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In this work, we demonstrate that readily available conjugated bis-aryl cyclobutenones undergo photoelectrocyclization reactions to give the corresponding dihydrophenanthrene cyclobutanones when exposed to 350 nm light, TFA, and TMSCl. We have also found that cyclobutenone electrocyclizations and cycloreversions are in equilibrium.

This article describes the synthesis of VLC-PUFA 32:6 n-3, D2-labeled 32:6 n-3, and the uptake of 32:6 n-3 into mouse retinal tissue.

Outlined here are studies exploring the scope of the sequential photoelectrocyclization, [1,5]-hydride shift of conjugated bis-aryl cycloalkenone substrates. We have found not only that the cyclization precursors can be synthesized in a modular fashion but also that the cyclization is efficient and amenable to the presence of a range of cycloalkenones and aromatic systems. Among the interesting discoveries from this work is that the electrocyclization intermediate can be competitively captured with protons and that the nature of the excited state (singlet vs triplet) is dependent on aromatic substitution.

Readily available acrylamide naphthoquinones can be converted into the corresponding aza-anthraquinones using 6π-photoelectrocyclization reactions. Not only do these reactions not proceed thermally but, as demonstrated here, they can also be used to generate a range of aza-anthraquinone and aza-tetracycline derivatives including the natural products griffithazanone A and marcanine A. Several of the aza-anthraquinones generated in this work showed antibacterial activity.

The unique attributes of very-long-chain polyunsaturated fatty acids (VLC-PUFAs), their long carbon chains (n 24) and high degree of unsaturation, impart unique chemical and physical properties to this class of fatty acids. The changes imparted by VLC-PUFA 32:6 n-3 on lipid packing and the compression moduli of model membranes were evaluated from π-A isotherms of VLC-PUFA in 1,2-distearoyl-sn-3-glycero-phosphocholine (DSPC) lipid monolayers. To compare the attractive or repulsive forces between VLC-PUFA and DSPC lipid monolayers, the measured mean molecular areas (MMAs) were compared with the calculated MMAs of an ideal mixture of VLC-PUFA and DSPC. The presence of 0.1, 1, and 10 mol % VLC-PUFA shifted the π-A isotherm to higher MMAs of the lipids comprising the membrane and the observed positive deviations from ideal behavior of the mixed VLC-PUFA:DSPC monolayers correspond to repulsive forces between VLC-PUFAs and DSPC. The MMA of the VLC-PUFA component was estimated using the measured MMAs of DSPC of 47.1 ± 0.7 Å

The photoelectrocyclization of conjugated vinyl biaryls has proven to be a valuable and efficient strategy for generating phenanthrene derivatives. Contained in this review is an overview of the mechanism for the transformation and a discussion of the reaction scope with a focus on the electrocyclization itself, rearomatization, and the application of the reaction in natural product synthesis.1 Introduction2 The Synthesis of Conjugated Vinyl Biaryls3 Mechanistic Studies4 Substrate Scope5 Applications6 Conclusions

Described here are tandem photoelectrocyclization and [l,5]-hydride shift reactions of heteroaryl-containing bis-aryl cyclohexenone derivatives that give heteroaryl-substituted dihydrophenanthrenes. This Letter demonstrates that electrocyclization intermediates can be trapped with acid when the [l,5]-hydride shift is relatively slow. From a practical perspective, the observation that the acid-mediated reaction gives a divergent stereochemical outcome when compared with the reaction run under neutral conditions makes these transformations powerful.

This work outlines a suitable method for the synthesis of oxepane skeleton using iterative C-glycoside technology on the oxepene intermediate, which was synthesized utilizing Wilkinson’s catalyst [Rh(PPh3)3Cl] to generate the isomerized product in a linear synthetic manner. The central core of the oxepene motif was achieved via an olefin metathesis reaction using the Grubbs second-generation and Schrock catalysts. The synthesis of the functionalized oxepane having the desired adriatoxin E-ring relative stereochemistry was achieved starting from commercially available homopropargylic alcohol.

