Transition metals in organic synthesis, part 96. First total synthesis of streptoverticillin: Unambiguous confirmation of the absolute configuration

Article abstract of DOI:10.1055/s-0031-1289551

Using an iron-mediated construction of the carbazole framework, the first synthesis of streptoverticillin is described and the absolute configuration of the natural product is confirmed. The synthesis exploits a novel oxygen-mediated aromatization of tric

Full text of DOI:10.1055/s-0031-1289551

LETTER
2663
Transition Metals in Organic Synthesis, Part 96.1 First Total Synthesis of
Streptoverticillin: Unambiguous Confirmation of the Absolute Configuration
Configuration of
l
Strepto
a
verticillin udia Thomas, Olga Kataeva, Hans-Joachim Knölker*
Department Chemie, Technische Universität Dresden, Bergstr. 66, 01069 Dresden, Germany
Fax +49(351)46337030; E-mail: hans-joachim.knoelker@tu-dresden.de
Received 18 August 2011
by hydride abstraction of the tricarbonyliron complex 8
Abstract: Using an iron-mediated construction of the carbazole
framework, the first synthesis of streptoverticillin is described and
the absolute configuration of the natural product is confirmed. The
synthesis exploits a novel oxygen-mediated aromatization of tricar-
bonyliron-coordinated dihydrocarbazoles. Moreover, non-natural
(R)-streptoverticillin is prepared for comparison.
(Scheme 2).11,12
MeO
HO
OMe
Me
OMe
Me
Key words: alkaloids, carbonyl complexes, cyclization, iron, total
synthesis
N
H
N
H
OH
OH
streptoverticillin (1)
neocarazostatin B (2)
A range of structurally diverse carbazole alkaloids has
been isolated from different natural sources over the past
decades.2 The useful biological properties of carbazole
natural products have inspired the development of several
novel methods for their synthesis.3,4 The iron-mediated
route provides easy access to 1-oxygenated, 3-oxygenat-
ed, and 3,4-dioxygenated carbazoles.5,6 The 1-(2-hydroxy-
propyl)-substituted 3,4-dioxygenated carbazole alkaloids
1–4 have been obtained from microorganisms (Figure 1).
A recent report described the isolation of the antifungal
streptoverticillin (1) from the ethanol extract of Strep-
toverticillium morookaense strain SC1169.7 It is notewor-
thy that an S configuration has been assigned to the
stereogenic center of the side chain at C-1, whereas neo-
carazostatin B (2),8 carquinostatin A (3),9 and lavandu-
quinocin (4)10 all have R configuration at the stereogenic
center of the 2-hydroxypropyl side chain. The assignment
of the absolute configuration of streptoverticillin (1) was
based solely on comparison of the value for its optical ro-
tation ([a]D20 = +18.4) with the value we had reported for
neocarazostatin B (2; [a]D25 = –16) from our enantioselec-
tive synthesis.7,8c
O
O
O
Me
OH
O
N
H
Me
OH
lavanduquinocin (4)
N
H
carquinostatin A (3)
Figure 1 Naturally occurring 1-(2-hydroxypropyl)-substituted 3,4-
dioxygenated carbazole alkaloids
OMe
MeO
OMe
OMe
+
(OC)3Fe
+
Me
OH
H2N
Me
–
BF4
N
H
OAc
5
1
6
Scheme 1 Retrosynthetic analysis of streptoverticillin (1)
Access to larger amounts of streptoverticillin (1) would
enable a more detailed study of the biological activities
and provide confirmation of its absolute configuration.
Therefore, we embarked on the total synthesis of this
novel natural product. Our retrosynthetic analysis of 1 led
us to the iron complex salt 5 and the (S)-arylamine 6
(Scheme 1).
+
(OC)3Fe
a
b
(OC)3Fe
–
BF4
5
7
8
Scheme 2 Synthesis of the complex salt 5. Reagents and conditions:
(a) Fe(CO)5, cat. 1-(4-methoxyphenyl)-4-phenyl-1-azabutadiene,
dioxane, 101 °C, 45 h, 99%; (b) Ph3CBF4, CH2Cl2, r.t., 40 min, 98%.
