Atroposelective biaryl coupling with chiral catalysts: Total synthesis of the antileishmanial naphthylisoquinoline alkaloids ancistrotanzanine B and ancistroealaine A

Article abstract of DOI:10.1021/ol0347693

(Matrix presented) The first total synthesis of the naphthylisoquinoline alkaloid ancistrotanzanine B and its atropo-diastereomer, ancistroealaine A, is described. The key step is the construction of the rotationally hindered and thus stereogenic biaryl a

Full text of DOI:10.1021/ol0347693

ORGANIC
LETTERS
2003
Vol. 5, No. 16
2805-2808
Atroposelective Biaryl Coupling with
Chiral Catalysts: Total Synthesis of the
Antileishmanial Naphthylisoquinoline
Alkaloids Ancistrotanzanine B and
Ancistroealaine A†
Gerhard Bringmann,* Andreas Hamm, and Michaela Schraut
Institut fu¨r Organische Chemie, UniVersita¨t Wu¨rzburg,
Am Hubland, 97074 Wu¨rzburg, Germany
bringman@chemie.uni-wuerzburg.de
Received May 7, 2003
ABSTRACT
The first total synthesis of the naphthylisoquinoline alkaloid ancistrotanzanine B and its atropo-diastereomer, ancistroealaine A, is described.
The key step is the construction of the rotationally hindered and thus stereogenic biaryl axis by Suzuki coupling. While only weak internal
asymmetric inductions by the stereogenic center in the dihydroisoquinoline part were observed, much better atropisomeric ratios in favor of
ancistrotanzanine B were achieved by the use of chiral catalysts. Both alkaloids, in particular ancistrotanzanine B, show high antileishmanial
activities.
The naphthylisoquinoline alkaloids constitute a rapidly
growing class of structurally1,2 (presence of both stereogenic
centers and chiral axes) and biosynthetically3,4 (the first
polyketide-derived isoquinoline alkaloids) interesting natural
biaryl compounds.5 They have so far been found only in two
small tropical plant families, the Ancistrocladaceae and the
Dioncophyllaceae.1 Of particular interest is the antimalarial
activity of some of these natural products, both in vitro and
in vivo, while, more recently, also other promising anti-
protozoal activities have been found.6,7 Thus, ancistroealaine
A (1a, see Scheme 1), a naphthylisoquinoline alkaloid
recently isolated from the Central African liana Ancistro-
† Part 105 of the Series Novel Concepts in Directed Biaryl Synthesis.
For part 104, see: Bringmann, G.; Pfeifer, R.-P.; Rummey, C.; Pabst, T.;
Leusser, D.; Stalke, D. Z. Naturforsch. 2003, 58b, 231-236.
(1) Bringmann, G.; Pokorny, F. In The Alkaloids; Cordell, G. A., Ed.;
Academic Press: New York, 1995; Vol. 46, pp 127-271.
(2) Bringmann, G.; Franc¸ois, G.; Ake´ Assi, L.; Schlauer, J. Chimia 1998,
52, 18-28.
(5) For a review on biaryl secondary metabolites, see: Bringmann, G.;
Gu¨nther, C.; Ochse, M.; Schupp, O.; Tasler, S. In Progress in the Chemistry
of Organic Natural Products; Herz, W., Falk, H., Kirby, G. W., Moore,
R. E., Tamm, C., Eds.; Springer: Wien, Austria, 2001; Vol. 82, pp
1-249.
(6) Bringmann, G.; Feineis, D. Act. Chim. The´rapeut. 2000, 26, 151-
171.
(3) Bringmann, G.; Wohlfarth, M.; Rischer, H.; Schlauer, J. Angew.
Chem., Int. Ed. 2000, 39, 1464-1466.
(7) Bringmann, G. In Guidelines and Issue for the DiscoVery and Drug
DeVelopment Against Tropical Diseases; Vial, H., Fairlamb, A., Ridley,
R., Eds.; World Health Organisation: Geneva, in press.
(4) Bringmann, G.; Feineis, D. J. Exp. Bot. 2001, 52, 2015-2022.
