C−H Acetoxylation‐Based Chemical Synthesis of 17 β‐Hydroxymethyl‐17 α‐methyl‐18‐norandrost‐13‐ene Steroids

Abstract

Palladium-catalyzed C-H acetoxylation has been proposed as a key transformation in the first chemical synthesis of steroids bearing a unique 17β-hydroxymethyl-17α-methyl-18-nor-13-ene D-fragment. This C-H functionalization step was crucial for inverting the configuration at the quaternary stereocenter of a readily available synthetic intermediate. The developed approach was applied to prepare the metandienone metabolite needed as a reference substance in anti-doping analysis to control the abuse of this androgenic anabolic steroid.

Palladium‐Catalyzed 2‐(Neopentylsulfinyl)aniline Directed C–H Acetoxylation and Alkenylation of Arylacetamides

“…[4e] All of these reactions were β‐selective and proceeded through the five‐membered palladacyclic intermediates. Our studies commenced with the investigation of palladium‐catalyzed acetoxylation of acetamide 1 (Scheme ), which unexpectedly led to the α‐functionalization product 2 in a moderate 60 % yield. The 2‐(neopentylsulfinyl)‐aniline unit in 1 served as a coordinating auxiliary that was also found to assist the α‐arylation.…”

Synthesis and Pharmacological Properties of Modified A- and D-Ring in Dehydroepiandrosterone (DHEA): A Review

“…39 Similarly, in 2017, Hurski and co-workers reported the Pdcatalyzed D-ring modified long-term metabolites of C−H acetoxylation of 17 β-methylated androgenic anabolic steroids (AAS) metandienone 248 (17β-Hydroxymethyl-17α-methyl-18-norandrost-13-ene) (Scheme 33). 40 The Pd-catalyzed C−H acetoxylation of the 17β-methyl group was employed to invert the configuration at a quaternary stereocenter of the epimeric synthetic intermediate. The proposed technique was utilized to manufacture metandienone metabolite 248, which is employed as a reference drug in antidoping testing, to regulate the abuse of this androgenic anabolic steroid.…”

Recent progress in catalytic acyloxylation of C(sp3)‐H bonds

“…Hurski et al applied palladium‐catalyzed C(sp 3 )‐H activation to the synthesis of 17b‐hydroxymethyl‐17a‐methyl‐18‐norandrost‐13‐ene steroids ( 70 )—analogs of human androgenic anabolic steroids metabolites. [ 62 ] C‐H acetoxylation was a crucial step for the formal inversion of the absolute configuration at the quaternary stereocenter in the synthetic intermediate 67 (Scheme 12). The oxazoline DG was used in combination with Pd(OAc) 2 and PhI(OAc) 2 , affording acetoxylation product 69 in high yield.…”