Stereocontrolled synthesis of rosuvastatin calcium via iodine chloride-induced intramolecular cyclization

Abstract

A novel, stereoselective approach towards rosuvastatin calcium from the known (S)-homoallylic alcohol has been developed. The synthesis is highlighted by a regio- and stereocontrolled ICl-induced intramolecular cyclization of chiral homoallylic carbonate to deliver the C6-formyl statin side chain with a syn-1,3-diol moiety. An improved synthesis of the rosuvastatin pyrimidine core moiety is also included. Moreover, this methodology is useful in the asymmetric synthesis of structural variants of statins such as pitavastatin calcium and atorvastatin calcium and their related analogs.

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.…”

Chiral Syn-1,3-diol Derivatives via a One-Pot Diastereoselective Carboxylation/ Bromocyclization of Homoallylic Alcohols

“…Despite the considerable efficacy, cryogenic reaction conditions are required to achieve high diastereoselectivity. Notably, among several possible approaches to prepare functionalized chiral syn -1,3-diols, the direct diastereoselective electrophilic iodocarboxylation of homoallylic alcohols is clearly underexploited ( Scheme 2 C) ( Ahmad et al., 1977 , Bartlett et al., 1982 , Duan et al., 1993 , Xiong et al., 2016 ). Although this method requires additional transformation to extend the nucleophilic character of β -hydroxy group by forming esters such as cyclic phosphates and carbonates, the method allows the installation of the functionalized chiral syn -1,3-diol subunits in one step with high efficiency.…”

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

“…Recently, our own studies on the stereoselective construction of chiral statin side‐chains suggested that the asymmetric synthesis of statin molecules such as rosuvastatin ( 2 ) and pitavastatin ( 3 ) could be markedly simplified by using iodine‐halide‐induced intramolecular iodocyclization reactions of homoallylic tert ‐butyl carbonates (Figure ). We also developed an alternative approach to the synthesis of the syn ‐1,3‐diol scaffold based on a Br 2 ‐induced intramolecular bromocyclization of homoallylic carbonates .…”

“…As part of our ongoing research into statins and their analogues, we are developing new strategies for the preparation of statins,[1e], and exploring new methods for the preparation of analogue compounds and derivatives to evaluate their HMG‐CoA reductase inhibition properties. In this paper, we report the outcome of a study that has established a new method for the construction of the syn ‐1,3‐diol subunit based on an intramolecular oxidative oxygen‐nucleophilic bromocyclization.…”