Preparation of some angularly substituted and highly functionalized quinolizidines as building blocks for the synthesis of various alkaloids and related scaffolds of medicinal interest

The epimeric forms of the angularly substituted quinolizidine 6, representing potentially useful building blocks for the synthesis of various alkaloids, have been prepared via a pathway involving two consecutive ring-closing metathesis reactions. Variously hydroxy-protected derivatives (21, 22, and 26-29) of these compounds have also been generated.     

A convergent total synthesis of a new antiepileptic ceramide and its triacetyl derivative using olefin cross metathesis

A convergent total synthesis of a new antiepileptic ceramide 1b and its triacetyl derivative 1b′ was completed by using two important C-C bond forming reactions, Wittig methylenation and olefin cross metathesis as the key steps. The easily available 3,4,6-tri-O-benzyl-d-galactal was used as a chiral pool for the synthesis of highly functionalized amide 3 and the commercially available 1,12-dodecanediol for the long chain olefin counterpart 4. The long hydrocarbon chain of the new ceramide 1b was installed by using olefin cross metathesis between amide 3 and long chain terminal olefin 4 followed by hydrogenation.     

A highly efficient olefin metathesis initiator: improved synthesis and reactivity studies

The synthesis of ligand 8, required for the preparation of catalyst 4c has been optimised. Ligand exchange studies indicate that biphenyl-based alkylidene 4c initiates considerably faster than its unsubstituted analogue 4a. The performance of 4c in ring-opening cross metathesis reactions involving substrates containing unprotected chelating atoms is also reported.     

Formal total synthesis of (−)-spongidepsin

The formal total synthesis of (−)-spongidepsin is described. Three fragments I, II, and III were first prepared from readily available starting materials and then assembled to the target compound. The key steps involved in the synthesis are asymmetric α-hydroxylation, Ender's alkylation, and ring-closing metathesis reactions. An alternative route for the fragment II is also achieved involving Sharpless asymmetric epoxidation and Gilman's alkylation as key reactions.     

Understanding the effect of allylic methyls in olefin cross-metathesis

A series of NMR spectroscopy experiments have been conducted with both the model compound, 3-methyl-1-pentene and the corresponding ADMET monomer 3,6,9-trimethylundeca-1,10-diene (11) to better understand the effect of allylic methyls during olefin metathesis chemistry. Traditional ADMET catalysts such as Schrock’s molybdenum (1), and Grubbs’ ruthenium 1st and 2nd generation (2 and 3) were examined under cross-metathesis and ADMET conditions. Regardless of catalyst selection, 50% or less metathesis conversion was observed for all reactions, especially in the case of the more sterically encumbered diene. With Schrock’s molybdenum catalyst 1, the reaction leads to an accumulation of the non-productive metallacyclobutane, trapping the catalyst in an inactive form. With Grubbs’ ruthenium catalysts 2 and 3, the substrate coordinates to the metal center primarily to yield non-productive metathesis, which results in a build-up of the methylidene complex leading to catalyst decomposition. These results are directly correlated to the orientation of the substrate’s bulk during the metallacyclobutane formation, the alkyl branch being adjacent to the metal center in the case of the molybdenum catalyst 1, and opposite to it in the case of ruthenium catalyst 2 and 3.     

A complete asymmetric synthesis of polyhydroxypiperidines

A new general methodology for the asymmetric synthesis of polyhydroxypiperidines is described. The readily available achiral olefin 4 was transformed to 5-des(hydroxymethyl)-1-deoxynojirimycin (1) and its mannose analog 10 via regioselective aminohydroxylation (AA), ring-closing metathesis (RCM), and diastereoselective dihydroxylation reactions. Thus, the developed methodology made it possible to install all stereocenters in 1 and 10 in a highly stereocontrolled fashion.     

Latent ruthenium olefin metathesis catalysts featuring a phosphine or an N-heterocyclic carbene ligand

The synthesis and characterization of latent 18-electron ruthenium benzylidene complexes (PCy₃)((^κN,O)-picolinate)₂RuCHPh (5) and (H₂IMes)((^κN,O)-picolinate)₂RuCHPh (6) are described. Both complexes appear as two isomers. The ratio between the isomers is dependent on l-type ligand. The complexes are inactive in ring-closing metathesis and ring-opening metathesis polymerization reactions even at elevated temperatures in the absence of stimuli. Upon addition of HCl, complexes 5 and 6 become highly active in olefin metathesis reactions. The advantage of the latent catalysts is demonstrated in the ring-opening metathesis polymerization of dicyclopentadiene, where the latency of 6 assures adequate mixing of catalyst and monomer before initiation. Trapping experiments suggests that the acid converts the 18-electron complexes into their corresponding highly olefin metathesis active 14-electron benzylidenes.     

