Control of regioselectivity and stereoselectivity in (4 + 3) cycloadditions of chiral oxyallyls with unsymmetrically disubstituted furans.

The regioselectivities and stereoselectivities of ZnCl2-catalyzed (4 + 3) cycloadditions between chiral oxazolidinone-substituted oxyallyls and unsymmetrical disubstituted furans have been determined. The substitution pattern on the furan is found to provide a valuable tool for controlling the stereochemistry (endo-I or endo-II) of the 7-membered cycloadduct. While cycloadditions with monosubstituted furans usually favor endo-I products, from addition of the furan to the more crowded face of the oxyallyl, cycloadditions with 2,3- and 2,5-disubstituted furans instead favor the endo-II stereochemistry. Density functional theory calculations are performed to account for the selectivities. For monosubstituted furans, the crowded transition state leading to the endo-I cycloadduct is stabilized by an edge-to-face interaction between the furan and the oxazolidinone 4-Ph group, but this stabilization is overcome by steric clashing if the furan bears a 2-CO2R group or is 2,3-disubstituted.

Stereoselectivities and regioselectivities of (4 + 3) cycloadditions between allenamide-derived chiral oxazolidinone-stabilized oxyallyls and furans: experiment and theory.

A systematic investigation of the regioselectivities and stereoselectivities of (4 + 3) cycloadditions between unsymmetrical furans and a chiral oxazolidinone-substituted oxyallyl is presented. Cycloadditions were performed using an oxyallyl containing a (R)-4-phenyl-2-oxazolidinone auxiliary (2(Ph)), under either thermal or ZnCl(2)-catalyzed conditions. Reactions of 2(Ph) with 2-substituted furans gave syn cycloadducts selectively, while cycloadditions with 3-substituted furans gave selectively anti cycloadducts. The stereoselectivities were in favor of a single diastereoisomer (I) in all but one case (2-CO(2)R). Density functional theory calculations were performed to explain the selectivities. The results support a mechanism in which all cycloadducts are formed from the E isomer of the oxyallyl (in which the oxazolidinone C═O and oxyallyl oxygen are anti to each other) or the corresponding (E)-ZnCl(2) complex. The major diastereomer is derived from addition of the furan to the more crowded face of the oxyallyl. Crowded transition states are favored because they possess a stabilizing CH-π interaction between the furan and the Ph group.

(4+3) cycloaddition reactions of nitrogen-stabilized oxyallyl cations.

The use of heteroatom-substituted oxyallyl cations in (4+3) cycloadditions has had a tremendous impact on the development of cycloaddition chemistry. Extensive efforts have been exerted toward investigating the effect of oxygen, sulfur, and halogen substituents on the reactivity of oxyallyl cations. Most recently, the use of nitrogen-stabilized oxyallyl cations has gained prominence in the area of (4+3) cycloadditions. The following article will provide an overview of this concept utilizing nitrogen-stabilized oxyallyl cations.

Developing a diastereoselective intramolecular [4+3] cycloaddition of nitrogen-stabilized oxyallyl cations derived from N-sulfonyl-substituted allenamides.

Efforts toward achieving a practical and diastereoselective intramolecular [4+3] cycloaddition of nitrogen-stabilized oxyallyl cations with tethered dienes are described. Epoxidation of N-sulfonyl substituted allenamides with dimethyldioxirane (DMDO) generates nitrogen-stabilized oxyallyl cations that readily undergo stereoselective [4+3] cycloaddition with dienes. Selectivity is found to depend on the tethering length as well as the stability of the oxyallyl cation intermediate, whether generated from N-carbamoyl- or N-sulfonyl-substituted allenamides. The use of chiral N-sulfonyl-substituted allenamides provided minimal diastereoselectivity in the cycloaddition, while high diastereoselectivity can be achieved with a stereocenter present on the tether. These studies provide further support for the synthetic utility of allenamides.

N-allyl-N-sulfonyl ynamides as synthetic precursors to amidines and vinylogous amidines. An unexpected N-to-C 1,3-sulfonyl shift in nitrile synthesis.

A detailed study of amidine synthesis from N-allyl-N-sulfonyl ynamides is described here. Mechanistically, this is a fascinating reaction consisting of diverging pathways that could lead to deallylation or allyl transfer depending upon the oxidation state of palladium catalysts, the nucleophilicity of amines, and the nature of the ligands. It essentially constitutes a Pd(0)-catalyzed aza-Claisen rearrangement of N-allyl ynamides, which can also be accomplished thermally. An observation of N-to-C 1,3-sulfonyl shift was made when examining these aza-Claisen rearrangements thermally. This represents a useful approach to nitrile synthesis. While attempts to render this 1,3-sulfonyl shift stereoselective failed, we uncovered another set of tandem sigmatropic rearrangements, leading to vinyl imidate formation. Collectively, this work showcases the rich array of chemistry one can discover using these ynamides.

