First total syntheses of dihydroflustramine C and flustramine E, alkaloids from the marine bryozoan Flustra foliacea

Article abstract of DOI:10.1016/S0040-4020(02)00011-X

We have developed a simple and practical method for providing the common tricyclic skeleton of physostigmine type alkaloids, and demonstrated its utility for indole alkaloid synthesis. Thus, we achieved the first total syntheses of (±)-dihydroflustramine C and (±)-flustramine E, as well as the total syntheses of their debromoanalogues from the corresponding 2-hydroxyindolenines in five steps with 31, 27, 39 and 23% overall yields, respectively. The structures of some intermediates were confirmed by single crystal X-ray diffraction analyses.

Full text of DOI:10.1016/S0040-4020(02)00011-X

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 1479±1484
First total syntheses of dihydro¯ustramine C and ¯ustramine E,
alkaloids from the marine bryozoan Flustra foliacea
p
 Â
Martha S. Morales-Rõos, Oscar R. Suarez-Castillo and Pedro Joseph-Nathan
  Â
Departamento de Quõmica del Centro de Investigacion y de Estudios Avanzados, Instituto Politecnico Nacional, Apartado 14-740,
 Â
Mexico, D.F., 07000 Mexico
Received 3 December 2001; accepted 18 December 2001
AbstractÐWe have developed a simple and practical method for providing the common tricyclic skeleton of physostigmine type alkaloids,
and demonstrated its utility for indole alkaloid synthesis. Thus, we achieved the ®rst total syntheses of (^)-dihydro¯ustramine C and
(^)-¯ustramine E, as well as the total syntheses of their debromoanalogues from the corresponding 2-hydroxyindolenines in ®ve steps with
31, 27, 39 and 23% overall yields, respectively. The structures of some intermediates were con®rmed by single crystal X-ray diffraction
analyses. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
We report herein the ®rst total syntheses of dihydro¯ustra-
mine C (1) and ¯ustramine E (2), and the total syntheses of
their debrominated analogues 3 and 4 (Fig. 1) by applying a
highly ef®cient version of the synthetic methodology that
we ®rstly employed for the total syntheses of ¯ustramines A
(5) and B (6), ¯ustramides A (7) and B (8) and debromo-
¯ustramine B (9),8 as well as for the formal total syntheses
of physostigmine (10) and physovenine (11)9 (Fig. 2). It is
remarkable to point out that this synthetic strategy requires
only minor variation to be adapted for the synthesis of this
class of compounds, which differ mainly for variation in
appendages. To achieve this aim, the corresponding
2-hydroxyindolenines 12a or 12b were converted to the
key tricyclic precursor(s) 13a and 14a or 13b and 14b in a
combined yield of 76% (53:47 ratio) or 77% (61:39 ratio),
respectively, via a one step Grignard alkylation and
lactonization.8 The 2-oxofuroindolines thus obtained can
be easily decyanated10 by reacting with wet alumina to
In recent years, a number of brominated indole alkaloids
were isolated frombryozoans of the family Flustridae
(Flustra foliacea). Among these, the marine alkaloids
dihydro¯ustramine C (1) and ¯ustramine E (2) were isolated
from F. foliacea collected in the Minas Basin, Nova Scotia1
and in the North Sea,2 respectively. These alkaloids have
proven to show antibacterial activity against Bacillus
subtilis, Botrytis cinerea, Rhizotonia solani, Enterobacter
cloacea, Escherichia coli, Klebsiella pneumoniae, Proteus
vulgaris,
Pseudomonas
aeruginosa,
Salmonella
tryphimurium, Serratia marcescens, Staphylococcus
aureus, and Staphylococcus epidermidis.1,2 While
possessing the physostigmine skeleton,3 dihydro¯ustramine
C (1) contains an inverted prenyl unity at the 3a position
instead of the prenyl group of ¯ustramine E (2). Although to
date no published syntheses for these alkaloids exist, for
their debromoanalogues few are reported. Thus, the
synthesis of debromodihydro¯ustramine C (3) has been
performed via a thio-Claisen type rearrangement strategy
4
froma sulphoniumcation of 2-methylthioindole derivative.
