Navigating the Pauson–Khand Reaction in Total Syntheses of Complex Natural Products

Abstract

Conspectus “Total synthesis endeavors provide wonderful opportunities to discover and invent new synthetic reactions as a means to advance organic synthesis in general. Such discoveries and inventions can occur when the practitioner faces intransigent problems that cannot be solved by known methods and/or when method improvements are desired in terms of elegance, efficiency, cost-effectiveness, practicality, or environmental friendliness” (K. C. Nicolaou et al. from their review in CCS Chem.20191337). To date tens of thousands of bioactive compounds have been isolated from plants, microbes, marine invertebrates, and other sources. These chemical structures have been studied by chemists who scanned the breadth of natural diversity toward drug discovery efforts. Drug-likeness of natural products often possesses common features including molecular complexity, protein-binding ability, structural rigidity, and three-dimensionality. Considering certain biologically important natural products are scarce from natural supply, total synthesis may provide an alternative solution to generating these compounds and their derivatives for the purpose of probing their biological functions. Natural products bearing quaternary carbon stereocenters represent a group of biologically important natural entities that are lead compounds in the development of pharmacological agents and biological probes. However, the stereocontrolled introduction of quaternary carbons, with vicinal patterns that substantially expand the complexity of molecular architectures and chemical space in particular, presents distinct challenges because of the high steric repulsion between substituents. Though remarkable advance has been seen for quaternary carbon stereocenter generation, the process remains a daunting challenge given that the formation of highly congested stereocenters increases the difficulty in achieving orbital overlap. In the past two decades, our group has initiated a program to develop synthetic strategies and methods with the aim of advancing the frontiers of the total syntheses of biologically important complex natural products bearing all-carbon quaternary stereogenic centers. Typical endeavors have involved the use of a Pauson–Khand (PK) reaction as a key step in constructing core structures with all-carbon quaternary stereogenic center(s), with the aid of well-orchestrated thiourea–Co- and thiourea–Pd-catalyzed PK reactions. These methodological advances have enabled us to achieve total syntheses of a series of topologically complex natural products with diverse structural features. These methods will enable the assembly of molecules with improved biological functions and provide tool compounds for elucidation of mechanism of action or identification of potential cellular targets.

Dearomative (3 + 2) Cycloadditions of Unprotected Indoles

“…Of those two options, oxyallyl cyclopentannulation methodology has to date been the least developed, although cyclopentanoid scaffolds are widespread and medicinally relevant motifs, for which only few general approaches exist . The development of generic methods that allow the parallel synthesis of variously substituted cyclopentanoids is thus of high interest, and allyl cation (3 + 2) cycloadditions are placed among a select few synthetic organic transformations that are well-suited for this purpose, together with the better-known Pauson–Khand reaction, and trimethylenemethane (TMM) cycloaddition . More recently, donor–acceptor cyclopropanes have emerged as a potent class of amphiphilic reagents for (3 + 2) cycloadditions …”

“…Scheme d). Cyclopentane-fused indoles are indeed common motifs found in bioactive natural products. ,, The derivatization of indoles via a cyclopentannulation also offers an attractive perspective for “late stage” derivatization of typical scaffolds that are found in compound screening libraries, although existing methods do require protecting groups and/or specific substitution patterns of indoles and dearomatizing reaction partners. , …”

Fe-Catalyzed Selective Formal Insertion of Diazo Compounds into C(sp)–C(sp3) Bonds of Propargyl Alcohols: Access to Alkyne-Substituted All-Carbon Quaternary Centers

“…All-carbon quaternary centers have rigidity and structural diversity and are key structural units in many natural products, pharmaceuticals, as well as biologically active molecules. − Hence, the construction of all-carbon quaternary centers is quite attractive for organic synthetic chemists; structures containing alkyne-substituted framework are versatile intermediates and basic structural motifs in organic transformations. , The most common method for obtaining alkyne-substituted all-carbon quaternary centers is through the whole assembly of alkynyl groups into other substrates (Figure a), such as Sonogashira coupling, − electrophilic alkynylation, − enantioselective conjugate alkynylation, − and so on. , Major obstacles to these aforementioned transformations include dimerization of terminal alkynes, reliance on functionalized precursors, and the β-H elimination of branched tertiary alkyl units. In this case, as an alternative strategy to solve these problems, we questioned whether a specific protocol could be realized through selective cleavage of C­(sp)–C­(sp 3 ) bonds of internal alkynes and subsequent insertion of carbon sources to construct alkyne-substituted all-carbon quaternary centers (Figure b). − …”

Application of Pauson–Khand reaction in the total synthesis of terpenes

“…Therefore, IPKR has found several applications in the total synthesis of natural products frequently used as the key step. 6,[24][25][26] Synthetic organic chemistry has developed momentously owing to the exponential growth in transition-metal-catalyzed reactions. The effect of transition-metal-catalyzed reactions on organic synthesis could be evaluated by the wide range of molecules that have been developed from simple compounds to complex natural products.…”