Enantioselective Total Syntheses of (+)-Arborescidine A, (-)-Arborescidine B, and (-)-Arborescidine C

Article abstract of DOI:10.1021/jo035165f

Described are the first enantioselective total syntheses of (+)-arborescidine A ((+)-1), (-)-arborescidine B ((-)-2), and (-)-arborescidine C ((-)-3), via routes that proceeded in five steps and 50% overall yield, eight steps and 61% overall yield, and ni

Full text of DOI:10.1021/jo035165f

En a n tioselective Tota l Syn th eses of (+)-Ar bor escid in e A,
(-)-Ar bor escid in e B, a n d (-)-Ar bor escid in e C
Leonardo S. Santos,† Ronaldo A. Pilli,*,† and Viresh H. Rawal*,‡
Instituto de Quimica, Universidade Estadual de Campinas (Unicamp), CP 6154,
13084-971 Campinas, SP, Brazil, and Department of Chemistry, The University of Chicago,
Chicago, Illinois 60637
pilli@iqm.unicamp.br; vrawal@uchicago.edu
Received August 7, 2003
Described are the first enantioselective total syntheses of (+)-arborescidine A ((+)-1), (-)-
arborescidine B ((-)-2), and (-)-arborescidine C ((-)-3), via routes that proceeded in five steps and
50% overall yield, eight steps and 61% overall yield, and nine steps and 51% overall yield,
respectively, from 6-bromotryptamine (7). The syntheses feature the use of the Noyori catalytic
asymmetric hydrogen-transfer reaction to introduce chirality in dihydro-â-carbolines 6 and 8. On
the basis of an ample precedent from Noyori’s work, the reduction produces dihydro-â-carbolines,
and ultimately the natural products, possessing the R absolute configuration. The synthetic
arborescidines displayed optical rotations that were opposite in sign those of the natural products,
thereby supporting the S configuration for natural arborescidines A (1) and B (2) and the (3S,17S)
configuration for natural arborescidine C (3). Our results are in agreement with the initial
stereochemical assignment by Pa¨ıs and co-workers, and are counter to their recently revised
assignment.
In tr od u ction
ses of these alkaloids by taking advantage of the Noyori
asymmetric hydrogen-transfer reaction of appropriately
functionalized â-carboline derivatives.5
A wide variety of biologically active 6-bromoindole
derivatives have been isolated from marine invertebrates,
such as sponges, coelenterates, and tunicates. These
secondary metabolites are believed to function as chemi-
cal defense agents against parasites.1 In 1993, Pa¨ıs and
co-workers isolated four new brominated alkaloids of the
tetrahydro-â-carboline family from the marine tunicate
Pseudodistoma arborescens and characterized them as
arborescidine A (1), arborescidine B (2), arborescidine C
(3), and arborescidine Dsa diastereoisomer of 3 that
possesses the opposite configuration at C-17 (Figure 1).2
The absolute stereochemistry of 1 was initially suggested
to be S on the basis of circular dichroism studies by Pa¨ıs
and co-workers. Assuming a common biosynthesis for all
four compounds, the same C-3 configuration was also
tentatively assigned to arborescidines B-D. However,
recent X-ray crystallography studies using the anomalous
dispersion of the bromine atom have resulted in the
assignment of arborescidine C to be changed to 3R,17R.3
Inspired in part by this controversy, we undertook the
stereoselective synthesis of 1-3. In 1998, Koomen and
co-workers reported a racemic approach to these alka-
loids.4 We envisaged efficient, enantiocontrolled synthe-
Resu lts
Structurally, the arborescidines comprise a tetracyclic
framework featuring a common octahydropyrido[2,1-a]-
â-carboline core. The retrosynthetic analysis for the basic
framework of arborescidines A-C is depicted in Figure
1 and features the Noyori asymmetric hydrogen-transfer
reaction (6 to 5 and 8 to 9) as a key step. Although
demonstrated as a useful synthetic method, this asym-
metric reduction remains to be fully explored in the arena
of total synthesis of alkaloid natural products.6
The ubiquitous nature of the indole framework has
stimulated the development of numerous methods for the
(5) (a) Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori,
R. J . Am. Chem. Soc. 1996, 118, 4916. (b) Yamakawa, M.; Ito, H.;
Noyori, R. J . Am. Chem. Soc. 2000, 122, 1466. (c) Mao, J .; Baker, D.
C. Org. Lett. 1999. 1, 841. (d) J ames, B. R. Catal. Today 1997, 37,
209. (e) Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069.
(6) The Noyori enantioselective hydrogenation was utilized to
introduce the initial chirality in the asymmetric total synthesis of (+)-
geissoschizine: Reddy, T. J .; Birman, V. B. Unpublished results. See:
(a) Birman, V. B. Ph.D. Dissertation, The University of Chicago, 2000.
(b) Reddy, T. J .; Birman, V. B.; Rawal, V. H. Catalytic Asymmetric
Total Synthesis of (+)-Geissoschizine. Abstracts of Papers, 226th ACS
National Meeting, New York, Sept 7-11, 2003; American Chemical
Society: Washington, DC, 2003. For other applications of the Noyori
reduction toward alkaloid compounds, see: (c) Santos L. S.; Fernandes
S. A.; Pilli, R. A.; Marsaioli, A. J . Tetrahedron: Asymmetry 2003, 14,
2515-2519. (d) Kaldor I.; Feldman, P. L.; Mook, R. A.; Ray, J . A.;
Samano, V.; Sefler, A. M.; Thompson, J . B.; Travis, B. R.; Boros, E. E.
J . Org. Chem. 2001, 66, 3495-3501. (e) Tietze, L. F.; Zhou, Y. F.;
Topken, E. Eur. J . Org. Chem. 2000, 2247-2252. (f) Meuzelaar, G. J .;
van Vliet, M. C. A.: Maat, L.; Sheldon, R. A. Eur. J . Org. Chem. 1999,
2315, 5-2321.
† Unicamp.
‡ The University of Chicago.
(1) Baker, J . T.; Murphy, V. Handbook of Marine Science: Com-
pounds from Marine Organisms; CRC: Cleveland, OH, 1976; Vol. 1.
