Stereoselective asymmetric synthesis of (+)-sedamine and (+)-allosedamine

Article abstract of DOI:10.1002/chir.20729

A convenient method for the generation of (+)-sedamine and (+)-allosedamine in high optical purity has been elaborated. The key steps are the highly stereoselective 1,2-nucleophilic addition to SAMP hydrazones allowing the installation of the stereogenic center at C2 and ring closing metathesis.

Full text of DOI:10.1002/chir.20729

CHIRALITY 22:212–216 (2010)
Stereoselective Asymmetric Synthesis of (1)-Sedamine
and (1)-Allosedamine
1,2
STEPHANE LEBRUN,1,2 AXEL COUTURE,1,2 ERIC DENIAU, AND PIERRE GRANDCLAUDON1,2
´
*
1Universite´ des Sciences et Technologies de Lille 1, LCOP, Baˆtiment C3(2), 59655 Villeneuve d’Ascq, France
2CNRS, UMR 8009 ‘‘Chimie Organique et Macromole´culaire’’, 59655 Villeneuve d’Ascq, France
ABSTRACT
A convenient method for the generation of (1)-sedamine and (1)-allo-
sedamine in high optical purity has been elaborated. The key steps are the highly ste-
reoselective 1,2-nucleophilic addition to SAMP hydrazones allowing the installation of
the stereogenic center at C2 and ring closing metathesis. Chirality 22:212–216,
C
VV
2010.
2009 Wiley-Liss, Inc.
KEY WORDS: alkaloids; diastereoselective nucleophilic addition; hydrazones
ring closing metathesis
INTRODUCTION
features of the synthetic strategy are (i) the early creation
of the C2 stereogenic center of the piperidine unit relying
on the highly diasteroselective nucleophilic 1,2-addition to
chiral SAMP hydrazones42; (ii) the creation of the piperi-
dine ring template by ring closing metathesis which ranks
highly in the hierarchy of synthetic tactics for the elabora-
tion of nitrogen containing ring systems43–46; and (iii) the
installation of the hydroxylated benzylic stereogenic cen-
ter at C8 by chirality transfer to a ketyl functionality while
retaining the configuration at C2.
The 1,3-aminoalcohol moiety is found in many synthetic
and natural products possessing physiological activities
and is an integral part of a variety of potent drugs.1,2 It is
also the most distinctive structural feature of 2-(2-hydrox-
yalkylsubstituted)piperidine-based alkaloids which display
a wide range of biological activities.3 Consequently these
bifunctional compounds have been the subject of consider-
able synthetic efforts, prompting an exceptional develop-
ment of methodologies for the asymmetric approaches.4
Sedamine, allosedamine, and their stereoisomers, 1a,b
and 2a,b respectively, (see Fig. 1) fall into this category.
Sedamine (1a) was the first alkaloid isolated from Sedum
acre5,6 and the enantiomeric forms 1a,b have been
obtained later from a number of Sedum species.7–11 This
type of alkaloid has been shown to display memory-
enhancing properties and may be effective for the treat-
ment of cognitive disorders.12,13 (1)-Allosedamine (2a)
and its levorotary enantiomer 2b are lipophilic alkaloidal
constituents of Lobelia inflata L INN which has a long his-
tory of therapeutic activities14 ranging from respiratory
stimulant to tobacco smoking cessation agent.14,15 As
these alkaloids are only available in trace amounts from
natural sources, the last decade has witnessed a strong in-
centive in the development of asymmetric synthetic
approaches to these naturally occurring substances.
MATERIALS AND METHODS
Tetrahydrofuran (THF) and diethyl ether (Et2O) were
predried with anhydrous Na2SO4 and distilled over sodium
benzophenone ketyl under Ar before use. Methanol
(MeOH) and ethanol (EtOH) were distilled from magne-
sium turnings and dichloromethane (CH2Cl2) from CaH2,
˚
before storage on 4 A molecular sieves. Dry glassware
was obtained by oven-drying and assembly under dry Ar.
