Abstract
The first total synthesis of marine-derived penicimonoterpene (±)-1 has been achieved in four steps from 6-methylhept-5-en-2-one using a Reformatsky reaction as the key step to construct the basic carbon skeleton. A total of 24 new derivatives of 1 have also been designed and synthesized. Their structures were characterized by analysis of their 1H NMR, 13C NMR and HRESIMS data. Some of them showed significant antibacterial activity against Aeromonas hydrophila, Escherichia coli, Micrococcus luteus, Staphylococcus aureus, Vibrio anguillarum, V. harveyi and/or V. parahaemolyticus, and some showed activity against plant-pathogenic fungi (Alternaria brassicae, Colletotrichum gloeosporioides and/or Fusarium graminearum). Some of the derivatives exhibited antimicrobial MIC values ranging from 0.25 to 4 μg/mL, which were stronger than those of the positive control. Notably, Compounds 3b and 10 showed extremely high selectively against plant-pathogenic fungus F. graminearum (MIC 0.25 μg/mL) and pathogenic bacteria E. coli (MIC 1 μg/mL), implying their potential as antimicrobial agents. SAR analysis of 1 and its derivatives indicated that modification of the carbon-carbon double bond at C-6/7, of groups on the allylic methylene unit and of the carbonyl group at C-1, effectively enhanced the antimicrobial activity.
Highlights
In recent years, there has been increasing interest in research on marine natural products, since an enormous range of chemically diverse biologically active metabolites have been discovered from marine organisms [1,2,3,4]
We report a practical and efficient racemic synthesis of 1 from 6-methylhept-5-en-2-one using a Reformatsky reaction as the key step
Retrosynthetic analysis (Figure 2) led to 5 as the key target intermediate, which could be accessible via three routes, as listed in Scheme I
Summary
There has been increasing interest in research on marine natural products, since an enormous range of chemically diverse biologically active metabolites have been discovered from marine organisms [1,2,3,4]. Terpenoids comprise an important class of bioactive agents Despite their relatively simple structures, some of these compounds exhibit interesting biological activities [10,11,12,13,14]. We have recently reported the isolation and identification of a new monoterpenoid, penicimonoterpene (+)-1 (Figure 1), from a marine-derived endophytic isolate of the fungus, Penicillium chrysogenum QEN-24S [15]. This compound exhibited potent activity against the plant pathogen, Alternaria brassicae, comparable to that of a positive control [15].
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