,
6390. (c) Lee, C. W.; Hwang, G. T.; Kim, B. H. Tetrahedron Lett. 2000,
41, 4177. (d) Asaoka, M.; Abe, M.; Takei, H. Bull. Chem. Soc. Jpn.
1985, 58, 2143.
(4) (a) Kozikowski, A. P.; Mugrage, B. B. J. Chem. Soc., Chem.
Commun. 1988, 198. (b) Rai, K. M. L.; Hassner, A. Heterocycles 1990,
30, 817. (c) Bode, J. W.; Carreira, E. M. J. Org. Chem. 2001, 66, 6410.
(5) (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413. (b)
Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199.
(6) Majumdar, S.; Mukhopadhyay, R.; Bhattacharjya, A. Tetra-
hedron 2000, 56, 8945.
(7) (a) Whistler, R. L.; Frorein, A. J. Org. Chem. 1961, 26, 3946. (b)
Hodosi, G.; Kova´c, P. Carbohydr. Res. 1998, 308, 63. (c) Vanbaeling-
hem, L.; Gode´, P.; Goethals, G.; Martin, P.; Ronco, G.; Villa, P.
Carbohydr. Res. 1998, 311, 89. (d) Haines, A. H. Tetrahedron Lett.
2004, 45, 835. (e) Haines, A. H. Org. Biomol. Chem. 2004, 2, 2353.
10.1021/jo050689w CCC: $30.25 © 2005 American Chemical Society
Published on Web 09/14/2005
J. Org. Chem. 2005, 70, 8579-8582
8579

SCHEME 1. Synthesis of the Pseudodisaccharides 4 and 14 and Their Conversion to Nitrile Oxidesa
a Reagents: (a) (Bu)4NBr, 11% aq. NaOH, 70 °C, 70 h, 80% (4), 84% (14). (b) 50% aq. AcOH, 25 °C, 15 h, 98% (5), 97% (15). (c) NaIO4,
MeOH-H2O, 25 °C, 2 h, 94% (6), 95% (16). (d) NH2OH‚HCl, py, EtOH, reflux, 4 h, 88% (7), 80% (17). (e) i. MeNO2, i-PrOH, KF, 25 °C,
24 h, ii. Ac2O, DMAP, Et2O, 0 °C, 2 h, iii. NaBH4, EtOH, 25 °C, 6 h, 52% (9), 56% (19). (f) N-Chlorosuccinimide, DMAP, CH2Cl2, 25 °C,
48 h. (g) 4-Chlorophenylisocyanate, Et3N, benzene, 25 °C, 48 h. (h) MeSO2Cl, Et3N, CH2Cl2, 1 h, 0-25 °C, 90%.
SCHEME 2. Synthesis of 23 and Its Conversion to Nitrile Oxidesa
a Reagents and conditions: (a) MeSO2Cl, Et3N, CH2Cl2, 1 h, 0-25 °C, 97%. (b) (Bu)4NBr, 11% aq. NaOH, 70 °C, 70 h, 93%. (c) 50% aq.
AcOH, 25 °C, 15 h, 97%. (d) NaIO4, MeOH-H2O, 25 °C, 2 h, 98%. (e) NH2OH.HCl, py, EtOH, reflux, 4 h, 90%. (f) i. MeNO2, i-PrOH, KF,
25 °C, 24 h, ii. Ac2O, DMAP, Et2O, 0 °C, 2 h, iii. NaBH4, EtOH, 25 °C, 6 h, 65%. (g) N-Chlorosuccinimide, DMAP, CH2Cl2, 25 °C, 48 h.
(h) 4-Chlorophenylisocyanate, Et3N, benzene, 25 °C, 48 h.
tetrabutylammonium bromide successfully led to the
formation of the 3,5′-ether-linked pseudodisaccharide 4
in 80% yield (Scheme 1).10 The structure of 4 was secured
from NMR and mass spectral analyses. A sequence of
reactions involving selective deprotection by treatment
with 50% aqueous HOAc to 5, vicinal diol cleavage with
NaIO4 to 6, and subsequent oximation gave 7. In a
separate route, aldehyde 6 was converted to nitro com-
pound 9 following a known protocol involving reaction
with nitromethane, acetylation, and reduction with so-
dium borohydride without isolating or purifying the
intermediates.11 Similarly, the pseudodisaccharide de-
rivative 14 was prepared from 3-O-allyl-1,2:5,6-diisopro-
pylideneallofuranose (13)12 and the known mesyl deriva-
tive 12,8 which was prepared from the known8 alcohol
11 by mesylation with MeSO2Cl in the presence of
triethylamine. Ether 14 was then converted to oxime 17
and nitro derivative 19 by the earlier mentioned methods.
