Intramolecular nitrone cycloaddition reaction on carbohydrate-based precursors: Application in the synthesis of spironucleosides and spirobisnucleosides

Article abstract of DOI:10.1021/jo035813v

A simple synthesis of chiral spironucleosides and spirobisnucleosides is described. Intramolecular 1,3-dipolar nitrone cycloaddition reaction of D-glucose-derived precursors having olefin at C-3 and nitrone at C-5, C-1, or C-2 (in nor-series) furnished bi

Full text of DOI:10.1021/jo035813v

In tr a m olecu la r Nitr on e Cycloa d d ition
Rea ction on Ca r boh yd r a te-Ba sed
P r ecu r sor s: Ap p lica tion in th e Syn th esis of
Sp ir on u cleosid es a n d Sp ir obisn u cleosid es
Kaushik Singha, Atanu Roy, Pradeep K. Dutta,
Subhankar Tripathi, Sk. Sahabuddin,
Basudeb Achari, and Sukhendu B. Mandal*
F IGURE 1. A general scheme for the synthesis of spirocyclic
nucleosides.
Division of Medicinal Chemistry, Indian Institute of
Chemical Biology, J adavpur, Kolkata 700 032, India
et al.9 However, development of newer and versatile
synthetic routes to enantiomerically pure products with
structural variations, starting from the readily available
chiral pool constituted by sugars, remains a relevant
task.
We have recently demonstrated the applicability of
intramolecular nitrone cycloaddition (INC) reaction on
glucose-derived enose-nitrones for enantioselective as
well as enantiodirecting synthesis of carbocyclic nucleo-
sides of varying ring sizes.10 We reasoned that if a C-allyl
as well as an O-allyl group could be introduced at C-3 of
the glucose ring, consecutive INC reactions (Figure 1)
involving the olefins with a C-1 aldehyde and an aldehyde
generated at C-5 through simple functional group ma-
nipulations should lead to optically active and structur-
ally unique spirocyclic nucleosides. The present commu-
nication deals with the results derived from such studies.
Compound 1, generated10c from a D-glucose-derived
substrate through INC reaction of C-5 nitrone with C-3
allyl function, could be converted to the masked aldehyde
2, which in turn afforded the nor-aldehyde 3 via periodate
cleavage. INC reaction of 2 with BnNHOH afforded the
tetracyclic spirocycles 4 (43%) and 5 (27%), and similar
treatment of 3 furnished 6 (65%) and 7 (4%), presumably
through a nonisolable enose-nitrone (Scheme 1). The
gross structures of the products11 were evident from their
mass spectra, which showed an identical molecular ion
peak for 4 and 5 (at m/z 438) and for 6 and 7 (at m/z
408). Further, the stereochemistry for the A/B rings of
the spirocycles, as also for C-7 of 4 and 5, should be the
same as for the corresponding centers in 1. Only those
of the newly formed stereocenters (C/D ring juncture)
remained to be determined. The cis geometry assumed
sbmandal@iicb.res.in
Received December 13, 2003
Abstr a ct: A simple synthesis of chiral spironucleosides and
spirobisnucleosides is described. Intramolecular 1,3-dipolar
nitrone cycloaddition reaction of D-glucose-derived precur-
sors having olefin at C-3 and nitrone at C-5, C-1, or C-2 (in
nor-series) furnished bisisoxazolidinospirocycles 4-7, 11,
and 12 in good yields. Reductive ring opening of the
isoxazolidine moieties in 4-6 followed by construction of a
nucleoside base upon the generated amino groups smoothly
yielded spirobisnucleosides 17 and 18 and spironucleosides
20 and 21.
Synthesis of enantiomerically pure carbocyclic amino
alcohols en route to carbocyclic nucleosides,1-4 many of
which are of interest in search of therapeutic agents for
dreaded diseases such as HIV, HSV, and cancer, remains
a cherished goal of synthetic organic chemists. Since the
discovery of the nucleoside hydantocidin5 possessing a
spirocyclic ring at the anomeric center, the area of
synthetic spirocyclic nucleosides also started to develop.
