Large-scale synthesis solution phase

SAPPHO is a powerful new innovative technology for the automated large scale synthesis of peptides in solution phase, which can lead to significant cost saving of up to 50 % compared to the traditional technologies (in homogeneous phase or Merrifield phase). 

The parent [3]radialene (2) has been obtained by 1,2- and 1,4-elimination reactions from cyclopropane derivatives 8 [2,11], 9 [12], 10 [12], and 11 [13] in very low to moderate yields (Scheme 4.1). Later, a practical large-scale synthesis of triethyl cyclopropane-la,2a,3P-tricarboxylate [14] has facilitated the synthesis of 2 via l,2,3-tris(iodomethyl)cyclopropane (10). All transformations were performed as gas-phase reactions, and the radialene was condensed in a cold trap. Liquid 2 is stable at -78 °C for some days, but it easily polymerizes under other conditions (in the presence of oxygen, in CCl solution at 0 C, by bringingthe vapor to room temperature). 

The synthetic 21-amino acid polypeptide KL4 [(KL4)4K] was developed as a pulmonary surfactant to be used in treatment of respiratory distress syndrome (RDS) in infants (IRDS) and in adults (ARDS). KL4 is designed to contain intermittent hydrophobic (Leucine) and hydrophilic (Lysine) regions to mimic the structure of the natural surfactant protein B (SP-B). The solution phase synthesis of KL4 is a challenging task. The protection and deprotection patterns, the possibility of diastereomer formation in every coupling step, the solubility (or lack of it) of the different fragments and the isolation of intermediates are among the potential problems that face such a synthesis. The process research work resulted in a successful and efficient large scale synthesis of KL4 which will be discussed. 

Today peptide synthesis is a mainstream operation in many big laboratories. Several companies have in addition specialized in providing custom-ordered peptides, e.g., large-scale peptides (made in solution), peptide libraries (made on cellulose membranes), or most commonly small peptide quantities (made on resin, solid phase synthesis). Although peptides are considered rather stabile in many test assays, concerns have been raised regarding their stability in presence of human serum. 

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