Catalytic Enantioselective Reactions with (Benzo)Pyrylium Salts

InnovatIve tools In organIc / organometallIc chemIstry CHIMIA 2020, 74, No. 11 857

doi:10.2533/chimia.2020.857 Chimia 74 (2020) 857–865 © S. Joseph, G. Khassenova, O. García Mancheño Catalytic Enantioselective Reactions with (Benzo)Pyrylium Salts

Sumi Josepha, Gaukhar Khassenovaa, and Olga García Mancheño*

Abstract: The use of (benzo)pyrylium salts as versatile synthetic building blocks has become an attractive plat- form for the preparation of valuable heterocyclic compounds. Besides other numerous direct applications of (benzo)pyryliums, the intrinsic electrophilic nature of these species or the dipole character of the related oxidopyrylium derivatives have been exploited towards the development of enantioselective transformations such as nucleophilic dearomatization and cycloaddition reactions. This review aims at providing an overview on the relevant catalytic enantioselective methodologies developed in the past years, which are presented considering the involved metal- and/or organic catalytic system, as well as the type of reaction. Keywords: Enantioselective catalysis · Metal catalysis · O-heterocycles · Organocatalysis · Pyrylium salts

Prof. K.A. Jørgensen (University of Aarhus). She next moved to RWTH-Aachen for her postdoctoral research in the group of Prof. C. Bolm (2005–2008), followed by the start of her inde- pendent career at the University of Münster in 2008. In 2013, she was appointed as joint Chemistry Professor at the University of Regensburg and TUM-Campus Straubing, and since 2017 she is Professor for Organic Chemistry at the University of Münster.

1. Introduction (Benzo)pyrylium salts are privileged six-membered aromatic heterocycles containing a positively charged oxygen atom.[1] Important naturally occurring examples include the flavylium plant pigments,[2] while synthetic derivatives present fluorescence[3] and photocatalytic activity,[4] among other properties S. Joseph, O. García Mancheño and G. Khassenova (Fig. 1, top). Moreover, the electronegativity of the oxygen atom in the aromatic ring induces a strong single perturbation, which Sumi Joseph was born in Kerala, southernmost part of India. makes it highly reactive towards nucleophilic additions leading to She earned her BSc in Chemistry from Calicut University in 2014 non-aromatic adducts, while it does not undergo typical aromatic and did her MSc (2016) studies at Mahathma Gandhi University electrophilic substitutions. with specialization in Organic Chemistry. In 2018, she was award- Several synthetic approaches have been developed for the ed a DAAD fellowship and joined the research group of Prof. Dr. preparation of (benzo)pyrylium salts (Fig. 1, bottom).[1] The Olga García Mancheño at the Westfälische Wilhelms-Universität most common method relies on the condensation of carbonyl Münster, where she is currently in her second year of the PhD compounds in the presence of a strong acid (e.g. TfOH, HBF , 4 Program in Organic Chemistry. Her research interests include etc.) as shown in Fig. 1a. However, in most cases this method non-covalent asymmetric anion-binding organocatalysis and total leads to 2,4,6-trisubstituted derivatives, in which all the nucleo- synthesis of natural products. philic sites are blocked. The second most employed synthesis of Gaukhar Khassenova was born in Karaganda, an industrial (benzo)pyrylium derivatives embraces substrates bearing a leav- city in central Kazakhstan. She completed both her Bachelor and ing group (LG) at the alpha position of the oxygen atom, which Master studies in the Department of Organic Chemistry with spe- facilitates the elimination of this group (normally RO- or RCO -) 2 cialization in Chemical Technology from the Karaganda State and formation of the corresponding salt (Fig. 1b). Besides these University. In 2019, she was awarded a DAAD fellowship and methodologies, several annulation reactions, as well as enoliza- moved to Germany to pursue her doctoral studies in the group tions of (benzo)pyranones have also been widely used to generate of Prof. Dr. Olga García Mancheño at the Institute of Organic the aromatic pyrylium core (Fig. 1c and 1d, respectively). Hence, Chemistry of the Westfälische Wilhelms-Universität Münster. multiple possibilities for the synthesis of these compounds exist, Her work primarily focuses on non-covalent asymmetric anion- which make them very interesting synthetic building blocks with binding organocatalysis. a rich chemistry as they can act as electrophiles (at the ortho and Olga García Mancheño received her PhD in 2005 from the para positions) or, in the case of oxidopyryliums, as dipoles.[1] Universidad Autónoma de Madrid under the supervision of Prof. Consequently, these salts can act as versatile synthetic interme- J.C. Carretero. During her PhD she realized two short research diates for the preparation of highly added derivatives. However, stays with Prof. M.T. Reetz (MPI für Kohlenforschung) and most of the (benzo)pyrylium compounds obtained through the

*Correspondence: Prof. O. García Mancheño, E-mail: [email protected] Organic Chemistry Institute, Münster University, Corrensstrasse 36, D-48149 Münster, Germany aThese authors contributed equally. 858 CHIMIA 2020, 74, No. 11 InnovatIve tools In organIc / organometallIc chemIstry

above-mentioned methods are quite unstable, except for the more ion intermediate (Scheme 1).[5] To achieve this, they combined a robust 2,4,6-trisubstituted or flavin-type derivatives, and there- tartaric acid amide as chiral Brønsted acid and a lanthanoid tri- fore they are normally formed in situ and reacted without prior flate complex as Lewis acid system to simultaneously activate isolation. Moreover, in the past few years, their extremely high the boronate and chromene, respectively. In this case, the formed potential for the synthesis of chiral molecules has gained more reactive dioxoborolane intermediate added to the pyrylium ion, attention. Nonetheless, due to their intrinsic high reactivity, ef- which was formed upon action of the achiral inorganic cerium or ficient catalytic enantioselective transformations are still scarce. ytterbium Lewis acid.

O OH Bn N HO Bn 1 CO2H R OH Ar R1 OEt OH O (5 mol%) OH B + EtO R3 O R3 Ce(OTf) (4.5 mol%) or Et O OEt R2 4 R2 OH N O Yb(OTf)3 (4.5-13.5 mol%) HO O Ar O Ar Et R EtOAc, 4to-40 °C 68-85% yield O O N 88-98% ee Cyanidin photocatalysts tartrate-type OH Ln(OTf)n catalyst -2EtOH (Flavylium) fluorescence probes R (e.g.Ar=Ph, TPT)

Condensation O Bn N R1 HO 2 O O O O R1 O O O O 2x + Ln B R R H O B O O H Bn N O R3 O (mostly to 2,4,6-trisubstitution) 3 Et EtO Ln Bn 2 R R R2 Elimination of α-LG a) Enolization Scheme 1. Enantioselective addition of boronates to in situ-formed ben- O b) O d) zopyrylium ions. or O LG O O O or electrophile dipole In 2012, the Rueping group embraced a similar approach for O c) the generation of the active chromenium intermediate from (iso)

