Biomimetic total synthesis of (-)-isatisine a

Article abstract of DOI:10.1021/ol300379g

The biomimetic total synthesis of (-)-isatisine A, a novel alkaloid with an unprecedented fused tetracyclic skeleton, was accomplished in 8 steps from indole and 4,6-O-isopropylidene-protected glucal. The synthesis features a convergent synthetic strategy which relies on nucleophilic addition and a biomimetic benzilic ester rearrangement as key reactions.

Full text of DOI:10.1021/ol300379g

ORGANIC
LETTERS
2012
Vol. 14, No. 6
1624–1627
Biomimetic Total Synthesis of
(ꢀ)-Isatisine A
Wei Wu, Mingxing Xiao, Jiangbing Wang, Ying Li, and Zhixiang Xie*
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and
Chemical Engineering, Lanzhou University, Lanzhou, 730000, P. R. China
xiezx@lzu.edu.cn
Received February 16, 2012
ABSTRACT
The biomimetic total synthesis of (ꢀ)-isatisine A, a novel alkaloid with an unprecedented fused tetracyclic skeleton, was accomplished in 8 steps
from indole and 4,6-O-isopropylidene-protected glucal. The synthesis features a convergent synthetic strategy which relies on nucleophilic
addition and a biomimetic benzilic ester rearrangement as key reactions.
The leaves and root of Isatis indigotica Fort., named
“Da-Qing-Ye” and “Ban-Lan-Gen” respectively in Chinese,
have been used in traditional Chinese medicine for the
treatment of viral diseases for hundreds of years in China.1
Chemical investigations of its root and leaves have led to
the isolation of compounds with diverse structures and
significant biological activities.2 In 2007, Chen and co-
workers reported the isolation of isatisine A acetonide (1)
from the leaves (Da-Qing-Ye) (Figure 1).3 This com-
pound showed moderate anti-HIV-1 activity with EC50
=
37.8 μM and selectivity index (SI) = 7.98. Isatisine A
acetonide (1) also exhibited cytotoxicity against C8166
with CC50 = 302 μM.
Figure 1. Original proposed structure of isatisine A (2) and its
acetionide (1) and revised structure of isatisine A (3).
The structure and relative configuration of 1 was eluci-
dated by NMR experiments and finally determined by
single-crystal X-ray diffraction.3 The structural features of
1 possess a fused pentacyclic framework containing a
densely substituted furan subunit, one aza-quaternary
carbon center, and one oxo-quaternary carbon center. In
addition, an unusual isopropylidenyl group was embedded
in the core. The isopropylidenyl group that has been
relatively rare in natural products prompted further inves-
tigation by Chen and co-workers, which indicated aceto-
nide derivative 1 was an isolation artifact, and isatisine
A (2) was proposed as the genuine natural product.3 How-
ever, the bioactivity of 2 was not reported due to limited
supply. Its uncharacterized bioactivity and intriguing
molecular architecture have drawn a great amount
of attention from the synthetic community. In 2010,
Kerr et al. reported the first total synthesis and structural
revision of (ꢀ)-isatisine A (3).4 The revised structure was
further confirmed by the total syntheses of (þ)-isatisine
(1) Zheng, H. Z.; Dong, Z. H.; Yu, Q. Modern Study of Traditional
Chinese Medicine; Xueyuan Press: Beijing, 1997; Vol. 1, p 328.
(2) (a) Huang, Q. S.; Yoshihira, K.; Natori, S. Planta Med. 1981, 42,
308. (b) Wu, X. Y.; Liu, Y. H.; Sheng, W. Y.; Sun, J.; Qin, G. W. Planta
Med. 1997, 63, 55. (c) Wu, X. Y.; Qin, G. W. Tetrahedron 1997, 53,
13323. (d) Mak, N. K.; Leung, C. Y.; Wei, X. Y.; Shen, X. L.; Wong,
R. N.; Leung, K. N.; Fung, M. C. Biochem. Pharmacol. 2004, 67, 167. (e)
Peng, S. P.; Gu, Z. L. Chin. Wild Plant Resources 2005, 24, 4. (f) Shi, X.;
Ni, Y.; Liu, Y. H. Chin. Hosp. Pharm. J. 2006, 26, 1397.
(3) Liu, J. F.; Jiang, Z. Y.; Wang, R. R.; Zheng, Y. T.; Chen, J. J.;
Zhang, X. M.; Ma, Y. B. Org. Lett. 2007, 9, 4127.
r
10.1021/ol300379g
Published on Web 02/28/2012
2012 American Chemical Society

