Statine synthesis, aldol reaction

The aldol reaction between a chiral a-amino aldehyde 16 and an acetate derived enolate 17 creates a new stereogenic center and two possible diastereomers. Several different methods for the synthesis of statine derivatives following an aldol reaction have been reported most of them lead to a mixture of the (35,45)- and (3/ ,45)-diastereomers 18 (Scheme 3), which have to be separated by laborious chromatographic methods.[17 211 Two distinct approaches for stereochemical control have been used substrate control and reagent control. 

In Masamune s initial synthesis of the C -Cn polyacetate region of the bryo-statins (Scheme 9-37), the chiral reagents (S)- and (R)-53 were used to control the stereocenters at C3, C7 and Cn [36], The first of these reactions used R)-53 to set the C3 center in 115 and then two subsequent double asymmetric induction aldol reactions, to give 116 and 117, set the remaining stereocenters. 

In the previous synthesis, two asymmetric aldol reactions using dienyl silyl ethers were described, one using a chiral Lewis acid for stereoinduction while the other used substrate control from a chiral aldehyde. This can be compared with the use of chiral dienolate 131 in the synthesis of a Ci-Cie fragment of the bryo-statins (Scheme 9-41) [59J. Here, the menthyl-derived auxiliary is covalently attached to the enolate, and again an excellent level of asymmetric induction was achieved on addition to aldehyde 132 to give adduct 133. 

Aldol reactions. This reagent (1) prepared from (-)-menthone and the (15, 3R, 41 )-isomer (2) from (+)-menthone separately induce the formation of 3,4-amino thioesters, respectively, from the condensation of ketene S-t-butylthioacetal and a-amino aldehydes. The method is well suited for the synthesis of (35, 45)-statine. 

This sequential aldol reactions has attracted much attention for the synthesis of a chiral precursor for the side chain of the statin drugs (Figure 10.9). 

This mutant was also shown to accept 3-azidopropanal 39 as a new substrate in a sequential aldol reaction to form a novel azidopyranose 40, offering a new pathway for the synthesis of one of the building blocks 41 of atorvastatin (Scheme 28.19). Atorvastatin is the best-selling statin (marketed under the name of Lipitor by Pfizer, New York, NY), drug used to lower the cholesterol levels by inhibiting the HMG CoA (3-hydroxy-3-methyl-glutaryl coenzyme A) reductase, which plays a central role in the production of cholesterol in the fiver. ... 

DSM also developed an industrial process based on a DERA catalysis for the synthesis of the side chain of the statins. A sequential one-pot two-step aldol addition of two molecules of acetaldehyde to an acceptor aldehyde 42 was implemented. It uses a mutant enzyme obtained by directed evolution presenting an increasing resistance and activity with the chloroacetaldehyde substrate 42. This reaction affords the enantiopure trideoxypyranose product 43 then oxidized to the corresponding hydroxylactone 44 (Scheme 28.19). This ring closure explains that the reaction is restricted to only two aldol reactions. 

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