Approaches to Obtaining Fluorinated α-Amino Acids

Abstract

Fluorine does not belong to the pool of chemical elements that nature uses to build organic matter. However, chemists have exploited the unique properties of fluorine and produced countless fluoro-organic compounds without which our everyday lives would be unimaginable. The incorporation of fluorine into amino acids established a completely new class of amino acids and their properties, and those of the biopolymers constructed from them are extremely interesting. Increasing interest in this class of amino acids caused the demand for robust and stereoselective synthetic protocols that enable straightforward access to these building blocks. Herein, we present a comprehensive account of the literature in this field going back to 1995. We place special emphasis on a particular fluorination strategy. The four main sections describe fluorinated versions of alkyl, cyclic, aromatic amino acids, and also nickel-complexes to access them. We progress by one carbon unit increments. Special cases of amino acids for which there is no natural counterpart are described at the end of each section. Synthetic access to each of the amino acids is summarized in form of a table at the end of this article with the aim to make the information easily accessible to the reader.

Indole‐N‐Carboxylic Acids and Indole‐N‐Carboxamides in Organic Synthesis

“…The Yu group found that isocyanides are also active in CÀ H activation reactions of indole-N-carboxamides (Scheme 27). [37] By treating indole-N-carboxamides or aza-indole-N-carboxamides 105 and tert-butyl isocyanide 106 with 5 mol % Pd 2 (dba) 3 at 60°C in methanol and air, a type of intriguing medicinally important imidazo[1,5-a]indole and pyrrolo[1,2-c]imidazole 107 could be constructed in good yields. Of note, when indole-Ncarboxamides were functionalized with various heteroaryl groups, corresponding products 110 bearing diverse heterocycles could be isolated efficiently.…”

“…They are easily found in the pages of commercial chemical supplier catalogs and widely used as versatile starting materials in various types of organic reactions. [3] Comparing with the common C-carboxylic acids, heteroatom-carboxylic acids (e. g. O-carboxylic acids and N-carboxylic acids) are relatively rarely studied, due to their common instability and hard preparation. [4] Indole-N-carboxylic acids are a type of intriguing N-carboxylic acids, which might serve as elegant reagents in the development of new indolesrelated reactions.…”

“…For example, indole 1 could be lithiated in nitrogen atom by the treatment of a slight access of n-butyllithium followed by carbonated with solid or gaseous CO 2 to give indole-N-carboxylic acid (2) in excellent yields (Scheme 1A). [5] However, when indole Grignard reagent was used, the indole-N-carboxylic acid (2) formed in only 27% yield, while indole-3-carboxylic acid (3) was isolated in a comparable yield (Scheme 1B). [6] In 2014, the Ikariya group disclosed an interesting work about carboxylation of indoles using a bifunctional Ru-catalyst for the preparation of indole-Ncarboxylic acids (Scheme 1C).…”

Fluoroalkylation of Diazo Compounds with Diverse Rfn Reagents

“…Fluoroalkylation has become one of the most important approaches to incorporate fluorinated motifs with interesting topographies and physicochemical features and to desirably modulate the attributes of the target molecules. [6] With a deeper understanding of how to take full advantage of the unique nature of fluorine by chemists, deployment of late-stage fluoroalkylation in the construction of sophisticated compounds has emerged in the last decade.…”

Highly Chemoselective gem‐Difluoropropargylation of Aliphatic Alcohols

“…Among the ethers, a-fluoroetherssuch as difluoromethylethers are important components because the introduction of fluorine atom(s) changes the chemical, physical, and biological properties of organic compounds. [1] For example, a-fluoroethersi mprovedt he lipophilicity andi nv ivo oxidative stabilityo fd rugs compared with alkyl ethers. [1a, 2] However,o nly al imited number of practical a-fluoroalkylations of aliphatic alcohols have been reported.…”