Introduction of vinyl and hydroxymethyl functionalities at C-4 of glucose-derived substrates: Synthesis of spirocyclic, bicyclic, and tricyclic nucleosides

Article abstract of DOI:10.1021/jo8002826

(Chemical Equation Presented) Installing hydroxymethyl and hydroxyethyl substitutions at C-4 through vinylation and hydroboration-oxidation reactions of the C-4 bis-hydroxymethyl derivative of D-glucose based substrate, and inserting heteroatoms thereafter permitted formation of N-, O-, or S-heterocycles leading to [4,5]-or [5,5]-spirocycles and a bicyclo[3.3.0]octane product. Some of the spirocycles were converted to spironucleosides under Vorbrueggen glycosidation reaction conditions. Similarly, the bicyclic product was elaborated to the corresponding bicyclic nucleoside as well as an unexpected tricyclic nucleoside.

Full text of DOI:10.1021/jo8002826

Introduction of Vinyl and Hydroxymethyl
Functionalities at C-4 of Glucose-Derived
Substrates: Synthesis of Spirocyclic, Bicyclic, and
Tricyclic Nucleosides
Joy Krishna Maity,† Ramprasad Ghosh,†
Michael G. B. Drew,‡ Basudeb Achari,† and
Sukhendu B. Mandal*,†
Department of Chemistry, Indian Institute of Chemical
Biology, 4, Raja S. C. Mullick Road, JadaVpur,
Kolkata 700 032, India, and Department of Chemistry,
UniVersity of Reading, Whiteknights, Reading RG6 6AD,
United Kingdom
sbmandal@iicb.res.in
FIGURE 1. An approach to produce spirocycles and spironucleosides.
ReceiVed February 4, 2008
of a carbocyclic ring (a bulky substituent) at C-4′ of furanose/
thiofuranose rings. This was expected to fix the glycosyl
torsional angle around the C-4′ bond, while the void space below
C-4′ would be sufficient to avoid nonbonded steric superimposi-
tion. In addition, the free radical-induced degradation of the
ribose ring of nucleosides by C-4′-H abstraction can be
precluded. Various other synthetic routes to C-2′-spiro,5 C-3′-
spiro,6 and C-4′-spironucleosides4 as conformationally restricted
or biased analogues have appeared in the literature. Some of
these nucleosides display anti-HIV and antivirus activity.7 We
have earlier reported8 on the synthesis of spironucleosides
having 4- and 7-membered spiro rings at C-4′ through nucleo-
philic substitution and intramolecular nitrone cycloaddition
reaction. The work encouraged us to take up the synthesis of
spirocycles based on five-membered heterocyclic rings from a
D-glucose-derived precursor carrying two hydroxymethyl groups
at C-4. One of these groups was planned to be utilized to
introduce a vinyl group via oxidation and Wittig reaction, and
thenconvertedtoahydroxyethylgroupbyhydroboration-oxidation
reaction. Subsequent intra/intermolecular cyclization through the
participation of oxygen, nitrogen, and sulfur nucleophiles (Figure
1) was expected to furnish the desired heterocyclic systems. In
the process, we also encountered newer 4,5-spirocyclic and
bicyclo[3.3.0]octane systems. The products could be elaborated
to interesting spirocyclic and bicyclic nucleosides in addition
to an unexpected 5,5,5-tricyclic conformationally locked nucleo-
side as discussed in the sequel.
Installing hydroxymethyl and hydroxyethyl substitutions at
C-4 through vinylation and hydroboration-oxidation reac-
tions of the C-4 bis-hydroxymethyl derivative of D-glucose
based substrate, and inserting heteroatoms thereafter permit-
ted formation of N-, O-, or S-heterocycles leading to [4,5]-
or [5,5]-spirocycles and a bicyclo[3.3.0]octane product. Some
of the spirocycles were converted to spironucleosides under
Vorbru¨ggen glycosidation reaction conditions. Similarly, the
bicyclic product was elaborated to the corresponding bicyclic
nucleoside as well as an unexpected tricyclic nucleoside.
Hydantocidin, a pseudonucleoside possessing a spirocyclic
ring at the anomeric center, was reported from a natural source.1
Its unusual structure and bioactivity inspired Miyasaka2 and
others3 to synthesize C-1′-spironucleosides as conformationally
restricted molecules. Subsequently, Paquette4 introduced the
concept of spirocyclic restriction in nucleosides through insertion
(4) (a) Dong, S.; Paquette, L. A. J. Org. Chem. 2005, 70, 1580–1596. (b)
Hortung, R.; Paquette, L. A. J. Org. Chem. 2005, 70,1597–1604. (c) Paquette,
L. A.; Dong, S. J. Org. Chem. 2005, 70, 5655–5664. (d) Paquette, L. A. Aust.
J. Chem. 2004, 57, 7–17, and references cited therein.
† Indian Institute of Chemical Biology.
