Base‐Dependent Stereodivergent Intramolecular Aza‐Michael Reaction: Asymmetric Synthesis of 1,3‐Disubstituted Isoindolines

The nucleophilic addition (A_N) / intramolecular aza‐Michael reaction (IMAMR) process on Ellman’s tert‐butylsulfinyl imines, bearing a Michael acceptor in the ortho position, is studied. This reaction affords 1,3‐disubstituted isoindolines with a wide range of substituents in good yields and diastereoselectivities. Interestingly, careful choice of the base for the aza‐Michael step allows either the cis or the trans diastereoisomers to be exclusively obtained. This stereodivergent cyclization has enabled the synthesis of C₂‐symmetric bisacetate‐substituted isoindolines. In addition, bisacetate isoindolines bearing two well‐differentiated ester moieties are also noteworthy because they may allow for the orthogonal synthesis of β,β′‐dipeptides using a single nitrogen atom as a linchpin.     

One‐Pot Synthesis of (−)‐Oseltamivir and Mechanistic Insights into the Organocatalyzed Michael Reaction

The one‐pot sequential synthesis of (?)‐oseltamivir has been achieved without evaporation or solvent exchange in 36 % yield over seven reactions. The key step was the asymmetric Michael reaction of pentan‐3‐yloxyacetaldehyde with (Z)‐N‐2‐nitroethenylacetamide, catalyzed by a diphenylprolinol silyl ether. The use of a bulky O‐silyl‐substituted diphenylprolinol catalyst, chlorobenzene as a solvent, and HCO₂H as an acid additive, were key to produce the first Michael adduct in both excellent yield and excellent diastereo‐ and enantioselectivity. Investigation into the effect of acid demonstrated that an acid additive accelerates not only the E–Z isomerization of the enamines derived from pentan‐3‐yloxyacetaldehyde with diphenylprolinol silyl ether, but also ring opening of the cyclobutane intermediate and the addition reaction of the enamine to (Z)‐N‐2‐nitroethenylacetamide. The transition‐state model for the Michael reaction of pentan‐3‐yloxyacetaldehyde with (Z)‐N‐2‐nitroethenylacetamide was proposed by consideration of the absolute configuration of the major and minor isomers of the Michael product with the results of the Michael reaction of pentan‐3‐yloxyacetaldehyde with phenylmaleimide and naphthoquinone.     

Organocatalyzed Cascade Aza‐Michael/Michael Addition for the Asymmetric Construction of Highly Functionalized Spiropyrazolone Tetrahydroquinolines

An organocatalyzed diastereo‐ and enantioselective cascade aza‐Michael/Michael addition of 2‐tosylaminoenones to unsaturated pyrazolones has been developed to afford novel chiral spiropyrazolone tetrahydroquinolines containing three contiguous stereocenters. This cascade reaction proceeded well with 2 mol % chiral bifunctional tertiary amine squaramide catalyst to give the desired products in excellent yields (up to 99 %) with excellent diastereoselectivity (up to >25:1 diastereomeric ratio) and high enantioselectivity (up to 91 % enantiomeric excess).     

Diastereodivergent Asymmetric Michael Addition of Cyclic Azomethine Ylides to Nitroalkenes: Direct Approach for the Synthesis of 1,7‐Diazaspiro[4.4]nonane Diastereoisomers

The first highly diastereoselective and enantioselective catalytic asymmetric Michael addition of cyclic azomethine ylides with nitroalkenes have been developed to diastereodivergently generate either the syn or anti adducts by employing N,O‐ligand/Cu(OAc)₂ and N,P‐ligand/Cu(OAc)₂ catalytic systems. Both catalytic systems exhibit broad substrate applicability to afford the corresponding Michael adducts in good to excellent yields, with excellent levels of diastereo‐ (up to 99:1 diastereomeric ratio) and enantioselectivities (up to >99 % enantiomeric excess). Importantly, the chiral 1,7‐diazaspiro[4.4]nonane diastereomer derivatives can be easily obtained in good yields through facile NaBH₄ reduction of the Michael adducts.     

Cinchonamine Squaramide Catalyzed Asymmetric aza‐Michael Reaction: Dihydroisoquinolines and Tetrahydropyridines

The first example of a chiral cinchona‐squaramide catalyzed enantioselective intramolecular aza‐Michael addition for the synthesis of dihydroisoquinolines and tetrahydropyridines has been developed. In general, good yields and excellent enantioselctivities were observed. Broad classes of Michael acceptors, such as enones, esters, thioesters, and Weinreb amides, were successful substrates. The possibility of recycling the catalysts has also been demonstrated. An oxidation of combined enamine and keto functionalities on chiral dihydroisoquinolines leads to a single diastereomer of an architecturally unprecedented tetracyclic core without loss in enantioselectivity.     

To be or not to be butterfly: New mechanistic insights in the Aza‐Michael asymmetric addition of lithium (R)‐N‐benzyl‐N‐(α‐methylbenzyl)amide

The asymmetric Aza‐Michael addition of homochiral lithium benzylamides to α,β‐unsaturated esters represents an extended protocol to obtain enantioenriched β‐amino esters. An exhaustive mechanistic revision of the originally proposed mechanism is reported, developing a quantum mechanics/molecular mechanics protocol for the asymmetric Aza‐Michael reaction of homochiral lithium benzylamides. Explicit and implicit solvent schemes were considered, together with a proper account of long‐range dispersion forces, evaluated through a density functional theory benchmark of different functionals. Theoretical results showed that the diastereoselectivity is mainly controlled by the N‐α‐methylbenzyl moiety placing, deriving a Si/Re 99:1 diastereoselective ratio, in good agreement with reported experimental results. The main transition state geometries are two transition state conformers in a “V‐stacked” orientation of the amide's phenyl rings, differing in the tetrahydrofuran molecule arrangement coordinated to the metal center. Extensive conformational sampling and quantum‐level refinement give reasonable good speed/accuracy results, allowing this protocol to be extended to other similar Aza‐Michael reaction systems. © 2014 Wiley Periodicals, Inc.     

