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  Total Synthesis of Limaol

Hess, S. (2022). Total Synthesis of Limaol. PhD Thesis, Technische Universität Dortmund, Dortmund.

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Hess, Stephan1, Author           
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1Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society, ou_1445584              

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 Abstract: The total synthesis of natural products is among the core disciplines of organic chemistry. It enables thorough scrutiny of synthetic methods and simultaneously functions as a rich source for new transformations itself. Additionally, it allows for improved access to scantily available bioactive compounds of natural origin, accelerating innovation in both biology and medicine.
Dinoflagellates form an especially diverse group of marine organisms, morphologically as well as biochemically. These algae produce complex polyketides such as the brevetoxins, the amphidinolides, and okadaic acid. Limaol joined the ranks of these interesting molecules in 2017, when it was isolated from the benthic marine dinoflagellate Prorocentrum lima. It is a C40-polyketide with striking structural features such as an array of four skipped exo-methylene groups in its northern section and a chiral spiroketal core.
The work presented in this thesis describes the total synthesis of limaol. Due to the size of the target, a fragment-based approach was chosen. Retrosynthetically, the molecule was split into three building blocks of approximately equal complexity, allowing for a convergent synthesis. The northern fragment would be introduced by an allyl-alkenyl cross-coupling between the northern triene allyl electrophile and an alkenyl nucleophile comprising the rest of the target molecule. The central and southern fragments would be united by an asymmetric allylation, concomitantly setting the stereochemistry at C27.
In a forward sense, the northern fragment was assembled in a two-directional approach, starting from a 1,4-diene-containing allyl electrophile synthesized via a Baylis–Hillman reaction. It was coupled to an alkenylzinc nucleophile derived in several steps from propylene oxide to give the desired all-skipped triene. Conversion of the terminus to the allyl acetate completed the construction of the electrophile for the envisioned final allyl-alkenyl cross-coupling.
The synthesis of the central section commenced from α-D-glucopyranosyl pentaacetate, which was elaborated by selective allylation, standard protecting group modifications, asymmetric propargylation, and Sonogashira cross-coupling with an epichlorohydrin-derived alkenyl iodide into an enyne. Gold-catalyzed spiroketalization and Lemieux–Johnson oxidation of a terminal olefin furnished the tricyclic central fragment ketoaldehyde.
The southern section was prepared from tri-O-acetyl-D-glucal, which was converted to the allyl 2-deoxy-C-glucoside. Chain elongation by olefin cross-metathesis and lead-mediated dehydroxy-methylative cleavage gave the anomeric acetate, which after selective allylation furnished the 2,6-trans-tetrahydropyran bearing an allyl chloride. Nucleophilic substitution with tributylstannyl lithium gave the corresponding allyl stannane nucleophile.
Lewis acid-mediated allylation of the central fragment aldehyde with the southern fragment allyl stannane proceeded with the inverse of the stereoselectivity that was expected according to the Cram-chelate model. The stereochemistry on C27 was corrected a posteriori by Mitsunobu inversion. The ketone “tether” was converted first to the alkenyltriflate and then to the alkenylstannane, which underwent Stille cross-coupling with the northern allyl acetate under mild conditions to afford the all-skipped tetraene. Global deprotection gave limaol in a total yield of 1.5% over 20 steps in longest linear sequence starting from α-D-glucopyranosyl pentaacetate. Overall, 3.3 mg of limaol were prepared using this route.
In an effort to increase the material output for biological testing, a second-generation synthesis was devised. The main bottlenecks of the first-generation approach seemed to be the result of unfavorable sterics of the central fragment. A change in protecting groups was projected to alleviate problems such as the undesired selectivity of the allylative fragment coupling, the low-yielding alkenylstannane formation, and the sluggish global deprotection. The central fragment synthesis was thus changed to incorporate acetate protecting groups by simply including de- and reprotection steps in the route. In addition, the northern fragment could be prepared in a more efficient fashion by asymmetric hydrogenation of commercial 4,6- imethyl-2-pyrone, ring opening of the resulting lactone, and silylation to give a known intermediate of the first-generation northern fragment synthesis.
The allylative fragment coupling between the central fragment aldehyde and the southern fragment allyl stannane could now be performed with the desired stereoselectivity, obviating the Mitsunobu inversion. Moreover, alkenylstannane formation now commenced from the corresponding terminal alkyne, improving selectivity and yield significantly. After fragment union by Stille allyl-alkenyl cross-coupling, a two-step deacetylation and desilylation gave limaol in a total of 7.0% yield over 19 steps in longest linear sequence starting from α-D-glucopyranosyl pentaacetate. This signifies a fourfold increase in yield over the first-generation approach. The revised route also proved scalable, providing 277 mg of limaol in one pass.

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Language(s): eng - English
 Dates: 2022-07-082022-07-08
 Publication Status: Issued
 Pages: 222
 Publishing info: Dortmund : Technische Universität Dortmund
 Table of Contents: -
 Rev. Type: -
 Identifiers: -
 Degree: PhD

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