Attacking olefins with chiral acids: A little acid can accelerate a wide range of chemical reactions. The advent of chiral phosphoric acid derivatives has been useful for biasing these reactions toward just one of two mirror-image products. For the most part, though, these chiral catalysts have interacted with basic sites such as carbonyl groups. Tsuji et al. now extend asymmetric acid catalysis to simple carbon-carbon double bonds. Their custom imidodiphosphate forms a pocket that orients olefins to achieve mainly intramolecular alkoxylation on just one face after protonation. Science , this issue p. 1501

Cytochrome P450 monooxygenases play a crucial role in the biosynthesis of many natural products and in the human metabolism of numerous pharmaceuticals. This has inspired synthetic organic and medicinal chemists to exploit them as catalysts in regio- and stereoselective CH-activating oxidation of structurally simple and complex organic compounds such as steroids. However, levels of regio- and stereoselectivity as well as activity are not routinely high enough for real applications. Protein engineering using rational design or directed evolution has helped in many respects, but simultaneous engineering of multiple catalytic traits such as activity, regioselectivity and stereoselectivity, while overcoming tradeoffs and diminishing returns, remains a challenge. Here we show that the exploitation of information derived from mutability landscapes and molecular dynamics simulations for rationally designing iterative saturation mutagenesis constitutes a viable directed evolution strategy. This combined approach is illustrated by the evolution of P450BM3 mutants which enable nearly perfect regio- and diastereoselective hydroxylation of five different steroids specifically at the C16-position with unusually high activity, while avoiding activity-selectivity tradeoffs as well as keeping the screening effort relatively low. The C16 alcohols are of practical interest as components of biologically active glucocorticoids.

Cysteine conjugation is an important tool in protein research and relies on fast, mild and chemoselective reactions. Cysteinyl thiols can either be modified with prefunctionalized electrophiles, or converted into electrophiles themselves for functionalization with selected nucleophiles in an independent step. Here we report a bioconjugation strategy that uses a vinyl thianthrenium salt to transform cysteine into a highly reactive electrophilic episulfonium intermediate in situ, to enable conjugation with a diverse set of bioorthogonal nucleophiles in a single step. The reactivity profile can connect several nucleophiles to biomolecules through a short and stable ethylene linker, ideal for introduction of infrared labels, post-translational modifications or NMR probes. In the absence of reactive exogenous nucleophiles, nucleophilic amino acids can react with the episulfonium intermediate for native peptide stapling and protein–protein ligation. Ready synthetic access to isotopologues of vinyl thianthrenium salts enables applications in quantitative proteomics. Such diverse applications demonstrate the utility of vinyl-thianthrenium-based bioconjugation as a fast, selective and broadly applicable tool for chemical biology.

Many polycyclic marine alkaloids are thought to derive from partly reduced macrocyclic alkylpyridine derivatives via a transannular Diels–Alder reaction that forms their common etheno-bridged diaza-decaline core (“Baldwin–Whitehead hypothesis”). Rather than trying to emulate this biosynthesis pathway, a route to these natural products following purely chemical logic was pursued. Specifically, a Michael/Michael addition cascade provided rapid access to this conspicuous tricyclic scaffold and allowed different handles to be introduced at the bridgehead quarternary center. This flexibility opened opportunities for the formation of the enveloping medium-sized and macrocyclic rings. Ring closing alkyne metathesis (RCAM) proved most reliable and became a recurrent theme en route to keramaphidin B, ingenamine, xestocyclamine A, and nominal njaoamine I (the structure of which had to be corrected in the aftermath of the synthesis). Best results were obtained with molybdenum alkylidyne catalysts endowed with (tripodal) silanolate ligands, which proved fully operative in the presence of tertiary amines, quinoline, and other Lewis basic sites. RCAM was successfully interlinked with macrolactamization, an intricate hydroboration/protonation/alkyl-Suzuki coupling sequence, or ring closing olefin metathesis (RCM) for the closure of the second lateral ring; the use of RCM for the formation of an 11-membered cycle is particularly noteworthy. Equally rare are RCM reactions that leave a pre-existing triple bond untouched, as the standard ruthenium catalysts are usually indiscriminative vis-à-vis the different π-bonds. Of arguably highest significance, however, is the use of two consecutive or even concurrent RCAM reactions en route to nominal njaoamine I as the arguably most complex of the chosen targets.