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Biological background

Ladderane lipids present in anammoxasomes.

Ladderanes were first identified in a rare group of anaerobic ammonium oxidizing (anammox) bacteria belonging to the phylum Planctomycetes. These bacteria sequester the catabolic anammox reactions to intracellular compartments called anammoxasomes. The anammox process involves the oxidation of ammonium to nitrogen gas with nitrite as the final electron acceptor. Intermediates in this process are two highly toxic compounds, hydrazine (N₂H₄) and hydroxylamine (NH₂OH). The oxidation process involves the generation of a proton gradient on the intracytoplasmic face of the anammoxasome. Dissipation of the proton gradient is coupled to the phosphorylation of ADP through membrane-bound ATPases.

Anammoxasomes are enriched in the ladderane lipids shown at right. Analysis of the anammoxasome membranes from the bacterial species Borcadia anammoxidans and Kuenenia stuttgartiensis has revealed that ladderanes constitute greater than 50% of membrane lipids. The high abundance of ladderane lipids in the anammoxasome results in an exceptionally dense membrane with reduced permeability. The reduced permeability may decrease the passive diffusion of protons across the membrane that would dissipate the electrochemical gradient. This would be especially detrimental to anammox bacteria, due to the relatively slow anammox metabolism. The decreased permeability also sequesters the highly toxic and mutagenic intermediates, hydrazine and hydroxylamine, which can readily diffuse through biomembranes. The loss of these key intermediates would damage key cellular components such as DNA, as well as reduce the catabolic efficiency of the cell.

Synthesis of pentacycloanammoxic acid

A naturally occurring n = 4 ladderane compound, pentacycloanammoxic acid, has been synthesized by Corey and coworkers. The first step in this reaction involves the bromination followed by cyclization of cyclooctatriene to form a cyclohexadiene. This cyclohexadiene is trapped by dibenzyl azodicarboxylate. Functional group modifications are made to produce a cyclobutane which is reacted through a [2+2] photocycloaddition with cyclopentenone to produce a second cyclobutane ring. Protection of the carbonyl group, followed by a N₂ extrusion reaction, yields two more fused cyclobutane rings. The final cyclobutane is formed by a Wolff rearrangement, and the alkyl chain is installed by a Wittig olefination.

Pentacycloanammoxic acid synthesis involving ladderanes.

In 2016, Burns and co-workers at Stanford University reported an enantioselective synthesis of both the [3]- and [5]-ladderane lipid tails and their incorporation into a full phosphatidylcholine.

Both routes leverage a small [2]-ladderene building block bicyclo[2.2.0]hexene prepared by a Ramberg–Bäcklund reaction reaction. The route to a [5]-ladderane-containing fatty acid involves dimerization of this intermediate to form a an all-anti [5]-ladderane hydrocarbon. C–H chlorination by a manganese porphyrin catalyst and subsequent elimination introduces unsaturation to produce a [5]-ladderene. Hydroboration and a Zweifel reaction install the linear alkyl group.

The route to a [3]-ladderane fatty alcohol begins with a [2+2] photocycloaddition between a brominated benzoquinone and bicyclo[2.2.0]hexene. Elimination of H–Br and addition of an organozinc compound installs the alkyl alcohol. A hydrazine-mediated deoxygenation reaction followed by hydrogenation with Crabtree's catalyst effects reduction to the cyclohexane ring.