A highly facile and efficient one-step synthesis of N6-adenosine and N6-2′-deoxyadenosine derivatives

Article abstract of DOI:10.1021/ol052424+

(Chemical Equation Presented) A highly facile and efficient one-step synthesis of N⁶-adenosine and N⁶-2′-deoxyadenosine derivatives has been developed. Treatment of inosine or 2′-deoxyinosine, without protection of sugar hydroxyl groups, with alkyl or arylamines, in the presence of BOP and DIPEA in DMF, led to the formation of N⁶- adenosine and N⁶-2′-deoxyadenosine derivatives in good to excellent yields. Carcinogenic polyaromatic hydrocarbon (PAH) N ⁶-2′-deoxyadenosine adduct 10 and a rare DNA constituent 11 were thus synthesized directly from 2′-deoxyinosine both in 98% yield.

Full text of DOI:10.1021/ol052424+

ORGANIC
LETTERS
2005
Vol. 7, No. 26
5877-5880
A Highly Facile and Efficient One-Step
Synthesis of N6-Adenosine and
N6-2
′-Deoxyadenosine Derivatives
Zhao-Kui Wan,* Eva Binnun, Douglas P. Wilson, and Jinbo Lee
Chemical and Screening Sciences, Wyeth Research, 200 Cambridge Park DriVe,
Cambridge, Massachusetts 02140
zwan@wyeth.com
Received October 6, 2005
ABSTRACT
A highly facile and efficient one-step synthesis of N6-adenosine and N6-2
inosine or 2 -deoxyinosine, without protection of sugar hydroxyl groups, with alkyl or arylamines, in the presence of BOP and DIPEA in DMF,
led to the formation of N6-adenosine and N6-2
-deoxyadenosine derivatives in good to excellent yields. Carcinogenic polyaromatic hydrocarbon
(PAH) N6-2
-deoxyadenosine adduct 10 and a rare DNA constituent 11 were thus synthesized directly from 2 -deoxyinosine both in 98% yield.
′-deoxyadenosine derivatives has been developed. Treatment of
′
′
′
′
Amino heterocycles are common biological and pharmaceu-
tical components the synthesis of which often dictates the
success of drug discovery and related research. We have been
involved in direct amination of cyclic amide systems (Figure
1), with early emphasis on the synthesis of nucleosides to
be reported herein.
to the discovery of numerous biologically active compounds.1
N6-Amino purines are key members of the nucleoside family.
The broad spectrum of their functionality has long piqued
research interests. However, formation of a C-N bond in
such biologically important systems remains challenging. A
common approach is SNAr displacement of amines with C6
halopurines2 that often require extra steps to synthesize. Since
the modern chemistry has not yet rendered syntheses without
a protection/deprotection protocol, the typical four-step
(1) Suhadolnik, R. J. Nucleosides as Biological Probes; Wiley: New
York, 1979.
(2) For representative references, see: (a) Srivastava, P. C.; Robins, R.
K.; Meyer, R. B., Jr. In Chemistry of Nucleosides and Nucleotides;
Townsend, L. B., Ed.; Plenum: New York, 1988; Vol. 1, pp 113-281. (b)
Liu, J.; Janeba, Z.; Robins, M. J. Org. Lett. 2004, 6, 2917-2920. (c) Han,
S.; Harris, C. M.; Harris, T. M.; Kim, H.-Y. H.; Kim, S. J. J. Org. Chem.
1996, 61, 174. (d) Nair, V.; Richardson, S. G. J. Org. Chem. 1980, 45,
3969. (e) Ve´liz, E. A.; Beal, P. A. Tetrahedron Lett. 2000, 41, 1695-
1697. (f) Ve´liz, E. A.; Beal, P. A. J. Org. Chem. 2001, 66, 8592 and
references therein. For recent reviews, see: (g) Lakshman, M. K. J.
Organomet. Chem. 2002, 653, 234-251. (h) Hocek, M. Eur. J. Org. Chem.
2003, 245-254.
Figure 1. Direct amination of amide systems.
