Synthesis of polyketide-derived natural products from carbohydrates: Application of the (2,3)-Wittig rearrangement of carbohydrate-derived alpha-alkoxy tertiary allylic ethers to the syntheses of Adda and rapamycin

Considerable effort has focused on the development of synthetic methodology to effectively construct the unique structural subunits found within biologically active, polyketide-derived natural products. One successful approach begins with carbohydrates as chiral building blocks from which the complex structure and stereochemistry of polyketide-related intermediates can be elaborated. This dissertation describes the development of a synthetic strategy which utilizes carbohydrates in combination with the (2,3) -Wittig rearrangement for the synthesis of polyketide-derived natural products. The synthesis of the novel $\beta$-amino acid (2S, 3S, 8S, 9S)-Adda, a component of hepatotoxic cyclic peptides, such as the microcystins, nodularin and motuporin, isolated from fresh water cyanobacteria is described. The present approach uses the (2,3) -Wittig rearrangement of a carbohydrate-derived tertiary allylic ether to establish the stereochemistry at the C\rm\sb6,\ C\sb8 and C\sb9 stereocenters of Adda. A stereoselective and efficient synthesis of an advanced C\sb{24}-C\sb{42} fragment of rapamycin from a carbohydrate template is presented. This fragment was rapidly assembled by serial sigmatropic rearrangements of carbohydrate-derived allylic ethers. The (2,3) -Wittig rearrangement was used to install the C\sb{29} trisubstituted olefin and the C\sb{31} and C\sb{32} chiral centers of the target compound. Subsequently, the (3,3) -Claisen rearrangement was employed to introduce the cyclohexyl unit and the C\sb{35} methyl group of rapamycin

Silver Benzoate Facilitates the Copper-Catalyzed C-N Coupling of Iodoazoles with Aromatic Nitrogen Heterocycles.

In the literature, C-N coupling methods for the reaction of iodo-oxazole with 2-pyridinone were found to be low yielding. C-N coupling using silver benzoate additives with CuI catalysts and 4,7-dimethoxy-1,10-phenanthroline ligands has been developed to afford synthetically useful yields of the desired heterobicycle product. The reaction conditions are applied to the coupling of a range of iodo-heterocycles with 2-pyridinone. The coupling of a variety of NH-containing heterocycles with 4-iodo-oxazole is also demonstrated. The use of 2-, 4-, or 5-iodo-oxazole allows for the coupling of pyridinone to each oxazole position

Oral Efficacy of a Respiratory Syncytial Virus Inhibitor in Rodent Models of Infection

BMS-433771 is a potent inhibitor of respiratory syncytial virus (RSV) replication in vitro. Mechanism of action studies have demonstrated that BMS-433771 halts virus entry through inhibition of F protein-mediated membrane fusion. BMS-433771 also exhibited in vivo efficacy following oral administration in a mouse model of RSV infection (C. Cianci, K. Y. Yu, K. Combrink, N. Sin, B. Pearce, A. Wang, R. Civiello, S. Voss, G. Luo, K. Kadow, E. Genovesi, B. Venables, H. Gulgeze, A. Trehan, J. James, L. Lamb, I. Medina, J. Roach, Z. Yang, L. Zadjura, R. Colonno, J. Clark, N. Meanwell, and M. Krystal, Antimicrob. Agents Chemother. 48:413-422, 2004). In this report, the in vivo efficacy of BMS-433771 against RSV was further examined in the BALB/c mouse and cotton rat host models of infection. By using the Long strain of RSV, prophylactic efficacy via oral dosing was observed in both animal models. A single oral dose, administered 1 h prior to intranasal RSV inoculation, was as effective against infection as a 4-day b.i.d. dosing regimen in which the first oral dose was given 1 h prior to virus inoculation. Results of dose titration experiments suggested that RSV infection was more sensitive to inhibition by BMS-433771 treatment in the BALB/c mouse host than in the cotton rat. This was reflected by the pharmacokinetic and pharmacodynamic analysis of the efficacy data, where the area under the concentration-time curve required to achieve 50% of the maximum response was ∼7.5-fold less for mice than for cotton rats. Inhibition of RSV by BMS-433771 in the mouse is the result of F1-mediated inhibition, as shown by the fact that a virus selected for resistance to BMS-433771 in vitro and containing a single amino acid change in the F1 region was also refractory to treatment in the mouse host. BMS-433771 efficacy against RSV infection was also demonstrated for mice that were chemically immunosuppressed by cyclophosphamide treatment, indicating that compound inhibition of the virus did not require an active host immune response

HIV Disclosure and sexual transmission behaviors among an internet sample of HIV-positive men who have sex with men in Asia: Implications for prevention with positives

The relationship between HIV disclosure and sexual transmission behaviors, and factors that influence disclosure are unknown among HIV-positive men who have sex with men (MSM) in Asia. We describe disclosure practices and sexual transmission behaviors, and correlates of disclosure among this group of MSM in Asia. A crosssectional multi-country online survey was conducted among 416 HIV-positive MSM. Data on disclosure status, HIV-related risk behaviors, disease status, and other characteristics were collected. Multivariable logistic regression was used to identify significant correlates of disclosure. Only 7.0% reported having disclosed their HIV status to all partners while 67.3% did not disclose to any. The majority (86.5%) of non-disclosing participants had multiple partners and unprotected insertive or receptive anal intercourse with their partners (67.5%). Non-disclosure was significantly associated with non-disclosure from partners (AOR = 37.13, 95% CI: 17.22, 80.07), having casual partners only (AOR = 1.91, 95% CI: 1.03, 3.53), drug use before sex on a weekly basis (AOR: 6.48, 95% CI: 0.99, 42.50), being diagnosed with HIV between 1 and 5 years ago (AOR = 2.23, 95% CI: 1.05, 4.74), and not knowing one's viral load (AOR = 2.80, 95% CI: 1.00, 7.83). Given the high HIV prevalence and incidence among MSM in Asia, it is imperative to include Prevention with Positives for MSM. Interventions on disclosure should not solely focus on HIV-positive men but also need to include their sexual partners and HIV-negative men. © Springer Science+Business Media, LLC 2011