David R. Fenwick

Enantio- and diastereoselective catalytic alkylation reactions with aziridines.

The first asymmetric phase transfer catalyzed alkylation reaction of a range of carbon acids with N-sulfonyl aziridines is reported. When 10 mol % of a cinchona derived quaternary ammonium salt was employed as the catalyst under mildly basic conditions, N-o-(trifluoromethane)benzenesulfonyl aziridine was efficiently ring-opened to afford the amino ethylene products in consistently high yields and high enantioselectivities (up to 97% ee). By employing substituted aziridines in single enantiomeric form, the corresponding enantiopure alkylation products could be obtained with a range of pronucleophiles in high yields and moderate to high diastereoselectivities (up to 30:1 dr).

[5]Helicenes by tandem radical cyclisation

A new and rapid approach to [5]helicenes is described. A central feature is the use of a sequential, non-reducing radical cyclisation reaction of (Z,Z)-1,4-bis(2-iodostyryl)benzene derivatives, viz. 3→1, mediated by tributyltin hydride.

Radical cyclisations to arenes for the synthesis of phenanthrenes

6-exo/endo-Trig intramolecular additions of aryl radicals to electron-rich, unsubstituted and electron-deficient arenes have all been shown to proceed efficiently to give the corresponding phenanthrenes in high yield.

A new cascade radical reaction for the synthesis of biaryls and triaryls from benzyl iodoaryl ethers

The paper describes a new method of synthesizing biaryls and triaryls through an intramolecular ipso-substitution reaction initiated by the addition of an aryl radical to a benzyl ether. A tandem variant of the reaction has also been demonstrated. A short synthesis of isoaucuparin 27, a natural product found in the sapwood tissue of Sorbus aucuparia, is also described.

[5]Helicenes by iterative radical cyclisations to arenes

Abstract The paper describes a synthesis of 1,2,3,12,13,14-hexamethoxy[5]helicene 1 . The synthesis features two sp 2 – sp 2 bond forming reactions, each involving a 6- exo / endo -trig cyclisation of an aryl radical intermediate to an arene.

The first total synthesis of toddaquinoline, an alkaloid from Toddalia asiatica

The paper describes the first total synthesis of toddaquinoline, an alkaloid from the root bark of Formosan Toddalia asiatica. The key step is cobalt(I) mediated radial cyclisation to a pyridine. Cobalt appears to play a dual role in the reaction, firstly initialising homolysis of the carbon to halogen bond then acting as a Lewis acid to promote cyclisation to C-6. Other approaches examined are also outlined. These include a photocyclisation of an azastilbene; a cyclisation induced by halogen to metal exchange and a tin mediated radical cyclisation.

Catalytic Enantio‐ and Diastereoselective Alkylations with Cyclic Sulfamidates

The enantioselective construction of derivatives of g-amino butyric acid and d-amino pentanoic acid from simple starting materials using asymmetric catalysis provides convenient access to a range of structurally diverse natural products, pharmaceutical compounds, and potential building blocks for g-peptides and foldamer chemistry. Several natural products containing the aminoethylene and aminopropylene scaffolds attached to a quaternary stereocenter have been isolated. Developments in the field of enantioselective Michael

An Imidazopiperidine Series of CCR5 Antagonists for the Treatment of HIV: The Discovery of N-{(1S)-1-(3-Fluorophenyl)-3-[(3-endo)-3-(5-isobutyryl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-1-yl)-8-azabicyclo[3.2.1]oct-8-yl)propyl}acetamide (PF-232798)

Preventing entry of HIV into human host cells has emerged as an attractive approach to controlling viral replication. Maraviroc 1 is an approved antagonist of the human CCR5 receptor which prevents the entry of HIV. Herein, we report the design and discovery of a series of imidazopiperidine CCR5 antagonists which retain the attractive antiviral profile and window over hERG activity of maraviroc 1, combined with improved absorption profiles in rat and dog. Furthermore, this series of compounds has been shown to retain activity against a laboratory generated maraviroc-resistant HIV-1 strain, which indicates an alternative resistance profile to that of maraviroc 1. Compound 41f (PF-232798) was selected as a clinical candidate from the imidazopiperidine series and is currently in phase II clinical trials.

A total synthesis of toddaquinoline exposes a dual role for cobalt in radical additions to pyridines

Abstract This paper describes the first total synthesis of toddaquinoline, an alkaloid from the root bark of Formosan Toddalia asiatica . Importantly, the synthesis has exposed a dichotomy in radical reactions mediated by tin and cobalt(I) that involve additions to pyridines. Our observations suggest that cobalt plays a dual role in such reactions: firstly initiating homolysis of the carbon to halogen bond, then acting as a Lewis acid to promote radical additions to the carbon centre adjacent to nitrogen.

The design and discovery of novel amide CCR5 antagonists.

The synthesis of a range of novel amine-containing structures and their primary potency as inhibitors of HIV-1 fusion via blocking of the CCR5 receptor is described. The development of the medicinal chemistry strategy and SARs which led to the identification of the piperidine amide compounds 33 and 36 as excellent leads for further evaluation is described, along with key physicochemical data which highlighted their lead potential.