Synthesis of a Complex Brasilicardin Analogue Utilizing a Cobalt-Catalyzed MHAT-Induced Radical Bicyclization Reaction

Niman, Scott W.; Buono, Roberta; Fruman, David A.; Vanderwal, Christopher D.

doi:10.1021/acs.orglett.3c01019

Cited by 4 publications

(3 citation statements)

References 23 publications

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“…These reactions have been hypothesized to proceed via metal hydride hydrogen-atom transfer (MHAT), an outer-sphere elementary step that directly generates carbon-centered radicals (open-shell carbon intermediates) from alkenes . MHAT tends to tolerate alkene polysubstitution, steric repulsion, and Lewis basic functional groups to a higher degree than inner-sphere, coordinative pathways characteristic of precious metals. ,, Therefore, MHAT is a particularly powerful reaction pathway for complex, natural product-like substrates, which is where our interest originated. ,,, Many of these reactions are catalyzed by commercially available first-row transition metals complexed with inexpensive ligands (acetylacetone, acac; dipivaloylmethane, dpm; etc. ), providing a barrierless entry for any practitioner.…”

Section: Alkene Hydrofunctionalizations By Outer-sphere Cross-couplingmentioning

confidence: 99%

“…3,22,11 Therefore, MHAT is a particularly powerful reaction pathway for complex, natural product-like substrates, which is where our interest originated. 3,12,23,24 Many of these reactions are catalyzed by commercially available first-row transition metals complexed with inexpensive ligands (acetylacetone, acac; dipivaloylmethane, dpm; etc. ), providing a barrierless entry for any practitioner.…”

Section: Alkene Hydrofunctionalizations By Outer-sphere Cross-couplingmentioning

confidence: 99%

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Inner- and Outer-Sphere Cross-Coupling of High F_sp3 Fragments

Kotesova,

Shenvi

2023

Acc. Chem. Res.

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Metrics & MoreArticle Recommendations CONSPECTUS: Natural product research originates from a desire to explore, understand, and perturb biological function with atomic precision. To reach these goals at all, let alone efficiently, requires thoughtful and creative problem solving. Often this means bold disconnections that would simplify access to complex structures, if only the methods existed to bridge these theoretical gaps. Whereas biological interrogations provide long-term intellectual value and impetus, methods come as attractive fringe benefits of natural product synthesis. This Account describes strategic, methodological solutions to the syntheses of natural products [(−)-eugenial C, Galbulimima alkaloids GB18, GB22, GB13, and himgaline] featuring new, convergent disconnections as important problemsolving steps, which themselves were inspired by recent methods that arose from our group. Each target required the invention of first-row transition metal-catalyzed cross-coupling procedures to satisfy the biological goals of the project. In these cases, synthetic strategy identified the methodological gap (the absence of stereoand chemoselective couplings of appropriate fragments), but the tactical advantage conferred by first-row metals met the challenge. These methods were competent to handle the dense, sterically encumbered motifs common to natural products due to, in many cases, elementary steps that did not require bond formation between the hindered substrate and the metal center. Instead, these sterically lenient reactions appeared to involve metal−ligand−substrate reactions (i.e., outer-sphere steps), in contrast to the metal− substrate, coordinative reactions of precious metals (i.e., inner-sphere steps). Key observations from our previous studies, combined with the observations in seminal publications from other laboratories (Mattay, Weix, and MacMillan), led to the optimization of ligand-controlled, stereoselective reactions and the introduction of complementary catalytic cycles that revealed new modes of reactivity and generated novel structural motifs. Optimized access to bioactive natural product space accelerated our timeline of biological characterization, fulfilling a common premise of natural products research. The integration of methodology, complex natural product synthesis, diversification, and bioassay into a single Ph.D. dissertation would have been unmanageable in a prior era.The unique ability of first-row transition metals to effect Csp 3 −Csp 3 cross-coupling with high chemo-and stereoselectivity has significantly lowered the barrier to reach the avowed goal of natural product synthesis and reduced the burden (real or perceived) of integrating natural products into functional campaigns.