Besides notable contributions from Miyasaka’s labora-
tory6 and others,7 the field has been enriched by publica-
tions of Paquette’s group8 on the synthesis of nucleosides
bearing a spiro ring juncture at the anomeric center, as
well as of other carbaspironucleosides. Syntheses of 5/5
and 6/5 spironucleosides with unusual heterocycles spiro-
fused to the ribose ring has also been reported by Gasch
(1) (a) Borthwick, A. D.; Biggadike, K. Tetrahedron 1992, 48, 571.
(b) Agrofoglio, L.; Suhas, E.; Farese, A.; Condom, R.; Challand, S. R.;
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T. Tetrahedron 1998, 54, 9229. (d) Huryn, D.; Okabe, M. Chem. Rev.
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(2) (a) Borthwick, A. D.; Crame, A. J .; Exall A. M.; Weingarten, G.
G.; Mahmoudian, M. Tetrahedron Lett. 1995, 36, 6929. (b) Yoshida,
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64, 2240. (d) Crimmins, M. T.; King, B. W.; Zuercher, W. J .; Choy, A.
L. J . Org. Chem. 2000, 65, 8499. (e) Kuang, R.; Ganguly, A. K.; Chan,
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Tetrahedron Lett. 2000, 41, 9575. (f) Comin, M. J .; Rodriguez, J . B.
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(3) (a) Gillaizeau, I.; Charamon, S.; Agrofoglio, L. A. Tetrahedron
Lett. 2001, 42, 8817. (b) Ono, M.; Nishimura, K.; Tsubouchi, H.;
Nagaoka Y.; Tomioka, K. J . Org. Chem. 2001, 66, 8199. (c) Choo, H.;
Chong, Y.; Chu, C. K. Org. Lett. 2001, 3, 1471. (d) Santana, L.; Teijeira,
M.; Teran, C.; Uriarte, E.; Vina, D. Synthesis 2001, 10, 1532. (e) Kitade,
Y.; Kozaki, A.; Yatome, C. Tetrahedron Lett. 2001, 42, 433. (f)
Rajappan, V. P.; Schneller, S. W. Tetrahedron 2001, 57, 9049.
(4) (a) Hong, J . H.; Shim, M. J .; Ro, B. O.; Ko, O. H. J . Org. Chem.
2002, 67, 6837. (b) Velcicky, J .; Lex, J .; Schmalz, H. G. Org. Lett. 2002,
4, 565. (c) Moon, H. R.; Kim, H. O.; Kee, K. M.; Chun, M. W.; Kim, J .
H.; J eong, L. S. Org. Lett. 2002, 4, 3501. (d) Kim, H. S.; J acobson, K.
A. Org. Lett. 2003, 5, 1665.
(6) (a) Kittaka, A.; Tanaka, H.; Odanaka, Y.; Ohnuki, K.; Yamaguchi,
K.; Miyasaka, T. J . Org. Chem. 1994, 59, 3636. (b) Kittaka, A.; Tanaka,
H.; Yamada, N.; Miyasaka, T. Tetrahedron Lett. 1996, 37, 2801. (c)
Kittaka, A.; Asakura, T.; Kuze, T.; Tanaka, H.; Yamada, N.; Nakamura,
K. T.; Miyasaka, T. J . Org. Chem. 1999, 64, 7081.
(7) Gimisis, T.; Chatgilialoglu, C. J . Org. Chem. 1996, 61, 1908.
(8) (a) Paquette, L. A.; Bibart, R. T.; Seekamp, C. K.; Kahane, A. L.
Org. Lett. 2001, 3, 4039. (b) Paquette, L. A.; Owen, D. R.; Bibart, R.
T.; Seekamp, C. K. Org. Lett. 2001, 3, 4043. (c) Paquette, L. A.;
Hartung, R. E.; France, D. J . Org. Lett. 2003, 5, 869.
(9) Gasch, C.; Pradera, M. A.; Salameh, B. A. B.; Molina, J . L.;
Fuentes, J . Tetrahedron: Asymmetry 2001, 12, 1267.
(10) (a) Roy, A.; Patra, R.; Achari, B.; Mandal, S. B. Synlett 1997,
1237. (b) Roy, A.; Chakrabarty, K.; Dutta, P. K.; Bar, N. C.; Basu, N.;
Achari, B.; Mandal, S. B. J . Org. Chem. 1999, 64, 2304. (c) Bar, N. C.;
Roy, A.; Achari, B.; Mandal, S. B. J . Org. Chem. 1997, 62, 8948. (d)
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Tetrahedron 1996, 52, 11265.
