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

SYNOPEN2509-9396 Georg Thieme Verlag Stuttgart · New York 2019, 3, 77–90 short review 77 en

Syn Open Z. Zhu et al. Short Review

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

Zhengbo Zhua HO HO Brønsted acid Alafate Adilia OH catalysis O Chenfei Zhaob 0000-0003-3960-3047 up to R Daniel Seidel*a 0000-0001-6725-111X RCHO 99% ee a Center for Heterocyclic Compounds, Department of Chemis- Dual anion-binding OH O try, University of Florida, Gainesville, Florida 32611, USA iminium catalysis [email protected] N N H H b Department of Chemistry, University of California–Berkeley; R Materials Sciences Division, Lawrence Berkeley National Labo- up to 95% ee ratory; Kavli Energy NanoSciences Institute at Berkeley; Berke- ley Global Science Institute, Berkeley, California 94720, USA

Received: 24.08.2019 aryl substituent.9 In this Short Review, we provide exam- Accepted after revision: 04.09.2019 ples of asymmetric oxa-Pictet–Spengler cyclizations that Published online: 25.09.2019 DOI: 10.1055/s-0039-1690686; Art ID: so-2019-d0023-r are under substrate control, discuss all known catalytic en- License terms: antioselective variants of the oxa-Pictet–Spengler cycliza- 10 © 2019. The Author(s). This is an open access article published by Thieme under the tion, and provide an overview of other catalytic enanti- terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, oselective reactions that lead to isochromans and tetrahy-

permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes or adapted, remixed, dropyrano[3,4-b]indoles. In addition, we outline remaining transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/) challenges in this area.

Abstract This Short Review provides an analysis of the state-of-the-art HO Me O i-Pr in catalytic enantioselective oxa-Pictet–Spengler cyclizations. Also dis- O O O O cussed are other catalytic reactions providing access to enantio- HO O O enriched isochromans and tetrahydropyrano[3,4-b]indoles. Context is O OMe MeO C provided and remaining challenges are highlighted. 2 i-Pr OHC (+)-penicisochroman B Key words oxa-Pictet–Spengler cyclization, isochromans, tetrahydro- Me ISO-09 pyrano[3,4-b]indoles, oxocarbenium ions, asymmetric catalysis, ion ilexisochromane pairing

HO O Me OMe O N Among compounds containing a 3,6-dihydropyran core, HO H O isochromans and tetrahydropyrano[3,4-b]indoles have cap- N tured particular interest in the synthetic and medicinal N HO chemistry communities. A small selection of compounds PNU-109291 OH containing these core frameworks is shown in Figure 1. The blapsin B isochroman heterocycle is a ubiquitous component of natu- Bn CN ral products often possessing intriguing bioactivities, such 1 2 3 as ilexisochromane, penicisochroman B, and blapsin B. O O O Synthetic isochromans include the antiapoptotic agent ISO- N N N 4 5 Et H Et H Et Me H n-Pr 09 and the 5-HT1D agonist PNU-109291. Examples of bio- CO2H CO2H CO2H active tetrahydropyrano[3,4-b]indoles are the anti-inflam- (S)-etodolac pemedolac HCV-371 matory agent etodolac,6 the potent analgesic agent pe- Figure 1 Examples of naturally occurring and artificial bioactive iso- medolac,7 and the non-nucleoside inhibitor of hepatitis C chromans and tetrahydropyrano[3,4-b]indoles virus HCV-371.8 The perhaps most desirable way to access isochromans and tetrahydropyrano[3,4-b]indoles in a The Pictet–Spengler reaction was discovered in 1911 stereocontrolled fashion is by means of the oxa-Pictet– and involves the HCl-promoted condensation of - Spengler cyclization; a process in which an oxocarbenium phenethylamine and formaldehyde dimethyl acetal to form ion intermediate undergoes ring-closure onto a pendent 1,2,3,4-tetrahydroisoquinoline (Scheme 1).11 The definition

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Syn Open Z. Zhu et al. Short Review of the Pictet–Spengler reaction was later expanded to Wünsch and Zott only in 1992.14 While it was found that - include cyclizations of imines or iminium ions possessing a phenylethanol can condense directly with formaldehyde or covalently linked aryl group that undergoes substitution paraformaldehyde in the presence of aqueous HCl to form upon ring-closure.12 While the apparently first example of isochroman without the need to first isolate 1, this ap- an oxa-Pictet–Spengler reaction dates back to 1935,13 when proach inadvertently leads to side products containing the synthesis of isochroman from chloroether 1 was dis- chloromethyl groups on the phenyl ring (not shown).14,15 As closed in a patent by Buschmann and Michel (Scheme 1), outlined in Scheme 1, the general mechanism of the oxa- the term oxa-Pictet–Spengler cyclization was coined by Pictet–Spengler reaction involves the formation of an oxo-

Biographical Sketches

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

Alafate Adili was born and nology of China (USTC) working Seidel. In August of 2017, he raised in Xinjiang, China. He with Prof. Liu-Zhu Gong. In moved with the Seidel group to

earned his B.Sc. degree in the 2016, he started his Ph.D. re- the University of Florida. His re- Department of Chemistry at the search at Rutgers University un- search focuses on asymmetric University of Science and Tech- der the direction of Prof. Daniel catalysis.

