[1,3]-Dipolar intramolecular nitrone olefin cycloaddition reaction of a sugar-derived α,β-unsaturated ester: A new diastereo- and regioselective synthesis of an aminocyclopentitol

Article abstract of DOI:10.1016/S0040-4039(01)00877-2

The reaction of hemiacetal 2a, from the sugar derived α,β-unsaturated ester 1a, with N-benzylhydroxylamine hydrochloride in situ generates an N-benzylnitrone as a 1,3-dipole, which spontaneously undergoes diastereo- and regioselective intramolecular nitro

Full text of DOI:10.1016/S0040-4039(01)00877-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4925–4928
[1,3]-Dipolar intramolecular nitrone olefin cycloaddition reaction
of a sugar-derived a,b-unsaturated ester: a new diastereo- and
regioselective synthesis of an aminocyclopentitol
Santosh M. Jachak, Navnath P. Karche and Dilip D. Dhavale*
Department of Chemistry, Garware Research Centre, University of Pune, Pune 411 007, India
Received 29 March 2001; revised 19 April 2001; accepted 23 May 2001
Abstract—The reaction of hemiacetal 2a, from the sugar derived a,b-unsaturated ester 1a, with N-benzylhydroxylamine
hydrochloride in situ generates an N-benzylnitrone as a 1,3-dipole, which spontaneously undergoes diastereo- and regioselective
intramolecular nitrone olefin cycloaddition to afford
a hydroxy functionalised 4-exo-ethoxycarbonyl-3-oxa-2-azabicy-
clo[3.3.0]octane system, a precursor to a hitherto unknown aminocyclopentitol derivative. © 2001 Elsevier Science Ltd. All rights
reserved.
Amongst 1,3-dipolar cycloaddition reactions,1 the
intramolecular nitrone olefin cycloaddition (INOC)
methodology has received a lot of attention in recent
years for the synthesis of novel heterocyclic ring sys-
tems and aminocarbocycles with different ring sizes.2 In
the case of simple alkenes containing achiral nitrones,
the INOC proceeds well and results in the formation of
fused bicyclic isoxazolidines in which the configuration
of the olefin dictates and stereoselectivity of product
formation.3 However, the INOC of achiral or chiral
nitrones having an electron deficient alkene substituent
such as an a,b-unsaturated esters is intriguing and very
few examples of this type are known.4 The stereochem-
ical outcome in such concerted reactions is determined
by steric factors and secondary orbital interactions;
while the regioselectivity of the cycloaddition is con-
trolled by the transition state invoking both steric and
electronic effects. As far as the regiochemical outcome
is concerned, there are two possibilities: either the for-
mation of a-oxido ester or b-oxido ester isoxazolidine
derivatives. As a part of our continuing interest in
vated alkene to give an isoxazolidine—a precursor to a
five or six membered aminocarbocycle. This class of
compounds, namely aminocyclopentitols are known to
be powerful inhibitors of glycosidases.6 In the search
for structure–activity relationships, the synthesis and
evaluation of the glycosidase inhibitory activities of
natural and unnatural analogues of aminocyclitols is a
subject of current interest.7 Our results in this direction
are reported herein.
Recently, we have reported the preparation and utility
of ethyl 3-O-benzyl-5,6-dideoxy-1,2-O-isopropylidene-
a- -xylo-5(E)-eno-heptofuranuronoate (1a) in the syn-
D
thesis of polyhydroxylated piperidine and indolizidine
alkaloids.8 The cleavage of the acetonide functionality
in 1a with TFA–water afforded hemiacetal 2a
(anomeric mixture, a:b=7:3) with the exclusively E-
geometry at the double bond.† The one pot reaction of
2a with N-benzylhydroxylamine hydrochloride (1.0
equiv.) in the presence of sodium acetate (2 equiv.) in
aq. ethanol (20%) afforded 4-exo-ethoxycarbonyl-3-
oxa-2-azabicyclo [3.3.0]octane (a-oxido-ester isoxazo-
lidine) 3 as a white solid in 65% yield (Scheme 1).‡
nitrone cycloaddition reactions,5 we have exploited
D-
glucose derived a,b-unsaturated ester 1 as an appropri-
ate substrate for the INOC. We envisioned that the
reaction of hemiacetal 2, derived from 1 by acetonide
cleavage, with N-benzyl hydroxylamine hydrochloride
would generate the N-benzylnitrone (1,3-dipole), which
will undergo the INOC reaction in situ with an acti-
† As indicated from the 1H NMR spectrum the cleavage of the
acetonide group in the la with TFA–H2O afforded hemiacetal 2a as
an anomeric mixture (a:b=7:3) with exclusive E-geometry. The
same reaction with a mixture of 1a and 1b or with 1b (Z-isomer),
however, led to hemiacetal 2a with E-geometry as reported by us
earlier.8a Our attempts to isolate 2b (Z-isomer) in pure form were
unsuccessful.
