- Stereocontrolled organocatalytic synthesis of prostaglandin PGF 2α in seven steps
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Prostaglandins are hormone-like chemical messengers that regulate a broad range of physiological activities, including blood circulation, digestion and reproduction. Their biological activities and their complex molecular architectures have made prostaglandins popular targets for synthetic organic chemists for over 40 years. Prostaglandin analogues are widely used as pharmaceuticals and some, such as latanoprost, which is used to treat glaucoma, have become billion-dollar drugs. Previously reported syntheses of these compounds are quite lengthy, and every chemical step costs time and energy, generates waste and is accompanied by material losses. Using a new bond disconnection, here we report a concise synthesis of the most complex prostaglandin, PGF 2α, with high levels of control of relative and absolute stereochemistry, and fewer steps. The key step is an aldol cascade reaction of succinaldehyde using proline organocatalysis to create a bicyclic enal in one step and an enantiomeric excess of 98%. This intermediate bicyclic enal is fully primed with the appropriate functionality for attachment of the remaining groups. Access to this bicyclic enal will not only render existing prostaglandin-based drugs more affordable, but will also facilitate the rapid exploration of related chemical structures around the ubiquitous five-membered ring motif, such as potentially therapeutic prostaglandin analogues.
- Coulthard, Graeme,Erb, William,Aggarwal, Varinder K.
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p. 278 - 281,4
(2020/07/31)
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- Prostaglandins and Prostaglandin Intermediates. Part 26 A Novel Route to PGF2α using Triisopropoxy-hept-1-ynyl-titanium as Precursor for the β-Side Chain
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The benzoylated Corey aldehyde 1a can be alkynylated with hept-1-ynyl-triisopropoxytitanium in good chemical yield and high diastereoselectivity to the (R)-alcohol 3c admixed with about 10percent of the diastereomeric (S)-alcohol 2c.Without removal of thi
- Mahrwald, Rainer,Schick, Hans,Pivnitsky, Kasimir K.,Schwarz, Sigfrid
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p. 403 - 413
(2007/10/02)
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- BF3-MEDIATED REACTION OF A SULPHONE WITH ALDEHYDES. A METHOD FOR STEREOSPECIFIC CONSTRUCTION OF PROSTAGLANDIN ω-CHAIN
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A new method for stereospecific construction of the allylic alcohol moiety of prostaglandins, based on application of optically active α-hydroxy aldehydes, is described.In the presence of BF3*Et2O, lithiated sulphones 1 prepared from Corey aldehyde, and carbonyl compounds 2 give the corresponding adducts 3 in moderate to excellent yields, while in the absence of the Lewis acid either no products or only their traces were formed.The addition products 3, in the form of benzoates, mesylates or free alcohols, were subjected to reductive elimination by means of sodium amalgam to give the alkenes 4.Compounds 4d and 4f were transformed into racemic and natural PGF2α, respectively, in line with the known method.
- Achmatowicz, B.,Baranowska, E.,Daniewski, A. R.,Pankowski, J.,Wicha, J.
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p. 4989 - 4998
(2007/10/02)
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- Regio- and Stereoselectivity of the Reaction between Cyanocuprates and Cyclopentene Epoxides. Application to the Total Synthesis of Prostaglandins
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A systematic study of the reaction between cyclopentene epoxides and alkyl-, alkenyl-, and arylcyanocuprates is described.Alkylcyanocuprates react with complete regio- and stereoselectivity to provide trans-4-alkylcyclopent-2-enols in excellent yields.Vin
- Marino, Joseph P.,Pradilla, Roberto F. de la,Laborde, Edgardo
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p. 4898 - 4913
(2007/10/02)
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- A NOVEL APPROACH TO PROSTAGLANDINS FROM THE COREY LACTONE INVOLVING BF3-MEDIATED REACTIONS OF A SULPHONE AND ALDEHYDES
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Transformation of the diol 1 via epimeric sulphones 7 to PGF2α is described.Alkylation of lithiated sulphones 7 with aldehydes 8a, 8b or 8c in the presence of BF3 efficiently gives corresponding adducts.
- Achmatowicz, B.,Baranowska, E.,Daniewski, A. R.,Pankowski, J.,Wicha, J.
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p. 5597 - 5600
(2007/10/02)
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- Stereocontrolled Synthesis of Prostaglandins from Cyclopentadiene Monoepoxide
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Two complementary syntheses of prostaglandins from the same key intermediate 3, available in four steps from cyclopentadiene monoepoxide, are described.In one approach, a saturated α-chain is introduced via a 1,4-addition of an appropriately functionalized cyanocuprate reagent onto silyl enol ether 3.The resulting prostanoid compound was converted into the bronchodilator 1-decarboxy-1-hydroxymethyl PGE1, PGE1, and PGF1α.The second approach involves the transformation of silyl enol ether 3 into the known prostanoid precursor 11 via selective addition of carbethoxycarbene and subsequent fluoride-induced ring opening of the resulting (silyloxy)cyclopropane carboxylate ester.
- Marino, Joseph P.,Pradilla, Roberto Fernandez de la,Laborde, Edgardo
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p. 5279 - 5280
(2007/10/02)
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- Total Synthesis of Prostaglandin-F2α, and the 9-O-Benzyl Derivatives of Prostaglandins-F2α, -F1α, -D2, and -D1
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As an extension of the method whereby prostaglandin-F2α may be prepared by homoconjugate addition of an organocuprate reagent to the 3-endo-silyloxytricyclo2,7>heptan-6-one (3), 3-endo-benzyloxytricyclo2,7
- Cave,Richard J.,Newton, Roger F.,Reynolds, Derek P.,Roberts, Stanley M.
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p. 646 - 652
(2007/10/02)
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- Biosynthesis of a prostaglandin by a plant enzyme.
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Lipoxygenase-2 from soybeans catalyzes the oxygenation of arachidonic acid to form significant amounts of a prostaglandin product. Results obtained with the dithionite-reduced derivatized product upon combined gas chromatography-mass spectroscopy are consistent with structures of the stereoisomers of 9,11,15-trihydroxyprosta-5,13-dienoic acid. A portion of the material formed by reduction of the enzyme product with dithionite reacts positively in a radioimmunoassay against rabbit anti-prostaglandin F2alpha antibody. This appears to be the first report of the synthesis of a prostaglandin by a non-animal enzyme.
- Bild,Bhat,Ramadoss,Axelrod
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- Racemic fluoro-substituted PGF2 α analogs
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This invention is racemic PGE2, racemic PGF2α, racemic PGF2β, racemic PGA2, racemic PGB2, analogs of those, and processes for making them. These compounds are useful for a variety of pharmacological purposes, including anti-ulcer, inhibiton of platelet aggregation, increase of nasal patency, abortion, and wound healing.
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- Racemic prostaglandins of the 2-series and analogs thereof
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This invention is racemic PGE2, racemic PGF2α, racemic PGF2β, racemic PGA2, racemic PGB2, analogs of those, and processes for making them. These compounds are useful for a variety of pharmacological purposes, including anti-ulcer, inhibition of platelet aggregation, increase of nasal patency, abortion, and wound healing.
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- Racemic prostaglandins of the 2-series and analogs thereof
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This invention is racemic PGE 2, racemic PGF 2 α, racemic PGF 2 β, racemic PGA 2, racemic PGB 2, analogs of those, and processes for making them. These compounds are useful for a variety of pharmacological purposes, including anti-ulcer, inhibition of platelet aggregation, increase of nasal patency, abortion, and wound healing.
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