De Novo Design, Synthesis, and X-ray Crystal Structures of Pyrrolinone-Based .beta.-Strand Peptidomimetics

Development of small molecules designed to modulate protein–protein interactions

“…Gellman and his colleagues [156,157] suggested that heterochiral dinipecotic acid segments, R-Nip-S-Nip and S-Nip-R-Nip, could also promote reverse-turn formation. Smith et al also established the 3,5- [158,159] (nitrogen displaced) and 2,5-linked [160] (carbonyl displaced) homochiral polypyrrolinone motif as excellent b-sheet/b-strand mimetics both in the solid state and in solution, and further demonstrated that 3,5-linked heterochiral polypyrrolinones preferentially adopt a turn conformation [161]. Che and Marshall [162] suggested a combined approach -CTPs based on heterochiral dipeptides of chimeric amino acids -to be used as novel conformational templates (Figure 13), for instance, cyclo-(D-Pro-L-Pro-D-Pro), as synthetic routes to chimeric prolines containing 2-, 3-, 4-, or 5-substituents are abundant.…”

Non-covalent S⋯O interactions control conformation in a scaffold that disrupts islet amyloid polypeptide fibrillation

“…This increases the population of the desired conformer and thus reduces the entropic cost of binding. Previous non-peptidic scaffolds have taken advantage of hydrogen bonding, 12–16 the stereoelectronic preferences of secondary aryl amides, 13,17,18 steric repulsion between vicinal cyclic systems, 19,20 dipolar repulsion, 21,22 cyclisation, 23 and metal templation 24 to provide conformational pre-organisation (Fig. 1).…”

A Pictet-Spengler Cyclisation Methodology for the Construction of Nonproteinogenic Tetrahydroisoquinoline Quaternary Amino Acids

“…The colourless imine precipitated and was collected, dried, and treated with allyl chloroformate to induce cyclisation to the corresponding cis-oxazolidinone 9 with concomitant N-acylation in excellent yield. 6 We found that the addition of a catalytic amount of BF 3 ·OEt 2 reduced the reaction time of this last step from two weeks to three days while retaining a similar high yield. Diastereoselective alkylation of 9 by deprotonation with KHMDS in THF at -78°C followed by addition of iodomethane furnished the a-methylated oxazolidinone 10 in excellent yield with a >20:1 ratio of stereoisomers.…”

“…Smith has published a highly enantioselective synthesis of a-alkylated amino acids including derivatives of leucine, valine, and phenylalanine (8). 6 Following the work of Smith (Scheme 1), the dried sodium salt of phenylalanine was treated with pivaldehyde under reflux in toluene. The colourless imine precipitated and was collected, dried, and treated with allyl chloroformate to induce cyclisation to the corresponding cis-oxazolidinone 9 with concomitant N-acylation in excellent yield.…”

“…The alloc protecting group was then removed using catalytic Pd(PPh 3 ) 4 in the presence of dimedone, providing the required amino ester 13 in 91% yield. 6 We then returned to the Pictet-Spengler reaction to form the required tetrahydroisoquinoline. This step, however, now proved to be problematic.…”