Construction of Spiro[3-azabicyclo[3.1.0]hexanes] via 1,3-Dipolar Cycloaddition of 1,2-Diphenylcyclopropenes to Ninhydrin-Derived Azomethine Ylides

Siqi Wang; Alexander S. Filatov; Stanislav V. Lozovskiy; Stanislav V. Shmakov; Olesya V. Khoroshilova; Anna G. Larina; Stanislav I. Selivanov; Vitali M. Boitsov; Alexander V. Stepakov

doi:10.1055/a-1360-9716

Synthesis, Inhaltsverzeichnis

Synthesis 2021; 53(12): 2114-2132
DOI: 10.1055/a-1360-9716

paper

Construction of Spiro[3-azabicyclo[3.1.0]hexanes] via 1,3-Dipolar Cycloaddition of 1,2-Diphenylcyclopropenes to Ninhydrin-Derived Azomethine Ylides

Siqi Wang

^aSaint Petersburg State University, Universitetskaya nab. 7/9, 199034 St. Petersburg, Russian Federation

,

Alexander S. Filatov

^aSaint Petersburg State University, Universitetskaya nab. 7/9, 199034 St. Petersburg, Russian Federation

,

Stanislav V. Lozovskiy

^aSaint Petersburg State University, Universitetskaya nab. 7/9, 199034 St. Petersburg, Russian Federation

,

Stanislav V. Shmakov

^bSaint Petersburg Academic University Nanotechnology Research and Education Centre RAS, ul. Khlopina 8/3, 194021 St. Petersburg, Russian Federation

,

Olesya V. Khoroshilova

^aSaint Petersburg State University, Universitetskaya nab. 7/9, 199034 St. Petersburg, Russian Federation

,

Anna G. Larina

^aSaint Petersburg State University, Universitetskaya nab. 7/9, 199034 St. Petersburg, Russian Federation

,

Stanislav I. Selivanov

^aSaint Petersburg State University, Universitetskaya nab. 7/9, 199034 St. Petersburg, Russian Federation

,

Vitali M. Boitsov∗

^bSaint Petersburg Academic University Nanotechnology Research and Education Centre RAS, ul. Khlopina 8/3, 194021 St. Petersburg, Russian Federation

^cPavlov First Saint Petersburg State Medical University, ul. L’va Tolstogo 6/8, 197022 St. Petersburg, Russian Federation

,

Alexander V. Stepakov∗

^aSaint Petersburg State University, Universitetskaya nab. 7/9, 199034 St. Petersburg, Russian Federation

^dSaint Petersburg State Institute of Technology, Moskovskii pr. 26, 190013 St. Petersburg, Russian Federation

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Abstract

Alle Artikel dieser Rubrik

Dedicated to the memory of Dr. Yuri B. Koptelov

Abstract

The multi-component 1,3-dipolar cycloaddition of ninhydrin, α-amino acids (or peptides), and cyclopropenes for the synthesis of spirocyclic heterocycles containing both 3-azabicyclo[3.1.0]hexane and 2H-indene-1,3-dione motifs has been developed. This method provides easy access to 3-azabicyclo[3.1.0]hexane-2,2′-indenes with complete stereoselectivity and a high degree of atom economy under mild reaction conditions. A broad range of cyclopropenes and α-amino acids have been found to be compatible with the present protocol, which offers an opportunity to create a new library of biologically significant scaffold (3-azabicyclo[3.1.0]hexane). In addition, the сomprehensive study of mechanism of azomethine ylide formation from ninhydrin and sarcosine was performed by means of M11 density functional theory (DFT) calculations. It has been revealed that experimentally observed 1-methylspiro[aziridine-2,2′-indene]-1′,3′-dione is a kinetically controlled product of this reaction and appears to act as a 1,3-dipole precursor. This theoretical study also shed light on the main transformations of the azomethine ylide derived from ninhydrin and sarcosine such as a 1,3-dipolar cycloaddition to cyclopropene dipolarophiles, a dimerization reaction and a (1+5) electrocyclization reaction. The antitumor activity of some synthesized compounds against cervical carcinoma (HeLa) cell line was evaluated in vitro by MTS-assay.

Key words

cyclopropenes - α-amino acids - peptides - stereoselectivity - reaction mechanism - DFT calculations - antitumor activity - cervical carcinoma (HeLa) cell line

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