Asymmetric reactions involving isobenzopyrylium ion intermediates

Isobenzopyrylium ions are highly reactive intermediates which have wide applications in synthetic chemistry. A range of catalytic reactions based on isobenzopyrylium, such as 1,2-nucleophilic addition, [4+2] and [3+2] cycloaddition provide a powerful protocol for constructing complex natural and unnatural products. Their asymmetric variations have been less explored, possibly owing to the lack of coordination sites within their planar structures. This mini-review summarizes the asymmetric transformations developed involving isobenzopyrylium ion intermediates. These works are arranged according to the reaction types. The catalytic systems and reaction mechanisms are described

Since its discovery, the rich chemistry of isobenzopyrylium has been amply demonstrated in the literature, and has provided a powerful protocol for constructing complex natural and unnatural products.8][39][40][41][42][43][44] The asymmetric transformations of isobenzopyrylium ions have been less explored. 45This may be because the planar 10 π-electron aromatic structure of the isobenzopyrylium ion lacks an obvious coordination site for a chiral catalyst which is often crucial for achieving high stereoselectivity.Their highly reactive properties also increased the difficulty in obtaining ideal enantioselective results.
This mini-review summarizes the asymmetric transformations involving isobenzopyrylium intermediates.The works are organised according to the different reaction types, aiming to encourage chemists to think about such cation intermediate from different points of view, thereby identifying new enantioselective transformations with these species.

Asymmetric [4+2] Cycloaddition and Related Cascade Reactions
The first asymmetric transformation of isobenzopyrylium was achieved by Tanaka's group in 2009. 46Prior to that, this group had discovered a highly enantioselective annulation of 2-alkynylbenzaldehydes 1 with isatins 2 catalyzed by a cationic rhodium(I)/chiral bisphosphine complex. 47A variety of spirocyclic isatin derivatives 3 were obtained in good yields with high ee values.These spiro-compounds were believed to be formed through the [4+2] cycloaddition of carbonyl compounds 2 with five-membered acylrhodacycle intermediates 2B, which were formed by the intramolecular addition of a rhodium hydride species 2A to the pendant alkyne group (Scheme 2a).Both alkyl-and aryl-substituted 2-alkynylbenzaldehydes could react smoothly with N-protected or NH-free isatin.However, when 2-alkynylbenzaldehyde with a cyclohexenyl group at the alkyne terminus was tested, a moderate yield of tetrasubstituted (helical) alkene 4 was unexpectedly isolated along with a small amount of the expected spirocyclic isatin 3 (Scheme 2b).The reaction selectivity could be greatly improved through a change of chiral ligand (L2 vs L1, 99:1 vs 3:2 ratio).After further optimization, the authors found addition of AgBF4 and PPh3 was beneficial for the formation of chiral tetrasubstituted alkenes 4 (Scheme 3).A possible reaction pathway was proposed as follows: the intramolecular cyclization of 2alkynylbenzaldehydes 1 under the activation of π-electrophilic cationic transition-metal complex generated isobenzopyrylium intermediate 3A, which reacted with the C=O bond of N-methylisatin 2 via [4+2] enantioselective cycloaddition pathway to form ketoaldehyde 3C through adduct intermediate 3B.
Enantioselective intramolecular ketone hydroacylation of 3C proceeded through rhodacycle 3D to furnish the desired tetrasubstituted alkene 4. Control experiments suggested AgBF4 was necessary for good yields.It was believed to promote the π-electrophilicity of the cationic rhodium(I) complex, which is essential for the formation of intermediate 3A.But its precise role is not clear at present.PPh3 was envisaged to occupy free coordination sites of the rhodium catalyst, with the result of preventing the interaction of rhodium with AgBF4.This interaction was believed to lower the catalytic activity towards both π-and σ-bond activation.With the optimal reaction conditions, a variety of tetrasubstituted helical alkenes 4 were obtained in good yields with excellent enantioselectivities, which might be applied to light-driven molecular motors, owing to their fascinating switching properties under UV irradiation. 48cheme 2. Different reaction results of 2-alkynylbenzaldehydes with isatins.

