A new synthetic route to (North)-methanocarba nucleosides designed as A3 adenosine receptor agonists

Article abstract of DOI:10.1021/jo0487606

(Chemical Equation Presented) Activation of the A₃ adenosine receptor (AR) is associated with cerebroprotective, cardioprotective, and anticancer effects. Among potent and selective A₃ AR agonists are novel methanocarba adenosine analogues in which the conformation of a pseudo-ribose moiety is locked in the North (N) hemisphere of the pseudorotational cycle. 5′-Uronamide (N)-methanocarba nucleosides, such as MRS1898 and MRS2346, are examples of full agonists of the human A₃ AR. An improved convergent approach from easily accessible 2,3-O-isopropylidene- D-erythrose (2b), and the combination of a strategic intramolecular cyclopropanation step plus the acid-catalyzed isomerization of an isopropylidene group, provided a suitable pseudosugar precursor (23) for the synthesis of MRS1898, MRS2346, and related analogues. This new synthetic route uses readily available building blocks and opens the way for the preparation of a variety of targets on a reasonable scale.

Full text of DOI:10.1021/jo0487606

A New Synthetic Route to (North)-Methanocarba Nucleosides
Designed as A3 Adenosine Receptor Agonists
Bhalchandra V. Joshi,† Hyung Ryong Moon,§ James C. Fettinger,‡ Victor E. Marquez,*,§ and
Kenneth A. Jacobson*,†
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and
Digestive and Kidney Diseases, National Institutes of Health, DHHS Bethesda, Maryland 20892,
Laboratory of Medicinal Chemistry, Center for Cancer Research, NCI-Frederick, National Institutes of
Health, Frederick, Maryland 21702, and Department of Chemistry and Biochemistry,
University of Maryland, College Park, Maryland 20748
kajacobs@helix.nih.gov; marquezv@dc37a.nci.nih.gov
Received July 20, 2004
Activation of the A3 adenosine receptor (AR) is associated with cerebroprotective, cardioprotective,
and anticancer effects. Among potent and selective A3 AR agonists are novel methanocarba
adenosine analogues in which the conformation of a pseudo-ribose moiety is locked in the North
(N) hemisphere of the pseudorotational cycle. 5′-Uronamide (N)-methanocarba nucleosides, such
as MRS1898 and MRS2346, are examples of full agonists of the human A3 AR. An improved
convergent approach from easily accessible 2,3-O-isopropylidene-D-erythrose (2b), and the combina-
tion of a strategic intramolecular cyclopropanation step plus the acid-catalyzed isomerization of
an isopropylidene group, provided a suitable pseudosugar precursor (23) for the synthesis of
MRS1898, MRS2346, and related analogues. This new synthetic route uses readily available building
blocks and opens the way for the preparation of a variety of targets on a reasonable scale.
Introduction
nearly always purine nucleoside analogues, mostly syn-
thetic adenosine derivatives that activate the receptor
at nanomolar concentrations.8-12 Among potent and
selective A3 AR agonists are some novel methanocarba
adenosine analogues, in which the furanose moiety has
been replaced by a bicyclo[3.1.0]hexane scaffold.13-16 With
Activation of the A3 adenosine receptor (AR)1-3 is
associated with cerebroprotective,4 cardioprotective,5,6
and anticancer7 effects. Agonists of this receptor are
* Address correspondence to these authors. Jacobson: phone 301-
496-9024, fax 301-480-8422. Marquez: phone 301-846-5954, fax 301-
846-6033.
(7) Fishman, P.; Bar-Yehuda, S. Curr. Top. Med. Chem. 2003, 3,
463-469.
(8) Kim, H. O.; Ji, X.-D.; Siddiqi, S. M.; Olah, M. E.; Stiles, G. L.;
Jacobson, K. A. J. Med. Chem. 1994, 37, 3614-3621.
(9) van Tilburg, E. W.; van der Klein, P. A.; von Frijtag Drabbe
Ku¨nzel, J.; de Groote, M.; Stannek, C.; Lorenzen, A.; IJzerman, A. P.
J. Med. Chem. 2001, 44, 2966-2975.
(10) Mogensen, J. P.; Roberts, S. M.; Bowler, A. N.; Thomsen, C.;
Knutsen, L. J. Bioorg. Med. Chem. Lett. 1998, 8, 1767-1770.
(11) DeNinno, M. P.; Masamune, H.; Chenard, L. K.; DiRico, K. J.;
Eller, C.; Etienne, J. B.; Tickner, J. E.; Kennedy, S. P.; Knight, D. R.;
Kong, J.; Oleynek, J. J.; Tracey, W. R.; Hill, R. J. J. Med. Chem. 2003,
46, 353-355.
(12) Volpini, R.; Costanzi, S.; Lambertucci, C.; Taffi, S.; Vittori, S.;
Klotz, K. N.; Cristalli, G. J. Med. Chem. 2002, 45, 3271-3279.
(13) Marquez, V. E.; Siddiqui, M. A.; Ezzitouni, A.; Russ, P.; Wang,
J.; Wagner, R. W.; Matteucci, M. D. J. Med. Chem. 1996, 39, 3739-
3747.
† National Institute of Diabetes and Digestive and Kidney Diseases,
NIH.
§ Center for Cancer Research, NIH.
‡ University of Maryland.
(1) Fredholm, B. B.; IJzerman, A. P.; Jacobson, K. A.; Klotz, K. N.;
Linden, J. Pharmacol. Rev. 2001, 53, 527-552.
(2) Zhou, Q. Y.; Li, C.; Olah, M. E.; Johnson, R. A.; Stiles, G. L.;
Civelli, O. Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 7432-7436.
(3) Salvatore, C. A.; Jacobson, M. A.; Taylor, H. E.; Linden, J.;
Johnson, R. G. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 10365-10369.
(4) von Lubitz, D. K.; Lin, R. C.; Popik, P.; Carter, M. F.; Jacobson,
K. A. Eur. J. Pharmacol. 1994, 263, 59-67.
(5) Liang, B. T.; Jacobson, K. A. Proc. Natl. Acad. Sci. U.S.A. 1998,
95, 6995-6999.
(6) Tracey, W. R.; Magee, W. P.; Oleynek, J. J.; Hill, R. J.; Smith,
A. H.; Flynn, D. M.; Knight, D. R. Am. J. Physiol. Heart Circ. Physiol.
2003, 285, H2780-H2787.
10.1021/jo0487606 CCC: $30.25 © 2005 American Chemical Society
Published on Web 11/24/2004
J. Org. Chem. 2005, 70, 439-447
439

Joshi et al.
SCHEME 1. Synthesis of 9a
a Reagents and conditions: (a) DIBAL-H, CH2Cl2, -78 °C; (b) methyltriphenylphosphonium bromide, KOBut, THF, -78 °C to room
temperature; (c) DMSO, (COCl)2, CH2Cl2, -78 °C; (d) NaOCl; (e) N2CHCOOEt, SnCl2, CH2Cl2, room temperature; (f) 1,1′-carbonyldiimi-
dazole, LDA, CH3COOEt, THF, -78 °C; (g) TsN3, CH3CN, TEA, room temperature; (h) CuI, toluene, reflux; (i) NaBH4, MeOH, room
temperature.
formation of the ribose, or ribose-like moiety, more closely
corresponds to the biologically active, receptor bound
conformation. Specifically, the structurally optimized
agonists (N)-methanocarba-2-chloro-5′-N-methyluron-
amide analogues of adenosine, e.g., (1′S,2′R,3′S,4′R,5′S)-
[4′-(2-chloro-6-{[(3-iodophenyl)methyl]amino}purin-9-
yl)-2′,3′-dihydroxybicyclo[3.1.0]hexyl]-N-methylcarbox-
amide (MRS1898, 1a), and the 6-methylamino derivative
(MRS2346, 1b), were found to fully activate the human
FIGURE 1. Structure of A3 AR agonists containing a (N)-
methanocarba ring system.
A3 AR with EC50 values of 3.3 and 1.4 nM, respectively
(Figure 1).18,19
Unfortunately, currently available synthetic me-
thods13-18 are not amenable to perform the extensive
probing at the N6 and C2 positions that is required for a
systematic analysis of the structure activity relationship
(SAR) of this (N)-methanocarba-5′-N-methyluronamide
series.13-17 In addition, more efficient synthetic proce-
an appropriate substitution pattern, this methanocarba
template is able to lock the conformation of the pseudo-
furanose moiety into either the North (N) or South (S)
hemisphere of the pesudorotational cycle. We have shown
that the (N)-methanocarba analogues are substantially
more potent in receptor binding than their isomeric (S)-
methanocarba analogues,17 suggesting that the N con-
(17) Jacobson, K. A.; Ji, X.-d.; Li, A. H.; Melman, N.; Siddiqui, M.
A.; Shin, K. J.; Marquez, V. E.; Ravi, R. G. J. Med. Chem, 2000, 43,
2196-2203.
