Application of Intramolecular Nitrone Cycloaddition Reaction: Synthesis of Chiral Aminocarbocycles and Carbocyclic Nucleosides from Carbohydrate Precursors

Full text of DOI:10.1021/jo971342z

8948
J . Org. Chem. 1997, 62, 8948-8951
ing stereochemistry based upon the respective D-glucose
Ap p lica tion of In tr a m olecu la r Nitr on e
derived intermediates, leading to the synthesis of the
isoxazolidinocarbocyclic derivatives 2a -f, 3a , 4, 7, and
8. As an example, a simple and convenient transforma-
tion of 2e to a carbocyclic nucleoside analogue 11 has also
been presented.
Cycloa d d ition Rea ction : Syn th esis of
Ch ir a l Am in oca r bocycles a n d Ca r bocyclic
Nu cleosid es fr om Ca r boh yd r a te P r ecu r sor s
Narayan C. Bar, Atanu Roy, Basudeb Achari, and
Sukhendu B. Mandal*
Indian Institute of Chemical Biology, J adavpur,
Calcutta 700 032, India
Received J uly 22, 1997
Intramolecular olefin-nitrone cycloaddition (INC) re-
action constitutes a simple and promising method for the
construction of carbocycles of different ring-sizes by
varying the mode of cyclization and judicious manipula-
tion of the substituents in the substrates.1 In recent
years, much effort has been expended in exploring
carbohydrate derived enose-nitrone cycloaddition meth-
odology toward the synthesis of chiral aminocarbocycles,
many of which exhibit glycosidase inhibitory activity.2
In addition, this class of compounds is an attractive
precursor for carbocyclic nucleoside analogues,3 often
possessing enhanced activity with better resistance to
most of the phosphorylase enzymes3i in comparison to
their furanose counterparts. As a carbohydrate precur-
sor, D-glucose is very useful due to its easy accessibility,
and it has been possible to synthesize enantiomerically
pure target molecules4 by utilizing the carbon skeleton
and the resident chirality of D-glucose.5 An added
attraction is the possibility of synthesizing both the pure
enantiomers of a product from a common intermediate
through INC reaction, by generating aldehyde precursors
of nitrones at the appropriate end.6 In this paper, we
report the details of our work undertaken to investigate
the scope and feasibility of such a strategy for developing
chiral aminocarbocycles of different ring-sizes and vary-
Resu lts a n d Discu ssion s
(1) (a) Torsell, K. B. G. Nitrile Oxides, Nitrones, and Nitronates in
Organic Synthesis, Novel Strategies in Synthesis; VCH: New York,
1988. (b) Bernet, B.; Vasella, A. Helv. Chim. Acta 1979, 62, 1990. (c)
Hassner, A.; Maurya, R.; Mesko, E. Tetrahedron Lett. 1988, 29, 5313.
(2) (a) Shing, T. K. M.; Elsley, D. A.; Gillhouley, J . G. J . Chem. Soc.,
Chem. Commun. 1989, 1280. (b) Peet, N. P.; Huber, E. W.; Farr, R. A.
Tetrahedron 1991, 47, 7537. (c) Duclos, O.; Dure′ault, A.; Depezay, J .
C. Tetrahedron Lett. 1992, 33, 1059. (d) Tatsuta, K.; Niwata, Y.;
Umezawa, K.; Toshima, K.; Nakata, M. Tetrahedron Lett. 1990, 31,
1171. (e) Ferrier, R. J .; Prasit, P. J . Chem. Soc., Chem. Commun. 1981,
983. (f) Farr, R. A.; Peet, N. P.; Kang, M. S. Tetrahedron Lett. 1990,
31, 7109. (g) Nakata, M.; Akazawa, S.; Kitamura, S.; Tatsuta, K.
Tetrahedron Lett. 1991, 32, 5363.
(3) (a) Borthwick, A. D.; Biggadike, K. Tetrahedron 1992, 48, 571.
(b) Agrofoglio, L.; Edouard, S.; Audrey, F.; Roger, C.; Challand, S.R.;
Earl, R.A.; Guedj, R. Tetrahedron 1994, 50, 10611. (c) Hsiao, C.-N.;
Hannick, S. M. Tetrahedron Lett. 1990, 31, 6609. (d) Zhao, Y.; Yang,
M.; Chun, B. K.; Du, J .; Schinazi, R. F.; Lee, D.; Newton, M. G.; Chu,
C. K. Tetrahedron Lett. 1994, 35, 5405. (e) Wachtmeister, J .; Classon,
B.; Samuelsson, B. Tetrahedron 1995, 51, 2029. (f) Marco-Contelles,
J .; Bernabe, M. Tetrahedron Lett. 1994, 35, 6361. (g) Maycock, C. D.;
Barros, M. T.; Santos, A. G.; Godinho, L. S. Tetrahedron Lett. 1993,
34, 7985. (h) Ichikawa, Y.; Narita, A.; Shiozawa, A.; Hayashi, Y.;
Narasaka, K. J . Chem. Soc., Chem. Commun. 1989, 1919. (i) Des-
granges, C.; Razaka, G.; Rabaud, M.; Bricaud, H.; Balzarini, J .;
DeClercq, E. Biochem. Pharmacol. 1983, 3583.
