Catalytic Enantioselective Hydrovinylation of Trialkylsilyloxy and Acetoxy-1,3-Dienes: Cationic Co(I) Complexes for the Synthesis of Chiral Enolate Surrogates and Their Applications for Synthesis of Ketones and Cross-Coupling Reagents in High Enantiomeric Purity.

(E)-2-Trialkylsilyloxy-1,3-dienes and the corresponding 2-acetoxy derivatives participate in cobalt-catalyzed heterodimerization reactions with ethylene, giving mostly 4,1-hydrovinylation products with addition of the vinyl group to C4 and H at C1 of the diene. The reaction, which gives highly functionalized, protected enolates, is best carried out at room temperature with the diene dissolved in methylene chloride and ethylene delivered from a balloon in the presence of a catalyst generated in situ by the reaction of (P~P)CoCl2 with methylaluminoxane (MAO). Commercially available chiral ligands, 2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis-(diphenylphosphino)butane (DIOP) and 2,4-bis-diphenylphosphinopentane (BDPP) in combination with the earth-abundant metal cobalt, gave excellent regio- and enantio-selectivities (up to 99% ee) for the chiral enolate surrogates from both silyloxy and acetoxydienes. Hydrolyses of the silyl enol ethers lead to ß-vinyl ketones, thus providing a practical two-step approach to these valuable synthons starting from α,ß-unsaturated ketones and ethylene. The hydrovinylated silyl enol ethers undergo typical nucleophilic reactions such as alkylation, aldol, Michael and Mannich reactions with varying degrees of diastereoselectivity (2:1-13:1). The silyl enol ethers are convenient source of lithium enolates which are readily converted into other vinyl derivatives such as vinyl acetates and vinyl triflates. The vinyl triflates are excellent partners for cross-coupling chemistry, giving potentially useful, polyolefinic chiral synthons for further applications. Chemoselective reduction and hydrosilylation of the vinyl group in the chiral ß-vinyl silyl enol ether further illustrate other potential reactivities of these versatile synthons. Since isolated cationic [(P~P)Co(I)]+ [BARF]- appears to be an excellent catalyst for the heterodimerization of silyl enol ethers and ethylene giving products very similar in yield and selectivities to what is observed in the MAO-mediated reactions, we propose that a previously invoked a Co(I)/Co(III) cycle, common to other similar heterodimerization reactions, might be involved in these reactions as well.

A New Paradigm in Enantioselective Cobalt Catalysis: Cationic Cobalt(I) Catalysts for Heterodimerization, Cycloaddition, and Hydrofunctionalization Reactions of Olefins.

One of the major challenges facing organic synthesis in the 21st century is the utilization of abundantly available feedstock chemicals for fine chemical synthesis. Regio- and enantioselective union of easily accessible 1,3-dienes and other feedstocks like ethylene, alkyl acrylates, and aldehydes can provide valuable building blocks adorned with latent functionalities for further synthetic elaboration. Through an approach that relies on mechanistic insights and systematic examination of ligand and counterion effects, we developed an efficient cobalt-based catalytic system [(P∼P)CoX2/Me3Al] (P∼P = bisphosphine) to effect the first enantioselective heterodimerization of several types of 1,3-dienes with ethylene. In addition to simple cyclic and acyclic dienes, siloxy-1,3-dienes participate in this reaction, giving highly functionalized, nearly enantiopure silyl enolates, which can be used for subsequent C-C and C-X bond-forming reactions. As our understanding of the mechanism of this reaction improved, our attention was drawn to more challenging partners like alkyl acrylates (one of the largest volume feedstocks) as the olefin partners instead of ethylene. Prompted by the intrinsic limitations of using aluminum alkyls as the activators for this reaction, we explored the fundamental chemistry of the lesser known (P∼P)Co(I)X species and discovered that in the presence of halide sequestering agents, such as sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (NaBARF) or (C6F5)3B, certain chiral bisphosphine complexes are superb catalysts for regio- and enantioselective heterodimerization of 1,3-dienes and alkyl acrylates. We have since found that these cationic Co(I) catalysts, most conveniently prepared in situ by reduction of the corresponding cobalt(II) halide complexes by zinc in the presence of NaBARF, promote enantioselective [2 + 2]-cycloaddition between alkynes and an astonishing variety of alkenyl derivatives to give highly functionalized cyclobutenes. In reactions between 1,3-enynes and ethylene, the [2 + 2]-cycloaddition between the alkyne and ethylene is followed by a 1,4-addition of ethylene in a tandem fashion to give nearly enantiopure cyclobutanes with an all-carbon quaternary center, giving a set of molecules that maps well into many medicinally relevant compounds. In another application, we find that the cationic Co(I)-catalysts promote highly selective hydroacylation and 1,2-hydroboration of prochiral 1,3-dienes. Further, we find that a cationic Co(I)-catalyst promotes cycloisomerization followed by hydroalkenylation of 1,6-enynes to produce highly functionalized carbo- and heterocyclic compounds. Surprisingly the regioselectivity of the alkene addition depends on whether it is a simple alkene or an acrylate, and the acrylate addition produces an uncommon Z-adduct. This Account will provide a summary of the enabling basic discoveries and the attendant developments that led to the unique cationic Co(I)-complexes as catalysts for disparate C-C and C-B bond-forming reactions. It is our hope that this Account will stimulate further work with these highly versatile catalysts which are derived from an earth-abundant metal.

