Cracking Cyclopropane

Welcome to this week’s Organic Synthesis Newsletter.

Monday 7^th October – Sunday 13^th October 2024

SCIENCE
Catalytic Asymmetric Fragmentation of Cyclopropanes

R. K. Raut, S. Matsutani, F. Shi, S. Kataoka, M. Poje, B. Mitschke, S. Maeda, N. Tsuji* & B. List*

Science 2024, 386, 225–230 (DOI: 10.1126/science.adp9061)

The stereoselective activation of alkanes constitutes a long-standing and grand challenge for chemistry. Although metal-containing enzymes oxidize alkanes with remarkable ease and selectivity, chemical approaches have largely been limited to transition metal–based catalytic carbon–hydrogen functionalizations. Alkanes can be protonated to form pentacoordinated carbonium ions and fragmented into smaller hydrocarbons in the presence of strong Brønsted acids. However, catalytic stereocontrol over such reactions has not previously been accomplished. Here, the authors show that strong and confined acids catalyze highly enantioselective fragmentations of a variety of cyclopropanes into the corresponding alkenes, expanding the boundaries of catalytic selective alkane activation. Computational studies suggest the involvement of the long-debated cycloproponium ions.

Catalytic Prenyl Conjugate Additions for Synthesis of Enantiomerically Enriched PPAPs

S. Ng, C. Howshall, T. N. Ho, B. K. Mai, Y. Zhou, C. Qin, K. Z. Tee, P. Liu*, F. Romiti* & A. H. Hoveyda*

Science 2024, 386, 167–175 (DOI: 10.1126/science.adr8612)

Polycyclic polyprenylated acylphloroglucinols (PPAPs) are a class of >400 natural products with a broad spectrum of bioactivity, ranging from antidepressant and antimicrobial to anti-obesity and anticancer activity. Here, the authors present a scalable, regio-, site-, and enantioselective catalytic method for synthesis of cyclic β-prenyl ketones, compounds that can be used for efficient syntheses of many PPAPs in high enantiomeric purity. The transformation is prenyl conjugate addition to cyclic β-ketoesters promoted by a readily accessible chiral copper catalyst and involving an easy-to-prepare and isolable organoborate reagent. Reactions reach completion in just a few minutes at room temperature and the enantioselective synthesis of nemorosonol is presented (14 steps, 20% yield) alongside its one-step conversion to another PPAP, garcibracteatone (52% yield).

NATURE
Emergence of a Distinct Mechanism of C–N Bond Formation in Photoenzymes

F. C. Raps, A. Rivas-Souchet, C. M. Jones & T. K. Hyster*

Nature 2024 (DOI: 10.1038/s41586-024-08138-w)

C–N bond formation is integral to modern chemical synthesis due to the ubiquity of nitrogen heterocycles in small-molecule pharmaceuticals and agrochemicals. Alkene hydroamination with unactivated alkenes is an atom economical strategy for constructing these bonds. However, these reactions are challenging to render asymmetric when preparing fully substituted carbon stereocenters. Here, the authors report a photoenzymatic alkene hydroamination to prepare 2,2-disubstituted pyrrolidines by a Baeyer-Villiger Monooxygenase. Five rounds of protein engineering afforded a mutant, providing excellent product yield and stereoselectivity. Unlike related photochemical hydroaminations, which rely on the oxidation of the amine or alkene for C–N bond formation, this work exploits a through-space interaction of a reductively generated benzylic radical and the nitrogen lone pair. This antibonding interaction lowers the oxidation potential of the radical, enabling electron transfer to the flavin cofactor.

NATURE CHEMISTRY
Triazenolysis of Alkenes as an Aza Version of Ozonolysis

A. Koronatov, P. Sakharov, D. Ranolia, A. Kaushansky, N. Fridman & M. Gandelman*

Nat. Chem. 2024 (DOI: 10.1038/s41557-024-01653-3)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2023-h5jnz) 🔓

Alkenes are broadly used in synthetic applications, thanks to their abundance and versatility. Ozonolysis is one of the most canonical transformations that converts alkenes into molecules bearing carbon–oxygen motifs via C=C bond cleavage. Despite its extensive use in both industrial and laboratory settings, the aza version—cleavage of alkenes to form carbon–nitrogen bonds—remains elusive. Here, the authors report the conversion of alkenes into valuable amines via complete C=C bond disconnection. This process, termed “triazenolysis”, is initiated by a (3+2) cycloaddition of triazadienium cation to an alkene. The triazolinium salt formed accepts hydride from borohydride anion and spontaneously decomposes to create new C–N motifs upon further reduction. The developed reaction is applicable to a broad range of cyclic alkenes to produce diamines, while various acyclic C=C bonds may be broken to generate two separate amine units.

