Sequential Pd(0)-, Rh(I)-, and Ru(II)-Catalyzed Reactions in a Nine-Step Synthesis of Clinprost

Abstract

A step-economical synthesis of clinprost is reported that concludes with 3 different transition metal-catalyzed reactions: Pd-catalyzed decarboxylation with allylic rearrangement, Rh-catalyzed diene-ene [2+2+1] reaction, and Ru-catalyzed cross-metathesis reaction. The complexity bestowed to the molecule from these reactions converts a readily accessible ester to clinprost without using protecting groups in only 9 total steps.

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

“…The step-economical synthesis of clinprost (3) reported by the Croatt Group was further optimized to make isocarbacyclin's bicyclic building block (11, Scheme 1), which was made in only 6 steps from commercially available materials. 40 This route was designed to enable latestage diversification by using a cross-metathesis reaction of different commercially available alkenes to afford isocarbacyclin and different analogues. The synthesis of the core begins by reacting excess pimelic acid (4) with bis-allylic alcohol (5) to generate monoester 6 as a major product, followed by an aldol condensation with acrolein.…”

“…39 3) in only 9 total steps utilizing inexpensive and commercially available starting materials. 4,40 This synthetic route was used, with several optimizations presented herein, to synthesize isocarbacyclin (2) and new bicyclic analogues in which the ω-side chain was diversified at a late stage in the synthesis using different alkenes. Moreover, efforts toward the synthesis of tricyclic analogues will be described herein by a different synthetic approach using the same metal-catalyzed key reactions used in the synthesis of isocarbacyclin.…”

Decarboxylative and dehydrative coupling of dienoic acids and pentadienyl alcohols to form 1,3,6,8-tetraenes

“…It is rare to use a pentadienyl electrophile [35], or to have a diene or simple alkene adjacent to the carboxyl group [20,36–39]. Despite the absence of this type of reactivity, the decarboxylative coupling of a pentadienyl dienoate ( 9 ; Scheme 2) was desirable enough for our group’s synthesis of clinprost that we attempted the reaction [40–41]. Fortunately, this coupling reaction was successfully employed in our reported nine-step synthesis of clinprost [41].…”

“…Despite the absence of this type of reactivity, the decarboxylative coupling of a pentadienyl dienoate ( 9 ; Scheme 2) was desirable enough for our group’s synthesis of clinprost that we attempted the reaction [40–41]. Fortunately, this coupling reaction was successfully employed in our reported nine-step synthesis of clinprost [41]. A structurally related compound ( 11 ) reacted similarly, however, the sorbate derivative ( 13 ) was low yielding with the majority of the material only rearranging to the linear ester.…”

Pot-Economical Total Synthesis of Clinprost

“…Control of the stereogenic centers and regioselective formation of the endocyclic alkene are the other key issues. Because of its important biological properties, there have been several syntheses of clinprost ( 1 ) . Shibasaki and Ikegami reported the first synthesis of clinprost ( 1 ) from the intermediate of prostaglandins, employing the pinacol coupling reaction as a key step, and also developed several other synthetic routes.…”