Furan → Pyrrole

Welcome to this week’s Organic Synthesis Newsletter.

Monday 30^th September – Sunday 6^th October 2024

SCIENCE
Photocatalytic Furan-to-Pyrrole Conversion

D. Kim,^† J. You,^† D. H. Lee, H. Hong, D. Kim & Y. Park*

Science 2024, 386, 99–105 (DOI: 10.1126/science.adq6245)

The identity of a heteroatom within an aromatic ring influences the chemical properties of that heterocyclic compound. Systematically evaluating the effect of a single atom, however, poses synthetic challenges, primarily as a result of thermodynamic mismatches in atomic exchange processes. The authors present a photocatalytic strategy that swaps an oxygen atom of furan with a nitrogen group, directly converting the furan into a pyrrole analog in a single intermolecular reaction. High compatibility was observed with various furan derivatives and nitrogen nucleophiles commonly used in drug discovery, and the late-stage functionalization furnished otherwise difficult-to-access pyrroles from naturally occurring furans of high molecular complexity.

A Chiral Hydrogen Atom Abstraction Catalyst for the Enantioselective Epimerization of meso-Diols

A. S. K. Lahdenperä, J. Dhankhar,^‡ D. J. Davies,^‡ N. Y. S. Lam, P. D. Bacoş, K. de la Vega-Hernández & R. J. Phipps*

Science 2024, 386, 42–49 (DOI: 10.1126/science.adq8029)

Hydrogen atom abstraction is an important elementary chemical process but is very difficult to carry out enantioselectively. The authors have developed catalysts, readily derived from the Cinchona alkaloid family of natural products, which can achieve this by virtue of their chiral amine structure. The catalyst, following single-electron oxidation, desymmetrizes meso-diols by selectively abstracting a hydrogen atom from one carbon center, which then regains a hydrogen atom by abstraction from a thiol. This results in an enantioselective epimerization process, forming the chiral diastereomer with high enantiomeric excess. Cyclic and acyclic 1,2-diols are compatible, as are acyclic 1,3-diols. Additionally, the viability of combining this approach with carbon-carbon bond formation in Giese addition was demonstrated.

NATURE CHEMISTRY
Cobalt-Catalysed Desymmetrization of Malononitriles via Enantioselective Borohydride Reduction

Y. Zheng,^† T. Yang,^† K. F. Chan, Z. Lin* & Z. Huang*

Nat. Chem. 2024 (DOI: 10.1038/s41557-024-01592-z)

The high nitrogen content and diverse reactivity of malononitrile are widely harnessed to access nitrogen-rich fine chemicals. Although the facile substitutions of malononitrile can give structurally diverse quaternary carbons, their access to enantioenriched molecules, particularly chiral amines that are prevalent in bioactive compounds, remains rare. Here, the authors report a cobalt-catalysed desymmetric reduction of disubstituted malononitriles to give highly functionalized β-quaternary amines. The pairing of cobalt salt and sodium borohydride is proposed to generate a cobalt-hydride intermediate and initiate the reduction. Meanwhile, the enantiocontrol of the dinitrile is achieved through a tailored bisoxazoline ligand with two large flanks that create a narrow gap to host the bystanding nitrile and thus restrict the C(ipso)−C(α) bond rotation of the complexed one.

NATURE CATALYSIS
Organocatalytic Asymmetric α-C–H Functionalization of Alkyl Amines

T. Deng,^† X.-L. Han,^† Y. Yu, C. Cheng, X. Liu, Y. Gao, K. Wu, Z. Li, J. Luo* & L. Deng*

Nat. Catal. 2024 (DOI: 10.1038/s41929-024-01230-4)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2023-flm08) 🔓

Catalytic enantioselective α-C–H functionalization of widely available achiral alkyl amines could provide an ideal synthetic approach towards chiral amines. However, the inert nature of the α-C–H of alkyl amines renders their activation as carbanionic nucleophiles for catalytic asymmetric reactions an important yet unmet challenge. Here, the authors describe how N-arylidene-protected alkyl amines can be activated as carbanions for asymmetric conjugate addition and the Mannich reaction. These results represent an intriguing and useful approach to the synthesis of chiral α,α-dialkyl amines.

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Radical Polarity

J. J. A. Garwood, A. D. Chen & D. A. Nagib*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c06774, printable summary here)

The polarity of a radical intermediate profoundly impacts its reactivity and selectivity. To quantify this influence and predict its effects, the electrophilicity/nucleophilicity of >500 radicals has been calculated. This database of open-shell species entails frequently encountered synthetic intermediates, including radicals centered at sp³, sp², and sp hybridized carbon atoms or various heteroatoms (O, N, S, P, B, Si, X). Importantly, these computationally determined polarities have been experimentally validated for electronically diverse sets of >50 C-centered radicals, as well as N- and O- centered radicals. High correlations are measured between calculated polarity and quantified reactivity, as well as within parallel sets of competition experiments (across different radical types and reaction classes). These multipronged analyses show a strong relationship between the computed electrophilicity, ω, of a radical and its relative reactivity (k_rel vs. Δω slopes up to 40; showing mere Δω of 0.1 eV affords up to 4-fold rate enhancement).

