Targeting C–H for Total Synthesis

Welcome to this week’s Organic Synthesis Newsletter.

Monday 4^th November – Sunday 10^th November 2024 | Volume 1, Issue 33

HIGHLIGHT OF THE WEEK
Total Synthesis of (−)-Cylindrocyclophane A Facilitated by C−H Functionalization

A. T. Bosse, L. R. Hunt,^‡ C. A. Suarez,^‡ T. D. Casselman, E. L. Goldstein, A. C. Wright, H. Park, S. C. Virgil, J.-Q. Yu, B. M. Stoltz* & H. M. L. Davies*

Science 2024, 386, 641–646 (DOI: 10.1126/science.adp2425)

(−)-Cylindrocyclophane A is a 22-membered C2-symmetric [7.7]paracyclophane that bears bis-resorcinol functionality and six stereocenters. Here, the authors report a synthetic strategy for (−)-cylindrocyclophane A that uses 10 C−H functionalization reactions, resulting in a streamlined route with high enantioselectivity and efficiency (17 steps). The use of chiral dirhodium tetracarboxylate catalysis enabled the C–H functionalization of primary and secondary positions, which was complemented by palladium-catalyzed C(sp²)–C(sp²) cross-couplings, resulting in the rapid formation of the macrocyclic core and all stereocenters with high regio-, diastereo-, and enantioselectivity. The use of a late-stage palladium-catalyzed fourfold C(sp²)–H acetoxylation installed the bis-resorcinol moieties.

NATURE
Autonomous Mobile Robots for Exploratory Synthetic Chemistry

T. Dai,^† S. Vijayakrishnan,^† F. T. Szczypiński,^† J.-F. Ayme,^† E. Simaei,^† T. Fellowes, R. Clowes, L. Kotopanov, C. E. Shields, Z. Zhou, J. W. Ward & A. I. Cooper*

Nature 2024 (DOI: 10.1038/s41586-024-08173-7) 🔓

Autonomous laboratories can accelerate discoveries in chemical synthesis, but this requires automated measurements coupled with reliable decision-making. Most autonomous laboratories involve bespoke automated equipment, and reaction outcomes are often assessed using a single, hard-wired characterization technique. Here, the authors show that a synthesis laboratory can be integrated into an autonomous laboratory by using mobile robots that operate equipment and make decisions in a human-like way. The modular workflow combines mobile robots, an automated synthesis platform, a liquid chromatography–mass spectrometer and a benchtop nuclear magnetic resonance spectrometer. A heuristic decision-maker processes orthogonal measurement data, selecting successful reactions to take forward and automatically checking the reproducibility of any screening hits. This approach was exemplified in three areas of structural diversification chemistry, supramolecular host–guest chemistry and photochemical synthesis.

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Enantioselective [2π+2σ] Photocycloaddition Enabled by Brønsted Acid Catalyzed Chromophore Activation

E. F. Plachinski, R. Z. Qian, R. Villanueva, D. L. Poole, T. Rosenthal & T. P. Yoon*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c13596)

Bicyclo[2.1.1]hexanes have emerged as valuable scaffolds for the design of new pharmaceutical and agrochemical active ingredients. These structures can be efficiently synthesized via [2π+2σ] photocycloadditions; however, control over the absolute stereochemistry of these strain-releasing reactions has remained challenging. Herein, the authors demonstrate that Brønsted acid catalyzed chromophore activation of C-acyl imidazoles enables highly enantioselective [2π+2σ] photocycloadditions. Because this approach is agnostic to the identity of the coupling partner, the same strategy can be used to synthesize several other medicinally relevant strained small-ring structures.

Visible-Light-Mediated Vicinal Dihalogenation of Unsaturated C–C Bonds Using Dual-Functional Group Transfer Reagents

R. Giri,^† E. Zhilin,^† M. Kissling, S. Patra, A. J. Fernandes & D. Katayev*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c09039) 🔓

The growing demand for chemical production continues to drive the development of sustainable and efficient methods for introducing molecular complexity. In this context, the exploration of unconventional functional group transfer reagents (FGTRs) has led to significant advancements in practical and atom-efficient synthetic protocols. Herein, the authors report the successful development of carbon-based, bench-stable, modular, and inexpensive reagents implemented in dual halogen transfer to unsaturated hydrocarbons via photocatalytic activation of reagents based on a radical-polar crossover mechanism. This method beneficially enables vicinal dichlorination, dibromination, and bromo-chlorination reactions of olefins, offering practical alternatives to the use of toxic binary halogens.

