Merging α-Lithiation and Aldol-Tishchenko Reaction to Construct Polyols from Benzyl Ethers

Abstract

-Lithiobenzyl ethers, generated by selective -lithiation, undergo an Aldol-Tishchenko reaction upon treatment with carboxylic esters and paraformaldehyde. The reaction of the organolithium with the carboxylate generates an intermediate enolate that, after formaldehyde addition, affords 1,2,3-triol derivatives in a straightforward and one-pot manner. These products are obtained as single diastereoisomers bearing a quaternary stereocenter. The complete diastereocontrol of the Aldol-Tishchenko process is attributed to stereoelectronic preferences in the transition state.

Aldol–Tishchenko Reaction of α-Oxy Ketones: Diastereoselective Synthesis of 1,2,3-Triol Derivatives

“…For this reason, we tried the reaction with MOMprotected benzoin 8 and, gratifyingly, the expected 1,2,3-triol derivative 9 was obtained in good yield (Scheme 4). Finally, as it was demonstrated in our previous work, 8 the obtained 1,3-diols serve as an excellent platform for the synthesis of the relevant oxetane moiety. 20 The broader scope observed for the aldol−Tishchenko reaction of α-oxyketones with paraformaldehyde also renders in a wider variety of oxetanes 10, allowing the substitution in α-position even with a cycloalkyl group (10e).…”

“…Interestingly, apart from alkoxyfunctionalized aryl groups as substituents of the oxygen atom (entries 5 and 6), aryloxy groups bearing an electronwithdrawing group like ethoxycarbonyl, which would be completely incompatible with the -lithiation strategy, are also tolerated under the reaction conditions (entry 7). One of the main limitations of our previously developed methodology 8 for the synthesis of triol derivatives 2 was that the R 3 substituent (see Scheme 1) could be only a phenyl group, as only the lithiation of benzyl ethers proceeds satisfactorily. For this reason, we turned our attention to -oxygenated alkyl phenyl ketones 1h-w that will provide polyols 2h-w with an alkyl group at C-2 (Table 4).…”

“…General experimental procedure E (GEP-E): 8 To a clean and oven-dried flask under nitrogen atmosphere the corresponding Weinreb amide (1 equiv) and THF were added. The mixture was cooled down to 0 °C (when using cyclohexylmagnesium chloride) or to −78 °C (when using an organolithium reagent) and the corresponding organometallic compound was added dropwise.…”

“…General experimental procedure G (GEP-G): 8 A solution of the corresponding propane-1,3-diol derivative 2 (0.2 mmol) in dioxane (1 mL) was treated with a solution of aqueous NaOH (1 mL, 10% w/w) for 15 min. Then, a solution of p-toluenesulfonyl chloride (114 mg, 0.6 mmol) in dioxane (1 mL) was added and the reaction was…”

“…7 More recently, we have taken advantage of this process by merging the -lithiation of benzyl ethers with the aldol−Tishchenko reaction to synthesize polyols in a diastereoselective manner (Scheme 1, a). 8 In the hetero-aldol−Tishchenko reaction, a ketone enolate reacts with an excess of aldehyde to form 1,2-anti, 1,3-anti 1,3diol monoesters (Scheme 1, b). 9 Lithium amides like LDA, LiHDMS or LTMP are typically employed for the enolate generation, usually at −78 °C in THF.…”