Boosting Conjugate Addition to Nitroolefins Using Lithium Tetraorganozincates: Synthetic Strategies and Structural Insights

We report the first transition metal catalyst- and ligand-free conjugate addition of lithium tetraorganozincates (R₄ZnLi₂) to nitroolefins. Displaying enhanced nucleophilicity combined with unique chemoselectivity and functional group tolerance, homoleptic aliphatic and aromatic R₄ZnLi₂ provide access to valuable nitroalkanes in up to 98 % yield under mild conditions (0 °C) and short reaction time (30 min). This is particularly remarkable when employing β-nitroacrylates and β-nitroenones, where despite the presence of other electrophilic groups, selective 1,4 addition to the C=C is preferred. Structural and spectroscopic studies confirmed the formation of tetraorganozincate species in solution, the nature of which has been a long debated issue, and allowed to unveil the key role played by donor additives on the aggregation and structure of these reagents. Thus, while chelating N,N,N’,N’-tetramethylethylenediamine (TMEDA) and (R,R)-N,N,N’,N’-tetramethyl-1,2-diaminocyclohexane (TMCDA) favour the formation of contacted-ion pair zincates, macrocyclic Lewis donor 12-crown-4 triggers an immediate disproportionation process of Et₄ZnLi₂ into equimolar amounts of solvent-separated Et₃ZnLi and EtLi.     

In 2- und 3-Stellung verzweigte,enantiomerenreine 4,4,4-Trifluor-3-hydroxy-buttersäure-Derivate aus 6-Trifluormethyl-1,3-dioxan-und -dioxin-4-onen

Preparation of Enantiomerically Pure 4,4,4-Trifluoro-3-hydroxy-butanoic Acid Derivatives, Branched in the 2- or 3-Position, from 6-Trifluoromethyl-1,3-dioxan- and -dioxin-4-ones Enantiomerically pure 3-hydroxy-3-trifluoromethyl-propionic acid and esters, substituted in the 2- or 3-position, are prepared (13 examples) from (R)- or (S)-4,4,4-trifluoro-3-hydroxy-butanoic acid. Key intermediates are the 2-t-butyl-6-trifluoromethyl-1,3-dioxan- and -dioxin-4-ones. The Li enolate of the cis-dioxanone is generated with t-BuLi and reacts with electrophiles (alkyl halides, aldehydes, imines, nitroolefins, Br₂, I₂) with predominant formation of trans,trans-2,5,6-trisubstituted dioxanones (9 examples). Elimination of HBr from the 5-Br-substituted dioxanone gives the (R)- or (S)-dioxinone, a chiral derivative of 4,4,4-trifluoro-3-oxo-butanoic acid (trifluoro-acetoacetate). Michael additions of cuprates or of CuCl-doped Grignard reagents to the dioxinone produce 6,6-disubstituted dioxanones (10 examples) bearing a CF₃ group in the 6-position. In most cases this addition is highly diastereoselective, with the new substituent winding up in the trans position. There are, however, surprising exceptions, such as the product formed with benzylmagnesium chloride which is an abnormal adduct with a p-quinoid structure ( 26 ) and with the newly introduced group in the cis position with respect to the t-Bu group. The structures of four trisubstituted dioxanones bearing CF₃ groups are determined by X-ray crystal structure analysis (Figure 1, Table 1), one of them including the absolute configuration (by anomalous diffraction). Besides the well-known sofa, a twist-boat conformation of dioxanones appears to be favorable. The solution conformations of the different types of CF₃-substituted dioxanones are derived from Nuclear Overhauser NMR measurements and compared with the crystal structures (Figure 3).     

Calixarene-based highly efficient primary amine–thiourea organocatalysts for asymmetric Michael addition of aldehydes to nitrostyrenes

The synthesis of calix[4]arene-based chiral bifunctional primary amine–thiourea catalysts has been described from p-tert-butylcalix[4]arene for the first time. The calix[4]arene-based catalysts were successfully applied to promote Michael addition of aldehydes with nitroalkenes affording preferentially the (R)- or (S)-adducts in high yields (up to 95%) and excellent enantioselectivities (up to 99% ees).     

Chiral Phosphoric Acid Catalyzed Asymmetric Friedel–Crafts Alkylation of Indoles with Nitroolefins

Abstract

Asymmetric Michael-type Friedel–Crafts (F–C) alkylations of indoles with nitroolefins catalyzed by a chiral H₈-BINOL-based phosphoric acid were investigated. The reactions took place very smoothly in the presence of only 5 mol-% of catalyst at room temperature to afford the desired F–C alkylation products in good yields and with moderate enantioselectivities.

GRAPHICAL ABSTRACT      

Organocatalytic Enantio‐ and Diastereoselective Conjugate Addition to Nitroolefins: When β‐Ketoamides Surpass β‐Ketoesters

Our findings on the bifunctional squaramide‐catalyzed enantioselective conjugate addition of β‐ketoamides to nitroolefins are disclosed. It appears that simple acyclic methylene β‐ketoamides, unlike the extensively studied β‐ketoesters, afford the products in excellent diastereoselectivities, and maintain high yields and enantioselectivities. Moreover, competition and kinetic studies were conducted to rationalize the observed reactivity and selectivity. The high level of diastereocontrol, along with the amenability of the amide group to postfunctionalization, dramatically increase the synthetic usefulness of the transformation.     

Organocatalytic Strategy for the Enantioselective Cycloaddition to Trisubstituted Nitroolefins to Create Spirocyclohexene‐Oxetane Scaffolds

The first catalytic enantioselective cycloaddition reaction to α,β,β‐trisubstituted nitroolefins is reported. For this purpose, nitroolefin oxetanes were employed in the reaction with 2,4‐dienals promoted by trienamine catalysis. This methodology provides a facile and efficient strategy for the synthesis of highly functionalized chiral spirocyclohexene‐oxetanes with two adjacent tetrasubstituted carbon atoms in high yields and excellent selectivities. This strategy also enabled access to chiral spirocyclohexene‐cyclobutanes and ‐azetidines. Additionally, the obtained scaffolds can undergo diverse transformations leading to complex structures with up to four stereocenters, and we demonstrate that the nitro group, under nucleophilic conditions, can be applied for ring‐opening of the oxetane.     

Adapting to substrate challenges: peptides as catalysts for conjugate addition reactions of aldehydes to α,β-disubstituted nitroolefins

Conjugate addition reactions of aldehydes to α,β-disubstituted nitroolefins are important because they provide synthetically useful γ-nitroaldehydes bearing three consecutive stereogenic centers. Such reactions are challenging due to the drastically lower reactivity of α,β-disubstituted nitroolefins compared to, for example, β-monosubstituted nitroolefins. The testing of a small collection of peptides of the type Pro-Pro-Xaa (Xaa=acidic amino acid) led to the identification of H-Pro-Pro-D-Gln-OH and H-Pro-Pro-Asn-OH as excellent stereoselective catalysts for this transformation. In the presence of 5 mol% of these peptides different combinations of aldehydes and α,β-disubstituted nitroolefins react readily with each other providing γ-nitroaldehydes in good yields and diastereoselectivities as well as excellent enantioselectivities. Chiral pyrrolidines as well as fully substituted γ-butyrolactams and γ-amino acids are easily accessible from the γ-nitroaldehydes. Mechanistic studies demonstrate that the configuration at all three stereogenic centers is induced by the peptidic catalysts. Only a minimal amount of products from homo-aldol reactions is observed demonstrating the high chemoselectivity of the peptidic catalysts.