Amino aldehydes, asymmetric

The /J-amino aldehyde 1. readily available from aspartic acid, is configurationally very stable. No epimerization of the stereocenter is observed upon addition of Grignard Or cuprate reagents and the transformations display relatively high levels of 1,3-asymmetric induction73. This C-3-directing effect is superimposed upon the 1,2-directing effects of the C-2-substituents (Rl). 

Double asymmetric induction operates when the azomethine compound is derived from a chiral a-amino aldehyde and a chiral amine, e.g., the sulfin-imine 144 [70]. In this case, the R configuration at the sulfur of the chiral auxihary, N-tert-butanesulfinamide, matched with the S configuration of the starting a-amino aldehyde, allowing complete stereocontrol to be achieved in the preparation of the diamine derivatives 145 by the addition of trifluo-romethyl anion, which was formed from trifluoromethyltrimethylsilane in the presence of tetramethylammonium fluoride (Scheme 23). The substituents at both nitrogen atoms were easily removed by routine procedures see, for example, the preparation of the free diamine 146. On the other hand, a lower diastereoselectivity (dr 80 20) was observed in one reaction carried out on the imine derived from (it)-aldehyde and (it)-sulfinamide. 

Metal-catalyzed asymmetric addition of dialkyl phosphites to aldehydes (Pudovik reaction) has been extensively developed since the initial reports in 1993 by Shibuya. Scheme 5-25 illustrates the use of TiCh to promote diastereoselective addition of diethyl phosphite to an a-amino aldehyde. 

This imide system can also be used for the asymmetric synthesis of optically pure a,a-disubstituted amino aldehydes, which can be used in many synthetic applications.31 These optically active a-amino aldehydes were originally obtained from naturally occurring amino acids, which limited their availability. Thus, Wenglowsky and Hegedus32 reported a more practical route to a-amino aldehydes via an oxazolidinone method. As shown in Scheme 2 20, chiral diphenyl oxazolidinone 26 is first converted to allylic oxazolidinone 27 subsequent ozonolysis and imine formation lead to compound 28, which is ready for the a-alkylation using the oxazolidinone method. The results are shown in Table 2-6. 

Since a-branched aldehydes gave rather higher asymmetric induction (Scheme 6.166), Nagasawa et al. extended the biphasic strategy to the diastereoselective Henry reaction of nitromethane with enantiomerically pure (S)-configured N,N -dibenzyl protected a-amino aldehydes and a-hydroxy aldehydes protected as silyl ethers. The screening reaction (Scheme 6.169) demonstrated a match/mismatch... 

Jurczak, A. Golpbiowski, and J. Raczko, High-pressure [4+2]cycloaddition of 1-methoxybuta 1,3-diene to a-amino aldehydes. Influence of N-protecting groups on asymmetric induction Tetrahedron Lett. 29 5975 (1988). 

As indicated in Scheme 14, introduction of the rp[CH(CN)NH] peptide bond surrogate into pseudopeptides 28 is carried out via a modified asymmetric Strecker synthesis by the Lewis acid catalyzed reaction of N -protected a-amino aldehydes 26 with a-amino esters 27.11791... 

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. 

A novel approach to the asymmetric synthesis of epoxides, allylic alcohols, a-amino ketones, and a-amino aldehydes from carbonyl compounds through a,/i-epoxy sulfoxides using the optically active p-tolylsulfmyl group to induce chirality./. Org. Chem. 1989, 54, 3130-3136. 

Hertweck, C. Boland, W. Asymmetric a-chloroallylboration of amino aldehydes a novel and highly versatile route to D- and L-erythro-sphingoid bases. /. Org. Chem. 1999, 64, 4426-4430. 

The corresponding /i-amino aldehydes are reduced in situ and the corresponding amino alcohols are isolated in good yield with up to >99 % ee. The Mannich reactions proceed with excellent chemoselectivity and inline formation occurs with the acceptor aldehyde at a faster rate than C-C bond-formation. Moreover, the one-pot three-component direct asymmetric cross-Mannich reaction enables aliphatic aldehydes to serve as acceptors. The absolute stereochemistry of the reaction was determined by synthesis and reveled that L-proline provides syn /i-amino aldehydes with (S) stereochemistry of the amino group. In addition, the proline-catalyzed direct asymmetric Mannich-type reaction has been connected to one-pot tandem cyanation and allylation reaction in THF and aqueous media affording functional a-amino acid derivatives [39, 42]. 

Thayumanavan, R. Tanaka, F. Barbas, C. F., Ill Direct organocatalytic asymmetric aldol reactions of amino aldehydes Expedient syntheses of highly enantiomerically enriched awfi-hydroxy-amino acids, Org. Lett. 2004, 6, 3541-3544. 

The use of Al(III) complexes as catalysts in Lewis acid mediated reactions has been known for years. However, recent years have witnessed interesting developments in this area with the use of ingeiuously designed neutral tri-coordinate Al(lll) chelates. Representative examples involving such chelates as catalysts include (1) asymmetric acyl halide-aldehyde cyclocondensations, " (2) asymmetric Meerwein-Schmidt-Ponndorf-Verley reduction of prochiral ketones, (3) aldol transfer reactions and (4) asymmetric rearrangement of a-amino aldehydes to access optically active a-hydroxy ketones. It is important to point out that, in most cases, the use of a chelating ligand appears critical for effective catalytic activity and enantioselectivity. 

