First total synthesis of rhuscholide A, glabralide B and denudalide

Article abstract of DOI:10.1016/j.tetlet.2019.151059

The first total synthesis of rhuscholide A, a benzofuran lactone possessing anti-HIV-1 activity, had been accomplished in 14 linear steps with 10.6% overall yield. In this synthesis, base-mediated phenol ortho-alkylation and piperidine promoted aldol condensation were exploited as key steps. The synthesis was flexible and allowed for the convenient preparation of two analogous natural products glabralide B and denudalide.

Full text of DOI:10.1016/j.tetlet.2019.151059

Tetrahedron Letters xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
First total synthesis of rhuscholide A, glabralide B and denudalide
Tian-Ze Li a, Chang-An Geng a, Ji-Jun Chen a,b,
⇑
a State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Yunnan Key Laboratory of Natural
Medicinal Chemistry, Kunming 650201, PR China
b University of Chinese Academy of Sciences, Beijing 100049, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The first total synthesis of rhuscholide A, a benzofuran lactone possessing anti-HIV-1 activity, had been
accomplished in 14 linear steps with 10.6% overall yield. In this synthesis, base-mediated phenol ortho-
alkylation and piperidine promoted aldol condensation were exploited as key steps. The synthesis was
flexible and allowed for the convenient preparation of two analogous natural products glabralide B
and denudalide.
Received 30 May 2019
Revised 14 August 2019
Accepted 16 August 2019
Available online xxxx
Ó 2019 Published by Elsevier Ltd.
Keywords:
Total synthesis
Rhuscholide A
Glabralide B
Denudalide
Introduction
r/mHM-SFME-1 cell lines. The biological activity of glabralide B
has not been investigated due to its limited availability from natu-
Benzofuran-2(3H)-ones is an important structural motif present
in many biologically active natural products [1] and pharmaceuti-
cal compounds [2]. Over the years, several synthetic strategies had
been developed for the construction of such framework, including
the lactonization of 2-hydroxyphenylacetic acid derivatives [3],
tandem Friedel–Crafts/lactonization [4], Reppe-type cyclocarbony-
lation of alkenyl- or allylphenols [5], Palladium-catalyzed CAH
activation of phenylacetic acid followed by lactonization [6], tran-
sition-metal-catalyzed coupling reaction [7]. In our search for
potent anti-HIV-1 agents from natural products [8], two benzofu-
ranone-type compounds, rhuscholide A and compound 2, had been
isolated from Rhus chinensi [8b]. Rhuscholide A showed anti-HIV-1
activity with EC50 and CC50 values of 1.62 and 68.69 lM,
respectively, and a therapeutic index of 42.31. Compound 2,
which shares the same skeleton with 1 but lacks substituent at
C-3, exhibited moderate activity with an EC50 value of 3.70 lM
(TI > 3.28). This finding suggested propan-2-ylidene group is
important for anti-HIV-1 activity. Action mechanisms study
indicated 1 might target on late-steps of HIV-1 life cycle [9]. Anal-
ogous natural products glabralide B (3) and denudalide (4) with
variations in the side chain had been isolated from Sarcandra glabra
[10] and Magnolia denudate [11], respectively. Denudalide had also
been found in the extracts of Lettowianthus stellates [12], and this
compound exhibited cytotoxic activities against the SFME and
ral source.
Given the promising bioactivity of 1, it is highly desirable to
establish an efficient access to 1 and its analogues to fulfill further
pharmacological investigation. No synthetic studies on rhuscholide
A and 2–4 have been reported so far. Herein, we describe the first
total synthesis of 1–4.
Results and discussion
General structural features of 1–4 include a benzofuran-2-one
motif and a C20 or C10 side chain. We envisioned that rhuscholide
A and glabralide B could be obtained from 2 and 4, respectively,
via an aldol condensation with acetone. The requisite c-lactone
motif was envisioned to arise from advanced intermediates 5 or
6, both of them could be divided in half via phenol ortho-alkylation
to deliver phenol 7 and bromides. The desired geranylgeranyl bro-
mide could be prepared from related alcohol [13], while geranyl
bromide was commercially available (Scheme 1).
The known compound 7 was readily prepared from hydro-
quinone via a three-step sequence (benzylation/allylation/Claisen
rearrangement) [14]. For the synthesis of rhuscholide A, the treat-
ment of 7 with allylic bromine 8 and NaH in toluene afforded phe-
nol ortho-alkylation product 5 in 68% yield [15]. Increase the NaH
loading from 1 to 1.2 equivalent led to a slightly decrease in the
yield (64%). It was planned to generate the requisite
c-lactone
⇑
motif from 5 by employing the sequence: oxidative terminal dou-
ble bond cleavage [16], oxidation and lactonization. Unfortunately,
Corresponding author.
E-mail address: chenjj@mail.kib.ac.cn (J.-J. Chen).
https://doi.org/10.1016/j.tetlet.2019.151059
0040-4039/Ó 2019 Published by Elsevier Ltd.
Please cite this article as: T.-Z. Li, C. A. Geng and J. J. Chen, First total synthesis of rhuscholide A, glabralide B and denudalide, Tetrahedron Letters, https://
doi.org/10.1016/j.tetlet.2019.151059

2
T.-Z. Li et al. / Tetrahedron Letters xxx (xxxx) xxx
Scheme 1. Retrosynthetic analysis of 1–4.
the first dihydroxylation step proved unexpectedly challenging.
The treatment of 5 with a variety of standard oxidants (e.g.,
OsO4, RuO4) routinely used for alkene cleavage gave complicated
products. Extensive attempts to optimize the reaction conditions
(such as using acetyl group to protect hydroxyl group) did not
improve the outcome (Scheme 2). With this setback, we revised
Protection of the phenol in 7 with acetate was achieved under a
standard acetylization protocol to give compound 14. Osmium-cat-
alyzed dihydroxylation followed by cleavage of the diol with NaIO4
[17] and acid catalyzed acetalization delivered 15 in 68% yield over
3 steps. Subsequent deacetylization using NaOH led to the forma-
tion of phenol 16 in nearly quantitative yield. Notably, these steps
were readily scalable and allowed for the production of multigram
quantities of phenol 16 (Scheme 3).
our approach to initially prepare the
the C20 side chain installation.
c-lactone precursor before
Scheme 2. Tentative approach toward rhuscholide A.
Please cite this article as: T.-Z. Li, C. A. Geng and J. J. Chen, First total synthesis of rhuscholide A, glabralide B and denudalide, Tetrahedron Letters, https://
doi.org/10.1016/j.tetlet.2019.151059

T.-Z. Li et al. / Tetrahedron Letters xxx (xxxx) xxx
3
In the forward synthesis, the C20 side chain was introduced via
NaH-mediated phenol ortho-alkylation as previously demonstrated
in the synthesis of 5 (Scheme 4). Deprotection of the acetal protect-
ing group followed by concomitant cyclization afforded hemiacetal
18 in 91% yield. For the conversion of lactol to lactone, the tradi-
tional pyridinium dichromate (PDC) mediated oxidation resulted
in low yield. A two-step process of Pinnick oxidation followed by
lactonization afforded benzofuran-2-one 19 in a high yield (92%).
Removal of the benzyl group with BCl3 [18] led to the first total
synthesis of 2. Conversion of 2 to rhuscholide A was conveniently
achieved upon the treatment of 2 with piperidine in a 1:1 ace-
tone-ethanol mixture [19].
The availability of this synthesis was further demonstrated in
the synthesis of glabralide B and denudalide. 16 was cleanly alky-
Scheme 3. Preparation of phenol 16.
Scheme 4. Final steps leading to rhuscholide A.
Scheme 5. Total synthesis of glabralide B and denudalide.
Please cite this article as: T.-Z. Li, C. A. Geng and J. J. Chen, First total synthesis of rhuscholide A, glabralide B and denudalide, Tetrahedron Letters, https://
doi.org/10.1016/j.tetlet.2019.151059

4
T.-Z. Li et al. / Tetrahedron Letters xxx (xxxx) xxx
(b) J.K. Chakrabarti, R.J. Eggleton, P.T. Gallagher, J. Harvey, T.A. Hicks, E.A.
Kitchen, C.W. Smith, J. Med. Chem. 30 (1987) 1663–1668;
(c) E. Rizzi, S. Dallavalle, L. Merlini, G.L. Beretta, G. Pratesi, F. Zunino, Bioorg.
Med. Chem. Lett. 15 (2005) 4313–4316;
lated with geranyl bromide affording 20 in 69% yield. Finally, ben-
zofuran lactones 4 and 3 were obtained successively from 20 fol-
lowing the route and conditions already established in the
synthesis of 1 (Scheme 5). Our NMR data of synthetic compounds
1–4 are in agreement with the reported values of the natural
products.
(d) K. Suzuki, T. Okawara, T. Higashijima, K. Yokomizo, T. Mizushima, M.
Otsuka, Bioorg. Med. Chem. Lett. 15 (2005) 2065–2068.
[3] (a) Y. Kita, S. Akai, M. Yamamoto, M. Taniguchi, Y. Tamura, Synthesis 1989
(1989) 334–337;
(b) S. Venkateswarlu, G.K. Panchagnula, M.B. Guraiah, G.V. Subbaraju,
Tetrahedron 61 (2005) 3013–3017;
(c) M.W. Pertino, C. Theoduloz, J.A. Rodríguez, T. Yáñez, V. Lazo, G. Schmeda-
Hirschmann, J. Nat. Prod. 73 (2010) 639–643.
Conclusion
[4] (a) L. Chen, F. Zhou, T.-D. Shi, J. Zhou, J. Org. Chem. 77 (2012) 4354–4362;
(b) F. Vetica, R.M. de Figueiredo, E. Cupioli, A. Gambacorta, M.A. Loreto, M.
Miceli, T. Gasperi, Tetrahedron Lett. 57 (2016) 750–753;
(c) Z. Tang, Z. Tong, Z. Xu, C.-T. Au, R. Qiu, S.-F. Yin, Green Chem. 21 (2019)
2015–2022.
[5] (a) H. Wang, B. Dong, Y. Wang, J. Li, Y. Shi, Org. Lett. 16 (2014) 186–189;
(b) V. Hirschbeck, I. Fleischer, Chem.–Eur. J. 24 (2018) 2854–2857.
[6] (a) M. Yang, X. Jiang, W.-J. Shi, Q.-L. Zhu, Z.-J. Shi, Org. Lett. 15 (2013) 690–693;
(b) X.-F. Cheng, Y. Li, Y.-M. Su, F. Yin, J.-Y. Wang, J. Sheng, H.U. Vora, X.-S.
Wang, J.-Q. Yu, J. Am. Chem. Soc. 135 (2013) 1236–1239.
[7] (a) X. Qi, H.-P. Li, X.-F. Wu, Chem. –Asian J. 11 (2016) 2453–2457;
(b) H.-P. Li, H.-J. Ai, X. Qi, J.-B. Peng, X.-F. Wu, Org. Biomol. Chem. 15 (2017)
1343–1345.
In conclusion, we have performed an efficient route for the first
total synthesis of rhuscholide A (1) from commercially available
hydroquinone and geranyllinalool. This synthesis utilized base-
mediated phenol ortho-alkylation and piperidine promoted aldol
condensation as key steps and furnished rhuscholide A in 10.6%
overall yield in 14 linear steps. Two analogous natural products
glabralide B (3) and denudalide (4) were also synthesized, which
should facilitate the investigation of structure-activity relation-
ships for anti-HIV-1 activity.
[8] (a) R.-R. Wang, Q. Gu, L.-M. Yang, J.-J. Chen, S.-Y. Li, Y.-T. Zheng, J.
Ethnopharmacol. 105 (2006) 269–273;
Acknowledgments
(b) Q. Gu, R.-R. Wang, X.-M. Zhang, Y.-H. Wang, Y.-T. Zheng, J. Zhou, J.-J. Chen,
Planta Med. 73 (2007) 279–282;
(c) J.-F. Liu, Z.-Y. Jiang, R.-R. Wang, Y.-T. Zheng, J.-J. Chen, X.-M. Zhang, Y.-B.
Ma, Org. Lett. 9 (2007) 4127–4129;
