A New Method for Enantioconvergence

Vol. 1, Issue 5

Good morning. Welcome to this week’s Organic Synthesis Newsletter where we’ll be highlighting the latest in synthetic organic chemistry literature published between Monday 15th April – Sunday 21st April 2024.

Let’s get into it. 👇

Nature Chemistry

Stereoretentive Enantioconvergent Reactions

S. H. Bennett, J. S. Bestwick, V. P. Demertzidou, D. J. Jones, H. E. Jones, F. Richard, J. A. Homer, R. Street-Jeakings, A. F. Tiberia & A. L. Lawrence*

Nat. Chem. 2024 (DOI: 10.1038/s41557-024-01504-1) 🔓

Enantioconvergent reactions are pre-eminent in contemporary asymmetric synthesis as they convert both enantiomers of a racemic starting material into a single enantioenriched product, thus avoiding the maximum 50% yield associated with resolutions. All currently known enantioconvergent processes necessitate the loss or partial loss of the racemic substrate’s stereochemical information, thus limiting the potential substrate scope to molecules that contain labile stereogenic units. Here, the authors present an alternative approach to enantioconvergent reactions that can proceed with full retention of the racemic substrate’s configuration. This uniquely stereo-economic approach is possible if the two enantiomers of a racemic starting material are joined together to form one enantiomer of a non-meso product. Experimental validation of this concept is presented using two distinct strategies: (1) a direct asymmetric coupling approach, and (2) a multicomponent approach, which exhibits statistical amplification of enantiopurity. Thus, the established dogma that enantioconvergent reactions require substrates that contain labile stereogenic units is shown to be incorrect.

Editor’s Note: I had the privilege of working on this project during my time as a post-doctoral research associate. It’s not often you get to work on such a well designed and creative project alongside talented colleagues. This was one of those times. Congratulations to all who worked so hard towards this outcome.

A para- to meta-Isomerization of Phenols

S.Edelmann & J.-P. Lumb*

Nat. Chem. 2024 (DOI: 10.1038/s41557-024-01512-1)

Phenols and their derivatives are ubiquitous in nature and critically important industrial chemicals. Their properties are intimately linked to the relative substitution pattern of the aromatic ring, reflecting well-known electronic effects of the OH group. Because of these ortho-, para-directing effects, meta-substituted phenols have historically been more difficult to synthesize. Here, the authors describe a procedure to transpose phenols that hinges on a regioselective diazotization of the corresponding ortho-quinone. The procedure affords the meta-substituted phenol directly from its more common and accessible para-substituted isomer, and demonstrates good chemoselectivity that enables its application in late-stage settings.

Journal of the American Chemical Society

Total Synthesis of the Diterpenes (+)-Randainin D and (+)-Barekoxide via Photoredox-Catalyzed Deoxygenative Allylation

O. Vyhivskyi & O. Baudoin*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c02224) 🔓

The authors report the first enantioselective total synthesis of diterpenoid randainin D, which possesses a hydroazulenone core with a β-substituted butenolide moiety on the cycloheptane ring. The trans-5/7 ring system was formed via a highly challenging ring-closing metathesis delivering the tetrasubstituted cycloheptenone. The butenolide moiety was installed via a novel deoxygenative allylation under Ir-photoredox catalysis, employing methyl oxalate as a red/ox tag. Moreover, the developed allylation was successfully utilized in the 7-step total synthesis of (+)-barekoxide.

Chemoselective Diazine Dearomatization: The Catalytic Enantioselective Dearomatization of Pyrazine

D. R. Ketelboeter, M. Pappoppula & A. Aponick*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c02979)

Despite much progress in the area of dearomatization, the enantioselective dearomatization of heterocycles is limited to those with a single heteroatom. Here, the authors report a highly enantioselective copper-catalyzed dearomatization of pyrazine, a diazine, leading to chiral C-substituted piperazines. When exposed to a chloroformate and an alkyne in the presence of a catalyst derived from a copper salt and the chiral ligand StackPhos, pyrazine is readily dearomatized to provide a 2,3-disubstituted dihydropyrazine as single diastereomer in high enantiomeric excess. The synthetically useful dihydropyrazine products, obtained in up to 95% yield and 99% e.e., can be further manipulated to form optically active C-substituted piperazines and C1-symmetric 1,2-diamines.

