Total synthesis of (±)-paroxetine by diastereoconvergent cobalt-catalysed arylation

A total synthesis of paroxetine is reported, with a diastereoselective and diastereoconvergent cobalt-catalysed sp3–sp2 coupling reaction involving a 3-substituted 4-bromo-N-Boc-piperidine (Boc = tert-butoxycarbonyl) substrate as a key step. A 9:1 diastereoselectivity was obtained, while a control experiment involving a conformationally locked 3-substituted 4-bromo-tert-butyl cyclohexane ring proceeded with essentially complete stereoselectivit

Gas lubricant compositions Patent

High temperature gas lubricant consisting of two fluoro-bromo-methane

Efficient routes to epimerically-pure side-chain derivatives of lanosterol

A technically simple route is described to individual epimers of side-chain derivatives of lanosterol (3-hydroxy-5-lanosta-8,24-diene). Epimerically pure 24,25-epoxy-, 24,25-dihydroxy- and 24-bromo-25-hydroxy-lanosterol have been prepared in good yield from commercial (50-60%) lanosterol. Hypophosphorous acid was used as a catalyst for the cohalogenation of the 24(25) bond and also for the efficient conversion of 24,25-epoxy- and 24-bromo-25-hydroxylanosterol to epimerically pure 24(R) or 24(S)-24,25-dihydroxylanosterols

Synthesis of stereodefined 1-aryl(heteroaryl) substituted 1,2-bis(2-bromopyridin-3-yl)ethenes by selective tandem Suzuki-Miyaura Cross-coupling reactions

In this communication we show the preparation of stereodefined trisubstituted alkenes 2 can be achieved by sequential selective Suzuki-Miyaura reactions of 2-bromo-3-(2,2-dibromovinyl)pyridines. The potentiality of this strategy to obtain 5-aryl-1,10-phenanthrolines is also demonstrated

Peripherally-metallated porphyrins: meso-n1-porphyrinyl-platinum(II) complexes of 5,15-diaryl- and 5,10,15-triarylporphyrins

Attempted metathesis reactions of peripherally-metallated meso-η1-porphyrinylplatinum(II) complexes such as trans-[PtBr(NiDPP)(PPh3)2] (H2DPP = 5,15-diphenylporphyrin) with organolithium reagents fail due to competitive addition at the porphyrin ring carbon opposite to the metal substituent. This reaction can be prevented by using 5,10,15-triarylporphyrins, e.g. 5,10,15-triphenylporphyrin (H2TrPP) and 5-phenyl-10,20-bis(3’,5’-di-t-butylphenyl)porphyrin (H2DAPP) as substrates. These triarylporphyrins are readily prepared using the method of Senge and co-workers by addition of phenyllithium to the appropriate 5,15-diarylporphyrins, followed by aqueous protolysis and oxidation. They are convenient, soluble building blocks for selective substitutions and subsequent transformations at the remaining free meso carbon. The sequence of bromination, optional central metallation and oxidative addition of Pt(0) tris(phosphine) complexes generates the organoplatinum porphyrins in high overall yields. The bromo ligand on the Pt(II) centre can be substituted by alkynyl nucleophiles, including 5-ethynylNiDPP, to form the first examples of meso-η1-porphyrinylplatinum(II) complexes with a second Pt-C bond. The range of porphyrinylplatinum(II) bis(tertiary phosphine) complexes was extended to the triethylphosphine analogues, by oxidative addition of H2TrPPBr to Pt(PEt3)3, and the initially-formed cis adduct is only slowly thermally transformed to trans-[PtBr(H2TrPP)(PEt3)2] 16. The molecular structures of NiDAPP 9b, trans-[Pt(NiDPP)(C2NiDPP)(PPh3)2] 14 and 16 were determined by X-ray crystallography

Photochemical Electrocyclic Ring Closure and Leaving Group Expulsion from N-(9-oxothioxanthenyl)Benzothiophene Carboxamides

