First total synthesis of the 7,6′-coupled antifungal naphthylisoquinoline alkaloid dioncophylline

Article abstract of DOI:10.1016/S0040-4020(00)01110-8

The first total synthesis of the antimalarial alkaloid dioncophylline B (2) from Triphyophyllum peltatum (Dioncophyllaceae), and thus the first preparation of a 7,6′-coupled naphthylisoquinoline, is described. Key steps within this synthesis are the ortho-functionalization of the MOM-protected naphthalene and isoquinoline moieties 14 and 7 by directed ortho-metalation, with subsequent stannylation of the naphthalene part and bromination of the isoquinoline portion, and the regioselective intermolecular Stille coupling reaction of these building blocks. The presented synthesis opens the way for the preparation of further 7-coupled compounds of this class of alkaloids.

Full text of DOI:10.1016/S0040-4020(00)01110-8

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 1253±1259
First total synthesis of the 7,60-coupled antifungal
naphthylisoquinoline alkaloid dioncophylline Bq
Gerhard Bringmann,a,p Christian GuÈnther,a Eva-Maria Petersb and Karl Petersb
a
È È È È
Institut fur Organische Chemie, Universitat Wurzburg, Am Hubland, D-97074 Wurzburg, Germany
b
È
È
Max-Planck-Institut fur Festkorperforschung, Heisenbergstraûe 1, D-70506 Stuttgart, Germany
Dedicated to Professor T. R. Govindachari, on the occasion of his 85th birthday
Received 8 November 2000; accepted 22 November 2000
AbstractÐThe ®rst total synthesis of the antimalarial alkaloid dioncophylline B (2) from Triphyophyllum peltatum (Dioncophyllaceae), and
thus the ®rst preparation of a 7,60-coupled naphthylisoquinoline, is described. Key steps within this synthesis are the ortho-functionalization
of the MOM-protected naphthalene and isoquinoline moieties 14 and 7 by directed ortho-metalation, with subsequent stannylation of the
naphthalene part and bromination of the isoquinoline portion, and the regioselective intermolecular Stille coupling reaction of these building
blocks. The presented synthesis opens the way for the preparation of further 7-coupled compounds of this class of alkaloids. q 2001 Elsevier
Science Ltd. All rights reserved.
1. Introduction
insect antifeedant13,14 and molluscicidal15 alkaloid from
Triphyophyllum peltatum (Hutch. and Dalz.) Airy Shaw
(Dioncophyllaceae), has its biaryl axis between C-7 of the
isoquinoline part and C-10 of the naphthalene half. By
contrast, dioncophyllines B16 (2) and C17 (3), which have
been isolated from the same plant and exhibit strong fungi-
cidal7 and in vivo antimalarial18 activities, respectively, are
7,60- and 5,10-coupled. Depending on the degree of steric
hindrance at the biaryl axis between the naphthalene moiety
and the isoquinoline portion, most of the naphthylisoquino-
line alkaloids show the phenomenon of axial chirality,
giving rise to con®gurationally stable atropisomeric forms,
as is the case for 1 and 3. Dioncophylline B (2), however,
with its only two small hydroxy functions next to the biaryl
The naphthylisoquinoline alkaloids2,3 are structurally
diverse natural products from tropical Ancistrocladaceae
and Dioncophyllaceae plants, exhibiting a broad spectrum
of bioactivities, like antimalarial,4 anti-HIV,5 antitrypano-
somal,6 and fungicidal7 properties. For this reason and
because of the structural variety arising from the different
ways by which the isoquinoline moiety and the naphthalene
portion are linked to each other, from the substitution
patterns, the hydrogenation degrees, and the con®gurations
at the various stereogenic elements, these secondary
metabolites constitute challenging synthetic goals.2,8±11 As
an example, dioncophylline A (1, see Fig. 1),12 an
Figure 1. Three bioactive naphthylisoquinoline alkaloids: dioncophyllines A (1), B (2), and C (3).
q Acetogenic Isoquinoline Alkaloids, Part 147.1
Keywords: dioncophylline B; naphthylisoquinoline alkaloids; total synthesis; cross coupling; directed ortho-metalation.
Corresponding author. Tel.: 149-931-888-5323; fax: 149-931-888-4755; e-mail: bringman@chemie.uni-wuerzburg.de
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01110-8

1254
G. Bringmann et al. / Tetrahedron 57 (2001) 1253±1259
axis, is con®guratively unstable and undergoes rapid
atropisomeric interconversion at room temperature.16 Most
of the numerous naphthylisoquinoline alkaloids that have
meanwhile been synthesized (among them 1),19,20 have
been built up by our `lactone method'.21 This technique
relies on the intramolecular coupling of the ester-type
pre-linked aromatic moieties and subsequent atropo-
selective ring cleavage of the resultingÐmostly still con-
®gurationally unstableÐbiaryl lactones. A fundamental
precondition for the method is, however, the presence of
an oxygen function next to the axis (e.g. 8-OH in 1) and a
C1-containing group (e.g. 20-CH3 in 1), as bridge heads for
the lactone constructionÐbut the latter prerequisite is not
ful®lled for 2. Although the lactone method has already
proved to be ¯exible enough to provide ef®cient synthetic
access even to compounds that do not correspond to these
structural requirements (e.g. with no ortho-oxygen function
next to the axis as in 3,8 or with the C1-unit being `cryptic',
as part of the naphthalene system),11 it here seemed more
favorable to build up the 7,60-coupled target molecule
dioncophylline B (2) by an intermolecular coupling
reaction. The otherwise remarkable properties of the lactone
methodÐto overcome even highest steric hindrance in the
coupling step with mostly excellent chemical and optical
yieldsÐwere not really required for the preparation of 2,
with its small ortho-substituents next to the axis and thus
con®gurational instability. In this paper, we report on the
®rst total synthesis of dioncophylline B (2), thus relying on
an intermolecular coupling step, based on theÐto the best
of our knowledgeЮrst double `Directed ortho-Metalation
(DoM)22!cross coupling' approach for the synthesis of
biaryl alkaloids.