Almost quantitative access to the iron complex salt 5 was
provided by the 1-azadiene-catalyzed complexation of
cyclohexa-1,3-diene (7) with pentacarbonyliron followed
The synthesis of the (S)-arylamine 6 started from 3-meth-
ylveratrole (9) following the route described for the
corresponding R enantiomer (Scheme 3).9d,10c Bromina-
tion of 9 to the bromoarene 10 followed by halogen–metal
exchange using butyllithium and reaction with (S)-
propene oxide (>99% ee) provided the (S)-carbinol 11.
SYNLETT 2011, No. 18, pp 2663–2666
x
x
.x
x
.2
0
1
1
Advanced online publication: 19.10.2011
DOI: 10.1055/s-0031-1289551; Art ID: B15711ST
© Georg Thieme Verlag Stuttgart · New York

2664
C. Thomas et al.
LETTER
OMe
Acetylation of 11 led to the (S)-acetate 12, and subsequent
regioselective nitration using claycop (clay-supported
copper(II) nitrate)13 afforded (S)-nitroarene 13. Catalytic
hydrogenation of 13 provided (S)-arylamine 6 in five
steps and 59% overall yield.
+
(OC)3Fe
OMe
a
+
–
BF4
H2N
Me
5
OAc
Construction of the carbazole framework was achieved by
oxidative coupling of the complex salt 5 with (S)-aryl-
amine 6. The conditions previously applied to the synthe-
sis of neocarazostatin B (2), carquinostatin A (3), and
lavanduquinocin (4) (2 equiv of arylamine, MeCN, air,
r.t., 7 d, exclusion of light)8c,9c provided 64% of the tricar-
bonyliron-coordinated dihydrocarbazole 14 along with
18% of the aromatized carbazole 15 (Scheme 4).
6
MeO
MeO
OMe
OMe
(OC)3Fe
+
Me
OAc
Me
N
H
N
H
OAc
14
15
b
OMe
OMe
OMe
OMe
Me
OMe
Me
OMe
MeO
MeO
a
c
b
OMe
Me
Br
OMe
d
c
Me
OH
15
Me
OH
Br
10
N
H
N
H
OH
9
11
1
16
OMe
OMe
OMe
Scheme 4 Synthesis of streptoverticillin (1) and 6-bromostrepto-
verticillin (16). Reagents and conditions: (a) (1) 5 (1.0 equiv), 6 (2.0
equiv), MeCN, air, r.t., 7 d; (2) oxygen, r.t., 18 h, 12% of 14, 71% of
15; (b) (1) (CH3)3CNO (8.0 equiv), acetone, 56 °C, 4 h; (2) 10%
Pd/C, o-xylene, 145 °C, 4 h, 86%; (c) LiAlH4 (1.5 equiv), Et2O,
35 °C, 4 h, 87%; (d) NBS (1.03 equiv), CCl4, 77 °C, 30 min, 89%.
OMe
OMe
OMe
d
e
Me
O2N
Me
H2N
Me
OAc
OAc
OAc
12
13
6
synthetic 1 was [a]D20 = +24.0 (c = 0.1, MeOH). In order
to confirm the absolute configuration, 6-bromostreptover-
ticillin (16) was prepared by electrophilic bromination of
1. An X-ray crystal structure determination of compound
16 unequivocally confirmed the S configuration of the ste-
reogenic center of the side chain at C-1 by anomalous dis-
persion [Flack parameter: c = –0.006(6); Figure 2].15,16
Scheme 3 Synthesis of (S)-arylamine 6. Reagents and conditions:
(a) NBS (1.05 equiv), MeCN, r.t., 27 h, 98%; (b) (1) BuLi (1.5 equiv),
THF, –78 °C, 30 min; (2) (S)-propene oxide (3.0 equiv), –78 °C, 18
h, 79%; (c) Ac2O (1.1 equiv), Et3N (1.2 equiv), cat. DMAP, CH2Cl2,
r.t., 2 h, 97%; (d) claycop, CCl4, Ac2O, 0 °C, 1.5 h, 84%; (e) 10% Pd/
C, H2, MeOH, r.t., 5 h, 93%.
