Synthesis of (−)-Verbenone-Derived Triazolium Salts and Their Application in Enantioselective Intramolecular Stetter Reaction

Abstract

Two novel chiral verbenone-derived triazolium salts have been synthesized from readily available (−)-verbenone and found to be efficient for the enantioselective intramolecular Stetter reaction. The approach, based on the intramolecular annulation between acyl anion equivalents and Michael acceptors, benefits from broad substrate scope, high chemical and stereochemical efficiency, and operational simplicity. Mono-, and disubstituded chromanone derivatives have been obtained in excellent yields and in a highly stereochemical manner.Catalysts 2019, 9, 117 2 of 12 ketooxime 4 in 87% yield by treatment with isoamyl nitrite. Due to the fact, that verbenone is not commercially available in an enantiomerically pure form, attempts of enantiomeric enrichment through crystallization at the ketoxime stage failed. Hence, we decided to reduce the carbonyl group by treatment of 4 with sodium borohydride in ethanol. Gratifyingly, crystallization of the crude 5 gave the enantiomerically pure hydroxyoxime 5 in 99% ee. Stereoselective reduction of 5 with lithium aluminium hydride afforded the amino alcohol 6 in 63% yield, which was immediately used to the next step without further purification. The lactam 8 was prepared by previously reported two-step procedure involving the formation of chloroamide 7, followed by the cyclization reaction with the use of potassium tert-butoxide. Finally, a one-pot procedure was used for the three-step conversion into triazolium salts 1A-B. The NHC precatalyst 1B could be easily and cleanly isolated as a tetraphenyl borate salt. For the salt 1A, preparation does not require chromatographic purification. Evaporation of the solvent followed by washing with diethyl ether provided a pure product that was air-and water-stable solid.

Recent Advances in Stetter Reaction and Related Chemistry: An update

“…Moreover, various ester groups, including ethyl and benzyl were examined ( 146 b , 146 b′ , 146 d , 146 d′ ). In addition, different functionalized salicylaldehyde‐derived substrates 146 i – m , such as those having electron‐donating and electron‐withdrawing groups at various positions on the aromatic ring, afforded the relevant products 146 i – m , 146 i′ – m′ in very good yields and very high ee s. This approach shows an efficient NHC‐catalyzed asymmetric intramolecular Stetter reaction with the application of β,β‐difunctionalized Michael acceptors to obtain enantioenriched all‐carbon quaternary 2,2‐difunctionalized naphthofuranones and coumaranones [55] …”

“…A Camphor‐derived 145 and pinene‐derived 141 triazolium salts as N ‐heterocyclic carbine have been known to be effective for the asymmetric intramolecular Stetter reaction with diverse α,β‐functionalized Michael acceptors. Commonly, by using the NHC catalysts 145 or 141 , the expected 2,2‐difunctionalized coumaranones and naphthofuranones having fully‐functionalized quaternary chiral centers can be synthesized with very high yields and ee (up to 99%) [55] . This reaction was performed using catalyst 141 and potassium bis(trimethylsilyl)amide (KHMDS) as base to provide the corresponding products 146 a – p or catalyst 145 and potassium tert ‐butoxide as base to form the corresponding products 146 a′ – p′ in cyclohexane as solvent and at room temperature (Scheme 35).…”

“…[53] Rafiński and co-worker in 2019 reported the preparation of chiral verbenone-obtained triazolium salts from easily accessible (À )-verbenone, that were effectively used as catalysts in the asymmetric intramolecular Stetter reaction. [54] Based on this method, mono-, and disubstituded chromanones have been synthesized in a very stereochemical manner with excellent yields. This reaction was accomplished using triazolium salt 143 (as catalyst) and DIPEA (as base) in cyclohexane (as solvent) at room temperature.…”

Synthesis and Application of 1,2-Aminoalcohols with Neoisopulegol-Based Octahydrobenzofuran Core

“…1,2-aminoalcohols have also been demonstrated to be excellent chiral auxiliaries and chiral catalysts in asymmetric synthesis [33]. To achieve new, efficient, and commercially available chiral catalysts, natural chiral terpenes, such as α-pinene [34][35][36][37][38], β-pinene [34,39], (-)-3-carene [39,40], (-)verbenone [41,42], (-)-fenchone [43,44], (+)-camphor [43,45,46], and (-)-menthone [47] have proven to be excellent sources for the synthesis of bifunctional chiral compounds and heterocycles.…”

N‐Heterocyclic Carbene‐Catalyzed Enantioselective Intramolecular Annulations to Construct Benzo‐Fused Pyranones with Quaternary Stereocenter

“…[13,14] In recent years N-heterocyclic carbene catalysis has emerged as an attractive and ideal strategy to synthesize complex heterocyclic molecules via umpolung reactivity. [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] Among various asymmetric catalytic strategies for the stereoselective construction and selective functionalization of the six-membered motifs, the Stetter reaction proved to be one of the universal and fundamental tool of the N-heterocyclic carbene (NHC) catalysis [30][31][32][33][34][35][36] After Ciganek initial contribution on intramolecular NHC-catalyzed synthesis of chromanones, during next years many highly enantioselective approaches have been developed (Scheme 1, eq a). [30,[37][38][39][40] In the later stage, Rovis and coworkers disclosed a highly enantioselective and diastereoselective Stetter reaction of salicylaldehyde-derived bearing a tethered α,β-disubstituted Michael acceptors (eq b).…”