Synthesis of sedamine by tethered cyclofunctionalisation

Article abstract of DOI:10.1039/b415297b

The piperidine alkaloid, (+)-sedamine has been synthesised starting from (S)-1-phenyl-3-butenol using a stereoselective, intramolecular palladium-catalysed cyclocarbonylation reaction of a substituted hydroxylamine.

Full text of DOI:10.1039/b415297b

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A R T I C L E
Synthesis of sedamine by tethered cyclofunctionalisation
Roderick W. Bates*a and Jutatip Boonsombatb
a Department of Chemistry, University of Exeter, Stocker Road, Exeter, UK EX4 4QD.
E-mail: R.W.Bates@exeter.ac.uk; Fax: +44 01392 263434; Tel: +44 01392 263465
b Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, Vibhavadi-Rangsit
Highway, Laksi, 10210, Bangkok, Thailand
Received 5th October 2004, Accepted 15th November 2004
First published as an Advance Article on the web 6th January 2005
The piperidine alkaloid, (+)-sedamine has been synthesised starting from (S)-1-phenyl-3-butenol using a
stereoselective, intramolecular palladium-catalysed cyclocarbonylation reaction of a substituted hydroxylamine.
with J = 12.6 Hz. It may be suggested that the intermediate
Introduction
alkoxide cyclises to carbamate 7 which then undergoes further
reduction to the aminal. Aminal 8 appears to be resistant to
further reduction (e.g. H+, NaCNBH3).
We recently reported the palladium catalysed cyclisation of
readily available O-homoallylic hydroxylamines 4 to give cis-
disubstituted isoxazolidines 5.1 Given the ease with which the
N–O bond may be reduced, this can be considered as a tethered
cyclofunctionalisation (Scheme 1).
On the other hand, careful reduction of the corresponding
t-Boc protected isoxazolidine 5b led cleanly to the expected
alcohol 9. Careful temperature control of this reaction is
essential. Oxidation to the corresponding aldehyde 10 with
IBX,6 followed by Wittig olefination allowed installation of
the required pair of carbon atoms. A short cut is possible, as
DIBAL reduction of the ester group of 5b, followed by Wittig
olefination in one pot leads to the same ester 11 in similar
yield, although chromatographic removal of any unreacted
starting material is difficult. After routine removal of the t-
Boc group, hydrogenation of isoxazolidine 12 using palladium
on carbon resulted in a tandem process; the alkene double
bond and the O–N bond were cleaved, although, happily,
no cleavage of the benzylic C–O bond was observed. It is
known that amino groups can inhibit hydrogenolysis of benzylic
bonds.7 The resulting amino ester 13 cyclised on standing to
lactam 14. This could be easily converted to norsedamine 15
by LiAlH4 reduction. The spectroscopic data (1H NMR, 13C
NMR, IR) of our synthetic material were in good agreement
with those reported by Pilli for the racemate.8 Although a one
step methylation of norsedamine 15 to sedamine 6 has been
reported, we found that a more convenient method was to
proceed via the known bicyclic oxazine 16 which, following
the reported procedure, gave sedamine 6 on lithium aluminium
hydride reduction, accompanied by a small amount of the
aminal 17. The spectroscopic data, melting point and optical
rotation of the synthetic (+)-sedamine 6 were in agreement with
those previously reported.3b,9,10
Scheme 1 Isoxazolidine synthesis.
We now wish to report the application of this reaction to the
synthesis of the alkaloid sedamine, 6. This compound is the
best known of a large group of piperidine alkaloids that have
been isolated from Sedum and other species. They may be of
interest in the treatment of cognitive disorders.2 While numerous
syntheses of sedamine have been reported,3 typically they result
in mixtures of sedamine and its diastereoisomer, allosedamine.
Isoxazolidine intermediates have been used, formed by 1,3-
dipolar cycloadditions of nitrones with styrene.4 However, these
reactions lead to allosedamine, a diastereomer, as the major
product. On the other hand, cis-isoxazolidines, such as 5, have
the appropriate stereochemistry to lead to 6.
