Lactam bridge

The following data are closely related to the results of a Russian team, who synthesized lactone- and lactam-bridged photochromes and studied their transformations. 2,5-Dimethyl-3-thienylacetic acid with a-chloro ketone in base gives ester 206, which undergoes cyclization when heated with K2CO3 in DMF under an inert atmosphere to give lactone 207 in 70-75% yields (Scheme 61). The reaction can be performed in situ without isolation of the ester (06ZOR1827)... 

Similarly, the mixed homodetic/heterodetic bicyclic structures containing a disulfide bridge are preferably produced as monocyclic compounds that are then typically oxidized in solution adopting standard procedures as described in Section 6.1.1 (Scheme 23, path Bl). If even disulfide formation is performed on resin by the procedures reported in Section 6.1.2, an additional level of selective protection is required for the cysteine thiol functions. The synthetic paths Bl and B2 are also applicable for the synthesis of type II and III bicyclic peptides, independent of whether only lactam bridges are produced or mixtures of lactam/ disulfide bridges. 

Insertion of two overlapping i, i + 4 lactam bridges in the terminally protected hexa-peptide Boc-Lys-Lys-Ala-Ala-Asp-Asp-OPac results in a highly conformationally constrained structure 27 (Scheme 16).[l52 CD spectra showed a rigid structure that exhibited only partial melting at high temperature, while NMR studies in TFE-d3/H20 revealed a predominantly a-helical structure, as judged by observed NOEs. 

Scheme 16 A Terminally Protected Hexapeptide with Two Lactam Bridges 1521...

The field of peptide synthesis is never far removed from the study of natural products, many of which exhibit peptide and peptidomimetic structures. It is fitting that this treatise be concluded with a section on the synthesis of key peptide-based natural products. Section 16 commences with the synthesis of bacitracin)30 a cyclic peptide with antibiotic properties. The synthesis of this target structure is carried out in solution and by solid-phase chemistry. The molecule contains a lactam-bridged cyclic heptapeptide with a pendent tripeptide (Section 16.1.1). An elegant route to the synthesis of the thiazoline building block is included. 

Table 1 Amino Acid Sequences and Circular Dichroism Results of Lactam-Bridged and Linear Pep-tides[117-118l...

Although not shown in Table 1, other peptides synthesized with different lactam sizes (one or two i, i+3 lactams) or different orientations of the lactam bridge (Glu-Lys versus... 

All peptides were prepared by solid-phase peptide synthesis on a peptide synthesizer. [1171 Various protection groups were used for the terminal positions and side-chain functionalities of the amino acids. The coupling mixture consisted of HBTU/HOBt/amino acid/NMM. Deprotection of the desired side chains with piperidine in NMP, followed by cyclization with HBTU/HOBt/NMM in HFIP/NMP, led to the formation of lactam bridges on the resin. 

Scheme 9 Lactam-Bridged Coiled-Coil Library Templatel12512"10 11...

Above Linear peptide sequence. The letters a to g denote the heptad repeat, while the five sites for library display are represented by the letter X. Lactam bridges are formed between Glu6 and LyslO and between Glu23 and Lys27. 

Synthesis of Lactam-Bridge-Stabilized Coiled-Coil Templates for Combinatorial Peptide Libraries... 

A summary of the fragment condensation approach to synthesis of the coiled-coil library is shown in Scheme 10. The library was synthesized in two fragments using Fmoc chemistry the C-terminal fragment (residues 11-27) housed the library positions (labeled X in Scheme 10) and the C-terminal lactam the N-terminal fragment (residues 1-10) contained the Cys-Gly-Gly linker and N-terminal lactam bridge. 

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