A Highly Efficient Pinacol Coupling Approach to Trehazolamine Starting from d-Glucose

Abstract

A short and very efficient synthesis of trehazolamine (3), the aglycon of the potent trehalase inhibitor trehazolin (2), has been achieved starting from D-glucose. The key transformation in this approach is a high-yielding two-step, one-pot sequence consisting of a Swern oxidation of a 1,5-diol followed by a reductive carbocyclization of the resultant 1,5-dicarbonyl compound promoted by samarium diiodide. The overall yield of 3 is 39% over nine steps from 2,3,4,6-tetra-O-benzyl-D-glucose (5). An even shorter synthesis of 30, a diastereoisomeric analogue of 3, is also described starting from 5. The key transformation in this second route is a highly stereoselective ketone oxime ether reductive carbocyclization promoted also by samarium diiodide. The overall yield of 30 is 57% over four steps from 5.

Synthesis, Inhibition Properties, and Theoretical Study of the New Nanomolar Trehalase Inhibitor 1‐Thiatrehazolin: Towards a Structural Understanding of Trehazolin Inhibition

“…We have previously described two different synthetic approaches to 5 from readily available carbohydrate precursors, based on a reductive carbocyclization reaction promoted by samarium diiodide as a key step. In the first approach, [18] a highly efficient two-step, onepot oxidation-reductive coupling sequence [19] served to transform the 1,5-diol 12, derived from d-glucose, into a 1:1 mixture of carbocyclic cis-diols 13, from which trehazolamine (8) and then the final target 5 were readily prepared by simple synthetic manipulations (Scheme 1 a). A second and more efficient route [20] (Scheme 1 b) was developed later, and utilized a carbonyl-oxime ether reductive carbocyclization with subsequent NÀO reductive cleavage, a highly efficient one-pot sequence first described by our group in 1995.…”

Design, Synthesis, and Evaluation of α‐(Hydroxymethyl)cycloalkanols

“…This reaction, using SmI 2 , gave 70 a in good yield as the only diastereoisomer [100] . Similarly, Chiara and coworkers [101] achieved a short and very efficient synthesis of trehazolamine starting from readily available hemiacetal 71 . Sodium borohydride reduction afforded D‐glucitol derivative 72 quantitatively, which was then converted to 73 via Swern oxidation.…”

Sequential Norrish Type II Photoelimination and Intramolecular Aldol Cyclization of 1,2‐Diketones in Carbohydrate Systems: Stereoselective Synthesis of Cyclopentitols

“…The oxidation of compounds 7 and 11 under these conditions and subsequent treatment with diazomethane afforded 15 and 16, which represent a new type of cyclopentitol (Scheme 3). [21] In the case of compound 11, better results were obtained by b fragmentation induced by the alkoxyl radical formed at the hydroxy group of the hemiacetal in the presence of the reagent system PhI(OAc) 2 / I 2 . [22] We believe that the examples shown in Table 1 demonstrate the general efficiency and usefulness of this methodology for the diastereoselective synthesis of densely functionalized cyclopentitols of this new type from the pyranose series of carbohydrates.…”