Lactams, conjugated, reaction with

On the basis of the reaction of conjugated dienes with unsaturated halides in the presence of external nucleophiles, an elegant intramolecular version leading to a-alkylidene-y-lactams, has been developed (Scheme 8.19). Starting with an aryl halide, the regioselective insertion of an arylpalladium halide to the triple bond of acyclic compound 42 gives the c-vinylpalladium intermediate 43. Subsequent intramolecular carbopalladation of the diene affords a re-allyl palladium intermediate... 

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. 

The lactam derivative dibenz[h/]l 4-oxazepin-ll-(lOH)-one is a primary metabolic product of metabolism and a direct precursor of the urinary hydroxylated metabolites. In rats, the lactam, a dihydro-CR metabolite, an amino alcohol of CR, and an arene oxide are metabolites in CR degradation. In the rat, the major mechanism for elimination is sulfate conjugation and biliary excretion to a limited extent. Phase I metabolism by microsomal mixed fimction oxidases involves reduction of CR to the amino alcohol, oxidation to form the lactam ring, and hydroxylation to form the hydroxylactams. Phase II conjugation reactions sulfate the hydroxylactam intermediates for renal elimination. Amino alcohol intermediates are conjugated with glucuro-nide for biliary secretion. 

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). 

Annulation. Allyldimethyltritylsilane reacts with electron-deficient alkenes to afford silylcyclopentanes. However, the reaction with bicyclic conjugated y-lactams at low temperatures leads mainly to cyclobutane derivatives. 

Aryl transfer from ArSi(OEt)3 to conjugated ketones, lactones and lactams is achieved with the aid of a palladium(ll) salt supported by 116. It is a variation of the reaction involving ArB(OH)2 with a similar system. The P,P -dioxide of the same ligand complements CuOTf to serve as catalyst for the addition of R2Zn to nitroalkenes. ... 

The new primary amine anion (HI), unlike the lactam anion (II), is not stabilized by conjugation with a carbonyl group. It is therefore highly reactive and, once it is formed, it undergoes a rapid proton-abstraction reaction with a caprolactam monomer producing the dimer compound A -caproylcaprolactam (TV), which is a //-acyllactam, and regenerating the lactam anion (II) ... 

The only drugs which in fact have been shown to be capable of reacting covalently with proteins in vitro and for which such conjugation reactions in vivo appear to be of marked immunologic significance are the jS-lactam antibiotics, penicillins and cephalosporins (for a recent review, see Dewdney 1977). 

The addition of nitroalkanes to chalcones is more attractive since the Michael adducts are useful intermediates for a variety of further elaborated stmctures such as chiral aminocarbonyls, pyrrolidines, y-lactams, and y-amino acids. Thus, many elegant organocatalysts such as cinchona alkaloid-derived chiral tertiary amine thiourea 69 [67] or suqaramide 70 [68] and bisquaternary ammonium salts [69] 71a or 71b have been developed for such a reaction in recent years (Scheme 5.33). In addition, a,(3-unsaturated A -acylpyrroles [70] and 4-oxo-enoates [71] were also applicable in the highly enantioselective conjugated addition with nitroalkanes (Scheme 5.34). 

Another route to this cyclohexyl derivative involves the preparation of 6.183 via an olefmation reaction with a substituted phenylalinal derivative followed by reduction of the phenyl ring. The alcohol moiety in 6.183 was converted to the N-phthal-oyl derivative (6.184) by a Mitsunobu inversion.m Conjugate addition with a higher order silyl cuprate gave 6.185. The silyl moiety was converted to an alcohol (6.186) by treatment with tetrafluoroboric acid and then KF/m-chloroperoxy-benzoic acid. Removal of the phthalimidoyl group with hydrazine led to an amino-ester, which cyclized to lactam 5.757.11 Hydrolysis gave 4-amino-5-cyclohexyl-3-hydroxypentanoic acid (6.188) in 60% yield. 

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. 

As part of a projected synthesis of corrins, a simple synthesis of y-substi-tuted y-butyrolactams via the conjugate addition of hydrogen cyanide to unsaturated ketones is described contrary to a much earlier report, the )S-cyanohydrin (101) is not produced, but a mixture of the two butyro-lactams (102) and (103) is isolated, (103) being convertible into (102) by reaction with basic cyanide solution. Reaction of one of those, (102), with potassium t-butoxide in t-butyl alcohol gave, inter alia, the semi-corrinoid (104), These transformations are outlined in Scheme 35. 

---