Synthesis of the Spirastrellolide A, B/C Spiroketal: Enabling Solutions for Problematic Au(I)-Catalyzed Spiroketalizations

Abstract

A synthesis of the spirastrellolide A, B/C-ring monounsaturated spiroketal is reported. The key step relies on a Au-catalyzed spiroketalization of a propargyl triol employing an acetonide as a regioselectivity regulator. Through observation and analysis, a set of conditions has been developed that facilitates the use of a mixture of diastereomeric substrates, obviating the need to control the stereochemistry of the propargyl stereocenter and enabling a convenient retrosynthetic disconnection. The key reaction proceeds in 80% yield in 1 min at ambient temperature with the Me3PAuCl/AgOTf catalyst system. These conditions should be widely applicable for new synthetic endeavors as they appear to overcome all issues with the Au-catalyzed spiroketalization.

Synthesis and Biological Evaluation of the Southern Hemisphere of Spirastrellolide A and Analogues

“…Previously, we reported synthetic efforts toward the B, C-ring spiroketal and successfully synthesized intermediate 10 via Au-catalyzed spiroketalization. 71 Unfortunately, deprotection of the catechol ketal in 10 to obtain methyl ketone-containing spiroketal 5 was unsuccessful after extensive screening (Figure 4). Despite the successful deployment of our methodology, this recalcitrant deprotection of the catechol required a modified strategy.…”

“…With Weinreb amide 11 in hand and alkyne 9 available using our previously reported protocol, 71 we turned our attention to the synthesis of spiroketal 5. A union of the fragments was accomplished by the addition of the acetylide resulting from alkyne 9 to Weinreb amide 11 to yield compound 21 in an 87% yield (Scheme 2).…”

“…We previously reported that mixtures of diastereomers could be used as the corresponding acetonide to give single diastereomers of products and these substrates also function to regulate the regiochemistry of spiroketalization with respect to the alkyne. 71 Accordingly, the protection of 1,3-diol 22 was needed to address both regioand stereochemical issues. In the event, acetonide protection of diol 22 under acidic conditions proved to be problematic due to the presence of the acid-labile C11 ketal.…”

Designed Spiroketal Protein Modulation

“…Spiroketals are archetypal spirocyclic compounds, found abundantly in the CAS registry (Supporting Information), of which many are bioactive natural products . Besides being attractive targets for total synthesis, spiroketal‐derived natural products have contributed to a renaissance of thinking towards intelligent library design, grounded in principles of diversity‐oriented synthesis (DOS) and biology‐oriented synthesis (BIOS) . Spiroketals are arguably well‐adapted to both philosophical approaches in being biologically relevant while fulfilling the three criteria for molecular diversity set out by Schreiber and co‐workers—appendage, stereochemistry, skeletal diversity—owing in particular to the conformational and configurational flexibility of these scaffold structures.…”

Designed Spiroketal Protein Modulation

“…Spiroketals are archetypal spirocyclic compounds, found abundantly in the CAS registry (Supporting Information), of which many are bioactive natural products . Besides being attractive targets for total synthesis, spiroketal‐derived natural products have contributed to a renaissance of thinking towards intelligent library design, grounded in principles of diversity‐oriented synthesis (DOS) and biology‐oriented synthesis (BIOS) . Spiroketals are arguably well‐adapted to both philosophical approaches in being biologically relevant while fulfilling the three criteria for molecular diversity set out by Schreiber and co‐workers—appendage, stereochemistry, skeletal diversity—owing in particular to the conformational and configurational flexibility of these scaffold structures.…”