Direct Asymmetric Michael Reaction of α,β‐Unsaturated Aldehydes and Ketones Catalyzed by Two Secondary Amine Catalysts

A direct asymmetric Michael reaction of α,β‐unsaturated aldehydes and ketones proceeded in the presence of two pyrrolidine‐type catalysts, a diphenylprolinol silyl ether and hydroxyproline, to afford synthetically useful δ‐keto aldehydes with excellent diastereo‐ and enantioselectivity. Although there are several iminium ions and enamines in the reaction mixture, the iminium ion generated by the former catalyst reacts preferentially with the enamine generated by the latter catalyst.     

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.     

Diastereodivergent Asymmetric 1,3‐Dipolar Cycloaddition of Azomethine Ylides and β‐Fluoroalkyl Vinylsulfones: Low Copper(II) Catalyst Loading and Theoretical Studies

A Cu^II‐catalyzed asymmetric 1,3‐dipolar cycloaddition using β‐fluoroalkyl alkenyl arylsulfones as dipolarophiles and glycine/alanine iminoesters as azomethine ylide precursors has been developed. Remarkably, a catalyst loading as low as 0.5 mol % is highly efficient. Accordingly, a wide range of enantioenriched 3‐fluoroalkyl pyrrolidines, as well as Δ²‐pyrroline and pyrrole derivatives, are generated in good to excellent yields with high asymmetric induction. This synthetic approach is diastereodivergent in that exo‐adducts could be converted into the corresponding exo′‐adducts by 1,8‐diazabicyclo[5.4.0]undec‐7‐ene mediated epimerization at C2 of the pyrrolidine core. The free‐energy profiles from DFT calculations suggest the Michael addition of the 1,3‐dipole to be the rate‐ and enantiodetermining step, and the origin of stereoselectivity is studied by means of the noncovalent interaction (NCI) analysis.     

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.     

Synthesis of 11‐cis‐Retinoids by Hydrosilylation–Protodesilylation of an 11,12‐Didehydro Precursor: Easy Access to 11‐ and 12‐Mono‐ and 11,12‐Dideuteroretinoids

An expeditious, highly efficient approach to 11‐cis‐retinoids was achieved by semihydrogenation of a readily available 11‐yne precursor through a hydrosilylation–protodesilylation protocol. The complete chemo‐, regio‐, and syn‐stereoselectivity of the method also allowed direct access to 11‐ and 12‐monodeutero‐, and 11,12‐dideutero‐11‐cis‐retinoids. The analogous trans series was not accessible by this route, and was synthesized by means of Hiyama coupling.     

(+)‐Tartaric Acid‐Catalyzed High Regio‐ and Stereoselective Aminobromination of Olefins

(+)‐Tartaric acid‐catalyzed aminobromination of α,β‐unsaturated ketones, α,β‐unsaturated esters and simple olefins utilizing TsNH₂/NBS as the nitrogen/halogen sources at room temperature without protection of inert gases achieved good yields (up to 92% yield) of vicinal haloamino products with excellent regio‐ and stereoselectivity, even just 10% of (+)‐tartaric acid was used as catalyst. The regio‐ and stereochemistry was unambiguously confirmed by X‐ray structural analysis of products 2b and 12c . The electron‐rich and deficient olefins show significant differences in activity to the aminobromination reaction and give the opposite regioselectivities. The 21 cases have been investigated which indicated that our protocol has the advantage of a large scope of olefins. Additionally, tartaric acid as catalyst has the advantage of avoiding any hazardous metals retained in products.     

Importance of the nature of α-substituents in pyrrolidine organocatalysts in asymmetric Michael additions

