Enantioselective synthesis of unprotected 2-quinolinone-based cyclic amino acids via sequential palladium-catalyzed asymmetric allylation/desymmetrization

doi:10.1016/S1872-2067(23)64390-6

Abstract

Abstract:

Chiral unprotected 3-amino-2-quinolinone and 2-quinolinone-based cyclic amino acids have been recognized as important scaffolds in the structures of various drugs and bioactive molecules. However, a direct asymmetric method for the synthesis of these structures remains elusive. In this study, we report a Pd(0)-catalyzed enantioselective sequential decarboxylative allylation/desymmetrization protocol. Various vinyl benzoxazinanones can be used as substrates to react with unprotected amino esters, affording enantioenriched 2-quinolinone-based cyclic amino acids with high enantioselectivities (up to 96% ee) and good diastereoselectivities (up to 15:1 dr). Moreover, the products could be successfully transformed to chiral 3-amino-2-quinolinone derivatives after treatment with aqueous HCl. Mechanistic studies revealed that the double-hydrogen-bond-directing effect between the enolate (2-aminomalonate) and π-allyl Pd(II) complex plays an important role in the control of regioselectivity, and the steric hindrance between tert-butyl group on the ligand and allyl group on the substrate is responsible for the high enantioselectivity.

Key words: Pd catalysis, Asymmetric allylation, Desymmetrization, Vinyl benzoxazinanone, Free amino acid

Qian Li, Yan Liu, Can Li. Enantioselective synthesis of unprotected 2-quinolinone-based cyclic amino acids via sequential palladium-catalyzed asymmetric allylation/desymmetrization[J]. Chinese Journal of Catalysis, 2023, 47: 222-228.

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URL: https://www.cjcatal.com/EN/10.1016/S1872-2067(23)64390-6

https://www.cjcatal.com/EN/Y2023/V47/I4/222

Figures/Tables 6

Scheme 1. Synthesis of 2-quinolinone-based cyclic amino acids.

Table 1 Optimization of conditions for asymmetric α-allylation of 2-aminomalonates with vinyl benzoxazinanones. a

Entry	Ligand	Solvent	Yield ^b (%)	ee ^c (%)
1^d	PPh₃	DCE	54	—
2	L1	DCE	<10	45
3	L2	DCE	19	20
4	L3	DCE	—	—
5	L4	DCE	70	60
6	L5	DCE	75	40
7	L6	DCE	77	73
8	L7	DCE	24	77
9	L8	DCE	76	86
10	L8	xylene	92	89
11^e	L8	xylene	89	93
12^e,f	L8	xylene	90	93

Scheme 2. Desymmetrization and a sequential allylation/desymmetrization.

Scheme 3. Substrate scope. a The allylation was performed with 1 (0.30 mmol), 2 (0.45 mmol), Pd(dba)2 (1 mol%), L8 (2 mol%) in xylene (2 mL) at room temperature. The desymmetrization was performed with TFA (1 mL) in DCM (5 mL) at room temperature for 4 h. b Catalyst loading: 5 mol%, 1 (0.20 mmol), 2 (0.30 mmol). c Catalyst loading: 5 mol%, 1 (0.20 mmol), 2 (0.30 mmol), DBU (0.30 mmol).

Scheme 4. Scaled-up experiment and synthetic applications.

Fig. 1. Control experiment and proposed catalytic cycles.

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