The first enantioselective total syntheses of the tetrahydroxanthenone (-)-blennolide C (ent-4) and related γ-lactonyl chromanone (-)-gonytolide C (ent-3) are reported. Key to the syntheses is an enantioselective domino-Wacker/carbonylation/methoxylation reaction to set up the stereocentre at C-4a. Various chiral BOXAX ligands were investigated, including novel (S,S)-iBu-BOXAX, and allowed access to chromane 8 in an excellent enantioselectivity of 99 %. The second stereocentre at C-4 was established employing a diastereoselective Sharpless dihydroxylation. An extensive survey of (DHQ)- and (DHQD)-based ligands enabled the preparation of both the anti-isomer 14 a and the syn-isomer 14 b in very good to reasonable selectivities of 13.7:1 and 1:3.7, respectively. While 14 a was further converted to ent-3 and ent-4, 14 b was elaborated to syn-acid 25 and 2'-epi-gonytolide C 28.

Syntheses of the lactonyl chromanones ent-3c and ent-3d ..

High-throughput phenotypic screens have re-emerged as screening tools in antibiotic discovery. The advent of such technologies has rapidly accelerated the identification of ‘hit’ compounds. A pre-requisite to medicinal chemistry optimisation programmes required to improve the drug-like properties of a ‘hit’ molecule is identification of its mode of action. Herein, we have combined phenotypic screening with a biased target-specific screen. The inosine monophosphate dehydrogenase (IMPDH) protein GuaB2 has been identified as a drugable target in Mycobacterium tuberculosis, however previously identified compounds lack the desired characteristics necessary for further development into lead-like molecules. This study has identified 7 new chemical series from a high-throughput resistance-based phenotypic screen using Mycobacterium bovis BCG over-expressing GuaB2. Hit compounds were identified in a single shot high-throughput screen, validated by dose response and subjected to further biochemical analysis. The compounds were also assessed using molecular docking experiments, providing a platform for their further optimisation using medicinal chemistry. This work demonstrates the versatility and potential of GuaB2 as an anti-tubercular drug target.

Blennolide A can be synthesized through an enantioselective domino-Wacker/carbonylation/methoxylation reaction of 7a with 96 % ee and an enantioselective Wacker oxidation of 7b with 89 % ee. Further transformations led to the α,β-unsaturated ester (E)-17, which was subjected to a highly selective Michael addition, introducing a methyl group to give 18a. After a threefold oxidation and an intramolecular acylation, the tetrahydroxanthenone 4 was obtained, which could be transformed into (-)-blennolide A (ent-1) in a few steps.

For the synthesis of (-)-diversonol (ent-1), an enantioselective domino-Wacker/carbonylation/methoxylation reaction and an enantioselective Wacker oxidation were used to give the chroman in high yield and 96% and 93% ee, respectively. Dihydroxylation at the vinyl moiety using the Sharpless procedure and a Wittig-Horner reaction followed by hydrogenation, benzylic oxidation, and an intramolecular acylation provided the tetrahydroxanthenone, from which ent-1 is accessible in a few steps. Furthermore, the synthesis of the diastereomeric diversonol rac-1,9a-epi-diversonol (rac-41) is also described.