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Haematopodin an Unusual Pyrroloquinoline Derivative Isolated from the Fungus Mycena haematopus Agaricales.

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[61 This compound has been fully characterized spectrally, and the elemental
composition has been established by high-resolution mass spectrometry
andior combustion analysis.
[7] The valence isomer of 7, a metallacyclobutene, may also be considered as
an intermediate, but does not account for the products as straightforwardly as the carbene complex.
[S] For Pd-catalyzed cyclopropanation, see: a) K. Shimamoto, M. Ishida, H.
Shinozaki, Y Ohfune, J Org. Chem. 1991, 56, 4167; b) Y.V. Tomilov,
A. B. Kostitsyn, E. V. Shulishov, 0. M. Nefedov, Synfhesis 1990, 246;
T. R. Hoye, C. J. Dmsmore, D. S. Johnson, P. F. Korkowski, J. Org. Chem.
1990, 55, 4518, M. W. Majchrzak, A. Kotelko, J. B. Lambert, Synthesis
1983. 469; M. Suda. ihid. 1981, 714; A. J. Anciaux. A. J. Hubert, A. F.
Noels, N . Petiniot, P. Teyssik, J. Org. Chem. 1980,45,695; A. Nakamura,
T. Koyama. S. Otsuka, Bull. Chem. SOC.Jpn. 1978, 51, 593; S. Bien, Y
Segal. J. Org. Chrm. 1977, 42, 1685.
[9] For other metalssee: a) M. Buchert. H. U. Reissig, Chrm. Ber. 1992, 125,
2723: b) D. F. Harvey, K. P. Lund, J. Am. Chem. SOC.
1991. ti3, 5066; c)
H. Fischer, J. Hofmann. Chem. Ber. 1991,124,981 ;d) D. F. Harvey, K. P.
Lund, J. Am. Chem. SOC.1991, 113, 8916; e) J. W. Herndon, S. U. Tumer,
J. Orx. Chem. 1991.56.286; f) W. D. Wulff, D. C. Yang, C. K. Murray, J.
Am. Chrm. SOC.1988, 110, 2653.
[lo] T. Hud1icky.T. M . Kutchan. S. M. Naqvi, Org. Reurl. 1985,33,247;H:U.
Reissig, in The Chemisfry of the Cyclopropyl Group (Eds.: S. Patai, 2.
Rappoport, Wiley, Chichester. 1987, pp. 375-443; J. Salaiin, ibid.
pp. 809-878.
(111 Vinylalkylidene metal complexes are reported to serve as dienophiles in
[4+2] cycloadditions and not as the diene unit. For an excellent leading
reference to this type of behavior, see W. D. Wulff, W. E. Bauta, R. W.
Kaesler. P. J. Lankford, R. A. Miller, C. K . Murray, D. C. Yang, J. Am.
C%em.Sor. 1990, 112, 3642. While this report deals with Fischer-type
carbene complexes, and there are notable effects of the alkoxy group and
metal ligands on the behavior of the carbene complex, this type ofcomplex
is the only current analogy. Clearly, the contrasting behavior, if any, of less
stabilized vinylalkylidene metal complexes is an exciting topic for future
endeavors.
[12] For such complexes, see [9e] and J. W. Herndon, G. Chatterjee. P. P. Patel,
J. U. Matasi, S. U. Tumer, J. J. Harp, M. D. Reid, J. A m . Chem. SOC.1991,
lt3. 7808; J. W. Herndon, S. U . Tumer, W. F. K . Schnatter, ibid. 1988, il0,
3334.
Haematopodin, an Unusual Pyrroloquinoline
Derivative Isolated from the Fungus Mycena
haematopus, Agaricales**
By Carsten Baumann, Martin Brockelmann,
Burkhard Fugmann, Bert Steffan, Woljigang Steglich,*
and William S. Sheldrick
Dedicated to Professor Meinhart H. Zenk
on the occasion of his 60th birthday
Fruiting bodies of the toadstool Mycena haematopus
(Pers. ex Fr.) Kummer, contain a red-brown sap which up
until now has not been the subject of detailed chemical analysis. We have isolated a pigment from this fungus for which
we propose the name haematopodin.
