Catalytic Enantioselective Desymmetrization of Meso

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

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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

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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 detection 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

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 project 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. Enantioselective catalysis cir- due to the fact that they both incorporate enantiotopic po- cumvents these drawbacks enabling the use a small sitions. The confusion is also enhanced by the fact that a amount of chiral catalyst. Hence, coupled with enantiose- meso compound may bear a prostereogenic center. We pro- lective catalysis, the desymmetrization of meso com- pose to distinguish meso compounds without prostereo- pounds5 appear then as a clever strategy. Indeed complex genic center from meso compounds with prostereogenic chiral building blocks with several stereogenic elements center(s) into Type I/Type II categories, respectively can be prepared in a single enantioselective step using this (Scheme 1, d). strategy.

Syn thesis J. Merad et al. Short Review

In the context of total synthesis these types of building qualified the kinetic resolution step as a chiroablative10 step blocks prove to be highly useful to rapidly reach the molec- since the chirality of the minor enantiomer is deleted ular complexity encountered in natural products. This re- through the second transformation, which leads to an achi- quires detecting, within the structure of the target, a local6 ral sacrificial byproduct. or hidden symmetry that may be exploited to introduce a highly symmetrical intermediate into the synthetic plan, which could be a meso compound. Practically, this strategy changes the sense of the stereocontrol during the synthesis. Indeed in the classical approach the enantiocontrol precedes the diastereocontrol (Scheme 2, a), while in the hidden symmetry approach, the diastereocontrol precedes the enantiocontrol (Scheme 2, b). Hence, this strategy offers the possibility of a late-stage desymmetrizing enantioselective step. The preparation of the meso intermediate requires a high level of diastereocontrol before the enantioselective desymmetrization step occurs. It is important to mention that the ‘Meso Trick’7 can be extremely efficient in a synthetic sequence if the preparation of the meso intermediate is not demanding.

2a. Classical approach Scheme 3 Horeau amplification of enantioselectivity during the desymmetrization of meso compounds in the case of no creation of addi- enantio- diastereo- Starting selective Chiral * selective tional stereocenters material intermediate step steps

In the second possible scenario, the meso compound Target presents at least two functional groups with facial prochi- molecule 2b. Hidden symmetry approach rality in addition to the pre-existing stereogenic centers (Scheme 4).5g,h The catalytic enantioselective reaction diastereo- enantio- steps transforms one of these two positions producing major A Starting selective Meso selective Chiral * material intermediate intermediate and minor ent-A enantiomers through the creation of a new step(s) step stereocenter. Then the major enantiomer A can undergo a Scheme 2 Classical and hidden symmetry approaches in enantioselec- second diastereoselective transformation leading either to tive synthesis an ultra major enantiomer B (due to a second sorting) or a sacrificial meso compound C. The same situation appears Another possible advantage to employ the catalytic en- for the minor enantiomer ent-A, which can be transformed antioselective desymmetrization of meso compounds is the either into a meso compound D or into the ultra minor en- possible benefit offered by Horeau-type amplifications.8 antiomer ent-B. In brief, a synergy between desymmetriza- Two scenarios can be involved, but in both situations meso tion and kinetic resolution leads to enantioselectivity am- intermediates generally present at least two enantiotopic plification of the global transformation. reactive functional groups due to their symmetry.

The first possible scenario occurs when the enantio- 1.3 Toward an Economy of Chiral Reagents This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. topic functional groups are directly borne on the pre-existing stereogenic centers (Scheme 3). No additional stereo- From the combination of the hidden symmetry detec- center is created in this case. Here a desymmetrization and tion strategy and the catalytic enantioselective desymme- a kinetic resolution work in synergy. A first enantioselec- trization of meso compounds, a new type of economy tive transformation leads to the production of major and emerges: the economy of chiral reagents. This latter can be minor enantiomers. In the minor enantiomer, the fast re- added to the previous economies of atoms,11 steps,12 and acting enantiotopic position, which has remained intact, redox steps.13 As mentioned previously, the cost of optically undergoes a fast selective transformation leading to the active chiral reagents is potentially very high. The control of production of a symmetrical byproduct. The transforma- the different stereogenic elements of a complex target can tion of the minor enantiomer in a sacrificial meso byprod- require the use of several chiral reagents, especially when uct results in the improvement of the enantiomeric excess. the target molecule is acyclic, since no cyclic stereocontrol In some cases the level of enantioselectivity can be particu- can be involved. Indeed, the substrate-control may not be larly enhanced.9 The complete double reaction is not desir- sufficiently diastereoselective leading to the necessary use able because the resulting product is a meso compound. We of a chiral reagent to ensure, via reagent-control, better ste-

Syn thesis J. Merad et al. Short Review

Kinetic Resolution ultra major enantiomer final product X X fast Desymmetrization * * R R X X R' B R' fast * R R R' R' A X X slow major enantiomer * * R R X X R' C R' meso sacrificial byproducts R R R' R' X X fast * * meso substrate R R X X R' D R' slow * R R

R' ent-A R' X X slow minor enantiomer * * R R pre-existing R' ent-B R' stereocenter ultra minor enantiomer

Scheme 4 Horeau amplification of enantioselectivity during the desymmetrization of meso compounds in the case of the creation of additional stereocenters

reocontrol. The simultaneous stereocontrol of several ste- biosynthetic route seems to involve a dimerization through reogenic elements obtained in the catalytic enantioselec- a [2+2] photocycloaddition, despite the fact that this natu- tive desymmetrization of meso intermediates is an interest- ral product was found in ocean depths. In 2004, the Baran ing strategy that avoids the extensive use of chiral reagents. group described its total synthesis in racemic series.15 Two The present review aims to illustrate, through signifi- years later, the same group published the enantioselective cant and recent total syntheses of natural products from version still starting from the meso cycloadduct 1 obtained various classes (terpenes, polyketides, alkaloids) described through the reaction between 2,5-dimethylfuran and di- between 2002 and 2016, the power of catalytic enantiose- methyl acetylenedicarboxylate (Scheme 5).16 After the de- lective desymmetrization of meso compounds to achieve an symmetrization of meso compound 1 the oxabicyclic struc- economy of chiral reagents. The review is organized accord- ture is rearranged under photochemical conditions to af- ing to the type of catalysis involved in the enantioselective ford the tetrasubstituted cyclobutane.17 desymmetrization key step.

