An enantioselective total synthesis of the norditerpenoid alkaloid nigelladine A is described. Strategically, the synthesis relies on a late stage C-H oxidation of an advanced intermediate. While traditional chemical methods failed to deliver the desired outcome, an engineered cytochrome P450 enzyme was employed to effect a chemo- and regioselective allylic C–H oxidation in the presence of four oxidizable positions. The enzyme variant was readily identified from a focused library of three enzymes, allowing for completion of the synthesis without the need for extensive screening.

The first total synthesis of the norcembranoid diterpenoid scabrolide A is disclosed. The route begins with the synthesis of two chiral pool-derived fragments, which undergo a convergent coupling to expediently introduce all 19 carbon atoms of the natural product. An intramolecular Diels-Alder reaction and an enone-olefin cycloaddition/fragmentation sequence are then employed to construct the fused [5-6-7] linear carbocyclic core of the molecule and to complete the total synthesis. File list (3) download file view on ChemRxiv ScabrolideAManuscriptFinalDraft.pdf (479.10 KiB) download file view on ChemRxiv TOCGraphic.pdf (129.56 KiB) download file view on ChemRxiv ScabrolideSIFinal.pdf (13.10 MiB)

Abstract. The elevational gradient in plant defense (EGPD) hypothesis posits that natural enemy pressures increase alongside temperature across elevational climatic gradients, thereby selecting for enhanced defenses at lower elevations while leaving plants less defended at higher elevations. Phylogenetically constrained tests of this hypothesis are uncommon, with tests focused on defenses of mature trees in natural settings being exceedingly rare. In the absence of this information, predicting the spatiotemporal dynamics of forest pests that preferentially attack mature trees is rendered more difficult. Tree properties such as age, growth rate, and size have all been correlated with levels of tree defenses against insect pests. Thus, we sought to disentangle the interacting influences of these properties from possible elevational climatic effects on monoterpene concentrations, diversity, and intraspecific dissimilarity of constitutive resin within three widespread pines (Pinus contorta, Pinus ponderosa, and Pinus flexilis) across a 1530-m elevational transect in the Rocky Mountains, Colorado, USA. Overall, we found some support for the EGPD hypothesis within all three of the pine species studied. However, while elevation and tree properties were strong predictors of the variation in monoterpene concentration and moderate predictors of variation in diversity and dissimilarity in P. contorta, they were a relatively weak set of predictors in P. ponderosa and P. flexilis. Significant, (negative) elevational effects were found for total monoterpene concentration in P. contorta and monoterpene diversity in P. ponderosa, while elevation had a significant negative effect on monoterpene concentration and diversity, and a positive effect on dissimilarity in P. flexilis. Nevertheless, tree age, size, and/or growth measures had significant influences on one or more monoterpene measures in all three of the pine species indicating a need to parse effects of these factors within studies of tree defenses across environmental gradients. Our results offer some support for the EGPD hypothesis while suggesting the presence of a variable hierarchy of drivers of pine defense and resistance across congeners in shared environments-a situation that presents challenges for predicting spatiotemporal patterns in secondary chemistry across species from a common set of potential drivers.

Neoglycosylations are increasingly being employed in the synthesis of natural products, drug candidates, glycopeptide mimics, oligosaccharide analogues, and other applications, but the efficiency of these reactions is usually limited by slow reaction times. Here, we show that aniline derivatives such as 2-amino-5-methoxybenzoic acid enhance the rate of acid-catalyzed neoglycosylation for a range of sugar substrates up to a factor of 32 relative to the uncatalyzed reaction.

The first general method for the enantioselective construction of all-carbon quaternary centers on cyclopentanones by enantioselective palladium-catalyzed decarboxylative allylic alkylation is described. Employing the electronically modified (S)-(p-CF3)3-t-BuPHOX ligand, α-quaternary cyclopentanones were isolated in yields up to >99% with ee’s up to 94%. Additionally, in order to facilitate large-scale application of this method, a low catalyst loading protocol was employed, using as little as 0.15 mol % Pd, furnishing the product without any loss in ee.