First total synthesis of clausine L and pityriazole, a metabolite of the human pathogenic yeast Malassezia furfur

Article abstract of DOI:10.1039/b805451g

The first total synthesis of the alkaloid pityriazole is described using three consecutive palladium-catalyzed coupling reactions. The Royal Society of Chemistry 2008.

Full text of DOI:10.1039/b805451g

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First total synthesis of clausine L and pityriazole, a metabolite of the human
pathogenic yeast Malassezia furfur†‡
Ronny Forke, Anne Ja¨ger and Hans-Joachim Kno¨lker*
Received 1st April 2008, Accepted 25th April 2008
First published as an Advance Article on the web 22nd May 2008
DOI: 10.1039/b805451g
The first total synthesis of the alkaloid pityriazole is de-
scribed using three consecutive palladium-catalyzed coupling
reactions.
Our previous synthesis of mukonidine using an iron-mediated
approach was limited (4 steps, 17% overall yield).7 In the present
approach, we applied our palladium-catalyzed construction of
the carbazole framework (Scheme 1). The coupling of iodoben-
zene (4) with the commercial arylamine 5 via a palladium(0)-
catalyzed Buchwald–Hartwig amination8 led quantitatively to the
diarylamine 6. The subsequent palladium(II)-catalyzed oxidative
cyclization via a double C–H bond activation provides clausine L
(3) as the major product. Clausine L (3), obtained by total
synthesis for the first time, has been characterized by comparison
of its spectroscopic data with those reported for the natural
product6 and an X-ray analysis (Fig. 2).§ For steric reasons, the
regioselective cyclization to clausine L (3) predominates. Only on
a large scale could the minor regioisomer 7 be isolated (2% yield)
and fully characterized.§
The lipophilic yeast Malassezia furfur is believed to represent one
of the pathogenic agents responsible for pityriasis versicolor, a
Malassezia-associated common skin disease characterized by flaky
lesions.2 Recently, Steglich and co-workers have isolated eleven
novel tryptophan metabolites from the cultures of M. furfur,
among them the hitherto unprecedented 1-(indol-3-yl)carbazole
alkaloid pityriazole 1 (Fig. 1).3 Carbazole alkaloids are of general
interest due to their broad range of biological activities.4,5 Thus,
the report from Steglich et al. prompted us to develop an
efficient synthetic approach to pityriazole (1) using our palladium-
catalyzed route.
Fig. 1 Pityriazole (1) and structurally related 2-oxygenated carbazoles.
Generally carbazole alkaloids having a carbon substituent at
the 3-position biogenetically derive from the anthranilic acid
pathway and have been isolated from terrestrial plants of the
Rutaceae family. While carbazole alkaloids from other sources
are biosynthesized from tryptophan and have the carbon sub-
stituent at C2.4a Steglich et al. could demonstrate that pityriazole
with a carbon substituent at C3 biogenetically derives from
tryptophan.3 We realized the structural similarity of pityriazole
(1) to mukonidine (2) and clausine L (O-methylmukonidine) (3),
both isolated by Wu and co-workers from the Chinese medicinal
plant Clausena excavata.6 Therefore, we envisaged a synthetic
approach to pityriazole (1) using mukonidine (2) and clausine L
(3) as intermediates.
Scheme 1 Palladium-catalyzed synthesis of clausine L (3). Reagents
and conditions: (a) 5 mol% Pd(OAc)2, 6 mol% BINAP, 1.5 equiv.
Cs2CO3, toluene, Ar, reflux, 2 d, 100%; (b) 12 mol% Pd(OAc)2, 10 mol%
Mn(OAc)3·2 H2O, pivalic acid, air, 100 ◦C, 3 d, 62% of 3, 2% of 7.
Department Chemie, Technische Universita¨t Dresden, Bergstrasse 66,
01069 Dresden, Germany. E-mail: hans-joachim.knoelker@tu-dresden.de;
Fax: +49 351-463-37030
† Part 86 of ‘Transition Metals in Organic Synthesis’; for Part 85, see:
ref. 1.
‡ Electronic supplementary information (ESI) available: Additional details
of the crystal structure determinations. CCDC reference numbers 683126
and 683127. For crystallographic data in CIF or other electronic format
and ESI see DOI: 10.1039/b805451g
Fig. 2 Molecular structure of clausine L (3) in the crystal.
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Table 1 Palladium(II)-catalyzed cyclization of 6 to clausine L (3)a
a considerably improved route (cf. ref. 7) to this natural product
(3 steps, 59% overall yield).¶ All electrophilic halogenations of
mukonidine including the iodination16 take place exclusively at C1
(85–99% yield).
