Synthesis of the Chiral Side Chain of Statins – Lactone versus Lactol Pathway

4‐ O ‐Protected (4 R ,6 S )‐4‐hydroxy‐6‐(hydroxymethyl)tetrahydropyran‐2‐ones ( 3 ) derived from enantiomerically pure (3 R ,5 S )‐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 (3 R ,5 S )‐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 t BuPh 2 SiOH 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)