Lithium-stabilized nucleophilic addition of thiamin to a ketone provides an efficient route to mandelylthiamin, a critical pre-decarboxylation intermediate

• Published in: Bioorganic chemistry Vol. 62; pp. 124 - 129
• Main Authors: Bielecki, Michael, Howe, Graeme W., Kluger, Ronald
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2015
• Subjects: Analysis; Benzoylformate; Chemistry Techniques, Synthetic; Equilibrium; Ketones - chemistry; Lewis Acids - chemistry; Lithium - chemistry; Lithium ion stabilization; Mandelic Acids - chemical synthesis; Nucleophilic carbene; Predecarboxylation intermediate; Protecting group; Synthesis; Thiamin; Thiamine - analogs & derivatives; Thiamine - chemical synthesis; Thiamine - chemistry; Nucleophilic carbene; Protecting group; Synthesis; Analysis; Predecarboxylation intermediate; Benzoylformate; Lithium ion stabilization; Equilibrium; Thiamin
• ISSN: 0045-2068; 1090-2120; 1090-2120
• DOI: 10.1016/j.bioorg.2015.08.004

[Display omitted] •Mandelylthiamin (MT) is a key pre-decarboxylation intermediate.•Condensation to produce esters of MT is thermodynamically controlled.•Lithium ions dramatically shift condensation toward product.•Isolated yield of MT is ∼50% vs <5% by previous routes.•Lithium-enhancement of addition to hindered ketone may be general. Mandelylthiamin (MTh) is an accurate model of the covalent intermediate derived from the condensation of thiamin diphosphate and benzoylformate in benzoylformate decarboxylase. The properties and catalytic susceptibilities of mandelylthiamin are the subjects of considerable interest. However, the existing synthesis gives only trace amounts of the precursor to MTh as it is conducted under reversible conditions. An improved approach derives from the unique ability of lithium ions to drive to completion the otherwise unfavorable condensation of the conjugate base of thiamin and methyl benzoylformate. The unique efficiency of the condensation reaction in the presence of lithium ions is established in contrast to the effects of other Lewis acids. Interpretation of the pattern of the results indicates that the condensation of the ketone and thiamin is thermodynamically controlled. It is proposed that the addition of lithium ions displaces the equilibrium toward the product through formation of a stable lithium-alkoxide.