Synthesis of Carbohydrate Based Macrolactones and Their Applications as Receptors for Ion Recognition and Catalysis

Glycomacrolactones exhibit many interesting biological properties, and they are also important in molecular recognitions and for supramolecular chemistry. Therefore, it is important to be able to access glycomacrocycles with different sizes and functionality. A new series of carbohydrate-based macrocycles containing triazole and lactone moieties have been designed and synthesized. The synthesis features an intramolecular nucleophilic substitution reaction for the macrocyclization step. In this article, the effect of some common sulfonate leaving groups is evaluated for macrolactonization. Using tosylate gave good selectivity for monolactonization products with good yields. Fourteen different macrocycles have been synthesized and characterized, of which eleven macrocycles are from cyclization of the C1 to C6 positions of N-acetyl D-glucosamine derivatives and three others from C2 to C6 cyclization of functionalized D-glucosamine derivatives. These novel macrolactones have unique structures and demonstrate interesting anion binding properties, especially for chloride. The macrocycles containing two triazoles form complexes with copper sulfate, and they are effective ligands for copper sulfate mediated azide-alkyne cycloaddition reactions (CuAAC). In addition, several macrocycles show some selectivity for different alkynes.

Chemodivergent assembly of ortho-functionalized phenols with tunable selectivity via rhodium(III)-catalyzed and solvent-controlled C-H activation

Ortho-functionalized phenols and their derivatives represent prominent structural motifs and building blocks in medicinal and synthetic chemistry. While numerous synthetic approaches exist, the development of atom-/step-economic and practical methods for the chemodivergent assembly of diverse ortho-functionalized phenols based on fixed catalyst/substrates remains challenging. Here, by selectively controlling the reactivities of different sites in methylenecyclopropane core, Rh(III)-catalyzed redox-neutral and tunable C-H functionalizations of N-phenoxyacetamides are realized, providing access to both ortho-functionalized phenols bearing linear dienyl, cyclopropyl or allyl ether groups, and cyclic 3-ethylidene 2,3-dihydrobenzofuran frameworks under mild cross-coupling conditions. These divergent transformations feature broad substrate compatibility, synthetic applications and excellent site-/regio-/chemoselectivity. Experimental and computational mechanistic studies reveal that distinct catalytic modes involving selective β-C/β-H elimination, π-allylation, inter-/intramolecular nucleophilic substitution cascade and β-H’ elimination processes enabled by different solvent-mediated and coupling partner-controlled reaction conditions are crucial for achieving chemodivergence, among which a structurally distinct Rh(V) species derived from a five-membered rhodacycle is proposed as the corresponding active intermediates.

Synthesis of tetrafluorinated piperidines from nitrones via a visible-light-promoted annelation reaction

A method for the one-step construction of 3,3,4,4-tetrafluorinated piperidines from nitrones and readily accessible tetrafluorinated iodobromobutane is described. The reaction requires an excess amount of ascorbic acid as the terminal reductant and is performed in the presence of an iridium photocatalyst activated by blue light. The annelation is a result of a radical addition at the nitrone, intramolecular nucleophilic substitution, and reduction of the N–O bond.

Sterically Facilitated Intramolecular Nucleophilic NMe2 Group Substitution in the Synthesis of Fused Isoxazoles: Theoretical Study

The influence of steric repulsion between the NMe2 group and a second ortho-(peri-)substituent in the series of 1-dimethylaminonaphthalene and N,N-dimethylanilene ortho-oximes on the ease of the NMe2 group’s intramolecular nucleophilic substitution is studied. Possible reaction intermediates for three mechanisms are calculated (ωB97xd/def-2-TZVP), and their free Gibbs energies are compared to model reaction profiles. Supporting experiments have proved the absence of studied reactivity in the case of simple 2-dimethylaminobenzaldoxime, which allowed us to establish reactivity limits. The significant facilitation of NMe2 group displacement in the presence of bulky substituents is demonstrated. The possibility of fused isoxazoles synthesis via the intramolecular nucleophilic substitution of a protonated NMe2 group in the aniline and naphthalene series is predicted.

Uncovering the cytochrome P450-catalyzed methylenedioxy bridge formation in streptovaricins biosynthesis

Streptovaricin C is a naphthalenic ansamycin antibiotic structurally similar to rifamycins with potential anti-MRSA bioactivities. However, the formation mechanism of the most fascinating and bioactivity-related methylenedioxy bridge (MDB) moiety in streptovaricins is unclear. Based on genetic and biochemical evidences, we herein clarify that the P450 enzyme StvP2 catalyzes the MDB formation in streptovaricins, with an atypical substrate inhibition kinetics. Furthermore, X-ray crystal structures in complex with substrate and structure-based mutagenesis reveal the intrinsic details of the enzymatic reaction. The mechanism of MDB formation is proposed to be an intramolecular nucleophilic substitution resulting from the hydroxylation by the heme core and the keto-enol tautomerization via a crucial catalytic triad (Asp89-His92-Arg72) in StvP2. In addition, in vitro reconstitution uncovers that C6-O-methylation and C4-O-acetylation of streptovaricins are necessary prerequisites for the MDB formation. This work provides insight for the MDB formation and adds evidence in support of the functional versatility of P450 enzymes.

Novel Synthesis of β-Keto Cycloacetals via Organoboranes

(Z)-1-Bromo-1-alkenylboronate esters were easily synthesized from the hydroboration of terminal alkynes with dibromoborane dimethyl complex under nitrogen atmosphere followed by treatment with propne-1,3-diol. These boronate esters are readily reacted with 1,3-dioxan-2-ylethyl)magnesium bromide in ether and tetrahydrofuran at -78 ºC for 1 h. The resulting "ate" complex upon addition of sodium methoxide in methanol undergo intramolecular nucleophilic substitution reactions to produce the corresponding (E)-alkenylboronate esters containing (1,3-dioxan-2-ylethyl) moiety in 70-82% isolated yields. The resulting intermediates are oxidized with sodium acetate and hydrogen peroxide to provide the corresponding β-keto cycloacetals in good yields (68-84%).

Intramolecular nucleophilic addition of carbanions generated from N-benzylamides to cyclopropenes

An unusual reaction is described, involving a formal intramolecular nucleophilic substitution of bromocyclopropanes with nitrogen ylides generated in situ from N-benzyl carboxamides. This reaction involves cyclopropene intermediates and allows for the facile preparation of 3-azabicyclo[3.1.0]hexan-2-ones.