Novel supramolecular palladium catalyst for the asymmetric reduction of imines in aqueous media

Article abstract of DOI:10.1021/ol9011772

A novel approach to the asymmetric reduction of dihydro-β-carboline derivatives to the corresponding tetrahydro-β-carbolines is described based on the supramolecular lyophilized complex formed from β-cyclodextrin/ imines as an enzyme mimetic and palladium hydride as the reducing agent. The methodology allowed us to develop a short and efficient preparation of (R)-harmicine and (R)-deplancheine alkaloids in high overall yields and ee of 89 and 90%, respectively.

Full text of DOI:10.1021/ol9011772

ORGANIC
LETTERS
2009
Vol. 11, No. 15
3238-3241
Novel Supramolecular Palladium
Catalyst for the Asymmetric Reduction
of Imines in Aqueous Media
Wender A. da Silva,†,‡ Manoel T. Rodrigues, Jr.,§ N. Shankaraiah,†
Renan B. Ferreira,§ Carlos Kleber Z. Andrade,‡ Ronaldo A. Pilli,*,§
and Leonardo S. Santos*,†
Laboratory of Asymmetric Synthesis, Chemistry Institute of Natural Resources,
UniVersidad de Talca, Talca, PO Box 747, Talca, Chile, Institute of Chemistry,
UniVersidade de Bras´ılia, UnB, Bras´ılia, Brazil, and Institute of Chemistry,
UniVersidade Estadual de Campinas, UNICAMP, Campinas, Brazil
pilli@iqm.unicamp.br; lssantos@utalca.cl
Received May 27, 2009
ABSTRACT
A novel approach to the asymmetric reduction of dihydro-ꢀ-carboline derivatives to the corresponding tetrahydro-ꢀ-carbolines is described
based on the supramolecular lyophilized complex formed from ꢀ-cyclodextrin/imines as an enzyme mimetic and palladium hydride as the
reducing agent. The methodology allowed us to develop a short and efficient preparation of (R)-harmicine and (R)-deplancheine alkaloids in
high overall yields and ee of 89 and 90%, respectively.
Drug chirality is now a major theme in the design, discovery,
development, launching and marketing of new drugs and
stereochemistry is an essential dimension in pharmacology.
In past decades, the pharmacopoeia was dominated by
racemates, but since the emergence of new technologies in
the 1990s that allowed the preparation of pure enantiomers
in significant quantities, the awareness and interest in the
stereochemistry of drug action has increased. Perhaps part
of the interest in chirality is the fascination with the elegance
of the underlying concepts. However, the most important
motivation for developing enantiomers has been a genuine
desire to improve efficacy and reduce adverse effects of drugs
through exploitation of stereospecific differences in phar-
macodynamics and pharmacokinetics.
Based on this concept, we pursued the development of an
efficient methodology for the stereoselective synthesis of
structurally complex compounds. Numerous methods for the
synthesis of optically active amines are known, few being
based on catalytic asymmetric synthesis. Among the most
popular is the asymmetric hydrogenation of ketimines or
enamides using chiral Rh(I), Ir(I), or Ru(II) complexes.1 A
particularly efficient method for the reduction of dihydro-
† Universidad de Talca.
‡ Universidade de Bras´ılia.
(1) Surendra, K.; Krishnaveni, N. S.; Sridhar, R.; Rao, K. R. J. Org.
Chem. 2006, 71, 5819–5821.
§ Universidade Estadual de Campinas.
10.1021/ol9011772 CCC: $40.75
Published on Web 07/02/2009
 2009 American Chemical Society

