Catalytic Enantioselective Desymmetrization of Meso Compounds in Total Synthesis of Natural Products: Towards an Economy of Chiral Reagents Jérémy Mérad, Mathieu Candy, Jean-Marc Pons, Cyril Bressy To cite this version: Jérémy Mérad, Mathieu Candy, Jean-Marc Pons, Cyril Bressy. Catalytic Enantioselective Desym- metrization of Meso Compounds in Total Synthesis of Natural Products: Towards an Economy of Chiral Reagents. SYNTHESIS, Georg Thieme Verlag, 2017, 49 (09), pp.1938-1954. 10.1055/s-0036- 1589493. hal-01687264 HAL Id: hal-01687264 https://hal.archives-ouvertes.fr/hal-01687264 Submitted on 18 Jan 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. SYNTHESIS0039-78811437-210X © Georg Thieme Verlag Stuttgart · New York 2017, 49, 1938–1954 1938 short review Syn thesis J. Merad et al. Short Review Catalytic Enantioselective Desymmetrization of Meso Compounds in Total Synthesis of Natural Products: Towards an Economy of Chiral ReaGents OH Jérémy Merad1 HO O Me Mathieu Candy O O Me O Jean-Marc Pons O ( )8 O ( )9 N H H H H Cyril Bressy* MeO Me HO OH O OMe Aix Marseille Univ, CNRS, Centrale Marseille, iSm2, Catalytic Marseille, France Detection of Hidden Economy of Enantioselective Desymmetrization of [email protected] Symmetry Strategy Chiral Reagents Meso Compounds Me In memory of our friend and colleague, Professor MeO2C Me Teodor Silviu Balaban Me O Me OMe OMe Me H Me H2N N H N Me Me H Me OHC O Received: 20.02.2017 1 Introduction Accepted: 28.02.2017 Published online: 23.03.2017 DOI: 10.1055/s-0036-1589493; Art ID: ss-2017-z0105-sr 1.1 What Is a Meso Compound? Abstract Meso compounds represent a particular family of achiral Symmetry is a fascinating aspect of matter, which can molecules bearing elements of chirality. Their desymmetrization be admired in vegetal and animal reigns of Nature. It also through enantioselective catalytic methods usually leads to elaborate chiral building blocks containing several stereogenic elements, which influences, as a stimulating concept, human creativity in can be a very useful and elegant approach in the context of total syn- the arts, like painting, sculpture, or even literature (one of thesis. In the present review, the power of this strategy is illustrated the longest palindromes, a highly symmetrical sentence, through the different possibilities of catalytic enantioselective de- was written by Georges Pérec).2 Symmetry is also a funda- symmetrization. From the combination of the hidden symmetry detec- tion and the catalytic enantioselective transformations a new type of mental concept in various fields of science like mathemat- economy emerges: the economy of chiral reagents. ics, physics, or chemistry. Molecular symmetry can be clas- 1 Introduction sified, according to group theory, through different ele- 1.1 What Is a Meso Compound? ments of symmetry.3 Among achiral molecules, prochiral 1.2 Why Is the Catalytic Enantioselective Desymmetrization of Meso and meso compounds can be distinguished. These both Compounds a Powerful Strategy in Total Synthesis? 1.3 Toward an Economy of Chiral Reagents types of achiral molecules can become chiral in a single de- 2 Enzymatic Desymmetrization symmetrization step. Prochiral molecules can be subdivid- 2.1 (–)-Sceptrin (Baran, 2006) ed into trigonal systems, such as carbonyls or alkenes with 2.2 cis-Solamin (Stark, 2006) enantiotopic faces (Scheme 1, a), and tetrahedral systems 2.3 Crocacin C (2010, Bressy/Pons) 3 where an sp atom, the prostereogenic center, bears two This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. 3 Metallocatalyzed Desymmetrization 3.1 Quadrigemine C (2002, Overman) enantiotopic groups (Scheme 1, b). A meso molecule has 3.2 (+)-Homochelidonine (2007, Lautens) been defined by IUPAC as ‘an achiral member(s) of a set of 3.3 (–)-Cyanthiwigin F (2008, Stoltz) diastereomers which also includes one or more chiral mem- 3.4 [5]-Ladderanoic Acid (2016, Gonzalez-Martinez/Boxer/Burns) bers’.4 With this definition, it is difficult to visualize which 4 Organocatalyzed Desymmetrization reality it may cover. Unlike prochiral molecules, meso com- 4.1 (+)-Hirsutene (2008, List) 4.2 Alstoscholarines (2011, Neuville/Zhu) pounds contain pair(s) of stereogenic elements (central, ax- 4.3 (–)-Diospongin A (2015, Chuzel/Bressy) ial, planar, or helical), but remain achiral due to the pres- 5 Conclusion ence of a symmetry element, a plan of symmetry (S1), an inversion point i (S ), or an improper axis of symmetry (S ) Key words total synthesis, natural product, meso compounds, de- 2 n symmetrization, enantioselective catalysis, economy of chiral reagents, (Scheme 1, c). hidden symmetry, amplification © Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, 1938–1954 1939 Syn thesis J. Merad et al. Short