2,6-Diamino-5,8-diaza-7,9-dicarba-purine

Article abstract of DOI:10.1021/ol030044n

(Matrix presented) The title compound, a constitutional isomer of the natural nucleobase 2,6-diaminopurine, undergoes regioselective electrophilic substitutions at carbon C-9.

Full text of DOI:10.1021/ol030044n

ORGANIC
LETTERS
2,6-Diamino-5,8-diaza-7,9-dicarba-purine1
2003
Vol. 5, No. 12
2067-2070
Zhijun Wang,† Hoan K. Huynh,† Bo Han,‡ Ramanarayanan Krishnamurthy,*,†,§ and
,†,‡,
Albert Eschenmoser*
The Skaggs Institute for Chemical Biology at the Scripps Research Institute,
10550 North Torrey Pines Road, La Jolla, California 92037,
and Laboratory of Organic Chemistry, Swiss Federal Institute of Technology,
Hoenggerberg, HCI-H309, CH-8093 Zu¨rich, Switzerland
eschenmoser@org.chem.ethz.ch
Received March 17, 2003
ABSTRACT
The title compound, a constitutional isomer of the natural nucleobase 2,6-diaminopurine, undergoes regioselective electrophilic substitutions
at carbon C-9.
In the wake of the observation that (L)-R-threofuranosyl-(3′
f 2′)-oligonucleotides (TNAs) constitute an efficient Wat-
son-Crick base-pairing system capable of cross-pairing with
RNA and DNA,2 we recently became involved in systemati-
cally studying the properties of a family of TNA-related
oligomer systems that could, in principle, derive from (C2
+ C2 f C4) assembly processes involving nitrogenous
intermediates at the oxidation level of glycolaldehyde.3,4 We
had previously argued that TNA could be considered as the
limiting case of the fully oxygenous variant within a library
of base-pairing systems derived from oxygenous and nitrog-
enous C4-backbone units joined together by a variety of
linker groups.2 The alternative limiting case would be a four-
carbon backbone unit in which all of the oxygens of threose
were replaced by nitrogen (Scheme 1). Such considerations
raise questions concerning the formation and the stability of
corresponding nucleosides, because the nucleosidic C-N
bond in (N)-nucleosides becomes labile when the ring oxygen
of the furanose sugar unit is replaced by a free NH group;5
(C)-nucleosides of such systems, on the other hand, can be
stable.6
In considering heterocycles that could conceivably be
formed as alternatives to the natural nucleobases from
Scheme 1a
† The Scripps Research Institute.
‡ Swiss Federal Institute of Technology.
§ Fax: ++1-858-784-9573. Email: rkrishna@scripps.edu
Fax: ++41-1-632-1043.
(1) Chemistry of R-Aminonitriles. Part 39. For Part 38, see: Jungmann,
O.; Beier, M.; Luther, A.; Huynh, H. K.; Ebert, M. O.; Jaun, B.;
Krishnamurthy, R.; Eschenmoser, A. HelV. Chim. Acta 2003, in press.
(2) Scho¨ning, K.-U.; Scholz, P.; Guntha, S.; Wu, X.; Krishnamurthy,
R.; Eschenmoser, A. Science 2000, 290, 1347. Scho¨ning, K.-U.; Scholz,
P.; Wu, X.; Guntha, S.; Delgado, G.; Krishnamurthy, R.; Eschenmoser, A.
HelV. Chim. Acta 2002, 85, 4111.
a In a TNA-like system in which all oxygens of the threose units
were replaced by nitrogen, these units would have to be (C)-
nucleosides in order to be stable.
(3) Wu, X.; Guntha, S.; Ferencic, M.; Krishnamurthy, R.; Eschenmoser,
A. Org. Lett. 2002, 4, 1279.
(4) Wu, X.; Delgado, G.; Krishnamurthy, R.; Eschenmoser, A. Org. Lett.
2002, 4, 1283.
10.1021/ol030044n CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/16/2003

