Applications of Chiral Three-membered Rings for Total Synthesis: A Review Renato Dalpozzo, Alessandra Lattanzi, Helene Pellissier To cite this version: Renato Dalpozzo, Alessandra Lattanzi, Helene Pellissier. Applications of Chiral Three-membered Rings for Total Synthesis: A Review. Current Organic Chemistry, Bentham Science Publishers, 2017, 21 (13), pp.1143-1191. 10.2174/1385272821666170221151356. hal-01683218 HAL Id: hal-01683218 https://hal.archives-ouvertes.fr/hal-01683218 Submitted on 16 Apr 2018 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Applications of Chiral Three-Membered Rings for Total Synthesis: A Review Renato Dalpozzoa, Alessandra Lattanzib and Hélène Pellissierc* aDipartimento Chimica e Tecnologie Chimiche, Ponte Bucci Cubo 12/c VI piano, 87036 Arcavacata di Rende (Cs), Italy; bUniversità di Salerno, Dipartimento di Chimica e Biologia, Via Giovanni Paolo II, 132, 84084, Fisciano, Italy; cAix Marseille Univ, CNRS, Centrale Marseille, iSm2, Marseille, France Abstract: This review updates recent applications of asymmetric aziridination, azirination, thiirination, epoxi- dation, and cyclopropanation in the total synthesis of biologically active compounds, including natural prod- ucts, using chiral substrates or chiral catalysts, covering the literature since 2000. The interest towards these synthetic methodologies of chiral three-membered rings has increased in the last decade, dictated either by the A R T I C L E H I S T O R Y biological activities that display many naturally occurring products bearing a three-membered unit or by the ring strain of three-membered rings making them useful precursors of many more complex interesting mole- Received: December 16, 2016 Revised: January 25, 2017 cules. Classic as well as modern protocols in asymmetric aziridinations, azirinations, epoxidations, thiirina- Accepted: February 13, 2017 tions, and cyclopropanations have been widely applied as key steps of a number of syntheses of important DOI: products. Although the use of chiral substrates and auxiliaries is still highly employed particularly in asymmet- 10.2174/1385272821666170221151356 ric aziridination and cyclopropanation, the development of enantioselective catalytic methodologies has wit- nessed exponential growth during the last decade. The present review is subdivided into three parts, dealing successively with the use of chiral nitrogen-containing three-membered rings, chiral epoxides and thiiranes, and chiral cyclopropanes in total synthesis. Keywords: Asymmetric synthesis, biological activity, chirality, natural products, strained molecules, total synthesis. 1. INTRODUCTION chiral azirines. The second part of the review is also subdivided into two sections, dealing successively with chiral epoxides and thi- Chiral three-membered rings are useful building blocks in syn- iranes. The third part of the review is subdivided into four sections, thesis, as well as important synthetic targets. The interest towards treating successively asymmetric SimmonsSmith cyclopropana- synthetic methodologies for their preparation has increased in the tions as key steps, asymmetric transition-metal decomposition of last decade, dictated either by the biological activities displayed by diazoalkanes as key steps, asymmetric Michael-initiated ring clo- many naturally occurring products bearing a three-membered unit sures as key steps, and miscellaneous asymmetric cyclopropana- or by being useful precursors for accessing more complex interest- tions as key steps. ing molecules [1]. The goal of the present review is to highlight the major developments and applications in the use of asymmetric three-membered ring formations in total synthesis reported in the 2. CHIRAL NITROGEN-CONTAINING THREE- last fifteen years. It must be noted that a range of reviews, which MEMBERED RINGS IN TOTAL SYNTHESIS will be cited in the respective sections of the present review, have 2.1. Chiral Aziridines been separatively devoted to asymmetric aziridinations, epoxida- Aziridines are among the most fascinating heterocyclic inter- tions, or cyclopropanations [2]. On the other hand, to the best of our mediates in organic synthesis [5], acting as precursors of many knowledge, no previous review compiling all types of chiral three- complex molecules including natural and biologically active prod- membered rings and their synthetic applications exists. In 2000, a ucts due to the high strain incorporated in their skeletons [6]. The book dedicated to cyclopropanes in synthesis was published by