Construction of the bicyclo[3.1.0]hexane template of a conformationally locked carbocyclic adenosine via an olefin keto-carbene cycloaddition

Article abstract of DOI:10.1021/jo9917691

An intramolecular olefin keto-carbene cycloaddition reaction created the bicyclo[3.1.0]hexane template 10 that was necessary for the synthesis of carbocyclic amine 15. This amine is a direct precursor to a family of rigid nucleosides that are conformationally locked in the Southern hemisphere of the pseudorotational cycle. The synthesis of the conformationally locked adenosine analogue is reported herein as an illustrative example of the methodology. The racemic (South)methanocarba adenosine analogue (±)-4 is the first example of a conformationally locked ribonucleoside version in the Southern hemisphere.

Full text of DOI:10.1021/jo9917691

2172
J . Org. Chem. 2000, 65, 2172-2178
Con str u ction of th e Bicyclo[3.1.0]h exa n e Tem p la te of a
Con for m a tion a lly Lock ed Ca r bocyclic Ad en osin e via a n Olefin
Keto-Ca r ben e Cycloa d d ition
Kye J ung Shin,† Hyung Ryong Moon,† Clifford George,‡ and Victor E. Marquez*,†
Laboratory of Medicinal Chemistry, Division of Basic Sciences, National Cancer Institute,
National Institutes of Health, Bethesda, Maryland 20892, and Laboratory for the Structure of Matter,
Naval Research Laboratory, Washington, D.C. 20375
Received November 15, 1999
An intramolecular olefin keto-carbene cycloaddition reaction created the bicyclo[3.1.0]hexane
template 10 that was necessary for the synthesis of carbocyclic amine 15. This amine is a direct
precursor to a family of rigid nucleosides that are conformationally locked in the Southern
hemisphere of the pseudorotational cycle. The synthesis of the conformationally locked adenosine
analogue is reported herein as an illustrative example of the methodology. The racemic (South)-
methanocarba adenosine analogue (()-4 is the first example of a conformationally locked
ribonucleoside version in the Southern hemisphere.
In tr od u ction
potency of carbocyclic nucleosides relative to the corre-
sponding nucleoside counterparts.2
Carbocyclic nucleosides have been devised to overcome
cleavage of the glycosyl bond, an event that occurs readily
in conventional nucleosides by chemical or enzymatic
means.1,2 Although the expected similarity in bond
lengths and bond angles between the tetrahydrofuran
and cyclopentane rings allows carbocyclic nucleosides to
be recognized as substrates or inhibitors of various
enzymes, these two classes of rings are far from being
identical. First and foremost, the removal of the 4′-oxygen
completely abolishes the anomeric effect, and also im-
portant gauche interactions between the furan oxygen
and the 2′- and 3′-hydroxyl groups, when present, are
missing.3,4 These interactions are responsible for deter-
mining the shape and conformation of the tetrahydrofu-
ran ring, which generally adopts a ring pucker close to a
2′-exo/ 3′-endo (3T2, North, P ) 0°) or 2′-endo/ 3′-exo (2T3,
South, P ) 180°) conformation, as defined in the pseu-
dorotational cycle (Figure 1).3-5 In the solid state, one of
these forms usually predominates, whereas in solution
the two conformations appear to exist in a rapid dynamic
equilibrium between a range of North (2E f 3T2 f 3E, P
) 0° ( 18°) and opposing South (2E f 2T3 f 3E, P ) 180°
( 18°) conformations.3-5 In the absence of the aforemen-
tioned forces, the cyclopentane ring in carbocyclic nucleo-
sides adopts an unusual 1′-exo (1E, P ) 126°) conforma-
tion that is relatively far from the characteristic North
or South conformations observed in the typical nucleo-
sides.6,7 This conformational deviation from the norm
may explain the generally observed weaker biological
For the past several years we have synthesized a
number of purine and pyrimidine carbocyclic nucleosides
built on a rigid bicyclo[3.1.0]hexane template, a system
that mimics extremely well either the North envelope (2E)
conformation (e.g., compounds 1 and 2), or the South
envelope (3E) conformation (e.g., compounds 3 and 4) of
conventional nucleosides, depending on the point of
attachment of the base relative to the position of the
fused cyclopropane ring.8 Since the bicyclo[3.1.0]hexane
(6) Kishi, T.; Muroi, M.; Kusaka, T.; Nishikawa, M.; Kamiya, K.;
Mizuno, K. Chem. Pharm. Bull. 1972, 20, 940-946.
(7) Kalman, A.; Koritsanszky, T.; Beres, J .; Sagi, G. Nucleosides
Nucleotides 1990, 9, 235-243.
(8) (a) Rodriguez, J . B.; Marquez, V. E.; Nicklaus, M. C.; Barchi, J .
J ., J r. Tetrahedron Lett. 1993, 34, 6233-6236. (b) Rodriguez, J . B.;
Marquez, V. E.; Nicklaus, M. C.; Mitsuya, H.; Barchi, J . J ., J r. J . Med.
Chem. 1994, 37, 3389-3399. (c) Ezzitouni, A.; Barchi, J . J ., J r.;
Marquez, V. E. J . Chem. Soc., Chem. Commun. 1995, 1345-1346. (d)
J eong, L. S.; Marquez, V. E.; Yuan, C.-S.; Borchardt, R. T. Heterocycles
1995, 41, 2651-2656. (e) Siddiqui, M. A.; Ford, H., J r.; George, C.;
Marquez, V. E. Nucleosides Nucleotides 1996, 15, 235-250. (f) J eong,
L. S.; Marquez, V. E. Tetrahedron Lett. 1996, 37, 2353-2356. (g)
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.
(h) Ezzitouni, A.; Marquez, V. E. J . Chem. Soc., Perkin Trans. 1 1997,
1073-1078. (i) Ezzitouni, A.; Russ, P.; Marquez, V. E. J . Org. Chem.
1997, 62, 4870-4873. (j) Marquez, V. E.; Ezzitouni, A.; Russ, P.;
Siddiqui, M. A.; Ford, H, J r.; Feldman, R. J .; Mitsuya, H.; George, C.;
Barchi, J . J ., J r. J . Am. Chem. Soc. 1998, 120, 2780-2789. (k) Marquez,
V. E.; Ezzitouni, A.; Russ, P.; Siddiqui, M. A.; Ford, H., J r.; Feldman,
R. J .; Mitsuya, H.; George, C.; Barchi, J . J ., J r. Nucleosides Nucleotides
1998, 17, 1881-1884. (l) J eong, L. S.; Buenger, G.; McCormack, J . J .;
Cooney, D. A.; Hao, Z.; Marquez, V. E. J . Med. Chem. 1998, 41, 2572-
2578. (m) Marquez, V. E.; Russ, P.; Alonso, R.; Siddiqui, M. A.; Shin,
K. J .; George, C.; Nicklaus, M. C.; Dai, F.; Ford, H., J r. Nucleosides
Nucleotides 1999, 18, 521-530. (n) Moon, H. R.; Kim, H. O.; Chun, M.
