Hydroxy amides, preparation

Oxazolines.1 Hydroxy amides, prepared from p-hydroxy amines and acid chlorides, are converted into 2-oxazolines with the Mitsunobu reagent at 0 — 25° (equation I). 

In 1949, Comforth showed that preparation of 2,5-disubstituted oxazoles was not limited to diaryloxazoles through condensation of aldehydes (benzaldehyde, n-hept-aldehyde) with a-hydroxy-amides (lactamide). The intermediate oxazolidone 13 were converted into oxazoles 14 on warming with phosphoryl chloride. ... 

Wipf and Miller have reported side-chain oxidation of 3-hydroxy amides with the Dess-Martin periodinane, followed by immediate cyclodehydration with triphenylphosphine-iodine, which provides a versatile extension of the Robinson-Gabriel method to substituted oxazoles. Application of this method was used to prepare the oxazole fragment 10 in 55% overall yield from 3-hydroxy amide 8. 

Activated A-alkyl-O-acylhydroxamic acid derivatives 75 undergo base catalysed rearrangement to give 2-acyloxyamides 76 in good to excellent yields (50-100%) (equation 26). These precursors of 2-hydroxy amides (77) are good intermediates to prepare ethanol-amines, oxindoles and oxazolidinediones. 

The most versatile syntheses of 3-unsubstituted-2,4-oxazolidinediones involve either cyclization of a-hydroxy esters with urea or cyclization of a-hydroxy amides with a carbonate or phosgene. A third very useful approach is cyclodehydration of 0-carbamoyloxy acetic acids. Normally, this method affords 3-substituted analogues in which the 3-substitutent is derived from an isocyanate. However, examples in which an a-O-carbamoyloxy ester has been prepared via chlorosulfo-nyl isocyanate or an equivalent will also be described in this section. Extensions of these methodologies together with new approaches to 2,4-oxazolidinediones follow. Many of the analogues prepared, particularly as potential antidiabetic agents, employ a-hydroxy esters or a-hydroxy amides as precursors, which provides clear evidence of the versatility and generality of these classical approaches. A selection of recent examples will illustrate this point. 

Wuts and co-workers recently reported that the Vilsmeier reagent is superior to thionyl chloride for the cyclodehydration of primary and secondary p-hydroxy amides to prepare oxazolines, in particular, for oxazoline 18b, which is used in Taxol synthesis (Scheme 8.10). Some other examples are shown in Table 8.5 (Fig. 8.3). As expected, inversion of configuration at the alcohol bearing carbon atom is observed. Of the examples examined, serine afforded low yields due to the formation of dehydroalanine. The reaction is conveniently carried out in pyridine at room temperature. p-Chloro amides are also formed, which can be converted to the oxazoline with DBU, generally using the same mixture without isolation. The... 

The Mitsunobu reaction has also been applied successfully for the preparation of oxazolines from p-hydroxy amides. This method provides an alternative to the Burgess reagent. Some recent examples are listed in Table... 

The preparation of oxazolines from p-hydroxy amides and SOCI2 via the corresponding p-chloro amides under basic conditions is well known and has been discussed earlier. Potassium fluoride on alumina has been reported as a mild alternative to the aqueous or alcoholic bases that are commonly used. The reaction is typically carried out in acetonitrile or tetramethylene sulfone and moderate to good yields of oxazolines and oxazines can be obtained as shown in Scheme 8.29. 

In 1973 Koda el al. 122) exposed pilocarpine to aminolysis and lithium aluminum hydride reduction, and then obtained several analogs. Treatment with ammonia or with aqueous methylamine or isopropylamine at room temperature gave the hydroxy amides 64-66. Reaction of pilocarpine with ammonia at 200-210°C yielded a lactam, the pilocarpine analog 67. Similarly, the /V-methyllactam 68 was prepared by reaction with liquid methylamine at 225°C. Reduction of pilocarpine with lithium aluminum hydride (LAH) in tetrahydrofuran yielded the tetrahydrofuran analog 69. Preliminary pharmacological studies indicated interesting cholinergic activity. 

The asymmetric hydroxylation of ester enolates with N-sulfonyloxaziridines has been less fully studied. Stereoselectivities are generally modest and less is known about the factors influencing the molecular recognition. For example, (/J)-methyl 2-hydroxy-3-phenylpropionate (10) is prepared in 85.5% ee by oxidizing the lithium enolate of methyl 3-phenylpropionate with (+)-( ) in the presence of HMPA (eq 13). Like esters, the hydroxylation of prochiral amide enolates with N-sulfonyloxaziridines affords the corresponding enantiomerically enriched a-hydroxy amides. Thus treatment of amide (11) with LDA followed by addition of (+)-( ) produces a-hydroxy amide (12) in 60% ee (eq 14). Improved stereoselectivities were achieved using double stereodifferentiation, e.g., the asymmetric oxidation of a chiral enolate. For example, oxidation of the lithium enolate of (13) with (—)-(1) (the matched pair) affords the a-hydroxy amide in 88-91% de (eq 15). (+)-(Camphorsulfonyl)oxaziridine (1) mediated hydroxylation of the enolate dianion of (/J)-(14) at —100 to —78 °C in the presence of 1.6 equiv of LiCl gave an 86 14 mixture of syn/anti-(15) (eq 16). The syn product is an intermediate for the C-13 side chain of taxol. 

