Chiral carbocyclic nucleosides from D-glucose: Enantiodivergent synthesis and one-pot entry of dimethylamino functionality in the purine rings

Article abstract of DOI:10.1021/jo981955r

Cyclization of appropriately designed enose-nitrones derived from D- glucose, having nitrone at C-5 or C-1 and allylic/homoallylic functionalities at C-3 of the sugar backbone, afforded polyhydroxylated aminocarbocycles which were subsequently used as the precursors for carbocyclic nucleoside analogues (11, 13, 16, 21, and 23). The enantiodirecting synthesis of both the enantiomeric pairs of nucleoside analogues 11 and 13, 21a and 23a, and 21c and 23c, has also been demonstrated by judiciously applying intramolecular nitrone cycloaddition (INC) reaction. An interesting observation was that in the cyclization reaction of pyrimidine ring to purine ring in DMF solvent, the substitution of C-6 chloro group with a dimethylamino functionality also occurred spontaneously under mild condition, though similar reactions are reported to occur at higher temperature. The hydrogen bonding between N-3 of the purine ring and an appropriate hydroxy substituent in the carbocycle seems to play a crucial role in this reaction.

Full text of DOI:10.1021/jo981955r

2304
J . Org. Chem. 1999, 64, 2304-2309
Ch ir a l Ca r bocyclic Nu cleosid es fr om D-Glu cose: En a n tiod iver gen t
Syn th esis a n d On e-P ot En tr y of Dim eth yla m in o F u n ction a lity in
th e P u r in e Rin gs
Atanu Roy, Kuheli Chakrabarty, Pradeep K. Dutta, Narayan C. Bar, Nupur Basu,
Basudeb Achari, and Sukhendu B. Mandal*
Indian Institute of Chemical Biology, J adavpur, Calcutta 700 032, India
Received September 28, 1998
Cyclization of appropriately designed enose-nitrones derived from D-glucose, having nitrone at
C-5 or C-1 and allylic/homoallylic functionalities at C-3 of the sugar backbone, afforded polyhy-
droxylated aminocarbocycles which were subsequently used as the precursors for carbocyclic
nucleoside analogues (11, 13, 16, 21, and 23). The enantiodirecting synthesis of both the
enantiomeric pairs of nucleoside analogues 11 and 13, 21a and 23a , and 21c and 23c, has also
been demonstrated by judiciously applying intramolecular nitrone cycloaddition (INC) reaction.
An interesting observation was that in the cyclization reaction of pyrimidine ring to purine ring in
DMF solvent, the substitution of C-6 chloro group with a dimethylamino functionality also occurred
spontaneously under mild condition, though similar reactions are reported to occur at higher
temperature. The hydrogen bonding between N-3 of the purine ring and an appropriate hydroxy
substituent in the carbocycle seems to play a crucial role in this reaction.
The significant bioactivities displayed by many of the
nucleoside analogues1 have directed considerable atten-
tion toward the synthesis of these compounds. In par-
ticular, the compounds derived from the replacement of
the oxygen in the furanose ring of a normal nucleoside
by a carbon, resulting in the respective carbocyclic
analogues,2 exhibit greater stability against enzymes3
that cleave the glycosidic linkage of the former. The
remarkable antitumor and anti-HIV activities shown by
the carbocyclic nucleosides,4 such as aristeromycin (1),2j
neplanocin A (2),1f carbovir (3),4j carboxetanocin G (4),4a
(1) (a) Marquez, V. E.; Lim, M.-I. Med. Res. Rev. 1986, 6, 1. (b)
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Thomas, M. Bioorg. Med. Chem. Lett. 1997, 7, 247. (m) Toyota, A.;
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1997, 38, 2803. (o) Wang, P.; Agrofoglio, L. A.; Newton, M. G.; Chu, C.
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F igu r e 1.
and cyclopropane nucleoside (5)4k (Figure 1), have led to
intensive search for newer compounds through modifica-
tion of both the heterocyclic base as well as the sugar
moieties of the nucleosides. Moreover, it is highly desir-
able that the synthetic nucleoside analogues be stereo-
chemically well defined5 as biological activity of these
compounds normally depends on the nature of chirality
(4) (a) Slusarchyk, W.; Bisacchi, G. S.; Field, A. K.; Hockstein, D.
R.; J acobs, G. A.; McGeever-Rubin, B.; Tino, J . A.; Tuomari, A. V.;
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10.1021/jo981955r CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/16/1999

Chiral Carbocyclic Nucleosides from D-Glucose
J . Org. Chem., Vol. 64, No. 7, 1999 2305
Sch em e 1a
a
Reagents: (a) HC(OEt)3, p-TSA, DMF, 20 °C; (b) HOAc:H2O (1:1), 60 °C; (c) NaIO4, EtOH, H2O; (d) NaBH4, MeOH; (e) 4% H2SO4,
dioxane, H2O; (f) BnNHOH, 2-fluoroethanol, rt; (g) 10% Pd/C, cyclohexene, EtOH, reflux; (h) 5-amino-4,6-dichloropyrimidine, Et3N, n-BuOH,
reflux.