(14) Marquez, V. E.; Russ, P.; Alonso, R.; Siddiqui, M. A.; Hernandez,
S.; George, C.; Nicklaus, M. C.; Dai, F.; Ford, H. Helv. Chim. Acta 1999,
82, 2119-2129.
(15) Lee, K.; Cass, C.; Jacobson, K. A. Org. Lett. 2001, 3, 597-599.
(16) Choi, Y.; Moon, H. R.; Yoshimura, Y.; Marquez, V. E. Nucleo-
sides Nucleotides Nucleic Acids 2003, 22, 547-557.
(18) Lee, K.; Ravi, R. G.; Ji, X.-d.; Marquez, V. E.; Jacobson, K. A.
Biorg. Med. Chem. Lett. 2001, 11, 1333-1337.
(19) Gao, Z. G.; Kim, S.-K.; Biadatti, T.; Chen, W.; Lee, K.; Barak,
D.; Kim, S. G.; Johnson, C. R.; Jacobson, K. A. J. Med. Chem. 2002,
45, 4471-4484.
440 J. Org. Chem., Vol. 70, No. 2, 2005

Synthetic Route to (North)-Methanocarba Nucleosides
SCHEME 2. Attempted Synthesis of 14a
dures are needed to provide sufficient material for
continuing biological studies.20 We have devised an
improved convergent synthetic route for this class of
compounds that introduces the purine ring in one step.
This feature is ideally suited for the use of parallel
synthetic methods designed to explore chemical diversity.
Furthermore, the readily available building blocks for
this synthesis would allow the preparation of target
compounds on a reasonably large scale. The approach is
based on two key steps: (1) an intramolecular cyclopro-
panation reaction performed on an appropriately substi-
tuted carbohydrate chiral synthon and (2) a key acid-
catalyzed isomerization of an isopropylidene group. The
biological characterization at ARs of a large series of
these analogues will be described later.21
Our initial approach for a convergent strategy was to
utilize either a cyclic sulfite or a cyclic sulfate as
pseudoglycosyl donors (compounds 12 and 13, Scheme
2) to introduce the purine moiety in one step.22 The
synthesis started with commercially available 2,3-O-
isopropylidene-D-erythronolactone (2a), which was re-
duced with DIBAL-H to provide 2,3-O-isopropylidene-D-
erythrose (2b) according to published methods (Scheme
1).23 This lactol underwent Wittig olefination with the
corresponding methylenetriphenylphosphine ylide to af-
ford the ring-opened alcohol 3 in 60% yield. At this stage,
a Swern oxidation protocol was chosen among several
methods tested to oxidize 3 to the corresponding aldehyde
4a. The resulting aldehyde was found to be unstable and
therefore it was utilized immediately for the next reac-
tion. Oxidation of the aldehyde to the acid (4b) with
sodium chlorite, followed by Dieckmann condensation of
the activated acid with ethyl 2-lithioacetate, afforded the
desired â-keto ester 5a (59%) plus an unwanted epimer-
ized derivative 5b (9%) as a mixture of separable di-
astereoisomers. This epimerization problem was sur-
mounted by treating aldehyde 4a directly with ethyl
diazoacetate in the presence of tin(II) chloride to provide
the keto ester 5a as the sole product in 36% overall yield
from alcohol 3. Using a standard protocol, the unsatur-
ated keto ester 5a was converted to the diazo compound
6, which underwent a thermally induced intramolecular
cyclopropanation to give the bicyclo[3.1.0]hexan-2-one
derivatives 7 and 8 in a combined 48% yield with a
favorable diastereoisomeric ratio (3:1) for the desired
isomer 7. The bicyclo derivative 7 was isolated chromato-
graphically and reduced stereospecifically with NaBH4
to give alcohol 9 as a single product in 72% yield. The
structure of 9 was confirmed by X-ray analysis, which
unambiguously validated the suitability of our synthetic
approach to construct (N)-methanocarba carbocyclic nu-
cleosides.
a Reagents and conditions: (a) (i) CH3NH2, room temperature;
(ii) BzCl, pyridine, CH2Cl2, room temperature; (b) 10% CF3COOH
in MeOH, H2O, room temperature; (c) SOCl2, TEA, CH2Cl2, 0 °C;
(d) NaIO4, RuCl3, CCl4, H2O, room temperature; (e) NaH, CH3CN,
2,6-dichloropurine, room temperature.
diol 11, which readily reacted with thionyl chloride to
give cyclic sulfite 12. Further oxidation of 12 with NaIO4
afforded cyclic sulfate 13. After achieving the syntheses
of 12 and 13, our plan was to couple these bicyclo
derivatives with a suitable purine base. Accordingly, we
initially attempted the regioselective opening of sulfite
12 with 2,6-dichloropurine. However, several attempts
with this reaction failed to give the requisite pseudo-
nucleoside derivative 14. Also, the sodium salt of 2,6-
dichloropurine reacted with cyclic sulfate 13 and the
resulting isolated product obtained on further treatment
with an excess of CH3NH2 did not give the expected,
previously reported compound 1b.18
The failure of the cyclic sulfite/sulfate approach in a
convergent methodology contrasts with its utility in
linear approaches, which appear to be better suited for
accessing pyrimidine targets. Indeed, the set of analogous
cyclic sulfite/sulfate derivatives 18 and 19, prepared in
a similar fashion as illustrated in Scheme 3, reacted well
with sodium azide to give the azido derivative 20 in 82%
yield, along with a small amount of its regioisomer 21.
Reduction of azide 20 to the corresponding amine 22
provides a useful starting material for the synthesis of
5′-hydroxymethyl (N)-methanocarba nucleosides, which
are also targets of interest for ARs17 as well as other
biological receptors. The bicyclic amine 22 (to which
synthetic approaches were presented at a recent Round-
table Conference16) can therefore be used as a direct
precursor of purine and pyrimidine analogues by using
well-established linear approaches.22 However, our need
to develop parallel methods to explore diversity is not
well served by this approach where each complex mul-
tisubstitued purine has to be individually assembled on
the requisite bicyclo[3.1.0]hexane scaffold.
The ester group in 9 was converted to the correspond-
ing N-methyl amide, and protection of the free hydroxyl
group afforded 10 in 55% overall yield (Scheme 2).
Removal of the acetonide group in aqueous TFA provided
(20) Gao, Z.-G.; Chen, A.; Barak, D.; Kim, S.-K.; Mu¨ller, C. E.;
Jacobson, K. A. J. Biol. Chem. 2002, 277, 19056-19063.
(21) Tchilibon, S.; Joshi, B. V.; Kim, S.-K.; Gao, Z. G.; Duong, H. T.;
Jacobson, K. A. J. Med. Chem. In press.
(22) Moon, H. R.; Kim, H. O.; Chun, M. W.; Jeong, L. S.; Marquez,
V. E. J. Org. Chem. 1999, 64, 4733-4741.
(23) Cohen, C.; Banner, B. L.; Lopresti, R. J.; Wong, F.; Rosenberger,
M.; Liu, Y. Y.; Thom, E.; Liebman, A. L. J. Am. Chem. Soc. 1983, 105,
3661-3672.
The problems described above prompted us to look for
an alternative strategy to nucleobase coupling via a
Mitsunobu reaction (Scheme 4). Accordingly, alcohol 9
was subjected to an acid-catalyzed equilibration to pro-
J. Org. Chem, Vol. 70, No. 2, 2005 441

Joshi et al.
SCHEME 3. Synthesis of 24a
a Reagents and conditions: (a) DIBAL-H, -78 °C to room temperature; (b) BnBr, NaH, DMF, 0 °C to room temperature; (c) Dowex ion
exchange resin, MeOH, room temperature; (d) SOCl2, TEA, CH2Cl2, 0 °C; (e) NaIO4, RuCl3, CCl4, H2O, room temperature; (f) NaN3, DMF,
100 °C; (g) Lindlar catalyst, H2.
