Bimetallic-bienzyme-cofactor Co-immobilized catalyst for continuous-flow concurrent chemoenzymatic ketone formation-conversion cascade

doi:10.1016/S1872-2067(26)65145-5

Abstract

Abstract:

Chemoenzymatic ketone formation-conversion cascades represent a powerful strategy in asymmetric synthesis, yet their efficiency is often limited by catalytic incompatibility and poor operational sustainability. Here, we develop a continuous-flow concurrent chemoenzymatic cascade that integrates a metal-catalyzed Heck coupling of aryl iodides with allylic alcohols (for ketone formation) and an enzymatic asymmetric reductive amination of the resulting ketones, enabling efficient one-pot access to chiral γ-arylamines. The cascade is powered by a bimetallic-bienzyme-cofactor co-immobilized catalyst, which is constructed by spatially incorporating palladium-iron nanoalloy catalysts and a cofactor-self-sufficient biocatalytic system consisting of an amine dehydrogenase, a glucose dehydrogenase and phosphorylated NADH on polydopamine-coated, quaternary-ammonium-functionalized mesoporous organosilica nanoflowers. Implementing this integrated catalyst in a continuous-flow system offers a cost-effective and sustainable platform for asymmetric amine synthesis, delivering markedly enhanced overall catalytic efficiency, high space-time yield, and excellent operational stability.

Key words: Chemoenzymatic cascade, Continuous flow, Organosilica nanoflowers, Co-immobilization, Chiral amines

Pengbo Liu, Liya Zhou, Xinlong Liu, Kesheng Fu, Zhongxu Guo, Quan Yuan, Hengquan Yang, Yunting Liu, Yanjun Jiang. Bimetallic-bienzyme-cofactor Co-immobilized catalyst for continuous-flow concurrent chemoenzymatic ketone formation-conversion cascade[J]. Chinese Journal of Catalysis, 2026, 88: 457-467.

×
share this article

Add to citation manager EndNote|Ris|BibTeX

URL: https://www.cjcatal.com/EN/10.1016/S1872-2067(26)65145-5

https://www.cjcatal.com/EN/Y2026/V88/I9/457

Figures/Tables 8

Scheme 1. Sequential (a-c) and concurrent (d,e) chemoenzymatic ketone formation-conversion cascades for the synthesis of chiral alcohols and amines.

Fig. 1. (a) Schematic illustration of the preparation of the bimetal-bienzyme-cofactor co-immobilized catalyst. Representative structural and compositional characterization of M2@PDA@E2C@PMON? at x = 0.3: SEM image (b), TEM image (c), HAADF-STEM image (d), and corresponding elemental mapping for C (e), N (f), Si (g), Pd (h), and Fe (i). (j) High-resolution TEM image of M2@PDA@E2C@PMON?. Compositional and chemical state analysis of the catalysts with varying Fe/Pd ratios (x = 0.2, 0.3, 0.5, 1.0, 2.0, and 3.0): (k) XRD patterns; XPS spectra of the Pd 3d (l) and Fe 2p (m) regions.

Fig. 2. (a) The catalytic performance of PdMx@PDA@E2C@PMON catalysts with different bimetallic ratios (PdMx) in Heck coupling reaction. (b) Reusability of PdFe0.3@PDA@E2C@PMON (0.3 mol% with respect to Pd) in Heck coupling reaction. Reaction conditions: [1a] = 200 mmol/L, [but-3-en-2-ol] = 300 mmol/L, [TEA] = 300 mmol/L, iPrOH/H2O (v:v, 1:1, 4 mL), 80 °C, 12 h. Yields were determined by GC.

Fig. 3. (a) Potential energy profile for the Heck coupling of 1a by PdFe0.3 (111) and Pd (111). (b) Potential energy profile for the product desorption. (c) Structures of the adsorption states and the intermediates in the Heck coupling of 1a by PdFe0.3 (111) and Pd (111).

Fig. 4. (a) Immobilized content of cofactors on PMON? under different conditions: (I) Immobilization of phosphorylated cofactors on PMON? (the initial amount of NADH added is 25-150 μmol). (II) Residual NADH to PMON? after washing treatments with 50 mmol/L PBS buffer at pH 8. (III) Residual NADH to PMON? after washing treatments with 2 mol/L NH4Cl/NH4OH buffer at pH 10.5. The pH-stability (b) and the thermal-stability (c) of M2@PDA@E2C@PMON? compared with free CalAmDH. (d) The yield of 2-Amino-4-phenylbutane (3a) using M2@PDA@E2C@PMON? with different NADH loadings. (e) The yield of AmDH-catalyzed ARA as a function of time. (f) Reusability of M2@PDA@E2C@PMON?. Reaction conditions: [2a] = 100 mmol/L, [glucose] = 150 mmol/L, [M2@PDA@E2C@PMON?] = 25 mg, and NH4Cl/NH4OH buffer (2 mol/L, pH = 10.5)/DMSO (v/v, 2:1, 3 mL).

