4-acetoxy-1,3-dioxanes

Axial addition to oxocarbenium ions derived from 1,3-dioxanes provides protected a f/-l,3-diols. Our group has developed 4-acetoxy-1,3-dioxanes as oxocarbenium ion precursors. This general strategy for the convergent preparation of anfz-l,3-diols complements cyanohydrin acetonide methodology, which gives access to sy -l,3-diol synthons (Sect. 2). 

Acetoxy-1,3-dioxanes can be prepared directly from the corresponding jS-hydroxy aldehydes [45] (Scheme 20). j3-Hydroxy aldehyde 122 exists in an... 

New synthetic methods are the lifeblood of organic chemistry. Synthetic efforts toward natural products often provide the impetus for the development of novel methodology. Reactive synthons derived from 1,3-dioxanes have proven to be valuable intermediates for both syn- and anfz-1,3-diols found in many complex natural products. Coupling reactions at the 4-position of 1,3-dioxanes exploit anomeric effects to generate syu-1,3-diols (cyanohydrin acetonides), autz-1,3-diols (4-acetoxy-1,3-dioxanes), and either syn- or azztz-1,3-diols (4-lithio-1,3-dioxanes). In the future, as biologically active polyol-containing natural products continue to be discovered, the methods described above should see much use. 

Protected 1,3-an/i-diols 14 are accessible by the highly stereoselective Lewis acid promoted addition of dialkylzinc compounds to 4-acet-oxy-1,3-dioxanes 13 (Scheme 3) [5]. The two d, -orientated alkyl substituents at C2 and C6 fix the carboxonium ion 15 in the half-chair conformation, which undergoes preferential axial attack by the dialkylzinc under stereoelec-tronic control. The 4-acetoxy-1,3-dioxanes 13 may be synthesized from the Seebach 1,3-diox-an-4-ones 12 by reduction with diisobutylalumi-num hydride (DIBAH) and acetylation. Since dialkylzinc compounds are now readily available and are compatible with many functional groups, this... 

Scheme 3. Preparation of the 1,3-anti-diol acetal 14 by dialkylzinc addition to 4-acetoxy-1,3-dioxanes 13 according to Rychnovsky et al. TMSOTf = tri-methylsilyltrifluoromethane sulfonate.

Compounds in which conformational, rather than configurational, equilibria are influenced by the anomeric effect are depicted in entries 4—6. Single-crystal X-ray dilfiaction studies have unambiguously established that all the chlorine atoms of trans, cis, ira j-2,3,5,6-tetrachloro-l,4-dioxane occupy axial sites in the crystal. Each chlorine in die molecule is bonded to an anomeric carbon and is subject to the anomeric effect. Equally striking is the observation that all the substituents of the tri-0-acetyl-/ -D-xylopyranosyl chloride shown in entry 5 are in the axial orientation in solution. Here, no special crystal packing forces can be invoked to rationalize the preferred conformation. The anomeric effect of a single chlorine is sufficient to drive the equilibrium in favor of the conformation that puts the three acetoxy groups in axial positions. 

Ester functions are not saponified under these ring opening conditions. However, a trans-a-acetoxy function hinders the epoxide opening reaction and a noticeable decrease in yield is observed in comparison to the cw-a-acetoxy isomer. The ring opening reaction is also dependent on the concentration of sulfuric acid. Polymer formation results when the acid concentration is too low and the reaction is markedly slower with excessive concentrations of acid. A 0.5% (vol./vol.) concentration of acid in DMSO is satisfactory. Ring opening does not occur when ethanol, acetone, or dioxane are used as solvent. 

A solution of 500 mg 3 -acetoxypregn-5-en-20-one-[17a,16a-c]-A -pyrazoline in 100 ml of anhydrous dioxane is stirred with a magnetic stirrer and irradiated in a water-cooled quartz reactor with a high pressure Biosol Philips 250 W quartz lamp for 1 hr. The solvent is removed at reduced pressure and the residue is chromatographed on alumina (activity III). Elution with petroleum ether-benzene (3 1) gives 0.2 g (42%) of 3 -acetoxy-16a,17a-methylene-pregn-5-en-20-one mp 193-193.5° after two recrystallizations from methylene dichloride-ethyl acetate. 

The acetoxy dienone (218) gives phenol (220). Here, an alternative primary photoreaction competes effectively with the dienone 1,5-bonding expulsion of the lOjS-acetoxy substituent and hydrogen uptake from the solvent (dioxane). In the case of the hydroxy analog (219) the two paths are balanced and products from both processes, phenol (220) and diketone (222), are isolated. In the formation of the spiro compound (222) rupture of the 1,10-bond in the dipolar intermediate (221) predominates over the normal electron transmission in aprotic solvents from the enolate moiety via the three-membered ring to the electron-deficient carbon. While in protic solvents and in 10-methyl compounds this process is inhibited by the protonation of the enolate system in the dipolar intermediate [cf. (202), (203)], proton elimination from the tertiary hydroxy group in (221) could reverse the efficiencies of the two oxygens as electron sources. 

B) 20 -cyano-4Q ,5Q -epoxandrostan-17(3-ol-3-one was prepared by treating 17(3-acetoxy-40 , 50 -epoxyandrostano [2,3-d] isoxazole with sodium methoxide, and was obtained in the form of tan crystals, melting point 257.8°C to 270.0°C (decomposition) (corrected) when recrystallized from a pyridine-dioxane mixture. 

Monosubstituierte Carbamidsaureester lassen sich dagegen in 1,4-Dioxan durch Na-trium-acetoxy-trihydrido-borat in Ausbeuten von 65-80% d.Th. zu den entspre-chenden sekundaren Aminen reduzieren (s. S. 240)7. Die Reduktion mit Natriumboranat in Athanol ist dagegen iiber die entsprechenden Kohlensaure-imid-ester-Tetrafluorobo-rate moglich (s.S. 350f.)8. 

Sinz CJ, Rychnovsky SD (2001) 4-Acetoxy- and 4-Cyano-l,3-dioxanes in Synthesis. 216 51-92... 

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). 

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