First total synthesis and assignment of the absolute configuration of the neuronal cell protecting alkaloid carbazomadurin B

Article abstract of DOI:10.1055/s-2006-933102

Using a palladium-catalyzed approach, the first enantio-selective synthesis of the neuronal cell protecting agent carbazomadurin B is described and its absolute configuration is assigned. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-933102

LETTER
651
First Total Synthesis and Assignment of the Absolute Configuration of the
Neuronal Cell Protecting Alkaloid Carbazomadurin B
Synthesis
a
of the
N
eur
n
onal Cell Protectin
K
g Alkaloid
C
arbaz
n
omadurin B öll, Hans-Joachim Knölker*
Department Chemie, Technische Universität Dresden, Bergstraße 66, 01069 Dresden, Germany
Fax +49(351)46337030; E-mail: hans-joachim.knoelker@tu-dresden.de
Received 16 December 2005
Dedicated to Professor K. Peter C. Vollhardt on the occasion of his 60th birthday.
24
by Seto for 1b is: [a]D +4 (c 0.05, MeOH). Compound
2c with a double bond in the same distance to the stereo-
Abstract: Using a palladium-catalyzed approach, the first enantio-
selective synthesis of the neuronal cell protecting agent carbazoma-
durin B is described and its absolute configuration is assigned.
25
genic center as in 1b has a specific rotation of [a]D
+10.30.6 Although the absolute value of specific rotation
reported for the natural product is much lower, they both
have a positive value. Based on this comparison we
proposed an S configuration for the stereogenic center of
the chiral side chain of 1b.
Key words: alkaloids, aminations, cross-coupling, cyclizations,
palladium
Due to their useful pharmacological activities, carbazole
alkaloids are continuing to attract strong interest by many
research groups.1–4 The carbazomadurins A (1a) and B
Table 1 Specific Rotations of (S)-Ethyl(methyl)(substituted-
ethyl)methane Derivatives 2 and Comparison with Carbazomadurin
(1b) have been isolated in 1997 by Seto and his group B (1b)
from the microorganism Actinomadura madurae 2808-
SV1 (Figure 1).5 These alkaloids exhibit a strong neuronal
R
cell protecting activity against L-glutamate induced cell
death. The observed biological effect is found to be de-
2
25, a
pendent on their function as antioxidants.5 The structures
for both compounds have been assigned based on their
spectroscopic data. However, the absolute configuration
of carbazomadurin B (1b) has remained unknown. Here-
in, we describe the first enantioselective total synthesis of
carbazomadurin B and the assignment of its absolute con-
figuration.
Compound
R
[a]D
1b
2a
2b
2c
2d
2e
2f
C(CH3)=CHAr
CH3
+4 (24 °C)5
+8.67
CH2CH3
CH=CH2
CHBrCH2Br
C≡CH
+9.34
+10.30
+4.67
HO
HO
OH
CH3
OH
CH3
+14.87
+9.30
COCH3
COOH
N
H
N
H
HO
HO
2g
+10.69
a Specific rotations of the compounds 2a–g as reported in ref. 6.
carbazomadurin A (1a)
carbazomadurin B (1b)
Figure 1 Carbazomadurins A and B
We envisaged a highly convergent total synthesis of car-
bazomadurin B (1b) by sequential palladium-catalyzed
cross-coupling reactions of three building blocks
(Scheme 1).
For a tentative assignment of the absolute configuration of
carbazomadurin B (1b) we compared its specific rotation
with values of related compounds given in the literature
(Table 1). Lardicci reported the specific rotations for a
series of chiral compounds 2 with a methyl, an ethyl and
a 2-substituted ethyl group at the stereogenic center.6
With an S configuration at the stereogenic center, they all
show a positive value for the specific rotation as reported
for carbazomadurin B (1b). The specific rotation reported
The aryl triflate 3 is available from isovanillic acid (two
steps, 91% yield).4c The arylamine 4 was prepared from 2-
bromo-6-nitrotoluene (five steps, 44% yield).4c Assuming
an S configuration for carbazomadurin B (1b), the synthe-
sis of the chiral alkenylstannane 5 has been achieved in six
steps and 11% overall yield starting from commercial (S)-
(–)-2-methyl-1-butanol (6) (Scheme 2).