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Regiodivergent Radical-Relay Alkene Dicarbofunctionalization

Z. Liu, F. D’Amico & R. Martin*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c10204)

The authors report a regiodivergent 1,n-dicarbofunctionalization of unactivated olefins enabled by a Ni-catalyzed radical relay that forges both C(sp³)-C(sp³) and C(sp²)–C(sp³) linkages, even at long-range. Initial studies support an intertwined scenario resulting from the merger of an atom-transfer radical addition (ATRA) and a chain-walking event, with site-selectivity being dictated by a judicious choice of the ligand backbone.

Visible-Light Photoredox-Catalyzed Direct Carboxylation of Tertiary C(sp³)–H Bonds with CO₂: Facile Synthesis of All-Carbon Quaternary Carboxylic Acids

Y. Liu, G.-H. Xue, Z. He, J.-P. Yue, M. Pan, L. Song,* W. Zhang, J.-H. Ye & D.-G. Yu*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c09558)

The direct carboxylation of C–H bonds with CO₂ represents an attractive strategy to synthesize carboxylic acids with high atom, step, and redox economy. Although great progress has been achieved in this field, catalytic carboxylation of tertiary C(sp³)–H bonds still remains challenging. Herein, the authors report a direct carboxylation of tertiary benzylic C(sp³)–H bonds with CO₂ via visible-light photoredox catalysis. Various all-carbon quaternary carboxylic acids are obtained in high yields and the process is characterized by good functional group tolerance, broad substrate scope, and mild conditions. Furthermore, the methodology enables the efficient and rapid synthesis of key drugs and bioactive molecules, such as carbetapentane, caramiphen, and PRE-084 (σ1 receptor agonist).

Multicomponent Construction of Tertiary Alkylamines by Photoredox/Nickel-Catalyzed Aminoalkylation of Organohalides

T. Yang,* W. Xiong, G. Sun, W. Yang, M. Lu & M. J. Koh*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c11602)

Tertiary alkylamines are privileged structural motifs widely present in natural products, pharmaceutical agents, and bioactive molecules, and their efficient synthesis has been a longstanding goal in organic chemistry. The functionalization of α-amino radicals derived from abundant precursors represents an emerging approach to accessing alkylamines, but application of this strategy to obtain tertiary alkylamines remains challenging. Here, the authors show that dual photoredox/nickel catalysis enables aminoalkylation of organohalides (sp²- and sp³-hybridized) in combination with secondary alkylamines and aldehydes. The multicomponent process proceeds through selective generation of α-amino radicals from the reduction of in situ-generated iminium ions by photoredox catalysis, followed by nickel-catalyzed cross-coupling to build a wide array of functionally diverse tertiary alkylamines. This strategy could also be extended to unprecedented four-component reactions and their asymmetric variants to deliver enantioenriched α-aryl-substituted γ-amino acid derivatives.

Electrocatalytic Hydrogenation of Pyridines and Other Nitrogen-Containing Aromatic Compounds

N. Shida,* Y. Shimizu, A. Yonezawa, J. Harada, Y. Furutani, Y. Muto, R. Kurihara, J. N. Kondo, E. Sato, K. Mitsudo, S. Suga, S. Iguchi, K. Kamiya & M. Atobe*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c09107) 🔓

The production of cyclic amines, which are vital to the pharmaceutical industry, relies on energy-intensive thermochemical hydrogenation. Herein, the authors demonstrate the electrocatalytic hydrogenation of nitrogen-containing aromatic compounds, specifically pyridine, at ambient temperature and pressure via a membrane electrode assembly with an anion-exchange membrane. Piperidine was synthesized using a carbon-supported rhodium catalyst, achieving a current density of 25 mA cm^–2 and a current efficiency of 99% under a circular flow until 5 F mol^–1. Quantitative conversion of pyridine into piperidine with 98% yield was observed after passing 9 F mol^–1, corresponding to 65% of current efficiency. The proposed process is applicable to other nitrogen-containing aromatic compounds and could be efficiently scaled up. This method presents clear advantages over traditional high-temperature and high-pressure thermochemical catalytic processes.

