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. 2023 Dec 6;145(48):25954-25961.
doi: 10.1021/jacs.3c10024. Epub 2023 Nov 27.

Bicyclopentylation of Alcohols with Thianthrenium Reagents

Zibo Bai  1 , Beatrice Lansbergen  1 , Tobias Ritter  1
Affiliations

Bicyclopentylation of Alcohols with Thianthrenium Reagents

Zibo Bai et al. J Am Chem Soc. .

Erratum in

Abstract

Herein we present the first method for the synthesis of bicyclo[1.1.1]pentyl (BCP) alkyl ethers from alcohols. The reaction uses BCP-thianthrenium reagents and is catalyzed by a dual copper/photoredox catalyst system. Unlike known alkylations of tertiary alcohols via carbocation intermediates, our Cu-mediated radical process circumvents the labile BCP carbocations. The approach demonstrates a broad tolerance for functional groups when applied to primary, secondary, and even tertiary alcohols. In addition, we highlight the utility of this method in late-stage functionalizations of both natural products and pharmaceuticals as well as in the rapid construction of BCP analogs of known pharmaceuticals that would otherwise be difficult to access.

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Conflict of interest statement

The authors declare the following competing financial interest(s): T.R. and Z.B. may benefit from thianthrene compound-based sales.

Figures

Figure 1
Figure 1
Synthesis of BCP alkyl ethers. LG, leaving group; PC, photocatalyst.
Figure 2
Figure 2
Reaction development and a mechanistic investigation. aYields were determined by 19F NMR. bIsolated yield. cThe TEMPO–BCP adduct was observed by HRMS. dThe Stern–Volmer plot of Cu(acac)2 was corrected due to the inner filter effect.
Figure 3
Figure 3
Substrate scope. aYields were determined by 19F NMR or 1H NMR.
Figure 4
Figure 4
Mechanistic analysis of the synthesis of BCP–TT+ reagents. (A) Chain process of synthesis of BCP–TT+ reagents. (B) BDEs of different TT+ reagents. (C) Comparison of CF3-TT+ (31) and CF2H-TT+ (32). Ar = 3-fluoro-4-methoxyphenyl.
Figure 5
Figure 5
Synthesis of BCP pharmaceutical analogs. (A) Synthesis of BCP-fluoxetine hydrochloride. (B) Synthesis of BCP-butoxycaine. (C) Synthesis of BCP-safinamide. (D) Synthesis of BCP-pranlukast. (E) Further transformations of 43.
See this image and copyright information in PMC