usually deliberated from 5a by repeated column chromato-
graphy,26 has now been puri®ed most conveniently, by
precipitation of its methanesulfonate salt. The following
removal of the 6-hydroxy and the 8-O-methyl groups was
performed as reported earlier.26 Introduction of the MOM
group into 6, by reaction with (chloromethoxy)methane,27
gave 7. Interestingly, 7 crystallizes from CHCl3 with
1 equiv. of the solvent, as seen by an X-ray structure
analysis (see Scheme 1). The anticipated DoM reaction on
7 by n-butyllithium/N,N,N0,N0-tetramethylethylendiamine
(TMEDA), with subsequent careful treatment of the meta-
lated intermediate with 1,2-dibromotetrachloroethane at
2788C, gave the desired building block 8 in good yield
and excellent regioselectivity: By HMBC investigations
(not shown) and by an X-ray structure analysis of 8 (see
Scheme 1), the bromo substituent was found to be located in
the required 7-position of the isoquinoline, and no regio-
isomeric or overreacted halogenation products were
detected. If, however, the halogen source was added at
room temperature, inseparable mixtures of the corresponding
2. Results and discussion
The intended intermolecular coupling strategy to dionco-
phylline B (2) required an appropriate functionalization of
the two molecular moieties. Thus, a `DoM!cross coupling'
sequence was chosen to achieve a short and convergent
synthetic access to 2. The DoM strategy has been
established as a valuable tool for the regioselective intro-
duction of substituents into aromatic compounds.22 It takes
advantage of the complexing activity of `Directed Metala-
tion Groups' (DMG's) like carbamate and methoxymethoxy
(MOM) functions.22 These groups direct metals (e.g.
lithium) into the adjacent ortho position; the resulting
lithiated arene may then be trapped using a broad range of
electrophiles. For the synthesis of 2, we chose the MOM
group23 as the DMG and, simultaneously, protecting group
for both, the naphthalene and the isoquinoline building
blocks, since it is strongly ortho-directing and can easily
be introduced and later removed under mild acidic condi-
tions.24 According to previous experience during our ®rst
total synthesis of the structurally related korupensamines,25
we decided to use the isoquinoline as the brominated start-
ing material and the naphthalene as the stannylated reaction
partner for the Stille coupling. The enantio- and diastereo-
merically pure isoquinoline building block 6 (see Scheme 1)
was prepared according to a synthesis elaborated earlier,26
but with an additional signi®cant improvement in the reso-
lution of the two regioisomeric Pictet±Spengler products 5a
and 5b obtained from 4. The desired isomer 5b, hitherto
Scheme 1. Synthesis of the isoquinoline building block 8. Reagents and
conditions: (a) CH3CHO, iPrOH, H2O, rt, 92%; (b) (i), crystallization of
5b´MeSO3H, (ii), (F3CSO2)2O, DABCO, 94%; (iii), Pd(OAc)2, (n-Bu)3N,
HCOOH, 93%, (iv), EtSNa, DMF, re¯ux, 85%; (c) NaH, THF, MOMCl,
87%; (d) n-BuLi, TMEDA, petroleum ether, 2788C, then (CBrCl2)2, 82%.

G. Bringmann et al. / Tetrahedron 57 (2001) 1253±1259
1255
bromo and chloro derivatives resulted. The now syntheti-
cally available 7-functionalized isoquinoline is a new valu-
able building block not only for the synthesis of 2 as
described here, but also for the preparation of further
7-coupled naphthylisoquinolines and theirÐpotentially
bioactiveÐderivatives.
For the preparation of the naphthalene, a Diels±Alder
procedure according to Watanabe28 was selected, starting
with the amide enolate 11 (generated in situ from the acrylic
amide 9,29 see Scheme 2) and the aryne 12 (from the MOM-
protected 2-bromophenol 10, likewise prepared in situ).30
The transformation delivered the appropriately substituted
building block 13 in only one step. Its methyl ether 14,
whose structure was con®rmed by X-ray crystallography,
was lithiated and subsequently quenched with tri-n-butyltin
chloride to give stannane 15.
