CC BY-ND-NC 4.0 · SynOpen 2019; 03(03): 77-90
DOI: 10.1055/s-0039-1690686
short review
Copyright with the author(s) (2019) The author(s)

Catalytic Enantioselective Approaches to the oxa-Pictet–Spengler Cyclization and Other 3,6-Dihydropyran-Forming Reactions

Zhengbo Zhu
a  Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, Florida 32611, USA   eMail: seidel@chem.ufl.edu
,
Alafate Adili
a  Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, Florida 32611, USA   eMail: seidel@chem.ufl.edu
,
b  Department of Chemistry, University of California–Berkeley; Materials Sciences Division, Lawrence Berkeley National Laboratory; Kavli Energy NanoSciences Institute at Berkeley; Berkeley Global Science Institute, Berkeley, California 94720, USA
,
a  Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, Florida 32611, USA   eMail: seidel@chem.ufl.edu
› Institutsangaben
This material is based upon work supported by the National Science Foundation under grant CHE–1856613.
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Publikationsverlauf

Received: 24. August 2019

Accepted after revision: 04. September 2019

Publikationsdatum:
25. September 2019 (online)

 


Abstract

This Short Review provides an analysis of the state-of-the-art in catalytic enantioselective oxa-Pictet–Spengler cyclizations. Also discussed are other catalytic reactions providing access to enantio­enriched isochromans and tetrahydropyrano[3,4-b]indoles. Context is provided and remaining challenges are highlighted.


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Biographical Sketches

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Zhengbo Zhu was born and raised in Jiangxi, China. He earned his B.Sc. degree in the Department of Chemistry and Chemical Engineering at Nanjing University working with Prof. Chengjian Zhu. In 2014, he moved to Rutgers University for his graduate studies, joining the group of Prof. Daniel Seidel. In August of 2017, he moved with the Seidel group to the University of Florida. His research focuses on asymmetric Brønsted acid catalysis and redox-neutral α-C–H bond functionalization of cyclic amines.

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Alafate Adili was born and raised in Xinjiang, China. He earned his B.Sc. degree in the Department of Chemistry at the University of Science and Technology of China (USTC) working with Prof. Liu-Zhu Gong. In 2016, he started his Ph.D. research at Rutgers University under the direction of Prof. Daniel Seidel. In August of 2017, he moved with the Seidel group to the University of Florida. His research focuses on asymmetric catalysis.

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Chenfei Zhao was born in China in 1989 and received his B.Sc. at Wuhan University of Technology in 2012. He obtained his Ph.D. (2017) from Rutgers University working on cooperative catalysis under the direction of Prof. Daniel Seidel. He is currently a postdoctoral researcher in Prof. Omar M. Yaghi’s lab at UC Berkeley working on reticular chemistry.

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Daniel Seidel studied chemistry at the Friedrich-Schiller-Universität Jena, Germany, and at the University of Texas at Austin (Diplom 1998). He performed his graduate studies in the laboratory of Prof. Jonathan L. Sessler­, obtaining his Ph.D. in 2002. From 2002 to 2005, he was an Ernst Schering Postdoctoral Fellow in the group of Prof. David A. Evans at Harvard University. He started his independent career at Rutgers University in 2005 and was promoted to Associate Professor in 2011 and Full Professor in 2014. In the summer of 2017, his research group moved to the University of Florida.

Among compounds containing a 3,6-dihydropyran core, isochromans and tetrahydropyrano[3,4-b]indoles have captured particular interest in the synthetic and medicinal chemistry communities. A small selection of compounds containing these core frameworks is shown in Figure [1]. The isochroman heterocycle is a ubiquitous component of natural products often possessing intriguing bioactivities, such as ilexisochromane,[1] penicisochroman B,[2] and blapsin B.[3] Synthetic isochromans include the antiapoptotic agent ISO-09[4] and the 5-HT1D agonist PNU-109291.[5] Examples of bioactive tetrahydropyrano[3,4-b]indoles are the anti-inflammatory agent etodolac,[6] the potent analgesic agent pemedolac,[7] and the non-nucleoside inhibitor of hepatitis C virus HCV-371.[8] The perhaps most desirable way to access isochromans and tetrahydropyrano[3,4-b]indoles in a stereocontrolled­ fashion is by means of the oxa-Pictet–Spengler cyclization; a process in which an oxocarbenium ion intermediate undergoes ring-closure onto a pendent aryl substituent.[9] In this Short Review, we provide examples of asymmetric oxa-Pictet–Spengler cyclizations that are under substrate control, discuss all known catalytic enantioselective variants of the oxa-Pictet–Spengler cyclization,[10] and provide an overview of other catalytic enantioselective reactions that lead to isochromans and tetrahydropyrano[3,4-b]indoles. In addition, we outline remaining challenges in this area.

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Figure 1 Examples of naturally occurring and artificial bioactive isochromans and tetrahydropyrano[3,4-b]indoles

The Pictet–Spengler reaction was discovered in 1911 and involves the HCl-promoted condensation of β-phenethylamine and formaldehyde dimethyl acetal to form 1,2,3,4-tetrahydroisoquinoline (Scheme [1]).[11] The definition of the Pictet–Spengler reaction was later expanded to ­include cyclizations of imines or iminium ions possessing a covalently linked aryl group that undergoes substitution upon ring-closure.[12] While the apparently first example of an oxa-Pictet–Spengler reaction dates back to 1935,[13] when the synthesis of isochroman from chloroether 1 was disclosed in a patent by Buschmann and Michel (Scheme [1]), the term oxa-Pictet–Spengler cyclization was coined by Wünsch and Zott only in 1992.[14] While it was found that β-phenylethanol can condense directly with formaldehyde or paraformaldehyde in the presence of aqueous HCl to form isochroman without the need to first isolate 1, this approach inadvertently leads to side products containing chloromethyl groups on the phenyl ring (not shown).[14] [15] As outlined in Scheme [1], the general mechanism of the oxa-Pictet–Spengler reaction involves the formation of an oxocarbenium ion, followed by ring closure and subsequent deprotonation/rearomatization. Both the Pictet–Spengler cyclization and the oxa-Pictet–Spengler cyclization can be viewed as variants of an intramolecular Friedel–Crafts alkylation.[16] In addition, the oxa-Pictet–Spengler cyclization is mechanistically related to certain types of the Prins reaction.[17]

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Scheme 1 Original reports on the Pictet–Spengler reaction and its oxygen analogue, along with its general mechanism

