本文报道了一种零价钯与手性磷酸 (CPA)协同催化1,3-烯炔不对称发散性单次及连续氢官能团化反应。该方法以含烯炔片段的酰胺为底物,基于零价钯π-路易斯碱促进质子化的协同活化模式,通过对催化体系中配体与CPA的选择,实现单次与连续氢官能团化路径的调控: 采用Pd/PPhos/3,3′-(SiPh3)2-BINOL骨架CPA时,反应停留在单氢烷基化阶段,生成含轴手性和中心手性的中环联烯产物;而改用Pd/P(2-furyl)3配合 3,3′-(9-anthryl)₂-BINOL骨架CPA时,则能高效驱动后续的分子内氢胺化,构建结构复杂的手性多环螺环骨架。而后者催化体系也能促进中环联烯的进一步氢胺化,但获得非对映选择性的多环产物,从而实现多样化手性产物的高效制备。
Here we report asymmetric and divergent mono and sequential hydrofunctionalization reactions of 1,3-enyne-containing amide substrates under the cooperative catalysis of Pd(0)/chiral phosphoric acid (CPA). By utilizing Pd(0) π-Lewis base-promoted protonation and tuning the modulation of both the ligand and the CPA, this protocol enables precise control over single and sequential hydrofunctionalization pathways. Specifically, the combination of Pd/PPhos and 3,3′-(SiPh₃)₂-BINOL-derived CPA halts the reaction at the initial hydroalkylation stage, delivering the medium ring-sized allenes containing both axial and central chirality, whereas an intramolecular hydroamination reaction is followed to construct complex chiral polycyclic skeletons by switching to an assembly of Pd/P(2-furyl)₃ and 3,3′-(9-anthryl)₂-BINOL-derived CPA. Furthermore, the latter catalytic system can facilitate the hydroamination reaction of the previously obtained chiral allene products, but furnishing the polycyclic architectures with different diastereoselectivity. This work not only expands the application of cooperative catalytic systems, but also provides a practical strategy for the efficient, modular, and divergent construction of axially chiral medium ring-sized molecules and complex spirocyclic frameworks. Accordingly, for the synthesis of medium ring-sized allene 2, substrate 1 (0.1 mmol), [Pd(cinnamyl)Cl]2 (0.005 mmol, 2.6 mg), ligand L3 (0.011 mmol, 7.1 mg), and chiral phosphoric acid A4 (0.02 mmol, 17.3 mg) were introduced into an oven-dried Schlenk tube under an argon atmosphere. After dry toluene (0.5 mL) and H2O (40 μL) were added, the mixture was stirred at 30 °C for 12 h. Alternatively, for the synthesis of polycyclic product 3, substrate 1 (0.1 mmol), cinnamyl(cp)Pd (0.01 mmol, 2.9 mg), ligand L4 (0.02 mmol, 4.6 mg), and chiral phosphoric acid A3 (0.02 mmol, 14.0 mg) were mixed in dry toluene (2.0 mL) under an argon atmosphere and stirred at 40 °C for 48-72 h. The progress of the reaction was monitored by TLC. Upon completion, the mixture was directly purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate) to afford the desired product 2 or 3, respectively.
[1] (a) Xiao B.-Y.; Huang W.; Zhang, F.-H. Eur. J. Org. Chem.2025, 28, e202500302.
(b) Liu X.; Jiao C.; Cui S.; Liu Q.; Zhang X.; Zhang G. ChemCatChem2023, 15, e202300601.
(c) Xiao W.; Wu, J. Org. Chem. Front.2022, 9, 5053-5073.
(d) Yu Y.; Zhang, J. Eur. J. Org. Chem.2022, 2022, e202201017.
(e) Li Y.; Bao H. Chem. Sci.2022, 13, 8491-8506.
(f) Muresan M.; Subramanian H.; Sibi M. P.; Green, J. R. Eur. J. Org. Chem.2021, 2021, 3359-3375.
(g) Fu L.; Greßies S.; Chen P.; Liu, G. Chin. J. Chem.2020, 38, 91-100.
(h) Lu F.-D.; Jiang X.; Lu L.-Q.; Xiao, W.-J. Acta Chim. Sinica2019, 77, 803-813.
(i) Sun L.-L.; Sun, K. Chin. J. Org. Chem.2025, 45, 3655-3671.
(j) Liu P.; Ye F.; Yuan, W. Chin. J. Org. Chem.2026, 46, 2563-2580.
[2] (a) Gan L.; Wan X.; Pang Y.; Zou Y.; Deng Y.-H.; Shao, Z. Org. Chem. Front.2025, 12, 1001-1064.
(b) Li, L.; Wang, S.; Jakhar, A.; Shao, Z.Green Synth. Catal. 2023, 4, 124-134.
(c) Xiao W.; Wu, J. Org. Chem. Front.2022, 9, 5053-5073.
(d) Kuai C.-S.; Wang Y.; Yang T.; Wu, X.-F. J. Am. Chem. Soc.2025, 147, 7950-7964.
(e) You C.; Shi M.; Mi X.; Luo S. Nat. Commun.2023, 14, 2911.