10.1021/ol0347693 CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/16/2003

presence of only three ortho-substituents next to the axis
should make it possible to use methods such as the Suzuki
coupling10-12 (which is more sensitive to steric hindrance)
for the construction of the axis. Thus, the use of the lactone
methodology, which can even build up 4-fold ortho-
substituted biaryls with the largest steric hindrance next to
the axis,21,22 would not be necessary for a first rapid
construction of 1a and 1b for further pharmacological
investigations. Moreover, we found it interesting to test how
far it would be possible to control the axial configuration of
the product by an internal asymmetric induction by the
stereogenic center at C-3; in previous cases, using related
tetrahydroisoquinoline moieties, atropisomeric ratios of only
55:45 to 60:40 had been attained.23-25 In addition, the
example seemed of interest to check whether in this case
the atropisomeric selectivities might be improved by chiral
catalysts, applying enantioselective coupling techniques, e.g.,
by Buchwald and Cammidge,26,27 which, however, had so
far been applied mainly to simple, not sterically hindered,
electron-poor model compounds, none of them containing
nitrogen, while Nicolaou et al. had used related catalysts in
the synthesis of a vancomycin-related compound,28 but
without larger steric hindrance. But even in those cases, the
coupling yields were decreased as compared to the nonselec-
tive coupling reaction, and still the atropisomeric ratios
obtained were often only moderate.
Scheme 1
cladus ealaensis, was found to be highly active in vitro
against Leishmania donoVani, the pathogen of visceral
leishmaniasis (“Kala Azar”), even more active than the stand-
ard, pentostam.8 More recently also its atropo-diastereomer,
ancistrotanzanine B (1b), has been isolated from the East
African species A. tanzaniensis and has been found to show
a still higher activity than 1a.9 In this paper, we report on
the first total synthesis of ancistrotanzanine B (1b) and
ancistroealaine A (1a).
Among the methods10-14 developed for the directed, i.e.,
regio- and stereoselective construction of biaryl systems, only
a few have so far proven suited for the synthesis of
naphthylisoquinoline alkaloids.15-18 The first total syntheses
in this fieldsand by far the largest number of successful
examplesswere achieved by using the “lactone method”,17,18
which allows the atropo-divergent construction of any of the
two possible atropo-diastereomers in high chemical and
optical yields. Within this concept, however, the target
molecule should ideally have a C1 unit and an oxygen
function in opposite ortho-positions next to the biaryl axis,
to be used as the “bridge heads” for the prefixation of the
two molecular moieties via an ester bridge, for the subsequent
intramolecular biaryl coupling. Although several examples
have meanwhile been accomplished without these require-
ments,19,20 we decided to try a direct, intermolecular biaryl
coupling for the synthesis of 1a and 1b, also because the
As the immediate precursors for the biaryl coupling, we
chose the naphthalene building block 2, activated as a boronic
acid, and the heterocyclic portion 3 in the form of a halogen-
substituted (initially brominated) dihydroisoquinoline (see
Scheme 1), even though no such coupling reaction in the
presence of a free iminic nitrogen in any of the coupling
partners had so far succeeded. On the other hand, to protect
this nitrogen at the same oxidation level (e.g., as an
N-acylenamide) would have caused additional problems.
By contrast, previous strategies to do the coupling at the
level of the corresponding 1,3-dimethyltetrahydroisoquinoline
would have required either the respective N-protected (yet
quite unstable29) cis-diastereomer or the corresponding trans-
isomer, which, however, can be oxidized to the respective
dihydroisoquinolines only under drastic conditions and with
extremely low yields.30
(8) Bringmann, G.; Hamm, A.; Gu¨nther, C.; Michel, M.; Brun, R.;
Mudogo, V. J. Nat. Prod. 2000, 63, 1465-1470.
(9) Bringmann, G.; Dreyer, M.; Faber, J.; Dalsgaard, P. W.; Stærk, D.;
Jaroszewski, J.; Ndangalasi, H.; Mbago, F.; Brun, R.; Reichert, M.;
Maksimenka, K.; Christensen, S. B. J. Nat. Prod. Submitted for publi-
cation.
