First total synthesis of (±)-epocarbazolin A and epocarbazolin B, and asymmetric synthesis of (-)-epocarbazolin A via Shi epoxidation

Article abstract of DOI:10.1016/j.tetlet.2006.06.095

Epoxidation of the trisilyl-protected carbazomadurins A and B with dimethyldioxirane followed by desilylation provides a simple route to racemic epocarbazolin A and a non-diastereoselective access to epocarbazolin B. The Shi epoxidation has been applied t

Full text of DOI:10.1016/j.tetlet.2006.06.095

Tetrahedron Letters 47 (2006) 6079–6082
First total synthesis of ( )-epocarbazolin A and epocarbazolin B,
and asymmetric synthesis of (ꢀ)-epocarbazolin A
via Shi epoxidation
Jan Knoll and Hans-Joachim Knolker*
¨
¨
Department Chemie, Technische Universita¨t Dresden, Bergstrasse 66, 01069 Dresden, Germany
Received 10 May 2006; revised 14 June 2006; accepted 19 June 2006
Available online 10 July 2006
Abstract—Epoxidation of the trisilyl-protected carbazomadurins A and B with dimethyldioxirane followed by desilylation provides
a simple route to racemic epocarbazolin A and a non-diastereoselective access to epocarbazolin B. The Shi epoxidation has been
applied to an asymmetric synthesis of the non-natural (ꢀ)-epocarbazolin A.
Ó 2006 Elsevier Ltd. All rights reserved.
Recent isolations emphasize that nature appears to offer
an enormous reservoir of structurally interesting carb-
azole alkaloids with useful pharmacological activities.
These findings induced a strong research activity by sev-
eral groups.1–3 In 1993 a Japanese research group of the
company Bristol-Myers on screening for 5-lipoxygenase
inhibitors identified epocarbazolin A 1a and epocarb-
azolin B 1b (Fig. 1).4 These compounds were isolated from
the actinomycete strain Streptomyces anulatus T688-8.
resent potential therapeutics for the treatment of these
diseases. The epocarbazolins exhibit a potent inhibition
of rat 5-lipoxygenase (IC50 = 2.4 and 2.6 lM for 1a and
1b, respectively).4 The 5-lipoxygenase inhibitory activity
presumably relies on their radical scavenger activity.
Both compounds also show weak antibacterial activity.
The structural elucidation of the epocarbazolins was
based on their spectral data. They are remarkable by
their substitution pattern and the epoxide ring in the
side chain. However, the absolute configuration at the
stereogenic centers of the epocarbazolins has remained
unknown. The framework of the epocarbazolins A 1a
and B 1b resembles that of the carbazomadurins A 2a
and B 2b (Fig. 2).5 Because of the structural similarity
we considered the carbazomadurins 2 as precursors for
a total synthesis of the epocarbazolins 1. In the most
simple approach epoxidation of the former would lead
to the latter natural products.
5-Lipoxygenase metabolites of arachidonic acid are
known as mediators of inflammatory and allergic pro-
cesses such as psoriasis, asthma, and hypersensitivity.
Thus, inhibitors of 5-lipoxygenase are considered to rep-
HO
HO
OH
CH3
OH
CH3
N
H
N
H
HO
HO
O
O
HO
HO
OH
CH3
OH
CH3
Epocarbazolin A 1a
Epocarbazolin B 1b
Figure 1. Epocarbazolin A 1a and epocarbazolin B 1b.
N
H
N
H
HO
HO
Keywords: Alkaloids; Asymmetric catalysis; Carbazoles; Epoxides;
Total synthesis.
Carbazomadurin A 2a
Carbazomadurin B 2b
*
Corresponding author. Fax: +49 351 463 37030; e-mail:
hans-joachim.knoelker@tu-dresden.de
Figure 2. Carbazomadurin A 2a and carbazomadurin B 2b.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.095

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J. Kno¨ll, H.-J. Kno¨lker / Tetrahedron Letters 47 (2006) 6079–6082
sition of starting material. Epoxidation of the disilyl-
CO2CH3
OCH3
CH3
protected carbazomadurin A 6a was unsuccessful as
well. Therefore, we decided to convert compound 6a
to the trisilyl-protected carbazomadurin A 7a by reac-
tion with tert-butyldiphenylchlorosilane in the presence
of stoichiometric amounts of DMAP (Scheme 2).9 As
reaction of the tri-O-silylcarbazomadurin A 7a with m-
chloroperbenzoic acid in dichloromethane also led to
complete decomposition, milder epoxidizing agents were
required. Dimethyldioxirane can be applied for epoxida-
tions under neutral and almost non-aqueous reaction
conditions.8 Following a procedure of Adam, we pre-
pared a solution of dimethyldioxirane in acetone by
reaction of acetone with potassium peroxymonosulfate
under buffered conditions and subsequent distillation.10
Reaction of a solution of 7a in dichloromethane using
dimethyldioxirane in acetone at ꢀ20 °C afforded the
( )-tri-O-silylepocarbazolin A ( )-8a, representing a
stable compound, which was purified by flash chroma-
tography on silica gel. Both epocarbazolins were
reported to be photolabile.4 Thus, deprotection and
workup were carried out in the absence of light. Desily-
lation of ( )-8a with tetrabutylammonium fluoride pro-
vided ( )-epocarbazolin A ( )-1a in only moderate
yield. An intense red color, immediately generated dur-
ing this reaction, indicated oxidation to quinoid systems.
