Synthesis of an (±)‐Estrone Precursor: The Scope of Zr‐ and Co‐Mediated Cycloannulations

Abstract

Keywords: Zirconium / Cobalt / Cyclization / Carbonylation / SteroidsThe synthesis of an estrone intermediate based on a new approach was studied. The construction of the basic framework was carried out in three steps from a simple styrene derivative. The crucial reaction sequence for the steroid skeleton construction relied on a Zr-mediated cyclization (Zr-ene reaction)/propargylation followed by a Co-mediated diastereoselective Pauson-Khand reaction that afforded various Dring-substituted tetracyclic ketones 11 with natural trans-anti stereochemistry. The conjugated addition reaction of Me 2 Cu-

Transition‐Metal‐Mediated or ‐Catalyzed Syntheses of Steroids and Steroid‐Like Compounds

“…The second approach [76] also used the diene 49 as a starting compound. Treatment with the zirconocene-(but-1-ene) complex yielded an organozirconium intermediate that reacted with 3-bromobuta-1,2-diene in the presence of CuCl by the S N 2Ј reaction mechanism, giving rise to the enyne 86 in a very good yield of 87 % over the two steps (Scheme 35).…”

Enantioselective Synthesis of (–)‐Methoxyestrone

“…In the next four steps, bromodiene 5 was converted into a tetracyclic estrone precursor in an analogous manner to our previously reported racemic synthesis. [5] Firstly, dehydrobromination of 5 with TBAF yielded enyne 6 (96 %), its terminal triple bond was metalated with nBuLi, and the formed acetylide was treated with MeI to give enyne 7 in 92 % yield. Then, the Pauson-Khand reaction of 7 with Co 2 CO 8 proceeded diastereoselectively to give rise to a single stereoisomer of tetracyclic ketone 8 in 95 % yield.…”

“…[4] The second one utilized two previous Cp 2 ZrBu 2 -mediated reactions for the construction of the A and B rings followed by a Co-mediated Pauson-Khand reaction that allowed the C and D rings to be assembled in one step. [5] These procedures led to the straightforward synthesis of the known tetracyclic intermediate over nine steps from the commercially available starting material; nonetheless, attempts to develop an enantioselective variant of this procedure were not met with success. Although the key synthetic step, the closing of the B ring, could furnish a substituted tetrahydronaphthalene [ intermediate with the correct relative stereochemistry under racemic conditions by using Cp 2 ZrBu 2 , the use of a chiral zirconocene derivative under catalytic or stoichiometric conditions did not lead to the expected intermediates; moreover, loss of stereoselectivity was observed.…”

Formal Total Synthesis of (±)-Estrone via the Furano Diene Approach

“…Estrone is one of the most popular synthetic targets due to its important physiological properties and characteristic steroidal skeleton . Although numerous synthetic methods have been developed to date, , the diene approach based on the Diels−Alder cycloaddition enjoys a privileged strategic choice in terms of convergence and stereo- and enantioselective control . For example, Dane’s diene ( 2 ), first introduced in 1939, has been employed in recent asymmetric total synthesis of estrone via catalytic enantioselective Diels−Alder strategies …”