Synthesis of oxepane ring containing monocyclic, conformationally restricted bicyclic and spirocyclic nucleosides from D-glucose: A cycloaddition approach

Article abstract of DOI:10.1021/jo070846m

(Chemical Equation Presented) Carbohydrate-derived substrates having (i) C-5 nitrone and C-3-O-allyl, (ii) C-4 vinyl and a C-3-O-tethered nitrone, and (iii) C-5 nitrone and C-4-allyloxymethyl generated tetracyclic isoxazolidinooxepane/-pyran ring systems upon intramolecular nitrone cycloaddition reactions. Deprotection of the 1,2-acetonides of these derivatives followed by introduction of uracil base via Vorbrueggen reaction condition and cleavage of the isooxazolidine rings as well as of benzyl groups by transfer hydrogenolysis yielded an oxepane ring containing bicyclic and spirocyclic nucleosides. The corresponding oxepane based nucleoside analogues were prepared by cleavage of isoxazolidine and furanose rings, coupling of the generated amino functionalities with 5-amino-4,6-dichloropyrimidine, cyclization to purine rings, and finally aminolysis.

Full text of DOI:10.1021/jo070846m

to become more selective and less toxic potential therapeutic
agents3 for cancer and deadly viral diseases. Recent years have
therefore seen a surge in interest in the synthesis of unnatural
nucleoside analogues having conformational restrictions in the
pentofuranose moiety.4,5
Synthesis of Oxepane Ring Containing
Monocyclic, Conformationally Restricted Bicyclic
and Spirocyclic Nucleosides from D-Glucose: A
Cycloaddition Approach
To impart some degree of conformational restriction to the
natural nucleosides, several possibilities have been suggested.
These include (i) synthesis of locked bicyclic nucleoside
analogues by inserting an extra ring fused to the furanose moiety,
(ii) synthesis of spironucleosides,6-10 and (iii) synthesis of
nucleosides of varied ring structures.11 Some examples of
conformationally constrained synthetic bicyclic and spirocyclic
nucleosides are shown in structures 1-9. We have therefore
Subhankar Tripathi,†,§ Biswajit G. Roy,†,§
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
ReceiVed April 23, 2007
taken up a scheme to synthesize new classes of bicyclic
nucleosides and C-4′ spiroannulated nucleosides. The present
Note deals with the application of 1,3-dipolar nitrone cycload-
dition reactions (INC) toward this goal, which also delivered,
with suitable modification of the scheme, newer nucleosides
based on oxepanes.
An interesting and flexible strategy12 suitable for the con-
struction of oxepane-fused furano sugars involves an INC
reaction between C-5 nitrone and C-3 olefin (C-3-O-allyl) of
D-glucose derived substrates (Scheme 1, Path I). We rationalized
that cyclization involving a C-4 vinyl and a C-3 tethered nitrone
Carbohydrate-derived substrates having (i) C-5 nitrone and
C-3-O-allyl, (ii) C-4 vinyl and a C-3-O-tethered nitrone, and
(iii) C-5 nitrone and C-4-allyloxymethyl generated tetracyclic
isoxazolidinooxepane/-pyran ring systems upon intramolecu-
lar nitrone cycloaddition reactions. Deprotection of the 1,2-
acetonides of these derivatives followed by introduction of
uracil base via Vorbru¨ggen reaction condition and cleavage
of the isooxazolidine rings as well as of benzyl groups by
transfer hydrogenolysis yielded an oxepane ring containing
bicyclic and spirocyclic nucleosides. The corresponding
oxepane based nucleoside analogues were prepared by
cleavage of isoxazolidine and furanose rings, coupling of
the generated amino functionalities with 5-amino-4,6-dichlo-
ropyrimidine, cyclization to purine rings, and finally ami-
nolysis.
(3) (a) Shin, K. J.; Moon, H. R.; Georgen, C.; Marquez, V. E. J. Org.
