Many drugs are administered at sites that are remote from their site of action. The most common route of drug delivery is the oral route. The optimal physicochemical properties to allow high transcellular absorption following oral administration are well established and include a limit on molecular size, hydrogen bonding potential and adequate lipophilicity. For many drug targets, synthetic strategies can be devised to balance the physicochemical properties required for high transcellular absorption and the SAR for the drug target. However, there are drug targets where the SAR requires properties at odds with good membrane permeability. These include a requirement for significant polarity and groups that exhibit high hydrogen bonding potential such as carboxylic acids and alcohols. In such cases, prodrug strategies have been employed. The rationale behind the prodrug strategy is to introduce lipophilicity and mask hydrogen bonding groups of an active compound by the addition of another moiety, most commonly an ester. An ideal ester prodrug should exhibit the following properties: 1). Weak (or no) activity against any pharmacological target, 2). Chemical stability across a pH range, 3). High aqueous solubility, 4). Good transcellular absorption, 5). Resistance to hydrolysis during the absorption phase, 6). Rapid and quantitative breakdown to yield high circulating concentrations of the active component post absorption. This paper will review the literature around marketed prodrugs and determine the most appropriate prodrug characteristics. In addition, it will examine potential Discovery approaches to optimising prodrug delivery and recommend a strategy for prosecuting an oral prodrug approach.

Epicolactone is a recently isolated fungal metabolite that is highly complex for its size, and yet racemic. With its array of quaternary stereocentres, high degree of functionalization and intricate polycyclic structure, it poses a considerable challenge to synthesis, a challenge that can be met by understanding its biosynthetic origin. If drawn in a certain way, epicolactone reveals a pattern that resembles purpurogallin, the archetype of ubiquitous natural colourants formed via oxidative dimerization. Based on this insight, we designed a biomimetic synthesis of epicolactone that proceeds in only eight steps from vanillyl alcohol. We have isolated a key intermediate that supports our biosynthetic hypothesis and anticipate that an isomer of epicolactone stemming from our synthetic efforts could also be found as a natural product.

A Rh(I) catalyzed regiodivergent addition of heteroatom nucleophiles to racemic oxabicyclic alkenes produces good yields of regioisomeric products each in high ee. Powerful reagent control is demonstrated, as the inherent reactivity of the substrate is completely dominated by the chiral catalyst complex, which is shown to require the use of cationic Rh(I). The process affords rapid access to multiple 1,2-dihydronapthalene products in high enantioselectivity from simple starting materials.

A highly regioselective synthesis of 1-aryl-3,4,5-substituted pyrazoles based on the condensation of 1,3-diketones with arylhydrazines is described. The reaction proceeds at room temperature in N,N-dimethylacetamide and furnishes pyrazoles in 59-98% yields.Pyrazole heterocycles are found as core structural components of numerous agrochemicals and pharmaceutical agents such as antiinflammatories, 1 anticoagulants, 2 cannabinoid receptor ligands, 3 and antimicrobials. 4 The cyclocondensation of 1,3-dicarbonyl compounds with hydrazine derivatives represents one of the simplest and most general approaches to the synthesis of pyrazoles. However, with unsymmetrical 1,3-dicarbonyl substrates this method often suffers from the formation of regioisomeric pyrazoles with generally poor selectivity. 5 Moreover, the two pyrazole regioisomers can often be difficult to separate by chromatography and repeated crystallization may be necessary to reject the undesired regioisomer. This usually results in substantial decrease in isolated yields of the desired heterocycles. Therefore, various alternative strategies have appeared in the literature as potential solutions to the problem of regioselective synthesis of pyrazoles. 6 We wish to report herein an improved protocol for the highly regioselective synthesis of 1-aryl-3,4,5-substituted pyrazoles of pharmaceutical importance. The reaction proceeds under operationally simple, mild, safe, volumetrically efficient and readily scaleable conditions.We have found that in the cyclocondensation of arylhydrazine hydrochlorides with 1,3-diketones, aprotic solvents with strong dipole moments and dielectric constants consistently gave much improved results relative to polar, protic solvents such as ethanol and acetic acid which are typically used for this type of reaction. 7 Our initial evaluation of solvents for the condensation of aryl-1,3-diketones with phenylhydrazine hydrochloride indicated that amide solvents such as N,N-dimethylacetamide (DMAc), N,N-dimethylformamide (DMF), N-methylpyrrolidinone (NMP) and urea solvents such as 1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)-pyrimidinone (DMPU) and N,N-tetramethylurea (TMU) provided highest and consistent regioselectivity (>99.8:0.2) of condensation. After optimization of reaction parameters with amide solvents, we found that addition of 50 mol% of 10 N aqueous hydrochloric acid gave increased yields by presumably favoring the second dehydration reaction of the Narylhydrazone intermediate towards the pyrazole heterocycle. For operational convenience and consistency, pyrazole syntheses presented in Tables 1-4 were run on gramscale at room temperature for 24 hours and at 0.25 M in DMAc. Table 1, the condensation of 4-substituted arylhydrazines with 4,4,4-trifluoro-1-arylbutane-1,3-diones 1a-d proceeded to afford pyrazoles 2a-l in 59-83% yields with selectivity ranging from 96.7:3.3 to >99.8:0.2. 8 By comparison, reactions run in ethanol at room temperature generally gave poor selectivity. The cyclocondensations of 1,3-diketones with 4-sulfonamidop...

Catalyst-controlled asymmetric ring opening of a racemic oxabicyclic alkene leads to two readily separable regioisomeric products both in excellent ee. A cationic Rh catalyst, with added NH(4)BF(4) to modulate reactivity, was required to obtain synthetically useful yields. The utility of each substituted aminotetralin product has been demonstrated by their conversion to different biologically relevant molecules in a highly efficient and practical manner.