For the majority of the history of the oxa-Pictet–Spengler reaction, asymmetric variants were limited to cyclizations of enantioenriched starting materials.[9] Several illustrative examples of such diastereoselective oxa-Pictet–Spengler cyclizations are provided in Scheme [2]. A chiral auxiliary based approach was reported by Costa et al., utilizing β-ketoester 3 derived from (–)-β-pinene.[18] Condensation of tryptophol (2)[19] with β-ketoester 3 is facilitated by SnCl4, resulting in the formation of product 4 with excellent diastereoselectivity. Interestingly, the use of BF3 etherate in place of SnCl4 provides a 1:1 mixture of product diastereomers. The ratio of the starting materials and the amount of the Lewis acid are not specified in this report. Also, the absolute configuration of product 4 remains unknown. A highly diastereoselective oxa-Pictet–Spengler cyclization was reported by Fernandes­ and Brückner in the course of a synthesis of (+)-kalafungin.[20] Exposure of 5 to two equivalents of acetaldehyde dimethyl acetal and excess BF3 etherate provides product 6 as a single diastereomer in excellent yield. As part of their synthesis of (–)-platensimycin, Eey and Lear explored the conversion of 7 into 8 via an interesting type of oxa-Pictet–Spengler cyclization under a variety of conditions.[21] Although the reaction can be facilitated with a large excess of SnCl4 (8 equiv), the optimal conditions involve exposure of 7 to a catalytic amount of Bi(OTf)3 (5 mol%) in the presence of lithium perchlorate (3 equiv) and molecular sieves in dichloromethane at room temperature, allowing for the isolation of polycyclic product 8 in excellent yield. A recent example of a Brønsted acid catalyzed diastereoselective oxa-Pictet–Spengler cyclization was reported by Da and co-workers.[22] Tryptophol derivative 9, derived from the enantioselective CBS reduction of the corresponding ketone, engages benzaldehyde dimethyl acetal in the presence of a catalytic amount of trifluoroacetic acid to furnish tetrahydropyrano[3,4-b]indole 10 in excellent yield and dr. Consistent with the expected mechanism of this transformation, the ee of product 10 matches that of the starting material 9.

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Scheme 2 Examples of diastereoselective oxa-Pictet–Spengler reactions with optically active starting materials

The first documented efforts toward developing a catalytic enantioselective variant of the oxa-Pictet–Spengler reaction were disclosed by Doyle in 2008.[23] Evaluation of a number of (thio)urea catalysts in direct condensations of tryptophol with a range of aldehydes and ketones, either in the absence or presence of various Brønsted and Lewis acid additives and dehydrating agents, was reported to lead to tetrahydropyrano[3,4-b]indole products with low levels of enantioinduction (<15% ee, not shown). Significant increases in reactivity and appreciable levels of enantioselectivity are observed with tryptophol-derived mixed acetoxy-acetals­ such as 11; precursors that enable the formation of the requisite oxocarbenium ion intermediates under milder conditions (Scheme [3]). Exposure of 11 to trimethylsilyl chloride in the presence of thiourea catalyst 13 furnishes product 12 in excellent yield and encouraging 49% ee (absolute configuration not established). Higher levels of enantioselectivity are obtained with N-MOM protected tryptophol acetals 14 (Scheme [4]). Reactions of acetals 14, performed under identical conditions, provide the corresponding products 15 with up to 81% ee (absolute configuration of products not established). Promising preliminary results for catalytic enantioselective oxa-Pictet–Spengler cyclizations were also obtained with acetoxy-acetals derived from a number of β-heteroaryl ethanols (Scheme [5]). Regarding the mechanism of these transformations, the hydrogen-bond donor[24] thiourea catalyst most likely interacts with chloride via anion-binding,[25] forming a chiral ion pair with the oxocarbenium ion.

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Scheme 3 Thiourea-catalyzed enantioselective oxa-Pictet–Spengler cyclization with mixed acetals derived from tryptophol
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Scheme 4 Thiourea-catalyzed enantioselective oxa-Pictet–Spengler cyclization with N-MOM protected tryptophol acetals, selected scope
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Scheme 5 Thiourea-catalyzed enantioselective oxa-Pictet–Spengler cyclizations involving various heterocycles

Another early example of a catalytic enantioselective oxa-Pictet–Spengler cyclization was reported by Scheidt and co-workers in 2013 (Scheme [6]).[26] Chiral phosphoric acid catalyst 19 is capable of converting preformed enol ether 17 into the corresponding cyclization product 18 with a moderate level of enantiocontrol (absolute configuration not established). Here, the intermediate oxocarbenium ion is generated by protonation of enol ether 17 by the chiral Brønsted acid 19.[27]

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Scheme 6 Brønsted acid catalyzed enantioselective oxa-Pictet–Spengler­ cyclization with a preformed enol ether

Shortly thereafter, Nielsen and co-workers reported a related approach in which enol ethers are generated in situ from allyl ethers via a ruthenium catalyzed isomerization process (Scheme [7]).[28] Application of this strategy to allyl ether 20, in the presence of chiral imidodiphosphoric acid 22, furnishes product 21 in good yield. While the enantio­selectivity achieved in this reaction is only moderate (absolute configuration not established), this is the only example thus far that generates a tetrasubstituted stereogenic center in the course of an oxa-Pictet–Spengler cyclization. The E/Z selectivity of the initial isomerization step is unknown.

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Scheme 7 Dually catalyzed enantioselective oxa-Pictet–Spengler cyclization of an allyl ether

The first highly enantioselective catalytic oxa-Pictet–Spengler cyclization was reported by our group in 2016 (Scheme [8]).[29] In the presence of thiourea catalyst 24 and ammonium salt catalyst 25, tryptophol (2) undergoes an oxa-Pictet–Spengler reaction with benzaldehyde to form product 23a in excellent yield and ee. Substituted benzaldehydes also participate in this reaction. While para-substituted benzaldehydes provide products with excellent ee, meta-substitution leads to a slight drop-off in enantioselectivity, and ortho-substitution results in a significant erosion of ee (e.g., product 23f). Substitution of the indole ring is compatible with the catalytic system, whereas aliphatic aldehydes are not viable reaction partners. Mechanistically, this method is based on a dual catalysis strategy that avoids the need for strongly acidic conditions commonly required for accessing oxocarbenium ions via direct condensation of aldehydes and alcohols. The ammonium salt catalyst 25 is thought to first engage the aldehyde to form an iminium ion[30] that then reacts with tryptophol, ultimately resulting in the formation of an oxocarbenium ion that likely interacts with the catalyst via anion-binding. A plausible transition state for the key C–C bond-forming step is shown in Scheme [8]. This model is supported by the following observations: (1) there is a strong dependence on the nature of the anion with regard to reactivity and product ee; (2) The enantioselectivity of the reaction is solely dependent on catalyst 24 (e.g., almost identical results are obtained with the enantiomer of 25 or racemic 25), and (3) The reaction with N-methyl tryptophol provides racemic product (e.g., product 23k), indicating an important interaction of the indole N-H with a hydrogen-bond acceptor site on the catalyst (e.g., the S-atom of the electron-rich thiourea moiety) in the enantio-determining step of the reaction. Interestingly, catalyst 25 can be replaced with HCl to provide the product with nearly identical ee but in a significantly more sluggish reaction.