Scheme 3. Asymmetric [4+2] cycloaddition of isobenzopyrylium with isatins.
Following the interest in exploring the chemistries of isobenzopyrylium salts, many cascade transformations based on [4+2] cycloadditions were found to show high efficiency in constructing complex multiring structures with multiple stereogenic centers.In 2013, Yao's group reported an asymmetric cascade annulation between 2-hydroxystyrenes and in situ generated isobenzopyrylium intermediates based on the enantioselective [4+2] cycloaddition by cooperative binary catalysis of Pd(OAc)2 and chiral phosphoric acid (CPA-1, S-Trip). 49The developed method could construct a chiral tetrahydronaphthalene framework in a highly efficient manner.Such a skeleton represents a new type of conformationally constrained analog of podophyllotoxin (PPT), a well-known anticancer natural drug lead. 50,51Mechanistic investigation suggested that the counter-anion of Pd(II) was very important for the reaction (AcO -vs Cl -) (Scheme 4a), and the orthophenolic hydroxyl group in the styrene substrate was also essential to achieve this type of highly enantioselective cascade transformations (Scheme 4b).Based on these results, a possible reaction pathway was proposed (Scheme 5).Firstly, the alkyne bond of o-alkynylbenzaldehyde 5 was activated by Pd(OAc)2 to faciliate the intramolecular cycloisomerization, affording Pd(II)-isobenzopyrylium intermediate 5A.The suitable anion of the isobenzopyrylium salt favored the anionic exchange with (S)-Trip.The resulting intermediate 5B linked with the o-hydroxystyrene 6 through hydrogen-bond between the phenolic OH of the styrene and the P=O of Trip to assemble a highly ordered supramolecular assembly transition state.Then "intramolecular" asymmetric [4+2]-cycloaddition generated carbocation 5C, which was quickly trapped by the internal phenol hydroxyl to provide 5D.Finally, the protonation of 5D with HOAc delivered product 7 and regenerated the metal catalyst Pd(OAc)2.The high degree of enantioselectivity was considered to stem from both the steric hindrance of the bulky 1,3,5-triisopropylphenyl group of (S)-Trip moiety and the hydrogenbond interactions between the phenolic hydroxyl group of substrate 6 with the P=O functionality of (S)-Trip.1,2-Dihydronaphthalenes represent an important structural motif in many natural products and biologically active molecules. 52,53They are also important synthetic intermediates toward various tetrahydronaphthalene molecules.5][56] However, regarding their asymmetric synthesis, for a long time the traditional dearomatization of electron-deficient naphthalene has been the major approach.It not only suffers from limited substrate scope (electron-deficient) but also requires the use of either chiral auxiliary or stoichiometric chiral ligands. 57,58Indeed, truly catalytic asymmetric approaches remain few.In 2015, the Sun group disclosed an organocatalytic enantio-and diastereoselective synthetic method for 1,2-dihydronaphthalenes based on the [4+2] cycloaddition of isobenzopyrylium intermediate with boronic acid (Scheme 6). 59In this work, acetal 8 was chosen as isobenzopyrylium precursor.Obviously different from other asymmetric transformation of isobenzopyrylium, this excellent asymmetric induction is achieved for the first time without an anchoring group or a metal catalyst in the 4-position of isobenzopyrylium.Only by treatment with chiral phosphoric acid (CPA-2), did the elimination of the alkoxy group from acetal 8 afford an isobenzopyrylium intermediate and generate a well-organized cyclic counteranion in the process, which was formed in situ by the combination of the leaving alkoxy group, the boronic acid 9 and the chiral phosphate.Such an unusual chiral counteranion served as a reactive nucleophile with chiral moiety in close proximity to react with isobenzopyrylium intermediate in sufficient chiral induction manner.Then the resulting bicyclic zwitterion underwent intramolecular elimination to give the desired dihydronaphthalene product 10 with satisfactory selectivity.
The authors believed that excellent enantioselectivity was attributed to the well-organized cyclic counteranion.