The same group further developed the asymmetric aldol reaction of A -methoxy-A -methyl-a-isocyanoacetamide (a-isocyano Weinreb amide) with aldehydes (Sch. 25). The reaction of the Weinreb amide 96 with acetaldehyde in the presence of 86c Au(I) catalyst gives the optically active tram-oxazoline 98 (E = CON(Me)OMe R = Me) with high diastereo- and enantioselectivities similar to those of 95 [49], The oxazoline can be transformed into A,0-protected /3-hydroxy-a-amino aldehydes or ketones. 

A chelation-controlled mechanism was discussed in the asymmetric hetero-Diels-Alder reaction of a-alkoxy aldehydes and A-protected amino aldehydes with Brassard s diene mediated by Eu(hfc)3 (eq. (9) BOC = r-butoxycarbonyl) [107]. 

The asymmetric synthesis of enantiomerically pure (R)- or (S)-a-amino aldehyde acetals 2 was achieved in essentially two steps formation of imines of simple ot-oxo aldehyde acetals with (R)- or (S)-a-phenylethylamine and subsequent catalytic reduction21. 

Asymmetric 1,4-diamino-2,3-diols. (S)-N-Cbz-amino aldehydes 2 undergo pina-eol homoeoupling in the presence of 1 to afford (1S,2R,3R,4S)-1,4 bis(Cbz-amino)-2,3-diols (3) in good yield and high diastcreosclcctivity. 

Bpgevig A, Juhl K, Kumaragurubaran N, Zhuang W, Jprgensen KA (2002) Direct organo-catalytic asymmetric a-amination of aldehydes - a simple approach to optically active a-amino aldehydes, a-amino alcohols, and a-amlno acids. Angew Chem Int Ed 41 1790-1793... 

Scheme 5.7 Asymmetric cross-aldol reaction of a-amino aldehydes.

Almost inevitably, a method to eany out a proline-eatalysed, asymmetric cross-aldol reaction was shortly after described by Tanaka and Barbas et al. The reaction of the protected a-amino aldehyde 8 with branched aldehyde 9 gave access to y-branched p-hydro gr-a-amino aldehyde 10, which was further used to generate the respective amino acid derivative 11 (Scheme 5.7). The surrounding study showed that the roles of the individual aldehydes as donor or acceptor were invertible, depending on whether branched or nonbranched aldehydes were applied. When a-nonbranched aldehydes were... 

To facilitate the use of p-amino-aldehydes or -alcohols, obtained through asymmetric Mannich reactions, List et al. provided a procedure to use N-Boc-protected, preformed imines (21, 22) (Scheme 5.13a). While this method requires the formation of the imines, it provides products that can be deprotected under mild conditions, as compared to the widely used and robust PMB-protection in these reactions. Even acetaldehyde is applicable as aldehyde source (Scheme 5.13b). The p-amino-aldehydes (23, 24) obtained from this transformation are extremely valuable building blocks in organic synthesis, making this discovery one of the most useful applications of proline catalysis to date. 

Erase et al. later added ot,ot-disubstituted aldehydes (Scheme 5.17) to the scope of the asymmetric ot-amination addition, thereby forming config-urationally-stable a-amino aldehydes (27). ... 

In 2003, the groups headed by Hayashi [80], Barbas [81], and Cordova [82] simultaneously extended the scope of this asymmetric MCR using aldehyde donors in the presence of chiral pyrrolidine-based catalysts for the so-called enantioselective cross-Mannich reaction (Scheme 16.39). This efficient combination of two different aldehydes has led to a highly stereoselective synthesis of 3-amino aldehydes and y-amino alcohols. Recently, chiral ionic liquids have been efficiently used as catalysts for similar asymmetric Mannich reactions [83]. 

We have focused our attention on the solid phase synthesis of such compounds and described our results here. Alternative routes for the preparation of peptide aldehydes and side-chain protected peptide aldehydes in solid phase synthesis are described. Three new linkers that are stable tmder classical Fmoc or Boc strategies have been developed to obtain the peptide aldehyde from the solid support. One of these linkers was conceptualized on the basis of the Weinreb amide (49) and the other on the basis of phenolic esters (50). Both strategies required the reduction with hydrides of the peptide-linker-resin to release the peptidic aldehydic function. The use of these two different approaches was demonstrated by the synthesis of N-protected a-amino-aldehydes and peptide aldehydes, llie third approach used the ozonolysis reaction for the generation of the desired aldehyde. This concept requires a linker incorporating a double bond in the a-position of the asymmetric carbon of the C-terminal residue that will be cleaved by ozone to produce the carbonyl function. 

On the other hand, diaryl prolinol silyl ethers have been applied as orga-nocatalysts for the asymmetric Mannich reaction of acetaldehyde with N-benzoyl-, iV-Boc- and iV-Ts-imines in the presence of para-aiirobtnzoic acid in THF. The generated (3-amino aldehyde products were isolated in good to high yields and excellent enantioselectivities (95-98% ee) after conversion into the corresponding alcohols by reduction with L1A1H4 (Scheme 3.10). 

In addition, Erase et al. have studied the thermal elfects in the L-proline-catalysed asymmetric a-amination of disubstituted aldehydes with azodi-carboxylates, demonstrating that this reaction was accelerated under micro-wave conditions at 60 Compared to the results previously obtained at room temperature, both the yield and the enantioselectivity could be significantly increased and the reaction time considerably reduced. As shown in Scheme 5.15, this improved protocol allowed the fast and efficient synthesis of chiral a,a-disubstituted amino aldehydes with enantioselectivities of up to 90% ee, providing the best results for the a-amination of a-branched aldehydes to date. Significantly, the amination of branched aldehydes is one of the few organocatalytic reactions where good to moderate levels of enantioselection can be achieved at high temperatures (60-70 °C). 

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