W.; J eong, L. S.; Marquez, V. E. J . Org. Chem. 1999, 64, 4733-4741.
(o) Marquez, V. E.; Russ, P.; Alonso, R.; Siddiqui, M. A.; Hernandez,
S.; George, C.; Nicklaus, M. C.; Dai, F.; Ford, H., J r. Helv. Chim. Acta
1999, 82, 2119-2129.
† National Institutes of Health.
‡ Naval Research Laboratory.
(1) Marquez, V. E.; Lim, M.-I. Med. Res. Rev. 1986, 6, 1-40.
(2) Marquez, V. E. Carbocyclic Nucleosides. In Advances in Antiviral
Drug Design; De Clercq, E., Ed.; J ai Press Inc.: Greenwich, CT, 1996;
Vol. 2, pp 89-146.
(3) Saenger, W. Principles in Nucleic Acid Structure; Springer-
Verlag: New York, NY, 1984.
(4) Thibaudeau, C.; Chattopadhyaya, J . Stereoelectronic Effects in
Nucleosides and Nucleotides and their Structural Implications; Upp-
sala Univesity Press: Uppsala, Sweden, 1999.
(5) The commonly described shapes of ring puckering, such as 2′-
exo/ 3′-endo and 2′- endo/ 3′-exo, correspond to a pentofuranose num-
bering system described in the pseudorotational cycle: Altona, C.;
Sundaralingam, M. J . Am. Chem. Soc. 1972, 94, 8205-8212.
10.1021/jo9917691 This article not subject to U.S. Copyright. Published 2000 by the American Chemical Society
Published on Web 03/14/2000

Construction of a Bicyclo[3.1.0]hexane Template
J . Org. Chem., Vol. 65, No. 7, 2000 2173
F igu r e 1. Pseudorotational cycle displaying all the puckering modes (P) in conventional nucleosides.
Sch em e 1
template is known to exist rigidly in a pseudoboat shape,
these compounds are able to maintain identical confor-
mations in the solid state and in solution.8-10 Several
studies with these methanocarba nucleosides, mostly in
their 2′-deoxyribo configuration, have helped defined the
role of sugar puckering in nucleosides by stabilizing the
active receptor-bound conformation, and thereby identi-
fying the biologically favored sugar conformer.8b,d,e,g,h,j-m,o
Thus far, the only compound with the ribo configuration
that has been synthesized and studied is the North
adenosine analogue (2, B ) adenine),8d and until now,
no South (3E)-ribo version has yet been synthesized.
Therefore, in the present work, we wish to report a novel
approach to these types of carbocyclic nucleosides based
on an intramolecular cyclopropanation reaction that
culminated with the successful synthesis of the South
(3E)-ribo version of adenosine (4, B ) adenine).
common intermediate to all purines and pyrimidine
nucleosides by means of conventional linear approach-
es.12-14 The choice of isopropylidene protection is conve-
nient but other protective groups are possible. As in the
case of the synthesis of the South (3E)-2′-deoxyribo
version,8c,h the ester in II could be conveniently trans-
formed into the amine I after hydrolysis to the acid and
Curtius rearrangement. The precursor of II is the keto
intermediate III, where hydride reduction is anticipated
to occur from the less hindered side of the bicyclic system
to give the cis-diol. The critical bicyclic system III is
envisioned to arise from an intramolecular carbene
insertion on the olefin in IV following thermolysis of the
progenitor diazo compound.11 The diazo precursor is
expected to be readily accessible from the corresponding
â-ketoester, which can be obtained from acid V after
Resu lts a n d Discu ssion
Syn th esis. The intramolecular cyclopropanation of
alkenes to generate bicyclo[3.1.0]hexane systems has
been extensively studied in natural product syntheses.11
However, the key to using this approach successfully in
carbocyclic nucleoside chemistry relies on the proper
choice of starting materials to make the synthesis adapt-
able to all types of purine and pyrimidine nucleosides.
The retrosynthetic analysis that fulfills such a premise
is outline in Scheme 1. Carbocyclic amine I represents a
(9) Altmann, K.-H.; Kesselring, R.; Francotte, E.; Rihs, G. Tetrahe-
dron Lett. 1994, 35, 2331-2334.
(10) Altmann, K.-H.; Imwinkelried, R.; Kesselring, R.; Rihs, G.
Tetrahedron Lett. 1994, 35, 7625-7628.
(11) (a) Davies, H. M. L. Addition of Ketocarbenes to Alkenes,
Alkynes and Aromatic Systems. In Comprehensive Organic Synthesis.
Selectivity, Strategy and Efficiency in Modern Organic Chemistry;
Trost, B. M., Fleming, I., Semmelhack, M. F., Eds.; Pergamon Press:
New York, 1991; Vol. 4, pp 1031-1067. (b) Burke, S. D.; Grieco, P. A.
Org. React. 1979, 26, 361-475.
(12) Borthwick, A. D.; Biggadike, K. Tetrahedron 1992, 48, 571-
623.
(13) Agrofoglio, L.; Suhas, E.; Farese, A.; Condom, R.; Challand, S.
R.; Earl, R. A.; Guedj, R. Tetrahedron 1994, 50, 10611-10670.
(14) Crimmins, M. T. Tetrahedron 1998, 54, 9229-9272.

2174 J . Org. Chem., Vol. 65, No. 7, 2000
Shin et al.
Sch em e 2a
Sch em e 3a
a
(a) PMBOCH2COOH, DCC, DMAP, CH2Cl2 (99%); (b) (i) LDA,
THF; (ii) TMSCl, Et3N (91%); (c) (i) carbonyldiimidazole, THF; (ii)
LiCH2CO2CH3, THF (90%); (d) TsN3, Et3N, CH3CN (95%); (e)
cupric acetylacetonate, cyclohexane (10, 52%; 11, 26%).
a
(a) NaBH4, MeOH/CH2Cl2 (2:1) (91%); (b) CuSO4, cat. H2SO4,
acetone (93%); (c) 1 N NaOH, MeOH (100%); (d) (i) (PhO)2PON3,
Et3N, benzene; (ii) 2 N NaOH, THF (64%); (e) (i) 5-formamido-
4,6-dichloropyrimidine, Et3N, THF (78%); (ii) CH3CO2CH(OEt)2
(93%); (f) NH3/MeOH (99%); (g) Pd black, 4.4% HCO2H/MeOH
(86%); (h) 80% AcOH (76%).
Dieckmann condensation of the activated acid with
methyl 2-lithioacetate. Finally, acid V can be conceived
as being generated by an enolate [3,3]-sigmatropic rear-
rangement15,16 of VI [R1 ) Bn and R2 ) p-methoxybenzyl
(PMB)], which in turn can be prepared, in one step, from
known (E)-4-(benzyloxy)but-2-en-1-ol17 and p-methoxy-
benzyloxyacetic acid.18
sp2 carbonyl still maintains a pseudoboat conformation.20
Therefore, the singlet at δ 3.67 (J ) 0) for the H3 proton
signal in the 1H NMR spectrum of one of the isomers was
diagnostic of a H3-C3-C4-H4 dihedral angle of ∼90°
which is only possible in isomer 10.
