First total synthesis of prionoid E, A bioactive rearranged secoabietane diterpene quinone from Salvia prionitis

Article abstract of DOI:10.1002/hlca.201000435

The first total synthesis of prionoid E (1), a rearranged secoabietane diterpene quinone isolated from Salvia prionitis, was achieved efficiently by means of Wacker oxidation (Scheme 5) and aldol condensation (Scheme 7) as the key steps in the synthetic sequence. Thus 1 was prepared in 15 steps in 3.7% yield starting on one hand from anisole (=methoxybenzene) and methylsuccinic anhydride (=dihydro-3-methylfuran-2,5-dione) via 4 (Scheme 3 and 5), and on the other hand from 2-hydroxy-2-methylpropanoic acid via 5 (Scheme 6). Copyright

Full text of DOI:10.1002/hlca.201000435

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Helvetica Chimica Acta – Vol. 94 (2011)
First Total Synthesis of Prionoid E, A Bioactive Rearranged Secoabietane
Diterpene Quinone from Salvia prionitis
by Fei Deng*a), Jun Xua), Min Zhaoa), Hong-Ying Liub), Yang Ye*a), and Jin-Sheng Zhanga)
a) State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of
Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, P. R. China
(phone: þ 86-21-50805892; fax: þ 86-21-50807088; e-mail: fdeng@mail.shcnc.ac.cn,
yye@mail.shcnc.ac.cn)
b) College of Life Sciences, Northwest A & F University, Yangling 712100, P. R. China
The first total synthesis of prionoid E (1), a rearranged secoabietane diterpene quinone isolated
from Salvia prionitis, was achieved efficiently by means of Wacker oxidation (Scheme 5) and aldol
condensation (Scheme 7) as the key steps in the synthetic sequence. Thus 1 was prepared in 15 steps in
3.7% yield starting on one hand from anisole (¼ methoxybenzene) and methylsuccinic anhydride
(¼dihydro-3-methylfuran-2,5-dione) via 4 (Scheme 3 and 5), and on the other hand from 2-hydroxy-2-
methylpropanoic acid via 5 (Scheme 6).
Introduction. – Salvia prionitis, a medicinal herb distributed in the southern
provinces of the P. R. China, is used in Chinese folk medicine for the treatment of
tonsillitis, pharyngitis, pulmonary infection, and bacillary dysentery. More than 50
compounds have been isolated from this plant including a number of abietane
diterpenes such as 5,10-friedo-4,5-secoabietanediterpenes. Rearranged 4,5-secoabie-
tane diterpenoids represent a new class of compounds with intensive biological activity
[1 – 7]. Few research work on the bioactivity of this kind of diterpenoids has been
reported up to now for their scarcity in nature. To the best of our knowledge, the broad
spectrum of biological activity of Salvia prionitis is associated with the interesting
rearranged secoabietane diterpenoids in the plant. Previously, we have reported the
modification of saprorthoquinone and sapriparaquinone, two rearranged 4,5-seco-
abietane diterpenoids isolated from Salvia prionitis, and provided a series of novel
analogues with potent antitumor or antioxidation activity [8 – 10]. Recently, Chang
et al. reported the isolation of prionoid D (2) and prionoid E (1) from Salvia prionitis
[7], which showed significant cytotoxic activity against tumor cell lines in vitro (IC50 ¼
0.72 mm against P-388 and IC50 ¼ 0.41 mm against A-549, resp.). However, the further
investigation of biological activities of these compounds was frustrated by their small
amount in the plant.