SCHEME 4. Synthesis of A3 AR Agonistsa
a Reagents and conditions: (a) p-TsOH, acetone, reflux; (b) crystallization; (c) 2,6-dichloropurine, DIAD, TPP, THF, room temperature;
(d) 3-iodobenzylamine‚HCl, TEA (for 1a), 40% aq MeNH2 (for 1b), trans-2-phenylcyclopropylamine‚HCl, TEA (for 29), 2,2-diphenylethyl-
amine (for 30), in MeOH, room temperature; (e) 40% aq MeNH2; (f) 10% CF3COOH in MeOH, H2O, 70 °C.
duce the isomeric acetonide 23, which was isolated in 90%
yield (based on recovery of alcohol 9) by careful crystal-
lization from cyclohexane. The requisite alcohol 23 when
subjected to a Mitsunobu coupling reaction with 2,6-
dichloropurine afforded the condensed product 24 in 36%
yield. Treatment of 24 with an excess of CH3NH2 followed
by deprotection of the acetonide group afforded authentic
(N)-methanocarba nucleoside 1b (MRS 2346), whose
spectral properties matched those reported in the litera-
ture.18 In addition, reaction of 24 with 3-iodobenzylamine
in the presence of Et3N, followed by reaction with an
excess of CH3NH2, provided compound 26. Removal of
the acetonide by standard methods produced the other
target 1a (MRS 1898) in 74% yield. The spectral proper-
ties of 1a matched those of the identical compound
reported in the literature.18 To demonstrate the general-
ity of this route, other novel N6-substituted (N)-metha-
nocarba nucleosides, e.g., 29 and 30, were prepared in
reasonable yields. The detailed biological characterization
of this series of nucleosides as selective A3 AR agonists
will be reported separately.21 The experimental use of A3
AR agonists in models of cardiac ischemia and other
medical conditions provides a promising approach for
therapeutics.5-7,24
Experimental Section
General Experimental Details. 1H NMR spectra were
obtained with a Varian Gemini-300 spectrometer (300 MHz)
442 J. Org. Chem., Vol. 70, No. 2, 2005

Synthetic Route to (North)-Methanocarba Nucleosides
with D2O, CDCl3, CD3OD, and DMSO-d6 as solvents. Low-
resolution mass spectra were measured with a Finnigan-
Thermoquest LCQ with APCI (Atmospheric Pressure Chemical
Ionization) interface. Low-resolution and high-resolution FAB
(fast atom bombardment) mass spectrometry was performed
with a JEOL SX102 spectrometer with 6-kV Xe atoms follow-
ing desorption from a glycerol matrix.
continued for 30 min and then dry Et3N (8.0 g, 80 mmol) was
added at the same temperature. The mixture was allowed to
warm to room temperature, CH2Cl2 (100 mL) was subse-
quently added, and again the mixturet was cooled to -78 °C.
The solution was treated with saturated NaCl (40 mL) and
then the reaction mixture was allowed to warm to room
temperature. The organic layer was separated, dried (Na2SO4),
and concentrated under reduced pressure. The crude aldehyde
4a (3.0 g) was dissolved in CH2Cl2 (40 mL) and treated with
SnCl2 (5.10 g, 24 mmol) and ethyl diazoacetate (1.14 g, 10
mmol). The mixture was stirred at room temperature for 3 h.
The reaction mixture was filtered through a pad of Celite (20.0
g), and the resulting organic layer was concentrated. The
desired keto ester was purified by column chromatography
(silica gel; hexanes:EtOAc, 95:5) to furnish 5a as oil (0.69 g,
36%) with identical spectroscopic properties as those reported
under Method A.
Ethyl (4S,5S)-3-[2,2-Dimethyl-5-vinyl(1,3-dioxolan-4-
yl)]-2-diazo-3-oxopropanoate (6). To a stirred solution of
keto ester 5a (4.84 g, 20 mmol) in acetonitrile (40 mL) was
successively added tosyl azide (4.13 g, 21 mmol) and Et3N (4.4
g, 40 mmol). The resulting reaction mixture was concentrated
after being stirred for 30 min at room temperature The diazo
derivative was purified by column chromatography (silica gel;
hexanes:EtOAc, 95:5) to furnish 6 (3.75 g, 70%) as an oil; IR
(neat) 2141, 1713 cm-1; [R]25D +81.0 (c 2.02, CHCl3); 1H NMR
(CDCl3) δ 5.77 (ddd, 1 H, J ) 17.3, 10.1, 7.3 Hz), 5.70 (d, 1 H,
J ) 7.6 Hz), 5.45 (dm, 1 H, J ) 17.1 Hz), 5.30 (dm, 1 H, J )
10.2 Hz), 5.05 (t, 1 H, J ) 7.5 Hz), 4.36 (q, 2 H, J ) 7.1 Hz),
1.74 (s, 3 H), 1.51 (s, 3 H), 1.41 (t, 3 H, J ) 7.1 Hz); 13C NMR
(CDCl3) δ 188.16, 161.13, 132.79, 119.61, 110.74, 80.45, 78.97,
61.80, 51.63, 26.87, 25.47, 14.12 ppm. FAB MS m/z (rel
intensity) 269 (MH+, 86). This compound was used for the next
step without further purification.
2,3-O-Isopropylidene-D-erythrose (2b). 2b was prepared
from commercially available 2,3-O-isopropylidene-D-erythro-
nolactone (2a) by the procedure of Cohen et al.23 in 90% yield.
(4R,5S)-(2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl)methan-
1-ol (3). To a solution containing methyltriphenylphosphonium
bromide (7.85 g, 22 mmol) in dry THF (60 mL) was added
potassium tert-butoxide (2.2 g, 20 mmol). The resulting reac-
tion mixture was stirred at room temperature for 1 h under
nitrogen. The lactol 2 (1.60 g, 10 mmol) in dry THF (20 mL)
was added at -78 °C, and the reaction was allowed to reach
room temperature. After being stirred for an additional 3 h, it
was treated with saturated brine (100 mL). The aqueous layer
was extracted with ethyl acetate (50 mL). The combined
organic layers were washed with brine, dried (Na2SO4), and
concentrated. Purification by column chromatography (silica
gel; EtOAc:hexanes, 25:75) gave 3 (0.94 g, 60%) as an oil; [R]25
D
+41.2 (c 2.5 CHCl3) [lit.25 [R]25D +40.1] with identical spectral
properties as reported in the literature.25
Ethyl (4S,5S)-3-[2,2-Dimethyl-5-vinyl(1,3-dioxolan-4-
yl)]-3-oxopropanoate (5a). Method A. From compound 3,
the acid 4b was prepared according to the work of Rao and
Lahiri.25 A stirred solution of 4b (0.35 g, 2.03 mmol) in THF
(3 mL) maintained at 0 °C was treated with 1,1′-carbonyldi-
imidazole (0.43 g, 2.64 mmol). After 30 min, the temperature
was raised to 30 °C and additional stirring was continued for
2 h. After being cooled to room temperature, this solution was
added via cannula to a -78 °C solution of LiCH2CO2CH2CH3
obtained from EtOAc (0.6 mL, 6.14 mmol) and LDA (0.48 g,
6.1 mmol) in anhydrous THF (5 mL) during 1.5 h at -78 °C.
The reaction was quenched at the same temperature with 1
N HCl (6.1 mL), stirred further at -78 °C for 10 min, allowed
to warm to 0 °C, adjusted to pH 3, and extracted with EtOAc
(80 mL). The combined organic extract was washed with brine,
dried (MgSO4), and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography
(hexanes:EtOAc, 95:5) to give the desired â-keto ester 5a (0.293
g, 59%) as a clear oil. A small amount of the (4R,5S)-isomer
5b (0.038 g, 8%) was also obtained as a clear oil.
Ethyl (1S,3S,4S,5S)-3,4-O-Isopropylidene-2-oxobicyclo-
[3.1.0]hexanecarboxylate (7). To a stirred solution of diazo
compound 6 (5.36 g, 20 mmol) in dry toluene (15 mL) was
added CuI (0.190 g, 1 mmol) at room temperature and the
reaction mixture was refluxed for 8 h. The reaction mixture
was cooled to room temperature, concentrated, and purified
by column chromatography (silica gel; hexanes:EtOAc, 75:25)
to provide bicylic compound 7 (1.72 g, 36%) and compound 8
(0.57 g, 12%).
7: IR (neat) 1751, 1719 cm-1; [R]25 +33.6 (c 1.69, CHCl3);
D
1H NMR (CDCl3) δ 5.12 (ddd, 1 H, J ) 8.3, 5.4, 1.0 Hz), 4.45
(d, 1 H, J ) 8.3 Hz), 4.29 (q, 2 H, J ) 7.1 Hz), 2.84 (dt, 1 H, J
) 8.3, 5.3 Hz), 2.18 (dd, 1 H, J ) 8.1, 5.1 Hz), 1.89 (t, 1 H, J
≈ 5.2 Hz), 1.59 (s, 3 H), 1.39 (s, 3 H), 1.36 (t, 3 H, J ) 7.1 Hz);
13C NMR (CDCl3) δ 199.95, 167.12, 115.12, 80.63, 73.68, 61.95,
33.19, 25.85, 24.39, 20.88, 14.19 ppm; FAB MS m/z (rel
intensity) 241 (MH+, 100). Anal. Calcd for C12H16O5: C, 59.99;
H, 6.71. Found: C, 59.95; H, 6.80.
Ethyl (4R,5S)-3-[2,2-dimethyl-5-vinyl(1,3-dioxolan-4-
yl)]-3-oxopropanoate (5a): IR (neat) 1748, 1722 cm-1; [R]25
D
-42.7 (c 0.26, CHCl3); 1H NMR (CDCl3) δ 12.08 (s, 0.1 H, D2O
exchangeable, enolic OH), 5.92-6.06 (m, 1 H), 5.37-5.56 (m,
2 H), 4.51-4.62 (m, 1 H), 4.20-4.38 (m, 3 H), 3.75 (AB q, 2 H,
J ) 16.4 Hz), 1.54-1.57 (m, 6 H, 2), 1.34-1.41(m, 3H); 13C
NMR (CDCl3) δ 202.72, 166.98, 131.80, 119.35, 111.06, 83.00,
78.81, 61.41, 47.56, 26.81, 24.79, 14.23 ppm; FAB MS m/z (rel
intensity) 185 (7.2), 243 (MH+, 2).
