Nat. Catalyst: Organic catalyzed trans conjugate addition of aldehydes to unsaturated nitro compounds

In recent years, the asymmetric conjugation addition of aldehydes to Nitroalkenes catalyzed by small molecular organic amines has attracted more attention, which is due to the product of this reaction, i.e optically pure γ - nitroaldehydes are the synthetic blocks of a series of bioactive molecules including γ - amino acids, γ - butyrolactone, 3,4-disubstituted pyrrolidine At present, the products of this kind of reactions catalyzed by organic amines are mainly in the form of 1,2-syn, which is caused by Si / Si attack between amines intermediate with electrophilic s-trans-e configuration and Nitroalkenes (Fig 1-A) Among them, the electrostatic interaction between the nitrogen atom of the intermediate of nitro and enamine can promote the reaction process So far, the only trans conjugation addition of aldehydes to Nitroalkenes needs to take Nitroalkenes of Z-configuration as substrates, or to force the formation of Z-configuration enamine intermediates through hydrogen bond induction, and C 2 symmetrical secondary amines to form enamine intermediates However, these methods are only suitable for propionaldehyde with low steric resistance, so there is still a lack of a method for trans conjugation addition of nitroalkene with different aldehyde substrates (Fig 1-B) Recently, Professor helma wennemers of the Federal Institute of technology in Zurich, combined with his previous work, designed a tripeptide based organic amine catalyst, which introduced two methyl groups into the C δ position of the catalyst, forced the reaction to generate s-cis-structured enamine intermediates through steric hindrance effect, which attacked nitroolefins with RE / Si, and was able to trans The selective product is γ - nitroaldehydes (Fig 1-C) The reaction is suitable for different aldehyde and nitroolefin substrates, and has higher practical value than the traditional method The carboxyl group in the glutamic acid residue of the catalyst side chain can be used as the complexation group of nitro group and proton donor at the same time, which ensures the high activity of the catalyst After studying the reaction mechanism by NMR and DFT, the author believes that the reaction is based on the Curtin Hammett model, that is, the energy level of the intermediate rather than the components of the intermediate determines the stereoselectivity of the reaction Related work was published in NAT Catalyst (DOI: 10.1038 / s41929-019-0406-4) (photo source: Nat Catalyst.) the author first studied the feasibility of the reaction (Fig 2) The CIS selective catalyst 1 was used to catalyze the addition of butyraldehyde to nitrostyrene The CIS addition product can be obtained in the ratio of 1:35 However, when two methyl groups are introduced into C δ, a pair of mixtures can be obtained with anti / syn selectivity of 0.8:1 It is shown that the C δ substituted analogues of peptide catalysts can have a decisive effect on the stereoselectivity of the reaction (photo source: Nat Catalyst.) the author also found other problems in the research process: Although the above experiments prove that the strategy is feasible in theory, the EE value of the product is only 59%, indicating that the reaction conditions need to be further optimized (Table 1) Because the carboxyl group in the peptide catalyst is very important for its catalytic activity, the author designed a series of analogs of catalyst 2 to test its yield and stereoselectivity In addition, the proton solvent (MeOH, CHCl3 / I pruh (9:1)) and the non proton solvent (THF, MeCN, dioxane, CH2Cl2, DMSO) were screened Through a series of optimization of the reaction parameters, the author finally obtained the optimal conditions: with 5 mol% of organic amine 5 based on octahydropindole-2-carboxylic acid (OIC) as the catalyst, the substrate can react in dioxane / MeCN (1:1) at - 20 ℃, and the trans addition product 3A can be obtained with a conversion rate of more than 95%, trans selectivity of 6.5:1 and EE value of 98% (photo source: Nat Catalyst.) the author then expanded the substrate of the reaction under the optimal conditions (Fig 3) By combining a series of different aldehydes and Nitroalkenes, we found that the reaction has excellent trans selectivity (anti / syn 3.5:1 to > 20:1) and enantioselectivity (96-98% ee) Different from the methods developed before, aldehydes with larger sterically hindered substituents can also generate γ - nitroaldehydes with higher yield and stereoselectivity By increasing the catalyst loading (20 mol%), even alkyl Nitroalkenes can form trans products with high enantioselectivity All these results show that tripeptide catalyst 5 is of great value in the trans conjugation of aldehydes and Nitroalkenes (photo source: Nat Catalyst.) in order to study the reaction mechanism, the author studied the enamine intermediate of phenylacetaldehyde in the reaction by low temperature nuclear magnetic resonance technology and DFT calculation Through theoretical calculation, the author found two main low-energy conformations, both of which are highly conserved, showing bending shape and, more importantly, s-cis-configuration The low-temperature ROESY spectrum showed that the s-cis / s-trans ratio was about 3:1 in the reaction system, while the s-cis / s-trans ratio was 1:5.5 in the alkene amine mixture catalyzed by tripeptide catalyst 1 Although the ratio of the two qualitatively reflects the selective tendency of conjugated addition, the ratio of the two cannot quantitatively reflect the stereoselectivity Therefore, we speculate that the reaction is in accordance with Curtin Hammett model, that is, the main product is the product which undergoes the intermediate with low energy The relative energy of γ - nitroaldehydes is calculated by DFT It is found that the energy of CIS product is lower, which is advantageous in thermodynamics However, the energy of s-cis-configuration is far lower than that of s-trans-configuration enamine, so the reaction can generate the thermodynamic adverse trans addition product through s-trans-configuration enamine (photo source: Nat Catalyst.) Professor helma wennemers of the Federal Institute of technology in Zurich developed a trans conjugation addition reaction of aldehydes to Nitroalkenes by elaborately designing a tripeptide catalyst substituted by C δ dimethyl The reaction is suitable for different aldehydes and Nitroalkenes, which improves the traditional condition that only suitable for propionaldehyde substrate The mechanism of the reaction was studied by low temperature NMR and DFT calculation It was found that the reaction accords with Curtin Hammett model In the course of the reaction, the s-trans-enamine intermediate with low energy is attacked by RE / Si with Nitroalkenes to form a thermodynamically unfavorable trans addition product, which provides a novel method for the synthesis of these compounds with high application value.