(5) Ravindra Babu, B.; Keinicke, L.; Petersen, M.; Nielsen, C.; Wengel, J.
Org. Biomol. Chem. 2003, 1, 3514–3526.
‡ University of Reading.
(1) Haruama, H.; Takayama, T.; Kinoshita, T.; Kondo, M.; Nakajima, M.;
Haneishi, T. J. Chem. Soc., Perkin Trans. 1991, 1, 1637–1640.
(2) Kittaka, A.; Asakura, T.; Kuze, T.; Tanaka, H.; Yamada, N.; Nakamura,
K. T.; Miyasaka, T. J. Org. Chem. 1999, 64, 7081–7093, and references cited
therein.
(6) Nielsen, P.; Larsen, K.; Wengel, J. Acta Chem. Scand. 1996, 50, 1030–
1035.
(7) (a) De Castro, S.; Lobaton, E.; Perez-Perez, M.-J.; San-Felix, A.; Cordeiro,
A.; Andrei, G.; Snoeck, R.; De Clercq, E.; Balzarini, J.; Camarasa, M.-J.;
Velazquez, S. J. Med. Chem. 2005, 48, 1158–1168. (b) Crich, D.; Hao, X. J.
Org. Chem. 1999, 64, 4016–4024.
(3) (a) Gasch, C.; Pradera, M. A.; Salameh, B. A. B.; Molina, J. L.; Fuentes,
J. Tetrahedron: Asymmetry 2001, 12, 1267–1277. (b) Gimisis, T.; Chatgilialoglu,
C. J. Org. Chem. 1996, 61, 1908–1909. (c) Chatgilialoglu, C.; Gimisis, T.; Spada,
G. P. Chem. Eur. J. 1999, 5, 2866–2876.
(8) (a) Roy, A.; Achari, B.; Mandal, S. B. Tetrahedron Lett. 2006, 47, 3875–
3879. (b) Tripathi, S.; Roy, B. G.; Drew, M. G. B.; Achari, B.; Mandal, S. B.
J. Org. Chem. 2007, 72, 7427–7430.
10.1021/jo8002826 CCC: $40.75
Published on Web 04/24/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 4305–4308 4305

SCHEME 1. Introduction of a Vinyl Group at C-4 of 7
SCHEME 3. Synthesis of 5/4-Spirocycles 16, 18, and 19
SCHEME 2. Hydroboration-Oxidation Reaction of 10
SCHEME 4. Conversion of 14 to Bicycle 21 and Spirocycle
22
sodium hydride. In another approach, mesylation of the same
substrate 12 produced the dimesyl derivative 17, which upon
treatment with benzyl amine at elevated temperature cleanly
furnished the azetane derivative 18 (70%), wherein inversion
of configuration at the azetane methine center is anticipated. In
the same vein, compound 17 gave the thietane analogue 19
(77%). The relative configurations of 16 and 18 were easily
deduced from the structure of 19 assuming inversion at C-5
during cyclization to 18 and 19 based on mechanistic
consideration.
Transformation of 14 to Bicycle 21 and Spirocycle 22. We
next turned our attention to convert 14 to its dimesyl derivative
in the hope of generating spiroannulated 5-membered O-, N-,
and S-heterocycles. Toward this end, mesylation of 14 was
carried out with mesyl chloride in pyridine (Scheme 4).
Surprisingly, this afforded the chloro mesyl derivative 20 (34%)
instead of the expected dimesyl derivative, along with the
unexpected product 21 (51%). Fortunately, 20 turned out to be
a good substrate for transformation to the spiroannulated
thiophene analogue 22 (suggested mechanism for this reaction
is given in the Supporting Information).
The structures of 20 and 22 were deduced by spectral analyses
(1H, 13C NMR and MS). However, such analyses could not
furnish any conclusive proof for the structure of 21. Fortunately,
this could be achieved by a single-crystal X-ray diffraction
analysis.11
Synthesis of Spironucleosides 25-29. With a view to
generating spironucleosides, cleavage of the 1,2-acetonide rings
of 18 and 19 by acid treatment was followed by acetylation to
furnish the respective acetylated products 23 and 24 as anomeric
mixtures, which without purification were used to instal uracil
base at their anomeric centers using the Vorbru¨ggen glycosi-
dation procedure.13 This provided the nucleoside analogues 25
and 26 in 56-60% yields. Deacetylation of these products by
treatment with K2CO3 in MeOH smoothly produced 27 and 28
Preparation of Important Intermediates 10, 11, and 14.
