Enantiospecific and stereoselective synthesis of (-)-allosedamine

Article abstract of DOI:10.1016/S0040-4039(01)02105-0

A total synthesis of (-)-allosedamine (>99% ee, de) is described in 14 steps with an overall yield of 29% from benzaldehyde.

Full text of DOI:10.1016/S0040-4039(01)02105-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 225–227
Enantiospecific and stereoselective synthesis of (−)-allosedamine
Franc¸ois-Xavier Felpin and Jacques Lebreton*
Laboratoire de Synthe`se Organique, CNRS UMR 6513, Faculte´ des Sciences et des Techniques, 2 rue de la Houssinie`re,
BP 92208, 44322 Nantes Cedex 3, France
Received 19 October 2001; revised 31 October 2001; accepted 6 November 2001
Abstract—A total synthesis of (−)-allosedamine (>99% ee, de) is described in 14 steps with an overall yield of 29% from
benzaldehyde. © 2002 Elsevier Science Ltd. All rights reserved.
(−)-Allosedamine 13 has been isolated from Lobelia
inflata (also known as Indian tobacco).1 Although the
crude extract is toxic, it has been used for the treatment
of respiratory illnesses such asthma, bronchitis and
pneumonia.2 As little is known about the biological
properties of 13, we were interested to develop a novel
route to (−)-allosedamine 13 which could also be
adapted for the preparation of its analogues in order to
investigate structure–activity relationships. To our
knowledge, only one enantiomeric3 synthesis of this
alkaloid has been reported.
homoallylic alcohol (R)-2 was obtained in good yield
(80%) from benzaldehyde, in a multigram sequence
requiring no purification of the intermediates. The next
step was the stereoselective epoxidation of the CꢀC
double bond of homoallylic alcohol (R)-2. The initial
homoallylic epoxidation of 2 using Sharpless’ procotol9
with tert-butyl hydroperoxide in the presence of vana-
dium acetylacetonate led to the desired epoxyalcohol 5
in moderate yield (73%) with low (<4:1) selectivity. To
achieve this transformation with an excellent level of
diastereoselectivity, we used a sequence reported by
Cardillo and al.10 Following their procedure, the
homoallylic tert-butyl carbonate 3 was prepared from
the corresponding alcohol 2 via deprotonation with
n-BuLi followed by treatment with Boc-ON (2-(tert-
butoxycarbonyl)oxy)-imino)-2-phenylacetonitrile).11
The synthetic sequence starting from benzaldehyde is
depicted in Scheme 1. Brown’s asymmetric allylation4
of benzaldehyde with B-allyldiisopinocampheylborane,
prepared from (+)-B-chlorodiisopinocampheylborane
((+)-Ipc2BCl) and allylmagnesium bromide, afforded
the chiral homoallylic alcohol (R)-2 in 85% yield and
94.8% ee5 (best value). In our opinion, an improvement
of the ee was necessary, so we turned our attention to
a synthesis of enantiopure (R)-2, based on the enan-
tioselective reduction of the carbonyl of 1. The b,g-
unsaturated ketone 1 was obtained by treatment of
benzaldehyde with an excess of allylzinc bromide fol-
lowed by oxidation with the Dess–Martin periodinane
reagent (DMP).6 In order to save one step, we
attempted without success the direct preparation of
ketone 1 from benzoyl chloride. Thus, treatment of
benzoyl chloride with various allyl reagents afforded
mixtures of the desired adduct, recovered starting mate-
rial and the corresponding tertiary alcohol. The enan-
tioselective reduction of the stable b,g-unsaturated
ketone 1 with (+)-Ipc2BCl7 proceeded smoothly in THF
at −35°C.8 The enantiomerically pure (>99% ee5)
Then, diastereoselective iodine-induced electrophilic
cyclization of the homoallylic tert-butyl carbonate 3
was carried out by simple treatment with IBr at low
temperature (−85°C) to furnish the corresponding iodo-
carbonate 4,12 which under basic conditions led to the
desired epoxyalcohol 5,13 as a single diastereoisomer (as
1
judged by H and 13C NMR spectral analysis of the
crude reaction mixture) in 73% overall yield for the
three steps.
The epoxyalcohol
5 was protected as its tert-
butyldimethylsilyl (TBS) ether 6. Regioselective copper-
mediated Grignard allylation of the epoxide 6 afforded
the compound 7 in high yield (91%).14 Replacement of
the free hydroxy group of 7 by a N-Me functionality to
give 9 was carried out in an acceptable overall yield
(73%) with total inversion of configuration through the
nucleophilic displacement of the corresponding mesyl-
ate 8 by methylamine.15 Other classical methods of
introducing the nitrogen functionality with the requisite
* Corresponding author. Tel.: +33 2 51 12 54 03; fax: +33 2 51 12 54
02; e-mail: lebreton@chimie.univ-nantes.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02105-0

