Synthesis multi-step solution-phase

Watts et al. demonstrated multi-step solution-phase synthesis of peptides in a glass microreactor with quantitative yield in 20 min [94]. This should be compared with batch reactions where only moderate yields (40-50%) were obtained in 24 h. Common protecting groups were used, viz. Fmoc was selected for N-protection and Dmab ester for protection of the carboxylic add. The reaction was carried out in the microreactor under electroosmotic flow. Deprotection, which is required to extend the peptide chains beyond dipeptides, was also demonstrated with quantitative yield in the microreactor. In this first microreactor demonstration, only alanine-based peptides were synthesized in later work other amino acids were also used ]95, 96]. 

Vickerstaff, E., Ladlow, M., Ley, S.V., and Warrington. B., FuUy automated multi-step solution phase synthesis using polymer-supported reagents preparation of histone deacetylase inhibitors, Org. Bio-mol Chem., 1, 2419, 2003. 

Under certain condition, however, reactions are still preferably conducted in solution. This is the case e.g., for heterogeneous reactions and for conversions, which deliver complex product mixtures. In the latter case, further conversion of this mixture on the solid support is not desirable. In these instances, the combination of solution chemistry with polymer-assisted conversions can be an advantageous solution. Polymer-assisted synthesis in solution employs the polymer matrix either as a scavenger or for polymeric reagents. In both cases the virtues of solution phase and solid supported chemistry are ideally combined allowing for the preparation of pure products by filtration of the reactive resin. If several reactive polymers are used sequentially, multi-step syntheses can be conducted in a polymer-supported manner in solution as well. As a further advantage, many reactive polymers can be recycled for multiple use. 

The future of solid supported solution phase chemistry will continue to generate many exciting developments. Only in recent years have we truly perceived what might be possible to achieve with these systems in multi-step organic synthesis. Building upon this knowledge platform we believe it is certainly possible to use... 

These macromolecule-based purification methods isolate polymer-bound products from soluble impurities, but do not generally purify the product from other polymer-bound byproducts. Such byproducts arise from incomplete reactions or side reactions and in classical solution chemistry, similar byproducts are removed during product purification at each step of a multi-step synthesis. Support-based methodologies, while removing the multiple, laborious purification steps of a classical synthesis, generally do not provide a method for the purification of intermediates. Instead, these methodologies demand that reaction conditions be optimized such that reactions are driven to completion to avoid a complicated final mixture of products. However, some developed liquid-phase methods achieve high purity of products without quantitative reaction yields [21-26]. 

Paramount to the success of this approach is that efficient and reliable methods and multi-step sequences for the total synthesis of natural products and analogues thereof on polymeric supports are available. The corresponding transformations must proceed with a degree of selectivity and robustness typical of related classical solution phase transformations, irrespective of the stringencies and differing demands imposed by the anchoring to the polymeric support. 

Abstract Recent developments in the microwave-assisted synthesis of heterocycles are surveyed with the focus on diversity-oriented multi-component and multi-step one-pot procedures. Both solution- and solid-phase as well as polymer-supported methodologies for the preparation of libraries of heterocycles are reviewed. Advantages of microwave dielectric heating are highlighted by comparison with conventional thermal conditions. 

PhCH2NPPh3 affords the isocyanide derivative [Os3(CO)g(CNCH2Ph)(n3-ri rri iTi -Ceo)]. The Staudinger reaction in combination with an intramolecular aza-Wittig ring closure reaction has been applied in the synthesis of quinazolin-4-ones. Other examples of intramolecular aza-Wittig reactions are reported as parts in multi-step synthetic routes. A theoretical study of the aza-Wittig reaction of HN = PX3(X = H and Cl) with formaldehyde in the gas phase and in solution has been reported. ... 

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