Divergent Enantioselective Access to Diverse Chiral Compounds from Bicyclo[1.1.0]butanes and α,β-Unsaturated Ketones under Catalyst Control

J. Jeong,^† S. Cao,^† H.-J. Kang, H. Yoon, J. Lee, S. Shin, D. Kim & S. Hong*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c10153)

The authors report divergent catalytic methods that selectively yield either cycloaddition or addition/elimination products from bicyclo[1.1.0]butanes and α,β-unsaturated ketones. By employing chiral Lewis acid or Brønsted acid catalysts, excellent regio-, diastereo-, and enantioselectivity was achieved across all three distinct transformations, affording a diverse array of synthetically valuable chiral bicyclo[2.1.1]hexanes and cyclobutenes. The divergent outcomes are controlled by the differential activation of the substrates by the specific chiral catalyst with the reaction conditions dictating the pathway selectivity.

β-Selective 2-Deoxy- and 2,6-Dideoxyglucosylations Catalyzed by Bis-Thioureas

P. D. Beyer,^† M. M. Nielsen,^† E. Picazo & E. N. Jacobsen*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c11560)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-7414b) 🔓

The authors present methods for β-selective 2-deoxy- and 2,6-dideoxyglucosylations of natural products, carbohydrates, and amino acids using bis-thiourea hydrogen-bond-donor catalysts. Disarming ester protecting groups were necessary to counter the high reactivity of 2-deoxyglycosyl electrophiles toward non-stereospecific S_N1 pathways. Alcohol and phenol nucleophiles with both base- and acid-sensitive functionalities were compatible with the catalytic protocol, enabling access to a wide array of 2-deoxy-β-O-glucosides.

Catalytic Asymmetric Barbier Reaction of Ketones with Unactivated Alkyl Electrophiles

H. Xia, X. Jiang, D. Lin, S. Zhang, Z. Yu, X. Wu, J. Qu & Y. Chen*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c10809)

The Barbier reaction is a reductive-type addition of an aldehyde or ketone with an organic electrophile in the presence of a terminal metal reductant, providing a straightforward and efficient method for carbon–carbon bond formation. This reaction possesses the advantage of circumventing the preparation of moisture- and air-sensitive organometallic reagents. However, the catalytic Barbier reaction of ketones to construct tetrasubstituted stereogenic centers is largely underdeveloped, despite its potential for accessing synthetically challenging chiral tertiary alcohols. Herein, the authors disclose a photoredox-assisted cobalt-catalyzed asymmetric alkylative Barbier-type addition reaction of ketones, allowing for the construction of highly congested tetrasubstituted carbon centers. The alkyl addition fragments could be either readily accessible unactivated alkyl halides or redox-active esters generated through a decarboxylative pathway. This protocol has been applied to the expedient synthesis of the core structure of Sofdra, a recent FDA-approved drug.

ANGEWANDTE CHEMIE INTERNATIONAL EDITION
Total Synthesis of Ryanodane Diterpenoids Garajonone and 3-epi-Garajonone

J.-B. Qiao,^† L. Meng,^† J.-Y. Pei, H. Shao & Y.-M. Zhao*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202417647)

Ryanodane diterpenes are structurally complex natural products that are well-known for their high degree of oxidation and the challenges associated with their syntheses. Herein, the authors present a two-stage synthetic strategy that draws inspiration from the broad biosynthesis of terpenes, allowing them to successfully achieve the first chemical synthesis of garajonone, a ryanodane diterpenoid that occurs naturally at low abundance, as well as its epimer, 3-epi-garajonone. The key to this success lay in the rapid construction of the carbon framework by employing an early-stage palladium-catalyzed Heck/carbonylative esterification cascade annulation, followed by successive late-stage selective redox manipulation to establish the desired oxidation state of the molecule.

A General Hydrotrifluoromethylation of Unactivated Olefins Enabled by Voltage-Gated Electrosynthesis

E. M. Alvarez,* J. Li & C. Malapit*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202415218) 🔓

This work presents the discovery and development of a regioselective hydrotrifluoromethylation of olefins under electrochemical conditions. Guided by mechanistic studies, a voltage-gated electrolysis was designed by integrating two redox processes operating within a narrow potential window. This strategy facilitates olefin hydrotrifluoromethylation (over dibromination) that showcases broad functional group tolerance

CHEMRXIV
An Improved P(V) Oligonucleotide Synthesis Platform

M. Nassir,^† L. Gherardi,^† R. L. Redman,^† Y. Jin, F. Yao, Y. Yang, N. Raheja, A. Natarajan, D. Butler*, K. W. Knouse* & P. S. Baran*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-vj0vk) 🔓

Three critical advances in simplifying the adoption of P(V)-based stereopure, phosphorothioate-containing oligonucleotide synthesis are reported. A more inexpensive phosphorus-sulfur incorporation reagent (Ψ-Br) is introduced, a robust linker system was developed, and a systematic study of common nucleobase protecting groups performed to significantly reduce the barrier to adoption of this technology.

