Tautomerism in 5,8-diaza-7,9-dicarbaguanine ('alloguanine')

Article abstract of DOI:10.1002/hlca.200590150

An X-ray structure analysis of the title compound reveals that this purinoid exists in the crystal as two tautomers which interact with each other in the mode of a reverse-Watson - Crick base pair.

Full text of DOI:10.1002/hlca.200590150

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Helvetica Chimica Acta ± Vol. 88 (2005)
Tautomerism in 5,8-Diaza-7,9-dicarbaguanine (−Alloguanine×)1)
a
b
a
c
by Trixie Wagner* ), Bo Han ), Guido Koch ), Ramanarayanan Krishnamurthy ),
b
c
and Albert Eschenmoser* ) )
a) Novartis Pharma AG, NIBR Basel, CH-4002 Basel (e-mail: trixie.wagner@novartis.com)
b) Laboratory of Organic Chemistry, Swiss Federal Institute of Technology (ETH), Hˆnggerberg, HCIH309,
CH-8093 Z¸rich (e-mail: eschenmoser@org.chem.ethz.ch)
c) The Skaggs Institute for Chemical Biology at The Scripps Research Institute (TSRI),
10550 North Torrey Pines Road, La Jolla, CA-92037, USA
Rolf Huisgen zum 85. Geburtstag gewidmet
An X-ray structure analysis of the title compound reveals that this purinoid exists in the crystal as two
tautomers which interact with each other in the mode of a reverse-Watson ± Crick base pair.
We recently reported on the synthesis and chemical properties of a family of
2
purinoid heterocycles, 5,8-diaza-7,9-dicarba-purines (−allopurines× )), which undergo
regioselective C-nucleosidations with cyclic iminium salts under mild conditions to
afford C-nucleosides that are isosteric with N(9)-nucleosides of natural purines [3]
(
Fig. 1). While our interest in the chemistry of this family of purine analogs originated
in studies toward an etiology of the structure type of the natural nucleic acids, it became
clear that this family of heterocycles with its close structural relationship to the family
of the natural purines also deserves attention from a medicinal chemistry point of view.
In that context, the guanine member (alloG) was crystallized at Novartis and subjected
to an X-ray structure analysis. We report here the result of this analysis; it provides
information about the accessibility of a tautomeric form in this guanine-like hetero-
cycle. This is of interest in context with phenomena of self-recognition of (potential)
nucleobases through self-pairing between two different tautomeric forms of one and
the same heterocycle.
In our work on the properties of homo-DNA [1][5] and pyranosyl-RNA [6][7], we
had encountered very robust duplexes of oligonucleotides whose stability is exclusively
due to strong purine ± purine pairing in the Watson ± Crick mode between diamino-
purine and xanthine, and between guanine and isoguanine (Fig. 2). In the pyranosyl-
RNA series, it was furthermore demonstrated that purine ± purine pairing in this mode
requires equal sense of chirality of the two (homochiral) duplex strands. It was also in
this series that a clear-cut example of self-recognition through pairing between two
1)
2)
Chemistry of a-Aminonitriles, Part 44; for Part 43, see [1].
To circumvent confusion when dealing with the analog of isoguanine of the natural series, we refrain from
naming the family −isopurines× and propose to call them −allopurines× instead. Note the existence of
another family of purine isomers [2] that differs from the allopurine family by having interchanged in the
purine nucleus only the atoms of positions 5 and 7.
¹
2005 Verlag Helvetica Chimica Acta AG, Z¸rich

Helvetica Chimica Acta ± Vol. 88 (2005)
1961
Fig. 1. Juxtaposition of the chemical formulae of members of the purine family with those of corresponding
member of the −allo-purine× family
complementary tautomers of the same nucleobase was identified: p-RNA strands
(
hexamers and octamers) containing isoguanine as the only nucleobase undergo neat
duplex formation by virtue of what has to be the reverse-Watson ± Crick base-pairing
mode if, and only if, the backbones of the two homochiral strands have the opposite
3
sense of chirality ). This case of nucleobase self-recognition through pairing between
two (in the reverse-Watson ± Crick mode) complementary tautomers is a specific
property of isoguanine, which, in contrast to guanine, is known to exist in more than one
tautomer [10]. From our observations about the pairing properties of guanine and
isoguanine in both the homo-DNA [4][5] and pyranosyl-RNA [6][7] series, it must be
inferred that isoguanine as a pairing partner in oligonucleotide sequences can assume
both the NH(1)- and NH(3)-tautomeric form. The observed chiroselectivity in the
pyranosyl-RNA series of duplex formation that is based on isoG/isoG pairing
underscore this inference.
3)
Complex formation based exclusively on self-recognition of the same nucleobases is not that uncommon,
yet most often brought about either by one-sided protonation (or deprotonation) of the base (see, e.g., [8]),
or on double mode self-pairing (e.g., quadruplexes deriving from guanine-sequences, e.g., [9]).

