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Δ 12 -Prostaglandin J family is recently discovered and has potent anticancer activity. Concise syntheses of four Δ 12 -prostaglandin J natural products (7-8 steps in the longest linear sequences) are reported, enabled by convergent stereoretentive cross-metathesis. Exceptional control of alkene geometry was achieved through stereoretention.

In situ methylene capping is introduced as a practical and broadly applicable strategy that can expand the scope of catalyst-controlled stereoselective olefin metathesis considerably. By incorporation of commercially available Z-butene together with robust and readily accessible Ru-based dithiolate catalysts developed in these laboratories, a large variety of transformations can be made to proceed with terminal alkenes, without the need for a priori synthesis of a stereochemically defined disubstituted olefin. Reactions thus proceed with significantly higher efficiency and Z selectivity as compared to when other Ru-, Mo-, or W-based complexes are utilized. Cross-metathesis with olefins that contain a carboxylic acid, an aldehyde, an allylic alcohol, an aryl olefin, an α substituent, or amino acid residues was carried out to generate the desired products in 47-88% yield and 90:10 to >98:2 Z:E selectivity. Transformations were equally efficient and stereoselective with a ∼70:30 Z-:E-butene mixture, which is a byproduct of crude oil cracking. The in situ methylene capping strategy was used with the same Ru catechothiolate complex (no catalyst modification necessary) to perform ring-closing metathesis reactions, generating 14- to 21-membered ring macrocyclic alkenes in 40-70% yield and 96:4-98:2 Z:E selectivity; here too, reactions were more efficient and Z-selective than when the other catalyst classes are employed. The utility of the approach is highlighted by applications to efficient and stereoselective syntheses of several biologically active molecules. This includes a platelet aggregate inhibitor and two members of the prostaglandin family of compounds by catalytic cross-metathesis reactions, and a strained 14-membered ring stapled peptide by means of macrocyclic ring-closing metathesis. The approach presented herein is likely to have a notable effect on broadening the scope of olefin metathesis, as the stability of methylidene complexes is a generally debilitating issue with all types of catalyst systems. Illustrative examples of kinetically controlled E-selective cross-metathesis and macrocyclic ring-closing reactions, where E-butene serves as the methylene capping agent, are provided.

An efficient and trans-diastereoselective Rh(I)-catalyzed 1,4-conjugate addition reaction of alkenylboronic acids and a homochiral (R)-4-silyloxycyclopentenone useful for the synthesis of derivatives of prostaglandins E and F is described for the first time. The reaction functions under mild conditions and is particularly rapid (≤6 h) under low power (50 W) microwave irradiation at 30 °C in MeOH in the presence of a catalytic amount of KOH. Under these conditions, 3 mol % of [RhCl(COD)] 2 is typically required to produce high yields. The method also functions without microwave irradiation at 3 °C in the presence of a stoichiometric amount of KOH. Under these conditions, only 1.5 mol % of [RhCl(COD)] 2 is needed, but the reaction is considerably slower. The method accepts a range of aryl- and alkyl-substituted alkenylboronic acids, and its utility has been demonstrated by the synthesis of PGF 2α (dinoprost) and tafluprost.

The cyclopentenone unit is a very powerful synthon for the synthesis of a variety of bioactive target molecules. This is due to the broad diversity of chemical modifications available for the enone structural motif. In particular, chiral cyclopentenones are important precursors in the asymmetric synthesis of target chiral molecules. This Review provides an overview of reported methods for enantioselective and asymmetric syntheses of cyclopentenones, including chemical and enzymatic resolution, asymmetric synthesis via Pauson-Khand reaction, Nazarov cyclization and organocatalyzed reactions, asymmetric functionalization of the existing cyclopentenone unit, and functionalization of chiral building blocks.

In this paper we describe a novel general synthetic approach to B1- and L1-type phytoprostanes, which are formed in vivo from free-radical-catalyzed nonenzymatic peroxidation of α-linolenic acid (1). The synthesis of phytoprostanes (RS)-9-L1-PhytoP (5), (R)-9-L1-PhytoP (5a), (RS)-16-B1-PhytoP (6), and (RS)-16-L1-PhytoP (7) exemplifies this strategy. The common starting compound 8 has been proved to be synthetically equivalent to a cyclopent-2-en-1-one synthon having opposite donor and acceptor properties at carbons α and β, respectively. Key steps include the chemoselective lithiation of a 1-iodo-2-bromoolefin, the introduction of the side chains by transition-metal catalysis following Heck- or Suzuki-type protocols, the construction of an enone moiety by a mild Au(I)-catalyzed Meyer Schuster rearrangement, and a lipase-mediated hydrolysis of methyl esters to deliver the phytoprostanes as free carboxylic acids.

