Stereoselective synthesis of a novel carbocyclic nucleoside

Full text of DOI:10.1021/jo010718c

7552
J . Org. Chem. 2001, 66, 7552-7554
This report describes a strategy to synthesize such
carbocyclic nucleoside.
Ster eoselective Syn th esis of a Novel
Ca r bocyclic Nu cleosid e
Starting from 1,2;5,6-di-O-isopropylidene-R-D-gluco-
furanose (7), the requisite 3-C-allyl derivative (8) was
prepared in two high-yielding steps.6 Subsequent protec-
tion of the tertiary hydroxy group with MPM-bromide in
the presence of NaH-THF gave 9. The characteristic
Mukund K. Gurjar* and Kundarapu Maheshwar
National Chemical laboratory, Pune 411 008, India
1
gurjar@dalton.ncl.res.in
Received J uly 16, 2001
signals of MPM group were visualized in the H NMR
spectrum of 9. Successive transformations such as (1) acid
hydrolysis of the 5,6-acetonide group, (2) mesylation of
the resulting diol, and (3) olefination with NaI in 2-bu-
tanone gave the diene derivative 10 (Scheme 1).
The perpetual interest in carbocyclic nucleosides arose
because many normal nucleosides are chemically and
enzymatically less stable, but more importantly toxic and
resistant prone.1 Carbocyclic dideoxy nucleosides drugs
such as carbovir (1), neplanocin A (2), aristeromycin (3),
and nor-aristeromycin (4) have attracted unprecedented
attention because of potent activity and enhanced stabil-
ity.2
Ring-closing metathesis7 of 10 using Grubbs’ catalyst
at room temperature gave the bicyclic derivative 11. The
1H NMR spectrum of 11 indicated signals corresponding
to olefinic protons at 5.9 ppm, whereas the carbocyclic
methylene protons appeared at 2.33 and 2.86 ppm as
double doublets. Transformation of 11 into the diol
derivative (12) was accomplished by (1) hydrolysis of the
isopropylidene group, (2) NaIO4-promoted oxidative cleav-
age, and (3) NaBH4 reduction. Compound 12 was con-
verted into the cyclic carbonate (13) using carbonyl
1
diimidazole in refluxing benzene. The H and 13C NMR
and mass spectral studies confirmed the structure of 13.
The Pd-catalyzed allylic rearrangement2 of 13 with
6-aminopurine in the presence of (PPh3)4Pd and DMSO-
THF (1:1) gave the unsaturated carbocyclic nucleoside
14. Removal of MPM group with DDQ in dioxane-H2O
gave the target carbocyclic nucleoside 15. The 1H and 13C
NMR and elemental analysis of 15 provided the struc-
tural proof of this molecule.
In conclusion, this paper describes an efficient meth-
odology to prepare carbocyclic nucleosides having two
important chromophores, unsaturation, and tertiary hy-
droxyl center in its structural framework. The antiviral
activity of 15 is under investigation and will be published
in future.
Exp er im en ta l Section
The NMR spectra were recorded in CDCl3/CD3COCD3/DMSO-
d
6 with TMS as an internal standard on AC 200 MHz, DRX 500
MHz. Optical rotations were measured with a digital polarim-
eter. Mass spectra were recorded on an autospec mass spec-
trometer. Elemental analyses were done on an elemental
analyzer model 1108 EA. Column chromatography was carried
out with silica gel (60-120 mesh). TLC was performed on 0.25
mm precoated silica gel plates (60F-254) with UV or I2 or
anisaldehyde reagent in ethanol. Light petroleum refers to a
mixture of hexanes with bp 60-80 °C.