ACS CATALYSIS
Electrooxidative Pd-Catalyzed Remote Hydrofunctionalization of Alkenes with Nucleophiles

S. Park,^† B. Yang,^† D. Lee, H. Kim* & K. Shin*

ACS Catal. 2024, ASAP (DOI: 10.1021/acscatal.4c04279)

The catalytic hydrofunctionalization of alkenes with nucleophiles via the generation of carbocationic intermediates has been extensively studied as an efficient strategy for the regioselective installation of functional groups on alkene feedstocks. However, since the established methods are confined to functionalization of the position where the alkene is originally located, it would be highly desirable to develop a broadly applicable catalytic hydrofunctionalization platform that offers an alternative regioselectivity. Herein, the authors report a remote alkene hydrofunctionalization method enabled by electrooxidative palladium hydride catalysis. The key to success is the formation of a remote carbocation intermediate through a mechanistic pathway, which involves a chain-walking process followed by anodic oxidation of an organopalladium species. This method allows remote hydrofunctionalization of terminal and internal alkenes with a broad range of oxygen, carbon, nitrogen, and fluoride nucleophiles, including complex drug-like molecules.

Metallaphotoredox-Catalyzed Three-Component Asymmetric Cross-Electrophile Coupling for Chiral Boronate Synthesis

X. Li, Y. Hu, Z. Huang, S. Zhu, F.-L. Qing & L. Chu*

ACS Catal. 2024, ASAP (DOI: 10.1021/acscatal.4c04316)

The authors report a photoredox and nickel-catalyzed cross-electrophile coupling strategy for the asymmetric three-component 1,2-alkylarylation of vinyl boronates with (hetero)aryl bromides and (2°, 3°)-alkyl redox-active esters in the presence of Hantzsch ester. Using a fluorinated pyridyl-substituted chiral biimidazoline ligand, the reaction enables straightforward access to a wide variety of synthetically valuable chiral α-aryl boronates from readily available starting materials. The reaction features mild conditions, broad substrate scope, good functional group tolerance and proceeds without using metal reductants or alkyl halides. Furthermore, alkenyl halides and other electron-deficient alkenes such as acrylates and vinyl phosphonates can be applied successfully.

ANGEWANDTE CHEMIE INTERNATIONAL EDITION
Total Syntheses of β- and γ-Naphthocyclinones

Y. Ando,* T. Hoshino, N. Tanaka, M. M. Maturi, Y. Nakazawa, T. Fukazawa, K. Ohmori* & K. Suzuki

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202415108) 🔓

After half a century from their isolation in 1974, the authors report the first total syntheses of β- and γ-naphthocyclinones, two dimeric pyranonaphthoquinones featuring an unusual bicyclo[3.2.1]octadienone core. The syntheses were achieved with complete stereocontrol, relying on 1) enantioselective construction of the bicyclic core by Rh-catalyzed enantioselective 1,4-addition followed by thiolate-mediated reductive cyclization, and 2) judicious design of a chiral, non-racemic monomer unit that is capable of divergence into the donor and acceptor units, and finally their reunion to construct the bicyclo[3.2.1]octadienone core.

Electrochemical C-O and C-N Arylation using Alternating Polarity in Flow for Compound Libraries

J. Morvan, K. P. L. Kuijpers, D. Fanfair, B. Tang, K. Bartkowiak, L. Eynde, E. Renders, J. Alcazar, P. J. J. A. Buijnsters, M.-A. Carvalho* & A. X. Jones*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202413383)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-rr07j) 🔓

Etherification and amination of aryl halide scaffolds are commonly used reactions in parallel medicinal chemistry to rapidly scan structure-activity relationships with abundant building blocks. Electrochemical methods for aryl etherification and amination demonstrate broad functional group tolerance and extended nucleophile scope compared to traditional methods. Nevertheless, there is a need for robust and scale-transferable workflows for electrochemical compound library synthesis. Herein, the authors describe a platform for automated electrochemical synthesis of C-X arylation (X = NH, OH) in flow to access compound libraries. A comprehensive Design of Experiment (DoE) study identifies an optimal protocol which generates high yields across >30 aryl halide scaffolds, diverse amines (including electron-deficient sulfonamides, sulfoximines, amides, and anilines) and alcohols (including serine residues within peptides). Reaction sequences are automated on commercially available equipment to generate libraries of anilines and aryl ethers.

