Synthesis of sedamine by cycloisomerisation of an allenic hydroxylamine

Article abstract of DOI:10.1055/s-2008-1066985

Isoxazolidines have been prepared in a stereoselective manner by treatment of allenic hydroxylamines with silver(I). This methodology has been used in a short synthesis of the alkaloid (+)-sedamine. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1066985

PAPER
1033
Synthesis of Sedamine by Cycloisomerisation of an Allenic Hydroxylamine
Cycloisomerisation of
A
llenic
d
H
ydroxylam
e
ines rick W. Bates,* Joseph A. Nemeth, Robert H. Snell
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
Received 19 August 2007; revised 2 January 2008
NHPG
X
O
Abstract: Isoxazolidines have been prepared in a stereoselective
manner by treatment of allenic hydroxylamines with silver(I). This
methodology has been used in a short synthesis of the alkaloid (+)-
sedamine.
Ph
•
Ph
•
c
2a X = OH
3a PG = Boc
3b PG = Cbz
3c PG = o-Ns
a
Key words: cyclisation, allenes, heterocycles, alkaloids, stereose-
lectivity
d
e
2b X = ONPhth
2c X = ONH2
b
NHBoc
O
NHBoc
We recently reported a synthesis of the alkaloid sedamine
(1) (Figure 1), which involved the cyclocarbonylation of
a hydroxylamine onto an alkene, with a subsequent cleav-
age of the N–O bond.1 It may thus be considered as a vari-
ation on the idea of a tethered nitrogen.2
O
•
•
Ph
Ph
4
5
Scheme 1 Reagents and conditions: (a) PhthNOH, PPh3, DIAD,
THF, 81%; (b) H2NNH2, CH2Cl2, 91%; (c) Boc2O, NaOH, H2O,
CH2Cl2, 79%; (d) CbzCl, Na2CO3, H2O, CH2Cl2, 62%; (e) o-NsCl,
Na2CO3, H2O, CH2Cl2, 57%.
Me
HO
N
Ph
PG
NHPG
AgNO3
aq acetone
O
1
O
N
Figure 1 Sedamine 1
R
•
R
3a–c R = Ph
R = Me, PG = Boc
6a–c R = Ph
R = Me, PG = Boc
The drawback of this reaction is that, while it requires a
palladium catalyst, more than two equivalents of cop-
per(II) are required due to the redox nature of the process.
We, therefore, sought a process which would deliver a
similar cyclisation, but with greater atom efficiency. One
way to do this would be by silver-mediated intramolecular
addition to an allene, a reaction originally reported by
Claesson, and extended by others, notably, Reissig, Ars-
eniyadis and Gore, Gallagher, and Marshall.3 Such a pro-
cess would be expected to yield an isoxazolidine bearing
a pendant alkene substituent. It could, therefore, be con-
ceived that the synthesis of sedamine could be continued
using a ring-closing alkene metathesis reaction to intro-
duce the additional carbon atoms.
7
8
Scheme 2
NH2 compounds 2c, which could be N-functionalised as
required (Scheme 1). To explore the generality of the re-
action, the higher and lower homologues, 4 and 5, were
also prepared, using analogous chemistry.7
The N-unsubstituted compound 2c and the N-sulfonyl
compound 3c both failed to yield any cyclised product. In
contrast, N-carbamates 3a and 3b cyclised cleanly but
slowly on treatment with 10–20 mol% silver nitrate in wet
acetone (Table 1) to give the isoxazolidines 6 (Scheme 2).
The use of other silver salts, such as AgBF4, gave no ad-
vantage. Pleasingly, the reactions required no protection
Numerous syntheses of both racemic and optically active
sedamine have been reported.4 While some potentially
useful biological activity has been reported for sedamine
(1),5 it has also become something of a ‘benchmark mole-
cule’ for the demonstration of synthetic methodology.
