Divergent total synthesis of taiwaniaquinones A and F and taiwaniaquinols B and D

Article abstract of DOI:10.1021/ol400717h

A divergent approach was developed toward the total synthesis of taiwaniaquinoids. An advanced intermediate 5a with trans A/B ring junction was concisely assembled by employing a Bi(OTf)₃-catalyzed cationic cyclization and a Wolff-type ring contraction as key steps. This common intermediate was readily converted to racemic taiwaniaquinones A and F and taiwaniaquinols B and D, respectively.

Full text of DOI:10.1021/ol400717h

ORGANIC
LETTERS
2013
Vol. 15, No. 8
2022–2025
Divergent Total Synthesis of
Taiwaniaquinones A and F and
Taiwaniaquinols B and D
Jun Deng,† Ruofan Li,† Yijie Luo, Jian Li, Shupeng Zhou, Yongjian Li,
Jingyu Hu, and Ang Li*
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, China
ali@sioc.ac.cn
Received March 18, 2013
ABSTRACT
A divergent approach was developed toward the total synthesis of taiwaniaquinoids. An advanced intermediate 5a with trans A/B ring junction
was concisely assembled by employing a Bi(OTf)3-catalyzed cationic cyclization and a Wolff-type ring contraction as key steps. This common
intermediate was readily converted to racemic taiwaniaquinones A and F and taiwaniaquinols B and D, respectively.
Taiwaniaquinoids are a class of natural products posses-
sing an unusual 6,5,6-abeoabietane scaffold first isolated
from Taiwania cryptomerioides by Cheng and co-workers.1
To date, more than 20 members (e.g., 1ꢀ4, Figure 1)
from this diterpenoid family have been identified, some
ofwhich displayantitumor activities.1f,2 Inthe past decade,
taiwaniaquinoids attracted remarkable attention from
the synthetic community: a stream of total and formal
syntheses of these fascinating molecules have been ac-
complished,2c,3 during which a number of synthetically
useful reactions were developed.3b,e,f,o
Notably, intense efforts were focused on the synthesis
of taiwaniaquinoids with a cis A/B ring junction such as
(3) (a) Banerjee, M.; Mukhopadhyay, R.; Achari, B.; Banerjee, A. K.
Org. Lett. 2003, 5, 3931. (b) Fillion, E.; Fishlock, D. J. Am. Chem. Soc.
2005, 127, 13144. (c) Banerjee, M.; Mukhopadhyay, R.; Achari, B.;
Banerjee, A. K. J. Org. Chem. 2006, 71, 2787. (d) Planas, L.; Mogi, M.;
Takita, H.; Kajimoto, T.; Node, M. J. Org. Chem. 2006, 71, 2896.
(e) McFadden, R. M.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 7738.
(f) Liang, G. X.; Xu, Y.; Seiple, I. B.; Trauner, D. J. Am. Chem. Soc.
2006, 128, 11022. (g) Li, S. L.; Chiu, P. Tetrahedron Lett. 2008, 49, 1741.
(h) Tang, S. C.; Xu, Y. F.; He, J. M.; He, Y. P.; Zheng, J. Y.; Pan, X. F.;
She, X. G. Org. Lett. 2008, 10, 1855. (i) Majetich, G.; Shimkus,
J. M. Tetrahedron Lett. 2009, 50, 3311. (j) Alvarez-Manzaneda, E.;
Chahboun, R.; Cabrera, E.; Alvarez, E.; Alvarez-Manzaneda, R.;
Meneses, R.; Es-Samti, H.; Fernandez, A. J. Org. Chem. 2009, 74,
3384. (k) Alvarez-Manzaneda, E.; Chahboun, R.; Cabrera, E.; Alvarez,
E.; Haidour, A.; Ramos, J. M.; Alvarez-Manzaneda, R.; Charrah, Y.;
Es-Samti, H. Org. Biomol. Chem. 2009, 7, 5146. (l) Node, M.; Ozeki, M.;
Planas, L.; Nakano, M.; Takita, H.; Mori, D.; Tamatani, S.; Kajimoto,
T. J. Org. Chem. 2010, 75, 190. (m) Jana, C. K.; Scopelliti, R.;
Gademann, K. Synthesis 2010, 2223. (n) Jana, C. K.; Scopelliti, R.;
Gademann, K. Chem.;Eur. J. 2010, 16, 7692. (o) Liao, X.; Stanley,
L. M.; Hartwig, J. F. J. Am. Chem. Soc. 2011, 133, 2088. (p) Alvarez-
Manzaneda, E.; Chahboun, R.; Cabrera, E.; Alvarez, E.; Haidour, A.;
Ramos, J. M.; Alvarez-Manzaneda, R.; Hmamouchi, M.; Es-Samti, H.