Subsequent to the electrophilic substitution of (S)-aryl-
amine 6 by reaction with the complex salt 5 and air-
mediated oxidative cyclization to the tricarbonyliron-
coordinated dihydrocarbazole 14, a further air-mediated
oxidation leading to the final aromatized carbazole 15
occurred. This observation indicated, for the first time,
that the overall transformation of an arylamine and com-
plex salt 5 into an aromatized carbazole may be achieved
in a one-pot transformation under appropriate reaction
conditions. Thus, further modification of the protocol led
us to perform the coupling of complex salt 5 and (S)-aryl-
amine 6 by exclusion of light, first under air and then un-
der pure oxygen. These conditions led to almost complete
aromatization of the cyclized product and gave 71% O-
acetylstreptoverticillin (15) along with 12% of the dihy-
drocarbazole 14. Compound 14 could be additionally con-
verted into the aromatized carbazole 15 by using the
established sequence of demetalation and dehydrogena-
tion.9b–d Removal of the acetyl protecting group by treat-
ment with lithium aluminum hydride provided
streptoverticillin (1). The spectroscopic data for synthetic
1 are in full agreement with those reported for the natural
product.7,14 The value found for the optical rotation of
Figure 2 Molecular structure of 6-bromostreptoverticillin (16) in
the crystal
Finally, streptoverticillin (1) was compared with its non-
natural enantiomer (R)-streptoverticillin [(R)-1], which
Synlett 2011, No. 18, 2663–2666 © Thieme Stuttgart · New York

LETTER
Configuration of Streptoverticillin
2665
corresponds to the natural products 2–4 regarding the con-
figuration at the stereogenic center of the side chain. (R)-
O-Acetylstreptoverticillin [(R)-15] has been a central in-
termediate in our enantioselective total syntheses of car-
quinostatin A (3) and lavanduquinocin (4).9d,10c Treatment
of (R)-15 with lithium aluminum hydride afforded (R)-
Acknowledgment
We are grateful to the Deutsche Forschungsgemeinschaft for finan-
cial support (grant Kn 240/16-1) and to the BASF, Ludwigshafen,
for a gift of pentacarbonyliron.
References and Notes
20
streptoverticillin {(R)-1; [a]D = –23.0, c = 0.1, MeOH;
Scheme 5}. The enantiomeric purity of (R)-15 was >99%
ee.9d,10c Thus, the same enantiomeric purity can be con-
cluded for (R)-streptoverticillin [(R)-1] and also for our
synthetic streptoverticillin (1).
(1) For Part 95, see: Fuchsenberger, M.; Forke, R.; Knölker,
H.-J. Synlett 2011, 2056.
(2) For reviews, see: (a) Chakraborty, D. P.; Roy, S. In
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Vol. 57; Herz, W.; Grisebach, H.; Kirby, G. W.; Steglich,
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(b) Chakraborty, D. P. In The Alkaloids, Vol. 44; Cordell,
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(c) Knölker, H.-J.; Reddy, K. R. Chem. Rev. 2002, 102,
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Product Synthesis; Majumdar, K. C.; Chattopadhyay, S. K.,
Eds.; Wiley-VCH: Weinheim, 2011, 341.
MeO
MeO
OMe
OMe
a
Me
Me
N
H
N
H
OAc
OH
(R)-15
(R)-1
Scheme 5 Synthesis of (R)-streptoverticillin [(R)-1]. Reagents and
conditions: (a) LiAlH4 (1.5 equiv), Et2O, 35 °C, 4 h, 88%.
(3) (a) Knölker, H.-J. Curr. Org. Synth. 2004, 1, 309.
(b) Knölker, H.-J. Chem. Lett. 2009, 38, 8.
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Söderberg, B. C. G. Tetrahedron 2006, 62, 10835. (e) Liu,
Z.; Larock, R. C. Tetrahedron 2007, 63, 347.
Comparison of the CD spectra for streptoverticillin (1)
and (R)-streptoverticillin [(R)-1] confirmed that both
compounds are enantiomeric by their opposite Cotton ef-
fects (Figure 3).
(f) Ackermann, L.; Althammer, A. Angew. Chem. Int. Ed.
2007, 46, 1627. (g) Bernal, P.; Benavides, A.; Bautista, R.;
Tamariz, J. Synthesis 2007, 1943. (h) St. Jean, D. J.; Poon,
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(i) Ueno, A.; Kitawaki, T.; Chida, N. Org. Lett. 2008, 10,
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(b) Knölker, H.-J. Chem. Soc. Rev. 1999, 28, 151.