Table 1 Cyclisation of Allenic Hydroxylamines 2c, 3, 7
Allene
PG
R
Product,
Ratio (cis/trans)
The desired allenic hydroxylamines 3 could be prepared
by Mitsunobu reaction of the corresponding allenic alco-
hols 2 with N-hydroxyphthalimide.6 Cleavage of the
phthalimide (with hydrazine hydrate) yielded the free
yield (%)
2c
3a
3b
3c
7
H
Ph
Ph
Ph
Ph
Me
0
–
Boc
Cbz
o-Ns
Boc
6a, 98
6b, 93
0
7:1
5:1
–
SYNTHESIS 2008, No. 7, pp 1033–1038
x
x
.
x
x
.2
0
0
8
Advanced online publication: 06.03.2008
DOI: 10.1055/s-2008-1066985; Art ID: T13207SS
8, 83
4:1
© Georg Thieme Verlag Stuttgart · New York

1034
R. W. Bates et al.
PAPER
NHBoc
NHBoc
O
HO HN
AgNO3
O
O
N
O
O
b
a
aq acetone
•
Ph
Ph
Ph
Ph
Ph
5
9
11
13
O
Scheme 3
O
N
c
d
O
N
Me
N
R
N
O
N
O
O
b
c
Ph
14
15
Ph
Ph
Ph
11
12
Me
Me
e
HO
N
HO
N
6a R = Boc
10 R = H
a
Ph
Ph
16
1
Scheme 4 Reagents and conditions: (a) CF3CO2H, >99%; (b)
BrCH2CH2CH=CH2, NaHCO3, DMF, 56%; (c) MeOTs.
Scheme 5 Reagents and conditions: (a) Zn, AcOH, THF, 94%; (b)
COIm2, CH2Cl2, >99%; (c) (Cy3P)2Cl2Ru=CHPh, CH2Cl2, 81%; (d)
LiAlH4, THF, 56% (e) H2, Pd/C, MeOH, >99%.
from oxygen or atmospheric moisture. The only precau-
tion taken was the exclusion of light. In all cases, an insep-
arable mixture of cis- and trans-isoxazolidines 6 was
formed in good yield. The cis-isomer was the major iso-
mer in all cases. Gold(III) chloride8 was also employed as
a catalyst. In this case the reaction was less clean, perhaps
due to the stronger Lewis acidity of this reagent. The cor-
responding methyl substituted substrate 7 also cyclised
with useful stereoselectivity.
the carbamate to the desired methyl group (LiAlH4) and
reduction of the alkene (H2, Pd/C). No benzylic reduction
was observed in this last transformation, presumably due
to the presence of a basic nitrogen.13 The spectroscopic
data for the synthetic sedamine (1) were in good agree-
ment with those previously reported.
In conclusion, this variation on the Claesson cyclisation
provides a simple and easily executed route to functiona-
lised syn-1,3-amino alcohols that are useful intermediates
for alkaloid synthesis. This allows an efficient synthesis
of sedamine (1). The strategy is applicable to related alka-
loids.
The higher homologue 4 failed to cyclise and was recov-
ered unchanged. The lower homologue 5 also failed to cy-
clise, but was converted into its hydration product, methyl
ketone 9 (Scheme 3).
With the cyclisation methodology established, the synthe-
sis of sedamine (1) commenced. While the initial studies
of this methodology employed racemic compounds, for
the purpose of the synthesis of sedamine, allene 3a was
prepared as its S-enantiomer, starting from (S)-styrene ox-
ide.9 Cyclisation as described, gave the isoxazolidine 6a
as an inseparable cis/trans mixture. With the intention of
construction of the six-membered ring, the Boc group was
removed under the usual conditions and the nitrogen atom
of isoxazolidine 10 was alkylated with 1-bromobut-3-ene
(Scheme 4). At this point, the two stereoisomers of 11
could be easily separated by column chromatography. The
major isomer was subjected to ring-closing metathesis,10
but no product could be obtained using either the first- or
the second-generation Grubbs catalysts. As it is known
that nitrogen lone pairs may coordinate to the ruthenium
THF and CH2Cl2 were either distilled according to standard proce-
dures or obtained from a solvent purifier. Other reagents and sol-
vents were commercial and used as received. Petroleum ether (PE)
used refers to the fraction boiling between 40 and 60 °C.
IR spectra were recorded on a Nicolet Magna 550 or Bio-Rad FTS
165 spectrometer, either neat or as Nujol mulls using NaCl plates.
1H NMR spectra were recorded on a Bruker AM300 or DPX300
spectrometer at 300 MHz with residual protic solvent as the refer-
ence. 13C NMR spectra were recorded at the corresponding frequen-
cies on the same spectrometers. Chemical shifts are in ppm and
coupling constants; J are in Hz. Mass spectra were recorded on a
Finnigan GCQ instrument at 70 eV and high-resolution mass spec-
tra on a Micromass GCT instrument or a Finnigan MAT95XP in-
strument. Specific rotations, [a]D, were recorded on an Optical
Activity Ltd AA-1000 or a Jasco P-1030 polarimeter and are given
with units of 10–1degcm2g–1. Elemental analysis was carried out at
and inhibit catalysis,11 the nitrogen was quaternised by the University of Exeter.
treatment with methyl tosylate. The quaternary salt 12
(+)-(R)-2-(1-Phenylpenta-3,4-dienyloxy)isoindole-1,3-dione
(2b)
was obtained as a mixture of diastereoisomers, the major
one having the methyl cis to the vinyl group (NOE). Nei-
ther diastereoisomer, however, underwent ring-closing
metathesis using either of the Grubbs catalysts.
