Identification, Characterization, and In Silico Analysis of New Imine Reductases From Native Streptomyces Genomes

The development of biocatalytic tools for the synthesis of optically pure amines has been the focus of abundant research in recent years. Among other enzymes, imine reductases have attracted much attention associated with the possibility of attaining chiral secondary amines. Furthermore, the reductive aminase activity associated with some of these enzymes has facilitated the production of optically pure amines from a prochiral ketone, a transformation that opens doors to an incredible array of products. In this work, the genomes from native Streptomyces strains isolated in our lab have been explored on the search for novel imine reductases. Application of different structural criteria and sequence motif filters allowed the identification of two novel enzymes, Ss-IRED_S and Ss-IRED_R. While the former presented outstanding activity towards bulky cyclic imine substrates, the latter presented reductive aminase activity with the assayed ketones. A bioinformatic analysis based on modeling and docking studies was performed in order to explain the differences in enzyme activity, searching for additional criteria that could be used to analyze enzyme candidates in silico, providing additional tools for enzyme selection for a particular application. Our findings suggest that imine reductase activity could be predicted by this analysis, overall accounting for the number of docking positions that meet the catalytic requirements.

A New Organocatalytic Desymmetrization Reaction Enables the Enantioselective Total Synthesis of Madangamine E

The enantioselective total synthesis of madangamine E has been completed in 30 steps, enabled by a new catalytic and highly enantioselective desymmetrizing intramolecular Michael addition reaction of a prochiral ketone to a tethered β,β’-disubstituted nitroolefin. This key carbon–carbon bond forming reaction efficiently constructed a chiral bicyclic core in near-perfect enantio- and diastereo-selectivity, concurrently established three stereogenic centers, including a quaternary carbon stereocenter, and proved highly scalable. Furthermore, the pathway and origins of enantioselectivity in this catalytic cyclisation were probed using density functional theory (DFT) calculations, which revealed the crucial substrate/catalyst interactions in the enantio-determining step. Following construction of the bicyclic core, the total synthesis of madangamine E could be completed, with key steps including a mild one-pot oxidation-lactamisation, a two-step Z-selective olefination of a sterically hindered ketone, and ring-closing metatheses to install the two macrocyclic rings.

Kinetics of enzyme-catalysed desymmetrisation of prochiral substrates: product enantiomeric excess is not always constant

The kinetics of enzymatic desymmetrisation were analysed for the most common kinetic mechanisms: ternary complex ordered (prochiral ketone reduction); ping-pong second (ketone amination, diol esterification, desymmetrisation in the second half reaction); ping-pong first (diol ester hydrolysis) and ping-pong both (prochiral diacids). For plausible values of enzyme kinetic parameters, the product enantiomeric excess (ee) can decline substantially as the reaction proceeds to high conversion. For example, an ee of 0.95 at the start of the reaction can decline to less than 0.5 at 95% of equilibrium conversion, but for different enzyme properties it will remain almost unchanged. For most mechanisms a single function of multiple enzyme rate constants (which can be termed ee decline parameter, eeDP) accounts for the major effect on the tendency for the ee to decline. For some mechanisms, the concentrations or ratios of the starting materials have an important influence on the fall in ee. For the application of enzymatic desymmetrisation it is important to study if and how the product ee declines at high conversion.

Photo-Biocatalytic Cascades for the Synthesis of Volatile Sulfur Compounds and Chemical Building Blocks

Biocatalysis is a branch of catalysis that exploits enzymes to perform highly stereoselective chemical transformations under mild and sustainable conditions. This Synpact highlights how biocatalysis can be used in the synthesis of chiral 1,3-mercaptoalkanols, an important class of compounds responsible for the flavours and aromas of many foods and beverages. The identification of two ketoreductase (KRED) enzymes able to reduce prochiral ketone precursors enantioselectively to 1,3-mercaptoalkanols bearing a C–O stereocentre is presented. In addition, the combination of a photocatalytic thia-Michael reaction to access prochiral ketones with subsequent KRED-biocatalysed reduction in a one-pot cascade is presented. Photo-biocatalysed cascades represent one of the new and most intriguing challenges in synthetic chemistry, because the combination of different catalytic methodologies in domino processes offers unique opportunities to outperform sequential reactions with a high degree of selectivity and the avoidance of the need to isolate reaction intermediates.1 Introduction2 Biocatalytic Synthesis of 1,3-Mercaptoalkanols3 Photo-Biocatalytic Synthesis of 1,3-Mercaptoalkanols4 Photo-Biocatalysed Cascade Reactions5 Conclusions

Organocatalytic C-C Ring Construction: (+)-Ricciocarpin A (List) and (-)-Aromadendranediol (MacMillan)

Yoshiji Takemoto of Kyoto University designed (Organic Lett. 2009, 11, 2425) an organocatalyst for the enantioselective conjugate addition of alkene boronic acids to γ-hydroxy enones, leading to 1 in high ee. Attempted Mitsunobu coupling led to the cyclopropane 2, while bromoetherification followed by intramolecular alkylation delivered the cyclopropane 3. Jeffrey W. Bode of the University of Pennsylvania demonstrated (Organic Lett. 2009, 11, 677) a remarkable dichotomy in the reactivity of N-heterocyclic carbenes. A triazolium precatalyst combined 4 and 5 to give 6, whereas an imidazolium precatalyst combined 4 and 5 to give 7. Xinmiao Liang of the Dalian Institute of Chemical Physics and Jinxing Ye of the East China University of Science and Technology devised (Organic Lett. 2009, 11, 753) a Cinchona -derived catalyst that converted the prochiral cyclohexenone 8 into the diester 10 in high ee. Rich G. Carter of Oregon State University found (J. Org. Chem. 2009, 74, 2246) a simple sulfonamide-based proline catalyst that effected the Mannich condensation of the prochiral ketone with ethyl glyoxalate 12 and the amine 13, leading to the amine 14. In the first pot of a concise, three-pot synthesis of (-)-oseltamivir, Yujiro Hayashi of the Tokyo University of Science combined (Angew. Chem. Int. Ed. 2009, 48, 1304) 15 and 16 in the presence of a catalytic amount of diphenyl prolinol TMS ether to give an intermediate nitro aldehyde. Addition of the phosphonate 17 led to a cyclohexenecarboxylate, that on the addition of the thiophenol 18 equilibrated to the ester 19. Ying-Chun Chen of Sichuan University used (Organic Lett. 2009, 11, 2848) a related diaryl prolinol TMS ether to direct the condensation of the readily-prepared phosphorane 20 with the unsaturated aldehyde 21 to give the cyclohexenone 22. Armando Córdova of Stockholm University also used (Tetrahedron Lett. 2009, 50, 3458) diphenyl prolinol TMS ether to mediate the addition of 24 to 23. The subsequent intramolecular aldol condensation proceeded with high diastereocontrol, leading to 25. Benjamin List of the Max-Planck Institut, Mülheim employed (Nat. Chem. 2009, 1, 225) a MacMillan catalyst for the reductive cyclization of 26.