Asymmetric Hydrogenation
4] Nevertheless, the enantioselective version of this reaction has rarely been reported.In 2013, Akiyama and co-workers developed an alternative method for chiral 1-substituted-1H-isochromenes through the copper(II) phosphate-catalyzed intramolecular cyclization/asymmetric transfer hydrogenation sequence of o-alkynylacetophenone by asymmetric counterion-directed catalysis (ACDC). 65Since the term was coined in 2006, the use of enantiomerically pure counteranions for the induction of asymmetry in reactions proceeding through cationic intermediates has emerged as a powerful tool for a range of asymmetric transformations and greatly promoted by the incorporation of chiral binaphthyl phosphoric acids. 66,67Inspired by these great success, the Akiyama group surmised that intramolecular 6-endo-dig cycloisomerization of o-alkynyl acetophenone 11 activated by transition metal could afford a cationic metallic isobenzopyrylium intermediate, which could form a tight ion pair with the chiral phosphate counteranion to subsequently induce the desired asymmetric hydrogenation (Scheme 7).After careful screening of reaction conditions, this asymmetric sequence was achieved by the catalysis of copper(II)/ chiral phosphate which formed in situ from Cu(OTf)2, Ag2CO3 and chiral chiral phosphoric acid (CPA-3).With the stereocontrol of chiral counteranion, chiral 1substituted-1H-isochromenes containing various substituents were obtained in high yields with good to excellent enantioselectivities with Hantzsch esters as hydrogen source.

Scheme 7. Asymmetric hydrogenation of isobenzopyrylium by the catalysis of ACDC.
At almost the same time, the Terada group reported the chiral silver phosphate catalysed enantioselective transformation of ortho-alkynylaryl ketones into 1H-isochromene derivatives by ACDC.Different from Akiyama's work, this intramolecular-cyclization/enantioselective-reduction sequence was conducted with the chiral silver phosphate prepared in advance from Ag2CO3 and the corresponding binol-derived phosphoric acid. 680][71] Encouraged by these findings, the authors attempted to use these catalysts for the asymmetric hydrogenation of the highly reactive isobenzopyryliums.Because isobenzopyryliums were often generated in situ by treatment of ortho-alkynylaryl ketones with various metal catalysts, it was thus important to find two compatible catalysts for the overall reaction that also controlled the chemoselectivity and enantioselectivity.After optimization of reaction conditions, they successfully developed tandem catalysis with a binary system consisting of Cu(OTf)2 and chiral cationic ruthenium-diamine complex 13 (Scheme 8). 72heme 8. Asymmetric hydrogenation of isobenzopyrylium by tandem catalysis.
Activated by Cu(OTf)2, the intramolecular cyclization of ortho-alkynylaryl ketone 11 generated isobenzopyrylium 8A.Meanwhile, the ruthenium-diamine catalyst 13 reacted with dihydrogen to produce Ru-H complex 8C and TfOH.Then protonolysis of the C-Cu bond of 8A by TfOH regenerated Cu(OTf)2 and gave another isobenzopyrylium intermediate 8B.Finally, hydride transfer from the Ru-H complex 8C to isobenzopyrylium intermediate 8B afforded the desired product 12 and regenerated the ruthenium-diamine catalyst 13.

