Ewoud

Castoff to bioactive molecules: The diversified functionalization of propenylcatechol, a direct depolymerized product from naturally occurring catechyl lignin, resulted in a series of functional molecular skeletons. Starting from castor seed coats, annuloline (natural product) and CC-5079 (antitumor) were synthesized with a superior step-efficiency to that of reported synthetic routes.

Abstract

Catechyl lignin (C-lignin) is a naturally occurring linear homogeneous biopolymer composed solely of caffeyl alcohol subunits with cleavable benzodioxane linkages. The inherent structural features of propenylcatechol, a direct depolymerized product of castor seed coats C-lignin, render it a sustainable and promising platform for the synthesis of bioactive molecules. Herein, diversified transformations of propenylcatechol, including C=C bond difunctionalization, β-modification, β,γ-rearrangement, and γ-methyl derivatization, were reported based on known or developed methods. A series of functional molecular skeletons involved in the current synthetic routes for the preparation of pharmaceuticals and bioactive molecules were obtained. Starting from castor seed coats, annuloline (natural product) and CC-5079 (antitumor) were synthesized using facile and inexpensive reagents in only four- and five-sequence reactions, respectively, thereby demonstrating a superior step-efficiency to that of reported synthetic routes. Almost all atoms in the C-lignin biopolymer were incorporated into the final products owing to the intrinsic structures of naturally occurring C-lignin. Bioactive molecules produced from C-lignin integrate a low-carbon footprint with high-quality and economical manufacture of pharmaceuticals.

An efficient Lewis acid-assisted asymmetric carbonyl-ene reaction to set the 1α-hydroxyl functionality of enol-triflate, precursor of the A-ring of the hormone calcitriol and its 1α-hydroxyderivatives, is described.

Abstract

The secondary parallel hypercalcemic effects associated with the treatment of several hyperproliferative diseases with the natural hormone 1α,25-dihydroxyvitamin D₃ (calcitriol) and/or known active vitamin D metabolites and analogs, demand the development of efficient and rapid methods for the preparation of vitamin D receptor (VDR) ligands as new selective and non-calcemic agonists. Here we describe an efficient and adaptable multigram-scale synthetic sequence to access an A-ring synthon as useful precursor of the vitamin D triene system of 1α-hydroxylated vitamin D derivatives via Pd-catalyzed carbocyclization/Suzuki–Miyaura cross-coupling reactions in a protic medium. The key step is an asymmetric Lewis acid-promoted carbonyl-ene reaction to a chiral glyosylate ester to establish the 1α-hydroxyl group of 1α,25-dihydroxyvitamin D₃ and its derivatives.

Directed evolution rendered P450_BSβ capable of β-hydroxylating unactivated C−H bonds in aliphatic carboxylic acids with broad substrate scope and excellent chemo-, regio-, and enantioselectivity. The crystal structure of the evolved variant rationalizes the improved reactivity and selectivity. This study demonstrates the potential of exploring biocatalysts to fulfill reactions that are otherwise elusive with chemical strategies.

Abstract

Catalytic selective hydroxylation of unactivated aliphatic (sp³) C−H bonds without a directing group represents a formidable task for synthetic chemists. Through directed evolution of P450_BSβ hydroxylase, we realize oxyfunctionalization of unactivated C−H bonds in a broad spectrum of aliphatic carboxylic acids with varied chain lengths, functional groups and (hetero-)aromatic moieties in a highly chemo-, regio- and enantioselective fashion (>30 examples, Cβ/Cα>20 : 1, >99 % ee). The X-ray structure of the evolved variant, P450_BSβ-L78I/Q85H/G290I, in complex with palmitic acid well rationalizes the experimentally observed regio- and enantioselectivity, and also reveals a reduced catalytic pocket volume that accounts for the increased reactivity with smaller substrates. This work showcases the potential of employing a biocatalyst to enable a chemical transformation that is particularly challenging by chemical methods.