(2) Chbani, M.; Pa¨ıs, M. J . Nat. Prod. 1993, 56, 99.
(3) Schubot, F. D.; Hossain, M. B.; van der Helm, D.; Pa¨ıs, M.;
Debitus, C. J . Chem. Crystallogr. 1998, 28, 23.
(4) Burm, B. E. A.; Meijler, M. M.; Korver, J .; Warnner, M. J .;
Koomen, G.-J . Tetrahedron 1998, 54, 6135.
10.1021/jo035165f CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/28/2004
J . Org. Chem. 2004, 69, 1283-1289
1283

Santos et al.
F IGURE 1. Retrosynthetic analysis for arborescidines A-C.
SCHEME 1a
a
Reagents and conditions: (a) (COCl)2, Et2O, 0 °C, 2 h. (b) NH4OH, 50 °C, 30 min, 77%. (c) BH3‚SMe2, THF, reflux, 2 h; then HCl (1
M), reflux, 3 h, 30%. (d) Br2, AcOH, 15 °C, 40 min. (e) (Boc)2O, CH2Cl2, 30 min. (f) chromatographic separation, 15%. (g) 25% aq HCl,
EtOH, 30 min, quantitative. (h) Me2NCHdCHNO2, TFA, rt, 30 min, 96%. (i) NaBH4, BF3‚OEt2, THF, reflux, 2 h; then HCl (1 M), reflux,
2 h; NaOH, 73%.
synthesis of substituted indoles from benzenoid precur-
sors. Among these, the Fischer,7 Reissert,8 and Batcho-
Leimgruber9 indole syntheses have been widely utilized
for the synthesis of 4-, 5-, 6-, and 7-substituted indoles.
For the present project, we required an efficient synthesis
of 6-bromotryptamine (7), which was a key precursor to
â-carbolines 6 and 8 (Scheme 1). We have examined
several of the reported methods to 7, and have found the
Schumaker and Davidson10 method to be the most
efficient.
indole synthesis as reported by Rapoport et al.11 The
reaction of 10 with (COCl)2, followed by treatment with
aqueous NH4OH, afforded 3-glyoxyamide-6-bromoindole
(11a ), which upon borane reduction gave 7, albeit in low
yield (30%).
In another approach, glyoxyamide 11b was prepared
from indole through the same steps described above for
11a and was submitted to the following reaction se-
quence: (1) bromination to afford a mixture of 5- and
6-bromo glyoxyamides, (2) borane reduction, and (3)
N-Boc protection to give a mixture of 5- and 6-bromo-N-
Boc bromotryptamines 12 in 30% overall yield, which
after column chromatography separation and N-Boc
deprotection afforded 7 in 15% overall yield (Scheme 1).4
The most efficient route to 7 was through nitroethylene
The precursor to tryptamine 7 is 6-bromoindole (10),
which was prepared by a modified Batcho-Leimgruber
(7) (a) Uhle, F. C. J . Am. Chem. Soc. 1949, 71, 761. (b) Uhle, F. C.;
McEwen, C. M.; Schroter, H.; Yuan, C.; Baker, B. W. J . Am. Chem.
Soc. 1960, 82, 1200.
(8) Nagasaka, T.; Yuge, T.; Ohki, S. Heterocycles 1977, 8, 371.
(9) Clark, R. D.; Repke, D. B. Heterocycles 1984, 22, 195-221.
(10) Schumaker, R. W.; Davidson, B. S. Tetrahedron 1999, 55, 935.
(11) Moyer, M. P.; Shiurba, J . F.; Rapoport, H. J . Org. Chem. 1986,
51, 5106.
1284 J . Org. Chem., Vol. 69, No. 4, 2004

Total Syntheses of Arborescidines A-C
SCHEME 2a
a
Reagents and conditions: (a) glutaric anhydride, CH2Cl2, 0 °C to rt, 10 min. (b) SOCl2, MeOH, 0 °C to rt, 3 h, 83%. (c) POCl3, benzene,
reflux, 2 h, 86%. (d) (S,S)-TsDPEN-Ru(II) complex, HCO2H-Et3N (5:2), DMF, rt, 12 h, 89%. (e) AlH3, THF, rt, 10 min, 78%.
13. The reaction of 10 with 1-(dimethylamino)-2-nitro-
ethylene (DMANE)12 in the presence of TFA afforded
3-[(E)-2-nitroethenyl]-6-bromoindole (13) in 96% yield.
Attempted reduction of 13 to 7 with LiAlH4 in THF gave
a mixture in which the debrominated product predomi-
nated. On the other hand, reduction with borane, which
was generated in situ as described by Schumaker and
Davidson,10 proceeded smoothly to provide 7 in 73% yield.
With an efficient route to 7 in hand, we directed our
efforts to the synthesis of arborescidine A, following the
sequence depicted in Scheme 2. Thus, exposure of 7 to
glutaric anhydride in CH2Cl2 at room temperature formed
the corresponding amide carboxylic acid, which upon
treatment with SOCl2/MeOH afforded methyl ester 14
in 83% yield (two steps). Treatment of amide 14 with
POCl3 promoted the Bischler-Napieralsky cyclization to
produce imine 6 in 86% yield.
F IGURE 2. Asymmetric hydrogen-transfer reaction of beta-
Having prepared â-carboline imine 6, the stage was
carbolines catalyzed by Ru(II) complex.14
set to introduce the required asymmetry through the
Noyori asymmetric hydrogen-transfer reaction.5 In Na-
faces of the cyclic imine. The hydride transfer from the
ture, oxidoreductases catalyze remarkably selective trans-
ruthenium species to an imine requires an out-of-plane
fer hydrogenations of carbonyl compounds to alcohols
interaction between the Ru-H moiety and the CdN
bond. It is likely that the hydrogen transfer occurs via a
metal-ligand bifunctional catalysis14 and the NH linkage
further stabilizes the transition state by forming a
hydrogen bond with the nitrogen of the imine, as shown
in I, Figure 2.14b Thus, on the basis of this model, the
use of (S,S)-TsDPEN-Ru(II) complex in the hydrogen
transfer is expected to occur from the si face of imine 6
to provide (R)-5.
using cofactors such as NADH or NADPH.13 Noyori and
co-workers have shown that p-cymene-Ru(II) complexes
of certain chiral 1,2-diamines are highly effective as
catalysts for the asymmetric reduction of imines. This
method uses a formic acid-triethylamine azeotropic
mixture as the reductant and provides a convenient,
general route to natural and unnatural â-carboline
alkaloids.
