Enantioselective preparation of 2′,3′-dideoxynucleosides and their analogues from ring-expansion of cyclobutanones. 2. Synthesis of 2′,3′-dideoxyribosides and (1S,3R)-1-amino-3-(hydroxymethyl)cyclopentane

Full text of DOI:10.1021/jo9517151

J . Org. Chem. 1996, 61, 1547-1550
1547
Sch em e 1
En a n tioselective P r ep a r a tion of
2′,3′-Did eoxyn u cleosid es a n d Th eir
An a logu es fr om Rin g-Exp a n sion of
Cyclobu ta n on es. 2. Syn th esis of
2′,3′-Did eoxyr ibosid es a n d (1S,3R)-1-
Am in o-3-(h yd r oxym eth yl)cyclop en ta n e1
Edward Lee-Ruff,* Feng-de Xi, and J iang Hua Qie
Department of Chemistry, York University, Toronto,
Ontario M3J 1P3
Received September 19, 1995
Synthetic nucleosides have occupied a central role in
medicinal chemistry with the observation of their activity
as anticancer and antiviral agents.2-4 Specifically, a
number of 2′,3′-dideoxynucleosides have been shown to
be effective as inhibitors of human immunodeficiency
virus (HIV) responsible for the etiology of acquired
immune deficiency syndrome (AIDS), and a few of these
derivatives (AZT, ddI, d4T, and ddC) have been approved
by the US Food and Drug Administration for the treat-
ment of AIDS.5
Carbocyclic nucleoside analogues have also been of
interest in this area since it is known that these are more
stable than their oxygen heterocycles.6 In recent years,
a number of synthetic methods have been reported for
the preparation of carbocyclic6b and normal7 2′,3′-
dideoxynucleosides as potential anti-HIV agents. Many
of these methods are based on structural modifications
of heterocycles or sugar moieties not always readily
accessible.6b Other methods for preparation of furano-
sides involve the cyclization or annulation of chiral C-3
or C-4 open-chain fragments.3,8 In view of the availability
of cyclobutane derivatives9 and their tendency to undergo
ring-expansion reactions in a regio- and stereoselective
manner,10 we explored the possible use of cyclobutanones
as starting materials in the synthesis of carbocyclic and
normal nucleosides. We have recently reported a novel
approach to the synthesis of a series of 2′,3′-dideoxy-3′-
C-(hydroxymethyl)nucleosides and a key intermediate in
the synthesis of their carbocyclic analogues by ring-
expansion reactions of a chiral cyclobutanone.1 The key
step involved the photochemical isomerization of a cy-
clobutanone to a transient oxacarbene and the insertion
into the NH group of a purine.11 This reaction proceeded
with complete regio- and stereospecificity. The one-
carbon ring homologation of cyclobutanones giving cy-
clopentanones has also been shown to occur in a regio-
and stereospecific manner.1 The chiral cyclopentanone
can be structurally elaborated to cyclopentylamines
which were key intermediates in the preparation of
carbocyclic nucleosides.12 In the present study we report
on the photochemical ring-expansion of chiral 2(S)-
[(benzoyloxy)methyl]cyclobutanone (3) as a route to the
2′,3′-dideoxynucleoside series. We also report the diazo-
methane ring-expansion of ketone 3 to give the known
(1S,3R)-1-amino-3-(hydroxymethyl)cyclopentane13 which
is an important intermediate in the preparation of
carbocyclic nucleosides of the 2′,3′-dideoxy series.
Several different methods have been attempted to
prepare ketone 3. Cycloaddition of (-)-menthyl acrylate
to 1,1-dimethoxyethylene with Lewis acid catalysts did
not result in [2 + 2] cycloaddition but led principally to
mixtures of acyclic condensation products. Cycloaddition
of (-)-menthyl acrylate with 1,1-bis(methylthio)ethylene
gave the [2 + 2] cycloadduct 1 in 79% yield. However,
the diastereomeric enrichment was found to be only 25%
1
as determined by H NMR analysis of its alcohol deriva-
tive 2b obtained from hydride reduction of 1 followed by
esterification with (R)-(+)-R-methoxy-R-(trifluoromethyl)-
phenylacetic acid (MTPA). Furthermore, the enantio-
meric enrichment in 2 was in favor of the undesired (R)-
(+)-2a isomer.15 The racemate shows two sets of two
singlet signals at 1.89, 1.92 and 1.92, 1.95 ppm associated
with the methylthio substituents.15 The optically pure
(S)-derivative exhibits two singlet peaks at 1.92 and 1.95
ppm.15 Our sample showed peaks at 1.89, 1.92, and 1.95
with the former two being more intense. From integra-
tion the optical purity was found to be 25% in favor of
the (R)-derivative. The optical purity of our sample
determined from specific rotations was found to be 27%.