With the two coupling precursors now in hand, Stille
coupling31 of 15 (generated in situ) with 8 using bis(tri-
phenylphosphine)palladium(II) chloride as the catalyst,
yielded the desired, still protected naphthylisoquinoline 16
in a quite satisfying yield (see Scheme 3).32 Acid-catalyzed
removal of the two MOM groups and hydrogenolytic
cleavage of the benzyl function eventually afforded dionco-
Scheme 3. Completion of the synthesis of dioncophylline B (2). Reagents
and conditions: (a) Pd(PPh3)2Cl2, PPh3, CuBr, LiCl, DMF, 1358C, 56%
from 14; (b) HCl, iPrOH, THF, re¯ux, 91%; (c) Pd0, HCOOH, MeOH,
408C, 68%.
phylline B (2), which was found to be identical in all
respects with natural material from T. peltatum.16
In summary, the highly convergent synthesis of dioncophyl-
line B (2) described here, constitutes the ®rst synthetic
access to a 7,60-coupled naphthylisoquinoline alkaloid at
all. Especially with regard to the promising antimalarial
activity of 2 and of its likewise active dimer,33 the now
possible synthesis of further, structurally simpli®ed 7-
coupled derivatives is a rewarding goal. This work is in
progress.
3. Experimental
3.1. General
Melting points were measured on
a Reichert-Jung
Thermovar hot-plate and are uncorrected. IR spectra were
taken on a Perkin±Elmer 1420 infrared spectrophotometer
and are reported in wave numbers (cm21). NMR spectra
were recorded with Bruker AC 200, AC 250, and DMX
600 spectrometers. The chemical shifts d are given in
parts per million (ppm) with the proton signals in the
deuterated solvent as internal reference for 1H and 13C
NMR. Coupling constants, J, are reported in Hertz. The
mass spectra were obtained on Finnigan MAT 8200 and
MAT 90 mass spectrometers at 70 eV in the EI mode. Silica
gel (60±200 mesh, Merck) was used for column chromato-
graphy, and precoated silica gel 60 F254 plates (Merck) for
TLC. Spots were detected under UV light. Dioncophylline
B (2) was available by isolation from T. peltatum (Dionco-
phyllaceae). Compounds 626 (except for the improvement
Scheme 2. Preparation of the speci®cally stannyl-activated naphthalene 15.
Reagents and conditions: (a) LiN(iPr)(C6H11), THF, 2788C, 32%; (b)
K2CO3, Me2SO4, 88%; (c) n-BuLi, TMEDA, petroleum ether, 2508C,
then (n-Bu)3SnCl.

1256
G. Bringmann et al. / Tetrahedron 57 (2001) 1253±1259
described below), 9,29 10,30 and 1328 were prepared as
published previously.
the eluent, affording 31.0 mg (79.4 mmol, 82%) of 8. The
product was crystallized from methyl tert.-butyl ether/
25
petroleum ether: mp 118±1198C; [a]D ˆ287.78 (cˆ1.02
3.1.1. Separation of (1R,3R)-N-benzyl-8-hydroxy-6-
methoxy-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline (5a)
and (1R,3R)-N-benzyl-6-hydroxy-8-methoxy-1,3-dimethyl-
1,2,3,4-tetrahydroisoquinoline (5b). 2 ml (2.96 g, 30.8
mmol) of methanesulfonic acid were added dropwise to a
solution of 5 g (16.8 mmol) mixture of 5a and b in 100 ml
Et2O prepared according to Ref. 26 until there was no
further precipitation. After ®ltration, the solid was dried in
vacuo and dissolved again in acetone. A few seconds later a
white amorphous solid was formed, which was ®ltered and
rinsed with acetone. The solid consisted of 4.36 g
(11.1 mmol) of pure 5b methanesulfonate, which was trans-
formed to the free base (3.27 g, 11.0 mmol) by treatment
with NH3. The supernatant liquid contained a mixture of
about 80% 5a and 20% 5b. For physical and spectroscopic
data see Ref. 26.
in CHCl3); IR (KBr): n~ 2930 (s, C±H), 1440 (s), 1420 (s),
1360 (m), 1150 (s), 1070 (s), 975 (s), 910 (s), 790 (m), 730
1
(m), 690 (m); H NMR (200 MHz, CDCl3): dˆ1.30 (d,
Jˆ6.7 Hz, 3H, 3-CH3), 1.36 (d, Jˆ6.9 Hz, 3H, 1-CH3),
2.60 (d, Jˆ8.0 Hz, 2H, 4-CH2), 3.00 (s, 3H, OCH3), 3.30
(d, Jˆ14.0 Hz, 1H, NCHHPh), 3.49 (q, Jˆ6.7 Hz, 1H, 3-H),
3.87 (d, Jˆ14.3 Hz, 1H, NCHHPh), 4.05 (q, Jˆ6.8 Hz, 1H,
1-H), 4.80 (d, Jˆ5.9 Hz, 1H, OCHHO), 4.99 (d, Jˆ5.9 Hz,
1H, OCHHO), 6.78 (d, Jˆ8.2 Hz, 1H, 5-H), 7.20±7.44 (m,
5H, Ph), 7.32 (d, Jˆ8.3 Hz, 1H, 6-H); 13C NMR (50 MHz,
CDCl3): dˆ19.73 (3-CH3), 19.94 (1-CH3), 31.66 (C-4),
45.43 (C-3), 49.71 (NCH2Ph), 52.09 (C-1), 56.82 (OCH3),
99.64 (OCH2O), 114.06 (C-7), 126.31 (C-5), 126.59 (Ph),
128.14 (Ph), 128.41 (Ph), 130.56 (C-6), 135.54 (C-9),
135.99 (C-10), 140.75 (Ph), 152.79 (C-8); MS: m/z
(%)ˆ389/391 (1/1) [M]1, 374/376 (16/16) [M2CH3]1,
344/346 (1/2) [M2CH2OCH3]1, 265 (9) [M2Br±
CH2OCH3]1, 91 (100) [C7H7]1, 45 (21) [CH2OCH3]1.
