Asymmetric Synthesis of Spiropyrazolones through Phosphine‐Catalyzed [4+1] Annulation

Abstract

An enantioselective synthesis of spiropyrazolones from allenoate-derived MBH acetates and pyrazolones through a phosphine-mediated [4+1] annulation process has been developed. Spiropyrazolones were readily prepared in good chemical yields and good to high enantioselectivities. This is the first asymmetric example in which a-substituted allenoates were utilized as a C 4 synthon for phosphine-catalyzed [4+1] annulation.Over the past decade, nucleophilic phosphine catalysis has emerged as a powerful approach to structurally diverse and synthetically valuable carbocyclic and heterocyclic building blocks in organic chemistry. [1] Pioneered by Lu and coworkers, [2] different types of phosphine-catalyzed cycloaddition reactions have been developed over the years. In particular, [3+2] annulations of allenoates/alkynes or Morita-Baylis-Hillman (MBH) acetate/carbonates with alkenes or imines have been widely explored and established as an effective method for contructing a wide range of highly functionalized five-membered ring systems. [3] However, other types of [m+n] annulations were studied to a much lesser extent, [4] and the discovery of different cyclization modes with novel reaction partners is highly desirable.Phosphine-catalyzed [4+1] annulations represent an alternative approach for the formation of five-membered ring systems, and the successful development of this type of annulation is dependent on careful selection and utilization of C 4 and C 1 synthons for the projected cyclization. Recently, MBH carbonates were used as a new C 1 synthon in phosphine-catalyzed [4+1] annulations for the construction of five-membered heterocyclic ring structures by Zhang, [5] Chen, [6] and He. [7] Mechanistically, all the above reactions are initiated by the addition of a phosphine to an MBH carbonate to in situ generate a 1,1-dipolar synthon, which reacts with various conjugated electrophilic reaction partners. Another type of [4+1] annulation was disclosed by Tong in 2010, [8] in which 2,3-butadienoate, an a-substituted allenoate, was utilized as a C 4 synthon under phosphine catalysis, affording cyclopentene products (Scheme 1). Asymmetric versions of [4+1] annulations are very scarce; to the best of our knowledge, there is only one report in the literature. Shi utilized dicyano-2-methylenebut-3-enoates as a C 4 synthon in the annulation reaction with MBH carbonates, for the asymmetric synthesis of highly functionalized cyclopentenes. [9] However, the utilization of a-substituted allenoates in asymmetric [4+1] annulations is unknown. It thus became our goal to develop an asymmetric variant of this promising transformation.Pyrazolone and their derivatives are important structural motifs that widely occur in biologically active molecules and pharmaceutical agents, [10] and they are also synthetically valuable for the construction of heterocyclic and spirocyclic structures. [11] Recently, 4-spiro-5-pyrazolones were found to be inhibitors of type-4 phosphodiesterase, [12] resulting in the need for efficient synthetic approaches ...

Asymmetric, Three‐Component, One‐Pot Synthesis of Spiropyrazolones and 2,5‐Chromenediones from Aldol Condensation/NHC‐Catalyzed Annulation Reactions

“…Encouragedb yt his result,s everal chiral NHC pre-catalysts 4b-4f were employed (entries 2-6) revealing that the catalyst 4b provides the best ee of 94 %w ith 49 %y ield (entry 2). The screening of different bases (entries [7][8][9][10][11][12] showedt hat except for DBU, only KOtBu provided promising results in terms of ee;h owever,t he product was isolated in lower yield (entry 9). Further optimizationw as carried out by screening different solvents using DBU as base (entries 12-18).…”

“…Recently,L u's group reported an asymmetrics ynthesis of spirocyclopentane pyrazolones through ap hosphine-catalyzed [4+ +1] annulation reaction (Scheme 1a). [8] Currently,o ur group has also developed an ew strategy for the asymmetric synthesis of five-membered spiropyrazolones, starting from readily available pyrazolones and alkyne-tethered nitroalkenes through sequential organo-and silver catalysis (Scheme1b). [9] On the other hand, the NHC-catalyzed reactions of pyrazolones alwaysprovide annulated pyrazoles.…”

Phosphine‐mediated Highly Enantioselective Spirocyclization with Ketimines as Substrates

“…[13] Fort he efficient creation of 3,2'-pyrrolidinyl spirooxindoles,w hich contain at etrasubstituted stereogenic center at the 3-position, we reasoned that ap hosphine-catalyzed cycloaddition reaction employing isatin-derived ketimines would be an ideal strategy (Scheme 3). However,t he reactivity of the ketimine starting materials poses serious challenges.D espite the widespread use of isatin-derived ketimines in other reactions,f or example,Mannich reactions, [14] Strecker reactions, [15] (aza) FriedelCrafts additions, [16] aza-Morita-Baylis-Hillman reactions, [17] and aza-Henry reactions, [18] they have never been used in phosphine-catalyzed annulation reactions.W eh ypothesized that our amino acid based phosphine catalysts may provide sufficient activation for the challenging ketimine substrates, since such phosphines are very nucleophilic and are not hindered owing to the direct linkage of the phosphorus atom to ap rimary carbon.…”

Phosphine‐Catalyzed Annulations of 4,4‐Dicyano‐2‐Methylenebut‐3‐enoates with Maleimides and Maleic Anhydride

“…Moreover, a phosphinecatalyzed formal [3+2] annulation between 4,4-dicyano-2methylenebut-3-enoates and maleic anhydride has been also achieved, and maleic anhydride behaved as a C 3 synthon in the reaction, thus efficiently affording the functionalized cyclopentenones. [4] Apart from phosphine-catalyzed [3+2] annulations, phosphine-catalyzed [4+1] annulations [5] are also an efficient methodology to construct functionalized five-membered carbo-and heterocycles.Maleimides as electron-deficient olefins have been widely used in annulations to give functionalized carbocyclic compounds. Plausible mechanisms have been proposed on the basis of control experiments and deuteriumlabeling experiments.…”

“…[1] Recently, remarkable progress has been made in the development of nucleophilic phosphine organocatalysis, [2] and now phosphine-mediated/catalyzed reactions have emerged as a powerful tool for the synthesis of a wide variety of novel compounds. [4] Apart from phosphine-catalyzed [3+2] annulations, phosphine-catalyzed [4+1] annulations [5] are also an efficient methodology to construct functionalized five-membered carbo-and heterocycles. [4] Apart from phosphine-catalyzed [3+2] annulations, phosphine-catalyzed [4+1] annulations [5] are also an efficient methodology to construct functionalized five-membered carbo-and heterocycles.…”