A-oxoamide

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>. 

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 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). 

Peptide a-oxo acids 1 (R4=H), a-oxo esters 1 (R4= alkyl or substituted alkyl), and a-oxo-amides 2 (R5=R6=H, alkyl, substituted alkyl, aryl, and/or heteroaryl) are potent reversible inhibitors for cysteine and serine proteases (Scheme 1).[1 9 Their inhibitory potency is the result of their enhanced electrophilic a-carbonyl functional group that can better compete with the substrate in the formation of a tetrahedral adduct with the cysteine or serine residue at the protease active site. In the case of peptide a-oxo esters and a-oxoamides, the extension in PI and beyond gives the inhibitors additional interactions with the protease at the corresponding sites. 

Scheme 1 The Structures of Peptide a-Oxo Acids, a-Oxo Esters, and a-Oxoamides and Their Adducts with a Cysteine Residue...

A synthetic route via the Dakin-West acylation reaction followed by a hydrolysis step was first reported for the preparation of p-acylamino a-oxo esters from acylamino acidsJ10l This method was later modified and adapted for the synthesis of peptide a-oxo esters, a-oxo acids, and a-oxoamides (Scheme 2).[1A5111... 

Scheme 2 Synthesis of Peptide a-Oxo Esters, a-Oxo Acids, and a-Oxoamides via the Dakin-West Acylation Reaction1 -2 "1...

Peptide a-oxo esters 1 (R4= alkyl, substituted alkyl) and a-oxoamides 2 can be prepared by treatment of a-substituted carboxylic acid derivatives (X1 = H, X2=OH X1, X2=CH2, N2) with an oxidizing agent (Scheme 3).Pa6,s,9] The final peptidyl products can contain either a mixture of enantiomers at C2 in PI of the peptide or be optically pure depending on the method employed for the preparation of the key intermediates or peptide a-substituted carboxylic acid derivatives, or the choice of the oxidizing agent in the final step. 

A method utilizing the Dess-Martin periodinane[12 for the conversion of a peptide a-hy-droxy ester into the corresponding a-oxo ester was reported by Burkhart et al.[8l The final product, peptide a-oxo ester, obtained in this process contains a mixture of enantiomers at C2 in PI of the peptide. The optical impurity arises not from the oxidation reaction but the synthesis of one of the intermediates, 2-hydroxy-3-nitro-4-phenylbutanoic acid, which generates four diastereomers at two adjacent chiral carbons. This procedure is limited to the synthesis of peptide a-oxo esters with the phenylalanine residue at the PI position. A more diversified approach is achieved by using a-hydroxy- 3-amino acids 14 as the key intermediate that permits selective introduction of an amino acid residue at PI of the peptide it can also be coupled to N-protected amino acids or N-protected peptides and further transformations give a-oxo esters 19, a-oxo acids 20, and a-oxoamides 22 (Scheme 4)J3 61... 

The use of a-hydroxy- 3-amino acids 14 has extended to the synthesis of peptide a-oxoamides 22J31 The N-terminal of 14 is protected and the C-terminal is then coupled with an... 

Table 2 Peptide a-Oxo Esters and a-Oxoamides Prepared from Oxidation of Peptide a-Hydroxy Esters and a-Hydroxyamidesi5-6-7 ...

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