Synthesis of enantiomerically pure (-)-(S)-brevicolline

Article abstract of DOI:10.1021/np980492h

(-)-(S)-Brevicolline (1) and related β-carbolines were synthesized using an enantiomerically pure Michael-acceptor synthon (3). Subsequent Pictet-Spengler reaction afforded the tetrahydro-β-carboline skeleton, which, in turn, was transformed to the β-carboline by catalytic dehydrogenation.

Full text of DOI:10.1021/np980492h

J . Nat. Prod. 1999, 62, 577-579
577
Syn th esis of En a n tiom er ica lly P u r e (-)-(S)-Br evicollin e
Siavosh Mahboobi,* Wolfgang Wiegrebe, and Alfred Popp
Institute of Pharmacy, University of Regensburg, D-93040 Regensburg, Germany
Received November 2, 1998
(-)-(S)-Brevicolline (1) and related â-carbolines were synthesized using an enantiomerically pure Michael-
acceptor synthon (3). Subsequent Pictet-Spengler reaction afforded the tetrahydro-â-carboline skeleton,
which, in turn, was transformed to the â-carboline by catalytic dehydrogenation.
â-Carboline derivatives are commonly found in plants.1
Sch em e 1
Members of the structurally diverse family of â-carbolines
exhibit a wide range of biological activities. The reported
effects of these compounds include antineoplastic (tubuline
binding),2-4 anticonvulsive, hypnotic and anxiolytic (ben-
zodiazepine receptor inhibitoric),2,5-8 antiviral,9 antimicro-
bial,3 and topoisomerase II inhibition10 and inhibition of
cGMP-dependent processes.11
The â-carboline alkaloid brevicolline (1), the major
alkaloid of the plant Carex brevicollis DC (Cyperacee),
belongs to a group of pharmacologically interesting com-
pounds12 and was isolated,13,14 determined,15 and chemi-
cally modified16 30 years ago. Since that time, syntheses
of racemic 1 were carried out, for example, by Winterfeldt17
or Leete,18 both using tryptamine as starting compound.
A synthesis of the brevicolline enantiomers has yet not been
described. This is remarkable because of the known various
biological effects of 1, such as a phototoxic effect against
bacteria and fungi, a photosensitizing effect,19 and its
application against uterine inertia of pregnant women
because of its oxytocic effect.20 The â-carbolines and tet-
rahydro-â-carbolines of the “eudistomine family”, such as
woodinine (2),21 also have interesting biological activi-
ties22,23 and differ from 1 mainly in the position of the
pyrrolidine ring.
Resu lts a n d Discu ssion
Synthesis began using the chiral Michael-acceptor syn-
thon (3) (Scheme 1).24 Indole-anion, accessible from indole
and ethylmagnesium bromide, reacted with the nitroethene
derivative 3, afforded the precursor 4. The nitro indole 4
was converted to the amino indole 5 by catalytic hydroge-
nation over Pd/C. Subsequently, the â-carboline ring was
closed by Pictet-Spengler reaction using acetaldehyde and
trifluoroacetic acid. In our hands, imine formation pro-
ceeded very well at room temperature, using a molecular
sieve (4 Å) to remove H2O prior to addition of TFA at -78
°C. This modification makes isolation of the imine unneces-
sary. Aromatization of 6, forming the â-carboline system
7, was afforded by Pd in refluxing xylene.25 Reduction of
the Boc-protecting group with LiAlH4 yielded the N-methyl
group of title compound 1. We deliberately did not reduce
the Boc-protecting group at an earlier stage because it is
known that (N-methylpyrrolidinyl)-â-carbolines and related
compounds with a 3-(2-pyrrolidinyl)-1,2,3,4-tetrahydropy-
ridine skeleton lose the pyrrolidine residue under dehy-
drogenating conditions.26 To prevent this cleavage, the
pyrrolidine nitrogen should be protected as an amide or
carbamate (N-formyl, N-Boc).26
1H NMR, IR, and MS data match exactly with those
reported for natural 1.1,13 The melting point and optical
rotation, however, differ slightly from literature values. A
* To whom correspondence should be addressed. Tel.: (0049) 0941-943-
4825. Fax: (0049) 0941-943-4809. E-mail: siavosh.mahboobi@chemie.
uni-regensburg.de.
