Practical synthesis of enantiopure spiro[4.4]nonane C-(2′-deoxy) ribonucleosides

Article abstract of DOI:10.1021/jo0480601

(Chemical Equation Presented) The levorotatory diol 7 has been sequentially monosilylated, dehydrated, and oxidized at the allylic methylene group to provide (+)-12. The enantiomeric dextrorotatory diol 7 has been directed down a different sequence of ste

Full text of DOI:10.1021/jo0480601

Practical Synthesis of Enantiopure Spiro[4.4]nonane
C-(2′-Deoxy)ribonucleosides
Ryan Hartung† and Leo A. Paquette*
Evans Chemical Laboratories, The Ohio State University, Columbus, Ohio 43210
paquette.1@osu.edu
Received November 1, 2004
The levorotatory diol 7 has been sequentially monosilylated, dehydrated, and oxidized at the allylic
methylene group to provide (+)-12. The enantiomeric dextrorotatory diol 7 has been directed down
a different sequence of steps involving monosilylation, dehydration, hydroboration, Swern oxidation,
and regioselective introduction of a conjugated double bond to generate (-)-33. The novel feature
of these transformations is that two key deoxycarbospironucleoside intermediates of the proper
absolute configuration have been made available from enantiomerically related precursors. Also
reported is a highly practical and reliable means for the formation of novel 2′-deoxyribonucleosides
of novel structural type from these spirocyclic cyclopentenones.
The considerable attention that has been focused on
the capacity of carbocyclic nucleosides to function as
potent inhibitors of viral infection has been rewarded
with a number of striking successes. Aristeromycin (1)1
and neplanocin A (2)2 were among the early discoveries,
to be followed by the potent anti-HIV agent abacavir (3).3
Presently in advanced stages of clinical trial for chronic
hepatitis B virus infection is entecavir (4).4 Rounding out
the picture at this time are other carbocyclic nucleosides
active against the smallpox, monkeypox, and West Nile
viruses.5 An intriguing and persistent question surrounds
structure-activity relationships in this compound class.
Despite the significant effort made in recent years, the
design of analogues having predictable biological and
chemical profiles persists as a significant unmet chal-
lenge.
† Lubrizol Graduate Fellow, 2004-2005.
(1) Kusaka, T.; Yamamoto, H.; Muroi, M.; Kishi, T. J. Antibiot. 1968,
21, 255.
(2) Yaginuma, S.; Muto, N.; Tsujino, M.; Sudate, Y.; Hayashi, M.;
Otani, M. J. Antibiot. 1981, 34, 359.
(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.; Averett, D. R.; Krenitsky, T. A. Antimicrob. Agents Chemother.
1997, 41, 1082.
In continuation of our efforts to explore the feasibility
of synthesizing enantiopure spirocyclic nucleoside build-
ing blocks containing oxygen,6 sulfur,7 and carbon8 at the
apical position,9 we have turned attention to the elabora-
tion of nucleoside analogues of DNA of the general type
5 and 6. The impetus underlying this undertaking was
to evaluate this type of conformational restriction while
(4) Innaimo, S. F.; Seifer, M.; Bisacchi, G. S.; Standring, D. N.;
Zahler, R.; Colonno, R. J. Antimicrob. Agents Chemother. 1997, 41,
1444.
(5) (a) Song, G. Y.; Paul, V.; Choo, H.; Morrey, J.; Sidwell, R. W.;
Schinazi, R. F.; Chu, C. K. J. Med. Chem. 2001, 44, 3958. (b) Chu, C.
K.; Jin, Y. H.; Baker, R. O.; Huggins, J. Bioorg. Med. Chem. Lett. 2003,
13, 9.
10.1021/jo0480601 CCC: $30.25 © 2005 American Chemical Society
Published on Web 02/02/2005
J. Org. Chem. 2005, 70, 1597-1604
1597

Hartung and Paquette
SCHEME 1
SCHEME 2
simultaneously guarding against possible enzymatic
degradation under physiological conditions.
Results and Discussion
Retrosynthetic considerations led us back to the report
by Nieman and Keay that describes the resolution of
racemic cis,cis-spiro[4.4]nonane-1,6-diol via ketalization
with (1R)-(+)-camphor.10 So efficient is their process that
appreciable quantities of both (-)-7 and (+)-7 can be
generated. As seen in Scheme 1, the levorotatory enan-
tiomer was anticipated to serve as a suitable precursor
to 5 in light of their closely related absolute configura-
tions. Several stereocontrolled steps must be developed
to proceed from (-)-7 to 8 and onward from that point.
Fruitful deployment of (+)-9 as the progenitor of 6 would
require a different series of transformations to attain this
objective.
As expected, the nonbonded steric constraints resident
in 7 were found to impede the more advanced silylation
of 10 (Scheme 2) while complicating its dehydration to
give 11. Nevertheless, operation of a Wagner-Meerwein
ring expansion was minimized when recourse was made
to phosphorus oxychloride in pyridine at 0 °C.11 Conver-
sion to spirocyclopentene 11 was repeatedly achieved in
64% yield.
samarium diiodide in anhydrous THF containing ethyl-
ene glycol and DMPU.13 R-Deoxygenation in this manner
gave rise efficiently to 14, thereby setting the stage for
arrival at 15 by means of conventional silylation under
mild conditions. Were the hydroxyl group in 14 on the
â-face of this intermediate, its protection would be
strongly impeded as is the case with 10.
Ketone 15 was readily reduced with L-Selectride in
THF at -78 °C, these conditions giving rise quantita-
tively to the R-alcohol 16. Other hydride reagents did not
perform with comparably high stereoselectivity. For
example, Dibal-H dissolved in CH2Cl2 led, at the same
low temperature, to a chromatographically separable 3:1
mixture of 16 and its epimer. The availability of both
stereoisomers in pure condition allowed for confirmation
of stereochemical configuration by NOE methods (see A
and B).
Exposure of 12 to alkaline hydrogen peroxide12 resulted
in clean conversion to a single oxirane formulated as 13.
Past experience has shown that the bulky OTBS sub-
stituent directs the entry of reagents to the R-face in
related spirononanes,6 and no stereochemical crossover
should be operational here. More direct evidence was
secured following the reductive cleavage of 13 with
(6) (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.;
Seekamp, C. K.; Kahane, A. L. J. Org. Chem. 2003, 68, 8614. (d)
Paquette, L. A.; Kahane, A. L.; Seekamp, C. K. J. Org. Chem. 2004,
69, 5555. (e) Paquette, L. A.; Seekamp, C. K.; Kahane, A. L.; Hilmey,
D. G.; Gallucci, J. C. J. Org. Chem. 2004, 69, 7442.
(7) Paquette, L. A.; Fabris, F.; Gallou, F.; Dong, S. J. Org. Chem.
2003, 68, 8625.
This accomplished, 16 was transformed in turn into
mesylate 17 to prepare for direct SN2 displacement
involving a series of nucleoside bases. The protected
pyrimidine deoxycarbospironucleosides 18-20 were ob-
tained with modest efficiency by direct condensation of
17 with the sodium salts of uracil, cytosine, and thy-
mine.14 For the two related purines 21 and 22, the closely
comparable protocol developed by Robbins involving
(8) Paquette, L. A.; Hartung, R. E.; France, D. J. Org. Lett. 2003, 5,
869.
(9) Review: Paquette, L. A. Austr. J. Chem. 2004, 57, 7.
(10) Nieman, J. A.; Keay, B. A. Synth. Commun. 1999, 29, 3829.
(11) Wright, J.; Drtina, G. J.; Roberts, R. A.; Paquette, L. A. J. Am.
Chem. Soc. 1988, 110, 5806.
(12) (a) Bunton, C. A.; Minkoff, G. J. J. Chem. Soc. 1949, 665. (b)
House, H. O.; Ro, R. S. J. Am. Chem. Soc. 1958, 80, 2428.
(13) (a) Hanessian, S.; Girard, C.; Chiara, J. L. Tetrahedron Lett.
1992, 33, 573. (b) Molander, G. A. Org. React. 1994, 46, 211. (c) Kagan,
H. B. Tetrahedron 2003, 59, 10351.
1598 J. Org. Chem., Vol. 70, No. 5, 2005

Synthesis of Spiro[4.4]nonane C-(2′-Deoxy)ribonucleosides
adenine and 2-amino-6-chloropurine was adapted.15 Hy-
drolytic removal of the Cl substituent required for the
conversion of 22 into the guanine relative 23 was ac-
complished without complication6d,16 with 2-mercaptoet-
hanol in hot aqueous methanol.14a,17 Finally, global
deprotection of intermediates from the group 18-23 with
TBAF led efficiently to the targeted 2′-deoxy spironucleo-
sides 24-28.
