Effect of Counterion Structure on Rates and Diastereoselectivities in α,β-Unsaturated Iminium-Ion Diels–Alder Reactions

Marcoux, David; Bindschädler, Pascal; Speed, Alexander W. H.; Chiu, Anna; Pero, Joseph E.; Borg, George; Evans, David A.

doi:10.1021/ol201448h

Cited by 31 publications

(25 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Following these studies, in 2011, advances in intermolecular Diels-Alder reactions of iminium ions were reported by Evans and co-workers (Scheme 5). 44 Remarkably, sev-en-and six-membered NH-,-unsaturated iminium salts 27 and 28 were found to be isolable and stable to flash column chromatography. Iminium ions 27 and 28 were used in Diels-Alder reactions with simple dienes 29, with spirocyclic adducts 30 and 31 afforded in excellent yields and high endo selectivities (>90:10) due to LUMO-lowering activation of the iminium dienophiles.…”

Section: Use Of More Stable Iminium Ion Dienophiles For Diels-alder Reactionsmentioning

confidence: 96%

See 1 more Smart Citation

Synthetic Studies Towards Spirocyclic Imine Marine Toxins Using N-Acyl Iminium Ions as Dienophiles in Diels–Alder Reactions

Freeman

Furkert

et al. 2020

Synlett

View full text Add to dashboard Cite

Cyclic imine marine toxins have attracted considerable attention from the synthetic community in the past two decades due to their unique chemical structures and clinically relevant biological activities. This review presents recent efforts of our group in the development of various strategies to efficiently construct the common spirocyclic imine fragments of the cyclic imine toxins. In particular, the use of α,β-unsaturated N-acyl iminium ion dienophiles in Diels–Alder reactions are highlighted, whereby direct access to spirocyclic imine motifs was obtained and important mechanistic details were discovered. Alternative approaches to spirocyclic imine systems involving hydroamination of amino alkynes are also summarized. One such approach led to serendipitous access to N-vinyl amide products, while our most recently reported approach involving an intermolecular Diels–Alder/cross-coupling sequence using novel 2-bromo-1,3-butadienes to access 5,6-spirocyclic imines is also discussed. Additionally, the development of a novel method to construct another challenging motif present in the portimines is also introduced.1 Introduction2 Strategies towards the Spirocyclic Imine Fragment of Cyclic Imine Toxins2.1 Diels–Alder Cycloadditions of α,β-Unsaturated N-Acyl Iminium Dienophiles2.2 Early Studies Using in situ-Generated Iminium Ion Dienophiles2.3 Use of More Stable Iminium Ion Dienophiles for Diels–Alder Reactions2.4 Other Notable Strategies towards Spirocyclic Imines2.5 Recent Efforts towards the 5,6-Spirocyclic Imine Marine Toxin Portimine A2.6 Construction of Another Challenging Motif of Portimine A3 Conclusion and Future Perspectives

show abstract

Section: Use Of More Stable Iminium Ion Dienophiles For Diels-alder Reactionsmentioning

confidence: 96%

“…Scheme 5 Iminium ion Diels-Alder cycloadditions by Evans et al 44 Evans' work therefore prompted a redesign of our iminium ion dienophile scaffold to incorporate a methyl substituent at the imine center (Scheme 6, A), which would serve…”

Section: Use Of More Stable Iminium Ion Dienophiles For Diels-alder Reactionsmentioning

confidence: 99%

Synthetic Studies Towards Spirocyclic Imine Marine Toxins Using N-Acyl Iminium Ions as Dienophiles in Diels–Alder Reactions

Freeman

Furkert

et al. 2020

Synlett

View full text Add to dashboard Cite

show abstract

“…39 We found that exposure of the TFA salts 30 or 31 to 1 equiv of methanesulfonic acid at 55 °C induced counterion metathesis and efficient intramolecular cycloaddition. Monitoring the reactions by 1H NMR spectroscopy over 5 days allowed us to observe the formation of himandravine-type cycloadducts 32 or 33 , along with GB17-type cycloadducts 34 or 35 that underwent complete isomerization to the conjugated iminium ions 36 or 37 in situ.…”

Section: Resultsmentioning

confidence: 82%

Total Synthesis of the Galbulimima Alkaloids Himandravine and GB17 Using Biomimetic Diels–Alder Reactions of Double Diene Precursors

et al. 2015

View full text Add to dashboard Cite

The enantioselective total syntheses of himandravine and GB17 were completed through a common biomimetic strategy involving Diels–Alder reactions of unusual double diene containing linear precursors. The double diene precursors, containing or lacking a C12 substituent as required to produce GB17 or himandravine, respectively, were found to undergo Diels–Alder reactions to afford mixtures of regioisomeric cycloadducts that map onto the alternative carbocyclic frameworks of both himandravine and GB17. Computational investigations revealed that these Diels–Alder reactions proceed via transition state structures of similar energy that have a high degree of bispericyclic character and that the low levels of regioselectivity observed in the reactions are a consequence of competing orbital interaction and distortion energies. The combined experimental and computational results provide valuable insights into the biosynthesis of the Galbulimima alkaloids.

show abstract

“…Future computational work will be focused on the study of other factors influencing the interconversion of aminoketone and imine forms of PnTX A, e.g., the presence of two bridging water molecules to facilitate the proton transfer and the protonation state of the nitrogen atom (imine vs iminium), as well as the potential of the biomimetic Diels–Alder reaction to assemble the macrocyclic framework of pinnatoxins. 12 …”

Section: Discussionmentioning

confidence: 99%

Stability of Cyclic Imine Toxins: Interconversion of Pinnatoxin Amino Ketone and Pinnatoxin A in Aqueous Media

et al. 2012

View full text Add to dashboard Cite

Pinnatoxins belong to the cyclic imine (CI) group of marine toxins with a unique toxicological profile. The need for structural integrity of the aliphatic 7-membered cyclic imine for the potent bioactivity of pinnatoxins has been experimentally demonstrated. In this study, we probe interconversion of the natural cyclic imine and its open form, pinnatoxin A amino ketone (PnTX AK), under physiologically relevant aqueous conditions. Our studies demonstrate the high stability of PnTX A. The unusual stability of the imine ring in PnTX A has implications for its oral toxicity and detoxification. These studies, as well the access to PnTX amino ketone, were enabled by the total synthesis of (+)-pinnatoxin A completed previously in our laboratory.

show abstract

Effect of Counterion Structure on Rates and Diastereoselectivities in α,β-Unsaturated Iminium-Ion Diels–Alder Reactions

Abstract: The use of cyclic α,β-unsaturated iminium-ion dienophiles is documented in two highly diastereoselective Diels-Alder (DA) reactions. The dienophilic counterion was found to have a significant effect on reactivity.

Cited by 31 publications

References 24 publications

Synthetic Studies Towards Spirocyclic Imine Marine Toxins Using N-Acyl Iminium Ions as Dienophiles in Diels–Alder Reactions

Synthetic Studies Towards Spirocyclic Imine Marine Toxins Using N-Acyl Iminium Ions as Dienophiles in Diels–Alder Reactions

Total Synthesis of the Galbulimima Alkaloids Himandravine and GB17 Using Biomimetic Diels–Alder Reactions of Double Diene Precursors

Stability of Cyclic Imine Toxins: Interconversion of Pinnatoxin Amino Ketone and Pinnatoxin A in Aqueous Media

Contact Info

Product

Resources

About