Synthesis of xestomanzamines a and b

Article abstract of DOI:10.3987/com-00-9107

Synthetic pathways are described for the synthesis of two naturally occurring β-carbolines, xestomanzamine A and B. The synthesis of aromatic xestomanzamine A was most conveniently achieved by way of a Grignard reaction in dichloromethane. This route is suitable for the synthesis of analogues with modifications in the imidazole ring of xestomanzamine A. Xestomanzamine B, an oxidation-sensitive dihydro-β-carboline, was prepared by Pictet-Spengler condensation of tryptamine with a vicinal tricarbonyl substituted imidazole.

Full text of DOI:10.3987/com-00-9107

HETEROCYCLES, Vol. 55, No. 3, pp. 495 – 503, Received, 13th November, 2000
SYNTHESIS OF XESTOMANZAMINES AAND B
Brigitte E.A. Burm,# Peter Blokker, Edwin Jongmans, Erwin van Kampen, Martin
J. Wanner, and Gerrit-Jan Koomen*
Laboratory of Organic Chemistry, Institute of Molecular Chemistry, University of
Amsterdam, Nieuwe Achtergracht 129, 1018 WS Amsterdam, The Netherlands
Abstract - Synthetic pathways are described for the synthesis of two naturally
occurring β-carbolines, xestomanzamine A and B. The synthesis of aromatic
xestomanzamine A was most conveniently achieved by way of a Grignard
reaction in dichloromethane. This route is suitable for the synthesis of analogues
with modifications in the imidazole ring of xestomanzamine A. Xestomanzamine
B, an oxidation-sensitive dihydro-β-carboline, was prepared by Pictet-Spengler
condensation of tryptamine with a vicinal tricarbonyl substituted imidazole.
INTRODUCTION
In 1995 four new biologically active β-carbolines were isolated from the Okinawan marine sponge
Xestospongia sp.1 Amongst those xestomanzamine A (1) and B (2) were characterised, the latter
exhibiting cytotoxicity against human epidermoid carcinoma (KB) cells.2 It was found that the 3,4-
dihydro-β-carboline system in 2 was gradually converted to β-carboline derivative (1) by air-oxidation.
Figure 1. Naturally occurring xestomanzamines A and B and nazlinine and 5-HT3 antagonist ondansetron.
# Present address: Leiden Institute of Chemistry, Gorleaus Laboratories, Postbus 23, 2300 RA, Leiden, The Netherlands
* Fax: 0031-02-5255690; E-mail: gjk@org.chem.uva.nl

The alkaloid nazlinine (3) was isolated and characterised several years ago3 and has been the subject of
synthetic studies in our group4 and others5 for some time. In view of the structural similarities among 1-3,
1 and 2 can be regarded as conformationally restricted nazlinine analogues, in which one of the nitrogen
atoms is part of the imidazole ring. In addition, there is a resemblance between 1, 2 and ondansetron (4),
which is a known 5-HT3 antagonist.6
Untill now only one synthesis of xestomanzamine A (1) has been published7 with as a key step the
addition of a C2-protected 5-lithioimidazole to a β-carboline. We wish to report here a new
straightforward synthesis of xestomanzamine A (1), as well as a strategy to synthesise the air sensitive
xestomanzamine B (2). Due to the limited stability of 2, vide supra, the imine bond in the 3,4-dihydro-β-
carboline system had to be introduced in the last step of the synthesis.
RESULTS AND DISCUSSION
Synthesis of xestomanzamine A and some analogues.
1-Cyano-β-carboline (6), which is readily available from tryptamine (5),8 was chosen as electrophile in
addition reactions with imidazole anions. A suitable imidazole nucleophile is not found straightforwardly,
since the 4(5)-lithium- or magnesiumimidazoles, which are initially formed after halogen/ metal exchange,
rearrange to the thermodynamically more stabile 2-metallated isomers. This process can be prevented by
blocking the 2-position with a triethylsilyl substituent, as was applied in the xestomanzamine A synthesis
of Molina et al.7 We here report an alternative approach that prevents this 5 → 2 organometal
rearrangement, the so-called “dance reaction”,10,9 by using Grignard reagent (8) in dichloromethane as the
solvent instead of the more commonly used ether or THF (Scheme 1). Imidazolemagnesium bromide (8)
is prepared by an exchange reaction of 5-iodo-1-methylimidazole (7) with methylmagnesium bromide10.
Reaction of a dichloromethane solution of 8 with 1-cyano-β-carboline (6) followed by hydrolytic work-up
immediately produced xestomanzamine A (1) in 55% yield. Due to the acidity of the indole N-H two
equivalents of the imidazole anion were necessary to complete the reaction. Indeed when a co-ordinating
solvent like THF was used, isomer (10) of xestomanzamine A was obtained via rearrangement of 8 to 9.
Examples of such a base-catalysed halogen “dance reaction” have been reported for imidazoles,11,12 but
the reaction was first described to occur in aryl halides.13 Also halogenated thiophenes are known to
undergo this rearrangement.14 In order to demonstrate the general applicability of the route to 1, three
additional analogues (14-16) of xestomanzamine A (1) were synthesised (Scheme 2). Derivative (14), in
which the imidazole 2-position is substituted with a methyl group, was obtained by Grignard reaction of
tritylimidazole (11) with 1-cyano-β-carboline (6), followed by removal of the trityl-protecting group. The
dimethyl-substituted analogues (15) and (16) were obtained in good yield using the same procedure as
described for the synthesis of 1.

