Preparation of anti-vicinal amino alcohols: asymmetric synthesis of D-erythro-Sphinganine, (+)-spisulosine and D-ribo-phytosphingosine

Two variations of the Overman rearrangement have been developed for the highly selective synthesis of anti-vicinal amino alcohol natural products. A MOM-ether directed palladium(II)-catalyzed rearrangement of an allylic trichloroacetimidate was used as the key step for the preparation of the protein kinase C inhibitor D-erythro-sphinganine and the antitumor agent (+)-spisulosine, while the Overman rearrangement of chiral allylic trichloroacetimidates generated by asymmetric reduction of an alpha,beta-unsaturated methyl ketone allowed rapid access to both D-ribo-phytosphingosine and L-arabino-phytosphingosine

Directed Ring-Opening Of 1,5-Dioxaspiro[3.2]Hexanes: Selective Formation Of 2,2-Disubstituted Oxetanes

1,5-Dioxaspiro[3.2]hexanes undergo ring-opening reactions with many heteroatom nucleophiles to provide alpha-substituted-beta\u27-hydroxy ketones. However, certain Lewis acidic nucleophiles provide 2,2-disubstituted oxetanes. Herein, the results of reactions of 3-phenyl-1,5-dioxaspiro[3.2]hexane with a variety of nitrogen-containing heteroaromatic bases are reported. There appears to be a correlation between the pK(a) of the nucleophile and the reaction outcome with more acidic nucleophiles providing 2,2-disubstituted oxetanes. Moreover, the mode of ring opening can be directed toward the substituted oxetane by the addition of a Lewis acid. These results are rationalized by calculation of stationary points on the potential energy surfaces for the various possible reaction pathways using ab initio molecular orbital methods

Antimalarial Pyrido[1,2-a]benzimidazoles

A novel class of antimalarial pyrido[1,2-a]benzimidazoles were synthesized and evaluated for antiplasmodial activity and cytotoxicity following hits identified from screening commercially available compound collections. The most active of these, TDR86919 (4c), showed improved in vitro activity vs the drug-resistant K1 strain of Plasmodium falciparum relative to chloroquine (IC(50) = 0.047 muM v 0.17 muM); potency was retained against a range of drug-sensitive and drug-resistant strains, with negligible cytotoxicity against the mammalian (L-6) cell line (selectivity index of <600). 4c and several close analogues (as HCl or mesylate salts) showed significant efficacy in P. berghei infected mice following both intraperitoneal (ip) and oral (po) administration, with <90% inhibition of parasitemia, accompanied by an increase in the mean survival time (MSD). The pyrido[1,2-a]benzimidazoles appeared to be relatively slow acting in vivo compared to chloroquine, and metabolic stability of the alkylamino side chain was identified as a key issue in influencing in vivo activit

Operationalising sexual and reproductive health and rights in sub-Saharan Africa: constraints, dilemmas and strategies

BACKGROUND: The continued poor sexual and reproductive health (SRH) outcomes in sub-Saharan Africa highlight the difficulties in reforming policies and laws, and implementing effective programmes. This paper uses one international and two national case studies to reflect on the challenges, dilemmas and strategies used in operationalising sexual and reproductive health and rights (SRHR) in different African contexts. METHODS: The international case study focuses on the progress made by African countries in implementing the African Union’s Maputo Plan of Action (for the Operationalisation of the Continental Policy Framework for Sexual and Reproductive Health and Rights) and the experiences of state and non-state stakeholders in this process. The case was developed from an evaluation report of the progress made by nine African countries in implementing the Plan of Action, qualitative interviews exploring stakeholders’ experiences and perceptions of the operationalisation of the plan (carried out as part of the evaluation) in Botswana and Nigeria, and authors’ reflections. The first national case study explores the processes involved in influencing Ghana’s Domestic Violence Act passed in 2007; developed from a review of scientific papers and organisational publications on the processes involved in influencing the Act, qualitative interview data and authors’ reflections. The second national case study examines the experiences with introducing the 2006 Sexual Offences Act in Kenya, and it is developed from organisational publications on the processes of enacting the Act and a review of media reports on the debates and passing of the Act. RESULTS: Based on the three cases, we argue that prohibitive laws and governments’ reluctance to institute and implement comprehensive rights approaches to SRH, lack of political leadership and commitment to funding SRHR policies and programmes, and dominant negative cultural framing of women’s issues present the major obstacles to operationalising SRH rights. Analysis of successes points to the strategies for tackling these challenges, which include forming and working through strategic coalitions, employing strategic framing of SRHR issues to counter opposition and gain support, collaborating with government, and employing strategic opportunism. CONCLUSION: The strategies identified show future pathways through which challenges to the realisation of SRHR in Africa can be tackled