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  1. Abstract

    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‐cyclohexadienesorcyclobutenes from thesameprecursors. 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.

     
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  2. Abstract

    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.

     
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  3. ABSTRACT: Enantiopure homoallylic boronate esters are versatile intermediates because the C–B bond in these com-pounds 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 enanti-oselective 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 (examples: 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 providing excellent regioselectivities (rr >98:2) and enantioselectiv-ities (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 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 exper-iments. For the complexes we have examined thus far, the relative stabilities of the diastereomeric diene-bound complexes [(L*)Co(4-diene)]+ leads to the initial diastereofacial selectivity, which in turn is retained in the subsequent steps, providing exceptional enantioselectivity for the reactions. 
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  4. Warren Piers (Ed.)
    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. 
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  5. Asymmetric synthesis of substituted 1,4 cyclohexadienes and cyclobutenes has received great attention in recent years. Strategies such as base metal catalyzed cycloaddition bypass the need of harsh reaction conditions which are often required for synthesis of such motifs. These strategies using base-metals as catalysts are also valuable in constructing substituted cyclic motifs from readily available and inexpensive materials such as dienes and alkynes. Such reactions can be cost effective and environmentally friendly. In past decade, low valent cobalt has shown promising reactivity in forming new C-C and C-X (e. g., X= Si, B, N) bonds in high stereoselectivity. Through our studies, we found that cationic cobalt(I) complexes can catalyze intermolecular cycloaddition reactions of alkyne and 1,3-dienes in regio-and enantioselective manner. We also discovered that the involvement of 4 pi electrons or 2 pi electrons of 1,3-dienes can be controlled by the judicious choice of ligands employed on cobalt leading to [4+2] and [2+2] cycloaddition products respectively in high regio- and stereoselectivity. This excellent selectivity complimented with moderate to good yields provided us with broadly applicable protocol for synthesis of diversely substituted enantiopure cyclic motifs with enantiomeric excesses upto 99%. The scope of this method has been expanded over simple aliphatic and aromatic 1,3-dienes and alkynes bearing various functional groups. The methodical development of this transformation along with the ligand effects and possible mechanisms will be discussed in detail. 
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  6. Asymmetric synthesis of substituted 1,4 cyclohexadienes and cyclobutenes has received great attention in recent years. Strategies such as base metal catalyzed cycloaddition bypass the need of harsh reaction conditions which are often required for synthesis of such motifs. These strategies using base-metals as catalysts are also valuable in constructing substituted cyclic motifs from readily available and inexpensive materials such as dienes and alkynes. Such reactions can be cost effective and environmentally friendly. In past decade, low valent cobalt has shown promising reactivity in forming new C-C and C-X (e. g., X= Si, B, N) bonds in high stereoselectivity. Through our studies, we found that cationic cobalt(I) complexes can catalyze intermolecular cycloaddition reactions of alkyne and 1,3-dienes in regio-and enantioselective manner. We also discovered that the involvement of 4-pi electrons or 2-pi electrons of 1,3-dienes can be controlled by the judicious choice of ligands employed on cobalt leading to [4+2] and [2+2] cycloaddition products respectively in high regio- and stereoselectivity. This excellent selectivity complimented with moderate to good yields provided us with broadly applicable protocol for synthesis of diversely substituted enantiopure cyclic motifs with enantiomeric excesses upto 99%. The scope of this method has been expanded over simple aliphatic and aromatic 1,3-dienes and alkynes bearing various functional groups. The methodical development of this transformation along with the ligand effects and possible mechanisms will be discussed in detail. 
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  7. Carreira, E. M. ; Schoenebeck, F. (Ed.)
    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-disubstitued 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 ($1.4 /kg) and myrcene ($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. 
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  8. null (Ed.)
    ABSTRACT 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, yield-ing 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 b-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 rho- value of -0.4, indicating that more electron-rich substituents accelerate the rate of the reaction. 
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