Zinc reagents alkoxide preparation

Further optimization of this reaction was carried out with TFE as an achiral adduct, since reaction with TFE is much faster than that with neopentyl alcohol. We found that dimethyl- and diethylzinc were equally effective, and the chiral zinc reagent could be prepared by mixing the chiral modifier, the achiral alcohol and dialkylzinc reagent in any order without affecting the conversion and selectivity of the reaction. However, the ratio of chiral to achiral modifier does affect the efficiency of the reaction. Less than 1 equiv of the chiral modifier lowered the ee %. For example with 0.8 equiv of 46 the enantiomeric excess of 53 was only 58.8% but with 1 equiv of 46 it was increased to 95.6%. Reaction temperature has a little effect on the enantiomeric excess. Reactions with zinc alkoxide derived for 46 and TFE gave 53 with 99.2% ee at 0°C and 94.0% ee at 40°C. 

Ishizaki and Hoshino prepared optically active secondary alkynyl alcohols (up to 95% e.e.) by the catalytic asymmetric addition of alkyl zinc reagents to both aromatic and aliphatic aldehydes. The chiral ligands studied were based on the pyridine scaffold. Of the three aryl substitutions studied, the a-napthyl derivative was found to be superior (Scheme 21.10). Mechanistically, it was proposed that (S)-l would react with dialkynyl zinc alkoxide A and ethyl zinc alkoxide B. Coordination of additional di-alkynyl zinc and alkynylethyl zinc with these alkoxides (A, B) would give C and D, respectively (Scheme 21.11). More bulky alkoxide (C) would have severe steric interactions with the alkynyl group and pyridine moiety, which might cause undesired conformational changes of the l-zinc complexes. Consequently, the enatioselectivity would be decreased. 

The more recently reported route to diethyl 3-oxoalkylhosphonates uses a zinc carbenoid-mediated approach, which is believed to proceed through the intermediacy of a cyclopropylzinc alkoxide. Thus, treatment of simple diethyl 2-oxoaIkylphosphonates with the Furukawa-modifled Simmons-Smith reagent provides a rapid and efficient preparation of 3-oxoalkyIphosphonates. The chain extension of simple, unfunctionalized P-ketophosphonates requires an excess (6 eq) of both Et2Zn and CH2I2 at room temperature. The presence of a-substitution on the 2-oxoalkylphosphonate does not diminish the efficiency of the reaction (see Section 7.2.3.7). 

Allyliczinc halides reagents have been prepared from sterically hindered homoallylic alcohols, using a novel fragmentation reaction of the corresponding zinc alkoxide (Scheme 6). The interest of this reaction resides in the absence of the Wurtz homocoupling product, usually present in high proportion when the direct reaction of zinc with allylic halides is used. 

The enantioselective addition of dialkylzinc reagents to aldehydes is not limited to the homonuclear zinc complexes described above. Seebach has shown that Ti-TADDOL complexes can be effective catalysts for the preparation of a wide range of secondary alcohols (Equation 16) [102], The addition of Et2Zn to aldehydes is carried out with catalyst 165 in combination with 1.2 equiv Ti(Oi-Pr)4 to furnish products in 82-99% ee [17. 103). The use of excess Ti(Oi-Pr)4 is noteworthy, as it is of mechanistic significance. Catalyst turnover is only observed in this system because of the ability of the Ti(Oi-Pr)4 to serve as a reservoir for the alkoxide product. It is remarkable, however, that the presence of excess Ti(Oi-Pr)4 does not lead to any diminution in the enantioselectivity of the product formed. This represents a dramatic example of ligand-accelerated catalysis in C-C bond-forming reactions. 

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