Synthesis of Enantioenriched Indolines by a Conjugate Addition/Asymmetric Protonation/Aza‐Prins Cascade Reaction

Abstract

A conjugate addition/asymmetric protonation/aza-Prins cascade reaction has been developed for the enantioselective synthesis of fused polycyclic indolines. A catalyst system generated from ZrCl 4 and 3,3'-dibromo-BINOL enables the synthesis of a range of polycyclic indolines in good yields and high enantioselectivity. A key finding is the use of TMSCl and 2,6-dibromophenol as a stoichiometric source of HCl to facilitate catalyst turnover. This transformation is the first in which a ZrCl 4 •BINOL complex serves as a chiral Lewis acid-assisted Brønsted acid. KeywordsLewis acid-assisted Brønsted acid; catalysis; cascade; indoline; enantioselective Cascade reactions, in which a single substrate undergoes a series of chemical transformations, provide rapid access to molecular complexity. 1 Many beautiful examples of cascade reactions have emerged from total synthesis endeavors, both in the context of biomimetic and de novo synthetic strategies. 2 More recently, attention has turned to developing cascade reactions involving asymmetric catalysis, which can convert simple, achiral starting materials to complex products with control over both the absolute and relative stereochemistry. 3 These transformations powerfully merge the attributes of asymmetric catalysis and cascade reactions for the synthesis of stereochemically rich small molecules.In 2010, we reported a new method to prepare enantioenriched pyrroloindolines (5) from C3-substituted indoles (1) and 2-amidoacrylates (2) using SnCl 4 and catalytic (R)-BINOL (L1) (Scheme 1, a). 4,5 Mechanistic investigations suggest that this reaction proceeds by a reversible conjugate addition of 1 to 2, followed by a highly selective, catalyst-controlled protonation of enolate 3, in which a SnCl 4 ·L1 complex serves as a chiral Lewis acid-assisted Brønsted acid (LBA). 6 Subsequent studies in our group determined that persistent indolinium ion 4 can be trapped with hydride to provide direct access to the corresponding indoline 6. 7 Recognizing that iminium ions such as 4 can serve as electrophiles for C-C * reisman@caltech.edu, Homepage: http://reismangroup.caltech.edu. ‡ These authors contributed equally to this research. Here we report the successful realization of this concept, which has resulted in a direct synthesis of complex polycyclic indolines in a single step from simple indole derivatives (Scheme 1, b). HHS Public AccessWe began our studies with 3-(but-3-en-1-yl)-1-methylindole (7a), a substrate in which the pendant alkene is poised to undergo intramolecular attack to form a six-membered ring (Table 1). Exposure of a mixture of indole 7a and amidoacrylate 2a to SnCl 4 (1.2 equiv) and (R)-BINOL (L1, 20 mol %) -the standard conditions developed for the previously reported pyrroloindoline formation 4 -provided hexahydrocarbazole 8 in low yield but with promising levels of diastereo-and enantioselection (Table 1, entry 1). Presumably 8 arises from a conjugate addition/asymmetric protonation/aza-Prins cyclization cascade, with chloride trapping of the resulting carb...

Recent Developments in Enantioselective Metal‐Catalyzed Domino Reactions

“…In 2016, Reisman et al. reported a novel direct approach to chiral fused polycyclic indolines 51a–i based on an asymmetric zirconium‐mediated domino reaction of C‐3 substituted indoles 52a–i with an amidoacrylate 53 34. As shown in Scheme (first equation), the process required 1.6 equivalents of ZrCl 4 as precatalyst combined with 20 mol% of chiral BINOL‐derived ligand 54 to proceed.…”

Stereoselective intermolecular radical cascade reactions of tryptophans or ɤ-alkenyl-α-amino acids with acrylamides via photoredox catalysis

“…1A ). Consequently, great efforts have been devoted to the preparation of functionalized hexahydrocarbazoles 27 – 43 . Among those, direct catalytic dearomatization reaction of indole derivatives represents a straightforward and powerful strategy 44 – 50 .…”

“…Among those, direct catalytic dearomatization reaction of indole derivatives represents a straightforward and powerful strategy 44 – 50 . The cis- fused hexahydrocarbazoles are usually obtained through the dearomatization of substituted or pre-functionalized indole derivatives 27 – 33 . In contrast, the syntheses of the trans- fused hexahydrocarbazoles are less explored 36 – 43 .…”

Heumann Indole Flow Chemistry Process

“…For example, treatment of indole with methyl magnesium chloride and 4-bromobutene in benzene gave 5a in 41% yield. 29 Moreover, indole-3carbaldehyde reacted in indium-mediated allylation with allyl bromide in the presence of Hantzsch ester to provide 5a in 77% yield. 30 Notably, 3-(but-3-enyl)indole has been employed as a substrate in cross-metathesis chemistry 31 kanes, 32 pyrroloindolines, 33 a pentacyclic Strychnos alkaloid skeleton, 34 and hexahydrocarbazole alanine.…”

“…30 Notably, 3-(but-3-enyl)indole has been employed as a substrate in cross-metathesis chemistry 31 kanes, 32 pyrroloindolines, 33 a pentacyclic Strychnos alkaloid skeleton, 34 and hexahydrocarbazole alanine. 29 To the best of our knowledge, 3-(but-3-enyl)indole has, however, never been synthesized from an aromatic precursor. Previously, 1-[2aminophenyl]pent-4-en-1-one (1a; R Ar = H, R 3 = CH 2 CH 2 CHCH 2 ) has been prepared quantitatively from methyl anthranilate using the copper-catalyzed cascade addition of vinyl Grignard reagent 35 and used as an effective starting material for the syntheses of pyrroles, 36 quinazolinones, 36 quinolines, 35 benzodia-and triazepinones, 37−39 and pyrrolobenzodi-and trizepinones.…”