Pd(OAc)2
Reoxidant
Time
3, Yield (%)
6, Yield (%)
10 mol%
10 mol%
5 mol%
2.5 equiv. Cu(II)
10 mol% Cu(II)
10 mol% Cu(II)
10 mol% Mn(III)
1 d
44
55
61
62
55
38
24
15
Attempted coupling reactions of the 1-chloro derivatives 9
and 10a with 1-(phenylsulfonyl)indol-3-yl-boronic acid (11) using
tetrakis(triphenylphosphane)palladium as catalyst under the usual
conditions gave no product. But Suzuki–Miyaura coupling of
11 with the more reactive 1-bromomukonidine 10b afforded
the desired product 12 in up to 50% yield. Compound 12 has
been confirmed by an X-ray crystal structure determination
(Fig. 3).ꢀ Finally, Suzuki–Miyaura coupling of 1-iodomukonidine
(10c) with 11 using S-Phos (2-dicyclohexylphosphino-2ꢁ,6ꢁ-
dimethoxybiphenyl) as ligand under optimized conditions (mi-
crowave heating and moist potassium phosphate as base)17 led to
the 1-(indol-3-yl)carbazole 12 in 82% yield (Scheme 3). Cleavage
of the ester and the phenylsulfonyl group under basic conditions
provided, after purification by HPLC, pure pityriazole (1).** The
spectroscopic data of our synthetic pityriazole (1) were in full
agreement with those reported for the natural product. The
17 h
3.5 d
3 d
12 mol%
a All reactions have been carried out in pivalic acid as solvent at 100 ◦C in
the presence of air. Reoxidants: Cu(OAc)2 and Mn(OAc)3·2 H2O.
In an extension to our previous investigations on the catalytic
version of this reaction,9,10 we optimized the reaction conditions
for the palladium(II)-catalyzed cyclization (Table 1). Initiated
by a recent report of Fagnou et al.,11 we demonstrated in an
independent investigation that pivalic acid is superior to acetic acid
as solvent for this reaction.12 In the present study we could make
this reaction become catalytic not only in palladium(II) but also
in copper(II). The catalysis in palladium(II) as well as in copper(II)
is well-known for the Wacker oxidation,13 but for the C–C bond
formation by double aryl C–H bond activation it is reported for the
first time. Moreover, we have tested other agents for the oxidation
of palladium(0) to palladium(II). While iron(III) appears to be
inefficient, manganese(III) is almost as efficient as copper(II) for
the regeneration of palladium(II).
For the projected introduction of the indolyl substituent by a
Suzuki–Miyaura coupling,14 a halogenation at C1 of the carbazole
framework was required. Electrophilic bromination of clausine L
(3) under the usual conditions afforded 6-bromoclausine L (8)
(Scheme 2). This result corresponds to the general regioselectivity
of electrophilic substitutions at carbazoles. However, chlorination
under the same reaction conditions takes place exclusively at C1
providing 1-chloroclausine L (9). This outcome is explained by the
steric requirement of the bromo substituent. In the course of our
total synthesis of 6-chlorohyellazole, we observed a related regio-
selectivity reversal from halogenation at C6 versus halogenation at
C4 by switching from bromination to chlorination.15 We expected
that cleavage of the methyl ether for steric and electronic reasons
should favor even more the halogenation at C1. Cleavage of the
methyl ether of clausine L (3) afforded mukonidine (2), providing
Fig. 3 Molecular structure of compound 12 in the crystal.
Scheme 2 Halogenations of clausine L (3) and mukonidine (2). Reagents
and conditions: (a) 1.05 equiv. NBS, cat. HBr, CH2Cl2, 25 ◦C, 6 h, 84%;
(b) 1.05 equiv. NCS, cat. HCl, CH2Cl2, 25 ◦C, 22 h, 85%; (c) 2.2 equiv.
BBr3, CH2Cl2, −78 to −4 ◦C, 1 h, 95%; (d) 1.01 equiv. NCS, CH2Cl2,
25 ◦C, 7 h, 85% 10a; (e) 1.05 equiv. NBS, CH2Cl2, 25 ◦C, 4 h, 99% 10b;
(f) 1.05 equiv. I2, 1.05 equiv. Cu(OAc)2, 80 ◦C (microwave), 2 h, 85% 10c.
Scheme 3 Transformation of 1-iodomukonidine (10c) into pityriazole (1).
