Enantioselective biosynthesis of vicinal diamines enabled by synergistic photo/biocatalysis consisting of an ene-reductase and a green-light-excited organic dye

doi:10.1016/S1872-2067(24)60168-3

Abstract

Abstract:

Vicinal diamines are key motifs widely-found in many pharmaceuticals and biologically active molecules. An appealing approach for synthesizing these molecules is the amination of enamines, but few examples have been explored. With the utilization of nitrogen-centered radicals (NCRs), here we present the development of a dual bio-/photo-catalytic system for achieving enantioselective hydroamination of enamides, which can give easy access to diverse enantioenriched vicinal diamines. These reactions progress efficiently under green light excitation and exhibit excellent enantioselectivities (up to >99% enantiomeric excess). Mechanistic studies uncovered the synergistic effect of the enzyme and the externally added organophotoredox catalyst Rhodamine B (RhB). This work demonstrates the effectiveness of photobiocatalysis to generate and control high-energy radical intermediates, addressing a long-standing challenge in chemical synthesis.

Key words: Photobiocatalysis, Vicinal diamines, Asymmetric synthesis, Hydroamination, Green light excitation

Fengming Shi, Bin Chen, Jinhai Yu, Ruiqi Zhu, Yu Zheng, Xiaoqiang Huang. Enantioselective biosynthesis of vicinal diamines enabled by synergistic photo/biocatalysis consisting of an ene-reductase and a green-light-excited organic dye[J]. Chinese Journal of Catalysis, 2025, 68: 223-229.

×
share this article

Add to citation manager EndNote|Ris|BibTeX

URL: https://www.cjcatal.com/EN/10.1016/S1872-2067(24)60168-3

https://www.cjcatal.com/EN/Y2025/V68/I1/223

Figures/Tables 4

Fig. 1. Photodriven ERED-enabled modular access to chiral vicinal diamines. (A) Two pathways for amination of enamines. (B) Previously reported photoenzymatic hydroaminations of styrenes. (C) This work: hydroaminations of enamides through a non-natural green-light-tri- ggered N-N cleavage radical mechanism. NCRs, nitrogen-centered radicals; GDH, glucose dehydrogenase; NADP+, the oxidized form of nicotinamide adenine dinucleotide phosphate; Glu, glucose; FMNsq, flavin semiquinone; HAT, hydrogen atom transfer.

Table 1 Development of photoenzymatic hydroamination.

Entry	EREDs	Deviation from the above conditions ^a	Yield ^b (%)	e.e. ^c (%)
1	GluER-M5 ^d	w/o RhB, 420−430 nm LEDs	26	98
2	GluER-M5	none	72	98
3	GluER	none	45	99
4	YersER	none	46	96
5	XenA	none	trace	n.d.
6	OYE1-F296A	none	19	68
7	NostocER	none	65	72
8	CsER	none	42	71
9	GluER-M5	1 mol% enzyme loading	48	98
10	GluER-M5	w/o GDH / NADP⁺/ Glu	n.d.	n.a.
11	none	None	n.d.	n.a.
12	none	5 mol% FMN-Na added	n.d.	n.a.
13	GluER-M5	Dark	trace	n.a.
14	GluER-M5	w/o RhB, 300-320 nm LEDs	8	n.d.

Fig. 2. Scope Investigation. Standard conditions: enamide 1 (0.008 mmol), N-amidopyridinium salt 2 (0.032 mmol), GluER-M5 (2 mol%), GDH (4 U), NADP+ (1.5 mol%), glucose (0.024 mmol), 20% v/v DMSO in KPi buffer (100 mmol L-1, pH = 6.0) were stirred for 16 h at room temperature and illuminated with 530?540 nm LEDs under a N2 atmosphere, total volume of the reaction is 2.0 mL. The yields were determined by LC-MS and reported as the average of duplicates. The e.e. was determined by HPLC analysis on a chiral stationary phase. a Isolated yields were based on 0.10-mmol-scale reactions. b Mutant GluER-Y177F-F269V was used as the enzyme.

Fig. 3. Mechanism studies. (A) Radical trapping experiment with 1,1-diphenylethene. (B) UV-vis absorption spectra. 1a (0.4 mmol L-1), 2a (0.4 mmol L-1), GluER-M5 (0.05 mmol L-1), sodium dithionite (0.15 mmol L-1). (C) Emission spectrum of green LEDs and absorption spectra of key components. RhB (0.01 mmol L-1), GluER-M5 (0.05 mmol L-1), sodium dithionite (0.15 mmol L-1), 2a (0.4 mmol L-1). (D) Stern-Volmer quenching study. RhB (0.01 mM). Samples were irradiated at 530 nm and emission was measured at 582 nm. (E) Proposed catalytic cycle, where the dot curvature represents the chiral enzyme active site. EDA, electron donor-acceptor; ET, energy transfer; FMNox, flavin mononucleotide; FMNhq, flavin hydroquinone.