A (2) and (ꢀ)-isatisine A (3) by Panek5 and Liang,6
respectively. Interesting, Kerr, Panek, and Liang demon-
strated elegant synthetic strategies that first constructed
the densely substituted furan subunit and, subsequently,
installed the second indole moiety by a nucleophilic ad-
dition.4ꢀ6 Herein, we report our biomimetic total synthesis
of (ꢀ)-isatisine A (3). Our biomimetic synthetic strategy
features a convergent nucleophilic addition for installation
of the indole moiety and, subsequently, an unprecedented
benzilic ester rearrangement for construction of the dense-
ly substituted furan subunit.
Thus, a plausible biogenetic pathway for (ꢀ)-isatisine A
(3) was proposed by us as shown in Scheme 1. In the
proposed biogenetic route, indican (4) is first converted to
compound 5 via rearrangement and subsequent oxidation. 5
then undergoes a rapid nucleophilic addition by an indole
molecule to afford compound 6.4b,9 The key intermediate,
1,2-diketone 7, is expected to be obtained by selective
oxidation of compound 6. Finally, biogenetic benzilic acid
rearrangement10 of compound 7 could give rise to the
compound 8, which is converted to (ꢀ)-isatisine A (3)
through dehydration.
Scheme 1. Biogenetic Pathway Proposed for (ꢀ)-Isatisine A
Scheme 2. Retrosynthesis Analysis of (ꢀ)-Isatisine A
In order to support this biogenetic pathway, benzilic
ester rearrangement was devised as a key biomimetic
reaction for the synthesis of (ꢀ)-isatisine A. As shown in
retrosynthesis analysis (Scheme 2), we reasoned that the
synthesis of (ꢀ)-isatisine A (3) could be achieved from
compound 9 by a biomimetic oxidation, benzilic ester
rearrangement, and cyclization. The R-hydroxy ketone 9
would be prepared easily by deprotection from diketone
10. We envisioned that if electrophilic 11 and nucleophilic
13 could be merged together by base, a short, convergent,
We became interested in (ꢀ)-isatisine A (3) as a novel
alkaloid possessing an unprecedented fused-tetracyclic
skeleton which cannot be well explained from a biogenetic
point of view.3 Studies suggest that the polyhydroxy core
of some natural products is likely to arise in nature from