In some cases the resolution of the diastereomeric amides on silica gel is sufficiently large to achieve preparative separation. The preparative separation of diastereomeric hydroxy amides has proved useful in supplying quantities of enantiomerically pure lactones (eq 5). ... 

Aldol Reactions. Pseudoephedrine amide enolates have been shown to undergo highly diastereoselective aldol addition reactions, providing enantiomerically enriched p-hydroxy acids, esters, ketones, and their derivatives (Table 11). The optimized procedure for the reaction requires enolization of the pseudoephedrine amide substrate with LDA followed by transmeta-lation with 2 equiv of ZrCp2Cl2 at —78°C and addition of the aldehyde electrophile at — 105°C. It is noteworthy that the reaction did not require the addition of lithium chloride to favor product formation as is necessary in many other pseudoephedrine amide enolate alkylation reactions. The stereochemistry of the alkylation is the same as that observed with alkyl halides and the formation of the 2, i-syn aldol adduct is favored. The tendency of zirconium enolates to form syn aldol products has been previously reported. The p-hydroxy amide products obtained can be readily transformed into the corresponding acids, esters, and ketones as reported with other alkylated pseudoephedrine amides. An asymmetric aldol reaction between an (S,S)-(+)-pseudoephe-drine-based arylacetamide and paraformaldehyde has been used to prepare enantiomerically pure isoflavanones. ... 

Oxazolidinediones are generally readily prepared from amino acids and hydroxy-amides with a carbonate equivalent such as carbonyldiimidazole or diethyl carbonate itself. Isothiocyanates can also be used as starting materials for the synthesis of 2,5-oxazolidinediones (Equation 25) <2006TL3953>. 

When an isocyanide is treated with a carboxylic acid and an aldehyde or ketone, an a-acyloxy amide is prepared. This is called the Passerini reaction. A SiCl4-mediated reaction in the presence of a chiral bis-phosphoramide gives an a-hydroxy amide with good enantioselectivity. The following mechanism has been postu-... 

In Eq. (14), Yoda et al. [50] studied the preparation of optically active lactones, with three contiguous stereogenic centers, from imides with two stereogenic centers. The precursor chiral imide was easily prepared from tartaric acid. Silylation of the 2,3-diol and addition of lipophilic Grignard reagents to the imide gave the ( -hydroxy amide. The authors are investigating the stereochemical consequences of their work. 

The compound [2- C]5,5-dimethyloxazolidine-2,4-dione (10.47), used for the estimation of intracellular pH, is prepared by reaction of COCl with a dry ethanolic solution containing 2-hydroxy-2-methylpropanamide and sodium ethoxide [180,181]. This procedure involves the synthesis of diethyl carbonate in situ, which reacts in turn with the hydroxy amide [759]. 

Several natural products, for example siderophores, contain the N-hydroxy amide Y[CON(OH)] motif [138], Within a peptide backbone, this group increases the stability to enzyme degradation and induces characteristic conformational behavior [139]. In addition to the synthesis in solution of N-hydroxy amide-containing peptides (which is not trivial), a new solid-phase approach has recently been developed [140]. To explore the features of the N-hydroxy amide moiety using automated and combinatorial techniques, a method for the preparation of v /[CON(OH)] peptide ligands for MHC-I molecules has been elaborated [140], The strategy for the parallel preparation of these peptidomimetics on a solid support is illustrated in Scheme 7.9. The key step is the nucleophilic substitution reaction of resin-bound bromocarboxylic acids by O-benzylhydroxylamine, which requires several days. 

A tetraazadiol was recently prepared by first reacting chloroacetyl chloride with yV-ethylethanolamine to form a chloro hydroxy amide (Chadwick et al., 1984 Krakowiak et al., 1989d). This latter compound was reacted with N,N -dimethyl- or yV,A -diethylethylenediamine with subsequent reduction to give the tetraazadiol (Krakowiak et al., 1989d). This tetraazadiol was also obtained... 

Oxazoles. Acylation and pyrolysis of the hydroxy amides in decalin provides 2-substituted oxazoles by way of cyclodehydration and retro-Diels-Alder reaction. Imidazoles are similarly prepared from the vic-diamine. 

Wipf and Miller explored a number of reaction conditions for preparing highly functionalized oxazoles required for natural product synthesis. They introduced a mild two-step process (Scheme 1.142) wherein a p-hydroxy amide 520 is oxidized... 

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