Diastereoselective synthesis and biological evaluation of enantiomerically pure tricyclic indolines

He, Wei; Griffiths, Brendan M.; Wang, W.; Wang, X.

doi:10.1039/c7ob00897j

Cited by 9 publications

(2 citation statements)

References 27 publications

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“…Methods for the dearomatization of indole derivatives using electrophilic reagents are well established, − and the idea to trap the resulting products (usually indolenines) with a tethered nucleophile is also known; for example, Bandini et al demonstrated the power of this approach for the conversion of indole-tethered propargyl alcohols 14 into tetracyclic fused furoindolines 15 using a gold-catalyzed cyclization cascade (Scheme a) . Indeed, a similar strategy has also been used for the assembly of tetracyclic alkaloid scaffolds 17 via alkyne activation, exemplified by a gold(I)-catalyzed system reported by Wang et al (Scheme b); the same group also demonstrated the value of this method in the formal synthesis of minfiensine and used it for the generation of medicinally relevant scaffolds . Methods to prepare enantioenriched scaffolds in this way are less well established, and are most commonly achieved via transition-metal catalyzed asymmetric allylation reactions, exemplified by Jiao’s study summarized in Scheme c…”

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confidence: 99%

Modular Synthesis of Polycyclic Alkaloid Scaffolds via an Enantioselective Dearomative Cascade

et al. 2020

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The polycyclic core of the akuammiline alkaloids can be synthesized from simple tryptamine and tryptophol derivatives via a Ag(I)-catalyzed enantioselective dearomative cyclization cascade sequence. The complex tetracyclic scaffolds are prepared via a rapid, versatile, three-step modular synthesis from simple commercially available indole derivatives in high yields and enantiomeric excess (up to 99% yield and >99% ee).C omplex polycyclic scaffolds are widely present in biologically important alkaloid natural products. The akuammiline alkaloids (see 1−5, Scheme 1A) are prominent examples, with various members of this diverse family of bioactive compounds based on a common tetracyclic core 6. 1 Accordingly, these alkaloids have attracted considerable attention from both synthetic and medicinal chemists; several innovative total syntheses have been accomplished, 2 although these methods often require multiple linear synthetic operations and are typically directed toward selected akuammiline synthetic targets. Alkaloids are unquestionably highly important in medicine, and strategies to access core alkaloid frameworks, via short and flexible synthetic sequences, are arguably of even greater value in medicinally oriented discovery, given their potential for the rapid assembly of diverse collections of complex, natural product-like scaffolds. 3 The dearomatization of indoles through reactions with tethered ynones is well established, 4 with many of these methods generating quaternary centers and forming multiple stereoisomers. However, partly due to the linear nature of the alkyne unit, controlling the enantioselectivity of such dearomatization reactions is challenging. This is illustrated by the limited number of enantioselective dearomatization reactions of alkyne-tethered indoles reported in the literature. 5 Furthermore, to the best of our knowledge, examples of highly enantioselective (>80% ee) indole dearomatization reactions employing ynone-tethered precursors have not yet been reported.In this manuscript, we report the successful realization of a Ag(I)-catalyzed enantioselective dearomatizing 6 cascade sequence for the rapid construction of the akuammiline alkaloid core scaffold 9 via ynone-tethered indoles 7 (Scheme 1B). Key to the success of this process was the selection of a chiral πacid catalyst able to perform three roles in the proposed cascade: (1) activation of the ynone moiety tethered to the C2-

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confidence: 99%

Modular Synthesis of Polycyclic Alkaloid Scaffolds via an Enantioselective Dearomative Cascade

et al. 2020

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“…In this series we synthesized four esters of pyroglutamic acid, viz. methyl, ethyl, iso -propyl ( 1 ), and tert -butyl ( 2 ). The methyl and ethyl ester could only be recovered as oils, while 1 and 2 could be crystallized, followed by the determination of their X-ray structure.…”

