Organic Synthesis @ Beehiiv

Science

Alcohol-Alcohol Cross-Coupling Enabled by S_H2 Radical Sorting

R. Chen, N. E. Intermaggio, J. Xie, J. A. Rossi-Ashton, C. A. Gould, R. T. Martin, J. Alcázar & D. W. C. MacMillan*

Science, 2024, 383, 1350–1357 (DOI: 10.1126/science.adl5890)

Alcohols represent a functional group class with unparalleled abundance and structural diversity. In an era of chemical synthesis that prioritises reducing time to target and maximising exploration of chemical space, harnessing these building blocks for carbon-carbon bond-forming reactions is a key goal in organic chemistry. In particular, leveraging a single activation mode to form a new C(sp³ )–C(sp³ ) bond from two alcohol subunits would enable access to an extraordinary level of structural diversity. In this work, the authors report a nickel radical sorting–mediated cross-alcohol coupling wherein two alcohol fragments are deoxygenated and coupled in one reaction vessel, open to air.

Nature Chemistry

Enantioselective Propargylic Amination and Related Tandem Sequences to α-Tertiary Ethynylamines and Azacycles

Z. Zhang, Y. Sun, Y. Gong, D.-L. Tang, H. Luo, Z.-P. Zhao, F. Zhou,* X. Wang* & J. Zhou*

Nat. Chem. 2024 (DOI: 10.1038/s41557-024-01479-z)

Chiral α-tertiary amines and related azacycles are sought-after compounds for drug development. Despite progress in the catalytic asymmetric construction of aza-quaternary stereocentres, enantioselective synthesis of multifunctional α-tertiary amines remains underdeveloped. Enantioenriched α-disubstituted α-ethynylamines are attractive synthons for constructing chiral α-tertiary amines and azacycles, but methods for their catalytic enantioselective synthesis need to be expanded. Here, the authors describe an enantioselective asymmetric Cu(I)-catalysed propargylic amination (ACPA) of simple ketone-derived propargylic carbonates to give both α-dialkylated and α-alkyl–α-aryl α-tertiary ethynylamines. The syntheses of quaternary 2,5-dihydropyrroles, dihydroquinines, dihydrobenzoquinolines and dihydroquinolino[1,2-α]quinolines are reported, and the synthetic value is further demonstrated by the enantioselective catalytic total synthesis of a selective multi-target β-secretase inhibitor. Enantioselective Cu-catalysed propargylic substitutions with O- and C-centred nucleophiles are also realised, further demonstrating the potential of the PYBOX ligand.

Journal of the American Chemical Society

Enantioselective Divergent Syntheses of Diterpenoid Pyrones

Y. Ji, Y. Liu, W. Guan, C. Guo, H. Jia, B. Hong & H. Li*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c01788)

Capitalizing a synergy between late-stage C(sp³ )–H alkynylation and a series of transition metal-catalyzed alkyne functionalization reactions, the authors report the enantioselective divergent synthesis of 10 diterpenoid pyrones within 14–16 steps starting from chiral pool enoxolone, including the first enantioselective synthesis of higginsianins A, B, D, E, and metarhizin C. The synthesis also highlights an unprecedented biomimetic oxidative rearrangement of α-pyrone into 3(2H)-furanone, as well as applications of Echavarren C(sp³ )–H alkynylation reaction and Toste chiral counterion-mediated Au-catalyzed intramolecular allene hydroalkoxylation in natural product synthesis.

