Integrated Biocatalysis in Multistep Drug Synthesis without Intermediate Isolation: A de Novo Approach toward a Rosuvastatin Key Building Block

Abstract

In this contribution, we report the chemoenzymatic preparation of a key building block for the active pharmaceutical ingredient rosuvastatin, one of the "top 5 blockbuster drugs" with a worldwide market value of 6.25 billion USD in 2012, via a seven-step synthesis without isolation of intermediates and with incorporation of two highly efficient biotransformations. This chemoenzymatic process reaches excellent space-time yields by using high substrate concentrations (several hundred grams per liter), emphasizing the potential of biocatalysis for industrial processes related to pharmaceutical drug synthesis and the compatibility of enzyme chemistry with classical organic synthesis.

Synthesis of Heterocycles in Contemporary Medicinal Chemistry

“…This will trigger the continuous search for the more efficient, cheaper, and sustainable synthesis of statins [137] and in particular super-statins. This has already been reflected in some reports that have appeared in the literature since this review was written [138][139][140][141][142][143][144]. …”

Tandem Reactions Combining Biocatalysts and Chemical Catalysts for Asymmetric Synthesis

“…Careful reaction design led to efficient chemoenzymatic transformations catalyzed by immobilized chemical catalysts and biocatalysts, which are utilized in different compartments. Those multi-pot reactions were generally ecofriendly by avoiding intermediate isolation steps [64][65][66]. Recently, one-pot compartmentations also have been achieved by using membrane or encapsulation techniques.…”

The Application of Dioxygenase‐Based Chemoenzymatic Processes to the Total Synthesis of Natural Products

“…[3] Furthermore, the opportunities for deploying enzymes in ap lethora of diverse settings, including one-pot chemoenzymatic reactions equences or in combinationw ith, for example, metal-mediated processes, has seen ad ramatic increase in their applicationso ver the last two decades or so. [4] The capacity of biocatalysis to underpin or create sustainable chemical manufacturing processes [3,5] represents yet another motivation for the development of chemoenzymatic methods and these have now been deployed in the production of, inter alia, carbohydrates, [6] glycoproteins, [7] polypetides (including for use as functional and structural materials), [8] active pharmaceutical ingredients (APIs), [9] agrochemicals [10] and natural products. [11] Given the diversity and versatility of biocatalytic transformations now available, the enzymatic component(s)o fachemoenzymatic synthesis can, in principle, appear at almost any point(s) in ar eaction sequence.…”