Reagents and conditions: (a) 1.6 equiv. 11, 0.2 equiv. Pd(OAc)2, 0.4 equiv.
S-Phos, 2 equiv. moist K3PO4, dioxane, Ar, 90 ◦C (microwave), 3 h, 82%;
(b) 15 equiv. KOH, EtOH, Ar, 40 ◦C, 2 d, 86%.
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identity has been additionally confirmed by comparison of the UV,
ꢀ Crystal data for compound 12: C28H20N2O5S, crystal size: 0.25 × 0.09 ×
0.08 mm3, Mr = 496.52 g mol−1, monoclinic, space group P21/c k =
1
IR, H NMR and 13C NMR spectra of our synthetic compound
◦
˚
˚
0.71073 A, a = 12.061(1), b = 22.545(1), c = 9.161(1) A, b = 107.45(1) ,
with the corresponding original spectra of the natural product,
kindly provided by Professor W. Steglich.
3
V = 2376.4(3) A , Z = 4, qcalcd = 1.388 g cm−3, l = 0.180 mm−1, T = 293(2)
˚
K, h range = 3.06–27.00◦; reflections collected: 36307, independent: 5184
(Rint = 0.0590). The structure was solved by direct methods and refined
by full-matrix least-squares on F2; R1 = 0.0524, wR2 = 0.1031 [I > 2r(I)];
In conclusion, we have developed a highly efficient route which
provides pityriazole (1) in six steps and 35% overall yield via three
palladium-catalyzed coupling reactions. In the course of our work,
we have also achieved the first synthesis of clausine L (3) (2 steps,
62% overall yield) and an improved access to mukonidine (2)
(3 steps, 59% overall yield). As only 1.0 mg of pityriazole (1) has
been obtained by Steglich et al. from natural sources, an investig-
ation of the bioactivity of this natural product as well as its struc-
tural analogues can be initiated based on our synthetic approach.
We are grateful to Professor Wolfgang Steglich, Univer-
sita¨t Mu¨nchen, for providing us the files of the original spectra
for natural pityriazole.
maximal residual electron density: 0.226 e A−3. CCDC 683127.
˚
** Spectroscopic data for pityriazole (1): Colorless crystals, mp 236 ◦C
(decomp.); UV (MeOH): k = 223, 282, 327, 338 nm; IR (ATR): m = 3398,
3037, 1628, 1609, 1542, 1477, 1456, 1410, 1375, 1328, 1310, 1253, 1219,
1135, 1098, 1056, 1015, 993, 889, 793, 736, 716 cm−1; 1H NMR (500 MHz,
DMSO-d6): d = 6.99 (t, J = 7.5 Hz, 1 H), 7.15 (t, J = 7.5 Hz, 2 H),
7.28–7.31 (m, 2 H), 7.40 (d, J = 8.0 Hz, 1 H), 7.50 (d, J = 8.0 Hz, 1 H),
7.59 (s, 1 H), 8.11 (d, J = 7.7 Hz, 1 H), 8.62 (s, 1 H), 10.83 (s, 1 H), 11.44 (s,
1 H), 11.91 (br s, 1 H), 13.63 (br s, 1 H); 13C NMR and DEPT (125 MHz,
DMSO-d6): d = 104.62 (C), 105.14 (C), 106.81 (C), 111.45 (CH), 111.59
(CH), 115.64 (C), 118.79 (CH), 119.56 (CH), 119.73 (CH), 120.31 (CH),
121.12 (CH), 121.42 (CH), 123.28 (C), 125.16 (CH), 125.50 (CH), 126.91
=
(C), 136.36 (C), 140.89 (C), 144.60 (C), 157.84 (C), 173.55 (C O); MS
(EI): m/z (%) = 342 (M+, 48), 324 (100), 298 (93), 297 (22), 296 (24), 269
(21), 268 (16), 267 (22), 241 (12), 240 (11), 162 (16); HRMS: m/z calc. for
C21H14N2O3 (M+): 342.1004, found: 342.0989.