Scheme 1. Synthesis of xestomanzamine A (1) and demonstration of the "dance reaction".
Scheme 2. Application of the Grignard reaction in the synthesis of xestomanzamine A analogues (14 – 16).

Synthesis of xestomanzamine B.
For the synthesis of the partially reduced xestomanzamine B (2) a different strategy had to be employed
since selective reduction of the 3,4-double bond in 1 was not succesful. Working with the dihydro-β-
carboline ring system should be kept to a minimum, because oxidation by air-oxygen easily gives the
fully aromatised 1. For this reason the sensitive 3,4-dihydro bond in 2 was introduced in the last step of
the synthesis. The key reaction of this approach is Pictet-Spengler condensation of tryptamine (5) with
tricarbonyl substituted imidazole (21). Vicinal tricarbonyl compounds have been employed successfully
in the syntheses of eudistomins T, I and M,15 and isoquinoline16 and vincamine-related alkaloids.17
Vicinal tricarbonyl substituted N-methylimidazole (21) was prepared from N-methyl-5-
imidazolecarboxylic acid (17). A convenient large scale synthesis of the corresponding methyl ester has
been described;18 hydrolysis of the methyl ester and reaction of acid (17) with oxalyl chloride afforded
the acid chloride (18). Condensation of 18 with the stabilised phosphorane (19)19 yielded crystalline ylide
(20). Ozonolysis of 20 in a mixture of dichloromethane and methanol followed by reductive work-up
Scheme 3. Synthesis of xestomanzamine B (2).

