Thiamin a Vital Amin

From Rice Peel to Modern Organocatalysis

  • Fig. 1: Biomimetics: Development of modern organocatalysts from the rice plant to the carboranyl hybrid.Fig. 1: Biomimetics: Development of modern organocatalysts from the rice plant to the carboranyl hybrid.
  • Fig. 1: Biomimetics: Development of modern organocatalysts from the rice plant to the carboranyl hybrid.
  • Fig. 2: The thiamin based drugs Benfotiamin, Sulbutiamin and Chlomethiazol.
  • Fig. 3: Aryl mimetic replacement: aryl-residues of successful lead-compounds are replaced by carborane cluster.

Bionics are based on the assumption that the living nature develops optimized structures and processes within the framework of evolution from which mankind can learn [1]. That is why nature is gladly taken as source of inspiration when it comes to solving technical problems.
The imitation of biogenic models, also known as biomimetics, aside from development and improvement always also entails insight into just this living nature. Successful modification of a natural principle thus conversely allows conclusions on the processes in the living organism. Such a process is the interaction of thiamin dependent enzymes (ThDPs) and its co-factor, thiamin. Like clockwork gears this system mediates uncounted metabolic transformations.

Bionics from Rice Peel

Thiamin, probably better known as vitamin B1, was isolated in 1926 from rice peel and, being a vital amine, is eponymous for the heterogeneous substances group of vitamins. As a main key player in glucose metabolism, thiamins essential character predominantly manifests in organs with a high energy requirement: A lack of thiamin becomes apparent particularly in a disease called Beri-Beri. Malfunctions in nerve and muscle cells cause manifold symptoms and, untreated, Beri-Beri in early days was a death sentence. Recent research findings moreover indicate that the lack of thiamin might play an important role in Alzheimers disease [2].

In the living organism thiamin serves as co-factor. Aside from the substrate those co-factors are necessary for enzymes to do their work. The vitamin thereby, so to say, acts as the enzymes tool. Since the elucidation of its molecular structure in 1934 and total synthesis in 1936, thiamin also found its way into the “toolbox” of organic chemistry [3]: More than 70 years ago the catalytic activity of thiamin was discovered and within the fundamentals of its action − in the organism as well as in the test tube [4]. The co-factor thiamin was able to catalyze chemical transformations without the aid of the corresponding enzyme, only surrounded by solvent and a base.

Beginning with the dimerization of benzaldehyde to α-hydroxy ketones (benzoin-reaction), the complexity of possible reactions increased, and with it the demands on this biogenic catalyst.

Thus after successful imitation of the natural reaction behaviour the thiamin molecule was chemically modified to perfectly tailor parameters like solubility, acid-base-behaviour, stability and last but not least reactivity for the requirements of modern organocatalysis. The eponymous sulphur (Thi-amin: from greek theion ‚Sulphur‘; a sulphur containing amine) in the catalytically active central ring of the vitamin was replaced by nitrogen and in the periphery of the molecule a variety of different functionalities were introduced [5]. Insights into synthesis strategies and behaviour of these thiamin descendants gathered on the way in turn lead to the development of several new drugs (Chlometiazol Benfotiamin, Sulbutiamin, etc.) for the treatment of diseases like fatigue, depression, alcoholism and not least Beri-Beri.

Carbon and Boron

Being an organocatalyst the scaffold of thiamin and its countless analogues predominantly consists of carbon, the building material of living matter. Since the carbon based structure motifs have been extensively investigated in seventy years of research, it was decided to synthesize a completely new artificial vitamin B1: parts of said carbon scaffold were to be replaced by the neighbour in the periodic table of elements, boron [6]. In a yet comparably young research branch of inorganic chemistry, since the initial publications, the chemistry of carboranes is investigated. Carboranes, a portmanteau of carbon and borane, are compounds made up of carbon, boron and hydrogen [7]. Because of their electronic structure they preferably form highly symmetric clusters that, in the case of C2B10H12, are quite similar to their carbon analogous aryl derivatives concerning stability and size. With their three dimensional icosahedric shape these literally multi-facetted clusters allow for promising possibilities of modification.

The carboranes originate in the beginning of Cold War where they were evaluated as potential highly energetic propellant for rockets and aircrafts. Being top secret military research the results were made accessible to the world of civil science not before 1963. From this point on the rapid development of this research field ran its course and by now is found practically in all branches of modern chemistry. Most of all inorganic and bioinorganic chemistry spawned countless developments. A widely used strategy therein is arylmimetic replacement where the spacial chemical similarity to the benzene ring (Van-der-Waals-radius of ortho-carborane C2B10H12: 148 Å, for a rotating aryl ring: 102 Å) [8] is exploited to replace it with a carborane cluster. A prominent example for this strategy is Asborin, the biological active carborane analogue to the pain killer and anti-inflammatory acetylsalicylic acid, better known by its trade name Aspirin [9].

