A new synthesis of (-)-debromoflustramine B, (+)-ent-debromoflustramine B and (+)-debromoflustramide B

Article abstract of DOI:10.1016/S0040-4039(01)01359-4

The first synthesis of (-)-debromoflustramine B is reported. Appropriate structural modifications of an optically pure Barton ester, obtained in five steps from N-acetyl-L-tryptophan methyl ester, lead to the alkaloid.

Full text of DOI:10.1016/S0040-4039(01)01359-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6663–6666
A new synthesis of (−)-debromoflustramine B,
(+)-ent-debromoflustramine B and (+)-debromoflustramide B
A. Sofia Cardoso, Natarajan Srinivasan, Ana M. Lobo* and Sundaresan Prabhakar*
Secc¸a˜o de Qu´ımica Orgaˆnica Aplicada, Departamento de Qu´ımica,
Centro de Qu´ımica Fina e Biotecnologia and SINTOR-UNINOVA, campus Faculdade de Cieˆncias e Tecnologia,
Universidade Nova de Lisboa, Quinta da Torre, 2829 Monte de Caparica, Portugal
Received 25 July 2001; accepted 26 July 2001
Abstract—The first synthesis of (−)-debromoflustramine B is reported. Appropriate structural modifications of an optically pure
Barton ester, obtained in five steps from N-acetyl-L-tryptophan methyl ester, lead to the alkaloid. © 2001 Elsevier Science Ltd.
All rights reserved.
1
2
3
4
R = CH2CH=CMe2 ; X = H ; Y = H,H
(-)-debromoflustramine B
Debromoflustramine B1 (1) incorporating the hexahy-
dropyrrolo[2,3-b]indole skeleton and other structurally
related alkaloids, such as flustramines A (2) and B (3)
have been isolated from Flustra foliacea.2
R = CMe2CH=CH2 ; X = Br ; Y = H,H
(-)-flustramine A
R
Y
X
N
H
R = CH2CH=CMe2 ; X = Br ; Y = H,H
(-)-flustramine B
N
R
Me
Whilst various syntheses for racemic debromoflus-
tramine B3 as well as one for its (+)-ent-isomer4 are
reported, there is no synthesis available to-date for the
natural product. We report herein the first such
synthesis.
R = CH2CH=CMe2 ; X = Br ; Y = O
(-)-flustramide B
nantly C-allylation (NaH, dimethylallyl bromide,
DMF) to provide a diastereoisomeric mixture of prenyl-
ated compounds 7 and 87 (60%) and the N-allyl isomer
9 (11%). The N-allyl pyrrole 9 was readily removed
from its isomers by chromatography and the separation
of the diastereoisomers 7 and 8 (0.9:1 ratio) was
deferred to a later stage8 in the synthesis. The mixture
was reduced and the resulting secondary amines 10 and
The requisite starting material (−)-1-acetyl-2,3-dihy-
dropyrrolo[2,3-b]indole-2-carboxylate (5) (Scheme 1)
[enantiomerically pure, as determined by 1H NMR with
the shift reagent, Eu(tfc)3], was obtained from N-acetyl-
L
-tryptophan methyl ester (6) using the procedure of
Witkop.5 Under conditions generally considered to
favour N-alkylation6 the indole 5 underwent predomi-
R
CO2Me
CO2Me
N
a
b
N
CO2Me
Ac
Ac
CO2Me
Ac
6
7
N
(88%)
N
H
5
Ac
N
R
N
R
9
N
N
8
b. NaH, DMF, Br-CH2CH=CMe2
a. tert-BuOCl, CCl4,CH2Cl2, Et3N
R = CH2CH=CMe2
Scheme 1.
Keywords: alkaloids; amino alcohols; cyclization; indoles; oxygenation.
* Corresponding authors. Tel.: +351-21-2948387; fax: +351-21-2948550; e-mail: aml@mail.fct.unl.pt; sp@dq.fct.unl.pt
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01359-4

