Transition metal complexes in organic synthesis, part 69. Total synthesis of the Amaryllidaceae alkaloids anhydrolycorinone and hippadine using iron-and palladium-mediated coupling reactions

Article abstract of DOI:10.1055/s-2003-41438

A novel synthesis of the Amaryllidaceae alkaloids anhydrolycorinone and hippadine has been developed using an iron-mediated oxidative alkylamine cyclization and an intramolecular palladium-mediated biaryl coupling as the key steps.

Full text of DOI:10.1055/s-2003-41438

1752
LETTER
Transition Metal Complexes in Organic Synthesis, Part 69.1 Total Synthesis of
the Amaryllidaceae Alkaloids Anhydrolycorinone and Hippadine Using Iron-
and Palladium-Mediated Coupling Reactions
Iron-
a
nd Palladium
a
-Mediated
n
T
otal Synth
s
e
sis of
H
i
-
ppadine Joachim Knölker,* Salima Filali
Institut für Organische Chemie, Technische Universität Dresden, Bergstraße 66, 01069 Dresden, Germany
Fax +49(351)46337030; E-mail: hans-joachim.knoelker@chemie.tu-dresden.de
Received 30 June 2003
Using various methods for the oxidative cyclization,6 the
Abstract: A novel synthesis of the Amaryllidaceae alkaloids anhy-
drolycorinone and hippadine has been developed using an iron-me-
diated oxidative alkylamine cyclization and an intramolecular
palladium-mediated biaryl coupling as the key steps.
iron-mediated oxidative coupling of arylamines and
cyclohexa-1,3-diene was applied to the total synthesis of
a wide range of biologically active carbazole alkaloids.7
Moreover, the oxidative cyclization of tricarbonyl[h4-
cyclohexa-1,3-diene]iron complexes with an appropriate
alkylamine side chain afforded 2,3,3a,7a-tetrahydro-
indoles.8 The implementation of this iron-mediated alkyl-
amine cyclization is the characteristic feature of our
present synthesis of pyrrolophenanthridine alkaloids.
Key words: alkaloids, cyclizations, dehydrogenations, iron, palla-
dium
The lycorine alkaloids 1–4 isolated from Amaryllidaceae
plants have a pyrrolo[3,2,1-de]phenanthridine skeleton
and show interesting biological activities (Figure 1).
Hippadine (2) reversibly inhibits the fertility in male rats.2
Anhydrolycorinium chloride (3) and kalbretorine (4)
show antitumor activity.3,4 Anhydrolycorinone (1) repre-
sents a precursor for the synthesis of the biologically
active natural products 2 and 3.2a
(OC)3Fe
N
I
[Pd]
N
O
O
O
5
O
O
1 Anhydrolycorinone
N
N
[Fe]
O
O
O
NH2
+
+
O
O
OCH3
I
6
7
8
O
O
O
O
Scheme 1 Retrosynthetic analysis of anhydrolycorinone (1)
1 Anhydrolycorinone
2 Hippadine
An iron-mediated oxidative coupling of cyclohexa-1,3-
diene (6) with methyl acetate (7) and iodopiperonylamine
8 to the iron-complexed tetrahydroindole 5 followed by a
sequence of aromatization, intramolecular palladium-
mediated biaryl coupling, and oxidation at the benzylic
position should provide anhydrolycorinone (1).
N
N
+
Cl
O
OH
O
O
O
O
3 Anhydrolycorinium chloride
4 Kalbretorine
O
O
O
O
I
2, AgO2CCF3
OH
OH
Figure 1 Pyrrolophenanthridine alkaloids
CHCl3, -5°C
83%
I
10
9
The potent biological activities found for many pyrrol-
ophenanthridine alkaloids induced the development of
diverse synthetic approaches.5 Herein, we report a novel
synthesis based on an iron-mediated indole annulation
followed by an intramolecular palladium-mediated biaryl
coupling with concomitant oxidation (Scheme 1).
O
PBr3, pyridine
NaN3
Br
Et2O, -20°C
80%
DMF
98%
O
I
11
O
O
PPh3
N3
NH2
THF/H2O
89%
O
O
I
I
12
8
Synlett 2003, No. 11, Print: 02 09 2003. Web: 25 08 2003.
Art Id.1437-2096,E;2003,0,11,1752,1754,ftx,en;G15003ST.pdf.
DOI: 10.1055/s-2003-41438
Scheme 2 Synthesis of the iodopiperonylamine 8
© Georg Thieme Verlag Stuttgart · New York

