A-hydroxy amides

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. ... 

When an a-hydroxy amide is treated with Br2 in aqueous NaOH under Hofmann rearrangement conditions, loss of C02 occurs and a chain-shortened aldehyde is formed. Propose a mechanism. 

Racemic a-amino amides and a-hydroxy amides have been hydrolyzed enantio-selectively by amidases. Both L-selective and o-selective amidases are known. For example, a purified L-selective amidase from Ochrobactrum anthropi combines a very broad substrate specificity with a high enantioselectivity on a-hydrogen and a,a-disubstituted a-amino acid amides, a-hydroxyacid amides, and a-N-hydroxya-mino acid amides [102]. A racemase (a-amino-e-caprolactam racemase, EC 5.1.1.15) converts the o-aminopeptidase-catalyzed hydrolysis of a-amino acid amides into a DKR (Figure 6.38) [103]. 

Treatment of D-glucoascorbic acid (XV) with diazomethane gives a 2,3-dimethyl derivative (LXXIX) and this upon repeated treatment with silver oxide and methyl iodide yields 2,3,5,6,7-pentamethyl-D-glucoascorbic acid (LXXX). Ozonization of the latter followed by hydrolysis gives oxalic acid and 3,4,5-trimethyI-D-arabonic acid (LXXXI). This acid was shown to possess a free hydroxyl group at C2 by reason of the fact that the amide of LXXXI gives a positive Weerman reaction for a-hydroxy amides, i.e., when the amide is treated with sodium hypochlorite, sodium isocyanate is produced, the latter being identified by... 

N. Kambe, T. Inoue, and N. Sonoda 154 SYNTHESIS OF AN a-HYDROXY-AMIDE N.N-DIETHYL-2-HYDROXY-4-PHENYLBUTANAMIDE. GENERATION OF N.N-DIETHYL-CARBAMOYLLITHIUM VIA LITHIUM-TELLURIUM EXCHANGE AND ITS REACTION WITH 3-PHENYLPROPANAL... 

By analogy with the synthesis of a-hydroxy acids one can envisage a one-pot synthesis of a-hydroxy amides from aldehydes via hydrocyanation and in situ NHase-catalyzed hydrolysis to the amide. Since enantioselective NHases are very rare, the enantioselectivity should be derived from HnL-catalyzed hydrocyanation. The second step has been described for the Rhodococcus erythropolis NHase-catalyzed hydration of (R)-mandelonitrile to give the (R)-amide with retention of enantiopurity [43]. 

A-hydroxy hexapeptide 135, with alternating A-hydroxy amide units, introduced by Akiyama and coworkers ", is an additional fragment for introducing chirality to ferriox-... 

Heating a-hydroxy amides 135 in xylene with the cumulated phosphoms ylide 134 gives the 2(3//)-oxazolones 140. The reaction proceeds via an addition-cyclization-intermolecular-Wittig olefination sequence, which imphes three different types of phosphorus ylides, 134,136, and 137, respectively, of increasing ylide activity (Fig. 5.33 Table 5.7, Figs. 5.34, 5.35). 

TABLE 5.7. 2(3//)-OXAZOLONES FROM a-HYDROXY AMIDES AND PHOSPHORUS YLIDE 134 ... 

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. 

Masakatsu Shibasaki of the University of Tokyo has developed effective procedures for the epoxidation of a,P-unsaturated amides with high . He has now reported (Angew. Chem. Int. Ed. 2004, 43y 317) reagents for the selective reduction of the epoxy amide 9 to either the p-hydroxy amide 10 or the a-hydroxy amide 11. 

Marraud et alJ31 demonstrated that incorporation of an A-hydroxy amide into model dipeptides induced a y-turn-like structure 4, as do hydrazino peptides 5 (Scheme 5). 

Optically active a -hydroxy acids The enolate of the amide (2) derived from phenylacetic acid and L-prolinol (10,332) is oxidized by 2-(phenylsulfonyl)-3-phen-yloxaziridine (1) to give optically active a-hydroxy amides (3). Significantly, the configuration of 3 depends upon the base. The lithio enolate (LDA) is converted to the (S)-isomer in >95% de, whereas the sodio enolate, generated with NaN[Si(CH3)3]2, is converted into the (R)-isomer in 93% de. 

Norephedrine, 200 Organoaluminum reagents, 202 Organotitanium reagents, 213 9-(Phenylseleno)-9-borabicyclo-[3.3.1]nonane, 245 Tin(II) chloride, 298 Titanium(IV) chloride, 304 Trityllithium, 338 Trityl perchlorate, 339 Zinc chloride, 349 By other reactions Chloromethyl ethyl ether, 75 Dibutyltin oxide, 95 Samarium(II) iodide, 270 Tributyltin hydride, 316 Hydroxy amides a-Hydroxy amides... 

