A new strategy is described for the total synthesis of halichondrin B featuring reversal of the sequential construction of a number of its cyclic ethers from the classical approach by instead forming C–O bonds first followed by C–C bond formation. Employing the Nicholas reaction to generate linear ethers as precursors for the total synthesis of halichondrin B and other members of the halichondrin and eribulin families of compounds, this novel approach provides new opportunities for the development of improved syntheses of these complex and valuable compounds. In this Article, we report the syntheses of defined fragments I, MN, EFG, and A. Fragments I and MN were then coupled and elaborated to advanced intermediate IJKLMN, which was joined with fragment EFG to afford, after appropriate elaboration and macrolactonization, the more advanced polycyclic intermediate EFGHIJKLMN. Elaboration of the latter and coupling with fragment A followed by further functionalization completed the total synthesis of halichondrin B through a short and convergent pathway.
The first total syntheses of asperchalasines A-E, a collection of unprecedented merocytochalasans, are reported. Aspochalasin B, a key tricyclic cytochalasan monomer, was first synthesized through a unified approach that hinges on a Diels-Alder reaction and a ring-closing metathesis reaction. The bioinspired Diels-Alder reactions of aspochalasin B with different epicoccine precursors were then explored, which enabled the divergent access of the heterodimers asperchalasines B-E as well as related congeners. Furthermore, the heterotrimer asperchalasine A was obtained from one epicoccine unit and two aspochalasin B units through a biomimetic Diels-Alder reaction followed by an oxidative [5+2]-cycloaddition.
Starting from xanthatin, the biomimetic synthesis of 4β,5β-epoxyxanthatin-1α,4α-endoperoxide, a novel monomeric xanthanolide, has been achieved. Moreover, four unprecedented xanthanolide dimers were synthesized by three different dimerizations of xanthatin, either in a head-to-head or head-to-tail fashion. Notably, these dimeric compounds were firstly identified as artifacts in the laboratory, and two of them, mogolides A and B, proved to be natural products present in the Xanthium mogolium Kitag plant.
Conspectus Total synthesis of natural products has been one of the most exciting and dynamic areas in synthetic organic chemistry. Nowadays, the major challenge in this field is not whether a given target of interest can be synthesized but how to make it with commendable efficiency and practicality. To meet this grand challenge, a wise way is to learn from Mother Nature who is recognized for her superb capability of forging complicated and sometimes beyond-imagination molecules in her own delicate way. Indeed, since Sir Robert Robinson published his groundbreaking synthesis of tropinone in 1917, biomimetic synthesis of natural products, a process of imitating nature’s way to make molecules, has evolved into one of the most popular research directions in organic synthesis. Our group has been engaging in biomimetic synthesis of natural products in the past decade. During this time, we have come to realize that the successful implementation of a biomimetic synthesis entails the orchestrated combination of bioinspiration and rational design. On the one hand, we prefer to utilize some elegant bioinspired transformations (e.g., Diels–Alder dimerization, 6π-electrocyclization, and [2 + 2]-photocycloaddition) as the key steps of our synthesis, which enable rapid construction of the core skeletons of the chased targets with high efficiency; on the other hand, various powerful reactions (e.g., dyotropic rearrangement of β-lactone, tandem aldol condensation/Grob fragmentation reaction, and organocatalytic asymmetric Mukaiyama–Michael addition) are rationally designed by us, which allow for facile access to the requisite precursors for attempting biomimetic transformations. In some cases, the proposed biomimetic transformation may fail to give a satisfactory result in practice, and thus we opt to develop creative tactics (e.g., hydrogen atom transfer-triggered vinyl cyclobutane ring opening/oxygen insertion/cyclization cascade) that can meet the challenge. Guided by this synthesis concept, we have achieved the total syntheses of multiple families of natural products of great importance in both chemistry and biology, representatives of which include xanthanolides, cytochalasans, and plakortin-type polyketides. Of note, most of these targets could be accessed in a concise, efficient, and scalable manner, which paves the way for further exploration of their biological functions and medicinal potential. Moreover, owing to their biomimetic nature, our syntheses provide valuable information for deciphering the underlying biosynthetic pathways of the chased targets, which could not be attained by other synthetic modes.
An enantioselective synthesis of (+)-8-epi-xanthatin hinging on a chiral phosphoric acid catalyzed tandem allylboration/lactonization reaction is reported. With (+)-8-epi-xanthatin as the precursor, the collective synthesis of a series of synthetically challenging xanthanolides was also accomplished. Among them, xanthipungolide, one of the most complex xanthanolide monomers, was accessed through a bioinspired tandem double-bond isomerization/6π electronic cyclization/intramolecular Diels-Alder reaction, and pungiolides A, B, D, E, and L-N, a group of xanthanolide dimers, were assembled through a bioinspired Diels-Alder dimerization followed by late-stage diversification.
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