Stereochemistry benzyl ethers

Arguably the most challenging aspect for the preparation of 1 was construction of the unsymmetrically substituted sec-sec chiral bis(trifluoromethyl)benzylic ether functionality with careful control of the relative and absolute stereochemistry [21], The original chemistry route to ether intermediate 18 involved an unselective etherification of chiral alcohol 10 with racemic imidate 17 and separation of a nearly 1 1 mixture of diastereomers, as shown in Scheme 7.3. Carbon-oxygen single bond forming reactions leading directly to chiral acyclic sec-sec ethers are particularly rare since known reactions are typically nonstereospecific. While notable exceptions have surfaced [22], each method provides ethers with particular substitution patterns which are not broadly applicable. 

Olefmic benzyl ethers can also be submitted to ethercychzation with aryltellurium trichlorides. The yields and the reaction times are close to those observed for the cycliza-tion of the corresponding alcohols. The stereochemistry of the reaction is low. ... 

In the complexes of w/Ao-substituted benzyl ethers, the benzylic hydrogen atoms are diastereotopic. Alkylation of the derived lithium compounds occurs completely stereoselective-ly anti to the tricarbonylchromium face from a rotamer in which the benzylic methoxy group is anti to the or/Ao-substituent2,3. The stereochemistry of the alkylation was confirmed unambiguously by X-ray analysis of the product3. 

Azadienes of this sort were studied simultaneously by Mariano et al., who reacted mixtures of (1 ,3 ) and (1E, 3Z)-l-phenyl-2-aza-l,3-pentadiene 275 with several electron-rich alkenes, e.g., enamines and enol ethers (85JOC5678) (Scheme 61). They found the (l ,3 )-stereoisomer to be reactive in this process affording stereoselectively endo 276 or exo 277 piperidine cycloadducts in 5-39% yield, after reductive work-up with sodium borohydride. The stereochemistry of the resulting adducts is in agreement with an endo transition state in the case of dienophiles lacking a cis alkyl substituent at the /8-carbon (n-butyl vinyl ether, benzyl vinyl ether, and 1-morpholino cyclopentene), whereas an exo transition state was involved when dihydropyrane or c/s-propenyl benzyl ether were used. Finally, the authors reported that cyclohexene and dimethyl acetylenedi-carboxylate failed to react with these unactivated 2-azadienes. 

A diastereoisomeric mixture of dicobalt hexacarbonyl complexes 33 reacted with trifluoroborane etherate at -20 °C to give the reduced product 3.3 (minus a benzyl ether) as a single diastereoisomer after decomplexation of the metal with cerium(IV) ammonium nitrate. Suggest a mechanism for the formation of 33 which accounts for the stereochemistry of the product. 

Many functional groups are stable under conditions for the alkylation of pseudoephedrine glycinamide enolates, including aryl benzenesulfonate esters (eq 18), rert-butyl carbamate and rerf-butyl carbonate groups (eq 19), tert-butyldimethylsilyl ethers, benzyl ethers, ferf-butyl ethers, methoxymethyl ethers, and alkyl chlorides. The stereochemistry of the alkylation reactions of pseudoephedrine glycinamide and pseudoephedrine sarcosinamide is the same as that observed in alkylations of simple A(-acyl derivatives of pseudoephedrine. 

Preliminary to a second-generation synthesis of the 3-(9-methyl-y-( 1 -4)-mannans, Kishi and co-workers screened a series of mannosyl phosphates for the influence of the 0-2 protecting group and the anomeric stereochemistry of the donor on the outcome of the glycosylation reaction. As may be seen from Scheme 26, the use of benzyl ether protection under these homogeneous solution-phase conditions gave selectivities that were insufficient, whereas the 2-benzoates gave exquisite a-selectivity.34... 

Unnatural d-DET was needed to get the right absolute stereochemistry and 37 was not isolated but protected as a benzyl ether 39 before reaction with allylamine gave the carbon chain of 35. Conversion of OH into NH2 now required inversion. 

Therefore, despite lower stereoselectivity (3 1) in the epoxidation step the benzyl ether 118 (Scheme 20) was converted into 123 and then converted into tetrahydrofu-ran 124. After Swem oxidation a mixture of the aldehydes is generated the isomer with the correct stereochemistry at C-2 cyclizes to the hemiacetal 125 whereas the second C-2 epimer did not cyclize and was thus easily removed by chromatography. By Wittig reaction 125 was transformed into 126 which was smoothly debenzylated under Hanesssian s conditions (15) to give alcohol 127. Inversion of configuration at C-2 was achieved by an oxidation reduction sequence with complete stereocontrol. 

Benzylic carbocations are also stabilized by complexation to chromium and a number of interesting reactions have been reported. Again, reaction of the carbocations with nucleophiles occurs from the exo face of the complex, relative to the metal. Carbocations are readily formed by treatment of benzylic alcohols with a strong acid, such as sulfuric acid, tetrafluoroboric acid, or borontrifluoride etherate. The cation can be trapped with water, alcohols, nitriles, and mono-or disubstituted amines to form alcohols, ethers, amides, and di- or trisubstituted amines respectively. Scheme 96 illustrates the formation of a benzylic carbocation followed by intramolecular trapping, resulting in a net inversion of stereochemistry. Benzylic acetates react with trimethyl aluminium introducing a methyl group from the opposite face of the metal. 

There are many methods that can be used to tackle this question. The only snags are protecting the OH group if necessary and care in isolating the Z-compound as it may isomerize easily to the E-compound by reversible conjugate addition. One way to the Z-alkene uses reduction of an alkyne to control the stereochemistry. The OH group is protected as a benzyl ether removed by hydrogenation, perhaps under the same conditions as the reduction of the alkyne. 

One of the diastereomers of 2,6-dimethylcyclohexyl benzyl ether exhibits an AB quartet for the benzylic protons in its NMR spectrum. Deduce the stereochemistry of this isomer. 

In the example shown in eq 6, the benzylic ether is part of a ring. A number of other examples are recorded, including cases where complex functionality and stereochemistry are unaffected by the procedure, as illustrated in eq 7 ... 

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