Optically active N-protected a-amino aldehydes

J. Jurczak and A. Golfbiowski, Optically active N-protected a-amino aldehydes in organic synthesis, Chem. Rev. 89 149 (1989). 

In conclusion, the organocatalytic asymmetric a-amination of aldehydes and ketones using proline as catalyst is a new and attractive access to optically active N-protected a-amino aldehydes and ketones and related derivatives, e.g. a-amino acid esters. 

J. Jurczak, A. Golebiowski, Optically Active N-Protected a-Amino Aldehydes in Organic Synthesis, Chem. Rev. 1989, 89, 149-164. 

DMP is especially useful for the oxidation of the optically active, epimerization-sensitive substrates without loss of enantiomeric purity [1224,1241,1242], In a typical example, DMP was found to be a superior oxidant for the efficient, epimerization-free synthesis of optically active N-protected a-amino aldehydes 879 from the corresponding N-protected 3-amino alcohols 878 (Scheme 3.353) [1224]. In contrast, the Swern oxidation of amino alcohols 878 afforded products 879 of only 50-68% ee. 

Jurczak, J. and Golebiowski, A., Optically active N-protected alpha-amino aldehydes in organic synthesis. Ghent. Rev. 1989,89 (1), 149-164. 

As mentioned in Section 10.6.2, synthesis of 1-hydroxyethylene peptides can be initiated by adding a ferf-butoxycarbonyl N-protected a-amino aldehyde to an optically active Grignard reagent (Scheme 7)J11-13 This reaction affords a diastereomeric mixture of the C4 epimers of the hydroxy ether in good yields. In most cases the mixture is enriched in the 45-epimer and the epimers are readily separable. The yields and the ratios of the resulting 45- and 4R-epimers obtained from several examples of this reaction are summarized in Table 1. When this reaction was attempted with the aldehyde prepared from Aa,Ae-bis-tert-butoxycarbonyl-protected Lys, the desired product was not obtained. The anion of the Lys Ne-tert-butoxy-carbonylamino group probably reacts with the aldehyde to form a cyclic aminol that does not... 

In conclusion, doubly protected a-amino aldehydes are extremely useful optically active building blocks. The benzyl groups are readily removed via hydrogenolysis using Pd-black. The chiral center exerts an unusually pronounced directing effect on the aldehyde function. This is likely to be the case not only for C=0 functions, but also for C=N and C=C functionalities as well. 

This route has been widely exploited because of the availability of a-amino azomethine compoimds from natural (S)-a-amino acids, through the corresponding a-amino aldehydes, which are configurationally stable provided that the amino function is suitably protected. Moreover, some a-amino acids are available with the R configuration and a number of enzymatic and chemical transformations have been described for the preparation of optically active unnatural a-amino acids. Overall, the route suffers from the additional steps required for protection/deprotection of the amino function and, in the case of hydrazones and nitrones, cleavage of the N - N or N - O bond. 

N-Protected optically active a-amino aldehydes in synthesis of heterocycles 89CRV149. 

Several transformations of 6 and 7 were also conducted successfully [6, 7]. For example, oxidation of the aldehyde group of the N-protected amino aldehydes 7 and subsequent standard transformations lead to non-proteinogenic optically active a-amino acid esters [7]. 

Swern oxidation is a key step in the preparation of N-protected amino aldehydes. The N-protected amino aldehyde function is a key feature of intermediates en route to reduced-form peptides containing a CH2NH bond, e.g. (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid (statine), and derivatives thereof, e.g. (3S,4S)-4-amino-5-cyclohexyl-3-hydroxypentanoic acid (cyclostatine), which, in turn, is an important intermediate for inhibitors of acidic protease such as renin. This process is accompanied by little racemization and gives products with excellent optical activities in excellent yields [1365]. 

Duthaler and co vorkers used carbohydrate-titanium complexes for synthesis of optically active syn-/i-hydroxy-a-amino acids [51]. These syn-a-aminoaldols vere obtained in moderate yield and excellent syn diaster-eoselectivity, as shosvn in Table 2.25. Transmetalation of the lithium enolate of glycine ester derivative 145 svith chiral titanium complex 146 provided a titanium enolate svhich upon reaction svith a svide variety of aldehydes provided syn-j5-hydroxy-a-amino esters 148. Subsequent hydrolysis and N-protection gave a-aminoaldols 149. 

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