The fundamental factors contributing toward the stereoselectivity in organocatalyzed asymmetric Michael reaction between aldehydes (propanal and 3-phenyl propanal) and methyl vinyl ketone (MVK) are established by using density functional theory methods. Three of the most commonly employed α-substituted pyrrolidine organocatalysts are examined. Several key stereochemical modes of addition between (i) a model enamine or (ii) pyrrolidine enamines derived from aldehydes and secondary amine to MVK are examined. Among these possibilities, the addition of (E)-enamine to cis-MVK is found to have a lower activation barrier. The stereochemical outcome of the reaction is reported on the basis of the relative energies between pertinent diastereomeric transition states. Moderate selectivity is predicted for the reaction involving pyrrolidine catalysts I and II, which carry relatively less bulky α-substituents dimethylmethoxymethyl and diphenylmethyl, respectively. On the other hand, high selectivity is computed in the case of catalyst III having a sufficiently large α-substituent (diarylmethoxymethyl or diphenylprolinol methyl ether). The enantiomeric excess in the case of 3-phenyl propanal is found to be much higher as compared to that with unsubstituted propanal, suggesting potential for improvement in stereoselectivity by substrate modifications. The computed enantiomeric excess is found to be in reasonable agreement with the reported experimental stereoselectivities. A detailed investigation on the geometries of the crucial transition states reveals that apart from steric interactions between the α-substituent and MVK, various other factors such as orbital interactions and weak stabilizing hydrogen-bonding interactions play a vital role in stereoselectivity. The results serve to establish the importance of cumulative effects of various stabilizing and destabilizing interactions at the transition state as responsible for the stereochemical outcome of the reaction. The limitations of commonly employed qualitative propositions, relying on the steric protection of one of the prochiral faces of enamines offered by the bulky α-substituent, are presented.     

Diversity‐Oriented Enantioselective Synthesis of Highly Functionalized Cyclic and Bicyclic Alcohols

The copper‐catalyzed hetero‐allylic asymmetric alkylation (h‐AAA) of functionalized Grignard reagents that contain alkene or alkyne moieties has been achieved with excellent regio‐ and enantioselectivity. The corresponding alkylation products were further transformed into a variety of highly functionalized cyclic and bicyclic alcohols with excellent control over the chemo‐, regio‐, and stereoselectivity.     

Amide‐Controlled Highly Selective Catalytic Borylcupration of Allenes

A novel copper‐catalyzed, highly regio‐ and stereoselective borylcupration of substituted 2,3‐allenamides with bis(pinacolato)diboron producing Z‐β‐borylated β,γ‐unsaturated enoamides has been demonstrated. Due to the unique effect of the amide‐group, perfect regio‐ and stereoselectivity and good to excellent yields have been achieved, which were rationalized by a DFT study.     

Photoinitiated Thiol−Ene Reactions of Various 2,3‐Unsaturated O‐, C‐ S‐ and N‐Glycosides – Scope and Limitations Study

The photoinitiated thiol?ene addition reaction is a highly stereo‐ and regioselective, and environmentally friendly reaction proceeding under mild conditions, hence it is ideally suited for the synthesis of carbohydrate mimetics. A comprehensive study on UV‐light‐induced reactions of 2,3‐unsaturated O‐, C‐, S‐ and N‐glycosides with various thiols was performed. The effect of experimental parameters and structural variations of the alkenes and thiols on the efficacy and regio‐ and stereoselectivity of the reactions was systematically studied and optimized. The type of anomeric heteroatom was found to profoundly affect the reactivity of 2,3‐unsaturated sugars in the thiol?ene couplings. Hydrothiolation of 2,3‐dideoxy O‐glycosyl enosides efficiently produced the axially C2‐S‐substituted addition products with high to complete regioselectivity. Moderate efficacy and varying regio‐ and stereoselectivity were observed with 2,3‐unsaturated N‐glycosides and no addition occurred onto the endocyclic double bond of C‐glycosides. Upon hydrothiolation of 2,3‐unsaturated S‐glycosides, the addition of thiyl radicals was followed by elimination of the thiyl aglycone resulting in 3‐S‐substituted glycals.     

Are Oxazolidinones Really Unproductive,Parasitic Species in Proline Catalysis? – Thoughts and Experiments Pointing to an Alternative View