A recent report on the preparation of enantiomerically
pure (S)-(-)-2a 15 prompted us to use this cyclobutane
derivative as the precursor to ketone 3. The enantiose-
lective synthesis of (S)-(-)-2a is based on the cycloaddi-
tion of 3-acryloyl-1,3-oxazolidin-2-one and 1,1-bis(meth-
(1) For part 1 see: Lee-Ruff, E.; Wan, W.-Q.; J iang, J .-L. J . Org.
Chem. 1994, 59, 2114.
(2) Hertel, L. W.; Kroin, J . S.; Misner, J . W.; Tustin, J . M. J . Org
Chem. 1988, 53, 2406.
(3) Chou, T. S.; Heath, P. C.; Patterson, L. E.; Poteet, L. M.; Lakin,
R. E.; Hunt, A. H. Synthesis 1992, 565.
(4) Robins, R. K.; Revankar, G. R. in Antiviral Drug Development;
De Clercq, E., Walker, R. T., Eds.; Plenum Press: New York, 1988; p
11.
(5) Mitsuya, H.; Yarchoan, R.; Broder, S. Science 1990, 249, 1533
and references cited therein.
(6) (a) Marquez, V. E.; Lim, M.-I. Med. Res. Rev. 1986, 611. (b)
Borthwick, A. D.; Biggadike, K. Tetrahedron 1992, 48, 571. (c)
Niitsuma, S.; Ichikawa, Y.-I.; Takita, T. Studies in Natural Products
Chemistry; Elsevier Science Publishers: Amsterdam, 1992; p 585.
(7) (a) Manchand, P. S.; Belica, P. S.; Holman, M. J .; Huang, T.-N.;
Maehr, H. Tam, S. Y.-K; Yang, R. T. J . Org. Chem. 1992, 57, 3473. (b)
Beach, J . W.; Kim, H. O.; J eong, L. S.; Nampalli, S.; Islam, Q.; Ahn, S.
K.; Babu, J . R.; Chu, C. K. Ibid. 1992, 57, 3887.
(8) Svannson, L.; Kvarnstro¨m, I.; Classon, B.; Samuelsson, B. J . Org.
Chem. 1991, 56, 2993.
(9) Lee-Ruff, E. In Methods in Organic Chemistry; De Meijere, A.,
Ed.; Houben-Weyl; G. Thieme Verlag: Stuttgart, Chapter 1.3, Vol. E17
(in press).
(11) Hayes, I. E. E.; J andrisits, L.; Lee-Ruff, E. Can. J . Chem. 1989,
67, 2057.
(12) (a) Boumchita, H.; Legraverend, M.; Bisagni, E. Heterocycles
1991, 32, 1785. (b) Rosenquist, A.; Kvarnstro¨m, I.; Svensson, S. C. T.;
Classon, B.; Sammuelsson, B. J . Org. Chem. 1994, 59, 1779. (c) Park,
K. H.; Rapoport, H. J . Org. Chem. 1994, 59, 394.
(13) (a) Bergmeier, S. C.; Lee, W. K.; Rapoport, H. J . Org. Chem.
1993, 58, 5019. (b) Bergmeier, S. C.; Cobas, A. A.; Rapoport, H. J . Org.
Chem. 1993, 58, 2369.
(14) Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969, 34,
2543.
(10) Lee-Ruff, E. In Advances in Strain in Organic Chemistry;
Halton, B., Ed.; G. Thieme Verlag: Stuttgart, 1991; Vol. 1, p 167.
(15) Narasaka, K.; Kusama, H.; Hayashi, Y. Bull Chem. Soc. J pn.
1991, 64, 1471.
0022-3263/96/1961-1547$12.00/0 © 1996 American Chemical Society

1548 J . Org. Chem., Vol. 61, No. 4, 1996
Notes
Sch em e 2
expected for 8 since hydride reduction of oxime 7 would
preferentially occur from the side opposite to the (ben-
zoyloxy)methyl substituent in the cyclopentane ring of
7.
In summary, 2′,3′-dideoxypurinyl nucleosides can be
readily prepared from the photochemical ring-expansion
of chiral (S)-2-(benzoyloxy)cyclobutanone in the presence
of purines yielding both anomers in about equal propor-
tions. Debenzoylation of the photoproducts with satu-
rated ammonia methanol gave the known 6-substituted
purine nucleosides, a number of which have been shown
to be inhibitors of the cytopathic effect of HIV.16,17
A key intermediate, (1S,3R)-1-amino-3-(hydroxymeth-
yl)cyclopentane (8), which can be used in the preparation
of carbocyclic nucleosides, has been synthesized from
chiral (S)-2-[(benzoyloxy)methyl]cyclobutanone ((-)-3) by
one-carbon homologation with diazomethane and struc-
tural elaboration of the corresponding cyclopentanone.
The ring-expansion occurs in a regio- and stereoselective
manner.