The fruiting bodies were placed in methanol immediately
after collection and turned the solvent red-violet. The
methanol was removed in vacuum leaving a red-brown, watery residue which was then subjected to chromatography on
Sephadex LH-20, eluting with methanol. The haematopodin
fraction can be distinguished from the red-violet main fraction as a slower moving rose-colored band. Every time the
main fraction was rechromatographed, the haematopodin
band reformed, allowing the isolation of the haematopodin
in sufficient quantities for further investigations. Final purification by flash chromatography (silica gel, CHC1,/
CH,OH IOjl) yielded pure haematopodin, which crystallized as a monohydrate from dichloromethane/methanol.lll
The compound is optically active ([a]i3+ 571, c = 0.14 in
CH,OH) and shows absorption maxima in the UVjVIS
spectrum (measured in CH,OH) at 208 (log E 3.99), 242
(4.27), 344 (4.03), and 514 nm (2.95, broad absorption). The
results of high-resolution EI mass spectroscopy indicate an
empirical formula of C,,H,,N,O,, which was confirmed by
the FAB' mass spectrum. An intense ( M i + 2H) peak and
the loss of CO from the molecular ion are indicative of the
presence of an quinoid structural element.
The aliphatic region of the 'H NMR spectrum (Table 1)
shows signals corresponding to the structural elements
OCH,CH,CH,N and CH,CH(N,O), singlets at 6 = 5.37
and 7.12 characteristic of arene protons, and a broad NH
signal at 6 =12.5. The analysis of the arene and carbonyl
Table 1. 'H and I3C Data for haematopodin (1) (400 and 100.6 MHz, respectively, in [DJDMSO, TMS).
'H N MR [a]: d = I S 3 (m, 9b-H), 1.91 (ddddd, 9a-H), 2.78 (dd, 6/3-H), 3.10
(dd, 6a-H), 3.40 (ddd, lOB-H), 3.86 (ddd, 88-H), 3.95 (m, 1Oa-H). 3.96 (m,
8a-H), 5.10 (dd, 6a-H), 5.37 (s, 1-H), 7.12 (s, 5-H), 12.5 (br. s, NH).
I3C NMR Ibl: 6 = 24.76 (t, J = 130 Hz, C-9), 26.13 (t, J = 132 Hz, C-6), 46.24
tm, J = 142 Hz, C-lo), 67.58 (tm, J = 145,7 Hz, C-8). 87.88 (dq. J = 161.7 Hz,
C-6a), 94.87 (d, J =162 Hz. C-l), 114.06 (m, C-5a [ c ] ) . 123.11 (m, C - l l b [c]),
124.64(d,J=8Hz,C-3a), 124.88(d,J=188Hz,C-5),151.43(br.s,C-lla),
169.50 (d [d], J = 5.5 Hz,C-3), 180.28 (s, C-2).
[a] Jvalues[Hz]: J,,,,,=17Hz,J6,,,.=6,
J,p,6a=3.5, J8.,8p=11.5, J8..y,=
5, Jap.y.=12, J9p.yB ~ 2 . 5Jy,,gp=13,
,
Jy.,io,=
5, Jy,,,op ~ 1 3 . 2Jy,,,,p=3.2,
,
Jlo.,log = 13.5. [b] ' J and 'J relationships in 2D COLOC spectrum: C-3: 1-H;
C-3a: 5-H; C-5: 6P-H; C-5a: 5-H, 6a-H, 6B-H; C-6a: 6B-H, 8a-H, SB-H,
IOa-H; C-8: 1Oa-H; C-9: IOa-H, lop-H; C-lla: 1Oa-H, IOB-H; C - l l b : 1-H,
5-H, 6B-H. [c] Signals could not be assigned unequivocally. [d] In CDCIJ
CD,OD (l/l).
signals in the 'H-coupled 13CNMR spectrum (Table 1) indicates the presence of an indole-6,7-quinone chromophore.
