A new synthesis is reported for 4-aminoimidazo[l,2-~]-1,3,5-triazin-2( IH)-one ( = 5-aza-7-deaza-isoguanosine; S), a purine analog that, when incorporated into an oligonucleotide chain, presents a H-bond donor-acceptor-acceptor pattern to a complementary pyrimidine analog. A protected ribose derivative was coupled to 8 to yield 4-amin0-8-(8-~-ribofuranosyl)imidazo[ 1,2-~]-1,3,5-triazin-2(8H)-one ( = 5-aza-7-deaza-isoguanosine; 11) after deprotection, Alternatively, direct synthesis of both the ribo derivative 11 and the corresponding deoxyribo derivative 17 as the 8-D-anomers was achieved using the enzyme purine nucleoside phosphorylase in a one-pot reaction. This adapts a known synthetic approach to yield a new strategy for obtaining diastereoisomerically pure deoxyribonucleoside analogs on 1-gram scales.
A novel strategy for the synthesis of (R)- and (S)-alpha-methyl(alkyl)serine-containing peptides is presented. Using (S)-phenylalanine cyclohexylamide 6 as chiral auxiliary, the optically pure azlactones (R)- and (S)-2 were synthesized via a novel azlactone/oxazoline interconversion reaction (Figures 3 and 6). These azlactones constitute fully protected and activated synthetic equivalents of (R)- and (S)-alpha-methylserine and can be directly incorporated into peptides without further protective group manipulations. Like other alpha,alpha-dialkylated glycines, optically pure alpha-alkylserines can be used to stabilize beta-turn and alpha-helical conformations in short peptides.
Abstract:The present work describes three novel nonpolar host peptide sequences that provide a ready assessment of the 3 10 -and a-helix compatibilities of natural and unnatural amino acids at different positions of small-to medium-size peptides. The unpolar peptides containing Ala, Aib, and a C-terminal p-iodoanilide group were designed in such a way that the peptides could be rapidly assembled in a modular fashion, were highly soluble in solvent mixtures of nmr spectroscopic analyses, and showed excellent crystallinity suited for x-ray structure analysis. To validate our approach we synthesized 9-mer peptides 79a-96 (Table IV), 12-mer peptides 99-110c (Table V), and 10-mer peptides 120a-125d and 129-133 (Table VI and Scheme 8)
incorporating a series of optically pure cyclic and open-chain (R)-and (S)-a,a-disubstituted glycines 1-10 (Figure 2). These amino acids are known to significantly modulate the conformations of small peptides.Based on x-ray structures of 9-mers 79a, 80, and 87 (Figures 4-7), 10-mers 124c, 131, and 132 (Figures 9-12), and 12-mer peptide 102b (Figure 13)
Parallel synthesis of focused compound libraries for hit confirmation and lead optimization are certainly important drivers for shortening the lead discovery phase in the pharmaceutical and crop protection industries. In this article we show with permission of Roche and Syngenta three
real case studies where Polyphor synthesized focused libraries for lead validation and optimization using high-throughput parallel synthesis and purification techniques. The three examples differ significantly in the synthetic strategies which were employed as well as in the chemical complexity
of the final products. A multigeneration approach towards insecticidal triazines, the application of a sequential three-component reaction towards insecticidal and fungicidal thiazoles and finally a multistep synthesis approach of advanced building blocks followed by a two-step final derivatization
towards novel antiviral N-hydroxy-indolin-2-ones are presented. In all cases 100–200 analogues were synthesized using parallel synthesis in solution followed by purification of the final products by parallel flash or high-throughput (unattended) HPLC (coupled to MS) within four months.
Promising biological results were obtained in all three cases.
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