Enantioselective Synthesis of All‐Carbon Quaternary Stereogenic Centers via Copper‐Catalyzed Asymmetric Allylic Alkylation of (Z)‐Allyl Bromides with Organolithium Reagents

A copper/phosphoramidite catalyzed asymmetric allylic alkylation of Z trisubstituted allyl bromides with organolithium reagents is reported. The reaction affords all‐carbon quaternary stereogenic centers in high yields and very good regio‐ and enantioselectivity. This systematic study illustrates the crucial role of the olefin geometry of the allyl substrate on the outcome of the reaction and provides a viable alternative to access these important structural motifs.     

Enantioselective Rhodium‐Catalyzed Allylic Alkylation of β,γ‐Unsaturated α‐Amino Nitriles: Synthetic Homoenolate Equivalents

An enantioselective rhodium‐catalyzed allylic alkylation of β,γ‐unsaturated α‐amino nitriles is described. This protocol provides a novel approach for the construction of β‐stereogenic carbonyl derivatives via the catalytic asymmetric alkylation of a homoenolate equivalent. The particularly challenging nature of this transformation is highlighted by the fact that three modes of selectivity must be manipulated, namely regio‐ and enantioselectivity, in addition to geometrical control. The γ‐stereogenic cyanoenamine products can be readily hydrolyzed in situ to afford the β‐substituted carboxylic acids, which in turn provide expedient access to a number of related carbonyl derivatives. Additionally, control experiments indicate that the chiral rhodium‐allyl intermediate facilitates the selective formation of the E‐cyanoenamine products, which is critical since the Z‐isomer affords significantly lower enantiocontrol.     

Cobalt‐Catalyzed Regio‐ and Stereoselective Hydroboration of Allenes

An efficient pincer‐ligand‐based cobalt‐complex‐catalyzed allene hydroboration affording Z‐allylic boronates is described. The reaction demonstrates an excellent regio‐ as well as Z‐stereoselectivity and a wide substrate scope that tolerates many functional groups. Based on solvent‐assisted electrospray ionization mass spectrometry (SAESI‐MS) studies, a rationale for the cobalt‐catalyzed hydroboration involving the highly selective insertion of an allene into the Co?H bond to form Z‐allylic cobalt intermediates is proposed.     

Copper‐Catalyzed Borylcupration of Allenylsilanes

A highly regio‐ and stereoselective copper‐catalyzed borylcupration of 1,2‐allenylsilanes affords an unexpected regioreversed allylic boronate bearing an extra C?Si bond at the 3‐position, with a thermodynamically disfavored Z geometry. Such stereodefined allylic boronates containing an extra alkenyl silane moiety are very useful organodimetallic reagents for organic synthesis.     

Regio‐ and Enantioselective Synthesis of Trifluoromethyl‐Substituted Homoallylic α‐Tertiary NH2‐Amines by Reactions Facilitated by a Threonine‐Based Boron‐Containing Catalyst

A method for catalytic regio‐ and enantioselective synthesis of trifluoromethyl‐substituted and aryl‐, heteroaryl‐, alkenyl‐, and alkynyl‐substituted homoallylic α‐tertiary NH₂‐amines is introduced. Easy‐to‐synthesize and robust N‐silyl ketimines are converted to NH‐ketimines in situ, which then react with a Z‐allyl boronate. Transformations are promoted by a readily accessible l ‐threonine‐derived aminophenol‐based boryl catalyst, affording the desired products in up to 91 % yield, >98:2 α:γ selectivity, >98:2 Z:E selectivity, and >99:1 enantiomeric ratio. A commercially available aminophenol may be used, and allyl boronates, which may contain an alkyl‐, a chloro‐, or a bromo‐substituted Z‐alkene, can either be purchased or prepared by catalytic stereoretentive cross‐metathesis. What is more, Z‐trisubstituted allyl boronates may be used. Various chemo‐, regio‐, and diastereoselective transformations of the α‐tertiary homoallylic NH₂‐amine products highlight the utility of the approach; this includes diastereo‐ and regioselective epoxide formation/trichloroacetic acid cleavage to generate differentiated diol derivatives.     

Amide‐Controlled Highly Selective Catalytic Borylcupration of Allenes

A novel copper‐catalyzed, highly regio‐ and stereoselective borylcupration of substituted 2,3‐allenamides with bis(pinacolato)diboron producing Z‐β‐borylated β,γ‐unsaturated enoamides has been demonstrated. Due to the unique effect of the amide‐group, perfect regio‐ and stereoselectivity and good to excellent yields have been achieved, which were rationalized by a DFT study.     

Copper‐Catalyzed Enantioselective Allyl–Allyl Coupling between Allylic Boronates and Phosphates with a Phenol/N‐Heterocyclic Carbene Chiral Ligand

Copper‐catalyzed enantioselective allyl–allyl coupling between allylboronates and either Z‐acyclic or cyclic allylic phosphates using a new chiral N‐heterocyclic carbene ligand, bearing a phenolic hydroxy, is reported. This reaction occurs with exceptional S_N2′‐type regioselectivities and high enantioselectivities to deliver chiral 1,5‐diene derivatives with a tertiary stereogenic center at the allylic/homoallylic position.     

