Statine analogue

Asymmetric hydrogenation of enamido (3-keto esters was carried out in the presence of both Rh(I)- and Ru(II)-chiral phosphine complexes as catalysts[1]. This is the efficient method to prepare statin analogues. The process independently induces two stereo centres in a molecule in a simple manner. 

A direct method for the respective preparation of the core units of statin analogues (3R,AR)-2, (3S,AS)-2, (3R,AS)-3, and (3S,AR)-3 in enantiomerically pure form is described. These analogues are prepared from the same molecule 1 in a one-pot, sequential asymmetric hydrogenation process utilizing Rh(I)-and Ru(II)-chiral phosphine complexes. Some other examples are depicted in Table 13.1. 

STATINE ANALOGUE DIFLUORO KETONE HYDRATE HYDROXYETHYLAMINE... 

The intense interest in y - am i n o - (i -hydroxy acid related peptides has led to a great deal of effort devoted to their synthesis. Statine analogues Ahppa (11), Achpa (12), and Dahoa (13) (Scheme 2), which correspond to the replacement of the chain equivalent of leucine in statine by those of phenylalanine, cyclohexylalanine, and lysine, respectively, were used to synthesize inhibitors of pepsin, renin, and penicillinopepsinJ1314] With the objective of developing highly specific inhibitors, C2-substituted analogues have also been introduced into short, substrate-derived inhibitors, e.g. the a,a-difluoro statine 14 in renin inhibitors,1151 and N -substituted statine derivatives like 15 in HIV-1 protease inhibitors.[16]... 

Scheme 2 Statine Analogues Used as Inhibitors of Aspartyl Protease Synthesis...

To evaluate the enantiomeric purity of (S,S)/(R,R)-statine, racemic mixtures and en-antiomerically enriched samples are analyzed by HPLC after derivatization with 2,3,4,6-tetra-0-acetyl- 3-D-glucopyranosyl isothiocyanate (GITC, 51 Scheme 21 and Table 7).[49 The GITC method also allows the determination of the enantiomeric composition of ethyl esters of statine analogues.[44 491 Another assay to determine the optical purity of statine has been developed, and uses l-G1u-NCA to produce dipeptides with different retention times in HPLC.[18]... 

The enantiomeric purity of a,a-difluoro statine analogues is determined via their diastereomeric Mosher s esters 52 and 53 by reaction with (S)-(+)-a-methoxy-a-(trifluorometh-yl)phenylacetyl chloride. The 19F NMR signals from the Tfm groups are well-resolved singlets and permit evaluation of their enantiomeric ratio (Scheme 22)J151... 

The research teams of Merck, Sharpe and Dohme (USA) were the first to succeed in finding a synthetic statin analogue that contained a biphenyl moiety [2] instead of a decalin ring (Fig. 4.4). 

Tab. 4.3 Effects of metabolic interactions on the plasma level of statin analogues in clinical use.

The enantiomer separation of another unusual amino add is given in Fig. 8. 4-Amino-3 hydroxy-5-phenylpentanoic acid is an intermediate in the synthesis of a statin analogue. Statin-type amino adds are essential... 

Hydroxyalkyt and Epoxyalky Acids. The reaction of aldehydes or ketones with dialkyl hydrogenphosphonate continues to be widely used for the synthesis of a-hydroxyalkylphosphonates ° and magnesium oxide has been reported to be an effective catalyst for the reaction. The reaction has been used in enantioselective synthesis. For example, in the preparation of chiral a, -dihydroxyphosphonic acids 171 and 172 (Scheme 14), with preferential formation of the jyn-isomer 171, and the statin analogue 2-amino-1-hydroxy-3-phenylpropylphosphonic acid (173) (Scheme 15). Catalytic asymmetric... 

Diastereoselective hydrogenation with BINAP-Ru combines chirality transfer from the catalyst and intramolecular asymmetric induction, providing an efficient entry to statine analogues ... 

In 2005, Kambourakis et al. reported the biocatalytic reduction of a-alkyl-1,3-diketones and a-alkyl-/l-ketoesters by employing isolated NADPH-dependent ketoreductases (KREDs). The corresponding optically pure single keto alcohols and hydroxy esters were obtained in quantitative yields (Scheme 3.9). The same group had previously reported the total synthesis of a new class of triterpene derivatives with anti-HIV activity, statin and statin analogues, based on a diastereoselective reduction of a 2-alkyl-substituted 3-ketoglutarate by a KRED. The results are summarised in Scheme 3.9. 

Farran, D., Toupet, L., Martinez, J., and Dewynter, G., StereocontroUed synthesis of 2,4-diamino-3-hydroxyacids starting from diketopiperazines Anew route for the preparation of statine analogues. Org. Lett. 2007,9 (23), 4833-4836. 

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