A short and efficient synthesis of 5-hydroxymethylcyclopent-2-enol from d-glucose and its elaboration to the carbanucleoside (-)-carbovir

Article abstract of DOI:10.1016/j.tetlet.2007.01.016

Introduction of an allyl functionality at C-3 of 1,2:5,6-di-O-isopropylidene-α-d-glucofuranose followed by olefination at C-5 and C-6 provided 1,6-diene 5 which, upon ring closing metathesis and subsequent functional group manipulation, furnished the key cyclopentene diacetate 7, which was elaborated to carbanucleoside (-)-carbovir 1.

Full text of DOI:10.1016/j.tetlet.2007.01.016

Tetrahedron Letters 48 (2007) 1563–1566
A short and efficient synthesis of 5-hydroxymethylcyclopent-2-enol
from D-glucose and its elaboration to the
carbanucleoside (ꢀ)-carbovir
Biswajit G. Roy, Prithwish K. Jana, Basudeb Achari and Sukhendu B. Mandal*
Department of Chemistry, Indian Institute of Chemical Biology, Jadavpur, Kolkata 700 032, India
Received 26 October 2006; revised 18 December 2006; accepted 4 January 2007
Available online 7 January 2007
Abstract—Introduction of an allyl functionality at C-3 of 1,2:5,6-di-O-isopropylidene-a-D-glucofuranose followed by olefination at
C-5 and C-6 provided 1,6-diene 5 which, upon ring closing metathesis and subsequent functional group manipulation, furnished the
key cyclopentene diacetate 7, which was elaborated to carbanucleoside (ꢀ)-carbovir 1.
ꢀ 2007 Elsevier Ltd. All rights reserved.
An increased interest in carbanucleosides1 for the treat-
ment of human immunodeficiency virus (HIV) and hep-
atitis B virus (HBV) resulted in the discovery of carbovir
1,2 abacavir 22f,3 and bis(hydroxymethyl)-cyclopentenyl
adenine (BCA) 3.4 The promising antiviral properties
exhibited by these nucleosides, arising from the replace-
ment of the furanose ring oxygen of the parent nucleo-
sides by carbon, may be due to their metabolic and
chemical stability towards various phosphorylases and
cleaving agents.5 The realization that carbovir is an
inhibitor of HIV, the causative agent for the acquired
immune deficiency syndrome (AIDS), has initiated vig-
orous efforts for its synthesis,2 culminating in several
syntheses based on carbohydrate or non-carbohydrate
precursors. The methodologies for the preparations of
precursors mostly involved (i) appropriate installation
of two olefin functionalities on suitable backbones for
ring closing metathesis (RCM)6 to create a targeted
cyclopentene ring, (ii) Dieckman condensation of a car-
bohydrate-derived diester to a cyclopentanone ring,7 (iii)
Diels–Alder reaction between cyclopentadiene and
appropriate dienophiles8 or (iv) the structural rearrange-
ment of a norbornadiene skeleton.4a However, most of
the methods involve lengthy procedures and use costly
reagents, so the development of expedient and flexible
synthetic routes to 1 and other related nucleosides con-
tinues unabated. As a part of our programme directed
towards the synthesis of carbanucleosides bearing cyclo-
pentane/cyclopentene rings from D-glucose-based sub-
strates, we report herein a short and simple synthesis
of (ꢀ)-carbovir 1.
HN
O
N
N
N
N
N
NH
NH2
N
NH2
HO
N
HO
1
2
NH2
N
N
N
HO
N
HO
3
Figure 1 summarizes our envisioned approach, which
requires a ready access to enantiomerically pure cyclo-
pentene diacetate 7. This precursor could conceivably
be obtained from the tricyclic cyclopentene derivative
6 through the cleavages of dioxolane and furanose
rings. Product 6 could be prepared by RCM of diene
5, itself obtainable from the D-glucose-derived product
3-C-allyl-1,2-di-O-isopropylidene-a-D-glucofuranose 4b
through deprotection and deoxidative olefination.
Keywords: Carbanucleoside; Carbovir; Synthesis; Grubbs’ catalyst;
Ring closing metathesis; D-Glucose.