Broadly Applicable Stereoselective Syntheses of Serrulatane, Amphilectane Diterpenes, and Their Diastereoisomeric Congeners Using Asymmetric Hydrovinylation for Absolute Stereochemical Control.

A stereogenic center, placed at an exocyclic location next to a chiral carbon in a ring to which it is attached, is a ubiquitous structural motif seen in many bioactive natural products, including di- and triterpenes and steroids. Installation of these centers has been a long-standing problem in organic chemistry. Few classes of compounds illustrate this problem better than serrulatanes and amphilectanes, which carry multiple methyl-bearing exocyclic chiral centers. Nickel-catalyzed asymmetric hydrovinylation (AHV) of vinylarenes and 1,3-dienes such as 1-vinylcycloalkenes provides an exceptionally facile way of introducing these chiral centers. This Article documents our efforts to demonstrate the generality of AHV to access not only the natural products but also their various diastereoisomeric derivatives. Key to success here is the availability of highly tunable phosphoramidite Ni(II) complexes useful for overcoming the inherent selectivity of the chiral intermediates. The yields for hydrovinylation (HV) reactions are excellent, and selectivities are in the range of 92-99% for the desired isomers. Discovery of novel, configurationally fluxional, yet sterically less demanding 2,2'-biphenol-derived phosphoramidite Ni complexes (fully characterized by X-ray) turned out to be critical for success in several HV reactions. We also report a less spectacular yet equally important role of solvents in a metal-ammonia reduction for the installation of a key benzylic chiral center. Starting with simple oxygenated styrene derivatives, we iteratively install the various exocyclic chiral centers present in typical serrulatane [e.g., a (+)- p-benzoquinone natural product, elisabethadione, nor-elisabethadione, helioporin D, a known advanced intermediate for the synthesis of colombiasin and elisapterosin] and amphilectane [e.g., A-F, G-J, and K,L pseudopterosins] derivatives. A concise table showing various synthetic approaches to these molecules is included in the Supporting Information. Our attempts to synthesize a hitherto elusive target, elisabethin A, led to a stereoselective, biomimetic route to pseudopterosin A-F aglycones.

Enantioselective Synthesis of N,S-Acetals by an Oxidative Pummerer-Type Transformation using Phase-Transfer Catalysis.

Reported is the first enantioselective oxidative Pummerer-type transformation using phase-transfer catalysis to deliver enantioenriched sulfur-bearing heterocycles. This reaction includes the direct oxidation of sulfides to a thionium intermediate, followed by an asymmetric intramolecular nucleophilic addition to form chiral cyclic N,S-acetals with moderate to high enantioselectivites. Deuterium-labelling experiments were performed to identify the stereodiscrimination step of this process. Further analysis of the reaction transition states, by means of multidimensional correlations and DFT calculations, highlight the existence of a set of weak noncovalent interactions between the catalyst and substrate that govern the enantioselectivity of the reaction.

Selective Cobalt-Catalyzed Reduction of Terminal Alkenes and Alkynes Using (EtO)2Si(Me)H as a Stoichiometric Reductant.

While attempting to effect Co-catalyzed hydrosilylation of ß-vinyl trimethylsilyl enol ethers we discovered that depending on the silane, solvent and the method of generation of the reduced cobalt catalyst, a highly efficient and selective reduction or hydrosilylation of an alkene can be achieved. This paper deals with this reduction reaction, which has not been reported before in spite of the huge research activity in this area. The reaction, which uses an air-stable [2,6-di(aryliminoyl)pyridine)]CoCl2 activated by 2 equivalents of NaEt3BH as a catalyst (0.001-0.05 equiv) and (EtO)2SiMeH as the hydrogen source, is best run at ambient temperature in toluene and is highly selective for the reduction of simple unsubstituted 1-alkenes and the terminal double bonds in 1,3- and 1,4-dienes, ß-vinyl ketones and silyloxy dienes. The reaction is tolerant of various functional groups such as a bromide, alcohol, amine, carbonyl, and di or trisubstituted double bonds, and water. Highly selective reduction of a terminal alkyne to either an alkene or alkane can be accomplished by using stoichiometric amounts of the silane. Preliminary mechanistic studies indicate that the reaction is stoichiometric in the silane and both hydrogens in the product come from the silane.