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

Daniel Seidel studied chemis- Sessler, obtaining his Ph.D. in University in 2005 and was pro- try at the Friedrich-Schiller-Uni- 2002. From 2002 to 2005, he moted to Associate Professor in versität Jena, Germany, and at was an Ernst Schering Postdoc- 2011 and Full Professor in 2014. the University of Texas at Austin toral Fellow in the group of Prof. In the summer of 2017, his re- (Diplom 1998). He performed David A. Evans at Harvard Uni- search group moved to the Uni- his graduate studies in the labo- versity. He started his indepen- versity of Florida. ratory of Prof. Jonathan L. dent career at Rutgers

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Syn Open Z. Zhu et al. Short Review carbenium ion, followed by ring closure and subsequent sieves in dichloromethane at room temperature, allowing deprotonation/rearomatization. Both the Pictet–Spengler for the isolation of polycyclic product 8 in excellent yield. A cyclization and the oxa-Pictet–Spengler cyclization can be recent example of a Brønsted acid catalyzed diastereoselec- viewed as variants of an intramolecular Friedel–Crafts al- tive oxa-Pictet–Spengler cyclization was reported by Da and kylation.16 In addition, the oxa-Pictet–Spengler cyclization co-workers.22 Tryptophol derivative 9, derived from the en- is mechanistically related to certain types of the Prins reac- antioselective CBS reduction of the corresponding ketone, tion.17 engages benzaldehyde dimethyl acetal in the presence of a catalytic amount of trifluoroacetic acid to furnish tetrahy- Synthesis of 1,2,3,4-tetrahydroisoquinoline (THIQ) by Pictet and Spengler (1911)11 dropyrano[3,4-b]indole 10 in excellent yield and dr. Consis- tent with the expected mechanism of this transformation, HCl (concd) + MeO OMe the ee of product 10 matches that of the starting material 9. NH2 heat, 5–6 h NH

(1.6 equiv) THIQ, 36% OMe 3 Me Me 13 Synthesis of isochroman by Buschmann and Michel (1935) O O

HCl (concd, 1 equiv) OH O Me O isochroman, 64% * O O 20–40 °C, 2 h N SnCI , THF, rt N H 4 H Me Cl CO R* 1 2 2 4, 59%, de >95% –HCl deprotonation/rearomatization

OMe OMe OMe OMe Me ring-closure Cl H CCH(OMe) (2 equiv) O O OH 3 2 O BF3•Et2O (3 equiv) H Cl oxocarbenium Et2O/THF (4:1), rt, 12 h intermediate OMe O OMe O O O Scheme 1 Original reports on the Pictet–Spengler reaction and its ox- 56, 92% ygen analogue, along with its general mechanism

HO Bi(OTf)3 (5 mol%) For the majority of the history of the oxa-Pictet–Spengler OBn OBn LiClO4 (3 equiv) reaction, asymmetric variants were limited to cyclizations O O OMe 4Å MS, CH2Cl2, rt, 3.5 h 9 OMe Me of enantioenriched starting materials. Several illustrative Me OTs examples of such diastereoselective oxa-Pictet–Spengler cy- OTs clizations are provided in Scheme 2. A chiral auxiliary based 7 8, 94% approach was reported by Costa et al., utilizing -ketoester 18 3 derived from (–)--pinene. Condensation of tryptophol Ph Ph (2)19 with -ketoester 3 is facilitated by SnCl , resulting in PhCH(OMe)2 (2.5 equiv) 4 TFA (20 mol%) the formation of product 4 with excellent diastereoselectiv- OH O CH Cl , rt, 48 h N 2 2 N ity. Interestingly, the use of BF3 etherate in place of SnCl4 H H Ph provides a 1:1 mixture of product diastereomers. The ratio 9, 92% ee 10, 83%, 92% ee of the starting materials and the amount of the Lewis acid dr >20:1 are not specified in this report. Also, the absolute configura- Scheme 2 Examples of diastereoselective oxa-Pictet–Spengler reaction of product 4 remains unknown. A highly diastereose- tions with optically active starting materials lective oxa-Pictet–Spengler cyclization was reported by Fernandes and Brückner in the course of a synthesis of (+)- The first documented efforts toward developing a cata- kalafungin.20 Exposure of 5 to two equivalents of acetalde- lytic enantioselective variant of the oxa-Pictet–Spengler re- 23 hyde dimethyl acetal and excess BF3 etherate provides action were disclosed by Doyle in 2008. Evaluation of a product 6 as a single diastereomer in excellent yield. As part number of (thio)urea catalysts in direct condensations of of their synthesis of (–)-platensimycin, Eey and Lear ex- tryptophol with a range of aldehydes and ketones, either in plored the conversion of 7 into 8 via an interesting type of the absence or presence of various Brønsted and Lewis acid oxa-Pictet–Spengler cyclization under a variety of condi- additives and dehydrating agents, was reported to lead to tions.21 Although the reaction can be facilitated with a large tetrahydropyrano[3,4-b]indole products with low levels of excess of SnCl4 (8 equiv), the optimal conditions involve ex- enantioinduction (<15% ee, not shown). Significant increas- posure of 7 to a catalytic amount of Bi(OTf)3 (5 mol%) in the es in reactivity and appreciable levels of enantioselectivity presence of lithium perchlorate (3 equiv) and molecular are observed with tryptophol-derived mixed acetoxy-

