A Novel Resin Linker for Solid-Phase Peptide Synthesis Which Can Be Cleaved Using Two Sequential Mild Reactions

Abstract

The interest in developing new linkers for solid-phase peptide and organic synthesis has increased tremendously as a result of the rapid development of combinatorial chemistry. Herein, we report the development of a new redox-sensitive linker for solid-phase peptide synthesis. This linker can be readily cleaved under mild conditions by using two sequential mild reactions, a reduction followed by a base (Bu4N+F-)-catalyzed cyclic ether formation. By using this new linker, two short peptides, a tetrapeptide [Boc-Trp-Ala-Gly-Gly-OH] and a pentapeptide [Boc-Asn-Ala-Ser(OBn)-Gly-Glu(OBn)-OH)], were synthesized. Because the cleavage does not use acidic conditions, this resin linker provides an alternative when acidic conditions are not desirable. Furthermore, the cleavage conditions do not affect most of the side chain protecting group. Therefore, the peptides synthesized can be used for the segment synthesis of larger peptides without the need to reprotect the side chain functional groups.

Self‐Immolative Spacers: Kinetic Aspects, Structure–Property Relationships, and Applications

“…Self-Immolation by Cyclization Self-immolative spacers exploiting cyclization for their disassembly,i ncorporate linkers based on alkyl chains (Figure 3a,b), [15,[59][60][61][62][63] or on ortho mono-or disubstituted aromatic spacers (Figure 3c-e). [62,[64][65][66][67][68][69][70] Once activated, their disassembly involves anucleophilic attack on acarbonyl group (Figure 3a-d) or an electrophilic aliphatic carbon atom ( Figure 3e). [68] Thea ssociated cyclization occurs directly after activation or after apreliminary elimination step (Figure 3b).…”

“…[62,[64][65][66][67][68][69][70] Once activated, their disassembly involves anucleophilic attack on acarbonyl group (Figure 3a-d) or an electrophilic aliphatic carbon atom ( Figure 3e). [68] Thea ssociated cyclization occurs directly after activation or after apreliminary elimination step (Figure 3b). [59] As with electronic delocalization, self-immolation is driven by ap ositive reaction entropy and by the formation of thermodynamically stable products (5-and 6-membered rings).…”

Selbstzerlegende Spacer: kinetische Aspekte, Struktur‐Eigenschafts‐Beziehungen und Anwendungen

“…62, 64–70 Nach der Aktivierung verläuft ihr Abbau über den nukleophilen Angriff auf eine Carbonylgruppe (Abbildung 3 a–d) oder ein elektrophiles aliphatisches Kohlenstoffatom (Abbildung 3 e). 68 Die zugehörige Cyclisierung erfolgt unmittelbar nach der Aktivierung oder im Anschluss an einen vorherigen Eliminierungsschritt (Abbildung 3 b). 59 Die Selbstzerlegung wird wie die Elektronendelokalisierung durch die positive Reaktionsentropie und die Bildung thermodynamisch stabiler Produkte (fünf‐ und sechsgliedrige Ringe) gesteuert.…”

Effect of bond‐length alternation on the dipole hyperpolarizability of phenol blue

“…An alternative cleavage strategy to access carboxylic acids employs the so‐called “safety‐catch” linkers: Hulme et al have described a Boc activation of a benzamide linker45a immediately prior to cleavage with LiOH (PACT HO−C(O)), and Backes and Ellman have employed Kenner's acylsulfonamide linker45b which is stable under basic conditions but activated to nucleophilic displacement with LiOH by N‐methylation with diazomethane. Along similar lines, an unusual linking device possessing the redox‐sensitive p ‐benzoquinone core (Scheme ) cyclizes on reduction to the hydroquinone to expel the acid 45c. The mild reduction and base‐catalyzed formation of the cyclic ether (using Na 2 S 2 O 4 and Bu 4 N + F − , respectively) provide an alternative procedure where acid conditions are undesirable.…”