Metathesis Catalysed by the Platinum Group Metals
Metathesis Catalysed by the Platinum Group Metals
A New Strategy for the Synthesis of Organic Compounds and Polymers Part II: Applications of Platinum Metals Metathesis Catalysts in Ring-Closing Reactions
In the first part of this review, published in the April issue of this Journal, the main catalyst systems used for metathesis catalysis were examined, and followed by a short report on metathesis activity and selectivity. In this second part, attention is now drawn to specific applications of platinum group metals metathesis catalysts, in particular, to a variety of ring-closing metathesis reactions. The last part of this review will be published in the October issue of this Journal.
The rapid development of platinum group metals metathesis catalysts, tolerant of functional groups and aqueous media, has enabled a range of applications in organic and polymer chemistry to emerge. A selection of these will now be reviewed.
Ring-closing metathesis (RCM), has been shown to be a powerful tool for the synthesis of cyclic compounds in organic chemistry (7). The reaction can be applied in two variations, one to functionalised dienes forming carbocyclic compounds (38) and the other to heteroatomcontaining dienes leading to heterocyclic compounds (1(d), 24, 39, 40). While the former process is also promoted by some classical (1(a), 1(b)) and well-defined carbene initiators (4(a), 4(b), 41), the latter can be induced only by catalysts that are tolerant of functional groups (24).
In addition to the general class of molybdenum initiators of the Schrock type (4(a), 4(b), 41), the ruthenium carbene initiators, disclosed by Grubbs, are efficient catalysts, particularly for RCM of dienes which contain functional groups. Thus, oxygen- (42), nitrogen- (43) or even phosphorus-containing (44) heterocycles can be easily prepared from the corresponding heteroatom-containing dienes using a ruthenium carbene, 2, RuCl2(=CHCH=CPh2)(PCy3)2, (Cy = cyclohexyl), as the catalyst, Equation (xi).
Synthesis of Carbocycles
The ruthenium carbene initiator, 2, RuCl2(=CHCH=CPh2)(PCy3)2 was found to be extremely efficient for the synthesis of cycloalkenes bearing functional groups such as carboxylic acids, alcohols and aldehydes (38) which readily destroy the classical or well-defined tungsten and molybdenum initiators, see Equation (xii), (4(a), 4(b), 41). The yields are substantial and such compounds can be easily handled and separated from the reaction mixture.
A new strategy for the diastereoselective synthesis of bicyclic derivatives such as substituted decalins makes use of readily available acyclic tetraenes, C, which can ring-close using the transition metal catalysed olefin metathesis approach, see Equation (xiii), (45).
The resulting decalins, D, are symmetrical, affording the opportunity to perform enantio-selective desymmetrisation reactions to yield non-racemic compounds. Enantioselective sigmatropic rearrangements can lead to bicyclic structures of type E, reminiscent of the decalin moiety of a number of reductase inhibitors used to lower cholesterol levels.
Synthesis of Heterocycles
A large number of heterocycles containing endocyclic oxygen, nitrogen, phosphorus and other heteroatoms can now be prepared by using the widely tolerant ruthenium carbene initiators (42–44). A first set of such heterocycles comprises the synthesis of five-, six- and seven-membered oxygen-containing rings, and uses a ruthenium vinylidene complex 2 as a catalyst, see Equations (xiv) to (xvi), (42).
Nitrogen-containing heterocycles have become readily available in high yield by RCM of amino dienes (43). Remarkably, the ruthenium vinylalkylidene complex 2 tolerates common protecting groups, for example, trifluoroacetyl, tert -butoxycarbonyl (Boc) and benzyl, see Equations (xviii) and (xix).
A large variety of nitrogen-containing compounds (heterocycles, carbocycles, alkaloids and peptidomimetics) obtained by RCM have recently been reviewed (46). The preparation of enantiomeric cyclic compounds, see Figure 1, through RCM by using either benzylidene or vinylidene ruthenium complexes, of basic structures 1 and 2 has recently been reported (47). It is worth mentioning the substantial enantiomeric yield which is obtained – much higher than given by the conventional methods which synthesise such compounds.
