A Amino P lactams

Quite important is also the a-methoxylation of A -carbomethoxylated a-amino acid esters and a-amino-p-lactams (Table 4, No. 53-55) a-Methoxylation was... 

Scheme 64 Synthesis of a amino P lactams via ynamide Kinugasa reaction...

The group of Palomo has reported in 2003 the preparation of short pseudopeptides containing enantiopure a-substituted a-amino-p-lactam fragments (II, Fig. 11) by a-alkylation of suitable V-[bis(trimethylsilyl)methyl]-p-lactams through a totally stereocontrolled way [270]. 

The utility of these promoters to achieve an efficient coupling of a-amino p-lactams with a-amino acid esters has also been documented [89]. For example, p-lactam 51, Scheme 19, upon treatment with (5)-PheOMe and (5)-ValOMe in DMF, in the presence of NaNs, furnishes dipeptides 52 and 53 respectively, in good... 

Bose AK, Jayaraman M, Okawa A, Bari SS, Robb EW, Manhas MS (1996) Microwave assisted rapid synthesis of a-Amino-P-Lactams. Tetrahedron Lett 37 6989-6992... 

Bromolactamization (11, 76). This reaction can be used for stereoselective preparation of 3,4-disubstituted 3-lactams.1 Thus the P,-y-unsaturated hydroxamic acid 1, prepared in several steps from tiglic acid, on reaction with bromine and K2C03 in aqueous CH,CN cyclizes mainly to a rrans-p-lactam (2). In contrast, the protected a-amino-p,y-unsaturated hydroxamic acid 3, prepared in several steps from L-methionine, cyclizes on reaction with bromine mainly to a ris-p-lactam (4). 

Monosubstituted-5(4//)-oxazolones behave differently upon reaction with imines. Here, 4-methyl-2-phenyl-5(4/7)-oxazolone 196 (Ri = Ph, R2 = Me) reacts with imines derived from 2-furancarboxaldehyde or 2-thiophenecarboxaldehyde to give 3-amino-p-lactams 197. On the other hand, 196 reacts with chlorosul-fonyl isocyanate in a [2 + 2] cycloaddition to give dioxazabicycloheptanones 198 as shown in Scheme 7.60. ... 

The effectiveness of KCN in promoting difficult couplings can be further shown in the reaction of a-amino a-branched p-lactams with a-amino esters [90]. 

Scheme 24 Ring opening of a-azido P-lactams with a-amino acid esters...

Work from this laboratory has demonstrated the synthetic potential of the ring opening at C2-C3 bond of a-hydroxy p-lactams to produce a-amino acid derivatives, Fig. 7. 

Ring opening of p-lactams at C2-C3 with application in peptide synthesis was first reported on a-keto p-lactams 126 ([116] for applications of a-keto p-lactams, see [117]), Scheme 42. These p-lactams, readily available via oxidation of 3-hydroxy p-lactams 125, undergoes a Baeyer-Villiger reaction upon exposure to m-CPBA and affords /V-carboxy a-amino acid anhydrides (NCAs) 127 [118]. Shortly after, it was discovered that a more direct, one pot route to these NCAs is feasible by treatment of 3-hydroxy p-lactams with a solution of commercial bleach... 

Scheme 43 Amine promoted transformation of a-keto P-lactams to a-amino acid derivatives...

The NCA 138 represents the amino-protected and carboxy-activated form of poly-oxamic acid 140, the hydroxylic amino acid portion of the antifungal family of polyoxins 139, Fig. 8. Other polyolic NCAs such as 141,142, and 143, Fig. 9, have also been prepared from the corresponding a-hydroxy p-lactams with equal success [123, 124]. 

Gallop et al. [80] reported the preparation of p-lactams via a [2+2] cycloaddition reaction of ketenes with resin-bound imines derived from amino acids (Scheme 9). This is another solid-phase adaptation of the Staudinger reaction, which could lead to the synthesis of structurally diverse 3,4-bis-substituted 2-azetidinones [81]. In addition, a novel approach to the synthesis of A-unsubstituted-p-lactams, important building blocks for the preparation of p-lactam antibiotics, and useful precursors of chiral p-amino acids was described [82]. 