Hydroalkylation of Vinylarenes via Transition Metal-Free In-Situ Generation of Benzylic Nucleophiles using Tetramethyldisiloxane and KOt-Bu

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

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-5rwk3-v2) 🔓

Hydrosilanes and Lewis bases are known to promote various reductive defunctionalizations, rearrangements, and silylation reactions, facilitated by enigmatic silicon/Lewis base-derived reactive intermediates. Despite the wide variety of transformations enabled by this reagent combination, no examples of intermolecular C(sp³)–C(sp³) 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 a new C(sp³)–C(sp³) linkage via formal hydroalkylation.

A General Photocatalytic Platform for the Regio- and Stereoselective β-Chloroacylation of Olefins using a Heteroleptic Copper(I) Complex

T. Mandal,^† M. Ghosh^† & O. Reiser*

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

Atom Transfer Radical Addition (ATRA) of aroyl chlorides to access β-chloroacyl derivatives via photoredox catalysis remains severely limited by the use of precious iridium photocatalysts and activated alkenes as acceptors. This has prevented the implementation of a general catalytic strategy for the β-chloroacylation of alkenes. Here, the authors report a unified platform for the regioselective chlorocarbonylation of alkenes via visible-light-mediated ATRA of aroyl chlorides catalyzed by a heteroleptic Cu(I)-complex that enables rapid access to β-chloroketones. The process has extensive substrate scope, functional group tolerance and its synthetic utility has been demonstrated through the functionalization of complex substrates and application to the formal synthesis of pharmacologically relevant haloperidol, seratrodast, and naturally occurring piperidine alkaloid (−)-sedamine.

Highly Parallel Optimisation of Nickel-Catalysed Suzuki Reactions through Automation and Machine Intelligence

J. W. Sin,* S. L. Chau, R. P. Burwood, K. Püntener, R. Bigler & P. Schwaller*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-m12s4) 🔓

The authors report the development and application of a scalable machine learning optimisation framework for batched multi-objective reaction optimisation. Through experimental data-derived benchmarks, the authors demonstrate the approach’s capacity to efficiently handle large parallel batches and high-dimensional search spaces characteristic of high-throughput experimentation (HTE). They also establish the framework’s robustness to reaction noise and handling of batch constraints encountered in real-world chemical laboratories. The approach was applied experimentally through an automated 96-well HTE reaction optimisation campaign for a nickel-catalysed Suzuki reaction. The optimisation framework effectively navigates the complex reaction landscape with unexpected chemical reactivity, revealing advantages over traditional, purely experimentalist-driven HTE plate design.

Switchable and Stereospecfic C-Glycosylation Strategy via Formal Functional Group Deletion

X. Ma* & S. J. Sujansky

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-rwz5n) 🔓

Carbohydrates constitute an important class of biologically relevant natural products. Among the synthetic glycomimetics, C-glycosides are particularly interesting due to their chemical and metabolic stability towards acidic and enzymatic hydrolysis at the anomeric position. The stereochemical outcomes of traditional methodologies to access C-glycosides rely heavily on substrate control. Herein, the authors report the first synthetic strategy to access diverse C-glycosides with precise stereochemical control at the anomeric position via formal functional group deletion, where both α- and β-anomers of furanoses and pyranoses can be obtained as single stereoisomers.

ORGANIC LETTERS
Conversion of Carboxylic Acids to Sulfonamide Bioisosteres via Energy Transfer Photocatalysis

Z. Zong, J. Yang, L. Yuan, X. Wang, J.-Q. Chen* & J. Wu*

Org. Lett. 2024, ASAP (DOI: 10.1021/acs.orglett.4c03325)

More than 450 drugs containing a carboxylic acid functional group have been marketed worldwide. Herein, the authors report a concise and environmentally friendly organic photoinduced protocol for the interconversion of carboxylic acids into their sulfonamide bioisosteres. With this strategy, a variety of substrates, including alkyl, (hetero)aryl, and alkenyl acids, as well as various biologically relevant acids are successfully converted into primary sulfonamides.

OUTSIDE OF SYNTHESIS, INSIDE OF SCIENCE
Blue Lava

🔭 Blue lava. Nature have just released their selection of the best science images in September, featuring bioluminescent plankton that resembles “blue lava” on the shores of Medhufaru, Maldives.

💻️ A noble cause. With the 2024 Nobel Prizes being announced this week, Nature have crunched the numbers (346 prizes, 646 winners) to find out what kind of scientist is most likely to win a Nobel Prize.

🔦 Lighting the way. Since 2003, 98% of Phase II & III clinical trials for Alzheimer’s disease have ended in failure. Now, an experimental therapy involving pulses of light and sound tuned to 40-hertz is showing promise at slowing cognitive decline with none of the severe side-effects associated with approved therapies.