Enantioselective [2π + 2σ] Cycloadditions of Bicyclo[1.1.0]butanes with Vinylazaarenes through Asymmetric Photoredox Catalysis

Q. Fu, S. Cao, J. Wang, X. Lv, H. Wang, X. Zhao & Z. Jiang*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.3c14077)

The authors present a highly enantioselective [2π + 2σ] photocycloaddition of bicyclo[1.1.0]butanes (BCBs). The reaction uses a variety of vinylazaarenes as partners and is catalyzed by a polycyclic aromatic hydrocarbon (PAH)-containing chiral phosphoric acid as a bifunctional chiral photosensitizer. A wide array of pharmaceutically important bicyclo[2.1.1]hexane (BCH) derivatives have been synthesized with high yields, enantioselectivity, and diastereoselectivity. In addition to the diverse 1-ketocarbonyl-3-substituted BCBs, α/β-substituted vinylazaarenes are compatible with such an unprecedented photoredox catalytic pathway, resulting in the successful assembly of an all-carbon quaternary stereocenter or two adjacent tertiary stereocenters on the product.

Red Light–Blue Light Chromoselective C(sp²)–X Bond Activation by Organic Helicenium-Based Photocatalysis

M. M. Hossain, A. C. Shaikh, R. Kaur & T. L. Gianetti*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.3c13380)

Chromoselective bond activation has been achieved in organic helicenium (n-Pr-DMQA⁺ )-based photoredox catalysis. Consequently, control over chromoselective C(sp² )–X bond activation in multi-halogenated aromatics has been demonstrated. n-Pr-DMQA⁺ can only initiate the halogen atom transfer (XAT) pathway under red light irradiation to activate low-energy-accessible C(sp2)–I bonds. In contrast, blue light irradiation initiates consecutive photoinduced electron transfer (conPET) to activate more challenging C(sp² )–Br bonds. Comparative reaction outcomes have been demonstrated in the α-arylation of cyclic ketones with red and blue lights. Furthermore, red-light-mediated selective C(sp² )–I bonds have been activated in iodobromoarenes to keep the bromo functional handle untouched.

Enantioselective Construction of Quaternary Stereocenters via Cooperative Photoredox/Fe/Chiral Primary Amine Triple Catalysis

L.-J. Li, J.-C. Zhang, W.-P. Li, D. Zhang, K. Duanmu, H. Yu, Q. Ping & Z.-P. Yang*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c01842)

The catalytic and enantioselective construction of quaternary (all-carbon substituents) stereocenters poses a formidable challenge in organic synthesis due to the hindrance caused by steric factors. One conceptually viable and potentially versatile approach is the coupling of a C–C bond through an outer-sphere mechanism, accompanied by the realization of enantiocontrol through cooperative catalysis; however, examples of such processes are yet to be identified. Herein, the authors present such a method for creating different compounds with quaternary stereocenters by photoredox/Fe/chiral primary amine triple catalysis. This approach facilitates the connection of an unactivated alkyl source with a tertiary alkyl moiety, which is also rare. The scalable process exhibits mild conditions, does not necessitate the use of a base, and possesses a good functional-group tolerance.

Nickel-Catalyzed Hydrofluorination in Unactivated Alkenes: Regio- and Enantioselective C–F Bond Formation

C. Lee, M. Kim, S. Han, D. Kim & S. Hong*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c01548)

Catalytic formation of a regio- and enantioselective C–F bond chiral center from readily available alkenes is a crucial goal, yet it continues to pose significant challenges in organic synthesis. Here, the authors report the regioselective formation of C–F bonds facilitated by NiH catalysis and a coordination directing strategy that enables precise hydrofluorination of both terminal and internal alkenes. Notably, they have optimized this methodology to achieve high enantioselectivity in creating aliphatic C–F stereogenic centers especially with β,γ-alkenyl substrates, using a tailored chiral Bn-BOx ligand. Another pivotal finding is the identification of the (+)-nonlinear effect under optimized conditions, allowing for high enantioselectivity even with moderately enantiomerically enriched chiral ligands. Given the significant role of fluorine in pharmaceuticals and synthetic materials, this research offers essential insights into the regioselective and enantioselective formation of C–F bond chiral centers, paving the way for the efficient production of valuable fluorinated compounds.

