P-Unsaturated Lactams

The application of olefin metathesis to the synthesis of piperidines continues to be widely employed. The use of ring closing metathesis (RCM) in the synthesis of fluorovinyl-containing a,P-unsaturated lactams 148 and cyclic amino acid derivatives 149 is shown below. A key improvement in these reactions is the addition of the Grubbs 2nd generation catalyst (G2) in small portions during the reaction to compensate for catalyst decomposition that occurs at elevated reaction temperatures <06EJOl 166>. 

Table 33. asymmetric organosilane reduction of a,p-Unsaturated Lactams... 

TMS)3SiH has also been used as the mediator of C—C bond formation between an acyl radical and an a, p-unsaturated lactam ester (Reaction 7.9). The resulting ketone can be envisaged as potentially useful for the synthesis of 2-acylindole alkaloids [17]. Here, the effects of both H-donating ability and steric hindrance given by the silicon hydride can be seen. 

Cycloaddition to endocyclic unsaturation has been used by many researchers for the preparation of isoxazoUdinyl adducts with y-lactams derived from pyrogluta-minol and is discussed later in this chapter as a synthesis of unusual amino acids (Scheme 1.20, Section 1.6) (79,80). A related a,p-unsaturated lactam has been prepared by a nitrone cycloaddition route in the total synthesis of the fungal metabolite leptosphaerin (81). A report of lactam synthesis from acyclic starting materials is given in the work of Chiacchio et al. (82) who prepared isoxazolidine (47) via an intramolecular nitrone cycloaddition reaction (Scheme 1.11). 

Cycloaddition to an ot,p-unsaturated lactam. Ficini et al. have extended cycloaddition reactions of diethylaminoalkynes (5, 219 7,107-108) to include the a,j3-unsaturated lactam 1. N,N-Diethylaminobutyne condenses with lactam 1 in the presence of MgBr2 to afford enamine 2. This product is hydrolyzed and esterifled to afford 3 in 50% overall yield from 1. The intermediate 3 is converted into the indole alkaloid ( )-dihydroantirhine (4) by LiAlH4 reduction and debenzylation. 

These unsaturated, bicyclic lactams are also precursors to a variety of chiral nonracemic cyclopropanes. Treatment of the parent a,p-unsaturated lactam with Dimethylsulfoxonium Methylide generates the endo cyclopropanated adduct (eq 9).. io... 

The radical perfluoroalkyl-iodination reaction of a,P-unsaturated lactam 154 proceeds diastereoselectively. The stereospecific azide formation and subsequent chemical transformation of the (R)-isomer result in the synthesis of a series of perfluoroalkylated a-amino acids 156 (see Scheme 9.34) [60]. 

Among other carboxylic acid derivatives, the a,p-unsaturated lactams 1.92 proposed by Meyers and cowotkers [327] give useful results. No catalysis is needed in cydoadditions with silyloxydienes reactions with 2,3-dimethylbutadiene (R = R I Me) (F %... 

Construction of the hydroxy amino acid fragment (60) (shown in Scheme 5) commenced from the N,0-benzylidene derivative (65) of (R)-pyroglutaminol prepared from D-glutamic acid. Key features of the synthetic sequence were the conversion of (65) to the a, p-unsaturated lactam (66) by selenylation followed by... 

The original method for a,p-unsaturated lactams 243 obtained from 2-triiluor-omethylfurans 244 was proposed. °... 

The reaction of butenolides or a,P-unsaturated lactams (35 X = O or NBoc) reacts with ethylene diamine to form the reduced chiral 7-(a-hydroxyalkyl)- and... 

Bennasar extended his research on 2- and 3-indolylacyl radicals to intramolecular cyclizations to yield 2,3-fused indoles [112], Under nomeductive conditions (n-Bu6Sn2, hv), radical 201 underwent a cascade addition-oxidative cyclization sequence with a number of alkene acceptors including dimethyl fumarate (45%), methyl 1-cyclohexenecarboxylate (53%), methyl crotonate (71%), vinyl sulfone (22%), and the a,p-unsaturated lactam ester, 2-oxo-5,6-dihydro-2H-pyridine-l,3-dicarboxylic acid dibenzyl ester (41%) to form cyclopenta[h]indol-3-ones 202. Reaction of 201 with acrylonitrile and methyl acrylate, however, generated cyclo-hepta[h]indoles, the products of bis-addition-cyclization sequences. 

In the first case (path A), a,p-unsaturated lactams 56 were accessed from substrates of type 57 using RCM. In this route, the amide nitrogen was protected as a benzyloxy group. This benzyloxy protecting group provided an inbuilt access to the pyridine oxidation level via elimination after RCM. The lactam carbonyl moiety could also be transformed into a triflate group (R = OTQ, which is a useful functional handle for further functionalization of the target pyridine 55. In the second case (path B), cylic enones of type 58... 

The versatile phosphinamine ligands are also suitable for the copper-catalysed ECA of organoaluminium reagents to a,p-unsaturated lactams, including p-methyl-substituted 8-lactams, whose reaction allows the formation of all-carbon quaternary stereogenic centres in moderate yields and good enantioselectivities, as exemplified in Scheme 22 [57]. 

Qiu and co-workers failed to oxidize the dihydropyrrole 436 to the a,p-unsaturated lactam with CrOs in pyridine. Instead, the oxidation in the presence of dimethylpyrazol provided the 3-trifluoromethyl-pyrrole 437 in good yield [143]. 

Crisp, G.T. and Meyer, A.G. (1995) Synthesis of a,P-unsaturated lactams by palladium-catalysed intramolecular carbonylative coupling. Tetrahedron, 51, 5585-55%. 

Iron-catalyzed aqueous phase cyanohydroxycarbonylation of a-ketoalkynes with CO and KCN gave moderate to high yields of carboxy-substituted a, P-unsaturated lactams 47 under mild conditions (Equation 10.23) [43]. On the basis of IR spectroscopic evidence and previous literature precedent the active catalyst was suggested to be [Fe (CN)4(C0)2] , generated in situ by ligand exchange between K4[Fe(CN)6] and carbon monoxide. 

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