Organocatalytic Conjugate Addition of Cyclopropylacetaldehyde Derivatives to Nitro Olefins: en Route to β‐ and γ‐Amino Acids

Abstract

Cyclopropane‐containing amino acids are important pharmaceuticals and biologically active compounds. A new organocatalytic asymmetric Michael reaction has been developed. This allows the one‐step introduction of the cyclopropane ring, as well as two different nitrogen‐containing functional groups (tert‐butoxycarbonylamino and nitro) into the target compounds. All the products were isolated in good yields with moderate to excellent enantio‐ and diastereoselectivities.

Enamine/Iminium‐based Dual Organocatalytic Systems for Asymmetric Catalysis and Synthesis

“…The inclusion of an achiral thiourea ( Cat 6) as a co‐catalyst with a chiral amine catalyst ( Cat E‐6) enabled the formation of cyclopropane containing β‐ and γ‐amino acid precursors on reacting cyclopropylacetaldehyde derivative 39 and nitro alkenes 40 in a report by Kanger and group (Scheme 15). [75] The selectivity of the Michael products is attributed to the Z ‐configuration of enamine that is stabilised by the intramolecular hydrogen bonding between the ‐NH of the NHBoc and the nitrogen of the amine catalyst ( Int‐27 ). As a consequence, the nucleophilic attack on the Si ‐face of the nitrostyrene occurs through the less hindered Re ‐face of the enamine ( Int‐28 ).…”

Nitroenynes as Electrophiles in Organocatalysis and their Application in the Synthesis of Chiral Heterocycles

“…Kanger and coworkers, in 2015, described one example of organocatalytic conjugate addition of a cyclopropylacetalde-hyde derivative to phenylnitroenyne (Scheme 10). [20] Cyclopropane-containing amino acids are important pharmaceuticals and biologically active compounds. The authors developed an organocatalytic methodology for the conjugate addition of cyclopropylaldehydes to different nitroalkenes.…”

Amine Catalysis with Substrates Bearing N‐Heterocyclic Moieties Enabled by Control over the Enamine Pyramidalization Direction

“…We startedw ith (E)-3-(2-nitrovinyl)pyridine, the nitroolefin that had been used before in organocatalytic reactions but necessitatedt he use of high catalyst loadings. [8] Reassuringly,arange of different aldehydes including derivatives bearing sterically bulky substituents or functional groupss uch as esters anda lkenes, reactedr eadily with (E)-3-(2-nitrovinyl)pyridine in the presence of as little as 0.5 mol %o f peptide 5 and the products 7a-7i were obtained in yields of Scheme3.Comparison of the catalytic performanceo f1 and 5 in conjugate additionr eactionso fa ldehydes to nitroolefins (yields of the isolatedp roduct are > 80 %). 1mol %o ft he peptideT FA salt and an equimolar amountofNmethylmorpholine( NMM) were used since previouss tudies showedt hat the presence of TFA/NMM does not affectt he performance of the tripeptidic catalyst, ref.…”

“…[8,9] All reported examples requiree ither high catalyst loadings (5-20 mol %), the use of protecting groups on the N-het-erocycle, and/ors uffer from low enantio-and diastereoselectivities. [8][9][10] Peptide H-dPro-Pro-Glu-NH 2 (1)a nd relatedp eptides are powerful organocatalysts for CÀCb ond formations and enabled access to g-nitroaldehydes with aromatic and aliphatic substituents in excellent yields and stereoselectivities. [11][12][13][14][15] Peptide 1 is so robust that functional groups such as esters and acetals are tolerated.…”

“…[2,4,7] Despite intense research on this reaction, examples with N-heterocyclic substituted g-nitroaldehydes are seldom and mainly limited to 3-pyridyl moieties. [8,9] All reported examples requiree ither high catalyst loadings (5-20 mol %), the use of protecting groups on the N-het-erocycle, and/ors uffer from low enantio-and diastereoselectivities. [8][9][10] Peptide H-dPro-Pro-Glu-NH 2 (1)a nd relatedp eptides are powerful organocatalysts for CÀCb ond formations and enabled access to g-nitroaldehydes with aromatic and aliphatic substituents in excellent yields and stereoselectivities.…”