Calculations on the Ruthenium-Catalyzed Diene and Dienyne Ring-Closing Metathesis Reactions in the Synthesis of Taxol Derivatives.

Density-functional and semiempirical calculations (M06, M06L, and PM6) on intermediates in the ring-closing metathesis (RCM) reactions in the synthesis of Taxol derivatives give results in excellent agreement with the results of previous experimental work. The results suggest that the degree of steric overloading plays a decisive role in determining the outcome (ene-ene or ene-yne-ene metathesis). Due to the rigidity of the Taxol skeleton being formed in the ene-yne-ene cascade reaction, the transition states in its final ene-ene metathesis reaction stage are particularly sensitive to steric effects. Thus, the reaction is predicted to be preferred for one diastereomer of the precursor in which the diol functionality is protected with a compact cyclic carbonate moiety, whereas the use of a bulkier benzoate-protecting group results in activation barriers for Taxol formation that are prohibitive. The reason why one diastereomer of the carbonate-protected precursor undergoes formation of a tricycle via an ene-yne-ene RCM cascade, whereas the other diastereomer undergoes cyclooctene formation via an ene-ene RCM, likely lies in the orientation of the pseudoaxial methyl group on the cyclohexene ring, which in the latter case would unfavorably point toward the reactive center of the Ru-complex, leading to Taxol formation.

Diastereoselective synthesis of trisubstituted olefins using a silicon-tether ring-closing metathesis strategy.

The diastereoselective synthesis of trisubstituted olefins with concomitant C-C bond formation is still a difficult challenge, and olefin metathesis reactions for the formation of such alkenes are usually not high yielding or/and diastereoselective. Herein we report an efficient and diastereoselective synthesis of trisubstituted olefins flanked by an allylic alcohol, by a silicon-tether ring-closing metathesis strategy. Both E- and Z-trisubstituted alkenes were synthesised, depending on the method employed to cleave the silicon tether. Furthermore, this methodology features a novel Peterson olefination for the synthesis of allyldimethylsilanes. These versatile intermediates were also converted into the corresponding allylchlorodimethylsilanes, which are not easily accessible in high yields by other methods.

An alternative approach to the synthesis of the three fragments of anachelin H.

The synthesis of the fully protected peptide, polyketide and alkaloid fragments of anachelin H is presented. The peptide fragment was prepared using a liquid phase peptide synthesis; the polyketide fragment was synthetized using a cross metathesis and an intramolecular oxa-Michael reaction as the key steps to introduce the desired stereochemistry; finally, the alkaloid fragment was obtained by an oxidative cyclization of a catechol derivative using potassium ferricyanide. The synthesis of all fragments was based on the use of natural amino acids as sources of asymmetry. The independent synthesis of the three fragments should allow more efficient biological studies on the fragments instead of the whole natural product. Experiments to illustrate the coupling of fragments and the effectiveness of the convergent strategy are also described.

Ti(II) and Rh(I) Complexes as Reagents toward a Thapsigargin Core.

A novel approach toward the [5-7]fused bicyclic core of thapsigargin, a subnanomolar inhibitor of the endo/sarcoplasmic calcium ATPase (SERCA), is presented. The synthetic route includes an original Ti(II)-mediated hydroxy-directed reductive coupling of an enantiomerically enriched propargylic alcohol and an intramolecular Rh(I)-catalyzed cyclocarbonylation reaction as key steps. Interestingly, through the first experiments of titanocene-mediated reductive cyclization of a 1,8-enyne, a seven-membered cycle was isolated as a unique product with a total diastereoselectivity.

Functionalizable Stereocontrolled Cyclopolyethers by Ring-Closing Metathesis as Natural Polymer Mimics.

Whereas complex stereoregular cyclic architectures are commonplace in biomacromolecules, they remain rare in synthetic polymer chemistry, thus limiting the potential to develop synthetic mimics or advanced materials for biomedical applications. Herein we disclose the formation of a stereocontrolled 1,4-linked six-membered cyclopolyether prepared by ring-closing metathesis (RCM). Ru-mediated RCM, with careful control of the catalyst, concentration, and temperature, selectively affords the six-membered-ring cyclopolymer. Under optimized reaction conditions, no metathetical degradation, macrocycle formation, or cross-linking was observed. Post-polymerization modification by dihydroxylation afforded a novel polymer family encompassing a poly(ethylene glycol) backbone and sugar-like functionalities ("PEGose"). This strategy also paves the way for using RCM as an efficient method to synthesize other stereocontrolled cyclopolymers.