Several by-products have been separated by chromato-
graphy but could not be identified. However, the spectro-
6 steps
ref.6,7
+
+
Bu3Sn
R
OTf
OCH3
3
Br
NH2
5a: R = CH3
5b: R = C2H5
4
HO
HO
OSiR'3
CH3
OH
TBAF
THF, r.t.
CH3
N
N
H
R'3SiO
HO
H
R
R
2a: R = CH3 (70%)
2b: R = C2H5 (88%)
6a: R = CH3 (18% overall yield)
6b: R = C2H5 (17% overall yield)
Scheme 1. Total synthesis of carbazomadurin A 2a and B 2b.6,7
Protecting group: SiR0 =Sit-BuPh2.
3
Recently, we have developed a convergent synthetic
route to the carbazomadurins by using a palladium-cat-
alyzed coupling of three building blocks (Scheme 1).6,7
The aryl triflate 3 is readily prepared from isovanillic
acid (two steps, 91% yield). Starting from commercial
2-bromo-6-nitrotoluene, the arylamine 4 is obtained in
five steps and 44% yield. The alkenylstannanes 5 are
available via Negishi’s zirconium-catalyzed carboalumi-
nation as the key-step (5a: two steps, 52% yield; 5b: six
steps, 11% yield). The assembly of the carbocyclic
framework led to the intermediates 6a and 6b in six
steps: (1) Buchwald–Hartwig amination, (2) palla-
dium(II)-mediated oxidative cyclization, (3) cleavage of
the methyl ethers, (4) di-O-silylation, (5) Stille coupling
with the alkenylstannanes 5a and 5b, and (6) DIBAL
reduction of the methyl ester. Desilylation of the disi-
lyl-protected carbazomadurins 6a and 6b completed
the total syntheses of carbazomadurin A 2a and carbazo-
madurin B 2b.6,7
1
scopic data (UV, IR, H NMR, 13C NMR, and MS) of
our racemic epocarbazolin A ( )-1a11 were in full agree-
ment with those reported for the natural product.4
The absolute configuration at the stereogenic center in
the side chain of epocarbazolin B 1b is still unknown.4
We recently assigned unambiguously the absolute
stereochemistry of carbazomadurin B 2b by an enantio-
selective total synthesis.7 As both natural products have
been isolated from similar sources (microorganisms), we
assume an identical absolute configuration at this stere-
ogenic center.
Starting from enantiopure di-O-silylcarbazomadurin B
6b (enantiopurity: >99% ee),7 silylation to the tri-O-silyl-
carbazomadurin B 7b and epoxidation using dimethyldi-
oxirane provided the tri-O-silylepocarbazolin B 8b and
diastereoisomer 9 as a 1:1 mixture (Scheme 2). Desilyl-
ation of this mixture afforded epocarbazolin B 1b along
All attempts to achieve a direct transformation of
carbazomadurin A 2a into epocarbazolin A 1a by epoxi-
dation, using either m-chloroperbenzoic acid in dichloro-
methane or dimethyldioxirane in acetone at room
temperature,8 failed and resulted in complete decompo-
HO
R'3SiO
R'3SiO
HO
OSiR'3
CH3
OSiR'3
CH3
OSiR'3
CH3
OH
CH3
c
b
a
N
H
N
H
N
H
N
H
R'3SiO
R'3SiO
R'3SiO
HO
O
O
R
R
R
R
6a: R = CH3
6b: R = C2H5
7a: R = CH3
7b: R = C2H5
rac-8a: R = CH3
8b/9: R = C2H5
rac-1a: R = CH3
1b/10: R = C2H5
Scheme 2. Synthesis of ( )-epocarbazolin A ( )-1a and epocarbazolin B 1b. Protecting group: SiR0 =Sit-BuPh2. Reagents and conditions: (a)
3
t-BuPh2SiCl ð¼ R03SiClÞ, DMF, DMAP, rt, 4.5 h (7a: 100%, 7b: 100%); (b) dimethyldioxirane, acetone/CH2Cl2, ꢀ20 °C, 24 h (( )-8a: 53%, 8b/9:
53%); (c) 3 equiv TBAF, THF, rt (in the dark), 6 h (( )-1a: 24%, 1b/10: 18%).