An alternative approach to 3 has been reported by reduction
of the marine alkaloid ¯ustramine C.5 For debromo¯ustra-
mine E (4), two syntheses have been recently described
involving either a Claisen type rearrangement as the key
step of 2-allyloxy-3-(2-nitrovinyl)indole,6 or via a C-3
alkylation±cyclization of the methylamide of indole-3-
acetic acid as the key reaction.7
Keywords: dihydro¯ustramine C; ¯ustramine E; indole alkaloids; total
synthesis.
p
Corresponding author. Tel.: (152)-55 5747-7112; fax: (152)-55 5747-
7137; e-mail: pjoseph@nathan.chem.cinvestav.mx
Figure 1.
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00011-X

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M. S. Morales-Rõos et al. / Tetrahedron 58 (2002) 1479±1484
1480
Figure 2. Versatile intermediate 12, for the synthesis of physostigmine type
alkaloids.
give the intermediates 15a, 16a, 15b, and 16b in 89, 83, 95
and 86% yield, respectively (Scheme 1).
2. Results and discussion
Scheme 1. Key synthetic strategy of precursors 15a, 15b, 16a and 16b.
Compounds 14a and 14b are anti±syn mixtures.
The structure and relative stereochemistry of the tricyclic
precursors 13a, 13b and 14b were unambiguously deter-
mined by X-ray crystallography, namely 13a and 13b
were 3Sp, 3aSp, 8aRp and 14b was 3Sp, 3aRp, 8aRp (Fig.
3). These structures are characterized by a folded shape
along the C-3a±C-8a bond, with the CN group at C-3 and
the corresponding alkyl group at C-3a arranged in an anti
relationship with each other. In DMSO-d6 solution,11 the 1H
NMR spectra of 13a and 13b indicate that these compounds
exist as single isomers with the CN group and the 1,1-
dimethylallyl group at C-3a in an anti orientation, whereas
for 14b, the populations of the anti±syn isomers were found
by 1H NMR to be in an equilibrated 12:1 ratio. NOE experi-
ments on 14b support the stereochemical preference, since
irradiation of the signal centered at d 2.64 ppm(methylene
protons of the prenyl group) enhances the signals at d 7.58
(H-4), d 6.42 (H-8a) and d 5.18 ppm(exchangeable H-3) by
5, 16, and 17%, respectively.
to be used in the next step, without recourse to chromato-
graphic procedures. The latter was inferred fromthe 1H
NMR spectra of the respective crude reaction mixtures.
The kind of solvent used for NMR measurements has an
important effect on the speed of decomposition. DMSO-d6
and CDCl3 lead to fast decomposition, whereas in CD3OD
1
this effect is slower. Thus, the H NMR spectrumof 18a
measured in CD3OD allows to observe two singlets at d 1.09
and 0.97 ppmof the allylic methyl groups, the AB pattern of
the carboxymethylenic protons appears at d 3.16 and
2.76 ppm(geminal coupling constant of 17.9 Hz). In
addition, the H-8a signal and the aromatic protons H-7
and H-5 ortho and para to the NH, respectively, are shifted
high®eld to d 5.98, 6.67 and 6.78 ppmwith respect to the
same protons of 16a (dDMSO-d6 6.29, 7.67 and 7.13 ppm,
respectively).8b
Since lactones 17a, 17b, 18a and 18b proved to decompose
slowly on standing at roomtepmerature they were
immediately transformed to the corresponding lactams
19a, 19b, 20a and 20b, respectively, by reaction with
methylamine in MeOH at room temperature, in nearly
quantitative yields for the two steps (Scheme 2). A readily
After decyanation, the starting N-protected 2-oxofuroindo-
lines 15a, 15b, 16a and 16b were converted into deprotected
analogues 17a, 17b, 18a and 18b, respectively, by cleavage
of the indoline ester group with MeONa/MeOH at re¯ux.