Annulations chromene acetals and described the first enantioselective addition O OR R1 of aldehydes to oxocarbenium ions for the synthesis of 2-sub- [6] LG O O stituted chiral chromenes (Scheme 2). They also used a dual or ,etc catalytic system consisted of Yb(OTf) as achiral Lewis acid and N2 3 O R2 a chiral imidazolidinone catalyst, in which the latter reacts with Fig. 1. Representative examples, synthetic approaches and reactivity of the carbonyl reagent to form the reactive enamine nucleophile. pyrylium derivatives. In order to facilitate the handling of the obtained chromene-aldehyde products, a final reduction to the corresponding alcohol was performed. Under these conditions, the desired chiral substituted In this review, we present the state of the art on catalytic enan- chromenes were obtained in good yields and enantioselectivities tioselective reactions involving (benzo)pyrylium salts. The review up to 96% ee. is divided in metal-catalyzed and organocatalytic approaches, which provide access to valuable O-heterocycles or important 1) O synthetic building blocks towards the synthesis of bioactive prod- N (20 mol%) ucts. Thus, the methodologies discussed here are classified based Bn N H R H OH on the catalytic system involved and type of key reaction, includ- O R Yb(OTf)3 (10 mol%) O ing diverse nucleophilic dearomatization and cycloaddition reac- + R1 O OEt H H R1 tions. 2) NaBH4,MeOH 0 °Ctor.t., 2h 13 examples 72-89% yield Yb(OTf) amino 2. Metal Catalysis 3 catalyst 75-96% ee

2.1 Metal-catalyzed Nucleophilic Dearomatization O NaBH4 N Reactions H O R 2 Ongoing efforts in this area are directed towards the devel- Bn R H O O N -aminocat. O opment of effective methodologies for the synthesis of chiral R1 EtO [Yb] 1 O-heterocycles. In this regard, the stereo-controlled synthesis of H H R biologically relevant chromenes and chromones can be achieved Scheme 2. Ytterbium-amino co-catalysis for the asymmetric addition of through the nucleophilic addition to a variety of in situ gener- aldehydes to chromeniums. ated pyrylium-type electrophilic reactive species. Two main approaches have been employed to date, which involve i) an achiral metallic Lewis acid catalyst for the formation of the pyrylium spe- Later on, Schaus and co-workers further investigated the ef- cies in combination with a chiral organocatalyst that activates the fect of Lewis and Brønsted acid cooperative catalysis for the ad- nucleophile, or ii) chiral organometallic nucleophiles, obtained dition reaction of diazoesters to 2H‐chromene acetals (Scheme by using a chiral metal catalyst formed with the appropriate chiral 3).[7] In particular, efficient C–C bond formation between pro- ligand. Thus, several lanthanoid-, gold- and copper-based cata- chiral oxocarbenium ions and ethyl diazoacetate were promoted lyzed reactions have been described so far and are presented in using Yb(OTf) and commercially available chiral phosphoric ac- 3 the next sections. ids to yield valuable chiral 2H-chromene-diazomethane scaffolds. Although most of the examples were described with a non-chiral 2.1.1 Lanthanoid Lewis Acid-catalyzed Reactions catalytic system, the asymmetric version was also explored. Thus, In 2010, Schaus and coworkers reported an example of enan- the best results were obtained with (S)-TRIP, providing the de- tioselective addition of boronates to chromene acetals involving sired enantioenriched product in 62% ee (R1 = H). a Lewis acid-promoted in situ formation of a reactive pyrylium InnovatIve tools In organIc / organometallIc chemIstry CHIMIA 2020, 74, No. 11 859

flate is carried out in order to generate in situ the corresponding si- R lyloxybenzopyrylium ion, which then reacts with a chiral copper- O O P O OH acetylene. In 2019, Aponick described the alkynylation reaction using TMSOTf as silylating agent and CuI in combination with the R 1 (S)-TRIP R1 R chiral StackPhos ligand (Scheme 6, left).[11] This method is high R1 O O R=2,4,6-(iPr)3C6H2 yielding over a broad substrate scope, providing a variety of use- + OEt O O OEt Yb(OTf)3 (5 mol%) O OEt N2 N ful chromanones in high enantioselectivity up to 95% ee. Within DCM EtO [Yb] 2 54-87% yield the framework of the research, the strong influence of the elec- 10-62% ee tronic nature of the substitution on the ligand on both the chemical Scheme 3. Enantioselective addition of diazoesters to 2H‐chromene yield and the selectivity was shown. In 2020, Mattson presented acetals. a highly stereoselective Cu-catalyzed alkyne addition to an array of chromones using in this case TBSOTf as silylating reagent and 2.1.2 Gold-catalyzed Reactions (S,S)-BnBox as chiral bis(oxazoline) ligand (Scheme 6, right).[12] Gold catalysts were also shown to be a good choice for con- Excellent levels of enantiocontrol were achieved, affording desir- ducting addition reactions on benzopyrylium-type intermediates. able 2-ethynyl chromanones in good yields and up to 98% ee. Consequently, Slaughter et al. reported in 2012 an enantioselective chiral gold(i) acyclic diaminocarbene complex catalyzed acetalization of in situ-formed isochromenylium intermediates via CuI /L* O 1 O 1 [8] R iPr2NEt (1.5-1.6 equiv.) OSiR R annulation reaction (Scheme 4). Interestingly, they observed R1 3 that the stereoselective outcome correlates with the presence of R3SiOTf (1.3 equiv.) R2 (1.3 equiv.) O O Au–arene interactions with electron‐deficient aryl groups within O -78 to -20 °C, 18 -48h OTf R2 the catalyst. Thus, the best results were obtained with a catalyst then 3or6NHCl bearing a 3,5-(CF ) C H substitution at the bi-naphthyl back- 3 2 6 3 CuI (5 mol%) Ph Ph CuI (10 mol%) bone, providing the products in excellent enantioselectivities (up L* (5.5 mol%) L* (12 mol%) N N O O to 99% ee). TMSOTf F5 TBSOTf toluene, 18 h o-xylene, 48 h PPh2 N N Bn Bn 45-98% yield 45-98% yield (S,S)-BnBox 82-95% ee (S)-StackPhos 71-98% ee 2 iPr O L*AuCl (5 mol%) OR H N LiNTf (4.5 mol%) i N H 2 O O Pr Scheme 6. Enantioselective alkynylation of chromones via in situ formed R2 OH R1 R1 Au DCE, r.t. benzopyrylium salts. R1 F C 5-87% yield 3 Cl 56-99% ee CF3 L*AuCl

