Syntheses and Biological Evaluation of Iriomoteolide 3a and Analogues

Abstract

Amphidinium species are an extremely prolific source of marine secondary metabolites.[1] Structurally unique polyketides such as amphidinolides, caribenolide I, and amphidinolactones have fostered the interest of chemists not only as challenging targets for total synthesis but also because of their potent anticancer activity.[2] Recently, the Amphidinium strain HYA024 was found to produce cytotoxic compounds such as iriomoteolides 1a-c, [3] and a rare 15-membered macrolide, iriomoteolide 3a (1).[4] With a novel carbon framework comprising eight stereogenic centers, four of them in allylic positions, compound 1 represents the first member of a unique and unprecedented 15-membered macrolide class. Compound 1 represents the first member of a unique and unprecedented 15-membered macrolide class. In addition, the preliminary physiological properties disclosed for 1 and its 7,8-O-isopropylidene derivative 2 are very promising, showing potent cytotoxicity against lymphoma cell lines in the low nanomolar range. [4] To confirm the assigned structure, further evaluate its biological activity, and determine whether its cellular targets are related to those of larger congeners such as amphidinolides, [5] substantial quantities of these compounds are required. Our retrosynthetic approach to 1 involved four major disconnections, which revealed key fragments 3-6 as summarized in Scheme 1. Fragment 6 was planned to be incorporated at the end of our synthetic sequence by a JuliaKocienski olefination because of its widely recognized performance in the elaboration of such sensitive settings and also to ensure a flexible late-stage diversification of the parent compound. An intermolecular esterification was envisioned to assemble fragments 3 and 4. Finally, we hypothesized that the C 2 -symmetry of the diol precursor of fragment 5 could be advantageously used to construct the 1,5-diene upon ring closure by a cross-metathesis (CM)/ringclosing metathesis (RCM) approach. We were relying on the excellent results achieved by the Grubbs-type carbene complexes in both CM and RCM processes with the expectation that the formation of a medium-sized ring would also be E,E stereoselective (Scheme 1).The required building block 3 (Scheme 2) was prepared by alkylation of the Evans oxazolidinone 7[6] with iodide 8.[7]Scheme 2. a) Na[N( , THF, 73 %; n) DDQ, CH 2 Cl 2 , pH 7 buffer, RT, 85 %. CSA = camphorsulfonic acid, DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, DIBAL-H = diisobutylaluminium hydride, DIPT = diisopropyl tartrate, DMF = N,N-dimethylformamide, DMSO = dimethylsulfoxide, MS = molecular sieves, PMB = para-methoxybenzyl, PPTS = pyridinium para-toluenesulfonate, TBAF = tetra-n-butylammonium fluoride, TBDPS = tert-butyldiphenylsilyl, TBS = tert-butyldimethylsilyl.Scheme 1. Retrosynthetic analysis for iriomoteolide 3a (1).

Enantiospecific Formal Total Synthesis of Iriomoteolide 3a

“…Interestingly, deprotection of the acetonide in 2 to parent macrolide 1 is problematic, and hence, protection of the vicinal diol present in the macrolide with other protecting groups is essential in the total synthesis. A solitary total synthesis of 1 was reported by the Nevado group,2 whereas the synthesis of a macrocyclic core structurally similar to that of 2 was reported by Reddy’s group 3. The synthesis of the isopropylidene derivative of iriomoteolide 3a, that is, 2 , has also surfaced in the literature 4a.…”

2nd PSL Chemical Biology Symposium (2019): At the Crossroads of Chemistry and Biology

“…[30] Then, she presented the total synthesis of the complex natural product iriomoteolide 3A and non-naturala nalogues. [31] Nevados howed that these molecules interactw ith actin in a noncovalent and reversible manner,u nlike other natural products harboring as imilars tructure such as amphidinolide H. Because of these studies, iriomoteolide and derivatives represent novel chemical tools to study actin and its implication in cell division, motility, and invasion in cancer. [32] Daniela Dieterich:Probing neural proteostasis with click…”

“…For this, virtual docking by AutoCouple, a new software, developed in collaboration with A. Caflisch (Department of Βiochemistry, University of Zurich) for the design of structurally diverse molecules, was used . Then, she presented the total synthesis of the complex natural product iriomoteolide 3A and non‐natural analogues . Nevado showed that these molecules interact with actin in a noncovalent and reversible manner, unlike other natural products harboring a similar structure such as amphidinolide H. Because of these studies, iriomoteolide and derivatives represent novel chemical tools to study actin and its implication in cell division, motility, and invasion in cancer …”

Efficient Synthesis of the C1‐C9 Fragment of 7,8‐O‐Isopropylidene Protected Iriomoteolide 3a Derivative

“…In 2009, the successful total synthesis of iriomoteolide 3a and various analogues was achieved by Nevado et al, and these compounds were used for biological evaluation. 2 More recently, the synthesis of the macrocyclic core of iriomoteolide 3a was published by Reddy and co-workers. In this work, the C1-C9 fragment was synthesized in eight steps in 34% yield from (S)-(-)-citronellol.…”