Ethyl (1R,3S,4S,5R)-3,4-O-isopropylidene-2-oxobicyclo-
[3.1.0]hexanecarboxylate (8): IR (neat) 1755, 1722 cm-1
;
5b: IR (neat) 1750, 1721 cm-1; [R]25 +29.9 (c 1.23 CHCl3);
1
[R]25 +67.9 (c 1.12, CHCl3); H NMR (CDCl3) δ 4.81 (d, 1 H,
D
D
1H NMR (CDCl3) δ 12.00 (s, 1 H, D2O exchangeable, enolic
OH), 5.72-5.90 (m, 1 H), 5.30-5.57 (m, 2 H), 4.85-4.99 (m, 1
H), 4.22-4.33 (m, 2 H), 3.69 (d, 1 H, J ) 16.4 Hz), 3.43 (d, 1
H, J ) 16.4 Hz), 1.70 (s, 3 H), 1.48 (s, 3 H), 1.32-1.40 (m, 3
H); FAB MS m/z (rel intensity) 185 (98), 243 (MH+, 38).
Method B. A solution of dry DMSO (1.75 g, 22.4 mmol) in
dry CH2Cl2 (20 mL) was added to a solution of (COCl)2 (1.52
g, 12 mmol) in dry CH2Cl2 (40 mL), which had been cooled to
-78 °C under a nitrogen atmosphere. The resulting reaction
mixture was further stirred at the same temperature for
another 15 min before a solution of alcohol 3 (1.27 g, 8 mmol)
in dry CH2Cl2 (15 mL) was added carefully over 10 min, while
the temperature was kept at -78 °C. The stirring was
J ) 5.1 Hz), 4.38 (dd, 1 H, J ) 4.8, 1.7 Hz), 4.32 (dq, 2 H, J )
7.1, 1.5 Hz), 2.96 (dd, 1 H, J ) 8.7, 5.7 Hz), 2.21 (ddd, 1 H, J
) 8.8, 5.7, 1.7 Hz), 1.53 (s, 3 H), 1.45 (s, 3 H), 1.37 (t, 3 H, J
) 4.1 Hz), 1.35 (irregular t, 1 H); 13C NMR (CDCl3) δ 204.00,
168.89, 115.87, 81.10, 77.23, 63.40, 37.36, 29.20, 27.39, 22.34,
15.84 ppm; FAB MS m/z (rel intensity) 241 (MH+, 100). Anal.
Calcd for C12H16O5‚0.45H2O: C, 58.03; H, 6.86. Found: C,
57.96; H, 6.76.
Ethyl (1S,2R,3S,4S,5S)-3,4-O-isopropylidene-2-hydroxy-
bicyclo[3.1.0]hexanecarboxylate (9). To a stirred solution
of 7 (1.20 g, 5 mmol) in methanol (20 mL) at room temperature
was added NaBH4 (0.19 g, 5 mmol) while stirring was
continued for an additional 1 h. The reaction mixture was then
treated with acetone (2 mL) and concentrated to dryness. The
residue was purified by column chromatography (silica gel;
hexanes:EtOAc, 70:30) to give compound 9 (0.87 g, 72%) as a
white solid; mp 109 °C (cyclohexane); [R]25D +72.0 (c 0.15, CH2-
(24) Auchampach, J. A.; Rizvi, A.; Qiu, Y.; Tang, X. L.; Maldonado,
C.; Teschner, S.; Bolli, R. Circ. Res. 1997, 80, 800-809.
(25) Rao, B. V.; Lahiri, S. J. Carbohydr. Chem. 1996, 15, 975-984.
J. Org. Chem, Vol. 70, No. 2, 2005 443

Joshi et al.
Cl2); 1H NMR (CDCl3) δ 4.95 (t, 1 H, J ) 7.5 Hz), 4.88 (t, 1 H,
J ) 6 Hz), 4.60 (t, 1 H, J ) 7 Hz), 4.12-4.24, (m, 2 H), 2.48 (d,
1 H, J ) 12 Hz, OH), 2.16-2.26 (m, 1 H), 1.48-1.61 (m, 5 H),
1.32 (s, 3 H), 1.26 (t, 3 H, J ) 6.5 Hz); 13C NMR (CDCl3) δ
172.13, 113.20, 79.77, 79.41, 70.35, 61.24, 41.03, 32.74, 26.33,
24.80, 16.07, 14.42 ppm; FAB MS m/z (rel intensity) 243 (MH+,
100). Anal. Calcd for C12H18O5 : C, 59.49; H, 7.49. Found: C,
59.36; H, 7.54.
(1S,2R,3S,4S,5S)-3,4-O-Isopropylidene-1-(N-methyl-
carbamoyl)bicyclo[3.1.0]hex-2-yl Benzoate (10). Com-
pound 9 (0.240 g, 1 mmol) was stirred with aqueous CH3NH2
(1 mL, 40%) for 8 h. The mixture was concentrated to dryness
under reduced pressure and the residue was dissolved in
pyridine (2 mL). Benzoyl chloride (0.168 g, 1.2 mmol) was
added and the resulting reaction mixture was stirred at room
temperature for 4 h. After being reduced to dryness under
vacuum the residue was dissolved in CHCl3 (25 mL) and
washed with water, and the organic layer was dried (Na2SO4).
Purification by column chromatography (silica gel; CHCl3:
MeOH, 90:10) furnished 10 (0.175 g, 55%) as a solid, mp 75
°C; [R]25D +90.0 (c 0.1, CH2Cl2); 1H (CDCl3) δ 8.12-8.22 (m, 2
H), 7.42-7.65 (m, 3 H), 6.82 (br s, 1 H), 5.82-5.89 (m, 1 H),
4.78-5.05 (m, 2 H), 2.82 (br s, 3 H), 2.25-2.42 (m, 1 H), 1.42-
1.81 (m, 5 H), 1.24 (s, 3H); FAB MS m/z (rel intensity) 332.1
(MH+, 62). Anal. Calcd for C18H21NO5‚H2O: C, 61.88; H, 6.64;
N, 4.01. Found: C, 62.18; H, 6.39; N, 4.07.
(1S,2R,3S,4S,5S)-3,4-Dihydroxy-1-(N-methylcarbamoyl)-
bicyclo[3.1.0]hex-2-yl Benzoate (11). A mixture of amide
10 (0.319 g, 1 mmol) containing 10% trifluoroacetic acid/MeOH
(5 mL) and H2O (0.5 mL) was stirred at room temperature for
10 h. The solvent was removed, and the residue was dried by
coevaporation with toluene. Purification by column chroma-
tography (silica gel; CHCl3:MeOH, 90:10) afforded 11 (0.165
g, 57%) as a white solid; mp 112 °C; [R]25D +100.0 (c 0.1, CH2-
Cl2); 1H NMR (CDCl3) δ 8.14 (d, 2 H, J ) 6 Hz), 7.22-7.65 (m,
3 H), 7.18 (br s, 1 H), 5.62 (d, 1 H, J ) 4.5 Hz), 4.48 (t, 1 H, J
) 3.5 Hz), 4.24 (t, 1 H, J ) 3.1 Hz), 2.83 (d, 3 H, J ) 6.6 Hz),
2.43-2.74 (m, 3 H), 1.78 (t, 1 H, J ) 2.5 Hz), 1.22-1.38 (m, 1
H); FAB MS m/z (rel intensity) 292.1 (MH+, 50). Anal. Calcd
for C15H17NO5 : C, 61.85; H, 5.88; N, 4.81. Found: C, 61.53;
H, 6.12; N, 4.68.
