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The relevance of the melanocortin system to sexual activity is well established, and nonselective peptide agonists of the melanocortin receptors have shown evidence of efficacy in human sexual dysfunction. The role of the MC4 receptor subtype has received particular scrutiny, but the sufficiency of its selective activation in potentiating sexual response has remained uncertain owing to conflicting data from studies in preclinical species. We describe here the discovery of a novel series of small-molecule MC4 receptor agonists derived from library hit 2. The addition of methyl substituents at C3 and C5 of the 4-phenylpiperidin-4-ol ring was found to be markedly potency-enhancing, enabling the combination of low nanomolar potencies with full rule-of-five compliance. In general, the series shows only micromolar activity at other melanocortin receptors. Our preferred compound 40a provided significant systemic exposure in humans on both sublingual and oral administration and was safe and well tolerated up to the maximum tested dose. In a pilot clinical study of male erectile dysfunction, the highest dose of 40a tested (200 mg) provided a similar level of efficacy to sildenafil.

Unsaturated epsilon-lactones bearing an alpha-arylsulfonyl or alpha-arylsulfoximinyl substituent undergo stereoselective transannular, decarboxylative Claisen rearrangement to give substituted vinylcyclopropanes.

The decarboxylative Claisen rearrangement of a range of substituted diallyl 2-sulfonylmalonates is described. The reaction displays a very high degree of regioselectivity, with allylic substituents possessing electron-rich substituents at the 3-position rearranging preferentially. The substrates are made by C-carboxylation of the corresponding allyl sulfonylacetates with allyl para-nitrophenyl carbonates. In one instance, the presence of a highly electron-withdrawing side-chain led to the competing formation of a γ-lactone by-product. The Claisen rearrangement continues to be the focus of considerable research effort. [1] Since its introduction in 1972, [2] the Ireland silyl ketene acetal variant in particular has been widely used in complex target-oriented synthesis. [3] This modified process benefits from the ease of preparation of the ketene acetal substrates and the relatively mild conditions for the sigmatropic rearrangement. In addition, it enables overall C-allylation of carboxylic acids using allylic alcohols as the surrogate electrophiles, with regiospecific allylic double-bond transposition. We recently reported [4,5] a novel variant of the Ireland-Claisen rearrangement reaction in which α-tosyl silyl keteneacetals formed in situ from allylic tosylacetates 1 in the presence of N,O-bis(trimethylsilyl)acetamide (BSA) and

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