Ethers anomeric effect

The general features of the monensin synthesis conducted by Kishi et al. are outlined, in retrosynthetic format, in Scheme 1. It was decided to delay the construction of monensin s spiroketal substructure, the l,6-dioxaspiro[4.5]decane framework, to a very late stage in the synthesis (see Scheme 1). It seemed reasonable to expect that exposure of the keto triol resulting from the hydrogen-olysis of the C-5 benzyl ether in 2 to an acidic medium could, under equilibrating conditions, result in the formation of the spiroketal in 1. This proposition was based on the reasonable assumption that the configuration of the spiroketal carbon (C-9) in monensin corresponds to the thermodynamically most stable form, as is the case for most spiroketal-containing natural products.19 Spiro-ketals found in nature usually adopt conformations in which steric effects are minimized and anomeric effects are maximized. 

The influence of solvents in glycosylation reactions has been observed and discussed extensively already (1,4,74). For instance, the participation of ethers, when anomeric leaving-groups are removed under SNl-type conditions, results [because of the reverse anomeric effect (75,76)] in the genera-... 

Carbohydrates have been included in the wide range of molecules used in the parameterization of MM2 and of MM3. Alcohol and ether parameters have usually been determined from simple alcohols and ethers themselves. However, carbohydrates contain some unusual features in the acetal linkages, and in the many vicinal hydrogen-bonded hydroxyl groups. The "anomeric effect", first discovered by Edward (15) and popularized by Lemieux (16.), is best known in carbohydrates, although, of course, it occurs in other classes of compounds as well. One apparent result of this effect is that an axial alkoxy substituent is often more stable than the corresponding equatorial substituent when attached at the Cl position of a tetrahydropyranyl ring. This effect can be... 

Another anomeric effect is that acetal C-0 bonds, and to a lesser extent, the bonds between acetal carbons and ether oxygens, are shortened or elongated as a function of their associated torsional angles. Jeffrey and Taylor modified MMl to account for these anomeric effects (17) and similar additions were put in the standard 1985 version of MM2 (11). The parameterization of MM3 for anomeric effects is preliminary, with recent (18-20) results being monitored. 

Of particular interest is the influence of solvents under SNl-type conditions, as has been well studied for ethers [1,2,8]. The participation of ethers results, owing to the reverse anomeric effect [28] under SNl-type conditions, in the generation of equatorial oxonium ions (see Scheme 6, S = OEtj), which again favor the formation of thermodynamically more stable axial a- products [see Sec. 11I.B, Eqs. (6), (11), (16)]. 

Anet and Yavari (44) have studied chloromethyl methyl ether by low temperature proton nmr spectroscopy. Their results show that this compound exists in the gauche conformation 38 and they observed a barrier of 4.2 kcal/mol for the rotation of the O-CHjCl bond. This barrier is appreciably higher than that expected on the basis of steric repulsion alone. A rough estimate of the steric barrier is 2 kcal/mol, and they concluded that the anomeric effect increases the barrier to rotation of the O-CHgCl bond by approximately 2 kcal/mol. 

The hemiacetal thiol 75 (Fig. 13) gave on acid cyclization an equilibrium mixture of cis and trans monothioacetals 76 and 77 in a 1 1 ratio (63). If a value of 1.7 kcal/mol is accepted for the steric effects in 76 (two gauche forms of SCl XCHg = 0.8 kcal/mol and one gauche form of butane= 0.9 kcal/mol), the anomeric effect for the ether oxygen in 76 must also be equal to 1.7. 

A should be shorter than a normal C —0 ether bond because it has a partial double-bond character due to the anomeric effect, whereas the C - 0 R bond... 

Recently, Crabb, Turner, and Newton (68) have observed that perhydropyrido-[1.3]oxazine exists as a =9 1 mixture of the trans and the cis forms 97 and 98. The cis form 98 has two anomeric effects (-2.8 kcal/mol), two gauche forms of butane (1.8 kcal/mol) and one gauche form of -propyl ether (0.4 kcal/mol) whereas the trans form 97 has only one anomeric effect (-1.4 kcal/ mol). On that basis, the trans form 97 should be more stable than the cis form 98 by about 0.8 kcal/mol, in agreement with the experimental result. Katritzky and co-workers (69) have also shown that 1-oxa-3,5-diaza and 1,3-dioxa-5-aza cyclohexane derivatives exist respectively in the conformations 99 and 100. With an alkyl group in the axial orientation, both conformations gain two anomeric effects. 

The stereoselective formation of spiroketals 242 can be explained in terms of the thermodynamic stability of the three possible products. Oxonium cation 245, formed by the condensation of ortholactone 244b and allylsilyl ether 106a, is in equilibrium with the starting materials. Spiroketal 242 also equilibrates under the reaction conditions with the other anomers. The thermodynamically more stable product 242b, stabilized by a double anomeric effect, is obtained as the only product of the reaction (Scheme 13.89) as the substituents attempt to occupy equatorial positions in the newly generated tetrahydropyran ring. 

Starting with /jemi-acetal 12 the anomeric center has to be protected. Under acidic conditions in methanol the C-l methyl ether is obtained as a mixture of anomers. Therefore the a-anomer is favored because of the anomeric effect (see p. 251). Separation of the two anomers by crystallization is possible. This reaction is connected to the research of E. Fischer (Fischer-Helferich method).13... 

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. 

As indicated in Scheme VII/32, cyclononanone (VII/165) is transformed into hydroperoxide hemiacetal, VII/167, which is isolated as a mixture of stereoisomers. The addition of Fe(II)S04 to a solution of VII/167 in methanol saturated with Cu(OAc)2 gave ( )-recifeiolide (VII/171) in quantitative yield. No isomeric olefins were detected. In the first step of the proposed mechanism, an electron from Fe2+ is transferred to the peroxide to form the oxy radical VII/168. The central C,C-bond is weakened by antiperiplanar overlap with the lone pair on the ether oxygen. Cleavage of this bond leads to the secondary carbon radical VII/169, which yields, by an oxidative coupling with Cu(OAc)2, the alkyl copper intermediate VII/170. If we assume that the alkyl copper intermediate, VII/170, exists (a) as a (Z)-ester, stabilized by n (ether O) —> <7 (C=0) overlap (anomeric effect), and (b) is internally coordinated by the ester to form a pseudo-six-membered ring, then only one of the four -hydrogens is available for a syn-//-elimination. [111]. This reaction principle has been used in other macrolide syntheses, too [112] [113]. 

Glycosyl acetates react with tributyltin methoxide to give glycosyl tributylstannyl ethers. As with glycosyl anions,337"339 the anomeric effect causes... 

---