Palladium-mediated reductive coupling, a stereoselective approach to the 8-dehydropumiliotoxin skeleton

Reductive cyclisation of ail E-vinyl bromide with ail allylic acetate proceeds under palladium catalysis 10 give the 8-dehydropumiliotoxin skeleton, a potential advanced precursor to 8-deoxypumiliotoxin alkaloids. Control of the stereochemistry of the E-vinyl bromide precursor is achieved readily using the Kogen or Bruckner bromophosphonate reagents and the reductive cyclisation proceeds with retention of the vinyl bromide stereochemistry. The mechanism for the cyclisation involves an in situ conversion of the allylic acetate to ail allyl stannane followed by ail intramolecular Stille-type coupling.

Stereoselective synthesis of (8R,8aS)-8-methylhexahydroindolizin-5-one

Catalytic hydrogenation of dihydroindolizidinone occurred preferentially from the endo-face giving rapid entry to (8R,8aS)-8-methylhexahydroindolizin-5-one, a key intermediate in the synthesis of 5,8-disubstituted indolizidines and deoxypumiliotoxin 25 1 H. The selectivity could be improved further by diimide reduction though this also resulted in some oxidation of the alkene to the diene. The basis of the unusual stereoselectivity in the diimide reduction is believed to be stereoelectronic in origin. (c) 2005 Elsevier Ltd. All rights reserved.

Synthesis of the heterocyclic core of the alkaloids martinelline and martinellic acid

The tricyclic core of martinelline and martinellic acid was rapidly assembled utilising an imino Diels-Alder reaction of an imine derived from cinnamaldehyde with a cyclic enamide. The cycloaddition was completely regioselective though the exo endo selectivity was poor. These diastercoisomers were readily separated by flash chromatography and the relative stereochemistry of the exo-isomer confirmed by single crystal X-ray crystallography. This intermediate was converted to the central core of the aforementioned alkaloids in five additional synthetic operations. (C) 2001 Elsevier Science Ltd. All rights reserved.

Synthesis of (+)-piclavines A1 and A2

Piclavines AI and A2 have been synthesised for the first time. The route is short with the key step being the reaction of a bicyclic N-acyl iminium ion with 3-trimethysilyl-1-decene. This convergent strategy gave exclusively compounds in which the pendant decenyl group was axial, as a 6:1 mixture of E:Z-alkene diastereoisomers. Reduction of the lactam carbonyl group gave a 6:1 mixture of piclavines Al and A2, (C) 2000 Published by Elsevier Science Ltd.

Expedient synthesis of (+)-trans-5-allylhexahydroindolizidin-3-one

Treatment of the bicyclic iminium ion derived from 5-methoxyhexahydroindolizidin-3-one with allyltrimethylsilane gave exclusively the diastereoisomer in which the allyl group was axial. This substrate is a useful precursor to 5-propyl-3-alkylindolizidine alkaloids. (C) 1999 Elsevier Science Ltd. All rights reserved.

Discovery and Evaluation of BMS-708163, a Potent, Selective and Orally Bioavailable gamma-Secretase Inhibitor

During the course of our research efforts to develop a potent and selective gamma-secretase inhibitor for the treatment of Alzheimer's disease, we investigated a series of carboxamide-substituted sulfonamides. Optimization based on potency, Notch/amyloid-beta precursor protein selectivity, and brain efficacy after oral dosing led to the discovery of 4 (BMS-708163). Compound 4 is a potent inhibitor of gamma-secretase (A beta 40 IC50 = 0.30 nM), demonstrating a 193-fold selectivity against Notch. Oral administration of 4 significantly reduced A beta 40 levels for sustained periods in brain, plasma, and cerebrospinal fluid in rats and dogs.

Reactivity of 1,2-cyclic sulfite xylosides towards nucleophiles

1,2-Cyclic sulfite xylosides offer facile access to 1,2-oxazolines upon reaction with aromatic and alkyl nitrites under Lewis or Bronsted acid conditions. Additionally, hydrophobic ionic liquids facilitate acid-catalysed formations of such oxazolines and C- and O-linked xylosides, providing means to carry out fast reactions at room temperature, and this in yields comparable to reactions conducted in xylene at high temperature for extended reaction time. (c) 2009 Elsevier Ltd. All rights reserved.

A study of Heck cyclization reactions to form phenanthridine ring systems

A survey of conditions for the palladium catalyzed intramol. Heck cyclization of protected amines has shown that the Herrmann-Beller palladacycle can be exploited under 'cationic' conditions to provide a robust and rapid route (

New pinene-derived pyridines as bidentate chiral ligands

A synthesis of new bidentate pyridines has been developed, starting from ?-pinene. A copper complex of the pyridine-oxazoline ligands catalyzes asym. allylic oxidn. of cyclic olefins with good conversion rates and acceptable enantioselectivity (?67% ee). The imidazolium salt I has been identified as a precursor of the N,N'-unsym. N-heterocyclic carbene ligand, which upon complexation with palladium, catalyzed the intramol. amide enolate ?-arylation leading to oxindole in excellent yield but with low enantioselectivity.

Studies on acyl pyrrolidine inhibitors of HCV RNA-dependent RNA polymerase to identify a molecule with replicon antiviral activity

The SAR development is described for a series of N-acyl pyrrolidine inhibitors of the Hepatitis C virus RNA-dependent RNA polymerase, NS5B, from tractable Delta 21 enzyme inhibitors to an example with antiviral activity in a cellular assay (HCV replicon). (c) 2007 Elsevier Ltd. All rights reserved.

