100-Year-Old Rule Broken

Welcome to this week’s Organic Synthesis Newsletter.

Monday 28^th October – Sunday 3^rd November 2024 | Volume 1, Issue 32

HIGHLIGHT OF THE WEEK
A Solution to the anti-Bredt Olefin Synthesis Problem

L. McDermott,^† Z. G. Walters,^† S. A. French,^‡ A. M. Clark,^‡ J. Ding,^‡ A. V. Kelleghan, K. N. Houk & N. K. Garg*

Science 2024, 386, eadq3519 (DOI: 10.1126/science.adq3519)

The π-bonds in unsaturated organic molecules are typically associated with having well-defined geometries that are conserved across diverse structural contexts. Nonetheless, these geometries can be distorted, leading to heightened reactivity of the π-bond. Although π-bond–containing compounds with bent geometries are well utilized in synthetic chemistry, the corresponding leveraging of π-bond–containing compounds that display twisting or pyramidalization remains underdeveloped. Perhaps the most notorious class of geometrically distorted molecules that contain π-bonds are anti-Bredt olefins (ABOs). ABOs have been known since 1924, and conventional wisdom maintains that ABOs are difficult or impossible to access. Here, the authors provide a solution to this long-standing problem.

NATURE COMMUNICATIONS
Shuttle HAT for Mild Alkene Transfer Hydrofunctionalization

T. C. Jankins, P. M. Blank, A. Brugnetti, P. Boehm, F. A. Aouane & B. Morandi*

Nat. Commun. 2024, 15, 9397 (DOI: 10.1038/s41467-024-53281-7) 🔓

Hydrogen atom transfer (HAT) from a metal-hydride is a reliable and powerful method for functionalizing unsaturated C–C bonds in organic synthesis. Cobalt hydrides (Co–H) have garnered significant attention in this field, where the weak Co–H bonds are most commonly generated in a catalytic fashion through a mixture of stoichiometric amounts of peroxide oxidant and silane reductant. Here, the authors show that the reverse process of HAT to an alkene, i.e. hydrogen atom abstraction of a C–H adjacent to a radical, can be leveraged to generate catalytically active Co–H species in an application of shuttle catalysis coined shuttle HAT. This method obviates the need for stoichiometric reductant/oxidant mixtures thereby greatly simplifying the generation of Co–H.

Ligand-Controlled Regiodivergent Aminocarbonylation of Cyclobutanols Toward 1,1- and 1,2-Substituted Cyclobutanecarboxamides

X.-W. Gu,^† Y.-H. Zhao^† & X.-F. Wu*

Nat. Commun. 2024, 15, 9412 (DOI: 10.1038/s41467-024-53571-0) 🔓

Four-membered carbocycles are one of the most commonly sought-after structures in biologically active molecules. However, access to these type of structures is challenging due to their highly strained nature. Here, the authors report the regioselective aminocarbonylation of cyclobutanols. The method exhibits good functional group compatibility alongside high regio- and stereoselectivity.

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Programmable Piperazine Synthesis via Organic Photoredox Catalysis

A. J. Boley,^† J. C. Genova^† & D. A. Nicewicz*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c12028)

Piperazine cores have long been identified as privileged scaffolds in the development of pharmaceutical compounds. Despite this, the facile synthesis of diverse C-substituted piperazines remains a challenge without prefunctionalized substrates/cores. Herein, the authors describe a programmable approach to highly diversifiable piperazine cores, which circumvents the typical need for radical precursors. The use of organic photoredox catalysis renders this method operationally simple, as direct substrate oxidation followed by 6-endo-trig radical cyclization with in situ generated imines may furnish the product. Additionally, the photoredox-catalyzed anti-Markovnikov hydroamination of readily accessible ene-carbamates provides a modular approach to functionalized diamine starting materials which are shown to generate more complex piperazine cores.

Formal meta-C–H-Fluorination of Pyridines and Isoquinolines through Dearomatized Oxazinopyridine Intermediates

M. Haring,^† K. Balanna,^† Q. Cheng, J. Lammert & A. Studer*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c11759)

Organofluorine compounds, including fluorinated pyridines and isoquinolines, play a crucial role in pharmaceuticals, agrochemicals, and materials science. However, step-economic selective C–H-functionalization to access these fluorinated azaarenes is still underexplored, with selective meta-C–H-fluorination proving to be especially elusive. Here, the authors present a practical method for formal meta-C–H-fluorination of pyridines and isoquinolines. By applying an oxazinoazaarene-based temporary pyridine dearomatization strategy with Selectfluor as an electrophilic F-source, fluorination of pyridines was achieved with exclusive C3-selectivity in moderate to good yields. The same strategy can also be applied to the formal meta-C–H-fluorination of isoquinolines. Late-stage-functionalization of drugs, drug precursors, and ligands as well as a large-scale one-pot dearomatization–fluorination–rearomatization reaction further demonstrate the synthetic utility of this approach.

