Photochemical Editing of Pyridines to Pyrazoles

Nature

A General Strategy for the Synthesis of Taxane Diterpenes

L. Pan,^† F. Schneider,^† M. Ottenbruch, R. Wiechert, T. List, P. Schoch, B. Mertes & T. Gaich*

Nature 2024 (DOI: 10.1038/s41586-024-07675-8)

Previously: Research Square (DOI: 10.21203/rs.3.rs-4019390/v1) 🔓

The carbon skeleton of any organic molecule serves as the foundation for its three-dimensional structure, playing a pivotal role in determining its physical and biological properties. As such, taxane diterpenes are one of the most well known natural product families, primarily owing to the success of their most prominent compound, paclitaxel, an effective anti-cancer therapeutic for more than 25 years. In contrast to classical taxanes, the bioactivity of cyclotaxanes (also referred to as complex taxanes) remains significantly underexplored. The carbon skeletons of these two groups of taxanes differ significantly, and so would typically their own distinct synthetic approaches. Here, the authors report a versatile synthetic strategy based on the interconversion of complex molecular frameworks, providing general access to the wider taxane diterpene family. A range of classical and cyclotaxane frameworks was prepared including, among others, the first total syntheses of taxinine K, canataxapropellane and dipropellane C from a single advanced intermediate.

Dynamic Stereomutation of Vinylcyclopropanes with Metalloradicals

M. Mendel, T. M. Karl, J. Hamm, S. J. Kaldas, T. Sperger, B. Mondal & F. Schoenebeck*

Nature 2024 (DOI: 10.1038/s41586-024-07555-1) 🔓

Contrary to the well-established reactivity paradigm that organic free radicals, upon addition to a vinylcyclopropane, lead to rapid ring opening under strain release, the authors show that a Ni(I) metalloradical triggers reversible cis/trans isomerization instead of opening. The isomerization proceeds under chiral inversion and, depending on the substitution pattern, occurs at room temperature in less than 5 min, requiring solely the addition of the non-precious catalyst. Mechanistic studies support metalloradical catalysis as origin of this profound reactivity, rationalize the observed stereoinversion and reveal key reactivity features of the process, including its reversibility. These insights enabled the iterative thermodynamic enrichment of enantiopure cis/trans mixtures towards a single diastereomer through multiple Ni(I) catalysis rounds and also extensions to divinylcyclopropanes. While the trans-isomer usually requires heating at approximately 200 °C to trigger thermal isomerization under racemization to cis-divinylcyclopropane, which then undergoes facile Cope-type rearrangement, the analogous contra-thermodynamic process is herein shown to proceed under Ni(I) metalloradical catalysis under mild conditions without any loss of stereochemical integrity, enabling a mild and stereochemically pure access to seven-membered rings, fused ring systems and spirocycles.

Nature Synthesis

C(sp³)–C(sp³) Bond Formation through Nitrogen Deletion of Secondary Amines using O-Diphenylphosphinylhydroxylamine

T. Guo,^† J. Li,^† Z. Cui, Z. Wang & H. Lu*

Nat. Synth. 2024 (DOI: 10.1038/s44160-024-00559-9)

The nitrogen deletion of secondary amines has emerged as an effective strategy for direct molecular skeletal editing and carbon–carbon bond formation. However, current methods are often limited to acyclic bis(α-primary) amines and cyclic amines, which possess two stabilizing elements at the α-position of amine. Here, the authors report the use of O-diphenylphosphinylhydroxylamine as a reagent for nitrogen deletion of secondary amines to form C(sp³ )–C(sp³ ) bonds. This method overcomes substrate requirements of other methods and tolerates a range of secondary amine substrates. The process can be readily applied to multiple nitrogen deletion processes, is tolerant of both air and water, forms water-soluble byproducts and can be readily scaled to a hundred-gram scale. The versatility of the method is further showcased through the direct editing of natural products, pharmaceutical compounds, N-coordinated ligands, a three-dimensional amine cage and the synthesis of several bioactive compounds.

