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. 2022 Mar 9;144(9):3939-3948.
doi: 10.1021/jacs.1c11921. Epub 2022 Feb 25.

Pd(II)-Catalyzed Enantioselective C(sp3)-H Arylation of Cyclopropanes and Cyclobutanes Guided by Tertiary Alkylamines

Jesus Rodrigalvarez  1 , Luke A Reeve  1 , Javier Miró  1 , Matthew J Gaunt  1
Affiliations

Pd(II)-Catalyzed Enantioselective C(sp3)-H Arylation of Cyclopropanes and Cyclobutanes Guided by Tertiary Alkylamines

Jesus Rodrigalvarez et al. J Am Chem Soc. .

Abstract

Strained aminomethyl-cycloalkanes are a recurrent scaffold in medicinal chemistry due to their unique structural features that give rise to a range of biological properties. Here, we report a palladium-catalyzed enantioselective C(sp3)-H arylation of aminomethyl-cyclopropanes and -cyclobutanes with aryl boronic acids. A range of native tertiary alkylamine groups are able to direct C-H cleavage and forge carbon-aryl bonds on the strained cycloalkanes framework as single diastereomers and with excellent enantiomeric ratios. Central to the success of this strategy is the use of a simple N-acetyl amino acid ligand, which not only controls the enantioselectivity but also promotes γ-C-H activation of over other pathways. Computational analysis of the cyclopalladation step provides an understanding of how enantioselective C-H cleavage occurs and revealed distinct transition structures to our previous work on enantioselective desymmetrization of N-isobutyl tertiary alkylamines. This straightforward and operationally simple method simplifies the construction of functionalized aminomethyl-strained cycloalkanes, which we believe will find widespread use in academic and industrial settings relating to the synthesis of biologically active small molecules.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
(A) Selected pharmaceuticals containing cyclobutanes and cyclopropanes. (B) Selected C–H activation reactions on cyclobutanes and cyclopropanes. (C) Pd(II)-catalyzed enantioselective C(sp3)–H arylation of aminomethyl-cyclopropanes and -cyclobutanes directed by unbiased tertiary alkylamine.
Figure 2
Figure 2
Previous work on Pd(II)-catalyzed γ-C(sp3)–H arylation of tertiary alkylamines.
Figure 3
Figure 3
(A) Computational analysis of the enantiodetermining C–H cleavage on aminomethyl-cyclopropanes. Basis set B3LyP-D3(BJ)/[6-311+G(2d,p)/ SDD(Pd)]. (B) Proposed pathway for of aminomethyl-cyclopropanes via Pd(II)-catalyzed enantioselective γ-methylene-C(sp3)–H arylation.
Chart 1
Chart 1. Scope of Enantioselective γ-Methylene C(sp3)–H Arylation of Aminomethyl-cyclopropanes
Scheme 1
Scheme 1. Reaction of Racemic Disubstituted Aminomethyl-cyclopropanes to Form Enantioenriched Trisubstituted Products
Chart 2
Chart 2. (A, B) Scope of Enantioselective γ-Methylene C(sp3)–H Arylation of Aminomethyl-cyclobutanes and (C) Late-Stage Functionalization of Pharmaceutical Agents
Figure 4
Figure 4
Computational analysis of the enantiodetermining C–H cleavage in cyclobutane rings. Basis set B3LyP-D3(BJ)/[6-311+G(2d,p)/ SDD(Pd)].
See this image and copyright information in PMC

References

    1. Talele T. T. The “Cyclopropyl Fragment” is a Versatile Player that Frequently Appears in Precilinal/Clinical Drug Molecules. J. Med. Chem. 2016, 59, 8712–8756. 10.1021/acs.jmedchem.6b00472. - DOI - PubMed
    2. Bauer M. R.; Di Fruscia P.; Lucas S. C. C.; Michaelides I. N.; Nelson J. E.; Storer R. I.; Whitehurst B. C. Put a ring on it: application of small aliphatic rings in medicinal chemistry. RSC Med. Chem. 2021, 12, 448–471. 10.1039/D0MD00370K. - DOI - PMC - PubMed
    1. Hsin L.-W.; Chang L.-T.; Rothman R. B.; Dersch C. M.; Fishback J. A.; Matsumoto R. R. Synthesis and Opioid Activity of Enantiomeric N-Substituted 2,3,4,4a,5,6,7,7a-Octahydro-1H-benzofuro[3,2-e]isoquinolines. J. Med. Chem. 2010, 53, 1392–1396. 10.1021/jm901503e. - DOI - PubMed
    2. Flick A. C.; Ding H. X.; Leverett C. A.; Fink S. J.; O’Donnell C. J. Synthetic Approaches to New Drugs Approved During 2016. J. Med. Chem. 2018, 61, 7004–7031. 10.1021/acs.jmedchem.8b00260. - DOI - PubMed
    3. Domon Y.; Arakawa N.; Inoue T.; Matsuda F.; Takahashi M.; Yamamura N.; Kai K.; Kitano Y. Binding Characteristics and Analgesic Effects of Mirogabalin, a Novel Ligand for the α2δSubunit of Voltage-Gated Calcium Channels. J. Pharmacol. Exp. Ther. 2018, 365, 573–582. 10.1124/jpet.117.247551. - DOI - PubMed
    4. Flick A. C.; Leverett C. A.; Ding H. X.; McInturff E.; Fink S. J.; Mahapatra S.; Carney D. W.; Lindsey E. A.; DeForest J. C.; France S. P.; Berritt S.; Bigi-Botterill S. V.; Gibson T. S.; Liu Y.; O’Donnell C. J. Synthetic Approaches to the New Drugs Approved during 2019. J. Med. Chem. 2021, 64, 3604–3657. 10.1021/acs.jmedchem.1c00208. - DOI - PubMed

