Enantioselective Intramolecular C−H Insertion of Donor and Donor/Donor Carbenes by a Nondiazo Approach

The first enantioselective intramolecular C?H insertion and cyclopropanation reactions of donor‐ and donor/donor‐carbenes by a nondiazo approach are reported. The reactions were conducted in a one‐pot manner without slow addition and provided the desired dihydroindole, dihydrobenzofuran, tetrahydrofuran, and tetrahydropyrrole derivatives with up to 99 % ee and 100 % atom efficiency.     

Chemo‐, Diastereo‐, and Enantioselective Iridium‐Catalyzed Allylic Intramolecular Dearomatization Reaction of Naphthol Derivatives

An iridium‐catalyzed intramolecular asymmetric allylic dearomatization reaction of naphthol derivatives is described. Challenges confronted in this reaction include chemoselectivity between carbon and oxygen atoms as nucleophilic centers, diastereoselectivity when contiguous chiral centers are generated, and enantioselective control for constructing an all‐carbon quaternary stereocenter. In the presence of an iridium catalyst generated from [{Ir(dbcot)Cl}₂] (dbcot=dibenzocyclooctatetraene) and a new THQphos (tetrahydroquinolinedinaphthophosphoramidite) ligand, various spironaphthalenones were obtained with up to greater than 95:5 C/O selectivity, greater than 95:5 d.r., and 99 % ee, thus providing a general method for the dearomatization of naphthols.     

Enantioselective Allylic C−H Oxidation of Terminal Olefins to Isochromans by Palladium(II)/Chiral Sulfoxide Catalysis

The enantioselective synthesis of isochroman motifs has been accomplished by palladium(II)‐catalyzed allylic C−H oxidation from terminal olefin precursors. Critical to the success of this goal was the development and utilization of a novel chiral aryl sulfoxide‐oxazoline (ArSOX) ligand. The allylic C−H oxidation reaction proceeds with the broadest scope and highest levels of asymmetric induction reported to date (avg. 92 % ee, 13 examples with greater than 90 % ee).     

Elevated Catalytic Activity of Ruthenium(II)–Porphyrin‐Catalyzed Carbene/Nitrene Transfer and Insertion Reactions with N‐Heterocyclic Carbene Ligands

Bis(NHC)ruthenium(II)–porphyrin complexes were designed, synthesized, and characterized. Owing to the strong donor strength of axial NHC ligands in stabilizing the trans M?CRR′/M?NR moiety, these complexes showed unprecedently high catalytic activity towards alkene cyclopropanation, carbene C? H, N? H, S? H, and O? H insertion, alkene aziridination, and nitrene C? H insertion with turnover frequencies up to 1950 min^?1. The use of chiral [Ru(D₄‐Por)(BIMe)₂] ( 1 g ) as a catalyst led to highly enantioselective carbene/nitrene transfer and insertion reactions with up to 98 % ee. Carbene modification of the N terminus of peptides at 37 °C was possible. DFT calculations revealed that the trans axial NHC ligand facilitates the decomposition of diazo compounds by stabilizing the metal–carbene reaction intermediate.     

Rhodium-Catalyzed Chemodivergent Regio- and Enantioselective Allylic Alkylation of Indoles

The control of C3/N1 chemoselectivity in indole alkylation with the same electrophiles is still challenging. An Rh/bisoxazolinephosphane-catalyzed chemodivergent regio- and enantioselective allylic alkylation of indoles was developed. Chiral C3- and N1-allylindoles can be selectively obtained with high branched/linear ratio and up to 99 % ee by changing the counteranion of Rh, the allylic carbonate, the reaction temperature, and the ligand.     

An Iridium(I) N‐Heterocyclic Carbene Complex Catalyzes Asymmetric Intramolecular Allylic Amination Reactions

A chiral iridium(I) N‐heterocyclic carbene complex was reported for the first time as the catalyst in the highly enantioselective intramolecular allylic amination reaction. The current method provides facile access to biologically important enantioenriched indolopiperazinones and piperazinones in good yields (74–91 %) and excellent enantioselectivities (92–99 % ee). Preliminary mechanistic investigations reveal that the C?H activation occurs at the position ortho to the N‐aryl group of the ligand.     