Chem. 2000, 65, 2172-2178. (b) Russ, P.; Schelling, P.; Scapozza, L.;
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5054.
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Singh, S. K.; Wengel, J. J. Am. Chem. Soc. 1998, 120, 13252-13253. (b)
Rajwanshi, V. K.; Håkansson, A. E.; Sørensen, M. D.; Pitsch, S.; Singh, S.
K.; Kumar, R.; Nielsen, P.; Wengel, J. Angew. Chem., Int. Ed. 2000, 39,
1656-1659. (c) Kværnø, L.; Wrightman, R. H.; Wengel, J. J. Org. Chem.
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(6) 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.
(7) Ravindra Babu, B.; Keinicke, L.; Petersen, M.; Nielsen, C.; Wengel,
J. Org. Biomol. Chem. 2003, 1, 3514-3526.
The natural nucleosides experience rapid flipping between
the two preferential conformations of the ribose ring,1,2 viz. the
C-3′-endo (N-type) and the C-2′-endo (S-type), due to the low-
energy barriers. If this conformational flipping is stopped or
restricted to some extent, the nucleoside analogues are expected
(8) Nielsen, P.; Larsen, K.; Wengel, J. Acta Chem. Scand. 1996, 50,
1030-1035.
(9) (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.
(10) (a) Roy, A.; Achari, B.; Mandal, S. B. Tetrahedron Lett. 2006, 47,
3875-3879. (b) Sahabuddin, Sk.; Roy, A.; Drew, M, G. B.; Roy, B. G.;
Achari, B.; Mandal, S. B. J. Org. Chem. 2006, 71, 5980-5992.
(11) Mandal, S. B.; Sahabuddin, Sk.; Singha, K.; Roy, A.; Roy, B. G.;
Maity, J. K.; Achari, B. Proc. Indian Natl. Sci. Acad., Part A 2005, 71,
283-307.
* Address correspondence to this author. Fax: +91 (33) 24735197.
† Indian Institute of Chemical Biology.
§ These authors contributed equally to this paper.
‡ University of Reading.
(1) Saenger, W. Principles of Nucleic Acid Structures; Springer: New
York, 1984; pp 51-104
(2) Altona, C.; Sunderalingam, M. J. Am. Chem. Soc. 1972, 94, 8205-
8212.
(12) Bhattacharjee, A.; Dutta, S.; Chattopadhyay, P.; Ghoshal, N.; Kundu,
A. P.; Pal, A.; Mukhopadhyay, R.; Chowdhury, S.; Bhattacharjya, A.; Patra,
A. Tetrahedron 2003, 59, 4623-4639.
10.1021/jo070846m CCC: $37.00 © 2007 American Chemical Society
Published on Web 08/23/2007
J. Org. Chem. 2007, 72, 7427-7430
7427

SCHEME 1. Methods for the Construction of Oxepane/
Pyran Fused Nucleoside Analogues
SCHEME 3. Synthesis of Oxepanyl Nucleosides 19-22, 26,
and 27
SCHEME 2. Conversion of Tetracyclic Oxepano
Derivatives 10 and 11 to the Bicyclic Nucleosides
SCHEME 4. Synthesis of Tetracyclic Oxepane Derivative
31
(generated from a C-3-O-formylmethyl derivative) could con-
stitute (Path II) an additional strategy to produce oxepanes/
pyrans of different substitution patterns upon INC reaction. On
the other hand, the same reaction performed on substrates having
nitrone functionality at C-5 and olefin at C-4 (e.g., C-
allyloxymethyl) would be expected (Path III) to generate a
spirocyclic ring structure depending on the mode of cyclization.
The products may then be used to synthesize the projected
classes of nucleosides through established routes.