10.1021/np980492h CCC: $18.00
© 1999 American Chemical Society and American Society of Pharmacognosy
Published on Web 04/03/1999

578 J ournal of Natural Products, 1999, Vol. 62, No. 4
Mahboobi et al.
Sch em e 2
refluxed until all Mg was dissolved (ca. 30 min). After cooling
to room temperature, indole (2.88 g, 24.6 mmol), dissolved in
THF (13 mL), was added slowly, and the mixture was stirred
for 45 min at 45 °C. When the mixture cooled to room
temperature, a solution of 324 (5.70 g, 23.5 mmol) in dry THF
(25 mL) was added drop by drop over 1 h, and the resulting
solution was heated to reflux overnight. Ice and 20% citric acid
(50 mL) were then added, the organic layer was separated,
and the aqueous phase was extracted with Et2O (4 × 40 mL).
The combined organic phases were washed with H2O, dried
over Na2SO4, and evaporated in vacuo. The crude product was
separated from remaining starting material and byproducts
by column chromatography (CH2Cl2-EtOAc 20:0.5) affording
product 4 (mixture of diastereomers) as a yellowish powder
(3.94 g, 11.0 mmol, 47%): melting range 104-111 °C; UV
(EtOH) λmax (log ꢀ) 288 (3.80), 279 (3.88), 217 (4.65) nm; IR
(KBr) ν 3419, 3321 (NH), 3060, 2977 (CH), 1673 (CdO), 1553
1
(NO) cm-1; H NMR (DMSO-d2, 250 MHz) δ 1.40-1.99 (13H,
m), 2.88-3.70 (2H, m), 4.22-4.62 (2H, m), 4.67-5.06 (2H, m),
7.02-7.25 (3H, m), 7.31-7.43 (1H, m), 7.63-7.82 (1H, m), 8.18
(1H, s); FABMS m/z 360 [M + H]+, 719 [2M + H]+; anal. C
63.40%, H 6.89%, N 11.52%, calcd for C19H25N3O4 (359.43), C
63.49%, H 7.01%, N 11.69%.
3-{2-Am in o-1-[(2S)-N-(ter t-bu tyloxycar bon yl)pyr r olidin -
2-yl]eth yl}-1H-in d ole (5). A solution of compound 4 (3.24 g,
9.01 mmol) and 10% Pd/C (1.60 g) in dry EtOH (100 mL) was
stirred for 24 h at a H2 pressure of 10 bar. When the reaction
ceased (TLC control) the catalyst was filtered off through
Celite, the filter was washed with warm EtOH (200 mL), and
the solvent was evaporated. The residue was purified by
column chromatography (CH2Cl2-MeOH 9:2) yielding 5 (mix-
ture of diastereomers) as a white foam (1.84 g, 5.59 mmol,
62%): mp 160 °C (dec); IR (KBr) 3298 (NH), 3060, 2975 (CH),
1684 (CdO) cm-1; UV (EtOH) λmax (log ꢀ) 288 (4.00), 280 (4.07),
218 (4.80) nm; 1H NMR (DMSO-d6) (250 MHz) δ 1.19-1.88
(16H, m), 2.72-3.15 (3H, m), 3.37-3.51 (1H, m), 4.00-4.26
(1H, m), 6.87-7.08 (2H, m), 7.09-7.18 (1H, m), 7.26-7.40 (1H,
m), 7.54-7.75 (1H, m), 10.89 (1H, s, indole-NH); FABMS m/z
330 [M + H]+, 659 [2M + H]+; anal. C 69.63%, H 8.65%, N
12.13%, calcd for C19H27N3O2 (329.45), C 69.27%, H 8.26%, N
12.75%.
