Diethyl ether stereochemistry

The influence that a possible chelation has on the stereochemistry of the bromine-lithium exchange in dibromoaUcenes was first studied in the chiral MEM (methoxyethoxymethyl) ether 40. When this compound is treated with 1.2 equivalents of n-butyllithium in tetrahydrofnran, the acids E- and Z-42 are obtained in a ratio of 32 68 after carboxylation. Obvionsly, a kinetically favored substitution of the more easily accessible trans bromine atom occurs. When, however, slightly less than one equivalent (0.95-0.98 equiv) of -bntyllithinm is slowly added to a solution of 40 in diethyl ether at — 105°C, the -confignrated carbenoid 41 forms almost exclusively, and the carboxylic acids E- and Z-42 are obtained after reaction with dry ice in a ratio of over 99 1 (Scheme 9) ,i93 ... 

Improved reactivity is offered by 3-hydroxy-A -(4-methylphenylsulfonyl)-4-pentenamine under different conditions (/V-bromosuccinimide in 1,2-dimethoxyethane/water or iodine and sodium hydrogen carbonate in diethyl ether/water). The reactions proceeded at 0-20 °C to give the corresponding 2-haloalkyl-iV-(4-methylphenylsulfonyl)-3-pyrrolidinols in good yield, high diastereoselectivity was observed in favor of the 2,3-m-isomer (Table 5). In this cyclization even the presence of a phenyl substituent at C-5 does not affect the relative stereochemistry of the C-2 and C-3 substituents92-94. 

The first enantioselective total synthesis of tetracyclic sesquiterpenoid (+)-cyclomyltaylan-5a-ol, isolated from a Taiwanese liverwort, was accomplished by H. Hagiwara and co-workers. They started out from Hajos-Parrish ketone analogue, (S)-(+)-4,7a-dimethyl-2,3,7,7a-tetrahydro-6/-/-indene-1,5-dione, that could be synthesized from 2-methylcyclopentane-1,3-dione and ethyl vinyl ketone in an acetic acid-catalyzed Michael addition followed by an intramolecular aldol reaction. The intramolecular aldol reaction was carried out in the presence of one equivalent (S)-(-)-phenylalanine and 0.5 equivalent D-camphorsulfonic acid. The resulting enone was recrystallized from hexane-diethyl ether to yield the product in 43% yield and 98% ee. Since the absolute stereochemistry of the natural product was unknown, the total synthesis also served to establish the absolute stereochemistry. 

These arrangements are presumably controlled in part by the intramolecular nature of the proton transfer stage of the reaction. While the same stereochemistry is obtained with a variety of Lewis acids, e.g., dimethylaluminum chloride, boron trifluoride-diethyl ether complex, tin(IV) chloride, the opposite preference is observed with bis[4-bromo-2,6-di-/m-buty]phen-oxy](methyl)aluminum (MABR)104 (see Table 6, entries 4-7 and the following example). 

A different stereochemical outcome is observed in the reduction of the tetracyclic indanone derivative using lithium aluminum hydride in diethyl ether to afford the rranx-alcohol (83 %)212 or the cw-alcohol in the Meerwein-Ponndorf-Verley reduction employing aluminum isopropox-ide and isopropanol (99% 212 83 %213). The stereochemistry of the products were confirmed by mass spectroscopy giving a high M+-water peak (.vyn-climination) in the case of the c/.v-al-cohol213. 

Following resolution of /F-dimelhyluntino it methyl-propiophenonc with diben/oyl-< - Muriatic acid, the chiral ketone is added to a solution of benzylmagnesium chloride in diethyl ether. %. see. Scheme 6.6. Liberation of the alcohol product. 25, provides the product with the carbon backbone and stereochemistry in place. The tertiary alcohol... 

The product of another approach to replacement of the ketone in erythromycin is dirithromycin (14), a 9-A, ll-0-oxazine derivative of 9(S)-amino-9-deoxoerythromycin (9(5)-erythromycylamine, 15) [101, 102]. R stereochemistry of the substituent at C-2 of the oxazine was established by X-ray crystallography [101]. Condensation of erythromycylamine with 2-methoxyethoxyacetaldehyde initially gives the 2(5)-oxazine, which was isolated using diethyl ether as solvent, but it rapidly epimerizes to dirithromycin [103, 104]. A related compound with 5 stereochemistry of the oxazine substituent has also been crystallized [105]. Both epimers readily... 

Consideration of Scheme 6 and of (1) leads directly to the hypothesis that the explanation of any factors affecting the stereochemistry of glycosylation reactions can be found in the manner in which these factors influence the equilibrium between the contact and solvent separated ion pairs. For example, polar solvents support charge separation better than nonpolar solvents and so are likely to shift the equilibrium toward the solvent separated ion pair and increase the proportion of a-glycoside formation. The difference in selectivity noted earlier between the use of diethyl ether and dichloromethane as solvent [14], as well as the increased p-selectivity with weaker nucleophiles in toluene solution (see Sect. 2.1) [80, 81], are thus readily understood. The importance of the concentration of the alcohol on selectivity is also apparent from (1) as is the expected influence of the concentration of the triflate counterion. To favor p-mannoside formation it is necessary to shift the contact ion pair-solvent separated ion pair equilibrium as far as possible toward the contact ion pair. However, any factors favoring the contact ion pair over the solvent separated ion pair are also likely to favor the covalent glycosyl triflate over the... 

Under the optimized conditions, allyl 2-bromophenyl ethers were treated with 2.0 equiv. of tert-butyllithium in diethyl ether at —78 °C to afford allyl 2-lithiophenyl ethers 166, which were stable at low temperature. Addition of TMEDA to the reaction mixture, followed by warming to 0°C, and subsequent treatment with various electrophiles led to the functionalized dihydrobenzofuran derivatives 165 in moderate to good yields (Scheme 10.53, path A). It is interesting to note that the 1,3-elimination pathway (Scheme 10.53, path B) could be avoided. Furthermore, this intramolecular carbolithiation reaction was completely diastereoselective, and only the trans diastereomers were obtained. This stereochemistry was explained considering the chairlike transition state 166 in which the a-substituent predominantly occupies a pseudoequatorial position resulting in high levels of... 

A full study of the stereochemistry of the addition to (22) of the Grignard reagent MegCCOCHMeMgX (X = Cl or Br) has been made. The trans-isomers (23a and b) are formed almost exclusively (98 %) at short reaction times (minutes) via a stereospecific equatorial attack on the carbonyl of (22), whereas at much longer reaction times, e.g. 72 h, the cis-isomers are formed in 96% yield. The diastereoiso-meric ratio of (23a) to (23b) was found to be dependent on solvent, i.e. in diethyl ether 48 52, in dimethoxymethane 62 38, in tetrahydrofuran 70 30, and in hexa-methylphosphortriamide (HMPA) 50 50. 

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