Ether-directed, stereoselective aza-Claisen rearrangements: synthesis of the piperidine alkaloid, alpha-conhydrine

[reaction: see text] A new approach for the stereoselective synthesis of the piperidine alkaloid (+)-alpha-conhydrine and its pyrrolidine derivative has been developed using a palladium(II)-catalyzed, MOM-ether-directed aza-Claisen rearrangement and ring-closing metathesis to effect the key steps.     

Scope and limitations of chiral B-

A new chiral oxazaborolidine catalyst was prepared in situ from 3, 5-bis(trifluoromethyl)phenylboron dichloride and N-(p-toluenesulfonyl)-(S)-tryptophan. This catalyst is much more active than Corey's original catalyst for the Mukaiyama aldol reaction of aldehydes with silyl enol ethers. The observed syn selectivities and re-face attack of silyl enol ethers on carbonyl carbon of aldehydes imply that the extended-transition state model is applicable.     

Structural influence of steric factors and donor functions on lithium silylamides in non-coordinating solvents

We herein present the synthesis and crystallographic characterisation of lithium silylamides displaying different coordination numbers and aggregation states according to the number of N- and O-donor functions in the starting material, (aminomethyl) substituted silazane ligands. The dimeric dimethyl-(N-lithio-tert-butylamino)-piperidinomethyl)-silane and dimethyl-(N-lithio-iso-propylamino)-piperidinomethyl)-silane, with three-coordinate lithium centres, were prepared by deprotonation of the corresponding silazane with (n)BuLi. Using the tridentate silazane (1R,2R)-N(1)-[{(tert-butylamino)-dimethylsilyl}methyl]-N(1),N(2),N(2)-trimethylcyclohexane-1,2-diamine a mixed "dimer" of lithium silylamide and lithium silanolate with four-coordinate lithium centres was obtained. Additionally, a monomeric lithium silylamide was synthesised using the tridentate [bis(methoxyethyl)aminomethyl] side arm.     

Palladium-catalyzed synthesis of tetrahydrofurans from gamma-hydroxy terminal alkenes: scope, limitations, and stereoselectivity

A new, stereoselective synthesis of substituted tetrahydrofurans via Pd-catalyzed reactions of aryl and vinyl bromides with gamma-hydroxy terminal alkenes is described. This transformation affords trans-2,5- and trans-2,3-disubstituted tetrahydrofurans with up to >20:1 dr. This methodology also provides access to bicyclic and spirocyclic tetrahydrofuran derivatives in good yield with 10-20:1 dr. The scope and limitations of these transformations are discussed in detail, as are the effect of substrate sterics and electronics on yield and stereoselectivity. A proposed mechanism of these transformations is presented along with a model that rationalizes the stereochemical outcome of the reactions.     

Chiral enolates for highly stereoselective aldol reactions—Scope and limitations

Enantioselective approaches to the formation of α,β-disubstituted ketones through aldol reactions are compared. A one-pot ACA/aldol domino process is lower yielding than alternative procedures involving enantiomerically pure β-substituted silyl enol ethers. The use of chiral acetals derived from hydrobenzoin provides access to syn and anti diols in moderate to good yields and high diastereoselectivities. A novel synthesis of functionalized β,γ-unsaturated acetals is also described.     

Stereocontrol of palladium(II)-catalysed aza-Claisen rearrangements using a combination of 1,3-allylic strain and a solvent mediated directing effect

The use of a non-coordinating solvent for the aza-Claisen rearrangement of delta,epsilon-disubstituted acetimidates switches on a substrate directing effect that gives excellent stereoselectivity.     

Polar,non-coordinating ionic liquids as solvents for the alternating copolymerization of styrene and CO catalyzed by cationic palladium catalysts

The palladium-catalyzed copolymerization of styrene and CO in an ionic liquid solvent, 1-hexylpyridinium bis(trifluoromethanesulfonyl)imide, gave improved yields and increased molecular weights compared to polymerizations run in methanol.     

Scope and limitations of cyclopropanations with sulfur ylides

The rates of the reactions of the stabilized and semistabilized sulfur ylides 1a-g with benzhydrylium ions (2a-e) and Michael acceptors (2f-v) have been determined by UV-vis spectroscopy in DMSO at 20 °C. The second-order rate constants (log k(2)) of these reactions correlate linearly with the electrophilicity parameters E of the electrophiles 2 as required by the correlation log k(2) = s(N + E), which allowed us to calculate the nucleophile-specific parameters N and s for the sulfur ylides 1a-g. The rate constants for the cyclopropanation reactions of sulfur ylides with Michael acceptors lie on the same correlation line as the rate constants for the reactions of sulfur ylides with carbocations. This observation is in line with a stepwise mechanism for the cyclopropanation reactions in which the first step, nucleophilic attack of the sulfur ylides at the Michael acceptors, is rate determining. As the few known pK(aH) values for sulfur ylides correlate poorly with their nucleophilic reactivities, the data reported in this work provide the first quantitative approach to sulfur ylide reactivity.     

Scope and limitations of a novel synthesis of 3-arylazonicotinates

The reaction of 3-oxo-3-phenyl-2-phenylhydrazonal with functionally substituted and heteroaromatic substituted acetonitrile to yield arylazonicotinic acid derivatives and 5-arylsubstituted pyridines was established. In some cases the produced nicotinates could not be isolated as they underwent thermally induced 6π-electrocyclization yielding polynuclear pyridine derivatives.     