In conclusion, we have succeeded in preparing sedamine
in a straightforward way, using 1,3-asymmetric induction to
introduce the N-substituted chiral centre. The efficiency of the
route rests on the rapid introduction of the required nitrogen,
minimising the use of protecting groups, and the use of a tandem
process to construct the piperidine ring. Application of this
strategy to other targets is in hand.
Support of this work by the Thailand Research Fund, the
University of Exeter and Pfizer Global Research and Develop-
ment is gratefully acknowledged. The part of this work carried
out in Thailand was made possible by the generous provision of
facilities by the Chulabhorn Research Institute.
Results and discussion
The isoxazolidines 5a,b were prepared as reported previously,1
with alcohol 1 of ca. 95% ee as the starting material. There
are a number of ways to prepare alcohol 1 in an optically
active form. For this work, the method of Maruoka was used,
involving allylation of benzaldehyde in the presence of a chiral
Lewis acid derived from chlorotitanium triisopropoxide, silver
oxide and (S)-BINOL.5 Using the isoxazolidines 5a,b for the
synthesis of sedamine 6 (Scheme 2) would require addition of a
further two carbon atoms in order to construct the piperidine
ring. The Wittig reaction with a stabilised ylide was selected for
this transformation because of the mildness of the conditions.
Attempts to selectively reduce the ester group of the methyl
carbamate-protected isoxazolidine 5a, in order to prepare for
such a Wittig reaction, led to the aminal 8, rather than the
expected alcohol. The identity of the aminal was indicated by a
pair of doublets in the 1H NMR spectrum (4.60 and 5.04 ppm)
Experimental
General
IBX and bis(acetonitrile)palladium(II) chloride were prepared
by the reported methods. THF was distilled from sodium–
benzophenone, acetonitrile and dichloromethane were distilled
from calcium hydride and methanol was distilled from activated
5 2 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 5 2 0 – 5 2 3
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
©

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Scheme 2 Sedamine synthesis.
magnesium. Other reagents and solvents were commercial and
used as received. Petrol refers to the fraction boiling between 40
and 60 ◦C.
63.56; H, 7.36; N, 4.27. Calc. for C18H15NO3: C, 63.54; H, 7.36;
N 4.27. Other data have been reported previously.
IR spectra were recorded on a Nicolet Magna 550 spectrom-
eter either neat or as nujol mulls using NaCl plates. H NMR
2-((3R,5R)-2-t-butoxycarbonyl-5-phenylisoxazolidin-
3-yl)ethanol (9)
1
spectra were recorded on a Bruker AM300 or a Varian Gemini
at 300 or 200 MHz with residual protic solvent as the reference.
13C spectra were recorded at the corresponding frequencies on
the same machines. Chemical shifts are in ppm and coupling
constants, J, are in Hz. Mass spectra were recorded on a Finigan
GCQ instrument at 70 eV and high resolution mass spectra
on a Micromass GCT instrument. Specific rotations, [a]D, were
recorded on an Optical Activity Ltd AA-1000 polarimeter and
are given with units of 10−1 deg cm2 g−1. Elemental analysis was
carried out at the University of Exeter.
A solution of the ester 5b (500 mg, 1.6 mmol) in THF (6 ml) was
cooled to −78 ◦C. LiAlH4 (121 mg, 3.2 mmol) was gradually
added to the cool solution◦ from a solid addition tube. The
mixture was stirred at −78 C for 2 h and left to warm up to
−20 ◦C. Water was added to the mixture and it was stirred until
a white crystalline precipitate formed. The mixture was then
filtered through celite, washing with EtOAc, and evaporated to
give the alcohol 9 as a colourless oil (434 mg, 94%) [a]2D9 + 32
(c = 4.9, CH2Cl2). mmax/cm−1 3450, 2875, 2930, 2979, 1708; dH
(200 MHz; CDCl3) 1.50 (9H, s, t-Bu), 1.65–2.05 (3H, m, H4,
CH2), 2.87 (1H, ddd, J 6.6 8.8 12.5, H4), 2.97 (1H, brs, OH),
3.71 (1H, ddd, J 3.7 5.9 12.0, CHHOH), 3.81 (1H, ddd, J 4.4
9.5 11.7, CHHOH), 4.49 (1H, dddd, J 4.4 7.3 8.8 11.0, H3),
4.82 (1H, dd, J 10.3 5.9, H5), 7.3 (5H, m); dC (50 MHz; CDCl3)
28.1, 38.8, 43.6, 57.9, 59.6, 82.5, 83.2, 126.6, 128.5, 136.9, 159.2;
m/z 294 (28%, M + H+), 293 (26, M+), 238 (32, M + H+–C4H8),
193 (36, M + H+-Boc), 117 (100, M + H+-Boc-Ph). m/z (FI)
293.1617 (M+ C16H23NO4 requires 263.1627).