The fact that the singlet at 6 =180.28 exhibits no H,C coupling indicates that this signal is due to the 6-carbonyl group,
whereas the signal due to the 7-carbonyl group at 6 = 169.50
(in CDCI,/CD,OD (1/1)) is split into a doublet by spin-spin
coupling with the proton at C-5 (3J = 5.5 Hz). Selective decoupling experiments in [DJDMSO showed the proton at
C-5 to have an additional 3J coupling of 1.5 Hz with the
indole-NH. COLOC experirnentsIzJallow the structural elements to be pieced together showing that haematopodin is
identical with the structure 6,6a,9,10-tetrahydro-4H,8H[1,3]oxazinol[3,2-a]pyrrolo[4,3,2-de]quino~ine-2,3-dione
(1).
I*] Prof Dr. W. Steglich, DipLChem. C. Baumann, Dr. M. Brockelmann,
[**I
Dr. B. Fugmann, Dr. B. Steffan
Institut fur Organische Chemie der Universitit
Karlstrasse 23, D-80333 Miinchen (FRG)
Telefax: Int. code +(89)5902-483
Prof. Dr. W. S. Sheldrick
Lehrstuhl fur Analytische Chemie der Ruhr-Universitat Bochum NC 4/72
Pigments of Fungi, Part 62. This work was supported by the Bundesministerium fur Wissenschaft und Technologie and by the Fonds der Chemischen Industrie. Part 61: H. Besl, A. Bresinsky, G. Geigenmuller, R.
Herrmann, C. Kilpert, W. Steglich, Liebigs Ann. Chem. 1989, 803.
~
Anxrw Chm. I n f . Ed. Engl. 1993. 32, No. 7
0 VCH
VerlagsgesellschujfmbH, 0-69451 Weinheim, 1993
1
2
0570-0833/93j0707-l087~10.00+ .25/0
1087
The structural formula of haematopodin (1) was confirmed by X-ray crystallography (Fig.
The asymmetric
unit (space group P2,)was found to contain two molecules
of water in addition to two independent molecules of haematopodin. The molecules of 1 are linked together by NH . . . O(water) and 0 2 . . H -O(water) hydrogen bonds and
in this manner form a 3-D structure. The results of the X-ray
crystallographic studies indicate that both molecules of 1
have a 6a-(R) configuration.[31
I
BnO
H
I
BnO
H
4
3
H
c, d
b
__t
+
BnO
0121
W
BnO
Nn
X
M
e
M
@
2
0
n
0
5
6
C
o
Me
7
Scheme 1. Synthesis of damirone B (6) and damirone A (7). Reagents and
reaction conditions: a) 1 equiv 3, 2.0 equiv MeNH, x HCI, 4.0 equiv Et,N,
CH,CI,, room temperature (RT), 0.5 h (91 %). b) 10equiv LiAIH,, THF, reflux, 4 h (51 %). c) H,, 10% Pd/BaSO,, MeOH, RT, 1.5 h. d) 0, from the air,
Et,N. MeOH, RT, 1 h (76%, 2 steps). e) 1.0 equiv 6 , 1 equiv K,CO,, 3 equiv
CHJ, EtOH, reflux, 1.5 h (89%).
benzyl protecting groups are removed by hydrogenolysis.
The resulting dihydroxyindole derivative is stirred in
methanol and triethylamine under air and cyclizes to provide
damirone B (6). According to spectroscopic data, the synthetic product is identical to the naturally occurring compound.[61Methylation with methyl iodide and addition of
potassium carbonate yielded damirone A (7). In an
Table 2. Selected physical and spectroscopic data for compounds 4-7 and 2.
Fig. 1. Top: The structure of the first independent molecule of 1 in the unit cell
(projection in accordance with IUPAC guidelines). Bottom: Linkage of the
molecules of 1 by hydrogen bonds.
As mentioned in the introduction, haematopodin occurs,
when at all, only in trace amounts in fresh fruiting bodies. It
is formed by the breakdown of a very sensitive native pigment, which we have not yet been able to isolate in pure
f0rm.1~'For example, if a fungal extract is left in methanol in
a sealed flask exposed to light for a few weeks, only haematopodin can be detected.