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Scheme 8 Dually catalyzed enantioselective oxa-Pictet–Spengler reactions of tryptophols with aldehydes

Nearly simultaneously to our report, the List group reported a distinct strategy for realizing highly enantioselective oxa-Pictet–Spengler cyclizations (Scheme [9]).[31] Nitrated imidodiphosphoric acid catalyst 28 was found to efficiently catalyze reactions of hydroxy-substituted β-phenylethanols with aldehydes. Catalyst 28 is significantly more active than the analogous imidodiphosphoric acid catalyst lacking the two nitro groups. The corresponding BINOL-based phosphoric acid 29 is also a competent catalyst but affords the products with significantly lower levels of enantioselectivity. Catalyst 28 provides products 27 with excellent ee values while accommodating a range of aromatic and aliphatic aldehydes, with the latter requiring elevated reaction temperatures­ (50 °C). An additional methoxy group on 26a is also tolerated. The proposed transition state for the C–C bond-forming step involves a critical hydrogen-bonding interaction of the catalyst anion with the phenol O-H moiety, as elucidated by DFT calculations. An alternate transition state in which ring-closure occurs in ortho- rather than para-position of the phenol O-H moiety was calculated to be 6.3 kcal/mol higher in free energy (not shown). Consistent with these calculations, these regioisomers are not observed.

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Scheme 9 Imidodiphosphoric acid catalyzed enantioselective oxa-Pictet­–Spengler reactions of hydroxy-substituted β-phenylethanols with aldehydes

Interesting observations were made in the course of the List study, outlining remaining challenges (Scheme [10]). Consistent with the calculated transition state depicted in Scheme [9], the presence of a 3-hydroxy substituent on the β-phenylethanol is a strict requirement. In the presence of catalyst 29, β-phenylethanols 26bd react with aldehydes to provide symmetrical acetals 30 as the only products. On the other hand, the 2-hydroxy substrate 31 undergoes formation of seven-membered cyclic acetal 32, whereas 33 affords complex mixtures in reactions with aldehydes.

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Scheme 10 Current limitations in oxa-Pictet–Spengler reactions with β-phenylethanols

In 2018, Scheidt and co-workers published an alternate strategy to access tetrahydropyrano[3,4-b]indoles in highly enantioenriched form.[32] A combination of chiral phosphoric acid catalyst 36 and achiral urea catalyst 37 facilitates cyclizations of tryptophol-derived enol ethers such as 34a to generate oxa-Pictet–Spengler products with high levels of enantioselectivity (e.g., 35a). The presence of a urea-type protecting group on the tryptophol nitrogen is a crucial design element of this approach (vide infra). While chiral phosphoric acid 36 is capable of catalyzing the reaction in the absence of urea 37, reaction rates are dramatically retarded (incomplete reaction after 18 h vs. complete reaction within 15 min) and afford product 35a in only 36% ee (not shown). Regarding the scope of this transformation, substitution of different indole ring positions is readily accommodated. While most products contain a gem-dimethyl group adjacent to the tetrahydropyrano oxygen atom, products lacking these substituents are also obtained with excellent ee values. Interestingly, this study contains the only example thus far reported in which a seven-membered ring is constructed enantioselectively in the course of an oxa-Pictet–Spengler cyclization, albeit in only 32% ee (product 35i). As an application of their method, the authors reported a facile synthesis of coixspirolactam C from oxa-Pictet–Spengler­ product 35h. Regarding the mechanism of this transformation, it was proposed that a network of hydrogen-bonding interactions is responsible for achieving high levels of reactivity and enantiocontrol (see proposed TS in Scheme [11]). Specifically, the thiourea catalyst is thought to bind to the chiral phosphate anion via dual hydrogen bonding while engaging in an additional hydrogen-bonding interaction with the carbonyl group of the protonated substrate.

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Scheme 11 Dually catalyzed enantioselective oxa-Pictet–Spengler reactions of tryptophol-derived enol ethers

While not aiming to be complete, the following section provides an overview of catalytic enantioselective reactions that lead to oxa-Pictet–Spengler type products by alternate pathways also involving the intermediacy of oxocarbenium ions. As exemplified in the synthesis of enantioenriched isochromans, nucleophilic additions to cyclic oxocarbenium ions provide an alternative to the oxa-Pictet–Spengler cyclization (Figure [2]). While cyclic isochroman-type oxocarbenium ions are more stable than their corresponding acyclic counterparts by virtue of conjugation with the fused and necessarily coplanar aryl ring, they offer an expanded array of opportunities for designing enantioselective variants. To render oxa-Pictet–Spengler cyclizations catalytic and enantioselective, the anion X has to be homochiral (e.g., conjugate base of a chiral Brønsted acid catalyst). Alternatively, if achiral, X has to be tightly associated with a chiral anion receptor catalyst (or catalyst ensemble) in order to facilitate the ring-closure step in an enantioselective fashion. These modes of enantiocontrol are also available in nucleophilic additions to cyclic oxocarbenium ions. In addition, the otherwise achiral nucleophile can be rendered chiral by interaction with a chiral catalyst. Nucleophiles can be carbon- or heteroatom-based, enabling the formation of monosubstituted isochromans via a reductive process.

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Figure 2 Different pathways to enantioenriched isochromans.

A 2008 landmark study by the Jacobsen group accomplished the first catalytic enantioselective synthesis of 1-substituted isochromans (Scheme [12]).[33] [34] Treatment of isochroman-derived acetal 38 with BCl3 results in the in situ formation of 1-chloroisochroman (not shown), which is then converted into product 39a upon treatment with silyl ketene acetal 41 in the presence of thiourea catalyst 40. Binding of the chloride counter anion of the transient oxocarbenium ion to thiourea catalyst 40 is thought to form a chiral ion pair responsible for controlling the facial selectivity in the silyl ketene acetal addition step. Isochromans containing substituents on different positions of the aryl ring and a range of silyl ketene acetals participate in this transformation to provide products 39 in good yields and excellent ee values.

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Scheme 12 Catalytic enantioselective additions of silyl ketene acetals to cyclic oxocarbenium ions
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Scheme 13 Catalytic enantioselective alkynylation of isochroman-derived­ oxocarbenium ions

In 2011, Watson and co-workers reported a conceptually different strategy for the catalytic enantioselective addition of nucleophiles to isochroman-derived oxocarbenium ions (Scheme [13]).[35] Specifically, catalytic enantioselective alkynylation of acetal 38 with phenylacetylene is achieved with a Cu(I) complex of bisoxazoline ligand 43. Hünig’s base facilitates the formation of a chiral Cu acetylide complex that adds to the oxocarbenium ion derived from acetal 38 and TMSOTf. The reaction tolerates substituents on different positions of the isochroman aryl ring and is applicable to a range of terminal alkynes. Some products are somewhat sensitive to oxidative decomposition (e.g., lactone formation). This is particularly true for product 42h (the yield shown corresponds to the product obtained from subsequent reduction of the alkyne moiety to the corresponding alkane via hydrogenation). An impressive extension of this chemistry was reported in 2015 (Scheme [14]).[36] A modified catalyst system derived from Pybox ligand 46 enables the synthesis of highly enantioenriched isochromans 45 from 1-substituted isochroman ketals 44. This is a rare example of a catalytic enantioselective process generating isochromans containing challenging tetrasubstituted stereogenic centers.