The synthesis was realized as planned, and the re-
agents and conditions employed are shown in Schemes
2 and 3. DCC-catalyzed esterification of (E)-butenol 5 and
p-methoxybenzyloxyacetic acid gave the glycolate ester
6, which, as expected, underwent an enolate Claisen-
Ireland rearrangement15,16 in the presence of LDA and
Me3SiCl with excellent diastereoselectivity to give the
desired (2R*,3R*)-γ,δ-unsaturated acid 7 in a 95:5 ratio
over the (2S*,3R*)-isomer. This favorable outcome can
be explained by a chairlike transition state that is
controlled by the trans-geometry of the starting olefin and
the local geometry of the enolate induced by the coordi-
nated metal, as illustrated in Scheme 2.15,16 Activation
of the acid with carbonyldiimidazole followed by Dieck-
mann condensation with methyl 2-lithioacetate19 pro-
duced the â-ketoester 8, which following diazo transfer
with tosyl azide in the presence of triethylamine gave
the diazo compound 9 in good yield. Thermolysis of 9 was
investigated with a couple of soluble catalysts, such as
copper(II) acetylacetonate and rhodium(II) acetate dimer,
and copper (II) sulfate as a heterogeneous catalyst.
Copper(II) acetylacetonate gave the best results, forming
the corresponding bicyclo[3.1.0]hexane system in 78%
yield as a separable, 2:1 mixture of diastereoisomers (10
and 11) favoring 10. The initial tentative assignment of
structures 10 and 11 was made on the basis of the
predictable dihedral angles for a rigid bicyclo[3.1.0]-
hexane template,8 which even with the presence of an
Additional confirmation of this assignment was ob-
tained after the hydride reduction of the keto group in
diastereoisomer 10, which in diol 12 and all the products
derived from it (i.e., 13-18 and 4, Scheme 3) displayed
NMR signals for H3 and H2 (12-15) and H3′ and H2′ (16-
18 and 4) as doublets, thus confirming a value of ∼90°
for the H3-C3-C4-H4 torsion angle. Full confirmation
of this assignment, however, was obtained later from the
X-ray structure of the final adenosine analogue 4 (B )
adenine, vide infra). Simultaneous deprotection of the
PMB group and acetonide formation occurred in the
presence of Cu(II) sulfate and catalytic amounts of
sulfuric acid to give 13 (Scheme 3). Saponification of ester
13 was followed by a modified Curtius rearrangement of
the resulting acid 14 with diphenylphosphoryl azide21 in
refluxing benzene to give a rather stable isocyanate
intermediate that required further hydrolysis with so-
dium hydroxide to generate the corresponding amine 15.
Finally, the purine base was constructed as shown in
Scheme 3 following the same approach that was used for
the South (3E)-2′-deoxyribo version (3).8c,h
Cr ysta l Str u ctu r e a n d Con for m a tion a l An a lysis.
The X-ray structure of compound 4 (B ) adenine, Figure
2) confirmed the fitness of the synthetic approach to
construct the rigid, South (3E)-ribo version of the requi-
site carbocyclic amine 15 and the interpretation of the
1H NMR spectra of the intermediates leading to it (vide
supra). The conformation of the pseudosugar ring in 4
(B ) adenine) is nearly identical to that of the South (3E)-
2′-deoxyribo version of 3 (B ) adenine).8m,o It has a P
(15) Burke, S. D.; Fobare, W. F.; Pacofsky, G. J . J . Org. Chem. 1983,
48, 5221-5228.
(16) Panek, J . S.; Clark, T. D. J . Org. Chem. 1992, 57, 4323-4326.
(17) Harding, K. E.; Hollingsworth, D. R. Tetrahedron Lett. 1988,
29, 3789-3792.
(18) Glover, S. A.; Golding, S. L.; Goosen, A.; McCleland, C. W. J .
Chem. Soc., Perkin Trans. 1 1983, 2479-2483.
(19) Hamada, Y.; Kondo, Y.; Shibata, M.; Shioiri, T. J . Am. Chem.
Soc. 1989, 111, 669-673.
(20) Lightner, D. A.; Pak, C. S.; Crist, B. V.; Rodgers, S. L.; Givens,
J . W., III. Tetrahedron 1985, 41, 4321-4330.
(21) Shioiri, T.; Ninomiya, K.; Yamada, S. I. J . Am. Chem. Soc. 1972,
94, 6203-6205.

Construction of a Bicyclo[3.1.0]hexane Template
J . Org. Chem., Vol. 65, No. 7, 2000 2175
Exp er im en ta l Section
X-r a y Cr ysta llogr a p h y. The adenosine nucleoside 4 was
recrystallized by evaporation from methanol/water (10:1) and
from 2-butanone/water (3:1) as hydrates to form two poly-
morphs (p and c), a primitive and C-centered monoclinic,
respectively. The conformation of the molecule in the two
polymorphs is essentially identical and differs only with
respect to the location of the hydroxyl and water hydrogens.
There are five hydrogen bonds in the primitive cell and six in
the C-centered cell. The additional hydrogen bond in the
C-centered cell involves the water, which acts as a donor to
the hydroxy methyl oxygen.
Sin gle-Cr ysta l X-r a y Diffr a ction An a lysis of 4 (B )
a d en in e). (p) C12H15N5O3‚H2O, fw ) 295.31, monoclinic space
group P21/c, a ) 15.200(2), b ) 7.802(1), c ) 11.432(1) Å, â )
91.01(1)°, V ) 1355.5(2) Å3, Z ) 4, Fcalc ) 1.477 mg mm-3, λ(Cu
KR) ) 1.54184 Å, µ ) 0.936 mm-1, F(000) ) 624, T ) 295°K.
.
(c) C12H15N5O3 H2O, fw ) 295.31, monoclinic space group
C2/c, a ) 32.029(2), b ) 7.983(1), c ) 11.332(3) Å, â ) 109.44-
(1)°, V ) 2732.2(4) Å3, Z ) 8, Fcalc ) 1.436 mg mm-3, λ(Cu KR)
) 1.54184 Å, µ ) 0.928 mm-1, F(000) ) 1248, T ) 295°K. The
following parameters are common to p and c, and where
different they are indicated by enclosure in brackets [ ] for c.
A clear colorless 0.02 × 0.20 × 0.24 [0.06 × 0.44 × 0.52]
mm crystal was used for data collection on an automated
Bruker P4 diffractometer equipped with an incident beam
monochromator. Lattice parameters were determined from 42
[52] centered reflections within 14° < 2θ < 50° [6° < 2θ < 60°].
