Aldehydes, amino stereoselectivity

SCHEME 21. Synthesis of N-protected a-amino acids and aldehydes by stereoselective addition of bromohthioalkene 5 -41 to sulfonyhmines. Mukaiyama aldol reaction of a-aminoaldehydes... 

The area of reactions of phosphate derivatives has been dominated by highly stereoselective reactions in which the latter were used as chiral catalysts or achiral reagents. Among this group of reactions, it is worthy to note several asymmetric reactions ring opening of w 50-aziridinium and episulfonium ions, addition of alcohols to imines, 1,3-dipolar addition of aldehydes, amino esters and dipolarophiles, protonation of silyl enol ethers, epoxidation of a,p-unsaturated aldehydes, aza-ene-type reactions as well as asymmetric versions of named reactions Mannich, Friedel-Crafts, Kabachnik-Fields, aza-Darzens and aza-Henry. 

Synthesis from Aldehydes and Ketones. Treatment of aldehydes and ketones with potassium cyanide and ammonium carbonate gives hydantoias ia a oae-pot procedure (Bucherer-Bergs reactioa) that proceeds through a complex mechanism (69). Some derivatives, like oximes, semicarbazones, thiosemicarbazones, and others, are also suitable startiag materials. The Bucherer-Bergs and Read hydantoia syntheses give epimeric products when appHed to cycloalkanones, which is of importance ia the stereoselective syathesis of amino acids (69,70). 

As described in Section 2.3.2, vinylaziridines are versatile intermediates for the stereoselective synthesis of (E)-alkene dipeptide isosteres. One of the simplest methods for the synthesis of alkene isosteres such as 242 and 243 via aziridine derivatives of type 240 and 241 (Scheme 2.59) involves the use of chiral anti- and syn-amino alcohols 238 and 239, synthesizable in turn from various chiral amino aldehydes 237. However, when a chiral N-protected amino aldehyde derived from a natural ot-amino acid is treated with an organometallic reagent such as vinylmag-nesium bromide, a mixture of anti- and syn-amino alcohols 238 and 239 is always obtained. Highly stereoselective syntheses of either anti- or syn-amino alcohols 238 or 239, and hence 2,3-trans- or 2,3-as-3-alkyl-2-vinylaziridines 240 or 241, from readily available amino aldehydes 237 had thus hitherto been difficult. Ibuka and coworkers overcame this difficulty by developing an extremely useful epimerization of vinylaziridines. Palladium(0)-catalyzed reactions of 2,3-trons-2-vinylaziri-dines 240 afforded the thermodynamically more stable 2,3-cis isomers 241 predominantly over 240 (241 240 >94 6) through 7i-allylpalladium intermediates, in accordance with ab initio calculations [29]. This epimerization allowed a highly stereoselective synthesis of (E) -alkene dipeptide isosteres 243 with the desired L,L-... 

A very efficient and universal method has been developed for the production of optically pue L- and D-amino adds. The prindple is based on the enantioselective hydrolysis of D,L-amino add amides. The stable D,L-amino add amides are effidently prepared under mild reaction conditions starting from simple raw materials (Figure A8.2). Thus reaction of an aldehyde with hydrogen cyanide in ammonia (Strecker reaction) gives rise to the formation of the amino nitrile. The aminonitrile is converted in a high yield to the D,L-amino add amide under alkaline conditions in the presence of a catalytic amount of acetone. The resolution step is accomplished with permeabilised whole cells of Pseudomonas putida ATCC 12633. A nearly 100% stereoselectivity in hydrolysing only the L-amino add amide is combined with a very broad substrate spedfidty. 

Good to excellent diastereoselectivities have been reported when 2-(trimethylsilyl)thiazole (3), an effective equivalent of an aldehyde group, is used as nucleophile24,27. Thus, addition to TV-Boc-protected amino aldehydes in dichloromethane at — 30 C afforded mixtures of amino alcohols in comparatively good yields with reasonable syn selectivity. However, the stereoselectivity decreased substantially when the reaction was carried out in tetrahydrofuran at 25 °C. 

The extent of the stereoselectivity depends on the protection of the nitrogen and also on the catalyzing Lewis acid. However, the monoprolected a-amino aldehydes 1 (R3 = H) show good to excellent chelation-controlled syn preference, independent of the Lewis catalyst employed6fi S9. 

For the monoprotected a-amino aldehydes, the best results in yield and stereoselectivity were obtained under kinetic control conditions which gave the expected sw-com pounds. The addition of tin(lV) chloride did not result in increased syn selectivity, and the use of boron trifluoride diethyl ether complex did not provide the ann -isomer as the major product. 