(c) Knölker, H.-J.; Braier, A.; Bröcher, D. J.; Cämmerer, S.;
Fröhner, W.; Gonser, P.; Hermann, H.; Herzberg, D.; Reddy,
K. R.; Rohde, G. Pure Appl. Chem. 2001, 73, 1075.
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Bauermeister, M.; Bläser, D.; Boese, R.; Pannek, J.-B.
Angew. Chem., Int. Ed. Engl. 1989, 28, 223; Angew. Chem.
1989, 101, 225. (b) Knölker, H.-J.; Bauermeister, M.
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H.-J.; Bauermeister, M. J. Chem. Soc., Chem. Commun.
1990, 664. (d) Knölker, H.-J.; Bauermeister, M.
Figure 3 CD spectra of streptoverticillin (1) and (R)-streptoverticil-
lin [(R)-1]
In conclusion, by using our iron-mediated approach, we
have achieved the first synthesis of streptoverticillin (1) in
three steps and 71% overall yield based on the complex
salt 5. The absolute configuration of the natural product,
which was reported to be the S enantiomer, has been un-
ambiguously confirmed by X-ray analysis of 6-bromo-
streptoverticillin (16) and comparison of the values for the
optical rotation and of the CD spectra of streptoverticillin
(1) with non-natural (R)-streptoverticillin [(R)-1].
Heterocycles 1991, 32, 2443. (e) Knölker, H.-J.;
Bauermeister, M.; Pannek, J.-B. Chem. Ber. 1992, 125,
2783. (f) Knölker, H.-J.; Bauermeister, M.; Pannek, J.-B.;
Bläser, D.; Boese, R. Tetrahedron 1993, 49, 841.
(g) Knölker, H.-J.; Bauermeister, M. Tetrahedron 1993, 49,
11221. (h) Knölker, H.-J.; Bauermeister, M.; Pannek, J.-B.;
Wolpert, M. Synthesis 1995, 397. (i) Knölker, H.-J.;
Hopfmann, T. Tetrahedron Lett. 1995, 36, 5339.
(j) Knölker, H.-J.; Fröhner, W. Tetrahedron Lett. 1997, 38,
1535. (k) Knölker, H.-J.; Baum, E.; Hopfmann, T.
Tetrahedron 1999, 55, 10391. (l) Knölker, H.-J.; Fröhner,
W. Tetrahedron Lett. 1999, 40, 6915. (m) Knölker, H.-J.;
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Synlett 2011, No. 18, 2663–2666 © Thieme Stuttgart · New York

2666
C. Thomas et al.
LETTER
Wolpert, M. Tetrahedron 2003, 59, 5317. (n) Knölker,
H.-J.; Fröhner, W.; Reddy, K. R. Eur. J. Org. Chem. 2003,
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Chem. Commun. 2009, 1467.
(14) Spectroscopic data for synthetic streptoverticillin (1): Light-
yellow solid; mp 156–157 °C; [a]D20 +24.0 (c = 0.1, MeOH)
(Lit.6 [a]D20 +18.4, c = 0.179, MeOH); UV (MeOH):
l = 220, 242, 251, 262, 283, 293, 328, 340 nm; IR (ATR):
3475, 3293, 3055, 2955, 2926, 2850, 2823, 1608, 1500,
1451, 1398, 1348, 1318, 1304, 1271, 1225, 1194, 1166,
1148, 1086, 1060, 1001, 965, 934, 888, 872, 839, 787, 743,
702, 642 cm–1; 1H NMR (500 MHz, methanol-d4): d = 1.27
(d, J = 6.2 Hz, 3 H), 2.45 (s, 3 H), 3.04 (dd, J = 14.1, 6.6 Hz,
1 H), 3.13 (dd, J = 14.1, 6.9 Hz, 1 H), 3.90 (s, 3 H), 4.10 (s,
3 H), 4.15 (sext, J = 6.4 Hz, 1 H), 7.14 (t, J = 7.8 Hz, 1 H),
7.35 (t, J = 8.1 Hz, 1 H), 7.47 (d, J = 8.1 Hz, 1 H), 8.16 (d,
J = 7.8 Hz, 1 H), 10.30 (br s, 1 H); 13C NMR and DEPT (75
MHz, methanol-d4): d = 13.32 (CH3), 23.42 (CH3), 39.19
(CH2), 61.07 (CH3), 61.57 (CH3), 69.17 (CH), 111.79 (CH),
115.90 (C), 117.36 (C), 119.93 (CH), 123.39 (CH), 123.76
(C), 126.16 (CH), 130.30 (C), 139.14 (C), 141.84 (C),
145.50 (C), 147.80 (C); MS (EI): m/z (%) = 299 (71) [M+],
284 (25), 254 (100), 240 (7), 224 (8), 210 (10); HRMS:
m/z calcd for C18H21NO3: 299.1521; found: 299.1518.
