A Twist on Facial Selectivity of Hydride Reductions of Cyclic Ketones: Twist-Boat Conformers in Cyclohexanone, Piperidone, and Tropinone Reactions

The role of twist-boat conformers of cyclohexanones in hydride reductions was explored. The hydride reductions of a cis-2,6-disubstituted <i>N</i>-acylpiperidone, an <i>N</i>-acyltropinone, and <i>tert</i>-butylcyclohexanone by lithium aluminum hydride and by a bulky borohydride reagent were investigated computationally and compared to experiment. Our results indicate that in certain cases, factors such as substrate conformation, nucleophile bulkiness, and remote steric features can affect stereoselectivity in ways that are difficult to predict by the general Felkin–Anh model. In particular, we have calculated that a twist-boat conformation is relevant to the reactivity and facial selectivity of hydride reduction of cis-2,6-disubstituted <i>N</i>-acylpiperidones with a small hydride reagent (LiAlH₄) but not with a bulky hydride (lithium triisopropylborohydride)

Multiple Mechanisms for the Thermal Decomposition of Metallaisoxazolin-5-ones from Computational Investigations

The thermal decompositions of metallaisoxazolin-5-ones containing Ir, Rh, or Co are investigated using density functional theory. The experimentally observed decarboxylations of these molecules are found to proceed through retro-(3+2)-cycloaddition reactions, generating the experimentally reported η² side-bonded nitrile complexes. These intermediates can isomerize in situ to yield a η¹ nitrile complex. A competitive alternative pathway is also found where the decarboxylation happens concertedly with an aryl migration process, producing a η¹ isonitrile complex. Despite their comparable stability, these η¹ bonded species were not detected experimentally. The experimentally detected η² side bound species are likely involved in the subsequent C–H activation reactions with hydrocarbon solvents reported for some of these metallaisoxazolin-5-ones

Mechanism of Alkoxy Groups Substitution by Grignard Reagents on Aromatic Rings and Experimental Verification of Theoretical Predictions of Anomalous Reactions

The mechanism of direct displacement of alkoxy groups in vinylogous and aromatic esters by Grignard reagents, a reaction that is not observed with expectedly better tosyloxy leaving groups, is elucidated computationally. The mechanism of this reaction has been determined to proceed through the inner-sphere attack of nucleophilic alkyl groups from magnesium to the reacting carbons via a metalaoxetane transition state. The formation of a strong magnesium chelate with the reacting alkoxy and carbonyl groups dictates the observed reactivity and selectivity. The influence of ester, ketone, and aldehyde substituents was investigated. In some cases, the calculations predicted the formation of products different than those previously reported; these predictions were then verified experimentally. The importance of studying the actual system, and not simplified models as computational systems, is demonstrated

Computations Reveal That Electron-Withdrawing Leaving Groups Facilitate Intramolecular Conjugate Displacement Reactions by Negative Hyperconjugation

Intramolecular conjugate displacement (ICD) reactions, developed by the Clive group, form carbocycles and polycyclic amines by intramolecular nucleophilic attack on a Michael acceptor with an allylic leaving group. Quantum mechanical investigations with density functional theory show that ICDs involve a stepwise addition, forming an intermediate stabilized carbanion, followed by elimination. The electron-withdrawing nature of the allylic leaving group facilitates the addition by negative hyperconjugation; the twist-boat conformation of the addition and intermediate is stabilized by this interaction. In the absence of an activating electron-withdrawing group as part of the Michael acceptor, a high energy concerted S_N2′ reaction occurs. The reactions of carbon nucleophiles have lower activation energies than those of amines

Enantioselective Synthesis of Dialkylated <i>N</i>‑Heterocycles by Palladium-Catalyzed Allylic Alkylation

The enantioselective synthesis of α-disubstituted <i>N</i>-heterocyclic carbonyl compounds has been accomplished using palladium-catalyzed allylic alkylation. These catalytic conditions enable access to various heterocycles, such as morpholinone, thiomorpholinone, oxazolidin-4-one, 1,2-oxazepan-3-one, 1,3-oxazinan-4-one, and structurally related lactams, all bearing fully substituted α-positions. Broad functional group tolerance was explored at the α-position in the morpholinone series. We demonstrate the utility of this method by performing various transformations on our useful products to readily access a number of enantioenriched compounds

1,3-Dipolar Cycloaddition Reactions of Low-Valent Rhodium and Iridium Complexes with Arylnitrile N‑Oxides

The reactions between low-valent Rh(I) and Ir(I) metal-carbonyl complexes and arylnitrile oxides possess the electronic and structural features of 1,3-dipolar cycloadditions. Density functional theory (DFT) calculations on these reactions, involving both cyclopentadienyl and carboranyl ligands on the metal carbonyl, explain the ease of the chemical processes and the stabilities of the resulting metallaisoxazolin-5-ones. The metal-carbonyl bond has partial double bond character according to the Wiberg index calculated through NBO analysis, and so the reaction can be considered a normal 1,3-dipolar cycloaddition involving M═C bonds. The rates of formation of the metallacycloadducts are controlled by distortion energy, analogous to their organic counterparts. The superior ability of anionic Ir complexes to share their electron density and accommodate higher oxidation states explains their calculated higher reactivity toward cycloaddition, as compared to Rh analogues

Oxidative Activation of C−S Bonds with an Electropositive Nitrogen Promoter Enables Orthogonal Glycosylation of Alkyl over Phenyl Thioglycosides

A method for the selective activation ofthioglycosides that uses the N+-thiophilic reagentO-mesitylenesulfonylhydroxylamine (MSH) as a promoter ispresented. The reaction proceeds via anomeric mesitylensul-fonate intermediates, which could be isolated and fully characterized by placing afluorine atom at the C2 position.In the presence of a soft Lewis acid, glycosylation reaction proceeds at ambient temperature with good yields. It is further demonstrated that it is possible to orthogonally activateS-ethylin the presence ofS-phenyl donors, enabling the design of sequential glycosylation strategies.We thank the European Commission (Marie Curie CIG and Marie Skłodowska-Curie ITN projectGlycoVaxto G.J.L.B. andA.K.; Marie Skłodowska-Curie IEF to E.J.M.), MINECO (RYC-2015-17705 to O.B. and CTQ2015-70524-R and RYC-2013-14706 to G.J.O.), FCT Portugal (FCT Investigator to G.J.L.B.),the European Regional Development Fund, Generalitat de Catalunya (M.S.), and the Universitat Rovira i Virgili (Martı́ Franquès Research Fellowship Programme to J.M.) forfinancia lsupport. BIFI (Memento cluster) is acknowledged for computer support. G.J.L.B. is a Royal Society University Research Fellowand holds an ERC Starting Grant (TagIt).Peer reviewe

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

A Biomimetic Approach to Lanthionines

The asymmetric sulfa-Michael additions of appropriately protected l- and d-cysteine derivatives to new chiral dehydroamino acid derivatives have been developed as key steps in the synthesis of biologically important cysteine derivatives, such as lanthionine (Lan) and β-methyllanthionine (MeLan), which are unusual bis-α-amino acids found in the emerging lantibiotics such as nisin