First, the commercial (S)-(–)-2-methyl-1-butanol (6)7 was
converted to the corresponding (R)-Mosher ester by reac-
tion with (S)-(+)-a-methoxy-a-(trifluoromethyl)phenyl-
acetyl chloride (pyridine–CCl4, r.t., 3 h, 97% yield).8 The
SYNLETT 2006, No. 4, pp 0651–0653
Advanced online publication: 20.02.2006
DOI: 10.1055/s-2006-933102; Art ID: G40205ST
© Georg Thieme Verlag Stuttgart · New York
0
2.
0
3.
2
0
0
6

652
J. Knöll, H.-J. Knölker
LETTER
HO
zirconocene dichloride and subsequent treatment of the
resulting alkenylaluminum with iodine led to the alkenyl
iodide 8. A halogen–metal exchange reaction using tert-
butyllithium, followed by addition of tributyltin chloride
to the alkenyllithium intermediate, afforded the alkenyl-
stannane 5.
OH
[Pd]
CH3
N
H
HO
carbazomadurin B (1b)
CO2CH3
OCH3
CH3
CO2CH3
OCH3
CH3
a
CO2CH3
OCH3
CH3
+
OTf
OCH3
3
Br
N
+
+
Bu3Sn
NH2
CH3O
H
Br
OTf
OCH3
3
Br
4
9
NH2
5
4
CO2CH3
CO2CH3
OSiR3
CH3
OCH3
Scheme 1 Retrosynthetic analysis of carbazomadurin B (1b)
c
b
CH3
d
N
H
N
H
R3SiO
HO
Br
Br
H3CO
500 MHz 1H NMR spectrum of the (R)-Mosher ester and
doping with the corresponding diastereoisomeric Mosher
esters resulting from racemic 6 confirmed an enantiomer-
ic purity of >99% ee for our starting material. Substitution
of the chiral alcohol 6 gave the bromide 7.9 Conversion of
7 to the Grignard reagent and Wurtz coupling with allyl
bromide using a literature procedure10 led to (S)-(+)-5-
10
11
CO2CH3
OH
CH3
OSiR3
CH3
e
f
g
N
H
N
H
R3SiO
HO
23
methyl-1-heptene (2c, [a]D +10.1, neat). Subsequent
bromination in chloroform at 0 °C afforded the dibromide
2d as a 1:1 mixture of diastereoisomers [a]D23 +5.9 (c 4.9,
CHCl3).6 Double elimination of HBr from 2d with potas-
sium tert-butoxide in the presence of catalytic amounts of
12
carbazomadurin B (1b)
[18]-crown-6 provided (S)-(+)-5-methyl-1-heptyne (2e,
Scheme 3 Synthesis of carbazomadurin B (1b). Reagents and con-
23
[a]D +15.3, c 5.1, CHCl3). Using this method, no ditions: a) 5 mol% Pd(OAc)2, 7.5 mol% BINAP, Cs2CO3, toluene,
isomerization to allenes or internal alkynes occurs.11
100 °C, 10 h (62%); b) Pd(OAc)2, dioxane–HOAc (3:1), 100 °C, 40 h
(43%); c) 5 equiv BBr3, CH2Cl2, –78 °C to r.t., 5 d (77%); d) 5 equiv
Moreover, it is known that the double dehydrobromina-
t-BuPh2SiCl (= R3SiCl), 9 equiv imidazole, DMF, 70 °C, 19 h (91%);
tion takes place without racemization,6 which is con-
e) 5, 10 mol% Pd(PPh3)4, toluene, 110 °C, 72 h (90%); f) DIBAL-H,
toluene, 0 °C, 2 h (100%); g) TBAF, THF, r.t., 1.5 h (88%).
