4-acetoxy-l,3-dioxane

Alkylations of 4-cyano-l,3-dioxanes (cyanohydrin acetonides) represent a highly practical approach to syn-l,3-diol synthesis. Herein we present a comprehensive summary of cyanohydrin acetonide chemistry, with particular emphasis on practical aspects of couplings, as well as their utility in natural product synthesis. Both 4-acetoxy-l,3-dioxanes and 4-lithio-1,3-dioxanes have emerged as interesting anri-l,3-diol synthons. The preparation and utility of these two synthons are described. 

A more general route to 4-acetoxy-l,3-dioxanes utilizes the reductive acylation of l,3-dioxane-4-ones [46] (Scheme 21). l,3-Dioxane-4-ones 126 are prepared from the corresponding -hydroxy carboxylic acids. Low temperature reduction with DIBALH generates a diisobutylaluminum hemiacetal (127) which undergoes acylation in situ with AC2O in the presence of pyridine and DMAP. This method allows for the preparation of a wide range of 4-acetoxy-l,3-dioxanes, without the problem of a-epimerization. This method also represents a general approach to acylic a-acetoxy ethers, which are themselves useful synthetic intermediates [47,48]. 

Allylsilane additions were used in a formal synthesis of roflamycoin [51] (Eq. 24). A one-pot, three-component sequential coupling of bis-allylsilane 138 with 4-acetoxy-l,3-dioxanes 137 and 139 provided the C11-C22 polyol chain (140) in moderate yield. 

Addition of crotyl metal reagents to 4-acetoxy-l,3-dioxanes was utilized in the synthesis of dipropionate synthons [52] (Scheme 22). These reactions... 

GC analysis revealed > 290 1 selectivity anti. syn) in the diethylzinc addition. The 4-acetoxy-l,3-dioxane 152 used in the above experiments was a 24 1 mixture of diastereomers, epimeric at the 2-position. This implies that the acetal stereocenter undergoes isomerization to the most stable oxocarbenium ion prior to reaction with Et2Zn. Conclusive evidence for this was obtained when submission of compound 156 to the identical conditions produced 155 as the major product (Eq. 26). 

Phenylthio acetals are much more easily prepared from the corresponding 4-acetoxy-l,3-dioxanes [45] (Eq. 29). The dioxane 125 gave the phenyl sulfides 185 in essentially quantitative yield on treatment with BF3 OEt2 and thiophenol at -78 °C. This method has been used to prepare compound 185 on a 40 g scale. 

The Lewis acid-catalyzed reaction of 4-acetoxy-l,3-dioxanes with nucleophiles has been reviewed <2001TCC(216)51>. The principles of the reaction are displayed in (Equation 44). The combination of boron trifluoride and organozinc compounds was found to be very efficient <1997JOC6460, 1999JOC2026> but allylsilanes react as well <19%SL536, 1998TL6811>. 

The nucleophilic displacement of the acetoxy group of 4-acetoxy-l,3-dioxanes was also effected by metalated alkynes. Organoaluminium and organotin compounds have been employed <1998TL3103>. The stereochemical outcome is similar to that of the analogous reaction with a high preference for the 7 //-product (Equation 45). 

SL1622>, and chiral 4-acetoxy-l,3-dioxanes as precursors for the initial reaction of a multi component synthesis (cf Equation (44), Section 8.11.6.4.3) <2006JA16480> have also been successfully demonstrated. 

Alkynyltins couple with 4-acetoxy-l,3-dioxane in the presence of BF3-OEt2 to give acetal protected propargylic anti- 1,3-diols (Equation (63)).217... 

Lewis acids such as SnBr4 promote the coupling of 4-acetoxy-l,3-dioxanes with cro-tyl-metal species to generate propionate motifs (Eq. 40) [67]. The reactions show a marked dependence on Lewis acid, crotyl metal species, and the presence and stereochemical disposition of a C5 methyl group. A 1,3-syn methyl relationship is favored in these additions. 

Zincio-I,3-dithianes are valuable reagents. Based on reactions of organozincs 4-acetoxy-l,3-dioxanes serve as precursors of anti-l,3-diols." A synthesis of 1,1-diarylallenes involves Pd-catalyzed coupling of the organozinc species which are derived from 1-arylpropynes by lithiation and Li/Zn exchange with aryl halides. By an sp -sp bond formation process to introduce a dienyl substituent to C-2 of 2-cyclopentenones a facile synthesis of nakienone-A was developed. - ... 

Scheme 5.2.28). Anticipated production of oxonium 133 leads to the C-1 alkylation products 134 and 135 in a 3 1 ratio, which can be rationalized via synclinal 136 and antiperiplanar 137, respectively. The lack of facial basis in the oxocarbenium 133 leads equally to attack from above and below the plane of the conjugated cation, yielding an additional pair of syn and anti adducts analogous to 134/135 in similar ratio (dr 4 1). In related fashion, Rychnovsky has described the allylation reactions of 4-acetoxy-l,3-dioxanes.43 The presence of the 5-methyl substituent in 138 requires treatment with reactive -2-butenyl tri-n-butylstannane, affording 139 as the major product (dr 4 1) via the antiperiplanar transition state arrangement analogous to 137. 

Acetoxy-l,3-dioxanes undergo a facile coupling reaction with dialkylzinc reagents which exhibits high anfi-selectivity <97JOC6460>. Chiral Rh-catalysed decomposition of... 

DialkyIzincs couple with 4-acetoxy-l,3-dioxane (49) in the presence of (la) to form 4-alkyl-1,3-dioxanes (50) with good to excellent trans diastereoselectivity [88]. A variety of functionalities can be introduced because of the stability of the C-Zn bond. The diastereoface selectivity is reasonably explained by the kinetically favored... 

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