Ryanodine (1) is a potent modulator of intracellular calcium release channels, designated as ryanodine receptors. The exceptionally complex molecular architecture of 1 comprises a highly oxygenated pentacyclic system with eleven contiguous stereogenic centers, which makes it a formidable target for organic synthesis. We identified the embedded C₂-symmetric tricyclic substructure within 1. This specific recognition permitted us to design a concise synthetic route to enantiopure tricycle 9 by utilizing a series of pairwise functionalizations. The four tetrasubstituted carbon centers of 9 were effectively constructed by three key reactions, a dearomatizing Diels–Alder reaction, the kinetic resolution of the obtained racemic 14 through asymmetric methanolysis, and the transannular aldol reaction of the eight-membered diketone 10. A new combination of cobalt-catalyzed hydroperoxidation and NfF-promoted elimination enabled conversion of the hindered olefin of 9 into the corresponding ketone, thus realizing the desymmetrization. Finally, the tetrasubstituted carbon was stereospecifically installed by utilizing the α-alkoxy bridgehead radical to deliver the core tetracycle 7 with the six contiguous tetrasubstituted carbon centers. Consequently, the present work not only accomplishes efficient assembly of four out of the five fused rings of 1, but also develops two new powerful methodologies: two-step ketone formation and bridgehead radical reaction.

(+)-Ryanodine (1) is the ester derivative of 1H-pyrrole-2-carboxylic acid and the complex terpenoid (+)-ryanodol (2), which possesses eleven contiguous stereogenic centers on the ABCDE-ring system. Compound 1 is known to be a potent modulator of intracellular calcium release channels, whereas the activity of 2 is significantly weaker. To chemically construct 1, the multiple oxygen functional groups must be installed on the fused pentacycle in stereoselective fashions and the extremely hindered C3-hydroxy group must be acylated in a site-selective manner. First, the total synthesis of 2 was accomplished by introducing the five stereocenters from the previously prepared enantiopure ABDE-ring 7. Stereoselective construction of the C3-secondary, C2- and C6-tertiary alcohols was achieved by three nucleophilic reactions. The C9- and C10-trisubstituted carbon centers were regio- and stereoselectively introduced by hydroboration/oxidation of the six-membered C-ring, which was formed by the ring-closing metathesis reaction. Direct esterification of the C3-alcohol with pyrrole-2-carboxylic acid proved unsuccessful; therefore, we developed a new, two-step protocol for attachment of the pyrrole moiety. The C3-hydroxy group was first converted into the less sterically cumbersome glycine ester, which was then transformed into the pyrrole ring through condensation with 1,3-bis(dimethylamino)allylium tetrafluoroborate. This procedure resulted in the first total synthesis of 1.

Ryanodane diterpenoids structurally share an extremely complex fused ring system, but differ in the substitution patterns of the hydroxy groups. Since these congeners exhibit various biologically important functions, their efficient chemical constructions have been greatly anticipated. We previously accomplished the total synthesis of ryanodine (1) using pentacycle 8 as the advanced intermediate. Here, we report the unified total syntheses of four distinct diterpenoids, 3-epi-ryanodol (3), cinnzeylanol (4), cinncassiols B (5), and A (6), from 8, all within 10 steps. A series of highly optimized chemo- and stereoselective reactions and protecting-group manipulations enabled assembly of the densely oxygenated structures of 3–6. Furthermore, the present synthetic studies established the C13S stereochemisty of 5–7 and revised the proposed structures of natural ryanodol (2) and cinnacasol (7) to be those of 3 and 6, respectively.

Ryanodane diterpenoids structurally share an extremely complex fused ring system, but differ in the substitution patterns of the hydroxy groups. Since these congeners exhibit various biologically important functions, their efficient chemical constructions have been greatly anticipated. We previously accomplished the total synthesis of ryanodine (1) using pentacycle 8 as the advanced intermediate. Here, we report the unified total syntheses of four distinct diterpenoids, 3-epi-ryanodol (3), cinnzeylanol (4), cinncassiols B (5), and A (6), from 8, all within 10 steps. A series of highly optimized chemo- and stereoselective reactions and protecting-group manipulations enabled assembly of the densely oxygenated structures of 3–6. Furthermore, the present synthetic studies established the C13S stereochemisty of 5–7 and revised the proposed structures of natural ryanodol (2) and cinnacasol (7) to be those of 3 and 6, respectively.

