Total synthesis of (+)-isatisine A

Article abstract of DOI:10.1021/ol102848w

Total synthesis of (+)-isatisine A is described based on the application of a silyl-directed Mukaiyama-type [3 + 2]-annulation for the preparation of a fully substituted furan core. The indole branch forming the quaternary carbon center at C2 was construc

Full text of DOI:10.1021/ol102848w

ORGANIC
LETTERS
2011
Vol. 13, No. 3
502-505
Total Synthesis of (+)-Isatisine A
Jihoon Lee and James S. Panek*
Department of Chemistry and Center for Chemical Methodology and Library
DeVelopment, Metcalf Center for Science and Engineering, Boston UniVersity 590
Commonwealth AVenue, Boston, Massachusetts 02215, United States
panek@bu.edu
Received November 24, 2010
ABSTRACT
Total synthesis of (+)-isatisine A is described based on the application of a silyl-directed Mukaiyama-type [3 + 2]-annulation for the preparation
of a fully substituted furan core. The indole branch forming the quaternary carbon center at C2 was constructed by addition to an intermediate
N-acyliminium ion derived from aminal 4. In addition, the fused tetracyclic framework including furan core was built up using modified Buchwald
amidation conditions.
The roots and leaves of Isatis indigotica Fort. (Cruciferae), a
plant species widely cultivated in China and East Asia, have
been traditionally used for treatment of viral diseases such as
influenza, viral pneumonia, mumps, and hepatitis. In 2007, Chen
and co-workers reported isolation of isatisine A (1), which was
the only alkaloid among 12 compounds isolated from I.
Indigotica.1 Initially, it was isolated as its acetonide derivative
2, and the structure elucidation was established by 1D and 2D
NMR experiments, then subsequent X-ray crystallographic
analysis secured the structure assignment, as well as the relative
and absolute stereochemistries. Biological evaluation of the
acetonide derivative 2 reveals that this material exhibits cyto-
toxicity against C8166 with CC50 ) 302 µM and anti-HIV
activity of EC50 ) 37.8 µM. However, its unusual dioxolane
group which is rarely found in natural products led to further
investigations to determine whether the acetonide derivative 2
was an artifact formed during the isolation processes using
acetone as an eluent, which lead to the natural product, isatisine
A (1). Recently, the first total synthesis, achieved by Kerr
revealed that the assignment of absolute configuration originally
provided by Chen’s group is antipodal to the natural product.2
Figure 1. Revised structure of isatisine A (1) and original proposed
structure of its acetionide 2.
The challenging structural features of isatisine A (1)
include a fused tetracyclic framework containing a densely
substituted furan subunit and two fully substituted carbon
centers (C2 and C9) embedded in the core. In addition, an
indole branch forms the C-2 quarternary carbon center. Our
interest in this alkaloid arose from its challenging tetracyclic
skeleton, as well as its potent anti-HIV activity, and a
successful approach to developing an efficient synthetic
(2) (a) Karadeolian, A.; Kerr, M. A. Angew. Chem., Int. Ed. 2010, 49,
1133–1135. (b) Karadeolian, A.; Kerr, M. A. J. Org. Chem. 2010, 75, 6830–
6841.
(1) 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, 4127–4129.
10.1021/ol102848w  2011 American Chemical Society
Published on Web 12/28/2010