P-lactams from Arnstein tripeptide derivatives had not yet been carried out (Fig. 40). The intramolecular Pummerer-type cyclization of the closely related (fi)-Am-stein tripeptide analogues with SKA predominantly gave the cw-P-lactams and the (S)-Arnstein tripeptide analogues gave a mixture of cis and trans P-lactams.59a It is noteworthy that cw-P-lactams were preferentially obtained from the (/ )-substrate considering the fact that the 3-amino-P-lactam moiety of naturally occurring... 

The mechanism of absorption must always be evaluated when a sustained-release dosage form is considered. A drug that is passively absorbed throughout the GI tracts is an ideal candidate for sustained release. Drugs such as riboflavin, folic acid, aminopenicillins, amino-p-lactams and nucleoside analogs, which have windows of absorption due to site-specific and/or active transport processes, may have incomplete bioavailability when formulated in oral, sustained-release dosage forms. 

Van Koten and coworkers prepared zinc ester enolates of IV-protected a-amino esters from the corresponding lithium enolates and allowed them to react with imines at low temperature to obtain trans-3-amino-P-lactams, often with high stereoselectivity as shown in Scheme 19. Interestingly, the authors interpreted their results in terms of an internally chelated zinc-oxygen bonded enolate (37). 

Jakowiecki, J. Loska, R. Makosza, M. S3mthesis of a-trifluoromethyl-P-lactams and esters of P-amino acids via 1,3-dipolar cycloaddition of nitrones to fluoroalkenes. J. Org. Chem. 2008, 75(14), 5436-5441. 

The extension of the above radical intramolecular cychzation of A-haloaryl-p-lactams to 2-azetidinones bearing the proradical center at C3 was also explored. The treatment of haloarenes 109a-c under similar conditions for the preparation of benzocarbapenems and benzocarbacephems 104—108 gave the fused tricyclic p-lactams llOa-c (Scheme 37, Table 2). Compounds 110a and 110b were obtained as mixtures of diastereomers, which are epimers at the newly formed C5 stereocenter, while the amino derivative 110c could be prepared as a single isomer. 

A mixture of diastereomeric azides EjZ) in fast equilibrium (III, Fig. 19) has been obtained by treatment of 3-alkenyl-3-bromoazetidin-2-ones with NaNs [291]. The subsequent hydrogenation and the following protection with CBz derivatives afforded 3-(2 -amino)-p-lactams as single diastereomers (IV, Fig. 19). 

The key step of the approach to 45 is the ring opening of A -Boc p-lactam 43 with ammonia. Scheme 17. The synthesis starts from the 4-carboxy azetidin-2-one 41, which is a p-hydroxy aspartic acid form possessing the p-carboxyl group and the ot-amino moiety simultaneously protected. The dipeptide unit 42 is obtained in 95% overall yield after activation of the a-carboxy group with cyanuric fluoride and... 

By analogy with the above reactions that use O- and A -nucleophiles, it has been shown that ring opening of A -Boc p-lactams can be achieved by reaction with metallated carbon nucleophiles. For instance, Baldwin developed the reaction of a-lithiated sulfones, Scheme 30, with p-lactams, such as 89, to provide access to y-keto a-amino esters 90, after desulfonation of the resulting intermediates. In particular, the angiotensin converting enzyme inhibitor WF-10129 91 has been synthesized by this route [97]. 

Other carbon nucleophiles may also be employed in such a coupling reaction that provides p-amino ketones and polyol intermediates. As shown in Scheme 32, aryl-Grignard reagents react at low temperature with the A -Boc p-lactam 96 to afford p-aminoketones 97 in 90 96% yields as the exclusive products. In no case over-addition is observed, even when an excess of the Grignard reagent is present in the reaction medium. On the other hand, when the reaction is performed at room temperature, only tertiary carbinols 98 are produced. 

Although more rare, the ring opening of A-acyl p-lactams has also been realized by using hydrides, giving rise to the corresponding reduction products. In this context, Scheme 40, Lee and Pak [107] have described the treatment of A-Boc p-lactam 119 with lithium aluminium hydride to give A-protected amino alcohol 120. Compound 120 could serve as potential intermediate for the synthesis of various hydroxylated indolizidine alkaloids. 

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