Catalytic asymmetric total synthesis of tangutorine

Article abstract of DOI:10.1021/ol902929a

(Figure Presented) The first enantioselective total synthesis of tangutorine has been achieved, wherein a Pd-catalyzed asymmetric allylic amination using a chiral diaminophosphine oxide (DIAPHOX) preligand was the key step.

Full text of DOI:10.1021/ol902929a

ORGANIC
LETTERS
2010
Vol. 12, No. 4
872-875
Catalytic Asymmetric Total Synthesis of
Tangutorine
Tetsuhiro Nemoto, Eri Yamamoto, Robert Franze´n, Takashi Fukuyama, Riliga Wu,
Toshihiko Fukamachi, Hiroshi Kobayashi, and Yasumasa Hamada*
Graduate School of Pharmaceutical Sciences, Chiba UniVersity, 1-33, Yayoi-cho,
Inage-ku, Chiba 263-8522, Japan
hamada@p.chiba-u.ac.jp
Received December 21, 2009
ABSTRACT
The first enantioselective total synthesis of tangutorine has been achieved, wherein a Pd-catalyzed asymmetric allylic amination using a chiral
diaminophosphine oxide (DIAPHOX) preligand was the key step.
In 1999, Che and co-workers reported the isolation of a novel
ꢀ-carboline alkaloid, tangutorine (1), from the leaves of the
Chinese medicinal plant Nitraria tangutorum.1 Tangutorine
is the only known natural product that possesses a benz[f]in-
dolo[2,3-a]quinolizidine skeleton. It is noteworthy that this
alkaloid naturally occurs as a racemate, despite the presence
of three chiral centers in the quinolizidine moiety. Recent
studies revealed that tangutorine exhibits cytotoxic activity
against human colon cancer HT-29 cells.2 This bioactivity
originates from the induction of cyclin kinase inhibitor p21
and the inhibition of topoisomerase II expression. These
structural and biological profiles make tangutorine an at-
tractive target for synthetic organic chemists. So far, total
syntheses of racemic tangutorine have been reported by
Jokela et al.,3 Hsung et al.,4 Ho et al.,5 and Poupon et al.6 A
formal synthesis7 and synthetic approaches8 have also been
reported. There are no reports, however, of an asymmetric
total synthesis of tangutorine.9 This background led us to
focus our attention on enantioselective synthesis of tangu-
torine and evaluation of its cytotoxic activity using optically
pure tangutorine. Herein, we report the first enantioselective
total synthesis of tangutorine, wherein a Pd-catalyzed asym-
metric allylic amination using a chiral diaminophosphine
oxide (DIAPHOX) preligand was the key step. The cytotoxic
activity of each enantiomer was also evaluated.
The plan for the enantioselective synthesis of tangutorine
is shown in Scheme 1. Our retrosynthetic disconnection
began with compound 2, which was utilized as the key
intermediate in previous racemic syntheses.4,5 Control of the
stereochemical arrangement on the piperidine ring is a
challenging task in this synthesis. We envisioned that an
(1) Duan, J.-A.; Williams, I. D.; Che, C.-T.; Zhou, R.-H.; Zhao, S.-X.
Tetrahedron Lett. 1999, 40, 2593–2596.
(2) Liu, B. P. L.; Chong, E. Y. Y.; Cheung, F. W. K.; Duan, J.-A.; Che,
C.-T.; Liu, W. K. Biochem. Pharmacol. 2005, 70, 287–299.
(3) (a) Putkonen, T.; Tolvanen, A.; Jokela, R. Tetrahedron Lett. 2001,
42, 6593–6594. (b) Putkonen, T.; Tolvanen, A.; Jokela, R.; Caccamese, S.;
Parrinello, N. Tetrahedron 2003, 59, 8589–8595.
(6) Salame, R.; Gravel, E.; Leblanc, K.; Poupon, E. Org. Lett. 2009,
11, 1891–1894.
(7) Luo, S.; Zhao, J.; Zhai, H. J. Org. Chem. 2004, 69, 4548–4550.
(8) Wilkinson, J. A.; Ardes-Guisot, N.; Ducki, S.; Leonard, J. Tetra-
hedron Lett. 2005, 46, 8053–8056.
