Metal triflate-catalyzed cyclization of arylvinylcarbinols: Formal synthesis of (±)-dichroanone and (±)-taiwaniaquinone H

Article abstract of DOI:10.1039/c3ra41497c

A formal synthesis of diterpenoids viz. the taiwaniaquinoids (±)-dichroanone (1a) and (±)-taiwaniaquinone H (1b) possessing an all carbon quaternary stereocenter has been reported. The key step involves a metal triflate-catalyzed cyclization of arylvinylc

Full text of DOI:10.1039/c3ra41497c

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Metal triflate-catalyzed cyclization of
arylvinylcarbinols: formal synthesis of ( )-dichroanone
Cite this: RSC Advances, 2013, 3, 8176
and ( )-taiwaniaquinone H3{
Received 23rd February 2013,
Accepted 4th April 2013
Badrinath N. Kakde, Subhadip De, Dhananjay Dey and Alakesh Bisai*
DOI: 10.1039/c3ra41497c
www.rsc.org/advances
A formal synthesis of diterpenoids viz. the taiwaniaquinoids ( )-
dichroanone (1a) and ( )-taiwaniaquinone H (1b) possessing an
all carbon quaternary stereocenter has been reported. The key
step involves a metal triflate-catalyzed cyclization of arylvinylcar-
binols, prepared from b-cyclocitral. The reaction possibly follows a
stepwise mechanism via the intermediacy of arylallyl carbocatio-
nic species.
catalyzed borylation and a palladium-catalyzed asymmetric
a-arylation by Hartwig,11 a Lewis acid-promoted synthesis of a
carbotricycle by Fillion,12 a sequential cationic cyclization by
Chiu,13 a Friedel–Crafts acylation/alkylation approach by She,14
and an intramolecular Friedel–Crafts alkylation by Alvarez-
Manzaneda15 and Majetich.16 Recent efforts include a thermal
6p-electrocyclization,17 a semisynthetic approach involving the
cleavage of the C7–C8 double bond of abietane diterpenes by
Alvarez-Manzaneda,18 from commercially available methyl dehy-
droabietate by Gademann,19 and others, to address the core
carbocyclic structure.1,20 We envisioned that a catalytic approach
to the carbotricyclic core of the type 3a (Table 1) using a metal-
triflate as a Lewis acid could offer an excellent platform for the
total synthesis of various taiwaniaquinoids (Fig. 1). We also
reasoned that an enantioselective method can be realized using an
enantioenriched ligand-accelerated Lewis acid catalyzed cycliza-
tion. Herein, we report an efficient metal triflate-catalyzed
cyclization of arylvinyl carbinols of the type 2a to give 3a (Table 1).
We examined the cyclization of arylvinyl carbinol 2a21 using
various metal triflates to affect the synthesis of the carbotricyclic
structure of taiwaniaquinoids (Table 1). Initial attempts afforded
Diterpenoids possessing a fused 6,5,6-abeo-abietane skeleton (1a–
e, Fig. 1) have gained substantial interest owing to their significant
biological properties and interesting architecture.1 They are a
family of carbotricyclic diterpenoids bearing an unusual 4a-
methyltetra- (and hexa-) hydrofluorene skeleton. Taiwaniaquinoids
are abeo-abietanes isolated from different East Asian conifers viz.
the Taiwanese pine tree Taiwania cryptomerioides, which they were
named after.2 Recently, various merosesquiterpenes (1f–h) posses-
sing similar abeo-abietane type cores with an additional isoprene
unit have also been isolated from various sources.3
Merosesquiterpenes containing a sesquiterpene unit joined to a
phenolic (such as 1f–h) or quinone moiety are another vital group
of natural products with potential biological activities.4 Reportedly,
a few members of taiwaniaquinoids are found to exhibit potent
cytotoxic activity against KB epidermoid carcinoma cancer cells,5
and one of them, standishinal (1e), could be a promising
candidate in breast cancer therapy due to its aromatase inhibitory
potential.6
These biological activities together with their intriguing
carbotricyclic structure make taiwaniaquinoids attractive synthetic
targets, which led to the development of numerous efficient
approaches. These include the synthesis by Banerjee7 and Node8
via a Pd(0)-catalyzed intramolecular Heck cyclization, a Nazarov
cyclization by Trauner,9 an enantioselective approach following a
Pd(0)-catalyzed decarboxylative allylation by Stoltz,10 an iridium-
Department of Chemistry, Indian Institute of Science Education and Research
Bhopal, Bhopal, M.P.–460 023, India. E-mail: alakesh@iiserb.ac.in
Electronic supplementary information (ESI) available: Experimental procedures,
3
characterization data, NMR spectra. For crystallographic information of compounds
3o and 8, see CCDC 926020 and 926021. See DOI: 10.1039/c3ra41497c
Fig. 1 Representatives of the taiwaniaquinoids and related structures.
This journal is ß The Royal Society of Chemistry 2013
{ This paper is dedicated to Professor Sukh Dev on the occasion of his 90th birthday.
