Sn(OTf)₂ as an Effective Lewis Acid in Reactions of Cyclopropyl Ketones with Acetic Anhydride: Application in the Synthesis of a 19‐Nor‐B‐homo Steroid

Abstract

Attempts to convert 3β‐acetoxy‐5,19‐cyclo‐pregna‐6,20‐dione (8) into a cyclocitrinol‐related steroid with a bicyclo[4.4.1]‐undecane AB‐ring substructure through a Lewis acid‐assisted fragmentation failed. Instead, treating 8 with an excess of Ac2O and BF3·Et2O afforded B‐homo steroid 9 in 90 % yield. This unexpected rearrangement is assumed to proceed via an intermediate bicyclobutonium cation. Remarkably, tricyclo[4.4.1.0]undecane‐1‐one (rac‐13), prepared as a model substrate, did not react under the same conditions. However, by screening various Lewis acids, stannous triflate was identified as a particularly efficient reagent for this and related Lewis acid‐assisted ring‐opening reactions of cyclopropyl ketones in the presence of Ac2O, and even catalytic amounts of Sn(OTf)2 (5 mol‐%) proved to be effective.

Absolute structure of (3aS,5S,7aS,7bS,9aR,10R,12aR,12bS)-7b-hydroxy-4,4,7a,9a,12a-pentamethyl-10-[(2′R)-6-methylheptan-2-yl]-2,8,9-trioxooctadecahydrobenzo[d]indeno[4,5-b]azepin-5-yl acetate from 62-year-old crystals

“…There is only one entry with the same six-, seven-, six-and five-membered ring combination containing O instead of N (HIXSAI; Morales et al, 1999) but the configuration of C5 is inverted and therefore the dihedral angle between mean planes of the six-and seven-membered rings differ significantly and thus also the molecular conformation. There are also three tetracyclic compounds with no heteroatom in the ring arrangement [OQIVIU (Kranz et al, 2011), UBEDIO (Wang et al, 2000) and WECQAY (Kranz et al, 2012)] all showing very different stereochemistry; therefore, the molecular conformations are not comparable. This is, therefore, the first report of this 6-7-6-5 ring system containing the azepine ring.…”

3β-Acetoxy-19-hydroxy-Δ5-pregnen-20-one

“…For the first synthesis of the title compound, see: Halpern et al (1963). For examples of the title compound as an intermediate for rearranged A/B-ring systems, see: Knox et al (1965); Kranz et al (2011). For a description of the Cambridge Structural Database, see: Allen (2002).…”

“…During our synthesis of diverse B-homo-steroids the C-19-hydroxy-steroid (I) was isolated as an intermediate (Kranz et al, 2011). The C/D and D/E rings in C 23 H 34 O 4 are trans fused and the A/B ring possesses an anti fusion.…”

“…The title compound C 23 H 34 O 4 was prepared in 3 steps starting from commercial pregnenolone-acetate (Kranz et al, 2011).…”

Scalable Synthesis of Cyclocitrinol

“…Central to this synthetic design is the identification of an appropriate promoter (X) that would act as a nucleophile to enable the cyclopropane formation in 6, while behaving as a leaving group in 7 to facilitate the subsequent cyclopropane fragmentation. Notwithstanding the documented challenges to execute this bioinspired synthetic strategy, 14 we envisioned that this cascade rearrangement could offer a concise strategy to access the cyclocitrinol core structure.…”