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Scheme 14 Formation of tetrasubstituted stereogenic centers via catalytic enantioselective alkynylation of isochroman-derived oxocarbenium ions

Acetals such as 38 are typically obtained from their corresponding isochromans via an oxidative process. In 2014, the Liu group reported a strategy that obviates the need for preparing acetals in a separate step (Scheme [15]).[37] [38] Oxocarbenium ions are accessed in situ by oxidation of isochromans with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). Addition of the aldehyde substrate is facilitated by catalyst 48 via an enamine mechanism. Reduction of the initially formed aldehyde products with sodium borohydride provides substituted isochromans (e.g., 47ag) and related products with excellent levels of enantioselectivity, albeit with moderate diastereoselectivity. As part of this study, the Liu group achieved the catalytic enantioselective addition of boronic ester 51 to isochroman (Scheme [16]). This reaction is facilitated by tartaric-acid-derived catalyst 50 and provides product 49 with moderate ee after hydrogenation in situ.[39]

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Scheme 15 Catalytic enantioselective addition of enolizable aldehydes to isochromans
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Scheme 16 Catalytic enantioselective addition of a boronic ester to isochroman

In 2017, the Liu group reported an interesting redox deracemization strategy that provides highly enantioenriched isochromans 52 (Scheme [17]).[40] Racemic starting materials such as (±)-52a are oxidized in situ by DDQ to the corresponding oxocarbenium ions, which initially form acetals in the presence of methanol. The subsequent reduction step with Hantzsch ester 54 is rendered enantioselective by imidodiphosphoric acid catalyst 53. In a subsequent study, similar products were obtained by reduction of preformed racemic acetals (not shown).[41] Products 52a could potentially be obtained more directly via an oxa-Pictet–Spengler cyclization from the corresponding β-phenylethanols. However, current limitations make this an elusive goal (see discussion centered around Scheme [10]). The Liu group further applied their redox deracemization strategy to the synthesis of highly enantioenriched tetrahydropyrano[3,4-b]indoles, as highlighted in Scheme [18].[42] For these substrates, SPINOL-derived phosphoric acid 55 and Hantzsch ester 56 provide optimal results. Tetrahydropyrano[3,4-b]indoles containing an aryl substituent are typically obtained in excellent yields and ee values. Unfortunately, just like the previously discussed oxa-Pictet–Spengler reaction of tryptophol is incompatible with aliphatic aldehydes (see Scheme [8]), the deracemization process does not tolerate 1-alkyl substituents as these substrates fail to undergo oxidation under the standard reaction conditions.

Another strategy for synthesizing enantioenriched isochromans, different from everything discussed thus far, involves reactions in which the enantio-determining step is C–O bond formation. Scheme [19] highlights seminal work in this area, published by Kitamura and co-workers in 2011.[43] Ruthenium complex 59, at a catalyst loading of only 0.1 mol%, facilitates intramolecular dehydrative O-allylation of 57 to furnish 1-vinyl isochroman 58a in excellent yield and ee in a sequence that proceeds via the intermediacy of a Ru-π-allyl species.

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Scheme 17 Catalytic redox deracemization of isochromans
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Scheme 18 Catalytic redox deracemization of tetrahydropyrano-[3,4-b]indoles

A mechanistically distinct approach published by White and co-workers in 2016 accomplishes the synthesis of related isochroman products by intramolecular catalytic enantio­selective allylic C–H oxidation (Scheme [20]).[44] A complex derived from palladium acetate and ligand 61, in the presence of diphenylphosphinic acid, catalyzes the transformation of β-arylethanols such as 60 to 1-vinyl isochromans 58, and the products are obtained with excellent levels of enantioselectivity. 2,6-Dimethylbenzoquinone (2,6-DMBQ) serves as the terminal oxidant in this process.

The catalytic enantioselective synthesis of 1-alkynyl isochromans was reported by Nishibayashi and co-workers in 2019 (Scheme [21]).[45] A Cu(I)-complex derived from Pybox ligand 46 catalyzes the enantioselective intramolecular etherification of propargylic esters (e.g., 62) to provide products 63 in good to excellent yields and ee values. A nonlinear relationship exists between the enantiopurity of ligand 46 and product, leading the authors to propose the intermediacy of a dicopper-allenylidene species.

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Scheme 19 Synthesis of enantioenriched isochromans via intramolecular dehydrative O-allylation
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Scheme 20 Synthesis of enantioenriched isochromans via intramolecular allylic C–H oxidation
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Scheme 21 Synthesis of enantioenriched isochromans via intramolecular etherification of propargylic esters

In 2015, Ghorai and co-workers reported a catalytic enantioselective method for the synthesis of highly enantioenriched 1-substituted isochromans (Scheme [22]).[46] This method is based on intramolecular conjugate addition. Reduction of the aldehyde functionality of ketoaldehydes such as 64 by pinacolborane (pinBH) provides an alkoxyboronate intermediate that then undergoes conjugate addition to form products 65 with excellent ee values. Reactions are catalyzed by quinine-derived squaramide-containing bifunctional organocatalyst 66 and exhibit a broad scope. This method also enables the synthesis of isochromans containing a substituent in the 3-position. An example is provided in Scheme [23]. Ketoaldehyde 67, a constitutional isomer of 64, undergoes reduction followed by intramolecular conjugate addition to provide product 68 in 81% ee.

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Scheme 22 Synthesis of enantioenriched isochromans via intramolecular conjugate addition
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Scheme 23 Synthesis of enantioenriched 3-substituted isochromans via intramolecular conjugate addition

Another rare example of a catalytic enantioselective process leading to isochromans containing a substituent in the 3-position was reported in 2009 (Scheme [24]).[47] As part of a broader effort directed at preparing a range of structurally diverse compounds, Chung and Fu achieved the catalytic enantioselective synthesis of isochroman 70 from α,β-alkynyl ester 69. This isomerization reaction is catalyzed by chiral phosphine 71, operating in concert with benzoic acid.

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Scheme 24 Synthesis of enantioenriched 3-substituted isochromans via phosphine-catalyzed isomerization of α,β-alkynyl esters

Examples of catalytic enantioselective reactions that provide enantioenriched tetrahydropyrano[3,4-b]indoles containing substituents in other than the 1-position are shown in Scheme [25] and Scheme [26]. In 2011, the You group achieved enantioselective intramolecular Friedel–Crafts alkylation reactions of indolyl enones (e.g., 72), providing products such as 73 with exceptional efficiency (Scheme [25]).[48] Reactions are catalyzed by chiral N-triflyl phosphoramide 74, a catalyst that is remarkably active at –70 °C. In earlier work published in 2009, the same group showed that products such as 73 can be obtained by olefin cross-metathesis/Friedel–Crafts alkylation cascades using a compatible combination of a Ru catalyst and a chiral phosphoric acid catalyst (not shown).[49]

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Scheme 25 Synthesis of enantioenriched tetrahydropyrano[3,4-b]-indoles by intramolecular Friedel–Crafts alkylation
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Scheme 26 Synthesis of enantioenriched tetrahydropyrano[3,4-b]-indoles by a Pd-catalyzed cascade reaction

Highly enantioenriched tetrahydropyrano[3,4-b]indoles containing a fused ring and two stereogenic centers (e.g., 76) can be prepared from substrates such as 75, as reported by Lu and co-workers in 2017.[50] This transformation involves a Pd(II)-catalyzed aminopalladation/1,4-addition sequence that is facilitated by chiral bipyridine ligand 77.