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Table 1 Optimization of cyclization of arylvinylcarbinolsa
% Of
% Of
Entry Catalyst (mol%)
Solvent Temp. Time ¡ (3a) (4a)
1.
2.
3.
4.
5.
6.
7.
8.
Cu(OTf)2 (10 mol%) CH2Cl2 rt
24 h 78%
24 h 82%
12 h 60%
12 h 70%
12 h 56%
12 h 45%
12%
11%
25%
16%
23%
37%
00%
00%
00%
15%
13%
06%
40%
15%
00%
00%
00%
00%
00%
Sn(OTf)2 (10 mol%) CH2Cl2 rt
Zn(OTf)2 (10 mol%) CH2Cl2 rt
Bi(OTf)3 (10 mol%) CH2Cl2 rt
In(OTf)3 (10 mol%) CH2Cl2 rt
Sm(OTf)3 (10 mol%) CH2Cl2 rt
Sn(OTf)2 (10 mol%) CH2Cl2 40 uC 09 h 98%
Cu(OTf)2 (10 mol%) CH2Cl2 40 uC 09 h 96%
9.
Cu(OTf)2 (10 mol%) PhMe
Cu(OTf)2 (10 mol%) THF
Cu(OTf)2 (10 mol%) Et2O
90 uC 12 h 88%
70 uC 18 h 60%
35 uC 12 h 72%
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
Sn(OTf)2 (10 mol%) dioxane 75 uC 12 h 80%
Sn(OTf)2 (10 mol%) DMF
Sn(OTf)2 (10 mol%) THF
Sn(OTf)2 (10 mol%) PhMe
Sn(OTf)2 (10 mol%) DMSO
Sn(OTf)2 (10 mol%) DCE
90 uC 12 h 42%
70 uC 12 h 79%
90 uC 12 h 93%
90 uC 12 h 95%
70 uC 12 h 93%
Fig. 2 Substrate scope of the metal triflate catalyzed cyclization.
Cu(OTf)2 (5 mol%)
Sn(OTf)2 (5 mol%)
CH2Cl2 40 uC 18 h 90%
CH2Cl2 40 uC 18 h 89%
a
Reactions were carried out with 1.0 mmol of ¡(2a) in 5 mL of
solvent. Isolated yields after column chromatography are reported.
taiwaniaquinone H (1b) starting from arylvinylcarbinols 2k–m. As
shown in Scheme 3, bromoarenes 9c, 9g, and 9i (see ESI for
3
details) were treated with n-BuLi followed by treatment with
aldehyde 10 to afford 2k–m. These arylvinylcarbinols were cyclized
in the presence of 10 mol% of Sn(OTf)2 and Cu(OTf)2.
the required product along with the elimination product 4a
(entries 1–6). Further optimization (entries 7–17) revealed that 10
mol% of Sn(OTf)2 (condition A) and Cu(OTf)2 (condition B) in
refluxing dichloromethane resulted in a sole cyclization product in
98% and 96% yields (entries 7,8), respectively. On decreasing
catalyst loadings to 5 mol%, we found that the reaction required
more time to complete (entries 18,19). With the standard protocol,
we then probed a diverse set of arylvinyl carbinols 2b–i for the
cyclization. Impressively, Fig. 2 clearly depicts the generality of our
strategy to construct 4a-methyltetra-hydrofluorene structures in
good to excellent yields (up to 99%) in 9–12 h. The arylvinyl
carbinols 2a–h containing one or more electron-donating groups
As shown in Scheme 4, we observed that 2k afforded solely 3l,
where the cyclization was followed by elimination leading to
carbotricyclic a-methylstyrene derivative 3l as the major product
(95–97%) via an intermediate carbotricycle 3k. Under similar
conditions, 2l afforded carbotricycle 3m in 86–90% yields along
with regioisomer 3n in 6–8% yields (Scheme 4). In the case of 2m,
the cyclization provided 3o in 93% yield as the sole product in the
presence of Sn(OTf)2. However, in the case of Cu(OTf)2, a small
amount of aryldiene 4b (8%) was obtained together with 3o (88%).
It is noteworthy that, upon prolonged reaction time, Cu(OTf)2 also
provided 3o as the sole product in 96% yield, which supports the
theory that the cyclization might also proceed through an
aryldiene 4 (Schemes 1 and 4).22
were found to be superior to arylvinyl carbinol 2i (see ESI for
3
details) in this process.
A plausible mechanism for the formation of carbotricycles is
shown in Scheme 1. We hypothesize that aryl dienes 4 can be
formed easily through intermediate arylallyl cation 6,15 which in
turn could undergo a Friedel–Crafts type cyclization in the
presence of a Lewis acid. However, at the same time, one can
not rule out the possibility of cyclization via a concerted
mechanism for the formation of 3 following 5-endo cyclization.21b
To validate this hypothesis, we synthesized compound 2j (see
ESI for details). It is interesting to note that, under the influence
3
of 10 mol% of Sn(OTf)2 and Cu(OTf)2, 2j afforded only furan
derivative 8 as the sole product in almost quantitative yields
(Scheme 2). This indicates a stepwise process via a stable arylallyl
cation 6, which might be involved in the cyclization step.
