Tricyclic Fused Lactams by Mukaiyama Cyclisation of Phthalimides and Evaluation of their Biological Activity

Abstract

We report that phthalimides may be cyclized using a Mukaiyama-type aldol coupling to give variously substituted fused lactam (1,2,3,9b-tetrahydro-5H-pyrrolo[2,1-a]isoindol-5-one) systems. This novel process shows a high level of regioselectivity for o-substituted phthalimides, dictated by steric and electronic factors, but not for m-substituted phthalimides. The initial aldol adduct is prone to elimination, giving 2,3-dihydro-5H-pyrrolo[2,1-a]isoindol-5-ones, and the initial cyclisation can be conducted in such a way that aldol cyclisation-elimination is achievable in a one-pot approach. The 2,3-dihydro-5H-pyrrolo[2,1-a]isoindol-5-ones possess cross conjugation and steric effects which significantly influence the reactivity of several functional groups, but conditions suitable for epoxidation, ester hydrolysis and amide formation, and reduction, which provide for ring manipulation, were identified. Many of the derived lactam systems, and especially the eliminated systems, show low solubility, which compromises biological activity, although in some cases, antibacterial and cytotoxic activity was found, and this new class of small molecule provides a useful skeleton for further elaboration and study.

Cascade 1,3-Dipolar Cycloaddition and Lactamization for Diastereoselective Synthesis of Pyrrolidinedione-Fused Tetrahydropyrroloisoindolones

“…4 The unique structures and interesting bioactivities of tetrahydropyrroloisoindolone-related compounds continuously attract interest for the development of new synthetic methods for such ring systems. 5 For the synthesis of tetrahydro-5H-pyrrolo[2,1-a]isoindol-5one skeleton, Piva and co-workers reported a one-pot synthesis involving ring-closure metathesis, RuH-promoted isomerization, and radical cyclization sequence (Scheme 1A). 6 Gu's group introduced an intramolecular Schmidt rearrangement reaction of acyl chlorides with alkyl azides.…”

“…Compound D, (−)-Chlorizidine A, is a natural marine product active to HCT-116 human colon cancer cells (Figure ). The unique structures and interesting bioactivities of tetrahydropyrroloisoindolone-related compounds continuously attract interest for the development of new synthetic methods for such ring systems …”