Protecting-group-free synthesis of taiwaniaquinone H using a one-pot thermal ring expansion/4π-electrocyclization strategy

Article abstract of DOI:10.1021/jo5008652

A strategy to the 6-5-6 tricyclic scaffold of taiwaniaquinoids was established on the basis of a one-pot thermal ring expansion/4π- electrocyclization process. The efficiency of this methodology has been demonstrated through its application in the total synthesis of taiwaniaquinone H, which has been accomplished in three steps and 14% overall yield in a protecting-group-free manner starting from commercially available materials.

Full text of DOI:10.1021/jo5008652

Article
pubs.acs.org/joc
Protecting-Group-Free Synthesis of Taiwaniaquinone H Using a One-
Pot Thermal Ring Expansion/4π-Electrocyclization Strategy
Xiuxiang Yan and Xiangdong Hu*
Department of Chemistry & Material Science, Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry
of Education of China, Northwest University, Xi’an 710069, People’s Republic of China
S
* Supporting Information
ABSTRACT: A strategy to the 6-5-6 tricyclic scaffold of taiwaniaquinoids was established on the basis of a one-pot thermal ring
expansion/4π-electrocyclization process. The efficiency of this methodology has been demonstrated through its application in the
total synthesis of taiwaniaquinone H, which has been accomplished in three steps and 14% overall yield in a protecting-group-free
manner starting from commercially available materials.
because of the unusual molecular skeleton and promising
biological activities, such as the antitumor activity of stand-
ishinal (6)2 and cytotoxicity of taiwaniaquinol D (8).3 Basically,
there were five models applied to the construction of the 6-5-6
ABC tricyclic core of taiwaniaquinoids in literatures. The A-AB-
ABC model was utilized in the synthesis of (+)-dichroanone
(5) by Stoltz involving an asymmetric palladium-catalyzed
allylation4 and in the synthesis of A/B trans-fused taiwaniaqui-
none G (3) by Alvarez-Manzaneda involving a thermal 6π-
electrocyclization process,5 respectively. The C-ABC model was
applied to the synthesis of taiwaniaquinol B (7) by Fillion6 and
Chiu7 through an intramolecular Friedel−Crafts acylation/
carbonyl α-tert-alkylation cascade or intramolecular successive
cationic cyclization, respectively. The AC-ABC model has been
repetitively proven to be a divergent strategy to multiple
taiwaniaquinoids by groups of Node,8 Banerjee,9 Trauner,10
INTRODUCTION
■
Extensive research on taiwania cryptomerioides Hayata
(Taxodiaceae) has uncovered a large number of natural
products, including sesquiterpenes, diterpenes, lignans, and
biflavones.1 Among them, taiwaniaquinoids (Figure 1) are an
attractive family of terpenoids bearing an uncommon 6-5-6
tricyclic scaffold.
Various synthetic approaches have been developed for the
total synthesis of taiwaniaquinoids in the past few decades
Alvarez-Manzaneda,11 Majetich,12 Hartwig,13 and Ozeki.14
A
highly efficient one-step approach to the ABC tricyclic scaffold
was developed by She in the synthesis of 5 and 7 through a
Friedel−Crafts acylation/alkylation process.15 The B ring
contraction of the 6-6-6 ABC tricyclic core has been achieved
through three strategies: (1) the benzilic acid rearrangement/
decarboxylation cascade in the synthesis of (−)-taiwaniaqui-
none H (4) by Gademann,16 (2) the B ring-opening−ring-
closure pathway to multiple A/B trans-fused taiwaniaquinoids
through an ozonolysis−aldol reaction process in the synthesis
of standishinal (6) by Node17 and in the synthesis of
(−)-taiwaniaquinone A (1), (−)-taiwaniaquinone F (2),
(−)-3, (−)-4, (−)-5, and (−)-7 by Alvarez-Manzaneda,18,19
and (3) the Wolff-rearrangement-promoted ring contraction, a
divergent approach to multiple A/B trans-fused taiwaniaqui-
Received: April 17, 2014
Published: May 16, 2014
Figure 1. Representative taiwaniaquinoids.
