Synthesis of Endocyclic Cycloalkyne Amino Acids

“Click-ligation”
is a widely adopted and valuable
means to ligate biomolecules whereby two appended biologically inert
moieties, such as alkynes and azides, link by cycloaddition. For terminal
alkynes, Cu+1 catalysis is required which degrades oligonucleotides
by catalyzing their hydrolysis but is also physiologically incompatible.
The smallest activated alkynes that do not require Cu+1 catalysis are cyclooctynes or dibenzo-cyclooctynes. For this purpose,
there are commercially available nucleosides and amino acids that
are appended to these moieties. However, these structures are bulky,
dissimilar to native amino acids, and when incorporated within biological
molecules could likely perturb native structural configuration. Presented
are the syntheses of structural analogues of proline with an inserted
propargyl moiety within a series of ring sizes. Moreover, a synthetic
pathway to medium-size ring heterocycloalkynes mediated by using mild
Mitsunobu conditions in tandem with a Nicholas-related strategy for
cyclization is introduced. Avoiding the usual harsh acidic conditions
for the Nicholas reaction allows improved functional group compatibility.