The photochemical and one-carbon ring-expansion of
chiral ketone 3 constitutes a simple enantioselective
route to 2′,3′-dideoxy-nucleosides and carbocyclic ana-
logues. The photochemical route is, however, limited by
the formation of both anomers. The advantage of this
method, apart from its simplicity, is the potential for
preparing the enantiomeric forms of these nucleosides
by using the optical antipode of the chiral titanium
catalyst (derived from (+)-tartaric acid) in the prepar-
ation of cyclobutane 2a . Recently, a number of investi-
gators have looked at the anti-HIV activity of the
enantiomeric forms of these nucleosides with promising
results.19-22
ylthio)ethylene using a chiral titanium catalyst.15
Cyclobutanone 3 was obtained in 85% yield by benzoyl-
ation and dethioketalization of (-)-2a .
Irradiation of ketone 3 in either THF or acetonitrile
solutions (10-2 to 10-3 M) with water, methanol, purine,
6-chloro-, 6-methoxy-, and 6-(hexyloxy)purine using a
medium pressure mercury lamp gave in separate experi-
ments the ring-expanded derivatives 4 as principal
products (36-80% yields). In all cases a mixture of
approximately equal amounts of both anomers were
Exp er im en ta l Section
Gen er a l. Melting points (mp) were uncorrected. Infrared
(IR) spectra were recorded as thin films or KBr pellets. NMR
spectra were recorded on a Bruker ARX-400 (400 MHz) spec-
trometer in CDCl3 solutions with TMS as internal reference
(unless otherwise specified). Mass spectra were recorded on a
VG Micromass 16F spectrometer. High resolution mass spectra
were obtained on a VG Analytical-SE spectrometer at the
University of Toronto Carbohydrate Research Center. Elemen-
tal analyses were performed by Guelph Chemical Laboratories
Ltd. Photolyses were carried out using a Hanovia 450-W
medium pressure mercury arc lamp in a water-cooled Pyrex
immersion well. Pyrex tubes containing the samples were
strapped around this well, and the assembly was immersed in
an ice-water bath. The samples were degassed for 30 min prior
to irradiation. All solvents used were dried and distilled.
Preparative thin-layer chromatography was conducted on BDH
silica gel 60F 254 precoated glass plates. Ketene dimethylthio-
acetal was prepared according to the literature.23
1
obtained as evident from the H-NMR signals of equal
intensities associated with the anomeric protons and the
doubling of the methoxy signals in 4b and 4e.
Debenzoylation of 4c-f was accomplished by treatment
with methanolic ammonia. The resultant deprotected
nucleosides 5c-f could be separated by preparative thin-
layer chromatography. The â-anomers of 5c,d exhibited
similar spectral data as reported in the literature.16,17
Debenzoylation of the chloro derivative 4d gave in
addition to 5d some of the methoxy nucleoside 5e arising
from nucleophilic displacement by methanol.
In order to explore the regio- and stereoselectivity of
the one-carbon homologation of ketone 3 for the prepara-
tion of the corresponding (1S,3R)-1-amino-3-(hydroxy-
methyl)cyclopentane (8), ketone 3 was treated with
diazomethane. This reaction led to a 49% conversion to
the corresponding cyclopentanone 6. The regiochemistry
of the cyclopentanone was established by conversion to
the cyclopentylamine 8 via oxime 7. A racemic modifica-
tion of cyclopentylamine 8 was prepared independently
according to the literature starting from bicyclo[2.2.1]-
hept-2-ene18 and showed identical spectral properties
(NMR and IR spectra) with the amine prepared from
optically pure ketone (-)-3. The cis stereochemistry was
(-)-Men th yl Acr yla te. To a cooled solution (0 °C) containing
(-)- menthol (1.56 g, 10 mmol) and pyridine (0.95 mL) in 10 mL
of heptane was added acryloyl chloride (1.09 g, 12 mmol) over a
period of 20 min. Stirring was continued for a further 30 min
at 0 °C and 3 h at room temperature. The reaction mixture was
washed with aqueous sodium bicarbonate (5%, 2 × 8 mL) and
water (2 × 8 mL) and dried over sodium sulfate. After evapora-
tion of the solvent at reduced pressure, the residue was purified
by column chromatography with silica gel (hexane:ethyl acetate,
9:1), giving a colorless oil (1.52 g, 72%): [R]25 -85.4° (c, 0.97,
D
CH2Cl2); IR (neat) 1708, 1182 cm-1
;
1H NMR δ 6.3 (d, J ) 21
Hz, 1H), 6.0 (dd, J ) 22, 11 Hz, 1H), 5.7 (d, J ) 11 Hz 1H), 4.7
(16) Burns, C. L.; St. Clair, M. H.; Frick, L. W.; Spector, T.; Averett,
D. R.; English, M. L.; Holmes, T. J .; Krenitsky, T. A.; Koszalka, G. W.
J . Org. Chem. 1993, 36, 378.
(17) Chu, C. K.; Ullas, G. V.; J eong, L. S.; Ahn, S. K.; Doboszewski,
B.; Lin, Z. X.; Beach, J . W.; Schinazi, R. F.; J . Med. Chem. 1990, 33,
1553.
(19) Schinazi, R. F. et al. Antimicrob. Agents Chemother. 1994, 38,
2172.
(20) Lin, T. S. et. al. Biochem. Pharmacol. 1994, 47, 171.