To realize our goals, we set about as follows. One of the
hydroxyl groups of the D-glucose derived substrate 79 (derived
from D-glucose in five steps, 36% overall yield) was preferen-
tially protected as tert-butyldimethylsilyl ether to provide 8.
Submitting 8 to Swern oxidation (Scheme 1) afforded the
aldehyde 9. When the crude product was subjected to Wittig
reaction with methylenetriphenylphosphorane, it yielded the
vinylated compound 10 in 45% yield (over two steps).
Diborane reaction of 10 followed by oxidation with alkaline
hydrogen peroxide resulted in a mixture of products, which after
chromatographic purification and spectroscopic analysis pro-
vided (Scheme 2) a mixture of both Markownikov and anti-
Markownikov products (11, 13) along with their desilylated
derivatives (12, 14) as established by correlation analysis. The
expected anti-Markownikov addition products were formed in
higher yields (combined yield 49% vs 35% for the other
mode).10
1
The structure of 8 was deduced from the H-1H COSY,
1H-13C HSQC, 1H-13C-HMBC, and NOESY spectra (vide the
Supporting Information). The absolute configuration at the newly
generated asymmetric center of 11 and 12 was deduced
subsequently from an X-ray analysis of the derived product 19.11
Cyclization of 12 to the Heterocycles 16, 18, and 19.
Toward the generation of spiroannulated heterocycles, phos-
phonium ion induced iodination12 of the primary hydroxyl group
of 12 produced (Scheme 3) the expected intermediate 15 without
affecting the secondary hydroxyl group. The intermediate was
cyclized in situ to the oxetane derivative 16 upon addition of
(9) Youssefyeh, R. D.; Verheyden, J. P. H.; Moffatt, J. G. J. Org. Chem.
1979, 44, 1301–1309.
(10) Hydroboration of 10 with 9-BBN was not successful possibly due to
the steric hindrance offered to the approach of the reagent by the bulky tert-
butyldimethylsilyloxymethyl functionality at C-4′.
(11) ORTEP diagram(s) are given in the Supporting Information.
(12) Roy, B. G.; Roy, A.; Achari, B.; Mandal, S. B. Tetrahedron Lett. 2006,
47, 7783–7787.
(13) Vorbru¨ggen, H.; Krolikiewicz, K.; Bennua, B. Chem. Ber. 1981, 114,
1234–1255.
4306 J. Org. Chem. Vol. 73, No. 11, 2008

SCHEME 5. Nucleosidation on Spirocycles 18 and 19
SCHEME 7. Nucleosidation of Spirocycle 22
through nucleophilic attack by the alkoxide ion on the mesyl
bearing carbon. As anticipated, 33 delivered 34 in 95% yield
upon prolonged exposure to deacetylation reaction condition.
The structures of the nucleosides were determined by spectral
analyses.
Synthesis of Spironucleoside 37. Removal of the 1,2-
acetonide (Scheme 7) from the spiroannulated sulfur heterocycle
22 followed by peracetylation (furnishing 35) and nucleosidation
by Vorbru¨ggen methodology produced the nucleoside derivative
36 in 48% yield. This could be deacetylated to furnish 37 (97%).
The presence of the four structural unitssuracil ring, tetrahy-
drothiophene moiety, benzyl group, and furanose function-
SCHEME 6. Conversion of 21 to Bi-/Tricyclic Nucleosides
1
alityswas confirmed by the examination of H and 13C NMR
spectral data.
In conclusion, utilizing a 4-formyl group of an appropriate
precursor to insert a (1- or 2-) hydroxyethyl group through the
intermediacy of a vinyl group permitted nucleophilic insertion
of heteroatoms in the carbohydrate framework of D-glucose-
derived substrates, allowing access to new classes of spiro-
nucleosides. An unexpected bicyclic (furano-furan derivative)
compound was also encountered. This was eventually trans-
formed to a bicyclic nucleoside and, surprisingly, to a confor-
mationally locked tricyclic nucleoside. The strategy for the
precursor assembly for the targeted reactions is simple and
attractive.
in excellent yields (Scheme 5). Exposure of 27 to transfer
hydrogenolysis with cyclohexene and Pd/C in pure EtOH
yielded the N-ethyl derivative 29 rather than the expected
secondary amine. Incorporation of ethyl moiety could be
rationalized from the Pd-catalyzed oxidation of EtOH to
acetaldehyde,14,15 which was reductively trapped by the free
amine to produce 29. However, the same reaction with the sulfur
compound 28 failed to yield the desired product, possibly due
to poisoning of the catalyst. On the other hand, the failure of
the oxetane spirocycle 16 to afford any isolable nucleoside is
attributed to the vulnerability of the oxetane ring under
Vorbru¨ggen reaction conditions.
