💡 Enzymes 🤝 Radicals

Welcome to this week’s Organic Synthesis Newsletter.

This will be the last issue of the year with the next issue coming out on Monday 13th January 2025 when most journals will have returned to business as usual. Thank you all for your support throughout the year, enjoy the holidays and we’ll see you next year!

Monday 16^th December – Sunday 22^nd December 2024 | Volume 1, Issue 39

HIGHLIGHT OF THE WEEK
Biocatalytic C–H Oxidation Meets Radical Cross-Coupling: Simplifying Complex Piperidine Synthesis

J. He,^† K. Yokoi,^† B. Wixted, B. Zhang, Y. Kawamata*, H. Renata* & P. S. Baran*

Science 2024, 386, 1421–1427 (DOI: 10.1126/science.adr9368)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-9ks60) 🔓

Modern medicinal chemists are targeting more complex molecules to address challenging biological targets, which leads to synthesizing structures with higher sp³ character (Fsp³). Although traditional flat, high-fraction sp² molecules, such as pyridine, can be decorated through electrophilic aromatic substitution and palladium (Pd)–based cross-couplings, general strategies to derivatize three-dimensional (3D) saturated molecules are far less developed. In this work, the authors present an approach for the rapid, modular, enantiospecific, and diastereoselective functionalization of piperidine, combining robust biocatalytic carbon-hydrogen oxidation with radical cross-coupling.

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Single-Carbon Insertion into Single C–C Bonds with Diazirines

V. G. Alfonso, K. de la Vega-Hernández & M. G. Suero*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c12632) 🔓

A novel platform for the skeletal editing of single C–C bonds via a single-carbon insertion has been developed using diazirines. This strategy involves the photogeneration of arylchlorocarbenes as carbynoid species that undergo site-selective carbene insertion into tertiary C–H bonds and a subsequent Wagner–Meerwein rearrangement promoted by a silver salt. This skeletal editing strategy has been demonstrated in six core-to-core conversions, including linear and cyclic benzylic substrates, alkanes and late-stage functionalizations.

Biomimetic Synthesis of Azorellolide via Cyclopropylcarbinyl Cation Chemistry

J. Y. Artzy, D. J. Tantillo* & D. H. Trauner*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c14664) 🔓

A concise synthesis of the complex diterpene azorellolide, inspired by speculations on biosynthetic cationic cascades, is presented. The approach, guided by computation, relies on the intramolecular interception of a cyclopropylcarbinyl cation by an appended carboxylate. The successful execution of this strategy was achieved through acid-catalyzed isomerization of a β-lactone in competition with a type I dyotropic rearrangement.

Total Syntheses of Scabrolide B, Ineleganolide, and Related Norcembranoids

E. J. Simmons, D. B. Ryffel, D. A. Lopez, Y. D. Boyko & D. Sarlah*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c16629)

Concise total syntheses of several 5/7/6 norcembranoids, including ineleganolide, scabrolide B, sinuscalide C, and fragilolide A have been achieved through a fragment coupling/ring closure approach. The central seven-membered ring was forged through sequential Mukaiyama–Michael/aldol reactions using norcarvone and a decorated bicyclic lactone incorporating a latent electrophile. Subsequent manipulations installed the reactive enedione motif and delivered scabrolide B in 11 steps from a chiral pool-derived enone. Finally, ineleganolide, sinuscalide C, and fragilolide A were each accessed in one additional step.

Total Synthesis of (+)-Mannolide B

P. Chen,^† L. Chen,^† H. Lin & Y. Jia*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c12767)

(+)-Mannolide B possesses an intriguing and complex 5/7/5/6/6/6-fused hexacyclic scaffold including two bridged-lactone moieties and nine contiguous stereocenters, representing a formidable challenge for total synthesis. Herein, the evolution of a successful strategy for the synthesis of mannolide B is described. The 7/5 ring system of the 7/5/6/6 tetracyclic carbon skeleton was efficiently constructed by a ring-closing metathesis starting from commercially available (−)-methyl jasmonate. Attempts to access the 6/6 ring system were unexpectedly challenging: initially, an intramolecular Diels–Alder reaction was designed; however, the desired cyclization precursor could not be obtained. Following this, a radical cascade cyclization was investigated but produced only one six-membered ring with poor stereoselectivity. Finally, the 6/6 ring system was successfully generated through a Pauson–Khand reaction, followed by a highly regioselective Büchner–Curtius–Schlotterbeck reaction, enabling the first total synthesis of (+)-mannolide B in 24 steps.