Bicyclic Nucleosides 14 and 15 (Path I). INC reactions of
3-O-allyl-6-nor furanose aldehydes have been reported by
Bhattacharjya and his group12 to culminate in bridged ox-
epanoisoxazolidines (10 and 11) in both the glucose and allose
derived substrates. Deprotection of the 1,2-acetonide moiety
(Scheme 2) of the products with dilute sulfuric acid followed
by peracetylation with acetic anhydride-pyridine and subse-
quent nucleosidation under Vorbru¨ggen condition13 with uracil
base furnished 12 (52%) and 13 (48%), respectively. Cleavage
of the isoxazolidine rings by transfer hydrogenolysis afforded
the corresponding aminoalcohols, purified as acetates.
The structure and stereochemistry of 10 has been conclusively
settled by X-ray crystal structural determination.14 Spectroscopic
analyses (1H, 13C NMR, MS) of 12-15 helped deduce their
structures.
transfer hydrogenolysis. The aminoxepane was coupled with
5-amino-4,6-dichloropyrimidine to produce the aminopyrim-
idinyl oxepane 18 (51%). Transformation of the pyrimidine ring
to the purine ring by reaction with triethyl orthoformate
generated a mixture of purine nucleosides 19-21 (56%). Our
earlier observations in related systems suggested that use of
higher temperatures may be the cause for the undesirable
transformation to the dimethylaminopurine nucleoside 19, while
the minor methoxypurine nucleoside 20 is generated during
purification of nucleosides by reversed-phase HPLC with use
of H2O-MeOH. Repeating the reaction at lower temperature,
to our gratification, gave the chloropurine 21 as the sole product
in 60% yield. Substitution of the chloro group of the adenine
ring by an amino group furnished 22 (72%). On the other hand,
the isoxazolidinooxepane 2312 could be similarly converted (via
24 and 25) to 26 and 27 in good yields. The enantiomeric
nucleoside pairs 21/26 and 22/27 exhibited optical rotations
virtually identical in magnitude but opposite in sign. All the
nucleosides exhibited 1H NMR and mass spectra fully in
conformity with the structures.
Cyclization Involving C-3-O-Tethered Nitrone and C-4
Vinyl (Path II). Selective removal of the 5,6-O-isopropylidene
protection of 2815 by dilute acetic acid treatment (Scheme 4)
followed by mesylation of the hydroxy groups set up the
substrate for successive steps of iodination and deiodination,
affording the olefinic ester 29. Reduction of the carbomethoxy
group with NaBH4-tBuOH-MeOH reagent to furnish 30
Oxepanyl Nucleosides 19-22, 26, and 27 (Path I). Isoxazo-
lidinooxepane 16, derived from 10 following the reported
procedure,12 yielded (Scheme 3) the aminoalcohol 17 upon
(13) Vorbru¨ggen, H.; Krolikiewicz, K.; Bennua, B. Chem. Ber. 1981,
114, 1234-1255.
(14) ORTEP diagrams are given in the Supporting Information.
(15) Tripathi, S.; Maity, J. K.; Achari, B.; Mandal, S. B. Carbohydr.
Res. 2005, 360, 1081-1087.
7428 J. Org. Chem., Vol. 72, No. 19, 2007

SCHEME 5. Synthesis of Tetracyclic Pyran Derivative 35
SCHEME 7. Synthesis of Spirocyclic Nucleoside 45 from
the Precursor 39
SCHEME 6. Conversion of 31 to Bicyclic Oxepanyl
Nucleoside 37
crystal X-ray analysis.14 This information clinched the structures
of 44 and 45 with the help of NMR analyses.
In conclusion, this study describes both linear and convergent
approaches in which conformationally constrained oxepane-
fused bicyclic and C-4′ oxepane-spiroannulated nucleosides can
be synthesized from D-glucose derived substrates through the
application of INC reactions followed by nucleosidation. The
results may be extended to other systems utilizing different
substitution patterns judiciously derived from carbohydrates.
followed by Swern oxidation furnished an aldehyde, which
without purification was subjected to nitrone formation-
cyclization by treatment with N-benzylhydroxylamine, affording
the tetracyclic oxepane 31.
