Finn Moeller

Nature Chemistry, Published online: 24 February 2025; doi:10.1038/s41557-025-01749-4

A copper-catalyzed enantioselective and 1,4-selective hydropyridylation has been developed. Using 2-fluoropyridine as the electrophile and a copper catalyst in conjunction with (R)-Tol-BINAP, the desired chiral 1,1-diaryl product was synthesized via a concerted nucleophilic aromatic substitution mechanism.

Abstract

The synthesis of chiral 1,1-diaryl compounds, particularly those containing a pyridine moiety, is of significant interest due to their pharmaceutical applications. Here, we report the development of a copper-catalyzed enantioselective 1,4-hydropyridylation of conjugated dienes. Utilizing 2-fluoropyridine as the electrophile, CuOAc, and the chiral ligand Tol-BINAP, we optimized reaction conditions to achieve the desired chiral 1,1-diaryl products containing both a pyridine and a cis-crotyl group. Mechanistic studies and DFT calculations revealed that the 1,2-hydrocupration step is enantio-determining, and the concerted nucleophilic aromatic substitution proceeds via six-membered cyclic transition states.

Nature, Published online: 21 February 2025; doi:10.1038/d41586-025-00538-w

The first insertion of arynes into non-enolizable ketones is demonstrated in this ortho-phenylene ring expansion of benzocyclobutenones using 2-haloaryl boronates as the coupling partner. In this transformation, Pd plays a dual role in both aryne formation and C−C activation.

Abstract

Insertion of arynes into cyclic C−C bonds provides a straightforward approach for ring expansion with an ortho-phenylene moiety; however, the current scope of substrates has been restricted to enolizable ketones. Here we report the first example of aryne-insertion into non-enolizable ketones through Pd-catalyzed C−C bond activation of benzocyclobutenones. 2-Haloaryl boronates were employed as an unconventional aryne precursor. The reaction shows a wide substrate scope and high functional group tolerance. The mechanistic studies reveal an interesting dual role of the Pd catalyst for both aryne generation and C−C bond activation.

We illustrate the first Pd catalyzed regioselective distal and atroposelective olefination through dynamic kinetic resolution of simple arenes/biaryl via an electrooxidative reaction pathway. Electricity plays a significant role in streamlining the ‘regio-resolved’ reaction furnishing chiral molecules synthesis without the requirement of metal oxidants and thermal energy. Both electroanalytical studies and DFT calculation suggest the involvement of a Pd(II)/Pd(IV) catalytic cycle via a Pd(III) intermediate for both the distal and atroposelective olefination reaction.@dm_lab; @maiti_iitb

Abstract

Regioselective and enantioselective C-H functionalization is a valuable method for synthesizing chiral and complex molecules. However, it often requires large amounts of toxic oxidants and high temperature, making it environmentally and economically adverse. Additionally, these traditional approaches generally suffer from regioselectivity and enantioselectivity issues. To overcome these limitations, a new mechanism is needed to control both of these simultaneously. Herein, we report the first Pd catalyzed regioselective distal and atroposelective olefination of simple arenes/biaryls via an electrooxidative reaction pathway. This unique electro-oxidative strategy with Pd(II) catalysis demonstrates unprecedented access to ‘regio-resolved’ reactions, furnishing chiral molecule synthesis under dynamic kinetic resolution without the conventional requirement of metal-based oxidants and thermal energy. Both electroanalytical studies and DFT calculations suggest the involvement of a Pd(II)/Pd(IV) catalytic cycle via a crucial Pd(III) intermediate that initiates both the distal and atroposelective olefination reactions.

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

Nature Communications, Published online: 15 February 2025; doi:10.1038/s41467-025-56956-x

The application of gem-hydrogenation, which exploits the electrophilic character of the ruthenium carbene intermediates transiently formed, to natural product total synthesis allowed the stereostructure of a pair of diastereomeric seco-cembranoids that are almost indistinguishable by NMR to be rigorously assigned. Computational analysis of the data by the CP probabilistic method provided independent confirmation.

Abstract

As the spectra of the diastereomeric marine seco-cembranoids caucanolide E and F are almost identical, the isolation team had not been able to firmly assign their stereostructure. The puzzle has now been solved by a synthetic approach predicated on biogenetic considerations, which suggested that both natural products are 10S configured but differ in the configuration of their C8 stereocenter. Under this proviso, they can be distinguished by comparison with synthetic samples that are deliberately 8S,10S and 8S,10R configured: only one natural product can match sign and magnitude of the [α]_D of one of these reference compounds; this particular caucanolide must be the 8S,10S isomer. Both reference compounds needed for this benchmarking exercise were accessible from a single precursor via ruthenium catalyzed gem-hydrogenation of an enyne to furnish an alkoxyfuran in the first place, followed by hydrolysis; this key transformation leverages the electrophilic character of the pianostool ruthenium carbene intermediates passed through. The recorded data showed that the assignment proposed in the literature is incorrect and needs to be reversed; this conclusion was independently confirmed by a combined NMR/DFT approach using a CP3 probability analysis.

Despite the established state of knowledge, synthetically useful diazotation of aliphatic amines is possible. The key of this process is the use of 1,1,1,3,3,3-hexafluoroisopropanol as a solvent. It improves the selectivity of the process and enables the transformation of the intermediates into the desired Friedel–Crafts products. In this way, after more than 150 years, also the diazotation of aliphatic amines is gaining its place in synthesis.

Abstract

While aromatic diazonium salts are important reagents in organic synthesis, ‘Diazonium ions generated from ordinary aliphatic primary amines are usually useless for preparative purposes, since they lead to a mixture of products giving not only substitution by any nucleophile present, but also elimination and rearrangements if the substrate permits.’¹ In this work, we report that this statement is no longer valid, and it is now possible to control diazotization of aliphatic amines by utilizing isopentyl nitrite in HFIP. This transformation enabled electrophilic aromatic substitution with these highly abundant and commercially available alkyl reagents, as well as transforming them into building blocks typically employed in organic synthesis. The methodology opens an avenue for reactions involving aliphatic amines, even such demanding substrates as amino acids, as a source of carbocations thus expanding the degree of chemical space.

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 Reviews Chemistry, Published online: 31 January 2025; doi:10.1038/s41570-025-00688-5