Acetoxyfulvene surrended to asymmetric Diels-Alder cycloaddition, paving the way to the development of a unified strategy for the stereodivergent synthesis of both prostaglandins and isoprostanoids. In fact, the cycloadduct was subsequently converted to a common intermediate, which through two different stereoselective pathways afforded the two lactones 1 and 2, which are key building blocks in the synthesis of prostaglandins and isoprostanoids, respectively.

A new approach to the synthesis of prostaglandin and phytoprostanes B(1) is described. The key step is an intermolecular Pauson-Khand reaction between a silyl-protected propargyl acetylene and ethylene. This reaction, promoted by NMO in the presence of 4 A molecular sieves, afforded the 3-tert-butyldimethylsilyloxymethyl-2-substituted-cyclopent-2-en-1-ones (III) in good yield and with complete regioselectivity. Deprotection of the silyl ether, followed by Swern oxidation, gave 3-formyl-2-substituted-cyclopent-2-en-1-ones (II). Julia olefination of the aldehydes II with the suitable chiral sulfone enabled preparation of PPB(1) type I and PGB(1).

[reaction: see text] The total synthesis of racemic clavubicyclone (1), which was isolated from Okinawan soft coral by our group, is described. The bicyclo[3.2.1]octane skeleton was prepared by Cope rearrangement of a divinylcyclopropane derivative. Three functional groups on the skeleton were constructed by Barton decarboxylation, Wittig reaction, and alkylation.

[reaction: see text] The [4 + 3]-cycloadduct derived from the reaction of 2,5-dibromocyclopentanone with cyclopentadiene was converted via a quasi-Favorskii rearrangement and ring-opening, ring-closing metathesis sequence to the carbocyclic core of the prostanoid tricycloclavulone.

The first total synthesis of (+)-tricycloclavulone having a unique tricyclo[5,3,0,01,4]decane skeleton and six chiral centers was achieved in a highly stereoselective manner. It includes a catalytic enantioselective [2+2]-cycloaddition reaction using novel chiral copper catalyst, extremely effecting an intramolecular ester transfer reaction, and asymmetric reduction of the carbonyl group on the alpha-chain using Noyori's chiral ruthenium catalyst.

A practical methodology for the synthesis of J-type prostaglandins has been developed starting from the well-consolidated approaches established for the synthesis of A-type prostaglandins. An efficient 1,3-allylic transposition of the C-9 hydroxyl group of intermediate 4 furnished the advanced precursor 5 for J(2) synthesis. Our optimized A-J swap protocol employed selenium chemistry, involving the [2,3] sigmatropic rearrangement of secondary allylic selenoxide 11a.

To construct a new strategy for synthesis of cyclopentanoids, the transition metal-catalyzed coupling reaction of cis 4-cyclopentene-1,3-diol monoacetate 1 with hard nucleophiles, R(T)-m, was investigated (eq 1 in Chart 1). Although preliminary experiments using PhZnCl, PhSnMe(3), [Ph-B(Me)(OCH(Me)CH(Me)O)]-Li(+) (6a) (derived from boronate ester 4a (R(T) = Ph) and MeLi) in the presence of a palladium or a nickel catalyst resulted in production of unidentified compounds, enone 16, and/or ketone 17 or recovery of 1, a new borate 5a (derived from 4a and n-BuLi) in the presence of a nickel catalyst (NiCl(2)(PPh(3))(2)) in THF at room temperature furnished the trans coupling products 2a (R(T) = Ph) and 3a (R(T) = Ph) in high combined yield, but with a low product ratio of 0.9:1. The ratio was improved to 13:1 by addition of t-BuCN and NaI into the reaction mixture. This is the first successful example of the reaction of 1 with a hard nucleophile, and the increase in the ratio, realized with the additives, is unprecedented. This reagent system (borate 5 (1.2-1.8 equiv), NiCl(2)(PPh(3))(2) (5-10 mol %), t-BuCN (2-5 equiv), NaI (0.5-1 equiv), THF, room temp) was further investigated with aryl borates 5b-g and alkenyl borates 5h-n to afford 2b-n in moderate to good yields (52-89%) with practically acceptable levels of the regioselectivity (5 approximately 21:1), thus establishing the generality of the reaction (Table 2, eqs 6 and 7). Starting with the products of the coupling reaction, syntheses of the prostaglandin intermediates 13 and 14 (for 11-deoxy-PGE(2) and PGA(2)) and Delta(7)-PGA(1) methyl ester (15) were accomplished efficiently. During these investigations, LDA, LiCA, and LHMDS were found to be equally efficient bases for aldol reaction at the alpha' (alpha prime) position of cyclopentenones 39, 40, and 41 (Table 3).