*
To realize our objective, allylation at C-3 of 1,2-di-O-
isopropylidene-a-D-glucofuranose with b-stereochemistry
Corresponding author. Tel.: +91 33 24733491; fax: +91 33
24735197; e-mail: sbmandal@iicb.res.in
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.016

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B. G. Roy et al. / Tetrahedron Letters 48 (2007) 1563–1566
different solvents and substrates; the results are pre-
H
O
OAc
O
sented in Table 1. The best result was obtained using
20 mol % AIBN and 2.5 equiv of allyl tri-n-butyltin in
refluxing toluene. Although the yields were somewhat
better using iodide 10, overall methyl xanthate 9 is rec-
ommended as it can be prepared in a near quantitative
yield from the same starting material (diacetone D-glu-
cose). The isomeric mixture of products could be sub-
mitted next to deoxidative olefination followed by
RCM steps directly; only the diolefin with 3,4-cis-substi-
tution would react, rendering the separation of isomers
easier. The RCM reaction of the mixture of cis and trans
diolefins (generated from 4a,b) indeed afforded the
cis-fused bicyclic cyclopentene 6; the trans-diolefin did
not cyclize. Separation of the cyclized and uncyclized
products was carried out uneventfully by silica gel col-
umn chromatography.
1
O
H
OAc
7
6
O
O
O
O
O
O
O
O
5
4b
Figure 1. Retrosynthetic analysis of carbovir 1.
was desired. This could indeed be carried out by treating
phenoxythiocarbonyl ester 89 (but not the methyl xan-
thate 910 or iodide 1011) with allyl tri-n-butyltin under
UV light at a low temperature (10 ꢁC), yielding 4b (b-
isomer only) in a high yield; but this required a pro-
longed reaction time (40 h). On the other hand, a ther-
mal radical reaction with 8–10 using AIBN and allyl
tri-n-butyltin was much faster and problem free but
yielded a difficultly separable mixture of a-12 and b-iso-
mers.9 An optimization study was then carried out using
Selective removal of the 5,6-O-isopropylidene group of
4b under mild acidic condition and subsequent treatment
of the vicinal diol with PPh3–I2–imidazole provided
diolefin 5.13 RCM of 5 using the first generation Grubbs
catalyst smoothly furnished the cyclopentene fused furan
613 (Scheme 1). Opening the 1,2-acetonide of 6 using
Table 1. Chemical and photochemical radical induced allylation of 8–10
O
O
O
O
O
O
O
O
a/b/c/d
R1
O
O
R2
8, R1 = O-(C=S)-OPh, R2 = H
9, R1 = O-(C=S)-SMe, R2 = H
10, R1 = H, R2 = I
4a,b (α- and β-isomers)
Substrates
Reagents/conditionsa
Product 4
Yields (%)
Ratio (b:a)
8
9
(a) (b) (c) (d)
(a) (b) (c)
(60) (50) (40) (80)
(55) (50) (38)
(2:1) (3.5:2) (1:1) (b only)
(9:4) (3:2) (1:1)
10
(a) (b) (c)
(65) (55) (40)
(3:1) (2:1) (5:4)
a (a) Allyl tri-n-butyl tin, AIBN, toluene, reflux, 30 min; (b) allyl tri-n-butyl tin, AIBN, m-xylene, 120 ꢁC, 30 min; (c) allyl tri-n-butyl tin, AIBN,
m-xylene, reflux, 30 min; (d) allyl tri-n-butyl tin, benzene/toluene, 350 nm light (460 W Lamp), 10 ꢁC, 40 h.
O
H
OAc
O
O
O
O
O
O
d-g
57%
O
a, b
c
O
OAc
68%
O
90%
H
O
7
6
4b
5
O
N
Cl
N
N
N
N
NH
NH2
N
h
i
HO
AcO
N
NH2
60%
60%
11
1
Scheme 1. Synthesis of carbanucleoside carbovir (1) from 3-C-allyl-1,2-di-O-isopropylidene-a-D-glucofuranose (4b). Reagents and conditions: (a)
aqueous HOAc (75%), rt, 14 h; (b) Ph3P (3.75 equiv), imidazole (3.75 equiv), iodine (2.4 equiv), toluene, reflux, 3 h; (c) PhCH@Ru(Pcy3)2Cl2, DCM,
rt, 6 h; (d) CH3CN–H2O–H2SO4 (18:6:1), rt, 24 h; (e) aqueous NaIO4, MeOH, rt, 45 min; (f) NaBH4, MeOH, rt, 2 h; (g) Ac2O, Et3N, rt, 12 h; (h) 2-
amino-6-chloropurine, Pd(Ph3P)4, NaH, DMSO–THF (1:1), rt, 24 h; (i) aqueous NaOH (5 N), reflux, 5 h.

