Sequential methylation

In an effort to make productive use of the undesired C-13 epimer, 100-/ , a process was developed to convert it into the desired isomer 100. To this end, reaction of the lactone enolate derived from 100-) with phenylselenenyl bromide produces an a-selenated lactone which can subsequently be converted to a,) -unsaturated lactone 148 through oxidative syn elimination (91 % overall yield). Interestingly, when 148 is treated sequentially with lithium bis(trimethylsilyl)amide and methanol, the double bond of the unsaturated lactone is shifted, the lactone ring is cleaved, and ) ,y-unsaturated methyl ester alcohol 149 is formed in 94% yield. In light of the constitution of compound 149, we were hopeful that a hydroxyl-directed hydrogenation52 of the trisubstituted double bond might proceed diastereoselectively in the desired direction In the event, however, hydrogenation of 149 in the presence of [Ir(COD)(py)P(Cy)3](PF6)53 produces an equimolar mixture of C-13 epimers in 80 % yield. Sequential methyl ester saponification and lactonization reactions then furnish a separable 1 1 mixture of lactones 100 and 100-) (72% overall yield from 149). 

Relative yields were such as to suggest sequential methylation from inorganic tin by an initial oxidation-addition process involving free radicals53. 

Phenol methylation to 2,6-xylenol has been widely studied for the past few deeades owing to the room for improvisation from the viewpoint of product selectivity. Generally during phenol methylation to 2,6-xylenol, occurs via sequential methylation of phenol to o-cresol to 2,6-xylenol, various reaction parameters mediate the selectivity between the two. For instance, when the reaetants stoichiometry of methanol to phenol molar ratio > 2, and significant residence time of o-cresol may favor 2,6-xylenol selectivity. However, excess methanol is often used, sinee some amount of methanol tend to undergo oxidation into various reformate produets [71] under vapor phase condition. Similarly, reaction temperature, catalyst acid-base property, and space velocity of the reaetant are the parameters that govern the selectivity to 2,6-xylenol. 

Figure 4. Phenol conversion, and o-cresol and 2,6-xylenol selectivity dependence on catalyst composition and reaction temperature with a feed composition of MeOH PhOH = 5 1, at time on stream = 3h. Note that 2,6-xylenol selectivity increases with phenol conversion, and at the expense of o-cresol with all catalyst compositions, indicating the first order conversion dependence and the sequential methylation, respectively.

A recent approach toward ( )-guanacastepene (rac-187) published by Kwon in 2003 employed a sequential methyl cuprate 1,4-addition to the en-one 281 followed by an intramolecular Mukaiyama aldol condensation to construct the B ring (Eq. 9) [142, 143] ... 

Figure 13.2 (a) Sequential methylation and demethylation of lysines catalyzed by histone methyl transferases (HMTs) and histone demethylases (HDMs), respectively, (b) Sequential methylation and demethylation of arginines catalyzed by HMTs and HDMs, respectively, leading to symmetric and asymmetric dimethylarginines. 

First of all, we may compare the values for this species and its lesser-methylated derivatives, the parent ethanedial and 1,2-propanedione dioximes, respectively. The former are only for the solid state. The differences for sequential methylation are the all but indistinguishable 36.2 and 36.1 kJmol and so we feel confident in this set of numbers. We also find that, at least for unstrained species, the gas phase olefin and aldehyde reactions in equations 29 and 30 are roughly endothermic by ca 4 kJmol . ... 

Cacace, S. et al., A fiavonol 0-methyltransferase from Catharanthus roseus performing two sequential methylations. Phytochemistry, 62, 127, 2003. 

Cyclic nitrones also undergo intramolecular cycloaddition to an alkenyl group with very high regio-selectivity. For example, ( )-cocaine was synthesized via cyclization of the cyclic nitrone (50), obtained from reduction of a nitroacetal or from thermolysis of an isoxazolidine, to isoxazolidine (51 Scheme 12).23 Sequential methylation, reductive N—O cleavage and benzoylation of (51) provided ( )-cocaine. 

Sequential Methylation Technique. A sequential methylation-extraction technique has been devised primarily to separate phenolics from aromatic and aliphatic acids. The procedure, outlined below, allows quantitative conversion of phenolic hydroxyls to methyl ethers in one step and esterification of carboxyl groups in another. 