(R)-2-(1-Phenylbut-3-en-1-yloxy)isoindole-1,3-dione (2)
This compound was prepared following the previously reported
procedure and purified by flash chromatography on silica gel
◦
eluting with 5% ethyl acetate–petrol. mp 85–86 C, [a]2D9 + 193
(c = 1.5, CH2Cl2). Found: C, 73.49; H, 5.12; N, 4.50. Calc. for
C18H15NO3: C, 73.71; H, 5.15; N 4.78; mmax/cm−1 2918, 2930,
2852 (CH), 1793,1728 (CO); dH (300 MHz; CDCl3) 2.72 (1H,
dtt, J 14.5, 7, 1.5, CHH), 2.95 (1H, dtt, J 14.5, 7, 1.5, CHH),
2-((3R,5R)-2-t-Butoxycarbonyl-5-phenylisoxazolidin-
3-yl)acetaldehyde (10)
=
5.07 (1H, ddd, J 1.5, 2, 10, CH), 5.15 (1H, ddd, J 1.5, 2, 17,
=
CH), 5.39 (1H, t, J 7, CHON), 5.79 (1H, ddt, J 17, 10, 7,
=
CH), 7.32 (3H, m, Ar), 7.47 (2H, m, Ar), 7.70 (4H, m, Ar) dC
(75 MHz; CDCl3) 39.0, 88.1, 117.9, 123.1, 128.0, 128.1, 128.3,
128.6, 128.9, 133.4, 132.8, 137.3, 163.5.
IBX (229 mg, 0.68 mmol) was added to a solution of the alcohol
9 (229 mg, 0.8 mmol) in DMSO (1.7 ml). The solution was
stirred for 5 h, then diluted with water. The precipitate was
removed by filtration through celite, washing thoroughly with
ethyl acetate. The layers were separated, and the aqueous layer
was re-extracted with ethyl acetate. The combined organic layers
were washed (brine), dried (Na2SO4) and evaporated to give
the aldehyde as yellow oil (254 mg) which was used without
purification. mmax/cm−1 2930, 2980, 1724; dH (200 MHz; CDCl3)
1.50 (9H, s, t-Bu), 1.93 (1H, ddd, J 6.6 10.3 12.5, H4), 2.73
(1H, ddd, J 1.5 8.0 16.9, CHHCHO), 2.90 − 3.05 (2H, m, H4,
CHHCHO), 4.75 (1H, ddd, J 6.6 8.0 13.2, H3), 4.89 (1H, dd,
J 6.6 10.3, H5), 7.18 (5H, m, Ph), 9.82 (1H, t, J 1.5, CHO); dC
(50 MHz; CDCl3) 28.1, 43.3, 49.8, 56.0, 82.5, 82.8, 126.5, 128.5,
136.7, 157.5, 200.5; m/z 291 (10%, M+), 236 (16, M + H+–C4H8),
191 (19, M+-Boc), 131 (100, C9H11+).
N-t-Butoxycarbonyl-O-((R)-1-phenylbut-3-en-1-yl)hydro-
xylamine (4b)
This compound was prepared following the previously reported
procedure. [a]2D9 + 131 (c = 4.9, CH2Cl2). Other data have been
reported previously.