Keywords: nitrones; cycloadditions; cyclitols; isoxazolidines; enzyme
inhibitors; glycosidation.
* Corresponding author. E-mail: ddd@chem.unipune.ernet.in
‡ The reaction afforded an unidentified compound in ꢀ10% yield at
a higher Rf value than 3.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00877-2

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S. M. Jachak et al. / Tetrahedron Letters 42 (2001) 4925–4928
Scheme 1. (i) Ref. 8a; (ii) TFA–H2O (3:2), 0°C to rt, 2.5 h, 80%; (iii) HN(OH)Bn·HCl (1 equiv.), CH3COONa (2 equiv.), aq.
ethanol, rt for 8 h and then reflux, 4 h, 65%; (iv) Ac2O (32 equiv.), pyridine (19 equiv.), DMAP (0.01%), rt, 18 h; (v) LAH (5
equiv.), THF, 0°C, 1 h, 83%; (vi) 10% Pd/C, HCOONH4 (7 equiv.), methanol, reflux, 45 min, 84%; (vii) methanolic-HCl, (0.5 M,
0.6 ml), rt, 40 h, 90%.
The spectroscopic and analytical data obtained for 3
were in agreement with the assigned structure.§ The
configurations at the newly generated contiguous stere-
ocentres (C1, C4 and C5) were determined from the
4, the high value of J1,5 (ꢀ9.3 Hz) indicated the five
membered cis ring fusion. The relative trans stereo-
chemical assignment between H-4 and H-5 was estab-
lished by the low value of J4,5 (ꢀ4.5 Hz). Similarly, the
small values for J5,6 (ꢀ5.2 Hz) and J1,8 (ꢀ5.1 Hz)
indicated the trans relative stereochemistry H-5, H-6
and H-1, H-8, respectively.¶ The geometry of the start-
ing compound ensures that the substituents at C-6, C-7
and C-7, C-8 are trans related supporting the structure
1
high field H NMR, 13C DEPT, TOCSY. However, in
order to confirm the assignment, the isoxazolidine 3
was converted to the di-acetyl derivative 4 and the
coupling constant information was derived from proton
decoupling experiments. In both the compounds 3 and
§ The coupling constant information of isoxazolidine 3 was found to be in good agreement with those reported by Ferrier et al.4b for the closely
related compound in which they assigned a cis configuration at the ring junction and a trans relationship between the cyclopentyl substituents
at C-1 and C-8 and at C-5 and C-6.
¶ Selected physical data for 3: white solid, mp=135°C, [h]D=−22.5 (c 0.32, CHCl3); Rf =0.37, (ethyl acetate:hexane=6:4); wmax (Nujol) 3600–3240
(br.), 1699 cm−1. lH (CDCl3, 300 MHz): l 1.29 (3H, t, J=7.0 Hz, CH3), 1.57–2.10 (2H, bs, exchanges with D2O, OH), 3.20 (1H, ddd, J=9.3,
5.2, 4.8 Hz, H-5), 3.44–3.54 (1H, m, H-1), 3.72 (1H, t, J=7.6 Hz, H-7), 3.91 (1H, d, J=13.0 Hz, NCH2Ph), 3.96–4.04 (1H, m, H-8) 4.13 (1H,
dd, J=7.6, 5.2 Hz, H-6), 4.24 (2H, q, J=7.0 Hz, OCH2CH3), 4.39 (1H, d, J=13.0 Hz, NCH2Ph), 4.48 (1H, d, J=4.8 Hz, H-4), 4.73 (2H, ABq,
J=12.0 Hz, OCH2Ph), 7.18–7.40 (10H, m, Ar-H); 13C NMR (CDCl3, 75 MHz): l 13.9, 52.4, 54.7, 61.6, 72.5, 74.6, 77.2, 81.2, 89.2, 126.8, 127.7,
127.8, 128.0, 128.2, 128.4, 136.4, 138.2, 171.1. Anal. calcd for C23H27NO6: C, 66.81; H, 6.58. Found: C, 66.69; H, 6.32. For 4: (ethyl
acetate:hexane=1:1); wmax (Nujol) 1735 cm−1. lH (CDCl3, 300 MHz): 1.26 (3H, t, J=7.0 Hz, CH3), 1.94 (3H, s, CH3), 2.06 (3H, s, CH3),
3.33–3.40 (1H, bm, H-5), 3.57–3.65 (1H, bm, H-1), 3.98–4.10 (3H, bm, H-7, NCH2Ph), 4.20 (2H, q, J=7.0 Hz, OCH2CH3), 4.62 (2H, s,
OCH2Ph), 4.75 (1H, d, J=4.0 Hz, H-4), 5.07 (1H, bt, J=5.5 Hz, H-8), 5.25–5.32 (1H, bm, H-6), 7.20–7.38 (10H, m, Ar-H). 13C NMR (CDCl3,
75 MHz): l 14.0, 20.8, 20.9, 29.7, 53.2, 53.4, 61.5, 72.2, 77.4, 81.1, 85.1, 127.3, 127.6, 127.7, 128.2, 128.3, 128.7, 136.6, 138.7, 169.4, 170.3, 170.7.