As is clear from the transformations discussed in this Short Review, access to highly enantioenriched isochromans and tetrahydropyrano[3,4-b]indoles by means of asymmetric catalysis has improved dramatically over the past 10 years, with most advances having emerged only in the past 5 years. It is also clear that significant challenges remain. Although highly desirable, for instance for a more efficient synthesis of drug molecules such as etodolac, methods that efficiently install tetrasubstituted stereogenic centers remain rare and have largely been limited to additions to cyclic oxocarbenium ions (Scheme [14]). Thus far, there is only one example with low enantioselectivity in which a tetrasubstituted stereogenic center was generated via an oxa-Pictet–Spengler cyclization (Scheme [7]). Pictet–Spengler cyclizations of tryptophols or β-arylethanols with ketones or ketone surrogates would provide the most direct access to isochromans and tetrahydropyrano[3,4-b]indoles containing a tetrasubstituted stereogenic center in the 1-position. While such reactions are well known in a racemic sense, catalytic enantioselective variants have remained elusive. In addition, highly enantioselective oxa-Pictet–Spengler reactions of tryptophols have not yet been accomplished with aliphatic aldehydes, and reactions with β-phenylethanols require the presence of a hydroxyl group in a specific position of the aryl ring. All three of the highly enantioselective oxa-Pictet–Spengler reactions reported to date (Scheme [8], Scheme [9], and Scheme [11]) require the presence of hydrogen-bonding donor or acceptor sites on the alcohol substrate. However, encouraging findings such as those summarized in Scheme [6] suggest that such reactions could potentially be rendered highly enantioselective in the absence of obvious directing groups. Overall, there is cause for optimism that many of these limitations will be addressed in the not-too-distant future. We look forward to learning about new advances and hope that this Short Review will motivate others to tackle the remaining challenges.


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  • 3 Yan Y.-M, Dai H.-Q, Du Y, Schneider B, Guo H, Li D.-P, Zhang L.-X, Fu H, Dong X.-P, Cheng Y.-X. Bioorg. Med. Chem. Lett. 2012; 22: 4179
  • 4 Zhang L, Zhu X, Zhao B, Zhao J, Zhang Y, Zhang S, Miao J. Vasc. Pharmacol. 2008; 48: 63
  • 5 Ennis MD, Ghazal NB, Hoffman RL, Smith MW, Schlachter SK, Lawson CF, Im WB, Pregenzer JF, Svensson KA, Lewis RA, Hall ED, Sutter DM, Harris LT, McCall RB. J. Med. Chem. 1998; 41: 2180
    • 6a Demerson CA, Humber LG, Philipp AH, Martel RR. J. Med. Chem. 1976; 19: 391
    • 6b Brenna E, Fuganti C, Fuganti D, Grasselli P, Malpezzi L, Pedrocchi-Fantoni G. Tetrahedron 1997; 53: 17769
  • 7 Katz AH, Demerson CA, Shaw CC, Asselin AA, Humber LG, Conway KM, Gavin G, Guinosso C, Jensen NP. J. Med. Chem. 1988; 31: 1244
  • 8 Howe AY. M, Bloom J, Baldick CJ, Benetatos CA, Cheng H, Christensen JS, Chunduru SK, Coburn GA, Feld B, Gopalsamy A, Gorczyca WP, Herrmann S, Johann S, Jiang X, Kimberland ML, Krisnamurthy G, Olson M, Orlowski M, Swanberg S, Thompson I, Thorn M, Del Vecchio A, Young DC, van Zeijl M, Ellingboe JW, Upeslacis J, Collett M, Mansour TS, O’Connell JF. Antimicrob. Agents Chemother. 2004; 48: 4813

    • For reviews on the oxa-Pictet–Spengler reaction, see:
    • 9a Larghi EL, Kaufman TS. Synthesis 2006; 187
    • 9b Larghi EL, Kaufman TS. Eur. J. Org. Chem. 2011; 5195
    • 9c Moyano A, Rios R. Chem. Rev. 2011; 111: 4703
  • 10 For a very brief summary of this topic (in Japanese), see: Kawato Y. J. Synth. Org. Chem. Jpn. 2017; 75: 673
  • 11 Pictet A, Spengler T. Ber. Dtsch. Chem. Ges. 1911; 44: 2030

    • Selected reviews on the Pictet–Spengler reaction:
    • 12a Cox ED, Cook JM. Chem. Rev. 1995; 95: 1797
    • 12b Youn SW. Org. Prep. Proced. Int. 2006; 38: 505
    • 12c Lorenz M, Van Linn ML, Cook JM. Curr. Org. Synth. 2010; 7: 189
    • 12d Stockigt J, Antonchick AP, Wu FR, Waldmann H. Angew. Chem. Int. Ed. 2011; 50: 8538
    • 12e Glinsky-Olivier N, Guinchard X. Synthesis 2017; 49: 2605
    • 12f Rao RN, Maiti B, Chanda K. ACS Comb. Sci. 2017; 19: 199
    • 13a Buschmann H, Michel R. German Patent 614461, 1935
    • 13b Buschmann H, Michel R. German Patent 617646, 1935
  • 14 Wünsch B, Zott M. Liebigs Ann. Chem. 1992; 39
  • 15 For an early review on the chemistry of isochromans, see: Markaryan EA, Samodurova AG. Russ. Chem. Rev. 1989; 58: 479
  • 16 Zeng M, You S.-L. Synlett 2010; 1289
  • 17 Liu L, Kaib PS. J, Tap A, List B. J. Am. Chem. Soc. 2016; 138: 10822
  • 18 Costa PR. R, Cabral LM, Alencar KG, Schmidt LL, Vasconcellos ML. A. A. Tetrahedron Lett. 1997; 38: 7021
  • 19 For a review on tryptophol and its derivatives, see: Palmieri A, Petrini M. Nat. Prod. Rep. 2019; 36: 490
  • 20 Fernandes RA, Brückner R. Synlett 2005; 1281
  • 21 Eey ST.-C, Lear MJ. Chem. Eur. J. 2014; 20: 11556
  • 22 Wang P, Zhao J.-Z, Li H.-F, Liang X.-M, Zhang Y.-L, Da C.-S. Tetrahedron Lett. 2017; 58: 129
  • 23 Doyle AG. Ph.D. Thesis . Harvard University; Cambridge: 2008

    • Selected reviews on hydrogen bonding catalysis:
    • 24a Schreiner PR. Chem. Soc. Rev. 2003; 32: 289
    • 24b Takemoto Y. Org. Biomol. Chem. 2005; 3: 4299
    • 24c Taylor MS, Jacobsen EN. Angew. Chem. Int. Ed. 2006; 45: 1520
    • 24d Connon SJ. Chem. Eur. J. 2006; 12: 5418
    • 24e Doyle AG, Jacobsen EN. Chem. Rev. 2007; 107: 5713
    • 24f Yu X, Wang W. Chem. Asian J. 2008; 3: 516
    • 24g Hydrogen Bonding in Organic Synthesis . Pihko PM. Wiley-VCH; Weinheim: 2009
    • 24h Schenker S, Zamfir A, Freund M, Tsogoeva SB. Eur. J. Org. Chem. 2011; 2209
    • 24i Auvil TJ, Schafer AG, Mattson AE. Eur. J. Org. Chem. 2014; 2633
    • 24j Žabka M, Šebesta R. Molecules 2015; 20: 15500
    • 24k Nishikawa Y. Tetrahedron Lett. 2018; 59: 216
    • 24l Reep C, Sun S, Takenaka N. Asian J. Org. Chem. 2019; 8: 1306