Conformations of primary, secondary, and tertiary amides of (R,R)-tartaric acid, both symmetrically and asymmetrically substituted, have been studied ciys-tallographically [22, 24, 29, 30-40] Moreover, ab initio studies up to MP2 / 6-31G //RHF/6-31G level [41] for both the diamide and N,N,N ,N -tctramcthyl-diamide of (/ ,/ [-tartaric acid have been carried out [20, 22]. X-ray results have shown that primary and secondary amides of (R,R [-tartaric acid tend to adopt a conformation with the extended carbon chain - the Taa structure. In this Taa conformation both the a-hydroxy-amide moieties form planes and the structure gains stabilization from hydrogen bonding between donors, the NH, and acceptors, the proximal OH groups. Moreover, the Taa structure is favorably stabilized by the attraction of antiparallel local dipoles formed along distal C H and Csp2=0 bonds [18, 21, 22],... 

In the case of tertiary amides, the planar arrangement of a-hydroxy-amide moieties is not favored due to bulky substituents. The repulsion between the N-alkyl substituents and the hydrogen atom attached to the distal Csp3 atom destabilizes the T structures of tertiary amides of (R,R [-tartaric acid [18,21,22]. As a result, the N,N,N ,N -tetramethyldiamide of (R,R [-tartaric acid is found in crystals in the G-p+p+ conformation, in which the main carbon chain is bent and the... 

Details of the oxidation and rearrangement of tabersonine (126) to (+)-14,15-dehydrovincamine (127) and (+)-14,15-dehydro-16-cp/-vincamine (128), which were previously recorded only in the patent literature, have now been published.90 A minor product in this sequence of reactions was formulated as (129), since hydrogenation, hydrolysis, and decarboxylation afford a hydroxy-amide (130), which can be reduced to rhazinilam (131) (Scheme 18). The reaction of 14,15-dehydrovincamine (127) with iodine and potassium iodate results in the formation of a dehydro-derivative (not isolated), followed by closure of the tetrahydrofuran ring. The product is the iodo-compound (132), which, as an iodo-enamine, loses its iodine when treated with acid, with formation of the alkaloid criocerine (133).90... 

Condensation of an a-hydroxy amide with chloromethyldimethylchlorosilane leads to a pentacoordinated silicon species that isomerizes upon distillation into the corresponding oxazasilacyclohexanone.78 See also Section II.B. 

Schultz and co-workers have, however, successfully extended this basic approach to obtain antibodies that act as bona fide catalysts. Using phosphonate 141 as a hapten, they generated an antibody that accelerates the reduction of keto amides (142) by sodium cyanoborohydride at pH 5.0 with multiple turnovers.120 In one case, the product a-hydroxy amide 143S was obtained with greater than... 

A related reaction is the addition of isonitriles 75 to aldehydes 1 (the Passerini reaction). Denmark has demonstrated that SiCU, upon activation by a chiral Lewis base, which increased the Lewis acidity of the silicon (vide supra Scheme 7.14), can mediate this reaction to produce a-hydroxy amides 77 after aqueous work-up (Scheme 7.16). Phosphoramide 60 was employed as the chiral Lewis-basic catalyst [74]. Modification of the procedure for hydrolysis of 76 gives rise to the corresponding methyl ester (rather than the amide 77) [74]. (For experimental details see Chapter 14.5.5). 

This reaction can be also performed asymmetrically, when it is applied to a, 3-unsaturated amide derivatives bearing a chiral auxiliary [299]. Among several common auxiliaries, the frans-2,5-dinaphthylpyrrolidine unit proved to be optimal, giving a-hydroxy amides in 62-87% yield and diastereomeric ratios ranging from 78 22 up to 97 3 for the compound with (R)-configuration. 

Hydration of cyanohydrins.1 The cyanohydrins derived from aldehydes undergo hydration when treated with borax in water at 80° to give a-hydroxy amides in 65-85% yield. In some cases addition of a trace of KCN can increase the yield. 

Hofmann rearrangement (the mechanism is shown in Section 24.6) of an a-hydroxy amide produces a carbinolamine intermediate that expels ammonia to give an aldehyde. 

During model studies directed towards the synthesis of the Mycalamides, Hoffmann and co-workers 41 discovered a reduction reaction which accompanied the deprotection of an /V-SEM derivative [Scheme 8.152]. Treatment of 152 1 with TT1AF in DMPU at 45 returned the a-hydroxy amide 152 2 as a 3 1 mixture of diastereoisomers. The authors speculate that the reduction reaction was caused by a reagent of the type N-CH2-0 or F-CH2-0 derived from cleavage of the SEM group. The reduction was a welcome and useful surprise since the nascent hydroxyl group is present in the natural product. 

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