Pd-Catalyzed Migratory 1,1-Cycloannulation Reaction of Alkenes

J.-P. Wang, T. Liu, Y. Wu & P. Wang*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c14153)

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

The authors report a novel strategy for the preparation of diverse heterocycles via a Pd-catalyzed migratory 1,1-cycloannulation reaction (MCAR) of alkenes. Starting from alkenyl amines and alkenyl alcohols, a wide range of five- to seven-membered aza-heterocycles and oxa-heterocycles were prepared with high efficiency and good functional group tolerance. The key to this reaction is the use of 4-iodophenol or 2-iodophenol derivatives where the phenolic hydroxyl group plays a critical role in controlling the direction of migration and the ring-size of the heterocycles through the formation of a quinone methide intermediate.

Palladium Bisphosphine Monoxide Complexes: Synthesis, Scope, Mechanism, and Catalytic Relevance

S. Yang, M. Deng, R. A. Daley, A. Darù, W. J. Wolf, D. T. George, S. Ma, B. K. Werley, E. Samolova, J. B. Bailey, M. Gembicky, J. Marshall, S. R. Wisniewski, D. G. Blackmond* & K. M. Engle*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c10718)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-8qcg4) 🔓

Recent studies in transition metal catalysis employing chelating phosphines have suggested a role for partial ligand oxidation in formation of the catalytically active species. The authors examine the internal redox reaction of Pd^II(bisphosphine)X₂ (X = Cl, OAc, etc.) complexes to reveal underexplored aspects of bisphosphine monoxides (BPMOs), including evaluation of ligand structure and development of general reaction conditions to access a collection of structurally diverse BPMO precatalysts. In particular, a series of Pd^II(BPMO)(R)(X) (R = aryl, alkyl; X = I, Br) oxidative addition complexes bearing 24 different BPMO ligands were characterized. Comparison of the catalytic performance of the oxidative addition complexes of bisphosphine vs. bisphosphine monoxides as precatalysts is demonstrated to be an enabling diagnostic tool in Pd catalytic reaction development. Finally, the differences in catalytic behavior between bisphosphine and bisphosphine monoxide complexes were rationalized.

Migratory Aryl Cross-Coupling

Y. Sekiguchi, P. Onnuch, Y. Li & R. Y. Liu*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c15086)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-z2z04-v2) 🔓

A fundamental property of cross-coupling reactions is regiospecificity, meaning that the site of bond formation is determined by the leaving group’s location on the electrophile. As an alternative, the authors propose the development of a cross-coupling variant that would access multiple structural isomers from the same coupling partners. They demonstrate that a bulky palladium catalyst can facilitate the efficient, reversible transposition of aryl halides by temporarily forming metal aryne species. Despite the nearly thermoneutral equilibrium governing this process, combining it with the gradual addition of a suitable nucleophile results in dynamic kinetic resolution of the isomeric intermediates and high yields of unconventional product isomers. The method accommodates a range of oxygen- and nitrogen-centered nucleophiles and tolerates numerous common functional groups.

Borenium-Catalyzed “Boron Walking” for Remote Site-Selective Hydroboration

Z. Zhu, W. C. Chan, B. Gao, G. Hu, P. Zhang, Y. Fu, K. S. Ly, Z. Lin* & Y. Quan*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c13726)

Remote functionalization through progressive olefin isomerization enables site-selective modification at a distal position. However, developed protocols have long relied on transition metal catalysis. In this work, the authors present a new approach that employs a borenium ion as a catalyst for site-selective, remote borylation, eliminating the need for metal catalysts. As the reaction progresses, borylation isomers at different positions emerge, gradually and ultimately converging into the predominant α-borylation product—a process akin to “walking” of a boron moiety along a carbon skeleton toward an aryl terminus. This remote borylation exhibits good functional group compatibility and permits the convenient synthesis of silyl-remote-boryl compounds, demonstrating an opposite regioselectivity to that observed in transition-metal-catalyzed tandem silylation-borylation reactions.

Catalytic Asymmetric Oxidative Coupling between C(sp³)–H Bonds and Carboxylic Acids

X.-M. Liu,^† F. Li,^† T. Wang, L. Dai, Y. Yang, N.-Q. Jiang, L.-Y. Xue, J.-Y. Liu, X.-S. Xue,* L.-J. Xiao* & Q.-L. Zhou*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c12544)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-hqqb0) 🔓

The direct enantioselective functionalization of C(sp³)–H bonds in organic molecules could fundamentally transform the synthesis of chiral molecules. In particular, the enantioselective oxidation of these bonds would dramatically change the production methods of chiral alcohols and esters, which are prevalent in natural products and pharmaceuticals. Remarkable advances have been made in the enantioselective construction of C–C and C–N bonds through C(sp³)–H bond functionalization; however, the formation of C–O bonds remains challenging. Here, the authors report a highly enantioselective C(sp³)–H bond oxidative coupling with carboxylic acids. The method applies to allylic and propargylic C–H bonds, employs various carboxylic acids as oxygenating agents, and successfully synthesizes a range of chiral esters directly from readily available alkenes and alkynes.

