Conformationally restricted nucleocyclitols: A study into their conformational preferences and supramolecular architecture in the solid state

Article abstract of DOI:10.1002/ejoc.200900611

With the intent of probing the feasibility of employing annulation as a tactic to engender axial rich conformations in nucleoside analogues, two adenine-derived, "conformationally restricted" nucleocylitols, 9 and 10, have been conceptualized as representatives of a hitherto unexplored class of nucleic acid base-cyclitol hybrids. A general synthetic strategy, with an inherent: scope for diversification, allowed, rapid functionalization of indane and tetralin to furnish 9 and 10 respectively in fair yield. Single-crystal X-ray diffraction analysis revealed that the two nucleocyclitols under study, though homologous, present completely dissimilar modes of molecular packing, marked, in particular, by the nature of involvement of the adenynyl NH ₂ group in the supramolecular assembly. In addition, the crystal structures of 9 and 10 also exhibit two different conformations of the functionalized cyclohexane ring. Thus, while the six-membered carbocycle in cyclopenta-annulated 9 exists in the expected chair (C) conformation that in cyclohexaannulated 10, which crystallizes as a dihydrate, shows an unusual twist-boat (TB) conformation. From a close analysis of the ¹HNMR spectroscopic data recorded, for 9 and 10 in CD₃OD, it was possible to put forth a putative explanation for the uncanny conformational preferences of crystalline 9 and 10. Wiley-VCH Verlag GmbH & Co. KGaA.

Full text of DOI:10.1002/ejoc.200900611

FULL PAPER
DOI: 10.1002/ejoc.200900611
Conformationally Restricted Nucleocyclitols: a Study into their Conformational
Preferences and Supramolecular Architecture in the Solid State
Goverdhan Mehta,*[a] Pinaki Talukdar,[b] Venkatesh Pullepu,[b] and Saikat Sen[a]
Keywords: Chirality / Structure elucidation / Solid-state structures / Hydrogen bonding / Supramolecular chemistry /
Adenine
With the intent of probing the feasibility of employing annu-
lation as a tactic to engender axial rich conformations in nu-
cleoside analogues, two adenine-derived, “conformationally
ular assembly. In addition, the crystal structures of 9 and 10
also exhibit two different conformations of the functionalized
cyclohexane ring. Thus, while the six-membered carbocycle
restricted” nucleocylitols, 9 and 10, have been conceptual- in cyclopenta-annulated 9 exists in the expected chair (C)
ized as representatives of a hitherto unexplored class of nu-
cleic acid base-cyclitol hybrids. A general synthetic strategy,
with an inherent scope for diversification, allowed rapid
functionalization of indane and tetralin to furnish 9 and 10
respectively in fair yield. Single-crystal X-ray diffraction
analysis revealed that the two nucleocyclitols under study,
though homologous, present completely dissimilar modes of
molecular packing, marked, in particular, by the nature of
conformation that in cyclohexaannulated 10, which crys-
tallizes as a dihydrate, shows an unusual twist-boat (TB) con-
formation. From a close analysis of the 1HNMR spectroscopic
data recorded for 9 and 10 in CD3OD, it was possible to put
forth a putative explanation for the uncanny conformational
preferences of crystalline 9 and 10.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
involvement of the adenynyl NH2 group in the supramolec- Germany, 2009)
Introduction
In 2003, a flexible de novo synthetic strategy was delin-
eated to transform stereoselectively the aromatic nucleus of
hydrocarbons, such as tetralin and indane, into inositol
moieties, transcribed onto a trans-decalin/trans-hydrindane
framework.[1a] In these conformationally locked inositols,
as they were named, annulation was used as a tool not only
to freeze the cyclitols into a high-energy axial-rich confor-
mation, but also to fine-tune the hydrophilic-hydrophobic
balance in the otherwise polar inositols (see Figure 1 for a
comparison between natural 1 and annulated myo-inositol
2).[1a,2] The versatility of this manoeuvre was further dem-
onstrated by us towards the synthesis of a new class of cy-
clohexane-annulated, conformationally locked hexoses
from tetralin.[1b] Like their inositol siblings, these annulated
sugars also retained the hydroxy configuration of their nat-
ural counterparts but were pre-destined to have an unnatu-
ral conformation with preponderance of axial OH groups
(see Figure 2 for a comparison between natural 3 and annu-
lated β-glucopyranose 4).
Figure 1. Conformationally locked, axial-rich annulated myo-inos-
itol 2.
