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Herein, we report room temperature, atom-economic protocols for high regio- and enantioselective tandem cycloisomerization-hydroarylation and cycloisomerization-hydroalkenylation of 1,6-enynes leading to vicinal carba -functionalized pyrrolidines, tetrahydrofurans, and cyclopentanes. The latter steps in these processes involve carbonyl-coordination-assisted ortho- C-H activation of aromatic aldehydes and esters, and, a similar, yet rarely seen, β-C-H activation in the case of the acrylates. Synthetically useful enantioselective versions of such reactions are rare and are limited to the C 2 -H activation of indoles and pyrroles. A similar reaction is also observed with N -vinylphthalimide, which also has a carbonyl group suitable for C-H activation. A dibenzooxaphosphole ligand, (2 S ,2 S' ,3 S, 3 S' )-MeO-BIBOP was uniquely identified as crucial to achieving the challenging regio- and enantioselectivity. This methodology gives access to substituted five-membered carbo- and heterocyclic compounds in good yields and excellent enantioselectivities under a low catalyst loading. A primary KIE of 3.5 is observed in an intermolecular competition experiment with methyl benzoate and d 5 -methyl benzoate, which indicates that the C-H cleavage is the turnover-limiting step of this process. Unlike the acrylates, which undergoes exclusive hydroalkenylation, a β, γ-unsaturated ester, methyl but-3-enoate, undergoes the highly enantioselective cycloisomerization-coupling sequence with a 1,6-enyne giving either a [2 + 2 + 2]-cycloaddition with ( S, S )-BDPP or hydroalkenylation with (2 S ,2' S ,3 S ,3' S )-MeO-BIBOP depending on the ligand employed. The ( E )-configuration of the newly formed double bond at the terminal alkynyl carbon (of the starting enyne) in the hydroalkenylation product of β,γ-unsaturated ester suggests a more classical migratory insertion-β-hydride elimination route for the formation of this product.

Even though metal-catalyzed enantioselective hydroborations of alkenes have attracted enormous attention, few preparatively useful reactions of α-alkyl acrylic acid derivatives are known, and most use rhodium catalysts. No examples of asymmetric hydroboration of the corresponding α-arylacrylic acid esters are known. In our continuing efforts to search for new applications of earth-abundant cobalt catalysts for broadly applicable organic transformations, we have identified 2-(2-diarylphosphinophenyl)oxazoline ligands and mild reaction conditions for efficient and highly regio- and enantioselective hydroboration of α-alkyl- and α-aryl- acrylates, giving β-borylated propionates. Since the C-B bonds in these compounds can be readily replaced by C-O, C-N, and C-C bonds, these intermediates could serve as valuable chiral synthons, some from feedstock carbon sources, for the synthesis of propionate-bearing motifs including polyketides and related molecules. Two-step syntheses of "Roche" ester from methyl methacrylate (79%; er 99:1), arguably the most widely used chiral fragment in polyketide synthesis, and tropic acid esters (∼80% yield; er ∼93:7), which are potential intermediates for several medicinally important classes of compounds, illustrate the power of the new methods. Mechanistic studies confirm the requirement of a cationic Co(I) species [( L )Co] + as the viable catalyst in these reactions and rule out the possibility of a [ L ]Co-H-initiated route, which has been well-established in related hydroborations of other classes of alkenes. A mechanism involving an oxidative migration of a boryl group to the β-carbon of an η 4 -coordinated acrylate-cobalt complex is proposed as a plausible route.

Enantiopure homoallylic boronate esters are versatile intermediates because the C-B bond in these compounds can be stereospecifically transformed into C-C, C-O, and C-N bonds. Regio- and enantioselective synthesis of these precursors from 1,3-dienes has few precedents in the literature. We have identified reaction conditions and ligands for the synthesis of nearly enantiopure (er >97:3 to >99:1) homoallylic boronate esters via a rarely seen cobalt-catalyzed [4,3]-hydroboration of 1,3-dienes. Monosubstituted or 2,4-disubstituted linear dienes undergo highly efficient regio- and enantioselective hydroboration with HBPin catalyzed by [( L *)Co] + [BARF] - , where L* is typically a chiral bis-phosphine ligand with a narrow bite angle. Several such ligands (e.g., i -PrDuPhos, QuinoxP*, Duanphos, and BenzP*) that give high enantioselectivities for the [4,3]-hydroboration product have been identified. In addition, the equally challenging problem of regioselectivity is uniquely solved with a dibenzooxaphosphole ligand, ( R,R )-MeO-BIBOP. A cationic cobalt(I) complex of this ligand is a very efficient (TON >960) catalyst while also providing excellent regioselectivities (rr >98:2) and enantioselectivities (er >98:2) for a broad range of substrates. A detailed computational investigation of the reactions using Co complexes from two widely different ligands (BenzP* and MeO-BIBOP) employing the B3LYP-D3 density functional theory provides key insights into the mechanism and the origins of selectivities. The computational results are in full agreement with the experiments. For the complexes we have examined thus far, the relative stabilities of the diastereomeric diene-bound complexes [( L* )Co(η 4 -diene)] + lead to the initial diastereofacial selectivity, which in turn is retained in the subsequent steps, providing exceptional enantioselectivity for the reactions.

