Substituent Dependence of the Diastereofacial Selectivity in Iodination and Bromination of Glycals and Related Cyclic Enol Ethers

Abstract

The stereochemical course of the electrophilic iodination and bromination of tri-O-benzyl-D-glucal under various conditions has been compared to that of substituted dihydropyrans 2-5. IN(3) addition in acetonitrile affords trans-alpha-iodoazides (80-87%), besides small amounts of trans-beta-adducts, in the presence or the absence of benzyloxy substituents at C-3 or C-4, and in agreement with bridged iodonium ion intermediates. In contrast, the diastereofacial selectivity of bromine addition in dichloroethane going through open bromo oxocarbenium ions depends strongly on the substituents. Whereas the trans-alpha-dibromides are the main (85-95%) adducts in the absence of C-4 and C-5 substituents, in their presence a moderate to exclusive selectivity for cis-alpha-addition (60-99%) is observed. The predominance of trans-alpha-addition is again observed whatever the substituents when the bromination is carried out in the same solvent but with a tribromide ion salt, supporting a concerted addition of the two bromine atoms under these conditions. Finally, bromine addition in methanol exhibits a completely different behavior with the nonselective formation of trans-alpha- and trans-beta-methoxybromides and a small dependence on the substituents. In agreement with the absence of azide trapping of any cationic intermediate, it is concluded that these brominations which do not go through an ionic intermediate are concerted additions of bromine and methanol with very loose rate- and product-determining transition states. Finally, the substituent conformation at C-4 influences drastically the stereoselectivity in all these brominations. Evidence for alpha-anomeric control of the nucleophile approach at C-1 is given by the highly predominant formation of alpha-adducts, except in the methanolic bromination. The factors determining the versatile selectivity of the electrophile approach are discussed in terms of PPFMO theory and of the special mechanisms of glycal reactions.

1‐exo‐Alkylidene‐2,3‐anhydrofuranoses: Valuable Synthons in the Preparation of Furanose‐Based Templates

“…In our opinion, the sequence will probably start with the stereoselective bromination of the electron-rich double bond [15] (step i, Scheme 2) to furnish the dibromide 6. No reaction intermediate (7 or 8) has ever been observed (TLC) in these transformations, so a 6 Ǟ 8 Ǟ 1 pathway involving a reactive allylic bromide seems more likely.…”

Unexpected Anomeric Selectivity of a 1-C-Arylglycal Donor in Kdo Glycoside Synthesis

“…In addition, when closely examining the crystal structure of compound 14, we observed that in the skewed conformation, the 2-iodide and anomeric β-hydrogen in fact have a pseudo trans-diaxial relationship, we conjecture that for β-glycosides E, the pyranose ring should adopt similar skewed conformation as 14, this would set the 2-iodide in pseudo transdiaxial position relative to the anomeric OR group; thus, it appears that although our glycal 17 provides the unexpected β-glycosides compared to glycal 3, the NIS-mediated glycosylations still follow similar electronic regime. 38 Therefore, we think that it is reasonable to conclude that the origin of the high β-anomeric selectivity for glycal 17 is governed by both steric and stereoelectronic controls. Although the strong stabilization effect of the aromatic ring could also favor the formation of a 2-iodo benzylic carbocation intermediate, this does not appear to be the main glycosylation pathway, as the alcohol could attack the benzylic cation from either the top (β-face) or bottom (α-face).…”

Synthesis and Preliminary Anticancer Activity Assessment of N-Glycosides of 2-Amino-1,3,4-thiadiazoles

“…Stereoselectivity of the iodonium-promoted electrophile addition to glycals is controlled, among others, by the preferred initial attack on the glycal. It is well accepted that iodine-based electrophiles preferentially react from the top-face of glycals in their half-chair more stable conformation ( Scheme 3 ) and the formation of bridged iodonium intermediate 1a – d , whose further trapping by nucleophiles can easily account for the regiospecificity and the high trans stereoselectivity observed [ 17 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ].…”