Methyl ((3S,5R)-2-t-butoxycarbonyl-5-phenylisoxazolidin-3-yl)
acetate (5b)
This compound was prepared following the previously reported
procedure. mp 47–49 ◦C; [a]D29 −2.3 (c = 5.5, CH2Cl2). Found: C,
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 5 2 0 – 5 2 3
5 2 1

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Methyl 4-((3R,5R)-2-t-butoxycarbonyl-5-phenylisoxazolidin-
3-yl)but-2-enoate (11)
1.8 (5H, m, CH2), 2.22 (1H, ddd, J 18, 11, 6, CH), 2.35 (1H,
ddt, J, 18, 5, 2, CH), 3.63 (1H, tt, J 8.8, 3, H3), 3.80 (1H, brs,
OH), 4.85 (1H, dd, J 3.5 9.5, CHOH), 7.2 (5H, m, Ph), 7.72
(1H, s, NH); dC (50 MHz; CDCl3) 19.9, 29.4, 30.5, 45.3, 53.8,
74.5, 125.3, 127.2, 128.3, 145.2, 172.2; m/z 220 (M + H+), 201
(M+–H2O), 112 (MH+–PhCH2OH), 98 (C5H8NO+), 77 (Ph+);
m/z 219.1248 (M+ C13H17NO2 requires 219.1259).
From the isolated aldehyde: methyl (triphenylphosphoranyli-
dene)acetate (97 mg, 0.27 mmol) was added to a solution of
aldehyde 10 (40 mg, 0.14 mmol) in CH2Cl2 (1 ml). The mixture
was stirred overnight, then pre-absorbed onto silica gel and
purified by flash chromatography on silica gel (1.2 g) using 5–
10% EtOAc–hexane as eluent to give the Z and E alkenes 11
(33 mg, 67%).
(+)-Norsedamine (15)
In situ generation of the aldehyde: DIBAL (357 ll of a 1M
solution in hexane, 03.7 mmol) was added dropwise to a solution
of the ester 5b (100 mg, 0.31 mmol) in THF (2 ml) under N2
at −55 ◦C. This was stirred for 2 h, then a solution of the
ylide (221 mg, 0.62 mmol) in 1 : 1 THF : CH2Cl2 (2 ml) was
transferred to the reaction flask by canula. The mixture was
allowed to warm up to room temperature and stirred overnight.
Water was added and the mixture was stirred for 30 min followed
by addition of Na2SO4 until all of the white jelly-like precipitate
turned crystalline. It was filtered, washed with EtOAc and
the filtrate was evaporated. The residue was purified by flash
chromatography on silica gel (3 g) using 5–10% EtOAc–hexane
as eluent to give the Z alkene as an oil and the E alkene as a
colourless solid (70 mg, 64%).
LiAlH4 was added to a solution of the lactam 14 (1g, 4.6 mmol)
in THF (20 ml) at 0 ◦C. This mixture was gradually allowed to
warm up to room temperature and was then stirred for 1 h. H2O
was added dropwise until a white precipitate had completely
formed. The mixture was filtered, washing with EtOAc and
evaporated to give norsedamine as a colourless solid (926 mg,
98%) which was used without further purification. mp 57–60 ◦C
[a]2D9 + 1 (c = 1.7, CH2Cl2); mmax/cm−1 3298, 3087, 2820, 2933; dH
(300 MHz; CDCl3) 1.0–2.0 (8H, m, CH), 2.66 (1H, ddd, J 14,
11.6, 3, CH), 2.92 (1H, tt, J 10.5, 3, CH), 3.09 (1H, brd, J 14,
CHN), 3.2 (2H, br, CH2N), 4.94 (1H, dd, J 2.9 10.3, CHOH),
7.1 (5H, m, Ph); dC (50 MHz; CDCl3) 24.2, 26.9, 33.8, 44.9, 45.8,
57.9, 75.1, 125.4, 126.8, 128.0, 145.1; m/z 206 (29%, M + H+),
84 (100, C5H10N+), 77 (50, Ph+), 56 (35, C4H8+).