Scheme 4. Au(I)-diaminocarbene complex-catalyzed acetalization of isochromenylium intermediates. 2.2 Enantioselective Metal-catalyzed Cycloadditions Involving (Benzo)pyrylium Intermediates 2.2.1 Reactions with 2-Benzopyrylium-4-olates 2.1.3 Copper-catalyzed Reactions Intramolecular carbenoid-carbonyl cyclizations represent As commented above, besides the use of achiral lanthanoid one of the most effective approaches towards target synthesis of catalysts in combination with a chiral organocatalyst, chiral cop- heterocyclic skeletons and biologically active natural products. per complexes have also been applied for achieving effective Usually, the required non-isolable reactive carbonyl ylide inter- enantioselective additions to chromene and chromone deriva- mediates are generated in situ from the corresponding diazo com- tives. Hence, in 2015 Watson described the first enantioselective pound, for which rhodium catalysts demonstrated their superior copper-catalyzed alkynylation of chromene acetals (Scheme 5).[9] efficiency in such transformations. Thus, in a first step, the reac- Following his previous work on enantioselective transition-met- tion with 2-diazo-3,6-diketoesters leads to the formation of the al-catalyzed addition to prochiral oxocarbenium ions,[10] a Lewis metal-carbonyl ylide. This intermediate can then react with vari- acid was also employed for the in situ formation of the benzopyry- ous alkene dipolarophiles as reaction partners, which normally lium intermediate. In this case, BF ·Et O was applied as Lewis 3 2 proceed in the presence of a rare earth metal triflate complex of acid instead of TMSOTf. Moreover, a chiral copper acetylide chiral 2,6-bis(oxazolinyl)pyridine (Pybox) as chiral Lewis acid was simultaneously formed in the presence of CuI and a chiral co-catalyst in order to achieve highly enantioselective 1,3-dipolar bis(oxazoline) ligand. Under these conditions, the desired chiral cycloadditions reactions. α-alkynyl oxygen heterocycles were obtained in good yields and In 1997, the first example of catalytic enantioselective tandem high enantioselectivities (up to 95% ee). carbonyl ylide formation–cycloaddition using unsaturated α-diazo- β-keto esters in the presence of Rh (S-DOSP) was reported by 2 4 Hodgson and co-workers, obtaining a moderate enantioselectivity O O (52% ee) (Scheme 7, top).[13] The same group made further efforts N N R2 R2 R2 to extend this chemistry to other types of substrates with differ- Bn (12 mol%) Bn R1 X (R,R)-BnBox ent chiral dirhodium complexes for related tandem oxidopyrylium R1 R1 formation – intramolecular 1,3-dipolar cycloaddition reactions, CuI (10 mol%) O O O OMe 3 R R3 however in all cases very poor enantioselectivities were obtained 3 28 examples BF .Et O, Cy NMe R CuL* 3 2 2 49-90% yield (<20% ee; Scheme 7, bottom).[14] Despite the moderate chiral in- toluene, -22°C 70-95% ee ductions within these initial reports, a chiral rhodium(ii)-bounded Scheme 5. Copper(I)-catalyzed additions of terminal alkynes. ylide-type was then proposed as key intermediate, which was cru- cial for the later development of further methodologies.[13,15] As a result, the enantioselective rhodium-catalyzed genera- Alternatively, the enantioselective alkynylation of 4-chromones tion of carbonyl ylides and their study in cycloaddition reactions was investigated independently by Aponick[11] and Mattson.[12] has become a vast and rapidly growing field.[15] However, only Embracing the same approach, a first treatment with a silane tri- few examples with the challenging (benzo)pyrylium derivatives 860 CHIMIA 2020, 74, No. 11 InnovatIve tools In organIc / organometallIc chemIstry

In 2010, Suga expanded his study of Rh and chiral Lewis Rh2(S-DOSP)4 acid co-catalyzed asymmetric cycloadditions of cyclic carbonyl (1 mol%) O O ylides with olefinic substrates (Scheme 9).[16d] This time, other O tBuO2C O N2 O O H (+) O Rh tBuO C lanthanoids such as Eu(OTf) , Ho(OTf) , Gd(OTf) or Lu(OTf) CO tBu 2 Rh2Ln 93% yield 3 3 3 3 2 N O Rh 52% ee (10 mol %) were used as Lewis acids in combination with the SO2Ar 4 (4S,5S)-PyBox-Ph chiral ligand, which allowed the cycloaddi- Ar =4-C12H25C6H4 2

