Chiral hydroxyaldehydes, preparation

Several enzymatic procedures have been developed for the synthesis of carbohydrates from acyclic precursors. Aldolases appear to be useful catalysts for the construction of sugars through asymmeteric C-C bond formation. 2-deoxy-KDO, 2-deoxy-2-fluoro-KDO, 9-0-acetyl sialic acid and several unusual sugars were prepared by a combined chemical and enzymatic approach. Alcohol dehydrogenases and lipases have been used in the preparation of chiral furans, hydroxyaldehydes, and glycerol acetonide which are useful as building blocks in carbohydrate synthesis. 

Enzymatic reduction of carbonyl compounds and enzymatic enantioselective transformation of racemic or meso alcohols (25,43.) are two methodologies that have proven to be beneficial in the preparation of optically active hydroxyl compounds, key chiral building blocks used in carbohydrate and natural product syntheses (44-45. Our interest in this area is to develop enzymatic routes to optically active glycerol and furan derivatives, and hydroxyaldehydes. 

The diamine (99) was applied 117) to the synthesis of chiral a-hydroxyaldehydes. Thus, treatment of the aminal (100), prepared from the chiral diamine (99) and phenylglyoxal, with the Grignard reagent affords the hydroxyaminal, which in turn was hydrolyzed to yield a-alkyl-a-hydroxyphenylacetaldehyde (101). The chiral auxiliary was recovered ll7). 

Mukaiyama et al. developed a rather general and versatile method for the preparation of optically active a-hydroxyaldehydes by using the diamine (99) as chiral adjuvant. Thus, one Grignard reagent (R MgX) is reacted with the aminal (102) of methyl glyoxylate. In the next step a second kind of Grignard reagent (R2-MgX) is diastereoselectively added to the ketoaminal, and the desired chiral a-hydroxy-aldehyde (103) is obtained by hydrolysis 117-1I8). 

Asymmetric hydrogenation of either a carbonyl or an imino group to a hydroxyl group or an amino group has frequently been employed for the introduction of chirality in amino acid syntheses. Corey s catecolborane-oxazaborolidine protocol enables transformation of difluoromethyl ketone 1 into alcohol 2 with excellent enantioselectivity. The reaction of diastereoselective amination of a-hydroxyaldehyde 3 with A,A-diallylamine and 2-furyl-boronic acid provides furyl amino alcohol 4 in good chemical yield along with excellent diastereoselectivity. This protocol is applicable for the preparation of amino acids and amino alcohols with a trifluoromethyl group by the combination of /V,/V-diallyl or N,N-dibenzyl amine and aromatic, heteroaromatic and alkenyl boronic acids [7]. The usual chemical transformations as shown in steps 5 to 8 in Scheme 9.1 lead to (2S,3R) difluorothreonine 5 [8]. 

The diamine (R=Ph) was also applied to the synthesis of optically active a-hydroxyaldehydes. Treatment of the aminal, prepared from the chiral diamine and phenylglyoxal, with Grignard... 

Variable enantioselectivities are observed during allylation of aldehydes in the presence of ligand 35. P-Hydroxyaldehydes can be allylated in the unprotected form with a chiral allyltitanium species 36, whereas a-hydroxyaldehydes are readily prepared from 37 by various organometallic reactions. Cinchona alkaloids, being commercially available and inexpensive, are suitable chiral promoters for the indium-mediated allylation, even though they induce only moderate enantioselectivities. Allylation such as that effected by 38 affords products useful for substrate-based alkylation. ... 

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