The Noyori reduction of imine 6 was accomplished with
preformed (S,S)-TsDPEN-Ru(II) complex in DMF and
a HCO2H-Et3N mixture, which afforded, after in situ
cyclization, lactam 5 in 89% yield and 96% ee, as
determined by HPLC analysis using a ChiralCel OD
column. On the basis of the examples that have been
reported by Noyori, the absolute stereochemistry of 5 is
expected to be R, as shown. This outcome is consistent
with the general model that Noyori had proposed,
depicted in Figure 2, for the asymmetric hydrogen-
transfer reactions with TsDPEN-Ru(II) complexes. The
chiral ruthenium species in the stereodeterminant hy-
drogen-transfer step discriminates between the enantio-
Exposure of lactam 5 to borane reduction in THF
resulted in the formation of the desired product (+)-
arborescidine A ((+)-1), albeit in disappointingly low yield
(10%). On the other hand, reduction of lactam 5 pro-
15
ceeded smoothly with AlH3 at room temperature to
furnish (+)-1 in 78% yield. The optical rotation of our
synthetic arborescidine A, [R]D +82 (c ) 1, CHCl3), was
opposite that reported for natural arborescidine A, [R]D
-82 (c ) 1, CHCl3).2 Our result supports the S absolute
stereochemistry originally assigned to arborescidine A.
(14) (a) Haack, K.-J .; Hashiguchi, S.; Fujii, A.; Noyori R. Angew.
Chem., Int. Ed. Engl. 1997, 36, 285. (b) Noyori, R.; Hashiguchi, S. Acc.
Chem. Res. 1997, 30, 97. (c) Hashiguchi, S.; Fujii, A.; Haack, K.-J .;
Matsumura, K.; Noyori, R. Angew. Chem., Int. Ed. Engl. 1997, 36, 288.
(15) (a) Yoon, N. M., Brown, H. C., J . Am. Chem. Soc. 1968, 90, 2927.
(b) Santos, L. S., Pilli, R. A., Tetrahedron Lett. 2001, 42, 6999.
(12) Severin, T.; Bruck, B. Chem. Ber. 1965, 98, 3847.
(13) (a) J ones, J . B. Tetrahedron 1986, 42, 3351. (b) Schoffers, E.;
Golebiowski, A.; J ohnson, C. R. Tetrahedron 1996, 52, 3769.
J . Org. Chem, Vol. 69, No. 4, 2004 1285

Santos et al.
SCHEME 3a
a
Reagents and conditions: (a) 5-hexenoic acid, HOBt, EDC, CH2Cl2, rt, 10 h, 99%. (b) POCl3, MeCN, reflux, 3 h, 90%, or POCl3,
benzene, reflux, 2.5 h, 75%. (c) (S,S)-TsDPEN-Ru(II) complex, HCO2H-Et3N (5:2), DMF, rt, 12 h, 96%. (d) MeOCOCl, Et3N, CH2Cl2,
99%. (e) OsO4/t-BuOH, NMO, THF-H2O, 0 °C to rt, 10 h, 88%. (f) NaIO4, THF-H2O (1:2), 90%. (g) aq TFA, THF, 1 h, 95% (>20:1
trans/cis). (h) AlH3, THF, rt, 15 min, 96%. (i) MeO2CNSO2NEt3, benzene, 8 h, 84%.
With an efficient approach to arborescidine A secured,
the stage was now set for the total synthesis of arbores-
cidines B and C. Treatment of 7 with 5-hexenoic acid16
in the presence of EDC/HOBt gave amide 15 in 99% yield
(Scheme 3). This compound was also prepared through
the reaction of the corresponding acyl chloride (SOCl2, 0
°C to rt, 98%) with 7 in the presence of K2CO3 in CH2Cl2
(95% yield) or MeCN (90% yield).
THF-H2O at 0 °C to room temperature, 88% yield), on
the other hand, proceeded well provided the reaction was
carried out in the dark. Surprisingly, it was noted that
if the reaction flask was not protected from light the
yields decreased significantly.
Oxidative cleavage of diol 18, accomplished using
NaIO4 in a THF-H2O (1:2 v/v) mixture, proceeded cleanly
to give the rather unstable aldehyde 9 in excellent yield
(90%). Treatment of the crude aldehyde 9 with aqueous
TFA in THF afforded a >20:1 mixture of trans/cis-19
(95% yield), which after AlH3 reduction provided 3 in 96%
yield (mp 171-172 °C, lit.2 mp 172-173 °C). As with
arborescidine A, the sign of the absolute configuration
of our synthetic sample, [R]D -3.1 (c ) 1, CHCl3), was
opposite that reported for natural arborescidine C, lit.2
[R]D +3 (c ) 1, CHCl3).
Finally, the conversion of 3 to arborescidine B requires
only dehydration of the alcohol. This was best ac-
complished using the Burgess reagent in benzene,18
which afforded 2 in 84% yield. As was observed for the
other arborescidines, synthetic 2 displayed the opposite
absolute configuration, [R]D -71 (c ) 0.6, CHCl3), when
compared to natural 2, [R]D +70 (c ) 0.6, CHCl3).2
In conclusion, we have completed the first enantio-
selective total syntheses of (+)-arborescidine A ((+)-1),
(-)-arborescidine B ((-)-2), and (-)-arborescidine C
The Bischler-Napieralsky reaction in benzene afforded
imine 8 in 75% yield from 15, and this yield was improved
to 90% when the reaction was carried out in acetonitrile.
Noyori asymmetric hydrogen-transfer reaction of imine
8 in DMF afforded amine 16 in 96% yield. Interestingly,
when the imine was subjected to Noyori asymmetric
hydrogen-transfer reaction in acetonitrile as the solvent,
in accordance with a described procedure,17 no reaction
took place, only the starting material being observed. At
this stage, the free amine 16 was converted to the
corresponding methyl carbamate 17, and the enantio-
meric excess was determined by HPLC analysis (93% ee).
