Nitroalkanes cyclic enones

Yamaguchi et al. also showed that Rb-L-prolinate catalyzes enantioselective addition of nitroalkanes to several acyclic and cyclic enones [25, 26]. For acyclic enone acceptors the best result, i.e. 74% yield and 68% ee of the S product, was achieved in the addition of 2-nitropropane to -3-penten-2-one (40a, Scheme 4.13) [25]. Screening of several proline derivatives and cyclic amino acids of other ring size resulted in the identification of the O-TBDMS-derivative of 4-hydroxyproline as the best catalyst for addition of nitrocyclohexane to cycloheptenone. In this particular reaction 74% yield and 86% ee were achieved [26]. 

The proline-catalyzed conjugate addition of nitroalkanes was further developed by Hanessian and Pham, resulting in enantiomeric excesses up to 93% in the addition of a variety of nitroalkanes to cyclic enones (Scheme 4.14) [27]. In their catalytic system, L-proline (3-7 mol%) was employed together with equimolar amounts (relative to the substrate enones) of trans-2,5-dimethylpiperazine. The latter addi-... 

Scheme 3.20 Enantioselective Michael addition of nitroalkanes to cyclic enones catalyzed by chiral secondary amines.

After the preliminary studies on the reaction, a wide variety of efficient chiral organocatalysts has been developed by dilferent groups for the Michael addition of nitroalkanes to enones. For instance, Jprgensen s group has reported that imidazolidine catalyst 106 (Scheme 2.54), easily prepared from phenylalanine, promotes the conjugate addition of acyclic- and cyclic nitroalkanes with a wide variety of acyclic... 

On the other hand, V-spiro Cj-symmetric chiral biaryl derivative 119 shows remarkable reactivity and selectivity in the conjugate addition of nitroalkanes to cyclic enones under mild solid-liquid PTC (Scheme 2.62) [174], This class of... 

The quinine-derived primary amine (265a) (10mol%) has been reported to catalyse the Michael addition of nitroalkanes RR CHN02 to both cyclic and non-cyclic enones in THF at r.t. over 5 days with <99% In a similar way, addition of 3(2//)-furanones (267) to enones (268), catalysed by the cinchonidine-derived amine (265b), afforded the 3(2//)-furanones (269) with <98% ee and <86 14 dr ... 

Tsogoeva and coworkers reported the use of oligopeptides of 4-tram-aminopro-hne (tetra- and dipeptides 3 and 4, respectively) as organic catalysts for the Michael reaction of nitroalkanes to cyclic enones. The reaction, in the presence of the achiral additive trans-2,5-dimethylpiperazine, afforded the conjugate addition product in excellent yield and ee up to 88% (Scheme 5.2) [14]. Other dipeptides, with a primary amine at the N-terminus and containing a histidine derivative, were definitely less selective [15] (under the same reaction conditions), while L-proline alone afforded the same product in 93% ee [16]. 

Another important reaction by which to form C-C bonds is the nitroalkane Michael addition. The first attempt to obtain a nitroalkane enantioselective addition to enones was reported by Yamaguchi in 1994, using as a catalyst rubinate salts of proline. The first truly enantioselective organocatalytic addition of nitroalkanes to enones was developed by Hanessian using proline as catalyst in the presence of an amine additive. The reaction affords good yields and enantioselectivities when cyclic enones were used (up to 93% ee) however, the addition to chalcones renders the products in lower enantioselectivities (up to 68% ee) [90]. 

In 2010, Du reported the use of chiral squaramides as catalyst for the Michel addition of nitroalkanes to chalcones with excellent results in terms of yields and enantioselectivities [97]. However, when cyclic enones were used the enantioselec-tivity dropped dramatically and when prochiral nitroalkanes were used the diastereoselectivity was very low. 

Yamaguchi and coworkers have found that proline rubidium salts catalyze the asymmetric Michael addition of nitroalkanes to prochiral acceptors. When (25)-L-prolines are used, acyclic ( )-enones give (S)-adducts. Cyclic (Z)-enones give (R)-adducts predominantly (Eq. 4.139).203 Recently, Hanessianhas reported that L-proline (3 7% mol equiv) and 2,5-dimethylpiperazine are more effective to induce catalytic asymmetric conjugate addition of nitroalkanes to cycloal-kanones.204... 

