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 SynOpen 2019, 3, 77–90 Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany 78 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 SynOpen 2019, 3, 77–90 79 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.