Synthesis of Bicyclic Nucleosides 32 and 33, and of the
Tricyclic Nucleoside 34. Toward this objective, 21 was
subjected to acetonide removal followed by peracetylation to
furnish a mixture of anomeric acetates 31, which was routinely
elaborated to the corresponding nucleoside 32 in 46% yield
(Scheme 6). Deacetylation of 32 with K2CO3 in MeOH produced
the expected nucleoside 33 in only 25% yield. The major product
was identified as the tricyclic nucleoside 34 (55%), formed
Experimental Section
3-O-Benzyl-1,2-O-isopropylidene-5-O-tert-butyldimethylsily-
loxymethyl-4-vinyl-ꢀ-L-arabinofuranose (10). To a solution of
oxalyl chloride (2.24 mL, 25.96 mmol) in dry CH2Cl2 (20 mL)
cooled to -65 °C was added a solution of dry DMSO (4.02 mL,
2.46 mmol) in CH2Cl2 (15 mL) dropwise under N2 and the mixture
was stirred for 15 min. A solution of 8 (10.0 g, 23.60 mmol) in
CH2Cl2 (40 mL) was added to the above mixture during 1 h and
the stirring was continued for another 1 h. Et3N (20 mL) was added
to it and the reaction was allowed to reach room temperature. After
quenching the reaction by the addition of water (10 mL), the mixture
was extracted with CH2Cl2 (3 × 30 mL). The combined extract
was washed with water (2 × 30 mL) and dried (Na2SO4); the
solvent was evaporated in vacuo to furnish the crude aldehyde 9.
This was dried under vacuum (P2O5) and subsequently used without
further purification. To a solution of methyltriphenylphosphonium
bromide (14.32 g, 40.13 mmol) and potassium tert-butoxide (3.91
g, 32.08 mmol) in dry THF (80 mL) at 0 °C under N2 was added
a solution of the aldehyde in THF (10 mL) dropwise during 45
min. The mixture was stirred for 2 h at 0 °C and another 2 h at
room temperature. The reaction was quenched by the addition of
saturated aqueous NH4Cl solution (20 mL). The solvent was
evaporated in vacuo and the residue was extracted with CHCl3 (3
× 40 mL). The CHCl3 solution was washed with H2O (2 × 40
(14) (a) Fu, X.; Cook, J. M. J. Am. Chem. Soc. 1992, 114, 6910–6912. (b)
Bailey, P. D.; Beard, M. A.; Dang, H. P. T.; Phillips, T. R.; Price, R. A.;
Whittaker, J. H. Tetrahedron Lett. 2008, 49, 2150–2153.
(15) The use of 2,2,2-trifluoroethanol as the solvent for debenzylation14b of
27 unexpectedly removed the uracil moiety along with removal of benzyl groups.
J. Org. Chem. Vol. 73, No. 11, 2008 4307

mL), dried (Na2SO4), and evaporated to a crude product, which
was purified by column chromatography on silica gel (60-120
mesh) by using ethyl acetate-petroleum ether (2:23) as eluent to
afford 10 (4.854 g, 45%) as a colorless liquid. [R]D25 +15.9 (c 0.1,
CHCl3); 1H NMR (CDCl3, 300 MHz) δ 0.04 (s, 6H), 0.88 (s, 9H),
1.40 (s, 3H), 1.61 (s, 3H), 3.55 (d, 1H, J ) 10.4 Hz), 3.67 (d, 1H,
J ) 10.4 Hz), 4.35 (d, 1H, J ) 2.1 Hz), 4.59 (d, 1H, J ) 11.8 Hz),
4.66 (dd, 1H, J ) 2.4, 4.3 Hz), 4.73 (d, 1H, J ) 11.8 Hz), 5.24
(dd, 1H, J ) 1.5, 10.9 Hz), 5.50 (dd, 1H, J ) 1.7, 17.4 Hz), 5.90
(d, 1H, J ) 4.6 Hz), 6.08 (dd, 1H, J ) 10.9, 17.4 Hz), 7.30-7.37
(m, 5H); 13C NMR (CDCl3, 75 MHz) δ -5.6 (CH3), -5.4 (CH3),
18.3 (C), 25.8 (3 × CH3), 27.1 (CH3), 27.6 (CH3), 65.7 (CH2),
72.2 (CH2), 83.5 (CH), 86.5 (CH), 88.3 (C), 103.6 (CH), 113.2
(C), 115.4 (CH2), 127.6 (2 × CH), 127.7 (CH), 128.3 (2 × CH),
135.1 (CH), 137.6 (C); ESIMS, m/z 443 (M + Na)+. Anal. Calcd
for C23H36O5Si: C, 65.68; H, 8.63. Found: C, 65.45; H, 8.48.