(4) Borthwick, A. D.; Butt, S.; Biggadike, K.; Exall, A. M.; Roberts,
S. M.; Youds, P. M.; Kirk, B. E.; Booth, B. R.; Cameron, J . M.; Cox, S.
W.; Marr, C. L. P.; Shill, M. D. J . Chem. Soc., Chem. Commun. 1988,
656.
(5) Hanessian, S. The Total Synthesis of Natural Products: The
Chiron Approach; Oxford Univ. Press: New York, 1983, pp 21-26.
(6) Bhattacharjee, A.; Bhattacharjya, A.; Patra, A. Tetrahedron Lett.
1995, 36, 4677.
(7) Patra, R.; Bar, N. C.; Roy, A.; Achari, B.; Ghoshal, N.; Mandal,
S. B. Tetrahedron 1996, 52, 11265.
(8) It appears plausible that the C-3 hydroxyl substituent with its
hydrogen bonding ability to the nitrone oxygen suitably alters the
transition state leading to different cyclization products.
P r ep a r a tion of Ca r bocyclic Der iva tives of Dif-
fer en t Rin g Sizes. To understand the role of a 3-oxy
substituent on the cyclization mode, enose-nitrone sub-
strates 1b-d ,f were prepared and subjected to cyclization
as follows. 1,2:5,6-Di-O-isopropylidene 3-allyl or 3-ho-
moallyl furanose derivatives7 were converted to their
3-alkoxy derivatives via reaction with the appropriate
alkyl halides (BnBr, allyl bromide, CH3I) under phase
transfer reaction condition. Treatment with aqueous
HOAc followed by NaIO4 afforded the 6-nor aldehydes
which were converted to the nitrones with benzyl hy-
droxylamine in alcohol. In situ cyclization afforded the
corresponding products 2b-d and 2f in 50-60% overall
yield.
Comparison of the results of cyclization with those
reported by us7 for 3-hydroxy substituents 1a and 1e
shows that isomeric cyclization products differing in ring-
sizes can be constructed by taking advantage of the
profound influence of a hydroxy substituent at C-3 over
the course of the cyclization. Thus, 1e formed a seven-
membered ring product 2e exclusively, but 1f bearing an
alkoxy substituent gave a six-membered ring product 2f.
Similarly, 1a carrying a hydroxyl group yielded a mixture
of 2a and 3a upon cyclization, but only the five-membered
products 2b-d could be isolated8 with the alkoxy bearing
substrates 1b-d .
Syn th esis of En a n tiom er ic a n d Dia ster eom er ic
Ca r bocyclic Der iva tives. The transformation of allyl
diisopropylidene allofuranose intermediate 5 to the enan-
S0022-3263(97)01342-X CCC: $14.00 © 1997 American Chemical Society

Notes
J . Org. Chem., Vol. 62, No. 25, 1997 8949
Sch em e 1a
tiomerically pure isoxazolidinocarbocycles 4 and 7 could
be realized by subjecting the C-3 allyl group to undergo
cyclization with the nitrones generated from the respec-
tive C-5 and C-1 aldehydes (Scheme 1). Thus, the
treatment of 5 with 60% HOAc and subsequent diol
cleavage gave an aldehyde which on treatment with
benzyl hydroxylamine led to the addition product 2c.
Acid-induced opening of the isopropylidene ring of 2c
followed successively by diol cleavage with NaIO4 and
NaBH4 reduction afforded 4 in 80% yield. On the other
hand 7 in its pure enantiomeric form could be obtained
in good yield by INC reaction (in DMF or DMSO at 50
°C) of the nitrone generated in situ from the hemiacetal
6a with benzyl hydroxylamine. This masked aldehyde
in turn was readily obtained from the respective alcohol
6, which was prepared from 5 by selective cleavage of
the 5,6-isopropylidene group, followed by vicinal diol
cleavage with NaIO4 and NaBH4 reduction. The two
products 4 and 7 had identical melting points, superim-
Sch em e 2a
1
posable IR as well as H NMR, and optical rotations of
equal magnitude but opposite signs.
The cyclization of the nitrone derived from 6a , how-
ever, was strongly dependent on the nature of the solvent.
Thus, the reaction proceeded smoothly in polar aprotic
solvents such as DMF and DMSO leading to the desired
product 7. However, no reaction occurred in protic
solvents such as EtOH, MeOH, or n-BuOH. The cycliza-
tion reaction also failed in benzene under reflux; however,
a different mode of cyclization9 took place in boiling
toluene or xylene resulting exclusively in the product 8.
ogy for synthetic entry to carbocyclic nucleoside ana-
logues with varying ring-sizes or stereochemistry, the
isoxazolidinofuranocarbocyclic derivative 2e was sub-
jected to the sequence of transformations shown in
Scheme 2. Thus, trimming of the furanose ring involving
deprotection with acid, diol cleavage with NaIO4 and
reduction of aldehyde with NaBH4 converted 2e to
isoxazolidinocycloheptane derivative 9. Further cleavage
of the isoxazolidine ring in 9 by catalytic transfer
hydrogenation (Pd/C, cyclohexene)11 followed by reaction
with 5-amino-4,6-dichloropyrimidine, and ring closure by
treatment with triethyl orthoformate afforded the chlo-
ronucleoside 10. This was finally converted to the seven-
1
The compound 8 differed significantly from 7 in its H
NMR, 13C NMR, and IR spectra. Since bicyclo[3.3.0]-
octanes10 prefer a cis-ring juncture, the diastereomeric
structure 8 was assigned to it.
