Chiral Brønsted Acid Catalyzed Stereoselective [3+3] Cycloaddition Reaction of Azomethine Ylide to Vinylimine Intermediates: Constructing Fully Functionalized Chiral Tetrahydro-β-Carboline

Abstract

An asymmetric three-component formal [3＋3] cycloaddition reaction of aldehyde, diethyl 2-aminomalonate and substituted indolyl alcohols, has been investigated with chiral BINOL-derived monophosphoric acids as catalysts. The active azomethine ylide intermediate can be readily formed from the condensation of aldehyde and diethyl 2-aminomalonate under the promotion of the chiral phosphoric acids and is thereby able to undergo nucleophilic addition reaction to electron-deficient carbon-carbon double bonds as reported previously in the multicomponent reactions. On the other hand, the indolyl alcohols are able to participate in a dehydration reaction in the presence of the phosphoric acids to generate transient vinyliminium intermediates, which are principally reactive toward nucleophiles. Thus, we envisioned that the two types of active intermediates could undergo an asymmetric formal [3＋3] cycloaddition to stereoselectively produce functionalized tetrahydro-β-carbolines under the catalysis of the chiral phosphoric acids. Consequently, a variety of 3,3'-disubstituted BINOL-phosphoric acids were initially evaluated for the reaction. As a result, the 3,3'-bis(p-ClPh) BINOL-phosphoric acid proved to perform most successfully in non-polar solvents, such as toluene. This reaction actually provides a highly straightforward access to functionalized tetrahydro-β-carboline derivatives. A number of substituted indolyl alcohols bearing either electronically donating or withdrawing groups are well tolerated, affording highly functionalized tetrahydro-β-carbolines in high yields ranging from 70% to 91% and with excellent enantioselectivities of up to 93% ee. A representative procedure for the enantioselective formal [3＋3] cycloaddition reaction is as following: After a mixture of p-nitrobenzaldehyde (0.06 mmol), diethyl 2-amino-malonate (0.05 mmol), 3 Å MS (100 mg) and chiral phosphoric acid (10 mol%) in toluene (1.0 mL) was stirred at the r.t. for 15 min, the substituted indolyl acohol (0.1 mmol) was added. After completion of the addition, the reaction mixture was stirred for additional 12 h at the same temperature. The reaction solution was filtrated and the residue was washed three times with ethyl acetate (5 mL×3). The combined organic solutions were evaporated under the reduced pressure to give corresponding crude products, which were purified by column chromatography on silica gel (eluent: light petroleum ether∶ethyl acetate, V∶V＝3∶1) to give analytically pure tetrahydro-β-carboline derivatives.

Indolylmethanols as Reactants in Catalytic Asymmetric Reactions

“…In addition to [3 + 2] cyclization, the catalytic asymmetric [3 + 3] cyclization of 3-indolylmethanols has been of substantial interest to organic chemists because of the remarkable ability of this class of reaction to construct indole-fused six-membered rings with optical activity . In 2014, the Shi group established the CPA-catalyzed highly enantioselective [3 + 3] cyclizations of 3-indolylmethanols 47 with azomethine ylides 56 generated in situ from aldehydes or isatins, affording structurally diverse spirooxindoles or bispirooxindoles 57 in high yields and good enantioselectivities (68% to >99% ee) (Scheme ).…”

Regioselective and Stereoselective [3+3] Annulation of Ketones Derived Azomethine Ylides with 2‐Indolylethylenes: Direct Access to Highly Substituted Tetrahydro‐γ‐Carbolines

“…In the past decade, a great deal of effort has been focused on the development of asymmetric [3+2] annulation of azomethine ylides with a variety of electrondeficient alkenes, which have been widely applied for the construction of structurally diversed chiral pyrrolidines . In contrast, the enantioselective [3+3] annulation of azomethine ylides with three‐atom dipolarophiles only limited reported by Gong, Wang, Tu, Shi,, Guo and our group (Scheme ). Additionally, due to the steric hindrance and low reactivity of ketones derived azomethine ylides, to the best of our knowledge, asymmetric [3+3] annulation of this kind of challenging azomethine ylides has not yet been reported.…”

Stereoselective Organocatalytic Addition of Nucleophiles to Isoquinolinium and 3,4-dihydroisoquinolinium Ions: A Simple Approach for the Synthesis of Isoquinoline Alkaloids

“…In a similar fashion, Gong and Luo described a multicomponent reaction that occurred with p-nitrobenzaldehyde, diethyl 2-aminomalonate, and 3-indolyl(aryl)methanols [90]. A formal, highly diastereoselective, chiral catalystcontrolled aza-Diels-Alder reaction between a 6-methoxytryptamine-derived dihydro-b-carboline 74 and an enantioenriched substituted enone 75 was described by Jacobsen (Scheme 24) [91,92].…”