Search

Prostaglandins have garnered significant attention from synthetic chemists due to their exceptional biological activities. In this report, we present a concise chemoenzymatic synthesis method for several representative prostaglandins, achieved in 5 to 7 steps. Notably, the common intermediate bromohydrin, a radical equivalent of Corey lactone, is chemoenzymatically synthesized in only two steps, which allows us to complete the synthesis of prostaglandin F 2α in five steps on a 10-gram scale. The chiral cyclopentane core is introduced with high enantioselectivity, while the lipid chains are sequentially incorporated through a cost-effective process involving bromohydrin formation, nickel-catalyzed cross-couplings, and Wittig reactions. This cost-efficient synthesis route for prostaglandins holds the potential to make prostaglandin-related drugs more affordable and facilitate easier access to their analogues., (© 2024. The Author(s).)

In the kidney, prostaglandins formed by cyclooxygenase 1 and 2 (COX-1 and COX-2) play an important role in regulating renal blood flow. In the present study, we report our observations regarding a unique modulatory effect of renal microsomal preparation on COX-1/2-mediated formation of major prostaglandin (PG) products in vitro. We found that microsomes prepared from pig and rat kidneys had a dual stimulatory-inhibitory effect on the formation of certain PG products catalyzed by COX-1 and COX-2. At lower concentrations, kidney microsomes stimulated the formation of certain PG products, whereas at higher concentrations, their presence inhibited the formation. Presence of kidney microsomes consistently increased the K m values of the COX-1/2-mediated reactions, while the V max might be increased or decreased depending on stimulation or inhibition observed. Experimental evidence was presented to show that a protein component present in the pig kidney microsomes was primarily responsible for the activation of the enzyme-catalyzed arachidonic acid metabolism leading to the formation of certain PG products.

Prostaglandins are among the most important natural isolates owing to their broad range of bioactivities and unique structures. However, current methods for the synthesis of prostaglandins suffer from low yields and lengthy steps. Here, we report a practicability-oriented synthetic strategy for the enantioselective and divergent synthesis of prostaglandins. In this approach, the multiply substituted five-membered rings in prostaglandins were constructed via the key enyne cycloisomerization with excellent selectivity (>20:1 d.r., 98% e.e.). The crucial chiral centre on the scaffold of the prostaglandins was installed using the asymmetric hydrogenation method (up to 98% yield and 98% e.e.). From our versatile common intermediates, a series of prostaglandins and related drugs could be produced in two steps, and fluprostenol could be prepared on a 20-gram scale.

In the total stereo-controlled synthesis of natural prostaglandins (PGs) and their structural analogs, a vast class of compounds and drugs, known as the lactones, are encountered in a few key steps to build the final molecule, as: δ-lactones, γ-lactones, and 1,9-, 1,11-, and 1,15-macrolactones. After the synthesis of 1,9-PGF 2α and 1,15-PGF 2α lactones, many 1,15-lactones of E 2 , E 3 , F 2 , F 3 , A 2 , and A 3 were found in the marine mollusc Tethys fimbria and the quest for understanding their biological role stimulated the research on their synthesis. Then 1,9-, 1,11-, and 1,15-PG lactones of the drugs were synthesized as an alternative to the corresponding esters, and the first part of the paper describes the methods used for their synthesis. The efficient Corey procedure for the synthesis of prostaglandins uses the key δ-lactone and γ-lactone intermediates with three or four stereocenters on the cyclopentane fragment to link the PG side chains. The paper describes the most used procedures for the synthesis of the milestone δ-Corey-lactones and γ-Corey-lactones, their improvements, and some new promising methods, such as interesting, new stereo-controlled and catalyzed enantioselective reactions, and methods based on the chemical/enzymatic resolution of the compounds in different steps of the sequences. The many uses of δ-lactones not only for the synthesis of γ-lactones, but also for obtaining 9β-halogen-PGs and halogen-substituted cyclopentane intermediates, as synthons for new 9β-PG analogs and future applications, are also discussed.