With asymmetry incorporated, we turned our attention
to the exploration of methods for the oxidative cleavage
of the alkene moiety. The carbamate group of 17 was
required for dihydroxylation of the double bond. Attempts
to use the corresponding N-methyl derivative of 16 in the
dihydroxylation step failed, despite attempts under sev-
eral different conditions, such as AD-mix, NMO/OsO4,
and catalytic K2OsO4./NaIO4/EtOAc-H2O. The dihy-
droxylation of carbamate 17 (OsO4/t-BuOH, NMO in
(18) (a) Burgess, E. M.; Penton, H. R., J r.; Taylor, E. A. J . Org.
Chem. 1973, 38, 26. (b) Horiguchi, Y.; Nakamura, E., Kuwajima, I. J .
Am. Chem. Soc. 1989, 111, 6257. (c) Duncan, J . A.; Hendricks, R. T.;
Kwong, K. S. J . Am. Chem. Soc. 1990, 112, 8433. (d) Pegg, N. A.;
Paquette, L. A. J . Org. Chem. 1991, 56, 2461. (e) Campbell, E.; Martin,
J . J .; Bordner, J .; Klunman, E. F. J . Org. Chem. 1996, 61, 4806. (f)
Papagni, A.; Mariorana, S.; Licandro, E.; Manzotti, R.; Baldoni, C. Eur.
J . Org. Chem. 2001, 1149.
(16) J uaristi, E., J imenez-Vasquez H. A. J . Org. Chem. 1991, 56,
1623.
(17) Tietze, L. F., Zhou, Y., Topken, E. Eur. J . Org. Chem. 2000,
2247.
1286 J . Org. Chem., Vol. 69, No. 4, 2004

Total Syntheses of Arborescidines A-C
ylenediamine (0.79 g, 2.16 mmol, 92%) as a cream-colored solid
that was identical spectroscopically to the previously reported
compound.17 The (S,S)-TsDPEN-Ru(II) complex was prepared
by stirring 4.56 µg (7.44 µmol) of dichloro(η6-p-cymene)-
ruthenium(II) dimer, 2.72 µg of (1S,2S)-1,2-diphenyl-N-(p-
tolylsulfonyl)ethylenediamine, and triethylamine (1.04 µL) in
degassed dry DMF (0.5 mL) at 90 °C for 1 h. Then, the
preformed catalyst solution was added to a mixture of imine
6 (0.130 g, 0.372 mmol) in 3.7 mL of DMF, followed by a
mixture of HCO2H-Et3N (5:2 v/v, 19.0 µL) at room tempera-
ture. After the resulting solution was stirred at room temper-
ature for 12 h, the DMF was distilled off under high vacuum,
and the crude purified by flash chromatography (CHCl3/MeOH,
10%, Rf ) 0.7) to afford 0.106 g (89%) of lactam 5 as a creamy
solid. [R]D +1.0 (c ) 1, CHCl3). Mp: 242-243 °C. 1H NMR
(CDCl3, 300 MHz): δ 1.71-1.94 (3H, m), 2.34-2.66 (2H, m),
2.73 (1H, m), 2.84 (2H, d, J ) 9.5 Hz), 2.94 (1H, d, J ) 22.7
Hz), 4.74 (1H, br dd, J ) 9.1 and 3.3 Hz), 5.16 (1H, d, J ) 8.8
Hz), 7.19 (1H, dd, J ) 8.4 and 0.7 Hz), 7.33 (1H, d, J ) 8.4
Hz), 7.46 (1H, s), 8.62 (1H, s). 13C NMR (CDCl3, 75 MHz): δ
19.4, 21.0, 29.0, 32.5, 40.1, 54.4, 109.4, 113.9, 115.2, 119.5,
122.9, 125.7, 134.0, 137.0, 169.1. IR (KBr film, cm-1): 3265,
3101, 2924, 2854, 1616, 1462, 1442, 1311, 1269, 1232, 1038,
754. HRMS (70 eV): C15H15N2OBr m/z calcd 318.0368, found
318.0366.
(+)-Ar bor escid in e A ((+)-1). To a solution of lactam 5
(0.160 g, 0.502 mmol) in dry THF (6.0 mL) was added a
solution of AlH3 in THF (1.55 M, 1.94 mL, 3.01 mmol)15 at
room temperature. After 10 min, the reaction was quenched
with saturated aq sodium sulfate solution and filtered. The
solids were washed with CH2Cl2 (200 mL), dried with Na2SO4,
and evaporated in vacuo. Purification by chromatography
eluting with EtOAc/Et3N (5%) afforded a white solid in 78%
yield, which was characterized as arborescidine A (1), in full
agreement with the reported data.2 [R]D +82 (c ) 1, CHCl3).
Mp: 203-204 °C. 1H NMR (CDCl3, 300 MHz): δ 1.44-1.48
(1H, m), 1.49-1.65 (1H, m), 1.70-1.79 (2H, m), 1.86-1.97 (1H,
m), 2.03-2.09 (1H, m), 2.34-2.42 (1H, m), 2.57-2.69 (2H, m),
2.92-3.09 (3H, m), 3.19 (1H, d, J ) 8.8 Hz), 7.16 (1H, dd, J )
8.4 and 1.5 Hz), 7.30 (1H, d, J ) 8.4 Hz), 7.42 (1H, d, J ) 1.5
Hz), 7.75 (1H, s). 13C NMR (CDCl3, 75 MHz): δ 21.4, 24.3, 25.7,
29.9, 53.4, 55.7, 60.0, 108.3, 113.7, 114.5, 119.3, 122.7, 126.4,
135.8, 136.7. HRMS (70 eV): C15H17N2OBr m/z calcd 304.0575,
found 304.0574.