firmed by the specific rotation of 2e. Transformation of
the alkyne 2e to the required alkenylstannane 5 was
achieved by a two-step process using Negishi’s zirconi-
Coupling of the aryl triflate 3 and the arylamine 4 to the
um-catalyzed carboalumination as the key step.12 Reac-
N,N-diarylamine 9 was achieved by a palladium(0)-cata-
tion of 2e with trimethylalane in the presence of
lyzed Buchwald–Hartwig amination (Scheme 3).13 A sub-
sequent palladium(II)-mediated oxidative cyclization14 of
b
a
9 led to the carbazole 10. Using an appropriate reoxidant,
e.g. copper(II) acetate, this reaction can also be carried out
using catalytic amounts of palladium(II).15 Cleavage of
both methyl ethers with boron tribromide followed by
double silylation afforded the bis(tert-butyldiphenylsilyl)
ether 11.16 Palladium(0)-catalyzed Stille coupling17 of the
1-bromocarbazole 11 and the alkenylstannane 5 furnished
the 1-alkenylcarbazole 12 in 90% yield. Reduction of the
methyl ester using diisobutylaluminum hydride (DIBAL-
H) to the corresponding benzylic alcohol and subsequent
removal of the silyl protecting groups with tetrabutylam-
monium fluoride (TBAF) provided carbazomadurin B
(1b). The spectroscopic data of our product (UV, IR, 1H
NMR, 13C NMR and MS)18 were in full agreement with
those reported for the natural product by Seto and co-
workers.5 The value for the specific rotation of our syn-
OH
Br
6
7
2c
2e
Br
d
c
Br
2d
f
e
I
SnBu3
8
5
Scheme 2 Synthesis of the alkenylstannane 5. Reagents and condi-
tions: a) PBr3, pyridine, 0 °C to r.t., 2 h (63%); b) 1. Mg, Et2O; 2. allyl
bromide, r.t., 16 h (58%); c) Br2, CHCl3, 0 °C (93%); d) KOt-Bu, cat.
[18]-crown-6, hexane, D, 3 h (69%); e) 1. Me3Al, Cp2ZrCl2, CH2Cl2,
r.t.; 2. I2, THF, 0 °C (60%); f) 1. t-BuLi, Et2O, –78 °C; 2. Bu3SnCl,
–78 °C to r.t. (78%).
24
thetic carbazomadurin B is: [a]D +13.0 (c 0.05,
MeOH),18 which confirms the absolute configuration to
Synlett 2006, No. 4, 651–653 © Thieme Stuttgart · New York

LETTER
Synthesis of the Neuronal Cell Protecting Alkaloid Carbazomadurin B
653
(8) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512.
(9) Reichardt, C.; Wilk, M. Liebigs Ann. Chem. 1990, 189.
(10) Mori, K. Tetrahedron 1974, 30, 3817.
(11) Dehmlow, E. V.; Lissel, M. Liebigs Ann. Chem. 1980, 1.
(12) (a) Van Horn, D. E.; Negishi, E. J. Am. Chem. Soc. 1978,
100, 2252. (b) Negishi, E.; Van Horn, D. E.; King, A. O.;
Okukado, N. Synthesis 1979, 501. (c) Rand, C. L.; Van
Horn, D. E.; Moore, M. W.; Negishi, E. J. Org. Chem. 1981,
46, 4097. (d) Negishi, E.; Van Horn, D. E.; Yoshida, T. J.
Am. Chem. Soc. 1985, 107, 6639.
be S, but is considerably higher than the one reported by
24
Seto for the natural product: [a]D +4 (c 0.05, MeOH).5
An elemental analysis proved the high purity of our prod-
uct.18 On conversion to the chiral alkyne 2e the enantio-
meric purity of our chiral starting material 6 has been
preserved (cf. above). Since racemization during the syn-
thesis beyond compound 2e is not feasible, an enantio-
meric excess of >99% can be expected for 1b.
In conclusion, using our palladium-catalyzed approach
carbazomadurin B (1b) has been obtained in nine steps
and 13% overall yield starting from commercial iso-
vanillic acid. Based on the specific rotation, we assigned
an S configuration to the stereogenic center of the natural
product.
(13) (a) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 1997, 62,
1264. (b) Louie, J.; Driver, M. S.; Hamann, B. C.; Hartwig,
J. F. J. Org. Chem. 1997, 62, 1268. (c) Åhman, J.;
Buchwald, S. L. Tetrahedron Lett. 1997, 38, 6363.
