Research: Our group’s programs are firmly rooted in synthetic organic chemistry with an emphasis on methods development and applications in complex molecule synthesis. In particular, a focus on heterocycle synthesis and total synthesis of alkaloids isolated from marine invertebrates has captured our attention. Broadly speaking, we have adopted two complementary approaches which involve functionalization of pre-existing heterocyclic frameworks or the de novo construction of the ring. Our methodological investigations are driven by roadblocks and problems encountered in the course of a synthetic problem. In particular, we have developed approaches to alkaloids belonging to the oroidin and Leucetta families as well as other polyguanidine-containing alkaloids.

Depicted above (Figure 1) are some completed targets. All cases depicted in Figure 1 required the development of new synthetic methods to enable completion of the syntheses. For example, construction of the main framework of nagelamide D required the chemoselective functionalization of imidazole frameworks to prepare the coupling partners for a Stille reaction. In addition, a new pyrrole hydantoin was developed for use as a nucleophile in a Mitsunobu reaction to telescope the incorporation of the signature pyrrole carboxamides. Further applications of this chemistry en route to other nagelamides are in progress.

In addition to these examples of completed natural products, we have several ongoing targets showcasing new methodology. For example, in a planned 10-step total synthesis of the oroidin dimer ageliferin (Figure 2a), we developed a bis Tsuji-Trost reaction for allylating urazoles and then using the thus formed adduct to perform a templated dearomatizing Diels-Alder reaction to afford the polysubstituted tetrahydrobenzimidazole as a single diastereomer. Four additional steps would then afford the natural product constituting the shortest synthesis to date. As it stands, this particular approach gives rise to racemic material and thus we are very interested in developing solutions to address the challenge of asymmetric variants of this chemistry in the future. In Figure 2b, an approach to the as-yet unsynthesized spirocalcaridines, which relies on new chemistry reported by our group, assembles the complete alkaloid skeleton in one synthetic operation using a hypervalent iodine reagent. Three additional steps would then afford the natural product. Currently, the synthesis is racemic, but extension to an asymmetric variant is envisioned. Further, our experience with dearomatization chemistries suggests that development of a metal-catalyzed variant is conceivable.

Other projects in our lab (depicted in Figure 3) are at various stages of completion, but all take advantage of new methods discovered in our group. Ceratinadin B is a bromotyrosine-derived marine alkaloid with potential as an anti-tubercular agent, for which we have developed a concise synthesis of the des-3’-hydroxy imidazolyl quinoline moiety through a fairly classical route (Figure 3b). A new asymmetric dearomatization is under investigation for the synthesis of the spiroisoxazoline fragment to complete the synthesis. A final project, which takes advantage of a dearomatization of an N-methoxy urea derivative to form the CD-rings of KB343, has recently been investigated. A sequence for introduction of the E-ring has been developed, allowing assembly of the CDE-tricycle. Current studies are focused on the development of a tandem sequence involving a dearomatization followed by an intramolecular Sakurai reaction to construct the BCD-substructure. In addition, we have developed an interest in using DFT methods to calculate NMR data to assist in structural assignments. One reaction in particular (see Figure 3a, lower) gives rise to spiro-fused ring systems where assigning relative stereochemistry is challenging without recourse to crystallography. Obviously, not all products give rise to crystalline materials, and so alternatives for reliably assigning stereochemistry are required. To facilitate this, we have developed Python code to automate some of the more routine aspects of this process.

1. “Investigation of Dearomatizing Spirocyclizations and Spirocycle Functionalization En Route to Spirocalcaridines A and B—Some Trials and Tribulations” Singh, R.P.; Gout, D.; Mao, J.X.; Kroll, P.; Lovely, C.J. Molecules 2025, 30, 1143. https://doi.org/10.3390/molecules30051143
2. “Computationally Assisted Stereochemical Elucidation of Intermediates Encountered En Route to Pyrrole-Imidazole Natural Products; NMR Chemical Shift Calculations Utilizing CREST/DP4+ Applied to Oxidative Spirocyclizations of Tetrahydrobenzimidazoles” Fulton, B.B.; Lovely, C.J. J. Org. Chem. 2025, 90, 9355–9364. https://doi.org/10.1021/acs.joc.5c00600
3. “Synthesis and Isomerization of Tetrahydrochromene Derivatives” Burk, R.J.; Ghorai, A.; Mao, X.; Phan, V.Q.H.; Dias, H.V.R.; Gündüz, M.G.; Lovely, C.J.; Armstrong, D.W. J. Org. Chem. 2025, 90, 14106–14117. https://doi.org/10.1021/acs.joc.5c01569
4. “Dearomatization of N-methoxy ureas” Parveen, N.; Aziz, M.N.; Gout, D.; Lovely, C.J. Org. Lett. 2025, 27, 11307–11312. https://doi.org/10.1021/acs.orglett.5c03607
5. “Elaboration of an Intermolecular Diels-Alder Adduct En Route to the Spiro Fused Oroidin Alkaloids” Fulton, B.B.; Gout, D.; Dias, H.V.R.; Lovely, C.J. Synlett. 2025, 3064–3070. https://doi.org/10.1055/a-2644-2641