A-Hydroxyamides

Oxazole synthesis tram aldehydes and a-hydroxyamides or cyanohydnns. 

Lithium enolates of carboxylic acids such as phenylacetic acid or of amides such as N-methyl-N-phenylvaleric acid amide 1974 are oxidized by BTSP 1949 to a-hydroxy acids, which are isolated after esterification, e.g., to 1973, or to a-hydroxyamides such as 1975 [155] (Scheme 12.43) (cf. also the formation of 3-hydroxybutyrolactam 1962). 

The pyruvaldehyde and phenylglyoxal adducts (19) with trimethyl phosphite reacted with isocyanates to give the carbamoyl-1,3,2-dioxa-phospholens (20), probably as shown. These, with hydrogen chloride, gave phosphate esters of )3-keto-a-hydroxyamides. 

SYNTHESIS OF AN a-HYDROXYAMIDE N.N-DIETHYL-2-HYDROXY-4-PHENYLBUTANAMIDE. GENERATION OF N,N-DIETHYLCARBAMOYLLITHIUM VIA LITHIUM-TELLURIUM EXCHANGE AND ITS REACTION WITH 3-PHENYLPROPANAL (Benzenebutanamide, N,N-dlethyl-a-hydroxy-)... 

Not only cyanide but also an isocyanide behaves as a nucleophile to attack a carbonyl compound or an imine that is prepared in situ from an carbonyl compound. " In these reactions, an isocyanide is a synthetic equivalent to an aminocarbonyl anion. Asymmetric version of this reaction appeared in 2003. Using a combination of Lewis acid SiCU and a Lewis base chiral bisphosphora-mide, the corresponding a-hydroxyamide is obtained in 96% yield with >98% ee (Scheme 4.23). 

Aromatic or conjugated aldehydes react in excellent yields, whereas the reaction with aliphatic aldehydes requires longer times and leads to A-hydroxyamides in lower, althongh satisfactory, yield. When both aldehyde and ketone gronps are present on the same... 

Pantothenic acid (8.48), a hydroxyamide, occurs mainly in liver, yeast, vegetables, and milk, but also in just about every other food source, as its name implies [pantos (Greek) = everywhere]. It is part of coenzyme A, the acyl-transporting enzyme of the Krebs cycle and lipid syntheses, as well as a constituent of the acyl carrier protein in the fatty-acid synthase enzyme complex. 

Punniyamurthy, T. Iqbal, J. Polyaniline Supported Cobalt(II) Salen Catalyzed Synthesis of Pyrrolidine Containing a-Hydroxyamide Core Structures as Inhibitors for HIV Proteases, Tetrahedron Lett. 1997, 38, 4463. 

A relatively small number of (A-hydroxyamide) peptides have been prepared using the step-by-step or the fragment coupling strategy in solution,l45 4648-50 or the solid-phase synthesis approach. 51 The (A-hydroxyamide) tetrapeptide H-D,L-(BzlO)Ala-Glyt t[CO-N(OBzl)]D,L-Ala-Gly-NHPh 41 has been prepared by a step-by-step procedure, 45 which has been extended to the synthesis of the terminally blocked (A-hydroxyamide) hexapeptide Aci >[CO-N(OH)]Ala- Glyi >[CO-N(OH)]Ala 2-Gly-NHPh 42 having alternate A-hydroxyamide/ amide links (Scheme 13). 461... 

Finally a fourth way to achieve asymmetric induction in the Passerini reaction is by way of a chiral catalyst, such as a Lewis acid. This approach is not trivial since in most cases the Lewis acid replaces the carboxylic acid as third component, leading to a-hydroxyamides or to other kinds of products instead of the classical adducts 7 (vide infra). After a thorough screening of combinations of Lewis acids/ chiral ligands, it was possible to select the couple 13 (Scheme 1.6), which affords clean reaction and a moderate ee with a model set of substrates [17]. Although improvements are needed in order to gain higher ees and to use efficiently sub-stoichiometric quantities of the chiral inducer, this represents the first example of an asymmetric classical Passerini reaction between three achiral components. 