The resulting unstable lactones were isolated pure-enough

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M. S. Morales-Rõos et al. / Tetrahedron 58 (2002) 1479±1484
1481
Scheme 2. Synthesis of dihydro¯ustramine E and their debrominated ana-
logues (1-4). (a) MeONa/MeOH. (b) MeNH2/MeOH. (c) 19a and 20a:
EtN(Me)2´AlH3/THF. (d) 19b and 20b: LiAlH4/THF.
recognizable characteristic feature in all lactams is the
observation of three-bond HMBC correlations between the
N-Me signal at dH 2.6 with the carbon signals at dC 171
(C-2) and 79±81 (C-8a) ppm. Other 13C NMR signals also
matched literature data.12
The ®nal reduction of 19a and 20a turned out to be some-
what delicate due to the inherent lability of the aromatic
bromides toward the non-selective nature of LiAlH4.13
Thus, conversion of brominated lactams 19a and 20a into
the corresponding natural products 1 and 2 was therefore
accomplished by treatment with alane-N,N-dimethylethyl-
amine complex at room temperature for 45 min in excellent
yields (90 and 93%, respectively). This completes the total
synthesis of dihydro¯ustramine C (1) and ¯ustramine E (2).
The spectral properties of 1 and 2 are identical (IR, EIMS,
1H and 13C NMR) to those reported for the marine natural
products dihydro¯ustramine C1 and ¯ustramine E,2 except
for the optical activity.
The analogues debrominated lactams 19b and 20b7 were
reduced with LiAlH4 in re¯uxing THF to give debromo-
dihydro¯ustramine C (3) and debromo¯ustramine E (4) in
90 and 92% yield, respectively. The spectral properties of 3
1
and 4 are identical (IR, EIMS, H and 13C NMR) to those
reported for the unnatural products.4±7
3. Conclusions
Figure 3. X-Ray structures of 13a (top), 13b (center), and 14b (bottom).
In summary, as an extension of our ongoing work on the

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M. S. Morales-Rõos et al. / Tetrahedron 58 (2002) 1479±1484
1482
total synthesis of indole alkaloids, we have now exploited
the application of the convertible 2-hydroxyindolenine
approach in order to synthesize dihydro¯ustramine C (1)
and ¯ustramine E (2) alkaloids frommarine bryozoan F.
foliacea.
as described above for 19a. Extractive workup and puri®ca-
tion by ¯ash column chromatography (1:1 EtOAc/hexane)
gave lactam 19b as colorless crystals (148 mg, 97%); mp
167±1688C (EtOAc/hexane); Rf 0.40 (EtOAc). IR (CHCl3)
n
max 3428, 3006, 1674, 1606, 1484 cm21; 1H NMR (DMSO-
d6) d 7.09 (1H, d, Jˆ7.4 Hz, H-4), 7.02 (1H, td, Jˆ7.6,
1.3 Hz, H-6), 6.67 (1H, d, Jˆ2.5 Hz, N-H), 6.64 (1H, td,
Jˆ7.4, 1.1 Hz, H-5), 6.54 (1H, d, Jˆ7.8 Hz, H-7), 5.97 (1H,
dd, Jˆ17.3, 10.9 Hz, H-12), 5.10 (1H, dd, Jˆ10.8, 1.4 Hz,
H-13), 5.08 (1H, d, Jˆ2.1 Hz, H-8a), 5.03 (1H, dd, Jˆ17.3,
1.4 Hz, H-130), 2.76 and 2.37 (1H each, AB, Jˆ17.3 Hz,
H-3, H-30), 2.67 (3H, s, N-Me), 0.99 and 0.89 (3H
each, both s, Me-10 and Me-11); 13C NMR (DMSO-
d6) d 171.2 (s, CvO), 149.5 (s, C-7a), 144.2 (d,
C-12), 132.1 (s, C-3b), 128.4 (d, C-6), 125.1 (d, C-4),
117.7 (d, C-5), 113.9 (t, C-13), 109.4 (d, C-7), 79.0 (d,
C-8a), 56.1 (s, C-3a), 40.8 (s, C-9), 39.3 (t, C-3), 26.0
(q, N-Me), 22.3 and 21.7 (both q, Me-10 and Me-11);
EIMS m/z (relative intensity) 256 (M1, 19), 187 (92),
130 (100); HRMS (FAB) m/z 257.1649 (MH1,
C16H20N2O requires 257.1654).
