Lactam-Based Analogs

Lactam-based analogs of epothilones were conceived by the BMS group as metabolically more stable alternatives to the lactone-based natural products (which exhibit limited metabolic stability in rodent plasma). It is worth noting, however, that despite its short plasma half-life in rodent species, Epo B shows potent antitumor activity in a variety of nude mouse human tumor models,and the same is tme for Epo D (vide infra). In addition, Epo D has subsequently been demonstrated to 

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By analogy, the acetylene aldehyde 500 gives, on addition of the chiral Li-enolate 501 [79-82], the chiral //-lactams 502 and 503 in 75% yield [80-82]. Similar (fhc-tam-forming reactions are discussed elsewhere [70, 83-88]. The ketone 504 affords, with the lithium salt of the silylated lithium amide 505, the Schiff base 506, in 74% yield (Scheme 5.27). The Schiff base 506 is also obtained in 25% yield by heating ketone 504 with (C6H5)3P=N-C6H4Me 507 in boiling toluene for 7 days... 

Also, Bose et al. [76] have shown that the steric course of /J-lactam formation can be influenced by the MW heating rate. For example, in the reaction of the benzoylox-yacetyl chloride 53 with the Schiff base 54 (Scheme 4.28) the cis adduct 55 is the main product at low irradiation power whereas high power favors the formation of the trans adduct 56. Lactams of this type can serve as intermediates for the side chain oftaxol and its analogs. 

In 2006, our research group reported a novel MCR based on the reactivity of a-acidic isocyano esters (1) toward 1-azadienes (84) generated by the 3CR between phosphonates, nitriles, and aldehydes [169]. Remarkably, the dihydropyridone products (85) for this 4CR contained the intact isonitrile function at C3. The exceptional formation of the 3-isocyano dihydropyridone scaffold can be explained by the Michael-attack of the a-deprotonated isonitrile (1) to the (protonated) 1-azadiene (84), followed by lactamization via attack of the ester function by the intermediate enamine. Although in principle the isocyano functionality is not required for the formation of the dihydropyridone (85) scaffold, all attempts using differently functionalized esters (e.g., malonates, ot-nitro, and a-cyano esters) gave lower yields of the dihydropyridone analogs [170] (Fig. 26). 

In addition to the use of salt combinations to produce nylons described in Chapter 4, nylons may also be produced by the anionic ROP of lactams. In fact, this method was largely developed to overcome patent rights held by DuPont based on the work of Carothers and his group. This is the preferred method for the production of nylon-6, structurally analogous to nylon-6,6, and is widely practiced in Europe. 

A dipolar route of heterocyclization of a monocyclic enallenyl nitrone (from precursor 126 by base-catalyzed propargyl-allenyl isomerization) leads to lactam 127 (05EJO2715) that is an analog of astrocasine (8). 

The anionic polymerization of lactams proceeds by a mechanism analogous to the activated monomer mechanism for anionic polymerization of acrylamide (Sec. 5-7b) and some cationic polymerizations of epoxides (Sec. 7-2b-3-b). The propagating center is the cyclic amide linkage of the IV-acyllactam. Monomer does not add to the propagating chain it is the monomer anion (lactam anion), often referred to as activated monomer, which adds to the propagating chain [Szwarc, 1965, 1966]. The propagation rate depends on the concentrations of lactam anion and W-acy I lactam, both of which are determined by the concentrations of lactam and base. 

A method to prepare 2a based on the work of a related analog [4] was employed for the first mulh-kilogram campaign. In this approach, 2a was prepared from lactam 5, which is derived from an optically enriched P-hydroxy acid. This method requires introduction of the amino group as an 0-benzylhydroxylamine, which we hoped would sufficiently protect the amino group of 2b during amide formation with triazole 3. 

Being very strong bases, organometallic compounds are capable to start the polymerization (7, 12, 30, 51, 62). If organomagnesium compounds are used, the interaction of magnesium cations with lactam anions can probably reduce the dissociation of the salt analogous the basic character is certainly weakened in lactam complexes formed by addition of hydrated oxides of Ti, Zr, Hf, Th or Ce (48). 

The sulfur-free analogs of penicillins and cephalosporins have attracted much attention of both synthetic and medicinal chemists, since the successful development of new 1-oxacepham antibiotics by the Shionogi group17 . Namely, oxazoline-azeti-dinone derivatives 19 have been used as key intermediates in the synthetic chemistry of new beta-lactam antibiotics 18). The compounds 19 have usually been prepared by a two-step operation involving the reaction of 79 with chlorine or t-butylhypochlorite followed by treatment with a base. 

If a nucleophilic group is placed in a side chain which is located at /3-lactam position 4, as shown in Scheme VI/21, the size of the new ring formed be six. The transformation from VI/99 to VI/100 takes place in acid or base [57]. The analogous formation of VI/102 has been observed when the trimethylsilyl protected /3-lactam Vl/lOlwas deprotected [81]. In both cases, retention (C(3)) and inversion (C(4)) of the configuration was found. 

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