Aziridine Group Transfer via Transient N-Aziridinyl Radicals

P. Biswas, A. Maity, M. T. Figgins & D. C. Powers*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c14169) 🔓

Aziridines are the smallest nitrogen-containing heterocycles and their strain-enhanced electrophilicity renders them as useful synthetic intermediates. Classical aziridine syntheses—based on either [2+1] cycloadditions or intramolecular substitution chemistry—assemble aziridines from acyclic precursors. Here, the authors introduce N-aziridinyl radicals as reactive intermediates that enable the transfer of intact aziridine fragments. Transient N-aziridinyl radicals are generated by the reductive activation of N-pyridinium aziridines and in the presence of O₂, N-aziridinyl radicals are added to styrenyl olefins to afford 1,2-hydroxyaziridination products.

Overcoming Copper Reduction Limitation in Asymmetric Substitution: Aryl-Radical-Enabled Enantioconvergent Cyanation of Alkyl Iodides

S. Chen, D. Ding, L. Yin, X. Wang, J. A. Krause & W. Liu*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c11888)

Cu-catalyzed enantioconvergent cross-coupling of alkyl halides has emerged as a powerful strategy for synthesizing enantioenriched molecules. However, this approach is intrinsically limited by the weak reducing power of copper(I) species, which restricts the scope of compatible nucleophiles and necessitates extensive ligand optimization or the use of complex chiral scaffolds. To overcome these challenges, the authors introduce an aryl-radical-enabled strategy that decouples the alkyl halide activation step from the chiral Cu center. They demonstrate that merging aryl-radical-enabled iodine abstraction with Cu-catalyzed asymmetric radical functionalization enables the conversion of racemic α-iodoamides to enantioenriched alkyl nitrile products with good yield and enantioselectivity.

Homogenous Palladium-Catalyzed Dehalogenative Deuteration and Tritiation of Aryl Halides with D₂/T₂ Gas

J. Li,* Q. Lin,* O. Dungan, Y. Fu, S. Ren, S. Ruccolo, S. Moor & E. M. Phillips

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c08176)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-cmj3q) 🔓

Hydrogen isotopically labeled compounds have extensive utility across diverse domains, especially in drug discovery and development. However, synthesis of the labeled compounds with exclusive site selectivity and/or high isotope incorporation is challenging. One widely employed method is heterogeneous palladium(0)-catalyzed (such as Pd/C) dehalogenative deuteration and tritiation with D₂/T₂ gas. While commonly used, the method faces two long-standing challenges related to insufficient isotope incorporation and functional group tolerance, particularly with aryl bromides and chlorides. Herein, the authors present a novel palladium catalytic system using Zn(OAc)₂ as an additive, enabling novel homogenous dehalogenative deuteration/tritiation using D₂/T₂ gas. Under mild reaction conditions, a wide range of drug-like aryl halides and pseudohalides undergo selective deuteration with complete isotope incorporation. The reaction displays excellent compatibility with diverse functional groups, including multiple bonds and O/N-benzyl, and cyano groups, which are frequently problematic in the Pd/C reactions. Furthermore, this method was successfully applied to the tritiation of four halogenated pharmaceutically relevant molecules, resulting in predictable high specific activity per halogen atom (26.5–27.7 Ci/mmol). Notably, the developed system allows gram-scale preparation of a deuterium-containing intermediate, a crucial step in synthesizing a deuterium-labeled drug molecule.

Catalytic Concerted S_NAr Reactions of Fluoroarenes by an Organic Superbase

M. Shigeno,* K. Hayashi, O. Sasamoto, R. Hirasawa, T. Korenaga,* S. Ishida, K. Nozawa-Kumada & Y. Kondo

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c09042) 🔓

Classic stepwise S_NAr reactions require the use of electron-deficient aromatic halides to stabilize Meisenheimer intermediates. However, recent efforts have been made to develop concerted S_NAr reactions involving a single transition state, allowing the use of electron-rich substrates based on the use of stoichiometric amounts of strong bases or reactive nucleophiles. This study demonstrates that, without the use of such reagents, the organic superbase t-Bu-P4 efficiently catalyzes the concerted S_NAr reactions of aryl fluorides regardless of their electronic nature. The key to establishing this system is the dual activation of aryl fluoride and anionic nucleophiles by the t-Bu-P4 catalyst. Furthermore, this catalysis allows excellent functional group tolerance, utilization of diverse nucleophiles, and late-stage functionalization of bioactive compound derivatives.

