Practical Synthesis of Fluorine-Containing α- and β-Amino Acids: Recipes from Kiev, Ukraine

Abstract

Naturally occurring compounds containing a C-F bond are extremely rare; only a handful of fluorine-containing carboxylic acids have been described so far. By contrast, man-made fluorine-containing derivatives of all major classes of biologically important compounds are extremely promising medicinal targets used in the elucidation of biochemical, metabolic transformations and the development of new pharmaceuticals. Among the fluorine-containing derivatives of natural products, fluorinated analogs of amino acids are of particular interest and medicinal potential. This article presents a concise review of various synthetic methods, developed by the Kiev's school of bioorganic chemistry, for the preparation of fluorine-containing analogs of α- and β-amino acids, α-hydroxy acids, amines, as well as their phosphorus and sulfur-derived compounds, in enantiomerically pure form. One of the major methodological goals of the study was practicality, which is understood by us as stereochemical generality, operational convenience and synthetic affordance for each reaction step and isolation of the target products. The synthetic methods developed by our group can be roughly divided in two general categories: fluorine-adaptation of known synthetic approaches and discovery of new reactions. The former approach is most prominently represented by asymmetric homologation of nucleophilic glycine equivalents using fluorinated substrates via alkyl halide alkylations, aldol and Michael addition reactions. A plethora of discovered unexpected reaction outcomes, in particular stereochemical, are emphasized in this review and the particular role of fluorine, in altering the 'normal' reaction result, is explained. The latter direction is notably represented by the novel 1,3-proton shift reaction, a biomimetic reductive amination of fluorinated carbonyl compounds to the corresponding amines and amino acids, as well as the development of α-fluoroalkyl epoxides as true fluorinated synthons for generalized asymmetric synthesis of various biologically relevant compounds. Despite the highly anticipated potential of fluorine-containing amino compounds, their medicinal chemistry still remains underexplored. The major obstacle, in our opinion, is that these selectively fluorinated compounds are generally unavailable to the medicinal chemists for comprehensive, systematic study. We hope this review of synthetic methods will highlight and bring attention to particular types of fluorinated amino acids and related compounds readily available on a laboratory scale using methods developed by our group.

Internal chirality descriptors iR and iS and ire and isi. A proposed notation to extend the usefulness of the R/S system by retaining the sense of stereochemistry in cases of ligand ranking changes

“…For instance, the authors were forced [13][14][15][16][17][18] to use the archaic ᴅ/ʟ system to avoid confusion when describing the haloalanines thus rendering it impractical to maintain the use of only one system. Moreover, the number of such cases has grown exponentially due to the efforts of synthetic chemists in producing a large number [9][10][11][12]19,20 of tailor-made α-amino acids 21 whereby fluorine-containing amino acids [22][23][24][25] in particular have been utilized by the pharmaceutical industry, 26,27 in medical research, and for other applications. With new synthetic compounds or compounds isolated from natural sources, the perception of the wrong stereochemistry is easily misconstrued by readers due to the changing R/S descriptors without necessary explanation by the author(s) or due care taken by the readers.…”

Self-disproportionation of enantiomers (SDE) of chiral sulfur-containing compounds via achiral chromatography

“…First of all they are recognized as valuable and efficient reagents in synthetic chemistry, particularly for asymmetric synthesis due to high asymmetric induction exerted by a sulfinyl fragment, and its configurational stability. 69,71,[74][75][76] Several review articles are devoted to this topic. [77][78][79][80][81][82][83][84] Moreover, sulfoxides are present in many natural products and they play an important role in biology.…”

Facile synthesis of hybrid sulfonophosphinodipeptides composing of taurines and 1-aminoalkylphosphinic acids

“…Recently, some sulfino amino acid derivatives, considered as mimetics of sulfonopeptides, have been synthesized (Kukhar et al 2009;Sorochinsky and Soloshonok 2010).…”