The highly diastereoselective conjugate additions of the novel lithium amide reagents lithium (R)-N-(3-chloropropyl)-N-(α-methylbenzyl)amide and lithium (R)-N-(3-chloropropyl)-N-(α-methyl-p-methoxybenzyl)amide to α,β-unsaturated esters were used as the key steps in syntheses of the homalium alkaloids (-)-(S,S)-homaline and (-)-(R,R)-hopromine. The asymmetric synthesis of (-)-(S,S)-homaline was achieved in 8 steps and 18% overall yield, and the asymmetric synthesis of (-)-(R,R)-hopromine was achieved in 9 steps and 23% overall yield, from commercially available starting materials in each case. These syntheses therefore represent by far the most efficient total asymmetric syntheses of these alkaloids reported to date. A sample of the (4'R,4''S)-epimer of hopromine was also produced using this approach, which provided the first unambiguous confirmation of its absolute configuration and therefore that of natural (-)-(R,R)-hopromine.

The development of a stereoselective total synthesis of β-dihydroagarofuran 4 is described. This compound contains the same oxygenation pattern on its 'lower-rim' as found in the natural sesquiterpene (-)-euonyminol (1) and it is expected that the route described should be applicable to the synthesis of that complex natural product. (-)-Euonyminol is found as the core scaffold of a series of complex macrodilactone sesquiterpenoids isolated from the Celastraceae which possess interesting biological activities (e.g. anti-HIV activity). The synthetic route builds upon an epoxidative asymmetric desymmetrisation of meso-diallylic alcohol 10 that we have reported previously. It features a lactate Ireland-Claisen rearrangement to establish the quaternary stereocentre at C11 (27→28a) and an unusual dealkylative intramolecular epoxide-opening by the C11 methyl ether to establish the tetrahydrofuranyl C-ring of the β-dihydroagarofuran skeleton (35→36).

A practical and pragmatic method is demonstrated that aligns lead-like properties with compound diversity for the picking of compounds to synthesise from large virtual libraries. Methods are highlighted for decreasing synthetic attrition through the prior filtration of reagents sets grouped by reaction type. Also disclosed are protocols that use a combination of predicted physicochemical parameters and potential toxicological liabilities to enable the synthesis of lead-like compounds with a low potential risk of exhibiting toxicity or undesirable physicochemical properties. Lastly, a compound-picking process for a 2D compound matrix is demonstrated that maximises the diversity coverage whilst minimising synthetic effort. Thus a very highly optimised process is shown that delivers premium sample quality where lead-likeness and novelty are aligned to afford the best possible enhancement for the corporate compound collection.