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acetals such as 11; precursors that enable the formation of catalyst 16 (20 mol%) the requisite oxocarbenium ion intermediates under milder TMSCl (0.7 equiv) n-C5H11 TBME (0.2 M) conditions (Scheme 3). Exposure of 11 to trimethylsilyl O O OAc –30 °C, 18 h * chloride in the presence of thiourea catalyst 13 furnishes X X product 12 in excellent yield and encouraging 49% ee (abso- n-C5H11 CF lute configuration not established). Higher levels of enanti- 3 oselectivity are obtained with N-MOM protected tryptop- Me t-Bu S O N * hol acetals 14 (Scheme 4). Reactions of acetals 14, per- N N CF3 N H H n-C H formed under identical conditions, provide the Me O SEM 5 11 corresponding products 15 with up to 81% ee (absolute con- 16 24%, 20% ee figuration of products not established). Promising prelimi- nary results for catalytic enantioselective oxa-Pictet–Spen- O O O gler cyclizations were also obtained with acetoxy-acetals * * * S S O derived from a number of -heteroaryl ethanols (Scheme n-C5H11 n-C5H11 n-C5H11 5). Regarding the mechanism of these transformations, the 20% conv., 16% ee 20% conv., 35% ee 35% conv., 55% ee 24 hydrogen-bond donor thiourea catalyst most likely inter- Scheme 5 Thiourea-catalyzed enantioselective oxa-Pictet–Spengler acts with chloride via anion-binding,25 forming a chiral ion cyclizations involving various heterocycles pair with the oxocarbenium ion.

catalyst 13 (20 mol%) ether 17 into the corresponding cyclization product 18 with TMSCl (0.7 equiv) n-C5H11 TBME (0.2 M) a moderate level of enantiocontrol (absolute configuration O O OAc –30 °C, 24 h * not established). Here, the intermediate oxocarbenium ion N N H H n-C5H11 is generated by protonation of enol ether 17 by the chiral (±)-11 12, 98%, 49% ee 27 CF3 Brønsted acid 19.

Me t-Bu S Ph Ph N Me N N CF3 catalyst 19 (10 mol%) H H Et Me O N PhMe (0.1 M), 4 Å MS N * 13 23 °C, 3 d O O Scheme 3 Thiourea-catalyzed enantioselective oxa-Pictet–Spengler Ar 17 18, 75%, 60% ee cyclization with mixed acetals derived from tryptophol O O P R catalyst 13 (20 mol%) R TMSCl (0.7 equiv) O OH R' TBME (0.2 M) O O Ar OAc –30 °C, 3 d * N N 19 [Ar = 3,5-(CF ) -C H ] R' 3 2 6 3 MOM MOM Scheme 6 Brønsted acid catalyzed enantioselective oxa-Pictet– 14 15 Spengler cyclization with a preformed enol ether

O MeO O F O Shortly thereafter, Nielsen and co-workers reported a * * * N N N related approach in which enol ethers are generated in situ n-C H n-C H n-C H MOM 5 11 MOM 5 11 MOM 5 11 from allyl ethers via a ruthenium catalyzed isomerization 28 15a, 88%, 73% ee 15b, 95%, 69% ee 15c, 89%, 81% ee process (Scheme 7). Application of this strategy to allyl Scheme 4 Thiourea-catalyzed enantioselective oxa-Pictet–Spengler ether 20, in the presence of chiral imidodiphosphoric acid cyclization with N-MOM protected tryptophol acetals, selected scope 22, furnishes product 21 in good yield. While the enantioselectivity achieved in this reaction is only moderate (abso- Another early example of a catalytic enantioselective lute configuration not established), this is the only example oxa-Pictet–Spengler cyclization was reported by Scheidt thus far that generates a tetrasubstituted stereogenic center and co-workers in 2013 (Scheme 6).26 Chiral phosphoric in the course of an oxa-Pictet–Spengler cyclization. The E/Z acid catalyst 19 is capable of converting preformed enol selectivity of the initial isomerization step is unknown.

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catalyst 22 (5 mol%) catalyst 24 (10 mol%) O catalyst 25 (10 mol%) RuHCl(CO)(PPh3)3 (5 mol%) O * OH PhCHO (1.2 equiv), PhMe (0.05 M) O N PhMe, reflux, 1 h N H H Et Me N 4 Å MS, –30 °C, 48 h N H H 20, racemic 21, 75%, 47% ee Ph 2 23a, 90%, 91% ee Ar Ar

O N O S S P P NH HN N CO2Me O HO O O R N HN CF H2 2 3 Cl Ar Ar 24 (R = cyclooctyl) 25

22 (Ar = 2-i-Pr-5-Me-C6H3) Selected scope: Scheme 7 Dually catalyzed enantioselective oxa-Pictet–Spengler cyclization of an allyl ether O O O N N N H H H The first highly enantioselective catalytic oxa-Pictet–