Nature Communications

Functional Group Tolerant Hydrogen Borrowing C-Alkylation

E. P. Bailey, T. J. Donohoe* & M. D. Smith*

Nat. Commun. 2024, 15, 5131 (DOI: 10.1038/s41467-024-49249-2) 🔓

Hydrogen borrowing is an attractive and sustainable strategy for carbon–carbon bond formation that enables alcohols to be used as alkylating reagents in place of alkyl halides. However, despite intensive efforts, limited functional group tolerance is observed in this methodology, which is hypothesized due to the high temperatures and harsh basic conditions often employed. Here, the authors demonstrate that room temperature and functional group tolerant hydrogen borrowing can be achieved with a simple iridium catalyst in the presence of substoichiometric base without an excess of reagents. Achieving high yields necessitates the application of anaerobic conditions to counteract the oxygen sensitivity of the catalytic iridium hydride intermediate, which otherwise leads to catalyst degradation. Substrates containing heteroatoms capable of complexing the catalyst exhibit limited room temperature reactivity, but the application of moderately higher temperatures enables extension to a broad range of medicinally relevant nitrogen rich heterocycles. These newly developed conditions allow alcohols possessing functional groups that were previously incompatible with hydrogen borrowing reactions to be employed.

Journal of the American Chemical Society

Photochemical Skeletal Editing of Pyridines to Bicyclic Pyrazolines and Pyrazoles

J. Luo,^† Q. Zhou,^† Z. Xu, K. N. Houk* & K. Zheng*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c03713)

The authors present an efficient one-pot photochemical skeletal editing protocol for the transformation of pyridines into diverse bicyclic pyrazolines and pyrazoles under mild conditions. The method requires no metals, photocatalysts, or additives and allows for the selective removal of specific carbon atoms from pyridines, allowing for unprecedented versatility. The approach offers a convenient and efficient means for the late-stage modification of complex drug molecules by replacing the core pyridine skeleton. Moreover, the authors have successfully scaled up this procedure in stop-flow and flow-chemistry systems, showcasing its applicability to intricate transformations such as the Diels–Alder reaction, hydrogenation, [3+2] cycloaddition, and Heck reaction.

Modular, Enantioselective Entry into Polysubstituted Shapeshifting Molecules

A. Sanchez,^† V. M. Gonzalez,^† J. Sakamoto, A. Gurajapu & T. J. Maimone*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c03323)

Dynamic, shapeshifting hydrocarbons have emerged as enabling frameworks across drug discovery, materials science, and catalysis. Their employment, however, is often hampered by a lack of efficient synthetic methods for their preparation. Herein, the authors report a unified, concise, and modular synthesis of enantioenriched shapeshifting hydrocarbons (barbaralones and bullvalones) and multisubstituted bullvalenes, leveraging mild photochemical and base-induced rearrangements.

Enantioselective Synthesis of Sealutomicin C

S. M. Astle, S. Guggiari, J. R. Frost, H. B. Hepburn, D. J. Klauber, K. E. Christensen & J. W. Burton*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c02969) 🔓

The sealutomicins are a family of anthraquinone antibiotics featuring an enediyne (sealutomicin A) or Bergman-cyclized aromatic ring (sealutomicins B–D). Herein, the authors report the development of an enantioselective organocatalytic method for the synthesis of dihydroquinolines and the use of the developed method in the total synthesis of sealutomicin C which features a transannular cyclization of an aryllithium onto a γ-lactone as a second key step.

Modular Access to Functionalized Oxetanes as Benzoyl Bioisosteres

D. Tian, G. Chen, X. Wang & H.-J. Zhang*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c04504)

Bioisosterism is a valuable principle exploited in drug discovery to fine-tune physicochemical properties of bioactive compounds. Functionalized 3-aryl oxetanes, as an important class of bioisosteres for benzoyl groups (highly prevalent structures in approved drugs), have been rarely utilized in agrochemicals and pharmaceuticals due to significant synthetic challenges. Here, the authors present a modular synthetic strategy based on the unexplored yet readily available reagents, oxetanyl trichloroacetimidates, inspired by Schmidt glycosylation, enabling easy access to a library of functionalized oxetanes. This operationally simple protocol leverages the vast existing libraries of aryl halides and various nucleophiles. The power and generality of this approach is demonstrated by late-stage functionalization of complex molecules, as well as the rapid synthesis of oxetane analogues of bioactive molecules and marketed drugs.

