“<scp>K‐synthesis</scp>”: Recent advancements in natural product synthesis enabled by unique methods and strategies development in Korea

Han, Sunkyu

doi:10.1002/bkcs.12654

Cited by 32 publications

(16 citation statements)

References 197 publications

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“…Considering the biosynthetic diversity of Securinega alkaloids, we believe that many other fascinating natural products are awaiting to be discovered. Our exciting synthetic journey in the uncharted “sea” of high-order and high-oxidation-state Securinega alkaloids will continue …”

Section: Summary and Outlookmentioning

confidence: 99%

Synthesis of High-Order and High-Oxidation State Securinega Alkaloids

2023

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Conspectus Securinega alkaloids, composed of more than 100 members characterized by the compact tetracyclic scaffold, have fascinated the synthetic community with their structural diversity and notable bioactivities. On the basis of the structural phenotype, oligomerizations and oxidations are major biosynthetic diversification modes of the basic Securinega framework. Despite the rich history of synthesis of basic monomeric Securinega alkaloids, the synthesis of oligomeric Securinega alkaloids, as well as oxidized derivatives, has remained relatively unexplored because of their extra structural complexity. In the first half of this Account, our synthetic studies toward high-order Securinega alkaloids are described. We aimed to establish a reliable synthetic method to form C14–C15′ and C12–C15′ bonds, which are prevalent connection modes between monomers. During our total synthesis of flueggenine C (9), we have invented an accelerated Rauhut–Currier reaction capable of forming the C14–C15′ bond stereoselectively. Installation of the nucleophilic functionality to the Michael acceptor, which ushers the C–C bond forming conjugate addition to follow the intramolecular pathway, was the key to success. The C12–C15′ linkage, which was inaccessible via an accelerated Rauhut–Currier reaction, was established by devising a complementary cross-coupling/conjugate reduction-based dimerization strategy that enabled the total synthesis of flueggenines D (11) and I (14). In this approach, the C12–C15′ linkage was established via a Stille cross-coupling, and the stereochemistry of the C15′ position was controlled during the following conjugate reduction step. In the later half of this Account, our achievements in the field of high-oxidation state Securinega alkaloids synthesis are depicted. We have developed oxidative transformations at the N1 and C2–C4 positions, where the biosynthetic oxidation event occurs most frequently. The discovery of a VO(acac)2-mediated regioselective Polonovski reaction allowed us to access the key 2,3-dehydroallosecurinine (112). Divergent synthesis of secu′amamine A (62) and fluvirosaones A (60) and B (61) was accomplished by exploiting the versatile reactivities of the C2/C3 enamine moiety in 112. We have also employed a fragment-coupling strategy between menisdaurilide and piperidine units, which allowed the installation of various oxygen-containing functionality on the piperidine ring. Combined with the late-stage, light-mediated epimerization and well-orchestrated oxidative modifications, collective total synthesis of seven C4-oxygenated securinine-type natural products was achieved. Lastly, the synthesis of flueggeacosine B (70) via two synthetic routes from allosecurinine (103) was illustrated. The first-generation synthesis (seven overall steps) employing Pd-catalyzed cross-coupling between stannane and thioester to form the key C3–C15′ bond enabled the structural revision of the natural product. In the second-generation synthesis, we have invented visible-light-mediated, Cu-catalyzed cross-d...

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Section: Summary and Outlookmentioning

confidence: 99%

Synthesis of High-Order and High-Oxidation State Securinega Alkaloids

2023

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“…Optically active cyclic amides are important molecular scaffolds in organic synthesis and medicinal chemistry. − Among those, δ-lactams (six-membered cyclic amides) bearing a stereogenic carbon center adjacent to the N atom are widely present in numerous bioactive molecules, pharmaceuticals, and their analogs (Scheme a). − Furthermore, the competent reactivity of the amide group allows access to additional privileged heterocycles such as chiral piperidines or indolizidines. − As a result, the development of asymmetric synthetic approaches toward the chiral δ-lactam skeleton has attracted the attention of the synthetic community. In this context, a handful of elegant methodologies have been developed: a cascade of asymmetric reductive amination and cyclization, − an enantioselective aza-Diels–Alder reaction, − and a tandem process of C–H activation and [4 + 2] annulation. − Despite these notable achievements, there is still room for improvement, especially regarding the development of a new mechanistic approach, the scope of readily available substrates, and the introduction of quaternary carbon stereocenters.…”

Section: Introductionmentioning

confidence: 99%

Regio- and Enantioselective Catalytic δ-C–H Amidation of Dioxazolones Enabled by Open-Shell Copper-Nitrenoid Transfer

et al. 2023

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Controlling regio- and enantioselectivity in C–H functionalization reactions is of paramount importance due to their versatile synthetic utilities. Herein, we describe a new approach for the asymmetric δ-C(sp3)–H amidation catalysis of dioxazolones using a Cu(I) precursor with a chiral bisoxazoline ligand to access six-membered lactams with high to excellent regio- and enantioselectivity (up to >19:1 rr and >99:1 er). Combined experimental and computational mechanistic studies unveiled that the open-shell character of the postulated Cu-nitrenoids enables the regioselective hydrogen atom abstraction and subsequent enantio-determining radical rebound of the resulting carbon radical intermediates. The synthetic utility of this asymmetric cyclization was demonstrated in the diastereoselective introduction of additional functional groups into the chiral δ-lactam skeleton as well as in the rapid access to biorelevant azacyclic compounds.

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“…Naphthalene analogs are among the most interesting discoveries in the field of natural products, pharmaceuticals, and material science. Particularly, naphthalene derivatives, such as naproxen, propranolol, and terbinafine, have attracted significant attention by virtue of their interesting biological properties . In addition, naphthalene is an intriguing building block for the preparation of optical and electronic materials .…”

Section: Introductionmentioning

confidence: 99%

Rh(III)-Catalyzed C8-Spiroannulation of 1-Aminonaphthalenes with Maleimides

et al. 2023

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The rhodium(III)-catalyzed C8-spiroannulation of 1-aminonaphthalenes with maleimides is described herein. Initially formed C8-alkenylated 1-aminonaphthalenes can intercept nucleophilic 1-amino groups through the intramolecular aza-Michael reaction, resulting in the formation of spirofused tetracyclic frameworks. This protocol displayed a wide substrate scope and a broad functional group compatibility. The synthetic utility of this process is demonstrated by the gram-scale synthesis, late-stage modification, and synthetic transformations.

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“K‐synthesis”: Recent advancements in natural product synthesis enabled by unique methods and strategies development in Korea

Cited by 32 publications

References 197 publications

Synthesis of High-Order and High-Oxidation State Securinega Alkaloids

Synthesis of High-Order and High-Oxidation State Securinega Alkaloids

Regio- and Enantioselective Catalytic δ-C–H Amidation of Dioxazolones Enabled by Open-Shell Copper-Nitrenoid Transfer

Rh(III)-Catalyzed C8-Spiroannulation of 1-Aminonaphthalenes with Maleimides

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