Catalytic asymmetric formal total synthesis of (+)-dichroanone and (+)-taiwaniaquinone H

Article abstract of DOI:10.1016/j.tetlet.2014.08.110

Catalytic asymmetric formal total synthesis of (+)-dichroanone and (+)-taiwaniaquinone H has been achieved. Key step involved construction of all-carbon quaternary carbon by palladium-catalyzed conjugate addition of arylboronic acid to 3-methyl cyclohexenone. Furthermore, a new approach to build [6-5-6] tricyclic backbone via formyl introduction and subsequent aldol-type condensation was also explored.

Full text of DOI:10.1016/j.tetlet.2014.08.110

Tetrahedron Letters 55 (2014) 5960–5962
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Catalytic asymmetric formal total synthesis of (+)-dichroanone and
(+)-taiwaniaquinone H
Liang-Qun Li a,b,c, Ming-Ming Li b, Dong Chen b,c, Hao-Miao Liu b,c, Hui-chun Geng b,c, Jun Lin a,
,
⇑
Hong-Bo Qin b,
⇑
a Key Laboratory of Medicinal Chemistry for Natural Resources (Yunnan University), Ministry of Education, School of Chemical Science and Technology, Yunnan University,
Kunming 650091, China
b State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China
c University of Chinese Academy of Sciences, Beijing 100049, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Catalytic asymmetric formal total synthesis of (+)-dichroanone and (+)-taiwaniaquinone H has been
achieved. Key step involved construction of all-carbon quaternary carbon by palladium-catalyzed conju-
gate addition of arylboronic acid to 3-methyl cyclohexenone. Furthermore, a new approach to build [6-5-
6] tricyclic backbone via formyl introduction and subsequent aldol-type condensation was also explored.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 30 June 2014
Revised 12 August 2014
Accepted 29 August 2014
Available online 6 September 2014
Keywords:
Stereoselective formal synthesis
(+)-Dichroanone
(+)-Taiwaniaquinone H
Conjugate addition
Reetz reagent
Taiwaniaquinoids represent a family of over 20 diterpenes with
unusual abeo-abietane skeleton and have been mainly isolated from
Taiwaniacryptomerioides, SalviadichroanthaandThujastandishii, dur-
ing the past decade (Fig. 1).1 Standishinal (3) is a potential antitumor
agent for treating estrogen-dependent cancer due to its aromatase
inhibitory activity. Thus, diterpenoids possessing the same skeleton
of this family, such as (À)-dichroanone (1) and (À)-taiwaniaquinone
H (2), are expected to be antitumor active.2 The promising biological
properties and distinctive [6-5-6] fused ring system of these com-
pounds have been attracting considerable attention of several syn-
thetic groups. Among many total syntheses of these diterpenes,3
only few enantioselective syntheses of taiwaniaquinoids have been
reported. In Stoltz’s total synthesis of (+)-dichroanone, a quaternary
stereogenic center was formed by an asymmetric Tsuji allylation.3e
Node’s group utilized the enantioselective intramolecular Heck
reaction to complete total synthesis of (À)-dichroanal B, (À)-dichro-
anone, and taiwaniaquinone H.3m Hartwig reported an enantioselec-
tivetotalsynthesisof(À)-taiwaniaquinolBand(À)-taiwaniaquinone
syntheses of the taiwaniaquinoids, enantioselective construction of
quaternary carbon has to be addressed.3
To develop general synthetical strategy of abietane diterpenes,
we focused on Palladium catalyzed enantioselective conjugate
addition of arylboronic acid to cyclic enone, a methodology
pioneered by Lu4a and developed by Stoltz,4b–d to construct quater-
nary carbon. Since no such application in total synthesis of
abietane diterpenes has been reported, a new strategy to build
[6-5-6] tricycle skeleton remains to be explored. Herein, we report
our preliminary results on the aspects.
Our retrosynthetic analysis is depicted in Scheme 1. According
to related literature’s report,3h,m we found that enantioselective
formal syntheses of (+)-dichroanone (1) and (+)-taiwaniaquinone
H (2) could be accomplished through same intermediate tetrahy-
drofluorene 7. Geminal dimethyl unit was supposed to be accessi-
ble from ketone 9 via methylation of tertiary alcohol 8 using Reetz
reagent.5–7 Tricyclic enone 9, would be easily obtained by a consec-
utive operation of formyl introduction into the aromatic ring and a
subsequent aldol condensation with ketone 10. Compound 10
would be obtained by Palladium-catalyzed enantioselective conju-
gate addition of known aryl boronic acid 128 to 3-methyl-2-cyclo-
hexenone 11 as mentioned before.4
H by asymmetric palladium-catalyzed a-arylation of a ketone with
an aryl bromide.3q Apparently, to achieve catalytic asymmetric
⇑
Corresponding authors. Tel./fax: +86 871 6503 3215 (J.L.), +86 871 6523 8010
(H.-B.Q.).
Our synthesis commenced with the enantioselective conjugate
addition between 3-methyl-2-cyclohexenone 11 and 3-methoxy-
4-isopropyl benzeneboronic acid 12 in the presence of Pd (OCOCF3)2
E-mail addresses: linjun@ynu.edu.cn (J. Lin), qinhongbo@mail.kib.ac.cn
(H.-B. Qin).
http://dx.doi.org/10.1016/j.tetlet.2014.08.110
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