Rare, nondietary very-long-chain polyunsaturated fatty acids (VLC-PUFAs) are uniquely found in the retina and a few other vertebrate tissues. These special fatty acids play a clinically significant role in retinal degeneration and development, but their physiological and interventional research has been hampered because pure VLC-PUFAs are scarce. We hypothesize that if Stargardt-3 or age-related macular degeneration patients were to consume an adequate amount of VLC-PUFAs that could be directly used in the retina, it may be possible to bypass the steps of lipid elongation mediated by the retina’s ELOVL4 enzyme and to delay or prevent degeneration. We report the synthesis of a VLC-PUFA (32:6 n-3) in sufficient quantity to study its bioavailability and functional benefits in the mouse retina. We acutely and chronically gavage fed wild-type mice and Elovl4 rod–cone conditional knockout mice this synthetic VLC-PUFA to understand its bioavailability and its role in visual function. VLC-PUFA-fed wild-type and Elovl4 conditional knockout mice show a significant increase in retinal VLC-PUFA levels in comparison to controls. The VLC-PUFA-fed mice also had improvement in the animals’ visual acuity and electroretinography measurements. Further studies with synthetic VLC-PUFAs will continue to expand our understanding of the physiological roles of these unique retinal lipids, particularly with respect to their potential utility for the treatment and prevention of retinal degenerative diseases.

The marine polycyclic-ether toxin gambierol and 1-butanol (n-alkanol) inhibit Shaker-type Kv channels by interfering with the gating machinery. Competition experiments indicated that both compounds do not share an overlapping binding site but gambierol is able to affect 1-butanol affinity for Shaker through an allosteric effect. Furthermore, the Shaker-P475A mutant, which inverses 1-butanol effect, is inhibited by gambierol with nM affinity. Thus, gambierol and 1-butanol inhibit Shaker-type Kv channels via distinct parts of the gating machinery.

It is a deeply engrained notion that the visual pigment rhodopsin signals light as a monomer, even though many G protein-coupled receptors are now known to exist and function as dimers. Nonetheless, recent studies (albeit all in vitro) have suggested that rhodopsin and its chromophore-free apoprotein, R-opsin, may indeed exist as a homodimer in rod disk membranes. Given the overwhelmingly strong historical context, the crucial remaining question, therefore, is whether pigment dimerization truly exists naturally and what function this dimerization may serve. We addressed this question in vivo with a unique mouse line (S-opsin+Lrat−/−) expressing, transgenically, short-wavelength–sensitive cone opsin (S-opsin) in rods and also lacking chromophore to exploit the fact that cone opsins, but not R-opsin, require chromophore for proper folding and trafficking to the photoreceptor’s outer segment. In R-opsin’s absence, S-opsin in these transgenic rods without chromophore was mislocalized; in R-opsin’s presence, however, S-opsin trafficked normally to the rod outer segment and produced functional S-pigment upon subsequent chromophore restoration. Introducing a competing R-opsin transmembrane helix H1 or helix H8 peptide, but not helix H4 or helix H5 peptide, into these transgenic rods caused mislocalization of R-opsin and S-opsin to the perinuclear endoplasmic reticulum. Importantly, a similar peptide-competition effect was observed even in WT rods. Our work provides convincing evidence for visual pigment dimerization in vivo under physiological conditions and for its role in pigment maturation and targeting. Our work raises new questions regarding a potential mechanistic role of dimerization in rhodopsin signaling.

Yessotoxin and adriatoxin are members of the polycyclic ether family of marine natural products. Outlined in this article is our synthetic approach to two subunits of these targets. Central to our strategy is a coupling sequence that employs an olefinic-ester cyclization reaction. As outlined, this sequence was used in two coupling sequences. First, it was used to merge the A, B- and E, F-bicyclic precursors and in the process generate the C- and D-rings. Second, it was used to couple the F- and I-rings while building the eight-membered G-ring and subsequently the H-ring pyran.

Synthetic peptides derived from transmembrane segments of G protein-coupled receptors (GPCR) are used to disrupt GPCR dimer interface. This peptide competition technique is an effective approach to map the dimer interface of GPCR and its functional significance. Here we present a technique to deliver synthetic transmembrane peptides to living mouse rod photoreceptors to disrupt rhodopsin (a prototypical member of Class A GPCRs) dimer formation in the endoplasmic reticulum (ER). We have shown that rhodopsin helix H1- or H8-peptide caused mislocalization of rhodopsin to the perinuclear endoplasmic reticulum (ER).