226
F.-X. Felpin, J. Lebreton / Tetrahedron Letters 43 (2002) 225–227
OH
O
O
a, b
c
d
H
O
1
2, ee>99%
O
OR
O
O
O
O
O
I
f
e
4
3
5 R = H
6 R = TBS
g
OTBS
OTBS
h
j
l
OR
NR
Me
7 R = H
8 R = Ms
9
R = H
i
k
10 R = Boc
OH
OTBS
N
n
N
OR
Me Boc
Me
11 R = H
12 R = Ms
m
(-)-Allosedamine 13
Scheme 1. Reagents and conditions: (a) allylbromide, Zn, THF, rt, 1 h, 98%; (b) DMP, CH2Cl2, rt, 1 h, 97%; (c) (+)-Ipc2BCl,
THF, −35°C, 12 h, 84%; (d) n-BuLi, Et2O, −78°C, 30 min then Boc-ON, THF, 0°C to rt, 2 h, 90%; (e) IBr, toluene, −85°C, 1
h, 85%; (f) K2CO3, MeOH, rt, 2 h, 96%; (g) TBDMSCl, Et3N, DMAP, DMF, rt, 3 h, 96%; (h) AllylMgBr, CuI, Et2O, −40°C,
30 min, 91%; (i) MsCl, Et3N, CH2Cl2, 0°C, 10 min, 88%; (j) MeNH2, DMF, H2O, 60°C, 20 h, 83%; (k) (Boc)2O, Et3N, CH2Cl2,
rt, 6 h, 95%; (l) Cy2BH, CH2Cl2, 0°C, to rt, 6 h, then H2O2, NaOH, 0°C to rt, 1 h, 90%; (m) MsCl, Et3N, CH2Cl2, 0°C, 40 min,
95%; (n) 1% HCl conc., MeOH, 60°C, 3 h, 94%.
stereochemistry failed. On standard Mitsunobu reaction
with alcohol 7, diethyl azodicarboxylate (DEAD),
triphenylphosphine and phthalimide, the expected N-
phtalimide was obtained in 70% yield, but its hydrolysis
to the corresponding amine failed. On the other hand,
the same reaction carried on with diphenylphosphoryl
azide (DPPA) afford the corresponding azide which
spontaneously decomposed via an intramolecular 1,3-
dipolar cycloaddition.16
recorded for the natural material, including specific
optical rotation, [h]2D0=−28.6 (c 0.84, MeOH), lit.3
[h]2D0=−29.8 (c 0.2, MeOH).
In summary, we have achieved an enantiocontrolled
synthesis of (−)-allosedamine 13 via the epoxyalcohol 5,
using a strategy that could be applied to the prepara-
tion of piperidine alkaloids, such as (−)-lobeline. In
addition, this synthetic scheme is adaptable to the
preparation of a range of substituted analogues.
At this point of the synthesis, it seemed appropriate to
protect the amino function of 9 to avoid its oxidation in
the next step. Our synthetic plan required a protecting
group prone to be cleaved in acidic conditions, con-
comitantly with the silylether. Accordingly, N-Me
amine 9 was treated with di-tert-butyl dicarbonate
(Boc2O) employing a standard procedure, to afford the
Boc-derivative 10 in high yield (95%). Selective hydro-
boration of the terminal olefin of 10 was achieved with
dicyclohexylborane, and oxidation of the borane inter-
mediate to give alcohol 11 in high yield (90%).17 This
intermediate 11 was converted to the corresponding
mesylate 12 under standard conditions.
Acknowledgements
This work was supported by the ‘Ministe`re de l’Educa-
tion Nationale de la Recherche et de la Technologie’
with a doctoral fellowship for F.-X.F. We thank
Gilbert Nourrisson for recording the mass spectra and
Marie-Jo Bertrand for skilled experimental assistance
with HPLC. Finally, we thank Drs. Richard J. Robins
and Giang Vo-Thanh for friendly and fruitful
discussions.
Then, Boc and TBS protecting groups of 12 were
cleaved in a single step under acidic conditions, and the
resulting amino derivative spontaneously cyclized by
displacing the mesylate to afford (−)-allosedamine 13 in
References
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94% yield after purification. Spectral data (IR, H, 13C
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NMR) for 13 were in excellent agreement with those
W.; Linde, W. Liebigs Ann. Chem. 1939, 540, 103.

F.-X. Felpin, J. Lebreton / Tetrahedron Letters 43 (2002) 225–227
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5.51 (dd, 1H, J=2.9 Hz, J=11.9 Hz), 7.38 (s broad, 5H);
13C NMR l (ppm) 5.6, 35.6, 77.2, 79.5, 125.9, 129.0,
129.3, 137.2, 148.4.
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13. Representative procedure for compound 5. To a solution
of cyclic carbonate 4 (4.14 g, 13.02 mmol) in anhydrous
MeOH (52 mL) at room temperature, was added K2CO3
(5.57 g, 40.36 mmol) and the reaction was stirred for 2 h.
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1
1494, 2921, 3061, 3418 cm−1. H NMR l (ppm) 1.80–2.07
(m, 2H), 2.47 (dd, 1H, J=2.7 Hz, J=4.9 Hz), 2.72 (dd,
1H, J=4.4 Hz, J=4.9 Hz), 2.77 (s broad, 1H), 2.92–3.02
(m, 1H), 4.89 (dd, 1H, J=5.5 Hz, J=7.8 Hz), 7.27–7.37
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127.9, 128.6, 144.0. HRMS (CI/NH3) calcd for
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−85°C, was slowly added a solution of IBr (1 M in
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1 h, the resulting mixture was quenched with (1:1) 20%
aqueous Na2S2O3: 5% aqueous NaHCO3 solution and
diluted with ether (120 mL). The aqueous phase was
extracted with ether (2×). The organic extracts were
washed with brine, dried over anhydrous MgSO4, filtered
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solid which was quickly used in the next step due to its
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