RCM of vinyl- and allylphosphonamides using the ruthenium carbene initiator, RuCl2(=CHPh)-(PCy3)2, 1, is an interesting method of synthesis for five- or six-membered P-heterocycles, starting from vinyl- or allylphosphonamides (n = 0 or 1), see Equation (xxii), (45).
Using this same technique, when the reaction is applied to diallyl vinylphosphonates, heterocycles having both oxygen and phosphorus in the ring can be obtained, see Equations (xxiii) and (xxiv), (45).
Synthesis of Metallacycles
The cyclisation of divinyl derivatives containing two or three silicon atoms linked by hydrocarbon bridges, in the presence of ruthenium catalysts, leads to the formation of six- and seven-membered unsaturated heterocycles, as can be seen from Equations (xxv) and (xxvi), (48).
Synthesis of Crown Ethers
A large number of compounds such as crown ethers which are important for a variety of applications have become available in high yield through the RCM of unsaturated polyethers, due to the tolerance of benzylidene ruthenium carbene complexes toward oxygen functionalities (49, 50). One interesting example is the synthesis of the unsaturated trans -isomer of a 17-membered crown ether in 90 per cent yield, from the corresponding polyether diene under the influence of benzylidene ruthenium complex, 1, see Equation (xxvii).
In the same way, the synthesis of 17-, 20- and 26-membered dibenzo crown ethers has been carried out in good yield, using the above benzylidene ruthenium complex, 1, even at moderate substrate concentrations (0.35 M) at room temperature, see Equation (xxviii), (49).
Synthesis of Polycyclic Polymers
By using the ruthenium carbene complex, RuCl2(=CH2)(PCy3)2, it has become possible to perform the highly selective and quantitative cyclisation of neighbouring vinyl groups in 1,2-polydienes, see Equation (xxix), (51).
Thus, 1,2-polybutadiene underwent cyclisation of the vinyl side-groups in the presence of the ruthenium complex with > 97 per cent yield, leading selectively to poly(cyclopentenylenemethylene). Hydrogenation of this product yielded a saturated polymer with NMR spectra identical to those of atactic poly(cyclopentylenemethylene).
Synthesis of Natural Compounds
A method for the synthesis of (R)-(+)-lasiodiplodin, a natural compound that can be isolated from a culture broth of the fungus Botryodiplodia theobromae, which displays plant growth regulation properties, has been developed by efficiently employing RCM (90 per cent yield). The ruthenium vinylidene complex 2 induces the reaction, and produces compound F as an intermediate step, see Equation (xxx), (52).
The formation of the 12-membered ring in the RCM reaction was nearly quantitative. The chiral centre bearing the methyl group was derived from that in the starting compound (S )-propene oxide.
(-)-Stemoamide, a polycyclic alkaloid with powerful insecticide properties, which can be isolated from the roots and rhizomes of stemonaceous plants, has been synthesised using the convenient RCM process, see Equation (xxxi), (53).
The formation of the 7-membered ring was accomplished by RCM of an enyne moiety in the substrate under the influence of the ruthenium benzylidene complex RuCl2(=CHPh)(PCy3)2. A third ring was subsequently formed by bromolactonisation in the final stage of the reaction.
Several procedures using a RCM reaction as an intermediate step have been reported for synthesising Epothilone A, a natural compound with great importance for cancer therapy (54). According to one of these procedures, the ruthenium benzylidene complex RuCl2(=CHPh)(PR3)2 has been effidently employed to give the required cis isomer in 50 per cent yield, see Equation (xxxii), (54a)
Nicolaou and coworkers have synthesised a library of epothilone analogs using a solid-phase RCM-cleavage approach (55).
Other Polycyclic Polyethers
Ciguatoxin-3C (56(a)) and hemibrevetoxin-B (56(b)) were obtained with the same ruthenium benzylidene catalyst as in the two previous reactions. Three RCMs were involved in the synthesis of the second polyether.
