Ming‐Phos/Gold(I)‐Catalyzed Stereodivergent Synthesis of Highly Substituted Furo[3,4‐d][1,2]oxazines†

A gold(I)‐catalyzed asymmetric intermolecular tandem [3+3]‐cyclization reaction of 2‐(1‐alkynyl)‐2‐ alken‐1‐ones with nitrones has been developed by using Ming‐Phos as a chiral ligand. This method enables access to the stereodivergent synthesis of highly substituted furo[3,4‐d][1,2]oxazines in excellent efficiency and stereoselectivity (up to 99% yield, 99% ee, >20 : 1 dr).     

Nickel(II)‐Catalyzed Asymmetric Propargyl and Allyl Claisen Rearrangements to Allenyl‐ and Allyl‐Substituted β‐Ketoesters

Highly efficient catalytic asymmetric Claisen rearrangements of O‐propargyl β‐ketoesters and O‐allyl β‐ketoesters have been accomplished under mild reaction conditions. In the presence of the chiral N,N′‐dioxide/Ni^II complex, a wide range of allenyl/allyl‐substituted all‐carbon quaternary β‐ketoesters was obtained in generally good yield (up to 99 %) and high diastereoselectivity (up to 99:1 d.r.) with excellent enantioselectivity (up to 99 % ee).     

The First Modular Route to Core‐Chiral Bispidine Ligands and Their Application in Enantioselective Copper(II)‐Catalyzed Henry Reactions

The first modular and flexible synthesis of core‐chiral bispidines was achieved by using an “inside‐out” strategy. The key intermediate, a NBoc‐activated bispidine lactam, was constructed in enantiomerically pure form from a chirally modified β‐amino acid and 2‐(acetoxymethyl)acrylonitrile in just five steps and good 48 % yield. A simple addition–reduction protocol permitted a highly endo‐selective introduction of substituents and, thus, a fast and variable access to 2‐endo‐substituted and 2‐endo,N‐fused bi‐ and tricyclic bispidines. The new diamines were evaluated as the chiral ligands in asymmetric Henry reactions. Excellent enantioselectivities of up to 99 % ee and good diastereomeric ratios of up to 86:14 were reached with a copper(II) complex modified by a 2‐endo,N‐(3,3‐dimethylpyrrolidine)‐annelated bispidine. Its performance is superior to that of the well‐known bispidines (?)‐sparteine and the (+)‐sparteine surrogate.     

Asymmetric Catalytic Formal 1,4‐Allylation of β,γ‐Unsaturated α‐Ketoesters: Allylboration/Oxy‐Cope Rearrangement

A highly enantioselective formal conjugate allyl addition of allylboronic acids to β,γ‐unsaturated α‐ketoesters has been realized by employing a chiral Ni^II/N,N′‐dioxide complex as the catalyst. This transformation proceeds by an allylboration/oxy‐Cope rearrangement sequence, providing a facile and rapid route to γ‐allyl‐α‐ketoesters with moderate to good yields (65–92 %) and excellent ee values (90–99 % ee). The isolation of 1,2‐allylboration products provided insight into the mechanism of the subsequent oxy‐Cope rearrangement reaction: substrate‐induced chiral transfer and a chiral Lewis acid accelerated process. Based on the experimental investigations and DFT calculations, a rare boatlike transition‐state model is proposed as the origin of high chirality transfer during the oxy‐Cope rearrangement.     

Asymmetric Hydrolytic Kinetic Resolution with Recyclable Macrocyclic CoIII–Salen Complexes: A Practical Strategy in the Preparation of (R)‐Mexiletine and (S)‐Propranolol

A chiral cobalt(III) complex ( 1 e ) was synthesized by the interaction of cobalt(II) acetate and ferrocenium hexafluorophosphate with a chiral dinuclear macrocyclic salen ligand that was derived from 1R,2R‐(?)‐1,2‐diaminocyclohexane with trigol bis‐aldehyde. A variety of epoxides and glycidyl ethers were suitable substrates for the reaction with water in the presence of chiral macrocyclic salen complex 1 e at room temperature to afford chiral epoxides and diols by hydrolytic kinetic resolution (HKR). Excellent yields (47 % with respect to the epoxides, 53 % with respect to the diols) and high enantioselectivity (ee>99 % for the epoxides, up to 96 % for the diols) were achieved in 2.5–16 h. The Co^III macrocyclic salen complex ( 1 e ) maintained its performance on a multigram scale and was expediently recycled a number of times. We further extended our study of chiral epoxides that were synthesized by using HKR to the synthesis of chiral drug molecules (R)‐mexiletine and (S)‐propranolol.     

