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.

Catalysis of Reactions by Amino Acids

“…A catalyst system using (S)-proline and imidazole has been reported by Barbas et al to be effective for the formation of aza-MBH adducts using various b-substituted a,b-unsaturated aldehydes and a-imino esters protected with a PMP group as substrates (Scheme 7.58) [93]. Aza-MBH adducts were isolated with moderate yields and excellent enantioselectivities.…”

Catalytic Asymmetric Baylis–Hillman Reactions and Surroundings

“…However, Barbas and coworkers [72] reported that a combination of l-proline and imidazole could promote the reactions between β-substituted α,β-unsaturated aldehydes and α-imino esters protected with a p-methoxyphenyl (PMP) group. Although the corresponding Baylis-Hillman adducts were obtained in good yields and excellent enantioselectivities (Scheme 10.57), the mechanism was considered to be a Mannich-type reaction, followed by isomerization of the double bond instead of the typical MBH reaction pathway.…”

Asymmetric Aza‐Morita–Baylis–Hillman‐Type Reactions: The Highly Enantioselective Reaction between Unmodified α,β‐ Unsaturated Aldehydes and N‐Acylimines by Organo‐co‐catalysis

“…[4] Recently, the first asymmetric addition of a,b-unsaturated aldehydes to N-PMP-protected a-imino glyoxylate was reported. [7] Our group reported the first addition of a,bunsaturated aldehydes to N-Boc-protected imines (Scheme 1). [8] The organo-co-catalytic system that we developed was also applied for the direct addition of enals to N-carbamate-protected a-amido sulfones.…”