The key objectives of medicinal chemistry are to efficiently design and synthesize bioactive compounds that have the potential to become safe and efficacious drugs. Most medicinal chemistry programmes rely on screening compound collections populated by a range of molecules derived from a set of known and robust chemistry reactions. Analysis of the role of synthetic organic chemistry in subsequent hit and lead optimization efforts suggests that only a few reactions dominate. Thus, the uptake of new synthetic methodologies in drug discovery is limited. Starting from the known limitations of reaction parameters, synthesis design tools, synthetic strategies and innovative chemistries, here we highlight opportunities for the expansion of the medicinal chemists' synthetic toolbox. More intense crosstalk between synthetic and medicinal chemists in industry and academia should enable enhanced impact of new methodologies in future drug discovery.

Expanding the medicinal chemistry synthetic toolbox

Amides are unquestionably one of the most important functional groups in organic chemistry because of their presence in numerous interesting molecules such as peptides, pharmaceutical agents, naturally occurring molecules, proteins and alkaloids, among others. This synopsis surveys the diverse recent approaches to amide synthesis from nonactivated carboxylic acids and derivatives as well as noncarboxylic compounds, highlighting the most innovative methodologies and those that are more eco-friendly compared to traditional methods while focusing on recent developments during the past two years.

Recent Developments in Amide Synthesis Using Nonactivated Starting Materials.

Protein engineering has as its goals the design and construction of new peptides and proteins with novel binding and catalytic properties. In one approach to protein engineering, new active sites have been introduced into naturally occurring proteins either by site-directed mutagenesis or by chemical modification. Providing that important changes in the tertiary structures do not result from such alterations, at least a portion of the binding site of the original protein should be available for the formation of complexes between the altered enzyme and its substrates. Many examples of active-site mutations have been described, including the generation by us of a cysteine mutant of alkaline phosphatase. A fundamental limitation of the site-directed mutagenesis methodology is that replacements of residues are restricted to the twenty naturally occurring amino acids. The alternative, chemical modification, is difficult to carry out for the specific replacement of one amino acid by another. However, we have shown that through such modification coenzyme analogues can be introduced covalently into appropriate positions in proteins, allowing us to produce semisynthetic enzymes with catalytic activities radically altered from those of their precursor proteins. In another approach to protein engineering efforts have focused on the construction of systems where, as a first approximation, folding can be neglected and the preparation of secondary structural units is the target. Examples of the successful design of biologically active peptides and proteins along such lines, taken from our own work, include molecules mimicking apolipoproteins, toxins, and many hormones. In recent studies we have progressed to the stage where we are starting to combine the two general approaches to protein engineering we have described and are able to construct small enzymes like ribonuclease T1 and its structural analogues.

Catalytic Activity of Enzymes Altered at Their Active Sites

We report here a mechanistically distinct approach to achieve Suzuki–Miyaura-type cross-couplings between alkyl iodides and aryl organoborons. This process requires a copper catalyst but, in contrast with previous approaches based on palladium and nickel systems, does not utilizes the metal for the activation of the alkyl electrophile. Instead, this strategy exploits the halogen-atom-transfer ability of α-aminoalkyl radicals to convert secondary alkyl iodides into the corresponding alkyl radicals that then are coupled with aryl, vinyl, alkynyl, benzyl, and allyl boronate species. These novel coupling reactions feature a simple setup and conditions (1 h at room temperature) and facilitate access to privileged motifs targeted by the pharmaceutical sector.

https://pubs.acs.org/doi/pdf/10.1021/jacs.1c12649

Merging Halogen-Atom Transfer (XAT) and Copper Catalysis for the Modular Suzuki–Miyaura-Type Cross-Coupling of Alkyl Iodides and Organoborons

This study reports the first example of a heterogeneous catalytic system for the direct amidation of various esters with amines. Of 25 types of catalyst, Nb2O5 shows the highest activity in the amidation of methyl benzoate with aniline. Nb2O5 gives high yields in the amidation of various esters and amines under solvent‐free conditions, is reusable, and shows higher turnover numbers than previously reported homogeneous catalysts such as La(OTf)3. IR spectroscopic studies of ethyl acetate adsorbed on the catalysts show a strong acid–base interaction between the Nb5+ Lewis acid site and carbonyl oxygen, which can result in high reactivity of the ester with a nucleophile (amine) and, thus, high activity of Nb2O5. Kinetic results show that the activity of Nb2O5 does not markedly decrease with increasing aniline concentration, in contrast to reference catalysts TiO2 and La(OTf)3. The relatively low negative impact of basic molecules on the Lewis acid catalysis of Nb2O5 also enables its high activity.

A Heterogeneous Niobium(V) Oxide Catalyst for the Direct Amidation of Esters

A catalytic protocol for the base-mediated amidation of unactivated esters with amino alcohol derivatives is reported. Investigations into mechanistic aspects of the process indicate that the reaction involves an initial transesterification, followed by an intramolecular rearrangement. The reaction is highly general in nature and can be extended to include the synthesis of oxazolidinone systems through use of dimethyl carbonate.

/pdf/amidation-of-esters-with-amino-alcohols-using-organobase-2i5dbqc9vy.pdf

Amidation of Esters with Amino Alcohols Using Organobase Catalysis

BEMP is an efficient catalyst for reactions of amino alcohols with dimethyl carbonate and a variety of methyl esters.

Amidation of Esters with Amino Alcohols Using Organobase Catalysis.

Reaction of a six-membered cyclic sulfonate ester, beta-(2-hydroxy-3,5-dinitro-phenyl)ethane sulfonic acid sultone with the active site of papain

Die reversible nucleophile rk. von imidazol mit beta-(2-hydroxy-3,5-dinitro-phenyl)-aethansulfonsaeuresulton

Practical synthesis of pharmaceutically relevant molecules enriched in sp3 character

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