Diisopropylazodicarboxylate (1.27 mL, 6.88 mmol) was added
dropwise to a stirred solution of 1-phenylpenta-4,5-dien-1-ol (2a;
1.00 g, 6.25 mmol), N-hydroxyphthalimide (1.02 g, 6.25 mmol),
and PPh3 (1.638 g, 6.25 mmol) in THF (30 mL) under N2. The mix-
ture was then stirred at r.t. for 16 h. Silica gel (10 g) was added to
the mixture and the solvent was evaporated. The powder was then
transferred to the top of a silica gel column (30 g). Flash chromatog-
raphy eluting with 10% EtOAc–PE gave the title compound (1.551
g, 81%) as a colourless crystalline solid; mp 87–91 °C.
Consequently, the N–O bond of isoxazolidine 11 was
cleaved with zinc and acetic acid. The resulting amino al-
cohol 13 was reprotected as cyclic carbamate 14, which
underwent ring-closing metathesis very efficiently on
treatment with the Grubbs first-generation catalyst12
(Scheme 5). The synthesis was completed by reduction of
IR (Nujol): 1956, 1789, 1729, 1466, 705 cm–1.
Synthesis 2008, No. 7, 1033–1038 © Thieme Stuttgart · New York

PAPER
Cycloisomerisation of Allenic Hydroxylamines
1035
1H NMR (300 MHz, CDCl3): d = 7.75 (4 H, m, ArH), 7.48 (2 H, m,
ArH), 7.30 (3 H, m, ArH), 5.40 (1 H, t, J = 7.0 Hz, PhCHON), 5.10
(1 H, app quint, J = 7.0, 7.0 Hz, HC=C=CCH2), 4.64 (2 H, dt, J =
3.0, 6.6 Hz, C=C=CH2), 2.90 (1 H, m, CH2), 2.69 (1 H, m, CH2).
13C NMR (75 MHz, CDCl3): d = 209.9, 164.1, 138.2, 134.7, 129.5,
129.2, 128.7, 128.6, 123.8, 88.8, 85.6, 75.8, 34.4.
MS (CI): m/z (%) = 306 (MH+, 16), 192 (22), 164 (50), 143 (100),
107 (62).
HRMS: m/z calcd for C19H15NO3 (M+): 306.1130; found: 306.1135.
Hz, PhCH), 4.4–4.5 (2 H, m, =CH2), 2.52–2.70 (1 H, m, CHH),
2.30–2.48 (1 H, m, CHH).
13C NMR (75 MHz, CDCl3): d = 209.4, 156.9, 139.1, 135.5, 128.6
(2 C), 128.5, 128.4, 128.3, 127.3, 87.4, 84.5, 75.0, 67.5, 34.3.
MS (CI): m/z (%) = 310 (MH+, 11), 266 (21), 233 (30), 143 (100),
106 (34).
HRMS: m/z calcd for C19H20NO3 (MH+): 310.1443; found:
310.1446.
2-Nitro-N-(1-phenylpenta-3,4-dienyloxy)benzenesulfonamide
(3c)
(R)-O-(1-Phenylpenta-3,4-dienyl)hydroxylamine (2c)
Allene 2b (621 mg, 2.03 mmol) was dissolved in CH2Cl2 (4 mL).
Hydrazine monohydrate (590 mL, 12.2 mmol) was added to the so-
lution and the mixture was stirred at r.t. for 1 h. The precipitate was
filtered off under suction and the filtrate collected. The solvent was
evaporated to give the title compound (323 mg, 91%) as a colourless
oil. This compound was then used without further purification due
to its instability.