Taming CO2^•– via Synergistic Triple Catalysis in Anti-Markovnikov Hydrocarboxylation of Alkenes

P. Ghosh,^† S. Maiti,^† A. Malandain, D. Raja, O. Loreau, B. Maity, T. K. Roy, D. Audisio* & D. Maiti*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c12294)

The direct utilization of carbon dioxide as a one-carbon source in value-added chemical synthesis has significant potential from a global sustainability standpoint. In this regard, the photo/electrochemical reduction of CO₂ offers great promise for the transition to a carbon-neutral economy. Therefore, a robust and general method for the conversion of CO₂ into the polarity-reversed carbon dioxide radical anion, CO₂^•–, is critical for the successful valorization of CO₂. Herein, the authors demonstrate a hydride and hydrogen atom transfer synergy driven catalytic platform involving CO₂^•– for highly selective anti-Markovnikov hydrocarboxylation of alkenes via triple photoredox, hydride, and hydrogen atom transfer catalysis. The method is mild, selective, and capable of accommodating a wide range of activated and unactivated alkenes.

Remote Catalytic C(sp³)–H Alkylation via Relayed Carbenoid Transfer upon Olefin Chain Walking

Q. Wang, J. Kweon, D. Kim & S. Chang*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c11014)

Transition metal carbenes have emerged as versatile intermediates for various types of alkylations. While reactions of metal carbene species with alkenes have been extensively studied, most examples focus on cyclopropanation and allylic C–H insertion. Herein, the authors present the first example of a catalytic strategy for the carbene-involved regioselective remote C–H alkylation of internal olefins by synergistically combining two iridium-mediated reactivities of olefin chain walking and carbenoid migratory insertion. The present method, utilizing sulfoxonium ylides as a bench-stable robust carbene precursor, was found to be effective for a series of olefins tethered with alkyl chains, heteroatom substituents, and complex biorelevant moieties.

Arylthianthrenium Salts for Triplet Energy Transfer Catalysis

Y. Cai, T. K. Roy, T. J. B. Zähringer, B. Lansbergen, C. Kerzig* & T. Ritter*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c11099) 🔓

Sigma bond cleavage through electronically excited states allows synthetically useful transformations with two radical species. Direct excitation of simple aryl halides to form both aryl and halogen radicals necessitates UV-C light, so undesired side reactions are often observed and specific equipment is required. Moreover, only aryl halides with extended π systems and comparatively low triplet energy are applicable to synthetically useful energy transfer catalysis. Here, the authors show the conceptual advantages of arylthianthrenium salts (ArTTs) for energy transfer catalysis with high energy efficiency compared to conventional aryl (pseudo)halides and their utility in arylation reactions of ethylene. The fundamental advance is enabled by the low triplet energy of ArTTs that may originate in large part from the electronic interplay between the distinct sulfur atoms in the tricyclic thianthrene scaffold, which is not accessible in either simple (pseudo)halides or other conventional sulfonium salts.

Iterative Catalyst-Controlled Diastereoselective Matteson Homologations Enables the Selective Synthesis of Benzestrol Isomers

S. R. Angle, H. A. Sharma, C. K. Choi, K. E. Carlson, Y. Hou, J. C. Nwachukwu, S. H. Kim, B. S. Katzenellenbogen, K. W. Nettles, J. A. Katzenellenbogen & E. N. Jacobsen*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c12857)

The authors report the development of an iterative Matteson homologation reaction with catalyst-controlled diastereoselectivity through the design of a new catalyst. This reaction was applied to the selective synthesis of each stereoisomer of benzestrol, a bioactive compound with estrogenic activity featuring three contiguous stereocenters. The different stereoisomers were assayed to determine their binding affinity for the estrogen receptor α (ERα), and the absolute configuration of the compound having uniquely high activity was determined.