(11) The alternative bridged ring structures could be easily excluded
from NMR evidence (absence of upfield signals for the methylene
bridge).
(5) Haruama, H.; Takayama, T.; Kinoshita, T.; Kondo, M.; Nakajima,
M.; Haneishi, T. J . Chem. Soc., Perkin Trans. 1 1991, 1637.
10.1021/jo035813v CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/21/2004
J . Org. Chem. 2004, 69, 6507-6510
6507

SCHEME 1. Syn th esis of Bisisoxa zolid in osp ir ocycles 4-7 Usin g INC Rea ction a
a
Reagents and conditions: (a) 4% H2SO4, MeCN, H2O; (b) NaIO4, EtOH, H2O; (c) BnNHOH, EtOH, rt, 24 h, then 60 °C, 1 h.
1
in all of the cases was fully supported by extensive H
NMR spectral analyses (COSY, TOCSY, and NOESY
experiments) of the compounds or their derivatives as
discussed below.
and one of C-4′ H signals (δ 1.82), placing the three
protons on the same face of the molecule and in close
proximity in space. With 6 on the other hand, the C-6a
H signal (δ 4.02) showed no cross-peaks with signals
either of the C-4′ protons (δ 1.32 or δ 2.58) or of C-3′a H,
suggesting their segregation; instead the C-6′a H signal
(δ 2.34) showed a correlation with it, demonstrating their
proximity. The above evidences showed that the isoxazo-
lidine ring D in 6 was in the face opposite to that in 7.
As expected from the structures, C-6a H signal showed
correlation with C-3a H signal and C-6′a H signal with
C-3′a H signal, in both 6 and 7.
The 1H NMR spectra of 4 and 5, however, failed to
afford any conclusive evidence for the structures, as
signals for many of the protons overlapped with each
other. The compounds were, therefore, acetylated to
afford the derivatives 4a and 5a .12 The TOCSY spectrum
of 4a , in conjunction with the COSY spectrum, showed
the presence of two seven-proton spin systems: (a) δ 5.42
d (H-6′)-4.02 unresolved-3.72 unresolved-3.22 dd (H-
6′a)-3.08 m (H-3′a)-2.18 dd (H-4′R)-1.85 dd (partly
overlapped, H-4′â) and (b) δ 5.17 d (H-7)-4.09 t-3.89
unresolved-3.80 dd-3.71 unresolved-3.13 t (partly over-
lapped, H-7a)-2.92 m (H-3a). The former system having
the most upfield signal (δ 1.85) was assigned to the 5/5-
ring moiety, while the latter must belong to the 6/5-ring
moiety. Similarly, in the 1H NMR spectrum of 5a the two
spin systems consisted of signals at (i) δ 5.30 d (H-6′)-
4.08 t-3.69 unresolved-3.27 dd (H-6′a)-3.17 m (H-3′a)-
3.05 dd (H-4′R)-1.82 dd (H-4′â) and (ii) δ 5.20 d (H-7)-
4.00 unresolved-3.88 t-3.67 unresolved-3.59 dd-3.44
dd (H-7a)-2.90 m (H-3a). In the NOESY spectrum of 4a ,
the signal for H-7 (δ 5.17) showed no cross-peak with the
signal for H-3a (δ 2.92), while the corresponding proton
signals of 5a (δ 5.20 for H-7 and δ 2.90 for H-3a) showed
distinct cross-peaks, clearly indicating trans relationship
of the protons in 4a and cis relationship in 5a .
With the structure and stereochemistry of 4-7 satis-
factorily established, we decided to test the applicability
of the strategy with the bridged-ring product 8 synthe-
sized10d earlier by INC reaction on a D-glucose-derived
product. The olefinic moiety was inserted by allylation
of the hydroxyl group of 8 to 9. Subsequent deprotection
of isopropylidene group and vicinal diol cleavage to the
1
aldehyde 10 (IR at 1730 cm-1, H NMR peak at δ 9.82)
and treatment with benzyl hydroxylamine spurred the
desired INC reaction (Scheme 2), furnishing the spiro-
cycles 11 (50%) and 12 (25%). Again, no product possess-
ing bridged-ring structure could be isolated. The FAB
mass spectra of both the products showed peaks at m/z
409 (MH+) and 431 (MNa+) for their pseudo molecular
ions, indicating their isomeric relationship.