((-)-3), via routes that proceeded in five steps and 50%
overall yield, eight steps and 61% overall yield, and nine
steps and 51% overall yield, respectively, from 7. The
syntheses feature the use of the Noyori catalytic asym-
metric hydrogen-transfer reaction to introduce the chiral-
ity in dihydro-â-carbolines 6 and 8. The reductions were
performed using the (S,S)-TsDPEN-Ru(II) catalyst,
which, on the basis of the ample precedent from Noyori’s
work, produced chiral dihydro-â-carbolinessand ulti-
mately the natural productsspossessing the R absolute
configuration. The optical rotations of our synthetic
arborescidines were opposite in sign those of the natural
products. Taken together, our results support the S
configuration for natural 1 and 2 as well as the (3S,17S)
configuration for natural 3.
Exp er im en ta l Section
Meth yl 4-[2-(6-Br om o-1H-3-in d olyl)eth ylca r ba m oyl]-
bu ta n oa te (14). Glutaric anhydride (63.5 mg, 0.556 mmol)
was added to a solution of 6-bromotryptamine (7)10 (0.133 g,
0.556 mmol) in CH2Cl2 (5.6 mL) at 0 °C. The mixture was
warmed to room temperature, concentrated in vacuo, and used
without purification in the esterification step. To a solution of
crude acid in dry MeOH (1.0 mL) was added SOCl2 (40.4 µL,
0.556 mmol) at 0 °C. The mixture was stirred for 3 h, then
neutralized with saturated aq NaHCO3, extracted with CH2-
Cl2, dried over MgSO4, and concentrated in vacuo. Purification
by flash chromatography (CHCl3/MeOH, 10%, Rf ) 0.79)
afforded a white solid, which was characterized as 14 in 83%
yield. Mp: 159.7-160.1 °C. 1H NMR (d6-DMSO, 300 MHz): δ
1.73 (2H, quint, J ) 7.3 Hz), 2.08 (2H, t, J ) 7.3 Hz) 2.26 (2H,
t, J ) 7.3 Hz), 2.78 (2H, t, J ) 7.3 Hz), 3.30 (2H, q, J ) 7.3
Hz), 3.57 (3H, s), 7.09 (1H, dd, J ) 8.4 and 0.7 Hz), 7.16 (1H,
br s), 7.47 (1H, d, J ) 1.5 Hz), 7.50 (1H, d, J ) 1.5 Hz), 7.89
(1H, t, J ) 5.5 Hz), 10.94 (1H, s). 13C NMR (d6-DMSO, 75
MHz): δ 20.5, 25.0, 32.7, 34.4, 40.1, 51.2, 112.2, 113.6, 113.8,
119.9, 120.9, 123.6, 126.2, 136.9, 171.1, 172.8. IR (KBr film,
cm-1): 3317, 3186, 3101, 3059, 2951, 2906, 2879, 2854, 1711,
1631, 1545, 1442, 1315, 1201, 791, 678. HRMS (70 eV):
C
16H19N2O3Br m/z calcd 366.0579, found 366.0577.
Meth yl 4-(7-Br om o-4,9-d ih yd r o-3H-â-ca r bolin -1-yl)bu -
N1-[2-(6-br om o-1H-3-in d olyl)eth yl]-5-h exen a m id e (15).
To a solution of 7 (0.284 g, 1.19 mmol) and 5-hexenoic acid
(0.136 g, 1.19 mmol) in CH2Cl2 (12.0 mL) at 0 °C were added
HOBt (0.177 g, 1.31 mmol) and EDC (0.251 g, 1.31 mmol). The
reaction mixture was stirred at room temperature for 10 h,
then washed with 5% aqueous HCl (3 × 15.0 mL), 5% aqueous
NaHCO3 (20.0 mL), H2O (20.0 mL), and brine (20.0 mL), and
dried (Na2SO4). Purification by flash chromatography (CH3-
Cl/MeOH, 10%, Rf ) 0.43) afforded amidoalkene 15 in 99%
ta n oa te (6). Amido ester 14 (0.136 g, 0.371 mmol) in 9.25 mL
of dry benzene and 242 µL of POCl3 was heated to reflux for
2 h, cooled to room temperature, and then concentrated. The
resulting orange viscous oil was purified by chromatography
(CH3Cl/MeOH, 10%, Rf ) 0.30) to afford a yellow solid in 86%
yield, which was characterized as imine 6. Mp: 151.3-152.0
°C. 1H NMR (CDCl3, 300 MHz): δ 1.94-2.06 (2H, m), 2.50 (2H,
t, J ) 6.2 Hz), 2.65 (2H, t, J ) 7.7 Hz), 2.84 (2H, t, J ) 9.1
Hz), 3.77 (3H, s), 3.87 (2H, t, J ) 8.4 Hz) 7.21 (1H, dd, J ) 8.4
and 1.5 Hz), 7.42 (1H, d, J ) 8.4 Hz), 7.60 (1H, d, J ) 1.5 Hz),
10.14 (1H, s). 13C NMR (CDCl3, 75 MHz): δ 19.2, 22.0, 32.7,
35.1, 48.2, 52.1, 115.0, 116.2, 117.5, 120.9, 123.2, 124.2, 128.8,
137.3, 160.3, 175.1. IR (KBr film, cm-1): 3348, 3016, 2924,
2846, 1736, 1620, 1543, 1435, 1365, 1311, 1242, 1041, 802, 756.
1
yield as a brown oil. H NMR (CDCl3, 400 MHz): δ 1.70 (2H,
quint, J ) 7.6 Hz), 2.03 (2H, q, J ) 7.1 Hz), 2.14 (2H, t, J )
7.7 Hz), 2.93 (2H, t, J ) 6.8 Hz), 3.56 (2H, q, J ) 6.5 Hz), 4.96
(1H, d, J ) 10.3 Hz), 4.97 (1H, d, J ) 17.6 Hz), 5.64 (1H, br s),
5.73 (1H, ddt, J ) 17.6, 10.3, and 6.5 Hz), 6.97 (1H, d, J ) 1.3
Hz), 7.19 (1H, dd, J ) 8.4 and 0.9 Hz), 7.43 (1H, d, J ) 8.4
Hz), 7.51 (1H, s), 8.67 (1H, s). 13C NMR (CDCl3, 100 MHz): δ
24.6, 25.2, 33.0, 35.9, 39.7, 112.9, 114.2, 115.3, 115.6, 119.8,
122.6, 122.6, 126.2, 137.1, 137.8, 173.0. IR (KBr film, cm-1):
3288, 3076, 2931, 2861, 1647, 1542, 1456, 1417, 912, 802.