The data collection range of hkl was -16 e h e 16, -1 e k e
8, 0 e l e 12, [-34 e h e 34, -8 e k e 0, -11 e l e 11], with
{(sin θ)/λ}max ) 0.55. Three standards, monitored after every
97 reflections, exhibited random variations with deviations up
to (2.5% [1.3%] during the data collection. A set of 2396 [3849]
reflections was collected in the θ/2θ scan mode, with scan width
[2θ(KR1) - 1.0]° to [2θ(KR2) + 1.0]° and ω scan rate (a function
of count rate) from 5.0°/min [7.5°/min] to 30.0°/min. There were
1862 [1863] unique reflections, and 1294 [1646]were observed
with Fo > 4σ(Fo). The structure was solved and refined with
the aid of the SHELX-9722 system of programs. The full-matrix
least-squares refinement varied 222 [221] parameters: atom
coordinates and anisotropic thermal parameters for all non-H
atoms. H atoms were included using a riding model [coordinate
shifts of C applied to attached H atoms, C-H distances set to
F igu r e 2. The molecular structure and numbering scheme
for 4 (B ) adenine, polymorph c). The hydrate is omitted. The
dashed line is an intramolecular hydrogen bond.
value of 201.16° and a νmax of 28.63°, which indicates that
the conformation is nearly a perfect 3E envelope (P )
198°). In the unit cell of the chiral compound 3 (B )
adenine), there were two molecules that, although identi-
cal relative to the value of P, had different ø torsion
angles corresponding to both anti- and syn-conformers.8m,o
In the case of (()-4 (B ) adenine), the cell contains both
hands, but the torsion angle ø in both structures is firmly
in the syn range (ø ) +58.2°). The intramolecular
hydrogen bond, which may help stabilize the syn-
conformation in the crystal structure, also fixes the
torsion angle γ in the +sc range (+47.5°). All of these
values are in the normal range of torsion angles found
in conventional nucleosides, except that the sugar ring
(pseudosugar ring) is confined to the Southern hemi-
sphere. Therefore, this compound represents a useful tool
to study of the conformational preferences of adenosine-
metabolizing enzymes. Preliminary results indicate that
4 (B ) adenine) is an extremely poor substrate for
adenosine deaminase (ADA). Indeed, initial attempts to
use ADA to resolve the racemate failed. A variant of this
approach designed to obtain the chiral, D-ribo version of
carbocyclic amine 15 is in progress, as well as the
synthesis of other purine and pyrimidine analogues with
a South-constrained pseudosugar conformation.
0.96-0.93 Å, H angles idealized, Uiso(H) were set to 1.2 Ueq
-
(C)]. The amine, hydroxyl, and water hydrogens coordinates
were refined with fixed isotropic thermal values. Final residu-
als were R1 ) 0.071 [0.052] with final difference Fourier
excursions of 0.53 and -0.44 [0.41 and -0.46] e Å-3
.
Tables of coordinates, bond distances and bond angles, and
anisotropic thermal parameters have been deposited with the
Crystallographic Data Centre, Cambridge, CB2, 1EW, En-
gland.
Gen er a l P r oced u r es. All chemical reagents were com-
mercially available. Melting points were determined on a
Fisher-J ohns melting point apparatus and are uncorrected.
Column chromatography was performed on silica gel 60, 230-
400 mesh (E. Merk), and analytical TLC was performed on
Analtech Uniplates silica gel GF. Routine IR and 1H and 13C
NMR spectra were recorded using standard methods. Positive-
ion fast-atom bombardment mass spectra (FABMS) were
obtained at an accelerating voltage of 6 kV and a resolution
of 2000. Glycerol was used as the sample matrix, and ioniza-
tion was effected by a beam of xenon atoms. Elemental
analyses were performed by Atlantic Microlab, Inc., Norcross,
GA.
(E)-4-(P h en ylm eth oxy)bu t-2-en -1-ol (5). A stirred solu-
tion of LAH (0.45 g, 12 mmol) in anhydrous THF (50 mL) was
maintained at -20 °C and treated with 3.5 g (20 mmol) of
4-(phenylmethoxy)but-2-yn-1-ol,17 which was added slowly and
allowed to react further for 2 h at 0 °C. The cold reaction
mixture was quenched by the careful addition of water (1 mL),
Con clu sion s
A new and efficient approach for the synthesis of
carbocyclic amine 15 based on an intramolecular olefin
keto-carbene cycloaddition reaction was successful in
creating the requisite bicyclo[3.1.0]hexane template.
Amine 15 represents a common intermediate for the
synthesis of all purine and pyrimidine analogues, which
can be accessed by various linear approaches. The
synthesis of the adenosine analogue 4 (B ) adenine)
represents the first example of a conformationally rigid,
South (3E)-ribonucleoside version built on a bicyclo[3.1.0]-
hexane template. The structure of 4 (B ) adenine) was
confirmed by X-ray analysis.
(22) Sheldrick, G. M. SHELXTL Version 5.1; Bruker Analytical
X-ray Instruments: Madison, WI, 1997.

2176 J . Org. Chem., Vol. 65, No. 7, 2000
Shin et al.
15% NaOH (1 mL), and water (3 mL). After further stirring
at room temperature, the reaction mixture was filtered
through a pad of Celite and concentrated under reduced
pressure. Flash column chromatography (25% EtOAc in hex-
ane) gave 3.2 g of the (E)-isomer (5) as a clear oil.17
167.78, 159.32, 137.96, 134.92, 129.48, 129.25, 128.19, 127.49,
127.41, 117.92, 113.72, 84.41, 73.21, 72.91, 68.92, 55.16, 52.00,
47.04, 45.30; IR (neat) 1748 cm-1; FAB MS m/z (relative
intensity) 413 (MH+, 0.6), 276 (1.4), 121 (100), 91 (24.5). Anal.
Calcd for C24H28O6: C, 69.89; H, 6.84. Found: C, 69.73; H,
6.80.
