Enantioselective Total Synthesis of [3]‐Ladderanol through Late‐Stage Organocatalytic Desymmetrization**

Abstract

Ladderane phospholipids, with their unusual ladder‐like arrangement of concatenated cyclobutane rings, represent an architecturally unique class of natural products. However, despite their fascinating structure and other necessary impetus, only a few synthetic studies of these molecules have been reported so far. We have now devised a concise total synthesis of [3]‐ladderanol, a component of natural ladderane phospholipids, using an organocatalytic enantioselective desymmetrizing formal C(sp2)−H alkylation. Our synthetic strategy rests on the late‐stage introduction of chirality, thus allowing facile access to both enantiomers of [3]‐ladderanol as well as an analogue. This is the first time a desymmetrization strategy is applied to the synthesis of [3]‐ladderanol. The scope of this desymmetrizing C(sp2)−H alkylation of meso‐cyclobutane‐fused cyclohexenediones is also presented.

Synthesis, characterization and absolute configurations of methyl ladderanoates

“…A recent review by Hancock and Brown 5 provides a summary of the advances in the synthesis of 1a and also of [3]-ladderanol, 2d. Enantioselective syntheses of 1d by Mercer et al 6 and of 2d by Ray et al 7 also appeared recently. 1b has been reported before by Mascitti and Corey.…”

“…1a contains five linearly fused cyclobutane rings, while 2a has three cyclobutane rings fused to a cyclohexane ring. The synthetic literature 3 has referred to tricyclo[4.2.0.0 2,5 ]octane as [3]‐ladderane, but in the natural product literature, 1,2,4–7 [3]‐ladderane derivatives ( 2 ) include the fused cyclohexane ring as part of the C 12 H 17 fragment.…”

Catalysts’ evolution in the asymmetric conjugate addition of nitroalkanes to electron-poor alkenes

“…The procedure devised for the alkylative desymmetrization of meso-cyclopenten-1,3-diones portrayed in Scheme 33 has been successfully employed for the total synthesis of (+)-[3]ladderanol, a component of natural ladderane phospholipids (Scheme 70). 137 The cyclohexenedione 93 required for the asymmetric conjugate addition has been prepared by [2+2] photocycloaddition of cyclohex-2-ene-1,4-dione with bicyclo[2.2.0]hex-2-ene followed by oxidation with selenium dioxide. Reaction of 93 with an appropriate nitroalkane in the presence of bifunctional squaramide catalyst 94 gave the expected optically active cyclohexenedione in 9:1 er.…”

Mechanism and Origin of Remote Stereocontrol in the Organocatalytic Enantioselective Formal C(sp2)–H Alkylation Using Nitroalkanes as Alkylating Agents

“…The generality of this strategy was subsequently demonstrated for the enantioselective desymmetrization of meso-norbornenoquinones 13 and recently applied to the enantioselective total synthesis of [3]-ladderanol. 14 These transformations do not lead to the creation of any stereocenter at the reaction site but allow for the generation of stereocenter(s) remote from the reaction site�a phenomenon often termed as remote stereocontrol. 15 While the initial findings have already led to the development of other transformations 16,17 and applied to the enantioselective synthesis of complex targets, 14 a detailed mechanistic study of this reaction holds the potential to unearth valuable information.…”