Total Synthesis of Leuconoxine,Melodinine E,and Mersicarpine through a Radical Translocation–Cyclization Cascade

The Aspidosperma alkaloids leuconoxine, melodinine E, and mersicarpine were synthesized. The approach features a key cascade radical reaction. A 1,5‐hydrogen atom transfer is followed by spontaneous 5‐exo‐trig cyclization to construct the central indoline architecture. Late‐stage differentiation of the radical cyclization product by chemoselective oxidation allows production of either the leuconoxine/melodinine E or mersicarpine structure.     

A Photoinduced Cyclization Cascade—Total Synthesis of (−)‐Leuconoxine

A protecting‐group‐free and enantioselective total synthesis of the monoterpenoid indole alkaloid (?)‐leuconoxine was accomplished. The key step comprises a novel photoinduced domino macrocyclization/transannular cyclization involving the Witkop cyclization, for which additional mechanistic evidence is provided. This process furnishes a diaza[5.5.6.6]fenestrane skeleton, which is a hitherto unprecedented structure element.     

Scalable Total Synthesis of rac‐Jungermannenones B and C

Reported is the first scalable synthesis of rac‐jungermannenones B and C starting from the commercially available and inexpensive geraniol in 10 and 9 steps, respectively. The unique jungermannenone framework is rapidly assembled by an unprecedented regioselective 1,6‐dienyne reductive cyclization reaction which proceeds through a vinyl radical cyclization/allylic radical isomerization mechanism. DFT calculations explain the high regioselectivity observed in the 1,6‐dienyne reductive radical cyclization.     

The Investigation of Free Radical Intermolecular Addition Following Free Radical SH2′ Cyclization Reactions

The photolytic radical intermolecular addition following S_H2′ cyclization reactions of t‐BuHgCl with 1‐bromo‐4‐(2‐choroallyloxy)‐but‐2‐ene and (E)‐4‐bromobut‐2‐enyl acrylate gave the good yields and the chemoselectivity of the cyclized product. The high stereoselectivity of the reactions is discussed.     

Esters as Radical Acceptors: β‐NHC‐Borylalkenyl Radicals Induce Lactonization by C−C Bond Formation/Cleavage on Esters

Substituted propargyl acetates are converted into 4‐boryl‐2(5H)‐furanones upon thermolysis in the presence of an N‐heterocyclic carbene borane (NHC‐borane) and di‐tert‐butyl peroxide. The acetyl methyl group is lost during the reaction as methane. Evidence suggests that the reaction proceeds by a sequence of radical events including: 1) addition of an NHC‐boryl radical to the triple bond; 2) cyclization of the resultant β‐borylalkenyl radical to the ester carbonyl group; 3) β‐scission of the so‐formed alkoxy radical to provide the 4‐boryl‐2(5H)‐furanone and a methyl radical; and 4) hydrogen abstraction from the NHC‐borane to return the initial NHC‐boryl radical and methane.     

Collective Synthesis of Schilancidilactones A,B and Schilancitrilactones A,B, C, 20‐epi‐Schilancitrilactone A

Schisandraceae triterpenoids are novel natural products that contain highly fused ring systems bearing multiple chiral centers surrounding. Some of them exhibit promising bioactivities, such as antitumor, anti‐HIV, etc. In this article, we describe our efforts to the collective total synthesis of schilancidilactones A, B, schilancitrilactones A, B, C, and 20‐epi‐schilancitrilactone A from common precursors. An intramolecular radical cyclization, late‐stage halogenation and AIBN‐mediated or Ni‐catalyzed intermolecular radical cross coupling reaction were employed as the key steps.     

Catalytic Dibenzocyclooctene Synthesis via Cobalt(III)–Carbene Radical and ortho‐Quinodimethane Intermediates

The metalloradical activation of ortho‐benzallylaryl N‐tosyl hydrazones with [Co(TPP)] (TPP=tetraphenylporphyrin) as the catalyst enabled the controlled exploitation of the single‐electron reactivity of the redox non‐innocent carbene intermediate. This method offers a novel route to prepare eight‐membered rings, using base metal catalysis to construct a series of unique dibenzocyclooctenes through selective C_carbene?C_aryl cyclization. The desired eight‐membered‐ring products were obtained in good to excellent yields. A large variety of aromatic substituents are tolerated. The proposed reaction mechanism involves intramolecular hydrogen atom transfer (HAT) to Co^III–carbene radical intermediates followed by dissociation of an ortho‐quinodimethane that undergoes 8π cyclization. The mechanism is supported by DFT calculations, and the presence of radical‐type intermediates was confirmed by trapping experiments.     

