A simple synthetic route to statine and statine analogues

Abstract

The biologically important amino acid statine, (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid, as well as optically active statine analogues, are readily accessible in the ester form by simple reduction of the corresponding N,N-dibenzyl P-keto esters using NaBH4 followed by deprotection.Chiral p-amino alcohols are biologically and pharmacologically interesting compounds.1 An example is statine (l), a constituent of the naturally occurring small peptide pepstatin which is a strong inhibitor of such aspartic proteinases as pepsin, renin, and cathepsin.2 Since renin inhibitors are currently of great interest in the treatment of hypertension and congestive heart failure, considerable efforts have gone into the synthesis of statine and statine analogues.3Since the (3S,4S)-configuration is an essential requirement for biological activity, stereoselective routes are required. The most efficient approach to date involves the conversion of t-butoxycarbonyl (Boc) protected L-amino acids into the corresponding P-keto esters (2) followed by reduction to (3). Unfortunately, common achiral reducing agents such as NaBH4 or NaCNBH3 lead to mixtures of diastereoisomers (3)/(4) or to the wrong (3R74S)-diastereoisomer (4) , and bulky reagents such as K(Bus)~BH afford <25% of (3).3-5 Therefore, chiral reducing agents had to be applied, e.g., enzymes5 or optically active Wilkinson catalysts.6

Synthesis and Diastereoselective Reactions of N,N-Dibenzylamino Aldehydes and Related Compounds

“…Formally, these are the products that arise from chelation controlled C−C bond forming reactions of aldehydes 10 . Because the latter are not as general as one would like, nonchelation controlled hydride reduction of ketones 11 constitutes an important complementary strategy. ,, Moreover, ketones 11 can be transformed in other ways as well, reduction in the final step then being an option.…”

“…In most cases it is more elegant to prepare the ketones directly from activated amino acid derivatives which in turn are accessible from the N , N -dibenzylamino acids 172 . ,, Accordingly, the latter are first prepared by tribenzylation of amino acids 1 with BnBr/K 2 CO 3 in water followed by the addition of KOH, 1,4-dioxane and methanol to the reaction mixture containing the intermediate esters 14 . A reflux period of 6−28 h is then necessary for ester hydrolysis, depending upon the particular substrate. ,33b, More traditional conditions fail to effect hydrolysis .…”

Synthesis and Synthetic Applications of &#945;-Amino Ketones Derived from Natural &#945;-Amino Acids

“…Reetz et al employed the addition of a magnesium enolate to an imidazolide being this process utilised during the synthesis of Statine and its analogues [32] (Scheme 28).…”

Approaches to the synthesis of (2R,3S)-2-hydroxymethylpyrrolidin-3-ol (CYB-3) and its C(3) epimer: a cautionary tale

“…Saponification of the methyl ester to acid 26 and conversion to the imidazolide (acylimidazole) 27 is well-precedented in the literature for other α-amino esters. 24, 25 However, in itself this presented problems in that methyl ester 12 was found to be relatively unreactive towards saponification under a range of standard conditions, including those recently published for sterically congested methyl esters of this type. 24 The most efficient conditions were found to be heating ester 12 to reflux in a THF-water solvent mixture in the presence of LiOH (Scheme 4).…”