(R)-2-Methylpentanol is an important chiral intermediate for the synthesis of certain medicinally important compounds, natural products, and liquid crystals. Here we describe the development of a practical kinetic resolution utilizing an enantiospecific biocatalytic reduction of racemic 2-methylvaleraldehyde. The process utilizes an evolved ketoreductase enzyme to selectively reduce the (R)-enantiomer of racemic 2-methylvaleraldehyde to the desired product with high volumetric productivity. A scaleable method for separating the desired product from the off-enantiomer of the starting material is also described. The process is cost-effective, green, and amenable to manufacturing scale.
The solid-phase library synthesis of trisubstituted guanidines was accomplished. Amines were loaded onto the 4-formyl-3,5-dimethoxyphenoxymethyl linker via reductive amination. Subsequent acylation with Fmoc-4-aminomethylbenzoic acid followed by Fmoc deprotection gave solid-supported primary amines. Alternatively, sulfonylation of resin-bound secondary amines with 4-cyanobenzenesulfonyl chloride followed by borane reduction also gave solid-supported primary amines. Both resins were acylated with isocyanates to furnish solid-supported ureas. Dehydration of ureas with p-toluenesulfonyl chloride in pyridine gave solid-supported carbodiimides. Nucleophilic addition of amines to the carbodiimide bond followed by cleavage off the solid support gave trisubstituted guanidines.
The library synthesis of alkoxyprolines was achieved using an acid-stable, nucleophile-cleavable solid support. A hydroxythiophenol linker derived from Merrifield resin was esterified with the corresponding ethers of BOC-hydroxyproline. Removal of the BOC protecting group with trifluoroacetic acid followed by acylation gave solid-supported hydroxyproline derivatives. Cleavage from the solid support with excess primary amines or excess secondary amines followed by purification of the crude products from the excess amine by supported liquid-liquid extraction gave the alkoxyproline library in high purity.
The solution-phase synthesis of amido-, urea-, and aminofuranoses was achieved. Alkylated furanose aldehydes were treated with primary amines in the presence of sodium triacetoxyborohydride to give secondary amines. Subsequent acylation with acid chlorides and isocyanates afforded amidofuranoses and ureafuranoses, respectively. Second, reductive amination of furanose aldehydes with secondary amines yielded tertiary amines. The resulting acetonides were treated with alcohols in the presence of acid to yield mixed acetals. In the library syntheses, functionalized scavenger resins were used in the purification of intermediates and products.
Solution-Phase Library Synthesis of Furanoses.-Reductive amination of alkylated furanose aldehydes (V) with primary or secondary amines in the presence of NaBH(O-Ac) 3 provides access to the corresponding aminomethyl derivatives. In the reductive amination with primary amines (VI) and (IX), secondary amines are obtained, which can be further acylated with acid chlorides (VII) or isocyanates (X) to afford amido (VIII) or urea derivatives (XI), resp., in moderate yields. Removal of excess amounts of reagents and purification of the intermediate amines and target N-acyl derivatives is achieved using ion-exchange resins as well as special functionalized scavenger resins. In a similar manner, reductive amination with secondary amines (XII) affords tertiary amine intermediates, which on reaction with alcohols furnish mixed acetals (XIV). -(KRUEGER, ELAINE B.; HOPKINS, THUTAM P.; KEANEY, MEGHAN T.; WALTERS, MICHAEL A.; BOLDI, ARMEN M.; J.
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