1-Meth yl-4-[(2S)-N-(ter t-bu tyloxyca r bon yl)p yr r olid in -
2-yl]-1,2,3,4-tetr a h yd r o-â-ca r bolin e (6). The solution of 5
(1.00 g, 3.04 mmol) and acetaldehyde (0.17 mL, 3.02 mmol) in
dry CH2Cl2 (60 mL) was stirred with molecular sieve (4 Å) (500
mg) under N2 for 1 h at room temperature. After filtration and
washing with dry CH2Cl2, the solution of the intermediate
imine was cooled to -78 °C. TFA (0.73 mL, 9.48 mmol) was
added drop by drop over 2.5 h at -78 °C, the solution was
allowed to warm to room temperature overnight, poured into
ice water, basified with 2N Na2CO3 at 0 °C, washed with H2O
(2 × 20 mL), dried over Na2SO4, and evaporated under reduced
pressure. The residue was purified by column chromatography
(CH2Cl2-MeOH 9:2) yielding the tetrahydro-â-carboline 6
(0.51 g, 1.43 mmol, 47%) as an off-white foam (mixture of
diastereomers): melting range 113-120 °C; IR (KBr) 3299
(NH), 3058, 2973 (CH), 1669 (CdO) cm-1; UV (EtOH) λmax (log
ꢀ) 281 (3.88), 222 (4.46) nm; 1H NMR (DMSO-d6) (250 MHz) δ
1.42 (3H, d, J ) 6.4 Hz), 1.48 (9H, s), 1.53-1.81 (4H, m), 2.06-
2.22 (1H, m), 2.71-2.89 (1H, m), 2.94-3.14 (3H, m), 3.18-
3.28 (1H, m), 3.87-3.99 (1H, m), 4.02 (1H, q, J ) 6.4 Hz), 6.87-
7.05 (2H, m), 7.21-7.34 (2H, m), 10.83 (1H, s); FABMS m/z
356 [M + H]+, 711 [2M + H]+; anal. C 70.50%, H 8.25%, N
11.45%, calcd for C21H29N3O2 (355.48), C 70.96%, H 8.22%, N
11.82%.
higher melting point (232-233 °C instead of 223-224 °C)
and an increased [R]20D (-164.5 instead of -145.8) indicate
higher purity.
The same reactions were used for synthesis of the
eudistomine analogue 8. By the enantiomeric pure alde-
hyde 9 a second stereogenic center was introduced into the
molecule (Scheme 2). In accordance with McNulty et al.,25
dehydrogenation of the tetrahydro-â-carboline 10 affects
the stereogenic center in the pyrrolidine ring. High and
low temperature 1H NMR experiments (in order to sup-
press effects of E/Z-isomerism of the Boc-protecting groups)
and HPLC analysis proved the existence of two diastere-
omeric â-carbolines 11, which could not be preparatively
separated. This holds true also for the diamine 8.
Thus, a facile synthesis was established, stereospecific
for (-)-(S)-brevicolline (1) and diastereoselective for related
alkaloids, for example, 8 in good overall yields. The
functionality of the starting materials, which, in addition,
are easily accessible, allows the synthesis of a wide
spectrum of optically active derivatives.
Exp er im en ta l Section
Gen er a l Exp er im en ta l P r oced u r es. Melting points were
measured with a Reichert Thermovar 300419 microscope
heating stage, standardized with gauge substances, and are
not corrected. 1H NMR data were obtained on a Bruker AC250
(250 MHz) spectrometer. All chemical shifts are quoted on the
δ-scale. FT-IR spectroscopy was performed on a Nicolet 510
FT-IR spectrometer. MS were recorded on a Varian MAT 311
A, 70 eV for electron impact ionization (EI), or on a Finnigan
MAT 95 for fast atomic bombardment (FAB) and for field
desorption (FD) as stated. Optical rotations were measured
on a Perkin-Elmer 241 MC polarimeter. Microanalyses were
performed by Analytisches Lab., University Regensburg. TLC
was carried out on Al sheets coated with 60F245 silica.
Compounds were detected using sprays of 3% w/v vanillin in
96% EtOH followed by 5% w/v H2SO4 in 96% EtOH. Column
chromatography was carried out using Merck 60 (70-230
mesh ASTM) silica. Solvents and commercially available
reagents were dried and purified before use according to
standard procedures. All reactions were carried out under
dried N2 in flame- or oven-dried vessels.