(E)-4-(P h en ylm eth oxy)bu t-2-en yl 2-[(4-Meth oxyph en yl)-
m eth oxy]a ceta te (6). To a stirred solution of 5 (8.5 g, 48
mmol) in CH2Cl2 (140 mL) were added 2-[(4-methoxyphenyl)-
methoxy]acetic acid (12.1 g, 62 mmol), 1,3-dicyclohexylcarbo-
diimide (DCC, 11.8 g, 57 mmol), and 4-(dimethylamino)-
pyridine (DMAP, 0.3 g, 2.5 mmol) at 0 °C. The reaction was
allowed to warm slowly to room temperature. After being
stirred for 20 h, the reaction mixture was filtered to remove
the precipitated urea, and the filtrate was evaporated under
reduced pressure. The residue was dissolved in ether, filtered,
and reconcentrated under reduced pressure. Flash column
chromatography (10% f 20% EtOAc in hexane) gave 16.9 g
(99.6%) of ester 6 as a clear oil: 1H NMR (250 MHz, CDCl3) δ
7.43-7.44 (m, 5 H), 7.39 (d, 2 H, J ) 8.5 Hz), 6.97 (d, 2 H, J
) 8.5 Hz), 6.00 (m, 2 H), 4.76 (d, 2 H, J ) 4.2 Hz), 4.66 (s, 2
H), 4.61 (s, 2 H), 4.17 (s, 2 H), 4.12 (d, 2 H, J ) 3.7 Hz), 3.86
(s, 3 H); 13C NMR (62.5 MHz, CDCl3) δ 169.94, 159.35, 137.96,
131.44, 129.65, 129.01, 128.28, 127.58, 127.55, 125.86, 113.76,
(4R*,5R*)-Methyl2-Diazo-4-[(4-methoxyphenyl)methoxy]-
3-oxo-5-[(p h en ylm eth oxy)m eth yl]h ep t-6-en oa te (9). To a
stirred solution of â-ketoester 8 (6.1 g, 15 mmol) in CH3CN
(30 mL) maintained at 0 °C were added Et3N (4 mL, 29 mmol)
and p-toluenesulfonyl azide (2.96 g, 15 mmol). The reaction
solution was allowed to reach room temperature and stirred
overnight. After partitioning between ether and 2 N NaOH
under vigorous stirring for 10 min, the ether layer was
separated, washed successively with 2 N NaOH and brine, and
then dried (MgSO4). Removal of the solvent under reduced
pressure gave a crude product, which was purified by flash
column chromatography (10% EtOAc in hexane) to afford 6.2
g (94.9%) of the diazo compound 9 as an oil: 1H NMR (250
MHz, CDCl3) δ 7.29-7.31 (m, 5 H), 7.25 (d, 2 H, J ) 8.5 Hz),
6.85 (d, 2 H, J ) 8.5 Hz), 5.81-5.96 (m, 1 H), 5.12-5.27 (m, 2
H), 4.93 (d, 1 H, J ) 5.1 Hz), 4.57 (d, 1 H, J ) 11.2 Hz), 4.48
(d, 1 H, J ) 11.7 Hz), 4.41 (d, 1 H, J ) 11.7 Hz), 4.35 (d, 1 H,
J ) 11.2 Hz), 3.79 (s, 3 H), 3.78 (s, 3 H), 3.69 (dd, 1 H, J ) 5.8,
9.3 Hz), 3.62 (dd, 1 H, J ) 5.6, 9.3 Hz), 2.86-2.93 (m, 1 H);
13C NMR (62.5 MHz, CDCl3) δ 191.07, 161.33, 159.19, 138.25,
135.67, 129.63, 128.10, 127.49, 127.40, 127.30, 117.57, 113.51,
81.00, 75.59, 73.02, 72.46, 69.41, 55.14, 52.17, 47.16; FAB MS
m/z (relative intensity) 439 (MH+, 2), 121 (100). The thermal
instability of this sample produced an inaccurate elemental
analysis.
(1R*,3R*,4R*,5S*)-Meth yl 3-[(4-Meth oxyp h en yl)m eth -
oxy]-2-oxo-4-[(p h e n ylm e t h oxy)m e t h yl]b icyclo[3.1.0]-
h exa n eca r boxyla te (10). A stirred solution of diazoester 9
(4.0 g, 9 mmol) in cyclohexane (100 mL) was treated with
copper(II) acetylacetonate (2.4 g, 9 mmol), and the reaction
mixture was placed in a preheated oil bath (115-120 °C). After
5 h, the insolubles were removed by filtration through Celite,
and the solid cake was washed with ether. The filtrate was
concentrated under reduced pressure, and the resulting resi-
due was purified by flash column chromatography (20% f 33%
EtOAc in hexane) to give 1.9 g (52%) of pure bicyclic compound
10 as an oil and its isomer 11 (0.9 g, ca. 26%), which coeluted
with another contaminant.
72.87, 72.31, 69.58, 66.73, 64.47, 55.17; IR (neat) 1753 cm-1
;
FAB MS m/z (relative intensity) 356 (M+, 4.3), 195 (17), 121
(100), 91 (44). Anal. Calcd for C21H24O5: C, 70.77; H, 6.79.
Found: C, 70.55; H, 6.83.
(2R*,3R*)-2-[(4-Met h oxyp h en yl)m et h oxy]-3-[(p h en yl-
m eth oxy)m eth yl]p en t-4-en oic Acid (7). Ester 6 (10.3 g, 29
mmol) was added slowly to a stirred solution of lithium
diispropylamide (LDA, 3.4 g, 32 mmol) in anhydrous THF (100
mL) at -78 °C. After 1 h, 8.3 mL of a clear, 1:1 solution of
Me3SiCl and Et3N was added, and the mixture was stirred
for an additional 1 h at -78 °C. During the course of the
ensuing 18 h, the reaction mixture was allowed to reach room
temperature. The solution was poured into 5% NaOH, stirred
for 15 min, and extracted twice with ether. The aqueous layer
was acidified to pH 5 with concentrated HCl at 0 °C and
extracted thrice with CH2Cl2. The combined organic extract
was dried (MgSO4) and concentrated under reduced pressure
to give 7.6 g of 7 (91.2% based on recovery of 2 g of starting
material from the ether extract) as a clear oil: 1H NMR (250
MHz, CDCl3) δ 11.18 (br s, 1 H), 7.30-7.50 (m, 7 H), 6.96 (d,
2 H, J ) 8.5 Hz), 5.84-6.00 (m, 1 H), 5.25 (m, 2 H), 4.78 (d, 1
H, J ) 11.1 Hz), 4.58 (d, 2 H, J ) 3.9 Hz), 4.49 (d, 1 H, J )
11.1 Hz), 4.19 (d, 1 H, J ) 5.1 Hz), 3.88 (s, 3 H), 3.78 (dd, 1 H,
J ) 6.9, 9.3 Hz), 3.70 (dd, 1 H, J ) 5.6, 9.3 Hz), 3.03 (m, 1 H);
13C NMR (62.5 MHz, CDCl3) δ 176.18, 159.29, 138.08, 134.85,
129.65, 129.08, 128.16, 127.39, 127.35, 118.04, 113.69, 72.99,
72.57, 69.19, 67.80, 55.18, 46.85; IR (neat) 1720 cm-1; FAB
MS m/z (relative intensity) 357 (MH+, 1.6), 121 (100), 91 (33).
Anal. Calcd for C21H24O5‚0.2H2O: C, 70.06; H, 6.83. Found:
C, 70.10; H, 6.79.