Scope and limitations of the Julia-Kocienski reaction with fluorinated sulfonylesters

The study of the Julia-Kocienski reaction between fluorinated arylsulfone and ketones is described. The corresponding fluoroalkenes were isolated in moderate to good yields from β- and δ-substituted cyclic ketones. From acyclic ketones and α-substituted cyclic ketones a decarbethoxylation reaction of the sulfonylesters occurred. This decarbethoxylation reaction opened a new route for the preparation of a variety of fluoroalkylsulfones as potential building blocks for the preparation of fluoroalkenes.     

Asymmetric chelated Claisen rearrangements in the presence of chiral ligands--scope and limitations

Claisen rearrangements of glycine crotyl ester enolates in the presence of chelating metal salts and chiral ligands provide ,-unsaturated amino acids in a highly stereoselective fashion. Best results are obtained with electron withdrawing protecting groups, isopropylates of aluminum and magnesium, and the cinchona alkaloids as chiral ligands. While the use of quinine gives rise to the (2R)-configured amino acids, quinidine provides the opposite enantiomer. The different enantiomers can also be obtained by using only one of the chiral ligands by simply changing the reaction conditions. A mechanistic rational for the stereochemical outcome of the reaction is given, which is supported by several experiments.     

Scope and limitations of 1,1-diphenylethylene chemistry in anionic polymer synthesis

The scope and limitations of the addition reactions of simple and polymeric organolithium compounds with substituted 1,1-diarylethylenes to prepare in chain- and chain-end functionalized polymers is presented. The application of this general living functionalization reaction for the preparation of ω-functionalized polymers is illustrated for hydroxyl, carboxyl, dimethylamine, and primary amine groups, as well as for the fluorescent naphthalene and pyrene labels. The use of this chemistry to prepare functionalized initiators is described, as well as the copolymerization of substituted 1,1-diphenylethylenes with monomers to prepare in-chain functionalized polymers with alternating structures.     

Imidazolium and pyridinium salts – solvents influencing the rate and direction of the Fries,Beckmann, and Claisen rearrangements

The Fries, Beckmann, and Claisen rearrangements have been investigated in ionic liquid media. The effect of the structural elements of the latter on the direction of these rearrangements and the product yields has been studied.     

Scope, limitations and mechanistic aspects of the photo-induced cross-linking of proteins by water-soluble metal complexes

BACKGROUND: Chemical cross-linking is a valuable tool with which to study protein-protein interactions. Recently, a new kind of cross-linking reaction was developed in which the photolysis of associated proteins with visible light in the presence of ammonium persulfate and tris(2,2'-bipyridyl)ruthenium(II) dication or palladium(II) porphyrins results in rapid and efficient covalent coupling (Fancy, D.A. & Kodadek, T. (1999). Proc. Natl. Acad. Sci. USA 96, 6020-6024 and Kim, K., Fancy, D.A. & Kodadek, T. (1999). J. Am. Chem. Soc. 121, 11896-11897). Here, mechanistic and practical aspects of the reaction of importance for its application to biochemical problems are examined. RESULTS: It is shown that the photo-initiated cross-linking chemistry can be optimized for the analysis of protein-protein interactions in crude cell extracts. A number of commonly used epitope or affinity tags survive the reaction in functional form, allowing the simple visualization of the cross-linked products, or their isolation. It is shown that very little light-independent oxidation of protein residues occurs and that significant perturbation of complexes of interest prior to the brief photolysis period does not occur. Finally, evidence is presented that is consistent with a mechanistic model in which ammonium persulfate functions simply as an electron acceptor, facilitating the generation of the key high valent metal complex from the photoexcited species by electron transfer. In the absence of an electron acceptor, a much lower efficiency reaction is observed that appears to involve products resulting from reaction of the excited state metal complex with molecular oxygen. CONCLUSIONS: These results provide useful practical information for chemists and biochemists who may wish to employ this new cross-linking chemistry for the analysis of protein complexes. They also shed new light on the mechanism of this interesting reaction.     

Scope and limitations of the Minisci reaction for the synthesis of aza-heterocycles

Attempts to prepare several classes of aza-heterocycles by application of the Minisci radical cyclisation reaction are described. Competing β-scission, hydrolytic cleavage and lactonisation reactions were found to be major hurdles to adopting this strategy for the synthesis of such targets.     

Scope and limitations of the Pd/BINAP-catalyzed amination of aryl bromides

Mixtures of Pd(2)(dba)(3) or Pd(OAc)(2) and BINAP catalyze the cross-coupling of amines with a variety of aryl bromides. Primary amines are arylated in high yield, and certain classes of secondary amines are also effectively transformed. The process tolerates the presence of several functional groups including methyl and ethyl esters, enolizable ketones, and nitro groups provided that cesium carbonate is employed as the base. Most reactions proceed to completion with 0.5-1.0 mol % of the palladium catalyst; in some cases, catalyst levels as low as 0.05 mol % Pd may be employed. Reactions are considerably faster if Pd(OAc)(2) is employed as the precatalyst, and the order in which reagents are added to the reaction has a substantial effect on reaction rate. It is likely that the catalytic process proceeds via bis(phosphine)palladium complexes as intermediates. These complexes are less prone to undergo undesirable side reactions which lead to diminished yields or catalyst deactivation than complexes of the corresponding monodentate triarylphosphines.     

Syntheses of tetrahydro-beta-carbolines via a tandem hydroformylation-Pictet-Spengler reaction. Scope and limitations

A novel one-pot synthesis of tetrahydro-beta-carboline systems via tandem hydroformylation-Pictet-Spengler reaction starting from olefins and aryl ethylamines is described. This tandem procedure allows fast and convenient synthesis of various substituted tetrahydro-beta-carbolines.