biogenesis of the unusual 6ꢀ5ꢀ6 ring system have been
proposed by us5o,p and others5h,s,6 based on the structural
features of isolated C20 diterpenoids.
diastereoselectivity (20:1). Interestingly, this rearrangement
could also be performed under bright sunlight giving
identical results. The relative configuration of the major
diastereoisomer 6 was established as (6S) by NMR analysis
(8.3 Hz coupling constant between H5 and H6) and was
confirmed by subsequent X-ray crystal structure analysis
(see Scheme 1). A possible explanation for the formation
of the kinetic cis product would be a protonation from the
sterically less hindered face of the enolate double bond
(denoted HA in red, Scheme 1, 9).9 A subsequent epimer-
ization of the C6 stereogenic center was achieved using
NaOMe in MeOH giving the (6R)-ester 7 in a quantitative
yield and a dr of 33:1 (as determined by NMR analysis).
When the same substrate 6 was subjected to aqueous
KOH, the (6R)-carboxylic acid 8 was obtained in 88%
yield and a dr of 8.3:1. The configuration at C6 was
established by NMR analysis (11.6 Hz coupling constant
between H5 and H6) and confirmed by subsequent X-ray
crystal structure analysis. The same (6R)-ester 7 required
for the next steps was obtained quantitatively by methyla-
tion of 8 using TMSCHN2. Subsequently, LiAlH4 reduc-
tion of the (6R)-ester 7 afforded the corresponding alcohol
10 in quantitative yield.
Taiwaniaquinone F (1)7a and taiwaniaquinol A (2)6 are
two prominent members of this family, characterized
by the presence of a 1,4-quinone and a methylene-bridged
catechol, respectively (Figure 1).7 Preliminary studies
showed that many taiwaniaquinoids possess intriguing
biological activities, and 1 and 2 showed potent cytotoxi-
city against the epidermoid carcinoma (KB) cancer cell
line.7b
In this communication, we report on the preparation
of taiwaniaquinone F (1) from abietic acid via a carbene
mediated ring contraction followed by aromatic oxidation
reactions. In addition, taiwaniaquinol A (2) was obtained
for the first time in synthetic form via an unusual
rearrangement.
With the alcohol 10 in hand, the oxidation of the
aromatic ring system was addressed next (Scheme 2).
The crude alcohol 10 was brominated (Br2 in CH2Cl2)
to give 11 in good yields. Initially, a one pot lithiationꢀ
boronationꢀoxidation reaction using n-BuLi, TMEDA,
B(OMe)3, and H2O2 was attempted toconvert 11tophenol
12. However, traces of product could already be detected
by TLC after the lithiation step, which led us to the
conclusion that O2 (dissolved in the solvent) could operate
as the oxidant in this reaction. To our great satisfaction, a
simplified procedure using a one pot lithiation/oxygenation
protocol with n-BuLi, TMEDA, and dioxygen10 afforded
the phenol 12 in 58% yield from 11. Oxidation of phenol 12
to the corresponding p-quinone 13 was accomplished using
Co(salen)11 with dioxygen in CH3CN in quantitative yield.
It is noteworthy that this reaction and the purification of
the product were carried out under exclusion from light
to avoid decomposition of this sensitive compound. Final
oxidation of alcohol 13 was accomplished by treatment
with DessꢀMartin periodinane (DMP) in CH2Cl2 in the
dark, to produce (ꢀ)-taiwaniaquinone F (1) in quantitative
yield. All spectroscopic data of this synthetic compound
were in agreement with those reported for the authentic
natural product.6
Figure 1. Structures of (ꢀ)-taiwaniaquinone F and (þ)-taiwa-
niaquinol A.
The synthesis of taiwaniaquinone F (1) started from
the natural product sugiol methyl ether (4), which was
prepared from commercially available abietic acid (3) in
36% yield over nine steps interconnecting eight natural
intermediates in multigram scale following known syn-
thetic procedures with some experimental modifications8
(Scheme 1).
The establishment of the characteristic 6ꢀ5ꢀ6 ring sys-
tem through ring contraction of the B ring of sugiol methyl
ether (4) was addressed next. Diazotization of ketone 4
using p-acetamidobenzenesulfonyl azide (p-ABSA) and
DBU afforded diazoketone 5 in 65% yield together
with a smaller amount of remaining starting material 4
(30%). When diazoketone 5 was subjected to irradiation
of a medium pressure Hg lamp in a dilute solution of
dry MeOH, it underwent a smooth Wolff rearrangement
yielding the ring contracted product 6 with excellent
To avoid decomposition of the natural product
(ꢀ)-taiwaniaquinone F (1), it was also essential in this
step to perform the workup and purification under strict
exclusion from light. To our great surprise, if such pre-
cautions were not taken, minor amounts of impurities
(6) Lin, W. H.; Fang, J. M.; Cheng, Y. S. Phytochemistry 1995, 40,
871.
(7) (a) Chang, C.-I.; Chien, S.-C.; Lee, S.-M.; Kuo, Y.-H. Chem.
Pharm. Bull. 2003, 51, 1420. (b) Chang, C.-I.; Cheng, J.-Y.; Kuo, C.-C.;
Pan, W.-Y.; Kuo, Y.-H. Plant Med. 2005, 71, 72.
(8) See Supporting Information for additional details: (a) Portmann,
C.; Prestinari, C.; Myers, T.; Scharte, J.; Gademann, K. ChemBioChem
(9) (a) Zimmerman, H. E. J. Org. Chem. 1955, 20, 549. (b) Zimmerman,
H. E.; Linder, L. W. J. Org. Chem. 1985, 50, 1637.
(10) Parker and co-workers reported the oxygenation of similar
lithiated aromatic species with O2: Parker, K. A.; Koziski, K. A.
J. Org. Chem. 1987, 52, 674.
ꢁ
ꢁ
2009, 10, 889. (b) Gonzalez, M. A.; Perez-Guaita, D.; Correa-Royero, J.;
Zapata, B.; Agudelo, L.; Mesa-Arango, A.; Betancur-Galvis, L. Eur. J.
Med. Chem. 2010, 45, 811. (c) Fujimoto, Y.; Tatsuno, T. Tetrahedron
Lett. 1976, 37, 3325. (d) Akita, H.; Oishi, T. Chem. Pharm. Bull. 1981, 29,
1567. (e) Brandt, C. W.; Neubaeur, L. G. J. Chem. Soc. 1939, 1031. (f)
Gan, Y.; Li, A.; Pan, X.; Chan, A. S. C.; Yang, T.-K. Tetrahedron:
Asymmetry 2000, 11, 781.
(11) Liu, W.; Liao, X.; Dong, W.; Yan, Z.; Wang, N.; Liu, Z.
Tetrahedron 2012, 68, 2759.
Org. Lett., Vol. 15, No. 6, 2013
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