Methylalumination

Scheme 27 Stereoisomerization of the methylalumination product derived from 3-butyn-1 -ol.

Although the application of carboalumination to the synthesis of natural products is still in its infancy, a few preliminary results shown in Scheme 1.50 [167,168,171,172] suggest that it promises to become a major asymmetric synthetic reaction, provided that (i) the singularly important case of methylalumination can be made to proceed with S90% ee, and (ii) satisfactory and convenient methods for enantiomeric and diastereo-meric separation/purification can be developed. In this context, significant increases in ee in the synthesis of methyl-substituted alkanols from around 75 % to 90—93 % achieved through some strategic modifications are noteworthy (Scheme 1.50) [168]. Shortly before the discovery of the Zr-catalyzed enantioselective carboalumination, a fundamentally discrete Zr-catalyzed asymmetric reaction of allylically heterosubstituted alkenes proceeding via cyclic carbozirconation was reported, as discussed later in this section. 

Most probably, Zr-catalyzed C—C bond formation by cyclic carbozirconation was first observed in 1978, when the Zr-catalyzed reaction of alkynes with Et3Al was reported [13,56]. An acyclic carbozirconation mechanism similar to that of methylalumination was initially... 

In 1978, Negishi et al. reported highly regio- and stereoselective methylalumination of alkynes with Me3Al using a zirconocene catalyst [59]. The involvement of cationic zirconocene species in the activation of carbon—carbon triple bonds was suggested in a reaction mechanism featuring electrophilic activation by aluminum (Scheme 8.30). 

A remarkable feature of the methylalumination reaction is that the addition of water to the reaction mixture has an accelerating effect. An in situ generated aluminoxane species (similar to MAO) is most probably responsible for this effect. The methylalumination then proceeds at —23 °C without any loss of regioselectivity [63],... 

Attempts to use the isobutyl group in the carbometalation of alkynes only give rise to hy-drometalated products, but ethyl and n-propyl groups can be successfully transferred from the corresponding dialkylaluminum chlorides. The regioselectivity in these reactions is lower than that for the methyl transfer. Indeed, the reaction mechanism may be different from that of methylalumination [62]. 

Despite the formal similarity of the reaction, the mechanism of Cp2ZrCl2-catalyzed ethylalumination [64] with AlEt3 is different from that of either methylalumination with AlMe3 or ethylalumination with Et2AlCl [62]. The involvement of dimetallic species was confirmed by NMR spectroscopy as well as deuterolysis (Scheme 8.31). The proposed mechanism features an interesting zwitterionic bimetallic species, in which the zirconium center is cationic. A highly instructive treatise on the mechanistic pathways of carbometalation is presented in [65],... 

Scheme 8.37. Enantioselective methylalumination in the synthesis of isoalkyl alcohols.

The zirconocene-catalyzed enantioselective methylalumination is accelerated by the addition of water to the reaction mixture. Styrene derivatives in particular, which are unreactive under the aforementioned conditions, readily undergo methylalumination at —5 °C. The reaction of water and AlMe3 most probably yields aluminoxanes. MAO was also shown to accelerate the reaction, although less markedly [78] (Scheme 8.39). 

Scheme 8.39. Asymmetric methylalumination reaction accelerated by addition of water.

Alternatively, by performing a zirconium-catalyzed Negishi methylalumination on 1-hexyne, it is possible to produce stereochemically pure alkenylcopper species 62, which adds to enones in a 1,4-fashion, to give compounds such as 63 (Scheme... 

A highly stereoselective synthesis of retinol via a Cm + C6 route was depicted by De Lera et al. [52]. A Suzuki reaction of a C14 alkenyliodide with a Cg alkenylboronic acid afforded retinol in 83% yield, with retention of the geometries of the coupling partners. The alkenyliodide was obtained by a zirconium-mediated methylalumination and a subsequent Al/I exchange by slow addition of ICN. Coupling with the C6 boronic acid (12 hrs to reach completion), afforded retinol in 83% yield [53], Fig. (21). 

Zirconium-Catalyzed Enantioselective Methylalumination of Unactivated Alkenes... 

TABLE 4.1. Zirconinm-Catalyzed Methylalumination of Monosnbstitnted Alkenes"... 

Only monosubstituted terminal alkenes, including some terminal dienes, have so far been successfully methylaluminated. Within this restriction, however, the reaction appears to be reasonably general, as shown in Table 4.1. Specifically, n-alkyl, isoalkyl, and secondary alkyl substituents can be accommodated, but tertially alkyl-substituted ethylenes, such as r-BuCH=CH2, fail to react under the same conditions. In contrast with styrene, allylbenzene reacts normally. 

To further probe the potential synthetic utility of the Zr-catalyzed enantioselective carboalumination of alkenes, the C14 sidechain units of vitamin E, that is, (2R,6R)-2.6.10-trimethyl-1 -undecanol (4) and the corresponding iodide 5, have been synthesized as summarized in Scheme 4.10 [15]. Whereas the enantioselectivity in each methylalumination step must be significantly improved, the four-step synthesis of 4 and 5 summarized in Scheme 4.10 appears to provide one of the most efficient enantioselective routes to the C14 sidechain units of vitamin E [16]. 

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