Spengler cyclization was reported by our group in 2016 23b, 91% 23c, 90% 23d, 73% 29 Cl (Scheme 8). In the presence of thiourea catalyst 24 and 93% ee Br 95% ee Me 82% ee ammonium salt catalyst 25, tryptophol (2) undergoes an oxa-Pictet–Spengler reaction with benzaldehyde to form product 23a in excellent yield and ee. Substituted benzalde- O O O N N Me N hydes also participate in this reaction. While para-substi- H H H tuted benzaldehydes provide products with excellent ee, 23f, 91% 23g, 86% meta-substitution leads to a slight drop-off in enantioselec- 23e, 82% 86% ee OMe 48% ee 88% ee tivity, and ortho-substitution results in a significant erosion Me of ee (e.g., product 23f). Substitution of the indole ring is Br compatible with the catalytic system, whereas aliphatic al- O O dehydes are not viable reaction partners. Mechanistically, O N N this method is based on a dual catalysis strategy that avoids H Ph H Ph H H 23h, 75% 23i, 91% the need for strongly acidic conditions commonly required N 81% ee 92% ee Cl for accessing oxocarbenium ions via direct condensation of H H aldehydes and alcohols. The ammonium salt catalyst 25 is S H H N N thought to first engage the aldehyde to form an iminium Cl O O R N 30 N H Ar ion that then reacts with tryptophol, ultimately resulting N N S H Ph Me Ph H in the formation of an oxocarbenium ion that likely inter- R 23j, 89% 23k, 62% (rt, 24 h) Stereochemical model acts with the catalyst via anion-binding. A plausible transi- 94% ee racemic tion state for the key C–C bond-forming step is shown in Scheme 8 Dually catalyzed enantioselective oxa-Pictet–Spengler reac- Scheme 8. This model is supported by the following obser- tions of tryptophols with aldehydes vations: (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 Nearly simultaneously to our report, the List group re- catalyst 24 (e.g., almost identical results are obtained with ported a distinct strategy for realizing highly enantioselec- the enantiomer of 25 or racemic 25), and (3) The reaction tive oxa-Pictet–Spengler cyclizations (Scheme 9).31 Nitrated with N-methyl tryptophol provides racemic product (e.g., imidodiphosphoric acid catalyst 28 was found to efficiently product 23k), indicating an important interaction of the in- catalyze reactions of hydroxy-substituted -phenylethanols dole N-H with a hydrogen-bond acceptor site on the cata- with aldehydes. Catalyst 28 is significantly more active than lyst (e.g., the S-atom of the electron-rich thiourea moiety) the analogous imidodiphosphoric acid catalyst lacking the in the enantio-determining step of the reaction. Interest- two nitro groups. The corresponding BINOL-based phos- ingly, catalyst 25 can be replaced with HCl to provide the phoric acid 29 is also a competent catalyst but affords the product with nearly identical ee but in a significantly more products with significantly lower levels of enantioselectivi- sluggish reaction. ty. Catalyst 28 provides products 27 with excellent ee values while accommodating a range of aromatic and aliphatic aldehydes, with the latter requiring elevated reaction

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Syn Open Z. Zhu et al. Short Review temperatures (50 °C). An additional methoxy group on 26a catalyst 29, -phenylethanols 26b–d react with aldehydes is also tolerated. The proposed transition state for the C–C to provide symmetrical acetals 30 as the only products. On bond-forming step involves a critical hydrogen-bonding in- the other hand, the 2-hydroxy substrate 31 undergoes for- teraction of the catalyst anion with the phenol O-H moiety, mation of seven-membered cyclic acetal 32, whereas 33 af- as elucidated by DFT calculations. An alternate transition fords complex mixtures in reactions with aldehydes. state in which ring-closure occurs in ortho- rather than para-position of the phenol O-H moiety was calculated to R catalyst 29 R'' R''CHO be 6.3 kcal/mol higher in free energy (not shown). Consis- OH O O tent with these calculations, these regioisomers are not ob- R' 26b (R = R' = H) served. 26c (R = OMe, R' = H) 26d (R = R' = OMe) R 30 R HO catalyst 28 (10 mol%) HO Ar R' R' PhCHO (1.2 equiv), MTBE (0.2 M) OH O O 5 Å MS, rt, 72 h O R P 26a Ph O OH O 27a, 91%, 96% ee R' R'' O2N Ar Ar Ar 27 (not observed) 29 (Ar = 2,4,6-Et3-C6H2) O N O P P O O O HO OH R catalyst 29 O RCHO O2N Ar Ar O OH 28 (Ar = 2,4,6-Et3-C6H2) 31 32 Selected scope: HO HO HO catalyst 29 O RCHO complex reaction mixtures O O OH HO 33

Ph Me Br Scheme 10 Current limitations in oxa-Pictet–Spengler reactions with 27b, 81%, 95% ee 27c, 82%, 96% ee 27d, 87%, 99% ee -phenylethanols

HO HO HO In 2018, Scheidt and co-workers published an alternate O O O 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 cy- Br OMe clizations of tryptophol-derived enol ethers such as 34a to 27e, 75%, 98% ee 27f, 73%, 90% ee 27g, 93%, 96% ee generate oxa-Pictet–Spengler products with high levels of

O enantioselectivity (e.g., 35a). The presence of a urea-type O P N protecting group on the tryptophol nitrogen is a crucial de- HO H O O P HO O sign element of this approach (vide infra). While chiral O O O phosphoric acid 36 is capable of catalyzing the reaction in O MeO H MeO Me the absence of urea 37, reaction rates are dramatically re- O Ph tarded (incomplete reaction after 18 h vs. complete reaction Me within 15 min) and afford product 35a in only 36% ee (not 27h, 98%, 97% ee 27i, 92%, 99% ee Calculated TS shown). Regarding the scope of this transformation, substitution of different indole ring positions is readily accommo- Scheme 9 Imidodiphosphoric acid catalyzed enantioselective oxa- dated. While most products contain a gem-dimethyl group Pictet–Spengler reactions of hydroxy-substituted -phenylethanols adjacent to the tetrahydropyrano oxygen atom, products with aldehydes lacking these substituents are also obtained with excellent ee values. Interestingly, this study contains the only exam- Interesting observations were made in the course of the ple thus far reported in which a seven-membered ring is List study, outlining remaining challenges (Scheme 10). constructed enantioselectively in the course of an oxa-Pic- Consistent with the calculated transition state depicted in tet–Spengler cyclization, albeit in only 32% ee (product 35i). Scheme 9, the presence of a 3-hydroxy substituent on the As an application of their method, the authors reported a -phenylethanol is a strict requirement. In the presence of facile synthesis of coixspirolactam C from oxa-Pictet–

