The synthesis of the C-1-C-28 ABCD fragment of spongistatin is described. Anti-selective boron-mediated aldol coupling of a CD spiroketal ketone fragment to an AB spiroketal aldehyde unit forms the desired C1-C28 advanced intermediate. Other features include the double conjugate addition of a dithiol to an ynone to generate the key beta-keto-dithiane unit required for the synthesis of the AB spiroketal fragment. [reaction: see text]

A safe, practical and selective process for the aerobic oxidation of alcohols to aldehydes and ketones has been developed using a Ru catalyst in a continuous flow reactor. Benzylic and allylic alcohols were oxidised selectively to their corresponding aldehydes and ketones, including substrates containing N-and S-heteroatoms. Rate of turnover is compatible with that previously 10 reported, using batch or microchannel reactors, under optimised conditions. A preliminary kinetic model was derived, which is supported by experimental observations. Last but not least, tandem oxidation-olefination may be achieved without the need to isolate the alcohol intermediate/solvent switching.

A branching synthetic strategy was used to efficiently generate structurally diverse scaffolds, which span a broad area of chemical descriptor space, and their biological activity against MRSA was demonstrated.

The transient receptor potential (TRP) family of ion channels comprises nonselective cation channels that respond to a wide range of chemical and thermal stimuli. TRPM8, a member of the melastatin subfamily, is activated by cold temperatures (<28 °C), and antagonists of this channel have the potential to treat cold induced allodynia and hyperalgesia. However, TRPM8 has also been implicated in mammalian thermoregulation and antagonists have the potential to induce hypothermia in patients. We report herein the identification and optimization of a series of TRPM8 antagonists that ultimately led to the discovery of PF-05105679. The clinical finding with this compound will be discussed, including both efficacy and its ability to affect thermoregulation processes in humans.

A series of 4-substituted pyrimido[4,5-d]azepines that are potent, selective 5-HT2C receptor partial agonists is described. A rational medicinal chemistry design strategy to deliver CNS penetration coupled with SAR-based optimization of selectivity and agonist potency provided compounds with the desired balance of preclinical properties. Lead compounds 17 (PF-4479745) and 18 (PF-4522654) displayed robust pharmacology in a preclinical canine model of stress urinary incontinence (SUI) and no measurable functional agonism at the key selectivity targets 5-HT2A and 5-HT2B in relevant tissue-based assay systems. Utilizing recent advances in the structural biology of GPCRs, homology modeling has been carried out to rationalize binding and agonist efficacy of these compounds.

Two mo I ecu I es of Zr4,6-tris[4-( 2-p henyl pro pa n-2-yl ) p henoxyl-1,3,5-t riazi ne 1 undergo self-assem bly to produce a composite unit, termed Piedfort unit, which acts as a single hexa-host molecule; the structure of this new host unit, found both in the Ir4-dioxane inclusion compound of 1 and in its unsolvated crystal, has been elucidated by X-ray methods.

No abstract

The spongistatins comprise an important family of architecturally complex marine macrolides that display extraordinary antitumor activities against a variety of human cancer cell lines. These unique natural products were isolated independently by Pettit, Kitagawa and Fusetani in 1993, [1] although the absolute structure remained unknown until confirmation by synthesis in 1997.[2] The spongistatin family includes 9 macrolides, all of which possess remarkable growth inhibition properties against the US National Cancer Institutes panel of sixty human cancer cell lines. Spongistatin 1 (1) was extremely potent against a subset of highly chemoresistant tumor types, with typical GI 50 values of 2.5-3.5 10 À1 m. Cell lines derived from human melanoma were also found to be especially sensitive to Spongistatin 1, [1f, h] the most active of this family of macrolides (Scheme 1).Spongistatin 1 (1) comprises a 42-membered macrolide ring, 24 asymmetric centers, a chlorodiene sidechain, two spiroketals (of which only one contains full anomeric stabilization) and two pyranyl units. The complex molecular architecture and exciting biological profile of these natural products have attracted significant interest resulting in total syntheses by six groups. [2][3] Our initial synthetic analysis for 1 was consistent with established endgame strategies and corresponded to a C1ÀC41(OH) macrolactonization and C28ÀC29 Wittig olefination, resulting in two advanced fragments (ABCD fragment 2 and EF fragment 3) and hence enabling a convergent approach to the target (Scheme 1). [2][3] Furthermore, we recognized the utility of the anti-selective aldol coupling demonstrated by the groups of Evans, [2a] Paterson, [3d] Heathcock [3f] and more recently Smith [3a] and Crimmins, [3e] to join the AB and CD units together to form the basis of fragment 2 in their total syntheses. Accordingly, we envisaged that appropriately protected AB aldehyde 4 and Scheme 1. Structure and retrosynthetic analysis of Spongistatin 1 (1). TES = triethylsilyl, TBS = tert-butyldimethylsilyl, PMB = p-methoxybenzyl.