SCHEME 3
Preparation of members of the R subset of carbocyclic
spironucleosides began with the dehydration of 10,
although now in the form of its dextrorotatory enanti-
omer. This transformation resulted in the formation of
(+)-11 (Scheme 3). The next important step concerned
proper regiodirected hydration of the cyclopentene double
bond. The steric shielding provided by the structural
scaffold resident in 11 served to guide hydroboration in
the proper direction. From among a number of organobo-
ranes examined, disiamylborane emerged as a reasonable
compromise in that 29 and 30 were isolated in 19% and
51% yield, respectively. Although not needed for the
present purposes, it proved possible to maximize the
availability of 30 by means of the Mitsunobu reaction.19
To develop the synthetic route, the 29/30 mixture was
directly subjected to Swern oxidation. The ketone 31, so
generated in 80% yield, proved in turn to be amenable
to regiodirected R-deprotonation in view of the steric
shielding existent at the alternative neighboring site.
Direct treatment of the silyl enol ether with N-bromo-
succinimide19 resulted in formation of a diastereomeric
mixture of the R-bromo ketones 32. The dehydrobromi-
nation of 32 with lithium bromide and lithium carbonate
in DMF at 120 °C20 led smoothly to 33. It is pertinent to
underscore that “migration” of the double bond from its
original position in 11 to its ultimate location along the
leading edge constitutes a practical crossover into the
series diastereomeric to 12. The brevity of steps allows
for the conversion of very reasonable quantities of (+)-
10 into 33, whose elaboration into 45-49 was subse-
quently accomplished in a manner similar to that devel-
oped earlier. Attention is called in particular to the
parallel behavior of 15 and 36 to reduction with L-
Selectride, which occurs totally from the â-face in both
series and is therefore independent of the configuration
at the carbon atom bearing the -OTBS substituent.
These and related results form the basis of the structural
assignments given in Scheme 3.
the synthesis of stereoisomeric deoxycarbospironucleo-
sides. The adoption of two different reaction pathways
allows for the direct conversion of the two enantiomers
into the key enone intermediates 12 and 33. This “merger
of chirality” illustrates a principle that should find
application in a variety of contexts.
In summary, the unique characteristics of (-)-7 and
(+)-7 permit their development as starting materials for
(14) (a) Pathak, T.; Bazin, H.; Chattopadhyaya, J. Tetrahedron 1986,
42, 5427. (b) Wu, J. C.; Bazin, H.; Chattopadhyaya, J. Tetrahedron
1987, 43, 2355. (c) Pathak, T.; Chattopadhyaya, J. Tetrahedron 1987,
43, 4227.
(15) (a) Kazimierczuk, Z.; Revankar, G. R.; Robins, R. K. Nucleic
Acids Res. 1984, 12, 1179. (b) Kazimierczuk, Z.; Cottam, H. B.;
Revankar, G. R.; Robins, R. K. J. Am. Chem. Soc. 1984, 106, 6379. (c)
Revankar, G. R.; Gupta, P. K.; Adams, A. D.; Dalley, N. K.; McKernan,
P. A.; Cook, P. D.; Canonico, P. G.; Robins, R. K. J. Med. Chem. 1984,
27, 1389.
Experimental Section
(-)-Monoprotected Diol 10. To a solution of (-)-7 (2.77
g, 17.7 mmol), DMAP (0.43, 3.5 mmol), and imidazole (1.81 g,
26.6 mmol) in CH2Cl2 (94 mL) was added TBSCl (3.99 g, 26.6
mmol), and the solution was brought to reflux for 12 h. The
reaction mixture was quenched with saturated NaHCO3
solution, transferred to a separatory funnel, and extracted with
ether (3 × 50 mL). The combined organic phases were dried,
concentrated in vacuo, and purified by chromatography on
silica gel (10:1 hexanes:ethyl acetate) to give 4.69 g (98%) of
10 as a yellowish oil: IR (neat, cm-1) 3483, 1471, 1252; 1H
NMR (300 MHz, CDCl3) δ 4.21 (s, 1H), 4.15-4.09 (m, 2H),
(16) Hodge, R. P.; Brush, C. K.; Harris, C. M.; Harris, T. M. J. Org.
Chem. 1991, 56, 1553.
(17) Johnston, T. P.; Holum, L. B.; Montgomery, J. A. J. Am. Chem.
Soc. 1958, 80, 6265.
(18) Hughes, D. L. Org. React. 1992, 42, 335.
(19) (a) Piers, E.; Yeung, B. W. A.; Rettig, S. J. Tetrahedron 1987,
43, 5521. (b) Blanco, L.; Amice, P.; Conia, J. M. Synthesis 1976, 194.
(20) (a) Vidari, G.; Ferrino, S.; Grieco, P. A. J. Am. Chem. Soc. 1984,
106, 3539. (b) Ohkita, M.; Tsuji, T.; Suzaki, M.; Murakami, M.; Nishida,
S. J. Org. Chem. 1990, 55, 1506.
J. Org. Chem, Vol. 70, No. 5, 2005 1599

Hartung and Paquette
1.90-1.53 (series of m, 10H), 1.31-1.26 (m, 2H), 0.90 (s, 9H),
0.11 (s, 3H), 0.10 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 80.7,
78.9, 56.5, 34.2, 33.7, 33.5, 32.9, 25.7 (3C), 20.8, 19.9, 17.7,
-4.3, -5.2; ES HRMS m/z calcd 293.1907, obsd 293.1925;
[R]25D -54 (c 1.2, CHCl3). Anal. Calcd for C15H30O2Si: C, 66.61;
H, 11.18. Found: C, 66.48; H, 11.10.
mL), and (-)-13 (26.5 mg, 0.095 mol). The reaction mixture
was stirred for 1.5 h, diluted with petroleum ether, filtered
through a pad of Celite, and concentrated. The residue was
purified by chromatography on silica gel (3:1 hexanes/ethyl
acetate) to give 14 as a yellowish oil (18.3 mg, 95%); IR (neat,
cm-1) 3390, 1745, 1244; 1H NMR (300 MHz, CDCl3) δ 4.58 (t,
J ) 7.6 Hz, 1H), 3.99 (m, 1H), 2.83 (s, 1H), 2.69-1.60 (m, 1H),
2.32-2.21 (m, 3H), 2.02-1.62 (m, 4H), 1.37-1.26 (m, 1H), 0.92
(s, 9H), 0.12 (s, 3H), 0.11 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 213.9, 82.7, 72.1, 55.1, 49.7, 45.5, 34.7, 27.4, 25.8 (3C), 21.2,
17.9, -4.4-4.9; ES HRMS m/z (M + Na)+ calcd 307.1699, obsd
(-)-Unsaturated Silyl Ether 11. A solution of (-)-10 (2.71
g, 10.0 mmol) in pyridine (68 mL) was cooled to 0 °C, and
POCl3 (1.87 mL, 20.07 mmol) was added dropwise. The
reaction mixture was stirred for 8 h at 0 °C, allowed to warm
to rt overnight, transferred to a separatory funnel, diluted with
270 mL of 10% HCl, and extracted with ether (4 × 75 mL).
The combined ether layers were washed with 10% HCl (1 ×
100 mL), dried, and concentrated. The residue was purified
by chromatography on silica gel (petroleum ether) to give 1.80
g (64%) of 11 and 0.70 g (25%) of i.
307.1708; [R]20 +36.9 (c 1.1, CHCl3).
D
O-Silylation of (+)-14. A solution of (+)-14 (56 mg, 0.2
mmol), CH2Cl2 (5 mL), and 2,6-lutidine (114 µL, 0.98 mmol)
was blanketed with N2, cooled to -78 °C, treated with TBSOTf
(90 µL, 0.39 mmol), and stirred for 45 min. The reaction mixure
was warmed to rt, quenched with saturated CuSO4 solution,
stirred for 15 min, and extracted with CH2Cl2 (3 × 25 mL).
The combined organic layers were dried and concentrated to
leave a residue that was purified by chromatography on silica
gel (10:1 hexanes:ethyl acetate) to give 15 as a yellowish oil
(72 mg, 92%): IR (neat, cm-1) 1750, 1472, 1257; 1H NMR (300
MHz, CDCl3) δ 4.55 (t, J ) 2.2 Hz, 1H), 3.76 (t, J ) 5.5 Hz,
1H) 2.57 (dd, J ) 18.3, 5.3, 1H), 2.34-1.49 (m, 9H), 0.92 (s,
9H), 0.91 (s, 9H), 0.11 (s, 3H), 0.08 (s, 6H), 0.05 (s, 3H);13C
NMR (75 MHz, CDCl3) δ 217.9, 79.4, 72.3, 57.0, 48.5, 47.7,
33.8, 31.1, 26.19 (3C), 26.17 (3C), 20.6, 18.3 (2C), -3.8, -4.0,
-4.4, -4.6; ES HRMS m/z (M + Na)+ calcd 421.2564, obsd
For 11: IR (neat, cm-1) 1461, 1358, 1250; 1H NMR (300
MHz, CDCl3) δ 5.38 (d, J ) 2.1 Hz, 1H), 4.52 (t, J ) 2.7 Hz,
1H), 2.79 (m, 1H), 2.33-1.22 (series of m, 10H), 0.92 (s, 9H),
0.03 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 121.9, 99.8, 67.4,
41.5, 35.9, 35.8, 31.0, 30.2, 25.8 (3C), 22.6, 20.2, -4.6, -5.1;
ES HRMS m/z (M)+ calcd 252.1909, obsd 252.1891; [R]25D -73
(c 1.05, CHCl3).
