LongLarf

Synlett
DOI: 10.1055/a-2099-6478

This research Account describes the development of chiral organocatalysts, focusing on diphenyl-2-pyrrolidinemethanol and its derivatives as valuable tools in asymmetric transformations. The research also includes the discovery of a novel anionic Si→C alkyl migration method, which has been developed into a one-pot procedure for synthesizing (E)-chalcones from hydroxyamide and N,N-diethylcarbamates. The findings underscore the potential of sulfide and silicon as valuable reagents for organic synthesis and emphasize the importance of exploring new reaction pathways and mechanisms to discover novel synthetic methods.1 Introduction2 Synthesis of 2 and Sulfur Reagent as Chiral Lewis Acid3 Sulfur/Selenium Reagent as Chiral Lewis Base4 Anionic Si→C Alkyl Migration5 Conclusion
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A PNP pincer manganese complex was applied as catalyst for transfer hydrogenation of quinolines with ammonia borane as hydrogen source. 1,2,3,4-Tetrahydroquinolines were obtained under mild conditions with good to excellent yields. 1,2-Dihydroquinolines were detected by ¹H NMR in the progress and isotopic labelling experiments were performed to determine the destination of ammonia-borane hydrogen atoms.

Abstract

Herein, an efficient methodology for the homogeneous manganese-catalysed transfer hydrogenation of N-heterocycles by using ammonia-borane as a hydrogen source under mild reaction conditions is reported. Good to excellent isolated yields are achieved by applying a PNP manganese pincer complex. In the reaction, 1,2-dihydroquinoline is detected as intermediate by NMR spectra analysis and deuterium labelling experiment. The catalytic reaction likely proceeded by an outer-sphere pathway based on the bifunctional pincer complex.

Science, Volume 381, Issue 6661, Page 1011-1014, September 2023.

Science, Volume 381, Issue 6662, Page 1079-1085, September 2023.

The creation of enzymes containing non-biological functionalities with activation modes outside of Nature’s canon paves the way towards fully programmable biocatalysis. Here, we present a fully genetically encoded boronic acid containing designer enzyme with organocatalytic reactivity not achievable with natural or engineered biocatalysts. This boron enzyme catalyzes the kinetic resolution of hydroxyketones by oxime formation where crucial interactions with the protein scaffold assist in the catalysis. A directed evolution campaign lead to a variant with natural enzyme like enantioselectivities for a number of different substrates. The unique activation mode of the boron enzyme was studied via X-ray crystallography, high resolution mass spectrometry and 11B NMR spectroscopy and opens up the possibility for a new class of boron dependent biocatalysts.

Novel boronic acids have been developed for the catalyzed amide synthesis. Lewis acidity estimation using DFT, associated with collected kinetic data, allowed to uncover ortho-(sulfonyloxy)benzeneboronic acids that compared favorably with the established state-of-the-art boronic acids. Efficient coupling of aliphatic, aromatic, and heteroaromatic carboxylic acids as well as primary and secondary amines were obtained.

Abstract

This study outlines the development of novel boronic acids as catalysts for the direct synthesis of amides from carboxylic acids and amines. The Lewis acidity of the boronic acids was estimated by means of computational techniques, and the observed increase in catalytic activity was corroborated by kinetic data derived from a model reaction. Our investigations led to the discovery of a set of ortho-(sulfonyloxy)benzeneboronic acids that compared favorably with the established state-of-the-art. These newly developed catalysts demonstrated efficacy in the coupling of aliphatic, aromatic, and heteroaromatic acids, as well as primary and secondary amines.

An organocatalytic direct functionalization/acylation of strong aliphatic C(sp³)-H bonds is disclosed via an N-heterocyclic carbene (NHC)-catalyzed dehydrogenative coupling of aldehydes with simple alkanes. The inert aliphatic C−H bonds are efficiently cleaved through intermolecular hydrogen atom transfer, providing an alternative organocatalytic approach for alkane C−H functionalization under transition metal- and light free conditions.

Abstract

The direct functionalization of inert C(sp³)-H bonds to form carbon-carbon and carbon-heteroatom bonds offers vast potential for chemical synthesis and therefore receives increasing attention. At present, most successes come from strategies using metal catalysts/reagents or photo/electrochemical processes. The use of organocatalysis for this purpose remains scarce, especially when dealing with challenging C−H bonds such as those from simple alkanes. Here we disclose the first organocatalytic direct functionalization/acylation of inert C(sp³)-H bonds of completely unfunctionalized alkanes. Our approach involves N-heterocyclic carbene catalyst-mediated carbonyl radical intermediate generation and coupling with simple alkanes (through the corresponding alkyl radical intermediates generated via a hydrogen atom transfer process). Unreactive C−H bonds are widely present in fossil fuel feedstocks, commercially important organic polymers, and complex molecules such as natural products. Our present study shall inspire a new avenue for quick functionalization of these molecules under the light- and metal-free catalytic conditions.