Alkynes and 1,3-dienes are among the most readily available precursors for organic synthesis. We report two distinctly different, catalyst-dependent, modes of regio- and enantioselective cycloaddition reactions between these classes of compounds providing rapid access to highly functionalized 1,4-cyclohexadienes or cyclobutenes from the same precursors. Complexes of an earth abundant metal, cobalt, with several commercially available chiral bisphosphine ligands with narrow bite angles catalyze [4+2]-cycloadditions between a 1,3-diene and an alkyne giving a cyclohexa-1,4-diene in excellent chemo-, regio- and enantioselectivities. In sharp contrast, complex of a finely tuned phosphino-oxazoline ligand promotes unique [2+2]-cycloaddition between the alkyne and the terminal double bond of the diene giving a highly functionalized cyclobutene in excellent regio- and enantioselectivities., (© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

A selective, remote desaturation has been developed to rapidly access homoallyl amines from their aliphatic precursors. The strategy employs a triple H-atom transfer (HAT) cascade, entailing (i) cobalt-catalyzed metal-HAT (MHAT), (ii) carbon-to-carbon 1,6-HAT, and (iii) Co-H regeneration via MHAT. A new class of sulfonyl radical chaperone (to rapidly access and direct remote, radical reactivity) enables remote desaturation of diverse amines, amino acids, and peptides with excellent site-, chemo-, and regioselectivity. The key, enabling C-to-C HAT step in this cascade was computationally designed to satisfy both thermodynamic (bond strength) and kinetic (polarity) requirements, and it has been probed via regioselectivity, isomerization, and competition experiments. We have also interrupted this radical transfer dehydrogenation to achieve γ-selective C-Cl, C-CN, and C-N bond formations.

Although cobalt(I) bis-phosphine complexes have been implicated in many selective C-C bond-forming reactions, until recently relatively few of these compounds have been fully characterized or have been shown to be intermediates in catalytic reactions. In this paper we present a new practical method for the synthesis and isolation of several cobalt(I)-bis-phosphine complexes and their use in Co(I)-catalyzed reactions. We find that easily prepared ( in situ generated or isolated) bis-phosphine and (2,6- N -aryliminoethyl)pyridine (PDI) cobalt(II) halide complexes are readily reduced by 1,4-bis-trimethylsilyl-1,4-dihydropyrazine or commercially available lithium nitride (Li 3 N), leaving behind only innocuous volatile byproducts. Depending on the structures of the bis-phosphines, the cobalt(I) complex crystallizes as a phosphine-bridged species [(P∼P)(X)Co I [μ-(P∼P)]Co I (X)(P∼P)] or a halide-bridged species [(P∼P)Co I [μ-(X)] 2 Co I (P∼P)]. Because the side-products are innocuous, these methods can be used for the in situ generation of catalytically competent Co(I) complexes for a variety of low-valent cobalt-catalyzed reactions of even sensitive substrates. These complexes are also useful for the synthesis of rare cationic [(P∼P)Co I -η 4 -diene] + X - or [(P∼P)Co I -η 6 -arene] + X - complexes, which are shown to be excellent single-component catalysts for the following regioselective reactions of dienes: heterodimerizations with ethylene or methyl acrylate, hydroacylation and hydroboration. The reactivity of the single-component catalysts with the in situ generated species are also documented.

( 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 C 4 and H at C 1 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)CoCl 2 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 β-vinyl ketones, thus providing a practical two-step approach to these valuable synthons starting from α,β-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 β-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., Competing Interests: The authors declare no financial interest.

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 )CoX 2 /Me 3 Al] ( 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 (C 6 F 5 ) 3 B, 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.

Ketones are among the most widely used intermediates in organic synthesis, and their synthesis from inexpensive feedstocks could be quite impactful. Regio- and enantioselective hydroacylation reactions of dienes provide facile entry into useful ketone-bearing chiral motifs with an additional latent functionality (alkene) suitable for further elaboration. Three classes of dienes, 2- or 4-monosubstituted and 2,4-disubstituted 1,3-dienes, undergo cobalt(I)-catalyzed regio- and enantioselective hydroacylation, giving products with high enantiomeric ratios (er). These reactions are highly dependent on the ligands, and we have identified the most useful ligands and reaction conditions for each class of dienes. 2-Substituted and 2,4-disubstituted dienes predominantly undergo 1,2-addition, whereas 4-substituted terminal dienes give highly enantioselective 4,1- or 4,3-hydroacylation depending on the aldehyde, aliphatic aldehydes giving 4,1-addition and aromatic aldehydes giving 4,3-addition. Included among the substrates are feedstock dienes, isoprene (US$1.4/kg) and myrcene (US$129/kg), and several common aldehydes. We propose an oxidative dimerization mechanism that involves a Co(I)/Co(III) redox cycle that appears to be initiated by a cationic Co(I) intermediate. Studies of reactions using isolated neutral and cationic Co(I) complexes confirm the critical role of the cationic intermediates in these reactions. Enantioselective 1,2-hydroacylation of 2-trimethylsiloxy-1,3-diene reveals a hitherto undisclosed route to chiral siloxy-protected aldols. Finally, facile syntheses of the anti-inflammatory drug ( S )-Flobufen (2 steps, 92% yield, >99:1 er) and the food additive ( S )-Dihydrotagetone (1 step, 83% yield; 96:4 er) from isoprene illustrate the power of this method for the preparation of commercially relevant compounds.

