Stereoselective Construction of Tertiary Homoallyl Alcohols and Ethers by Nucleophilic Substitution at Quaternary Carbon Stereocenters.

An efficient method for the stereoselective construction of tertiary C-O bonds via a stereoinvertive nucleophilic substitution at the quaternary carbon stereocenter of cyclopropyl carbinol derivatives using water, alcohols and phenols as nucleophiles has been developed. This substitution reaction proceeds under mild conditions and tolerates several functional groups, providing a new access to the stereoselective formation of highly congested tertiary homoallyl alcohols and ethers.

Photocatalytic Metal Hydride Hydrogen Atom Transfer Mediated Allene Functionalization by Cobalt and Titanium Dual Catalysis.

Catalytic metal hydride hydrogen atom transfer (MHAT) reactions have proven to be a powerful method for alkene functionalization. This work reports the discovery of Co-porphines as highly efficient MHAT catalysts with a loading of only 0.01 mol % for unprecedented chemoselective allene functionalization under photoirradiation. Moreover, the newly developed bimetallic strategy by the combination of photo Co-MHAT and Ti catalysis enabled the successful carbonyl allylation with a wide range of amino, oxy, thio, aryl, and alkyl-allenes providing expedient access to valuable ß-functionalized homoallylic alcohols in over 100 examples with exceptional regio- and diastereoselectivity. Mechanism studies and DFT calculations supported that selectively transferring hydrogen atoms from cobalt hydride to allenes and generating allyl radicals is the key step in the catalytic cycle.

Ni-Catalyzed Regio- and Enantioselective Homoallylic Coupling: Synthesis of Chiral Branched 1,5-Dienes Featuring a Quaternary Stereogenic Center and Mechanistic Analysis.

Asymmetric synthesis of small molecules comprising quaternary stereogenic carbon centers represents a challenging objective. Here regio- and enantioselective synthesis of chiral 1,5-dienes featuring quaternary stereocenters is reported via nickel-promoted by reductive homoallylic coupling. The developed methodology features an atypical preference for the formation of unusual branched regioisomers (rr >20 : 1) in a sterically challenging allylic substitution event and furnishes the products with enantiomeric ratios of up to 98 : 2 and with high chemo- and E-selectivity. A range of experimental evidences suggest that zinc plays a dual role to generate electrophilic and nucleophilic Ni(II)-allyl intermediates empowering a unique formal bimetallic cross-electrophile manifold in two separate kinetic regimes.

Synthesis of Homoallylic Amines by Radical Allylation of Imines with Butadiene under Photoredox Catalysis.

Ionic (2 e- ) nucleophilic addition of allylmetal regents to imines dominates the synthesis of homo-allyl amine; however, single electron (1 e- ) mediated imine allylation with feedstocks butadiene as an alternative allyl source remains unexplored. In this work, we report a conceptually different radical-radical cross-coupling strategy for the synthesis of a homoallyl amine between an α-amino alkyl radical and a transient allylic radical. This metal-free method provided a novel approach for the synthesis of homoallylic amines (>80 examples) from readily available materials with excellent regioselectivity and exceptional broad functional group compatibility.

Enantioselective Lactonization by π-Acid-Catalyzed Allylic Substitution: A Complement to π-Allylmetal Chemistry.

Asymmetric allylic alkylation (AAA) is a powerful method for the formation of highly useful, non-racemic allylic compounds. Here we present a complementary enantioselective process that generates allylic lactones via π-acid catalysis. More specifically, a catalytic enantioselective dehydrative lactonization of allylic alcohols using a novel PdII -catalyst containing the imidazole-based P,N-ligand (S)-StackPhos is reported. The high-yielding reactions are operationally simple to perform with enantioselectivities up to 99 % ee. This strategy facilitates the replacement of a poor leaving group with what would ostensibly be a better leaving group in the product avoiding complications arising from racemization by equilibration.

Photocatalytic Generation of π-Allyltitanium Complexes via Radical Intermediates.

The addition of π-allylmetal complexes to carbonyls is the most important route to homoallylic alcohols. This study reports the first photocatalytic generation of π-allyltitanium complexes by a radical strategy. This novel strategy enables the three-component allylation of carbonyls with 1,3-butadiene, providing rapid access to valuable homoallylic alcohols (over 60 examples). The exceptional regio- and diastereoselectivity provided by dual photoredox/Ti catalysis is comparable to that of the Cr-catalyzed Nozaki-Hiyama-Kishi allylation reaction.

Annulative Allylic Alkylation Reactions between Dual Electrophiles and Dual Nucleophiles: Applications in Complex Molecule Synthesis.

Metal-catalyzed allylic alkylation reactions between dual nucleophiles and dual electrophiles represent a powerful set of methods for the synthesis of small-, medium-, and even large-sized rings. Using this strategy, a handful of simple allylic diol derivatives can be transformed into a broad array of complex carbo- and heterocycles of varying ring sizes in just a single step. Because of their ability to rapidly generate complexity, annulative allylic alkylation reactions between dual nucleophiles and dual electrophiles have been extensively employed in the total synthesis of both natural products and pharmaceutical compounds.