Purine bases play paramount roles in numerous biological
processes.1 Structurally modified purine bases, nucleosides,
and nucleotides have drawn considerable attention and led
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Sung13 and Mansour14 reported formation of protected C4-
(1,2,4-triazol-1-yl) and C4-imidazole uracil derivatives with
4-Cl-PhOPOCl2, respectively.
We were interested in exploring our phosphonium salt
mediated C-N bond formation with two goals in mind: (1)
to achieve amination with arylamines under mild and non-
metal-catalyzed conditions; and (2) to conduct reactions
directly with unprotected nucleosides, i.e., 4 to 3 in a single
step, a type of transformation that has not been docu-
mented.15. In this communication, we report a highly facile
and convenient one-step synthesis of N6-adenosine and N6-
2′-deoxyadenosine derivatives including arylamine analogues
and carcinogenic amine adducts of 2′-deoxyribonucleosides
through phosphonium salt intermediates.
Figure 2. Conventional formation of adenosine derivatives.
procedure (Figure 2) begins with protection of the sugar
moiety followed by halide formation, often under harsh
conditions. This transformation can lead to cleavage of the
glycosyl bond, so acid-labile protecting groups for the sugar
hydroxyl groups must be avoided. Subsequent SNAr reactions
performed with strong nucleophiles such as aliphalic amines3
are somewhat satisfactory, but reactions with less nucleo-
philic aromatic amines are often unsuccessful.2a,4 Lakshman,5
Johnson,6 Rizzo,7 and Harvey8 have recently applied the
Buchwald-Hartwig chemistry to the preparation of carci-
nogenic N6-nucleoside adducts. The development of a facile
C-N bond-forming reaction would allow an easy access to
thesebiologicallyimportantandcomplexnucleosidesystems.1,5-8
1-H-Benzotriazol-1-yloxy-tris(dimethylamino)phosphoni-
um hexafluorophosphate (BOP) and other phosphonium salts
have been used for amide bond formation.9 It is assumed
that the formation of an (acyloxy)phosphonium salt is
involved.9 In our research, we discovered that BOP was
suitable for the activation of certain cyclic amide bonds.10
We reasoned that formation of a phosphonium salt may
provide sufficient activation in a nucleoside system as well,
thus allowing a C-N bond-forming reaction in such a
system. Beal2e,f recently reported the synthesis of 6-bro-
mopurine and 6-chloropurine ribosides by treatment of
protected nucleosides with NBS or CX4 with P(NMe2)3 and
a halide source. Robins11 also reported that treatment of
protected inosine and 2′-deoxyinosine derivatives with a
cyclic secondary amine or imidazole with I2/Ph3P/EtN(i-Pr)2
in CH2Cl2 or toluene under modified Appel combinations12
gave rise to N6-substituted purine nucleosides. In addition,
Our work began with screening some common amide
coupling activators as well as other reaction conditions16 and
ultimately led to the successful synthesis of adenosine
analogue 7a (Scheme 1). Activation of 2′,3′,5′-tri-O-acetyli-
Scheme 1
nosine 5 with BOP reagent (1.2 equiv) in the presence of
DIPEA (1.5 equiv) in DMF at room temperature was
followed by treatment with benzylamine (1.2 equiv). The
desired N6-benzyladenosine 7a was formed in near quantita-
tive yield (98%, Table 1). It is our belief that the phospho-
nium salt 6 was involved in this facile C-N bond-forming
process.17 Subsequent substitution by a variety of amines led
to the formation of desired products upon elimination of a
molecule of HMPA (Table 1).
(3) Robins, M. J.; Basom, G. L. Can. J. Chem. 1973, 51, 3161-3169.
(4) (a) Maruenda, H.; Chenna, A.; Liem, L.-K.; Singer, B. J. Org. Chem.
1998, 63, 4385-4389. (b) Lakshman, M. K.; Keeler, J. C.; Hilmer, J. H.;
Martin, J. Q. J. Am. Chem. Soc. 1999, 121, 6090-6091. (c) Lakshman, M.
K.; Sayer, J. M.; Jerina, D. M. J. Am. Chem. Soc. 1991, 113, 6589-6594.