Syn th esis of Ca r bocyclic Nu cleosid es. To demon-
strate the feasibility and scope of the present methodol-
(9) We believe that the possibility of dipole-dipole interaction
between the nitrone and solvents such as DMSO or DMF favors the
formation of the transition state intermediate, and cyclization occurs
to give the product 7. In apolar solvents such as toluene or xylene the
dihydroxy-bearing group and the nitrone come closer, away from the
solvent, and cyclization is arrested. However, at elevated temperature
(refluxing temperature) the existing arrangement breaks down; the
nitrone group moves about and comes closer to the allyl group when
cyclization occurs, giving rise to the product 8. In protic solvents, e.g.
EtOH, MeOH or n-BuOH the formation of nitrone is prevented, as
evident from the recovery of the starting material from the reaction
mixture.
(10) Nasipuri, D. Stereochemistry of Organic Compounds; Wiley:
Eastern, N. Delhi, 1992, p 316.
(11) Collins, P. M.; Ashwood, M. S.; Eder, H.; Wright, S. H. B.;
Kennedy, D. J . Tetrahedron Lett. 1990, 34, 3585.
(12) (a) Tadano, K.; Hoshino, M.; Ogawa, S.; Suami, T. J . Org. Chem.
1988, 53, 1427. (b) Merquez, V. E.; Lim, M.-I.; Tseng, C. K. H.;
Markovac, A.; Priest, M. A.; Khan, M. S.; Kaskar, B. J . Org. Chem.
1988, 53, 5709. (c) Yoshikawa, M.; Nakae, T.; Cha, B. C.; Yokokawa,
Y.; Kitagawa, I. Chem. Pharm. Bull. 1989, 37, 545. (d) Kitagawa, I.;
Cha, B. C.; Nakae, T.; Okaichi, Y.; Takinami, Y.; Yoshikawa, M. Chem.
Pharm. Bull. 1989, 37, 542.

8950 J . Org. Chem., Vol. 62, No. 25, 1997
Notes
91. Anal. Calcd for C25H29NO5: C, 70.90; H, 6.90; N, 3.31.
Found: C, 70.69; H, 7.12; N, 3.19.
membered carbocyclic nucleoside analogue 11 through
ammonolysis.12
For the preparation of 1d , 1,2:5,6-di-O-isopropylidene-3-prop-
1-enyl-R-D-allofuranose7 (885 mg, 2.6 mmol) was allylated with
allyl bromide (3 × 1 mL) following the procedure adopted for 5.
The crude diallylated compound thus obtained was then con-
verted to the nonisolable 1d according to the method as described
for 1b. The nitrone 1d on in situ cyclization afforded a crude
material which was purified on silica gel using the same solvent
as used for 1b to furnish 2d (550 mg, 57%). 2d : mp 82-83 °C;
[R]27D -5.8° (c 0.31, CHCl3); IR (KBr) 1653, 1498, 1250, 929, 878
In conclusion, the present investigation offers simple
and flexible strategies to synthesize different function-
alized carbocycles and chiral carbocyclic nucleoside ana-
logues varying in ring-sizes and stereochemistry.
Exp er im en ta l Section
Melting points were determined in open capillaries and are
uncorrected. 1H NMR spectra were measured on a 100 MHz or
a 300 MHz spectrometer using TMS as internal standard. Mass
spectra were recorded under electron impact at 70 eV. Reagents
and solvents were of analytical grade or were purified by
standard procedures prior to use. Merck silica gel 60 F254
(thickness 0.2 mm) was used for TLC visualization of nucleo-
sides.
cm-1 1H NMR (CDCl3, 100 MHz) δ 1.32 (s, 3H), 1.52 (s, 3H),
;
2.12 (d, 1H, J ) 14 Hz), 3.28 (app quintet, 1H, J ) 8 Hz), 3.56
(d, 1H, J ) 8 Hz), 3.76 (dd, 1H, J ) 6, 8 Hz), 3.92 (d, 1H, J ) 14
Hz), 4.06 (d, 1H, J ) 14 Hz), 4.08 (t-like, 1H, J ) 8 Hz), 4.22
(m, 2H), 4.40 (s, 1H), 4.42 (d, 1H, J ) 4 Hz), 5.04-5.48 (m, 2H),
5.72 (d, 1H, J ) 4 Hz), 5.80-6.20 (m, 1H), 7.34 (m, 5H); 13C
NMR (CDCl3, 25 MHz) δ 26.7 (q), 26.9 (q), 36.0 (t), 47.6 (d), 61.2
(t), 66.6 (t), 71.9 (t), 75.3 (d), 82.2 (d), 87.4 (d), 93.3 (s), 104.9
(d), 112.7 (s), 115.7 (t), 127.1 (d), 128.1 (d), 128.2 (d), 134.9 (d),
137.0 (s); EIMS, m/z: 373 (M+), 358 (M+ - 15), 216, 123, 91.
