An Approach to Some Spiro Oxindole Alkaloids Through Cycloaddition Reactions of 3-Methylideneindolin-2-one

Bell, Stephanie E. V.; Brown, R. F. C.; Eastwood, F. W.; Horvath, J.

doi:10.1071/ch00016

Cited by 18 publications

(4 citation statements)

References 32 publications

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“…Scheme summarizes the synthesis of the required building block 2 . Subjecting 5‐methoxyisatin ( 5 )6 and methoxy enone 6 to a two‐step Friedlander quinoline synthesis7 via intermediate 7 afforded the keto carboxylate 8 , which was reduced in situ (NaBH 4 ) to furnish the tricyclic lactone 9 in 86 % overall yield. Exchange of the phenolic methyl group for a DMB group led to 10 (50 % overall yield for the two steps).…”

Section: Methodsmentioning

confidence: 99%

Total Synthesis and Stereochemistry of Uncialamycin

et al. 2007

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Uncialamycin (1 a or 1 b, Scheme 1) is a newly discovered enediyne antibiotic that possesses an intriguing molecular architecture and extremely potent biological properties. [1] Uncialamycin was isolated from an unreported strain of Streptomycete, related to Streptomyces cyanogenus, and exhibits potent plasmid DNA cleavage and phenomenal in vitro activity against Staphylococcus aureus (MIC 0.0000064 mg mL À1 ), as well as activity against Escherichia coli (MIC 0.002 mg mL À1 ) and Burkholderia cepacia (MIC 0.001 mg mL À1 ).[1] The scarcity of uncialamycin (only 300 mg were isolated) limited both the structural elucidation (the stereochemistry of the C26 hydroxy group remained unassigned) and the biological investigation. In view of this state of affairs and our earlier experience with enediyne antitumor antibiotics, [2] we set out to synthesize the two C26 epimers of uncialamycin (1 a and 1 b) to address the above issues. Herein we report the first total synthesis of both C26 epimers of racemic uncialamycin and assign the 26R* structure (1 b) as that of the natural substance through spectroscopic studies and X-ray analysis.Our strategy for the construction of uncialamycin centered around three key reactions: addition of an acetylide to a pyridinium species, an intramolecular acetylide addition to form the enediyne ring system, and Hauser annulation to form the anthraquinone moiety.[3] Fragments 2-4 were thus identified as the key building blocks for the projected synthesis.Scheme 2 summarizes the synthesis of the required building block 2. Subjecting 5-methoxyisatin (5) [6] and methoxy enone 6 to a two-step Friedlander quinoline synthesis [7] via intermediate 7 afforded the keto carboxylate 8, which was reduced in situ (NaBH 4 ) to furnish the tricyclic lactone 9 in 86 % overall yield. Exchange of the phenolic methyl group for a DMB group led to 10 (50 % overall yield for the two steps). The lactone moiety of 10 was reduced (DIBAL-H) and protected as a TES lactol to afford the Scheme 1. Structures and retrosynthetic analysis of (26S*)-and (26R*)-uncialamycins (1 a and 1 b). DMB = 3,4-dimethoxybenzyl, TES = triethylsilyl, TMS = trimethylsilyl.Scheme 2. Synthesis of quinoline system 2: a) KOH (1.0 equiv), H 2 O, 25 8C, 5 min; then 6 (1.5 equiv), 25 8C, 30 min; b) 10 % aq Na 2 CO 3 , 80 8C, 30 min; then NaBH 4 (4.0 equiv), 80 8C, 5 min, 86 % over 2 steps; c) aq HBr, 120 8C, 18 h, then DMBBr (2.5 equiv), K 2 CO 3 (10 equiv), [18]crown-6 (0.1 equiv), DMF, 25 8C, 4 h, 50 %; d) DIBAL-H (1.1 equiv), CH 2 Cl 2 , À78 to 25 8C over 1 h; e) TESCl (1.3 equiv), imidazole (2.6 equiv), DMF, 25 8C, 20 min, 86 % over 2 steps, ca. 1:1 mixture of diastereoisomers. DIBAL-H = diisobutylaluminum hydride.

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Section: Methodsmentioning

confidence: 99%

Total Synthesis and Stereochemistry of Uncialamycin

et al. 2007

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“…To conclude, we have aimed to synthesize different 1-(phenylsulfonyl)indolines (scaffold 32 ), being substituted in the 1′-pyrrolidine nitrogen with either basic-nitrogen containing, or lipophilic groups, presented in Scheme 4 —compounds 39a – b . Based on these considerations, first we benzylated [ 44 ] the tryptoline ( 25 ) to afford 36a , further converting it to the corresponding spiro-derivative [ 45 ] 37a . The reduction of the oxindole oxo-group was performed by applying borane-tetrahydrofuran complex in refluxing absolutized tetrahydrofuran [ 46 ].…”

Section: Resultsmentioning

confidence: 99%

Spiro[pyrrolidine-3,3′-oxindoles] and Their Indoline Analogues as New 5-HT6 Receptor Chemotypes

et al. 2017

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Synthetic derivatives of spiro[pyrrolidinyl-3,3′-oxindole] alkaloids (coerulescine analogues) were investigated as new ligands for aminergic G-protein coupled receptors (GPCRs). The chemical starting point 2′-phenylspiro[indoline-3,3′-pyrrolidin]-2-one scaffold was identified by virtual fragment screening utilizing ligand- and structure based methods. As a part of the hit-to-lead optimization a structure-activity relationship analysis was performed to explore the differently substituted 2′-phenyl-derivatives, introducing the phenylsulphonyl pharmacophore and examining the corresponding reduced spiro[pyrrolidine-3,3′-indoline] scaffold. The optimization process led to ligands with submicromolar affinities towards the 5-HT6 receptor that might serve as viable leads for further optimization.

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“…Recently, Horvath and co-workers reported that azomethine ylides generated from silylaminonitriles and 3-methyleneindolin-2-one react to give the corresponding cycloadduct in 70% yield . However, the dipolarophile was generated by flash vacuum pyrolysis and did not seem compatible with the synthesis of the methoxy-substituted derivative we required.…”

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confidence: 95%