A selective synthesis of new hydrophobic cobalamin derivatives bearing two different spacers has been accomplished via ring-opening reaction of c-lactone. The reaction of c-lactone with various amines afforded three types of amides (a, b, and c) depending on the reaction conditions. The structure of lactone b was determined by the X-ray analysis confirming the position of ring closure. It also reveals the presence of a hydrogen bond between the terminal hydroxy group and one of the axial cyanide ligands.

The synthesis of a new hydrophobic cobalamin derivative through intramolecular aminolysis is described. Under acidic conditions, (CN)2CobIII(10‐NH2)7C1‐ester formed a seven‐membered lactam between the ester and amino groups present at the C8 and C10 positions. Subsequent Boc protection of the NH group enabled ring opening with primary amines, leading to derivatives functionalized at the C8 and C10 positions.

Heptamethyl cobyrinate was transformed into hexamethyl 8-nor-cobyrinate. The crucial step involved the synthesis of new, vitamin B12 derived cobryketone via palladium-catalyzed cleavage of the sp(3)-sp(3) carbon-carbon bond with the liberation of the ketone. The replacement of sp(3) carbon atom with sp(2) (C═O) at the 8-position produces a bathochromic shift of all absorption bands and makes α and β bands equal as a consequence of the expansion of the existing conjugated system of double bonds.