(d) W.-Y. Song, Y.-B. Ma, X. Bai, X.-M. Zhang, Q. Gu, Y.-T. Zheng, J. Zhou, J.-J.
Chen, Planta Med. 73 (2007) 372–375;
We are grateful for the financial support from the National Nat-
ural Science Foundation of China (Grant No. 81803405), the China
Postdoctoral Science Foundation-Chinese Academy of Sciences
Joint Grant, the Program of Yunling Scholarship, and the Youth
Innovation Promotion Association CAS (2013252).
(e) M.-H. Yan, P. Cheng, Z.-Y. Jiang, Y.-B. Ma, X.-M. Zhang, F.-X. Zhang, L.-M.
Yang, Y.-T. Zheng, J.-J. Chen, J. Nat. Prod. 71 (2008) 760–763.
[9] R.-R. Wang, Q. Gu, Y.-H. Wang, X.-M. Zhang, L.-M. Yang, J. Zhou, J.-J. Chen, Y.-T.
Zheng, J. Ethnopharmacol. 117 (2) (2008) 249–256.
[10] W.-Q. Yang, P. Hai, H. Xiao, Y. Gao, Y.-H. Tao, D.-R. Miao, F. Wang, Tetrahedron
74 (2018) 341–347.
[11] T. Noshita, H. Kiyota, Y. Kidachi, K. Ryoyama, S. Funayama, K. Hanada, T.
Murayama, Biosci. Biotechnol. Biochem. 73 (2009) 726–728.
[12] J.J. Makangara, M.H.H. Nkunya, S.S. Jonker, Nat. Prod. Res. 24 (2010) 710–717.
[13] A.K. Bakkestuen, L.-L. Gundersen, D. Petersen, B.T. Utenova, A. Vik, Org. Biomol.
Chem. 3 (6) (2005) 1025–1033.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2019.151059.
References
[14] (a) R. Frlan, S. Gobec, D. Kikelj, Tetrahedron 63 (2007) 10698–10708;
(b) D. Gaertner, H. Konnerth, A.J. von Wangelin, Catal. Sci. Technol. 3 (2013)
2541–2545;
(c) A. Roy, B. Biswas, P.K. Sen, R.V. Venkateswaran, Tetrahedron Lett. 48 (2007)
6933–6936.
[15] P.Y. Toullec, T. Blarre, V. Michelet, Org. Lett. 11 (2009) 2888–2891.
[16] M.G. Kalshetti, N.P. Argade, J. Org. Chem. 82 (2017) 11126–11133.
[17] R. Pappo, J.D.S. Allen, R.U. Lemieux, W.S. Johnson, J. Org. Chem. 21 (1956) 478–
479.
[18] K. Okano, K.-I. Okuyama, T. Fukuyama, H. Tokuyama, Synlett 2008 (2008)
1977–1980.
[19] B.M. Trost, N. Cramer, S.M. Silverman, J. Am. Chem. Soc. 129 (41) (2007)
12396–12397.
[1] (a) S. Piacente, P. Montoro, W. Oleszek, C. Pizza, J. Nat. Prod. 67 (2004) 882–
885;
(b) C. Balestrieri, F. Felice, S. Piacente, C. Pizza, P. Montoro, W. Oleszek, V.
Visciano, M.L. Balestrieri, Biochem. Pharmacol. 71 (2006) 1479–1487;
(c) Y.-J. Kwon, M.-J. Sohn, C.-J. Zheng, W.-G. Kim, Org. Lett. 9 (2007) 2449–
2451;
(d) H.M. Ge, C.H. Zhu, D.H. Shi, L.D. Zhang, D.Q. Xie, J. Yang, S.W. Ng, R.X. Tan,
Chem. –Eur. J. 14 (2008) 376–381;
(e) E.M. Wenzig, W. Oleszek, A. Stochmal, O. Kunert, R. Bauer, J. Agric. Food.
Chem. 56 (2008) 8885–8890;
(f) S.-I. Wada, T. Hitomi, H. Tokuda, R. Tanaka, Chem. Biodivers. 7 (2010)
2303–2308.
[2] (a) A. Closse, W. Haefliger, D. Hauser, H.U. Gubler, B. Dewald, M. Baggiolini, J.
Med. Chem. 24 (1981) 1465–1471;
Please cite this article as: T.-Z. Li, C. A. Geng and J. J. Chen, First total synthesis of rhuscholide A, glabralide B and denudalide, Tetrahedron Letters, https://
doi.org/10.1016/j.tetlet.2019.151059