Cyclopentenone prostaglandins

Tius and co-workers elegantly applied a variant of the Nazarov reaction to the preparation of cyclopentenone prostaglandins (Scheme 19.39) [46]. Moreover, it was demonstrated that the chirality of non-racemic allenes is transferred to an sp3-hybridized carbon atom. Preparation of allenic morpholinoamide 214 and resolution of the enantiomers by chiral HPLC provided (-)- and (+)-214. Compound (-)-214 was exposed to the vinyllithium species 215 to afford a presumed intermediate which was not observed but spontaneously cyclized to give (+)- and (—)-216 as a 5 1 mixture. Compound (+)-216 was obtained with an 84% transfer of chiral information and (-)-216 was obtained in 64% ee. The lower enantiomeric excess of (—)-216 indicates that some Z to E isomerization took place. This was validated by the conversion of 216 to 217, where the absolute configuration was established. The stereochemical outcome of this reaction has been explained by conrotatory cyclization of 218 in which the distal group on the allene rotates away from the alkene to give 216. 

Kondo, M., Oya-Ito, T., Kumagai, T., Osawa, T., and Uchida, K. Cyclopentenone prostaglandins as potential inducers of intracellular oxidative stress. J. Biol. Chem. 276 2001 12076-12083. 

Short chain aldehydes Cyclopentenone prostaglandins Electrophilic oxo-derivates Oxidized phospholipids Nitrated fatty-acids... 

Satoh, T., Furuta, K., Tomokiyo, K., Namura, S., Nakatsuka, D., Sugie, Y., Ishikawa, Y., Hatanaka, H., Suzuki, M., and Watanabe, Y. 2001. Neurotrophic actions of novel compounds designed from cyclopentenone prostaglandins. 77, 50-62. 

A domino process of enamine 136 formation, N-allylation, aza-Claisen rearrangement and a final Mannich condensation was introduced by Florent [22g]. Aldehyde 135 was subsequently treated with pyrrolidine and allyl iodide 137 to give an E/Z mixture of the ammonium salts 138. Heating to 80 °C induced the Claisen rearrangement. The newly formed iminium ions 139 underwent intramolecular Mannich cycUzations. The final amine eUmination delivered the spiro ketones 140 with 38% yield as a 2 1 mixture of diastereomers. The formed material should serve as a key compound in diverse cyclopentenone prostaglandine total syntheses (Scheme 10.30). 

Rossi, A., Kapahi, P., Natoli, G., Takahashi, T., Chen, Y., Karin, M., and Santoro, M. G. (2000). Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IkB kinase. Nature 403, 103-108. 

Strans, DS and Glass, CK (2001) Cyclopentenone prostaglandins new insights on biological activities and cellular targets. Med Res Rev, 21, 185-210. 

The Julia-Lythgoe olefination and Kocienski modification have applied broadly in the synthesis of nature products. Isoprostane of A2 and h are isomeric of the cyclopentenone prostaglandins A2 and J2, respectively, which are reported to exert unique biological effects. Prostaglandins of A2 and J2 series have been reported to be active against a wide variety of DNA and RNA viruses, including HIV-1 and influenza virus. They also possess a potent anti-inflammatory activity due to the inhibition and modification of the subunit IKKP of the enzyme IA B kinase. Zanoni and co-workers reported the first total synthesis of A2 Isoprostane 101 employed a stereoselective Julia-Lythgoe olefination in the formation of C 13 14 double bond. The intermediate 99, obtained in 87% yield by addition of sulfone 97 to aldehyde 98, was reduced by Na(Hg) to alkene 100 in 81% yield. 

Review Problem 14 Cyclopentenones (e.g. TM 190) occur in nature and are important in prostaglandin synthesis. How would you make this one ... 

Alkenylation of cyclopentenone with the alkenylstannane 719 has been used for the introduction of an a,>-chain into a prostaglandin derivative[590]. Even the vinyl mesylate (methanesulfonate) 720 can be used for coupling with alkenylstannanes[59l]. 

The Michael acldiQon of rutromethane to cyclopentenone clenvaQves is used for synthesis of prostaglandins fScheme 4 20 Here, the aruon of rutromethane is used as a formyl aruon synthon... 

In a study concerned with the synthesis of prostaglandins, it was reported that the anion of 3-phenylsulfinyl-l-octene underwent addition to 2-cyclopentenone to give a y-1,4-adduct (57%), which appeared to be a single diastereomer by 13C NMR16... 

The Michael addition of nitromethane to cyclopentenone derivatives is used for synthesis of prostaglandins (Scheme 4.20).158 Here, the anion of nitromethane is used as a formyl anion synthon. 

These predictions correspond closely to the experimental observations and the mechanism suggested in the literature 74>. The conversion of furans to cyclopentenones is used industrially to obtain intermediates for the synthesis of insecticides, prostaglandins, perfumes, and compounds for energy storage 75 ... 

This example does not illustrate the highest yield application of this chemistty. Coupling of 1-octyne and cyclopentenone was selected because these materials are commercially available and because this coupling exemplifies, in a prototypical fashion, the application of this powerful chemistry to prostaglandin synthesis. Several additional examples are presented in the original publication.3... 

An efficient kinetic resolution of 4-hydroxy-2-cyclopentenone was achieved using [kh((/ )-UINAI))(CIIjOHl JCKT as catalyst.1 The reaction proceeded with a 5 1 discrimination rate between the two enantiomers, and (.S l-isoincr, which is a useful intermediate in prostaglandin synthesis, was obtained with 91% ee at 72% conversion (Scheme 31).54... 

Optically active cyclopentanes are useful structural units for many natural products such as steroids, terpenoids, and prostaglandins, but the development of highly enantioselective catalytic 1,4-addition reactions to 2-cyclopentenones has proved to be a challenging goal. Besides the very low stereoselectivities, a major problem with this substrate is the... 

The first catalytic 1,4-addition of diethylzinc to 2-cyclopentenone with over 90% ee was described by Pfaltz and Escher, who used phosphite 54 with biaryl groups at the 3,3 -positions of the BINOL backbone.46 Chan and co-workers achieved high enantioselectivity in the same reaction (up to 94% ee) by using chiral copper diphosphite catalyst (R,R,R)-41 48,48a 48d Hoveyda and co-workers used ligand 46 to realize excellent enantiocontrol (97% ee) in the 1,4-additions of 2-cyclopentenones,52 which may be used in the practical asymmetric synthesis of some substituted cyclopentanes (including prostaglandins). 

In a similar manner, Brummond et al. demonstrated the first total synthesis of 15-deoxy-A12,14-prostaglandin J2 (162) that was completed using a silicon-tethered allenic Pauson-Khand reaction to obtain the highly unsaturated cyclopentenone substructure [36]. Treatment of alkynylallene 160 with molybdenum hexacarbonyl and dimethyl sulfoxide affords the desired cycloadduct 161 in 43% yield (Scheme 19.30). Trienone 161 was obtained as a 2 1 Z E mixture of isomers in which the Z-isomer could be isomerized to the desired E-isomer. The silicon tether was cleaved and the resulting product converted to 15-deoxy-A12,14-prostaglandin J2 (162). 

Scheme 6.2. Diastereoselective addition of a functionalized cuprate to cyclopentenone 14 in the synthesis of prostaglandin E2 (PGE2) (TBS = t-butyidimethylsilyl,...

---