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Fig. 2. Watson ± Crick (WC) and reverse-Watson ± Crick (RWC) modes of purine ± purine base-pairing observed
in the homo-DNA and pyranosyl-RNA series
An interesting constitutional difference between the purine base isoguanine and the
purinoid base allo-isoguanine consists in that the latter ± in contrast to the former ±
cannot (be expected to) adopt the form of an NH(1)-tautomer but should exist
exclusively as NH(3)-tautomer (Fig. 1). On the other hand, the question arises whether
in the allo-purine family in which the six-membered part of the heterocycle is a 1,3,5-
triazine (and not a pyrimidine) derivative, it might be the guanine member that, besides
its conventional NH(1)-form, has access to the NH(3)-tautomeric form. If this were the
case, nucleobase self-recognition in the reverse Watson ± Crick mode due to pairing
between different tautomers of the same nucleobase could be expected for guanine in
the allopurine series, as observed for isoguanine in the purine series (Fig. 3).
Interestingly enough, it is exactly this kind of reverse Watson ± Crick base pair that
the X-ray structure analysis of alloG has uncovered to exist in the crystal structure of
this purinoid.
The constitution of alloG ± one that is not easily deducible from the mode of the
purinoid×s formation (see the Scheme in Exper. Part) ± was previously determined by X-
ray analysis of an N-(dimethylamino)formamidine derivative [2c]. It is fully confirmed
by the X-ray analysis of the free base itself (Fig. 4). What is remarkable in the outcome
of this latter analysis is the fact that it discloses a crystal structure in which alloG occurs
in two tautomeric forms, and that these two forms interact with each other exactly in
the way that corresponds to base pairing in the reverse-Watson ± Crick mode. This type
of pairing interaction between tautomers in the crystalline state is similar to what has
been described for isocytosine [11]. The pairing is clearly evidenced by the packing
diagram depicted in Fig. 5. Each of the two crystallographically independent molecules
is located near a center of inversion which places the symmetry-related atoms N(10'),

Helvetica Chimica Acta ± Vol. 88 (2005)
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Fig. 3. Watson ± Crick (WC) and reverse-Watson ± Crick (RWC) modes of (hypothetical) allopurine ± allopur-
ine base-pairing in informational oligomers
Fig. 4. Structure of compound 4 in the crystal [13]. The asymmetric unit comprises two independent molecules
(
2
I and II) of alloG and three molecules of H O. Atomic displacement ellipsoids drawn at the 50% probability
level, H-atoms drawn as spheres of arbitrary radius. The H-atoms H(2)/H(22), H(20)/H(21), and H(9)/H(29)
are disordered over two sites with a 0.5 :0.5 distribution.

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Fig. 5. Packing of alloG in the crystal (view down a) visualizing the co-existence of the two tautomers and the
reverse-Watson ± Crick pairing of molecules I and II with their symmetry mates [14]. Primed/double-primed
atoms are related to unprimed atoms by the crystallographic symmetry operations 1 À x, À y, À z (inversion
center between N(2) and N(2')) and 1 À x, À y, 1 À z (inversion center between N(22) and N(22'')); molecules I
and I' (II and II'') are coplanar. The H-atoms at N(2') and N(22) are disordered about the centers of symmetry.
H-Bond donor/acceptor distances in ä. For each disordered site only one orientation is shown.
N(2'), and O(11') (N(30'), N(22'), and O(31')) in reverse-Watson ± Crick manner
4
within H-bonding distance of N(10), N(2), and O(11) (N(30), N(22), and O(31)) ).
These distances demand that the H-atoms at N(2) and N(22), respectively, have to be
disordered about those centers of symmetry, and that the molecules must be present in
a 0.5 :0.5 ratio in both tautomeric forms. This disorder is propagated through the
adjacenta to m O20 5). After the final least-squares cycles with a model that is complete
except for the H-atoms in question, the first four peaks in the resulting DF map are
located at the positions that correspond to N(1) and N(3) of the allopurine ring with
3
approximately equal peak heights (Fig. 6). The average number of electrons per ä for
the top six peaks (including the H-atoms at O(20)) is half of the number one obtains
when omitting a C-bonded H-atom from the calculations (0.79). A similar distribution
of the residual electron density is observed even if the space group symmetry is lowered
to P1. Here, too, the structure is non-ordered with half-occupied H-positions and,
therefore, we believe that it is best described in the centrosymmetric space group P-1.
Fig. 7 gives the transcription of the structural observation of the alloG/alloG
interaction into the corresponding chemical formula.
4)
5)
Note that the atom numbering used in describing the crystal structure does not correspond to the
conventional purine numbering in the chemical formula of alloG.
A similar behavior has been described, e.g., for isocytosine carboxylic acids [12].