(4) Luo, S.; Zificsak, C. A.; Hsung, R. P. Org. Lett. 2003, 5, 4709–
4712.
(9) Optical resolution studies of racemic tangutorine using chiral HPLC
have been reported (ref 3b). The reported optical rotations of each
enantiomer, however, imply the difficulty of effective resolution.
(5) Ho, T.-L.; Chen, C.-K. HelV. Chim. Acta 2006, 89, 122–126.
10.1021/ol902929a  2010 American Chemical Society
Published on Web 01/21/2010

responding chiral amine 5 in 99% yield with 95% ee. The
absolute configuration of 5 was determined to be S by
comparing the optical rotation with that of an authentic
sample prepared from the known N-benzyl derivative.16
Protection of the secondary amine with a 2-nitrobenzene-
sulfonyl (Ns) group, followed by reduction of the R,ꢀ-
unsaturated ester with diisobutylaluminum hydride (DIBALH),
proceeded smoothly to provide the corresponding allylic
alcohol 9 in 87% yield (two steps). The following Sharpless
asymmetric epoxidation of enantiomerically enriched 9 (95%
ee) was performed in the presence of 10 mol % of Ti(Oi-
Pr)4, 10 mol % of (+)-diisopropyl tartrate, 2 equiv of tert-
butyl hydroperoxide, and MS 4 Å at 4 °C, giving the
corresponding epoxy alcohol 10 with the R-epoxide in 94%
yield with a high diastereomeric ratio. Enantiomeric excess
of the major isomer was determined by chiral HPLC analysis
(99% ee).
Scheme 1. Synthetic Plan for the Asymmetric Synthesis of 1
With nearly optically pure epoxy alcohol in hand, we next
tried to establish an efficient synthetic route to a substrate
for the intramolecular Pictet-Spengler reaction (Scheme 3).
Although the regioselective epoxide opening reaction of
epoxy alcohol 10 was first examined under several reaction
conditions, the desired product with three contiguous chiral
centers could not be obtained, probably due to the severe
steric hindrance around the quaternary carbon. We thus
attempted to perform this pivotal transformation at a more
advanced stage. After detailed examination, the following
three-step sequence was found to be an efficient method of
synthesizing the functionalized cyclohexane ring with the
requisite stereochemistry. Dess-Martin oxidation of the
alcohol, followed by treatment of the resulting aldehyde with
a Wittig reagent, afforded R,ꢀ-unsaturated ester 11 in 94%
yield over two steps. Subsequent reductive epoxide opening
intramolecular Pictet-Spengler reaction of amino acetal 3
would be applicable to construct the quinolizidine moiety.
The present reaction would preferentially provide the con-
figurationally more stable diastereomer, in which all sub-
stituents on the piperidine ring are in the equatorial positions.
Compound 3, bearing three contiguous chiral centers on the
cyclohexane ring, would be prepared from epoxy alcohol 4
using an epoxide opening reaction with a hydride nucleo-
phile, which, in turn, would be obtained by catalytic
asymmetric epoxidation.10 Finally, compound 5, a reasonable
precursor of the chiral epoxy alcohol, would be prepared
via asymmetric allylic amination of 6 with Nin-Boc-
tryptamine (7) using the Pd-DIAPHOX catalyst system that
was recently developed in our laboratory.11,12
(10) For reviews on catalytic asymmetric epoxidation, see: (a) Katsuki,
T.; Martin, V. S. Org. React. 1996, 48, 1–299. (b) Johnson, R. A.; Sharpless,
K. B. Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH:
Weinheim, 2000; pp 231-280.
Our synthesis began with a Pd-catalyzed asymmetric
allylic amination of readily available cyclic allylic carbon-
ate 613 with 7 (Scheme 2).11a,14,15 Using 1 mol % of [η3-
(11) (a) Nemoto, T.; Fukuyama, T.; Yamamoto, E.; Tamura, S.; Fukuda,
T.; Matsumoto, T.; Akimoto, Y.; Hamada, Y. Org. Lett. 2007, 9, 927–930.