4. Experimental
4.1. General experimental procedures
Melting points were uncorrected. IR spectra were recorded
on a Perkin Elmer 16F PC FT spectrophotometer. H and
1
13C NMR spectra were measured on Varian XL-300GS and
Mercury spectrometers working at 300 and 75 MHz, respec-
tively. Chemical shifts are reported in ppm down®eld from
tetramethylsilane. EIMS were obtained on Hewlett Packard
5989A or Varian Saturn 2000 mass spectrometers. HRMS
were measured on a Jeol JMS-SX 102A spectrometer.
Analytical thin-layer chromatography was performed on
silica gel F254 coated aluminium sheets. Flash chromato-
graphy was performed using silica gel 60 (230±400 mesh)
fromAldrich.
4.1.3. 6-Bromo-1-methyl-3a-(3-methyl-2-buten-1-yl)-2-
oxo-2,3,3a,8a-tetrahydro-8H-pyrrolo[2,3-b]indole (20a).
This compound was prepared from 16a (230 mg,
0.60 mmol) as described above for 19a. Extractive workup
and puri®cation by ¯ash column chromatography (1:1
EtOAc/hexane) gave lactam 20a as colorless crystals
(197 mg, 98%): mp 168±1698C (Et2O); Rf 0.12 (1:1
EtOAc/hexane). IR (CHCl3) nmax 3432, 3018, 1682, 1600,
1482 cm21; 1H NMR (DMSO-d6) d 7.02 (1H, d, Jˆ7.8 Hz,
H-4), 7.02 (1H, br d, Jˆ1.2 Hz, N-H), 6.75 (1H, dd, Jˆ7.9,
1.8 Hz, H-5), 6.66 (1H, d, Jˆ1.8 Hz, H-7), 5.07 (1H, br t,
Jˆ7.3 Hz, H-10), 4.93 (1H, d, Jˆ1.7 Hz, H-8a), 2.67 (3H, s,
N-Me), 2.57 and 2.46 (1H each, AB, Jˆ17.0 Hz, H-3, H-30),
2.35 (1H, dd, Jˆ14.6, 8.1 Hz, H-9), 2.29 (1H, dd, Jˆ14.6,
6.7 Hz, H-90), 1.65 (3H, s, Me-12), 1.49 (3H, s, Me-13); 13C
NMR (DMSO-d6) d 171.3 (s, CvO), 150.4 (s, C-7a), 134.4
(s, C-11), 133.7 (s, C-3b), 125.2 (d, C-4), 120.9 (s, C-6),
120.1 (d, C-5), 118.8 (d, C-10), 111.3 (d, C-7), 81.3 (d,
C-8a), 49.6 (s, C-3a), 41.1 (t, C-3), 35.8 (t, C-9), 26.2 (q,
N-Me), 25.7 (q, Me-12), 17.8 (q, Me-13); EIMS m/z
(relative intensity) 334/336 (M1, 28/29), 265/267 (100/
94), 208/210 (91/91); HRMS (FAB) m/z 335.0773 (MH1,
C16H19BrN2O requires 335.0759).
4.1.1. 6-Bromo-1-methyl-3a-(2-methyl-3-buten-2-yl)-2-
oxo-2,3,3a,8a-tetrahydro-8H-pyrrolo[2,3-b]indole (19a).
To a solution of the lactone 15a (230 mg, 0.60 mmol) in
MeOH (15 mL) at 08C was added NaH (1.20 mmol). The
mixture was heated at re¯ux for 2 h, and the volatiles were
evaporated. The residue was dissolved in EtOAc (100 mL)
and saturated aqueous NH4Cl (5 mL). The organic phase
was washed with brine (3£20 mL), and the combined
aqueous phases were extracted with EtOAc (3£20 mL).
The combined organic layers were dried over Na2SO4 and
evaporated to give 17a which was used without puri®cation.