Two intermolecular hydroalkenylation reactions of 1,6-enynes are presented which yield substituted 5-membered carbo- and -heterocycles. This reactivity is enabled by a cationic bis -diphenylphosphinopropane (DPPP)Co I species which forms a cobaltacyclopentene intermediate by oxidative cyclization of the enyne. This key species interacts with alkenes in distinct fashion, depending on the identity of the coupling partner to give regiodivergent products. Simple alkenes undergo insertion reactions to furnish 1,3-dienes whereby one of the alkenes is tetrasubstituted. When acrylates are employed as coupling partners, the site of intermolecular C-C formation shifts from the alkyne to the alkene motif of the enyne, yielding Z-substituted-acrylate derivatives. Computational studies provide support for our experimental observations and show that the turnover-limiting steps in both reactions are the interactions of the alkenes with the cobaltacyclopentene intermediate via either a 1,2-insertion in the case of ethylene, or an unexpected β-C-H activation in the case of most acrylates. Thus, the H syn to the ester is activated through the coordination of the acrylate carbonyl to the cobaltacycle intermediate, which explains the uncommon Z -selectivity and regiodivergence. Variable time normalization analysis (VTNA) of the kinetic data reveals a dependance upon the concentration of cobalt, acrylate, and activator. A KIE of 2.1 was observed with methyl methacrylate in separate flask experiments, indicating that C-H cleavage is the turnover-limiting step in the catalytic cycle. Lastly, a Hammett study of aryl-substituted enynes yields a ρ value of -0.4, indicating that more electron-rich substituents accelerate the rate of the reaction., Competing Interests: The authors declare no competing financial interest.

While writing a comprehensive review on the reactions of epoxides with titanium(III) reagents, we encountered a series of mechanistic puzzles. Using clues from the literature, many of which were not available at the time that the mysteries emerged, it was possible to demystify a number of these conundrums. We discuss four examples, which we believe will significantly change the way in which titanium(III) chemistry is practiced. Our experience underscores the importance of comprehensive and critical reviews in chemistry and the truism that the authors are prime beneficiaries of the review process., (© 2020 Wiley-VCH GmbH.)

Coupling reactions of feedstock alkenes are promising, but few of these reactions are practiced industrially. Even though recent advances in the synthetic methodology have led to excellent regio- and enantioselectivies in the dimerization reactions between 1,3-dienes and acrylates, the efficiency as measured by the turnover numbers (TON) in the catalyst has remained modest. Through a combination of reaction progress kinetic analysis (RPKA) of a prototypical dimerization reaction, characterization of isolated low-valent cobalt catalyst precursors involved, several important details of the mechanism of this reaction have emerged. (i) The prototypical reaction has an induction period that requires at least two hours of stir time to generate the competent catalyst. (ii) Reduction of a Co(II) complex to a Co(I) complex, and subsequent generation of a cationic [Co (I) ] + species are responsible for this delay. (iii) Through RPKA using in situ IR spectroscopy, same excess experiments reveal inhibition by the product towards the end of the reaction and no catalyst deactivation is observed as long as diene is present in the medium. The low TON observed is most likely the result of the inherent instability of the putative cationic Co(I)-species that catalyzes the reaction. (iv) Different excess experiments suggest that the reaction is first order in the diene and zero order in the acrylate. (v) Catalyst loading experiments show that the catalyst is first order. The orders in the various regents were further confirmed by Variable Time Normalization Analysis (VTNA). (vi) A mechanism based on oxidative dimerization [via Co(I)/Co(III)-cycle] is proposed. Based on the results of this study, it is possible to increase the TON by a factor of 10 by conducting the reaction at an increased concentration of the starting materials, especially, the diene, which seems to stabilize the catalytic species., Competing Interests: The authors declare no competing financial interest.

Discovery of enantioselective catalytic reactions for the preparation of chiral compounds from readily available precursors, using scalable and environmentally benign chemistry, can greatly impact their design, synthesis, and eventually manufacture on scale. Functionalized cyclobutanes and cyclobutenes are important structural motifs seen in many bioactive natural products and pharmaceutically relevant small molecules. They are also useful precursors for other classes of organic compounds such as other cycloalkane derivatives, heterocyclic compounds, stereodefined 1,3-dienes, and ligands for catalytic asymmetric synthesis. The simplest approach to make cyclobutenes is through an enantioselective [2 + 2]-cycloaddition between an alkyne and an alkenyl derivative, a reaction which has a long history. Yet known reactions of this class that give acceptable enantioselectivities are of very narrow scope and are strictly limited to activated alkynes and highly reactive alkenes. Here, we disclose a broadly applicable enantioselective [2 + 2]-cycloaddition between wide variety of alkynes and alkenyl derivatives, two of the most abundant classes of organic precursors. The key cycloaddition reaction employs catalysts derived from readily synthesized ligands and an earth-abundant metal, cobalt. Over 50 different cyclobutenes with enantioselectivities in the range of 86-97% ee are documented. With the diverse functional groups present in these compounds, further diastereoselective transformations are easily envisaged for synthesis of highly functionalized cyclobutanes and cyclobutenes. Some of the novel observations made during these studies including a key role of a cationic Co(I)-intermediate, ligand and counterion effects on the reactions, can be expected to have broad implications in homogeneous catalysis beyond the highly valuable synthetic intermediates that are accessible by this route.