© 2014 American Chemical Society
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noids, applied to the synthesis of (−)-2 and (−)-taiwaniaquinol
A by Gademann20 and the synthesis of 1, 2, 7, and 8 by Li.21 As
mentioned above, there have already been a number of reports
on the total synthesis of taiwaniaquinoids employing different
models to construct the 6-5-6 tricyclic scaffold efficiently.
However, the development of a new synthetic strategy with
higher efficiency is still required but is challenging.
The synthesis began with the preparation of 10 (Scheme 2).
Cyclobutenedione 13 was first prepared in 90% yield from
Scheme 2. Synthesis of Cyclobutenone 10
The thermal ring expansion of cyclobutenones has initially
been proven by the seminal explorations of Moore to be a
powerful class of transformations and an efficient synthetic
strategy to the total synthesis of various natural products.22−32
Notably, the thermal ring expansion of alkynyl cyclobuteneones
has been established as an efficient access to quinones by
Moore,24,28,29,31 which has been utilized in our study to
construct ring C of 4. Investigations from other groups,
including Lieberskind,33−35 Paquette,36−40 and Martin,41,42 also
made important contributions to the continuing development
of this field. Following our interest in the development of new
transformations of cyclobutenones and their applications in the
synthesis of natural products,43,44 we developed a one-pot
thermal ring expansion/4π-electrocyclization strategy of cyclo-
butenones as a concise approach to the 6-5-6 tricyclic scaffold
of taiwaniaquinoids. The application of this methodology
facilitated the total synthesis of 4 in only three steps starting
from commercially available materials, providing, so far, the
shortest synthetic route to 4. In addition, the approach features
an A-AC-ABC construction pattern to the tricyclic scaffold, and
no protecting groups were required.
dimethyl squarate 14 and isopropylmagnesium bromide 15
through Moore’s method,45 completing the introduction of the
methoxy group and the isopropyl group of the final target at the
early synthetic stage. The commercially available 11 was treated
with 12, t-BuLi, and 13 sequentially at −30 °C, affording 10 in
one pot and 39% yield. The employment of n-BuLi led to a
poorer yield. The synthesis of 10 was also executed stepwise in
an attempt to optimize the synthesis of 10. The treatment of 11
with 12 formed intermediate 16 in excellent yield. The
following process of the connection of 16 and 13 using the
procedure of Liu46 gave 10 in 41% yield, affording an overall
yield similar to that of the one-pot procedure.
RESULTS AND DISCUSSION
Our retrosynthetic analysis is shown in Scheme 1. Cyclo-
butenone 10 is furnished from the stepwise nucleophilic attack
■
Scheme 1. Retrosynthetic Pathway to 4
With 10 in hand, the accomplishment of the expected
thermal ring expansion/4π-electrocyclization process is the
challenge that we faced. We first checked the thermal
conditions with different solvents (Scheme 3). The best result
came from the treatment in toluene at 80 °C. The electrocyclic
ring-opening/ring-closure cascade31 of 10 occurred smoothly
and gave the desired ring expansion product 9 in 69% yield.
Higher temperature led to the decomposition of 9, giving a
decrease in the yield in the end. However, no formation of 4
was observed under these conditions. We then turned our
attention to the employment of acids. Various acids have been
tested in this regard. Only the reaction with TiCl4 was
confirmed as the effective access to the expected thermal ring
expansion/4π-electrocyclization process, generating 4 in 41%
yield from 10. The spectroscopic properties of 4 were identical
with those of taiwaniaquinone H reported in the litera-
ture.9−11,13,16 Notably, worse yields were obtained when TiCl4
was added before the thermal ring expansion was complete.
The application of other reagents, including SnCl4, BF3·Et2O,
TMSOTf, AgSbF6, and Pd(OAc)2, all led to a complex reaction
system without the generation of 9 or 4 in the end.47 To this
point, the total synthesis of 4 has been achieved in only three
steps.
of ethynylmagnesium bromide 12 to β-cyclocitral 11 and
cyclobutenedione 13, which is obtained from 14 and 15
according to a known procedure.45 As the crucial part, the one-
pot thermal ring expansion/4π-electrocyclization process of
cyclobutenone 10 accomplishes not only the construction of
the B and C rings but also the total synthesis of 4.
