Enhancing the Methyl‐Donor Activity of Methylcobalamin by Covalent Attachment of DNA

The preparation of a covalent DNA conjugate of vitamin B 12 by means of heterogeneous solid‐phase synthesis is reported. The cyano‐corrinoid made available, dipotassium Co β ‐cyanocobalamin‐(3″→2′),(3″→5′)‐bis‐2″‐deoxythymidyl‐3″‐ate (K 2 ‐ 4 ), was cleanly methylated at the Co center by electrosynthetic means. Aqueous solutions of the resulting organometallic DNAB 12 conjugate K 2 ‐ 5 exhibited spectroscopic properties indicative of significant weakening of the axial (CoN) bond, together with a 25‐times higher basicity relative to Co β ‐methylcobalamin ( 2 ). Methyl‐transfer equilibria of pH‐neutral aqueous solutions of K 2 ‐ 5 and cob(I)alamin (K‐ 7 ) on one side, and of cob(I)alamin‐(3″→2′),(3″→5′)‐bis‐2″‐deoxythymidyl‐3″‐ate (K 3 ‐ 8 ) and methylcobalamin ( 2 ) on the other, were studied at room temperature ( Scheme 3 ). The NMR‐derived data provided an equilibrium constant of ca. 0.3. Activation of K 2 ‐ 5 for abstraction of its Co‐bound Me group by a nucleophile (such as cob(I)alamin) was, thus, indicated.