ꢀ-carbolines is the asymmetric transfer hydrogenation.1
During the course of our total synthesis of the alkaloid
Quinolactacin B, the opportunity arouse to investigate a new
approach to the asymmetric reduction of dihydro-ꢀ-carbolines
through a host-guest mediated process based on CD(host)/
PdCl2(guest)-Et3SiH (hydride source).2
We used ꢀ-CD as cocatalyst in the reaction as it is a mild
and efficient biomimetic catalysts in various transforma-
tions.1,2 Cyclodextrins (CDs) are cyclic oligosaccharides
possessing hydrophobic cavities, which bind substrates
selectively and catalyze chemical reactions with high selec-
tivity. CDs catalyze reactions via supramolecular arrangement
involving reversible formation of host/guest complexes by
noncovalent bonding. Complexation depends on the size,
shape, and hydrophobicity of the guest molecule.
However, we noticed that when lyophilized host-guest
complexes of ꢀ-CD and PdCl2 were used, considerably
higher ee% values were obtained in the reduction of dihydro-
ꢀ-carbolines. A representative protocol used was: overnight
PdCl2/ꢀ-CD (1:2 molar ratio) complex formation in aqueous
Na2CO3 solution (0.2 mol/L), followed by lyophilization of
the resulting mixture. The lyophilized powder was resus-
pended in water and a solution of imines 1a-g in CH2Cl2
was added (method A, Table 1). Finally, the solution was
Table 1. ꢀ-Cyclodextrin Mediated Reduction of Imines 1 to
Amines 2
Asymmetric Supramolecular Reduction of Dihydro-
ꢀ-carbolines. The search for novel enantioselective imine
reduction methods was inspired by the cyclodextrin (CD)/
NaBH4 asymmetric reduction of carbonyl compounds which
however provided poor ee% when applied to imines.2,3 Based
on our previous preliminary results,2 we initially investigated
the supramolecular induction of chirality in the reduction of
dihydro-ꢀ-carbolines promoted by the ꢀ-cyclodextrin/PdCl2-
Et3SiH catalytic system. Our choice of dihydro-ꢀ-carbolines
as substrates was dictated by our interest to apply the
methodology to the asymmetric total synthesis of some indole
alkaloids and also because it would allow us to compare our
results with those provided by the Noyori asymmetric transfer
hydrogenation which is based on the utilization of ruthe-
nium(II)-DPEN complexes and is carried out in the presence
of HCO2H-Et3N azeotropic mixture.2b,4,5 Despite its ef-
fectiveness of the reduction of dihydro-ꢀ-carbolines, we
considered to be of interest to develop alternatives, particu-
larly those based on a different concept such as the use of a
chiral host-guest complex in aqueous media.
method method method method
Aa ee% Bb ee% Cc ee% Dd ee%
entry
R
(yield %) (yield %) (yield %) (yield %)
a
b
c
d
e
f
Me (1a)
Et (1b)
iPr (1c)
92 (92) 90 (95) 80 (90) 95 (96)
78 (94) 83 (94) 76 (75) 92 (90)
70 (82) 70 (92) 70 (80) 94 (98)
76 (80) 70 (93) 70 (80) 92 (90)
90 (85) 88 (90) 80 (90) 92 (98)
1-pentenyl (1d)
Ph (1e)
(CH2)2CO2Me (1f) 89 (95) 89 (86) 76 (75) 90 (85)
(CH2)3CO2Me (1g) 90 (80) 85 (82) 92 (84)
g
-
a Method A: PdCl2/CD then imine and Et3SiH. b Method B: Imine (1)/
CD then PdCl2 and Et3SiH. c Method C: Imine (1)/CD then NaBH4. d Method
D: TsDPEN-Ru(II) complex, HCO2H/Et3N, DMF, rt, 12 h.
The methodology developed in our laboratory is based on
ꢀ-cyclodextrin host-guest chiral complexes.6 Previously, we
have described the CD/imine complexes reduction employing
NaBH4 as the reducing agent but the corresponding amines
were obtained with low enantiomeric excess (ee 25%).2a
kept at 0 °C and Et3SiH was added dropwise. After 12 h,
(R)-amines 2a-g were obtained in good to excellent yields
(78-95%) and good ee% values (70-92%).
To test whether the order of addition might influence the
ee% values, we added PdCl2 followed by Et3SiH in the
resuspended lyophilized complex imine/ꢀ-CD in water
(method B, Table 1). The ee% values were slightly lower
than previously observed in method A. Another protocol
tested was based on ꢀ-CD/imine complex formation, fol-
lowing the same steps described above, but using NaBH4 as
reducing agent (method C, Table 1). (R)-Amines 2a-g were
obtained in ee% values around 70-80% and excellent yields.
Finally, Noyori asymmetric hydrogenation with (S,S)-
TsDPEN-Ru(II) catalyst (method D, Table 1) was used to
compare the ee% values and determine the absolute config-
uration of the newly formed stereogenic center in methods
A-C. The ee% values were determined by chiral HPLC
(Welk-01 column, 90:10:0.1 hexanes/isopropanol/diisopro-
pyl-amine; 0,8 mL/min, λ 263 nm).
(2) (a) Santos, L. S.; Fernandes, S. A.; Pilli, R. A.; Marsaioli, A. J.
Tetrahedron: Asymmetry 2003, 14, 2515–2519. (b) Shankaraiah, N.; da
Silva, W. A.; Andrade, C. K. Z.; Santos, L. S. Tetrahedron Lett. 2008, 49,
4289–4291.
(3) (a) Fornasier, R.; Reniero, F.; Scrimin, P.; Tonellato, U. J. Org.
Chem. 1985, 50, 3209–3211. (b) Kawajiri, Y.; Motohashi, N. J. Chem. Soc.,
Chem. Commun. 1989, 1336–1337. (c) Sakuraba, H.; Inomata, N.; Tanaka,
Y. J. Org. Chem. 1989, 54, 3482–3484
.
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J. Am. Chem. Soc. 1996, 118, 4916–4917. (b) Yamakawa, M.; Ito, H.;
Noyori, R. J. Am. Chem. Soc. 2000, 122, 1466–1478. (c) Mao, J. M.; Baker,
D. C. Org. Lett. 1999, 1, 841–843. (d) James, B. R. Catal. Today 1997, 37,
209–221. (e) Kobayashi, S.; Ishitani, H. Chem. ReV. 1999, 99, 1069–1094
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(5) For other applications of the Noyori hydrogenation toward alkaloid
compounds, see: (a) Shankaraiah, N.; Santos, L. S. Tetrahedron Lett. 2009,
50, 520–523. (b) Santos, L. S.; Pilli, R. A.; Rawal, R. H. J. Org. Chem.
2004, 69, 1283–1289. (c) Kaldor, I.; Feldman, P. L.; Mook, R. A.; Ray,
J. A.; Samano, V.; Sefler, A. M.; Thompson, J. B.; Travis, B. R.; Boros,
E. E. J. Org. Chem. 2001, 66, 3495–3501. (d) Tietze, L. F.; Zhou, Y. F.;
Topken, E. Eur. J. Org. Chem. 2000, 2247–2252. (e) Meuzelaar, G. J.;
The use of the PdCl2/ꢀ-CD/Et3SiH protocol (method A)
provided good enantiomeric excesses, particularly for dihy-
dro-ꢀ-carbolines 1a and 1e-g. In these particular examples,
the supramolecular reducing condition (method A) performed
van, Vliet; Maat, L.; Sheldon, R. A. Eur. J. Org. Chem. 1999, 2315–2321
.
(6) (a) Schlatter, A.; Woggon, W. D. AdV. Synth. Catal. 2008, 350, 995–
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Ed. 2004, 43, 6731–6734.
Org. Lett., Vol. 11, No. 15, 2009
3239

