催化学报  2016, Vol. 37 Issue (8): 1389-1395   PDF (573 KB)    
扩展功能
加入收藏夹
复制引文信息
加入引用管理器
Email Alert
RSS
本文作者相关文章
Chen Xiushuai
Hou Chuanjin
Li Qing
Liu Yanjun
Yang Ruifeng
Hu Xiangping
Enantioselective synthesis of chiral phosphonylated 2,3-dihydrofurans by copper catalyzed asymmetric formal [3+2] cycloaddition of propargylic esters with β-keto phosphonates
Chen Xiushuaia,b, Hou Chuanjina, Li Qinga,b, Liu Yanjuna, Yang Ruifenga, Hu Xiangpingb     
a. School of Light Industry and Chemical Engineering, Dalian Polytechnic University, Dalian 116034, Liaoning, China ;
b. Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, Liaoning, China
Received 21 May 2016
Foundation Item: This work was supported by the National Natural Science Foundation of China (21403022, 21572226) and the Natural Science Foundation of Liaoning Province of China (2015020194)
* Corresponding author. Chuanjin Hou, E-mail: houcj@dlpu.edu.cn Yanjun Liu,E-mail: yjliu65@sohu.com Xiangping Hu,xiangping@dicp.ac.cn
Abstract: Copper catalyzed asymmetric formal [3+2] cycloaddition of propargylic esters to β-keto phosphonates for the synthesis of chiral phosphonylated 2,3-dihydrofurans was developed. By using a bulky and structurally rigid tridentate ketimine P,N,N ligand, a series of optically active phosphonylated 2,3-dihydrofurans were prepared in high yield and up to 92% ee.
© 2016, Dalian Institute of Chemical Physics, Chinese Academy of Sciences.
Published by Elsevier B.V. All rights reserved.
Key words: Copper     Asymmetric synthesis     [3+2] Cycloaddition     β-Keto phosphonates     Phosphonylated 2,3-dihydrofurans    
铜催化炔丙醇酯与β-羰基膦酸酯的不对称[3+2]环加成反应合成手性膦酰化2,3-二氢呋喃
陈修帅a,b, 侯传金a, 李晴a,b, 刘彦军a, 杨瑞丰a, 胡向平b     
a. 大连工业大学轻工与化学工程学院, 辽宁 大连 116034 ;
b. 中国科学院大连化学物理研究所, 辽宁 大连 116023
收稿日期: 2016-05-21
基金项目：国家自然科学基金（21403022，21572226）；辽宁省自然科学基金（2015020194）
通讯作者： 电子信箱: houcj@dlpu.edu.cn 电子信箱: yjliu65@sohu.com 电子信箱:xiangping@dicp.ac.cn
摘要：手性2, 3-二氢呋喃衍生物是一类重要的杂环化合物, 广泛存在于天然产物和生物活性分子中.它们也经常被用于手性四氢呋喃化合物的不对称合成.因此, 人们发展了很多合成手性2, 3-二氢呋喃化合物的方法, 如有机小分子催化的多米诺迈克尔-烷基化反应、“中断的”Feist-Bénary反应或改进的Feist-Bénary反应.此外, 过渡金属催化的手性2, 3-二氢呋喃的不对称合成在近些年引起了人们的极大关注.Ozawa等通过Pd-催化2, 3-二氢呋喃的动力拆分方法获得了手性2-芳基-2, 3-二氢呋喃.Evans发展了一种Sc-催化联烯硅和乙醛酸乙酯的[3+2]环加成反应合成手性2, 3-二氢呋喃的方法.最近, Fu和Tang等发展了Cu催化烯酮和重氮化合物的[4+1]环加成反应合成手性2, 3-二氢呋喃的方法.在Nishibayashi和van Maarseveen的开创性工作之后, Cu催化的不对称炔丙基转化反应取得了很大的进展.最近, 我们发展了一类新的三齿手性P, N, N-配体, 在Cu催化不对称炔丙基取代、脱羧炔丙基取代、[3+2]、[3+3]和[4+2]环加成反应中表现出优秀的对映和非对映选择性.其中, 我们发现采用Cu催化炔丙醇酯和β-酮酯的[3+2]环加成反应, 能高对映选择性地获得手性2, 3-二氢呋喃.我们设想, 采用β-羰基膦酸酯代替β-酮酯, 通过这种Cu催化[3+2]环加成反应, 将可以合成一类具有重要生物活性的手性膦酰化2, 3-二氢呋喃化合物.基于这种设想, 本文使用手性P, N, N-配体, 通过Cu催化炔丙醇酯与β-羰基膦酸酯的不对称[3+2]环加成反应, 以很好的收率和最高92% ee的对映选择性获得了一系列光学活性的膦酰化2, 3-二氢呋喃化合物.我们以炔丙醇酯1a与β-羰基膦酸酯2a为标准底物, 优化了反应条件, 考察了配体、Cu盐、碱和反应温度等对反应收率和对映选择性的影响.我们确定了最佳的反应条件:以4b为配体, 以Cu(OTf)2为铜盐, 以t-BuOK为碱, 以MeOH为溶剂, -20o. C反应24h.在此条件下, 我们对β-羰基磷酸酯2的适用范围进行了考察.结果表明, 各种苯基取代的β-羰膦磷酸酯均能得到很好的收率和对映选择性.苯环上取代基的空间效应对反应的对映选择性影响不大, 但对反应收率影响较大, 与相应3-取代或4-取代底物相比较, 2-取代的底物获得的收率较低.苯环对位取代基的电子效应对反应的影响不大, 给电子基或吸电子基的底物, 均得到了较好的收率和对映选择性.杂环取代的底物同样适用于该反应, 以90%的收率和89% ee的对映选择性获得了相应的[3+2]环加成产物.对于烷基底物, 虽然反应的产率略低, 但是得到了高达92% ee的产物.此外, 我们对炔丙醇酯底物的适用范围也进行了考察.结果表明, 该体系对于各种取代的炔丙醇酯底物均可以获得较高的收率和良好的对映选择性.总之, 本文发展了一种铜催化炔丙醇酯与β-羰基膦酸酯的不对称[3+2]环加成反应的方法, 成功合成了手性膦酰化2, 3-二氢呋喃化合物.通过使用一个结构刚性的酮亚胺三齿P, N, N-配体, 以很好的收率和最高92% ee的对映选择性获得了一系列光学活性的膦酰化2, 3-二氢呋喃化合物.
关键词： 铜     不对称合成     [3+2]环加成     β-羰基膦酸酯     膦酰化2,3-二氢呋喃    
1 Introduction