Anal. calcd for C27H31NO8: C, 65.18; H, 6.28. Found: C, 65.49; H, 6.02. For 6: white solid, mp=121°C, [h]D=+16.2 (c 0.25, CHCl3); Rf=0.63
(ethyl acetate:hexane=1:1); wmax (Nujol) 1735 cm−1; lH (CDCl3, 300 MHz): 1.97 (3H, s, CH3), 2.04 (6H, s, CH3), 2.78 (1H, ddd, J=9.3, 5.3,
4.8 Hz, H-5), 3.38 (1H, bd, J=9.3 Hz, H-1), 3.94 (1H, d, J=14.0 Hz, NCH2Ph), 4.08 (1H, t, J=5.9 Hz, H-7), 4.12–4.18 (3H, m, CH2OAc,
NCH2Ph), 4.38–4.44 (1H, m, H-4), 4.61 (2H, ABq, J=12.3 Hz, OCH2Ph), 5.07 (1H, t, J=5.8 Hz, H-8), 5.15–5.22 (1H, bm, H-6), 7.20–7.40
(10H, m, Ar-H). 13C NMR (CDCl3, 75 MHz): l 20.9, 21.0, 29.7, 53.6, 59.9, 63.7, 72.1, 72.4, 76.6, 80.0, 86.9, 127.3, 127.5, 127.6, 128.1, 128.2,
136.2, 137.5, 169.4, 170.1, 170.5. Anal. calcd for C27H31NO8: C, 65.18; H, 6.28. Found: C, 65.39; H, 6.55. For 8: white solid, mp=118°C,
[h]D=+38.4 (c 0.25, CHCl3); Rf=0.34 (ethyl acetate:hexane=1:1); wmax 3600–3220, 1741 cm−1; lH (CDCl3, 300 MHz): 2.00 (3H, s, CH3), 2.05
(3H, s, CH3), 2.07 (3H, s, CH3), 2.09 (3H, s, CH3), 2.10 (6H, s, CH3), 2.78 (1H, ddd, J=7.6, 7.9, 8.2 Hz, H-5), 4.06 (1H, dd, J=12.3, 6.3 Hz,
H-7a), 4.23 (1H, dd, J=12.3, 3.3 Hz, H-7b), 4.58–4.68 (1H, m, H-4), 4.98–5.05 (2H, m, H-2, H-3), 5.24–5.36 (2H, m, H-1, H-6), 6.19 (1H, d,
J=8.7 Hz, exchanges with D2O, NH). The assignment of protons was made by 2D 1H COSY experiment. 13C NMR (CDCl3, 75 MHz): l 20.9,
21.0, 21.1, 21.2, 23.5, 44.9, 52.9, 63.9, 69.3, 76.5, 79.4, 81.5, 170.0, 170.1, 170.4, 170.8. Anal. calcd for C19H27NO11: C, 51.23; H, 6.11. Found:
C, 51.43; H, 6.30. For 9: [h]D=−19.1 (c 0.20, MeOH); Rf=0.19 (methanol:chloroform=1:1); wmax (Nujol) 3700–3060 (br.) cm−1; lH (D2O, 300
MHz): 2.14 (1H, ddd or apparent q, J=8.0 Hz, H-5), 3.40–3.85 (7H, m). 13C NMR (D2O, 75 MHz): l 43.8, 54.2, 64.4, 69.8, 73.8, 75.9, 79.4.