Asymmetric Nucleophilic Addition
Following the electrophilic cyclization of o-alkynylaryl carbonyl compounds, nucleophilic addition reactions at the 1-position of isobenzopyrylium ions have been demonstrated as another efficient method for the construction of 1-substituted 1H-isochromene derivatives.A wide variety of nucleophiles involving oxygen, [73][74][75][76] nitrogen, 77 phosphites, 78 terminal alkynes, 79 allyl trialkysilanes 80,81 and activated methylenes 82-86 proved to be applicable substrates.][89][90] Nevertheless, their asymmetric version remains underdeveloped.Thus far, the reported asymmetric nucleophilic addition of isobenzopyrylium has been limited only to the addition of alcohols and activated methylene compounds.
In 2012, Slaughter and co-workers achieved asymmetric formation of chiral 1-alkoxyisochromenes through the enantioselective addition of alcohols to isobenzopyryliums in the presence of a gold(I) acyclic diaminocarbene complex (Scheme 9). 74[99][100] However, in some intriguing reports, the secondary interactions of ligands-Au were found to be helpful to overcome the inherent difficulty of achieving chiral environment, and thus high enantioselective results have been achieved with gold catalysts in some asymmetric reactions. 101Encouraged by these findings, Slaughter's group firstly created three gold acyclic diaminocarbene complexes 14-16, and then investigated their solidstate structural differences through their X-ray crystal structures.Compared with 14 and 15, a significantly more pronounced chiral environment at the metal center was observed in 16 owing to the presence of the aryl group adjacent to Au.This difference was directly reflected on the ability of chiral induction.Only with gold complex 16 were good yields and high enantioselectivities attained.However, for alcohols containing shorter n-alkyl chains or alkynes containing n-propyl instead of an aryl group, a new Au(I)/ADC complex 17 must be employed for ideal results.The chiral amine substituent in this modified catalyst 17 was believed to augment the chiral environment at the metal through steric interactions with the binaphthyl moiety.
3][104] In 2016, the Enders group demonstrated the type of asymmetric addition could be realized under a combination of Ag2CO3 and chiral phosphoric acid, but only with moderate success (Scheme 10a). 105Just recently, Peng and his co-workers disclosed an efficient asymmetric addition of isobenzopyrylium with diazomethylphosphonate as Cnucleophile (Scheme 10b). 106Considering that transition-metal catalyst was still attached to the isobenzopyrylium ion at the 4-position after it activated the alkyne bond to conduct the intramolecular cyclization, the authors surmised that it could be exploited to create a chiral environment.The central metal coordinated with a chiral ligand possessing a sufficiently long arm, which might pass on chiral environment proximity to the 1-position, and thus, asymmetric nucleophile addition could be achieved at this position.8][109][110] The results of ligand screening showed that the BOXes with a cyclic ring at the bridging carbon gave better stereoselectivity than these with simple substituents, and the substituents at the 4,4'-position of the ligand also had a great effect on the catalytic performance.Ultimately, bis(oxazoline) ligand 18 combining with AgOTf was established as the optimal catalytic system.A variety of functional phosphine-containing isochromenes derivatives bearing tetrasubstituted stereocenters at the 1-position were easily prepared with up to 94% enantiomeric excess.The deuterium labeling experiment and DFT calculation were further performed to get more insight into the reaction mechanism.The steric hindrance between the isobenzopyrylium and attacking diazomethylphosphonate affected the facial coordination of Ag (I) and chiral ligand, which was considered to be the main reason for the satisfactory stereoselectivity.Scheme 9. Asymmetric nucleophilic addition of alcohols to isobenzopyrylium.Scheme 10.Asymmetric C-nucleophilic addition to isobenzopyryliums.

Conclusions
Although the planar aromatic structure of isobenzopyrylium intermediates posed great challenges to their asymmetric transformations, many asymmetric reactions have been achieved with good to excellent diastereoselectivities by asymmetric counterion-directed catalysis, cooperative catalysis or unusual chiral ligands in recent years.And thus, a series of optically pure 1H-isochromene derivatives, 1,2dihydronaphthalenes or complex polycyclic compounds could be obtained in efficient and straightforward manners through asymmetric hydrogenation, asymmetric nucleophilic addition and asymmetric [4+2] cycloaddition and related cascade reactions.Inspired by these works, we believe that more interesting asymmetric reactions will be disclosed, such as asymmetric [3+2] cycloaddition reactions which remain unexplored in this stage.

Scheme 4 .
Scheme 4. Control experiments for the investigation of mechanism.

Shuyan
Yu was born in Anhui province, China, in 1985.She is presently an assistant professor at Material and Chemical Engineering College, Zhengzhou University of Light Industry.She received her BSc and MSc degree in 2007 and 2010, respectively, in chemistry and organic chemistry from School of Chemistry and Materials Science, Anhui Normal Universty, Wuhu, Anhui province, China.She graduated with PhD degree in organic chemistry from Nanjing Universtity, Jiangsu provinve, China in 2013.Her research interests focus on the development of efficient methods for heterorcyclic compounds based on alkyne functionalization.Hengyu Qian was born in Shandong province, China, in 1979.He is presently an associate professor at Material and Chemical Engineering College, Zhengzhou University of Light Industry.He graduated with BSc in chemistry from School of Chemistry and Chemical Engineering, Qufu Normal University in 2000.And then received Master's degree in organic chemistry at College of Chemistry, Zhengzhou University in 2004.His research interests focus on the synthesis of palladium complexes and their application in C-C cross-coupling reaction.