Enantiomerically enriched 2,3-dihydrofuran derivatives are very important compounds which are found in a variety of natural products and biological molecules [1, 2]. They are also convenient precursors for the asymmetric synthesis of tetrahydrofurans [3-5]. Thus,much effort have been de-voted to developing efficient methods for the synthesis of chiral 2,3-dihydrofurans,such as the organocatalytic domino Michael-alkylation reaction [6-8],interrupted Feist-Bénary reaction [9, 10] or modified Feist-Bénary reaction [11]. In addition,the transition metal catalyzed asymmetric synthesis of chiral 2,3-dihydrofurans has also attracted much attention in the past few decades. Ozawa et al. [12] obtained chiral 2-aryl-2,3- dihydrofurans by Pd catalyzed asymmetric aryla-tion of 2,3- dihydrofuran involving a kinetic resolution process. Evans et al [13] developed a Sc catalyzed [3+2] cyc-loaddition of allenylsilanes with ethyl glyoxylate for the syn-thesis of chiral 2,3- dihydrofurans. Recently,Son et al. [14] and Zhou et al. [15] reported the enantioselective synthesis of chiral 2,3- dihydrofurans by Cu catalyzed asymmetric [4+1] cycloaddition of enones with diazo compounds. Despite these advances,the development of new catalysts for the enantioselective synthesis of chiral 2,3- dihydrofurans is still in demand.

Following the pioneering works of Nishibayashi et al. [16] and van Maarseveen et al. [17],Cu catalyzed asymmetric propargylic transformation has made significant progress [18-21]. Recently,we have developed a series of chiral tri-dentate P,N,N-ligands which showed excellent diastereo- and enantioselectivity in the Cu catalyzed asymmetric propargylic substitution [22-26],decarboxylative propargylic substitu-tion [27-29],[3+3] cycloaddition [30],[3+2] cycloaddition [31, 32] and [4+2] cycloaddition [33]. In particular,we re-ported an example of Cu catalyzed formal [3+2] cycloadditon of propargylic esters with β-ketoesters for the enantioselec-tive synthesis of chiral 2,3-dihydrofurans [31]. Considering the important biological activity of phosphonylated hetero-cyclic compounds,we envisioned that this strategy is also suitable for the synthesis of chiral phosphonylated 2,3-dihydrofurans if a β-keto phosphonate is employed as the substrate instead of β- ketoester. As a result,here we report the Cu catalyzed formal [3+2] cycloadditon of pro-pargylic esters with β-keto phosphonates for the synthesis of chiral phosphonylated 2,3- dihydrofurans with a bulky and structurally rigid tridentate ketamine P,N,N ligand.

2 Experimental
2.1 General

All reactions were carried out under a nitrogen atmos-phere using standard Schlenk techniques. All solvents were purified by standard procedures and stored under nitrogen. 1H NMR and 13C NMR spectra were recorded at 400 MHz and 100 MHz,respectively,on a Bruker DPX400 NMR spectro-meter (Bruker,Switzerland). Enantiomeric ratios were de-termined by chiral HPLC using n-hexane and i-PrOH as the mobile phases. Optical rotations were recorded on a JASCO P-1020 polarimeter (JASCO Corporation,Tokyo,Japan).

2.2 General procedure for Cu catalyzed formal [3+2] cycloaddition of propargylic esters with β-keto phosphonates

Cu(OTf)2 (5.4 mg,0.015 mmol) and (S)-L4b (7.8 mg,0.0165 mmol) were added to anhydrous methanol (1 mL). The resulting mixture was stirred at room temperature un-der a nitrogen atmosphere for 1 h. Then,a solution of pro-pargylic ester 1 (0.6 mmol) and β-keto phosphonate 2 (0.3 mmol) in 2 mL of anhydrous methanol was added. The re-sulting mixture was stirred at -20 °C for 24 h. The reaction mixture was then concentrated under vacuum and the resi-due was purified by silica gel chromatography to afford the corresponding chiral phosphonylated 2,3-dihydrofurans 3.