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).     

Diastereo‐ and Enantioselective Intramolecular [2+2] Photocycloaddition Reactions of 3‐(ω′‐Alkenyl)‐ and 3‐(ω′‐Alkenyloxy)‐Substituted 5,6‐Dihydro‐1H‐pyridin‐2‐ones

3‐(ω′‐Alkenyl)‐substituted 5,6‐dihydro‐1H‐pyridin‐2‐ones 2 – 4 were prepared as photocycloaddition precursors either by cross‐coupling from 3‐iodo‐5,6‐dihydro‐1H‐pyridin‐2‐one ( 8 ) or—more favorably—from the corresponding α‐(ω′‐alkenyl)‐substituted δ‐valerolactams 9 – 11 by a selenylation/elimination sequence (56–62 % overall yield). 3‐(ω′‐Alkenyloxy)‐substituted 5,6‐dihydro‐1H‐pyridin‐2‐ones 5 and 6 were accessible in 43 and 37 % overall yield from 3‐diazopiperidin‐2‐one ( 15 ) by an α,α‐chloroselenylation reaction at the 3‐position followed by nucleophilic displacement of a chloride ion with an ω‐alkenolate and oxidative elimination of selenoxide. Upon irradiation at λ=254 nm, the precursor compounds underwent a clean intramolecular [2+2] photocycloaddition reaction. Substrates 2 and 5 , tethered by a two‐atom chain, exclusively delivered the respective crossed products 19 and 20 , and substrates 3 , 5 , and 6 , tethered by longer chains, gave the straight products 21 – 23 . The completely regio‐ and diastereoselective photocycloaddition reactions proceeded in 63–83 % yield. Irradiation in the presence of the chiral templates (?)‐ 1 and (+)‐ 31 at ?75 °C in toluene rendered the reactions enantioselective with selectivities varying between 40 and 85 % ee. Truncated template rac‐ 31 was prepared as a noranalogue of the well‐established template 1 in eight steps and 56 % yield from the Kemp triacid ( 24 ). Subsequent resolution delivered the enantiomerically pure templates (?)‐ 31 and (+)‐ 31 . The outcome of the reactions is compared to the results achieved with 4‐substituted 5,6‐dihydro‐1H‐pyridin‐2‐ones and quinolones.     

Asymmetric Hetero‐Diels–Alder Reaction of Danishefsky’s Diene with α‐Ketoesters and Isatins Catalyzed by a Chiral N,N′‐Dioxide/Magnesium(II) Complex

A highly enantioselective hetero‐Diels–Alder reaction of Danishefsky’s diene with α‐ketoesters and isatins has been realized by using a chiral N,N′‐dioxide/Mg^II complex. In the presence of only 0.1–0.5 mol % catalyst, a series of substrates were transformed into the corresponding tetrasubstituted 2,3‐dihydropyran‐4‐ones in up to 99 % yield and more than 99 % ee in two hours.     

Majority‐Rules‐Type Helical Poly(quinoxaline‐2,3‐diyl)s as Highly Efficient Chirality‐Amplification Systems for Asymmetric Catalysis

A highly efficient majority‐rules effect of poly(quinoxaline‐2,3‐diyl)s (PQXs) bearing 2‐butoxymethyl chiral side chains at the 6‐ and 7‐positions was established and attributed to large ΔG_h values (0.22–0.41 kJ mol^?1), which are defined as the energy difference between P‐ and M‐helical conformations per chiral unit. A PQX copolymer prepared from a monomer derived from (R)‐2‐octanol (23 % ee) and a monomer bearing a PPh₂ group adopted a single‐handed helical structure (>99 %) and could be used as a highly enantioselective chiral ligand in palladium‐catalyzed asymmetric reactions (products formed with up to 94 % ee), in which the enantioselectivity could be switched by solvent‐dependent inversion of the helical PQX backbone.     

