A concise and scalable chemoenzymatic synthesis of prostaglandins.

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 F2α 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.

Concise, scalable and enantioselective total synthesis of prostaglandins.

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.

Lactones in the Synthesis of Prostaglandins and Prostaglandin Analogs.

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-PGF2α and 1,15-PGF2α lactones, many 1,15-lactones of E2, E3, F2, F3, A2, and A3 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 9ß-halogen-PGs and halogen-substituted cyclopentane intermediates, as synthons for new 9ß-PG analogs and future applications, are also discussed.

Modulation of Enzyme-Catalyzed Synthesis of Prostaglandins by Components Contained in Kidney Microsomal Preparations.

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 Km values of the COX-1/2-mediated reactions, while the Vmax 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.

Prostaglandin Total Synthesis Enabled by the Organocatalytic Dimerization of Succinaldehyde.

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.

Concise Syntheses of Δ12-Prostaglandin J Natural Products via Stereoretentive Metathesis.

Δ12-Prostaglandin J family is recently discovered and has potent anticancer activity. Concise syntheses of four Δ12-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.

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

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 Δ12 -prostaglandin J3 , a compound with known anti-leukemic properties.

Graphene oxide as a catalyst for the diastereoselective transfer hydrogenation in the synthesis of prostaglandin derivatives.

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: A General Strategy for Efficient Stereoretentive Catalytic Olefin Metathesis. The Concept, Methodological Implications, and Applications to Synthesis of Biologically Active Compounds.

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.

Recent advances in asymmetric total synthesis of prostaglandins.

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.

Rh(I)-Catalyzed 1,4-Conjugate Addition of Alkenylboronic Acids to a Cyclopentenone Useful for the Synthesis of Prostaglandins.

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 PGF2α (dinoprost) and tafluprost.

Total Synthesis of Δ(12) -Prostaglandin J3 : Evolution of Synthetic Strategies to a Streamlined Process.

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.

Synthesis of Chiral Cyclopentenones.

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.

First total synthesis of the marine natural products clavulolactones II and III.

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 ß-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.

General strategy for the synthesis of B1 and L1 prostanoids: synthesis of phytoprostanes (RS)-9-L1-PhytoP, (R)-9-L1-PhytoP, (RS)-16-B1-PhytoP, and (RS)-16-L1-PhytoP.

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 ß, 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.

Synthesis and the absolute configuration of both enantiomers of 4,5-dihydroxy-3-(formyl)cyclopent-2-enone acetonide as a new chiral building block for prostanoid synthesis.

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 carbon­carbon 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.

Total synthesis of Δ¹²-prostaglandin J3, a highly potent and selective antileukemic agent.

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.

A unified stereodivergent strategy for prostaglandin and isoprostanoid synthesis.

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.

Biology and chemistry of neuroprostanes. First total synthesis of 17-A4-NeuroP: validation of a convergent strategy to a number of cyclopentenone neuroprostanes.

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.

Synthesis and evaluation of 2,3-dinorprostaglandins: Dinor-PGD1 and 13-epi-dinor-PGD1 are peroxisome proliferator-activated receptor α/γ dual agonists.

2,3-Dinorprostaglandins (dinor-PGs) have been regarded as ß-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.