Chemical Clockwise Tridifferentiation of α‐ and β‐Cyclodextrins: Bascule‐Bridge or Deoxy‐Sugars Strategies

Abstract

The selective and efficient functionalisation of large concave molecules is a chemical challenge opening the door to various applications, such as artificial enzymes. We propose here a method, based on deprotection of benzylated cyclodextrins, to selectively access a variety of complex structures with two or three new different functionalities on the primary platform. Our strategy is based on a mechanistic hypothesis involving the approach of an aluminium reagent between the primary oxygen atom and the endocyclic one of the same sugar unit. Due to its cyclic directionality, a change in steric hindrance on a given position of the cyclodextrin has a different effect on the clockwise or the counterclockwise directions. This concept is illustrated and exploited in two complementary ways: deoxygenation of the primary position of two diametrically opposed sugars induces a debenzylation reaction on the neighbouring clockwise sugars of alpha- and beta-cyclodextrins. Reversible capping, or bascule-bridging, of the same pair of sugars has the same effect on the debenzylation of alpha-cyclodextrin, but induces an important change of the geometry of beta-cyclodextrin, hence allowing the selective access to yet another functionalisation pattern. A combined use of deoxygenation and bascule-bridging allows the access to an alpha-cyclodextrin with its three pairs of primary functions differentiated and ready for further modifications. Bascule-bridge or deoxy-sugars are two complementary means to operate steric decompression and induce selective reactions to efficiently access a number of new patterns of functionalities on concave molecules.

Can Hetero‐Polysubstituted Cyclodextrins be Considered as Inherently Chiral Concave Molecules?

“…[18] When the hydroxy groups of 1 are converted into R groups, and provided R is judiciously chosen to induce local steric decompression in CD 2, a second deprotection of CD 2 with DIBAL-H exclusively delivers the face-to-face diol 3 as a single regioisomer, with no traces of the alternative regioisomer CD 4 (Scheme 1). [14,15] Both CDs 3 and 4 are chiral enantiopure molecules with C 2 symmetry. Compounds 3 and 4 do not share the same connectivity and are therefore constitutional isomers, however, they exhibit mirror-image functionalization patterns at their upper rims because of their opposing topologies (A and B, Scheme 1).…”

“…Finally, diphosphine L3 was obtained in 56 % yield from diol 1. [15,18] To validate our concept and probe the anticipated topological pseudoenantiomeric relationship between L1 and L2, the popular Tsuji-Trost Pd 0 -catalyzed substitution of 1,3-diphenylallyl acetate with the dimethylmalonate anion [28] was selected as a benchmark reaction. Classical conditions were used to test ligands L1-L3 (10 mol %), using dimeric allyl palladium chloride as the Pd 0 precursor (10 mol %) and the couple BSA (3 equiv)/AcOK (3 mol %) as the enolizing system.…”

“…[13] However, we have devised a unique methodology to regioselectively functionalize the primary rim of CDs by using an iterative deprotection strategy. [14][15][16][17] An initial diisobutylaluminum hydride (DIBAL-H) induced deprotection of a perbenzylated a-CD affords diol 1, which has diametrically opposed alcohol functions (face-to-face diol). [18] When the hydroxy groups of 1 are converted into R groups, and provided R is judiciously chosen to induce local steric decompression in CD 2, a second deprotection of CD 2 with DIBAL-H exclusively delivers the face-to-face diol 3 as a single regioisomer, with no traces of the alternative regioisomer CD 4 (Scheme 1).…”

“…[27] Based on our knowledge of regioselective deprotection of CDs, we synthesized the dideoxy CD 5 using the DIBAL-H deprotection method starting from a-CD (62 % yield over four steps). Regioselective deprotection of 5 was driven by steric orienting effects to afford face-to-face diol 6 [15] in 75 % yield. Diol 6 was then conveniently converted into the diphosphine CD L1 in 68 % yield, by using the methodology developed by Matt, Armspach, and co-workers, [24] in which mesylation followed by nucleophilic substitution by lithium diphenylphosphide was employed (Scheme 4).…”

“…Accordingly, the divinyl CD 7 was first synthesized from a-CD (57 % over four steps) and then deprotected with DIBAL-H (90 % yield) to give the face-to-face diol 8. [15] This compound was then converted into the dideoxy CD 9 through mesylation, subsequent hydride reduction (80 % yield), and reductive ozonolysis (93 % yield). Diol 9 is the topological regioisomer of the face-to-face diol 6 produced by the direct DIBAL-H deprotection of 5.…”