One Reacts as Two: Applications of N-Isocyaniminotriphenylphosphorane in Diversity-Oriented Synthesis.

N-Isocyaniminotriphenylphosphorane (NIITP) is a functionalized isonitrile that has been extensively applied in a variety of organic reactions during the last two decades. This Review summarizes the most important applications in organic synthesis of this versatile reactant, with the focus posed on mechanistic and methodological aspects allowing the generation of molecular diversity. NIITP combines the reactivity of isonitriles with that of phosphoranes to enable chemical transformations employed in the construction of compound libraries. Here, we cover from the initial applications of NIITP in the Nef isocyanide reaction to further derivations that render a variety of heterocyclic scaffolds. The presence of the isonitrile moiety in this singular compound makes possible the double addition of nucleophiles and electrophiles, which followed by inter(intra)molecular aza-Wittig type transformations enable several multicomponent and tandem processes. In particular, we stress the impact of NIITP in oxadiazole chemistry, from the early two-component transformations to recent examples of multicomponent reactions that take place in the presence of suitable electrophiles. In addition, we briefly describe the role of NIITP chemistry in generating skeletal and conformational diversity in cyclic peptides. The reaction of NIITP with alkynes is thoroughly revised, with particular emphasis on silver-catalyzed processes that have been developed in the last years. Biomedicinal applications of some reaction products are also mentioned along with a perspective of future applications of this reactant.

Computational-aided design of a library of lactams through a diversity-oriented synthesis strategy.

Small molecule libraries for virtual screening are becoming a well-established tool for the identification of new hit compounds. As for experimental assays, the library quality, defined in terms of structural complexity and diversity, is crucial to increase the chance of a successful outcome in the screening campaign. In this context, Diversity-Oriented Synthesis has proven to be very effective, as the compounds generated are structurally complex and differ not only for the appendages, but also for the molecular scaffold. In this work, we automated the design of a library of lactams by applying a Diversity-Oriented Synthesis strategy called Build/Couple/Pair. We evaluated the novelty and diversity of these compounds by comparing them with lactam moieties contained in approved drugs, natural products, and bioactive compounds from ChEMBL. Finally, depending on their scaffold we classified them into ß-, γ-, δ-, ε-, and isolated, fused, bridged and spirolactam groups and we assessed their drug-like and lead-like properties, thus providing the value of this novel in silico designed library for medicinal chemistry applications.

Molecular Diversity by Olefin Cross-Metathesis on Solid Support. Generation of Libraries of Biologically Promising ß-Lactam Derivatives.

The application of the reagent-based diversification strategy for generation of libraries of biologically promising ß-lactam derivatives is described. Key features are the versatility of the linker used and the cross-metathesis functionalization at the cleavage step. From an immobilized primary library, diversity was expanded by applying different cleavage conditions, leading to a series of cholesterol absorption inhibitor analogues together with interesting hybrid compounds through incorporation of a chalcone moiety.

Strategies towards expansion of chemical space of natural product-based compounds to enable drug discovery

Natural products (NPs) are an excellent source of biologically active molecules that provide many biologically biased features that enable innovative designing of synthetic compounds. NPs are characterized by high content of sp3-hybridized carbon atoms; oxygen; spiro, bridged, and linked systems; and stereogenic centers, with high structural diversity. To date, several approaches have been implemented for mapping and navigating into the chemical space of NPs to explore the different aspects of chemical space. The approaches providing novel opportunities to synthesize NP-inspired compound libraries involve NP-based fragments and ring distortion strategies. These methodologies allow access to areas of chemical space that are less explored, and consequently help to overcome the limitations in the use of NPs in drug discovery, such as lack of accessibility and synthetic intractability. In this review, we describe how NPs have recently been used as a platform for the development of diverse compounds with high structural and stereochemical complexity. In addition, we show developed strategies aiming to reengineer NPs toward the expansion of NP-based chemical space by fragment-based approaches and chemical degradation to yield novel compounds to enable drug discovery