at the optically active centers. In the previous paper we
described a simple procedure for the enantioselective
synthesis of a seven-membered carbocyclic nucleoside6
analogue using readily accessible precursors from D-
glucose through an intramolecular nitrone cycloaddition
reaction (INC). In a more versatile endeavor toward the
extension of this methodology for realizing the synthesis
of both the pure enantiomers of a nucleoside analogue
incorporating five- and seven-membered carbocyclic rings,
we envisioned to achieve the goal through INC reaction7,8
of appropriately designed enose-nitrones from D-glucose,
having nitrone functionality at C-5 or C-1 with the olefin
at C-3 (Figure 2). The success of such a scheme, however,
hinged upon the mode of the cycloaddition leading to the
desired stereochemistry at the newly generated chiral
center at the ring junction. We report herein in detail
F igu r e 2. A general presentation for the preparation of
enantiomeric pair of carbocyclic nucleosides through INC
reaction.
the realization of this objective of enantiodirecting syn-
thesis leading to a simple and efficient route to nucleoside
analogues with five- and seven-membered carbocyclic
rings, along with an interesting one-pot synthesis of
(dimethylamino)purine nucleoside derivatives.
Resu lts a n d Discu ssion
The synthesis of polyhydroxylated aminocarbocycle
precursors and their transformation to the carbocyclic
nucleosides 11, 13, 16a -c, 21a , 21c, 23a , and 23c (of
which 11 and 13, 21a and 23a , and 21c and 23c
represent enantiomeric pairs) are presented in Schemes
1-3. The successful synthesis of a seven-membered
carbocyclic nucleoside analogue 13 by the application of
INC reaction between C-5 nitrone and C-3 olefin (glucose
numbering) prompted us to extend the process to its
enantiomer by taking advantage of the latent C-1 alde-
hyde and C-3 olefin functionality. Thus, selective removal
of the 5,6-O-isopropylidene group of 69 (Scheme 1) under
mild acidic conditions followed successively by vicinal diol
cleavage with NaIO4 and reduction with NaBH4 provided
compound 7 in excellent yield (80%). Next, opening of the
1,2-O-isopropylidene group with dilute H2SO4 furnished
tetraol 8 which was directly reacted with BnNHOH in
EtOH to form the corresponding C-1 nitrone. Although
the attempted cyclization of the nitrone at the double
bond of the homoallylic functionality at C-3 failed using
various solvents and reaction conditions, the desired
(5) (a) Borth, 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. (b) Herdewijn, P.; Balzarini, J .; De Clercq, E.; Vanderhaeghe, H.
J . Med. Chem. 1985, 28, 1385. (c) Ikbal, M.; Cerecau, C.; Le Goffic, F.;
Sicsic, S. Eur. J . Med. Chem. 1989, 24, 415.
(6) Bar, N. C.; Roy, A.; Achari, B.; Mandal, S. B. J . Org. Chem. 1997,
62, 8948 [ In Scheme 2 of this paper one of the reagents was omitted
by mistake. Now the reagent is included: (f) HC(OEt)3, p-TSA, DMF,
32-35 °C, 24 h].
(7) (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.
(d) Shing, T. K. M.; Elsley, D. A.; Gillhouley, J . G. J . Chem. Soc., Chem.
Commun. 1989, 1280. (e) Peet, N. P.; Huber, E. W.; Farr, R. A.
Tetrahedron 1991, 47, 7537. (f) Duclos, O.; Dureault, A.; Depezay, J .
C. Tetrahedron Lett. 1992, 33, 1059. (g) Tatsuta, K.; Niwata, Y.;
Umezawa, K.; Toshima, K.; Nakata, M. Tetrahedron Lett. 1990, 31,
1171. (h) Ferrier, R. J .; Prasit, P. J . Chem. Soc., Chem. Commun. 1981,
983. (i) Farr, R. A.; Peet, N. P.; Kang, M. S. Tetrahedron Lett. 1990,
31, 7109. (j) Nakata, M.; Akazawa, S.; Kitamura, S.; Tatsuta, K.
Tetrahedron Lett. 1991, 32, 5363. (k) Bhattacharjee, A.; Bhattacharjya,
A.; Patra, A. Tetrahedron Lett. 1995, 36, 4677.
(8) Collins, P. M.; Ashwood, M. S.; Eder, H.; Wright, S. H. B.;
Kennedy, D. J . Tetrahedron Lett. 1990, 31, 2055.

2306 J . Org. Chem., Vol. 64, No. 7, 1999
Roy et al.
Sch em e 2a
and 23a in 50-53% yields. The minor products isolated
from the chromatography were proved to be the respec-
tive enantiomeric pairs of methoxypurine analogues 21c
and 23c, presumably resulting from the displacement of
chloro group from the compounds 21b and 23b. At-
tempted isolation of the chloro intermediates even by
reversed phase HPLC (H2O-MeOH, 9:1) failed, yielding
only the respective methoxy-substituted analogues in-
stead. The chloronucleoside 16b was, however, un-
changed, and isolated by chromatography.
