Azlactones rearrangement

In 1998 Fu and Ruble reported that the planar chiral 4-(diakylamino)pyridine derivatives 79a and 79b (Scheme 13.42) induce high enantiomeric excesses in the catalytic O-acyl azlactone rearrangement [85, 86]. In particular with the PPY-derivative 79b, O-acyl azlactones 80 were smoothly rearranged to the products 81 in almost quantitative yields and enantiomeric excesses up to 92% (Scheme 13.42) [85]. 

Additions to prochiral ketenes [13.2] Desymmetrization of meso-diols [13.3] Dynamic kinetic resolution of azlactones rearrangement of O-acyl azlactones, O-acyl oxindoles, O-acyl benzofuranones [13.6]... 

Benzilic acid rearrangement Benzoin reaction (condensation) Blanc chloromethylation reaction Bouveault-Blanc reduction Bucherer hydantoin synthesis Bucherer reaction Cannizzaro reaction Claisen aldoi condensation Claisen condensation Claisen-Schmidt reaction. Clemmensen reduction Darzens glycidic ester condensation Diazoamino-aminoazo rearrangement Dieckmann reaction Diels-Alder reaction Doebner reaction Erlenmeyer azlactone synthesis Fischer indole synthesis Fischer-Speior esterification Friedel-Crafts reaction... 

Bergmann s synthesis unsaturated azlactones, 6, 226 Berkelheide rearrangement heterophanes, 7, 777 Berninamycin A, 6, 232 Berninamycinic acid appiications, 6, 709 X-ray diffraction, 6, 669 Betahistine as vasodiiator, 2, 5i9 Betaines... 

There is usually no reaction with nitrobenzene as solvent. However, in this medium acetoxybenzylidene azlactones undergo a Fries rearrangement [Eq. (16)]. 

Ruble JC, Fu GC (1998) Enantioselective construction of quaternary stereocenters rearrangements of 0-acylated azlactones catalyzed by a planar-chiral derivative of 4-(pyrrolidino) pyridine. J Am Chem Soc 120 11532-11533... 

Scheme 12 Fu s, Vedejs , Johannsen s and Richards chiral DMAP-catalyzed rearrangements of O-acyl azlactones [103-107]...

Rearrangement of O-Acyl Azlactones, O-Acyl Oxindoles, and O-Acyl Benzofuranones... 

In 1970 Steglich and Hofle reported that 4-dimethylaminopyridine (DMAP) and 4-(pyrrolidino)pyridine (PPY) are excellent catalysts for isomerization of O-acyl azlactones E to their C-acylated isomers F [79-81], In this rearrangement, a new quaternary stereocenter is generated (Scheme 13.41). Clearly, DMAP or PPY afford the rearrangement products F in the racemic form. 

The rearranged azlactones 81 are versatile starting materials for further transformation, e.g. for reduction to a-substituted serin derivatives such as 82 or for coupling with amino acids, affording, e.g., the dipeptide 83 (Scheme 13.43). 

Construction of quaternary stereocenters by enantiocontrolled oxygen to carbon acyl shift is not limited to the azlactone structure. Using the pentaphenylated planar chiral DMAP derivative 79c (Scheme 13.42) Fu and Hills achieved rearrangement of O-acylated oxindoles 84 (Scheme 13.45) and benzofuranones 85 (Scheme 13.46) with very good yields and enantiomeric excesses up to 99% [88]. 

This chapter summarizes three related and highly effective approaches to the catalytic asymmetric generation of quaternary stereocenters - organocatalytic rearrangements of O-acyl azlactones to their C-acylated isomers and analogous isomer-izations of O-acyl oxindoles and O-acyl benzofuranones. All three processes hold great promise for application in, e.g., natural product synthesis [91-93],... 

In 1970, Steglich reported that DMAP catalyzed the rearrangement of O-acylated azlactones to their C-acylated isomers (the Steglich rearrangement) [166, 167]. This process effects C-C bond formation and concomitant construction of a qua-... 

Other rearrangements have been used as well to create quaternary stereocenters of , -disubsti-tuted amino acids. The rearrangement of 0-acy-lated azlactones 16, described by Steglich in 1970... 

Chromatography) (equation 82). These complexes are used as enantioselective nucleophilic catalysts for reactions such as the rearrangements of O-acylated azlactones, oxindoles, and benzofuranones, and the kinetic resolution of secondary alcohols via acylation. X-ray crystal structures have been obtained for iV-acylated derivatives of (366), allowing for characterization of a likely intermediate along the catalytic pathway. 

Benzoyl-p-methoxyphenyl-L-alanyl chloride (or bromide) exists only momentarily, rearranging rapidly into the corresponding salt of the azlactone, which racemizes quickly. The carbobenzoxy and p-toluene-... 