strategy would allow further SAR (structure-activity rela-
tionship) and SSAR (stereostructure activity relationship)
studies.
stereochemically well-defined and highly functionalized
furans. In this regard, use of the allyl silanes 7,5 prepared
from the known epoxy-silanes6 in two steps, as a reaction
partner afforded silyl-substituted furans with an aryl and
aliphatic aldehyde (eqs 1 and 2 in Figure 2). The annulations
Scheme 1. Retrosynthetic Analysis of (+)-Isatisine A (1)
Figure 2. Asymmetric Mukaiyama-type [3 + 2]-annulation of anti-
and syn-ethoxy allyl silane 7.
took place with high levels of selectivity, which illustrates
that the configuration of the C-SiR3 bond functions as a
reliable stereocontrol element during the reaction. In this
synthesis, we describe examples of a silyl-directed [3 +
2]-annulation and how it’s used in the synthesis of a complex
natural product.
Our synthesis began with the preparation of tetra-
substituted furan 6e through [3 + 2]-annulation of silane
anti-7 with 2-bromocinnamyl aldehyde 8 (Scheme 2). Thus,
using 2.0 equiv of aldehyde 87 in the presence p-TSA (1.0
equiv) at 0 °C afforded desired furan 6e in 87% yield with
high dr (>20:1). Selective R-bromination in the presence of
the conjugated olefin was achieved using PTAB (phenyl-
trimethylammonium tribromide),8 that material was directly
treated with TBAF at 0 °C to form an R,ꢀ-unsaturated
aldehyde. This resulting unstable intermediate unsaturated
aldehyde was immediately subjected to oxidation with MnO2
in the presence of NaCN to afford the R,ꢀ-unsaturated methyl
ester 9 in 57% yield from tetrahydrofuran 6e.9
The styrene-like olefin of 9 was selectively oxygenated
by a catalytic OsO4 dihydroxylation using 1.0 equiv of NMO,
which afforded diol 10 as a 1.5:1 mixture of diastereomers.
Formation of the undesired diol was not detected by
spectroscopic methods. Conversion of the mixture of diols
to a cyclic carbonate and subsequent dihydroxylation of R,ꢀ-
unsaturated ester 11 still gave 1.5:1 mixture of diasteromers,
In our synthetic plan described in Scheme 1, we intended
to apply a Mukaiyama-type [3 + 2]-annulation of silane
anti-7 with a suitably functionalized aldehyde to construct
tetrahydrofuran core. Subsequent use of a CuI-mediated aryl
amidation3 would assemble the tetracyclic skeleton of
isatisine A. Accordingly, our retrosynthetic plan began with
disconnection of C7a-N to afford an advanced intermediate
aryl bromide 3. Further disconnection occurred at the indole
side chain C2-C3′, which led to an indole and aminal 4.
This intermediate aminal would spontaneously form in the
course of oxidation of the amido-diol. Disconnection between
the amide nitrogen N1 and C2 led to protected furan 5, which
possesses the required oxidation state to access the aminal
4. The tetrahydrofuran intermediate 6e would be constructed
from silyl-directed Mukaiyama-type [3 + 2]-annulation of
silane anti-7 with bromocinnamyl aldehyde 8.
Mukaiyama [3 + 2]-annulation strategy to construct
functionalized furans was initially developed by Hoppe.4 In
that context, we have learned that enantioenriched silane
reagents bearing C-centered chirality can participate in
stereoselective [3 + 2]-annulation sequence resulting in
(5) For the preparation of syn and anti-ethoxy allyl silane 7, see the
Supporting Information.
(3) (a) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am.
Chem. Soc. 2001, 123, 7727–7729. (b) Klapars, A.; Huang, X.; Buchwald,
S. L. J. Am. Chem. Soc. 2002, 124, 7421–7428.
(6) Lowe, J. T.; Youngsaye, W.; Panek, J. S. J. Org. Chem. 2006, 71,
3639–3642.
(4) (a) Hoppe, D.; Kramer, T.; Erdbriigger, C. F.; Egert, E. Tetrahedron
Lett. 1989, 30, 1233–1236. (b) Bru¨ns, A.; Wibbeling, B.; Fro¨hlich, R.;
Hoppe, D. Synthesis 2006, 3111–3121. (c) Kollmann, S.; Fro¨hlich, R.;
Hoppe, D. Synthesis 2007, 883–892. (d) Becker, J.; Fro¨hlich, R.; Salorinne,
K.; Hoppe, D. Eur. J. Org. Chem. 2007, 3337–3348.
(7) Kim, J. H.; Lee, S.; Kwon, M.-G.; Park, Y. S.; Choi, S.-K.; Kwon,
B.-M. Synth. Commun. 2004, 34, 1223–1228.
(8) Ager, D. J.; Fleming, I.; Patel, S. K. J. Chem. Soc., Perkin Trans 1
1981, 2520–2526.
(9) Corey, E. J.; Posner, G. H. J. Am. Chem. Soc. 1968, 90, 5616–5617.
Org. Lett., Vol. 13, No. 3, 2011
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Scheme 2
.
Preparation of Intermediate 5
Scheme 3. Completion of Synthesis of (+)-Isatisine A (1)
(In(OTf)3, BF3·OEt2, CSA, and p-TSA). However, addition
to hydroxyl-lactam 4 failed to afford the desired adduct. In
order to convert the aminal into a better leaving group, a
mesylate was generated in situ by treatment of 4 with MsCl
(1.2 equiv) at 0 °C, and subsequent addition of a solution of
indole (5.0 equiv) in CH2Cl2 gave the desired indole adduct
3 in 54% yield as a single diastereomer. Optimal conversion
was acquired upon using TFAA instead of MsCl, which
afforded 3 in 82% yield as a single stereoisomer. The
stereochemistry and absolute configuration of the indole
branched quarternary carbon center of 3 was confirmed by
single crystal X-ray crystallographic analysis (Figure 3).
which means this second dihydroxylation proceeded in a fully
stereoselective manner. Subsequent acetonide protection of
the resulting diol afforded an intermediate 5 in 67% yield
(3 steps) from diol 10. The relative configuration of bicyclic
dioxolane 5 was confirmed by NOE measurement after
separation of the two diastereomers.10
Removal of carbonate of 5 under basic conditions also
resulted in the cleavage of the methyl ester to form an
intermediate dihydroxy acid which is spontaneously latonized
in CHCl3 to give bicyclic lactone 12 (Scheme 3). Treatment
of this material with anhydrous NH3 solution in MeOH
provided an intermediate amide, which was subjected to
oxidation with TEMPO and NaOCl at room temperature.11
As we anticipated, the oxidation of the dihydroxy amide
spontaneously cyclized to afford a key intermediate aminal
4 as a single diastereomer.
With availibity of intermediate hydroxyl-lactam 4, we
turned our attention to the stereoselective indole incorpora-
tion. This type of addition is typically carried out under acidic
conditions and presumably proceeds through the formation
and trapping of an acyl iminium ion.12 In this case, it was
expected that the indole would approach the iminium ion
from the less hindered convex face of the bicycle. In our
evaluation of this reaction, indole addition was initially
conducted under Lewis and Bro¨nsted acidic conditions
Figure 3. X-ray structure of the indole adduct 3.
(10) For the spectroscopic anlysis, see the Supporting Information.
(11) (a) Slee, D. H.; Romano, S. J.; Yu, J.; Nguyen, T. N.; John, J. K.;
Raheja, N. K.; Axe, F. U.; Jones, T. K.; Ripka, W. C. J. Med. Chem. 2001,
44, 2094–2107. (b) Tron, G. C.; Pagliai, F.; Grosso, E. D.; Genazzani, A. A.;
Sorba, G. J. Med. Chem. 2005, 48, 3260–3268.
A modified Buchwald intramolecular amidation in the
presence of CuI was used to assemble the fused tetracylclic
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Org. Lett., Vol. 13, No. 3, 2011

