Gold(I)-catalysed synthesis of a furan analogue of thiamine pyrophosphate

Abstract

SummaryAn analogue of thiamine having a furan ring in place of the thiazolium ring has been synthesised by a short and efficient route, involving gold(I)-catalysed cyclisation of an alkynyl alcohol to form the furan ring. The furan analogue of thiamine diphosphate (ThDP) was also made and tested for binding to and inhibition of pyruvate decarboxylase (PDC) from Zymomonas mobilis (overexpressed in E. coli with a N-terminal His-tag). It is a very strong inhibitor, with a K i value of 32.5 pM. It was also shown that the furan analogue of thiamine can be functionalised at the C-2 position, which will allow access to mimics of reaction intermediates of various ThDP-dependent enzymes.

Gold(I)-Catalyzed Activation of Alkynes for the Construction of Molecular Complexity

“…60b , 77 As an example, alkynediols 18 underwent a gold(I)-catalyzed cyclization leading to furans 20 after elimination of H 2 O from intermediate 19 in the presence of very low catalyst loadings (Scheme 8 ). 78 The alcohol moiety may already be present in the precursor of the gold(I)-catalyzed transformation 79 or may be generated in situ from epoxides by ring opening. 80 Carbonyls can also act the nucleophiles.…”

“…Moreover, in the presence of gold(I) complexes, dithiols can also add to alkynes to form cyclic thioacetals, 72 and homopropargylthiols bearing a propargylic alcohol lead to thiophenes after addition of the thiol to the gold-activated alkyne followed by dehydration. 78 …”

“…The high activity of gold­(I) salts and complexes for C–O bond formation has been widely exploited intramolecularly to construct oxygen containing heterocycles. In this context, one of the most studied transformations is the intramolecular gold­(I)-catalyzed cyclization of unactivated alkynols. , As an example, alkynediols 18 underwent a gold­(I)-catalyzed cyclization leading to furans 20 after elimination of H 2 O from intermediate 19 in the presence of very low catalyst loadings (Scheme ) . The alcohol moiety may already be present in the precursor of the gold­(I)-catalyzed transformation or may be generated in situ from epoxides by ring opening .…”

Unusual Nucleophilic Addition of Grignard Reagents in the Synthesis of 4-Amino-pyrimidines

“…Pyrimidines are also investigated for the treatment of the neurological disorders Beriberi and Korsakoff syndrome and as a recognition motif for binding in thiamine diphosphatedependent enzymes (compound 4, Figure 1). 6,7 Because of their versatile hydrogen-bonding interactions, these small fragments have been intensively investigated by medicinal chemists during the past decade. Their applications in GSK's antimalaria drug trimethoprim 5, 8 antibiotic bacimethrin 6, 9 and in the treatments of thiamine deficiency, 10−12 are well-documented (Figure 2).…”

“…Pyrimidines are also investigated for the treatment of the neurological disorders Beriberi and Korsakoff syndrome and as a recognition motif for binding in thiamine diphosphate-dependent enzymes (compound 4 , Figure ). , …”