A total synthesis of estrone based on a novel cascade of radical cyclizations

Abstract

Two conceptually different and novel radical-mediated cascade reactions leading to a total synthesis of the steroid (؎)-estrone 1 and to a synthesis of 14-epiestrone 40 are described. Treatment of the iododienynone 23 with Bu3SnH͞2,2-azobis(isobutyronitrile) (AIBN) triggers a 13-endo-dig radical macrocyclization followed by two sequential radical transannulation reactions leading to the crystalline estrane 24 in 50% yield. The x-ray crystal structure of 24 established its trans, syn, stereochemistry. Transposition of the enone functionality in 24 next led to 38, which was then converted into 39 by reductive methylation. Deprotection of the methyl ether 39 finally gave 14-epiestone 40. When the substituted iodovinylcyclopropane 55 was treated similarly with Bu3SnH͞AIBN, the resulting radical center underwent a different sequence of cascade macrocyclization-transannulation reactions producing the trans, anti, trans estrane 56 in 12% overall yield. Oxidation of 56, using CrO 3-H2SO4 next led to the cyclopentanone 57, which, on deprotection using BBr3 gave (؎)-estrone 1. A number of alternative substituted iodopolyenynones and iodovinylcyclopropanes, i.e., 8a, 8b, 33, 49a, and 49b, underwent similar radical-mediated cascade cyclizations leading to other estranes, i.e., 21a, 21b, 35, and 50, and, in one case, to the 6,6,5,6-tetracycle 51, in variable overall yields. The structures and stereochemistries of several estranes were established by using x-ray crystal structure measurements in combination with analysis of their NMR spectroscopic data and correlation with literature precedent. Since the synthesis of the female sex hormone estrone 1 by Anner and Miescher in 1948 (1), and the syntheses of nonaromatic steroids, such as cortisone 2 and aldosterone 3 during the 1950s, a plethora of ingenious designs have been explored to synthesize members of the steroid family of natural products. Prominent among the methods that have been developed are those based on Diels-Alder reactions (2-12), transition metal-catalyzed cyclizations of enynes and triynes (13-16), and biogenetic-type electrophilic cyclizations of polyene precursors (17-21).Over the past 10 years, we (22-26) and others (27-38) have examined the scope of a variety of cascade radical-mediated processes to elaborate steroids and other polycyclic ring systems. Thus, we have already described an approach to steroids based on consecutive 6-endo-trig (ref. 39 and references therein) and sequential transannular (40) radical cyclizations from appropriate polyene selenyl ester precursors, illustrated in the conversions 4 3 5 and 6 3 7, respectively.We have now extended our studies and examined a different approach to estrone 1 and estranes, whereby the nonaromatic tricyclic B,C,D ring system is produced in a single step by radical-mediated macrocyclizations in tandem with consecutive transannulations from an appropriate ortho-disubstituted arylpolyene precursor.These approaches to estranes are captured in a retrosynthetic manner in Scheme 1. Thus, in one approach, we ha...

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

“…The former process, Cp 2 ZrBu 2 -mediated cyclization/allylation (propargylation), selectively furnished compounds with a trans-substituted steroidal B ring, and the latter process, Co 2 (CO) 8 -mediated cyclocarbonylation, gave rise diastereoselectively to unsaturated tetracyclic ketones with natural trans-anti stereochemistry. It could be also substituted by the Cp 2 ZrBu 2 -mediated cyclocarbonylation reaction (Negishi protocol).…”

“…To a solution of enyne 5a-f (1 mmol) in toluene (5 mL) was added Co 2 (CO) 8 (1.3 mmol, 445 mg), and the reaction mixture was stirred at 20°C for 4 h. Then, DMSO (5 mmol, 354 µL, 390 mg) was added, and the reaction mixture was stirred at 80°C for 5 h. It was quenched with HCl (1 %, 100 mL) and extracted with CH 2 Cl 2 (3 ϫ 15 mL); the combined organic fractions were dried with anhydrous MgSO 4 , and the volatiles were removed under reduced pressure. Column chromatography of the residue on silica gel yielded the desired products.…”

“…[33] The Pauson-Khand reaction of prepared enynes 5 was studied under various reaction conditions ( Table 1). The best results were obtained with the classical procedure (method A), relying on the use of a stoichiometric amount of Co 2 (CO) 8 , followed by decomplexation of the formed complex with DMSO instead of N-methylmorpholine N-oxide (NMO). [33] Under these conditions, the corresponding estratetraenes 11a, 11b, 11d-f were isolated in high yields (84-95 %; Table 1, Entries 1, 2, 4-6).…”

“…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.…”

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

“…Last but not least, mention should also be made of syntheses of steroids accomplished by use of classical organic methodology. Typical examples include the syntheses of (+)-or (Ϯ)-estrone reported by Corey et al, [6][7][8] Pattenden et al, [9] Mukai et al, [10] Göbel et al, [11] and Li et al, [12] or the syntheses of ent-desmosterol, [13] ent-cholesterol, [14,15] and ent-estradiol [16] by Covey et al and by Rychnowski et al…”