A Way to Highly Enantiomerically Enriched aza‐Morita–Baylis–Hillman–Type Products

Abstract

Enantiomerically enriched b-amino carbonyl compounds bearing an a-alkylidene group can be prepared by azaMorita-Baylis-Hillman (aza-MBH) reactions and are versatile chiral building blocks for pharmaceutical candidates and other important compounds. [1,2] Consequently, the development of efficient methods for enantioselective aza-MBH reactions is of interest.[1] For example, quinidine derivatives, [1a-c] 1,1'-bi-2-naphthol (binol) derivatives containing a pyridyl group, [1d,e] phosphinyl derivatives, [1f-i] and thiourea derivatives [1j] have been used as catalysts for enantioselective aza-MBH reactions. These methods are, however, typically limited to the reactions of cyclic enones (such as 2-cyclopenten-1-one) or of b-unsubstituted acyclic enones and related esters (such as methyl vinyl ketone and methyl acrylate). There have been no reports of highly enantioselective aza-MBH reactions of b-substituted a,b-unsaturated acyclic carbonyl compounds.[3] It has been demonstrated that aza-MBH and MBH reactions of b-substituted acyclic enones are more problematic than those of b-unsubstituted enones. [3, 4] This may be related to a relatively slow Michael addition of a nucleophilic reagent (or Lewis base) to bsubstituted enones because of steric interaction between the nucleophilic reagent and the b substituent on the enones.[4] To overcome this difficulty, we propose an alternative route to access aza-MBH-type products with b-substituted a,b-unsaturated carbonyl moieties: Mannich-type reaction of in situ generated enamines of b-substituted a,b-unsaturated carbonyl compounds followed by isomerization of the double bond (Scheme 1). Here we report the catalytic enantioselective formation of aza-MBH-type products from b-substituted a,b-unsaturated aldehydes and a-imino esters protected with a p-methoxyphenyl (PMP) group through a Mannich-type reaction/isomerization sequence.We used (S)-proline to demonstrate the Mannich/isomerization sequence as it is a good asymmetric catalyst for Mannich-type reactions of alkyl aldehydes.[5] We reasoned that isomerization of the double bond of the Mannich products should occur spontaneously, because epimerization at the a-position of the aldehyde group of Mannich products generated from alkyl aldehydes is facile.[5] In the case of Mannich products generated from b-substituted a,b-unsaturated aldehydes, the acidity of the proton at the a-position of the aldehyde group of the product is increased by the presence of a neighboring alkene; this increased acidity should favor the isomerization of the double bond. Table 1 shows the results of the (S)-proline-catalyzed reaction Scheme 1. a) An aza-MBH reaction route. b) Formation of aza-MBHtype products through Mannich-type reaction/isomerization.

Asymmetric Organocatalysed [1,3]‐Sigmatropic Rearrangements

“…This result is in agreement with the proposed S N 2' mechanism, in which the trisubstituted alkene prevents the nucleophilic attack of the catalyst. [15] The optically active products obtained by the asymmetric [1,3]-sigmatropic rearrangement reaction, have several functional groups, which can be modified, offering a broad range of applications. The ester functionality can be hydrolysed under acidic conditions; this gives the N-protected b-amino acid derivatives.…”

Asymmetric Aminocatalysis—Gold Rush in Organic Chemistry

“…However, a recent paper by Barbas and co-workers demonstrated that the reactivity of this conjugate enamine can be selectively controlled. [146] Proline (I) catalyzes the direct a-functionalization of a,bunsaturated aldehydes with N-PMP-protected a-imino ethyl glyoxylate instead of the addition at the g-carbon atom (Scheme 53). The products 45 of the aza-Morita-Baylis-Hillman (MBH) reaction are formed in moderate yields (39-68 % yield), but with excellent enantioselectivities (up to 99 % ee).…”

Cinchona‐based Primary Amine Catalysis in the Asymmetric Functionalization of Carbonyl Compounds

“…Surprisingly, dienamine catalysis has since found only limited application in asymmetric synthesis, [88b-d] probably because g-amination of enals was originally proposed to follow a particular [4+2] cycloaddition path, [88a] instead of a more general nucleophilic addition route. [89] Recently, cinchona-based primary amine catalysis has greatly expanded the potential of this approach, promoting vinylogous nucleophilicity within Michael addition patterns, upon selective activation of unmodified cyclic a,b-unsaturated ketones (Scheme 25).…”