Synthesis of Quaternary and Tertiary Carbon-Substituted Arenes by Lewis Base Promoted Site-Selective Coupling with Allylic Nucleophiles.

A practical method for the preparation of quaternary and tertiary allyl-substituted heteroarenes by site-selective couplings of heteroaryl nitriles and allylic nucleophiles is disclosed. Transformations utilize readily accessible stable reagents, proceed in the presence of a Lewis base activator, and undergo aryl-C(sp3 ) quaternary and tertiary carbon formation with high γ-selectivity (up to >98 : 2 γ : α).

A Catalytic Method for the Enantioselective Synthesis of α-Quaternary Ketones, α-Ketoesters and Aldehydes.

A practical method for the efficient and enantioselective preparation of versatile ketones and aldehydes that contain an α-quaternary stereocenter is described. Reactions utilize simple carboxylic acid or ester starting materials, a monodentate chiral phosphine, and afford a variety of aryl, alkenyl, alkynyl, and alkyl-substituted ketone and aldehyde products in 25-94 % yield and 90 : 10 to >99 : 1 enantiomeric ratio. Reactions proceed by acyl substitution with in situ formed chiral allylic nucleophiles, and display selectivity and conversion dependence on a protic additive. The utility of the approach is demonstrated through several product transformations.

Efficient Enantio-, Diastereo, E/Z-, and Site-Selective Nickel-Catalyzed Fragment Couplings of Aldehydes, Dienes, and Organoborons.

The enantioselective synthesis of bis-homoallylic alcohols through nickel-catalyzed three-component fragment couplings of simple aldehydes, dienes, and aryl organoborons is disclosed. The reactions proceed through diene dicarbofunctionalization that concurrently forms two C-C bonds and two stereogenic centers. The transformations are promoted by a 5.0 mol % loading of a readily accessible chiral phosphine-nickel complex and afford products with high stereoselectivity.

Diastereo-, Enantio-, and anti-Selective Formation of Secondary Alcohol and Quaternary Carbon Stereocenters by Cu-Catalyzed Additions of B-Substituted Allyl Nucleophiles to Carbonyls.

A general method for the synthesis of secondary homoallylic alcohols containing α-quaternary carbon stereogenic centers in high diastereo- and enantioselectivity (up to >20:1 dr and >99:1 er) is disclosed. Transformations employ readily accessible aldehydes, allylic diboronates, and a chiral copper catalyst and proceed by γ-addition of in situ generated enantioenriched boron-stabilized allylic copper nucleophiles. The catalytic protocol is general for a wide variety of aldehydes as well as a variety of 1,1-allylic diboronic esters. Hammett studies disclose that diastereoselectivity of the reaction is correlated to the electronic nature of the aldehyde, with dr increasing as aldehydes become more electron poor.

Synthesis of Quaternary Carbon Stereogenic Centers by Diastereoselective Conjugate Addition of Boron-Stabilized Allylic Nucleophiles to Enones.

A method for the site-selective and diastereoselective conjugate addition of boron-stabilized allylic nucleophiles to α,ß-unsaturated ketones is disclosed. Transformations involve easily prepared γ,γ-disubstituted allyldiboron reagents and proceed in the presence of a fluoride activator at 80 °C. Reactions proceed with a wide variety of enones and allyldiboron reagents efficiently to deliver ketone products that contain otherwise difficult-to-access vicinal ß-tertiary and γ-quaternary carbon stereogenic centers and an alkenylboron moiety. The utility of the method is highlighted by several transformations, including cross-coupling and carbocyclizations.

Enantioselective Synthesis of Functionalized Arenes by Nickel-Catalyzed Site-Selective Hydroarylation of 1,3-Dienes with Aryl Boronates.

A catalytic method for the site-selective and enantioselective synthesis of functionalized arenes by the intermolecular hydroarylation of terminal and internal 1,3-dienes with aryl pinacolato boronates is reported. The reactions are promoted by 5.0 mol % of a readily available monodentate phosphoramidite-Ni complex in ethanol, affording a variety of enantioenriched products in up to 96 % yield and 99:1 er. Mechanistic studies indicate that Ni-allyl formation is irreversible and related to the nature of the arylboronate.

Cu-Catalyzed Diastereo- and Enantioselective Reactions of γ,γ-Disubstituted Allyldiboron Compounds with Ketones.

A catalytic diastereo- and enantioselective method for the preparation of complex tertiary homoallylic alcohols containing a vicinal quaternary carbon stereogenic center and a versatile alkenylboronic ester is disclosed. Transformations are promoted by 5 mol % of a readily available copper catalyst bearing a bulky monodentate phosphoramidite ligand, which is essential for attaining both high dr and er. Reactions proceed with a wide variety of ketones and allylic 1,1-diboronate reagents, which enables the efficient preparation of diverse array of molecular scaffolds.