References

[1]	D. Lucet, T. Le Gall, C. Mioskowski, Angew. Chem. Int. Ed., 1998, 37, 2580-627.
[2]	J.-C. Kizirian, Chem. Rev., 2008, 108, 140-205.
[3]	F. Foubelo, C. Nájera, M. G. Retamosa, J. M. Sansano, M. Yus, Chem. Soc. Rev., 2024, 53, 7983-8085.
[4]	Y. Zhu, R. G. Cornwall, H. Du, B. Zhao, Y. Shi, Acc. Chem. Res., 2014, 47, 3665-3678.
[5]	N. Fu, G. S. Sauer, A. Saha, A. Loo, S. Lin, Science, 2017, 357, 575-579.
[6]	Z. Tao, B. B. Gilbert, S. E. Denmark, J. Am. Chem. Soc., 2019, 141, 19161-19170.
[7]	R. Matsubara, S. Kobayashi, Angew. Chem. Int. Ed., 2006, 45, 7993-7995.
[8]	L. Yu, P. Somfai, Angew. Chem. Int. Ed., 2019, 58, 8551-8555.
[9]	A. Dumoulin, C. Lalli, P. Retailleau, G. Masson, Chem. Commun., 2015, 51, 5383-5386.
[10]	Y. F. Cao, X. Y. Li, J. Ge, Trends Biotechnol., 2021, 39, 1173-1183.
[11]	A. O’Connell, A. Barry, A. J. Burke, A. E. Hutton, E. L. Bell, A. P. Green, E. O’Reilly, Chem. Soc. Rev., 2024, 53, 2828-2850.
[12]	D. Mondal, H. M. Snodgrass, C. A. Gomez, J. C. Lewis, Chem. Rev., 2023, 123, 10381-10431.
[13]	E. O. Romero, A. T. Saucedo, J. R. Hernández-Meléndez, D. Yang, S. Chakrabarty, A. R. H. Narayan, JACS Au, 2023, 3, 2073-2085.
[14]	E. L. Bell, W. Finnigan, S. P. France, A. P. Green, M. A. Hayes, L. J. Hepworth, S. L. Lovelock, H. Niikura, S. Osuna, E. Romero, K. S. Ryan, N. J. Turner, S. L. Flitsch, Nat. Rev. Methods Primers, 2021, 1, 46.
[15]	K. Chen, F. H. Arnold, Nat. Catal., 2020, 3, 203-213.
[16]	E. N. Kissman, M. B. Sosa, D. C. Millar, E. J. Koleski, K. Thevasundaram, M. C. Y. Chang, Nature, 2024, 631, 37-48.
[17]	R. Buller, S. Lutz, R. J. Kazlauskas, R. Snajdrova, J. C. Moore, U. T. Bornscheuer, Science, 2023, 382, eadh8615.
[18]	M. T. Reetz, G. Qu, Z. Sun, Nat. Synth., 2024, 3, 19-32.
[19]	W. Harrison, X. Huang, H. Zhao, Acc. Chem. Res., 2022, 55, 1087-1096.
[20]	L. Schmermund, V. Jurkaš, F. F. Özgen, G. D. Barone, H. C. Büchsenschütz, C. K. Winkler, S. Schmidt, R. Kourist, W. Kroutil, ACS Catal., 2019, 9, 4115-4144.
[21]	S. Zhang, S. Liu, Y. Sun, S. Li, J. Shi, Z. Jiang, Chem. Soc. Rev., 2021, 50, 13449-13466.
[22]	C.-H. Yun, J. Kim, F. Hollmann, C. B. Park, Chem. Sci., 2022, 13, 12260-12279.
[23]	M. A. Emmanuel, S. G. Bender, C. Bilodeau, J. M. Carceller, J. S. DeHovitz, H. Fu, Y. Liu, B. T. Nicholls, Y. Ouyang, C. G. Page, T. Qiao, F. C. Raps, D. R. Sorigué, S.-Z. Sun, J. Turek-Herman, Y. Ye, A. Rivas-Souchet, J. Cao, T. K. Hyster, Chem. Rev., 2023, 123, 5459-5520.
[24]	Y. Ming, B. Chen, X. Huang, Synth. Biol. J., 2023, 4, 651-675.
[25]	S. Mondal, F. Dumur, D. Gigmes, M. P. Sibi, M. P. Bertrand, M. Nechab, Chem. Rev., 2022, 122, 5842-5976.
[26]	M. A. Emmanuel, N. R. Greenberg, D. G. Oblinsky, T. K. Hyster, Nature, 2016, 540, 414-417.
[27]	K. F. Biegasiewicz, S. J. Cooper, X. Gao, D. G. Oblinsky, J. H. Kim, S. E. Garfinkle, L. A. Joyce, B. A. Sandoval, G. D. Scholes, T. K. Hyster, Science, 2019, 364, 1166-1169.
[28]	H. Fu, J. Cao, T. Qiao, Y. Qi, S. J. Charnock, S. Garfinkle, T. K. Hyster, Nature, 2022, 610, 302-307.
