Asymmetric Α-fluorination Research Articles

Direct syntheses of stereoisomers of 3-fluoro GABA and β-fluoroamine analogues of the calcium receptor (CaR) agonists, cinacalcet, tecalcet, fendiline and NPS R-467

Synthetic routes following a sequential MacMillan organocatalytic asymmetric α-fluorination protocol for aldehydes and then reductive amination, have allowed ready access to bioactive β-fluoroamines. The approach is demonstrated with a short synthesis of (S)-3-fluoro-γ-aminobutyric acid (3F-GABA) and was extended to β-fluoroamine stereoisomers of cinacalcet, tecalcet, fendiline and NPS R-467, all allosteric modulators of the calcium receptor (CaR). Stereoisomers of the fluorinated calcimimetic analogues were then assayed in a CaR receptor assay and a comparison of β-fluoroamine matched pair stereoisomers revealed a binding mode preference to the receptor as deduced from conformations which will be favoured as a consequence of the electrostatic gauche effect.

Asymmetric α-Fluorination of α-Branched Enals

Asymmetric α-Fluorination of α-Branched Enals

Cinchona-Based Primary Amine Catalyzed a Proximal Functionalization of Dienamines: Asymmetric α-Fluorination of α-Branched Enals

Fluorination of dienamines generated by α-branched enals and 6′-hydroxy-9-amino-9-deoxy-epi-quinidine (30 mol %) with NSFI show excellent α-regioselectivity to construct allylic fluorides containing a highly stereocontrolled quaternary fluorinated carbon (E/Z ≥ 20/1 and up to 93% enantiometric excess (ee)). By DFT calculation, the quinuclidine moiety of the catalyst was shown to function as a coordinating group to promote a reaction at the proximal α-position, and the nonclassical CH hydrogen bond plays an important role in the high enantioselectivity.

Reagent-controlled enantioselectivity switch for the asymmetric fluorination of β-ketocarbonyls by chiral primary amine catalysis.

A reagent-controlled enantioselectivity switch was uncovered in the asymmetric α-fluorination of β-ketocarbonyls by a chiral primary amine catalyst. By a simple swap of fluorination reagents, both enantiomers of the quaternary fluorination adducts could be obtained with good yields and high enantioselectivity. Mechanistic studies disclosed dual H-bonding and electrostatic stereocontrolling modes for the catalysis.

Stereoselective α-Fluorination of N-Acyloxazolidinones at Room Temperature within 1 h

A direct α-fluorination of N-acyloxazolidinones based on the unique reactivity of group IVa metal enolates has been developed. The reaction is an experimentally simple, low-cost, quick, and energy-efficient alternative for asymmetric α-fluorination of N-acyloxazolidinones. Preliminary studies have shown compatibility with alkyl, alkenyl, and alkynyl, aromatic, and several heteroaromatic substituents. High diastereoselectivities have been achieved with most substrates tested, and the reaction is typically complete within 1 h at ambient temperature.

Syntheses and Applications of (Thio)Urea-Containing Chiral Quaternary Ammonium Salt Catalysts.

We herein report our efforts to obtain a new class of systematically modified bifunctional (thio)urea-containing quaternary ammonium salts based on easily obtainable chiral backbones. Among the different classes of catalysts that were successfully synthesized, those based on trans-1,2-cyclohexane diamine were found to be the most powerful for the asymmetric α-fluorination of β-keto esters. Selectivities up to 93:7 could be obtained by using only 2 mol-% of the optimized catalyst. The importance of the bifunctional nature of these catalysts was demonstrated by control experiments using simplified monofunctional catalyst analogues, which gave almost racemic product only.

ChemInform Abstract: Substrate Range of the Titanium TADDOLate Catalyzed Asymmetric Fluorination of Activated Carbonyl Compounds

Abstract59 examples

Substrate Range of the Titanium TADDOLate Catalyzed Asymmetric Fluorination of Activated Carbonyl Compounds

AbstractThe substrate range of the [TiCl2(TADDOLate)] (TADDOL=α,α,α′,α′‐tetraaryl‐1,3‐dioxolane‐4,5‐dimethanol)‐catalyzed asymmetric α‐fluorination of activated β‐carbonyl compounds has been investigated. Optimal conditions for catalysis are characterized by using 5 mol‐% of TiCl2(naphthalen‐1‐yl)‐TADDOLate) as catalyst in a saturated (0.14 mol/l) MeCN solution of F‐TEDA (1‐(chloromethyl)‐4‐fluoro‐1,4‐diazoniabicyclo[2.2.2]octane bis‐[tetrafluoroborate]) at room temperature. A series of α‐methylated β‐keto esters (3‐oxobutanoates, 3‐oxopentanoates) with bulky benzyl ester groups (60–90% ee) or phenyl ester (67–88% ee) have been fluorinated readily, whereas α‐acyl lactones were also readily fluorinated, but gave lower inductions (13–46% ee). Double stereochemical differentiation in β‐keto esters with chiral ester groups raised the stereoselectivity to a diastereomeric ratio (dr) of up to 96.5 : 3.5. For the first time, β‐keto S‐thioesters were asymmetrically fluorinated (62–91.5% ee) and chlorinated (83% ee). Lower inductions were observed in fluorinations of 1,3‐diketones (up to 40% ee) and β‐keto amides (up to 59% ee). General strategies for preparing activated β‐carbonyl compounds as important model substrates for asymmetric catalytic α‐functionalizations are presented (>60 examples).

