2.2- dimethyl-l,3-dioxane-5-one

The boron enolates derived from (5)-4-silylated 2,2-dimethyl-l,3-dioxan-5-one undergo anti diastereoselective aldol reactions which provide access to protected oxopolyols of high stereochemical integrity <96SYN1095>. 

The focus in this section is the electrophilic a-functionalization of 2,2-dimethyl-l,3-dioxan-5-one. Various reactions have been carried out, such as alkylations, aldol additions, Mannich reactions, and transition metal-catalyzed reactions. Conditions were described for diastereoselective transformations, or auxiliary controlled diastereoselective transformations, providing enantiomerically pure products, and enantioselectively catalyzed reactions using organo-catalysts. 

Stereoselective) additions of nucleophiles to 5-alkylidene Meldmm s acid as displayed in Scheme 17 (Section 8.11.6.1.3) <2006TA2957, 2007AGE4964> and to the carbonyl group of 2,2-dimethyl-l,3-dioxan-5-one (Scheme 47, Section 8.11.6.3.3) either in a three component transformation <2006OL3689> or in a nickel-catalyzed reaction... 

The SAMP-hydrazone derived from 2,2-dimethyl-l,3-dioxan-5-one is used as a chiral 1,3-di-hydroxy-2-propanone enolate equivalent and transformed to the corresponding 4-alkyl derivatives in good yield and high enantiomeric purity (89 to >95% ee, see Table 2)15. 

Retrosynthetic considerations among our group have revealed the possibility of using our SAMP/RAMP hydrazone methodology in combination with the synthetic building block 2,2-dimethyl-l,3-dioxan-5-one. Thus starting from the... 

As already demonstrated in the previous natural product synthesis, the alkylation of 2,2-dimethyl-l,3-dioxan-5-one SAMP/RAMP hydrazones is a reliable tool with which to synthesize chiral 4-substituted 2,2-dimethyl-l,3-dioxan-5-ones in gram quantities and with high enantiomeric excesses [68]. Thus, after metalla-tion of the RAMP hydrazone (R) -96 the corresponding lithio azaenolate was alkyl-... 

As is depicted in Scheme 1.2.29, the epoxide 128 was synthesized starting from 2,2-dimethyl-l,3-dioxan-5-one RAMP hydrazone (R)-96, which was double-alkylated with methyl iodide at a- and a -positions leading to the trons-dimethylated hydrazone 131 in 79% yield over two steps and excellent stereoselectivity (de, ee > 96%) [68]. The quaternary stereocenter bearing the desired tertiary alcohol function was generated using benzyloxymethyl chloride (BOMCl) as the electrophile to trap the lithiated hydrazone 131, providing the a-quaternary hydrazone 132 in very good yield (92%), excellent diastereomeric and enantiomeric excesses (de, ee > 96%) and with the required cis relationship of the methyl substituents. 

Mannich reactions varied from excellent to low depending on the reactants Table 2.16 includes the results of highly enantioselective reactions. Reactions using 2,2-dimethyl-l,3-dioxane-5-one (5) provide for concise syntheses of enantiomerically enriched protected amino sugars (entries 8-10) [91]. In reactions using 5, the addition of 1 to 10 equiv. of H20 increased the rate and stereoselectivity of the reaction. 

Enders D, Bockstiegel B (1989) Enantioselective alkylation of 2,2-dimethyl-l,3-dioxan-5-one using the SAMP-/RAMP-hydrazone method. Synthesis... 

Dimethyl-l,3-dioxan-5-one SAMP/RAMP hydra-zones j were used as dihydroxyacetonephosphate equivalents in the synthesis of C2 symmetric ketones (eq 5), aza sugars with novel substitution patterns, or C5 to C9 deoxy sugars. SAMP hydrazones of 2-oxo esters represent novel phosphoenolpyruvate (PEP) equivalents. a,a-Disubstituted spiroacetals are accessible via the alkylation of ketone SAMP/RAMP hydrazones. ... 

Enders and co-workers [162] have reported a protocol for the synthesis of aminopentoses and aminohexoses based on the use of 2,2-dimethyl-l,3-dioxan-5-one (25) as the ketone donor in a three-component Mannich reaction with several aldehydes and p-anisidine in the presence of L-proline or (fert-butyl)dimethylsilyloxy-L-proline as organocatalysts. 

The precursor to amidoacrolein 64, 1,3-dioxin 66, was prepared as follows [39] the imine derived from the condensation of 2,2-dimethyl-l,3-dioxan-5-one with aminoacetaldehyde dimethyl acetal was acetylated with acetic anhydride/triethylamine to afford dioxin 66 in 83% yield (Scheme 24). Retro Diels-Alder of dioxin 66 in warm benzonitrile (120 C, 16 h) generated the amidoacrolein 64, which was trapped in situ with the silyloxydiene 65 to afford the desired cycloadduct 63 (64%). An aldol cyclization between the acetamide and neighboring aldehyde functionalities within 63 proceeded smoothly (2 equiv. of KCh-Bu, 10 equiv. of EtOAc, THF, 0 °C, 40 min) and directly afforded the corresponding conjugated lactam. This product was of sufficient purity for the second aldol reaction, which was best accomplished under acidic conditions, presumably proceeding through the achiral keto aldehyde intermediate 62 enroute to the desired, but racemic, (3-hydroxy ketone 61 obtained in 79% yield after the two consecutive ring closures. 

Lewis acids have also been used to synthesize highly functionalized furan derivatives with biological signalling capabilities. For example, Sello and co-workers used scandium(III) triflate in their biomimetic synthesis of several signalling molecules of the bacterium Streptomyces. Reaction of methyl 5-methyl-3-oxohexanoate and 2,2-dimethyl-l,3-dioxan-5-one in the presence of scandium (III) triflate in methanol gave the corresponding furan in 60% yield. 

Enders and Chow further evaluated the use of 3a for the addition of 2,2-dimethyl-l,3-dioxan-5-one to nitroalkenes. Interestingly, the addition of a water molecule accelerated the reaction, though a prolonged reaction time was required and the desired products were obtained in moderate yields and with enantioselectivities of 77-85% (Scheme 9.21). ... 

Iterative Strategy for the Synthesis of Polyacetates Enders identified 2,2-dimethyl-l,3-dioxan-5-one 12 [15] as a particularly interesting building block for the synthesis of polyacetates using the SAMP/RAMP hydrazone sbategy [16]. Indeed, this building block can play the role of a synthetic equivalent of dihydroxyacetone phosphate (DH AP)... 

SCHEME 2.32 Diastereoselective alkylation of 2,2-dimethyl-l,3-dioxan-5-one hydrazone. 

The first of the two key fragments bearing the C12-C21 carbon backbone was synthesized starting from 2,2-dimethyl-l,3-dioxan-5-one SAMP hydrazone 13, which underwent two successive diastereoselective alkylations using (2-bromoethoxy)-tert-butyldimethylsilane and... 

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