Consecutive π-Lewis acidic metal-catalysed cyclisation/photochemical radical addition promoted by in situ generated 2-benzopyrylium as the photoredox catalyst.

A π-Lewis acidic metal-catalysed cyclisation/photochemical radical addition sequence was developed, which utilises in situ generated 2-benzopyrylium cation intermediates as photoredox catalysts and electrophilic substrates to form 1H-isochromene derivatives in good yields in most cases. The key 2-benzopyrylium intermediates were generated through the activation of the alkyne moiety of ortho-carbonyl alkynylbenzene derivatives by such π-Lewis acidic metal catalysts as AgNTf2 and Cu(NTf2)2, and the subsequent intramolecular cyclisation and proto-demetalation using trifluoroacetic acid. Further photo-excitation of the 2-benzopyrylium intermediates facilitated single-electron transfer from a benzyltrimethylsilane derivative as a donor molecule to promote the radical addition of arylmethyl radicals to the 2-benzopyrylium intermediates.

Scalable Total Synthesis of Leucascandrolide A Macrolactone Using a Chiral Phosphoric Acid/CuX Combined Catalytic System.

A scalable total synthesis of leucascandrolide A macrolactone has been accomplished with a longest linear sequence of 17 steps from readily available feedstocks in 31.2% yield. The key steps in this synthesis are the enantioselective allylation reaction by chiral phosphoric acid (CPA)/CuBr cooperative catalysis and the diastereoselective catalytic crotylation in the presence of CPA with CuCl. These catalytic reactions can be performed on a gram scale to afford the desired products with excellent stereoselectivities.

Kinetic resolution of racemic tertiary allylic alcohols through SN2' reaction using a chiral bisphosphoric acid/silver(i) salt co-catalyst system.

A highly efficient kinetic resolution (KR) of racemic tertiary allylic alcohols was achieved through an intramolecular allylic substitution reaction using a co-catalyst system composed of chiral bisphosphoric acid and silver carbonate. This reaction afforded enantioenriched diene monoepoxides along with the recovery of tertiary allylic alcohols in a highly enantioselective manner, realizing an extremely high s-factor in most cases. The present method provides a new access to enantioenriched tertiary allylic alcohols, multifunctional compounds that are applicable for further synthetic manipulations.

Catalytic Enantioselective Allylation of Acetylenic Aldehydes by Chiral Phosphoric Acid/Transition Metal Cooperative Catalysis: Formal Synthesis of Fostriecin.

An enantioselective allylation of silyl-substituted acetylenic aldehydes by chiral phosphoric acid (CPA)/transition metal cooperative catalysis was developed. Enantioenriched homoallylic propargyl alcohols were obtained in good yields with excellent enantioselectivities (>99% ee) under mild conditions. Moreover, the shortest formal synthesis of fostriecin was achieved by the present enantioselective allylation protocol as the key step. The known intermediate of fostriecin reported by McDonald and co-worker was synthesized in only nine steps in 39% total yield.

Two-Phase Synthesis of Taxol.

Taxol (a brand name for paclitaxel) is widely regarded as among the most famed natural isolates ever discovered, and has been the subject of innumerable studies in both basic and applied science. Its documented success as an anticancer agent, coupled with early concerns over supply, stimulated a furious worldwide effort from chemists to provide a solution for its preparation through total synthesis. Those pioneering studies proved the feasibility of retrosynthetically guided access to synthetic Taxol, albeit in minute quantities and with enormous effort. In practice, all medicinal chemistry efforts and eventual commercialization have relied upon natural (plant material) or biosynthetically derived (synthetic biology) supplies. Here we show how a complementary divergent synthetic approach that is holistically patterned off of biosynthetic machinery for terpene synthesis can be used to arrive at Taxol.

Chiral Brønsted Acid Catalyzed Enantioconvergent Propargylic Substitution Reaction of Racemic Secondary Propargylic Alcohols with Thiols.

