Macrocycles by Ring-Closing Metathesis

Fürstner, Alois; Langemann, Klaus

doi:10.1055/s-1997-4472

Cited by 331 publications

(152 citation statements)

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“…This intermediate VI has been synthesized by reducing the 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid with lithium aluminium hydride, followed by tosylation with 4-methylbenzene-1-sulfonyl chloride (see supplementary information, scheme S1). 28 Reductive amination of different commercially available aldehydes with the tryptamine, using sodium triacetoxyborohydride as reductive agent gave the final compounds 15-21 in 51% -85% yields (Scheme 2). 21 Finally, treatment of derivative 21 with methyl iodide using NaH as a base allowed us to obtained the dimethyl derivative 22 in 37% yield.…”

Section: Scheme 1 Synthesis Of the N 2-substituted Indolethanamine mentioning

confidence: 99%

Tryptamine-Based Derivatives as Transient Receptor Potential Melastatin Type 8 (TRPM8) Channel Modulators

et al. 2016

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Pharmacological modulation of the transient receptor potential melastatin type 8 (TRPM8) is currently under investigation as a new approach mainly for the treatment of pain. In this study, a series of N-substituted tryptamines was prepared to explore the structural requirements determining TRPM8 modulation. As a result of a fluorescence-based screening assay, we identified two compounds acting as an activator (2-(1H-indol-3-yl)-N-(4-phenoxybenzyl) ethanamine, compound 21) or an inhibitor (N,N-dibenzyl-2-(1H-indol-3-yl) ethanamine, compound 12) of calcium influx in HEK293 cells. In patch-clamp recordings, compound 21 displayed a significantly higher potency (EC 50 = 40±4 µM) and a similar efficacy when compared to menthol; by contrast, compound 12 produced a concentrationdependent inhibition of menthol-induced TRPM8 currents (IC 50 = 367±24 nM). Molecular modelling studies using a homology model of a single TRPM8 subunit identified a putative binding site located between the VSD and the TRP box, disclosing two different binding modes for the agonist and the antagonist.

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Section: Scheme 1 Synthesis Of the N 2-substituted Indolethanamine mentioning

confidence: 99%

Tryptamine-Based Derivatives as Transient Receptor Potential Melastatin Type 8 (TRPM8) Channel Modulators

et al. 2016

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“…10 Fürstner and co-workers have noted a similar "relay effect" of appropriately positioned heteroatoms in RCM macrocycle synthesis. 11 Vinyl sulfides are poor substrates in aqueous metathesis, likely leading to Fischer carbenes sensitive to water (Table 1, Entry 7). The decreasing reactivity of .g., 7-8 and 11-12) may be attributed to the formation of unproductive five-or six-membered chelates, respectively (Scheme 1b).…”

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confidence: 99%

Allyl Sulfides Are Privileged Substrates in Aqueous Cross-Metathesis: Application to Site-Selective Protein Modification

et al. 2008

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Olefin metathesis has become a mainstay in organic synthesis. 1 Cross-metathesis (CM), however, is largely underdeveloped compared to ring closing metathesis (RCM) and ring opening metathesis polymerization since CM does not have the entropic driving force of RCM and is complicated by self-metathesis. 2 Our group has a long-term interest in site-selective chemical modification of proteins in an effort to study and modulate their function. 3 Olefin metathesis is an attractive way to install these protein modifications through a stable carbon-carbon bond. Indeed, incorporation of olefins into proteins has been possible for nearly a decade, 4 but metathesis at such residues has not been realized. Despite recent reports of olefin metathesis in water, the current benchmark for homogeneous aqueous CM is the self-metathesis of simple unsaturated alcohols such as allyl alcohol. 5,6 The limited examples revealed to date highlight the challenges for aqueous CM and the gap in substrate complexity that must be bridged to carry out metathesis on protein surfaces.To determine the viability of CM on protein surfaces, simple amino acid models were investigated. Substrates were selected on the basis of potential incorporation into proteins. A reasonable starting point was homoallylglycine (Hag) since its in ViVo incorporation by methionine auxotrophic Escherichia coli is known. 4 Hoveyda-Grubbs second generation catalyst 1 7 was selected since it is phosphine free and therefore more likely to be compatible with protein disulfides than other conventional catalysts. A simple test metathesis with allyl alcohol 2 was carried out to assess the reactivity of Hag derivative 3. At the outset, we limited ourselves to temperatures generally compatible with proteins (e37°C ) and made no effort to exclude oxygen. Since 1 is not freely soluble in water, it was added as a solution in t BuOH. Unfortunately, despite repeated attempts, only starting material 3 was recovered (Table 1, Entry 1). We turned next to cysteine derivatives since incorporation into proteins should be possible by either chemical or genetic means if they proved reactive in CM. Remarkably, S-allylcysteine (Sac) derivative 4 underwent metathesis with allyl alcohol (Entry 2), affording the CM product in 56% isolated yield (74% based on recovered 4). This result was noteworthy given the number of instances where thioethers were detrimental to rutheniumbased metathesis catalysts. 8 The metathesis was also efficient with allyl homocysteine 5 and bisamide Sac derivative 6. Yet when the alkene was extended by one or two methylene units from the sulfur center, only allyl alcohol self-metathesis was observed along with recovered starting material (Entries 5 and 6). Other allylheteroatom substrates were screened, but allyl sulfides remained the most efficient metathesis substrates under the conditions employed (Entries 7-13).While the self-metathesis of allyl sulfides has been carried out in organic solvents, the efficiency relative to other heteroatom or hydrocarbon analogues was...