(4R*,5R*)-Met h yl 4-[(4-Met h oxyp h en yl)m et h oxy]-3-
oxo-5-[(p h en ylm eth oxy)m eth yl]h ep t-6-en oa te (8). Car-
bonyldiimidazole (3.1 g, 19 mmol) was added to a stirred
solution of acid 7 (6.2 g, 17.5 mmol) in THF at 0 °C. The
temperature was maintained at 0 °C for 30 min and then
allowed to reach room temperature after 2 h. This solution
was added via cannula to a -78 °C solution of LiCH2COOCH3
obtained from MeOAc (4.2 mL, 52 mmol) and LDA (5.6 g, 52
mmol) in anhydrous THF (100 mL) after 1 h at -78 °C. After
the addition, the reaction was stirred further for 1.5 h at -78
°C, quenched with 1 N HCl solution (53 mL), allowed to reach
0 °C, acidified to pH 3 with additional HCl, and extracted with
EtOAc. The combined organic extract was dried (MgSO4) and
concentrated under reduced pressure. The residue was purified
by flash column chromatography (10% EtOAc in hexane) to
give 6.4 g (89.5%) of the â-ketoester 8 as a clear oil: 1H NMR
(250 MHz, CDCl3) δ 7.35-7.40 (m, 5 H), 7.33 (d, 2 H, J ) 8.5
Hz), 6.97 (d, 2 H, J ) 8.5 Hz), 5.79-5.92 (m, 1 H), 5.21-5.29
(m, 2 H), 4.66 (d, 1 H, J ) 11.0 Hz), 4.45-4.68 (m, 3 H), 4.10
(d, 1 H, J ) 5.1 Hz), 3.86 (s, 3 H), 3.73-3.83 (m, 2 H), 3.74 (s,
3 H), 3.62 (dd, 1 H, J ) 5.0, 9.1 Hz), 3.54 (d, 1 H, J ) 15.9
Hz), 2.93-3.11 (m, 1 H); 13C NMR (62.5 MHz, CDCl3) δ 204.15,
Compound 10: 1H NMR (250 MHz, CDCl3) δ 7.28-7.45 (m,
7 H), 6.93 (d, 2 H, J ) 8.5 Hz), 4.75 (d, 1 H, J ) 11.2 Hz), 4.56
(d, 1 H, J ) 11.2 Hz), 4.55 (s, 2 H), 3.88 (s, 3 H), 3.82 (s, 3 H),
3.67 (s, 1 H), 3.57 (d, 2 H, J ) 5.6 Hz), 2.40-2.55 (m, 2 H),
2.13 (dd, 1 H, J ) 4.7, 7.9 Hz), 1.98 (uneven triplet, 1 H, J 5.2
Hz); 13C NMR (62.5 MHz, CDCl3) δ 203.04, 168.57, 159.22,
137.67, 129.63, 129.21, 128.24, 127.54, 127.30, 113.68, 81.59,
73.11 (CH2), 72.05 (CH2), 71.07 (CH2), 55.16, 52.30, 42.15,
36.87, 33.08, 22.47 (CH2); IR (neat) 1736 cm-1; FAB MS m/z
(relative intensity) 411 (MH+, 2.8), 121 (100), 91 (33). Anal.
Calcd for C24H26O6: C, 70.23; H, 6.38. Found: C, 69.97; H,
6.50.
Compound 11: 1H NMR (250 MHz, CDCl3) δ 7.25-7.50 (m,
7 H), 6.93 (d, 2 H, J ) 8.8 Hz), 5.05 (d, 1 H, J ) 11.2 Hz),
4.45-4.65 (m, 3 H), 3.85 (s, 6H), 3.79 (d, 1 H, J ) 8.6 Hz),
3.72 (dd, 1 H, J ) 3.3, 9.5 Hz), 3.57 (dd, 1 H, J ) 5.8, 9.5 Hz),
2.70 (m, 2 H), 2.05 (m, 1 H), 1.70 (uneven triplet, 1 H, J = 5.1
Hz).
(1R*,2S*,3R*,4R*,5S*)-Meth yl 2-Hyd r oxy-3-[(4-m eth ox-
yp h en yl)m et h oxy]-4-[(p h en ylm et h oxy)m et h yl]b icyclo-
[3.1.0]h exa n eca r boxyla te (12). A stirred solution of bicyclic
ketoester 10 (1.8 g, 4 mmol) in a 2:1 mixture of MeOH/CH2Cl2
(30 mL) was cooled to - 20 °C and treated with NaBH4 (0.17
g, 4.5 mmol). The temperature was allowed to reach 0 °C, and
stirring was continued for 30 min before quenching of the
reaction with 1 N H2SO4 (3 mL). The resulting solution was
extracted with CH2Cl2, washed with brine, dried (MgSO4), and
reduced to dryness under vacuum. Purification by flash column
chromatography (25% EtOAc in hexane) afforded the corre-
sponding alcohol 12 (1.6 g, 91%) as a clear oil: 1H NMR (250
MHz, CDCl3) δ 7.36-7.45 (m, 5 H), 7.29 (d, 2 H, J ) 8.7 Hz),

Construction of a Bicyclo[3.1.0]hexane Template
J . Org. Chem., Vol. 65, No. 7, 2000 2177
6.94 (d, 2 H, J ) 8.7 Hz), 5.06 (d, 1 H, J ) 6.8 Hz), 4.59 (d, 1
H, J ) 11.2 Hz), 4.57 (s, 2 H), 4.45 (d, 1 H, J ) 12.2 Hz), 3.87
(br s, 4 H), 3.77 (s, 3 H), 3.50 (dd, 1 H, J ) 5.5, 9.2 Hz), 3.40
(dd, 1 H, J ) 6.7, 9.2 Hz), 2.92 (br s, 1 H), 2.51 (uneven t, 1 H,
J = 6 Hz), 1.85 (dd, 1 H, J ) 5.3, 8.5 Hz), 1.63 (uneven t, 1 H,
J = 5 Hz), 1.51 (ddd, 1 H, J = 1, 4.2, 8.5 Hz); 13C NMR (62.5
MHz, CDCl3) δ 173.46, 159.23, 137.99, 129.41, 129.36, 128.24,
127.48, 127.27, 113.75, 80.81, 73.07 (CH2), 72.09, 71.98 (CH2),
71.47 (CH2), 55.17, 51.90, 45.01, 36.13, 30.54, 16.78 (CH2); IR
(neat) 3526, 1719 cm-1; FAB MS m/z (relative intensity) 413
(MH+, 0.7), 411 (MH+ - H2, 2), 121 (100), 91 (27). Anal. Calcd
for C24H28O6: C, 69.89; H, 6.84. Found: C, 69.86; H, 6.91.
(1R*,2S*,3R*,4R*,5S*)-Meth yl 2,3-O-Isop r op ylid en e-4-
[(p h e n y lm e t h o x y )m e t h y l]b ic y c lo [3.1.0]h e x a n e c a r -
boxyla te (13). A stirred solution of bicyclic alcohol 12 (0.72
g, 1.7 mmol) in acetone (35 mL) was cooled to 0 °C and treated
with anhydrous CuSO4 (0.12 g, 0.7 mmol) and 4 drops of
concentrated H2SO4. The reaction mixture was stirred over-
night at room temperature, and the solid material was
removed by filtration through a pad of Celite. The filtrate was
neutralized with saturated NaHCO3 solution and extracted
with ether. The organic solution was washed with brine, dried
(MgSO4), and reduced to dryness under reduced pressure. The
residue was purified by flash column chromatography (10%
EtOAc in hexane) to give 13 (0.5 g, 93%) as a clear oil: 1H
NMR (250 MHz, CDCl3) δ 7.35-7.45 (m, 5 H), 5.43 (d, 1 H, J
) 6.8 Hz), 4.61 (d, 1 H, J ) 6.8 Hz), 4.59 (s, 2 H), 3.77 (s, 3 H),
3.45-3.62 (m, 2 H), 2.54 (t, 1 H, J ) 5.2 Hz), 2.12 (dd, 1 H, J
) 6.2, 8.5 Hz), 1.51-1.67 (m, 2H), 1.58 (s, 3 H), 1.36 (s, 3 H);
13C NMR (62.5 MHz, CDCl3) δ 173.05, 137.99, 128.19, 127.43,
127.17, 110.86, 85.32, 80.54, 73.01(CH2), 71.84 (CH2), 51.95,
44.59, 37.60, 36.29, 26.18, 24.12, 19.87 (CH2); IR (neat) 1723
cm-1; FAB MS m/z (relative intensity) 333 (MH+, 7), 275 (10),
91 (100). Anal. Calcd for C19H24O5: C, 68.66; H, 7.28. Found:
C, 68.83; H, 7.39.