1-Meth yl-4-[(2S)-N-(ter t-bu tyloxyca r bon yl)p yr r olid in -
2-yl]-â-ca r bolin e (7). A suspension of 6 (0.10 g, 0.28 mmol)
and 10% Pd/C (60.0 mg) in dry xylene (10 mL) was refluxed
for 2 h. When the reaction ceased the catalyst was filtered off
through Celite, the filter was washed with warm EtOH (50
mL), and the solvent was evaporated. The residue was purified
by column chromatography (CH2Cl2-MeOH 9:1) yielding the
â-carboline 7 as colorless prisms (77.6 mg, 0.22 mmol, 79%):
3-{2-Nitr o-1-[(2S)-N-(ter t-bu tyloxyca r bon yl)p yr r olid in -
2-yl]eth yl}-1H-in d ole (4). Magnesium shavings (0.66 mg,
25.0 mmol) and ethyl bromide (0.96 mL, 12.5 mmol) were
added to dry THF (13 mL). When the reaction began, further
ethyl bromide (0.96 mL, 12.5 mmol) was added drop by drop
so that the solution was refluxing slightly. The solution was
mp 243-244 °C (dec) (EtOH); [R]20 ) -85.6° (c 2.4, EtOH);
D
IR (KBr) 3298 (NH), 3060, 2975 (CH), 1684 (CdO) cm-1; UV

Synthesis of (-)-(S)-Brevicoline
J ournal of Natural Products, 1999, Vol. 62, No. 4 579
(EtOH) λmax (log ꢀ) 349 (4.15), 336 (4.12), 286 (4.44), 278 (4.25),
234 (4.66) nm; 1H NMR (DMSO-d6) (250 MHz) δ 1.04 (4H, s),
1.43 (5H, s), 1.69-2.00 (3H, m), 2.53-2.65 (1H, m), 2.73 (3H,
s, CH3), 3.41-3.58 (1H, m), 3.61-3.78 (1H, m), 5.62-5.74 (1H,
m), 7.25 (1H, t, J ) 8.0 Hz), 7.53 (1H, t, J ) 8.0 Hz), 7.62 (1H,
d, J ) 8.0 Hz), 7.85 (1H, s), 8.15 (1H, d, J ) 8.0 Hz), 11.63
(1H, s); FABMS m/z 352 [M + H]+, 703 [2M + H]+, 1054 [3M
+ H]+; anal. C 70.92%, H 7.44%, N 11.54%, calcd. for
1,4-Di[(2S)-N-m eth ylpyr r olidin -2-yl]-â-car bolin e (8). The
reduction of 11 (85.0 mg, 0.17 mmol) with LiAlH4 (0.15 g, 3.95
mmol) was executed as described for compound 7, yielding
product 8 as a off-white powder (40.0 mg, 0.12 mmol, 70%):
melting range 87-93 °C; IR (KBr) 3359 (NH), 2966, 2779 (CH)
cm-1; UV (EtOH) λmax (log ꢀ) 352 (4.59), 339 (4.57), 288 (4.79),
243 (5.14), 212 (5.01) nm; 1H NMR (CDCl3) (250 MHz) δ 1.81-
2.14 (m, 6H), 2.30, 2.31 (2 s, 3H), 2.32, 2.33 (2 s, 3H), 2.37-
2.56 (m, 4H), 3.34-3.46 (m, 2H), 3.72-3.86 (m, 1H), 3.87-
3.99 (m, 1H), 7.21-7.31 (m, 1H), 7.48-7.61 (m, 2H), 8.40-
8.50 (m, 2H), 10.37 (br s, 1H); EIMS m/z 334 [M]•+ (88), 278
(100); anal. C 75.22%, H 7.64%, N 17.00%, calcd for C21H26N4
(334.47), C 75.41%, H 7.84%, N 16.75%.
C
21H25N3O2 (351.45), C 70.77%, H 7.17%, N 11.96%.
1-Me t h yl-4-[(2S )-N -m e t h ylp yr r olid in -2-yl]-â-ca r b o-
lin e (1). A solution of compound 7 (0.15 g, 0.43 mmol) in THF
(2.5 mL) was added drop by drop to a suspension of LiAlH4
(0.18 g, 4.74 mmol) in THF (10 mL) with ice cooling. The
resulting mixture was refluxed for 12 h. When the reaction
was finished (TLC), the mixture was allowed to cool to room
temperature. Ice water was then carefully added, and the
resulting suspension was basified with 10% NaOH. The
resulting mixture was extracted with Et2O (4 × 15 mL), the
EtOH extract was dried over Na2SO4, and the solvent was
removed under reduced pressure. The residue was purified by
column chromatography (CH2Cl2-MeOH 9:1) and recrystal-
lized from MeOH yielding (-)-(S)-brevicolline as colorless
Refer en ces a n d Notes
(1) Lazurjevski, G.; Terentjeva, I. Heterocycles 1976, 4, 1783-1816.