The idea of employing the tactic of annulation as a novel
method of engendering conformational restriction in nu-
cleosides and their analogues[3] appealed to us as a natural
extension to the foregoing studies. A major impetus for
such an endeavor also came from the observation that
among the various structurally modified nucleosides which
have been developed in recent years, those involving confor-
mationally constrained analogues have offered promising
therapeutic leads. These include the bridged nucleic acids 5
(LNA/BNA),[4] hexitol nucleic acids (HNA) 6,[5] tricyclo-
DNA (tc-DNA) 7[6] and very recently, [4.3.0]bicyclo-DNA
[a] Department of Organic Chemistry, Indian Institute of Science,
Bangalore 560012, India
Fax: +91-80-23600283
E-mail: gm@orgchem.iisc.ernet.in
[b] Institute of Life Sciences, University of Hyderabad Campus,
Gachibowli, Hyderabad 500046, India
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by Carceller and Cadenas, which revealed that 3-(adenin-9-
yl)-3-deoxy-1,5,6-tri-O-(methylsulfonyl)-muco-inositol ex-
hibited cytokinin-like activity in promoting cell prolifera-
tion in soybean cotyledon callus tissue, cell expansion in
excised radish cotyledons, and delay of senescence in de-
tached leaves.[8b] Though dwarfed in comparison to other
nucleoside analogues in respect to the body of literature
dealing with their chemistry and interaction with biological
systems, nucleocyclitols presented themselves to us as ideal
starter systems for studying the effect of annulation on the
conformation and self-assembling process of nucleic acid
base-cyclitol hybrids. Tweaking with our earlier synthetic
strategies towards polycyclitols and amino alcohols,[9] we
therefore sought a general scheme that would allow rapid
functionalization of the aromatic nucleus of indane and
tetralin to lend acess to the first two chosen examples of
conformationally restricted nucleocyclitols, 9 and 10.
Figure 2. Conformationally locked, axial-rich annulated β-gluco-
pyranose 4.
(bc4,3-DNA) 8,[7] which incorporates interestingly a six-
membered ring, fused in a cis-fashion to the furanose unit
(Figure 3).
Results and Discussion
Synthesis of the Nucleocyclitols 9 and 10
Synthesis of the nucleocyclitols 9 and 10 was ac-
complished from the annulated trans-4-cyclohexene-1,2-di-
ols, 11 and 12, which were readily obtained from indane
and tetralin respectively.[1a] mCPBA mediated epoxidation
in 11 and 12, followed by LiClO4 catalyzed ring opening in
the epoxy diols 13 and 14[9a] with sodium adeninide, fur-
nished the desired nucleocyclitols 9 and 10 in fair yield,
which were conveniently purified via their corresponding
acetates 15 and 16 (Scheme 1). The nucleocyclitols 9 and
10 as well as all their precursors were duly characterized
spectroscopically prior to detailed single-crystal X-ray dif-
fraction analysis.
Figure 3. Examples of conformationally restricted analogues of nu-
cleic acids.
In effect, the present study was conceptualized as a pre-
lude to the actual construction of an “annulated nucleo-
side” architecture and focused on examining the feasibility
of engaging annulation as a tool to generate “axial rich”
conformations in a simpler, yet interesting class of nucleo-
side analogues termed nucleocyclitols.[8]
Interest in the synthesis of nucleocyclitols, a term coined
by Cadenas for hydrid molecules obtained by condensing
cyclitols with purine or pyrimidine bases, largely stemmed
as an offshoot from the efforts towards the development of
novel nucleoside analogues as potential antitumor, antiviral
or antibiotic agents. Devoid of an endocyclic oxygen and
thus the “oside” structure, nucleocyclitols present a base-
cyclitol C–N bond which, unlike that present in nucleosides,
is stable towards both chemical and enzymatic hydrolysis, a
property perceived as a definite vantage point for in vivo
testing.[8a] However, literature reports on the bioactivity
Scheme 1. Reagents and conditions. (a) mCPBA, CH2Cl2, 0 °C to
room temp.; (b) i) adenine, NaH, LiClO4, dry DMF, 100 °C; (ii)
profile of nucleocyclitols are rather sparse, barring a study Ac2O, DMAP, room temp.; (c) 10% NH3 (aq.), room temp.
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Conformationally Restricted Nucleocyclitols
X-ray Crystallographic Studies on the Nucleocyclitols 9 and
10
On account of their polar nature and tendency to form
at times tenaciously gummy materials upon evaporation of
their solution, a judicious choice of the solvent proved cru-
cial for obtaining crystals of 9 and 10, suitable for single-
crystal X-ray crystallography. Accordingly, crystallization
of the nucleocyclitols 9 and 10 were carried out under ambi-
ent conditions from their dilute solutions in 1:1 MeOH/
EtOAc and 2:1 MeOH/H2O respectively, employing the
slow solvent evaporation method. Unlike 9, the nucleocycli-
tol 10 crystallized, under these conditions, as a hydrate (vide
infra) and displayed a profound tendency to undergo dehy-
dration, upon exposure to air, even at low temperatures.