Highly Diastereo‐ and Enantioselective Michael Addition of Nitroalkanes to 2‐Enoyl‐Pyridine N‐Oxides Catalyzed by Scandium(III)/Copper(II) Complexes

A C₂‐symmetric Schiff‐base ligand, derived from tridentate‐Schiff‐base, was developed and successfully applied to the asymmetric Michael addition of nitroalkanes to 2‐enoyl‐pyridine N‐oxides. With this newly catalytic system, an unprecedented diastereoselectivity was obtained in the asymmetric Michael addition of nitroalkanes to 2‐enoyl‐pyridine N‐oxides. In addition, a switch in enantioselectivity was achieved by using this newly catalytic system and our previous catalyst. After a facile reduction, the optically active adduct was converted to a biologically active dihydro‐2H‐pyrrol 4 a . Furthermore, a connection of two tridentate‐Schiff‐base subunits proved to be an effective strategy in ligand design.     

Catalytic Asymmetric Michael Reaction of 5H‐Oxazol‐4‐Ones with α,β‐Unsaturated Acyl Imidazoles

The asymmetric Michael reaction between 5H‐oxazol‐4‐ones and α,β‐unsaturated acyl imidazoles is reported. A novel 2‐benzo[b]thiophenyl‐modified chiral ProPhenol species is synthesized and used as a ligand, leading to good enantioselectivities in this asymmetric conjugate addition reaction. Furthermore, the introduction of phenol additives as achiral co‐ligands is found to improve the reaction’s chemical yields, diastereoselectivities, and enantioselectivities.     

Tuning Catalysts to Tune the Products: Phosphine‐Catalyzed Aza‐Michael Addition Reaction of Hydrazones with Allenoates

A new tunable phosphine‐catalyzed aza‐Michael β‐addition reaction between allenoates and various hydrazones has been developed. These reactions are most‐efficiently promoted by a catalytic amount of phosphine catalysts. These atom‐economical reactions are operationally simple and their corresponding adducts can been achieved in high yields and high selectivity under mild reaction conditions. Further studies revealed that different phosphine catalyst can produce different adducts from the same starting materials.     

1,4‐Addition of TMSCCl3 to Nitroalkenes: Efficient Reaction Conditions and Mechanistic Understanding

Improved synthetic conditions allow preparation of TMSCCl₃ in good yield (70 %) and excellent purity. Compounds of the type NBu₄X [X=Ph₃SiF₂ (TBAT), F (tetrabutylammonium fluoride, TBAF), OAc, Cl and Br] act as catalytic promoters for 1,4‐additions to a range of cyclic and acyclic nitroalkenes, in THF at 0–25 °C, typically in moderate to excellent yields (37–95 %). TBAT is the most effective promoter and bromide the least effective. Multinuclear NMR studies (¹H, ¹⁹F, ¹³C and ²⁹Si) under anaerobic conditions indicate that addition of TMSCCl₃ to TBAT (both 0.13 M ) at ?20 °C, in the absence of nitroalkene, leads immediately to mixtures of Me₃SiF, Ph₃SiF and NBu₄CCl₃. The latter is stable to at least 0 °C and does not add nitroalkene from ?20 to 0 °C, even after extended periods. Nitroalkene, in the presence of TMSCCl₃ (both 0.13 M at ?20 °C), when treated with TBAT, leads to immediate formation of the 1,4‐addition product, suggesting the reaction proceeds via a transient [Me₃Si(alkene)CCl₃] species, in which (alkene) indicates an Si???O coordinated nitroalkene. The anaerobic catalytic chain is propagated through the kinetic nitronate anion resulting from 1,4 CCl₃^? addition to the nitroalkene. This is demonstrated by the fact that isolated NBu₄[CH₂?NO₂] is an efficient promoter. Use of H₂C?CH(CH₂)₂CH?CHNO₂ in air affords radical‐derived bicyclic products arising from aerobic oxidation.     

不对称Michael反应在有机合成中应用的进展

本文综述了不对称 Michael 加成反应的某些应用和进展,并分别讨论了各种不同类型的手性 Michael 加成反应。     

Highly Enantioselective Aza‐Michael Reaction between Alkyl Amines and β‐Trifluoromethyl β‐Aryl Nitroolefins

The aza‐Michael addition reaction is a vital transformation for the synthesis of functionalized chiral amines. Despite intensive research, enantioselective aza‐Michael reactions with alkyl amines as the nitrogen donor have not been successful. We report the use of chiral N‐heterocyclic carbenes (NHCs) as noncovalent organocatalysts to promote a highly selective aza‐Michael reaction between primary alkyl amines and β‐trifluoromethyl β‐aryl nitroolefins. In contrast to classical conjugate‐addition reactions, a strategy of HOMO‐raising activation was used. Chiral trifluoromethylated amines were synthesized in high yield (up to 99 %) with excellent enantioselectivity (up to 98 % ee).     

L-丙氨酰Betti碱催化环己酮对硝基烯不对称Michael加成反应

合成了3个手性Betti碱的L-丙氨酰衍生物, 并用它们来催化环己酮与硝基烯的Michael加成反应. 发现1a是其中最有效的催化剂, ee值最高大于99%, dr值最高大于99∶1. 考察了催化剂结构与用量、添加剂用量、底物结构等因素对反应的化学产率和光学收率的影响.