Optically active N-protected a-amino

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... 

Shibata and Tom used this strategy for a highly enantioselective mono-fluoromethylation by an asymmetric Mannich reaction using 1-fluorobi-s(phenylsulfonyl)methane (FBSM) with quinidine-derived catalyst 49c and subsequent removal of the sulfonyl group by treatment with magnesium powder (99% enantiomeric excess). Palomo and coworkers used sulfonyl acetonitrile as a synthetic equivalent of acetonitrile and obtained the optically active p-aminonitriles 97 (76% enantiomeric excess). Bernard , Ricci, and coworkers also introduced the same strategy to synthesise N-protected p -amino acid esters 98 (R = Ph, 92% enantiomeric excess) and a-alkylidene-p-aminoesters 99 (R = Ph, 91% enantiomeric excess) by an asymmetric Mannich reaction of sulfonylacetate followed by the subsequent reductive removal of the sulfonyl moiety and olefination with formaldehyde, respectively (Scheme 16.32). ... 

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. 

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]. 

Addition of nucleophiles to electrophilic glycine templates has served as an excellent means of synthesis of a-amino acid derivatives [2c, 4—6]. In particular, imines derived from a-ethyl glyoxylate are excellent electrophiles for stereoselective construction of optically active molecules [32], This research and retrosyn-thetic analysis led us to believe that amine-catalyzed asymmetric Mannich-type additions of unmodified ketones to glyoxylate derived imines would be an attractive route for synthesis of y-keto-ce-amino acid derivatives [33], Initially, L-proline-catalyzed direct asymmetric Mannich reaction with acetone and N-PMP-protected a-ethyl glyoxylate was examined in different solvents. The Mannich-type reaction was effective in all solvents tested and the corresponding amino acid derivative was isolated in excellent yield and enantioselectivity (ee >95 %). Direct asymmetric Mannich-type additions with other ketones afford Mannich adducts in good yield and excellent regio-, diastereo- and enantioselectivity (Eq. 8). 

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

Acid anhydrides in the presence of basic catalysts can be used instead of acyl chlorides in acylation reactions of thiols.Mixed anhydrides of N-protected amino acids and ethyl carbonate yield the corresponding S-f-butyl thiocarboxylic esters, which are useful reagents for peptide syntheses (equation 22). Acylation of thiols with ketenes (equation 23) is a method of long standing. In many cases the yields are nearly quantitative. Functionalities such as acetamino groups or carbon-carbon double bonds in the thiol are not attacked under the mild reaction conditions and optically active thiol esters are obtained without racemization. 3 ... 

---