One of the major problems encountered in this synthesis is the difficulty of obtaining the starting materials (either the a-aminocarbonyl compounds or their acylated derivatives). The former may be prepared by Neber rearrangement of ketoxime tosylates with a base such as ethoxide or pyridine.46 a-Acylamino carbonyl compounds can be prepared directly by the reductive acetylation of oximino ketones.28 38 Balaban and his collaborators47-60 have developed an excellent method for the synthesis of a-acylamino ketones (5). They are obtained in yields of 50-90% by the reaction of azlactones (2-aryl-5-oxazolone, 4) with aromatic hydrocarbons in the presence of aluminum chloride under Friedel-Crafts conditions the reaction may proceed either intermolecularly or intramolecularly. 

On this topic, several outstanding contributions were reported by Fu and coworkers,in which new asymmetric nucleophilic catalysts based on chiral ferrocene-type heterocycles were designed. To this end the planar-chiral PPY ferrocene complex (PPY = 4-(pyrrolidino)-pyridine (3.61) was prepared and resolved. Complex 3.61 catalysed the enantioselective rearrangement of A-acylated Azlactones to give C-acylated isomers with high yields and ee of 82-90%. The powerful effect of the chiral ferrocene scaffold was clearly evident if compared to the same reaction with the organic catalyst DMAP reported in 1970 by Steglich and Hofle where only racemic compounds were formed (Scheme 3.26). 

This reaction has been extended to the translocation of the acyl group for indole derivatives. In addition, a chiral planar DMAP derivative has been developed and applied for the enantioselective rearrangement of 0-acylated azlactone and the same catalyst recently has been used for an intermolecular reaction to form 1,3-diketones. Moreover, 3-(2,2,2-triphenyl-1 -acetoxyethyl)-4-(dimethylamino) pyridine (TADMAP) has been applied as a chiral nucleophilic catalyst to catalyze the carboxyl migration of oxazolyl, furanyl, and benzofuranyl enol carbonates with good to excellent levels of enantioselec-tivity. The rearrangement for oxazole derivatives are particularly efficient for giving chiral lactams and lactones. ... 

Selective a-addition of C4-substituted azlactones was observed in the Michael addition-[1,2]-sulfone rearrangement sequence, which proceeded with moderate to good enantioselectivity (Scheme 20) [37]. Although 5% of the y-addition product was detected in the reaction with triethylamine as a base, the use of bifunctional amino-thiourea 20 was pivotal for achieving complete site-selectivity and high enantioselectivity. 

Erdmann (see Volhard-Erdmann Cyclization) Erlenmeyer-Plochl Azlactone and Amino Acid Synthesis Eschenmoser Coupling Reaction Eschenmoser Fragmentation Eschenmoser-Claisen Rearrangement Eschenmoser-Tanabe Fragmentation Eschweiler-Clarke Reaction Etard Reaction... 

But the formation of azlactones as intermediates cannot explain all the observations made in this field. Thus it has been mentioned already that ketene racemizes AT-methyltryptophan. Carter and Stevens (1940) state that certain acyl derivatives of ir-proline and W-methyl-n-phenyl-alanine are rapidly racemized by the action of acetic anhydride in glacial acetic acid. In the same paper it is also reported that the addition of various azlactones to a solution of benzoyl-p-methoxyphenylalanine in acetic acid produces fairly rapid racemization of the acyl derivative. An azlactone can obviously not be formed from a compound such as proline, and there is no evidence that structures such as XLIII exist and even if they exist, there is no apparent reason why they should be so easily racemized. There is a possibility of the transient formation of a dipolar structure such as XLV, which is analogous to the formula proposed for sydnones (Baker and Ollis, 1946). But a more likely explanation is that both ketene and acetic anhydride can form mixed anhydrides with acylamino acids, which can then rearrange to form azlactones and acetic acid. Reference has already been made to the action of ketene on carboxylic acids to produce mixed anhydrides and similar reactions have been observed with acetic anhydride. The marked racemization of such structures is partly explained by the strongly electronegative character of the anhydride group. Such an explanation is supported by the findings... 

In the proposed mechanism, it is assumed that the azlactone I reacts with the acid II to form a mixed anhydride if the acid II can also form an azlactone, the mixed anhydride can rearrange itself either to give azlactone I and acid II, or azlactone II and acid I. The hypothesis of the mixed anhydride as the important intermediate in racemization could, of course, be used for the interpretation of all the results discussed in this section, including those for which the temporary formation of an azlactone was assumed. But the fact that acetylproline was not racemized under the conditions used by du Vigneaud indicates that the azlactone cannot be discarded as an intermediate. To what extent each of these two mechanisms operates in a given case, is a subject for further research. 

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