**1. Introduction**

The Castagnoli–Cushman reaction (CCR) [1] is a remarkably versatile [4 + 2]-type cyclocondensation of a-C-H-acidic cyclic anhydrides **1** with imines **2** leading, depending on the specific anhydride employed [2], to skeletally diverse [3] lactams **3** bearing multiple substituents, which in many cases proceeds in diastereoselective fashion. This reaction is multicomponent in nature because the requisite imine can be generated in situ from the respective amine and aldehyde [4], which makes this reaction particularly suitable for generating compound libraries in array format for drug discovery (Figure 1).

**Figure 1.** The Castagnoli–Cushman reaction.

Considering the fact that the cyclic anhydride (**1**) for the CCR input primarily controls the skeletal nature of the lactam product **3**, involvement of novel anhydrides in the reaction promises to deliver molecular frameworks which are either completely novel [5] or carry unprecedented substitution patterns around known cores.

Homophthalic anhydride (HPA) is one of the most popular and most reactive anhydrides used in the CCR. The reaction with HPA delivers tetrahydroisoquinolones (THIQs) with good control of diastereoselectivity [6–8]. The THIQ scaffold is of undisputable medicinal relevance, as evidenced by various molecular series possessing diverse biological

**Citation:** Moshnenko, N.; Kazantsev, A.; Bakulina, O.; Dar'in, D.; Krasavin, M. The Use of Aryl-Substituted Homophthalic Anhydrides in the Castagnoli–Cushman Reaction Provides Access to Novel Tetrahydroisoquinolone Carboxylic Acid Bearing an All-Carbon Quaternary Stereogenic Center. *Molecules* **2022**, *27*, 8462. https:// doi.org/10.3390/molecules27238462

Academic Editors: Mircea Darabantu, Alison Rinderspacher and Gloria Proni

Received: 22 October 2022 Accepted: 29 November 2022 Published: 2 December 2022

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**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

activities reported in the literature. These can be exemplified by such compounds as adrenocorticotropic hormone receptor modulator **4** [9], apoptosis regulator **5** [10], trypanocidal cysteine protease inhibitor **6** [11], as well as antimalarial **7** [12] (Figure 2).

**Figure 2.** Examples of diversely biologically active tetrahydroisoquinolones.

The peripheral group diversity of HPA has been largely limited to the substitutions in the benzene ring [13], while substitutions at the methylene position remain almost completely unexplored except for methyl- [14,15] and benzyl- [15] substituted variants. We became interested in synthesizing novel HPA versions bearing an aryl group at the methylene linker (**8**) and exploring them as partners in the CCR. Our interest was fueled by the prospect of obtaining, possibly in diastereoselective manner, densely substituted THIQs **9** where the α-position (position 4 of the THIQ scaffold) of the hitherto undescribed carboxylic acid would be an all-carbon stereogenic center (Figure 3). Herein, we present the results obtained in the course of pursuing this goal.

**Figure 3.** (**a**) Traditional CCR of HPA. (**b**) Synthetic goal pursued in this work.
