Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Oct 8;10(46):10716-10722.
doi: 10.1039/c9sc03790j. eCollection 2019 Dec 14.

Synthesis of bicyclo[3.1.0]hexanes by (3 + 2) annulation of cyclopropenes with aminocyclopropanes

Bastian Muriel  1 , Alec Gagnebin  1 , Jerome Waser  1
Affiliations

Synthesis of bicyclo[3.1.0]hexanes by (3 + 2) annulation of cyclopropenes with aminocyclopropanes

Bastian Muriel et al. Chem Sci. .

Abstract

We report the convergent synthesis of bicyclo[3.1.0]hexanes possessing an all-carbon quaternary center via a (3 + 2) annulation of cyclopropenes with cyclopropylanilines. Using an organic or an iridium photoredox catalyst and blue LED irradiation, good yields were obtained for a broad range of cyclopropene and cyclopropylaniline derivatives. The reaction was highly diastereoselective when using difluorocyclopropenes together with a removable substituent on the cyclopropylaniline, giving access to important building blocks for medicinal chemistry. With efficient methods existing for the synthesis of both reaction partners, our method grants a fast access to highly valuable bicyclic scaffolds with three contiguous stereocenters.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1. Natural products and synthetic bioactive compounds containing the bicyclo[3.1.0]hexane scaffold.
Scheme 1
Scheme 1. Synthesis of bicyclo[3.1.0]hexanes. (A) Synthetic strategies towards bicyclo[3.1.0]hexanes. (B) (3 + 2) cycloaddition to access hetero bicyclo[3.1.0]hexanes from cyclopropenes. (C) Reported syntheses of bicyclo[3.1.0]hexanes from cyclopropenes. (D) This work: (3 + 2) annulation of aminocyclopropanes and cyclopropenes).
Scheme 2
Scheme 2. First attempts of (3 + 2) annulation.
Scheme 3
Scheme 3. Scope of the (3 + 2) annulation. Reaction conditions: cyclopropene (1.0 equiv., 0.3 mmol), 4DPAIPN (5 mol%) and cyclopropylaniline (1.8 equiv.) in CH3NO2 (0.4 M) at rt. Isolated yields are given. dr determined by 1H NMR of the crude products. (A) Scope of substituents R1 on cyclopropene. (B) Scope of substituents R2 on cyclopropene. (C) Scope of aryl substituents on cyclopropylamine.
Scheme 4
Scheme 4. Diastereoselective (3 + 2) cycloaddition with difluoro-cyclopropenes. Reaction conditions: difluorocyclopropene (1.0 equiv., 0.30 mmol), [Ir(dtbbpy)(ppy)2]PF6 (5 mol%) and N-cyclopropyl-4-methoxy-2,6-dimethylaniline (37) (2.5 equiv.) in CH3NO2 (0.4 M) at rt. Isolated yields are given. The dr was determined by 19F NMR spectroscopy of the crude products.
Scheme 5
Scheme 5. Gram-scale (3 + 2) annulation and product modifications. (A) Removal of PMP-derived protecting group and further functionalization of 47. (B) Gram-scale reaction and divergent reactivity of 10a and 10b. (C) Acetal deprotection/Favorskii rearrangement/elimination.
See this image and copyright information in PMC

References

    1. Kim H. S., Ohno M., Xu B., Kim H. O., Choi Y. S., Ji X. D., Maddileti S., Marquez V. E., Harden T. K., Jacobson K. A. J. Med. Chem. 2003;46:4974. - PMC - PubMed
    2. Parks J., Gyeltshen T., Prachyawarakorn V., Mahidol C., Ruchirawat S., Kittakoop P. J. Nat. Prod. 2010;73:992. - PubMed
    3. Boatman P. D., Lauring B., Schrader T. O., Kasem M., Johnson B. R., Skinner P., Jung J. K., Xu J., Cherrier M. C., Webb P. J., Semple G., Sage C. R., Knudsen J., Chen R., Luo W. L., Caro L., Cote J., Lai E., Wagner J., Taggart A. K., Carballo-Jane E., Hammond M., Colletti S. L., Tata J. R., Connolly D. T., Waters M. G., Richman J. G. J. Med. Chem. 2012;55:3644. - PubMed
    4. Liu M. L., Duan Y. H., Hou Y. L., Li C., Gao H., Dai Y., Yao X. S. Org. Lett. 2013;15:1000. - PubMed
    1. Fenical W., Sims J. J. Tetrahedron Lett. 1974;15:1137.
    2. Ireland C., Faulkner J. Tetrahedron. 1981;37:233.
    3. Garcia-Davis S., Viveros-Valdez E., Diaz-Marrero A. R., Fernández J. J., Valencia-Mercado D., Esquivel-Hernández O., Carranza-Rosales P., Carranza-Torres I. E., Guzman-Delgado N. E. Mar. Drugs. 2019;17:201. - PMC - PubMed
    1. Monn J. A., Valli M. J., Massey S. M., Wright R. A., Salhoff C. R., Johnson B. G., Howe T., Alt C. A., Rhodes G. A., Robey R. L., Griffey K. R., Tizzano J. P., Kallman M. J., Helton D. R., Schoepp D. D. J. Med. Chem. 1997;40:528. - PubMed
    1. Csuk R., Heinold A., Siewert B., Schwarz S., Barthel A., Kluge R., Ströhl D. Arch. Pharm. 2012;345:215. - PubMed
    1. Wang Z., Silverman R. B. Bioorg. Med. Chem. 2006;14:2242. - PubMed