All the in situ generated chloropurine derivatives
underwent facile transformation to the respective (di-
methylamino)purines 11, 13, 16a , 21a , and 23a , conceiv-
ably through nucleophilic displacement of the chloro
group by dimethylamine derived from DMF. However,
similar nucleophilic substitutions of aromatic chloro
compounds in DMF are reported to require higher
temperature.11 The possibility of hydrogen bonding be-
tween N-3 and 2′-OH causing the formation of a partial
positive charge on the N atom and thereby increasing
the electrophillicity at C-6 cannot be ruled out.
a
Reagents: (a) 4% H2SO4, MeCN, H2O, rt; (b) NaIO4 (2.2 equiv),
EtOH, H2O, 10 °C; (c) NaBH4, MeOH, 10 °C; (d) 10% Pd/C,
cyclohexene, EtOH, reflux; (e) 5-amino-4,6-dichloropyrimidine,
Et3N, n-BuOH, reflux; (f) HC(OEt)3, p-TSA, DMF, 20 °C; (g) NH3,
MeOH, 80 °C, sealed tube.
transformation could finally be achieved in 2-fluoroeth-
anol as the reaction solvent. The cyclized product was
directly transformed to the isoxazolidinocarbocycle 9
(62%) through sequential treatments with NaIO4 (1.2
equiv) and NaBH4. Hydrogenolysis of 9 with Pd/C (10%)/
cyclohexene8 afforded a tetrahydroxy aminocarbocycle
derivative which was then coupled with 5-amino-4,6-
dichloropyrimidine to provide the diaminopyrimidine
compound 10 (81%). Treatment of 10 with HC(OEt)3/p-
TSA in DMF at a lower temperature (18-20 °C) than
reported earlier6 furnished an unexpected 6-(dimethyl-
amino)purine carbocyclic nucleoside analogue 11 (69%
yield). Similar treatment of 126 also afforded 13 (63%).
The two enantiomeric compounds 11 and 13 exhibited
The structure of the isoxazolidine 9 was based upon
the appearance of a one-proton doublet at δ 2.06 and a
1
one-proton doublet of a triplet at δ 2.44 in its H NMR
spectrum as well as an upfield triplet at δ 29.4 in its 13C
NMR spectrum assigned to the bridge methylene group.
The enantiomeric nature of the compounds 11 ([R]D
-34.1°) and 13 ([R]D +34.2°) was clearly established by
1
their superimposable H NMR, 13C NMR, and IR spectra
as well as from their optical rotations. Similarly, both
the pair of enantiomers 21a ([R]D +36.8°) and 23a ([R]D
-36.2°), and 21c ([R]D +51.6°) and 23c ([R]D -51.0°),
generated from D-glucose had comparable spectral data
and optical rotations.
superimposable H NMR, 13C NMR, and IR spectra as
well as optical rotations of equal magnitude but opposite
sign, confirming their assigned stereostructures.
1
The isoxazolidine 14, obtained in eight steps9 from
D-glucose, furnished 15 (58%) through a sequence of
reactions (Scheme 2) involving opening of isopropylidene
protection with dilute H2SO4 and cleavage of resulting
triol with NaIO4 (2.2 equiv) followed by NaBH4 reduction.
The relative trans disposition of the 2,3-hydroxyl groups
was indicated by the recovery of diol 15 from attempted
periodate oxidation, presumably due to nonformation of
the cyclic intermediate for the cleavage reaction. Opening
up of the isoxazolidine ring followed by coupling with
5-amino-4,6-dichloropyrimidine and application of the
usual ring closure reaction smoothly converted the isox-
azolidine 15 to the carbocyclic nucleoside analogues 16a
and 16b in the ratio of 8:1 (Scheme 2). Ammonolysis10 of
16b in MeOH furnished 16c in good yield.
In an analogous manner (Scheme 3), the enantiomeri-
cally pure five-membered isoxazolidino-carbocycles 17
and 18, obtained from D-glucose via similar routes,6 were
subjected to transfer hydrogenolysis (Pd/C,cyclohexene)
furnishing the enantiomeric pairs of tetrahydroxy ami-
nocyclopentane derivatives 19 ([R]D +10.5°) and 22 ([R]D
-10.8°). Each of the amines 19 and 22, on coupling with
5-amino-4,6-dichloropyrimidine and subsequent ring clo-
sure with HC(OEt)3 in DMF in the presence of p-TSA
followed by chromatography on silica gel using CHCl3-
MeOH (9:1) as eluent, gave the desired enantiomerically
pure (dimethylamino)purine nucleoside analogues 21a
Further, formation of the products from the coupling
reactions of the aminocarbocycles with 5-amino-4,6-
dichloropyrimidine was evident from the appearance of
1
a one-proton singlet at δ ∼7.8 in the H NMR spectrum
which is characteristic for the aromatic H-2 proton. On
cyclization, the two aromatic proton singlets appeared
at δ 8.3-8.5 in the products. The characteristic feature
1
in the H NMR spectrum of 21a (DMSO-d6) was a very
broad signal at δ 3.45 assigned to NMe2, along with a
doublet at δ 4.68 and a triplet at δ 4.85 attributed to H′-2
and H′-1 discernible after addition of D2O. The aromatic
signals at δ 8.16 (two overlapping peaks), 8.183 and 8.188
arise possibly due to the existence of two equilibrium
forms. At 60 °C (in DMSO-d6), these signals were
transformed to two discrete peaks at δ 8.12 and 8.17, and
the broad peak assigned to NMe2 was changed to a sharp
singlet due to fast exchange of the two forms. Surpris-
ingly, the 13C signal for NMe2 of this compound (in
DMSO-d6) could not be discerned at normal temperature
but appeared as a sharp singlet at δ 38.8 at elevated
temperature (60 °C). A similar spectral behavior was
observed in the case of compound 23a . The 1H NMR
spectrum of each of the enantiomeric pairs 21c and 23c
exhibited a sharp singlet at δ 4.10, a doublet at δ 4.75
and a triplet at δ 4.98, characteristic signals for the
OCH3, H′-2 and H′-1, in addition to the aromatic proton
(9) Patra, R.; Bar, N. C.; Roy, A.; Achari, B.; Ghoshal, N.; Mandal,
S. B. Tetrahedron 1996, 52, 11265.
(10) (a) Yoshikawa, M.; Nakae, T.; Cha, B. C.; Yokokawa, Y.;
Kitagawa, I. Chem. Pharm. Bull. 1989, 37, 545. (b) Kitagawa, I.; Cha,
B. C.; Nakae, T.; Okaichi, Y.; Takinami, Y.; Yoshikawa, M. Chem.
Pharm. Bull. 1989, 37, 542.