(-)-Dimethyl(5-methylene-2,4-diphenyl-4,5- dihydrofu-ran- 3- yl)phosphonate (3aa). A colorless oil was obtained in 88% yield after purification with column chromatography on silica gel (hexane/ethyl acetate,4:1-1:1). 90% ee was determined by chiral HPLC (Chiralcel OJ-H,n-hexane/i-PrOH = 90/10,0.8 mL/min,254 nm,40 °C): tR (major) = 14.5 min,tR (mi-nor) = 8.7 min. [α]D22 = -84.9 (c 1.13,CH2Cl2). 1H NMR (400 MHz,DMSO-d6): δ 7.91 (d,J = 7.5 Hz,2H),7.58-7.50 (m,3H),7.41-7.27 (m,5H),5.12-5.03 (m,1H),4.85-4.73 (m,1H),4.20 (s,1H),3.39 (d,J = 3.6 Hz,3H),3.21 (d,J = 11.3 Hz,3H); 13C NMR (100 MHz,DMSO-d6): δ 164.4 (d,J = 13.9 Hz),163.5 (d,J = 25.7 Hz),142.6,131.6,129.1,129.0,128.7,128.6,128.2,127.7,102.7 (d,J = 214.2 Hz),88.0,54.7 (d,J = 10.1 Hz),52.5 (d,J = 5.7 Hz),52.3 (d,J = 5.5 Hz); 31P NMR (162 MHz,DMSO-d6): δ 16.5; HRMS calc. for C19H20O4P [M+H]+: 343.1099,found: 343.1094.

1H NMR (400 MHz,CDCl3): δ 7.93 (d,J = 8.0 Hz,2H),7.50-7.39 (m,7H),5.16 (d,J = 2.2 Hz,1H),4.88 (d,J = 2.3 Hz,1H),4.31 (s,1H),3.49 (d,J = 11.3 Hz,3H),3.33 (d,J = 11.3 Hz,3H).

(-)-Dimethyl (5-methylene-4-phenyl-2-(p-tolyl)-4,5- di-hydrofuran-3-yl)phosphonae (3ba). A colorless oil was ob-tained in 79% yield after purification with column chroma-tography on silica gel (hexane/ethyl acetate,4:1-1:1). 89% ee was determined by chiral HPLC (Chiralcel OJ-H,n-hexane/i-PrOH = 90/10,0.8 mL/min,254 nm,40 °C): tR (major) = 10.6 min,tR (minor) = 7.9 min. [α]D21 = -89.2 (c 1.12,CH2Cl2). 1H NMR (400 MHz,DMSO-d6): δ 7.76 (d,J = 8.0 Hz,2H),7.33-7.22 (m,7H),5.02-4.95 (m,1H),4.72-4.68 (m,1H),4.13 (s,1H),3.32 (d,J = 11.3 Hz,3H),3.16 (d,J = 11.3 Hz,3H),2.33 (s,3H); 13C NMR (100 MHz,DMSO-d6): δ 169.2 (d,J = 13.9 Hz),168.3 (d,J = 26.0 Hz),147.5,146.4,134.1,133.8,133.7,132.9,132.4,130.5,106.6 (d,J = 214.3 Hz),92.6,59.5 (d,J = 10.1 Hz),57.2 (d,J = 5.8 Hz),57.0 (d,J = 5.5 Hz),26.3; 31P NMR (162 MHz,DMSO-d6): δ 21.6; HRMS calc. for C20H22O4P [M+H]+: 357.1256,found: 357.1253.

(-)-Dimethyl (5-methylene-4-phenyl-2-(m-tolyl)-4,5- di-hydrofuran-3-yl)phosphonate (3ca). A colorless oil was ob-tained in 84% yield after purification with column chroma-tography on silica gel (hexane/ethyl acetate,4:1-1:1). 90% ee was determined by chiral HPLC (Chiralcel OJ-H,n-hexane/i-PrOH = 90/10,0.8 mL/min,254 nm,40 °C): tR (major) =10.5 min,tR (minor) =7.3 min. [α]D22 = -81.3 (c1.10,CH2Cl2). 1H NMR (400 MHz,DMSO-d6): δ 7.75-7.69 (m,2H),7.40-7.28 (m,7.3 Hz,7H),5.07-5.02 (m,1H),4.79-4.75 (m,1H),4.19 (s,1H),3.37 (d,J = 11.3 Hz,3H),3.21 (d,J = 11.3 Hz,3H),2.38 (s,3H); 13C NMR (100 MHz,DMSO-d6): δ 164.4 (d,J = 14.0 Hz),163.6 (d,J = 25.8 Hz),142.7,138.0,132.2,129.3,129.1,128.6,128.5,128.2,127.7,126.3,102.6 (d,J = 214.7 Hz),87.9,54.7 (d,J = 10.1 Hz),52.5 (d,J = 5.8 Hz),52.3 (d,J = 5.5 Hz),21.4; 31P NMR (162 MHz,DMSO-d6): δ 16.6; HRMS calc. for C20H22O4P [M+H]+: 357.1256,found: 357.1252.

(-)-Dimethyl (5-methylene-4-phenyl-2-(o-tolyl)-4,5- di-hydrofuran-3-yl)phosphonae (3da). A colorless oil was ob-tained in 61% yield after purification with column chroma-tography on silica gel (hexane/ethyl acetate,4:1-1:1). 88% ee was determined by chiral HPLC (Chiralcel OJ-H,n-hexane/i-PrOH = 90/10,0.8 mL/min,254 nm,40 °C): tR (major) = 14.2 min,tR (minor) = 9.1 min. [α]D21 = -89.2 (c 1.10,CH2Cl2). 1H NMR (400 MHz,DMSO-d6): δ 7.48 (d,J = 7.5 Hz,1H),7.42-7.29 (m,8H),5.08-5.02 (m,1H),4.76-4.70 (m,1H),4.17 (s,1H),3.26 (d,J = 11.3 Hz,3H),3.12 (d,J = 11.3 Hz,3H),2.40 (s,3H); 13C NMR (100 MHz,DMSO-d6): δ 165.3 (d,J = 3.3 Hz),165.1 (d,J = 15.2 Hz),142.3,137.1,130.8,130.6,130.4,129.4,129.1,128.3,127.7,125.8,105.4 (d,J = 214.7 Hz),88.0,53.6 (d,J = 10.5 Hz),52.2 (d,J = 5.6 Hz),52.0 (d,J = 5.4 Hz),19.8; 31P NMR (162 MHz,DMSO-d6): δ 15.4; HRMS calc. for C20H22O4P [M+H]+: 357.1256,found: 357.1258.