Cl Br H N O 2 Enzymatic Desymmetrization H2N O Me HN NH N H CO2Me This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Historically, and in term of popularity, enzymatic trans- Br Cl Me formation was the first explored catalytic approach to de- HN NH CO2Me H N 1 symmetrize meso compounds.5d Transesterifications, hy- 2 N N H O H drolysis of esters, and some oxidations are the predominant (–)-Sceptrin reactions involved in the desymmetrization of meso sub- Scheme 5 Baran’s retrosynthetic plan for (–)-sceptrin strates. The catalytic enzymatic process is extremely interesting due to the mildness of the conditions and the high selectivity often obtained. The synthesis began with the hydrolytic desymmetrization of meso compound 1 using pig liver esterase (PLE) to 2.1 (–)-Sceptrin (Baran, 2006) obtain carboxylic acid 2 in quantitative yield, but modest enantiomeric excess (Scheme 6). Oxabicycle 2 was then es- (–)-Sceptrin, isolated in 1981 from Agelas sceptrum by terified with isopropyl alcohol using 4-(4,6-dimethoxy- Faulkner and Clardy,14 presents a wide range of biological 1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (3) be- activities (antibacterial, antiviral, antihistaminic, etc.). The fore being converted into the corresponding amide in two

Syn thesis J. Merad et al. Short Review steps. Amide 4 was submitted to photochemical conditions guanidinium parts were prepared by -chlorination of the that promoted an intramolecular [2+2] photocycloaddition ketones, before displacement with sodium diformylamide, leading to the formation of oxaquadricyclane 5. This then hydrolysis of the imides, and treatment with cyanamide. underwent fragmentation under acidic conditions (follow- The overall yield was excellent with 24% over 18 steps ing the red bonds) leading to bicyclic carbocation 6. The lat- from dimethyl acetylenedicarboxylate. Additionally the er intermediate allowed the production of cyclobutane 7 by Baran group found a pathway to transform sceptrin into addition of water and a final fragmentation (following the ageliferin.18 red bond). It is noteworthy to mention that the enantiomer- The hidden symmetry of the target molecule was bril- ic excess is conserved through the rearrangement and can liantly exploited in the synthetic plan by taking advantage even be improved by recrystallization. Under acidic condi- of the epimerization of 7 and the rearrangement of the in- tions, trans,cis,cis-cyclobutane 7 was epimerized into termediate oxaquadricyclane 5. The central carbon skeleton trans,trans,trans-cyclobutane 8 and the carboxylic func- of the target molecule is already included in cycloadduct 1. tions were converted into methyl esters. The temporary Only five steps were necessary to obtain the cyclobutane protection of the ketones as acetals allowed the formation ring with the substituents in the correct configurations of diazide 9. The reduction of the azide functions was nec- from the desymmetrized molecule 2. Indeed, the final steps essary to install the amide side chains using reagent 10. The only consisted of post-functionalizations of the side chains.

O PLE, acetone/ O O Me phosphate Me 1- 3, i-PrOH Me CO2Me buffer CO2H 2- LiOH CO2i-Pr

pH 8, rt, 7 d 3- 3, BnNH Me Me 2 Me CO2Me CO2Me CONHBn 1 2 4 100%, 75% ee 80% (3 steps)

hν, THF, 72 h then H2SO4 THF/H2O O Me CO i-Pr O Me Me 2 H CO2i-Pr CO2i-Pr

Me Me NHBn CONHBn Me CONHBn O O HO 7 6 5 50%, 75% ee (> 95% ee after recryst.)

TsOH MeOH 1- MeOH 1- MeOH, HC(OMe) O O 3 HC(OMe)3 TsOH, 50 °C CO Me 2- H , Lindlar cat. Me 2 TsOH, 50 °C Me N 2 2- DIBAL-H 3 3- 10, MeCN

CH2Cl2, –78 °C 4- BnNMe3 ICl2 Me Me N3 CO2Me then AcOH, H2O THF, 60 °C Br O 8 3- MsCl, Py O 9 90% 4- NaN3, DMF O This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. O Cl NH N 1- NaN(CHO)2 H

2- HCl, MeOH Br 3- NH2CN, H2O NH Cl Cl Br O H O N N O H H2N 11 68% (8 steps) N HN NH H OMe Br Cl Cl Br HN NH N N O HN Me N N N N OMe H O H N Cl3C H (–)-Sceptrin 3 10 72% (3 steps) O Scheme 6 Total synthesis of (–)-sceptrin

Syn thesis J. Merad et al. Short Review

Wittig olefination Me OTBDPS TBDPSO Me O ( )8 O ( )9 O H H H H HO OH O HO OH 12 Alder–ene reaction

