Michael addition propanoate

Michael adducts are also formed from the reactions of pyrroles with ethyl propiolate and with but-l-yn-3-one. In addition to the expected acrylic ester, 1-methylpyrrole also yields ethyl 3,3-bis(l-methyl-2-pyrrolyl)propanoate in its reaction with ethyl propiolate (67MI30500, 67MI30501), whilst if both a -positions of the pyrrole ring are unsubstituted, a twofold Michael addition with but-l-yn-3-one occurs to give the 2,5-disubstituted pyrrole (76JHC1145). 

The reaction of 3-(3,4-dimethoxyphenyl)propanoic acid with thallium(III) trifluoroace-tate in the presence of boron trifluoride etherate leads to a mixture of the dihydrocoumarin (574) and the spirolactone (572) (78JOC3632). It is suggested that these products arise through an initial one-electron oxidation to the radical cation, the fate of which may vary. Thus, intramolecular reaction with the carboxyl group gives the radical (571) and eventually the spirolactone. Alternatively, capture of the radical ion by solvent and further oxidation affords the radical (573), whereupon an intramolecular Michael addition to the carboxyl group and aromatization lead to the dihydrocoumarin (Scheme 218) (81JA6856). 

Enolates derived from 2-phenylselanyl esters can react with various electrophiles. The Michael addition of the enolate formed from /-butyl 2-phenylselanyl propanoate 129 to furanone 130 followed by iodination afforded the key intermediate 131 for the total synthesis of (—)-avenaciolide 132 (Scheme 33).213... 

Michael addition of methyl acrylate to azonane gave methyl 3-(azonan-l-yl)propanoate <2002JOC245>, while addition of acrylonitrile to l,4-diisopropyl-l,4,7-triazonane resulted in 95% of a heterocyclic nitrile <2000NJG575>. 

KF/AI2O3 catalyzed hetero-Michael addition of ethyl acrylate with pyrrole as weakly nucleophile gives ethyl pyrrol-l-yl)propanoate 145 in moderate yield <2005TL3279>. 

Isoxazolidin-5-ones 549 can be prepared by 1,3-dipolar cycloaddition of nitrones and ketenes or ynolates or, alternatively, by cyclization of 3-(hydroxyamino)propanoates 550 in turn obtained by addition of ketene acetals to nitrones or by Michael addition of hydroxylamine derivatives to a,/3-unsaturated esters (Scheme 132). 

The functionalisation at the N1-position of 2 -deoxy-pseudouridine by Michael addition of methyl acrylate offered access to the phosphoramidites (61). The precursor to (61) was also functionalised as an amine derivative, which was transformed into the fluorescein-labelled phosphoramidites (62a-b). Fluorescent oligonucleotides were synthesised either from these latter building blocks or by post-synthetic modifications of oligomers containing the 2 -deoxy-pseudouridine-1 -propanoate units. ... 

Acrolein is the prototype a,[3-unsaturated aldehyde, and reacts across N2 and N1 of dG to add three carbons and generate the exocyclic tetrahydropyrimidopurinone ring (propano ring) (Figure 5.4). The reaction occurs via Michael addition of the olefin to either N1 or N2 followed by 1,2-addition of the aldehyde to N2 or Nl, respectively. l,N2-8-Hydroxy-propanodeoxyguanosine (y-OH-PdG) and l,N2-6-OH-PdG (a-OH-PdG) are the principal products with the former being the major isomer [60, 61]. 

Stereospecific Michael addition reactions also may be catalyzed by hydrolytic enzymes (Scheme 2.205). When ot-trifluoromethyl propenoic acid was subjected to the action of various proteases, lipases and esterases in the presence of a nucleophile (NuH), such as water, amines, and thiols, chiral propanoic acids were obtained in moderate optical purity [1513]. The reaction mechanism probably involves the formation of an acyl enzyme intermediate (Sect. 2.1.1, Scheme 2.1). Being an activated derivative, the latter is more electrophilic than the free carboxylate and undergoes an asymmetric Michael addition by the nucleophile, directed by the chiral environment of the enzyme. In contrast to these observations made with crude hydrolase preparations, the rational design of a Michaelase from a lipase-scaffold gave disappointingly low stereoselectivities [1514-1517]. 

Aside from Coreys phenylmenthyl propanoate 424, several chiral enolates have been utilized for Michael additions with substantial degrees of diastereoselectiv-ity. Yamaguchi s group developed a series of chiral amide enolates 436 and studied the conjugate addition to crotonates [210]. Another remarkable early contribution came from Oppolzer and coworkers who used dienolate 437 for diastereoselec-tive consecutive additions to cyclopentenone and allylation [211]. The auxiliaries 436 and 437 served for total syntheses of terpenoid natural products. Diastereos-elective Michael additions were also achieved by means of imidazolidinone-based lithium enolate 438 [212] - another showcase of the efficiency of imidazolidinone 118 [54] (Scheme 4.94). 

Conjugate addition of the lithium salt of a chiral amine to a -substituted a, 3-unsaturated ester leads to formation of a chiral, nonracemic amino acid. Addition of the chiral, nonracemic lithium amide 5.143 (contains a phenethyl auxiliary) to 5.142 gave the amino-ester.63 Catalytic hydrogenation removed both benzylic groups (the auxiliary and the benzyl group) and acid hydrolysis of the ester moiety led to 3-amino-3-(4-benzyloxyphenyl)-propanoic acid, 5.144. The initial Michael adduct was formed with >99% dr (dr is diastereomeric ratio), leading to high enantioselectivity in 5.144 after removal of the auxiliary. 

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