The 1H NMR spectra of the compounds failed to provide
any light on the stereochemistry of C/D ring juncture.
They were thereafter subjected to transfer hydrogenolysis
followed by selective acetylation of the newly generated
amino functions to yield 13 and 14, respectively. To our
satisfaction, 1H NMR analysis of the diamide derivatives
provided the desired information on stereochemistry. The
C-10 Hb signal (δ 2.90) showed NOE with the C-4 NHAc
signal (δ 8.88) in 13 but with the C-4 H signal (δ 5.69)
instead in 14. Additionally, C-4 H (δ 5.74) of 13 showed
NOE with signals for C-9 H (δ 4.20) and C-7 H (δ 4.75),
establishing the stereochemistry of C/D ring juncture in
11 and 12 as indicated.
The 1H-1H COSY spectra of both 6 and 7 clearly
identified most of the signals, including those of all ring
juncture protons, except for a few overlapping signals.
In the NOESY spectrum of 7, the most informative
correlations were from C-6a H (δ 3.77) to C-3′a H (δ 2.71)
(12) 1H NMR (CDCl3, 500 MHz). 4a : δ 1.82 (s, 3 Η), 1.85 (dd, 1 H,
J ) 6.0, 14.0 Hz), 2.02 (s, 3 H), 2.18 (dd, 1 H, J ) 9.0, 14.0 Hz), 2.92
(m, 1 H), 3.08 (m, 1 H), 3.13 (t, 1H, J ) 6.2 Hz), 3.22 (dd, 1 H, J ) 3.0,
9.0 Hz), 3.71 and 3.72 (unresolved, 2 H), 3.80 (dd, 1 H, J ) 5.5, 12.6
Hz), 3.89 and 3.90 (unresolved, 2 H), 3.95 (d, 1 H, J ) 14.0 Hz), 4.00
and 4.02 (unresolved, 2 H), 4.09 (t, 1 H, J ) 7.7 Hz), 4.15 (d, 1 H, J )
14.0 Hz), 5.17 (d, 1 H, J ) 6.2 Hz), 5.42 (d, 1 H, J ) 3.0 Hz), 7.22-
7.36 (m, 10 H). 5a : δ 1.79 (s, 3 H), 1.82 (dd, 1 H, J ) 7.3, 13.4 Hz),
2.04 (s, 3 H), 2.90 (m, 1 H), 3.05 (dd, 1 H, J ) 9.0, 13.4 Hz), 3.17 (m,
1 H), 3.27 (dd, 1 H, J ) 5.0, 8.5 Hz), 3.44 (dd, 1 H, J ) 4.5, 7.0 Hz),
3.59 (dd, 1 H, J ) 4.2, 8.0 Hz), 3.67 and 3.69 (unresolved, 2 H), 3.83
(d, 1 H, J ) 13.6 Hz), 3.85 and 3.88 (unresolved, 2 H), 3.92 (d, 1 H, J
) 13.6 Hz), 3.98 and 4.00 (unresolved, 2 H), 4.08 (t, 1 H, J ) 8.0 Hz),
5.20 (d, 1 H, J ) 4.5 Hz), 5.30 (d, 1 H, J ) 5.0 Hz), 7.23-7.33 (m, 10
H).
6508 J . Org. Chem., Vol. 69, No. 19, 2004

SCHEME 2. Syn th esis of Bisisoxa zolid in osp ir ocycles 11 a n d 12 via INC Rea ction a
a
Reagents and conditions: (a) allyl Br, NaH, THF, reflux, 3 h; (b) 4% H2SO4, MeCN, H2O; (c) NaIO4, EtOH, H2O; (d) BnNHOH, EtOH,
rt, 20 h, then 60 °C, 1 h.
SCHEME 3. Con ver sion of Sp ir ocycles 4 a n d 5 to
Sp ir obisn u cleosid es 17 a n d 18a
Having established the structure and stereochemistry
of the spiro products, we next turned our attention to
construct the purine nucleoside bases. Thus, transfer
hydrogenolysis of 4 and 5 cleaved both of the isoxazoli-
dine rings13 to afford the respective trihydroxydiamino
spirocycles, which were directly coupled with 5-amino-
4,6-dichloropyrimidine (2.1 equiv) to obtain the bispyri-
midinyl spirocycles 15 (59%) and 16 (55%), respectively
(Scheme 3). Conversion of these pyrimidinyl spironucleo-
side derivatives to the corresponding 6-dimethylami-
nopurine spironucleosides 17 (38%) and 18 (35%) was
accomplished10b by treatment with HC(OEt)3/p-TSA in
DMF followed by chromatographic purification (LiChro-
prep RP-18).