1H NMR (300 MHz, CDCl3): d = 7.36 (5 H, m, ArH), 5.27 (2 H, s,
NH2), 5.06 (1 H, app quint, J = 7.0, 7.0 Hz, =CH), 4.65 (2 H, dt, J =
6.8, 3.0 Hz, =CH2), 4.59 (1 H, dd, J = 1.5, 7.5 Hz, PhCHON), 2.51
(1 H, m CH2), 2.37 (1 H, m, CH2).
o-Nosyl chloride (616 mg, 2.78 mmol), was added to a solution of
the hydroxylamine 2c (323 mg, 1.85 mmol) and Na2CO3 (295 mg,
2.78 mmol) in H2O–CH2Cl2 (1:1, 7.5 mL) and the mixture was
stirred for 15 h. The organic layer was collected and the aqueous
layer was further extracted with CH2Cl2 (3 × 5 mL). The combined
organic extracts were dried (MgSO4) and the solvent evaporated in
vacuo to give the title compound (377 mg, 57%) as a light brown
solid; mp 102–105 °C.
IR (Nujol): 3261, 1971, 1947, 1539, 1456, 1377, 1172 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.25 (1 H, m, ArH), 7.80 (3 H, m,
ArH), 7.34 (5 H, m, ArH), 5.15 (1 H, dd, J = 1.7, 6.0 Hz, PhCH),
5.07 (1 H, app quint, J = 6.9, 7.2 Hz, CH=C), 4.59 (2 H, m, C=CH2),
2.44–2.52 (2 H, m, CH2).
13C NMR (75 MHz, CDCl3): d = 209.9, 148.9, 139.4, 137.0, 135.2,
134.4, 133.2, 130.8, 88.7, 86.1, 75.6, 34.9.
MS (CI): m/z (%) = 361 (MH+, 100), 291 (92), 225 (16), 98 (14).
HRMS: m/z calcd for C17H17O5N2S (MH+): 361.0858; found:
(R)-(+)-N-(1-tert-Butoxycarbonyl)-O-(1-phenylpenta-3,4-di-
enyl)hydroxylamine (3a)
A solution of the allenic hydroxylamine 2c (0.903 g, 5.16 mmol),
di-tert-butyl dicarbonate (1.126 g, 5.16 mmol) and NaOH (0.413 g,
10.32 mmol) in H2O–CH2Cl2 (1:1, 20 mL) was stirred for 16 h at r.t.
The mixture was extracted with CH2Cl2 (3 × 10 mL), and the com-
bined organic extracts were dried (MgSO4), and the solvent evapo-
rated in vacuo. Purification of the residue by flash chromatography
on silica gel (28 g) eluting with 5% EtOAc–PE gave the title com-
pound as a colourless crystalline solid (1.126 g, 79%); mp 48–
51 °C; [a]D32 +115.30 (c 1.02, CHCl3).
361.0849.
N-(1-tert-Butoxycarbonyl)-O-(1-phenylhexa-4,5-dienyl)hydrox-
ylamine (4)
The title compound (194 mg, 79%) was obtained as a light yellow
oil from the higher homologue of allenic alcohol 2a via its hydrox-
ylamine derivative by the method described for 3a.
IR (Nujol): 3256 (NH), 1955 (C=C=C), 1720 cm–1 (C=O).
1H NMR (300 MHz, CDCl3): d = 7.25–7.35 (5 H, m, ArH), 6.93 (1
H, s, NH), 5.11 (1 H, app quint, J = 7.0, 7.0 Hz, =CH), 4.80 (1 H, t,
J = 7.0 Hz, PhCHON), 4.62 (2 H, dt, J = 7.0, 3.0 Hz, =CH2), 2.55–
2.7 (1 H, m, CH2), 2.35–2.5 (1 H, m, CH2), 1.41 (9 H, s, t-C4H9).
13C NMR (75 MHz, CDCl3): d = 209.8, 159.9, 140.0, 128.9, 128.7,
127.7, 87.5, 86.0, 82.1, 75.3, 34.8, 28.6.
MS (CI): m/z (%) = 276 (MH+, 4), 220 (12), 144 (16).
HRMS: m/z calcd for C16H22NO3 (MH+); 276.1600; found:
IR (neat): 3303, 1956, 1717 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.34 (5 H, m, ArH), 6.89 (1 H, s,
NH), 5.17 (1 H, app quint, J = 6.5 Hz, CH=C), 4.76 (1 H, t, J = 6.5
Hz, PhCH), 4.67 (2 H, m, C=CH2), 2.09 (3 H, m, 2 × CH2), 1.87 (1
H, m, CH2), 1.47 (9 H, s, t-C4H9).