B. G. Roy et al. / Tetrahedron Letters 48 (2007) 1563–1566
1565
571–623; (b) Agrofoglio, L.; Suhas, E.; Farese, A.;
Condom, R.; Challand, S. R.; Earl, R. A.; Guedj, R.
Tetrahedron 1994, 50, 10611–10670; (c) Crimmins, M. T.
Tetrahedron 1998, 54, 9229–9272; (d) Huryn, D.; Okabe,
M. Chem. Rev. 1992, 92, 1745–1768; (e) Ferrero, M.;
Gotor, V. Chem. Rev. 2000, 100, 4319–4347.
dilute H2SO4, diol cleavage with NaIO4, NaBH4 reduc-
tion of the resulting aldehyde, and the subsequent acety-
lation of the diol (5-hydroxymethyl-cyclopent-2-enol)
25
yielded the desired diacetate 7, ½aꢁD ꢀ174.4 (c 0.31,
25
CHCl3) [lit.2f ½aꢁD ꢀ178.0 (c 0.45, CH2Cl2)]. Palladium-
catalyzed coupling of 7 with 2-amino-6-chloropurine in
the presence of tetrakis(triphenylphosphine)palla-
dium(0) and sodium hydride in DMSO–THF (1:1) at
room temperature produced purine carbanucleoside 11,
2. Few syntheses of carbovir: (a) Berranger, T.; Langois, Y.
Tetrahedron Lett. 1995, 36, 5523–5526; (b) Jung, M. E.;
Rhee, H. J. Org. Chem. 1994, 59, 4719–4720; (c) Evans, C.
T.; Robert, S. M.; Shoberu, K. A.; Sutherland, A. G. J.
Chem. Soc., Perkin Trans. 1 1992, 589–592; (d) Trost, B.
M.; Leping, L.; Guile, S. D. J. Am. Chem. Soc. 1992, 114,
8745–8747; (e) Hodgson, D. M.; Witherington, J.; Molo-
ney, B. A. J. Chem. Soc., Perkin Trans. 1 1994, 3373–3378;
(f) Crimmins, M. T.; King, B. W. J. Org. Chem. 1996, 61,
4192–4193; (g) Hildebrand, S.; Troxler, T.; Scheffold, R.
Helv. Chim. Acta 1994, 77, 1236–1240; (h) Diaz, M.;
Ibarzo, J.; Jimenez, J. M.; Ortuno, R. M. Tetrahedron:
Asymmetry 1994, 5, 129–140.
3. Daluge, S. M.; Good, S. S.; Faletto, M. B.; Miller, W. H.;
St. Clair, M. H.; Boone, L. R.; Tisdale, M.; Parry, N. R.;
Reardon, J. E.; Dornsife, R. E.; Averette, D. R.; Krenit-
sky, T. A. Antimicrob. Agents Chemother. 1997, 41, 1082–
1093.
4. (a) Tanaka, M.; Norimine, Y.; Fujita, T.; Suemune, H.;
Sakai, K. J. Org. Chem. 1996, 61, 6952–6957; (b) Katagiri,
N.; Nomura, M.; Sato, H.; Kaneko, C.; Yusa, K.; Tsuruo,
T. J. Med. Chem. 1992, 35, 1882–1886.
25
25
½aꢁD ꢀ85.6 (c 0.18, CHCl3) [lit.2f ½aꢁD ꢀ88.6 (c 0.43,
CH2Cl2)]. Finally, the chlorine in 11 was hydrolyzed with
25
aqueous sodium hydroxide to furnish carbovir 1, ½aꢁD
20
ꢀ66.6 (c 0.22, MeOH) [lit.14 ½aꢁD ꢀ68.0 (c 1.0, MeOH)].