Anal. calcd for C20H24BrNO2 (390.32): C, 62.36; H, 6.20;
N, 3.59. Found: C, 62.86; H, 6.16; N, 3.58.
3.1.2. (1R,3R)-N-Benzyl-8-(methoxymethoxy)-1,3-dimethyl-
1,2,3,4-tetrahydroisoquinoline (7). A mixture of 200 mg
(749 mmol) 626 in 5 ml dry THF and 26.9 mg (1.12 mmol)
NaH was stirred for 30 min at room temperature. After
addition of 187 ml (1.12 mmol) of a 6 M solution of (chloro-
methoxy)methane prepared according to Ref. 27, the
suspension was ®ltered and the solid was rinsed with
Et2O. Column chromatography of the ®ltrate on deactivated
(5% NH3) silica gel afforded 202 mg (650 mmol, 87%) of 7
3.1.4. 4-Methoxy-5-(methoxymethoxy)-2-methylnaphtha-
lene (14). To a solution of 1.00 g (4.59 mmol) 1328 in
15 ml dry acetone, 1.90 g (13.8 mmol) K2CO3 and 1.74 g
(1.31 ml, 13.8 mmol) Me2SO4 were added. After 8 h re¯ux-
ing, the mixture was treated with 4 ml concentrated NH3 and
again heated under re¯ux for 45 min. The crude product,
after removal of the solvent in vacuo, was puri®ed by
column chromatography on silica gel with CH2Cl2/
petroleum ether (50:50!100:0), yielding 938 mg
(4.04 mmol, 88%) of 14 as a crystalline powder from methyl
tert.-butyl ether/petroleum ether: mp 75±768C; IR (KBr): n~
2940 (m, C±H), 1590 (m), 1570 (s), 1380 (m), 1370 (m),
1350 (m), 1270 (s), 1150 (s), 1120 (s), 1090 (s), 1030 (s),
as a bright yellow oil; its hydrochloride was crystallized
from CHCl3/petroleum ether: mp 228±2298C; [a]D
25
ˆ
110.0 (cˆ1.01 in CHCl3); IR (KBr): n~ 2900 (s, C±H),
2520 (m), 1570 (s), 1438 (s), 1245 (s), 1135 (s), 1040 (s),
1020 (s), 1000 (s), 935 (m), 910 (m), 740 (s), 690 (m); H
1
NMR (200 MHz, CDCl3): dˆ1.29 (d, Jˆ6.7 Hz, 3H,
3-CH3), 1.35 (d, Jˆ6.7 Hz, 3H, 1-CH3), 2.65 (d,
Jˆ6.9 Hz, 2H, 4-CH2), 3.28 (d, Jˆ14.1 Hz, 1H, NCHHPh),
3.35 (s, 3H, OCH3), 3.54 (m, 1H, 3-H), 3.86 (d, Jˆ14.0 Hz,
1H, NCHHPh), 4.00 (q, Jˆ6.7 Hz, 1H, 1-H), 5.12 (s, 2H,
OCH2O), 6.77 (d, Jˆ7.6 Hz, 1H, 5-H), 6.88 (d, Jˆ7.3 Hz,
1H, 7-H), 7.10 (dd, Jˆ7.9 Hz, Jˆ7.9 Hz, 1H, 6-H), 7.20±
7.42 (m, 5H, Ph); 13C NMR (63 MHz, CDCl3): dˆ19.67
(3-CH3), 20.00 (1-CH3), 31.91 (C-4), 45.62 (C-3), 49.73
(NCH2Ph), 51.39 (C-1), 55.90 (OCH3), 93.86 (OCH2O),
110.84 (C-7), 122.20 (C-5), 126.32 (C-6), 126.41 (Ph),
128.05 (Ph), 128.48 (Ph), 128.56 (Ph), 136.29 (C-9),
141.19 (C-10), 154.77 (C-8). MS: m/z (%)ˆ311 (1) [M]1,
296 (44) [M2CH3]1, 280 (1) [M2OCH3]1, 266 (3)
[M2CH2OCH3]1, 252 (16), 91 (100) [PhCH2]1, 45 (66)
[CH2OCH3]1.
1
960 (s), 940 (s), 840 (m), 760 (m); H NMR (250 MHz,
CDCl3): dˆ2.46 (d, Jˆ0.8 Hz, 3H, 2-CH3), 3.61 (s, 3H,
CH2OCH3), 3.96 (s, 3H, 5-OCH3), 5.26 (s, 2H, OCH2O),
6.68 (d, Jˆ1.4 Hz, 1H, 3-H), 7.00 (dd, Jˆ7.4 Hz, Jˆ
1.3 Hz, 1H, 6-H), 7.19 (br. s, 1H, 1-H), 7.31 (dd, Jˆ
7.8 Hz, Jˆ7.8 Hz, 1H, 7-H), 7.40 (dd, Jˆ8.2 Hz, Jˆ
1.2 Hz, 1H, 8-H); 13C NMR (63 MHz, CDCl3): dˆ21.81
(2-CH3), 56.24 (4-OCH3), 56.38 (CH2OCH3), 96.90
(OCH2O), 107.71, 108.36 (C-3), 112.85 (C-6), 120.04 (C-
1), 122.23 (C-8), 126.35 (C-7), 136.03, 137.56, 153.80,
156.38; MS: m/z (%)ˆ232 (45) [M]1, 202 (44)
[M2H2CO]1, 186 (10) [M2C2H6O]1, 159 (10), 129 (16),
128 (18), 115 (12), 45 (100) [CH2OCH3]1. Anal. calcd for
C14H16O3 (232.28): C, 72.39; H, 6.94. Found: C, 72.49; H,
6.69.
