Ligand Effects in Carboxylic Ester- and Aldehyde-Assisted ß-C-H Activation in Regiodivergent and Enantioselective Cycloisomerization-Hydroalkenylation and Cycloisomerization-Hydroarylation, and [2 + 2 + 2]-Cycloadditions of 1,6-Enynes.

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, ß-C-H activation in the case of the acrylates. Synthetically useful enantioselective versions of such reactions are rare and are limited to the C2-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, (2S,2S',3S,3S')-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 d5-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 ß, 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 (2S,2'S,3S,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 ß,γ-unsaturated ester suggests a more classical migratory insertion-ß-hydride elimination route for the formation of this product.

Cobalt-Catalyzed Enantioselective Hydroboration of α-Substituted Acrylates.

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 ß-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 ß-carbon of an η4-coordinated acrylate-cobalt complex is proposed as a plausible route.

Ligand Control in Co-Catalyzed Regio- and Enantioselective Hydroboration: Homoallyl Secondary Boronates via Uncommon 4,3-Hydroboration of 1,3-Dienes.

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(η4-diene)]+ lead to the initial diastereofacial selectivity, which in turn is retained in the subsequent steps, providing exceptional enantioselectivity for the reactions.

Chemodivergent, Regio- and Enantioselective Cycloaddition Reactions between 1,3-Dienes and Alkynes.

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.

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.

γ C-H Functionalization of Amines via Triple H-Atom Transfer of a Vinyl Sulfonyl Radical Chaperone.

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.

Activator-free single-component Co(I)-catalysts for regio- and enantioselective heterodimerization and hydroacylation reactions of 1,3-dienes. New reduction procedures for synthesis of [L]Co(I)-complexes and comparison to in situ generated catalysts.

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 (Li3N), 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)CoI[µ-(P∼P)]CoI(X)(P∼P)] or a halide-bridged species [(P∼P)CoI[µ-(X)]2CoI(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)CoI-η4-diene]+ X- or [(P∼P)CoI-η6-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.

Cationic Co(I) Catalysts for Regiodivergent Hydroalkenylation of 1,6-Enynes. An Uncommon cis-ß-C-H Activation Leads to Z-Selective Coupling of Acrylates.

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)CoI 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 ß-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.

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.

α- and ß-Functionalized Ketones from 1,3-Dienes and Aldehydes: Control of Regio- and Enantioselectivity in Hydroacylation of 1,3-Dienes.

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.

Four Mechanistic Mysteries: The Benefits of Writing a Critical Review.

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.

Mechanism of Cobalt-Catalyzed Heterodimerization of Acrylates and 1,3-Dienes. A Potential Role of Cationic Cobalt(I) Intermediates.

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.

Catalytic Enantioselective Synthesis of Cyclobutenes from Alkynes and Alkenyl Derivatives.

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.

Cationic Co(I)-Intermediates for Hydrofunctionalization Reactions: Regio- and Enantioselective Cobalt-Catalyzed 1,2-Hydroboration of 1,3-Dienes.

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 [Ph2P-(CH2) n-PPh2]CoX2; n = 1-5) or from (2-oxazolinyl)phenyldiarylphosphine complexes [(G-PHOX)CoX2] (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)CoCl2, 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)CoX2] (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)3Co2Cl2 and [( S,S)-BDPP]3Co2Cl2, 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.

Tandem catalysis for asymmetric coupling of ethylene and enynes to functionalized cyclobutanes.

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.

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.

Demystifying Cp2Ti(H)Cl and its Enigmatic Role in the Reactions of Epoxides with Cp2TiCl.

The role of Cp2Ti(H)Cl in the reactions of Cp2TiCl with trisubstituted epoxides has been investigated in a combined experimental and computational study. Although Cp2Ti(H)Cl has generally been regarded as a robust species, its decomposition to Cp2TiCl and molecular hydrogen was found to be exothermic (ΔG = -11 kcal/mol when the effects of THF solvation are considered). In laboratory studies, Cp2Ti(H)Cl was generated using the reaction of 1,2-epoxy-1-methylcyclohexane with Cp2TiCl as a model. Rapid evolution of hydrogen gas was demonstrated, indicating that Cp2Ti(H)Cl is indeed a thermally unstable molecule, which undergoes intermolecular reductive elimination of hydrogen under the reaction conditions. The stoichiometry of the reaction (Cp2TiCl: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, Cp2TiCl 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.

Catalytic Enantioselective Hetero-dimerization of Acrylates and 1,3-Dienes.

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.