LETTER
Iron- and Palladium-Mediated Total Synthesis of Hippadine
1753
+
Fe(CO)3
OCH3
H
OLi
OCH3
DIBAL
toluene, -78°C
61%
THF
-78°C
95%
+
(OC)3Fe
(OC)3Fe
O
O
BF4
14
13
15
16
(OC)3Fe
(OC)3Fe
N
H
I
Cp2FePF6, Na2CO3
+ 8 · HCl, MeOH
N
NaBH3CN, 4Å MS
87%
CH2Cl2, 25°C, 3 d
86%
I
O
17
5
O
O
O
I
Me3NO, Me2CO
Pd(PPh3)4, DMF
DDQ, CH2Cl2
N
N
N
reflux, 2 h
80%
100°C, air, 35 min
29%
reflux, 12 h
78%
O
O
O
O
O
O
18
O
O
2 Hippadine
1 Anhydrolycorinone
Scheme 3 Iron- and palladium-mediated total synthesis of anhydrolycorinone (1) and hippadine (2)
Iodopiperonylamine 8 is readily prepared on large scale in We envisaged to achieve the final intramolecular biaryl
four steps and 58% overall yield from commercially coupling by a Heck-type reaction.18 Miki et al.
available piperonyl alcohol 9 (Scheme 2).9 The silver tri- synthesized pyrrolophenanthridines by a Heck coupling
fluoroacetate promoted iodination of 9 afforded iodo- in a related system with an aromatized indole.5b After
piperonyl alcohol 10. Consecutive treatment with variation of several reaction parameters, we found a biaryl
phosphorus tribromide to iodopiperonyl bromide 11 and coupling procedure that proceeded with concomitant aro-
then with sodium azide led to iodopiperonyl azide 12. matization of the cyclohexadiene ring and oxidation at the
Subsequent
iodopiperonylamine 8.
Staudinger
reduction
provided benzylic position to the lactam. Treatment of compound
18 with a stoichiometric amount of tetrakis[triphe-
nylphosphine]palladium in DMF at 100 °C under air for
Using three transition metal-mediated bond formations,
we elaborated a concise synthesis of the Amaryllidaceae
alkaloids anhydrolycorinone (1) and hippadine (2)
(Scheme 3). Cyclohexa-1,3-diene (6) was almost quanti-
tatively transformed to the complex salt 13 by azadiene-
catalyzed complexation with pentacarbonyliron10 and
subsequent hydride abstraction using trityl tetrafluoro-
35 min gave anhydrolycorinone (1) (mp 226–228 °C).
The oxidation of anhydrolycorinone (1) with 2,3-dichlo-
ro-5,6-dicyano-1,4-benzoquinone (DDQ) provided hippa-
dine (2) (mp 207–208 °C).2 The spectral data of both
alkaloids were in good agreement with those reported for
the natural products.2,14
borate.11 The introduction of the side chain was achieved In conclusion, we developed a novel approach to the
by nucleophilic addition of the lithium ester enolate 14 pyrrolophenanthridine alkaloids anhydrolycorinone (1)
[prepared by deprotonation of methyl acetate (7) with and hippadine (2). Iron-mediated C–C and C–N bond for-
LDA] to the complex salt 13.12 Our modified procedure mations are applied to construct the indole nucleus. Thus,
(reaction at –78 °C for 2 h) afforded complex 15 in 95% this route features the first application of the iron-
yield.8 Using the low temperature reduction with mediated alkylamine cyclization in natural product syn-
DIBAL,13 ester 15 was converted into aldehyde 16. The thesis. The palladium-mediated intramolecular Heck
two building blocks were then combined to alkylamine- coupling with concomitant aromatization and oxidation to
substituted iron complex 17 by a reductive amination of the lactam provides directly anhydrolycorinone (1). The
aldehyde 16 with the hydrochloride of iodopiperonyl- synthesis affords the biologically active Amaryllidaceae
amine 8 using sodium cyanoborohydride as the reducing alkaloid hippadine (2) in seven steps and 8% overall yield
agent.14 Oxidative cyclization of complex 17 with based on the complex salt 13. Further applications of this
ferricenium hexafluorophosphate in the presence of methodology in natural product synthesis are in progress.
sodium carbonate afforded the tetrahydroindole complex
5.14,15 The SET reagent has been applied previously to the
Acknowledgment
iron-mediated oxidative cyclization of alkylamines8 and
arylamines.16 Demetalation of complex 5 with anhydrous
This work was supported by the Deutsche Forschungsgemeinschaft
and the Fonds der Chemischen Industrie. We thank the BASF AG,
Ludwigshafen, for a gift of pentacarbonyliron.
trimethylamine N-oxide17 led to tetrahydroindole 18.14
Synlett 2003, No. 11, 1752–1754 © Thieme Stuttgart · New York

