Synthesis of prostanoids
Inventors
Yiannikouros, George Petros • Kalaritis, Panos • Gamage, Chaminda Priyapushpa • Abernathy, Stephanie Bosse
Assignees
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Publication Number
US-8476471-B2
Publication Date
2013-07-02
Expiration Date
Abstract
The presently disclosed subject matter provides a method of synthesizing prostaglandins and prostaglandin analogs comprising the ring closing metathesis of compounds of Formula (I). Also provided are novel compounds of Formula (I) and Formula (II). In addition to their use as synthetic intermediates in the presently disclosed methods, compounds of Formula (II) can be used as prostaglandin and/or prostaglandin analog prodrugs.
Core Innovation
The disclosed invention provides a method of preparing a prostaglandin or prostaglandin analog by providing a compound of Formula (I) in which n and m are integers between 0 and 4 with n+m being 3 or 4, and wherein R1, R2, R3, and R4 are defined with cis/trans orientation on a cyclopentane ring. The substituents at carbons 1 and 2 are oriented cis to one another and trans to the substituent at carbon 3.
A transition metal carbene complex catalyst performs a ring closing metathesis reaction on the Formula (I) compound, thereby forming a lactone. The formed lactone is then reacted with a nucleophile to produce a ring-opened product that is a prostaglandin, prostaglandin analog, or a synthetic intermediate thereof.
In the further refinement for prostaglandin analog preparation, after ring closing metathesis to form a lactone and nucleophile ring-opening to form a ring-opened product comprising a hydroxyl group, the hydroxyl group is oxidized to form a ketone. The hydroxyl protecting group R1 is then removed to form a prostaglandin analog having the defined formula.
Claims Coverage
Two independent claims are identified. The claims center on Formula (I) selection, ring-closing metathesis to form a lactone, and conversion of the lactone to a ring-opened prostaglandin/prostaglandin analog product, with one claim further requiring oxidation to a ketone and removal of a hydroxyl protecting group.
Formula (I) prostaglandin precursor with defined stereochemistry
Providing a compound of Formula (I) where n and m are integers between 0 and 4 with n+m being 3 or 4, R1 is H or a hydroxyl protecting group, R2 is H, alkyl or aralkyl, R3 and R4 are independently H or alkyl, and the cyclopentane-ring substituents at carbons 1 and 2 are oriented cis to one another and trans to the substituent at carbon 3.
Transition metal carbene ring closing metathesis to form a lactone
Reacting the compound of Formula (I) with a transition metal carbene complex catalyst to perform a ring closing metathesis reaction, thereby forming a lactone.
Nucleophile ring-opening to form a prostaglandin or analog or intermediate
Reacting the lactone with a nucleophile to form a ring-opened product wherein the ring-opened product is a prostaglandin, prostaglandin analog or synthetic intermediate thereof.
Oxidation of ring-opened hydroxyl to form a ketone and deprotection to prostaglandin analog
Reacting the lactone with a nucleophile to form a ring-opened product comprising a hydroxyl group; oxidizing the hydroxyl group of the ring-opened product to form a ketone; and removing the hydroxyl protecting group R1, thereby forming a prostaglandin analog having the defined formula.
The inventive coverage centers on a Formula (I) cyclopentane precursor with specified substituent definitions and cis/trans stereochemical orientation, conversion to a lactone via transition metal carbene ring closing metathesis, and conversion of the lactone to prostaglandin/prostaglandin analog via nucleophile ring-opening. The second independent claim further requires oxidation of a ring-opened hydroxyl to a ketone followed by removal of the hydroxyl protecting group to yield the prostaglandin analog.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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