ACS CATALYSIS
Csp³–Csp² Coupling of Isonitriles and (Hetero)arenes through a Photoredox-Catalyzed Double Decyanation Process

M. Martín, R. M. Romero, C. Portolani & M. Tortosa*

ACS Catal. 2024, ASAP (DOI: 10.1021/acscatal.4c06269) 🔓

The authors demonstrate the ability of isonitriles to be used as alkyl radical precursors in a photoredox-catalyzed transformation involving selective C–N cleavage and Csp³–Csp² bond formation. This protocol allows for the preparation of functionalized heteroarenes from readily available isonitriles through a decyanation process. The reaction is general for primary, secondary, and tertiary substrates, including amino acid derivatives and drug-like molecules.

ANGEWANDTE CHEMIE INTERNATIONAL EDITION
Revisiting the Baddeley Reaction: Access to Functionalized Decalins by Charge-Promoted Alkane Functionalization

M. Vavrík, P. S. Grant, D. Kaiser, T. Grüne & N. Maulide*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202418067)

C–H functionalization of purely aliphatic substrates is a challenging endeavor, as the absence of directing groups generally thwarts attempts at regiocontrol. This is particularly true for difunctionalization reactions, where the control of relative stereochemistry poses an additional obstacle. The Baddeley reaction of decalins, despite suffering from strong limitations with regard to yield and generality, stands as one of only few known transformations capable of regio- and stereocontrol in aliphatic C–H functionalization. Herein, the authors report a regio- and diastereoselective method for the double functionalization of decalins enabling access to a novel, unreported regioisomer in synthetically useful yields. This method was also successfully applied to a range of other alkane substrates, enabling a straightforward synthesis of keto alcohols from the simplest alkane building blocks.

CHEMRXIV
Triply Convergent Ni-Electrocatalytic Assembly of 1,1-Diaryl Cyclobutanes, Azetidines, and Oxetanes

L. Massaro,^† P. Neigenfind,^† A. Feng, G. Kuehn, F. C. Attard, A. DeSanti, M. R. Collins, M. Bravo, R. K. Twumasi, D. Chen, P. N. Bolduc, M. Nicastri, M. A. Emmanuel, M. S. Oderinde, M. D. Palkowitz, X. Zheng, A. C. Hunter, K. C. Harper, C. C. Tyrol, P. K. Mykhailiuk, Y. Kawamata & P. S. Baran*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-67bb8) 🔓

Increasingly complex, three-dimensional leads for drug discovery are testing the limits of modern organic synthesis. In this context, the need for new methods to access gem-diarylated cyclobutanes, azetidines, and oxetanes is apparent. The present study outlines a modular, scalable, chemoselective approach to solve this problem using simple α-bromoacids and aryl halides as intuitive starting materials. As demonstrated herein, a sequential series of Ni-electrocatalytic cross-couplings can be enlisted to enable rapid access to such structures, many of which have never been accessible before. The scalability of this new reaction sequence is demonstrated, alongside direct applications to known patented structures. A simple user guide is also presented to accelerate adoption of this strategy in medicinal chemistry.

Electrifying P(V): Access to Polar and Radical Reactivity

M. Jafarzadeh,^† M. Nassir,^† L. Gherardi, N. Raheja, Y. Kawamata & P. S. Baran*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-m5v9g) 🔓

Electrochemical, fully stereoselective P(V)-radical hydrophosphorylation of olefins and carbonyl compounds using a P(V) reagent is disclosed. By strategically selecting the anode material, radical reactivity is accessible for alkene hydrophosphorylation whereas a polar pathway operates for ketone hydrophosphorylation.

Synthesis of Diverse Terpenoid Frameworks via Enzyme-Enabled Abiotic Scaffold Hop

H. Deng, J. Yang, F. Li, J. Li* & H. Renata*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-4kpr3-v2) 🔓

Owing to their structural complexity, target-oriented syntheses of natural products usually requires the design of individualized routes that are tailor-made for the specific targets. As such, route re-design is needed when targets of different skeletal connectivities are considered. Here, the authors report a versatile synthetic strategy that runs counter to this conventional wisdom and allows access to a range of terpenoids with distinct skeletal frameworks from the sesquiterpene lactone sclareolide as the starting material. By viewing a biocatalytically-installed alcohol as an exploitable motif rather than a structural endpoint, a number of abiotic skeletal rearrangements were designed, resulting in significant structural divergence from the original drimane ring system of sclareolide. Using this approach, the syntheses of four terpenoid natural products, namely merosterolic acid B, cochlioquinone B, (+)-daucene and dolasta-1(15),8-diene, were achieved.

