A brief total synthesis of eupolauramine

Article abstract of DOI:10.1055/s-2004-830889

A concise synthesis of the alkaloid eupolauramine has been achieved. The key step was a benzotriazolyl-mediated connection of a bromoaryl unit to the azaisoindolinone framework by an enol ether function. Free radical cyclization then provided the natural product.

Full text of DOI:10.1055/s-2004-830889

LETTER
2233
A Brief Total Synthesis of Eupolauramine
A
B
rie
f
Total Synt
é
hesis of
E
u
r
polauram
o
ine nique Rys, Axel Couture,* Eric Deniau, Stéphane Lebrun, Pierre Grandclaudon
Laboratoire de Chimie Organique Physique, UMR 8009 ‘Laboratoire de Chimie Organique et Macromoléculaire’, Université des Sciences
et Technologies de Lille, Bâtiment C3(2), 59655 Villeneuve d’Ascq Cédex, France
Fax +33(3)20336119; E-mail: axel.couture@univ-lille1.fr
Received 14 May 2004
the alkaloid skeleton by free radical cyclization of 4b
Abstract: A concise synthesis of the alkaloid eupolauramine has
were fruitless. It then occurred to us that the creation of
been achieved. The key step was a benzotriazolyl-mediated connec-
the enol ether unit (methylated or in some protected form)
tion of a bromoaryl unit to the azaisoindolinone framework by an
would be achievable by an olefination process applied to
an azaisoindolinone precursor 5 equipped with a pendant
hydroxybenzyl appendage on the benzylic position and a
temporary blocking group X as well (retrosynthetic
Scheme 1, path b). We assumed that such an adduct might
in turn be obtained by sequential metallation of the aza-
isoindolinone derivative 6 and quenching with the appro-
priate aromatic aldehyde.
enol ether function. Free radical cyclization then provided the natu-
ral product.
Key words: alkaloids, carbanions, enols, ring closure, total synthe-
sis
Eupolauramine (1) is a structurally unique azaphenan-
threne alkaloid extracted from Eupomatia species.1 This
natural product was first isolated in 1972 by Taylor et al.
from the bark of Eupomatia laurina2 and is considered to
be biogenetically derived from an oxoaporphine precur-
sor, probably liriodenine.3 Due to its architecturally so-
phisticated structure in conjunction with its low natural
occurrence this alkaloid represents a challenging synthet-
ic target and an interesting proving ground for organic
chemists. Most of the synthetic routes to this phenan-
threne lactam rely upon the construction of the ben-
zo[h]quinoline unit equipped with appropriate
functionalities, i.e. an ester-4–7 or an acid8 group on the py-
ridine unit, and a remote nitro-4,5 or amino6–8 function,
able to secure the generation of the lactam ring. Eupolau-
ramine was also obtained by decarboxylation of imbiline,9
by sequential bromination of the azaphenanthrene lactam
and ultimate replacement of the halogen atom by the
methoxy functionality,10 and by combining two photoini-
tiated processes, i.e. a SRN1 reaction and a 6p-electron cy-
clization process, for the creation of the lactam- and
azaphenanthrene ring systems.11
O
O
N
Me
N
Me
N
N
Br
OR
OMe
2
3
R = Me
R = Protecting Group
1
path b
Me
path a
O
O
N
N
Me
N
N
X
Br
OR
Br
OH
4a
5
All these methods have been developed owing to the dif-
ficulties associated with the elaboration of the rather ap-
pealing intermediates 2 and 3. Indeed, compounds 2 and 3
display all the mandatory structural specifications to
straightforwardly reach the target natural alkaloid, i.e. the
presence of an enol ether moiety integrated in an (aza)bro-
mostilbenic unit likely to ensure the assemblage of the
benzoquinoline ring system (retrosynthetic Scheme 1,
path a). Unfortunately, all attempts to synthesize com-
pound 2 by O-methylation of the enol form 4a of the
acylated compound 4b were unrewarding and only the C-
methylation product was obtained.6,11 Furthermore, at-
tempts to generate the azaphenanthrene unit embedded in
path b
O
O
N
Me
N
CHO
Br
Br
O
N
X
Me
+
N
4b
6
Scheme 1
Critical to the success of this strategy was then the ability
to identify a temporary activating group X liable to allow
and if feasible to facilitate the metallation/hydroxyalkyla-
tion sequence, to survive the O-substitution reaction and
above all to be labile enough to promote the ultimate for-
mation of the exocyclic enol function.
SYNLETT 2004, No. 12, pp 2233–2235
0
1
.1
0
.2
0
0
4
Advanced online publication: 04.08.2004
DOI: 10.1055/s-2004-830889; Art ID: G17604ST
© Georg Thieme Verlag Stuttgart · New York