To illustrate the synthetic versatility of our approach, we
undertook the formal synthesis of (¡)-dichroanone (1a) and
Scheme 1 Plausible mechanism of the metal triflate catalyzed cyclization.
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Scheme 2 Cyclization of 2j in the presence of Sn(OTf)2 and Cu(OTf)2.
For further synthetic elaboration, we undertook the hydro-
genation of the carbotricycle 3o. As envisioned, the hydrogenation
of 3o in the presence of H2 (1 atm.) and Pd/C afforded cis-fused 3p
as the sole product (Scheme 5). We confirmed the cis-fusion at the
ring junction by carrying out an NOE experiment. The X-ray
structure of 3o (Scheme 5) also clearly depicts a high degree of
concavity in carbotricyclic core due to the gem-dimethyl groups
and a double bond, which restricts the hydrogenation process at
the a-face of the carbotricycle 3o.
Interestingly, compound 3p could serve as an advanced
intermediate for the synthesis of various taiwaniaquinoids
possessing similar cis-fused carbotricyclic cores such as dichroanal
A (1c, Fig. 1).
Scheme 4 Substrate scope using arylvinylcarbinols (2k–m).
Eventually, demethylation of 3o using NaSEt in DMF afforded
11 in 75% yield, which turns out to be the formal total synthesis of
(¡)-dichroanone (1a) and (¡)-taiwaniaquinone H (1b) as shown
in Scheme 6.
Conclusions
In conclusion, an efficient method for the synthesis of 4a-
methyltetra-hydrofluorenes of taiwaniaquinoids has been devel-
oped. The methodology affords
a variety of carbotricyclic
structures under operationally simple conditions. We also believe
that an enantioselective approach to the synthesis of 4a-
methyltetra-hydrofluorenes could be achieved by using chiral
metal triflate complexes. The extension of this approach to the
other abeo-abietanes shown in Fig. 1, such as the tetracyclic
natural products pelorol (1f), akaol A (1g), dasyscyphin B (1h) as
well as an enantioselective approach to 4a-methyltetra-hydrofluor-
enes having all-carbon quaternary stereocenters is under active
investigation.
Scheme 5 The hydrogenation of the carbotricycle ¡(3o).
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Scheme 3 Synthesis of arylvinylcarbinols ¡(2k–m) of b-cyclocitral.
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4 J. W. Blunt, B. R. Copp, M. H. G. Munro, P. T. Northcote and M.
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Scheme 6 The formal total synthesis of (¡)-dichroanone (1a) and (¡)-
taiwaniaquinone H (1b).
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Experimental
Representative experimental procedure for the metal-triflate
catalyzed cyclization of aryl-vinyl carbinols
In an oven-dried round-bottom flask, the arylcarbinols of
b-cyclocitral (1.0 mmol; 1.0 equiv.) and Sn(OTf)2 (0.1 mmol; 10
mol%) [Condition A] or Cu(OTf)2 (0.1 mmol; 10 mol%) [Condition
B] were dissolved in dichloromethane (5 mL). The mixture was
stirred at 40 uC for the indicated time (9–12 h). Upon completion
of the reactions (TLC indicated the complete consumption of the
starting material), the reaction mixture was quenched with
saturated NaHCO3 solution, diluted with 5 mL of dichloro-
methane and extracted with 5 mL of water. The organic filtrate
was dried over Na2SO4 and concentrated in a rotary evaporator
under vacuum. The crude products were purified by flash
chromatography (10 : 1 hexanes/EtOAc) to afford the Friedel–
Crafts alkylation products.
Acknowledgements
15 E. Alvarez-Manzaneda, R. Chahboun, E. Cabrera, E. Alvarez,
R. Alvarez-Manzaneda, R. Meneses, H. Es-Samti and
A. B. thanks the Board of Research in Nuclear Sciences (BRNS),
the Department of Atomic Energy (DAE) for a research grant
through the Young Scientist Award [Sanction No.: 2011/20/
37C/12/BRNS/1731]. We are grateful to the Department of
Science and Technology (DST), Government of India, for
generous funding [Sanction No.: SERB/F/5532/2012-13]. B. N.
K. and S. D. thank the Council of Scientific and Industrial
Research (CSIR), New Delhi, for predoctoral fellowships. We
sincerely thank Professor Vinod K. Singh, the Director, IISER
Bhopal for creating excellent research facilities. Our sincere
thanks to Dr Deepak Chopra, Assistant Professor of Chemistry,
IISER Bhopal for the assistance with X-ray crystallography.
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21 (a) For stoichiometric approaches using 1.5 equiv. of SnCl4, see
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22 Interestingly, 5 mol% of BF3?OEt2 catalyzes the cyclization of 2k
in only 2–5 min, leading to the formation of 3k in 90% yield
along with 8% of the carbotricyclic diene 3l.
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RSC Adv., 2013, 3, 8176–8179 | 8179