Masanori Nagatomo

Metal-Free Fluorination of C(sp3)–H Bonds Using a Catalytic N-Oxyl Radical

A direct conversion of C(sp(3))-H bonds to C(sp(3))-F bonds has been developed. In this process, a catalytic N-oxyl radical generated from N,N-dihydroxypyromellitimide abstracts hydrogen from the C(sp(3))-H bond and Selectfluor acts to trap the resulting carbon radical to form the C(sp(3))-F bond. This simple metal-free protocol enables the chemoselective introduction of a fluorine atom into various aromatic and aliphatic compounds and serves as a powerful tool for the efficient synthesis of fluorinated molecules.

Photochemically induced radical alkenylation of C(sp3)–H bonds

The direct alkenylation of C(sp3)–H bonds was achieved by employing benzophenone and 1,2-bis(phenylsulfonyl)ethylene under photo-irradiation conditions. This simple metal-free reaction enables the substitution of heteroatom-substituted methine, methylene and aliphatic C(sp3)–H bonds by (E)-sulfonylalkene units in a highly chemoselective manner. The derived sulfonylalkenes were further converted in a single step to the prenyl derivatives via a second photo-induced radical substitution and to the pyrrole derivatives via cyclization and aromatization steps. The present protocol thus serves as an efficient method for the direct extension of carbon skeletons for the synthesis of structurally complex natural products and pharmaceuticals.

Total Synthesis of Ryanodol

Ryanodol (1) exists in nature in the form of the 1H-pyrrole-2-carboxylate ester derivative known as ryanodine, which is a potent modulator of the calcium release channel. The pentacyclic ABCDE-ring system of 1 is fabricated with eight oxy groups, three methyl groups, and one isopropyl group. All the eight tetrasubstituted stereocenters are concentrated within the 10-carbon ABDE framework. The total synthesis of this exceptionally complex molecule was achieved in 22 steps from the simple C2-symmetric tricycle 8. The synthetic route is based on installation of the seven stereogenic centers and formation of the four C-C bonds within the highly congested multicyclic format. The novel and flexible strategy developed here will enable the generation of chemical derivatives with different functional properties toward calcium release channels.

Et3B-mediated radical-polar crossover reaction for single-step coupling of O,Te-acetal, α,β-unsaturated ketones, and aldehydes/ketones.

Et3B-mediated three-component coupling reactions between O,Te-acetal, α,β-unsaturated ketones, and aldehydes/ketones were developed. Et3B promoted the generation of the potently reactive bridgehead radical from the O,Te-acetal of the trioxaadamantane structure and converted the α-carbonyl radical of the resultant two-component adduct to the boron enolate, which then underwent a stereoselective aldol reaction with the aldehyde/ketone. This powerful, yet mild, radical-polar crossover reaction efficiently connected the hindered linkages between the three units and selectively introduced three new stereocenters.

Enantioselective Radical Alkynylation of C(sp3)‐H Bonds Using Sulfoximine as a Traceless Chiral Auxiliary

Enantioselective alkynylation of C(sp(3) )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.

Application of Two Direct C(sp3)–H Functionalizations for Total Synthesis of (+)-Lactacystin

Herein, we report a new synthetic route from (S)-pyroglutaminol to (+)-lactacystin, a potent inhibitor of the 20S proteasome. The photoinduced intermolecular C(sp(3))-H alkynylation and intramolecular C(sp(3))-H acylation chemo- and stereoselectively constructed the tetra- and trisubstituted carbon centers, respectively. The obtained bicycle was transformed into the target compound in a concise manner. The present total synthesis demonstrates the power of the direct C(sp(3))-H functionalizations for the assembly of multiple functionalized structures of natural products.

Decarbonylative Radical Coupling of α‐Aminoacyl Tellurides: Single‐Step Preparation of γ‐Amino and α,β‐Diamino Acids and Rapid Synthesis of Gabapentin and Manzacidin A

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 Et3 B 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.

Symmetry-Driven Strategy for the Assembly of the Core Tetracycle of (+)-Ryanodine: Synthetic Utility of a Cobalt-Catalyzed Olefin Oxidation and α-Alkoxy Bridgehead Radical Reaction.

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.

Symmetry-driven synthesis of 9-demethyl-10,15-dideoxyryanodol

Ryanodine, a potent modulator of calcium release channels, possesses a highly oxygenated multicyclic structure. To develop a new unified strategy for the construction of ryanodine and its derivatives, we designed 9-demethyl-10,15-dideoxyryanodol (1) as a model compound. Here we report an efficient synthesis of 1 with seven contiguous tetrasubstituted carbons by taking advantage of the C2-symmetric substructure embedded within its main structure.

Asymmetric Total Synthesis of (+)-Ryanodol and (+)-Ryanodine.

(+)-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.