Facilitated Intramolecular Conjugate Addition of Amides of 3-(3',6'-Dioxo-2',4'-dimethyl-1',4'-cyclohexadienyl)-3,3-dimethylpropionic Acid. 2. Kinetics of Degradation.
The chemical stability studies of amides of 3-(3',6'-dioxo-2',4'-dimethyl-1',4'-cyclohexadienyl)-3,3-dimethylpropionic acid (Qa) [Qop(a-j)] were conducted in order to determine the utility of this redox-sensitive system as a potential prodrug promoiety or redox-sensitive protecting group in organic synthesis. This study showed that quinone propionic amides of aniline derivatives [Qop(a-d)] underwent rapid degradation in mildly acidic conditions (pH 4.5-6.0) to yield degradation products resulting from the intramolecular 1,2- or 1,4- conjugate addition of the amide nitrogen to the quinone ring. This conjugate addition was found to be specific base-catalyzed and independent of the para substituent on the aromatic ring of the amine. The predominant route of degradation yielded a five-membered ring spirolactam. By altering the nature of the amine component of the amide, these degradation reactions were prevented. Amides of Qa other than those of the aniline type [Qop(e-j)] were found to be substantially more stable and were thus proposed as the more suitable candidates for this potential redox-sensitive prodrug system and redox-sensitive protecting group for amines and alcohols in organic synthesis.
Nicolaou
Michalis G.
MG
Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas 66047-2504.
Wolfe
Janet L.
JL
Schowen
Richard L.
RL
Borchardt
Ronald T.
RT