Benzyl ethers steric effects

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. 

John Ward has functionalized an indane using method D in route to tetra-petalone A (46) (Fig. 4.24).25 The o-OBoc benzyl alcohol 44 undergoes addition with two equivalents of Grignard and affords after acidic workup the phenolic indane 45 in 73% yield. Because of steric effects, only one diastereomer is observed after hydrolysis of the enol ether and thermodynamic equilibration of the... 

In this case, the 6-O-trityl group improved the a-sclcctivity of the glycosylation because of the steric effects. The trityl ether of the resulting product can act as an acceptor when it is glycosylated with a fully benzylated thioglycosyl donor using NIS... 

Previous discussions (20, 39) on the propagation rate, kp, point out the effect caused by the resonance energy of the radical formed. Our results support this view and enable us to complete the arrangement by families according to the groups adjacent to the attacked function—alkyl, benzyl, alkoxy, allyl, hydroxyl. The steric effect does not reveal itself in any important way—e.g., a-methylbenzylic ether has a kp which is close to that of benzylic ether, and the tertiary carbons in the former product are generally attacked at rates comparable with that of a less-encumbered carbon. 

Iodolactonization of y, o-unsaturated alcohols results in preferential formation of tram-2, 5-disubstituted tetrahydrofuranes. However, the corresponding benzyl ethers cyclize preferentially to the cis-isomers. The alkyl group must be bulky enough to exert a steric effect, but not to prevent cyclization. Substituted benzyl ethers are particularly useful. Examples of this steric control are illustrated for the preparation of tram- and c/s-linalyl oxide (equations I and II).10... 

Under these optimized conditions, di-tert-butylsilylene could be transferred to a range of acyclic and cyclic olefins (Schemes 7.9 and 7.10).11,74 The method was not sensitive to the steric nature of the R substituent nearly quantitative silylene transfer to olefins bearing ra-butyl, isopropyl, or tert-butyl groups was observed. Vinylsilanes were also tolerated as substrates. Olefins containing silyl ether, benzyl ether, and pivolate substituents were all effective traps of di-tm-butylsilylene. 

The effects of changes in the nature of the aikoxy group (equation 3) are evident in Table 2. High levels of asymmetric induction are achieved by the use of a-substituents such as methoxymethyl ether, benzyl ether, and methylthiomethyl (MTM) ether. The sterically demanding tetrahydropyranyl ether substituent, however, interferes with chelate formation, and its use generates poor selectivities. 

In a study by Narasaka, et al.,105406 the variability of the reaction of 2-deoxyribose with silylenol ethers was addressed. As shown in Scheme 2.5.5, the yields, as well as the anomeric ratios, are dependent upon the nature of the protecting group used on the 3-hydroxyl group possibly reflecting steric effects. Consequently, the best results were obtained utilizing benzyl groups. 

Both steric and electronic effects favored the observed ring opening in 28 producing the /S-methyl aldehyde (Scheme Addition of Et3N helped in suppressing the hydrogenolysis of the benzyl ether functional group. 

For example, stabilization of the resulting benzylic free radical, by ring substituents, after the thermolysis of a benzyl ether moiety or the activation effect of oxygen (e.g., phenolic) substituents on an aromatic ring (McMillen et al., 1981) may be cited as examples where the order dictated by bond dissociation energies might be modified under the prevalent conditions. Steric factors may, more than likely, also be a consideration. 

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