Total Synthesis of Δ¹²‐Prostaglandin J₃: Evolution of Synthetic Strategies to a Streamlined Process

Abstract

The total synthesis of Δ(12) -prostaglandin J3 (Δ(12) -PGJ3 , 1), a reported leukemia stem cell ablator, through a number of strategies and tactics is described. The signature cross-conjugated dienone structural motif of 1 was forged by an aldol reaction/dehydration sequence from key building blocks enone 13 and aldehyde 14, whose lone stereocenters were generated by an asymmetric Tsuji-Trost reaction and an asymmetric Mukaiyama aldol reaction, respectively. During this program, a substituent-governed regioselectivity pattern for the Rh-catalyzed C-H functionalization of cyclopentenes and related olefins was discovered. The evolution of the synthesis of 1 from the original strategy to the final streamlined process proceeded through improvements in the construction of both fragments 13 and 14, exploration of the chemistry of the hitherto underutilized chiral lactone synthon 57, and a diastereoselective alkylation of a cyclopentenone intermediate. The described chemistry sets the stage for large-scale production of Δ(12) -PGJ3 and designed analogues for further biological and pharmacological studies.

Reoptimization of the Organocatalyzed Double Aldol Domino Process to a Key Enal Intermediate and Its Application to the Total Synthesis of Δ12‐Prostaglandin J3

“…In order to construct Δ 12 ‐PGJ 3, disconnection of the C12−C13 bond through an aldol/dehydration reaction sequence would require β‐boryl aldehyde 8 and enone 9 (Scheme B). This type of aldol/dehydration strategy was originally reported by Kobayashi and has subsequently been applied to the syntheses of Δ 12 ‐PGJ 3 3 , and other closely related prostaglandins . Boryl aldehyde 8 was selected as a masked hydroxy aldehyde equivalent because it can be easily prepared by catalytic enantioselective conjugate borylation, and subsequently unmasked later in the synthesis by stereospecific oxidation of the boronic ester.…”

Empowering Synthesis of Complex Natural Products

“…D 12 -Prostaglandin J 3 (Nicolaou, 2016) The prostaglandin natural productsh ave captured the minds of chemists for years, with many synthetic strategies developed to access them in as calablem anner. [51] However,t here is still room for improvement as af ragment-based synthesis would allow for even greater scalability.…”

“…Nicolaou and coworkers developed as treamlined synthesis of D 12 -prostaglandin J 3 (172)t hat would allow for variability and scalability. [53] Opening of epoxide 173 with lithium acetylide under Lewis acidic conditions with concomitantTBS protection commenced the synthesis on 12.1 gs cale to yield protectedd iol 174 (A14). The resultant alkyne was reduced with nickel boride to form the desired Z-olefin of the natural product.…”

“…A treatment that targets CSCs would increase life expectancy and reduce the chance for reemergence of the cancers. Nicolaou and co‐workers developed a streamlined synthesis of Δ 12 ‐prostaglandin J 3 ( 172 ) that would allow for variability and scalability …”

The Evolution and Impact of Total Synthesis on Chemistry, Biology and Medicine

“…This promise coupled with the severe scarcity of the molecule prompted us to undertake its chemical synthesis. From the several total syntheses we developed in our attempts to optimize the process, the one summarized in Figure (from building blocks A – C through intermediates 57 – 62 ) was the most streamlined and practical . Our objective was not only to render this compound readily available for further biological investigations but also to apply our developed strategies and technologies to synthesize designed analogues of Δ 12 ‐PGJ 3 for biological investigations as part of a drug discovery and development program.…”