Rh2(S-DOSP)4 tion reaction with electron-rich dipolarophiles such as allyl alco- O Rh2(S-DOSP)4 O (1 mol%) O hol, 2,3-dihydrofuran, butyl-tert-butyldimethylsilylketene acetal O C6H6,7°C O N2 O H and vinyl ethers, affording the adducts in moderate and good yield O O O 76% yield, 19% ee and moderate to high enantioselectivities depending on the addition sequence, the dipolarophile and the Lewis acid used (up to Scheme 7. Pioneer asymmetric Rh-catalyzed cycloaddition with car- 96% ee). Alternatively, a binaphthyldiimine (BINIM)–Ni(ii) com- bonyl ylides. plex (10 mol %) was more effective in the reaction with butyl or cyclohexyl vinyl ethers, leading to the corresponding products in have been described.[16] Thus, in 2002, Suga et al. developed the high enantioselectivities (up to 97% ee). first asymmetric 1,3-dipolar cycloaddition reaction of 2-benzopyrylium-4-olates catalyzed by a chiral 2,6-bis(oxazolinyl) Ln(OTf)3 OMe MeO H MeO R3 Pybox-Ph 3 pyridine (PyBox)−rare earth metal triflate complex as chiral CO2Me Rh2(OAc)4 2 R H (2 mol%) O (10 mol%) 2 OR1 O R + O [16a] CHN2 1 R2 Lewis acid catalyst (Scheme 8, A). The substrate for the cy- DCM R2 OR O r.t. -reflux O OR1 O O cloaddition reaction, the 2-benzopyrylium-4-olate, was formed 3 R endo exo 1 from 2-methoxycarbonyl-α-diazoacetophenone (R = Me) us- Eu/Gd/Ho(OTf)3 Lu(OTf)3 O OTBS 75:25-90:10 endo/exo 13:87-8:92 endo/exo dipolarophiles OH OR ing commercially available Rh (OAc) in catalytic amounts (2 61-99% yield 52-98% yield 2 4 OBu mol%). Depending on the dipolarophile reagent used, two dif- 51-96% ee 60-84% ee ferent Lewis acid catalytic systems were identified. The Sc(iii)− OMe MeO Pybox-iPr (10 mol%) proved highly selective for the reactions Rh (OAc) BINIM–Ni(II) CO2Me 2 4 2 N (2 mol%) O (10 mol%) with benzyloxyacetaldehydes and pyruvates (R = H), affording 2 O OR N N R' DCM, reflux R' OR R' the endo-adducts in a high enantioselectivity up to 93% ee and O O R=Bu, Bn, Cy O N O O O N endo reverse exo-selectivity with 87% ee, respectively. Alternatively, 66-99% yield theYb(iii)−Pybox-Ph catalyst provided the best results with 3-ac- 42-97% ee (R)-BINIM ryloyl-2-oxazolidinone (R4 = H), this time giving the exo-adduct Scheme 9. Asymmetric cycloadditions of cyclic carbonyl ylides with ole- (exo/endo = 88:12) with an extremely high enantioselectivity of finic substrates. 98% ee. A few years later, the same group was able to extend the method to other diazoacetophenones and improve the reaction with pyruvates and α-ketoesters (R2 = Alk, Ph, CO Et) by add- 2 2.2.2 Reactions Comprising Metallo-benzopyrylium ing a different organic acid as additive (10-20 mol% TFA instead Complexes of pyruvic acid) using the same co-catalysis with Rh (OAc) and 2 4 Several highly enantioselective oxa-Diels−Alder cycloaddi- the chiral PyBox-lanthanoid metal complexes (Scheme 8, B).[16b] tion reactions of in situ generated metallo-isochromenyliums have Based on these results, the stereoselective cycloaddition reactions been described, leading to efficient one-step access to a broad with 3-(2-alkenoyl)-2-oxazolidinones as dipolarophiles catalyzed spectrum of enantiopure natural product-like derivatives of me- by PyBox-Yb(OTF) complexes was further developed (Scheme 3 dicinal interest. 8, C).[16c] They found out that the use of the 5-substituted Pybox- In 2009, Tanaka reported the first cooperatively catalyzed cas- Ph ligand (20 mol%) led to cycloaddition reaction products with cade reaction by cationic rhodium(i) and silver(i) complexes via high endo- (>99:1) and enantioselectivity (up to 96% ee), while a isochromenylium intermediates between o-alkynylbenzaldehydes disubstitution (PyBox-Ph ) provided the exo-adducts with lower 2 and N-substituted isatin derivatives in the presence of a ferrocenyl- selectivities (exo/endo ≤ 82:18). phosphine ligand complex (Scheme 10).[17] As a result, the corresponding helical tetrasubstituted alkenes in high enantio- and diastereoselectivities were obtained. Accordingly, a possible mechanism was proposed starting from the intramolecular reaction of the O OR1 O R MeO 2-alkynylbenzaldehyde to form rhodiumbenzopyrylium complex O O N A: O O endo/exo =18:82 A. Although there is no precedent for a cycloaddition between the O O 96% ee R Rh (OAc) R4 metalbenzopyrylium intermediate and a C=O bond, it was antici- 2 4 O N O Yb(III)-PyBox-Ph 1 4 OR (2 mol%) O R =H (10-20 mol%) exo pated that the reaction with isatin could form B. The intermediate CHN2 Lewis acid 1 DCM OR O R O B further evolved to a rhodacycle C, which finally gave the tetra- O C: O R1O R N O endo/exo >1:99 substituted alkene upon elimination of the Rh(i) catalytic species. 4 up to >99% ee O O R Later, Yao et al. reported in 2013 the enantioselective oxa- O Yb(III)-PyBox-Ph or O Ar H 4 Yb(III)-PyBox-Ph Diels−Alder cycloaddition reaction involving isochromenium in- O endo O R ≠H 2 OR3 (10-30 mol%) termediates by cooperative binary catalysis employing Pd(OAc) A: Sc(III)-PyBox-i-Pr R2 2 (10-20 mol%) O and (S)-Trip (Scheme 11).[18] Particularly, they described the MeO MeO O O asymmetric cascade annulation between 2-hydroxystyrenes and O O Me R’’ N R’’ O O N N 2-alkynylbenaldehydes or 1-(2-alkynylphenyl)ketones affording CO Bn 2 R’ PyBox R’ OCH2Ar the corresponding bridged cyclic products with good to excellent O O (S,S)-PyBox-i-Pr R’ = i-Pr,R’’ =H endo exo enantioselectivities (up to >99.5% ee). This method could be ap- ’ ’’ endo/exo =upto91:9 endo/exo =upto3:97 (S,S)-PyBox-Ph R =Ph, R =H ’ ’’ plied with high efficiency for a broad spectrum of substrates, al- up to 93% ee A: +piruvic acid ≤87% ee (4S,5S)-PyBox-Ph2 R ,R =Ph B: +TFA up to 95% ee lowing the simultaneous creation of dense multiple chiral centers Scheme 8. One-pot Rh-mediated generation of 2-benzopyrylium- including quaternary carbons. 4-olates for Sc(II) or Yb(III)-PyBox catalyzed 1,3-dipolar cycloaddition In the following year, Yao extended his research on enantiose- reactions by Suga et al. lective annulation via pyrylium-type intermediates using syner- InnovatIve tools In organIc / organometallIc chemIstry CHIMIA 2020, 74, No. 11 861

O O H OMe O [Rh(cod)2]BF4 (5 mol%) Me Me PPh2 F C CF (R,R)-SL-W005-1 (5 mol%) H 3 3 PPh2 1 PPh (5 mol%) 1 Me R1 R 3 R Me CF3 R1 AgBF4 (10 mol%) P BnO C + O O 2 MeO P O DCM,r.t. O N Fe Me H BnO C Me H (R)-H8-BINAP (3 mol%) 2 R2 CF3 Z H O AuCl(SMe) (5 mol%) 19-96% yield (R,R)-SL-W005-1 Z 2 O N 2 20- >99% ee Cu(OTf)2 (5 mol%) R minor product 2 1 (1.1 equiv) R d.r.>99:1 R2 DCE,r.t. R 5-19% yield, 78-93% ee I 20-94%yield -[Rh ] Z=C(CO R) ,NTs (rt to -80 °C) 2 2 4-53% ee H I 1 O O [Rh] [Rh ] H R H R1 O O O O O O R1 1 [Rh] O 1 O R N 2 1 Z R R N R2 Z R [Au] [Rh] O Z AB C R2 R2 [Au] Z [Au] [Au] R2 Scheme 10. Rh(I) and Ag(I) co-catalyzed synthesis of chiral helical tetra- 2 R R1 substituted alkenes. Scheme 13. Asymmetric Au-catalyzed intramolecular [4+2]-annulation of ene-yne-carbonyls. 5 6 2 O R R 1 R O 1 R R Pd(OAc)2 (2.5 mol%) R4 6 R2 (S)-TRIP (3.75 mol%) R R R7 R5 + R4 3. Organocatalysis DCM, N ,r.t. R7 OH 2 O 3 O Enantioselective organocatalysis has become an important R O R3 P 38-92% yield O OH tool in organic synthesis for the efficient preparation of chi- * 19- >99.5% ee O P [21] [Pd] ral molecules. Particularly, highly efficient chiral Brønsted R1 O R R3 (S)-TRIP acid,[22] hydrogen-bonding[23] and amino[24] catalysts have been H R=2,4,6-(iPr)3C6H2 O O R7 developed for a broad spectrum of asymmetric transformations, R2 including enantioselective organocatalytic reactions of (benzo) R5 R6 R4 pyrylium derivatives, which will be discussed in the next sections.