Helvetica Chimica Acta ± Vol. 88 (2005)
1965
Fig. 6. Residual electron-density peaks (green) in the final refinement stages demonstrate the co-existence of two
3
tautomeric forms (numbers in parentheses in electrons per ä ). In this crystal structure, a fully occupied H-atom
À
3
can be expected to appear with a peak height of ca. 0.8 e /ä in the DF map.
Fig. 7. Triply H-bonded motif observed for both independent molecules of alloG in the crystal. One half of the
molecules are present in the NH(1) tautomeric form and the other half in the NH(3) form (allopurine
numbering).
We have not performed any spectroscopic and/or chemical studies that would
reveal the position of the equilibrium between the two alloG tautomers in solution.
Since an essential part of the stabilization of the observed reverse-Watson ± Crick pair
in the crystalline state is presumably due to the crystal lattice, no conclusions are to be
drawn with regard to the equilibrium between the tautomers in solution. However,
from a qualitative organo-chemical point of view, it would seem not unreasonable that
in allo-guanine the NH(3) tautomer is more easily accessible relative to the (NH-(1))
tautomer than it is in the natural guanine. The chemical formulae of G and alloG
tautomers may be considered to illustrate this reasoning: in the NH(1) tautomer of G
(
Fig. 1), the C(6)ˆO group enjoys linear conjugation with the exocyclic NH group at
2
C(2), whereas in the corresponding tautomer of alloG it does not. On the other hand,
there is linear conjugation between these two functional groups in the NH(3)
tautomers of both G (not shown) and alloG (shown). The question to which this
qualitative reasoning is referring is clearly one that should be subjected to a genuinely
theoretical treatment.