See also: (b) Nemoto, T.; Masuda, T.; Akimoto, Y.; Fukuyama, T.; Hamada,
Y. Org. Lett. 2005, 7, 4447–4450. (c) Nemoto, T.; Tamura, S.; Sakamoto,
T.; Hamada, Y. Tetrahedron: Asymmetry 2008, 19, 1751–1759.
(12) For reviews on transition-metal-catalyzed asymmetric reactions
using chiral diaminophosphine oxides and related pentavalent phosphorus
compounds, see: (a) Dubrovina, N. V.; Bo¨rner, A. Angew. Chem., Int. Ed.
2004, 43, 5883–5886. (b) Ackermann, L. Synthesis 2006, 1557–1571. (c)
Nemoto, T.; Hamada, Y. Chem. Rec. 2007, 7, 150–158. (d) Nemoto, T.
Chem. Pharm. Bull. 2008, 56, 1213–1228.
Scheme 2. Catalytic Asymmetric Approach to Optically Pure 10
(13) The corresponding allylic alcohol can be prepared from glutaral-
dehyde and trimethyl phosphonoacetate in a single-step reaction. See: Graff,
M.; Al Dilaimi, A.; Seguineau, P.; Rambaud, M.; Villieras, J. Tetrahedron
Lett. 1986, 27, 1577–1578.
(14) For examples of Pd-catalyzed asymmetric allylic substitutions of
ester-conjugated cycloalkenyl alcohol derivatives, see: (a) Trost, B. M.;
Oslob, J. D. J. Am. Chem. Soc. 1999, 121, 3057–3064. (b) Mori, M.;
Nakanishi, D.; Kajishima, D.; Sato, Y. J. Am. Chem. Soc. 2003, 125, 9801–
9807. (c) Trost, B. M.; Machacek, M. R.; Tsui, H. C. J. Am. Chem. Soc.
2005, 127, 7014–7024. (d) Trost, B. M.; Tang, W.; Toste, F. D. J. Am.
Chem. Soc. 2005, 127, 14875–14803. (e) Trost, B. M.; Malhotra, S.; Olson,
D. E.; Maruniak, A.; Du Bois, J. J. Am. Chem. Soc. 2009, 131, 4190–
4191.
(15) For reviews on Pd-catalyzed asymmetric allylic substitution, see:
(a) Trost, B. M. Chem. Pharm. Bull. 2002, 50, 1–14. (b) Trost, B. M.;
Crawley, M. L. Chem. ReV. 2003, 103, 2921–2943. (c) Lu, Z.; Ma, S. Angew.
Chem., Int. Ed. 2008, 47, 258–297.
C3H5PdCl]2, 4 mol % of (S,RP)-DIAPHOX 8, and N,O-
bis(trimethylsilyl)acetamide (BSA), asymmetric allylic
amination proceeded smoothly at -30 °C, providing the cor-
(16) For the determination of the absolute configuration of 5 and other
discussions, see the Supporting Information.
Org. Lett., Vol. 12, No. 4, 2010
873

Scheme 3. Construction of the Pentacyclic Skeleton
reaction via a π-allyl palladium intermediate proceeded in
the presence of 5 mol % of Pd(PPh3)4, providing alcohol 12
in 98% yield in a highly diastereoselective manner.17
Conversion of R,ꢀ-unsaturated ester 12 to aldehyde 13 was
achieved by a two-step process involving DIBALH reduction,
followed by MnO2 oxidation (90% yield, two steps). After
transformation of the aldehyde moiety into dimethyl acetal,
the Ns group was deprotected with thiophenol to give
compound 14 in 94% yield over two steps. The following
hydrogenation of an olefin, as well as protection of the
secondary alcohol with a TBS group, proceeded smoothly
to provide compound 15 in 90% yield over two steps. Finally,
deprotection of the Boc group was performed under basic
conditions, affording amino acetal 16 in 94% yield.
