A simple synthesis of (+)-isocarbacyclin via a convergent process

Abstract

A convergent and practical synthesis of (+)-isocarbacyclin has been accomplished, incorporating novel methods for linking (Y and o appendages with a chiral bicyclo[3.3.0]octane nucleus.

Diastereotopos-differentiating C–H activation reactions at methylene groups

“…Regioselective and diastereoselective carbene insertion was also applied to the synthesis of (+)-isocarbacyclin and its analogues. [11][12][13] Diazo esters rac-7 were intramolecularly cyclised in the presence of 2 mol% of sterically demanding dirhodium(II)tetra(triphenylacetate) [Rh 2 (tpa) 4 ] catalyst to afford products rac-8 exclusively as cis diastereoisomers in good yields (eqn (4)). ð4Þ Doyle et al showed that diazoacetates 9 and ent-9 derived from (À)-menthol and (+)-menthol furnished under reflux in benzene in the presence of 1 mol% of Rh 2 (OAc) 4 stereochemically pure bicyclic products 10 and ent-10 in very good yields (Scheme 2).…”

Synthetic approaches to isocarbacyclin and analogues as potential neuroprotective agents against ischemic stroke

“…Both molecules were synthesized by several groups with diverse approaches, however, most were 20 or more steps with the shortest reported syntheses requiring 15 steps. [25][26][27][28][29][30][31][32][33][34][35][36][37] Isocarbacyclin (2) possesses a bicyclo[3.3.0]octene system with four contiguous stereocenters and two side chains; an octenol ω-side chain and an α-side chain that contains the pentanoic acid connected to the endocyclic alkene. 4 Synthetic challenges, including the construction of the bicyclic ring system and regioselectivity of both the endocyclic double bond (C6-C9α) and the αsidechain, are some of the difficulties that must be surmounted in the synthetic approaches.…”

α-Vinylation of 1,3-Dicarbonyl Compounds with Alkenyl(aryl)iodonium Tetrafluoroborates: Effects of Substituents on the Aromatic Ring and of Radical Inhibitors

“…Alkenyllead triacetates are highly labile and undergo relatively fast reductive elimination of lead(II) acetate, yielding an alkyne or an enol acetate. , Rapid generation of alkenyllead triacetates (<2 min in most cases), however, makes the α-vinylation of carbonyl compounds possible . Ikegami and Hashimoto in their elegant synthesis of (+)-isocarbacyclin relied on this direct vinylation of β-keto esters as a key step …”

“…10 Ikegami and Hashimoto in their elegant synthesis of (+)-isocarbacyclin relied on this direct vinylation of β-keto esters as a key step. 11 Because of an excellent nucleofugality of a phenyliodonio group, which shows a leaving group ability about 10 6 times greater than triflate, 12 alkenyl(phenyl)iodonium salts serve as the highly activated species of alkenyl halides in nucleophilic vinylic substitution reactions with a number of nucleophiles, such as organocuprates, sulfinates, thiolates, nitrites, halides, cyanides, azides, and phosphines. [13][14][15][16] Few studies of the reaction of alkenylphenyliodonium salts with enolate anions are available.…”