(d) Hartwig, J. F. Angew. Chem. Int. Ed. 1998, 37, 2046;
Angew. Chem. 1998, 110, 2154. (e) Muci, A. R.; Buchwald,
S. L. Top. Curr. Chem. 2002, 219, 131.
(14) (a) Åkermark, B.; Eberson, L.; Jonsson, E.; Pettersson, E. J.
Org. Chem. 1975, 40, 1365. (b) Miller, R. B.; Moock, T.
Tetrahedron Lett. 1980, 21, 3319. (c) Ames, D. E.; Opalko,
A. Tetrahedron 1984, 40, 1919. (d) Furukawa, H.; Ito, C.;
Yogo, M.; Wu, T.-S. Chem. Pharm. Bull. 1986, 34, 2672.
(e) Hall, R. J.; Marchant, J.; Oliveira-Campos, A. M. F.;
Queiroz, M.-J. R. P.; Shannon, P. V. R. J. Chem. Soc.,
Perkin Trans. 1 1992, 3439. (f) Knölker, H.-J.; O’Sullivan,
N. Tetrahedron Lett. 1994, 35, 1695.
Acknowledgment
This work was supported by the Fonds der Chemischen Industrie.
References and Notes
(1) Transition Metal Complexes in Organic Synthesis, Part 78.
For part 77, see ref. 4h.
(15) (a) Knölker, H.-J.; O’Sullivan, N. Tetrahedron 1994, 50,
10893. (b) Åkermark, B.; Oslob, J. D.; Heuschert, U.
Tetrahedron Lett. 1995, 36, 1325. (c) Knölker, H.-J.;
Fröhner, W. J. Chem. Soc., Perkin Trans. 1 1998, 173.
(d) Knölker, H.-J.; Reddy, K. R.; Wagner, A. Tetrahedron
Lett. 1998, 39, 8267. (e) Knölker, H.-J.; Fröhner, W.;
Reddy, K. R. Synthesis 2002, 557.
(16) (a) Hanessian, S.; Lavalee, P. Can. J. Chem. 1975, 53, 2975.
(b) Hanessian, S.; Lavalee, P. Can. J. Chem. 1977, 55, 562.
(17) (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508;
Angew. Chem. 1986, 98, 483. (b) McKean, D. R.;
(2) For reviews, see: (a) Chakraborty, D. P.; Roy, S. In Progress
in the Chemistry of Organic Natural Products, Vol. 57;
Herz, W.; Grisebach, H.; Kirby, G. W.; Steglich, W.; Tamm,
C., Eds.; Springer: Wien, 1991, 71. (b) Chakraborty, D. P.
In The Alkaloids, Vol. 44; Cordell, G. A., Ed.; Academic
Press: New York, 1993, 257. (c) Knölker, H.-J.; Reddy, K.
R. Chem. Rev. 2002, 102, 4303. (d) Fröhner, W.; Krahl, M.
P.; Reddy, K. R.; Knölker, H.-J. Heterocycles 2004, 63,
2393. (e) Knölker, H.-J. Top. Curr. Chem. 2005, 244, 115.
(3) For recent synthetic approaches from other groups, see:
(a) Aygün, A.; Pindur, U. J. Heterocycl. Chem. 2003, 40,
411. (b) Scott, T. L.; Söderberg, B. C. G. Tetrahedron 2003,
59, 6323. (c) Rawat, M.; Wulff, W. D. Org. Lett. 2004, 6,
329. (d) Crich, D.; Rumthao, S. Tetrahedron 2004, 60,
1513. (e) Benavides, A.; Peralta, J.; Delgado, F.; Tamariz, J.
Synthesis 2004, 2499. (f) Duval, E.; Cuny, G. D.
Tetrahedron Lett. 2004, 45, 5411. (g) Kuwahara, A.;
Nakano, K.; Nozaki, K. J. Org. Chem. 2005, 70, 413.
(h) Pelly, S. C.; Parkinson, C. J.; van Otterlo, W. A. L.; de
Koning, C. B. J. Org. Chem. 2005, 70, 10474. (i) Fürstner,
A.; Domostoj, M. M.; Scheiper, B. J. Am. Chem. Soc. 2005,
127, 11620.