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Spengler product 35h. Regarding the mechanism of this While not aiming to be complete, the following section transformation, it was proposed that a network of hydro- provides an overview of catalytic enantioselective reactions gen-bonding interactions is responsible for achieving high that lead to oxa-Pictet–Spengler type products by alternate levels of reactivity and enantiocontrol (see proposed TS in pathways also involving the intermediacy of oxocarbenium Scheme 11). Specifically, the thiourea catalyst is thought to ions. As exemplified in the synthesis of enantioenriched bind to the chiral phosphate anion via dual hydrogen bond- isochromans, nucleophilic additions to cyclic oxocarbenium ing while engaging in an additional hydrogen-bonding in- ions provide an alternative to the oxa-Pictet–Spengler cy- teraction with the carbonyl group of the protonated sub- clization (Figure 2). While cyclic isochroman-type oxocar- strate. benium ions are more stable than their corresponding acy- clic counterparts by virtue of conjugation with the fused Me Me Me catalyst 36 (10 mol%) Me and necessarily coplanar aryl ring, they offer an expanded catalyst 37 (10 mol%) O O array of opportunities for designing enantioselective vari- PhMe (0.02 M), –40 °C, 2 h N N ants. To render oxa-Pictet–Spengler cyclizations catalytic Me Et and enantioselective, the anion X– has to be homochiral ArHN O ArHN O (e.g., conjugate base of a chiral Brønsted acid catalyst). Al- 34a (Ar = 3,5-(CF3)2-C6H3) 35a, 89%, 94% ee ternatively, if achiral, X– has to be tightly associated with a

Ar chiral anion receptor catalyst (or catalyst ensemble) in or-

O der to facilitate the ring-closure step in an enantioselective O O P Ar Ar fashion. These modes of enantiocontrol are also available in N N O OH H H nucleophilic additions to cyclic oxocarbenium ions. In addi-

37 [Ar = 3,5-(CF3)2-C6H3] tion, the otherwise achiral nucleophile can be rendered chi- Ar ral by interaction with a chiral catalyst. Nucleophiles can be 36 [Ar = 3,5-(CF ) -C H ] 3 2 6 3 carbon- or heteroatom-based, enabling the formation of Selected scope: monosubstituted isochromans via a reductive process.

F Me Cl Me MeO Me oxa-Pictet-Spengler Nucleophilic addition to Me Me Me cyclization cyclic oxocarbenium ion O O O vs. N N N O Et Et Et O X R ArHN O ArHN O ArHN O X Nu R' R 35b, 73%, 84% ee 35c, 88%, 94% ee 35d, 90%, 92% ee Figure 2 Different pathways to enantioenriched isochromans.

Me Me Me Me

MeO O O O A 2008 landmark study by the Jacobsen group accom- N N N plished the first catalytic enantioselective synthesis of 1- Et Me Et Et substituted isochromans (Scheme 12).33,34 Treatment of iso- ArHN O ArHN O ArHN O chroman-derived acetal 38 with BCl results in the in situ 35e, 93%, 90% ee 35f, 89%, 60% ee 35g, 54%, 96% ee 3 formation of 1-chloroisochroman (not shown), which is Ar then converted into product 39a upon treatment with silyl O Me N H ketene acetal 41 in the presence of thiourea catalyst 40. Me O O N Binding of the chloride counter anion of the transient oxo- O P O H Ar O N N Ar carbenium ion to thiourea catalyst 40 is thought to form a Me O Et Et O NH ArHN O ArHN O N chiral ion pair responsible for controlling the facial selectiv- H ity in the silyl ketene acetal addition step. Isochromans con- 35h, 76%, 94% ee 35i, 64%, 32% ee O taining substituents on different positions of the aryl ring Proposed TS and a range of silyl ketene acetals participate in this trans- Scheme 11 Dually catalyzed enantioselective oxa-Pictet–Spengler re- formation to provide products 39 in good yields and excel- actions of tryptophol-derived enol ethers lent ee values.

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i) BCl3, CH2Cl2, 0 °C to rt Cu(MeCN)4PF6 (10 mol%) O O O ligand 43 (12 mol%) ii) catalyst 40 (10 mol%), TMSOTf (1.2 equiv), i-Pr NEt (1.3 equiv) silyl ketene acetal 41 (1.5 equiv) 2 OMe (±)-38 OMe O TBME, –78 °C, 24 h Me CO Me Me 2 Et O (0.4 M), –22 °C, 12 h (±)-38 + 2 CF3 39a, 92%, 92% ee H Ph Me Me t-Bu S O O Ph OTMS (1.1 equiv) N 42a, 89%, 89% ee N N CF3 Me N N H H OMe O Bn Bn Me 43

40 41 Selected scope: F

Selected scope: O O O O Me F

O O O O Me Me

CO2Me CO2Me CO2Me CO2Me Cl 39b, 87%, 85% ee 39c, 71%, 90% ee 39d, 70%, 90% ee 39e, 82%, 87% ee 42b, 83%, 91% ee 42c, 73%, 85% ee CF3 42e, 64%, 67% ee 42d, 77%, 87% ee R' t-Bu S N Ar R N N Me MeO O O H H O O O O Cl MeO MeO2C MeO2C key ion pair O

