Direct palladium-mediated on-resin disulfide formation from Allocam protected peptides

Abstract

The synthesis of disulfide-containing polypeptides represents a long-standing challenge in peptide chemistry, and broadly applicable methods for the construction of disulfides are in constant demand. Few strategies exist for on-resin formation of disulfides directly from their protected counterparts. We present herein a novel strategy for the on-resin construction of disulfides directly from Allocam-protected cysteines. Our palladium-mediated approach is mild and uses readily available reagents, requiring no special equipment. No reduced peptide intermediates or S-allylated products are observed, and no residual palladium can be detected in the final products. The utility of this method is demonstrated through the synthesis of the C-carboxy analog of oxytocin.

Epimerization-free access to C-terminal cysteine peptide acids, carboxamides, secondary amides, and estersviacomplimentary strategies

“…Next, we sought to demonstrate the viability of this cleavage strategy in the context of more complex peptides. Because of our interest in disulfide-linked neuroactive peptides, 29 we targeted the C-terminal carboxamide α-conotoxin ImI ( 10 ), a sub-type selective nicotinic acetylcholine receptor antagonist 30 isolated from the venom of Conus imperialis marine snails ( Scheme 2 ). 31 , 32 Both the C-terminal carboxamide and the correct disulfide bond connectivity are important to the bioactivity of α-ImI ( 10 ).…”

Stepwise Construction of Disulfides in Peptides

“…The photolabile thiol protecting group 2‐nitroveratryl (oNv) could be removed upon irradiation at 350 nm for 30 min . Both allyl‐based groups, allyloxycarbonyl‐aminomethyl (Allocam) and allyl (All) can be cleaved under Pd 0 π–allyl conditions . Recently, it was reported that the Acm group could be cleaved by the use of Pd II Cl 2 .…”

“…The treatment of two S−Allocam groups of a resin‐bound peptide by Pd(OAc) 2 in a mixed solvent of DMSO/NMM/AcOH has been successfully used to construct a disulfide . Although such Pd‐mediated conditions are orthogonal to most protecting groups, it is worth noting that PdCl 2 was recently found to deprotect the S−Acm group …”

Raising the bar on-bead: Efficient on-resin synthesis of α-conotoxin LvIA

“…8 As a first step toward expanding the toolbox of on-resin disulfide-forming methods, 9 we recently reported a new strategy for on-resin disulfide formation by Pd-mediated 10 removal of the allyloxycarbonyl aminomethyl (Allocam, Figure 1B) protecting group with in situ oxidation. 11 In this manuscript, we harness the utility of the Allocam group to develop three new on-resin methods for the synthesis of the two-disulfide polypeptide α4/7-conotoxin LvIA.…”

“…To determine the stability of common protecting groups to our Allocam removal conditions, we synthesized model peptides 2-TGT bearing four common protecting groups and subjected them to our previously optimized Allocam removal/oxidation conditions (Scheme l). 11,18 Treatment of the mono- methoxytrityl (Mmt)-protected peptide 2-TGT led to a mixture of partial cleavage products, disulfide 3 , and starting peptide 2-OH . The acetamidomethyl (Acm) group was also unstable, leading mainly to oxidized peptide 3 .…”