The Correct Structures of “Dihydrothiamine”. Resolution of a Long-Standing Controversy

Reduction of thiamin (1) by a borohydride in water first gives bicyclic perhydrofuro[2,3-d]thiazole 3. Heating 3 in water generates fused tricyclic pyrimido[4,5-d]thiazolo[3,4-a]pyrimidine 4. X-ray crystal structures indicate the stereocenters are cis in 3 and cis-cis in 4. The kinetics of reduction of both 3 and 4 to tetrahydrothiamin 5 by additional aqueous borohydride show that 3 is the kinetic product of the reduction of 1 while 4 is the thermodynamic product produced from 3 in an acid-catalyzed ring-opening ring-closing isomerization process. Several structural assignments of “dihydrothiamine” presented some 40 years ago are incorrect. Subsequent reports based on the incorrect structures need to be reinterpreted.