This necessitated an expeditious data collection strategy for
10 in order to obtain a decent X-ray diffraction data, ame-
nable to structure solution and providing the desired con-
vergence upon refinement. Details of the molecular confor-
mations and packing patterns of the nucleocyclitols 9 and
10, as gleaned from analysis of their respective crystal data
(see Table 3), are discussed below.
Figure 4. ORTEP diagram of the nucleocyclitol 9, with the atom
numbering scheme for the asymmetric unit. Displacement ellip-
soids have been drawn at 30% probability level and H atoms are
shown as small spheres of arbitary radii. The grey dotted lines indi-
cate the intramolecular O–H···O hydrogen bonds.
Crystal Structure of (3aR*,5S*,6S*,7aR*)-6-(6-Amino-
9H-9-purinyl)perhydro-3a,5,7a-indenetriol (9)
Table 1). Following the 21 symmetry parallel to the c axis,
intermolecular O–H···N H-bonding, involving O2···N1,
link the molecules to form zigzag strands along [001] direc-
tion. These molecular strands are interconnected, following
the 21 symmetry parallel to the a and b axes, by N–H···N
hydrogen bonds, involving N1···N4 and N1···N2, and O–
H···N H-bonds, involving O3···N3, respectively. The intri-
cate three-dimensional supramolecular assembly of 9, thus
generated, is further supported by C–H···O hydrogen bond-
ing, involving C1···O3 and C14···O1 (Figure 5, Table 1).
Though the synthetic route, adopted in the study, yields
9 in the racemic form, spontaneous resolution during
crystallization causes the nucleocyclitol to pack in the chiral
orthorhombic space group P212121 (Z = 4).[10,11] Since it is
well known that 90% of the compounds, that are capable
of crystallizing in racemic or chiral space groups, prefer the
former,[12] the preference of 9 to crystallize as a conglomer-
ate of its two enantiomeric forms is interesting and proba-
bly the consequence of a kinetically favoured pathway. Em-
bedded in the rigid trans-hydrindane scaffold, the nucleocy-
clitol moiety in 9 exhibits the expected high energy, all-axial
conformation of the adenynyl and three hydroxy groups
(Figure 4). Owing to the resulting non-bonding 1,3-diaxial
interactions, particularly between the purine nucleus at C1
and the OH group at C5, the cyclohexane ring in 9 distorts
Table 1. Hydrogen bond geometry in the nucleocyclitol 9.
D–H···A
D–H [Å]
H···A [Å]
D···A [Å] D–H···A [°]
O1–H1O···O2 i
O2–H2O···N1 ii
O3–H3O···N3 iii
N1–H1N···N4 iv
0.82
0.82
0.82
0.86
0.86
0.98
0.93
2.06
2.25
2.10
2.10
2.20
2.60
2.56
2.731(3)
2.953(3)
2.897(3)
2.922(3)
2.992(4)
3.561(4)
3.436(4)
140
144
165
158
153
168
158
significantly from an ideal chair conformation. This distor- N1–H2N···N2 v
C1–H1···O3 vi
tion is evident not only from an analysis of the puckering
C14–H14···O1 vii
parameters[13] of the cyclohexane ring [q2 = 0.1315(28) Å,
Symmetry codes: (i) x, y, z; (ii) –x + 1/2, –y + 1, z – 1/2; (iii) –x, y –
1/2, –z + 1/2; (iv) x – 1/2, –y + 1/2, –z + 1; (v) x + 1/2, –y + 1/2,
–z + 1; (vi) –x, y + 1/2, –z + 1/2; (vii) –x + 1, y – 1/2, –z + 1/2
q3 = 0.5019(29) Å, φ2 = –160.4(14)°, QT = 0.5188(29) Å, θ2
= 14.68(32)°], but also from the apparent flattening of the
C1–C6–C5 bond angle (ca. 113°) from the ideal tetrahedral
value. On the other hand, puckering parameters of the cy-
clopentane annulus in 9 are q2 = 0.4417(31) Å, φ2
=
A novel feature of the self-assembly in crystalline 9 is
that the amino group of the adenynyl moiety engages not
only its H-atoms in intermolecular N–H···N hydrogen
32.88(50)° and therefore describe a slightly distorted Cs-
symmetric envelope (E) conformation.[13]
Besides tipping the cyclohexane ring from an ideal chair bonding with an R2 (9) motif, but also its lone pair in an
2
to a near twist-boat conformation, the all-axial disposition O–H···N H-bond (Figure 5). Indeed, the crystal structure of
of the functional groups in 9 also favorably positions the the nucleocyclitol 9 presents the first instance of molecular
1,3-syndiaxial hydroxy groups at C2 and C4 to participate packing in an adenine derivative in which such a H-bonding
in intramolecular O–H···O hydrogen bonding (Figure 4, pattern, involving the amino group, has been observed.[14]
Eur. J. Org. Chem. 2009, 4691–4698
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G. Mehta, P. Talukdar, V. Pullepu, S. Sen
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Figure 6. ORTEP diagram of the nucleocyclitol 10, with the atom
numbering scheme for the asymmetric unit. Displacement ellip-
soids have been drawn at 30% probability level and H atoms are
shown as small spheres of arbitary radii.
