Triol protection with 6-benzoyl-3,4-dihydro-(2H)-pyran{

Ketones (or gem-dimethoxyalkanes) can react with 1,2 or 1,3-diols with acid catalysis to form acetals, and dihydropyrans react with alcohols under similar conditions to form tetrahydropyrans. Ley and co-workers recently introduced bis-dihydropyrans to protect a wide range of 1,2-diols as their dispiroketals, the products being formed were those with maximum anomeric stabilisation at newly formed centres. The Ley group has exploited the rigid architecture of these ‘bispoke’ derivatives in subsequent asymmetric reactions, and exploited the bispoke derivatives of vicinal equatorial carbohydrate diols to tune glycoside reactivity. Ley and coworkers have also developed 1,2-diketones (as 1,1,2,2tetramethoxy derivatives) as 1,2-diol protecting groups, forming in acidic methanol the corresponding 2,3-dimethoxy-1,4-dioxane. Reaction with glycerol gave triol protection resulting in 2-methoxy-3,7,8-trioxabicyclo[3.2.1]octane. Reaction with vicinal equatorial carbohydrate diols resulted in a glycosidation reactivity tuning effect between that of the corresponding benzylated and benzoylated systems. In contrast to that of diols, the protection of triols has been neglected. In this paper, we combine the protecting capability of dihydropyran and a carbonyl group in a single molecule to protect triols. 6-Benzoyl-3,4-dihydro-(2H)-pyran 1 can be conveniently prepared in large multigramme quantities. Addition of tert-butyl lithium (34 mmol) to 3,4-dihydro-(2H)-pyran (33 mmol) at220 uC forms the vinyl anion. Cooling to 278 uC followed by addition of N,N-dimethylbenzamide (31 mmol) and warming to room temperature gave a crude product (.95% pure) that was adequate for subsequent reactions, and could be kept in the fridge for weeks. Initial experiments involved the reaction of 1 with glycerol and camphorsulfonic acid (CSA) in toluene under Dean and Stark conditions which gave two products, the expected trioxabicyclo[3.2.1]octane 2, and a second compound whose spectral characteristics were consistent with a 2,5,7-trioxabicyclo[2,2,2]octane. However reaction of glycerol (2.7 mmol), CSA (5.5 mmol), trimethylorthoformate (5.5 mmol) and 1 (5.5 mmol) in refluxing (12 h) methanol (‘orthoformate’ conditions) rapidly formed a single racemic crystalline triol protected product (1R,4(29)S,5S)-spiro[5-phenyl-3,6,8-trioxabicyclo[3.2.1]octane-4,29tetrahydropyran] 2 in good yield (42%) (Scheme 1). In the product, 2, the tetrahydropyranyl oxygen is axial relative to the 1,4-dioxane chair due to the anomeric effect, as shown in the X-ray structure (Fig. 1). Refluxing 2 in aqueous acid led to the recovery of 1. { Electronic supplementary information (ESI) available: experimental and X-ray diffraction data. See http://www.rsc.org/suppdata/cc/b4/b418035f/ *bjr2@le.ac.uk

Ketones (or gem-dimethoxyalkanes) can react with 1,2 or 1,3-diols with acid catalysis to form acetals, and dihydropyrans react with alcohols under similar conditions to form tetrahydropyrans. Ley and co-workers recently introduced bis-dihydropyrans to protect a wide range of 1,2-diols as their dispiroketals, the products being formed were those with maximum anomeric stabilisation at newly formed centres. 1 The Ley group has exploited the rigid architecture of these 'bispoke' derivatives in subsequent asymmetric reactions, 2 and exploited the bispoke derivatives of vicinal equatorial carbohydrate diols to tune glycoside reactivity. 3Ley and coworkers have also developed 1,2-diketones (as 1,1,2,2tetramethoxy derivatives) as 1,2-diol protecting groups, forming in acidic methanol the corresponding 2,3-dimethoxy-1,4-dioxane. 4 Reaction with glycerol gave triol protection resulting in 2-methoxy-3,7,8-trioxabicyclo[3.2.1]octane.Reaction with vicinal equatorial carbohydrate diols resulted in a glycosidation reactivity tuning effect between that of the corresponding benzylated and benzoylated systems. 5n contrast to that of diols, the protection of triols has been neglected.In this paper, we combine the protecting capability of dihydropyran and a carbonyl group in a single molecule to protect triols.
Reaction with meso-erythritol under orthoformate conditions gave one major racemic product 4 which was readily separable by flash chromatography from a second minor isomer.Derivatisation of the major isomer to the 4-nitrobenzoate and analysis by X-ray crystallography showed that the remaining hydroxymethyl group was attached to C-2.This equatorial hydroxymethyl group could be converted into the corresponding bromide (PPh 3 , CBr 4 ), or oxidised (Swern conditions) to the aldehyde and reacted with Grignard or Wittig reagents, or the alcohol converted into an alkene in one pot using manganese dioxide and the Wittig reagent. 8Refluxing 4 in water-THF with CSA led to the recovery of erythritol (as the tetraacetate) in 75% yield.
Reaction of 1 with the meso-pentol xylitol under the orthoformate conditions gave two isomeric products 5 and 6.Derivatisation of the isomer 6 to the bis-4-nitrobenzoate followed by X-ray crystallography showed that 6 had the residual 1,2dihydroxyethyl group attached to C-7.
X-Ray analysis of the bis-4-nitrobenzoate derivative of 7 showed that reaction of 1 with d-gluconolactone gave methoxycarbonyl 7, where reaction had occurred on the three terminal hydroxyl groups of the open chain form.
In these preliminary studies, a convenient procedure for the protection of triols has been developed, that should prove valuable in synthesis of highly functionalised polyhydroxylated natural products, desymmetrisation of meso-polyols and the synthesis of isotopically labelled compounds.