Much of the recent work on catalytic hydroboration of alkenes has focused on simple alkenes and styrene derivatives with few examples of reactions of 1,3-dienes, which have been reported to undergo mostly 1,4-additions to give allylic boronates. We find that reduced cobalt catalysts generated from 1,n- bis-diphenylphosphinoalkane complexes [Ph 2 P-(CH 2 ) n -PPh 2 ]CoX 2 ; n = 1-5) or from (2-oxazolinyl)phenyldiarylphosphine complexes [(G-PHOX)CoX 2 ] (G = 4-substituent on oxazoline ring) effect selective 1,2-, 1,4-, or 4,3-additions of pinacolborane (HBPin) to a variety of 1,3-dienes depending on the ligands chosen. Conditions have been found to optimize the 1,2-additions. The reactive catalysts can be generated from the cobalt(II)-complexes using trimethylaluminum, methyl aluminoxane, or activated zinc in the presence of sodium tetrakis[(3,5-trifluoromethyl)phenyl]borate (NaBARF). The complex, (dppp)CoCl 2 , gives the best results (ratio of 1,2- to 1,4-addition >95:5) for a variety of linear terminal 1,3-dienes and 2-substituted 1,3-dienes. The [(PHOX)CoX 2 ] (X = Cl, Br) complexes give mostly 1,4-addition with linear unsubstituted 1,3-dienes, but, surprisingly, selective 1,2-additions with 2-substituted or 2,3-disubstituted 1,3-dienes. Isolated and fully characterized (X-ray crystallography) Co(I)-complexes, (dppp) 3 Co 2 Cl 2 and [( S,S)-BDPP] 3 Co 2 Cl 2 , do not catalyze the reaction unless activated by a Lewis acid or NaBARF, suggesting a key role for a cationic Co(I) species in the catalytic cycle. Regio- and enantioselective 1,2-hydroborations of 2-substituted 1,3-dienes are best accomplished using a catalyst prepared via activation of a chiral phosphinooxazoline-cobalt(II) complex with zinc and NaBARF. A number of common functional groups, among them, -OBn, -OTBS, -OTs, N-phthalimido- groups, are tolerated, and er's > 95:5 are obtained for several dienes including 1-alkenylcycloalk-1-enes. This operationally simple reaction expands the realm of asymmetric hydroboration to provide direct access to a number of nearly enantiopure homoallylic boronates, which are not readily accessible by current methods. The resulting boronates have been converted into the corresponding alcohols, potassium trifluororoborate salts, N-BOC amines, and aryl derivatives by C-BPin to C-aryl transformation.

The role of Cp 2 Ti(H)Cl in the reactions of Cp 2 TiCl with trisubstituted epoxides has been investigated in a combined experimental and computational study. Although Cp 2 Ti(H)Cl has generally been regarded as a robust species, its decomposition to Cp 2 TiCl and molecular hydrogen was found to be exothermic (ΔG = -11 kcal/mol when the effects of THF solvation are considered). In laboratory studies, Cp 2 Ti(H)Cl was generated using the reaction of 1,2-epoxy-1-methylcyclohexane with Cp 2 TiCl as a model. Rapid evolution of hydrogen gas was demonstrated, indicating that Cp 2 Ti(H)Cl is indeed a thermally unstable molecule, which undergoes intermolecular reductive elimination of hydrogen under the reaction conditions. The stoichiometry of the reaction (Cp 2 TiCl:epoxide = 1:1) and the quantity of hydrogen produced (1 mole per 2 moles of epoxide) is consistent with this assertion. The diminished yield of allylic alcohol from these reactions under the conditions of protic versus aprotic catalysis can be understood in terms of the predominant titanium(III) present in solution. Under the conditions of protic catalysis, Cp 2 TiCl complexes with collidine hydrochloride and the titanium(III) center is less available for "cross-disproportionation" with carbon-centered radicals; this leads to by-products from radical capture by hydrogen atom transfer, resulting in a saturated alcohol., Competing Interests: The authors declare no competing financial interest.

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.