Experimental Section
Retracing the above reaction route beginning with 3215 (C-3
epimer of 28) furnished (Scheme 5) the tetracyclic pyran
derivative 35 (19% overall yield) via 33 and 34.
(1S,2R,4R,5R,6S,9R)- 5-Acetoxy-11-benzyl-4-(2,4-dioxo-3,4-
dihydro-2H-pyrimidin-1-yl)-3,7,10-trioxa-11-azatricyclo[7.2.1.02,6]-
dodecane (12). A solution of 10 (1.20 g, 3.60 mmol) in a CH3CN-
H2O-H2SO4 mixture (18:6:1, 25 mL) was stirred at room temperature
for 20 h. Solid CaCO3 was added portionwise to neutralize the acidic
solution and the precipitate was filtered off. The solvent was
evaporated to a gummy mass, which was acetylated at room
temperature by using pyridine (3 mL) and Ac2O (1 mL) to furnish
the anomeric mixture of diacetates. A mixture of uracil (345 mg),
hexamethyldisilazane (10 mL), and freshly distilled TMSCl (2-3
drops) was heated at reflux under N2 for 12 h. Excess solvent was
distilled off; a solution of the residue in DCE (5 mL) was added to
a stirred DCE solution (25 mL) of the above diacetates containing
TMS-OTf (0.4 mL) and the stirring was continued for 5 h. The
reaction mixture was neutralized by solid NaHCO3 and H2O (2-3
drops). The solvent was evaporated and the residue was extracted
with 2% MeOH in CHCl3 (3 × 20 mL). The solvent was washed
with brine (20 mL), dried (Na2SO4), and concentrated to a mass,
which was purified over a silica gel (60-120 mesh) column with
3% MeOH in CHCl3 as eluent to furnish 12 (224 mg, 48%) as a
foam: [R]20D -84.0 (c 0.61, CHCl3). 1H NMR (300 MHz, CDCl3)
δ 2.10 (s, 3H), 2.41-2.50 (m, 1H), 2.56 (d, 1H, J ) 12.7 Hz),
3.70 (d, 1H, J ) 12.9 Hz), 3.74-3.81 (m, 3H), 3.92 (br s, 1H),
4.07 (d, 1H, J ) 1.5 Hz), 4.10 (d, 1H, J ) 12.7 Hz), 4.68 (br d,
1H, J ) 8.1 Hz), 4.93 (d, 1H, J ) 1.6 Hz) 5.75 (dd, 1H, J ) 1.8,
8.1 Hz), 5.99 (d, 1H, J ) 1.6 Hz), 7.34 (m, 5H), 7.72 (d, 1H, J )
8.1 Hz), 8.83 (br d, 1H). 13C NMR (75 MHz, CDCl3) δ 21.0 (CH3),
27.9 (CH2), 62.4 (CH), 62.6 (CH2), 73.4 (CH2), 78.6 (CH), 81.5
(CH), 81.7 (CH), 82.3 (CH), 87.6 (CH), 103.8 (CH), 128.3 (CH),
129.0 (2 × CH), 129.5 (2 × CH), 136.8 (C), 141.2 (CH), 150.5
(C), 163.1 (C), 169.7 (C). FABMS, m/z 430 (MH)+. Anal. Calcd
for C21H23N3O7: C, 58.74; H, 5.40; N, 9.79. Found: C, 58.54; H,
5.23; N, 9.55.
The structures of 29-35 were deduced with NMR and mass
spectral analysis. The stereochemistry of the newly generated
ring juncture in 31 and 35 was, however, determined from the
NOESY correlation of the energy-minimized structures (Figures
1-4 in the Supporting Information).