nitrogenous molecules presumed to belong to the prebiotic
building blocks of the natural purines,7 we came across the
structural and generational relationship depicted in Scheme
2. The analysis alludes to the existence of the title compound,
Scheme 3. Preparation and Derivatization of Purinoid 1a
Scheme 2. Structural and Generational Relationship between
2,6-Diaminopurine and a
2,6-Diamino-5,8-diaza-7,9-dicarba-purine
a Numbers in brackets denote mole equiv referring to starting
compound. Numbers before these brackets denote concentrations
in M. (a) 0.43 M (1.0 mole equiv) 3, 0.86 (2.0) 2, MeOH, rt, 2 h
f 45 °C, 3 h, 65%. (b) 0.24 (1.0) 4, (45) POCl3, 75 °C, 2 h f 110
°C, 3 h, 80%. (c) 1.6 (1.0) 5, 7.8 (5.0) 6, H2O, pH 1.6, rt, 48 h;
neutralization followed by chromatography on silica gel, maximally
21%. (d) 0.25 (1.0) 1, 4.0 (6.0) dimethylformamide dimethylacetal,
MeOH, rt, 7 days, 90%.
a heterocyclic system isomeric to the 2,6-diamino derivative
of the natural purines. The heterocycle caught our attention
because it can be expected to have the propensity of reacting
with aldosugars or aldosugar-derived iminium ions regiose-
lectively at carbon C-9 to form (C)-nucleosides that would
be isosteric to normal (N)-nucleosides of 2,6-diamino-purine.
This communication describes the preparation of the title
compound and reports exploratory examples of the smooth
occurrence of electrophilic substitution at carbon C-9 with
iminium ions.
The purinoid 1 was synthesized by two different routes
(Scheme 3).8 One of them, starting from N-formyl-glycine
ethyl ester 29 and biguanide 3,10 represents a preparatively
satisfactory and efficient procedure. According to known
lines of biguanide chemistry11 compounds 2 and 3 smoothly
condense in methanolic solution to the triazine derivative 4,
which on heating in POCl3 cyclizes to the purinoid 1 in up
to 82% yield. The product is obtained as a white solid. Its
1
expected constitution is supported by the H and 13C NMR
spectra,12 mass spectrum,13 and UV-absorption spectra
(Figure 1). For further characterization the purinoid was
converted to the bisamidine derivative 7, an easily soluble
crystalline compound (mp 137°, from MeOH) whose X-ray
structure analysis14 (Figure 2) corroborates the structure
assignment of the parent purinoid.
The alternative mode of formation for 1 follows more
closely the conceptual pattern depicted in Scheme 2 and,
therefore, is the one that had been explored first. However,
in retrospect, it turned out to be the less satisfactory route