E isomer: mp 57–58 ◦C, [a]D29 + 10 (c = 4.7, CH2Cl2). Found: C,
65.61; H, 7.47; N, 3.95. Calc. for C19H25NO5: C, 65.69; H, 7.25;
N 4.03. mmax/cm−1 2981, 1724, 1660; dH (200 MHz; CDCl3) 1.50
(9H, s, t-Bu), 1.94 (1H, ddd, J 6.0, 10.3, 12.0, H4), 2.45–2.90
(3H, m, H4, CH2), 3.66 (3H, s, OMe), 4.44 (1H, app q, J 7.0,
(3R,5R)-3-Phenylhexahydro-3H-pyrido[1,2-c][1,3]oxazin-1-one
(16)
Carbonyl diimidazole (101 mg, 0.62 mmol) was added to a
solution of crude norsedamine 15 (106 mg, 0.52 mmol) in
THF (2 mL). The solution was stirred at room temperature
overnight, then diluted with ethyl acetate and washed with
dilute hydrochloric acid. The aqueous layer was re-extracted
with ethylacetate. The combined organic extracts were washed
with brine, dried (MgSO4) and evaporated. The residue was
purified by flash chromatography on silica gel (3 g) eluting with
30% ethy◦l acetate–petrol to give the oxazine 16 (71 mg, 59%). mp
135–138 C (lit.9 127–129 ◦C), [a]D32 + 61.5 (c = 0.55, CHCl3), dH
(300 MHz; CDCl3) 1.0–1.9 (7H, m, CH), 2.25 (1H, ddd, J 13.9,
5.7, 2.0, CH), 2.67 (1H, dt, J 12.6, 2.8, CHN), 3.43 (1H, ddt,
J 11.1, 5.5, 2.5, CHN), 4.54 (1H, brd, J 13.4, CHN), 5.17 (1H,
dd, J 11.7, 2.0, CHO), 7.3 (5H, m, Ph), dC (75 MHz; CDCl3)
23.4, 24.1, 24.8, 33.3, 38.1, 54.0, 76.3, 126.6, 128.1, 128.3, 138.8,
153.4.
=
H3), 4.87 (1H, dd, J 6.6, 10.3, H5), 5.93 (1H, d, J 15.4, CH),
6.98 (1H, dt, J 15.4, 7.3, CH), 7.38 (5H, m, Ph); dC (50 MHz;
=
CDCl3) 28.0, 38.6, 42.6, 51.3, 59.3, 82.1, 82.8, 123.3, 126.4, 128.3,
128.4, 136.9, 144.6, 157.4, 166.4; m/z 292 (M + H+–C4H8), 148
(M+-Boc-C3H4CO2Me), 130 (M+-Boc-C3H4CO2Me–H2O), 105
(PhC2H4+), 103 (PhC2H2+), 77 (Ph+).
Z isomer: dH (200 MHz; CDCl3) 1.52 (9H, s, t-Bu), 1.98
(1H, ddd, J 6.6 10.3 12.5, H4), 2.81 (1H, ddd, J 6.6 8.0 12.5,
H4), 3.00–3.15 (2H, m, CH2), 3.50 (3H, s, OMe), 4.47 (1H,
app tt, J 6.6 8.0, H3), 4.82 (1H, dd, J 6.6 10.3, H5), 5.92
=
=
(1H, td, J 2.0 11.7, CH), 6.42 (1H, td, J 7.3 11.7, CH),
7.35 (5H, m, Ph).
Methyl 4-((3R,5R)-5-phenylisoxazolidin-3-yl)but-2-enoate (12)
Trifluoroacetic acid(222ll, 2.9mmol)was addeddropwise tothe
isoxazolidine 11 (100 mg, 0.29 mmol) at room temperature under
nitrogen. The mixture was stirred for 1 h, then the volatiles were
evaporated under reduced pressure. Saturated NaHCO3 (aq) was
added to the residue and the mixture was extracted with EtOAc
(3 times). The combined organic layers were dried (Na2SO4)
and evaporated to give the deprotected isoxazolidine 12 as a
pale yellow oil (97 mg) which was used without purification.