Related 1,3,4,5-tetrahydropyrrolo[4,3,2-de]quinoline
pigments such as bat~ellins[~]
and damironesl6I have been isolated from sea sponges. It is assumed that for these compounds the key step in the biosynthesis is the intramolecular
cyclization of a tryptamine-6,7-quinone. In the case of
haematopodin, the open chain compound 2 may be formed
first which then undergoes oxidative cyclization to yield the
oxazine derivative 1.
A simple biomimetic synthesis along these lines starting
from damirone B (6) and compound 2 is possible (Scheme 1,
Table 2). The reaction sequence starts from the known compound 6,7-dibenzyloxyindolyl-3-glyoxylic acid chloride
(3)"' which in the case of 6 is converted to amide 4 by reaction with methylamine. After reduction to yield amine 5, the
1088
0 VCH
Verlogsgesell~~choJl
mbH, 0-69451 Weinheim, 1993
4: Yellowcrystals, m.p. 186°C; ' H NMR (400 MHz, [D,]DMSO): 6
= 2.75 (d,
J = 4 . 8 H Z , 3 H ) , 5 . 1 8 ( ~ , 2 H ) , 5 . 2 1( ~ , 2 H ) , 7 . 1 7 ( d . J =8.4Hz,lH),7.31-7.52
(m, lOH), 7.87 (d, J = 8.4 Hz, 1 H), 8.64 (s, 1 H), 8.65 (9, J = 4.8 Hz, amideNH); EI-MS (70eV): m / z 414.1582 (15%, M + ) , calcd. (C,,H,,N,O,)
414.1579.
5-oxalate: M.p. 156°C; ' H N M R (400 MHz, [DJDMSO): 6 = 2.56 (s, 3H),
2.99(t, J = 8.0 Hz,2H),3.15(t, J = 8.0 Hz,2H), 5.13(~.2H)5.15(~,2H),6.93
(d, J = 8.8 Hz, 1 H), 7.12 (d, J = 2.5 Hz, 1 H), 7.23 (d, J = 8.8 Hz, 1 H), 7.327.53 (m, 10H), 10.87 (d, J = 2.5 Hz, indole-NH).
6 : Dark violet crystals, m.p. 250°C (decomp); R, = 0.28 (silica gel, CHCI,/
CH3OH lO/lf; ' H NMR (400 MHz, CDCI,/[D,]DMSO): 6 = 2.92 (t,
J=6.8Hz,2H),3.14(s,3H),3.67(t,J=6.8Hz,2H),4.00(s,lH,NH),5.29
(S, 1 H), 6.89 ( s , 1 H); "C NMR (100.6 MHz, CDCI,/[D,]DMSO): 6 = 20.3,
38.2, 51.7, 92.9, 116.7, 124.3, 125.0, 125.3, 154.0, 170.9, 179.1.
7: Dark violet crystals, m.p. 240°C (decomp); Rr = 0.38 (silica gel, CHCI,/
CH,OH lS/l); ' H N M R (400 MHz, CDCL,/[D,]DMSO): 6 = 2.86 (t.
J=6.8Hz,2H),3.09(~,3H),3.61(t,J=6.8Hz,2H),3.91 (s,3H).5.27(~,
1 H), 6.67 ( S , 1 H); "C NMR (100.6 MHz, CDCl,/[D,]DMSO): 6 = 20.3, 36.0,
38.4, 51.9, 93.2, 115.9, 124.8, 125.0. 127.6, 154.5, 171.7. 179.4.
2 : Dark violet crystals, m.p. 230°C (decomp); R, = 0.31 (silica gel, CHCI,/
CH,OH 511); ' H N M R (400 MHz, [DJDMSO): 6 = 1.77 (quint. J = 6.8 Hz,
2H), 2.80 (t, J = 6.8 Hz, 2 H), 3.45 (1. J = 6.8 Ha, 2H). 3.49(t, J = 6.8 Hz, 2H),
3.63 (t>J = 6.8 Hz, 2H). 4.63 (s, 1 H, OH), 5.20 (s, 1 H), 7.08 (s, 1H), 12.36 (s,
1 H, indole-NH); "C NMR (100.6 MHz, [D,JDMSO): 6 = 19.7, 29.7, 47.5,
49.4, 58.0, 92.0, 116.4, 123.8, 124.5, 125.0, 152.6, 170.5, 178.4; IR (KBr):
qmAX= 3423, 3117,2934,2866,1670, 1608, 1587,1543, 1432, 1417, 1323, 1241,
1078, 762. 745cm-I: EI-MS (70eV): m / z 248 (68%, M + + 2H), 247 (44,
M + + H). 246.1006 (42, M ' ) , calcd. (C,,H,,N,O,) 246.1004, 232 (26). 203
(loo), 202 (88), 187(54), 174 (50). 146 (79); UV/VIS: 2,,, (CH,OH) = 207,245,
349, 521 nm.