Synthesis of Sub-units of Biologically Active Compounds
α-Amino Acid Esters
The stereoselective synthesis of α-amino acids having the a-carbon atom incorporated in a five-, six- or seven-membered ring has been effected using the ruthenium benzylidene complex RuCl2(=CHPh)(PR3)2 as a RCM catalyst, see Equation (xxxiii), (57(a)). TFA is trifluoroacetic acid.
When m = n = 1, a better yield of final product is obtained by first hydrolysing the diene derivative of the pyrazine and then carrying out the RCM reaction. When m is different from n, the resulted amino acid ester is chiral.
Supramolecular Peptide Assemblies
Blackwell and Grubbs used RCM for preparing helical polypeptides (57(b)). Clark and Ghadiri linked, by a double intramolecular RCM, two cyclic octapeptides that were held parallel on top of each other by eight intermolecular hydrogen bonds (57(c)).
The synthesis of azasugars (polyhydroxylated pyrrolidines) has been effected starting from vinyl glycine methyl ester and using RCM in a subsequent step (58). Both ruthenium alkylidene catalysts have been efficient in forming the fivemembered ring, Equations (xxxiv) and (xxxv).
These compounds have potential biological and pharmaceutical activities, based on the inhibition of glycosidases which play an important role in metabolism. Their applications include diabetes, cancer and viral diseases.
The RCM reaction has been successfully applied to produce a variety of new compounds with the β-lactam structure, see Equation (xxxvi), (59). Such compounds are essential sub-units in some drugs, such as penicillin G, and may have important antibiotic properties.
Substituted chromene units are found – within a multitude of medicinally important compounds. The synthesis of a wide range of substituted chromenes has been effected from substituted dienes using ruthenium carbene initiators in the RCM step, Equation (xxxvii), (60).
Thus, with dienes containing only R1 substituents, cyclisation was nearly quantitative using only 2 mol % of the ruthenium complex RuCl2(=CHPh)(PCy3)2 in methylene chloride for two hours at room temperature. Chromenes having NO2, Et2N, Br or MeO groups in the aromatic ring could be prepared efficiently by this method. On the other hand, 2-substituted chromenes have been obtained using the ruthenium vinylidene complex RuCl2(PCy3)2(=CHCH=CPh2) as a ring-closing catalyst, Equation (xxxviii), (61).
The net result is the opening of the seven-membered ring and the closing of the less strained six-membered ring. The function of the ethylene is to prevent the occurrence of an intermolecular metathesis reaction leading to a dimeric product. Preparation of an optically active substrate has been achieved using zirconium-catalysed kinetic resolution.
This concludes Part II of the paper on metathesis reactions catalysed by the platinum group metals, concerning applications of platinum metals metathesis catalysts in ring-closing reactions. The last part of this review, on acyclic diene metathesis reactions and ring opening metathesis reactions will appear in the October issue of Platinum Metals Review .
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Valerian Dragutan is a Senior Researcher at the Institute of Organic Chemistry of the Romanian Academy. His current research interests are homogeneous catalysis by transition metals and Lewis acids; olefin metathesis and ROMP of cycloolefins; bioactive organometallic compounds; mechanisms and stereochemistry of reactions in organic and polymer chemistry.
Ileana Dragutan is a Senior Researcher at the Institute of Organic Chemistry of the Romanian Academy. Her research interests include sterically hindered amines; synthesis of olefinic monomers via olefin metathesis; stable organic free radicals as spin probes for ESR of organised systems and membrane bioenergetics; and transition metal complexes with free radical ligands.
Professor A. T. Balaban, a member of the Romanian Academy, taught organic chemistry for over 40 years, until 1999, at Bucharest Polytechnic University. He now teaches at Texas A & M University, Galveston, TX. His Interests include homogeneous catalysis, heterocyclic compounds (pyrylium, pyrldinium, oxazole), stable free radicals, and theoretical chemistry including chemical applications of graph theory and topological indices.