421.2576; [R]20 -44.8 (c 1.12, CHCl3).
D
Hydride Reduction of (-)-15. A. With L-Selectride. A
cold (-78 °C) solution of (-)-15 (100 mg, 0.24 mmol) in THF
(3.2 mL) was treated with L-Selectride (260 µL, 0.26 mmol,
1.1 equiv) and stirred for 10 min. The reaction mixture was
quenched with saturated NaHCO3 solution and extrated with
ether (3 × 30 mL). The combined organic layers were dried
and concentrated to leave a residue that was purified by
chromatography on silica gel (20:1 hexanes:ethyl acetate) to
give 16 (99 mg, 99%) as a colorless oil: IR (neat, cm-1) 3384,
1471, 1463; 1H NMR (300 MHz, CDCl3) δ 4.40 (m, 1H), 4.24-
4.22 (m, 1H) 3.55-3.54 (m, 1H), 2.16-2.13 (m, 1H), 1.92-1.28
(series of m, 9H), 0.93 (s, 9H), 0.91 (s, 9H), 0.14 (s, 3H), 0.12
(s, 3H), 0.06 (s, 3H), 0.04 (m, 3H);13C NMR (75 MHz, CDCl3)
δ 80.8, 74.5, 74.0, 60.1, 47.6, 43.9, 26.5, 26.3, 26.1 (3C), 25.9
(3C), 20.9, 18.3 (2C), -3.9, -4.0, -4.4, -4.5; ES HRMS m/z
(M + Na)+ calcd 423.2721, obsd 423.2752; [R]20D -1.4 (c 1.02,
CDCl3).
With Dibal-H. A solution of (-)-15 (42 mg, 0.106 mmol) in
CH2Cl2 (4 mL) was blanketed with N2, cooled to -78 °C, and
treated with a 1M solution of Dibal-H in hexanes (127 µL, 0.13
mmol) in dropwise fashion. The reaction mixture was stirred
for 45 min, quenched at -78 °C with saturated sodium
potassium tartrate solution, and warmed to rt. After 30 min,
the products were extracted into CH2Cl2 (3 × 25 mL), the
combined organic phases were dried and concentrated, and the
residue was purified by chromatography on silica gel (10:1
hexanes/ethyl acetate) to give (31 mg, 71%) of 16 and (10 mg,
26%) of ii, both as colorless oils.
For i: IR (neat, cm-1) 1461, 1358, 1250; 1H NMR (300 MHz,
CDCl3) δ 5.38 (d, J ) 2.1 Hz, 1H), 4.52 (t, J ) 2.7 Hz, 1H),
2.79 (m, 1H), 2.33-1.22 (series of m, 10H), 0.92 (s, 9H), 0.03
(s, 6H); 13C NMR (75 MHz, CDCl3) δ 121.9, 99.8, 67.4, 41.5,
35.9, 35.8, 31.0, 30.2, 25.8 (3C), 22.6, 20.2, -4.6, -5.1; ES
HRMS m/z (M)+ calcd 252.1909, obsd 252.1891.
(+)-Spiro Enone 12. A solution of CrO3 (10.17 g, 101.8
mmol) and 3,5-dimethylpyrazole (9.77 g, 101.8 mmol) in CH2-
Cl2 (30 mL) was stirred at 0 °C for 20 min, cooled to -15 °C,
and treated with a solution of (-)-11 (1.71 g, 6.8 mmol) in CH2-
Cl2 (30 mL). The reaction mixture was stirred for 7 h, quenched
with ether, filtered through a pad of silica gel, and concen-
trated. The residue was purified by chromatography on silica
gel (10:1 hexanes/ethyl acetate) to give 0.96 g (53%) of 12 as a
yellowish oil: IR (neat, cm-1) 1716, 1462, 1252; 1H NMR (300
MHz, CDCl3) δ 7.65 (dd, J ) 5.7, 0.8 Hz, 1H), 7.26 (dd, J )
5.6, 1.5 Hz, 1H), 3.90 (m, 1H), 2.09-1.51 (series of m, 8H),
0.86 (s, 9H), 0.01 (s, 3H), -0.01 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 209.1, 170.1, 133.0, 81.8, 57.3, 46.8, 35.2, 34.3, 25.7
(3C), 21.6, 18.0, -4.9, -5.0; ES HRMS m/z (M + Na)+ calcd
289.1594, obsd 289.1571; [R]25 +32.6 (c 1.35, CHCl3).
D
(-)-Epoxy Ketone 13. Methanol (0.2 mL), (+)-12 (0.163
g, 0.61 mmol), and 30% H2O2 (0.13 mL, 1.84 mmol) were
combined and cooled to 0 °C. Aqueous 1 M NaOH (0.2 mL,
0.31 mmol) was added dropwise via syringe. The reaction
mixture was allowed to warm to rt, stirred for 4 h, and diluted
with ether (5 mL) and saturated NaHCO3 solution. The
separated aqueous phase was extracted with ether (3 × 25
mL), and the combined organic phases were dried and con-
centrated. The residue was purified by chromatography on
silica gel (10:1 hexanes/ethyl acetate) to yield 13 as a colorless
oil (125 mg, 73%): IR (neat, cm-1) 1751, 1471, 1408; 1H NMR
(300 MHz, CDCl3) δ 3.87-3.84 (m, 2H), 3.36 (d, J ) 2.5 Hz,
1H), 2.31-1.62 (m, 8H), 0.84 (s, 9H), 0.02 (s, 3H), 0.00 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 208.8, 803, 61.5, 56.5, 50.2, 42.1,
32.7, 31.1, 25.6 (3C), 19.9, 17.7, -4.5, -5.3; ES HRMS m/z (M
For ii: IR (neat, cm-1) 3355, 1472, 1360; 1H NMR (300 MHz,
CDCl3) δ 4.47 (t, J ) 6.0 Hz, 1H), 4.32-4.30 (m, 1H), 3.91 (t,
J ) 7.2 Hz, 1H), 2.15-1.27 (m, 10H), 0.95 (s, 9H), 0.91 (s, 9H),
0.11 (s, 6H), 0.088 (s, 3H), 0.086 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 80.6, 73.3, 71.6, 57.1, 46.0, 45.9, 33.3, 31.0, 26.3 (3C),
26.2 (3C), 20.3, 18.4, 18.3, -3.74, -3.75, -4.3, -4.5; ES HRMS
+ Na)+ calcd 305.1543, obsd 305.1545; [R]20 -50.2 (c 1.1,
D
CHCl3).
(+)-â-Hydroxy Ketone 14. Into a flame-dried 10 mL pear-
shaped flask equipped with a magnetic stirring bar was
introduced a 0.1 M solution of SmI2 in THF (2.82 mL, 0.282
mmol), THF (2 mL), DMPU (0.18 mL), ethylene glycol (0.1
m/z (M + Na)+ calcd 423.2721, obsd 423.2752; [R]20 +2.0 (c
D
0.8, CHCl3).
1600 J. Org. Chem., Vol. 70, No. 5, 2005

Synthesis of Spiro[4.4]nonane C-(2′-Deoxy)ribonucleosides
Mesylate (+)-17. A solution of (+)-16 (60 mg, 0.15 mmol)
and Et3N (63 µL, 0.45 mmol) in CH2Cl2 (5 mL) was cooled to
0 °C and treated dropwise with MsCl (24 µL, 0.3 mmol). The
reaction mixture was stirred for 3 h, allowed to warm to rt,
quenched with saturated NaHCO3 solution, and extracted with
Et2O (3 × 25 mL). The combined organic phases were dried
and concentrated. The residue was purified by chromatography
on silica gel (10:1 hexanes/ethyl acetate) to give 60 mg (81%)
58.3, 53.8, 42.6, 41.0, 33.4, 31.3, 26.3 (3C), 26.2 (3C), 20.5, 18.4,
18.3, -3.8 (2C), -4.3, -4.4; ES HRMS m/z (M + Na)+ calcd
518.3341, obsd 518.3326; [R]20 -10.6 (c 1.0, CHCl3).
