Recent developments in isocyanide based multicomponent reactions in applied chemistry

Multicomponent reactions (MCRs) are fundamentally different from two-component reactions in several aspects. Among the MCRs, those with isocyanides have developed into popular organic-chemical reactions in the pharmaceutical industry for the preparation of compound libraries of low-molecular druglike compounds. With a small set of starting materials, very large libraries can be built up within a short time, which can then be used for research on medicinal substances. Due to the intensive research of the last few years, many new backbone types have become accessible. MCRs are also increasingly being employed in the total synthesis of natural products. MCRs and especially MCRs with isocyanides offer many opportunities to attain new reactions and basic structures. However, this requires that the chemist learns the “language” of MCRs, something that this review wishes to stimulate.

Multicomponent Reactions with Isocyanides.

/pdf/aryl-aryl-bond-formation-one-century-after-the-discovery-of-1jdyxlkwix.pdf

Aryl-aryl bond formation one century after the discovery of the Ullmann reaction.

Multicolor optical coding for biological assays has been achieved by embedding different-sized quantum dots (zinc sulfide-capped cadmium selenide nanocrystals) into polymeric microbeads at precisely controlled ratios. Their novel optical properties (e.g., size-tunable emission and simultaneous excitation) render these highly luminescent quantum dots (QDs) ideal fluorophores for wavelength-and-intensity multiplexing. The use of 10 intensity levels and 6 colors could theoretically code one million nucleic acid or protein sequences. Imaging and spectroscopic measurements indicate that the QD-tagged beads are highly uniform and reproducible, yielding bead identification accuracies as high as 99.99% under favorable conditions. DNA hybridization studies demonstrate that the coding and target signals can be simultaneously read at the single-bead level. This spectral coding technology is expected to open new opportunities in gene expression studies, high-throughput screening, and medical diagnostics.

https://faculty.washington.edu/xgao/Images/QD-beads.pdf

Quantum-dot-tagged microbeads for multiplexed optical coding of biomolecules.

https://www.erowid.org/archive/rhodium/pdf/suzuki.cross-coupling.review.1995-1998.pdf

Recent advances in the cross-coupling reactions of organoboron derivatives with organic electrophiles, 1995–1998

Historically, the paradigm of drug development has followed an iterative cycle of screening and synthesis, involving the manipulation of individual structures. The feedstock of molecules for this process has traditionally incorporated both natural products and proprietary and commercial compound collections. The latter usually represent a collectively monumental effort of synthesis over a period of many years. The introduction of high-throughput biological screening and the accelerated discovery of new biological targets has increased the demand on synthetic chemists to produce new compounds for testing. One response to this demand has been the development of techniques to greatly increase the speed and efficiency of compound synthesis. In the case of peptides1-4 and oligonucleotides,5,6 combinatorial libraries containing large numbers of individual components have afforded high-affinity ligands and potent inhibitors to a variety of targets. However, synthetic methods for these biopolymers are well-established, and it is only recently that chemists have applied some of these strategies to the currently more difficult task of generating libraries of small-molecule therapeutics. In this Account, we will focus on multiple-component condensations (MCCs) as one subset of strategies for the generation of compound libraries. While most libraries have been generated using a linear, multistep process, MCCs provide a complementary approach to a number of structures and should find applications in library generation. Multiple-component condensations are those reactions in which three or more reactants come together in a single reaction vessel to form a new product which contains portions of all the components. These reactions may be carried out in solution or on a solid support. A catalyst or other additive which might facilitate the coupling of two other components in a reaction but which does not structurally contribute to the product is not considered a component in an MCC reaction. It is not necessary that all components condense in a mechanistically concerted fashion; however, the MCC reactions considered herein do not require extensive manipulations: they are one-pot reactions. In this and the succeeding section, it is instructive to contrast this approach with linear synthesis to highlight the differences in methods, potential library size, and output format. For example, an MCC reaction with four components provides, in a single step, a molecular scaffold characterized by a core set of atoms common to the condensation reaction and displaying aspects of the four components. In contrast, to achieve the same structure in a linear fashion, multiple steps with attendant workup cycles may be required. It is our belief that the methods used to synthesize a particular library are dictated by (1) the need for a specific core structure and (2) the commercial availability or ease of access to inputs which give the structural variability to the core. Approaches to desired core structures vary greatly, and the chosen route may be a linear synthesis, an MCC, or a combination of the two. The term linear synthesis as used in this Account refers to a multistep process requiring the isolation of intermediates or washing of the solid support resin and re-exposure to new reagents for each step of the synthesis. While synthetic chemists may be more familiar with the distinction between “linear” and “convergent” when applied to synthetic strategies, in this Account we refer to as linear any library strategy that builds up the target molecule one step at a time. By this definition, both a solid-phase peptide synthesis and, for example, Ellman’s 1,4-benzodiazepine synthesis7 (Figure 1) constitute linear syntheses, because each constructs the target skeleton in a stepwise manner. We define “linear” in this manner as a means of distinguishing the MCC strategy, which we feel is an underutilized tool for library synthesis.8 This Account will focus on two related core struc-

Multiple-Component Condensation Strategies for Combinatorial Library Synthesis

Radio Frequency Tag Encoded Combinatorial Library Method for the Discovery of Tripeptide-Substituted Cinnamic Acid Inhibitors of the Protein Tyrosine Phosphatase PTP1B

The concept of a “universal isocyanide” that enables postcondensation modification of Ugi four-component condensation products is introduced. This strategy is suited for the synthesis of libraries. By using 1-isocyanocyclohexene as the isocyanide input in the Ugi reaction, the product cyclohexenamides can be converted to a variety of products. From the original α-(acylamino) amides, new carboxylic acids, esters, and thioesters are produced from acid-activated conversion of the cyclohexenamide moiety. It has been determined that the intermediate in conversion of this type is an oxazolinium-5-one (munchnone) that reacts with many nucleophiles to yield the products above. The munchnone can also undergo cycloaddition with acetylenic dipolarophiles to form pyrroles. Through internal nucleophilic attack, Ugi products are shown to convert to a protected monosaccharide derivative and to 1,4-benzodiazepine-2,5-diones. All of the conversions described consist of a single step. Resin capture of Ugi products is demon...

Postcondensation Modifications of Ugi Four-Component Condensation Products: 1-Isocyanocyclohexene as a Convertible Isocyanide. Mechanism of Conversion, Synthesis of Diverse Structures, and Demonstration of Resin Capture

Dramatic rate enhancement of Suzuki diene synthesis. Its application to palytoxin synthesis

The present invention provides labeled synthetic libraries of random oligomers and methods and apparatus for generating labeled synthetic oligomer libraries. Each member of such a library is labeled with a unique identifier tag that specifies the structure or sequence of the oligomer. In a preferred embodiment of the present invention the identifier tag is a microchip that is pre-encoded or encodable with information that is related back to a detector when the identifier tag is pulsed with electromagnetic radiation.

Robert W. Armstrong

Papers

Multiple-Component Condensation Strategies for Combinatorial Library Synthesis

Radio Frequency Tag Encoded Combinatorial Library Method for the Discovery of Tripeptide-Substituted Cinnamic Acid Inhibitors of the Protein Tyrosine Phosphatase PTP1B

Postcondensation Modifications of Ugi Four-Component Condensation Products: 1-Isocyanocyclohexene as a Convertible Isocyanide. Mechanism of Conversion, Synthesis of Diverse Structures, and Demonstration of Resin Capture

Dramatic rate enhancement of Suzuki diene synthesis. Its application to palytoxin synthesis

Methods and apparatus for synthesizing labeled combinatorial chemistry libraries