Wiberg and coworkers published relative rate constants and the products of reaction of silene 6 with a number of alkenes and dienes in ether solution at 100 °C6 106-108. These data are listed in Table 2 along with an indication of the type of product formed in each case. As is the norm in Diels-Alder additions by more conventional dienophiles, the rate of [2 + 4]-cycloaddition of 6 to dienes increases with sequential methyl substitution in the 2- and 3-positions of the diene, as is illustrated by the data for 2,3-dimethyl-1,3-butadiene (DMB), isoprene and 1,3-butadiene. The well-known effects of methyl substitution at the 1- and 4-positions of the diene in conventional Diels-Alder chemistry are also reflected with 6 as the dienophile. For example, lruns-1,3-pen tadiene reacts significantly faster than the f/.v-isorrier, an effect that has been attributed to steric destabilization of the transition state for [2 + 4]-cycloaddition. In fact, the reaction of c/s-l,3-pentadiene with 6 yields silacyclobutane adducts, while the trans-diene reacts by [2 + 4]-cycloaddition108. No detectable reaction occurs with 2,5-dimethyl-2,4-hexadiene. The reaction of 6 with isoprene occurs regioselectively to yield adducts 65a and 65b in the ratio 65a 65b = 8.5 (equation 50)106,107. 

Carbohydrate SVI titrated as a monobasic acid, pK = 2.0, as expected for a phosphate diester, - and mild alkaline hydrolysis cleaved the labile, phosphate diester linkage, to produce a serologically inert monoester, [a]D -M06°, which was not precipitated by alcohol in the presence of calcium acetate. Acidic or enzymic hydrolysis of the monoester yielded a crystalline, nonreducing, chromatographically homogeneous tetrasaccharide which, after sequential methylation and acidic hydrolysis, yielded 2,3,4,6-... 

The compound was quite obviously an amine due to its basic character. Von Braun degradation (NMe - NCN) and Hofmann degradation (sequential methylation -elimination) implied a cyclic tertiary amine. Further exhaustive Hofmann degradation led to an unusual net elimination of both trimethylamine and ethylene. (This reaction was driven by aromatization of the C-ring after elimination of the Q5-C16-N17 ethylamine bridge). 

As shown, under the reducing ligation conditions, 0—>S acyl transfer occurred at the o-disulfide phenolic ester as previously described (see above), to provide the thioester, which underwent transthioesteriflcation with the thiol-containing glyco-peptide (upon in situ reduction of the auxiliary disulfide bond) the transient intermediate underwent an S N acyl transfer to generate the thermodynamically favored amide bond of the doubly glycosylated peptide adduct. The auxiliary was subsequently removed through sequential methylation of the fi-ee thiol to prevent the reverse acid-mediated N S acyl shift, followed by TFA treatment. 

In nature, where free choline is limiting, the plant must rely on the methylation of the ethanolamine head group to generate PC. Another critical component of PC biosynthesis, therefore, is the methyltransferase(s) responsible for this sequential methylation of ethanolamine. The availability of the ESTs has facilitated our current efforts to isolate and characterize a higher plant representative of this important class of enzymes (P.K. Dinsmore, unpublished results). 

The utility of 2,2 -biindolyl derivatives as indolocarbazole ptecursors has also been exploited extensively by Somei and co-workers, who reported the first syntheses of the naturally occurring indolo[2,3-a]carbazoles 16 and 17 (Scheme 9). A chloroacetylation of 2,2 -biindolyl (46) followed by treatment of the resulting product 58 with sodium cyanide in formamide-methanol provided 59. Transformation of 59 into the acetoxy derivative 60, followed by hydrolysis to 61, finally led to the target compounds after subsequent sequential methylations [97H(45)1647]. 

Isotopic labeling studies of methanol co-fed with an aromatic show that aromatic methylation reactions involve sequential methylation steps however, varying incorporation of atoms into methylbenzenes also shows that aromatic methylation is not the only route by which methylbenzenes are formed [62],... 

Alkyl 2-(phenylsulfonyl)[ C]acrylates Treatment of alkyl bromo[ C]acetates with sodium benzenesulfinate provides alkyl 2-(phenylsulfonyl][ C]acetates 230 (Figure 6.68). Sequential methylation, selenylation and oxidative elimination of PhSeOH coverts 230 into alkyl 2-(phenylsulfonyl)[ C]acrylates 231. powerful and versatile Michael... 

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