To the crude compound 17a in MeOH (10 mL) was added
MeNH2 (3 mL of a 2.0 M solution in MeOH, 6 mmol), the
reaction mixture was stirred for 20 h at room temperature,
the volatiles were evaporated, and the resultant crude
product was puri®ed by silica gel ¯ash column chromato-
graphy (1:1 EtOAc/hexane) to give lactam 19a as colorless
solid (193 mg, 96%): mp 199±2018C (Et2O/hexane); Rf 0.16
(1:1 EtOAc/hexane). IR (CHCl3) nmax 3432, 3008, 1682,
1
1598, 1482 cm21; H NMR (DMSO-d6) d 7.02 (1H, br s,
N-H), 7.01 (1H, d, Jˆ7.8 Hz, H-4), 6.75 (1H, dd, Jˆ8.0,
1.8 Hz, H-5), 6.65 (1H, d, Jˆ1.8 Hz, H-7), 5.93 (1H, dd,
Jˆ17.3, 10.9 Hz, H-12), 5.11 (1H, d, Jˆ1.7 Hz, H-8a), 5.07
(1H, dd, Jˆ10.9, 1.4 Hz, H-13), 5.01 (1H, dd, Jˆ17.3,
1.4 Hz, H-130), 2.75 and 2.35 (1H each, AB, Jˆ17.3 Hz,
H-3, H-30), 2.66 (3H, s, N-Me), 0.96 and 0.89 (3H each,
both s, Me-10 and Me-11); 13C NMR (DMSO-d6) d 170.9
(s, CvO), 151.3 (s, C-7a), 143.8 (d, C-12), 131.5 (s, C-3b),
126.8 (d, C-4), 121.2 (s, C-6), 119.7 (d, C-5), 114.1 (t,
C-13), 111.4 (d, C-7), 79.1 (d, C-8a), 55.7 (s, C-3a), 40.7
(s, C-9), 39.0 (t, C-3), 26.0 (q, N-Me), 22.3 and 21.5 (both q,
Me-10 and Me-11); EIMS m/z (relative intensity) 334/336
(M1, 11/11), 265/267 (100/96), 208/210 (82/79); HRMS
(FAB) m/z 335.0770 (MH1, C16H19BrN2O requires
335.0759).
4.1.4. 1-Methyl-3a-(3-methyl-2-buten-1-yl)-2-oxo-2,3,3a,
8a-tetrahydro-8H-pyrrolo[2,3-b]indole, debromo¯ustra-
mide E (20b). This compound was prepared from 16b
(180 mg, 0.60 mmol) as described above for 19a. Extractive
workup and puri®cation by ¯ash column chromatography
(1:1 EtOAc/hexane) gave lactam 20b (150 mg, 98%) as
colorless oil (lit.7 yellow oil); Rf 0.38 (EtOAc). IR 3428,
3008, 1682, 1608, 1484 cm21 1H NMR (DMSO-d6) d
;
7.08 (1H, d, 7.4 Hz, H-4), 6.99 (1H, td, Jˆ7.6, 1.3 Hz,
H-6), 6.69 (1H, br d, Jˆ1.7 Hz, N-H), 6.63 (1H, td,
Jˆ7.4, 1.0 Hz, H-5), 6.54 (1H, d, Jˆ7.6 Hz, H-7), 5.09
(1H, br t, Jˆ6.6 Hz, H-10), 4.90 (1H, d, Jˆ2.1 Hz, H-8a),
2.67 (3H, s N-Me), 2.57 and 2.46 (1H each, AB, Jˆ16.9 Hz,
H-3 and H-30), 2.36 (1H, dd, Jˆ14.2, 7.5 Hz, H-9), 2.29
(1H, dd, Jˆ14.2, 6.3 Hz, H-90), 1.65 (3H, s, Me-12), 1.50
(3H, s, Me-13); 13C NMR (DMSO-d6) d 171.4 (s, C-2),
148.5 (s, C-7a), 134.4 (s, C-3b), 134.1 (s, C-11), 128.1 (d,
4.1.2. 1-Methyl-3a-(2-methyl-3-buten-2-yl)-2-oxo-2,3,3a,
8a-tetrahydro-8H-pyrrolo[2,3-b]indole
compound was prepared from 15b (180 mg, 0.60 mmol)
(19b).