Enantioselective Synthesis of Aminals via Nickel-Catalyzed Hydroamination of 2-Azadienes with Indoles and N-Heterocycles

Y. Du, S. Duan,* S. Huang, T. Liu, H. Zhang, P. J. Walsh* & X. Yang*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c09750)

New methods for the enantioselective synthesis of N-alkylated indoles and their derivatives are of great interest because indoles are pivotal structural elements in biologically active molecules and natural products. Among well-established asymmetric hydroamination methods, the asymmetric hydroamination with indole-based substrates is a formidable challenge. This observation is likely due to the reduced nucleophilicity of the indole nitrogen. Herein, a unique nickel-catalyzed enantio- and branched-selective hydroamination of 2-azadienes with indoles and structurally related N-heterocycles is reported for the generation of enantioenriched N,N-aminals. Salient features of this reaction include good yields, mild reaction conditions, high enantioselectivities, and broad substrate scope (60 examples, up to 96% yield and 99% e.e.).

ANGEWANDTE CHEMIE INTERNATIONAL EDITION
Copper-Catalyzed γ-C(sp³)−H Lactamization and Iminolactonization

T. Sheng,^† Z. Zhuang,^† Z. Zhao, Md. E. Hoque & J.-Q. Yu*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202416634)

Despite extensive efforts to develop γ-lactamization reactions for pyrrolidinone synthesis using either cyclometallation, C−H insertion, or radical C−H abstraction strategies, γ-lactamization reactions of aliphatic amides using practical catalysts and common protecting groups remain extremely rare. Herein, the authors report copper-catalyzed γ-C(sp³)−H lactamization and iminolactonization of tosyl-protected aliphatic amides using inexpensive Selectfluor as the sole oxidant. A switchable selectivity of γ-Lactams or γ-iminolactones can be obtained by using two different sets of reaction conditions. Notably, structurally diverse spiro-, fused-, and bridged-lactams and iminolactones, as well as isoindolinones are accessible by this method.

Pd(II)-Catalyzed Asymmetric [2+2] Annulation for the Construction of Chiral Benzocyclobutenes

P. K. Pramanick,^† S. Zhao,^† H.-T. Ji,^† X. Chen* & G. Yang*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202415927)

The authors report a Pd/Pyrox-catalyzed asymmetric [2+2] annulation between arylboronic acids and functionalized alkenes, providing an efficient protocol to access various enantioenriched benzocyclobutenes in a modular manner under mild conditions. A broad substrate scope with excellent enantioselectivity has been achieved under the current protocol.

CHEMRXIV
Skeletal Editing of Indoles and Benzofurans to give Indazoles, Benzimidazoles, Benzoxazoles and Benzisoxazoles

Z. Wang, P. Xu,^‡ S.-M. Guo,^‡ C. G. Daniliuc & A. Studer*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-vtg73) 🔓

Skeletal editing comprises the structural reorganization of compounds. Such editing can be achieved through atom swapping, atom insertion, atom deletion or reorganization of the compound's backbone structure. Conducted at a late stage in drug development campaigns, skeletal editing enables diversification of an existing pharmacophore, enhancing the efficiency of drug development. Herein, the authors present C to N atom swapping in indoles at the C2 position to give indazoles through oxidative cleavage of the indole heteroarene core and subsequent ring closure. Importantly, these ring deconstructed intermediates can also be diverted into benzimidazoles resulting in an overall C to N atom swapping with concomitant skeletal reorganization. The same structural diverting strategies are equally well applicable to benzofurans leading to either benzisoxazoles or benzimidazoles.

OUTSIDE OF SYNTHESIS, INSIDE OF SCIENCE
Solar Power

🔭 Solar power. Nature have just released their selection of the best science images in October, featuring the sun at its solar maximum (right, May 2024) vs. solar minimum (left, Dec. 2019). The solar maximum is the peak of the sun’s 11-year solar cycle, during which time surface activity increases and the sun releases an immense amount of energy and solar radiation as its magnetic poles prepare to flip. It is this activity that has been responsible for the increased visibility of aurorae in recent months.

🍰 Sweet tooth. In September 1953, the United Kingdom ended the rationing of sugar that had been in place since World War II and by the end of the year, the nation’s sugar consumption doubled. Now, over 70 years later, new research has found that those conceived or born just after sugar rationing ended had a higher risk of diabetes and hypertension. By the numbers, the researchers found that early-life rationing (within the first 1000 days) reduced the risk of diabetes and hypertension by 35% and 20%, respectively, delaying disease onset by 4 and 2 years.