1754
H.-J. Knölker, S. Filali
LETTER
109.71 (CH), 118.46 (CH), 135.61 (C), 147.35 (C), 148.34
(C), 212.06 (3 CO). 5: d = 34.64 (CH2), 43.22 (CH), 54.31
(CH2), 60.16 (CH), 60.85 (CH2), 63.78 (CH), 66.32 (CH),
85.85 (CH), 86.70 (CH), 87.25 (C), 101.53 (CH2), 110.19
(CH), 118.45 (CH), 135.01 (C), 147.36 (C), 148.44 (C),
211.75 (3 CO). 18: d = 32.95 (CH2), 36.46 (CH), 49.25
(CH2), 59.56 (CH), 62.43 (CH2), 87.26 (C), 101.50 (CH2),
110.51 (CH), 118.25 (CH), 119.80 (CH), 122.92 (CH),
124.79 (CH), 130.31 (CH), 135.29 (C), 147.33 (C), 148.43
(C). Anhydrolycorinone (1): d = 27.45 (CH2), 46.52 (CH2),
100.89 (CH), 102.05 (CH2), 106.83 (CH), 116.79 (C),
119.46 (CH), 123.10 (C), 123.27 (CH), 123.82 (CH), 130.66
(C), 130.87 (C), 139.39 (C), 148.43 (C), 151.85 (C), 159.52
(C=O). Hippadine (2): d = 101.75 (CH), 102.29 (CH2),
108.05 (CH), 110.82 (CH), 116.71 (C), 118.38 (CH), 122.51
(C), 122.63 (CH), 123.55 (CH), 124.00 (CH), 128.42 (C),
130.97 (C), 131.66 (C), 148.54 (C), 152.60 (C), 158.19
(C=O).
References
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(15) Iron-mediated oxidative alkylamine cyclization of 17 to 5:
Ferricenium hexafluorophosphate (291 mg, 0.88 mmol) and
anhyd. Na2CO3 (374 mg, 3.53 mmol) were added to a
solution of complex 17 (185 mg, 0.354 mmol) in degassed
anhyd CH2Cl2 (15 mL) under an argon atmosphere. The
resulting dark green suspension was stirred at r.t. for 3 d.
During this time the color turned to orange (formation of
ferrocene). The reaction mixture was filtered through a short
path of Celite which was subsequently washed with CH2Cl2.
Removal of the solvent from the combined filtrates and flash
chromatography (hexane–EtOAc, 9:1) of the residue on
silica gel provided complex 5 as light yellow crystals, yield:
158 mg (86%), mp 122 °C.
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NMR, 13C NMR, MS, and elemental analysis or HRMS). 13
NMR and DEPT spectral data (125 MHz, CDCl3) of
C
representative compounds. 17: d = 30.75 (CH2), 35.90 (CH),
40.27 (CH2), 47.66 (CH2), 57.97 (CH2), 59.76 (CH), 66.57
(CH), 84.39 (CH), 85.53 (CH), 86.99 (C), 101.53 (CH2),
Synlett 2003, No. 11, 1752–1754 © Thieme Stuttgart · New York