L.-Q. Li et al. / Tetrahedron Letters 55 (2014) 5960–5962
5961
O
O
OMe
OHC
H
OH
OH
O
O
OH
2
1
)
(-)-Taiwaniaquinone H ( )
(-)-Dichroanone (
3
Standishinal ( )
O
O
HO
OMe
OMe
OH
O
OH
H
O
H
CHO
O
6
(-)-Taiwaniaquinone B (
)
4
)
(-)-Taiwaniaquinone G (
5
(-)-Taiwaniaquinone D ( )
Figure 1. Representative taiwaniaquiniods.
OMe
ref.3h
OMe
(+)-Dichroanone (1)
HO
H
H
O
7
(+)-Taiwaniaquinone H (2)
ref.3m
oxidation
8
Palladium-catalyzed
conjugate addition
OMe
OMe
+
OMe
O
B(OH)2
12
O
O
10
11
formylation and
aldol condensation
9
Scheme 1. Retrosynthetic analysis.
O
N
OMe
N
t-Bu
OMe
Cl2CHOCH3,TiCl4
Pd(OCOCF3)2 ,NH4PF6
+
DCM,-78 oC-rt
76%
ClCH2CH2Cl, 60 o
C
O
O
OMe
O
B(OH)2
12
89%, 85% ee
11
9
(R)-10
OMe
OMe
OMe
oxidative
1)MeMgI/Et2O
rearrangement
2)THF,0 oC-rt
89%
H
OH
O
O
14
7
13
Scheme 2. Construction of [6-5-6] tricyclic backbone.
(6 mol %) catalyst and (s)-t-BuPyOX ligand (5 mol %) (Scheme 2). b-
Aryl ketone 10 was isolated in 89% yield and 85% ee determined by
chiral HPLC analysis. The absolute configuration of compound (À)-
10 was confirmed to be R according to Stoltz’s report.4 Due to no fur-
ther improvement in ee after optimization process (ligand, solvent
etc.) or chiral resolution, it was used in following synthesis.
Cyclization could be realized by introducing a formyl group and
subsequent aldol condensation. In fact, on treatment with 1,
1-dichlorodimethyl ether and TiCl4, a formyl group was introduced
into the para-position of the methoxyl aromatic ring and to our
delight, tricyclic enone 9 was isolated directly from b-aryl ketone
10 in 76% yield in one-pot, which means a spontaneous aldol-type
condensation occurred in situ. Thus the basic [6-5-6]-tricyclic
skeleton containing an all-carbon quaternary benzylic stereogenic
center was furnished smoothly.
Michael acceptor 14. However, attempts to convert allyl alcohol 13
into b-Me enone 14 via oxidative rearrangement using TEMPO/
NaIO4–SiO2 only led to the recovery of 13 even under refluxing
condition.9 We were forced to try another way to install the
geminal dimethyl group.
Direct conversion of ketone 9 into germinal dimethyl was
attempted with Reetz reagent, but no desired product was isolated.
Therefore, an alternative way is illustrated in Scheme 3. Hydroge-
nation of allyl alcohol 13 catalyzed by 5% Pd–C afforded saturated
tertiary alcohol 8 in 97% yield. Satisfactorily, geminal dimethyl was
installed in 72% yield through methylation of compound 8 using
the excessive Reetz reagent in CH2Cl2 from À40 °C to room temper-
ature. Oxidation of compound 15 with CrO3 in aqueous acetic acid
(90% v/v) gave key intermediate tetrahydrofluorene 7 as a single
diastereomer in 81% yield. Its enantiomeric excess was determined
to be 82.6% by chiral HPLC analysis. The relative stereochemistry of
7 was assigned as cis by the ROESY (see Supporting information).
The 1H and 13C spectrum data of (+)-7 are in agreement with the
literatures.3o,3h The tetrahydrofluorene 7 can serve as a common
Next, germinal dimethyl group is to be installed and conjugate
addition of Methyl to b-Me enone 14 seemed to be effective. Addi-
tion of methyl magnesium iodide to ketone 9 proceeded smoothly
to give allyl alcohol 13 in 89% yield which could be oxidized into an