Iridium-Catalyzed Enantioconvergent Construction of Piperidines and Tetrahydroisoquinolines from Racemic 1,5-Diols

H. Diao, K. Liu, R. Yu, J. Chen, Y. Liu,* B.-M. Yang* & Y. Zhao*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c12466)

The authors report a one-step synthesis of valuable enantioenriched piperidines and tetrahydroisoquinolines from readily available racemic 1,5-diols. Key to the success is the development of new iridacycle catalysts that enable efficient redox-neutral construction of two C–N bonds between diols and amines in an enantioconvergent fashion. Mechanistic studies identified an intriguing preferential oxidation of secondary vs. primary alcohol by the iridacycle catalyst, which set a challenging intermolecular amination of aryl–alkyl-substituted alcohol as the enantiodetermining step for this catalytic N-heterocycle synthesis. Application of this catalytic method to the preparation of important drugs and bioactive compounds is also demonstrated.

Contrasteric Glycosylations of Cotylenol and 1,2-Diols by Virtual Linker Selection

D. W. Snelson,^† S. I. Ting^† & R. A. Shenvi*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c15719)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-j7c15) 🔓

Many terpene glycosides exhibit contrasteric patterns of 1,2-diol glycosylation in which the more hindered alcohol bears a sugar; protection of the less hindered alcohol only increases steric repulsion. Here, the authors report a method for contrasteric glycosylation using a new sugar-linker that forms a cleavable, 10-membered ring with high efficiency, leading to syntheses of cotylenin E, J, and ISIR-050. Linker selection was aided by DFT calculations of side reactions and stereoselectivity, as well as conformational analyses using autoDFT, a Python script that converts SMILES strings to DFT-optimized conformational ensembles.

Enantioselective α-C(sp³)–H Borylation of Masked Primary Alcohols Enabled by Iridium Catalysis

Q. Gao,^† Y. Li,^† L. Chen, L.-J. Xie, X. Shao & Z. Ke* & S. Xu*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c14890)

The authors report the first example of iridium-catalyzed asymmetric α-C(sp³)–H borylation of primary alcohol-derived carbamates by the judicious choice of directing groups. A variety of chiral borylated carbamates were obtained with good to high enantioselectivities and their synthetic utility was demonstrated by taking advantage of the highly transformable features of C–B bonds and the leaving group ability of carbamates.

ANGEWANDTE CHEMIE INTERNATIONAL EDITION
Hydroalkylation of Vinylarenes by Transition-Metal-Free in situ Generation of Benzylic Nucleophiles Using Tetramethyldisiloxane and Potassium tert-Butoxide

P. St. Onge, H. Nugraha & S. G. Newman*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202421077) 🔓

Hydrosilanes and Lewis bases are known to promote reductive defunctionalizations, rearrangements, and silylation reactions, facilitated by enigmatic silicon/Lewis base-derived reactive intermediates. Despite the wide variety of transformations enabled by this combination, no examples of intermolecular C(sp³)–C(sp³) bond forming reactions have been reported. In this work, the authors identified 1,1,3,3-tetramethyldisiloxane (TMDSO) and KOt-Bu as a unique reagent combination capable of generating benzylic nucleophiles in situ from styrene derivatives, which can subsequently react with alkyl halides to give new C(sp³)–C(sp³) linkages via formal hydroalkylation.

Solvent-Dependent Divergent Cyclization of Bicyclo[1.1.0]butanes

F. Zhang, S. Dutta, A. Petti, D. Rana, C. G. Daniliuc & F. Glorius*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202418239) 🔓

Bicyclo[1.1.0]butanes (BCBs) have recently garnered significant research interest as versatile precursors for synthesizing potential [n.1.1] bioisosteres and multi-functionalized cyclobutanes in a straightforward and atom-economical manner. Here, the authors report a solvent-dependent divergent cyclization of BCBs that provides highly diastereospecific decorated cyclobutanes and oxygen-containing bicyclo[3.1.1]heptanes (BCHeps), which serve as bioisosteres of meta-substituted arenes. This novel strategy employs precision-oriented control to achieve the desired divergence. Additionally, an unprecedented 1,2-difunctionalization reaction mode for BCBs was explore, expanding the available methods for efficiently exploring the chemical space of arene bioisosteres and highly functionalized cyclobutanes.