(4) For recent synthetic approaches from our group, see:
(a) Knölker, H.-J.; Fröhner, W.; Reddy, K. R. Eur. J. Org.
Chem. 2003, 740. (b) Knölker, H.-J.; Reddy, K. R.
Heterocycles 2003, 60, 1049. (c) Knölker, H.-J.; Knöll, J.
Chem. Commun. 2003, 1170. (d) Knölker, H.-J.; Wolpert,
M. Tetrahedron 2003, 59, 5317. (e) Knölker, H.-J.; Krahl,
M. P. Synlett 2004, 528. (f) Knölker, H.-J.; Fröhner, W.;
Heinrich, R. Synlett 2004, 2705. (g) Kataeva, O.; Krahl, M.
P.; Knölker, H.-J. Org. Biomol. Chem. 2005, 3, 3099.
(h) Czerwonka, R.; Reddy, K. R.; Baum, E.; Knölker, H.-J.
Chem. Commun. 2006, 711.
Parrinello, G.; Renaldo, A. F.; Stille, J. K. J. Org. Chem.
1987, 52, 422. (c) Kalivretenos, A.; Stille, J. K.; Hegedus, L.
S. J. Org. Chem. 1991, 56, 2883. (d) Mitchell, T. N.
Synthesis 1992, 803.
(18) Carbazomadurin B (1b): light-yellow crystals, mp 165 °C
(dec.). [a]D24 +13.0 (c 0.05, MeOH); [a]D19 +16.8 (c 0.37,
MeOH). UV (MeOH): l = 237, 249 (sh), 289 (sh), 299, 347,
356 nm. UV (MeOH, NaOH): l = 236, 257, 303, 363 nm. IR
(KBr): n = 3477, 3431, 2959, 2929, 2873, 1618, 1584, 1524,
1426, 1377, 1269, 1168, 1075, 972, 819 cm–1. 1H NMR (500
MHz, acetone-d6): d = 0.94 (t, J = 7.3 Hz, 3 H), 0.99 (dd,
J = 6.3, 5.4 Hz, 3 H), 1.22–1.28 (m, 1 H), 1.42–1.53 (m, 3
H), 1.57 (d, J = 1.1 Hz, 3 H), 1.67–1.73 (m, 1 H), 2.27 (s, 3
H), 2.30–2.42 (m, 2 H), 3.93 (br s, 1 H), 5.02 (s, 2 H), 6.44
(s, 1 H), 6.73 (d, J = 7.7 Hz, 1 H), 6.92 (d, J = 7.7 Hz, 1 H),
7.60 (s, 1 H), 7.79 (br s, 1 H), 8.40 (br s, 1 H), 8.87 (br s, 1
H). 13C NMR and DEPT (125 MHz, acetone-d6): d = 11.36
(CH3), 13.22 (CH3), 17.65 (CH3), 19.11 (CH3), 29.70 (CH2),
34.65 (CH), 35.30 (CH2), 37.14 (CH2), 63.49 (CH2), 106.70
(CH), 109.34 (CH), 118.61 (CH), 120.12 (CH), 121.14 (C),
122.08 (C), 122.14 (C), 123.29 (C), 128.13 (C), 130.21 (C),
133.37 (C), 142.47 (C), 142.62 (C), 149.63 (C). MS (EI):
m/z (%) = 367 (73) [M+], 366 (10), 365 (27), 351 (100), 349
(11). HRMS: m/z calcd for C23H29NO3 [M+]: 367.2147;
found: 367.2157. Anal. Calcd for C23H29NO3: C, 75.17; H,
7.95; N, 3.81. Found: C, 75.12; H, 7.99; N, 3.57.
(5) Kotada, N.; Shinya, K.; Furihata, K.; Hayakawa, Y.; Seto, H.
J. Antibiot. 1997, 50, 770.
(6) Lardicci, L.; Botteghi, C.; Benedetti, E. J. Org. Chem. 1966,
31, 1534.
(7) (S)-(–)-2-Methyl-1-butanol (99% purity) from Aldrich.
Synlett 2006, No. 4, 651–653 © Thieme Stuttgart · New York