Chemical Tagging of Bioactive Amides by Cooperative Catalysis: Applications in the Syntheses of Drug Conjugates.

We disclose a practical catalytic method for arming bioactive amide-based natural products and other small-molecule drugs with various functional handles for the synthesis of drug conjugates. We demonstrate that a set of readily available Sc-based Lewis acids and N-based Brønsted bases can function cooperatively to deprotonate amide N-H bonds in polyfunctional drug molecules. An aza-Michael reaction between the resulting amidate and α,ß-unsaturated compounds produces an array of drug analogues that are equipped with an alkyne, azide, maleimide, tetrazine, or diazirine moiety under redox and pH-neutral conditions. The utility of this chemical tagging strategy is showcased through the production of drug conjugates by the click reaction between the alkyne-tagged drug derivatives and an azide-containing green fluorescent protein, nanobody, or antibody.

Enantioselective Organocopper-Catalyzed Hetero Diels-Alder Reaction through in Situ Oxidation of Ethers into Enol Ethers.

We disclose a catalytic method for the enantio- and diastereoselective union of alkyl ethers and heterodienes. We demonstrate that a chiral Cu-BOX complex catalyzes the efficient oxidation of ethers into enol ethers in the presence of trityl acetate. Then, the organocopper promotes stereoselective hetero Diels-Alder reaction between the in situ generated enol ethers and ß,γ-unsaturated ketoesters, allowing for rapid access to an array of dihydropyran derivatives possessing three vicinal stereogenic centers.

Enantioselective Synthesis of N-Alkylamines through ß-Amino C-H Functionalization Promoted by Cooperative Actions of B(C6F5)3 and a Chiral Lewis Acid Co-Catalyst.

We disclose a catalytic method for ß-C(sp3)-H functionalization of N-alkylamines for the synthesis of enantiomerically enriched ß-substituted amines, entities prevalent in pharmaceutical compounds and used to generate different families of chiral catalysts. We demonstrate that a catalyst system comprising of seemingly competitive Lewis acids, B(C6F5)3, and a chiral Mg- or Sc-based complex, promotes the highly enantioselective union of N-alkylamines and α,ß-unsaturated compounds. An array of δ-amino carbonyl compounds was synthesized under redox-neutral conditions by enantioselective reaction of a N-alkylamine-derived enamine and an electrophile activated by the chiral Lewis acid co-catalyst. The utility of the approach is highlighted by late-stage ß-C-H functionalization of bioactive amines. Investigations in regard to the mechanistic nuances of the catalytic processes are described.

Sequential Conia-ene-type cyclization and Negishi coupling by cooperative functions of B(C6F5)3, ZnI2, Pd(PPh3)4 and an amine.

We disclose a method for sequential Conia-ene-type cyclization/Negishi coupling for the union of alkynyl ketones and aryl iodides. This process is promoted through cooperative actions of Lewis acidic B(C6F5)3, ZnI2, Pd-based complex, and a Brønsted basic amine. The three Lewis acid catalysts with potential overlapping functions play their independent roles as activators of carbonyl group, alkyne moiety, and alkenyl zinc intermediate, respectively. A variety of 1,2,3-substituted cyclopentenes can be synthesized with high efficiency.

Direct Conversion of N-Alkylamines to N-Propargylamines through C-H Activation Promoted by Lewis Acid/Organocopper Catalysis: Application to Late-Stage Functionalization of Bioactive Molecules.

An efficient catalytic method to convert an α-C-H bond of N-alkylamines into an α-C-alkynyl bond was developed. In the past, such transformations were carried out under oxidative conditions, and the enantioselective variants were confined to tetrahydroisoquinoline derivatives. Here, we disclose a method for the union of N-alkylamines and trimethylsilyl alkynes, without the presence of an external oxidant and promoted through cooperative actions of two Lewis acids, B(C6F5)3 and a Cu-based complex. A variety of propargylamines can be synthesized in high diastereo- and enantioselectivity. The utility of the approach is demonstrated by the late-stage site-selective modification of bioactive amines. Kinetic investigations that shed light on various mechanistic nuances of the catalytic process are presented.

