Organo-Catalyzed Asymmetric Michael–Hemiketalization–Oxa-Pictet–Spengler Cyclization for Bridged and Spiro Heterocyclic Skeletons: Oxocarbenium Ion as a Key Intermediate

Abstract

A Michael-hemiketalization-oxa-Pictet-Spengler cyclization has been developed for the construction of chiral bridged and spiro heterocyclic skeletons with one spiro stereogenic carbon center and two bridgehead carbon centers, utilizing cooperative catalysts of a Takemoto thiourea catalyst and a triflimide. In particular, an oxocarbenium ion acts as a key intermediate for this cyclization reaction. Additionally, biological evaluation of this type of novel structure has revealed obvious antiproliferative activity against some cancer cell lines.

Further developments of β,γ-unsaturated α-ketoesters as versatile synthons in asymmetric catalysis

“…By using a similar modified β,γ -unsaturated α -ketoesters 1m, Qiao and Wang et al. reported a Takemoto thiourea catalyst and triflimide cooperatively catalyzed Michael/hemiketalization/Pictet−Spengler cyclization with 3-pyrrolyloxindoles 108 for the construction of bridge-ring skeletons ( scheme 21 C) ( Fan et al., 2017 ). The projected reaction was initiated by organo-catalyzed Michael addition, which was the enantio-determining step.…”

Mechanism and origins of selectivity in the enantioselective oxa-Pictet–Spengler reaction: a cooperative catalytic complex from a hydrogen bond donor and chiral phosphoric acid

“…1A). Reports from the Seidel group furnish chiral polysubstituted tetrahydropyranoindoles (THPIs) through cooperative amine (NH 2 )/hydrogen bond donor [9][10][11][12] (HBD) and bifunctional Brønsted acid (BA)/HBD chiral catalysis. Similarly, the List group utilized sterically-congested imidodiphosphate (IDP) catalysts to produce substituted isochromanes with high stereochemical delity.…”

Trifluoroacetic Anhydride Mediated One-Pot Synthesis of 1-Aryl Isochroman-3-ones via the Carboxy-Pictet–Spengler Reaction

“…On the basis of the Pictet–Spengler-type reactions (Scheme , eq 1, X = NH), many review articles have documented synthetic applications for diversified natural products, bioactive molecules, functionalized materials, and synthetic blocks. − After ca. 90 years, an oxa-Pictet–Spengler reaction (X = O) was developed by Wunsch and Zott to construct the core skeleton of substituted isochroman with modest to good yields by the combination of ZnCl 2 , p -TsOH, and HCl (g) or Lewis acid (e.g., TiCl 4 , AlCl 3 , and SnCl 2 )-mediated intermolecular annulation of 2-arylethanol with aldehydes or ketones. − In recent years, the evaluated scope has been extended to a thia-Pictet–Spengler reaction (X = S) in the formation of a thiaisochroman skeleton. − Overall, the facile intermolecular annulation of 2-arylethyl amines, alcohols, and thiols with a variety of carbonyl synthons has seen growing interest with Brønsted acid or Lewis acid promoted routes.…”

“…13 C{1 H} NMR (100 MHz, CDCl 3 ): δ 172 9,. 159.3, 150.3, 148.2, 142.2, 131.2 (2C), 128.7, 128.0, 127.3, 125.8, 114.4 (2C), 112.5, 110.5, 55.8, 55.3, 55.2.…”