Scheme 11. Enantioselective oxa-Diels−Alder cycloaddition via isochro- 3.1 Brønsted Acid-catalyzed Reactions menium intermediates. The first asymmetric Brønsted acid (BH) catalyzed hydrogenation of benzopyrylium ions was reported by Rueping and co- getic catalysis by applying AgOAc and the chiral phosphoric acid workers (Scheme 14).[25] They described a photo-assisted in situ (S)-TRIP as catalytic system (Scheme 12).[19] In this case, they generation of 2-chromenols derived from chalcones, followed by investigated the reaction of 3-alkynylacrylaldehydes with styrene- benzopyrylium ion formation and hydrogenation employing a type olefins, affording the corresponding products with moder- Hantzsch allyl ester (HaE). A mechanism involving a Brønsted ate to excellent enantioselectivities (up to 95% ee). The proposed acid-catalyzed chromenol protonation and successive elimina- mechanism implies a cascade reaction pathway that involves the tion of a H O molecule resulted in an intermediary chiral ion pair 2 in situ generation of a pyrylium intermediate by Ag(i)-catalyzed consisting of the benzopyrylium and the chiral B– anion. Then, alkyne/carbonyl cycloisomerization, followed by an oxa-[4+2]- subsequent enantioselective hydride nucleophilic addition at cycloaddition and an intramolecular nucleophilic substitution. the 4-position of the benzopyrylium ion gave rise to the desired 4H-chromenes with a broad substrate scope.

1 1 R 2 R R R3 1 O O H R 2 H AgOAc R R2 H B* (2.5 mol%) 3 R 1 1 + OH + Ar O Ar (S)-TRIP (3.75 mol%) * O O O 1 BH (5 mol%) 1 H R 2 R 50-98% yield 3 DCE, r.t. Ar HaE (1.3 equiv) R 23-50% 12-80% 80-94% ee 15-95% ee 20-92% ee OH Toluene, -20 oC, hv O Ar2 2 R2 R [Ag] 1 “H-“ R =H,Me, OMe O hv Ar1 =Ph, 4-MePh, 4-tBuPh, O 1 O 1 P R R * P O 1 4-FPh,4-ClPh, 3-BrPh O or 1 Ar H * O Ar Ar2 =Ph, 3-MePh,4-MePh, 1 1 R O H O R H B* 4-PentPh OH Type 1 Type 2 3 3 R -H O 2 R O Ar2 2 O Ar B* Scheme 12. Silver-TRIP-catalyzed enantioselective annulation of chiral ion pair 3-alkynylacrylaldehydes. Ar O O O H H O P O O O OH More recently, in 2019, Tanaka and co-workers reported an N asymmetric intramolecular [4+2]-annulation of ene-yne-carbon- Ar H yls via benzopyrylium-type intermediates catalyzed by a cationic *BH Hantzsch allyl ester Ar = [H8]-2,4,6-(iPr) C H (HaE) gold(i)/(R)-H -binap complex (Scheme 13).[20] Under these condi- 3 6 2 8 tions, the targeted chiral tricyclic compounds bearing two stereo- Scheme 14. Asymmetric ion-pair catalysis for the enantioselective genic centers were obtained as single diastereomers but with only hydrogenation of pyrylium ion. moderate enantiomeric excess (up to 53% ee). Additionally, when more sterically demanding naphthalene-linked ene-yne carbonyls reacted with the gold(i) catalyst, not only [4+2]-annulation took Shortly after, Terada and coworkers reported a similar enan- place, but also [3+2]-annulation adducts were obtained as minor tioselective reduction of benzopyrylium ions with the Hantzsch products with good enantioselectivity (up to 93% ee). ester (HE) in the presence of the same chiral Brønsted acid (*BH) 862 CHIMIA 2020, 74, No. 11 InnovatIve tools In organIc / organometallIc chemIstry

(Scheme 15). The only difference was that the benzopyrylium is OH *BH (10 mol%) R1 derived directly from the corresponding chromenol, showing the Na3PO4 (2 equiv) O OH best enantioselectivities (up to 96% ee) when substituted as tert- R2 toluene, r.t. PF [26] 6 R1 butyl ether in the 6-position. 1 R =Cl, Br,OMe O R2 =H,Me, tBu, Ph, Br,OMe R2 52-83% yield Ar1 Ar1 71-96% ee *BH (5 mol%) H PF6 t tBuO HE (1.2 equiv) BuO 85-99% yield Base-H O O O R OH 74-96% ee * O P insoluble o O O Ar2 toluene, -20 C, hv O Ar2 PF Base 6 R2 C8H17 Ar Ar1 =Ph, 4-MePh, 4-MeOPh, 4-ClPh 1 O O R 2 O O -H2O Ar =Ph, 4-MeOPh, 4-MePh * P * O P O O O OH O O R P 3 *BH soluble O OH O R * B* O O P C8H17 Ar chiral ion pair HO O O *BH O R Ar =2,4,5 (iPr) C H Scheme 15. Chiral anion catalysis of the enantioselective reduction of H 3 6 2 O R O 1-benzopyrylium ion. OH