Pseudodisaccharide 23, oxime 26, and nitro compound
28 were prepared by the abovementioned methods from
3 and the known8 3-C-allyl ribose derivative 21 (Scheme
2).
ation. Oxime 35 and nitro derivative 37 were prepared
in the usual manner (Scheme 3).
To our knowledge, the pseudooligosaccharide deriva-
tives cited in the above schemes are the first examples
of 3,5′-ether-linked species, and the method used for their
synthesis constitutes an operationally simple alternative
to existing protocols.7
Oximes 7, 17, 26, and 35 were converted to their
respective nitrile oxides 8, 18, 27, and 36 by treatment
with N-chlorosuccinimide and DMAP,13 while nitro com-
pounds 9, 19, 28, and 37 furnished nitrile oxides 10, 20,
(8) Tripathi, S.; Singha, K.; Achari, B.; Mandal, S. B. Tetrahedron
2004, 60, 4959; corrigendum, Tetrahedron 2005, 61, 6154.
(9) Tranmer, G. K.; Tam, W. J. Org. Chem. 2001, 66, 5113.
(10) A minor olefinic product derived by the elimination of MsOH
from the mesylate 2 was obtained in this reaction. The 1H NMR
spectrum of the compound suggested the structure shown below.
Scaling up of the alkylation resulted in the increased formation of this
side product. Similar olefinic minor products were also encountered
in the other alkylation reactions described in this work.
Pseudotrisaccharide 32 was synthesized by coupling
3 with the mesyl derivative 31, which was obtained by
NaBH4 reduction of aldehyde 6 f 30 followed by mesyl-
(11) Kozikowski, A. P.; Li, C.-S. J. Org. Chem. 1985, 50, 778.
(12) Baker, D. C.; Horton, D.; Tindal, C. G., Jr. Carbohydr. Res.
1972, 24, 192.
8580 J. Org. Chem., Vol. 70, No. 21, 2005

SCHEME 3. Synthesis of the Pseudotrisaccharide 32 and Its Conversion to Nitrile Oxidesa
a Reagents and conditions: (a) NaBH4, MeOH, 25 °C, 6 h, 89%. (b) MeSO2Cl, Et3N, CH2Cl2, 1 h, 0-25 °C, 93%. (c) (Bu)4NBr, 11% aq.
NaOH, 70 °C, 70 h, 83%. (d) 50% aq. AcOH, 25 °C, 15 h, 99%. (e) NaIO4, MeOH-H2O, 25 °C, 2 h, 98%. (f) NH2OH‚HCl, py, EtOH, reflux,
4 h, 71%. (g) i. MeNO2, i-PrOH, KF, 25 °C, 24 h, ii. Ac2O, DMAP, Et2O, 0 °C, 2 h, iii. NaBH4, EtOH, 25 °C, 6 h, 52%. (h) N-Chlorosuccinimide,
DMAP, CH2Cl2, 25 °C, 48 h. (i) 4-Chlorophenylisocyanate, Et3N, benzene, 25 °C, 48 h.
29, and 38 by reaction with 4-chlorophenylisocyanate.14
The concomitant cycloaddition of these nitrile oxides
occurs in situ; the results of these cycloadditions are
presented in Table 1.
As seen from Table 1, all the nitrile oxides except 18
and 27 (entries 3 and 5) underwent cycloaddition giving
rise to the oxacycle-fused isoxazolines 39-44. Intractable
mixtures were obtained from the reactions of 18 and 27.
