Conjugate addition lactams

Formal oxidation of pyrrolidine to the succinimide stage affords a series of compounds used as anticonvulsant agents for treatment of seizures in petit mal epilepsy. Knoevnagel condensation of benzaldehyde with ethyl cyanoacetate affords the unsaturated ester, 9. Conjugate addition of cyanide ion leads to the di-nitrile ester (10). Hydrolysis in mineral acid affords the succinic acid (11), presumably by decarboxylation of the intermediate tricarboxyllie acid. Lactamization with methylamine gives phensuximide (12). ... 

The palladium-catalysed decarboxylative carbonylation of 5-vinyloxazolidin-2-ones 218 caused, unexpectedly, a ring enlargement process to 5-lactams 219 <00JA2944>. The conjugate addition of 4-phenyloxazolidin-2-one to a nitroalkene was used for the synthesis of diastereoisomers of dethiobiotin <00EJO3575>. Attempted deprotection of the O-TBDMS... 

Unlike with sodium borohydride (see Section 11.01.5.2), pyrrolizin-3-one 2 reacts with lithium aluminohydride mainly as an amide. No conjugate addition occurs, and only the reductive lactam cleavage takes place to give stereoselectively the (Z)-allylie alcohol 77. Similarly, benzo-annulated pyrrolizin-3-one 17 gives the corresponding benzylic alcohol 78. The same reactivity was observed with organometallics such as methyllithium which gives exclusively the tertiary (Z)-allylic alcohol 79 (Scheme 7). 

The conjugate addition of activated nitrogen nucleophiles, such as hydroxylamine and hydrazine derivatives, to a,/3-unsaturated bicyclic lactam 284 gave the corresponding /3-amino product 285 in good yield and excellent diastereoselectivity. These products can be manipulated to afford enantiopure /3-aminopyrrolidinones of potential application as conformationally constrained, substituted glutamate templates (Equation 45) <2001J(P1)2997>. 

Conjugate addition.1 This base undergoes efficient 1,4-addition to a,(i-un-saturated esters to give the enolate of a (3-amino ester, which can be trapped by an alkyl halide to give a-alkyl-(3-amino esters (2) as a mixture of syn- and antiisomers (about 1 1). These esters can be converted into 3-lactams (3) by hydrolysis and dehydration (11, 449) or into a-alkyl-a,3-unsaturated esters (4) by N-quater-nization and 3-elimination on silica gel ( 75% yield). 

N-alkinyldihydropyridone 72 yields bicyclic lactam 73 (92JA7292), and rhodium-complex-catalyzed intramolecular conjugate addition of vinylstan-nanes 74a and b (formed by aza-Diels-Alder reaction) leads to chiral piperidones 75a and b (08T3464). 

Conjugate addition to (35 ,7a/ )-3,7a-dihydro-3-phenyl-l//,5f/-pyrrolof1,2-r ]oxazol-5-onc (8) yields the saturated -substituted bicyclic lactams 9 with complete diastereoselectivity13. Treatment of the latter with 2.2 equivalents of lithium diisopropylamide in tetrahydrofuran at — 78 °C, followed by alkylation with a haloalkane, furnishes the a,/i-dialkylatcd products 10 with excellent selectivity (d.r. >98.5 1.5, determined by H and 13CNMR)13. In this case the major diastereomer has the cw-relationship between the newly introduced substituent (R2) in the pyrrolidine ring and the fused oxazolidinc ring rcsiduc13. 

In an analogous manner the enantiomeric unsaturated bicyclic lactam 11 was transformed via conjugate addition of dimethyl 1,3-propanedioate (sodium amide/hexamethylphosphoric triamide) and subsequent alkylation with (bromomethyl)benzene to give the dialkylated product 12 in 20% yield12. 

Since the trapping of the lactam enolate with electrophiles should not be limited to nitroolefins, extension to conjugate additions to alkenylsulfones, the ring opening of N-tosylaziridines, alkylation with functionalized halides, and silylation with chlorotrimethylsilane were explored. 

This product is then treated with acryloyl chloride. The initial step in this case probably involves the acylation of nitrogen on the enamine conjugate addition then completes the formation of the lactam ring (23-5). Treatment of that product with triethyl silane then reduces the ring unsaturation and cleaves the benzylic nitrogen bond on the auxiliary to yield (23-6) as the optically pure tmns isomer. Displacement of bromine with the mercapto benzthiazole (23-7) completes the synthesis of izonsteride (23-8) [25]. 

The most reactive Michael acceptors, such as alkylidene malonates, gem-dicyanoalkenes and nitroalkenes, react with a-halozinc esters in a conjugate fashion. Beautiful examples were offered by two stereocontrolled conjugate additions to piperidinone 102 and pyrro-lidinone 104 leading to optically active bicyclic lactams 103147 (equation 60) and 105 (equation 61)148. With these electron-poor alkenes a Grignard two-step protocol is to be adopted in order to avoid the single electron transfer reactions from the metal to the Michael acceptor, which should afford olefin dimers. The best solvent is found to be a... 

Samuel Danishefsky of Columbia University has also described (J. Am. Chem. Soc. 2005, 127, 8298) a total synthesis of 1, starting from the pyroglutamate derivative 10. Conjugate addition followed by alkylation established the lactam framework. Intramolecular cyclization of 12 gave 13, establishing the aminated quaternary center. The oxygenated quaternary center was then constructed by phenylselenyl-mediatcd cyclization of 14. The end game of this synthesis used the already-established cyclohexenyl zinc addition, which worked as well with 16 as it had with 7. 

While sluggish under thermal conditions,274-275 the asymmetric conjugate addition of amines to alkyl crotonates is achieved at room temperature under high pressure (15 kbar).276 Thus, benzylamine can be added to the crotonate derived from 8-p-naphthyl menthol, with virtually complete diastereoselectivity. A related intramolecular 1,4-addition of an amine to a chiral enoate was used in a total synthesis of the alkaloid (-)-tylophorine.277 Additions of amines to chiral iron complexes of type (116) proceed with excellent selectivity and allow the preparation of homochiral p-lactams.l27128,l3() l32 In contrast, the addition of amine nucleophiles to chiral vinylic sulfoxides278-2811 and to chiral vinylsulfoximines281 proceeds with comparably low selectivities. 

Enantiopure a, ft -unsaturated 5-lactams react stereoselectively with carbon-, nitrogen-, sulfur-, and oxygen-centred nucleophiles [N3-, Me(CH2)nS, MeO-, and n-Bu-]. The synthetic potential of these conjugate additions has been demonstrated through the synthesis of two new substituted indolizidines, (7/f)-7-amino-8-deoxy-swainsonine and (7/ )-7-acetylaminoswainsonin.133... 

The stereochemical outcome of the conjugate addition of sulfur-stabilized nucleophiles to the 5-lactam unit of tetrahydrobenzo[a]benzoquinolizines (83) has been (g) shown to depend on the nature of the substituent at the angular position (R1) thus,... 

Magnus, P. Lacour, J. Evans, P. A. Rigollier, P. Tobler, H. Applications of the /i-azidonation reaction to organic synthesis. a,/i-Enones, conjugate addition, and /-lactam annulation. 

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