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THE ALICYCLIC CLAISEN REARRANGEMENT IN NATURAL PRODUCT SYNTHESIS
Abstract
A new and general strategy for hetero- and carbocycle synthesis has been developed. The n-membered macrocyclic lactones 2, readily available from the corresponding hydroxy acids 1, can be smoothly contracted to the n-4 membered hetero- (X = N, O etc.) or carbocycles (X = C) 4 by Claisen rearrangement of intermediate ketene acetals 3. (DIAGRAM, TABLE OR GRAPHIC OMITTED...PLEASE SEE DAI) This four-atom ring contraction process is subject to high internal asymmetric induction as well as relative asymmetric induction in the preparation of five and six-membered rings. For example, lactone upon deprotonation, rearranges to carboxylic acid stereospecifically, and was thus converted, in a total synthesis, to ((+OR-))-dihydronepeta- lactone, a major constituent of catnip oil. See p. 25 in dissertation for illustration. Application of the alicyclic Claisen rearrangement to fused bicycloannulation, i.e. 199A,B (--->) 155 has resulted in the efficient preparation of the unnatural tricyclopentanoid 202, the cis, syn, cis isomer of the nor-ketone of hirsutene. See p. 54 in dissertation for illustration. The alicyclic Claisen rearrangement can also be used in the construction of bridged bicycloalkanes as has been demonstrated in the formal total synthesis of ((+OR-)) quadrone. Lactone 229 in the key step, rearranged at or below room temperature, to provide diene 231 which was subsequently converted to an advanced intermediate enroute to quadrone. See p. 69 in dissertation for illustrations. The alicyclic Claisen rearrangement has also been used to prepare the strained inside-outside bicyclo 4.4.1 undecanone ring system 291 (--->) 298 as is found in the natural product ingenol, of which several esterified derivatives are known to be potent tumor promoters. See p. 88 in dissertation for illustrations. It was also discovered that the Mukaiyama reagent (2-chloro- N-methylpyridinium iodide), used in the macrolactonization of our hydroxy acids, is capable of forming ketene intermediates from the 2-acyloxypyridinium salt. The ketenes, thus formed, participate in intramolecular 2+2 cycloadditions with olefinic appendages to provide the corresponding substituted cyclobutanones. See p. 77 in dissertation for illustration.
Subject Area
Organic chemistry
Recommended Citation
ABELMAN, MATTHEW MARK, "THE ALICYCLIC CLAISEN REARRANGEMENT IN NATURAL PRODUCT SYNTHESIS" (1986). ETD collection for University of Nebraska-Lincoln. AAI8704536.
https://digitalcommons.unl.edu/dissertations/AAI8704536