(21) Gosselin G. et al. Antimicrob. Agents Chemother. 1994, 38, 1292.
(22) Lin, T. S.; Luo, M.-Z.; Liu, M. C. Tetrahedron Lett. 1994, 35,
3477.
(18) Hronowshi, L. J . J .; Szarek, W. A. Can. J . Chem. 1988, 66, 61.
(23) Kaya, R.; Beller, N. R. J . Org. Chem. 1981, 46, 196.

Notes
J . Org. Chem., Vol. 61, No. 4, 1996 1549
Sch em e 3
(m, 1H), 1.95 (m, 1H), 1.80 (m, 1H), 1.60 (m, 3H), 1.4 (m, 2H),
0.95 (m, 2H), 0.80 (dd, 6H), 0.70 (d, 3H). Anal. Calcd for
was irradiated for the length of time indicated below. After
evaporation of the solvent, the residue was purified by prepara-
tive thin-layer chromatography using silica gel.
C
13H22O2: C, 74.28; H, 10.48. Found: C, 74.13; H, 10.45.
5-O-Ben zoyl-2,3-d id eoxy-r- a n d â-D-er yth r o-p en tofu r a -
n ose (4a ). From 0.204 g (1 mmol) of ketone 3 in 35 mL of THF
containing 3 mL of water after irradiation for 30 min gave, after
purification (TLC, hexane:ethyl acetate, 6:4), 0.127 g (55%) of a
colorless oil; [R]28D +6.67° (c, 0.99, CH2Cl2); IR (neat) 3400, 1705,
(-)-Men th yl 2,2-Bis(m eth ylth io)-1-cyclobu ta n eca r box-
yla te (1). To a CH2Cl2 solution (5 mL) of 1,1-bis(methylthio)-
ethylene23 (0.24 g, 2.0 mmol) and menthyl acrylate (0.22 g, 1.2
mmol) was added dropwise diethylaluminum chloride (1.2 mmol,
1.0 M hexane solution) at 0 °C. The mixture was stirred for 1
h after which the reaction was quenched with ten drops of
triethylamine and with 10% aqueous sodium bicarbonate (1 mL).
The inorganic materials were removed by filtration. The organic
materials were extracted with 30 mL of CH2Cl2 and dried over
sodium sulfate. After removal of the solvent, the residue was
purified on a silical gel column (hexane:ethyl acetate, 10:1) to
1
1260 cm-1; H NMR δ 8.06, 8.03 (two d, 2H), 7.54 (t, 1H), 7.40,
(t, 2H), 5.63, 5.50 (two d, 1H), 4.45 (m, 2H), 3.80 (m, 1H), 2.4-
1.8 (m, 4H); MS (EI) m/ z 205 (M - OH); HRMS calcd for
+
C
12H13O3 (M+ - OH) m/ z 205.0865; found m/ z 205.0849.
Met h yl 5-O-Ben zoyl-2,3-d id eoxy-r- a n d -â-D-er yth r o-
p en tofu r a n osid e (4). From 0.200 g (1 mmol) of ketone 3 in
36 mL of THF containing 3.5 mL of methanol after irradiation
for 30 min gave, after purification by TLC (hexane:ethyl acetate,
give an oil (0.313 g, 79%); [R]25 -29.36° (c, 4.7, CH2Cl2); IR
D
(neat) 1730, 1240, 1170 cm-1; 1H NMR δ 4.73 (m, 1H), 3.43 (dd,
J ) 12, 10 Hz, 1H), 2.55 (m, 1H), 2.1-2.4 (m, 4H), 2.15 (s, 3H),
2.04 (s, 3H), 1.95 (m, 1H), 1.05-1.75 (m, 7H), 0.95 (dd, J ) 7, 3
Hz, 6H), 0.78 (d, J ) 6 Hz, 3H). Anal. Calcd for C17H30O2S2:
C, 61.77; H, 9.15. Found: C, 62.17; H, 9.20.
8:2), 0.181 g (77%) of a colorless oil: [R]28 +4.92° (c, 1.28, CH2-
D
1
Cl2); IR (thin film) 1720, 1270, 1300 cm-1, H NMR δ 8.12, 8.05
(two d, 2H), 7.58 (t, 1H), 7.45 (t, 2H), 5.12, 5.03 (two d, 1H),
4.40 (m, 2H), 3.47, 3.34 (two s, 3H), 2.0 (m, 4H); MS (EI) m/ z
235 (M+ - H), 205 (M - OCH3). Anal. Calcd for C13H16O4: C,
66.10; H, 6.78. Found: C, 65.82, H, 6.80.
(R)-(+)-[2,2-Bis(m eth ylth io)-1-cyclobu tyl]m eth a n ol (2a ).
To a THF suspension (40 mL) of lithium aluminum hydride (1.0
g, 26 mmol) was added a THF solution (25 mL) of 2,2-bis-
(methylthio)-1-cyclobutanecarboxylic acid (-)-menthyl ester (1)
(4.29 g, 13 mmol) at 0 °C. The mixture was stirred for 30 min.
