Transition metal complexes in organic synthesis. Part 58: First enantioselective total synthesis of the potent neuronal cell protecting substance carquinostatin a from (R)-propene oxide

Article abstract of DOI:10.1016/S0040-4039(99)02257-1

Starting from enantiopure (R)-propene oxide the first enantioselective total synthesis of the potent neuronal cell protecting alkaloid carquinostatin A has been accomplished by using iron- and nickel-mediated coupling reactions. (C) 2000 Elsevier Science

Full text of DOI:10.1016/S0040-4039(99)02257-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1171–1174
Transition metal complexes in organic synthesis. Part 58:1
First enantioselective total synthesis of the potent neuronal cell
protecting substance carquinostatin A from (R)-propene oxide
Hans-Joachim Knölker,a,∗ Elke Baum b and Kethiri R. Reddy a
aInstitut für Organische Chemie, Universität Karlsruhe, Richard-Willstätter-Allee, 76131 Karlsruhe, Germany
bInstitut für Anorganische Chemie, Universität Karlsruhe, Engesserstraße, 76128 Karlsruhe, Germany
Received 18 November 1999; accepted 1 December 1999
Abstract
Starting from enantiopure (R)-propene oxide the first enantioselective total synthesis of the potent neuronal cell
protecting alkaloid carquinostatin A has been accomplished by using iron- and nickel-mediated coupling reactions.
© 2000 Elsevier Science Ltd. All rights reserved.
A broad range of biologically active carbazole alkaloids has been obtained from natural sources.2
In 1993 Seto et al. isolated carquinostatin A, the first example of a carbazole-3,4-quinone alkaloid, from
Streptomyces exfoliatus 2419-SVT2.3 Carquinostatin A was shown to be a potent neuronal cell protecting
substance which also exhibits a free radical scavenging activity. We have a continuous program directed
towards the development of novel methodologies for the total synthesis of pharmacologically active
carbazole alkaloids.4 So far only two total syntheses for racemic carquinostatin A have been reported.5
The first route used an iron-mediated oxidative coupling of cyclohexadiene with a fully substituted
arylamine5a and the second approach proceeded via a palladium-mediated oxidative coupling of p-
prenylaniline and an ortho-benzoquinone.5b In the present work we describe the first enantioselective
total synthesis of carquinostatin A based on the iron-mediated synthesis (Scheme 1).
Scheme 1.
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02257-1
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The precursors for the carbazole framework are the complex salt 1 and the enantiopure (R)-arylamine
2. Introduction of the prenyl group was projected by a regioselective nickel-mediated coupling using
prenyl bromide 3 at a later stage of the synthesis. The chiral side chain of the required (R)-arylamine 2
should derive from (R)-propene oxide.
Hydrolytic kinetic resolution of racemic propene oxide using the (R,R)-(salen)cobalt(II) complex as
20
described by Jacobsen6 afforded the enantiopure (R)-propene oxide ([α] =+11.96, neat). Because of
D
contradictory assignments,6 the absolute configuration at the stereogenic center was unambiguously
confirmed by an X-ray crystal structure determination at the stage of the 6-bromocarbazole (see below).
By modification of the original procedure7 for the regioselective bromination of 3-methylveratrole 4,
the bromo derivative 5 was prepared almost quantitatively (Scheme 2). Halogen–metal exchange using
n-butyllithium followed by reaction with the (R)-propene oxide, obtained by Jacobsen’s method6 (see
20
above), afforded the (R)-carbinol 6 ([α] =−34.4, c=1, CHCl3). Protection of 6 as the (R)-acetate 7
D
20
([α] =−16.5, c=1, CHCl3) and subsequent regioselective nitration led to the (R)-nitro compound 8
D
20
D
20
D
([α] =+173.2, c=1, CHCl3). Catalytic hydrogenation of 8 provided the (R)-arylamine 2 ([α] =−1.7,
c=1, CHCl3). This route affords the (R)-arylamine 2 in five steps and 57% overall yield from commercial
3-methylveratrole 4.
Scheme 2.
Treatment of a 6-bromocarbazole with bis[(µ-bromo)(η3-prenyl)nickel] 9 was envisaged for the
regioselective prenylation.8 Complex 9 was prepared by reaction of prenyl bromide 3 with 3 equiv. of
tetracarbonylnickel in benzene at 60°C (Scheme 3) and is used in situ.
Scheme 3.
Construction of the carbazole framework was achieved using the previously reported conditions for
the oxidative coupling of the complex salt 1 with arylamines.5a,9 Reaction of 1 with 2 equiv. of the
(R)-arylamine 2 in acetonitrile at room temperature for 9 days in the air provided in 94% yield the
20
tricarbonyl(η4-4a,9a-dihydro-9H-carbazole)iron complex 10 ([α] =−6.50, c=0.5, CHCl3) (Scheme 4).
D
Demetalation of the tricarbonyliron complex 10 with trimethylamine N-oxide in acetone at reflux10 and
subsequent aromatization11 by dehydrogenation using 10% palladium on activated carbon in boiling
20
D
o-xylene with 1-hexene for the trapping of hydrogen provided the carbazole 11 ([α] =−95.3, c=1,