0570-0833193/0?07-1088 $10.00+ .25/0
Angew Chem. Int. Ed. Engl. 1993. 32, No. 7
analogous manner the hypothetical precursor of haematopodin, 2, was synthesized starting from acid chloride 3 and
3-aminopropanol. However, attempts to oxidatively cyclize
this compound to yield 1 by using Hg(OAc), or other
reagents have not been successful up until now.
These syntheses demonstrate that 6,7-dihydroxytryptamine derivatives are easily converted by oxygen to pyrroloquinolines. Further studies on the chemistry of the Mycena
pigments and the chemical synthesis of haematopodin are
being carried out at the present time.
Received: March 13, 1993 [Z 5921 IE]
German version: A n g w . Chem. 1993, 105, 1120
[l] 1 x H,O: black crystals; R, = 0.61 (silica gel, CHCI,/CH,OH 10/1); CD
= 0, [HI,,, = f2.35 x lo3, [HI,,, = 0,
= - 6.30 x
(CH,OH).
lo'.
= 0, [H],,, = f5.32 x 10'. [O],,, = 0; IR (KBr): i.,,, = 3440
(sst), 3120, 3060, 2980. 2950, 2840, 2820 (all m), 1680 (sst), 1640 (w), 1590,
1560. 1520 (br). 1490, 1455 (all sst), 1420 (st), 1400. 1380, 1350(all w), 1340
(sst), 1300(m), 1290(m), 1250(st), 1180, 1150, 1120(sllm), 1060(sst), 1090
(st). 1050 (st), 1000. 940, 910 (all w). 900 (m), 870 (m), 800 (w). 680 (w)
c m - ': El-MS. (180°C. DE): m / z 244.0850 (42%, M ' ) , calcd.
(C,,H,,N,O,): 244.0848.
[2] H. Kessler, C. Griesinger, Z. Zarbock, H. R. Loosli, J. Magn. Reson. 1984,
57. 331.
[3] Crystal data for 1: C,,H,,N,O, x H,O, monoclinic, space group
P2,. u = 8.030(2), b =11.603(4), c =12.751(2) A, p = 92,7915)". V =
1186.6(9) A', M = 262.3. Z = 4, e,,,, =1.47 g ~ m - 4115
~ ; observed reflections (including Friedel pairs), Enraf-Nonius CAD4 diffractometer, Cu,,
radiation, o adjustment, 2ff,,, = 140". After refinement R = 0.054 and
R, = 0.053. The factor as defined by Rogers was refined to 0.8(6) for the
6a-(R) configuration. Further details of the crystal structure investigation
may be obtained from the Fachinformationszentrum Karlsruhe,
Gesellschaft fur wissenschaftlich-technische Information mbH, D-76 344
Eggenstein-Leopoldshafen (FRG), on quoting the depository number
CSD-57095, the names of the authors, and the journal citation.
141 The UVjVIS spectrum of the raw extract corresponds in most respects to
that of 1, however, it IS markedly bathochromically shifted in the longwavelength region [&,ex (CH,OH) = 242, 356, 530 nm].
[5] S. sdkemi, H. H. Sun, C. W. Jefford, G. Bernardinelh, Teirahedron Lett.
1989. 30. 2517; synthesis of batzellin C: X. L. Tao, S. Nishiyama, S . Yamamura, Chem. Lerr. 1991, 1785.
[6j D. B. Stierle, D. J. Faulkner, J. Nai. Prod. 1991. 5 4 , 1131.
[7] F. G. Lee. D. E Dickson, J. Suzuki, A. Zirnis. A. A. Manian. J. Heterocycl.
