Rising Stars in Organic Synthesis, Session 3

Abstract

The Science of Synthesis Early Career Board (ECAB), established in 2022, and the Thieme Chemistry Journal Awards recognize some of the most up-and-coming young organic chemists. We are very proud to present both ECAB members and journal award winners as speakers in this Rising Stars Cheminar.Constructive Ozonolysis: Capturing Primary OzonidesWe have found that primary ozonides have predictable lifetimes and can be harnessed as synthetic intermediates providing us an avenue to explore new carbon oxygen bond forming reactions. In this work, we describe the proof-of-principle development of a new, simple, and green syn dihydroxylation reaction through trapping primary ozonides with nucleophiles. Although there are currently many options to choose from when preparing syn-glycols a green and sustainable alternative to the transition metal-based approach is of great benefit on many fronts and its wide utility in chemistry made it the ideal reaction to launch our research program in constructive ozonolysis. Specifically, we show that primary ozonides are reactive intermediates that have definitive lifetimes at -80 C and can be captured in continuous flow. This becomes especially important because this method has virtually zero peroxide accumulation and eliminates the need to store hazardous oxidizing agents. We have demonstrated that our flow method can produce pharmaceutically relevant compounds by preparing guaifenesin, the active component in Mucinex, and a precursor to Ponesimod, a recently approved drug for multiple sclerosis.Cyclopropane Synthesis using Palladium CarbenesMethods to synthesize strained rings are a critical component of drug discovery programs. Herein, we describe a platform to obtain orphaned cyclopropanes and cyclobutanes rings using α,α-disubstituted vinyl-, crotyl- and allylhydrazone reagents. We found that the oxidation state of palladium carbene intermediate impacts the mode of carbene reactivity (i.e. cyclopropanation vs C–H insertion). Lastly, highly strained [2.1.0]-bicycles can be obtained by an intramolecular cyclopropanation reaction using Pd(0)-NHC complexes. Access to Previously "Inaccessible" Arynes Using Transition MetalsResearch in the Roberts group involves looking at unsolved problems in organic synthesis through the perspective of organometallic/inorganic chemistry. One main area of interest for the group is the synthesis of heterocycles through aryne intermediates. Despite their useful reactivity, a number of challenges still remain in the use of arynes including problems with regioselectivity and the synthesis of N-heterocyclic arynes. Using fundamental principles of Ni chemistry, our group is the first to be able to access previously “inaccessible” 5-membered heterocyclic arynes for the first time since they were hypothesized to exist 120 years ago.The use of C―H bond oxidations in the synthesis of natural productsSelective oxidations play an important role in chemical access to more diverse products in a regio-, chemo- and diastereoselective manner. More specifically, the oxidation of C–H bonds has emerged as a powerful tool in the insertion of oxygenated functionalities at a late stage in the synthesis of complex molecules, eliminating the need for additional manipulations of functional groups. In this sense, we will show our recent efforts in the synthesis of natural diterpenes through selective oxidation reactions.Sulfonylcyclopropanols as Modular Cyclopropanone EquivalentsCyclopropanone derivatives have long been regarded as unusable and elusive synthetic intermediates, mainly owing to their prominent ring strain and kinetic instability. In this work, we report the stereospecific synthesis of sulfonylcyclopropanols, shown to be modular and versatile synthetic equivalents of the corresponding cyclopropanone derivatives. These reagents were found to smoothly react in a variety of reaction manifolds, including organometallic 1,2-addition affording cyclopropanols, nitrene chemistry to access chiral β-lactams, nickel-catalyzed C–C activation to cyclopentenones, as well as olefination chemistry as a general platform to chiral alkylidenecyclopropanes and other substituted cyclopropanes. Moreover, we have shown that sulfonylcyclopropanols can behave as sources of ‘C(1)-oxidized cyclopropanols’ when treated successively with amines and oxidants, effectively acting as ring-opened 3-carbon linchpin reagents. This work constitutes the first general route to enantioenriched cyclopropanone equivalents, thus unlocking a number of novel synthetic disconnections relevant to various chemical industries.