Despite the significant progress of the enantioselective reaction using chiral catalysts, the enantioselective nucleophilic substitution reaction at the chiral sp3 -hybridized carbon atom of a racemic electrophile has not been largely explored. Herein, we report the enantioconvergent propargylic substitution reaction of racemic propargylic alcohols with thiols using chiral bis-phosphoric acid as the chiral Brønsted acid catalyst. The substitution products were formed in high yields with high enantioselectivities in most cases. The cation-stabilizing effect of the sulfur functional group introduced at the alkynyl terminus is the key to achieving the efficient enantioconvergent process, in which chiral information originating from not only the racemic stereogenic center but also the formed contact ion pair is completely eliminated from the present system.

Inversion of the Axial Information during Oxidative Aromatization in the Synthesis of Axially Chiral Biaryls with Organocatalysis as a Key Step.

Invited for the cover of this issue is the group of Yujiro Hayashi at the University of Tohoku University. The image depicts the spinning motion of a figure skater, which illustrates the transformation of the chiral information investigated in this work. Read the full text of the article at 10.1002/chem.201905814.

Inversion of the Axial Information during Oxidative Aromatization in the Synthesis of Axially Chiral Biaryls with Organocatalysis as a Key Step.

The pot-economical, highly enantioselective synthesis of axially chiral biaryls was developed by using one-pot organocatalyst-mediated domino and aromatization reactions as key steps. The axial information of the precursor, which also has central chirality, was completely inverted in the final biaryls. The inversion of the axial information occurred in the conversion of the central chirality to the axial chirality of an oxidative aromatization step.

Diarylprolinol-Mediated Asymmetric Direct Cross-Aldol Reaction of α,ß-Unsaturated Aldehyde as an Electrophilic Aldehyde.

The diarylprolinol-mediated asymmetric direct cross-aldol reaction of α,ß-unsaturated aldehyde as an electrophilic aldehyde was developed. The reaction becomes accelerated by an acid when a carbonyl group is introduced at the γ-position of the α,ß-unsaturated aldehyde. Synthetically useful γ,δ-unsaturated ß-hydroxy aldehydes were obtained with high anti-selectivity and excellent enantioselectivity.

Asymmetric Michael Reaction of α-CF3 Thioester and α,ß-Unsaturated Aldehyde Catalyzed by Diphenylprolinol Silyl Ether.

Asymmetric Michael reaction of α-CF3 thioester and α,ß-unsaturated aldehyde is catalyzed by diphenylprolinol silyl ether to afford the trifluoromethyl substituted Michael product with excellent enantioselectivity. Although the Michael products were generated as a mixture of syn- and anti-isomers, they can be transformed to single isomers of other useful compounds, such as lactone, lactam, piperidine, dihydropyran containing trifluoromethyl groups, or fluoro substituents.

Enantio- and Diastereoselective Synthesis of Latanoprost using an Organocatalyst.

An enantioselective total synthesis of latanoprost was achieved. Its chiral cyclopentane core structure was constructed through an organocatalyst-mediated [3+2]-cycloaddition reaction, and chirality in the ω-side chain was generated by prolinate-anion-mediated α-aminoxylation of an aldehyde. Highly diastereoselective domino acetalization and an oxy-Michael reaction were key steps for the generation of C9 chirality.

Enantioselective Total Synthesis of Beraprost Using Organocatalyst.

A convergent and enantioselective total synthesis of the most active isomer of beraprost was achieved in 17 pots. A unique tricyclic core in beraprost was synthesized efficiently by utilizing the asymmetric organocatalyst-mediated formal [3 + 2] cycloaddition reaction of succinaldehyde with nitroalkene as a key step. The synthesis of the optically active Horner-Wadsworth-Emmons reagent for the construction of the ω-side chain was also established by means of the enantioselective Michael reaction of crotonaldehyde with nitromethane catalyzed by the organocatalyst developed by our group.

11-Step Total Synthesis of Pallambins C and D.