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“…To this end, we have deliberately chosen a remote COC bond within the aliphatic tether of the target rather than the lactam as the site of macrocyclization, because this allows one to implement ring-closing metathesis (RCM) as a key transformation (Scheme 1). Although RCM was shown recently to be among the most efficient entries into carbo-and heterocyclic rings of virtually any size (17)(18)(19), the efficiency of RCM-based macrocyclizations is known to be strongly affected by heteroelements in proximity to the reacting alkenes, which can attenuate the reactivity of the emerging metal carbenes by formation of (stable) chelate complexes (20,21). To avoid such complications, the C.15OC.16 bond (isooncinotine numbering) seemed best suited for this maneuver, because the carbonyl group of the amide is then sufficiently remote.…”

Section: Resultsmentioning

confidence: 99%

Catalysis-based enantioselective total synthesis of the macrocyclic spermidine alkaloid isooncinotine

Scheiper

Glorius

Leitner

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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A concise and efficient total synthesis of the spermidine alkaloid (؊)-isooncinotine (1) incorporating a 22-membered lactam ring is outlined. The approach is largely catalysis-based, involving a selective iron-catalyzed alkyl-aryl cross-coupling reaction of a difunctionalized pyridine substrate, a heterogeneous asymmetric hydrogenation step to set the chiral center of the target, and a highly integrated ring-closing metathesis͞hydrogenation sequence to forge the saturated macrocyclic edifice in a single operation. Despite the prevalence of the biogenetic bases spermidine and spermine in nature and their widespread use as tools in biochemical research (1), little is known about the physiological properties of the small but structurally rather unique class of alkaloids incorporating these polyamines into their macrocyclic skeletons (2-4). This may be due, in part, to the difficulties in obtaining pure samples of these compounds from the natural sources † as well as to the fact that most syntheses described thus far provided only racemic material. Prototype spermidine alkaloids are (Ϫ)-isooncinotine (1), (Ϫ)-oncinotine (2), (Ϫ)-neooncinotine (3), and oncinodin-12-one (4), which were isolated from the stem bark of Oncinotis nitida and Oncinotis tenuiloba (Apocynaceae) (5-7) and have been repeatedly targeted in the past (8-12) (Fig. 1). Only recently has one member of this series (i.e., compound 2) been made available in an optically active form through total synthesis by using a diastereoselective 1,3-dipolar cycloaddition for the formation of the stereogenic center at the junction of the piperidine and the macrocyclic ring (13).In pursuit of previous work in the field of polyamine alkaloids (14, 15), we were prompted to develop a complementary, practical, and potentially scaleable entry into this family of natural products, choosing the 22-membered macrolactam (Ϫ)-isooncinotine 1 as our initial target. The envisaged route, however, should not only provide material for further evaluation but also meet a set of stringent chemical criteria. Specifically, it is felt that contemporary organic chemistry must (i) prioritize catalysis-based bond formations, (ii) try to control absolute stereochemistry by asymmetric catalysis, and (iii) aim at high convergence combined with an overall ''economy of steps'' (16). Furthermore, the total synthesis of 1 should provide us with the possibility to scrutinize methodology developed in our laboratories. Outlined below is the successful reduction of this plan to practice. Materials and MethodsGeneral. All reactions were carried out under Ar in flame-dried glassware. The solvents used were purified by distillation over the drying agents indicated and were transferred under Ar: tetrahydrofuran (THF) (Na), CH 2 Cl 2 (P 4 O 10 ), MeCN, Et 3 N, pyridine, NMP, hexamethylphosphoramide (HMPA), tetramethylethylenediamine (CaH 2 ), dimethylformamide (DMF) (dibutyltin dilaurate͞Desmodur), MeOH, EtOH (Mg), and toluene (Na͞K). For flash chromatography, Merck silica gel 60 (230-400 mesh) was used. F...

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Macrocycles by Ring-Closing Metathesis

Cited by 331 publications

References 0 publications

Tryptamine-Based Derivatives as Transient Receptor Potential Melastatin Type 8 (TRPM8) Channel Modulators

Tryptamine-Based Derivatives as Transient Receptor Potential Melastatin Type 8 (TRPM8) Channel Modulators

Allyl Sulfides Are Privileged Substrates in Aqueous Cross-Metathesis: Application to Site-Selective Protein Modification

Catalysis-based enantioselective total synthesis of the macrocyclic spermidine alkaloid isooncinotine

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