1173
CHCl3) in 87% yield over both steps. Regioselective bromination of the carbazole 11 by electrophilic
substitution using N-bromosuccinimide in the presence of catalytic amounts of hydrogen bromide in
20
D
acetonitrile at room temperature afforded quantitatively the 6-bromocarbazole 12 ([α] =−43.0, c=0.5,
CHCl3). The X-ray analysis of the 6-bromocarbazole 12 (Fig. 1)12 showed unequivocally that the
absolute configuration is R by the anomal dispersion (Flack parameter: χ=−0.010(9)).13
Scheme 4. Reagents and conditions: (a) MeCN, air, 25°C, 9 days (94%); (b) 1. Me3NO·2H2O (8 equiv.), acetone, 56°C, 4 h,
2. 10% Pd/C, o-xylene/15 vol.-% 1-hexene, reflux, 4 h (87%, two steps); (c) NBS, HBr (cat.), MeCN, 25°C, 1 h (100%); (d)
complex 9 (2 equiv.), DMF, 65°C, 15 h (94%); (e) LiAlH4 (1.6 equiv.), Et2O, 25°C, 45 min (98%); (f) CoF3 (4 equiv.), dioxane
(2 equiv.)/water (10 equiv.), 25°C, 1 h (70%)
Prenyl coupling of the 6-bromocarbazole 12 by reaction with 2 equivalents of the in situ-prepared
dimeric nickel complex 9 in dry and degassed N,N-dimethylformamide at 65°C provided the 6-
20
D
prenylcarbazole 13 ([α] =−47.2, c=0.5, CHCl3) in 94% yield (Scheme 4). Removal of the acetyl
group by reduction with lithium aluminum hydride afforded almost quantitatively the carbinol 14
20
D
([α] =−10.5, c=0.5, CHCl3). Recently, Nakata et al. reported the oxidative demethylation of 1,4-
dimethoxybenzenes to p-benzoquinones using cobalt(III) fluoride.14 We could now demonstrate that
this method is also useful for the transformation of 1,2-dimethoxybenzenes to o-benzoquinones. Thus,
oxidation of 14 with cobalt(III) fluoride provided enantiopure carquinostatin A (m.p. 179–180°C) which
was in agreement with the natural product (m.p. 144–145°C)3 in all spectral data. Conversion of the
synthetic carquinostation A to the (R)-Mosher ester,3,15 addition of 1% of the diastereoisomeric (R)-
1
Mosher esters obtained from (±)-carquinostatin A,5 and comparison of the corresponding H NMR
spectra at 500 MHz confirmed that the enantiomeric purity of our product is >99% ee.
The present synthesis provides enantiopure carquinostatin A in seven steps and 53% overall yield
based on 1.

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Fig. 1. Molecular structure of 12 in the crystal. Selected bond lengths (Å): C8–Br 1.906(3), C1–C13 1.501(4), C13–C14
1.523(5), C14–C15 1.500(5), C14–O3 1.470(4)
Acknowledgements
This work was supported by the ‘Fonds der Chemischen Industrie’ and the ‘Alexander von Humboldt
Stiftung’. We are grateful to the BASF AG, Ludwigshafen, for a generous gift of pentacarbonyliron.
References
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12. Crystal data for 12: C20H22BrNO4; M=420.30 g/mol, crystal size: 0.8×0.7×0.3 mm, orthorhombic, space group P212121,
λ=0.71073 Å, a=9.4004(12) Å, b=10.1916(14) Å, c=20.098(3) Å, V=1925.5(5) Å3, Z=4, µ=2.159 mm−1, ρcalc=1.450 g/cm3,
T=200(2) K, θ range: 2.03–26.12°, reflections collected: 11941, independent reflections: 3761 (Rint=0.0584), refinement
method: full-matrix least-squares on F2 (program: SHELXL-93), final R values [I>2σ(I)]: R1=0.0358, wR2=0.0891, absolute
structure (Flack parameter)13: χ=−0.010(9), maximal residual electron density: 0.427 e/Å3. Diffractometer: STOE IPDS
area detector. Graphical representation: SCHAKAL-97. Crystallographic data (excluding structure factors) for this structure
have been deposited at the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC-137202, and
may be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: +44 1223-336-033;
e-mail: deposit@ccdc.cam.ac.uk).
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