D
Incorporation of 2-Amino-6-chloropurine. A mixture of
NaH (16 mg, 0.65 mmol) and 2-amino-6-chloropurine (107 mg,
0.63 mmol) in DMF (9 mL) was treated with (+)-17 (100 mg,
0.21 mmol) in DMF (1 mL), brought to 80 °C, stirred for 12 h,
allowed to cool to rt, quenched with saturated NaHCO3
solution, and extracted with ether (3 × 30 mL). The combined
ether layers were dried and concentrated. The residue was
purified by chromatography on silica gel (3:1 hexanes:ethyl
acetate) to give 22 (31 mg, 27%, 90% brsm) as a white solid:
mp > 300 °C; IR (neat, cm-1) 1609, 1566, 1456; 1H NMR (500
MHz, CDCl3) δ 7.79 (s, 1H), 5.06 (s, NH), 4.98-4.95 (m, 1H),
4.59 (t, J ) 8.7 Hz, 1H), 4.26 (t, J ) 4.3 Hz, 1H), 2.40-1.39
(series of m, 10H), 0.94 (s, 9H), 0.93 (s, 9H), 0.10 (s, 3H), 0.09
(s, 6H), 0.08 (s, 3H);13C NMR (125 MHz, CDCl3) δ 158.6, 153.6,
151.2, 141.1, 126.0, 79.0, 72.8, 57.6, 53.3, 41.6, 40.3, 32.9, 30.7,
25.9 (3C), 25.8 (3C), 20.0, 18.0, 17.9, -4.2, -4.3, -4.7 (2C);
1
of 17 as a colorless oil: IR (neat, cm-1) 1472, 1359, 1256; H
NMR (300 MHz, CDCl3) δ 5.11-5.06 (m, 1H), 4.27 (dd, J )
5.0, 0.9 Hz, 1H), 3.71 (t, J ) 6.8 Hz, 1H), 3.00 (s, 3H), 2.46-
2.40 (m, 1H), 2.22-2.16 (m, 1H), 2.04-1.41 (series of m, 8H),
0.93 (s, 9H), 0.92 (s. 9H), 0.09 (s, 6H), 0.08 (s, 3H), 0.07 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 80.8, 79.2, 72.8, 57.5, 42.6,
42.5, 38.8, 26.2 (3C), 26.1 (3C), 20.4, 18.37, 18.33, -3.85, -3.86,
-4.5, -4.6; ES HRMS m/z (M + Na)+ calcd 501.2496, obsd
501.2508; [R]20 +10.4 (c 1.4, CHCl3).
D
Incorporation of Uracil. To a mixture of NaH (6 mg, 0.25
mmol) and uracil (28 mg, 0.25 mmol) in DMF (5.2 mL) was
added (+)-17 (80 mg, 0.16 mmol) dissolved in DMF (1 mL).
The reaction mixture was brought to 80 °C, stirred for 12 h,
allowed to cool to rt, quenched with saturated NaHCO3
solution, and extracted with ether (3 × 30 mL). The combined
ether layers were dried and concentrated to leave a residue
that was purified by chromatography on silica gel (3:1 hexanes:
ethyl acetate) to give 18 (13 mg, 16%, 43% brsm) as a white
ES HRMS m/z (M + Na)+ calcd 574.2770, obsd 574.2780; [R]20
-2.5 (c 0.8, CHCl3).
D
Hydrolysis of 22 to Guanine Derivative 23. To a solution
of 22 (12 mg, 0.022 mmol) in MeOH (5.0 mL) was added
2-mercaptoethanol (30 µL, 0.43 mmol) and a 5.25 M solution
of NaOMe in MeOH (87 µL, 0.45 mmol). The reaction mixture
was heated to 60 °C for 4 h, cooled, and concentrated.
Purification of the residue by chromatography on silica gel (9:1
dichlromethane/methanol) gave 23 as a white solid: mp > 300
1
solid: mp 118 °C; IR (neat, cm-1) 1684, 1464, 1257; H NMR
(500 MHz, CDCl3) δ 8.47 (s, NH), 7.20 (d, J ) 8.1 Hz, 1H),
5.73 (dd, J ) 7.0, 2.3 Hz, 1H), 5.07-5.04 (m, 1H), 4.46 (t, J )
5.5 Hz, 1H), 3.85 (t, J ) 7.0 Hz, 1H), 2.18-1.26 (series of m,
10H), 0.94 (s, 9H), 0.91 (s, 9H), 0.09 (s, 6H), 0.08 (s, 3H), 0.07
(s, 3H);13C NMR (125 MHz, CDCl3) δ 162.8, 150.6, 1411, 102.4,
78.9, 72.0, 56.6, 54.1, 40.6, 39.6, 32.7, 30.3, 25.9 (3C), 25.7 (3C),
19.3, 18.0, 17.8, -4.2 (2C), -4.81, -4.83; ES HRMS m/z (M +
Na)+ calcd 517.2888, obsd 517.2871; [R]20D -10.7 (c 1.0, CHCl3).
1
°C (10 mg, 87%); H NMR (500 MHz, CD3OD) δ 7.67 (s, 1H),
5.00-4.93 (m, 1H), 4.66-4.64 (m, 1H), 4.01 (t, J ) 5.9 Hz, 1H),
2.38-1.46 (series of m, 10H), 0.96 (s, 9H), 0.95 (s, 9H), 0.14
(s, 3H), 0.13 (s, 3H), 0.12 (s, 3H), 0.11 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 159.6, 155.3, 152.3, 134.3, 114.4, 79.0, 73.1,
57.5, 51.9, 42.0, 40.1, 32.7, 30.5, 25.0 (3C), 24.9 (3C), 19.5, 17.5,
17.4, -5.3, -5.5, -5.8, -5.9; ES HRMS m/z (M + Na)+ calcd
556.3109, obsd 556.3080; [R]20 -2.5 (c 0.8, CHCl3).
D
Incorporation of Cytosine. From 124 mg (0.26 mmol) of
(+)-17, adaptation of the preceding conditions in the presence
of cytosine afforded 15 mg (12%) of 19 as a colorless oil: IR
General Procedure for the Global Deprotection of 18-
23. A solution of 18 (11 mg, 0.02 mmol) and 1M TBAF in THF
(0.13 mL, 0.13 mmol) in THF (1 mL) was stirred at rt for 32
h. The reaction mixture was concentrated and the crude
product was purified by chromatography on silica gel (9:1
dichloromethane/methanol) to give 24 (5.4 mg, 92%) as a white
1
(neat, cm-1) 1635, 1591, 1559; H NMR (500 MHz, CDCl3) δ
8.05 (d, J ) 5.7 Hz, 1H), 6.09 (d, J ) 5.6 Hz, 1H), 5.44-5.40
(m, 1H), 4.86 (s, NH2), 4.45 (t, J ) 5.2 Hz, 1H), 4.15 (t, J ) 7.1
Hz, 1H), 2.24-1.28 (series of m, 10H), 0.93 (s, 9H), 0.92 (s,
9H), 0.09 (s, 3H), 0.08 (s, 3H), 0.07 (s, 3H), 0.06 (s, 3H);13C
NMR (125 MHz, CDCl3) δ 164.9, 164.2, 157.9, 99.3, 78.8, 76.6,
74.5, 58.5, 42.4, 41.7, 26.2 (6C), 20.8, 18.4, 18.3, -3.9 (2C),
-4.3, -4.4; ES HRMS m/z (M + Na)+ calcd 516.3054, obsd
1
solid: mp 179 °C; IR (neat, cm-1) 3415, 1687, 1463, 1382; H
NMR (500 MHz, CD3OD) δ 7.69 (d, J ) 8.0 Hz, 1H), 5.70 (d,
J ) 8.0 Hz, 1H), 5.06-5.03 (m, 1H), 4.50 (t, J ) 5.6 Hz, 1H),
3.93 (t, J ) 5.0 Hz, 1H), 2.22-1.36 (series of m, 10H);13C NMR
(125 MHz, CD3OD) δ 164.8, 151.3, 143.1, 101.2, 79.6, 72.2,
56.4, 54.3, 39.9, 37.9, 32.5, 28.8, 19.9; ES HRMS m/z (M +
Na)+ calcd 289.1158, obsd 289.1169; [R]20D -9.8 (c 1.0, CHCl3).
516.2900; [R]20 -7.8 (c 1.1, CHCl3).