(2) Molina, P.; Fresneda, P. M. J . Chem. Soc., Perkin Trans. 1 1988,
1819-1822.
(3) Molina, P.; Fresdena, P. M.; Garc´ıa-Zafra, S.; Almendros, P. Tetra-
hedron Lett. 1994, 35, 8851-8854.
(4) Behforouz, M.; Merriman, R. L. (Ball State University, USA), US Pat.
Appl. 5 646 150, 1997; Chem. Abstr. 1997, 127, 149043q.
(5) Braestrup, C.; Nielsen, M.; Olsen, C. E. Proc. Natl. Acad. Sci. U.S.A.
1980, 77, 2288-2292.
prisms (91.0 mg, 0.34 mmol, 79%): mp 232-233 °C;1,13 [R]20
D
(6) Schlecker, W.; Huth, A.; Ottow, E.; Mulzer, J . Synthesis 1995, 1225-
) -164.5° (c 1.8, EtOH); IR (KBr) 3422 (NH), 3147, 2089, 2873
(CH), 1684 (CdO) cm-1; UV (EtOH) λmax (log ꢀ) 351 (4.12), 337
(4.09), 287 (4.39), 279 (4.19), 232 (4.68), 213 (4.54) nm; 1H NMR
(CDCl3) (250 MHz) δ 1.87-2.11 (3H, m), 2.30 (3H, s), 2.38-
2.51 (2H, m), 2.83 (3H, s), 3.34-3.44 (1H, m), 3.87-3.97 (1H,
m), 7.26-7.33 (1H, m), 7.50-7.56 (2H, m), 8.45 (1H, d, J )
8.3 Hz), 8.50 (1H, s), 9.07 (1H, s); EIMS m/z 265 [M]•+ (6), 84
(100), 42 (90).
1227.
(7) Batch, A.; Dodd, R. H. J . Org. Chem. 1988, 36, 872-877.
(8) Seidelmann, D.; Huth, A.; Ottow, E.; Olesen, P. H.; Turner, J .;
Hillman, M.; Cole, B. (Schering AG), Ger. Offen. DE 195 14 524 A1,
1996; Chem. Abstr. 1997, 126, P 8106e.
(9) Molina, P.; Fresdena, P. M.; Garcı´a-Zafra, S. Tetrahedron Lett. 1995,
36, 3581-3582.
(10) Pommier, Y.; MacDonald, T. L.; Madalengoitia, J . S. (Department of
Health and Human Services, USA), PCT Int. Appl. WO94/101751 A1,
1997; Chem. Abstr. 1997, 126, 343431.
1,4-Bis[(2S)-N-(ter t-bu tyloxyca r bon yl)p yr r olid in -2-yl]-
1,2,3,4-tetr a h yd r o-â-ca r bolin e (10). The reaction of 5 (1.10
g, 3.34 mmol) with 9 (0.67 g, 3.36 mmol) was performed as
described for compound 6, yielding products 10 as a white foam
(1.08 g, 2.11 mmol, 63%): melting range 128-135 °C; IR (KBr)
3332 (NH), 2975 (CH), 1690 (CdO) cm-1; UV (EtOH) λmax (log
ꢀ) 281 (4.07), 224 (4.60), 203 (4.47) nm; 1H NMR (CDCl3) (250
MHz) δ 1.21-1.86 (22H, m), 1.91-2.36 (4H, m), 2.91-3.05 (1H,
m), 3.13-3.86 (7H, m), 3.95-4.13 (1H, m), 4.44-4.57 (1H, m),
4.66-4.78 (1H, m), 7.01-7.21 (2H, m), 7.29-7.42 (1H, m),
7.58-7.70 (1H, m), 7.89-7.14 (1H, m); FABMS m/z 511 [M +
H]+, 411, 1021 [2M + H]+; anal. C 67.99%, H 8.31%, N 10.72%,
calcd for C29H42N4O4 (510.68), C 68.21%, H 8.29%, N 10.97%.