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Helvetica Chimica Acta ± Vol. 88 (2005)
This work was supported by Novartis AG, Basel, and the Skaggs Foundation (TSRI).
6
Experimental Part )
Procedure Referring to the Scheme: N-Formyl-glycyl-guanidine (1). This compound was prepared
according to Hoffmann×s procedure for the synthesis of N-formyl-l-valyl-guanidine [15]. Guanidine hydro-
chloride (15.00 g, 157 mmol) was added to a turbid suspension of MeONa (8.48 g, 157 mmol) in 200 ml of anh.
MeOH. The resulting suspension was stirred at r.t. for 40 min. The formed precipitate, NaCl, was filtered off via
Celite and washed with 50 ml of MeOH. To the colorless filtrate thus obtained was added N-formylglycine ethyl
ester [16] (41.14 g, 314 mmol, 2.0 equiv.) in 20 ml of MeOH. The mixture was stirred at r.t. for 6 h, during which
a white precipitate appeared within min. After cooling at 48 for 2 h, the white solid was filtered, washed with
1
5
0 ml of cold MeOH, dried under h.v. (r.t., overnight) to give 15.60 g (69%) of 1 as white solid. H-NMR
1
3
(
(
300 MHz, (D
D
6
)DMSO): 3.67 (d, J ˆ 5.1, NHCH
2
); 6.20 ± 8.40 (5m, NH); 8.03 (s, CHO). C-NMR (75 MHz,
)DMSO): 44.05; 161.07; 162.23; 165.54; 179.40. ESI-MS (pos.): 145.3 (28, [M ‡ H] ), 167.2 (20, [M ‡ Na] ),
‡
‡
6
‡
‡
2
89.2 (52, [2 M ‡ H] ), 311.2 (100, [2 M ‡ Na] ).
Scheme. Synthesis of 5,8-Diaza-7,9-dicarbapurine (−Alloguanine×; 4)
2-Amino-4-[(formylamino)methyl]-6-(trichloromethyl)-1,3,5-triazine (2). This compound as well as its
hydrolysis product 3 were prepared according to methodology described by Kelarev et al. [17]. To a suspension
of 1 (14.4 g, 0.1 mol) in 100 ml of DMF was added dropwise of Cl CCN (28.8 g, 0.2 mol, 2 equiv.). After adding,
the mixture was stirred at r.t. for 30 min until the soln. became clear. After heating at 808 (bath temp.) for 1 h,
the light brown soln. was evaporated to dryness. The white solid thus obtained was washed with H O (200 ml),
3
2
7
1
dried under h.v. (P
.0, CH
); 8.15 (d, J ˆ 1.2, CHO); 8.23 (br., 1 H, NH
75 MHz, (D
70.0 (96), 272.0 (30).
-Amino-6-[(formylamino)methyl]-1H-[1,3,5]triazin-2-one (3). Compound 2 (13.5 g, 50 mmol) was
suspended in 250 ml of 0.8m aq. Na CO soln. The mixture was stirred at 808 for 2 h, atwhich it me 2 was
2
O
5
) to give 26.5 g (98%) of 2 as white solid ). H-NMR (300 MHz, (D
6
)DMSO): 4.29 (d, J ˆ
13
6
(
2
2
2
); 8.27 (br., 1 H, NH
2
); 8.51 (t, J ˆ 5.7, NHCHO). C-NMR
À
6
)DMSO): 42.89; 95.99; 161.28; 166.87; 172.06; 176.65. ESI-MS (neg.): 268.0 (100, [M À H] ),
4
2
3
6)
7)
For general remarks, see, e.g., [7]. See also [3c] and supplemental information referring to it.
2-Amino-4-formylaminomethyl-6-trichloromethyl-s-triazine 2 can be dissolved well in MeOH. Itis
sparingly soluble in H O.
2