No nitrile oxide dimers or dimeric isoxazolines could be
isolated from these reactions. The majority of the prod-
ucts were bridged isoxazolines with the exception of 42,
which was a fused isoxazoline. The reasons for the failure
of 18 and 27 to undergo cycloaddition are not known,
FIGURE 1. ORTEP view of 39.
although it is possible that the unfavorable steric and
Supporting Information) led to the assigned stereochem-
transannular interaction in the medium-ring transition
istry in 41 and 42. The stereochemistry of 43 and 44
states prevented the reaction. The gross structures of
1
could not be established due to their poorly resolved H
these isoxazolines were easily ascertained by NMR and
NMR spectra and the failure to obtain suitable crystals
mass spectral analyses. The presence of the bridge
for X-ray analysis. However, their gross structures could
-CH2- in a bridged isoxazoline was established by the
be unambiguously determined by the appearance of the
appearance of two sets of doublets with a large Jgem (∼16
signals due to the bridge -CH2- with high geminal
Hz) in the 1H NMR spectrum as well as a high-field
coupling constants in the 1H NMR spectra as well as by
methylene carbon signal in the 13C NMR spectrum. The
the adequate 13C NMR and mass spectral data.
yields (50-87%) observed in these cycloadditions are
quite impressive considering the sizes of the oxacycles
formed, which ranged between 10 and 16. The dia-
stereoselectivity and the regioselectivity of these cyclo-
Nitrile oxides 8, 10, 20, and 29 (entries 1, 2, 4, and 6)
gave rise to products that contain medium-sized
(10-12-membered) oxacycles fused to isoxazoline rings.
additions warrant special mention because a single
product was obtained in each of the successful reactions.
(13) Liu, K.-C.; Shelton, B. R.; Howe, R. K. J. Org. Chem. 1980, 45,
3916.
The stereochemistry of the newly formed chiral center
in 39 was established by X-ray diffraction analysis
(Figure 1),15 whereas in 40, 41, and 42, it was established
by NOESY analysis. The NOESY spectrum of 39 did not
reveal any NOE correlation of the bridge methylene
protons or of the newly formed chiral center with any
existing chiral center. The NOESY spectrum of the
higher homologue 40 was very similar to that of 39 and
did not exhibit any NOE of the proton attached to the
newly formed chiral center with those of the existing
chiral centers. It was apparent that 39 and 40 should
have closely similar structures, and hence the stereo-
chemistry of the newly formed centers in these com-
pounds is expected to be identical. The assignment also
appeared logical from the viewpoint of the faciality of
approach of the reacting dipole and the dipolarophile in
the nitrile oxide 10, which should be similar to that
observed in its lower homologue 8. The observation of
the relevant NOE correlations shown in Figure 2 (in the
(14) Mukaiyama, T.; Hoshino, T. J. Am. Chem. Soc. 1960, 82, 5339.
(15) Crystal data for 39 C19H27NO9 M ) 413.42, crystal dimensions
0.36 × 0.18 × 0.12 mm3, orthorhombic, space group P2(1)2(1)2(1), a )
6.8229(8), b ) 15.4730(17), c ) 18.734(2) Å, V ) 1977.8(4) Å3, Z ) 4;
Fcalcd ) 1.388 g cm-3, µ (Mo KR) ) 0.111 mm-1, 2θmax ) 50.0°, 9953
reflections collected, 3443 unique, 2897 observed (I > 2σ(I)) reflections,
226 refined parameters, R value 0.0456, wR2 ) 0.0755 (all data R )
0.0586, wR2 ) 0.0789), S ) 1.097, maximum and minimum residual
electron densities 0.127 and -0.128 Å-3. X-ray data intensity was
collected on a SMART APEX CCD diffractometer with omega and phi
scan mode, λMoKR ) 0.71073 Å at T ) 293(2) K. All the data were
corrected for Lorentzian, polarization, and absorption effects using
SAINT and SADABS programs. SHELX-97 (Sheldrick, G. M. SHELX-
97: Program for Crystal Structure Solution and Refinement; University
of Go¨ttingen: Go¨ttingen, Germany, 1997) was used for structure
solution and full-matrix least squares refinement on F2. Hydrogen
atoms were located in the difference Fourier map but were refined
using riding model option in the least-squares refinement. Crystal-
lographic data (excluding structure factors) for 39 reported in this
note have been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication number CCDC 258842. These
data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/
retrieving.html (or from Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, U.K.; fax: (+44)-1223-336-033; or
deposit@ccdc.cam.ac.uk).