(11) (a) Lord, W. M.; Peters, A. T. Chem., Ind. 1973, 227. (b) Lord,
W. M.; Peters, A. T. J . Chem. Soc. (C) 1968, 783. (c) Asquith, R. S.;
Lord, W. M.; Peters, A. T.; Wallace, F. J . Chem. Soc. (C) 1966, 95. (d)
Lunt, E. Comprehensive Organic Chemistry; Barton, D., Ollis, W. D.,
Eds.; 1979; pp 515-516.

Chiral Carbocyclic Nucleosides from D-Glucose
J . Org. Chem., Vol. 64, No. 7, 1999 2307
Sch em e 3a
a
Reagents: (a) 10% Pd/C, EtOH, reflux; (b) 5-amino-4,6-dichloropyrimidine, Et3N, n-BuOH, reflux; (c) HC(OEt)3, p-TSA, DMF, 20 °C.
signals at δ 8.40 and 8.50. The 13C peaks at δ 60.9, 79.5
and 53.7 are also in conformity with the assigned
silica gel 60 F254 precoated plates. High performance liquid
chromatography (HPLC) was done on Waters Associates model
440 instrument using Nova Pak reverse phase C-18 column
structures.
(particle size 5 µm, column size 3.0 mm × 150 mm).
The presence of four methylene triplets in the 13C NMR
spectrum of 15 clearly indicated the elimination of a two-
carbon residue from 14 during oxidative degradation with
1,2-O-Isop r op ylid en e-3-(bu t -1-en yl)-r-D-xylofu r a n ose
(7). The diisopropylidene compound 6 (2.00 g, 6.37 mmol)
dissolved in HOAc-H2O (1:1) mixture (50 mL) was heated at
60 °C for 45 min. The solvent was evaporated in vacuo, the
gummy residue was extracted with CHCl3 (2 × 40 mL), the
CHCl3 solution was washed with H2O (2 × 40 mL) and dried
(Na2SO4), and the solvent was removed to give a crude
material. To this material dissolved in EtOH (25 mL) and
cooled to 10 °C was added an aqueous solution (25 mL) of
NaIO4 (1.63 g, 7.6 mmol, 1.2 equiv) dropwise with vigorous
stirring. After 40 min stirring, the mixture was filtered, the
filtrate was evaporated, and the residue was dissolved in
CHCl3 (100 mL). The CHCl3 solution was washed with H2O
(2 × 40 mL) and dried (Na2SO4); evaporation of the solvent
afforded the crude aldehyde (1.58 g) (IR: 1745 cm-1).
1
NaIO4. In the H NMR spectrum of 16a , a singlet was
observed at δ 3.44 assigned to NMe2, along with the
aromatic proton signals at δ 8.16 and 8.24. Τhe four
upfield 13C signals for 3 × CH2 and NMe2 appeared at δ
25.1, 31.5, 36.5, and 37.7; appropriate spectral profiles
were also obtained for compounds 16b and 16c.
In conclusion, a short and efficient route toward
enantiomerically pure and optically active five- and
seven-membered carbocyclic nucleosides has been devel-
oped. We have also established a simple method for the
preparation of a pair of enantiomers of carbocyclic
nucleoside analogues starting with enose-nitrones de-
rived from D-glucose as the chiral source. The present
method might be applicable to synthesize both the
enantiomers of carbocycles and heterocycles of different
ring-sizes. Further, in the cyclization reaction leading to
purine ring formation in DMF, the likelihood of hydrogen
bonding between N-3 of the purine ring and an appropri-
ate hydroxy substituent on the carbocycle appears to
facilitate the substitution of the 6-chloro group with a
dimethylamino functionality, providing a one-pot syn-
thetic route to such purine nucleoside analogues.
To this aldehyde dissolved in MeOH (40 mL) at 10 °C was
added NaBH4 (2 × 125 mg) portionwise, and the mixture was
stirred for 5 h. The solvent was evaporated, H2O (25 mL) was
added to the residue, and the crude product was extracted with
CHCl3 (2 × 50 mL). The CHCl3 solution was washed with H2O
(2 × 25 mL), dried (Na2SO4), and evaporated to give a residue
which was purified by column chromatography, eluting with
CHCl3-MeOH (100:1) mixture to afford 7 (1.25 g, 80%): gum;
[R]25 +40.2° (c 0.15, CHCl3); 1H NMR (CDCl3, 100 MHz) δ
D
1.36 (s, 3H), 1.58 (s, 3H), 2.12 (m, 2H), 2.44 (m, 2H), 3.84 (d,
2H, J ) 6 Hz), 4.32 (t, 1H, J ) 6 Hz), 4.38 (brs, 1H,
exchangeable), 4.46 (d, 1H, J ) 4 Hz), 4.70 (s, 1H, exchange-
able), 5.12-5.30 (m, 2H), 5.74 (d, 1H, J ) 4 Hz), 5.90 (m, 1H);
13C NMR (CDCl3, 25 MHz) δ 26.3, 27.2, 27.9, 31.8, 60.8, 80.8,
83.2, 85.0, 103.5, 112.6, 114.9, 138.7; EIMS, m/z: 244 (M+),
229 (M+ - 15), 226,186.
