Haystack Follow-up – Familiar Faces, Ladderanes



V. Mascitti (credit: Pfizer)

Regular readers of The Haystack over at CENtral Science Blog network might have seen my post on Pfizer’s modified dapagliflozin-inspired leads. While writing, I couldn’t fight the nagging feeling that I had heard the head Pfizer scientist’s name (Vincent Mascitti) before, perhaps from another paper.  I poked around through some old literature, and it hit me: he’s the ladderane guy!

Back in 2005, Corey and Mascitti prepared the first enantioselective (single mirror image of a compound) synthesis of pentacycloanammoxic acid (JACS 2006, 128, 3118-3119). This C₂₀ fatty acid, first discovered in deep-sea bacteria by Dutch researchers in 2002, provides an extremely rigid lipid bilayer to bacterial cell membranes, which biologists believe shields them from their own toxic metabolic byproducts – anammoxic bacteria utilize ammonia for energy, and produce hydrazine (rocket fuel) and hydroxylamine as waste products en route to N₂ and H₂O.

Mascitti finished the total synthesis in about 20 steps, most of which are variations on [2+2] photoaddition (making 4-membered rings from 2 alkenes), followed by ring contractions to access linear cyclobutane “chains.” The authors relate that the molecule is highly strained (roughly 75 kcal / mole), which surrounds its biosynthesis in a shroud of mystery: how does one make these energetically unfavorable ring systems, and especially in the dark? (Deep sea, remember?)

L. MacGillivray (credit: U. Iowa)

Two suggestions play out in the recent literature. In 2004, Len MacGillivray, a materials chemist at U-Iowa, demonstrated solid-state ladderane formation by nudging two conjugated polyolefins next to each other and adding a dash of UV light to promote [2+2] ring formation. Corey, meanwhile, suggested that an unknown enzymatic pathway from a highly unsaturated docosahexaenoic (22 carbons) acid derivative might produce these lipids.

A 2009 paper by the original isolation team (Damsté and coworkers) performed in silico comparisons of the genetic machinery required for lipid synthesis between anammoxic and aerobic bacteria. Their conclusions? Most of the enzymatic evidence supports radical cyclization of a long conjugated tail (see below), although the authors tease that the ladderane portion could be made by a separate process, and recruited into the fatty acid later on.

credit: Biology Direct, 2009, 4, p. 12