Anal. Calcd for C21H27NO5: C, 67.54; H, 7.29; N, 3.75. Found:
C, 67.51; H, 7.21; N, 3.39.
P r ep a r a tion of Nitr on es 1b-d a n d 1f, a n d Th eir Con -
ver sion to 1-Ben zyl-5:6-O-isop r op ylid en e-4a -m eth oxy-p er -
h yd r ofu r o[2′,3′:2,1]cyclop en t[3,4-c]isoxa zole (2b), 1-Ben -
zyl-5,6-O-isopr opyliden e-4a-(ben zyloxy)-per h ydr ofu r o[2′,3′:
2,1]cyclop en t[3,4-c]isoxa zole (2c), 1-Ben zyl-5,6-O-isop r o-
p ylid en e-4a -(a llyloxy)-p er h yd r ofu r o[2′,3′:2,1]cyclop en t -
[3,4-c]isoxa zole (2d ), a n d 1-Ben zyl-6,7-O-isop r op ylid en e-
5a -(ben zyloxy)-p er h yd r ofu r o[2′,3′:2,1]cycloh ex[3,4-c]isox-
a zole (2f). Oil free NaH (72 mg, 3 mmol) was added to a stirred
and ice-cooled solution of 1,2:5,6-di-O-isopropylidene-3-prop-1-
enyl-R-D-allofuranose7 (450 mg, 1.5 mmol) in diethyl ether (50
mL). After 30 min the solution was heated at reflux under N2,
MeI (1 mL) was added dropwise to it, and heating was continued
for 5 h. Excess NaH was decomposed with cold H2O (1 mL).
The ethereal solution was washed with H2O (2 × 10 mL), dried
(Na2SO4), and evaporated to a crude residue (405 mg) which,
without further purification, was treated with HOAc-H2O (3:
2) mixture (30 mL) at 70 °C for 50 min to remove 1,2-
isopropylidene group. The solvent was evaporated to afford a
dihydroxy compound (340 mg). To the cooled ethanolic solution
(20 mL) of it was added an aqueous solution (20 mL) of NaIO4
(200 mg) dropwise, and the mixture was stirred for 1 h and then
filtered. The filtrate was evaporated, the residue was dissolved
in CHCl3 (30 mL), and the CHCl3 solution was washed with H2O
(2 × 10 mL) and dried (Na2SO4). Evaporation of the solvent
afforded the crude aldehyde (285 mg). The aldehyde was
dissolved in EtOH (15 mL) and treated with BnNHOH (185 mg,
1.5 mmol) to obtain a crude oil (via in situ cyclization of the
nonisolable nitrone 1b). The oily mixture was purified by
column chromatography on silica gel eluting with petroleum
The generation of the nonisolable nitrone 1f and its corre-
sponding cyclization product 2f (234 mg, 54%) was similarly
carried out from 1,2:5,6-di-O-isopropylidene-3-prop-1-enyl-R-D-
allofuranose7 (405 mg, 1 mmol). Benzylation was done with
benzyl bromide (3 × 0.3 mL), according to the procedure as
adopted for 5. The rest of the reactions were performed following
the method as described for 1b. 2f: mp 78-80 °C; [R]26D +53.5°
(c 0.18, CHCl3); IR (KBr) 1605, 1495, 1375, 731, 680 cm-1 1H
;
NMR (CDCl3, 300 MHz) δ 1.33 (s, 3H), 1.54 (s, 3H), 1.83 (m,
3H), 2.11 (m, 1H), 3.11 (m, 1H), 3.48 (t, 1H, J ) 8.1 Hz), 3.56
(brt, 1H, J ) 8.6 Hz), 3.95 (d, 1H, J ) 14 Hz), 4.05 (d, 1H, J )
8.7 Hz), 4.06 (d, 1H, J ) 13.8 Hz), 4.16 (t, 1H, J ) 8.5 Hz), 5.55
(ABq, 2H, J ) 12 Hz overlapping an 1H signal), 5.98 (d, 1H, J
) 3.7 Hz), 7.34 (m, 10H); 13C NMR (CDCl3, 75 MHz) δ 20.8 (t),
21.0 (t), 26.2 (q), 26.8 (q), 39.8 (d), 60.7 (t), 64.2 (t), 65.2 (d), 70.2
(t), 79.7 (d, 2C), 84.9 (s), 105.9 (d), 112.2 (s), 126.5 (d, 2C), 127.0
(d), 127.5 (d), 128.2 (d, 2C), 128.4 (d, 2C), 128.9 (d, 2C), 137.9
(s), 138.3 (s); FABMS, m/z: 437 (M+ + 1). Anal. Calcd for
C
26H31NO5: C, 71.37; H, 7.14; N, 3.20. Found: C, 71.12; H, 7.02;
N, 3.13.
