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

Abstract

Stereoselective organocatalytic C−C bond formations that tolerate N‐heterocycles are valuable since these moieties are common motifs in numerous chiral bioactive compounds. Such transformations are, however, challenging since N‐heterocyclic moieties can interfere with the catalytic reaction. Here, we present a peptide that catalyzes conjugate addition reactions between aldehydes and nitroolefins bearing a broad range of different N‐heterocyclic moieties with basic and/or H‐bonding sites in excellent yields and stereoselectivities. Tuning of the pyramidalization direction of the enamine intermediate enabled the high stereoselectivity.

Tripeptide Organocatalysts for Stereoselective Conjugate Addition Reactions with N‐Heterocyclic Substituents

“…27 Mechanistic studies, including back‐reaction monitoring of quasi‐enantiomers by mass spectrometry, [15] revealed that the intermediate enamine is involved in the rate‐ and enantioselectivity determining step [14–17,28] . Further studies showed how the reactivity and stereoselectivity of peptide catalysts can be improved by (a) tuning the trans : cis ratio of the tertiary d Pro‐Pro bond (Scheme 2a) [29] and (b) endowing the enamine with an endo ‐pyramidalized enamine‐N (Scheme 2b) [18,30] . These insights allowed us to establish catalyst H−Oic‐ d Pip‐ d Glu−NH 2 ( B , H−Oic−OH: (2 S ,3a S ,7a S )‐octahydro‐1 H ‐indole‐2‐carboxylic acid; H−Pip−OH: ( R )‐piperidine‐2‐carboxylic acid) for conjugate addition reactions with nitroolefins bearing N‐heterocycles [18] .…”

“…Secondary amines catalyze this reaction by the formation of an enamine with the aldehyde followed by reaction with the nitroolefin [12–17] . Despite more than 500 reports, only a few examples with nitroolefins bearing N‐heterocyclic substituents have been reported [18–20] . Only a single study used, in a cascade reaction, an aldehyde with an N‐heterocyclic moiety (Scheme 1b) [21] …”

“…We then probed whether the lessons for catalyst optimization through a high trans : cis amide bond ratio and endo ‐pyramidalization at the enamine‐N allow for increasing the selectivity. Thus, we tested derivatives of ent ‐ A with a bicyclic N‐terminal proline residue that increases the endo conformation of the enamine intermediate [18,30] . Peptides C (H−Oic‐ d Pro‐ d Glu−NH 2 ) and D (H−MetPro‐ d Pro‐ d Glu−NH 2 ) with Oic and MetPro (H−MetPro−OH: (1 S ,3 S ,5 S )‐2‐azabicyclo‐[3.1.0]‐hexane‐3‐carboxylic acid) residues improved the enantioselectivity to 93% ee and 94% ee, respectively (Table 1, entries 2 and 3).…”

“…[12][13][14][15][16][17] Despite more than 500 reports, only a few examples with nitroolefins bearing Nheterocyclic substituents have been reported. [18][19][20] Only a single study used, in a cascade reaction, an aldehyde with an N-heterocyclic moiety (Scheme 1b). [21] A catalyst that is compatible with N-heterocycles must be sufficiently robust and chemoselective to maintain turnover and stereoselectivity even in the presence of these competing functional groups, preferably at low catalyst loadings.…”

Hybrid Peptide–Thiourea Catalyst for Asymmetric Michael Additions of Aldehydes to Heterocyclic Nitroalkenes

“…However, systematic investigations using heterocyclic nitroalkenes are very rare. Only very recently, Wennemers described peptide catalyzed Michael reactions of nitroalkenes bearing N-heterocycles …”