Ruthenium–Porphyrin‐Catalyzed Diastereoselective Intramolecular Alkyl Carbene Insertion into CH Bonds of Alkyl Diazomethanes Generated In Situ from N‐Tosylhydrazones

With a ruthenium–porphyrin catalyst, alkyl diazomethanes generated in situ from N‐tosylhydrazones efficiently underwent intramolecular C(sp³)? H insertion of an alkyl carbene to give substituted tetrahydrofurans and pyrrolidines in up to 99 % yield and with up to 99:1 cis selectivity. The reaction displays good tolerance of many functionalities, and the procedure is simple without the need for slow addition with a syringe pump. From a synthetic point of view, the C? H insertion of N‐tosylhydrazones can be viewed as reductive coupling between a C?O bond and a C? H bond to form a new C? C bond, since N‐tosylhydrazones can be readily prepared from carbonyl compounds. This reaction was successfully applied in a concise synthesis of (±)‐pseudoheliotridane.     

Stereoselective Synthesis of Highly Functionalized Nitrocyclopropanes through the Organocatalyic Michael‐Addition‐Initiated Cyclization of Bromonitromethane and β,γ‐Unsaturated α‐Ketoesters

A highly diastereo‐ and enantioselective cyclopropanation of β,γ‐unsaturated α‐ketoesters with bromonitromethane has been successfully developed through a domino Michael‐addition/intramolecular‐alkylation strategy. Acceptable yields (up to 89 %) and enantioselectivities (up to 96 % ee) have been obtained.     

Ruthenium–Porphyrin‐Catalyzed Diastereoselective Intramolecular Alkyl Carbene Insertion into C?H Bonds of Alkyl Diazomethanes Generated In Situ from N‐Tosylhydrazones

With a ruthenium–porphyrin catalyst, alkyl diazomethanes generated in situ from N‐tosylhydrazones efficiently underwent intramolecular C(sp³) H insertion of an alkyl carbene to give substituted tetrahydrofurans and pyrrolidines in up to 99 % yield and with up to 99:1 cis selectivity. The reaction displays good tolerance of many functionalities, and the procedure is simple without the need for slow addition with a syringe pump. From a synthetic point of view, the C H insertion of N‐tosylhydrazones can be viewed as reductive coupling between a CO bond and a C H bond to form a new C C bond, since N‐tosylhydrazones can be readily prepared from carbonyl compounds. This reaction was successfully applied in a concise synthesis of (±)‐pseudoheliotridane.     

Scalable,Stereocontrolled Formal Syntheses of (+)‐Isoschizandrin and (+)‐Steganone: Development and Applications of Palladium(II)‐Catalyzed Atroposelective C−H Alkynylation

Dibenzocyclooctadiene lignans are an interesting class of molecules because of their unique structure based on an axially chiral biaryl moiety as well as their significant biological activity. Herein, we describe the development of a palladium‐catalyzed atroposelective C−H alkynylation and its application in gram‐scale, stereocontrolled formal syntheses of (+)‐isoschizandrin and (+)‐steganone. tert‐Leucine was identified as an efficient, catalytic transient chiral auxiliary. A wide range of enantiomerically enriched biaryl compounds were prepared by this approach in good yields (up to 99 %) with excellent enantioselectivity (up to >99 % ee).     

Donor Rhodium Carbenes by Retro‐Buchner Reaction

Rhodium carbenes are key intermediates in a range of cycloadditions and insertion reactions. Herein, we report the first generation of donor Rh^II carbenes by decarbenation of 7‐substituted 1,3,5‐cycloheptatrienes. This discovery unlocks an improved retro‐Buchner‐cyclopropanation sequence, a Si?H insertion reaction for a broad‐scope synthesis of allylsilanes, and a new method for the vinylogation of aldehydes. The last strategy led to the development of an iterative synthesis of E‐polyenes, and to the total synthesis of navenones B and C.     

