Phosphine Catalysis DOI: 10.1002/anie.201311214 Asymmetric Synthesis of Spiropyrazolones through Phosphine- Catalyzed [4+1] Annulation** Xiaoyu Han, Weijun Yao, Tianli Wang, YongRen Tan, Ziyu Yan, Jacek Kwiatkowski, and Yixin Lu* 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 alle- noates 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 co- workers, [2] different types of phosphine-catalyzed cycloaddi- tion 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 knowl- edge, 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 asymmet- ric synthesis of highly functionalized cyclopentenes. [9] How- ever, 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 transforma- tion. 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 to this challenging structural motif. We envisioned that 4-spiro-5-pyrazolone structural motifs may be conveniently assembled through a phosphine-mediated [4+1] annulation reaction. The high acidity of two protons at position 4 of 5-pyrazolone suggests that it may be a suitable C 1 synthon in the proposed annulation. By employing 2,3-butadienoate as a reaction partner, 4-spiro-5-pyrazolones could be readily constructed (Scheme 2). In recent years, our group has investigated enantioselective processes promoted by amino acid based chiral phosphines, and the reactions we have disclosed include: (aza)-MBH reactions, allylic alkylation, Michael addition, g addition, and a number of [3+2] and [4+2] cycloaddition reactions. [13] Herein, we describe the first Scheme 1. Reported [4+1] annulations. [*] Dr. X. Han Zhejiang Provincial Key Laboratory for Chemical & Biochemical Processing Technology of Farm Products, School of Biological and Chemical Engineering, Zhejiang University of Science and Tech- nology No. 318 Liuhe Road, Hangzhou, 310023 (China) Dr. X. Han, Dr. W. Yao, Dr. T. Wang, Y.R. Tan, [+] Z. Yan, J. Kwiatkowski, Prof.Dr. Y. Lu Department of Chemistry & Medicinal Chemistry Program Life Sciences Institute, National University of Singapore (NUS) 3 Science Drive 3, Singapore 117543 (Singapore) E-mail: chmlyx@nus.edu.sg [ + ] Exchange student from Imperial College. [**] We thank the NUS (R-143-000-469-112) and the Ministry of Education of Singapore (R-143-000-494-112) for generous financial support. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/anie.201311214. A ngewandte Chemi e 5643 Angew. Chem. Int. Ed. 2014, 53, 5643 –5647  2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim