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Gold-Catalyzed Synthesis of Icetexane Cores: Short Synthesis of

Taxamairin B and Rosmaridiphenol
Quynh Thuy Le, Lihui Guo, Seung Lyeol Lee, Junseong Lee, and Chang Ho Oh*
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ABSTRACT: We report the short synthesis of two natural products, rosmaridiphenol and taxamairin B, from key intermediates 5a
and 5b, which were prepared from enynals 8a and 9b, respectively, by using a gold-catalyzed cyclization reaction. This approach can
be widely applied in the synthesis of [6,7,6]-fused tricyclic compounds found in many icetexane diterpenoids.

I cetexanes are natural diterpenoid products that have been

isolated from a variety of Salvia species.1 These compounds
contain a [6,7,6]-tricyclic core that is supposed to be
constructed via natural rearrangement of more common
[6,6,6]-fused abietane diterpenoids.2
The icetexane diterpenoid shows potential biological activity
such as antibacterial,3 antifungal,4 and antioxidant5 activity and
anti-HIV6 and anticancer7 effects. The syntheses of these
natural products have attracted research groups to the
development of efficient synthetic methods.8
Rosmaridiphenol was isolated from leaves of Rosmarinus
of f icinalis L in 1984 and showed antioxidant activity Figure 1. Icetexane diterpenoids.
approaching that of BHT.9 The structure of rosmaridiphenol
was revised by NMR analysis and single-crystal X-ray study of
rosmaridiphenol diacetate.10 In 2016, Matsushita’s group taxamairin B in 1995,13 and a second-generation synthesis was
reported the semisynthesis of (+)-rosmaridiphenol from published in 1999.14
(+)-pisiferic acid in 13% yield (nine steps).11 There has In recent years, new processes based on intramolecular
been no further report of the synthesis of this compound. transition-metal cyclization led to diverse products in good
Along with rosmaridiphenol, taxamairins A and B were first yields. In 2005, Padwa reported the construction of
isolated in 1987 from the bark of Taxusmairei, a plant that komaroviquinone using a Rh-catalyzed cyclization/cyclo-
grows in Fujiang Province, China. The structure of taxamairin addition cascade of an o-carbomethoxyaryl diazo.15 One year
later, Sarpong and co-workers achieved total synthesis of
was determined by X-ray crystallographic analysis with its
oxygenated derivative at both C1 and C8 (Figure 1).
Taxamairins A and B show inhibitory activity against hepatoma Received: October 13, 2020
(liver tumor) cells in vitro, with IC50 values of 30.21 and 26.78
μg/mL, respectively.12 Attracted by the structural character-
istics and biological activity of taxamairins, several groups have
attempted to synthesize taxamairins and related compounds.
Pan’s research group reported the first total synthesis of

© XXXX American Chemical Society https://dx.doi.org/10.1021/acs.orglett.0c03415

A Org. Lett. XXXX, XXX, XXX−XXX
Organic Letters pubs.acs.org/OrgLett Letter

(±)-salviasperanol using Ga(III)-catalyzed cycloisomeriza- Scheme 2. Gold-Catalyzed Cyclization of 3a and 4a

tion.16 In previous research, we have synthesized faveline and
komaroviquinone using a Pt-catalyzed hydrative cyclization
reaction.17 Recently, we reported the total synthesis of
taxamairin B (six steps from o-bromobenzyl bromide) in
good yield under mild conditions. The [6,7,6]-tricyclic core
was constructed by an intramolecular hydrative Heck
strategy.18 The catalysts provide an efficient synthetic method
for many natural products and useful building blocks in organic
synthesis.
In this research, we focus on use of gold catalysts to
construct the corresponding [6,7,6]-tricyclic skeletons as key
intermediates for the synthesis of taxamairin B and
rosmaridiphenol.
We first prepared a substrate for gold-catalyzed cyclization Table 1. Optimization of the Gold-Catalyzed Cyclization of
from starting materials 1a, 1b, and 2 via Sonogashira reaction 5a
with PdCl2(PPh3)2, CuI, and n-Bu4NI at 80 °C in triethyl-
amine for 9 h to produce alcohols 3a and 3b in 85% and 80%
yields, respectively. Then, TBS-protected alcohols 3a and 3b
under a basic condition gave compounds 4a and 4b in 88%
and 85% yields, respectively. Swern oxidation of 3a and 3b entry catalyst (mol %) solvent temp (°C) product yield (%)a
afforded compounds 5a and 5b, respectively, in excellent yield 1 AuBr3 (30) EDC 60 10a 65
(95%) (Scheme 1). 2 AuBr3 (10) EDC 80 9a 42
3 PPh3Au(NTf)2 (5) EDC 80 9a 50
Scheme 1. Synthesis Substrate for Gold-Catalyzed 4 NaAuCl4 (5) EDC 60 10a 70
Cyclization 5 COAuCl (5) EDC 60 8a 55
6 COAuCl (5) toluene 60 − nrb
7 COAuCl (5) THF 60 − nrb
a
Isolated yields of indicated products. bNo reaction.

NaAuCl4 (Table 1, entries 1 and 4). However, when the same

reaction was performed at 80 °C with AuBr3 (10 mol %) as a
catalyst, compound 9a was isolated in 42% yield (Table 1,
entry 2). Another gold catalyst, PPh3Au(NTf)2, was tested,
where compound 9a was also isolated as a major product in
50% yield (Table 1, entry 3).
Finally, treatment of 5a with COAuCl in EDC at 50 °C led
to the desired product 8a as a key intermediate for further
On the basis of previous work in our laboratory using gold- synthesis (Table 1, entry 5). When the same reaction was
catalyzed cycloisomerization of diynals and enynals to performed in toluene and tetrahydrofuran, no reaction has
synthesize [6,7,n]-tricyclic compounds, we chose AuBr3 as a occurred (Table 1, entries 6 and 7).
catalyst for this cyclization reaction.19 We next examined gold-catalyzed cyclization of compounds
First, we treated compound 3a with AuBr3 in EDC at 60 °C 3b, 4b, and 5b. When compound 4b was treated with AuBr3 in
for 1 h. Unfortunately, our desired compound was not formed, EDC at room temperature for 8 h, compound 7b was
although compound 6a was synthesized in 90% yield. The produced in 73% yield. Surprisingly, oxidative cyclization of
formation of this dihydronaphthofuran ring system by gold- compound 7b with PCC at room temperature for 6 h gave
catalyzed cascade annulation has been reported by Ham- compound 8b. The structure of 8b was determined by X-ray
mond’s group.20 Next, enynal 4a underwent cyclization to diffraction. The X-ray structures of compound 8b showed that
afford 7a in 70% yield. The structure of 7a was confirmed as a this PCC oxidation reaction formed one C−O−C bridge
diastereomeric mixture by spectroscopic analysis. Compound between positions C8 and C11 and a carbonyl group in position
7a is a pseudoisomer of 7a′, which was the compound C12 (Figure 2). On the basis of this X-ray analysis, we could
previously isolated from Pt-catalyzed hydrative cyclization of confirm this structure. Compound 8b also was the cyclic
4a′ during the synthesis of komaroviquinone (Scheme 2).17a product when compound 3b was treated with AuBr3 at 60 °C
Searching for a suitable intermediate for synthesis of for 2 h and then oxidized by PCC at room temperature for 3 h.
taxamairin B, we tested substrate 5a with various metal Fortunately, when we treated compound 5b with AuBr3 at 80
catalysis conditions, and the results are summarized in Table 1. °C for 2 h, intermediate 9b was formed in 80% yield and was
Treatment of compound 5a with silver triflate in toluene used for subsequent synthesis of rosmaridiphenol (Scheme 3).
caused decomposition of the starting material. With PtCl2 as a Mechanistically, we proposed that the formation of 9b is
catalyst, only hydration of the triple bond of 5a was achieved. initiated by activation of alkyne by Au(III) species to generate
However, performing the reaction with AuBr3 (30 mol %) in zwitterion A or B that would undergo cycloaddition to form
EDC led to the formation of compound 10a in 60% yield, the Au-carbene species C. The deprotonation from C by a base
same product produced when compound 5a was treated with (likely solvent or another source) led to the formation of D,
B https://dx.doi.org/10.1021/acs.orglett.0c03415
Org. Lett. XXXX, XXX, XXX−XXX
Organic Letters pubs.acs.org/OrgLett Letter

