Controlling Regiochemistry in the Gold-Catalyzed Synthesis of Unsaturated Spiroketals

Abstract

A novel gold-catalyzed synthesis of unsaturated spiroketals that addresses regioselectivity issues commonly reported in metal-catalyzed spiroketalization of alkynes is reported. The reaction sequence is regulated by an acetonide protecting group which undergoes extrusion of acetone to deliver the desired spiroketals in good yields and diastereoselectivities. The reaction, which is carried out under very mild conditions employing AuCl as the catalyst, should be widely applicable in the synthesis of a broad range of spiroketals.

Gold(I)-Catalyzed Activation of Alkynes for the Construction of Molecular Complexity

“… 79 , 99 The use of an acetonide moiety to function as a regioselectivity regulator in the spiroketalization process has been proposed to address the possible regioselectivity issues in the formation of monounsaturated spiroketals. 100 The first multicomponent enantioselective gold(I)-catalyzed synthesis of spiroketals 59 has been recently described using a gold-phosphate catalytic system in a three-component coupling between alkynols, anilines, and glyoxylic acid (Scheme 21 ). 101 More recently, another synthesis of spiroketals has been reported combining a gold(I)-catalyzed cycloisomerization of an alkynol with an inverse-electron-demand hetero Diels–Alder mediated by Y(OTf) 3 .…”

Gold‐Catalyzed Hydrofunctionalizations and Spiroketalizations of Alkynes as Key Steps in Total Synthesis

“…To overcome the drawback of this strategy a solution presented by the Aponick group was applied. [81] Herein the syn-diol is protected via an acetonide moiety which ensures that the remaining free hydroxyl moiety initiates the cyclisation (6-exo in this case) which triggers the selectivity towards the desired reaction. By following this approach 24 % (over the 2 steps) of the final target could be also obtained from syn-diol 56 (Scheme 19).…”

“…Like in the Okadaic Acid case (Scheme ), selectivity problems occurred with the corresponding syn ‐56 building block and only product 58 derived from an initial exo cyclisation was isolated. To overcome the drawback of this strategy a solution presented by the Aponick group was applied . Herein the syn ‐diol is protected via an acetonide moiety which ensures that the remaining free hydroxyl moiety initiates the cyclisation (6‐ exo in this case) which triggers the selectivity towards the desired reaction.…”

Catalytic Asymmetric Synthesis of Geminal-Dicarboxylates

“…1 The ability to control the stereochemistry of carbon centers featuring two heteroatoms is also important in the development of pharmaceuticals. 1,2 For many years, stereocontrolled access to chiral acetal derivatives relied on derivatisation of chiral starting materials, [3][4][5][6][7][8] metal mediated desymmetrisations, [9][10][11] or kinetic or thermodynamically controlled cyclisation of carbonyl containing chiral-compounds. [12][13][14][15][16][17] A recent approach to bis-heteroatom containing stereogenic centers involves catalysis with very sterically hindered chiral Brønsted acids.…”