(15) Flack, H. D. Acta Crystallogr., Sect. A: Found. Crystallogr.
1983, 39, 876.
(7) Feng, N.; Ye, W.; Wu, P.; Huang, Y.; Xie, H.; Wei, X.
J. Antibiot. 2007, 60, 179.
(8) (a) For isolation, see: Kato, S.; Shindo, K.; Kataoka, Y.;
Yamagishi, Y.; Mochizuki, J. J. Antibiot. 1991, 44, 903.
(b) For racemic synthesis, see: Knölker, H.-J.; Fröhner, W.;
Wagner, A. Tetrahedron Lett. 1998, 39, 2947. (c) For
enantioselective synthesis, see: Czerwonka, R.; Reddy, K.
R.; Baum, E.; Knölker, H.-J. Chem. Commun. 2006, 711.
(9) (a) For isolation, see: Shin-ya, K.; Tanaka, M.; Furihata, K.;
Hayakawa, Y.; Seto, H. Tetrahedron Lett. 1993, 34, 4943.
For racemic synthesis, see: (b) Knölker, H.-J.; Fröhner, W.
Synlett 1997, 1108. (c) Fröhner, W.; Reddy, K. R.; Knölker,
H.-J. Heterocycles 2007, 74, 895. (d) For enantioselective
synthesis, see: Knölker, H.-J.; Baum, E.; Reddy, K. R.
Tetrahedron Lett. 2000, 41, 1171.
(10) (a) For isolation, see: Sin-ya, K.; Shimizu, S.; Kunigami, T.;
Furihata, K.; Seto, H. J. Antibiot. 1995, 48, 574. (b) For
racemic synthesis, see: Knölker, H.-J.; Fröhner, W.
Tetrahedron Lett. 1998, 39, 2537. (c) For enantioselective
synthesis, see: Knölker, H.-J.; Baum, E.; Reddy, K. R.
Chirality 2000, 12, 526.
(16) Crystal data for 6-bromostreptoverticillin (16):
C18H20BrNO3; crystal size: 0.49 × 0.11 × 0.11 mm3;
M = 378.26 g mol–1; monoclinic; space group: P21;
l = 0.71073 Å; a = 12.8825 (10), b = 4.8516 (4),
(11) (a) Knölker, H.-J.; Gonser, P. Synlett 1992, 517.
(b) Knölker, H.-J.; Gonser, P.; Jones, P. G. Synlett 1994,
405. (c) Knölker, H.-J.; Baum, G.; Foitzik, N.; Goesmann,
H.; Gonser, P.; Jones, P. G.; Röttele, H. Eur. J. Inorg. Chem.
1998, 993. (d) Knölker, H.-J.; Baum, E.; Gonser, P.; Rohde,
G.; Röttele, H. Organometallics 1998, 17, 3916.
c = 13.7636 (11) Å, b = 108.909 (4)°; V = 813.81 (11) Å3;
Z = 2; rc = 1.544 g cm–3; m = 2.540 mm–1; T = 198 (2) K;
q range = 1.56–30.00°; reflections collected: 16453,
independent: 4653 (Rint = 0.0532). The structure was solved
by direct methods and refined by full-matrix least squares on
F2; R1 = 0.0290, wR2 = 0.0586 [I > 2s(I)]; maximal residual
electron density: 0.395 e Å–3; absolute structure (Flack
parameter): c = –0.006 (6). CCDC-835819.
(e) Knölker, H.-J. Chem. Rev. 2000, 100, 2941.
(12) Fischer, E. O.; Fischer, R. D. Angew. Chem. 1960, 72, 919.
(13) (a) Cornélis, A.; Laszlo, P. Synthesis 1985, 909. (b) Laszlo,
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(c) Gigante, B.; Prazeres, A. O.; Marcelo-Curto, M. J.;
Cornélis, A.; Laszlo, P. J. Org. Chem. 1995, 60, 3445.
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