Asymmetric Catalysis with Ethylene. Synthesis of Functionalized Chiral Enolates.

Trialkylsilyl enol ethers are versatile intermediates often used as enolate surrogates for the synthesis of carbonyl compounds. Yet there are no reports of broadly applicable, catalytic methods for the synthesis of chiral silyl enol ethers carrying latent functionalities useful for synthetic operations beyond the many possible reactions of the silyl enol ether moiety itself. Here we report a general procedure for highly catalytic (substrate:catalyst ratio up to 1000:1) and enantioselective (92% to 98% major enantiomer) synthesis of such compounds bearing a vinyl group at a chiral carbon at the ß-position. The reactions, run under ambient conditions, use trialkylsiloxy-1,3-dienes and ethylene (1 atm) as precursors and readily available (bis-phosphine)-cobalt(II) complexes as catalysts. The silyl enolates can be readily converted into novel enantiopure vinyl triflates, a class of highly versatile cross-coupling reagents, enabling the syntheses of other enantiomerically pure, stereodefined trisubstituted alkene intermediates not easily accessible by current methods. Examples of Kumada, Stille, and Suzuki coupling reactions are illustrated.

Triarylphosphine Ligands with Hemilabile Alkoxy Groups. Ligands for Nickel(II)-Catalyzed Olefin Dimerization Reactions. Hydrovinylation of Vi-nylarenes, 1,3-Dienes, and Cycloisomerization of 1,6-Dienes.

Substitution of one of the phenyl groups of triphenylphosphine with a 2-benzyloxy-, 2-benzyloxymethyl- or 2-benzyloxyethyl-phenyl moiety results in a set of simple ligands, which exhibit strikingly different behaviour in various nickel(II)-catalyzed olefin dimerization reactions. Complexes of ligands with 2-benzyloxyphenyl-, 2-benzyloxymethylphenyl-diphenylphosphine (L5 and L6 respectively) are most active for hydrovinylation (HV) of vinylarenes, with the former leading to extensive isomerization of the primary 3-aryl-1-butenes into the conjugated 2-aryl-2-butenes even at -55 °C. However, 2-benzyloxymethyl-substituted ligand L6 is slightly less active, leading up to quantitative yields of the primary products of HV at ambient temperature with no trace of isomerization, thus providing the best option for a practical synthesis of these compounds. In sharp contrast, hydrovinylation of a variety of 1,3-dienes is best catalyzed by nickel(II)-complexes of 2-benzyloxyphenyldiphenylphosphine, L5. The other two ligands, 2-benzyloxymethyl-(L6) and 2-benzyloxyethyl-diphenylphosphine (L7) are much less effective in the HV of 1,3-dienes. Nickel(II)-catalyzed cycloisomerization of 1,6-dienes into methylenecyclopentanes, a reaction mechanistically related to the other hydrovinylation reactions, is also uniquely effected by nickel(II)-complexes of L5, but not of L6 or L7. In an attempt to prepare authentic samples of the methylencyclohexane products, nickel(II)-complexes of N-heterocyclic carbene-ligands were examined. In sharp contrast to the phosphines, which give the methylenecyclopentanes, methylenecyclohexanes are the major products in the (N-heterocyclic carbene)nickel(II)-mediated reactions.

Chemoselective reactions of (E)-1,3-dienes: cobalt-mediated isomerization to (Z)-1,3-dienes and reactions with ethylene.

In the asymmetric hydrovinylation (HV) of an E/Z-mixture of a prototypical 1,3-diene with (S,S)-(DIOP)CoCl2 or (S,S)-(BDPP)CoCl2 catalyst in the presence of Me3Al, the (E)-isomer reacts significantly faster, leaving behind the Z-isomer intact at the end of the reaction. The presumed [LCo-H](+)-intermediate, especially when L is a large-bite angle ligand, similar to DIOP and BDPP, promote an unusual isomerization of (E/Z)-mixtures of 1,3-dienes to isomerically pure Z-isomers. A mechanism that involves an intramolecular hydride addition via an [η(4)-(diene)(LCo-H)](+) complex, followed by π-σ-π isomerization of the intermediate Co(allyl) species, is proposed for this reaction.