Eine Totalsynthese der enantiomerenreinen 19-Nor-Steriode Ostron (la), 19-Norandrost-4-en-3.17-dion (Za), Ostradiol-17b (3a) und 19-Nortestosteron (4a) wird beschrieben. Sie folgt dem A + D +AD +ABCD-Aufbauprinzip, durchlauft ein lichtinduziertes, kinetisch instabiles o-Chinodimethan-Derivat und verwendet den chiralen Synthesebaustein (R)-2-Vinyl-l,1 -cyclopropandicarbonsaure-dimethylester (12b). 12b ist durch eine Asymmetrie induzierende ScW-Reaktion (s. Abb. 2) bequem zuganglich. Bei der Synthese fallt 12b enantiomerenrein an. Das analytische Procedere offenbart, daD 12b mit einer optischen Reinheit oder mit einem EnantiomerenUberschuR jeweils von 95% tustande kommt. Asymmetric Total Synthesis of 19-Nor-Steroids V~Q a Photochemical Key Reaction: Enanliomerically Pure Target Compounds 1.3)A total synthesis of the enantiomerically pure 19-nor-steroids estrone (la), 19-norandrost-4-en-3.17-dione (2a), estradiol-170 (3a), and 19-nortestosterone (4a) is described. It follows the A + D -AD-ABCD sequence, proceeds via a kinetically unstable o-quinodimethane derivative obtained in a light induced reaction, and employs the chiral synthetic building block dimethyl ( R ) -2-vinyl-l , 1-cyclopropanedicarboxylate (12b). The latter is easily accessible by an asymmetry inducing SCNr reaction. During the synthetic procedure it is isolated enantiomerically pure. The analytic procedure reveals that 12b is formed with an optical purity or an enantiomeric excess, respectively, of 95%. Nach den racemischen nun die enantiomerenreinen 19-Nor-SteroideEine Totalsynthese der racemischen 19-Nor-Steroide rac-la bis rac-4a (s. Schema 1) wurde kiirzlich *) ausfiihrlich beschrieben. Sie ging von wohlfeilen Industriechemikalien aus, enthielt eine photochemische Schlusselreaktion und folgte dem A + D +AD -ABCD-Aufbauprinzip: Zwei Synthesewurzeln miindeten in einen Synthesestamm, der sich zu den diversen Zielverbindungen vermeigte (s. Abb. 1).Kernstuck der fruheren Mitteilung waren die beiden Transformationen, bei denen die diseco-steroidale Schlusselverbindung rac-9a zum entsprechenden Photo-Enol rac-10 und dieses zu den steroidalen Cycloaddukten rac-7b und rac-8b isomerisierten (s. Schema 2).
4] Under the conditions chosen (vide inJra), the thermodynamically more stable of the two enolate anions of the D ring component adds, in extremely regioselective manner, to (12). The (CH,),Si ligand ensures that the reaction also produces rac-(lO) in extremely high stereoselectivity. m-Cresol methyl ether (3-melhylanisole) is brominated analogously to 3ethylanisole: D. J. Nelson, E. A Uschak, J. Org. Chem. 42, 3308 (1977).[5][6] A. Ottolenghi, M. Friedkin, A . Zrlkha, Can. J. Chem 41. 2977 (1963.[7] rac-/8), R =C2Hr. was synthesized by R. W . Kzersread, R. P. Linsfead, B. C. L Weedon, J. Chem. SOC. 1952,3613; we adopted to procedure of J. M. Stewart, G. K. Pagenkopf, J. Org. Chem. 34, 7 (1969), but used (61, R=CH,. Concerning nucleophilic ring opening of cyclopropane derivatives activated by electron acceptors, see S. Danishefsky, Acc. Chem. Res. 12, 66 (1979).[8] The diastereomer of rac-(5) having 2-configurated 9.10-double bond traverses mainly that transition structure in which the dienophilic vinyl group approaches the o-quinonoid dienic moiety from the @-side, from the ex0 orientation: this affords rac-(3). A competition reaction, of admittedly subordinate proportions, proceeds via that transition structure in which the vinyl group approaches the diene unit from the a-side, from the endo orientation- this gives rac-(14). rac-(3) and roc-(14) are separated only for identification. mc-(2) and rac-(l5) are separated only for identification. The mixture rac-(2) + rac-(15) is reduced by potassium in liquid ammonia in the presence of aniline and then oxidized by chromic acid to give rac-(l), The mixture rac-(2) + roc-(IS) is reduced by potassium in liquid ammonia in the presence of aniline and then treated with diisobutylaluminum hydride rac-(16); R = H: J.-C. Hilscher, DBP 2409991 (1976); Schering; Chem. Abstr. 84, 59862v (1976). The mixture rac-(2) + rac-(l5) is converted by Birch reduction into rac-(17) [by analogy with the procedure of W. S. Johnson, W. A. Vredenburgh, J. E. Pike. J. Am. Chem. SOC. 82, 3409 (1960)l.Since mc-(l0) undergoes at least 61% conversion into [roc-(2) + rac-(l5)], the overall yield of this mixture is 22% for m-cresol methyl ether and 12% for (E)-l.4-dibromo-2-butene or dimethyl malonate.
Albert Eschenmoser zum 60. Geburtstag gewidmet (9.1V.85) Total-Synthesis of (-)-Norgestrel (-)-Norgestrel (la) or (-)-norethindrone (Ib), two active progestational ingredients of currently used contraceptives have been synthesized stereoselectively. Compound l a has been obtained starting from m-cresol methyl ether, dimethyl malonate, and (E)-1,4-dibromo-2-butene. The steroid skeleton has been constructed using an intramolecular Diets-Alder reaction of an o-quinodimethane derivative preceeded by a photo-enolization of an appropriate methyl-substituted acetophenone derivative. Chirality has been introduced at an early stage during an ScN reaction (cf. Scheme Z). Compound l h has been obtained similarly using a previously reported mixture of the enantiomerically pure constitutional isomers 18b/19b (cf. Scheme 3).1. Einleitung. -(-)-Norgestrel (la) wird weltweit als gestagene Komponente Nummer Eins in oralen Kontrazeptiva verwendet [3a]. Als 13-Ethylgonan-Derivat kann diese Verbindung bislang jedenfalls nicht durch Partialsynthese aus einem naturlich vorkommenden Steroid gewonnen werden: Die Totalsynthese ist daher nach wie vor der Weg zum biologisch aktiven la.
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