[29]	Y. Ouyang, C. G. Page, C. Bilodeau, T. K. Hyster, J. Am. Chem. Soc., 2024, 146, 13754-13759.
[30]	X. Huang, B. Wang, Y. Wang, G. Jiang, J. Feng, H. Zhao, Nature, 2020, 584, 69-74.
[31]	X. Huang, J. Feng, J. Cui, G. Jiang, W. Harrison, X. Zang, J. Zhou, B. Wang, H. Zhao, Nat. Catal., 2022, 5, 586-593.
[32]	M. Li, Y. Yuan, W. Harrison, Z. Zhang, H. Zhao, Science, 2024, 385, 416-214.
[33]	Y. Peng, Z. Wang, Y. Chen, W. Xu, Y. Hu, Z. Chen, J. Xu, Q. Wu, Angew. Chem. Int. Ed., 2022, 61, e202211199.
[34]	X. Duan, D. Cui, Z. Wang, D. Zheng, L. Jiang, W. Y. Huang, Y. X. Jia, J. Xu, Angew. Chem. Int. Ed., 2022, 62, e202214135.
[35]	L. Cheng, D. Li, B. K. Mai, Z. Bo, L. Cheng, P. Liu, Y. Yang, Science, 2023, 381, 444-451.
[36]	T.-C. Wang, B. K. Mai, Z. Zhang, Z. Bo, J. Li, P. Liu, Y. Yang, Nature, 2024, 629, 98-104.
[37]	C. Zhu, Z. Yuan, Z. Deng, D. Yin, Y. Zhang, J. Zhou, Y. Rao, Angew. Chem. Int. Ed., 2023, 62, e202311762.
[38]	J. Zheng, Z. Shen, J.-M. Gao, J. Zhou, Y. Gu, Org. Lett., 2023, 25, 8564-8569.
[39]	Y. Liu, L. Zhu, X. Li, Y. Cui, A. Roosta, J. Feng, X. Chen, P. Yao, Q. Wu, D. Zhu, JACS Au, 2023, 3, 3005-3013.
[40]	V. Tseliou, L. Kqiku, M. Berger, F. Schiel, H. Zhou, G. J. Poelarends, P. Melchiorre, Nature, 2024, DOI: https://doi.org/10.1038/s41586-024-08004-9.
[41]	Y. Ye, J. Cao, D. G. Oblinsky, D. Verma, C. K. Prier, G. D. Scholes, T. K. Hyster, Nat. Chem., 2022, 15, 206-212.
[42]	Z. Zhang, J. Feng, C. Yang, H. Cui, W. Harrison, D. Zhong, B. Wang, H. Zhao, Nat. Catal., 2023, 6, 687-694.
[43]	W. Harrison, G. Jiang, Z. Zhang, M. Li, H. Chen, H. Zhao, J. Am. Chem. Soc., 2024, 146, 10716-10722.
[44]	X. Chen, D. Zheng, L. Jiang, Z. Wang, X. Duan, D. Cui, S. Liu, Y. Zhang, X. Yu, J. Ge, J. Xu, Angew. Chem. Int. Ed., 2023, 62, e202218140.
[45]	L. Jiang, D. Zheng, X. Chen, D. Cui, X. Duan, Z. Wang, J. Ge, J. Xu, ACS Catal., 2024, 14, 6710-6716.
[46]	Q. Shi, X.-W. Kang, Z. Liu, P. Sakthivel, H. Aman, R. Chang, X. Yan, Y. Pang, S. Dai, B. Ding, J. Ye, J. Am. Chem. Soc., 2024, 146, 2748-2756.
[47]	Y. Xu, H. Chen, L. Yu, X. Peng, J. Zhang, Z. Xing, Y. Bao, A. Liu, Y. Zhao, C. Tian, Y. Liang, X. Huang, Nature, 2023, 625, 74-78.
[48]	B. Zhao, J. Feng, L. Yu, Z. Xing, B. Chen, A. Liu, F. Liu, F. Shi, Y. Zhao, C. Tian, B. Wang, X. Huang, Nat. Catal., 2023, 6, 996-1004.
[49]	J. Zhang, Q. Zhang, B. Chen, J. Yu, B. Wang, X. Huang, ACS Catal., 2023, 13, 15682-15690.
[50]	J. Yu, Q. Zhang, B. Zhao, T. Wang, Y. Zheng, B. Wang, Y. Zhang, X. Huang, Angew. Chem. Int. Ed., 2024, 63, e202402673.
[51]	B. Chen, R. Li, J. Feng, B. Zhao, J. Zhang, J. Yu, Y. Xu, Z. Xing, Y. Zhao, B. Wang, X. Huang, J. Am. Chem. Soc., 2024, 146, 14278-14286.
[52]	J.-R. Chen, X.-Q. Hu, L.-Q. Lu, W.-J. Xiao, Chem. Soc. Rev., 2016, 45, 2044-2056.
[53]	J. H. Horner, O. M. Musa, A. Bouvier, M. Newcomb, J. Am. Chem. Soc., 1998, 120, 7738-7748.
[54]	P. T. Cesana, C. G. Page, D. Harris, M. A. Emmanuel, T. K. Hyster, G. S. Schlau-Cohen, J. Am. Chem. Soc., 2022, 144, 17516-17521.
[55]	G. E. M. Crisenza, D. Mazzarella, P. Melchiorre, J. Am. Chem. Soc., 2020, 142, 5461-5476.