Many syntheses of the diterpenoids were reported, and the research work mainly
concentrated on the construction of the B-ring of the diterpenoids [11 – 19]. However,
there were few reports on the synthesis of rearranged 4,5-secoditerpenoids, especially
for those molecules with a novel side chain, which is believed to have great influence on
the bioactivity of this sort of compounds. Prionoid E (1), a rearranged 4,5-secoabietane
diterpene quinone, bears a novel side chain characterized as a 4-hydroxy-1-oxopent-2-
ꢀ 2011 Verlag Helvetica Chimica Acta AG, Zꢁrich

Helvetica Chimica Acta – Vol. 94 (2011)
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en-1-yl chain with (2E) configuration. Its unusual structure and potential bioactivity
combine to make the compound an attractive synthetic target.
Results and Discussion. – The retro-synthesis of prionoid E (1) is shown in
Scheme 1. Considering the long side chain of the target compound, we chose the
stepwise ring-construction method to furnish ring B of 1 and thus provide compound 6
as an intermediate to carry out the following side-chain construction. Indeed, the
stepwise B-ring construction maneuver was widely used in the synthesis of tanshinone
and its analogues [19]. However, there were few reports on the synthesis of rearranged
4,5-secoditerpenoids bearing a 5-Me group. Previously, Duan and Cai reported a
synthetic route for the preparation of compound 6 from (4-methoxyphenyl)acetic acid
in seven steps [15]. However, the approach was a little tedious. To form the side chain,
the strategy of preparing methyl ketone 4 as the key intermediate was chosen, which
upon aldol condensation with the corresponding aldehyde 5 should afford compound 3,
the precursor of 1.
Scheme 1
Compound 8 was easily accessible and was widely used in the synthesis of
tanshinones and its analogues [19]. However, in our hands, introducing the Me group to
8 by methylation with MeI/NaH only resulted in quite a low yield of 9, apparently due
to the bimethylation product produced and the difficulty in the isolation of 9
(Scheme 2). The two-step transformation via 10 also did not afford satisfactory results.

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Helvetica Chimica Acta – Vol. 94 (2011)
Scheme 2
a) MeI, NaH, benzene, ꢀ 208, 1 h; 21%. b) CuBr2, AcOEt, reflux, 2 h; 94%. c) MeI, DMSO, r.t., 3 h;
30%.
To avoid the harsh reaction conditions associated with the methylation, we tried to
introduce the desired Me group to 8 by using methylsuccinic anhydride (¼dihydro-3-
methylfuran-2,5-dione) under ambient reaction conditions, which turned out to be a
more efficient way (Scheme 3). Anisole (7) reacted with methylsuccinic anhydride in
the presence of AlCl3 in toluene to give the desired product 11 as the major product in
60% yield, and only a trace of by-product 12 was produced, which was easily separated
by column chromatography. Compound 11 was treated with Zn powder, HgCl2, and
conc. HCl solution to provide reduction product 13 in 92% yield. The latter, upon
Scheme 3
a) Methylsuccinic anhydride, AlCl3, nitrobenzene, r.t., overnight; 60%. b) Zn(Hg), conc. HCl soln.,
toluene, reflux, 24 h; 92%. c) PPA (¼ polyphosphoric acid), 808, 3 h; 90%. d) i-PrOH, PPA, 808, 3 h;
81%.

Helvetica Chimica Acta – Vol. 94 (2011)
1329
treatment with polyphosphoric acid (PPA) at 808, underwent cyclization to afford
compound 9 in 90% yield. Subsequent alkylation with i-PrOH in PPA at 808 afforded
regioselectively compound 6 in 81% yield.
With compound 6 in hand, we then constructed the side chain. Considering the
cyano group as prone to react with a nucleophilic methylation reagent and considering
the product obtained as easily transformable to the corresponding methyl ketone by
hydrolysis, a synthetic route to introduce a cyano group at C(1) of 6 for further
functional-group transformation was envisaged (Scheme 4). Thus, starting from 6, the
aromatic nitrile 14 was synthesized via three steps with 76% overall yield [20].
However, the subsequent reaction of 14 with a nucleophilic methylation reagent such
as MeMgBr, MeLi, or MeCeCl2 to give the desired compound 4 was unsuccessful,
probably due to steric hiderance caused by the ortho-Me group. In fact, Timberlake and
co-workers previously reported the steric hinderance effect of an ortho-Me group on
the cyano group in cumyl systems [21].