Friedel-Crafts Reactivity with Sulfondiimidoyl Fluorides for the Synthesis of Heteroaryl Sulfondiimines

M.-K. Wei, Z.-X. Zhang, M. Ding & M. C. Willis*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202416638)

Sulfur functional groups are ubiquitous in molecules used in the pharmaceutical and agrochemical industries, and within these collections sulfones hold a prominent position. The double aza-analogues of sulfones, sulfondiimines, offer significant potential in discovery chemistry but to date their applications have been limited by the lack of convenient synthetic routes. Herein, the authors describe a Friedel-Crafts-type reaction of sulfondiimidoyl fluorides with (hetero)aryls. This new SuFEx reactivity benefits from broad functional group tolerance, mild reaction conditions, and does not require the use of pre-formed organometallic reagents. The efficient use of unprotected indoles and pyrroles, as well as furan, thiophene and carbocyclic aromatics, further demonstrates the advantages of these reactions. The utility of the transformation is exemplified by the synthesis of the sulfondiimine analogue of the HIV-I reverse transcriptase-inhibitor L-737,126.

Access to Alkenyl Cyclobutanols by Ni-Catalyzed Regio- and Enantio-selective syn-Hydrometalative 4-exo-trig Cyclization of Alkynones

X.-L. Li,^† J.-L. Deng,^† J. Long, Y.-F. Fu, Y.-Q. Zheng & W.-B. Liu*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202415164)

Enantioselective synthesis of (spiro)cyclobutane derivatives poses significant challenges yet holds promising applications for both synthetic and medicinal chemistry. Here, the authors report a nickel-catalyzed asymmetric syn-hydrometalative 4-exo-trig cyclization of alkynones to synthesize alkenyl cyclobutanols with a tetrasubstituted stereocenter. This strategy features a broad substrate scope, delivering a variety of trifluoromethyl-containing rigid (spiro)carbocycle skeletons in good yields and high enantioselectivities (up to 84% yield and 98.5:1.5 e.r.). The synthetic utility is demonstrated through stereospecific transformations into fused spirocycles.

CHEMRXIV
Merging Photoexcited Nitroarenes with Lewis Acid Catalysis for the Anaerobic Oxidation of Alkenes

J. M. Paolillo, M. R. Saleh, E. W. Junk & M. Parasram*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-3mcc5) 🔓

A protocol for the oxidation of alkenes to carbonyls and acetonides via the interplay of photoexcited nitroarenes and Lewis acid catalysis is described. Terminal 1,1-disubstitued alkenes were oxidized selectively to the aldehyde products, while tri- and tetrasubstituted alkenes generated ketone products with anti-Markovnikov selectivity. Terminal mono-substituted alkenes were oxidized to acetonides when acetone was employed as a co-solvent. The mild conditions of the reaction allow for a wide range of alkenes to be oxidized.

Harnessing Oxetane and Azetidine Sulfonyl Fluorides for Opportunities in Drug Discovery

O. L. Symes, H. Ishikura, C. S. Begg, J. J. Rojas, H. A. Speller, A. M. Cherk, M. Fang, D. Leung, R. A. Croft, J. I. Higham, K. Huang, A. Barnard, P. Haycock, A. J. P. White, C. Choi & J. A. Bull*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-l567g) 🔓

Please see here for a recent, complementary publication by H.-J. Zhang and co-workers.

