Grignard reagents, bonding diastereoselective reactions

The diastereoselectivity of the reaction may be rationalized by assuming a chelation model, which has been developed in the addition of Grignard reagents to enantiomerically pure a-keto acetals7,8. Cerium metal is fixed by chelation between the N-atom, the methoxy O-atom and one of the acetal O-atoms leading to a rigid structure in the transition state of the reaction (see below). Hence, nucleophilic attack from the Si-face of the C-N double bond is favored4. 

However, in a recently published, detailed study on the stereochemistry of the addition reaction of allylic Grignard reagents (mainly crotylmagnesium chloride) with a,/ -ethylenic ketones [15], addition to aryl-substituted enones occurred without any selectivity at all. The authors suggested that this was due to a single-electron transfer, since poor diastereoselectivity is observed when a carbon-carbon bond is formed by a radical- radical combination [64]. No further mechanistic details on this difference in reactivity were given. 

The first synthesis of an (a-haloalkyl)boronic ester [8], a free radical addition of a tetrahalomethane, was followed by mechanistic studies that indicated the potential for stereospecific alkylation with Grignard reagents via borate intermediates [9], if only there had been a way to obtain asymmetric examples. The discovery of the efficient reaction of (dichloromethyl)lithium with boronic esters to form (a-chloroalkyl)boron-ic esters by insertion of a CHCl group into the B-C bond opened a new opportunity [10]. Boronic esters of pinanediol, prepared from (+)-a-pinene by osmium tetroxide catalyzed oxidation, were soon found to undergo the insertion reaction with a strong asymmetric bias, with diastereomeric selectivities frequently in the 90-95% range [llj. It was subsequently found that anhydrous zinc chloride promotes the reaction and increases diastereoselectivity to as high as 99.5% in some cases [12]. 

An actual synthesis corresponding to this pattern is shown in Scheme 11.4. It relies on well-known reaction types. Steps I, J, K correspond to the disconnection leading to intermediate I. The bond connection at C-9, C-10, corresponding to conversion of intermediate II to I, is done using a Grignard reagent in step E. This results in an alcohol oxidation level at C-9 which is adjusted to the required carbonyl much later in the synthesis (step J). The conversion of IV to III in the retrosynthetic scheme corresponds to step A in the synthesis. A Reformatsky reaction is employed. The overall synthesis is not stereocontrolled. The relative stereochemistry at C-4 and C-7 is established by the catalytic hydrogenation in step H of the synthesis. In principle, this reaction could be diastereoselective since the adjacent chiral center... 

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