Michael-type addition amides

Dyong and Bendlin52 pointed out the possibility of functionalization of sorbic acid at C-3, -4, and -5 in the desired way. Introduction of two hydroxyl groups, at CA and C-5, may be accomplished stereospecifi-cally by means of cis-hvdroxylation, or by intermediation of an epoxide. Michael-type addition of a nucleophile to C-3 of the conjugated double-bond provides the possibility of obtaining all four diastereo-isomeric products. In this way, N-acetyl-DL-acosamine (137, 3-acet-amido-2,3,6-trideoxy-DL-arabmo-hexopyranose) was synthesized from 133 (obtained from the epoxide 129 in an aluminum chloride-catalyzed reaction with acetone). The amide 134 wasN-acetylated and... 

The most common preparations of amines on insoluble supports include nucleophilic aliphatic and aromatic substitutions, Michael-type additions, and the reduction of imines, amides, nitro groups, and azides (Figure 10.1). Further methods include the addition of carbon nucleophiles to imines (e.g. the Mannich reaction) and oxidative degradation of carboxylic acids or amides. Linkers for primary, secondary, and tertiary amines are discussed in Sections 3.6, 3.7, and 3.8. 

Scheme 7.11 Formation of alginate-PEGA. Amidation reaction of alginate followed by a Michael-type addition...

There are four different chemical reactions that have been used to crosslink polymers with peptide sequences (Fig. 6.8) (i) amide bond formation (ii) Michael-type addition (iii) Huisgen cycloaddition (click reaction) and (iv) radical polymerisation. The amide bond formation follows typical solid phase peptide synthesis (SPPS) protocols and does not require functionalisation of the termini of the peptide sequence. Fluorenyhnethoxycarbonyl (Fmoc) protection of the N-terminus allows attachment of the peptide sequence to an amine-bearing polymer. After removal of the Fmoc group, the amine-terminated peptide-polymer conjugate can be reacted with a second polymer bearing carboxylic acid functionalities using the same coupling chemistry (Maier et al, 2011). For Michael-type additions the peptide... 

The mode in which the cross-hnker is introduced into the polymer differs and is sometimes determined by the chemical reaction used. In the case of acrylated peptides, the polymer is not prepared in advance but formed in the presence of the cross-linker. When the unmodified peptide is attached to the polymer via amide bonds, the introduction of the linker has to be carried out in two stages. First, a peptide-polymer conjugate with an amine-functionalised polymer is formed, then the conjugate is reacted with a carboxylic acid-functionalised polymer. The other two methods - Huisgen cycloaddition and Michael-type addition - allow direct cross-linking of the polymer with the peptide. 

Active hydrogen compounds, such as aliphatic nitro-compounds may be added to the double bond of acrylamide in a Michael-type addition to produce saturated amides. 

Tomalia presented the synthesis of dendrimers as Starburst polymers, which consisted of poly(amide-amine)s as shown in Scheme 1 [2]. The core molecule in this case was ammonia, and the building block was methylacrylate. First, ammonia reacted with methylacrylate by a Michael-type addition. The obtained ester-terminated molecule was treated with a large excess amount of ethylene-diamine to form amino groups at the terminal positions (generation 0, GO). In this reaction, the methylester is the protected form of the amine, and the treatment with ethylenediamine (ester-amide transformation) corresponds to the deprotection of the ester function. Treatment of this amine-terminated molecule again with methylacrylate results in the formation of another terminal methyl-ester group. The molecule can be extended by repeating these operations. 

The answer suggests the Michael-type asymmetric addition of an enantiopure amine or its more reactive anion to enone to 23b. The authors used a lithium amide reagent for the addition to obtain the key chiral intermediate 23c (Scheme 3.9) [14]. The selected (S)-configuration of the phenyl ethylamino unit in the chiral amide anion induces the (7 )-configuration in the precursor of —)- R)-sitagliptin. 

Aziridines can add to carbon—carbon multiple bonds. Elevated temperature and alkali metal catalysis are required in the case of nonpolarized double bonds (193—195). On the other hand, the addition of aziridines onto the conjugated polarized double or triple bonds of a,p-unsaturated nitriles (196—199), ketones (197,200), esters (201—205), amides (197), sulfones (206—209), or quinones (210—212) in a Michael addition-type reaction frequendy proceeds even at room temperature without a catalyst. The adducts obtained from the reaction of aziridines with a,p-unsaturated ketones, eg, 4-aziridinyl-2-butanone [503-12-8] from 3-buten-2-one, can be converted to 1,3-substituted pyrrolidines by subsequent ring opening with acyl chlorides and alkaline cyclization (213). 

Reaction of the dilithio anion of 1-vinylbenzotriazole 90 with 2equiv of an aryl isocyanate led to a fused 1,4-diazepine ring formation via an intramolecular Michael addition of the intermediate aryl amide to the vinyl moiety, a type c ring closure that proceeded in good overall yield (Scheme 44) <2003JOC5713>. 

A number of selective transformations (Fig. 10) have been described which include the selective allylation on alcohols in the presence of amides [47], the Lewis acid catalyzed cleavage of benzyl alcohol esters with secondary amines to afford tertiary amides [48], the synthesis of ketones from Weinreb-type amides [49], and the synthesis of tertiary amines by a Michael addition/alkylation/Hoffman elimination sequence [50],... 

Asymmetric -methylation of a, -enones. Chiral bidendate ligands derived from L-prolinol can be used for asymmetric Michael additions to a, 3-enones with cuprates of the type CH,L CuMgBr (10, 266). The highest optical yield in conjugate addition to chalcone is observed when L is (S)-N-methylprolinol (88% ee). The tridentate chiral ligand 1 is equally effective for asymmetric 3-methylation of chalcone with CH,L CuLi and CuBr the chemical yield is 95%. Reduction of the amide carbonyl group of 1 results in practically total loss of chiral induction. 

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