Polypoidal choroidal vasculopathy (PCV) is a common subtype of wet age-related macular degeneration in Asian populations, whereas choroidal neovascularization is the typical subtype in Western populations. The cause of PCV is unknown. By comparing the phenotype of a PCV mouse model expressing protease high temperature requirement factor A1 (HTRA1) in retinal pigment epithelium with transgenic mice expressing the inactive HTRA1S328A, we showed that HTRA1-mediated degradation of elastin in choroidal vessels is critical for the development of PCV, which exhibited destructive extracellular matrix remodeling and vascular smooth muscle cell loss. Compared with weak PCV, severe PCV exhibited prominent immune complex deposition, complement activation, and infiltration of inflammatory cells, suggesting inflammation plays a key role in PCV progression. More important, we validated these findings in human PCV specimens. Intravitreal delivery of an HTRA1 inhibitor (DPMFKLboroV) was effective (36% lesion reduction; P = 0.009) in preventing PCV initiation but ineffective in treating existing lesions. Anti-inflammatory glucocorticoid was effective in preventing PCV progression but ineffective in preventing PCV initiation. These results suggest that PCV pathogenesis occurs through two stages. The initiation stage is mediated by proteolytic degradation of extracellular matrix proteins attributable to increased HTRA1 activity, whereas the progression stage is driven by inflammatory cascades. This study provides a basis for understanding the differences between PCV and choroidal neovascularization, and helps guide the design of effective therapies for PCV.

Treatment of diazo vinyl phosphonate with alcohols, amines, and thiols in the presence of Rh(II) results in the chemo- and stereoselective generation of enol ethers, enamines and vinyl sulfides via an X-H insertion process. The utility of the products from these reactions was demonstrated through their conversion into quaternary substituted heterocycles including furans and oxetanes as highlighted by the generation of a bicyclic phosphonate analogue of neodysiherbaine.

Gambierol is a marine polycyclic ether toxin produced by the marine dinoflagellate Gambierdiscus toxicus and is a member of the ciguatoxin toxin family. Gambierol has been demonstrated to be either a low-efficacy partial agonist/antagonist of voltage-gated sodium channels or a potent blocker of voltage-gated potassium channels (Kvs). Here we examined the influence of gambierol on intact cerebrocortical neurons. We found that gambierol produced both a concentration-dependent augmentation of spontaneous Ca(2+) oscillations, and an inhibition of Kv channel function with similar potencies. In addition, an array of selective as well as universal Kv channel inhibitors mimicked gambierol in augmenting spontaneous Ca(2+) oscillations in cerebrocortical neurons. These data are consistent with a gambierol blockade of Kv channels underlying the observed increase in spontaneous Ca(2+) oscillation frequency. We also found that gambierol produced a robust stimulation of phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2). Gambierol-stimulated ERK1/2 activation was dependent on both inotropic [N-methyl-d-aspartate (NMDA)] and type I metabotropic glutamate receptors (mGluRs) inasmuch as MK-801 [NMDA receptor inhibitor; (5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate], S-(4)-CGP [S-(4)-carboxyphenylglycine], and MTEP [type I mGluR inhibitors; 3-((2-methyl-4-thiazolyl)ethynyl) pyridine] attenuated the response. In addition, 2-aminoethoxydiphenylborane, an inositol 1,4,5-trisphosphate receptor inhibitor, and U73122 (1-[6-[[(17b)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione), a phospholipase C inhibitor, both suppressed gambierol-induced ERK1/2 activation, further confirming the role of type I mGluR-mediated signaling in the observed ERK1/2 activation. Finally, we found that gambierol produced a concentration-dependent stimulation of neurite outgrowth that was mimicked by 4-aminopyridine, a universal potassium channel inhibitor. Considered together, these data demonstrate that gambierol alters both Ca(2+) signaling and neurite outgrowth in cerebrocortical neurons as a consequence of blockade of Kv channels.

Described herein is the generation and use of iodohexahydropyridoindolines and their free radical atom transfer reactions with aryl acetylenes to generate quaternary substituted pyridoindolones.

The generation of indolines and benzofurans from the combination of Suzuki-Miyaura coupling reactions with oxidative cyclizations is described.

