Hydroxy acids Tributyltin hydride

Intramolecular substitutions offer a convenient and stereoselective method for the introduction of amino functionalities. A strategy for the preparation of vicinal m-hydroxy amino moieties entails the halocy-clisation of allylic trichloroacetimidates.77 Conversion of the hydroxyl of unsaturated sugar derivatives into a trichloroacetimidate, followed by Ar-bromosucciniinide (NBS) or JV-iodosuccinimide (NIS) mediated intramolecular cyclisation, gives bromo- and iodo-oxazoline derivatives (Scheme 3.13a). The oxazoline can be hydrolysed with mild acid to unmask the amino functionality, and the halogen can be removed by treatment with tributyltin hydride. 

This fragmentation step was earlier reported in 1997 by Easton and coworkers in the tributyltin hydride-mediated conversion of nitrate esters of -hydroxy-a-amino acids to glycyl radicals (Scheme 19a) [25]. Attack of the... 

The halolactonization reaction can be utilized to synthesize enantiomerically pure ot-hydroxy acids. In fact, cyclization of the (S)-/V-(a,/ii-unsaturated acyl)proline 1, prepared by the condensation of ( S )-pi oline and ( )-2-methyl-2-butenoyl chloride in 86 % yield, proceeds stereoselec-tively. The halolactonization, carried out by stirring the unsaturated amide with an equivalent of jY-bromosuccinimide in dimethylformamide for 20 hours, provides the bromolactone 2 in 84% yield and a diastereomeric ratio of 94.5 5.5. Debromination with tributyltin hydride in benzene affords the crude lactone 3 which is hydrolyzed with 36% hydrochloric acid at reflux to give (R)-2-hydroxy-2-methylbutanoic acid (4)1,2,4b. 

A related route to a-hydroxyalkanoic acids is illustrated by the synthesis of / (-)-2-hydroxy-2-methylbutyric acid (407) from (5)(-)-tigloylproline (403). The initial step of halolactonization of 403 with N-bromosuccini-mide in DMF proceeds stereospecifically to give 405 (94.5%) and 407 (5.5%). Debromination of 405 to 409 with tributyltin hydride in benzene, followed by hydrolysis, gave the desired compound 410 (77TL1005 79T2337, 79T2345). 

A potentially attractive route to 0-roethylnucleosldes is based on the use of the [[2-(methylthio)phenyl]thio]methyl group for the protection of primary and secondary hydroxy functions.This protecting group is stable under both acidic and basic conditions and functions as a latent 0-methyl group. For example, 5 -0-[[[2-(methylthio)phenyl]thio]methyl]-2 -deoxythymldine (105) is readily converted into 5 -0-methylthymidine in 68Z yield by treatment with tributyltin hydride and azobls(isobutyronitrile). Alternatively, deprotection to give thymidine can be accomplished using mercury (II) chloride in aqueous acetonitrile. 

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