Enantioselective Synthesis of 15-Deoxy-Δ^12,14-Prostaglandin J₂

Abstract

An enantioselective synthesis of 15-deoxy-Δ12,14-prostaglandin J2 is reported. The synthesis begins with the preparation of enantiopure 3-oxodicyclopentadiene by a lipase-mediated kinetic resolution. A three-component coupling followed by a retro-Diels–Alder reaction provides the C8 stereochemistry of the prostaglandin skeleton with high enantioselectivity. Stereoretentive olefin metathesis followed by a Pinnick oxidation affords 15-deoxy-Δ12,14-prostaglandin J2 in high enantiopurity.

An enantiodivergent synthesis of N-Boc-protected (R)- and (S)-4-amino cyclopent-2-en-1-one

“…2 This type of prostaglandin possesses an interesting biological profile and attempts to explore how the structure of this compound affects its activity are hampered because it is not amenable to ready synthetic divergence from an advanced intermediate. [3][4][5][6][7][8][9][10] In relation to this point, we demonstrated that incorporation of a nitrogen atom at the 4-position in the cyclopentenone enabled ready modification of the α-prostanoid side chain. 2 In addition, alkylidination/arylidination was successfully used to instal the unsaturated exocyclic side chain present in the natural product analogue 1.…”

A Single-Atom Upgrade to Polydicyclopentadiene

“…Monomer 4 m (oxaDCPD) was synthesized in one step from dicyclopentadiene ( 1 m ), using 0.01 mol % of a commercially available photocatalyst ( meso -tetraphenyl­porphyrin) and employing air as the stoichiometric oxidant (Scheme ). Other groups have described the photocatalytic production of 4 m from DCPD but have always used oxygen gas as the oxidant; ,− optimization of the reaction toward the use of air in place of O 2 was done with the goal of improving scalability and operator safety. While the synthesis of 4 m proceeded smoothly and in near-quantitative conversion on a 10 g scale using optimized conditions (resulting in a 73% isolated yield), the reaction rate decreased substantially on larger scale due to the inability of light to penetrate into the dark-colored reaction mixture.…”

“…Seeking to combine the positive attributes of 2 (easy monomer synthesis) and 3 (desirable polymer properties), while eliminating the disadvantages noted above (e.g., the use of toxic oxidants or the need to purify away regioisomers at the monomer stage), we were attracted to the possibility of polymerizing dicyclopentadien-1-one (oxaDCPD; 4 m ). Ketone 4 m has long been known (in both endo and exo diastereomeric forms) as an intermediate in complex-molecule synthesis, − but its polymerization by ring-opening metathesis polymerization (ROMP) methods has not previously been described. − Compellingly, the one-step oxidation of DCPD ( 1 m ) to 4 m has been reported previously under photocatalytic conditions and is known to afford only a single regioisomer of the target compound, in good yield. − If this reaction could be adapted toward large-scale production, it could provide an attractive monomer synthesis that is both economically and environmentally sustainable. Moreover, if polymerization of 4 m were to proceed similarly to the previously known functionalized monomers 2 m and 3 m , this could afford a novel functionalized polydicyclopentadiene ( 4 p and/or 4 p,c ) that has a somewhat increased surface energy relative to the parent PDCPD (due to the polar ketone group), while also encoding a useful synthetic handle for further derivatization and avoiding the labile allylic alcohol (or allylic ester) functionality that limited the high-temperature performance and T g in polymer 2 p .…”

Metathesis Reactions in Natural Product Fragments and Total Syntheses

“…Grubbs, Stoltz, and co‐worker reported the concise enantioselective synthesis of 15d‐prostaglandin J 2 1027 (Scheme 159). [341] In this synthetic strategy, stereoretentive CM was one the crucial steps employed to couple two major fragments in Z ‐stereoselective manner. Three components reaction between enone 1021 , aldehyde 1022 and allylmagnesium bromide followed by elimination with MsCl/DMAP resulted in the formation of bicyclic enone 1023 , which upon EtAlCl 2 ‐mediated retro‐Diels‐Alder reaction afforded a CM precursor 1024 .…”