An alternative example of the asymmetric reaction of the pla- Scheme 17. CAPT-catalyzed enantioselective addition of phenol to nar isobenzopyrylium species was reported by Sun and coworkers benzopyrylium ion. in 2014 (Scheme 16).[27] They proposed a highly enantio- and diastereoselective synthesis of dihydronaphthalenes by nucleophilic the asymmetric synthesis of methyl rocaglate[29] by an enantiose- addition of a styryl boronic acid to isobenzopyrylium ions in the lective [3+2]-photocycloaddition of an oxidopyrylium derivate presence of a chiral phosphoric acid as catalyst (*BH) and MgSO with methyl cinnamate in the presence of a TADDOL derivative 4 as the additive. The excellent stereocontrol is presumably attribu- I (Scheme 18).[30] The observed diastero- and enantioselectivity ted to the unusual chiral counteranion generated in situ from the was rationalized by the formation of an assembly between the chiral phosphoric acid and the boronic acid nucleophile, as well oxidopyrylium and the catalysts by hydrogen bonding with the as the employed ethylenglycol leaving group that also activates free hydroxyl groups of TADDOL-I, stabilizing the dipole. the nucleophile. Moreover, the reaction is compatible to both electron-withdrawing and electron-donating groups on the acetal 1) hv >350 nm HO HO OMe O MeO CO2Me o MeO CO2Me HO substrates. OH TADDOL-I,-70 C HO toluene /DCM MeO O 2) NaOMe /MeOH MeO MeO 3) Me4NBH4(OAc)3 2 2 OMe R R endo methyl rocaglate exo methyl rocaglate OMe *BH (10 mol%) Ar Ph OMe 1 7% yield R CO2Me 52% yield O 89% ee 78% ee (HO)2B O PMP R1 O O PMP P O MeO Ar Ar MgSO4 O OH Ar Ar OMe OH Ph HO O O OH O DCM, 0°C, 22 h O OH Ar 72-97% yield HO O O OH *BH MeO O Ar O O 77-97% ee Ar Ar Ar R2 Ar =9-anthryl TADDOL-I * O P OMe Ar :pyren-1-yl OH R-B(OH)2 R1 Ar Scheme 18. Synthesis of methyl rocaglate via asymmetric [3+2]-photo- -H2O [4+2] O O * [BX]3 cycloaddition of oxidopyrylium ions. P O PMP O R1 PMP B R1 =F,CF ,Me, MeO,TBSO O O H 3 R2 =H,nBu, F, Br,OMe, CN, HO etc.. However, despite the high synthetic potential of HB-catalysis, the first organocatalytic enantioselective reaction of benzopyry- Scheme 16. Enantio- and diastereoselective synthesis of 1,2-dihydro- liums was reported by Mattson and coworkers in 2016 (Scheme naphthalenes from isobenzopyryliums. 19).[31] They developed an intermolecular addition to 4-chromenones via the corresponding 4-siloxy benzopyrylium triflate Likewise, Toste and coworkers employed chiral phosphoric intermediates in the presence of 3,3’-substituted BINOL-based acids (*BH) for the enantioselective synthesis of flavonoids from silanediol as a H-bond donor catalyst. The reaction mechanism benzopyrylium ions using chiral anion phase transfer (CAPT) ca- proceeds via the in situ generation of a chiral benzopyrylium ion talysis (Scheme 17).[28] The proposed biosynthetic pathway pro- pair from a chromenone and silyl triflate in the presence of the ceeds through the generation of a soluble chiral benzopyrylium bidentate silanediol catalyst, followed by a biased addition of silyl ion pair from an insoluble benzopyrylium cation in the presence ketene acetals as nucleophiles. However, this method required a of the deprotonated chiral phosphoric acid catalyst. Thus, this high catalyst loading of 20 mol% to achieve moderate enanti- soluble ion pair can then react with phenols to generate the enan- oselectivities. Moreover, the substrate scope of this reaction was tioenriched flavonoid-type products. examined, showing that chromenones substituted with electron- withdrawing groups were higher yielding and more selective than 3.2 Hydrogen-bond Donor-catalyzed Nucleophilic substrates possessing electron-donating groups. Additions to (Benzo)pyryliums A few years later, the group of García Mancheño devel- Chiral hydrogen-bond (HB) donor catalysis[23] has also been oped a related highly enantioselective nucleophilic dearomatiza- employed to effect the activation of (benzo)pyrylium electro- tion reaction of in situ formed pyrylium-type derivatives using a philes towards cycloaddition or nucleophilic addition reactions. chiral multi-coordination triazole anion-binding catalyst (Scheme As the first non-catalytic example using stoichiometric HB- 20).[32] The high activity observed with this type of catalyst, which donors as promoters, in 2006, Porco and coworkers described allows remarkably low catalytic loadings (down to 0.05 mol%), is InnovatIve tools In organIc / organometallIc chemIstry CHIMIA 2020, 74, No. 11 863

OSiR2 O R CHO 1 O OSiR2 R H O Me R1 OMe O N R2SiOTf TfO catalyst (20 mol%) O OMe tBu 2 O Ph O Ph N O R =(i-Pr) 1-4 h, -78 °C 2,6-lutidine (1 equiv.) O Ph H TFA toluene (0.05 M) 50-90% yield + + OTf DCM, -25 °C or 0°C 1 20-50% ee R =F,Cl, Br,CF3, O H R CHO Si R CHO 13-97% yield NO ,CH * 2 3 O H H 1:1 -9:1 d.r. R=nHex, iPr,Bn (20 mol%) major: 52-92% ee OSiR3 minor: 2-76% ee O Ph OMe Scheme 21. Organocatalytic stereoselective oxidative benzylic C–H functionalization of flavenes.

Nap2- 2-Nap OSiR

Si 3 * type intermediates under H-bond donor cooperative catalysis was HO OH O H Si reported by Jacobsen and co-workers in 2011 (Scheme 22).[36] O TfO O H They identified a cooperative chiral aminothiourea–achiral thio- chiral ion-pair urea catalytic system for the intramolecular [5+2]-cycloadditions of pyrylium ylides with olefins to access tricyclic structures. This Scheme 19. Silanediol-catalyzed enantioselective benzopyrylium ion reaction relies on properties of the achiral thiourea anion-binding functionalization. co-catalyst II to facilitate the cleavage of corresponding carbox- ylate anion, while the chiral amino catalyst III activates the sub- due to the presence of four strongly polarized C–H bonds at the strate by covalent bonding to form the reactive 3-aminopyrylium triazole units and further multiple coordination sites of neighboring intermediate. Moreover, the addition of acetic acid as a second C–H bonds. Moreover, they are able to form helical structures with cocatalyst enhanced the yield with no effect on the product enan- distinct anion-binding pockets, as well as to potentially interact with tioselectivity. The substrate scope of this reaction was examined, the pyrylium species through the lone pair of the nitrogen atoms in showing that various terminal substituted olefins and allenes were the triazole rings. This method proved to be highly enantioselective tolerated, despite diminished reactivity upon increased substitu- (up to 96% ee) and broad in scope, allowing not only the reaction tion, while alkyne-bearing substrates were unreactive under the with the more stable chromenium salts, but also with simple pyryli- reported reaction conditions. ums, with no ring opening or decomposition of the latter.

‡ O II (15 mol%) S Ph * S O OTBS OTBS O III (15 mol%) Ar Ar O OBzSp-Me AcOH (15 mol%) N N 3 O Triazole-cat* R R N N R R R3 O H H OiPr H H 2 (0.05-5 mol%) O 1 Ph NH R R toluene (0.4 M), 40 °C 1 OO R TBSOTf * O O OTf O OiPr R2 O 45-77% yield 60-94%yield 1 Ar 80-95% ee R=H, F, Cl, Br,NO2, chiral contact ion pair 56-96% ee R =H,Me, CO2Me Me, OMe, Bn, etc... R2 =H,Me, Ph 3-aminopyrylium R3 =TBSOMe OMe MeO CF CF N N 3 3 Ph N N N N S S H H N N H H H F3C N N CF3 Ph NH H H H 2 N H H N II III N N H H N N

CF F C 3 3 Scheme 22. Intramolecular enantioselective oxidopyrylium-based F3C CF3 Triazole-cat* [5+2]-cycloadditions.