Then saturated aqueous sodium sulfate was added until hydro-
gen evolution ceased. The precipitate was filtered off and
washed with THF. The filtrate was concentrated under reduced
pressure and the residue purified by column chromatography
using silica gel (hexane:ethyl acetate, 9:1) to give a colorless oil:
1-C-(P u r in -N9-yl)-5-O-ben zoyl-1,2,3-d id eoxy-r- a n d -â-D-
er yth r o-fu r a n ose (4c). From a solution containing 0.020 g (0.1
mmol) of ketone 3 and 0.018 g (0.15 mmol) of purine in 60 mL
of acetonitrile after 36 h of radiation gave upon purification by
TLC (CH2Cl2:CH3OH, 95.5) 0.012 g (36%) of a yellow oil: 1H
NMR δ 9.17, 9.14 (two s, 1H), 8.97, 8.93 (two s, 1H), 8.36, 8.24
(two s, 1H), 8.10, 8.02 (two d, 2H), 7.60 (m, 1H), 7.45 (m, 2H),
6.50, 6.48 (two d, 1H), 4.43-4.66 (m, 3H), 2.12-2.82 (m, 4H).
1-C-(6-Ch lor op u r in -N9-yl)-5-O-b en zoyl-1,2,3-d id eoxy-r-
a n d -â-D-er yth r o-fu r a n ose (4d ). From a solution containing
0.02 g (0.1 mmol) of ketone 3 and 0.023 g (0.15 mmol) of
6-chloropurine in 50 mL of acetonitrile after 36 h radiation was
obtained upon purification by TLC (CH2Cl2:CH3OH 96:4) 0.014
g of (39%) of a yellow oil: [R]22D -3.46° (c, 0.2, CH2Cl2); UV (CH2-
[R]25 +9.36° (c, 1.00, CH2Cl2). Our sample showed similar IR
D
1
and H NMR spectral data to that reported in the literature for
the optically pure (S)-derivative.15
(S)-2-[(Ben zoyloxy)m eth yl]cyclobu ta n on e Bis(m eth ylth -
io)k eta l. To a pyridine solution (6 mL) containing (S)-[2,2-bis-
(methylthio)-1-cyclobutyl]methanol ((-)-2a) (0.482 g, 2.48 mmol)15
was added dropwise benzoyl chloride (0.524 g, 3.73 mmol) at 5
°C. The solution was stirred for 30 min and then treated
successively with saturated aqueous sodium bicarbonate and
brine. The reaction mixture was extracted with ethyl acetate
(2 × 50 mL), and the combined organic extracts were washed
with brine and dried over sodium sulfate. After evaporation of
the solvent, the crude product was purified by column chroma-
tography (silica gel, hexane:ethyl acetate, 10:1) to give a colorless
oil (0.617 g, 88%); [R]28D +5.59° (c, 1.02, CH2Cl2); IR (neat) 1710,
1260 cm-1; 1H NMR δ 8.05 (d, J ) 7 Hz, 2H), 7.55 (t, J ) 7 Hz,
1H), 7.45 (t, J ) 7 Hz, 2H), 4.50 (m, 2H), 3.0 (m, 1 H), 2.48 (m,
1H); 2.45 (m, 3H), 2.13 (s, 3H), 2.07 (s, 3H), MS (EI) m/ z 282
(M+). Anal. Calcd for C14H18O2S2: C, 59.54; H, 6.42; S, 22.71.
Found: C, 59.89; H, 6.25; S, 22.75.
1
Cl2) λmax 244 nm (ꢀ ) 3264); H NMR δ 8.77, 8.73 (two s, 1H),
8.38, 8.26 (two s, 1H), 8.11, 8.01 (two d, 2H), 7.60 (m, 1H), 7.45
(m, 2H), 6.50, 6.42 (two m, 1H), 4.85 (m, 1H), 4.50 (m, 2H), 2.14-
2.77 (m, 4H); MS (LSIM) m/ z 359 (M + H).
1-C -(6-M e t h o x y p u r i n -N 9 -y l)-5-O -b e n z o y l-1,2,3-d i -
d eoxy-r- a n d â-D-er yth r o-fu r a n ose (4e). From a solution
containing 0.200 g (1.0 mmol) of ketone 3 and 0.225 g (1.5 mmol)
of 6-methoxypurine in 100 mL of acetonitrile after 38 h radiation
was obtained upon purification by TLC (CH2Cl2:CH3OH 95:5)
0.244 g of (69%) of a light yellow oil: [R]22 -5.17° (c, 0.6, CH2-
D
Cl2); UV (CH2Cl2); λmax 240 nm (ꢀ ) 8875); IR (neat) 1705, 1580,
1260 cm-1; 1H NMR δ 8.56, 8.52 (two s, 1H), 8.55 (m, 1H), 8.50
(m, 2H); 8.18, 8.08 (two s, 1H), 8.05, 8.00 (two d, 2H), 6.45, 6.35
(two m, 1H), 4.90 (m, 1H), 4.40-4.62 (m, 2H), 4.22, 4.20 (two s,
3H), 2.05-2.79 (m, 4H); MS (LSIM) m/ z 355 (M + H); HRMS
(FAB) calcd for C18H19O4N4, (M + H) m/ z 355.1406; found m/ z
355.1425.
