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Highly Selective Oxidations of Fe(CO)3-Cyclohexadiene Complexes Synthesis of 4b 8a-Dihydrocarbazol-3-ones and the First Total Synthesis of Carbazomycin A.

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[I21 M.p. 166°C; 90 MHz "F NMR: 6 = -61.5.
[I31 6 crystallizes in the space group Pc2,n; u=8.057(1), b=11.443(1),
c = 26.738(2) A, Y = 2465 A', Z = 8 (two crystallographically independent
molecules). 2 102 observed reflections ( I r a ( I ) , two-circle diffractometer, (I) scan). The refinement (S, F, 0, N, C anisotropic, six H atoms fixed
in calculated positions, the rest in observed positions refined isotropically) gave R=0.040, R,=0.038 [17].
[I41 U. Rheude, W. Sundermeyer, Chem. Ber. 118 (1985) 2208.
[I51 T. Kempe, T. Norin, Acfu Chem. Scund. Ser. B28 (1974) 609.
1161 R. Allmann, W. Hanefeld, M. Krestel, B. Spangenberg, Angew. Chem. 99
(1987) 1175; Angew. Chem. Inf. Ed. Engl. 26 (1987) 1133.
[I71 Further details of the crystal structure investigations are available on
request from the Fachinformationszentrum Energie, Physik, Mathematik GmbH, D-7514 Eggenstein-Leopoldshafen2 (FRG), on quoting
the depository number CSD-53391, the names of the authors, and the
journal citation.
Using the methodology described above, 4-deoxycarbazomycin B 4 has been synthesized in two steps from the
cation l a o (Scheme 1). Reaction of 3a (see above) with
very active
Mn02
3a
PhCHJ. 2 5 O C
I
Highly Selective Oxidations of
Fe(C0)3-CyclohexadieneComplexes:
Synthesis of 4b,Sa-DihydrocarbazoI-3-onesand
the First Total Synthesis of Carbazomycin A**
CH3
H
very active
25 O C
By Hans-Joachim Knolker*, Michael Bauermeister,
Dieter Blaser, Roland Boese, and Jorn-Bernd Pannek
Tricarbonyl(~5-cyclohexadienylium)ironcations l Q are
very useful reagents for regio- and stereoselective C-C
bond formation. They afford a wide range of 5-exo-substituted tricarbonyl(q4-cyc1ohexadiene)iron complexes[" in
the electrophilic substitution of electron-rich aromatic systems such as indole, pyrrole, furan, and aniline.12,31Furthermore, some 5-exo-substituted cyclohexadiene iron
complexes bearing a hydroxy or an amino group in the
side chain have been observed to undergo oxidative cyclizations to give fused ring system^.'^'^]
Our intention is to use a methodology of consecutive
iron-induced C-C and C-N bond formation for the total
synthesis of pharmacologically active heterocyclic natural
products. Here we report a very direct route to tricyclic
carbazole alkaloids and a stereoselective access to various
metal-complexed dihydrocarbazole derivatives including
the hitherto unknown 4b,8a-dihydrocarbazol-3-one7.
The iron complexes 3 were prepared stereoselectively
from the cations l o and the amine 2 by modified literature
procedures[31(3a, 95%; 3b, 64%) (Scheme 1). However, the
described cyclization procedure (reaction with iodine in
pyridine)13'was ineffective for our highly donor substituted
compounds. We found that employment of milder oxidizing agents leads to a very reagent-sensitive and selective
reaction furnishing either the aromatized cyclization products (e.g., 4 ) or the corresponding iron-complexed dihydro
derivatives (e.g., 5 ) depending on the reaction conditions.
This method opens up the way to a very direct synthesis of
many naturally occurring carbazole alkaloids which are
oxygenated in the 3- or in the 2- and 6 - p o ~ i t i o nWe
. ~ ~en~
visaged an application in the total synthesis of the carbazomycins, which are the first antibiotics with a carbazole
skeleton."]
/.
I
H
a: R
.