D
Incorporation of Thymine. When 80 mg (0.16 mmol) of
(+)-17 was processed in analogous fashion with thymine, there
was isolated 20 mg (25%, 27% brsm) of 20 as a colorless oil:
IR (neat, cm-1) 1689, 1666, 1471; 1H NMR (500 MHz, CDCl3)
δ 8.46 (s, NH), 6.99 (s, 1H), 5.08-5.05 (m, 1H), 4.47 (t, J )
5.9 Hz, 1H), 3.85 (t, J ) 7.1 Hz, 1H) 2.19-1.28 (series of m,
10H), 1.94 (s, 3H), 0.95 (s, 9H), 0.91 (s, 9H), 0.09 (s, 6H), 0.08
(s, 3H), 0.07 (s, 3H);13C NMR (125 MHz, CDCl3) δ 163.4, 150.7,
136.9, 111.0, 78.7, 71.9, 56.3, 53.3, 40.7, 39.6, 32.6, 30.1, 25.9
(3C), 25.7 (3C), 19.7, 18.0, 17.8, 12.6, -4.1, -4.2, -4.8, -4.9;
For 25: white solid; mp 164-165 °C; 84% yield; IR (neat,
1
cm-1) 3335, 3206, 1632, 1596; H NMR (500 MHz, CDCl3) δ
7.83 (d, J ) 6.0 Hz, 1H), 6.13 (d, J ) 5.9 Hz, 1H), 5.43-5.38
(m, 1H), 4.45 (t, J ) 5.9 Hz, 1H), 3.94 (t, J ) 2.6 Hz, 1H),
2.21-1.37 (series of m, 10H);13C NMR (125 MHz, CDCl3) δ
166.2, 164.6, 155.5, 98.9, 79.4, 75.8, 74.1, 57.5, 42.5, 40.8, 33.3,
29.8, 20.7; EI HRMS m/z (M+) calcd 265.1420, obsd 265.1393;
[R]20 -17.3 (c 0.6, MeOH).
D
ES HRMS m/z (M + Na)+ calcd 531.3044, obsd 531.3023; [R]20
-25.2 (c 1.0, CHCl3).
For 26: colorless oil; 73% yield; 1H NMR (500 MHz, C5D5N)
δ 7.50 (d, J ) 1.2 Hz, 1H), 5.05-5.02 (m, 1H), 4.51 (t, J ) 6.7
Hz, 1H), 3.94 (t, J ) 5.3 Hz, 1H), 2.23-1.39 (series of m, 10H),
1.95 (3H); 13C NMR (125 MHz, C5D5N) δ 165.0, 151.5, 138.8,
110.2, 79.6, 72.1, 56.3, 53.9, 39.9, 37.8, 32.5, 28.7, 19.5, 12.6;
D
Incorporation of Adenine. A mixture of 17 (39 mg, 0.08
mmol), adenine (16.5 mg, 0.122 mmol), and NaH (3 mg, 0.122
mmol) in 3 mL of DMF was heated to reflux for 18 h, allowed
to cool to rt, quenched with saturated NaHCO3 solution, and
extracted with Et2O (3 × 25 mL). The combined organic phases
were dried and concentrated. The residue was purified by
chromatography on silica gel (2:1 hexanes/ethyl acetate) to give
25 mg (60%) of 21 as a colorless oil: IR (neat, cm-1) 1650, 1598,
1471;1H NMR (300 MHz, CDCl3) δ 8.37 (s, 1H), 7.87 (s, 1H),
5.14-5.10 (m, 1H), 4.62 (dd, J ) 5.4, 3.9 Hz, 1H), 4.07 (t, J )
6.1 Hz, 1H), 2.50-1.42 (series of m, 10H), 0.96 (s, 9H), 0.94
(s, 9H), 0.13 (s, 3H), 0.11 (s, 3H), 0.10 (s, 6H);13C NMR (75
MHz, CDCl3) δ 155.4, 152.2, 150.4, 139.7, 120.6, 79.4, 73.5,
ES HRMS m/z (M + Na)+ calcd 303.1315, obsd 303.1296; [R]20
D
-12.3 (c 0.70, C5H5N).
For 27: white solid; mp > 300 °C; 93% yield; IR (neat, cm-1
)
3321, 1478, 1415; 1H NMR (500 MHz, CD3OD) δ 8.20 (s, 1H),
5.20-5.15 (m, 1H), 4.58 (m, 1H), 4.06 (t, J ) 5.0 Hz, 1H), 2.61-
2.55 (m, 1H), 2.28-2.19 (m, 3H), 2.04-1.94 (m, 2H), 1.84-
1.80 (m, 1H), 1.72-1.65 (m, 2H), 1.54-1.49 (m, 1H);13C NMR
(125 MHz, CD3OD) δ 156.3, 152.2, 149.4, 140.5, 119.7, 80.2,
72.9, 57.5, 53.7, 41.6, 40.2, 32.6, 29.7, 20.2; EI HRMS m/z (M+)
calcd 289.1533, obsd 289.1502; [R]20 -3.0 (c 1.0, MeOH).
D
J. Org. Chem, Vol. 70, No. 5, 2005 1601

Hartung and Paquette
For 28: white solid; mp > 300 °C; 62% yield; 1H NMR (500
MHz, C5D5N) δ 8.10 (s, 1H), 5.16 (t, J ) 5.6 Hz, 1H), 4.72 (t,
J ) 5.4 Hz, 1H), 4.25-4.24 (m, 1H), 2.71-1.30 (series of m,
10H);13C NMR (125 MHz, C5D5N) δ 158.5, 157.2, 154.5, 143.4,
119.0, 79.9, 72.7, 57.6, 52.3, 42.5, 41.6, 33.8, 29.8, 20.9; ES
NaHCO3 solution, transferred to a separatory funnel, and
extracted 3 times with ether. The combined organic phases
were dried and concentrated. Purification of the residue by
chromatography on silica gel (10:1 hexanes:ethyl acetate) gave
31 as a colorless oil (27.9 mg, 80%): IR (neat, cm-1) 1745, 1472,
1
HRMS m/z (M + Na)+ calcd 328.1380, obsd 328.1395; [R]20
1406; H NMR (300 MHz, CDCl3) δ 3.83 (t, J ) 6.9 Hz, 1H),
D
-5.7 (c 0.2, C5H5N).
2.54-2.48 (m, 1H), 2.26-223 (m, 2H), 1.93-1.52 (series of m,
9H), 0.85 (s, 9H), 0.02 (s, 6H); 13C NMR (75 MHz, CDCl3) δ
219.8, 79.4, 51.1, 45.0, 37.6, 34.8, 32.8, 32.6, 25.6 (3C), 19.5,
17.8, -4.3, -5.1; ES HRMS m/z (M + Na)+ calcd 291.1750,
Dehydration of (+)-10. A procedure identical to those
utilized above for the levorotatory enantiomer furnished 56%
of (+)-11 and 25% of i. The 1H and 13C NMR of (+)-11 are
identical to those of (-)-11: ES HRMS m/z (M + H)+ calcd
obsd 291.1770; [R]20 +43.1 (c 1.22, CHCl3).
D
253.1982, obsd 253.1992; [R]23 +89 (c 1.2, CHCl3).
Regioselective Bromination of (+)-31 A solution of (+)-
31 (67 mg, 0.25 mmol) in THF (1.5 mL) was cooled to -78 °C.
A 1M solution of lithium hexamethyldisilazide in THF (300
µL, 0.3 mmol) was added and the mixture was stirred for 1 h.
TMSCl (44 µL, 0.35 mmol) was introduced and stirring was
maintained for an additional hour with warming to rt. The
reaction mixture was quenched with saturated NaHCO3
solution and extracted with ether (3 × 15 mL). The combined
organic solutions were dried and concentrated. The crude
product was redissolved in a mixture of THF and H2O (5:1, 3
mL), at which point NBS (134 mg, 0.75 mmol) was added. After
4 h of stirring, the reaction mixture was quenched with
saturated NaHCO3 solution and extracted with ether (3 × 15
mL). The combined organic solutions were dried and concen-
trated to leave a residue that was purified by chromatography
on silica gel (hexanes:ethyl acetate 10:1) to give 32 as a
mixture of diastereomers; colorless oil (67 mg, 77%): IR (neat,
cm-1) 1750, 1471, 1257; 1H NMR (300 MHz, CDCl3) δ 4.40 (s,
1H), 4.00 (t, J ) 6.9 Hz, 1H), 2.41-1.54 (series of m, 10H),
0.84 (s, 9H), 0.24 (s, 3H), 0.15 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 210.5, 81.0, 57.3, 34.4, 33.4, 32.0, 28.1, 26.1 (3C), 22.7,
20.2, 18.3, -3.9, -4.7; ES HRMS m/z (M + Na)+ calcd
369.0855, obsd 369.0862.
D
Hydroboration of (+)-11. A cold (0 °C) 1 M solution of
BH3•THF (8.37 mL, 8.37 mmol) was treated with 2-methyl-2-
butene (1.79 mL, 16.76 mmol), allowed to warm to rt during
30 min, returned to 0 °C, and treated with a solution of (+)-
11 (0.70 g, 2.8 mmol) in 1 mL of THF. The reaction mixture
was stirred for 12 h with warming to rt, treated with 3 M
NaOH solution (2.29 mL) and 30% H2O2 (7.34 mL), washed
with saturated NaHCO3 solution, and extracted with ether (3
× 25 mL). The combined organic solutions were dried and
concentrated to leave a residue that was purified by chroma-
tography on silica gel (10:1 hexanes:ethyl acetate) to give 500
mg (66%) of 30 and 140 mg (19%) of 29, both as colorless oils.