13C NMR (75 MHz, CDCl3): d = 208.9, 156.8, 140.8, 128.9, 128.6,
127.6, 89.9, 87.7, 75.7, 35.0, 28.6, 24.6.
MS (CI): m/z (%) = 290 (M+, 17), 235 (17), 234 (93), 230 (43), 175
276.1605.
(78).
N-Benzyloxycarbonyl-O-(1-phenylpenta-3,4-dienyl)hydroxyl-
amine (3b)
HRMS: m/z calcd for C17H23NO3 (M+): 290.1756; found: 290.1754.
Benzyl chloroformate (230 mL, 1.64 mmol) was added to a solution
of hydroxylamine 2c (273 mg, 1.56 mmol) and Na2CO3 (165 mg,
1.56 mmol) in H2O–CH2Cl2 (1:1, 6.20 mL) and the mixture was
stirred for 4 h. The aqueous layer was extracted with CH2Cl2 (2 × 5
mL). The combined organic extracts were dried (MgSO4) and the
solvent evaporated in vacuo. The crude residue was purified by
flash chromatography (10% EtOAc–PE) on silica gel (12 g), to give
the title compound (297 mg, 62%) as a colourless crystalline solid;
mp 34–37 °C.
N-(1-tert-Butoxycarbonyl)-O-(1-phenylbuta-3,4-dienyl)hydrox-
ylamine (5)
The title compound (312 mg, 76%), was obtained as a colourless oil
from the lower homologue of allenic alcohol 2a via its hydroxyl-
amine derivative by the method described for 3a.
1H NMR (300 MHz, CDCl3): d = 7.39 (5 H, m, ArH), 7.14 (1 H, br
s, NH), 5.48 (1 H, dt, J = 7.8, 6.6 Hz, CH=C), 5.32 (1 H, br d, J =
7.8 Hz, PhCH), 4.89 (1 H, ddd, J = 1.6, 6.6, 11.4 Hz), 4.83 (1 H,
ddd, J = 1.7, 6.6, 11.4 Hz), 1.48 (9 H, s, 3 × CH3).
13C NMR (75 MHz, CDCl3): d = 210.2, 156.9, 139.0, 128.9 (2 C),
127.9, 90.9, 85.9, 82.1, 77.3, 28.6.
MS (EI): m/z (%) = 262 (MH+, 10), 130 (11), 129 (100), 57 (45).
HRMS: m/z calcd for C15H19NO3 (M+): 262.1443; found: 262.1450.
IR (Nujol): 3238 (NH), 1956, 1727 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.2–7.4 (5 H, m, ArH), 7.07 (1 H,
s, NH), 5.09 (1 H, d, J = 12 Hz, PhCH2), 5.05 (1 H, d, J = 12 Hz,
PhCH2), 5.02 (1 H, app quint, J = 7 Hz, =CH), 4.76 (1 H, t, J = 6.9
Synthesis 2008, No. 7, 1033–1038 © Thieme Stuttgart · New York

1036
R. W. Bates et al.
PAPER
2-tert-Butoxycarbonyl-5-phenyl-3-vinylisoxazolidine (6a); Typ-
ical Procedure
10.2, 1.1 Hz, =CH), 4.59 (1 H, m, H-3), 4.02 (1 H, m, H-5), 2.57 (1
H, ddd, J = 12.1, 8.4, 5.6 Hz, H-4), 1.67 (1 H, ddd, J = 12.1, 9.8, 7.1
Hz, H-4), 1.48 (9 H, s, t-C4H9), 1.34 (3 H, d, J = 6 Hz, CH3).
13C NMR (75 MHz, CDCl3): d = 157.6, 138.4, 114.4, 81.8, 77.1,
62.9, 41.9, 28.6, 18.0.
A solution of the Boc-protected hydroxylamine 3a (2.097 g, 7.63
mmol), AgNO3 (0.259 g, 1.53 mmol) and 1,1,3,3-tetramethylguani-
dine (96 mL, 0.76 mmol) in acetone–H2O (5:1, 25 mL) was stirred
in the absence of light at r.t. for 30 h. The mixture was partitioned
between EtOAc (20 mL) and H2O (20 mL). The aqueous layer was
extracted with EtOAc (2 × 20 mL) . The organic extracts were com-
bined, washed sequentially with H2O (10 mL) and brine (10 mL),
dried (MgSO4), and the solvent removed in vacuo to give the title
compound (2.057 g, 98%) as a colourless oil.
HRMS: m/z calcd for C11H19O3N: 213.1365; found: 213.1365.
