Abstract: Chiral cyclopropanols are highly desirable building blocks for medicinal chemistry, but the stereoselective synthesis of these molecules remains challenging. Here, a novel strategy is reported for the diastereo- and enantioselective synthesis of cyclopropanol derivatives via the biocatalytic asymmetric cyclopropanation of vinyl esters with ethyl diazoacetate (EDA). A dehaloperoxidase enzyme from Amphitrite ornata was repurposed to catalyze this challenging cyclopropanation reaction, and its activity and stereoselectivity were optimized via protein engineering. Using this system, a broad range of electron-deficient vinyl esters were efficiently converted to the desired cyclopropanation products with up to 99.5:0.5 diastereomeric and enantiomeric ratios. In addition, the engineered dehaloperoxidase-based biocatalyst is able to catalyze a variety of other abiological carbene transfer reactions, including N?H/S?H carbene insertion with EDA as well as cyclopropanation with diazoacetonitrile, thus adding to the multifunctionality of this enzyme and defining it as a valuable new scaffold for the development of novel carbene transferases.
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With dimethyl amine; In ethanol; isopropyl alcohol;
a) 200 kg of 2-methoxyethyl acetoacetate and 185.1 kg of 3-nitrobenzaldehyde are suspended in 800 l of isopropanol. Then 5.65 kg of p-anisic acid and 5.05 kg of 33percent dimethylamine in ethanol are added, heating for about 30' at about 35° C. to obtain a solution. The reaction mixture is left to cool at 20/25° C. and then it is cooled for about 12 hours with running water and for a further 24 hours at about 0° C. with brine, then is centrifuged, washing with isopropanol. After drying, 327 kg of 2-methoxyethyl 2-(3-nitrobenzylidene) acetoacetate are obtained, in an about 91percent yield.
N-(1,8-naphthyridin-2-yl)-4-methoxybenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With 1,1'-carbonyldiimidazole; In propan-1-ol; water;
EXAMPLE 20 The procedure is similar to that described in Example 1, but starting with 4-methoxybenzoic acid (4.55 g), N,N'-carbonyldiimidazole (6.55 g) and <strong>[15992-83-3]2-amino-1,8-naphthyridine</strong> (5.2 g). The product produced by precipitation in water (8.35 g; m.p. 85 C., viscous) is filtered and then dissolved in boiling 1-propanol (50 cc). After 1 hour's cooling at 4 C., the crystallized solid is separated by filtration, washed with 1-propanol (2*5 cc) and dried at 35 C. under reduced pressure (0.067 kPa). N-(1,8-naphthyridin-2-yl)-4-methoxybenzamide (6.9 g) is produced, m.p. 150 C. 2-Amino-1,8-naphthyridine can be prepared according to U.S. Pat. No. 3,948,917.
Example 143 Amethyl 2-(4-methoxyphenylbenzo[d]oxazole-7-carboxylate; 4-Methoxybenzoic acid (152 mg, 1.0 mmol) and <strong>[17672-21-8]methyl 2-amino-3-hydroxybenzoate</strong> (167 mg, 1.0 mmol) were added to PPA (1 g), the mixture was stirred at 180 C. for 2 hr. After cooled to room temperature, water (50 mL) was added and filtered and the cake was washed with water and dried in vacuum to give methyl 2-(4-methoxyphenylbenzo[d]oxazole-7-carboxylate. LC-MS (ESI) m/z 240 [M+1]+.
ethyl 6-fluoro-3-(4-methoxybenzoyl)-1H-indole-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71.8%
To a 100 mL flask was added (4-methoxybenzoic acid)(976 mg, 6.41 mmol) and acetonitrile (11 mL) were added and dissolved,85% Phosphoric Acid (0.125 mL, 6.41 mmol) and trifluoroacetic anhydride (3 mL, 21.39 mmol) were added and stirred for 10 minutes.Then, <strong>[348-37-8]ethyl-6-fluoro-1H-indole-2-carboxylate</strong> (1.1 g, 4.28 mmol) synthesized in the above Step 2 was added,Stir for 10 hours.After completion of the reaction, the organic layer was separated using ethyl acetate and water, and the organic layer was further treated with saturated sodium hydrogencarbonate and sodium chloride, and water was removed with magnesium sulfate.After filtration, the mixture was purified by column chromatography (EA / n-Hex = 1: 4) to give ethyl 6-fluoro-3- (4- methoxybenzoyl) -1H-indole- Rate(1.2 g, 3.06 mmol, 71.8%).
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