Recent Progress Toward the Asymmetric Synthesis of Carbon-Substituted Piperazine Pharmacophores and Oxidative Related Heterocycles RSC Medicinal Chemistry
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Volume 11 Number 7 July 2020 RSC Pages 735–850 Medicinal Chemistry rsc.li/medchem ISSN 2632-8682 REVIEW ARTICLE Plato A. Magriotis Recent progress toward the asymmetric synthesis of carbon-substituted piperazine pharmacophores and oxidative related heterocycles RSC Medicinal Chemistry View Article Online REVIEW View Journal | View Issue Recent progress toward the asymmetric synthesis Cite this: RSC Med. Chem.,2020,11, of carbon-substituted piperazine pharmacophores 745 and oxidative related heterocycles Plato A. Magriotis † The important requirement for approval of a new drug, in case it happens to be chiral, is that both enantiomers of the drug should be studied in detail, which has led synthetic organic and medicinal chemists to focus their attention on the development of new methods for asymmetric synthesis especially of relevant saturated N-heterocycles. 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). Indeed, 13 of the 200 best-selling small molecule drugs in 2012 contained a piperazine ring. Nevertheless, analysis of the piperazine substitution pattern reveals a lack Creative Commons Attribution 3.0 Unported Licence. of structural diversity, with almost every single drug in this category (83%) containing a substituent at both Received 16th February 2020, the N1- and N4-positions compared to a few drugs having a substituent at any other position (C2, C3, C5, Accepted 27th April 2020 and C6). Significant chemical space that is closely related to that known to be biologically relevant, therefore, remains unexplored. In order to explore this chemical space, efficient and asymmetric syntheses DOI: 10.1039/d0md00053a of carbon-substituted piperazines and related heterocycles must be designed and developed. Initial, recent rsc.li/medchem efforts toward the implementation of this particular target are in fact the subject of this review. This article is licensed under a Department of Pharmacy, Laboratory of Medicinal Chemistry, University of Patras, Introduction Rio26504, Greece. E-mail: [email protected] † This review is dedicated to Professor Francis Johnson (Stony Brook University) Heterocyclic small molecules are of exceedingly high on the occasion of his ninetieth birthday and in acknowledgement of his importance in medicinal chemistry and drug discovery. Open Access Article. Published on 22 May 2020. Downloaded 9/29/2021 10:42:44 PM. immense contributions to Medicinal Chemistry. Recently, the focus has shifted from purely aromatic N-heterocycles to substituted saturated N-heterocycles that have been indicated as the most valuable scaffolds for the Since 2006, Plato A. Magriotis, development of new pharmaceuticals.1 Naturally, the latter Ph.D., has been an Associate entail a higher number of stereogenic centers. Consequently, Professor of Medicinal Chemistry new methods that allow practical access to these scaffolds in the Department of Pharmacy with both absolute and relative stereocontrol are of very high at the University of Patras in and continuous interest. Furthermore, the important Greece and a Research Affiliate requirement for approval of a new drug, in case it happens to with the Department of Chemistry be chiral, is that both enantiomers of the drug should be at New York University. Magriotis studied in detail,2 which has led synthetic organic and received his Ph.D. in Chemical medicinal chemists to focus their attention on the Biology with Professor Francis development of new methods for asymmetric syntheses Johnson at Stony Brook University especially of relevant saturated N-heterocycles. in 1983 and did postdoctoral On the other hand, the piperazine ring, besides defining a Plato A. Magriotis work at Harvard University with major class of saturated N-heterocycles, has been classified Nobel Laureate Professor E. J. as a privileged structure in medicinal chemistry,3 since it is Corey. His career started at West Virginia University and continued more than frequently found in biologically active compounds at Merck & Co. as well as New York University in the U.S., prior to including several marketed blockbuster drugs such as Glivec his return to Greece. Magriotis' research program focuses on the (imatinib) and Viagra (sildenafil).4 Actually, an analysis of all development of new methodology for the synthesis of relevant U.S. FDA approved small molecule drugs found that 21% pharmacophores applied in drug discovery. contained saturated 6-membered N-heterocycles with an This journal is © The Royal Society of Chemistry 2020 RSC Med. Chem.,2020,11,745–759 | 745 