Alkenes, reductive metathesis

An obvious drawback in RCM-based synthesis of unsaturated macrocyclic natural compounds is the lack of control over the newly formed double bond. The products formed are usually obtained as mixture of ( /Z)-isomers with the (E)-isomer dominating in most cases. The best solution for this problem might be a sequence of RCAM followed by (E)- or (Z)-selective partial reduction. Until now, alkyne metathesis has remained in the shadow of alkene-based metathesis reactions. One of the reasons maybe the lack of commercially available catalysts for this type of reaction. When alkyne metathesis as a new synthetic tool was reviewed in early 1999 [184], there existed only a single report disclosed by Fiirstner s laboratory [185] on the RCAM-based conversion of functionalized diynes to triple-bonded 12- to 28-membered macrocycles with the concomitant expulsion of 2-butyne (cf Fig. 3a). These reactions were catalyzed by Schrock s tungsten-carbyne complex G. Since then, Furstner and coworkers have achieved a series of natural product syntheses, which seem to establish RCAM followed by partial reduction to (Z)- or (E)-cycloalkenes as a useful macrocyclization alternative to RCM. As work up to early 2000, including the development of alternative alkyne metathesis catalysts, is competently covered in Fiirstner s excellent review [2a], we will concentrate here only on the most recent natural product syntheses, which were all achieved by Fiirstner s team. 

Rhenium oxide-alumina catalysts are reduced at ambient temperatures and sub-atmospheric pressure by propene and higher alkenes, generating metathesis activity. Ethylene at these conditions did not show any reduction capabilities. Reduction with CO or NH3 at 300-500° C did not result in metathesis activity. At room temperature CO did not adsorb on reduced catalysts however, NO adsorbs and is a poison for the olefin metathesis reaction. Water generated in reducing catalysts with alkenes is mainly associatively adsorbed and, at ambient temperatures, exchanges hydrogen atoms with propene and butene. Activity for double-bond isomerization is partly accounted for by associatively adsorbed water, which generates acidity. ... 

In the presence of excess hydrogen, metathesis catalysts can become hydrogenation catalysts, so that metathesis and reduction can be carried out in a one-pot process (Scheme 8.125). " In contrast, addition of a diamine as well as hydrogen generates a species that is highly selective for ketone rather than alkene reduction, allowing a choice of products after cross-metathesis with an a,p-unsaturated ketone (Scheme 8.126). 

Synthesis of anthramycin derivative 69a was achieved using RCM and alkene cross-metathesis (CM) (Scheme 6.16) [19]. L-Methionine was converted to ene-yne 61, and subsequent RCM with catalyst [Ruj-I under an atmosphere of ethylene gave pyrrolidine derivative 62. After deprotection and condensation with the commercially available acid chloride 63, the resulting amide 64 underwent reductive cyclization using Zn/AcOH followed by treatment with diluted HCl to... 

Similar reactivity is observed in the cyclization of enynes in the presence of the yttrium-based catalyst 70 and a silane reductant [53,54]. The 1,6- and 1,7-enynes 90 and 91 provide -E-alkylidene-cyclopentancs 92 and -cyclohexanes 93 in very good yield (Eq. 15, Scheme 20) [55]. These transformations likely proceed by syn hydrometallation of the 7r-basic alkyne, followed by insertion of the alkene and a-bond metathesis. The reaction of 1,6-enynes tolerated... 

The mechanism for the reaction catalyzed by cationic palladium complexes (Scheme 24) differs from that proposed for early transition metal complexes, as well as from that suggested for the reaction shown in Eq. 17. For this catalyst system, the alkene substrate inserts into a Pd - Si bond a rather than a Pd-H bond [63]. Hydrosilylation of methylpalladium complex 100 then provides methane and palladium silyl species 112 (Scheme 24). Complex 112 coordinates to and inserts into the least substituted olefin regioselectively and irreversibly to provide 113 after coordination of the second alkene. Insertion into the second alkene through a boat-like transition state leads to trans cyclopentane 114, and o-bond metathesis (or oxidative addition/reductive elimination) leads to the observed trans stereochemistry of product 101a with regeneration of 112 [69]. 

The olefin metathesis of 3-hydroxy-4-vinyl-l,2,5-thiadiazole 112 and a McMurry coupling reaction (Ti3+ under reductive conditions) of the aldehyde 114 were both unsuccessful <2004TL5441>. An alternative approach via a Wittig reaction was successful. With the use of the mild heterogenous oxidant 4-acetylamino-2,2,6,6-tetramethyl-piperidine-l-oxoammonium perfluoroborate (Bobbitt s reagent), the alcohol 113 was converted into the aldehyde 114. The phosphonium salt 115 also obtained from the alcohol 113 was treated with the aldehyde 114 to give the symmetrical alkene 116 (Scheme 16) <2004TL5441>. 

Metathesis reactions may be intramolecular and ring-closing diene metathesis (RCM, implicated in Scheme 1.13, see Chapter 12) allows disconnections in retro-synthetic analysis otherwise of little use. The normal disconnection of the macrocyclic amide in Scheme 1.13 would be at the amide but, because of the ready reduction of alkenes to alkanes, the alternative disconnection now becomes a viable option. And since any of the C—C linkages could be formed by RCM, such a disconnection allows far greater synthetic flexibility than the conventional disconnection at the functional group. 

With the advances in pro-catalyst design that have been witnessed over the last decade or so, the transition-metal-catalysed alkene metathesis reaction has now become a practical procedure that can be utilised by the chemist at the bench. Undeniably, this has added a new dimension to the repertoire of synthetic organic chemistry as it facilitates disconnections that, pre-metathesis, simply would not have been considered. Take, for example, a macro-cyclic amide where the normal disconnection would be at the amide. Now, with the ready reduction of alkenes to alkanes, a ring-closing diene metathesis (RCM), followed by hydrogenation, becomes an alternative disconnection. And, when one considers that any of the C—C linkages could be established in such a manner, the power of the RCM disconnection becomes obvious. 

The elimination of a-hydrogen is not general and observed only with limited numbers of metal complexes. The elimination of a-hydrogen from the methyl group in the dimethylmetal complex 68 generates the metal hydride 69 and a carbene that coordinates to the metal. Liberation of methane by the reductive elimination generates the carbene complex 70. Formation of carbene complexes of Mo and Wis a key step in alkene metathesis. The a-elimination is similar to the 1,2-hydride shift observed in organic reactions. 

The yields from aldehyde alkylidenation is somewhat lower due to the reductive dimerization of aldehydes with low-valent Ti. Alkylidenation of esters is possible by the reaction of 1,1 -dibromoalkane. TiCU and Zn in the presence of TMEDA to give (Z) vinyl ethers [60], Cyclic vinyl ethers are prepared from unsaturated esters in two steps. The first step is formation of the acyclic enol ethers using a stoichiometric amount of the Ti reagent, and the second step is ring-closing alkene metathesis catalysed by Mo complex 19. Thus the benzofiiran moiety of sophora compound I (199, R = H) was synthesized by the carbonyl alkenation of ester in 197 with the Ti reagent prepared in situ, and the subsequent catalytic RCM of the resulting enol ether 198 catalysed by 19 [61]. 

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