The structurally intriguing terpenes pallambins C and D have been assembled in only 11 steps from a cheap commodity chemical: furfuryl alcohol. This synthesis, which features a redox-economic approach free of protecting-group manipulations, assembles all four-ring systems via a sequential cyclization strategy. Of these four-ring constructing operations, two are classical (Robinson annulation and Mukaiyama aldol) and two are newly devised. During the course of this work a method for the difunctionalization of enol ethers was developed, and the scope of this transformation was explored.

Oxidative Amidation of Nitroalkanes with Amine Nucleophiles using Molecular Oxygen and Iodine.

The formation of amides and peptides often necessitates powerful yet mild reagent systems. The reagents used, however, are often expensive and highly elaborate. New atom-economical and practical methods that achieve such goals are highly desirable. Ideally, the methods should start with substrates that are readily available in both chiral and non-chiral forms and utilize cheap reagents that are compatible with a wide variety of functional groups, steric encumberance, and epimerizable stereocenters. A direct oxidative method was developed to form amide and peptide bonds between amines and primary nitroalkanes simply by using I2 and K2 CO3 under O2 . Contrary to expectations, a 1:1 halogen-bonded complex forms between the iodonium source and the amine, which reacts with nitronates to form α-iodo nitroalkanes as precursors to the amides.

Total Synthesis of Verruculogen and Fumitremorgin A Enabled by Ligand-Controlled C-H Borylation.

Verruculogen and fumitremorgin A are bioactive alkaloids that contain a unique eight-membered endoperoxide. Although related natural products such as fumitremorgins B and C have been previously synthesized, we report the first synthesis of the more complex, endoperoxide-containing members of this family. A concise route to verruculogen and fumitremorgin A relied not only on a hydroperoxide/indole hemiaminal cyclization, but also on the ability to access the seemingly simple starting material, 6-methoxytryptophan. An iridium-catalyzed C-H borylation/Chan-Lam procedure guided by an N-TIPS group enabled the conversion of a tryptophan derivative into a 6-methoxytryptophan derivative, proving to be a general way to functionalize the C6 position of an N,C3-disubstituted indole for the synthesis of indole-containing natural products and pharmaceuticals.

Nef reaction with molecular oxygen in the absence of metal additives, and mechanistic insights.

A Nef reaction has been developed that is conducted under mildly basic conditions with molecular oxygen as an oxidant, without the need for metal additives. Whereas nitroalkanes are converted into ketones in good yield, nitroalkenes are transformed into α,ß-unsaturated ketones in one-pot by double-bond isomerization followed by the oxygen-mediated Nef reaction. The reaction protocol is both mild and general, and tolerates acid- and base-labile functionality or protecting groups. When oxygen-saturated solvents are employed, the reaction completes within 20 min. Mechanistically, the addition of nitronate ion and molecular oxygen is proposed to proceed initially through a single-electron transfer event, as indicated by radical clock experiments. This ultimately generates a putative 1,1-dioxirane, which reacts further with another nitronate ion to generate the ketone. Involvement of a 1,1-dioxirane is supported by intramolecular trapping experiments with sulfide at the γ-position of the nitro-moiety.

Diphenylprolinol silyl ether catalyzed asymmetric Michael reaction of nitroalkanes and ß,ß-disubstituted α,ß-unsaturated aldehydes for the construction of all-carbon quaternary stereogenic centers.

The asymmetric Michael reaction of nitroalkanes and ß,ß-disubstituted α,ß-unsaturated aldehydes was catalyzed by diphenylprolinol silyl ether to afford 1,4-addition products with an all-carbon quaternary stereogenic center with excellent enantioselectivity. The reaction is general for ß-substituents such as ß-aryl and ß-alkyl groups, and both nitromethane and nitroethane can be employed. The addition of nitroethane is considered a synthetic equivalent of the asymmetric Michael reaction of ethyl and acetyl substituents by means of radical denitration and Nef reaction, respectively. The short asymmetric synthesis of (S)-ethosuximide with a quaternary carbon center was accomplished by using the present asymmetric Michael reaction as the key step. The reaction mechanism that involves the E/Z isomerization of α,ß-unsaturated aldehydes, the retro-Michael reaction, and the different reactivity between nitromethane and nitroethane is discussed.