      Selected reviews on asymmetric anion-binding catalysis:
    • 25a Zhang Z, Schreiner PR. Chem. Soc. Rev. 2009; 38: 1187
    • 25b Mahlau M, List B. Angew. Chem. Int. Ed. 2013; 52: 518
    • 25c Brak K, Jacobsen EN. Angew. Chem. Int. Ed. 2013; 52: 534
    • 25d Seidel D. Synlett 2014; 25: 783
    • 25e Busschaert N, Caltagirone C, Van Rossom W, Gale PA. Chem. Rev. 2015; 115: 8038
    • 25f Attard JW, Osawa K, Guan Y, Hatt J, Kondo S.-i, Mattson A. Synthesis 2019; 51: 2107
  • 26 Lombardo VM, Thomas CD, Scheidt KA. Angew. Chem. Int. Ed. 2013; 52: 12910

    • Selected reviews on asymmetric Brønsted acid catalysis:
    • 27a Yamamoto H, Futatsugi K. Angew. Chem. Int. Ed. 2005; 44: 1924
    • 27b Akiyama T. Chem. Rev. 2007; 107: 5744
    • 27c Terada M. Synthesis 2010; 1929
    • 27d Rueping M, Nachtsheim BJ, Ieawsuwan W, Atodiresei I. Angew. Chem. Int. Ed. 2011; 50: 6706
    • 27e Yu J, Shi F, Gong LZ. Acc. Chem. Res. 2011; 44: 1156
    • 27f Parmar D, Sugiono E, Raja S, Rueping M. Chem. Rev. 2014; 114: 9047
    • 27g Akiyama T, Mori K. Chem. Rev. 2015; 115: 9277
    • 27h Rueping M, Parmar D, Sugiono E. Asymmetric Brønsted Acid Catalysis . Wiley-VCH; Weinheim: 2015
    • 27i Mitra R, Niemeyer J. ChemCatChem 2018; 10: 1221
    • 27j Sedgwick DM, Grayson MN, Fustero S, Barrio P. Synthesis 2018; 50: 1935
  • 28 Ascic E, Ohm RG, Petersen R, Hansen MR, Hansen CL, Madsen D, Tanner D, Nielsen TE. Chem. Eur. J. 2014; 20: 3297
  • 29 Zhao C, Chen SB, Seidel D. J. Am. Chem. Soc. 2016; 138: 9053

    • For reviews on iminium catalysis, see:
    • 30a Erkkilae A, Majander I, Pihko PM. Chem. Rev. 2007; 107: 5416
    • 30b Brazier JB, Tomkinson NC. O. In Asymmetric Organocatalysis . List B. Springer; Berlin: 2010: 281
  • 31 Das S, Liu L, Zheng Y, Alachraf MW, Thiel W, De C K, List B. J. Am. Chem. Soc. 2016; 138: 9429
  • 32 Maskeri MA, O’Connor MJ, Jaworski AA, Davies AV, Scheidt KA. Angew. Chem. Int. Ed. 2018; 57: 17225
  • 33 Reisman SE, Doyle AG, Jacobsen EN. J. Am. Chem. Soc. 2008; 130: 7198
  • 34 For the first report describing catalytic enantioselective additions to oxocarbenium ions, see: Braun M, Kotter W. Angew. Chem. Int. Ed. 2004; 43: 514
    • 35a Maity P, Srinivas HD, Watson MP. J. Am. Chem. Soc. 2011; 133: 17142
    • 35b Watson MP, Maity P. Synlett 2012; 23: 1705
  • 36 Dasgupta S, Rivas T, Watson MP. Angew. Chem. Int. Ed. 2015; 54: 14154
  • 37 Meng Z, Sun S, Yuan H, Lou H, Liu L. Angew. Chem. Int. Ed. 2014; 53: 543
  • 38 While not catalytic, enantioselective modification of parent isochroman had previously been achieved by deprotonation with t-BuLi in the presence of superstoichiometric amounts of a chiral ligand, followed by treatment with various electrophiles, see: Tomooka K, Wang L.-F, Okazaki F, Nakai T. Tetrahedron Lett. 2000; 41: 6121
  • 39 Catalytic enantioselective additions of boronic acids to structurally related chrome acetals are significantly more developed. See, for example: Moquist PN, Kodama T, Schaus SE. Angew. Chem. Int. Ed. 2010; 49: 7096
  • 40 Wan M, Sun S, Li Y, Liu L. Angew. Chem. Int. Ed. 2017; 56: 5116
  • 41 Li Y, Wan M, Sun S, Fu Z, Huang H, Liu L. Org. Chem. Front. 2018; 5: 1280
  • 42 Lu R, Li Y, Zhao J, Li J, Wang S, Liu L. Chem. Commun. 2018; 54: 4445
    • 43a Miyata K, Kutsuna H, Kawakami S, Kitamura M. Angew. Chem. Int. Ed. 2011; 50: 4649
    • 43b Miyata K, Kitamura M. Synthesis 2012; 44: 2138
  • 44 Ammann SE, Liu W, White MC. Angew. Chem. Int. Ed. 2016; 55: 9571
  • 45 Liu S, Nakajima K, Nishibayashi Y. RSC Adv. 2019; 9: 18918
  • 46 Ravindra B, Maity S, Das BG, Ghorai P. J. Org. Chem. 2015; 80: 7008
  • 47 Chung YK, Fu GC. Angew. Chem. Int. Ed. 2009; 48: 2225
  • 48 Zhang J.-W, Cai Q, Shi X.-X, Zhang W, You S.-L. Synlett 2011; 1239
  • 49 Cai Q, Zhao Z.-A, You S.-L. Angew. Chem. Int. Ed. 2009; 48: 7428
  • 50 Chen J, Han X, Lu X. Angew. Chem. Int. Ed. 2017; 56: 14698