Transformation of simple precursors into structurally complex cyclobutanes, present in many biologically important natural products and pharmaceuticals, is of considerable interest in medicinal chemistry. Starting from 1,3-enynes and ethylene, both exceptionally inexpensive starting materials, we report a cobalt-catalyzed route to vinylcyclobutenes, as well as the further enantioselective addition of ethylene to these products to form complex cyclobutanes with all-carbon quaternary centers. These reactions can proceed in discrete stages or in a tandem fashion to achieve three highly selective carbon-carbon bond formations in one pot using a single chiral cobalt catalyst., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

1,3-Dienes are ubiquitous and easily synthesized starting materials for organic synthesis, and alkyl acrylates are among the most abundant and cheapest feedstock carbon sources. A practical, highly enantioselective union of these two readily available precursors giving valuable, enantio-pure skipped 1,4-diene esters (with two configurationally defined double bonds) is reported. The process uses commercially available cobalt salts and chiral ligands. As illustrated by the use of 20 different substrates, including 17 prochiral 1,3-dienes and 3 acrylates, this hetero-dimerization reaction is tolerant of a number of common organic functional groups (e.g., aromatic substituents, halides, isolated mono- and di-substituted double bonds, esters, silyl ethers, and silyl enol ethers). The novel results including ligand, counterion, and solvent effects uncovered during the course of these investigations show a unique role of a possible cationic Co(I) intermediate in these reactions. The rational evolution of a mechanism-based strategy that led to the eventual successful outcome and the attendant support studies may have further implications for the expanding use of low-valent group 9 metal complexes in organic synthesis.

Molecular baskets capture various tris(2-pyridylmethyl)amine ligands, with and without zinc(II) cation, to form nesting complexes. The results of our computational (MD) and experimental ( 1 H NMR/ITC) studies suggest that the assembly is driven by the hydrophobic effect with the charge of complementary molecular components playing an important role in the formation of nesting complexes. In brief, the complexation only takes place when the basket and the ligand carry either oppositely charged or noncharged groups.

Readily accessible ( i -Pr PDI)CoCl 2 [ i -Pr PDI = 2,6- bis (2,6-diisopropylphenyliminoethyl)pyridine] reacts with 2 equivalents of NaEt 3 BH at -78 °C in toluene to generate a catalyst that effects highly selective anti-Markovnikov hydrosilylation of the terminal double bond in 1,3- and 1,4-dienes. Primary and secondary silanes such as PhSiH 3 , Ph 2 SiH 2 and PhSi(Me)H 2 react with a broad spectrum of terminal dienes without affecting the configuration of the other double bond. When dienes conjugated to an aromatic ring are involved, both Markovnikov and anti-Markovnikov products are formed. The reaction is tolerant of various functional groups such as an aryl bromide, aryl iodide, protected alcohol, and even a silyl enol ether. Reactions of 1-alkene under similar conditions cleanly lead to a mixture of Markovnikov and anti-Markovnikov hydrosilation products, where ratio of the products increasingly favors the latter, as the size of the 2,6-substituents in the iminoylaryl group becomes larger. The complex ( i -Pr PDI)CoCl 2 gives exclusively the linear silane for a wide variety of terminal alkenes. Mechanistic studies suggest a pathway that involves a key role for an in situ generated metal hydride, (L )Co(I)-H. Exclusive reduction of the terminal double bond (vis-a-vis hydrosilylation) when (EtO) 2 Si(Me)H is used in the place of PhSiH 3 is explained on the basis of an alternate silane-mediated decomposition path for the linear Co(I)-alkyl intermediate., Competing Interests: Notes The authors declare no financial interest.

While attempting to effect Co-catalyzed hydrosilylation of β-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)]CoCl 2 activated by 2 equivalents of NaEt 3 BH as a catalyst (0.001-0.05 equiv) and (EtO) 2 SiMeH 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, β-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.

In this study, we examined the structural and electronic complementarities of convex 1-Zn(II), comprising functionalized tris(2-pyridylmethyl)amine (TPA) ligand, and concave baskets 2 and 3, having glycine and (S)-alanine amino acids at the rim. With the assistance of (1)H NMR spectroscopy and mass spectrometry, we found that basket 2 would entrap 1-Zn(II) in water to give equimolar 1-Zn⊂2in complex (K = (2.0 ± 0.2) × 10(3) M(-1)) resembling Russian nesting dolls. Moreover, C3 symmetric and enantiopure basket 3, containing (S)-alanine groups at the rim, was found to transfer its static chirality to entrapped 1-Zn(II) and, via intermolecular ionic contacts, twist the ligand's pyridine rings into a left-handed (M) propeller (circular dichroism spectroscopy). With molecular baskets embodying the second coordination sphere about metal-containing TPAs, the here described findings should be useful for extending the catalytic function and chiral discrimination capability of TPAs.

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 β-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.