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A. S. Cardoso et al. / Tetrahedron Letters 42 (2001) 6663–6666
11 (0.7:1.0 ratio) converted into the C,N-diallyl esters
12 and 13 (1:2 ratio) (Scheme 2). This unfortunate
progressive reduction in the diastereoisomeric mixture
ratio in favour of the undesired isomer was due to the
greater intrinsic instability of the exo isomers vis a` vis
the corresponding endo isomers,9 both during their
reactions and work-up. This was reflected in the isola-
tion of the ring-opened product 14 resulting only from
the exo isomer 7 during the reduction.10
to the imine 20, could be accomplished with a methano-
lic methoxide solution containing hydrazine. LAH
reduction of 20 yielded the secondary amine 21.
Although the conversion of the latter in its racemic
form to the ( )-alkaloid is reported3a to occur with
NaCNBH3/H2CꢀO in 57% yield, the amine 21 however
did not yield the desired product. An 18% yield (46%
based on recovered starting material) of (−)-debro-
moflustramine B (1) [h]2D5=−97.5 (c=0.06, CHCl3), lit1
[h]2D0=−98.2 (c=0.02, CHCl3)], possessing NMR spec-
tra (1H; 13C) identical with those reported for the
natural product, was however obtained on methylation
of the same with MeI.
Saponification of 12 and 13, followed by acidification
of the mixture, provided the corresponding acids from
which the requisite Barton esters11 15 and 16 (1:2 ratio)
were readily secured. Although sensitive to heat and
light, they could nevertheless be separated efficiently by
column chromatography into pure exo 15 and endo 16
isomers. Exposure of an ethereal solution of 15 to
Sb(SPh)3 and air12 furnished the hydroxy-amide 17
(Scheme 3). Similarly 16 yielded 18. All attempts to
impart hydrolytic instability to the N-acetyl group by
oxidation of the adjacent OH group of either 17 or 18
(Swern; Dess–Martin periodinane; Pt/O2) to the car-
bonyl compound failed.
Similarly 18, furnished (+)-ent-debromoflustramine B
[(+)-ent-1] [h]D20=+96.4 (c=0.06, CHCl3).
The Barton ester 1613 (Scheme 5) on treatment with
KOBu-tert-BuOH in THF saturated with dried air
(P2O5) led after acidification of the mixture, to the
carboxylic acid 22 (40%), thiopyridone 23 (18%), 1,3-
bis-dimethylallylindole 24 (30%) and the pyrrolidone
25a (15%). The latter on methylation furnished (+)-
debromoflustramide B (25b) [92%; [h]2D5=36 (c=0.03,
1
However, the N-deacetylation of the enamide 19
(Scheme 4) obtained by heating a xylene solution of 17,
CH2Cl2)], the H and 13C spectra of which were identi-
cal with those reported for the racemic substance.3c,3e
S
R
R
R
O N
CO2Me
Ac
CO2Me
Ac
7
+
8
N
N
O
N
N
N
H
N
R
Ac
H
H
R
H
b
a
c,d,e
10
15 exo
exo
12
(62%)
(71%)
CO2Me
S
R
R
CO2Me
Ac
R
O N
(85%)
N
N
N
Ac
N
O
H
N
H
H
R
N
R
Ac
H
11 endo
13
16 endo
R = CH2CH=CMe2
CO2Me
R
Ac
HN
OMe
b. K2CO3, THF, Br-CH2CH=CMe2
a. NaBH3CN, MeOH
N
c. NaOH, aq. MeOH d. H3O+ e.
, PBu3, CH2Cl2, 0°C.
14
N
O
S)2
Scheme 2.
R
R
OH
OH
N
H
16
15
a
a
N
H
endo
exo
(64%)
N
R
(74%)
N
R
Ac
Ac
17
18
R = CH2CH=CMe2
a. Sb(SPh)3 , O2, Et2O, 0 - 18°C.
Scheme 3.

A. S. Cardoso et al. / Tetrahedron Letters 42 (2001) 6663–6666
6665
R
R
R
a
d
c
b
17
18
(-)-1
N
N
NH
(72%)
(46%)
N
R
(54%)
Ac
N
R
(70%)
N
R
19
20
21
a,b,c,d
(+)-ent-1
a. xylene, ∆ , 12 h b. 4.7 M NaOMe, MeOH,
NH2NH2, H2O, ∆ c. LAH, Et2O, 0°C. d. NaH,
THF, MeI.
R = CH2CH=CMe2
Scheme 4.
R
R
R
O
a
CO2H
16
NR1
N
N
R
N
R
N
R
Ac
24
S
N
22
H
25a R1 = H
25b R1 = Me
23
b
(92%)
a. KOtert-Bu, O2, THF; H3O+ b. NaH, DMF, MeI.
R = CH2CH=CMe2
Scheme 5.
O
O
O
O
CO2
R
R
R
O
O
N
O
S
S
O
O
N
N
N
N
Ac
N
S
O
N
N
R
N
R
Ac
R Me
O
26
27
via
ketene
R
OOAc
24
22
N
S
N
N
R
28
Scheme 6.
A possible mechanism for the formation of these prod-
ucts is outlined below (Scheme 6). Thus, whilst the
unimolecular fragmentation of the carbanion 26
accounts for 22 and 24, its reaction with O2 could
generate the hydroperoxide anion 27 from which the
imino peracetate 28 and pyridine-2-thiolate are formed.
An oxidation–reduction reaction between the latter two
species would lead to 25a.
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Acknowledgements
We thank Fundac¸a˜o para a Cieˆncia e a Tecnologia
(FEDER, POCTI) (Lisbon, Portugal), for partial finan-
cial support and Dr. S. N. Swami (Pfizer, UK) for the
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A. S. Cardoso et al. / Tetrahedron Letters 42 (2001) 6663–6666
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