Q5(c). Photoenolisation and intramolecular Diels–Alder: estrone skeleton

Introduction. An aryl ketone with an ortho-methyl group undergoes photoenolisation: light gives the excited ketone, which takes an H atom from the o-methyl group to form a hydroxy-o-quinodimethane (a photoenol). This reactive diene is trapped by the vinyl group of the same molecule in an intramolecular Diels–Alder reaction that builds rings B and C of a steroid in one step (Quinkert's estrone synthesis).

Scheme: Excited C=O abstracts an H from the o-CH₃ (via a 1,4-biradical); the E-photoenol is the diene.

Scheme: The diene termini (o-CH₂ and the carbinol carbon) bond to the two carbons of the vinyl group: rings B and C form together.

1. Excitation. Light above 340 nm is absorbed only by the aryl ketone (n→π*); the cyclopentanone and the product do not absorb, so they are not destroyed.
2. Hydrogen abstraction. The half-filled n orbital of the excited oxygen removes a hydrogen from the o-CH₃ through a six-membered transition state (a 1,5-H shift, Norrish type II-like), giving a 1,4-biradical that collapses to the photoenol.
3. E and Z photoenols. The Z-enol (OH towards the CH₂) returns quickly to the ketone; the longer-lived E-photoenol is the reactive diene.
4. Diels–Alder. The tethered vinyl group is the dienophile. The o-CH₂ bonds to its terminal carbon (C-7) and the carbinol carbon bonds to its internal carbon (C-8), closing the new six-membered ring B and, through the tether, ring C at the same time. The exo transition state sets the trans B/C fusion (8β-H, 9α-OH); the trans C/D relationship (13β-CH₃, 14α-H) is already present in the starting ketone.
5. Product. 9α-hydroxy-3-methoxyestra-1,3,5(10)-trien-17-one (9α-hydroxyestrone 3-methyl ether). Pyridine and mesitol are added to the irradiated solution to suppress acid-catalysed side reactions of the photoenol and of the tertiary alcohol.

Conclusion. Intermediates: the excited ketone, the 1,4-biradical and the E-photoenol (hydroxy-o-quinodimethane). Product: 9α-hydroxyestrone 3-methyl ether, formed by photoenolisation followed by an intramolecular Diels–Alder reaction.

Application. Dehydration of the 9α-alcohol and reduction lead to estrone, the female sex hormone; photoenol Diels–Alder reactions are a general route to the tetralin rings of steroids and anthracyclines.