Prostaglandins have been attractive targets in total synthesis for over 50 years, resulting in the development of new synthetic strategies and methodologies that have served the broader chemical community. However, these molecules are not just of academic interest, a number of prostaglandin analogues are used in the clinic, and some are even on the WHO list of essential medicines. In this personal account, we describe our own approach to the family of prostaglandins, which centers around the synthesis of a key enal intermediate, formed from the l-proline catalysed dimerization of succinaldehyde. We highlight the discovery and further optimization of this key reaction, its scale up, and subsequent application to a range of prostaglandins., (© 2020 The Authors. Published by The Chemical Society of Japan & Wiley-VCH Verlag GmbH & Co. KGaA.)

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.

Re-investigation of the l-proline catalyzed double aldol cascade dimerization of succinaldehyde for the synthesis of a key bicyclic enal intermediate, pertinent in the field of stereoselective prostaglandin synthesis, is reported. The yield of this process has been more than doubled, from 14 % to a 29 % isolated yield on a multi-gram scale (32 % NMR yield), through conducting a detailed study of the reaction solvent, temperature, and concentration, as well as a catalyst screen. The synthetic utility of this enal intermediate has been further demonstrated through the total synthesis of Δ 12 -prostaglandin J 3 , a compound with known anti-leukemic properties., (© 2018 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

Modification of GO by organic molecules changes its catalytic activity in the hydrogen transfer from i-propanol to enones, affecting the selectivity to allyl alcohol and diastereoselectivity to the resulting stereoisomers. It is noteworthy the system does not contain metals and is recyclable.

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.

Prostaglandins (PGs) are a series of hormone-like chemical messengers and play a critical role in regulating physiological activity. The diversified therapeutic activities and complex molecular architectures of PGs have attracted special attention, and huge progress has been made in asymmetric total synthesis and discovery of pharmaceutically useful drug candidates. In the last 10 years, several powerful syntheses have emerged as new solutions to the problem of building PGs and represent major breakthroughs in this area. This review highlights the advances in methodologies for the asymmetric total synthesis of prostaglandins. The application of these methodologies in the syntheses of medicinally useful prostaglandins is also described. The study has been carefully categorized according to the key procedures involved in the syntheses of various prostaglandins, aiming to give readers an easy understanding of this chemistry and provide insights for further improvements.

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 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., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

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.

The first total synthesis of the marine prostanoids clavulolactones II and III is presented from an easily accessible chiral, non-racemic cyclopentenone intermediate. Key steps involve selective TBDMS deprotection, selective reduction of the β-side chain and aldol condensation. Clavulolactones II and III were successfully prepared from (S)-4-((tert-butyldimethylsilyl)oxy) cyclopent-2-en-1-one over nine steps, in overall yields of 21 and 7% respectively.

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.

The synthesis of both enantiomers of 4,5-dihydroxy-3-(formyl)cyclopent-2-enone acetonide (5) was accomplished in five steps starting from meso-tartaric acid (6). The key steps involved are preparation of the isopropylidene protected 3-[(dimethoxyphosphoryl)methyl]-4,5-dihydroxycyclopent-2-enone (9), resolution of the diastereoisomeric products 10 of the Horner reaction of racemic 9 with (R)-glyceraldehyde acetonide and the final regioselective ozonolysis of the exocyclic carbon–carbon double bond of the separated dienones 10 leading to both enantiomeric title compounds 5. The absolute configuration of both enantiomers was initially assigned based on the comparison of the chiroptical properties obtained from the DFT calculations with the experimental data and finally confirmed by X-ray analysis.

A catalytic asymmetric total synthesis of the potent and selective antileukemic Δ(12)-prostaglandin J3 (Δ(12)-PGJ3) is described. The convergent synthesis proceeded through intermediates 2 and 3, formed enantioselectively from readily available starting materials and coupled through an aldol reaction followed by dehydration to afford stereoselectively the cyclopentenone alkylidene structural motif of the molecule., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

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.

