The ever-expanding role of asymmetric covalent organocatalysis in scalable, natural product synthesis

Abstract

Following the turn of the millennium, the role of asymmetric covalent organocatalysis has developed into a scalable, synthetic paradigm galvanizing the synthetic community toward utilization of these methods toward more practical, metal-free syntheses of natural products. A myriad of reports on asymmetric organocatalytic modes of substrate activation relying on small, exclusively organic molecules are delineating what has now become the multifaceted field of organocatalysis. In covalent catalysis, the catalyst and substrate combine to first form a covalent, activated intermediate that enters the catalytic cycle. Following asymmetric bond formation, the chiral catalyst is recycled through hydrolysis or displacement by a pendant group on the newly formed product. Amine- and phosphine-based organocatalysts are the most common examples that have led to a vast array of reaction types. This Highlight provides a brief overview of covalent modes of organocatalysis and applications of scalable versions of these methods applied to the total synthesis of natural products including examples from our own laboratory.

Novel β‐amino Amide Organocatalysts for the Synthesis of Pharmaceutically Relevant Oxindoles

“…Organocatalytic transformations, as an alternative to complex metal catalysts, have gained extensive attention for their stereoselective control, as well as the potential of adapting their mode of activation to suit a wide scope of reactions. [3] The book Sustainable Catalysis [2] highlights key catalytic transformations applied towards pharmaceuticals and fine chemicals. Suggested by the authors, the main limitation of this field is the challenges associated with bridging research and industrial applications.…”

Utility and NMR studies of α,β-unsaturated acylammonium salts: synthesis of polycyclic dihydropyranones and a dihydropyridone

“…In the area of asymmetric organocatalysis, chiral α,β-unsaturated acylammonium salts are beginning to draw greater attention. 13 A remarkable innovation in this area occurred when Fu and co-workers discovered a [3 + 2] annulation of an indene with a chiral α,β-unsaturated acylammonium salt derived from α,β-unsaturated acid fluorides to produce diquinanes, catalyzed by a chiral PPY derivative.…”

“…Table 3. 13 C NMR analysis of various acylammonium salts and comparison to an acid chloride and amide.…”

“…The 13 C chemical shifts of crotonyl chloride (δ 152.9) and the derived morpholino amide 9a (δ 142.0) were measured and used as comparators (Table 3, entries 1 and 2). As expected, the acid chloride has a significant downfield chemical shift for the β-carbon (∆δ −10.9) compared to the amide.…”

Organocatalysts for enantioselective synthesis of fine chemicals: definitions, trends and developments

“…In fact, within the catalytic cycle, the key intermediate is an iminium ion (I), which lowers the LUMO energy of the electrophilic double bond of substrate. The subsequent stereoselective addition of the hydroperoxide anion, followed by the cyclisation, leads to the enantioenriched product (Figure 8c) [34]. The understanding of the mechanisms for covalent organocatalysis is growing and an ever-increasing number of evidences highlight that the reactivity in organocatalytic reactions is often influenced and modulated by secondary non-covalent interactions [35].…”