Prostanoids synthetic

The necessity for producing large amounts of synthetic prostaglandins and analogs provided the impetus for a number of improvements in the bicyclo[2.2.1]heptene approach. Especially important was the development of an enantioselective modification for the synthesis of chiral prostanoids without resolution (1975) and the invention of a chiral catalyst for the stereocontrolled conversion of 15-keto prostanoids to either 15(5)- or 15(7 )- alcohols. 

Significant synthetic advantage has been attained from the already mentioned sequence 8- 9- -11. This sequence, based on the appropriate lithium cuprate 6 and the alkyl halide JT7, was successfully used for the preparation of diastereomeric 11-deoxy-9-prostanoids 1 8. The natural trans-configuration of the prostanoids was obtained by alkylation of the intermediate complex in the presence of hexamethylphosphorous triamide. It seems likely that the observed alteration of stereochemistry is closely con-... 

At the commencement of the project there were several routes available for the synthetic construction of prostanoid compounds our challenge was which to choose. For this, we were mindful of the stereochemical features of the molecule and the need for a full stereochemical characterization of the active pharmaceutical ingredient (API) produced. This was required in the regulatory submissions,... 

Serious drawbacks of the natural occurring compounds however do not allow their general use in therapy. The rapid metabolic deactivation21-25 and the too wide range of activity are the main problems which have to be overcome. The development of other clinical applications awaits further progress in prostanoid research and this meant a challenge to the synthetic chemists to develop chemical total syntheses which could effectively compete with biosynthesis and which could be easily modified in order to prepare analogs with improved selectivity and stability to metabolic deactivation. 

Many groups of synthetic chemists have succeeded in the meantime in solving the problem of total synthesis of the natural prostanoids by developing more or less elegant routes303 3ob 31 33). The total synthesis developed by Corey34) however which has been modified in many ways35) is without doubt the most successful and most commonly used synthetic method in the prostanoid field. 

This collection begins with a series of three procedures illustrating important new methods for preparation of enantiomerically pure substances via asymmetric catalysis. The preparation of 3-[(1S)-1,2-DIHYDROXYETHYL]-1,5-DIHYDRO-3H-2.4-BENZODIOXEPINE describes, in detail, the use of dihydroquinidine 9-0-(9 -phenanthryl) ether as a chiral ligand in the asymmetric dihydroxylation reaction which is broadly applicable for the preparation of chiral dlols from monosubstituted olefins. The product, an acetal of (S)-glyceralcfehyde, is itself a potentially valuable synthetic intermediate. The assembly of a chiral rhodium catalyst from methyl 2-pyrrolidone 5(R)-carboxylate and its use in the intramolecular asymmetric cyclopropanation of an allyl diazoacetate is illustrated in the preparation of (1R.5S)-()-6,6-DIMETHYL-3-OXABICYCLO[3.1. OJHEXAN-2-ONE. Another important general method for asymmetric synthesis involves the desymmetrization of bifunctional meso compounds as is described for the enantioselective enzymatic hydrolysis of cis-3,5-diacetoxycyclopentene to (1R,4S)-(+)-4-HYDROXY-2-CYCLOPENTENYL ACETATE. This intermediate is especially valuable as a precursor of both antipodes (4R) (+)- and (4S)-(-)-tert-BUTYLDIMETHYLSILOXY-2-CYCLOPENTEN-1-ONE, important intermediates in the synthesis of enantiomerically pure prostanoid derivatives and other classes of natural substances, whose preparation is detailed in accompanying procedures. 

Numerous synthetic applications of the intermolecular Pauson-Khand reaction have been reported. Pauson has reported a number of very direct applications of cycloadditions of ethylene in the synthesis of prostanoids and jasmone analogs (e.g. equations 15 and This is a reliable entry to 2-sub-... 

Homoconjngate addition to cyclopropanes. Corey and Fuchs have investigated the reaction of cyclopropanes with organocopper reagents as a possible synthetic route to prostanoids. For example, the tricyclic lactone ester (1) reacts with divinylcopper-lithiura (2.0 eq.) in ether at -12° (19 hr.) to give the vinylcyclopentane lactone ester (2). Tliis product was treated directly with lithium iodide (5 eq.) in pyridine (1,615-616) at reflux for 3 hr. to give the lactone (3) in about 37% yield. 

Eicosanoids, also referred to as icosanoids, are so named because of the 20-carbon constituency that identifies this class of oxygenated lipid molecules. A primary synthetic pathway for these molecules involves the phospholipase-mediated cleavage of a membrane phospholipid to produce arachidonic acid [(all-Z)-ik osa-5,8,ll,14-tetraenoic acid]. From this biologically essential intermediate fatty acid, two major subclasses of eicosanoids can be produced 1) leukotrienes, via the action of lipooxygenases, and 2) prostanoids, via the action of cyclooxygenases (COX-1 and COX-2). Examples of chemical structures for a leukotriene (Fig. la) and three types of prostanoids (Fig. Ib-d) underscore their shared arachidonate origin. 

A new initiative is a prostaglandin analogue latanoprost, a synthetic derivative of PGFja, used topically in open-angle glaucoma and ocular hypertension in patients unresponsive to other drugs (see prostanoid receptor AGONIST), antihaemophilic factor factor VIII. 

Froben " flurbiprofen, froxiprost [inn] (ONO 995) is a prostaglandin and synthetic analogue of dinoprost, and is a ( elective FP) PROSTANOID RECEPTOR AGONIST, active in contracting uterine smooth muscle. It is used as a pharmacological tool, frusemide [ban] (furosemide [inn.jan. usan) Fursemide Lasix etc.) is a (loop) DIURETIC which can be used as an ANITHYPERTENSIVE and to treat pulmonary oedema. 

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