HRMS (70 eV):
348.0474.
C16H17N2O2Br m/z calcd 348.0473, found
(12b R)-10-Br om o-1,2,3,4,6,7,12,12b -oct a h yd r op yr id o-
[2,1-a ]-â-ca r bolin -4-on e (5). A solution of p-TsCl (0.45 g, 2.40
mmol) in 5 mL of dry THF was added to a mixture of (1S,2S)-
(+)-1,2-diphenylethylenediamine (0.50 g, 2.40 mmol) in THF
(20 mL) and triethylamine (1.0 mL) over a period of 30 min at
0 °C. After the resulting solution was stirred for 12 h, the
solvent was removed under reduced pressure. The solid residue
was treated with aqueous saturated NaHCO3 solution (40 mL)
and CH2Cl2 (40 mL). The organic phase was washed with
brine, dried over Na2SO4, and evaporated in vacuo. The crude
product was purified by column chromatography with ethyl
acetate to afford (1S,2S)-1,2-diphenyl-N-(p-tolylsulfonyl)eth-
HRMS (70 eV):
334.0683.
C16H19N2OBr m/z calcd 334.0681, found
7-Br om o-1-(4-p en ten yl)-4,9-d ih yd r o-3H-â-ca r bolin e (8).
A solution of 15 (1.65 g, 4.94 mmol) and 3.21 mL of POCl3 in
123 mL of dry MeCN was heated to reflux for 3 h, cooled to
room temperature, and then concentrated. The resulting
orange viscous oil was purified by flash chromatography (CH3-
Cl/MeOH, 10%, Rf ) 0.71) to afford a yellow oil in 90% yield.
The spectroscopic properties of the product were in accordance
J . Org. Chem, Vol. 69, No. 4, 2004 1287

Santos et al.
1
with imine 8. H NMR (CDCl3, 500 MHz): δ 1.82 (2H, quint,
(3H, s), 4.26 (1H, br d, J ) 13.0 Hz), 5.15 (1H, dd, J ) 8.9 and
4.2 Hz), 7.07 (1H, dd, J ) 8.4 and 1.5 Hz), 7.32 (1H, d, J ) 8.4
Hz), 7.47 (1H, d, J ) 1.5 Hz), 10.83 (1H, s). 13C NMR
(d6-DMSO, 343 K, 100 MHz): δ 20.3, 21.4, 32.9, 33.9, 37.5,
50.9, 51.9, 65.6, 70.7, 106.5, 113.0, 113.3, 118.8, 120.9, 125.2,
135.8, 136.5, 155.4. IR (KBr film, cm-1): 3400, 1679. HRMS
(70 eV): C18H23N2O4Br m/z calcd 410.0841, found 410.0845.
J ) 7.7 Hz), 2.11 (2H, q, J ) 7.1 Hz), 2.70 (2H, t, J ) 7.7 Hz),
2.87 (2H, t, J ) 8.5 Hz), 3.89 (2H, t, J ) 8.5 Hz), 4.91 (1H, dd,
J ) 10.3 and 1.5 Hz), 4.94 (1H, dd, J ) 17.9 and 1.5 Hz), 5.73
(1H, ddt, J ) 17.6, 10.3, and 6.7 Hz), 7.12 (1H, dd, J ) 8.5
and 1.5 Hz), 7.45 (1H, d, J ) 8.5 Hz), 7.52 (1H, d, J ) 1.5 Hz),
9.99 (1H, br s). 13C NMR (CDCl3, 125 MHz): δ 19.2, 26.0, 33.3,
34.7, 47.7, 114.8, 114.9, 115.3, 116.9, 117.7, 121.2, 123.5, 124.3,
Met h yl (1R)-7-Br om o-1-(3-for m ylp r op yl)-2,3,4,9-t et -
r a h yd r o-1H-â-ca r bolin e-2-ca r box yla te (9). A solution of
18 (0.240 g, 0.584 mmol) in 58.4 mL of THF-H2O (1:2) was
treated at 0 °C with a solution of 0.131 g (0.613 mmol) of
sodium metaperiodate (NaIO4) in 6 mL of water. After the
resulting solution was stirred for 1 h at 0 °C, the reaction
mixture was diluted with H2O and extracted with CHCl3. The
CHCl3 extracts were washed with brine, dried, and concen-
trated in vacuo to give aldehyde 9 as a cream-colored solid in
90% yield. Mp: 64-65 °C. Rf ) 0.83 (CHCl3/MeOH, 10%). [R]D
129.2, 137.6, 161.6. HRMS (70 eV):
316.0575, found 316.0554.
C16H17N2Br m/z calcd
(R)-7-Br om o-1-(4-pen ten yl)-2,3,4,9-tetr ah ydr o-1H-â-car -
bolin e (16). The preformed catalyst solution (prepared as
described previously) was added to a mixture of imine 8 (0.750
g, 2.37 mmol) in 24 mL of DMF, followed by a mixture of
HCO2H-Et3N (5:2 v/v, 1.22 mL) at room temperature. After
the resulting solution was stirred at room temperature for 12
h, the DMF was distilled off under a high vacuum, and the
crude purified by flash chromatography (CHCl3/MeOH, 10%,
Rf ) 0.52) to afford 0.726 g (96%) of amine 16 as a brown solid.
1
-47 (c ) 1, CHCl3). H NMR (CDCl3, 500 MHz): δ 1.77-1.92
(4H, m), 2.47-2.52 (2H, m), 2.65 (1H, dd, J ) 15.4 and 3.6
Hz), 2.72-2.84 (1H, m), 3.11-3.22 (1H, m), 3.77 (3H, s), 4.32-
4.49 (1H, m), 5.16-5.30 (1H, m), 7.17 (1H, dd, J ) 8.5 and 1.3
Hz), 7.29 (1H, d, J ) 8.3 Hz), 7.42 (1H, d, J ) 1.3 Hz), 8.43
and 8.75 (1H, br s and br s), 9.69 and 9.76 (1H, br s and br s).
