Synthesis of ethyl (1S,2R,3S,4S,5S)-2,3-O-(isopropylidene)-4-hydroxy-bicyclo[3.1.0]hexane-carboxylate from L-ribose: a versatile chiral synthon for preparation of adenosine and P2 receptor ligands

Abstract

Substitution of the ribose moiety of various nucleosides and nucleotides with the (N)-methanocarba ring system increases the potency and selectivity as ligands at certain subtypes of adenosine and P2 receptors. We have prepared a key intermediate in the synthesis of these derivatives, ethyl (1S,2R,3S,4S,5S)-2,3-O-(isopropylidene)-4-hydroxybicyclo[3.1.0]hexane-carboxylate (15), starting from L-ribose (8) as a readily available, enantiopure building block. L-ribose was converted to the corresponding 5'-iodo derivative (9), which was cleaved reductively with Zn. Improvements were made in subsequent steps corresponding to a published route to biologically important (N)-methanocarba 5'-uronamido nucleosides, and new steps were added to prepare related 5'-nucleotides.

CHART 1

Structures of biologically-important (N)-methanocarba nucleoside derivatives 1a, b that act as adenosine A₃ receptor ligands and nucleotides 2, 3 that act as P2 receptor ligands.

SCHEME 1

Previously reported initial steps in the synthesis of (N)-methanocarba nucleoside and nucleotide derivatives 1–3.

SCHEME 2

Improved synthesis of a key (N)-methanocarba bicyclic pseudosugar intermediate 15 starting from L-ribose 8.

SCHEME 3

Synthesis of the (N)-methanocarba nucleoside derivative MRS3558 1a and nucleotide derivative MRS2339 2.