B(C6F5)3-Catalyzed α-Deuteration of Bioactive Carbonyl Compounds with D2O.

An efficient deuteration process of α-C-H bonds in various carbonyl-based pharmaceutical compounds has been developed. Catalytic reactions are initiated by the action of Lewis acidic B(C6F5)3 and D2O, converting a drug molecule into the corresponding boron-enolate. Ensuing deuteration of the enolate by in situ-generated D2O+-H then results in the formation of α-deuterated bioactive carbonyl compounds with up to >98% deuterium incorporation.

Catalytic Deuterium Incorporation within Metabolically Stable ß-Amino C-H Bonds of Drug Molecules.

An efficient deuteration process of ß-amino C-H bonds in various N-alkylamine-based pharmaceutical compounds has been developed. Catalytic reactions begin with the action of Lewis acidic B(C6F5)3 and Brønsted basic N-alkylamine, converting a drug molecule into the corresponding enamine. The acid/base catalysts also promote the dedeuteration of acetone-d6 to afford a deuterated ammonium ion. Ensuing deuteration of the enamine then leads to the formation of ß-deuterated bioactive amines with up to 99% deuterium incorporation.

Enantioselective Synthesis of α-Allyl Amino Esters via Hydrogen-Bond-Donor Catalysis.

We report a chiral-squaramide-catalyzed enantio- and diastereoselective synthesis of α-allyl amino esters. The optimized protocol provides access to N-carbamoyl-protected amino esters via nucleophilic allylation of readily accessible α-chloro glycinates. A variety of useful α-allyl amino esters were prepared, including crotylated products bearing vicinal stereocenters that are inaccessible through enolate alkylation, with high enantioselectivity (up to 97% ee) and diastereoselectivity (>10:1). The reactions display first-order kinetic dependence on both the α-chloro glycinate and the nucleophile, consistent with rate-limiting C-C bond formation. Computational analysis of the uncatalyzed reaction predicts an energetically inaccessible iminium intermediate, and a lower energy concerted SN2 mechanism.

Enantioselective Conia-Ene-Type Cyclizations of Alkynyl Ketones through Cooperative Action of B(C6F5)3, N-Alkylamine and a Zn-Based Catalyst.

An efficient and highly enantioselective Conia-ene-type process has been developed. Reactions are catalyzed by a combination of B(C6F5)3, an N-alkylamine and a BOX-ZnI2 complex. Specifically, through cooperative action of B(C6F5)3 and amine, ketones with poorly acidic α-C-H bonds can be converted in situ to the corresponding enolates. Subsequent enantioselective cyclization involving a BOX-ZnI2-activated alkyne leads to the formation of various cyclopentenes in up to 99% yield and 99:1 er.

B(C6F5)3-Catalyzed C-H Alkylation of N-Alkylamines Using Silicon Enolates without External Oxidant.

An efficient method for the coupling of N-alkylamines with silicon enolates to generate ß-amino carbonyl compounds is disclosed. These reactions proceed by activation of α-amino C-H bonds by B(C6F5)3, which likely generates a "frustrated" acid/base complex in the presence of large N-alkylamines. The transformation requires no external oxidant and releases hydrosilane as a byproduct. The utility of this method is demonstrated in the late-stage functionalization of bioactive molecules such as citalopram, atomoxetine, and fluoxetine.

C-H Functionalization of Amines via Alkene-Derived Nucleophiles through Cooperative Action of Chiral and Achiral Lewis Acid Catalysts: Applications in Enantioselective Synthesis.