For 29: IR (neat, cm-1) 3378, 1471, 1254; 1H NMR (300
MHz, CDCl3) δ 4.22 (s, 1H), 3.81 (t, J ) 7.7 Hz, 1H), 3.04-
3.01 (m, 1H), 1.97-1.47 (series of m, 12H), 0.91 (s, 9H), 0.10
(s, 3H), 0.09 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 80.8, 73.8,
52.8, 45.1, 42.3, 37.6, 35.5, 32.9, 31.7, 25.9 (3C), 19.4, -4.2,
-4.7; ES HRMS m/z (M + Na)+ calcd 293.1907, obsd 293.1919;
[R]20 +30 (c 0.82, CHCl3).
D
For 30: IR (neat, cm-1) 3372, 1471, 1255; 1H NMR (300
MHz, CDCl3) δ 4.30-4.32 (m, 1H), 3.66 (t, J ) 5.4 Hz, 1H),
2.25 (dd, J ) 7.5, 6.5 Hz, 1H), 1.90-1.24 (series of m, 11H),
0.88 (s, 9H), 0.03 (s, 6H);13C NMR (75 MHz, CDCl3) δ 80.2,
74.2, 53.2, 41.4, 37.5, 35.3, 34.5, 32.9, 25.8 (3C), 20.1, 17.9,
-4.3, -4.9; ES HRMS m/z (M + Na)+ calcd 293.1907, obsd
Unsaturated Ketone (-)-33. A solution of 32 (1.12 g, 3.23
mmol), LiBr (489 mg, 5.49 mmol), and Li2CO3 (597 mg, 8.07
mmol) in DMF (62 mL) was heated to 120-130 °C for 2h,
quenched with saturated NaHCO3 solution, and extracted with
ether (3 × 15 mL). The combined organic phases were dried
and concentrated. The residue was purified by chromatography
on silica gel (hexanes:ethyl acetate 10:1) to give 33 as a
colorless oil (680 mg, 80%): IR (neat, cm-1) 1716, 1472, 1401;
1H NMR (300 MHz, CDCl3) δ 7.33 (d, J ) 5.6 Hz, 1H), 6.12 (d,
J ) 5.6 Hz, 1H), 4.02 (t, J ) 8.1 Hz, 1H), 2.79 (d, J ) 18.1 Hz,
1H), 2.20-1.52 (series of m, 6H), 1.94 (d, J ) 18.1 Hz, 1H),
0.84 (s, 9H), 0.03 (s, 3H), -0.01 (s, 3H); 13C NMR (75 MHz,
CDCl3): δ 210.4, 169.9, 134.1, 77.9, 57.1, 42.1, 35.3, 33.4, 26.0
(3C), 20.2, 18.3, -4.2, -4.5; ES HRMS m/z (M + Na)+ calcd
293.1913; [R]20 +38 (c 1.47, CHCl3).
D
Mitsunobu Inversion of (+)-29. A solution of DIAD (86
µL, 0.45 mmol) and triphenylphosphine (118 mg, 0.45 mmol)
in cold (0 °C) THF (2 mL) was stirred for 10 min prior to the
addition of a solution of (+)-29 (61.4 mg, 0.23 mmol) and
PhCO2H (55 mg, 0.45 mmol) in 0.5 mL of THF at rt. The
reaction mixture was stirred for 12 h and concentrated. The
residue was purified by chromatography on silica gel (10:1
hexanes:ethyl acetate) to give 0.36 g (86%) of inverted benzoate
1
as a yellowish oil; IR (neat, cm-1) 1710, 1421, 1264; H NMR
(300 MHz, CDCl3) δ 8.05 (d, J ) 8.2 Hz, 2H), 7.55 (t, J ) 6.2
Hz, 1H), 7.46-7.41 (m, 2H), 5.47-5.40 (m, 1H), 3.77 (t, J )
5.8 Hz, 1H), 2.39 (dd, J ) 7.8, 6.5 Hz, 1H), 2.16-2.04 (m, 1H),
1.95-1.12 (series of m, 10H), 0.91 (s, 9H), 0.08 (s, 3H), 0.06
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.2, 132.5, 130.9, 129.4
(2C), 128.2 (2C), 80.2, 77.9, 53.4, 38.3, 36.8, 34.8, 33.1, 32.5,
25.8 (3C), 20.2, 17.9-4.3, -4.9; ES HRMS m/z (M + Na)+ calcd
289.1594, obsd 289.1604; [R]20 -94.6 (c 0.89, CHCl3).
D
Epoxy Ketone (+)-34. Methanol (0.2 mL), (-)-33 (0.163
g, 0.61 mmol), and 30% H2O2 (0.13 mL, 1.84 mmol) were
combined and cooled to 0 °C. 1 M NaOH (0.2 mL, 0.31 mmol)
was added dropwise via syringe. The reaction mixture was
allowed to warm to rt, stirred for 4 h, quenched with saturated
NaHCO3 solution, and extracted with ether (3 × 15 mL). The
combined organic solutions were dried and concentrated. The
residue was purified by chromatography on silica gel (hexanes/
ethyl acetate 10:1) to give 34 as a colorless oil (130 mg, 78%):
IR (neat, cm-1) 1720, 1445, 1360; 1H NMR (300 MHz, CDCl3)
δ 4.03 (t, J ) 7.8 Hz, 1H), 3.56 (d, J ) 2.3 Hz, 1H), 3.36 (d, J
) 2.4 Hz, 1H), 2.40-1.59 (series of m, 8H), 0.87 (s, 9H), 0.06
(s, 3H), 0.04 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 208.7, 142.0,
77.3, 66.2, 38.9, 32.8, 32.0, 29.7, 25.9 (3C), 20.1, 18.2, -4.0,
-4.7; ES HRMS m/z (M + Na)+ calcd 305.1543, obsd 305.1519;
[R]2D0 +8.4 (c 0.5, CHCl3).
397.2169, obsd 397.2185; [R]20 -2 (c 1.23, CHCl3).
D
A 5.25 M solution of NaOMe in MeOH (36 µL, 0.19 mmol)
was added to the above benzoate (599 mg, 0.16 mmol) dissolved
in MeOH (0.5 mL). The reaction mixture was stirred for 30
min, quenched with saturated NaHCO3 solution, transferred
to a separatory funnel, and extracted with ether (3 × 10 mL).
The combined ether layers were dried and concentrated to
leave a residue that was purified by chromatography on silica
gel (10:1 hexanes/ethyl acetate) to give 30 mg (71%) of (+)-30
as a colorless oil. The spectral features of this product were
identical to those reported above.
Swern Oxidation of 29/30. A solution of oxalyl chloride
(17 µL, 0.195 mmol) in CH2Cl2 (1 mL) was brought to -78 °C
where DMSO (28 µL, 0.39 mmol) was added dropwise. After
15 min, a mixture of 39 and 40 (35.1 mg, 0.13 mmol) in 1 mL
of CH2Cl2 was introduced dropwise. After an additional hour,
Et3N (54 µL, 0.39 mmol) was added, and the solution was
allowed to come to rt prior to quenching with saturated
Samarium Iodide-Promoted Reduction of (+)-34. Eth-
ylene glycol (4.13 mL, 74.1 mmol), DMPU (7.82 mL, 64.8 mmol)
and (+)-34 (1.1 g, 3.9 mmol) were dissolved in THF (83 mL).
The solution was degassed with argon, at which point a 0.1 M
solution of SmI2 in THF (117 mL, 11.7 mmol) was added. The
reaction mixture was stirred for 1 h, quenched with saturated
NaHCO3 solution, transferred to a separatory funnel, and
1602 J. Org. Chem., Vol. 70, No. 5, 2005

Synthesis of Spiro[4.4]nonane C-(2′-Deoxy)ribonucleosides
extracted with Et2O (3 × 100 mL). The combined organic
solutions were dried and concentrated. The residue was
purified by chromatography on silica gel (2:1 hexanes/ethyl
acetate) to give 35 as a colorless oil (0.84 g, 76%): IR (neat,
Incorporation of Cytosine. When 74 mg (0.16 mmol) of
(+)-38 was processed in analogous fashion with cytosine, there
was isolated 9 mg (12%, 40% brsm) of 40 as a colorless oil: IR
1
(CH2Cl2, cm-1) 3315, 3178, 1631; H NMR (500 MHz, CDCl3)
1
cm-1) 3434, 1735, 1466; H NMR (500 MHz, CDCl3) δ 4.16-
δ 8.02 (d, J ) 5.7 Hz, 1H), 6.10 (d, J ) 5.7 Hz, 1H), 5.34-5.30
(m, 1H), 4.93 (s, NH2), 4.11 (t. J ) 8.3 Hz, 1H), 3.88 (t, J ) 7.0
Hz, 1H), 2.10-1.26 (series of m, 8H), 0.89 (s, 9H), 0.86 (s, 9H),
0.05 (s, 3H), 0.04 (s, 3H), 0.03 (s, 6H); 13C NMR (125 MHz,
CDCl3) δ 164.6, 157.0, 149.7, 139.3, 76.5, 74.7, 73.8, 56.6, 40.7,
36.2, 33.8, 28.3, 25.88 (3C), 25.84 (3C), 20.1, 18.0, 17.9, -4.0,
-4.09, -4.8, -4.9; ES HRMS m/z (M + Na)+ calcd 516.3048,
4.09 (m, 1H), 3.97 (t, J ) 7.8 Hz, 1H), 2.70-1.43 (series of m,
10H), 0.84 (s, 9H), 0.03 (s, 3H), 0.02 (s, 3H);13C NMR (125 MHz,
CDCl3) δ 217.7, 77.2, 74.8, 55.8, 47.4, 43.5, 33.6, 29.5, 26.1
(3C), 19.7, 18.2, -3.8, -4.7; ES HRMS m/z (M + Na)+ calcd
307.1699, obsd 307.1722; [R]20 +22.0 (c 1.3, CHCl3).