(d) Lakshman, M. K.; Lehr, R. E. Tetrahedron Lett. 1990, 31, 1547-1550.
(e) Kim, S. J.; Harris, C. M.; Jung, K.-Y.; Koreeda, M.; Harris, T. M.
Tetrahedron Lett. 1991, 32, 6073-6076.
It was determined that preactivation was not necessary as
demonstrated in various C-N bond-forming reactions with
(5) Lakshman, M. K.; Keeler, J. C.; Hilmer, J. H.; Martin, J. Q. J. Am.
Chem. Soc. 1999, 121, 6090-6091.
(6) De Riccardis, F.; Bonala, R. R.; Johnson, F. J. Am. Chem. Soc. 1999,
121, 10453-10460.
(13) Sung, W. L. J. Org. Chem. 1982, 47, 3623-3628.
(14) Mansour, T. S.; Evans, C. A.; Siddiqui, M. A.; Charron, M.;
Zacharie, B.; Nguyen-Ba, N.; Lee, N.; Korba, B. Nucleosides Nucleotides
1997, 16, 993-1001.
(15) Phosphonium salts of primary and secondary alcohols readily
undergo nucleophilic substitutions. (a) Castro, B.; Chapleur, Y.; Gross, B.;
Selve, C. Tetrahedron Lett. 1972, 5001-5004. (b) Castro, B.; Selve, C.
Tetrahedron Lett. 1973, 4459-4463. (c) Downie, I. M.; Heaney, H.; Kemp,
G. Tetrahedron 1988, 44, 2619-2624 and references therein.
(16) PyBOP and PyBroP were also active towards activation of inosine
but less effective. DMF was found to be the best solvent.
(17) The phosphonium salt was observed on LCMS.
(7) Elmquist, C. E.; Stover, J. S.; Wang, Z.; Rizzo, C. J. J. Am. Chem.
Soc. 2004, 126, 11190-111201.
(8) (a) Dai, Q.; Ran, C.; Harvey, R. G. Org. Lett. 2005, 7, 999-1002.
(b) Lee, H.; Luna, E.; Hinz, M.; Stezowski, J. J.; Kiselyov, A. S.; Harvey,
R. G. J. Org. Chem. 1995, 60, 5604-5613.
(9) (a) Castro, B.; Dormoy, J. R.; Evin, C. Tetrahedron Lett. 1975, 14,
1219-1222. (b) Campagne, J.-M.; Coste, J.; Jouin, P. J. Org. Chem. 1995,
60, 5214-5223 and references therein.
(10) Wan, Z.-K. Unpublished results.
(11) Lin, X.; Robins, M. J. Org. Lett. 2000, 2, 3497-3499.
(12) Appel, R. Angew. Chem., Int. Ed. Engl. 1975, 14, 801-811.
5878
Org. Lett., Vol. 7, No. 26, 2005

Table 1. Amination of Sugar-Protected Inosine
Table 2. Amination of Sugar-Unprotected Inosine and
2′-Deoxyinosine
a panel of amines (Table 1). With the exception of aromatic
amines, all reactions were completed overnight at ambient
temperature providing the desired adenosine analogues 7a-
7e in good to excellent yields (70-99%). The aromatic
amines reacted more slowly as expected. For instance,
reaction with p-anisidine (Table 1, entry 7) was accomplished
at room temperature to produce the desired product 7g (74%
isolated yield and 20% recovered starting material), whereas
heating (80 °C, 10 h) was required for the reaction with
p-toluidine to give the desired product 7f (Table 1, entry 6).
