1,3-Diaza-Claisen Rearrangements of Vinyl Pyrrolidines Tethered to In Situ Generated Carbodiimides Afford Ring-Expanded [9,5]- and [9,6]-Bicyclic Guanidines.

Vinyl pyrrolidines tethered to isothioureas are activated to the corresponding carbodiimides with AgOTf and EtN. Intramolecular addition of the vinyl pyrrolidine amine to the carbodiimide followed by a 1,3-diaza-Claisen rearrangement affords [9,5]- and [9,6]-bicyclic guanidines depending on the tether length in good to excellent yields. Density functional theory calculations reveal that the pathway involving intramolecular addition of the amine to carbodiimide to afford a zwitterionic intermediate followed by the zwitterionic 1,3-diaza-Claisen rearrangement was consistently a higher energy pathway than the path involving protonation of the zwitterionic intermediate followed by the cationic 1,3-diaza-Claisen rearrangement.

Broadening the Scope of the Zwitterionic 1,3-Diaza-Claisen Rearrangement through a Tethering Strategy.

Expansion of the scope of the 1,3-diaza-Claisen rearrangement beyond bridged-bicyclic tertiary allylic amines has been investigated through a tethering strategy. Isothioureas tethered to tertiary allylic amines are converted to carbodiimides through a reaction with AgOTf/EtN. Intramolecular cyclization of the tertiary allylic amine to the carbodiimide equilibrates with a zwitterionic intermediate.

Intramolecular Formation of Zwitterionic Intermediates in 1,3-Diaza-Claisen Rearrangements.

Isothioureas tethered to bridged-bicyclic tertiary allylic amines can be converted to carbodiimides through reaction with Hg(II) salts. Intramolecular cyclization of the tethered tertiary allylic amines to the carbodiimides afford zwitterionic intermediates that undergo 1,3-diaza-Claisen rearrangements, affording highly substituted tricyclic guanidines.

Structure-reactivity relationships of zwitterionic 1,3-diaza-Claisen rearrangements.

Bridged bicyclic tertiary allylic amines aza-norbornene 1 and isoquinuclidene 2 add to isocyanates, isothiocyanates, and in situ-generated carbodiimides to form zwitterionic intermediates that undergo 1,3-diaza-Claisen rearrangements to afford highly substituted ureas, thioureas, and guanidines, respectively. Aza-norbornene 1 is significantly more reactive toward 1,3-diaza-Claisen rearrangements than isoquinuclidene 2. This reactivity difference is most likely due to the inherent ring strain in the aza-bicyclo[2.

On-resin synthesis of novel arginine-isostere peptides bearing substituted amidine headgroups.

A methodology is presented for the facile synthesis of Arg-containing peptides modified at the guanidine headgroup as substituted amidine cores. This process allows for the iterative construction of these Arg isosteres while the peptide is being built out on the solid support, providing a high potential for diversity in substitution pattern in the resulting peptide. A series of N-Pmc-substituted thioamides were condensed with deprotected δ-N Orn-bearing peptides while attached to the solid support using Mukaiyama's reagent as coupling reagent, yielding isosteric Arg-containing analogs.

Facile 1,3-diaza-Claisen rearrangements of tertiary allylic amines bearing an electron-deficient alkene.

Tertiary allylic amines with an electron-deficient alkene react with isocyanates and isothiocyanates to give highly substituted ureas and thioureas arising from formal 1,3-diaza-Claisen rearrangements. Isocyanates and isothiocyanates with strong electron-withdrawing groups are more reactive. Similarly, the data suggest that a stronger electron-withdrawing substituent on the alkene favors a faster reaction, but this may be offset by sterics in the cyclic transition state.

Strategies for the solid-phase diversification of poly-L-proline-type II peptide mimic scaffolds and peptide scaffolds through guanidinylation.

A strategy for the solid-phase diversification of PPII mimic scaffolds through guanidinylation is presented. The approach involves the synthesis N-Pmc-N'-alkyl thioureas as diversification reagents. Analogues of Fmoc-Orn(Mtt)-OH can be incorporated into a growing peptide chain on Wang resin.

Synthesis of conformationally constrained lysine analogues.

The synthesis of two conformationally constrained lysine analogues is reported. The synthesis of the novel analogue 1 based on the 3-aza-bicyclo[3.1.

A 1,3-Diaza-Claisen rearrangement that affords guanidines.

[reaction: see text] N-Alkyl-N'-tosylthioureas activated by EDCI react with azanorbonenes at room temperature through a 1,3-diaza-Claisen rearrangement, affording highly substituted, bicyclic guanidines in moderate to good yields.