3-C-Allyl-1,2;5,6-di-O-isopr opyliden e-3-O-(4-m eth oxyph en -
ylm eth yl)-r-D-a llofu r a n ose (9). Compound 86 (9.0 g, 30.0
mmol) in THF (30 mL) was added to a solution of sodium hydride
(50% dispersion in oil, 2.16 g, 45.0 mmol washed with 10 mL of
hexane) in THF (50 mL). After 1 h at room temperature, MPM
bromide (7.23 g, 36.0 mmol) in THF (20 mL) was added, and
the mixture was stirred for 6 h and then concentrated. The
residue was partitioned between ethyl acetate and water. The
ethyl acetate layer was washed with brine, dried (Na2SO4), and
concentrated. The residue was purified on silica gel by using
Introduction of an efficient strategy by Trost,3 founded
on Pd-catalyzed allylic rearrangement of cyclic allylic
substrate leading to the addition of a nucleoside base
with concomitant installation of a double bond, has
indeed enabled synthesis of several complex unsaturated
nucleosides.4
Structurally modified cyclopentane nucleosides (5 and
6), containing a stereochemically well-defined tertiary
hydroxyl/fluoro group, have been shown to posess potent
activity against viruses with a low level of toxicity.2,5 To
our knowledge, no attempts have yet been made to
synthesize and screen those novel carbocyclic nucleosides
having both a tertiary hydroxyl group and unsaturation.
(1) Agrofoglio, L.; Suhas, E.; Farese, A.; Condom, R.; Challand, S.
R.; Earl, R. A.; Guedj, R. Tetrahedron 1994, 50, 10611-10670.
(2) Borthwick, A. D.; Biggadike, K. Tetrahedron 1992, 48, 571-623.
(3) Trost, B. M.; Kuo, G.-H.; Benneche, T. J . Am. Chem. Soc. 1988,
110, 621-622.
(4) Crimmins, M. T.; King, B. W. J . Org. Chem. 1996, 61, 4192-
4193.
(5) Storer, R.; Paternoster, I. L.; Borthwick, A. D.; Biggadike, K.
Eur. Pat. Appl. 0430518, 1991.
(6) Patra, R.; Bar, N. C.; Roy, A.; Achari, B.; Mandal, S. B.
Tetrahedron 1996, 52, 11265-11272.
(7) (a) Phillips, A. J .; Abell, A. D. Aldrichim. Acta 1999, 32, 75-88.
(b) Roy, R.; Das, S. K. Chem. Commun. 2000, 519-529. (c) Grubbs, R.
H.; Chang, S. Tetrahedron 1998, 54, 4413-4450. (d) Furstner, A.
Angew. Chem., Int. Ed. 2000, 38, 3012-3043.
10.1021/jo010718c CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/06/2001

Notes
J . Org. Chem., Vol. 66, No. 22, 2001 7553
Sch em e 1a
a
Key: (a) MPM-Br/NaH, THF, rt, 6 h; (b) 0.8% H2SO4, MeOH, rt, 10 h; (c) MeSO2Cl, Et3N, DMAP, CH2Cl2, rt, 1 h; (d) Nal, EtCOMe,
reflux, 8 h; (e) Grubbs’ catalyst, CH2Cl2, rt, 6 h; (f) 0.4% H2SO4, dioxane, reflux, 2 h; (g) NalO4, CH2Cl2, SiO2, rt, 1 h; (h) NaBH4, MeOH,
rt, 1 h; (i) Im-CO-Im, C6H6, reflux, 4 h; (j) 6-aminopurine, Pd(PPh3)4, DMSO/THF (1:1), 45 °C, 2 h; (k) DDQ, MeCN/H2O, rt, 2 h.
hexanes-ethyl acetate (4:1) to give 9 (10.83 g, 86%), as a
mL) were stirred for 6 h at room temperature and then
evaporated. The residue was purified on silica gel with hexanes-
ethyl acetate (4:1) to give 11 (1.27 g, 80%), as a solid: mp 79-
81 °C; [R] +24° (c 1, CHCl3); 1H NMR (200 MHz, CDCl3) δ 1.35,
1.60 (2s, 6 H), 2.33 (brd, 1 H, J ) 17.5 Hz), 2.86 (dd, 1 H, J )
1.0, 17.5 Hz), 3.77 (s, 3 H), 4.43 (d, 1 H, J ) 9.2 Hz), 4.52 (d, 1
H, J ) 3.0 Hz), 4.64 (d, 1 H, J ) 9.2 Hz), 4.98 (brs, 1 H), 5.81 (d,
1 H, J ) 3.0 Hz), 5.90 (m, 2 H), 6.81 (d, 2 H, J ) 7.7 Hz), 7.26
(d, 2 H, J ) 7.7 Hz); 13C NMR (50 MHz, CDCl3) δ 27.2, 37.6,
39.6, 54.9, 67.3, 83.3, 90.5, 91.0, 106.5, 113.4, 128.9, 130.3, 134.0;
EIMS m/z 318 (M+). Anal. Calcd for C18H22O5: C, 67.92; H, 6.91.