J. Org. Chem, Vol. 70, No. 21, 2005 8581

SCHEME 4. Degradation of 39, 41, and 44a
TABLE 1. Intramolecular Nitrile Oxide Cycloaddition
of Pseudooligosaccharide Derivativesa
a Reagents: (a) i. 4% aq. H2SO4-CH3CN, 25 °C, 48 h, ii. NaIO4,
MeOH-H2O, 25 °C, 2 h, iii. NaBH4, EtOH, 0-25 °C, 6 h, iv. Ac2O,
Et3N, DMAP, EtOAc, 25 °C, 6 h, 14%. (b) i. LiAlH4, Et2O, 25 °C,
24 h, ii. Ac2O, py, 25 °C, 12 h, 50% (46), 67% (47). (c) Raney-Ni,
H2, MeOH-H2O (10:1), HOAc, 25 °C, 36 h, 75%.
pseudotrisaccharide scaffolds having multiple substitu-
tions and three ether linkages in the acyclic backbone.
The resulting cycloadducts 43 and 44 are characterized
by the presence of polyether macrocycles of ring sizes 15
and 16.
The advantage of the isopropylidene-protected fur-
anoside ring in the above cycloadducts was demonstrated
by the facile degradation of 39 to 45 in 14% overall yield
via a well-established sequence of reactions involving
removal of the isopropylidene groups, vicinal diol cleav-
age by NaIO4, reduction of the resulting aldehyde by
NaBH4, and acetylation (Scheme 4).16 Alternatively, the
isoxazoline rings in 39 and 41 were cleaved by LiAlH4,
and the resulting amino alcohols were acetylated to
furnish the furanoside-fused oxacycles 46 and 47 in 50
and 67% overall yields, respectively (Scheme 4). The
reduction was found to be stereoselective in both cases,
although the stereochemistry of the carbon atoms bearing
the acetamido groups could not be established. In a
different approach, reductive cleavage of isoxazoline 44
by hydrogenation in the presence of Raney nickel and
acetic acid afforded the keto alcohol 48 in 75% yield
(Scheme 4).11
In conclusion, the work in this note presents a
convenient method for the synthesis of 3,5′-ether-
linked pseudooligosaccharides and a novel approach to
chiral macrooxacycles by the application of nitrile oxide
cycloaddition. These 3,5′-ether-linked pseudooligosaccha-
rides are potentially important for the synthesis of RNA
analogues, and work toward this goal will be reported in
due course.
Acknowledgment. J.S. is grateful to CSIR, India,
for the award of a Senior Research Fellowship. Thanks
are due to Mr. A. Banerjee, Mr. K. Sarkar, and Mr. S.
Chowdhury for spectral analyses.
a Nitrile oxides were generated from the oximes by treatment
with N-chlorosuccinimide at 25 °C and DMAP or from the nitro
compounds by treatment with 4-chlorophenylisocyanate and tri-
ethylamine at 25 °C. The cycloadditions took place in situ.
b Chromatographically isolated yields. c Intractable mixtures were
obtained in these reactions.
The formation of “fused” isoxazoline 42 from 29 reflected
the conformational intricacies associated with these
medium rings. The presence of the O-benzyl group in one
of the furanoside rings in the nitrile oxide 29 probably
contributed to enhanced transannular and steric interac-
tions in the transition state involved in the formation of
the alternative “bridged” bicyclic ring. Nitrile oxides 36
and 38 (entries 7 and 8) represent two particularly
interesting substrates incorporating 3,5′-ether-linked
Supporting Information Available: Experimental pro-
cedure, NMR spectra, and CIF file. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO050689W
(16) Bhattacharjee, A.; Datta, S.; Chattopadhyay, P.; Ghoshal, N.;
Kundu, A. P.; Pal, A.; Mukhopadhyay, R.; Chowdhury, S.; Bhatta-
charjya, A.; Patra, A. Tetrahedron 2003, 59, 4623.
8582 J. Org. Chem., Vol. 70, No. 21, 2005