Scheme 7 Stark’s retrosynthetic plan of cis-solamin

2.2 cis-Solamin (Stark, 2006) aldehyde function on the left side of the molecule. A Wittig olefination was performed in situ with the ylide formed cis-Solamin belongs to the Annonaceous acetogenins, a from the reaction between KHMDS and phosphonium salt class of natural products isolated from the tropical plant 16 to afford bicyclic compound 17. The use of DIBAL-H al- Annonacea.19 Due to the range of biological activities (anti- lowed the removal of the acetate group and the conversion tumor, immuno-suppressor, etc.), the synthesis of several of the lactone moiety into a lactol, which was involved, also acetogenins have been conducted.20 In 2006, Göksel and in situ, in a second Wittig reaction with the ylide preformed Stark described the synthesis of cis-solamin, an acetogenin from n-BuLi and phosphonium salt 18. cis-Solamin was bearing a polyhydroxylated cis-tetrahydrofuran and a achieved by the construction of the butenolide moiety in- butenolide moiety.21 Due to the apparent symmetry of the volving a ruthenium-catalyzed Alder–ene reaction between tetrahydrofuran diol central part, the authors proposed a triene 19 and propargylic alcohol 20 described by Trost23 synthetic sequence involving meso-diol 12 (Scheme 7). and followed by chemoselective reduction with diimide. The preparation of meso-diol 12 relies on a methodolo- The rapid preparation of the meso precursor together gy developed in the Stark group and based on the highly with the efficient distinction between the terminal hydrox- diastereoselective oxidative cyclization of 1,5-dienes.22 The yl functions, via a relay of the desymmetrization from the synthetic sequence begins with a selective monodihydrox- secondary alcohols, led to an efficient synthesis of this nat- ylation of (E,E,E)-cyclododeca-1,5,9-triene (13) followed by ural product. its oxidative cleavage promoted by sodium periodate (Scheme 8). The corresponding aldehydes were reduced to 2.3 Crocacin C (2010, Bressy/Pons) alcohols with sodium borohydride and then protected as si- lyl ethers. The resulting (E,E)-1,5-diene 14 was transformed Crocacin C is one of the four members of the crocacin into dihydroxylated tetrahydrofuran 12 with complete di- subfamily. It was isolated in 1994 by Janssen and co-work- astereoselection. ers from the myxobacterium Chondromyces crocactus and exhibits moderate antibacterial activity, accompanied by antifungal and cytotoxic properties.24 This polyketide con- 1- OsO4 (cat.), NMO, H2O/CH2Cl2 2- NaIO4, H2O/CH2Cl2/acetone gener containing a (E,E)-dienamide and (E)-styryl moiety 3- NaBH4, MeOH displays a stereotetrad anti-anti-syn. Several syntheses of 4- TBDPSCl, EtN(i-Pr)2, DMAP, CH2Cl2 25 13 this natural product have been developed that mainly us- OTBDPS TBDPSO ing starting material from the chiral pool or stoichiometric 14 chiral reagents to install new stereogenic centers. In 2009, 68% (4 steps) we described an enzymatic desymmetrization of meso in- OTBDPS TBDPSO

termediates leading to tetrahydropyran building blocks This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. RuCl3 (0.2 mol%) 26 O NaIO4 on wet silica bearing up to five stereogenic centers. To illustrate its syn- H H THF, 0 °C HO OH thetic value, we applied it to the total synthesis of crocacin 12 83%, dr > 98:2 C. The detection of a hidden symmetric guided our retrosynthetic analysis toward the use of meso-diol 21 through Scheme 8 Synthesis of meso-diol 12 a convergent strategy (Scheme 10).27 The scalable and diastereoselective synthesis of meso Stark adopted an indirect strategy desymmetrizing the compound 21 was accomplished in three steps from the secondary alcohols to discriminate the endpoints of the easily available oxabicyclic compound 22 (Scheme 11).28 side chains. Indeed, the enantioselective desymmetrization The desymmetrization of meso intermediate 21 was cat- of meso-diol 12 was efficiently performed through transes- alyzed by Rhizomucor miehei leading to monoester 24 in terification using lipase Amano AK as a biocatalyst (Scheme 87% yield and >99:1 er (Scheme 12). Then, a sequence of 9). After desilylation, triol 15 was oxidized using a catalytic Swern oxidation/Julia modified olefination with sulfone 25 amount of tetrapropylammonium perruthenate leading to allowed installation of the styryl moiety. After saponifica- the formation of a -lactone moiety on the right side and an tion and chlorination of the corresponding alcohol, (chloro-

Syn thesis J. Merad et al. Short Review

1- lipase Amano AK OTBDPS TBDPSO vinyl acetate, hexane OH HO 60 °C, 5–7 d O O H H 2- HF/pyridine, THF H H HO OH pyridine, rt AcO OH 12 15 80% (2 steps), > 99% ee

TPAP, NMO, MS 4 Å CH2Cl2, rt then 16, KHMDS, –78 °C to rt

Me Me ( )6 ( )6

DIBAL-H (2 equiv) then 18, n-BuLi O O H H H H HO OH ( )6 AcO O

19 17 O 45% (one pot) 45% (one pot)

Me O ( )8 O ( )9 H H 1- CpRu(MeCN)3PF6 (cat.) HO OH O 20, DMF, rt cis-Solamin 2- H NNHTs, NaOAc 2 81% (2 steps)

Br Br Me EtO2C PPh3 Me ( )7 Ph3P ( )5 OH 16 18 20 Scheme 9 Desymmetrization of meso-diol 12 and completion of the synthesis

Julia-type olefination MeO In this synthesis, the four stereogenic centers of the tar- O Me MeO MeO Me Me get were enantioselectively controlled in a single step. Ad-

H2N HO OH 29 O ditionally, no protecting group was required. Only eleven Me Me H H steps were needed to obtain, with an excellent 22% overall 21 Hydrostannylation/Stille coupling yield, the natural product from oxabicyclic compound 22.

Scheme 10 Bressy/Pons’ Retrosynthetic analysis of crocacin C 3 Metallocatalyzed Desymmetrization

O OMe MeO Me Me Me Me Me Me 1- NaBH4 O3, MeOH/ The variety of the enantioselective metallocatalyzed O MeOH O CH2Cl2 then HO OH transformations offers multiple possibilities to promote de- O 2- KH, MeI NaBH4 H H symmetrization. Schreiber was probably one of the first to This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. THF (excess) 22 23 21 involve enantioselective metal-catalyzed reactions in strat- 90% (2 steps) 78% egies based on the detection of hidden symmetry.30 His Scheme 11 Preparation of meso-diol 21 group employed mainly Katsuki–Sharpless epoxidation to prepare polyketide natural products.