Diastereo- and Enantioselective Synthesis of Homoallylic Amines Bearing Quaternary Carbon Centers.

A Cu-catalyzed method for the efficient enantio- and diastereoselective synthesis of chiral homoallylic amines bearing a quaternary carbon and an alkenylboron is disclosed. Transformations are promoted by a readily prepared (phosphoramidite)-Cu complex and involve bench-stable γ,γ-disubstituted allyldiborons and benzyl imines; products are obtained in up to 82% yield, >20:1 dr, and >99:1 er. Reactions proceed via stereodefined boron-stabilized allylic Cu species formed by an enantioselective transmetalation. Utility of the 1-amino-3-alkenylboronate products is highlighted by a variety of synthetic transformations.

Catalytic Enantioselective Synthesis of 1,4-Keto-Alkenylboronate Esters and 1,4-Dicarbonyls.

A catalytic enantioselective method for the synthesis of 1,4-keto-alkenylboronate esters by a rhodium-catalyzed conjugate addition pathway is disclosed. A variety of novel, bench-stable alkenyl gem-diboronate esters are synthesized. These easily accessible reagents react smoothly with a collection of cyclic α,ß-unsaturated ketones, generating a new C-C bond and stereocenter. Products are isolated in up to 99 % yield with greater than 20:1 E/Z and greater than 99:1 e.r. Mechanistic studies show the site-selectivity of transmetalation and reactivity is ligand dependent. The utility of the approach is highlighted by gram-scale synthesis of enantioenriched cyclic 1,4-diketones, and stereoselective transformations of the products by hydrogenation, allylation, and isomerization.

Enantio- and Diastereoselective Synthesis of Functionalized Carbocycles by Cu-Catalyzed Borylative Cyclization of Alkynes with Ketones.

A single-pot Cu-catalyzed enantio- and diastereoselective tandem hydroboration/borylative cyclization of alkynes with ketones for the synthesis of carbocycles is reported. The reaction proceeds via desymmetrization and generates four contiguous stereocenters, including an all-carbon quaternary center. The method provides rapid access to [6,5]- and [5,5]-bicycles and cyclopentane products. Catalyst-controlled diastereoselectivity by selection of bisphosphine ligand is noted. Utility of the products is demonstrated by site- and chemoselective transformations that afford valuable alkenyl and allyl organoborons.

Synthesis of Alkenyl Boronates from Epoxides with Di-[B(pin)]-methane via Pd-Catalyzed Dehydroboration.

A practical and broadly applicable catalytic method for the synthesis of (E)-alkenylborons is presented. Reactions are promoted by [Pd(Cl)(η3-C3H5)]2 and proceed by the dehydroboration of cyclic borates. Through the use of epoxides and readily available di-B(pin)-methane (pin = pinacolato), a range of allylic alcohol-containing alkenyl boronates, including those that contain a tertiary alcohol, may be prepared in up to 75% yield and >20:1 E/Z.

Chiral Pincer Carbodicarbene Ligands for Enantioselective Rhodium-Catalyzed Hydroarylation of Terminal and Internal 1,3-Dienes with Indoles.

Catalytic enantioselective addition of N-heteroarenes to terminal and internal 1,3-dienes is reported. Reactions are promoted by 5 mol % of Rh catalyst supported by a new chiral pincer carbodicarbene ligand that delivers allylic substituted arenes in up to 95% yield and up to 98:2 er. Mechanistic and X-ray evidence is presented that supports that the reaction proceeds via a Rh(III)-η3-allyl.

Stereoselective Tandem Bis-Electrophile Couplings of Diborylmethane.

A copper-catalyzed three-component linchpin coupling method for the stereoselective union of readily available epoxides and allyl electrophiles is disclosed. Transformations employ [B(pin)]2-methane as a conjunctive reagent, resulting in the formation of two C-C bonds at a single carbon center bearing a C(sp3) organoboron functional group. Products are obtained in 42-99% yield, and up to >20:1 dr. The utility of the approach is highlighted by stereospecific transformations entailing allylation, tandem cross coupling, and application to the synthesis 1,3-polyol motifs.

Diastereoselective Synthesis of γ-Substituted 2-Butenolides via (CDC)-Rh-Catalyzed Intermolecular Hydroalkylation of Dienes with Silyloxyfurans.

