Enrico

ABSTRACT: We report the first total synthesis of (+)-daphnepapytone A, an unprecedented member of the guaiane-derived sesquiterpenoids, and several related guaiane-derived natural products including diarthroncha C, daphnenicillata W, and oleodaphnone. Our first-generation strategy was thwarted by an unsuccessful late-stage biomimetic [2+2] cycloaddition, however our second-generation de novo approach provided expedient access to the tetracyclic core of daphnepapytone A through an intramolecular allenyl thermal [2+2] cycloaddition and a cage-like Pauson–Khand reaction with a labile cyclobu-tane.

A seminal example of aryl silicon nucleophiles in Bi catalysis is reported, in the context of the synthesis of aromatic fluorinated thiosulfones. The protocol is compatible with a wide range of anionic and neutral Ar-Si compounds, including heterocycles. Stoichiometric investigations of individual organometallic steps provide strong evidence supporting a Bi-redox-neutral catalytic cycle.

Abstract

We present a catalytic protocol utilizing bismuth for the synthesis of aromatic fluorinated thiosulfones, showcasing a seminal example of aryl silicon nucleophiles in Bi catalysis. This catalytic process is enabled by a series of Bi-based organometallic transformations, including an unprecedented transmetalation of aryl silicates to Bi(III) complexes and the formal migratory insertion of sulfur dioxide (SO₂) into the Bi-C bond. The protocol is compatible with a wide range of anionic and neutral Ar-Si compounds, including heterocycles. Stoichiometric investigations of individual organometallic steps provide strong evidence supporting a Bi-redox-neutral catalytic cycle.

Nature, Published online: 19 February 2025; doi:10.1038/d41586-025-00455-y

A first-of-its-kind analysis by Nature reveals which institutions are retraction hotspots.

The challenging C3-hydroxylation of valuable aza-arene cores is presented. Nucleophilic dearomatized intermediates react with electrophilic peracids and peroxides in a highly regioselective manner. This protocol is distinguished by its broad scope, exceptional regioselectivity, scalability, and potential for late-stage diversification.

Abstract

The functionalization of C−H bonds in heterocycles holds considerable importance in chemical synthesis and drug discovery. Recently, the regioselective introduction of various functionalities at the meta-position of azines, utilizing readily accessible dearomatized intermediates, has emerged as a highly attractive approach. Along these lines, the meta-hydroxylation of azines is an appealing but challenging transformation due to the inherent electronic nature of these heterocycles. Herein, we report a meta-selective hydroxylation of pyridines, quinolines and isoquinolines through easily accessible oxazinoaza-arene intermediates. The nucleophilic C3-position of these dienamine-type intermediates engages in highly regioselective hydroxylation upon treatment with electrophilic peroxides.

Nature Chemistry, Published online: 28 January 2025; doi:10.1038/s41557-024-01710-x

Substituted bicyclo[1.1.1]pentanes (BCPs) are widely used as bioisosteres for para-substituted phenyl rings, providing improved pharmacological profiles for drug candidates, but strategies for the preparation of chiral BCPs remain limited. Now a route to chiral bridge-substituted BCPs has been developed via a nitrogen-atom insertion-and-deletion strategy, enabling a practical avenue towards chiral BCP bioisosteres of lomitapide.

Nature Chemistry, Published online: 06 February 2025; doi:10.1038/s41557-024-01714-7

Preliminary clinical trials suggest that ibogaine and its active metabolite noribogaine have powerful anti-addictive properties, Now, a strategy for the scalable, asymmetric total synthesis of ibogaine has been developed that also provides access to iboga analogues. Biological testing identified a psychoplastogenic iboga analogue that is a potent modulator of the serotonin transporter.

Ring contraction reactions facilitate easy access to carbo- and heterocyclic scaffolds from readily available precursors and have therefore enjoyed great popularity as a strategy in organic synthesis for a long time. By repurposing commercial alcohol dehydrogenases as borrowing hydrogen biocatalysts, we were able to develop a rare example of an enzymatic ring contraction methodology, where racemic 2-hydroxypyranones can be converted in an enantioconvergent manner to the corresponding 5-membered butenolides. The redox self-sufficient transformation delivers gamma-lactones in excellent optical purities and was successfully employed in the total synthesis of an Osmunda metabolite. Moreover, the biocatalytic tool was incorporated into a multi-step cascade consisting of six enzymes, achieving the formal enantioselective dearomatization of a furfuryl alcohol to deliver the corresponding saturated gamma-lactone in >99% ee.

Nature Synthesis, Published online: 22 January 2025; doi:10.1038/s44160-024-00716-0

A general homogeneous hydrogen isotope labelling strategy for unactivated alkyl halides is reported. This approach overcomes the limited selectivity of traditional methods by combining bioinspired carbon–halogen activation and hydrogenation catalysis, enabling the selective and controlled synthesis of deuterium- and tritium-labelled drug molecules, which are crucial for drug discovery.

Nature Chemistry, Published online: 06 January 2025; doi:10.1038/s41557-024-01691-x

Heavier analogues of unsaturated organic molecules are of interest because of their bonding situation and their potential use in synthesis. Now, a Bi(I)-based allyl cation, which can be seen as a heavy congener of all-carbon π-allyl cations, has been reported. This complex serves as a synthon for Bi(I) transfer, enabling access to low-valent organobismuth compounds.