(1R*,2S*,3R*,4R*,5S*)-2,3-O-Isop r op ylid en e-4-[(p h e-
n ylm eth oxy)m eth yl]-bicyclo[3.1.0]h exan ecar boxylic Acid
(14). To a stirred solution of the bicyclic ester 13 (0.08 g, 0.25
mmol) in MeOH (1 mL) was added 1 N NaOH (0.5 mL). After
heating to 50 °C for 2 h, the cooled solution was treated with
1 N HCl to pH 5 and extracted with CH2Cl2. The organic
extract was washed with brine, dried (MgSO4), and reduced
to dryness under reduced pressure to give acid 14 (0.08 g,
100%) as a white solid, mp 129-130 °C: 1H NMR (250 MHz,
CDCl3) δ 11.90 (br s, 1 H), 7.33-7.46 (m, 5 H), 5.43 (d, 1 H, J
) 6.8 Hz), 4.61 (d, 1 H, J ) 6.8 Hz), 4.60 (s, 2H), 3.55 (d, 2 H,
J ) 5.3 Hz), 2.56 (t, 1 H, J ) 5.2 Hz), 2.20 (dd, 1 H, J ) 6.3,
8.5 Hz), 1.75 (m, 1 H), 1.59 (overlapped s and m, 4 H), 1.37 (s,
3 H); 13C NMR (62.5 MHz, CDCl3) δ 179.45, 137.86, 128.25,
127.49, 127.30, 110.97, 85.23, 80.18, 73.05 (CH2), 71.60 (CH2),
44.67, 37.56, 37.26, 26.18, 24.11, 20.41 (CH2); IR (KBr) 3752,
1686 cm-1; FAB MS m/z (relative intensity) 319 (MH+, 24),
261 (42), 91 (100). Anal. Calcd for C18H22O5: C, 67.91; H, 6.97.
Found: C, 67.68; H, 7.12.
cm-1; FAB MS m/z (relative intensity) 290 (MH+, 70), 232 (12),
91 (100). Anal. Calcd for C17H23NO3‚0.25H2O: C, 69.69; H,
8.05; N, 4.78. Found: C, 69.86; H, 7.93; N, 4.66.
(1R*,2S*,3R*,4R*,5S*)-1-(6-Ch lor op u r in -9-yl)-2,3-O-iso-
p r op ylid en e-4-[(p h en ylm et h oxy)m et h yl]b icyclo[3.1.0]-
h exa n e (16). To a stirred solution of bicyclic amine 15 (0.04
g, 0.14 mmol) in dioxane (3 mL) were added 4,6-dichloro-5-
formamidopyrimidine (0.027 g, 0.14 mmol) and Et3N (0.08 mL,
0.6 mmol). The reaction mixture was heated at reflux for 24
h. After cooling to room temperature, the solution was filtered
to remove the precipitated salt, and the filtrate was reduced
to dryness under reduced pressure. The residue was purified
by flash chromatography (50% EtOAc in hexane) to give 0.05
g (78%) of the 4-chloro-5-formamidopyrimidin-6-yl intermedi-
ate as a thick oil. This compound was immediately treated with
diethoxymethyl acetate (1 mL, 6 mmol) and heated to 120 °C
for 20 h. After cooling, the excess diethoxymethyl acetate was
evaporated under reduced pressure, and the residue was
purified by flash chromatography to give 16 (0.04 g, 93%) as
a thick oil: 1H NMR (250 MHz, CDCl3) δ 8.68 (s, 1 H), 8.22 (s,
1 H), 7.29-7.36 (m, 5 H), 5.03 (d, 1 H, J ) 6.8 Hz), 4.66 (br s,
3 H), 3.85 (m, 2 H), 2.59 (t, 1 H, J ) 5.7 Hz), 2.06 (dd, 1 H, J
) 5.5, 9.9 Hz), 1.75 (uneven t, 1 H, J 6 Hz), 1.60 (s, 3 H), 1.53-
1.57 (m, 1 H), 1.26 (s, 3 H); 13C NMR (62.5 MHz, CDCl3) δ
152.30, 151.91, 150.59, 145.96, 137.53, 131.55, 128.33, 127.78,
127.71, 111.69, 84.77, 84.33, 73.40 (CH2), 71.46 (CH2), 48.42,
44.60, 31.08, 26.27, 24.02, 16.43 (CH2); IR (neat) 1560, 1493
cm-1 ; FAB MS m/z (relative intensity) 427 (MH+, 100), 91
(88). Anal. Calcd for C22H23ClN4O3: C, 61.25; H, 5.49; N, 12.99.
Found: C, 61.32; H, 5.58; N, 12.54.
(1R*,2S*,3R*,4R*,5S*)-1-(6-Am in op u r in -9-yl)-2,3-O-iso-
p r op ylid en e-4-[(p h en ylm et h oxy)m et h yl]b icyclo[3.1.0]-
h exa n e (17). A steel pressure vessel containing a solution of
chloropurine 16 (0.94 g, 2 mmol) in saturated methanolic
ammonia (43 mL) was heated at 80 °C for 18 h. After cooling
to room temperature, the solvent was removed under reduced
pressure, and the residue was purified by flash column
chromatography (EtOAc f 20% acetone in EtOAc) to give 17
(0.88 g, 99%) as a white solid, mp 65-67 °C: 1H NMR (250
MHz, CDCl3) δ 8.37 (s, 1 H), 7.92 (s, 1 H), 7.35-7.43 (m, 5 H),
6.58(br s, 2 H), 5.14 (d, 1 H, J ) 6.8 Hz), 4.70 (br s, 3 H), 3.91
(m, 2 H), 2.62 (t, 1 H, J ) 6.2 Hz), 2.04 (dd, 1 H, J ) 5.4, 9.3
Hz), 1.73 (uneven t, 1 H, J = 6 Hz), 1.65 (s, 3 H), 1.56 (dd, 1
H, J ) 6.1, 9.7 Hz), 1.31 (s, 3 H); 13C NMR (62.5 MHz, CDCl3)
δ 155.60, 153.00, 150.60, 140.97, 137.79, 128.34, 127.75,
127.72, 119.55, 111.54, 84.85, 84.29, 73.36 (CH2), 71.57 (CH2),
48.01, 44.84, 30.95, 26.31, 24.06, 16.29 (CH2); IR (KBr) 3325,
1648 cm-1; FAB MS m/z (relative intensity) 408 (MH+, 100),
350 (3), 228 (7), 136 (15), 91 (49). Anal. Calcd for C22H25N5O3:
C, 64.85; H, 6.18; N, 17.19. Found: C, 64.61; H, 6.28; N, 17.02.
