First total synthesis of the neuronal cell protecting carbazole alkaloid carbazomadurin A by sequential transition metal-catalyzed reactions

Article abstract of DOI:10.1039/b301979a

The highly oxygenated neuronal cell protecting carbazole alkaloid carbazomadurin A was synthesized in nine steps and 11% overall yield from isovanillic acid.

Full text of DOI:10.1039/b301979a

First total synthesis of the neuronal cell protecting carbazole alkaloid
carbazomadurin A by sequential transition metal-catalyzed reactions
Hans-Joachim Knölker* and Jan Knöll
Institut für Organische Chemie, Technische Universität Dresden, Bergstrasse 66, 01069 Dresden, Germany.
E-mail: hans-joachim.knoelker@chemie.tu-dresden.de; Fax: 49 351 463 37030
Received (in Cambridge, UK) 20th February 2003, Accepted 28th March 2003
First published as an Advance Article on the web 15th April 2003
The highly oxygenated neuronal cell protecting carbazole
alkaloid carbazomadurin A was synthesized in nine steps
and 11% overall yield from isovanillic acid.
Carbazole alkaloids have attracted high interest because of their
broad range of useful biological activities.1–3 In 1997 Seto
isolated the structurally unique alkaloids carbazomadurin A
(1a) and B (1b) from the microorganism Actinomadura
madurae 2808-SV1.4 A biological screening of the carbazoma-
durins (1) showed a protecting activity for neuronal hybridoma
N18-RE-105 cells against -glutamate induced cell death. It is
Scheme 2 Preparation of the vinylstannane 4. Reagents and conditions: (i)
1. Me3Al, Cp2ZrCl2, CH2Cl2, rt; 2. I2, THF, 0 °C, 70%; (ii) 1. tBuLi, Et2O,
278 °C; 2. Bu3SnCl, 278 °C to rt, 74%.
L
known that the high extracellular concentration of the excitatory
amino acid -glutamate occurring after brain ischemic attack
L
leads to the destruction of cerebral tissue and therefore, radical
scavengers represent potential candidates for the treatment of
brain ischemia injury. The biological data suggested that the
protection from glutamate toxicity by the carbazomadurins is
based on their anti-oxidative activity.4 In the course of our
project focusing on the development of novel methodologies for
the synthesis of biologically active carbazole alkaloids,1 we
became interested in these compounds. Herein, we describe the
first total synthesis of carbazomadurin A (1a) by the palladium-
catalyzed fusion of the three building blocks 2–4 and a
zirconium-catalyzed generation of the E-configurated double
bond (Scheme 1).
and reaction of the intermediate vinyllithium compound with
tributyltin chloride provided the vinylstannane 4 in good yields
on a 10 g scale.
Transfer hydrogenation of 2-bromo-6-nitrotoluene (7) using
hydrazine hydrate afforded 3-bromo-2-methylaniline (8), which
was converted to the corresponding phenol 9 via diazotization
(Scheme 3). The transformation to the anisole 10 and sub-
sequent nitration using claycop6 provided the 4-nitroanisole 11
in 67% yield along with 26% of the 2-nitro derivative.
Reduction of 11 led to the arylamine 3, which was obtained in
44% overall yield.
The stereospecific construction of the trisubstituted double
bond of the side chain at C-1 of carbazomadurin A (1a) was
achieved by using the zirconium-catalyzed carboalumination of
alkynes developed by Negishi.5 Treatment of 5-methyl-1-hex-
yne (5) with trimethylalane in the presence of zirconocene
dichloride followed by addition of iodine afforded the vinyl
iodide 6 with the desired E configuration of the double bond
(Scheme 2). Halogen–metal exchange with tert-butyllithium
The aryl triflate 2 was easily prepared starting from
isovanillic acid (12) (Scheme 4). After formation of the methyl
ester 13, the phenolic hydroxy group was converted to the
triflate 2 by reaction with triflic anhydride using 2,6-lutidine as
base. For the crucial C–N bond formation we envisaged the
Buchwald–Hartwig coupling, a versatile method providing
N,N-diarylamines in a palladium(0)-catalyzed process from
arylamines and aryl halides or triflates.7,8 We decided to use the
procedure of Buchwald.7 Reaction of the aryl triflate 2 with one
equivalent of the arylamine 3 in the presence of catalytic
amounts of palladium(II) acetate and (±)-2,2A-bis(diphenylphos-
phino)-1,1A-binaphthyl (BINAP) and an excess of caesium
Scheme 3 Preparation of the arylamine 3. Reagents and conditions: (i)
N2H4·H2O, FeCl3, activated carbon, MeOH, 65 °C, 12 h, 96%; (ii) 1.
NaNO2, H2SO4, 0 °C; 2. H2SO4, H2O, D, 83%; (iii) MeI, KOH, DMSO, rt,
1 h, 91%; (iv) claycop, Ac2O, CCl4, rt, 2.5 h, 67%; (v) N2H4·H2O, FeCl3,
activated carbon, MeOH, 65 °C, 13 h, 91%.
Scheme 1 Retrosynthetic analysis of carbazomadurin A (1a).
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In conclusion, the present synthesis provides carbazomadurin
A (1a) in nine steps and 11% overall yield based on isovanillic
acid (12). It demonstrates that the palladium-catalyzed sequence
of Buchwald–Hartwig amination, oxidative cyclization and
Stille coupling represents a very efficient and flexible approach,
which can be readily utilized for the preparation of a wide range
of synthetic analogues as required for a structure–activity study.
This work is currently in progress in our laboratories and will be
reported in due course.
Financial support was provided by the Fonds der Chemischen
Industrie.
Notes and references
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Scheme 4 Synthesis of carbazomadurin A (1a). Reagents and conditions: (i)
MeOH, H2SO4, 65 °C, 16 h, 91%; (ii) 2,6-lutidine, Tf2O, CH2Cl2, 210 °C
to rt, 16 h, 100%; (iii) 3, 5 mol % Pd(OAc)2, 7.5 mol % BINAP, Cs2CO3,
toluene, 100 °C, 10 h, 62%; (iv) Pd(OAc)2, dioxane/HOAc (3+1), 100 °C,
40 h, 43%; (v) 1. BBr3, CH2Cl2, 278 °C to rt, 5 d, 77%; 2. tBuPh2SiCl,
ImH, DMF, 70 °C, 19 h, 91%; (vi) 4, 10 mol% Pd(PPh3)4, toluene, 110 °C,
67 h, 95%; (vii) DIBAL, toluene, 0 °C, 2 h, 100%; (viii) TBAF, THF, rt, 2
h, 70%.
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of the carbazole. Therefore, we switched to the tert-butyldiphe-
nylsilyl protecting group, which is stable and easily removed by
fluoride ions.14 Cleavage of both methyl ethers to the dihydrox-
ycarbazole using an excess of boron tribromide followed by
silylation gave the disilylether 16. The palladium(0)-catalyzed
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stannane 4 afforded almost quantitatively the 1-vinylcarbazole
17. Reduction of 17 with diisobutylaluminium hydride
(DIBAL) led quantitatively to the benzylic alcohol 18. Cleavage
of the silyl ethers using tetrabutylammonium fluoride (TBAF)
provided carbazomadurin A (1a). The spectroscopic data (UV,
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1
IR, H NMR, 13C NMR and MS) of our product were in full
agreement with those reported by Seto et al. for the natural
product.4
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