framework. This type of amidation has been studied and used
previously by us as a strategy for macrocyclization.13 In the
present case, the advanced tetracyclic intermediate 13 was
successfully generated through CuI-mediated coupling in
90% yield. Subsequent cleavage of the primary methyl
ether14 and acetonide with excess BBr3 (9.0 equiv, added in
three portions) in the presence of 15-crown-5 and NaI (3.0
equiv) provided (+)-isatisine A (1) in 80% yield.
In conclusion, a total synthesis of (+)-isatisine A has been
achieved in 13 steps with a 6.9% overall yield starting from
allyl silane anti-7. A key element of our synthesis includes
the formation of highly substituted tetrahydrofuran using a
silyl-directed Mukaiyama-type [3 + 2]-annulation strategy.
In addition, construction of nitrogen-containing tetracyclic
skeleton through CuI-mediated amidation demonstrated that
this method can be useful for fused polycyclic systems in
complex molecule synthesis. Further studies and applications
of stereoselective [3 + 2]-annuation are currently underway.
Acknowledgment. Financial support was obtained from
NIH CA 53604. We are grateful to Dr. Paul Ralifo, Dr.
Norman Lee, and Dr. Jeffrey Bacon (Chemical Instrumenta-
tion Center at Boston University) for helpful discussions and
assistance with NMR, HRMS, and X-ray crystallographic
analysis experiments.
Note Added after ASAP Publication. Figure 2 contained
errors in the version published ASAP December 28, 2010;
the correct version reposted December 31, 2010.
(12) (a) Skarpos, H.; Vorob’eva, D. V.; Osipov, S. N.; Odinets, I. L.;
Breuer, E.; Ro¨schenthaler, G.-V. Org. Biomol. Chem. 2006, 4, 3669–3674.
(b) Abid, M.; Teixeira, L.; To¨ro¨k, B. Org. Lett. 2008, 10, 933–935. (c)
Higuchi, K.; Sato, Y.; Tsuchimochi, M.; Sugiura, K.; Hatori, M.; Kawasaki,
T. Org. Lett. 2009, 11, 197–199.
Supporting Information Available: Experimental details
and selected spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(13) (a) Wrona, I. E.; Gabarda, A. E.; Evano, G.; Panek, J. S. J. Am.
Chem. Soc. 2005, 127, 15026–1502. (b) Qin, H.-L.; Panek, J. S. Org. Lett.
2008, 10, 2477–2479.
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4239–4240. (b) Su, Q.; Panek, J. S. J. Am. Chem. Soc. 2004, 126, 2425–
2430.
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