View Article Online Review RSC Medicinal Chemistry additional heteroatom (N, piperazines; O, morpholines; S, cytotoxicity activities against several rodent tumors and 5 – thiomorpholines). Indeed, 13 of the 200 best-selling small human tumor xenografts with in vitro IC50 values in the 0.1 1 − molecule drugs in 2012 contain a piperazine ring.6 In the vast ng mL 1 range.13 The complex molecular architecture, the majority of these molecules, however, the piperazine ring is remarkable biological activity, and the restricted natural not substituted on any of its carbon atoms. Specifically, availability (1.0 g from about 1.0 ton of tunicate) made Et-743 analysis of the piperazine substitution pattern reveals a lack an exceedingly attractive target for total synthesis, and eight of structural diversity, with almost every single drug in this synthetic approaches to the stereochemically complex category (83%) containing a substituent at both the N1- and antitumor drug Et-743 completed between 1996 and 2015 N4-positions compared to a few drugs having a substituent at have been reviewed.13b,14 Additionally, a convergent formal any other position (C2, C3, C5, and C6).5 synthesis and a scalable total synthesis of Et-743 appeared in Significant chemical space that is closely related to that the literature in 2019.15 2-Oxopiperazines (piperazinones) and known to be biologically relevant, therefore, remains 2,5-diketopiperazines are heterocycles related to piperazine by unexplored. In order to explore this chemical space, efficient oxidation and they themselves represent key structural units and asymmetric syntheses of carbon-substituted piperazines of a great number of natural products such as agelastatins 4,5 and related heterocycles must be designed and developed. (7–10), pseudotheonamide A1 (11), and epicoccin G (12), as Initial, recent efforts toward the implementation of this well as haematocin (13), respectively (Fig. 2).16 particular target are in fact the subject of this review since recent, elegant racemic approaches to piperazine synthesis have been properly reviewed.7 Catalytic asymmetric syntheses of Since piperazine derivatives have been reported to elicit a carbon-substituted piperazines and broad spectrum of pharmacological activities including related heterocycles antidepressant, anticancer, anthelmintic, antibacterial, A. Catalytic enantioselective approaches Creative Commons Attribution 3.0 Unported Licence. antifungal, antimycobacterial, antimalarial, antituberculant, anticonvulsant,4a and anti-AIDS,8 one can easily comprehend Interestingly, SAR studies on piperazinone derivatives as a that the sky will be the limit, as far as novel drug novel class of potent HCV NS4B inhibitors have been development is concerned, once asymmetric syntheses of this reported,17 and a catalytic enantioselective synthesis of substituted heterocycle will be fully developed.4,9 Importantly, piperazinones from aldehydes was recently reported, marine bis-tetrahydroisoquinoline alkaloids, including entailing a four-step reaction sequence, not requiring any ecteinascidins (1 and 2), renieramycins (3 and 4), and intermediate purification, and employing MacMillan's third- saframycins (5 and 6, Fig. 1), besides sharing a densely generation catalyst 14 and chloroquinone as the chlorinating functionalized common pentacyclic scaffold (A–E rings), they reagent.18 Accordingly, mild catalytic asymmetric This article is licensed under a also feature a central C-polysubstituted piperazine as in the α-chlorination of heptanal was coupled with Pinnick ecteinascidins (1 and 2, Fig. 1, ring C). oxidation leading to homochiral α-chloroheptanoic acid 15. Significantly, the unique marine natural product Nucleophilic substitution of the latter by N,N′- Open Access Article. Published on 22 May 2020. Downloaded 9/29/2021 10:42:44 PM. ecteinascidin-743 (1, Et-743 also known as trabectedin or dibenzylethylenediamine (16) furnished the desired protected Yondelis™), isolated from the Caribbean tunicate 2-oxopiperazine 17 in good overall yield under specific Ecteinascidia turbinate,10 is a commercially available drug conditions (Scheme 1). against soft-tissue sarcoma approved by the European A few years prior to this advance, a general, Commission (EMEA) in 200711 and the U.S. Food and Drug enantioselective synthesis of protected morpholines and Administration (FDA) in 2015,12 and is also undergoing piperazines was disclosed by Lindsley and O'Reilly based on clinical trials for breast, prostate, ovarian, and pediatric Jørgensen's catalytic enantioselective α-chlorination of sarcomas in other countries, due to its extraordinarily potent aldehydes followed by reduction to their corresponding Fig. 1 Marine bistetrahydroisoquinoline