1,3-dioxane, anomeric effect

Eliel EL, Giza CA (1968) Conformational analysis of some 2-aIkoxytetrahydropyrans and 2-aIkoxy-l,3-dioxanes. Anomeric effect. J Org Chem 33 3754—3758... 

The Acid-Catalyzed Anomerization of the o-Glucose Penta Acetates. A Kinetic Thermodynamic and Mechanistic Study." /. Am. Chem. Soc. 73,2659 (1951). Anderson, C. B., and Sepp, D. T. "Conformation and the Anomeric Effect in 2-Halotetrahydropyrans."/. Org. Chem. 32,607 (1967). Eliel, E. L., and Giza, C. A. "Conformational Analysis. XVll1.2-Alkoxy- and 2-Alkylthiotetrahydropyrans and 2-Alkoxy-l,3-Dioxanes. Anomeric Effect." /. Org. Chem. 33,3754 (1968). Bottom Another example of a strong conformational bias introduced by the anomeric effect. 

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. 

In 1991, an important paper was published by Bock et a/.84 that described the steric and electronic effects on the formation of the dispiroketal dihexulose dianhydrides. The authors described the conformation of six dihexulose dianhydrides, as determined by X-ray crystallography or NMR spectroscopy. They concluded that these conformations are dictated by the anomeric and exo-anomeric effects. Thus, the dihexulose dianhydrides are disposed to adopt conformations that permit operation of these effects—even if this results in the dioxane ring having a boat conformation or all three substituents on one pyranose ring being axial. 

While the steric explanation is consistent with the observed selectivity, it nonetheless presents an incomplete explanation, as alkylation of 2-methyl-4-cyano-l,3-dioxane 17 also proceeded with very high syn-selectivity [11] (Eq. 5). The selective equatorial alkylation can be rationalized as an anfz-anomeric effect that disfavors axial alkylation of the ketene iminate through filled-shell repulsion. Simple lithiated nitriles are known to exist as ketene iminates, but it would be easy to rationalize the preference for equatorial alkylation by considering the relative stability of hypothetical equatorial and axial alkyllithium reagents, vide infra. Preferential equatorial alkylation was also observed by Beau... 

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. 

A few 2,2,5,5-tetrasubstituted 1,4-dioxane derivatives were reported OR substituents tend to adopt, because of the anomeric effect, axial positions [94AX(C)625, 94MI1]. By contrast, fra J-2,5-di-OCOOR- and 2,5-di-CH2. COOR-l,4-dioxane derivatives (R = aryl, alkyl) (84JHC1197), 2-(T-uracil)-6-CH20H-l,4-dioxane (92MI2), and 2,5-di-0H-3,6-di-CH20H-l,3-... 

Simple calculations (MM2 and HF/6-31G ), supported by a low-temperature NMR study, reveal that 2-NMc2-l,3-dioxane and the 5,5-dimethyl derivative exist exclusively in the conformation with the dimethylamino group in axial position <2001ARK(xii)58>, and DFT calculations at the B3LYP/6-31G(d,p) level of theory show that the anomeric effect of 2-Cl in 1,3-dioxane is of stereoelectronic origin while 2-F, 2-OMe, and 2-NH2 substituents on the same molecule are not <2000MI42>. 

The conformations of three 2,2 -disubstituted-l,3-dioxane derivatives 65-67 have been elucidated by NMR spectroscopy <1998CHE141, 1999PAC385, 2001ARK(xii)7> only the conformers with the more polar substituent in an axial position have been assessed as being in agreement with the anomeric effect. 

The acetonation under kinetically controlled conditions is also useful for the protection of vicinal rra/u-diols, which are quite reluctant to cyclization into five-membered rings. Although use of 2-methoxypropene has been successful in this objective [61,66], one should recommend the recently discovered uses of reagents that minimized the ring strain by obtaining six-membered rings from vicinal mmr-dials, which are protected (Scheme 10) as 1,4-dioxanes (dispiroacetals, rranr-decalinic system) stabilized by an anomeric effect... 

Fig. 7.7 Anomeric effect in sugars (left) preferentially stabilising the axial position of the anomeric C—O bond, and isomer energy difference between 1,3- and 1,4-dioxane at B3LYP/6-31 G(d) as clear evidence against steric (Pauli) repulsion arguments for the anomeric effect.

Some solvents may form complexes with the oxocarbenium ion intermediates, thereby affecting the anomeric outcome of a glycosylation. For example, diethyl ether is known to increase the a anomeric selectivity. Probably, diethyl ether participates by the formation of diethyl oxonium ion (Scheme 4.9a). The (3 configuration of this intermediate is favoured because of the operation of the reverse anomeric effect (see Chapter 1). Nucleophilic displacement with inversion of configuration will give an a glycoside. Recently, it was shown that a mixture of toluene and dioxane provides a more efficient participating solvent mixture. 

The conformational behaviour of 2-phosphoryl-l,3-dioxanes and dithianes continues to be an area of interest. Molecular mechanics methods have been applied to 2-phosphoryl-l,3-dioxane (34), the corresponding dithiane (35) and 2-thiophosphoryl-l, 3-dithiane (36).15 The relative stabilities of the axial and equatorial conformers in each case vary due to a combination of differing 1,3-axial interactions and anomeric effects. The conformer calculated to be the most stable for (34) and (35) is the structure given in each case. In the case of (36) the isomers are estimated to be of... 

Comparison of the O-C-O with the S-C-S anomeric interaction has been effected (2, 4 ) as shown in Scheme 2. In this case one can tell, unequivocally, that the O-C-O anomeric effect is the larger, for the overall AG° in the two systems is nearly the same and from the known conformational energies of 2-alkyl-l,3-dioxanes and -1,3-dithianes (5) it is obvious that the countervailing... 

A proper analysis of the above results has to take into consideration the particular conformational properties of DFAs, which are governed by stereoelectronic effects. The relatively flexible 1,4-dioxane central ring adopts a chair or boat conformation for dispiro-DFAs having different or identical configuration at the anomeric centers, respectively, in order to place the oxygen substituents in pseu-doaxial orientation, fitting the conformational anomeric effect [47], and the carbon substituents in pseudoequatorial position (Fig. 2). 

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