On the contrary, in the latter case, a total loss of stereoselectivity occurs68. TV-Bis-benzyl-a-amino aldehydes 1 (R = R3 = Bn) under the assistance of boron trifluoride, zinc bromide or tin(lV) chloride lead to the nonchclation-controlled adducts preferentially, whereas titanium(IV) chloride or magnesium bromide result in chelation control70. In some cases, the O-trimcthylsilyl cyanohydrins arc the primary products, but the workup procedure usually provides the desily-lated products. 

Addition of ( )-enamines 3, derived from aldehydes and ketones, to various benzylideneimini-um salts 2 has been investigated. The reaction exclusively gives the Mannich bases anti-4 in good to excellent yield (72-94%). Therefore, this method provides an efficient and highly stereoselective route to /i-amino ketones and aldehydes1415. 

Enzyme preparations from liver or microbial sources were reported to show rather high substrate specificity [76] for the natural phosphorylated acceptor d-(18) but, at much reduced reaction rates, offer a rather broad substrate tolerance for polar, short-chain aldehydes [77-79]. Simple aliphatic or aromatic aldehydes are not converted. Therefore, the aldolase from Escherichia coli has been mutated for improved acceptance of nonphosphorylated and enantiomeric substrates toward facilitated enzymatic syntheses ofboth d- and t-sugars [80,81]. High stereoselectivity of the wild-type enzyme has been utilized in the preparation of compounds (23) / (24) and in a two-step enzymatic synthesis of (22), the N-terminal amino acid portion of nikkomycin antibiotics (Figure 10.12) [82]. 

In many cases, the racemization of a substrate required for DKR is difficult As an example, the production of optically pure cc-amino acids, which are used as intermediates for pharmaceuticals, cosmetics, and as chiral synfhons in organic chemistry [31], may be discussed. One of the important methods of the synthesis of amino acids is the hydrolysis of the appropriate hydantoins. Racemic 5-substituted hydantoins 15 are easily available from aldehydes using a commonly known synthetic procedure (Scheme 5.10) [32]. In the next step, they are enantioselectively hydrolyzed by d- or L-specific hydantoinase and the resulting N-carbamoyl amino acids 16 are hydrolyzed to optically pure a-amino acid 17 by other enzymes, namely, L- or D-specific carbamoylase. This process was introduced in the 1970s for the production of L-amino acids 17 [33]. For many substrates, the racemization process is too slow and in order to increase its rate enzymes called racemases are used. In processes the three enzymes, racemase, hydantoinase, and carbamoylase, can be used simultaneously this enables the production of a-amino acids without isolation of intermediates and increases the yield and productivity. Unfortunately, the commercial application of this process is limited because it is based on L-selective hydantoin-hydrolyzing enzymes [34, 35]. For production of D-amino acid the enzymes of opposite stereoselectivity are required. A recent study indicates that the inversion of enantioselectivity of hydantoinase, the key enzyme in the... 

An efficient route for the synthesis of the Phe-Phe hydroxyethy-lene dipeptide isostere precursors utilized for the design of potential inhibitors of renin and HIV-protease was developed. The key step is the zinc-mediated stereoselective allylation of A-protected a-amino aldehydes in aqueous solution (Eq. 8.32).70 NaBF4/M (M = Zn or Sn) showed facilitating allylation of a variety of carbonyl compounds in water, and a-and y-addition products of crotylations could be alternatively obtained under the control of this novel mediator (Eq. 8.33).71... 

With the aid of BF3 OEt2, methoxyborolane (R,R)-114 reacts with (.E)- or (Z)-crotylpotassium to provide (is,R,R)-115 and (Z,R,R)-115, respectively. After adding the aldehyde to a solution of crotyl-borolane in THF at —78°C for 4 hours, 2-aminoethanol is added. The solution is warmed to room temperature, and oxidative cleavage at this point gives the homoallylic alcohols with high stereoselectivity. The borolane moiety can be recovered by precipitating it as an amino alcohol complex and can be reused without any loss of enantiomeric purity. As shown in Scheme 3-43, the (.E)- and (Z)-crotyl compounds lead to anti- and -products 116, respectively. The diastereoselectivity is about 20 1, and the ee for most cases is over 95% (Table 3-11). 

Stereoselective allylation of aldehydes is another preferred strategy for the synthesis of appropriate intermediates for the total synthesis and introduction of hydroxy functionalities. Park and co-workers <2003S2473> proposed a synthesis of castanospermine 228 through a key indium-mediated allylation in the presence of (+)-cinchonine of an a-amino aldehyde 247 derived from D-glucono-O-lactone (Scheme 53). 

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