130 hours when heated at 1058C and within 51 hours at
1108C. The activation energy (Ea) of atropisomerization of 1
was determined to be 54 kcalmolÀ1 by monitoring the change
in enantiomeric excess over time at two different temper-
atures (see the Supporting Information). Unfortunately, the
open biquinone 8 proved difficult to study owing to tautome-
rization (see Scheme 3), and the diphenyl homologue 12
underwent rapid racemization during its synthesis from the
corresponding dihydroquinone. The simplified quinone 13
was more stable than 12, but significantly less so than
bismurrayaquinone A (1); racemization was complete after
50 hours at room temperature. The Ea of atropisomerization
of 13 was determined to be 13 kcalmolÀ1, significantly lower
than for bismurrayaquinone A (1). The corresponding biphe-
nol 2 required heating to 1808C for racemization to be
observed, but competing decomposition afforded data that
was unacceptable for calculating the activation barrier of
atropisomerization.
Rationalization of the relative stability of bismurrayaqui-
none A (1) compared to the other biquinones studied was
challenging. We initially speculated that racemization might
be induced photochemically as related phenomena have been
reported for several axially chiral biaryls.[16] Racemization of
biquinone 8 proceeded just as rapidly in the dark as it did in
sunlight, however. Lumb and Trauner showed in their elegant
biomimetic synthesis of microphyllaquinone that binaptho-
quinones will undergo a tautomerization/6p-electrocycliza-
tion cascade.[17] If such a process was reversible this may
promote racemization, but under our neutral reaction con-
ditions we never observed the formation of a pyran species
that would indicate such a process was operative for 1 or 13.[18]
We next turned to the molecular modeling of the atropiso-
merization of 1 and 13; this process was carried out by
calculating an energy profile with a changing dihedral angle
Figure 1. X-ray structures of a) bismurrayaquinone A (1) and b) biqui-
none 13, with non-crucial atoms removed for clarity.
another sequentially during atropisomerization. Conse-
quently, more easily accommodated out-of-plane distortion
should lead to lower activation barriers of atropisomerization,
an outcome consistent with our experimental observations in
the current study. Related distortions are seen in the X-ray
structure of gossypolone,[22] a 2,2’-binaphthoquinone that
racemizes at room temperature.[7a,b]
Lastly, our X-ray structure of bismurrayaquinone A (1)
enabled us to confirm its absolute configuration though
Bijvoet-pair analysis.[23] Thus, the sequences outlined herein
provided (R)- or M-(+)-bismurrayaquinone A. We also
prepared (S)- or P-(À)-bismurrayaquinone A through an
analogous sequence, employing ent-4. Curiously, however, the
CD spectrum we recorded for M-1 and P-1 displayed the
opposite shape to that predicted by the calculations reported
by Bringmann and co-workers in 1995.[5a] Bringmann and co-
workers noted that application of the standard exciton
chirality method[24] was not possible, and so made recourse
to an alternative method involving semiempirical AM1 and
CNDO calculations to predict the CD spectrum of each
enantiomer. Advances in computational techniques, however,
have now allowed a recalculation of the CD spectrum using
the TDCAM-B3LYP/TZVP method.[25] These new results
support our X-ray crystallographic analysis that (+)-bismur-
rayaquinone A possesses the (R)- or M-configuration.
Despite the fact that any definitive statement as to the
naturally occurring configuration of bismurrayaquinone A (1)
will require reisolation from the curry-leaf tree, our work and
that of Bringmann and co-workers serves to highlight the
impact synthetic chemistry can have on fundamental ques-
tions of structure and stereochemistry.
In conclusion, we have completed the first enantioselec-
tive synthesis of bismurrayaquinone A (1) through a concise
strategy that employs traceless stereochemical transfer. The
approach utilized axially chiral bromide 6 as a late-stage
precursor, thus enabling a bidirectional palladium-catalyzed
carbazole synthesis. Future elaboration of this useful biphenyl
core will enable the synthesis and biological evaluation of
numerous bismurrayaquinone A analogues. The activation
parameter for atropisomerisation of bismurrayaquinone A
(1) was experimentally determined and a rationale based
upon X-ray data analysis has been proposed to account for
the observed differences in activation barriers of atropisome-
rization between related compounds. Further details of our
À
about the central C C bond (Spartan, B3LYP 6-31G*
level).[19] Unfortunately, at this level of theory both com-
pounds gave activation barriers of approximately 23–25 kcal
molÀ1, which are values significantly different than the
experimentally determined values. We could not make any
firm conclusions from these calculations.
Insight came when we succeeded in growing single crystals
of bismurrayaquinone A (1) and biquinone 13 that were
suitable for X-ray crystallographic analysis.[20] As anticipated
À
each of the biquinones possessed shorter C O bonds than the
corresponding biphenol 2[8] (1.22 ꢁ for 1 and 13 versus 1.37 ꢁ
for 2), thus establishing a rationale for the lower activation
barriers of atropisomerization of biquinones compared to
biphenols. In general, bond lengths for 1 and 13 were similar,
but we noted greater out-of-plane distortion for biquinone 13
in comparison to bismurrayaquinone A (1). A view of the X-
ray structures of each molecule, with an arrow highlighting
the effect of the distortion, clearly shows this interesting
phenomenon (Figure 1).
Out-of-plane distortion of the type exhibited by biquinone
13 has been proposed by Ling and Harris to explain observed
trends in the activation parameters for the racemization of
2,2’-diiodobiphenyls.[21] These deformations lead to significant
ground-state destabilization and allow the substituents on
either side of the central carbon–carbon bond to pass one
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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