Photoredox‐Catalyzed Cyclobutane Synthesis by a Deboronative Radical Addition–Polar Cyclization Cascade

Photoredox‐catalyzed methylcyclobutanations of alkylboronic esters are described. The reactions proceed through single‐electron transfer induced deboronative radical addition to an electron‐deficient alkene followed by single‐electron reduction and polar 4‐exo‐tet cyclization with a pendant alkyl halide. Key to the success of the methodology was the use of easily oxidizable arylboronate complexes. Structurally diverse cyclobutanes are shown to be conveniently prepared from readily available alkylboronic esters and a range of haloalkyl alkenes. The mild reactions display excellent functional group tolerance, and the radical addition‐polar cyclization cascade also enables the synthesis of 3‐, 5‐, 6‐, and 7‐membered rings.     

Synthesis of 1‐Difluoroalkylated Isoquinolines via Palladium‐Catalyzed Radical Cascade Difluoroalkylation–Cyclization of Vinyl Isocyanides with Bromodifluoroacetic Derivatives

A general method was developed for the synthesis of 1‐difluoroalkyl isoquinolines via the palladium‐catalyzed radical cascade difluoroalkylation–cyclization of vinyl isocyanides with bromodifluoroacetic derivatives. The difluoroalkylated cyclization products were readily converted to various other valuable gem ‐difluoro‐containing compounds.     

5‐exo versus 6‐endo Thiyl‐Radical Cyclizations in Organic Synthesis

Since the discovery of the radical mediated thiol‐ene and thiol‐yne reactions, these reactions have been employed in an intramolecular manner for the synthesis of sulfur‐containing heterocycles. Although closely related on a mechanistic basis, the thiol‐ene and thiol‐yne cyclization can differ greatly in regioselectivity and product distribution, with the thiol‐ene process being more predictable and thus attracting greater utilization. Herein, we review intramolecular thiyl‐radical addition reactions and the factors leading to the observed regioselectivity in examples in which both the 5‐exo and 6‐endo mode of cyclization are feasible. We highlight the applications of these important reactions for organic synthesis in the recent literature.     

Asymmetric Total Synthesis of ent‐Pyripyropene A

An asymmetric total synthesis of ent‐pyripyropene A was achieved by a convergent synthetic route. We used our originally developed Ti^III‐catalyzed radical cyclization to construct an AB‐ring portion that consisted of a trans‐decalin skeleton with five contiguous stereogenic centers. The coupling between the AB‐ring and the DE‐ring portions, and a subsequent C‐ring cyclization, led to the total synthesis of ent‐pyripyropene A. An evaluation of the insecticidal activity of ent‐pyripyropene A against two aphid species revealed that ent‐pyripyropene A was 35–175 times less active than naturally occurring pyripyropene A. This result indicated that the biological target of pyripyropene A recognizes the absolute configuration of pyripyropene A.     

Radical 4‐exo Cyclizations onto O‐Alkyloxime Acceptors: Towards the Synthesis of Penicillin‐Containing Antibiotics

The 4‐exo cyclizations of two types of carbamoyl radicals onto O‐alkyloxime acceptor groups were studied as potential routes to 3‐amino‐substituted azetidinones and hence to penicillins. A general synthetic route to ‘benzaldehyde oxime oxalate amides’ (= 2‐[(benzylideneamino)oxy]‐2‐oxoacetamides; see, e.g., 10c ) of 2‐{[(benzyloxy)imino]methyl}‐substituted thiazolidine‐4‐carboxylic acid methyl esters 9 was developed (Scheme 3). It was shown by EPR spectroscopy that these compounds underwent sensitized photodissociation to the corresponding carbamoyl radicals but that these did not ring close. An analogous open‐chain precursor, benzaldehyde O‐(benzylaminoacetaldehyde‐O‐benzyloxalyl)oxime, 15 , lacking the 5‐membered thiazolidine ring, was shown by EPR spectroscopy to release the corresponding carbamoyl radical (Scheme 4). The latter underwent 4‐exo cyclization onto its C?NOBn bond in non‐H‐atom donor solvents. The rate constant for this cyclization was determined by the steady‐state EPR method. Spectroscopic evidence indicated that the reverse ring‐opening process was slower than cyclization.     

Total Syntheses of Daphenylline,Daphnipaxianine A,and Himalenine D

We report the total syntheses of daphenylline ( 1 ), daphnipaxianine A ( 5 ), and himalenine D ( 6 ), three Daphniphyllum alkaloids from the calyciphylline A subfamily. A pentacyclic triketone was prepared by using atom‐transfer radical cyclization and the Lu [3+2] cycloaddition as key steps. Inspired by the proposed biosynthetic relationship between 1 and another calyciphylline A type alkaloid, we developed a ring‐expansion/aromatization/aldol cascade to construct the tetrasubstituted benzene moiety of 1 . The versatile triketone intermediate was also elaborated into 5 and 6 through a C=C bond migration/aldol cyclization approach.     