Exp er im en ta l Section
Gen er a l Meth od s. Melting points are uncorrected. 1H
NMR spectra were determined with a 100 MHz (13C at 25
MHz) or a 300 MHz (13C at 75 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. Column chromatography was performed with silica gel
(60-120 mesh; SRL, India). Flash column chromatography
was performed with silica gel (230-400 mesh; SRL, India).
Thin-layer chromatography (TLC) was carried out on Merck
3-(Bu t-1-en yl)-r,â-xylofu r a n ose (8). Compound 7 (980
mg, 4 mmol) was dissolved in 4% H2SO4 in dioxane-water (35
mL) and stirred at room temperature for 20 h. The solution
was neutralized with solid CaCO3 and filtered, and the solvent
was evaporated in vacuo to obtain a gummy material which
was chromatographed on a silica gel column, eluting with
CHCl3-MeOH (9:1) to afford an anomeric mixture of 8 (795
1
mg, 97%): gum; H NMR (DMSO-d6 + D2O) δ 2.42-2.63 (m,
merged with solvent peak), 3.92 (brd), 4.32 (brt), 4.42 (d), 4.44
(s), 5.28 (m), 5.72 (d), 5.76 (s), 6.08 (m).

2308 J . Org. Chem., Vol. 64, No. 7, 1999
Roy et al.
(1S,2S,5S,7S)-2-(Hyd r oxym eth yl)-8-ben zyl-5,7-(ep oxy-
im in o)cycloh ep ta n e-1,2-d iol (9). The anomeric mixture of
xylofuranose 8 (780 mg, 3.82 mmol) in 2-fluoroethanol (30 mL)
was treated with BnNHOH (565 mg, 4.6 mmol, 1.2 equiv), and
the solution was stirred at room temperature for 48 h. The
solvent was evaporated, and the crude mixture on subsequent
reaction with NaIO4 (980 mg) and NaBH4(150 mg) following
the method described earlier (in the preparation of 7) afforded
a product which was purified by column chromatography on
silica gel using CHCl3-MeOH (49:1) mixture as the eluent to
the sequence of reactions involving opening of isopropylidene
protection with dil H2SO4, cleavage of the diol with NaIO4, and
NaBH4 reduction according to the method described in the
preparation of 9.
15: thick oil; [R]25D +36.7° (c 0.36, MeOH); 1H NMR (CDCl3
+ D2O, 100 MHz) δ 1.48-2.20 (2×m, 5Η), 2.24-2.64 (m, 1Η),
3.32-4.12 (m, 7H consisting of two doublets at δ 3.74 and 4.00,
J ) 13 Hz each; 1H triplet at δ 3.40, J ) 4 Hz; 1H doublet of
a doublet at δ 3.55, J ) 4, 8 Hz; 1H multiplet at δ 3.75), 4.60
(brd, 1H), 7.35 (m, 5H); 13C NMR (CDCl3) δ 24.9 (t), 28.4 (t),
29.8 (t), 63.1 (t), 67.1 (d), 71.6 (d), 72.0 (d), 76.6 (d), 127.1 (d),
128.0 (d), 128.5 (d), 136.6 (s); FABMS, m/z: 250 (M+ + 1). Anal.
Calcd for C14H19NO3: C, 67.45; H, 7.68; N, 5.62. Found: C,
67.45; H, 7.65; N, 5.25.
furnish 9 (680 mg, 64%): gum; [R]25 -59.8° (c 0.42, MeOH);
D
1H 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 (2H, brs
becoming 1H, d, J ) 4 Hz on D2O exchange), 3.42 (3H, m
becoming 1H, t, 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); FABMS, m/z: 280 (M+ + 1). Anal. Calcd
for C15H21NO4: C, 64.50; H, 7.58. Found: C, 64.48; H, 7.59.
(1S,2S,3S,5S)-3-[(6-Ch lor o-5-a m in op yr im id in -4-yl)a m i-
n o]-1-(h yd r oxym eth yl)cycloh ep ta n e-1,2,5-tr iol (10). The
mixture of isoxazolidinocarbocycle 9 (600 mg, 2.15 mmol), Pd/C
(10%, 150 mg), and cyclohexene (7 mL) was heated at reflux
under N2 for 5 h. The Pd-C was filtered off, and the solvent
was evaporated in vacuo. The crude free amine, without
further purification, was taken in dry n-BuOH (25 mL), treated
with 5-amino-4,6-dichloropyrimidine (423 mg, 2.58 mmol, 1.2
equiv), and Et3N (4 mL), and then the mixture was heated at
reflux for 20 h under N2. The solvent was evaporated in vacuo,
and the residue was extracted with H2O (3 × 35 mL). The
aqueous part was washed with CHCl3 (2 × 25 mL) and then
evaporated to a thick oil. Purification by column chromatog-
raphy on silica gel and eluting with CHCl3-MeOH (23:1)
(1′R,2′R,3′R,5′R)-9-[1,2,5-Tr ih yd r oxycycloh ep t-3-yl]-6-
(d im eth yla m in o)a d en in e (16a ) a n d (1′R,2′R,3′R,5′R)-9-
[1,2,5-Tr ih yd r oxycycloh ep t-3-yl]-6-ch lor oa d en in e (16b).
