Stereodivergent, Diels–Alder-initiated organocascades employing α,β-unsaturated acylammonium salts: scope, mechanism, and application

Abbasov, Mikail E.; Hudson, Brandi M.; Tantillo, Dean J.; Romo, Daniel

doi:10.1039/c6sc04273b

Cited by 41 publications

(21 citation statements)

References 87 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this way, structure-activity relationship (SAR) studies could be conducted throughout the course of the total synthesis. We recognized that keto lactone 9 , accessible in gram quantities through our recently described Diels-Alder-lactonization organocascade, 40 would serve as a key intermediate to study the importance of the C8-exocyclic alkene ( e.g. derivative 6 ), the C9-appended cyclohexyl moiety ( e.g.…”

Section: Resultsmentioning

confidence: 99%

Simplified immunosuppressive and neuroprotective agents based on gracilin A

et al. 2019

Self Cite

View full text Add to dashboard Cite

The architecture and bioactivity of natural products frequently serves as an embarkation point for exploration of biologically-relevant chemical space. Total synthesis followed by derivative synthesis has historically enabled a deeper understanding of structure-activity relationships. However, synthetic strategies toward a natural product are not always guided by hypotheses regarding structural features required for bioactivity. Here we report an approach to natural product total synthesis that we term ‘pharmacophore-directed retrosynthesis’. A hypothesized, pharmacophore of a natural product is selected as an early synthetic target and this dictates the retrosynthetic analysis. In an ideal application, sequential increases in structural complexity of this minimal structure enables development of an SAR profile throughout the course of the total synthesis effort. This approach enables the identification of simpler congeners retaining bioactivity at a much earlier stage of a synthetic effort as demonstrated herein for the spongiane diterpenoid, gracilin A, leading to simplified derivatives with potent neuroprotective and immunosuppressive activity.

show abstract

Section: Resultsmentioning

confidence: 99%

Simplified immunosuppressive and neuroprotective agents based on gracilin A

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…Further extension of this method was applied to racemic dienes containing secondary and tertiary alcohols in the course of synthesizing bi‐ and tri‐cyclic γ ‐lactones via a stereo divergent DAL cascade. [ 49 ] The use of sterically hindered tertiary amine, 2,6‐lutidine, delivered products with highest enantioselctivity. It is clearly understood that competitive background reaction between Lewis base (BTM) and Brønsted base to form the acyl ammonium ion reduces enantiocontrol of the reaction as evidenced by lowering of ee in cases of triethyl amine and DIPEA as Brønsted bases.…”

Section: Six Membered Heterocycle Formation By Formal and Concerted [mentioning

confidence: 99%

Synthesis of Heterocycles by isothiourea organocatalysis

Biswas¹,

Mondal

Maji

2020

Journal of Heterocyclic Chem

View full text Add to dashboard Cite

Isothiourea was first employed as catalyst by Birman in 2006 for the enantioselective acyl transfer reaction. The catalyst was then well explored in the course of kinetic resolution and desymmetrization studies. A few years later, Romo and Smith applied isothiourea catalysis in enantioselective cascade reactions to prepare carbocycles and heterocycles acessing new reactivities of isothiourea. Several research groups were then attracted toward this new field of organocatalysis, and applied isothioureas as nucleophilic catalysts in executing cascade methodologies to synthesize various intresteting molecular scaffolds including heterocycles. The present review documents a summary on the construction of heterocyclic molecules by isothiourea organocatalysis. Heterocycles are of prime interest to organic chemists due to their omnipresence in natural products and bioactive molecules. The Lewis basic nucleophilic catalyst isothioureas play a pivotal role in the cascades to generate either α,β‐unsaturated acyl isothiouronium ion or isothiouronium enolate as the prime reaction intermediate. We have covered the reactions involving two intermediates of opposite reactivities affording various heterocycles.

show abstract

“…7 Building on our previous studies of Diels-Alder-initiated organocascades with chiral α,β-unsaturated acylammonium salts (Figure 1, e.g. 2 ), 8,9) we reasoned that the termination step of a Diels-Alder-lactamization (DAL) organocascade (Figure 1, e.g. 3 → 7 ) could provide a solution to the reversibility of these cycloadditions with furanyl dienes by careful choice of a suitable pendant, terminating nucleophile.…”

mentioning

confidence: 93%

“…Employing our standard conditions developed previously for other dienes 8,9 but employing less expensive levamisole hydrochloride (10 mol%) as Lewis base promoter, gave the oxa -bridged, trans -fused bicyclic γ-lactam 10 in 76% yield and 91% ee as a single exo -diastereomer (>19:1, 1 H NMR 500 MHz). Importantly, this bicyclic γ-lactam could be stored at ambient temperature (23 °C) for an extended period without racemization pointing to much greater stability compared to analogous lactone adducts.…”

mentioning

confidence: 99%

Enantioselective Diels-Alder-lactamization organocascades employing a furan-based diene

et al. 2017

Self Cite

View full text Add to dashboard Cite

α,β-Unsaturated acylammonium salts are useful dienophiles enabling highly enantioselective and stereodivergent Diels-Alder-initiated organocascades with furan-based dienes. Complex polycyclic systems can thus be obtained from readily prepared dienes, commodity acid chlorides, and a chiral isothiourea organocatalyst under mild conditions. We describe the use of a furan-based diene bearing pendant sulfonamides leading to the generation of oxa-bridged, trans-fused tricyclic γ-lactams. This process constitutes the first highly enantio- and diastereoselective, organocatalytic Diels-Alder cycloadditions with these typically problematic dienes due to their reversibility. Computational studies suggest that high diastereoselectivity with these furan dienes may be due to a reversible Diels-Alder cycloaddition for the endo adducts. In addition, the utility of this methodology is demonstrated through a concise approach to a core structure with similarity to the natural product isatisine A and a nonpeptidyl ghrelin-receptor inverse agonist.

show abstract

Stereodivergent, Diels–Alder-initiated organocascades employing α,β-unsaturated acylammonium salts: scope, mechanism, and application

Abstract: Chiral α,β-unsaturated acylammonium salts are novel dienophiles enabling enantioselective Diels–Alder-lactonization (DAL) organocascades leading to cis- and trans-fused, bicyclic γ- and δ-lactones.

Cited by 41 publications

References 87 publications

Simplified immunosuppressive and neuroprotective agents based on gracilin A

Simplified immunosuppressive and neuroprotective agents based on gracilin A

Synthesis of Heterocycles by isothiourea organocatalysis

Enantioselective Diels-Alder-lactamization organocascades employing a furan-based diene

Contact Info

Product

Resources

About