Stereoselective methylation

CHjTi(0-i-Pr)j (1). Addition of 1 (or CH3TiCl3) to y- and 8-lactols results in 1,4- and 1, 5-syn-diols with high stereoselectivity. Methylation with CH,Li, CH3MgBr, or (CH,)3A1 shows slight or no asymmetric induction.3... 

The first report of a successful a-alkylation of a lactone enolate was the high yielding conversion of the bicyclic y-lactone 1 into the stereoselectively methylated derivative 21. 

Table 2. 4-im-Butyl-2-methyltetrahydro-2//-thiopyran S-Oxide by Stereoselective Methylation of 4-/cr(-Butylletrahydro-2//-thiopy-ran i -Oxide... 

Stereoselective methyl addition occurs from the convex face (the 3°-amide is inert to the cuprate reagent). 

Of interest from the mechanistic point of view is the formation of only one diastereoisomer in the methylation step VII/119 — VII/124. Two possible explanations are discussed in the literature [3]. First, a stereoselective methylation of the aldehyde group takes place under the influence of the nitro group leading to the correct stereochemistry in VII/124. The second possibility involves the titanium reagent. An equilibrium can exist between the diastereoisomeric mixture VII/121 and the pure VII/123 via the isomer VII/122. By quenching the equilibrium mixture, only the thermodynamically most stable isomer would be obtained [3]. A differentiation of the two mechanisms seems possible using chiral reaction conditions. Treatment of the chiral (-)-VII/119 (50 % ee), prepared by an asymmetric Michael addition of acrylaldehyde and 2-nitrocyclohexa-none in the presence of cinchonine [84], with achiral dimethyltitaniumdiisopro-poxide yields only achiral methylation products. This experiment shows that no stereoselective methylation takes place. The second consideration, then seems to be more likely (Scheme VII/24)7). 

An alternative synthesis of ( )-sesquifenchene (53) has been described27 in which stereoselective methylation of an appropriate bicyclo[2,2,l]heptane derivative (52) is the key step (Scheme 11). Isoepicampherenol (54), a sesquiterpenoid whose... 

Enandoselective alkylation of HSCHJCOOH1 S-MBF-mercaptoacetic acid (3), colorless oil, otD + 270°, obtained by reaction of the acid with 2 in the presence of a trace of HC1, is stereoselectively methylated or ethylated in favor of the (R)-diastereomer (54% ee and 60% ee, respectively). The (S)-diastereomer is removed by esterification of the mixture and subsequent chromatography. 

Related results have been described from pyridyl alkenyl selenides which, contrary to odier aryl alkenyl selenides (see below)," are easily metallated at the vinyl site with LDA (Scheme 48, compare i and j with f and h). The ready deprotonation and stereoselective methylation of these selertides have been ascribed to the presence of the nitrogen atom which can reduce the electron density of the double bond and also chelate with the lithium counterion." "... 

In the laboratory of P. Kocovsky, novel pyridine-type P,A/-ligands were prepared from various monoterpenes. The key step was the Krohnke pyridine synthesis, and the chirality was introduced by the a,(3-unsaturated ketone component, which was derived from enantiopure monoterpenes. One of these ligands was synthesized from (+)-pinocarvone which was condensed with the acylmethylpyridinium salt under standard conditions to give good yield of the trisubstituted pyridine product. The benzylic position of this compound was deprotonated with butyllithium, and upon addition of methyl iodide the stereoselective methylation was achieved. The subsequent nucleophilic aromatic substitution (Sw/ r) gave rise to the desired ligand. 

The dienone 9 has been stereoselectively methylated, from the less hindered endo face of the molecule, to compound 10 having the methyl group in an a configuration. 

Sn2 Displacements. Regio- and stereoselective methylation of y-silylallyl phosphates has been observed. 

The s)9ithesis of modular pyridine-type F,iV-ligands from monoterpenes is described (eq 45). An a-picolyl-type lithiation with BuLi followed by a stereoselective methylation using Mel gives new EiV-ligands. ... 

They started synthesis by taking 2-(2,4,6-tribromo-3-methoxyphenyl)acetaldehyde 83 and (iS)-A-methylpyrrolidine-2-carboxamide 84 and achieved in two steps. Condensation of aldehyde 83 and amide 84 in anhydrous methanol yielded cyclize products 85 and 86. Stereoselective methyl quatemization of compoimd 86 yielded wilsoniamine A (80). 

