Carbometallation requirements

Lanthanide-catalyzed enyne cyclization/hydrosilylation was also applied to the synthesis of silylated alkylidene cyclohexane derivatives. For example, reaction of the 3-silyloxy-l,7-enyne 17 with methylphenylsilane catalyzed by Gp 2YMe(THF) at 50°G for 8h gave 18 in quantitative yield as a 4 1 mixture of trans cis isomers (Equation (11)). Employment of methylphenylsilane in place of phenylsilane was required to inhibit silylation of the initially formed yttrium alkenyl complex, prior to intramolecular carbometallation (see Scheme 8). 

Yttrocene complexes catalyze the cascade cyclization/hydrosilylation of trienes to form saturated silylated bicyclic compounds.For example, reaction of the 4-silyloxy-4-vinyl-l,6-hexadiene 69 and phenylsilane catalyzed by Gp 2YMe(THF) at room temperature for 1 h followed by oxidation of crude 70a gave [3.3.0]bicyclic diol 70b in 73% yield over two steps as a single diastereomer (Scheme 18). Selective conversion of 69 to 70a presumably requires initial 1,2-hydrometallation of one of the less-hindered G=G bonds to form alkylyttrium alkene complex II (Scheme 18). Selective S-exo carbometallation of II in preference to -exo carbometallation would form cyclopentyl-methylyttrium complex III (Scheme 18). Gyclization of III via a chairlike transition state would form the strained /r< /75 -fused alkylyttrium complex IIIl, which could undergo silylation to form 70a. 

In a series of late transition metal catalyzed processes the first step in the catalytic cycle is the coordination of the reagent to the metal atom, which is in a positive oxidation state, followed by its covalent attachment through the concomitant breaking of an unsaturated carbon-carbon bond or a carbon-hydrogen bond. These processes usually require a highly electrophilic metal centre and are frequently carried out in an intramolecular fashion. The carbometalation processes that follow a similar course, but take place only at a later stage in the catalytic cycle, will be discussed later. 

Despite mechanistic complications, however, it appears very likely that most, if not all, of the facile and synthetically attractive carbometallation reactions involve, at a critical moment, concerted addition of carbon-metal bonds where the synergistic HOMO-LUMO interactions shown in Scheme 4.3, akin to those for the concerted hydrometallation reactions, provide a plausible common mechanism. This mechanism requires the ready availability of a metal empty orbital. It also requires that addition of carbon-metal bonds be strictly syn, as has generally been observed. Perhaps more important in the present discussion is that concerted syn carbometallation must proceed via a transition state in which a carbon-metal bond and a carbon-carbon bond become coplanar. Under such constraints, one can readily see how chirally discriminated carbon-metal bonds can select either re or si face of alkenes. In principle, the mechanistic and stereochemical considerations presented above are essentially the same as for related concerted syn hydrometalla-tion. In reality, however, carbometallation is generally less facile than the corresponding hydrometallation, which may be largely attributable to more demanding steric and... 

In contrast to the carbometallation with aryl-Grignard reagents to unfunctionalized alkynes, this reaction does not require a co-catalyst such as copper. Only in one example, applying PhMgBr, was CuBr added in accord with the protocol reported by Hayashi s group. Although the nature of the catalytically active species remains unclear, an alkoxide-directed carbometallation which yields a (vinyl)iron intermediate is proposed. 

The central problem in the synthesis of acyclic polyunsaturated compounds (for example, many pheromones) is the construction of an aliphatic chain possessing double bonds of the required configuration in specified positions. The strategy of synthesis in this area could be based either at the identification of unsaturated synthons with double bonds in the needed configuration (as was done in the synthesis of the juvenile hormone, see Section 2.8), or the employment of stereoselective reactions in the process of chain construction, such as carbometallation of alkynes (see Section 2.3.3). 

Generation of stereo- and regio-defined alkenylmetals via hydrometallation or carbometallation of alkynes followed by cross-coupling (Scheme 1-11) is a synthetically attractive notion for preparing arylated alkenes, conjugated dienes, and conjugated enynes. Its feasibility was demonstrated in 1976 [14,15] in the prototypical examples shown in Schemes 1-4 and 1-5. In these processes, hydroalumination was employed for generating the required alkenylmetals. 

