Stereocontrolled transformations of cyclohexadienone derivatives to access stereochemically rich and natural product-inspired architectures

Al‐Tel, Taleb H.; Srinivasulu, Vunnam; Ramanathan, Mala; Soares, N.; Sebastian, Anusha; Bolognesi, María Laura; Abu‐Yousef, Imad A.; Majdalawieh, Amin F.

doi:10.1039/d0ob01550d

Cited by 52 publications

(15 citation statements)

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“…(2aR,6aR,14bS)-2a-Methoxy-2,2a,3,4,6,6a,8,9,14,14bdecahydroindolo[2′,3′:3,4]pyrido[1,2-a]quinolin-5(1H)-one (4a). White solid, 58 mg, 90% yield; mp 183−185 °C; R f = 0.45 (silica gel, 1:1 hexane/EtOAc); 1 [3,4-b]indol-5(2aH)-one (7). Off-white solid, 57.0 mg, 92% yield; mp 236−238 °C; R f = 0.5 (silica gel, 1:1 hexane/EtOAc); 1 H NMR (500 MHz, CDCl 3 ) δ 7.74 (s, 1H), 7.49 (d, J = 7.7 Hz, 1H), 7.32 (d, J = 7.9 Hz, 1H), 7.16 (t, J = 7.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

“…Several studies have reported on the use of nature-inspired compounds for developing next-generation high-sp 3 content therapeutics that effectively treat unmet medical needs. − This concept is further supported by the fact that natural products represent a rich source of structural diversity. However, several challenges continue to limit their utility in biological screening campaigns, relative to their limited quantities available for detailed structure–activity relationship studies. − Hence, complexity-to-diversity (CtD) strategies for the de novo design of nature-inspired compounds required for phenotypic screening programs have been employed by many groups. , Thus, the development of new CtD strategies for rapid access to complex compound collections exhibiting sufficient stereochemical and skeletal diversity remains a challenge.…”

Section: Introductionmentioning

confidence: 99%

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Stereodivergent Complexity-to-Diversity Strategy en Route to the Synthesis of Nature-Inspired Skeleta

et al. 2022

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The complexity-to-diversity (CtD) strategy has become one of the most powerful tools used to transform complex natural products into diverse skeleta. However, the reactions utilized in this process are often limited by their compatibility with existing functional groups, which in turn restricts access to the desired skeletal diversity. In the course of employing a CtD strategy en route to the synthesis of natural product-inspired compounds, our group has developed several stereodivergent strategies employing indoloquinolizine natural product analogues as starting materials. These transformations led to the rapid and diastereoselective synthesis of diverse classes of natural product-like architectures, including camptothecininspired analogues, azecane medium-sized ring systems, arborescidineinspired systems, etc. This manifestation required a drastic modification of the synthetic design that ultimately led to modular and diastereoselective access to a diverse collection of various classes of biologically significant natural product analogues. The reported strategies provide a unique platform that will be broadly applicable to other late-stage natural product transformation approaches.

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Section: ■ Experimental Sectionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Stereodivergent Complexity-to-Diversity Strategy en Route to the Synthesis of Nature-Inspired Skeleta

et al. 2022

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“…In fact, numerous transition metal catalysis and organocatalysis have been utilized for the asymmetric desymmetrization of cyclohexadienones. [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] Recently, aza-Michael/Michael cyclization, a potentially powerful reaction to construct aza-cyclic complex molecules, was designed for the asymmetric desymmetrization of aza-cyclohexadienones.…”

Section: Introductionmentioning

confidence: 99%

A hidden catalysis: metal-, and organocatalyst-free one-pot assembly of chiral aza-tricyclic molecules

