A new synthetic route to (North)-methanocarba nucleosides designed as A3 adenosine receptor agonists

Abstract

Activation of the A3 adenosine receptor (AR) is associated with cerebroprotective, cardioprotective, and anticancer effects. Among potent and selective A3 AR agonists are novel methanocarba adenosine analogues in which the conformation of a pseudo-ribose moiety is locked in the North (N) hemisphere of the pseudorotational cycle. 5'-Uronamide (N)-methanocarba nucleosides, such as MRS1898 and MRS2346, are examples of full agonists of the human A3 AR. An improved convergent approach from easily accessible 2,3-O-isopropylidene-d-erythrose (2b), and the combination of a strategic intramolecular cyclopropanation step plus the acid-catalyzed isomerization of an isopropylidene group, provided a suitable pseudosugar precursor (23) for the synthesis of MRS1898, MRS2346, and related analogues. This new synthetic route uses readily available building blocks and opens the way for the preparation of a variety of targets on a reasonable scale.

FIGURE 1.

Structure of A₃ AR agonists containing a (N)-methanocarba ring system.

SCHEME 1.. Synthesis of 9^a

^a Reagents and conditions: (a) DIBAL-H, CH₂Cl_2, −78 °C; (b) methyltriphenylphosphonium bromide, KOBu^t, THF, −78 °C to room temperature; (c) DMSO, (COCl)₂, CH₂Cl₂, −78 °C; (d) NaOCl; (e) N₂CHCOOEt, SnCl₂, CH₂Cl₂, room temperature; (f) 1,1′-carbonyldiimidazole, LDA, CH₃COOEt, THF, −78 °C; (g) TsN₃, CH₃CN, TEA, room temperature; (h) CuI, toluene, reflux; (i) NaBH₄, MeOH, room temperature.

SCHEME 2.. Attempted Synthesis of 14^a

^a Reagents and conditions: (a) (i) CH₃NH₂, room temperature; (ii) BzCl, pyridine, CH₂Cl₂, room temperature; (b) 10% CF₃COOH in MeOH, H₂O, room temperature; (c) SOCl₂, TEA, CH₂Cl₂, 0 °C; (d) NaIO₄, RuCl₃, CCl₄, H₂O, room temperature; (e) NaH, CH₃CN, 2,6-dichloropurine, room temperature.

SCHEME 3.. Synthesis of 24^a

^a Reagents and conditions: (a) DIBAL-H, −78 °C to room temperature; (b) BnBr, NaH, DMF, 0 °C to room temperature; (c) Dowex ion exchange resin, MeOH, room temperature; (d) SOCl₂, TEA, CH₂Cl₂, 0 °C; (e) NaIO₄, RuCl₃, CCl₄, H₂O, room temperature; (f) NaN₃, DMF, 100 °C; (g) Lindlar catalyst, H₂.

SCHEME 4.. Synthesis of A₃ AR Agonists^a

^a Reagents and conditions: (a) p-TsOH, acetone, reflux; (b) crystallization; (c) 2,6-dichloropurine, DIAD, TPP, THF, room temperature; (d) 3-iodobenzylamine‚HCl, TEA (for 1a), 40% aq MeNH₂ (for 1b), trans-2-phenylcyclopropylamine‚HCl, TEA (for 29), 2,2-diphenylethylamine (for 30), in MeOH, room temperature; (e) 40% aq MeNH₂; (f) 10% CF₃COOH in MeOH, H₂O, 70 °C.