Ethers sugar substrates

Although the rearrangement was initially identified in sugar substrates it is very general. For example, the lactoxime O-vinyl ethers 345 were synthesized in two straightforward steps from thiolactones 344. Thermolysis of 345 effects rearrangement to afford a series of 2-substituted-4,5-oxazoledicarboxylic acid dimethyl esters 346 from monocyclic precursors (Scheme 1.93). Additional examples of 2-substituted-4,5-oxazoledicarboxylic acid dimethyl esters available via this methodology are shown in Table 1.27. 

Acetylenic precursors employed in the syntheses of sugars may be divided into three groups (a) aldehydes (usually in the form of acetals), (b) alkyl alkynyl ethers, and (c) alkynols or alkynediols. Some of them are commercially available (for example, 2-butyne-l,4-diol), and others are prepared by Grignard-type reactions between 1-alkynylmag-nesium halides or lithium alkynes and suitable aldehydes, ketones, or epoxides. In this way, the synthesis of substrates having the desired number of carbon atoms, as well as the necessary functional groups, can be achieved. The next step consists in partial saturation of the triple bond to afford the desired cis- or trans-alkene. ct.s-Alkene systems... 

Fused ring heterocycles, prepared by cyclization of substrates with a tethered nitrogen nucleophile, have been used in the synthesis of amino sugars and aminocyclitols. The examples shown in Table 28 make use of imidate-type functionality (equation 101) to insure nucleophilic attack by nitrogen. The bro-mocyclization of N,W-dialkylaminomethyl ethers of 2-cyclohexen-l-ol to form bicyclic oxazolidine derivatives has been reported also.228b... 

In comparison to some of the other activation methods however, the dimethyl sulfoxide-acetic anhydride procedure has certain disadvantages. The method often requires the use of long reaction times (1 24 h), which can result in many side reactions, especially with sensitive substrates. Notable in this respect is that it is not uncommon for this procedure to result in the formation of substantial yields of the thiomethyl ethers obtained from the Pummerer rearrangement product as described above. In fact upon attempted oxidation of cholesterol with this system, the major product obtained was the corresponding (methylthio)methyl ether. Acetates may also be formed if the alcohol is unhindered. For example the sugar derivative (9) reacts under these conditions to form an enol acetate (derived from the requir carbonyl compound) in 40% yield contaminated with 30% of the acetate (10 equation S). ... 

The intramolecular aldol reaction in the presence of a titanium Lewis acid is a viable means of preparation of cyclic compounds. The cyclization is most conveniently performed between an enol silyl ether and an acetal, because the former is a reactive enol derivative and is readily prepared by silylation of the corresponding ketone in the presence of the acetal moiety in the same molecule. Equation (12) exemplifies a substrate undergoing intramolecular ring closure mediated by TiCU [74]. The conversion of sugar derivatives to carbocycles (called the Perrier reaction [75,76]) has been reported to occur in the presence of a Lewis acid. This process involves the aldol reaction between the enol ether and acetal moieties in the same molecule promoted by a titanium salt, as illustrated in Eq. (13) [77]. The similar reaction of a different type of substrate was also reported [78]. 

Glycals serve as activated sugars because of the inherent reactivity of the endocyclic enol ether. Consequently, they have been extremely useful substrates in their complementarity to native activated sugars. Additionally, they have been used to demonstrate versatility not directly available from other sugar derivatives. In a good example of the utility of allylsilanes and silylacetylenes in C-glycoside chemistry, Ichikawa et al. [91] demonstrated a preference for the a anomer in all cases. The results, shown in Scheme 7.17, included a demonstration that a characteristic nOe can be used to confirm the stereochemical outcome of the reaction with hw-trimethylsilylacetylene. 

Nogano and co-workers [3] reported similar examples of asymmetric induction for natural product synthesis using protected sugars and a variety of R MgX, where X = C1, Br, or 1. In Table 2, entries 3 and 4, the tetralose carbonyl can also contain in the Ri position an ether, ester, urethane, alkyl, or aryl group [13]. The authors reported the diastereometer ratio from the R substrate and the labeled carbon-2 varied from 80 20 to 10 90 (2S/2R). The variability was controlled by the nature of the nucleophile, the solvent, and the temperature. The authors rationalized the product distribution based on chelation of the metal and steric bulk of the reactants, favoring the R-isom.er. 

Functionalization of several pyranose sugar derivatives, e.g. 28, 30, 33, was achieved with a variant of this method in which 3-oxabicyclo[4.1.0]heptanyl radicals were generated, either photochemically from benzoate esters, or from bromides. These photochemical transformations left unprotected functional groups in the substrate intact, including bromomethyl, ester, and ether groups, and rather effectively demonstrated the tolerance of free-radical intermediates for such functionality. 

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