J. Kno¨ll, H.-J. Kno¨lker / Tetrahedron Letters 47 (2006) 6079–6082
6081
with its diastereoisomer 10.12 The spectroscopic data
(UV, IR, 1H NMR, 13C NMR, and MS) have been com-
pared with those described for the natural product.4
ral catalyst enantiomeric to 12, which can be prepared
from L-fructose,15a should lead to natural (+)-epocar-
bazolin A (+)-1a.
For the enantioselective synthesis of epocarbazolin A 1a
we envisaged an asymmetric epoxidation using chiral
non-racemic dioxiranes.13–15 Shi used catalytic amounts
of the chiral ketone 12, prepared from D-fructose 11
(Scheme 3), and oxoneÒ as stoichiometric oxidizing
agent for the in situ generation of a chiral dioxirane.15a
The method of Shi has been applied to the asymmetric
catalytic epoxidation of a wide variety of olefins includ-
ing conjugated trisubstituted double bonds.15–18
Acknowledgments
We thank the Fonds der Chemischen Industrie for
financial support of our project.
References and notes
1. Transition Metal Complexes in Organic Synthesis, Part
80. For part 79, see: Choi, T. A.; Czerwonka, R.; Fro¨hner,
W.; Krahl, M. P.; Reddy, K. R.; Franzblau, S. G.;
Kno¨lker, H.-J. ChemMedChem 2006 1, in press.
2. Reviews: (a) Chakraborty, D. P.; Roy, S. In Progress in
the Chemistry of Organic Natural Products; Herz, W.,
Grisebach, H., Kirby, G. W., Steglich, W., Tamm, C.,
Eds.; Springer: Wien, 1991; Vol. 57, p 71; (b) Chakra-
borty, D. P. In The Alkaloids; Cordell, G. A., Ed.;
Academic Press: New York, 1993; Vol. 44, p 257; (c)
Kno¨lker, H.-J.; Reddy, K. R. Chem. Rev. 2002, 102, 4303;
(d) Kno¨lker, H.-J. Curr. Org. Synth. 2004, 1, 309.
Using a modified Shi procedure,15b the tri-O-silylcarb-
azomadurin A 7a was transformed to the (ꢀ)-tri-O-silyl-
epocarbazolin A (ꢀ)-8a (Scheme 4).19 Removal of the
silyl protecting groups afforded (ꢀ)-epocarbazolin A
(ꢀ)-1a.20 The value for the specific rotation of our syn-
26
26
thetic (ꢀ)-1a is ½aꢁD ꢀ55,20 while a value of ½aꢁD +75 has
been reported for the natural product.4 Therefore, we
concluded that using catalyst 12 the non-natural enan-
tiomer of epocarbazolin is formed preferentially. How-
ever, we have not yet been able to assign the absolute
configuration of our product. Assuming a linear correla-
tion of specific rotation and enantiomeric excess, an
enantioselectivity of 73% ee can be estimated for the
Shi epoxidation of 7a described above.
3. For recent novel synthetic approaches to carbazoles, see:
(a) Aygun, A.; Pindur, U. J. Heterocycl. Chem. 2003, 40,
¨
411; (b) Kno¨lker, H.-J.; Fro¨hner, W.; Reddy, K. R. Eur. J.
Org. Chem. 2003, 740; (c) Kno¨lker, H.-J.; Reddy, K. R.
Heterocycles 2003, 60, 1049; (d) Kno¨lker, H.-J.; Wolpert,
M. Tetrahedron 2003, 59, 5317; (e) Scott, T. L.; So¨derberg,
B. C. G. Tetrahedron 2003, 59, 6323; (f) Rawat, M.; Wulff,
W. D. Org. Lett. 2004, 6, 329; (g) Kno¨lker, H.-J.; Krahl,
M. P. Synlett 2004, 528; (h) Crich, D.; Rumthao, S.
Tetrahedron 2004, 60, 1513; (i) Benavides, A.; Peralta, J.;
Delgado, F.; Tamariz, J. Synthesis 2004, 2499; (j) Kno¨lker,
H.-J.; Fro¨hner, W.; Heinrich, R. Synlett 2004, 2705; (k)
Duval, E.; Cuny, G. D. Tetrahedron Lett. 2004, 45, 5411;
(l) Kuwahara, A.; Nakano, K.; Nozaki, K. J. Org. Chem.