Table 2 Cofactor catalytic availability of soluble and immobilized CalAmDH with free (248 µmol/L in bulk) and immobilized NADH (36 µmol/gsupport = 248 µmol/L in bulk).

Enzyme form	Cofactor form	Specific activity (U/mg)	NADH available (μmol/L)	NADH available (%)
Soluble	soluble	1.32^a	248	100
Soluble	immobilized	0.17^b	17.5^c	7.1
Immobilized	soluble	0.84^a	248	100
Immobilized	immobilized	0.86^b	257.4^c	103.8

Scheme 2. The substrate scope of the chemoenzymatic enantioselective synthesis for chiral γ-arylamines. A feed solution containing the substrate (100 mmol/L), but-3-en-2-ol (150 mmol/L) and TEA (250 mmol/L) in NH4Cl/NH4OH buffer (2 mol/L, pH 10.5)/DMSO (v/v, 2:1) was pumped into the PBR (immersed in a 50 °C water bath) at a flow rate of 0.2 mL/min.

Fig. 5. (a) The remaining content of immobilized cofactor in the flow system as a function of time. (b) The operational stability of the flow system in the continuous synthesis of 3a.

References

[1]	Q. Meng, M. Hou, H. Liu, J. Song, B. Han, Nat. Commun., 2017, 8, 14190.
[2]	W. S. Bechara, G. Pelletier, A. B. Charette, Nat. Chem., 2012, 4, 228-234.
[3]	Y.-L. Zheng, P.-P. Xie, O. Daneshfar, K. N. Houk, X. Hong, S. G. Newman, Angew. Chem. Int. Ed., 2021, 60, 13476-13483.
[4]	F. Sun, J. Huang, Z. Wei, C. Tang, W. Liu, Angew. Chem. Int. Ed., 2023, 62, e202303433.
[5]	S. González-Granda, L. Escot, I. Lavandera, V. Gotor-Fernández, Angew. Chem. Int. Ed., 2023, 62, e202217713.
[6]	Y. Liu, P. Liu, S. Gao, Z. Wang, P. Luan, J. González-Sabín, Y. Jiang, Chem. Eng. J., 2021, 420, 127659.
[7]	B. Jia, Y. Liu, X. Geng, Y. Li, C. Zhang, Y. Qu, X. Liu, M. Zhao, Y. Yang, W. Li, Y. Li, Research, 2025, 8, 0732.
[8]	Q. Wang, X. Liu, H. Zhang, H. Chu, C. Shi, L. Zhang, J. Bai, P. Liu, J. Li, X. Zhu, Y. Liu, Z. Chen, R. Huang, H. Chang, T. Liu, Z. Chang, J. Cheng, H. Jiang, Research, 2024, 7, 0413.
[9]	X. Ren, H. Dai, X. Liu, Q. Yang, Chin. J. Catal., 2024, 62, 108-123.
[10]	S. Roscales, A. G. Csáky, Angew. Chem. Int. Ed., 2021, 60, 8728-8732.
[11]	H.-Y. Wang, X.-H. Wang, B.-A. Zhou, C.-L. Zhang, S. Ye, Nat. Commun., 2023, 14, 4044.
[12]	J. Jose, D. E. Jose, T. V. Mathew, J. Organomet. Chem., 2025, 1032, 123625.
[13]	T. Tachinami, T. Nishimura, R. Ushimaru, R. Noyori, H. Naka, J. Am. Chem. Soc., 2013, 135, 50-53.
[14]	Y. Xu, X. Hu, J. Shao, G. Yang, Y. Wu, Z. Zhang, Green Chem., 2015, 17, 532-537.
[15]	X. Wang, F. Liu, Z. Yan, Q. Qiang, W. Huang, Z.-Q. Rong, ACS Catal., 2021, 11, 7319-7326.
[16]	T.-L. Liu, T. W. Ng, Y. Zhao, J. Am. Chem. Soc., 2017, 139, 3643-3646.
[17]	Z.-J. Feng, H.-N. Liu, R. Guo, X. Tang, J.-A. Ma, F.-G. Zhang, Chin. J. Chem., 2026, 44, 939-945.
[18]	K. Fu, L. Dong, P. Liu, L. Zhou, G. Liu, J. Gao, B. Gao, Y. Liu, Y. Jiang, Chem. Synth., 2024, 4,3.
[19]	J. Liu, S. Wu, Z. Li, Curr. Opin. Chem. Biol., 2018, 43, 77-86.
[20]	S. Gergel, J. Soler, A. Klein, K. H. Schülke, B. Hauer, M. Garcia-Borràs, S. C. Hammer, Nat. Catal., 2023, 6, 606-617.
[21]	Q. Yuan, L. Ma, W. Kong, J. Liu, S. Zhang, J. Yan, J. Bai, Y. He, L. Zhou, Y. Liu, Y. Jiang, Catal. Rev., 2025, 67, 283-322.
