Palladium-catalyzed enolate arylation as a key C-C bond-forming reaction for the synthesis of isoquinolines.

The palladium-catalyzed coupling of an enolate with an ortho-functionalized aryl halide (an α-arylation) furnishes a protected 1,5-dicarbonyl moiety that can be cyclized to an isoquinoline with a source of ammonia. This fully regioselective synthetic route tolerates a wide range of substituents, including those that give rise to the traditionally difficult to access electron-deficient isoquinoline skeletons. These two synthetic operations can be combined to give a three-component, one-pot isoquinoline synthesis. Alternatively, cyclization of the intermediates with hydroxylamine hydrochloride engenders direct access to isoquinoline N-oxides; and cyclization with methylamine, gives isoquinolinium salts. Significant diversity is available in the substituents at the C4 position in four-component, one-pot couplings, by either trapping the in situ intermediate after α-arylation with carbon or heteroatom-based electrophiles, or by performing an α,α-heterodiarylation to install aryl groups at this position. The α-arylation of nitrile and ester enolates gives access to 3-amino and 3-hydroxyisoquinolines and the α-arylation of tert-butyl cyanoacetate followed by electrophile trapping, decarboxylation and cyclization, C4-functionalized 3-aminoisoquinolines. An oxime directing group can be used to direct a C-H functionalization/bromination, which allows monofunctionalized rather than difunctionalized aryl precursors to be brought through this synthetic route.

Synthesis of substituted isoquinolines utilizing palladium-catalyzed α-arylation of ketones.

The utilization of sequential palladium-catalyzed α-arylation and cyclization reactions provides a general approach to an array of isoquinolines and their corresponding N-oxides. This methodology allows the convergent combination of readily available precursors in a regioselective manner and in excellent overall yields. This powerful route to polysubstituted isoquinolines, which is not limited to electron rich moieties, also allows rapid access to analogues of biologically active compounds.

Diabetes mellitus and female lower urinary tract symptoms: a review.

Diabetes mellitus (DM) has reached epidemic proportions world wide. Many chronic complications of DM, including neuropathy, retinopathy and nephropathy, have been well studied and although urologic complications have been recognized since 1935, little is known about DM as a pathophysiological risk factor for development of lower urinary tract symptoms (LUTS) in women. Diabetic nephropathy, a life-threatening condition, has received considerable attention in the last few years. Diabetic cystopathy, on the other hand, has received far less attention despite having a significant impact on quality of life, and with significant individual health risks. Initial studies suggested that long standing DM causes paralysis of the detrusor muscle leading to voiding difficulties and this has been the received wisdom regarding diabetic cystopathy for many years. In this review, we discuss what is currently known about lower urinary tract function and urinary incontinence in diabetic females, with a critical analysis of the available evidence and suggest areas for future research.