Palau’amine has received a great deal of attention in the past two decades as an attractive synthetic target by virtue of its intriguing molecular architecture and significant immunosuppressive activity. Here, we report the total synthesis of palau’amine characterized by the Hg(OTf)2-catalyzed construction of tetra-substituted carbon center at the C16 position and the construction of an ABDE tetracyclic ring core including a trans-bicylo[3.3.0]octane skeleton at a middle stage of total synthesis. The ABDE tetracyclic ring core is constructed by a cascade reaction of a cleavage of the N-N bond, including simultaneous formation of imine, the addition of amide anion to the resulting imine (D-ring formation), and the condensation of pyrrole with methyl ester (B-ring formation) in a single step. The present synthetic route has the potential to help elucidate a pharmacophore as well as the mechanistic details of immunosuppressive activity.
Formal total synthesis of (−)-taxol is described herein. This convergent synthesis was accomplished by utilizing two chiral fragments, both of which were prepared via asymmetric catalysis. A palladium-catalyzed reaction was found to afford the eight-membered ring effectively, i.e., a B-alkyl Suzuki-Miyaura coupling reaction and an intramolecular alkenylation of a methyl ketone successfully constructed the B-ring of taxol in excellent yield. During the preparation of a substrate for the palladium-catalyzed reaction, a unique rearrangement of the epoxy benzyl ether, via a 1,5-hydride shift that generates the C3 stereogenic center and subsequently forms the C1-C2 benzylidene moiety, was observed. Strenuous efforts were required for transformations after the construction of the taxane scaffold to achieve the formal total synthesis of taxol because very few approaches are available for the synthesis of the target compound.
Five total syntheses of heteropolycyclic natural products, namely hyalodendrin, tryprostatins, spirotryprostatin A, the core of the stemofoline alkaloids, and hinckdentine A, are outlined. These syntheses share common characteristics; the sequences of transformations are facilitated through the development of new synthetic reactions and the discoveries of unknown molecular reactivities. Brief descriptions of new reactions, the mechanistic details of key transformations, and the resulting shortcuts and efficiencies made possible in relation to the overall “picture” of these total syntheses are described.
Fluorine is a key element by virtue of the unique properties associated with the atom itself and its bond to carbon, its high electronegativity and relatively small size. Due to these attractive properties, organofluorine compounds find diverse applications in the medicinal, agricultural, and material sciences. In particular, difluoromethylene compounds have received a great deal of attention due to their biological activities. This article deals with the synthetic applications of difluoroenol ethers and their derivatives, which are useful building blocks for a wide variety of difluoromethylene compounds.
Cross-coupling reactions based on catalytically generated organocopper species have been developed by cooperative Pd/Cu or Ni/Cu catalysis. Alkyl or alkenylcopper intermediates generated via the hydrocupration or borylcupration of alkenes or alkynes engage in Pd- or Ni-catalyzed reactions with organic electrophiles. These reactions circumvent the laborious pre-synthesis and isolation processes of organometallics that characterize conventional cross-coupling reactions, and they are hence more step-economical. Moreover, highly functionalized organocopper species, which are difficult to access using conventional methods, can be obtained from readily available alkenes and alkynes. Thus, cross-coupling reactions by cooperative Pd/Cu or Ni/Cu catalysis represent powerful tools for the construction of complex structures from readily available starting materials in a single operation.
By the end of the 20th century several advantages of organocatalysis, for example environmental friendliness, operational simplicity, mild reaction conditions etc., had led to its recognition as a powerful principle for the establishment of practical organic synthetic methods. Over the two decades since then tremendous effort has been devoted to the design of novel organocatalysts able to realize unprecedented reactions. In this review our recent results on the design and development of various types of organocatalysts, such as organobase, organoacid, organoacid/base and organoradical catalysts, and their application to a wide variety of synthetic transformations are described.
C-H transformations catalyzed by heterogeneous Pd and Au catalysts are disclosed. For palladium, Pd(0), PdO, and Pd(OH)2 worked as catalytically active species involved in oxidative addition, electrophilic substitution, and concerted metalation deprotonation pathways depending on the reaction under investigation. We also found that Au(0) nanoparticles catalyzed C-H coupling and discuss the difference in catalytic properties between Pd and Au. The role of metal oxide (MOx) supports is also mentioned: MOx not only stabilizes Pd and Au particles but also creates cationic metal sites at the perimeter interface, and these play an important role in activating the substrates.
To determine the molecular basis underlying the multiple biological functions of glycoconjugates, such as glycoproteins and glycolipids, the chemical synthesis of homogenous glycoconjugates is essential. Our research into developing synthetic methods for glycoconjugates has resulted in a convenient synthetic approach to diverse gangliosides, a family of sialic acid-containing glycosphingolipids. The major difficulties in ganglioside synthesis, which involve the construction of sialic acid-containing oligosaccharides and the conjugation of the oligosaccharide and lipid, were overcome by developing highly reactive synthetic units for glycosidating sialic acids and incorporating the lipid. Furthermore, a method for fine-tuning the hydroxyl group reactivity of sialic acids enabled the sialic acids to be dimerized and embedded in oligosaccharide sequences. These methods have been combined to synthesize diverse gangliosides and their analogs for functional studies.
Constrained peptides, namely macrocyclic and stapled peptides, are receiving increasing attention as a promising class of compounds for the inhibition of protein-protein interactions (PPI). The current state of peptide therapeutics is discussed, including their merits and challenges, as well as recent technological developments that have enabled a new era in peptide research and development. The technology behind PeptiDream’s Peptide Discovery Platform System (PDPS) is described, showing how it can be used to rapidly generate libraries of constrained peptides and obtain detailed SAR information. This technology can provide, with a high rate of success, potent peptide ligands that may be developed as drug candidates themselves, utilized in peptide-drug conjugates (PDC), or converted into small molecule drug leads. The outlook for the field of constrained peptides and their use in the clinic is also described.
Phosphole P-oxide is a useful building block for π-conjugated materials due to its nonaromatic and electron-accepting character. We have synthesized a series of ring-fused derivatives of phosphole P-oxide based on the intramolecular nucleophilic cyclization of appropriate alkyne precursors or radical phosphanylations. Some of the thus obtained compounds exhibited intriguing fluorescence properties and were applied to fluorescence imaging. A donor-acceptor-type benzo[b]phosphole P-oxide with a (diphenylamino)phenyl group exhibited large solvatochromism in its fluorescence spectra, and could hence be used as a staining agent for lipid droplets. C-Naphox and PB430, which consist of fully ring-fused π-conjugated ladder-type scaffolds, exhibited outstanding photostability and their absorption and emission properties were suitable for super-resolution STED imaging. Moreover, using PB430-conjugated antibodies, we carried out a 3-D reconstruction of the STED images and developed a photostability-based multicolor STED imaging technique.