Chem. Commun. 2009, 592. (q) Alvarez-Manzaneda, E.; Chahboun, R.;
Alvarez, E.; Tapia, R.; Alvarez-Manzaneda, R. Chem. Commun. 2010,
9244. (r) Tapia, R.; Guardia, J. J.; Alvarez, E.; Haidour, A.; Ramos,
J. M.; Alvarez-Manzaneda, R.; Chahboun, R.; Alvarez-Manzaneda, E.
J. Org. Chem. 2012, 77, 573.
† These authors contributed equally to this work.
(1) (a) Lin, W. H.; Fang, J. M.; Cheng, Y. S. Phytochemistry 1995, 40,
871. (b) Lin, W. H.; Fang, J. M.; Cheng, Y. S. Phytochemistry 1996, 42,
1657. (c) Kawazoe, K.; Yamamoto, M.; Takaishi, Y.; Honda, G.; Fujita,
T.; Sezik, E.; Yesilada, E. Phytochemistry 1999, 50, 493. (d) Ohtsu, H.;
Iwamoto, M.; Ohishi, H.; Matsunaga, S.; Tanaka, R. Tetrahedron Lett.
1999, 40, 6419. (e) Chang, C. I.; Chien, S. C.; Lee, S. M.; Kuo, Y. H.
Chem. Pharm. Bull. 2003, 51, 1420. (f) Chang, C. I.; Chang, J. Y.; Kuo,
C. C.; Pan, W. Y.; Kuo, Y. H. Planta Med. 2005, 71, 72. A comprehen-
sive review: (g) Majetich, G.; Shimkus, J. M. J. Nat. Prod. 2010, 73, 284.
(2) (a) Iwamoto, M.; Ohtsu, H.;Tokuda, H.; Nishino, H.; Matsunaga,
S.; Tanaka, R. Bioorg. Med. Chem. 2001, 9, 1911. (b) Minami, T.;
Iwamoto, M.; Ohtsu, H.; Ohishi, H.; Tanaka, R.; Yoshitake, A. Planta
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r
10.1021/ol400717h
Published on Web 04/11/2013
2013 American Chemical Society

epimerization under thermodynamic conditions.5 For the
construction of 5, a Wolff rearrangement6 reaction was
considered as a manner of ring contraction. Thus, ketone 6
would serve as the suitable precursor for preparing the
corresponding R-diazoketone. Assembly of 6 may require
a cationic cyclization of diene 7,7 which was further
traced back to readily available alkylborane 8 and alkenyl
halide 9.8
Figure 2. X-ray derived ORTEP of compound 15.
Based on the above analysis, we first focused our attention
to the assembly of the common intermediate 5, as shown
in Scheme 1. Aldehyde 10 was readily prepared from com-
mercially available 1,2,4-trimethoxybenzene in four steps.9
Treatment of 10 with methylenetriphenylphosphorane
furnished styrene 11 in 92% yield, which was hydroborated
with 9-BBN to afford the corresponding alkylborane.10,11
This in situ generated borane was subjected to Suzukiꢀ
Miyaura coupling conditions [Pd(dppf)Cl2 (5%), aq NaOH,
THF, 40 °C]11 in the presence of alkenyl iodide 128 to give
homogeranyl arene 7 in 83% overall yield from 11. A variety
of Brønsted and Lewis acids were examined to effect a
cationic cyclization of 7, and Bi(OTf)3 was the most efficient
promoter. Thus, treatment of Bi(OTf)3 (10%) in MeNO2 at
80 °C provided tricyclic compound 13 in 71% yield as a
single diastereomer. The trans A/B ring junction was secured
by the FriedelꢀCrafts process. Introduction of the benzylic
carbonyl functionality to 13 was achieved by oxidation with
freshly prepared CrO3/3,5-dimethylpyrazole12 at ꢀ10 °C
(89% yield), while other chromic oxidants such as PCC,3c
CrO3/AcOH,2c and Jones reagent resulted in modest to poor
Figure 1. Structures of selected taiwaniaquinoids (1ꢀ4) and
retrosynthetic analysis.
