Concise Total Synthesis of Trichodermamides A, B, and C Enabled by an Efficient Construction of the 1,2-Oxazadecaline Core

Abstract

We report herein a facile and efficient method of the construction of the cis-1,2-oxazadecaline system, distinctive of (pre)trichodermamides, aspergillazine A, gliovirin and FA-2097. The formation of the 1,2-oxazadecaline core was accomplished by a 1,2-addition of an αC-lithiated O-silyl ethyl pyruvate oxime to benzoquinone, that is followed by an oxa-Michael ring-closure. The method was successfully applied to the concise total synthesis of trichodermamide A (in gram quantities), trichodermamide B, as well as the first synthesis of trichodermamide C.

Identification of Inhibitors of CD36-Amyloid Beta Binding as Potential Agents for Alzheimer’s Disease

“…Both secondary metabolites were isolated in minute quantities 19 , thus necessitating development of a synthetic route to Trichodermamides to enable an in depth investigation of their bioactivity profile. The synthetic approach to Trichodermamides 17 also provided access to a variety of unnatural structural analogues that can have an improved activity and serve as a basis set for a structure-activity relationship study (Supplementary material). …”

“…In particular, 1,2-oxazines represent a new structural framework with significant potential for structure diversification. We focused on the Trichodermamide family of natural products that share the 1,2-oxazadecaline unit 17 . We choose Trichodermamides A ( 1 ) and B ( 2 ) (Figure 1) as well as a focused library of structural analogues (Table 1 and S1).…”

Cytotoxicity and Mechanism of Action of the Marine-Derived Fungal Metabolite Trichodermamide B and Synthetic Analogues

“…Compounds 9 – 18 as well as 1 – 3 were prepared and characterized as we described previously. 15 All compounds were prepared in racemic form. With the library of trichodermamides and their structural analogues 5-18 we set out to investigate their cytotoxicity and mechanisms of action.…”

“…We recently developed a general approach for the total synthesis of compounds 1 - 3 , 15 and several synthetic analogues and intermediates were generated (Table 1). Our synthetic strategy is based on the efficient construction of the cis -fused 1,2-oxazadecalin core of the trichodermamides.…”

Trichodermamides D–F, heterocyclic dipeptides with a highly functionalized 1,2-oxazadecaline core isolated from the endophytic fungus Penicillium janthinellum HDN13-309

“…5 Driven by the structural novelty and potent bioactivity, total synthesis of trichodermamides A-C have been achieved. [6][7][8] In our previous research, a serious of cytotoxic gliovirins (penicisulfuranols A-F) have been isolated from an active endophytic fungus Penicillium janthinellum HDN13-309. 9,10 To obtain enough amounts of these compounds for further bioactive study, P. janthinellum HDN13-309 was re-cultured in a larger scale under the same condition and a series of compounds with UV absorptions different from gliovirins were observed as minor components (Fig.…”