Androgenetic alopecia (AGA) is a common heritable polygenic disorder whose genetics is not fully understood, even though it seems to be X-linked. We carried out an epidemiological survey for AGA on 9,000 people from 8 isolated villages of a secluded region of Sardinia (Ogliastra), and identified a large cohort of affected individuals. We genotyped 200 cases and 200 controls (mean kinship 0.001) with the 500k chip array and conducted case-control association analysis on the X chromosome. We identified Xq11-q12 as strongly associated with AGA. In particular, we found that rs1352015 located 8 kb from the EDA2R gene showed the best result (P=7.77e(-7)). This region also contains the AR gene, hence we tested both genes in 492 cases and 492 controls. We found that the non-synonymous SNP rs1385699 on EDA2R gave the best result (P=3.9e(-19)) whereas rs6152 on the AR gene is less significant (P=4.17e(-12)). Further statistical analysis carried out by conditioning each gene to the presence of the other showed that the association with EDA2R is independent while the association with AR seems to be the result of linkage disequilibrium. These results give insight into the pathways involved in AGA etiology.

We report herein the discovery of a novel process for epoxidation of alkenes, using Oxone, which, remarkably, is catalyzed by simple amines. This process, which does not rely on transition metal catalysts, utilizes Oxone/NaHCO 3 as the oxidant and simple, cheap, and readily available amines (see Table 1) as catalyst precursors for alkene epoxidation. The standard reaction procedure is illustrated in Scheme 1.Normally, Oxone buffered with NaHCO 3 in MeCN:H 2 O epoxidizes unfunctionalized alkenes only when oxygen-transfer reagents such as ketones, 1 imines, 2 or iminium salts, 3 are present. Aqueous solutions of Oxone at approximately neutral pH are also known to oxidize alkenes to give epoxides but in variable yield. 4,5 At lower pH, mixtures of epoxides and diols are obtained. 4 During our studies on iminium salt-catalyzed epoxidations of alkenes 3b we discovered that simple amines were also capable of epoxidizing our test substrate, 1-phenylcyclohexene and so we tested a broad range of amines (Table 1). In a control experiment, alkene and oxidant were combined in the absence of amine, and essentially no epoxide was obtained (entry 1). Primary amines were not effective (entry 2), but in the presence of secondary and tertiary amines (entries 3, 4, 6-9) rapid epoxidation ensued. Secondary amines gave the highest yields, and within this class, pyrrolidine (entry 6) was optimum. 1,2-Diamines (entry 10) and amides (entry 11) were not effective catalysts. We therefore tested pyrrolidine at loadings of 10 and 5 mol % and discovered that good levels of turnover could be achieved (entries 12-15). Unfortunately, with lower amine loadings (entries 12,14) a significant amount of hydrolysis of the epoxide occurred despite the fact that an excess of NaHCO 3 was present. Although less hydrolysis could be achieved by increasing the ratio of water present, this also resulted in reduced conversion. 6 Attempts to increase the pH of the media with other inorganic bases were unsuccessful but the use of 0.5 equiv of pyridine did largely suppress epoxide hydrolysis 7 (entries 13 and 15). A control experiment showed that pyridine itself was not able to catalyze the epoxidation process (entry 16). Pyrrolidine and a chiral derivative [(S)-2-(diphenylmethyl)pyrrolidine-1 8 ] were tested as catalysts at just 5 mol % loading 9 with a range of alkenes (Table 2) and it was found that good yields of epoxides could be obtained in most cases although the reaction was sensitive to both the structure of the alkene and the amine. The substituted pyrrolidine 1 was a more effective catalyst for a broader range of alkenes than pyrrolidine itself (compare entries 5-7, and 9) and gave up to 57% enantioselectivity with 1-phenylcyclohexene (entry 5). Amine 1 was an effective catalyst for most alkenes; only stilbenes, aliphatic disubstituted and terminal alkenes gave low yields.We have carried out competition experiments with structurally similar alkenes, and found that the amine-catalyzed epoxidation reactions showed much greater selectivity compared ...

Heavily substituted cyclopropane esters were prepared in high yields, complete diastereoselection and high (up to 96%) enantioselectivity. The reaction described herein entailed reacting 4-nitro-5-styrylisoxazoles, a class of cinnamate synthetic equivalent, with 2-bromomalonate esters under the catalysis of 5 mol% of a Cincona derived phase-transfer catalyst. The reaction allowed multi-gram preparation of desired products.

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