Scheme 4
a) Me3SiCN, AlCl3, benzene, 708, 12 h. b) TsOH, benzene, reflux, 0.5 h. c) DDQ (¼4,5-dichloro-3,6-
dioxocyclohexa-1,4-diene-1,2-dicarbonitrile), benzene, reflux, 0.5 h; 76% over three steps.
Since the cyano-group transformation failed, we resorted to another strategy to
form methyl ketone 4, i.e., via Wacker oxidation of an alkene moiety (Scheme 5). Thus
compound 6 was treated with CH2¼CHMgBr in THFat 08 to yield the addition product,
followed by dehydration with p-toluenesulfonic acid (¼4-methylbenzenesulfonic acid;
TsOH) and MgSO4 in refluxing benzene for 1 h to provide product 15 in 65% yield over
two steps. Aromatization of compound 15 with DDQ in refluxing benzene for 0.5 h
gave naphthalene 16 in 96% yield. The vinyl group of 16 was converted into methyl
ketone 4 by using the Wacker-oxidation protocol. Thus, oxidation of 16 with O2 in the
Scheme 5
a) CH2¼CHMgBr, THF, 08, 2 h. b) TsOH, benzene, reflux, 0.5 h; 65% over two steps. c) DDQ, benzene,
reflux, 0.5 h; 96%. d) O2 , CuCl, PdCl2, THF/H2O, r.t., 12 h; 71%.

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presence of CuCl and PdCl2 in THF/H2O provided the key intermediate 4 in 71% yield
[22][23].
The silyloxy-substituted aldehyde 5 was synthesized according to a reported route
with some modifications [24]: starting from 2-hydroxy-2-methylpropanoic acid (17),
the aldehyde was synthesized in three steps with 62% overall yield (Scheme 6). Aldol
addition of methyl ketone 4 and aldehyde 5 in the presence of lithium bis(trimethylsi-
lyl)amide (LHMDS) in THF at ꢀ 788 proceeded smoothly to afford the corresponding
hydroxy compound 18, which after dehydration provided compound 3, the precursor of
prionoid E (1) (Scheme 7). However, elimination of the OH group to form the a,b-
unsaturated ketone was problematic due to the presence of the acid-sensitive (tert-
butyl)dimethylsilyl group which is prone to leave with concomitant dehydration under
acidic conditions. After failure with reagents such as TsOH or methanesulfonyl
chloride (MsCl)/Et3N, ultimately 18 was dehydrated to give the a,b-unsaturated ketone
3 by refluxing in benzene in the presence of a catalytic amount of TsOH/pyridine [25].
The product thus obtained was exclusively the (E)-isomer. Treatment of 3 with BBr3 in
CH2Cl2 at ꢀ 788 for 12 h only gave a desilylated product. Then, after increasing the
Scheme 6
a) EtOH, H2SO4, benzene, reflux, 12 h. b) TBSOTf (¼tBuMe2SiOSO2CF3), CH2Cl2, r.t., 12 h. c)
DIBALH (¼diisobutylaluminium hydride), Et2O, ꢀ 788, 1 h; 62% over three steps.
Scheme 7
a) LHMDS, THF, ꢀ 788, 1 h. b) Cat. TsOH/pyridine, benzene, reflux, 24 h; 65% over two steps. c) BBr3,
r.t., 5 h; 62%. d) Fremyꢂs salt, acetone, H2O, r.t., 12 h; 52%.

Helvetica Chimica Acta – Vol. 94 (2011)
1331
reaction temperature to room temperature and stirring for another 5 h, the desilylation
was complete in a one-pot procedure to provide compound 19 in 62% yield. Finally,
oxidation of 19 with Fremyꢂs salt in acetone at room temperature for 12 h gave the
target molecule prionoid E (1). The spectroscopic data of the synthesized product were
in excellent agreement with those of the natural product [7].