To perform this reaction on an unprotected system,
selective activation is required. We reasoned this was possible
due to the much lower pKa value of the cyclic amide group
compared to that of the sugar moiety. We thus began to look
into direct amination of unprotected nucleosides (Scheme
2).
a Method A: BOP (1.2 equiv), DIPEA (1.5 equiv), R-NH2 (1.2 equiv),
rt. Method B: BOP (1.5 equiv), DIPEA (2.0 equiv), R-NH2 (5.0 equiv), rt,
overnight, then 60 or 80 °C. Yield after recrystallization or HPLC
b
purification.
less, all of reactions provided the desired products in good
yields. HOBt adduct was also observed by LCMS in these
cases and is hypothesized to be an intermediate in the
reaction.19
With this facile and efficient methodology in hand, we
sought to demonstrate its utility in the synthesis of biologi-
cally important nucleosides. Polycyclic aromatic hydrocar-
bons (PAH) are potent mutagens and carcinogens that pose
synthetic challenges.4c,6-8 We felt that our chemistry could
aid the synthesis of these compounds. Therefore, we chose
to resynthesize compounds 108b and 1120 that were previously
reported in the literature (Scheme 3).
Scheme 2
Scheme 3
Table 2 demonstrates the high flexibility of this newly
discovered C-N bond formation in unprotected nucleoside
systems. Compared to protected inosine, reactions of un-
protected substrates with aliphatic and aromatic amines
require longer reaction times. The slower reaction rate was
partially due to the low solubility of inosine in DMF. The
reactions with benzylamine (Table 2, entries 1 and 2) were
completed at room temperature.18 The reactions with aromatic
amines also proceeded at room temperature; however, heating
was required to push the reactions to completion. Neverthe-
1-Methylpyrene is a common environmental pollutant.21
Its dA adduct 10 was synthesized in three steps from a
Org. Lett., Vol. 7, No. 26, 2005
5879

chlorofuranose (33% overall),8b and the dA adduct 11, a rare
DNA constituent, was synthesized through a six-step se-
quence (34% overall).20 In our hands, treatment of 2′-
deoxyinosine with BOP in the presence of DIPEA at ambient
temperature, followed by addition of 1-pyrenemethylamine,
led to the formation of the desired products 108b in just one
step in 98% yield (Scheme 3). Similarly, the reaction with
glycinamide gave 1120 also in 98% yield (Scheme 3).
In summary, a highly facile and efficient one-step,
phosphonium salt mediated C-N bond-forming reaction was
developed for the synthesis of N6-adenosine and N6-2′-
deoxyadenosine derivatives with both aliphatic and aromatic
amines. The one-step synthesis of PAH adduct 10 and DNA
constitutent 11 demonstrated the clear advantage of this new
methodoloy over the existent procedures. Further studies to
broaden its generality and applicability to many other
heterocyclic systems are underway, and results will be
reported later.
(18) Representative Procedure. To a solution of (-)-inosine (268 mg,
1.0 mmol) and BOP (530.7 mg, 1.2 mmol) in DMF (5 mL) was added
DIPEA (0.261 mL, 1.5 mmol), followed by addition of benzylamine (0.131
mL, 1.2 mmol) at room temperature under the nitrogen. The reaction mixture
was stirred overnight (∼16 h) at room temperature. The solvent was removed
under vacuum, and the crude product was purified on a silica gel column
eluted with 0-15% MeOH in DCM to give the desired product 9a as a
white solid (355 mg, 99+%). All products in both Table 1 and Table 2
have been fully characterized.
Acknowledgment. The authors wish to thank Drs. Wei
Li, Tarek Mansour, Steve Tam, and Eddine Saiah for helpful
discussions and Drs. Nelson Huang and Walter Massefski
and Mr. Stephen Huhn for technical support.
(19) Mechanistic studies are underway. For work on BtH, see: Katritzky,
R. A.; Manju, K.; Singh, S. K.; Meher, N. K. Tetrahedron 2005, 61, 2555-
2581 and references therein.
Supporting Information Available: Experimental pro-
cedures and spectral data. This material is available free of
charge via the Internet at http://pubs.acs.org.
(20) Seela, F.; Herdering, W.; Kehne, A. HelV. Chim. Acta 1987, 70,
1649-1660.
(21) (a) Harvey, R. G. Polycyclic Aromatic Hydrocarbons: Chemistry
and Carcinogenicity; Cambridge University Press: Cambridge, England,
1991. (b) Glatt, H.; Seidel, A.; Harvey, R. G.; Coughtrie, M. W. H.
Mutagenesis 1994, 9, 553-557.
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