Late-Stage Saturation of Drug Molecules

D.-H. Liu, P. M. Pflüger, A. Outlaw, L. Lückemeier, F. Zhang, C. Regan, H. Rashidi Nodeh, T. Cernak*, J. Ma* & F. Glorius*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c00807) 🔓

The available methods of chemical synthesis have arguably contributed to the prevalence of aromatic rings in modern pharmaceuticals. Many such sp2 -carbon-rich fragments are now easy to synthesize using high-quality cross-coupling reactions that click together an ever-expanding menu of commercially available building blocks, but the products are flat and lipophilic, decreasing their odds of becoming marketed drugs. Converting flat aromatic molecules into saturated analogues with a higher fraction of sp3 carbons could improve their medicinal properties and facilitate the invention of safe, efficacious, metabolically stable, and soluble medicines. In this study, the authors show that aromatic and heteroaromatic drugs can be readily saturated under exceptionally mild rhodium-catalyzed hydrogenation, acid-mediated reduction, or photocatalyzed-hydrogenation conditions, converting sp2 carbon atoms into sp3 carbon atoms and leading to saturated molecules with improved medicinal properties. The rhodium-catalyzed method tolerates traces of dimethyl sulfoxide (DMSO) or water, meaning that pharmaceutical compound collections, which are typically stored in wet DMSO, can finally be reformatted for use as substrates for chemical synthesis. This latter application is demonstrated through the late-stage saturation (LSS) of 768 complex and densely functionalized small-molecule drugs.

Selective Hydrofunctionalization of Alkenyl Fluorides Enabled by Nickel-Catalyzed Hydrogen Atoms and Group Transfer: Reaction Development and Mechanistic Study

F. Chen, Q. Zhang, Y. Li, Z.-X. Yu* & L. Chu*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c01506)

Due to the unique effect of fluorine atoms, the efficient construction of high-value alkyl fluorides has attracted significant interest in modern drug development. However, enantioselective catalytic strategies for the efficient assembly of highly functionalized chiral C(sp3 )-F scaffolds from simple starting materials have been underutilized. Herein, the authors demonstrate a nickel-catalyzed radical transfer strategy for the efficient, modular, asymmetric hydrogenation and hydroalkylation of alkenyl fluorides with primary, secondary, and tertiary alkyl halides under mild conditions. The transformation provides facile access to various structurally complex secondary and tertiary α-fluoro amide products from readily available starting materials with excellent substrate compatibility and distinct selectivity.

Angewandte Chemie International Edition

Unified Approach to Deamination and Deoxygenation Through Isonitrile Hydrodecyanation: A Combined Experimental and Computational Investigation

Z. Jiao, K. T. Jaunich, T. Tao, O. Gottschall, M. M. Hughes, A. Turlik* & A. Schuppe*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202405779) 🔓

The authors describe a general hydrodefunctionalization protocol of alcohols and amines through a common isonitrile intermediate. To cleave the relatively inert C–NC bond, they leveraged dual hydrogen atom transfer (HAT) and photoredox catalysis to generate a nucleophilic boryl radical, which readily forms an imidoyl radical intermediate from the isonitrile. Rapid β-scission then accomplishes defunctionalization. This method has been applied to the hydrodefunctionalization of both amine and alcohol-containing pharmaceuticals, natural products, and biomolecules. They also extended this approach to the reduction of carbonyls and olefins to their saturated counterparts, as well as the hydrodecyanation of alkyl nitriles.

Expedient Access to 18F-Fluoroheteroarenes via Deaminative Radiofluorination of Aniline-Derived Pyridinium Salts

J. Ford, S. Ortalli, Z. Chen, J. Sap,* M. Tredwell* & V. Gouverneur*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202404945) 🔓

The authors disclose that pyridinium salts derived from abundant (hetero)anilines represent a novel precursor class for nucleophilic aromatic substitution reactions with [18 F]fluoride. The value of this new 18 F-fluorodeamination is demonstrated with the synthesis of over 30 structurally diverse and complex heteroaryl 18 F-fluorides, several derived from scaffolds that were yet to be labelled with fluorine-18.

The 18F-Difluoromethyl Group: Challenges, Impact and Outlook

J. Ford, S. Ortalli & V. Gouverneur*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202404957)

The difluoromethyl functionality has proven useful in drug discovery, as it can modulate the properties of bioactive molecules. For PET imaging, this structural motif has been largely underexploited in (pre)clinical radiotracers due to a lack of user-friendly radiosynthetic routes. This Mini-review provides an overview of the challenges facing radiochemists and summarises the efforts made to date to access 18 F-difluoromethyl-containing radiotracers. Two distinct approaches have prevailed, the first of which relies on 18 F-fluorination. A second approach consists of a 18 F-difluoromethylation process, which uses 18 F-labelled reagents capable of releasing key reactive intermediates such as the [18 F]CF2H radical or [18 F]difluorocarbene. Finally, we provide an outlook for future directions in the radiosynthesis of [18 F]CF2H compounds and their application in tracer radiosynthesis.