3.1.3. (1R,3R)-N-Benzyl-7-bromo-8-(methoxymethoxy)-
1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline (8). 96.4 ml
(145 mmol) of a 1.5 M solution of n-BuLi in hexane and
11.2 mg (14.4 ml, 96.4 mmol) TMEDA were added at 08C
to a stirred solution of 30.0 mg (96.4 mmol) 7 in 2 ml dry
petroleum ether. After warming to 108C stirring was con-
tinued for 1 h. The resulting black suspension was cooled to
2788C and treated with 47.1 mg (145 mmol) (CBrCl2)2.
After allowing the mixture to warm up to room temperature
and removal of the solvent in vacuo, puri®cation of the
product was achieved by column chromatography on
deactivated (5% NH3) silica gel with CH2Cl2/methanol as
3.1.5. (1R,3R)-N-Benzyl-7-[40-methoxy-50-(methoxymeth-
oxy)-20-methyl-60-naphthyl]-8-(methoxymethoxy)-1,3-
dimethyl-1,2,3,4-tetrahydroisoquinoline (16). After addi-
tion of 288 ml (434 mmol) of a 1.5 M solution of n-BuLi in
hexane and 42.7 ml (33.5 mg, 288 mmol) TMEDA to a
cooled (2508C) suspension of 66.9 mg (288 mmol) of 14
in dry petroleum ether, the reaction mixture was allowed
to warm up to 08C over 2 h. The solution was again cooled
to 2708C and was augmented by 157 ml (187 mg,
577 mmol) tri-n-butyltin chloride. After having reached

G. Bringmann et al. / Tetrahedron 57 (2001) 1253±1259
1257
room temperature again, the mixture was hydrolyzed with
3 ml of saturated aqueous ammonium chloride and extracted
several times with Et2O. Drying of the combined organic
layers with magnesium sulfate and removal of the solvent in
vacuo afforded a colorless liquid, which was used for the
coupling reaction without further puri®cation. A mixture of
37.4 mg (95.5 mmol) 8, 15.0 mg (57.3 mmol) PPh3, 13.4 mg
(19.1 mmol) Pd(PPh3)2Cl2, 33.4 mg (788 mmol) dry LiCl,
and 1.23 mg (8.60 mmol) CuBr was dried for 40 min at
room temperature in vacuo and was subsequently dissolved
in 5 ml dry DMF. The solution was heated to 1358C in a pre-
heated bath. After 5 min (and after 30 min again) 1 ml of a
solution of the stannane 15 in 2 ml dry DMF was added.
When the reaction mixture had turned black (about 3 h), the
solvent was removed in vacuo. Puri®cation of the product
by column chromatography on deactivated (5% NH3) silica
gel using CH2Cl2/methanol (100:0!99:1) as the eluent gave
29.1 mg (53.7 mmol, 56% based on 8) 16 as an oil:
21.91 (3-CH3, 1-CH3, 20-CH3), 32.17 (C-4), 45.83 (C-3),
49.96 (CH2Ph), 52.21 (C-1), 56.37 (40-OCH3), 107.27
(C-30), 112.99 (C-100), 119.40 (C-60), 119.66 (C-80),
120.98 (C-10), 121.29 (C-5), 123.78 (C-7), 126.30 (C-9),
128.05 (C-6 and Ph), 128.47 (Ph), 131.13 (C-70), 135.72,
136.13, 136.28 (C-20, C-90, C-10), 141.50 (Ph), 149.14
(C-50), 151.60 (C-8), 155.77 (C-40); MS: m/z (%)ˆ453 (1)
[M]1, 438 (100) [M2CH3]1, 423 (9) [M22CH3]1, 219 (4)
[M2CH3]21, 91 (13) [CH2Ph]1. Exact mass calcd for
C29H28NO3 (M2CH3)1 438.2069. Found 438.2071.
