Total synthesis of the antitumour natural product, (-)- echinosporin

The following dissertation describes a collection of results that led to a successful formal total synthesis of a naturally-occurring antitumour antibiotic, (-)..echinosporin. To achieve that, various synthetic strategies were developed and examined, all of which relied on a cycloadditive event as a key step to prepare the [3.4.0J-bicyclic framework of (-)-echinosporin. The synthesis was eventually accomplished using the Padwa [3+2] cycloaddition-elimination of allenylphenylsulphone to a chiral sugar enone 6 as a key transformation. it provided the first recorded example of this reaction used in complex natural product total synthesis. Following a series of functional group interconversions on this cycloadduct, a mild new method for the C-carboxyalkylation of bromomagnesium ketone enolates was applied to install the C(11)~carboxylic group of (-)- echinosporin. The quaternary OH-bearing stereocentre was introduced via a substrate~directed osmylative dihydroxylation on a i3-keto ester enol 71 . The resulting ketone 77 was advanced into 70 via Barton deoxygenation. Following that, the crucial C(8)-C(9) unsaturation was introduced starting from the ketone 70 through a three-step sequence based on the Barton vinyl iodide synthesis and Pd(O)-mediated dehalogenation. Next, a TEMPO-based oxidation was used to bring the C(10)- position to a correct oxidation state. Following protection as the allyl ester, an E1cb silyloxy elimination installed the remaining C(4)-C(5) unsaturation. The allyl ester 90 was finally transformed into a primary amide and the C-2 ethyl glycoside was chemoselectively hydrolysed using aqueous HBF4 to reveal Smith's intermediate 1.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

A New Stereocontrolled Synthetic Route to (−)-Echinosporin from d-Glucose via Padwa Allenylsulfone [3 + 2]-Anionic Cycloadditive Elimination

A new formal total synthesis of (−)-echinosporin has been developed based upon the Padwa [3 + 2]-cycloadditive elimination reaction of allenylsulfone <b>4</b> with the d-glucose-derived enone <b>14</b> which provides cycloadduct <b>12</b>

A New Mild Method for the C‑Acylation of Ketone Enolates. A Convenient Synthesis of β‑Keto-Esters, -Thionoesters, and -Thioesters

A new method for ketone enolate C-acylation is described which utilizes alkyl pentafluorophenylcarbonates, thiocarbonates, and thionocarbonates as the reactive acylating agents, and MgBr₂·Et₂O, DMAP, and <i>i</i>-Pr₂NEt as the reagents for enolization. A wide range of ketones have been observed to undergo clean C-acylation via this protocol

Identification and Structure-Guided Development of Pyrimidinone Based USP7 Inhibitors

Ubiquitin specific protease 7 (USP7, HAUSP) has become an attractive target in drug discovery due to the role it plays in modulating Mdm2 levels and consequently p53. Increasing interest in USP7 is emerging due to its potential involvement in oncogenic pathways as well as possible roles in both metabolic and immune disorders in addition to viral infections. Potent, novel, and selective inhibitors of USP7 have been developed using both rational and structure-guided design enabled by high-resolution cocrystallography. Initial hits were identified via fragment-based screening, scaffold-hopping, and hybridization exercises. Two distinct subseries are described along with associated structure–activity relationship trends, as are initial efforts aimed at developing compounds suitable for <i>in vivo</i> experiments. Overall, these discoveries will enable further research into the wider biological role of USP7