This review presents the Analytical Quality by Design (AQbD) concept, an extension of Quality by Design (QbD), which was introduced in 2004 by the U.S. Food and Drug Administration (FDA) and approved in 2005 by the International Conference on Harmonisation (ICH). AQbD is a systematic approach to method development, controlling all stages of the analytical procedure life cycle. It includes a definition of the analytical target profile (ATP), identification of critical method parameters or factors, and selection of critical method attributes (CMAs) or responses. Screening and response-surface experimental designs allow the recognition of significant factors and their optimization by statistical analysis. The factor− response relationship is described by a mathematical model, which is able to predict the optimal response. Multivariate combinations of factors fulfilling the CMA requirements are presented in the design space or method operable design region (MODR), where robust method performance is ensured. This review presents the theoretical background of AQbD for method development and its workflow through recently published cases in which the AQbD concept proved to be a reliable and effective approach. Analytical methods developed by using the AQbD approach are highly robust, are easily validated, have shorter run times, and are capable of determining a higher number of analytes in one run compared with the methods developed by the one-factor-at-a-time (OFAT) approach.

Employing DERA (2-deoxyribose-5-phosphate aldolase), we developed the first whole-cell biotransformation process for production of chiral lactol intermediates useful for synthesis of optically pure super-statins such as rosuvastatin and pitavastatin. Herein, we report the development of a fed-batch, high-density fermentation with Escherichia coli BL21 (DE3) overexpressing the native E. coli deoC gene. High activity of this biomass allows direct utilization of the fermentation broth as a whole-cell DERA biocatalyst. We further show a highly productive bioconversion processes with this biocatalyst for conversion of 2-substituted acetaldehydes to the corresponding lactols. The process is evaluated in detail for conversion of acetyloxy-acetaldehyde with the first insight into the dynamics of reaction intermediates, side products and enzyme activity, allowing optimization of the feeding strategy of the aldehyde substrates for improved productivities, yields and purities. The resulting process for production of ((2S,4R)-4,6-dihydroxytetrahydro-2H-pyran-2-yl)methyl acetate (acetyloxymethylene-lactol) has a volumetric productivity exceeding 40 g L−1 h−1 (up to 50 g L−1 h−1) with >80% yield and >80% chromatographic purity with titers reaching 100 g L−1. Stereochemical selectivity of DERA allows excellent enantiomeric purities (ee >99.9%), which were demonstrated on downstream advanced intermediates. The presented process is highly cost effective and environmentally friendly. To our knowledge, this is the first asymmetric aldol condensation process achieved with whole-cell DERA catalysis and it simplifies and extends previously developed DERA-catalyzed approaches based on the isolated enzyme. Finally, applicability of the presented process is demonstrated by efficient preparation of a key lactol precursor, which fits directly into the lactone pathway to optically pure super-statins.

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The U.S. Food and Drug Administration approved 18 new drugs that incorporate the cyclopropyl structural motif in the time frame from 2012 to 2018. This review provides an overview of synthetic approaches to these drugs with emphasis on the construction of the cyclopropyl moiety or its incorporation into the key building blocks for assembly of the highlighted drugs. Based on the structural diversity of these drugs, synthetic approaches for the construction and introduction of the cyclopropyl moiety into their structure are diverse and include: cycloalkylation (double alkylation) of CH-acids, catalytic cyclopropanation of alkenes with diazo compounds, the Simmons–Smith reaction, the Corey–Chaykovsky reaction, the Kulinkovich reaction, the Horner–Wadsworth–Emmons reaction, and cycloaddition. In addition, the cyclopropyl structure was also introduced into the drug substance intermediates via simple cyclopropyl-moiety-containing building blocks, such as cyclopropylamine, cyclopropanesulfonamide, cyclopropanecarbonyl chloride, and cyclopropylmagnesium bromide.1 Introduction2 Synthesis of Recently Approved Cyclopropyl-Moiety-Containing Drugs2.1 Cabozantinib2.2 Trametinib2.3 Simeprevir2.4 Ledipasvir2.5 Olaparib2.6 Tasimelteon2.7 Finafloxacin2.8 Paritaprevir2.9 Lenvatinib2.10 Lumacaftor2.11 Lesinurad2.12 Grazoprevir2.13 Glecaprevir2.14 Ozenoxacin2.15 Voxilaprevir2.16 Naldemedine2.17 Tezacaftor2.18 Tecovirimat3 Conclusion

Aminoboronic acids and their derivatives are particularly useful as drugs, probes and synthons. Recent developments in their synthesis are highlighted.