A total synthesis of estrone based on a novel cascade of radical cyclizations.
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 Bu(3)SnH/2,2'-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 Bu(3)SnH/AIBN, 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)-H(2)SO(4) next led to the cyclopentanone 57, which, on deprotection using BBr(3) 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.
School of Chemistry, University of Nottingham, Nottingham NG7 2RD, England. gerald.pattenden@nottingham.ac.uk
Gerald
G
Pattenden
Miguel A
MA
Gonzalez
Stuart
S
McCulloch
Affo
A
Walter
Steven J
SJ
Woodhead
D002625:Chemistry, Organic / Q000379:methods; D004970:Estrone / Q000138:chemical synthesis* / Q000737:chemistry; D005609:Free Radicals / Q000737:chemistry; D015394:Molecular Structure; D013237:Stereoisomerism
D005609:Free Radicals; D004970:Estrone