A synthetic method to prepare bicyclo[6.3.0]undeca-2,4,9,trienyl esters efficiently from gold(I)-catalyzed Rautenstrauch rearrangement/1,5-hydride shift/8-endo-dig cyclization of 1-ene-4,10-diynyl esters is described. The suggested double cycloisomerization mechanism delineates the first example of an unactivated all-carbon tethered 1,7-enyne, either preformed or formed in situ, which undergoes an 8-endo-dig cyclization pathway to give a cyclooctane motif. It also offers an extremely rare synthetic method in organic chemistry that can sequentially assemble both ring components of the bicyclic motif from an acyclic precursor in one step.

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A synthetic method to prepare 11Hbenzo [a]fluorenes and 13H-indeno[1,2l]phenanthrenes that relies on the gold(I)-and Brønsted acid-mediated deacyloxylative cycloaromatisation of 1,6-diyne esters under reaction conditions that did not require the exclusion of moisture or air is described. The reaction mechanism was delineated to involve an initial gold(I)-catalysed 1,2-acyloxy migration and 5-exo-trig cyclisation pathway. This was followed by 1,5-enyne rearrangement and Brønsted acid-assisted deacyloxylative aromatisation to give the polyaromatic hydrocarbon (PAH) product.

The synthesis of 1,4-amino alcohols from THF treated with N-tosyliminobenzyliodinane (PhINTs) followed by a Grignard reagent under mild reaction conditions at room temperature is described herein. Various Grignard reagents were shown to be compatible, furnishing the corresponding 4-substituted-N-1,4-tosylamino alcohols in good to excellent yields. A partial or full detosylation of the N-tosyl-1,4-amino alcohol was observed in instances involving a sterically bulky Grignard reagent, leading to the deprotected 1,4-amino alcohol product in moderate to good yields. The synthetic utility of this protocol was demonstrated by the synthesis of a 5-substituted-N-tosyl-1,5-amino alcohol from THP and the conversion of two examples to their corresponding γ-lactam and pyrrolidine adducts.

Abstract Sympathetically mediated contractions of smooth muscle cells in vasa deferentia are mediated by neuronally released adenosine 5′-triphosphate (ATP) and noradrenaline, which stimulate P2X1-purinoreceptors and α1A-adrenoceptors respectively. This process is crucial for sperm transport, as demonstrated in knockout mouse studies where simultaneous genetic deletion of P2X1-purinoreceptors and α1A-adrenoceptors resulted in male infertility. We hypothesise that dual pharmacological antagonism of these two receptors could inhibit sperm transport sufficiently to provide a novel non-hormonal method of male contraception. To generate a suitable P2X1-purinoceptor antagonist, substituents were introduced on the phenyl moiety of 2-phenyl-5,6,7,8-tetrahydroquinoxaline to create a series of analogues that were tested for P2X1-purinoreceptor antagonism in isolated preparations of rat vas deferens. Novel compounds were initially screened for their ability to attenuate contractile responses to electrical field stimulation (EFS: 60 V, 0.5 ms, 0.2 Hz). The addition of polar substituents to the meta, but not ortho, position, markedly increased the inhibition of contractions, as did the addition of both polar and aliphatic substituents to the para position. Di-substituted compounds were also synthesised and tested, resulting in a compound 31 (2-hydroxy, 4-fluoro), which exhibited the greatest potency, with an IC50 of 14 μM (95% confidence limits: 12–16 μM). Additionally, compound 31 non-competitively antagonised contractions mediated by exogenously administered αß-methylene ATP (10 nM—30 μM) but had no inhibitory effect on contractions mediated by exogenously administered noradrenaline (30 nM—100 μM) or acetylcholine (30 nM—100 μM). These results have contributed to a structure activity relationship (SAR) profile for the P2X1-purinoreceptor that will inform future designs of more potent antagonists.