furnished the vicinal tricarbonyl derivative (21), which was used without further purification in the
condensation step with tryptamine (5). The central carbonyl group of 21 is activated by the two other
carbonyl functions for participation in the Pictet-Spengler condensation catalysed by trifluoroacetic acid.
In the same reaction, the tert-butyl ester is cleaved to form β-keto acid (22) (not isolated), followed by
facile decarboxylation to the tetrahydro-β-carboline (23). The intermediate (23) was oxidised in situ by
air-oxygen to give the final product xestomanzamine B (2) in a yield of 43% starting from ylide (20). The
reaction time and purification of 2 had to be controlled carefully in order to supress the second oxidation
step to the fully aromatised xestomanzamine A (1).
Synthetic xestomanzamine A (1)‡ and B (2) were identical in all aspects (mp, IR, MS, 1H and 13C NMR)
with the natural alkaloids.1
CONCLUSIONS
New routes were developed for the synthesis of the alkaloids xestomanzamine A (1) and B (2). A
modified Pictet-Spengler reaction between tryptamine and a vicinal tricarbonyl substituted imidazole is a
useful strategy for the synthesis of the air-sensitive xestomanzamine B (2). A second pathway via
Grignard reaction of imidazole magnesiumbromide with 1-cyano-β-carboline was more convenient for
the synthesis of xestomanzamine A (1) and is in particular suitable for the preparation of a variety of
analogues 10, 14, 15 and 16.
EXPERIMENTAL
General Remarks: See for general information ref. 20. For ozonolysis a Fischer Ozon-generator 500 was
used, which produces 1.2 g ozone per hour at an oxygen flow of 25 Lh-1.
(9H-β-Carbolin-1-yl)-(3-methyl-3H-imidazol-4-yl)-methanone (Xestomanzamine A) (1): To a
solution of 5-iodo-1-methylimidazole (7)21 (0.35 g, 1.68 mmol) in dichloromethane (3.5 mL) was added
dropwise at 0 °C a solution of methylmagnesium bromide in ether (0.61 mL, 1.83 mmol, 3 M). After
stirring during 30 min the mixture was allowed to warm to rt and slowly added to a solution of 1-cyano-β-
carboline8 (170 mg, 0.86 mmol) in dichloromethane (30 mL). The mixture was stirred during one night at
rt and then washed with water. The water layer was extracted with CH2Cl2 (3x) and the combined organic
layers were washed with water (3x), dried (Na2SO4) and evaporated. Crystallisation from methanol gave
1
1·MeOH as yellow plates (according to the H NMR spectrum these crystals contain one equivalent of
methanol, see also footnote ‡ to the text). Alternatively the product could also be purified by flash
1
chromatography (EtOAc) to afford 1 (130 mg, 55%) as yellow needles: mp 185 - 186 °C; H NMR
‡ Xestomanzamine A (1) was crystallised from methanol as yellow plates and contained one equivalent of methanol according
to its 1H NMR spectrum. Upon heating, the methanol evaporated and yellow needles (mp 185 - 186 °C) were formed.
Alternatively, purification by flash chromatography (EtOAc) also gave those yellow needles. Kobayashi et al.1 report the
isolation of xestomanzamine A (1) as yellow needles with mp 185 - 186 °C, although their crystal structure shows the presence
of one equivalent of methanol.