Heteroaromatic Swapping in Aromatic Ketones

H. Nakahara & J. Yamaguchi*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-pz3xw) 🔓

The modification of aromatic rings to heteroaromatic rings is a widely employed strategy in medicinal chemistry, often used to modulate lipophilicity and improve metabolic stability. However, achieving a one-step, generalizable transformation of aromatic rings into diverse heteroaromatic rings—termed "Heteroaromatic Swapping"—has been a persistent challenge. Existing methods, including skeletal editing and transition-metal-catalyzed aromatic ring exchange, face significant limitations in substrate scope. Here, the authors report an efficient approach to Heteroaromatic Swapping via a Claisen/retro-Claisen mechanism, utilizing heteroaryl esters and aromatic ketones. This method enables the selective exchange of aromatic rings with heteroaromatic rings across a broad substrate range.

Data Science-Driven Discovery of Optimal Conditions and a Condition-Selection Model for the Chan-Lam Coupling of Primary Sulfonamides

S. S. Gandhi, G. Z. Brown, S. Aikonen, J. S. Compton, P. Neves, J. I. M. Alvarado, I. I. Strambeanu,* K. A. Leonard* & A. G. Doyle*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-22jrq) 🔓

Secondary N-arylsulfonamides are common in pharmaceutical compounds owing to their valuable physicochemical properties. Direct N-arylation of primary sulfonamides presents a modular approach to this scaffold but remains a challenging disconnection for transition metal-catalyzed cross couplings, including the Chan-Lam (CL) coupling of nucleophiles with (hetero)aryl boronic acids. Although the CL coupling reaction typically operates under mild conditions, it is also highly substrate-dependent and prone to over-arylation. To address these gaps, the authors employed data science tools in tandem with high-throughput experimentation to study and model the CL N-arylation of primary sulfonamides. To minimize bias in training set design, unsupervised learning was applied to systematically select a diverse set of primary sulfonamides for high-throughput data collection and modeling, resulting in a novel dataset of 3,904 reactions. This workflow enabled the identification of broadly applicable, highly selective conditions for the CL coupling of aliphatic and (hetero)aromatic primary sulfonamides with complex organoboron coupling partners. A regression model was also generated that not only successfully identifies high-yielding conditions for the CL coupling of various sulfonamides, but also sulfonamide features that dictate reaction outcome.

Designing Target-Specific Datasets for Regioselectivity Predictions on Complex Substrates

J. Schleinitz, A. Carretero-Cerdán,^‡ A. Gurajapu,^‡ Y. Harnik, G. Lee, A. Pandey, A. Milo* & S. Reisman*

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

The development of machine learning models to predict the regioselectivity of C(sp³)–H functionalization reactions is reported. A dataset for dioxirane oxidations was curated from the literature and used to generate a model to predict the regioselectivity of C–H oxidation. To assess whether smaller, intentionally designed datasets could provide accuracy on complex targets, a series of acquisition functions were developed to select the most informative molecules for the specific target. Active learning-based acquisition functions that leverage predicted reactivity and model uncertainty were found to outperform those based on molecular and site similarity alone. The use of acquisition functions for dataset elaboration significantly reduced the number of datapoints needed to perform accurate prediction, and it was found that smaller, machine-designed datasets can give accurate predictions when larger, randomly selected datasets fail. Finally, the workflow was experimentally validated on five complex substrates and shown to be applicable to predicting the regioselectivity of arene C–H radical borylation.

