Total synthesis of potent antifungal marine bisoxazole natural products bengazoles A and B

The bengazoles are a family of marine natural products that display potent antifungal activity and a unique structure, containing two oxazole rings flanking a single carbon atom. Total syntheses of bengazole A and B are described, which contain a sensitive stereogenic centre at this position between the two oxazoles. Additionally, the synthesis of 10-epi-bengazole A is reported. Two parallel synthetic routes were investigated, relying on construction of the 2,4-disubstituted oxazole under mild conditions and a diastereoselective 1,3-dipolar cycloaddition. Our successful route is high yielding, provides rapid access to single stereoisomers of the complex natural products and allows the synthesis of analogues for biological evaluation.     

Total synthesis of natural products using a desymmetrization strategy

Total syntheses of SB-203207 (1) and sphingofungin E (2) were accomplished by utilizing an asymmetric desymmetrization strategy to introduce multiple stereogenic centers into meso starting compounds in a single step. Thus, rhodium carbenoid-mediated CH insertion into 3 provided the bicyclo[3.3.0]framework 4 for 1, while organocatalyst-mediated bromolactonization of 5 afforded 6 for the synthesis of 2. Similarly, we utilized desymmetric rhodium nitrenoid-mediated aziridination reaction of 5 to obtain a key intermediate required for a total synthesis of pactamycin (29), a complex aminocyclopentitol antibiotic featuring six contiguous stereogenic centers.     

Total synthesis of five thapsigargins: guaianolide natural products exhibiting sub-nanomolar SERCA inhibition

Herein we describe the total synthesis of five guaianolide natural products: thapsigargin, thapsivillosin C, thapsivillosin F, trilobolide and nortrilobolide. Prodrug derivatives of thapsigargin have shown selective in vivo cytotoxicity against prostate tumours and the need for further investigation of this phenomenon highlights the importance of these total syntheses. The first absolute stereochemical assignment of thapsivillosin C is also delineated.     

Total syntheses of polyketide-derived bioactive natural products

Recent progress of total syntheses in our laboratory has been described along with our background and methodologies. The target bioactive polyketides are classified into three categories according to their structures: (i) lactone-fused polycyclic compounds [(+)-cochleamycin A, (+)-tubelactomicin A, and (-)-tetrodecamycin], (ii) aromatic compounds [(-)-tetracycline, (-)-BE-54238B, lymphostin, and (-)-lagunamycin], and (iii) acyclic polyketides [xanthocillin X dimethylether, (+)-trichostatin D, and (+)-actinopyrone A]. Features of the total syntheses are described. Original methodologies have been developed and applied to construct the inherent structures of the target molecules. Most syntheses cited herein are the first total syntheses, and the absolute structures of the target molecules have been determined.     

Dearomatization strategies in the synthesis of complex natural products

Evolution in the field of the total synthesis of natural products has led to exciting developments over the last decade. Numerous chemoselective and enantioselective methodologies have emerged from total syntheses, resulting in efficient access to many important natural product targets. This Review highlights recent developments concerning dearomatization, a powerful strategy for the total synthesis of architecturally complex natural products wherein planar, aromatic scaffolds are converted to three-dimensional molecular architectures.     

Total synthesis of aldehyde-containing Garcinia natural products isomorellin and gaudichaudione A

The natural products, isomorellin and gaudichaudione A, with a 4-oxa-tricyclo[4.3.1.0^3,7] dec-8-en-2-one scaffold were synthesized for the first time using an efficient method. The key improvement of this method was the simultaneous bisalkylation of 5,6-dihydroxyxanthone with the bulky 2-methylbutyne group. This method obviously shortened the synthetic route and enhanced the total yield. Four analogues named forbesione, desoxymorellin, desoxygaudichaudione A, and gambogin containing the same caged structure were prepared using this method.     

Total synthesis of ent-(−)-azonazine using a biomimetic direct oxidative cyclization and structural reassignment of natural product

A biomimetic approach has been investigated and developed for the total synthesis of azonazine, an unusual marine natural cyclopeptide containing a rigid transannular 10-membered ring. A hypervalent iodine-mediated direct oxidative cyclization was successfully developed and applied to construct the highly strained core, which was the key step in the first total synthesis of ent-(−)-azonazine. Based on the physical evidences of synthesized diastereomer and enantiomer of azonazine, both the relative and absolute configurations of the natural product were revised. Two fluorinated azonazine derivatives were also synthesized in short convenient steps utilizing the same intermediate in this work. The established total synthesis opens a potential opportunity to study the structure–activity relationship of natural azonazine.     

A new synthesis of tanikolide

We report a concise synthesis of tanikolide 1, which was obtained from ethyl 2-oxocyclopentanecarboxylate in four steps: alkylation, Baeyer-Villiger reaction, saponification, and reduction/lactonization, in 70% overall yield. Our strategy should be suitable for the preparation of 1 in multigram or larger quantities. The net result of the last two steps (i.e. saponification and reduction/lactonization) is an efficient reduction of the ethoxycarbonyl of 3 while keeping the lactone carbonyl intact.