7 (2.0 g, 8.32 mmol) in toluene (30 mL) cooled to -78 °C was
treated dropwise with diisobutylaluminum hydride (DIBAL-
H, 21.1 mL, 1.5 M solution in THF) and stirred at that
temperature for 1 h. Methanol (15 mL) and EtOAc (70 mL)
were added and the resulting mixture was stirred for 5 h
allowing it to reach room temperature The generated gel was
filtered off through a pad of Celite, and the filtrate collected
was evaporated and concentrated under reduced pressure. The
residue was purified by silica gel flash column chromatography
(CH2Cl2:MeOH, 95:5) to give diol 15 (0.923 g, 55%) as an oil;
IR (neat) 3419 cm-1; [R]25 +19.6 (c 0.75, MeOH); 1H NMR
D
(CDCl3) δ 4.95 (t, 1 H, J ) 5.6 Hz), 4.60-4.70 (m, 2 H), 3.86
(d, 1 H, J ) 11.5 Hz), 3.60 (d, 1 H, J ) 11.5 Hz), 2.25 (br s, 2
H, 2 × OH), 1.71 (irregular quintet, 1 H), 1.63 (s, 3 H), 1.3 (s,
3 H), 1.27 (irregular t, 1 H), 0.77 (dd, 1 H, J ) 8.3, 5.4 Hz);
FAB MS m/z (rel intensitiy) 79 (100), 95 (33), 125 (91), 201
(MH+, 64). Anal. Calcd for C10H16O4‚0.1CH3OH: C, 59.63; H,
8.13. Found: C, 59.48; H, 8.21.
(1S,2R,3S,4S,5S)-3,4-O-Isopropylidene-1-[(phenyl-
methoxy)methyl]-2-(phenylmethoxy)bicyclo[3.1.0]-
hexane (16). A stirred solution of diol 15 (0.46 g, 2.31 mmol)
in DMF (14 mL) at 0 °C was treated portionwise with NaH
(0.23 g, 60% dispersion in mineral oil, 5.78 mmol). Stirring
was continued for 30 min allowing the temperature to reach
ambient conditions. Benzyl bromide (0.61 mL, 5.13 mmol) was
added and after warming to 75 °C the reaction was stirred for
3 h. After reaching room temperature, the mixture was
partitioned between Et2O (250 mL) and water (50 mL). The
organic layer was washed with brine (20 mL), dried (MgSO4),
filtered, and reduced to dryness under reduced pressure. The
residue was purified by silica gel column chromatography
(hexanes:EtOAc, 80:20) to give fully protected compound 16
(0.542 g, 62%) as an oil plus recovered starting material 15
(0.126 g).
16: IR (neat) 1076 cm-1; [R]25D +81.2 (c 1.2, CHCl3); 1H NMR
(CDCl3) δ 7.18-7.37 (m, 10 H), 4.78 (d, 1 H, J ) 5.8 Hz), 4.74
(d, 1 H, J ) 12.1 Hz), 4.50 (d, 1 H, J ) 12.1 Hz), 4.48 (m, 1 H),
4.36 (m, 3 H), 3.77 (d, 1 H, J ) 10.3 Hz), 2.94 (d, 1 H, J ) 10.3
Hz), 1.54 (s, 3 H), 1.50 (m, 1 H), 1.25 (s, 3 H), 1.43 (irregular
t, 1 H), 0.58 (m, 1 H); FAB MS m/z (rel intensity) 91 (100),
381 (MH+, 2). Anal. Calcd for C24H28O4: C, 75.76; H, 7.42.
Found: C, 75.50; H, 7.37.
(1S,2R,3S,4S,5S)-1-[(Phenylmethoxy)methyl]-2-(phen-
ylmethoxy)bicyclo[3.1.0]hexane-3,4-diol (17). A solution
of 16 (0.54 g, 1.42 mmol) in MeOH (30 mL) was stirred at room
temperature for 3 days in the presence of DOWEX ion-
exchange resin (3 g, 50WX8-100). After the resin was filtered
off, the filtrate was evaporated under reduced pressure and
the residue was purified by silica gel column chromatography
(EtOAc:hexanes, 30:70) to give diol 17 (0.438 g, 91%) as an
oil, plus recovered starting material 16 (0.049 g).
Methyl (1S,2R,3S,4S,5S)-3,4-Sulfinyldioxy-2-phenyl-
carbonyloxybicyclo[3.1.0]hexanecarboxamide (12). A so-
lution of 11 (0.29 g, 1 mmol) in CH2Cl2 (4 mL) at 0 °C was
stirred with Et3N (0.61 g, 6 mmol) and SOCl2 (0.24 g, 2 mmol)
for 10 min. Ether (40 mL) and H2O (20 mL) were added. The
organic layer was washed with brine, dried (Na2SO4), and then
reduced to dryness. The residue was purified by column
chromatography (silica gel; CHCl3:MeOH, 95:5) to furnish a
1
sulfite 12 (0.249 g, 74%) as a solid; H NMR (CDCl3) δ 8.18
(dd, 2 H, J ) 3.2, 2.5 Hz), 7.42-7.58 (m, 3 H), 7.14 (br s, 1 H),
5.95 (dd, 1 H, J ) 2.7, 2.4 Hz), 5.61-5.76 (m, 1H), 5.54 (t, 1
H, J ) 3.5 Hz), 5.36 (t, 1 H, J ) 4.2 Hz), 2.82 (d, 3 H, J ) 1.5
Hz), 2.52-2.61 (m, 1 H), 1.62-1.81 (m, 2 H); FAB MS m/z (rel
intensity) 338.1 (MH+, 64).
17: IR (neat) 3421 cm-1; [R]25D +44.9 (c 1.2, CHCl3); 1H NMR
(MeOH-d4) δ 7.20-7.35 (m, 10 H), 4.64 (d, 1 H, J ) 11.7 Hz),
4.46 (d, 1 H, J ) 11.7 Hz), 4.38 (AB q, 2 H, J ) 11.7 Hz), 4.19-
4.22 (m, 2 H), 3.92 (t, 1 H, J ) 6.1 Hz), 3.75 (d, 1 H, J ) 10.5
Hz), 3.08 (d, 1 H, J ) 10.5 Hz), 1.43-1.49 (m, 2 H), 0.41 (m,
1 H); FAB MS m/z (rel intensity) 91 (100), 341 (MH+, 5). Anal.
Calcd for C21H24O4: C, 74.09; H, 7.11. Found: 73.39; H, 7.10.
(1S,2R,3S,4S,5S)-3,4-O-Sulfinyl-1-[(phenylmethoxy)-
methyl]-2-(phenylmethoxy)bicyclo[3.1.0]hexane (18). In
the presence of triethylamine (0.71 mL, 5.10 mmol), a stirred
solution of diol 17 (0.43 g, 1.27 mmol) in CH2Cl2 (8 mL) at 0
°C was treated with SOCl2 (0.14 mL, 1.92 mmol). After 10 min,
the reaction was partitioned between Et2O (80 mL) and water
(10 mL), and the organic layer was washed with brine (10 mL),
dried (MgSO4), and filtered. The filtrate was reduced to
dryness under reduced pressure and residue was purified by
silica gel column chromatography (hexanes:EtOAc, 80:20) to
give the cyclic sulfite 18 (0.436 g, 89%) as an oil; IR (neat)
1027 cm-1; 1H NMR (C DCl3) δ (m, 10 H), 5.56 (t, 1 H, J ) 5.9
Hz), 5.19 (irregular t, 1 H), 4.73 (d, 1 H, J ) 11.7 Hz), 4.61 (d,
1 H, J ) 6.2 Hz), 4.52 (d, 1 H, J ) 11.7 Hz), 4.44 (AB q, 2 H,
Methyl (1S,2R,3S,4S,5S)-3,4-Sulfonyldioxy-2-phenyl-
carbonyloxybicyclo[3.1.0]hexanecarboxamide (13). A so-
lution of 12 (0.34 g, 1 mmol) in a mixture of CCl4 (2 mL), CH3-
CN (2 mL), and H2O (2 mL) was treated with NaIO4 (0.27 g,
1.25 mmol) and RuCl3‚3H2O (0.002 g). After 1 h of stirring,
the reaction mixture was partitioned between ether (40 mL)
and H2O (20 mL). The organic layer was washed with brine,
dried (Na2SO4), and evaporated. The residue was purified by
column chromatography (silica gel; CHCl3:MeOH, 95:5) to
furnish sulfone 13 (0.240 g, 67%) as a solid; [R]25 +16.0 (c
D
0.1, CH2Cl2); 1H NMR (CDCl3) δ 8.14 (dd, 2 H, J ) 1.4 Hz, 1.2
Hz), 7.42-7.76, (m, 3 H), 7.18 (br s, 1 H), 6.08 (d, 1 H, J ) 3.2
Hz), 5.55 (t, 1 H, J ) 3.6 Hz), 5.35 (t, 3 H, J ) 4.1 Hz), 2.83 (d,
3 H, J ) 3.6 Hz), 2.61-2.67 (m, 1 H), 1.82-1.89 (m, 1 H), 1.63-
1.76, (m, 1 H); FAB MS m/z (rel intensity) 354.1 (MH+, 50).
