Chiral nonracemic phosphorus compounds are ubiquitous in catalytic asymmetric synthesis, both as ligands in metal-based processes 1 and as organocatalysts in their own right. 2 However, although a very large number of such ligands have been tested, the great majority have their chirality located on the carbon backbone (C-stereogenic, e.g., BINAP and DuPHOS) 1a instead of on the phosphorus atom (P-stereogenic, e.g., DiPAMP). 1c This is despite the fact that better chiral induction might be expected by incorporation of chirality as close as possible to the catalytic center. 3 Although P-stereogenic ligands have proven to be effective, 4 relatively few have been studied because they are difficult to synthesize. 5 Early methods were based on resolution and the generation of unequal mixtures of diastereomers, 5a while more recent strategies include desymmetrization, enzymatic resolution, and catalytic asymmetric synthesis. 5b,6 Some of these methods can be very effective, but most are limited in scope in some way and there remains a clear need for a general solution. Herein we report on our efforts to provide such a methodology.We have been interested in this difficult problem for some time. 7 We felt that there was promise in strategies involving kinetic resolution (KR) or dynamic kinetic resolution (DKR) in P(III)/P(V) interconversions (Scheme 1). Our initial approach centered on KR in asymmetric reduction (Scheme 1a), but this gave uniformly low selectivity, 7a in line with previous reports, 8 and we turned our attention to asymmetric oxidation (Scheme 1b). There have been very few reported successes at KR/DKR in such systems, 5a,9 most notably by Perlikowska et al. 9a who reported up to 39% ee in the KR of P-stereogenic tertiary phosphines and 70% ee for a single example of the first DKR of a chlorophosphine. In our early experiments, 7b,c we reacted racemic phosphines with chiral nonracemic epoxides hoping that the high temperature of the reaction would allow DKR through racemization of the phosphine, but the selectivity was low (20% at best).A way to achieve facile interconversion of stereogenic phosphorus centers at low temperatures is via pseudorotation of pentavalent pentacoordinate phosphorus compounds (10P5). 10 We therefore explored a variety of processes that could involve 10P5, and we report now our preliminary results on an asymmetric version of the oxidation/reduction/dehydration system known as the Appel conditions. 11 Typically, these conditions involve use of PPh 3 /CCl 4 to convert an alcohol to an alkyl chloride in high yield. From our perspective, these conditions are an oxidation of a phosphine involving a potentially chiral reagent (Scheme 2). Therefore, we were encouraged when our first experiments with this system gave some selectivity. Treatment of racemic phenyl-ortho-anisylmethylphosphine (PAMP, the precursor of DiPAMP) with CCl 4 and (-)-menthol in benzene at reflux gave the phosphine oxide ((R)-PAMPO) in good yields and up to 24% ee.Subsequently, we used the more reactive hexachloroaceto...

We present the updated British Association for Sexual Health and HIV guideline for the management of non-gonococcal urethritis in men. This document includes a review of the current literature on its aetiology, diagnosis and management. In particular it highlights the emerging evidence that azithromycin 1 g may result in the development of antimicrobial resistance in Mycoplasma genitalium and that neither azithromycin 1 g nor doxycycline 100 mg twice daily for seven days achieves a cure rate of >90% for this micro-organism. Evidence-based diagnostic and management strategies for men presenting with symptoms suggestive of urethritis, those confirmed to have non-gonococcal urethritis and those with persistent symptoms following first-line treatment are detailed.

