Activation lactams

Since /1-lactams can be prepared via reactions of ester enolates with imines, these reactions are of great interest for synthetic and medicinal chemists. The synthesis of naturally occurring antibiotics and other physiologically active //-lactams is an objective of much current work. Though the stereocenters in those reactions are often established by addition of enolates to imines, they are discussed in Section D.1.6.1.3. In this section, only some basic results concerning //-lactams are presented. 

En gros, the N insertion reactions can be subdivided into a Beckmann type and a Schmidt-type rearrangement part. Furthermore, some photochemical rearrangements of chiral oxaziridines are known to generate a range of optically active lactams. 

Epoxidation of amino chalcone 17, followed by regioselective ring opening of the epoxide unit, demonstrates the formation of optically active lactam derivatives of type 18, which are highly important structures for use within the pharmaceutical industry. The reaction proceeds in good yield and without loss of stereochemical integrity (Scheme 15). 

A large number of inorganic compounds can be used as the activators of acid-ion (anionic) activated lactam polymerization. The activator in anionic activated lactam polymerization not only increases the process rate, but also changes the structure and functionality of a polymer formed, and, as a result an activator can regulate the properties of the end-product.1... 

Except for lactam n-acyl derivatives, compounds such as esters, anhydrides and halogen anhydrides of carboxylic acids, which can activate lactam polymerization, can also be used as activators (promoters). 

S)-Lactic aldehyde, HCOCHCH3 (1). Pn Optically active lactams.2 The reai... 

Three different approaches to the preparation of 5,6-dihydropyrrolopyrimidines (143) have been employed. The activated lactam (140) undergoes facile reaction with amidines to give 4-phenylamino derivatives (143 R1 = PhNH) (Scheme 9) <83S226>. 

After a metal hydride complex was prepared from LAH and quinine (1 1), irradiation of a mixture of the resulting solution containing the above chiral hydride agent and the enamide (133) led to the formation of two optically active lactams 158 [6%, [a]D —63° (c = 0.48, CHC13)] and 155 [ 13%, [a]D — 102° (c = 0.44, CHC13)] with 37% optical purity. Reduction of the lactam 155 with LAH furnished (—)-xylopinine (20) in 48% chemical yield. 

Interestingly, a similar irradiation of the enamide 133 in a dilute solution of the above mixture afforded the optically active lactam (155) [10%,[a]D—71° (c = 0.63, CHC13)] and the optically active amine (20) [38%,[a]D — 16 (C = 1.75, CHC13)]. The amine was identical to (—)-xylo-pinine, thus providing a one-step synthesis of this alkaloid from the corresponding enamide (Scheme 65). 

The most biologically active /(-lactams are a-amino substituted derivatives (9), which according to Hegedus retrosynthetically derive from amino carbene complexes of type 10 and cyclic imines (11) (Scheme 4). 

On account of their very important biological activity, -lactams are important synthetic targets [4-9]. Fused polycyclic -lactam subunits appear in many natural products such as penicillins [4-6] and trinems/tribac-tams [10-13]. Fu et al. reported that such frameworks can be prepared with high levels of enantioselectivity via the intramolecular Kinugasa reaction [14, 15] of alkyne-nitrone in the presence of a planar chiral Cu/phosphaferrocene-oxazoline catalyst [16]. For instance, compound 1 was transformed into tricyclic -lactam 3 in good stereoselectivity and yielded (88% ee and 74% yield) using 5 mol % of CuBr and 5.5 mol % of complex 2 (Scheme 1). 

The photochemical conversion of 78d in its chiral crystal to the optically active -lactam 79d was monitored by continuous measurements of CD spectra of Nujol mulls (Fig. 15-2). As the reaction proceeds, the CD spectra of 78d decrease and new spectra due to 79d appear. 

Photoreactions of Pyridones. - Enantioselective cyclizations have been carried out using the chiral molecule (91). Formation of inclusion compounds of this with pyridones (92), followed by irradiation, afforded the optically active lactams (93) with an ee of 91-99%. Irradiation of the pyridones (94) in water leads to a racemic mixture of the cyclized product (95). However, irradiation of... 

Chiral enolates in which the auxiliary is in the ester portion provide still another route to optically active lactams. Early results indicated that little asymmetric induction was obtained with menthyl enolates. Use of the enolate obtained from 24 did lead to high levels of asymmetric induction. Treatment of 24 with lithium diisopropylamide in tetrahydrofuran, followed by addition of imine 25, gives cf -/(-lactam 26 in 79% yield and 91%ee98. Optically active /3-lactams can be prepared by addition of chiral iron enolates (see Section D.l. 1.1.3.2.) to imines99-101. Addition of aluminum enolate 27 to imine 28, followed by oxidative cyclization with iodine and an amine, affords /(-lactam 29 in 54% yield and >95% ee. 

The behavior of cefoxitin is typical of a cell wall-active -lactam antibiotic (Zimmerman and Stapley, 1976). However, unlike the majority of penicillins and cephalosporins, which bind in a reversible manner to... 

Strong protic adds art through an easy protonation of the lactam amide group, while several metal halides, such as chro-mirrm, iron, alrrminum, tungsten, and calcium chlorides, can form complexes with lactams. It has been assumed that the O-coordination with Lewis adds activates lactam... 

The nature and concentration of the initiator play a cmcial role in the nonactivated anionic polymerization, where the growing centers are formed in the slow reaction [46] between the monomer and the lactam anion bringing about the presence of some induction periods. On the other hand, the evaluation of the specific action of a given initiator in the activated lactam polymerization is more complex, since it cannot be taken in consideration apart from the activator used. It is necessary to consider here the dual system initiator/activator. It seems that the activation energy for the anionic ring-opening polymerization of CL is almost independent of the activator used, " whilst it is probably a fimction of the initiator nature. 

For the synthesis of p-lactam antibiotics, the presence of asymmetrical carbon at the 3 and 4 positions is critical to prepare optically active -lactams [197]. Nagai et al. [198] developed enzymatic synthesis of optically active p-lactams by lipase-catalyzed kinetic resolution using the enantioselective hydrolysis of iV-acyloxymethyl p-lactams 108 in an organic solvent (isopropyl ether saturated with water) and the transesterification of N-hydroxymethyl P-lactam 109 in organic solvent (metiiylene chloride) in tiie presence of vinyl acetate as acyl donor (Fig. 37). The reaction yield of 35-50% and e.e. s of 93 to more than 99% were obtained depending on the specific substrate used in the reaction mixture, Lipase B from Pseudomonas fragi and lipase PS-30 from Pseudomonas sp. were used in the reaction mixture. 

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