Orthogonal scheme peptides

Redox-sensitive resin 24 designed for solid-phase peptide synthesis (SPPS) [29] was prepared from commercially available 2,5-dimethylben-zoquinone in seven steps [30] and loaded to a support via a Wittig reaction. Release of the peptide occurs using two sequential mild conditions, reduction with NaBH4 followed by TBAF-catalyzed cyclic ether formation (Scheme 8) which provide orthogonality to acid sensitive reactions. 

Due to the vast numbers and rapidity of novel developments in solid-phase synthesis over the past ten years, a number of reports currently found in the literature deal with solid-phase syntheses of lanthionine peptides. There are at least two different approaches to synthesize lanthionine peptides in which the sulfide bond links amino acid halves that are not direct neighbors within the peptide chain (Scheme 10). One obvious approach, method A, is based on the coupling of a preformed, orthogonally protected lanthionine monomer to the N-terminus of a peptide oxime resin. 48 This is then followed by acid-catalyzed cyclization and simultaneous release from the resin during amide bond formation with the C-terminal carboxy group via the peptide cyclization method on oxime resin (see Section 6.73.2.2). The alternative approach is lanthionine formation after peptide synthesis from amino acid derivatives, such as serine and cysteine (method B). 

Scheme 10 Orthogonally Protected Cystathionine Derivatives as Intermediates for Peptide Synthesis...

In the case of bi- or tricyclic peptides more than three levels of orthogonality in the protecting schemes is required (see Section 6.8.3.2.5). 

The majority of cyclic peptides synthesized on solid support are cyclized in the head-to-side-chain or side-chain-to-side-chain mode. For this purpose the amino acids involved in cyclization must be side-chain protected in a manner that allows for an additional level of orthogonal deprotection. Thus, upon assembly of the fully protected linear precursor on-resin, deprotection of the functionalities involved in the lactam ring formation is performed, followed by regio-selective cyclization by amide bond formation, and finally by the resin-cleavage/deprotection step as outlined in Scheme 16. In Table 8, examples of syntheses of such cyclic peptides are listed with the relevant information regarding protection scheme, resin anchor, and mode of cyclization. 

Scheme 5 Combined Solid-Phase and Solution Strategy for the Synthesis of Regioselectively Addressable Functionalized Templates (RAFT) with Four Orthogonally Protected Lysine Side Chains for Sequential Attachment of Four Different Peptide Sequences 171...

Two independent folding domains, e.g. a 4-helix bundle domain and a (3-barrel, can be combined in a TASP molecule by using a template molecule with suitably oriented, orthogonally protected functional groups as attachment sites for the stepwise assembly of the peptide segments (Scheme 12)J47l... 

The use of oxime bond formation with orthogonal protection techniques allows the efficient construction of an antiparallel four-helix-bundle TASP122 (Scheme 19) by condensing amphiphilic peptide blocks, containing aldehyde functions at the C- or N-terminus, to a topological template functionalized with selectively addressable aminooxy acetic acid moieties, t20,22,971... 

---