Pseudo-Stereodivergent Synthesis of Enantioenriched Tetrasubstituted Alkenes by Cascade 1,3-Oxo-Allylation/Cope Rearrangement.

The catalytic diastereodivergent construction of stereoisomers having two or more stereogenic centers has been extensively studied. In contrast, the switchable introduction of another stereogenic element, that is, Z/E configuration involving a polysubstituted alkene group, into the optically active stereoisomers, has not been recognized yet. Disclosed here is the pseudo-stereodivergent synthesis of highly enantioenriched tetrasubstituted alkene architectures from isatin-based Morita-Baylis-Hillman carbonates and allylic derivatives, under the cooperative catalysis of a tertiary amine and a chiral iridium complex. The success of the switchable construction of the tetrasubstituted alkene motif relies on the diastereodivergent 1,3-oxo-allylation reaction between N-allylic ylides and chiral π-allyliridium complex intermediates by ligand and substrate control, followed by the stereoselective concerted 3,3-Cope rearrangement process.

Catalytic Regioselective Isomerization of 2,2-Disubstituted Oxetanes to Homoallylic Alcohols.

The selective isomerization of strained heterocyclic compounds is an important tool in organic synthesis. An unprecedented regioselective isomerization of 2,2-disubstituted oxetanes into homoallylic alcohols is described. The use of tris(pentafluorophenyl)borane (B(C6 F5 )3 ), a commercially available Lewis acid was key to obtaining good yields and selectivities since other Lewis acids afforded mixtures of isomers and substantial polymerization. The reaction took place under exceptionally mild reaction conditions and very low catalyst loading (0.5 mol %). DFT calculations disclose the mechanistic features of the isomerization and account for the high selectivity displayed by the B(C6 F5 )3 catalyst. The synthetic applicability of the new reaction is demonstrated by the preparation of γ-chiral alcohols using iridium-catalyzed asymmetric hydrogenation.

Iodane-Guided ortho C-H Allylation.

A metal-free C-H allylation strategy is described to access diverse functionalized ortho-allyl-iodoarenes. The method employs hypervalent (diacetoxy)iodoarenes and proceeds through the iodane-guided "iodonio-Claisen" allyl transfer. The use of allylsilanes bearing electron-withdrawing functional groups unlocks the functionalization of a broad range of substrates, including electron-neutral and electron-poor rings. The resulting ortho-allylated iodoarenes are versatile building blocks, with examples of downstream transformation including a concise synthesis of the experimental antimitotic core of Dosabulin. DFT calculations shed additional light on the reaction mechanism, with notable aspects including the aromatic character of the transition-state structure for the [3,3] sigmatropic rearrangement, as well as the highly stereoconvergent nature of the trans-product formation.

Palladium(0)-Catalyzed Intermolecular Asymmetric Cascade Dearomatization Reaction of Indoles with Propargyl Carbonate.

An intermolecular asymmetric cascade dearomatization reaction of indole derivatives with propargyl carbonate was developed. The challenges associated with both the chemoselectivity between the carbon and nitrogen nucleophile and the enantioselective control during the formation of an all-carbon quaternary stereogenic center were well addressed by a Pd catalytic system derived from the Feringa ligand. A series of enantioenriched multiply substituted fused indolenines were provided in good yields (71-86 %) with excellent enantioselectivity (91-96 % ee) and chemoselectivity (3/4>19:1 in most cases).

Selective Aerobic Oxygenation of Tertiary Allylic Alcohols with Molecular Oxygen.

Aerobic epoxidation of tertiary allylic alcohols remains a significant challenge. Reported here is an efficient and highly chemoselective copper-catalyzed epoxidation and semipinacol rearrangement reaction of tertiary allylic alcohols with molecular oxygen. The solvent 1,4-dioxane activates dioxygen, thereby precluding the addition of a sacrificial reductant.

Cobalt-Catalyzed Allylic Alkylation Enabled by Organophotoredox Catalysis.

Co-catalyzed allylic substitution reactions have received little attention, arguably because of the lack of any known advantage of Co catalysis over either Rh or Ir catalysis. Described here is a general and regioselective Co-catalyzed allylic alkylation using an in situ catalyst activation by organophotoredox catalysis. This noble-metal-free catalytic system exhibits unprecedentedly high reactivities and regioselectivities for the allylation with an allyl sulfone, for the first time, representing the unique synthetic utility of the Co-catalyzed method compared to the related Rh- and Ir-catalyzed reactions.

Engaging Aldehydes in CuH-Catalyzed Reductive Coupling Reactions: Stereoselective Allylation with Unactivated 1,3-Diene Pronucleophiles.

