Article pubs.acs.org/JACS
Enantioconvergent Copper Catalysis: In Situ Generation of the Chiral Phosphorus Ylide and Its Wittig Reactions Kai Zhang,†,∥ Liang-Qiu Lu,†,‡,∥ Sheng Yao,† Jia-Rong Chen,† De-Qing Shi,† and Wen-Jing Xiao*,†,§
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†
Hubei International Scientific and Technological Cooperation Base of Pesticide and Green Synthesis, Key Laboratory of Pesticide and Chemical Biology Ministry of Education, College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan, Hubei 430079, P. R. China ‡ State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics (LICP), Chinese Academy of Sciences, Lanzhou 730000, P. R. China § Collaborative Innovation Center of Chemical Science and Engineering, Tianjin University, Tianjin 300072, P. R. China S Supporting Information *
ABSTRACT: The Wittig reaction, which produces alkenes from phosphorus ylides (P-ylides) and carbonyls, is one of the most powerful tools in chemical synthesis. This Nobel Prizewinning reaction is widely used in natural product synthesis, fine chemical production (i.e., medicines and agricultural agents), and polymer functionalization. Despite these great achievements, the potential of the Wittig reaction, particularly regarding the access of chiral alkene building blocks, has not been fully exploited. The main area that requires additional exploration is the development of general and practical methods to efficiently prepare chiral P-ylides. Here, we show that highly functionalized chiral P-ylides can be easily synthesized through a copper-catalyzed asymmetric propargylic alkylation reaction from phosphonium salts and racemic propargylic esters. The subsequent Wittig reactions enable the synthesis of versatile alkene building blocks, chiral α-propargylic acrylates, and α-propargylic allenoates, with a wide substrate scope and satisfactory functional group compatibility. This transformation features inexpensive transition-metal catalysts, user-friendly conditions, easily available feedstock, and high-valued products.
1. INTRODUCTION The Wittig reaction, a Nobel Prize-winning reaction, is among the premier methods for alkene synthesis.1 This reaction has attracted considerable research interest from academics and industry due to complete positioning and tunable stereoselectivity.2 Indeed, the Wittig reaction has been widely used in the synthesis of natural products and the production of functional molecules, such as pharmaceuticals, agrochemicals, perfumes, and polymers. The success of the Wittig reaction is attributed to the unique nature of phosphorus ylides (Pylides),3 which can be condensed with aldehydes or ketones to generate alkenes. However, the advancement of the Wittig reaction still has potential, particularly with respect to chiral Pylide synthesis and the resultant chiral unsaturated products.4 Chiral P-ylides possessing chiral substituents are difficult to prepare via classical routes from the corresponding halogen compounds and tertiary phosphines (Scheme 1a), because of the steric repulsion in the alkylation step and an unwanted 1,2elimination reaction. Therefore, an alternative route, the alkylation of functionalized singly substituted P-ylides, was developed by Bestmann and Schulz, affording doubly substituted P-ylides with good yields.5 Although more than © 2017 American Chemical Society
half a century has passed since the development of this method, highly enantioselective processes to achieve chiral P-ylides are still underdeveloped,6 which has severely limited the application of P-ylides to the production of significant chiral alkenes. Organometallic catalysis is well established as a powerful tool in modern synthetic chemistry.7 Transition-metal (TM)catalyzed alkylation reactions allow the formation of chemical bonds, including enantioselective allylic8 and propargylic alkylations,9 with good efficiencies and selectivities. However, to our surprise, the utilization of this technology to asymmetrically modify widely available and bench-stable P-ylides has not been disclosed. Presumably, the inherent characteristics of Pylides, including the strong σ-electron-donating abilities of the formal carbon anions, the weak inductive effects of the carbons, and the π-electron-accepting abilities of the formal phosphonium cations, allow these molecules to strongly coordinate with many TMs, such as rhodium, gold, palladium, silver, and mercury.10 These interactions potentially prevent the development of TM-catalyzed alkylations of stable P-ylides. Until 2010, Received: August 3, 2017 Published: August 21, 2017 12847
DOI: 10.1021/jacs.7b08207 J. Am. Chem. Soc. 2017, 139, 12847−12854
Article
Journal of the American Chemical Society Table 1. Selected Condition Optimizationa
Scheme 1. Synthesis of Chiral P-Ylides with Double Substituents
entry
L
temp. (°C)
time (h)
Yield (%)b
ee (%)c
1 2 3 4 5 6 7 8 9d 10e 11f,g 12g,h 13g−i 14g−j 15g−j
L1 L2 L3 L4 L5 L6 L7 L7 L7 L7 L7 L7 L7 L7 L7
rt rt rt rt rt rt rt 0 0 0 0 0 0 0 −20
3 3 3 3 3 3 3 12 12 12 12 12 12 12 20
− 16 86 66 71 59 94 97 85 95 78/15 96/