Scheme 5. Synthesis of Taxamairin B

Figure 2. X-ray spectra of compound 8b with ellipsoids shown at the

Hydrogenation of 9b (Scheme 6) afforded 10b in 82% yield
50% contour percent probability level (CCDC 2033257). (1:1 cis:trans ratio). Compound 10b then was treated with t-

Scheme 3. Gold-Catalyzed Cyclization of 3b, 4b, and 5b Scheme 6. Synthesis of Rosmaridiphenol

BuOK to achieve complete isomerization and yield the trans

isomer of 10b. Finally, cleavage of the methyl ethers using BBr3
gave rosmaridiphenol in excellent yield.
In conclusion, we successfully performed gold-catalyzed
and then simultaneously to the formation of four-membered cyclization of 5a and 5b to generate [6,7,6]-tricyclic
ring E. Then, reprotonation to E by liberated BH+ followed by compounds 8a and 9b, respectively, in moderate yields.
reductive elimination resulted in 9b via the release of an These were subsequently transformed into taxamairin B and
unprecedented Au(III)O species. This phenomenon might rosmaridiphenol, respectively. This method could allow
be proceeded by the action of solvent CH2Cl-CH2Cl as a application of gold-catalyzed cyclization to the synthesis of
reductant; thus, we tried this reaction in the presence of various natural products.
hydroquinone, where we found benzoquinone formation in 1H
NMR of the crude reaction mixture. Although reduction of
Au(III)O to Au(III) was not yet confirmed, we have carried
■
*
ASSOCIATED CONTENT
sı Supporting Information
out the following reactions to finish the synthesis of The Supporting Information is available free of charge at
rosmaridiphenol (Scheme 4). https://pubs.acs.org/doi/10.1021/acs.orglett.0c03415.
Scheme 4. Possible Mechanism for the Formation of 9b Experimental procedures and spectroscopic data for
adduct compounds (PDF)
Accession Codes
CCDC 2033257 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

■ AUTHOR INFORMATION
Corresponding Author
Chang Ho Oh − Department of Chemistry and Center for
New Directions in Organic Synthesis (CNOS), Hanyang
University, Seoul 04763, Korea; orcid.org/0000-0002-
7208-4261; Email: changho@hanyang.ac.kr

We next focused our attention on formation of taxamairin B. Authors

Mild conditions for oxidation of alcohol 8a afforded ketone Quynh Thuy Le − Department of Chemistry and Center for
11a in 98% yield. Selective dehydrogenation using 3 equiv of New Directions in Organic Synthesis (CNOS), Hanyang
DDQ at 80 °C for 3 h gave compound 12a in 90% yield. University, Seoul 04763, Korea
Further reaction beyond 3 h produced taxamairin B in 72% Lihui Guo − Department of Chemistry, Nankai University,
yield (Scheme 5). Tianjin 300071, China
C https://dx.doi.org/10.1021/acs.orglett.0c03415
Org. Lett. XXXX, XXX, XXX−XXX
Organic Letters pubs.acs.org/OrgLett Letter

Seung Lyeol Lee − Department of Chemistry and Center for (10) Muñoz, M. A.; Perez-Hernandez, N.; Pertino, M. W.; Schmeda-
New Directions in Organic Synthesis (CNOS), Hanyang Hirschmann, G.; Joseph-Nathan, P. J. Nat. Prod. 2012, 75, 779.
University, Seoul 04763, Korea (11) Nisigaki, E.; Sugamoto, K.; Nishida, M.; Matsushita, Y. Chem.
Junseong Lee − Department of Chemistry, Chonnam National Lett. 2016, 45, 746.
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University, Gwangju 500-757, Korea; orcid.org/0000- Chem. Pharm. Bull. 1987, 35, 2613. (b) Liang, J.; Min, Z.; Tanaka, T.;
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■ ACKNOWLEDGMENTS
This work was supported by a grant from the National
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Research Foundation of Korea (NRF), funded by the Korean (18) Le, T. Q.; Karmakar, S.; Lee, S.; Chai, U.; Le, M. H.; Oh, C. H.
Government, through the Center for New Directions in Chemistry Select. 2019, 4, 11926.
Organic Synthesis (NRF-2014R1A5A10 11165). (19) Kim, N.; Kim, Y.; Park, W.; Sung, D.; Gupta, A. K.; Oh, C. H.

■
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