(-)-Dimethyl (2-(2-bromophenyl)-5-methylene-4-phenyl- 4,5-dihydrofuran-3-yl)phosphonate (3ea). A colorless oil was obtained in 68% yield after purification with column chromatography on silica gel (hexane/ethyl acetate,4:1-1:1). 92% ee was determined by chiral HPLC (Chiralcel OJ-H,n-hexane/ i-PrOH = 80/20,0.8 mL/min,254 nm,40 °C): tR (major) = 13.2 min,tR (minor) = 9.1 min. [α]D24 = -92.8 (c 1.30,CH2Cl2). 1H NMR (400 MHz,DMSO-d6): δ 7.77 (d,J = 7.7 Hz,1H),7.62-7.60 (m,1H),7.53-7.30 (m,7H),5.07-5.02 (m,1H),4.77-4.73 (m,1H),4.18 (s,1H),3.35 (d,J = 11.3 Hz,3H),3.13 (d,J = 11.3 Hz,3H); 13C NMR (100 MHz,DMSO-d6): δ 165.3 (d,J = 13.9 Hz),163.8 (d,J = 25.4 Hz),142.0,132.9,132.7,132.6,131.2,129.0,128.6,127.9,127.7,122.4,106.4 (d,J = 212.8 Hz),88.4,53.4 (d,J = 10.1 Hz),52.3 (d,J = 5.4 Hz),52.2 (d,J = 5.2 Hz); 31P NMR (162 MHz,DMSO-d6): δ 14.4; HRMS calc. for C19H19BrO4P [M+H]+: 421.0204,found: 421.0201.

(-)-Dimethyl (2-(4-bromophenyl)-5-methylene-4-phenyl- 4,5-dihydrofuran-3-yl)phosphonate (3fa). A colorless oil was obtained in 95% yield after purification with column chro-matography on silica gel (hexane/ethyl acetate,4:1-1:1). 89% ee was determined by chiral HPLC (Chiralcel OJ-H,n-hexane/ i-PrOH = 80/20,0.8 mL/min,254 nm,40 °C): tR (major) = 7.9 min,tR (minor) = 6.1 min. [α]D24 = -80.4 (c 1.11,CH2Cl2). 1H NMR (400 MHz,DMSO-d6): δ 7.84 (d,J = 8.5 Hz,2H),7.73 (d,J = 8.5 Hz,2H),7.39-7.28 (m,5H),5.08-5.02 (m,1H),4.81-4.75 (m,1H),4.20 (s,1H),3.40 (d,J = 11.3 Hz,3H),3.21 (d,J = 11.3 Hz,3H).; 13C NMR (100 MHz,DMSO-d6): δ 164.3 (d,J = 13.8 Hz),162.4 (d,J = 25.6 Hz),142.4,131.8,131.0,129.1,128.2,127.7,125.3,103.5 (d,J = 213.4 Hz),88.2,54.7(d,J = 9.9 Hz),52.6 (d,J = 5.7 Hz),52.4 (d,J = 5.5 Hz); 31P NMR (162 MHz,DMSO-d6): δ 16.1; HRMS calc. for C19H19BrO4P [M+H]+: 421.0204,found: 421.0202.

(-)-Dimethyl (2-(4-methoxyphenyl)-5-methylene-4-phenyl- 4,5-dihydrofuran-3-yl)phosp-honate (3ga). A colorless oil was obtained in 88% yield after purification with column chromatography on silica gel (hexane/ethyl acetate,4:1-1:1). 90% ee was determined by chiral HPLC (Chiralcel OJ-H,n-hexane/ i-PrOH = 90/10,0.8 mL/min,254 nm,40 °C): tR (major) = 15.7min,tR (minor) =10.9 min. [α]D22 = -74.7 (c 1.17,CH2Cl2). 1H NMR (400 MHz,DMSO-d6): δ 7.90 (d,J = 8.8 Hz,2H),7.39-7.25 (m,5H),7.07 (d,J = 8.8 Hz,2H),5.05-4.96 (m,1H),4.80-4.71 (m,1H),4.18 (s,1H),3.83 (s,3H),3.37 (d,J = 11.3 Hz,3H),3.21 (d,J = 11.3 Hz,3H); 13C NMR (100 MHz,DMSO-d6): δ 169.1 (d,J = 14.0 Hz),168.1 (d,J = 26.0 Hz),166.6,147.7 ,135.5,133.8,132.9,132.4,125.4,118.9,105.2 (d,J = 214.8 Hz),92.4,60.6,59.5 (d,J = 10.1 Hz),57.2 (d,J = 5.7 Hz),57.0 (d,J = 5.5 Hz); 31P NMR (162 MHz,DMSO-d6): δ 22.0; HRMS calc. for C20H22O5P [M+H]+: 373.1205,found: 373.1204.

