Synthesis of ent-[3]-Ladderanol: Development and Application of Intramolecular Chirality Transfer [2+2] Cycloadditions of Allenic Ketones and Alkenes

Abstract

An enantioselective synthesis of ent-[3]-ladderanol is presented. The ladderanes are an interesting class of molecules for their unique structure of fused cyclobutane rings as well as their perceived biological function of organism protection. The route hinges on the development and application of a chirality transfer [2+2] cycloaddition of an allenic ketone and alkene. Further stereocontrolled transformations allowed for completion of the synthesis. The scope of the chirality transfer [2+2] cycloaddition is also presented.

Ladderane Natural Products: From the Ground Up

“…The following year, Brown and co‐workers published a complementary approach that featured an intramolecular chirality transfer [2+2]‐cycloaddition to access the [4.2.0] bicycle (red disconnection, Figure 3). [38] …”

Lessons in Strain and Stability: Enantioselective Synthesis of (+)‐[5]‐Ladderanoic Acid

“…An alternative strategy was developed to access 4 through implementation of a [2+2] cycloaddition with cyclopentenone and subsequent ring contraction by Wolff rearrangement (Scheme ). Design of this strategy was influenced by the proclivity of photochemical [2+2] cycloadditions to use cyclopentenone ( 17 ) and prior studies from the Corey group and our group in the synthesis of related structures . As such, the synthesis commenced with cycloaddition between 17 and 1,2‐dichloroethylene to generate the [3.2.0]‐bicycloheptane 18 .…”

“…Given our groupslong-standing interest in the chemistry surrounding cyclobutanes,werecently reported asynthesis of (À)- [3]-ladderanol [(À)1]. [6] Ther oute featured an intramolecular stereoselective [2+ +2] cycloaddition between achiral allenic ketone and an alkene to gain access to the [4.2.0]bicyclooctane core.I nt his report, we disclose as ynthesis of (+ +)-2,t he unexpected challenges we encountered as ar esult of working with ladderanes,and highlight the novel solutions we utilized to address them.…”

“…Given our group's long‐standing interest in the chemistry surrounding cyclobutanes, we recently reported a synthesis of (−)‐[3]‐ladderanol [(−) 1 ] . The route featured an intramolecular stereoselective [2+2] cycloaddition between a chiral allenic ketone and an alkene to gain access to the [4.2.0]‐bicyclooctane core.…”

Lessons in Strain and Stability: Enantioselective Synthesis of (+)‐[5]‐Ladderanoic Acid

“…Design of this strategy was influenced by the proclivity of photochemical [2+ +2] cycloadditions to use cyclopentenone (17) [10] and prior studies from the Corey group and our group in the synthesis of related structures. [4,6] As such, the synthesis commenced with cycloaddition between 17 and 1,2-dichloroethylene to generate the [3. With synthesis of 4 completed, the key enantioselective cycloaddition with the allenoate 24 was explored (Scheme 5).…”