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.     

Studies directed towards the stereoselective total synthesis of ilexlactone via a tandem ring-closing enyne metathesis protocol

Studies directed towards the stereoselective total synthesis of ilexlactone resulted in the synthesis of bicyclic systems 1a, 1b and ent-1a through tandem ring-closing enyne metathesis using Grubbs’ catalyst. The structures of synthetic 1a, 1b and ent-1a revealed that the proposed structure for ilexlactone is incorrect.     

Studies towards the synthesis of neopeltolide: synthesis of a ring-closing metathesis macrocyclization precursor

An advanced ring-closing metathesis precursor for the synthesis of the marine macrolide neopeltolide is prepared in a stereocontrolled manner by the coupling of the C2-C10 and C11-C16 subunits. The metathesis reaction of 4 with Grubbs’ II or Nolan’s indenylidene catalyst led to the unexpected formation of cycloheptene 18.     

Studies toward the total synthesis of di- and sesterterpenes with a dicyclopenta[a,d]cyclooctane skeleton. Construction of a versatile A/B ring building block via a ring-closing metathesis reaction and carbocationic rearrangement

The cyclopentacyclooctane derivative 1, chosen as the key building block in a synthesis of terpenoid ophiobolates and fusicoccins, has been prepared from 2-methylcyclo-pent-2-en-1-one 5. Cyclization of the intermediate 1,9-diene of l,u configuration 10 under metathesis conditions (Grubbs’ catalyst 15) afforded the eight-membered ring product 13, whereas cyclization of the l,l diastereomer 9 produced a seven-membered ring analog 12. Cationic rearrangement of epoxide 26 occurred with methyl group migration to give ketone 27 as the major product.     

Ring-opening metathesis polymerization with [2+2]-crosslinking to create new materials

There are almost no examples of Grubbs’-type ring-opening metathesis polymers that have been [2+2]-crosslinked. Two new monomers, 6 and 10, were used to construct two novel linear soluble polymers 7 and 11, bearing photochemically labile moieties for [2+2]-cycloaddition reactions. These soft polymers were photocrosslinked into very hard polymers, 8 and 12. Potential advantages of these new bioinspired materials include: (1) ready processing into flat, round, and cylindrical shapes; (2) reasonably low toxicity due to trace amounts of catalyst needed; and (3) rapid rate of polymerization and crosslinking that avoids acids and bases.     

Cross-metathesis reaction of vinyl sulfones and sulfoxides

Cross-metathesis reactions of α,β-unsaturated sulfones and sulfoxides in the presence of molybdenum and ruthenium pre-catalysts were tested. A selective metahesis reaction was achieved between functionalized terminal olefins and vinyl sulfones by using the ‘second generation’ ruthenium catalysts 1c-h while the highly active Schrock catalyst 1b was found to be functional group incompatible with vinyl sulfones. The cross-metathesis products were isolated in good yields with an excellent (E)-selectivity. Both the molybdenum and ruthenium-based complexes were, however, incompatible with α,β- and β,γ-unsaturated sulfoxides.     

Synthesis of ‘inside-outside’ medium-sized rings via ring-closing metathesis

Functionalized and unfunctionalized dienes were synthesized from lactones 7 and 6, respectively, which were subjected to ring-closing metathesis (RCM) using Grubbs’ catalysts. These dienes provide a systematic study of the stereochemical requirements for efficient cyclization. Moreover, it has been established that, within a uniquely defined oxabicyclo[3.3.0]octane template, medium sized rings bearing an ‘in-out’ intrabridgehead stereochemical relationship can been synthesized in good yield.     

A new stable Hoveyda-Grubbs catalyst with mixed anionic ligands

The synthesis and characterisation of a new highly active Hoveyda-Grubbs 2nd generation type catalyst is described. Substitution of one chloride ligand with a partially fluorinated trialkoxysilyl substituted carboxylate leads to the stable monocarboxylate ruthenium catalyst (3). This catalyst represents the first example of a stable and isolable mono-chloride exchanged carboxylate complex suitable for both homogeneous and heterogeneous metathesis. The reactivity of the new catalyst was tested in representative metathesis reactions and offers an activity comparable to the parent dichloride system (1).     