  • References and Notes

  • 1 Zhou YB, Wang J.-H, Li XM, Fu XC, Yan Z, Zeng YM, Li X. J. Asian Nat. Prod. Res. 2008; 10: 827
    • 2a Trisuwan K, Rukachaisirikul V, Sukpondma Y, Phongpaichit S, Preedanon S, Sakayaroj J. Tetrahedron 2010; 66: 4484
    • 2b Kuramochi K, Tsubaki K, Kuriyama I, Mizushina Y, Yoshida H, Takeuchi T, Kamisuki S, Sugawara F, Kobayashi S. J. Nat. Prod. 2013; 76: 1737
  • 3 Yan Y.-M, Dai H.-Q, Du Y, Schneider B, Guo H, Li D.-P, Zhang L.-X, Fu H, Dong X.-P, Cheng Y.-X. Bioorg. Med. Chem. Lett. 2012; 22: 4179
  • 4 Zhang L, Zhu X, Zhao B, Zhao J, Zhang Y, Zhang S, Miao J. Vasc. Pharmacol. 2008; 48: 63
  • 5 Ennis MD, Ghazal NB, Hoffman RL, Smith MW, Schlachter SK, Lawson CF, Im WB, Pregenzer JF, Svensson KA, Lewis RA, Hall ED, Sutter DM, Harris LT, McCall RB. J. Med. Chem. 1998; 41: 2180
    • 6a Demerson CA, Humber LG, Philipp AH, Martel RR. J. Med. Chem. 1976; 19: 391
    • 6b Brenna E, Fuganti C, Fuganti D, Grasselli P, Malpezzi L, Pedrocchi-Fantoni G. Tetrahedron 1997; 53: 17769
  • 7 Katz AH, Demerson CA, Shaw CC, Asselin AA, Humber LG, Conway KM, Gavin G, Guinosso C, Jensen NP. J. Med. Chem. 1988; 31: 1244
  • 8 Howe AY. M, Bloom J, Baldick CJ, Benetatos CA, Cheng H, Christensen JS, Chunduru SK, Coburn GA, Feld B, Gopalsamy A, Gorczyca WP, Herrmann S, Johann S, Jiang X, Kimberland ML, Krisnamurthy G, Olson M, Orlowski M, Swanberg S, Thompson I, Thorn M, Del Vecchio A, Young DC, van Zeijl M, Ellingboe JW, Upeslacis J, Collett M, Mansour TS, O’Connell JF. Antimicrob. Agents Chemother. 2004; 48: 4813

    • For reviews on the oxa-Pictet–Spengler reaction, see:
    • 9a Larghi EL, Kaufman TS. Synthesis 2006; 187
    • 9b Larghi EL, Kaufman TS. Eur. J. Org. Chem. 2011; 5195
    • 9c Moyano A, Rios R. Chem. Rev. 2011; 111: 4703
  • 10 For a very brief summary of this topic (in Japanese), see: Kawato Y. J. Synth. Org. Chem. Jpn. 2017; 75: 673
  • 11 Pictet A, Spengler T. Ber. Dtsch. Chem. Ges. 1911; 44: 2030

    • Selected reviews on the Pictet–Spengler reaction:
    • 12a Cox ED, Cook JM. Chem. Rev. 1995; 95: 1797
    • 12b Youn SW. Org. Prep. Proced. Int. 2006; 38: 505
    • 12c Lorenz M, Van Linn ML, Cook JM. Curr. Org. Synth. 2010; 7: 189
    • 12d Stockigt J, Antonchick AP, Wu FR, Waldmann H. Angew. Chem. Int. Ed. 2011; 50: 8538
    • 12e Glinsky-Olivier N, Guinchard X. Synthesis 2017; 49: 2605
    • 12f Rao RN, Maiti B, Chanda K. ACS Comb. Sci. 2017; 19: 199
    • 13a Buschmann H, Michel R. German Patent 614461, 1935
    • 13b Buschmann H, Michel R. German Patent 617646, 1935
  • 14 Wünsch B, Zott M. Liebigs Ann. Chem. 1992; 39
  • 15 For an early review on the chemistry of isochromans, see: Markaryan EA, Samodurova AG. Russ. Chem. Rev. 1989; 58: 479
  • 16 Zeng M, You S.-L. Synlett 2010; 1289
  • 17 Liu L, Kaib PS. J, Tap A, List B. J. Am. Chem. Soc. 2016; 138: 10822
  • 18 Costa PR. R, Cabral LM, Alencar KG, Schmidt LL, Vasconcellos ML. A. A. Tetrahedron Lett. 1997; 38: 7021
  • 19 For a review on tryptophol and its derivatives, see: Palmieri A, Petrini M. Nat. Prod. Rep. 2019; 36: 490
  • 20 Fernandes RA, Brückner R. Synlett 2005; 1281
  • 21 Eey ST.-C, Lear MJ. Chem. Eur. J. 2014; 20: 11556
  • 22 Wang P, Zhao J.-Z, Li H.-F, Liang X.-M, Zhang Y.-L, Da C.-S. Tetrahedron Lett. 2017; 58: 129
  • 23 Doyle AG. Ph.D. Thesis . Harvard University; Cambridge: 2008

    • Selected reviews on hydrogen bonding catalysis:
    • 24a Schreiner PR. Chem. Soc. Rev. 2003; 32: 289
    • 24b Takemoto Y. Org. Biomol. Chem. 2005; 3: 4299
    • 24c Taylor MS, Jacobsen EN. Angew. Chem. Int. Ed. 2006; 45: 1520
    • 24d Connon SJ. Chem. Eur. J. 2006; 12: 5418
    • 24e Doyle AG, Jacobsen EN. Chem. Rev. 2007; 107: 5713
    • 24f Yu X, Wang W. Chem. Asian J. 2008; 3: 516
    • 24g Hydrogen Bonding in Organic Synthesis . Pihko PM. Wiley-VCH; Weinheim: 2009
    • 24h Schenker S, Zamfir A, Freund M, Tsogoeva SB. Eur. J. Org. Chem. 2011; 2209
    • 24i Auvil TJ, Schafer AG, Mattson AE. Eur. J. Org. Chem. 2014; 2633
    • 24j Žabka M, Šebesta R. Molecules 2015; 20: 15500
    • 24k Nishikawa Y. Tetrahedron Lett. 2018; 59: 216
    • 24l Reep C, Sun S, Takenaka N. Asian J. Org. Chem. 2019; 8: 1306

      Selected reviews on asymmetric anion-binding catalysis:
    • 25a Zhang Z, Schreiner PR. Chem. Soc. Rev. 2009; 38: 1187
    • 25b Mahlau M, List B. Angew. Chem. Int. Ed. 2013; 52: 518
    • 25c Brak K, Jacobsen EN. Angew. Chem. Int. Ed. 2013; 52: 534
    • 25d Seidel D. Synlett 2014; 25: 783
    • 25e Busschaert N, Caltagirone C, Van Rossom W, Gale PA. Chem. Rev. 2015; 115: 8038
    • 25f Attard JW, Osawa K, Guan Y, Hatt J, Kondo S.-i, Mattson A. Synthesis 2019; 51: 2107
  • 26 Lombardo VM, Thomas CD, Scheidt KA. Angew. Chem. Int. Ed. 2013; 52: 12910

    • Selected reviews on asymmetric Brønsted acid catalysis:
    • 27a Yamamoto H, Futatsugi K. Angew. Chem. Int. Ed. 2005; 44: 1924
    • 27b Akiyama T. Chem. Rev. 2007; 107: 5744
    • 27c Terada M. Synthesis 2010; 1929
    • 27d Rueping M, Nachtsheim BJ, Ieawsuwan W, Atodiresei I. Angew. Chem. Int. Ed. 2011; 50: 6706
    • 27e Yu J, Shi F, Gong LZ. Acc. Chem. Res. 2011; 44: 1156
    • 27f Parmar D, Sugiono E, Raja S, Rueping M. Chem. Rev. 2014; 114: 9047
    • 27g Akiyama T, Mori K. Chem. Rev. 2015; 115: 9277
    • 27h Rueping M, Parmar D, Sugiono E. Asymmetric Brønsted Acid Catalysis . Wiley-VCH; Weinheim: 2015
    • 27i Mitra R, Niemeyer J. ChemCatChem 2018; 10: 1221
    • 27j Sedgwick DM, Grayson MN, Fustero S, Barrio P. Synthesis 2018; 50: 1935
  • 28 Ascic E, Ohm RG, Petersen R, Hansen MR, Hansen CL, Madsen D, Tanner D, Nielsen TE. Chem. Eur. J. 2014; 20: 3297
  • 29 Zhao C, Chen SB, Seidel D. J. Am. Chem. Soc. 2016; 138: 9053