1,4-Bis[(2S)-N-(ter t-bu tyloxyca r bon yl)p yr r olid in -2-yl]-
â-ca r bolin e (11). The dehydrogenation of 10 (0.24 g, 0.50
mmol) with Pd/C (600 mg) was effected as described for
compound 6, yielding products 11 as a white powder (0.15 g,
0.30 mmol, 59%): mp 225-228 °C; IR (KBr) 3267 (NH), 2970
(CH), 1700 (CdO) cm-1; UV (EtOH) λmax (log ꢀ) 350 (4.01), 339
(4.00), 288 (4.33), 235 (4.68), 213 (4.45), 203 (4.45) nm; 1H NMR
(CDCl3) (250 MHz) δ 1.37-1.69 (18H, m), 1.65-2.19 (6H, m),
2.38-2.64 (2H, m), 2.94-3.14 (1H, m), 3.24-3.44 (1H, s), 3.48-
3.71 (2H, m), 3.71-3.81 (1H, m), 5.73-5.97 (1H, m), 7.17-
7.33 (1H, m), 7.44-7.63 (2H, m), 8.03-8.15 (2H, m), 11.09-
11.36 (1H, m); FDMS m/z 506 [M+]; anal. C 68.60%, H 7.66%,
N 11.13%, calcd for C29H38N4O4 (506.65), C 68.75%, H 7.56%,
N 11.06%.
(11) Daugan, A. C. M.; Labaudiniere, R. F. (Glaxo Welcome Laboratories,
Fr.), PCT Int. Appl. WO 96/32003, 1996; Chem. Abstr. 1997, 126, P
18895a.
(12) Baumgarth, M. Chem.-Ztg. 1973, 97, 217-228.
(13) Vember, P. A.; Terent’eva, I. V.; Lazurevskii, G. Khim. Prir. Soedin.
1967, 4, 249-253; Chem. Abstr. 1967, 67, 108816t.
(14) Terent’eva, I. V.; Lazurevskii, G. V.; Shirshova, T. I. Khim. Prir.
Soedin. 1969, 5, 397-404; Chem. Abstr. 1970, 72, 67166p.
(15) Vember, P. A.; Terent’eva, I. V.; Ul’yanova, A. V. Khim. Prir. Soedin.
1968, 4, 98-101; Chem. Abstr. 1968, 69, 77569z.
(16) Shirshova, T. I.; Terent’eva, I. V.; Vember, P. A.; Lazurevskii, G. V.
Khim. Geterotsikl. Soedin. 1972, 7, 987-990; Chem. Abstr. 1972, 77,
140396y.
(17) Mu¨ller, W. H.; Preuss, R.; Winterfeldt, E. Chem. Ber. 1977, 110,
2424-2432.
(18) Leete, E. J . Chem. Soc., Chem. Commun. 1979, 821-822.
(19) Towers, G. H. N.; Abramovski, Z. J . Nat. Prod. 1983, 46, 572-577.
(20) Marcu, G. A. Tr. Tret’ei Nauchn. Konf. Molodykh Uchenykh Moldavii,
Biol. i Sel’skokhoz. Nauk 1965, 2, 243; Chem. Abstr. 1965, 63, 2297a.
(21) Mahboobi, S.; Dove, S.; Bednarski, P.; Kuhr, S.; Burgemeister, T.;
Schollmeyer, D. J . Nat. Prod. 1997, 60, 587-591 and literature cited
therein.
(22) Baker, B. J . In Alkaloids: Chemical and Biological Perspectives;
Pelletier, S. W., Ed.; Wiley: New York, 1996; Vol. 10, pp 357-407.
(23) Alvarez, M.; Salas, M. Heterocycles 1991, 32, 1391-1429.
(24) Mahboobi, S.; Popp, A.; Burgemeister, T.; Schollmeyer, D. Tetrahe-
dron: Asymmetry 1998, 9, 2369-2376.
(25) McNulty, J .; Still, I. W. J . J . Chem. Soc., Perkin Trans. 1 1994, 1329-
1338.
(26) Mahboobi, S.; Seidl, E.; Eibler, E.; Wiegrebe, W. Arch. Pharm.
(Weinheim) 1992, 325, 679-683 and literature cited therein.
NP980492H