from a preparative point of view. The hydrosulfate of the
deprotonated form of the (labile and oxygen-sensitive)
4-amino-imidazole15 5 reacts with sodium dicyanamide16 in
(5) Reist, E. J.; Fisher, L. V.; Goodman, L. J. Org. Chem. 1967, 32,
2541. Altman, K.-H. Tetrahedron Lett. 1993, 34, 7721. Rassu, G.; Pinna,
L.; Spanu, P.; Ulgheri, F.; Casiraghi, G. Tetrahedron Lett. 1994, 35, 4019.
(6) Ha¨berle, A.; Leumann, C. J. Org. Lett. 2001, 3, 489 and references
therein. Evans, G. B.; Furneaux, R. H.; Hutchinson, T. L.; Kezar, H. S.;
Morris, P. E., Jr.; Schramm, V. L.; Tyler, P. C. J. Org. Chem. 2001, 66,
5723.
(7) Oro, J. Nature 1961, 190, 389. Ferris, J. P.; Hagan, W. J., Jr.
Tetrahedron 1984, 40, 1093 (review).
(8) A preparation of 1 had been previously attempted in the course of
an extended study of the chemistry of substituted 5,8-diaza-7,9-dicarba-
purine derivatives by Al-Shaar, A. H. M.; Chambers, R. K.; Gilmour, D.
W.; Lythgoe, D. J.; McClenaghan, I.; Ramsden, C. A. J. Chem. Soc., Perkin
Trans. 1 1992, 2789.
1
(12) 1H and 13C NMR Data for 1. H NMR (600 MHz, DMSO(D6)):
6.14 ppm (s, 2H, NH2-(C6)), 6.44 ppm (s, 1H, H-(C9)), 7.95 ppm(s, 2H,
NH2-(C2)), 8.02 ppm(s, 1H, H-(C7)). 13C NMR (150.9 MHz, DMSO(D6)):
1
109.8 ppm (C9, correlates with signal at 6.44 ppm (H-(C9)) in H NMR),
122.1 (C7, correlates with 8.02 ppm (H-(C7)) in 1H NMR), 141.8 (C4),
1
149.3 (C6), 158.1 (C2). Assignments based on NOE, H-13C, and HMB
correlations.
(13) MS Data for 1. Electrospray-MS (pos.): 151 (100, [M + H]+),
301 (40, [2M + 1]+). Electrospray-MS (neg.): 149 (100, [M - H]-), 185
(100, [M + Cl]-).
(14) Carried out by Raj K. Chadha, TSRI. Crystallographic data for the
structure has been deposited with the Cambridge Crystallographic Data
Center as deposition no. CCDC 180981. Copies of the data can be obtained,
free of charge, on application to the CCDC, 12 union Road, Cambridge
CB12 1EZ UK (fax, + 44 (1233) 336 0333; E-mail, deposit@ccdc.cam.ac.uk).
Data for 7 in Supporting Information.
(9) Martin, K.; Matthews, H. R.; Rapoport, H.; Thyagarajan, G. J Org.
Chem. 1968, 33, 3758.
(10) Holter, S. N.; Fernlius, W. C. Inorg. Synth. 1963, 7, 58. Shirai, K.;
Sugino, K. J. Org. Chem. 1960, 25, 1045.
(11) Overberger, C. G.; Michelotti, F. W.; Carabateas, P. M. J. Am. Chem.
Soc. 1957, 941, 79.
(15) Rabinowitz, J. C. J. Biol Chem. 1956, 218, 175.
(16) Purchased from Aldrich, 96% purity.
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Org. Lett., Vol. 5, No. 12, 2003