In the presence of bidentate 1,n- bis -diphenylphosphinoalkane-CoCl 2 complexes {Cl 2 Co[P~P]} and Me 3 Al or methylaluminoxane, acyclic ( E )-1,3-dienes react with ethylene (1 atmosphere) to give excellent yields of hydrovinylation products. The regioselectivity (1,4- or 1,2-addition) and the alkene configuration ( E - or Z -) of the resulting product depend on the nature of the ligand and temperature at which the reaction is carried out. Cobalt(II)-complexes of 1,1-diphenylphosphinomethane and similar ligands with narrow bite angles give mostly 1,2-addition, retaining the E -geometry of the original diene. Complexes of most other ligands at low temperature (-40 °C) give almost exclusively a single branched product, ( Z )-3-alkylhexa-1,4-diene, which arises from a 1,4-hydrovinylation reaction. A minor product is the linear adduct, a 5-alkyl-hexa-1,4-diene, also arising from a 1,4-addition of ethylene. As the temperature is increased, a higher proportion of the major 1,4-adduct appears as the ( E )-isomer. The unexpectedly high selectivity seen in the Co-catalysed reaction as compared to the corresponding Ni-catalysed reaction can be rationalized by invoking the intermediacy of an η 4 -[(diene)[P~P]CoH] + -complex and its subsequent reactions. The enhanced reactivity of terminal E -1,3-dienes over the corresponding Z -dienes can also be explained on the basis of the ease of formation of this η 4 -complex in the former case. The lack of reactivity of the X 2 Co(dppb) (X = Cl, Br) complexes in the presence of Zn/ZnI 2 makes the Me 3 Al-mediated reaction different from the previously reported hydroalkenylation of dienes. Electron-rich phospholanes, bis -oxazolines and N -heterocyclic carbenes appear to be poor ligands for the Co(II)-catalysed hydrovinylation of 1,3-dienes. An extensive survey of chiral ligands reveals that complexes of DIOP, BDDP and Josiphos ligands are quite effective for these reactions even at -45 °C and enantioselectivities in the range of 90-99 % ee can be realized for a variety of 1,3-dienes. Cobalt(II)-complex of an electron-deficient Josiphos ligand is especially active, requiring only <1 mol% catalyst to effect the reactions.

5,10,15,20-Tetraphenylporphyrin chromium chloride (TPPCrCl) with added [Ph3P═N═PPh3](+)Cl(-) (PPN(+)Cl(-)) selectively polymerizes lactide (L and rac) dissolved in neat propylene oxide (PO) to yield polylactide (PLA) terminated by the -OCHMeCH2Cl group. At 0 °C and below, rac-LA yields polymers highly enriched in isotactic tetrads (iii). At 25 °C, some stereoselectivity is lost as transesterification becomes significant, and at 60 °C and above, enchainment of PO leads to the formation of 3,6-dimethyl-1,4-dioxan-2-one by a backbiting mechanism. At 0 °C, after the enchainment of L-(S,S)-LA in neat (R)-(+)-PO, the formation of (3S,6R)-3,6-dimethyl-1,4-dioxan-2-one occurs, while at higher temperatures the ratio of (3S,6R)-3,6-dimethyl-1,4-dioxan-2-one to (3R,6R)-3,6-dimethyl-1,4-dioxan-2-one falls to 3:2.

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.

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.

1-Vinylcycloalkenes undergo highly regio- and enantioselective (>98% ee) 1,4-hydrovinylation (HV) when treated with ethylene (1 atm) at room temperature in the presence of [(S,S)-2,4-bis-diphenylphosphinopentane (BDPP)]CoCl(2) (0.05 equiv) and methylaluminoxane. The minor 1,2-HV products, seen only in 1-vinylcyclohexene (~15%) and 1-vinylcycloheptene (2%), are formed as racemic mixtures. The corresponding Ni(II)-catalyzed HV reactions of these substrates give mostly the 1,2-adducts. Racemic 4-tert-butyl-1-vinylcyclohexene, when treated with Co[(S,S)-(BDPP)]Cl(2) and ethylene, undergoes a rare enantiodivergent reaction giving two diastereomers each in >98% ee., (© 2012 American Chemical Society)

Vinylindoles undergo Ni(II)-catalyzed asymmetric hydrovinylation under very mild conditions (-78 °C, 1 atm ethylene, 4 mol % catalyst) to give the corresponding 2-but-3-enyl derivatives in excellent yields and enantioselectivities. Hydroboration of the alkene and oxidation to an acid, followed by Friedel-Crafts annulation, gives an indole-annulated cyclopentanone that is a suitable precursor for the syntheses of cis-trikentrins and all known herbindoles. For example, the cyclopentanone from 4-ethyl-7-vinylindole is converted into (+)-cis-trikentin A in four steps (Wittig reaction, alkene isomerization, diastereoselective hydrogenation, and nitrogen deprotection). The previous synthesis of this molecule from (S)-(-)-malic acid involved more than 20 steps and a preparative HPLC separation of diastereomeric intermediates.

The asymmetric hydrovinylation (1 mol % Ni-cat., 1 atm, ethylene, >98% ee) products from 1-methylenetetralines are readily converted into 3,3-disubstituted oxindoles and subsequently to pyrrolidinoindolines. These hydrovinylation products are also useful for the syntheses of enantiopure benzomorphans.

In this report we highlight the significant potential of ethylene as a reagent for the introduction of a vinyl group with excellent stereoselectivity at three different stages in the synthesis of a broad class of natural products, best exemplified by syntheses of pseudopterosins. The late-stage applications of the asymmetric hydrovinylation reaction further illustrate the compatibility of the catalyst with complex functional groups. We also show that, depending on the choice of the catalyst, it is possible to either enhance or even completely reverse the inherent diastereoselectivity in the reactions of advanced chiral intermediates. This should enable the synthesis of diastereomeric analogs of several classes of medicinally relevant compounds that are not readily accessible by the existing methods, which depend on 'substrate control' for the installation of many of the chiral centers, especially in molecules of this class.