1H‐NMR Analysis of Intra‐ and Intermolecular H‐Bonds of Alcohols in DMSO: Chemical Shift of Hydroxy Groups and Aspects of Conformational Analysis of Selected Monosaccharides,Inositols, and Ginkgolides

The interpretation of ¹H‐NMR chemical shifts, coupling constants, and coefficients of temperature dependence (δ(OH), J(H,OH), and Δδ(OH)/ΔT values) evidences that, in (D₆)DMSO solution, the signal of an OH group involved as donor in an intramolecular H‐bond to a hydroxy or alkoxy group is shifted upfield, whereas the signal of an OH group acting as acceptor of an intramolecular H‐bond and as donor in an intermolecular H‐bond to (D₆)DMSO is shifted downfield. The relative strength of the intramolecular H‐bond depends on co‐operativity and on the acidity of OH groups. The acidity of OH groups is enhanced when they are in an antiparallel orientation to a C−O bond. A comparison of the ¹H‐NMR spectra of alcohols in CDCl₃ and (D₆)DMSO allows discrimination between weak and strong intramolecular H‐bonds. Consideration of IR spectra (CHCl₃ or CH₂Cl₂) shows that the rule according to which the downfield shift of δ(OH) for H‐bonded alcohols in CDCl₃ parallels the strength of the H‐bond is valid only for alcohols forming strong intramolecular H‐bonds. The combined analysis of J(H,OH) and δ(OH) values is illustrated by the interpretation of the spectra of the epoxyalcohols 14 and 15 (Fig. 3). H‐Bonding of hexopyranoses, hexulopyranoses, alkyl hexopyranosides, alkyl 4,6‐O‐benzylidenehexopyranosides, levoglucosans, and inositols in (D₆)DMSO was investigated. Fully solvated non‐anomeric equatorial OH groups lacking a vicinal axial OR group (R=H or alkyl, or (alkoxy)alkyl) show characteristic J(H,OH) values of 4.5 – 5.5 Hz and fully solvated non‐anomeric axial OH groups lacking an axial OR group in β‐position are characterized by J(H,OH) values of 4.2 – 4.4 Hz (Figs. 4 – 6). Non‐anomeric equatorial OH groups vicinal to an axial OR group are involved in a partial intramolecular H‐bond (J(H,OH)=5.4 – 7.4 Hz), whereas non‐anomeric equatorial OH groups vicinal to two axial OR form partial bifurcated H‐bonds (J(H,OH)=5.8 – 9.5 Hz). Non‐anomeric axial OH groups form partial intramolecular H‐bonds to a cis‐1.3‐diaxial alkoxy group (as in 29 and 41 : J(H,OH)=4.8 – 5.0 Hz). The persistence of such a H‐bond is enhanced when there is an additional H‐bond acceptor, such as the ring O‐atom ( 43 – 47 : J(H,OH)=5.6 – 7.6 Hz; 32 and 33 : 10.5 – 11.3 Hz). The (partial) intramolecular H‐bonds lead to an upfield shift (relative to the signal of a fully solvated OH in a similar surrounding) for the signal of the H‐donor. The shift may also be related to the signal of the fully solvated, equatorial HO−C(2), HO−C(3), and HO−C(4) of β‐D ‐glucopyranose ( 16 : 4.81 ppm) by using the following increments: −0.3 ppm for an axial OH group, 0.2 – 0.25 ppm for replacing a vicinal OH by an OR group, ca. 0.1 ppm for replacing another OH by an OR group, 0.2 ppm for an antiperiplanar C−O bond, −0.3 ppm if a vicinal OH group is (partially) H‐bonded to another OR group, and −0.4 to −0.6 for both OH groups of a vicinal diol moiety involved in (partial) divergent H‐bonds. Flip‐flop H‐bonds are observed between the diaxial HO−C(2) and HO−C(4) of the inositol 40 (J(H,OH)=6.4 Hz, δ(OH)=5.45 ppm) and levoglucosan ( 42 ; J(H,OH)=6.7 – 7.1 Hz, δ(OH)=4.76 – 4.83 ppm; bifurcated H‐bond); the former is completely persistent and the latter to ca. 40%. A persistent, unidirectional H‐bond C(1)−OH⋅⋅⋅O−C(10) is present in ginkgolide B and C, as evidenced by strongly different δ(OH) and Δδ(OH)/ΔT values for HO−C(1) and HO−C(10) (Fig. 9). In the absence of this H‐bond, HO−C(1) of 52 resonates 1.1 – 1.2 ppm downfield, while HO−C(10) of ginkgolide A and of 48 – 50 resonates 0.5 – 0.9 ppm upfield.     