(CDCl3, 400 MHz) δ 10.42 (br s, 1H, H-9), 8.93 (s, 1H, H-13), 8.59 (d, J = 4.9 Hz, 1H, H-3), 8.17 (d, J =
6.0 Hz, 1H, H-5), 8.15 (d, J = 4.9 Hz, 1H, H-4), 7.67 (s, 1H, H-15), 7.63 - 7.57 (m, 2H, H-7, H-8), 7.36 -
7.32 (m, 1H, H-6), 4.10 (s, 3H, NCH3); 13C NMR (CDCl3, 100 MHz) δ 184.3, 143.4, 143.1, 140.8, 138.0,
136.6, 136.4, 131.5, 129.2, 129.1, 121.7, 120.7, 120.6, 118.5, 111.8, 35.2; IR (KBr) ν 3427, 1612; HRMS
(FAB) obs. mass 277.1119, calcd for C16H13N4O (M + H) 277.1089.
(9H-β-Carbolin-1-yl)-(1-methyl-1H-imidazol-2-yl)-methanone (10): To a solution of 5-iodo-1-
methylimidazole (7)21 (50 mg, 0.24 mmol) in tetrahydrofuran (0.5 mL) a solution of methylmagnesium
bromide in ether (0.09 mL, 0.27 mmol, 3 M) was added dropwise at 0 °C. After stirring during 30 min the
mixture was allowed to warm to rt and slowly added to a solution of 1-cyano-β-carboline8 (20 mg, 0.11
mmol) in tetrahydrofuran (4 mL). The mixture was stirred during one night at rt and then concentrated in
vacuo. The residue was dissolved in CH2Cl2 (6 mL) and water (10 mL) was added. The layers were
separated and the water layer extracted with CH2Cl2 (2x). The combined organic layers were dried
(Na2SO4) and evaporated. Flash chromatography (EtOAc) afforded 10 (20 mg, 64%) as a foam: 1H NMR
(CDCl3, 400 MHz) δ 10.91 (br s, 1H, H-9), 8.52 (d, J = 5.1 Hz, 1H, H-3), 8.18 (d, J = 7.8 Hz, 1H, H-5),
8.08 (d, J = 5.1 Hz, 1H, H-4), 7.62 - 7.57 (m, 2H, H-7, H-8), 7.57 (br s, 1H, H-14), 7.42 (br s, 1H, H-13),
7.34 - 7.32 (m, 1H, H-6), 3.66 (s, 3H, NCH3); IR (CHCl3) ν 3460, 1618; HRMS (FAB) obs. mass
277.1084, calcd for C16H13N4O (M + H) 277.1089.
(9H-β-carbolin-1-yl)-(2-methyl-3H-imidazol-4-yl-methanone (14): The same procedure was used as
described for the synthesis of xestomanzamine A, using 11 (900 mg, 2.0 mmol), 1.1 eq. of MeMgBr and
6 (100 mg, 0.52 mmol). After work-up, the remaining residue was redissolved in ethanol (15 mL) and
concd hydrogen chloride (50 mL) was added. The mixture was stirred at rt during 3 h and subsequently
washed with ether and concentrated under reduced pressure. The residue was dissolved in a saturated,
aqueous K2CO3 solution which was extracted with EtOAc (3x). The combined organic layers were dried
(Na2SO4) and evaporated. Flash chromatography (EtOAc/ NEt3 90/ 10) afforded 14 (109 mg, 76%).
1
Crystallisation of the HCl salt from EtOH/ HCl gave a solid white material: mp 246 - 248 ºC; H NMR
(DMSO-d6, 400 MHz) δ 12.09 (br s, 1H, H-9), 8.94 (s, 1H, H-15), 8.62 (d, J = 4.9 Hz, 1H, H-3), 8.55 (d,
J = 4.9 Hz, 1H, H-4), 8.35 (d, J = 7.8 Hz, 1H, H-5), 7.88 (d, J = 8.2 Hz, 1H, H-8), 7.67 - 7.63 (m, 1H, H-
13
7), 7.37 - 7.34 (m, 1H, H-6), 2.73 (s, 3H, CH3). C NMR (DMSO-d6, 100 MHz) δ 180.4, 147.4, 141.9,
138.0, 135.3, 134.2, 131.6, 129.3, 129.2, 127.7, 122.0, 120.6, 120.1, 119.9, 113.2, 11.5; IR (KBr) ν 3347,
1621; HRMS (FAB) obs. mass 277.1086, calcd for C16H13N4O (M + H) 277.1089.
(9H-β-Carbolin-1-yl)-(1,2-dimethyl-1H-imidazol-4-yl)-methanone A (15): The same procedure was
used as described for the synthesis of xestomanzamine A, using 12 (444 mg, 2.0 mmol), 1.1 eq. of
MeMgBr and 6 (100 mg, 0.52 mmol). Flash chromatography (EtOAc/ NEt3 95/ 5) afforded 15 (122 mg,
81%) as a yellow solid: mp 200 - 204 ºC; 1H NMR (DMSO-d6, 400 MHz) δ 11.82 (br s, 1H, H-9), 8.53 (d,
J = 4.7 Hz, 1H, H-3), 8.31 - 8.29 (m, 3H, H-4, H-5, H-15), 7.87 (d, J = 8.2 Hz, 1H, H-8), 7.59 - 7.55 (m,
13
1H, H-7), 7.30 - 7.27 (m, 1H, H-6), 3.68 (s, 3H, NCH3), 2.41 (s, 3H, CH3); C NMR (DMSO-d6, 100
MHz) δ 167.1, 145.4, 140.9, 137.5, 137.0, 134.7, 134.3, 133.4, 129.5, 128.3, 121.6, 120.3, 119.7, 116.5,