(20) Bringmann, G.; Ochse, M.; Go¨tz, R. J. Org. Chem. 2000, 65, 2069-
2077.
(10) Stanforth, S. P. Tetrahedron 1998, 54, 263-303.
(11) Suzuki, A. J. Organomet. Chem. 1999, 576, 147-168.
(12) Lloyd-Williams, P.; Giralt, E. Chem. Soc. ReV. 2001, 30, 145-
157.
(13) Bringmann, G.; Breuning, M.; Pfeifer, R.; Schenk, W. A.; Kami-
kawa, K.; Uemura, M. J. Organomet. Chem. 2002, 661, 31-47.
(14) Hassan, J.; Se´vignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem.
ReV. 2002, 102, 1359-1469.
(15) Chau, P.; Czuba, I. R.; Rizzacasa, M. A.; Bringmann, G.; Gulden,
K.-P.; Scha¨ffer, M. J. Org. Chem. 1996, 61, 7101-7105.
(16) Bringmann, G.; Breuning, M.; Tasler, S. Synthesis 1999, 525-
558.
(21) Bringmann, G.; Hartung, T.; Go¨bel, L.; Schupp, O.; Peters, K.; von
Schnering, H. G. Liebigs Ann. Chem. 1992, 769-775.
(22) Bringmann, G.; Hinrichs, J.; Kraus, J.; Wuzik, A.; Schulz T. J. Org.
Chem. 2000, 65, 2508-2516.
(23) Hoye, T. R.; Chen, M. J. Org. Chem. 1996, 61, 7940-7942.
(24) Hobbs, P. D.; Upender, V.; Liu, J.; Pollart, D. J.; Thomas, D. W.;
Dawson, M. I. Chem. Commun. 1996, 923-924.
(25) Bringmann, G.; Go¨tz, R.; Keller, P. A.; Walter, R.; Boyd, M. R.;
Lang, F.; Garcia, A.; Walsh, J. J.; Tellitu, I.; Bhaskar, K. V.; Kelly, T. R.
J. Org. Chem. 1998, 63, 1090-1097.
(26) Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 12051-
12052.
(17) Bringmann, G.; Menche, D. Acc. Chem. Res. 2001, 34, 615-
624.
(27) Cammidge, A. N.; Cre´py, K. V. L. Chem. Commun. 2000, 1723-
1724.
(18) Bringmann, G.; Tasler, S.; Pfeifer, R.; Breuning, M. J. Organomet.
Chem. 2002, 661, 49-65.
(19) Bringmann, G.; Holenz, J.; Weirich, R.; Ru¨benacker, M.; Funke,
C.; Boyd, M. R.; Gulakowski, R. J.; Franc¸ois, G. Tetrahedron 1998, 54,
497-512.
(28) Nicolaou, K. C.; Li, H.; Boddy, C. N. C.; Ramanjulu, J. M.; Yue,
T. Y.; Natarajan, S.; Chu, X. J.; Bra¨se, S.; Ru¨bsam, F. Chem. Eur. J. 1999,
5, 2584-2601.
(29) Bringmann, G.; Weirich R.; Reuscher, H.; Jansen, J. R.; Kinzinger,
L.; Ortmann, T. Liebigs Ann. Chem. 1993, 877-888.
2806
Org. Lett., Vol. 5, No. 16, 2003

In analogy to a reaction sequence described earlier for a
related O-isopropyl derivative,31 the naphthylboronic acid 2
was prepared from the bromo compound 5 by phase-transfer-
catalyzed O-methylation of the phenolic OH-function, LAH
reduction of the carboxylate, and deoxygenation of the
resulting primary alcohol 7 (by hydroxy-halogen exchange
and subsequent renewed alanate reduction), followed by
lithiation and subsequent reaction with trimethyl borate. The
brominated dihydroisoquinoline 3 was prepared from the
known29 acetamide 6, which was brominated and cyclized
by the Bischler-Napieralski reaction.