The glassware was equipped with rubber septa and rea-
gent transfer was performed by syringe techniques. For
flash chromatography, Merck silica gel 60 (40–63 lm;
230–400 mesh ASTM) was used. Petroleum ether (PE,
boiling range 40–608C), ethyl acetate (AcOEt), acetone,
and methanol were used as eluents. The melting points
were obtained on a Reichert-Thermopan apparatus and are
not corrected. Optical rotations were measured on a Per-
kin Elmer P 241 polarimeter. NMR spectra: Bruker AM
While numerous and elegant synthetic routes have
been reported for the synthesis of (1)-sedamine (1a)16–24
and (2)-sedamine (1b)18,23,25-34 in optically active forms,
facile and direct application of these approaches to the syn-
thesis of (1)-allosedamine (2a)21,23,24 and (2)-allosed-
amine (2b)23,35–40 turned out to be difficult in most cases
and in particular, the synthesis of (1)-allosedamine has
received only minor attention.41
1
300 (300 MHz and 75 MHz, for H, and 13C), CDCl3 as
solvent, TMS as internal standard. Elemental analyses
were obtained using a Carlo-Erba CHNS-11110 equipment.
*Correspondence to: Axel Couture, Universite´ des Sciences et Technolo-
gies de Lille 1, LCOP, Baˆtiment C3(2), 59655 Villeneuve d’Ascq, France.
E-mail: axel.couture@univ-lille1.fr
Received for publication 6 June 2008; Accepted 20 February 2009
DOI: 10.1002/chir.20729
We were then interested in developing a feasible and
highly stereoselective route giving rise equally to the pi-
peridine-based alkaloids (1)-sedamine and (1)-allosed-
Published online 5 May 2009 in Wiley InterScience
amine featuring the 1,3-aminoalcohol moiety. The salient (www.interscience.wiley.com).
C
VV
2009 Wiley-Liss, Inc.

SYNTHESIS OF (+)-SEDAMINE AND ALLOSEDAMINE
213
dienehydrazide 6 (618 mg, 47%) as yellow oil. [a]2D0 232.7
(c 0.64, CHCl3); 1H NMR: d 5 1.62–1.83 (m, 4H), 2.33 (d, J
5 15.3 Hz, 1H), 2.51–2.62 (m, 1H), 2.74–2.78 (m, 2H), 2.82
(d, J 5 15.3 Hz, 1H), 2.95–3.06 (m, 1H), 3.14–3.28 (m, 6H),
3.35–3.47 (m, 1H), 3.68–3.76 (m, 2H, CH2O), 3.96–4.04 (m,
2H, CH2O), 4.92–5.03 (m, 2H, Hvinyl), 5.51 (dd, J 5 10.4,
2.2, 1H, Hvinyl), 5.64–5.82 (m, 1H, Hvinyl), 6.22 (dd, J 5
17.2, 2.2 Hz, 1H, Hvinyl), 7.03 (dd, J 5 17.2, 10.4, 1H,
Hvinyl), 7.23–7.41 (m, 5H, Harom); 13C NMR: d 5 21.1, 26.2,
37.7, 45.8, 51.8, 52.2, 55.7, 58.7, 64.1, 64.4, 73.9, 110.1,
116.6, 125.7, 125.8, 127.9, 128.1, 129.4, 136.9, 142.4, 169.0;
Anal. Calcd. for C23H32N2O4: C, 69.97; H, 8.05; N, 6.99.
Found: C, 70.11, H, 8.10, N, 7.15%.
(R)-1-((S)-2-Methoxymethylpyrrolidin-1-yl)-6-(2-
phenyl-1,3-dioxolan-2-ylmethyl)-5,6-dihydro-1H-pyri-
din-2-one (8). A solution of the dienehydrazide 6
(500 mg, 1.25 mmol) and the first generation Grubbs cata-
lyst (0.067 mmol, 5 mol %) in anhydrous CH2Cl2 (15 ml)
was refluxed for 12 h under Ar. The reaction mixture was
concentrated and the resulting residue was purified by col-
umn chromatography on silica gel using AcOEt/PE
(40:60) as eluent to give enehydrazide 8 (377 mg, 81%) as
yellow oil. [a]D20 224.9 (c 0.51, CHCl3); 1H NMR: d 5
1.31–1.50 (m, 4H), 1.55–1.71 (m, 1H), 1.91–2.03 (m, 1H),
2.29–2.34 (m, 1H), 2.58–2.63 (m, 1H), 3.05–3.22 (m, 6H),
3.47–3.53 (m, 1H), 3.65–3.74 (m, 2H), 3.76–3.83 (m, 2H,
CH2O), 3.91–4.04 (m, 2H, OCH2), 5.77 (d, J 5 9.8 Hz, 1H,
Hvinyl), 6.30–6.39 (m, 1H, Hvinyl), 7.22–7.41 (m, 5H, Harom);
13C NMR: d 5 23.3, 27.6, 29.1, 40.9, 52.6, 58.2, 58.7, 60.6,
63.6, 64.7, 76.8, 109.4, 125.6, 126.0, 128.1, 128.3, 137.6,
142.0, 162.9; Anal. Calcd. for C21H28N2O4: C, 67.72; H,
7.58; N, 7.52. Found: C, 67.90, H, 7.33, N, 7.41%.
