Chemists synthesize natural products to study their biological activity and architectural complexity. Guanidine-containing marine natural products exhibit antibiotic, anti-viral, anti-cancer, and anti-parasitic activity. Some act as peptide mimics and bind to the active sites of proteases. Serine proteases involved in blood coagulation are powerful targets for drug development to treat cardiovascular disorders such as thrombosis. Two recently discovered aminoguanidine-containing marine natural products, clavatadine A and B, are specific inhibitors of coagulation factor XIa. Each alkaloid features a central carbamate moiety that is cleaved by a nucleophilic serine residue in the active site, as well as a linear aminoguanidine that increases their affinity to the active site through binding to an aspartate residue. The first total synthesis of clavatadine B was completed by undergraduates and the PI at a teaching-intensive, primarily undergraduate institution. The principal synthetic challenge involved the disparate location of the aminoguanidine chain in clavatadine B in comparison with clavatadine A. Both molecules were conveniently prepared from 4,6-dibromohomogentisic acid lactone and the isocyanate derived from di-Boc agmatine. In practice, aminolysis of a protected 4,6-dibromohomogentisic acid lactone revealed the distal hydroxy group needed to unite both halves of the molecule in the key carbamate-forming step. The nearly identical chromatographic behavior of the aminolysis product and the carbamate required the development of a non-traditional method to separate the carbamate from unreacted starting material. The entire synthesis required only one purification. Also notable was the fact that a primary amide survived and did not interfere with the final two reactions. An overall yield of 75% over four steps (longest linear sequence from known compounds) was achieved following global deprotection.

Total synthesis of clavatadine B

Macromolecular Chemistry: The Second Century

[Author Benefits](https://scimeetings.acs.org/?utm_source=pubs_content_marketing&utm_medium=website&utm_campaign=0320_MCF_NPI_Launch_Spring_Homepage&ref=pubs_content_marketing)

[How to use SciMeetings](https://storage.googleapis.com/dl.morressier.com/acs/SciMeetings-ACSSpring2020-HowToGuide_M3020-Final.pdf)

[Frequently Asked Questions](https://storage.googleapis.com/dl.morressier.com/acs/SciMtng_ACSNMSp2020_FAQ_M3120_Final.pdf)

ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.