Anal. calcd for C7H16ClNO5·3H2O: C, 29.63; H, 7.81. Found: C, 29.25; H, 8.12.

S. M. Jachak et al. / Tetrahedron Letters 42 (2001) 4925–4928
4927
3. The cis relationship of the -COOEt group at C-4 and
the -OH functionality at C-6 was also indicated by the
IR spectrum of isoxazolidine 3. This showed a low
value for the ester carbonyl (1699 cm−1) indicating the
presence of intramolecular hydrogen bonding. In agree-
ment with this, in the acetate 4, such hydrogen bonding
is destroyed as -OH is converted to -OAc. The ester
carbonyl now appeared only at 1735 cm−1. In the
subsequent step, reduction of the ester functionality in
3 with LAH in THF afforded alcohol 5 which was
immediately acetylated to give the triacetate 6 as a
white solid in 81% yield.¶ The concomitant reductive
cleavage of the NꢀO bond and the hydrogenolysis of
the benzyl groups in 6, with 10% Pd/C using ammo-
nium formate as a hydride donor in refluxing methanol,
yielded the triacetylated amino alcohol 7 which on
treatment with Ac2O in pyridine gave peracetylated
amino alcohol 8 as a white solid.¶ The structure and
stereochemistry of the compound 8 was confirmed by
2D NMR experiments and the configurations were
found to be 1R,2S,3S,4R,5R, and 6R. Treatment of 8
with methanol–HCl (0.5 M) at reflux for 40 h gave
aminocyclopentitol 9 as a colourless, semisolid, amine-
hydrochloride. The analytical and spectroscopic data¶
were found to be in agreement with the proposed
structure 9.
disposition, while in TS B this bond has an axial-like
disposition.
In conclusion, we have demonstrated that the easily
available
could be easily converted to the hydroxy-functionalised
4-exo-ethoxycarbonyl-3-oxa-2-aza bicyclo[3.3.0]octyl
D
-glucose derived a,b-unsaturated ester 2a
derivative 3 via the INOC pathway. The isoxazolidine 3
thus obtained was transformed in to the hitherto
unknown aminocyclopentitol 9 in good yield. The easy
availability of starting material, few steps and high
yield of the products makes this approach practicable,
even on a multi-gram scale.
Acknowledgements
We are thankful to BRNS (98/37/11/BRNS/667) for the
financial support and JRF to S.M.J. We gratefully
acknowledge the help of Dr. Sudha Srivastava, for
recording 2D NMR experiments with the 500 MHz
NMR spectrometer at TIFR, Mumbai. We are thank-
ful to UGC, New Delhi for the financial support to
procure High field NMR (300 MHz) under the CAS
programme.
The overall two-step transformation of 2a involves the
in situ generation of an N-benzyl nitrone at the hemiac-
etal carbon, which spontaneously undergoes INOC
leading to the formation of the kinetically controlled
References
1. For reviews on 1,3-dipolar cycloadditions, see: (a)
Tufariello, J. J. In 1,3-Dipolar Cycloaddition Chemistry;
Padwa, A., Ed.; Wiley-Interscience: New York, 1984;
Chapter 9, p. 83; (b) Fisera, L.; Al-Timari, U. A. R.; Ertl,
P. In Cycloadditions in Carbohydrate Chemistry. ACS
Monograph. Am. Chem. Soc.; Washington, 1992; p. 158;
(c) Balasubramanian, N. Org. Prep. Proced. Int. 1985, 17,
23; (d) 1,3-Dipolar Cycloaddition Chemistry; Padwa, A.,
Ed.; Wiley-Interscience: New York, 1984; Chapter 9, p.
277; (e) Gothelf, K. V.; Jorgensen, K. A. Chem. Rev. 1998,
98, 863; (f) Torssell, K. B. G. In Organic Synthesis, Nitrile
Oxides, Nitrones and Nitronates. VCH: NewYork, 1988;
(g) Padawa, A. Angew. Chem., Int. Ed. Engl. 1976, 15, 123.
2. For intramolecular nitrone–olefin cyclizations, see: (a)
Wade, P. A. In Comprehensive Organic Synthesis; Trost, B.
M.; Fleming, I., Eds. Intramolecular 1,3-dipolar cycload-
ditions. Pergamon: Oxford, 1991; Vol. 4, p. 1111; (b)
Frederickson, M. Tetrahedron 1997, 53, 403.