113.0, 32.7, 12.5; IR (KBr) ν 3356, 1593; HRMS (FAB) obs. mass 291.1240, calcd for C17H15N4O (M +
H) 291.1246.
(9H-β-Carbolin-1-yl)-(2,3-dimethyl-3H-imidazol-4-yl)-methanone (16): The same procedure was used
as described for the synthesis of xestomanzamine A, using 13 (444 mg, 2.0 mmol), 1.1 eq. of MeMgBr
and 6 (100 mg, 0.52 mmol). Flash chromatography (EtOAc/ NEt3 95/ 5) afforded 16 (118 mg, 79%) as a
1
yellow solid: mp 264 - 267 °C; H NMR (DMSO-d6, 400 MHz) δ 11.99 (br s, 1H, H-9), 8.56 - 8.54 (m,
2H, H-3, H-15), 8.43 (d, J = 4.4 Hz, 1H, H-4), 8.32 (d, J = 7.6 Hz, 1H, H-5), 7.83 (d, J = 8.0 Hz, 1H, H-
8), 7.63 - 7.61 (m, 1H, H-7), 7.33 - 7.32 (m, 1H, H-6), 4.00 (s, 3H, NCH3), 2.47 (s, 3H, CH3); 13C NMR
(DMSO-d6, 100 MHz) δ 182.3, 151.4, 141.9, 141.6, 137.2, 137.0, 135.2, 131.0, 129.6, 128.8, 121.7,
120.1, 120.0, 118.6, 113.0, 33.0, 13.2; IR (KBr) ν 3244, 1609; HRMS (FAB) obs. mass 291.1276, calcd
for C17H15N4O (M + H) 291.1246.
3-Methyl-3H-imidazole-4-carbonyl chloride•HCl (18): A suspension of 1718,¶ (0.74 g, 5.8 mmol),
oxalyl chloride (5.4 mL, 60 mmol) and dimethylformamide (1 drop) in dichloromethane (10 mL) was
stirred vigorously during one night at rt. The suspension was filtered and the residue was washed with dry
CH2Cl2 to give 18 (0.90 g, 85%) as its solid hydrogen chloride salt which was immediately used in the
next step: IR (KBr) ν 2991, 2749, 2597, 1774, 1561, 1457.
3-(3-Methyl-3H-imidazol-4-yl)-3-oxo-2-(triphenyl-λ5-phosphanylidene)-propionic acid tert-butyl
ester (20): To a solution of tert-butyl(triphenylphosphoranylidene)acetate (19)19 (1.82 g, 4.83 mmol) and
N,N-diisopropylethylamine (2.18 mL, 15 mmol) in dichloromethane (25 mL), 18 (0.88 g, 4.83 mmol) was
added at 0 °C. The solution was subsequently stirred during 30 min at 0 °C and 4 h at rt. An saturated
aqueous Na2CO3 solution was added and the layers were separated. The water layer was extracted with
CH2Cl2 (3x) and the combined organic layers were dried (Na2SO4) and evaporated. Crystallisation from
EtOAc gave a first crop of 20. By flash chromatography (EtOAc/ EtOH 90/ 10) of the motherliquor
followed by crystallisation from EtOAc, 20 (1.12 g, 2.41 mmol) was obtained in a total yield of 41%: mp
168 - 169 °C; 1H NMR (CDCl3, 400 MHz) δ 7.77 - 7.72 (m, 6H, Ar-H), 7.57 (s, 1H, H-2), 7.56 - 7.51 (m,
3H, Ar-H), 7.48 - 7.44 (m, 6H, Ar-H), 7.33 (s, 1H, H-4), 3.69 (s, 3H, NCH3), 1.03 (s, 9H, C(CH3)3); 13C
2
NMR (CDCl3, 100 MHz) δ 181.2 (C-6, JCP = 8.0 Hz), 166.6 (C-8, 2JCP = 12.4 Hz), 139.4, 134.2, 133.5,
4
2
2
133.1 (Ar-C) 131.6 (Ar-C, JCP = 3.0 Hz), 128.4 (Ar-C, JCP = 13.1 Hz), 126.3 (Ar-C, JCP = 92.6 Hz),
78.5 (C(CH3)3), 69.7 (C-7, 1JCP = 111 Hz), 33.0 (NCH3), 27.9 (C(CH3)3); IR (KBr) ν 1669, 1657; HRMS
(EI) obs. mass 484.1902 calcd for C29H29N2O3P 484.1916.
Ozonolysis of phosphorane (20) to 3-(3-methyl-3H-imidazol-4-yl)-2,3-dioxo-propionic acid tert-butyl
ester (21): Ozone was passed through a solution of 20 (98 mg, 0.2 mmol) in a mixture of methanol (2
mL) and dichloromethane (6 mL) at -60 °C until the starting material had disappeared according to TLC
analysis (about 10 min). Nitrogen gas was bubbled through the solution during 15 min at -60 °C to
¶ 1-Methyl-5-imidazolecarboxylic acid (17) was synthesised by hydrolysis (6 M NaOH, 80 °C, 18 h) of the corresponding
methyl ester18 and obtained by crystallisation after adjusting the pH to 2 (concd HCl): mp 256 - 258 °C; 1H NMR (D2O, 400
MHz) δ 7.63 (s, 1H, H-2), 7.43 (s, 1H, H-4), 3.85 (s, 3H, NCH3); 13C NMR (D2O, 100 MHz) δ 170.6 (C-6), 144.4 (C-5), 135.9
(C-4), 132.1 (C-2), 36.4 (NCH3); IR (KBr) ν 1699.