Domino intramolecular enyne metathesis/cross metathesis approach to the xanthanolides. Enantioselective synthesis of (+)-8-epi-xanthatin

The first total synthesis of (+)-8-epi-xanthatin (1) has been achieved in 14 steps starting from the commercially available ester 24, which was converted into aldehyde 23 in six steps. An enantioselective aldol reaction of 23 gave 30, which was transformed into triflate 22 in four steps, setting the stage for a palladium-catalyzed carbonylation reaction to form acrylate 34. Compound 34 was then subjected to a deprotection/lactonization sequence to furnish enyne 21, which underwent a domino enyne ring-closing metathesis/cross metathesis process to form a seven-membered carbocycle and (E)-conjugated dienone, thereby completing the synthesis of 1. This domino ruthenium-catalyzed metathesis reaction thus serves as an efficient method to construct the core of xanthanolide and other sesquiterpene lactones.     

Bis- and tetracalix[4]arenes in the partial cone conformation: synthesis, structure and RCM reactions

The synthesis, structure and ring-closing metathesis (RCM) reactions of polyether bridged biscalix[4]arenes 6 in the partial cone conformation with upper rim allyl substituents are reported. The RCM reaction modes depend on the length of polyether chain. Diethylene glycolic chain produced the dimer 7a and linear oligomer 7a′ with multi-cavities, whereas triethylene and tetraethylene glycolic chains allowed direct cyclization through intramolecular head-to-tail pattern to yield novel bridged biscalix[4]arenes 7b-c.     

Conversion of chiral unsaturated cyanohydrins into chiral carba- and heterocycles via ring-closing metathesis

Aliphatic unsaturated cyanohydrins 1-3 served as starting materials in the synthesis of a set of new chiral unsaturated cyclic 1,2-ethanolamines. Combining a Grignard addition-NaBH₄ reduction sequence with a ring-closing metathesis afforded unsaturated cyclic 1,2-ethanolamines 7-11 and 22-25 in good yields and high ee (96-99%). The conversion of cyanohydrins 1-3 via a DIBAL reduction-transimination-NaBH₄ reduction sequence, using allylamine, followed by ring-closing metathesis yielded tetrahydropyridines 28, tetrahydroazepinols 33 and tetrahydroazocinols 34 in high yields and excellent ee (97-99%).     

Ene-yne-ene and ene-yne-yne metathesis of norbornene derivatives

Norbornene derivatives 4 and 5 containing sidechains bearing an internal alkyne and either a terminal alkene or a terminal alkyne were found to undergo a cascade of metathesis reactions when treated with ruthenium based metathesis catalysts to form highly functionalised pentacyclic products. The reactions illustrate an interesting difference in reactivity between Grubbs’ catalyst and the second generation catalyst, with the former being more reactive for the early steps of the cascade.     

Novel synthesis and functionalization of ortho-ortho disubstituted biphenyls and a highly condensed novel heterocycle using radical cyclization reaction

This paper describes a novel synthetic route for the preparation of ortho-ortho disubstituted biphenyls and compounds possessing highly condensed ring system represented by structures X and Y, respectively. Several approaches, such as intermolecular Grubb's olefin metathesis, Heck and, Suzuki reactions were incorporated to functionalize the core structures of X and Y making it suitable for the preparation of a library of compounds.     

A general asymmetric route for the synthesis of the alexine and australine family of pyrrolizidine alkaloids. The first asymmetric synthesis of 1,2-diepi-alexine and 1,2,7-triepi-australine

The first asymmetric synthesis of 1,2-diepi-alexine and 1,2,7-triepi-australine (both are unknown at present) is described, which utilized the regioselective asymmetric aminohydroxylation (RAA) reaction of the achiral olefin VI, the cross metathesis (CM) reaction of the terminal olefin 8, and the formation and subsequent intramolecular double cyclization (DC) reactions of the epoxides 10 and 11. The C1 stereocenter was diastereoselectively introduced by the reaction of the aldehyde 7 with vinylmagnesium bromide.     

Oxazine formation by MsCl/Et3N as a convenient tool for the stereochemical interconversion of the hydroxyl group in N-acetyl 1,3-aminoalcohols. Asymmetric synthesis of N-acetyl l-xylo- and l-arabino-phytosphingosines

Use of MsCl/Et₃N was proven to provide a convenient synthetic tool for the stereochemical intercoversion of the hydroxyl group in N-acetyl 1,3-aminoalcohols. Thus, under these conditions, the alcohols 4 and 6 smoothly converted to the oxazines 5 and 7, respectively, which were hydrolyzed to generate the corresponding inverted alcohols 6 and 4 in one pot. Further elaboration of 4 and 6 led to the efficient asymmetric synthesis of N-acetyl l-xylo- and l-arabino-phytosphingosines (11 and 15), respectively, via olefin cross metathesis reactions.     