CONCLUSIONS
■
In summary, a one-pot thermal ring expansion/4π-electro-
cyclization approach has been developed as a progress in our
endeavors to the development of new transformations of
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Scheme 3. Study of the One-Pot Thermal Ring Expansion/4π-Electrocyclization and Synthesis of 4
59.4, 39.3, 34.6, 33.5, 28.3, 27.5, 20.9, 19.0. HRMS (ESI+): m/z [M +
Na]+ calcd for C12H18NaO, 201.1250; found, 201.1259.
cyclobutenones and their practical applications. It serves as a
concise strategy to construct the 6-5-6 tricyclic scaffold of
taiwaniaquinoids in an A-AC-ABC pattern. The accomplish-
ment of protecting-group-free synthesis of taiwaniaquinone H
in three steps and 14% total yield clearly demonstrated the
efficiency of this strategy.
4-Hydroxy-4-(3-hydroxy-3-(2,6,6-trimethylcyclohex-1-enyl)-
prop-1-ynyl)-2-isopropyl-3-methoxycyclobut-2-enone (10). A
solution of methylmagnesium bromide (1.0 M in THF, 2.9 mL, 2.9
mmol) was added to a solution of compound 16 (428 mg, 2.4 mmol)
in THF (20 mL) at −30 °C under argon. The system was stirred for
15 min and warmed to 0 °C. The system was treated with n-BuLi (2.4
M in hexanes, 1.2 mL, 2.9 mmol) at −30 °C and warmed to 0 °C.
After 30 min of stirring, the system was added to a solution of 13 (740
mg, 4.8 mmol) in THF (5 mL). The resulting reaction mixture was
stirred at −30 °C for another 5 min and quenched with saturated
ammonium chloride solution. The aqueous phase was extracted with
EtOAc three times. The combined organic layers were washed with
saturated ammonium chloride solution and saturated brine and dried
over Na2SO4. The solvent was removed under reduced pressure. The
crude residue was purified by silica gel chromatography (PE/EtOAc,
5/1) to give 10 (326 mg, 41%) as a yellow oil. Rf = 0.2 (PE/EtOAc =
2/1). IR (neat): νmax 3364, 2930, 2871, 2225, 1752, 1675, 1622, 1465,
1361, 1308, 1134 cm−1. 1H NMR (400 MHz, CDCl3): δ 5.12 (s, 1H),
4.20 (s, 3H), 2.45−2.52 (m, 1H), 2.05 (s, 1H), 1.96 (t, J = 8 Hz, 2H),
1.90 (s, 3H), 1.55−1.57 (m, 2H), 1.45(t, J = 4 Hz, 2H), 1.15 (s, 3H),
1.13 (s, 3H), 1.09 (s, 3H), 1.01 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 187.1, 179.4, 137.1, 134.7, 134.4, 91.9, 82.4, 78.5, 59.6, 59.4,
39.4, 34.6, 33.5, 28.5, 27.5, 23.8, 21.0, 19.99, 19.95, 19.1. HRMS
(ESI+): m/z [M + Na]+ calcd for C20H28NaO4, 355.1880; found,
355.1898.
4-Hydroxy-4-(3-hydroxy-3-(2,6,6-trimethylcyclohex-1-enyl)-
prop-1-ynyl)-2-isopropyl-3-methoxycyclobut-2-enone (10). A
solution of ethynylmagnesium bromide (12; 0.5 M in THF, 2.4 mL,
1.2 mmol) was added to a solution of β-cyclocitral (11; 152 mg, 1.0
mmol) in THF (10 mL) at −30 °C under argon. The system was
stirred for 5 min and warmed to room temperature. The system was
treated with t-BuLi (1.3 M in pentane, 1.2 mL, 1.6 mmol) at −30 °C
and warmed to room temperature. After 10 min of stirring, the system
was added to a solution of 13 (305 mg, 2.0 mmol) in THF (5 mL).