Scheme 2
The first coupling reactions of the two building blocks 2
and 3 thus prepared, using Pd(PPh3)4, gave the desired biaryl
1 in traces only (see Table, entry 1), while under other
reaction conditions, no product was observed (not shown).
As indicated by the formation of the hydro-deboronation
product of 2, the palladium had indeed been inserted, but
apparently the bromide 3 was not reactive enough for the
final coupling to proceed in good yields (see Table 1). For
Table 1. Coupling Conditions, Yields, and Diastereomeric
Ratios in the Suzuki Coupling Reactions of 2 with the
Dihydroisoquinolines 3 or 4
yield
entry compds
conditions
(%)
M:P
1
2
3
4
5
6
2 + 3 toluene; 5 equiv of K3PO4;
0.1 equiv of Pd(PPh3)4
2 + 4 toluene/H2O; NaHCO3;
0.1 equiv of Pd(PPh3)4
2 + 4 toluene/H2O; NaHCO3; 0.05 equiv 38
of Pd2(dba)3; (Rc,Sp)-10
2 + 4 toluene/H2O; NaHCO3; 0.05 equiv 34
of Pd2(dba)3; (Sc,Rp)-10
2 + 4 toluene/H2O; NaHCO3; 0.1 equiv 45
of Pd2(dba)3; (M)-11
2 + 4 toluene/H2O; NaHCO3; 0.1 equiv 50
of Pd2(dba)3; (P)-11
traces n.d.
50
45:55
75:25
51:49
61:39
75:25
approach for their separation was to actually treat them as
enantiomers, here by chromatography on a chiral phase. This
was achieved, analytically, by using a Chiracel OD-H 250
column (4.6 mm; 5 µm; 0.5 mL/min; A, n-hexane (with 0.1%
TFA); B, 2-propanol (with 0.1% TFA); gradient ) 0 min
10% B, 10 min 10% B, 30 min 50% B, 60 min 50% B),
which gave the two expected peaks for the diastereomeric
products obtained above, in this case revealing a disappoint-
ing isomeric ratio of 55:45 in favor of the P-atropisomer,
i.e., ancistroealaine A (1a). That the two peaks thus obtained
in the LC-UV chromatogram were indeed the correspond-
ing atropisomers was evident from their opposite circular
dichroism (CD) effect as easily measured online, right from
the peaks, by LC-CD coupling, here by simply monitoring
the CD effect at one favorable wavelength, in this case the
best wavelength was 230 nm, where the CD spectrum of 1a
has a minimum and that of 1b a maximum. Thus, the LC-
CD chromatogram of the reaction product obtained above
gave the expected positive peak for 1b and a negative one
for 1a.
this reason, iodide 4, as prepared from acetamide 6 in a sim-
ilar reaction sequence (see Scheme 2), gave much better
coupling yields, straightaway, e.g., 50% again with Pd(PPh3)4
(see Table 1, entry 2). To avoid the still occurring hydro-
deboronation reaction, water-free conditions were likewise
tested, but did not yield any coupling product 1.
Given the stereogenic center (C-3) in the isoquinoline
portion, it was of interest how far this element of chirality
would govern the stereoisomeric ratio at the biaryl axis. The
stereoanalysis of 1a/1b was, however, hampered by the fact
that these two atropo-diastereomers behaved chromatographi-
cally identically, both on normal and reversed-phase silica
gel, so that, as already seen in previous cases,32,33 the best
(30) Bringmann, G.; Reuscher, H. Tetrahedron Lett. 1989, 30, 5249-
5252.
(31) Bringmann, G.; Go¨tz, R.; Harmsen, S.; Holenz, J.; Walter, R. Liebigs
Ann. Chem. 1996, 2045-2058.
(32) Bringmann, G.; Lisch, D.; Reuscher, H.; Ake´ Assi, L.; Gu¨nther, K.
Phytochemistry 1991, 30, 1307-1310.
(33) Bringmann, G.; Schneider, C.; Mo¨hler, U.; Pfeifer, R.-M.; Go¨tz,
R.; Ake´ Assi, L.; Peters, E.-M.; Peters, K. Z. Naturforsch. 2003, 58b, 577-
584.