We then examined the construction of the pentacyclic
skeleton through the intramolecular Pictet-Spengler reac-
tion.18 Initial screening revealed that the reaction proceeded
smoothly using trifluoroacetic acid (TFA) as a promoter in
a CH3CN-H2O solvent system (50% aq TFA/CH3CN )
1/5), although undesired isomer 17b was obtained as a major
product (24 h, 100% conversion, 17a/17b ) 9/91). There
was a gradual increase in the product ratio until the
proportion of 50% aq TFA to CH3CN decreased to 1:60 (24
h, 89% conversion, 17a/17b ) 52/37). Encouraged by this
result, we investigated the effect of an acid promoter in detail.
All trials, however, gave less satisfactory results. After all,
the intramolecular Pictet-Spengler reaction of 16 proceeded
to completion in 48 h under the aforementioned conditions
(50% aq TFA/CH3CN ) 1/60) to afford 17a and 17b in 55%
and 39% isolated yield, respectively.19
of the intramolecular Pictet-Spengler reaction was kineti-
cally controlled. On the other hand, we were pleased to find
that the C-3 epimerization of 17b proceeded under harsher
reaction conditions. When 17b was refluxed in a 4 N HCl/
dioxane-H2O solvent system for 18 h, both deprotection of
the TBS group and epimerization of the C-3 stereocenter
occurred simultaneously, affording 18b and 18a in 38% yield
and 40% yield, respectively.21 Compound 18a was trans-
formed into 17a in 95% yield. In addition, C-3 epimerization
of isolated 18b proceeded under the same conditions to
provide a mixture of 18a and 18b (18a:18b ) 45:55,
1
determined by H NMR analysis of the crude sample),
revealing an efficient recycling process for 17b.
The final stage of the asymmetric synthesis is outlined in
Scheme 4. Protection of the nitrogen on the indole ring of
Scheme 4. Enantioselective Total Synthesis of 1
Thermodynamically controlled C-3 epimerization of in-
dolo[2,3-a]quinolizidines proceeds under acidic conditions.20
There was no interconversion, however, between 17a and
17b in the presence of TFA, indicating that the product ratio
17a with a Boc group, followed by deprotection of the TBS
group using the HF·pyridine complex, afforded compound
19 in 95% yield over two steps. Subsequent oxidation of
the resulting hydroxyl group with Dess-Martin reagent gave
the known synthetic intermediate (-)-2 in 84% yield. The
enantiomeric excess of (-)-2, determined by chiral HPLC
(17) (a) Oshima, M.; Yamazaki, H.; Shimizu, I.; Nisar, M.; Tsuji, J.
J. Am. Chem. Soc. 1989, 111, 6280–6287. (b) David, H.; Dupuis, L.;
Guillerez, M.-G.; Guibe´, F. Tetrahedron Lett. 2000, 41, 3335–3338.
(18) For a review on the Pictet-Spengler reaction, see: Cox, E. D.; Cook,
J. M. Chem. ReV. 1995, 95, 1797–1842.
(19) For detailed data of the intramolecular Pictet-Spengler reaction,
see the Supporting Information.
874
Org. Lett., Vol. 12, No. 4, 2010

analysis (99% ee), indicated that no erosion of enantiomeric
purity had occurred over the course of the transformations.
Transformation of the known intermediate 2 into tangu-
torine was performed using the mixed enol acetalization
protocol.22 Introduction of a C1 unit on the R-position to
the ketone was achieved by the formation of an enolate with
KH at 0 °C, followed by the addition of ethyl formate. As
a result, enol 20 with a Z geometry was obtained in 78%
yield. After protection of the enol with an ethoxyethyl (EE)
group (89% yield), the resulting product was reduced with
NaBH4 to give alcohol 21 in a highly stereoselective manner.
The coupling constant of the newly introduced hydrogen in
In conclusion, we achieved the first enantioselective total
synthesis of tangutorine with a 15.8% overall yield in 24
steps.26 The three chiral centers were constructed by asym-
metric allylic amination using the Pd-DIAPHOX catalyst
system, catalytic asymmetric epoxidation, and a diastereo-
selective intramolecular Pictet-Spengler reaction. This
synthetic method will provide access to a variety of
compounds with the rare pentacyclic skeleton in an optically
active form, which should be an attractive resource for
medicinal chemistry. Moreover, the present enantioselective
synthesis clarified the cytotoxic activity of optically pure
tangutorine. This novel information will provide a useful
guideline for studies of the structure-activity relationship
of tangutorine. Further investigations into the biological
activity of tangutorine, as well as its structural analogues,
are in progress.
