Methyl groups are ubiquitous in biologically active molecules. Thus, new tactics to introduce this alkyl fragment into polyfunctional structures are of significant interest. With this goal in mind, a direct method for the Markovnikov hydromethylation of alkenes is reported. This method exploits the degenerate metathesis reaction between the titanium methylidene unveiled from Cp2Ti(μ‐Cl)(μ‐CH2)AlMe2 (Tebbe's reagent) and unactivated alkenes. Protonolysis of the resulting titanacyclobutanes in situ effects hydromethylation in a chemo‐, regio‐, and site‐selective manner. The broad utility of this method is demonstrated across a series of mono‐ and di‐substituted alkenes containing pendant alcohols, ethers, amides, carbamates, and basic amines.

Proteoglycans are heterogeneous macromolecular glycoconjugates that orchestrate many important cellular processes. While much attention has focused on the poly-sulfated glycosaminoglycan chains that decorate proteoglycans, other important elements of proteoglycan architecture, such as their core proteins and cell surface localization, have garnered less emphasis. Hence, comprehensive structure-function relationships that consider the replete proteoglycan architecture as glycoconjugates are limited. Here, we present a comprehensive approach to study proteoglycan structure and biology by fabricating defined semi-synthetic modular proteoglycans that can be tailored for cell surface display. To do so, we integrate amber codon reassignment in the expression of sequence-fined proteoglycan core proteins, metabolic oligosaccharide engineering to produce functionalizable glycosaminoglycans, and bioorthogonal click chemistry to covalently tether the two components. These materials permit the methodical dissection of the parameters required for optimal binding and function of various proteoglycanbinding proteins, and they can be modularly displayed on the surface of any living cell. We demonstrate that these sophisticated materials can recapitulate the functions of native proteoglycans in mouse embryonic stem cell differentiation and cancer cell spreading, while permitting the identification of the most important contributing elements of proteoglycan architecture toward function. This technology platform will confer structural resolution toward the investigation of proteoglycan structure-function relationships in cell biology.

A new polyene cyclization strategy exploiting β-ionyl derivatives was developed. Photoinduced deconjugation of the extended π-system within these chromophores unveils a contrathermodynamic polyene that engages in a Heck bicyclization to afford [4.4.1]-propellanes. This cascade improves upon the limited regioselectivity achieved using existing biomimetic tactics and tolerates both electron-rich and electron-deficient (hetero)­aryl groups. The utility of this approach was demonstrated with the diverted total synthesis of taxodione and salviasperanol, two isomeric abietane diterpenes that were previously inaccessible along the same synthetic pathway.

Methyl groups are ubiquitous in biologically active molecules. Thus, new tactics to introduce this alkyl fragment into polyfunctional structures are of significant interest. With this goal in mind, a direct method for the Markovnikov hydromethylation of alkenes is reported. This method exploits the degenerate metathesis reaction between the titanium methylidene unveiled from Cp2Ti(μ‐Cl)(μ‐CH2)AlMe2 (Tebbe's reagent) and unactivated alkenes. Protonolysis of the resulting titanacyclobutanes in situ effects hydromethylation in a chemo‐, regio‐, and site‐selective manner. The broad utility of this method is demonstrated across a series of mono‐ and di‐substituted alkenes containing pendant alcohols, ethers, amides, carbamates, and basic amines.