Angewandte
Chemie
Scheme 3. Formation of “cannabinoid” 15 from vinyl hydroquinone 9.
Figure 3. Elucidation of the relative (and absolute) configuration of
pycnanthuquinone C.
structure was confirmed by X-ray crystallography (Figure 2),
bears a strong resemblance to D9-tetrahydrocannabinol (D9-
THC). Indeed domino reactions of this type have been used
to synthesize cannabinoids, and our results could provide an
asymmetric entry to this class of natural products.[12]
hydrogen at C6 in anhydrous [D6]DMSO. This is possible only
if unnatural (ꢀ)-pycnanthuquinone C has the relative config-
uration indicated in Figure 3. Hence, the natural product (+)-
pycnanthuquinone C has the all-S configuration.
Our total synthesis provides evidence that pycnanthuqui-
none C arises biosynthetically from its known congener 17 by
means of epoxidation (!18), followed by formation of the
vinyl quinone (!19), VQDA reaction, addition of water and
aerobic reoxidation (Scheme 4). The fact that pycnanthuqui-
nones A (1) and B (2) are diastereomers with respect to the
secondary hydroxy group also supports this hypothesis, since
an enzymatic hydroxylation would be expected to be highly
diastereoselective.
Figure 2. X-ray crystal structure of 15.
A similar pathway could also occur in the biosynthesis of
the meroterpenoid rossinone B (6). We propose that this
natural product stems directly from rossinone A (20), which
was isolated from the same natural source. Oxidation of 20 to
21, followed by VQDA reaction, addition of water, and
further oxidation would initially afford quinone 22, which
closely resembles the pycnanthuquinones. In this case, how-
ever, the VQDA sequence is followed by an intramolecular
SNi’ reaction that yields the tetracyclic framework of rossino-
ne B.
In summary we have developed a three-step, protecting-
group-free synthesis of (ꢀ)-pycnanthuquinone C that extends
the reach of vinyl quinone Diels–Alder reactions. It also
provides strong evidence for the formation of the pycnanthu-
quinone skeleton through a biosynthetic cycloaddition and
has enabled the full elucidation of the stereochemistry of the
natural product. The VQDA chemistry developed herein
could be extended in a straightforward way towards the
synthesis of pycnanthuquinones A and B as well as pleurotin.
Having developed a concise asymmetric synthesis of
pycnanthuquinone C, we next turned our attention to the
issue of the relative and absolute configuration of the natural
product. Since the absolute configuration of (ꢀ)-linalool is
known, we were able to determine the absolute configuration
of our synthetic material at C3. In addition, we had
established the structure of isomer 13 by X-ray crystallog-
raphy, and the trans configuration of the hydrindane moiety
could be gleaned from the literature.[5,6] This left us with two
possible isomers, compounds 16 and (ꢀ)-3 (Figure 3). Com-
pounds (ꢀ)-3 and 13 would arise as a pair from a highly
diastereoselective Diels–Alder reaction and an unselective
attack of water, whereas 16 and 13 would be formed through
an unselective Diels–Alder reaction and a highly diastereo-
selective addition of water. Given the relative configuration
of pycnanthuquinones A (1) and B (2), the latter seemed
unlikely, but could not be ruled out.
After several unsuccessful attempts to prove the relative
configuration of pycnanthuquinone C through chemical deri-
vatization or interconversion, we focused our efforts on nOe
measurements, which had reportedly given inconclusive
results in the initial investigations.[5,6] However, with ample
material at hand, we were able to observe nOe signals
between the protons of both hydroxy groups and the methine
Received: March 29, 2010
Published online: July 19, 2010
Keywords: biomimetic synthesis · Diels–Alder reactions ·
.
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
pycnanthuquinones · total synthesis · vinyl quinones
Angew. Chem. Int. Ed. 2010, 49, 6199 –6202
Loebermann, Florian