Notes and references
1 C. Bo¨rger and H.-J. Kno¨lker, Synlett, 2008, in press.
§ Spectroscopic data for clausine L (3): Colorless crystals, mp 172–173 ◦C;
UV (MeOH): k = 235, 241, 269, 282 (sh), 319, 333 nm; IR (ATR): m =
3264, 2951, 2922, 2852, 1690, 1632, 1608, 1574, 1486, 1462, 1427, 1392,
1348, 1313, 1278, 1239, 1201, 1163, 1115, 1082, 1035, 979, 950, 909, 875,
825, 789, 775, 766, 750, 727 cm−1; 1H NMR (500 MHz, acetone-d6): d =
3.85 (s, 3 H), 3.92 (s, 3 H), 7.15 (s, 1 H), 7.20 (t, J = 7.8 Hz, 1 H), 7.35 (t,
J = 7.8 Hz, 1 H), 7.49 (d, J = 7.8 Hz, 1 H), 8.09 (d, J = 7.8 Hz, 1 H), 8.54
(s, 1 H), 10.53 (br s, 1 H); 13C NMR and DEPT (75 MHz, acetone-d6): d =
51.77 (CH3), 56.44 (CH3), 94.85 (CH), 111.83 (CH), 113.76 (C), 116.97
(C), 120.47 (CH), 120.63 (CH), 124.19 (C), 124.99 (CH), 126.00 (CH),
2 A. K. Gupta, R. Bluhm and R. Summerbell, J. Eur. Acad. Dermatol.
Venereol., 2002, 16, 19.
3 B. Irlinger, A. Bartsch, H.-J. Kra¨mer, P. Mayser and W. Steglich, Helv.
Chim. Acta, 2005, 88, 1472.
4 (a) H.-J. Kno¨lker and K. R. Reddy, in The Alkaloids, ed. G. Cordell,
Academic Press, Amsterdam, 2008, vol. 65, p. 1; (b) H.-J. Kno¨lker, Top.
Curr. Chem., 2005, 244, 115; (c) H.-J. Kno¨lker and K. R. Reddy, Chem.
Rev., 2002, 102, 4303.
5 For recent synthetic approaches to carbazoles, see: (a) A. Yamabuki,
H. Fujinawa, T. Choshi, S. Tohyama, K. Matsumoto, K. Ohmura, J.
Nobuhiro and S. Hibino, Tetrahedron Lett., 2006, 47, 5859; (b) R. B.
Bedford and M. Betham, J. Org. Chem., 2006, 71, 9403; (c) M.
Yamamoto and S. Matsubara, Chem. Lett., 2007, 36, 172; (d) R. Forke,
M. P. Krahl, T. Krause, G. Schlechtingen and H.-J. Kno¨lker, Synlett,
2007, 268; (e) Z. Liu and R. C. Larock, Tetrahedron, 2007, 63, 347;
(f) L. Ackermann and A. Althammer, Angew. Chem., Int. Ed., 2007,
46, 1627; (g) T. P. Lebold and M. A. Kerr, Org. Lett., 2007, 9, 1883;
(h) T. Watanabe, S. Ueda, S. Inuki, S. Oishi, N. Fujii and H. Ohno,
Chem. Commun., 2007, 4516; (i) D. J. St. Jean Jr., S. F. Poon and J. L.
Schwarzbach, Org. Lett., 2007, 9, 4893; (j) C.-Y. Liu and P. Knochel,
J. Org. Chem., 2007, 72, 7106; (k) M. R. Naffziger, B. O. Ashburn, J. R.
Perkins and R. G. Carter, J. Org. Chem., 2007, 72, 9857.
=
141.53 (C), 144.70 (C), 159.83 (C), 167.45 (C O); MS (EI): m/z (%) =
255 (M+, 100), 240 (5), 224 (89), 209 (18), 194 (9), 181 (7), 166 (14), 153
(15), 139 (11); HRMS: m/z calc. for C15H13NO3 (M+): 255.0895, found:
255.0889. Crystal data for clausine L (3): C15H13NO3, crystal size: 0.32 ×
0.11 × 0.10 mm3, Mr = 255.26 g mol−1, orthorhombic, space group Pna21,
˚
˚
k = 0.71073 A, a = 14.127(1), b = 11.910(2), c = 7.618(2) A, V = 1281.7(4)
3
A , Z = 4, qcalcd = 1.323 g cm−3, l = 0.093 mm−1, T = 198(2) K, h range =
˚
3.35–25.40◦; reflections collected: 7318, independent: 2201 (Rint = 0.0868).
