Stereoselective Synthesis of Sialylated Tumor-Associated Glycosylamino Acids

Suitably protected sialyl T_N and 2,6-sialyl T tumor-associated carbohydrate antigen-derived amino acids have been prepared stereoselectively using an oxazolidinone-derived sialoside donor. These glycosylamino acids can be employed directly in the solid-phase synthesis of glycopeptides, as demonstrated by the efficient preparation of tumor-associated MUC1 glycopeptide fragments

Total Synthesis of Polydiscamides B, C, and D via a Convergent Native Chemical Ligation–Oxidation Strategy

The first total syntheses of the marine sponge-derived cyclic depsipeptide natural products Polydiscamides B, C, and D are described. The molecules were constructed through the convergent fusion of cyclic and linear fragments via an unprecedented native chemical ligation–oxidation protocol

Synthesis and Utility of β-Selenol-Phenylalanine for Native Chemical Ligation–Deselenization Chemistry

An efficient synthetic route to a suitably protected β-selenol-phenylalanine derivative from commercially available Garner’s aldehyde is described. The incorporation of this building block into peptides and its application in native chemical ligation reactions with peptide thioesters are demonstrated. Ligation products were chemoselectively deselenized (including in the presence of unprotected cysteine residues) to provide native peptides

Total Synthesis of Cyclocitropside A and Its Conversion to Cyclocitropsides B and C via Asparagine Deamidation

The total syntheses of three closely related cyclic peptide natural products, cyclocitropsides A–C, are described. Cyclocitropside A could be readily converted into cyclocitropsides B and C through an asparagine deamidation pathway, indicating that this is a plausible biosynthetic route to these compounds

Native Chemical Ligation–Photodesulfurization in Flow

Native chemical ligation (NCL) combined with desulfurization chemistry has revolutionized the way in which large polypeptides and proteins are accessed by chemical synthesis. Herein, we outline the use of flow chemistry for the ligation-based assembly of polypeptides. We also describe the development of a novel photodesulfurization transformation that, when coupled with flow NCL, enables efficient access to native polypeptides on time scales up to 2 orders of magnitude faster than current batch NCL–desulfurization methods. The power of the new ligation–photodesulfurization flow platform is showcased through the rapid synthesis of the 36 residue clinically approved HIV entry inhibitor enfuvirtide and the peptide diagnostic agent somatorelin

Thiazolidine-Protected β‑Thiol Asparagine: Applications in One-Pot Ligation–Desulfurization Chemistry

The synthesis of a β-thiol asparagine derivative bearing a novel (2,4,6-trimethoxyphenyl)­thiazolidine protecting group is described. The efficient incorporation of the amino acid into the N-termini of peptides is demonstrated as well as the utility of the β-thiol asparagine moiety for rapid ligation reactions with peptide thioesters. The streamlined synthesis of native peptide products could be accomplished using a one-pot radical desulfurization of the β-thiol auxiliary following the ligation event. The utility of the amino acid is highlighted in the efficient one-pot assembly of the HIV entry inhibitor enfuvirtide

Evaluation of peptides derived from MccB17.

<p>(A) Cleavage-complex stabilisation assay of peptides resulting from MccB17(Asn53Lys) digested with trypsin (Mcc[Val27-Ser52]Lys and Mcc[tzoz54-Ile69); ciprofloxacin (CFX), MccB17, and MccB17(Asn53Lys) were included for comparison, as well as a side-product corresponding to Mcc[tzoz54-Ile69] lacking one oxazole ring: Mcc[tzoz54-Gly64-Ser65-Ile69]. The DNA species are annotated as follow: OC (open circular), SC (supercoiled), and Lin (linear). The cleaved DNA band for each compound was quantified, the results are summarized in (B), which presents the amount of cleaved DNA as a percentage of the entire DNA present in the corresponding lane. The mutated MccB17 and the two resulting fragments stabilise the cleavage complex: MccB17(Asn53Lys) and Mcc[Val27-Ser52]Lys show about 2/3rds of MccB17 activity, whereas Mcc[tzoz54-Ile69] has about 1/3rd. Mcc[tzoz54-Gly64-Ser65-Ile69], which is Mcc[tzoz54-Ile69] lacking an oxazole ring as a cleavage-complex stabilisation activity close to baseline (shown as a dotted line).</p

Comparison of MccB17 derivatives and fragments.

<p>Summary of the fragments of MccB17 studied in this work. Sequences, names used in this study, and qualitative stabilisation of cleavage are displayed. The cleavage activity (CA) is colour-coded: green, same level as MccB17; orange, low level of cleavage observed; red, no cleavage observed. The bottom schematic structure is the proposed model template for new gyrase poisons.</p

One-Pot Peptide Ligation–Desulfurization at Glutamate

An efficient methodology for ligation at glutamate (Glu) is described. A γ-thiol-Glu building block was accessed in only three steps from protected glutamic acid and could be incorporated at the N-terminus of peptides. The application of these peptides in one-pot ligation–desulfurization chemistry is demonstrated with a range of peptide thioesters, and the utility of this methodology is highlighted through the synthesis of the osteoporosis peptide drug teriparatide (Forteo)

Removal of the N- or C-terminal amino acids of MccB17.

<p>Comparison of the cleavage-complex stabilisation activity on <i>E. coli</i> gyrase between native MccB17 (Mcc) and MccB17 lacking the first 8 amino acids Mcc[Gly35-Ile69], (A); or MccB17 lacking 1, 2 or 3 C-terminal amino acids (respectively Mcc[Val27-His68]; Mcc[Val27-Ser67]; Mcc[Val27-Gly66]), (B). The DNA species are annotated as follow: OC (open circular), Rel (relaxed), SC (supercoiled), and Lin (linear). The activity is not altered by the removal of N-terminal residues (Mcc[Gly35-Ile69]) whereas removal of C-terminal residues causes the loss of the ability to stabilise the cleavage complex, with Mcc[Val27-Gly66] having no activity.</p