Asymmetric Diels–Alder and Inverse‐Electron‐Demand Hetero‐Diels–Alder Reactions of β,γ‐Unsaturated α‐Ketoesters with Cyclopentadiene Catalyzed by N,N′‐Dioxide Copper(II) Complex

Highly enantioselective Diels–Alder (DA) and inverse‐electron‐demand hetero‐Diels–Alder (HDA) reactions of β,γ‐unsaturated α‐ketoesters with cyclopentadiene catalyzed by chiral N,N′‐dioxide–Cu(OTf)₂ (Tf=triflate) complexes have been developed. Quantitative conversion of β,γ‐unsaturated α‐ketoesters and excellent diastereoselectivities (up to 99:1) and enantioselectivities (up to >99 % ee) were observed for a broad range of substrates. Both aromatic and aliphatic β,γ‐unsaturated α‐ketoesters were found to be suitable substrates for the reactions. Moreover, the chemoselectivity of the DA and HDA adducts were improved by regulating the reaction temperature. Good to high chemoselectivity (up to 94 %) of the DA adducts were obtained at room temperature, and moderate chemoselectivity (up to 65 %) of the HDA adducts were achieved at low temperature. The reaction also featured mild reaction conditions, a simple procedure, and remarkably low catalyst loading (0.1–1.5 mol %). A strong positive nonlinear effect was observed.     

Divergent reactivity of allene-containing α-diazoesters using Cu and Rh catalysis

A versatile intramolecular reaction of allene-containing diazomalonates that exhibits excellent chemoselectivity for either allenic C–H insertion or cyclopropanation is demonstrated. The identity of the product depends on the transition metal catalyst that is employed for the reaction. Rh catalysts promote exclusive C–H insertion with good diastereoselectivity for the trans product, while Cu catalysis enables intramolecular cyclopropanation to yield methylenecyclopropanes with moderate to good E:Z ratios.     

Ultrafast Iron‐Catalyzed Reduction of Functionalized Ketones: Highly Enantioselective Synthesis of Halohydrines,Oxaheterocycles, and Aminoalcohols

A molecularly defined chiral boxmi iron alkyl complex catalyzes the hydroboration of various functionalized ketones and provides the corresponding chiral halohydrines, oxaheterocycles (oxiranes, oxetanes, tetrahydrofurans, and dioxanes) and amino alcohols with excellent enantioselectivities (up to >99 %ee) and conversion efficiencies at low catalyst loadings (as low as 0.5 mol %). Turnover frequencies of greater than 40000 h⁻¹ at −30 °C highlight the activity of this earth‐abundant metal catalyst which tolerates a large number of functional groups.     