glycosides.7 Inspired by the multiple hydroxy groups and
indole moiety of (ꢀ)-isatisine A (3), indican (4), isolated
from the same species, seems to be the precursor of 3.
After further survey, indican (4) wasfoundinhigherconcen-
tration in the young leaves than the old leaves of I. indigotica
and as an important precursor for other compounds.8
(9) (a) Young, T. E.; Auld, D. S. J. Org. Chem. 1963, 28, 418. (b)
Chien, C. S.; Takanami, T.; Kawasaki, T.; Sakamoto, M. Chem. Pharm.
Bull. 1985, 33, 1843. (c) Ling, K. Q. Synth. Commun. 1996, 26, 149. (d)
Clawson, R. W., Jr.; Dacko, C. A.; Deavers, R. E., III; Akhmedov,
€
N. G.; Soderberg, B. C. G. Tetrahedron 2009, 65, 8786. (e) Higuchi, K.;
Sato, Y.; Kojima, S.; Tsuchimochi, M.; Sugiura, K.; Hatori, M.;
Kawasaki, T. Tetrahedron 2010, 66, 1236. (f) Rueping, M.; Raja, S.;
ꢀ~
Nunez, A. Adv. Synth. Catal. 2011, 353, 563.
(10) For reviews, see: (a) Selman, S.; Easthan, J. F. Quart. Rev.
Chem. Soc. 1960, 14, 221. (b) Rubin, M. B. Chem. Rev. 1975, 75, 177. (c)
Burke, A. J.; Marques, C. S. Mini-Rev. Org. Chem. 2007, 4, 310. For
recent examples: (d) Rajyaguru, I.; Rzepa, H. S. J. Chem. Soc., Perkin
Trans. 2 1987, 1819. (e) Stoltz, B. M.; Wood, J. L. Tetrahedron Lett.
1996, 37, 3929. (f) Hotchkiss, D. J.;Jenkinson, S. F.;Storer, R.;Heinzc, T.;
Fleet, G. W. J. Tetrahedron Lett. 2006, 47, 315. (g) Marques, C. S.;
Moura, N.; Burke, A. J. Tetrahedron Lett. 2006, 47, 6049. (h) Yamabe, S.;
Tsuchida, N.; Yamazaki, S. J. Org. Chem. 2006, 71, 1777. (i) Umland,
K. D.; Palisse, A.; Haug, T. T.; Kirsch, S. F. Angew. Chem., Int. Ed. 2011,
50, 9965.
(4) (a) Karadeolian, A.; Kerr, M. A. Angew. Chem., Int. Ed. 2010, 49,
1133. (b) Karadeolian, A.; Kerr, M. A. J. Org. Chem. 2010, 75, 6830.
(5) Lee, J.; Panek, J. S. Org. Lett. 2011, 13, 502.
(6) Zhang, X.; Mu, T.; Zhan, F. X.; Ma, L. J.; Liang, G. X. Angew.
Chem., Int. Ed. 2011, 50, 6164.
(7) Watanabe, H.; Nakada, M. J. Am. Chem. Soc. 2008, 130, 1150.
(8) (a) Kokubun, T.; Edmonds, J.; John, P. Phytochemistry 1998, 49,
79. (b) Maugarda, T.; Enauda, E.; Choisyb, P.; Legoya, M. D. Phyto-
chemistry 2001, 58, 897.
Org. Lett., Vol. 14, No. 6, 2012
1625