The trans relationship between H-2 and H-3 of 5 was
deduced from the appearance of the H-2 signal as a
doublet at d 4.52 (J = 3.6 Hz) in the 1H NMR spectrum;
this signal is observed as a triplet (J ꢂ 3.8 Hz) in the case
of cis-isomers. The appearance of two olefinic methine
proton signals (at d 5.70–5.89) and carbon signals (at d
133.5, 135.7) in addition to other requisite signals in
the NMR spectrum of 5 confirmed its structure. The
success of the RCM reaction on 5 was evident from
the location of two multiplets (d 5.83–5.85 and 5.91–
1
5.93) for two olefinic protons in the H NMR spectrum
of 6. The 13C NMR spectrum as well as the mass spec-
trum of 6 are in agreement with the assigned structure.
5. Jenkins, G. N.; Turner, N. J. Chem. Soc. Rev. 1995, 24,
169–176.
1
Compounds 7, 11 and 1 showed virtually identical H
6. (a) Banerjee, S.; Ghosh, S.; Sinha, S.; Ghosh, S. J. Org.
Chem. 2005, 70, 4199–4202; (b) Nayek, A.; Banerjee, A.;
Sinha, S.; Ghosh, S. Tetrahedron Lett. 2004, 45, 6457–
6460; (c) Gurjar, M. K.; Maheshwar, K. J. Org. Chem.
2001, 66, 7552–7554; (d) Sahabuddin, Sk.; Roy, A.; Drew,
M. G. B.; Roy, B. G.; Achari, B.; Mandal, S. B. J. Org.
Chem. 2006, 71, 5980–5992.
7. Park, K. H.; Rapoport, H. J. Org. Chem. 1994, 59, 394–
399.
8. Taylor, S. J. C.; Sutherland, A. G.; Lee, C.; Wisdom, R.;
Thomas, S.; Roberts, S. M.; Evans, C. J. Chem. Soc.,
Chem. Comm. 1990, 1120–1121.
and 13C NMR, and also MS, with those reported in
the literature.
In conclusion, the convergent approach to the carbo-
cyclic nucleoside carbovir starting from a D-glucose-
derived precursor described here is very simple and
efficient. The strategy deals with judicious introduction
of olefin moieties at appropriate positions to obtain a
1,6-diene, which is subjected to a ring closing metathesis
reaction to yield the desired enantiomerically pure cyclo-
pentene derivative required for nucleosidation. The
other enantiomer may be obtainable from the other
1,6-diene derived via inclusion of an olefin moiety at
C-1 of an appropriate derivative generated from the
same precursor, followed by ring closure and nucleosi-
dation. The results could be extended to other systems,
utilizing different substitution patterns on different
carbohydrate backbones. These carbanucleosides could
then be screened as potential inhibitors of HIV.
9. Roy, B. G.; Maity, J. K.; Drew, M. G. B.; Achari, B.;
Mandal, S. B. Tetrahedron Lett. 2006, 47, 8821–8825.
10. Iacono, S.; Rasmussen, J. R. Org. Synth. Coll. Vol. 7 1990,
139–142.
11. Preparation of 10: To a solution of 1,2:5,6-di-O-isopro-
pylidene-a-D-glucofuranose (500 mg, 1.9 mmol) in toluene
(26 mL) was added Ph3P (2.8 mmol) and imidazole
(2.8 mmol) and the mixture was heated. When reflux
started, iodine (2.3 mmol) was added and the refluxing was
continued for 2 h. The mixture was cooled; the solution
was washed successively with 30% Na2S2O3 solution
(20 mL) and water (3 · 10 mL), dried (Na2SO4), and
evaporated to a crude residue, which was purified by
silica gel column chromatography (petroleum ether:ethyl
acetate = 85:15) to furnish 10 (325 mg, 45%). ½aꢁ2D5 +14.5 (c
0.78, CHCl3); 1H NMR (CDCl3, 300 MHz): d 1.38 (s, 6H),
1.50 (s, 3H), 1.56 (s, 3H), 3.77 (dd, J = 4.5, 10.0 Hz, 1H),
4.07–4.16 (m, 2H), 4.24–4.34 (m, 2H), 4.61 (t-like,
J = 4.0 Hz, 1H), 5.83 (d, J = 3.6 Hz, 1H); FABMS, m/z:
371 (M+H)+. Anal. Calcd for C12H19IO5: C, 38.93; H,
5.17. Found: C, 38.66; H, 5.03.
Acknowledgements
The work has been supported by a grant (to S.B.M.)
from the Department of Science and Technology (Govt.
of India). The authors gratefully acknowledge the Coun-
cil of Scientific and Industrial Research (CSIR) for pro-
viding Research Fellowships (to B.G.R. and P.K.J.) and
Emeritus Scientist Scheme (to B.A.).
