Total Synthesis of (–)‐Isoamericanin A and (+)‐Isoamericanol A

Pilkington, Lisa I.; Barker, David

doi:10.1002/ejoc.201301363

Cited by 23 publications

(49 citation statements)

References 60 publications

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“…However, the current synthetic route would still require significant improvement to deliver a scalable, robust, and cost-effective chemical process, in line with the stated TPP objectives for an affordable drug. Possible alternatives include using the known 56 enantiomer of orthogonally diprotected triol 125 and following the pathway described for S- 6 in Scheme 4 B because this enantiomer could be obtained from the cheap, optically pure starting material d -mannitol (via the less expensive S -solketal). 57 …”

Section: Results and Discussionmentioning

confidence: 99%

Development of (6R)-2-Nitro-6-[4-(trifluoromethoxy)phenoxy]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (DNDI-8219): A New Lead for Visceral Leishmaniasis

et al. 2018

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Discovery of the potent antileishmanial effects of antitubercular 6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazoles and 7-substituted 2-nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazines stimulated the examination of further scaffolds (e.g., 2-nitro-5,6,7,8-tetrahydroimidazo[2,1-b][1,3]oxazepines), but the results for these seemed less attractive. Following the screening of a 900-compound pretomanid analogue library, several hits with more suitable potency, solubility, and microsomal stability were identified, and the superior efficacy of newly synthesized 6R enantiomers with phenylpyridine-based side chains was established through head-to-head assessments in a Leishmania donovani mouse model. Two such leads (R-84 and R-89) displayed promising activity in the more stringent Leishmania infantum hamster model but were unexpectedly found to be potent inhibitors of hERG. An extensive structure–activity relationship investigation pinpointed two compounds (R-6 and pyridine R-136) with better solubility and pharmacokinetic properties that also provided excellent oral efficacy in the same hamster model (>97% parasite clearance at 25 mg/kg, twice daily) and exhibited minimal hERG inhibition. Additional profiling earmarked R-6 as the favored backup development candidate.

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Section: Results and Discussionmentioning

confidence: 99%

Development of (6R)-2-Nitro-6-[4-(trifluoromethoxy)phenoxy]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (DNDI-8219): A New Lead for Visceral Leishmaniasis

et al. 2018

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“…In analogy to literature, 1,4‐dihydroxynaphthalene ( 1f , 1.602 g, 10.0 mmol), NEt 3 (4.16 mL, 30.0 mmol) and DMAP (0.122 g, 1.0 mmol) were dissolved in dry dimethylformamide (50 mL) under nitrogen. The solution was cooled to 0°C, triisopropyldimethylsilyl chloride (6.43 mL, 25.0 mmol) was added within 15 minutes, and the solution was stirred at rt for 3 hours.…”

Section: Methodsmentioning

confidence: 99%

Photooxygenation of oxygen‐substituted naphthalenes

Bauch

Krtitschka

Linker

2017

J of Physical Organic Chem

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The reaction of oxygen‐substituted naphthalenes with singlet oxygen (1O2) has been investigated, and labile endoperoxides have been isolated and characterized at –78°C for the first time. Low‐temperature kinetics by UV spectroscopy revealed that alkoxy and silyloxy substituents remarkably increase the rate of photooxygenations compared to 1,4‐dimethylnaphthalene, whereas acyloxy‐substituted acenes are inert towards 1O2. The reactivities nicely correlate with HOMO energies and free activation energies, which we determined by density functional theory calculations. The lability of the isolated endoperoxides is due to their very fast back reaction to the corresponding naphthalenes even at –20°C under release of 1O2, making them to superior sources of this reactive species under very mild conditions. Finally, a carbohydrate‐substituted naphthalene has been synthesized, which reacts reversibly with 1O2 and might be applied for enantioselective oxidations in future work.

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“…This route has also been applied to the synthesis of 2-hydroxymethyl-1,4-benzodioxane oxyneolignans through the synthesis of members of the isoamericanin family, isoamericanin A (3) and isoamericanol A (17). 98 Instead of using a lactate in the Mitsunobu coupling with a phenol (in this case 132), a glycerol derivative 133 was used to afford the 2-hydroxymethyl structural feature found in the nal products (Scheme 25).…”

Section: Mitsunobu Coupling Of Phenols and Chiral Alcoholsmentioning

confidence: 99%