Four-membered heterocycles such as oxetanes and azetidines represent attractive design options in medicinal chemistry due to their small, polar nature and potential to impact the physiochemical properties of drug molecules. However, the challenging preparation of these derivatives, especially in a divergent manner, has severely limited the combination of oxetanes with other medicinally important groups. Herein, the authors report the development and use of oxetane sulfonyl fluorides (OSF) and azetidine sulfonyl fluorides (ASF), which behave as precursors to carbocations in an unusual defluorosulfonylation reaction pathway (deFS). The small-ring sulfonyl fluorides are activated under mild thermal conditions (60 ºC), and the generated reactive intermediates couple with a broad range of nucleophiles. Notably, oxetane and azetidine-heterocyclic, -sulfoximine and -phosphonate derivatives are prepared, several of which do not have comparable carbonyl analogues. The synthetic utility of novel OSF and ASF reagents was demonstrated through the synthesis of 11 drug analogues and the application of these reagents as linker motifs was shown through the incorporation of pendant groups suitable for common conjugation reactions. Productive deFS reactions with E3 ligase recruiters such as pomalidomide and related derivatives provide new degrader motifs, and potential PROTAC linkers.

Enantioselective Energy Transfer-Enabled Cyclization using a Privileged Al-Salen Photocatalyst

J. Soika^†, C. Onneken^†, T. Wiegmann, T. Morack, L. Lindfeld, M. Hebenbrock, C. Mück-Lichtenfeld, J. Neugebauer* & R. Gilmour*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-9g3qz) 🔓

Chiral catalysts that can engage multiple substrates, via distinct activation modes, to deliver enantioenriched products with high levels of fidelity are often described as “privileged”. Antipodal to enzymatic specificity, this generality enables the reactivity - selectivity divide in ground state landscapes to be effectively reconciled. Achieving this latitude in excited state paradigms remains a frontier, and efforts to identify privileged chiral photocatalysts are currently a core area of research. Aluminum salen complexes are emergent contenders on account of their well-defined photophysical properties and competence in photo-induced single electron transfer processes. To expand the activation repertoire of Al-salen photocatalysts, an unprecedented enantioselective energy transfer (EnT) catalysis-enabled photocyclization of acrylanilides has been developed. This operationally simple strategy allows reactivity and enantioselectivity to be simultaneously regulated by an inexpensive, commercial chiral Al-salen complex upon irradiation at λ = 400 nm: this allows diverse cyclic products to be forged with high levels of enantioselectivity (up to 96:4 e.r.).

ORGANIC LETTERS
A General Entry to Ganoderma Meroterpenoids: Synthesis of Applanatumol E, H, and I, Lingzhilactone B, Meroapplanin B, and Lingzhiol

A. Rode, N. Müller, O. Kováč, K. Wurst & T. Magauer*

Org. Lett. 2024, ASAP (DOI: 10.1021/acs.orglett.4c03192) 🔓

Ganoderma meroterpenoids are a fungal derived hybrid natural product class containing a 1,2,4-trisubstituted benzene ring and a polycyclic terpenoid part. The representatives applanatumol E, H and I, lingzhilactone B, and meroapplanin B share the same bicyclic lactone moiety connected to the arene. Employing photo-Fries rearrangements as the key step enabled a general entry to these natural products. For the synthesis of the tetracyclic framework of lingzhiol, the authors made use of a powerful photoredox oxidative decarboxylation/Friedel–Crafts sequence.

OUTSIDE OF SYNTHESIS, INSIDE OF SCIENCE
Science 🤝 AI

🥇 Science 🤝 AI. The 2024 Nobel Prize in Chemistry has been awarded to David Baker (University of Washington) and to Demis Hassabis and John Jumper (Google DeepMind) for the development of computational—in part, AI-enabled—tools to design and study proteins. The Nobel Prize in Physics also followed suit and was awarded for the computational methods that power artificial neural networks, the approach that underpins AlphaFold and other AI technologies. According to recent analysis, the gap between the major scientific breakthrough and the conferment of a Nobel Prize in chemistry within the last decade (2011–2019) was 30 years. AlphaFold has broken that barrier in only 6 years.

🧪 The “holy grail” of cancer therapy. The German Chemical Society’s online Medicinal Chemistry webinar series continues on Tuesday 22nd October with “Translational Applications of Targeted Protein Degradation: Successes and Learnings along the MAPK Pathway”. The MAPK pathway is interesting due to its importance in regulating cell cycle control with pathway mutations causing unregulated cellular division, leading to cancer. Over 30% of human cancers are driven by RAS genes (85% being a result of KRAS mutations), which has led KRAS to be considered as the “holy grail” of cancer therapy. In this seminar, two PROTAC projects targeting proteins within the MAPK pathway will be discussed, which ultimately resulted in the discovery of a pan-KRAS bifunctional degrader (related publication here).