Asymmetric Synthesis of N‐Fmoc‐(S)‐7‐aza‐tryptophan via Alkylation of Chiral Nucleophilic Glycine Equivalent

Abstract

Dedicated to Professor Ferenc Fülöp on the occasion of his 70th birthday.Ni(II)-complexes, derived from glycine Schiff bases with chiral tridentate ligands, have been used as powerful tools for the synthesis of structurally diverse tailor-made amino acids. In this manuscript, asymmetric alkylation reaction between chiral nucleophilic glycine derived Ni-complex and 3-(chloromethyl)-1H-pyrrolo[2,3-b]pyridine has been developed under convenient conditions, which affords the corresponding alkylated Nicomplex in 74 % yield and excellent diastereoselectivity (only one isomer). This reaction features convenient conditions and completely controlled diastereoselectivity, which provides a highly valuable approach for asymmetric synthesis of 7-azatryptophan.Amino acids (AAs) belong to the most ubiquitous class of naturally occurring compounds, [1] which have been used as an important type of structural units in the design of modern drugs due to several advantageous features, such as high structural diversity, wide scope of functional groups, good solubility in aqueous media, and few safety concerns. [2] Currently, a number of small-molecule, peptidomimetics, and peptide containing residues of tailor-made AAs or their derivatives serve as key structural features in many blockbuster drugs. [3] Among these natural and non-natural AAs, 7-azatryptophan occupies an important position, which has been widely used as biological fluorescent probes, [4] antiplasmodial compounds, [5] and inhibitors of checkpoint kinase 1. [6,7] Although there have been several reports on the synthesis of aza-tryptophanes, [8] the synthesis of 7-aza-tryptophan still remained less developed, in particular in the asymmetric mode. One of the first asymmetric methods was based on alkylation reaction between (1R,4R)-camphor imine and tert-butylglycinate, which proceeded with poor chemical yield (Scheme 1a). [9] Chemoenzymatic synthesis represents an alternative strategy for the preparation of optical pure 7-aza-tryptophan using aspergillus genus acylase, [10] L-amino acid oxidase [11] or tryptophan synthase from Salmonella typhimurium [12] as biocatalyst[a] Y.

New pharmaceuticals approved by FDA in 2020: Small‐molecule drugs derived from amino acids and related compounds

“…In this regard, we would like to stress the growing need in availability and affordability of various tactual types of AAs. Indeed, the interest in the development of synthetic approaches for the preparation of tailor‐made AAs in enantiomerically pure form is currently at an all‐time high 82–135 . Some impressive developments have been made in the area of dynamic kinetic resolution of unprotected AAs, 136–139 a methodology which is best suited for large‐scale production and can rival biocatalytic approaches in affordability and low‐cost structure.…”

Structural and functional analysis of hyper thermostable ancestral L-amino acid oxidase that can convert Trp derivatives to D-forms by chemo-enzymatic reaction

“…Given the physiological and chemical importance of D-AAs, it is crucial to develop methods for their large-scale synthesis to evaluate their functions 2 . Both chemical and enzymatic syntheses have been employed for this purpose 2,[11][12][13] , with this study focusing on the latter one. The reductive amination of keto acids into D-AAs is commonly adopted due to its capacity to generate D-AAs in large quantities with high enantio-purity 14 .…”