CH3
5
= H; b : R = OCH3
Scheme 1.
very active manganese dioxide"] afforded, in 28% yield, 4,
whose spectral data were identical with those reported by
Nakamura et al. for the natural
An extensive
investigation of the oxidative cyclization of 3a showed
that the scope of this reaction is much larger than originally anticipated. The one-pot transformation of 3a to the
carbazole 4 involves cyclizing dehydrogenation, aromatizing dehydrogenation and demetalation. This mechanism is
supported by the isolation of the intermediate iron-complexed 4a,9a-dihydro-9H-carbazole 5 as a by-product in
the cyclization of 3a to 4 using FeCl, supported on silica
gel[91or 10% Pd/C at 80°C (Scheme 1). This strategy thus
provides access to the interesting 4a,9a-dihydro-9H-carbazole skeleton['o1 without additional annelated rings. The
structure of 5 has been confirmed by an X-ray analysis
(Fig. I).["] Single crystals of 5 exhibit optical anisotro-
"7 Dr. H.-J.
I**]
Knolker, DipLChem. M. Bauermeister, J.-B. Pannek
lnstitut fur Organische Chemie der Universitat
Schneiderberg 1 B, D-3000 Hannover I(FRG)
Dr. R. Boese, DipLlng. D. Blaser
lnstitut fur Anorganische Chemie der Universitat
Universitatsstrasse 5-7, D-4300 Essen I(FRG)
Transition Metal-Diene Complexes in Organic Synthesis, Part I . This
work was supported by the Deutsche Forschungsgemeinschaft. We wish
to thank Dr. V. Wruy. Gesellschaft fur Biotechnologische Forschung
(GBF), Braunschweig-Stockheim, for recording the COSY spectra and
Dr. K:H. Geiss, BASF Aktiengesellschaft, Ludwigshafen, for nonacarbonyldiiron.
Angew. Chem. In,. Ed. Engl. 28 (1989) No. 2
1
Fig. 1. Molecular structure of 5 [ I l l . Selected bond lengths [A]: Fe-CI
2.106(3), Fe-C2 2.060(3), Fe-C3 2.063(2), Fe-C4 2.11 1(2), CLC2 1.426(4), C2C3 1.398(4), C3-C4 1.423(3), C4-CIl 1.512(3), CI-CIO 1.515(3).
0 VCH Verlugsgesellschufi mbH, 0-6940 Weinheim, 1989
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223
pism. Rotation of these columnar crystals by 90" about the
longitudinal axis results in a colour change from red to yellow. This interesting feature can be explained by the crystal packing (Fig. 2). When looking at the plane of the aromatic rings (Fig. 2a), which are arranged in parallel layers,
the crystals appear red. Orthogonal to this direction (Fig.
2b) the crystals appear yellow. With very active manganese
d i ~ x i d e ' ~5 ]is smoothly converted into 4 (Scheme 1).
4b,8a-dihydrocarbazol-3-ones 7a (90%) and 7b (71%)
again using very active manganese d i 0 ~ i d e . I Structural
~'
assignments for 7 are based on 'H,13C and COSY NMR
spectra, and an X-ray crystal structure determination for
7a.I'I The complexes 7 are stable at room temperature for
at least several months, in contrast to the analogous 2,3dihydroindol-5-ones, which are reported to undergo immediate ismerization to the 5-indolyl alcohol^.^'^^ Upon demetalation of 7a, however, rearrangement to the 3-carbazolyl
alcohol 8 (93% yield) occurs instantaneously (Scheme 2).
Methylation of 8 yields again 4-deoxycarbazomycin B 4
(96%). Due to the cleaner course of the iminoquinone-cyclization this route to the aromatized carbazoles is much
better (48% overall yield of 4) than the direct oxidative cyclization of the complexed amine 3a (28% yield). Taking
advantage of the tricarbonyliron fragment as a protecting
group for the diene should allow exploitation of the iminoquinone reactivity in Michael and cycloaddition reactions.
2kCH3
CH3 1) Ac,O.
C5H5N
CH3
II
0
CH,
0
1) LiH. THF.
(CH3),S04
H~c/'&"'.
1 ) HNO,
SnC14,
CH2CIz
A
CH,
2) MCPBA, CHZCIZ
25 oc
/CH3
1) CHZNz
L
2) KOH, EtOH.
25 OC
Fig. 2. The unit cell in crystals of 5 [ I I]. a) View perpendicular to the aromatic rings, b) side view (rotated by 90" about the z axis.
