Recent Advances in Analytical Construct Resins

Abstract

The area of solid-phase synthesis has witnessed exponential growth in the last fifteen years, but difficulties associated with the monitoring and analysis of resin-bound reactions and products have been apparent due to a limited number of analytical methods available. With the substrate tethered to an insoluble support traditional chromatographic monitoring is only possible after cleavage. In order to address this 'analytical bottleneck' Geysen, in 1996 elaborated Merrifield's initial dual linker strategy by incorporating an encoding system between two in-line linkers. These analytical construct resins represented a new approach for both the quality control of solid-phase combinatorial libraries and for the development of new synthetic sequences on solid-support. This review will summarize the development and application of analytical construct resins focusing on recent applications of the technology.

High-Throughput Physical Organic Chemistry Hammett Parameter Evaluation

“…Spurred on by these developments in supported organic synthesis, resins have been exploited in an increasingly wide variety of areas, such as the heterogenization of homogeneous catalysts, the immobilization of pH and oligonucleotide sensors, , fluorescence resonance energy transfer (FRET)-based sensors for monitoring carbohydrate and glycoprotein binding to lectins, self-indicating catalysts with beads carrying both a catalyst and a pH indicator, and so-called dyad beads carrying both a catalyst and the acceptor half of a Diels−Alder reaction . With so many chemistries now taking place on solid supports, a variety of increasingly sophisticated techniques have been put into place to allow reactions to be analyzed and followed directly on the solid support, including, for example, attenuated total reflectance (ATR) Fourier transform infrared (FT-IR) and magic angle spinning nuclear magnetic resonance (MAS NMR) spectroscopies, , as well as a host of mass spectrometry (MS)-based approaches. − In this last area, a great enhancement has been brought about by a series of tools termed “analytical constructs” which have seen widespread application as a means of bead decoding, reaction monitoring, , reaction evaluation and optimization, , the development of new solid-phase linkers, , and studies of their chemical compatibility. , The “analytical construct” works by releasing from the solid support a molecule that is attached to a MS sensitizing moiety, which ensures uniformity of ionization and, ideally, an isotopic label (inducing peak splitting) to enable the rapid extraction of the desired product information from the background of the mass spectrum . Occasionally, an ultra violet (UV) chromophore has also been included .…”

“…Occasionally, an ultra violet (UV) chromophore has also been included . Typically, these analytical constructs have consisted of a dual solid-phase linker system providing two orthogonal cleavage points between the reactive site and the solid support, sometimes being achieved by use of photocleavable linkers . Despite recent developments, however, the technique of analytical constructs has remained mainly qualitative, with most attempts at drawing quantitative conclusions involving high performance liquid chromatography (HPLC) separation and UV-based quantitation. , …”