Recently, CuH-catalyzed reductive coupling processes involving carbonyl compounds and imines have become attractive alternatives to traditional methods for stereoselective addition because of their ability to use readily accessible and stable olefins as surrogates for organometallic nucleophiles. However, the inability to use aldehydes, which usually reduce too rapidly in the presence of copper hydride complexes to be viable substrates, has been a major limitation. Shown here is that by exploiting relative concentration effects through kinetic control, this intrinsic reactivity can be inverted and the reductive coupling of 1,3-dienes with aldehydes achieved. Using this method, both aromatic and aliphatic aldehydes can be transformed into synthetically valuable homoallylic alcohols with high levels of diastereo- and enantioselectivities, and in the presence of many useful functional groups. Furthermore, using a combination of theoretical (DFT) and experimental methods, important mechanistic features of this reaction related to stereo- and chemoselectivities were uncovered.

Synthesis of γ-Boryl-Substituted Homoallylic Alcohols with anti Stereochemistry Based on a Double-Bond Transposition.

The stereoselective synthesis of anti isomers of γ-boryl-substituted homoallylic alcohols is disclosed. (E)-1,2-Di(boryl)alk-1-enes undergo Ru-catalyzed double-bond transposition with control of the geometry. The in situ generated (E)-1,2-di(boryl)alk-2-enes add to aldehydes in a stereospecific manner. The alkenylboron group within the product is amenable to a variety of synthetic derivatizations.

Photoredox-Coupled F-Nucleophilic Addition: Allylation of gem-Difluoroalkenes.

A novel strategy for the expedient construction of CF3 -embeded tertiary/quarternary carbon centers was developed by taking advantage of photoredox catalysis. Thanks to a key step of single-electron oxidation, electron-rich gem-difluoroalkenes, which otherwise are essentially reluctant towards F-nucleoplilic addition, now readily participate in this fluoroallylation reaction. Furthermore, this strategy provides an elegant example for the generation, as well as functionalization, of α-CF3 -substituted benzylic radical intermediates using cheap and readily available starting materials.

Dehydrogenative Silylation of Alkenes for the Synthesis of Substituted Allylsilanes by Photoredox, Hydrogen-Atom Transfer, and Cobalt Catalysis.

A synergistic catalytic method combining photoredox catalysis, hydrogen-atom transfer, and proton-reduction catalysis for the dehydrogenative silylation of alkenes was developed. With this approach, a highly concise route to substituted allylsilanes has been achieved under very mild reaction conditions without using oxidants. This transformation features good to excellent yields, operational simplicity, and high atom economy. Based on control experiments, a possible reaction mechanism is proposed.

Palladium-Catalyzed Directed meta-Selective C-H Allylation of Arenes: Unactivated Internal Olefins as Allyl Surrogates.

Palladium(II)-catalyzed meta-selective C-H allylation of arenes has been developed utilizing synthetically inert unactivated acyclic internal olefins as allylic surrogates. The strong σ-donating and π-accepting ability of pyrimidine-based directing group facilitates the olefin insertion by overcoming inertness of the typical unactivated internal olefins. Exclusive allyl over styrenyl product selectivity as well as E stereoselectivity were achieved with broad substrate scope, wide functional-group tolerance, and good to excellent yields. Late-stage functionalisations of pharmaceuticals were demonstrated. Experimental and computational studies shed light on the mechanism and point to key steric control in the palladacycle, thus determining product selectivities.

Asymmetric Catalytic Formal 1,4-Allylation of ß,γ-Unsaturated α-Ketoesters: Allylboration/Oxy-Cope Rearrangement.

A highly enantioselective formal conjugate allyl addition of allylboronic acids to ß,γ-unsaturated α-ketoesters has been realized by employing a chiral NiII /N,N'-dioxide complex as the catalyst. This transformation proceeds by an allylboration/oxy-Cope rearrangement sequence, providing a facile and rapid route to γ-allyl-α-ketoesters with moderate to good yields (65-92 %) and excellent ee values (90-99 % ee). The isolation of 1,2-allylboration products provided insight into the mechanism of the subsequent oxy-Cope rearrangement reaction: substrate-induced chiral transfer and a chiral Lewis acid accelerated process. Based on the experimental investigations and DFT calculations, a rare boatlike transition-state model is proposed as the origin of high chirality transfer during the oxy-Cope rearrangement.

Iridium-Catalyzed Asymmetric Allylic Aromatization Reaction.

Described herein is an asymmetric allylic aromatization (AAAr) strategy that employs readily accessible equivalents of benzylic nucleophiles in iridium-catalyzed allylic substitution reactions with the concomitant formation of aromatic rings by aromatization. The optimized reaction conditions involving a catalyst derived from a commercially available iridium precursor and the Carreira ligand are compatible with equivalents of benzylic nucleophiles derived from 4- or 5-methyloxazoles, 5-methylthiazoles, 4- or 5-methylfurans, 2- or 3-methylbenzofurans, 3-methylbenzothiophene, 3-methylindole, 1-methylnaphthalene, and methylbenzene. This strategy provides straightforward accesses to valuable heterocyclic aromatic compounds, bearing a homobenzylic stereogenic center, in an enantiopure form and would be difficult to access otherwise. The versatility of the reaction was showcased by the further elaboration of the products into useful building blocks and a drug analogue.