Hemisynthesis of 2,3,4-¹³C3-1,4-Androstadien-3,17-dione: A Key Precursor for the Synthesis of ¹³C3-Androstanes and ¹³C3-Estranes

Abstract

In this contribution, we describe two simple and efficient routes for the preparation of keto-aldehyde 1, a key intermediate for the synthesis of C3-androstanes andC3-estranes. In the first route, the targeted aldehyde 1 was obtained in 40% overall yield from 1,4-androstadien-3,17-dione (3 mmol scale) via a two-step sequence involving a one-pot, abnormal ozonolysis/sulfur oxidation/retro-Michael/ozonolysis process. Alternatively, a second route from 4-androsten-3,17-dione, using a six-step sequence, was optimized to produce 40 mmol batches of the key intermediate 1 in 42% overall yield. At the final stage, the A-ring was reconstructed through a Wittig reaction with the 1-triphenylphosphoranylidene-C3-2-propanone 2, followed by an intramolecular condensation assisted by thioacetic acid via a Michael addition/retro-Michael reaction sequence to provide 2,3,4-C3-1,4-androstadien-3,17-dione.

Phenyl-Group Exchange in Triphenylphosphine Mediated by Cationic Gold–Platinum Complexes—A Gas-Phase Mimetic Approach

“…An excess of MeI was added to a part of the resulting solution to convert PPh 3 into (MePPh 3 )I. 64 After stirring for 1 h, all volatiles were removed under reduced pressure. The residue, containing (MePPh 3 -d 0 )I, (MePPh 3 -d 5 )I, (MePPh 3 -d 10 )I, and (MePPh 3 -d 15 )I, was dissolved in MeOH and analyzed massspectrometrically.…”

“…For this purpose, the mixture was filtered over alumina to remove the metal complex, and an excess of CH 3 I was added to a part of the resulting solution to convert PPh 3 into the corresponding phosphonium salt (CH 3 PPh 3 )I. 64 After stirring for 1 h, all volatiles were removed under reduced pressure. The residue, containing (CH 3 PPh 3 -d 0 )I, (CH 3 PPh 3 -d 5 )I, (CH 3 PPh 3 -d 10 )I, and (CH 3 PPh 3 -d 15 )I, was dissolved in methanol and analyzed mass spectrometrically.…”

Synthesis of 13C-Labeled Steroids

“…The latter was then reduced by treatment with NaBH 4 to the expected 2-oxa-3-oxo-Δ 4 In view of our long-standing interest in the synthesis of stable isotope labeled compounds, 63 we embarked on the development of an efficient, large-scale synthesis that would ensure the incorporation of 13 C atoms into the steroid framework. 64 From a strategic point of view, we were very interested in the approach previously reported by Vierhapper and co-workers, 53 which allowed for the latestage reconstruction of the A ring with a labeled Wittig reagent 85 ([ 13 C 3 ]-1-(triphenylphosphoranylidene)propan-2one) from a 10-formyl-5-oxo-des-A intermediate 99 (see Scheme 16). At this point, several questions remained to be answered.…”

“…First, we focused our attention on the double oxidative cleavage of the two C=C bonds in the A ring of 98 in order to access rapidly the desired ketoaldehyde 99. 64 Unfortunately, after extensive attempts we found that the A ring of 98 was either inert under standard ozonolysis conditions or led to decomposition under oxidative cleavage conditions with potassium permanganate (Scheme 22). At this point, we reasoned that disruption of the electronic conjugation of the dienone system in the A ring in 98 by a regioselective reduction of the carbonyl at C3 could be a solution to elabo-rate our previous plan.…”

“…To bypass the simultaneous oxidative cleavage of the two C=C bonds in the A-ring of 98, we envisaged performing the cleavage in a sequential manner using a one-pot procedure (Scheme 23). 64 A regioselective thio-Michael addition onto the more reactive C=C bond of 98 was considered as a temporary protection for one of the C=C bonds to permit the oxidative cleavage of the remaining 4,5-C=C bond by O 3 . 68…”