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Total Syntheses of Keramaphidin B and Nominal Njaoamine I & Studies towards the Total Synthesis of Providencin


Spohr,  Simon M.
Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

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Spohr, S. M. (2023). Total Syntheses of Keramaphidin B and Nominal Njaoamine I & Studies towards the Total Synthesis of Providencin. PhD Thesis, Technische Universität Dortmund, Dortmund.

Cite as: https://hdl.handle.net/21.11116/0000-000F-14CC-5
After the discovery of manzamine A, a macrocyclic marine alkaloid, Baldwin and Whitehead proposed the biogenesis of a whole class of natural products arising from partly reduced alkylpyridine derivatives. Although manzamine A was quickly conquered by total synthesis around the turn of the millennium, a family of alkaloids emerging early in the biogenesis of these natural products remained elusive. In a total synthesis campaign, alkaloids of the ingenamine estate were targeted, pursuing an approach purely based on chemical logic. Therein, a Michael/Michael cascade was developed forging the common tricyclic core in diastereoselective fashion. Furthermore, the transformation proved highly flexible concerning the introduction of requisite handles for macrocyclization.
For the total synthesis of keramaphidin B the macrocyclization strategy relied on the use of ring-closing alkyne metathesis (RCAM) for the 13-membered macrocycle and ring-closing olefin metathesis (RCM) for the 11-membered macrocycle. While the RCAM proved highly reliable, the RCM reaction had to be optimized carefully. Eventually, however, the inaugural total synthesis of keramaphidin B was accomplished in 19 steps along the longest linear sequence (LLS) and 0.93% overall yield.
As the more recently discovered njaoamines carry an additional Lewis basic amine functionality in the quinoline annulated to one of the macrocycles, the use of RCM became less inviting. After the identification of vic-dibromoalkenes as sufficient alkyne surrogates, nominal njaoamine I was synthesized employing two subsequent RCAMs in 21 steps LLS and 1.14% overall yield. The total synthesis revealed a positional misassignment of the triple bond in the 17-membered macrocycle, which was revised by an in-depth NMR study.
Furanocembranoids are a diverse family of diterpenes. Their macrocyclic framework features, in most cases, a furan and butenolide moiety of some sort. One of the most intriguing molecules found within this class is providencin. Apart from its highly oxygenated nature it is recognized easily by the trans-fused cyclobutane bearing an allylic alcohol and an exocyclic methylene unit. Despite numerous efforts to bring this target down by total synthesis, providencin remains elusive. In particular the exceptionally high ring-strain of the macrocycle and the highly functionalized cyclobutane represent major challenges in an attempted synthesis.
Herein, a new route towards the cyclobutane sector of providencin was established, which was used to evaluate the application of RCAM in the context of macrocyclization. At the centerpiece, an Ir-catalyzed photosensitized [2+2] cycloaddition was harnessed to build the furanyl-cyclobutanol fragment. Stereochemical relay of a neighboring stereocenter onto the cyclobutane rendered this approach asymmetric. Furthermore, this handle served as the linchpin to open the thus constructed bicycle via oxidative cleavage. Subsequent functionalization of the furan with a highly electrophilic hypoiodite reagent opened entry into a 2-iodofuran paramount for coupling requisite handles for macrocyclization.
At this stage, Suzuki coupling was found to be optimal and an alkyne-bearing E-olefinic fragment could be introduced into the molecule. After accessing a viable diyne it became clear that the macrocycle was too strained to be forged by RCAM, because this reaction is largely entropically driven.
These setbacks notwithstanding, a Suzuki coupling could be carried out with potassium vinyltrifluoroborate giving rise to an intermediate, which is expected to be elaborated into providencin via a literature known route previously established in the group of Mulzer.