Fig. 1. Stereoisomers of sedamine and allosedamine.
The masked oxocarboxaldehyde 5 was synthesized
according to literature methods.47
Experiment
((S)-2-Methoxymethylpyrrolidin-1-yl)-[2-(2-phenyl-
1,3-dioxolan-2-yl)-ethylidene]-amine (3). SAMP (4,
2.20 g, 0.017 mol) and MgSO4 (0.40 g) were added to a so-
lution of aldehyde 5 (2.69 g, 0.014 mol) in CH2Cl2 (25 ml).
The mixture was stirred at r.t. for 12 h. Filtration of
MgSO4 and evaporation of the solvent left a residue which
was purified by flash column chromatography on silica gel
using AcOEt/PE (15:85) as eluent to afford the hydrazone
3 (3.32 g, 78%) as colorless oil. [a]2D0 274.6 (c 2.2, CHCl3);
1H NMR (CDCl3, 300 MHz): d 5 1.73–1.96 (m, 4H), 2.68–
2.79 (m, 1H), 2.85 (d, J 5 4.8 Hz, 2H), 3.36–3.55 (m, 7H),
3.73–3.81 (m, 2H, OCH2); 3.96–4.04 (m, 2H, OCH2), 6.52
(brs, 1H, CH¼¼N), 7.25–7.36 (m, 3H, Harom), 7.43–7.49 (m,
2H, Harom); 13C NMR (CDCl3, 75 MHz): d 5 22.2, 26.6,
44.1, 50.2, 59.2, 63.1, 64.7, 74.6, 109.5, 125.7, 127.9, 128.1,
132.5, 142.1; Anal. Calcd. for C17H24N2O3: C, 67.08; H,
7.95; N, 9.20. Found: C, 67.29, H, 7.81, N, 9.02%.
(R)-1-((S)-2-Methoxymethylpyrrolidin-1-yl)-6-(2-
oxo-2-phenylethyl)-piperidin-2-one (9). A solution of
enehydrazide 8 (1.2 g, 3.2 mmol) in EtOH (15 ml) was
stirred with Pd/C (10%, 15 mg) under H2 (1 atm) for 12 h
at r.t. The mixture was filtered on a pad of Celite1 that
was further eluted with EtOH (30 ml), then CH2Cl2
(30 m). The filtrate was concentrated under vacuum and
the residue dissolved in acetone (20 ml). Water (1 ml) and
APTS (100 mg) were added and the mixture was refluxed
for 6 h. After evaporation of the solvent, the crude product
was purified by column chromatography on silica gel
using AcOEt as eluent to give ketone 9 (0.9 g, 85%) as yel-
N-((S)-2-Methoxymethylpyrrolidin-1-yl)-N-[(R)-1-
(2-phenyl-1,3-dioxolan-2-ylmethyl)-but-3-enyl]-ac-
rylamide (6). Phenyllithium (1.8 M in dibutyl ether,
3.65 ml, 6.58 mmol) was added dropwise to a solution of
allyltriphenyltin (2.57 g, 6.58 mmol) in Et2O (20 ml). After
stirring at r.t. for 30 min the suspension was cooled at
2788C and a solution of hydrazone 3 (1 g, 3.29 mmol) in
Et2O (5 ml) was added dropwise by syringe. The reaction
mixture was stirred at 2788C for 40 min then allowed to
warm to r.t. and stirred for an additional 12 h. The reaction
mixture was then recooled to 2788C and acryloyl chloride
(9.87 mmol, 0.8 ml) was added dropwise. After stirring at
this temperature for 30 min, the reaction mixture was
allowed to warm to r.t. over 3 h. Water (15 ml) was added
and the mixture was filtered and extracted with CH2Cl2
(3330 ml). The combined organic extracts were dried
1
low oil. [a]2D0 220.5 (c 0.81, CHCl3); H NMR: d 5 1.61–
1.83 (m, 5H), 1.88–2.05 (m, 3H), 2.36 (t, J 5 6.5 Hz, 2H,
CH2CO), 2.91–3.03 (m, 2H, CH2COPh), 3.19–3.25 (m, 5H),
3.51–3.70 (m, 2H), 3.80–3.89 (m, 1H), 4.28–4.36 (m, 1H),
7.45 (t, J 5 7.7 Hz, 2H, Harom), 7.57 (t, J 5 7.7 Hz, 1H,
H
arom), 7.90 (t, J 5 7.7 Hz, 2H, Harom); 13C NMR: d 5 17.9,
22.7, 27.4, 28.9, 34.2, 43.0, 53.0, 58.7, 59.8, 62.3, 76.5,
128.2, 128.6, 133.1, 137.0, 169.3, 198.3; Anal. Calcd. for
C19H26N2O3: C, 69.06; H, 7.93; N, 14.53. Found: C, 68.88,
H, 7.81, N, 14.76%.
