Biphenyl‐Derived Phosphepines as Chiral Nucleophilic Catalysts: Enantioselective [4+1] Annulations To Form Functionalized Cyclopentenes

Abstract

Due to the frequent occurrence of cyclopentane subunits in bioactive compounds, the development of efficient catalytic asymmetric methods for their synthesis is an important objective. In this report, we introduce a new family of chiral nucleophilic catalysts, biphenyl-derived phosphepines, and we apply them to an enantioselective variant of a useful [4+1] annulation first described by Tong. A range of one-carbon coupling partners can be employed, thereby generating cyclopentenes that bear a fully substituted stereocenter (either all-carbon or heteroatom-substituted (sulfur and phosphorus)). Stereocenters at the other four positions of the cyclopentane ring can also be introduced with good stereoselectivity. An initial mechanistic study indicates that phosphine addition to the electrophilic four-carbon coupling partner is not the turnover-limiting step of the catalytic cycle.Correspondence to: Gregory C. Fu, gcfu@caltech.edu. Supporting information for this article is given via a link at the end of the document. [1] but also as enantioselective nucleophilic catalysts for a broad spectrum of useful transformations. [2,3] Studies by our lab and by others have established that 1,1′-binaphthyl-derived phosphepines (e.g., 1) are effective for a diverse array of interesting processes; [4,5,6] in contrast, to the best of our knowledge, there have been no applications of axially chiral biphenyl-derived phosphepines (e.g., 2) as asymmetric nucleophilic catalysts. [7] The use of chiral phosphines as nucleophilic catalysts for the synthesis of five-membered rings has been a focus of particular interest, [8] due in part to the occurrence of cyclopentane subunits in a wide range of bioactive molecules, [9] and Lu's powerful methods for convergent [3+2] annulation have been especially well-explored. [10,11] With regard to the enantioselective construction of quaternary stereocenters, [12] nearly all reports have described the generation of spirocyclic structures. [8,13,14] One complication in some of these [3+2] reactions is the formation of regioisomeric products. [10] In 2010 approach obviates the formation of regioisomeric products. [16,17] As part of an ongoing program to demonstrate the utility and the versatility of asymmetric nucleophilic catalysis, [18] we embarked on the development of an enantioselective variant of this [4+1] annulation. At the point that we completed our study, [19] we were not aware of any progress by others toward this objective. However, this year Lu has described asymmetric reactions that furnish spirocyclic products in good ee [(Eq. 2)], [20] which has prompted us to disclose our independent investigation. Herein, we report the first use of biphenyl-derived phosphepines (3 and 4) as enantioselective nucleophilic catalysts, specifically, their application in [4+1] annulations that generate cyclopentenes that bear nonspirocyclic, fully substituted stereocenters (either all-carbon or heteroatom-substituted; Eq. 3). [21,22] Ziegler et al. HHS Public AccessUpon determining that an arra...

Phosphine Organocatalysis

“…In 2014, the Fu group employed the chiral phosphepine P42 to catalyze [4 + 1] annulations between α -cyanocarbonyls and β ′-acetoxy allenoates, generating several functionalized cyclopentenes in high yields and enantiomeric excesses (Scheme 170). 234 Various α -cyanoketones and amides were amenable to the reaction conditions. Although an α -cyanoester could also be used, the reaction required a higher catalyst loading to maintain the high yield.…”

Asymmetric Reactions Catalyzed by Chiral Tertiary Phosphines

“…[ 80 ] Asymmetric version of this kind of reaction was reported by Fu's group in 2014. [ 81 ] Fu and co‐workers synthesized and examined the utility of biphenyl‐derived phosphepines for this reaction, and established for the first time that biphenyl‐derived axially chiral phosphepines 237 can serve as useful enantioselective nucleophilic catalysts for this asymmetric [4+1] cycloaddition reaction. Specifically, they applied chiral phosphine 237 to catalyze asymmetric [4+1] cycloaddition reaction to provide functionalized cyclopentenes 238 and 239 in good yields with excellent enantioselectivities (Scheme 63).…”

Formal [4+1] Annulation Reactions in the Synthesis of Carbocyclic and Heterocyclic Systems

“…Under optimal conditions, an extensive range of N - tert -butyl-protected pyrozolones 300 that bear various electron-donating or electron-withdrawing groups at the aryl moiety were tolerated to produce the corresponding enantioenriched 4-spiro-5-pyrazolones 302 in acceptable yields with high ee values. Fu’s group also disclosed a highly efficient formal [4+1] annulation between 2,3-butadienoate 297 and a series of activated one-carbon coupling components 303 using the new chiral biphenyl-derived phosphepines ( R )- 304 or ( R )- 305 as nucleophilic catalysts, which caused the formation of the corresponding cyclopentane derivatives 306 with relatively superior enantioselectivities (Scheme b) . For both of these groups, the presence of water was deleterious to the reaction efficiency and enantioselectivities.…”