The resulting reaction mixture was stirred at −30 °C for another 5 min
and quenched with saturated ammonium chloride solution. The
aqueous phase was extracted with EtOAc three times. The combined
organic layers were washed with saturated ammonium chloride
solution and saturated brine and dried over Na2SO4. The solvent
was removed under reduced pressure. The crude residue was purified
by silica gel chromatography (PE/EtOAc, 5/1) to give 10 (130 mg,
39%), whose NMR spectra are consistent with those of compound 10
obtained from the connection of 16 and 13.
EXPERIMENTAL SECTION
■
General Experimental Methods. All of the reactions were
performed under an argon atmosphere. Commercial grade solvents
were distilled prior to use. Column chromatography was performed
using 200−300 mesh silica gel. Thin-layer chromatography (TLC) was
performed on silica gel GF254 plates. Visualization of spots on TLC
plates was accomplished with UV light (254 nm) and staining over a
phosphomolybdic acid alcohol solution or a solution of 2,4-
dinitrophenylhydrazine followed by heating. High-resolution mass
spectra (HRMS) were recorded in ESI mode using a Q-TOF analyzer.
Proton and carbon nuclear magnetic resonance spectra (1H NMR, 13
C
NMR) were recorded on the basis of the resonating frequencies as
follows: 1H NMR at 400 MHz and 13C NMR at 100 MHz having the
solvent resonance as internal standard (1H NMR, CDCl3 at 7.26 ppm
and DMSO-d6 at 2.50 ppm; 13C NMR, CDCl3 at 77.0 ppm). Chemical
shifts are reported in ppm with tetramethylsilane (TMS) at 0.00 ppm
used as an internal standard and the residual solvent peak as an
internal indicator.
3-Isopropyl-4-methoxycyclobut-3-ene-1,2-dione (13). Com-
pound 13 was prepared in 90% yield according to a known
procedure.45 Rf = 0.7 (PE/EtOAc = 2/1). IR (neat) :νmax 2972,
2876, 1792, 1762, 1599, 1469, 1368, 1318, 1029 cm−1. 1H NMR (400
MHz, CDCl3): δ 4.38 (s, 3H), 2.93−3.00 (m, 1H), 1.24 (s, 3H), 1.23
(s, 3H). 13C NMR (100 MHz, CDCl3): δ 197.7, 194.7, 194.4, 188.5,
60.9, 26.8, 19.0. HRMS (ESI+): m/z [M + Na]+ calcd for C8H10NaO3,
177.0522; found, 177.0525.
1-(2,6,6-Trimethylcyclohex-1-enyl)prop-2-yn-1-ol (16). A sol-
ution of ethynylmagnesium bromide (12; 0.5 M in THF, 2.4 mL, 1.2
mmol) was added to a solution of β-cyclocitral (11; 152 mg, 1.0
mmol) in THF (10 mL) at −30 °C under argon. The system was
stirred for 15 min and warmed to room temperature. The resulting
reaction mixture was stirred at room temperature for another 1 h and
quenched with saturated ammonium chloride solution. The aqueous
phase was extracted with diethyl ether three times. The combined
organic layers were washed with saturated ammonium chloride
solution and saturated brine and dried over Na2SO4. The solvent
was removed under reduced pressure. The crude residue was purified
by silica gel chromatography (PE/Et2O, 20/1) to give 16 (174 mg,
98%) as a colorless oil. Rf = 0.4 (PE/EtOAc = 10/1). IR (neat): νmax
5-(Hydroxy(2,6,6-trimethylcyclohex-1-enyl)ethyl)-3-isoprop-
yl-2-methoxycyclohexa-2,5-diene-1,4-dione (9). Compound 10
(102 mg, 0.306 mmol) was dissolved in toluene (8 mL) and purged
with argon for 15 min. The mixture was stirred at 80 °C for 6 h under
argon. The reaction was then cooled to room temperature, and the
solvent was removed under reduced pressure. The crude residue was
1
3392, 3306, 2930, 2867, 1459, 1370, 1023, 719, 654, 617 cm−1. H
NMR (400 MHz, CDCl3): δ 5.02 (s, 1H), 2.49 (s, 1H), 1.98 (t, 2H),
1.94 (s, 3H), 1.55−1.56 (m, 2H), 1.43−1.44 (m, 2H), 1.08 (s, 3H),
1.02 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 137.7, 134.5, 85.0, 72.3,
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purified by silica gel chromatography (PE/EtOAc, 20/1) to give 9 (70
mg, 69%) as a yellow oil. Rf = 0.5 (PE/EtOAc = 10/1). IR (neat): νmax
3523, 2933, 2871, 1649, 1598, 1460, 1365, 1215 cm−1. 1H NMR (400
MHz, CDCl3): δ 6.36 (s, 1H), 5.34 (s, 1H), 4.01 (s, 3H), 3.42 (s, 1H),
3.25−3.28 (m, 1H), 2.03 (t, 2H), 1.67 (s, 3H), 1.63 (m, 2H), 1.41−
1.48 (m, 2H), 1.23 (s, 3H), 1.22 (s, 3H), 1.13 (s, 3H), 0.83 (s, 3H).