Copper-Catalyzed Enantioconvergent Radical N-Alkylation of Diverse (Hetero)aromatic Amines

X.-Y. Du, J.-H. Fang, J.-J. Chen, B. Shen, W.-L. Liu, J.-Y. Zhang, X.-M. Ye, N.-Y. Yang, Q.-S. Gu, Z.-L. Li*, P. Yu* & X.-Y. Liu*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c02141)

The transition metal-catalyzed enantioconvergent radical cross-coupling provides a powerful tool for chiral molecule synthesis. In the classic mechanism, the bond formation relies on the interaction between nucleophile-sequestered metal complexes and radicals, limiting the nucleophile scope to sterically uncongested ones. The coupling of sterically congested nucleophiles poses a significant challenge due to difficulties in transmetalation, restricting the reaction generality. The authors describe a probable outer-sphere nucleophilic attack mechanism that circumvents the challenging transmetalation associated with sterically congested nucleophiles. This strategy enables a general copper-catalyzed enantioconvergent radical N-alkylation of aromatic amines with secondary/tertiary alkyl halides and exhibits catalyst-controlled stereoselectivity. It accommodates diverse aromatic amines, especially bulky secondary and primary ones to deliver value-added chiral amines (>110 examples).

Angewandte Chemie International Edition

Photocatalytic Functionalization of Dehydroalanine-Derived Peptides in Batch and Flow

N. Kaplaneris, M. Akdeniz, M. Fillols, F. Arrighi, F. Raymenants, G. Sanil, D. T. Gryko & T. Noel*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202403271) 🔓

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-6fgqv) - open paper

Unnatural amino acids, and their synthesis via the late-stage functionalization (LSF) of peptides, play a crucial role in areas such as drug design and discovery. In this study, the authors present a photocatalytic hydroarylation process targeting the electrophilic residue dehydroalanine (Dha). This residue possesses an α,β-unsaturated moiety and can be combined with various arylthianthrenium salts, both in batch and flow reactors. The photocatalytic approach, being inherently mild, permits the diversification of peptides even when they contain sensitive functional groups. The readily available arylthianthrenium salts facilitate the seamless integration of Dha-infused peptides with a wide range of arenes, drug blueprints, and natural products, culminating in the creation of unconventional phenylalanine derivatives. The synergistic effect of the high functional group tolerance and the modular characteristic of the aryl electrophile enables efficient peptide conjugation and ligation in both batch and flow conditions.

Total Synthesis of Pallamolides A–E

Y. Zhang, L. Chen & Y. Jia*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202319127)

The authors have achieved the first total synthesis of pallamolides A–E, of which pallamolides B–E possess intriguing tetracyclic skeletons with novel intramolecular transesterifications. Key transformations include highly diastereoselective sequential Michael additions to construct the bicyclo[2.2.2]octane core with simultaneous generation of two quaternary carbon centers, a one-pot SmI₂-mediated intramolecular ketyl-enoate cyclization/ketone reduction to generate the key oxabicyclo[3.3.1]nonane moiety, and an acid-mediated deprotection/oxa-Michael addition/β-hydroxy elimination cascade sequence to assemble pallamolides tetracyclic skeletons. Kinetic resolution of ketone 14 via Corey-Bakshi-Shibata reduction enabled the asymmetric synthesis of pallamolides A–E.

Stereodivergent, Kinetically Controlled Isomerization of Terminal Alkenes via Nickel Catalysis

C. Z. Rubel, A. K. Ravn, H. C. Ho, S. Yang, Z.-Q. Li, K. M. Engle* & J. C. Vantourout*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202320081)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2022-x8ssk-v2) - open paper

Because internal alkenes are more challenging synthetic targets than terminal alkenes, metal-catalyzed olefin mono-transposition (positional isomerization) approaches have emerged to afford valuable E- or Z-internal alkenes from their complementary terminal alkene feedstocks. However, the applicability of these methods has been hampered by lack of generality, commercial availability of precatalysts, and scalability. Here, the authors report a nickel-catalyzed platform for the stereodivergent E/Z-selective synthesis of internal alkenes at room temperature. Commercial reagents enable this one-carbon transposition of terminal alkenes to valuable E- or Z-internal alkenes via a Ni–H-mediated insertion/elimination mechanism.