(3a S ,5S ,6R ,6a S )-1-Be n zyl-5-(b e n zyloxy)-5-(h yd r oxy-
m eth yl)-6-h yd r oxycyclop en t[c]isoxa zole (4). Compound 2c
(1.75 g, 4.13 mmol) was treated with 4% H2SO4 in CH3CN-H2O
(30 mL) at rt for 24 h. The solution was neutralized with solid
CaCO3 and filtered, and the solvent was evaporated in vacuo to
obtain a crude material (1.50 g). To this material dissolved in
EtOH (20 mL) and cooled to 10 °C was added an aqueous
solution (20 mL) of NaIO4 (1.08 g, 5 mmol, 1.2 eq) dropwise with
stirring. After stirring at rt for 40 min, the mixture was filtered,
the solvent was evaporated, and the residue was dissolved in
CHCl3 (80 mL). The solution was washed with H2O (2 × 20
mL) and dried (Na2SO4). Evaporation of the solvent in vacuo
gave the crude aldehyde (1.60 g) (IR: 1740 cm-1).
ether-CHCl3 (1:1) to furnish 2b (260 mg, 50%). 2b: oil; [R]26
D
-12.4° (c 0.31, CHCl3); IR (neat) 1608, 1497, 1374, 735, 690 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 1.32 (s, 3H), 1.53 (s, 3H), 1.68 (dd,
1H, J ) 8, 14 Hz), 2.19 (d, 1H, J ) 14 Hz), 3.29 (m, 1H), 3.42 (s,
3H), 3.54 (d, 1H, J ) 8 Hz), 3.72 (dd, 1H, J ) 7, 8 Hz), 3.95 (d,
1H, J ) 13.5 Hz), 4.08 (d, 1H, J ) 13.5 Hz), 4.15 (t, 1H, J ) 8
Hz), 4.38 (s, 1H), 4.48 (d, 1H, J ) 3.7 Hz), 5.72 (d, 1H, J ) 3.7
Hz), 7.32 (m, 5H); FABMS, m/z: 347 (M+ + 1).