Conclusion. – We have achieved the first total synthesis of prionoid E (1) by an
efficient and practical route in 3.7% overall yield, with Wacker oxidation and aldol
condensation as the key steps. Application of this strategy to obtain prionoid E (1) and
its analogs for evaluation of their biological activity is under progress and will be
reported in due course.
This work was supported by the National Science Foundation of China (39830440, 30925043), the
State Key Laboratory of Drug Research of China (SIMM1004KF-04), and the Shanghai Committee of
Science and Technology, China (11ZR1444900).
Experimental Part
General. Solvents and org. reagents were purchased from Lancaster, Acros, and Shanghai Chemical
Reagent Company, and were used without further purification. TLC: HG F254 (150 – 200 mm thickness;
Yantai Huiyou Company, P. R. China). Column chromatography (CC): commercial silica gel (SiO2;
200 – 300 mesh; Qingdao Haiyang Chemical Group Co.). IR Spectra: Nicolet-Magna-750 spectropho-
tometer; films or KBr discs; ˜n in cmꢀ1. 1H- and 13C-NMR Spectra: Bruker-DRX-400 spectrometer; at 400
(1H) and 100 (13C); d in ppm rel. to Me4Si as internal standard, J in Hz. ESI-HR-MS: Finnigan MAT-95,
LCQ-DECA, and Agilent-1100 LC-MS spectrometer; in m/z.
4-(4-Methoxyphenyl)-2-methyl-4-oxobutanoic Acid (¼4-Methoxy-a-methyl-g-oxobenzenebutanoic
Acid; 11). To a soln. of methylsuccinic anhydride (5 g, 0.044 mol) and anisole (¼ methoxybenzene; 7;
10 ml) in nitrobenzene (40 ml) was slowly added AlCl3 (13.5 g, 0.1 mol) at 08. The resulting mixture was
stirred overnight at r.t. The mixture was then poured into ice-water (50 ml) and extracted with Et2O (3 ꢁ
50 ml). The aq. layer was acidified with 2n HCl and again extracted with AcOEt (3 ꢁ 50 ml). The
combined org. extract was washed with brine (2 ꢁ 100 ml), dried (MgSO4), and concentrated and the
residue purified by CC (petroleum ether/AcOEt 10 :1): 11 (5.8 g, 60%) and 12 (0.2 g, 2%). Spectra:
identical with those published in [26].
4-(4-Methoxyphenyl)-2-methylbutanoic Acid (¼4-Methoxy-a-methylbenzenebutanoic Acid; 13). Zn
powder (8.9 g, 0.04 mol), HgCl2 (0.9 g, 0.003 mol), conc. HCl soln. (1 ml), and H2O (10 ml) were mixed
under stirring for 10 min. The aq. layer was decanted, and the resulting mixture was washed with H2O.
Compound 11 (3.3 g, 0.015 mol) in toluene (30 ml) was added to the mixture, followed by conc. HCl soln.
(12 ml) and H2O (6 ml). The mixture was heated to reflux for 24 h. After cooling, H2O (50 ml) was
added. The resulting mixture was extracted with AcOEt (3 ꢁ 50 ml), the combined org. extract was
washed with H2O (3 ꢁ 50 ml), dried (MgSO4), and concentrated, and the crude product purified by CC
(petroleum ether/AcOEt 80 :1): 13 (2.9 g, 92%). Colorless oil. Spectra: identical with those published in
[15].
