Asymmetric 1,3-Dipolar Cycloadditions of Cyclic Stabilized Ylides Derived from Chiral 1,2-Amino Alcohols Martine Bonin, Laurent Micouin, Ariane Chauveau To cite this version: Martine Bonin, Laurent Micouin, Ariane Chauveau. Asymmetric 1,3-Dipolar Cycloadditions of Cyclic Stabilized Ylides Derived from Chiral 1,2-Amino Alcohols. SYNLETT, Georg Thieme Verlag, 2006, 2006 (15), pp.2349-2363. 10.1055/s-2006-949626. hal-02185347 HAL Id: hal-02185347 https://hal.archives-ouvertes.fr/hal-02185347 Submitted on 16 Jul 2019 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. ACCOUNT 2349 Asymmetric 1,3-Dipolar Cycloadditions of Cyclic Stabilized Ylides Derived from Chiral 1,2-Amino Alcohols AsymmetricMartine 1, 3-Dipolar Cycloadditions Bonin,* Ariane Chauveau, L. Micouin* Laboratoire de Chimie Thérapeutique, UMR 8638 associée au CNRS, Université René Descartes, Faculté des Sciences Pharmaceutiques et Biologiques, 4 av de l’Observatoire, 75270 Paris cedex 06, France Fax +33(1)43291403; E-mail: [email protected]; E-mail: [email protected] Received 2 March 2006 tionalized heterocycles in a very convergent manner with Abstract: The use of structurally similar chiral non-racemic 2 azomethine ylides, nitrones and azomethine imines derived from limited side reactions. 1,2-aminol alcohols in asymmetric dipolar cycloadditions is re- One more advantage of the 1,3-dipolar cycloaddition re- viewed. This general survey underlines the great synthetic potential action is its high stereospecificity, leading to the creation of dipolar cycloadditions, especially in a diversity-oriented ap- of up to four stereocenters in a single operation. Further- proach and enables a direct comparison of the reactivity of appar- ently closely related reactive systems. more, an appropriate set of reaction conditions and re- agents enables, in principle, the tuning of relative 1 Introduction configuration of the final cycloadduct by controlling the 2 Azomethine Ylides reactive configuration of the reaction partners.3 This ste- 2.1 Reactions Involving Ylides Derived from Formaldehyde reochemical diversity is a key element if one wishes to use 2.2 Reactions Involving Ylides Derived from Aliphatic or Aro- asymmetric multicomponent reactions in diversity-orient- matic Aldehydes ed syntheses.4 2.3 Reactions Involving Ylides Derived from Alkyl Glyoxy- lates or Ketones Several parameters are responsible for the stereochemical 2.4 Synthetic Applications outcome of a 1,3-dipolar cycloaddition (Scheme 1). The 3 Nitrones configuration of stereocenters a and c will be determined 3.1 Reactions with Alkenes by the configuration of the reactive dipole [with syn (anti) 3.2 Synthetic Applications 1 2 syn anti 4 Azomethine Imines dipoles leading to R ,R ( ) stereoisomers, respec- 4.1 Ylide Generation tively) as well as the facial selectivity of the reaction. The 4.2 Reactions Involving Ylides Derived from Aliphatic or Aro- relative configuration between stereocenters d and e is de- matic Aldehydes termined by the configuration of the double bond in its re- 4.3 Reactions Involving Ylides Derived from Alkyl Glyoxy- active form, the relative a,d or c,e configurations being lates determined by the facial as well as the endo-exo selectiv- 4.4 Synthetic Applications ities. All these rules, of course, only apply provided that 5 Conclusion the condensation occurs in a concerted manner, delivering Key words: cycloadditions, ylides, stereoselective synthesis, het- a non-epimerizable final cycloadduct. erocycles, multicomponent reactions 1 2 R b – R E,E (syn) ac+ 1 Introduction 2 b – R The power of multicomponent reactions (MCRs) as diver- Z,E (anti ) ac+ R4 R1 b R2 R1 de a c sity-generating processes for the convergent preparation 3 * * of combinatorial libraries of compounds having interest- R de 1 or 3 ** 4 E,Z (anti ) R b 3 4 R R ing chemical, physical, or biological properties is nowa- ac+ – R R 1 1 days widely recognized. In this context, [3+2] R2 de cycloadditions are particularly appealing, for numerous b reasons: they generally combine three widely available – Z,Z (syn) ac+ classes of compounds (i.e. aldehydes, amines and alk- 1 2 enes), with a good functional group tolerance, under ex- R R perimentally simple reaction conditions (generally Scheme 1 General five-membered-ring synthesis by a dipolar [3+2] thermal, aerobic conditions) leading to cyclic rigid func- cycloaddition process. As depicted in Scheme 1, a mixture of stereoisomers can be expected from a cycloaddition based on configuration- SYNLETT 2006, No. 15, pp 2349–2363 18.09.2006 ally labile dipoles, unless an efficient dynamic resolution Advanced online publication: 08.09.2006 can occur. The incorporation of the a–b or b–c bond of the DOI: 10.1055/s-2006-949626; Art ID: A41606ST © Georg Thieme Verlag Stuttgart · New York 2350 M. Bonin et al. ACCOUNT ylide into a cyclic, rigid element has therefore been pro- use of chiral 1,2-amino alcohols, and more particularly posed in order to increase rotational barriers in these reac- phenylglycinol, as a chiral element in three closely-related tive species. Furthermore, the use of a chiral tether in such cyclic ylides will be discussed. a strategy should enable the control of the facial selectiv- ity, leading to the control of the relative and absolute con- figuration of centers a and c of 1. 