Mechanistic Insight toward Understanding the Role of Charge in Thiourea Organocatalysis

Abstract

Pyranylation and glycosylation are pivotal for accessing a myriad of natural products, pharmaceuticals, and drug candidates. Catalytic approaches for enabling these transformations are of utmost importance and integral to advancing this area of synthesis. In exploring this chemical space, a combined experimental and computational mechanistic study of pyranylation and 2-deoxygalactosylation catalyzed by a cationic thiourea organocatalyst is reported. To this end, a thiourea−cyclopropenium organocatalyst was employed as a model system in combination with an arsenal of mechanistic techniques, including 13 C kinetic isotope effect experiments, deuterated labeling studies, variable-temperature 1 H NMR spectroscopy, and density functional theory calculations. From these studies, two distinct reaction pathways were identified for this transformation corresponding to either dual hydrogen bond (Hbond) activation or Brønsted acid catalysis. The former involving thiourea orchestrated bifurcated hydrogen bonding proceeded in an asynchronous concerted fashion. In contrast, the latter stepwise mechanism involving Brønsted acid catalysis hinged upon the formation of an oxocarbenium intermediate accompanied by subsequent alcohol addition.

Organocatalysis Linked to Charge-Enhanced Acidity with Superelectrophilic Traits

“…Our long-standing history in working with cyclopropenium ions − and catalysis ,, prompted this development. Coupled to this was the prospect of synthesizing a structurally unprecedented cationic catalyst, bearing two highly strained aromatic ring systems, namely, a cyclopropenium and a squaramide, together with an electron-deficient aryl group.…”

Anion-Activated Bases and Nucleophiles Characterized by Photoelectron Spectroscopy

“…Electric fields can impact bond energies and a wide range of chemical transformations. − One general application that has been explored over the past decade is the incorporation of a positively charged substituent into a neutral Brønsted acid so as to enhance its acidity and catalytic abilities. − Conversely, one would expect that a negatively charged substituent can be used to increase the basicity and nucleophilicity of a noncharged Brønsted base since a positive charge builds up at the basic or nucleophilic site. Given the tremendous importance of bases and nucleophiles in biological and industrial processes including the synthesis of pharmaceutical and agrochemicals, − we decided to investigate these species.…”

Bis(amino)cyclopropenium Ion as a Hydrogen-Bond Donor Catalyst for 1,6-Conjugate Addition Reactions

“…The role of H-bonding interactions of the N–H proton (N–H···X) in TDAC salt-catalyzed organic transformations has been investigated thoroughly ( I , Figure ). Nevertheless, the catalytic mode of activation through the H-bonding interaction by the C–H proton (C–H···X) of the cyclopropene ring in bis­(dialkylamino)­cyclopropenium salts in organic reactions is rather limited. For example, very recently, Dudding’s group demonstrated the existence of C–H···F – interactions ( II , Figure ) in O -silyl ether deprotection and benzylic fluorination reactions through experimental and computational methods.…”