In a process associated with ageing and neurodegeneration, radical peroxidation of docosahexaenoic acid (DHA) in neurons affords a multitude of prostaglandin-like neuroprostanes in a non-regioselective and non-stereoselective manner. In this paper, the synthesis of racemic 17-A4-NeuroP and 14-A4-NeuroP validated a general approach to several regioisomeric cyclopentenone A4- and J4-NeuroPs needed for biological tests. In preliminary experiments 17-A4-NeuroP, in analogy with 14-A4-NeuroP, readily adducted GSH free thiol, suggesting a similar mechanism of action for biological activity., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

2,3-Dinorprostaglandins (dinor-PGs) have been regarded as β-oxidation products of arachidonic-acid-derived prostaglandins, but their biological activities in mammalian cells remain unclear. On the other hand, C18 polyunsaturated fatty acids (PUFAs), such as γ-linolenic acid (GLA), have various biological activities, and dinor-PGs are speculated to be biosynthesized from GLA. Here, we synthesized dinor-PGs that may possibly be derived from GLA and examined their activities towards peroxisome proliferator-activated receptors (PPARs). Dinor-PGD1 (1) and its epimer 13-epi-dinor-PGD1 (epi-1) were found to be dual agonists for PPARα/γ, whereas PGD2 derived from arachidonic acid is selective for PPARγ. Thus, GLA-derived dinor-PGs may have unique biological roles., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

To identify chemically and metabolically stable subtype-selective EP4 agonists, design and synthesis of a series of modified γ-lactam prostanoids has been continued. Prostanoids bearing 2-oxo-1,3-oxazolidine, 2-oxo-1,3-thiazolidine and 5-thioxopyrrolidine as a surrogate for the γ-hydroxycyclopentanone without a troublesome 11-hydroxy group were identified as highly subtype-selective EP4 agonists. Among the tested, several representative compounds demonstrated in vivo efficacy after oral dosing in rats. Their pharmacokinetic and structure-activity relationship studies are presented., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Cu(I)-catalysed [2 + 2] photocycloaddition of 1,6-dienes embedded in a furano sugar is described in connection to a synthetic approach to an abnormal marine prostanoid tricycloclavulone. An unprecedented influence of remote substituents on the reactivity and stereoselectivity of the photocycloaddition reaction has been uncovered during this investigation. While an alkene substituent inhibits cycloaddition through steric effects, a substituent having a hydroxyl or alkoxy group at the same location facilitates cycloaddition exclusively from its own side. This investigation has led to the synthesis of a functionalised 5,4-fused core unit of tricycloclavulone.

The ability of natural prostaglandins (PGs) and synthetic prostanoids of B, H and E(1)-types to prevent CCl(4)-induced liver injury in vitro was examined. Seven analogs of PGB, 3 derivatives of PGH and two 11-deoxy-analogs of PGE(1) decreased cytotoxic index of CCl(4) by 2-fold and were more effective then such well-known hepatoprotectors as silymarin, curcumin and PGI(2). These prostanoids reduced trien conjugates formation by 25-95% and strongly prevented LDH leakage through plasma membrane. The results from the structure-activity relationship (SAR) analysis can be summarized as follows: (1) the presence of 2-pyridyl at the 15 position of ω-chain plays the main role in cytoprotection for synthetic analogs of PGH; (2) among 11-deoxy-analogs of PGE(1) the most active substances possess the phenyl residue at C-15 connected with C-13 isoxazolin or C-13 isoxazol; (3) C-13 cyclohexylamine or C-15 phenyl groups in ω-chain and metoxy-group in α-chain are important for protective activity of PGB analogs; (4) synthetic analogs of PGB demonstrate more pronounced cytoprotective properties than prostanoids of H and E-types. This information suggests paths for further exploration in the area of hepatoprotection and the design of novel therapeutic agents., (Copyright © 2010 Elsevier Inc. All rights reserved.)

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).

