Reformatsky reaction stereoselectivity

The complexation of achiral metal enolates by chiral additives, e.g., solvents or complexing agents could, in principle, lead to reagent-induced stereoselectivity. In an early investigation, the Reformatsky reaction of ethyl bromoacetate was performed in the presence of the bidentate ligand (—)-sparteine20. The enantioselectivity of this reaction varies over a wide range and depends on the carbonyl Compound, as shown with bcnzaldehyde and acetophenone. 

Stereoselective Reformatsky reaction. The Reformatsky reaction of the chiral 2-azetidinone 1 with 3-(2-bromopropionyl)-2-oxazolidone (2a) gives essentially a 1 1 mixture of the diastereomers 3a(3 and 3aa. However, introduction of two methyl groups at C4 in 2 markedly improves the (i-diastereoselectivity, as does an increase in the temperature from 0 to 67° (reflux, THF). The highest diastereoselectivity (95 5) is observed with the derivative of 4,4-dibutyl-5,5-pentamethylene-2-oxa-zolidone. The 3p-diastereomer is a useful intermediate to lp-methylcarbapenems.1... 

Gemcitabine (Gemzar ) is prepared from the 2,2-difluoro-2-deoxyribose, itself available by the addition of the Reformatsky reagent of ethyl bromodifluoroace-tate on the (R)-2,3-0-isopropylidene glyceraldehyde. The condensation of the corresponding mesylate with di(trimethylsilyloxy)pyrimidine provides gemcitabine [93]. The control of the stereoselectivity of the Reformatsky reaction is difficult (Fig. 30) [95]. Other approaches involving the fluorination of D-pyranoses have been proposed (Fig. 31) [96]. 

A Rh-catalyzed Reformatsky reaction of chiral imine (24) led to the stereoselective preparation of the a,a-difluoro-jS-amino acid (25). 25 was converted to difluor-oalkene (26), and subsequently L-Val-i/r[(Z)CF=CH]Gly derivative (23) in greater than 82% for both steps. The samarium diiodide-mediated reductive transformation of the y,y-difluoro-a, S-enoates proceeded via successive two-electron transfers to form a dienolate species which upon kinetically controlled trapping with fert-BuOH formed 23 (Scheme 6). 

Particularly challenging is the use of chiral ligands in order to impose enan-tiocontrol on a Reformatsky reaction. Although preparatively useful levels of asymmetric induction have been described in the recent literature by using enantiomerically pure amino alcohol ligands43 this reaction has not yet reached a similar level of perfection as the enantioselective addition of other organozinc reagents to aldehydes in the presence of the same type of additives. Some selected examples of stereoselective Reformatsky type reactions which delineate the present state of the art are summarized in Scheme 14.6. 

Scheme 14.6 Selected examples of stereoselective Reformatsky reactions.

More recently, Concellon has reported a stereoselective method for the formation of ( )-a,p-unsaturated esters that exploits a Sml2 Reformatsky reaction followed by an elimination.141 For example, ethyl dibromoacetate reacts with benzaldehyde in the presence of Sml2 to form samarium alkoxide 126, which is reduced further to give a second Sm(III) enolate 127. Elimination then affords ( )-a,p-unsaturated ester 128 in good yield (Scheme 5.90).141... 

Similar condensations can be accomplished with other types of stabilized carbanions, e.g. sulfonyl anions, as illustrated by equation (81). The resulting sulfonyl lactone (228) eliminates sulfinic acid on treatment with p-TsOH to furnish the a,3-unsaturated system (229).Spirolactonization is the result of the Reformatsky reaction of ester (231) with cyclic ketones. In equation (82), this reaction is applied to the synthesis of the lysergic acid precursor (232), which is formed stereoselectively from (230). ... 

Zhao and co-workers 48) reported the first synthesis of homoharringtonine (3) in 1980 (Scheme 20). Unsaturated keto acid 151, prepared either from 5,5-dimethyl-5-valeroIactone 150, or by chain extension from the commercially available bromide 149, was esterified with cephalotaxine to give the cephalotaxyl derivative 152, which reacted with methyl bromoacetate under Reformatsky conditions to yield a mixture of epimers of dehydro-homoharringtonine 153. This mixture was converted to homoharringtonine and its epimer by means of oxymercuration, as well as by acid catalysis. As in the aforementioned syntheses of harringtonine, the Reformatsky reaction proceeded with no stereoselectivity, and diastereomeric mixtures resulted from all of these approaches. 

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