(-)-Dimethyl (2-(4-chlorophenyl)-5-methylene-4-phenyl- 4,5-dihydrofuran-3-yl)posphonate (3ha). A colorless oil was obtained in 95% yield after purification with column chro-matography on silica gel (hexane/ethyl acetate,4:1-1:1). 90 % ee was determined by chiral HPLC (Chiralcel OJ-H,n-hexane/ i-PrOH = 90/10,0.8 mL/min,254 nm,40 °C): tR (major) = 11.3 min,tR (minor) = 8.1 min. [α]D22 = -93.6 (c 1.00,CH2Cl2). 1H NMR (400 MHz,DMSO-d6): δ 7.92 (d,J = 8.6 Hz,2H),7.59 (d,J = 8.6 Hz,2H),7.39-7.28 (m,5H),5.09-5.01 (m,1H),4.81-4.74 (m,1H),4.20 (s,1H),3.39 (d,J = 11.3 Hz,3H),3.20 (d,J = 11.3 Hz,3H); 13C NMR (100 MHz,DMSO-d6): δ 169.0 (d,J = 13.9 Hz),167.0 (d,J = 25.7 Hz),147.2,141.1,135.6,133.8,133.6,133.0,132.5,132.1,108.2 (d,J = 213.4 Hz),92.9,59.4 (d,J = 9.9 Hz),57.3 (d,J = 5.7 Hz),57.1 (d,J = 5.5 Hz); 31P NMR (162 MHz,DMSO-d6): δ 20.9; HRMS calc. for C19H19ClO4P [M+H]+: 377.0709,found: 377.0711.

(-)-Dimethyl (5-methylene-4-phenyl-4,5-dihydro-[2,2'- bifuran]-3-yl)phosphonate (3ia). A colorless oil was obtained in 90% yield after purification with column chromatography on silica gel (hexane/ethyl acetate,4:1-1:1). 89% ee was determined by chiral HPLC (Chiralcel OJ-H,n-hexane/i-PrOH = 70/30,0.8 mL/min,254 nm,40 °C): tR (major) = 11.5 min,tR (minor) = 5.6 min. [α]D24 = -146.8 (c 0.55,CH2Cl2). 1H NMR (400 MHz,DMSO-d6): δ 8.00-7.96 (m,1H),7.40-7.34 (m,3H),7.28-7.25 (m,3H),6.74-6.73 (m,1H),5.06-5.01 (m,1H),4.80-4.75 (m,1H),4.19 (s,1H),3.48 (d,J = 11.4 Hz,3H),3.28 (d,J = 11.4 Hz,3H); 13C NMR (100 MHz,DMSO-d6): δ 164.1 (d,J = 13.8 Hz),153.4 (d,J = 24.6 Hz),146.6,142.6,130.3,129.0,128.1,127.7,116.3,112.8,100.6 (d,J = 214.8 Hz),88.2,54.2 (d,J = 9.3 Hz),52.5 (d,J = 5.7 Hz),52.4 (d,J = 5.4 Hz); 31P NMR (162 MHz,DMSO-d6): δ 15.4; HRMS calc. for C17H18O5P [M+H]+: 333.0892,found: 333.0887.

(-)-Dimethyl (2-cyclohexyl-5-methylene-4-phenyl-4,5- dihydrofuran-3-yl)phosphonate (3ja). A colorless oil was obtained in 60% yield after purification with column chro-matography on silica gel (hexane/ethyl acetate,4:1-1:1). 92% ee was determined by chiral HPLC (Chiralcel OJ-H,n-hexane/i-PrOH = 90/10,0.8 mL/min,254 nm,40 °C): tR (major) = 6.2 min,tR (minor) = 5.0 min. [α]D24 = -134.9 (c 1.02,CH2Cl2). 1H NMR (400 MHz,DMSO-d6): δ 7.33 (t,J = 7.4 Hz,2H),7.25 (t,J = 7.3 Hz,1H),7.16 (d,J = 7.1 Hz,2H),4.76-4.70 (m,1H),4.69-4.63 (m,1H),4.07 (s,1H),3.50 (d,J = 11.3 Hz,3H),3.12 (d,J = 11.3 Hz,3H),; 1.88-1.64 (m,5H),1.63-1.13 (m,6H); 13C NMR (100 MHz,DMSO-d6): δ 173.8 (d,J = 30.0 Hz),165.3 (d,J = 13.9 Hz),142.6,128.9,128.0,127.5,99.8 (d,J = 213.3 Hz),87.7,52.5 (d,J = 10.3 Hz),52.1 (d,J = 5.3 Hz),51.8 (d,J = 4.8 Hz),36.5,30.4,29.8,25.9,25.8,25.7; 31P NMR (162 MHz,DMSO-d6): δ 17.5. HRMS calc. for C19H26O4P [M+H]+: 349.1569,found:349.1569.

(-)-Dimethyl (4-(4-bromophenyl)-5-methylene-2-phenyl- 4,5-dihydrofuran-3-yl)phosphonate (3ba). A colorless oil was obtained in 75% yield after purification with column chromatography on silica gel (hexane/ethyl acetate,4:1-1:1). 88% ee was determined by chiral HPLC (Chiralcel OJ-H,n-hexane/ i-PrOH = 90/10,0.8 mL/min,254 nm,40 °C): tR (major) = 12.6 min,tR (minor) =10.2 min. [α]D22 = -84.7 (c 0.97,CH2Cl2). 1H NMR (400 MHz,DMSO-d6): δ 7.89-7.87 (m,2H),7.59-7.50 (m,5H),7.28 (d,J = 8.4 Hz,2H),5.12-5.06 (m,1H),4.82-4.76 (m,1H),4.21 (s,1H),3.40 (d,J = 11.3 Hz,3H),3.27 (d,J = 11.3 Hz,3H); 13C NMR (100 MHz,DMSO-d6): δ 164.0 (d,J = 14.0 Hz),163.6,142.0,132.0,131.7,130.5,129.0,128.8,128.4,120.8,102.2 (d,J = 214.3 Hz),88.3,54.0 (d,J = 10.1 Hz),52.6 (d,J = 5.8 Hz),52.4 (d,J = 5.6 Hz). 31P NMR (162 MHz,DMSO-d6): δ 16.3; HRMS calc. for C19H19BrO4P [M+H]+: 421.0204,found: 421.0201.