Asymmetric Henry reactions of aldehydes with various nitroalkanes catalyzed by copper(II) complexes of novel chiral N‐monoalkyl cyclohexane‐1,2‐diamines

A number of novel chiral diamines 3 , (1R,2R)‐N‐monoalkylcyclohexane‐1,2‐diamines, were designed and synthesized from trans‐cyclohexane‐1,2‐diamine and applied to the catalytic asymmetric Henry reaction of benzaldehyde and nitromethane to provide β‐nitroalcohol in high yield (up to 99%) and good enantiomeric excess (up to 89%). By using ligand (1R,2R)‐N¹‐(4‐methylpentan‐2‐yl)cyclohexane‐1,2‐diamine ( 3g ), the reaction was optimized in terms of the metal ion, temperature, solvent and base. Further experiments indicated that the complex, 3g –Cu(OAc)₂, was an efficient catalyst in the asymmetric Henry reaction between different aldehydes and nitromethane, and the desired products have been obtained with high chemical yields (up to 99%) and high enantiomeric excess (up to 93%). The optimized catalyst promoted the diastereoselective Henry reaction of various aldehyde substrates and nitroalkane, which gave the corresponding anti‐selective adduct with up to 99% yield and 83:17 anti/syn selectivity. Upon scaling up to gram quantities, the β‐nitroalcohol was obtained in good yield (96%) with excellent selectivities (93% ee). The chiral induction mechanism was tentatively explained on the basis of a previously proposed transition‐state model. Copyright © 2014 John Wiley & Sons, Ltd.     

Enantioselective Syntheses of Lignin Models: An Efficient Synthesis of β‐O‐4 Dimers and Trimers by Using the Evans Chiral Auxiliary

We describe an efficient five‐step, enantioselective synthesis of (R,R)‐ and (S,S)‐lignin dimer models possessing a β‐O‐4 linkage, by using the Evans chiral aldol reaction as a key step. Mitsunobu inversion of the (R,R)‐ or (S,S)‐isomers generates the corresponding (R,S)‐ and (S,R)‐diastereomers. We further extend this approach to the enantioselective synthesis of a lignin trimer model. These lignin models are synthesized with excellent ee (>99 %) and high overall yields. The lignin dimer models can be scaled up to provide multigram quantities that are not attainable by using previous methodologies. These lignin models will be useful in degradation studies probing the selectivity of enzymatic, microbial, and chemical processes that deconstruct lignin.     

Catalytic Asymmetric Construction of α‐Quaternary Cyclopentanones and Its Application to the Syntheses of (−)‐1,14‐Herbertenediol and (−)‐Aphanorphine

A novel and efficient strategy to build α‐benzylic quaternary cyclopentanones with excellent enantioselectivities (up to 96 % ee) and high yields (up to 99 % yield) has been developed, and its application demonstrated by the first catalytic asymmetric total synthesis of (?)‐1,14‐herbertenediol and the formal synthesis of (?)‐aphanorphine.     

Highly Stereoselective [3+2] Cycloadditions of Chiral Palladium‐Containing N1‐1,3‐Dipoles: A Divergent Approach to Enantioenriched Spirooxindoles

A catalytic asymmetric [3+2] cycloaddition reaction of chiral palladium‐containing N¹‐1,3‐dipoles with methyleneindolinones has been successfully developed. The reaction allows an efficient construction of 3,3′‐pyrrolinyl spirooxindoles with high yields and excellent stereoselectivities (up to 93 % yield, 19:1 d.r. and >99 % ee). A synthetic application of this methodology is demonstrated and a stereocontrol mechanism is proposed.     

Bimetallic Gold(I)/Chiral N,N′‐Dioxide Nickel(II) Asymmetric Relay Catalysis: Chemo‐ and Enantioselective Synthesis of Spiroketals and Spiroaminals

A highly efficient asymmetric cascade reaction between keto esters and alkynyl alcohols and amides is reported. The success of the reaction was attributed to the combination of chiral Lewis acid N,N′‐dioxide nickel(II) catalysis with achiral π‐acid gold(I) catalysis working as an asymmetric relay catalytic system. The corresponding spiroketals and spiroaminals were synthesized in up to 99 % yield, 19:1 d.r., and more than 99 % ee under mild reaction conditions. Control experiments suggest that the N,N′‐dioxide ligand was essential for the formation of the spiro products.     