An efficient and practical entry to 2-amido-dienes and 3-amido-trienes from allenamides through stereoselective 1,3-hydrogen shifts.

Preparations of de novo acyclic 2-amido-dienes and 3-amido-trienes through 1,3-hydrogen shifts from allenamides are described. These 1,3-hydrogen shifts could be achieved thermally or they could be promoted by the use of Brønsted acids. Under either condition, these processes are highly regioselective in favour of the α-position, and highly stereoselective in favour of the E-configuration. In addition, 6π-electron electrocyclic ring-closure could be carried out with 3-amido-trienes to afford cyclic 2-amido-dienes, and such electrocyclic ring-closure could be rendered in tandem with the 1,3-hydrogen shift.

Photochemical synthesis of 3-alkynals from 1-alkynoxy-9,10-anthraquinones.

Photolysis of 1-(3-alkynoxy)-9,10-anthraquinones in deoxygenated methanol leads to moderate yields (35-45%) of 3-alkynals along with the unexpected formation of diacetals. Reaction of these 3-alkynals with Grignard and Wittig reagents occurs nearly quantitatively without rearrangement to their 2,3-dienal isomers.

Synthesis of amido-spiro[2.2]pentanes via Simmons-Smith cyclopropanation of allenamides.

A detailed account of Simmons-Smith cyclopropanations of allenamides en route to amido-spiro[2.2]pentanes is described here. While the diastereoselectivity was low when using unsubstituted allenamides, the reaction is overall efficient and general, representing the most direct synthesis of both chemically and biologically interesting amido-spiro[2.2]pentane systems. With alpha-substituted allenamides, while the diastereoselectivity could be improved significantly based on a series of conformational analyses, both mono- and bis-cyclopropanation products were observed. Consequently, several structurally intriguing amido-methylene cyclopropanes could also be prepared.

Aberrant analgesic response to medial branch blocks in patients with characteristics of fibromyalgia.

BACKGROUND AND OBJECTIVES: Facet interventions for spine pain have high failure rates, and preprocedural prediction of response is nearly impossible. A potential explanation may be aberrant central pain processing as that existing in conditions like fibromyalgia. To test this hypothesis, we conducted a retrospective study investigating the impact of having characteristics of fibromyalgia on the acute analgesic response to a first diagnostic medial branch block (MBB). METHODS: We evaluated the analgesic responses of 187 patients that underwent MBB. Patients were categorized as "fibromyalgia-positive" or "fibromyalgia-negative" using the 2011 fibromyalgia survey criteria. Preprocedural and postprocedural pain scores and patient-completed pain diaries up to 24 hours postprocedure were collected. A linear mixed model was used to study longitudinal effects of MBB on pain responses. RESULTS: Fibromyalgia-positive patients had a worse preprocedural pain phenotype (ie, greater pain severity, higher levels of depressive and anxiety symptoms, reduced function). Binary categorization of fibromyalgia status was not associated with a difference in immediate postprocedural pain relief; however, the longitudinal analgesic response across time varied significantly between groups (P = 0.0005). Fibromyalgia-negative subjects showed the expected steep decline in pain scores, followed by gradual return to baseline, whereas a more aberrant pattern was noted in the fibromyalgia-positive group. Pain scores for fibromyalgia-negative patients were also lower by -1.07 (SE = 0.37) on average after the MBB (P = 0.005). CONCLUSIONS: Characteristics of fibromyalgia may indicate pain that is more centralized in nature, a factor that may explain the aberrant analgesic response to this peripheral intervention. This may have implications for future prediction of treatment response, although prospective studies are needed.

A divergent mechanistic course of Pd(0)-catalyzed aza-Claisen rearrangement and aza-Rautenstrauch-type cyclization of N-allyl ynamides.

A fascinating mechanistic study of ynamido-palladium-pi-allyl complexes is described that features isolation of a unique silyl ketenimine via aza-Claisen rearrangement, which can be accompanied by an unusual thermal N-to-C 1,3-Ts shift in the formation of tertiary nitriles and a novel cyclopentenimine formation via a palladium-catalyzed aza-Rautenstrauch-type cyclization pathway.

Stereoselectivity in Oxyallyl-Furan 4+3 Cycloadditions: Control of Intermediate Conformations and Dispersive Stabilisation with Evans' Oxazolidinones.

Chiral oxazolidinones were previously thought to control cycloaddition stereoselectivity by steric crowding of one face of the substrate. We have discovered that in 4+3 cycloaddition reactions of oxallyls, the stereoinduction is caused instead by stabilising CH-π interactions that lead to reaction at the more crowded face of the oxazolidinone. Density functional theory calculations on the 4+3 cycloadditions of oxazolidinone-substituted oxyallyls with furans establish unexpected transition state conformations and a new explanation of selectivity.