(1S,2R,3S,4S,5S)-3,4-O-Isopropylidene-1-(hydroxy-
methyl)bicyclo[3.1.0]hexane-2-ol (15). A stirred solution of
444 J. Org. Chem., Vol. 70, No. 2, 2005

Synthetic Route to (North)-Methanocarba Nucleosides
J ) 11.7 Hz), 3.84 (d, 1 H, J ) 10.3 Hz), 3.10 (d, 1 H, J ) 10.3
Hz), 1.72 (irregular quintet, 1 H), 1.18 (dd, 1 H, J ) 5.9, 4.4
Hz), 0.72 (irregular t, 1 H); FAB MS m/z (rel intensity) 91 (100),
387 (MH+, 3). Anal. Calcd for C21H22O5S: C, 65.27; H, 5.74; S,
8.30. Found: C, 65.33; H, 5.81; S, 8.20.
3346, 3278 cm-1; [R]25D +13.1 (c 0.78, MeOH); 1H NMR (CH3-
OH-d4) δ 7.28-7.40 (m, 10 H), 4.61 (AB q, 2 H, J ) 11.7 Hz),
4.48 (AB s, 2 H), 4.33 (d, 1 H, J ) 6.2 Hz), 3.81 (dd, 1 H, J )
6.2, 3.3 Hz), 3.68 (d, 1 H, J ) 10.3 Hz), 3.33 (d, 1 H, J ) 10.3
Hz), 3.05 (d, 1 H, J ) 3.3 Hz), 1.28 (irregular t, 1 H), 1.20 (dd,
1 H, J ) 8.6, 4.2 Hz), 0.73 (dd, 1 H, J ) 8.6, 4.9 Hz); FAB MS
m/z (rel intensity) 91 (100), 340 (MH+, 75). Anal. Calcd for
C21H25NO3‚0.5H2O: C, 72.39; H, 7.52; N, 4.02. Found: C,
72.23; H, 7.28; N, 3.95.
(1S,2R,3S,4S,5S)-3,4-O-Sulfonyl-1-[(phenylmethoxy)-
methyl]-2-(phenylmethoxy)bicyclo[3.1.0]hexane (19). A
stirred solution of cyclic sulfite 18 (0.25 g, 0.64 mmol) in CCl4
(2.5 mL), CH3CN (2.5 mL), and water (3.75 mL) was cooled to
0 °C and treated with NaIO4 (0.204 g, 0.95 mmol) and RuCl3
(0.005 g). After 30 min, the reaction mixture was partitioned
between Et2O (100 mL) and water (20 mL). The organic layer
was washed with brine (10 mL), dried (MgSO4), filtered, and
evaporated under reduced pressure. The residue was purified
by silica gel column chromatography (hexanes:EtOAc, 75:25)
Ethyl (1S,2R,3S,4S,5S)-2,3-O-(Isopropylidene)-4-hy-
droxybicyclo[3.1.0]hexanecarboxylate (23). A solution of
9 (0.48 g, 2.0 mmol) and p-TsOH‚H2O (0.19 g, 1 mmol) in
acetone (20 mL) was refluxed for 8 h. Following the addition
of NEt3 (1 mL), the solution was concentrated under reduced
pressure. Flash column chromatography (silica gel; CHCl3:
MeOH, 90:10) of the residue furnished a mixture of isomerized
alcohols 25 and 9 in a 6:4 ratio based on NMR. This crude
mixture was further purified by careful crystallization from
cyclohexane to obtain the requisite pure 23 (0.196 g, 41%) as
colorless crystals. The remaining alcohol 9 was recycled.
to give the cyclic sulfate 19 (0.254 g, 99%) as an oil; (IR) 1718
1
cm-1; [R]25 +76.6 (c 1.14, CHCl3); H NMR (CDCl3) δ 7.20-
D
7.36 (m, 10 H), 5.40 (t, 1 H, J ) 5.9 Hz), 4.96 (irregular t, 1
H), 4.68 (d, 1 H, J ) 11.7 Hz), 4.58 (dd, 1 H, J ) 6.2, 1.5, Hz),
4.48 (d, 1H, J ) 11.7 Hz), 4.42 (AB q, 2 H J ) 11.7 Hz), 4.10
(q, traces of EtOAc), 3.88 (d, 1 H, J ) 10.6 Hz), 3.00 (d, 1 H,
J ) 10.6 Hz), 1.81 (irregular quintet, 1 H), 1.62 (dd, 1 H, J )
6.6, 4.0 Hz), 1.25 (t, traces of EtOAc), 0.87 (br t, 1 H); FAB
MS m/z (rel intensity) 91 (100), 403 (MH+, 2). Anal. Calcd for
C21H22O6S‚0.2EtOAc: C, 62.33; H, 5.66; S, 7.63. Found: C,
62.10; H, 5.67; S, 7.72.
23: mp 80 °C; [R]25 +124.0 (c 0.15, CH2Cl2); 1H NMR
D
(CDCl3) δ 5.38 (d, 1 H, J ) 5.5 Hz), 4.42-4.64 (m, 2 H), 4.08-
4.21 (m, 2 H), 2.39-2.45 (m, 2 H), 1.42-1.62 (m, 5 H), 1.35 (s,
3 H), 1.12 (t, 2 H, J ) 3.2 Hz); FAB MS m/z (rel intensity)
243.1 (MH+, 100); 13C NMR (CDCl3) δ 172.21, 113.42, 79.97,
79.65, 70.20, 61.29, 39.25, 26.27, 24.74, 16.93, 14.43 ppm. Anal.
Calcd for C12H18O5: C, 59.49; H, 7.49. Found: C, 59.46; H,
7.59.
(1S,2R,3S,4R,5S)-4-Azido-2-(phenylmethoxy)-1-[(phen-
ylmethoxy)methyl]bicyclo[3.1.0]hexan-3-ol (20). Method
1. A stirred solution of cyclic sulfite 18 (0.25 g, 0.34 mmol)
and NaN3 (0.044 g, 0.68 mmol) in DMF (2 mL) was heated at
100 °C for 12 h. After reaching room temperature, the reaction
mixture was partitioned between Et2O (60 mL) and water (20
mL). The organic layer was washed with brine (10 mL), dried
(MgSO4), filtered, and evaporated. The residue was purified
by silica gel flash column chromatography (hexanes:EtOAc,
70:30) to give the desired azido compound 20 (0.102 g, 82%)
and its regiosomer 21 (0.012 g, 10%) as oils. Method 2. A
solution of cyclic sulfate 19 (0.023 g, 0.06 mmol) and NaN3
(0.011 g, 0.17 mmol) in CH3CN (2 mL) was stirred at room
temperature for 12 h. The reaction mixture was partitioned
between EtOAc (20 mL) and water (5 mL), and the organic
layer was washed with brine (2 mL), dried (MgSO4), filtered,
and evaporated. The residue was purified by silica gel column
chromatography (hexanes:EtOAc, 70:30) to give exclusively the
desired azido compound 20 (0.014 g, 70%) as an oil; IR (neat)
Ethyl (1′S,2′R,3′S,4′R,5′S)-4′-(2,6-Dichloropurin-9-yl}-
2′,3′-O-(isopropylidene)bicyclo[3.1.0]hexanecarbox-
ylate (24). A mixture of triphenyl phosphine (0.104 g, 0.4
mmol) and 2,6-dichloropurine (0.076 g, 0.4 mmol) in dry THF
(2 mL) was treated with diisopropylazodicarboxylate (0.080 g,
0.4 mmol) at room temperature. After 20 min of stirring, a
solution of 23 (0.048 g, 0.2 mmol) in THF (1 mL) was added
and the mixture was stirred further for 8 h. Concentration
and purification of the residue by column chromatography
(silica gel; CHCl3:MeOH, 90:10) furnished 24 (0.029 g, 36%)
as a white solid; mp 104 °C; [R]25D +34 (c 0.1, CH2Cl2); 1H NMR
(CDCl3) δ 8.09 (s, 1 H), 5.85 (d, 1 H, 6.5 Hz), 4.91 (s, 1 H), 4.72
(d, 1 H, J ) 5.5 Hz), 4.05-4.38 (m, 2 H), 2.14-2.2 (m, 1 H),
1.75-1.82 (m, 1 H), 1.52-1.62 (m, 4 H), 1.15-1.38 (m, 6 H);
13C NMR (CDCl3) δ 171.41, 153.39, 152.53, 144.90, 131.56,
112.97, 89.12, 80.83, 61.93, 61.38, 40.22, 36.78, 26.10, 24.35,
18.86, 14.48 ppm; FAB MS m/z (rel intensity) 413.1 (MH+,
100). Anal. Calcd for C17H18Cl2N4O4: C, 49.41; H, 4.39; N,
13.56. Found: C, 49.14; H, 4.64; N, 13.26.
2096 cm-1; [R]25 -58.4 (c 1.06, CHCl3); 1H NMR (CDCl3) δ
D
7.25-7.33 (m, 10 H), 4.63 (d, 1 H, J ) 11.3 Hz), 4.51 (AB d, 2
H, J ) 11.7 Hz), 4.45 (d, 1 H, J ) 11.3 Hz), 4.36 (br d, 1 H, J
) 6.2 Hz), 3.90 (dm, 1 H, J ) 6.2 Hz), 3.71 (br d, 1 H, J ) 2
Hz), 3.61 (d, 1 H, J ) 10.5 Hz), 3.28 (d, 1 H, J ) 10.5 Hz), 2.53
(br s, 1 H, OH), 1.38 (dd, 1 H, J ) 8.8, 4.1 Hz), 1.24 (dd, 1 H,
J ) 5.3, 4.1 Hz), 0.70 (ddd, 1 H, J ) 8.6, 5.5, 1.2 Hz). This
compound was used without further purification for the next
step.