(1R*,2S*,3R*,4R*,5S*)-1-(6-Am in op u r in -9-yl)-2,3-O-iso-
pr opyliden e-4-h ydr oxy-m eth yl]bicyclo[3.1.0]h exa n e (18).
A stirred solution of the protected bicyclic aminopurine 17
(0.75 g, 1.8 mmol) in 5% HCO2H/MeOH (52 mL) was treated
with palladium black (150 mg) and allowed to react overnight.
The suspension was filtered through Celite, and the filter cake
was washed with MeOH. The combined filtrate was concen-
trated under reduced pressure, and the residue was purified
by flash column chromatography (10% EtOAc in hexane) to
give 18 (0.5 g, 86%) as a white solid, mp 230-232 °C: 1H NMR
(250 MHz, CDCl3) δ 8.34 (s, 1 H), 7.97 (s, 1 H), 6.70 (br s, 2
H), 5.03 (dd, 1 H, J ) 1.1, 6.7 Hz), 4.90 (dd, 1 H, J ) 1.1, 6.7
Hz), 4.11 (d, 1 H, J ) 11.8 Hz), 3.91 (dd, 1 H, J ) 2.9, 11.8
Hz), 2.54 (br d, 1 H, J ) 2.9 Hz), 2.02 (dd, 1 H, J ) 4.5, 9.1
Hz), 1.71 (uneven t, 1 H, J 5.5 Hz), 1.63 (s, 3 H), 1.36 (m, 2
H), 1.32 (s, 3 H); 13C NMR (62.5 MHz, CDCl3) δ 155.88, 152.34,
149.59, 141.40, 119.26, 111.21, 85.07, 84.47, 65.18, 48.46, 46.35
(CH2), 30.54, 26.32, 24.12, 16.31 (CH2); IR (KBr) 3752, 3177,
1654 cm-1; FAB MS m/z (relative intensity) 318 (MH+, 100),
260 (5.6), 136 (21). Anal. Calcd for C15H19N5O3‚0.25H2O: C,
55.98; H, 6.11; N, 21.76. Found: C, 56.14; H, 6.03; N, 21.47.
(1R *,2S *,3R *,4R *,5S *)-1-(6-Am in op u r in -9-yl)-4-(h y-
d r oxym eth yl)bicyclo-[3.1.0]h exa n e-2,3-d iol (4). A stirred
solution of 18 (0.6 g, 1.8 mmol) in 80% aqueous AcOH was
heated to 100 °C for 3.5 h. After cooling, the solvent was
(1R*,2S*,3R*,4R*,5S*)-1-Am in o-2,3-O-isop r op ylid en e-
4-[(p h en ylm eth oxy)m eth yl]bicyclo[3.1.0]h exa n e (15). A
stirred solution of bicyclic acid 14 (0.08 g, 0.25 mmol) in
anhydrous benzene (3 mL) was treated with Et3N (0.1 mL,
0.75 mmol) and diphenylphosphoryl azide (0.16 mL, 0.75
mmol). The reaction mixture was heated at reflux temperature
overnight and then concentrated under reduced pressure. The
crude isocyanate was treated with 2 N NaOH (2 mL) and THF
(5 mL) and stirred for 20 min at room temperature. The
resulting solution was extracted twice with CH2Cl2, and the
organic extract was washed with brine, dried (MgSO4), and
concentrated under reduced pressure. Flash chromatography
of the crude (EtOAc) gave the bicyclic amine 15 (0.04 g, 64%)
as a clear oil: 1H NMR (250 MHz, CDCl3) δ 7.36-7.42 (m, 5
H), 4.76 (dd, 1 H, J ) 1.3, 6.9 Hz), 4.62 (s, 2 H), 4.54 (d, 1 H,
J ) 6.9 Hz), 3.55 (AB m, 2 H), 2.34 (t, 1 H, J ) 5.1 Hz), 1.93
(br s, 2 H), 1.58 (s, 3 H), 1.39 (dd, 1 H, J ) 4.6, 9.3 Hz), 1.34
(s, 3 H), 1.07 (uneven t, 1 H, J = 5 Hz), 0.95 (ddd, 1 H, J )
1.6, 4.9, 9.1 Hz); 13C NMR (62.5 MHz, CDCl3) δ 138.20, 128.25,
127.47, 127.35, 110.65, 88.29, 84.76, 73.10 (CH2), 72.42 (CH2),
48.24, 44.91, 31.96, 26.25, 24.29, 18.13 (CH2); IR (neat) 3364

2178 J . Org. Chem., Vol. 65, No. 7, 2000
Shin et al.
removed under reduced pressure, and the residue was purified
by reversed phase (Octadecyl-C18) chromatography (H2O f 2%
THF in H2O) to give 4 (0.39 g, 76%) as a white lyophilized
powder, mp 249-251 °C, and a second solid (0.09 g, 15%),
which according to 1H NMR corresponded to the monoacetate
of 4 at the primary alcohol position. Compound 4: 1H NMR
(250 MHz, DMSO-d6) δ 8.17 (s, 1 H), 8.07 (s, 1H), 7.37 (br s,
2 H), 5.53 (dd, 1 H, J ) 3.6, 8.3 Hz, D2O exchangeable), 4.86
(d, 1 H, J ) 8.1 H, D2O exchangeable), 4.69 (d, 1 H, J ) 3.2
Hz, D2O exchangeable), 4.57 (t converted to a d after D2O
exchange, 1 H, J ) 5.9 Hz), 3.90 (br d converted to a d after
D2O exchange, 1 H, J ) 5.9 Hz), 3.80 (m, 2 H), 2.15 (t, 1 H, J
) 4.7 Hz), 1.75 (dd, 1 H, J ) 4.8, 8.5 Hz), 1.70 (uneven t, 1 H,
J = 4.4 Hz), 1.25-1.29 (m, 1 H); 13C NMR (62.5 MHz, DMSO-
d6) δ 156.01, 152.04, 149.54. 141.70, 118.93, 75.25, 71.67, 63.47
(CH2), 49.84, 46.92, 23.82, 13.81 (CH2); IR (KBr) 3605, 3211,
1642 cm1; FAB MS m/z (relative intensity) 278 (MH+, 100),
136 (23). Anal. Calcd for C12H15N5O3‚H2O: C, 48.81; H, 5.80;
N, 23.72. Found: C, 49.11; H, 5.81; N, 23.46.
Ack n ow led gm en t. This work was supported by in
part by ONR and NIDA. The authors wish to thank Dr.
J ames A. Kelley from the Laboratory of Medicinal
Chemistry, DBS, NCI, for mass spectral analyses.
Su p p or t in g In for m a t ion Ava ila b le: Crystal data and
structure refinement, atomic coordinates and equivalent iso-
tropic displacement parameters, bond lengths and angles,
anisotropic displacement parameters, hydrogen coordinates
and isotropic displacement parameters, torsion angles, and
hydrogen bonds for both polymorphs (p and c) of structure 4.
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O9917691