Supports for immobilization of catalysts in flow reactors are outlined, with emphases on sustainable binding with channel walls and catalysts, boosted catalysts loading and ability to maintain fine flow properties. Particularly, the synergy of supports and catalysts are discerned, as well as the specific designs. In addition, fabrication of array-like catalytic supports and application of advanced fluidic devices are included.

Abstract

The rapid development of continuous flow processes is driving innovations in various chemical syntheses and industrial productions. Immobilizing catalysts in flow reactors allows transformations with high-efficiency and excludes the subsequent separation procedures. This concept outlines the approaches to incorporate catalysts within flow reactors, with particular focus on the application of additional supports including inorganic materials like silica, zeolite and reduced graphene oxide, polymeric materials like polymer packings, monoliths, cross-linked gels and polymer brushes, and other materials for specific conditions like transparent glass fibers and glass beads. Furthermore, advanced methods to develop ordered micro-/nanoarrays from internal walls of flow channels for immobilization of catalysts as well as application of innovative vortex fluidic devices are discussed to inspire new designs of supports for novel fluidic reactors with broad applications.

The first example of Mn-catalyzed asymmetric formal anti-Markovnikov hydroamination of allylic alcohols is described by using a chiral peraza N ₆-macrocyclic ligand. DFT calculations revealed that multiple noncovalent interactions existed among the ligand, solvent, and substrate in the transition states, showing a remarkable macrocyclic ligand effect.

Abstract

A unique family of chiral peraza N ₆-macrocyclic ligands, which are conformationally rigid and have a tunable saddle-shaped cavity, is described. Utilizing their manganese(I) complexes, the first example of earth-abundant transition metal-catalyzed asymmetric formal anti-Markovnikov hydroamination of allylic alcohols was realized, providing a practical access to synthetically important chiral γ-amino alcohols in excellent yields and enantioselectivities (up to 99 % yield and 98 % ee). The single-crystal structure of a Mn^I complex indicates that the manganese atom coordinates with the chiral dialkylamine moiety in a bidentate fashion. Further DFT calculations revealed that five of the six nitrogen atoms in the ligand were engaged in multiple noncovalent interactions with Mn, an isopropanol molecule, and a β-amino ketone intermediate via coordination, hydrogen bonding, and/or CH⋅⋅⋅π interactions in the transition state, showing a remarkable role of the macrocyclic framework.

Nature Chemistry, Published online: 04 April 2022; doi:10.1038/s41557-022-00913-4

Nature Catalysis, Published online: 31 March 2022; doi:10.1038/s41929-022-00759-6

Nature, Published online: 29 March 2022; doi:10.1038/d41586-022-00852-7

Nature, Published online: 29 March 2022; doi:10.1038/d41586-022-00807-y

A novel cobalt-catalyzed carbonylative coupling of ethers with amines to construct α-carbonylated ethers has been achieved. Alfuzosin, a medicine for treatment of benign prostatic hyperplasia (BPH), can be synthesized by this process straightforwardly.

Abstract

Ethers are of central importance in the fields of biomass, energy, and organic chemistry. Herein, a novel cobalt-catalyzed carbonylative coupling of ethers with amines to construct α-carbonylated ethers has been achieved. Remarkably, Alfuzosin, a medicine for treatment of benign prostatic hyperplasia (BPH), can be synthesized by this process straightforwardly. Notably, this protocol presents the first example on the direct carbonylative reaction of ethers.

Publication date: Available online 15 March 2022

Source: Chem

Author(s): Emilia Paone, Francesco Mauriello

Nature Reviews Chemistry, Published online: 21 March 2022; doi:10.1038/s41570-022-00372-y

The Cover Feature shows that two types of zeolites (BEA* and MFI) were used as catalysts (saws) to respectively break the C−O and C−C bonds of lignin-first monomers obtained from soft wood. The developed catalytic strategy provides a new approach to produce catechol from renewable feedstocks. More information can be found in the Research Article by X. Wu et al.