Terpenes represent one of the largest classes of natural products, valued for their diverse biological activity and utility in treatment of human diseases. However, challenges in controlling the selectivity of terpene cyclization reactions have made large-scale production of these compounds challenging. Nature is much more efficient, as enzymes can selectively promote tail-to-head (THT) terpene cyclizations within a defined pocket. Recently, a group of researchers led by Konrad Tiefenbacher have developed the first successful THT terpene cyclization inside a synthetic catalyst (Nature Chemistry, DOI: 10.1038/nchem.2181). The cavity within the supramolecular hydrogen-bond-based capsule mimics an enzyme pocket, providing a defined chemical environment for the substrate to bind and cyclize in a selective fashion.
Now the researchers have elucidated the substrate scope and mechanistic details concerning this discovery (DOI: 10.1021/jacs.7b04480). The authors demonstrate that noncovalent interactions between the enzyme-like capsule and leaving group of the substrate directly influence product selectivity. Moreover, a series of kinetic studies reveal the synergistic role between the capsule and trace acid in promoting catalytic activity. The fundamental insights gained from these studies will aid in the development of artificial catalysts capable of promoting transformations that were once only possible with natural enzymes.
How To Mimic Mussels’ Amazing Adhesive Properties
Christine Herman (Ph.D.)
Mussels have the amazing ability to adhere firmly to wet surfaces. They do so by sending out sticky filaments, known as byssus threads, which allow them to stay anchored to rocks in the midst of pounding waves. For years, researchers have been striving to recreate mussels’ adhesive properties in a laboratory setting, with a major focus on the functional group known as catechols, which are abundant in byssus threads and are comprised of benzene rings presenting hydroxyl groups that interact strongly with surfaces, for example, via hydrogen and coordination bondings.
In a new Perspective, Kollbe Ahn explains that the focus on catechols is too narrow and has hampered efforts to emulate mussel adhesion for applications ranging from dental and medical to industrial applications (DOI: 10.1021/jacs.6b13149). In an extensive review of the literature, he makes the case that mussels’ adhesive abilities also rely on a host of other functional groups on proteins that work together to achieve strong and robust adhesion. The paper highlights numerous recent advances that demonstrate a more holistic approach to biomimetic design, which may be key to future advances in the area of high-performance materials.
Metal-Free or Not Metal-Free, That Is the Question
Nicole Camasso (Ph.D.)
High-turnover catalysis (HTC) is a powerful method in organic synthesis that achieves high-yielding product formation with very small catalyst loadings (<0.1 mol%). Despite the benefits of this efficient and environmentally benign phenomenon, HTC can complicate the mechanistic understanding of a reaction that is thought to be “metal-free.” A means of identifying an active catalyst that may be present in trace amounts would mitigate this increasingly problematic area in catalysis.
Recently, Dean Tantillo, Richmond Sarpong, Jason Hein, and co-workers conduct a detailed investigation on the mechanism of a “metal-free” heterocycloisomerization that forms annulated aminopyrroles (DOI: 10.1021/jacs.7b06007). Through kinetic isotope effect studies and unexpected rate differences among starting materials with different purification methods, the authors identify a copper complex present in trace amounts as the active catalyst for this transformation. This discovery is enabled by combined experimental and computational evaluations of model systems as well as extensive analytical instrumentation. The reported work is an important contribution to the field of organic synthesis and provides a mechanistic model for systematically determining whether a no-metal-added catalytic system is truly metal-free.
New Insights for an Old Model Enzyme
Erika Gebel Berg (Ph.D.)
Triosephosphate isomerase (TIM) is a research workhorse; scientists have been studying its mechanism for decades to better understand biological catalysis in general. TIM’s main catalytic action is executed by a glutamic acid at position 165 (E165), which performs general acid base catalysis that converts dihydroxyacetone phosphate (DHAP) to d-glyceraldehyde phosphate (GAP). Before E165 gets in the game, TIM undergoes a large conformational change, bringing two key hydrophobic side chains, isoleucine at position 170 (I170) and a leucine at position 230 (L230), into close proximity to E165, forming a “hydrophobic clamp” around E165 that facilitates catalysis.
One unanswered question in TIM catalysis is how the closeness of I170 and L230 to E165 supports substrate deprotonation. John Richard, Shina Kamerlin, and colleagues perform empirical valence bond calculations on wild-type and mutant versions of TIM to elucidate the contribution of the hypdophobic side chains to deprotonation of DHAP (DOI: 10.1021/jacs.7b05576). The calculations reveal that I170 and L230 work by lowering the Gibbs free energy of substrate deprotonation. The disruption of the side chain placement within the active site weakens the interactions between enzyme and transition state, allowing for product release. The results square well with experimental findings and provide a new level of molecular detail on TIM’s mechanism.
Searching for Oceans in the Mantle of the Earth
Erika Gebel Berg (Ph.D.)
There may be more water beneath the Earth’s surface than in all the oceans. The Earth’s mantle contains mineral silicates, including wadsleyite (β-Mg2SiO4) and its polymorph ringwoodite (γ-Mg2SiO4), a spinel material. OH defects in the mantle’s minerals require charge compensation by cation vacancies, offering the potential for water formation. Some evidence suggests the mantle minerals could contain up to 3% water; however, it is difficult for scientists to gather samples from deep within Earth’s interior for direct measurements. The water content of Earth’s mantle is of interest because it influences convection, the force that allows tectonic plates to move around Earth’s surface.
While defect chemistry for wadsleysite is well understood, ringwoodite has remained a mystery due to challenges obtaining sample and difficulties interpreting its IR spectrum. Daniel Frost, Jürgen Senker, and colleagues combine multi-dimensional nuclear magnetic resonance spectroscopy with density functional theory calculations of electronic structure to explore defect chemistry and charge compensation in crystalline ringwoodite (DOI: 10.1021/jacs.7b05432). They find that, in addition to isolated Mg and Si defects, a significant proportion of coupled vacancies are also present, which was not observed for other anhydrous high-pressure minerals. Their findings may help clarify the properties of hydrous spinel type materials, such as ion conduction and heterogeneous catalysis.
Nurturing Nature: Engineered Enzyme Enables Efficient Total Synthesis
Nicole Camasso (Ph.D.)
Carbon–hydrogen oxidations are a powerful class of reactions that transform C–H bonds into oxidized products, enabling late-stage diversification of a wide range of molecules. As a result, the development of transition-metal-catalyzed C–H functionalizations remains a highly active area in organic synthesis. Despite great progress in this field, challenges in controlling the site-selectivity of non-directed C–H functionalizations limit the broad utility of these methods. An alternative approach would utilize enzyme catalysts to overcome the inherent limitations of classical organic chemistry.
In a collaborative research effort led by Frances Arnold and Brian Stoltz, the authors disclose the first enantioselective total synthesis of the norditerpenoid alkaloid, Nigelladine A, enabled by an engineered enzyme (DOI: 10.1021/jacs.7b05196). The concise synthetic sequence relies on the enzyme (a cytochrome P450 variant) to achieve the challenging late-stage allylic C–H oxidation of an advanced intermediate. While traditional synthetic methods give complex mixtures of products, the evolved enzyme-catalyzed reaction achieves a highly site-selective allylic oxidation. The engineered enzyme variant is easily identified without the need for extensive screening. The reported work demonstrates the complementary role biocatalysis can play in organic synthesis and the benefits of utilizing nature when chemical methods fall short.
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