as well as the Noyori asymmetric transfer hydrogenation
(method D) regarding the enantiomeric excess and therefore
it constitutes a novel asset in the asymmetric catalytic
reduction of prochiral dihydro-ꢀ-carbolines. In the last two
examples (1f and 1g), the asymmetric reduction was followed
by a spontaneous lactamization step affording the corre-
sponding tetracyclic lactams 3f and 3g.
well as from Alstonia undulata10 and from the South
American Aspidosperma maregraVianum,11 had its absolute
configuration established by Meyers and co-workers in 1986
through the total synthesis of the (S)-enantiomer.12 Due to
its deceptively simple structure, deplancheine has become a
preferential testing ground to evaluate the efficiency of
methodologies designed for the asymmetric synthesis of
alkaloids featuring the indolo[2,3-a]quinolizidine architec-
ture.13
Our approach to the asymmetric total synthesis of (R)-
deplancheine (9) was inspired by the construction of the
indolo[2,3-a]quinolizidine core via the Bischler-Napieralski/
supramolecular reduction protocol, followed by the introduc-
tion of the E-configured exocyclic double bond via stereo-
selective aldol-dehydration sequence employed in our total
synthesis of homopumiliotoxin.14
In fact, the reaction of tryptamine with glutaric anhydride,
followed by esterification with MeOH/SOCl2 afforded amide
6 in 96% yield. Bischler-Napieralski cyclization and su-
pramolecular reduction of the intermediate dihydro-ꢀ-car-
boline 1g provided tetracyclic lactam 3g in 85% overall yield
(two steps) and 90% ee, by chiral HPLC analysis (Scheme
2). Attempts to install the exocyclic double bond in lactam
Harmicine. The above methodology allowed us to develop
a short and efficient preparation of the indoloquinolizidine
alkaloid (R)-harmicine (5), isolated from the leaf extracts of
Kopsia griffithii, which is reported to display strong antile-
ishmania activity in preliminary screening.7 Recently, Ohsa-
wa reported the synthesis of ent-3 and assigned R absolute
configuration to the natural product based on a 11-step
protocol from the ꢀ-carboline precursor.8
The requisite amide 4 was straightforwardly prepared from
tryptamine and succinic anhydride in 92% yield (Scheme
1). Following the same approach which was successfully
Scheme 1
.
Supramolecular Approach to the Synthesis of
(R)-Harmicine (5)
Scheme 2
.
Supramolecular Approach to the Synthesis of
(R)-Deplancheine (9)
employed in the total synthesis of arborescidines A, B and
D,5b Bischler-Napieralski cyclization promoted by phospho-
rus oxychloride provided dihydro-ꢀ-carboline (1f) in 85%
yield which was submitted to the supramolecular reduction
conditions described above (Table 1, method A) to afford
lactam 3f in 95% yield and 89% ee after spontaneous
lactamization. This result compares favorably with those
obtained using the Noyori protocol (85% yield and 90%
enantiomeric excess, Table 1, method D). The total synthesis
of (R)-harmicine was thus accomplished in 5 steps and 67%
overall yield from tryptamine and succinic anhydride after
reduction of lactam 2f with recently prepared alane soln. in
THF.
3g via the aldol/dehydration sequence met with failure due
to the deprotonation of the indol nitrogen and its previous
protection with the terc-butoxycarbonyl group (Boc) was
required. Boc-protected lactam 7 was uneventfully prepared
(96% yield) and was successfully converted to the corre-
sponding E ethylydene derivative 8 in 67% overall yield,
after aldol reaction of the corresponding lithium enolate with
acetaldehyde, followed by mesylation and DBN elimina-
tion.13 Boc-deprotection of 8 followed by reduction of the
Deplancheine. The indolo[2,3-a]quinolizidine is the core
structure in several indole alkaloids such as yohimbine,
geissoschizine, and reserpine. (R)-(+)-Deplancheine (9),
isolated from the stems and bark of Alstonia deplanchei9 as
(7) Kam, T. S.; Sim, K. M. Phytochemistry 1998, 47, 145–147.
(8) Itoh, T.; Miyazaki, M.; Nagata, K.; Yokoya, M.; Nakamura, S.;
Ohsawa, A. Heterocycles 2002, 58, 115–118.
(9) Besselie`vre, R.; Cosson, J. P.; Das, B. C.; Husson, H. P. Tetrahedron
Lett. 1980, 121, 63–66.
3240
Org. Lett., Vol. 11, No. 15, 2009

