Carbon–Carbon Bond-Forming Reactions of α-Thioaryl Carbonyl Compounds for the Synthesis of Complex Heterocyclic Molecules

Biggs‐Houck, James E.; Davis, Rebecca L.; Wei, Jingqiang; Mercado, Brandon Q.; Olmstead, Marilyn M.; Tantillo, Dean J.; Shaw, Jared T.

doi:10.1021/jo201541e

Cited by 19 publications

(7 citation statements)

References 90 publications

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“…Although the observations reported here are primarily based on X-ray crystallographic data, they were supplemented by additional experiments.C onsideration solely of crystal data is perilous because crystal packing forces may influence the very conformational minimabeing discussed. Here we have used data from computationale xperiments, as othersh ave, [24,25] that is consistent with and reinforces the observations made from examination of the crystal structures. Moreover,w eh ave previously reported on the diastereoselectivity in the epoxidation of the alkene unit of the macrocycle.…”

Section: Absolute Configurationo Fk Ey Atoms Directsthe Planar Chiralsupporting

confidence: 85%

Rules of Macrocycle Topology: A [13]‐Macrodilactone Case Study

Magpusao

Rutledge

Hamlin

et al. 2016

Chemistry A European J

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Shape is an inherent trait of a molecule that dictates how it interacts with other molecules, either in binding events or intermolecular reactions. Large-ring macrocyclic compounds in particular leverage their shape when they are selectively bound by biomolecules and also when they exhibit macrocyclic diastereoselectivity. Nonetheless, rules that link structural parameters to the conformation of a macrocycle are still rudimentary. Here we use a structural investigation of a family of [13]-macrodilactones as a case study to develop rules that can be applied generally to macrocycles of different sizes and with a variety of functionality. A characteristic "ribbon" shape is adopted by the [13]-macrodilactones in the absence of stereogenic centres, which exhibits planar chirality. When one stereogenic centre at key positions on the backbone is incorporated into the structure, the planar chirality is dictated by the configuration of the centre. In cases where two stereogenic centres are present, their relationships can either reinforce the characteristic ribbon shape or induce alternative shapes to be adopted. The rules established in the case study are then applied to the analysis of a structure of the natural product migrastatin. They lay the groundwork for the development of models to understand macrocycle-biomolecule interactions and for the preparation of macrocycles with designed properties and activities.

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Section: Absolute Configurationo Fk Ey Atoms Directsthe Planar Chiralsupporting

confidence: 85%

Rules of Macrocycle Topology: A [13]‐Macrodilactone Case Study

Magpusao

Rutledge

Hamlin

et al. 2016

Chemistry A European J

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“…This led us to propose that the amide nitrogen was condensing with the aldehyde to form N -acyl iminium ion 17 , analogous to the proposed 3CR mechanism (Figure ). The previous work on the 4CR has described the scope and utility of the 4CR, including the expansion to a variety of amines, aldehydes, and chiral thiols, as well as applications to the synthesis of a complex natural product. ,− Although there are other possible nucleophiles capable of conjugate addition, most are insufficiently nucleophilic or undergo competitive reaction with the aldehyde. As a result, the 4CR has remained limited to thiol reaction partners.…”

Section: Introductionsupporting

confidence: 82%

Mechanistic Investigation of Castagnoli–Cushman Multicomponent Reactions Leading to a Three-Component Synthesis of Dihydroisoquinolones

et al. 2021

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The mechanisms for the three-and four-component variants of the Castagnoli−Cushman reaction (CCR) have been investigated. A series of crossover experiments were conducted to probe the structure and reactivity of known amide-acid intermediates for the three-and four-component variants of the CCR (3CR and 4CR, respectively). Control experiments paired with in situ reaction monitoring with infrared spectroscopy for the 4CR align with a mechanism in which amide-acids derived from maleic anhydride can reversibly form free amine and cyclic anhydride. Although this equilibrium is unfavorable, the aldehyde present can trap the primary amine through imine formation and react with the enol form of the anhydride through a Mannich-like mechanism. This detailed mechanistic investigation coupled with additional crossover experiments supports an analogous mechanism for the 3CR and has led to the elucidation of new 3CR conditions with homophthalic anhydride, amines, and aldehydes for the formation of dihydroisoquinolones in good yields and excellent diastereoselectivity. This work represents the culmination of more than a decade of mechanistic speculation for the 3-and 4CR, enabling the design of new multicomponent reactions that exploit this novel mechanism.

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“… , As part of a longstanding interest in accessing such lactam cores, our group has developed new methods for the formal [4 + 2] cycloaddition of imines and cyclic, enolizable anhydrides based on the foundational work of Castagnoli , and Cushman . To this end, our group has previously contributed to advances in mechanistic understanding of the Castagnoli–Cushman reaction, , which we now call the anhydride Mannich reaction (AMR), developed a novel four-component reaction − (4CR), and reported the first base-promoted AMR variant using N -sulfonyl imines in the synthesis of bisavenanthramide B-6 . While the AMR has proven a powerful means of synthesizing complex lactams in diversity-oriented and natural product syntheses, most reports of such reactions employ N -alkylimines, which react readily with many anhydrides in the absence of catalyst .…”

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confidence: 99%