A pair of intermolecular O–H···N hydrogen bonds, in-
volving O1 and N4, connect two enantiomerically related
molecules of 10 to form a centrosymmetric dimer [graph
set: R2 (14)] around the inversion center at (1/2, 0, 1/2).
2
Weak offset π-π stacking interactions between the two pu-
Figure 5. (a) Molecular packing in the nucleocyclitol 9, showing
details of the intra- and inter-strand hydrogen bond connectivity.
(b) Molecular packing in the nucleocycltol 9 along the a axis, show-
ing details of the N–H···N hydrogen bonding with an R2 (9) motif.
2
Non-interacting H-atoms have been omitted for clarity.
Crystal Structure of (2S*,3S*,4aR*,8aR*)-3-(6-Amino-
9H-9-purinyl)perhydro-2,4a,8a-naphthalenetriol (10)
The adenine-derived nucleocyclitol 10 crystallized as a
¯
dihydrate in the centrosymmetric triclinic space group P1
(Z = 2). Unlike that observed for its sibling 9, the function-
alized cyclohexane ring in 10 was found to adopt a twist-
boat conformation [q2 = 0.7281(41) Å, q3 = 0.0063(45) Å,
φ2 = 35.51(34)°, QT = 0.7282(41) Å, θ2 = 89.51(35)°][13] with
the effect that the adenynyl and secondary OH groups now
occupied the sterically less encumbered equatorial positions
on the six-membered carbocycle (Figure 6). Barring a slight
distortion, the cyclohexane annulus, on the other hand, re-
tained the expected chair conformation (q2 = 0.0502(56) Å,
q3 = 0.5292(50) Å, φ2 = 147(6)°, QT = 0.5316(51) Å, θ2 =
5.42(59)°].[13]
Figure 7. Details of the O–H···N hydrogen bonds (a), generating
the columnar self-assembly (b) in the nucleocyclitol 10. Non-inter-
acting H-atoms have been omitted for clarity.
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Conformationally Restricted Nucleocyclitols
rine rings of the molecular dimer, thus formed, impart fur- alized cyclohexane ring in 9 and 10. This conjecture derives
ther stability to the self-assembly. Intermolecular O–H···N support not only from earlier reports on the effect of the
hydrogen bonds, involving O2 and N3, connect the transla- solvation on the conformation preferences of cyclohex-
tionally related dimers around the inversion centers at (0, anes,[16] but also from a close analysis of the coupling
1
0, 0) to form a columnar self-assembly, growing essentially pattern observed for the H NMR signals (spectrum taken
parallel to the (1 –1 –1) plane (see part a of Figure 7, in CD3OD) of the protons attached to the carbon atoms,
Table 2). Characterized by a polar interior, defined by the bonded to the adenynyl and 2° hydroxy groups in 9 and 10.
purine and OH groups, and a non-polar exterior, formed These protons were found to exhibit a near identity in their
by the cyclohexane annuli disposed parallel to each other, coupling patterns, and that connected to the carbon atom
these columnar architectures interact among themselves bonded to the purine nucleus showed a dd splitting with the
with weak van der Waals forces along the b axis and via the larger coupling equating to 10 Hz, typical for that observed
agency of H-bonding with the sandwiched water molecules between two axial protons on a TB conformation of cyclo-
along the [1 0 –1] direction (see part b of Figure 7, Table 2). hexane.[16]
Table 2. Hydrogen bond geometry in the nucleocyclitol 10.
D–H···A
D–H [Å] H···A [Å] D···A [Å] D–H···A [°]
Conclusions
O1–H1O···N4 i
0.82
0.82
2.06
2.18
2.29
2.829(7)
2.950(7)
2.923(10) 134
155
157
In conclusion, the present study ushers two “conforma-
tionally restricted” adenine-derived nucleocyclitols, 9 and
10, as representatives of a hitherto unexplored class of nu-
cleoside analogues through a synthetic strategy which is
amenable to diversification and may enable access to other
members of this novel family of nucleocyclitols.
