Exploration of an epoxidation–ring-opening strategy for the synthesis of lyconadin A and discovery of an unexpected Payne rearrangement

Loertscher, Brad M.; Castle, Steven L.

doi:10.3762/bjoc.9.132

Cited by 7 publications

(2 citation statements)

References 36 publications

(43 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…214 In their synthetic studies toward lyconadin A (361), Castle and co-workers employed ketone 268 for epoxidation of olefin 357 to give epoxide 358 in 88% yield and >95:5 dr (Scheme 63). 215 Interestingly, treatment of epoxide 358 with vinylmagnesium bromide and CuBr−SMe 2 led to an unexpected Payne rearrangement product 359 in 81% yield, and desired homoallylic alcohol 360 was not obtained.…”

Section: Phase-transfer Catalystsmentioning

confidence: 99%

Organocatalytic Asymmetric Epoxidation and Aziridination of Olefins and Their Synthetic Applications

et al. 2014

View full text Add to dashboard Cite

Section: Phase-transfer Catalystsmentioning

confidence: 99%

Organocatalytic Asymmetric Epoxidation and Aziridination of Olefins and Their Synthetic Applications

et al. 2014

View full text Add to dashboard Cite

“…Cyclohexene oxides are valuable building blocks in synthetic chemistry, finding applications in many organic reactions . They can undergo chemical transformations with a broad scope of nucleophiles, making cyclohexene oxides useful building blocks for the synthesis of complex molecules . It is well known that nucleophilic ring-opening reactions of cyclohexene oxides can proceed with excellent regioselectivity .…”

Section: Introductionmentioning

confidence: 99%

How Lewis Acids Catalyze Ring-Openings of Cyclohexene Oxide

et al. 2021

View full text Add to dashboard Cite

We have quantum chemically studied the Lewis acid-catalyzed epoxide ring-opening reaction of cyclohexene epoxide by MeZH (Z = O, S, and NH) using relativistic dispersion-corrected density functional theory. We found that the reaction barrier of the Lewis acid-catalyzed epoxide ring-opening reactions decreases upon ascending in group 1 along the series Cs + > Rb + > K + > Na + > Li + > H + . Our activation strain and Kohn–Sham molecular orbital analyses reveal that the enhanced reactivity of the Lewis acid-catalyzed ring-opening reaction is caused by the reduced steric (Pauli) repulsion between the filled orbitals of the epoxide and the nucleophile, as the Lewis acid polarizes the filled orbitals of the epoxide more efficiently away from the incoming nucleophile. Furthermore, we established that the regioselectivity of these ring-opening reactions is, aside from the “classical” strain control, also dictated by a hitherto unknown mechanism, namely, the steric (Pauli) repulsion between the nucleophile and the substrate, which could be traced back to the asymmetric orbital density on the epoxide. In all, this work again demonstrates that the concept of Pauli-lowering catalysis is a general phenomenon.

show abstract

Divergent Total Syntheses of Lyconadins A and C

et al. 2014

View full text Add to dashboard Cite

Divergent and concise total syntheses of two lycopodium alkaloids, lyconadins A and C have been developed. The synthesis of lyconadin A with potent neurotrophic activity features an efficient ketal deprotective formal aza-[4+2] cyclization to form the cage-like core structure. A ketal deprotective Mannich reaction was developed to build the tricyclic structure of lyconadin C. Both lyconadins A and C were synthesized from pivotal intermediate 14. Each step to the synthesis of intermediate 14 was conducted on gram-scale. Keywords total synthesis; lycopodium alkaloid; lyconadin; neurodegenerative disease; formal [4+2] cyclizationWhile advances in therapeutic methods and strategies for the treatment of neurodegenerative diseases have been relatively limited in the past several decades, there is increasingly strong evidence to suggest that naturally-occurring polypeptide neurotrophic factors, [1] such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) may be of significant therapeutic benefit in treating neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis and Huntington's disease. [2] Unfortunately, these natural neurotrophic factors suffer from poor bioavailability and pharmacokinetics. In addition, direct administration to the brain is usually required. [3] Recently, small-molecule natural products have been identified to show activity for promoting the production of natural neurotrophic factors or functioning similarly as them for neuron growth and maintenance. [4] In comparison, small molecules are more likely to cross the blood brain barrier. Their potency, selectivity and pharmacological properties can be readily optimized through structural editing. [5] They may serve as valuable chemical probes as well. [6] In this context, we took note of the family of lycopodium alkaloids, which are enriched with molecules having neurotrophic activities. [7] Among them, lyconadins A (1) and B (2) (Figure 1), isolated by Kobayashi and co-workers, have been shown to enhance the mRNA expression for neurotrophic growth factor biosynthesis in 1321N1 human astrocytoma cells, suggesting that they may serve as promising lead compounds for anti-neurodegenerative drug discovery. [8] Structurally, lyconadin C (3) [9] and dihydrolycolucine (4) [10] share common motifs with lyconadins A (1) and B (2). In addition, lyconadin A has shown modest in vitro anti cancer cell proliferation activity. Their intriguing structural features and important biological activity have motivated many synthetic efforts directed toward their synthesis, [11] culminating in the elegant total syntheses of the lyconadins by Smith (lyconadins A and B), [12] Sarpong (lyconadin A), [13] Fukuyama (lyconadins A, B and C), [14] and Waters (lyconadin C). [15] In addition to the total syntheses of these challenging natural molecules, we are particularly interested in creating a focused small-molecule library based on these privileged structures in order to explore the related chemical sp...

show abstract

Exploration of an epoxidation–ring-opening strategy for the synthesis of lyconadin A and discovery of an unexpected Payne rearrangement

Cited by 7 publications

References 36 publications

Organocatalytic Asymmetric Epoxidation and Aziridination of Olefins and Their Synthetic Applications

Organocatalytic Asymmetric Epoxidation and Aziridination of Olefins and Their Synthetic Applications

How Lewis Acids Catalyze Ring-Openings of Cyclohexene Oxide

Divergent Total Syntheses of Lyconadins A and C

Contact Info

Product

Resources

About