With the full structure of 31 and 35 thus established,
introduction of uracil on the anomeric center of 31 was carried
out by the Vorbru¨ggen procedure13 (Scheme 6) to afford 36,
which was converted to the nucleoside 37 by adopting the earlier
described procedure. However, an attempt to install a nucleoside
base on 35 was unsuccessful. This may be due to the trans ring
juncture of the pyranofuranose ring, which upon deprotection
generated a furanose moiety that preferred to remain in the open
chain form. Therefore a complex mixture of acetates resulted
instead of 38.
Synthesis of Spirocyclic Nucleosides (Path III). Toward this
goal, we chose to utilize 39.16 Selective TBDMS protection by
using slightly less than 1 equiv of TBDMSCl (Scheme 7)
afforded the monosilyl ether 40 as the major product. Allylation
of the free hydroxy group of 40 to 41 and subsequent
desilylation produced the desired monoallyl ether 42. Swern’s
oxidation of the free primary hydroxyl group proved to be the
most satisfactory in regard to the yield of the aldehyde, which
without any purification was treated with N-benzylhydroxy-
lamine to precipitate a dipolar cycloaddition reaction. The
product on careful purification delivered the oxepanospirocycle
43 in 54% yield. Lewis acid-catalyzed nucleoside base coupling
then led to isoxazolidinospironucleoside 44 (63%). Finally, the
isooxazolidine ring was cleaved and the product was acetylated
to the fully protected C-4′ spironucleoside 45.
(2R,3R,4S,6R)-4-(6-Chloro-9H-purin-9-yl)-2-hydroxymethyl-
oxepane-3,6-diol (21). To a solution of 18 (350 mg, 1.15 mmol)
in DMF (10 mL) were added HC(OEt)3 (8 mL) and p-TSA (60
mg), and the mixture was stirred at 10 °C for 24 h under N2. The
solvent was evaporated in vacuo; the gummy residue was dissolved
in MeOH and neutralized by stirring with Dowex-1 OH- resin for
1 h at room temperature. The resin was filtered off and the solvent
The structure of 43 was deduced originally from 1H, 13C NMR
and mass spectroscopic evidence and finally settled by single-
(16) Youssefyeh, R. D.; Verheyden, J. P. H.; Moffatt, J. G. J. Org. Chem.
1979, 44, 1301-1309.
J. Org. Chem, Vol. 72, No. 19, 2007 7429

was evaporated to give a crude foamy material. Purification by
15 mL). The CHCl3 solution was washed with saturated brine
solution (3 × 10 mL), dried (Na2SO4), and concentrated to furnish
a gum, which was purified by silica gel column chromatography
with ethyl acetate-petroleum ether (1:4) as eluent to afford 31 (440
mg, 43%): [R]26D -7.7 (c 0.7, CHCl3). 1H NMR (500 MHz, CDCl3)
δ 1.30 (s, 3H), 1.48 (s, 3H), 2.19-2.23 (m, 1H), 2.64 (d, 1H, J )
12.2 Hz), 3.39 (t-like, 1H, J ) 6.7, 7.2 Hz), 3.48 (d, 1H, J ) 12.6
Hz), 3.78 (dd, 1H, J ) 6.0, 12.6 Hz), 3.80 (d, 1H, J ) 12.6 Hz),
4.09 (br s, 1H), 4.12-4.13 (m, 1H, partially merged), 4.14 (d, 1H,
J ) 12.9 Hz), 4.43 (d, 1H, J ) 3.6 Hz), 4.72 (dd, 1H, J ) 4.2, 7.5
Hz), 5.89 (d, 1H, J ) 3.6 Hz), 7.27-7.39 (m, 5H). 13C NMR (75
MHz, CDCl3) δ 26.6 (CH3), 27.1 (CH3), 28.9 (CH2), 63.9 (CH),
64.1(CH2), 74.6 (CH2), 76.9 (CH), 78.6 (CH), 83.6 (CH), 84.8 (CH),
105.1 (CH), 112.2 (C), 127.9 (CH), 128.9 (2 × CH), 129.6 (2 ×
CH), 137.5 (C). ESIMS, m/z 334 (MH)+, 356 (MNa)+. Anal. Calcd
for C18H23NO5: C, 64.85; H, 6.95; N, 4.20. Found: C, 64.55; H,
7.02; N 4.10.