ORGANIC PROCESS RESEARCH & DEVELOPMENT
Development of a Commercial Manufacturing Process for Vepdegestrant, an Orally Bioavailable PROTAC Estrogen Receptor Degrader for the Treatment of Breast Cancer

S. Avery, J. M. Buske, D. Chen, H. Chen, X. Chen, A. R. Davidson, J.-N. Desrosiers, H. Dong,* N. Fellah, D. F. Fernández,* J. Grosso, L. Han, T. Hochdorfer, A. M. Johnson, B. P. Jones, M. Kalinowski, K. D. Launer-Felty, J. Lopez, T. Makowski, C. Mastriano, T. N. Nguyen, N. D. Patel, Z. Peng,* T. Potter, R. P. Pritchard, A. M. Rane, M. Reeve, M. C. Richins, C. A. Salazar, J. J. Salisbury, R. Simpson,* L. Tabshey, E. J. Tweed, P. G. Wahome, N. Walsh-Sayles, J. A. Willie & E. Wood

Org. Process Res. Dev. 2024, ASAP (DOI: 10.1021/acs.oprd.4c00362)

A commercial process for vepdegestrant, the most advanced PROTAC protein degrader in human clinical trials, has been developed to support clinical and commercial needs. The process features an efficient convergent synthetic strategy through the final reductive amination of two advanced chiral intermediates, as well as several highly efficient telescoped processes and robust crystallization for purity control. The final commercial process of vepdegestrant consists of seven proposed regulatory GMP steps with five isolations in an overall yield of 29%.

Early Process Development of an LPAR1 Antagonist, GS-2278

N. Kadunce,* A. M. Wagner,* J. Cottell, K. Dao, D. D. Dixon, B. M. Hodur, D. Holte, M. A. Ischay, J. Kang, S. Kim, Y. H. Kim, S. M. Koo, W. Lew, L. Man, K. R. Methuku, H. Morrison, P. D. Parker, D. A. Siler & C. Y. Wong

Org. Process Res. Dev. 2024, ASAP (DOI: 10.1021/acs.oprd.4c00369)

GS-2278 is a lysophosphatidic acid receptor 1 antagonist under development for the treatment of idiopathic pulmonary fibrosis. GS-2278 is assembled in a 9-step sequence. Process development was conducted to determine reaction and isolation conditions to enable scale-ups to support preclinical and early clinical studies. This paper focuses on the development of conditions from the medicinal chemistry route to the Ph 1 manufacturing route.

ORGANIC LETTERS
Stereodivergent Synthesis of 6,12-Guaianolide C1 Epimers via a Rationally Designed Oxy-Cope/Ene Reaction Cascade

K. Mazaraki, C. Zangelidis, A. Kelesidis & A. L. Zografos*

Org. Lett. 2024, ASAP (DOI: 10.1021/acs.orglett.4c03504) 🔓

Nature synthesizes epimeric C1 guaianolide congeners, key components of major natural product classes, through a single structurally flexible macrocyclic germacranolide core. Herein, the authors rationally designed an elemanolide-type scaffold that mimics this natural process, enabling the stereodivergent synthesis of both C1 epimers of 6,12-guaianolide lactone motifs. An oxy-Cope/ene cascade acts as the key step of this process, generating two distinct conformers of an intermediate germacranolide, each leading to a specific C1 epimer. Highly stereoselective redox manipulations follow, culminating in the efficient syntheses of diverse osmitopsin-type guaianolides.

JOURNAL OF ORGANIC CHEMISTRY
Reductive Amination of Carbonyl C–C Bonds Enables Formal Nitrogen Insertion

C. Amber, L. T. Göttemann, R. T. Steele, T. M. Petitjean & R. Sarpong*

J. Org. Chem. 2024, ASAP (DOI: 10.1021/acs.joc.4c02400)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-z8lw3) 🔓

Given its relevance across numerous fields, reductive amination is one of the oldest and most widely used methods for amine synthesis. As a cornerstone of synthetic chemistry, it has largely remained unchanged since its discovery over a century ago. Herein, the authors report the mechanistically driven development of a complementary reaction, which reductively aminates the C–C σ-bond of carbonyls, not the carbonyl C–O π-bond, generating value-added linear and cyclic 3° amines in a modular fashion. The method enables net transformations that would otherwise require lengthy synthetic sequences using pre-existing technologies. This is highlighted by its application to a two-step protocol for the valorization of hydrocarbon feedstocks, the late-stage C–C amination of complex molecules, diversity-oriented synthesis of isomeric amines from a single precursor, and transposition of nitrogen to different positions within a heterocycle.

OUTSIDE OF SYNTHESIS, INSIDE OF SCIENCE
Dry as a Bone

🐕️ Dry as a bone. New research has identified C-fiber low-threshold mechanoreceptors (C-LTMRs) as the sensory neurons responsible for causing the vigorous full-body shake that dogs, alongside other mammals, exhibit following a swim. This “wet dog shake” is an instinctive behaviour that serves a protective function, effectively removing water, dirt, and even parasites from the animals coat.