(R)-6-((R/S:25/75)-2-Hydroxy-2-phenylethyl)-1-
(MgSO4), the solvent was removed under vacuum, and ((S)-2-methoxymethylpyrrolidin-1-yl)-piperidin-2-one
the product was purified by flash column chromatography (10 and 11). A solution of K-Selectride1 (1 M in THF,
on silica gel using AcOEt/PE (20:80) as eluent to afford 2.3 ml) was added to a solution of ketone 9 (500 mg,
Chirality DOI 10.1002/chir

214
LEBRUN ET AL.
1.51 mmol) in THF (10 ml) at 2788C under Ar. After stir- according to the same procedure. TLC purification
ring for 3 h, water (15 ml) was added and the mixture was afforded 2a as a colorless oil (72 mg, 67%); [a]2D0 126.0 (c
extracted with CH2Cl2 (3 3 40 ml). Combined extracts 0.73, MeOH), Ref. 16 {[a]2D0 128.8 (c 0.16, MeOH).
were dried (MgSO4) and the solvent was evaporated
under vacuum to afford the alcohol 10, 11 as a mixture of
unseparable diastereoisomers (1:3, 448 mg, 89%). 1H NMR
RESULTS AND DISCUSSION
(mixture of diastereoisomers): d 5 1.42–1.86 (m, 8H),
The first facet of the synthesis which is depicted in
Scheme 1 was the elaboration of the protected parent hy-
drazone 3. This compound was easily obtained by simply
mixing the enantiomerically pure hydrazine (S)-(2)-
1-amino-2-(methoxymethyl)pyrrolidine (SAMP, 4) with
the aromatic masked oxocarboxaldehyde 5.
1.93–2.08 (m, 2H), 2.26–2.34 (m, 2H), 3.22–3.36 (m, 7H),
3.55–3.66 (m, 1H, 11), 3.74–3.86 (m, 2H, 10), 3.87–3.95
(m, 1H, 11), 4.68–4.73 (m, 1H, 11), 4.76–4.82 (br. s, 1H,
10), 4.93–4.99 (m, 1H, 10), 5.31–5.36 (brs, 1H, 11), 7.19–
7.38 (m, 5H); 13C NMR (mixture of diastereoisomers): d
17.7 (11), 17.8 (10), 23.0 (10), 23.05 (11), 27.2 (10),
27.25 (11), 30.6 (10), 30.8 (11), 34.0 (10), 34.2 (11),
45.2 (10), 46.4 (11), 53.0 (10), 53.2 (11), 58.4 (10), 58.7
(11), 58.8 (10), 60.6 (11), 60.7 (10), 61.1 (11), 70.8 (10),
72.6 (11), 75.1 (10), 75.9 (11), 125.6 (10), 125.7 (11),
127.1 (10), 127.3 (11), 128.3 (10), 128.35 (11), 144.5
(10), 145.0 (11), 168.8 (11), 169.3 (10).
Addition of allyllithium followed by interception of the
transient hydrazide salt with acryloyl chloride allowed the
installation of the mandatory diolefinic system and deliv-
ered the opened dienehydrazide 6, candidate for the
planned RCM reaction with a satisfactory yield. It is note-
worthy that this synthetic route proved more judicious
than that based upon trapping of the hydrazide salt with
allyl bromide. Indeed only traces of the diallylated com-
pound 7 were detected in this synthesis. NMR spectro-
scopic investigation indicated the presence of a single
diastereoisomer (de > 95%) making evident the remark-
able stereoselectivity of the initial 1,2-nucleophilic addi-
tion process securing the absolute stereochemistry at the
a-position of the nitrogen atom, i.e., at C2 in the final
compound.
The bis olefin 6 obtained after chromatographic treat-
ment was subjected to RCM using 1st generation Grubbs
catalyst, Cl2Ru(5 CHPh)(PCy3)2 (5% mol) in refluxing
CH2Cl2 to provide a very satisfactory yield of the virtually
diastereopure enehydrazide (S,R)-8. Catalytic hydrogena-
tion of the olefinic double bond was readily achieved with
the subsequent retrieval of the carbonyl functionality to
afford the cyclic hydrazide (S,R)-9 in high diastereoselec-
tivity (de > 95%).