39f, 84%, 94% ee 39g, 85%, 92% ee Ph Ph 3-MeC6H4

Scheme 12 Catalytic enantioselective additions of silyl ketene acetals 42f, 73%, 94% ee 42g, 88%, 87% ee 42h, 50%, 85% ee to cyclic oxocarbenium ions Scheme 13 Catalytic enantioselective alkynylation of isochroman- derived oxocarbenium ions In 2011, Watson and co-workers reported a conceptual- ly different strategy for the catalytic enantioselective addi- of a catalytic enantioselective process generating isochro- tion of nucleophiles to isochroman-derived oxocarbenium mans containing challenging tetrasubstituted stereogenic ions (Scheme 13).35 Specifically, catalytic enantioselective centers. alkynylation of acetal 38 with phenylacetylene is achieved Acetals such as 38 are typically obtained from their cor- with a Cu(I) complex of bisoxazoline ligand 43. Hünig’s base responding isochromans via an oxidative process. In 2014, facilitates the formation of a chiral Cu acetylide complex the Liu group reported a strategy that obviates the need for that adds to the oxocarbenium ion derived from acetal 38 preparing acetals in a separate step (Scheme 15).37,38 Oxo- and TMSOTf. The reaction tolerates substituents on differ- carbenium ions are accessed in situ by oxidation of isochro- ent positions of the isochroman aryl ring and is applicable mans with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone to a range of terminal alkynes. Some products are some- (DDQ). Addition of the aldehyde substrate is facilitated by what sensitive to oxidative decomposition (e.g., lactone for- catalyst 48 via an enamine mechanism. Reduction of the mation). This is particularly true for product 42h (the yield initially formed aldehyde products with sodium borohy- shown corresponds to the product obtained from subse- dride provides substituted isochromans (e.g., 47a–g) and quent reduction of the alkyne moiety to the corresponding related products with excellent levels of enantioselectivity, alkane via hydrogenation). An impressive extension of this albeit with moderate diastereoselectivity. As part of this chemistry was reported in 2015 (Scheme 14).36 A modified study, the Liu group achieved the catalytic enantioselective catalyst system derived from Pybox ligand 46 enables the addition of boronic ester 51 to isochroman (Scheme 16). synthesis of highly enantioenriched isochromans 45 from This reaction is facilitated by tartaric-acid-derived catalyst 1-substituted isochroman ketals 44. This is a rare example 50 and provides product 49 with moderate ee after hydrogenation in situ.39

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i) DDQ, H2O, C2H4Cl2 then catalyst 50 (30 mol%) O 51 (1.5 equiv), rt, 24 h O CuSPh (10 mol%), ligand 46 (12 mol%) Ph OMe O MTBD (1.55 equiv), BF3•OEt2 (2 equiv) O (±)-44 ii) H2, Pd/C, MeOH Ph + Et2O (0.15 M), 4 °C, 48 h Ph Ph H Ph O OH Bn 49, 62%, 61% ee 45a, 92%, 78% ee OEt (1.2 equiv) N N HO Bn B O O EtO Ph N OH O N N N N 50 51 Me Ph 46 Ph MTBD Scheme 16 Catalytic enantioselective addition of a boronic ester to Selected scope: isochroman

O O O In 2017, the Liu group reported an interesting redox de- MeO S racemization strategy that provides highly enantioenriched Ph Ph Ph 40 Me isochromans 52 (Scheme 17). Racemic starting materials 45b, 66%, 70% ee 45c, 86%, 96% ee 45d, 71%, 87% ee 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 O O O with Hantzsch ester 54 is rendered enantioselective by imidodiphosphoric acid catalyst 53. In a subsequent study, NPhth CN SiPhMe2 similar products were obtained by reduction of preformed 41 OMe racemic acetals (not shown). Products 52a could poten- 45f, 53%, 81% ee 45g, 80%, 93% ee 45e, 87%, 97% ee tially be obtained more directly via an oxa-Pictet–Spengler cyclization from the corresponding -phenylethanols. How- Scheme 14 Formation of tetrasubstituted stereogenic centers via cat-

alytic enantioselective alkynylation of isochroman-derived oxocarbeni- ever, current limitations make this an elusive goal (see dis- um ions cussion centered around Scheme 10). The Liu group further applied their redox deracemization strategy to the synthe-

i) DDQ (1 equiv), H2O (1.1 equiv), C2H4Cl2 sis of highly enantioenriched tetrahydropyrano[3,4-b]in- then catalyst 48•TFA (20 mol%) doles, as highlighted in Scheme 18.42 For these substrates, aldehyde (3 equiv) SPINOL-derived phosphoric acid 55 and Hantzsch ester 56 LiOTf (1 equiv), MeNO2, 0 °C, 30–48 h O H provide optimal results. Tetrahydropyrano[3,4-b]indoles O ii) NaBH , MeOH H 4 HO containing an aryl substituent are typically obtained in ex- O Me n-Pr N 47a, 69%, 96% ee cellent yields and ee values. Unfortunately, just like the pre- Me dr = 72:28 Bn viously discussed oxa-Pictet–Spengler reaction of tryptop- N Me H hol is incompatible with aliphatic aldehydes (see Scheme 48 Selected scope: 8), the deracemization process does not tolerate 1-alkyl substituents as these substrates fail to undergo oxidation 47b (R = Me), 66%, 93% ee, dr = 69:31 47c (R = Bn), 79%, 96% ee, dr = 73:27 under the standard reaction conditions. O 47d (R = PMB), 73%, 95% ee, dr = 75:25 Another strategy for synthesizing enantioenriched iso- H 47e (R = C H OBn), 63%, 90% ee, dr = 71:29 HO H 4 8 R 47f (R = C4H8OTBS), 65%, 94% ee, dr = 70:30 chromans, different from everything discussed thus far, involves reactions in which the enantio-determining step is MeO C–O bond formation. Scheme 19 highlights seminal work in 43 O S PMP OMe this area, published by Kitamura and co-workers in 2011. MeO O H H H H Ruthenium complex 59, at a catalyst loading of only 0.1 HO H HO H HO H HO H n-Pr n-Pr n-Pr n-Pr mol%, facilitates intramolecular dehydrative O-allylation of