Copper‐Catalyzed Alkylarylation of Unactivated Alkenes: Synthesis of 3‐Alkyl Indolines from N‐Allyl Anilines and Alkanes

A rare example of C(sp³)?H functionalization of simple alkanes with unactivated alkenes is presented. In the presence of a copper salt and di‐tert‐butyl peroxide (DTBP), N‐allyl anilines underwent exo‐selective alkylation/cyclization cascade with unactivated alkenic bonds as radical acceptors and simple alkanes as radical precursors, providing a direct access to 3‐alkyl indolines. The present protocol features simple operation, broad substrate scope and great exo selectivity.     

Studies on the Radical Cyclization of 3‐Oxopropanenitriles and Alkenes with Cerium(IV) Ammonium Nitrate in Ether Solvents

The radical cyclization of 3‐oxopropanenitriles 1a – 1e and alkenes 2a – 2g with cerium(IV) ammonium nitrate (CAN) in ether solvents was investigated (Tables 1 and 2). In the optimization study, 1,3‐dioxolane, 1,4‐dioxane, 1,2‐dimethoxyethane, Et₂O, and THF were used as ether‐based solvents, and the latter was found to be the most effective solvent in radical cyclizations mediated by cerium(IV). This system (cerium(IV)/THF) was applied to cyclizations of various 3‐oxopropanenitriles and 1,3‐dicarbonyl compounds with alkenes resulting in the formation of 4,5‐dihydrofurans in high yields (Table 2 and Scheme 2). The results of the cerium(IV)/THF radical cyclization were compared with those obtained with manganese(III) acetate/AcOH; the cerium(IV)/THF system turned out to be much more efficient.     

Total Syntheses of Daphenylline,Daphnipaxianine A,and Himalenine D

We report the total syntheses of daphenylline ( 1 ), daphnipaxianine A ( 5 ), and himalenine D ( 6 ), three Daphniphyllum alkaloids from the calyciphylline A subfamily. A pentacyclic triketone was prepared by using atom‐transfer radical cyclization and the Lu [3+2] cycloaddition as key steps. Inspired by the proposed biosynthetic relationship between 1 and another calyciphylline A type alkaloid, we developed a ring‐expansion/aromatization/aldol cascade to construct the tetrasubstituted benzene moiety of 1 . The versatile triketone intermediate was also elaborated into 5 and 6 through a C=C bond migration/aldol cyclization approach.     

Radical Cyclization/ipso‐1,4‐Aryl Migration Cascade: Asymmetric Synthesis of 3,3‐Difluoro‐2‐propanoylbicyclo[3.3.0]octanes

A novel method for the asymmetric synthesis of 3,3‐difluoro‐2‐propanoylbicyclo‐[3.3.0]octanes involves an unprecedented intramolecular radical cyclization/ipso‐1,4‐aryl migration cascade.     

Synthesis of Polysubstituted γ‐Butenolides via a Radical Pathway: Cyclization of α‐Bromo Aluminium Acetals and Comparison with the Cyclization of α‐Bromoesters at High Temperature

Polysubstituted butenolides were obtained in good to high yields from α‐bromoesters derived from propargyl alcohols by a one‐pot reaction involving the radical cyclization of α‐bromo aluminium acetals, followed by the oxidation of the resulting cyclic aluminium acetals in an Oppenauer‐type process and migration of the exocyclic C?C bond into the α,β‐position. Comparison with the direct cyclization of α‐bromoesters at high temperature and under high dilution conditions is described. Deuterium‐labelling experiments allowed us to uncover “invisible” 1,5‐hydrogen atom transfers (1,5‐HATs) that occur during these cyclization processes, together with the consequences of the latter in the epimerization of stereogenic centres. Compared to the classical approach, the cyclization of aluminium acetals proved to be highly chemoselective and its efficiency was illustrated by the short total syntheses of optically enriched γ‐butenolides isolated from Plagiomnium undulatum and from Kyrtuhrix maculans.     

Enantioselective Radical‐Polar Crossover Reactions of Indanonecarboxamides with Alkenes

Highly efficient asymmetric intermolecular radical‐polar crossover reactions were realized by combining a chiral N,N′‐dioxide/Ni^II complex catalyst with Ag₂O under mild reaction conditions. Various terminal alkenes and indanonecarboxamides/esters underwent radical addition/cyclization reactions to afford spiro‐iminolactones and spirolactones with good to excellent yields (up to 99 %) and enantioselectivities (up to 97 % ee). Furthermore, a range of different radical‐mediated oxidation/elimination or epoxide ring‐opening products were obtained under mild reaction conditions. The Lewis acid catalysts exhibited excellent performance and precluded the strong background reaction.     

Copper‐Catalyzed Electrophilic Cyclization of N‐Propargylamines with Sodium Sulfinate for the Synthesis of 3‐Sulfonated Quinolines

A convenient and effective protocol for the synthesis of 3‐sulfonated quinolines via copper‐catalyzed electrophilic cyclization of N‐propargylamines has been developed, in which cheap and stable sodium sulfinates were utilized as green sulfonylation reagents. This cascade transformation involves radical addition, cyclization and dehydrogenative aromatization processes in a one‐pot reaction under mild conditions.