Found: C, 68.12; H, 6.85.
1
liquid: [R]D +62° (c 2.8, CHCl3); H NMR (200 MHz, CDCl3) δ
1.32, 1.38, 1.43, 1.63 (4s, 12 H), 2.42 (dd, 1 H, J ) 6.45, 12.9
Hz), 2.67 (dd, 1 H, J ) 3.9, 12.9 Hz), 3.77 (s, 3 H), 3.93 (m, 1 H),
4.09 (m, 1 H), 4.16 (m, 2 H), 4.45 (d, 1 H, J ) 3.2 Hz), 4.68 (ABq,
2 H, J ) 12.9 Hz), 5.32 (m, 2 H), 5.61 (d, 1 H, J ) 3.2 Hz), 6.00
(m, 1 H), 6.84 (d, 2 H, J ) 8.0 Hz), 7.29 (d, 2 H, J ) 8.0 Hz); 13
C
NMR (50 MHz, CDCl3) δ 25.1, 26.3, 26.7, 35.6, 54.9, 66.4, 67.6,
72.8, 81.0, 82.7, 83.3, 103.2, 109.2, 112.3, 113.2, 118.2, 128.4,
131.07, 132.5; EIMS m/z 420 (M+). Anal. Calcd for C23H32O7:
C, 65.71; H, 7.62. Found: C, 65.33; H, 7.40.
3-C-Allyl-5,6-d id eoxy-1,2-O-isop r op ylid en e-3-O-(4-m eth -
oxyp h en ylm eth yl)-r-D-r ibo-h ex-5-en ofu r a n ose (10). Com-
pound 9 (8.4 g, 20.0 mmol) and 0.8% sulfuric acid (3 mL) in
methanol (50 mL) were stirred at room temperature for 10 h
and neutralized with solid NaHCO3. The solid was filtered, and
the filtrate was concentrated. The residue was purified on silica
gel with CHCl3-MeOH (10:1) to afford the 5,6-diol (5.7 g, 75%),
as a thick liquid: 1H NMR (200 MHz, CDCl3) δ 1.37, 1.62 (2s, 6
H), 2.62 (m, 2 H), 3.62 (dd, 1 H, J ) 6.2, 12.5 Hz), 3.75 (dd, 1 H,
J ) 4.7, 12.5 Hz), 3.78 (s, 3 H), 3.90 (m, 1 H), 4.06 (d, 1 H, J )
10.0 Hz), 4.47 (d, 1 H, J ) 3.1 Hz), 4.62 (s, 2 H), 5.25 (m, 2 H),
5.65 (d, 1 H, J ) 3.1 Hz), 6.0 (m, 1 H), 6.90 (d, 2 H, J ) 7.5 Hz),
7.34 (d, 2 H, J ) 7.5 Hz). It was taken up in Et3N (6.3 mL),
DMAP (0.18 g), and CH2Cl2 (30 mL), and MeSO2Cl (3.6 mL, 36.0
mmol) was added. After 1 h, the reaction mixture was washed
with saturated Na2CO3 and water, dried (Na2SO4), and concen-
trated. The crude dimesylate (7.4 g, 13.8 mmol) and NaI (10.34
g, 69.0 mmol) in 2-butanone (50 mL) were heated under reflux
for 8 h and concentrated. The residue was partitioned between
ethyl acetate and saturated sodium thiosulfate. The organic
layer was washed with brine, dried (Na2SO4), and concentrated.