1
the H NMR spectrum (J ) 7.2 Hz) revealed that the
hydroxyl group was in the axial position. The obtained crude
residue was treated with PPTS without purification, affording
the R,ꢀ-unsaturated aldehyde 22 in 95% yield over two
steps.23 Finally, reduction of the R,ꢀ-unsaturated aldehyde
with DIBALH, followed by deprotection of the Boc group
on the indole, afforded tangutorine (-)-1 in 86% yield over
two steps ([R]D21 -99.1 [c 0.23, DMF]) (57% overall yield
in six steps from 2).24 The NMR data (1H NMR and 13C
NMR) were identical to the reported data for 1, and
enantiomeric excess of (-)-1 was unequivocally determined
by chiral HPLC analysis (99% ee). On the basis of the present
synthetic method, (+)-1 (99% ee) was also prepared using
the Pd-(R,SP)-DIAPHOX catalyst system.
Acknowledgment. This work was supported by Grant-in
Aid for Encouragement of Young Scientists (B), Grant-in
Aid for Scientific Resarch on Priority Areas, Chemistry of
Concert Catalysis, from the Ministry of Education, Culture,
Sports, Science, and Technology, Japan. Prof. R. Franze´n
(Tampere University of Technology, Finland) thanks JSPS
invitation fellowship programs for research in Japan.
Supporting Information Available: Experimental pro-
cedures, supplementary data, compound characterization, and
NMR charts. This material is available free of charge via
the Internet at http://pubs.acs.org.
Cytotoxic activity against HT-29 cells was evaluated using
optically pure (-)-1, (+)-1, and racemic 1 (Figure 1). The
OL902929A
(20) (a) Lounasmaa, M.; Berner, M.; Tolvanen, A. Heterocycles 1998,
48, 1275–1290. (b) Berner, M.; Tolvanen, A.; Jokela, R. Tetrahedron Lett.
1999, 40, 7119–7122.
(21) The product ratio of 18a and 18b, determined by 1H NMR analysis
of the crude sample, was 45:55. Prolonging the reaction time (30 h) did
not affect the product ratio. Enantiomeric excess of 18a was determined
by chiral HPLC analysis (99% ee) after converting into compound 2.
(22) (a) Kawanobe, T.; Iwamoto, M.; Kogami, K.; Matsui, M. Agric.
Biol. Chem. 1987, 51, 791–796. (b) Zhang, F.; Danishefsky, S. J. Angew.
Chem., Int. Ed. 2002, 41, 1434–1437. (c) Watanabe, K.; Iwasaki, K.; Abe,
T.; Inoue, M.; Ohkubo, K.; Suzuki, T.; Katoh, T. Org. Lett. 2005, 7, 3745–
3748.
(23) It is assumed that transformation of 21 into 22 was initiated by
protonation of the hydroxyl group with PPTS. The molecular conformation,
in which the hydroxyl group is in the axial position, likely facilitates this
reaction.
Figure 1. Cytotoxic activity of (-)-1, (+)-1, and (()-1. HT-29
cells were incubated with (-)-1, (+)-1, or (()-1 for 48 h at the
concentrations of 6.25, 12.5, 25, 50, 100, and 200 µg/mL. The
absorbance without cell was taken as 100%. Means for three
independent measurements are represented.
(24) This overall yield is superior to those of the previous synthesis
(refs 4 and 5). Hsung’s method: 46% overall yield. Ho’s method: 23%
overall yield.
(25) See Supporting Information for details. The racemic sample was
prepared using Ho’s method.
(26) The effect of recycling 17b into 17a is not taken into account to
calculate the overall yield.
cells were incubated with serial dilutions of tangutorine (6.25
to 200 µg/mL) for 48 h and then subjected to WST assay.25
Although a dose-dependent increase in cell death was
observed in each sample, cytotoxic activity did not signifi-
cantly differ between the enantiomers.
Org. Lett., Vol. 12, No. 4, 2010
875