CHEMRXIV
Size-Programmable Matteson-Type Annulation: Construction of Spirocycles from Simple Cyclic Ketones

W. Jo, J. K. Scholz, H. Lyu, S. H. Cho & G. Dong*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-28587) 🔓

Despite recent advancements, Matteson-type reactions are almost exclusively used to construct linear molecules. Here, the authors report an iterative boron-homologation approach to construct various carbocycles from a single precursor. This method utilizes an electron-withdrawing group (EWG) as a handle to enable intramolecular Matteson-type couplings, leading to the enantio- and diastereoselective formation of carbocycles with different ring sizes and multiple stereocenters. The process is scalable, the products can undergo various transformations to synthetically valuable structural motifs and the method can be extended to the preparation of challenging spirocyclic analogues alongside the iterative synthesis of double spirocycles.

Site-Selective Catalytic Saturation of Unactivated Arenes via Directed 6π-Activation

C. Yu, L. Yiu, Z. Zhang & G. Dong*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-kt0lk) 🔓

Catalytic hydrogenation of arenes to the corresponding saturated carbo- or heterocycles provides a straightforward approach to increase three-dimensionality and sp³-carbons in molecules of pharmaceutical interests; however, it remains challenging to achieve site-selective dearomatization among electronically and sterically unbiased arenes. Here, the authors report an unprecedented, directed Ru-catalyzed arene saturation approach, which selectively reduces the aryl group adjacent to the directing moiety with excellent cis-selectivity. The reaction is enabled by a removable directing group, shows broad functional group tolerance and an excellent substrate scope. Remarkably, a number of easily reducible functional groups, such as alkenes, heteroarenes, ketones, and aryl bromides, can survive under the relatively mild conditions. The synthetic utility of this method is demonstrated in the streamlined synthesis of cis-Atovaquone, gram-scale preparations, and late-stage saturation of complex bioactive compounds.

Downsizing Lactams via Rh-Catalyzed C–C Activation

R. Zhang, K. Wen & G. Dong*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-rqq9s) 🔓

Ring-contraction reactions are valuable transformations to access hard-to-synthesize smaller-sized rings from more available larger-sized precursors. Herein, the authors report an unprecedented lactam downsizing strategy by taking advantage of removable directing groups (DGs) and Rh-catalyzed C–C activation. The ring-contraction reaction exhibits a broad substrate scope, excellent functional group tolerance, and high selectivity for yielding γ-lactams, facilitating “6-to-5”, “7-to-5”, and “8-to-5” ring contractions. Additionally, through careful selection of DGs and ligands, preliminary results on selective “7-to-6” ring contraction has been obtained.

ORGANIC PROCESS RESEARCH & DEVELOPMENT
Pd-Catalyzed Miyaura Borylations Mediated by Potassium Pivalate with Alcohol Cosolvents

J. M. Ganley,* S. Ma,* C. Peng & E. M. Simmons

Org. Process Res. Dev. 2024, ASAP (DOI: 10.1021/acs.oprd.4c00419)

The use of carboxylate bases with low solubility in organic solvents often poses a challenge in the large-scale application of palladium-catalyzed Miyaura borylation of aryl halides due to variability in the kinetic behavior of the reaction stemming from scale-dependent mass-transfer effects. Herein, the authors report that a combination of potassium pivalate (KOPiv, a base with improved solubility in organic solvents) and 2-PrOH cosolvent obviates the challenges associated with performing Miyaura borylation with insoluble carboxylate bases on scale. This solubility-driven protocol improves both the physical properties and the kinetic behavior of the reaction, and is compatible with a one-pot borylation-Suzuki telescope sequence to furnish structurally diverse biaryl products. The improved protocol for Miyaura borylation was applied toward the synthetic sequence of bromodomain and extra-terminal (BET) inhibitor BMS-986378 on a decagram scale.

OUTSIDE OF SYNTHESIS, INSIDE OF SCIENCE
Looking Forward and Back

🔭 Looking forward and back. To wrap up the year, Science looks back on their favorite online news stories of 2024 including “cocaine sharks” that were found in waters off Brazil—just when you thought a cocaine bear was bad enough… Meanwhile, Nature looks forward with events to watch for in the coming year featuring NASA’s SPHEREx space observatory, which eyes a February 2025 launch in its mission to create a 3D map of the sky, consisting of hundreds of millions of stars and galaxies. The observatory aims to shed new light on what happened after the big bang and scour the Milky way in the search for the building blocks of life.