Total Synthesis of [3aS‐(3aα,9aα,9bβ)]‐3a,4,5,9,9a,9b‐Hexahydro‐3a,6‐dimethyl‐1H‐benz[e]indene‐3,7(2H,8H)‐dione and Derivatives, Building Blocks for the Synthesis of Glucocorticoids

Abstract

Total Synthesis of [3aS-(3aar,9aa,9bp)]-3a,4,5,9,9a,9b-Hexahydru-3a,6dimethyl-lH-benz[e]indene-3,7(2H,The natural and synthetic glucocorticoids are very important compounds commonly used as drugs against many diseases. Recently, we have reported the synthesis of some of the title compounds and their transformations into 6-methyl-5-androstene-3,11,17-trione 3-ethyleneacctal, a building block for the anti-inflammatory drug 6a-methylprednisolone. We now present a shorter synthesis of the tricyclic systems (title compounds), which can be converted into glucocorticoids and, as reported by Nedelec at aL2), can also be used as antiandrogens. We have also reported3) a stereoselective reductive addition of the hydride anion and some electrophiles to the enedione 1, mediated by tert-bu-L J

A Systematic Study of the Effects of Relative Configuration, Protecting Group, and Enolate Type on the Diastereoselectivities of Aldol Reactions of a Chiral Ethyl Ketone with 2-Methylpropanal

“…ref ) at ambient temperature overnight gave 15 in 90% yield (75% based on 14 ; 50 g scale) with excellent purity after a simple workup (without distillation). Conversion of 15 to 16 was achieved in analogy to previous reports. , …”

“…Conversion of 15 to 16 was achieved in analogy to previous reports. 20,23 Reaction of 16 with the (E)-enol dicyclohexylborinate derived from 12 at −78 °C gave the 4,5-anti-5,6-syn Felkin adduct 17a with excellent stereoselectivity (Scheme 3). The remaining diastereomers were obtained by Mukaiyama aldol reactions of 16 with 13 [Z:E, 4−5:1], prepared by adapting the method of Iqbal et al 24 Using BF 3 •OEt 2 as the promoter at −78 °C gave a 10:1 mixture of 18a and 17a, respectively, from which 18a was obtained in good yield by careful fractionation over silica gel.…”

“…Ethylene glycol (12.7 mL, 14.1 g, 0.226 mol) and p-TsOH•H 2 O (1.66 g, 8.71 mmol) were added to a stirred solution of 15 (27.6 g, 0.175 mol) in benzene (200 mL), and the mixture was heated under reflux with removal of water via a Dean−Stark trap. After 24 h, the mixture was diluted with ethyl acetate, washed sequentially with saturated aq NaHCO 3 , water, and brine, dried over Na 2 SO 4 , and concentrated to give the known 23 crude ketal-ester as a light yellow oil (34.2 g, ca. 95% pure).…”

A Short Enantioselective Total Synthesis of the Third-Generation Oral Contraceptive Desogestrel

“…In this procedure, only a catalytic amount of t -BuCu (∼0.3 equiv) is used along with the stoichiometric reductant diisobutylaluminum hydride (2 equiv)−hexamethylphosphoric triamide (HMPA) complex, which is added slowly to the mixture of t -BuCu and 4 at −78 °C. Our results on the efficient and stereoselective conversion of 4 to 5 recommend the use of this methodology as an excellent solution to the longstanding problem of trans-fused hydrindanone synthesis 7d. α-Methoxycarbonylation of 5 with dimethyl carbonate−sodium methoxide−sodium hydride in 1:1 THF−hexane (optimum) proceeded regioselectively (6.3:1) to give the enolic β-keto ester 6 .…”

“…Keto alcohol 3 was efficiently converted to the tert -butyldimethylsilyl (TBS) ether 4 . An excellent procedure was developed for the hydridoalkyl cuprate-induced reduction 7a-c of the α,β-double bond in 4 to form stereoselectively the trans-fused indanone 5 in >90% yield. In this procedure, only a catalytic amount of t -BuCu (∼0.3 equiv) is used along with the stoichiometric reductant diisobutylaluminum hydride (2 equiv)−hexamethylphosphoric triamide (HMPA) complex, which is added slowly to the mixture of t -BuCu and 4 at −78 °C.…”