3.1 Quadrigemine C (2002, Overman) methyl)tetrahydropyran 27 was subjected to excess LDA, thereby opening the cyclic ether and revealing the stereo- In 2002, Overman’s group reported a straightforward tetrad terminated by an alkyne function; subsequent meth- total synthesis of quadrigemine C, a higher-order member ylation afforded diether 28. The synthesis was completed of the pyrrolidinoindoline alkaloids.31 This natural product with a one-pot hydrostannylation/Stille coupling with io- was described in 1987 in New Caledonia from Psychotria doenamide 29 using the same source of palladium. oleoides, a plant used for pain treatment.32 As a key step of the synthesis, Overman proposed to desymmetrize a highly elaborated meso precursor 30 due to the local symmetry in

Syn thesis J. Merad et al. Short Review

MeO MeO Rhizomucor Me Me Me Me miehei 1- Swern i-Pr2O oxidation HO OH AcO OH 2- 25, KHMDS O O H H OAc H H DME –78 °C to 0 °C 21 24 87% (2 grams scale) er > 99:1

MeO MeO Me Me Me Me 1- K2CO3 MeOH Cl AcO O O H H 2- PPh3, CCl4 H H 27 Imidazole 26 80% (2 steps) 75% (2 steps) 1- LDA (excess) THF, –78 °C to –30 °C 2- NaH, MeI, THF

PdCl2(PPh3)2 MeO MeO Bu3SnH, THF O Me MeO MeO 0 °C, 15 min H2N Me Me then 29, MW Me Me 100 °C, 15 min 28 Crocacin C 80% (2 steps) 73%

N O Me

S S H2N I 25 O O 29

Scheme 12 Desymmetrization of meso-diol 21 and completion of the synthesis the central part of the target alkaloid (Scheme 13). The was installed on the free aminal functions of meso-chi- strategy was based on a late double intramolecular enantio- monanthine 31 in order to guide the orthometalation step. selective Heck reaction. The double lithiation was followed by iodination before the removal of the carbamate groups. Diiodo intermediate 34 Me H H NMeTs was then coupled with stannane 35 in a palladium-cata- N N O lyzed Stille reaction to form meso precursor 30, which was Me N Me H H H H desymmetrized in the key step using a catalytic amount of a N N OTf Bn N N chiral palladium complex. Indeed it serves to promote an

Double intramolecular enantioselective double intramolecular Heck coupling, enantioselective which introduced two new quaternary stereocenters Heck coupling during the transformation. This strategy involved a meth- N N OTf Bn N N odology previously developed by Overman’s group.35 It is H H H H Me N Me

noteworthy to mention that in addition to the desired prod- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. N N O uct 36, obtained with good enantioselectivity, significant H H NMeTs Me amounts of meso stereoisomers (14% + 7%) were also pro- Quadrigemine C 30 duced during this key step, thus highlighting a strong Scheme 13 Overman’s retrosynthetic analysis of quadrigemine C Horeau amplification. The catalytic hydrogenation of the double bond followed by the use of sodium in ammonia provided quadrigemine C, which is also a precursor of psy- The synthesis started from a symmetric natural prod- choleine obtained through rearrangement under acidic uct, meso-chimonanthine 31, previously prepared by the conditions. same group from oxindole and isatin in 13 steps and 35% The bidirectional strategy, adopted in this total synthe- overall yield (Scheme 14).33 The sequence is typical of a bi- sis, allowed the rapid preparation of an advanced meso pre- directional approach with a symmetrical double reactivity cursor, demonstrating the power of the enantioselective for each step of the synthesis.34 First of all, Boc protection catalytic desymmetrization of meso compounds.

Syn thesis J. Merad et al. Short Review

NMeTs R Me I R Me O H H N N N N N 35 1- s-BuLi, TMEDA OTf Bn SnBu3 Et2O, –78 °C

2- ICH2CH2I, Et2O Pd2(dba)3.CHCl3 –78 °C to 0 °C P(2-furyl)3, CuI NMP, rt N N N N H H R Me I R Me

31: R = H 33: R = Boc Boc2O, THF TMSOTf NaHMDS, rt CH Cl , rt 32: R = Boc 34: R = H 2 2

66% (3 steps) Bn NMeTs N O O NMeTs Me N Me H H H H N N OTf Bn N N Pd(OAc)2 2 meso (R)-Tol-BINAP + isomers (21%) PMP, MeCN, 80 °C

N N OTf Bn N N H H H H Me N Me NMeTs N O O NMeTs Bn 36 30 60%, 90% ee 71%

Me H H N N 1- Pd(OH)2 (cat.), H2, EtOH, MeOH, 80 °C 2- Na, NH , THF, –78 °C 3 Me Me H H H H N N N N Me N H N AcOH N N N H 100 °C H H N Me Me N N N N H H H H Me Me Psycholeine Quadrigemine C 38% 22% (2 steps)

Scheme 14 Synthesis of quadrigemine C from meso-chimonanthine

3.2 (+)-Homochelidonine (2007, Lautens) This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. R Enantioselective HO ring-opening O N In 2007, Lautens’ group described the first enantioselec- O tive total synthesis of (+)-homochelidonine,36 an alkaloid O N 37 isolated, in 1839, from the roots of Chelidonium majus. MeO Me O This group adopted a convergent strategy based on a palla- OMe (+)-Homochelidonine 37 dium-catalyzed enantioselective ring opening of the meso- Scheme 15 Lautens’ retrosynthetic analysis of (+)-homochelidonine azabicycle 37 using an elaborated boronic acid (Scheme 15). The meso intermediate was prepared in four steps, from After optimization, it was found that (S)-Tol-BINAP was dibromoveratrole 38, through the generation of a benzyne the most selective ligand to promote the coupling between intermediate, acting as a dienophile in a Diels–Alder reac- meso-azabicycle 37a (or 37b) and boronic acid 41 affording tion with a protected pyrrole (Scheme 16). product 42a (or 42b) under mild conditions (Scheme 17). Here two out of three stereogenic centers were installed through the enantioselective desymmetrization step.

