Two DAEHs were reported to be optically inactive,10 and
the remaining four DAEHs were isolated without mention
of optical activity.9b,11 It is unclear if the optically inactive
members are achiral or are racemic. Similarly, it is unclear
if the DAEHs with unreported optical activity are achiral,
chiral racemic, or chiral nonracemic compounds. Although
the more substituted members of this class are commonly
optically active (e.g., myricatomentogenin, 1), some mole-
cules that have relatively little substitution (e.g., garuganin
IV, 8) are also optically active. In this report, we disclose the
synthesis of the “heptanone-type” DAEHs (1ꢀ6), determi-
nation of their free energy of activation for racemization,
and absolute stereochemistry.
DAEHs are commonly isolated by Soxhlet extraction
using hot solvents for hours or days. Elevated tempera-
tures could lead to racemization of these conformationally
chiral molecules. We considered the possibility that the
optically inactive members of this class had beenracemized
during isolation.
Insight into the chiral properties of the DAEHs can be
gleaned from data presented in the isolation reports. Inspec-
tion of the 1H NMR data of 1ꢀ4 reveals that the geminal
methylene hydrogens are chemical-shift inequivalent. This
observation is consistent with the presence of an element of
chirality on the NMR time scale. All geminal methylene
protons of 5 and 6 are chemical-shift equivalent, suggesting
the natural products are achiral at rt on the NMR time scale.
With these considerations in mind, the heptanone
DAEHs (1ꢀ6) were prepared to investigate their chiral
properties. Our retrosynthetic analysis of 1 and 2 simplifies
the molecules by disconnection of the ether linkage to give
achiral bromophenols 16 (Scheme 1). Positioning the
phenolic functional group on the more electron-rich phe-
nyl ring was anticipatedtogivea smoothercyclization than
an alternative approach with an electron-rich bromide.
Further simplification leads to aldehydes 17 and 18. Dif-
ferentially functionalized aldehyde 18 was envisioned to
arise from commercially available 7-hydroxycoumarin.
Figure 1. Diarylether heptanoid natural products that lack
stereogenic centers.
DAEHs can be divided into two distinct classes: (1)
DAEHs with a heptanone ansa bridge (1ꢀ6); (2) DAEHs
with multiple sp2-hybridized carbons in the ansa bridge
(7ꢀ15). Galeon (3) has been isolated on two separate
occasions as both a levo- and dextrorotary compound.7
Jugcathanin (2) was isolated without mention of optical
activity or chirality, and it was later isolated as an optically
active molecule and named juglanin A.8 Seven other
DAEHs were isolated as optically active compounds.5a,7b,9
Scheme 1. Retrosynthesis of Myricatomentogenin and Jugcathanin
(6) During the preparation of this manuscript tedarene A was
isolated. It has an estimated free energy of activation for interconversion
of enantiomeric conformers of 14.0 kcal/mol at ꢀ40 °C. See: Costantino,
V.; Fattorusso, E.; Mangoni, A.; Perinu, C.; Teta, R.; Panza, E.; Ianaro,
A. J. Org. Chem. 2012, ASAP. DOI: 10.1021/jo300295j.
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K.-i.; Nagai, M. Chem. Pharm. Bull. 1997, 45, 820–823.
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