taiwaniaquinol B (3, Figure 1), as well as those containing
a C5 sp2 center such as taiwaniaquinol D (4, Figure 1).3aꢀo
However, only two total syntheses of taiwaniaquinone
A (1) or F (2) possessing a trans A/B ring junction have
been disclosed; both started with stereochemically ad-
vanced precursors (e.g., naturally occurring abietic acid
and manool).3q,r,4 Herein, we report a concise and scalable
route leading to the total synthesis of racemic taiwania-
quinones A and F and taiwaniaquinols B and D (1ꢀ4,
Figure 1).
In their original isolation report, Cheng et al. proposed a
biosynthetic hypothesis of the 6,5,6-tricyclic core of taiwa-
niaquinoids involving a pinacol type rearrangement of a
6,6,6-tricyclic diol precursor. Inspired by this speculation,
we devised a ring contraction strategy for the divergent
synthesis of taiwaniaquinoids 1ꢀ4, as shown in Figure 1;
6,5,6-tricyclic aldehyde 5 with a trans A/B ring junction
was considered as a common intermediate. Taiwaniaqui-
nol D (4) bearing a C5 sp2 center should be readily
accessible by dehydrogenation, while cis-fused taiwania-
quinol B (3) could be reached through oxidative cleav-
age of the carbonyl functionality of 5 followed by C5
(5) Gordon, H. L.; Freeman, S.; Hudlicky, T. Synlett 2005, 2911.
(6) A comprehensive review: Kirmse, W. Eur. J. Org. Chem. 2002,
2193.
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Sames, D. Org. Lett. 2004, 6, 581. (e) Youn, S. W.; Pastine, S. J.; Sames,
D. Org. Lett. 2004, 6, 581. (f) Godeau, J.; Olivero, S.; Antoniotti, S.;
~
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~
Antoniotti, S.; Dunach, E. Chem.;Eur. J. 2012, 18, 16815. (h) Surendra,
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1980, 102, 3298.
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Tetrahedron 2008, 64, 4758.
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2006, 8, 4815.
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43, 2057.
(4) Gademann et al. pubished the synthesis of taiwaniaquinone F and
taiwaniaquinol A using a similar ring contraction strategy when this
manuscript was being written: Thommen, C.; Jana, C. K.; Neuburger,
M.; Gademann, K. Org. Lett. 2013, 15, 1390.
Org. Lett., Vol. 15, No. 8, 2013
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Scheme 1. Construction of a Common Intermediate 5a Employing a Ring-Contraction Strategy
rendered methyl ester 15 as a single diastereomer in 30%
yield, the structure of which was unambiguously verified by
X-ray crystallographic analysis (Figure 2, mp 139ꢀ141 °C,
EtOAc/petroleum ether 1:1). However, the efficiency of this
reaction decreased drastically on a more practical scale
(>50 mg), which hampered the subsequent progress toward
the collective synthesis of taiwaniaquinoids. To our delight,
thermal conditions (BnOH, 2,4,6-collidine, 160 °C)6,16 were
found to be superior to the above photochemical conditions
on a large scale, affording the corresponding benzyl ester 16
as a single detectable diastereomer in 56% yield. Reduction
of 16 with LiAH4 followed by oxidation with DessꢀMartin
periodione furnished aldehyde 5a in 75% yield over the two
steps. The above sequence scaled reliably, and 1 g of 5a was
readily prepared.
