Methods for synthesis of the tricyclic prostaglandin D

1 . A method for synthesis of a tricyclic-prostaglandin D 2 metabolite (PGDM) methyl ester or a pharmaceutically acceptable salt thereof, the method comprising:

(a) converting a first compound having the structure

 to an iodo-acetal compound by:

(1) combining the first compound with anhydrous dichloromethane (DCM) and N-iodosuccinimide to form a solution; and

(2) adding ethyl vinyl ether to the solution and mixing at about −20° C. for at least 30 minutes and mixing at about 0° C. for at least 4 hours to produce the iodo-acetal compound having the structure

(b) subjecting the iodo-acetal compound to either a first cyclization reaction with a methyl ester or a second cyclization reaction with a methyl ester to provide a cyclization product having the structure

wherein the first cyclization reaction comprises:

combining the iodo-acetal compound with 2,2′-azobis (2-methylpropionitrile) (AIBN), sodium cyanoborohydride (NaCNBH 3 ), tert-Butyl alcohol (BuOH), methyl acrylate, and nBu 3 SnCl to form an iodo-acetal solution; and

heating the iodo-acetal solution to about 85° C. and mixing for at least 72 hours to produce the cyclization product; and

wherein the second cyclization reaction comprises:

combining the iodo-acetal compound with nickel (II) chloride ethylene glycol dimethyl ether complex and neocuproine to form a mixture;

stirring the mixture at room temperature for at least 10 minutes, and then to 40° C. for at least 10 minutes; and

adding Zn nanopowder and methyl acrylate and stirring at 40° C. for at least 1 hour to produce the cyclization product;

(c) reacting the cyclization product to form a cyclopropanol compound by:

combining the cyclization product with ClT i (O i Pr) 3 or titanium tetrachloride/tetra n-butyl titanate (TiCl 4 ) to form a second solution; and

adding a Grignard reagent and mixing at about 0° C. for at least one hour and then to room temperature for at least 30 minutes to produce the cyclopropanol compound having the structure

(d) deprotecting the cyclopropanol compound to form a deprotected cyclopropanol compound by:

combining the cyclopropanol compound with anhydrous tetrahydrofuran (THF) to form a third solution and cooling to about 0° C.;

adding tetra-n-butylammonium fluoride (TBAF) and allowing the third solution to warm to room temperature; and

mixing the third solution for at least 43 hours to give the deprotected cyclopropanol compound having the structure

(e) hydrolyzing the deprotected cyclopropanol compound by combining the deprotected cyclopropanol compound with THF and HCl and stirring to form a hemi-acetal compound

(f) reacting the hemi-acetal compound by:

combining methyltriphenylphosphonium bromide (CH 3 PPh 3 Br) with anhydrous THF, and potassium hexamethyldisilazanide (KHMDS) and mixing at room temperature for at least 1 hour and, subsequently, mixing at about 0° C. for at least another 1 hour to form a cooled ylide solution;

combining the cooled ylide solution and a hemi-acetal solution comprising the hemi-acetal and THF; and

stirring the combined hemi-acetal and cooled ylide solution at about 0° C. for at least 37 minutes to form an olefin compound having the structure

(g) subjecting the olefin compound to a carbonylative spirolactonization reaction by:

to form a solution, combining and mixing (1) the olefin compound with anhydrous benzene or anhydrous THE, and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), and (2) palladium(II) acetate (Pd(OAc) 2 ) or palladium(II) trifluoroacetate (Pd(TFA) 2 ; and

quenching the solution with triethyl amine (TEA) and mixing for at least 30 minutes to produce a compound having an oxaspirolactone moiety having the structure

and

(h) combining the compound having an oxaspirolactone moiety with a solvent, dichloroethane (DCE) or THF, a molecule having a terminal olefin, and a Z-selective catalyst comprising Ru-Mes or DIPP, and allowing the resulting combination to mix for at least 2 hours at between 30-53° C. to produce tricyclic-PGDM methyl ester or a pharmaceutically acceptable salt thereof;

wherein the molecule having a terminal olefin has the structure

wherein R a is alkyl, alkenyl, heteroalkyl, heteroalkenyl, aryl, heteroaryl, or acyl.

2 . The method of claim 1 , wherein the Grignard reagent is selected from the group consisting of: ethyl magnesium bromide, methyl magnesium chloride, and methyl magnesium bromide.

3 . The method of claim 1 , further comprising quenching hydrolysis with K 2 CO 3 when at or about 5-10% of the deprotected cyclopropanol compound remains as detected by thin-layer chromatography (TLC).

4 . The method of claim 1 , further comprising concentrating the hemi-acetal compound with dichloromethane (DCM).

5 . The method of claim 1 , further comprising monitoring a reaction solution of step (f) to form the olefin compound using thin-layer chromatography (TLC) and quenching the Wittig reaction or olefination upon detection of a byproduct.

6 . The method of claim 1 , wherein the molecule having a terminal olefin is methyl 3-butenoate.