carbonyl group with alane in THF afforded (R)-deplancheine
(9) in 44% overall yield from tryptamine and glutaric
anhydride. The final compound proved to be identical to the
natural product and to (R)-deplancheine (9) prepared via
Noyori asymmetric hydrogen transfer using (S,S)-TsDPEN/
Ru(II) catalyst.
The lyophilized host-guest complex involving ꢀ-CD/
dihydro-ꢀ-carbolines/PdCl2 and Et3SiH provided higher %ee
than previously reported systems using ꢀ-CD/dihydro-ꢀ-
carbolines and NaBH4 as the reducing agent. We have
demonstrated the feasibility of this novel protocol for the
asymmetric reduction of dihydro-ꢀ-carbolines with yields and
%ee comparable to those obtained by the Noyori methodol-
ogy (TsDPEN-Ru(II) complex and azeotropic HCO2H/Et3N).
The utility of our protocol was demonstrated with the total
synthesis of the indole alkaloids (R)-harmicine (5) and (R)-
deplancheine (9) in 5 (67% overall yield, 89% ee) and 10
steps (44% overall yield, 90% ee), respectively. The su-
pramolecular protocol presented here opens up several
possibilities for its application to the asymmetric reduction
of imines and to the total synthesis of enantiomerically
enriched nitrogenated compounds.
Acknowledgment. L.S.S. thanks FONDECYT (Project
1085308) for financial support. C.K.Z.A., R.A.P. and W.A.S.
thank CNPq for financial support. R.A.P., M.T.R. and R.B.F.
acknowledge support from FAPESP. PBCT (PSD-50, S.N.)
and IFS (F/4195-1) are acknowledged for financial support.
Supporting Information Available: Copies of the 1H and
13C NMR spectra of compounds 1a, 1d, 1f, 2f-g, 3-8,
precursor amides as well as detailed experimental procedures
of all synthesized compounds are available. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL9011772
(12) Meyers, A. I.; Sohda, T.; Loewe, M. F. J. Org. Chem. 1986, 51,
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Nishida, N.; Tomimura, A.; Ihara, M. J. Org. Chem. 2005, 70, 3957–3962.
(b) Sydorenko, N.; Zificsak, C. A.; Gerasyuto, A. I.; Hsung, R. P. Org.
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M.; Karinen, K.; Tovanen, A. Heterocycles 1997, 45, 1397–1404. (e)
Tirkkonen, B.; Miettinen, J.; Salo, J.; Jokela, R.; Lounasmaa, M. Tetrahe-
dron 1994, 50, 3537–3556. (f) Mandal, S. B.; Giri, V. S.; Sabeena, M. S.;
Pakrashi, S. C. J.Org. Chem. 1988, 53, 4236–4241.
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1981, 23, 1987–1990. (b) Guillaume, D.; Morfaux, A. M.; Richard, B.;
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