ISSN:
1434-193X
Keywords:
Isocarbacyclin
;
Asymmetric olefination
;
Allylic sulfoximine
;
Cross-coupling reaction
;
Chiral lithium amide
;
Chemistry
;
General Chemistry
Source:
Wiley InterScience Backfile Collection 1832-2000
Topics:
Chemistry and Pharmacology
Notes:
An asymmetric synthesis of isocarbacyclin (2) was achieved from ketone 7 by the olefination-isomerization-coupling process with chiral sulfoximines. The vinylic sulfoximine 6 (≥98% de) was prepared from ketone 7 and lithiosulfoximine 8 by an asymmetric olefination via an addition-elimination process. Model experiments, aiming at a rationalization of the asymmetric induction in the elimination of β-hydroxysulfoximines, with ketone 12 and lithiosulfoximine ent-8 revealed formation of the silyl ether 15 as an intermediate which eliminated LiOSiMe3 upon reaction with nBuLi under formation of (S,Z)-alkene 17 (≥98% de). Reaction of the C, O-dilithiosulfoximine 19 with ClSiMe3 led to elimination of LiOSiMe3 and also gave 17 (≥98% de). Methylation of 19, however, furnished the corresponding α-methyl-substituted β-hydroxysulfoximines, 20 and 21, in a ratio of 75:25. Isomerization of sulfoximine 6 gave the allylic sulfoximine 5 (96% de) whose absolute configuration was determined by X-ray structure analysis. Cross-coupling reaction of 5 with cuprate 23 delivered with high regioselectivity alkene 25. A similar 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 material for the asymmetric synthesis of 3-oxaisocarbacyclin. Besides alkenes 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 sequence leading to the construction of the ω-side chain was the deprotonation of ketone 4b with a complex of lithium (R,R)-bis(α-phenylethyl)amide and lithium chloride, 29 · LiCl, which gave enolate 3. The use of ent-29 · LiCl in the deprotonation of 4b afforded the isomeric enolate 30. Enolates 3 and 30 were trapped as the silyl ethers 31 (90% ie) and 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 stage of the aldol reaction of 3 where the unwanted diastereomers 35 and epi-35, stemming from 30, could be separated. Reduction of ketones 34 and epi-34 afforded diols 36 (≥98% de) and 37 (93% de), respectively. The Pd-catalyzed rearrangement of the allylic diacetates 39 and 41 was highly stereoselective (≥98% de) but incomplete and led to formation of mixtures of 40 and 39 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 purification by crystallization isocarbacyclin (2) in 38% yield. Diol 45, having the undesired (15R) configuration, was selectively oxidized with dichlorodicyanobenzoquinone to enone 46 (81%).
Type of Medium:
Electronic Resource
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