A new process for SPPS is presented that allows for cycle times of only 4 minutes along with up to 90% reduction in total chemical waste compared to existing methods. In all cases this new process has met or exceeded the maximum purity we have observed using either conventional or standard microwave assisted SPPS with close scrutiny of well-known side reactions such as aspartimide formation and epimerization. Substantial economic and environmental value is realized from major solvent reduction, replacement of the controlled substance piperidine with a novel piperazine deblocking cocktail, use of a low cost enhanced carbodiimide based activation, and the ability to use high substitution resins (> 0.6 mmol/g). Recently developed derivatives for cysteine and histidine were also explored and will be discussed.
The application of these new methods is demonstrated on a new automated microwave peptide synthesizer which allows the total synthesis and cleavage of average length peptides to be as short as standard purification methods. The scalability of this new process was then demonstrated utilizing a new automated 2.5 liter microwave peptide synthesizer. This new process for SPPS will have a major impact on synthesis of difficult peptides, high throughput peptide production, and larger scale peptide production as it offers improvements in speed, chemical usage, and synthesis efficiency.