[22]	J. Gu, W. Mu, Y. Xu, Y. Nie, Biotechnol. Adv., 2025, 79, 108496.
[23]	J. Liu, W. Kong, J. Bai, Y. Li, L. Dong, L. Zhou, Y. Liu, J. Gao, R. T. Bradshaw Allen, N. J. Turner, Y. Jiang, Chem Catal., 2022, 2, 1288-1314.
[24]	B. Yuan, D. Yang, G. Qu, N. J. Turner, Z. Sun, Chem. Soc. Rev., 2024, 53, 227-262.
[25]	F.-X. Dong, T. Jin, X. Yu, H.-Y. Wang, Q. Chen, J.-H. Xu, G.-W. Zheng, Chin. J. Catal., 2025, 68, 345-355.
[26]	H. Leisch, K. Morley, P. C. K. Lau, Chem. Rev., 2011, 111, 4165-4222.
[27]	M. J. L. J. Fürst, A. Gran-Scheuch, F. S. Aalbers, M. W. Fraaije, ACS Catal., 2019, 9, 11207-11241.
[28]	Y. Wu, Q. Chen, Q. Chen, Q. Geng, Q. Zhang, Y. C. Zheng, C. Chen, Y. Zhang, J, Zhou, B. Wang, J. H. Xu, H. L. Yu, Chin. J. Catal., 2023, 51, 157-167.
[29]	H. Sato, W. Hummel, H. Gröger, Angew. Chem. Int. Ed., 2015, 54, 4488-4492.
[30]	S. Mathew, A. Sagadevan, D. Renn, M. Rueping, ACS Catal., 2021, 11, 12565-12569.
[31]	Y. Zhang, C. Huang, W. Kong, L. Zhou, J. Gao, F. Hollmann, Y. Liu, Y. Jiang, ACS Catal., 2024, 14, 17405-17412.
[32]	N. Ríos-Lombardía, C. Vidal, E. Liardo, F. Morís, J. García-Lvarez, J. González-Sabín, Angew. Chem. Int. Ed., 2016, 55, 8691-8695.
[33]	J. Liu, J. Bai, Y. Liu, L. Zhou, Y. He, L. Ma, G. Liu, J. Gao, Y. Jiang, JACS Au, 2024, 4, 2281-2290.
[34]	P. Liu, W. Kong, L. Zhou, Z. Guo, L. Ma, Y. He, G. Liu, Y. Jiang, Y. Liu, ACS Sustainable Chem. Eng., 2025, 13, 8939-8950.
[35]	S. Schmidt, K. Castiglione, R. Kourist, Chem. Eur. J., 2018, 24, 1755-1768.
[36]	S. Gao, Z. Wang, L. Ma, Y. Liu, J. Gao, Y. Jiang, ACS Catal., 2020, 10, 1375-1380.
[37]	S. Gao, Y. Liu, L. Wang, Z. Wang, P. Liu, J. Gao, Y. Jiang, ACS Catal., 2021, 11, 5544-5553.
[38]	T. Chen, Y. Lu, X. Xiong, Z. Xu, Chem. Catal., 2024, 4, 100894.
[39]	C. Huang, Y. Liu, W. Kong, G. Liu, L. Zhou, Y. He, J. Gao, Y. Jiang, ACS Catal., 2023, 13, 12960-12969.
[40]	J. M. Bolivar, F. López-Gallego, Curr. Opin. Green Sustain. Chem., 2020, 25, 100349.
[41]	E. Broumidis, P. Díaz-Kruik, F. Paradisi, Nat. Rev. Meth. Primers, 2025, 5, 59.
[42]	W. Kong, J. Zhang, L. Zhou, G. Liu, Y. He, L. Ma, F. Hollmann, L. Wang, Y. Liu, Y. Jiang, ACS Catal., 2025, 15, 34-43.
[43]	M. Guo, X. Weng, T. Wang, Z. Chen, Sep. Purif. Technol., 2017, 175, 222-228.
[44]	M. N. Nadagouda, A. B. Castle, R. C. Murdock, S. M. Hussain, R. S. Varma, Green Chem., 2010, 12, 114-122.
[45]	G. E. Hoag, J. B. Collins, J. L. Holcomb, J. R. Hoag, M. N. Nadagouda, R. S. Varma, J. Mater. Chem., 2009, 19, 8671-8677.
[46]	P. Isacsson, K. Jain, A. Fall, V. Chauve, A. Hajian, H. Granberg, L. Boiron, M. Berggren, K. Håkansson, J. Edberg, I. Engquist, L. Wågberg, J. Mater. Chem. A, 2022, 10, 21579-21589.
[47]	W. Zhang, C. Sun, Y. Zhao, X. Lu, Int. J. Biol. Macromol., 2011, 49, 688-692.
[48]	Z. Guo, W. Kong, L. Zhou, Y. He, L. Ma, G. Liu, Y. Liu, Y. Jiang, ACS Catal., 2025, 15, 3955-3966.
[49]	S. Velasco-Lozano, A. I. Benítez-Mateos, F. López-Gallego, Angew. Chem. Int. Ed., 2017, 56, 771-775.