    • For reviews on iminium catalysis, see:
    • 30a Erkkilae A, Majander I, Pihko PM. Chem. Rev. 2007; 107: 5416
    • 30b Brazier JB, Tomkinson NC. O. In Asymmetric Organocatalysis . List B. Springer; Berlin: 2010: 281
  • 31 Das S, Liu L, Zheng Y, Alachraf MW, Thiel W, De C K, List B. J. Am. Chem. Soc. 2016; 138: 9429
  • 32 Maskeri MA, O’Connor MJ, Jaworski AA, Davies AV, Scheidt KA. Angew. Chem. Int. Ed. 2018; 57: 17225
  • 33 Reisman SE, Doyle AG, Jacobsen EN. J. Am. Chem. Soc. 2008; 130: 7198
  • 34 For the first report describing catalytic enantioselective additions to oxocarbenium ions, see: Braun M, Kotter W. Angew. Chem. Int. Ed. 2004; 43: 514
    • 35a Maity P, Srinivas HD, Watson MP. J. Am. Chem. Soc. 2011; 133: 17142
    • 35b Watson MP, Maity P. Synlett 2012; 23: 1705
  • 36 Dasgupta S, Rivas T, Watson MP. Angew. Chem. Int. Ed. 2015; 54: 14154
  • 37 Meng Z, Sun S, Yuan H, Lou H, Liu L. Angew. Chem. Int. Ed. 2014; 53: 543
  • 38 While not catalytic, enantioselective modification of parent isochroman had previously been achieved by deprotonation with t-BuLi in the presence of superstoichiometric amounts of a chiral ligand, followed by treatment with various electrophiles, see: Tomooka K, Wang L.-F, Okazaki F, Nakai T. Tetrahedron Lett. 2000; 41: 6121
  • 39 Catalytic enantioselective additions of boronic acids to structurally related chrome acetals are significantly more developed. See, for example: Moquist PN, Kodama T, Schaus SE. Angew. Chem. Int. Ed. 2010; 49: 7096
  • 40 Wan M, Sun S, Li Y, Liu L. Angew. Chem. Int. Ed. 2017; 56: 5116
  • 41 Li Y, Wan M, Sun S, Fu Z, Huang H, Liu L. Org. Chem. Front. 2018; 5: 1280
  • 42 Lu R, Li Y, Zhao J, Li J, Wang S, Liu L. Chem. Commun. 2018; 54: 4445
    • 43a Miyata K, Kutsuna H, Kawakami S, Kitamura M. Angew. Chem. Int. Ed. 2011; 50: 4649
    • 43b Miyata K, Kitamura M. Synthesis 2012; 44: 2138
  • 44 Ammann SE, Liu W, White MC. Angew. Chem. Int. Ed. 2016; 55: 9571
  • 45 Liu S, Nakajima K, Nishibayashi Y. RSC Adv. 2019; 9: 18918
  • 46 Ravindra B, Maity S, Das BG, Ghorai P. J. Org. Chem. 2015; 80: 7008
  • 47 Chung YK, Fu GC. Angew. Chem. Int. Ed. 2009; 48: 2225
  • 48 Zhang J.-W, Cai Q, Shi X.-X, Zhang W, You S.-L. Synlett 2011; 1239
  • 49 Cai Q, Zhao Z.-A, You S.-L. Angew. Chem. Int. Ed. 2009; 48: 7428
  • 50 Chen J, Han X, Lu X. Angew. Chem. Int. Ed. 2017; 56: 14698

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Figure 1 Examples of naturally occurring and artificial bioactive isochromans and tetrahydropyrano[3,4-b]indoles
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Scheme 1 Original reports on the Pictet–Spengler reaction and its oxygen analogue, along with its general mechanism
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Scheme 2 Examples of diastereoselective oxa-Pictet–Spengler reactions with optically active starting materials
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Scheme 3 Thiourea-catalyzed enantioselective oxa-Pictet–Spengler cyclization with mixed acetals derived from tryptophol
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Scheme 4 Thiourea-catalyzed enantioselective oxa-Pictet–Spengler cyclization with N-MOM protected tryptophol acetals, selected scope
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Scheme 5 Thiourea-catalyzed enantioselective oxa-Pictet–Spengler cyclizations involving various heterocycles
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Scheme 6 Brønsted acid catalyzed enantioselective oxa-Pictet–Spengler­ cyclization with a preformed enol ether
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Scheme 7 Dually catalyzed enantioselective oxa-Pictet–Spengler cyclization of an allyl ether
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Scheme 8 Dually catalyzed enantioselective oxa-Pictet–Spengler reactions of tryptophols with aldehydes
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Scheme 9 Imidodiphosphoric acid catalyzed enantioselective oxa-Pictet­–Spengler reactions of hydroxy-substituted β-phenylethanols with aldehydes
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Scheme 10 Current limitations in oxa-Pictet–Spengler reactions with β-phenylethanols
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Scheme 11 Dually catalyzed enantioselective oxa-Pictet–Spengler reactions of tryptophol-derived enol ethers
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Figure 2 Different pathways to enantioenriched isochromans.
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Scheme 12 Catalytic enantioselective additions of silyl ketene acetals to cyclic oxocarbenium ions
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Scheme 13 Catalytic enantioselective alkynylation of isochroman-derived­ oxocarbenium ions
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Scheme 14 Formation of tetrasubstituted stereogenic centers via catalytic enantioselective alkynylation of isochroman-derived oxocarbenium ions
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Scheme 15 Catalytic enantioselective addition of enolizable aldehydes to isochromans
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Scheme 16 Catalytic enantioselective addition of a boronic ester to isochroman
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Scheme 17 Catalytic redox deracemization of isochromans
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Scheme 18 Catalytic redox deracemization of tetrahydropyrano-[3,4-b]indoles
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Scheme 19 Synthesis of enantioenriched isochromans via intramolecular dehydrative O-allylation
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Scheme 20 Synthesis of enantioenriched isochromans via intramolecular allylic C–H oxidation
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Scheme 21 Synthesis of enantioenriched isochromans via intramolecular etherification of propargylic esters
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Scheme 22 Synthesis of enantioenriched isochromans via intramolecular conjugate addition
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Scheme 23 Synthesis of enantioenriched 3-substituted isochromans via intramolecular conjugate addition
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Scheme 24 Synthesis of enantioenriched 3-substituted isochromans via phosphine-catalyzed isomerization of α,β-alkynyl esters
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Scheme 25 Synthesis of enantioenriched tetrahydropyrano[3,4-b]-indoles by intramolecular Friedel–Crafts alkylation
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Scheme 26 Synthesis of enantioenriched tetrahydropyrano[3,4-b]-indoles by a Pd-catalyzed cascade reaction