Org. Lett., Vol. 5, No. 16, 2003
2807

filtration prior to use. By using the (Rc,Sp)-enantiomer of 10,
the two alkaloids 1a and 1b were obtained in as much as
52% yield and in an atropisomeric ratio of 75:25, i.e., with
a preference opposite to that with an achiral catalyst, giving
rise to the hope that this would be the “mismatched” case
and that the (Sc,Rp)-enantiomer of 10 would give an even
better ratio, now in favor of the P-enantiomer, 1a. This,
however, was not the case, since (besides delivering a lower
chemical yield of only 34%) the reaction did not provide
any preference for one of the diastereomers (dr 51:49). The
catalyst derived from (M)-11, by contrast, gave a yield of
45%, with a dr of 61:39 in favor of the M-isomer, again
suggesting that the use of (P)-11 would permit an even higher
diastereomeric ratio in favor of P. Indeed, an isomeric ratio
of 75:25 was obtained, with an even higher chemical yield
(now 50%), but unexpectedly again in favor of M.
For the likewise difficult preparative separation of two
atropo-diastereomeric products, 1a and 1b, a similar chro-
matographic device was applied, this time by using a
semipreparative Chiracel OD column (250 × 10 mm; 10 µm;
3.0 mL/min; see above for solvents and gradient).34 The two
pure products, 1a and 1b, proved to be identical in all
spectroscopic, chromatographic, and physical (in particular
chiroptical) properties with the authentic natural products,
ancistroealanine A and ancistrotranzanine B, thus completing
the first total synthesis of these two natural products, which,
in addition, confirms the structures of these bioactive
alkaloids.
Still, in view of the nearly equal formation of 1a and 1b
and the hence lacking internal asymmetric induction,35 it
seemed rewarding to try chiral catalysts, thus hopefully
influencing the atropisomeric ratio more efficiently. Attempts
to generate chiral catalysts first from PdCl2 by addition of
the previously successful27 chiral ligands 10 or 11 failed,
while with catalysts prepared from Pd2(dba)3 and those
ligands, the biaryl coupling worked well (see Table 1, entries
3-6). For each of these cases, the ligand-palladium ratio
was optimized (not shown) since different metal-ligand
ratios can provide different selectivities in such analytical
processes.36 In the case of ferrocene 10 as the ligand, the
complex was first prepared and even purified by column
In summary, the work described in this paper constitutes
the first total synthesis of the two bioactive naphthyl-
isoquinoline alkaloids ancistroealaine A (1a) and ancistro-
tanzanine B (1b) via a short and efficient synthetic pathway.
Particularly remarkable is the fact that the Suzuki coupling
still worked in the presence of a free imino function and
when using chiral palladium catalysts and even gave quite
good asymmetric inductions, leading to atropisomeric ratios
of up to 75:25, in favor of ancistrotanzanine B (1b), although
it was not yet possible to likewise produce the other
atropisomer, 1a, preferentially, by using the other reagent
enantiomers. The reasons for this absence of atropo-
divergence16 remain to be investigated.
Acknowledgment. This work was supported by the
Deutsche Forschungsgemeinschaft (Br 699/7-1) and by the
Fonds der Chemischen Industrie (fellowship to A.H. and
research funds).
Supporting Information Available: Experimental pro-
cedure and characterization data for compounds 1-9. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(34) Different from previous preparative atropo-diastereomeric separa-
tions by enhancing the diastereomeric differentiation through attachment
of a chiral electrophile, this approach was not possible here due to the
absence of free OH- or NH-functions.
(35) For a promising approach to the achievement of a better stereocontrol
in related couplings, by prefixation of the two molecular portions through
complexation, see: Lipshutz, B. H.; Keith, J. M. Angew. Chem., Int. Ed.
1999, 38, 3530-3533.
OL0347693
(36) Castanet, A.-S.; Colobert, F.; Broutin P.-E.; Obringer, M. Tetra-
hedron: Asymmetry 2002, 13, 659-665.
2808
Org. Lett., Vol. 5, No. 16, 2003