3,4-Dihydro-7-methoxy-2-methylnaphthalen-1(2H)-one (9). Compound 13 (3.5 g, 0.017 mol) was
added to PPA (100 g) at 808, and the mixture was stirred at 808 for 3 h. Ice-water (50 ml) was added to
decompose PPA, and the mixture was extracted with Et2O (3 ꢁ 50 ml). The combined Et2O extract was
washed with 10% aq. K2CO3 soln. (2 ꢁ 30 ml) and brine (2 ꢁ 30 ml), dried (MgSO4), and concentrated
and the residue purified by CC (petroleum ether/AcOEt 100 :1): 9 (2.9 g, 90%). Colorless oil. Spectra:
identical with those published in [15].
3,4-Dihydro-7-methoxy-2-methyl-6-(1-methylethyl)naphthalen-1(2H)-one (6). Compound 9 (2.0 g,
10.5 mmol) and i-PrOH (2.5 ml) were added to PPA (8.0 g) at 808, and the resulting mixture was stirred
at 808 for 3 h. Ice-water (30 ml) was added to decompose PPA, and the mixture was extracted with Et2O

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Helvetica Chimica Acta – Vol. 94 (2011)
(3 ꢁ 30 ml). The combined Et2O extract was washed with 10% aq. K2CO3 soln. (2 ꢁ 20 ml) and brine
(2 ꢁ 20 ml), and dried (MgSO4), and concentrated: 6 (1.95 g, 81%). Colorless oil. IR (KBr): 2960, 1682,
1608, 1497, 1464, 1414, 1357, 1331, 1250, 1200, 1074, 1053, 1014, 889, 766, 536. 1H-NMR (CDCl3): 7.46 (s,
1 H); 7.02 (s, 1 H); 3.84 (s, 3 H); 3.32 (sept., J ¼ 6.9, 1 H); 2.91 – 2.95 (m, 2 H); 2.53 – 2.56 (m, 1 H); 2.15 –
2.19 (m, 1 H); 1.81 – 1.85 (m, 1 H); 1.24 (d, J ¼ 6.9, 3 H); 1.20 (d, J ¼ 6.9, 6 H). 13C-NMR (CDCl3): 155.6;
143.5; 136.9; 130.7; 126.2; 107.4; 55.4; 42.2; 31.7; 28.0; 26.9; 22.3; 15.5. HR-MS: 232.1461 (Mþ, C15H20O2þ ;
calc. 232.1463).
7-Methoxy-2-methyl-6-(1-methylethyl)naphthalene-1-carbonitrile (14). To a soln. of 6 (250 mg,
1.08 mmol) in benzene (10 ml) was added Me3SiCN (122 mg, 1.23 mmol) and a cat. amount of AlCl3, and
the mixture was stirred at 708 for 12 h. Then, TsOH (2 mg) was added to the mixture, which was heated to
reflux for an additional 0.5 h, and after addition of DDQ (320 mg, 1.41 mmol), heating was continued for
another 0.5 h. The mixture was cooled to r.t., and the precipitate was filtrated off through Celite. The
solvent was evaporated and the residue purified by CC (petroleum ether): 14 (197 mg, 76%). Colorless
oil. IR (KBr): 2962, 2871, 2213,1627, 1498, 1460, 1407, 1228, 1168, 1020, 845, 765, 447. 1H-NMR (CDCl3):
7.81 (d, J ¼ 8.6, 1 H); 7.60 (s, 1 H); 7.39 (s, 1 H); 7.20 (d, J ¼ 8.7, 1 H); 4.01 (s, 3 H); 3.40 (sept., J ¼ 6.9,
1 H); 2.70 (s, 3 H); 1.28 (d, J ¼ 6.8, 6 H). 13C-NMR (CDCl3): 158.5; 142.3; 139.7; 133.2; 132.1; 126.7;
125.3; 125.2; 117.8; 107.3; 102.2; 55.5; 26.9; 22.4; 21.1. HR-MS: 239.1312 (Mþ, C16H17NOþ; calc.
239.1310).
