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Download fileApproach toward the Total Synthesis of Orevactaene. 2. Convergent and Stereoselective Synthesis of the C18−C31 Domain of Orevactaene. Evidence for the Relative Configuration of the Side Chain
journal contribution
posted on 2002-06-20, 00:00 authored by Michael G. Organ, Yaroslav V. Bilokin, Svetoslav BratovanovThe synthesis of the C18−C31 subunit of orevactaene (1) in an enantioselective and convergent
manner is reported. Four chiral centers in the structure (i.e., carbons 23, 25, 32, and 33) have
unknown configuration; thus, a modular approach has been devised to link the two stereocenter-containing ends of the structure together via a trisubstituted olefin template to ultimately produce
all possible diastereomers of the target. Keys to the success of this approach include (i) an efficient
synthesis of four diastereomeric hydrophobic tails (C22−C29) of the molecule with two stereogenic
centers at C23 and C25; (ii) the synthesis of three stereodefined trisubstituted olefins 37, 38, and
43 using palladium(0)-catalyzed hydrometalation and metallometalation; and (iii) the convergent
assembly of the aforementioned sections by a ‘one-pot' lithium/halogen exchange, boron/lithium
exchange, borate ester saponification, and Suzuki cross-coupling followed by oxidative deprotection.
The sequence provided the desired aldehydes 49 and 50 as single isomers in good yields. Compiled
spectroscopic data from the literature and present work provides evidence that the relative
configuration of the methyl groups in the side chain of orevactaene may be 1,3-syn, which will be
confirmed when the total synthesis has been completed. These results have paved the way for a
parallel synthesis approach to prepare all 16 possible stereoisomers of orevactaene so that the
relative and absolute stereochemistry of this compound can be determined.
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Keywords
borate ester saponificationsynthesis approachTotal SynthesisRelative ConfigurationStereoselective Synthesisconvergent assemblyside chainoxidative deprotectionOrevactaeneconfigurationSide Chainstereogenic centerstrisubstituted olefin templatestereodefined trisubstituted olefins 372. Convergentchiral centersmethyl groupsC 23orevactaenespectroscopic dataconvergent manneraldehydes 49