47g, 92%, 96% ee 47h, 85%, 90% ee 47i, 55%, 96% ee 47j 57 to furnish 1-vinyl isochroman 58a in excellent yield and dr = 79:21 dr = 67:33 dr = 63:37 not formed ee in a sequence that proceeds via the intermediacy of a Ru- Scheme 15 Catalytic enantioselective addition of enolizable aldehydes -allyl species. to isochromans 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

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DDQ (1.05 equiv), MeOH (3 equiv) DDQ (1.1 equiv), EtOH (3 equiv) then catalyst 53 (5 mol%) then catalyst 55 (5 mol%) 54 (1.4 equiv), Na2CO3 (0.5 equiv) O 56 (1.4 equiv) O O O N N CH2Cl2/PhMe, 5 Å MS, –10 °C H CH2Cl2/Et2O, 4 Å MS, 0 °C H PMP PMP Ph Ph (±)-52a 52a, 90%, 90% ee (±)-23a 23a, 90%, 95% ee Ar Ar Ar O O EtO2C CO2Et O O P N EtO C CO Et O OH P P 2 2 n-Pr N n-Pr H O HO O O Ar Me N Me 56 H Ar Ar 55 (Ar = 9-phenanthryl) 54 53 (Ar = 3,5-(CF3)2-C6H3) Selected scope: Selected scope: AcO AcO O O O O O O O N N N AcO H H H

23b, 88% 23c, 91% 23e, 80% MeO MeO 91% ee Br 92% ee Me 90% ee SMe OMe OMe Br 52b, 91%, 90% ee 52c, 80%, 91% ee 52d, 93%, 92% ee 52e, 70%, 73% ee (performed at rt) O O O Scheme 17 Catalytic redox deracemization of isochromans N OMe N N H H H O S

23l, 72% 23m, 86% 23n, 81% complex derived from palladium acetate and ligand 61, in 90% ee 92% ee 80% ee the presence of diphenylphosphinic acid, catalyzes the Br MeO transformation of -arylethanols such as 60 to 1-vinyl isochromans 58, and the products are obtained with excellent O O O N N N levels of enantioselectivity. 2,6-Dimethylbenzoquinone H H H Me (2,6-DMBQ) serves as the terminal oxidant in this process. The catalytic enantioselective synthesis of 1-alkynyl 23o, 90% 23p, 94% 23q, racemic 92% ee 95% ee (no reaction) isochromans was reported by Nishibayashi and co-workers OMe OMe in 2019 (Scheme 21).45 A Cu(I)-complex derived from Pybox Scheme 18 Catalytic redox deracemization of tetrahydropyrano- ligand 46 catalyzes the enantioselective intramolecular [3,4-b]indoles etherification of propargylic esters (e.g., 62) to provide products 63 in good to excellent yields and ee values. A vided in Scheme 23. Ketoaldehyde 67, a constitutional iso- nonlinear relationship exists between the enantiopurity of mer of 64, undergoes reduction followed by intramolecular ligand 46 and product, leading the authors to propose the conjugate addition to provide product 68 in 81% ee. intermediacy of a dicopper-allenylidene species. In 2015, Ghorai and co-workers reported a catalytic en- OH catalyst 59 (0.1 mol%), TsOH (0.1 mol%) OH O antioselective method for the synthesis of highly enantio- CH2Cl2, reflux, 1 h enriched 1-substituted isochromans (Scheme 22).46 This 57 method is based on intramolecular conjugate addition. Re- 58a, 98%, >98% ee duction of the aldehyde functionality of ketoaldehydes such PF6 as 64 by pinacolborane (pinBH) provides an alkoxyboronate N N intermediate that then undergoes conjugate addition to N N Ru form products 65 with excellent ee values. Reactions are O O O O catalyzed by quinine-derived squaramide-containing bi- i-Pr i-Pr i-Pr 59 i-Pr functional organocatalyst 66 and exhibit a broad scope. This method also enables the synthesis of isochromans con- Scheme 19 Synthesis of enantioenriched isochromans via intramolec- taining a substituent in the 3-position. An example is pro- ular dehydrative O-allylation

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Pd(OAc)2 (10 mol%), ligand 61 (10 mol%) pinBH ( 3 equiv), catalyst 66 (10 mol%) OH 2,6-DMBQ (1.1 equiv), Ph PO H (10 mol%) MeNO , 0 °C, 2 h 2 2 CHO 2

PhMe (0.15 M), 45 °C, 8–10 h O then i-PrOH, 45 °C, 14 h O

O 60 Ph H

58a, 70%, 92% ee O OMe Ph O O Ph 64 N 65a, 81%, 92% ee N

NH 66 [Ar = 3,5-(CF ) -C H ] S Me Me 3 2 6 3 N O O O NH 61 t-Bu 2,6-DMBQ Ar O Selected scope: Selected scope: F Me

O O O O O O O Me O O O O

58b, 69%, 92% ee 58c, 68%, 93% ee 58d, 64%, 92% ee O S

Br Cl OMe Br O O O F 65b, 68%, 89% ee 65c, 80%, 96% ee 65d, 81%, 96% ee 65e, 68%, 94% ee

Cl O 58e, 76%, 93% ee 58f, 61%, 91% ee 58g, 55%, 92% ee O O O Scheme 20 Synthesis of enantioenriched isochromans via intramolec- O Me ular allylic C–H oxidation O O O