From acyclic to cyclic α-amino vinylphosphonates by using ring-closing metathesis.

Acyclic α-amino vinylphosphonates were alkylated through the Mitsunobu reaction then diolefinic compounds hence formed were subjected to RCM. Studies on the scope and limitations of RCM with these sterically hindered α-amino vinylphosphonates are detailed.

Diastereoselective synthesis of trifluoromethylated 1,3-dioxanes by intramolecular oxa-Michael reaction.

A highly diastereoselective synthesis of trifluoromethylated 1,3-dioxanes is described. The reaction proceeds by an addition/oxa-Michael sequence and works efficiently under mild reaction conditions, with a good substrate scope and acceptable to good yields.

Cascade Metathesis Reactions for the Synthesis of Taxane and Isotaxane Derivatives.

Tricyclic isotaxane and taxane derivatives have been synthesized by a very efficient cascade ring-closing dienyne metathesis (RCDEYM) reaction, which formed the A and B rings in one operation. When the alkyne is present at C13 (with no neighboring gem-dimethyl group), the RCEDYM reaction leads to 14,15-isotaxanes 16 a,b and 18 b with the gem-dimethyl group on the A ring. If the alkyne is at the C11 position (and thus flanked by a gem-dimethyl group), RCEDYM reaction only proceeds in the presence of a trisubstituted olefin at C13, which disfavors the competing diene ring-closing metathesis reaction, to give the tricyclic core of Taxol 44.

Study of Cascade Ring-Closing Metathesis Reactions en Route to an Advanced Intermediate of Taxol.

A highly functionalized intermediate in the synthesis of Taxol has been synthesized, which features the tricyclic core and the required oxygen substituents at C1, C2, C7, C10, and C13. The key step, a ring-closing dienyne metathesis (RCDEYM) reaction, has been thoroughly optimized to favor the tricyclic product over the undesired bicyclic product resulting from diene metathesis.

Synthesis of PEG-Polycycloether Block Copolymers: Poloxamer Mimics Containing a Rigid Helical Block.

Poloxamers are amphiphilic block copolymers consisting of poly(ethylene glycol) (PEG) and poly(propylene glycol) segments. Their self-assembly and interfacial properties are tied to the relative hydrophilicity and hydrophobicity of each block and can therefore be adjusted by changing block lengths. Here, a series of PEG-polycycloether block copolymers is synthesized that have the same structure as a poloxamer, but they encompass a rigid polycyclic backbone as the hydrophobic block. A variety of polymer structures are synthesized, for example diblock or triblock architectures, with/without olefinic units, atactic or isotactic backbone, and different block lengths. Due to their amphiphilicity, self-assembly into spherical aggregates (diameters ranging from 64 to 132 nm) at low concentrations (critical aggregation concentration as low as 0.04 mg mL-1) is observed in water. Low surface tensions (as low as 26.7 mN m-1) are observed as well as the formation of stable high internal phase emulsions (HIPEs) irrespective of the oil/water ratio. This contrasts with the properties of the commonly used poloxamers P188 or P407 and illustrates the significance of the rigid polycycloether block. These new colloidal properties offer new prospects for applications in emulsion formulations for biomedicine, cosmetics, and the food industry.

PEGose Block Poly(lactic acid) Nanoparticles for Cargo Delivery.

Hydrophilic polymers have found ubiquitous use in drug delivery and novel polymer materials to advance drug delivery systems are highly sought after. Herein, an amylose mimic (PEGose) was combined with poly(lactic acid) (PLA) in an amphiphilic block copolymer to form PEG-free nanoparticles as an alternative to PEG-based nanomedicines. The block copolymer self-assembled into 150-200 nm particles with a narrow dispersity in aqueous environment. The formed nanoparticles were capable of encapsulation, the sustained release of both hydrophilic and hydrophobic dyes. Moreover, the nanoparticles were found to be remarkably stable and had a very low cytotoxicity and a high propensity to penetrate cells. These results highlight the potential of PEGose-b-PLA to be used in drug delivery with a new hydrophilic building block.

Highly demanding cross-metathesis in the synthesis of the C16-C30 fragment of dolabelide C.

A highly demanding cross-metathesis (CM) reaction for the formation of the C24-C25 trisubstituted olefin of dolabelide C has been optimized. A difference in reactivity between the E and Z enone isomers in this reaction was uncovered, and the selection of the Z isomer of the starting enone was critical for the success of the cross-metathesis. Application to the synthesis of the C16-C30 fragment of dolabelide C is reported.