3.1.7. Dioncophylline B (2). A mixture of 12.4 mg
(27.1 mmol) 17 in 1 ml dry methanol, 3.45 mg Pd0, and
100 ml (82.0 mg, 1.78 mmol) HCOOH was stirred for 2 h
at 408C. After repeated extraction with CH2Cl2/water, the
solvent of the combined organic layers was removed in
vacuo, and the residue was resolved by column chromato-
graphy on deactivated (5% NH3) silica gel using CH2Cl2/
methanol 9:1, yielding 6.68 mg (18.4 mmol, 68%) 2:
20
[a]D ˆ160.38 (cˆ0.25 in CHCl3); IR (KBr): n~ 3400 (m,
20
[a]D ˆ234.28 (cˆ0.12 in CHCl3); Ref. 16 237.68
O±H), 2940 (m, C±H), 1610 (m), 1550 (m), 1440 (m), 1325
(m), 1145 (s), 1085 (m), 980 (s), 930 (m); 1H NMR
(200 MHz, CDCl3): dˆ1.33 (d, Jˆ6.6 Hz, 3H, 3-CH3),
1.47 (d, Jˆ6.8 Hz, 3H, 1-CH3), 2.48 (d, Jˆ0.4 Hz, 3H, 20-
CH3), 2.75 (m, 5H, 4-Heq, 4-Hax, CH2OCH3), 2.92 (d,
Jˆ13.6 Hz, 1H, NCHHPh), 3.91 (d, J<14.0 Hz, 1H,
NCHHPh), 3.58 (m, 1H, 3-H), 3.96 (s, 3H, 40-OCH3),
4.10 (q, Jˆ6.7 Hz, 1H, 1-H), 4.35 (d, Jˆ5.9 Hz, 1H,
OCHHO), 4.96 (d, Jˆ5.4 Hz, 1H, OCHHO), 6.70 (s, 1H,
30-H), 6.94 (d, Jˆ7.8 Hz, 1H, 5-H), 7.18±7.50 (m, 9H,
Ar±H); 13C NMR (50 MHz, CDCl3): dˆ19.76, 20.42,
21.79 (3-CH3, 1-CH3, 20-CH3), 31.87 (C-4), 45.52 (C-3),
49.73 (CH2Ph), 51.91 (C-1), 56.00, 56.35 (40-OCH3, 2
CH2OCH3), 98.64 (OCH2O), 100.85 (OCH2O), 108.18
(C-30, C-100), 118.11 (C-60, C-80), 120.27 (C-10), 121.84
(C-5), 123.47 (C-7), 126.43 (C-9), 128.11 (C-6 and Ph),
128.37 (Ph), 129.68 (Ph), 131.34 (C-70), 135.21, 136.03,
137.18 (C-20, C-90, C-10), 141.08 (Ph), 150.41 (C-50,
C-8), 155.77 (C-40); MS: m/z (%)ˆ541 (0.5) [M]1, 526
(100) [M2CH3]1, 482 (7) [M2CH3±C2H4O]1, 450 (12)
[M2CH2Ph]1, 420 (14) [M2CH2Ph±2CH3]1, 91 (15)
[CH2Ph]1, 45 (5) [CH2OCH3]1. Exact mass calcd for
C33H36NO5 (M2CH3)1 526.2593. Found 526.2592.
(cˆ0.37 in CHCl3). Exact mass calcd for C22H22NO3
(M2CH3)1 297.1600. Found 297.1596. All spectroscopic
and physical data were in accordance with those published
in the literature.16
3.2. Single-crystal X-ray diffraction analyses of 7, 8 and
14
All measurements of diffraction intensities were performed
on a Bruker AXS P4 diffractometer with an incident beam
Ê
graphite monochromator (MoKa radiation, lˆ0.71073 A)
in v-scan mode in the range of 1.758,u,27.58.34 The
structures were solved by direct phase determination and
re®ned by full-matrix anisotropic least-squares with the
aid of the program Shelxtl-Plus.35 All non-hydrogen
atoms were re®ned anisotropically. The hydrogen positions
were calculated using a riding model and were considered
®xed with isotropic thermal parameters in all re®nements.
Software used to prepare material for publication: Schakal
88.36
3.2.1. Crystal data for 7. The crystal chosen for X-ray
investigations was a clear colorless plate with the
approximate dimensions 0.35£0.65£0.85 mm. C20H25NO2´
HCl´CHCl3 (467.26 g mol21) crystallizes in the monoclinic
system, space group P21, with aˆ13.2511 (9), bˆ7.3856
3.1.6. (1R,3R)-N-Benzyl-7-(50-hydroxy-40-methoxy-20-
methyl-60-naphthyl)-8-hydroxy-1,3-dimethyl-1,2,3,4-tetra-
hydroisoquinoline (17). A solution of 20.0 mg (36.9 mmol)
16, 500 ml 1N aqueous HCl and 500 ml isopropanol in 1 ml
THF was re¯uxed for 45 min. Removal of the solvent in
vacuo and subsequent column chromatography on deacti-
vated silica gel using CH2Cl2/methanol (100:0!98:2) as the
eluent yielded 15.3 mg (33.7 mmol, 91%) 17 as an amor-
Ê
Ê 3
(6), cˆ13.527 (1) A, bˆ118.479 (5)8, Vˆ1163.7 (2) A ,
Zˆ2, m(MoKa)ˆ0.53 mm21, and Dcalcdˆ1.334 g cm23
.
The unit cell parameters were determined by least-squares
re®nement using 61 centered re¯ections within
12.68,u,17.58. A total of 6033 re¯ections were collected
in v-scan mode to 2umaxˆ558 (h: 21!17, k: 29!9, l:
217!15), of which 5339 were unique. In re®nements,
weights were used according to the scheme wˆ1/[s2(Fo)].