Voltage-gated potassium (Kv) and sodium (Nav) channels are key determinants of cellular excitability and serve as targets of neurotoxins. Most marine ciguatoxins potentiate Nav channels and cause ciguatera seafood poisoning. Several ciguatoxins have also been shown to affect Kv channels, and we showed previously that the ladder-shaped polyether toxin gambierol is a potent Kv channel inhibitor. Most likely, gambierol acts via a lipid-exposed binding site, located outside the K+ permeation pathway. However, the mechanism by which gambierol inhibits Kv channels remained unknown. Using gating and ionic current analysis to investigate how gambierol affected S6 gate opening and voltage-sensing domain (VSD) movements, we show that the resting (closed) channel conformation forms the high-affinity state for gambierol. The voltage dependence of activation was shifted by >120 mV in the depolarizing direction, precluding channel opening in the physiological voltage range. The (early) transitions between the resting and the open state were monitored with gating currents, and provided evidence that strong depolarizations allowed VSD movement up to the activated-not-open state. However, for transition to the fully open (ion-conducting) state, the toxin first needed to dissociate. These dissociation kinetics were markedly accelerated in the activated-not-open state, presumably because this state displayed a much lower affinity for gambierol. A tetrameric concatemer with only one high-affinity binding site still displayed high toxin sensitivity, suggesting that interaction with a single binding site prevented the concerted step required for channel opening. We propose a mechanism whereby gambierol anchors the channel’s gating machinery in the resting state, requiring more work from the VSD to open the channel. This mechanism is quite different from the action of classical gating modifier peptides (e.g., hanatoxin). Therefore, polyether toxins open new opportunities in structure–function relationship studies in Kv channels and in drug design to modulate channel function.

This article describes the synthesis of kapakahines E and F, along with what we believe to be a general method for the total synthesis of the kapakahine family of marine natural products. The method utilizes a unique heterodimerization reaction between bromopyrroloindolines and indole nucleophiles, a novel pyrroloindoline-to-α-carboline rearrangement, and a Negishi coupling reaction of C(3)-iodoindoles.

This manuscript describes the total synthesis of the marine ladder toxin brevenal utilizing a convergent synthetic strategy. Critical to the success of this work was the use of olefinic-ester cyclization reactions and the utilization of glycal epoxides as precursors to C–C and C–H bonds.

The total synthesis of the cyclic peptides kapakahine E and F using bromopyrroloindoline heterodimerization reactions, indoline to alpha-carboline rearrangements, and Negishi coupling reactions is described.

Acid-sensing ion channels (ASICs) respond to acidosis that normally occurs after inflammation. We examined the expression of ASIC1 , ASIC2 , and ASIC3 mRNAs in lumbar dorsal root ganglion neurons before and 24 hours after carrageenan-induced muscle inflammation. Muscle inflammation causes bilateral increases of ASIC2 and ASIC3 but not ASIC1 (neither ASIC1a nor ASIC1b ) mRNA, suggesting differential regulation of ASIC1 versus ASIC2 and ASIC3 mRNA. Similar mRNA increases were observed after inflammation in knockout mice: ASIC2 mRNA increases in ASIC3-/- mice; ASIC2 and ASIC3 mRNAs increase in ASIC1-/- mice. Prior behavioral studies in ASIC3-/- mice showed deficits in secondary hyperalgesia (increased response to noxious stimuli outside the site of injury) but not primary hyperalgesia (increased response to noxious stimuli at the site of injury). In this study, we show that ASIC1-/- mice do not develop primary muscle hyperalgesia but develop secondary paw hyperalgesia. In contrast, and as expected, ASIC3-/- mice develop primary muscle hyperalgesia but do not develop secondary paw hyperalgesia. The pharmacological utility of the nonselective ASIC inhibitor A-317567, given locally, was tested. A-317567 reverses both the primary and the secondary hyperalgesia induced by carrageenan muscle inflammation. Thus, peripherally located ASIC1 and ASIC3 play different roles in the development of hyperalgesia after muscle inflammation. Perspective This study shows changes in ASIC mRNA expression and behavioral hyperalgesia of C57Bl/6 (wild type), ASIC1-/-, and ASIC3-/- mice before and after the induction of muscle inflammation. A-317567 was effective in reversing hyperalgesia in these animals, suggesting the potential of ASICs as therapeutic targets for muscle inflammatory pain.

No animal models replicate the complexity of human depression. However, a number of behavioral tests in rodents are sensitive to antidepressants and may thus tap important underlying biological factors. Such models may also offer the best opportunity to discover novel treatments. Here, we used several of these models to test the hypothesis that the acid-sensing ion channel-1a (ASIC1a) might be targeted to reduce depression. Genetically disrupting ASIC1a in mice produced antidepressant-like effects in the forced swim test, the tail suspension test, and following unpredictable mild stress. Pharmacologically inhibiting ASIC1a also had antidepressant-like effects in the forced swim test. The effects of ASIC1a disruption in the forced swim test were independent of and additive to those of several commonly used antidepressants. Furthermore, ASIC1a disruption interfered with an important biochemical marker of depression, the ability of stress to reduce BDNF in the hippocampus. Restoring ASIC1a to the amygdala of ASIC1a−/−mice with a viral vector reversed the forced swim test effects, suggesting that the amygdala is a key site of ASIC1a action in depression-related behavior. These data are consistent with clinical studies emphasizing the importance of the amygdala in mood regulation, and suggest that ASIC1a antagonists may effectively combat depression.