The scope of Ni(II)-catalyzed hydrovinylation has been extended to strained alkenes such as heterobicyclic [2.2.1]heptanes and cylobutenes. Reactions involving the heterobicyclic compounds are rare examples for this class of compounds where the metal-catalyzed C-C bond-forming reactions proceed without a concomitant ring-opening process. While the enantioselectivity in these systems remains modest, hydrovinylation of endo-5,6--bis-benzyloxymethylbicyclo[2.2.1]hept-2-ene gives excellent yield (>90%) of the product with one of the highest enantioselectivities (95-99% ee) reported for a C-C bond-forming reaction of norbornenes.

The borylstannane [-N(Me)CH(2)CH(2)(Me)N-]B-SnMe(3) is a superior reagent capable of effecting bisfunctionalization-cyclization in several highly functionalized 1,n-diynes, 1,n-enynes, and 1,n-allenynes (including 1,2-dipropargylbenzenes, 2,2'-dipropargylbiphenyls, 4,5-dipropargyldioxolanes, and 1,4-dipropargyl-β-lactams) where the more well-known silylstannanes fail. Variable-temperature NMR studies showed that conformational restraints imposed by selected backbones increase the activation barrier for the helical isomerization in (Z,Z)-dienes that are generated in the cyclization of the diynes. In the biphenyl and dioxolane systems, the reactions proceed with surprisingly good regio- and stereoselectivity. The resulting diazaborolidine derivatives are hydrolytically unstable but can be isolated by recrystallization or precipitation. For further synthetic applications, it is advantageous to convert these compounds in situ into the corresponding dioxaborolidines with either retention of the Me(3)Sn group or replacement of this group via halodestannylation. The configurations of the vinyl moieties are preserved in these reactions. Highly functionalized dibenzocyclooctadienes, which adorn the carbon frames of several important cytotoxic natural products, can be synthesized using this chemistry.

The utility of the hetero-bismetallating reagent 1,3-dimethyl-2-trimethylstannyl-2-bora-1,3-diazacyclopentane (1) has not been fully realized because of the hydrolytic instability of the products derived from catalyzed vicinal syn-additions to alkynes. The isolation of a variety of such adducts derived from alkynes (and also from hitherto unreported additions to 1,3-enynes) as stable boron pinacolates is reported. Examples of the applications of resulting products in tandem cross-coupling reactions and as dienes in Diels-Alder reactions are illustrated.

Facile CuI-mediated N-arylation of diketopiperazine using the Fukuyama modification of the Ullmann-Goldberg reaction can be exploited in new approaches to enantiopure polycyclic diketopiperazines from easily assembled dipeptides or functionalized Schöllkopf reagents.

Density functional theory calculations were performed to evaluate the proposed mechanism of a yttrium-salen complex-catalyzed acylation of secondary alcohols using an enol acetate as the acyl-transfer agent. A key step in the proposed mechanism is an intramolecular nucleophilic reaction between the coordinated alcohol and enol ester, brought into close proximity by the yttrium catalyst. The use of the BP86 pure density functional for reproduction of the geometry of the yttrium complex was validated by comparison with the experimental crystal structure. Mapping of the free energy surface of the reaction followed, employing both the BP86 and B3LYP functionals, and results suggest that the proposed mechanism (Org. Lett. 2002, 4, 1607-1610) is a reasonable pathway for the reaction. Reproduction of the experimentally observed enantioselectivity of the reaction was subsequently attempted, with diastereomeric transition states identified for the turnover-limiting step in the reaction, the intramolecular nucleophilic attack of the alcohol into the enol ester reagent. The predicted experimental enantioselectivities were successfully reproduced for the three ligands studied, although the energetic predictions did not perfectly correlate with the experimental enantioselectivities.

Monosubstituted acyclic (E)-1,3-dienes undergo efficient hydrovinylation giving (Z)-3-alkylhexa-1,4-dienes upon treatment with catalytic amounts of bidentate phosphine-CoCl(2) complexes {[P~P](CoCl(2))} and Me(3)Al in an atmosphere of ethylene. The regioselectivity of the reaction (i.e., 1,4- or 1,2-addition) depends on the nature of the ligand and temperature at which the reaction is carried out. Complexes derived from (RR)-DIOP and (SS)-BDDP at -45 degrees C give very high enantioselectivities for several prototypical 1,3-dienes. In sharp contrast to the corresponding Ni(II)-catalyzed hydrovinylation, 1-aryl-substituted 1,3-dienes give almost exclusively achiral linear 1,4-addition products, unless the 2-position is also substituted. Solid-state structures of the precatalysts are presented.

Aryl bromides and iodides in the presence of catalytic amounts of a palladacycle derived from acetophenone oxime and 2 equivalents of potassium acetate react with ethylene under ambient pressure (15-30 psi) to give the corresponding vinylarenes. The reactions work with both electron-deficient and electron-rich aryl compounds and tolerate wide variety of common functional groups. Vinyl bromides lead to 1,3-dienes in moderate yields.

