ASYMMETRIC-SYNTHESIS OF ISOCARBACYCLIN BASED ON THE OLEFINATION-ISOMERIZATION-COUPLING PROCESS WITH CHIRAL SULFOXIMINES

An asymmetric synthesis of isocarbacyclin (2) was achieved from ketone 7 by the olefination-isomerization-coupling process with chiral sulfo ximines. The vinylic sulfoximine 6 (greater than or equal to 98% de) w as prepared from ketone 7 and lithiosulfoximine 8 by an asymmetric ole fination via an addition-elimination process. Model experiments, aimin g at a rationalization of the asymmetric induction in the elimination of hydroxysulfoximines, with ketone 12 and lithiosulfoximine ent-8 rev ealed formation of the silyl ether 15 as an intermediate which elimina ted LiOSiMe3 upon reaction with nBuLi under formation of (S,Z)-alkene 17 (greater than or equal to 98% de). Reaction of the C,O-dilithiosulf oximine 19 with ClSiMe3 led to elimination of LiOSiMe3 and also gave 1 7 (greater than or equal to 98% de). Methylation of 19, however, furni shed the corresponding alpha-methyl-substituted beta-hydroxysulfoximin es, 20 and 21, in a ratio of 75:25. Isomerization of sulfoximine 6 gav e the allylic sulfoximine 5 (96% de) whose absolute configuration was determined by X-ray structure analysis. Cross-coupling reaction of 5 w ith cuprate 23 delivered with high regioselectivity alkene 25. A simil ar reaction of 5 with the organocopper reagent 26, which was prepared from (benzyloxy)methylmagnesium chloride, in the presence of BF3. OEt2 and halide afforded alkene 27. Ketone 28 is a potential starting mate rial for the asymmetric synthesis of 3-oxaisocarbacyclin. Besides alke nes 25 and 27 sulfinamide 24 (97% ee), whose conversion to 8 has been already described, was isolated in 90% yield. The key step in the sequ ence leading to the construction of the omega-side chain was the depro tonation of ketone 4b with a complex of lithium (R,R)-bis(alpha-phenyl ethyl)amide and Lithium chloride, 29.LiCl, which gave enolate 3. The u se of ent-29.LiCl in deprotonation of 4b afforded the isomeric enolate 30. Enolates 3 and 30 were trapped as the silyl ethers 31 (90% ie) an d 32 (92% ie), respectively. The aldol reaction of 3 with (E)-octenal proceeded highly selective in regard to C-12 but unselective in regard to C-13 and gave aldols 34 (42%) and epi-34 (36%). It was at the stag e of the aldol reaction of 3 where the unwanted diastereomers 35 and e pi-35, stemming from 30, could be separated. Reduction of ketones 34 a nd epi-34 afforded diols 36 (greater than or equal to 98% de) and 37 ( 93% de), respectively. The Pd-catalyzed rearrangement of the allylic d iacetates 39 and 41 was highly stereoselective (greater than or equal to 98% de) but incomplete and led to formation of mixtures of 40 and 3 9 as well as of 42 and 41 in ratios of 84:16 and 86:14, respectively. A two-step oxidation of alcohol 43, contaminated by 5% of the isomeric alcohol stemming from acetate 39, via aldehyde 44 gave after purifica tion by crystallization isocarbacyclin (2) in 38% yield. Diol 45, havi ng the undesired (15R) configuration, was selectively oxidized with di chlorodicyanobenzoquinone to enone 46 (81%).