have the opposite absolute configuration to zeylenone 4, as
shown by chemical correlation.5 This implies that both
configurations at the quaternary center are biosyntheti-
cally accessible, a proposal supported by previous work on
the biosynthesis of R- and β-senepoxide and related cyclo-
hexene oxides.6 In view of the above ambiguity, confirma-
tion of the absolute configuration of grandifloracin by
total synthesis is required.
a Claisen condensation to access the dimerization
precursor. In the context of grandifloracin, we have
adopted a conceptually distinct approach, namely micro-
bial arene dihydroxylation; this has not been employed
to date to access cyclohexa-2,4-dienone dimer natural
products.
Grandifloracin is believed to arise by the cyclodimeriza-
tion of 2 equivalents of precursor 6 (Scheme 1). Cyclodi-
merizations of cyclohexa-2,4-dienones areknown to exhibit
remarkable levels of regio-, site-, and stereoselectivity,
and the origins of this selectivity have been studied.7 They
have also been proposed to occur in the biosynthesis of
related natural products; of these, total syntheses of
aquaticol,8,9 asatone,10 biscarvacrol,3,9,11 bisorbicillinol,12
heterotropatrione,13 and isoheterotropatrione13 have been
reported that exploit such dimerizations. Advanced inter-
mediates toward bacchopetiolone14 and celastroidins15
accessed by such dimerizations have also been described.
Scheme 2. Regio- and Stereoselectivity of Dioxygenases
Enzymatic dihydroxylation of arenes to produce enan-
tiopure building blocks is established methodology.16 The
most common regiochemical outcome is installation of the
diol ortho,meta to the arene substituent (8, Scheme 2a).17
However, R. eutrophus B918 and certain other organisms19
are able to metabolize benzoate to the corresponding ipso,
ortho diol (10, Scheme 2b). Chiron 10 has found diverse
synthetic applications,20 and we have demonstrated its use
in a concise synthesis of new azacarbasugars.21 The abso-
lute configuration of 10 has been proven.20a,b Great syn-
thetic utility derives from the densely packed, differentiated
functionality in arene dihydrodiols. For example, 8 (R =
C2H3) has been employed in the synthesis of zeylena,
isolated fromUvariazeylanica.22 However, the useof arene
dihydrodiols is sometimes hampered by their facile dehy-
dration/rearomatization at extremes of pH or at elevated
Scheme 1. Proposed Biosynthetic Origin of Grandifloracin
Of these reported total syntheses, most accessed the
dimerization precursor by oxidative dearomatization of a
phenol, either by chemical3,8,9,10c,11,12aꢀd,14,15 or electro-
chemical10a,b,13 methods. In Deng’s synthesis of bisorbi-
cillinol12e an alternative approach was adopted, employing
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