The Synthetic Versatility of Titanocene Methylidene Sources and Their Utility in the Total Synthesis of Capnellene

The development and application of a synthetically useful metallacycle are described. Using this metallacycle reagent to generate the reactive titanocene methylidene, the methylenation of dialkyl carbonates occurs, producing ketene ketals. The transformation of carbonates to ketene ketals varies dramatically with the O-alkyl substituents on the carbonate. Due to the sensitivity of titanocene methylidene toward steric interference, conversion is substantially higher for dimethyl carbonate than for diphenyl carbonate. Restricting the carbonates to the s-trans, s-trans conformation, such as in cyclic carbonates, the steric effects are completely overcome. The reaction of titanocene methylidene sources with acid chloride substrates produces the titanocene chloride enolate of the corresponding methyl ketone. Enolate formation occurs specifically at the methyl group, resulting in only the kinetic enolate, even in a case where the thermodynamic enolate would be stabilized by conjugation to aromatic functionality. Enolate formation with an α-chiral acid chloride followed by hydrolysis showed that less than 0.5% racemization had occurred. The titanocene methylidene selectively attacks the acid chloride functional group even when an ester carbonyl is present. Condensation of the enolate with aldehydes occurs regiospecifically to produce β-hydroxy ketones. Titanocene methylidene also methylenates silyl esters to produce the corresponding kinetic silyl enol ether. Using a reported method for the generation of bridged titanocene alkylidene complexes, the first trisubstituted titanacyclobutane has been isolated and characterized. A general method by which titanocene alkylidene complexes may be prepared has also been investigated. The transmetallation of 1,1-dimetallo complexes of aluminum and zinc to titanocene chloride, forming the heterobimetallic bridged alkylidenes, was also studied. Although the aluminum complexes do not afford bridged complexes, the 1,1-dizincalkyls appear to undergo transmetallation to give a species which will methylenate ketone functionality. Cyclopentadiene compounds, tethered to α,β-unsaturated ester functionality, have been prepared by the direct alkylation of the corresponding iodide with cyclopentadienylmagnesium chloride. The cyclopentadienyl Grignard reagent does not display the undesired reactions found to occur with the use of the more basic compounds of lithium and sodium; the organometallic reagent does not catalyze the isomerization of the cyclopentadiene isomers. Alkylation of the iodide is preferred over Michael Addition to the unsaturated ester functional group, but using the corresponding tosylate, conjugate addition is the more prominent reaction. Several functionalized cyclopentadienes are prepared which differed in tether length. These substrates readily undergo intramolecular [4+2] cycloaddition at mild temperatures to produce tricyclic ring systems. The cycloaddition will proceed at even lower temperatures if catalyzed by diethylaluminum chloride. Pathways of cycloaddition favor incorporation of the tether linkage into a five- or six-membered ring. The reaction of titanocene methylidene with norbornene substrates containing endo ester substituents results in metallacycle formation with the strained olefin. The regiochemistry of the cycloaddition to the strained olefin can be completely controlled through the use of a 1-methyl substituent. Thermolysis of these metallacycles proceeds predominantly by ring-opening metathesis of the norbornene substrate to produce a titanocene alkylidene intermediate. This intermediate is subsequently trapped by the intramolecular ester substituent to produce the corresponding bicyclo[3.2.0]heptene enol ether. Similar results are obtained using substituted titanocene alkylidene complexes. The intermediate trisubstituted metallacycles display an enhanced propensity for ring-opening metathesis to occur. The synthetic versatility of titanocene methylidene is demonstrated in the total synthesis of (±)Δ(9,12)-capnellene from α,α-dimethyl-γ-butyrolactone. Using the intramolecular cycloaddition of the appropriate functionalized cyclopentadiene, the relative stereochemistry of all four asymmetric centers in the natural product is established. Ring-opening metathesis of the resulting strained olefin by titanocene methylidene, followed by intramolecular trapping of the intermediate titanocene alkylidene, produces the required skeleton for capnellene. Only standard modification of existing functionality is required to obtain the reported ketone precursor. Methylenation of this ketone with titanocene methylidene occurs much more efficiently than with the standard Wittig reagent to produce capnellene. This synthesis of capnellene is the first reported to establish the relative stereochemistry of all four asymmetric centers using a single cycloaddition step. The use of titanocene methylidene has led to an efficient synthesis of (±)Δ(9,12)-capnellene in 20% overall yield.