Syn thesis J. Merad et al. Short Review

CH2BrCl O MeO Br HO Br O Br O BBr3, CH2Cl2 Cs2CO3 O rt DMF, 110 °C O O MeO Br HO Br Br 1- HCl, i-PrOH/ HN 38 39 40 MeO Cbz THF, rt N quant. 75% MeO Cbz OMe OMOM 2- CBr4, PPh3 OMe R 42b CH2Cl2, 0 °C then N N NaH, DMF, 0 °C 43 68% (2 steps) Boc O n-BuLi, PhMe O NBS, THF/ O –78 °C to rt H2O, rt O O OH 37a (R = Boc) 71% TMSI, Et N, CH Cl 3 2 2 O reflux then CbzCl, rt t-BuOK, THF Br O 37b (R = Cbz) 80% –78 °C O Scheme 16 Preparation of meso aza-bridged intermediates 37a and O N 37b MeO Cbz N MeO Cbz OMe 45 OMe 44 quant. 75% B(OH)2

HO O MeO O LiAlH4 OMe OMOM O 41 (1.5 equiv) O dioxane, reflux Pd(MeCN)2Cl2 (5 mol%) N + (S)-Tol-BINAP (5.5 mol%) MeO Me R HN N MeO R OMe CsCO3, MeOH, rt OMe OMOM (+)-Homochelidonine 87% O 42a (R = Boc) 90%, 91% ee 42b (R = Cbz) 89%, 90%ee Scheme 18 Completion of the synthesis O (80%, 99% ee after 37a (R = Boc) or one recrystallization) 37b (R = Cbz)

Scheme 17 Pd-catalyzed enantioselective ring opening of the meso in- ring junctions. The Stoltz group planned to build the five- termediates 37a and 37b and seven-membered rings after ensuring the stereocontrol of the quaternary stereocenters around the central six- membered ring. Unlike the other examples reviewed in this The nitrogen-containing heterocyclic compound 43 was paper, the authors harnessed a scarcely employed cen- then formed after deprotection of the methoxymethyl trosymmetric meso compound (Scheme 19).39 group in 42b under acidic conditions and bromination of Me the corresponding alcohol using Appel’s conditions O O Me RCM Me (Scheme 18). The third stereogenic center was introduced Radical- Me H Me O induced diastereoselectively using an olefin epoxidation on the cyclization O most hindered face of the molecule. This epoxidation re- H Me O O quired a two-step sequence, first a regio- and stereoselec- Me O 46 tive formation of bromohydrin 44 followed by the ring-clo- Double stereoablative 1:1 mixture of stereoisomers sure step under basic conditions. Lastly, the corresponding (–)-Cyanthiwigin F allylic alkylation meso + racemic

epoxide 45 was regioselectively opened using LiAlH to af- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. 4 Scheme 19 Stoltz’s retrosynthetic analysis of (–)-cyanthiwigin F ford (+)-homochelidonine. This enantioselective synthesis in only 11 steps from dibromoveratrole 38 appeared highly efficient in term of se- Diallyl succinate (47) was self-condensed through a lectivities and overall yield (15%). Claisen–Dieckmann process. This reaction was followed by a double alkylation, promoted under basic conditions lead- 3.3 (–)-Cyanthiwigin F (2008, Stoltz) ing to a 1:1 diastereomeric mixture of diketo diester 46 (Scheme 20). In 2008, Enquist and Stoltz disclosed an extremely effi- From the mixture of meso and racemic diketo ester 46 a cient and elegant total synthesis of (–)-cyanthiwigin F,38 a stereoconvergent enantioselective palladium-catalyzed al- member of the cyathane family, isolated from the marine lylic alkylation was performed leading to enantiopure C2- sponge Myrmekioderma styx. The natural product exhibits symmetric diketone (R,R)-48 accompanied by its diastereo- interesting biological activity, such as cytotoxicity against mer meso diketone meso-48 (Scheme 21). A double ste- human tumor cells. (–)-Cyanthiwigin F presents a tricyclic reoablative process40 takes place through the generation of structure with two quaternary stereogenic centers at the