(S)-2-[(Ben zoyloxy)m eth yl]cyclobu ta n on e [(-)-3]. To a
well stirred solution of N-chlorosuccinimide (2.01 g, 15 mmol)
and silver nitrate (2.89 g, 17.0 mmol) in aqueous 90% acetonitrile
was added a solution of (S)-2-[(benzoyloxy)methyl]cyclobutanone
bis(thiomethyl)ketal (1.41 g, 5.0 mmol) at 0 °C. The mixture
was stirred for 10 min and treated successively with saturated
aqueous sodium sulfite, sodium bicarbonate and brine. The
inorganic materials were removed by filtration. The filtrate was
extracted with 100 mL of ethyl acetate, washed with brine, and
dried over Na2SO4. After evaporation of the solvent, the crude
product was purified by column chromatography (silica gel,
1-C-[6-(Hexyloxy)pu r in -N9-yl]-5-O-ben zoyl-1,2,3-dideoxy-
r- a n d -â-D-er yth r o-fu r a n ose (4f). From a solution containing
0.02 g (0.1 mmol) of ketone 3 and 0.066 g (0.3 mmol) of
6-(hexyloxy)purine in 160 mL of acetonitrile after 36 h radiation
was obtained upon purification by TLC (CH2Cl2:CH3OH 95:5)
0.019 g of (45%) of a colorless oil: [R]22 -2.4° (c, 0.125, CH2-
D
Cl2); UV (CH2Cl2) λmax 246 nm (ꢀ ) 2792); IR (neat) 1714, 1574,
1176, cm-1; 1H NMR δ 8.53, 8.51, (two s, 1H), 8.38, 8.23 (two s,
1H), 8.26, 8.05 (two d, 1H), 7.60 (m, 1H), 7.50 (m, 2H), 6.44,
6.33 (two d, 1H), 4.84 (m, 1H), 4.44-4.62 (m, 6H), 2.04-2.69
(m, 4H), 1.91 (m, 2H), 1.51, (m, 2H), 1.36 (m, 4H), 0.92 (t, 3H);
MS (LSIM) m/ z 425 (M + 1).
hexane:ethyl acetate 10:1) to give a colorless oil; [R]28 -13.8°
D
(c, 1.06, CH2Cl2); IR (neat) 1780, 1715, 1270 cm-1
;
1H NMR δ
8.0 (d, J ) 7 Hz, 2H), 7.07 (t, J ) 7 Hz, 1H), 7.50 (t, J ) 7 Hz,
2H), 4.54 (d, J ) 5 Hz, 2H), 3.76 (m, 1H), 3.10 (m, 2H), 2.30 (m,
1H), 2.10 (m, 1H); MS (EI) m/ z 205 (M + 1). Anal. Calcd for
12H12O3: C, 70.06; H, 5.92. Found: C, 69.80, H, 6.00.
P h otolysis of Keton e (-)-3. Gen er a l P r oced u r e. A solu-
tion of ketone 3 in THF or acetonitrile containing the carbene
Deben zoyla tion of Nu cleosid es 4c-f. Gen er a l P r oce-
d u r e. A solution consisting of 1 mmol of protected nucleoside
in 60 mL of methanol saturated with ammonia was stirred for
24 h at room temperature. The solvent was removed and the
residue was dissolved in water and washed with CH2Cl2 (3 × 6
C
scavenger was degassed with argon for 30 min. The solution

1550 J . Org. Chem., Vol. 61, No. 4, 1996
Notes
mL). After evaporation of the water in the aqueous layer by
rotoevaporation at a temperature <40 °C, the residue was
purified by preparative thin-layer chromatography (CH2Cl2:CH3-
OH, solvent ratio specified below).
1H NMR (D2O referenced to H2O) δ 8.52 (s, 1H), 8.47 (s, 1H),
6.52 (t, 1H), 4.70 (m, 1H), 3.80 (m, 1H), 3.69 (m, 1H), 2.66 (m,
2H), 2.36 (m, 1H), 2.08 (m, 1H), 1.93 (m, 2H), 1.54 (m, 2H), 1.38
(m, 4H), 0.92 (t, 3H).
1-C-(P u r in -N9-yl)-1,2,3-d id eoxy-r- a n d -â-D-er yth r o-fu r a -
n ose (5c). Total yield 69% (35% â- and 34% R-anomer). Solvent
for TLC separation was CH2Cl2:CH3OH, 100:10.
