Process for making (2S, 3S, 5S) oxetanone derivatives

A process for making in at least 70% enantiomeric purity a (3S, 4S, 6S) oxetanone compound of the formula (I):

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• or a salt thereof
• wherein:
• R1 and R3 are each independently a C1 to C18 straight or branched alkyl hydrocarbon chain, and
• R2 is hydrogen or an alcohol protecting group R10, wherein R10 can be replaced by a hydrogen atom via ester hydrolysis or hydrogenation ether degradation, comprising the steps of:
• (a) selectively hydrogenating a composition comprising a compound which is a member selected from the group consisting of (6R) tetrahydro-2H-pyran-2-one compound of formula (II) and (6R) 5,6-dihydro-2H-pyran-2,4-dione of formula (IIa):
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• wherein
• R5 is hydrogen or an alcohol protecting group, which can be replaced by a hydrogen atom via hydrogenation, and R1 and R3 are defined as in formula (I), by hydrogenating the compound of formula II with a hydrogenation catalyst selected from the group consisting of PtO2, Raney Nichel and the like, and exchanging hydrogen atoms at the 3 and 4 ring positions or oxidizing the 4-oxo group to provide a (3S, 4S, 6R) 4-hydroxy-tetrahydro-2H-pyran-2-one compound of the formula (III):
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• wherein R1 and R3 are defined as in formula (I);
• (b) re-protecting the 4-hydroxy group of the compound of formula (II) produced in (a) with an ether protecting group R6, which can be replaced by a hydrogen atom via ester hydrolysis or hydrogenation ether degradation, opening the lactone ring and esterifying the resulting free acid group to provide a (2S, 3S, 5R) [R7]2-[R3]-3-[R6-oxy]-5-[hydroxy, R1]pentanoic acid ester compound of the formula (IV):
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• wherein
• R1 and R3 are defined as in formula (I), R6 is an alcohol protecting group, which can be replaced by a hydrogen atom via ester hydrolysis or hydrogenation ether degradation, and
• R7 is an ester group which can be removed by base or acid hydrolysis, or by hydrogenation;
• (c) inverting the chirality of the 5-hydroxy group of the compound of formula (IV) produced in step (b), wherein the inversion comprises a step which is a member selected from the group consisting of
• (iv) a Mitsunobu reaction,
• (v) esterifying the 5-hydroxy group to a carboxylic acid ester such as the trichloroacetic acid ester, and the like, and hydrolyzing the resultant ester in a water ether solvent such as 3:1 H2O/dioxane, and
• (vi) esterifying the 5-hydroxy group to a sulfonic acid ester, such as p-toluene sulfonic acid ester and the like, and reacting the ester with an excess of an organic acid salt selected from the group consising of potassium acetate, sodium acetate, tetraethylammonium acetate, and the like, to provide an ester exchange with the organic acid,
• wherein the free inverted (5S) 5-hydroxy group of (i) and (ii) is esterified with a hydroxy protecting group R10 which can be which can be replaced by a hydrogen atom via ester hydrolysis or hydrogenation ether degradation, to provide a compound of the formula (V):
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• wherein
• R1 and R3 are defined as in formula (I),
• R6 is an alcohol protecting group, which can be replaced by a hydrogen atom via ester hydrolysis or hydrogenation ether degradation,
• R9 is an ester group which can be removed by base or acid hydrolysis, or by hydrogenation, and
• R10 is an alcohol protecting group, which can be replaced by a hydrogen atom via ester hydrolysis or hydrogenation ether degradation, and wherein R10 is selectively removable with respect to the R6 alcohol protecting group;
• and
• (d) selectively removing the R6 alcohol protecting group and R9 ester group of the compound of formula (V) produced in (c), and cyclizing the 3 position alcohol group with the 1 position acid group using a lactone cyclizing catalyst, such as benzene-sulphonyl chloride, in a solvent such as pyridine at a temperature of about −10 to 10° C. and optionally replacing the R10 alcohol protecting group of formula (V) with a hydrogen atom, to yield a (3S, 4S, 6S) oxetanone compound of the formula (I):
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• or a salt thereof.