References

    1. Nilova A.; Campeau L.-C.; Sherer E. C.; Stuart D. R. Analysis of benzenoid substitution patterns in small molecule active pharmaceutical ingredients. J. Med. Chem. 2020, 63, 13389–13396. 10.1021/acs.jmedchem.0c00915. - DOI - PubMed
    1. Subbaiah M. A. M.; Meanwell N. A. Bioisosteres of the Phenyl Ring: Recent Strategic Applications in Lead Optimization and Drug Design. J. Med. Chem. 2021, 64, 14046–14128. 10.1021/acs.jmedchem.1c01215. - DOI - PubMed
    1. Pellicciari R.; Raimondo M.; Marinozzi M.; Natalini B.; Costantino G.; Thomsen C. (S)-(+)-2-(3′-Carboxybicyclo[1.1.1]pentyl)-glycine, a Structurally New Group I Metabotropic Glutamate Receptor Antagonist. J. Med. Chem. 1996, 39, 2874–2876. 10.1021/jm960254o. - DOI - PubMed
    2. Filosa R.; Carmela Fulco M.; Marinozzi M.; Giacchè N.; Macchiarulo A.; Peduto A.; Massa A.; de Caprariis P.; Thomsen C.; Christoffersen C. T.; Pellicciari R. Design, synthesis and biological evaluation of novel bicyclo[1.1.1]pentane-based ω-acidic amino acids as glutamate receptors ligands. Bioorg. Med. Chem. 2009, 17, 242–250. 10.1016/j.bmc.2008.11.015. - DOI - PubMed
    1. Stepan A. F.; Subramanyam C.; Efremov I. V.; Dutra J. K.; O’Sullivan T. J.; DiRico K. J.; McDonald W. S.; Won A.; Dorff P. H.; Nolan C. E.; Becker S. L.; Pustilnik L. R.; Riddell D. R.; Kauffman G. W.; Kormos B. L.; Zhang L.; Lu Y.; Capetta S. H.; Green M. E.; Karki K.; Sibley E.; Atchison K. P.; Hallgren A. J.; Oborski C. E.; Robshaw A. E.; Sneed B.; O’Donnell C. J. Application of the bicyclo[1.1.1]pentane motif as a nonclassical phenyl ring bioisostere in the design of a potent and orally active gamma-secretase inhibitor. J. Med. Chem. 2012, 55, 3414–3424. 10.1021/jm300094u. - DOI - PubMed
    2. Auberson Y. P.; Brocklehurst C.; Furegati M.; Fessard T. C.; Koch G.; Decker A.; La Vecchia L.; Briard E. Improving Nonspecific Binding and Solubility: Bicycloalkyl Groups and Cubanes as para-Phenyl Bioisosteres. ChemMedChem 2017, 12, 590–598. 10.1002/cmdc.201700082. - DOI - PubMed
    3. Goh Y. L.; Cui Y. T.; Pendharkar V.; Adsool V. A. Toward Resolving the Resveratrol Conundrum: Synthesis and in Vivo Pharmacokinetic Evaluation of BCP-Resveratrol. ACS Med. Chem. Lett. 2017, 8, 516–520. 10.1021/acsmedchemlett.7b00018. - DOI - PMC - PubMed
    4. Measom N. D.; Down K. D.; Hirst D. J.; Jamieson C.; Manas E. S.; Patel V. K.; Somers D. O. Investigation of a Bicyclo[1.1.1]pentane as a Phenyl Replacement within a LpPLA2 Inhibitor. ACS Med. Chem. Lett. 2017, 8, 43–48. 10.1021/acsmedchemlett.6b00281. - DOI - PMC - PubMed
    1. Gianatassio R.; Lopchuk J. M.; Wang J.; Pan C.-M.; Malins L. R.; Prieto L.; Brandt T. A.; Collins M. R.; Gallego G. M.; Sach N. W.; Spangler J. E.; Zhu H.; Zhu J.; Baran P. S. Strain-release amination. Science 2016, 351, 241–246. 10.1126/science.aad6252. - DOI - PMC - PubMed
    2. Kanazawa J.; Maeda K.; Uchiyama M. Radical Multicomponent Carboamination of [1.1.1]Propellane. J. Am. Chem. Soc. 2017, 139, 17791–17794. 10.1021/jacs.7b11865. - DOI - PubMed
    3. Hughes J. M. E.; Scarlata D. A.; Chen A. C.; Burch J. D.; Gleason J. L. Aminoalkylation of [1.1.1]Propellane Enables Direct Access to High-Value 3-Alkylbicyclo[1.1.1]pentan-1-amines. Org. Lett. 2019, 21, 6800–6804. 10.1021/acs.orglett.9b02426. - DOI - PubMed
    4. Zhang X.; Smith R. T.; Le C.; McCarver S. J.; Shireman B. T.; Carruthers N. I.; MacMillan D. W. C. Copper-mediated synthesis of drug-like bicyclopentanes. Nature 2020, 580, 220–226. 10.1038/s41586-020-2060-z. - DOI - PMC - PubMed
    5. Pickford H. D.; Nugent J.; Owen B.; Mousseau J. J.; Smith R. C.; Anderson E. A. Twofold Radical-Based Synthesis of N,C-Difunctionalized Bicyclo[1.1.1]pentanes. J. Am. Chem. Soc. 2021, 143, 9729–9736. 10.1021/jacs.1c04180. - DOI - PubMed
    6. Shin S.; Lee S.; Choi W.; Kim N.; Hong S. Visible-Light-Induced 1,3-Aminopyridylation of [1.1.1]Propellane with N-Aminopyridinium Salts. Angew. Chem., Int. Ed. 2021, 60, 7873–7879. 10.1002/anie.202016156. - DOI - PubMed
    7. Livesley S.; Sterling A. J.; Robertson C. M.; Goundry W. R. F.; Morris J. A.; Duarte F.; Aissa C. Electrophilic Activation of [1.1.1]Propellane for the Synthesis of Nitrogen-Substituted Bicyclo[1.1.1]pentanes. Angew. Chem., Int. Ed. 2022, 61, e202111291 10.1002/anie.202111291. - DOI - PMC - PubMed
    8. Alvarez E. M.; Bai Z.; Pandit S.; Frank N.; Torkowski L.; Ritter T. O-, N- and C-bicyclopentylation using thianthrenium reagents. Nat. Synth. 2023, 2, 548–556. 10.1038/s44160-023-00277-8. - DOI