P-Hydroxy-y-amino acids

Kambourakis S, Rozzell JD. Ketoreductases in the synthesis of valuable chiral intermediates Application in the synthesis of a-hydroxy p-amino and p-hydroxy y-amino acids. Tetrahedron 2004 60 663-669. 

Jackson and coworkers have used a new approach to the synthesis of P-hydroxy-a-amino acids using (arylthio)nitrooxiranes. D-Isopropylideneglyceraldehyde is converted into the corresponding 1-arylthio-l-nitroalkene, which is a key material for stereoselective synthesis of P,y-dihydroxyamino acids (Scheme 4.6). The key step is stereoselective nucleophilic epoxida-tion of the 1-arylthio-l-nitroalkene. Syn and anti epoxides are selectively obtained by appropriate choice of epoxidation reagent.51... 

Steinreiber J, Fesko K et al (2007) Synthesis of y-halogenated and long-chain P-hydroxy-a-amino acids and 2-amino-l,3-diols using threonine aldolases. Tetrahedron 63 8088-8093... 

Makino, K., Goto, T., Hiroki, Y., Hamada, Y. Stereoselective synthesis of anti-P-hydroxy-a-amino acids through dynamic kinetic resolution. Angew. Chem., Int. Ed. Engl. 2004,43, 882-884. 

Ring-opening of aziridinecarboxylic acids has been used in the conversion of threonine into /Areo-3-methylcysteine and in the synthesis of p-alkoxy-a-amino-acids. Improved methods have appeared for the synthesis of iV-(phosphono-acetyl)-amino-acids and for the preparation of y-esters of glutamic acid and (3-esters of aspartic acid. The protected P-hydroxy-a-amino-acids (278) are converted into a-fluoro-P-amino-acids (279) with DAST (Scheme 137). ... 

In addition, 1,3-diols can be converted to boron analogs of 1,3-dioxanes. Among a number of other compound types which have converted to boronates are P- and y-amino alcohols and a- and j8-hydroxy carboxylic acids. 

Carboxylic acid esters. A mixture of acetic acid, 1.5 eqs. (trimethylsilyl)ethoxyacety-lene, and a little yellow HgO in 1,2-dichloroethane treated with benzyl alcohol and a little DMAP, and stirred at 40° for 25 min - benzyl acetate. Y 83%. This method is simple and suitable for compds. containing acid- and/or moisture-sensitive groups. The by-product, ethyl (trimethylsilyl)acetate, is volatile and easily removed. F.e. and with a little p-TsOH, also lactones and lactams (from the respective hydroxy- and amino-acids), and dipeptides, s. Y. Kita et al.. Synthesis 1989, 334-7. 

Our explorative chemistry approach was considerably facilitated by the fact that a variety of a-, p-, y-amino acid derivatives is commercially available. And the other starting material - the 5-hydroxy-pyrazole-3-carboxylic acids - for the amide coupling reaction delivering our target molecules was accessible by only one synthetic step (Scheme 23.2) [2]. 

The a,p-double bond in amino acid derivatives and peptides represents, in addition to the amino and carboxy groups, the introduction of a third highly reactive function into the molecule. It is therefore pertinent in a discussion of the a,P-dehydroamino acids to devote some attention to their primary addition products, such as derivatives of a-mercapto- and a-hydroxy-a-amino acids. Further topics relevant in this context are their relationship to P-hydroxy- and P-mercapto-a-amino acid derivatives (elimination-addition sequence), as well as syntheses and reactions of pyruvoylamino acids, which result from the hydrolysis of dehydropeptides and can possibly serve as precursors of the latter by condensation with amino acid amides. On the other hand, p,y- and y S-dehydroamino acids will be excluded from the scope of this discussion. The isolated double bonds of these compounds undergo the normal olefin reactions and display no unusual characteristics. 

This chapter deals mainly with the 1,3-dipolar cycloaddition reactions of three 1,3-dipoles azomethine ylides, nitrile oxides, and nitrones. These three have been relatively well investigated, and examples of external reagent-mediated stereocontrolled cycloadditions of other 1,3-dipoles are quite limited. Both nitrile oxides and nitrones are 1,3-dipoles whose cycloaddition reactions with alkene dipolarophiles produce 2-isoxazolines and isoxazolidines, their dihydro derivatives. These two heterocycles have long been used as intermediates in a variety of synthetic applications because their rich functionality. When subjected to reductive cleavage of the N—O bonds of these heterocycles, for example, important building blocks such as p-hydroxy ketones (aldols), a,p-unsaturated ketones, y-amino alcohols, and so on are produced (7-12). Stereocontrolled and/or enantiocontrolled cycloadditions of nitrones are the most widely developed (6,13). Examples of enantioselective Lewis acid catalyzed 1,3-dipolar cycloadditions are summarized by J0rgensen in Chapter 12 of this book, and will not be discussed further here. 

Since the allyl function represents a latent carboxy unit, diastereomerically pure homoallylic alcohols syn-21 or anti-21, obtained by condensation of allylic metals 26 with chiral a-amino aldehydes or acetals (Scheme 6), have been used to prepare the corresponding y-amino-p-hydroxy acids (Scheme 7). 

Pure homoallylic alcohols are converted into y-amino-p-hydroxy acids by protection as the TBDMS ether or A(0-acetonide followed by degradative oxidation of the terminal alkene using a catalytic amount of ruthenium(III) chloride and sodium periodate (Scheme... 

The use of the aldol condensation to synthesize y-amino-p-hydroxy acids suffers from several drawbacks, such as possible racemization either of the initial carboxy group during its transformation to the a-amino aldehyde, or during any subsequent manipulations of the sensitive CHO moiety. An alternative route involves the direct activation of the carboxy group of the N-protected a-amino acids 30 followed by alkylation with enolates 17 to produce the corresponding p-oxo esters 31.[36 521 The P-oxo esters can be selectively reduced under various conditions to produce diastereomeric mixtures of the target compounds 18 but with retention of the chirality of the initial a-amino acid (Scheme 8). 

Scheme 9 Tetramic Acid Route to y-Amino-p-hydroxy Acids153 57 ...

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