mmax/cm−1 3234 (NH), 2950, 1719, 1658; 1.85 (1H, ddd, J 5.5 8.1
12.5, H4), 2.38 (1H, dtd, J 1.5 7.3 13.9, CH2), 2.60 (1H, dtd, J 1.5
7.3 13.9, CH2), 2.82 (1H, ddd, J 7.3 8.1 12.5, H4), 3.60–3.75 (4H,
m, H3, OMe), 4.68 (1H, brs, NH), 4.88 (1H, t, J 8.1, H5), 5.89
(+)-Sedamine (6)
LiAlH4 (23 mg, 0.6 mmol) was added to a solution of the oxazine
16 (70 mg, 0.3 mmol) in THF (2 mL) under nitrogen. The
mixture was heated at reflux for 2 h, then cooled and quenched
by the cautious addition of the minimum amount of water. The
colourless, precipitated solids were removed by filtration through
celite, washing thoroughly with ethyl acetate. The filtrate was
evaporated and the residue was purified by flash chromatography
on silica gel (2 g) eluting with 30% ethyl acetate–petrol to give
the aminal 17 (5 mg, 8%) and 20% methanol–chloroform to give
sedamine 6 (50 mg, 76%) as a viscous◦oil which solidified slowly
on standing; mp (ether–petrol) 57–59 C, (lit.,3b,10 54–56, 59–61);
[a]D29 + 80 (c = 1.2, EtOH), (lit.3b [a]2D0 + 87 (c = 1.1, EtOH));
dH (200 MHz; CDCl3) 1.20–1.90 (7H, m, CH), 2.24 (1H, ddd,
J 14.3, 10.5, 9.2, CH), 2.50 (3H, s, Me), 2.57 (1H, m, CHN),
2.86 (1H, m, CHN), 3.07 (1H, m, CHN), 4.89 (1H, dd, J 2.9
10.5, CHOH), 7.3 (5H, m, Ph); dC (75 MHz; CDCl3) 20.5, 22.3,
25.8, 39.7, 39.9, 51.4, 60.8, 74.3, 125.5, 126.9, 128.2, 145.5; m/z
220 (25%, M + H+), 98 (100, C6H12N+), 77 (14, Ph+), 70 (37,
C5H10+).
=
=
(1H, td, J 1.5, 16.0, CH), 6.98 (1H, td, J 7.3 16.0, CH ), 7.30
(5H, m, Ph); dC (50 MHz; CDCl3) 37.6, 43.8, 51.4, 59.9, 84.5,
123.0, 126.0, 127.8, 128.5, 139.4, 145.4, 166.6; m/z 248 (4%,
M + H+), 149 (10, M+–C5H7O2), 130 (100, M+–C5H7O2–H2O),
103 (71, PhC2H2+), 77 (32, Ph+).
(6R)-6-((2R)-2-Hydroxy-2-phenylethyl)piperidin-2-one (14)
A solution of the alkene 12 (167 mg, 0.68 mmol) in MeOH (4 ml)
containing Pd/C (17 mg, 10%) was stirred under H2 (1 atm) for
7 h. The mixture was filtered through celite and the filtrate was
evaporated. The residue was purified by flash chromatography
on silica gel (3 g) eluting with 75% EtOAc–hexane to give lactam
14 as a colourless solid (148 mg, 100%) mmax/cm−1 3300, 3187,
2900, 2948, 1652; dH (300 MHz; CDCl3) 1.3 (1H, m, CH), 1.5–
1H NMR data for aminal 17 dH (200 MHz; CDCl3) 1.3 (2H,
m), 1.7 (5H, m), 2.04 (1H, m), 2.28 (1H, m), 2.83 (1H, brd, J
11.1), 3.94 (1H, d, J 8.1), 4.50 (1H, dd, J 9.6, 4.5), 4.58 (1H, d,
J 8.1), 7.3 (5H, m).
5 2 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 5 2 0 – 5 2 3

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References
1 R. W. Bates and K. Sa-Ei, Org. Lett., 2002, 4, 4225.
2 (a) O. Meth-Cohn, C.-Y. Yu, P. Lestage, M.-C. Lebrun, D.-H.
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58, 5957; (b) More recent syntheses: J. Cossy, C. Willis, V. Bellosta
and S. Bouzbouz, J. Org. Chem., 2002, 67, 1982; (c) F.-X. Felpin and
J. Lebreton, J. Org. Chem., 2002, 67, 9192; (d) M. Angoli, A. Barilli,
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O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 5 2 0 – 5 2 3
5 2 3