This

Â
M. S. Morales-Rõos et al. / Tetrahedron 58 (2002) 1479±1484
1483
1
C-6), 123.4 (d, C-4), 119.2 (d, C-10), 118.0 (d, C-5), 109.2
(d, C-7), 81.1 (d, C-8a), 50.1 (s, C-3a), 41.3 (t, C-3), 36.0 (t,
C-9), 26.2 (q, N-Me), 25.7 (q, Me-12), 17.8 (q, Me-13);
EIMS m/z (relative intensity) 256 (M1, 81), 187 (100),
130 (98); HRMS (FAB) m/z 257.1653 (MH1, C16H20N2O
requires 257.1654).
(MH1, C16H22N2 requires 243.1861). The IR, EIMS, H
and 13C NMR spectral data were identical to those of the
known sample.7
4.2. X-Ray structure determination of 13a
X-Ray data for 13a were collected on a Bruker Smart 6000
CCD diffractometer. Single crystals of 13a were grown
fromhexane±CH 2Cl2. A total of 1321 frames were collected
at a scan width of 0.38 and an exposure time of 10 s/frame.
The frames were processed with the SAINT software pack-
age, provided by the diffractometer manufacturer, by using a
narrow-frame integration algorithm, and the structure was
solved and re®ned by using SHELX97. An empirical
absorption correction was applied. Pertinent crystal data,
collection and re®nement parameters are given in Table 1.
The CCDC deposition number is 176720.
4.1.5. 6-Bromo-1-methyl-3a-(2-methyl-3-buten-2-yl)-1,2,
3,3a,8,8a-hexahydropyrrolo[2,3-b]indole, dihydro¯us-
tramine C (1). To a stirred solution of 19a (64 mg,
0.19 mmol) in 10 mL of dry THF was added alane-N,N-
dimethylethylamine complex (0.6 mL of a 0.5 M solution
in toluene, 0.3 mmol) and the reaction mixture was stirred
for 45 min at ambient temperature. The reaction was
quenched by adding slowly a mixture of THF±H2O (1:1,
10 mL) followed by EtOAc (70 mL). The insoluble part was
removed by ®ltration and washed with EtOAc (3£10 mL).
The combined organic phases were washed with brine, dried
over Na2SO4 and evaporated to afford the crude alkaloid 1,
which was puri®ed by ¯ash chromatography on silica gel
(EtOAc). Colorless solid (56 mg, 90%): mp 82±848C (lit.1a
mp 82±848C); Rf 0.29 (1:9 MeOH/CHCl3); HRMS (FAB)
m/z 321.0958 (MH1, C16H21BrN2 requires 321.0966). The
Table 1. X-Ray data collection and processing parameters for 13a, 13b and
14b
Compound
13a
13b
14b
Formula
Size (mm3)
Crystal systemMonoclinic
C18H17BrN2O4
C18H18N2O4
C18H18N2O4
0.34£0.10£0.05 0.20£0.08£0.40 0.30£0.12£0.50
Triclinic Triclinic
P1 (bar) P1 (bar)
1
IR, EIMS, H and 13C NMR spectral data were identical to
those of the known sample.1a
Space group
Ê
P21/n
a (A)
Ê
13.0749(5)
9.2227(3)
15.5121(6)
90.000
112.410(1)
90.000
1729.28
1.56
4
7.761(2)
13.092(2)
8.180(1)
87.843(8)
90.453(8)
84.673(9)
826.96
1.31
8.946(2)
9.733(2)
11.055(2)
77.58(1)
77.53(1)
64.19(1)
838.01
1.29
b (A)
Ê
c (A)
4.1.6. 6-Bromo-1-methyl-3a-(3-methyl-2-buten-1-yl)-1,2,
3,3a,8,8a-hexahydropyrrolo[2,3-b]indole, ¯ustramine E
(2). This compound was prepared from 20a (64 mg,
0.19 mmol) in a similar manner to that described previously
for 1. Extractive workup and puri®cation by ¯ash column
chromatography (EtOAc) gave 2 as colorless solid (58 mg,
