Current diversity of cyclic anhydrides for the Castagnoli–Cushman-type formal cycloaddition reactions: prospects and challenges

A General Way to Construct Arene‐Fused Seven‐Membered Nitrogen Heterocycles

“…[23] However, we [24] and others [25] recently demonstrated that ε-lactams are also accessible by the CCR of o-phenylenediacetic acid anhydride (4). [23] However, we [24] and others [25] recently demonstrated that ε-lactams are also accessible by the CCR of o-phenylenediacetic acid anhydride (4).…”

Stereochemistry and reactivity of the HPA-imine Mannich intermediate

“…Despite earlier considerations of alternative mechanisms, 2,14,21 more recent analysis of the HPA-imine reaction seems to have settled on a two-step process centered on Mannich-type amino-anhydride intermediate 5 , 3,13,15,22 the stereochemistry of which translates to the C-3 and C-4 stereocenters of the THIQ product. Under certain conditions, elimination of amine from 5 to afford a Knoevenagel-type alkene product 6 has been observed.…”

“…The reaction of imines with cyclic carboxylic anhydrides generally, 1,2,3 and homophthalic acid (HPA, 1 ) in particular, 4,5 has become an important method for the efficient assembly of lactams with useful biological activity. Such compounds have seen application toward potential anticancer treatments, 6,,8,9 and include a new group of antimalarials from which a clinical candidate has recently emerged.…”

“…Such compounds have seen application toward potential anticancer treatments, 6,,8,9 and include a new group of antimalarials from which a clinical candidate has recently emerged. 10,11,12 Synthetic 2,3 and computational 13,14 aspects of the HPA-imine reaction, formally a [4+2] cycloaddition of the enolized form of HPA ( 2 , Scheme 1), have been investigated extensively. A wide variety of solvents and additives have been shown to accommodate or modify the tranformation, which nonetheless occurs rapidly at modest temperatures even in the absence of added acid or base promoters.…”

Convenient modular construction of medicinally important 5-acylamino-4,5-dihydroisoxazoles featuring four elements of diversity

“…Indeed, the nature of the molecular scaffold is determined by the specific multicomponent reaction (MCR) as well as various skeleton-defining post-MCR modifications, while the periphery-by a specific selection of reagents for the synthetic array. Prominent MCRs such as the Ugi 3 or Castagnoli-Cushman 4 reactions have a large enough scope to permit a wide range of side-chain variations. Strategies based on sequential MCRs introduce even more diversity elements which can be altered to fine-tune the compounds' desired biological activity and suppress side-effects.…”