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Total Syntheses of the Phytotoxic Lactones Herbarumin I and II and a Synthesis-Based Solution of the Pinolidoxin Puzzle
journal contribution
posted on 2002-05-22, 00:00 authored by Alois Fürstner, Karin Radkowski, Conny Wirtz, Richard Goddard, Christian W. Lehmann, Richard MynottA concise approach to a family of potent herbicidal 10-membered lactones is described on the
basis of ring-closing metathesis (RCM) as the key step for the formation of the medium-sized ring. This
includes the first total syntheses of herbarumin I (1) and II (2) as well as the synthesis of several possible
macrolides of the pinolidoxin series. A comparison of their spectral and analytical data with those of the
natural product allowed us to establish the stereostructure of pinolidoxin, a potent inhibitor of induced
phenylalanine ammonia lyase (PAL) activity, as shown in 46. This finding, however, makes clear that a
previous study dealing with the relative and absolute stereochemistry of this phytotoxic agent cannot be
correct. An important aspect from the preparative point of view is the fact that the stereochemical outcome
of the RCM reaction can be controlled by the choice of the catalyst. Thus, use of the ruthenium indenylidene
complex 16 always leads to the corresponding (E)-alkenes, whereas the second generation catalyst 17
bearing an N-heterocyclic carbene ligand affords the isomeric (Z)-olefin with good selectivity. This course
is deemed to reflect kinetic versus thermodynamic control of the cyclization reaction and therefore has
potentially broader ramifications for the synthesis of medium-sized rings in general. A further noteworthy
design feature is the fact that d-ribose is used as a convenient starting material for the preparation of both
enantiomers of the key building block 14 by means of a “head-to-tail” interconversion strategy.
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herbicidalmetathesiheterocyclic carbene ligandstereochemical outcomeisomericPALgeneration catalyst 17alkenematerialchoicestereochemistrymemberedstereostructureaspectTotal Synthesesselectivityolefinlactoneapproachbuilding block 14formationruthenium indenylidenedesign featureinhibitorPhytotoxic Lactones HerbaruminPinolidoxin Puzzlephytotoxic agentbasisstrategyenantiomersynthesispinolidoxin seriespreparationcyclization reactionRCM reactionherbaruminSolutionIIphenylalanine ammonia lyasesynthesedatamacrolideinterconversionramification
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