Aim: The elucidation of mechanism of A-type synthetic prostanoids inhibitory action on microsomal cytochrome P(450)2E1 (CYP2E1) from rat liver activity was carried out., Results: Analogs U-34 and U-26 in a final concentration of 1 x 10(-5)M inhibited CYP2E1 activity by 93% and 46%, respectively; however natural prostaglandins had no effect. These synthetic prostanoids of A-type (5 x 10(-8) to 10(-4)M) inhibited chlorzoxazone hydroxylation in a dose-dependent manner while IC(50)=7.1 x 10(-7)M and 8.0 x 10(-7)M for U-26 and U-34, respectively. The curves of CYP2E1 activity in the presence of different concentrations of chlorzoxazone and varying concentration of prostanoids were hyperbolic. Double-reciprocal plots of these results 1/V=f(1/S) indicated that prostanoids inhibit CYP2E1 through a competitive mechanism with particular effect., Conclusion: CYP2E1 is a target for A-type prostanoids, possessing 2-oxo-4-amino-oct-3(E)-enyl in alpha- or omega-chain, which are able to inhibit its action through a competitive mechanism.

Methods of synthesis of prostaglandin fluorides were developed and their properties were investigated. These compounds were shown to be convenient synthetic precursors for obtaining esters and amides of natural prostaglandins and their fluorodeoxy analogues.

The review of works of the authors devoted to the synthesis of low-molecular bioregulators with the use of unsaturated sugars is presented. The schemes of synthesis of insect pheromones and acetogenins and glycosphingolipids on the basis of glycals are discussed. The pathways of synthesis of triterpene 2-deoxy-alpha-glycosides are shown. The synthesis of prostanoids from levoglucosenone is considered.

[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.

Solid-phase chemistry, first introduced for peptide synthesis in the 1960's, has become an integral part of organic synthetic methodology. Presented herein is an overview of recent examples of the use of solid-phase in the preparation of non-peptidic natural products and related compounds, encompassing on-resin total syntheses as well as the use of polymer-supported reagents in solution.

[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 synthesis of a series of brominated cross-conjugated dienones, marine prostanoid analogues, was considered using two cyclopentannelation processes, from enamine (by a domino 3-aza Claisen/Mannich reaction) and from dioxolane ester alkylation followed by intramolecular Wittig reaction. All the compounds synthesized featured the same cross-conjugated dienone system, with a vicinal syn or anti diol on the omega-chain. The replacement of the omega-side-chain of the natural prostanoids with a 1-hydroxyphenyl-butyl moiety gave new prostanoids (32-34) with good cytotoxicities. In a second series of products, the possibility of a shorter alpha-side-chain bearing a simple phenyl ester was investigated. The results indicated a dramatic increase in the cytotoxicity (39, 40, 43, 44). Finally, in a third series, the omega-1-hydroxyphenyl-butyl was replaced by a 1-hydroxymethyloxybenzyl chain. These simpler compounds (45, 46, 47, 48, 60) are still highly cytotoxic, in the medium range of 60 nM, close to the value of natural punaglandins.

A novel series of 15-fluoro prostaglandins with phenoxy termination of the omega-chain was synthesized and evaluated for binding and functional activation of the prostaglandin FP receptor in vitro and for side effect potential and topical ocular hypotensive efficacy in vivo. Compounds with the 15alpha-fluoride relative stereochemistry displayed EC50 values of

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.

Nowadays, about 150 natural products comprising an allenic or cumulenic structure are known. The chemistry of these compounds has turned out to be a very attractive and prolific area of interest: advances in the isolation and characterization of new allenic natural products have led to the establishment of efficient synthetic procedures which in many cases also open up an access to enantiomerically pure target molecules. Inspired by the intriguing biological activities of many allenic natural products, allene moieties are now systematically introduced in pharmacologically active classes of compounds (steroids, prostaglandins, amino acids, nucleosides). The functionalized allenes thus obtained often exhibit impressive activities as mechanism-based enzyme inhibitors, cytotoxic, or antiviral agents. A prerequisite for further developments in this field is the efficient stereoselective synthesis of allene derivatives.

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.