Review 1a. Facial prochirality 1b. Tetrahedral prochirality Si face H OH O (behind) CO2Me MeO2C CO2Me Me Me Re face Ph (behind) proS group proR group Si face Re face (front) prostereogenic center (front) Jérémy Merad received his Bachelor of Science at the Université de 1c. Elements of symmetry of meso compounds Toulon before moving to the Université de Montpellier to obtain his σ H Master of Science with Dr. Camille Oger and Dr. Jean-Marie Galano N Me MeO C CO Me (S) Me Me working on the synthesis of neuroprostanes. In 2015 he completed his 2 2 i Ph.D. under the supervision of Prof. Jean-Marc Pons and Prof. Cyril (R) S4 (R) Me Me (S) Me N Bressy at Aix-Marseille Université. His thesis focused on the preparation H Me Me of acyclic 1,3-diols using chiral isothioureas and involving enantioselec- plane of symmetry (S1) inversion center (S2) improper axis of symmetry tive amplification processes. At the beginning of 2016 he joined the group of Prof. Nuno Maulide in Vienna, Austria as postdoctoral re- 1d. Type I / Type II categories of meso compounds searcher. Mathieu Candy studied at the Aix-Marseille Université (AMU) where he Type I: without Type II: with prostereogenic center prostereogenic center obtained his Ph.D. in 2010 under the supervision of Prof. Jean-Marc (r) Pons and Prof. Cyril Bressy. His thesis topic focused on hidden symme- (s) OH OH try in total synthesis using desymmetrization of meso diols. He then MeO2C CO2Me MeO2C CO2Me MeO2C CO2Me joined the group of Prof. Dr. Carsten Bolm in Aachen, Germany as a Humboldt post-doctoral researcher, where he worked on the chemistry (R) Me Me (S) (R) Me Me (S) (R) Me Me (S) of sulfondiimines. Back in France, he joined the group of Prof. J. M. Campagne and then Dr. T. Durand, both in Montpellier, as a post- Scheme 1 Prochiral and meso compounds doctoral researcher working on the total synthesis of natural products. He is now completing an industrial project in Toulouse, France in the group of Dr. Y. Genisson. The distinction between prochiral and meso compounds Jean-Marc Pons studied at the Université de Provence in Marseille is a crucial aspect of the desymmetrization step, which is where he obtained his Ph.D. in 1982 under the supervision of Prof. defined as a decrease in the number of symmetric ele- Maurice Santelli. He then entered the CNRS as Chargé de Recherches ments. Indeed, while the desymmetrization of prochiral and defended a Thèse d’Etat in 1987 on low valent transition metal complexes in organic synthesis. In 1988, he spent a year as a post- molecules leads to the creation of a stereogenic center in doctoral fellow in the group of Prof Philip Kocienski in Southampton, place of the previous prostereogenic center, the desymme- where he worked on natural product total synthesis. Back in Marseille, trization of meso compounds ‘reveals’ their pre-existing ste- he was appointed professor at Aix-Marseille Université in 1999. He is reogenic elements. currently involved in organocatalyzed transformations, and is also dean of the faculty of sciences of Aix-Marseille Université. Cyril Bressy studied at the Université Claude Bernard in Lyon where he 1.2 Why Is the Catalytic Enantioselective De- obtained his Ph.D. in 2004 under the supervision of Prof. Olivier Piva. symmetrization of Meso Compounds a Powerful He then joined, as post-doctoral researcher, the group of the Prof. Mark Strategy in Total Synthesis? Lautens in Toronto, Canada where he developed a novel variant of the Catellani reaction. Back in France, he worked on a total synthesis proj- ect in Paris at Ecole Supérieure de Physique et Chimie Industrielle (ESP- Chiral compounds constitute, in general, the most ex- CI-ParisTech) with Prof. Janine Cossy. In 2006 he held the position of pensive reagents of a synthetic sequence. Because of the ad- Maître de Conférences at Aix-Marseille Université (AMU). In 2012 he ditional difficulty that the preparation of perfectly stereo- obtained a Habilitation à Diriger les Recherches (HDR) and was promot- defined molecules represents, enantioenriched compounds This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. ed as full Professor in 2015 at AMU. His research focuses on total syn- are among the most expensive in a synthetic sequence. thesis using desymmetrization strategies and organocatalyzed transformations. Consequently, the use of stoichiometric amounts of such molecules as substrates (chiral pool) or reagents appears fi- nancially unfavorable. Moreover from an eco-compatible point of view, the use of chiral reagents bearing a chiral It is noteworthy that much confusion does exist in liter- moiety that is not embedded in the final target molecule ature between prochiral and meso compounds probably results in expensive waste.