Regioselectivities of (4 + 3) cycloadditions between furans and oxazolidinone-substituted oxyallyls.

The (4 + 3) cycloadditions of oxazolidinone-substituted oxyallyls and unsymmetrically substituted furans lead to syn regioselectivity when the furan has a 2-Me or 2-COOR substituent, while anti regioselectivity is obtained with a 3-Me or 3-COOR group. DFT calculations are performed to explain the selectivities. The reactivities and regioselectivities are consistent with the ambiphilic reactivity of amino-oxyallyls with furans.

Thermal intramolecular [4 + 2] cycloadditions of allenamides: a stereoselective tandem propargyl amide isomerization-cycloaddition.

A stereoselective intramolecular normal demand [4 + 2] cycloaddition of allenamides under thermal conditions without metal assistance is described. This work led to the development of a stereoselective tandem propargyl amide-isomerization-[4 + 2] cycloaddition sequence amenable for rapid assembly of complex nitrogen heterocycles.

Challenges in the synthesis of a unique mono-carboxylic acid antibiotic, (+)-zincophorin.

(+)-Zincophorin, also referred to as M144255 or griseocholin, is a polyoxygenated ionophoric antibiotic that was isolated from Streptomyces griseus in 1984. It possesses strong in vivo activity against Gram-positive bacteria and Clostridium coelchii. Its methyl ester was reported in a patent as having strong inhibitory properties against influenza WSN/virus with reduced toxicity for the host cell. Its ability to strongly bind with Zn2+, which is also present in its X-ray structure, is the basis for its name. Over the last two decades, (+)-zincophorin has attracted an impressive array of synthetic efforts including Danishefsky's first total synthesis, along with two recent elegant total syntheses reported by Cossy and Miyashita as well as our own formal total synthesis. This review provides a comparison of the different synthetic efforts on this novel mono-carboxylic acid antibiotic and documents its interesting isolation, structure determination, and biological activities.

Regio- and stereoselective isomerizations of allenamides: synthesis of 2-amido-dienes and their tandem isomerization-electrocyclic ring-closure.

A regio- and stereoselective isomerization of allenamides is described, leading to preparations of de novo 2-amido-dienes and a tandem isomerization-6pi-electron electrocyclic ring-closure.

Synthesis of amidines using N-allyl ynamides. A palladium-catalyzed allyl transfer through an ynamido-pi-allyl complex.

A de novo transformation of N-allyl-N-sulfonyl ynamides to amidines is described featuring a palladium-catalyzed N-to-C allyl transfer via ynamido-palladium-pi-allyl complexes.

Studies on a urea-directed Stork-Crabtree hydrogenation. Synthesis of the C1-C9 subunit of (+)-zincophorin.

A detailed account on the stereoselective synthesis of the C1-C9 subunit of (+)-zincophorin is described here. This approach features the first application of a stereoselective inverse electron demand hetero-[4 + 2] cycloaddition of chiral allenamides in natural product synthesis. The C1-C9 subunit matches Cossy's intermediate, thereby constituting a formal total synthesis. In addition, details of an unusual urea-directed Stork-Crabtree hydrogenation observed during these efforts are also disclosed here.

Transport of galectin-3 between the nucleus and cytoplasm. I. Conditions and signals for nuclear import.

Galectin-3, a factor involved in the splicing of pre-mRNA, shuttles between the nucleus and the cytoplasm. We have engineered a vector that expresses the fusion protein containing the following: (a) green fluorescent protein as a reporter of localization, (b) bacterial maltose-binding protein to increase the size of the reporter polypeptide, and (c) galectin-3, whose sequence we wished to dissect in search of amino acid residues vital for nuclear localization. In mouse 3T3 fibroblasts transfected with this expression construct, the full-length galectin-3 (residues 1-263) fusion protein was localized predominantly in the nucleus. Mutants of this construct, containing truncations of the galectin-3 polypeptide from the amino terminus, retained nuclear localization through residue 128; thus, the amino-terminal half was dispensable for nuclear import. Mutants of the same construct, containing truncations from the carboxyl terminus, showed loss of nuclear localization. This effect was observed beginning with truncation at residue 259, and the full effect was seen with truncation at residue 253. Site-directed mutagenesis of the sequence ITLT (residues 253-256) suggested that nuclear import was dependent on the IXLT type of nuclear localization sequence, first discovered in the Drosophila protein Dsh (dishevelled). In the galectin-3 polypeptide, the activity of this nuclear localization sequence is modulated by a neighboring leucine-rich nuclear export signal.