Negishi, E.-i., Kondakov, D. Y., Choueiry, D., Kasai, K., Takahashi, T. Multiple Mechanistic Pathways for Zirconium-Catalyzed Carboalumination of Alkynes. Requirements for Cyclic Carbometalation Processes Involving C-H Activation. J. Am. Chem. Soc. 1996,118, 9577-9588. 

Even today, carotenoids and other natural products represented by 1 and/or 2 are synthesized by using the Wittig and related carbonyl oleflnation reactions that are often not highly stereoselective, thus requiring delicate and tedious separations. Carbometallation reactions of alkynes, " ° especially the Zr-catalyzed carboalumination discovered in 1978,[236].[237] jjj conjunction with Pd-catalyzed cross-coupling have provided a totally different carbometallation-cross-coupling tandem protocol for the synthesis of 1 and 2 (Scheme 59). 

Since the preparation of /3,/3-substituted alkenylmetals as the first-generation organometals has been achieved mostly by Zr-catalyzed carboalumination " and carbocupration, the exploitation of Protocol I has largely resorted to these two carbometallation reactions, as indicated by the results summarized in Table 13. Moreover, since it is impractical to carry out methylcupration of alkynes requiring several days at -25 the synthesis of natural products represented by 1 and 2 by the use of Protocol I has mostly been limited to those cases where Zr-catalyzed carboalumination is... 

Since most of the facile and general hydro- and carbometallation reactions involve syn-addition, the preparation of trans-a.jS-substituted alkenylmetals via 5yn-addition of alkynes would require carbometallation of terminal alkynes placing the metal in the internal position. Although such reactions exemplified by carbopalladationf are known, they are still more exceptional than normal. From the perspective of the current discussion, more commonly used are (i) some anfi-hydrometallation reactions of proximally heterofunctional internal alkynes and (ii) the hydroboration-migratory insertion tandem process of 1-haloaIkynes. Whereas the H migration produces (Z)-/3-substituted alkenylboranes (Sect. D.iii), the corresponding C migration provides trans-a,/3-substituted alkenyhnetals. (See Table 15.)... 

For successful application of this strategy, ready access to vinyl halides with defined configuration of the carbon-carbon double bond is required. Such building blocks can be obtained via carbometallation of terminal alkynes [26] or by hydrometallation of internal alkynes, often with appropriate re-gioselectivity [27] (Scheme 3.16). 

As shown in the mechanism depicted in (Scheme 18), the Pd-catalyzed silyl-carbocyclization of 1,6-dienes involves a reversible insertion of an olefin moiety into the [Pd]-Si bond (E-II to E-III). However, the coordination of the second olefin moiety to the Pd metal (forming E-IV) would fill the coordination site required for the j8-silyl-elimination and would therefore render the C—Si bond formation irreversible, which leads to the irreversible carbometalation to jdeld E-V. Accordingly, when the chiral Pd(pyridine-oxazoline) complex is used as the catalyst, the enantioselectivity should be determined at the first olefin insertion step forming -silylalkyl-[Pd] complex E-III. 

In the course of these studies, it was found that Cul and CuCN could effectively promote additions of diorganozinc reagents. In contrast, Ph2Zn was the most effective in terms of reagent economy, as 1.0 or 0.6 equiv. of this organometaUic reagent is required to complete the reaction at the same level of eflBciency (Scheme 10.37). Another essential parameter influencing the diastereoselectivity of the reaction was the nature of the solvent. Toluene was found to be the most effective, while THF or diethyl ether led to an erosion of the diastereomeric ratio of the carbometallated... 

Insertion of alkynes can also be used to form a carbon-carbon bond at the same time as the carbon-zirconium bond. This process, carbometallation, is useful for the stereospecific construction of trisubstituted alkenes (Scheme 5.63). The active reagent is formed by mixing zirconocene dichloride and trimethylaluminium. Both metals are required for the reaction to proceed. The vinyl organometallic 5.221 produced may be subjected to protonolysis or halogenation. An application with iodination can be found in Scheme 8.121. 

---