Published: 24 June 2024
Unnatural amino acids are key building blocks in medicinal chemistry. These motifs are frequently integrated into drug-like compounds, providing a source of chirality and dense functionality. Furthermore, the amine and acid functional group handles provide convenient vectors for elaboration. There are many examples of marketed drugs containing an amino acid group (scheme 1).
Despite their prevalence, the synthesis of unnatural amino acids remains a challenge. The classical Strecker synthesis of amino acids has been updated and improved over the years to include asymmetric and catalytic versions, however it still suffers from drawbacks such as the use of toxic cyanide reagents and incompatibility with certain functional groups. New and convenient methods for the synthesis of unnatural amino acids are therefore highly valuable to the medicinal chemistry community. In this blog, we highlight a new approach from the Baran group, along with other recent advances in unnatural amino acid synthesis.
Scheme 1. Marketed drugs containing an amino acid group.
Simple Synthesis of Unnatural Amino Acids via Ni/Ag-Electrocatalytic Cross-Coupling
Access to enantiopure unnatural amino acids containing bespoke heteroaromatic sidechains would typically involve a multi-step synthesis, including several protecting group manipulations and the use of organometallic reagents. Baran and co-workers have been able to circumvent this by leveraging the native functionality of inexpensive and commercially available glutamate and aspartate precursors (scheme 2).1
Scheme 2. General scheme for Baran’s synthesis of unnatural amino acids via electrocatalytic cross-coupling.
The authors were able to exploit the pendant carboxylic acid sidechain of glutamate and aspartate derivatives as latent radical precursors to enable a decarboxylative cross-coupling to take place under an Ag/Ni-electrocatalytic platform with a broad range of heteroaryl halides. To demonstrate the value of this methodology in a medicinal chemistry context towards the generation of a library of unnatural amino acids, the authors devised a parallel reaction set-up, making use of IKA’s Electrasyn E-hive module (figure 1). This allowed them to take a set of 4 redox-active esters and screen them against 20 arenes in a 24-well plate format using small quantities (0.03 mmol) of material, allowing for precious or late-stage products to be used with minimal concern. The results of the parallel screen were rapidly analysed using UPLC, providing a readout of the success of the reaction and an indication of its viability towards scale-up.
Figure 1. Parallel reaction platform set up for electrochemical reaction screening.
The reaction was carried out on a wide range of functionalised heteroarenes, including those that would be commonplace within a drug discovery programme: azaindoles, indazoles, pyrimidines and imidazopyridazines (scheme 3). Several useful functional group handles were also tolerated, including alcohols, amines and esters, and the reaction showed chemoselectivity for heteroaryl iodides over their more electron-rich counterparts. This allows for the use of feedstock multi-halogenated arenes that can be cross-coupled downstream using traditional Pd-catalysis.
Scheme 3. Example of the scope for the reaction.
In total, 27 examples were successfully scaled-up (0.20 mmol) and isolated in moderate to good yields with no loss in enantiopurity. A direct comparison between this methodology and common 2-electron syntheses of medicinally relevant unnatural amino acids showed that step-count could be drastically cut (e.g. 7 vs. 1) allowing for the synthesis of future analogues to be undertaken in a less labour-intensive manner.
The selling point of this methodology is the generality of conditions; no individual reactions were optimised beyond the original conditions and while they did not provide high yields of product in every case, they did provide enough material for use in a traditional drug discovery programme.
An Interrupted Polonovski Strategy for the Synthesis of Functionalised Amino Acids and Peptides
Recently Waser and co-workers from EPFL reported a novel method for the α-functionalization of protected hydroxylamine glycine derivatives, via an interrupted Polonovski reaction.2 This methodology allows for the creation of imine surrogates in situ, followed by addition of a nucleophile in a one-pot procedure, to afford complex amino acid derivatives under mild conditions in a racemic manner (scheme 4A).
The reaction can be carried out with a range of nucleophiles to provide the desired product in moderate to excellent yields. The scope of nucleophiles tolerated includes various common functional groups such as alcohols and thiols, facilitating the synthesis of N,O-acetals and complex thioacetals. A number of nitrogen and carbon nucleophiles were compatible with the reaction such as amines, N-heterocycles, enol ethers and several organometallic reagents. Additionally, complex nucleophiles can be employed successfully in the reaction as demonstrated by use of the nonsteroidal anti-inflammatory drug celecoxib as a nucleophile to afford compound 1 (scheme 4B).
The scope of this methodology was successfully extended to modify dipeptides at both N- and C-termini, demonstrating broad applicability and efficiency.
Scheme 4A. General representation for the synthesis of a-functionalised amino acids; 4B. Scope of the reaction.
Asymmetric Synthesis of α‑Amino Acid Esters, Thioesters, Amides, and Peptides
In this work, Prasad and co-workers highlight the synthesis of amino acid derivatives through the addition of lithio tris(methylthio)methane to various sulfinimines with an emphasis on achieving high diastereoselectivity. The group then explored the transformation of the resulting trithioformate products into more complex compounds like thioesters, esters, anilides, amides, and di- and tripeptides without epimerisation of the chiral centres (scheme 5A).3
The reaction is compatible with both aryl and aliphatic aldehydes as the sulfinimine precursor. This methodology stands out due to its remarkable diastereoselectivity (exceeding 99:1 in most cases), which is a significant advantage for the synthesis of amino acid derivatives. This approach not only enhances the synthetic toolbox for creating complex organic molecules, such as amino acids, peptides, and their derivatives, with high stereocontrol but also introduces practical pathways to diversify the functionalities of these molecules through further transformations like conversion to thioesters, esters, and amides (scheme 5B).
Scheme 5A. Representative example; 5B. Selected examples of compounds synthesised using this methodology.
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References:
About the authors:
Steven Bennett is a Scientist in the Chemistry department at BioAscent. Prior to joining BioAscent, he was a post-doctoral research associate within the group of Prof. Andrew L. Lawrence at the University of Edinburgh working on stereoretentive enantioconvergent reactions. Steven received his PhD in synthetic organic chemistry under the supervision of Prof. Varinder K. Aggarwal at the University of Bristol where he worked on the total synthesis of prostanoids and the development of strained bicyclo[1.1.0]butyl boronate complexes.
Mounir Al Masri is a Senior Scientist in the Medicinal Chemistry Department at BioAscent. With over 7 years of experience, he has worked in several pharmaceutical companies, including BioAscent, Charles River, and Prestwick. He earned his PhD in organic chemistry from Université de Haute Alsace, focusing on inhibitors of the M1 family of aminopeptidases for the treatment of malaria, spondyloarthritis, and cancer. Mounir also holds an engineering degree from École Européenne de Chimie, Polymères et Matériaux, and an MSc in molecular and supramolecular chemistry from Université de Strasbourg.