93%): mp 82±858C (on standing) (lit.2 brown oil); Rf 0.28
(1:9 MeOH/CHCl3); HRMS (FAB) m/z 321.0956 (MH1,
a (8)
b (8)
g (8)
Ê 3
V (A )
Dcalcd (g cm23
Z-value
)
2
2
m (mm21
T (K)
)
2.4(Mo Ka)
293
0.73(Cu Ka)
298
0.76(Cu Ka)
298
2urange (8) 3.48±46.56
Total re¯ections 8813
Unique re¯ections 2492
3±110
2313
2078
3±110
2332
2117
1
C16H21BrN2 requires 321.0966). The IR, EIMS, H and
13C NMR spectral data were identical to those of the
known sample.2
Rint (%)
4.0
1859
229
3.2, 7.3
0.36
1.1
1863
217
4.6, 5.8
0.35
8.0
1930
217
5.4, 6.9
0.35
I$3s(I)
Parameters
R (%), Rw (%)
4.1.7. 1-Methyl-3a-(2-methyl-3-buten-2-yl)-1,2,3,3a,8,8a-
hexahydropyrrolo[2,3-b]indole, debromodihydro¯ustra-
mine C (3). To a stirred suspension of LAH (2.5 mmol in
10 mL of dry THF) was added lactam 19b (84 mg,
0.31 mmol) in THF (5 mL), and the mixture was heated at
re¯ux for 3 h. After the mixture was cooled to 08C, the
reaction was quenched by adding dropwise EtOAc
(120 mL), washed with brine, dried over Na2SO4, and
evaporated. The resultant crude tetrahydropyrrole 3 was
puri®ed by silica gel ¯ash column chromatography
(EtOAc) to give colorless solid (68 mg, 90%): mp 57±
598C (on standing) (lit.4 colorless oil); Rf 0.17 (1:9
MeOH/CHCl3); HRMS (FAB) m/z 243.1855 (MH1,
Ê 23
max (eA )
r
4.3. X-Ray structure determination of 13b and 14b
X-Ray data for 13b and 14b were collected on a Nicloet
R3mdiffractometer. Single crystals of 13b and 14b were
grown fromhexane±Et 2O and Et2O solutions, respectively.
The measured data were corrected for Lorentz and polariza-
tion effects and for absortion. The structures were solved by
direct methods using SHELX86. For the structural re®ne-
ment, the non-hydrogen atoms were treated anisotropically,
and the hydrogen atoms, included in the structure factor
calculation, were re®ned isotropically. Crystal data, collec-
tion and re®nement parameters are given in Table 1. The
CCDC deposition numbers are 176719 and 176716,
respectively.
1
C16H22N2 requires 243.1861). The IR, EIMS, H and 13C
NMR spectral data were identical to those of the known
sample.4
4.1.8. 1-Methyl-3a-(3-methyl-2-buten-1-yl)-1,2,3,3a,8,8a-
hexahydropyrrolo[2,3-b]indole, debromo¯ustramine E
(4). This compound was prepared from 20b (84 mg,
0.31 mmol) in a similar manner to that described previously
for 3. Extractive workup and puri®cation by ¯ash column
chromatography (EtOAc) gave 4 as colorless solid (69 mg,
92%): mp 57±598C (on standing) (lit.6 mp 57±598C); Rf
0.27 (1:9 MeOH/CHCl3); HRMS (FAB) m/z 243.1864
Acknowledgements
This research was partially supported by CONAYT
(Mexico). The authors thank I. Q. Luis Velasco Ibarra
Â
(Instituto de Quõmica, UNAM) for recording HRMS.

Â
M. S. Morales-Rõos et al. / Tetrahedron 58 (2002) 1479±1484
1484
 Â
8. (a) Morales-Rõos, M. S.; Suarez-Castillo, O. R.; Joseph-
Â
Nathan, P. J. Org. Chem. 1999, 64, 1086. (b) Morales-Rõos,
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