(1′S,2′R,3′S,4′R,5′S)-{4′-[2-Chloro-6-(methylamino)-
purin-9-yl]-2′,3′-O-(isopropylidene)bicyclo[3.1.0]hexyl}-
N-methylcarboxamide (25). A stirred solution of 24 (0.041
g, 0.1 mmol) in MeOH (2 mL) was treated with aqueous CH3-
NH2 (0.5 mL, 40%) for 8 h at room temperature. The reaction
mixture was concentrated to dryness and the product was
purified by preparative TLC, using CHCl3:MeOH (90:10) as
(1S,2R,3S,4R,5S)-3-Azido-4-(benzyloxy)-5-[(benzyloxy)-
the mobile phase, to afford 25 (0.022 g, 60%) as white solid;
methyl]bicyclo[3.1.0]-hexan-2-ol (21): IR (neat) 2098 cm-1
;
1
mp 221 °C; [R]25 +10.0 (c 0.05, MeOH); H NMR (CDCl3) δ
D
1H NMR (CDCl3) δ 7.19-7.33 (m, 10 H), 5.54 (irregular t, 1
H), 5.17 (irregular t, 1 H), 4.70 (d, 1 H, J ) 11.7 Hz), 4.58 (d,
1 H, J ) 5.5 Hz), 4.48 (d, 1 H, J ) 11.7 Hz), 4.40 (AB q, 2 H,
J ) 11.7 Hz), 3.81 (d, 1 H, J ) 10.5 Hz), 2.91 (d, 1 H, J ) 10.5
Hz), 1.66 (irregular quintuplet, 1 H), 1.13 (dd, 1 H, J ) 5.9,
4.3 Hz), 0.69 (br t, 1 H).
7.71 (s, 1 H), 6.92 (br s, 1 H), 6.08 (s, 1 H), 5.65 (d, 1 H, J )
5.4 Hz), 4.63-4.84 (m, 2 H), 3.11 (br s, 3 H), 2.95 (d, 3 H, J )
3.8 Hz), 1.95-2.06 (m, 1 H), 1.61-1.66 (m, 1 H), 1.56 (s, 3 H),
1.08-1.24 (m, 4 H); FAB MS m/z (rel intensity) 393.1 (MH+,
100). Anal. Calcd for C17H21ClN6O3: C, 51.98; H, 5.39; N, 21.39.
Found: C, 51.71; H, 5.86; N, 20.82.
(1S,2R,3S,4R,5S)-4-Amino-2-(phenylmethoxy)-1-[(phen-
ylmethoxy)methyl]bicyclo[3.1.0]hexan-3-ol (22). A solu-
tion of azido compound 20 (0.012 g, 0.03 mmol) in a mixture
of CH2Cl2 (1.2 mL) and MeOH (1.2 mL) was stirred for 3 days
under a balloon filled with a hydrogen atmosphere in the
presence of Lindlar’s catalyst (0.002 g). The catalyst was
filtered off with Celite as a filtering aid, and the filtrate was
reduced to dryness under vacuum. The residue was purified
by silica gel flash column chromatography (CH2Cl2:MeOH, 90:
10) to give amine 22 (0.009 g, 81%) as a clear oil; IR (neat)
(1′S,2′R,3′S,4′R,5′S)-{4′-[2-Chloro-6-(methylamino)-
purin-9-yl]-2′,3′-dihydroxybicyclo[3.1.0]hexyl}-N-meth-
ylcarboxamide (1b). A mixture of amide 25 (0.016 g, 0.04
mmol) containing 10% trifluoroacetic acid/MeOH (5 mL) and
H2O (0.5 mL) was heated at 70 °C for 3 h. The solvent was
removed and the residue was dried by coevaporation with
toluene. The residue was purified by using preparative TLC
(CHCl3:MeOH, 90:10) to afford 1b (0.010 g, 71%) as a white
1
solid; mp 248 °C dec; [R]25 +16.0 (c 0.05, CH2Cl2); H NMR
D
(DMSO-d6) δ 8.22 (br s, 1 H), 8.05 (s, 1 H), 7.55 (br s, 1H),
J. Org. Chem, Vol. 70, No. 2, 2005 445

Joshi et al.
5.38 (d, 1 H, J ) 2.5 Hz), 4.80-4.94 (m, 2 H), 4.61 (s, 1 H),
3.76-3.86 (m, 2 H), 3.30 (br s, 3 H), 2.74 (d, 3 H, J ) 2.5 Hz),
1.74-1.83 (m, 1 H), 1.61 (t, 1 H, J ) 2.4 Hz), 1.21-132 (m, 1
H); FAB MS m/z (rel intensity) 353.07 (MH+, 100). Anal. Calcd
for C14H17ClN6O3‚0.25H2O: C, 47.06; H, 4.94; N, 23.52.
Found: C, 47.06; H, 5.24; N, 23.98.
(1′S,2′R,3′S,4′R,5′S)-(4′-{2-Chloro-6-[(trans-2-phenylcy-
clopropyl)amino]purin-9-yl}-2′,3′-dihydroxybicyclo[3.1.0]-
hexyl)-N-methylcarboxamide (29). Starting from compound
27 and following the same procedure described for the syn-
thesis of 1a, compound 29 (0.013 g, 72%) was obtained as a
solid; mp 230 °C dec; [R]25 +19.0 (c 0.1, MeOH); 1H NMR
D
(CDCl3) δ 7.82 (s, 1 H), 7.23-7.38 (m, 5 H), 6.92 (br s, 1 H),
6.31 (br s, 1 H), 4.98 (d, 1 H, J ) 4.8 Hz), 4.83 (s, 1 H), 4.08-
4.29 (m, 2 H), 2.92 (d, 3 H, J ) 4.8 Hz), 2.08-2.23 (m, 1 H),
1.62-1.96 (m, 2 H), 1.21-1.44 (m, 3 H); 13C NMR (CDCl3) δ
171.98, 156.37, 140.15, 139.25, 128.59, 127.32, 126.57, 119.68,
72.66, 62.31, 39.28, 26.88, 26.56, 25.75, 14.31 ppm; FAB MS
m/z (rel intensity) 455.2 (MH+, 100). Anal. Calcd for C22H23-
ClN6O3‚0.5H2O: C, 56.96; H, 5.21; N, 18.12. Found: C, 57.17;
H, 4.93; N, 16.47.
(1′S,2′R,3′S,4′R,5′S)-(4′-{6-[(2,2-Diphenylethyl)amino]-
2-chloropurin-9-yl}-2′,3′-dihydroxybicyclo[3.1.0]hexyl)-
N-methylcarboxamide (30). Starting from compound 28 and
following the same procedure described for the synthesis of
1a, compound 30 (0.014 g, 70%) was obtained as a solid; mp
232 °C dec; [R]25D +6.0 (c 0.1, MeOH); 1H NMR (CDCl3) δ 7.76
(s, 1 H), 7.21-7.38 (m, 10 H), 6.83 (br s, 1 H), 5.97 (br s, 1 H),
4.96 (d, 1 H, J ) 4.8 Hz), 4.80 (br s, 1H), 4.02-4.38 (m, 4 H),
2.91 (d, 3 H, J ) 4.8 Hz), 2.12-2.21 (m, 1 H), 1.21-1.39 (m, 2
H); 13C NMR (CDCl3) δ 171.87, 155.42, 141.70, 139.14, 129.04,
128.34, 127.23, 119.23, 72.75, 62.41, 50.69, 45.36, 39.35, 26.86,
26.55, 14.30 ppm; FAB MS m/z (rel intensity) 519.3 (MH+,
100). Anal. Calcd for C27H27ClN6O3‚H2O: C, 60.39; H, 5.44;
N, 15.65. Found: C, 60.61; H, 5.34; N, 15.64.
X-ray Crystallographic Structure Determination. A
colorless plate with approximate orthogonal dimensions 0.346
× 0.213 × 0.120 mm3 was placed and optically centered on a
Bruker SMART CCD system at -80 °C. The initial unit cell
was indexed by using a least-squares analysis of a random
set of reflections collected from three series of 0.3° wide
ω-scans, 10 s per frame, and 25 frames per series that were
well distributed in reciprocal space. Data frames were collected
[Mo KR] with 0.2° wide ω-scans, 30 s per frame, and 909
frames per series. Five complete series were collected at
varying æ angles (æ ) 0°, 72°, 144°, 216°, 288°). Additionally,
300 frames, a partial repeat of the first series, were also
collected for redundancy and decay purposes. The crystal to
detector distance was 4.913 cm, thus providing a complete
sphere of data to 2θmax ) 55.0°. A total of 37686 reflections
were collected and corrected for Lorentz and polarization
effects and absorption, using Blessing’s method as incorporated
into the program SADABS26,27 with 5784 unique [R(int) )
0.0350].