N-(9-Oxothioxanthenyl)benzothiophene carboxamides bearing leaving groups (LG− = Cl−, PhS−, HS−, PhCH2S−) at the C-3 position of the benzothiophene ring system photochemically cyclize with nearly quantitative release of the leaving group, LG−. The LG− photoexpulsions can be conducted with 390 nm light or with a sunlamp. Solubility in 75% aqueous CH3CN is achieved by introducing a carboxylate group at the C-6 position of the benzothiophene ring. The carboxylate and methyl ester derivatives regiospecifically cyclize at the more hindered C-1 position of the thioxanthone ring. Otherwise, the photocyclization favors the C-3 position of the thioxanthone. Quantum yields for reaction are 0.01–0.04, depending on LG− basicity. Electronic structure calculations for the triplet excited state show that excitation transfer occurs from the thioxanthone to the benzothiophene ring. Subsequent cyclization in the triplet excited state is energetically favourable and initially generates the triplet excited state of the zwitterionic species. Expulsion of LG− is thought to occur once this species converts to the closed shell ground state

Synthetic Analogues of the Snail Toxin 6-Bromo-2-mercaptotryptamine Dimer (BrMT) Reveal That Lipid Bilayer Perturbation Does Not Underlie Its Modulation of Voltage-Gated Potassium Channels

Drugs do not act solely by canonical ligand–receptor binding interactions. Amphiphilic drugs partition into membranes, thereby perturbing bulk lipid bilayer properties and possibly altering the function of membrane proteins. Distinguishing membrane perturbation from more direct protein–ligand interactions is an ongoing challenge in chemical biology. Herein, we present one strategy for doing so, using dimeric 6-bromo-2-mercaptotryptamine (BrMT) and synthetic analogues. BrMT is a chemically unstable marine snail toxin that has unique effects on voltage-gated K+ channel proteins, making it an attractive medicinal chemistry lead. BrMT is amphiphilic and perturbs lipid bilayers, raising the question of whether its action against K+ channels is merely a manifestation of membrane perturbation. To determine whether medicinal chemistry approaches to improve BrMT might be viable, we synthesized BrMT and 11 analogues and determined their activities in parallel assays measuring K+ channel activity and lipid bilayer properties. Structure–activity relationships were determined for modulation of the Kv1.4 channel, bilayer partitioning, and bilayer perturbation. Neither membrane partitioning nor bilayer perturbation correlates with K+ channel modulation. We conclude that BrMT’s membrane interactions are not critical for its inhibition of Kv1.4 activation. Further, we found that alkyl or ether linkages can replace the chemically labile disulfide bond in the BrMT pharmacophore, and we identified additional regions of the scaffold that are amenable to chemical modification. Our work demonstrates a strategy for determining if drugs act by specific interactions or bilayer-dependent mechanisms, and chemically stable modulators of Kv1 channels are reported

cAMP-Inhibits Cytoplasmic Phospholipase A(2) and Protects Neurons against Amyloid-beta-Induced Synapse Damage

A key event in Alzheimer’s disease (AD) is the production of amyloid-β (Aβ) peptides and the loss of synapses. In cultured neurons Aβ triggered synapse damage as measured by the loss of synaptic proteins. α-synuclein (αSN), aggregates of which accumulate in Parkinson’s disease, also caused synapse damage. Synapse damage was associated with activation of cytoplasmic phospholipase A2 (cPLA2), an enzyme that regulates synapse function and structure, and the production of prostaglandin (PG) E2. In synaptosomes PGE2 increased concentrations of cyclic adenosine monophosphate (cAMP) which suppressed the activation of cPLA2 demonstrating an inhibitory feedback system. Thus, Aβ/αSN-induced activated cPLA2 produces PGE2 which increases cAMP which in turn suppresses cPLA2 and, hence, its own production. Neurons pre-treated with pentoxifylline and caffeine (broad spectrum phosphodiesterase (PDE) inhibitors) or the PDE4 specific inhibitor rolipram significantly increased the Aβ/αSN-induced increase in cAMP and consequently protected neurons against synapse damage. The addition of cAMP analogues also inhibited cPLA2 and protected neurons against synapse damage. These results suggest that drugs that inhibit Aβ-induced activation of cPLA2 and cross the blood–brain barrier may reduce synapse damage in AD