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Review
. 2021 Jan 7;27(2):565-576.
doi: 10.1002/chem.202002866. Epub 2020 Oct 14.

Ladderane Natural Products: From the Ground Up

Erin N Hancock  1 , M Kevin Brown  1
Affiliations
Review

Ladderane Natural Products: From the Ground Up

Erin N Hancock et al. Chemistry. .

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.

Keywords: cycloaddition; fused ring systems; natural products; small ring systems; strained molecules.

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Conflict of interest statement

Conflict of interest

The authors declare no conflict of interest.

Figures

Figure 1.
Figure 1.
Ladderane natural products.
Figure 2.
Figure 2.
Key retrosynthetic disconnections for [5]-ladderanoic acid from Corey, Burns, and Brown.
Figure 3.
Figure 3.
Key retrosynthetic disconnections for [5]-ladderanoic acid from Corey, Burns, and Brown.
Scheme 1.
Scheme 1.
Methods to assemble ladderane molecules. Abbreviations: med-Hg = medium-pressure Hanovia Hg lamp, CAN = ceric ammonium nitrate, p-NBSA = p-nitrobenzene sulfonyl azide.
Scheme 2.
Scheme 2.
Corey’s synthesis of (±)-[5]-ladderanoic acid. Abbreviations: p-TSA = p-toluenesulfonic acid, TsN3 = tosyl azide, LDA = lithium diisopropyl amine.
Scheme 3.
Scheme 3.
Corey’s synthesis of (+)-[5]-ladderanoic acid. Abbreviations: NBS = N-bromosuccinimide, TBAF = tert-butyl ammonium fluoride, NaHMDS = sodium bis(trimethylsilyl)amide.
Scheme 4.
Scheme 4.
Burns’ synthesis of (−)-[5]-ladderanoic acid. Abbreviations: MsCl = mesyl chloride, TBAC = tetra-butyl ammonium chloride.
Scheme 5.
Scheme 5.
Brown’s synthesis of (+)-[5]-ladderanoic acid. Abbreviations: T3P = propanephosphonic acid anhydride, DMAP = 4-(dimethyl-amino)pyridine, 9-BBN = 9-borabicyclo[3.3.1]nonane, p-ABSA = p-acetamidobenzenesulfonyl azide; TPAP = tetrapropyl-ammonium perruthenate, TCNHPI = N-hydroxytetrachloro-phthalimide, DCC = dicyclohexylcarbodiimide, tBuBIPY = 4,4’-di-tert-butyl-2,2-dipyridyl.
Scheme 6.
Scheme 6.
Burns’ synthesis of (+)-[3]-ladderanol. Abbreviations: PMB = para-methoxybenzene, DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.
Scheme 7.
Scheme 7.
Brown’s synthesis of (−)-[3]-ladderanol. Abbreviations: DMP = Dess-Martin periodinane, NMO = i-methylmorpholine N-oxide.
Scheme 8.
Scheme 8.
Burns’ synthesis of the naturally occurring ladderane phospholipid 1. Abbreviations: EDC·HCl = N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride, HOBt·H2O = 1-hydroxybenzotriazole hydrate.
Scheme 9.
Scheme 9.
Ring opening reactions by propagation of diradical intermediates and electrocyclic ring opening of ladderane molecules in comparison with analogous reactions.
Scheme 10.
Scheme 10.
Ring strain-induced pericyclic cascade and known enantioselective alkene-allenoate [2+2]-cycloaddition.
Scheme 11.
Scheme 11.
Generation of ladderane radicals and intermolecular capture.
Scheme 12.
Scheme 12.
Cascade biological and supramolecular approaches to access ladderane molecules. Abbreviations: SAM = S-adenosylmethionine.
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