Synthesis of modified methyl furanosides by intramolecular oxa-Michael reaction followed by Pummerer rearrangement.

A new method is described for the synthesis of ribofuranoses modified at the C3 and C5 positions. The key step is an intramolecular oxa-Michael reaction on a vinyl sulfoxide to install the C2 hydroxy group. The methyl furanosides are obtained by Pummerer rearrangement of the sulfoxide into the corresponding aldehyde, acidic deprotection of the benzylidene acetal, and cyclization.

Olefin Cross Metathesis as a Versatile Method for the Facile Functionalization of Porous Polymers.

Olefin cross metathesis has been employed for the first time for the postpolymerization chemical modification of porous polymers. High quality microspheres of poly(divinylbenzene) were synthesized by the precipitation polymerization of divinylbenzene-55 in porogenic solvents, and the olefin cross metathesis reactions of the pendent (polymer-bound) vinyl groups not consumed by polymerization were performed with diverse coupling partners in dichloromethane using the Grubbs 2 catalyst, leading to microspheres decorated with a wide range of functional groups.

Synthesis of functionalized Morita-Baylis-Hillman adducts by a conjugate addition-elimination sequence.

We have developed a new conjugate addition-elimination sequence for the diastereoselective synthesis of protected allylic syn 1,3-diols which are Morita-Baylis-Hillman adducts. The synthesis of the substrates involves a challenging cross-metathesis reaction that leads to hindered trisubstituted olefins.

Novel Synthesis of Trisubstituted Olefins for the Preparation of the C16-C30 Fragment of Dolabelide C.

A silicon-tether ring-closing metathesis strategy is reported for the synthesis of trisubstituted olefins flanked by allylic or homoallylic alcohols, which are difficult to obtain by classical ring-closing or cross-metathesis reactions. In addition, a novel Peterson olefination reaction has been developed for the preparation of the allyldimethylsilane precursors, which are versatile synthetic intermediates. This method was then applied to the synthesis of the C16-C30 fragment of dolabelide C.

Dramatic solvent effect on the diastereoselectivity of Michael addition: study toward the synthesis of the ABC ring system of hexacyclinic acid.

During our studies toward the synthesis of the ABC ring system of hexacyclinic acid, we have observed a dramatic influence of the solvent on both our key steps. The diastereoselectivity of the intermolecular Michael addition could be totally reversed by changing the polarity of the solvent, and trifluoroethanol was found to be the optimal solvent for the following Mn(III)-promoted radical cyclization.

Tailoring Polyethers for Post-polymerization Functionalization by Cross Metathesis.

Olefin cross metathesis is reported for the first time to attach small molecules to a range of novel polyethers with a poly(ethylene glycol) backbone and pendent alkene groups, allowing for a loading of up to one compound per monomer unit. These polymers are tailored to prevent the occurrence of self metathesis (reaction of the polymer with itself) by varying the substitution on the pendent alkenes, thus steering their reactivity toward olefin cross metathesis. Efficient functionalization has been observed for a range of coupling partners as a proof of concept for the use of olefin metathesis to graft small and larger molecules to polyethers for drug delivery. This approach also paves the way for the use of olefin cross metathesis as an efficient method to functionalize a wide variety of polymers with pendent olefin groups.

Diastereoselective Synthesis of an Advanced Intermediate of Thapsigargin and Other 6,12-Guaianolides Using a RCEYM Strategy.

A new and flexible approach toward the synthesis of 6,12-guaianolide anticancer drugs such as trilobolides or thapsigargin has been developed that could be applied to the preparation of analogues with a modified ring system. The synthesis starts from commercial 2-methylcyclopentane-1,3-dione, only relying on diastereoselective reactions for the construction of the stereogenic centers at C1, C3, C6, and C10 and features a high-yielding ring-closing enyne metathesis (RCEYM) step for the formation of the [5,7] bicyclic core.

Tandem conjugate addition-elimination for the diastereoselective synthesis of 4E-alkenyl syn-1,3-diols.

We have developed a tandem conjugate addition-elimination sequence for the diastereoselective synthesis of protected allylic syn-1,3-diols, starting from vinyl sulfones. The sulfonyl group was then reduced with sodium amalgam to furnish the E-olefin as the major isomer. This method was applied to the synthesis of a trisubstituted alkene modeling the C21-C25 fragment of Dolabelide C.