Total Synthesis of the Euphorbia Diterpenoid Pepluacetal

M. Liu, C. Wu, X. Xie, H. Li & X. She*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202400943)

The first total synthesis of the Euphorbia diterpenoid pepluacetal is disclosed in both racemic and chiral fashions. The synthesis strategically relies on a photo-induced Wolff rearrangement/lactonization cascade (WRLC) reaction to access the cyclobutane moiety, a ring-closing metathesis/cyclopropanation sequence to rapidly forge the 7–3 bicyclic system, and a late-stage Rh-catalyzed transannular carbenoid insertion to C(sp³ )–H bond followed by a Baeyer-Villiger oxidation and ring-opening manipulations to install the side chain. The synthetic route demonstrates excellent stereochemical control on the non-classical concave-face bond formation and high scalability to provide 20 mg of (+)-pepluacetal.

Organic Letters

Functionalization of Alkenes with Difluoromethyl Nitrile Oxide to Access the Difluoromethylated Derivatives

B. A. Chalyk, O. Zginnyk, A. V. Khutorianskyi & P. K. Mykhailiuk*

Org. Lett. 2024, ASAP (DOI: 10.1021/acs.orglett.4c00431) 🔓

Electron-rich, electron-deficient, and non-activated alkenes can be rapidly functionalized by in situ-generated difluoromethyl nitrile oxide. The (3+2) cycloaddition proceeds at room temperature, has broad functional group tolerance, and can be used for the late-stage modification of bioactive molecules (finasteride and carbamazepine). The obtained CF₂H-isoxazolines can be easily transformed into CF₂H-containing building blocks for medicinal chemistry: amines, amino acids, amino alcohols, and spirocyclic scaffolds.

Utilization of High-Throughput Experimentation (HTE) and ChemBeads Toward the Development of an Aryl Bromide and Benzyl Bromide Photoredox Cross-Electrophile Coupling

M. P. Glogowski, N. Cercizi, T. Lynch-Colameta, L. H. Ridgers, J. P. Phelan, A. M. Rowley & M. P. Rauch*

Org. Lett. 2024, ASAP (DOI: 10.1021/acs.orglett.4c00577)

The discussion herein describes a metallaphotoredox reaction that allows for efficient exploration of benzyl structure–activity relationships in medicinal chemistry. The use of HTE (high-throughput experimentation) and ChemBeads allows for rapid reaction optimization. The formation of di(hetero)arylmethanes via cross-electrophile coupling between aryl bromides and benzyl bromides provides access to diverse chemical space. The breadth of the substrate scope will be discussed, along with the utilization of batch photochemistry for the preparation of this di(hetero)arylmethane motif on a larger scale.

Journal of Organic Chemistry

Construction of Seven-Membered Oxacycles Using a Rh(I)-Catalyzed Cascade C–C Formation/Cleavage of Cyclobutenol Derivatives

J. S. Ham, M. Son, C. G. Na, B. Park, M.-H. Baik* & R. Sarpong*

J. Org. Chem. 2024, ASAP (DOI: 10.1021/acs.joc.3c02914)

The authors describe the synthesis of substituted oxepane derivatives through the skeletal remodeling of 4-hydroxy-2-cyclobutenones, which are readily prepared from commercially available dialkyl squarates upon their reaction with acrylonitrile. Mechanistically, a Rh(I)-catalyzed C–C bond formation and cleavage cascade is proposed. Specifically, a fused [3.2.0] bicycle is proposed to form from dialkyl squarate-derived cyclobutenols via an unusual Rh(I)-catalyzed intermolecular oxa-Michael addition of a tertiary alcohol with acrylonitrile, followed by an intramolecular conjugate addition/migratory insertion. Subsequent C(sp³ )–C(sp³ ) bond cleavage through a Rh-catalyzed β-carbon elimination is then theorized to furnish the oxepane scaffold.

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