Background Anogenital warts ( AGW ) can cause economic burden on healthcare systems and are associated with emotional, psychological and physical issues. Objective To provide guidance to physicians on the diagnosis and management of AGW . Methods Fourteen global experts on AGW developed guidance on the diagnosis and management of AGW in an effort to unify international recommendations. Guidance was developed based on published international and national AGW guidelines and an evaluation of relevant literature published up to August 2016. Authors provided expert opinion based on their clinical experiences. Results A checklist for a patient's initial consultation is provided to help physicians when diagnosing AGW to get the relevant information from the patient in order to manage and treat the AGW effectively. A number of frequently asked questions are also provided to aid physicians when communicating with patients about AGW . Treatment of AGW should be individualized and selected based on the number, size, morphology, location, and keratinization of warts, and whether they are new or recurrent. Different techniques can be used to treat AGW including ablation, immunotherapy and other topical therapies. Combinations of these techniques are thought to be more effective at reducing AGW recurrence than monotherapy. A simplified algorithm was created suggesting patients with 1–5 warts should be treated with ablation followed by immunotherapy. Patients with >5 warts should use immunotherapy for 2 months followed by ablation and a second 2‐month course of immunotherapy. Guidance for daily practice situations and the subsequent action that can be taken, as well as an algorithm for treatment of large warts, were also created. Conclusion The guidance provided will help physicians with the diagnosis and management of AGW in order to improve the health and quality of life of patients with AGW .

To assess the effectiveness of 5% imiquimod cream (IQ) in the treatment of vulvar, penile and anal intraepithelial neoplasias (VIN, PIN and AIN), we searched Medline, Embase, PubMed and Cochrane Library databases. With regard to VIN there were two randomized controlled trials (RCTs), eight uncontrolled/cohort studies, nine case reports and one review article. Use of IQ in PIN and AIN were only supported by cohort studies (two each for PIN and AIN) and case reports (15 for PIN and 3 for AIN). On pooled analysis of RCTs, uncontrolled and cohort studies, the mean complete response (CR) rate for VIN, PIN and AIN were 51%, 70% and 48%, respectively. The mean partial response (PR) rate for VIN, PIN and AIN were 25%, 30% and 34% respectively. The recurrence (RR) rate for VIN, PIN and AIN were 16%, 0% and 36%, respectively. The follow-up period for VIN, PIN and AIN ranged from 2 to 32 months, 10 to 12 months and 11 to 39 months, respectively. Although the results for PIN look the best, the strongest evidence regarding efficacy of IQ in anogenital intraepithelial neoplasia is for VIN supported by RCTs. Evidence for use of IQ in AIN was essentially limited to HIV-positive men who have sex with men. IQ was reasonably well tolerated with side-effects being managed with reduction in frequency of drug usage and/or rest periods. Based on these results, IQ seems to be a safe mode of treatment and is possibly an alternative to currently available methods of treatment. However, there are no comparative studies assessing its efficacy against traditional modes of treatment.

ObjectiveTo generate estimates of comparative clinical effectiveness for interventions used in the treatment of anogenital warts (AGWs) through the systematic review, appraisal and synthesis of data from randomised controlled trials (RCTs).DesignSystematic review and network meta-analysis of RCTs. Search strategies were developed for MEDLINE, Embase, the Cochrane Library and the Web of Science. For electronic databases, searches were run from inception to March 2018. The systematic review was carried out following the general principles recommended in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement.ParticipantsPeople aged ≥16 years with clinically diagnosed AGWs (irrespective of biopsy confirmation).InterventionsTopical and ablative treatments recommended by the British Association for Sexual Health and HIV for the treatment of AGWs, either as monotherapy or in combination versus each other.Outcome measuresComplete clearance of AGWs at the end of treatment and at other scheduled visits, and rate of recurrence.ResultsThirty-seven RCTs met inclusion criteria. Twenty studies were assessed as being at unclear risk of bias, with the remaining studies categorised as high risk of bias. Network meta-analysis indicates that, of the treatment options compared, carbon dioxide laser therapy is the most effective treatment for achieving complete clearance of AGWs at the end of treatment. Of patient-applied topical treatments, podophyllotoxin 0.5% solution was found to be the most effective at achieving complete clearance, and was associated with a statistically significant difference compared with imiquimod 5% cream and polyphenon E 10% ointment (p<0.05). Few data were available on recurrence of AGWs after complete clearance. Of the interventions evaluated, surgical excision was the most effective at minimising risk of recurrence.ConclusionOf the studies assessed, as a collective, the quality of the evidence is low. Few studies are available that evaluate treatment options versus each other.Trial registration numberCRD42013005457