Preparation of the title compound has been reported by two procedures. Catalytic hydrogenation of benzofuran-4-carboxylic acid (I) over Pd/C afforded the dihydrobenzofuran (II). Carboxyl group reduction in (II) with LiAlH4 and further Swern oxidation of the resulting alcohol (III) furnished aldehyde (IV). Knoevenagel condensation of aldehyde (IV) with dimethyl malonate provided the benzylidenemalonate (V), which was converted to the key cyclopropane derivative (VII) upon treatment with 2-nitropropane (VI) and potassium tert-butoxide. Hydrolysis and decarboxylation of the malonate ester (VII) was performed using NaCN in hot DMSO to yield acid (VIIIa-b) as a diastereomeric mixture. Recrystallization of (VIIIa-b) from acetonitrile-water allowed the separation of the major (+/-)-trans-isomer, which was then resolved by preparative chiral HPLC. The desired (R,R)-isomer (IX) was finally coupled with guanidine (X) via activation with CDI
In a different procedure, the previously reported acetal (XI) was hydrolyzed under acidic conditions to give triol (XII). Oxidative cleavage of the cyclic diol function of (XII) by means of NaIO4 gave rise to the dialdehyde (XIII), which was further subjected to a reductive treatment with NaBH4, yielding triol (XIV). Tosylation of the aliphatic hydroxyl groups of (XIV) produced the ditosylate (XV) which, upon treatment with K2CO3 in MeOH, underwent intramolecular cyclization to the dihydrobenzofuran (XVI). Elimination of the remaining tosylate group of (XVI) in the presence of potassium tert-butoxide afforded the styrene derivative (XVII). Subsequent cycloaddition between styrene (XVII) and the enol triflate generated from N,N-dimethylisobutyramide (XVIII) produced the cyclobutanone (XIX). Halogenation of the lithium enolate of ketone (XIX) with N-bromosuccinimide in cold THF yielded the bromo ketone (XX). This underwent a Favorskii rearrangement in the presence of NaOH, producing the corresponding racemic cyclopropanecarboxylic acid, which was resolved by formation of the diastereomeric salts with (+)-alpha-methylbenzylamine. The desired (R,R)-acid (IX) was finally coupled with guanidine (X) via activation with CDI as above.