5-aryl-pyrazolo[3,4-b]pyridazines: Potent inhibitors of glycogen synthase kinase-3 (GSK-3)

Introduction of a nitrogen atom into the 6-position of a series of pyrazolo[3,4-b]pyridines led to a dramatic improvement in the potency of GSK-3 inhibition. Rationalisation of the binding mode suggested participation of a putative structural water molecule, which was subsequently confirmed by X-ray crystallography. (C) 2003 Elsevier Science Ltd. All rights reserved.

3-anilino-4-arylmaleimides: Potent and selective inhibitors of glycogen synthase kinase-3 (GSK-3)

Potent 3-anilino-4-arylmaleimide glycogen synthase kinase-3 (GSK-3) inhibitors have been prepared using automated array methodology. A number of these are highly selective, having little inhibitory potency against more than 20 other protein kinases. (C) 2001 Elsevier Science Ltd. All rights reserved.

The inhibition of human cytomegalovirus (hCMV) protease by hydroxylamine derivatives.

Aryl hydroxylamine derivs. have been synthesized that are some of the most potent inhibitors of hCMV protease prepd. to date (IC50 14-60 nM). Mass spectrometry studies indicate that oxazinone derived hydroxylamines inhibit the enzyme by acylation of Ser132 whereas non-oxazinone derived hydroxylamines appear to inhibit via formation of a sulfinanilide at Cys138.

Chemoenzymatic Synthesis of Carbasugars (+)-Pericosines A-C from Diverse Aromatic cis-Dihydrodiol Precursors

cis-Dihydrocatechols, derived from biological cis-dihydroxylation of methyl benzoate, iodobenzene and benzonitrile, using the microorganism Pseudomonas putida UV4, were converted into pericosines A, C, and B, respectively. This approach constitutes the shortest syntheses, to date, of these important natural products with densely packed functionalities.

Antitumour prodrug development using cytochrome P450 (CYP) mediated activation

An ideal cancer chemotherapeutic prodrug is completely inactive until metabolized by a tumour-specific enzyme, or by an enzyme that is only metabolically competent towards the prodrug under physiological conditions unique to the tumour. Human cancers, including colon, breast, lung, liver, kidney and prostate, are known to express cytochrome P450 (CYP) isoforms including 3A and 1A subfamily members. This raises the possibility that tumour CYP isoforms could be a focus for tumour-specific prodrug activation. Several approaches are reviewed, including identification of prodrugs activated by tumour-specific polymorphic CYPs, use of CYP-gene directed enzyme prodrug therapy and CYPs acting as reductases in hypoxic tumour regions. The last approach is best exemplified by AQ4N, a chemotherapeutic prodrug that is bioreductively activated by CYP3A. This study shows that freshly isolated murine T50/80 mammary carcinoma and RIF-1 fibrosarcoma 4-electron reduces AQ4N to its cytotoxic metabolite, AQ4 (T50/80 K-m = 26.7 mu M, V-max = 0.43 mu M/mg protein/min; RIF-1 K-m = 33.5 mu M, V-max = 0.42 mu M/mg protein/min) via AQM, a mono-N-oxide intermediate (T50/80 K-m = 37.5 mu M; V-max = 1.4 mu M/mg protein/min; RIF-1 K-m = 37.5 mu M; V-max = 1.2 mu M/mg protein/min). The prodrug conversion was dependent on NADPH and inhibited by air or carbon monoxide. Cyp3A mRNA and protein were both present in T50/80 carcinoma grown in vivo (RIF-1 not measured). Exposure of isolated tumour cells to anoxia (2 h) immediately after tumour excision increased cyp3A protein 2-3-fold over a 12 h period, after which time the cyp protein levels returned to the level found under aerobic conditions. Conversely, cyp3A mRNA expression showed an initial 3-fold decrease under both oxic and anoxic conditions; this returned to near basal levels after 8-24 h. These results suggest that cyp3A protein is stabilized in the absence of air, despite a decrease in cyp3A mRNA. Such a 'stabilization factor' may decrease cyp3A protein turnover without affecting the translation efficiency of cyp3A mRNA. Confirmation of the CYP activation of AQ4N bioreduction was shown with human lymphoblastoid cell microsomes transfected with CYP3A4, but not those transfected with CYP2B6 or cytochrome P450 reductase. AQ4N is also reduced to AQ4 in NADPH-fortified human renal cell carcinoma (K-m = 4 mu M, V-max = 3.5 pmol/mg protein/min) and normal kidney (K-m = 4 mu M, V-max = 4.0 pmol/mg protein/min), both previously shown to express CYP3A. Germane to the clinical potential of AQ4N is that although both normal and tumour cells are capable of reducing AQ4N to its cytotoxic species, the process requires low oxygen conditions. Hence, AQ4N metabolism should be restricted to hypoxic tumour cells. The isoform selectivity of AQ4N reduction, in addition to its air sensitivity, indicates that AQ4N haem coordination and subsequent oxygen atom transfer from the active-site-bound AQ4N is the likely mechanism of N-oxide reduction. The apparent increase in CYP3A expression under hypoxia makes this a particularly interesting application of CYPs for tumour-specific prodrug activation.