Method for synthesizing polyhydroxy pyrroline acridine alkaloid

Abstract

The present invention discloses a method of synthesizing multi-hydroxy pyrrolidine alkaloid. The present invention comprises the following steps: 1) the multi-hydroxy ring-shaped nitrone of the structure in formula II reacts to prepare Cbz-protected amide of the structure in formula III; 2) the amide of the structure in formula III is changed into an alpha, beta-unsaturated ketone of the structure IV; 3) the alpha, beta-unsaturated ketone of the structure IV and ketone do the dual-hydroxylation reaction with the influence of osmium tetroxide and NMO system to get a structure in formula V; 4) the formula V is catalyzed and hydrogenated to get the multi-hydroxy pyrrolidine alkaloid of the structure in formula I. The present invention startes from the low-cost and easily accessible raw materials; the sugar derived multi-hydroxy chiral nitrone is used as a key chiral intermediate; a set of simple, effective and practical methods of highly three-dimensional selectivity and high production rate to synthesize the multi-hydroxy pyrrolidine alkaloid of hyacinthacine C1 category is formed through the pro-nuclear addition, Wittig reaction, double-hydroxylation and reductive amination and other reactions.

Description

technical field

[0001] The present invention relates to a kind of hyacinthacine C 1 A simple, practical and effective synthesis method of polyhydroxypyrrolidinoid alkaloids. Background technique

[0002] Glycosidase-catalyzed hydrolysis of glycosidic bonds in carbohydrate complexes and carbohydrate conjugates is the most common biochemical reaction in living organisms. Glycosidases have a wide variety of functions and provide the most basic guarantee for the survival of all living organisms. Polyhydroxyalkaloids act on glycosidases directly or indirectly by simulating the pyran or furan ring part of natural substrates instead of natural substrates, thereby directly or indirectly inhibiting glycosidases. The glycosidase inhibitory effects of these polyhydroxyalkaloids could make them potential antiviral, anticancer, antidiabetic drugs, and may be applied in agrochemicals. With the approval of Zavesca (N-butyl-deoxynojirimycin) in the European Union in 2002 for the treatmen...

Examples

Embodiment 1

[0028] Example 1, (3S, 4R, 5R)-3,4-2H-3,4-two-(benzyloxy)-5-benzyloxymethyl-2H-pyrrole 1-oxide (compound 2) synthesis

[0029]

[0030] To a solution of 2,3,5-tri-O-benzyl-ribofuranose (20 g, 47.6 mmol) in DCM (150 ml) was added pyridine (8 ml, 104.8 mmol) and NH 2 OH.HCl (3.7 g, 52.4 mmol). The reaction mixture was heated to reflux for 12 hours, cooled to room temperature, and diluted with DCM (200ml). The reaction mixture was washed with saturated brine (100ml×2), and washed with anhydrous Na 2 SO 4dry. After filtration, pyridine (8ml, 104.8mmol) and TBDMSCl (9g, 60mmol) were added to the filtrate. The reaction mixture was stirred at room temperature for 12 hours and then washed with saturated NaHCO 3 washed with aqueous solution, followed by anhydrous Na 2 SO 4 Dry, filter, and concentrate the filtrate to a yellow oil. This crude product was dissolved in toluene (150ml), and PPh 3 (25.8g, 98.4mmol), imidazole (6.7g, 98.4mmol) and I 2 (25 g, 98.4 mmol). The rea...

Embodiment 2

[0034] Example 2: Synthesis of (2S, 3S, 4R, 5R)-N-hydroxyl-2-vinyl-3,4-bis-(benzyloxy)-5-benzyloxymethylpyrroline (compound 3)

[0035]

[0036] A THF (40ml) solution of nitrone compound 2 (1.8g, 4.3mmol) was cooled to -78°C, and a 1.6M THF solution of vinylmagnesium chloride (4.0ml, 6.4mmol) was added dropwise. The reaction mixture was stirred at -78°C for 0.5 h and then washed with saturated NH 4 Aqueous Cl solution quenched the reaction. The organic phase was separated, the aqueous phase was extracted with EtOAc (50ml×2), and the combined organic phases were washed with anhydrous Na 2 SO 4 dry. Column chromatography (PE:EA=5:1) gave compound 3 (1.8 g, 90%) as a white solid.

[0037] Its NMR H spectrum and C spectrum are shown in Figure 3 and Figure 4, respectively.

[0038] Mp 71-72°C; [α] D 20 -6.5 (c 2.15, CHCl 3 ); 1 H NMR (300MHz, CDCl 3 )δ7.24-7.38 (15H, m, Ar-H), 5.89-5.79 (1H, m, CH 2 =CH), 5.45 (1H, dd, J=17.1, 0.9Hz, CH 2 =CH), 5.27 (1H, dd, J=10.2, ...

Embodiment 3

[0039] Example 3: Synthesis of (2S, 3S, 4R, 5R)-2-vinyl-3,4-bis-(benzyloxy)-5-benzyloxymethylpyrroline (compound 4)

[0040]

[0041] Cu(OAc) 2 ·H 2 O (86mg) was added to a suspension of zinc powder (880mg, 13.5mmol) and acetic acid (10ml), and the mixture was stirred at room temperature for 15 minutes, and then 20ml of hydroxylamine compound 3 (1.25g, 2.7mmol) was added in acetic acid-water ( 6:1, v:v) solution. The reaction mixture was heated to 70°C for half an hour. The solvent was distilled off under reduced pressure, and the aqueous phase was adjusted to pH=10 with 6N NaOH. Filtration, the filtrate was extracted with DCM (25ml×3), and the organic phases were combined with anhydrous Na 2 SO 4 dry. The crude product was separated by column chromatography (PE:EA=1:2) to obtain compound 4 (1.15 g, 95%) as a colorless oil.

