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
. 2023 Mar 14;14(15):4134-4142.
doi: 10.1039/d3sc00118k. eCollection 2023 Apr 12.

Enantio- and diastereodivergent synthesis of fused indolizines enabled by synergistic Cu/Ir catalysis

Bing-Ke Zhu  1   2 , Hui Xu  3 , Lu Xiao  1 , Xin Chang  1 , Liang Wei  1 , Huailong Teng  4 , Yanfeng Dang  3 , Xiu-Qin Dong  1 , Chun-Jiang Wang  1   2
Affiliations

Enantio- and diastereodivergent synthesis of fused indolizines enabled by synergistic Cu/Ir catalysis

Bing-Ke Zhu et al. Chem Sci. .

Abstract

Highly diastereo-/enantioselective assembly of 2,3-fused indolizine derivatives could be easily available through a cascade allylation/Friedel-Crafts type reaction enabled by a synergistic Cu/Ir catalysis. This designed protocol provides an unprecedented and facile route to enantioenriched indolizines bearing three stereogenic centers in moderate to high yields with excellent stereoselective control, which also featured broad substrate generality. Remarkably, four stereoisomers of the 2,3-fused indolizine products could be efficiently constructed in a predictable manner through the pairwise combination of copper and iridium catalysts. The synthetic utility of this method was readily elaborated by a gram-scale reaction, and synthetic transformations to other important chiral indolizine derivatives. Quantum mechanical explorations constructed a plausible synergetic catalytic cycle, revealed the origins of stereodivergence, and rationalized the protonation-stimulated stereoselective Friedel-Crafts type cyclization to form the indolizine products.

PubMed Disclaimer

Conflict of interest statement

There are no conflicts to declare.

Figures

Fig. 1
Fig. 1. Examples of bioactive compounds and organic fluorophores bearing indolizine heterocycles.
Scheme 1
Scheme 1. Catalytic asymmetric synthesis of chiral indolizine derivatives.
Scheme 2
Scheme 2. Scale-up experiments and synthetic elaborations. Reaction conditions: (a) POCl3, DMF, 0 °C; (b) Pd(OAc)2 (1 mol%), CH2N2 Et2O, −20 °C; (c) Pd/C, H2, rt; (d) [Ir(COD)Cl]2 (5 mol%), dppm (10 mol%), HBpin, DCM, rt.
Fig. 2
Fig. 2. (A) In situ generation and the structures of diastereomeric prochiral nucleophiles IM1 and IM1′. (B) The generation of π-allyliridium(iii) species IM4 and IM4′via oxidative addition. Free energies are given in kcal mol−1.
Fig. 3
Fig. 3. Mechanism for the allylation of Cu(i)-azomethine ylide IM1 by allyliridium(iii) IM4, and the key structures of bond-forming transition states. Free energies are given in kcal mol−1 (energy zero: IM1 and IM4), and selected distances are shown in Å.
Fig. 4
Fig. 4. Free energy profile for Friedel–Crafts type cyclization leading to the indolizine product 3a.
Scheme 3
Scheme 3. Catalytic cycle for the cascade allylation/Friedel–Crafts type reaction via synergistic Cu/Ir catalysis.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Lovering F. Bikker J. Humblet C. J. Med. Chem. 2009;52:6752–6756. doi: 10.1021/jm901241e. - DOI - PubMed
    1. Sharma V. Kumar V. Med. Chem. Res. 2014;23:3593–3606. doi: 10.1007/s00044-014-0940-1. - DOI - PMC - PubMed
    2. Gundersen L.-L. Negussie A. H. Rise F. Østby O. B. Arch. Pharm. 2003;336:191–195. doi: 10.1002/ardp.200390019. - DOI - PubMed
    3. Bedjeguelal K. Bienaymé H. Dumoulin A. Poigny S. Schmitt P. Tam E. Bioorg. Med. Chem. Lett. 2006;16:3998–4001. doi: 10.1016/j.bmcl.2006.05.014. - DOI - PubMed
    4. James D. A. Koya K. Li H. Chen S. Xia Z. Ying W. Wu Y. Sun L. Bioorg. Med. Chem. Lett. 2006;16:5164–5168. doi: 10.1016/j.bmcl.2006.07.020. - DOI - PubMed
    5. Xue Y. Tang J. Ma X. Li Q. Xie B. Hao Y. Jin H. Wang K. Zhang G. Zhang L. Zhang L. Eur. J. Med. Chem. 2016;115:94–108. doi: 10.1016/j.ejmech.2016.03.016. - DOI - PubMed
    6. Park S. Kim E. H. Kim J. Kim S. H. Kim I. Eur. J. Med. Chem. 2018;144:435–443. doi: 10.1016/j.ejmech.2017.12.056. - DOI - PubMed
    1. Kim E. Lee Y. Lee S. Park S. B. Acc. Chem. Res. 2015;48:538–547. doi: 10.1021/ar500370v. - DOI - PubMed
    2. Kim E. Koh M. Ryu J. Park S. B. J. Am. Chem. Soc. 2008;130:12206–12207. doi: 10.1021/ja8020268. - DOI - PubMed
    3. Li J. Zhang S. Zou H. Org. Chem. Front. 2020;7:1218–1223. doi: 10.1039/D0QO00274G. - DOI
    4. Meador W. E. Autry S. A. Bessetti R. N. Gayton J. N. Flynt A. S. Hammer N. I. Delcamp J. H. J. Org. Chem. 2020;85:4089–4095. doi: 10.1021/acs.joc.9b03108. - DOI - PMC - PubMed
    1. Ratmanova N. K. Andreev I. A. Leontiev A. V. Momotova D. Novoselov A. M. Ivanova O. A. Trushkov I. V. Tetrahedron. 2020;76:131031. doi: 10.1016/j.tet.2020.131031. - DOI
    1. Singh G. S. Mmatli E. E. Eur. J. Med. Chem. 2011;46:5237–5257. doi: 10.1016/j.ejmech.2011.08.042. - DOI - PubMed
    2. Dong S. Fu X. Xu X. Asian J. Org. Chem. 2020;9:1133–1143. doi: 10.1002/ajoc.202000276. - DOI
    3. Khan I. Ibrar A. Zaib S. Top. Curr. Chem. 2021;379:3. doi: 10.1007/s41061-020-00316-4. - DOI - PubMed
    4. Neto J. S. S. Zeni G. Asian J. Org. Chem. 2021;10:1282–1318. doi: 10.1002/ajoc.202100013. - DOI