.alpha.-phosphonosulfonate squalene synthetase inhibitors and method

A method for forming an enantiomer of a phosphonosulfonate compound having the structure ##STR122## wherein R.sup.2 is OR.sup.5,

• R.sup.3 and R.sup.5 represents an alkali metal ion;
• R.sup.4 is an alkali metal ion;
• R.sup.1 is a lipophilic group containing at least 7 carbons;
• Z is H, halogen, lower alkyl or lower alkenyl, by any of the following processes:
• A) which comprises providing a methylphosphondiamide compound of the structure ##STR123## wherein R.sup.9 is alkyl or arylalkyl, treating the above diamide with a metalating agent to form an anion of the diamide,
• alkylating the anion of the diamide by treating with a halide of the structure
• R.sup.1 X
• where X is I, Cl, Br, tosylate, or CF.sub.3 SO.sub.3 --, to form the alkylated compound ##STR124## treating the above alkylated diamide with a metalating agent to form the metalated alkylated compound,
• subjecting the metalated alkylated compound to sulfuration with tetramethylthiuram disulfide, to form a mixture of isomers of the structures ##STR125## separating the isomers into the .alpha.-(S) isomer and .alpha.-(R) isomer, treating the desired isomer with an acid to form the desired diacid ##STR126## treating the diacid with an oxidizing agent and then with base to form the desired enantiomer ##STR127## where M is an alkali metal;
• or B) forming an enantiomer of said phosphonosulfonate compound, which comprises providing a methylphosphondiamide of the structure ##STR128## wherein R.sup.9 is alkyl or arylalkyl, treating the above diamide with a metalating agent to form the corresponding anion salt,
• treating the anion salt with sulfur and a dialkylthiocarbamoyl halide to form a dithiocarbamoylate of the structure ##STR129## treating the dithiocarbamoylate with a metalating agent to form the corresponding metalated compound,
• treating the so-formed metalated compound with an alkylating agent
• R.sup.1 X
• to form a mixture of isomers of the structure ##STR130## separating the isomers, treating the desired isomer with an acid to form the desired diacid ##STR131## treating the desired diacid with an oxidizing agent and then with base to form the desired enantiomer ##STR132## where M is an alkali metal;
• or C) forming an enantiomer of said phosphonosulfonate compound, which comprises providing a phosphorous diamide of the structure ##STR133## wherein R.sup.9 is alkyl, aryl or arylalkyl, treating the diamide with an aldehyde of the structure
• R.sup.1 --CHO
• and a silylating compound to form a mixture of protected isomers of the structures ##STR134## separating the isomers, reacting the desired isomer with a fluoride source to form a deprotected compound of the structure ##STR135## treating either deprotected isomer with dimethyldithiocarbamic acid, zinc salt and triphenylphosphine and diisopropylazodicarboxylate (DIAD) to form the isomer ##STR136## treating the desired isomer with an acid to form the desired diacid ##STR137## treating the desired diacid with an oxidizing agent and then with base to form the desired enantiomer ##STR138## where M is an alkali metal;
• or D) forming an enantiomer of said phosphonosulfonate compound, which comprises providing a phosphorous diamide of the structure ##STR139## wherein R.sup.9 is alkyl or arylalkyl, treating the diamide with an aldehyde of the structure
• R.sup.1 --CHO
• and a base including a fluoride source to form a mixture of isomers of deprotected compound of the structures ##STR140## separating the isomers, treating either deprotected isomer with dimethyldithiocarbamic acid, zinc salt, triphenyl-phosphine and DIAD to form the isomer ##STR141## treating the desired isomer with an acid to form the desired diacid ##STR142## treating the desired diacid with an oxidizing agent and then with base to form the desired enantiomer ##STR143## where M is an alkali metal;
• or E) forming an enantiomer of said phosphonosulfonate compound, which comprises providing an acid chloride of the structure ##STR144## reacting the acid chloride with the metalated anion ##STR145## (where R.sup.a is alkyl or cycloalkyl) to form ##STR146## treating the product with (alkyl).sub.4 N.sup..sym. I.sup..crclbar. to form the corresponding ammonium compound ##STR147## treating the above dealkylated compound with a metalating agent and then with an alkylating agent
• R.sup.1 X
• to form the alkylated compound ##STR148## treating the desired isomer with an acid and then with an ion exchange resin to form the desired enantiomer ##STR149## where M is an alkali metal;
• or F) forming an enantiomer of said phosphonsulfonate compound, which comprises treating an aldehyde of the structure
• R.sup.1 CHO
• where R.sup.1 is as defined in claim 1 with an (S,S)-diol ##STR150## in the presence of an acid catalyst to form the acetal of the structure ##STR151## treating the acetal with a trialkylphos-phite in the presence of titanium tetrachloride to form the alcohol ##STR152## treating the above alcohol with an oxidizing agent to form a compound of the structure ##STR153## treating the above with p-toluenesulfonic acid in the presence of dioxane to form the diester ##STR154## treating the above diester with triphenyl phosphine, dimethyldithiocarbamic acid, zinc salt and diisopropyl azodicarboxylate to form ##STR155## treating the above diester with a bromotrimethylsilane to form the diacid ##STR156## treating the diacid with an oxidizing agent and then with a strong base to form the desired enantiomer ##STR157## where M is an alkali metal.