Meta-Selective Copper-Catalyzed C–H Arylation of Pyridines and Isoquinolines through Dearomatized Intermediates

S.-M. Guo, P. Xu & A. Studer*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202405385) 🔓

C(sp2 )–H functionalization offers an efficient strategy for the synthesis of various elaborated N-containing heteroarenes. Along these lines, oxazino pyridines that can be readily prepared from pyridines, have been introduced as powerful substrates in radical- and ionic-mediated meta-C–H functionalization. However, the regioselective meta-C–H arylation of pyridines remains a great challenge. Herein, a copper-catalyzed meta-selective C–H arylation of pyridines and isoquinolines through bench-stable dearomatized intermediates is reported. Electrophilic aryl-Cu(III) species, generated from readily accessible aryl I(III) reagents, enable the efficient meta-arylation of a broad range of pyridines and isoquinolines.


Direct C4- and C2 C–H Amination of Heteroarenes Using I(III) Reagents via a Cross Azine Coupling

B. J. Motsch, A. H. Quach, J. L. Dutton,* D. J. D. Wilson* & S. E. Wengryniuk*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-n14xq) 🔓

Aminated nitrogen heterocycles are valuable motifs across numerous chemical industries, perhaps most notably small molecule pharmaceuticals. While numerous strategies exist to install nitrogen atoms onto azaarenes, most require pre-functionalization and methods for direct C–H amination are almost entirely limited to the C2-position. Herein, the authors report a method for the direct C2 and C4 C–H amination of fused azaarenes via in situ activation with a bispyridine-ligated I(III)-reagent, [(Py)2IPh]2OTf, or Py-HVI. Unlike commonly used N-oxide chemistry, the method requires no pre-oxidation of the azaarene and it provides unprecedented access to C4-amination products. The resulting N-heterocyclic pyridinium salts can be isolated via simple trituration, and the free amine can be liberated under mild Zincke aminolysis, or the amination and cleavage can be telescoped to a one-pot process.

A New Reagent to Access Methyl Sulfones

Y. Poplavsky, V. Ripenko, S. Bova, A. Biitseva, Y. V. Dmitriv, A. A. Tolmachev, I. V. Sadkova, V. Q. H. Phan, H. V. R. Dias* & P. K. Mykhailiuk*

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

A new chemical reagent to access methyl sulfones has been developed. Its reaction with various bis-nucleophiles leads to the rapid formation of previously unknown heteroaromatic methyl sulfones. Analogous strategy can also be used to construct alkyl-, CHF2-, CF3- and even bicyclo[1.1.1]pentane-containing derivatives. These compounds have been demonstrated to have a high potential for use in medicinal chemistry and coordination chemistry.

Organic Process Research & Development

What Does it Take to Develop Structurally Complex Molecules by Total Synthesis? Rapid Process Development and GMP Manufacturing of E7130 Drug Substance for First-in-Human Clinical Study

T. Sasaki*, K. Yahata, M. Isomura*, I. Ohashi, T. Fukuyama, Y. Miyashita, Y. Watanabe, N. Murai, M. Matsuda, A. Kamada, Y. Kaburagi, K. Kira, K. Iso, Y. Sato, F. Matsuura, Y. Matsumoto, H. Azuma, D. Iida, T. Ishida, W. Itano, S. Nagao, M. Seki, A. Yamamoto, Y. Yamamoto, N. Yoneda, M. Matsukura, O. Asano, A. Kayano*, K. Tagami, T. Owa & Y. Kishi

Org. Process Res. Dev. 2024, ASAP (DOI: 10.1021/acs.oprd.4c00016)

Process development of E7130 Drug Substance, which is a novel anticancer drug candidate, is described. To accomplish rapid delivery of such a large and structurally complex drug substance for first-in-human (FIH) clinical trial, close collaboration among medicinal chemistry, process chemistry, and academia teams was required. The successful establishment of a suitable synthetic route in a concise time frame while negotiating challenging chemical reactions (e.g., asymmetric catalytic Nozaki–Hiyama–Kishi (NHK) reaction and Zr/Ni-mediated ketone coupling reaction) is described herein. Experience with the development of eribulin mesylate was helpful in anticipating and overcoming the chemical and logistical challenges encountered in the E7130 project. Based on this background, more than 10 g of E7130 Drug Substance has been successfully manufactured under Good Manufacturing Practice (GMP) controls within 1.5 years after the medicinal chemistry team succeeded in the first total synthesis.

