New methods for preparation of tailor-made fluorine-containing compounds are in extremely high demand in nearly every sector of chemical industry. The asymmetric construction of quaternary C–F stereogenic centers is the most synthetically challenging and, consequently, the least developed area of research. As a reflection of this apparent methodological deficit, pharmaceutical drugs featuring C–F stereogenic centers constitute less than 1% of all fluorine-containing medicines currently on the market or in clinical development. Here we provide a comprehensive review of current research activity in this area, including such general directions as asymmetric electrophilic fluorination via organocatalytic and transition-metal catalyzed reactions, asymmetric elaboration of fluorine-containing substrates via alkylations, Mannich, Michael, and aldol additions, cross-coupling reactions, and biocatalytic approaches.

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Modern Approaches for Asymmetric Construction of Carbon–Fluorine Quaternary Stereogenic Centers: Synthetic Challenges and Pharmaceutical Needs

Decarboxylative reactions with and without light – a comparison

Fluorination reactions of medicinal and biologically-active compounds will be discussed. Late stage fluorination strategies of medicinal targets have recently attracted considerable attention on account of the influence that a fluorine atom can impart to targets of medicinal importance, such as modulation of lipophilicity, electronegativity, basicity and bioavailability, the latter as a consequence of membrane permeability. Therefore, the recourse to late-stage fluorine substitution on compounds with already known and relevant biological activity can provide the pharmaceutical industry with new leads with improved medicinal properties. The fluorination strategies will take into account different fluorinating reagents, either of nucleophilic or electrophilic, and of radical nature. Diverse families of organic compounds such as (hetero)aromatic rings, and aliphatic substrates (sp(3), sp(2), and sp carbon atoms) will be studied in late-stage fluorination reaction strategies.

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Fluorination methods in drug discovery

Recent developments in catalytic asymmetric aldol reactions have been summarized. Enantioselective aldol reactions are important methods to synthesize β-hydroxy carbonyl compounds in optical pure form, and as such, numerous successful chiral catalysts were designed and applied for asymmetric aldol reactions. This review article is organized under the categories of: (1) catalytic enantioselective aldol reactions of preformed enolates, (2) catalytic enantioselective direct-type aldol reactions using chiral metal catalysts, (3) catalytic enantioselective direct-type aldol reactions using organocatalysts, (4) catalytic enantioselective aldol reactions in aqueous media. Examples of the aldol reactions that employ simple carbonyl compounds will be also the focus of this review.

Catalytic enantioselective aldol reactions

The chemistry of the carbonyl group is essential to modern organic synthesis. The preparation of substituted, enantioenriched 1,3- or 1,5-dicarbonyls is well developed, as their disconnection naturally follows from the intrinsic polarity of the carbonyl group. By contrast, a general enantioselective access to quaternary stereocenters in acyclic 1,4-dicarbonyl systems remains an unresolved problem, despite the tremendous importance of 2,3-substituted 1,4-dicarbonyl motifs in natural products and drug scaffolds. Here we present a broad enantioselective and stereodivergent strategy to access acyclic, polysubstituted 1,4-dicarbonyls via acid-catalyzed [3,3]-sulfonium rearrangement starting from vinyl sulfoxides and ynamides. The stereochemistry at sulfur governs the absolute sense of chiral induction, whereas the double bond geometry dictates the relative configuration of the final products.

Stereodivergent synthesis of 1,4-dicarbonyls by traceless charge–accelerated sulfonium rearrangement

Enantioselective aldol reactions with fluoroacetate would enable access to numerous fluorinated analogues of therapeutically important compounds but have been a long-standing unsolved challenge. Now, bioinspired fluoromalonic acid half thioesters (F-MAHTs) have been devised and allow for highly stereoselective reactions with aldehydes under mild organocatalytic conditions.

Enantioselective aldol reactions with masked fluoroacetates

α-Fluorinated β-amino thioesters were obtained in high yields and stereoselectivities by organocatalyzed addition reactions of α-fluorinated monothiomalonates (F-MTMs) to N-Cbz- and N-Boc-protected imines. The transformation requires catalyst loadings of only 1 mol % and proceeds under mild reaction conditions. The obtained addition products were readily used for coupling-reagent-free peptide synthesis in solution and on solid phase. The α-fluoro-β-(carb)amido moiety showed distinct conformational preferences, as determined by crystal structure and NMR spectroscopic analysis.

Stereoselective Organocatalyzed Synthesis of α-Fluorinated β-Amino Thioesters and Their Application in Peptide Synthesis

Stereoselective Synthesis of α-Fluoro-γ-nitro Thioesters under Organocatalytic Conditions

Enantioselective Aldol Reactions with Masked Fluoroacetates.

Monothiomalonates (MTMs) are surrogates of thioester enolates that allow for stereoselective C–C bond formations under mild conditions and thereby afford access to synthetically versatile thioester derivatives. Here we present a straightforward synthetic route to monothiomalonates (MTMs) that proceeds through nucleophilic ring-opening of Meldrum's acid derivatives followed by O-alkylation of the resulting malonic acid half thioesters (MAHTs) with alkyl triflates or acetimidates as electrophiles. The method affords MTMs in overall yields of 34–92 % and allows for variations of the oxo- and thioester moieties as well as the substituent at the Cα position.

This article is protected by copyright. All rights reserved.

Jakub Saadi

Papers

Enantioselective aldol reactions with masked fluoroacetates

Stereoselective Organocatalyzed Synthesis of α-Fluorinated β-Amino Thioesters and Their Application in Peptide Synthesis

Stereoselective Synthesis of α-Fluoro-γ-nitro Thioesters under Organocatalytic Conditions

Enantioselective Aldol Reactions with Masked Fluoroacetates.

Synthesis of Monothiomalonates – Versatile Thioester Enolate Equivalents for C–C Bond Formations