13C NMR (CDCl3, 125 MHz): δ 18.4, 21.0, 33.9, 38.4, 43.3, 51.0,
52.6, 108.2, 113.9, 115.0, 119.2, 122.6, 125.6, 134.7, 136.9,
156.5, 202.4. IR (KBr film, cm-1): 3309, 1699, 1681. HRMS
(70 eV): C17H19N2O3Br m/z calcd 378.0579, found 378.0578.
1
[R]D -21 (c ) 1, CHCl3). H NMR (CDCl3, 500 MHz): δ 1.51-
1.69 (4H, m), 1.70-74 (1H, m), 2.11 (2H, quint, J ) 6.5 Hz),
2.64-2.74 (2H, m), 3.00 (1H, ddd, J ) 12.8, 8.5, and 5.5 Hz),
3.33 (1H, dt, J ) 13.0 and 4.5 Hz), 4.01 (1H, ddd, J ) 8.5, 3.5,
and 2.0 Hz), 4.98 (1H, br dd, J ) 10.0 and 1.5 Hz), 5.03 (1H,
dd, J ) 17 and 1.5 Hz), 5.80 (1H, ddt, J ) 17.0, 13.0, and 10.0
Hz), 7.16 (1H, dd, J ) 8.5 and 1.5 Hz), 7.31 (1H, d, J ) 8.5
Hz), 7.38 (1H, d, J ) 1.5 Hz). 13C NMR (CDCl3, 125 MHz): δ
22.5, 24.9, 33.6, 34.1, 42.3, 52.4, 109.0, 113.6, 114.5, 115.0,
119.12, 122.4, 126.4, 136.4, 136.9, 138.3. HRMS (70 eV):
Meth yl (3a R,7R)-10-Br om o-7-h yd r oxy-1,2,3,3a ,4,5,6,7-
octah ydr oazepin o[1,2,3-lm]-â-car bolin e-3-car boxylate (19).
To a solution of aldehyde 9 (0.185 g, 0.488 mmol) in 0.80 mL
of THF was added aqueous TFA (3.75 mL, 10% v/v in water).
The reaction mixture was stirred for 1 h at room temperature,
treated with saturated aq Na2CO3 (pH 9), and stirred for
another 1 h. The product was extracted with EtOAc (3 × 10
mL), and the combined organic layers were washed with H2O
and brine and dried over Na2SO4. The solvent was removed
and the residue purified by flash chromatography (CHCl3/
MeOH, 10%, Rf ) 0.76) to give 0.176 g (95%) of 19 as a colorless
C
16H19N2Br m/z calcd 318.0732, found 318.0730.
(R)-Meth yl 7-Br om o-1-(4-p en ten yl)-2,3,4,9-tetr a h yd r o-
1H-â-ca r bolin e-2-ca r boxyla te (17). To a cold solution of
amine 16 (1.81 g, 5.67 mmol) and triethylamine (0.861 g, 8.50
mmol) in dry CH2Cl2 (94.0 mL) kept at 0 °C was added
dropwise a solution of methyl chloroformate (1.07 g, 11.3 mmol)
in CH2Cl2 (10 mL). After 1 h, the reaction mixture was diluted
with water (60.0 mL), followed by saturated aq NH4Cl solution
(100 mL) and extracted with CH2Cl2. The organic layers were
washed with saturated aq NaHCO3 solution (100 mL) and
water (100 mL) and dried. The solvent was removed and the
residue purified by flash chromatography (CHCl3/MeOH, 2.5%,
Rf ) 0.51) to give 2.12 g (99%) of 17 as a brown solid. [R]D
1
oil. [R]D -25 (c ) 1, CHCl3). H NMR (d6-DMSO, 343 K, 400
MHz): δ 1.69-1.82 (3H, m), 1.92-1.98 (1H, m), 2.20-2.25 (2H,
m), 2.62-2.70 (2H, m), 3.06 (1H, ddd, J ) 12.8, 11.2, and 4.79
Hz), 3.69 (3H, s), 4.30 (1H, dd, J ) 12.6 and 3.0 Hz), 5.30 (1H,
d, 10.9), 6.17 (1H, d, J ) 4.2 Hz), 6.29 (1H, br s, OH), 7.12
(1H, dd, J ) 8.4 and 1.4 Hz), 7.34 (1H, d, J ) 8.4 Hz), 7.70
(1H, br s). 13C NMR (d6-DMSO, 343 K, 100 MHz): δ 18.9, 20.7,
32.8, 33.8, 38.1, 51.8, 75.1, 78.7, 107.6, 112.1, 113.5, 118.9,
121.2, 124.4, 136.2, 136.4, 154.6. IR (KBr film, cm-1): 3380,
1678. HRMS (70 eV): C17H19N2O3Br m/z calcd 378.0579, found
378.0782.
1
-3.9 (c ) 1, CHCl3). Mp: 62-63 °C. H NMR (d6-DMSO, 343
K, 400 MHz): δ 1.45-1.55 (2H, m), 1.73-1.82 (1H, m), 1.89-
1.91 (1H, m), 2.09 (2H, quint, J ) 5.9 Hz), 2.64 (1H, dd, J )
5.9 and 2.2 Hz), 2.63-2.67 (1H, m), 3.16 (1H, ddd, J ) 12.8,
10.2, and 6.6 Hz), 3.66 (3H, s), 4.25 (1H, dd, J ) 15.2 and 3.2
Hz), 4.96 (1H, dd, J ) 10.3 and 1.5 Hz), 5.02 (1H, dd, J ) 17.1
and 1.5 Hz), 5.16 (1H, dd, J ) 9.2 and 4.1 Hz), 5.82 (1H, ddt,
J ) 17.1, 10.3, and 6.7 Hz), 7.07 (1H, dd, J ) 8.4 and 1.5 Hz),
7.31 (1H, d, J ) 8.4 Hz), 7.48 (1H, d, J ) 1.5 Hz), 10.83 (1H,
s). 13C NMR (d6-DMSO, 343 K, 100 MHz): δ 20.3, 24.6, 32.5,
33.4, 37.5, 50.7, 51.9, 106.6, 113.1, 113.3, 114.3, 118.8, 121.0,
125.2, 135.6, 136.6, 138.1, 155.4. IR (KBr film, cm-1): 3306,
1680. HRMS (70 eV): C18H21N2O2Br m/z calcd 376.0786, found
376.0788.
