Oxoamide

These workers also prepared the thio analog of 17 (R = H) by treating 16 (R = H) with aqueous ammonia to provide the P-oxoamide, which was converted into the corresponding enolized P-thioxoamide 18 by treatment with hydrogen sulfide and hydrogen chloride in ethanol. Compound 19 was synthesized by oxidation of 18 with iodine in ethanol under basic conditions. 

If the AM 1 -hydroxyalkyl)amide is not stable enough for isolation it is still possible to perform the amidoalkylation in a one-pot reaction. Thus the amide and the carbonyl compound (or the oxoamide) are treated with an acid catalyst in the presence of the carbon nucleophile, so that the equilibrium amount of the (hydroxyalkyl)amide is converted in situ into the /V-acyliminium ion, which is subsequently attacked by the nucleophile. This principle is often applied in the total synthesis of alkaloids -8. 

Development of new synthetic routes to optically active (3-lactam derivatives is still an attractive problem in organic chemistry. As a synthetic approach to penicillin derivatives, photocyclization of oe-oxoamides 76 to (3-lactams has long been studied 41, 42). This reaction (Scheme 6), however, results in a complex mixture of racemic cis-and trans-isomers of (3-lactams 72 and of oxazolidin-4-ones 73, since the reaction proceeds via a zwitterionic intermediate 7143>. Of these isomers, only the optically... 

Table 10. Solid-state photocyclization of oxoamides to p-lactams using inclusion complexation...

The most successful enantiocontrol of photocyclization of a a-oxoamide to a P-lactam in an inclusion complex is represented by the photoreaction of the 1 1 complex... 

The most exciting enantioselective photochemical conversion of a a-oxoamide to a P-lactam has been found in the case of N,N-diisopropylbenzoylformamide (96) which gives P-lactam 97. In the photocyclization of plain 96 in the solid state, optically active P-lactam 97 of high optical purity was obtained in high chemical yield. Thus no optically active host compound is necessary for the enantioselective reaction 48>. 

The reduction of 2-oxoacids bound to different chiral auxiliaries gave the 2-hydroxyacid derivatives in a 64 to 76% yield and 42 to 86% de depending on solvent, proton donor, supporting electrolyte, temperature, and substituent R in the oxoacid. The results are in accordance with an ECE reduction of the 2-oxoamide to an enolate anion, which subsequently undergoes a face-selective protonation to the hydroxy acid [346, 347]. 

A second example of the use of optically pure coordinatoclathrate hosts in controlling the enantioselectivity of photochemical reactions in the crystalline state is found in the case of the a-oxoamide derivative 13, which forms a crystalline 1 1 complex with host (S,S)-8 [18,19]. Irradiation of these crystals led to the P-lactam derivative (-)-14 in 90% yield and a reported ee of 100% (Scheme 3). The X-ray crystal structure of the complex showed that oxoamide 13 adopts a helical conformation that favors the formation of a single enantiomer of photoproduct 14. The reaction is thus conformationally controlled in a way exactly analogous to the examples discussed earlier in the review. 

Compound 13 is only one of a number of differently substituted a-oxoamides investigated by Toda et al. Depending on the optically pure host molecule used, yields and enantiomeric excesses of the corresponding P-lactams varied widely, and in some instances new photoproducts were observed. For example, irradiation of the crystalline complex formed between a-oxoamide 13 and host 9b... 

In principle, the approach outlined above for the a-oxoamides can be applied to any reaction, ground or excited state, which converts an achiral reactant into a chiral product, and Toda, Tanaka, and coworkers have investigated a wide variety of such processes [ 15,16]. A complete discussion of their work is beyond the scope of this review, and we illustrate the general approach taken with one final example. As shown in Scheme 4, irradiation of crystalline complexes of ene-diones 20a-f with chiral host (R,R)-(-)-9b led to cyclized products 21a-f in the variable yields and ee values indicated in Table 1 [22]. Remarkably, for reasons that were not clear (there was no accompanying X-ray crystallography), the R=n-propyl derivative 20g was found to give a completely different photoproduct, spiro compound 22 (69% yield, 97% ee, stereochemistry unknown), a result that once again illustrates the rather capricious nature of the use of chiral hosts for asymmetric induction. 

It is important to mention again at this point that a general feature of the solid-state ionic chiral auxiliary approach to asymmetric synthesis is that not all chiral auxiliaries lead to high enantiomeric excesses. A case in point is found in the work of Natarajan et al. on the a-oxoamide-containing salts 43 (Scheme 10) [29]. Like the nonionic a-oxoamides discussed previously (Sect. 2.2), these compounds undergo photocyclization to p-lactam derivatives, and while the prolinamide salt behaves perfectly, leading to p-lactam 44 in 99% ee at 99% conversion, the corresponding 1-phenylethylamine salt affords nearly racemic photoproduct (3% ee at 99% conversion). The reason for this difference is... 

Scheme 10 Ionic chiral auxiliary-induced asymmetric induction in a-oxoamide photochemistry...

Fig. 3 Prolinamide (a) and 1-phenylethylamine (b) a-oxoamide salts. In the former, the anions are homochiral, while in the latter the anions have a near-mirror-image relationship...

The oxoamide 310 with R= NEt2 or SEt can be converted into the fullerene anhydride 311 by heating in toluene at 100 °C in the presence ofp-TsOH (Scheme 4.59) [346]. 

The alkylation of enolates from 1-acyl-2-pyrrolidinemethanols is not limited to compounds carrying two a-hydrogens. An example of an interesting type of dianion is that derived from the a-oxoamide 17, which is then alkylated with iodomethane to give a 87 13 ratio of diastereomers, as determined by NMR7. 

Peptide a-oxo acids, a-oxo esters, and a-oxoamides are also potent inhibitors of cysteine and serine proteases. Oxidation of peptide a-substituted carboxylic acid derivatives provides a general route to these compounds (Section 15.1.5). Peptide hydroxamic acids have been shown to be inhibitors of metalloproteinase and some have been reported to have antibiotic, anticarcinogenic, and antiviral activities. Peptide hydroxamic adds may be prepared by solution and solid-phase methods using a variety of resins (Section 15.1.6). a-Aminoboronic acids may be prepared by several routes and are reported to be inhibitors of aminopepti-dases. Procedures have been developed for their incorporation into peptides (Section 15.1.7). 

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