Crystallographic calculations were performed on a personal
computer (PC) with a Pentium 1.80 GHz processor and 512MB
of extended memory. The SHELXTL28 program package was
implemented to determine the probable space group and set
up the initial files. System symmetry, systematic absences,
and intensity statistics indicated the unique chiral orthor-
hombic space group P212121 (no. 19). The structure was
determined by direct methods with the successful location of
nearly all non-hydrogen atoms, using the program XS.29 The
structure was refined with XL.30 One least-squares difference
Fourier cycle was required to locate the remaining non-
hydrogen atoms. All non-hydrogen atoms were refined aniso-
tropically. Hydrogen atoms were initially placed in calculated
positions but allowed to refine freely during the final refine-
ment stages. The absolute structure parameter, Flack (x),31
(1′S,2′R,3′S,4′R,5′S)-(4′-{2-Chloro-6-[(3-iodophenyl)ami-
no]purin-9-yl}-2′,3′-O-(isopropylidene)bicyclo[3.1.0]hexyl)-
N-methylcarboxamide (26). A solution of 24 (0.042 g, 0.1
mmol) in MeOH (2 mL) was treated with 3-iodobenzylamine
hydrochloride (0.078 g, 0.15 mmol) and Et3N (0.5 mL) and
stirred at room temperature for 3 h. The reaction mixture was
concentrated to dryness and the resulting residue was purified
by flash column chromatography (silica gel; CHCl3:MeOH, 90:
10). The intermediate product was dissolved in MeOH (3 mL),
treated with an excess of aqueous CH3NH2 (0.5 mL, 40%), and
stirred at room temperature for 6 h. After being evaporated
to dryness and preparative TLC purification (CHCl3:MeOH,
90:10) 26 (0.028 g, 46%) was obtained as a white solid; mp
156 °C; [R]25D + 7.50 (c 0.04, MeOH); 1H NMR (CDCl3) δ 7.61-
7.78 (m, 3 H), 7.38 (d, 1 H, J ) 5.4 Hz), 7.09 (t, 1 H, J ) 5.7
Hz), 6.82 (br s, 1 H), 6.35 (br s, 1 H), 5.63 (d, 1 H, J ) 6.3 Hz),
4.65-4.82 (m, 3 H), 2.91 (d, 3 H, J ) 2.5 Hz), 2.02-2.11 (m, 1
H), 1.11-1.92 (m, 8 H); FAB MS m/z (rel intensity) 595.1
(MH+, 100). Anal. Calcd for C23H24ClIN6O3‚0.5H2O: C, 45.75;
H, 4.17; N, 13.92. Found: C, 45.92; H, 4.16; N, 13.89.
(1′S,2′R,3′S,4′R,5′S)-[4′-(2-Chloro-6-{[(3-iodophenyl)-
methyl]amino}purin-9-yl)-2′,3′-dihydroxybicyclo[3.1.0]-
hexyl]-N-methylcarboxamide (1a). A mixture of amide 26
(0.024 g, 0.04 mmol) containing 10% trifluoroacetic acid in
MeOH (5 mL) and H2O (0.5 mL) was heated at 70 °C for 3 h.
The solvent was removed, and the residue was dried by
coevaporation with toluene. The residue was purified with
preparative TLC (CHCl3: MeOH, 90:10) to afford 1a (0.016 g,
74%) as a white solid; mp 230 °C; [R]25 +7.0 (c 0.1, MeOH);
D
1H NMR (DMSO-d6) δ 8.84 (br s, 1 H), 8.11 (s, 1 H), 7.78 (s, 1
H), 7.42-7.62 (m, 2 H), 7.36 (d, 1 H, J ) 3.5 Hz), 7.14 (t, 1 H,
J ) 4.5 Hz), 5.44 (d, 1 H, J ) 4.8 Hz), 4.75-4.91 (m, 2 H),
4.56-4.69 (m, 2 H), 3.86-3.92 (m, 1 H), 2.67 (d, 1 H, J ) 2.5
Hz), 1.81-1.89 (m, 1 H), 1.61-165 (m, 1 H), 1.23-1.29 (m, 1
H); 13C NMR (DMSO-d6) δ 171.06, 154.79, 152.95, 149.46,
141.96, 139.44, 136.05, 135.56, 130.54, 126.85, 94.76, 76.11,
71.05, 61.19, 42.50, 38.12, 37.82, 27.63, 26.13, 13.71 ppm; FAB
MS m/z (rel intensity) 555.1 (MH+, 100). Anal. Calcd for C20H20-
ClIN6O3‚0.5H2O: C, 42.61; H, 3.75; N, 14.91. Found: C, 42.54;
H, 3.76; N, 14.52.
(1′S,2′R,3′S,4′R,5′S)-(4′-{2-Chloro-6-[(trans-2-phenyl-
cyclopropyl)amino]purin-9-yl}-2′,3′-O-(isopropyli-
dene)bicyclo[3.1.0]hexyl)-N-methylcarboxamide (27). With
the same procedure described for the synthesis of 26, except
for the use of trans-2-phenylcyclopropylamine hydrochloride,
compound 27 (0.023 g, 48%) was obtained as a solid; mp 168
°C; [R]25 +4.0 (c 0.1, MeOH); 1H NMR (CDCl3) δ 7.71 (s, 1
D
H), 7.19-7.38, (m, 5 H), 6.98 (br s, 1 H), 6.18 (br s, 1 H), 5.68
(d, 1H, J ) 5.2 Hz), 5.76-5.82 (m, 3 H), 2.91 (d, 1 H, J ) 3.6
Hz), 2.18-2.23 (m, 1 H), 1.97-2.08 (m, 1 H), 1.54-1.78 (m, 5
H), 1.22-1.34 (m, 5 H); FAB MS m/z (rel intensity) 495.3
(MH+, 100). Anal. Calcd for C25H27ClN6O3‚0.25H2O: C, 58.02;
H, 5.75; N, 16.24. Found: C, 58.17; H, 5.46; N, 15.85.
(1′S,2′R,3′S,4′R,5′S)-(4′-{6-[(2,2-Diphenylethyl)amino]-
2-chloropurin-9-yl}-2′,3′-O-(isopropylidene)bicyclo[3.1.0]-
hexyl)-N-methylcarboxamide (28). With the same proce-
dure described for the synthesis of 26, except for the use of
(26) Blessing, R. H. Acta Crystallogr. 1995, A51, 33-38.
(27) Sheldrick, G. M., SADABS, Siemens Area Detector Absorption
Correction; Universita¨t Go¨ttingen: Go¨ttingen, Germany, 1996.
(28) Sheldrick, G. M. SHELXTL/PC Version 5.03; Siemens Analyti-
cal X-ray Instruments Inc.: Madison, Wisconsin, 1994.
(29) Sheldrick, G. M. Acta Crystallogr. 1990, A46, 467-473.
(30) Sheldrick, G. M. Shelxl93, Program for the Refinement of
Crystal Structures; University of Go¨ttingen: Go¨ttingen, Germany,
1993.
2,2-diphenylethylamine, compound 28 (0.023 g, 42%) was
1
obtained as a solid; mp 145° C; [R]25 +8.0 (c 0.1, MeOH); H
D
NMR (CDCl3) δ 7.21-7.78 (m, 11 H), 6.83 (br s, 1 H), 6.26 (br
s, 1H), 5.66 (d, 1 H, J ) 5.6 Hz), 4.21-4.83 (m, 5 H), 2.91 (d,
3 H, J ) 4.8 Hz), 1.97-2.03 (m, 1 H), 1.23-1.78 (m, 8 H); FAB
MS m/z (rel intensity) 559.3 (MH+, 100). Anal. Calcd for C30H31-
ClN6O3‚H2O: C, 63.43; H, 5.68; N, 14.79. Found: C, 63.19; H,
5.71; N, 15.05.
(31) Flack, H. D. Acta Crystallogr. 1983, A39, 876-881.
446 J. Org. Chem., Vol. 70, No. 2, 2005

Synthetic Route to (North)-Methanocarba Nucleosides
was found to be 0.0(9), indicating, additionally from the known
precursor, that the correct enantiomorph has been chosen. The
final structure was refined to convergence [∆/σ e 0.001] with
R(F) ) 4.06%, wR(F2) ) 8.04%, GOF ) 1.123 for all 2753
unique reflections [R(F) ) 3.23%, wR(F2) ) 7.66% for those
2424 data with Fo > 4σ(Fo)]. The final difference Fourier map
was featureless, indicating that the structure is both correct
and complete.
Acknowledgment. We thank Dr. Tom Spande and
Dr. Victor Livengood (NIDDK) for mass spectral mea-
surements and Wesley White (NIDDK) for NMR spec-
tra.
Supporting Information Available: X-ray structural
coordinates and 3D representation of compound 9. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The function minimized during the full-matrix least-squares
refinement was ∑w(Fo2 - Fc2), where w ) 1/[σ2(Fo2) + (0.0366P)2
2
+ 0.1908P] and P ) (max(Fo ,0) + 2Fc2)/3. An empirical
correction for extinction was also attempted but found to be
negative and therefore not applied.
JO0487606
J. Org. Chem, Vol. 70, No. 2, 2005 447