Concept: Asymmetric induction
The enantioselective allylation of ketones is a problem of fundamental importance in asymmetric reaction design, especially given that only a very small number of methods can generate tertiary carbinols. Despite the vast amount of attention that synthetic chemists have given to this problem, success has generally been limited to just a few simple ketone types. A method for the selective allylation of functionally complex ketones would greatly increase the utility of ketone allylation methods in the chemical synthesis of important targets. Here we describe the operationally simple, direct, regioselective and enantioselective allylation of β-diketones. The strong tendency of β-diketones to act as nucleophilic species was overcome by using their enol form to provide the necessary Brønsted-acid activation. This reaction significantly expands the pool of enantiomerically enriched and functionally complex tertiary carbinols that may be easily accessed. It also overturns more than a century of received wisdom regarding the reactivity of β-diketones.
The first example of Ir-catalyzed asymmetric substitution reaction with vinyl trifluoroborates is described. The direct reaction between branched, racemic allylic alcohols and potassium alkenyltrifluoroborates proceeded with high site selectivity and excellent enantioselectivity (up to 99%) mediated by an Ir-(P,olefin) complex. This method allows rapid access to various 1,4-dienes or trienes including the biologically active natural products (-)-nyasol and (-)-hinokiresinol.
We report the chiral diene ligated rhodium-catalyzed dynamic kinetic asymmetric transformation (DYKAT) of racemic secondary allylic trichloroacetimidates with a variety of N-methyl anilines, providing allylic N-methyl arylamines in high yields, regioselectivity, and enantiomeric excess. The rhodium-catalyzed DYKAT method addresses limitations previously associated with this particular class of aromatic nitrogen nucleophiles.
We present a general model for understanding the stereochemical course of intramolecular Michael reactions. We show that the addition of beta-ketoester enolates to alpha,beta-unsaturated esters and imides bearing adjacent stereocenters X and Y leads to high levels of asymmetric induction. Reinforcing and non-reinforcing (X-Y, syn, anti) stereochemical relationships are present. On the basis of synthetic, spectroscopic, and computational studies, we propose that the outcomes of these reactions may be rationalized by a dipole-minimized chair transition state model.
A stereoconvergent access to chiral carbocyclic building blocks is reported. 6-(3'-Hydroxy-4'-methylpent-4'-enyl)-3-methoxy cyclohex-2-enone () that consists of four stereoisomers, i.e., racemic ca. 1 : 1 diastereomers, is converted to enantiomerically pure carbocycles through a combination of regioselective catalytic asymmetric reduction and alkylative remote stereoinduction. The present stereoconvergent strategy has allowed the formal synthesis of bioactive (-)-dysidiolide.
A highly regio- and enantioselective cobalt-catalyzed sequential hydrosilylation/hydrogenation of alkynes was developed to afford chiral silanes. This one-pot method is operationally simple and atom economic. It makes use of relatively simple and readily available starting materials, namely alkynes, silanes, and hydrogen gas, to construct more valuable chiral silanes. Primary mechanistic studies demonstrated that highly regioselective hydrosilylation of alkynes with silanes occurred as a first step, and the subsequent cobalt-catalyzed asymmetric hydrogenation of the resulting vinylsilanes showed good enantioselectivity.
The steroidal neurotoxin (-)-batrachotoxin functions as a potent agonist of voltage-gated sodium ion channels (NaVs). Here we report concise asymmetric syntheses of the natural (-) and non-natural (+) antipodes of batrachotoxin, as well both enantiomers of a C-20 benzoate-modified derivative. Electrophysiological characterization of these molecules against NaV subtypes establishes the non-natural toxin enantiomer as a reversible antagonist of channel function, markedly different in activity from (-)-batrachotoxin. Protein mutagenesis experiments implicate a shared binding side for the enantiomers in the inner pore cavity of NaV These findings motivate and enable subsequent studies aimed at revealing how small molecules that target the channel inner pore modulate NaV dynamics.
The enzymatic β-C-H hydroxylation of the feedstock chemical isobutyric acid has enabled the asymmetric synthesis of a wide variety of polyketides. The analogous transition metal-catalyzed enantioselective β-C-H functionalization of isobutyric acid-derived substrates should provide a versatile method for constructing useful building blocks with enantioenriched α-chiral centers from this abundant C-4 skeleton. However, the desymmetrization of ubiquitous isopropyl moieties by organometallic catalysts has remained an unanswered challenge. Herein, we report the design of chiral mono-protected aminomethyl oxazoline ligands that enable desymmetrization of isopropyl groups via palladium insertion into the C(sp(3))-H bonds of one of the prochiral methyl groups. We detail the enantioselective β-arylation, -alkenylation, and -alkynylation of isobutyric acid/2-aminoisobutyric acid derivatives, which may serve as a platform for the construction of α-chiral centers.
The first general asymmetric synthesis of alfa,alfa-disubstituted allylic amines based on a palladium-catalyzed allylic amination has been developed. The protocol uses highly modular vinyl cyclic carbonates and unactivated aromatic amine nucleophiles as substrates. The catalytic process features minimal waste production, ample scope in reaction partners, high asymmetric induction up to 97% ee and operational simplicity.
Amines bearing γ-stereocenters are highly important structural motifs in many biologically active compounds. However, reported enantioselective syntheses of these molecules are indirect and often require multiple steps. Herein, we report a general asymmetric route for the one-pot synthesis of chiral γ-branched amines through the highly enantioselective isomerization of allylamines, followed by enamine exchange and subsequent chemoselective reduction. This protocol is suitable for establishing various tertiary stereocenters, including those containing dialkyl, diaryl, cyclic, trifluoromethyl, difluoromethyl, and silyl substituents, which allows for a rapid and modular synthesis of many chiral γ-branched amines. To demonstrate the synthetic utility, Terikalant and Tolterodine are synthesized using this method with high levels of enantioselectivity.