Total Synthesis of 19-Norsteroids. I. d,l-Estrone Methyl Ether

Ab + D → Abd → Abcd

“…The condensation step between the vinyl alcohol 13 and the cyclic diketone was originally thought to be base catalyzed; benzyltrimethylammonium hydroxide (Triton B) [1,2,6,[9][10][11][12][13], potassium hydroxide and potassium i-butoxide [10], triethylamine [14], and sodium bicarbonate [15] have been used. Recently, however, Kuo, Taub, and Wendler have shown that the condensation is acid catalyzed, the enolic form of the dione itself furnishing the acid to bring about the reaction [16; see also refs.…”

“…Another variation in the Torgov synthesis employs the N-substituted pyrrolidine 20, which gives 14 in 80% yield [18]; piperidine and morpholine have been used in the same way [19]. In most applications of the Torgov synthesis the ABD intermediate is isolated, after which ring C is closed with the use of phosphorus pentoxide [7,14,20], p-toluensulfonic acid [1], formic acid [3], or concentrated hydrochloric acid [2,6]. Ring closure of 14 under mild acid conditions (dilute HC1) gave the 14-hydroxy intermediate 21, which was readily dehydrated to the pentaene 15 [14,21].…”

“…Condensation of 2-methyl-1,3-cyclopentanedione with the vinyl alcohol 13 gave the ABD intermediate 14, which was ring closed under acid catalysis to the methyl ether (15) of 3-hydroxy-l,3,5(10),8,14-estrapentaen-17-one. Catalytic hydrogénation produced the tetraene 16, which was subjected to further reduction with potassium in liquid ammonia [2][3][4][5]. Some reduction of the 17-oxo group occurred simultaneously, so that the product mixture was oxidized with chromic oxide to give racemic estrone methyl ether (17).…”

“…The success of this synthesis emerged out of four years of intensive investigations by the Russian group as well as by others. Four other groups published estrone syntheses very similar to Torgov's at essentially the same time [3,[6][7][8].…”

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

“…The first synthesis of estrone was based on the hydrogenation of equilenine, [2] also a natural hormone, and was soon followed by a total synthesis. [3] Starting with pioneering synthetic work in the 1940s, [4] a number of other syntheses based on condensation reactions, [5] the Diels-Alder reaction, [6] cleavage of the cyclobutane ring, [7] a radical cascade reaction, [8] Friedel-Crafts alkylation, [9] and photochemically induced cycloaddition, [10] to name a few, appeared. Some of the early syntheses still serve even today as an inspiration for more sophisticated approaches, Torgov's intermediate being a typical example.…”