Reaction at the C atom of nitronate salts is known with a variety of electrophiles, such as aldehydes (Henry reaction) and epoxides (191-193). Thus the incorporation of the nitro moiety and the cyclization event can be combined into a tandem sequence. Addition of the potassium salt of dinitromethane to an a-haloaldehyde affords a nitro aldol product that can then undergo intramolecular O-alkylation to provide the cyclic nitronate (208, Eq. 2.17) (59). This process also has been expanded to a-nitroacetates and unfunctionalized nitroalkanes. Other electrophiles include functionalized a-haloaldehydes (194,195), a-epoxyaldehydes (196), a-haloenones (60), and a-halosulfonium salts (197), (Chart 2.2). In the case of unsubstituted enones, it is reported that the intermediate nitronate salt can undergo formation of a hemiacetal, which can be acetylated in moderate yield (198). 

A rubidium salt of proline (5-10 mol%) has been reported to catalyse the asymmetric Michael addition of nitroalkanes to prochiral acceptors. When L-proline was used, acyclic (I )-enones produced (.S )-adducts. whereas cyclic (Z)-enones gave (R )-adducts.88... 

These malonate and nitroalkane reactions gave the adducts with the predicted absolute configurations (i )-adducts were obtained from cyclic (Z)-enones and (S)-adducts from acyclic ( )-enones when (S)-21 was employed. The stereochemical outcome can be summarized as M(a)-attack. The involvement of the a-enantioface-discriminating mechanism suggests that the chiral catalysts are located in the vicinity of the enone carbonyl group at the transition state. The reaction of the primary nitroalkane mentioned above also supports this explanation. 

Cyclic ketones or acetone react with nitro-olefins, giving the corresponding -adducts hy action of the potassium salt of chiral p-chlorophenyl amino acid catalyst (18 examples, 40-99% anti syn 42 58-4 96 ee 61-95%). Malonates,2-nitroalkanes or p-ketoesters are useful Michael donors and can react with enones in the presence of lithium salts of primary amino acids to create a new carhon-carhon hond at the p-position of the ketone (Scheme 12.9). However in some cases p-amino acids were more efficient than the a-amino acids. ... 

Pyrrolidine-tetrazole 108 is also a very useful catalyst for the conjugate addition of a wide variety of nitroalkanes to cyclic and acyclic enones using /ranx-2,5-dime-thylpiperazine as base (Scheme 2.55) [161]. Excellent enantioselectivities (94-97% ee) are obtained for the addition of primary and secondary nitroalkanes to cyclohex-enone and 3-methyl-2-cyclohexenone. On the other hand, the level of enantioselection displayed by catalyst 108 in the case of the conjugate addition to acyclic enones is similar to that obtained with catalyst 107 (Scheme 2.55). 

Nitroalkanes are a particularly useful source of stabilised carbanions for the asymmetric addition to electron-poor alkenes. This type of nucleophiles has been added to cyclic and acyclic a,p-unsaturated enones in the presence of a novel class of organocatalysts, such as chiral a-aminophosphonates.This study revealed that the hydrate salt of a pyrrolidine-based catalyst bearing a phosphonate group, depicted in Scheme 1.14, was found to be the best catalytic species, providing, in the presence of tra i-2,5-dimethylpiperazine as an additive, moderate to good results for a range of substrates, as summarised in Scheme 1.14. 

A closely related catalyst to the above was applied by the same workers to the asymmetric Michael addition of nitroalkanes to both cyclic and acyclic a,p-unsaturated enones, allowing the corresponding Michael products to be obtained in good yields and excellent enantioselectivities of up to 98% ee (Scheme 1.18). " This process offered a new way to construct quaternary stereocentres from enones and nitroalkanes. 

Zhao and co workers [54] developed simply primary-secondary diamine catalysts derived from primary amino acids. This type of catalysts such as 105 was found to catalyze the asymmetric Michael addition of malonates to acyclic a,p-unsaturated ketones with good activity and excellent enantioselectivity (Scheme 5.27). Liang and coworkers designed a new primary amine catalyst combining two privileged skeletons, cinchona and cylohexanediamine [55], The obtained optimal catalysts 107 and 110 were applicable to the Michael additions reactions of malonate or nitroalkanes to a,p-unsaturated ketones. The reactions worked well with both cyclic and acyclic enones (Scheme 5.28). 

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