Process for the synthesis of chirally pure beta-amino-alcohols

A process for preparing chirally pure S enantiomers of β-amino alcohols, comprising the steps of:

• a) preparing an organometallic reagent from a halide of the formula (R)2CH(CH2)nCH2X;
• wherein X is Cl, Br or I and n is 0 to about 10;
• b) adding said organometallic reagent to carbon dioxide to afford a carboxylic acid;
• c) activating said carboxylic acid with an acid halide, phosphorus trichloride, acid anhydride, or thionyl chloride in the presence of a tertiary amine base;
• d) reacting the product of step c) with an alkali metal salt of S-4-benzyl-2-oxazolidinone;
• e) treating the product of step d) with a strong non-nucleophilic base to form an enolate anion;
• f) trapping said enolate anion with 2,4,6-triisopropylbenzenesulfonyl azide to afford the oxazolidinone azide;
• g) hydrolyzing said oxazolidinone azide with an aqueous base to afford an α-azido acid;
• h) reducing said α-azido acid to an α-amino acid;
• i) reducing said α-amino acid to an β-amino alcohol;
• and
• j) recrystallizing said β-amino alcohol to form said chirally pure β-amino alcohol.

A process for preparing chirally pure S enantiomers of N-sulfonyl β-amino alcohols of the general formula:

• 22
• wherein:
• R is selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, CH2cycloalkyl, CH2-3-indole, CH(loweralkyl)-2-furan, CH(loweralkyl)-4-methoxyphenyl, CH(loweralkyl)phenyl, and CH(OH)-4-SCH3-phenyl;
• wherein said process comprises the steps of:
• a) reducing an α-amino acid to an β-amino alcohol of the formula:
• 23
• b) sulfonylating said β-amino alcohol with 5-chloro-thiophene-2-sulfonyl halide;
• and
• c) recrystallizing the product of step b) to afford said chirally pure N-sulfonyl β-amino alcohols.

A process for preparing chirally pure S enantiomers of N-sulfonyl β-amino alcohols of the general formula:

• 24
• wherein:
• R is selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, CH2cycloalkyl, CH2-3-indole, CH(loweralkyl)-2-furan, CH(loweralkyl)-4-methoxyphenyl, CH(loweralkyl)phenyl, and CH(OH)-4-SCH3-phenyl;
• wherein said process comprises the steps of:
• a) preparing a Grignard reagent from a halide of the formula (R)2CHCH2X;
• wherein X is Cl, Br or I;
• <b) adding said Grignard reagent to carbon dioxide to afford a carboxylic acid of the formula:
• 25
• c) activating said carboxylic acid with an acid chloride in the presence of a tertiary amine base;
• d) reacting the product of step c) with a lithium salt of S-4-benzyl-2-oxazolidinone to afford the following compound:
• 26
• e) treating the product of step d) with potassium hexamethyldisilazide to form an enolate anion;
• f) trapping said enolate anion with 2,4,6-triisopropylbenzenesulfonyl azide to afford the oxazolidinone azide of the formula:
• 27
• g) hydrolyzing said oxazolidinone azide with an aqueous base selected from the group consisting of lithium hydroxide, potassium hydroxide, and sodium hydroxide to afford an α-azido acid of the formula:
• 28
• h) reducing said α-azido acid using hydrogen gas in the presence of 10% palladium on carbon catalyst to an α-amino acid of the formula:
• 29
• i) reducing said α-amino acid using catalytic hydrogenation, diborane, catecholborane, lithium borohydride/TMSCl, lithium aluminum hydride, DiBAL-H, Red-Al, or alane to an β-amino alcohol of the formula:
• 30
• j) sulfonylating said β-amino alcohol with 5-chloro-thiophene-2-sulfonyl chloride;
• and
• k) recrystallizing the product of step j) to afford said chirally pure N-sulfonyl β-amino alcohols.