The first ("by definition") cyanide-free enantioselective synthetic approach towards chiral aand b-branched nitriles is reported. This process is based on a biocatalytic dehydration of racemic aldoximes by using an aldoxime dehydratase and proceeds with high conversion and excellent enantioselectivity (up to 98 % ee) with water as the only side-product when starting from a racemic substrate with a high E/Z ratio. Thus, in combination with the facile generation of aldoximes through condensation of readily accessible aldehydes with hydroxylamine, this methodology offers an attractive and efficient path to chiral nitriles with excellent atom economy in aqueous solution. Furthermore, this study shows a surprising enzymatic dependency of the enantiopreference on the E or Z configuration of the aldoxime moiety. Notably, the whole stereochemical course of this enzymatic reaction has been rationalized by means of a computational study.From the early days of organic chemistry, (chiral) nitriles have been widely used as versatile intermediates in the synthesis of carboxylic acids (by hydrolysis) and amines (by hydrogenation). [1] A selected recent example underlining the importance of chiral nitrile intermediates is the synthesis of boceprevir (Merck) as a drug for treatment of hepatitis C. [2] Furthermore, recently chiral a-branched nitrile motifs have increasingly been part of the key structural framework in novel final drug molecules that have already been clinically approved, such as vildagliptin (Novartis) and saxagliptin (Bristol Myers Squibb). [3,4] Thus, the search for efficient enantioselective synthetic strategies towards chiral nitriles has gained tremendous significance for organic chemists and the pharmaceutical industry. Hitherto, the preferred introduction of a chiral nitrile moiety into a molecule has proceeded through reactions with cyanide (either by substitution or addition reactions). Besides using cy-anide in the synthesis of racemic or prochiral substrates for subsequent resolutions [5][6][7] or asymmetric reactions [8][9][10] with the formed nitriles, a range of asymmetric catalytic cyanations have been developed. [11][12][13][14][15][16] Cyanide, however, is highly toxic and there is a strong demand for developing methods that avoid the use of cyanide in the asymmetric or preceding synthetic steps for the nitrile substrates. Ideally, such alternative methods should also be attractive for applications on the industrial scale. Notably, until now there has not been a single asymmetric method for synthesizing a-branched chiral nitriles that "by definition" does not rely on the use of cyanide: for existing routes cyanide is either required or conceivably used in the substrate synthesis (if chiral, racemic, or prochiral nitriles serve as substrates) or in the enantioselective step (through enantioselective cyanation reactions).Looking at Nature's way to prepare nitriles, which notably are found in several natural products, [17] we became inspired to use enzymes for the enantioselective synthesis of chiral...

Recently, the Kemp elimination reaction has been extensively studied in computational enzyme design of new catalysts, as no natural enzyme has evolved to catalyze this reaction. In contrast to in silico enzyme design, we were interested in searching for Kemp eliminase activity in natural enzymes with catalytic promiscuity. Based on similarities of substrate structures and reaction mechanisms, we assumed that the active sites of naturally abundant aldoxime dehydratases have the potential to catalyze the non-natural Kemp elimination reaction. We found several aldoxime dehydratases that are efficient catalysts of this reaction. Although a few natural enzymes have been identified with promiscuous Kemp eliminase activity, to the best of our knowledge, this is a rare example of Kemp elimination catalyzed by naturally occurring enzymes with high catalytic efficiency.

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.

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