Gold catalysis: synthesis of spiro, bridged, and fused ketal natural products

Abstract

In the last decade the use of homogenous gold catalysts has rapidly grown and become a valuable tool for complex natural product synthesis. Spiroketal natural products are valuable targets for total synthesis and medicinal chemistry applications. The use of gold catalysts has emerged as a useful tool to synthesise these privileged scaffolds. This review summarises the application of gold catalysis for the syntheses of spiro, bridged and fused ketal natural products.

The Formosalides: Structure Determination by Total Synthesis

“…[52,53] Theresulting 17-and 19-membered macrolides 21 and 22 can be separated by ordinary flash chromatography.The macrocyclization worked equally well in the diastereomeric series (25/26), thus showing the robustness of RCAM. [18,19] Subsequent oxidative cleavage of the PMB ether gave alcohols 30 and 33 in readiness for acetal formation via pacid-catalyzed transannular addition of the free -OH group across the triple bond, [20] to be followed by addition of MeOH (or H 2 O) to the resulting enol ether to form the desired (hemi)ketal (Scheme 4). [20] [(C 2 H 4 )PtCl 2 ] 2 (Zeisess alt) in Et 2 Op roved to be the promotor of choice for the 6-exo-dig hydroalkoxylation step, [20,54] which has apparently not yet found any application in transannular format.…”

“…A)s hould allow the macrocyclic frame and the yet missing ketal subunit to be formed. Thel atter maneuver, however, bore considerable risk since 6-exo-dig hydroalkoxylations of alkynes in general are challenging; [20][21][22] in the projected transannular format, the conformation of the macrocycle might intervene. [23,24] If successful, however,such am erger of RCAM and p-acid catalysis [25] streamlines the assembly process and hence minimizes the synthetic exertion.…”

A Silver‐Catalyzed Modular Intermolecular Access to 6,6‐Spiroketals

“…The most common and widely used path towards spiroketals is based on the intramolecular acid-assisted cyclization of dihydroxy ketones. [9] Furthermore, several elegant and enantioselective methods for 6,6-spiroketals have been published recently, using different metal salts or organocatalysts. [7] An alternative to this Brønsted acid based approach is the intramolecular cyclization of dihydroxy alkynes via π-acid catalysis.…”

“…[8] This method uses alkynes as less reactive surrogates for a ketone, which enables the use in late stage steps in a complex molecular environment and has been used in several total synthesis, e. g. involving gold catalysis. [9] Furthermore, several elegant and enantioselective methods for 6,6-spiroketals have been published recently, using different metal salts or organocatalysts. [10] Despite these advances, only a limited number of intermolecular spiroketal formations have been reported, which often require highly reactive compounds such as organolithium compounds or Grignard reagents, accompanied by a low functional group tolerance.…”

Total Synthesis of (±)-Leonuketal

“…We planned to assemble the spirocyclic core of 7 by Au-mediated cyclisation of alkyne 8, which could be accessed from halide 9 through appendage of the lactone moiety by alkylation. 23 Efficient synthesis of the alkyne-substituted cyclohexanol ring of 9 posed a challenge. While related cyclohexanols have been assembled from geraniol derivatives, we sought an efficient method to incorporate the requisite alkynyl moiety.…”