To the aldehyde in MeOH (35 mL) at 0 °C was added NaBH4
(240 mg) portionwise and the mixture was kept at ice temper-
ature for 14 h. The solvent was evaporated, and the residue
was taken up in H2O (30 mL), and was extracted with CHCl3 (2
× 45 mL). The CHCl3 solution was washed with H2O (1 × 30
mL), dried (Na2SO4), and evaporated to give a residue which
was purified by column chromatography, eluting with CHCl3 to
The preparation of 1c from 5 was carried out following a
procedure similar to that described for 1b. Compound 5 (1.17
g, 3 mmol) was treated with aqueous HOAc to cleave 1,2-O-
isopropylidene protection. Usual workup followed by NaIO4 (600
mg) afforded the crude aldehyde (680 mg). The ethanolic
solution (40 mL) of the aldehyde, on reaction with BnNHOH
(310 mg, 2.5 mmol), furnished the nonisolable nitrone 1c which
was immediately cyclized to afford 2c. The impure compound
2c was purified by column chromatography on silica gel eluting
with the same solvent as used for 1b to give pure 2c (760 mg,
afford 4 (1.12 g, 80%): mp 130-132 °C; [R]26 -30.8° (c 0.5,
D
1
CHCl3); IR (KBr) 3346, 1451, 724, 689 cm-1; H NMR (CDCl3,
300 MHz) δ 1.67 (dd, 1H, J ) 8.2, 13.4 Hz), 2.15 (dd,1H, J )
9.2, 13.3 Hz), 3.00 (quintet of doublets, 1H, J ) 9, 9, 9, 9, 3 Hz),
3.46 (brt, 1H, J ) 8 Hz), 3.60 (dd, 1H, J ) 3.5, 8.8 Hz), 3.76 (d,
2H, J ) 13 Hz), 3.93 (d, 1H, J ) 12.2 Hz), 4.03 (d, 1H, J ) 13
Hz), 4.09 (t, 1H, J ) 8 Hz), 4.27 (brd, 1H, J ) 6.6 Hz), 4.48 and
4.64 (2×d, 1H each, J ) 11.2 Hz), 7.32 (m, 10H); 13C NMR
(CDCl3, 75 MHz) δ 35.7 (t), 41.1 (d), 59.9 (t), 63.4 (t), 65.7 (t),
72.1 (t), 75.4 (d), 81.0 (d), 84.9 (s), 127.6 (d), 128.4 (d), 128.5 (d),
129.0 (d), 136.8 (s), 138.7 (s); EIMS, m/z: 355 (M+), 252, 232,
174, 161, 91. Anal. Calcd for C21H25NO4: C, 70.96; H, 7.09; N,
3.94. Found: C, 70.48; H, 7.02; N, 3.62.
60%). 2c: mp 95-96°; [R]26 -21.9° (c 0.75, CHCl3); IR (KBr)
D
1607, 1498, 1374, 1042, 734, 689 cm-1
;
1H NMR (CDCl3, 300
MHz) δ 1.35 (s, 3H), 1.56 (s, 3H), 1.64 (m, 1H), 2.17 (d, 1H, J )
14.6 Hz), 3.32 (app quintet, 1H, J ) 7.5 Hz), 3.57 (d, 1H, J )
8.2 Hz), 3.76 (dd, 1H, J ) 6.4, 8.1 Hz), 3.97 (d, 1H, J ) 13.3
Hz), 4.05 (d, 1H, J ) 13.3 Hz), 4.12 (t, 1H, J ) 8.4 Hz), 4.51
(merged 1×s and 1×d), 4.78 (2×d, 1H each, J ) 10.6 Hz), 5.74
(d, 1H, J ) 3.8 Hz), 7.34 (m, 10H); 13C NMR (CDCl3, 75 MHz) δ
26.9 (q), 27.1 (q), 36.5 (t), 47.8 (d), 61.5 (t), 67.7 (t), 72.2 (t), 75.6
(d), 82.6 (d), 87.1 (d), 93.7 (s), 105.2 (d), 113.0 (s), 127.3 (d), 127.4
(d), 127.7 (d), 128.2 (d), 128.3 (d), 129.0 (d) 137.2 (s), 138.7 (s);
EIMS, m/z: 422 (M+ - 1), 408 (M+ - 15), 346, 317, 230, 217,
1,2:5,6-Di-O-isop r op ylid en e-3-p r op -1-en yl-3-O-ben zyl-r-
D-a llofu r a n ose (5). Benzyl bromide (3 × 0.5 mL) was added

Notes
J . Org. Chem., Vol. 62, No. 25, 1997 8951
to a stirred, refluxing mixture of 1,2:5,6-di-O-isopropylidene-3-
prop-1-enyl-R-D-allofuranose7 (600 mg, 2 mmol), tetrabutylam-
monium bromide (80 mg, 0.25 mmol), NaOH solution (50%, 15
mL), and benzene (20 mL) over 20 h. The benzene solution was
separated, and the aqueous layer was extracted with benzene
(2 × 20 mL). The combined benzene extract was washed with
H2O (3 × 30 mL) and dried (Na2SO4), and the solvent was
evaporated to give a material which was purified by column
chromatography on silica gel, eluting with petroleum ether-
CHCl3 (7:3) to afford a solid which was recrystallized from
[R]25 +59.2° (c 0.29, MeOH); IR (neat) 3412, 725, 692 cm-1; 1H
D
NMR (CDCl3, 100 MHz) δ 1.24-1.88 (m, 4H), 2.06 (d, 1H, J )
14 Hz), 2.44 (dt, 1H, J ) 8, 8, 14 Hz), 3.28 (brs, 2H, becoming
1H doublet, J ) 4 Hz on D2O exchange), 3.42 (m, becoming t,
1H, J ) 10 Hz on D2O exchange), 3.58-3.68 (m, 2H), 3.77 (d,
1H, J ) 14 Hz), 4.06 (d, 1H, J ) 14 Hz), 4.68 (m, 1H), 7.34 (m,
5H); 13C NMR (CDCl3, 25 MHz) δ 27.2 (t), 28.4 (t), 29.4 (t), 62.3
(t), 68.6 (d), 69.3 (t), 72.7 (d), 74.8 (s), 76.8 (d), 127.5 (d), 128.3
(d, 2C), 128.8 (d, 2C), 136.7 (s); EIMS, m/z: 279 (M+), 159, 81.
Anal. Calcd for C15H21NO4: C, 64.50; H, 7.58; N, 5.01. Found:
C, 64.38; H, 7.53; N, 4.88.
petroleum ether to furnish
5 (688 mg, 88%) as colorless