O2–H2O···N3 ii
O3–H3O···O2W iii 0.82
Symmetry codes: (i) x, y – 1, z; (ii) –x, –y, –z; (iii) x, y, z
It is well known that in crystal structures of adenine, its
hydrates and salts, the hydrogen atoms of the amino group
of adenine participate actively in H-bonding in the supra-
molecular assembly.[14] However, in distinct contrast to this
literature precedence, the H-atoms of the amino group in
the adenynyl moiety in 10 remain largely as bystanders and
engage themselves in, at best, extremely weak hydrogen
bonding. This unusual abstinence of the amino hydrogens
in 10 to hydrogen bonding should also be compared to the
maximization of hydrogen bonding observed for the amino
group in the crystal structure of its lower homologue 9 (vide
supra). This maverick behaviour of the amino hydrogen
atoms in 10 might be caused by the inability of the NH2
group, buried within the polar interior of the columnar
architecture, to find a suitable H-bonding partner.[9b]
Experimental Section
General: Melting points were recorded with a Büchi B-540 appara-
tus and are uncorrected. Infrared spectra were recorded with a JA-
SCO FT-IR 410 spectrometer. H and 13C NMR spectra were re-
1
corded with a BRUKER 400 and JEOL JNM-LA 300 spectrome-
ters; chemical shifts δ in ppm are reported relative to Me4Si (δ =
0 ppm) by using solvent signals as internal reference [CDCl3: δ =
7.26 ppm (1H NMR) and 77.0 ppm (13C NMR). CD3OD: δ =
3.31 ppm (1H NMR) and 49.2 ppm (13C NMR); D2O: δ =
4.81 ppm (1H NMR)].
The standard abbreviations s, d, t, q, dd and m refer to singlet,
doublet, triplet, quartet, doublet of doublet and multiplet, respec-
tively. Coupling constant (J), wherever discernible, are reported in
Hz. Both low-resolution (LRMS) and high-resolution mass spectra
(HRMS) were recorded with a Q-TOF Micromass mass spectrome-
ter. Reactions were monitored by thin-layer chromatography (TLC)
performed either on (10ϫ5 cm) glass plates, coated with silica gel
GF254, containing 15% calcium sulfate as a binder. Visualization
of the spots on the TLC plates was achieved by exposure to iodine
vapor or UV radiation, or by spraying with either ethanolic vanillin
or 30% sulfuric acid-methanol solution and heating the plates at
120 °C. Commercial silica gel (100–200 mesh particle size) was used
for column chromatography. All moisture-sensitive reactions were
performed under nitrogen atmosphere with dry, freshly distilled sol-
vents under anhydrous conditions using standard syringe-septum
technique. Dimethylformamide was distilled from calcium hydride
and stored over molecular sieves (4 Å). All solvent extracts were
concentrated under reduced pressure on a rotary evaporator unless
specified otherwise. Yields reported are isolated yields of materials
judged homogeneous by TLC and NMR spectroscopy.
Can Solvation Influence the Preferred Conformation of the
Conformationally Restricted Nucleocyclitols 9 and 10?
Our previous studies with polycyclitols and the dogma
of a conformationally “locked” trans-hydrindane/decalin
framework made it reasonable to anticipate that a chair
form, albeit distorted, would be the most stable conforma-
tion of the functionalized cyclohexane ring in the nucleocy-
clitols 9 and 10. DFT-based geometry optimization at
B3LYP/6-31+G(d) level, carried out on both chair (C) and
twist-boat (TB) conformations of the nucleocyclitol moie-
ties in 9 and 10, revealed that the C form was evidently
more stable than the TB form by around 3.2 kcalmol–1 in
case of 9 and 1.6 kcalmol–1 in case of 10.[15] Hence, the
observed TB conformation of the cyclohexane ring in the
crystal structure of hydrated 10, as opposed to the C form
noted for its lower homologue 9, was intriguing and goaded
speculation on plausible causes for its stability. Though
putative, it would appear that solvation might play a deter-
minant role in tilting the balance towards an otherwise en-
(1aS*,2aR*,5aR*,6aR*)-Octahydro-1aH-indeno[5,6-b]oxirene-
2a,5a-diol (13): A solution of mCPBA (384 mg, 1.56 mmol, 70%
purity) in dichloromethane (10 mL) was added dropwise to a solu-
tion of the diol 11 (200 mg, 1.30 mmol) in dichloromethane
ergetically less favourable TB conformation of the function- (20 mL) at 0 °C. The reaction was stirred at ambient temperature
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G. Mehta, P. Talukdar, V. Pullepu, S. Sen
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for 1 h and then quenched with saturated sodium hydrogen carbon-
ate solution (10 mL). The product was extracted with dichloro-
methane (2ϫ10 mL) and the combined extracts dried with anhy-
drous sodium sulfate. Removal of the solvent and subsequent puri-
(m, 9 H) ppm. 13C NMR (75 MHz, CD3OD, 25 °C): δ = 172.0,
171.6, 153.5, 152.8, 150.4, 145.0, 123.8, 73.4, 73.1, 72.1, 54.5, 42.4,
41.5, 36.0, 35.7, 24.6, 21.6 (2 C), 20.6 ppm. LRMS (ES, 70 eV): m/z
= 426 [M + Na]+. HRMS (ES): calcd. for C19H25N5NaO5 [M +
fication by column chromatography with 40% ethyl acetate/petro- Na]+ 426.1753; found 426.1746.