The structure was solved by direct methods and refined by full-matrix
least-squares on F2; R1 = 0.0464, wR2 = 0.0940 [I > 2r(I)]; maximal
residual electron density: 0.163 e A−3. CCDC 683126. Spectroscopic data
˚
for methyl 4-methoxycarbazole-3-carboxylate (7): Colorless crystals, mp
175–178 ◦C; UV (MeOH): k = 234, 244, 266, 307, 318, 331 nm; IR (ATR):
m = 3319, 2928, 2855, 1701, 1623, 1599, 1584, 1485, 1454, 1431, 1395, 1339,
1310, 1284, 1250, 1224, 1211, 1138, 1078, 1056, 1010, 970, 874, 833, 803,
748, 731 cm−1; 1H NMR (500 MHz, acetone-d6): d = 3.90 (s, 3 H), 4.10 (s,
3 H), 7.27 (t, J = 8.0 Hz, 1 H), 7.33 (d, J = 8.5 Hz, 1 H), 7.45 (t, J = 8.0 Hz,
1 H), 7.56 (d, J = 8.0 Hz, 1 H), 7.92 (d, J = 8.5 Hz, 1 H), 8.29 (d, J =
8.0 Hz 1 H), 10.78 (br s, 1 H); 13C NMR and DEPT (125 MHz, acetone-
d6): d = 51.86 (CH3), 61.77 (CH3), 107.40 (CH), 111.88 (CH), 114.74 (C),
117.57 (C), 120.87 (CH), 122.62 (C), 123.50 (CH), 126.76 (CH), 130.06
6 T.-S. Wu, S.-C. Huang, J.-S. Lai, C.-M. Teng, F.-N. Ko and C.-S. Kuoh,
Phytochemistry, 1993, 32, 449.
7 (a) H.-J. Kno¨lker and M. Wolpert, Tetrahedron Lett., 1997, 38, 533;
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8 (a) J. F. Hartwig, Angew. Chem., Int. Ed., 1998, 37, 2046; (b) A. R. Muci
and S. L. Buchwald, Top. Curr. Chem., 2002, 219, 131.
˚
9 B. Akermark, L. Eberson, E. Jonsson and E. Petersson, J. Org. Chem.,
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557; (c) H.-J. Kno¨lker and K. R. Reddy, Heterocycles, 2003, 60, 1049;
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Chem., 2006, 4, 3215.
=
(CH), 140.85 (C), 145.11 (C), 158.52 (C), 166.99 (C O); MS (EI): m/z
(%) = 255 (M+, 97), 224 (100), 222 (25), 212 (17), 209 (29), 194 (14), 181
(15), 169 (16), 166 (16), 153 (33), 139 (15), 126 (11).
¶ Spectroscopic data for mukonidine (2): Colorless crystals, mp 189 ◦C;
UV (MeOH): k = 235, 243, 270 (sh), 276 (sh), 284, 325, 338 nm; IR (ATR):
m = 3347, 2952, 2922, 2852, 1644, 1627, 1582, 1481, 1464, 1432, 1373, 1363,
1329, 1258, 1236, 1189, 1165, 1118, 1093, 1014, 991, 949, 898, 871, 821,
11 M. Lafrance and K. Fagnou, J. Am. Chem. Soc., 2006, 128, 16496.
12 R. Forke, M. P. Krahl, F. Da¨britz, A. Ja¨ger and H.-J. Kno¨lker, Synlett,
2008, in press.
13 (a) J. Tsuji, in Palladium Reagents and Catalysts – New Perspectives for
the 21st Century, Wiley, Chichester, 2004, ch. 2; (b) J. M. Takacs and
X.-t. Jiang, Curr. Org. Chem., 2003, 7, 369.
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Miyaura, Top. Curr. Chem., 2002, 219, 11.
15 H.-J. Kno¨lker, W. Fro¨hner and R. Heinrich, Synlett, 2004, 2705.
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17 P. Wawrzyniak and J. Heinicke, Tetrahedron Lett., 2006, 47, 8921.
784, 762, 740, 719 cm−1
;
1H NMR (500 MHz, acetone-d6): d = 4.00 (s,
3 H), 6.93 (s, 1 H), 7.20 (t, J = 7.8 Hz, 1 H), 7.36 (t, J = 7.8 Hz, 1 H),
7.47 (d, J = 7.8 Hz, 1 H), 8.09 (d, J = 7.8 Hz, 1 H), 8.62 (s, 1 H), 10.52
(br s, 1 H), 11.07 (s, 1 H); 13C NMR and DEPT (75 MHz, acetone-d6):
d = 52.60 (CH3), 97.70 (CH), 105.95 (C), 111.79 (CH), 117.85 (C), 120.58
(CH), 120.89 (CH), 123.41 (CH), 124.30 (C), 126.51 (CH), 141.96 (C),
+
=
146.62 (C), 161.62 (C), 172.22 (C O); MS (EI): m/z (%) = 241 (M , 46),
209 (100), 181 (20), 153 (33), 126 (10), 104 (10).
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