A new multi-step synthesis of the lipid-lowering agent rosuvastatin, involving two homogeneously catalyzed reaction steps, is described. The key building block, N-[4-(4-fluorophenyl)-5-formyl-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide (2), was prepared by Pd-catalyzed formylation with CO/H 2 (1:1, 50 bar, phosphane ligand/substrate ratio of 1:10). Several alternative pathways for the preparation of 2 were also tested, but were found to be in-
A search for the large-scale preparation of (5S)-5,6-(isopropylidenedioxy)-3-oxohexanoates (2) -a key intermediate in the synthesis of pharmacologially important statins -starting from (S)-malic acid is described. The synthesis of the required initial compound methyl (3S)-3,4-(isopropylidenedioxy)butanoate (1) by Moriwakes reduction of dimethyl (S)-malate (3) has been improved. Direct 2-C chain elongation of ester 1 using the lithium enolate of tert-butyl acetate has been shown to be successful at a 3-to 5-fold excess of the enolate. Unfortunately, the product, tert-butyl (5S)-5,6-(isopropylidenedioxy)-3-oxohexanoate (2a) is unstable during distillation. Ethyl (5S)-5,6-(isopropylidenedioxy)-3-oxohexanoate (2b) was prepared alternatively on a multigram scale from (3S)-3,4-(isopropylidenedioxy)butanoic acid (7) by activation with N,N'-carbonyldiimidazole and subsequent reaction with Mg(OOCCH 2 COOEt) 2 . A convenient pathway for the in situ preparation of the latter is also described. Ethyl ester (2b) can be advantageously purified by distillation. The stereochemistry of the catalytic hydrogenation of b-keto ester (2b) to ethyl (5S)-5,6-(isopropylidenedioxy)-3-hydrohyhexanoate (syn-6 and anti-6) has been studied using a number of homogeneous achiral and chiral Rh(I) and Ru(II) complexes with phosphine ligands. A comparison of Rh(I) and Ru(II) catalysts with (S)-and (R)-BINAP as chiral ligands revealed opposite activity in dependence on the polarity of the solvent. No influence of the chiral backbone of substrate 2b on the enantioselectivity was noted. A ratio of syn-6/anti-6 = 2.3 was observed with an achiral (Ph 3 P) 3 RuCl 2 catalyst. Ru[(R)-Tol-BINAP]Cl 2 neutralized with one equivalent of AcONa afforded the most efficient catalytic system for the production of optically pure syn-(5S)-5,6-isopropylidenedioxy-3-hydroxyhexanoate (syn-6) at a preparative substrate/catalyst ratio of 1000:1.
Abstract4‐O‐Protected (4R,6S)‐4‐hydroxy‐6‐(hydroxymethyl)tetrahydropyran‐2‐ones (3) derived from enantiomerically pure (3R,5S)‐3‐hydroxy‐5,6‐(isopropylidenedioxy)hexanoates (2) are frequently considered as pivotal intermediates for the synthesis of pharmacologically important statins. Remarkably, up to now no proof for this assumption can be derived from the literature. Our study revealed that only silyl‐type protecting groups can be successfully employed for 3‐O‐protection of initial ethyl (3R,5S)‐3‐hydroxy‐5,6‐(isopropylidenedioxy)hexanoate (1). After cyclization, hydroxy lactone 3b was transformed into tosylate 5b and successively into iodide 6b. The latter was converted into phosphonate 9b. All stereochemical assignments and the diastereomerical purity of the intermediates were confirmed by an X‐ray structural analysis of tosylate 5b. Surprisingly, neither tosylate 5b nor iodide 6b could be converted into corresponding nitrile 7b which is the key intermediate on the way to atorvastatin. Phosphonate 9b and aldehyde 4b are nearest intermediates to fluvastatin and rosuvastatin lactones. Unfortunately, Wittig–Horner‐reaction of phosphonate 9b under basic conditions was unsuccessful. Finally, it was not possible to oxidize hydroxy tetrahydropyranone 3b to related aldehyde 4b. Apparently the main reason for this unexpected behaviour of these compounds consists in the acidity of the hydrogen atoms in the 3‐position of the tetrahydropyranone‐2‐one ring which facilitates the fast elimination of tBuPh2SiOH and further decomposition of the pyranone core. In contrast, the desired transformations could be performed with related lactol 13 in hand. Thus, a successful alternative for the preparation of the side chain of statins was discovered. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)
The highly enantioselective hydrogenation of ethyl 5,5-dimethoxy-3-oxopentanoate (3) to ethyl 3-hydroxy-5,5-dimethoxypentanoate (4) -a key intermediate in the synthesis of pharmacologically important statin drugs -has been investigated. The stereochemistry of the catalytic hydrogenation of the β-keto ester in the presence of a number of homogeneous chiral Rh I and Ru II complexes with phosphane ligands has been studied. The highest enantioselectivity for the homo-
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