2005, 70, 413; (m) Kataeva, O.; Krahl, M. P.; Kno¨lker,
H.-J. Org. Biomol. Chem. 2005, 3, 3099; (n) Pelly, S. C.;
Parkinson, C. J.; van Otterlo, W. A. L.; de Koning, C. B.
In summary, we have demonstrated the feasibility to
transform the carbazomadurins 2 into the epocarbazo-
lins 1. Epoxidation of the tri-O-silyl-protected carba-
zomadurins A and B with dimethyldioxirane provides
a non-stereoselective access to the epocarbazolins A
and B. Moreover, our initial investigation shows that
the Shi epoxidation can be utilized for an asymmetric
synthesis of the epocarbazolins 1. Application of the chi-
J. Org. Chem. 2005, 70, 10474; (o) Furstner, A.; Domo-
¨
O
OH
CH2OH
OH
O
O
stoj, M. M.; Scheiper, B. J. Am. Chem. Soc. 2005, 127,
11620; (p) Czerwonka, R.; Reddy, K. R.; Baum, E.;
Kno¨lker, H.-J. Chem. Commun. 2006, 711.
O
2 steps (49% yield)
ref.15a
HO
O
O
4. Nihei, Y.; Yamamoto, H.; Hasegawa, M.; Hanada, M.;
Fukagawa, Y.; Oki, T. J. Antibiot. 1993, 46, 25.
5. Kotada, N.; Shin-ya, K.; Furihata, K.; Hayakawa, Y.;
Seto, H. J. Antibiot. 1997, 50, 770.
6. Kno¨lker, H.-J.; Kno¨ll, J. Chem. Commun. 2003, 1170.
7. Kno¨ll, J.; Kno¨lker, H.-J. Synlett 2006, 651.
8. (a) Adam, W.; Hadjiarapoglou, L. Top. Curr. Chem. 1993,
164, 45; (b) Murray, R. W. Chem. Rev. 1989, 89, 1187; (c)
Curci, R.; Dinoi, A.; Rubino, M. F. Pure Appl. Chem.
1995, 67, 811.
9. (a) Hanessian, S.; Lavalee, P. Can. J. Chem. 1975, 53,
2975; (b) Hanessian, S.; Lavalee, P. Can. J. Chem. 1977,
55, 562.
10. Adam, W.; Bialas, J.; Hadjiarapoglou, L. Chem. Ber.
1991, 124, 2377.
O
OH
11
12
Scheme 3. Synthesis of the Shi catalyst 12 from D-fructose 11.15a
R'3SiO
R'3SiO
HO
OSiR'3
CH3
OH
CH3
a
b
7a
N
H
N
H
HO
O
O
11. ( )-Epocarbazolin A ( )-1a: colorless powder; mp 150 °C
(dec.). UV (MeOH): k = 233, 250, 299, 345, 359 nm. IR
(DRIFT): m = 3461, 2955, 2929, 2869, 1620, 1585, 1523,
(
–
)-8a
(
–
)-1a
Scheme 4. Synthesis of (ꢀ)-epocarbazolin A (ꢀ)-1a. Protecting group:
1446, 1388, 1367, 1266, 1168, 1119, 1070, 988, 807 cmꢀ1
.
SiR0 =Sit-BuPh2. Reagents and conditions: (a) oxoneÒ, K2CO3,
1H NMR (500 MHz, acetone-d6): d = 0.970 (d,
J = 6.4 Hz, 3H), 0.972 (d, J = 6.4 Hz, 3H), 1.05 (s, 3H),
1.49–1.56 (m, 2H), 1.63–1.70 (m, 1H), 1.81–1.88 (m, 2H),
3
5 equiv 12, Bu4NHSO4, buffer, H2O/DME/hexane, rt, 8 h (18%); (b)
3 equiv TBAF, THF, rt (in the dark), 6 h (18%).