5962
L.-Q. Li et al. / Tetrahedron Letters 55 (2014) 5960–5962
OMe
OMe
CrO3
H2᧨ Pd/ C
1)(CH3)2Zn,TiCl4
13
2)DCM,-30 oC-rt
HOAc-H2O
EtOH-EtOAc
97%
HO
0
oC-rt
H
H
8
72%
15
O
O
OMe
OH
OMe
ref.3m
ref.3h
H
O
O
O
7
2
(+)-taiwaniaquinone H
1
(+)-dichroanone
81% ,83% ee
Scheme 3. Synthesis of key intermediate 7.
intermediate in She’s syntheses of (+)-dichroanone,3h and be
further converted into (+)-taiwaniaquinone H, following transfor-
mations reported by Node.3m
Honda, G.; Fujita, T.; Sezik, E.; Yesilada, E. Phytochemistry 1999, 50, 493; (e)
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Planta Med. 2005, 71, 72.
In conclusion, a catalytic asymmetric formal total synthesis of
(+)-dichroanone (1) and (+)-taiwaniaquinone H (2) has been
accomplished. Key tricyclic intermediate 7 was synthesized in 6
steps and 34% yield. Key reaction involves palladium-catalyzed
conjugate addition of arylboronic acids to 3-methyl-2-cyclohexe-
none to construct all-carbon quaternary stereocenter. Cyclization
was realized by a one-pot operation of formyl group introduction
and in situ aldol-type condensation. Furthermore, installing gemi-
nal dimethyl unit through methylation of tertiary alcohol using
Reetz reagent constitutes an efficient strategy to access abietane
diterpene skeleton. Further applications of this new strategy in
diterpenes total synthesis are currently underway in our lab.
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Acknowledgments
This work was financially supported by the National Natural
Science Foundation of China (21372229), the Natural Science
Foundation of Yunnan Province (2013FB064), a Program of ‘One
Hundred Talented People’.
Liang-Qun Li and Ming-Ming Li contributed equally.
Supplementary data
Supplementary data (experiment details and NMR spectra for
compounds 15, 13, 12, 10, 9, 8 and 7, chiral HLPC chromatograms
chart of compounds 10 and 7) associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.
2014.08.110.
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