5, Scheme 1) in the final step of the synthesis through a
Stork-Danheiser-type addition/rearrangement reaction.11
excellent enantiomeric excess.12a Isomerization of the ter-
minal alkene occurred upon exposure to catalytic
PdCl2(CH3CN)2 in hot benzene, resulting in quantitative
recovery of an inseparable 13:1 mixture of E-alkene 10 and
starting material 9.
Scheme 1. Retrosynthetic Analysis of (+)-Cassiol (1)
In order to convert the propenyl side chain of 10 into a
hydroxymethylene unit, we sought to carry out an oxidative
olefin cleavage reaction. This transformation, however,
proved challenging. Competing oxidative reactions of the
thioester moiety appeared to occur rapidly under ozonolysis
conditions. Modified Lemieux-Johnson conditions (OsO4,
NaIO4, 2,6-lutidine, dioxane/water)15 were also investigated
but led to a complex mixture of products lacking the desired
compound. Both Upjohn dihydroxylation (OsO4, NMO,
acetone)16 and Sharpless asymmetric dihydroxylation condi-
tions (AD-mix-R or AD-mix-ꢀ, t-BuOH/H2O)17 resulted in
slow and only partial conversion to the desired diol product.
Confronted by these difficulties, we considered possible
opportumities to improve reactivity for our system. We
wished to take advantage of the well-precedented rate-
acceleration of amine additives in osmium-catalyzed
dihydroxylation reactions,18 but we reasoned that the bulky
chiral ligands employed in the Sharpless protocol might
hamper reactivity toward our sterically encumbered,
enantiomerically enriched olefin. Warren, Wyatt, and co-
workers had found DABCO to be a convenient achiral
ligand for nonenantioselective dihydroxylations,19 and we
Precursors 3 and 5 would in turn be available from known
vinylogous thioester 412 and primary alcohol 6,13 respectively.
Our synthesis commenced with the deprotonation of
vinylogous thioester 4 with LDA and acylation of the
resulting enolate with allyl chloroformate (Scheme 2).
Scheme 2.
Enantioselective Synthesis of Alcohol (-)-3a
(5) One total synthesis of (-)-cassioside (2) using a chiral auxiliary has
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dron: Asymmetry 1999, 10, 3189–3196.
(9) For a review of enantioselective methodologies inspired by target-
directed synthesis, see: Mohr, J. T.; Krout, M. R.; Stoltz, B. M. Nature
2008, 455, 323–332.
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a pmdba ) bis(4-methoxybenzylidene)acetone; DABCO ) 1,4-
diazabicyclo[2.2.2]octane.
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vinylogous thioesters in a related system and the preparation of 4, see: (b)
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Subsequent position-selective alkylation with iodomethane
provided racemic ꢀ-ketoester 7 in 78% overall yield from
4. In the presence of the catalyst complex derived from
Pd2(pmdba)3 and (R)-t-BuPHOX (8),14 ꢀ-ketoester (()-7 was
readily transformed into allyl ketone (-)-9 in good yield and
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