Dehydrogenative Coupling of Alkylamines with Primary Alcohols Forming α-Amino Ketones

T. Kawasaki, T. Tosaki, S. Miki, T. Takada, M. Murakami & N. Ishida*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c02761)

Acceptorless dehydrogenative coupling reactions between C–H bonds offer straightforward and atom-economical methods connecting readily available materials while liberating gaseous hydrogen as the sole byproduct. Despite the growing interest in such transformations, their realization still poses a significant challenge. Here, the authors report a photoinduced dehydrogenative coupling reaction of alkylamines with primary alcohols. C–H bonds adjacent to nitrogen and oxygen are site-selectively cleaved, and a C–C bond is created between the carbon atoms in a cross-selective manner to produce α-amino ketones.

Versatile Copper-Catalyzed γ-C(sp³)–H Lactonization of Aliphatic Acids

Z. Zhuang, T. Sheng, J. X. Qiao, K.-S. Yeung & J.-Q. Yu*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c04043)

Site-selective C(sp³ )–H oxidation is of great importance in organic synthesis and drug discovery. γ-C(sp³ )–H lactonization of free carboxylic acids provides the most straightforward means to prepare biologically important lactone scaffolds from abundant and inexpensive carboxylic acids; however, a versatile catalyst for this transformation with a broad substrate scope remains elusive. Herein, the authors report a simple yet broadly applicable and scalable γ-lactonization reaction of free aliphatic acids enabled by a copper catalyst in combination with inexpensive Selectfluor as the oxidant. This lactonization reaction exhibits compatibility with tertiary, benzylic, allylic, methylene, and primary γ-C–H bonds, affording access to a wide range of structurally diverse lactones such as spiro, fused, and bridged lactones. Notably, exclusive γ-methylene C–H lactonization of cycloalkane carboxylic acids and cycloalkane acetic acids was observed, giving either fused or bridged γ-lactones that are difficult to access by other methods. δ-C–H lactonization was only favored in the presence of tertiary δ-C–H bonds.

Ni/Photoredox-Catalyzed Enantioselective Acylation of α-Bromobenzoates with Aldehydes: A Formal Approach to Aldehyde-Aldehyde Cross-Coupling

C. Li, J. Cheng, X. Wan, J. Li, W. Zu, Y. Xu, Y. Huang & H. Huo*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c03164)

The catalytic cross-coupling of identical or similar functional groups is a cornerstone strategy for carbon–carbon bond formation, as exemplified by renowned methods, such as olefin cross-metathesis. However, similar methodologies for coupling aldehydes remain underdeveloped. While the benzoin-type condensation, first reported in 1832, offers a reliable route for aldehyde dimerization, the chemo- and enantioselective cross-coupling of nonidentical yet similar aldehydes remains an unsolved challenge. Herein, the authors report a unified platform enabling highly chemo- and enantioselective cross-coupling of aldehydes. By leveraging nickel photoredox catalysis in tandem with discrete activation strategies for each aldehyde, this mechanistically distinct approach facilitates the enantioselective union of an aldehyde-derived α-oxy radical with an acyl radical, photocatalytically generated from a distinct aldehyde. This novel strategy enables modular access to enantioenriched α-oxygenated ketones with two minimally differentiated aliphatic substituents, a feat not achievable with existing chemocatalytic or biocatalytic techniques.

Enantioselective, Bro̷nsted Acid-Catalyzed Anti-selective Hydroamination of Alkenes

S. Guria, A. N. Volkov, R. Khudaverdyan, R. Van Lommel, R. Pan, C. G. Daniliuc, F. De Proft & U. Hennecke*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c03306)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2023-v0r6h) 🔓

Chiral pyrrolidines are common structural motives in natural products as well as active pharmaceutical ingredients, explaining the need for methods for their enantioselective synthesis. While several, often metal-catalyzed, methods for their preparation do exist, the enantioselective synthesis of pyrrolidines containing quaternary stereocenters remains challenging. Herein, the authors report a Bro̷nsted acid-catalyzed intramolecular hydroamination that provides such pyrrolidines from simple starting materials in high yield and enantioselectivity. Key to an efficient reaction was the use of an electron-deficient protective group on nitrogen, the common nosyl-protecting group, to avoid deactivation of the Bro̷nsted acid by deprotonation. The reaction proceeds as a stereospecific anti-addition indicating a concerted reaction.

