Shawn K. Collins

The “phase separation” strategy exploits aggregated solvent mixtures of poly(ethylene)glycol (PEG) solvents and hydrophilic organic solvents to control the effective molarity of substrates and catalysts in macrocyclization reactions. The slow diffusion of acyclic precursors from the PEG aggregate “phase” to the organic solvent/catalyst “phase” mimics the slow addition processes typically employed in the synthesis of macrocycles. With the aid of mechanistic studies, the strategy has been applied to copper-catalyzed Glaser–Hay couplings, copper-catalyzed azide–alkyne cycloadditions, copper-catalyzed azide-iodoalkyne cycloadditions, and ruthenium-catalyzed olefin metathesis processes. “Phase separation” has been used to form macrocycles of interest in aromachemicals, lipid-based macrocycles, bioactive natural products, macrocyclic peptides, and bioactive pharmaceuticals. The “phase separation” strategy has been proven to promote transition metal-catalyzed macrocyclization processes with increases in concentration up to three orders of magnitude larger than traditional methods like high dilution or pseudo high dilution/slow addition.

A strain release cycloaddition has been developed that exploits intermediate azirines formed via irradiation with blue LEDs. Subsequent cycloaddition with pyrones afforded novel aza-heterocycles (13 examples, 42%→66% yields). A variety of substituents were tolerated. Computational analysis suggests a kinetically favored endo-[4 + 2]cycloaddition that occurs from the least sterically encumbered face of the azirine. Distortion/interaction analysis suggests that the energetic penalty associated with azirine deformation is the primary factor contributing to the observed selectivity.

A terphenyl diyne (TPDY) macrocycle, 3,5-TPDY, has been developed incorporating a bent 1,3-diyne that is active in SPAAC processes affording atropoisomeric triazole products, as well as cycloadditions with diazoacetates and tetrazines. A pendant amine allowed bioconjugation of TPDY to two proteins in a microbial transglutaminase-catalyzed reaction. In contrast to many cycloalkyne SPAAC reagents, the TPDY stabilization occurs via interactions of π and π* orbitals of the adjacent alkynes.

Photocatalysis mediated by low energy light wavelengths has potential to enable safer, sustainable synthetic methods. A phenanthroline‐derived ligand bathocupSani, with a large two‐photon absorption (TPA) cross section was used to construct a heteroleptic complex [Cu(bathocupSani)(DPEPhos)]BF₄ and a homoleptic complex [Cu(bathocupSani)₂]BF₄. The ligand and the respective homoleptic complex with copper exhibit two‐photon upconversion with an anti‐Stokes shift of 1.2 eV using red light. The complex [Cu(bathocupSani)₂]BF₄ promoted energy transfer photocatalysis enabling oxidative dimerization of benzylic amines, sulfide oxidation, phosphine oxidation, boronic acid oxidation and atom‐transfer radical addition.

Photocatalysis mediated by low energy light wavelengths has potential to enable safer, sustainable synthetic methods. A phenanthroline‐derived ligand bathocupSani, with a large two‐photon absorption (TPA) cross section was used to construct a heteroleptic complex [Cu(bathocupSani)(DPEPhos)]BF₄ and a homoleptic complex [Cu(bathocupSani)₂]BF₄. The ligand and the respective homoleptic complex with copper exhibit two‐photon upconversion with an anti‐Stokes shift of 1.2 eV using red light. The complex [Cu(bathocupSani)₂]BF₄ promoted energy transfer photocatalysis enabling oxidative dimerization of benzylic amines, sulfide oxidation, phosphine oxidation, boronic acid oxidation and atom‐transfer radical addition.

Macrolactonization is a challenging process where high dilution and temperatures can extend reaction times and promote reagent degradation. Biocatalysis is a versatile strategy for synthesis but not traditionally associated within the toolbox of organic chemists for macrocyclization. Macrolactonization has been investigated using modern methods employing both catalysis and stoichiometric activation strategies on 20 different substrates with differing ring sizes and types (cyclophanes, macrolactones, macrodiolides) and structural features at the reaction site (central vs. planar chirality; primary vs. secondary alcohols). The data demonstrates that of all protocols examined, the biocatalytic route was superior, providing the highest average yields across all classes of macrocycles studied. From the stoichiometric activation strategies investigated, the Yamaguchi macrolactonization was the most versatile in terms of ring size and nature. Despite the advantages of biocatalytic macrolactonization, advances in developing supported, versatile non-enantioselective lipases would actually represent a useful tool in molecular synthesis.