For the subsequent step—the reduction of the carbonyl
functionality—a variety of reducing agents was screened.
While standard conditions by making use of NaBH4 fur-
nished an equimolar mixture of diastereoisomers (R,R,S)-
10 and (R,S,S)-11 we were pleased to observe that treat-
ment of 9 with K-Selectride1 furnished the diastereoiso-
meric mixture with the diastereoisomeric form 11 pre-
dominating by a large margin (10/11; 1:3). The diaster-
eoisomers could not be chromatographically separated
and the diastereoisomeric ratio was evaluated by 1H
NMR, namely from integration of the benzylic proton. At
this stage the structural assignments of the absolute con-
figuration of alcohols 10 and 11 could not be accessed a
priori.
(R)-2-((R)-2-Hydroxy-2-phenylethyl)-piperidine-1-
carboxylic acid tert-butyl ester (12) and (R)-2-((S)-2-
hydroxy-2-phenylethyl)-piperidine-1-carboxylic acid
tert-butyl ester (13). BH3-THF (1 M in THF, 30 ml)
was added slowly to a solution of alcohols 10, 11 (500 mg,
1.51 mmol) in dry THF (5 ml) at 08C. After refluxing for 48
h, the reaction mixture was cooled to r.t. and quenched
with aq NaOH (10%, 15 ml). The mixture was concentrated
to one-third in volume and refluxed for 5 h. After separation
of the organic layer, the aqueous layer was extracted with
Et2O (3 3 30 ml). The combined organic layers were dried
(Na2SO4) and concentrated under vacuum to afford a mix-
ture of aminoalcohols which were used directly in the next
step. Di-tert-butyl dicarbonate (446 mg, 2.04 mmol) was
added to a solution of crude amino alcohols (280 mg, 1.36
mmol) in toluene (10 ml) and refluxed for 5 h. The solvent
was evaporated, the diastereomeric ratio (1:3) was then
1
evaluated from H NMR spectrum and the products were
separated by flash column chromatography on silica gel
with AcOEt/PE (30:70) as eluent to afford the pure diaster-
eoisomers 12 (115 mg, 25%); [a]2D0 165.8 (c 0.71, EtOH),
Ref. 21 [a]2D0 144.8 (c 0.6, EtOH, ee 87%) and 13 (230 mg,
50%); [a]2D0 143.8 (c 0.65, EtOH), Ref. 21 [a]2D0 126.5 (c
0.60, EtOH, ee 89%), as colorless oil.
(1)-Sedamine (1a) and (1)-allosedamine (2a).
A
solution of 12 (50 mg, 0.16 mmol) in THF (2 ml)
wasadded dropwise to a stirred suspension of LiAlH4 (30.4
mg, 0.8 mmol) in THF (5 ml) under Ar. The mixture was
refluxed for 6 h then cooled to 08C. Aq NaOH solution
(15%, 0.5 ml) was carefully added followed by water (5ml).
The mixture was extracted with CH2Cl2 (3 3 30 ml) and
The determination of the absolute configuration of 10
the combined organic layers were dried (Na2SO4). Evapo- and 11 was achieved by their conversion to the corre-
ration of the solvent under vacuum left an oily residue (32 sponding N-Boc protected compounds 12 and 13. This
mg, 91%) which was purified by TLC (Merck precoated conversion was secured by sequential treatment of the dia-
neutral aluminum oxide 150F254-Typ T; CH2Cl2-MeOH, stereoisomeric mixture 10, 11 with BH3-THF and tert-
90:10, as eluent) to afford (1)-Sedamine (1a) as a color- butoxycarbonyl anhydride. This single operation triggered
less oil (22 mg, 62%); [a]2D0 185.3 (c 0.8, EtOH), Ref. 20 the reduction of the hydrazide carbonyl function with the
[a]2D0 187.0 (c 1.1, EtOH). Crude (1)-allosedamine 2a concomitant release of the chiral appendage and the ulti-
(100 mg, 93%) was obtained from 13 (150 mg, 0.48 mmol) mate installation of the Boc group. Flash chromatography
Chirality DOI 10.1002/chir

SYNTHESIS OF (+)-SEDAMINE AND ALLOSEDAMINE
215
Scheme 1. Total synthesis of (1)-sedamine and (1)-allosedamine.
LITERATURE CITED
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(1)-sedamine and (1)-allosedamine, respectively. The
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Chirality DOI 10.1002/chir