25
12. Data for 4a: ½aꢁD +15.6 (c 0.45, CHCl3); 1H NMR
(CDCl3, 300 MHz): d 1.30 (s, 3H), 1.35 (s, 3H), 1.42 (s,
3H), 1.52 (s, 3H), 1.87–1.92 (m, 1H), 2.34–2.47 (m, 2H),
3.79 (dd, J = 6.3, 9.7 Hz, 1H), 3.39–4.14 (m, 3H), 4.63 (t-
like, J = 3.8 Hz, 1H), 5.03–5.17 (m, 2H), 5.73 (d,
J = 3.4 Hz, 1H), 5.86–5.92 (m, 1H); 13C NMR (CDCl3,
References and notes
1. For recent reviews on the synthesis of carbanucleosides:
(a) Borthwick, A. D.; Biggadike, K. Tetrahedron 1992, 48,

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B. G. Roy et al. / Tetrahedron Letters 48 (2007) 1563–1566
25
75 MHz): d 25.2 (CH3), 26.3 (CH3), 26.7 (CH3), 27.4
(CH3), 29.3 (CH2), 48.1 (CH), 67.2 (CH2), 77.6 (CH), 81.3
(CH), 81.4 (CH), 104.7 (CH), 109.4 (C), 111.6 (C), 116.0
(CH2), 136.0 (CH); ESIMS, m/z: 307 (M+Na)+. Anal.
Calcd for C15H24O5: C, 63.36; H, 8.51. Found: C, 63.08;
Found: C, 68.25; H, 8.47. Data for 6: ½aꢁD ꢀ45.3 (c 0.26,
CHCl3); 1H NMR (CDCl3, 600 MHz): d 1.35 (s, 3H), 1.55
(s, 3H), 2.21–2.25 (m, 1H), 2.63–2.67 (m, 1H), 2.92–2.96
(m, 1H), 4.53 (d, J = 3.6 Hz, 1H), 5.30–5.32 (m, 1H), 5.80
(d, J = 3.6 Hz, 1H), 5.83–5.85 (m, 1H), 5.91–5.93 (m, 1H);
13C NMR (CDCl3, 150 MHz): d 26.9 (CH3), 27.9 (CH3),
35.4 (CH2), 47.1 (CH), 86.5 (CH), 88.4 (CH), 106.2 (CH),
112.0 (C), 130.8 (CH), 135.3 (CH); ESIMS, m/z: 205
(M+Na)+. Anal. Calcd for C10H14O3: C, 65.91; H, 7.74.
Found: C, 65.75; H, 7.57.
H, 8.37.
25
13. Data for 5: ½aꢁD ꢀ30.6 (c, 0.32, CHCl3); 1H NMR (CDCl3,
300 MHz): d 1.32 (s, 3H), 1.53 (s, 3H), 1.77–1.82 (m, 1H),
2.17–2.32 (m, 2H), 4.52 (d, J = 3.6 Hz, 1H), 4.78 (t-like,
J = 4.7, 5.3 Hz, 1H), 5.01–5.04 (m, 2H), 5.24–5.41 (m,
2H), 5.70–5.89 (m, 3H); 13C NMR (CDCl3, 75 MHz): d
26.0 (CH3), 26.6 (CH3), 29.9 (CH2), 47.6 (CH), 80.1 (CH),
83.6 (CH), 104.2 (CH), 110.7 (C), 116.8 (CH2), 117.3
(CH2), 133.5 (CH), 135.8 (CH); ESIMS, m/z: 233
(M+Na)+. Anal. Calcd for C12H18O3: C, 68.54; H, 8.63.
14. Exall, A. M.; Jone, M. F.; Mo, C. L.; Myers, P. L.;
Patermaster, I. L.; Singh, H.; Storer, R.; Weingarten, G.
G.; Williamson, C.; Brodie, A. C.; Cook, J.; Kake, D. E.;
Meerhlz, C. A.; Turnbull, P. J.; High, R. M. J. Chem.
Soc., Perkin Trans. 1 1991, 2479–2484.