(f) Bayeh Romero L.; Buchwald, S. L. J. Am. Chem. Soc.2019, 141, 13788-13794.
(g) Huang Y.; del Pozo J.; Torker S.; Hoveyda, A. H. J. Am. Chem. Soc.2018, 140, 2643-2655.
(h) Yang Y.; Perry I. B.; Lu G.; Liu P.; Buchwald S. L. Science2016, 353, 144-150.
(i) Zhang G.; Zhang, Q. Chin. J. Org. Chem.2022, 42, 3004-3006.
(j) Ma C.; Chen Y.-W.; He, Z.-T. Sci. Sin. Chim.2023, 53, 474-484.
[3] (a) Jiang Y.; Cheng K. W.; Yang Z.; Wang, J. Chin. Chem. Lett.2025, 36, 110231-110237.
(b) Lu W.; Zhao Y.; Meng, F. J. Am. Chem. Soc.2022, 144, 5233-5240.
(c) Guo J.; Shen X.; Lu, Z. J. Am. Chem. Soc.2020, 142, 16894-16902.
(d) Yang C.; Liu Z.-L.; Dai D.-T.; Li Q.; Ma W.-W.; Zhao M.; Xu Y.-H. Org. Lett.2020, 22, 1360-1367.
(e) Adamson N. J.; Jeddi H.; Malcolmson, S. J. J. Am. Chem. Soc.2019, 141, 8574-8583.
(f) Tsukamoto, H.; Konno, T.; Ito, K.; Doi, T. Org. Lett. 2019, 21, 6811-6814.
[4] (a) Ma Z.; Lu X.; Yao H.; Lin, A. Org. Chem. Front.2026, 13, 2768-2774.
(b) Mei Y.-K.; Xu S.-Y.; Wang Z.-H.; Ji D.-W.; Chen Q.-A. Adv. Sci.2025, 12, e11331.
(c) Ma Z.; Wang Q.; Lu X.; Li Q.; Lin A.; Yao H. Org. Lett.2025, 27, 8077-8082.
[5] (a) Eaton M.; Dai Y.; Wang Z.; Li B.; Lamine W.; Miqueu K.; Liu, S.-Y. J. Am. Chem. Soc.2023, 145, 21638-21645.
(b) You C.; Shi M.; Mi X.; Luo S. Nat. Commun.2023, 14, 2911.
(c) Yang S.-Q.; Wang Y.-F.; Zhao W.-C.; Lin G.-Q.; He, Z.-T. J. Am. Chem. Soc.2021, 143, 7285-7291.
[6] (a) Li Q.; Fang X.; Pan R.; Yao H.; Lin, A. J. Am. Chem. Soc.2022, 144, 11364-11376.
(b) Li L.; Wang S.; Luo P.; Wang R.; Wang Z.; Li X.; Deng Y.; Peng F.; Shao Z. Nat. Commun.2021, 12, 5667.
[7] Xie B.-Y.; He Z.-T. ACS Catal.2024, 14, 9742-9751.
[8] Li Q.; Wu R.; Wu T.; Wei R.; Li Z.; Gao S.; Wang M.; Yao H.; Lin A. Green Chem.2026, 28, 3232-3242.
[9] (a) Chen Z.; Wang X.-J.; Pi F.; Li Y.-F.; Tan S.-Z.; Zhu L.; Ouyang Q.; Du W.; Chen Y.-C. Org. Lett.2025, 27, 3302-3307.
(b) Pi F.; Chen Z.; Wang H.; Du W.; Chen Y.-C. Org. Lett.2025, 27, 10773-10777.
[10] Changotra A.; Das S.; Sunoj, R. B. Org. Lett.2017, 19, 2354-2357.
[11] (a) Shi B.; Liu J.-B.; Wang Z.-T.; Wang L.; Lan Y.; Lu L.-Q.; Xiao, W.-J. Angew. Chem. Int. Ed.2022, 61, e202117215.
(b) Ogasawara M.; Okada A.; Nakajima K.; Takahashi T. Org. Lett.2009, 11, 177-180.
(c) Zelder, C.; Krause, N.Eur. J. Org. Chem. 2004, 3968-3971.
(d) Sweeney Z. K.; Salsman J. L.; Andersen R. A.; Berman, R. G. Angew. Chem. Int. Ed.2000, 39, 2339-2343.
(e) Cope A. C.; Moore W. R.; Bach R. D.; Winkler, H. J. S. J. Am. Chem. Soc.1970, 92, 1243-1247.
[12] For more details, see the supplementary information.
[13] (a) Liu Y.; Chen Y.-W.; Yang Y.-X.; Hartwig J. F.; He, Z.-T. J. Am. Chem. Soc.,2024, 146, 29857-29864.
(b) Nilsson Y. I. M.; Andersson P. G.; Bäckvall, J.-E. J. Am. Chem. Soc.,1993, 115, 6609-6613.
[14] Deposition number 2575780(rac 3a) contains the supplementary crystallographic data for this paper. These data are provided free of charge by the joint Cambridge Crystallographic Data Centre.
[15] For the determination of the absolute configuration of the chiral products, see the supplementary information.