â-An om er : [R]22D -4.50° (c, 2.71, CH3OH); UV (CH3OH) λmax
250 nm (ꢀ ) 8016); IR 3371, 1599, 1180 cm-1 1H NMR (D2O
;
referenced to H2O) δ 8.57 (s, 1H), 8.55 (s, 1H), 6.48 (m, 1H), 4.45
(m, 1H), 3.88 (m, 1H), 3.73 (m, 1H), 2.67 (m, 2H), 2.43 (m, 1H),
2.15 (m, 1H), 1.95 (m, 2H), 1.57 (m, 2H), 1.39 (m, 4H), 0.92 (t,
3H); MS (LSIM) m/ z 321 (M + 1).
r-An om er : mp 119-120 °C (lit.17 mp 116-118 °C); [R]22
D
+6.0° (c, 2.82, CH3OH); λmax (CH3OH) 264 (ꢀ ) 13062), IR (KBr)
3609, 1595, 1152 cm-1; 1H NMR δ 9.15 (s, 1H), 8.98 (s, 1H), 8.22
(s, 1H), 6.43 (dd, J ) 6, 4 Hz, 1H), 4.59 (m, 1H), 3.65-3.86 (m,
2H), 2.05-2.72 (m, 4H), 1.80 (s, 1H); 13C NMR δ 152.6, 150.8,
149.0, 143.5, 134.8, 86.2, 81.6, 64.5, 32.1, 26.1.
(R)-(+)-3-[(Ben zoyloxy)m eth yl]cyclop en ta n on e (6). To
an ethereal solution (80 mL) of diazomethane (0.42 g, 10 mmol)
was added ketone (-)-3 (0.200 g, 1 mmol) in methanol (15 mL).
The solution was stirred for 20 h at room temperature. The
reaction was quenched by adding a few drops of acetic acid until
the yellow color disappeared. The solvent was removed under
reduced pressure and the product purified by column chroma-
tography (silica gel, hexane:ethyl acetate 9:1) to give a colorless
solid (0.107 g, 49%): mp 46-48 °C; [R]28D +26.45° (c, 1.07, CH2-
â-An om er : mp 141-142 °C (lit.17 mp 149-150 °C); [R]22
D
-3.58° (c, 2.01 CH3OH); λmax (CH3OH) 264 nm (ꢀ ) 7675); 1H
NMR δ 9.17 (s, 1H), 8.98 (s, 1H), 8.28 (s, 1H), 6.26 (t, 1H), 4.39
(m, 1H), 3.70 (m, 2H), 2.80 (m, 1H), 2.48 (m, 2H), 2.25 (m, 1H),
1.62 (s, 1H); 13C NMR δ 152.2, 150.4, 149.3, 144.3, 135.4, 87.3,
81.9, 64.5, 32.5, 25.9; MS (LSIM) m/ z 221 (M + 1).
1-C-(6-Ch lor opu r in -N9-yl)-1,2,3-dideoxy-r- an d -â-D-er yth -
r o-fu r a n ose (5d ). After debenzoylation 22% of the anomeric
mixture of 5d was obtained in addition to 14% of 6-methoxy
derivative 5e as an anomeric mixture. Solvent for TLC separa-
tion was CH2Cl2:CH3OH, 100:6.
Cl2); IR (KBr) 1730, 1700, 1255 cm-1 1H NMR δ 7.95 (d, 2H),
;
7.52 (t, 1H), 7.41 (t, 2H), 4.42 (d, 2H), 3.79 (m, 1H), 2.05-2.5
(m, 5H), 1.77 (m, 1H), MS (EI) m/ z 218 (M+) 106, 105, 96. Anal.
Calcd for C13H14O3: C, 71.56; H, 6.42. Found: C, 71.39; H, 6.40.
(R)-3-[(Ben zoyloxy)m eth yl]cyclop en ta n on e Oxim e (7).
To a solution of cyclopentanone 6 (0.114 g, 0.5 mmol) and
pyridine (0.316 g, 4 mmol) in ethanol (10 mL) was added
hydroxylamine hydrochloride (0.278 g, 4 mmol). The mixture
was stirred for 30 min at room temperature. This mixture was
extracted with CH2Cl2 (3 × 10 mL). The combined extracts were
dried over sodium sulfate and evaporated under reduced pres-
sure. The residue was purified by preparative TLC (silica gel,
CH2Cl2:CH3OH 9:1) to give a colorless solid (0.98 g, 84%): mp
102-104 °C; [R]28D +8.08 (c, 1.04, CH2Cl2); IR (KBr) 3220, 1703,
r-An om er : [R]22D +10.17 (c, 0.59, CH3OH); UV (CH3OH) λmax
260 nm (ꢀ ) 9283); IR (KBr) 3351, 1649, 1259 cm-1; 1H NMR δ
8.36 (s, 1H), 7.92 (s, 1H), 6.35 (t, 1H), 5.53 (s, 1H, OH), 4.57,
(m, 1H), 3.69 (m, 2H), 2.02-2.72 (m, 4H); 13C NMR δ 155.4,
153.1, 149.0, 142.3, 138.6, 85.9, 81.3, 64.5, 32.1, 26.0.