Nature Catalysis, Published online: 14 September 2023; doi:10.1038/s41929-023-01024-0

Non-natural photobiocatalysis is attractive but usually involves UV light activation or the formation of electron donor–acceptor complexes. Now direct visible-light excitation of flavin-dependent ene-reductases allows stereocontrolled intermolecular radical hydroarylation of alkenes initiated by single-electron oxidation.

Nature, Published online: 20 September 2023; doi:10.1038/s41586-023-06529-z

Heterogeneous geminal-atom catalysts, which pair single-atom sites in specific coordination and spatial proximity, offer a new avenue for the sustainable manufacture of fine chemicals.

The 2-oxoglutarate (2OG)-dependent non-heme enzyme FtmOx1 can catalyze the endoperoxidation of fumitremorgin B, producing verruculogen. The side product of deisoprenylation becomes the major product when the analogue 13-oxo-fumitremorgin B is used as the substrate. Fumitremorgin B and 13-oxo-fumitremorgin B show similar substrate-binding patterns with FtmOx1 but different enzymatic conversions.

Abstract

The high-resolution X-ray crystal structure of the ternary complex FtmOx1 ⋅ 2OG ⋅ fumitremorgin B and the catalytic mechanism were recently reported by us (DOI 10.1002/anie.202112063). In their Correspondence, Zhang, Costello, Liu et al. criticize our work in several aspects. Herein, we address these questions one by one. These structural clarifications and new computational results further support the CarC-like mechanistic model.

The biosynthetic origin of rhizonins, hepatotoxic cyclopeptides with unusual 3-furylalanine (Fua) residues, has been elucidated. Functional analysis of the biosynthesis gene cluster, labeling experiments, and heterologous reconstitution revealed the biosynthetic precursors and a novel dioxygenase (RhzB) that catalyzes Fua formation and allowed the discovery of the bingchamide biosynthesis gene cluster by genome mining.

Abstract

Rhizonin A and B are hepatotoxic cyclopeptides produced by bacterial endosymbionts (Mycetohabitans endofungorum) of the fungus Rhizopus microsporus. Their toxicity critically depends on the presence of 3-furylalanine (Fua) residues, which also occur in pharmaceutically relevant cyclopeptides of the endolide and bingchamide families. The biosynthesis and incorporation of Fua by non-ribosomal peptide synthetases (NRPS), however, has remained elusive. By genome sequencing and gene inactivation we elucidated the gene cluster responsible for rhizonin biosynthesis. A suite of isotope labeling experiments identified tyrosine and l-DOPA as Fua precursors and provided the first mechanistic insight. Bioinformatics, mutational analysis and heterologous reconstitution identified dioxygenase RhzB as necessary and sufficient for Fua formation. RhzB is a novel type of heme-dependent aromatic oxygenases (HDAO) that enabled the discovery of the bingchamide biosynthesis gene cluster through genome mining.

Biocatalytic group transfer reactions can efficiently generate highly complex molecules under mild and environmentally friendly conditions. This Minireview highlights inspiring examples of the development of non-natural donor reagents to power such enzymatic transformations, while discussing the design aspects behind the choice of reagent.

Abstract

Biocatalysis has become a major driver in the innovation of preparative chemistry. Enzyme discovery, engineering and computational design have matured to reliable strategies in the development of biocatalytic processes. By comparison, substrate engineering has received much less attention. In this Minireview, we highlight the idea that the design of synthetic reagents may be an equally fruitful and complementary approach to develop novel enzyme-catalysed group transfer chemistry. This Minireview discusses key examples from the literature that illustrate how synthetic substrates can be devised to improve the efficiency, scalability and sustainability, as well as the scope of such reactions. We also provide an opinion as to how this concept might be further developed in the future, aspiring to replicate the evolutionary success story of natural group transfer reagents, such as adenosine triphosphate (ATP) and S-adenosyl methionine (SAM).

N,O-benzylidene acetal dipeptides (NBDs) can serve as easy-to-handle and highly effective building blocks to enable syntheses of difficult peptides and proteins via a kinked peptide backbone strategy. The scalable and cost-effective synthesis and the proven effectiveness for the synthesis of difficult peptides render NBDs valuable tools for solid-phase peptide synthesis in both academic research and industrial applications.

