Synthesis of 3,6-dialkyl-5,6-dihydro-4-hydroxy-pyran-2-one
AssigneeRoche Colorado Corporation
InventorsPeter J. Harrington, Lewis M. Hodges, Kurt Puentener, Michelangelo Scalone
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Abstract
The present invention relates to a novel process for producing a δ-lactone of the formula: using an acyl halide of the formula: wherein R1, R2 R3 and X are described herein. In particular, the present invention relates to a process for enantioselectively producing the δ-lactone and novel intermediates disclosed herein.
Claims44
A process for producing a δ-lactone of the formula:
- said process comprising the steps of:
- (i)
- (a) treating an acyl halide of the formula:
- with a ketene acetal of the formula:
- under conditions sufficient to produce a coupled intermediate;
- and
- (b) providing conditions sufficient to produce said δ-lactone I from said coupled intermediate, or
- (ii)
- (a) treating an acyl halide of the formula:
- with a malonate half acid of the formula:
- under conditions sufficient to produce a δ-hydroxy-β-ketoester of the formula:
- (b) treating said δ-hydroxy-β-ketoester with an acid under conditions sufficient to produce said δ-lactone,
- wherein
- R1 is C1-C20 alkyl;
- R2 is H or C1-C10 alkyl;
- R3 is a hydroxy protecting group;
- each of R4 and R5 is independently C1-C6 alkyl, C5-C20 aryl, C6-C20 arylalkyl or —SiR8R9R10;
- R7 is H or R3
- each of R8, R9, R10 is independently C1-C6 alkyl or phenyl;
- and
- X is a halide.
A process for enantioselective preparation of a β-hydroxy ester of the formula:
- comprising hydrogenating a β-ketoester of the formula:
- in the presence of about 40 bar of pressure or less of hydrogen gas and a ruthenium hydrogenation catalyst comprising a halide and a chiral substituted biphenyl phosphorous ligand,
- wherein
- R1 is C1-20 alkyl, and
- R18 is H or C1-C6 alkyl, C5-C20 aryl or C6-C20 arylalkyl.
A process for enantioselectively producing a δ-lactone of the formula:
- said process comprising the steps of:
- (i)
- (a) reacting an acyl halide of the formula:
- with a silyl ketene acetal of the formula:
- under conditions sufficient to produce a δ-siloxy-β-silyl enol ether ester of the formula:
- (b) contacting said δ-siloxy-β-silyl enol ether ester with a base under conditions sufficient to remove at least one silyl group;
- and
- (c) contacting the product of said step (b) with an acid under conditions sufficient to produce said δ-lactone, or
- (ii)
- (a) reacting an acyl halide of the formula:
- with a malonate half acid of the formula:
- under conditions sufficient to produce a δ-hydroxy-β-ketoester of the formula:
- (b) contacting said δ-hydroxy-β-ketoester with an acid under conditions sufficient to produce said δ-lactone,
- wherein
- R5 is C1-C6 alkyl, C5-C20 aryl or C6-C20 arylalkyl;
- and
- each of R8, R9, R10, R11, R12 and R13 is independently C1-C6 alkyl or phenyl.
A compound selected from the group consisting of β-siloxy acyl halides of the formula:
- δ-siloxy-β-silyl enol ether esters of the formula:
- and δ-siloxy-β-ketoesters of the formula:
- wherein
- R1 is C1-C20 alkyl;
- R2 is H or C1-C10 alkyl;
- R5 is C1-C6 alkyl, C5-C20 aryl or C6-C20 arylalkyl;
- each of R8, R9, R10, R11, R12 and R13 is independently C1-C6 alkyl or phenyl;
- and
- X is a halide.
Dependencies are inferred from the claim text.