3-O-Benzyl-1,2-O-isopropylidene-5-O-mesyl-4-(2-chloroethyl)-
ꢀ-L-arabinofuranose (20) and 3,6-Anhydro-5-deoxy-1,2-O-iso-
propylidene-4-mesyloxymethyl-ꢀ-L-idofuranose (21). Mesyl chlo-
ride (1.86 mL, 23.91 mmol) was added to a solution of 14 (900
mg, 2.78 mmol) in pyridine (25 mL) at 0 °C; the mixture was stirred
at 0 °C for 30 min and then at room temperature for 20 h. The
solvent was evaporated in vacuo and the crude residue was extracted
with CHCl3 (3 × 30 mL). The combined extract was washed with
water (2 × 30 mL), dried (Na2SO4), and concentrated in vacuo.
The crude product was purified by silica gel column chromatog-
raphy by using ethyl acetate-petroleum ether (1:10) to afford 20
(399 mg, 34%) as a colorless liquid, while the same solvents in
the ratio 3:22 eluted 21 (417 mg, 51%) as a white solid.
Hz), 4.72 (d, 1H, J ) 11.6 Hz), 5.91 (d, 1H, J ) 4.1 Hz), 7.35-7.38
(m, 5H); 13C NMR (CDCl3, 75 MHz) δ 25.7 (CH3), 26.3 (CH3),
34.7 (CH2), 37.7 (CH3), 39.5 (CH2), 69.5 (CH2), 72.3 (CH2), 83.4
(CH), 84.3 (CH), 87.4 (C), 105.1 (CH), 112.6 (C), 127.8 (2 × CH),
128.2 (CH), 128.6 (2 × CH), 136.6 (C); ESIMS, m/z 443 [(M +
Na)+ for Cl35] and 445 [(M + Na)+ for Cl37]. Anal. Calcd for
C18H25O7SCl: C, 51.36; H, 5.99. Found: C, 51.09; H, 5.72.
25
21: mp 92-93 °C; [R]D -6.8 (c 0.27, CHCl3); 1H NMR
(CDCl3, 300 MHz) δ 1.30 (s, 3H), 1.58 (s, 3H), 2.04-2.25 (m,
2H), 3.13 (s, 3H), 3.81-3.89 (m, 1H), 3.96-4.03 (m, 1H), 4.29
(s, 1H), 4.33 (d, H, J ) 11.0 Hz), 4.64-4.67 (m, 2H), 5.93 (d, 1H,
J ) 3.6 Hz); 13C NMR (CDCl3, 75 MHz) δ 25.4 (CH3), 26.2 (CH3),
36.5 (CH2), 37.8 (CH3), 68.1 (CH2), 71.1 (CH2), 84.5 (CH), 85.5
(CH), 94.2 (C), 106.8 (CH), 112.1 (C); ESIMS, m/z 317 (M +
Na)+. Anal. Calcd for C11H18O7S: C, 44.89; H, 6.16. Found: C,
44.62; H, 6.03.
Acknowledgment. The authors thank CSIR, Government of
India for providing Senior Research Fellowships (to J.K.M. and
R.G.) and an Emeritus Scientist scheme (to B.A.). Partial
financial support from the CSIR Network Project is gratefully
acknowledged. We also thank EPSRC and the University of
Reading for funds for the Image Plate System.
Supporting Information Available: Characteristic spectral
analyses of compounds; mechanism for the formation of 20 and
21; ORTEP diagrams, and CIF files for 19 and 21; general and
1
experimental details; copies of H and 13C NMR spectra of 8,
20: [R]D25 -35.6 (c 0.23, CHCl3); 1H NMR (CDCl3, 300 MHz)
δ 1.33 (s, 3H), 1.58 (s, 3H), 2.21-2.35 (m, 2H), 3.01 (s, 3H),
3.53-3.71 (m, 2H), 3.93 (s, 1H), 4.25 (d, 1H, J ) 10.6 Hz), 4.31(d,
1H, J ) 10.6 Hz), 4.53 (d, 1H, J ) 11.6 Hz), 4.68 (d, 1H, J ) 4.1
10-14, 16-22, 25-29, 32-34, 36, and 37. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO8002826
4308 J. Org. Chem. Vol. 73, No. 11, 2008