Synthesis of furanoeremophilane sesquiterpenoids

Two approaches to the tricyclic core of the furanoeremophilane sesquiterpenoids are described. The first approach entails a projected Diels-Alder/retro Diels-Alder reaction of an acetylenic oxazole 64. Construction of the pivotal aldehyde 67 commenced from ketone 68. The acetyenic moiety was then introduced via a Felkin-Ahn addition of lithiopropyne to aldehyde 67. The final conversion of the cyclohexanone 83 to the acetylenic triflate 65 was unsuccessful. Attempts at addition of lithiated 2-methyloxazole 88 to ketone 83 were also unsuccessful. The second approach exploited a new annulation strategy. The aldehyde 64 was advanced to the 2, 4, 6-triisopropylbenzene sulfonylhydrazone 102 and a Shapiro reaction of 102 then provided alcohol 96. The furyl stananne 114 was readily prepared via a six-step sequence from acetylacetaldehyde dimethyl acetal 106. Unification of allylic bromide 90 and stannane 114 was accomplished through a Stille cross coupling methodology and the resulting product 113 was advanced to the aldehyde 116. However, attempts at further oxidation of this aldehyde to the required acid 89 failed. An alternative furyl stananne 124 with a tert-butyldimethylsilyl substituent at the C2 position was prepared from 3-furoic acid. An analogous sequence to that used with 113 led to aldehyde 131 which was successfully cyclized with the aid of trimethylsilyl trifluromethanesulfonate and 2, 6-lutidine to the tricyclic structure 132. Oxidation of the epimeric mixture of alcohols, followed by stereoselective reduction and removal of the tert-butyldimethylsilyl group from alcohol 134, gave (±)-6β-hydroxyeuroposin (4). Oxidation experiments with 134 were shown to convert the furan in this structure to a butenolide characteristic of the eremophilenolides

Ajoene, a sulfur rich molecule from garlic, inhibits genes controlled by quorum sensing

In relation to emerging multiresistant bacteria, development of antimicrobials and new treatment strategies of infections should be expected to become a high priority research area. Quorum Sensing (QS), a communication system used by pathogenic bacteria like Pseudomonas aeruginosa to synchronise the expression of specific genes involved in pathogenicity, is a possible drug target. Previous in vitro and in vivo studies revealed a significant inhibition of P. aeruginosa QS by crude garlic extract. By bioassay-guided fractionation of garlic extracts we determined the primary QS inhibitor present in garlic as ajoene, a sulfur-containing compound with potential as an antipathogenic drug. By comprehensive in vitro and in vivo studies of the effect of synthetic ajoene towards P. aeruginosa was elucidated. DNA microarray studies of ajoene treated P. aeruginosa cultures revealed a concentration dependent attenuation of a few, but central QS controlled virulence factors including rhamnolipid. Furthermore, ajoene treatment of in vitro biofilms demonstrated a clear synergistic, antimicrobial effect with tobramycin on biofilm killing and a cease in lytic necrosis of polymorphonuclear leukocytes. Furthermore, in a pulmonary infectious mouse model a significant clearing of infecting P. aeruginosa was detected in ajoene-treated mice compared to a non-treated control group. This study adds to the list of examples demonstrating the potential of QS interfering compounds in the treatment of bacterial infections