Regarding the structures of the nucleosides, the pres-
ence of two aromatic proton signals at δ 7.70 and 7.74 in
1
15 and at δ 7.74 and 7.76 in 16 in the H NMR spectra
indicated the introduction of two pyrimidinyl rings in
each of them. On the other hand, the corresponding
spectrum of 17 contained four aromatic singlets at δ 8.10,
8.17, 8.20, and 8.25. Besides, it showed a broad 12H
singlet at δ 3.46 changing to a sharp signal at 60 °C,
assignable to two NMe2 groups. Similar proton signals
were observed with 18. The 13C NMR spectra and the
FAB mass spectra of 15-18 were also in conformity with
the assigned structures.
a
Reagents and conditions: (a) Pd/C (10%), cyclohexene, EtOH,
reflux, 4 h, N2; (b) 5-amino-4,6-dichloropyrimidine, n-BuOH, Et3N,
reflux, 18 h; (c) HC(OEt)3/p-TSA, DMF, rt, 30 h.
Proceeding as with 4 and 5, compound 6 was converted
to 19 (52%); expected incorporation of the second chlo-
ropyrimidine moiety at the other amino group (in the
tetrahydro furan ring) did not take place, possibly due
to steric hindrance offered by the neighboring spirocyclic
ring (Scheme 4). Cyclization reaction of 19 followed by
chromatographic purification provided the 6-dimethy-
laminopurine nucleoside 20 (38%) and 6-methoxypurine
nucleoside 21 (13%). No 6-chloro-purine nucleoside could
be isolated; presumably, it is partly substituted by
dimethylamine generated from DMF to afford 20 and
partly by methanol during chromatography using CHCl3/
MeOH mixture to give the methoxy analogue 21.
The product 19 showed a one-proton singlet at δ 7.72
(assigned to C-2 H) in its 1H NMR spectrum and four
aromatic carbon signals at δ 123.4, 136.8, 145.6, and
SCHEME 4. Con ver sion of Sp ir ocycle 6 to
Sp ir on u cleosid es 20 a n d 21a
a
Reagents and conditions: (a) Pd/C (10%), cyclohexene, EtOH,
reflux, N2; (b) 5-amino-4,6-dichloropyrimidine, n-BuOH, Et3N,
reflux, 18 h; (c) HC(OEt)3/p-TSA, DMF, rt, 24 h.
1
152.4 in the 13C NMR spectrum. The H NMR spectrum
of 20 taken at 60 °C in DMSO-d6 exhibited a sharp singlet
(6H) at δ 3.45 (for NMe2) and two discrete (1H) peaks at
(13) Collins, P. M.; Ashwood, M. S.; Eder, H.; Wright, S. H. B.;
Kennedy, D. J . Tetrahedron Lett. 1990, 34, 3585.
J . Org. Chem, Vol. 69, No. 19, 2004 6509

δ 8.11 and 8.18; that of 21 (in DMSO-d6) showed a peak
(3H) at δ 4.18 characteristic for OCH3, in addition to 1H
signals at δ 8.41 and 8.50.
edged. A.R. and S.T. thank CSIR (Govt. of India) for
research fellowships.
In conclusion, the work has demonstrated successful
application of INC reaction on appropriate D-glucose-
derived enose-nitrones in generating spirocycles, which
have been extended to the synthesis of complex spirocy-
clic nucleosides having carbocycles as well as oxygen
heterocycles fused together in a spirocyclic manner.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for the preparation and characterization of compounds
1
and copies of H and 13C NMR spectra of 4-7, 11, 12, 17, 18,
20, and 21 including 1H-1H COSY, TOCSY, NOESY of 4a and
5a and1H-1H COSY, NOESY of 6 and 7. This material is
available free of charge via the Internet at http://pubs.acs.org.
Ack n ow led gm en t. Financial support from DST
(Govt. of India) given to S.B.M. is gratefully acknowl-
J O035813V
6510 J . Org. Chem., Vol. 69, No. 19, 2004