Total Synthesis of (R,R,R)‐γ‐Tocopherol through Cu‐Catalyzed Asymmetric 1,2‐Addition

Based on the asymmetric copper‐catalyzed 1,2‐addition of Grignard reagents to ketones, (R,R,R)‐γ‐tocopherol has been synthesized in 36 % yield over 12 steps (longest linear sequence). The chiral center in the chroman ring was constructed with 73 % ee by the 1,2‐addition of a phytol‐derived Grignard reagent to an α‐bromo enone prepared from 2,3‐dimethylquinone.     

Highly Enantioselective Direct Asymmetric Aldol Reaction Catalyzed by 4,5‐Methano‐L‐proline

The 4,5‐methano‐L‐proline was used as chiral organocatalysts in direct asymmetric aldol reactions. Under the optimal conditions, excellent enantioselectivities (up to 99% ee) were obtained with high chemical yields (up to 95%) for a series of aldehydes using only 5 mol% catalyst loading. To show the practicality of the method, the reaction was tested at a large scale. The reaction was complete in 16 h, and the aldol product was obtained in 86% yield and 93% ee.     

Remote Sulfonamido Group Enhances Reactivity and Selectivity for Asymmetric Michael Addition of Nitroalkanes to α,β‐Unsaturated Aldehydes

The pyrrolidine–camphorsulfonamide‐based catalyst 1 a catalyzes the enantioselective conjugate addition of nitroalkanes to α,β‐unsaturated aldehydes in the presence of five equivalents of water in iPrOH to give the corresponding chiral Michael adducts in good yields and high enantioselectivities (up to 99 % ee) with a catalyst loading as low as 1 mol %.     

Copper‐Complex‐Catalyzed Asymmetric Aerobic Oxidative Cross‐Coupling of 2‐Naphthols: Enantioselective Synthesis of 3,3′‐Substituted C1‐Symmetric BINOLs

A novel chiral 1,5‐N,N‐bidentate ligand based on a spirocyclic pyrrolidine oxazoline backbone was designed and prepared, and it coordinates CuBr in situ to form an unprecedented catalyst that enables efficient oxidative cross‐coupling of 2‐naphthols. Air serves as an external oxidant and generates a series of C₁‐symmetric chiral BINOL derivatives with high enantioselectivity (up to 99 % ee) and good yield (up to 87 %). This approach is tolerant of a broader substrates scope, particularly substrates bearing various 3‐ and 3′‐substituents. A preliminary investigation using one of the obtained C₁‐symmetric BINOL products was used as an organocatalyst, exhibiting better enantioselectivity than the previously reported organocatalyst, for the asymmetric α‐alkylation of amino esters.     

Chiral N,N′‐Dioxide–Scandium(III) Complex‐Catalyzed Asymmetric Friedel–Crafts Alkylation Reaction of ortho‐Hydroxybenzyl Alcohols with C3‐Substituted N‐Protected Indoles

The first Lewis acid catalyzed asymmetric Friedel–Crafts alkylation reaction of ortho‐hydroxybenzyl alcohols with C3‐substituted indoles is described. A chiral N,N′‐dioxide Sc(OTf)₃ complex served not only to promote formation of ortho‐quinone methides (o‐QMs) in situ but also induced the asymmetry of the reaction. This methodology enables a novel activation of ortho‐hydroxybenzyl alcohols, thus affording the desired chiral diarylindol‐2‐ylmethanes in up to 99 % yield and 99 % ee. A range of functional groups were also tolerated under the mild reaction conditions. Moreover, this strategy gives concise access to enantioenriched indole‐fused benzoxocines.     

Efficient Synthesis of β‐Hydroxy‐α‐Amino Acid Derivatives via Direct Catalytic Asymmetric Aldol Reaction of α‐Isothiocyanato Imide with Aldehydes

An easily available and efficient chiral N,N′‐dioxide–nickel(II) complex catalyst has been developed for the direct catalytic asymmetric aldol reaction of α‐isothiocyanato imide with aldehydes which produces the products in morderate to high yields (up to 98 %) with excellent diastereo‐ (up to >99:1 d.r.) and enantioselectivities (up to >99 % ee). A variety of aromatic, heteroaromatic, α,β‐unsaturated, and aliphatic aldehydes were found to be suitable substrates in the presence of 2.5 mol % L ‐proline‐derived N,N′‐dioxide L5 –nickel(II) complex. This process was air‐tolerant and easily manipulated with available reagents. Based on experimental investigations, a possible transition state has been proposed to explain the origin of reactivity and asymmetric inductivity.