The isoxazolidino-cycloheptane diol 15 (1.25 g, 5 mmol) was
hydrogenolyzed with Pd/C (10%, 300 mg) and cyclohexene (15
mL) in EtOH (20 mL) (procedure as adopted with 9). After
evaporation of the solvent, the crude aminocycloheptane triol
(780 mg) was coupled with 5-amino-4,6-dichloropyrimidine
(840 mg, 5.76 mmol) (similar procedure as adopted in the
preparation of 10). The coupling product was then cyclized,
using HC(OEt)3/p-TSA, to a mixture of 16a and 16b following
the procedure used for the preparation of 11. The two products
16a and 16b were purified by column chromatography over
silica gel using CHCl3-MeOH (19:1) as the eluent to get 16a
(610 mg, 40%) and 16b (75 mg, 5%).
1
16a : mp 201-202 °C dec; [R]25 +44.0° (c 0.3, MeOH); H
D
NMR (DMSO-d6, 100 MHz) δ 1.32-2.20 (m, 5H), 2.50 (1Η
signal, merged with solvent), 3.44 (s, 6H), 3.60 (br signal, 1H,
overlapped by NMe2 signal), 3.84 (brs, 2H), 4.52-4.88 (m, 3H
changing to a brd,1H, J ) 12 Hz on D2O exchange),5.24 (d,
1H, J ) 4 Hz, exchangeable), 8.16 (s, 1H), 8.24 (s, 1H); 13C
NMR (DMSO-d6, 25 MHz) δ 25.1 (t), 31.5 (t), 36.5 (t), 37.7 (q),
52.8 (d), 66.4 (d), 71.4 (d), 74.7 (d), 118.8 (s), 138.1 (d), 149.3
(d), 151.2 (d), 154.2 (s); FABMS,m/z: 324 (M+ + 1). Anal. Calcd
for C14H21N5O3: C, 52.00; H, 6.55; N, 21.66. Found: C, 52.01;
H, 6.45; N, 21.43.
furnished 10 (554 mg, 81%)) as a foam: [R]25 + 45.3° (c 0.63,
D
1
MeOH); H NMR (DMSO-d6,100 MHz) δ 1.44-2.48 (m, 6Η),
3.60-4.30 (m, 5H), 4.44 (s, 1H, exchangeable), 4.48 (m, 2H,
exchangeable), 4.90 (d, 1H, J ) 4 Hz, exchangeable), 5.26 (brs,
2H, exchangeable), 6.80 (d, 1H, J ) 8 Hz, exchangeable), 7.75
(s, 1H); 13C NMR (D2O + dioxane, 25 MHz) δ 28.9, 29.8, 36.4,
50.6, 68.6, 70.5, 74.8, 75.4, 123.8, 139.9, 148.1, 153.1; FABMS,
m/z: 319, and 321 (M+ + 1).
(1′S,2′S,3′S,5′S)-9-[1-(Hyd r oxym eth yl)-1,2,5-tr ih yd r oxy-
cycloh ep t-3-yl]-6-(d im eth yla m in o)a d en in e (11). To the
diaminopyrimidine derivative 10 (200 mg, 0.63 mmol) dis-
solved in freshly distilled dry DMF (7 mL) was added p-TSA
(144 mg, 0.76 mmol, 1.2 equiv) and HC(OEt)3 (4 mL), and the
mixture was stirred at 18-20 °C for 30 h under N2. The acid
was neutralized with Et3N (0.5 mL), and the solvent was
evaporated in vacuo to a gummy residue. This was dissolved
in MeOH (2 mL), and the solution was passed through Dowex-
1-OH- resin column. Elution with MeOH (4 × 20 mL) and
evaporation of the solvent afforded the impure nucleoside
which was further poured onto a Dowex-50W-H+ resin column.
Aqueous-NH3 (20%, 4 × 25 mL) eluted almost pure carbocyclic
(dimethylamino)nucleoside, which was again purified by col-
umn chromatography on silica gel eluting with CHCl3-MeOH
(9:1) mixture to afford 11 (146 mg, 69%): mp 210-212 °C dec;
16b: mp 184-186 °C; [R]25D +49.0° (c 0.2, MeOH); 1H NMR
(DMSO-d6, 100 MHz) δ 1.40-2.20 (m, 5H), 2.50 (1H, merged
with solvent peak), 3.84 (brs), 4.56-4.92 (m, 3H changing to
a brd, 1H, J ) 12 Hz on D2O exchange), 5.16 (d, 1H, J ) 4 Hz,
exchangeable), 8.70 (s, 1H), 8.82 (s, 1H); 13C NMR (DMSO-d6,
25 MHz) δ 25.0, 31.7, 36.1, 54.1, 66.4, 71.0, 74.3, 130.4, 134.4,
145.9, 150.9, 151.1; FABMS, m/z: 315, and 317 (M+ + 1). Anal.
Calcd for C12H15ClN4O3: C, 45.80; H, 4.80; N, 17.80. Found:
C, 45.76; H, 4.82; N, 17.46.