crystals: mp 95-96 °C; [R]26 +51.9° (c 0.62, CHCl3); IR (KBr)
D
(1R,2R,3R,5R)-9-[1,2,5-Tr ih yd r oxy-2-(h yd r oxym eth yl)cy-
cloh ep tyl]-6-ch lor oa d en osin e (10). To a solution of isoxazo-
lidinocarbocycle 9 (1.54 g, 5.52 mmol) in dry EtOH (50 mL) was
added Pd/C (10%, 200 mg) and cyclohexene (10 mL), and the
mixture was heated at reflux under N2 for 4 h. The Pd/C was
filtered off, solvent was evaporated in vacuo, and the crude
residue (800 mg) of free amino compound was used in the next
step without further purification. To the crude amine in dry
n-BuOH (25 mL) was added 4,6-dichloro-5-aminopyrimidine
(1.03 g, 6.28 mmol, 1.34 equiv) and Et3N (5 mL); the mixture
was then heated at reflux for 22 h under N2. The solvent was
evaporated, and the residue was extracted with H2O (3 × 30
mL). The aqueous part was washed with CHCl3 (2 × 30 mL)
[to remove free pyrimidine base] and evaporated to a gummy
thick oil which turned into a foam (1.20 g) under vacuum over
solid KOH. The material (1 g, 3.14 mmol) was dissolved in DMF
(30 mL) and then p-TSA (896 mg, 4.70 mmol, 1.5 equiv) and
HC(OEt)3 (30 mL) were added to it, and the mixture was stirred
at rt for 24 h under N2. After neutralization of acid with Et3N
(2 mL), the solvent was evaporated in vacuo to a gummy dark
brown material. The methanolic solution (10 mL) of it was
passed through Dowex 1-OH- resin. Elution with MeOH (4 ×
20 mL) and evaporation of the solvent gave the partially purified
chloronucleoside, which was again passed through Dowex 50W-
H+ resin. Aqueous-NH3 (5%, 100 mL) eluted almost pure
chloronucleoside (440 mg) which was further purified on silica
gel using CHCl3-MeOH (9:1) as the eluent to furnish pure
carbocyclic chloronucleoside 10 (400 mg, 22%): mp 198-199 °C
1
1638, 1373, 852, 726 cm-1; H NMR (CDCl3, 100 MHz) δ 1.34,
1.38, 1.58 (3×s, 12H), 2.56 (2×brdd, 1H each, J ) 7, 14 Hz),
3.90-4.30 (m, 4H), 4.50 (d, 1H, J ) 4 Hz), 4.80 (2×d, 1H each,
J ) 12 Hz), 5.18 (m, 2H), 5.64 (d, 1H, J ) 4 Hz), 6.04 (m, 1H),
7.34 (m, 5H); 13C NMR (CDCl3, 25 MHz) δ 25.3, 26.5, 26.6, 26.9,
35.8, 66.9, 68.0, 73.0, 81.3, 83.0, 83.6, 103.4, 109.5, 112.6, 118.5,
127.0, 127.9, 132.6, 139.2; EIMS, m/z: 375 (M+ - 15), 360, 216,
91. Anal. Calcd for C22H3006: C, 67.67; H, 7.74. Found: C,
67.63; H, 7.75.
1,2-O-Isop r op ylid en e-3-p r op -1-en yl-3-O-ben zyl-r-D-a llo-
fu r a n ose (6). The diisopropylidene compound 5 (1.17 g, 3
mmol) was left in HOAc-H2O (3:2) mixture (50 mL) at 60 °C
for 40 min. The solvent was evaporated, and the crude residue
was extracted with CHCl3 (2 × 25 mL). The CHCl3 solution was
washed with H2O (2 × 20 mL) and dried (Na2SO4), and the
solvent was evaporated to afford a dihydroxy material. This was
subsequently cleaved by NaIO4 and reduced with NaBH4 ac-
cording to the protocol described with 4 to afford a thick gum
which was purified by column chromatography on silica gel.
Elution with petroleum ether-CHCl3 (1:4) furnished 6 (537 mg,
56%): oil; [R]26 +35.2° (c 0.51, CHCl3); IR (neat) 3420, 1645,
D
1603, 1375, 734, 692 cm-1
;
1H NMR (CDCl3, 100 MHz) δ 1.36
(s, 3H), 1.56 (s, 3H), 2.44 (m, 2H), 3.82 (d, 2H, J ) 6 Hz), 4.30
(t, 1H, J ) 6 Hz), 4.42 (d, 1H, J ) 4 Hz), 4.68 (s, 2H), 5.08-5.32
(m, 2H), 5.72 (d, 1H, J ) 4 Hz), 5.92 (m, 1H), 7.36 (m, 5H); 13C
NMR (CDCl3, 25 MHz) δ 26.8, 27.1, 36.0, 66.7, 73.2, 81.4, 83.0,
83.8, 103.3, 112.8, 118.8, 127.5, 128.8, 132.3, 136.8; FABMS,
m/z: 321 (M+ + 1). Anal. Calcd for C18H24O5: C, 67.48; H, 7.55.
Found C, 67.23; H, 7.63.
dec; [R]25 +32.5° (c 0.24, MeOH); IR (KBr) 3428, 1689, 1404,
D
1214, 1039 cm-1; 1H NMR (DMSO-d6, 100 MHz) δ 1.68 (m, 5H),
3.38 (s, 1H), 3.44 (s, 2H), 3.70 (brd, 1H, J ) 5 Hz, becoming s at
3.72 on D2O exchange), 4.40 (s, 1H, exchangeable), 4.60-4.92
(m, 3H, including 2 exchangeable Hs), 5.32 (d, 1H, J ) 5 Hz,
exchangeable), 8.12 (s, 1H), 8.24 (s, 1H); 13C NMR (DMSO-d6,
25 MHz) δ 29.8, 30.1, 37.8, 52.0, 68.4, 70.1, 72.6, 73.5, 128.8,
138.1, 149.2, 151.4, 154.2; FABMS, m/z: 329 and 331 (M+ + 1).
Anal. Calcd for C13H17ClN4O4: C, 47.50; H, 5.21; N, 17.04.
Found: C, 47.39; H, 5.28; N, 16.88.