1-Ethenyl-3,4-dihydro-7-methoxy-2-methyl-6-(1-methylethyl)naphthalene (15). To a soln. of
6
(200 mg, 0.86 mmol) in anh. THF (10 ml) was slowly added 1.0m CH2¼CHMgBr in THF (1.72 ml,
1.72 mmol) at 08, and the mixture was stirred at 08 for 2 h. The reaction was quenched with sat. NH4Cl
soln. (10 ml), the aq. layer extracted with Et2O (3 ꢁ 20 ml), the Et2O extract was washed with sat.
NaHCO3 soln. (10 ml) and brine (10 ml), dried (Na2SO4), and concentrated, and the residue dissolved in
dry benzene (20 ml). MgSO4 (1 g, 8.3 mmol) and TsOH (2 mg) were added to the soln. The mixture was
refluxed for 0.5 h. After cooling to r.t., the MgSO4 was filtered off, the filtrate washed with sat. NaHCO3
soln. (10 ml) and brine (10 ml), dried (MgSO4), and evaporated, and the residue purified by CC
(petroleum ether): 15 (135 mg, 65%). Colorless oil. IR (KBr): 3081, 2958, 2929, 2831, 1627, 1610, 1562,
1500, 1463, 1407, 1317, 1203, 1062, 887, 763. 1H-NMR (CDCl3): 6.98 (s, 1 H); 6.85 (s, 1 H); 6.55 (dd, J ¼
17.5, 11.4, 1 H); 5.46 (dd, J ¼ 11.4, 2.4, 1 H); 5.30 (dd, J ¼ 17.6, 2.4, 1 H); 3.79 (s, 3 H); 3.27 (sept., J ¼ 6.9,
1 H); 2.64 (t, J ¼ 7.7, 2 H); 2.24 (t, J ¼ 7.6, 2 H); 1.98 (s, 3 H); 1.20 (d, J ¼ 6.8, 6 H). 13C-NMR (CDCl3):
154.9; 134.3; 134.1; 133.7; 133.4; 130.2; 127.6; 124.9; 118.5; 107.7; 55.6; 31.2; 27.5; 26.4; 22.8; 21.0. HR-MS:
265.1562 ([M þ Na]þ, C17H22NaOþ; calc. 265.1568).
1-Ethenyl-7-methoxy-2-methyl-6-(1-methylethyl)naphthalene (16). The mixture of 15 (500 mg,
2.0 mmol) and DDQ (750 mg, 3.0 mmol) in benzene (20 ml) was refluxed for 0.5 h. The mixture was
cooled to r.t., the precipitate filtrated off through Celite, the filtrate concentrated, and the residue
purified by CC (petroleum ether): 16 (496 mg, 96%). Colorless oil. IR (KBr): 2958, 1629, 1496, 1461,
1398, 1228, 1169, 1070, 1027, 889, 802, 769. 1H-NMR (CDCl3): 7.58 (overlapping, 2 H); 7.37 (s, 1 H); 7.18
(d, J ¼ 8.3, 1 H); 7.00 (dd, J ¼ 18.0, 11.3, 1 H); 5.75 (dd, J ¼ 11.4, 2.3, 1 H); 5.45 (dd, J ¼ 18.0, 2.2, 1 H);
3.93 (s, 3 H); 3.38 (sept., J ¼ 6.9, 1 H); 2.44 (s, 3 H); 1.28 (d, J ¼ 7.0, 6 H). 13C-NMR (CDCl3): 156.1; 137.3;
134.7; 132.9; 132.1; 131.1; 127.5; 126.3; 126.2; 124.7; 120.4; 102.6; 55.1; 27.0; 22.7; 20.8. HR-MS: 240.3405
(Mþ, C17H20Oþ; calc. 240.3401).
