The reagent [7,7-bis(trifluoroacetoxy)iodo]benzene, PIFA, brings about the facile oxidative rearrangement of aliphatic amides to amines in mildly acidic (pH 1-3) mixed aqueous-organic solvents. Aromatic amines are further oxidized by the reagent and therefore cannot be prepared by this method. The rearrangement, which is in effect an "acidic Hofmann rearrangement", occurs with complete retention of configuration in the migrating group,
ProP is a member of the major facilitator superfamily, a proton-osmolyte symporter, and an osmosensing transporter. ProP proteins share extended cytoplasmic carboxyl terminal domains (CTDs) implicated in osmosensing. The CTDs of the best characterized, group A ProP orthologs, terminate in sequences that form intermolecular, antiparallel a-helical coiled coils (e.g., ProPEc, from Escherichia coli). Group B orthologs lack that feature (e.g., ProPXc, from Xanthomonas campestris). ProPXc was expressed and characterized in E. coli to further elucidate the role of the coiled coil in osmosensing. The activity of ProPXc was a sigmoid function of the osmolality in cells and proteoliposomes. ProPEc and ProPXc attained similar activities at the same expression level in E. coli. ProPEc transports proline and glycine betaine with comparable high affinities at low osmolality. In contrast, proline weakly inhibited high-affinity glycine-betaine uptake via ProPXc. The K M for proline uptake via ProPEc increases dramatically with the osmolality. The K M for glycine-betaine uptake via ProPXc did not. Thus, ProPXc is an osmosensing transporter, and the C-terminal coiled coil is not essential for osmosensing. The role of CTD-membrane interaction in osmosensing was examined further. As for ProPEc, the ProPXc CTD co-sedimented with liposomes comprising E. coli phospholipid. Molecular dynamics simulations illustrated association of the monomeric ProPEc CTD with the membrane surface. Comparison with the available NMR structure for the homodimeric coiled coil formed by the ProPEc-CTD suggested that membrane association and homodimeric coiled-coil formation by that peptide are mutually exclusive. The membrane fluidity in liposomes comprising E. coli phospholipid decreased with increasing osmolality in the range relevant for ProP activation. These data support the proposal that ProP activates as cellular dehydration increases cytoplasmic cation concentration, releasing the CTD from the membrane surface. For group A orthologs, this also favors a-helical coiled-coil formation that stabilizes the transporter in an active form.
Novel analogues of C-2-substituted
thienopyrimidine-based bisphosphonates
(C2-ThP-BPs) are described that are potent inhibitors of the human
geranylgeranyl pyrophosphate synthase (hGGPPS). Members of this class
of compounds induce target-selective apoptosis of multiple myeloma
(MM) cells and exhibit antimyeloma activity in vivo. A key structural element of these inhibitors is a linker moiety
that connects their (((2-phenylthieno[2,3-d]pyrimidin-4-yl)amino)methylene)bisphosphonic
acid core to various side chains. The structural diversity of this
linker moiety, as well as the side chains attached to it, was investigated
and found to significantly impact the toxicity of these compounds
in MM cells. The most potent inhibitor identified was evaluated in
mouse and rat for liver toxicity and systemic exposure, respectively,
providing further optimism for the potential value of such compounds
as human therapeutics.
Background:
Oxabenzonorbornadiene (OBD) is a useful synthetic intermediate
capable of undergoing multiple types of transformations due to three key structural features:
a free alkene, a bridged oxygen atom, and a highly strained ring system. Most notably,
ring-opening reactions of OBD using transition metal catalysts and nucleophiles produce
multiple stereocenters in a single step. The resulting dihydronaphthalene framework
is found in many natural products, which have been shown to be biologically active.
Objective:
This review will provide an overview of transition metal-catalyzed reactions
from the past couple of years including cobalt, copper, iridium, nickel, palladium and rhodium-
catalyzed reactions. In addition, the recent derivatization of OBD to
cyclopropanated oxabenzonorbornadiene and its reactivity will be discussed.
Conclusion:
It can be seen from the review, that the work done on this topic has employed the use of many different
transition metal catalysts, with many different nucleophiles, to perform various transformations on the
OBD molecule. Additionally, depending on the catalyst and ligand used, the stereo and regioselectivity of the
product can be controlled, with proposed mechanisms to support the understanding of such reactions. The use
of palladium has also generated a cyclopropanated OBD, with reactivity similar to that of OBD. An additional
reactive site exists at the distal cyclopropane carbon, giving rise to three types of ring-opened products.
Thienopyrimidine-based allosteric inhibitors of the human farnesyl pyrophosphate synthase (hFPPS), characterized by a chiral α-aminophosphonic acid moiety, were synthesized as enantiomerically enriched pairs, and their binding mode was investigated by X-ray crystallography. A general consensus in the binding orientation of all (R)-and (S)-enantiomers was revealed. This finding is a prerequisite for establishing a reliable structure−activity relationship (SAR) model.
SummaryPalladium-catalyzed ring-opening reactions of C1 substituted 7-oxanorbornadiene derivatives with aryl iodides were investigated. The optimal conditions for this reaction were found to be PdCl2(PPh3)2, ZnCl2, Et3N and Zn in THF. Both steric and electronic factors played a role in the outcome of the reaction as increasing the steric bulk on the bridgehead carbon decreased the yield. These reactions were found to be highly regioselective, giving only one of the two possible regioisomers in all cases. A diverse collection of novel, highly substituted biphenyl derivatives were obtained.
SummaryPalladium-catalyzed ring-opening reactions of cyclopropanated 7-oxabenzonorbornadiene derivatives using alcohol nucleophiles were investigated. The optimal conditions were found to be 10 mol % PdCl2(CH3CN)2 in methanol, offering yields up to 92%. The reaction was successful using primary, secondary and tertiary alcohol nucleophiles and was compatible with a variety of substituents on cyclopropanated oxabenzonorbornadiene. With unsymmetrical C1-substituted cyclopropanated 7-oxabenzonorbornadienes, the regioselectivity of the reaction was excellent, forming only one regioisomer in all cases.
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