N‐Heterocyclic Carbene Iron(III) Porphyrin‐Catalyzed Intramolecular C(sp3)–H Amination of Alkyl Azides

Metal‐catalyzed intramolecular C?H amination of alkyl azides constitutes an appealing approach to alicyclic amines; challenges remain in broadening substrate scope, enhancing regioselectivity, and applying the method to natural product synthesis. Herein we report an iron(III) porphyrin bearing axial N‐heterocyclic carbene ligands which catalyzes the intramolecular C(sp³)–H amination of a wide variety of alkyl azides under microwave‐assisted and thermal conditions, resulting in selective amination of tertiary, benzylic, allylic, secondary, and primary C?H bonds with up to 95 % yield. 14 out of 17 substrates were cyclized selectively at C4 to give pyrrolidines. The regioselectivity at C4 or C5 could be tuned by modifying the reactivity of the C5–H bond. Mechanistic studies revealed a concerted or a fast re‐bound mechanism for the amination reaction. The reaction has been applied to the syntheses of tropane, nicotine, cis‐octahydroindole, and leelamine derivatives.     

Highly Regio‐ and Enantioselective Synthesis of N‐Substituted 2‐Pyridones: Iridium‐Catalyzed Intermolecular Asymmetric Allylic Amination

The first iridium‐catalyzed intermolecular asymmetric allylic amination reaction with 2‐hydroxypyridines has been developed, thus providing a highly efficient synthesis of enantioenriched N‐substituted 2‐pyridone derivatives from readily available starting materials. This protocol features a good tolerance of functional groups in both the allylic carbonates and 2‐hydroxypyridines, thereby delivering multifunctionalized heterocyclic products with up to 98 % yield and 99 % ee.     

Access to Chiral Hydropyrimidines through Palladium‐Catalyzed Asymmetric Allylic C−H Amination

A palladium‐catalyzed asymmetric intramolecular allylic C−H amination controlled by a chiral phosphoramidite ligand was established for the preparation of various substituted chiral hydropyrimidinones, the precursors of hydropyrimidines, in high yields with high enantioselectivities. In particular, dienyl sodium N ‐sulfonyl amides bearing an arylethene‐1‐sulfonyl group underwent a sequential allylic C−H amination and intramolecular Diels–Alder (IMDA) reaction to produce chiral fused tricyclic tetrahydropyrimidinone frameworks in high yields and with high levels of stereoselectivity. Significantly, this method was used as the key step in an asymmetric synthesis of letermovir.     

A Configurational Switch Based on Iridium‐Catalyzed Allylic Cyclization: Application in Asymmetric Total Syntheses of Prosopis,Dendrobate, and Spruce Alkaloids

A method for the stereoselective synthesis of 2,6‐disubstituted piperidines has been developed that is based on the use of an intramolecular iridium‐catalyzed allylic substitution as a configurational switch. The procedure allows the preparation of 2‐vinylpiperidines with enantiomeric excesses (ee) of greater than 99 %. As applications, total syntheses of piperidine alkaloids have been elaborated, most often by using Ru‐catalyzed cross‐metatheses as a key step for introduction of a side chain. Asymmetric total syntheses of the prosopis alkaloids (+)‐prosopinine, (+)‐prosophylline, (+)‐prosopine, and of the dendrobate alkaloid (+)‐241D and its C6 epimer are described.     

Regio‐ and Stereoselective Allylic Substitutions of Chiral Secondary Alkylcopper Reagents: Total Synthesis of (+)‐Lasiol, (+)‐13‐Norfaranal,and (+)‐Faranal

Chiral secondary alkylcopper reagents were prepared from chiral secondary alkyl iodides by a retentive I/Li exchange followed by a retentive transmetalation with CuBr?P(OEt)₃. Switching the solvent to THF significantly increased their configurational stability and made these copper reagents suitable for regioselective allylic substitutions. The optically enriched copper species underwent S_N2 substitutions with allylic bromides (up to >99 % S_N2 regioselectivity). The addition of ZnCl₂ and the use of chiral allylic phosphates allowed to switch the regioselectivity towards S_N2′ substitution (up to >99 % S_N2′ regioselectivity) and to perform highly selective anti‐S_N2′ substitutions with absolute control over two adjacent stereocenters. This method was applied in the total synthesis of the three ant pheromones (+)‐lasiol, (+)‐13‐norfaranal, and (+)‐faranal (up to 98:2 dr, 99 % ee).