Phase-transfer reactions, selective protection

LY311727 is an indole acetic acid based selective inhibitor of human non-pancreatic secretory phospholipase A2 (hnpsPLA2) under development by Lilly as a potential treatment for sepsis. The synthesis of LY311727 involved a Nenitzescu indolization reaction as a key step. The Nenitzescu condensation of quinone 4 with the p-aminoacrylate 39 was carried out in CH3NO2 to provide the desired 5-hydroxylindole 40 in 83% yield. Protection of the 5-hydroxyl moiety in indole 40 was accomplished in H2O under phase transfer conditions in 80% yield. Lithium aluminum hydride mediated reduction of the ester functional group in 41 provided the alcohol 42 in 78% yield. 

Another methodology applied to the monosubstitution of diols is the use of copper complexation of dianions. The dianion is first formed by reaction of a diol with two equivalents of NaH. The copper complex is then formed by addition of a copper salt. Reaction of the copper complex with various electrophiles (alkyl halides, acyl chlorides) then gives the selectively protected products. As with the phase-transfer technique, very little disubstitution is observed. However, as illustrated in Scheme 3.16, the regioselectivity is reversed (i.e., 4,6-diols give mainly 4-substitution and 2,3-diols give mainly 3-substitution). Using this technique, both alkylations (benzylation, allylation) and acylations (acetylation, benzoylation, pivaloylation) have been carried out. As usual, the degree of selectivity depends on reaction conditions and structural factors [44]. 

Sulfonates (58) are obtained by reaction of a sulfonyl chloride with an alcohol or phenol in the presence of a base, e.g. pyridine, at low temperatures to avoid side reactions (Scheme 42). In the reaction, yields of the sulfonate (58) may be enhanced under anhydrous conditions or by the use of phase transfer catalysts, and it is found that primary alcohols react must faster than secondary alcohols and the primary sulfonates are more stable. Tertiary alcohols only form alkenes. The selective sulfonation of a primary hydroxy group in the presence of a secondary hydroxy group is therefore possible and is a useful procedure for the selective protection of a primary alcohol group (Scheme 43). 

The first example of a fully recyclable fluorous chiral metal-free catalyst was reported by Maruoka and coworkers, who described the enantioselective alkylation of a protected glycine derivative (Scheme 5.17) with various benzyl- and alkyl bromides, in the presence of the quaternary ammonium bromide 62 as a phase-transfer catalyst [77]. Reactions were performed in a 50% aqueous KOH/toluene biphasic system in which 62 was poorly soluble. Nevertheless, the alkylated products were obtained in good yields (from 81 to 93%), with enantioselectivity ranging from 87 to 93% ee. Catalyst 62 was recovered by extraction with FC-72, followed by evaporation of the solvent, and could be used at least three times without any loss of activity and selectivity. 

Tetraalkylammonium salts have been used as phase transfer catalysts for alkylation [5], sulfonylation [46], and benzoylation reactions [47] of carbohydrate derivatives in mixed organic/aqueous solvent. For example, benzyhdene-protected methyl a-glucopyranoside underwent selective benzylation at the more acidic 2-OH group in the presence of a phase transfer catalyst (Scheme 11). 

Catechols likewise undergo 0-alkylation under phase transfer conditions, yielding methylenedioxy derivatives on reaction with methylene bromide [8]. This reaction constitutes a useful route to this commonly occurring oxygen heterocycle as well as providing a facile protection method for 1,2-dihydroxyarenes. Dibromo-methane rather than the more reactive diiodomethane was used in this reaction because the latter is a source of iodide ion which poisons the phase transfer catalyst by selectively ion-pairing with the quaternary ammonium cation. Phenoxide ion can apparently compete successfully with bromide but not iodide in the formation of an extractable ion pair under these conditions. 

Chiral two-center phase-transfer catalyst 202 possessing 2,6-disubstituted cyclohexane spiroacetal catalyzes the syn-selective Mannich-type reaction of glycine Schiff base 186 with N-Boc-protected aromatic imines as weU as enoUzable aUcyl imines (201) in high yields with moderate to good enantioselectivities (Scheme 28.24) [103],... 

Protection of Phenols. The reaction of MOMCl with a phenol under phase-transfer conditions works well to give phenolic MOM ethers and will selectivity protect a phenol in the presence of an alcohol. The more classical Williamson ether synthesis also provides excellent results, but may require the addition of a crown ether to enhance the nucleophilicity of the phenolate anion. As in the case of alcohol protection, alternatives using methylal have been developed for phenol protection which do not rely on the carcinogenic MOMCl.Phenolic silyl ethers can be converted directly to MOM ethers by reaction with TASF (Tris(dimethylamino)sulfonium Difluorotrimethyl-silicate) and MOMCl. ... 

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