Iron-Catalyzed Asymmetric Imidation of Sulfides via Sterically Biased Nitrene Transfer

Z. Liu, H. Wu, H. Zhang, F. Wang, X. Liu, S. Dong*, X. Hong* & X. Feng*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c04855)

Transition-metal-catalyzed enantioselective nitrene transfer to sulfides has emerged as one of the most powerful strategies for rapid construction of enantioenriched sulfimides. However, achieving stereocontrol over highly active earth-abundant transition-metal nitrenoid intermediates remains a formidable challenge compared with precious metals. Herein, the authors disclose a chiral iron(II)/N,N′-dioxide-catalyzed enantioselective imidation of dialkyl and alkyl aryl sulfides using iminoiodinanes as nitrene precursors. A series of chiral sulfimides were obtained in moderate-to-good yields with high enantioselectivities (56 examples, up to 99% yield, 98:2 e.r.). The utility of this methodology was demonstrated by late-stage modification of complex molecules and synthesis of the chiral insecticide sulfoxaflor and the intermediates of related bioactive compounds. Additionally, dioxazolones proved to be suitable acylnitrene precursors in the presence of an iron(III)/N,N′-dioxide complex, resulting in the formation of enantioselectivity-reversed sulfimides (14 examples, up to 81% yield, 97:3 e.r.).

Multielectron Reduction of Esters by a Diazabenzacenaphthenium Photoredox Catalyst

S. Okumura*, S. Hattori, L. Fang & Y. Uozumi*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c05272)

A novel diazabenzacenaphthenium photocatalyst, N-BAP, with high photoredox abilities and visible-light absorption was designed and prepared in one step. Under visible-light irradiation, N-BAP promoted the four-electron reduction of esters in the presence of ammonium oxalate as a “traceless reductant” to generate carbinol anion intermediates that underwent protonation with water to give the corresponding alcohols. The resulting carbinol anions also exhibited nucleophilic reactivity under the photocatalytic conditions to undergo a 1,2-addition to a second carbonyl compound, affording unsymmetric 1,2-diols.

Angewandte Chemie International Edition

Collective and Diverted Total Synthesis of the Strasseriolides: A Family of Macrolides Endowed with Potent Antiplasmodial and Antitrypanosomal Activity

X. Liu,^† D. Isak,^† L. A. Schwartz, S. Schulthoff, G. Pérez-Moreno, C. Bosch-Navarrete, D. González Pacanowska & A. Fürstner*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202408725) 🔓

The strasseriolide macrolides show promising in vitro and in vivo activities against P. falciparum and T. cruzi, the parasites causing malaria and Chagas disease, respectively. However, the as yet poor understanding of structure/activity relationships and the fact that one family member proved systemically toxic for unknown reasons render a more detailed assessment of these potential lead compounds difficult. To help overcome these issues, a collective total synthesis was devised. The key steps consisted of a ring closing alkyne metathesis (RCAM) reaction to forge a common macrocyclic intermediate followed by a hydroxy-directed ruthenium catalyzed trans-hydrostannation of the propargyl alcohol site thus formed. The resulting alkenyltin derivative served as the central node of the synthesis blueprint, which could be elaborated into the natural products themselves as well as into a set of non-natural analogues according to the concept of diverted total synthesis.

ChemRxiv

Enantioselective Decarboxylative C(sp³)-C(sp³) Cross-Coupling of Aliphatic Acids with gem-Borazirconocene Alkanes

J. Wang, S. Bai, C. Yang & X. Qi*

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

Asymmetric decarboxylative cross-couplings of carboxylic acids represent a powerful tool to synthesize chiral building blocks for medicinal chemistry and material science. However, synthesis of versatile chiral alkylboron derivatives via asymmetric decarboxylative C(sp³ )-C(sp³ ) cross-coupling from readily available primary aliphatic acids and mild organometallic reagents is still challenging. In this study, the authors report a visible-light-induced, Ni-catalyzed enantioconvergent C(sp³ )-C(sp³ ) cross-coupling of unactivated primary aliphatic acids with gem-borazirconocene alkanes, furnishing a diverse array of valuable chiral alkylboron building blocks. The broad substrate scope, high functional group tolerance, and the late-stage modification of complex drug molecules and natural products with high enantioselectivity demonstrate the synthetic potential of the method.

