Bioinspired design of a robust d ₃ -methylating agent

Abstract

Methods to incorporate deuterium atoms into organic molecules are valuable for the pharmaceutical industry. The introduction of deuterium atoms by a synthetic method enables the direct tracing of the drug molecule without substantially altering its structure or function. The methyl group is one of the most commonly occurring carbon fragments in biologically active molecules. Here, a biomimetic design reagent, 5-(methyl-d3)-5H-dibenzo[b,d]thiophen-5-ium trifluoromethane sulfonate (DMTT), as an analog of S-adenosylmethionine (SAM), has been developed for the selective d3-methylation of complex molecules bearing several possible reactive sites with excellent selectivity and high-level deuterium incorporation. A series of d3-methylated organic molecules and deuterated pharmaceuticals were synthesized under the mild system with excellent functional group compatibility.

The Deuterated “Magic Methyl” Group: A Guide to Site‐Selective Trideuteromethyl Incorporation and Labeling by Using CD3Reagents

“…Inspired by the reactivity profile of S‐adenosylmethionine (SAM) and making use of the design principle of the Umemoto reagent, the Shi group developed 5‐([D 3 ]methyl)‐5 H ‐dibenzo[ b,d ]thiophen‐5‐ium trifluoromethane sulfonate (DMTT) as a [D 3 ]methylating S‐adenosylmethionine (SAM) analog. [112] …”

Generation of non-stabilized alkyl radicals from thianthrenium salts for C–B and C–C bond formation

“…Moreover, direct cross-coupling of C(sp 3 )−H bonds in N-aryl tetrahydroisoquinoline 41 h with thianthrenium salt 1a by visible-light photoredox system could generate product 50 in an excellent yield 79 . In addition, S-(alkyl) thianthrenium salt can also serve as an electrophile reagent to provide an alkyl source with nucleophiles 80 . For example, when a complex molecule atorvastatin (51) with several possible reactive sites was examined with thianthrenium salt 1a, the reaction showed excellent selectivity for esterification product 52 in a good yield.…”

Broadening of horizons in the synthesis of CD3-labeled molecules

“…As a biomimetic methylating agent, DMTT has also been used in base-promoted selective trideuteromethylation of strongly acidic sulfonamide or dicarbonyl N-H bonds in complex molecules (Scheme 57). 71 Less acidic functional groups such as amine, amide, and hydroxyl groups remained intact under these reactions. Furthermore, using the Ni-catalyzed procedure, selective dimethylation-d6 and methylation-d3 were achieved for aryl/alkyl primary amines and secondary amines, respectively, without forming over-methylated quaternary ammonium salts.…”

“…Inspired by radical transferase S-adenosylmethionine (SAM) and the design principle of Umemoto's reagent, Shi and co-workers developed a biomimetic methylating agent DMTT (5-(methyl-d3)-5H-dibenzo[b,d]thiophen-5-ium trifluoromethane sulfonate) for mild and selective trideuteromethylation of various nucleophiles (Scheme 33). 71 DMTT is easily prepared as a bench-stable solid from dibenzo[b,d]thiophene and CD3OD. This reagent is utilized in Pdcatalyzed pyridine-or acetylamino-directed ortho-C(sp 2 )-H mono-or di-methylation of several organic and drug molecules.…”