This paper describes parallel and comparative experiments on the enzymatic cyclooxygenase (COX) driven conversion of arachidonic acid (AA, all-cis-5,8,11,14-eicosatetraenoic acid) into prostaglandins by using pure arachidonic acid and AA samples containing relatively small amounts of thiyl radical induced trans-isomers. The experiments were performed in a liquid aqueous model system using COX-1 as well as by the in vitro feeding of VD(3)-differentiated and LPS-stimulated promyelocytic HL-60 cells using the cell's own COX-2. In the model solution, all the different test methods used (oxygen consumption, ROS induced luminescence, and TMPD oxidation) indicated the greatly disproportionate, non-stoichiometric inhibition of the prostaglandin metabolism by the trans-isomers. Accordingly, measurements performed in the cell system gave comparable results: both luminescence ROS detection and the ELISA test on PGE(2) expression resulted in the strong inhibition of the prostaglandin metabolism. We interpret these findings as enzyme blocking caused by just one mono-trans-isomerized double bond of AA.

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).

The in vitro evaluation of a series of saturated prostaglandins revealed that compounds with omega chain aromatic rings retain nanomolar potency for the human prostaglandin F receptor (hFP receptor), exemplified by compound 8. In contrast, the double bonds are required for activity in the series with an acyclic omega chain as in PGF2alpha.

An asymmetric synthesis of prostanoids containing a six-membered ring core structure (11a-homoprostaglandins), both in solution and using non-cross-linked polystyrene (NCPS) as a soluble support, was developed. Target molecule 1 was generated in a convergent fashion using a three-component coupling strategy, wherein chiral enone (R)-2 was the precursor of the central ring and the cuprate 3 and triflate 4 were used to introduce the side chains. The chiral center of (R)-2 directed the facial selectivity of the conjugate addition reaction which then dictated the stereochemical outcome of the subsequent alpha alkylation. Attachment of a six-membered ring scaffold to NCPS facilitated purification without compromising synthetic yields, still allowed 1H-NMR analysis of the intermediates in the synthesis, and provided an avenue for the construction of six-membered ring prostanoid libraries.

Natural products cover a diversity space not yet available from synthetic libraries, with an unrivalled success rate as drug leads. The combinatorial synthesis of non-oligomeric natural-product-based libraries, however, is still limited to few examples because access to easily modified units strongly depends on the availability of a core structure either from a natural source, or through a suitable synthetic route. Only a few resourceful groups have managed the latter approach for more demanding multifunctional natural drug leads, such as epothilones.

[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.

We have synthesized a series of novel 1-isoindolinone derivatives, which inhibited the contraction of pig coronary artery induced by U-46619, a thromboxane A2 analog.

Isoprostanes are a new class of natural products formed in humans as a result of free-radical-catalyzed lipid peroxidation of polyunsaturated fatty acids. These endogenous compounds are isomeric with biologically active prostaglandins and have great promise as markers of oxidant stress in vivo. iPF2alpha-III (previously 8-iso-PGF2alpha), an isoprostane from Class III (previously known as Class IV), has been used as an index of free-radical-induced oxidative stress. This isoprostane is also produced by the cyclooxygenase enzymes COX1 and COX2. We are proposing a new reliable index of oxidative stress based on iPF2alpha-VI (previously IPF2alpha-I), a new Class VI isoprostane we recently discovered. The advantages of iPF2alpha-VI are that it is several fold more abundant in urine than iPF2alpha-III, hence allowing more accurate determinations. Equally, the proximity of the C-5 OH function to the carboxylic acid allows the formation of the lactone 35 which is easier to purify from other iPs which cannot form such lactones. We have performed the first total synthesis of d4-iPF2alpha-VI by using two synthons, (3,3,4,4-d4)-hexylphosphonium bromide 23 prepared from 5-hexynol and syn-anti-syn lactone 25 synthesized from d-glucose. We have developed two variants of a sensitive GC/MS assay using the synthetic d4-iPF2alpha-VI as an internal standard to determine the levels of endogenous iPF2alpha-VI in biological fluids. Quantification of iPF2alpha-VI formed in vivo may be a more reliable index to assess oxidant stress in humans., (Copyright 1998 Academic Press.)

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.

13-Dehydro derivatives of prostaglandin E1, E2, E3, F1 alpha and F2 alpha were synthesized. Compared with natural prostaglandins, 13-dehydro analogues were found to exhibit more potent inhibitory activity against human platelet aggregation and relaxation of guinea-pig isolated trachea, while they showed less potent activity of contraction of guinea-pig isolated ileum.