An even more striking example for the synthetic flexibility of these cyclizations is the first synthesis of the 4b,8adihydrocarbazol-3-ones 7 (Scheme 2). Selective oxidation
of the complexes 3 using commercial Mn02[131gave the
non-cyclized iminoquinones 6a (60%) and 6b (67%). The
iminoquinones 6 are readily cyclized in a regio- and stereoselective manner to afford the novel iron-complexed
-
H
Mn0,[13]
11
12
Scheme 3
PhCH3.
( C O ) 3 F e S
"OC
R
6
3
7a
(CH3),C0.
25 OC
NaH, (C2H5),0
(CH3)2S04
&CH3
I
>
4
Finally, to demonstrate the utility of these reactions in
alkaloid synthesis, we completed the first total synthesis of
the antibiotic carbazomycin A 11 (Scheme 3). The required
amine 9 was prepared in eight steps from 2,3-dimethylpheno1 (28% overall yield). Subsequent C-C bond formation
with l a to give the complex 10 (84% yield) and cyclization
using very active manganese dioxideI7] (25% yield) afforded carbazomycin A 11, the spectral data of which
(UV, IR, 'H NMR, "C NMR) are in full agreement with
those of the natural product.[61 The isolation of the ironcomplexed iminoquinone 12 as a byproduct in 17% yield
indicates that the imonoquinone-cyclization could also be
used for the synthesis of 11.
Received: September 16, 1988 [Z 2969 IE]
German version: Angew. Chem. 101 (1989) 225
CH3
H
8
a: R = H;
b: R
= OCH,
Scheme 2
224
0 VCH Verlagsgesellschafr mbH, 0-6940 Weinheim. 1989
111 A. J. Pearson, Acc. Chem. Res. 13 (1980) 463; A. J. Pearson in G. Wilkinson, F. G. A. Stone, E. W. Abel (Eds.): Comprehensive Organomelallic
Chemistry. Vol. 8 , Pergamon, Oxford 1982, Chap. 58, p. 939.
0570-0833/89/0202-0224 $ 02.50/0
Angew. Chem. Inr. Ed. Engl. 28 (1989) No. 2
121 L. A. P. Kane-Maguire, C. A. Mansfield, J. Chem. SOC.Chem. Commun.
1973. 540.
131 A. J . Birch, A. J. Liepa, G. R. Stephenson, Tetrahedron Lett. 1979.
3565.
[4] A. J. Birch, K. B. Chamberlain, D. J. Thompson, J. Chem. SOC.ferkin
Trans. I 1973, 1900; A. J. Pearson, M. Chandler, ibid. 1982, 2641.
[5] D. P. Chakraborty, frog. Cfiem. Org. Nut. Prod. 34 (1977) 299.
[6] K. Sakano, K. Ishimaru, S. Nakamura, J. Anfibiof.33 (1980) 683; K.
Sakano, S. Nakamura, ibid. 33 (1980) 961; M. Kaneda, K. Sakano, S.
Nakamura, Y. Kushi, Y. Iitaka, Heterocycles I5 (1981) 993.
[7] A. J. Fatiadi, Synrhesis 1976, 65.
[8] U. Pindur, L. Pfeuffer, Heterocycles 26 (1987) 325.
[9] E. Keinan, Y. Mazur, J. Org. Chem. 43 (1978) 1020; C. W. Ong, A. J.
Pearson, Tetrahedron Lett. 21 (1980) 2349.
[lo] D. B. Grotjahn, K. P. C. Vollhardt, J. Am. Chem. SOC.108 (1986) 2091.
1111 5 : monoclinic, pZ,/c, a: 10.105(1), b= 13.336(2), c = 12.297(2) A,
,9=96.27(1)", V= 1647.3(4)A3, 2 = 4 , pcllcd=
1.485 g cm-', p=9.30
cm ' ; MoKo radiation (graphite monochromator); scan range
3"126'545"; 2915 independent reflections, observed 2572 with
F,24a(F), R=0.037, R,=0.045 [12].
[I21 Further details of the crystal structure investigation may be obtained
from the
Fachinformationszentrum Energie, Physik; Mathematik
GmbH, D-7514 Eggenstein-Leopoldshafen2 (FRG), on quoting the depository number CSD-53429, the names of the authors, and the journal
citation.
[I31 Manganese dioxide (precipitated active) from Merck-Schuchardt, (art.
805958).