â-An om er : mp 101-102 °C (lit.17 mp 97-99 °C); [R]22D +8.89°
(c, 0.63, CH3OH); UV (CH3OH) λmax 260 nm (ꢀ )8041); IR (KBr)
3369, 1652, 1244 cm-1; 1H NMR δ 8.34 (s, 1H), 7.87 (s, 1H), 6.12
(t, 1H), 5.57 (s, 1H, OH), 4.39 (m, 1H), 3.90 (m, 1H), 2.19-2.88
(m, 4H); 13C NMR δ 155.2, 152.6, 148.9, 142.4, 139.9, 88.1, 81.7,
65.1, 32.3, 26.1; MS (LSIM) m/ z 255 (M + 1).
1260 cm-1 1H NMR δ 7.95 (d, 2H), 7.50 (t, 1H), 7.38 (t, 2H),
;
4.28 (m, 2H), 2.2-2.9 (m, 6H), 2.00 (m, 1H), 1.60 (m, 1H); Anal
Calcd for C13H15NO3: C, 66.95; H, 6.44. Found: C, 67.05; H,
6.35.
1-C-(6-Met h oxyp u r in -N9-yl)-1,2,3-d id eoxy-r- a n d -â-D-
er yth r o-fu r a n ose (5e). Total yield 43% consisting of 25% of
the R-anomer and 18% of the â-anomer. Eluent for TLC
separation was CH2Cl2:CH3OH, 96:6.
(1S,3R)-1-Am in o-3-(h ydr oxym eth yl)cyclopen tan e (8). To
a suspension of LiAlH4 (0.038 g, 1 mmol) in dry THF (5 mL)
was added a solution of oxime 7 (0.0233 g, 0.1 mmol) in dry THF
(5 mL) with stirring at -5 °C. The reaction mixture was stirred
for a further 5 h at 0 °C. The reaction was quenched with 0.5
mL of water and filtered. The filtrate was extracted with ether
(4 × 5 mL), dried over sodium sulfate, and evaporated under
reduced pressure to give a colorless oil (0.0047 g, 41%). The
hydrochloride salt was prepared by dissolving the oil in 0.1 mL
r-An om er : [R]22D -4.59° (c, 1.35, CH3OH); UV (CH3OH) λmax
250 nm (ꢀ ) 7880); IR (thin film) 3640, 1605, 1165 cm-1; 1H NMR
(D2O referenced to H2O) δ 8.52 (s, 1H), 8.47(s, 1H), 6.50 (t, 1H),
4.69 (m, 1H), 4.24, (s, 3H), 3.77 (m, 2H), 2.60 (m, 2H), 2.40 (m,
1H), 2.05 (m, 1H); 13C NMR (D2O referenced to TSP) δ 157.6,
148.5, 147.3, 138.4, 117.7, 82.5, 78.1, 60.0, 51.6, 27.9, 22.0.
â-An om er : mp 123-124 °C (lit.16 mp 122-123 °C); [R]22
D
-13.27° (c, 4.46, CH3OH); UV (CH3OH) λmax 250 nm (ꢀ ) 10417);
of concd HCl and evaporation to dryness. [R]23 -4.8° (c, 0.28,
D
IR (KBr) 3630, 1611, 1156 cm-1
;
1H NMR (D2O referenced to
1 M HCl) (lit.13b [R]20 -7.4°); 1H NMR (D2O) 3.55 (m, 2H), δ
D
H2O) δ 8.57 (s, 1H), 8.55 (s, 1H), 6.48 (m, 1H), 4.45 (m, 1H),
4.25 (s, 3H), 3.91 (m, 1H), 3.73 (m, 1H), 2.67 (m, 2H), 2.31 (m,
1H), 2.15 (m, 1H); 13C NMR (D2O referenced to TSP) δ 157.3,
148.4, 147.0, 138.3, 117.4, 82.5, 78.2, 60.1, 51.6, 28.0, 22.0; MS
(LSIM) m/ z 251 (M + 1).
3.53 (m, 1H), 2.26 (m, 2H), 2.07 (m, 1H), 1.85 (m, 1H), 1.69 (m,
1H), 1.50 (m, 1H), 1.29 (m, 1H). The 1H NMR data was identical
with those of a sample of racemic 8 prepared according to the
method of Hronowski and Szarek.18
1-C-(6-Hexyloxyp u r in -N9-yl)-1,2,3-d id eoxy-r- a n d -â-D-
er yth r o-fu r a n ose (5f). Total yield 80% consisting of 40% of
the R-anomer and 40% of the â-anomer. Eluent for TLC
separation was CH2Cl2:CH3OH, 100:6.
Ack n ow led gm en t. We thank the Natural Sciences
and Engineering Research Council for financial support
of this work. Feng-de Xi also thanks Scientech (Hong
Kong) for fellowship support.
r-An om er : [R]22 ) +12.12° (c, 2.64, CH3OH); UV (CH3OH)
D
λmax 250 nm (ꢀ ) 5,881); IR (thin film) 3356, 1600, 1180 cm-1
;
J O9517151