Syn thesis J. Merad et al. Short Review

O O O O O the formation of a seven-membered ring and also a cross- Me Me 1- allyl alcohol metathesis functionalizing the other pendant allyl group.42 O NaH, PhMe, reflux O O + O O O Subsequent oxidation converted the vinylboronate into an 2- K2CO3, MeI acetone, reflux Me Me aldehyde. Ketoaldehyde 51 was cyclized through a radical O O O O O process to obtain diketone 52. A chemoselective deprotona- 47 51% centrosymmetric racemic 46 meso 46 tion of the newly formed ketone function allowed the for- 1:1 mixture of stereoisomers mation of a novel vinyl triflate, which underwent subse- meso + racemic quent cross-coupling with isopropylcuprate. A mixture of Scheme 20 Preparation of key intermediate 46 the desired natural product and the reduced vinyl triflate 53 was then obtained. In 2016 the same group improved the synthetic path- intermediate enolates by decarboxylation.41 The power of way, using an anti-Markovnikov Wacker oxidation, to ob- the Horeau amplification through two successive stereose- tain ketoaldehyde 51 in better yield.43 lective reactions is perfectly illustrated in this case. In this total synthesis, the double stereoablative decar- boxylative allylation provided a chiral building block with O O O O Me Me Me high enantiopurity illustrating the power of the amplified Pd(dmdba)2 O Et2O, 25 °C process. This example presents also one of the rare use of a + O centrosymmetric meso compound in total synthesis. Me Me Me O O O O O 1:1 mixture of (R,R)-48 meso-48 3.4 [5]-Ladderanoic Acid (2016, Gonzalez- PPh2 N stereoisomers 99% ee Martinez/Boxer/Burns) meso + racemic t-Bu 4.4:1 dr 46 78% Recently, the synthesis of [5]-ladderanoic acid was Scheme 21 Palladium-catalyzed double stereoablative enantioselective allylic alkylation achieved thanks to the conjoint efforts of the groups of Gonzalez-Martinez, Boxer, and Burns during the total syn- 44 One of the two ketone functions of C2-symmetric com- thesis of a more complex ladderane phospholipid. This pound (R,R)-48 was then converted into a vinyl triflate and natural product presents an uncommon pentacyclobutane used as partner in a Negishi cross-coupling with an ho- framework. [5]-Ladderanoic acid was only previously syn- moallylzinc partner (Scheme 22). In the presence of me- thesized by Mascitti and Corey in racemic and enantiose- tathesis catalyst 50 and the vinylboronic pinacol ester, lective fashions.45 The authors elaborated a retrosynthetic triene 49 underwent a ring-closure–metathesis leading to plan involving a late desymmetrization of polycyclic cyclobutene 54, and a Zweifel cross-coupling to introduce the side chain (Scheme 23). 1- KHMDS cat. 50 (10 mol%) PhN(Tf) Me 2 Me Me THF, –78 °C Zweifel cross-coupling 2- Zn, TMSCl O Me O Me Me Br-CH2-CH2-Br Me HO B O Me Me I PhH, 60 °C, then O H O [5]-ladderanoic acid 54 NaBO3, THF/H2O Me Me O Me O Me Scheme 23 Retrosynthetic analysis of [5]-ladderanoic acid THF, 65 °C then O (R,R)-48 Pd(PPh ) 49 3 4 57% 51 This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. (2 steps) 51% meso-Cyclobutene 54 was prepared in seven steps start- t-BuSH PhH ing from commercially available meso-cyclobutanediol 55 80 °C AIBN (Scheme 24). Its double mesylation preceding double dis- Me Me placement by a sulfur atom source afforded a bicyclic tetra- NN R 1- KHMDS O hydrothiophene, which was successively oxidized to give H Me PhN(Tf) H Me Me Me 2 the sulfoxide and then chlorinated in the -position to the Cl THF, –78 °C Ru H H sulfur atom. The corresponding sulfoxide 56 was subjected Cl 2- i-PrMgCl O Me CuCN, THF Me to basic conditions, leading to cyclobutene 57 after a Me O Pd(dppf)Cl2 O R = i-Pr Ramberg–Bäcklung olefination. This bicyclic cyclobutene Me 52 (–)-Cyanthiwigin F 57% was then dimerized under photochemical conditions in the R = H (53) cat. 50 presence of copper triflate. Pentacyclic product 58 was then 38% (2 steps) (1.8:1 ratio of Cyanthiwigin F:53) the substrate of a tetramesitylporphyrinatomanganese(III) complex [Mn(TMP)Cl] catalyzed C–H chlorination accord- Scheme 22 Completion of the total synthesis ing to a procedure described by Liu and Groves in 2010.46

Syn thesis J. Merad et al. Short Review

Cl 4 Organocatalyzed Desymmetrization H 1- MsCl H H HO 2- Na2S, H2O2 t-BuOK, DMSO O S Organocatalysis has emerged as the third pillar of enan- HO 3- SO2Cl2 H H H tioselective catalysis since its conceptualization at the early 55 56 57 2000s. Several new tools were developed since this renais- 78% (3 steps) 49% sance displaying orthogonal modes of action compared to Me Me CuOTf metallocatalysis. The combination of the hidden symmetry hv (254 nm) Me Me 5b C6H6, –4 °C detection and organocatalytic processes has been fruitful and it has led to elegant total syntheses. Me N Me Cl N Mn N 4.1 (+)-Hirsutene (2008, List) Me N Me 58 42% In 2008, List’s group applied an organocatalyzed tran- Me Me sannular aldol reaction methodology to the total synthesis Me Me 49 Mn(TMP)Cl of (+)-hirsutene (Scheme 26). This sesquiterpene, isolated 1- Mn(TMP)Cl (cat.) 50 54 NaOCl from Basidiomycete Coriolus consors, is a biosynthetic in- 36% (2 steps) 2- t-BuOK termediate for other natural products with significant bio- Scheme 24 Preparation of meso-pentacyclic cyclobutene 54 logical activities, such as hirsutic acid and coriolin. List proposed a straightforward synthetic plan51 involving the meso [6.3.0] bicyclic intermediate 61, desymmetrized through a A subsequent elimination promoted by potassium tert- transannular contraction of the eight-membered ring to af- butoxide furnished the pentacyclic cyclobutene 54. Enanti- ford the triquinane core. oselective hydroboration catalyzed by a chiral copper complex recently described by the group of Tortosa was em- O H Me H ployed to manage the desymmetrization key step (Scheme Me Me 25).47 Impressively, the desymmetrization of meso-cyclobu- Me H Me tene 54 revealed eight stereogenic centers and created a H H Enantioselective transannular O new one. The corresponding pinacolboronate 59 was then (+)-Hirsutene organocatalyzed aldol reaction 61 subjected to Zweifel cross-coupling48 using a vinyllithium partner to introduce the side chain to obtain product 60. Scheme 26 List’s retrosynthetic analysis of (+)-hirsutene Three additional steps were required to obtain the natural product on a preparative scale. Bicyclic meso-1,4-dione 61 was synthesized in nine Here the late desymmetrization allowed the formula- steps from commercially available 3,3-dimethylpentanedi- tion of a scalable route to [5]-ladderanoic acid, a compound oic acid (Scheme 27). Diacid 62 was first converted into the convenient for further biological studies. All nine stereo- double Michael acceptor 63 through a bidirectional elonga- genic centers of the final product were efficiently con- tion using a three-step sequence. Then a magnesium-medi- trolled during the key desymmetrization step. ated radical cyclization led to the cyclopentane 64 as a mixture of diastereomers. The ester functions of compound 64