(fused) bicyclo[3.3.0]octyl derivative
3
over the
(bridged) bicyclo[3.2.1]octane system 10. We presume
that the transition state (TS) A (Fig. 1) that assumes
product-like geometry is stabilised by the significant s
overlap between the nitrone oxygen and C-6; and
between C-1 and C-5 during the formation of these
bonds in isoxazolidine 3, with the exo-ethoxycarbonyl
functionality, in a concerted pathway.3,4,9 The steric
destabilisation of the TS B, required for the formation
of a strained ring system, presumably precludes the
formation of bridged bicyclo[3.3.1]octane derivative 10.
In TS A the CꢀN sigma bond has an equatorial-like
3. (a) Gossinger, E.; Imhof, R.; Wehrli, H. Helv. Chim. Acta
1975, 58, 96; (b) Bernet, B.; Vasella, A. Helv. Chim. Acta
1979, 62, 1990; (c) Bar, N. C.; Roy, A.; Achari, B.;
Mandal, S. B. J. Org. Chem. 1997, 62, 8948; (d) Roy, A.;
Patra, R.; Achari, B.; Mandal, S. B. Synlett 1997, 1237; (e)
Moutel, S.; Shipman, M. Synlett 1998, 1333; (f) Arm-
strong, P.; Grigg, R.; Sivagnanasundram, S.; Warnock, W.
J. J. Chem. Soc., Chem. Commun. 1987, 11, 1327; (g)
Werner, K. M.; De los Santos, J. M.; Weinreb, S. M. J.
Org. Chem. 1999, 64, 4865; (h) Grigg, R.; Markandu, J.;
Perrior, T.; Sivagnanasundram, S.; Warnock, W. Tetra-
hedron Lett. 1990, 31, 559; (i) Lumma, W. C. J. Am.
Chem. Soc. 1969, 91, 2820.
4. (a) Tufariello, J. J.; Trybulski, E. J. J. Org. Chem. 1974,
39, 3378; (b) Ferrier, R. J.; Furneaux, R. H.; Prasit, P.;
Figure 1.

4928
S. M. Jachak et al. / Tetrahedron Letters 42 (2001) 4925–4928
Tyler, P. T. J. Chem. Soc., Perkin Trans. 1 1983, 1621;
Grandjean, C.; Siriwardena, A. Chem. Rev. 1999, 99, 779;
(b) Borthwick, A. D.; Biggadike, K. Tetrahedron 1992,
48, 571.
(c) Oppolzer, W.; Keller, K. Tetrahedron Lett. 1970,
4313; (d) Oppolzer, W.; Keller, K. Tetrahedron Lett.
1970, 1117; (e) Oppolzer, W.; Keller, K. Tetrahedron
Lett. 1970, 1121.
7. (a) Boss, O.; Leroy, E.; Blaser, A.; Reymond, J. Org.
Lett. 2000, 2, 151 and references cited therein; (b) Acar,
E. A.; Glarner, F.; Burger, U. Helv. Chim. Acta 1998, 81,
1095; (c) Wen, X.; Norling, H.; Hegedus, L. S. J. Org.
Chem. 2000, 65, 2096; (d) Li, J.; Lang, F.; Ganem, B. J.
Org. Chem. 1998, 63, 3403.
8. (a) Desai, V. N.; Saha, N. N.; Dhavale, D. D. J. Chem.
Soc., Chem. Commun. 1999, 11, 1719; (b) Patil, N. T.;
Tilekar, J. N.; Dhavale, D. D. J. Org. Chem. 2001, 66,
1065.
5. (a) Camiletti, C.; Dhavale, D. D.; Gentilucci, L.;
Trombini, C. J. Chem. Soc., Perkin Trans. 1 1993, 3157;
(b) Camiletti, C.; Dhavale, D. D.; Donati, F.; Trombini,
C. Tetrahedron Lett. 1995, 36, 7293; (c) Dhavale, D. D.;
Trombini, C. Heterocycles 1992, 34, 2253; (d) Dhavale,
D. D.; Donati, F.; Trombini, C. J. Chem. Soc., Chem.
Commun. 1992, 1268; (e) Saha, N. N.; Desai, V. N.;
Dhavale, D. D. Tetrahedron 2001, 57, 39.
6. (a) For reviews on aminocyclopentitol, see: Berecibar, A.;
9. Huisgen, R. J. Org. Chem. 1968, 33, 2291.
.