6-O-Methylerythromycin A (I) was protected as the 2'-acetate (II) and subsequently treated with chlorotrimethylsilane and pyridine to afford the 4''-O-silyl ether (III). Condensation of (III) with 1,1'-carbonyldiimidazole yielded the 12-O-acylimidazole derivative (IV), which was subsequently reacted with 3-chloro-4-fluorophenethyl amine (V) to form the 11,12-cyclic carbamate (VI). Deprotection of the acetate ester of (VI) on heating with methanol, followed by desilylation with tetrabutylammonium fluoride in THF yielded (VII).
Treatment of (VII) with iodine and sodium acetate under irradiation of a halogen lamp produced N-demethylation to furnish (VIII). Further demethylation of (VIII) to give (IX) was achieved by a similar treatment with iodine and tripotassium phosphate. Finally, reductive condensation of (IX) with cyclopropanecarbaldehyde (X) in the presence of sodium cyanoborohydride yielded the bis(cyclopropylmethyl) derivative.