[0042] Its NMR H spectrum and C spectrum are shown in Figure 5 and Figure 6, respectively.

[0043] [α] D 20 +11.9 (c 0.67, CHCl 3 ); 1 H ...

technical field

[0001] The present invention relates to a kind of hyacinthacine C 1 A simple, practical and effective synthesis method of polyhydroxypyrrolidinoid alkaloids. Background technique

[0002] Glycosidase-catalyzed hydrolysis of glycosidic bonds in carbohydrate complexes and carbohydrate conjugates is the most common biochemical reaction in living organisms. Glycosidases have a wide variety of functions and provide the most basic guarantee for the survival of all living organisms. Polyhydroxyalkaloids act on glycosidases directly or indirectly by simulating the pyran or furan ring part of natural substrates instead of natural substrates, thereby directly or indirectly inhibiting glycosidases. The glycosidase inhibitory effects of these polyhydroxyalkaloids could make them potential antiviral, anticancer, antidiabetic drugs, and may be applied in agrochemicals. With the approval of Zavesca (N-butyl-deoxynojirimycin) in the European Union in 2002 for the treatmen...

Examples

Embodiment 1

[0028] Example 1, (3S, 4R, 5R)-3,4-2H-3,4-two-(benzyloxy)-5-benzyloxymethyl-2H-pyrrole 1-oxide (compound 2) synthesis

[0029]

[0030] To a solution of 2,3,5-tri-O-benzyl-ribofuranose (20 g, 47.6 mmol) in DCM (150 ml) was added pyridine (8 ml, 104.8 mmol) and NH 2 OH.HCl (3.7 g, 52.4 mmol). The reaction mixture was heated to reflux for 12 hours, cooled to room temperature, and diluted with DCM (200ml). The reaction mixture was washed with saturated brine (100ml×2), and washed with anhydrous Na 2 SO 4dry. After filtration, pyridine (8ml, 104.8mmol) and TBDMSCl (9g, 60mmol) were added to the filtrate. The reaction mixture was stirred at room temperature for 12 hours and then washed with saturated NaHCO 3 washed with aqueous solution, followed by anhydrous Na 2 SO 4 Dry, filter, and concentrate the filtrate to a yellow oil. This crude product was dissolved in toluene (150ml), and PPh 3 (25.8g, 98.4mmol), imidazole (6.7g, 98.4mmol) and I 2 (25 g, 98.4 mmol). The rea...

Embodiment 2

[0034] Example 2: Synthesis of (2S, 3S, 4R, 5R)-N-hydroxyl-2-vinyl-3,4-bis-(benzyloxy)-5-benzyloxymethylpyrroline (compound 3)

[0035]

[0036] A THF (40ml) solution of nitrone compound 2 (1.8g, 4.3mmol) was cooled to -78°C, and a 1.6M THF solution of vinylmagnesium chloride (4.0ml, 6.4mmol) was added dropwise. The reaction mixture was stirred at -78°C for 0.5 h and then washed with saturated NH 4 Aqueous Cl solution quenched the reaction. The organic phase was separated, the aqueous phase was extracted with EtOAc (50ml×2), and the combined organic phases were washed with anhydrous Na 2 SO 4 dry. Column chromatography (PE:EA=5:1) gave compound 3 (1.8 g, 90%) as a white solid.

[0037] Its NMR H spectrum and C spectrum are shown in Figure 3 and Figure 4, respectively.

[0038] Mp 71-72°C; [α] D 20 -6.5 (c 2.15, CHCl 3 ); 1 H NMR (300MHz, CDCl 3 )δ7.24-7.38 (15H, m, Ar-H), 5.89-5.79 (1H, m, CH 2 =CH), 5.45 (1H, dd, J=17.1, 0.9Hz, CH 2 =CH), 5.27 (1H, dd, J=10.2, ...

Embodiment 3

[0039] Example 3: Synthesis of (2S, 3S, 4R, 5R)-2-vinyl-3,4-bis-(benzyloxy)-5-benzyloxymethylpyrroline (compound 4)

[0040]

[0041] Cu(OAc) 2 ·H 2 O (86mg) was added to a suspension of zinc powder (880mg, 13.5mmol) and acetic acid (10ml), and the mixture was stirred at room temperature for 15 minutes, and then 20ml of hydroxylamine compound 3 (1.25g, 2.7mmol) was added in acetic acid-water ( 6:1, v:v) solution. The reaction mixture was heated to 70°C for half an hour. The solvent was distilled off under reduced pressure, and the aqueous phase was adjusted to pH=10 with 6N NaOH. Filtration, the filtrate was extracted with DCM (25ml×3), and the organic phases were combined with anhydrous Na 2 SO 4 dry. The crude product was separated by column chromatography (PE:EA=1:2) to obtain compound 4 (1.15 g, 95%) as a colorless oil.

[0042] Its NMR H spectrum and C spectrum are shown in Figure 5 and Figure 6, respectively.

[0043] [α] D 20 +11.9 (c 0.67, CHCl 3 ); 1 H ...

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