Scheme 20. Dearomatization of pyrylium derivatives using helical multi- dentated anion-binding catalysts. In a continuation of the work, in 2014, the author reported a related intermolecular version of enantioselective [5+2]-cycloadditions of 3,4,5-trifluorobenzoyloxypyrylium salts with electron- 3.3 Amino and Dual Amino-HB-donor Catalysis rich olefins promoted by the same co-catalytic system to obtain In 2009, Cozzi and coworkers described an oxidative benzylic the corresponding 8-oxabicyclo[3.2.1]octane derivatives (Scheme C–H functionalization of 4H-flavene with octanal in the presence 23).[37] The need for an electron-rich 2π-reactant such as vinyl of a MacMillan imidazolidinonium-type catalyst. In this reaction, ethers is consistent with a mechanism involving a cationic, elec- DDQ was used as stoichiometric oxidant to generate in situ the fla- tron-poor aminopyrylium intermediate. Regarding the substrate vylium species, which was attacked by the nucleophilic enamine scope, pyranones bearing longer alkyl chains at the 6-position formed from the aldehyde and chiral amino-catalysts, yielding show high enantioselectivities, whereas β-branching in the side the corresponding 4-functionalized derivative in a moderate 62% chain had a deleterious effect on the reactivity. ee.[33] These initial results inspired them to pursue the synthesis of further chiral 4H-flavenes by enantioselective α-alkylation of aldehydes with stable flavylium triflate, leading to the desired products in moderate to good yields, diastereoselectivities and F II (20 mol%) enantioselectivities (Scheme 21).[34] F O III (20 mol%) O O Besides this nucleophilic enamine-type addition, amino and AcOH (15 mol%) 1 O + 3 R F O OR R2 the combination of amino and HB-donor catalysis have also been 2 toluene (0.2 M) 1 O R 3 reported for enantioselective cycloadditions. Pyrylium ylides are LG R (5 equiv) 72 h, 23 °C H OR versatile and reactive species that have been used widely in natu- 1 26-95% yield R =H,CH2OTBS 2 65-96% ee ral product synthesis, particularly due to their ability to undergo R =CH2,CH2iPr, nC6H13,CH2OTBS, Bn [5+2]-cycloaddition reactions.[35] In this regard, the first example R3 =Et, Bn, MOM of asymmetric [5+2]-cycloaddition involving 3-oxidopyrylium- Scheme 23. Intermolecular [5+2]-cycloadditions. 864 CHIMIA 2020, 74, No. 11 InnovatIve tools In organIc / organometallIc chemIstry