Catalytic transformations of α-amino C-H bonds to afford valuable enantiomerically enriched α-substituted amines, entities that are prevalent in pharmaceuticals and bioactive natural products, have been developed. Typically, such processes are carried out under oxidative conditions and require precious metal-based catalysts. Here, we disclose a strategy for an enantioselective union of N-alkylamines and α,ß-unsaturated compounds, performed under redox-neutral conditions, and promoted through concerted action of seemingly competitive Lewis acids, B(C6F5)3, and a chiral Mg-PyBOX complex. Thus, a wide variety of ß-amino carbonyl compounds may be synthesized, with complete atom economy, through stereoselective reaction of an in situ-generated enantiomerically enriched Mg-enolate and an appropriate electrophile.

Enantioselective Direct Mannich-Type Reactions Catalyzed by Frustrated Lewis Acid/Brønsted Base Complexes.

An enantioselective direct Mannich-type reaction catalyzed by a sterically frustrated Lewis acid/Brønsted base complex is disclosed. Cooperative functioning of the chiral Lewis acid and achiral Brønsted base components gives rise to in situ enolate generation from monocarbonyl compounds. Subsequent reaction with hydrogen-bond-activated aldimines delivers ß-aminocarbonyl compounds with high enantiomeric purity.

Palladium-Catalyzed Transformations of Alkyl C-H Bonds.

This Review summarizes the advancements in Pd-catalyzed C(sp3)-H activation via various redox manifolds, including Pd(0)/Pd(II), Pd(II)/Pd(IV), and Pd(II)/Pd(0). While few examples have been reported in the activation of alkane C-H bonds, many C(sp3)-H activation/C-C and C-heteroatom bond forming reactions have been developed by the use of directing group strategies to control regioselectivity and build structural patterns for synthetic chemistry. A number of mono- and bidentate ligands have also proven to be effective for accelerating C(sp3)-H activation directed by weakly coordinating auxiliaries, which provides great opportunities to control reactivity and selectivity (including enantioselectivity) in Pd-catalyzed C-H functionalization reactions.

Frustrated Lewis Acid/Brønsted Base Catalysts for Direct Enantioselective α-Amination of Carbonyl Compounds.

A method for enantioselective direct α-amination reaction catalyzed by a sterically "frustrated" Lewis acid/Brønsted base complex is disclosed. Cooperative functioning of the Lewis acid and Brønsted base components gives rise to in situ enolate generation from monocarbonyl compounds. Subsequent reaction with hydrogen-bond activated dialkyl azodicarboxylates delivers α-aminocarbonyl compounds in high enantiomeric purity.

Direct Mannich-Type Reactions Promoted by Frustrated Lewis Acid/Brønsted Base Catalysts.

Direct Mannich-type reactions that afford both α- and ß-amino esters by the reaction of a broad range of carbonyl compounds and aldimines are disclosed. The transformation is promoted by a sterically frustrated Lewis acid/Brønsted base pair, which is proposed to operate cooperatively: Within the catalyst complex, an enolate is generated that then reacts with a hydrogen-bond-activated imine. Noncovalent interactions between reactants and the catalyst provide selectivity and new opportunities for future catalyst design.

Enantioselective synthesis of tertiary α-chloro esters by non-covalent catalysis.

We report an enantioselective approach to tertiary α-chloro esters through the reaction of silyl ketene acetals and N-chlorosuccinimide. The reaction is promoted by a chiral squaramide catalyst, which is proposed to engage both reagents exclusively through non-covalent interactions. Application of the tertiary chloride products in stereospecific substitution reactions is demonstrated.

Asymmetric Mannich synthesis of α-amino esters by anion-binding catalysis.

We report a scalable, one-pot Mannich route to enantioenriched α-amino esters by direct reaction of α-chloroglycine ester as a practical imino ester surrogate. The reaction is promoted by a chiral aminothiourea, which is proposed to operate cooperatively by generating an iminium ion by chloride abstraction and an enolate by deprotonation, followed by highly stereoselective C-C bond formation between both reactive intermediates associated non-covalently within the catalyst framework.

Palladium(II)-catalyzed enantioselective C(sp³)-H activation using a chiral hydroxamic acid ligand.