leum ether afforded the epoxy diol 13 (260 mg, 72%) as a colorless
(3aR*,5S*,6S*,7aR*)-6-(6-Amino-9H-9-purinyl)perhydro-3a,5,7a-in-
denetriol (9): The diacetate 15 (13 mg, 0.03 mmol) was stirred at
ambient temperature with aqueous ammonia solution (2 mL, 10%
v/v in H2O) for 2 h. After completion of the reaction, the volatiles
were removed under vacuum and the crude product, thus obtained,
was purified by column chromatography with 20 % methanol/
dichloromethane to furnish the nucleocyclitol 9 (11 mg, quantita-
solid; m.p. 112–114 °C. IR (KBr): ν
= 3406, 3376, 2969, 2943,
˜
max
1647, 1416 cm–1. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 3.46 (br.
s, 2 H), 3.34 (t, J = 4.0 Hz, 1 H), 1.55–2.38 (m, 11 H) ppm. 13C
NMR (75 MHz, CDCl3, 25 °C): δ = 80.3, 79.6, 55.9, 51.9, 36.1,
34.6, 33.5, 30.0, 19.2 ppm. LRMS (ES, 70 eV): m/z = 193 [M +
Na]+. HRMS (ES): calcd. for C9H14O3Na [M + Na]+ 193.0841;
found 193.0840.
tive) as a colorless solid. IR (KBr): ν
= 3423, 2930, 1647, 1607
˜
max
cm–1. 1H NMR (400 MHz, CD3OD, 25 °C): δ = 8.23 (s, 1 H), 8.20
(s, 1 H), 5.03–4.97 (m, 1 H), 4.62 (dd, J = 10.0, 5.6 Hz, 1 H), 2.62
(dd, J = 14.8, 7.7 Hz, 1 H), 2.55 (dd, J = 14.4, 5.9 Hz, 1 H), 2.16
(dd, J = 14.9, 4.3 Hz, 1 H), 2.01–1.56 (m, 7 H) ppm. 13C NMR
(75 MHz, CD3OD, 25 °C): δ = 157.3, 153.4, 151.0, 142.7, 119.9,
83.0, 81.7, 70.5, 57.5, 38.4, 37.2, 37.1, 35.6, 20.7 ppm. LRMS (ES,
70 eV): m/z = 306 [M + H]+. HRMS (ES): calcd. for C14H20N5O3
[M + H]+ 306.1566; found 306.1566.
(3aR*,5S*,6S*,7aR*)-6-(6-Acetamido-9H-purin-9-yl)-3a,7a-di-
hydroxy-octahydro-1H-inden-5-yl Acetate (15): A mixture of the ep-
oxy diol 13 (40 mg, 0.24 mmol) and lithium perchlorate (80 mg,
1.25 mmol) in dry dimethylformamide (1 mL) was heated at 80 °C
under nitrogen for 2 h. The solution was then allowed to attain
room temperature and subsequently added to a suspension of so-
dium adeninide in dimethylformamide [generated by heating a mix-
ture of adenine (96 mg, 0.72 mmol) and sodium hydride (17 mg,
0.69 mmol, 95% in hexane) in dimethylformamide (2 mL) at 80 °C
under nitrogen for 2 h]. The reaction mixture, thus obtained, was
stirred vigorously at 100 °C under nitrogen for 15 h. The solvent
was then evaporated under vacuum; 4-(dimethylamino)pyridine
(80 mg, 0.65 mmol) and acetic anhydride (3.5 mL) were added to
the crude reaction mixture and the suspension stirred at room tem-
perature under nitrogen for 4 d. After completion of the reaction,
the reaction mixture was evaporated to dryness and the residue
purified by column chromatography with 10% methanol/dichloro-
methane to give 43 mg (48%) of the pure diacetate 15 as colorless
(2S*,3S*,4aR*,8aR*)-3-(6-Amino-9H-9-purinyl)perhydro-2,4a,8a-
naphthalenetriol (10): Treating 16 (63 mg, 0.16 mmol) with aqueous
ammonia solution (5 mL, 10% v/v in H2O) under the same condi-
tions as 15 gave a residue upon evaporation of the volatiles, which
was purified by column chromatography with 20% methanol/
dichloromethane to furnish the nucleocyclitol 10 (50 mg, quantita-
tive) as a colorless solid. IR (KBr): ν
= 3493, 3452, 3364, 3219,
˜
max
2924, 2854, 1641, 1384 cm–1. 1H NMR (400 MHz, CD3OD, 25 °C):
δ = 8.31 (s, 1 H), 8.20 (s, 1 H), 4.97–4.91 (m, 1 H), 4.52 (dd, J =
9.7, 4.9 Hz, 1 H), 2.51 (dd, J = 15.1, 7.4 Hz, 1 H), 2.42 (dd, J =
14.7, 5.3 Hz, 1 H), 1.91–1.61 (m, 6 H), 1.51–1.27 (m, 4 H) ppm.