Abstract

Proteins with highly hydrophobic regions or aggregation-prone sequences are typically difficult targets for chemical synthesis at the current stage, as obtaining such type of peptides via solid-phase peptide synthesis requires sophisticated operations. Herein, we report N,O-benzylidene acetal dipeptides (NBDs) as robust and effective building blocks to allow the direct synthesis of difficult peptides and proteins via a kinked backbone strategy. The effectiveness and easy accessibility of NBDs have been well demonstrated in our chemical syntheses of various challenging peptides and proteins, including chemokine, therapeutic hormones, histone, and glycosylated erythropoietin.

Efficient Mn artificial transfer hydrogenases (ATHases) were developed using the biotin-streptavidin technology, which exhibits high activity and enantioselectivity for the transfer hydrogenation of a wide range of aryl ketones. The S112Y-K121 M double mutation and the appropriate chemical structure of the Mn cofactor play critical roles in the reactivity and enantioselectivity of the enzymes.

Abstract

Artificial (transfer) hydrogenases have been developed for organic synthesis, but they rely on precious metals. Native hydrogenases use Earth-abundant metals, but these cannot be applied for organic synthesis due, in part, to their substrate specificity. Herein, we report the design and development of manganese transfer hydrogenases based on the biotin-streptavidin technology. By incorporating bio-mimetic Mn(I) complexes into the binding cavity of streptavidin, and through chemo-genetic optimization, we have obtained artificial enzymes that hydrogenate ketones with nearly quantitative yield and up to 98 % enantiomeric excess (ee). These enzymes exhibit broad substrate scope and high functional-group tolerance. According to QM/MM calculations and X-ray crystallography, the S112Y mutation, combined with the appropriate chemical structure of the Mn cofactor plays a critical role in the reactivity and enantioselectivity of the artificial metalloenzyme (ArMs). Our work highlights the potential of ArMs incorporating base-meal cofactors for enantioselective organic synthesis.

Abstract

Despite advances in the development of catalytic asymmetric Diels-Alder reactions, introducing α,β-unsaturated esters as dienophiles remains challenging owing to their low reactivity. Herein, we report that a chiral aminocatalyst in conjunction with a chiral isothiourea catalyst or a Brønsted acid can promote enantio- and diastereoselective Diels-Alder reactions between 2,4-dienals and α,β-unsaturated esters. This method proceeds through the formation of chiral trienamine intermediates for the exo-cycloaddition with activated dienophiles, α,β-unsaturated acylammonium species or protonated N-heteroaryl-substituted alkenes. Through synergistic activation of both dienes and ester dienophiles, densely functionalized cyclohexenes bearing multiple stereocenters can be afforded with up to >25:1 dr and >99% ee. Moreover, we show that variation of the configurations of the chiral catalysts and the olefin geometry allows the stereodivergent preparation of four stereoisomers of the enantiopure exo-products.

Abstract

An efficient and highly selective semi-hydrogenation of terminal alkynes to alkenes using neutral dimeric rhodium(I) complexes of the type [Rh(μ-Cl)(PP)]₂ is presented. Dehydroisophytol (DIP) was chosen as the alkyne for this study because of its high importance in the industrial production of synthetic vitamin E. Excellent selectivity of over 91% towards the alkene was achieved with known and new rhodium catalysts. No deactivation was observed for the [Rh(μ-Cl)(PP)]₂ complexes and the molar Rh:DIP ratio could be increased to 1:20 000, and importantly, no reduction in selectivity was observed. The results presented open the door to the industrial application of homogeneous rhodium complexes in the semi-hydrogenation of terminal alkynes.

Abstract

Due their multifaced applications, the access to organosulfur derivatives in an efficient and economical way is a challenge in organic synthesis. In this context photochemistry and photocatalysis play a crucial role in the development of innovative (and selective) Carbon-Sulphur bond formation processes. The present review aims to collect the most recent strategies to achieve this target under visible light driven conditions.

Nature Chemistry, Published online: 31 August 2023; doi:10.1038/s41557-023-01312-z

Pd/norbornene cooperative catalysis provides a strategy for arene functionalization, but the electrophile scope is typically limited to ‘soft’ elements such as carbon, nitrogen and sulfur. Now the ortho-C–H methoxylation of aryl halides has been realized using a polarity-reversed N−O reagent and facilitated by a C7-bromo-substituted norbornene mediator.