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2.1.4.2.1 Thiamine Diphosphate Dependent Decarboxylases

DOI: 10.1055/sos-SD-215-00069

Lewin, R.; Thompson, M. L.; Micklefield, J.Science of Synthesis: Biocatalysis in Organic Synthesis, (20152144.

Thiamine diphosphate (ThDP; 8, also known as thiamine pyrophosphate; TPP) is a cofactor in enzyme-catalyzed reactions that typically involve the formation and cleavage of C—C bonds adjacent to carbonyl groups.[‌52‌,‌53‌] Thiamine diphosphate dependent enzymes catalyze many important steps in metabolic pathways, including decarboxylation of α-oxo acids. For example, pyruvate decarboxylase catalyzes the decarboxylation of pyruvate (10, R1 = Me) to give acetaldehyde (14, R1 = Me) (Scheme 11). Here, the catalytically active thiamine diphosphate ylide (9), acts as a nucleophile attacking the ketone group of pyruvate[‌54‌,‌55‌] to give the C2 α-lactyl–thiamine diphosphate intermediate 11. The lactyl–thiamine diphosphate intermediate undergoes decarboxylation resulting in a C2 enamine/α-carbanion 12A/12B, which is protonated to give C2 α-hydroxyethylthiamine diphosphate 13, which breaks down to give acetaldehyde with regeneration of the thiamine diphosphate ylide 9. The thiamine diphosphate dependent enzyme benzoylformate decarboxylase catalyzes the decarboxylation of benzoylformate (10, R1 = Ph) to give benzaldehyde by the same mechanism.[‌56‌]

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M8 M8 Meeeeee ee (%) Meeeee Meeeee (%) Mee
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Me Me MeM >88 M e.e. [‌88‌]
8-eeeee Me MeM 88 M 88 [‌88‌]
8-eeeeeee Me MeM 88 M 88 [‌88‌]
8-eeeeeee Me MeM 88 M 88 [‌88‌]
Me Me MeM 88 M 88 [‌88‌]
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Me Me MeeM >88 M e.e. [‌88‌]
Me Me MeeM 88.8 M e.e. [‌88‌]
eMe Me MeeM 88 M e.e. [‌88‌]
eeeeeeeeeee Me MeeM 88 M e.e. [‌88‌]
Me Me MeM 88 M >88 [‌88‌]
Me Me MeM 88 M >88 [‌88‌]
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Me Me MeM 88 M >88 [‌88‌]
eMe eMe MeM 88 M 88 [‌88‌]

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(M)-8-Meeeeee-8-eeeeeeeeeeee-8-eee (88); Meeeeee Meeeeeeee Meeee Meeeeeeeeeeeee Meeeeeeeeeeee:[‌88‌]

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References