1-[7-Methoxy-2-methyl-6-(1-methylethyl)naphthalen-1-yl]ethanone (4). To a soln. of 16 (200 mg,
0.83 mmol) in THF (20 ml) and H2O (2 ml), PdCl2 (7.4 mg, 0.042 mmol) and CuCl (82 mg, 0.83 mmol)
were added. The mixture was stirred at 708 for 2 h. After cooling to r.t., the mixture was stirred vigorously
under a balloon of O2 for 12 h. The mixture was extracted with Et2O (3 ꢁ 20 ml), the combined org.
phase washed with brine (10 ml), dried (MgSO4), and concentrated, and the residue purified by CC
(petroleum ether/AcOEt 60 :1): 4 (153 mg, 71%). Colorless oil. IR (KBr): 3442, 2956, 2929, 2856, 1728,
1
1701, 1631, 1464, 1363, 1253, 1168, 1055, 835, 773, 689. H-NMR (CDCl3): 7.66 (d, J ¼ 8.2, 1 H); 7.59 (s,
1 H); 7.16 (d, J ¼ 8.3, 1 H); 6.80 (s, 1 H); 3.89 (s, 3 H); 3.37 (sept., J ¼ 6.9, 1 H); 2.62 (s, 3 H); 2.40 (s, 3 H);
1.28 (d, J ¼ 6.9, 6 H). 13C-NMR (CDCl3): 208.8; 156.8; 138.3; 137.2; 129.5; 128.2; 128.1; 127.2; 126.0;
124.9; 101.1; 55.2; 32.6; 27.0; 22.6; 19.5. HR-MS: 256.1461 (Mþ, C17H20O2þ ; calc. 256.1463).
4-{[(1,1-Dimethylethyl)dimethylsilyl]oxy}-1-[7-methoxy-2-methyl-6-(1-methylethyl)naphthalen-1-
yl]-4-methylpent-2-en-1-one (3). To a soln. of 4 (104 mg, 0.41 mmol) in dry THF (2 ml) was added 1.0m

Helvetica Chimica Acta – Vol. 94 (2011)
1333
LHMDS in THF (0.5 ml, 0.5 mmol) at ꢀ 788, and the resulting mixture was stirred at ꢀ 788 for 0.5 h. To
the mixture was slowly added a soln. of 5 (240 mg, 1.19 mmol) in dry THF (0.5 ml) at ꢀ 788, and the
mixture was stirred at ꢀ 788 for an additional hour. The reaction was quenched by the addition of sat.
NH4Cl soln. (10 ml), and the resulting mixture was extracted with CH2Cl2 (2 ꢁ 20 ml). The combined org.
phase was washed with 5% NaHCO3 soln. (10 ml) and brine (10 ml), dried (MgSO4), and concentrated:
18 as pale yellow solid which was used without further purification.
To a soln. of crude 18 in benzene (10 ml) was added TsOH (2 mg) and pyridine (5 ml), and the
mixture was refluxed for 24 h. The mixture was washed with brine (5 ml), dried (MgSO4), and
concentrated and the residue purified by CC (petroleum ether/AcOEt 80 :1): 3 (118 mg, 65% from 4).
Colorless oil . IR (KBr): 2956, 1660, 1629, 1496, 1463, 1413, 1361, 1319, 1232, 1169, 1041, 891, 837, 775, 696,
611. 1H-NMR (CDCl3): 7.67 (d, J ¼ 8.5, 1 H); 7.57 (s, 1 H); 7.15 (d, J ¼ 8.6, 1 H); 6.79 (s, 1 H); 6.59 (d, J ¼
15.7, 1 H); 6.48 (d, J ¼ 15.7, 1 H); 3.83 (s, 3 H); 3.37 (sept., J ¼ 6.9, 1 H); 2.33 (s, 3 H); 1.28 (overlapping,
12 H); 0.83 (s, 9 H); 0.01 (s, 6 H). 13C-NMR (CDCl3): 201.8; 159.4; 156.6; 138.1; 134.8; 131.3; 129.9; 128.2;
128.0; 127.2; 125.9; 124.6; 102.1; 72.9; 55.2; 29.7; 27.1; 25.7; 22.6; 19.8; 18.0; ꢀ 2.2. HR-MS: 440.2749 (Mþ,
C27H40O3Siþ; calc. 440.2747).