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J. Kno¨ll, H.-J. Kno¨lker / Tetrahedron Letters 47 (2006) 6079–6082
2.35 (s, 3H), 3.90 (t, J = 5.7 Hz, 1H), 4.24 (s, 1H), 4.99 (d,
30.41 and 30.56 (CH2), 32.95 (CH2), 35.88 and 35.90
(CH), 36.50 (CH2), 63.85 (C), 64.33 (CH2), 64.70 (CH),
108.55 (CH), 110.55 (CH), 118.55 (C), 119.57 (CH), 122.05
(C), 123.00 (C), 123.32 (C), 128.96 (C), 131.01 (C), 134.20
(C), 143.40 (C), 150.00 (C). MS (EI): m/z (%) = 383 (11)
[M+], 365 (4), 270 (6), 254 (5), 199 (41), 139 (7), 77 (21), 58
(27), 43 (100). HRMS: m/z calcd for C23H29NO4 [M+]:
383.2097; found: 383.2092.
J = 5.7 Hz, 2H), 6.76 (d, J = 7.7 Hz, 1H), 6.91 (d,
J = 7.7 Hz, 1H), 7.64 (s, 1H), 7.94 (br s, 1H), 8.64 (br s,
1H), 9.29 (br s, 1H). 13C NMR and DEPT (125 MHz,
acetone-d6): d = 12.86 (CH3), 17.48 (CH3), 23.26 (CH3),
23.40 (CH3), 29.53 (CH), 35.40 (CH2), 36.89 (CH2), 63.81
(C), 64.36 (CH2), 64.70 (CH), 108.59 (CH), 110.58 (CH),
118.58 (C), 119.60 (CH), 122.09 (C), 123.04 (C), 123.35
(C), 129.00 (C), 131.04 (C), 134.24 (C), 143.43 (C), 150.03
(C). MS (EI): m/z (%) = 369 (23) [M+], 270 (11), 200 (9),
199 (10), 153 (25), 136 (12), 107 (10), 106 (10), 89 (34), 77
(39), 71 (32), 58 (26), 43 (100). HRMS: m/z calcd for
C22H27NO4 [M+]: 369.1940; found: 369.1934.
13. Curci, R.; Fiorentino, M.; Serio, M. R. J. Chem. Soc.,
Chem. Commun. 1984, 155.
14. Denmark, S. E.; Wu, Z. Synlett 1999, 847.
15. (a) Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y.
J. Am. Chem. Soc. 1997, 119, 11224; (b) Tu, Y.; Wang, Z.-
X.; Frohn, M.; He, M.; Yu, H.; Tang, Y.; Shi, Y. J. Org.
Chem. 1998, 63, 8475; (c) Wang, Z.-X.; Miller, S. M.;
Anderson, O. P.; Shi, Y. J. Org. Chem. 2001, 66, 521.
16. Warren, J. D.; Shi, Y. J. Org. Chem. 1999, 64, 7675.
17. Tian, H.; She, X.; Shu, L.; Yu, H.; Shi, Y. J. Am. Chem.
Soc. 2000, 122, 11551.
12. Epocarbazolin B 1b and diastereoisomer 10: pale yellow
20
powder; mp 180 °C (dec.); ½aꢁD +9 (c 0.1, MeOH). UV
(MeOH): k = 233, 243, 249, 289 (sh), 299, 344, 359 nm. IR
(DRIFT): m = 3471, 2958, 2874, 1623, 1587, 1523, 1506,
1447, 1270, 1158, 1080, 1061, 999, 815 cmꢀ1 1H NMR
.
(500 MHz, acetone-d6): d = 0.91–0.96 (m, 6H), 1.05 (s,
3H), 1.23–1.29 (m, 1H), 1.44 (m, 3H), 1.62–1.69 (m, 1H),
1.74–1.93 (m, 2H), 2.35 (s, 3H), 3.95 (br s, 1H), 4.24 (s)
and 4.25 (s, R = 1H), 4.99 (br s, 2H), 6.76 (d, J = 7.7 Hz,
1H), 6.91 (d, J = 7.7 Hz, 1H), 7.64 (s, 1H), 7.98 (br s, 1H),
8.68 (br s, 1H), 9.29 (br s, 1H). 13C NMR and DEPT
(125 MHz, acetone-d6): d = 12.09 and 12.13 (CH3), 12.83
(CH3), 17.41 and 17.47 (CH3), 19.88 and 19.95 (CH3),
18. Shi, Y. Acc. Chem. Res. 2004, 37, 488.
19. (ꢀ)-Tri-O-(tert-butyldiphenylsilyl)epocarbazolin
A
(ꢀ)-
20
8a: colorless crystals; mp 85–86 °C; ½aꢁD ꢀ5.7 (c 0.5,
CHCl3).
20. (ꢀ)-Epocarbazolin A (ꢀ)-1a: colorless powder; mp 160 °C
26
(dec.); ½aꢁD ꢀ55 (c 0.067, MeOH); for spectroscopic data,
see above.11