(-)-Dimethyl (4-(4-fluorophenyl)-5-methylene-2-phenyl- 4,5-dihydrofuran-3-yl)phosphonate (3ca). A colorless oil was obtained in 78% yield after purification with column chromatography on silica gel (hexane/ethyl acetate,4:1-1:1). 85% ee was determined by chiral HPLC (Chiralcel OJ-H,n-hexane/ i-PrOH = 90/10,0.8 mL/min,254 nm,40 °C): tR (major) = 11.8 min,tR (minor) = 9.3 min. [α]D21 = -101.9 (c 1.00,CH2Cl2). 1H NMR (400 MHz,DMSO-d6):δ 7.90-7.88 (m,2H),7.56-7.49 (m,3H),7.37-7.33 (m,2H),7.22-7.18 (m,2H),5.11-5.09 (m,1H),4.82-4.75 (m,1H),4.21-4.20(m,1H),3.39 (d,J = 11.3 Hz,3H),3.25 (d,J = 11.3 Hz,3H); 13C NMR (100 MHz,DMSO-d6): δ 164.3 (d,J = 14.1 Hz),163.5 (d,J = 25.8 Hz),161.8 (d,J = 243.1 Hz),138.8,131.7,130.2 (d,J = 8.2 Hz),129.0,128.7,128.5,115.8 (d,J = 21.5 Hz),102.6 (d,J = 214.1 Hz),88.1,53.8 (d,J = 10.0 Hz),52.6 (d,J = 5.8 Hz),52.3 (d,J = 5.5 Hz); 31P NMR (162 MHz,DMSO-d6): δ 16.4; HRMS calc. for C19H19FO4P [M+H]+: 361.1005,found: 361.1003.

(-)-Dimethyl (4-(3-chlorophenyl)-5-methylene-2-phenyl- 4,5-dihydrofuran-3-yl)phosphoate (3da). A colorless oil was obtained in 90% yield after purification with column chro-matography on silica gel (hexane/ethyl acetate,4:1-1:1). 81% ee was determined by chiral HPLC (Chiralcel OJ-H,n-hexane/ i-PrOH = 90/10,0.8 mL/min,254 nm,40 °C): tR (major) = 10.0min,tR (minor) = 7.8 min. [α]D22 = -79.9 (c 1.10,CH2Cl2). 1H NMR (400 MHz,DMSO-d6): δ 7.91-7.89 (m,2H),7.56-7.50 (m,3H),7.42-7.35 (m,3H),7.29 (d,J = 7.5 Hz,1H),5.15-5.11 (m,1H),4.83-4.77 (m,1H),4.25 (s,1H),3.41 (d,J = 11.3 Hz,3H),3.28 (d,J = 11.3 Hz,3H); 13C NMR (100 MHz,DMSO-d6): δ 163.9 (d,J = 23.6 Hz),163.7 (d,J = 11.7 Hz),145.0,133.6,131.7,131.0,129.0,128.7,128.4,128.1,127.7,126.9,102.1 (d,J = 214.4 Hz),88.5,54.1 (d,J = 10.0 Hz),52.6 (d,J = 5.8 Hz),52.3 (d,J = 5.5 Hz); 31P NMR (162 MHz,DMSO-d6): δ 16.2; HRMS calc. for C19H19ClO4P [M+H]+: 377.0709,found:377.0711.

(-)-Dimethyl (5-methylene-4-(naphthalen-2-yl)-2-phenyl- 4,5-dihydrofuran-3-yl)phosphonate (3ea). A colorless oil was obtained in 81% yield after purification with column chromatography on silica gel (hexane/ethyl acetate,4:1-1:1). 87% ee was determined by chiral HPLC (Chiralcel OJ-H,n-hexane/ i-PrOH = 80/20,0.8 mL/min,254 nm,40 °C): tR (major) = 14.3 min,tR (minor) = 8.6 min. [α]D21 = -99.2 (c 1.02,CH2Cl2). 1H NMR (400 MHz,DMSO-d6): δ 7.99-7.85 (m,6H),7.60-7.43 (m,6H),5.29-5.23 (m,1H),4.84-4.79 (m,1H),4.23 (s,1H),3.38 (d,J = 11.3 Hz,3H),3.21 (d,J = 11.3 Hz,3H); 13C NMR (100 MHz,DMSO-d6): δ 164.3 (d,J = 13.9 Hz),163.7 (d,J = 25.8 Hz),139.9,133.5,132.7,131.7,129.1,128.9,128.8,128.6,128.2,128.0,126.9,126.8,126.4,126.2,102.5(d,J = 214.2 Hz),88.3,54.9 (d,J = 10.0 Hz),52.8 (d,J = 5.8 Hz),52.3 (d,J = 5.5 Hz). 31P NMR (162 MHz,DMSO-d6): δ 16.5; HRMS calc. for C23H22O4P [M+H]+: 393.1256,found: 393.1260.

