Synthesis of New Functionally Substituted 9-Azabicyclo[4.2.1]nona-2,4,7-trienes by Cobalt(I)-Catalyzed [6π + 2π]-Cycloaddition of N-Carbocholesteroxyazepine to Alkynes

Abstract

Catalytic [6π + 2π]-cycloaddition of N-carbocholesteroxyazepine with functionally substituted terminal alkynes and 1,4-butynediol was performed for the first time under the action of the Co(acac)2(dppe)/Zn/ZnI2 three-component catalytic system. The reaction gave previously undescribed but promising 9-azabicyclo[4.2.1]nona-2,4,7-trienes (in 79–95% yields), covalently bound to a natural metabolite, cholesterol. The structure of the synthesized azabicycles was confirmed by analysis of one- and two-dimensional (1H, 13C, DEPT 13C, COSY, NOESY, HSQC, HMBC) NMR spectra.

Cobalt(I)-Catalyzed [6π + 2π] Cycloaddition of 1,2-Dienes and 1,3-Diynes to N-Carbocholesteroxyazepine in the Synthesis of Previously Undescribed Heterofunctional 9-Azabicyclo[4.2.1]nonadi(tri)enes

“…In this case, both rotamers of cycloadducts 3a,c−e are characterized by the (E)-configuration of the exocyclic C(7)− C (10) double bond, as confirmed by the presence of crosspeaks between the methylene protons H 2 C( 8) and H 2 C(11) in the NOESY spectra (Figure 2).…”

“…synthesized according to reported procedures. 10 1,2-Dienes, 1,3-diynes, and Co(acac) 2 (dppe) were synthesized according to procedures described in the literature. 13 Cycloaddition of 1,2-Dienes and 1,3-Diynes to N-Carbocholesteroxyazepine (General Reaction Procedure).…”

“…Initially, we have found that [6π + 2π] cycloaddition of terminal 1,2-dienes 2a–e (including functionally substituted ones) to N -carbocholesteroxyazepine 1 under the action of the three-component catalytic system Co­(acac) 2 (dppe)/Zn/ZnI 2 , under the developed conditions (10 mol % Co­(acac) 2 (dppe), 30 mol % Zn, 20 mol % ZnI 2 , DCE (1,2-dichloroethane), 20 h, 60 °C), proceeds to produce substituted ( E )-9-azabicyclo­[4.2.1]­nona-2,4-dienes 3a–e in 79–92% yields. A double set of signals in a 1:1 ratio corresponding to two N–(CO)­O–cholesteryl rotamers are registered in the ( 1 H and 13 C) NMR spectra of cycloadducts 3a–e , emerging as a result of limited rotation of the substituents around the C–N bond ,,, (Table ).…”

“…All reactions were carried out under a dry argon atmosphere. N -Carbocholesteroxyazepine was synthesized according to reported procedures . 1,2-Dienes, 1,3-diynes, and Co­(acac) 2 (dppe) were synthesized according to procedures described in the literature …”

“…In the development of advanced research in the chemistry of 9-azabicyclo[4.2.1]­nonanes, we have recently synthesized for the first time N -carbocholesteroxyazepine in order to obtain on its basis novel 9-azabicyclo[4.2.1]­nonadi­(tri)­enes containing a fragment of the cholesterol molecule, an important natural steroid (Scheme ). It should be noted that cholesterol performs a wide range of key functions in the body: it opens the biosynthetic chain of steroid hormones and corticosteroids and serves as the basis for the formation of bile acids and D vitamins, including the presence in the cell membranes, ensuring their stability .…”