In contrast to vitamin B1 and its derivatives the carboranes do not have a direct biogenic precursor and thereby are strictly artificial, anthropogenic products.

Arylmimetics and biomimetics

Also with their boron containing catalyst the principle of arylmimetics was employed and assumed the successful design features of the well known modern thiamin-descendants albeit replaced the aryl substituent adjacent to the central triazolium ring by the artificial carborane. That way, with united expertise of the research fields of inorganic boron cluster chemistry and organocatalysis, a synthetic hybrid was born. This combination of biomimetics and arylmimetics represents a completely new class of thiamin based organocatalysts and it is yet hard to give viable prognoses on its reaction behaviour. That is why the new catalyst was tested in a reactivity screening with literature known applications: The reactions thereby constituted of transitions occurring in biological systems as well as reactions that completely originate from the organic chemical laboratory. At first the “juvenile catalyst” showed an astonishingly broad applicability in reactions that require, in parts, highly specialized catalyst systems with diametral sterical and electronic parameters. Albeit the performance, selectivity and yield of the established catalysts specifically tailor-made for the application was not always reached, the biological as well as the aryl based ancestor was already excelled by far in puncto versatility.


It was a long way from the rice peel to a modern hybrid organocatalyst but a glance at Mother Nature does pay: the biomimetic approach not only allowed for engineering achievements like the aircraft or the hook and loop fastener but also shows remarkable success on the molecular level. Thus in the time span between 1970 and today over 10000 articles on thiamin based organocatalysts were published in scientific journals. That particularly the interdisciplinary approach bears fruit was shown formidably by the two Leipzig based workgroups of Kirsten Zeitler and Evamarie Hey-Hawkins with their carborane-thiamin. Evamarie Hey-Hawkins thus concludes: „To solve current and future problems in a targeted way, innovative, interdisciplinary approaches are needed. Our publication shows how experts from organic and inorganic chemistry can jointly successfully develop new solutions in the promising field of catalysis research”.

C. Selg1

1 University of Leipzig, Fakultät für Chemie und Mineralogie, Institut für Organische Chemie, Arbeitskreis Prof. Dr. Kirsten Zeitler, Leipzig, Deutschland

M.Sc. Christoph Selg
University of Leipzig
Institut für Organische Chemie
Leipzig, Germany



[1]   E. Claes-May, S. Gorb, A. Kusserow, GIT Labor-Fachzeitschrift 12, 16–20 (2016).

[2]   a) G. E. Gibson, J. A. Hirsch, R. T. Cirio, B. D. Jordan, P. Fonzetti, J. Elder Molecular and Cellular   Neuroscience 55, 17–25 (2013), DOI:10.1016/j.mcn.2012.09.001; b) Y. Yu, C. Zhong et al. EBioMedicine 3, 155–162 (2016),DOI:10.1016/j.ebiom.2015.11.039; c) G. E. Gibson, J. A. Hirsch, P. Fonzetti, B. D. Jordan, R. T. Cirio, J. Elder Ann. N.Y. Acad. Sci. 1367, 21–30 (2016), DOI:10.1111/nyas.13031.

[3]   a) R. Williams, J. Am.Chem. Soc. 57, 229 (1935), b) R. Williams et al. J. Am. Chem. Soc. 57, 536 und 1093 (1935); c) Williams, R. R. Industrial & Engineering Chemistry 29, 980–984 (1937); d) Andersag, H., K. Westphal, Ber. deutsch. chem. Gesellsch.[B] 70, 2035–2054 (1937).

[4]   a) T. Ukai, R. Tanaka, T. A. Dokawa, J. Pharm. Soc. Jpn. 63, 296–304 (1943); Chem. Abstr. 45, 5148 (1951); b) R. Breslow, J. Am. Chem. Soc. 80, 3719–3726 (1958).

[5]   a) K. Zeitler, Angew. Chem. Int. Ed. 44, 7506–7510 (2005), DOI:10.1002/anie.200502617; b) D. M. Flanigan, F. Romanov-Michailidis, N. A. White, T. Rovis, Chem. Rev. 115, 9307–9387 (2015), DOI:10.1021/acs.chemrev.5b00060.

[6]   C. Selg, W. Neumann, P. Lönnecke, E. Hey-Hawkins, K. Zeitler, Chem. Eur. J. (2017), DOI:10.1002/chem.201700209; DOI:10.1002/chem.201701037

[7]   R. N. Grimes in Carboranes, Academic Press, New York, 2nd edition, S. 1–3 (2011).

[8]   M. Scholz, E. Hey-Hawkins, Chem. Rev. 111, 7035–7062 (2011), DOI:10.1021/cr200038x. [9]   M. Scholz, K. Bensdorf, R. Gust, E. Hey-Hawkins, ChemMedChem 4, 746–748 (2009), DOI:10.1002/cmdc.200900072.


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