An enantioselective method for Pd(II)-catalyzed cross-coupling of methylene ß-C(sp(3))-H bonds in cyclobutanecarboxylic acid derivatives with arylboron reagents is described. High yields and enantioselectivities were achieved through the development of chiral mono-N-protected α-amino-O-methylhydroxamic acid (MPAHA) ligands, which form a chiral complex with the Pd(II) center. This reaction provides an alternative approach to the enantioselective synthesis of cyclobutanecarboxylates containing α-chiral quaternary stereocenters. This new class of chiral catalysts also show promises for enantioselective ß-C(sp(3))-H activation of acyclic amides.

Ligand-enabled cross-coupling of C(sp3)-H bonds with arylboron reagents via Pd(II)/Pd(0) catalysis.

There have been numerous developments in C-H activation reactions in the past decade. Attracted by the ability to functionalize molecules directly at ostensibly unreactive C-H bonds, chemists have discovered reaction conditions that enable reactions of C(sp(2))-H and C(sp(3))-H bonds with a variety of coupling partners. Despite these advances, the development of suitable ligands that enable catalytic C(sp(3))-H bond functionalization remains a significant challenge. Herein we report the discovery of a mono-N-protected amino acid ligand that enables Pd(II)-catalysed coupling of γ-C(sp(3))-H bonds in triflyl-protected amines with arylboron reagents. Remarkably, no background reaction was observed in the absence of ligand. A variety of amine substrates and arylboron reagents were cross-coupled using this method. Arylation of optically active substrates derived from amino acids also provides a potential route for preparing non-proteinogenic amino acids.

Understanding the reactivity of Pd(0)/PR3-catalyzed intermolecular C(sp(3))-H bond arylation.

Mechanistic details pertaining to the Pd(0)/PCy3-catalyzed intermolecular arylation of a terminal ß-C(sp(3))-H bond aryl amide substrate (SM = EtCONH-Ar, where Ar = C6H5, C6F5 and CONH-Ar is a directing group (DG)) in the presence of CsF base were elucidated. Key mechanistic features of this reaction are (1) oxidative addition of the aryl halide PhI to Pd(0)/PCy3, (2) deprotonation of SM by CsF to form DG' = [EtCON-Ar]Cs(+) for subsequent coordination to intermediate I-Pd(II)(PCy3)Ph (the substantially lower pKa of the EtCONHC6F5 in comparison to EtCONHC6H5 is instrumental for the presence of a larger population of the reactive deprotonated amides for Ar = C6F5), (3) "Cs2-I-F" cluster formation upon external (the second) CsF molecule approach to the active site of the I-Pd(II)(PCy3)Ph(DG') intermediate, (4) "Cs2-I-F cluster" assisted ß-C(sp(3))-H bond activation via a concerted metalation-deprotonation (CMD) mechanism, and (5) reprotonation of the amide directing group to facilitate the C(sp(3))-Ph reductive elimination. The energy barriers, ΔG(‡) (ΔG(‡disp), associated with the "Cs2-I-F cluster" mediated ß-C(sp(3))-H bond activation transition state are 6.5 (8.7) and 10.2 (12.9) kcal/mol when DG = CONHC6H5, CONHC6F5, respectively. It was shown that (a) the PCy3 ligand only semidissociates upon ß-C(sp(3))-H bond cleavage and (b) the I-to-F substitution in I-[Pd(II)](Ph)(PCy3)(DG') is a facile process that makes the "direct-halide" assisted ß-C(sp(3))-H bond activation relatively less energy demanding and opens the possibility for a competing Ph-F bond formation reaction. It was shown that the "direct-I" assisted C-H bond activation TS, which associates with a relatively large energy barrier, is an H-atom insertion transition state into the Pd-I bond, while the "direct-F" assisted C-H bond activation TS, which occurs with a relatively low energy barrier (but still is much larger than that required for the "Cs2-I-F cluster" assisted pathway), is a direct proton abstraction transition state.