Azetidinones 1-amino- from

The ynamide-Kinugasa reaction has been used for the highly stereoselective synthesis of chiral cz-amino- (3-1 actams. The application of this reaction consists in the preparation of chiral a-amino-2-azetidinones starting from chiral ynamide (Scheme 64), [158]. 

In addition, there are many important nonantibiotic uses of 2-azetidinones in fields ranging from enzyme inhibition [15-21] to gene activation [22], Systems containing one carbon atom common to two rings, spirocyclic compounds, represent an important structural organization. Spirocyclic p-lactams (Fig. 3) behave as p-tum mimetics [23-26] as well as enzyme inhibitors [27, 28], they are precursors of a,a-disubstituted p-amino acids [29-32], and the spiranic p-lactam moiety is present in chartellines and chartelamides [33-38], a family of marine natural products. Synthetic studies and biosynthetic speculation inspired by an unexpected reaction on the marine alkaloid chartelline C have been described [38],... 

The formation of rings with more than seven atoms has unfavorable rates because the addition step is often too slow to allow it to compete successfully with other pathways open to the radical intermediate. In stannane based chemistry for example, premature hydrogen abstraction from the organotin hydride is difficult to avoid. However, Baylis-Hillman adducts 111 derived from enantiopure 1-alkenyl (or alkynyl)-4-azetidinone-2-carbaldehydes are used for the stereoselective and divergent preparation of highly functionalized bicycles 112 and 113 fused to medium-sized heterocycles (Scheme 38) [80, 81]. The Baylis-Hillman reaction using nonracemic protected a-amino aldehydes has been attempted with limited success due to partial racemization of the chiral aldehyde by DABCO after... 

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]. 

A further application of silylated amino acids is the formation of /3-lactams by treating N-TMS-0-amino acid-TMS-esters (497) with Grignard reagents under cycli-zation262 (Scheme 74). From N-TMS-a-phenyl-/ -alanin-TMS-ester (497) via the silylated product (498), 3-phenyl-2-azetidinone (499) can be obtained. 

Formation of a 3-amino azetidinone and its N-Boc protected form from oxazolidinone precursors shows that various reactions can be performed with good yields (67-95%) without affecting the 7V-[bis(trimethylsilyl)methyl] group... 

Amino-3-phenylazetidine is obtained in high yield in three steps from Al-benzhydryl-3-azetidinone by using dibenzylamine as an amine equivalent in a modified Strecker reaction (95SC803). 

The intramolecular nitrone-alkene cycloaddition reaction of monocyclic 2-azetidinone-tethered alkenyl(alkynyl) aldehydes 211, 214, and 216 with Ar-aIkylhydroxylamincs has been developed as an efficient route to prepare carbacepham derivatives 212, 215, and 217, respectively (Scheme 40). Bridged cycloadducts 212 were further transformed into l-amino-3-hydroxy carbacephams 213 by treatment with Zn in aqueous acetic acid at 75 °C. The aziridine carbaldehyde 217 may arise from thermal sigmatropic rearrangement. However, formation of compound 215 should be explained as the result of a formal reverse-Cope elimination reaction of the intermediate ct-hydroxy-hydroxylamine C1999TL5391, 2000TL1647, 2005EJ01680>. 

P-Lactams.1 A biomimetic synthesis of /3-lactams from chiral amino acids such as L-serine has been developed by Mattingly and co-workers. The protected amino acid (1) is first converted into the O-alkyl or O-acyl hydroxamate (2), which undergoes cyclization to derivatives of l-hydroxy-2-azetidinones on treatment with triphenylphosphine-carbon tetrachloride. This cyclization is also possible with triphenylphosphine-diethyl azodicarboxylate.2 The final step involves reduction of the N—OH group with TiClj.3 The advantage of this method over that of Wasserman (9,428), which involves cyclization of /3-haloamides, is that a strong base such as NaH is not required. 

Chirality also has been introduced on the inline. After treatment with Na/NHg, 3-amino-2-azetidinones are obtained from reactions of (R)- or (5)-l-phe-nethylamine imines and zinc enolates of ethyl bis-silylaminoacetate 6.109 (R = Et) [131,1289]. In Et20, trans isomers are formed, while in THF-HMPA, cis isomers predominate. The facial selectivity depends upon the (R)- or ( configuration of the imine W-substituent (Figure 6.91). If the inline C-substituent R is h CsC, then the selectivity is lower. Cyclic transition-state models account for the observed selectivities. From the titanium enolate of 2-pyridylthioester Me2CHCOS-2-Py and benzaldehyde (S)-1 -phenethylimines 6.111, Cinquini, Cozzi and cowork-... 

Phase-transfer catalysis has become highly useful in the synthesis of azetidinones. It facilitates the one-pot synthesis of azetidinones from 0 -amino-acids and acid chlorides such as (13). It also promotes the reaction of i8-amino-acids and methanesulphonyl chloride to form azetidinones. ... 

An improved synthesis of traws-3-amino-4-trifluoromethyl-2-azetidinone (105), a precursor of several monobactams, has been achieved129. 4-Phenylsulphonyl-2-azetidinone (106) has been used to synthesize the monobactam intermediates 107 and 108130. The utility of the imidazolylsulphonate group in the synthesis of monobactams has been demonstrated131. 6-Sulphoaminopenicillanic acid (110) has been both isolated and synthesized (from 6-aminopenicillanic acid)132. 

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