Broadly Applicable Z‐ and Diastereoselective Ring‐Opening/Cross‐Metathesis Catalyzed by a Dithiolate Ru Complex

A broadly applicable Ru‐catalyzed protocol for Z‐selective ring‐opening/cross‐metathesis (ROCM) is disclosed. In addition to reactions relating to terminal alkenes of different sizes, the first examples of Z‐selective ROCM processes involving heteroaryl olefins, 1,3‐dienes, and O‐ and S‐substituted alkenes as well as allylic and homoallylic alcohols are reported. Z‐Selective transformations with an α‐substituted allylic alcohol are shown to afford congested Z alkenes with high diastereoselectivity. Transformations are performed in the presence of 2.0–5.0 mol % of a recently disclosed Ru‐based dithiolate complex that can be easily prepared in a single step from commercially available starting materials. Typically, transformations proceed at ambient temperature and are complete within eight hours; products are obtained in up to 97 % yield, >98:2 Z/E, and >98:2 diastereomeric ratio. The present investigations reveal a mechanistically significant attribute of the Ru‐based dithiolates that arises from electrostatic interactions with anionic S‐based ligands.     

Ruthenium‐Catalyzed Tandem‐Isomerization/Asymmetric Transfer Hydrogenation of Allylic Alcohols

A one‐pot procedure for the direct conversion of racemic allylic alcohols to enantiomerically enriched saturated alcohols is presented. The tandem‐isomerization/asymmetric transfer hydrogenation process is efficiently catalyzed by [{Ru(p‐cymene)Cl₂}₂] in combination with the α‐amino acid hydroxyamide ligand 1 , and performed under mild conditions in a mixture of ethanol and THF. The saturated alcohol products are isolated in good to excellent chemical yields and in enantiomeric excess up to 93 %.     

Intermolecular 1,4‐Carboamination of Conjugated Dienes Enabled by Cp*RhIII‐Catalyzed C−H Activation

A protocol for the three‐component 1,4‐carboamination of dienes is described. Synthetically versatile Weinreb amides were coupled with 1,3‐dienes and readily available dioxazolones as the nitrogen source using [Cp*RhCl₂]₂‐catalyzed C?H activation to deliver the 1,4‐carboaminated products. This transformation proceeds under mild reaction conditions and affords the products with high levels of regio‐ and E‐selectivity. Mechanistic investigations suggest an intermediate Rh^III–allyl species is trapped by an electrophilic amidation reagent in a redox‐neutral fashion.     

Multicomponent Synthesis of Chiral Bidentate Unsymmetrical Unsaturated N‐Heterocyclic Carbenes: Copper‐Catalyzed Asymmetric CC Bond Formation

A multicomponent strategy was applied to the synthesis of chiral bidentate unsaturated hydroxyalkyl‐ and carboxyalkyl‐N‐heterocyclic carbene (NHC) precursors. The newly developed low‐cost chiral ligands derived from amino alcohols and amino acids were evaluated in copper‐catalyzed asymmetric conjugated addition and asymmetric allylic alkylation, which afforded the desired tertiary and quaternary carbon stereocenters with excellent regio‐ and enantioselectivities (up to 99:1 e.r.).     

Pentacoordinated Carboxylate π‐Allyl Nickel Complexes as Key Intermediates for the Ni‐Catalyzed Direct Amination of Allylic Alcohols

Direct amination of allylic alcohols with primary and secondary amines catalyzed by a system made of [Ni(1,5‐cyclooctadiene)₂] and 1,1′‐bis(diphenylphosphino)ferrocene was effectively enhanced by adding nBu₄NOAc and molecular sieves, affording the corresponding allyl amines in high yield with high monoallylation selectivity for primary amines and high regioselectivity for monosubstituted allylic alcohols. Such remarkable additive effects of nBu₄NOAc were elucidated by isolating and characterizing some nickel complexes, manifesting the key role of a charge neutral pentacoordinated η³‐allyl acetate complex in the present system, in contrast to usual cationic tetracoordinated complexes earlier reported in allylic substitution reactions.     

Diversity‐Oriented Enantioselective Synthesis of Highly Functionalized Cyclic and Bicyclic Alcohols

The copper‐catalyzed hetero‐allylic asymmetric alkylation (h‐AAA) of functionalized Grignard reagents that contain alkene or alkyne moieties has been achieved with excellent regio‐ and enantioselectivity. The corresponding alkylation products were further transformed into a variety of highly functionalized cyclic and bicyclic alcohols with excellent control over the chemo‐, regio‐, and stereoselectivity.     