D
Silylation of (+)-35. A solution of (+)-35 (197 mg, 0.7
mmol), 2,6-lutidine (0.4 mL, 3.5 mmol), and CH2Cl2 (20 mL)
was cooled to -78 °C, when TBSOTf (0.32 mL, 1.4 mmol) was
added. The reaction mixture was stirred for 1 h, allowed to
warm to rt, quenched with saturated NaHCO3 solution,
transferred to a separatory funnel, and extracted with Et2O
(3 × 50 mL). The combined organic phases were dried and
concentrated to leave a residue that was purified by chroma-
tography on silica gel (20:1 hexanes:ethyl acetate) to give 36
as a white solid: mp 58 °C (224 mg, 81%); IR (neat, cm-1) 1748,
obsd 516.3061; [R]20 +22.2 (c 0.9, CHCl3).
D
Incorporation of Thymine. Reaction of 80 mg (0.16 mmol)
of (+)-38 with thymine under the predescribed conditions
afforded 20 mg (25%, 27% brsm) of 41 as a white solid: mp
160-162 °C; IR (CH2Cl2, cm-1) 1687, 1471, 1255; 1H NMR (500
MHz, CDCl3) δ 8.51 (s, NH), 7.07 (d, J ) 1.1 Hz, 1H), 5.23-
5.16 (m, 1H), 4.09 (t, J ) 7.0 Hz, 1H), 3.91 (t, J ) 7.3 Hz, 1H),
2.02-1.24 (series of m, 8H), 1.94 (s, 3H), 0.93 (s, 9H), 0.91 (s,
9H), 0.11 (s, 3H), 0.09 (s, 3H), 0.08 (s, 3H), 0.07 (s, 3H);13C
NMR (125 MHz, CDCl3) δ 163.4, 150.8, 136.8, 111.1, 76.6, 74.6,
56.8, 52.2, 39.7, 34.3, 32.8, 28.2, 25.9 (3C), 25.8 (3C), 19.2, 18.0,
17.9, 12.5, -3.8, -4.1, -4.8, -4.9; ES HRMS m/z (M + Na)+
1
1472, 1255; H NMR (500 MHz, CDCl3) δ 4.10 (t, J ) 5.8 Hz,
1H), 3.94 (t, J ) 7.4 Hz, 1H), 2.57-1.42 (series of m, 10H),
0.88 (s, 9H), 0.85 (s, 9H), 0.07 (s, 3H), 0.04 (s, 3H), 0.03 (s,
6H);13C NMR (125 MHz, CDCl3) δ 216.7, 76.6, 74.4, 56.3, 47.8,
43.9, 34.0, 29.5, 26.14 (3C), 26.11 (3C), 19.8, 18.3, 18.2, -3.6,
-3.9, -4.6, -4.64; ES HRMS m/z (M + Na)+ calcd 421.2564,
calcd 531.3044, obsd 531.3070; [R]20 +26.2 (c 1.4, CHCl3).
D
Incorporation of Adenine. To a mixture of NaH (9 mg,
0.32 mmol) and adenine (41 mg, 0.3 mmol) in DMF (4.5 mL)
was added (+)-38 (72 mg, 0.15 mmol) in DMF (1.5 mL). The
reaction mixture was brought to 80 °C, stirred for 12 h, allowed
to cool to rt, quenched with saturated NaHCO3 solution, and
extracted with ether (3 × 30 mL). The combined ether layers
were dried and concentrated. The residue was purified by
chromatography on silica gel (1:1 hexanes/ethyl acetate) to give
42 (28 mg, 37%, 63% brsm) as a white solid: mp 142 °C; IR
obsd 421.2582; [R]20 +40.0 (c 1.4, CHCl3).
D
L-Selectride Reduction of (+)-36. A solution of (+)-36
(30 mg, 0.08 mmol) in THF (1 mL) was cooled to -78 °C,
treated with L-Selectride (83 µL, 0.08 mmol), stirred for 10
min, quenched with saturated NaHCO3 solution, and extracted
with ether (3 × 30 mL). The combined organic layers were
dried and concentrated. The residue was purified by chroma-
tography on silica gel (20:1 hexanes/ethyl acetate) to give 37
1
(CH2Cl2, cm-1) 3316, 3159, 1643; H NMR (500 MHz, CDCl3)
δ 8.36 (s, 1H), 7.91 (s, 1H), 5.84 (s, NH2), 5.13-5.10 (m, 1H),
4.29 (t, J ) 7.0 Hz, 1H), 3.96 (t, J ) 7.3 Hz, 1H), 2.37-1.41
(series of m, 8H), 0.91 (s, 9H), 0.90 (s, 9H), 0.10 (s, 3H), 0.09
(s, 3H), 0.07 (s, 3H), 0.05 (s, 3H);13C NMR (125 MHz, CDCl3)
δ 155.3, 152.5, 150.0, 138.8, 119.9, 76.6, 74.5, 57.1, 51.5, 41.0,
36.0, 33.2, 28.4, 25.8 (6C), 19.5, 18.0, 17.9, -4.0, -4.1, -4.7,
-4.9; ES HRMS m/z (M + Na)+ calcd 540.3160, obsd 540.3154;
(30 mg, 99%) as a white solid: mp 65-66 °C; IR (CH2Cl2, cm-1
)
1
3394, 1472, 1256; H NMR (500 MHz, CDCl3) δ 4.22 (t, J )
6.2 Hz, 1H), 3.83 (t, J ) 4.0 Hz, 1H), 3.71 (t, J ) 7.0 Hz, 1H),
2.41-1.44 (series of m, 8H), 0.91 (s, 9H), 0.88 (s, 9H), 0.10 (s,
3H), 0.08 (s, 3H), 0.04 (s, 3H), 0.03 (s, 3H);13C NMR (125 MHz,
CDCl3) δ 79.7, 78.2, 73.4, 58.1, 43.9, 40.7, 33.4, 31.5, 25.83
(3C), 25.82 (3C), 19.8, 18.0, 17.9, -4.1, -4.4, -5.0, -5.02; ES
[R]20 +40 (c 0.9, CHCl3).
D
HRMS m/z (M + Na)+ calcd 423.2721, obsd 423.2724; [R]20
42.5 (c 1.0, CHCl3).