Chemical Science

Asymmetric Synthesis of Unnatural α-Amino Acids Through Photoredox-Mediated C–O Bond Activation of Aliphatic Alcohols

G. Alvey, E. Stepanova, A. Shatskiy, J. Lantz, R. Willemsen, A. Munoz, P. Dinér & M. D. Kärkäs*

Chem. Sci. 2024, Accepted (DOI: 10.1039/D4SC00403E) 🔓

Unnatural α-amino acids constitute a fundamental class of biologically relevant compounds. However, despite the interest in these motifs, synthetic strategies have traditionally employed polar retrosynthetic disconnections. These methods typically entail the use of stoichiometric amounts of toxic and highly sensitive reagents, thereby limiting the substrate scope and practicality for scale up. In this work, an efficient protocol for the asymmetric synthesis of unnatural α-amino acids is realized through photoredox-mediated C–O bond activation in oxalate esters of aliphatic alcohols as radical precursors. The developed system uses a chiral glyoxylate-derived N-sulfinyl imine as the radical acceptor and allows facile access to a range of functionalized unnatural α-amino acids through an atom-economical redox-neutral process with CO2 as the only stoichiometric byproduct.

Organic Letters

Relay Catalysis for Selective Aerobic Oxidative Esterification of Primary Alcohols with Methanol

Y. Yu, J. Lin, A. Qin, H. Wang, J. Wang, W. Wang, G. Wu, Q. Zhang, H. Qian* & S. Ma*

Org. Lett. 2024, ASAP (DOI: 10.1021/acs.orglett.4c01059)

Esters are bulk and fine chemicals and ubiquitous in polymers, bioactive compounds, and natural products. Their traditional synthetic approach is the esterification of carboxylic acids or their activated derivatives with alcohols. Herein, a bimetallic relay catalytic protocol was developed for the aerobic esterification of one alcohol in the presence of a slowly oxidizing alcohol, which has been identified as methanol. A concise synthesis of phlomic acid was executed to demonstrate the practicality and potential of this reaction.

Journal of Organic Chemistry

Acetone Serving as a Solvent and Interaction Partner Promotes the Direct Olefination of N-Tosylhydrazones under Visible Light

D. Xia, T. Li, X.-Y. Ke, J. Wang, X. Luan, S.-F. Ni*, Y. Zhang* & W.-D. Zhang*

J. Org. Chem. 2024, ASAP (DOI: 10.1021/acs.joc.4c00184)

The authors describe a catalyst-free and non-covalent interaction-mediated strategy to access the olefination of N-tosylhydrazones using acetone as a solvent and an interaction partner. This protocol also features broad substrate scope, excellent functional group compatibility, and mild reaction conditions without transition metals.


Chemists Invent Drugs and Drugs Save Lives

D. F. Weaver*

ChemMedChem 2024, Early View (DOI: 10.1002/cmdc.202400074) 🔓

Drug molecules are the centrepiece of modern medical therapies, providing relief from pain, combatting infections and providing a myriad of other therapeutic effects. The quest for new and improved drug molecules drives medical research, and the introduction of a new drug frequently becomes a newsworthy event capturing the attention of the press and general public. And yet, misconceptions abound. Often, the general public thinks that drug molecules are designed, created, and invented by physicians rather than chemists – a misunderstanding that is merely one aspect of a widespread general underappreciation of the role of chemistry in the health and socioeconomic well-being of humankind. Chemistry as a discipline needs to change this narrative. Our journals, conferences, societies, mass media presence and social media postings need to better inform the general public about the societal value of chemistry. Though it is an arduous and time-demanding process, chemists, both in academia and industry, invent the drugs that are advancing medical care. We chemists need to do a better job educating policy makers, politicians, opinion leaders and fundraisers about the valuable contributions of chemistry. We need to have people know what we do, and why we became chemists; we need to engage the general public.

Outside of Synthesis, Inside of Science: 

• In 2022, the pharmaceutical sector accounted for two-thirds of Denmark’s economic growth, led primarily by sales of Novo Nordisk’s anti-diabetic and weight management medication, Semaglutide (Ozempic, WeGovy). However, with demand outstripping supply, those using Semaglutide for the latter may find themselves regaining two-thirds of what they lost without access to the medication.

• In a new partnership called CANGARU, researchers and publishers aim to provide a set of guidelines for when and how AI programmes should be used in the writing of manuscripts. This comes as an estimated 1–5% of publications may include AI-generated text.

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