13C NMR (100 MHz, CDCl3): δ 190.1, 184.6, 155.9, 147.5, 137.9,
136.0, 133.9, 131.0, 67.4, 61.0, 39.4, 34.6, 33.4, 28.4, 27.8, 24.6, 22.4,
20.4, 20.3, 19.0. HRMS (ESI+): m/z [M + Na]+ calcd for C20H28NaO4,
355.1880; found, 355.1871.
Taiwaniaquinone H (4). Compound 10 (31 mg, 0.095 mmol) was
dissolved in toluene (4 mL), and the solution was purged with argon
for 15 min. The mixture was stirred at 80 °C for 6 h under argon. The
reaction mixture was cooled to room temperature and treated with
titanium tetrachloride (1.0 M in methylene chloride, 0.095 mL, 0.095
mmol). After it was stirred for 30 min, the reaction mixture was
quenched with saturated sodium bicarbonate solution and extracted
with EtOAc three times. The combined organic layers were washed
with saturated sodium bicarbonate solution and saturated brine and
dried over Na2SO4. The solvent was removed under reduced pressure.
The crude residue was purified by silica gel chromatography (PE/
EtOAc, 20/1) to give taiwaniaquinone H (4; 12 mg, 41%) as a red-
orange solid. The analytical data for 4 agreed with those reported
previously.9−11,13,16 Rf = 0.6 (PE/EtOAc = 10/1). Mp: 81−83 °C. IR
(neat): νmax 2930, 2870, 1643, 1615, 1457, 1353, 1120 cm−1. 1H NMR
(400 MHz, CDCl3): δ 6.38 (s, 1H), 3.99 (s, 3H), 3.26 (septet, 1H),
2.36−2.42 (m, 1H), 1.87−1.97 (m, 1H), 1.67−1.71 (m, 1H), 1.60−
1.64 (m, 1H), 1.44 (s, 3H), 1.27 (s, 3H), 1.246 (d, 3H), 1.243 (d, 3H),
1.22 (s, 3H), 1.03−1.13 (m, 2H). 13C NMR (100 MHz, CDCl3): δ
186.3, 178.7, 175.7, 157.3, 150.5, 145.8, 135.9, 116.7, 61.3, 55.6, 43.3,
37.2, 36.7, 30.9, 24.8, 24.4, 20.7, 20.6, 20.1, 19.1. HRMS (ESI+): m/z
[M + Na]+ calcd for C20H26NaO3, 337.1774; found, 337.1781.
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ASSOCIATED CONTENT
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* Supporting Information
Figures giving 1H and 13C NMR spectra of related compounds.
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AUTHOR INFORMATION
Corresponding Author
*E-mail for X.H.: xiangdonghu@nwu.edu.cn.
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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We are grateful for financial support from the National Natural
Science Foundation of China (NSF 21002078 and , 21372184),
the State Education Ministry Scientific Research Foundation for
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(47) The transformation from 9 to taiwaniaquinone H was checked
using reagents including TiCl4, SnCl4, BF3·Et2O, TMSOTf, AgSbF6,
PtCl2, and Pd(OAc)2 in toluene. Taiwaniaquinone H was obtained in
60% yield only with the employment of TiCl4. Other reagents all led to
a complex reaction system without the generation of taiwaniaquinone
H.
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