Mechanism of olefin hydrosilylation catalyzed by [RuCl(NCCH3)5]: A DFT study

The hydrosilylation reaction between methyldimethoxysilane and methylvinyldimethoxysilane, catalyzed by the cationic species chloropenta(acetonitrile)ruthenium(II)⁺ (C1), was investigated with density functional theory (DFT). The Chalk-Harrod, Glaser-Tilley and σ-bond metathesis mechanisms were considered as mechanistic possibilities for the reaction and enthalpy profiles of each pathway were computed for the active form of C1. In contrast to the commonly accepted Chalk-Harrod mechanism of hydrosilylation, the computational results indicate that a σ-bond metathesis mechanism, involving the formation of a hydride analogue of C1, is most favored. The B3LYP calculated activation enthalpy for this pathway (ΔH_act = 13.1 kcal/mol) is consistent with the experimental observation that C1 is a reasonable catalyst for this reaction under the applied experimental conditions.     

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.     

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.     

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.     

Efficient synthesis of 16-28 membered macrocyclic crown amides via ring closing metathesis

Ring closing metathesis of suitable diamides containing 1,ω-dienes led to efficient synthetic approaches towards macrocylic polyoxadiamides 1-18 with 16-28 membered ring sizes in good to excellent yields using Grubbs' catalyst.     

Hydroacylation of 2-butyne from the alcohol or aldehyde oxidation level via ruthenium catalyzed C-C bond forming transfer hydrogenation

Under the conditions of ruthenium catalyzed transfer hydrogenation, 2-butyne couples to alcohols 1a-1j to deliver α,β-unsaturated ketones 3a-3j in good to excellent isolated yields with complete E-stereoselectivity. Under identical conditions, aldehydes 2a-2j couple to 2-butyne to provide an identical set of α,β-unsaturated ketones 3a-3j in good to excellent isolated yields with complete E-stereoselectivity. Nonsymmetric alkyne 4a couples to alcohol 1d or aldehyde 2d in good yield to deliver enone 3k as a 5:1 mixture of regioisomers. Thus, intermolecular alkyne hydroacylation is achieved from the alcohol or aldehyde oxidation level. In earlier studies employing the same ruthenium catalyst under slightly different conditions, alkynes were coupled to carbonyl partners from the alcohol or aldehyde oxidation level to furnish allylic alcohols. Therefore, under the conditions of C-C bond forming transfer hydrogenation, all oxidation levels of substrate (alcohol or aldehyde) and product (allylic alcohol or α,β-unsaturated ketone) are accessible.     

Efficient synthesis of various acycloalkenyl derivatives of pyrimidine using cross-metathesis and Pd(0) methodologies

Novel acyclonucleosides (9a-d, 10a-d, 18a,b and 19a,b) have been prepared using Pd(0) and cross-metathesis methodologies. The allylic N-alkylation under Tsuji-Trost conditions was used to introduce the nucleobase, while the Suzuki-Miyaura reaction afforded C-5 substituted uracil analogues. The cross-metathesis performed with a ruthenium catalyst was used to provide new acycloalkenyl nucleosides. The antiviral activities of all final compounds have been evaluated.     

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.     

Grubbs and Hoveyda-type ruthenium complexes bearing a cyclic bent-allene

Stable cyclic bent-allene 1 displaces the chelating ether linkage of the Hoveyda-Grubbs-type ruthenium complex 2 bearing triphenylphosphine. The resulting complex 3 features an unusual cis-arrangement of the phosphine and the cyclic bent-allene, while retaining a distorted square pyramidal geometry around the ruthenium center. Monitoring by ³¹P NMR spectroscopy the reaction of cyclic bent-allene 1 with the indenylidene bis(triphenylphosphine)ruthenium dichloride complex 4 allowed for the observation of dissociated triphenylphosphine, and the formation of a ruthenium complex featuring 1 and triphenylphosphine in the desired trans-configuration. However, continued reaction times saw the disappearance of this complex, and after workup complex 5 featuring a cis-arrangement was isolated.     

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.     

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%).     

A concise synthesis of Hagen’s gland lactones

A short synthesis of Hagen’s gland lactones 1 and 2 from commercially available pentanal and heptanal, respectively, is outlined. The approach relies on sequential ring closing metathesis and intramolecular oxy-Michael addition as the key transformations.