Me Me

Cu(MeCN) This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. 4PF6 O (R)-DM-SEGPHOS Me B Me O B2Pin2, t-BuONa 54 59 95%, 90% ee

1- TBSO 2- HF ( ) 5 Li pyridine NBS, NaOMe

1- H2, Raney-Ni HO HO ( )6 ( )5 2- CrO3, H2SO4 [5]-ladderanoic acid 60 86% (2 steps) 88% (2 steps) (> 600 mg prepared) Scheme 25 Completion of the [5]-ladderanoic acid total synthesis

Syn thesis J. Merad et al. Short Review were both transformed into diazo ketones through a three- nia, enone 70 was reduced to form an enolate, which was step sequence. Bisdiazo intermediate 65 cyclized when trapped with methyl iodide to give ketone 71. Ultimately, treated with catalyst 66, forming the cyclooctenedione 67 Wittig olefination provided the natural product. as a mixture of separable diastereomers.52 A final hydrogenation provided meso compound 61. O O R H Me H H Li, NH3 H NaOHaq THF Me Me Me HO2C CO2Et CO2Me 1- BH3, THF, 0 °C Et O then Me Mg, MeOH Me OH 2 Me H Me 2- Swern oxidation Me Me MeI H H H Me Me Me 3- Ph 3 P CO 2 Et 69 70 Ph3P=CH2 71 R = O, 75% HO2C CO2Et CO2Me CH2Cl2, 0 °C 99% PhMe 62 63 64 115 °C R = CH2, 87% 70% (3 steps) 88% (+)-Hirsutene cis/trans = 1.1:1 Scheme 29 Completion of the synthesis Ru 1- KOHaq, EtOH, 0 °C to rt PPh 2- (COCl)2, CH2Cl2, 0 °C to rt Ph3P Cl 3 3- TMSCHN2, THF, MeCN, 0 °C cat. 66 This remarkable synthesis, which involves a late or-

O ganocatalyzed desymmetrization, required only twelve O O H H steps. The transannular aldolization was highly efficient in cat. 66 N2 Me H2, Pd/C Me (3 mol%) Me term of yield and enantioselectivity. Me Me Me AcOEt CH Cl 2 2 N H H 55 °C 2 O O 4.2 Alstoscholarines (2011, Neuville/Zhu) O 61 67 65 91% 52% (cis) 42% (3 steps) Both (E)- and (Z)-alstoscholarines, two monoterpenoid indole alkaloids, were isolated from leaves of Alstonia schol- Scheme 27 Preparation of meso-diketone 61 aris, a plant used in asian traditional medicine.53 These two alkaloids present an unusual pentacyclic structure bearing The direct enantioselective transannular aldol reaction an indole and a pyrrole moieties connected by a central was performed using trans-4-fluoroproline (68) under mild [3.3.1] bicyclic framework. In 2011, Gerfaud, Neuville, and conditions to furnish tricyclic hydroxy ketone 69 as a single Zhu described the first straightforward enantioselective to- diastereomer in excellent yield and enantioselectivity tal synthesis of these two diastereomeric natural prod- (Scheme 28). List and co-workers proposed the well-orga- ucts.54 Their strategy involved the desymmetrization of nized transition state depicted in the Scheme 28 below to meso cyclic anhydride 72 (Scheme 30) and featured also explain the observed stereoselectivity. two other pivotal steps, which are the indole synthesis and a Pictet–Spengler cyclization. F

O O Chen–Zhu indole synthesis CO2Me CO2H H O H N H Me H 68 H Me (10 mol%) Me O Me Me DMSO, rt OH N N H H H H O F O 61 69 Pictet–Spengler cyclization OHC O 84%, 96% ee N (E)- and (Z)-Alstoscholarines 72 This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. O H O Scheme 30 Retrosynthetic analysis of alstoscholarines

Me H H The synthetic sequence started with the organocata- Me lyzed enantioselective desymmetrization of meso-anhy- Scheme 28 Enantioselective organocatalyzed desymmetrization of dride 72 triggered by Song’s catalyst 73 under mild condi- meso-diketone 61 through transannular aldol reaction tions, to give monoester 74 in excellent yield and enantioselectivity (Scheme 31).55 This last intermediate was Three additional steps were required to obtain (+)-hir- converted into pyrroloketone 76 through the transitory for- sutene (Scheme 29). First a base-promoted elimination mation of a thioester according to a Nicolaou’s procedure.56 gave enone 70 in quantitative yield without affecting the The double bond underwent an oxidative cleavage leading enantiomeric ratio, which might be possible through a to the formation of hemiaminal 77. Using the palladium- retro-aldol/aldol process. In presence of lithium in ammo- catalyzed Chen–Zhu indole synthesis,57 aldehyde 77 in the presence of o-iodoaniline (78) is converted into compound

Syn thesis J. Merad et al. Short Review

O instable intermediate 82 as a mixture of diastereomers, H 73 (5 mol%) H PyS-SPy, PPh3 H MeOH (10 equiv) CO2Me THF, rt, then CO2Me which was directly submitted to Vilsmeier–Haack formyla- O Et2O, rt 75, THF, –20 °C O tion to afford the two natural products in a 3:1 E/Z diaste- CO2H H H H O reomeric ratio. 72 74 76 29 95%, 93% ee 76% HN This elegant protecting-group-free total synthesis required only eight steps and gave a 14% overall yield. Its effi- 1- OsO4 (cat.) NMO, t-BuOH/ ciency is related to the straightforward strategy adopted by THF/H2O 2- NaIO4, H2O/ the authors, which included the detection of hidden sym- acetone, rt metry. Unlike many previous examples, the enantioselec- H H HN tive desymmetrizing step occurred very early in the syn- CO2Me O CO2Me Pd(OAc)2 (cat.) thetic sequence. HCO2H, rt O 78, DABCO H O H DMF, 85 °C 4.3 (–)-Diospongin A (2015, Chuzel/Bressy) HO N HO N

CO2Me Diospongin A belongs to the diarylheptanoid natural O 79 77 78% (2 steps) products family and presents anti-osteoporotic activities.59 N Despite the numerous reported syntheses of this natural H N 60 10 80a + product, its hidden symmetry remained unexploited.