(3a R ,5R ,6S ,6a R )-1-Be n zyl-5-(b e n zyloxy)-5-(h yd r oxy-
m eth yl)-6-h yd r oxycyclop en t[c]isoxa zole (7) a n d (3a S,5R,
6S,6a S)-1-Ben zyl-5-(b en zyloxy)-5-(h yd r oxym et h yl)-6-h y-
d r oxycyclop en t[c]isoxa zole (8). The 1,2-isopropylidene group
in 6 (320 mg, 1 mmol) was cleaved by 4% H2SO4 according to
the procedure described under the preparation of 4 to afford 6a
(280 mg). The trihydroxy compound 6a (140 mg, 0.5 mmol) in
DMF (5 mL) was treated with BnNHOH (74 mg, 0.6 mmol, 1.2
equiv), and the mixture was kept at 50 °C for 8 h. The solvent
was evaporated, and the crude mixture on subsequent reaction
with NaIO4 and NaBH4 according to the method described
earlier (in the preparation of 4) afforded a solid product which
was purified by column chromatography on silica gel using
CHCl3 as the eluent to furnish 7 (80 mg, 45%); mp 129-130 °C;
(1R,2R,3R,5R)-9-[1,3,5-Tr ih yd r oxy-2-(h yd r oxym eth yl)cy-
cloh ep tyl] a d en in e (11). Chloroadenosine derivative 10 (190
mg, 0.58 mmol) in dry methanolic ammonia (10 mL) was heated
at 100 °C for 50 h in a sealed tube. The tube was cooled and
opened up, and the reaction mixture was warmed on a water
bath to remove ammonia. The solvent was removed under vacuo
to obtain a crude product as a foam which was purified by flash
column chromatography over silica gel (mesh size 230-400)
using 8% MeOH in CHCl3 as eluent to furnish 11 (168 mg,
[R]26 +30.1° (c 0.5, CHCl3). Compound 6a (140 mg, 0.5 mmol)
D
on reaction with BnNHOH (75 mg, 0.6 mmol) in refluxing
toluene (10 mL) followed by cleavage with NaIO4 and then
reduction with NaBH4 yielded a thick oily product which was
purified by silica gel column chromatography to afford the
94%): mp 240-242 °C dec; [R]25 +38.3° (c 0.12, MeOH); IR
D
1
(KBr) 3418, 1667, 1397 cm-1; H NMR (DMSO-d6, 100 MHz) δ
product 8 (85 mg, 48%): gum; [R]26 -14.9° (c 0.47, CHCl3);
D
IR (neat) 3409, 1386, 708, 677 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 1.66 (dd, 1H, J ) 9.8, 13.8 Hz), 2.05 (brdd, 1H, J ) 7.9, 13.8
Hz), 3.20 (quintet of doublets, 1H, J ) 7, 7, 7, 7, 2 Hz), 3.59 (dd,
1H, J ) 2, 8.8 Hz), 3.68 (dd, 1H, J ) 1,6 Hz), 3.77 (dd, 1H, J )
5.7, 8.7 Hz), 3.81-3.88 (m, 3H), 4.02 (dd, 1H, J ) 6, 8.9 Hz),
4.16 (d, 1H, J ) 11.4 Hz), 4.30 and 4.42 (2×d, 1H each, J ) 11.4
Hz), 7.25 (m, 10H); 13C NMR (CDCl3, 75 MHz) δ 33.0 (t), 47.1
(d), 60.2 (t), 61.4 (t), 64.5 (t), 70.7 (t), 71.5 (d), 74.5 (d), 90.6 (s),
127.3 (d), 127.5 (d), 127.7 (d), 128.4 (d), 128.5 (d), 128.8 (d), 136.1
(s), 138.4 (s); EIMS, m/z: 355 (M+), 264, 248, 163, 149, 135, 106,
91. Anal. Calcd for C21H25NO4: C, 70.96; H, 7.09; N, 3.94.
Found: C, 70.83; H, 7.04; N, 3.83.
(1R,2R,5R,7R)-1,2-Dih yd r oxy-2-(h yd r oxym eth yl)-8-ben -
zyl-5,7-(ep oxyim in o)cycloh ep ta n e (9). Compound 2e7 (3.50
g, 10.1 mmol) was converted to 9 (1.86 g, 66%) by treatment
with (i) 4% H2SO4, (ii) NaIO4, and (iii) NaBH4 following the
procedure as described under the preparation of 4. 9: gum;
1.42-2.16 (m, 5H), 3.30 (s, 2H, seen after D2O exchange), 3.74
(brs, 2H), 4.44 (brs, 1H, exchangeable), 4.60-5.04 (m, 3H
changing to a brd, 1H, J ) 10 Hz on D2O exchange), 5.38 (d,
1H, J ) 4 Hz, exchangeable), 7.22 (s, 2H, exchangeable), 8.12
(s, 1H), 8.20 (s, 1H); FABMS, m/z: 332 (M+ + Na), 310 (M+
+
1). Anal. Calcd for C13H19N5O4‚ H2O: C, 47.70; H, 6.42; N, 21.39.
Found: C, 47.69; H, 6.47; N, 21.31.
Ack n ow led gm en t. The work has been supported by
a research grant from DST (Govt. of India) to S.B.M.
N.B. is grateful to UGC (Govt. of India) for Research
Fellowship. Thanks are due to Mr. P. P. Ghosh Dastidar
and R. C. Yadav for NMR spectra, Mr. A. K. Banerjee
for MS, and Mr. S. Bhattacharyya for manuscript
typing.
J O971342Z