(1′R,2′R,3′R,5′R)-9-[1,2,5-Tr ih yd r oxycycloh ep t-3-yl]a d -
en in e (16c). Chloroadenine 16b (65 mg, 0.22 mmol) was
dissolved in dry methanolic ammonia solution (5 mL) and
heated at 100 °C for 10 h in a sealed tube. Usual workup
followed by purification in flash chromatography using 4%
methanolic CHCl3 as the eluent furnished 16c (52 mg, 85%):
mp 208-210 °C; [R]25 +44.7° (c 0.41, MeOH); 1H NMR
D
[R]25 -34.1° (c 0.21, MeOH); 1H NMR (DMSO-d6) δ 1.48-
(DMSO-d6, 100 MHz) δ 1.40-2.20 (m, 5H), 2.51 (m, 1H,
overlapped with solvent signal), 3.60 (br signal, 1H), 3.86 (brs,
2H), 4.40-4.90 (m, 3H changing to a brd, 1H, J ) 10 Hz on
D2O exchange), 5.25 (br signal,1H, exchangeable), 7.24 (brs,
2H, exchangeable), 8.20 (s, 2H); 13C NMR (DMSO-d6, 25 MHz)
δ 25.1, 31.8, 36.5, 53.2, 66.4, 71.4, 74.8, 118.0, 140.4, 148.4,
150.4, 154.5; FABMS, m/z: 280 (M+ + 1). Anal. Calcd for
D
2.10 (m, 5H), 2.48 (m, 1H overlapped with DMSO signal), 3.46
(s, 6H), 3.72 (brd, 2H) 4.40 (s, 1H, exchangeable), 4.76 (m, 3H
changing to a brd, 1H, J ) 10 Hz on D2O exchange), 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, 36.7, 37.8, 52.0, 68.4,
70.1, 72.6, 73.5, 118.8, 138.1, 149.2, 151.4, 154.2; FABMS,
m/z: 338 (M+ + 1). Anal. Calcd for C15H23N5O4: C, 53.40; H,
6.87; N, 20.76. Found: C, 53.42; H, 6.64; N, 20.48.
C
12H17N5O3: C, 51.60; H, 6.14; N, 25.08. Found: C, 51.58; H,
6.08; N, 24.88.
(1′R,2′R,3′R,5′R)-9-[1-(Hydr oxym eth yl)-1,2,5-tr ih ydr oxy-
cycloh ept-3-yl]-6-(dim eth ylam in o)aden in e (13). Crude com-
pound 126 (320 mg) in DMF (10 mL) was treated with
HC(OEt)3 and p-TSA, following the procedure used in the
preparation of 11, and cyclized to the carbocyclic nucleoside
(1R,2R,3S,4S)-1,4-Bis(h yd r oxym et h yl)-3-a m in ocyclo-
p en ta n e-1,2-d iol (19), a n d (1S,2S,3R,4R)-1,4-Bis(h yd r oxy-
m eth yl)-3-a m in ocyclop en ta n e-1,2-d iol (22). Compounds 18
(480 mg, 1.35 mmol) and 17 (500 mg, 1.41 mmol) were
hydrogenolyzed separately with Pd/C (10%, 800 mg), cyclo-
hexene (4.5 mL), and EtOH (40 mL) to their respective
hydroxyaminocyclopentanes 19 (210 mg) and 22 (212 mg)
13 (205 mg, 63%): mp 182-183 °C; [R]25 +34.2° (c 0.36,
D
MeOH); FABMS, m/z: 338 (M+ + 1).
(1R,2R,3R,5R)-8-Ben zyl-5,7-(epoxyim in o)cycloh eptan e-
1,2-d iol (15). Compound 14 (1.25 g, 3.36 mmol) was converted
to the isoxazolidinocycloheptanediol 15 (520 mg, 58%) through
following the procedure used for 9.
1
19: [R]25 +10.5° (c 0.34, H2O); H NMR (D2O + acetone,
D
300 MHz) δ 1.40 (dd, 1H, J ) 7.5, 14.5 Hz), 1.94 (dd, 1H, J )

Chiral Carbocyclic Nucleosides from D-Glucose
J . Org. Chem., Vol. 64, No. 7, 1999 2309
7.5, 14.5 Hz), 2.27 (m, 1H), 3.11 (t, 1H, J ) 7.5 Hz), 3.43-3.70
(m, 4H), 3.87 (d, 1H, J ) 7.5 Hz); 13C NMR (D2O + acetone,
75 MHz) δ 35.3, 39.2, 58.1, 62.1, 64.7, 80.9, 84.6; FABMS,
m/z: 178 (M+ + 1).
21c: mp 190-191 °C dec; [R]25 +51.6° (c 0.45, MeOH); 1H
D
NMR (DMSO-d6 + D2O, 300 MHz) δ 1.69 (dd, 1H, J ) 6.5, 13
Hz), 2.23 (dd, 1H, J ) 9, 13 Hz), 2.51 (m, 1H overlapped with
solvent peak), 3.06 (d, 2H, J ) 6 Hz),3.47 and 3.62 (2×d, 1H
each, J ) 11 Hz), 4.11 (s, 3H), 4.75 (d, 1H, J ) 9.5 Hz), 4.90
(t, 1H, J ) 9.5 Hz), 4.98 (t, 1H, J ) 9.5 Hz), 8.40 (s, 1H), 8.51
(s, 1H); 13C NMR (DMSO-d6, 75 MHz) δ 35.5 (t), 37.7 (d), 53.7
(d), 60.9 (q), 61.2 (t), 62.4 (t), 77.7 (s), 79.5 (d), 120.5 (s), 143.1
(d), 150.9 (d), 152.9 (s), 160.0 (s); FABMS, m/z: 311 (M+ + 1).