The N,O‐acetal and N,O‐ketal derivatives (oxazolidinones) formed from proline, and aldehydes or ketones are well‐known today, and they are detectable in reaction mixtures involving proline catalysis, where they have been considered ‘parasitic dead ends’. We disclose results of experiments performed in the early 1970's, and we describe more recent findings about the isolation, characterization, and reactions of the oxazolidinone derived from proline and cyclohexanone. This oxazolidinone reacts (THF, room temperature) with the electrophiles β‐nitrostyrene and chloral (=trichloroacetaldehyde), to give the Michael and aldol adduct, respectively, after aqueous workup (Scheme 5). The reactions occur even at ?75° when catalyzed with bases such as 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU) or EtN(i‐Pr)₂ (DIPEA) (10%; Table 1). It is shown by NMR (Figs. 1 and 3) and IR analysis (Figs. 2 and 4) that the primarily detectable product (before hydrolysis) of the reaction with the nitro‐olefin is again an oxazolidinone. When dissolved in hydroxylic solvents such as MeOH, ‘hexafluoroisopropanol’ ((CF₃)₂CHOH; HFIP), AcOH, CF₃COOH, or in LiBr‐saturated THF, the ring of the oxazolidinone from cyclohexanone and proline opens up to the corresponding iminium ion (Tables 2–4), and when treated with strong bases such as DBU (in (D₈)THF) the enamino‐carboxylate derived from proline and cyclohexanone is formed (Scheme 8). Thus, the two hitherto putative participants (iminium ion and enamine) of the catalytic cycle (Scheme 9) have been characterized for the first time. The commonly accepted mechanism of the stereoselective C,C‐ or C,X‐bond‐forming step (i.e., A – D ) of this cycle is discussed and challenged by thoughts about an alternative model with a pivotal role of oxazolidinones in the regio‐ and diastereoselective formation of the intermediate enamino acid (by elimination) and in the subsequent reaction with an electrophile (by trans‐addition with lactonization; Schemes 11–14). The stereochemical bias between endo‐ and exo‐space of the bicyclo[3.3.0]octane‐type oxazolidinone structure (Figs. 5 and 6) is considered to possibly be decisive for the stereochemical course of events. Finally, the remarkable consistency, with which the diastereotopic Re‐face of the double bond of pyrrolidino‐enamines (derived from proline) is attacked by electrophiles (Schemes 1 and 15), and the likewise consistent reversal to the Si‐face with bulky (Aryl)₂C‐substituents on the pyrrolidine ring (Scheme 16) are discussed by invoking stereoelectronic assistance from the lone pair of pyramidalized enamine N‐atoms.     

Regio‐ and Enantio‐selective Chemo‐enzymatic C−H‐Lactonization of Decanoic Acid to (S)‐δ‐Decalactone

The conversion of saturated fatty acids to high value chiral hydroxy‐acids and lactones poses a number of synthetic challenges: the activation of unreactive C?H bonds and the need for regio‐ and stereoselectivity. Here the first example of a wild‐type cytochrome P450 monooxygenase (CYP116B46 from Tepidiphilus thermophilus) capable of enantio‐ and regioselective C5 hydroxylation of decanoic acid 1 to (S)‐5‐hydroxydecanoic acid 2 is reported. Subsequent lactonization yields (S)‐δ‐decalactone 3 , a high value fragrance compound, with greater than 90 % ee. Docking studies provide a rationale for the high regio‐ and enantioselectivity of the reaction.     

Generation of quaternary stereocenters by asymmetric Michael reactions: enamine regiochemistry as configuration switch

Regioselective enamine formation from cyclic β‐diketones 1 is obtained by the appropriate choice of activating agent: Brønsted acid catalyzed condensation gives endocyclic enamines 3 as the thermodynamically favored products. Activation with Lewis acid BF₃ ? OEt₂ affords betaines 8 as intermediate products, which can be reacted with L ‐valine diethylamide ( 2 ) to preferentially furnish exocyclic enamines 4 as kinetic products. Derivatives with quaternary stereocenters were accessible from both isomeric enamines by using asymmetric, copper(II )‐catalyzed Michael reactions at ambient temperature. Both regioisomers afford the triketones 7 with the same constitution but bearing the opposite absolute configuration at the quaternary stereocenter. Thus, both enantiomers of the product are prepared by using the same chiral auxiliary derived from L ‐valine.     

Synthesis of Novel Polycyclic Indole‐Annulated Thiopyranocoumarin Derivatives via Domino Knoevenagel–Hetero‐Diels–Alder Reaction in Aqueous Media

An efficient synthesis of polycyclic indole derivatives is achieved via domino Knoevenagel–hetero‐Diels–Alder reaction of O‐acrylated salicylaldehyde derivatives with dihydroindole‐2‐thiones in H₂O as solvent. The products are formed in good‐to‐excellent yields with high regio‐ and stereoselectivity.     