13C NMR (75 MHz, D2O, 25 °C): δ = 156.0, 152.8, 149.7, 142.0,
118.9, 73.9, 73.2, 68.6, 56.1, 41.0, 38.1, 34.5, 34.4, 20.4 (2 C) ppm.
LRMS (ES, 70 eV): m/z = 320 [M + H]+. HRMS (ES): calcd. for
C15H22N5O3 [M + H]+ 320.1722; found 320.1720.
solid. IR (KBr): ν
= 3472, 2926, 2855, 1722, 1616 cm–1. 1H
˜
max
NMR (300 MHz, CD3OD, 25 °C): δ = 8.62 (s, 1 H), 8.41 (s, 1 H),
6.03–5.94 (m, 1 H), 5.52–5.42 (m, 1 H), 2.69 (dd, J = 14.4, 9.6 Hz,
1 H), 2.64 (dd, J = 14.4, 9.0 Hz, 1 H), 2.36 (s, 3 H), 2.29 (t, J =
7.0 Hz, 2 H), 1.97–1.71 (m, 6 H), 1.64 (s, 3 H) ppm. 13C NMR
(75 MHz, CD3OD, 25 °C): δ = 172.0, 171.7, 153.5, 152.8, 150.4,
145.0, 123.8, 83.0, 82.6, 73.0, 54.9, 39.4, 38.5, 37.9, 37.6, 24.6, 21.7,
20.5 ppm. LRMS (ES, 70 eV): m/z = 426 [M + H + Na – Ac]+.
HRMS (ES): calcd. for C16H21N5NaO4 [M + H + Na – Ac]+
370.1491; found 370.1509.
Crystal Structure Analysis: Single-crystal X-ray diffraction data
were collected on a Bruker AXS SMART APEX CCD dif-
fractometer at 291 K. The X-ray generator was operated at 50 kV
and 35 mA using Mo-Kα radiation. The data was collected with a
(2S*,3S*,4aR*,8aR*)-3-(6-Acetamido-9H-purin-9-yl)-4a,8a-di- ω scan width of 0.3°. A total of 606 frames per set were collected
hydroxy-decahydronaphthalen-2-yl Acetate (16): LiClO4-catalyzed
ring opening in the epoxy diol 14 with sodium adeninide was car-
ried out under essentially the same conditions as described for 13.
Thus, a solution of 14 (50 mg, 0.27 mmol) and lithium perchlorate
(84 mg, 1.35 mmol) in dry dimethylformamide (1 mL), previously
heated at 80 °C under nitrogen for 2 h, was to a supension of so-
dium adeninide in dry dimethylformamide [generated by heating a
mixture of adenine (110 mg, 0.81 mmol) and sodium hydride
(18 mg, 0.87 mmol, 95% in hexane) in dimethylformamide (2 mL)
at 80 °C under nitrogen for 2 h]. After stirring the reaction mixture
for 15 h at 100 °C under nitrogen, the solvent was removed under
vacuum and the residue allowed react with acetic anhydride
(3.5 mL) in presence of 4-(dimethylamino)pyridine (80 mg,
0.65 mmol) for four days at ambient temperature. After completion
of the reaction, the reaction mixture was evaporated to dryness and
the residue purified by column chromatography with 10% meth-
using SMART[17] in four different settings of φ (0°, 90°, 180° and
270°) keeping the sample to detector distance of 6.062 cm and the
2θ value fixed at –28°. The data were reduced by SAINTPLUS;[17]
an empirical absorption correction was applied using the package
SADABS[18] and XPREP[17] was used to determine the space
group. The crystal structures were solved by direct methods using
SIR92[19] and refined by full-matrix least-squares methods using
SHELXL97.[20] Molecular and packing diagrams were generated
using ORTEP32,[21] CAMERON[22] and MERCURY[23] respec-
tively. The geometric calculations were done by PARST[24] and
PLATON.[25] The methine (CH) and methylene (CH2) H atoms
of the polycyclitol moiety were placed in geometrically idealized
positions and allowed to ride on their parent atoms with C–H dis-
tances in the range 0.97–0.98 Å and Uiso(H) = 1.2Ueq(C). The OH
hydrogen atoms were constrained to an ideal geometry with O–H
distances fixed at 0.82 Å and Uiso(H) = 1.5Ueq(O). During refine-
ment, each hydroxy group was however allowed to rotate freely
anol/dichloromethane to give 63 mg (58%) of the pure diacetate
1
16. IR (KBr): ν
= 3438, 2929, 2858, 1736, 1610, 1238 cm–1. H about its C–O bond. For the adenynyl group, the CH and NH2
˜
max
NMR (300 MHz, CD3OD, 25 °C): δ = 8.60 (s, 1 H), 8.41 (s, 1 H),
5.91–5.83 (m, 1 H), 5.39–5.29 (m, 1 H), 2.54–2.39 (m, 2 H), 2.35
hydrogen atoms were constrained to an ideal geometry with C–H
bond lengths fixed at 0.93 Å and Uiso(H) = 1.2Ueq(C), and N–H
(s, 3 H), 2.08 (dd, J = 14.7, 7.8 Hz, 1 H), 1.67 (s, 3 H) 1.60–1.43 bond lengths fixed at 0.86 Å and Uiso(H) = 1.2Ueq(N) (Table 3).