The crude was purified by silica gel with hexanes-ethyl acetate
(9:1) to give 10 (3.33 g, 64%) as a liquid: [R]D +53° (c 2, CHCl3);
1H NMR (200 MHz, CDCl3) δ 1.38, 1.60 (2s, 6 H), 2.31 (dd, 1 H,
J ) 6.1, 13.5 Hz), 2.55 (dd, 1 H, J ) 6.3, 13.5 Hz), 3.78 (s, 3 H),
4.44 (m, 3 H), 4.53 (s, 2 H), 4.60 (d, 1 H, J ) 3.0 Hz), 5.0-5.5
(m, 4 H), 5.64 (d, 1 H, J ) 3.0 Hz), 5.9 (m, 2 H), 6.8 (m, 2 H),
7.23 (m, 2 H); 13C NMR (50 MHz, CDCl3) δ 26.4, 26.7, 35.8, 55.0,
71.3, 81.5, 81.6, 84.0, 103.6, 112.3, 117.7, 117.9, 128.5-130.3,
132.3, 132.7; EIMS m/z 346 (M+). Anal. Calcd for C20H26O5: C,
69.36; H, 7.51. Found: C, 69.01; H, 7.42.
(1S,2R)-1-(4-Meth oxyp h en ylm eth oxy)-1-h yd r oxym eth yl-
cyclop en t-3-en -2-ol (12). Compound 11 (3.81 g, 12.0 mmol),
dioxane (30 mL), and 0.4% H2SO4 (40 mL) were heated under
reflux for 2 h. The reaction mixture was neutralized with
saturated Na2CO3 and evaporated. The residue was extracted
with ethyl acetate, dried (Na2SO4), and concentrated to give
crude hemiacetal (3.17 g). The above product (3.17 g, 11.4 mmol)
was vigorously stirred with CH2Cl2 (30 mL), 0.65 M NaIO4
solution (25 mL), and chromatography grade SiO2 (20 g) for 1
h. The solid was filtered and washed with CH2Cl2. The combined
filtrate was evaporated and then dissolved in MeOH (30 mL).
Solid NaBH4 (0.5 g) was added, and after 1 h at room temper-
ature, the reaction mixture concentrated. The residue was
extracted with ethyl acetate, washed with brine, dried (Na2SO4),
concentrated, and purified by silica gel by eluting with hexanes-
ethyl acetate (3:1) to give 12 (2.1 g, 70%), as a thick liquid: [R]D
1
-78° (c 2.5, CHCl3); H NMR (200 MHz, CDCl3) δ 2.45 (q, 2 H,
J ) 16.1 Hz), 3.89 (s, 3 H), 3.95 (m, 3 H), 4.43 (ABq, 2 H, J )
12.9 Hz), 4.91 (s, 1 H), 5.77 (brs, 1 H), 6.84 (d, 2 H, J ) 8.5 Hz),
7.25 (d, 2 H, J ) 8.5 Hz); 13C NMR (50 MHz, CDCl3) δ 38.8,
55.2, 64.0, 65.2, 82.9, 87.6, 128.7, 131.9, 132.5; EIMS m/z 250
(M+).
(1S,2R)-5-(4-Meth oxyp h en ylm eth oxy)-1,3-d ioxa bicyclo-
[4.3.0]n on -7-en -2-on e (13). A solution of compound 12 (0.275
g, 1.1 mmol) and N,N′-carbonyldiimidazole (0.27 g, 1.65 mmol)
in benzene (5 mL) was heated under reflux for 4 h and
concentrated. The residue was purified on silica gel with
hexanes-ethyl acetate (9:1) as eluent to give 13 (0.21 g, 69%)
1
as a colorless liquid: [R]D 40° (c 1, CHCl3); H NMR (200 MHz,
CDCl3) δ 2.53 (d, 1 H, J ) 12.7 Hz), 2.82 (d, 1 H, J ) 12.7 Hz),
3.78 (s, 3 H), 4.07 (d, 1 H, J ) 7.0 Hz), 4.48 (m, 4 H), 5.41 (s, 1
H), 5.82 (m, 1 H), 6.04 (m, 1 H), 6.81 (d, 2 H, J ) 6.8 Hz), 7.25
(d, 2 H, J ) 6.8 Hz); 13C NMR (50 MHz, CDCl3) δ 40.0, 55.1,
(2R,3R,4S,5R)-2,3-O-Isop r op ylid en e-4-O-(4-m eth ylp h en -
ylm eth yl)-1-oxa bicyclo[3.3.0]oct-6-en e (11). Compound 10
(1.73 g, 5.0 mmol) and Grubbs’ catalyst (0.20 g) in CH2Cl2 (50

7554 J . Org. Chem., Vol. 66, No. 22, 2001
Notes
66.0, 68.7, 81.2, 91.7, 128.2, 128.8, 129.2, 134.9, 150.4; EIMS
m/z 276 (M+). Anal. Calcd for C15H16O5: C, 65.21; H, 5.79.