[14] 7a: triclinic, Pi, a=7.697(4), b=9.305(5),C= 11.467(6) a = 107.92(4),
b= 100.53(4), y = 100.32(4)0, V=743.5(7) A', Z=2, pcold=1.58 g cm-';
!
.
i
= 10.3 cm -'; MoKa radiation (graphite monochromator); scan range
3O528552"; 2390 independent reflections, observed 2073 (Fo240(F)),
R=0.053, R,=0.051 [12].
[IS] H.-J. Teuber, G. Staiger, Chem. Ber. 87 (1954) 1251.
~
L
L
J
J
8
6
5
The constitution of 1Oc was additionally confirmed by the
result of hydrolysis in aqueous ether, which led with ringopening and cleavage of the P-Cl bond to the phosphonous acid 9 [colorless crystals, m.p. 87°C; IR (KBr):
V=2900 (POH), 2400 cm-' (PH); 'H NMR (CDC13):
6=1.39 (s, 9H, tBu), 7.21 (m, 6H, phenyl- and olefin-H),
7.35 (d, 'JpH=568 Hz, PH), 9.88 (br., 1 H, POH); I3C NMR
(CDC13): 6 ~ 2 9 . 8[d, 3Jpc=4.5 Hz, C(CH,),], 34.2 [d,
' J p c ~ 6 . 9 Hz,C(CH3)3], 119.5 (d, ' J p c = 125.8 Hz,CtBu),
153.9 (d, 'JpC=31.3 Hz, COPh); 31P NMR (CDCl3):
6 = 29.21.
A,
2-Chloro-2H-phosphirene/l-Chloro-lH-phosphirene
Isomerization by [1,3]-ChlorineShift**
1Oc
+
2 H20
- 78OC
11
Pk
12
tBu
w
P
I
fbp-c,
1
2
3
4
Ph
kynes 7J7]subsequent work-up by distillation affords the
1-chloro-1 H-phosphirenes 10 as stable, colorless
Their constitution was confirmed by elemental analyses,
the relatively high-field position of the "P-NMR signals
and the occurrence of two I3C-NMR signals characteristic
for olefinic three-membered ring carbon nuclei (Table 1).
' b P - N iPr,
Ph
N
When chlorocarbenes 6 are generated from diazirines
0
iPrzNLi. n-C5Hl,.
w
516' by thermal elimination of N2 in presence of phosphaal-
b H
-
N
I
OH
H
As primary products of the previously unknown intermolecular carbene addition to P-C triple bonds[*,91only the
2-chloro-2H-phosphirenes 8 are conceivable; but these
2H-Azirines 1 are stable and useful building blocks in
heterocyclic synthesis."] In contrast, the 1H-azirines 2 are
antiaromatic and short-lived, and consequently their existence could hitherto only be demonstrated by trapping
reactions.[21The energy gradient between the two azirine
systems clearly manifests itself in unidirectional isomerizations (2+l).[31We have now found exactly the opposite
situation in the case of unsaturated three-membered ring
systems with phosphorus as heteroatom: 2H-phosphirenes
314]are converted by a substituent-shift from carbon to
phosphorus into 1H-phosphirenes 4.151
P
"g;
9
By Oliver Wagner, Michael Ehle, and Manfred Regitz*
w
+
- HCI
-
-
Ph
tBu
13
tBuCXLi. n-C5Hl,,
1 Oo
- 78 oc
'hP-C=C
Ph
tBu
14
Me3SiN3. CDC13.
25 "C
')P-N3
15
Ph
[*] Prof. Dr. M. Regitz, Dip1.-Chem. 0. Wagner, M. Ehle
Fachbereich Chemie der Universitat
Erwin-Schrodinger-Strasse,D-6750 Kaiserslautern (FRG)
[**I Phosphorus Compounds of Unusual Coordination, Part 33. This work
was supported by the Deutsche Forschungsgemeinschaft, the Fonds der
Chemischen Industrie, and the Landesregierung von Rhein1and-Pfalz.Part 32: F. Zurmiihlen, M. Regitz, New J. Chem. 1988, in press.
Angew. Chem. Inl. Ed. Engl. 28 (1989) No. 2
Ph
N2
16
Scheme 1. Nucleophiiic substitutions of IOa. For data of the products see
Table 2.
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225
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oxidation, synthesis, ones, carbazomycin, tota, first, cyclohexadien, dihydrocarbazol, selective, complexes, highly
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