Sterically Constrained and Encumbered: An Approach to the Naturally Occurring Peptidomimetic Tetrahydropyrazino[1,2‐a]indole‐1,4‐dione Core

Abstract

The combination of two privileged motifs, that is, indoline and the constrained peptidomimetic piperazine‐2,5‐dione, within one tricyclic structure resulted in a scaffold that is abundant in nature but surprisingly scarce in the domain of synthetic bioactive molecules. Utilizing the power of the isocyanide‐based Joullié–Ugi reaction followed by postcondensation cyclization, we synthesized such compounds with four elements of diversity in good yields from readily available precursors. The compounds are constrained peptidomimetics distinctly encumbered in a steric sense and have a pronounced three‐dimensional character, which is a highly desirable feature in modern drug design.

Crystal structure of tert-butyl 4-[4-(4-fluorophenyl)-2-methylbut-3-yn-2-yl]piperazine-1-carboxylate

“…There were only 14 compounds viz. DIYWAK (McDermott et al, 2008), HEHZOL (Legnani et al, 2012), HICYID, HICYOJ (Sinha et al, 2013b), JIFHEO (Zhong et al, 2018), OFUDAW (Korotaev et al, 2012), PUYNUS (Jin & Liebscher, 2002), RIPWUJ (Bobeck et al, 2007), TILJIJ (Sinha et al, 2013a), UPIBIF, UPIBOL (Wiedner & Vedejs, 2010), UYIHOB (Chen & Cao, 2017), WANTAJ (Golubev & Krasavin, 2017), and WINMAH (Brouant & Giorgi, 1995) that were asymmetrically substituted on the piperazine ring, and none with a synthetically useful second nitrogen. All were effectively 'nonintermediate' compounds that could not reasonably serve for additional substitution at the second nitrogen and none had alkyne substitutions.…”

Highly Reactive Cyclic Monoaryl Iodoniums Tuned as Carbene Generators Couple with Nucleophiles under Metal-Free Conditions

“…Meanwhile, the terminal vinyl double bond in 4aa could be used as an acceptor for halogenation ( Meimetis et al., 2014 ; Song et al., 2013 ). Then, NBS was utilized to assemble 2-substituted 3-quaternary carbon-centered indole 6 that is not easily prepared via conventional methods (series 2) ( Golubev and Krasavin, 2017 ). As mentioned earlier, ortho -substituted functional groups in anilines were well tolerated in the amination ( Figure 3 , 4ai-4al).…”

A speedy route to sterically encumbered, benzene-fused derivatives of privileged, naturally occurring hexahydropyrrolo[1,2-b]isoquinoline

“…Investigation of the CCR leading to the formation of 10e undertaken in this work led to a serendipitous important observation that exposure of 9e to an equimolar amount of HPA in acetonitrile at low temperature (5 °C) and higher dilution (two-fold compared to that used throughout this study) over 2 days led to a predominant formation of the respective Mannich adduct 13e which crystallized out as a single diastereomer from the reaction mixture along with syn/anti - 10e mixture and was separated from the latter mechanically under a microscope. Adduct 13e (which has been postulated in the literature as a principal intermediate in the CCR [ 1 , 28 ] but never isolated) was characterized by means of 1 H and 13 C NMR spectroscopy as well as X-ray crystallography. The isolation, for the first time, of the Mannich-type adduct 13 between HPA and an imine clearly attests to the viability of mechanistic pathway (b) shown in Scheme 3 .…”

“…Considering the plethora of biological activities displayed by the lycorine and tylophorine alkaloids (such as pro-apoptotic [ 22 ], antiviral [ 23 ], hypoxia-inducible factor-1 inhibitory [ 24 ]), the scaffold can be confidently regarded as privileged [ 25 ]. Recently, we [ 26 ] and others [ 27 ] reported the use of indolenines as non-classical inputs for the Joullié–Ugi reaction and for subsequent preparation [ 28 ] of sterically encumbered, constrained peptidomimetic frameworks. Diversely substituted indolenines 9 are easy to prepare via the Fischer indole synthesis [ 26 ] and their use in the CCR can be expected to result in hexahydropyrrolo[1,2- b ]isoquinolone derivatives fused with benzene 10 that have pronounced three-dimensional features and potentially contain several quaternary carbon centers ( Fig.…”