Cyclopropanation zinc carbenoids

Enantioselective [2+1] Cycloaddition Cyclopropanation with Zinc Carbenoids... 

Whereas the utility of these methods has been amply documented, they are limited in the structures they can provide because of their dependence on the diazoacetate functionality and its unique chemical properties. Transfer of a simple, unsubstituted methylene would allow access to a more general subset of chiral cyclopropanes. However, attempts to utilize simple diazo compounds, such as diazomethane, have never approached the high selectivities observed with the related diazoacetates (Scheme 3.2) [4]. Traditional strategies involving rhodium [3a,c], copper [ 3b, 5] and palladium have yet to provide a solution to this synthetic problem. The most promising results to date involve the use of zinc carbenoids albeit with selectivities less than those obtained using the diazoacetates. 

The most logical starting point is a discussion of the structure of the zinc carb-enoid, followed by a somewhat chronological presentation of major advances in the use of zinc carbenoids in cyclopropanation. After a brief historical recounting of Simmons and Smith s original studies, the crucial implications of diastereose-... 

These early studies on zinc carbenoids provide an excellent foundation for the development of an asymmetric process. The subsequent appearance of chiral auxiliary and reagent-based methods for the selective formation of cyclopropanes was an outgrowth of a clear understanding of the achiral process. However, the next important stage in the development of catalytic enantioselective cyclopropanations was elucidation of the structure of the Simmons-Smith reagent. 

The possibility of a radical mechanism is supported by the observation of the accelerating effect of molecular oxygen on the cyclopropanation. Miyano et al. discovered that the addition of dioxygen accelerated the formation of the zinc carbenoid in the Furukawa procedure [24a, b]. The rate of this process was monitored by changes in the concentration of ethyl iodide, the by-product of reagent formation. Comparison of the reaction rate in the presence of oxygen with that in the... 

In 1963, Dauben and Berezin published the first systematic study of this syn directing effect (Scheme 3.15) [37]. They found that the cyclopropanation of 2-cyclohexen-l-ol 32 proceed in 63% yield to give the syn isomer 33 as the sole product. They observed the same high syn diastereoselectivity in a variety of cyclic allylic alcohols and methyl ethers. On the basis of these results, they reasonably conclude that there must be some type of coordinative interaction between the zinc carbenoid and the substrate. 

In this model, the intermediacy of a monomeric zinc species is postulated. To support this assumption, an examination of the effect of stoichiometry and solvent in cyclopropanation involving the 2,4-pentanediol auxiliary was preformed [59]. In the initial reaction protocol, a large excess of both diethylzinc and diiodo-methane is employed. Such excessive conditions are justified on account of the instability of the zinc carbenoid under the reaction conditions. To minimize the un-... 

The formulation of an additive for zinc carbenoid cyclopropanation that meets these criteria is severely compromised by the by the inherent Lewis acidity of the zinc atom. This Lewis acidity is required for methylene transfer and plays a major... 

For a reaction as complex as catalytic enantioselective cyclopropanation with zinc carbenoids, there are many experimental variables that influence the rate, yield and selectivity of the process. From an empirical point of view, it is important to identify the optimal combination of variables that affords the best results. From a mechanistic point of view, a great deal of valuable information can be gleaned from the response of a complex reaction system to changes in, inter alia, stoichiometry, addition order, solvent, temperature etc. Each of these features provides some insight into how the reagents and substrates interact with the catalyst or even what is the true nature of the catalytic species. 

Fig. 3.17 Cyclopropanation under protocol V using different zinc carbenoids...

SYNTHETIC SCOPE OF THE CYCLOPROPANATION USING ZINC CARBENOIDS. 246... 

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