CO2Me CO2Me Indeed, a new synthetic plan was imagined based on the 81, Cp2TiCl2 O key meso intermediate 83 (Scheme 32). P(OEt)3, Mg Me N THF, MS 4 Å N N OH Wacker oxidation H 70 °C H N 80b 82 O OH OH 60% (2 steps) 80a/80b = 1:5 DMF, POCl3 O DCE, rt H H

CO2Me CO2Me Me 83 Iodoetherification Me + N N Scheme 32 Chuzel/Bressy’s retrosynthetic analysis of (–)-diospongin A H N H N

OHC OHC (Z)-Alstoscholarine (E)-Alstoscholarine To achieve this goal, an associated methodology was de- 9% (2 steps) 31% (2 steps) veloped to desymmetrize acyclic meso-1,3-diols, which appeared rather difficult due to the high number of possible CF3 conformations. An organocatalyzed acyl transfer was envi-

O I SPh sioned to break the symmetry of diol 83, easily synthesized H N F3C S Me in scalable amounts in two steps (aldol reaction and then N O N SPh H NH2 syn-reduction of the ketone). Chiral isothioureas61 were MgBr MeO found to be efficient catalyst to promote such challenging 73 75 78 81 desymmetrization. The high level of enantioselectivity ob- N served could be explained by the synergy between the de- Scheme 31 Total synthesis of (E)- and (Z)-alstoscholarines

symmetrization step of diol 83 and the chiroablative kinetic This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. resolution step of monoester 84 involved in the second acy- 79 with a partial epimerization of the -position of the ke- lation (Scheme 33). The global transformation leads to an tone. To limit this deleterious problem, a shorter reaction improvement of the enantioselectivity of the reaction by time (40 min) was required. It is noteworthy that the Fischer forming a reusable byproduct 85. This subtractive Horeau- indole synthesis was not applicable due to the degradation type amplification has been observed only a few times in of aldehyde 77 under acidic conditions. Hemiaminal 79, in organocatalyzed enantioselective acyl transfer.62 It should the presence of formic acid, cyclized via a Pictet–Spengler also be noted that this enantioselective acylation is ex- reaction allowing the installation of the central bicyclic tremely efficient as only 0.5 mol% of the catalyst was neces- core. The resulting major isomer 80b was then transformed sary to achieve good yield and excellent ee in very short re- through two steps into the natural products. First a titani- action time (2.5 h) at –20 °C, which is rather uncommon in um-mediated olefination was performed using dithioacetal the field of organocatalysis. 81, according to Takeda’s procedure.58 The reaction gave the

Syn thesis J. Merad et al. Short Review

Desymmetrization O Chiroablative Me kinetic resolution O OH Fast Slow R R 84 O O 77% > 99:1 er Me Me OH OH O O

R R R R O 83 85 Me OH O (byproduct)

R R Slow ent-84 Fast

Ph S N R = Conditions: (EtCO)2O (1.2 equiv) N Me i-Pr2NEt (1.2 equiv) CH2Cl2, –20 °C, 2.5 h Me (0.5 mol%)

Scheme 33 Subtractive Horeau-type amplification during the organocatalyzed desymmetrization of meso-1,3-diol 83

From the desymmetrized hydroxyl ester 84, only few chiometric chiral reagents. Additionally this protecting steps were necessary to obtain the natural product (Scheme group free synthetic sequence constitutes one of the short- 34). First an iodocycloetherification was performed under est total syntheses of diospongin A with only seven steps.29 mild conditions to obtain compound 86 bearing a tetrahydropyran ring in high diastereoselectivity and yield without alteration of the enantiopurity. It is noteworthy that no ra- 5 Conclusion cemization by intramolecular acyl transfer was observed during this crucial step. Then a radical deiodination was Meso compounds hold a particular status in stereoselec- conducted on intermediate 86 before the hydrolysis of the tive synthesis due to their achirality despite the presence of ester function and a regioselective Wacker oxidation of the stereogenic elements. Their catalytic enantioselective de- styryl moiety led to the target molecule. symmetrization appears as a powerful tool to rapidly pro- vide complex building blocks bearing several stereogenic O centers. Applied to the total synthesis of natural products, O Me O this approach allows the control of stereogenic centers with Me I O OH I2, NaHCO3 a notably reduced amount of chiral agents or catalysts. As a MeCN, 0 °C consequence, a new type of economy emerged from the O H H junction between the hidden symmetry detection strategy

84 86 and the catalytic enantioselective desymmetrization of 85%, er = 99.3:0.7, dr > 20:1 meso molecules: the economy of chiral reagents/catalysts.

1- Bu3SnH, BEt3 We hope that the different examples of total synthesis PhMe, rt

highlighted in this review clearly illustrated this new at- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. 2- K2CO3, MeOH, rt tractive concept and highlighted the efficiency of this strat- OH OH egy.

O Pd(OAc)2 (cat.) HBF4, BQ O O Acknowledgment H H DMA/MeCN/H2O H H rt The author thank Aix-Marseille Université, The Centre National de la (–)-Diospongin A 87 Recherche Scientifique (CNRS) and the French Research Ministry 48% (79% brsm) 53% (2 steps) (grant to J.M.). C.B. acknowledges the Agence Nationale de la Scheme 34 Completion of the synthesis Recherche (ANR) for grant ANR-10-JCJC-0710 (Orcademe Project). The authors warmly thank Dr Xavier Bugaut (Aix-Marseille Université) for proof reading. This synthesis required only one catalytic enantioselective step to control the absolute configuration of the natural product while previous syntheses employed several stoi-

Syn thesis J. Merad et al. Short Review

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