Polytheonamide B (1) is a natural peptide that displays potent cytotoxicity against P388 mouse leukemia cells (IC₅₀=0.098 nm). Linear 48-mer 1 is known to form monovalent cation channels on binding to lipid bilayers. We previously developed a fully synthetic route to 1, and then achieved the design and synthesis of a structurally simplified analogue of 1, namely, dansylated polytheonamide mimic 2. Although the synthetically more accessible 2 was found to emulate the channel function of 1, its cytotoxicity was decreased 120-fold. Herein, the chemical preparation and biological evaluation of seven analogues 3–9 of 2 are reported. Compounds 3–9 were modified at their N terminus and/or the side chain of residue 44 of 2 to alter their physicochemical properties. The total synthesis of 3–9 was accomplished in a unified fashion by a combination of solid-phase and solution-phase chemistry. Systematic evaluation of the hydrophobicities, single-channel currents, ion-exchange activities, and cytotoxicities of 3–9 revealed that their hydrophobicities are correlated with the total magnitude of ion exchange and determine their cytotoxic potency. Consequently, the most hydrophobic analogue 9 exhibited the lowest IC₅₀ value, which is comparable to that of 1. Therefore, these results clarified that the bioactivity of the polytheonamide-based peptides can be rationally controlled by changing their hydrophobicity at the N and C termini of the 48-amino-acid sequence.

A new radical-based coupling method has been developed for the single-step generation of various γ-amino acids and α,β-diamino acids from α-aminoacyl tellurides. Upon activation by Et₃B and O₂ at ambient temperature, α-aminoacyl tellurides were readily converted into α-amino carbon radicals through facile decarbonylation, which then reacted intermolecularly with acrylates or glyoxylic oxime ethers. This mild and powerful method was effectively incorporated into expeditious synthetic routes to the pharmaceutical agent gabapentin and the natural product (−)-manzacidin A.

Lysocin E, a macrocyclic peptide, exhibits potent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) through a novel mechanism. The first total synthesis of lysocin E was achieved by applying a full solid-phase strategy. The developed approach also provides rapid access to the enantiomeric, epimeric, and N-demethylated analogues of lysocin E. Significantly, the antibacterial activity of the unnatural enantiomer was comparable to that of the natural isomer, suggesting the absence of chiral recognition in its mode of action.

The complex ABC-tricyclic structure of crotophorbolone, a derivative of the tigliane diterpenoids, was assembled by coupling of simple fragments. The six-membered C-ring fragment, having five contiguous stereocenters, was stereoselectively constructed from (R)-carvone. After attachment of the five-membered A-ring through the π-allyl Stille coupling reaction, the α-alkoxy bridgehead radical reaction effected the endo-cyclization of the seven-membered B-ring by forming the sterically congested bond at C9 and C10 stereospecifically and stereoselectively, respectively. Finally, the functional groups on the 5/7/6-membered ring system were manipulated by rhodium-catalyzed C2 olefin isomerization, C13 decarboxylative oxidation, and C4 hydroxylation, thus completing the first total synthesis of crotophorbolone.

A linear peptide, gramicidin A (GA), folds into a β^6.3-helix, functions as an ion channel in the cell membrane, and exerts antibacterial activity. Herein we describe the rational design, synthesis, and biological evaluation of lactam-bridged GA analogues. The GA analogue with a 27-membered macrolactam was found to adopt a stable β^6.3-helical conformation and exhibits higher ion-exchange activity than GA. Furthermore, this GA analogue retains the potent antibiotic activity of GA, but its hemolytic activity and toxicity toward mammalian cells are significantly lower than those of GA. This study thus dissociates the antibacterial and hemolytic/cytotoxic activities of GA, and charts a rational path forward for the development of new ion-channel-based antibiotics.

The complex ABC-tricyclic structure of crotophorbolone, a derivative of the tigliane diterpenoids, was assembled by coupling of simple fragments. The six-membered C-ring fragment, having five contiguous stereocenters, was stereoselectively constructed from (R)-carvone. After attachment of the five-membered A-ring through the π-allyl Stille coupling reaction, the α-alkoxy bridgehead radical reaction effected the endo-cyclization of the seven-membered B-ring by forming the sterically congested bond at C9 and C10 stereospecifically and stereoselectively, respectively. Finally, the functional groups on the 5/7/6-membered ring system were manipulated by rhodium-catalyzed C2 olefin isomerization, C13 decarboxylative oxidation, and C4 hydroxylation, thus completing the first total synthesis of crotophorbolone.

