Synthesis of Enantiopure Estrone via a Double Heck Reaction

Abstract

An novel efficient catalytic approach to steroids by a double Heck reaction of the vinyl bromides 2 and the CD-building block 3 is presented. The new estrogen analogues 1a and 1b are formed via 23a and 23b in a highly regio-and stereoselective manner in good yields. They contain a cis-BC ring junction and two double bonds in the 6,7-and the 11,12-positions which can be functionalized in a selective way. Inter alia, homogeneous hydrogenation with (PPh 3 ) 3 RhCl to give 28 followed by hydrogenation with 1,4cyclohexadiene in the presence of palladium affords the known estradiol derivative 29a in 76% yield which can easily be transformed into estrone 31.S0002-7863(98)01539-X CCC: $15.00

Palladium‐Catalyzed Cross‐Coupling Reactions in Total Synthesis

“…[49] An alternative approach to the steroid skeleton, based on palladium-catalyzed Heck reactions, has more recently been introduced by Tietze and his group and is exemplified by an elegant, enantioselective total synthesis of the female sex hormone estrone (31, Scheme 6). [50] The cornerstone of this strategy relies on the generation of the steroid ring B by the fusion of the functionalized aromatic compound 25 onto the enantiopure hydrindene derivative 26 [51] through consecutive inter-and intramolecular Heck reactions. Specifically, these researchers discovered that treatment of a mixture of 25 and 26 with catalytic amounts of Pd(OAc) 2 and PPh 3 in the presence of nBu 4 NOAc in a mixed DMF/MeCN/H 2 O solvent system at 70 8C led to the selective formation of the intermolecular Heck reaction product 28; when the latter was treated with a catalytic amount of the novel palladacycle 29 [52] in the same solvent system, but at a slightly higher temperature (115 8C), the desired intramolecular ring closure was effected, generating the estrone core structure 30 in quantitative yield.…”

High‐Turnover Palladium Catalysts in Cross‐Coupling and Heck Chemistry: A Critical Overview

“…[ 70] Use of 1 in solid phase Stille couplings gave better results than more conventional conditions (i.e., no deposition of Pd mirrors using 1).…”

Palladiumkatalysierte Kreuzkupplungen in der Totalsynthese

“…[49] Einen alternativen Weg zum Steroidgerüst auf der Grundlage palladiumkatalysierter Heck-Reaktionen wiesen in jün-gerer Vergangenheit Tietze und Mitarbeiter; als Beispiel für ihr Verfahren dient die elegante enantioselektive Totalsynthese des weiblichen Geschlechtshormons Östron (31, Schema 6). [50] Ein Eckpfeiler dieser Strategie war der Aufbau von Ring B des Steroidgerüsts durch Verknüpfung des funktionalisierten Arens 25 mit dem enantiomerenreinen Hydrinden-Derivat 26 [51] [54] Solche Cyclisierungskaskaden, anschaulich als "Reißverschlussreaktionen" bezeichnet, eröffnen ausgehend von einfachen acyclischen Verbindungen effiziente und ökonomische Zugänge zu komplexen Polycyclen -in einer Weise, die vor der Entdeckung der palladiumkatalysierten Kohlenstoff-Kohlenstoff-Kupplungen unmöglich gewesen wäre. [55,56] Eine Anwendung einer palladiumkatalysierten PolyenCyclisierung in der Totalsynthese findet sich in der bahnbrechenden Arbeit von Overman und Mitarbeitern zur Synthese der Diterpene der Scopadulcinsäure-Familie.…”