Found: C, 64.88; H, 5.62.
saturated NaHCO3 and brine and dried (Na2SO4). The solvent
was evaporated, and the residue was chromatographed on silica
gel with ethyl acetate-MeOH (5:1) to give compound 15 (44 mg,
72%) as a thick syrup: [R]D + 82° (c 0.3, MeOH); 1H NMR (500
MHz, CD3COCD3) δ 2.33 (dd, 1 H, J ) 3.3, 14.8 Hz), 2.60 (dd, 1
H, J ) 6.6, 14.8 Hz), 3.70 (ABq, 2 H, J ) 13.3 Hz), 5.90 (m, 1
(1′R,4′R)-(4′-H yd r oxy-4′-h yd r oxym et h ylcyclop en -2′-en -
yl)a d en in e (15). To a solution of 6-aminopurine (73 mg, 0.54
mmol) and Pd(PPh3)4 (62 mg) in DMSO (2 mL) under nitrogen
was added 13 (150 mg, 0.54 mmol) in THF (2 mL). After being
stirred for 2 h at 45 °C, the reaction mixture was diluted with
water and repeatedly extracted with ethyl acetate. The combined
organic layer was washed with water, dried (Na2SO4), and
concentrated. The residue was purified by silica gel with ethyl
acetate-MeOH (9:1) to give compound 14 (108 mg, 54%) as a
colorless solid: mp 167-169 °C; [R]D +124° (c 1, MeOH); 1H
NMR (200 MHz, DMSO-d6) δ 2.10 (dd, 1 H J ) 4.7, 13.3 Hz),
2.66 (dd, 1 H, J ) 6.0, 13.3 Hz), 3.53 (d, 1 H, J ) 12.6 Hz), 3.76
(s, 3 H), 4.36 (t, 2 H, J ) 13.3 Hz), 5.83 (brs, 1 H), 6.23 (m, 2 H),
6.90 (d, 2 H, J ) 6.8 Hz), 7.26 (d, 2 H, J ) 6.8 Hz), 8.10 (s, 1 H),
8.20 (s, 1 H); 13C NMR (50 MHz, DMSO-d6) δ 39.0, 55.8, 59.7,
65.2, 66.2, 92.0, 129.9, 131.8, 135.0, 139.0, 152.4.
H), 6.16 (m, 1 H), 6.26 (brs, 1 H), 8.03 (s, 1 H), 8.20 (s, 1H); 13
C
NMR (125 MHz, CD3COCD3) δ 42.7, 59.2, 67.8, 85.2, 132.0,
139.2, 140.9, 152.7. Anal. Calcd for C11H13N5O2: C, 53.44; H,
5.26. Found: C, 53.39; H, 5.60.
Ack n ow led gm en t. K.M. wishes to thank CSIR,
New Delhi for finanacial support in the form of Senior
Research Fellowship.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
11, 12, 13, 14 and 15 and 13C NMR of 11, 14 and 15. This
material is available free of charge via Internet at http://
pubs.acs.org.
The above product 14 (91 mg, 0.25 mmol) and DDQ (85 mg)
in dioxane containing two drops of water (3 mL) were stirred at
room temperature for 2 h. The reaction mixture was washed with
J O010718C