Kinetic resolution of strained three-membered rings has proven broadly useful for the generation of enantiopure organic intermediates. Herein we demonstrate a complementary approach whereby a single catalyst transforms a racemic mixture of aziridines to a pair of regioisomeric products, each in good yield with exceptionally high enantioselectivity. Specifically, the dimeric yttrium salen catalyst accelerates the ring opening of aliphatic aziridines by trimethylsilylazide, inducing nucleophilic attack at the primary position of one enantiomer and the secondary position of the other. Both rate and selectivity are highly sensitive to the catalyst structure.

Seleniranium ions at low temperatures (-90 to -78 degrees C) will initiate effective Friedel-Crafts cyclization if a suitably placed arene is allowed to react even when the arene is unactivated. These intermediates generated from N-aryl-N-tosylamides undergo a novel, surprisingly efficient, detosylative cyclization to form 5- or 6-membered nitrogen heterocycles. A debenzylation route is preferred if both benzyl and tosyl groups are present in the substrate.

We report a detailed and full computational investigation on the hydrovinylation reaction of styrene with the Ni(II)-phospholane catalytic system, which was originally presumed to proceed through a cationic mechanism involving a nickel hydride intermediate. The following general features emerge from this study on a specific catalyst complex that was found to give quantitative yield and moderate selectivity: (a) the activation barrier for the initiation (18.8 kcal/mol) is higher than that for the reaction due to a low-lying square-planar pentenyl chelate intermediate originating from a Ni(II)-allyl catalyst precursor. Consequently there is an induction period for the catalysis; (b) the exit of product from the catalyst is via a β-H-transfer step instead of the usual β-H elimination pathway, which has a very high activation energy due to a trans effect of the phospholane ligand; (c) the turnover-limiting and enantio- determining transition state is also the β-H-transfer; (d) because of the absence of a hydride intermediate, the unwanted isomerization of the product is prevented; (e) since the enantio-discrimination is decided at the H-transfer stage itself, the configuration of the product in a catalytic cycle influences the enantioselectivity in the subsequent cycle; (f) the trans effect of the sole strong ligand in the d8 square-planar Ni(II), the stability of the η(3)-benzyl intermediate, and the availability of three coordination sites enable regioselective hydrovinylation over the possible oligomerization/polymerization of the olefin substrates and linear hydrovinylation. This work has also confirmed the previously recognized role of the hemilabile group at various stages in the mechanism.

Mono- and 2,2'-disubstituted terminal alkenes can be isomerized into the more stable internal (Z)- and (E)-alkenes by treating them with catalytic amounts of [(allyl)PdCl](2) or [(allyl)NiBr](2), a triarylphosphine, and silver triflate at room temperature. The isomeric ratio (E:Z) depends on the alkenes, the E-isomer being the major one. The reaction is tolerant to a wide variety of functional groups including other reactive olefins. Unlike the more reactive Ir catalysts, monosubstituted alkenes give almost exclusively the 2-alkenes. Direct comparison to two of the best-known catalysts for this process {[Ir(PCy(3))(3)](+)[BPh(4)](-) and Grubbs generation II metathesis catalyst} is also described.

A three-step procedure for the synthesis of 2-arylpropionic acids (profens) from vinyl arenes in nearly enantiomerically pure form has been developed. Excellent yields (>97%), regioselectivities (>99%), and enantioselectivities (>97% ee) for the desired branched products were obtained in the asymmetric hydrovinylation reactions of vinyl arenes, and the products from these reactions were transformed into 2-arylpropionic acids via oxidative degradation. Subsequent Curtius or Schmidt rearrangements of these acids provided highly valued 1-arylethyl amines, including a prototypical primary amine with an alpha-chiral tertiary N-alkyl group, in very good yields.

Attempts to introduce the highly versatile vinyl group into other organic molecules in a chemo-, regio- and stereoselective fashion via catalytic activation of ethylene provided challenging opportunities to explore new ligand and salt effects in homogeneous catalysis. This review provides a personal account of the development of enantioselective reactions involving ethylene.

1-Alkylstyrenes undergo efficient hydrovinylation (addition of ethylene) in the presence of a Ni-catalyst prepared from [(allyl)NiBr](2), Na(+) [BAr(4)](-) (Ar = 3,5-bis-trifluromethylphenyl), and a phosphoramidite ligand giving products in excellent yields and enantioselectivities. In many cases phosphoramidites derived from achiral 2,2'-biphenol are almost as good as ligands derived from the more expensive enantiopure 2,2'-binaphthols. The hydrovinylation products, which carry two versatile latent functionalities, an aryl and a vinyl group, are potentially useful for the synthesis of several important natural products containing benzylic all-carbon quaternary centers.

The [B-Sn]-mediated cyclization of alpha,omega-diynes results in not only an increase in the functionalizable groups (incorporated as highly versatile vinyl-B and vinyl-Sn groups) but also an increase in new serviceable stereochemical elements. The alkylidene functionalities at C7 and C8 offer unprecedented opportunities for the synthesis of highly functionalized dibenzocyclooctadienes. Examples of interiotherins and gomisins are provided.