Nitrogen insertion as a strategy for the synthesis of γ-Lactams
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Abstract
In this thesis, four comprehensive methodologies have been conceived that combine ringexpansion, nitrogen insertion and desymmetrization for the access of achiral and chiral
γ-lactams, a pivotal core scaffold in numerous drug molecules.
In the first work, amino diphenylphosphinates have been identified as suitable amine source
for the ring-expansion of cyclobutanones towards γ-lactams. Through intensive mechanistic
studies, an aza-Baeyer-Villiger rearrangement has been unveiled, showing the tetrahedral
Criegee-type structure as important intermediate. The stereochemical course aligned
with the parent Baeyer-Villiger reaction, demonstrating a regioselective and siteselective
insertion process. Besides that, the synthesized drug molecule Rolipram and its N-substituted derivatives display the remarkable principle of late-stage skeletal editing.
The second work builds upon the achievements of my master’s thesis. Herein, the desymmetrization of prochiral cyclobutanones was described using a chiral amino alcohol, enabling the straightforward synthetic route to chiral N-protected γ-lactams. To conclude this project, an effective deprotection protocol showcased the access of synthetically useful pyrrolidines. In addition to that, the formal synthesis of the drug Pregabalin underscores the importance of this method within the realm of nitrogen insertion processes.
The third work of this research endeavor overcame some of the limitations encountered in
the previous works. A synthetic route for the construction of novel chiral amino phosphinates was developed. These chiral amine sources were successfully incorporated into the aza-Baeyer-Villiger methodology, enabling the direct access of γ-lactams in moderate enantioselectivities. Further investigation into the stability of these chiral aminating reagents unveiled slow racemization rates, partially explaining the observed insufficient stereoinduction. The final work describes a possible alternative for the low stereoinduction by using a catalytic approach. Here, organocatalysts and a chiral N,N’-dioxide-Sc-complex were employed, which showed a catalytic approach in the presence of Sc(OTf)3. However, neither the a chiral N,N’-dioxide-Sc-complex nor organocatalysts could induce the enantioselectivity.