Catalytic intermolecular hydroalkylation of dienes with silyloxyfuran nucleophiles is reported. Reactions are catalyzed by 5 mol % of a (CDC)-Rh complex and proceed in up to 87% yield and 6:1 dr (syn/anti) to provide allylic butenolides bearing vicinal stereocenters. Reactions proceed with terminal aryl and alkyl dienes and with modified silyl enol ether nucleophiles including a thiophenone variant. Utility of the products is demonstrated in the synthesis of a polypropionate anti,syn-stereotriad.

Enantio- and Diastereoselective Synthesis of Hydroxy Bis(boronates) via Cu-Catalyzed Tandem Borylation/1,2-Addition.

Catalytic enantioselective synthesis of 1-hydroxy-2,3-bisboronate esters through multicomponent borylation/1,2-addition is reported. Catalyst and substrates are readily available, form both a C-B and C-C bond, and generate up to three contiguous stereocenters. The reaction is tolerant of aryl, vinyl, and alkyl aldehydes and ketones in up to 95% yield, >20:1 dr, and 99:1 er. Intramolecular additions to aldehydes and ketones result in stereodivergent processes. The hydroxy bis(boronate) ester products are amenable to site-selective chemical elaboration.

Enantio- and Diastereoselective 1,2-Additions to α-Ketoesters with Diborylmethane and Substituted 1,1-Diborylalkanes.

The catalytic enantioselective synthesis of boronate-substituted tertiary alcohols through additions of diborylmethane and substituted 1,1-diborylalkanes to α-ketoesters is reported. The reactions are catalyzed by readily available chiral phosphine/copper(I) complexes and produce ß-hydroxyboronates containing up to two contiguous stereogenic centers in up to 99:1 e.r. and greater than 20:1 d.r. The utility of the organoboron products is demonstrated through several chemoselective functionalizations. Evidence indicates the reactions occur via an enantioenriched α-boryl-copper-alkyl intermediate.

Diastereoselective synthesis of vicinal tertiary and N-substituted quaternary stereogenic centers by catalytic hydroalkylation of dienes.

An efficient and diastereoselective (CDC)-Rh-catalyzed hydroalkylation of dienes with 1,3-oxazol-5(4H)-ones is reported. Aryl and alkyl substituted dienes are converted to α,α-substituted oxazolones (24 examples) by the formation of N-substituted quaternary carbon stereogenic centers in good yields (up to 96%) and with high diastereoselectivity (>20 : 1 dr). The reaction is tolerant of a range of dienes and oxazolones bearing various functional groups. Utility of the oxazolone products is illustrated through hydrolysis to form α,ß-substituted α-amino acid analogues and stereoselective epoxidation of the resultant alkene to create four contiguous stereocenters.

Silver(I)-Catalyzed Diastereoselective Synthesis of anti-1,2-Hydroxyboronates.

A catalytic protocol for the diastereoselective synthesis of anti-1,2-hydroxyboronates is described. The process provides access to secondary alkyl organoborons. The deborylative 1,2-addition reactions of alkyl 1,1-diborons proceed in the presence of a silver(I) salt with either KOtBu or nBuLi as an activator. The catalytic diastereoselective protocol can be extended to aryl, alkenyl, and alkyl aldehydes with up to 99:1 d.r.

Lewis acid activation of carbodicarbene catalysts for Rh-catalyzed hydroarylation of dienes.

The activation of carbodicarbene (CDC)-Rh(I) pincer complexes by secondary binding of metal salts is reported for the catalytic site-selective hydro-heteroarylation of dienes (up to 98% yield and >98:2 γ:α). Reactions are promoted by 5 mol % of a readily available tridentate (CDC)-Rh complex in the presence of an inexpensive lithium salt. The reaction is compatible with a variety of terminal and internal dienes and tolerant of ester, alkyl halide, and boronate ester functional groups. X-ray data and mechanistic experiments provide support for the role of the metal salts on catalyst activation and shed light on the reaction mechanism. The increased efficiency (120 to 22 °C) made available by catalytic amounts of metal salts to catalysts containing C(0) donors is a significant aspect of the disclosed studies.

Enantio- and Diastereoselective Synthesis of 1,2-Hydroxyboronates through Cu-Catalyzed Additions of Alkylboronates to Aldehydes.

The first catalytic enantio- and diastereoselective synthesis of 1,2-hydroxyboronates is reported. Reactions are promoted by a readily available chiral monodentate phosphoramidite-copper complex in the presence of an alkyl 1,1-diboron reagent. Products contain two contiguous stereogenic centers and are obtained in up to 91% yield, >98:2 d.r., and 98:2 e.r. The reaction is tolerant of aryl and vinyl aldehydes, and the 1,2-hydroxyboronate products can be transformed into versatile derivatives. Mechanistic experiments indicate control of absolute stereochemistry of the α-boryl component.