Total Synthesis of Halistatins 1 and 2

Abstract

The first total synthesis of halistatins 1 and 2 has been completed using Cr-mediated coupling reactions for the C11/C12, C17/C18, and C19/C20 bond formation. For the C11/C12 bond formation, a stoichiometric Ni/Cr-mediated reaction is used to couple an α-quaternary aldehyde with a vinyl iodide. The solubilized Cr-reagent, prepared from CrCl2 and a sulfonamide ligand, allows one to perform the coupling with ∼1 equiv of Cr-reagent. Catalytic, asymmetric Co/Cr-mediated iodoallylation is adopted to incorporate the requisite C17–C19 functionality in a stereoselective manner. Asymmetric Ni/Cr-mediated coupling is used to form the C19/C20 bond effectively. Through this study, it has been found that the stereoselectivity of [5,5]-spiroketalization dramatically depends on solvents; p-toluenesulfonic acid (PTSA) in 1:1 methanol–water gave a >20:1 stereoselectivity favoring the natural series. This condition is also effective to isomerize C38-epi-halichondrins into C38 natural halichondrins.

Marine natural products

“…483 The rst total synthesis of the structure reported for halisphingosine A has called into question the congurational assignment of the NP. 484 Other rst total syntheses include that of an acetylene, 485 two peptides, 486,487 and two macrolides, 488,489 the latter describing the construction of the highly complex halistatins 1 and 2. The synthesis of the proposed structure of poly-cationic alkaloid protoaculeine B has been achieved, although the spectroscopic data of the natural and synthetic material differ, suggesting revision is necessary.…”

A Highly Convergent Total Synthesis of Norhalichondrin B

“…The halichondrin family of natural products constitutes a group of challenging and inspiring molecules to synthetic and medicinal chemists due to their complex molecular structures and their potent antitumor properties. From this class (e.g., 1 – 5 , Figure ), halichondrin B ( 1 ) and norhalichondrin B ( 2 ) represent the two most pursued members due to their early isolation, rarity, and potent biological activities .…”

Nickel-Catalyzed Deaminative Ketone Synthesis: Coupling of Alkylpyridinium Salts with Thiopyridine Esters via C–N Bond Activation

“…An elegant work by Kishi and co-workers demonstrated that a higher coupling efficiency could be achieved with a 1:1 molar ratio of coupling partners using the NI/Zr-mediated one-pot ketone synthesis . The experimental simplicity of their method was perfectly applied to the late-stage couplings of halichondrins …”

“…Inspired by recent efforts by the Kishi group, we sought to employ thiopyridine esters as suitable coupling partners in direct ketone synthesis because of their ease of handling and storage. , Furthermore, the direct coupling of thiopyridine esters with primary alkylpyridinium salts has not been optimized yet.…”