    1. For selected reviews of cyclopropanation reactions, see:

    2. Davies H. M. L.; Antoulinakis E. G. Intermolecular Metal-Catalyzed Carbenoid Cyclopropanations. Organic Reactions 2001, 57, 1–326. 10.1002/0471264180.or057.01. - DOI
    3. Bartoli G.; Bencivenni G.; Dalpozzo R. Asymmetric cyclopropanation reactions. Synthesis 2014, 46, 979–1029. 10.1055/s-0033-1340838. - DOI
    4. Ebner C.; Carreira E. M. Cyclopropanation Strategies in Recent Total Syntheses. Chem. Rev. 2017, 117, 11651–11679. 10.1021/acs.chemrev.6b00798. - DOI - PubMed
    5. Wu W.; Lin Z.; Jiang H. Recent Advances in the Synthesis of Cyclopropanes. Org. Biomol. Chem. 2018, 16, 7315–7329. 10.1039/C8OB01187G. - DOI - PubMed
    6. Mato M.; Franchino A.; García-Morales C.; Echavarren A. M. Gold-Catalyzed Synthesis of Small Rings. Chem. Rev. 2021, 121, 8613–8684. 10.1021/acs.chemrev.0c00697. - DOI - PMC - PubMed

    7. For selected recent reviews on cyclobutane synthesis, see:

    8. Poplata S.; Troster A.; Zou Y.-Q.; Bach T. Recent advances in the synthesis of cyclobtanes by olefin [2 + 2] cycloaddition. Chem. Rev. 2016, 116, 9748–9815. 10.1021/acs.chemrev.5b00723. - DOI - PMC - PubMed
    9. Li J.; Gao K.; Bian M.; Ding H. Recent advances in the total synthesis of cyclobutane containing natural products. Org. Chem. Front. 2020, 7, 136–154. 10.1039/C9QO01178A. - DOI
    1. Wasa M.; Engle K. M.; Lin D. W.; Yoo E. J.; Yu J.-Q. Pd(II)-catalyzed Enantioselective C–H Activation of Cyclopropanes. J. Am. Chem. Soc. 2011, 133, 19598–19601. 10.1021/ja207607s. - DOI - PMC - PubMed
    2. Jerhaoui S.; Djukic J.-P.; Wencel-Delord J.; Colobert F. Asymmetric, Nearly Barrierless C(sp3)–H Activation Promoted by Easily-Accessible N-Protected Aminosulfoxides as New Chiral Ligands. ACS Catal. 2019, 9, 2532–2542. 10.1021/acscatal.8b04946. - DOI
    3. Chan K. S. L.; Fu H.-Y.; Yu J.-Q. Palladium(II)-Catalyzed Highly Enantioselective C–H Arylation of Cyclopropylmethyl-amines. J. Am. Chem. Soc. 2015, 137, 2042–2046. 10.1021/ja512529e. - DOI - PMC - PubMed
    4. Shen P.-X.; Hu L.; Shao Q.; Hong K.; Yu J.-Q. Pd(II)-Catalyzed Enantioselective C(sp3)–H Arylation of Free Carboxylic Acids. J. Am. Chem. Soc. 2018, 140, 6545–6549. 10.1021/jacs.8b03509. - DOI - PMC - PubMed
    5. Zhuang Z.; Yu J.-Q. Pd(II)-Catalyzed Enantioselective γ-C(sp3)-H Functionalizations of Free Cyclo-propylmethylamines. J. Am. Chem. Soc. 2020, 142, 12015–12019. 10.1021/jacs.0c04801. - DOI - PMC - PubMed
    1. Saget T.; Cramer N. Palladium(0)-Catalyzed Enantioselective C–H Arylation of Cyclopropanes: Efficient Access to Functionalized Tetrahydroquinolines. Angew. Chem., Int. Ed. 2012, 51, 12842–12845. 10.1002/anie.201207959. - DOI - PubMed
    2. Pedroni J.; Saget T.; Donets P. A.; Cramer N. Enantioselective Palladium(0)-Catalyzed Intramolecular Cyclo-propane Functionalization: Access to Dihydroquinolones. Chem. Sci. 2015, 6, 5164–5171. 10.1039/C5SC01909E. - DOI - PMC - PubMed
    3. Pedroni J.; Cramer N. Chiral γ–Lactams by Enantioselective Palladium(0)-Catalyzed Cyclo-propane Functionalizations. Angew. Chem., Int. Ed. 2015, 54, 11826–11829. 10.1002/anie.201505916. - DOI - PubMed
    4. Mayer C.; Ladd C. L.; Charette A. B. Utilization of BozPhos as an Effective Ligand in Enantioselective C–H Functionalization of Cyclopropanes: Synthesis of Dihydro-isoquinolones and Dihydroquinolones. Org. Lett. 2019, 21, 2639–2644. 10.1021/acs.orglett.9b00627. - DOI - PubMed

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