Catalytic Asymmetric Dearomatization of Indolyl Dihydropyridines through an Enamine Isomerization/Spirocyclization/Transfer Hydrogenation Sequence

Abstract

Ah ighly efficient synthesis of enantioenriched spiroindolines by catalytic asymmetric dearomatization of indolyl dihydropyridines through ac hiral phosphoric acid catalyzede namine isomerization/spirocyclization/transfer hydrogenation sequence has been developed. This reaction proceeds under mild reaction conditions,a ffording novel spiroindolines in good yields (up to 88 %) with excellent enantioselectivity (up to 97 %e e). DFT calculations provide insights into the reaction mechanism as well as the origin of stereochemistry.Synthetic studies of polycyclici ndole derivatives have attracted plenty of research interests due to the widespread occurrence of such structural cores in natural products as well as their biological activities. [1] Pictet-Spengler reactions are widely recognized as one of the most efficient and straightforward methods to afford tetrahydro-b-carbolines. [2] Tr aditionally,t ryptamine derivatives and carbonyl compounds are employed as the substrates of Pictet-Spengler reactions.A s part of our ongoing research on catalytic asymmetric dearomatization (CADA) reactions, [3] we recently developed an efficient asymmetric synthesis of tetrahydro-b-carbolines 2 through chiral phosphoric acid (CPA)-catalyzed sequential enamine isomerization/Pictet-Spengler reaction of indolyl dihydropyridines 1 (Scheme 1a). [4] Spiroindolenine has been generally regarded as ak ey intermediate in Pictet-Spengler reactions.T oc apture and further manipulate the spiroindolenine species would allow unprecedented access to novel polycyclic indole derivatives. [5] In this regard, we envisioned that the analogous reaction of indolyl dihydropyridine 3, which bears aone-methylene prolonged tether, would afford spiroindolenine 4,f rom which an in situ transfer hydrogenation with Hantzsch ester might lead to tetrahydrospiro[indoline-3.1'-quinolizine] 5 (Scheme 1b). Herein, we report the results of the study on this cascade reaction catalyzed by achiral phosphoric acid. [6] Our studies commenced with optimization of the reaction conditions with 3a as the model substrate (Table 1). It was Scheme 1. Reaction design. Table 1: Optimization of the reaction conditions. [a] Entry CHSolvent T [8 8C] t [h] Yield [%] ee [%] [b] 1 C1 H1 Cl(CH 2 ) c] C1 H1 EtOAc 40 36 82 93 [a] Unless otherwise noted, the reaction was performed with 3a (0.1 mmol), C (10 mol %), H (0.2 mmol) in 2.0 mL solvent. [b] Determined by HPLC analysis on achiral stationary phase. [c] 50 mg 3 MS were added and 6mLofEtOAc were used.found that in the presence of 10 mol %o fc hiral phosphoric acid C1 and 2.0 equiv of Hantzsch ester H1,the title reaction proceeded smoothly,d elivering the desired product 5a in 83 %y ield with 81 % ee as asingle diastereoisomer (Table 1, entry 1). Systematic evaluation of aseries of chiral phosphoric acids (C2-C7)r evealed that all of the catalysts tested can promote the reaction, albeit with varied yields and enantioselectivity (entries 2-7). With C1 as the optimal catalyst, the effects of different hydride donors were then examined. The...

A Thiol-Mediated Three-Step Ring Expansion Cascade for the Conversion of Indoles into Functionalized Quinolines

“…In recent years, ynones of this type have emerged as valuable precursors for the preparation of a diverse array of molecular scaffolds. 3 − 6 For example, our groups and others have shown that the activation of the alkyne moiety of 1 promotes efficient dearomatizing spirocyclization 7 , 8 to form medicinally important spirocyclic indolenines 2 ; 9 , 10 this is most commonly done using π-acidic catalysts (especially Ag(I) species), although Brønsted acids, palladium(II) complexes, and electrophilic halogenation reagents can also be used ( 1 → 2 , Scheme 1 a, step 1). 3 , 11 , 12 Our groups have also shown that dearomatization works well on 2-halogenated indoles (i.e., 1 where X = Cl, Br or I) and that the resulting indoleninyl halide products (i.e., 2 where X = Cl, Br or I) can be transformed further via reaction with nucleophiles, or via Pd-catalyzed cross-coupling, to substitute the halide for various other groups ( 2 → 3 , Scheme 1 a, step 2).…”