Spiroannulated nucleosides and process for the preparation thereof

摘要

We claim a simple strategy for the synthesis of a collection of C(3′)-spirodihydroisobenzo-furannulated and C(3′)-spirodihydroisobenzo-furannulated nucleosides featuring a [2+2+2]-cyclotrimerization as the key reaction. The cyclotrimerization reactions are facile with the unprotected nucleosides having a diyne unit. When both alkynes of the diyne are terminal, the regioselectivity is poor. However, when one of the terminal alkynes is additionally substituted, the cyclotrimerizations are highly diastereoselective. Since the key bicycloannulation is the final step, this strategy provides flexibility in terms of the alkynes and is thus amenable for the synthesis of a focussed small molecule library.

主权项

1. A process for the preparation of Spiro annulated nucleoside of general Formula I; where, R (in the base) is selected from H, C1-C4 alkyl, halogen, OR, NHR (R═H, COCH3, COOtBu); Q=H with the proviso that C—N double bond is absent, C—Z double bond is present and Z is O; Z is NH2 with the proviso that C—Z double bond is absent, Q≠H; Z is O with the proviso that C—N double bond is absent; A and A′ are selected from H, lower alkyl —OH, —OAc CH2OH, —CH2OAc, —CH2OPiv, —CH2OTBS; m and n are integers 0,1 A″ and A′″ are selected from 1,3-dihydroisobenzofuran (1a) or isochroman [3,4-dihydro-1H-benzo[c]pyran] represented by the formula (1b), where R, R′, R″ are selected from H, —OH, halo group, —CH2OH, —CH2OAc, —COOH, —COOMe, C1-C30 straight or branched alkyl group, optionally substituted with halogen or —OH or —NH2 or —NPhth; phenyl group optionally substituted with halogen, amino, nitro, C1-C6 alkyl; with the proviso that when n=1[i.e(CH2)n=1] and where m=0[i.e(CH2)m=0], A′″ is absent and A″ is 1,3-dihydro isobenzofuran (1a) or isochroman [3,4-dihydro-1H-benzo[c]pyran] represented by the formula (1b), directly annulated at C-3, A and A′ are selected from H, lower alkyl, OH, —OAc, —CH2OH—CH2OAc, —CH2OPiv, —CH2OTBS,; and R, R′ and R″ in 1,3-dihydro isobenzofuran (1a) or isochroman [3,4-dihydro-1H-benzo[c]pyran] represented by the formula (1b) are selected from H, —OH, halo group, —CH2OH, —CH2OAc, —COOH, —COOMe, C1-C30 straight or branched alkyl group, optionally substituted with halogen or —OH or —NH2 or —NPhth; phenyl group optionally substituted with halogen, amino, nitro, C1-C6 alkyl; R (in the base) is selected from H, C1-C4 alkyl, halogen; Q=H with the proviso that C—N double bond ( . . . . ) is absent, C—Z double bond ( . . . . ) is present and Z is O; Z is NH2 with the proviso that C—Z double bond is absent, Q≠H; Z is O with the proviso that C—N double bond ( . . . . ) is absent; the proviso that when both n=1 and m=1, A″ is absent and A″′ is selected from 1,3-dihydroisobenzofuran of formula (1a)) or isochroman [3,4-dihydro-1H-benzo[c]pyran] represented by the formula (1b), A and A′ are selected from H, lower alkyl, —OH, —OAc, —CH2OH, —CH2OAc; R, R′ and R″ in 1,3-dihydroisobenzofuran of formula (1a) or isochroman [3,4-dihydro-1H-benzo[c]pyran] represented by the formula (1b) are selected from H, —OH, —OAc, halo group, —CH2OH, —CH2OAc, —COOH, —COOMe, C1-C30 straight or branched alkyl group, optionally substituted with halogen or —OH or —NH2 or —NPhth; phenyl group optionally substituted with halogen, amino, nitro, C1-C6 alkyl; R (in the base) is selected from H, C1-C4 alkyl, halogen; Q=H with the proviso that C—N double bond ( . . . . ) is absent, C—Z double bond ( . . . . ) is present and Z is O; Z is NH2 with with the proviso that C—Z double bond is absent, Q≠H; Z is O with the proviso that C—N double bond ( . . . . ) is absent; with the proviso that both A and A″ can form together 1,3-dihydroisobenzofuran (1a) where R, R′ and R″, are selected from H, —OH, halo group, —CH2OH, —CH2OAc, —COOH, —COOMe, C1-C30 straight or branched alkyl group, optionally substituted with halogen or —OH or —NH2 or —NPhth; phenyl group optionally substituted with halogen, amino, nitro, C1-C6 alkyl when m=0[i.e(CH2)m=0], A″′ is absent and A′ is selected from H, lower alkyl, —OH, —OAc, —CH2OH, —CH2OAC, —CH2OMe, —CH2OEt, phenyl optionally substituted with halogen, amino, nitro, C1-C6 alkyl, wherein the said process comprising the steps of; a) Preparing solution of diyne and alkyne in mole ratio ranging between 1:1 to 1:3 in a solvent followed by degassing of solution with dry argon; b) adding a catalyst in mole ratio ranging between 0.02 to 0.05 into the degassed solution as obtained in step (a) followed by heating at temperature in the range of 70° C.-90° C. for a period in the range of 6 h-12 h; c) cooling the solution as obtained in step (b) to room temperature ranging between 25° C.-30° C. followed by solvent evaporation and purification to obtain spiroannulated nucleoside.