4696 Eur. J. Org. Chem. 2009, 4691–4698
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Conformationally Restricted Nucleocyclitols
E. Lescrinier, A. Van Aerschot, P. Herdewijn, J. Am. Chem.
Soc. 1998, 120, 5381–5394; d) I. A. Kozlov, B. De Bouvere, A.
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Kang, M. H. Fisher, D. Xu, Y. J. Miyamoto, A. Marchand, A.
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2008, 49, 6068–6070.
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11548–11549; b) R. Steffens, C. J. Leumann, J. Am. Chem. Soc.
1999, 121, 3249–3255; c) D. Renneberg, C. J. Leumann, J. Am.
Chem. Soc. 2002, 124, 5993–6002.
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1162.
a) R. A. Cadenas, J. Mosettig, M. E. Gelpi, Carbohydr. Res.
1984, 133, 33–43; b) M. Carceller, R. A. Cadenas, J. Plant
Growth Regul. 1988, 7, 153–159; c) G. J. Aguilar, M. E. Gelpi,
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Due to the absence of any significant anomalous scatterers
(ZϾSi), attempts to confirm the absolute structure by refine-
ment of the Flack parameter led to an inconclusive value of
1.2 (17) (see ref. [11]). Therefore the intensities of the Friedel
pairs (1073) were averaged prior to merging of data in P212121
and the absolute configuration was assigned arbitrarily. The
reported value of Rint corresponds to subsequent merging of
equivalent reflections in this space group.
Table 3. Summary of crystal data, data collection, structure solu-
tion and refinement details.
9
10
Formula
Mr
C14H19N5O3
305.34
C15H21N5O5
351.37
Crystal size [mm]
Crystal system
Space group
a [Å]
b [Å]
c [Å]
0.43, 0.29, 0.10
orthorhombic
P212121
6.8969(15)
10.135(2)
20.311(4)
90
90
90
1419.7(5)
4
0.30, 0.28, 0.26
triclinic
P1
¯
8.6370(13)
10.2022(15)
11.0208(17)
113.999(7)
106.939(7)
92.863(7)
832.8(2)
2
[6]
α [°]
β [°]
γ [°]
V [Å3]
[7]
[8]
Z
F (000)
648
1.429
0.104
372
1.401
0.107
ρcalcd. [gcm–3]
µ [mm–1]
Reflections collected
l.s. parameters
Unique reflections
Observed reflections
Index range
10420
201
1528
1354
–8ՅhՅ8
–12ՅkՅ12
–24ՅlՅ22
0.0430
0.0981
1.119
10462
229
3035
1376
–10ՅhՅ10
–12ՅkՅ12
–13ՅlՅ13
0.0723
0.1658
0.883
[9]
[10]
R1 [I Ͼ 2σ (I)]
wR2 [I Ͼ 2σ (I)]
Goodness of fit
∆ρmax./min. [eÅ–3]
0.199/–0.183
0.334/–0.253
[11]
[12]
a) H. D. Flack, Acta Crystallogr., Sect. A: Found. Crystallogr.
1983, 39, 876–888; b) H. D. Flack, G. Bernardinelli, J. Appl.
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a) C. P. Brock, B. Schweizer, J. D. Dunitz, J. Am. Chem. Soc.
1991, 113, 9811–9820; b) A. Gavezzotti, Synlett 2002, 201–214.
D. Cremer, J. A. Pople, J. Am. Chem. Soc. 1975, 97, 1354–1358.
This is based on a Cambridge Structural Database search [CSD
version 5.30 (November 2008 + 1 update)] on all reported crys-
tal structures of adenine derivatives.
CCDC-734567 (for 9) and -734568 (for 10) contain the supplemen-
tary crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
[13]
[14]
Acknowledgments
[15]
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We thank the Department of Science and Technology (DST), India
for the CCD facility at the Indian Institute of Science (IISc), Ban-
galore. We sincerely acknowledge Prof. K. Venkatesan for his criti-
cal comments and helpful advice in preparing the manuscript.
G. M. thanks the Council for Scientific and Industrial Research
(CSIR), India for research support and the award of the Bhatnagar
Fellowship.
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Eur. J. Org. Chem. 2009, 4691–4698
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4697

G. Mehta, P. Talukdar, V. Pullepu, S. Sen
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Received: June 2, 2009
Published Online: August 5, 2009
4698
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 4691–4698