4-Hydroxy-1-[7-hydroxy-2-methyl-6-(1-methylethyl)naphthalen-1-yl]-4-methylpent-2-en-1-one (19).
To a soln. of 3 (200 mg, 0.45 mmol) in dry CH2Cl2 (5 ml) was slowly added 1.0m BBr3 in CH2Cl2 (0.5 ml,
0.5 mmol) at ꢀ 788. The mixture was slowly warmed to r.t. and stirred at r.t. for 5 h. The reaction was
quenched by the addition of 10% NaHCO3 soln. (10 ml), and the resulting mixture was extracted with
CH2Cl2 (2 ꢁ 20 ml). The combined org. phase was washed with brine (10 ml), dried (MgSO4), and
concentrated and the residue purified by CC (CH2Cl2): 19 (88 mg, 62%). Colorless oil. IR (KBr): 3425,
2923, 2854, 1705, 1658, 1629, 1461, 1419, 1259, 1232, 1172, 1099, 804. 1H-NMR (CDCl3): 7.68 (d, J ¼ 8.6,
1 H); 7.60 (s, 1 H); 7.15 (d, J ¼ 8.5, 1 H); 6.92 (s, 1 H); 6.74 (d, J ¼ 16.0, 1 H); 6.44 (d, J ¼ 16.0, 1 H); 5.49
(br. s, 1 H); 3.32 (sept., J ¼ 6.9, 1 H); 2.42 (s, 3 H); 1.38 (d, J ¼ 6.9, 6 H); 1.34 (s, 3 H); 1.32 (s, 3 H).
13C-NMR (CDCl3): 201.6; 154.9; 153.2; 136.8; 133.2; 131.9; 129.8; 128.9; 127.5; 127.1; 125.9; 125.4; 106.6;
59.9; 32.4; 27.4; 19.8; 18.1. HR-MS: 312.1721 (Mþ, C20H24O3þ ; calc. 312.1725).
Prionoid E (¼ 8-[(2E)-4-Hydroxy-4-methyl-1-oxopent-2-en-1-yl]-7-methyl-3-(1-methylethyl)naph-
thalene-1,2-dione; 1). To a soln. of 19 (162 mg, 0.52 mmol) in acetone (5 ml) was added a soln. of
0.06m aq. Fremyꢂs salt soln. (30 ml) and 0.6m aq. KH2PO4 soln. (20 ml). The mixture was stirred in the
dark at r.t. for 12 h and then extracted with Et2O (2 ꢁ 50 ml). The combined org. phase was washed with
brine (2 ꢁ 20 ml), dried (MgSO4), and concentrated, and the residue purified by CC (CH2Cl2): 1 (84 mg,
52%). Red powder. IR (KBr): 3407, 2968, 2873, 1677, 1662, 1628, 1467, 1419, 1375, 1282, 1196, 1163, 1068,
943, 847, 601. 1H-NMR (CDCl3): 7.46 (d, J ¼ 7.8, 1 H); 7.26 (d, J ¼ 7.8, 1 H); 7.14 (s, 1 H); 6.52 (d, J ¼ 16.2,
1 H); 6.49 (d, J ¼ 16.2, 1 H); 3.03 (sept., J ¼ 6.9, 1 H); 2.21 (s, 3 H); 1.36 (s, 3 H); 1.31 (s, 3 H); 1.18 (d, J ¼
6.8, 6 H). 13C-NMR (CDCl3): 197.8; 179.7; 178.8; 154.1; 146.0; 143.7; 138.5; 137.5; 137.0; 133.7; 129.8;
127.4; 126.8; 70.6; 29.0; 28.8; 27.0; 21.4; 18.7. HR-MS: 326.1515 (Mþ, C20H24O3þ ; calc. 326.1518).
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Received November 29, 2010