2021

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Development of a rapid synthesis of complex molecules from simple building blocks under a metal-and organocatalyst-free condition is both conceptually and chemically challenging. Here, we developed a hidden catalysis that allow the straightforward assembly of enantiopure aza-tricyclic molecules containing six contiguous stereocenters from <a>aminophenols, α,β-unsaturated aldehydes </a>and α-amino acids. <a>Without using a metal or an organocatalyst, our approach relies on a temporary formation of a spiroimidazolidinone intermediate and its participation in a sequential aza-Michael/Michael reaction as both a substrate and a catalyst</a> under an iminium/enamine catalysis. The formation of the putative iminium intermediate was supported by spectroscopic data and its interruptive reduction derivative was isolated and fully characterized. Whereas a conventional catalyst is always present and does not undergo a permanent chemical change in a classic catalysis, the spiroimidazolidinone intermediate is conceptualized as a sub-catalyst as it is only temporary produced from precursors and catalyzes its own consumption. This unique substrate-catalyst (sub-catalyst) dual role of the spiroimidazolidinone induces a substantial steric discrimination in the transition state and an excellent overall diastereoselectivity (>20:1 dr). It allows the use of an amino acid precursor as the sole chirality genesis and avoids the use of transition metals or organocatalysts. An enantiomer of an aza-tricyclic imidazolidinone can be prepared from a commercially available amino acid precursor. The aqueous-based reaction is practical and scalable for multi-gram synthesis. The success of implementing this sub-catalysis concept in the synthesis will pave the way for many efficient chiral catalyst-free preparations of chiral complex molecules.

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“…Most of these functionalizations have been studied with protected pyrroles. ,, Furthermore, use of expensive metals, limited substrate scope, and regioselectivity are the major issues of concern (Scheme a). On the other hand, cyclohexa-2,5-dienones are potent prochiral building blocks and have been greatly used for the construction of bicyclic and polycyclic architectures . Along this line, most of the progress was achieved with alkynyl tethered dienone 1 in the presence of external or internal nucleophiles (Scheme b). , We have also used this line for the synthesis of hydronaphtho[1,8- bc ]furans and tetracyclic aminals .…”

mentioning

confidence: 99%

“…On the other hand, cyclohexa-2,5-dienones are potent prochiral building blocks and have been greatly used for the construction of bicyclic and polycyclic architectures . Along this line, most of the progress was achieved with alkynyl tethered dienone 1 in the presence of external or internal nucleophiles (Scheme b). , We have also used this line for the synthesis of hydronaphtho[1,8- bc ]furans and tetracyclic aminals . Furthermore, cyclohexa-2,6-dienones or p -quinols are known to be an “aromatic to be” electrophilic surrogate to afford functionalized arenes and biaryls .…”

mentioning

confidence: 99%

Catalytic Friedel–Crafts Alkylative Desymmetrization of Cyclohexa-2,5-dienones: Access to Linear and Bridged Polycyclic Pyrroles and 3-Arylpyrroles

et al. 2022

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A catalytic [3 + 2]-cycloaddition/Friedel−Crafts alkylative desymmetrization strategy has been developed for the stereoselective construction of linear and bridged polycyclic pyrroles from alkynylcyclohexa-2,5-dienones. This strategy was further explored for the synthesis of 3-arylpyrroles under Brønsted acid catalysis. Reaction is highly chemo-, regio-, and stereoselective and is compatible with wide range of functionalized cyclohexa-2,5-dienones/pyrroles (>51 examples, ≤98% yields). Gram-scale synthesis and synthetic utility of the products have also been demonstrated to showcase the robustness of present method.

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Stereocontrolled transformations of cyclohexadienone derivatives to access stereochemically rich and natural product-inspired architectures

Abstract: The last two decades or so have witnessed an upsurge in defining the art of designing complex natural products and nature-inspired molecules. Throughout these decades fundamental insights into stereocontrolled, step-economic...

Cited by 52 publications

References 128 publications

Stereodivergent Complexity-to-Diversity Strategy en Route to the Synthesis of Nature-Inspired Skeleta

Stereodivergent Complexity-to-Diversity Strategy en Route to the Synthesis of Nature-Inspired Skeleta

A hidden catalysis: metal-, and organocatalyst-free one-pot assembly of chiral aza-tricyclic molecules

Catalytic Friedel–Crafts Alkylative Desymmetrization of Cyclohexa-2,5-dienones: Access to Linear and Bridged Polycyclic Pyrroles and 3-Arylpyrroles

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