de last decade has witnessed tremendous activity in the area of discov- Meijere [3], while a special issue published in Chemical Reviews in ering new methodologies for their synthesis and transformations 2014 was consecrated to small heterocycles in synthesis but did not [7]. This growing interest is related to their striking chemical prop- especially focus on the asymmetric total synthesis of bioactive and erties. The high strain energy associated with the aziridine ring natural products [4]. The present review is subdivided into three enables easy cleavage of the CN bond, leading to a series of im- parts, dealing successively with the use of chiral nitrogen- portant nitrogen-containing products [8]. Obtaining aziridines, es- containing three-membered rings, chiral epoxides and thiiranes, and pecially optically active aziridines, has become of great importance chiral cyclopropanes in total synthesis. The first part is subdivided in organic chemistry for many reasons. These reasons may include into two sections successively devoted to chiral aziridines and the antitumor, antibacterial and other biological properties associ- ated with a great number of aziridine-containing compounds, such as mitomycins, azinomycins, and epothilones [9]. Indeed, as power- *Address correspondence to this author at the Aix Marseille Univ, CNRS, Centrale ful alkylating agents, aziridines have an inherent in vivo potency Marseille, iSm2, Marseille, France; Tel: 33491282765; through their ability to act as DNA cross-linking agents via nucleo- E-mail: [email protected] i-Pr i-Pr N N Ts Cu N i-Pr i-Pr Cl H H H H 2 Br Br N N N OMe N OMe PhI=NTs O O 1 3 52%, > 99% ee O N HO NH H H (+)-agelastatin A Br N NH O Scheme 1. Synthesis of (+)-agelastatin A. O Ses O PhI=NSes N CuOTf M.S./MeCN R R H 4 H R = O, OAc 5a: R = O: 53%, > 99% de 5b:R = -OAc: 45%, > 99% de Scheme 2. Synthesis of a pregnanolone and minaxolone analogue. philic ring opening of the aziridine moiety. Structureactivity rela- ability of olefinic starting materials and the direct nature of such a tionships have identified the aziridine ring is very essential for the process. antitumor activity, and a vast amount of work has concentrated on The nitrene (or nitrenoid) source for this reaction can be gener- synthesizing derivatives of these natural products with increased ated from various methodologies, such as the metal-catalyzed reac- potency. Various antitumor agents related to mitosanes and mito- tion of [N-(p-toluenesulfonyl)imino]aryliodinanes [10]. In 2006, mycins, for example, have been synthesized and demonstrated to Trost and Dong reported a total synthesis of (+)-agelastatin A, pos- possess activity against a variety of cancers. A number of other sessing nanomolar activity against several cancer cell lines, which synthetic chiral aziridines have also been shown to exhibit other was based on the aziridination of chiral piperazinone 1 (Scheme 1) useful biological properties such as enzyme-inhibitory activities. In [11]. This process was performed in the presence of PhI=NTs as the addition to these important biological activities related to the az- nitrene source and a catalytic amount of copper N-heterocyclic iridine unit, these molecules constitute key chiral building blocks carbene complex 2, providing the corresponding aziridine 3 as the for the easy construction of other types of biologically relevant as only detected stereoisomer in 52% yield. This chiral aziridine was well as naturally occuring chiral nitrogen-containing compounds. further converted into the expected (+)-agelastatin A in four sup- Chiral aziridines can be prepared by either asymmetric catalytic plementary steps. This natural product is also known to inhibit gly- methods or from chiral substrates. The main approaches to the syn- cogen synthase kinase-3b, a behaviour that might provide an ap- thesis of chiral aziridines can be classified as asymmetric nitrene proach for the treatment of Alzheimer’s disease. transfer to alkenes, asymmetric carbene transfer to imines such as In 2003, Dauban and Dodd applied the Ses iminoiodane ylide-mediated aziridinations, asymmetric cyclization reactions (PhI=NSes) to the copper-catalyzed aziridination of 11-pregnane through addition/elimination processes such as GabrielCromwell derivatives to prepare chiral 11,12-aziridino analogues of neuroac- reactions, and miscellaneous asymmetric reactions such as in- tive steroids [12]. As shown in Scheme 2, the reaction of chiral 11- tramolecular substitutions [7]. pregnene-3,20-dione