D
Incorporation of 2-Amino-6-chloropurine. To a mixture
of NaH (7 mg, 0.29 mmol) and 2-amino-6-chloropurine (48 mg,
0.28 mmol) in DMF (4 mL) was added (+)-38 (67 mg, 0.14
mmol) in DMF (1.4 mL). The reaction mixture was brought to
80 °C, stirred for 12 h, allowed to cool to rt, quenched with
saturated NaHCO3 solution, and extracted with ether (3 × 30
mL). The combined ether layers were dried concentrated to
leave a residue that was purified by chromatography on silica
gel (3:1 hexanes/ethyl acetate) to give 43 (15 mg, 20%, 35%
brsm) as a white solid: mp 200 °C; IR (neat, cm-1) 1609, 1566,
1456; 1H NMR (500 MHz, CDCl3) δ 7.88 (s, 1H), 5.06 (s, NH),
4.98-4.95 (m, 1H), 4.26 (t, J ) 6.8 Hz, 1H), 3.96 (t, J ) 7.3
Hz, 1H), 2.32-1.41 (series of m, 10H), 0.92 (s, 9H), 0.90 (s,
9H), 0.10 (s, 3H), 0.09 (s, 3H), 0.08 (s, 3H), 0.07 (3C); 13C NMR
(125 MHz, CDCl3) δ 158.6, 153.6, 151.1, 141.1, 126.0, 76.6,
74.6, 57.1, 51.8, 40.6, 35.6, 33.2, 28.4, 25.9 (3C), 25.8 (3C), 19.5,
18.07, 18.01, -3.9, -4.1, -4.7, -4.8; ES HRMS m/z (M + Na)+
Mesylate (+)-38. To a solution of (+)-37 (335 mg, 0.84
mmol) in CH2Cl2 (29 mL) cooled to 0 °C was added Et3N (0.35
mL, 2.5 mmol) followed by MsCl (0.2 mL, 2.5 mmol). The
reaction mixture was allowed to warm to rt, where after 3 h
it was quenched with saturated NaHCO3 solution, and ex-
tracted with Et2O (3 × 50 mL). The combined organic solutions
were dried and concentrated. The residue was purified by
chromatography on silica gel (10:1 hexanes/ethyl acetate) to
give 38 as a white solid: mp 50 °C (0.37 g, 92%); IR (CH2Cl2,
1
cm-1) 1472, 1361, 1257; H NMR (500 MHz, CDCl3) δ 5.09-
5.04 (m, 1H), 3.78-3.72 (m, 2H), 2.99 (s, 3H), 2.47-1.26 (series
of m, 8H), 0.91 (s, 9H), 0.90 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H),
0.05 (s, 6H);13C NMR (125 MHz, CDCl3) δ 80.4, 76.6, 75.0, 41.8,
38.3, 36.8, 33.5, 29.1, 25.8 (3C), 25.7 (3C), 19.7, 17.9 (2C), -4.0,
-4.2, -4.9 (2C); ES HRMS m/z (M + Na)+ calcd 501.2496, obsd
501.2499; [R]20 +28 (c 1.1, CHCl3).
calcd 574.2770, obsd 574.2795; [R]20 +29.9 (c 0.80, CHCl3).
D
D
Incorporation of Uracil. From 60 mg (0.13 mmol) of (+)-
38, adaptation of the preceding conditions in the presence of
uracil afforded 12 mg (19%, 46% brsm) of 39 as a colorless oil:
IR (CH2Cl2, cm-1) 1688, 1471, 1257; 1H NMR (500 MHz, CDCl3)
δ 8.41 (s, NH), 7.37 (d, J ) 8.1 Hz, 1H), 5.73 (dd, J ) 8.0, 2.2
Hz, 1H), 5.21-5.18 (m, 1H), 4.06 (t, J ) 6.6 Hz, 1H), 3.91 (t,
J ) 8.5 Hz, 1H), 2.06-1.26 (series of m, 8H), 0.92 (s, 9H), 0.90
(s, 9H), 0.10 (s, 3H), 0.09 (s, 3H), 0.07 (s, 3H), 0.06 (s, 3H);13C
NMR (125 MHz, CDCl3) δ 162.8, 150.7, 141.3, 102.5, 75.1, 56.9,
52.8, 40.0, 34.5, 32.9, 28.8, 25.9 (3C), 25.7 (3C), 19.2, 18.1, 17.9,
-4.0, -4.1, -4.6, -4.9; ES HRMS m/z (M + Na)+ calcd
Hydrolysis of 43 to Guanine Derivative 44. To a solution
of 43 (8.7 mg, 0.016 mmol) in MeOH (3.6 mL) was added
2-mercaptoethanol (27.4 µL, 0.31 mmol,) and a 5.25 M solution
of NaOMe in MeOH (63 µL, 0.33 mmol). The reaction mixture
was heated to 60 °C for 4 h and concentrated. The residue was
chromatographed on silica gel (9:1 dichlromethane:methanol)
1
to give 44 as a white solid: mp > 300 °C (5.3 mg, 63%); H
NMR (500 MHz, CD3OD) δ 7.72 (s, 1H), 4.97-4.91 (m, 1H),
4.31 (t, J ) 6.9 Hz, 1H), 4.02 (t, J ) 7.2 Hz, 1H), 2.32-1.46
(series of m, 10H), 0.94 (s, 9H), 0.90 (s, 9H), 0.13 (s, 3H), 0.12
(s, 3H), 0.11 (s, 3H), 0.10 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 158.8, 153.5, 151.5, 135.9, 116.6, 77.0, 74.8, 57.2, 51.3, 39.9,
517.2888, obsd 517.2897; [R]20 +26 (c 1.0, CHCl3).
D
J. Org. Chem, Vol. 70, No. 5, 2005 1603

Hartung and Paquette
36.3, 33.3, 28.4, 25.0 (3C), 24.9 (3C), 19.4, 17.4 (2C), -5.2, -5.3,
-5.8, -6.0; ES HRMS m/z (M + Na)+ calcd 556.3109, obsd
11.0; ES HRMS m/z (M + Na)+ calcd 303.1315, obsd 303.1325;
[R]20 +23.5 (c 0.4, CHCl3).
D
556.3104; [R]20 +48.6 (c 0.5, MeOH).
1
D
For 48: white solid; mp 178-180 °C; 93% yield; H NMR
Global Deprotection of 39-44. The procedure described
(500 MHz, CD3OD) δ 8.30 (s, 1H), 8.20 (s, 1H), 5.23-5.20 (m,
1H), 4.15 (t, J ) 5.1 Hz, 1H), 3.98 (t, J ) 6.7 Hz, 1H), 2.43-
1.41 (series of m, 8H); 13C NMR (125 MHz, CD3OD) δ 155.9,
151.9, 150.3, 140.1, 119.0, 76.6, 75.1, 57.3, 52.8, 39.9, 35.6, 32.8,
29.5, 19.8; ES HRMS m/z (M + Na)+ calcd 312.1430, obsd
earlier was adopted in all cases.
1
For 45: white solid; mp 156 °C; 80% yield; H NMR (500
MHz, CD3OD) δ 7.83 (d, J ) 8.1 Hz, 1H), 5.70 (d, J ) 8.1, Hz,
1H), 5.17-5.13 (m, 1H), 4.07 (t, J ) 5.5 Hz, 1H), 3.93 (t, J )
7.1 Hz, 1H), 2.14-1.40 (series of m, 8H); 13C NMR (125 MHz,
CD3OD) δ 164.8, 151.4, 143.1, 101.2, 76.6, 75.1, 56.6, 53.7, 38.2,
34.4, 32.6, 29.3, 19.4; ES HRMS m/z (M + Na)+ calcd 289.1158,
312.1428; [R]20 +31.1 (c 1.0, CHCl3).
D
For 49: white solid; mp > 300 °C; 62% yield; 1H NMR (500
MHz, C5D5N) δ 7.88 (s, 1H), 5.18-5.15 (m, 1H), 4.18 (t, J )
5.1 Hz, 1H), 3.97 (t, J ) 6.7 Hz, 1H), 2.33-2.01 (series of m,
8H); 13C NMR (125 MHz, C5D5N) δ 158.0, 153.7, 151.4, 136.7,
116.5, 76.4, 74.8, 56.9, 51.8, 39.7, 35.8, 32.7, 29.1, 19.6; ES
obsd 289.1155; [R]20 17 (c 0.7, CHCl3).
D
1
For 46: white solid; mp 156 °C; 86% yield; H NMR (500
MHz, CD3OD) δ 7.83 (d, J ) 5.9 Hz, 1H), 6.13 (d, J ) 5.9, Hz,
1H), 5.35-5.33 (m, 1H), 4.04 (t, J ) 7.1 Hz, 1H), 3.89 (t, J )
5.8 Hz, 1H), 2.13-1.41 (series of m, 8H); 13C NMR (125 MHz,
CD3OD) δ 165.8, 164.5, 155.5, 98.5, 76.0, 74.5, 73.7, 58.1, 40.2,
36.1, 32.4, 28.4, 19.7; ES HRMS m/z (M + Na)+ calcd 288.1318,
HRMS m/z (M + Na)+ calcd 305.1488, obsd 305.1492; [R]20
+82 (c 0.1, C5H5N).
D
obsd 288.1313; [R]20 +15.3 (c 0.6, CHCl3).
1
D
Supporting Information Available: High-field H and
1
13C NMR spectra for all compounds described herein. This
material is available free of charge via the Internet at
http://pubs.acs.org.
For 47: white solid; mp 218 °C; 73% yield; H NMR (500
MHz, CD3OD) δ 7.67 (s, 1H), 5.16-5.13 (m, 1H), 4.09 (t, J )
5.5 Hz, 1H), 3.93 (t, J ) 7.1 Hz, 1H), 2.12-1.53 (series of m,
8H), 1.90 (s, 3H); 13C NMR (125 MHz, CD3OD) δ 165.0, 151.6,
138.8, 110.2, 76.6, 75.0, 56.6, 53.3, 38.1, 34.3, 32.6, 29.3, 19.6,
JO0480601
1604 J. Org. Chem., Vol. 70, No. 5, 2005