Reductive amination plays a paramount role in pharmaceutical and medicinal chemistry owing to its synthetic merits and the ubiquitous presence of amines among biologically active compounds. It is one of the key approaches to C-N bond construction due to its operational easiness and a wide toolbox of protocols. Recent studies show that at least a quarter of C-N bond-forming reactions in the pharmaceutical industry are performed via reductive amination. This Review concisely compiles information on 71 medical substances that are synthesized by reductive amination. Compounds are grouped according to the principle of action, which includes drugs affecting the central nervous system, drugs affecting the cardiovascular system, anticancer drugs, antibiotics, antiviral and antifungal medicines, drugs affecting the urinary system, drugs affecting the respiratory system, antidiabetic medications, drugs affecting the gastrointestinal tract, and drugs regulating metabolic processes. A general synthetic scheme is provided for each compound, and the description is focused on reductive amination steps. The green chemistry metric of reaction mass efficiency was calculated for all reactions.

Reductive Amination in the Synthesis of Pharmaceuticals.

Acyl transfer is at the heart of functional-group transfers utilized both in nature and in the chemical laboratory. Acylations are part of the natural assembly machinery for the generation of complex molecules and for energy transport in biological systems. The recognition of covalent acyl-enzyme intermediates led to both mechanistic studies as well as the development of biomimetic approaches. Consequently, chemists first used the tools of nature in the form of enzymes and naturally occurring alkaloids as catalysts, before eventually developing a large variety of synthetic small molecules for selective acyl transfer. In contrast to nature, chemists utilize acylation reactions as a practical way for stereoselection and functional-group protection. Indeed, the number of studies concerning acyl transfer has significantly increased over the last 15 years. This Review examines and highlights these recent developments with the focus as given in the title.

Organocatalytic enantioselective acyl transfer onto racemic as well as meso alcohols, amines, and thiols.

γ-Amino acids have attracted considerable attention as biologically active compounds in the central nervous system (CNS) of mammals. Over the last few years, significant interest in the stereoselective synthesis and practical application of linear and cyclic chiral γ-amino acids in the synthesis and design of α,β- and β,γ-hybrid peptides with definite secondary structures and design of nanotubes has been reported, thus demonstrating the theoretical interest and the practical importance of γ-amino acids. An overview of synthetic approaches to linear and cyclic chiral γ-amino acids and derivatives is presented. Data on the practical applications of γ-amino acids are also discussed.

Stereoselective synthesis of γ-amino acids

Enantioselective Michael Addition of Nitromethane to α,β-Enones Catalyzed by Chiral Quaternary Ammonium Salts. A Simple Synthesis of (R)-Baclofen

Aminocyclopentadienyl ruthenium complexes, which can be used as room-temperature racemization catalysts with lipases in the dynamic kinetic resolution (DKR) of secondary alcohols, were synthesized from cyclopenta-2,4-dienimines, Ru3(CO)12, and CHCl3:  [2,3,4,5-Ph4(η5-C4CNHR)]Ru(CO)2Cl (4:  R = i-Pr; 5:  R = n-Pr; 6:  R = t-Bu), [2,5-Me2-3,4-Ph2(η5-C4CNHR)]Ru(CO)2Cl (7:  R = i-Pr; 8:  R = Ph), and [2,3,4,5-Ph4(η5-C4CNHAr)]Ru(CO)2Cl (9:  Ar = p-NO2C6H4; 10:  Ar = p-ClC6H4; 11:  Ar = Ph; 12:  Ar = p-OMeC6H4; 13:  Ar = p-NMe2C6H4). The tests in the racemization of (S)-4-phenyl-2-butanol showed that 7 is the most active catalyst, although the difference decreased in the DKR. Complex 4 was used in the DKR of various alcohols; at room temperature, not only simple alcohols but also functionalized ones such as allylic alcohols, alkynyl alcohols, diols, hydroxyl esters, and chlorohydrins were successfully transformed to chiral acetates. In mechanistic studies for the catalytic racemization, ruthenium hydride 14 app...

Aminocyclopentadienyl Ruthenium Complexes as Racemization Catalysts for Dynamic Kinetic Resolution of Secondary Alcohols at Ambient Temperature

A three step synthesis of (R)-(−)-baclofen is described. The key step is the orthoester Claisen rearrangement of enantiopure allylic alcohol (S,E)-(−)- 1a , affording γ,δ-unsaturated ester (S,E)-(+)- 6 with high stereoselectivity. This latter derivative is converted into ( R )-(−)-baclofen through a high yield one-pot reaction.

Enantioselective synthesis of β-substituted butyric acid derivatives via orthoester Claisen rearrangement of enzymatically resolved allylic alcohols: application to the synthesis of (R)-(−)-baclofen

On a baker's yeast-mediated approach to verapamil's optically active intermediates

Enantioselective Synthesis of β‐Substituted Butyric Acid Derivatives via Orthoester Claisen Rearrangement of Enzymatically Resolved Allylic Alcohols: Application to the Synthesis of (R)‐(‐)‐Baclofen.

Nicola Caraccia

Papers

Enantioselective synthesis of β-substituted butyric acid derivatives via orthoester Claisen rearrangement of enzymatically resolved allylic alcohols: application to the synthesis of (R)-(−)-baclofen

On a baker's yeast-mediated approach to verapamil's optically active intermediates

Enantioselective Synthesis of β‐Substituted Butyric Acid Derivatives via Orthoester Claisen Rearrangement of Enzymatically Resolved Allylic Alcohols: Application to the Synthesis of (R)‐(‐)‐Baclofen.