and efficient synthesis of key intermediate 10 would be
developed. Compounds 11 and 13 could be synthesized
from commercially available indole (12) and triacetyl-
D-glucal (14), respectively.
Scheme 3. Biomimetic Total Synthesis of (ꢀ)-Isatisine A
As shown in Scheme 3, nucleophilic partner 13 was
efficiently synthesized from the known compound 15,11
which was prepared from triacetyl-D-glucal in two steps.
Compound 15 was first protected with BOM to afford 16
in 93% yield. The subsequent hydroboration of enol ether
16 with BH3 and oxidative workup (H2O2, NaOH, 50 °C),
followed by DMP oxidation, afforded compound 13.
Another electrophilic precursor 11 was synthesized from
indole according to the literature reported method.12
With compounds 11 and 13 in hand, we started to
investigate the key coupling reaction. Although compound
11 was highly reactive toward a variety of nucleophiles,12c
the coupling reaction proved to be challenging due to the
steric hindrance. Through extensive reaction screening, we
identified a suitable condition, in which ketone 13 was
treated with LDA for 0.5 h at ꢀ78 °C and then coupled
with electrophilic 11, to provide diketone 10 as a diaster-
eomeric mixture in 75% yield. The two diastereomers of 10
were unstable and could not be separated and purified.
Further treatment of compound 10 with 2 N HCl in
methanol at room temperature smoothly removed the
acetonide protective group and generated 17a and 17b.
By spectroscopic analysis of the two isolated compounds,
we found that the major product isolated was compound
17b in 54% yield along with a 29% yield of compound 17a.
The new formed stereocenters of 17a and 17b were estab-
lished using its NOE experiment and the experimental and
computational optical rotation data.13
Based on Kerr’s report,4b the configuration of C2 in
compound 17b tends to isomerize to give the configuration
of C2 in 17a when the Tos was removed. In order to
support this assumption, we first use compound 17b as a
substrate for the next steps. Hydrogenation of 17b in the
presence of Pd(OH)2 provided the corresponding triol
18b.14 18b was unstable, which was used without further
purification and converted to 20b in moderate yield with
excellent chemo- and diastereoselectivity through CuCl-
mediated tandem biomimetic oxidation and benzilic ester
rearrangement.10 Due to the lability of compound 20b,
neutral conditions for deprotection were required. After
screening several reaction conditions, we found that
photoinduced deprotection of the Tos group afforded
the desired compound 21b in 46% yield.15 Ultimately,
treating compound 21b with CSA in CH2Cl2 at room
temperature furnished 3. The spectral data of synthetic
(ꢀ)-isatisine A (3) (1H, 13C NMR, IR, and HRMS) are
consistent with those of the natural product.3 (ꢀ)-Isatisine
A (3) was also synthesized from compound 17a following
the same procedure in 16% yield.16 Thus the separation of
compound 17a and 17b was unnecessary. Compound 3
was obtained from the mixture of 17a and 17b in 18% yield
by using the same procedure.
In summary, the biogenetic synthetic pathway toward
(ꢀ)-isatisine A has been proposed. Based on the biogenetic
pathway, the biomimetic total synthesis of (ꢀ)-isatisine
A has been accomplished in 8 steps from 4,6-O-isopropy-
lidene-protected glucal 15 in an overall yield of 8.6%.
Our synthetic strategy relies on a nucleophilic addition and
an unprecedented biomimetic benzilic ester rearrangement as
€
(11) Dotz, K. H.; Otto, F.; Nieger, M. J. Organomet. Chem. 2001,
621, 77.
(12) (a) Astolfi, P.; Panagiotaki, M.; Rizzoli, C.; Greci, L. Org.
Biomol. Chem. 2006, 4, 3283. (b) Ottoni, O.; Cruz, R.; Alves, R.
Tetrahedron 1998, 54, 13915. (c) Li, L. Q.; Han, M. Y.; Xiao, M. X.;
Xie, Z. X. Synlett. 2011, 12, 1727.
(13) See the Supporting Information.
(14) Hirai, G.; Watanabe, M.; Yamaguchi, K.; Miyagi, T.; Sodeoka,
M. J. Am. Chem. Soc. 2007, 129, 15420.
(15) (a) Li, Y. Z.; Zou, H. X.; Gong, J. X.; Xiang, J.; Luo, T. P.; Quan,
J. M.; Wang, G. X.; Yang, Z. Org. Lett. 2007, 9, 4057. (b) Reed, D. D.;
Bergmeier, S. C. J. Org. Chem. 2007, 72, 1024.
(16) See the Supporting Information.
1626
Org. Lett., Vol. 14, No. 6, 2012

key steps. The synthesis and biological investigation of
isatisine A analogues are currently underway and will be
reported in due course.
sincerely thank Prof. Xiaojun Yao (Lanzhou University)
for the absolute configuration of 17a and 17b established and
Dr. Wei Yu (Lanzhou University) for helpful discussions.
Supporting Information Available. Experimental pro-
cedures and NMR spectral data for all new compounds
prepared. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. This workis financially supported by
973 Program (Grant 2010CB833203), the National Nat-
ural Science Foundation of China (Grant Nos. 20772050
and 21072083), and the Fundamental Research Funds for
the Central Universities (Grant No. lzujbky-2009-75). We
The authors declare no competing financial interest.
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