2234
V. Rys et al.
LETTER
The choice of benzotriazole, which has proved to be of steric impact on the subsequent elimination process lead-
widespread applicability as a synthetic auxiliary in a mul- ing to 3 and force in particular the exocyclic olefinic sys-
titude of synthetic endeavors,12 originated from the fol- tem to adopt the more favorable Z-configuration. The O-
lowing premises: (i) the benzotriazolyl ring system has Piv functionality could be also straightforwardly convert-
been indiscriminately involved in the generation of stabi- ed into the required methoxy group. The oxanion 9 was
lized and non stabilized a-aminocarbanionic species;13 (ii) thus quenched in situ with pivaloyl chloride and the whole
N-benzotriazolylmethylcarboxamides have been shown operation delivered the rather congested adduct 10. The
to be excellent candidates for the generation of N-acylena- use of the pivaloyl group in conjunction with the choice of
mines under basic or acidic conditions.14 Consequently, the temporary auxiliary was rewarded here: treatment of
we embarked on the synthesis of the azaisoindolinone 6 the adduct 10 with pTSA afforded the enol lactam deriva-
equipped with the benzotriazolyl unit. The assembly of tive 3 according to the mechanistic pathway portrayed in
this polynitrogenated compound was accomplished by a the Scheme 2. The key model, compound 3, was obtained
two step sequence involving the quenching with dimeth- as a mixture of separable Z- and E-isomers with the re-
ylformamide (DMF) of the dilithiated species generated quired Z-isomer predominant by a large margin (Z:E
by treatment with n-butyllithium (BuLi) of the isonicoti- 80:20). The oxidative free radical cyclization reaction
namide derivative 7 (Scheme 2). Exposure of the N,O- (AIBN, Bu3SnH) of the major stereoisomer proceeded un-
hemiacetal 815 to a catalytic amount of para-toluene- eventfully to furnish the fused (aza)aristolactam 11. The
sulfonic acid (pTSA) then induced the formation of the ultimate replacement of the pivaloyloxy group by the
iminium salt which was trapped as it is formed with an ex- methoxy functionality was inspired by Nicolaou’s mild
cess of benzotriazole to provide the desired azaisoindoli- process for the transesterification of aromatic pivaloates
none 6. This compound was smoothly deprotonated with into phenols.16 Thus, removal of the pivaloate group by
BuLi in tetrahydrofuran (THF) at –78 °C and then al- exposure to Cs2CO3–18-crown-6 in methanol followed by
lowed to react with 2-bromobenzaldehyde. At this stage in situ trapping of the phenoxide anion with a methylating
we opted for the interception of the transient oxanion 9 agent delivered straightforwardly the target natural prod-
with the highly reactive pivaloyl chloride. In fact we an- uct eupolauramine (1) with 11.5% yield over the six
ticipated that the bulky pivaloyl group (Piv) could play a steps.17 The spectral data of 1 were identical to those re-
double role. Its presence in the adduct 10 could have a ported for the natural product eupolauramine.2
O
N
N
N
O
O
O
N
Me
Me
N
(BtH)
H
a
b
N
N
Me
N Me
H
N
N
N
N
N
(87%)
(78%)
N
7
OH
6
8
O
O
O
O
Cl
N
Me
N
Me
N
Me
d
N
Me
BtH
OPiv
I
O
N
N
N
N
e
c
Bt
Bt
(PivCl)
Br
OPiv
Br
Br
O
O
Br
H
CHO
Br
(53%)
H
(over 2 steps)
O
9
+ BtH
10
O
O
O
N
O
N
Me
Me
N Me
N
Me
N
f
(69%)
N
N
N
g
+
Br
(82%)
(71%)
OPiv
OMe
OPiv
11
Z/E 80:20)
PivO
Br
Z-3
E-3
1
Scheme 2 a) (i) BuLi (2.2 equiv), THF, –78 °C, 30 min, then 0 °C, 15 min; (ii) DMF, –78 °C, 1 h, then r.t., 2 h; b) pTSA, BtH, toluene, reflux,
3 h; c) (i) BuLi, THF, –78 °C, 20 min; (ii) 2-BrC6H4CHO, THF, –78 °C to –40 °C, 30 min; d) –78 °C, PivCl, –78 °C to r.t., 1 h; e) pTSA, toluene,
reflux, 1 h; f) (i) Separate Z-3 and E-3, flash column chromatography, SiO2, EtOAc–hexanes (40:60); (ii) Z-3, AIBN (1 equiv), Bu3SnH (1.5
equiv), benzene, reflux 5 h; g) Cs2CO3 (2 equiv), 18-crown-6 (0.6 equiv), Me2SO4 (2.2 equiv), MeOH, reflux, 24 h.
Synlett 2004, No. 12, 2233–2235 © Thieme Stuttgart · New York

LETTER
A Brief Total Synthesis of Eupolauramine
2235
(13) (a) Katritzky, A. R.; Yang, Z.; Lam, J. N. J. Org. Chem.
1991, 56, 6917. (b) Katritzky, A. R.; Qi, M. Tetrahedron
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Nichols, D. A. J. Org. Chem. 1997, 62, 4121.
(14) (a) Katritzky, A. R.; Ignatchenko, A. V.; Lang, H. J. Org.
Chem. 1995, 60, 4002. (b) Katritzky, A. R.; Ignatchenko, A.
V.; Lang, H. Synth. Commun. 1995, 25, 1197. (c) Deniau,
E.; Enders, D. Tetrahedron Lett. 2002, 43, 8055.
In summary, we have completed a concise synthesis of
eupolauramine. The advantage of this synthesis lies in the
ease of elaboration of the intermediates involved in the as-
sembly of this alkaloid and the reported synthetic tactics
emphasize the high versatility and potential of the benzo-
triazole as a temporary auxiliary for synthetic purposes.
(15) Ahmed, I.; Cheeseman, G. W. H.; Jaques, B. Tetrahedron
1979, 35, 1145.
Acknowledgment
(16) (a) Nicolaou, K. C.; Maligres, P.; Suzuki, T.; Wendeborn, S.
V.; Dai, W. M.; Chadha, R. K. J. Am. Chem. Soc. 1992, 114,
8890. (b) Cloninger, M. J.; Whitlock, H. W. J. Org. Chem.
1998, 63, 6153.
This research was supported by the CNRS and MENESR. Also we
acknowledge helpful discussions and advice from Dr. T. G. C. Bird
(Astra-Zeneca Pharma).
(17) All new compounds have been fully characterized. 1H NMR
(300 MHz, CDCl3), 13C NMR and APT spectral data (75
MHz, CDCl3) and elemental analysis of the key
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Synlett 2004, No. 12, 2233–2235 © Thieme Stuttgart · New York