Chrm. 1973. 10. 649.
Ylide-Substituted Thioxophosphanes and
Dithioxophosphoranes**
By Georg Jochem, Heinrich Noth and Alfred Schmidpeter *
Chalcogenophosphanes RP=Y (Y = 0, S, Se) are extremely reactive, and so far no compound of this type is
known that is stable at room temperature." b* 2 c s 31 Halothioxophosphanes 1 (R = F, CI, Br) were detected and studied in the gas phase and in argon
Other thioxophosphanes with R = Me, Et, nBu, Ph, NMe,, OCH,CCl,,
OPh, for example, could be generated but were detected only
indirectly as adducts and cycloadducts as well as coordinated
to metal complexes fragments.[lb] Four (!) independent experiments for the preparation of thioxophosphane 1 with
2,4,6-tri-tert-butylphenyl as the substituent R are found in
the literature. This substituent was used successfully for the
kinetic stabilization of lower coordinated main group elements in many cases before. In the attempted synthesis of I,
[*I
[**I
R = 2,4,6-tri-tert-butylphenyl, however, only the cyclic
trimer 2 and products of disproportionation were found.[*]
We have now succeeded in stabilizing thioxophosphanes
with an ylide substituent R and isolating them as stable compounds.
?
1
Dichloro[organo( triphenylphosphonio)methanidyl]phosphanes 3, R = Me, Etl4] react smoothly with sodium sulfide
in THF to form the ylide-substituted thioxophosphanes 423, b which can be isolated as orange-red crystals
(Scheme 1). The aryl derivatives 4c, d are prepared in the
same manner but are not stable in solution. Here the reaction
does not proceed uniformly. The selenoxophosphanes
RP=Se can be prepared analogously from 3 and Na,Se.[']
Thioxophosphanes 4 were characterized unequivocally by
their 31PNMR spectra (Scheme I), particularly by the lowfield signal of the two-coordinate phosphorus. Here the 3 1 P
3
Scheme 1.
4
R
d3'PPh3
fS3'PS
'J(P,P)
48
Me
28.9
485.0
116.0 Hz
4b
Et
27.9
488.2
116.0 Hz
4c
Ph
25.0
495.9
107.8 Hz
4d
3-MeC,H4
25.3
493.8
107.8 Hz
in THF
nucleus remains much more strongly shielded, though, than
would be expected from extrapolation from RP=SiR, and
RP=PR["*6] to RP=S. In keeping with this, the signal of the
ylide carbon atom of 4 (4b: 613C =137.2) is at lower field
than those of other ylides, even a-acyl-substituted triphenylphosphonium ylides.['] Both features point to a considerable
contribution of the dipolar resonance formula, in which 4 is
depicted as a phosphalkene. The relatively strong P-P coupling indicates that the sulfur atom and the phosphonio
group are trans to each otherfs1as is also found in the crystal
structure (see below) ; the polarity of the solvent (benzene/
THF) does not have a discernible influence on the coupling.
Thioxophosphanes 4 prove to be ambident nucleophiles.
Compound 4 b reacts with benzyl bromide by S-alkylation
forming 5 b (in THF: h31PPh, = 25.9, h3'PS = 245.1,
2J(P,P) = 173.9 Hz[''), but by P-oxidation with sulfur giving
6b. The latter is also directly accessible from 3 and Na,S,
like other dithioxophosphoranes Ph,P=Cr-PS, 6.['01Oxi-
5b
Prof. Dr. A. Schmidpeter, Dip].-Chem. G. Jochem, Prof. Dr. H. Noth
Institut fur Anorganische Chemie der Universitat
Meiserstrdsse 1, D-80333 Munchen (FRG)
Telefax: Int. code + (89) 5902-578
This work was supported by the Deutsche Forschungsgemeinschaft and
the Fonds der Chemischen lndustrie.
Angew. Chem. In{. Ed. Enxl. 1993, 32, N o . 7
2
0 VCH Verlagsgeseilschfr mbH, 0-69451
Et
Et
6b
Weinheim, 1993
0570-0833~93/0707-l089
$ 10.00+.25/0
1089
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