Simple Synthesis of Conformationally Fixed Glycosamine Analogues by Beckmann Rearrangement at the Carbohydrate Ring

Umbreen, Sumaira; Linker, Torsten

doi:10.1002/chem.201406546

Cited by 13 publications

(3 citation statements)

References 46 publications

(15 reference statements)

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“…Very recently, Umbreen and Linker applied known [2+2] cycloadditions41 of dichloroketene ( 85 ) to acetyl‐protected glycals 84 7 as a new means of access to 1,2‐annulated sugars. Beckmann rearrangement of the cyclobutanones 86 proceeded smoothly in moderate to good yields, affording conformationally fixed glycosamine analogues of hexoses, pentoses, and disaccharides, such as 87 , as single regio‐ and stereoisomers (Scheme ) 42…”

Section: 12‐annulated Carbohydratesmentioning

confidence: 99%

Recent Developments in the Synthesis of 2‐C‐Branched and 1,2‐Annulated Carbohydrates

Vankar

Linker

2015

Eur J Org Chem

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The importance of carbohydrate chemistry in biological and medicinal chemistry has led to enormous developments in the synthesis of carbohydrate mimics. In this context, the synthesis of branched sugars in general and of 2‐C‐branched carbohydrates in particular, as well as the synthesis of 1,2‐annulated sugars, have received immense attention. They serve not only as carbohydrate mimics in the form of stand‐alone molecules, but also as useful intermediates in the synthesis of many natural products, their analogues, and glycosidase inhibitors. This microreview covers the recent synthetic efforts in this area and puts the subject matter into proper perspective for future developments.

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Section: 12‐annulated Carbohydratesmentioning

confidence: 99%

Recent Developments in the Synthesis of 2‐C‐Branched and 1,2‐Annulated Carbohydrates

Vankar

Linker

2015

Eur J Org Chem

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“…Cycloadditions of endo ‐glycals and dichloroketene were investigated by several groups [15] to show the regio‐ and stereoselective formation of bicyclic glyco‐annulated cyclobutanones in good yields. Linker and co‐workers also presented the transformation of the cyclobutanone derivatives to γ‐lactones under Baeyer‐Villiger oxidation conditions, [15b] and to γ‐lactams via the corresponding oxime in a Beckmann rearrangement reaction [15c] …”

Section: Introductionmentioning

confidence: 99%

[2+2] Cycloadditions of Methylene exo‐Glycals: Synthesis of Glycopyranosylidene‐Spiro‐Azetidine‐2‐ones (β‐Lactams) and Cyclobutanones

et al. 2023

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[2+2] Cycloadditions of methylene exo‐glycal derivatives with chlorosulfonyl isocyanate and dichloroketene were studied in detail, investigating the effect of the carbohydrate moiety, protecting groups as well as reaction temperature on the yields of the transformations. These reactions gave new anomeric spiro‐β‐lactam and spiro‐cyclobutanone derivatives, whose structure was established by 1D and 2D NMR and MS experiments. The transformation of spiro‐cyclobutanone into spiro‐γ‐lactone was also demonstrated.

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“…To test this hypothesis, the cycloaddition was attempted with Zn(Cu) according to Umbreen and Linker's method. 204 Slow addition of acid chloride 125 to a mixture of Zn(Cu) and glucal 149 gave several more polar species by TLC analysis, and consumption of 149 had occurred within 3 h. However, analysis by 1 H NMR indicated the reaction had caused complex degradation of the starting materials, with no evidence of the desired cycloadduct. Direct reduction of acid chloride 125 with Zn(Cu) in the presence of glucal 149 gave no cycloadduct in this case; however, further explorations into this reaction are encouraged.…”

Section: Screening Of Ketene [2+2] Cycloaddition Conditionsmentioning

confidence: 99%

A structure-based approach to kinase inhibition based on the natural product (-)-TAN-2483B

McCone¹

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The natural product (-)-TAN-2483B (1) is a polyketide derived secondary metabolite isolated from the fermentation broth of a filamentous fungus at Takeda Industries, Japan. This compound possesses a densely functionalised furo[3,4-b]pyran-5-one framework rarely seen in natural products, and has displayed inhibitory activity against the c-SRC kinase and parathyroid-induced bone resorption in osteoclasts. Previous work in the Harvey group led to the synthesis of analogue 2, which significantly inhibits Bruton’s tyrosine kinase (BTK, 83% inhibition at 10 μM), a validated drug target for various diseases. The work presented herein describes the synthesis, molecular modelling, and BTK inhibitory activity of new analogues of 2. Also described is the first total synthesis of 1, and an assessment of its kinase-inhibitory activity. An efficient and flexible synthetic strategy was proposed (Chapter 2) to facilitate synthesis of the furo[3,4-b]pyran-5-one scaffold, achieve the total synthesis and further explore the structure-activity relationship (SAR) between 2 and BTK. It was envisaged that the furo[3,4-b]pyran-5-one core may be constructed through a [2+2]-cycloaddition of ketene 3 and glycal 4, followed by Baeyer-Villiger (BV) oxidation. However, all attempts to reach the intermediate 5 were unsuccessful. Attention shifted to the modelling of 2 in the BTK binding site to aid in rationally designing furo[3,4-b]pyran-5-one-based inhibitors. Structure-based methodology, including docking and molecular dynamics, was utilised to develop reasonable hypotheses for analogue binding (Chapter 3). To experimentally test the binding hypotheses and further develop the SAR, a series of new analogues (6-11) was synthesised by modifying and optimising the existing synthetic route, starting from the chiral building block D-mannose (Chapter 4). Generation of the 2,6-trans-disubstituted pyran 12 was enabled by ring-expansion of dibromocyclopropane 13 and subsequent α-selective alkynylation under Lewis acidic conditions. The (Z)-ethyl ester sidechain present in 2 was installed selectively by utilisation of a Still-Gennari reaction. Alkyne derivatisation and palladium-catalysed carbonylation established the lactone with the desired (S)-configuration at the methyl linkage, completing the bicyclic core. Determination of their BTK inhibitory activities revealed the importance of the endocyclic alkene and hydroxyl for retaining activity. Chapter 5 illustrates the successful total synthesis of 1 which was achieved using methodology related to that described in Chapter 4. The (E)-propenyl sidechain was introduced by a carefully orchestrated Julia-Kocienski olefination. A revision of the protecting group strategy enabled finalisation of the natural product synthesis, where the product spectroscopically conformed to the proposed structure, and the data reported for the natural product. Utilising the putative SAR data and modelling methodology developed herein, future efforts in this project should aim to rationalise the SAR data by further docking and biological studies, as well as targeted analogue synthesis that could aid in developing furo[3,4-b]pyran-5-ones with enhanced binding to BTK.

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Simple Synthesis of Conformationally Fixed Glycosamine Analogues by Beckmann Rearrangement at the Carbohydrate Ring

Cited by 13 publications

References 46 publications

Recent Developments in the Synthesis of 2‐C‐Branched and 1,2‐Annulated Carbohydrates

Recent Developments in the Synthesis of 2‐C‐Branched and 1,2‐Annulated Carbohydrates

[2+2] Cycloadditions of Methylene exo‐Glycals: Synthesis of Glycopyranosylidene‐Spiro‐Azetidine‐2‐ones (β‐Lactams) and Cyclobutanones

A structure-based approach to kinase inhibition based on the natural product (-)-TAN-2483B

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