Scheme 2. Conversion of 5a to Taiwaniaquinones A and F, and
Taiwaniaquinols B and D
With the advanced intermediate 5a in hand, we moved
forward to investigate its conversion to taiwaniaquinones
A and F and taiwaniaquinols B and D in a divergent
manner, as shown in Scheme 2. Epimerization of aldehyde
5a promoted by K2CO3/EtOH at 80 °C afforded 5b in 93%
yield, which established the desired C3 stereochemistry
for taiwaniaquinones A and F. Global demethylation of
5a with excess of BBr3 followed by spontaneous aerobic
oxidation furnished the former natural product in 76%
yield, while oxidation with CAN rendered the latter
natural product in 76% yield. The spectral data of the
synthetic taiwaniaquinones A and F are identical to those
reported for the natural products, respectively.1a,e In an-
other direction, treatment of 5a with TMSOTf and Et3N
gave silyl enol ether 17 (an inconsequential mixture of ca.
1.2:1 cis/trans isomers) in 92% yield, which underwent a
sequence of SaegusaꢀIto oxidation,17 monodemethylation,
efficiency. Ketone 6was then converted to R-diazoketone 14 in
78% yield by treatment of 2,4,6-triisopropylbenzenesulfonyl
azide and Bu4NOH,13 which set the stage for the devised
Wolff rearrangement. Attempts to initiate such rearrange-
ment using silver salts6,14 were fruitless, while irritation of a
solutionof14inMeOHwithamedium-pressureHglamp6,15
(14) (a) Jefford, C. W.; Tang, Q.; Zaslona, A. J. Am. Chem. Soc. 1991,
113, 3513. (b) Nicolaou, K. C.; Baran, P. S. Angew. Chem., Int. Ed. 2002,
41, 2678.
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2024
Org. Lett., Vol. 15, No. 8, 2013

and one-pot oxidation/reduction3f to afford taiwaniaquinol
D in 80% yield over the three steps. When 17 was subjected
to dihydroxylation conditions [K2OsO2(OH)4, NMO], a
cleavage product 18 (79% yield) was obtained directly,
together with a small amount of the expected R-hydroxy
aldehyde.18 Notably, compound 18 could be epimerized at
the C5 position under basic conditions (DBU, toluene,
80 °C)5 to generate the corresponding cis-fused isomer
that was widely used as a late intermediate in the previous
syntheses of taiwaniaquinol B.3c,i,g To our delight, the trans-
fused intermediate 18 underwent the same sequence used for
taiwaniaquinol D synthesis to render taiwaniaquinol B in
81% overall yield.3g It was detected by TLC analysis that
the epimerization at C5 occurred rapidly under the BBr3
conditions even before monodemethylation took place.19
The spectral data of the synthetic taiwaniaquinols B and
D are consistent with those of the naturally occurring
compounds, respectively.1a,b
In conclusion, we developed an efficient route for the
divergent total synthesis of taiwaniaquinones A and F and
taiwaniaquinols B and D in racemic forms. The common
intermediate 5a possessing a trans-fused 6,5,6-ring system
was synthesized on a large scale by using a Wolff type ring
contraction reaction as a key step. This intermediate was
further converted to the above natural products in 2ꢀ3steps.
This work may facilitate the biological studies on taiwania-
quinoids and analogues thereof. The asymmetric version of
the synthesis is currently underway in our laboratories.
Acknowledgment. We thank Prof. Guangxin Liang
(Nankai University) for helpful discussions. Financial
support was provided by the Ministry of Science & Techno-
logy (2013CB836900), National Natural Science Founda-
tion of China (21290180, 21172235, and 21222202), and
Chinese Academy of Sciences.
Supporting Information Available. Experimental pro-
cedures and compound characterization. This material
is available free of charge via the Internet at http://
pubs.acs.org.
(18) A mechanistically inspiring oxidative cleavage: Burden, P. M.;
Cheung, A. H. T.; Watson, T. R.; Ferguson, G.; Seymour, P. F. J. Chem.
Soc., Perkin Trans. 1 1987, 169.
(19) An AlCl3-promoted epimerization of a similar tricyclic system:
House, H. O.; Paragamian, V.; Ro, R. S.; Wluka, D. J. J. Am. Chem. Soc.
1960, 82, 1457.
The authors declare no competing financial interest.
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