Anal. Calcd for C13H18N4O5: C, 50.31; H, 5.85; N, 18.06.
Found: C, 50.24; H, 5.84; N, 17.93.
22: [R]25 -10.8° (c 0.34, H2O); FABMS, m/z: 178 (M+
+
D
H).
(1S,2R,3S,4S)-3-(6-Ch lor o-5-am in opyr im idin -4-yl)am in o-
1,4-bis(h yd r oxym eth yl)cyclop en ta n e-1,2-d iol (20). Com-
pound 19 (210 mg, 1.19 mmol) was coupled with 5-amino-4,6-
dichloropyrimidine (293 mg, 1.5 mmol), according to the
previous procedure to furnish 20 (290 mg, 80%): foam; [R]25
D
+25.7° (c 0.34, MeOH); 1H NMR (DMSO-d6, 100 MHz) δ 1.74
(dd, 1H, J ) 6, 13 Hz), 2.22 (dd, 1H, J ) 9, 13 Hz), 3.68-4.68
(m), 4.71 (s, 1H, exchangeable), 4.83 (d, 1H, J ) 6 Hz,
exchangeable), 5.22 (brs, 2H, exchangeable), 6.73 (d, 1H, J )
8 Hz, exchangeable), 7.78 (s, 1H); 13C NMR (DMSO-d6, 25
MHz) δ 35.2, 37.5, 53.9, 61.4, 62.6, 77.6, 79.4, 123.6, 139.8,
148.2, 153.2; FABMS, m/z: 305, and 307 (M+ + 1).
(1′R,2′S,3′R,4′R)-9-[1,4-Bis(h yd r oxym et h yl)-1,2-d ih y-
dr oxycyclopen t-3-yl]-6-(dim eth ylam in o)aden in e (23a) an d
(1′R,2′S,3′R,4′R)-9-[1,4-Bis(h ydr oxym eth yl)-1,2-dih ydr oxy-
cyclop en t-3-yl]-6-m eth oxya d en in e (23c). Compound 22
(204 mg) was converted to 23a (138 mg, 37%) and 23c (14 mg,
4.0%) following the method just described above. 23a : sticky
nature; [R]25 -36.2° (c 0.29, MeOH). Anal. Calcd for C14H21
-
D
(1′S,2′R,3′S,4′S)-9-[1,4-Bis(h yd r oxym et h yl)-1,2-d ih y-
d r oxycyclop en t-3-yl]-6-d im eth yla m in oa d en in e (21a ) a n d
(1′S,2′R,3′S,4′S)-9-[1,4-Bis(h ydr oxym eth yl)-1,2-dih ydr oxy-
cyclop en t-3-yl]-6-m eth oxya d en in e (21c). The diaminopy-
rimidine derivative 20 (280 mg, 0.92 mmol) was treated with
HC(OEt)3/p-TSA following the method adopted with compound
10. Usual workup and purification (as in the preparation of
11) afforded a mixture of 21a and 21c which was purified on
HPLC using H2O-MeOH (9:1) at a flow rate of 1 mL/min to
afford pure 21a (148 mg, 50%) and 21c (9 mg, 3%).
N5O4‚H2O: C, 49.24; H, 6.79; N, 20.52. Found: C, 49.26; H,
6.75; N, 20.42. 23c: mp 158-160 °C; [R]25 -51.0° (c 0.41,
D
MeOH). Anal. Calcd for C13H18N4O5‚2H2O: C, 49.77; H, 5.85;
N, 17.86. Found: C, 49.75; H, 5.86; N, 17.48.
Ack n ow led gm en t. The authors are grateful to Prof.
U. R. Ghatak for helpful discussion during the prepara-
tion of the manuscript. Financial support from DST
(Govt. of India) given to S.B.M is gratefully acknowl-
edged. A.R. and N.B. thank CSIR (Govt. of India) for
awarding research fellowships to them.
21a : sticky gum; [R]25 +36.8° (c 0.37, MeOH); 1H NMR
D
(DMSO-d6 + D2O, 300 MHz) δ 1.71 (dd, 1H, J ) 6, 13.5 Hz),
2.22 (dd, 1H, J ) 9, 13.5 Hz), 2.49 (m, 1H), 2.99 (m, 2H), 3.46
(brs, 6H), 3.44 and 3.64 (2×d, 1H each, J ) 11 Hz), 4.70 (d,
1H, J ) 9.5 Hz), 4.87 (t, 1H, J ) 9.5 Hz), 8.16 (s), 8.18 (s); 13
C
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
NMR (DMSO-d6, 75 MHz) δ 35.6 (t), 37.7 (d), 60.5 (d), 61.1
(t), 64.3 (t), 77.8 (s), 79.6 (d), 119.1 (s), 138.9 (d), 151.0 (s),
151.4 (d), 154.4 (s); FABMS, m/z: 324 (M+ + 1). Anal. Calcd
For C14H21N5O4‚1.5H2O: C, 47.99; H, 6.90; N, 20.00. Found:
C, 47.91; H, 6.93; N, 19.73.
1
spectra of 9, 11, 15, 16a -c, 21a , 21c, and H NMR spectra of
13 and 23a . This material is available free of charge via the
Internet at http://pubs.acs.org.
J O981955R