Lysocin E, a macrocyclic peptide, exhibits potent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) through a novel mechanism. The first total synthesis of lysocin E was achieved by applying a full solid-phase strategy. The developed approach also provides rapid access to the enantiomeric, epimeric, and N-demethylated analogues of lysocin E. Significantly, the antibacterial activity of the unnatural enantiomer was comparable to that of the natural isomer, suggesting the absence of chiral recognition in its mode of action.

A new radical-based coupling method has been developed for the single-step generation of various γ-amino acids and α,β-diamino acids from α-aminoacyl tellurides. Upon activation by Et₃B and O₂ at ambient temperature, α-aminoacyl tellurides were readily converted into α-amino carbon radicals through facile decarbonylation, which then reacted intermolecularly with acrylates or glyoxylic oxime ethers. This mild and powerful method was effectively incorporated into expeditious synthetic routes to the pharmaceutical agent gabapentin and the natural product (−)-manzacidin A.

Enantioselective alkynylation of C(sp³)H bonds adjacent to a nitrogen atom has been achieved using only chiral p-tolyl tert-butyldimethylsilylethynyl sulfoximine and benzophenone under photo-irradiation conditions. A two-carbon alkyne unit was chemo- and enantioselectively transferred at the nitrogen-substituted methylene to produce the optically active propargylic amines of various structures. Remarkably, the NH-unprotected sulfoximine group efficiently transmits its stereochemical information to the product and functions as a traceless chiral auxiliary.

Polytheonamide B, isolated from the Japanese marine sponge Theonella swinhoei, is by far the largest non-ribosomal peptide known to date, and displays potent cytotoxicity. Its 48 amino acid residues include a variety of non-proteinogenic D- and L-amino acids, and the chiralities of these amino acids alternate in sequence. These structural features induce the formation of a stable β^6.3-helical structure in the hydrophobic environment, giving rise to an overall tubular structure of 45 Å in length. In a biological setting, this fold is believed to transport cations across the lipid bilayer through a pore with an inner diameter of 4 Å, thereby acting as an ion channel. In this account, we describe in detail our total synthetic route to polytheonamide B. The total synthesis relies on a combination of four key stages: synthesis of eight non-proteinogenic amino acids and an N-terminus moiety, a solid phase assembly of four fragments of polytheonamide B, three Ag⁺-mediated couplings of the fragments, and finally, acid-promoted global deprotection. The generality and modularity of the developed strategy will enable future studies of the chemical and biological properties of this unusual ion-channel-forming peptide and its synthetic analogues.

Antillatoxin and polytheonamide B are cytotoxic non-ribosomal peptides, both isolated from marine sources. These molecules possess unique biological activities that relate to ion channel proteins. Antillatoxin binds and activates voltage-gated sodium channels, while polytheonamide mimics functions of an ion channel protein. The goal of this research program is to control the function and behavior of ion channels in a desired fashion by exploiting structural motifs of these natural products. In the opening phase of this program, we first developed general and efficient synthetic routes to antillatoxin and polytheonamide B. The strategies for the total syntheses were then applied to the preparation of structurally varied derivatives for studies of structure-function relationships, which resulted in deciphering important structural elements for the potent biological activities of these natural products. DOI 10.1002/tcr.201100014

Maresin is a potent anti-inflammatory lipid mediator derived from docosahexaenoic acid (DHA). A highly convergent total synthesis of two proposed structures of C7-epimeric maresins from the four known fragments was achieved in 17 steps. The three key coupling reactions were the BF₃-mediated alkyne attack on the epoxide, chiral titanium complex-promoted enantioselective alkyne addition to the aldehyde, and a Julia–Kocienski olefination. The two synthesized diastereomers were found to be comparably active in blocking neutrophil infiltration in the acute peritonitis model.

Maduropeptin, an extremely potent antitumor agent, consists of a 1:1 complex of a carrier protein and a chromophore. We report herein a general and efficient route for the synthesis of the highly strained bicyclo[7.3.0]dodecadiyne core of the chromophore. The key feature of the synthetic strategy is the use of two Sonogashira coupling reactions in a stepwise manner to construct the conjugated dienyne substructure of the fused-ring system, including the Z alkene at C4,C13.