SPANamine derivatives in the catalytic asymmetric α-fluorination of β-keto esters

The use of C 2-symmetric enantiopure nitrogen ligands in the asymmetric catalytic α-fluorination of β-ketoesters is described. SPANamine 1 in the presence of nickel salts gives up to 63% ee in the fluorination of tert-butyl 2-oxocyclopentanecarboxylate with N-fluorosuccinimide (NFSI). The same enantioselectivity is obtained when SPANamine 1 is used as an organocatalyst, although the reaction is much slower.

From bifunctional to trifunctional (tricomponent nucleophile-transition metal-lewis acid) catalysis: the catalytic, enantioselective α-fluorination of acid chlorides.

We report in full detail our studies on the catalytic, asymmetric α-fluorination of acid chlorides, a practical method that produces an array of α-fluorocarboxylic acid derivatives in which improved yield and virtually complete enantioselectivity are controlled through electrophilic fluorination of a ketene enolate intermediate. We discovered, for the first time, that a third catalyst, a Lewis acidic lithium salt, could be introduced into a dually activated system to amplify yields of aliphatic products, primarily through activation of the fluorinating agent. Through our mechanistic studies (based on kinetic data, isotopic labeling, spectroscopic measurements, and theoretical calculations) we were able to utilize our understanding of this "trifunctional" reaction to optimize the conditions and obtain new products in good yield and excellent enantioselectivity.

Enantioselective organocatalytic α-fluorination of cyclic ketones.

The first highly enantioselective α-fluorination of ketones using organocatalysis has been accomplished. The long-standing problem of enantioselective ketone α-fluorination via enamine activation has been overcome via high-throughput evaluation of a new library of amine catalysts. The optimal system, a primary amine functionalized Cinchona alkaloid, allows the direct and asymmetric α-fluorination of a variety of carbo- and heterocyclic substrates. Furthermore, this protocol also provides diastereo-, regio-, and chemoselective catalyst control in fluorinations involving complex carbonyl systems.

Enantioselective α-Fluorination and Chlorination of β-Ketoesters by Cobalt Catalyst

Abstract We demonstrated the cobalt-catalyzed asymmetric α-fluorination and α-chlorination of β-ketoesters. Both reactions were achieved using a catalytic amount of Co(acac)2 with (R,R)-Jacobsen’s salen ligand; α-fluorinated or α-chlorinated products were thus obtained with a good enentioselectivity.

Catalytic, Asymmetric α-Fluorination of Acid Chlorides: Dual Metal−Ketene Enolate Activation

In this Communication, we disclose a catalytic, highly enantioselective (up to >99% ee) alpha-fluorination of acid chlorides to produce a variety of optically active carboxylic acid derivatives from readily accessible and commercially available starting materials. The reaction depends on dually activated ketene enolates generated from two discrete catalysts--a chiral nucleophile and an achiral transition metal complex working in tandem. The active, putative alpha-fluorobis(sulfonimide) intermediates readily transacylate in situ under mild conditions upon addition of a wide variety of nucleophiles, including complex natural products. As a consequence, the power of this method is witnessed by the broad range of alpha-fluorinated products that can be accessed efficiently depending on the work up conditions.

Synthesis of Axially Chiral Cyclic Amine-Substituted 2-(Oxazolinyl)pyridine Ligands for Catalytic Asymmetric Fluorination of β-Keto Esters

Novel optically active N,N,N-tridentate ligands, which possess both binaphthyl axial chirality and carbon-centered chirality, were prepared and successfully used in the catalytic asymmetric α-fluorination of β-keto esters giving ee values up to 94%.

Direct Asymmetric α‐Fluorination of Aldehydes.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Direct Asymmetric α‐Fluorination of Aldehydes

Direct Asymmetric α‐Fluorination of Aldehydes

Enantioselective Formation of Stereogenic Carbon–Fluorine Centers by a Simple Catalytic Method

An easy protocol has been developed for the formation of stereogenic carbon–fluorine centers by the organocatalytic asymmetric α-fluorination of aldehydes 1. The 2-fluoroaldehydes 4 are formed with 2 as the fluorinating agent and only 1 mol % of a sterically demanding silylated prolinol 3 as catalyst. The 2-fluoroaldehydes are subsequently reduced to the corresponding alcohols 5 without loss of enantiomeric excess.