The re®nement converged to the ®nal agreement factors
Rˆ0.076, and Rwˆ0.081, for 257 parameters and 5089
observed re¯ections with F.3s(F); data-to-parameter
ratio being 19.80. The electron density of the largest differ-
20
phous solid: [a]D ˆ188.08 (cˆ0.48 in CHCl3); IR (KBr):
n~ 3230 (s, O±H), 2940 (m, C±H), 1620 (m), 1565 (m), 1440
(m), 1385 (m), 1350 (s), 1315 (m), 1240 (m), 1135 (m),
1
1100 (m), 1020 (m); H NMR (200 MHz, CDCl3): dˆ1.31
(d, Jˆ6.7 Hz, 3H, 3-CH3), 1.46 (d, Jˆ6.7 Hz, 3H, 1-CH3),
2.49 (d, Jˆ0.5 Hz, 3H, 20-CH3), 2.71 (m, 2H, 4-Heq and
4-Hax), 3.41 (d, Jˆ14.3 Hz, 1H, NCHHPh), 3.58 (m, 1H,
3-H), 3.90 (d, Jˆ14.4 Hz, 1H, NCHHPh), 4.07 (s, 3H, 40-
OCH3), 4.17 (q, Jˆ6.8 Hz, 1H, 1-H), 6.69 (d, Jˆ1.2 Hz, 1H,
30-H), 6.74 (s, 1H, 10-H), 6.83 (d, Jˆ7.9 Hz, 1H, 5-H), 7.16
(d, Jˆ7.8 Hz, 1H, 6-H), 7.21±7.46 (m, 7H, Ar±H), 10.32 (s,
1H, 50-OH); 13C NMR (50 MHz, CDCl3): dˆ19.69, 19.82,
Ê 23
ence peak was found to be 1.09 eA , while that of the
largest difference hole was 0.77 eA
Ê 23
.
3.2.2. Crystal data for 8. The crystal chosen for X-ray
investigations was a clear colorless plate with the

1258
G. Bringmann et al. / Tetrahedron 57 (2001) 1253±1259
E.-M.; Peters, K. Phytochemistry 2001, in press. Part of this
work has been published in a preliminary communication:
Bringmann, G.; GuÈnther, C. Synlett 1999, 216±218.
approximate dimensions 0.45£0.65£0.10 mm. C20H24BrNO2
(390.33 g mol21) crystallizes in the monoclinic system,
space group P21, with aˆ7.8942 (5), bˆ11.9839 (7),
Ê
Ê 3
cˆ10.3782 (8) A, bˆ103.443 (5)8, Vˆ954.9 (1) A , Zˆ4,
m(MoKa)ˆ2.16 mm21, and Dcalcdˆ1.385 g cm23. The unit
cell parameters were determined by least-squares re®ne-
ment using 61 centered re¯ections within 10.58,u,19.58.
A total of 5293 re¯ections were collected in v-scan mode to
2umaxˆ558 (h: 21!10, k: 215!15, l: 213!13), of which
4354 were unique. In re®nements, weights were used
according to the scheme wˆ1/[s2(Fo)]. The re®nement
converged to the ®nal agreement factors Rˆ0.072, and
Rwˆ0.063, for 217 parameters and 2983 observed re¯ec-
tions with F.3s(F); data-to-parameter ratio being 13.75.
The electron density of the largest difference peak was
2. Bringmann, G.; Pokorny, F. In The Alkaloids, Cordell, G. A.,
Ed.; Academic: New York, 1995; Vol. 46, pp 127±271.
Â
3. Bringmann, G.; FrancËois, G.; Ake Assi, L.; Schlauer, J.
Chimia 1998, 52, 18±28.
4. (a) 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, 2001 (in press). (b) Bringmann, G.; Feineis, D.
Â
Acta Chim. Therapeut. 2000, 26, 151±171.
5. Boyd, M. R.; Hallock, Y. F.; Cardellina II, J. H.; Manfredi,
K. P.; Blunt, J. W.; McMahon, J. B.; Buckheit Jr., R. W.;
È
Bringmann, G.; Schaffer, M.; Cragg, G. M.; Thomas, D. W.;
Jato, J. G. J. Med. Chem. 1994, 37, 1740±1745.
Ê 23
found to be 1.54 eA , while that of the largest difference
hole was 0.84 eA
Ê 23
.
6. Bringmann, G.; Hamm, A.; GuÈnther, C.; Michel, M.; Brun, R.;
Mudogo, V. J. Nat. Prod. 2000, 63, 1465±1470.
7. Bringmann, G.; RuÈbenacker, M.; Ammermann, E.; Lorenz,
3.2.3. Crystal data for 14. The crystal chosen for X-ray
investigations was a clear colorless prism with the approxi-
mate dimensions 0.15£0.20£0.65 mm. C14H16O3 (232.28
g mol21) crystallizes in the monoclinic system, space
group Pc, with aˆ8.5499 (6), bˆ8.5437 (5), cˆ8.7539
Â
G.; Ake Assi, L. (BASF AG); German Patent D.O.S. DE 41
17 080 A 1, disclosure 26.11.92; European Patent EP 0515 856
A1, disclosure 02.12.92.
8. Bringmann, G.; Holenz, J.; Weirich, R.; RuÈbenacker, M.;
Funke, C.; Boyd, M. R.; Gulakowski, R. J.; FrancËois, G.
Tetrahedron 1998, 54, 497±512.
