Asymmetric Synthesis of Atorvastatin Calcium through Intramolecular Oxidative Oxygen‐Nucleophilic Bromocyclization

Abstract

The stereocontrolled synthesis of atorvastatin calcium starting from commercially available d‐aspartic acid using an intramolecular oxidative oxygen‐nucleophilic bromocyclization of a homoallylic tert‐butyl carbonate is described. This strategy allows the formation of the chiral syn‐1,3‐diol moiety with the desired stereochemistry, and provides a functionalized bromomethyl group for the construction of the atorvastatin side‐chain with high regio‐ and diastereoselectivity. This route is attractive as it represents an efficient and environmentally sensitive approach to the large‐scale synthesis of statins and their analogues.

Atropostatin: Design and Total Synthesis of an Atropisomeric Lactone–Atorvastatin Prodrug

“…The experimental rotational energy barriers of atorvastatin models were determined after planning a feasible synthetic route with these bulky aryl substituents. A good survey of examples of atorvastatin synthesis is reported in the literature [ 23 , 24 , 25 ], but the aryl steric hindrance at position 3 poses additional issues, lowering the reaction yields. For this reason, we focused our attention on a zirconium-catalyzed method for pyrrole cascade cyclization [ 26 ], with appropriate modifications for our purposes.…”

Continuous-Flow Asymmetric Synthesis of (3R)-3-Hydroxyl-5-hexenoates with Co-Immobilized Ketoreductase and Lactobacillus kefir Dehydrogenase Integrating Greener Inline Microfluidic Liquid–Liquid Extractors and Membrane Separators

“…Enantiomerically pure (3 R )-3-hydroxyl-5-hexenoates ( 1 ) are crucial chiral intermediates in the synthesis of a wide variety of biologically active compounds and chiral drugs, such as (−)-mycalolide A, lankacidins, (−)-spirofungins, ulapualide A, macrosphelides, (+)-leucascandrolide A, (+)-neopeltolide, and statins. − From a synthetic perspective, the control of the stereochemistry of the hydroxyl moiety presents a major challenge due to the simultaneous presence of multiple reactive functionalities. Therefore, a considerable amount of effort has been devoted to the development of efficient synthetic protocols to access ( 1 ). − …”

“…1,4,10,11 In the second approach, crotonoyl chloride (6) was transformed into β,γ-unsaturated ester (7). Then, a reaction with m-CPBA led to racemic epoxide (8), and a Jacobsen hydrolytic kinetic resolution of racemate (8) using the (R,R)-salen-Co(III) complex led to (9). The epoxide function of (9) was opened by attack of vinylmagnesium bromide, leading to the desired (1) (Route 2 in Scheme 1).…”

“…Then, a reaction with m-CPBA led to racemic epoxide (8), and a Jacobsen hydrolytic kinetic resolution of racemate (8) using the (R,R)-salen-Co(III) complex led to (9). The epoxide function of (9) was opened by attack of vinylmagnesium bromide, leading to the desired (1) (Route 2 in Scheme 1). 1,4,12 The third approach commenced with catalytic asymmetric hydrogenation of 4-chloroacetoacetate (10) to βhydroxy ester (11), and subsequent halogen exchange led to iodine compound (12).…”

Development of a Practical, Biocatalytic Synthesis of tert-Butyl (R)-3-Hydroxyl-5-hexenoate: A Key Intermediate to the Statin Side Chain

“…Moreover, extensive research studies in the field indicate that statins have many other pharmacological activities, including anti-inflammatory and anticancer activity, as well as antioxidative effects. ,− Given their pharmaceutical importance, tremendous efforts have been devoted to the efficient and sustainable synthesis of statins. ,, In particular, various methods have been developed to build the chiral syn -3,5-dihydroxy-6-heptenoic or heptanoic acid side chain, the common and pharmacologically important structural feature of statins . Within this context, our group has longtime interests in the efficient and asymmetric synthesis of statins. − Recently, we have demonstrated a pilot-plant-scale synthesis of bromocarbonate 3a via a one-pot diastereoselective carboxylation/bromocyclization of tert -butyl ( R )-3-hydroxyl-5-hexenoate (( R )- 2a ) (Scheme A) . The bromocarbonate 3a was transformed further to Kaneka alcohol 4a , the common synthetic intermediate to statin molecules, in three steps with high yields.…”