Enantioselective synthesis of (+)-anatoxin-a via enyne metathesis

A concise synthesis of the potent nAChR agonist (+)-anatoxin-a (1) has been completed by a series of nine chemical operations and in 27% overall yield from commercially available d-methyl pyroglutamate (12). The strategy featured the application of a new protocol for the diastereoselective synthesis of cis-2,5-disubstituted pyrrolidines bearing unsaturated side chains and an intramolecular enyne metathesis to provide the bridged bicyclic framework of 1. Thus, d-methyl pyroglutamate (12) was converted in five steps to 32, which underwent facile enyne metathesis to deliver the bicyclic diene 33. Selective oxidative cleavage of the less substituted carbon-carbon double bond in 33 followed by deprotection furnished (+)-anatoxin-a (1).     

A furan route to the asymmetric synthesis of trans-fused polyether building blocks

A novel route towards chiral trans-fused polyether lactones 7 and 12 has been developed starting with commercially available furfural. Sharpless kinetic resolution and ring-closing metathesis reactions served as key steps in the strategy.     

Ring opening metathesis polymerisations of norbornene and norbornadiene derivatives containing oxygen: a study on the regeneration of Grubbs catalyst

Ring opening metathesis polymerisation (ROMP) of norbornene and norbornadiene derivatives containing oxygen are investigated using Grubbs well-defined ruthenium initiator. A series of 7-alkoxy norbornadiene monomers (2b-d), containing alkoxy groups with decreasing steric hindrance in the 7-position have been prepared. The ROMP reactions of monomers showed that as the reaction proceeds the initiator is consumed first and then is partially regenerated at the expense of the propagating species. A small amount of another carbene species X, giving a broad signal at 17.44 ppm, is also formed which is extremely stable in solution. The species X is an active metathesis species and is able to perform ROMP on strained cyclic olefins. ROMP of monomers without alkoxy groups in the 7-position (3, 4a, 4b, 5a and 5b) and also monomers with alkoxy groups in the 5 and/or 6 positions of norbornene (6 and 7) have been performed under similar conditions. None of these systems exhibited regeneration of the initiator and no resonances due to species X can be seen in the ¹H NMR spectra. The results confirm that the presence of oxygen in the 7-position of the norbornadiene monomer plays an important role in the process of regeneration of the initiator. It is found that the steric bulk and the position of substituents of the monomer have a pronounced influence on the extent of regeneration of the initiator.     

Synthesis of vinylcyclopropanes by allylation/ring-closing metathesis/Claisen rearrangement

A facile double allylation/ring-closing metathesis/Claisen rearrangement route for preparing vinylcyclopropanes 6 is developed. The efficient synthesis includes O-allylation of α-allyl-α-sulfonylketones 8 with allylic bromides, ring-closing metathesis of diallyl compounds 9 and sequential Claisen rearrangement of the resulting oxepines.     

Synthesis of extended spacer-linked neooligodeoxysaccharides by metathesis olefination and evaluation of their RNA-binding properties

The preparation of linear 1,4-butanediol-linked oligodeoxysugars 50-53, 58 and 60 is described which are potential binders to polynucleotides. Various aminodeoxymonosaccharides 9, 13-18, 30, 31 and 40-42 which are either allylated at the anomeric center or at C4 were subjected to the metathesis olefination protocol. Depending on the position of allylation E/Z-mixtures of C₂-symmetric head-to-head or tail-to-tail homodimers were formed. Among them, saccharides 13, 30, 31 and 40 were transformed into the corresponding 1,4-butanediol linked disaccharides 50-53 by catalytic hydrogenation of the central olefinic double bond and exhaustive deprotection. In order to target extended spacer-linked neooligosaccharides homodimeric aminoglycoside 37 was bisallylated and subjected to cross metathesis conditions using methyl 4-O-allyl daunosamide 40 as reaction partner which yielded two desired trimeric and tetrameric linearly spacer-linked daunosamine derivatives. After hydrogenation and deprotection two additional probes 58 and 60 for nucleic acid binding studies were at hand.     

Integrating chemosensors for amine-containing compounds into cross-linked dendritic hosts

Trifluoroacetylazo dye 1, a known chemosensor for amines, has been integrated into cross-linked dendrimer hosts. Thus, boronic acid 16 was linked to iododye 9 via a Suzuki coupling reaction. In situ deprotection and alkylation with dendrons 3 and 4, containing 8 homoallyl or allyl ether groups, respectively, afforded dendrons 18 and 19 with chemosensor units at their focal point. Conversion of 18 (19) to the bis-imine of butane 1,4-diamine, extensive cross-linking via the ring closing metathesis reaction with Grubbs catalyst 25, and hydrolysis produced dendrimer hosts 28 and 29. Host-guest studies with a small library of amines and alcohols showed 28 and 29 to selectively signal certain diamines but not due to template mediated imprinting.