Importance of Catalytic Asymmetric Synthesis of Saturated N-Heterocucles in Chemical Biology and Medicinal Chemistry
Plato A Magriotis*
Corresponding Author: Dr. Plato A Magriotis, Associate Professor, Laboratory of Pharmaceutical Chemistry, Department of Pharmacy, University of Patras, Greece
Received: January 29, 2019; Revised: June 25, 2020; Accepted: February 01, 2019 Available Online: May 27, 2019
Citation: Magriotis PA. (2020) Importance of Catalytic Asymmetric Synthesis of Saturated N-Heterocucles in Chemical Biology and Medicinal Chemistry. J Drug Design Discov Res, 1(1): 1-3.
Copyrights: ©2020 Magriotis PA. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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The important requirement for approval of a new drug, in case it happens to be chiral, that both enantiomers of the drug be studied in detail [1], have focused the attention of synthetic organic and medicinal chemists on the development of new methods for catalytic asymmetric synthesis especially of relevant saturated N-heterocycles. Despite the success of chirally modified transition-metal catalysts in asymmetric synthesis, in the form of the Nobel Prize in Chemistry in 2001, the field of asymmetric organic synthesis has since then been dominated by organocatalysts due to their ability to catalyze a variety of fundamentally important transformations in medicinal chemistry and therefore chemical biology. One example is the Staudinger synthesis of β-lactams representing one class of saturated N-heterocycles and continuing to provide unique opportunities for the discovery of new derivatives with novel pharmacological profiles [2,3]. Specifically, β-lactams have recently been found to have potential as the basis for treatments for neurological disorders including amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease [4]. Although significant progress has been made in asymmetric organocatalytic Staudinger synthesis of β-lactams since the inaugural and pioneering investigations by Lectka and coworkers around the turn of the century [5,6], the same did not hold true regarding the development of a novel Gilman-Speeter process for the catalytic enantioselective synthesis of β-lactams [7]. Efforts directed at this latter goal are ongoing in this Laboratory.

On the other hand, the piperazine ring, besides defining a major class of saturated N-heterocycles, has been classified as a privileged structure in Medicinal Chemistry since it is more than frequently found in biologically active compounds including several marketed blockbuster drugs such as Glivec (Imatinib) and Viagra (Sildenafil) [8,9]. Actually, an analysis of all U.S. FDA approved small molecule drugs found that 21% contained saturated 6-membered N-heterocycles with an additional heteroatom (N, piperazines; O, morpholines; S, thiomorpholines) [10]. Indeed, 13 of the 200 best-selling small molecule drugs in 2012 contain a piperazine ring [11]. In the vast majority of these molecules, however, the piperazine ring is not substituted on any of its carbon atoms. Specifically, analysis of the piperazine substitution pattern reveals a luck of structural diversity, with almost every single drug in this category (83%) containing a substituent at both the N1- and N4-positions compared to only a few drugs having a substituent at any other position (C2, C3, C5 and C6) [11]. Significant chemical space that is closely related to that known to be biologically relevant, therefore, remains unexplored. In order to explore this chemical space, an efficient and enantioselective synthesis of C-substituted piperazines must be designed and developed [12,13]. Efforts toward the implementation of this particular target are ongoing in this Laboratory. It must be emphasized, however, that these latter efforts were initiated by considering a novel retrosynthetic analysis of the unique marine natural product Ecteinascidin-743 (1, Et-743 also known as Trabectidin or Yondelis™, a commercially  available drug against soft-tissue sarcoma), centered at its piperazine ring shown in structure 1 (Figure 1) [14-16].

Since piperazine derivatives have been reported to elicit a broad spectrum of pharmacological activities including antidepressant, anticancer, anti-helminthic, anti-bacterial, antifungal, anti-mycobacterial, anti-malarial, anti-tuberculant, anti-convulsant [8] and anti-AIDS [17]; one can easily comprehend that the sky will be the limit, as far as novel drug development is concerned, once this catalytic enantioselective process will be fully developed [18].

Finally, aziridines are structurally fascinating, pharmaceutically important, and finding applications in synthetic organic and medicinal chemistry [19-20]. Thus, they can be readily converted into a variety of nitrogen-containing compounds due to the inherent reactivity of the constrained three-membered ring present in biologically active natural products such as the azinomycins [21] and the mitomycins [22]. Novel catalytic enantioselective synthesis of aziridines as well as their employment in piperazine syntheses is under active investigation in this Laboratory [23-25].


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