The stereocontrolled synthesis of phthalic acid 4,5-cis-dihydrodiol and the total synthesis of thiarubrine A.

The stereocontrolled synthesis of the extremely labile 4,5-cis-dihydrodiol metabolite (1,2-dihydroxy-4,5-dicarboxy-3,5-cyclohexadiene) of phthalic acid has been achieved in a highly efficient manner in seven steps. Diels-Alder reaction of di-2-(trimethylsilyl)ethyl fumarate with furan, followed by cis-dihydroxylation and protection of the cis-diol furnishes di-2-(trimethylsilyl)ethyl 5,6-dihydroxy-7-oxabicyclo(2.2.1) heptane-2,3-dicarboxylate acetonide. Base effected regioselective ether ring opening followed by introduction of the second double bond via the mesylate, and deprotection of the acetonide group with iodine produces di-2-(trimethylsilyl)ethyl cis-5,6-dihydroxy-1,3-cyclohexadiene-2,3-dicarboxylate. Finally, tetrabutylammonium fluoride mediated cleavage of the 2-(trimethylsilyl)ethyl group affords phthalic acid 4,5-cis-dihydrodiol, whose spectroscopic data are in complete agreement with those of the intermediate from metabolic reaction. This synthesis constitutes an unambiguous assignment of the structure and stereochemistry of the microbial metabolite of phthalic acid. An efficient, generally applicable method for the synthesis of a variety of 3,6-disubstituted 1,2-dithiins has been established. The method involves the regio- and stereoselective bisaddition of alkylthiols to 1,4-disubstituted 1,3-butadiyne at room temperature in N,N-dimethylformamide in the presence of potassium hydroxide catalyst. Subsequent removal of the thiol-protecting group with lithium in liquid ammonia at $-78\sp\circ\rm C$ followed by oxidative ring closure of the resulting dilithium dithioenolates with iodine provides the red-colored 1,2-dithiins. The above methodology has been applied to the first total synthesis of an antibiotic natural product thiarubrine A. The polyenyne side chains have been constructed by utilizing Corey-Fuchs' method of alkyne synthesis and $\rm Pd\sp0$ catalyzed coupling of alkyne with vinyl bromide. The unsymmetry of side chains has been efficiently introduced by monomethylation of a symmetric diacetylenic dianion. 2-(Trimethylsilyl)ethyl has been utilized as a protecting group for dithioenol, which can be oxidized to the dithiin ring by iodine after the deprotection under fluoride conditions. This total synthesis of thiarubrine A is achieved efficiently in eight overall steps.PhDChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/104225/1/9501069.pdfDescription of 9501069.pdf : Restricted to UM users only