reverse phase (LiChroprep RP-18, particle size 25-40 µm) flash
chromatography with H2O as the eluent furnished 21 (216 mg, 60%)
1
as a foamy solid: [R]26 +14.5 (c 0.32, MeOH). H NMR (D2O,
D
300 MHz) δ 2.16 (br d, 1H, J ) 13.5 Hz), 2.69 (dd, 1H, J ) 12.0
Hz), 3.28 (t, 1H, J ) 11.5 Hz), 3.62 (d, 2H, J ) 5.5 Hz), 3.97-
4.10 (m, 2H), 4.26 (dd, 1H, J ) 5.7, 12.0 Hz), 4.35 (dd, 1H, J )
3.4, 8.5 Hz), 4.69 (1H, overlapped by HOD proton signal), 8.51
(s, 1H), 8.60 (s, 1H). 13C NMR (D2O, 75 MHz) δ 37.7 (CH2), 59.4
(CH), 62.2 (CH2), 68.8 (CH), 74.3 (CH), 77.6 (CH2), 84.9 (CH),
131.5 (C), 147.5 (CH), 150.4 (C), 151.6 (C), 151.8 (CH). ESIMS,
m/z 315 (MH+, for Cl35) 317 (MH+, for Cl37). Anal. Calcd for
C12H15ClN4O4: C, 45.80; H, 4.80; N, 17.80. Found: C, 45.62; H,
4.66; N, 17.53.
(3aR,3bS,6R,9S,9aS,10aR)-7-Benzyl-2,2-dimethylperhydro-
6,9-methano-1,3-dioxolo[4′,5′:4,5]furo[2,3-d][1,5,2]dioxazocine
(31). Oxalyl chloride (0.3 mL, 3.14 mmol) was added to dry CH2-
Cl2 (5 mL) in a two-necked round-bottom flask under N2 and the
mixture was cooled to -65 °C. To this was added a solution of
dry DMSO (0.48 mL) in dry CH2Cl2 (3 mL) dropwise and the
mixture was stirred for 10 min. A solution of 30 (700 mg, 3.04
mmol) in CH2Cl2 (7 mL) was then added to the above solution,
which was then stirred for 1 h. The mixture was allowed to stir for
15 min, Et3N (1 mL) was added to it, and the solution was allowed
to reach room temperature. The reaction was quenched by addition
of H2O (1 mL) and extracted with CHCl3 (2 × 15 mL). The
combined extract was washed with H2O (2 × 10 mL) to remove
DMSO, dried (Na2SO4), and concentrated to a crude aldehyde (500
mg), which was used in the next step without purification. BnNHOH
(568 mg, 1.5 equiv) was added to the above aldehyde dissolved in
dry EtOH (20 mL), and the mixture was stirred at room temperature
for 24 h and then heated at reflux for 2 h. The solvent was
evaporated and the gummy mass was extracted with CHCl3 (3 ×
Acknowledgment. The authors acknowledge the CSIR for
providing Research Fellowships (to S.T. and B.G.R.) and an
Emeritus Scientist scheme (to B.A.). We thank EPSRC and the
University of Reading for funds for the Oxford Diffrraction
X-Calibur CCD System.
Supporting Information Available: Stereochemical discussion
of 31 and 35, general and detailed experimental procedures, ORTEP
diagrams, and CIF files for 10 and 43, experimental details for X-ray
data, and 1H and 13C NMR spectra (copies) of all new compounds,
except 18 (1H NMR only). This material is available free of charge
via the Internet at http://pubs.acs.org.
JO070846M
7430 J. Org. Chem., Vol. 72, No. 19, 2007