When a mineral or Lewis acid replaces the carboxylic component in the Passerini reaction, the final products are usually a-hydroxyamides. Also in this case, when chiral carbonyl compounds or isocyanides are employed, the asymmetric induction is, with very few exceptions, scarce [18, 19]. For example, the pyridinium trifluoroacetate-mediated reaction of racemic cyclic ketone 14 with t-butyl isocyanide is reported to afford a single isomer [19] (Scheme 1.7). This example, together with those reported in Schemes 1.3 and 1.4, suggests that high induction may be obtained only by using rigid cyclic or polycyclic substrates. 

Another approach to a-ketoamide peptide mimetics was employed by Xu et al. [33] for the preparation of a human cytomegalovirus protease inhibitor library. In this case the oxidizable -OH group, protected as formate, belonged to the starting isocyanides. Thus, the reaction between N-acylated a-amino acids, amines, aldehydes, and isocyanides 42 afforded the a-hydroxyamides 43 in modest yields. Cleavage of the O-formyl bond was accomplished during the reaction by employing two... 

Semple elegantly extended this initial transformation to allow the rapid assembly of relatively complex a-hydroxyamide-containing molecules that traditionally would... 

Concellon, J. M. Bardales, E. The first transformation of aliphatic a,/1-epoxyamides into a-hydroxyamides. Org. Lett. 2003, 5, 4783-4785. 

Little is known about the chemistry of 4- and 5-oxazolidinones. The former are hydrolyzed by dilute acids to give a-hydroxyamides and carbonyl compounds (equation 84) they form 0-methyl derivatives (267) by the action of methyl iodide and silver oxide. 

Oxazolidinones are the products of the acid-catalyzed condensation of a-hydroxyamides with aldehydes and ketones (equation 178). Tertiary amides derived from pyruvic acid undergo intramolecular cyclization when irradiated (equation 179) (78JOC419). Treatment of the a-bromo amide (308) with sodium hydride yields inter alia the dimeric oxazolidinone (309), presumably by way of an a-lactam, which adds to the carbonyl group of a second molecule of the amide (equation 180) (80JCS(P1)2249). 

Acid derivatives including esters, amides, halides and nitriles are readily accessible. Dicyanofuroxan (72) shows in its reactions some similarities to phthalonitrile (75LA1029) it also provides a source of fused pyridazino- and oxazino-furoxans (73) and (74) via addition with hydrazine and hydroxylamine, respectively (82H(19)1063). The tetronic acid compound (75) yields a hydroxyamide (76) on aminolysis (79S977). 

A stereochemical control of the Ugi reaction can be effected with carbohydrates as chiral templates (e.g. tetrakis(O-pivaloyl)galactosylamine), which gives rise to easily separable amides. From these a variety of non-natural amino acids can be derived after acidic hydrolysis. The Passerini reaction, related to the Ugi rearrangement, gives a-hydroxyamides. A modification of this reaction using titanium tetrachloride gives a-branched amides in high yields via C-metalated imidoyl chlorides (equation 38). 

A -Acyl-oxazolidin-2-ones, as 203, are widely used in aldol reactions, however an unprecedented use of the aldol adducts for a stereoselective synthesis of trisubstituted a, 3-unsaturated amides and acids was reported. The yy -aldol adduct 204 underwent clean elimination upon treatment with KHMDS and afforded the E -olefin 205 with a 97% ds. The reaction was wide in scope but with a loss in selectivity using a,P-unsaturated or chiral aldehydes <05OBC2976>. This synthetic approach found immediate application in the synthesis of semiplenamide C 206 <05TL5547>. Oxazolidin-2,4-diones 207, obtained from cyanohydrins, can be easily converted into the corresponding a-hydroxyamides 208 in a reaction that can be accelerated by microwaves <05T7247>. 

Scheme 7.35 Synthesis of a hydroxyamide by using the P-HOBt active ester-forming methodology.

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