Y-hydroxy amides

The method is not restricted to secondary aryl alcohols and very good results were also obtained for secondary diols [39], a- and S-hydroxyalkylphosphonates [40], 2-hydroxyalkyl sulfones [41], allylic alcohols [42], S-halo alcohols [43], aromatic chlorohydrins [44], functionalized y-hydroxy amides [45], 1,2-diarylethanols [46], and primary amines [47]. Recently, the synthetic potential of this method was expanded by application of an air-stable and recyclable racemization catalyst that is applicable to alcohol DKR at room temperature [48]. The catalyst type is not limited to organometallic ruthenium compounds. Recent report indicates that the in situ racemization of amines with thiyl radicals can also be combined with enzymatic acylation of amines [49]. It is clear that, in the future, other types of catalytic racemization processes will be used together with enzymatic processes. 

Figure 18.25. Dynamic kinetic resolution of racemic y-hydroxy amides 67.

Fransson, A. B. L., Boren, L., Pamies, O., and Backvall, J. 2005. Kinetic resolution and chemoenzymatic dynamic kinetic resolution of functionalized y-hydroxy amides. J. Org. Chem., 70(1) 2582-2587. 

A similar methodology was applied to the DKR of functionalised y-hydroxy amides by using Shvo s ruthenium catalyst in combination with immobilised Pseudomonas cepacia lipase (PS-C). This enzyme tolerated both variations in the chain length and different functionahties, giving fair to high enantioselectivities, as shown in Scheme 4.19. The synthetic utility of this procedure was illustrated by the practical synthesis of the versatile intermediate y-lactone, (R)- 5-methyltetrahydrofuran-2-one. 

Scheme 4.19 DKR of functionalised y-hydroxy amides with Shvo s catalyst.

Hydroxyamino acid derivatives are interesting compoxmds with multiple applications as synthetic building blocks. Lipases have effectively acylated by different substrates such as y-hydroxy amides using AK lipase and IPA [64], 3-(hetero)aryl-3-hydrox3q>ropanoates with a variety of lipases and vinyl esters with short or long chains, such as vinyl decanoate [65-67], and sulfur heterocyclic p-hydrox)mitriles with PSL and VinOAc [68]. 

Heterocyclic compounds carrying potential hydroxyl groups are cyclic amides or vinylogs of amides. There is much physical evidence that acyclic amides exist almost entirely in the oxo form (for references see reference 6), and the apparent contradiction that ultraviolet spectral data appeared to favor the imidol formulation has now been explained on steric grounds. The value of pKr is estimated to be about 7 on the basis of pK measurements for acyclic amides. Extensive evidence, summarized in the following sections, shows that for a- and y-hydroxy heterocyclic compounds, the cyclic amide form usually predominates by a substantial factor, often ca. 10 . 

Methanolysis of 696 followed by reaction with iodine, leads to syn y-hydrox-ylation relative to the amide group. Further, deiodination and subsequent hydrolysis affords the y-hydroxy-oc-amino acid derivative 698. This interesting reaction sequence opens the way for the synthesis of hydroxy substituted constrained phenylalanines with defined stereochemistry (Scheme 7.219). 

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). 

Scheme 5 Incorporation of an /V-Hydroxy Amide and a Hydrazine into Model Dipeptides to Induced y-Turn-Like Structures 31 ...

Lactones are usually prepared by treating y-hydroxy carboxylic acids, esters, or amides with acid. Preferentially hydrochloric acid is used or however,... 

The first example of this type of a catalytic conversion is indicated in Scheme 42 [123]. This refers to, y-unsaturated esters and amides 261, which, on treatment with an excess of ammonium persulfate and a catalytic amount of diphenyl diselenide, in methanol, ethylene glycol or in water, gave the addition products 262. These, by reaction with persulfate, afforded the y-alkoxy or the y-hydroxy-a, -unsaturated derivatives 263, respectively. 

Scheme 42. Phenylselenyl Sulfate Catalyzed One-Pot Conversion of )8,f-Unsaturated Esters and Amides into the f-Alkoxy or y-Hydroxy-a,)8-Unsaturated Derivatives...

Equations (71) and (72) illustrate the use of hydroxy amides as y-lactone presursors. Prolonged heating with strong base and subsequent acidification produces (192) and (194) in almost quantitative yields. 

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 wide repertoire of cleavage reactions demonstrates the synthetic potential of the pseudoephedrine amides, providing access to chiral a-branched carboxylic acids, aldehydes, ketones or primary alcohols with recovery of the auxiliary (Scheme 2). Moreover, efficient alkylation reactions utilizing epoxides and epoxide-derived electrophiles open up a route to chiral y-lactones and y-hydroxy ketones. [7]... 

Alkylations. The alkylation of pseudoephedrine amides with epoxides is a practical method for gaining access to chiral y-lactones. Reaction of the alkylation products with alkyllithiums leads to y-hydroxy ketones. 

Opening of a, -Epoxy Esters and Amides. Treatment of aromatic a,/3-epoxyamides with samarium iodide leads to the highly stereoselective synthesis of a./S-unsaturated amides with high diastereocontrol (eq 52). If the reaction is run on a substrate that contains y-protons, then a base-promoted reaction produces the (E)-a-hydroxy-, y-unsaturated amide (eq 53). ... 

A notable, earlier contribution from Weinreb s group which has found frequent employment, is the use of aluminum amide reagents derived from A,0-dimethylhydroxylamine for ready cleavage of lactones to give stable y-hydroxy carboxyamido derivatives [61]. An associated advantage is that the N-methoxy-... 

With A5 acids (such as the C20 acids in meadowfoam oil), the 8 lactone is formed in high yield when the acid is refluxed for 3 h with perchloric acid in dichloromethane. The proportion of 8 to y lactone depends on the reaction solvent. In hexane, the ratio is 6 1 and in dichloromethane almost 40 1. The 8-lactone is much more reactive than its y isomer. It can be converted to hydroxy amides (amines), hydroxy acids (alkali), and alkoxy esters (alcohol and acid) wifli the reagents indicated in parentheses. 

With the exception of a-keto glutaric acid the acids can be identified after total hydrolysis together with the amino acids. A distinction between succinic acid and its amide is possible by reduction with NaBH4 after esterification Only the ester will be reduced to y hydroxy butyric acid which can be identified as r-butyrolactone (ref. 18). 

Zhou G J, Wang S F, Zhang Y, Zhuang Q X and Han Z W (2008) In situ preparation and continuous fiber spinning of poly(p-phenylene benzobisoxazole) composites with oligo-hydroxy-amide-functionalized multi-walled carbon nanotubes, Polymer 49 2520-2530. 

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