First Total Syntheses And Biological Evaluation Of Marine-derived Monoterpenoid And Its Derivatives And Preliminary Study On Total Synthesis Of Tetranorditerpenoid

Terpenoids comprise an important class of bioactive agents. Despite their relativelysimple structures, some of these compounds exhibit interesting biological activities.We have recently reported the isolation and identification of a new monoterpenoid,penicimonoterpene (+)-1, from a marine-derived endophytic isolate of the fungusPenicillium chrysogenum QEN-24S. The first total racemic synthesis ofmarine-derived (±)-PMT has been achieved in four steps from6-methylhept-5-en-2-one using a Reformatsky reaction as the key step to construct thebasic carbon skeleton. This approach has the merits of low cost, mild reactionconditions, and easy access to diversity-oriented derivatives for potentialstructure-activity relationship (SAR) investigation. A total of24new derivatives of(±)-PMT have also been designed and synthesized. Their structures werecharacterized by analysis of their1H NMR,13C NMR and HRESIMS data. Some ofthem showed significant antibacterial activity against seven bacteria (Aeromonashydrophilia, Escherichia coli, Micrococcus luteus, Staphyloccocus aureus, Vibrioanguillarum, V. harveyi, and/or V. parahaemolyticus) and antifungal activity againstthree plant-pathogenic fungi (Alternaria brassicae, Colletotrichum gloeosporioides,and/or Fusarium graminearum). Notably, some of the derivatives (compoundsT-22-139, T-34-141, and T-33-140B) exhibited antimicrobial MIC values rangingfrom0.25to0.5μg/mL, which were stronger than those of the positive control. Somecompounds T-14-108B, T-21-124, T-31-135, and T-22-139also showed strongerantifungal activity. Compound T-14-108B showed extremely high selectively againstF. graminearum,128-fold more potent than amphotericin B, and might have potentialas an antifungal agent. SAR analysis of (±)-PMT and its derivatives indicated thatmodification of the carbon-carbon double bond at C-6/7, of groups on the allylicmethylene unit, and of the carbonyl group at C-1effectively enhanced antimicrobialactivity. Wentilactones, a kind of tetranorditerpenoids belonged to podolactones, wereisolated and identificated from the marine alga-derived endophytic fungus Aspergilluswentii EN-48. Six steps reactions (including chlorination at allylic hydroxyl group,cyano-substituted reaction, cyano hydrolysis reaction, carboxyl group protectionreaction, and allylic oxidation reaction) were finished to product alkylated precursor.It established the foundation to obtain cyclization precursor.This dissertation focused on synthesis of (±)-PMT and24related derivatives.Bioassay results revealed some compounds exhibited strong antibacterial activityagainst bacteria and plant-pathogenic fungi, which is much better than the positivecontrol, especially for marine Vibrio. The results may be helpful to the exploration ofpotential antibiotic for marine Vibrio. This dissertation also focused on preliminarystudy on total synthesis of tetranorditerpenoid. Alkylated precursor was finished aftersix steps reactions. It established the foundation to obtain cyclization precursor.