Cycloadditions of cyclohexynes and cyclopentyne.

We report the strategic use of cyclohexyne and the more elusive intermediate, cyclopentyne, as a tool for the synthesis of new heterocyclic compounds. Experimental and computational studies of a 3-substituted cyclohexyne are also described. The observed regioselectivities are explained by the distortion/interaction model

Cycloaddition Chemistry of a Silylene‐Nickel Complex toward Organic π‐Systems: From Reversibility to C−H Activation

The versatile cycloaddition chemistry of the Si−Ni multiple bond in the acyclic (amido)(chloro)silylene→Ni0 complex 1, [(TMSL)ClSi→Ni(NHC)2] (TMSL=N(SiMe3)Dipp; Dipp=2,6‐iPr2C6H4; NHC=C[(iPr)NC(Me)]2), toward unsaturated organic substrates is reported, which is both reminiscent of and expanding on the reactivity patterns of classical Fischer and Schrock carbene–metal complexes. Thus, 1:1 reaction of 1 with aldehydes, imines, alkynes, and even alkenes proceed to yield [2+2] cycloaddition products, leading to a range of four‐membered metallasilacycles. This cycloaddition is in fact reversible for ethylene, whereas addition of an excess of this olefin leads to quantitative sp2‐CH bond activation, via a 1‐nickela‐4‐silacyclohexane intermediate. These results have been supported by DFT calculations giving insights into key mechanistic aspects.DFG, 390540038, EXC 2008: UniSysCatTU Berlin, Open-Access-Mittel - 202

Photochemical Approaches to Complex Chemotypes: Applications in Natural Product Synthesis.

The use of photochemical transformations is a powerful strategy that allows for the formation of a high degree of molecular complexity from relatively simple building blocks in a single step. A central feature of all light-promoted transformations is the involvement of electronically excited states, generated upon absorption of photons. This produces transient reactive intermediates and significantly alters the reactivity of a chemical compound. The input of energy provided by light thus offers a means to produce strained and unique target compounds that cannot be assembled using thermal protocols. This review aims at highlighting photochemical transformations as a tool for rapidly accessing structurally and stereochemically diverse scaffolds. Synthetic designs based on photochemical transformations have the potential to afford complex polycyclic carbon skeletons with impressive efficiency, which are of high value in total synthesis.R01 GM073855 - NIGMS NIH HHS; R01 GM096129 - NIGMS NIH HHS; R35 GM118173 - NIGMS NIH HH

Stereodivergent, Diels-Alder-initiated organocascades employing α,β-unsaturated acylammonium salts: scope, mechanism, and application.

Chiral α,β-unsaturated acylammonium salts are novel dienophiles enabling enantioselective Diels-Alder-lactonization (DAL) organocascades leading to cis- and trans-fused, bicyclic γ- and δ-lactones from readily prepared dienes, commodity acid chlorides, and a chiral isothiourea organocatalyst under mild conditions. We describe extensions of stereodivergent DAL organocascades to other racemic dienes bearing pendant secondary and tertiary alcohols, and application to a formal synthesis of (+)-dihydrocompactin is described. A combined experimental and computational investigation of unsaturated acylammonium salt formation and the entire DAL organocascade pathway provide a rationalization of the effect of Brønsted base additives and enabled a controllable, diastereodivergent DAL process leading to a full complement of possible stereoisomeric products. Evaluation of free energy and enthalpy barriers in conjunction with experimentally observed temperature effects revealed that the DAL is a rare case of an entropy-controlled diastereoselective process. NMR analysis of diene alcohol-Brønsted base interactions and computational studies provide a plausible explanation of observed stabilization of exo transition-state structures through hydrogen-bonding effects

Unexpected = 4 + 2 Cycloaddition through Chromium Non-Heteroatom-Stabilized Alkynyl Carbene Complexes: Regioselective Access to Substituted 6-Azaindoles

This research was supported by the Spanish Government MINECO/FEDER (CTQ-2016-76840-R and CTQ-2017-87372-P (AEI/FEDER, UE)) and the Principality of Asturias, Spain (GRUPIN14-013

N-Methylimidazole Promotes The Reaction Of Homophthalic Anhydride With Imines

The addition of N-methylimidazole (NMI) to the reaction of homophthalic anhydride with imines such as pyridine-3-carboxaldehyde-N-trifluoroethylimine (9) reduces the amount of elimination byproduct and improves the yield of the formal cycloadduct, tetrahydroisoquinolonic carboxylate 10. Carboxanilides of such compounds are of interest as potential antimalarial agents. A mechanism that rationalizes the role of NMI is proposed, and a gram-scale procedure for the synthesis and resolution of 10 is also described

Synthesis of Highly Stable 1,3-Diaryl-1H-1,2,3-triazol-5-ylidenes and Their Applications in Ruthenium-Catalyzed Olefin Metathesis

The formal cycloaddition between 1,3-diaza-2-azoniaallene salts and alkynes or alkyne equivalents provides an efficient synthesis of 1,3-diaryl-1H-1,2,3-triazolium salts, the direct precursors of 1,2,3-triazol-5-ylidenes. These N,N-diarylated mesoionic carbenes (MICs) exhibit enhanced stability in comparison to their alkylated counterparts. Experimental and computational results confirm that these MICs act as strongly electron-donating ligands. Their increased stability allows for the preparation of ruthenium olefin metathesis catalysts that are efficient in both ring-opening and ring-closing reactions

Unusual structure-energy correlations in intramolecular Diels–Alder reaction transition states

Detailed analysis of calculated data from an experimental/computational study of intramolecular furan Diels–Alder reactions has led to the unusual discovery that the mean contraction of the newly forming C-C σ-bonds from the transition state to the product shows a linear correlation with both reaction Gibbs free energies and reverse energy barriers. There is evidence for a similar correlation in other intramolecular Diels–Alder reactions involving non-aromatic dienes. No such correlation is found for intermolecular Diels–Alder reactions

Recent progress in the synthesis of six-membered aminocyclitols (2008-2017)

Aminocyclitols are of interest as glucosidase inhibitors, as probes for the study of pseudoglycosyltransferases, and as potential therapeutics for the treatment of Gaucher’s disease. The synthesis of these targets was reviewed in early 2008, and the aim of this review is to cover material relevant to the synthesis of aminocyclitols since that time. While not a focus of this review, biological evaluation of compounds will be presented where it is recorded in the literature

Regioselective reactions of 3,4-pyridynes enabled by the aryne distortion model.

The pyridine heterocycle continues to play a vital role in the development of human medicines. More than 100 currently marketed drugs contain this privileged unit, which remains highly sought after synthetically. We report an efficient means to access di- and trisubstituted pyridines in an efficient and highly controlled manner using transient 3,4-pyridyne intermediates. Previous efforts to employ 3,4-pyridynes for the construction of substituted pyridines were hampered by a lack of regiocontrol or the inability to later manipulate an adjacent directing group. The strategy relies on the use of proximal halide or sulfamate substituents to perturb pyridyne distortion, which in turn governs regioselectivities in nucleophilic addition and cycloaddition reactions. After trapping of the pyridynes generated in situ, the neighbouring directing groups may be removed or exploited using versatile metal-catalysed cross-coupling reactions. This methodology now renders 3,4-pyridynes as useful synthetic building blocks for the creation of highly decorated derivatives of the medicinally privileged pyridine heterocycle