Scheme 4. Regioselective Electrophilic Substitution Reactions
at Position C-9 of Purinoid 1a
Figure 1. UV-absorption spectrum of purinoid 1 as compared
to that of 2,6-diaminopurine (c ) 2.66 × 10-5 M in H2O, rt).
Data for 1: ꢀ (220 nm) ) 28 400; λmax ) 265 nm (ꢀ ) 9300); ꢀ
(300-310 nm) ) 3100-3000. Data for 2,6-diaminopurine: ꢀ (220
nm) ) 24500, λmax ) 246 nm (ꢀ ) 7400), λmax ) 280 nm (ꢀ )
9100).
a (a) 0.05 mM (1.0 mole equiv) 1, 0.7 µM (0.03) CD3CO2D,
D2O/DMSO(D6) 4:1, pH 4.7, rt, (deuteration at C-9 within minutes).
(b) 0.1 M (1.0) 1, 0.1 (1.0) N,N-dimethyl-N-methylidene iminium
iodide, DMSO, rt, 5 min, 79%. (c) 0.13 (1.0) 1, 0.2 (1.5) pyrroline,
0.2 (1.5) BzOH, DMSO, rt, 1 h, 72%.
aqueous solution under argon atmosphere (pH ≈ 1.5) within
a day at room temperature to produce a product mixture from
which, after neutralization, it is possible to isolate by repeated
chromatography on silica gel (CH2Cl2/CH3OH/30% aqueous
NH3, 10:1:0.1, and AcOEt/CH3OH 4:1) samples of purinoid
1 in yields that range up to 20%. Not only are yields low
and fluctuating, but to obtain non-colored and spectroscopi-
cally and chromatographically pure samples of 1 is tedious.
Nevertheless, all spectral data of pure samples of 1 obtained
by this route were identical to those of samples obtained by
the other method.
solution at pH 1 (HCl) it undergoes hydrolytic ring opening
to a mixture of the triazine 4 and its deformylated derivative
within 3 days (see Supporting Information). In the solid state
(sealed under N2) the purinoid is thermally stable at 200 °C
(for at least 8 h); in solution it is moderately sensitive to
oxygen.
Similar to natural purines, purinoid 1 has little solubility
in organic liquids such as methanol, acetonitrile, or DMF. It
dissolves well in DMSO on heating and sonicating, remain-
ing in solution at room temperature. It dissolves in (hot) water
to an extent of ca. 1.5 mg/mL (after cooling to room
temperature) and remains unchanged in 0.01 M NaOH
solution (pH ca. 12) or in DMSO/aqueous HCl (1:20, pH
ca. 3) at room temperature for (at least) 7 days. In aqueous
In a solution of 1 in D2O/DMSO(D6) 4:1, at pH 4.0 (acetic
acid(D4)) at room temperature, the vinylic proton H-(C9)
(δ ) 6.44 ppm) undergoes exchange, within minutes, to
afford 8 (1H NMR); corresponding exchange of the H-(C7)
proton (δ ) 8.02 ppm) is much slower (less than 10% after
5 h and still incomplete after 3 days). In accordance with
expectation (for its rationale see Scheme 4) as well as the
observed ease of proton f deuterium exchange in acidic
solution, purinoid 1 undergoes (C9)-regioselective electro-
philic substitution with N,N-dimethyl-N-methylidene iminium
iodide17 within minutes in 0.1 M DMSO solution at room
temperature to give the dimethylaminomethyl purinoid-
derivative 9 in high (isolated) yields (Scheme 4).18 Assign-
ment of constitution rests on 1H and 13C NMR spectroscopic
data (in addition to UV and mass spectra). An analogously
smooth condensation was observed with pyrroline19 in 0.2
M DMSO solution in the presence of 1 mole equiv of benzoic
acid as catalyst affording 1020 (Scheme 4). These encouraging
observations led to an extended study on the capacity of
(17) Schreiber, J.; Maag, H.; Hashimoto, N.; Eschenmoser, A. Angew.
Chem., Int. Ed. Engl. 1971, 10, 330.
(18) Data for 9 in Supporting Information.
(19) Poisel, H. Monatsh. Chem. 1978, 109, 925.
(20) Data for 10 in Supporting Information.
Figure 2. X-ray structure analysis of the derivative 7.14 UV
data of 7 in H2O, rt: λmax ) 291 nm (ꢀ ) 47 600); ꢀ (355 nm) )
5900.
Org. Lett., Vol. 5, No. 12, 2003
2069

purinoid 1 to act as nucleobase partner in nucleophilic
coupling reactions with aldosugar- and azasugar-derived
iminium ions to form directly corresponding C-nucleosides.
Results of these studies are reported in the following
communication.21
Supporting Information Available: Experimental pro-
cedure for the synthesis of 2,6-diamino-purinoid 1 and data
for derivatives 7, 9, and 10. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL030044N
Acknowledgment. This work was supported by the
Skaggs Research Foundation and Novartis A.G. (Basel).
H.K.H and Z.W. have been Skaggs Postdoctoral Fellows.
(21) Han, B.; Wang, Z.; Krishnamurthy, R., Jaun, B., Eschenmoser, A.
Org. Lett. 2003, 5, 2071.
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