Ê
Ê 3
(6) A, bˆ110.118 (6)8, Vˆ600.44 (8) A , Zˆ4,
m(MoKa)ˆ0.09 mm21, and Dcalcdˆ1.285 g cm23. The unit
cell parameters were determined by least-squares re®ne-
ment using 60 centered re¯ections within 11.28,u,17.58.
A total of 3298 re¯ections were collected in v-scan mode to
2umaxˆ558 (h: 211!1, k: 211!11, l: 210!11), of which
1651 were unique. In re®nements, weights were used
according to the scheme wˆ1/[s2(Fo)]. The re®nement
converged to the ®nal agreement factors Rˆ0.056, and
Rwˆ0.055, for 153 parameters and 1601 observed re¯ec-
tions with F.3s(F); data-to-parameter ratio being 10.46.
The electron density of the largest difference peak was
9. Rizzacasa, M. A. In Studies in Natural Products Chemistry,
Atta-ur-Rahman, R., Ed.; Elsevier: Amsterdam, 1998; Vol. 20,
pp 407±453.
10. Bringmann, G.; Saeb, W.; RuÈbenacker, M. Tetrahedron 1999,
55, 423±432.
È
11. Bringmann, G.; Ochse, M.; Gotz, R. J. Org. Chem. 2000, 65,
2069±2077.
12. Bringmann, G.; RuÈbenacker, M.; Jansen, J. R.; Scheutzow, D.;
Â
Ake Assi, L. Tetrahedron Lett. 1990, 31, 639±642.
Ê 23
13. Bringmann, G.; Gramatzki, S.; Grimm, C.; Proksch, P.
Phytochemistry 1992, 31, 3821±3825.
found to be 0.40 eA , while that of the largest difference
.
Ê 23
hole was 0.36 eA
14. Bringmann, G.; Holenz, J.; Wiesen, B.; Nugroho, B. W.;
Proksch, P. J. Nat. Prod. 1997, 60, 342±347.
Â
15. Bringmann, G.; Holenz, J.; Ake Assi, L.; Hostettmann, K.
Tables of bond distances and angles, atomic coordinates,
and anisotropic thermal parameters for 7 (CCDC 151691),
8 (CCDC 151690), and 14 (CCDC 151689) have been
deposited with the Cambridge Crystallographic Data
Centre.37
Planta Med. 1998, 64, 485±486.
16. Bringmann, G.; RuÈbenacker, M.; Geuder, T.; Ake Assi, L.
Â
Phytochemistry 1991, 30, 3845±3847.
17. Bringmann, G.; RuÈbenacker, M.; Weirich, R.; Ake Assi, L.
Â
Phytochemistry 1992, 31, 4019±4024.
18. FrancËois, G.; Timperman, G.; Eling, W.; Ake Assi, L.; Holenz,
Â
Acknowledgements
J.; Bringmann, G. Antimicrob. Agents Chemother. 1997, 41,
2533±2539.
This work was supported by the Bundesministerium fuÈr
Bildung, Wissenschaft und Forschung (project no.
0310722) and by the Fonds der Chemischen Industrie
(generous fellowship to C. G. and ®nancial support). The
19. Bringmann, G.; Jansen, J. R.; Reuscher, H.; RuÈbenacker, M.;
Peters, K.; von Schnering, H. G. Tetrahedron Lett. 1990, 31,
643±646.
20. Bringmann, G.; Jansen, J. R. Synthesis 1991, 825±827.
21. Bringmann, G.; Breuning, M.; Tasler, S. Synthesis 1999, 525±
558.
Â
authors thank Professor L. Ake Assi (Centre National de
Floristique, Universite d'Abidjan, 08 BP 172, Abidjan 08,
Â
Ivory Coast) for providing the plant material, M. Cos, J.
Hahn, and K. Dumbuya for experimental assistance, Dr T.
Pabst for competent help in preparing the graphics, and E.
Ruckdeschel, Dr D. Scheutzow, Dr G. Lange, and F.
Dadrich for NMR and MS measurements.
22. (a) Snieckus, V. Chem. Rev. 1990, 90, 879±933. (b) Snieckus,
V. In Chemical Synthesis, Chatgilialoglu, C., Snieckus, V.,
Eds.; Kluwer Academic: Netherlands, 1996; pp 191±221.
23. (a) Winkle, M. R.; Ronald, R. C. J. Org. Chem. 1982, 47,
2101±2108. (b) Ronald, R. C. Tetrahedron Lett. 1975, 16,
3973±3974. (c) Townsend, C. A.; Bloom, L. M. Tetrahedron
Lett. 1981, 22, 3923±3924.
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1259
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binary Pd catalyst (obtained from Pd(OAc)2 and tris(ortho-
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E.; Hibino, S. J. Org. Chem. 1997, 62, 2535±2643.
È
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Ofele, K.; Broûmer, C. Angew. Chem. 1995, 107, 1992±1993;
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Henschel, P.; Schaffer, M.; Stablein, M.; Kelly, T. R.; Boyd,
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È
Gotz, R.; Harmsen, S.; Holenz, J.; Walter, R. Liebigs Ann.
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37. A complete listing of the atomic coordinates for 7, 8, and 14
can be obtained free of charge, on request, from the Director,
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: (1Int) 44-1223 336 033;
e-mail: deposit@ccdc.cam.ac.uk], on quoting the depository
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