Mikhail A. Kabeshov

Highly Enantio‐ and Diastereoselective Generation of Two Quaternary Centers in Spirocyclopropanation of Oxindole Derivatives.

Spirocyclopropanes: Only one out of eight possible stereoisomers was obtained in the asymmetric cascade cyclopropanation of alkylidene oxindoles with ethyl 2-chloroacetoacetate. Improved catalyst design ensured that spirocyclopropyl oxindoles featuring two quaternary centers were synthesized in high yield and high enantio- and diastereoselectivity (see scheme).

Expedient preparation of nazlinine and a small library of indole alkaloids using flow electrochemistry as an enabling technology

An expedient synthesis of the indole alkaloid nazlinine is reported. Judicious choice of flow electrochemistry as an enabling technology has permitted the rapid generation of a small library of unnatural relatives of this biologically active molecule. Furthermore, by conducting the key electrochemical Shono oxidation in a flow cell, the loading of electrolyte can be significantly reduced to 20 mol % while maintaining a stable, broadly applicable process.

Visible Light Activation of Boronic Esters Enables Efficient Photoredox C(sp2)–C(sp3) Cross-Couplings in Flow

Abstract We report herein a new method for the photoredox activation of boronic esters. Using these reagents, an efficient and high‐throughput continuous flow process was developed to perform a dual iridium‐ and nickel‐catalyzed C(sp2)–C(sp3) coupling by circumventing solubility issues associated with potassium trifluoroborate salts. Formation of an adduct with a pyridine‐derived Lewis base was found to be essential for the photoredox activation of the boronic esters. Based on these results we were able to develop a further simplified visible light mediated C(sp2)–C(sp3) coupling method using boronic esters and cyano heteroarenes under flow conditions.

Enantioselective and Catalytic Method for α‐Crotylation of Aldehydes with a Kinetic Self‐Refinement of Stereochemistry

Kinetic refinery: A practical, highly stereoselective, two-step catalytic protocol for the alpha-allylation of aldehydes, starting from crotyltrichlorosilanes, has been developed (see scheme). In each reaction step, one of the stereoisomers reacted faster than the other, which resulted in a kinetic stereochemical (E/Z) self-refinement of the system and led to the formation of virtually enantiomerically and geometrically pure linear homoallylic alcohols in high yield.

Highly Stereoselective Synthesis of Z‐Homoallylic Alcohols by Kinetic Resolution of Racemic Secondary Allyl Boronates

α to Z: Racemic α-chiral allyl boronates, which are readily synthesized from the respective primary allyl halides, undergo a highly efficient kinetic resolution in a face- and Z-selective allylation of aldehydes catalyzed by the chiral Bronsted acid (R)-TRIP (see scheme; Epin=tetraethylethylene glycol). Copyright

Stereoselective Palladium‐Catalyzed Functionalization of Homoallylic Alcohols: A Convenient Synthesis of Di‐ and Trisubstituted Isoxazolidines and β‐Amino‐δ‐Hydroxy Esters

Enantiopure, Boc-protected alkoxyamines 12 and 13, derived from the readily available homoallylic alcohols 4 via a reaction that involves either inversion or retention of configuration, undergo a diastereoselective Pd-catalyzed ring-closing carbonylative amidation to produce isoxazolidines 16/17 (≤50:1 diastereoisomer ratio (d.r.)) that can be readily converted into the N-Boc-protected esters of β-amino-δ-hydroxy acids and their γ-substituted homologues 37. The key carbonylative cyclization proceeds through an unusual syn addition of the palladium and the nitrogen nucleophile across the C=C bond (19→21), as revealed by the reaction of 15, which afforded isoxazolidine 18 with high diastereoselectivity.

Continuous‐Flow Synthesis and Derivatization of Aziridines through Palladium‐Catalyzed C(sp3)−H Activation

Abstract A continuous‐flow synthesis of aziridines by palladium‐catalyzed C(sp3)−H activation is described. The new flow reaction could be combined with an aziridine‐ring‐opening reaction to give highly functionalized aliphatic amines through a consecutive process. A predictive mechanistic model was developed and used to design the C−H activation flow process and illustrates an approach towards first‐principles design based on novel catalytic reactions.

Catalytic Asymmetric Crotylation of Aldehydes: Application in Total Synthesis of (−)‐Elisabethadione

A new, highly efficient Lewis base catalyst for a practical enantio- and diastereoselective crotylation of unsaturated aldehydes with E- and Z-crotyltrichlorosilanes has been developed. The method was employed as a key step in a novel asymmetric synthesis of bioactive serrulatane diterpene (-)-elisabethadione. Other strategic reactions for setting up the stereogenic centers included anionic oxy-Cope rearrangement and cationic cyclization. The synthetic route relies on simple, high yielding reactions and avoids use of protecting groups or chiral auxiliaries.

Exerting control over the acyloin reaction

A synthetic method for conducting the acyloin reaction using electron transfer in solution is reported. By linking two esters via their oxygen atoms, it was possible to perform crossed acyloin reactions between two different ester functionalities and display a high degree of preference for an intramolecular coupling process.

A green approach to Fenton chemistry: mono-hydroxylation of salicylic acid in aqueous medium by the electrogeneration of Fenton's reagent

First, the electrochemical characteristics of Fentons reagent (Fe(III), Fe(II) and hydrogen peroxide), including its catalytic (EC′) behaviour were investigated. Second, the electrogeneration of hydrogen peroxide by a two-electron reduction of dissolved oxygen was conducted at a carbon electrode in a divided electrolysis cell and the concentration of hydrogen peroxide obtained was determined by the titration. The two approaches were then combined to give a one-pot, relatively green approach to aromatic hydroxylation reactions, with the electro-Fenton method allowing the iron to be used catalytically and the oxygen/water employed as the hydroxylation reagent by the in situ production of hydrogen peroxide. In particular, the preparative-scale hydroxylation of salicylic acid has been studied in an oxygen-saturated 0.1 M Na2SO4 pH 3.0 solution containing 5 mM Fe(II) and 5 mM salicylic acid at the controlled potential of −1.0 V vs. SCE. The study showed that after the attack of the hydroxyl radical produced in situ by the electro-Fenton process on salicylic acid, 2,3- and 2,5-dihydroxybenzoic acids were detected as primary monohydroxylated products with the highest yield of ca. 21.6 ± 2.5%.