2 Azomethine Ylides In a general research project on the use of cyclic hydra- zines for the synthesis of polyfunctional amines,5 we were Although the use of chiral non-racemic morpholinones in asymmetric transformations had been described since the particularly interested by works reporting stereoselective 8 dipolar cycloadditions of azomethine ylides6 and nitrones7 late sixties, the first examples of stereoselective cycload- using similar cyclic templates derived from a common ditions of templated azomethine ylides derived from mor- pholinones were reported by the groups of L. M. morpholinone (Figure 1). The apparent excellent facial 9a 10 selectivities prompted us to investigate such cyclic pre- Harwood and R. M. Williams in the early 1990s. cursors in the azomethine imine series. In this account the 2.1 Reactions Involving Ylides Derived from O O X O O O O Formaldehyde N – – Ph N+ 2.1.1 Ylide Generation Ph N+ Ph N + O – R1 R1 Ylides are typically generated by condensation of the morpholinones 5–7 with an excess of paraformaldehyde Figure 1 Cyclic amino alcohol derived azomethine ylide, nitrones under thermal activation in the presence of molecular and azomethine imines. Biographical Sketches Martine Bonin was born in son’s group (1983), she on the development of new 1957. She trained as a phar- began collaboration with diastereoselective routes macist in the University of Dr. J.-C. Quirion on amino- giving access to polyfunc- Bordeaux (1979), and ob- nitrile and oxazolidine syn- tional nitrogen derivatives tained her PhD in Chemistry thons and followed that with for medicinal or pharmaco- from the University of Par- a one-year postdoc in Orsay logical applications. She is-Sud (Orsay) in 1986 on (Drs. G. Balavoine and F. then took a project manager the total synthesis of piperi- Guibe, organometallic and position at the INTAS orga- dine alkaloids. Enlisted as radical chemistry, 1992). nization in Brussels in 2004. researcher in CNRS in Pro- From 1998, she worked fessor Henri-Philippe Hus- with Dr. Laurent Micouin Ariane Chauveau was born tionale Supérieure de Chi- 1999. She obtained her PhD in 1977. She was trained as mie de Paris and received on azomethine imine cyclo- a chemist at the Ecole Na- her engineer diploma in additions reactions in 2003. Laurent Micouin was born fessor J.-C. Quirion in 1995. Directeur de Recherche. His in Clermont Ferrand in After a postdoctoral stay in scientific interests include 1968. He studied at the Marburg (Germany) as a the development of new Ecole Nationale Supérieure Humboldt Fellow under the methods in the field of de Chimie de Paris, where direction of Professor Paul asymmetric synthesis of ni- he obtained an engineer di- Knochel, he got a perma- trogen compounds, organo- ploma in 1990. He obtained nent position in CNRS in aluminum chemistry, as his PhD in the laboratory of 1996 and returned to Paris well as the development of Professor Henri-Philippe (Faculty of Pharmacy, Paris new tools in the field of Husson (University Paris V) V) as Chargé de Recherche, fragment-based approach under the guidance of Pro- and, since October 2005, as for the discovery of bioac- tive compounds. Synlett 2006, No. 15, 2349–2363 © Thieme Stuttgart · New York ACCOUNT Asymmetric 1,3-Dipolar Cycloadditions 2351 sieves,9a,b or in the presence of a catalytic amount of p-tol- In all the cases, complete facial selectivity has been ob- uenesulfonic acid at room temperature over extended pe- served, and the endo cycloadduct was isolated as a major riods.10a Due to their high reactivity, these species are diastereomer under thermal activation. When conducted trapped in situ by the dipolarophiles, generally used in ex- in the presence of MgBr2·OEt2, the cycloaddition led to cess. Another procedure involves the use of stable precur- the exo adduct as either the major product (entries 4 and sors, such as alkoxy amines 2–4,10a hemi-aminal 811 or 11) or almost exclusively (entries 5 and 8). All the reac- aminobenzotriazole 9 derivatives,12 which can regenerate tions performed on acyclic dipolarophiles were fully ste- the ylide under acidic or thermal conditions (Scheme 2).