Lactam synthesis nitrogen nucleophiles

We end this section with two examples of the effects amines may have on esterase activity. The aggressive nitrogen nucleophile can obviously interfere with ester formation or hydrolysis. In designing a synthesis based on these enzymes we must find a symmetrical intermediate that might be desymmetrised. In the synthesis of the simple P-lactam 48, simple disconnections led to the symmetrical amino-diester 50, with the nitrogen atom protected. 

Alcaide et al. [158] have used a similar approach for the synthesis of the tricyclic /3-lactam 314 starting from 313 (Scheme 8.78). In this domino process, a r-aUyl-palladium complex is formed by a nucleophilic attack of bromide at a divalent palladium-coordinated allene. Thereafter, the nitrogen nucleophile of the urethane moiety reacts with the primarily... 

Moreover, in the past 10 years, a number of works involving a nucleophilic attack of a nitrogen nucleophile over an acylpalladium intermediate, generated in situ from simple and easily prepared starting compounds, has been reported to be dealing with the synthesis of heterocyclic compounds, that is, 2,3,4,5-tetrahydro-lH-2,4-benzodi-azepine-l,3-dione derivatives 30 [39], tetrahydro-P-carboline/tetrahydriisoquinoline fused 5-lactam derivatives 31 and 32, respectively [40], and substituted hydantoins 33 [41] (Scheme 13.14). 

If a carboxylic acid ester side chain is introduced at the 3-position of a thiazine with a free NH group, lactam formation may occur <1987J(P1)1027>. Compound 78 is a result of lactam formation, and the synthesis of similar compounds is shown in Scheme 44 (Section 8.09.7). Reactions where the nitrogen reacts with a side chain introduced by a nucleophilic attack at the 3-carbon of 277-dihydrothiazines are shown in Schemes 6 and 27. 

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... 

Nitrogen-based nucleophiles continue to remain popular in ring-opening reactions of aziridines. a-Substituted-a-methoxycarbonyl-V-nosylaziridines were opened with a variety of functionalized amines to provide access to enantiopure a,a -disubstituted (3-lactam scaffolds for ditopic peptidomimetics <07OL101>. A related intramolecular regioselective 3,Y-aziridine ring opening with an a-amino functionality was reported in the synthesis of... 

Heterocycles are almost invariably formed by inter- and intramolecular Schiff base or lactam formation. We cite here the classical Knorr pyrrole synthesis (see Scheme 1.3.4) and Baeyer s barbituric acid synthesis, where the amide nitrogen atoms of urea are nucleophilic enough to add to malonic acid esters (Scheme 1.4.2). 

Additionally, Scheme 20.11 shows the versatility of Pummerer products. Under classical Pummerer conditions, heterocyclic conpounds behave as good nucleophiles, including for the production of tertiary bicyclic lactams 44. Kuhakarn et used a silicon-induced Pummerer reaction (this activation method will be explained in more detail later in this section) to generate the thionium intermediate, which was intramolecularly trapped by the lactamic nitrogen. Even when a mixture of S-stereoisomers was used, the reaction proved to be diastereoselective, and the lactam sulfide 44 was obtained as 5 1 mixture of trans cis products. Subsequent transformations led to the synthesis of a variety of bicyclic alkaloids 45-48 starting from the same sulfide lactam intermediate 44. 

Trapping by nucleophiles such as alcohols, which can also be drawn as insertion into the O-H bond, is a useful process. Cyclic ethers can be formed under very mild conditions (Scheme 8.136). Similarly, amines and other nitrogen derivatives can be employed to trap the carbene, most notably in the commercial synthesis of the antibiotic thienamycin in which a five-membered ring is annulated onto an existing p-lactam 8.507 (Scheme 8.137). °... 

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