The irones are oxidative degradation products of cycloiridal, which is derived itself from squalene. Key steps in the biosynthesis of cycloiridal are an enantioselective epoxidation for the construction of one ring, and a stereoselective methylation for the other ring system. 

An enantioselective route to 1,3-dithiane 1-oxide (33) (R = R = H) was subsequently developed [69]. It involves asymmetric oxidation of (32) (R = pivaloyl, R = H) by cumene hydroperoxide in presence of the chiral titanium complex. The syn/anti mixture (around 90% ee for each diastereoisomer) is recrystallized and then deacylated, giving the desired product in 80% yield. A recent application of this chemistry is the asymmetric synthesis of enantiopure (R)-(-)-2,6-dimethylheptanoic acid in two steps from (33) (R = C(0)Et, R = Et) [70]. The reaction involves a fully stereoselective methylation in the a-position of the keto group, followed by basic deacylation, which also regenerates enantiopure 2-ethyl-l,3-dithiane 1-oxide (33) (Ri = H, R = Et). A range of a-arylpropanoic acids have since been prepared by similar routes in high ee s. [162]... 

By using the Cinchona alkaloid-derived quaternary ammonium bromide 371, a stereoselective methylation of the phenylindanone 372 was achieved under biphasic conditions, thus representing one of the first examples of such a highly stereoselective organocatalytic asymmetric transformation. These types of transformations may be conducted in a stereoselective fashion using more commonly employed methods only with great difficulty. 

Strauch, J. W Faure, J.-L. Bredeau, S. Wang, C. Kehr, G Frohlich, R. Luftmann, H. Erker, G. (Butadiene)metallocene/B(C6F5)3 pathway to catalyst systems for stereoselective methyl methacrylate polymerization Evidence for an anion dependent metallocene catalyzed polymerization process. J. Am. Chem. Soc. 2004,126, 2089-2104. 

Stannylene-mediated glycosylation was first applied to alkyl mannosylations. Condensation of the stannylene acetal of 3,4,6-tri-O-benzyImannopyranose (44) with methyl iodide and allyl bromide in DMF afforded the desired methyl and allyl P-mannopyranosides, respectively, in almost quantitative yields [20]. Benzyl p-mannopyranoside was obtained from the same stannylene acetal by use of BU4NI in benzene [21]. The electrophilic leaving group is responsible for the reactivity and stereoselectivity. Methylation with methyl tosylate and dimethyl sulfate gave methyl mannopyranosides as anomeric mixtures at temperatures above 75 °C [20]. 

Cyclohepta-3,5-dienone)iron complexes can be stereoselectively methylated and hydroxylated. The electrophile adds exclusively anti to the tricarbonyliron fragment. Double methylation or hydroxylation of the a and a positions is accomplished in high overall yield (Scheme 4-146). Silyl enol ethers adjacent to tricarbonyl(Ti -diene)iron units can be subjected to Mukaiyama aldol reaction with aldehydes to provide aldol adducts with varying diastereoselectivity. This methodology has, for example, been applied to the enantioselective synthesis of the dienetriols streptenol C and D (Scheme 4-147). ... 

Modification at C-6(7).—The discovery of 7-methoxycephalosporins as potent antibacterials, coupled with an early prediction that alkylation at C-6 should enhance the biological activity of penicillin, generated considerable interest in the functionalization a to the p-lactam carbonyl group. Use of an aryl Schiif base to increase the acidity of the C-6 proton permitted the generation of anion (IQ by sodium hydride or other strong bases. Alkylation of (16) by methyl iodide occurred preferentially from the less hindered a face, affording (17) as the major isomer. Similarly, stereoselective methylation of the cephalosporin anions (18 X = H) - and (18 X = OAc) yielded o-methylated products (19 X = H or OAc). 

The stereoselectivity of the methylation of ketone enolates is determined by the structure of the substrate. Stereoselective methylation of cyclic ketone enolates has been examined in detail and current models reliably predict the stereochemical outcome (eqs 9-11). Diastereoselective methylation of acyclic ketone and ester enolates has been accomplished employing a variety of chiral auxiliaries (eq 12). Efficient catalytic enantioselective methylation of 6,7-dichloro-5-methoxy-l-indanone has been accomplished via a chiral phase-transfer catalyst (eq 13). An enantiomeric excess of 92% was observed when employing Chloromethane as the methylating agent, whereas... 

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