Ladderane Natural Products: From the Ground Up

Abstract

The ladderane family of natural products are well known for their linearly concatenated cyclobutane skeletal structure. Owing to their unique carbocyclic framework, several chemical syntheses have been reported since their discovery in 2002. The focus of this review is to showcase the novel tactics that have been used to generate the ladderane core and the challenges that are associated with the synthesis of these unusual and complex natural products.

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

“…As shown in Figure 1, these ladderane phospholipids are composed of either (+)‐[3]‐ladderanol ( 3 ) or a mixture of (+)‐[3]‐ladderanol ( 3 ) and (−)‐[5]‐ladderanoic acid ( 4 ) [7] . While several strategies were conceived for the construction of non‐natural ladderanes prior to 2002, [8] only a few research groups have invested into the synthesis of naturally occurring ladderane phospholipids so far [9] . [5]‐Ladderanoic acid ( 4 ) was the first member of the ladderane family of natural products to be synthesized.…”

Sulfoquinovosylglyceryl ether, a new group of ether lipids from lake ball‐forming green alga Aegagropilopsis moravica (family Pithophoraceae)

“…Since the first description of "astrol" (batyl alcohol) from starfish, [1] ether lipids have been discovered from a variety of organisms (Figure 1). Examples include etheric membrane lipids from Archaea, [2] ladderane membrane lipids from anaerobic ammonia-oxidizing (anammox) bacteria, [3] paramecyl alcohol from ciliate Paramecium tetraurelia, [4] diacylglyceryl ether from marine animals, [5] betaine lipids from micro-and macroorganisms except seed-bearing plants or metazoans, [6] plasmalogens, [7] seminolipids, [8] and platelet-activating factor [9] from mammals (Figure 1). The physiological roles of these molecules are yet fully understood, but some are known to be associated with the ability to adapt to extreme environments such as high temperature, low pH, high salinity, [10] and phosphorous deprivation, [11,12] or a variety of biological events including ATP synthesis, [13] establishment of infection, [14] phagocytosis, [15] to acquire buoyance in the deep sea, [16][17][18] spermatogenesis, [19] immunity, [7] neuronal development, [7] lens organization, lens transparency, [20] and for radical scavenging.…”

Stereoselective Synthesis of Cyclobutanes by Contraction of Pyrrolidines

“…Many natural cyclobutanes contain various substituents and possess an array of stereocenters in a contiguous fashion in a limited space. The congested, sp 3 enriched small carbocycle has attracted wide interest from the synthetic community due to its efficient synthesis. 4−7 Synthetic methods directly en route to multisubstituted cyclobutanes, such as [2 + 2] cycloaddition, 8 radical cyclization, 9,10 and ring contraction reactions including a Wolff rearrangement, 11−13 and oxidative pinacol rearrangement, 14 have been well documented.…”

“…Cyclobutanes are four-membered carbocycles which present a unique structural feature in bioactive natural products − (Figure A). Many natural cyclobutanes contain various substituents and possess an array of stereocenters in a contiguous fashion in a limited space.…”