3 Results and discussion

Our initial studies focused on probing the effects of dif-ferent ligands,copper salts,bases and reaction temperature on the efficiency of the reaction (Table 1). 1-Phenylprop-2-yn-1-yl acetate (1a) and dimethyl (2-oxo-2-phenylethyl)phosphonate (2a) were selected as model substrates for this reaction,which was performed in the presence of 5 mol% copper catalyst and 1.2 equiv. of t-BuOK in MeOH (3 mL) at room temperature for 12 h. We first investigated a variety of chiral ligands which were effi-cient in the Cu catalyzed asymmetric propargylic substitution and cycloaddtion reactions. However,with BINAP (L1) and Ph-pybox (L2) as ligands,no reaction was observed (Table 1,entries 1 and 2). Subsequent ligand screening identified chiral tridentate P,N,N ligands developed by our group as promising ligands (Table 1,entries 3-7). In particular,a bulky and structurally rigid tridentate ketamine P,N,N ligand (S)-L4b displayed good performance,affording the desired cycloadduct dimethyl (5-methylene-2,4-diphenyl-4,5-dihydrofuran3-yl) phos-phonate (3aa) in moderate yield and enantioselectivity (Ta-ble 1,entry 5). Thus,(S)-L4b was selected as the optimal ligand for further evaluation. A variety of copper salts were next investigated. The results revealed that copper salts had an important impact on the reactivity and enantioselectivity of the reaction (Table 1,entries 8-12). These results dem-onstrated that Cu(OTf)2 was the best Cu source for the reac-tion (Table 1,entry 5). The addition of a base was critical to the reaction since none of the desired product was observed in its absence (Table 1,entry 13). Of the base that we tested,t-BuOK provided the best result,while DBU showed a similar result (Table 1,entries 5 and 14). Other bases such as Cs2CO3,Et3N and i-Pr2Nt only gave a low yield or low ee value (Table 1,entries 15-17). Lowering the reaction temperature to -20 °C significantly improved the enantioselectivity,af-fording the [3+2] cycloadduct 3aa in 88% yield and with 90% ee (Table 1,entry 19).

Table 1
Screening the reaction conditions.

Having established the optimized conditions,we then examined the scope of the reaction using a variety of differ-ent β-keto phosphonates. The results are summarized in Table 2. The results indicated that the substitution pattern of the phenyl ring had no obvious impact on the enantioselec-tivity. Good enantioselectivites (88%-92% ee) were obtained for the β-keto phosphonates with both electron-donating and electron-withdrawing groups at the ortho,meta or para posi-tion of the phenyl ring (Table 2,entries 1-8). However,the 2-Me and 2-Br substituted substrates (2d and 2e) resulted in decreased yield,presumably due to the steric hindrance (Table 2,entries 4 and 5). The 2-furyl substrate 2i also per-formed well in the reaction,giving the corresponding cyc-loadduct 3ai in 90% yield and with 89% ee (Table 2,entry 9). For the aliphatic substrate 2j,a lower conversion was observed. The desired product 3aj was obtained in 60% yield and 92% ee (Table 2,entry 10).

Table 2
Substrate scope of β-keto phosphonates 2.

The scope of propargylic esters was also evaluated. Some representative results are shown in Fig. 1. The results re-vealed that the catalyst system could also be successfully applied to a variety of propargylic esters 1. For example,4-Br,4-F and 3-Cl substituted phenyl propargylic esters (1b,1c,1d),and 1-naphthyl substituted propargylic esters 1e all reacted smoothly under the optimized conditions to give the corresponding [3+2] cycloaddition products 3ba-3ea in good yields and enantioselectivities.

Fig. 1. Substrate scope of propargylic esters 1.

4 Conclusions

We developed copper catalyzed asymmetric formal [3+2] cycloaddition of propargylic esters with β-keto phosphonates for the synthesis of chiral phosphonylated 2,3-dihydrofurans. By using a bulky and structurally rigid tridentate ketamine P,N,N ligand,the cycloaddition reaction proceeded smoothly with a wide range of propargylic esters and β-keto phosphonates,affording the desired optically active phosphonylated 2,3-dihydrofurans in high yields and up to 92% ee.