remove excess ozone and the reaction was quenched with an excess of dimethyl sulfide. The reaction
mixture was concentrated in vacuo at rt to afford 21 which was immediately used in the Pictet-Spengler
condensation.
(4,9-Dihydro-3H-β-carbolin-1-yl)-(3-methyl-3H-imidazol-4-yl)-methanone (Xestomanzamine B) (2):
Freshly prepared 21 (from 20: 98 mg, 0.2 mmol) was dissolved in dichloromethane (5 mL) and a solution
of tryptamine (40 mg, 0.25 mmol) in dichloromethane (4 mL) was added. The reaction mixture was
stirred during 4 h at rt under nitrogen atmosphere. Trifluoroacetic acid (1 mL) was added and this solution
was stirred during 4 h in an open vessel. Saturated aqueous Na2CO3 solution (5 mL) and water (5 mL)
were added, the product was extracted with CH2Cl2 (3x) and the combined organic layers were dried
(Na2SO4) and evaporated. Flash chromatography (EtOAc/ EtOH 90/ 10 → 75/ 25) gave 2 (24 mg, 43%)
as a glass. The product had to be purified fast and kept strictly under a nitrogen atmosphere, otherwise
air-oxidation resulted in the formation of substantial amounts of the fully aromatised 1. In a separate
experiment following the same procedure, omitting the nitrogen atmosphere, 1 (20 mg, 0.06 mmol, 28%)
was isolated as a yellow crystalline compound. The spectral data of 1 were identical to those obtained
from the synthesis of 1 via the Grignard exchange reaction.
2: 1H NMR (CDCl3, 400 MHz) δ 9.53 (br s, 1H, H-9), 8.37 (s, 1H, H-13), 7.63 (s, 1H, H-15), 7.60 (d, J =
8.0 Hz, 1H, H-5), 7.40 (d, J = 8.3 Hz, 1H, H-8), 7.29 (dd, J = 8.3 Hz, J = 7.1 Hz, 1H, H-7), 7.14 (dd, J =
8.0 Hz, J = 7.1 Hz, 1H, H-6), 4.16 (dd, J = 8.9 Hz, J = 8.7 Hz, 2H, H-3), 4.00 (s, 3H, NCH3), 2.98 (dd, J
= 8.9 Hz, J = 8.7 Hz, 2H, H-4); 13C NMR (CDCl3, 100 MHz) δ 182.7, 155.7, 144.1, 144.0, 136.8, 128.5,
126.2, 125.0, 124.6, 120.2, 119.8, 117.9, 112.1, 49.0, 35.0, 18.7; IR ν 3459, 1641; HRMS (FAB) obs.
mass 279.1245 calcd for C16H15N4O (M + H) 279.1246.
ACKNOWLEDGEMENTS
This research was supported by the Netherlands Foundation for Chemical Research (SON) with financial
aid from the Netherlands Technology Foundation (STW).
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