Magnesium optically active

Still s synthesis of monensin (1) is based on the assembly and union of three advanced, optically active intermediates 2, 7, and 8. It was anticipated that substrate-stereocontrolled processes could secure vicinal stereochemical relationships and that the coupling of the above intermediates would establish remote stereorelationships. Scheme 3 describes Still s synthesis of the left wing of monensin, intermediate 2. This construction commences with an aldol reaction between the (Z) magnesium bromide enolate derived from 2-methyl-2-trimethylsilyloxy-3-pentanone (21) and benzyloxymethyl-protected (/ )-/ -hydroxyisobutyraldehyde (10).2° The use of intermediate 21 in aldol reactions was first reported by Heathcock21 and, in this particular application, a 5 1 mixture of syn aldol diastereoisomers is formed in favor of the desired aldol adduct 22 (85% yield). The action of lithium diisopropylamide (LDA) and magnesium(n) bromide on 21 affords a (Z) magnesium enolate that... 

The addition reaction requires the presence of 4 equivalents of HMPA, thus partial racemization of optically active aldehydes under these basic conditions is anticipated. Unfortunately, the addition of magnesium bromide, zinc chloride or cadmium iodide reverses the regioselectivity11 ... 

Optically active sulphoxides 311 and 312 have been prepared stereospecifically either by hydrolysis of the optically active sulphonium salt 313 or by the reaction of p-tolyl magnesium bromide with optically active sulphinate 314, respectively377 (equations 167 and 168). 

The stereospecific conversion of menthyl arenesulphinates into chiral aryl methyl sulphoxides may also be achieved by means of methyllithium . The reaction of methyllithium with diastereoisomerically or enantiomerically pure arenesulph-inamides 283 was found to give optically active aryl methyl sulphoxides 284 (equation 156). The preparation of optically active sulphoxides 285 and 286, which are chiral by virtue of isotopic substitution (H - D and - respectively), involves the reaction of the appropriate non-labelled menthyl sulphinates with fully deuteriated methyl magnesium iodide (equation 157) and with benzylmagnesium chloride prepared from benzyl chloride labelled with carbon (equation 158). 

If the alkenes and acetylenes that are subjected to the reaction mediated by 1 have a leaving group at an appropriate position, as already described in Eq. 9.16, the resulting titanacycles undergo an elimination (path A) as shown in Eq. 9.58 [36], As the resulting vinyltitaniums can be trapped by electrophiles such as aldehydes, this reaction can be viewed as an alternative to stoichiometric metallo-ene reactions via allylic lithium, magnesium, or zinc complexes (path B). Preparations of optically active N-heterocycles [103], which enabled the synthesis of (—)-a-kainic acid (Eq. 9.59) [104,105], of cross-conjugated trienes useful for the diene-transmissive Diels—Alder reaction [106], and of exocyclic bis(allene)s and cyclobutene derivatives [107] have all been reported based on this method. 

A metal-nucleotide complex that exhibits low rates of ligand exchange as a result of substituting higher oxidation state metal ions with ionic radii nearly equal to the naturally bound metal ion. Such compounds can be prepared with chromium(III), cobalt(III), and rhodi-um(III) in place of magnesium or calcium ion. Because these exchange-inert complexes can be resolved into their various optically active isomers, they have proven to be powerful mechanistic probes, particularly for kinases, NTPases, and nucleotidyl transferases. In the case of Cr(III) coordination complexes with the two phosphates of ATP or ADP, the second phosphate becomes chiral, and the screw sense must be specified to describe the three-dimensional configuration of atoms. 

Enantioselective protonation of ketone metal enolates constitutes an important method for the preparation of optically active ketones. Fuji and coworkers have shown interest in the magnesium countercation in the enantioselective protonation of such enolates. Pertinent results are obtained with protonation of Mg(II) enolates of 2-alkyltetralones and carbamates derived from l,l -binaphtalene-2,2 -diol as chiral proton sources, as indicated in equation 82 and Table 11. 

Asymmetric synthesis in aldol-type reaction involving magnesium ester or lactone enolates has also been reported. Enolate of (—)-menthyl or (-l-)-bornyl acetate reacts with substituted benzophenones or a-naphtophenones to yield, upon hydrolysis of the resulting esters, optically active /3-hydroxyacids. Although these results are interpreted in terms of a steric factor. Prelog s rules are not applicable to these reactions (equation 88). 

As mentioned above, the configuration of the magnesium carbenoid is rather stable at low temperature chiral Grignard reagents having over 90% ee could be generated from optically active 1-chloroalkyl aryl sulfoxides (Scheme 4)20-22... 

Hammerschmidt, F. Hanninger, A. Enantioselective deproto nation of benzyl phosphates by homochiral lithium amide bases. Configurational stability of benzyl carbanions with a dialkoxyphosphoryloxy substituent and their rearrangement to optically active a-hydroxy phosphonates. Chem. Ber. 1995, 328, 823-830. Avolio, S. Malan, C. Marek, I. Knochel, P. Preparation and reactions of functionalized magnesium carbenoids. Synlett 1999, 1820-1822. 

After the identification of aprepitant as a clinical candidate, Merck invested considerable process research toward an improved synthesis of aprepitant, which culminated in the elegant manufacturing process shown in Scheme 6.21,22 The key step relies on displacement of a trifluoroacetate from intermediate 48 by the optically active alcohol intermediate 49. The synthesis of 49 was accomplished via an oxazaborolidine-catalyzed borane reduction of the corresponding acetophenone. Although the displacement resulted in an almost equal mixture of the two diastereomers 50 and 51, the desired diastereomer 50 could be recovered in high yield by base-catalyzed equilibration of the mixture and crystallization. Addition of p-fluorophenyl magnesium bromide followed by hydrogenolysis afforded the key intermediate 40, which can be readily converted to 1 as detailed in the previous synthesis. 

Magnesium ion-mediated nitrile oxide 1,3-DC reactions to allylic alcohols have been reviewed <02SL1371>. New examples have been recently reported, in particular, cycloadditions of aromatic and aliphatic nitrile oxides with optically active a-silylallyl alcohols in the presence of magnesium cations. The substituted isoxazolines, which were obtained with high diastereo- and enantioselectivity, were smoothly converted to [1,2]-oxazine derivatives by treatment with TBAF. For example, oxazin-3-one (S)-58 was obtained in 81% ee starting from dipolarophile (S)-55 <02T9613>. 

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