References
[1] B. M. Fraga, Nat. Prod. Rep.,1992, 9 :217–241. doi:http://dx.doi.org/10.1039/np9920900217
[2] A. T. Merritt, S. V. Ley, Nat. Prod. Rep.,1992, 9 :243–287. doi:http://dx.doi.org/10.1039/np9920900243
[3] B. H. Lipshutz, Chem. Rev.,1986, 86 :795–819. doi:http://dx.doi.org/10.1021/cr00075a005
[4] R. S. Ward, Tetrahedron,1990, 46 :5029–5041. doi:http://dx.doi.org/10.1016/S0040-4020(01)87810-8
[5] M. M. Faul, B. E. Huff, Chem. Rev.,2000, 100 :2407–2474. doi:http://dx.doi.org/10.1021/cr940210s
[6] M. Rueping, A. Parra, P. U. Uria, F. Besselièvre, E. Merino, Org. Lett.,2010, 12 :5680–5683. doi:http://dx.doi.org/10.1021/ol102499r
[7] L. P. Fan, P. Li, X. S. Li, D. C. Xu, M. M. Ge, W. D. Zhu, J. W. Xie, J. Org. Chem.,2010, 75 :8716–8719. doi:http://dx.doi.org/10.1021/jo101935k
[8] J. H. Feng, L. L. Lin, K. R. Yu, X. H. Liu, X. M. Feng, Adv. Synth. Catal.,,2015, 357 :1305–1310. doi:http://dx.doi.org/10.1002/adsc.201401198
[9] M. A. Calter, R. M. Phillips, C. Flaschenriem, J. Am. Chem. Soc.,2005, 127 :14566–14567. doi:http://dx.doi.org/10.1021/ja055752d
[10] M. A. Calter, A. Korotkov, Org. Lett.,2011, 13 :6328–6330. doi:http://dx.doi.org/10.1021/ol2026697
[11] X. W. Dou, F. R. Zhong, Y. X. Lu, Chem. Eur. J.,2012, 18 :13945–13948. doi:http://dx.doi.org/10.1002/chem.v18.44
[12] F. Ozawa, A. Kubo, Y. Matsumoto, T. Hayashi, E. Nishioka, K. Yanagi , K. Moriguchi, Organometallics,1993, 12 :4188–4196. doi:http://dx.doi.org/10.1021/om00034a064
[13] D. A. Evans, Z. K. Sweeney, T. Rovis, J. S. Tedrow, J. Am. Chem. Soc.,2001, 123 :12095–12096. doi:http://dx.doi.org/10.1021/ja011983i
[14] S. Son, S. Son, G. C. Fu, J. Am. Chem. Soc.,2007, 129 :1046–1047. doi:http://dx.doi.org/10.1021/ja068344y
[15] J. L. Zhou, L. J. Wang, H. Zu, X. L. Sun, Y. Tang, ACS Catal.,2013, 3 :685–688. doi:http://dx.doi.org/10.1021/cs400019u
[16] G. Hattori, H. Matsuzawa, Y. Miyake, Y. Nishibayashi, Angew. Chem. Int. Ed.,2008, 47 :3781–3783. doi:http://dx.doi.org/10.1002/(ISSN)1521-3773
[17] R. J. Detz, M. M. E. Delville, H. Hiemstra, J. H. van Maarseveen, Angew. Chem. Int. Ed.,2008, 47 :3777–3780. doi:http://dx.doi.org/10.1002/(ISSN)1521-3773
[18] Y. Nishibayashi, Synthesis,2012, 44 :489–503.
[19] C. H. Ding, X. L. Hou, Chem. Rev.,2011, 111 :1914–1937. doi:http://dx.doi.org/10.1021/cr100284m
[20] D. Y. Zhang, X. P. Hu, Tetrahedron Lett.,2015, 56 :283–295. doi:http://dx.doi.org/10.1016/j.tetlet.2014.11.112
[21] X. H. Hu, Z. T. Liu, L. Shao, X. P. Hu, Synthesis,2015, 47 :913–923. doi:http://dx.doi.org/10.1055/s-00000084
[22] C. Zhang, Y. H. Wang, X. H. Hu, Z. Zheng, J. Xu, X. P. Hu, Adv. Synth. Catal.,2012, 354 :2854–2858. doi:http://dx.doi.org/10.1002/adsc.v354.14/15
[23] F. Z. Han, F. L. Zhu, Y. H. Wang, Y. Zou, X. H. Hu, S. Chen, X. P. Hu, Org. Lett.,2014, 16 :588–591. doi:http://dx.doi.org/10.1021/ol403469m
[24] D. Y. Zhang, F. L. Zhu, Y. H. Wang, X. H. Hu, S. Chen, C. J. Hou, X. P. Hu, Chem. Commun.,2014, 50 :14459–14462. doi:http://dx.doi.org/10.1039/C4CC06863G
[25] F. L. Zhu, X. P. Hu, Chin. J. Catal.,2015, 36 :86–92. doi:http://dx.doi.org/10.1016/S1872-2067(14)60230-8
[26] C. Zhang, Y. Z. Hui, D. Y. Zhang, X. P. Hu, RSC Adv.,2016, 6 :14763–14767. doi:http://dx.doi.org/10.1039/C5RA25627E
[27] F. L. Zhu, Y. Zou, D. Y. Zhang, Y. H. Wang, X. H. Hu, S. Chen, J. Xu, X. P. Hu, Angew. Chem. Int. Ed.,2014, 53 :1410–1414. doi:http://dx.doi.org/10.1002/anie.v53.5
[28] Y. Zou, F. L. Zhu, Z. C. Duan, Y. H. Wang, D. Y. Zhang, Z. Cao, Z. Zheng, X. P. Hu, Tetrahedron Lett.,2014, 55 :2033–2036. doi:http://dx.doi.org/10.1016/j.tetlet.2014.02.030
[29] F. L. Zhu, Y. H. Wang, D. Y. Zhang, X. H. Hu, S. Chen, C. J. Hou, J. Xu, X. P. Hu, Adv. Synth. Catal.,2014, 356 :3231–3236. doi:http://dx.doi.org/10.1002/adsc.201400218
[30] C. Zhang, X. H. Hu, Y. H. Wang, Z. Zheng, J. Xu, X. P. Hu, J. Am. Chem. Soc.,2012, 134 :9585–9588. doi:http://dx.doi.org/10.1021/ja303129s
[31] F. L. Zhu, Y. H. Wang, D. Y. Zhang, X. P. Hu, Angew. Chem. Int. Ed.,2014, 53 :10223–10227. doi:http://dx.doi.org/10.1002/anie.201405857
[32] L. Shao, Y. H. Wang, D. Y. Zhang, J. Xu, X. P. Hu, Angew. Chem. Int. Ed.,2016, 55 :.
[33] Z. T. Liu, Y. H. Wang, F. L. Zhu, X. P. Hu, Org. Lett.,2016, 18 :1190–1193. doi:http://dx.doi.org/10.1021/acs.orglett.6b00322