Lactams, alkylation conjugate addition

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). 

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. 

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. 

Now comes the key step intramolecular conjugate addition of the nitroalkane anion to the unsaturated ester. When catalysed by CsF and a tetra-alkyl ammonium salt, this is selective (1.5 1) for the all equatorial products 100. Reduction and cyclisation give the lactam 102 having the right stereochemistry for (Llycorane 72. 

Besides simple enones and enals, less reactive Michael acceptors like /3,/3-disubstituted enones, as well as a,/3-unsaturated esters, thioesters, and nitriles, can also be transformed into the 1,4-addition products by this procedure.44,44a,46,46a The conjugate addition of a-aminoalkylcuprates to allenic or acetylenic Michael acceptors has been utilized extensively in the synthesis of heterocyclic products.46-49 For instance, addition of the cuprate, formed from cyclic carbamate 53 by deprotonation and transmetallation, to alkyl-substituted allenic esters proceeded with high stereoselectivity to afford the adducts 54 with good yield (Scheme 12).46,46a 47 Treatment with phenol and chlorotrimethylsilane effected a smooth Boc deprotection and lactam formation. In contrast, the corresponding reaction with acetylenic esters46,46a or ketones48 invariably produced an E Z-mixture of addition products 56. This poor stereoselectivity could be circumvented by the use of (E)- or (Z)-3-iodo-2-enoates instead of acetylenic esters,49 but turned out to be irrelevant for the subsequent deprotection/cyclization to the pyrroles 57 since this step took place with concomitant E/Z-isomerization. 

Limitations of this method are the poor selectivity observed with 2-cyclo-hexencne and the lack of reactivity of these enolates toward (3-alkyl-a,p-un-saturated esters [413], Conjugate addition of the sodium enolate of 530 (R = H) to a substituted nitrostyrene 7.96 is the first step of the synthesis of an antidepres-sive drug [1448], The chiral auxiliary is excised by lactam formation induced by hydrogenation of the nitro group. This leads to pyrrolidine 7.97 (Figure 7.62). 

Lewis acid promoted reactions of silicon enolates, /.e., silyl enol ethers and ketene silyl acetals with various electrophiles have yielded a wealth of novel and selective synthetic methods. This combination of reagents has been used in the past to perform such reactions as aldol-condensations with aldehydes and acetals, imine-condensations, conjugate additions to a,P-enones, alkylations, electrophilic aminations, and Diels-Alder/cyclocondensations. Our own interest in this field has involved the use of titanium tetrachloride to promote the reaction of ketene silyl acetals with non-activated imines as an efficient route to P-lactams. This reaction has been applied to the asymmetric synthesis of P-lactams via a chiral imine-titanium tetrachloride template. We have also found that both ketene silyl acetals and vinylketene silyl acetals oxidativelly dimerize or cross-couple, in the presence of titanium tetrachloride to conveniently yield various diesters . Our present study concerns reactions of vinylketene silyl acetals with non-activated imines and vinylimines promoted by titanium and zirconium tetrachlorides. 

Amides are very weak nucleophiles, far too weak to attack alkyl halides, so they must first be converted to their conjugate bases. By this method, unsubstituted amides can be converted to N-substituted, or N-substituted to N,N-disubstituted, amides. Esters of sulfuric or sulfonic acids can also be substrates. Tertiary substrates give elimination. O-Alkylation is at times a side reaction. Both amides and sulfonamides have been alkylated under phase-transfer conditions. Lactams can be alkylated using similar procedures. Ethyl pyroglutamate (5-carboethoxy 2-pyrrolidinone) and related lactams were converted to N-alkyl derivatives via treatment with NaH (short contact time) followed by addition of the halide. 2-Pyrrolidinone derivatives can be alkylated using a similar procedure. Lactams can be reductively alkylated using aldehydes under catalytic hydrogenation... 

Reductions of alkyl pyridones with lithium aluminum hydride or alane are very complex and their results depend on the position of the substituents and on the reducing reagent. Since the pyridones can be viewed as doubly unsaturated lactams with a,/J- and )i, -conjugated double bonds, the products result from all possible additions of hydride ion 1,2,1,4 or 1,6. Consequently the products of reduction are alkylpiperidines and alkylpiperideines with double bonds in 3,4 or 4,5 positions [449, 7755]. 

Acyl isocyanates are more reactive than alkyl or aryl isocyanates. However, the presence of an additional rr-bond conjugated to the C>i-N bond of the isocyanate opens the possibility for [4 + 2] cycloadditions to compete with normal [2 + 2] additions. Reactions with alkyl and aryl substituted alkenes are rather slow. Propene, tranj-2-butene, styrene and conjugated dienes give only 3-lactams, albeit in moderate yields (Scheme 25). The strained double bond of norbomene, a reactive dienophile, adds across the conjugated 4iT-system of trichloroacetyl isocyanate (equation 51). 

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