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Section: Alkene Hydrofunctionalizations By Outer-sphere Cross-couplingmentioning

confidence: 99%

Section: Alkene Hydrofunctionalizations By Outer-sphere Cross-couplingmentioning

confidence: 99%

Inner- and Outer-Sphere Cross-Coupling of High F_sp3 Fragments

Kotesova,

Shenvi

2023

Acc. Chem. Res.

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“…Their characteristic biological properties and novel, complex structures render this family attractive targets by synthetic organic chemists. Several research groups have conducted synthetic studies [9][10][11][12], including the first total synthesis of BraA (1) and BraC (3) by Anada and Hashimoto in 2017 [13]. A semi-synthetic approach for the large-scale production of BraA (1) was also reported in 2021 [14].…”

Section: Introductionmentioning

confidence: 99%

A Journey to the Total Synthesis of Brasilicardins

Itoh,

Tanino,

Yoshimura

2024

Modern Natural Product Synthesis

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C(sp3)-rich natural products with quaternary carbon stereocenters have recently received increasing attention as formidable synthetic targets and higher lead and drug compounds. Among them, brasilicardins, which are terpenoids–amino acids–saccharide(s) hybrids, share a unique and highly strained anti-syn-anti-fused 6,6,6-tricyclic terpenoid skeleton containing two adjacent quaternary carbon stereocenters and have attracted attention as promising immunosuppressive drug lead compounds. Herein, we describe our endeavor toward a unified total synthesis of brasilicardins A–D, focusing on overcoming various synthetic challenges. In addition, we discuss several key lessons learned from our journey.

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Convergent and Scalable Second-Generation Synthesis of the Fully Functionalized HIJKLMN-Ring Segment of Caribbean Ciguatoxin C-CTX-1

Sasaki,

Ohba,

Murakami

et al. 2024

J. Org. Chem.

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A highly convergent and scalable second-generation synthesis of the fully functionalized HIJKLMN-ring segment of Caribbean ciguatoxin C-CTX-1, the primary toxin responsible for ciguatera fish poisoning in the Caribbean Sea and the Northeast Atlantic regions, has been accomplished. Key aspects of the synthetic approach include the efficient syntheses of the HI-and KLM-ring fragments on gram scales, a convergent fragment coupling toward the HIJKLM-ring skeleton based on the Suzuki−Miyaura coupling strategy, and optimized iron hydridecatalyzed hydrogen atom transfer-mediated olefin coupling conditions for constructing the N-ring. Article pubs.acs.org/joc

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Synthesis of a Complex Brasilicardin Analogue Utilizing a Cobalt-Catalyzed MHAT-Induced Radical Bicyclization Reaction

Cited by 4 publications

References 23 publications

Inner- and Outer-Sphere Cross-Coupling of High F_sp3 Fragments

Inner- and Outer-Sphere Cross-Coupling of High F_sp3 Fragments

A Journey to the Total Synthesis of Brasilicardins

Convergent and Scalable Second-Generation Synthesis of the Fully Functionalized HIJKLMN-Ring Segment of Caribbean Ciguatoxin C-CTX-1

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Synthesis of a Complex Brasilicardin Analogue Utilizing a Cobalt-Catalyzed MHAT-Induced Radical Bicyclization Reaction

Cited by 4 publications

References 23 publications

Inner- and Outer-Sphere Cross-Coupling of High Fsp3 Fragments

Inner- and Outer-Sphere Cross-Coupling of High Fsp3 Fragments

A Journey to the Total Synthesis of Brasilicardins

Convergent and Scalable Second-Generation Synthesis of the Fully Functionalized HIJKLMN-Ring Segment of Caribbean Ciguatoxin C-CTX-1

Contact Info

Product

Resources

About

Inner- and Outer-Sphere Cross-Coupling of High F_sp3 Fragments

Inner- and Outer-Sphere Cross-Coupling of High F_sp3 Fragments