Helvetica Chimica Acta ± Vol. 88 (2005)
1967
gradually dissolved, and a clear lightyellow soln. was ob ta ined. TLC (CHCl
consumption of 2 (R 0.86) and the formation of a major product (R
neutralized with conc. aq. HCl to pH 7. The white precipitate was filtered, washed with H
3
/MeOH, 25% aq. NH
3
) showed the
f
f
0.22). The mixture was cooled to 08 and
O (2 Â 100 ml),
O (2 Â 100 ml) to give 7.1 g (83%) of 3 as white solid ). H-NMR (300 MHz,
); 7.39 (br., 1 H, NH ); 7.51 (br., 1 H, NH
)DMSO, 608): 40.48; 156.00; 161.61; 165.06; 168.85. ESI-
2
8
1
MeOH (2 Â 100 ml), and Et
2
(
D
6
)DMSO): 4.05 (d, J ˆ 6.0, CH
2
2
2
); 8.10 (s, CHO); 8.36 (t, J ˆ 5.7,
1
3
NHCHO); 11.54 (br., NH). C-NMR (75 MHz, (D
6
‡
‡
‡
‡
MS(pos.): 142.3 (48, [M À CO ‡ H] ), 170.2 (36, [M ‡ H] ), 339.2 (100, [2 M ‡ H] ), 361.1 (38, [2 M ‡ Na] ),
‡
‡
‡
5
30.0 (34, [3 M ‡ Na] ), 698.9 (14, [4 M ‡ Na] ), 867.9 (5, [5 M ‡ Na] ).
-Amino-6-oxo-5,8-diaza-7,9-dicarbapurine (4). This compound was prepared following a protocol
described by Kim et al. [18]. Compound 3 (4.23 g, 25 mmol) was dissolved in 40 ml of 98% H SO , and the
resulting light brown soln. was stirred at 1008 for 5 h. After cooling to r.t., the acid soln. was carefully poured into
00 ml of Et O with rapid stirring. The Et O was decanted and fresh Et O was added; this sequence was
repeated twice. The precipitated salt was suspended in 100 ml of H O, and the soln. was made basic (pH 9) by
adding 25% aq. NH . To the clear light brown soln. thus obtained, AcOH was added dropwise until pH 6.5. The
2
2
4
5
2
2
2
2
3
light brown precipitate formed was filtered, washed with 50 ml of cold H
2
O, and dried under h.v. (P
2
O
5
) to give
9
À4
3
.21 g (85%) of 4 as lightbrown solid ). R
f
(CH
2
Cl
2
/MeOH, 4 :1) 0.33. UV (c ˆ 2.50  10 m in pH 7, 0.1m
1
phosphate buffer): 220, (10200), 261 (7300). H-NMR (300 MHz, (D
0
C(7); 137.79; 145.08; 149.45. ESI-MS (neg.): 150.0 (100, [M À H] ), 301.0 (32, [2 M À H] ), 452.0 (4, [3 M À
6
)DMSO): 6.46 (s, NH
2
); 6.52 (d, J ˆ
1
3
.9, HÀC(9)); 7.93 (d, J ˆ 0.9, HÀC(7)); 11.17 (br., NH). C-NMR (75 MHz, (D
6
)DMSO): 111.66 C(9); 125.37
À
À
À
H] ).
A sample of 1.80 g (11.9 mmol) of 4 obtained in an analogous experiment was crystallized by dissolving the
sample in 150 ml of boiling H
X-Ray Analysis of 4. Unit-cell determination and intensity-data collection were performed on a Bruker
AXS three-circle goniometer with a SMART 6000 CCD and graphite-monochromatized CuK radiation (l
.54178 ä) from a sealed tube generator10). A semi-empirical absorption correction was applied, based on the
2
O and collecting 1.18 g (66%) of colorless crystals at ca. 08. M.p. > 1508.
a
1
intensities of symmetry-related reflections measured at different angular settings (Tmin ˆ 0.8093, Tmax ˆ 0.9468)
2
[
19]. The structure was solved by direct methods and refined by full-matrix least-squares on F [20]. Compound
4
2
crystallizes with two independent molecules and three molecules of H O in the asymmetric unit in the
centrosymmetric space group P-1. Non-H-atoms were refined with anisotropic displacement parameters, H-
atoms at C-atoms were calculated in idealized positions and refined using a riding model. All H-atoms at N- and
O-atoms were located in DF maps and refined isotropically with suitable SIMU and SADI restraints. For both
independent molecules, two tautomeric forms are present in the crystal lattice, the NH(1) tautomer and the
NH(3) tautomer, with a 0.5 :0.5 distribution. Therefore, the multiplicity of H(2), H(9), H(22), H(29), H(20),
and H(21) is 0.5. For not fully occupied H-atoms the displacement parameter was set to be Uiso(H) ˆ 1.2 Uiso(N/
O).
3
Crystal Data of 4. Colorless rod from H
2
O, size 0.20 ¥ 0.05 ¥ 0.05 mm , C
5
H
8
N
5
O
2.5 (C
5
H
5
N
5
O ¥ 1.5 H
2
O),
M
r
ˆ 178.16 (151.14 ‡ 1.5 ¥ 18.01), triclinic, space group P-1 (No. 2) with a ˆ 3.672(2), b ˆ 9.475(3), c ˆ
0
3
À3
2
1.963(6) ä, a ˆ 98.296(9), b ˆ 92.669(9), g ˆ 94.987(9) , Vˆ 753.2(5) ä , Z ˆ 4, D
c
ˆ 1.570 g ¥ cm , m ˆ
À1
0
0
1.105 mm , 15793 reflections measured (w-scans), 2754 independent( Rint ˆ 0.0376), 2.04 < q < 69.14 , Tˆ
1
00 K, 280 parameters, 41 restraints, R
1
ˆ 0.0379, wR
2
ˆ 0.0850 for 2327 reflections with I > 2s(I), R
1
ˆ 0.0477,
À3
wR
2
ˆ 0.0901 for all 2754 data, GoF ˆ 1.072, restrained GoF ˆ 1.065, res. el. dens. ˆ ‡0.19/ À 0.24 e ¥ ä
.
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8)
9)
Compound 3 is soluble in DMSO, and insoluble in CH
Compound 4 can be dissolved in DMF, DMSO, hotH O and hotMeOH. Itis notsoluble in e th er, CH
It is thermally stable for 10 h at 1908, undergoing slow sublimation.
2 2 2
Cl , MeOH, and H O.
2
2 2
Cl .
10)
CCDC-267004 contains the supplementary crystallographic data for this paper (excluding structure
factors). These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/data_request/cif (or
from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB21EZ, UK; fax: ‡ 44-
(0)1223-336033; e-mail: deposit@ccdc.cam.ac.uk).

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Helvetica Chimica Acta ± Vol. 88 (2005)
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Received April 1, 2005