O O CuOTf•1/2 PhH (5 mol%) OH ligand 46 (10 mol%), K2CO3 (1.2 equiv) Br OAc CF CH OH (0.04 M), –20 °C, 51 h O 3 2 65f, 70%, 93% ee 65g, 72%, 93% ee 65h, 82%, 94% ee

Scheme 22 Synthesis of enantioenriched isochromans via intramolecular conjugate addition O O (±)-62 N 63, 89%, 93% ee N N pinBH (5 equiv) catalyst 66 (20 mol%) Ph Ph Ph Ph 46 MeNO2, 0 °C, 2 h Selected scope: O O O F CHO then i-PrOH, 45 °C, 16 h

Me 67 68, 56%, 81% ee O O O Scheme 23 Synthesis of enantioenriched 3-substituted isochromans Me via intramolecular conjugate addition

63b, 90%, 91% ee 63c, 75%, 88% ee 63d, 65%, 89% ee Another rare example of a catalytic enantioselective process leading to isochromans containing a substituent in 47 O O O the 3-position was reported in 2009 (Scheme 24). As part F MeO of a broader effort directed at preparing a range of structur- Me ally diverse compounds, Chung and Fu achieved the catalyt-

63e, 90%, 87% ee 63f, 72%, 93% ee 63g, 75%, 80% ee ic enantioselective synthesis of isochroman 70 from ,- alkynyl ester 69. This isomerization reaction is catalyzed by Scheme 21 Synthesis of enantioenriched isochromans via intramolecular etherification of propargylic esters chiral phosphine 71, operating in concert with benzoic acid.

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CO2Et O catalyst 71 (10 mol%) CO2Et PhCO2H (50 mol%) O H OH O NHTs Pd(OAc)2 (5 mol%) Et THF, 55 °C, 48 h ligand 77 (10 mol%) O 69 70, 82%, 94% ee DMF/H O/HOAc = 10:1:1, 50 °C N Et O 2 Ts

P Ph 75 Me 76, 90%, 95% ee N 71 O 77 O N Scheme 24 Synthesis of enantioenriched 3-substituted isochromans Me via phosphine-catalyzed isomerization of ,-alkynyl esters Scheme 26 Synthesis of enantioenriched tetrahydropyrano[3,4-b]- indoles by a Pd-catalyzed cascade reaction Examples of catalytic enantioselective reactions that provide enantioenriched tetrahydropyrano[3,4-b]indoles asymmetric catalysis has improved dramatically over the containing substituents in other than the 1-position are past 10 years, with most advances having emerged only in shown in Scheme 25 and Scheme 26. In 2011, the You the past 5 years. It is also clear that significant challenges group achieved enantioselective intramolecular Friedel– remain. Although highly desirable, for instance for a more Crafts alkylation reactions of indolyl enones (e.g., 72), pro- efficient synthesis of drug molecules such as etodolac, viding products such as 73 with exceptional efficiency methods that efficiently install tetrasubstituted stereogenic (Scheme 25).48 Reactions are catalyzed by chiral N-triflyl centers remain rare and have largely been limited to addi- phosphoramide 74, a catalyst that is remarkably active at tions to cyclic oxocarbenium ions (Scheme 14). Thus far, –70 °C. In earlier work published in 2009, the same group there is only one example with low enantioselectivity in showed that products such as 73 can be obtained by olefin which a tetrasubstituted stereogenic center was generated cross-metathesis/Friedel–Crafts alkylation cascades using a via an oxa-Pictet–Spengler cyclization (Scheme 7). Pictet– compatible combination of a Ru catalyst and a chiral phos- Spengler cyclizations of tryptophols or -arylethanols with phoric acid catalyst (not shown).49 ketones or ketone surrogates would provide the most direct access to isochromans and tetrahydropyrano[3,4-b]indoles O O containing a tetrasubstituted stereogenic center in the 1- Ph Ph position. While such reactions are well known in a racemic sense, catalytic enantioselective variants have remained

catalyst 74 (5 mol%) elusive. In addition, highly enantioselective oxa-Pictet– O O Br Br Spengler reactions of tryptophols have not yet been accom- N PhMe, –70 °C, 24 h N plished with aliphatic aldehydes, and reactions with - Me Me 72 Ar 73, 99%, 98% ee phenylethanols require the presence of a hydroxyl group in a specific position of the aryl ring. All three of the highly O O enantioselective oxa-Pictet–Spengler reactions reported to P Tf O N H date (Scheme 8, Scheme 9, and Scheme 11) require the presence of hydrogen-bonding donor or acceptor sites on Ar the alcohol substrate. However, encouraging findings such 74 (Ar = 9-anthryl) as those summarized in Scheme 6 suggest that such reac- Scheme 25 Synthesis of enantioenriched tetrahydropyrano[3,4-b]- tions could potentially be rendered highly enantioselective indoles by intramolecular Friedel–Crafts alkylation in the absence of obvious directing groups. Overall, there is Highly enantioenriched tetrahydropyrano[3,4-b]indoles cause for optimism that many of these limitations will be containing a fused ring and two stereogenic centers (e.g., addressed in the not-too-distant future. We look forward to 76) can be prepared from substrates such as 75, as reported learning about new advances and hope that this Short Re- by Lu and co-workers in 2017.50 This transformation in- view will motivate others to tackle the remaining challenges. volves a Pd(II)-catalyzed aminopalladation/1,4-addition sequence that is facilitated by chiral bipyridine ligand 77. Funding Information As is clear from the transformations discussed in this Short Review, access to highly enantioenriched isochro- This material is based upon work supported by the National Science mans and tetrahydropyrano[3,4-b]indoles by means of Foundation under grant CHE–1856613.Nationa lScience Foundation (CHE–1856613)

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