Structural studies of (rac)-BIPHEN organomagnesiates and intermediates in the halogen-metal exchange of 2-Bromopyridine

Four lithium magnesiate complexes (2−5) containing the dianionic (rac)-BIPHEN ligand have been prepared and characterized using X-ray crystallography and NMR spectroscopy. (THF)3·Li2Mg{(rac)-BIPHEN}nBu2, 2, (THF)3·Li2Mg{(rac)-BIPHEN}(CH2SiMe3)2, 3, and (THF)2·Li2Mg{(rac)-BIPHEN}neoPe2, 4, have been prepared by complexation of the appropriate dialkylmagnesium compound with in situ prepared Li(rac)-BIPHEN in a mixture of hydrocarbon/THF. For all structures, the Mg centers are four-coordinate (and retain the alkyl groups); however, in 2 and 3 the two Li centers have different coordination spheres (one binding to one THF molecule, the other to two). The solid-state structures of 2 and 3 are essentially isostructural with that of 4 except that both Li atoms in this molecule have equivalent coordination spheres. The solution behaviors of these three molecules have been studied by 1H, 13C, and DOSY NMR spectroscopy. During the synthesis of 2, it was discovered that a (rac)-BIPHEN-rich (or n-butyl-free) lithium magnesiate, (THF)4Li2Mg{(rac)-BIPHEN}fo2, 2b, could be isolated. The lithium precursor to 2−5, (THF)4·Li4{(rac)-BIPHEN)}2, 1, has also been isolated. Within the molecular structure of this tetranuclear complex, there are three different Li coordination environments. Finally, 2 has already shown promise as a reagent in a halogen−metal exchange reaction with 2-bromopyridine. The structural chemistry at play in this reaction was probed by X-ray crystallography and NMR spectroscopy. The organometallic intermediate pyridyl-magnesiated 5, (THF)2·Li2Mg{(rac)-BIPHEN}(2-pyridyl)2, was isolated in high yield

Hypoxanthine-guanine phosophoribosyltransferase (HPRT) deficiency: Lesch-Nyhan syndrome

Deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity is an inborn error of purine metabolism associated with uric acid overproduction and a continuum spectrum of neurological manifestations depending on the degree of the enzymatic deficiency. The prevalence is estimated at 1/380,000 live births in Canada, and 1/235,000 live births in Spain. Uric acid overproduction is present inall HPRT-deficient patients and is associated with lithiasis and gout. Neurological manifestations include severe action dystonia, choreoathetosis, ballismus, cognitive and attention deficit, and self-injurious behaviour. The most severe forms are known as Lesch-Nyhan syndrome (patients are normal at birth and diagnosis can be accomplished when psychomotor delay becomes apparent). Partial HPRT-deficient patients present these symptoms with a different intensity, and in the least severe forms symptoms may be unapparent. Megaloblastic anaemia is also associated with the disease. Inheritance of HPRT deficiency is X-linked recessive, thus males are generally affected and heterozygous female are carriers (usually asymptomatic). Human HPRT is encoded by a single structural gene on the long arm of the X chromosome at Xq26. To date, more than 300 disease-associated mutations in the HPRT1 gene have been identified. The diagnosis is based on clinical and biochemical findings (hyperuricemia and hyperuricosuria associated with psychomotor delay), and enzymatic (HPRT activity determination in haemolysate, intact erythrocytes or fibroblasts) and molecular tests. Molecular diagnosis allows faster and more accurate carrier and prenatal diagnosis. Prenatal diagnosis can be performed with amniotic cells obtained by amniocentesis at about 15–18 weeks' gestation, or chorionic villus cells obtained at about 10–12 weeks' gestation. Uric acid overproduction can be managed by allopurinol treatment. Doses must be carefully adjusted to avoid xanthine lithiasis. The lack of precise understanding of the neurological dysfunction has precluded development of useful therapies. Spasticity, when present, and dystonia can be managed with benzodiazepines and gamma-aminobutyric acid inhibitors such as baclofen. Physical rehabilitation, including management of dysarthria and dysphagia, special devices to enable hand control, appropriate walking aids, and a programme of posture management to prevent deformities are recommended. Self-injurious behaviour must be managed by a combination of physical restraints, behavioural and pharmaceutical treatments