Tandem Thorpe Reaction/Palladium Catalyzed Asymmetric Allylic Alkylation: Access to Chiral β‐enaminonitriles with Excellent Enantioselectivity

A new type of nucleophile, a 3‐imino nitrile carbanion generated in situ by Thorpe reaction of acetonitrile with a base, was developed successfully and applied in a Pd‐catalyzed asymmetric allylic alkylation with mono‐substituted allyl reagents under Pd/SIOCPhox catalysis, affording β‐enaminonitrile products in high yields with excellent regio‐ and enantioselectivities.     

(E/Z)‐Isomerization of (all‐E)‐5,6‐Diepikarpoxanthin

(all‐E)‐5,6‐Diepikarpoxanthin (=(all‐E,3S,5S,6S,3′R)‐5,6‐dihydro‐β,β‐carotene‐3,5,6,3′‐tetrol; 1 ) was submitted to thermal isomerization and I₂‐catalyzed photoisomerization. The structures of the main products, i.e. (9Z)‐ ( 2 ), (9′Z)‐ ( 3 ), (13Z)‐ ( 4 ), (13′Z)‐ ( 5 ), and (15Z)‐5,6‐diepikarpoxanthin ( 6 ), were determined by their UV/VIS, CD, ¹H‐NMR, and mass spectra. In addition, (9Z,13′Z)‐ or (13Z,9′Z)‐ ( 7 ), (9Z,9′Z)‐ ( 8 ), and (9Z,13Z)‐ or (9′Z,13′Z)‐5,6‐diepikarpoxanthin ( 9 ) were tentatively identified as minor products of the I₂‐catalyzed photoisomerization.     

Regio‐ and Stereospecific 1,3‐Allyl Group Transfer Triggered by a Copper‐Catalyzed Borylation/ortho‐Cyanation Cascade

A copper‐catalyzed borylation/ortho‐cyanation/allyl group transfer cascade was developed. Initiated by an unconventional copper‐catalyzed electrophilic dearomatization, this process features regio‐ and stereospecific 1,3‐transposition of the allyl fragment enabled by an aromatization‐driven Cope rearrangement. This method provides an effective means for the construction of adjacent tertiary and quaternary stereocenters with excellent diastereocontrol.     

Synthesis of Citronellal by RhI‐Catalysed Asymmetric Isomerization of N,N‐Diethyl‐Substituted Geranyl‐ and Nerylamines or Geraniol and Nerol in the Presence of Chiral Diphosphino Ligands,under Homogeneous and Supported Conditions

For the asymmetric isomerization of geranyl‐ or neryldiethylamine ((E)‐ or (Z)‐ 1 , resp.) and allyl alcohols geraniol or nerol ((E)‐ or (Z)‐ 2 , resp.) to citronellal ( 4 ) in the presence of a [Rh^I(ligand)cycloocta‐1,5‐diene)]⁺ catalyst, the atropic ligands 5 – 11 are compared under homogeneous and polymer‐supported conditions with the non‐C₂‐symmetrical diphosphino ferrocene ligands 12 – 16 . The ^tBu‐josiphos ligand 13 or daniphos ligand 19 , available in both antipodal series, already catalyse the reaction of (E)‐ 1 at 20° (97% e.e.) and favourably compare with the binap ligand 5 (see Table 1). Silica‐gel‐ or polymer‐supported diphosphino ligands usually afford similar selectivity as compared to the corresponding ligands applied under homogeneous conditions, but are generally less reactive. In this context, a polymer‐supported ligand of interest is the polymer‐anchored binap (R)‐ 6 , in terms of reactivity, selectivity, and recoverability, with a turnover of more than 14400.     

(E/Z)‐Isomerization of 3′‐Epilutein

3′‐Epilutein (=(all‐E,3R,3′S,6′R)‐4′,5′‐didehydro‐5′,6′‐dihydro‐β,β‐carotene‐3,3′‐diol; 1 ), isolated from the flowers of Caltha palustris, was submitted to both thermal isomerization and I₂‐catalyzed photoisomerization. The structures of the main products (9Z)‐ 1 , (9′Z)‐ 1 , (13Z)‐ 1 , (13′Z)‐ 1 , (15Z)‐ 1 , and (9Z,9′Z)‐ 1 were determined based on UV/VIS, CD, ¹H‐NMR, and MS data.     

Iridium‐Catalyzed Regio‐ and Enantioselective Allylic Substitution of Silyl Dienolates Derived from Dioxinones

Reported herein is the iridium‐catalyzed regio‐ and enantioselective allylic substitution reactions of unstabilized silyl dienolates derived from dioxinones. Asymmetric allylic substitution of a variety of allylic trichloroethyl carbonates with these silyl dienolates gave γ‐allylated products selectively in 60–84 % yield and 90–98 % ee.     

Transition‐Metal‐Free Borylation of Allylic and Propargylic Alcohols

The base‐catalyzed allylic borylation of tertiary allylic alcohols allows the synthesis of 1,1‐disubstituted allyl boronates, in moderate to high yield. The unexpected tandem performance of the Lewis acid–base adduct, [Hbase]⁺[MeO‐B₂pin₂]^? favored the formation of 1,2,3‐triborylated species from the tertiary allylic alcohols and 1‐propargylic cyclohexanol at 90 °C.