Scientists of the Independent Junior Research Group around Jun.-Prof. Martin Weissenborn, together with colleagues from RWTH Aachen University and the University of New South Wales (Australia), have developed a new chemical synthesis for tryptamine precursors using a new catalyst. They recently published their findings in the renowned journal Angewandte Chemie.
Tryptamines are produced by plants, animals, fungi and microorganisms. For example, the amino acid tryptophan and the sleep hormone melatonin are derivatives of tryptamine. The basic chemical structure of these compounds consists of an indole ring with an attached ethylamine group (see figure). Many medications are based on this basic structure. The challenge of synthesizing tryptamines chemically or biocatalytically - that is, with the aid of enzymes - is to link additional atoms to a non-reactive carbon (C) hydrogen (H) bond in exactly the right position. Chemists call this "functionalization of the C-H bond", as useful moieties with the capability to react further are attached.
Previously, obtaining tryptamines as starting materials for pharmaceuticals required a four-step chemical synthesis. This, however, yielded low amounts of desired product (yield 41%). The RWTH Aachen chemists* were now able to synthesize tryptamine precursors via a simpler, two-step procedure with much higher yields (90%). For that, they reacted highly explosive diazoacetonitrile with indoles. In order to tame the hazardous starting material, they utilized a continuous flow microreactor. This device allowed for producing diazoacetonitrile in small quantities from precursors and immediately passing it into the subsequent reaction with indoles, where it was consumed again. In addition, the researchers applied another groundbreaking innovation by using an iron-porphyrin complex as a catalyst. While the usual noble metal catalysts are very expensive this compound containing iron, a abundant metal, proved to be much cheaper and very efficient.
The IPB team around Jun. Prof. Weissenborn tested a biocatalytic variant of the reaction. Utilizing a bacterial enzyme containing a similar iron-porphyrin complex as a natural cofactor, they could also achieve the conversion of the starting materials to the desired tryptamine precursors. In addition, they introduced mutations in the active site of the enzyme, which could increase the turnover rate. Thus, they demonstrated the biocatalytic feasibility of the new synthesis and realized an enzymatic C-H functionalization.
The Australian cooperation partners eventually contributed to the elucidation of the reaction mechanism. Their results indicated that intermediates with unpaired, reactive electrons, called radicals, drive the reaction.
The authors of the study are confident that the new synthetic method will find wide-ranging applications from synthetic and medicinal chemistry to agrochemistry.
*Note:
This article was edited on July 25, 2019. The addition "RWTH Aachen" was made to the phrase "The chemists were now able ..." in order to clearly highlight the contributions of the individual cooperation partners. We apologize for the previous misleading wording.
Original publication:
K. J. Hock, A. Knorrscheidt, R. Hommelsheim, J. Ho, M. J. Weissenborn, R. M. Koenigs
Tryptamine Synthesis by Iron Porphyrin Catalyzed C−H Functionalization of Indoles with Diazoacetonitrile
Angew. Chem. Int. Ed. 2019, 58, 3630.
https://doi.org/10.1002/anie.201813631