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confidence: 99%

Does the Exception Prove the Rule? A Comparative Study of Supramolecular Synthons in a Series of Lactam Esters

Weck

Nauha

Gruber

2019

Crystal Growth & Design

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In this paper a series of simple lactam esters and carboxylic acids is studied with respect to their overall conformation and hydrogen bonding patterns. In total, eight lactams featuring Nαsubstitution have been synthesized. Additionally, the molecular structures of related lactam esters have been considered. The length of the amide bonds does not seem to be majorly influenced by different substituents unless the electron withdrawing N-Boc-protection group is introduced, resulting in a higher susceptibility towards hydrolytic ring opening. As known from other lactams, the Nα ester moiety of the title compounds can be in an axial or equatorial conformation. Smaller ester groups were found to prefer equatorial positions, while larger ones occupy axial sites. N-substitution seems to promote axial conformations of the respective Nα group, with enantholactams being the only studied exception. In addition to the two common amide packing motifs, i.e. the R 2 2 (8) amide dimer (NH•••O/NH•••O) and the C(4) amide chain, a third graph-set was found: the R 2 2 (8) NH•••O/CH•••O=C heterodimer. In general, there seems to be a tendency for medium-sized lactams as well as lactams with small esters to form R 2 2 (8) amide dimers. Larger esters and enantholactam esters lead to C(4) amide chains. In this respect the formation of R 2 2 (8) N-H•••O/C-H•••O=C heterodimers should be seen as a remarkable exception.

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7‐Oxa‐4‐thia‐1‐aza‐bicyclo[3.2.1]octane 4,4‐Dioxides: Mechanochemical Synthesis by Tandem Michael Addition–1,3‐Dipolar Cycloaddition of Aldoximes and Evaluation of Antibacterial Activities

et al. 2018

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A solvent‐free, green, and efficient mechanochemical method for the synthesis of a series of bridged bicyclo aza‐sulfone derivatives, namely 7‐oxa‐4‐thia‐1‐aza‐bicyclo[3.2.1]octane 4,4‐dioxides through tandem Michael addition–1,3‐dipolar cycloaddition of aldoximes was developed. Mechanochemical grinding/milling facilitates quick formation of aldoximes from corresponding aldehydes and hydroxylamine, which upon reaction with divinyl sulfone in a mixer mill affords 7‐oxa‐4‐thia‐1‐aza‐bicyclo[3.2.1]octane 4,4‐dioxide derivatives in good overall yields. The newly synthesized bicyclo aza‐sulfone derivatives 4 were screened for antibacterial activities. Mostly bicyclo aza‐sulfones derived from electron‐rich aromatic aldehydes inhibit the growth of Mycobacterium smegmatis (mc2155) and those from aliphatic aldehydes the growth of Escherichia coli (DH5α) in moderate to good effect. However, butyraldehyde‐derived compound 4r was very effective against both M. smegmatis and E. coli. The key advantages of this mechanochemical method are catalyst‐ and solvent‐free conditions, shorter reaction time, and formation of a new series of 7‐oxa‐4‐thia‐1‐aza‐bicyclo[3.2.1]octane 4,4‐dioxide derivatives, which are good antibacterial agents against M. smegmatis and E. coli.

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Diastereoselective synthesis and biological evaluation of enantiomerically pure tricyclic indolines

Cited by 9 publications

References 27 publications

Modular Synthesis of Polycyclic Alkaloid Scaffolds via an Enantioselective Dearomative Cascade

Modular Synthesis of Polycyclic Alkaloid Scaffolds via an Enantioselective Dearomative Cascade

Does the Exception Prove the Rule? A Comparative Study of Supramolecular Synthons in a Series of Lactam Esters

7‐Oxa‐4‐thia‐1‐aza‐bicyclo[3.2.1]octane 4,4‐Dioxides: Mechanochemical Synthesis by Tandem Michael Addition–1,3‐Dipolar Cycloaddition of Aldoximes and Evaluation of Antibacterial Activities

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