Two‐ and Three‐Component Reactions Leading to New Enamines Derived from 2,3‐Dicyanobut‐2‐enoates

The three‐component reactions of 1‐azabicyclo[1.1.0]butanes 1 , dicyanofumarates (E)‐ 5 , and MeOH or morpholine yielded azetidine enamines 8 and 9 with the cis‐orientation of the ester groups at the C?C bond ((E)‐configuration; Schemes 3 and 4). The structures of 8a and 9d were confirmed by X‐ray crystallography. The formation of the products is explained via the nucleophilic addition of 1 onto (E)‐ 5 , leading to a zwitterion of type 7 (Scheme 2), which is subsequently trapped by MeOH or morpholine ( 10a ), followed by elimination of HCN. Similarly, two‐component reactions between secondary amines 10a – 10c and (E)‐ 5 gave products 12 with an (E)‐enamine structure and (Z)‐oriented ester groups. On the other hand, two‐component reactions involving primary amines 10d – 10f or NH₃ led to the formation of the corresponding (Z)‐enamines, in which the (E)‐orientation of ester groups was established.     

Cu‐Catalyzed Formal Methylative and Hydrogenative Carboxylation of Alkynes with Carbon Dioxide: Efficient Synthesis of α,β‐Unsaturated Carboxylic Acids

The sequential hydroalumination or methylalumination of various alkynes catalyzed by different catalyst systems, such those based on Sc, Zr, and Ni complexes, and the subsequent carboxylation of the resulting alkenylaluminum species with CO₂ catalyzed by an N‐heterocyclic carbene (NHC)–copper catalyst have been examined in detail. The regio‐ and stereoselectivity of the overall reaction relied largely on the hydroalumination or methylalumination reactions, which significantly depended on the catalyst and alkyne substrates. The subsequent Cu‐catalyzed carboxylation proceeded with retention of the stereoconfiguration of the alkenylaluminum species. All the reactions could be carried out in one‐pot to afford efficiently a variety of α,β‐unsaturated carboxylic acids with well‐controlled configurations, which are difficult to construct by previously reported methods. This protocol could be practically useful and attractive because of its high regio‐ and stereoselectivity, simple one‐pot reaction operation, and the use of CO₂ as a starting material.     

Synthesis of β‐Arylacyl/β‐Heteroarylacyl‐β‐alkylidene Malonates and Their Application in Substituted Pyridone Synthesis

A novel approach has been developed for the synthesis of β‐arylacyl/β‐heteroarylacyl‐β‐alkylidine malonates in moderate to good yields by the reaction of Stork aryl and heteroaryl enamine with β‐chloroalkylidene malonates. The reaction involves conjugate (Michael) addition of Stork enamine on β‐chloroalkylidene malonates and elimination of chloride ion. These Michael adducts were utilized as intermediates for the synthesis of highly substituted 1,4‐dialkyl‐2‐oxo‐6‐aryl/hetreoaryl‐1,2‐dihydro‐pyridine‐3‐carboxylic acid ethyl esters via 5 + 1 ring annulation protocol.     

Base‐Catalyzed Stereoselective Vinylation of Ketones with Arylacetylenes: A New C(sp3)?C(sp2) Bond‐Forming Reaction

Alkylaryl‐ and alkylheteroarylketones, including those with condensed aromatic moieties, are readily vinylated with arylacetylenes (KOH/DMSO, 100 °C, 1 h) to give regio‐ and stereoselectively the (E)‐β‐γ‐ethylenic ketones ((E)‐3‐buten‐1‐ones) in 61–84 % yields and with approximately 100 % stereoselectivity. This vinylation represents a new C(sp³)? C(sp²) bond‐forming reaction of high synthetic potential.     

Rhodium(III)‐Catalyzed ortho Alkenylation of N‐Phenoxyacetamides with N‐Tosylhydrazones or Diazoesters through CH Activation

A coupling reaction of N‐phenoxyacetamides with N‐tosylhydrazones or diazoesters through Rh^III‐catalyzed C? H activation is reported. In this reaction, ortho‐alkenyl phenols were obtained in good yields and with excellent regio‐ and stereoselectivity. Rh–carbene migratory insertion is proposed as the key step in the reaction mechanism.     

Rhodium(III)‐Catalyzed ortho Alkenylation of N‐Phenoxyacetamides with N‐Tosylhydrazones or Diazoesters through C?H Activation

A coupling reaction of N‐phenoxyacetamides with N‐tosylhydrazones or diazoesters through Rh^III‐catalyzed C H activation is reported. In this reaction, ortho‐alkenyl phenols were obtained in good yields and with excellent regio‐ and stereoselectivity. Rh–carbene migratory insertion is proposed as the key step in the reaction mechanism.