This paper describes our synthesis of the A-E subunit of gambieric acid (GA) in addition to the synthesis of the A-ring and the C-E tricycle. The use of an enol ether-olefin RCM strategy to couple the A and C-E subunits and, in the process, generate the B-ring is noteworthy.

Marine ladder-shaped polyether toxins are implicated in neurological symptoms of fish-borne food poisonings. The toxin gambierol, produced by the marine dinoflagellate Gambierdiscus toxicus, belongs to the group of ladder-shaped polyether toxins and inhibits Kv3.1 channels with nanomolar affinity through a mechanism of gating modification. Binding determinants for gambierol localize at the lipid-exposed interface of the pore forming S5 and S6 segments, suggesting that gambierol binds outside of the permeation pathway. To explore a possible involvement of the voltage-sensing domain (VSD), we made different chimeric channels between Kv3.1 and Kv2.1, exchanging distinct parts of the gating machinery. Our results showed that neither the electro-mechanical coupling nor the S1-S3a region of the VSD affect gambierol sensitivity. In contrast, the S3b-S4 part of the VSD (paddle motif) decreased gambierol sensitivity in Kv3.1 more than 100-fold. Structure determination by homology modeling indicated that the position of the S3b-S4 paddle and its primary structure defines the shape and∖or the accessibility of the binding site for gambierol, explaining the observed differences in gambierol affinity between the channel chimeras. Furthermore, these findings explain the observed difference in gambierol affinity for the closed and open channel configurations of Kv3.1, opening new possibilities for exploring the VSDs as selectivity determinants in drug design.

Described herein is the generation and use of iodohexahydropyridoindolines and their free radical atom transfer reactions with aryl acetylenes to generate quaternary substituted pyridoindolones.

Diazo vinyl phosphonate (I) is regioselectively transformed in a rhodium-catalyzed reaction with nucleophiles such as alcohols, amines including guanidine and thiols in order to form enol ethers, enamines, and vinyl sulfides, respectively.

which contains vicinal quaternary centers, was established with the help of extensive 2DNMR experiments and was later validated by the total synthesis developed by Fuchs and Funk. Preliminary biological data indicated that perophoramidine is cytotoxic to HMT 116 colon carcinoma cells and is able to induce apoptosis by poly(adenosine-5’-diphosphateribose)polymerase (PARP) cleavage. Our interest in the synthetic chemistry of 2-thioindoles, combined with the novel structural features of perophoramidine and its preliminary biological data, induced us to initiate a program to target its synthesis. Described herein are our preliminary results in this area and the synthesis of ( )dehaloperophoramidine. We considered several synthetic routes to the perophoramidine skeleton, but ultimately settled upon the approach illustrated in Scheme 2. We envisioned that the intramolecular coupling between the 3-position of a 2-thioindole with a pendant electrophile would serve to generate one of the perophoramidine spiro-fused rings; the resulting thioimidate

Density functional theory (DFT) (Becke3LYP functional and the D95** basis set) was used to study the influence of substitution on the dimethyldioxirane epoxidation reaction of six- and seven-membered cyclic enol ethers. In agreement with our previously reported experimental results, the calculations predict that substitution on the cyclic enol ether influences the level of diastereoselectivity. Apparent only from the calculations is that the degree of synchronicity in the transition state is important in the diastereoselectivity.

The preceding manuscript detailed our synthesis of the gambierol A-C and F-H ring precursors. Reported herein is a description of the coupling of the two precursors and the conversion of the coupled material into gambierol. Coupling of the subunits involved ester formation, enol ether RCM, and mixed thioketal formation and reduction. By employing this strategy we were able to bring highly advanced subunits into the coupling and, as a result, we were able to minimize the number of post-coupling transformations required to complete gambierol. At the completion of the synthesis, we generated 7.5 mg (1.5 % overall yield) of (-)-gambierol in 44 steps (longest linear sequence).

[reaction: see text] C-Ketosides are valuable intermediates in chemical synthesis and as glycoside mimics. This manuscript describes the efficient generation of these substrates from alpha-alkyl-substituted glycals and an oxidative, C-C bond-forming sequence where the choice of C(3) protecting group was critical.

