the heterogeneity of aqueous reaction mixtures,12 indeed
performing this reaction in an aqueous 5% w/w PEG-600/
R-Tocopherol-based diester of Sebacic acid (PTS) solution
resulted in a 21% yield (Table 1, entry 10).13 Eventually
the optimal conditions were found to be slow addition of
diformylphloroglucinol 4 to a mixture of benzaldehyde 3 and
caryophyllene 2 in an aqueous 5% w/w PTS solution under
reflux, resulting in a 25% yield (Table 1, entry 11).
Interestingly when using neat caryophyllene 2 as both
reactant and solvent, the products were obtained in a 21%
yield (Table 1, entry 12). The reaction conditions screened
all gave a ratio of 80:20 for guajadial (1) and psidial A (15)
to diastereomer 14, which is in good agreement with the
relative populations of the ꢀR and ꢀꢀ conformers of
caryophyllene 2.
Figure 3. Molecular structure of guajadial (1) and psidial A (15)
from single crystal diffraction data.14
A preparative synthesis of guajadial (1) was carried out.
Subsequent column chromatography was followed by HPLC
purification of the cleanest fractions, resulting in an unop-
timized 6% isolated yield of guajadial (1) as a white powder.
Crystals of guajadial (1) and psidial A (15) suitable for X-ray
diffraction studies (Figure 3)14 were formed by cooling
saturated acetonitrile solutions from ambient temperature to
-25 °C.
Despite extensive HPLC purification and recrystallization,
it was observed that a small quantity of psidial A (15) was
always present in synthetic guajadial (1). Professor Liu kindly
provided us with an authentic sample of natural guajadial
(1) for direct comparison with our synthetic material.
However, their authentic sample was now also a mixture of
guajadial (1) and psidial A (15) (see the Supporting Informa-
tion). Liu et al. reported an [R]26D of -23.1 (c 0.5, acetone)
for natural guajadial (1).1 We obtained an [R]26D of +1.6 (c
0.5, acetone) for synthetic guajadial (1). However, synthetic
psidial A (15) has a large [R]26 of +88.8 (c 0.5, acetone),
D
and so the small quantity of 15 present in our synthetic
sample would obviously have a large effect upon the
recorded optical rotation.
In conclusion, a short biomimetic synthesis of guajadial
(1) and psidial A (15) has been achieved, providing
experimental support for the proposed biosynthesis.1 It was
found that the stereochemical outcome of the hetero-
Diels-Alder reaction is largely controlled by the local
conformation and intrinsic chirality of caryophyllene 2
(Figure 2).2 In addition the absolute configurations of
guajadial (1) and psidial A (15) were established. A
biomimetic hetero-Diels-Alder reaction, involving an o-
quinone methide, has been successfully conducted in water
as a green and universal biological solvent, without the use
of acid or base catalysis. We believe water has the potential
to become a very useful solvent for other o-quinone methide
reactions.
(12) Doncaster, J. R.; Ryan, H.; Whitehead, R. C. Synlett 2003, 5, 651.
(13) (a) Lipshutz, B. H.; Aguinaldo, G. T.; Ghorai, S.; Voigtritter, K.
Org. Lett. 2008, 10, 1325. (b) Lipshutz, B. H.; Taft, B. R. Org. Lett. 2008,
10, 1329. (c) Lipshutz, B. H.; Petersen, T. B.; Abela, A. R. Org. Lett. 2008,
10, 1333.
(14) Single crystal X-ray diffraction data were colleced on a sample
mounted using the oil drop technique at 150 K with an Oxford Cryosystems
Cryostream open flow N2 cooling device: Cosier?.; Glazer?. J. Appl.
Crystallogr. 1986, 19, 105. Data were collected using a Nonius Kappa-
CCD area detector diffractometer, with graphite-monochromated Mo KR
radiation (λ ) 0.71073 Å). Cell parameters and intensity data were processed
using the DENZO-SMN package and reflection intensities were corrected
for absorption effects by the multiscan method, based on multiple scans of
identical and Laue equivalent reflections. [Otwinowski; Minor, Processing
of X-ray Diffraction Data Collected in Oscillation Mode, Methods Enzymol-
ogy; Academic Press: New York , 1997; p 276]. The structures were solved
by direct methods [Altomare, A.; Cascarano, G.; Givcovazzo, C.; Guagliardi,
A.; Burla, M. C.; Polidori, G.; Camalli, M. J. Appl. Crystallogr. 1994, 27,
435]. and refined by full-matrix least squares on F2, using the CRYSTALS
suite. Betteridge, P. W.; Carruthers, J. R.; Cooper, R. I.; Prout, K.; Watkin,
D. J. J. Appl. Crystallogr. 2003, 36, 1487. The Flack x parameter [Flack,
H. D. Acta Crystallogr. 1983, A39, 876.] was determined for both compounds
and the Bijovet pairs analyzed to give the Hooft y parameters. Hooft,
R. W. W.; Straver, L. H.; Spek, A. L. J. Appl. Crystallogr. 2008, 41, 96.
Thompson, A. L.; Watkin, D. J. Tetrahedron: Asymmetry 2009, 20, 712.
Full refinement details including x, y, and derived probabilities are given
in the CIF. Crystallographic data (excluding structure factors) for the structures
of 1 and 15 have been deposited with the Cambridge Crystallographic Data
Centre (CCDC 767572 and 767573). Copies of these data can be obtained
Acknowledgment. We thank Givaudan SA, Gene`ve (Dr.
Philip Kraft) for the generous supply of caryophyllene. We
also thank Professor Ji-Kai Liu (Kunming Institute of
Botany) for providing us with an authentic sample of
guajadial, and Prof. Gouverneur’s group (Chemistry Research
Laboratory, University of Oxford) for the use of their HPLC
equipment.
Supporting Information Available: Synthetic procedures
and analytical data. This material is available free of charge
OL100138K
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