N-Alkynylazoles in Synthesis

    N-alkynylazoles are an underexplored class of compounds in which an acetylene group
is bonded to the nitrogen atom of a five-membered heteroaromatic ring. We seek to
develop unique transformations of N-alkynylazoles to enable efficient synthetic
strategies to complex heterocyclic compounds. This work will advance synthesis by
enabling novel, greatly simplifying disconnections in planning approaches to a range of
heterocyclic natural products and related biologically active heterocyclic compounds.


Our current efforts focus on three key N-alkynylazole transformations:


• Cyclizations to form 5- and 6-membered cyclic ethers.
• Formal [2+3] addition reactions to form 5-membered heterocycles.
• Aza-Bergman cyclization to form reactive carbenes that can be intercepted in
cascade reactions for construction of complex, multicyclic scaffolds.
We develop methodologies based on these transformations, added by computational
studies, and apply these to the synthesis of biologically interesting natural products.


Some of our recent and on-going targets included:


• The pyrrole spiroketal natural products, exemplified by shensongine B.
• Anticancer tubulin-interactive bicyclic peptide natural products exemplified by
moroidin.
• Complex nucleoside antibiotics and analogs, exemplified by pentostatin.


For additional information, see the following representative publications:


• Reinus, B.; Kerwin, S. M. “Preparation and Utility of N-Alkynyl Azoles in Synthesis”
Molecules, 2019, 24, 422.
• Reinus, B.; Kerwin, S. M. “N-Alkynyl Pyrrole Based Total Synthesis of
Shensongine A” Synthesis, 2019, 51, 4085-4105.
• Reinus, B.; Kerwin, S. M. “A Copper-Catalyzed N-Alkynylation Route to 2-
Substituted N-Alkynyl Pyrroles and Their Cyclization into Pyrrolo[2,1-c]oxazin-1-
ones: A Formal Total Synthesis of Peramine” Synthesis, 2017, 49(11), 2544–2554.