A Concise, Enantiospecific Total Synthesis of Chilocorine C Fueled by a Reductive Cyclization/Mannich Reaction Cascade

Lisnyak, Vladislav G.; Snyder, Scott A.

doi:10.1021/jacs.0c04914

Cited by 10 publications

(7 citation statements)

References 76 publications

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“…Not only was the synthesis of a pyrrole-based “monomer” needed, with some useful precedent from Meinwald showing one way in which it could be prepared, but the saturated counterparts ( cis , cis , trans -fused aza-tricycles) required the development of entirely new chemistry to access them in an appropriately functionalized form to merge with that pyrrole-containing domain. Although we ultimately found the means to synthesize both exochomine ( 11 ) and chilocorine C ( 15 ), we will focus here on the latter to give a sense of the core challenges presented by these targets. Again, cascade-based chemistry would prove essential.…”

Section: Total Synthesis Of Chilocorine C (15)mentioning

confidence: 99%

“…In this Account, we review our explorations to prepare this challenging collection of materials, efforts that have led to the controlled laboratory synthesis of 12 members via total and formal synthesis, including 1 – 11 and 15 . − In particular, we will focus our discussion on our routes to select dimeric members, particularly psylloborine A ( 10 ) and chilocorine C ( 15 ), in the hope that the lessons we learned as part of these endeavors, particularly in terms of the developed reaction cascades that proved essential for their synthesis, can serve as inspiration for others for the effective synthesis of additional compounds.…”

Section: Introductionmentioning

confidence: 99%

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The Development of Reaction Cascades to Synthesize Dimeric Coccinellid Alkaloids

2021

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Conspectus Over the course of the past decade, our group has been intensely interested in achieving the laboratory synthesis of varied members of the coccinellid alkaloid family of natural products. These compounds, produced by varied species of ladybugs throughout the world as defensive agents, include several polycyclic members that can formally be considered as either monomeric or dimeric with architectures that contain between 3 and 7 ring systems along with an array of stereocenters. As a result of their fascinating structures, many groups have achieved syntheses of varied monomeric members using a variety of synthetic strategies and tactics. However, no efforts to synthesize any of the dimeric structures had been reported at the time we began our studies, and only a modest amount of study had been performed as relates to their biosynthesis, with little knowledge of how the larger structures might actually arise in Nature. In this Account, we provide an overview of our general synthetic considerations to achieve a global synthesis of the collection, efforts that have led to date to the formal and total synthesis of 12 different members, 4 at the dimer level. Critical was (1) the identification of a key, common intermediate to enable access to a large number of monomeric substructures in short order, (2) careful thinking as to how the larger structures might arise biosynthetically to fuel building block design, and (3) the development of several reaction cascades that rapidly assembled the majority of their molecular complexity in single-pot operations. Key discoveries in the program include the finding that when efforts to achieve intermolecular dimerizations fail with advanced intermediates, attempts to couple more functionalized fragments earlier and then fold them into the desired structure can be an effective strategy. We also highlight suggestive evidence that a non-natural isomer we originally prepared from one of those cascades may, in fact, be a natural product. And, in particular, we will focus on how two key cascades were developed, as a result of synthetic challenges at varied points in our explorations, which proved capable of forging multiple bonds, rings, and stereocenters in the target structures. One of these includes a designed event that combined 9 different chemical reactions in a single pot and may prove useful for the synthesis of other targets.

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Section: Total Synthesis Of Chilocorine C (15)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Development of Reaction Cascades to Synthesize Dimeric Coccinellid Alkaloids

2021

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“…Indeed, such steric constraints can sometimes lead to an undesired stereochemical outcome and/or prevent hydrogenation entirely. Such issues arose in the Snyder group’s recent total syntheses of the coccinellid alkaloids, including targets such as exochomine, arborisidine, and chilocorine C. , For example, one of the final steps in the exochomine work required the selective 1,4-reduction of the hindered enone 1 to 2 (Scheme A). However, the dithiolane group, benzylic ketone, and acyl pyrrole all proved prone to reduction and/or side-product formation; the desired product was best obtained by reducing 1 with silanes in the presence of stoichiometric Mn(dpm) 3 , a procedure adapted from those reported by Magnus and Shenvi .…”

Section: Introductionmentioning

confidence: 99%

Highly Selective Hydrogenation of C═C Bonds Catalyzed by a Rhodium Hydride

Norton

Salahi

et al. 2021

J. Am. Chem. Soc.

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Under mild conditions (room temperature, 80 psi of H2) Cp*Rh(2-(2-pyridyl)phenyl)H catalyzes the selective hydrogenation of the CC bond in α,β-unsaturated carbonyl compounds, including natural product precursors with bulky substituents in the β position and substrates possessing an array of additional functional groups. It also catalyzes the hydrogenation of many isolated double bonds. Mechanistic studies reveal that no radical intermediates are involved, and the catalyst appears to be homogeneous, thereby affording important complementarity to existing protocols for similar hydrogenation processes.

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“…The Mannich reaction, which has been extensively studied in the past 100 years, − remains an enormously valuable method for C–C bond construction. Carbonyl catalysis is a prevailing activation mode in organocatalysis, − which involves the reaction of the carbonyl compound with amine leading to an imine intermediate, followed by the deprotonation process to generate the α-amino carbanion complex.…”

Section: Introductionmentioning

confidence: 99%

Mechanistic Study of the N-Quaternized Pyridoxal-Catalyzed Biomimetic Asymmetric Mannich Reaction: Insights into the Origins of Enantioselectivity and Diastereoselectivity

Cui

Yao

et al. 2021

J. Org. Chem.

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Density functional theory calculations have been performed to gain insights into the catalytic mechanism of the N-quaternized pyridoxal (i.e., 1a)-mediated biomimetic asymmetric Mannich reaction of tert-butyl glycinate 3 with N-diphenylphosphinyl imine 2a to give the diamino acid ester 4a in high yield with excellent enantiomeric and diastereomeric selectivity (Science 2018, 360, 1438). The study reveals that the whole catalysis can be characterized via three stages: (i) the catalyst 1a reacts with the tert-butyl glycinate 3 to generate the active carbanion complex IM3. (ii) IM3 then reacts with the N-diphenylphosphinyl imine 2a giving the imine intermediate IM8. (iii) IM8 undergoes hydrolysis to give the final product anti-4a and regenerate the catalyst 1a for the next catalytic cycle. Each stage is kinetically and thermodynamically feasible for experimental realization. The hydrolysis step in the stage III is predicted to be the rate-determining step during the whole catalytic cycle. Furthermore, the origins of the enantioselectivity and diastereoselectivity for the target reaction, as well as the deactivation of the catalyst 1b, are also discussed.

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A Concise, Enantiospecific Total Synthesis of Chilocorine C Fueled by a Reductive Cyclization/Mannich Reaction Cascade

Cited by 10 publications

References 76 publications

The Development of Reaction Cascades to Synthesize Dimeric Coccinellid Alkaloids

The Development of Reaction Cascades to Synthesize Dimeric Coccinellid Alkaloids

Highly Selective Hydrogenation of C═C Bonds Catalyzed by a Rhodium Hydride

Mechanistic Study of the N-Quaternized Pyridoxal-Catalyzed Biomimetic Asymmetric Mannich Reaction: Insights into the Origins of Enantioselectivity and Diastereoselectivity

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