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Concise Total Synthesis of Enigmazole A & Studies Towards the Total Synthesis of Rhizoxin D


Ahlers,  Andreas
Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

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Ahlers, A. (2017). Concise Total Synthesis of Enigmazole A & Studies Towards the Total Synthesis of Rhizoxin D. PhD Thesis, Technische Universität, Dortmund.

Cite as: http://hdl.handle.net/11858/00-001M-0000-002D-D3EB-A
Enigmazole A and its congeners, isolated form the sponge Cinachyrella enigmatica, are the first known phosphorylated macrolides of marine origin. Their structure features an 18-membered macrocycle which is decorated with a highly functionalized disubstituted oxazole and a phosphate ester, rarely found in natural polyketides. The macrolactone includes seven stereogenic centers and an embedded syn-2,6-disubstituted tetrahydropyran ring with an exo-methylene group. Enigmazole A shows cytotoxic activity against numerous cancer cell lines at significant concentrations. Structural siblings of it interfere selectively with mutant c-Kit signaling which is an important target for cancer treatment. The differentiation is found in less than 0.03% of tested natural products. This exceptional structure and the rare pharmacological activity make enigmazole A an attractive target for total synthesis. A concise and convergent synthesis of this natural product was envisioned featuring a sequence of a ring closing alkyne metathesis (RCAM) and a post-metathesis functionalization by a nobel metal-catalyzed rearrangement with subsequent hydroalkoxylation. The required fragment E was accessed in 11 steps from a commercial oxazole precursor by a palladium-catalyzed C–H activation and a Keck allylation reaction. Enantioselective allylation of aldehyde E and stannane C (5 steps) and subsequent Yamaguchi esterification with acid D (8 steps) afforded the metathesis precursor. Smooth RCAM created the 18-membered macrocycle in excellent yields. A gold-catalyzed [3,3]-sigmatropic rearrangement of the propargylic acetate (F) alongside the alkyne followed by a transannular hydroalkoxylation (H) of allene G gave exclusively the desired syn-tetrahydropyran ring A in excellent yields. The use of a chiral gold catalyst was mandatory in this transformation to obtain a diastereomerically matched system with the substrate B. Finally, enigmazole A was obtained after standard manipulations. Rhizoxin D was isolated from an endosymbiotic bacterium of the genus Burkholderia which causes the rice seedling blight disease. Its unprecedented structure exhibits a strained 16-membered macrocycle containing three (E)-olefins, a δ-lactone and a highly unsaturated sidechain which is terminated with an oxazole heterocycle. The selective cytotoxicity of rhizoxin D and its derivatives against cancer cell lines led to clinical trials as potential drug candidate. This high pharmacological potency and the strained structure drew attention to several research groups to pursue syntheses of this molecule. The designed synthesis featured two key transformations: a ring-closing diyne metathesis (RCDM) and a substrate-directed ruthenium-catalyzed hydrostannation of a 1,3-diyne to create the embedded 1,3-(E,E)-diene. For this strategy fragment K (6 steps) was prepared by an oxidation of thermodynamically resolved lactols. Fragment J (11 steps) was accessible by a challenging alkenylation and an esterification. The 1,3-diynes in both molecules were installed by alkynylation reactions with 1,3-pentadiyne. Horner–Wadsworth–Emmons coupling (HWE) of fragments J and K gave the metathesis precursor, which underwent RCDM to obtain macrocycle I in moderate yields. Further investigations on the final steps of the total synthesis of rhizoxin D are ongoing.