Giovanni Casiraghi

3‐Alkylidene‐2‐oxindoles represent a simple, yet enabling subfamily of indole alkaloids, and their ability to react as electron‐poor acceptors has largely been investigated. In contrast, their utility as pronucleophilic synthons remains elusive. In this context, the present article describes the successful execution of the direct, organocatalytic asymmetric Michael addition of prochiral 3‐alkylideneoxindoles to nitroolefins. A variety of γ‐substituted alkylideneoxindoles carrying two stereocenters at both the γ‐ and δ‐carbon sites was assembled with excellent stereoselectivity and without olefin isomerization or stereochemical ablation.

We introduce novel 3‐alkenyl‐2‐silyloxyindole nucleophiles and demonstrate their utility by developing an unprecedented vinylogous Mukaiyama‐type aldol reaction with aromatic aldehydes. This reaction displays excellent levels of γ‐site selectivity and diastereoselectivity and delivers valuable hydroxylated oxindoles bearing a substituted exocyclic double bond at the C‐3 position. A preliminary trial of an asymmetric, catalytic version was conducted, and it showed promising enantioselectivity for the desired vinylogous aldol products.

Pyrrole-based silyl dienolates undergo asymmetric vinylogous Mukaiyama Mannich reactions with a series of N-aryl aldimines in the presence of the Hoveyda−Snapper amino acid-derived silver(I) catalysts. The Mannich products—α,β-unsaturated δ-amino-γ-butyrolactams—are typically obtained in high yields, excellent γ-site selectivities and anti-diastereoselectivities, and up to 80% enantioselectivity.

Denmark’s chiral bisphosphoramide/silicon tetrachloride system performs as an excellent Lewis base‐Lewis acid catalyst for the vinylogous Mukaiyama aldol reaction of pyrrole‐ and furan‐based dienoxy silanes with aromatic and heteroaromatic aldehydes. This asymmetric methodology provides a powerful synthetic entry to a variety of δ‐hydroxylated γ‐butenolide‐type frameworks with high efficiency and valuable margins of regio‐, diastereo‐, and enantioselectivity. Notably, the nature of the heteroatom within the vinylogous dienoxy silane donor heavily impacts the diastereocontrol, with syn‐configured aldol adducts emerging from pyrroles bearing electron‐withdrawing N‐protecting groups (Boc, Ts, and Cbz) and anti‐configured adducts prevailing when furan‐ or N‐alkyl/alkenylpyrrole donors are involved.

An efficient, stereocontrolled synthesis of (6S,7S,8S,8aR)-6,7,8-trihydroxyindolizidine (alias 1-deoxy-7,8-di-epi-castanospermine) (14) has been developed, which exploits an asymmetric vinylogous Mukaiyama aldol reaction (VMAR) between N-(tert-butoxycarbonyl)-2-(tert-butyldimethylsilyloxy)pyrrole (1) and 2,3-O-isopropylidene-D-glyceraldehyde (2) to construct the initial pyrrolidine building block 3, and an ene-ene ring closing metathesis reaction (RCM) (9 to 10) to install the indolizidine skeleton. The synthetic sequence was 13 steps, proceeding in 19.5% overall yield. The configurational and conformational structure of 14 was ascertained unambiguously and confronted to previously published assignments of rac-14 and ent-14.

Eleven γ-aminocyclopentane carboxylic acid (Acpca) platforms, including four dihydroxy representatives (19−22), three hydroxy analogues (34−36), and four deoxy derivatives (30−33), were prepared in a chiral nonracemic format. These simple units were then grafted onto an Arg-Gly-Asp (RGD) tripeptide framework by a mixed solid phase/solution protocol delivering an ensemble of 11 macrocyclic analogues of type cyclo-[-Arg-Gly-Asp-Acpca-], 1−11. The individual compounds were evaluated for their binding affinity toward the α_Vβ₃ and α_Vβ₅ integrin receptors. The analogue 10 exhibited a very interesting activity profile (IC₅₀/α_Vβ₃ = 1.5 nM; IC₅₀/α_Vβ₅ = 0.59 nM), comparable to that of reference compounds EMD121974 and ST1646. Closely related congeners 6, 8, and 9 also proved to be excellent dual binders with activity levels in the low nanomolar range. The three-dimensional (3D) NMR solution structures were determined, and docking studies to X-ray crystal structure of the extracellular segment of integrin α_Vβ₃ in complex with the reference compound EMD121974 were performed on selected analogues to elucidate the interplay between structure and function in these systems and to evidence the subtle bases for receptorial recognition. The results prove that the principle of isosteric dipeptide replacement for peptidomimetics design and synthesis can be violated, without detriment to the development of highly effective integrin binders.