Pyridinium-based Fluorosulfonamide Reagents Enabled Photoredox Catalyzed Radical Fluorosulfonamidation

H. Li,^† X. Zhang,^† Z. Wang, C. Sun, M. Huang, J. Liu, Y. Li, Z. Zou, Y. Pan, W. Zhang* & Y. Wang*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-wgf8j) 🔓

Sulfamoyl fluorides, as a crucial building block of SuFEx, have garnered extensive research interest due to their applications in chemical biology, materials science, and drug discovery. Recently, considerable research has been dedicated to the synthesis of sulfamoyl fluorides. However, the direct radical fluorosulfonamidation process for the synthesis of sulfamoyl fluorides employing fluorosulfonamide radicals has largely been overlooked. Herein, the authors report a practical procedure for constructing a bench-stable redox-active fluorosulfonamide radical reagent from inexpensive SO₂F₂, which provides a solution to the long-standing issue of radical fluorosulfonamidation. Simultaneously, the radical fluorosulfonamidating reagent, namely fluorosulfonyl-N-pyridinium tetrafluoroborate (PNSF), can be readily scaled up and prepared under simple aerobic conditions. These practical and air-stable crystalline salts can effectively facilitate a range of reactions, including the N-(fluorosulfonyl) sulfonamidation of diverse (hetero)arenes, sequential radical stereoselective fluorosulfonamidation, and the 1,2-difunctionalization of various alkenes, enabling the construction of a diverse array of functionalized sulfamoyl fluoride compounds.

Adaptive Photochemical Amination via Co(II) Catalysis

G. Song, J. Song, Q. Li, T. Kang, J. Dong, G. Li, J. Fan, C. Wang & D. Xue*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-8pn7s) 🔓

Transition-metal-catalyzed amination of aryl halides is one of the most employed methods for constructing N-arylation adducts. However, the broad success of these reactions is largely relying on the screening of pre-catalysts, elaborating ligands, and case-by-case optimization of the reaction conditions (solvent, base, additive, temperature etc.) and electronic or structural diversities of nucleophiles, for forging diverse C-N coupling products. Herein, the authors report an adaptive photochemical C-N coupling of aryl halides with various nitrogen nucleophiles (aliphatic and aromatic amines, amides, sulfonamides, pyrazoles, and ammonium salts) by Co(II) catalysis under the same reaction conditions without the addition of any exogenous photocatalyst. This photochemical amination features a wide substrate scope (>130 examples, up to 95% yield) with excellent functional group tolerance.

Complementary Mn(II) approach by the same authors: ChemRxiv (DOI: 10.26434/chemrxiv-2024-7qtm0) 🔓

Organic Process Research & Development

Scale-Up Investigation of Aggarwal Enal Bicyclic Intermediate Synthesis

A. Pelšs* & K. Shubin

Org. Process Res. Dev. 2024, ASAP (DOI: 10.1021/acs.oprd.4c00209)

Recently, a multitude of modern and short syntheses of various prostanoids have been reported, rejuvenating this synthesis field. One such synthesis reported by Aggarwal et al. has good potential for industrialization. Herein, the synthesis of a bicyclic enal intermediate (Aggarwal enal) was demonstrated on a hectogram scale by finding an appropriate ʟ-proline source which is soluble under overhead stirring conditions in reactor. Kilogram scale synthesis of the volatile starting material, succinaldehyde, was also achieved in a high yield by finding a suitable isolation method.

Organic Letters

Discovery of an Azabicyclo[2.1.1]hexane Piperazinium Salt and Its Application in Medicinal Chemistry via a Rearrangement

C. He*, X. Ba, H. P. Shunatona, J. T. Edwards, Y.-X. Li, T. M. Keller, R. D. Sommer, C. W. Zapf & D. S. Mortensen

Org. Lett. 2024, ASAP (DOI: 10.1021/acs.orglett.4c01696) 🔓

The authors report the discovery of an azabicyclo[2.1.1]hexane piperazinium methanesulfonate salt from an unexpected rearrangement reaction in the preparation of ligand-directed degraders (LDDs). This bench-stable compound was found to be a versatile electrophile in a ring-opening reaction with various types of nucleophiles. Its utility as a versatile medicinal chemistry building block is further demonstrated in the synthesis of an LDD compound targeting degradation of the androgen receptor.

That’s all for this issue! Have a great week and we’ll see you next Monday.