(-)-Ar bor escid in e C ((-)-3). To a solution of 19 (0.097 g,
0.256 mmol) in dry THF (4.3 mL) was added a solution of AlH3
in THF (1.55 M, 0.330 mL, 0.512 mmol)15 at room temperature.
After 10 min, the reaction was quenched with saturated aq
sodium sulfate solution and filtered. The solids were washed
with CH2Cl2 (50 mL), and the filtrate was dried with Na2SO4,
evaporated, and concentrated in vacuo. Purification of the
residue by column chromatography (elution with 10% CHCl3/
MeOH, Rf ) 0.4) afforded a white solid in 96% yield, which
was characterized as arborescidine C, in full accordance with
the reported data.2 Mp: 171-172 °C. [R]D -3.1 (c ) 1, CHCl3).
1H NMR (CDCl3, 500 MHz): δ 1.33 (1H, q dist, J ) 15.6 Hz),
1.52 (1H, t, J ) 16.6 Hz), 1.73 (1H, br d, J ) 16.6 Hz), 2.07
(1H, q, J ) 15.8 Hz), 2.13 (1H, d, J ) 14.5 Hz), 2.23 (1H, br d,
J ) 16.7 Hz), 2.37 (3H, s), 2.60-2.70 (3H, m), 2.89 (1H, dd, J
) 13.3 and 5.9 Hz), 3.55 (1H, d, J ) 13.9 Hz), 6.00 (1H, d, J
) 2.9 Hz), 7.14 (1H, d, J ) 10.2 Hz), 7.22 (1H, d, J ) 10.2 Hz),
7.41 (1H, s). 13C NMR (CDCl3, 125 MHz): δ 20.3, 20.5, 31.5,
34.5, 42.8, 50.2, 61.1, 76.8, 108.9, 111.9, 114.9, 119.7, 122.6,
125.8, 137.1, 138.5. HRMS (70 eV): C16H19N2OBr m/z calcd
334.0681, found: 334.0733.
Meth yl (1R,4′R)- a n d (1R,4′S)-7-Br om o-1-(4′,5′-d ih y-
dr oxypen tyl)-2,3,4,9-tetr ah ydr o-1H-â-car bolin e-2-car box-
yla tes (18). Osmium tetroxide (67.0 µL of a freshly prepared
0.039 M solution in t-BuOH) was added to a solution of 17
(0.283 g, 0.775 mmol) and N-methylmorpholine N-oxide (0.256
mL, 50% v/v in water) in a 9:1 THF-H2O solution (9.70 mL)
at 0 °C. After 12 h at room temperature, the mixture was
treated with Florisil (0.350 g) and NaHSO3 (0.111 g), stirred
for 1 h, filtered, and concentrated. The residue was diluted
with EtOAc, and the organic layer was washed with 5% H3-
PO4 and brine, dried, and concentrated. Purification by flash
chromatography (CH3Cl/MeOH, 10%, Rf ) 0.45) gave a mix-
ture of diols 18 (0.280 g, 88%). 1H NMR (d6-DMSO, 343 K,
400 MHz): δ 1.37-1.55 (4H, m), 1.77-1.98 (2H, m), 2.65 (2H,
dd, J ) 8.9 and 3.3 Hz), 3.17 (1H, dt, J ) 13.0 and 7.9 Hz),
3.29 (2H, dd, J ) 5.5, and 1.1 Hz), 3.41-3.48 (1H, m), 3.65
(-)-Ar bor escid in e B ((-)-2). A solution of arborescidine
C (0.030 g, 0.0896 mmol) and Burgess reagent (0.043 g, 0.179
1288 J . Org. Chem., Vol. 69, No. 4, 2004

Total Syntheses of Arborescidines A-C
mmol) in dry benzene (9.0 mL) was heated to reflux for 8 h
under nitrogen atmosphere. The reaction solution was cooled,
diluted with EtOAc (9.0 mL), washed with brine (4 × 9.0 mL),
dried, and evaporated. Column chromatography of the residue
over silica gel (10% CHCl3/MeOH, Rf ) 0.64) gave arboresci-
dine B (2) as a colorless oil in 84% yield. [R]D -71 (c ) 0.6,
136.9. IR (KBr film, cm-1): 1674. HRMS (70 eV): C16H17N2Br
m/z calcd 316.0575, found 316.0539.
Ack n ow led gm en t. Financial support from Fapesp
(R.A.P. and L.S.S.) and CNPq (R.A.P.) are gratefully
acknowledged. V.H.R. thanks the NIH for partial sup-
port of L.S.S.’s research activity at The University of
Chicago.
1
CHCl3). H NMR (CDCl3, 500 MHz): δ 1.86 (1H, dq, J ) 10.0
and 4.3 Hz), 2.35-2.36 (1H, m), 2.40-2.44 (1H, m), 2.49-2.57
(1H, m), 2.54 (3H, s), 2.68 (1H, dd, J ) 12.4 and 4.1 Hz), 2.70
(1H, dd, J ) 11.2 and 3.9 Hz), 2.89 (1H, dddd, J ) 15.0, 11.2,
2.6, and 2.4 Hz), 3.12 (1H, ddd, J ) 15.0, 11.2, and 2.4 Hz),
3.36 (1H, d, J ) 10.0 Hz), 5.09 (1H, dt, J ) 9.8 and 4.1 Hz),
6.81 (1H, dt, J ) 9.8 and 1.8 Hz), 7.21 (1H, dd, J ) 9.8 and
1.5 Hz), 7.31 (1H, br d, J ) 9.8 Hz), 7.47 (1H, d, J ) 1.5 Hz).
13C NMR (CDCl3, 125 MHz): δ 20.6, 27.9, 29.8, 42.4, 52.6, 62.3,
76.8, 109.3, 111.2, 112.3, 115.2, 119.3, 121.6, 123.2, 125.8,
Su p p or tin g In for m a tion Ava ila ble: Copies of the 1H and
3C NMR spectra of compounds 1, 2, 3, 5, 6, 8, 17, and 19 (PDF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O035165F
J . Org. Chem, Vol. 69, No. 4, 2004 1289