[formula: see text] The prostaglandins are potent natural products taking part in many biological processes. The "convergent generation of diversity" from a "toolbox" of prostanoid components, augmented with additional polymer-supported transformations, can enable construction of valuable libraries. A parallel-pool strategy was used to assemble a small library of prostanoids. The inhibition of a herpes-family virus demonstrated the potential for new drug discovery.

microolecular design can overcome the metabolic instability of Delta7-PGA1, while maintaining its antitumor potency. Saturation of the C(13)-C(14) double bond enhances the biological stability but decreases the antiproliferative activity. Configurational inversion of the isomerase-sensitive C(12) stereocenter from the natural S to the unnatural R geometry not only enhances biological stability but also significantly suppresses the growth of the tumor cells. The 12R derivatives markedly increase the induction of p21, a Cdk inhibitor, leading to sharp cell cycle arrest at the G1 phase at a dose level so low that at this dose Delta7-PGA1 methyl ester scarcely exerts an effect. These conspicuous biological properties lead to long-term suppression of tumor cell growth. The structure-stability relationship demonstrates that the stability of prostaglandins (PGs) is crucially controlled by the C(12) configuration and is unaffected by the geometry of the hydroxy-bearing C(15). The successful design of antitumor PGs resistant to enzymatic metabolism provides a new strategy applicable to creating a useful PG for cancer chemotherapy.

A 4-fluoro analogue of enisoprost was prepared and evaluated for gastric antisecretory and mucosal protective activity in animals. The synthesis centered upon cuprate chemistry but also involved a Wittig reaction to produce a cis fluoro olefinic moiety, a furan rearrangement/isomerization reaction to provide the necessary hydroxycyclopentenone, and a two-carbon-homologation procedure. The fluoro analogue was much less potent as a gastric antisecretory and mucosal protective agent than enisoprost.

Certain structural similarities between prostaglandins with close-packed side chains and the perhydrocyclopentanophenanthrene nucleus of steroids prompted the synthesis and biological evaluation of 6beta, 17 beta-dihydroxy-5alpha-androstane-2alpha-carboxylic acid (30), its 6-deoxy derivative 28, and the corresponding 6-deoxy-2beta derivative 29 in an attempt to evaluate carbocyclic acids as potential prostaglandin analogs. Preliminary in vitro studies on isolated guinea pig ileum have shown weakly specific, prostaglandin-stimulated smooth muscle antagonism for 28 when compared with antagonism of bradykinin- and acetylcholine-induced contractions. Complete dose-response curves for 28 on prostaglandin-stimulated guinea pig ileum have shown a reduction in the maxium response and a decrease in the slope of the curve, indicating a noncompetitive type of inhibition for this type of derivative.

The synthesis is described of a series of acylhydroxyalkanoic acids which embody structural modifications of that class of secoprostaglandins which are formally derived from the natural substances by scission of the cyclopentane ring between carbon atoms 11 and 12. These analogues have been tested for their ability to stimulate cAMP formation in the mouse ovary, a characteristic action of the (E)-prostaglandins, and for their ability to bind to the rat lipocyte prostaglandin receptor. Certain members of the series that most closely resemble the prostaglandins in structure (e.g., 8-acetyl-12-hydroxyheptadecanoic acid) markedly stimulate cAMP formation at concentrations in the pharmacological range and show a significant affinity for the prostaglandin receptor. Conversely, these compounds are not substrates for prostaglandin 15-hydroxydehydrogenase which catalyzes a major reaction in the biological deactivation of the prostaglandins.

In the search for prostaglandin-like structures capable of exerting specific and desirable biological properties, a variety of simple heterocyclic homoprostanoidal derivatives was synthesized from readily available stearic acid derivatives. Compounds 5b and 5e were found to be more than 100 times as potent as PGE1 and PGE2 in a tracheal chain bioassay and, like 6, 9, and 12, inhibited PGE2-induced diarrhea. Derivatives 6 and 7a showed significant PG-synthetase inhibitor activity.

Simplified prostaglandin analogs were prepared and tested for inhibition of gastric acid secretion. An alkyl moiety of 1-8 carbon atoms was substituted for the C-13 to C-20 chain of the PG's. Analog variations included shortened and lengthened acid side chains, beta-oxidation blockage, beta-ketol, Falpha-hydroxyl, and cyclohexanone substitution. Maximal inhibitory activity was obtained with the shorter alkyl moieties.