Total synthesis of haplomintrins A and B and studies on enantioselective quinone Diels-Alder reactions

• Applicant: Dr. Stefan Wiesler
• Subject Area: Organic Molecular Chemistry - Synthesis and Characterisation
• Term: from 2021 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 456623941

The total synthesis of natural products (secondary metabolites) still remains an ongoing challenge and important part of organic chemistry, as natural products and their derivatives can often be used to identify new drugs or drug candidates. In order to accomplish the synthesis of mostly complex target frameworks, one typically relies on well-established reactions and methods. However, to tackle potential synthetic hardships or to circumvent a lack of existing approaches, new methods must be developed.One main class of plant secondary metabolites are terpenoids, some of which also possess significant biological activity. In 2015 Lou et al. reported two novel labdane-type diterpenoids, haplomintrins A and B, which they discovered from the Chinese liverwort Haplomitrium mnioides. The main objective of the present research proposal is to accomplish the first enantioselective total synthesis of haplomintrins A and B. In this vein, it is planned to carry out an enantioselective quinone Diels-Alder reaction as key step, using literature-known chiral catalysts. In addition, it should be tested whether a Nakada-type β-keto imide enables an improved chiral induction of copper bis(oxazoline) complexes, especially if the known chiral catalyst systems fail in this challenging quinone Diels-Alder reaction. With the Diels-Alder adduct in hand, a regio- and stereoselective addition of lithium furylacetylene to one of the carbonyl groups of the cis-decalin system is envisioned. The next step in the total synthesis of haplomitrin B is the transformation into the trans-decalin system, followed by cationic or radical deoxygenation and a subsequent alkynoic acid lactonization. Since one potential problem associated with the deoxygenation is the loss of stereo information at the propargylic position, it is also proposed to carry out the lactonization first. Then the deoxygenation of the structurally more rigid compound should not influence the stereo information. In order to prepare for further synthetic difficulties an alternative lactonization strategy is proposed involving a reduction of the propargyl group, followed by a hydroboration and lactonization of the resulting alcohol with the methylester. Finally, the last step toward haplomintrin B is a photoinduced [2+2] cycloaddition for which Lou et al. conducted some preliminary studies.With haplomintrin B in hand, a late-stage C–H functionalization by means of a Hartwig silylation should lead to haplomintrin A. Therefore, the carbonyl group of haplomintrin B should be stereoselectively converted to a hydroxy group using SmI2 as reducing agent. After subsequent silylation of the hydroxy group, the addition of RhCl(Xantphos) should provide the oxasilolane with the methyl group in δ-position. The subsequent Fleming-Tamao oxidation then leads to the δ-hydroxylated compound. Finally, a sequence of Swern oxidation, Pinnick oxidation and esterification should furnish haplomintrin A.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Richmond Sarpong, Ph.D.