In a similar manner, Vicario and coworkers proposed the use ment of new methods with enhanced stereocontrol and robustness, of chiral bifunctional secondary amine-squaramide catalysts for as well as broader substrate scope, is envisioned in the near future. the [5+2]-cycloaddition between α,β-unsaturated aldehydes and oxidopyrylium ylides (Scheme 24).[38] The mechanism of the Acknowledgements reaction is based on a dienamine activation of the enal by con- S.J. and G.K. acknowledge the financial support by the DAAD PhD- densation with amino group, while the bifunctional catalyst also program. directs the approach of the ylide through the squaramide unit by hydrogen-bonding interactions. Thus, the dienamine intermediate Received: June 8, 2020 participates as a chiral dipolarophile in the reaction with the in situ formed oxidopyrylium upon elimination of the acetate leaving [1] a) A. T. Balaban, A. Dinculescu, G. N. Dorofeenko, G. W. Fischer, A. V. Koblik, V. V. Mezheritskii, W. Schroth, ‘Pyrylium Salts: Syntheses, group, which results in the formation of the 8-oxabicyclo[3.2.1] Reactions and Physical Properties’, Vol. 2, Academic Press 1982; b) T. S. octane scaffold. Balaban, A. T. Balaban, ‘Pyrylium Salts’, in ‘Science of Synthesis’, Vol. 15, Georg Thieme Verlag: Stuttgart, 2004, pp 11–200; c) Y. Pang, D. Moser, J. Cornella, Synthesis 2020, 52, 489. O O [2] Ø. M. Andersen, K. R. Markham, ‘Flavonoids: Chemistry, biochemistry and applications’, CRC Press, Taylor & Francis, 2006. N N [3] See for example: a) P. Czerney, G. Graness, E. Birckner, F. Vo llmer, W. O H H CF3 NH Rettig, J. Photochem. Photobiol. A: Chem. 1995, 89, 31; b) B. K. Wetzl, S. (8 mol%) M. Yarmoluk, D. B. Craig, O. S. Wolfbeis, Angew. Chem. Int. Ed. 2004, 43, O F3C O ‡ O O 5400; c) H. Lv, X.-F.Yang,Y. Zhong,Y. Guo, Z. Li, H. Li, Anal. Chem. 2014, AcO DABCO (1.5 equiv) N H2O(3equiv) H 86, 1800; d) B. Dong, X. Song, X. Kong, C. Wang, Y. Tang, Y. Liu, W. Lin, O H O O THF,10°C Adv. Mat. 2016, 28, 8755. - H -AcO ,-H2O R [4] M. A. Miranda, H. García, Chem. Rev. 1994, 94, 1063. R [5] P. N. Moquist, T. Kodama, S. E. Schaus, Angew. Chem. Int. Ed. 2010, 49, R 60-92% yield R=H,Alk, Ar,Bz, CH2NHCbz, etc… dienamine activation 93-98% ee 7096. [6] M. Rueping, C. M. R. Volla, I. Atodiresei, Org. Lett. 2012, 14, 4642. Scheme 24. Enantioselective [5+2]-cycloaddition under dienamine acti- [7] Y. Luan, Y. Qi, H. Gao, Q. Ma, S. E. Schaus, Eur. J. Org. Chem. 2014, 6868. vation. [8] S. Handa, L. M. Slaughter, Angew. Chem. Int. Ed. 2012, 51, 2912. [9] H. D. Srinivas, P. Maity, G. P. A. Yap, M. P. Watson, J. Org. Chem. 2015, 80, 4003. More recently, an alternative approach for the chiral ami- [10] P. Maity, H. D. Srinivas, M. P. Watson, J. Am. Chem. Soc. 2011, 133, 17142. [11] L. G. DeRatt, M. Pappoppula, A. Aponick, Angew. Chem. Int. Ed. 2019, 58, no-catalyzed enantioselective [5+2]-dipolar cycloaddition of 8416. oxidopyrylium ylides with cinnamaldehydes was reported by [12] Y. Guan, J. W. Attard, A. E. Mattson, Chem. Eur. J. 2020, 26, 1742. Brenner-Moyer and coworkers (Scheme 25).[39] They employed [13] D. M. Hodgson, P. A. Stupple, C. Johnstone, Tetrahedron Lett. 1997, 38, oxidopyrylium dimers as the ylide precursors for the asymmetric 6471. cycloaddition reaction with electron-poor dipolarophiles acces- [14] D. M. Hodgson, P. A. Stupple, C. Johnstoneb, ARKIVOC 2003, 7, 49. [15] See for example: a) M. P. Doyle, D. C. Forbes, Chem. Rev. 1998, 98, 911; b) sible through iminium catalysis using the Jorgensen-Hayashi pyr- H. Suga, H. Ishida, T. Ibata, Tetrahedron Lett. 1998, 39, 3165; c) S. Kitagaki, rolidine catalyst. The oxidopyrylium ylide dimer reactant enabled M. Anada, O. Kataoka, K. Matsuno, C. Umeda, N. Watanabe, S. Hashimoto, the use of substoichiometric quantities of both TfOH as strong acid J. Am. Chem. Soc. 1999, 121, 1417. and N,N-diisopropylaniline (DIPEA) as a base, which was critical [16] a) H. Suga, K. Inoue, S. Inoue, A. Kakehi, J. Am. Chem. Soc. 2002, 124, 14836; b) H. Suga, K. Inoue, S. Inoue, A. Kakehi, M. Shiro, J. Org. Chem. to attain the best yields, selectivities and reaction times. Hence, 2005, 70, 47; c) H. Suga, T. Suzuki, K. Inoue, A. Kakehi, Tetrahedron 2006, excellent enantioselectivities (up to 99% ee) were achieved. 62, 9218; d) H. Suga, S. Higuchi, M. Ohtsuka, D. Ishimoto, T. Arikawa, Tetrahedron 2010, 66, 3070. [17] D. Hojo, K. Noguchi, K. Tanaka, Angew. Chem. Int. Ed. 2009, 48, 8129. Ph [18] S.-Y. Yu, H. Zhang, Y. Gao, L. Mo, S. Wang, Z.-J. Yao, J. Am. Chem. Soc. Ph MeO ‡ N 2013, 135, 11402. H O MeO O TMSO O [19] H. Zhang, L. Zhu, S. Wang, Z.-J. Yao, J. Org. Chem. 2014, 79, 7063. O OMe (20 mol%) O [20] T. Koshikawa, M. Satoh, K. Masutomi, Y. Shibata, K. Tanaka, Eur. J. Org. R O O O R Chem. 2019, 1488. O i-Pr2NPh /TfOH N OMe (0.4 equiv) R [21] P. I. Dalko, ‘Comprehensive Enantioselective Organocatalysis: Catalysts, O Reactions, and Applications’, Vol. 1-3, Wiley‐VCH Verlag, Weinheim, 2013. oxidopyrylium R=(het)Ar, TMSO Ph Ph 48-91% yield dimer CO2Me, etc... [22] a) M. Rueping, D. Parmar, E. Sugiono, ‘Asymmetric Brønsted Acid 91-99% ee Catalysis’, Wiley‐VCH Verlag, Weinheim, 2016. See also: b) J. Itoh, K. Scheme 25. Amino-catalyzed enantioselective dipolar cycloadditions. Yokota, K. Fuchibe, T. Akiyama, Angew. Chem. Int. Ed. 2004, 43, 1566; c) D. Uraguchi, M. Terada, J. Am. Chem. Soc. 2004, 126, 5356. [23] a) H. Miyabe, ‘Hydrogen-Bonding Activation in Chiral Organocatalysts’, I. Karame, H. Srour, IntechOpen, 2016. For few selected reviews, see: b) A. G. 4. Conclusions Doyle, E. N. Jacobsen, Chem. Rev. 2007, 107, 5713; c) M. S. Taylor, E. N. The application of both metal and organic catalysis for enan- Jacobsen, Angew. Chem. Int. Ed. 2006, 45, 1520. tioselective reactions of pyrylium species has evolved in recent [24] For a selected review, see: P. Melchiorre, M. Marigo, A. Carlone, G. Bartoli, years into a powerful methodology for the creation of diverse Angew. Chem. Int. Ed. 2008, 47, 6138. [25] C.-C. Hsiao, H.-H. Liao, E. Sugiono, I. Atodiresei, M. Rueping, Chem. Eur. molecular frameworks in a regio- and stereoselective fashion. J. 2013, 19, 9775. Most of the approaches employed to date deal with the intrin- [26] M. Terada, T. Yamanaka, Y. Toda, Chem. Eur. J. 2013, 19, 13658. sic electrophilic nature of the pyrylium salt or dipole character [27] H. Qian, W. Zhao, Z. Wang, J. Sun, J. Am. Chem. Soc. 2015, 137, 560. of the related oxidopyrylium derivatives. Thus, enantioselective [28] Z. Yang, Y. He, F. D. Toste, J. Am. Chem. Soc. 2016, 138, 9775. nucleophilic dearomatization and cycloaddition reactions domi- [29] P. Proksch, R. Edrada, R. Ebel, F. I. Bohnenstengel, B. W. Nugroho, Curr. Org. Chem. 2001, 5, 923. nates this research field, leading to single, fused or bridged chiral [30] B. Gerard, S. Sangji, D. J. O’Leary, J. A. Porco, J. Am. Chem. Soc. 2006, O-heterocycles. However, despite the substantial progress in this 128, 7754. field and the applied variety of approaches for the functionaliza- [31] A. M. Hardman-Baldwin, M. D. Visco, J. M. Wieting, C. Stern, S.-i. Kondo, tion of pyrylium ions, novel catalytic methodologies applicable A. E. Mattson, Org. Lett. 2016, 18, 3766. [32] T. Fischer, J. Bamberger, M. Gómez-Martínez, D. G. Piekarski, O. García in more complex sceneries towards biologically relevant chiral Mancheño, Angew. Chem. Int. Ed. 2019, 58, 3086. O-heterocycles are still of huge interest in the scientific commu- [33] F. Benfatti, M. G. Capdevila, L. Zoli, E. Benedetto, P. G. Cozzi, Chem. nity. Therefore, a substantial advance in this field by the develop- Commun. 2009, 45, 5919. InnovatIve tools In organIc / organometallIc chemIstry CHIMIA 2020, 74, No. 11 865

[34] F. Benfatti, E. Benedetto, P. G. Cozzi, Chem. Asian J. 2010, 5, 2047. License and Terms [35] For a review on [5+2]-cycloaddition reactions in organic and natural product This is an Open Access article under the synthesis: K. E. O. Ylijoki, J. M. Stryker, Chem. Rev. 2013, 113, 2244. terms of the Creative Commons Attribution [36] N. Z. Burns, M. R. Witten, E. N. Jacobsen, J. Am. Chem. Soc. 2011, 133, License CC BY_NC 4.0. The material may 14578. not be used for commercial purposes. [37] M. R. Witten, E. N. Jacobsen, Angew. Chem. Int. Ed. 2014, 53, 5912. [38] A. Orue, U. Uria, E. Reyes, L. Carrillo, J. L. Vicario, Angew. Chem. Int. Ed. The license is subject to the CHIMIA terms and conditions: (http:// 2015, 127, 3086. chimia.ch/component/sppagebuilder/?view=page&id=12). [39] K. N. Fuhr, D. R. Hirsch, R. P. Murelli, S. E. Brenner-Moyer, Org. Lett. The definitive version of this article is the electronic one that can be 2017, 19, 6356. found at https://doi.org/10.2533/chimia.2020.857