A convergent, stereocontrolled total synthesis of the architecturally complex tremorgenic indole alkaloid (-)-penitrem D (4) has been achieved. Highlights of the synthesis include an efficient, asymmetric synthesis of the western hemisphere; the stereocontrolled assembly of the I-ring; discovery of a novel autoxidation to introduce the C(22) tertiary hydroxyl group, required for tremorgenic activity; union of fully elaborated eastern and western hemispheres, exploiting an indole synthetic protocol developed expressly for this purpose; and a late-stage, stereoselective construction of the A and F rings exploiting a Sc(OTf)(3-)promoted reaction cascade. The longest linear sequence leading to (-)-penitrem D (4) was 43 steps.

We have examined the coupling reactions of 2-thioindoles with vinyl diazoacetates in the presence of Rh(II) catalysts. While attempted enantio- and/or diastereoselective couplings using chiral catalysts and/or chiral auxiliaries on the vinyl diazoacetate have been largely unsuccessful, substrates having resident chirality on fused thiopyrans gave thioindolines with moderate to high diastereoselectivities.

[structure: see text] This manuscript describes our synthesis of the F-H subunit of gambierol. In addition to the synthesis of the tricycle, of note is an interesting protecting group influence on the generation of a C(23) C-glycoside as well as the use of ring-closing metathesis to generate a tetrasubstituted enol ether.

Aims There is an ongoing need for fluorescent probes that specifically-target select organelles within mammalian cells. This study describes the development of probes for the selective labeling of the Golgi apparatus and offers applications for live cell and fixed cell imaging. Main methods The kapakahines, characterized by a common C (3)- N (1′) dimeric tryptophan linkage, comprise a unique family of bioactive marine depsipeptide natural products. We describe the uptake and subcellular localization of fluorescently-labeled analogs of kapakahine E. Using confocal microscopy, we identify a rapid and selective localization within the Golgi apparatus. Comparison with commercial Golgi stains indicates a unique localization pattern, which differs from currently available materials, therein offering a new tool to monitor the Golgi in live cells without toxic side effects. Key findings This study identifies a fluorescent analog of kapakahine E that is rapidly uptaken in cells and localizes within the Golgi apparatus. Significance The advance of microscopic methods is reliant on the parallel discovery of next generation molecular probes. This study describes the advance of stable and viable probe for staining the Golgi apparatus.

This manuscript describes the synthesis of fused polycyclic ethers from the coupling of C-glycoside forming reactions with ring closing metathesis and acid mediated annulation reactions.

Vinyl diazophosphonates can be stereoselectively synthesized and, depending upon their substitution pattern, undergo intramolecular C-H insertion reactions or sulfonium ylide rearrangements when exposed to Rh(2)(OAc)(4).

This Letter reports the synthesis of iron complexes of 3-oxocyclopentadienones from ynol ether–alkyne [2+2+1] cycloaddition reactions as well as the use of 3-alkoxycyclopentadienones in subsequent cycloaddition reactions.

Oxabicyclo[2.2.1]heptenones undergo 2-carbon ring expansion reactions when subjected to anionic condensations and Michael acceptors. They also undergo condensation, fragmentation, and elimination reactions in their anionic couplings with aldehydes. As an outgrowth of this interesting chemistry, we have been able to access the carbon skeleton of oxygenated cembranoids by subjecting bis-activated ene-yne 39 to the enolate from oxabicyclo[2.2.1]heptenone 1 .

This Letter describes our use of C-glycosides to synthesize the A−D ring system of the marine ladder toxin gambierol in 20 steps.

This manuscript describes the generation and use of a cyclopropylazetoindoline, a novel fused heterocycle, in coupling reactions with hetero- and carbon nucleophiles to give C(3)-quaternary-substituted pyrroloindolines.

[formula: see text] In this Letter we demonstrate the viability of a highly stereoselective tandem Mannich cyclization-grammine fragmentation/addition cascade, critical for assembly of the A and F rings of penitrem D. We also explored simultaneous execution of this tactic with concurrent construction of ring I. Reinvestigation of a model system provided an explanation for the unanticipated stereochemical outcome at C(28).

The use of a reduced titanium ethylidene reagent in an efficient two-directional approach to polycyclic ether skeletons is described.

An iterative synthesis of fused ether ring systems has been developed. This strategy couples a cyclic enol ether oxidation and carbon-carbon bond forming reaction in one flask with an acid catalyzed cyclic acetal formation and alkoxide elimination in another flask. The result is a general and highly efficient two flask synthesis of fused ethers as are present in a wide variety of bioactive natural products.

The generation of indolines and benzofurans from the combination of Suzuki–Miyaura coupling reactions with oxidative cyclizations is described.