Synthetic studies on statins. Part 1: a short and cyanide-free synthesis of atorvastatin calcium via an enantioselective aldol strategy

A short and cyanide-free enantioselective synthesis of atorvastatin calcium has been achieved starting from a commercially available highly substituted 1,4-diketone in an overall yield of 40%. The key step in this approach is the asymmetric aldol reaction of an aldehyde with diketene in the presence of Ti(O-i-Pr)4–Schiff base complex to create the (5R)-stereochemistry of atorvastatin calcium.

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(R)-Isopropyl 7-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-pheny1-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]-5-hydroxy-3-oxoheptanoateC36H39FN2O5Ee = 82%[α]D20=+9.1 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration (R)

(3R,5R)-Isopropyl 7-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoateC36H41FN2O5Ee = 99%[α]D20=+14.3 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration (3R,5R)

Isopropyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetateC39H45FN2O5[α]D20=+5.8 (c 1.0, CHCl3)Source of chirality: the precursorAbsolute configuration (4R,6R)

Atorvastatin calciumC33H40CaFN2O8[α]D20=-7.5 (c 1.0, DMSO)Source of chirality: the precursorAbsolute configuration (3R,5R)