N-(1-tert-Butoxycarbonyl)-O-(1-phenyl-3-oxobutyl)hydroxyl-
amine (9)
Treatment of allene 5 with AgNO3 as described for the preparation
of 6a gave the ketone 9.
1H NMR (300 MHz, CDCl3): d = 7.30 (5 H, m, ArH), 5.24 (1 H, dd,
J = 5.5, 7.9 Hz, PhCH), 3.13 (1 H, dd, J = 8.1, 16.2 Hz, CHH), 2.73
(1 H, dd, J = 5.5, 16.2 Hz, CHH), 2.21 (3 H, s, CH3), 1.48 (9 H, s,
t-C4H9).
IR (neat): 3075, 1726 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.35 (5 H, m, ArH), 5.91 (1 H,
ddd, J = 7.0, 10.0, 17.1 Hz, CH=CH2), 5.29 (2 H, dd, J = 10.0, 17.1
Hz, CH=CH2), 4.89 (1 H, dd, J = 10.0, 6.2 Hz, PhCHON), 4.76 (1
H, ddd, J = 7.0, 7.1, 8.1 Hz, CHN), 2.81 (1 H, ddd, J = 6.2, 8.1, 12.0
Hz, CH2), 2.02 (1 H, ddd, J = 7.1, 10.0, 12.0 Hz, CH2), 1.55 (9 H, s,
t-C4H9), [minor isomer: d = 2.54 (1 H, ddd, J = 6.0, 8.0, 13.0 Hz,
CH2), 2.40 (1 H, ddd, J = 5.0, 7.0, 13.0 Hz, CH2)].
13C NMR (75 MHz, CDCl3): d = 158.0, 138.2, 137.5, 128.9, 127.2,
126.9, 116.0, 83.1, 82.4, 63.1, 44.1, 28.6.
MS (CI): m/z (%) = 276 (MH+, 25), 221 (25), 176 (37), 175 (19).
HRMS: m/z calcd for C16H22O3N (MH+): 276.1600; found:
13C NMR (75 MHz, CDCl3): d = 204.6, 155.5, 138.1, 127.6, 127.5,
126.0, 82.7, 80.9, 49.9, 29.6, 27.1.
5-Phenyl-3-vinylisoxazolidine (10)
Trifluoroacetic acid (3.2 mL, 42.1 mmol) was added dropwise to the
isoxazolidine 6a (1.16 g, 4.21 mmol) with stirring, and the mixture
was stirred at r.t. for 2 h. The volatiles were removed in vacuo and
the residue was neutralised with aq sat. NaHCO3 (1 mL). The mix-
ture was partitioned between EtOAc (10 mL) and H2O (5 mL). The
aqueous layer was extracted with EtOAc (2 × 10 mL). The com-
bined organic extracts were washed with H2O (10 mL) and brine (5
mL), dried (MgSO4), and the solvent removed in vacuo to give the
title compound (0.737 g, ~100%) as a light yellow oil.
276.1602.
2-Benzyloxycarbonyl-5-phenyl-3-vinylisoxazolidine (6b)
The title compound (49 mg, 93%) was obtained from 3b following
the typical procedure for 6a as a colourless oil.
IR (neat): 3034, 2956, 1709, 1306 cm–1.
IR (neat): 3202, 3007, 3063, 1644, 1603 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.1–7.35 (5 H, m, ArH), 5.87 (1
H, ddd, J = 7.0, 10.2, 17.1 Hz CH=CH2), 5.28 (2 H, dd, J = 10.2,
17.1 Hz, CH=CH2), 5.14 (1 H, br s, NH), 5.05 (1 H, t, J = 7.6 Hz,
PhCHON), 4.10 (1 H, q, J = 7.0, 7.0 Hz, CHN), 2.88 (1 H, dt, J =
7.6, 12.5 Hz, CH2), 2.04 (1 H, dt, J = 7.6, 12.6 Hz, CH2), [minor
isomer: d = 2.42 (2 H, dt, J = 7.3, 12.6, 15.2 Hz, CH2)].
13C NMR (75 MHz, CDCl3): d = 141.1, 140.8, 129.0, 128.3, 126.6,
117.6, 84.2, 64.0, 45.0.
MS (CI): m/z (%) = 176 (MH+, 100), 143 (65), 122 (100), 107 (27),
104 (40).
1H NMR (300 MHz, CDCl3): d = 7.36 (10 H, m, ArH), 5.94 (1 H,
ddd, J = 6.4, 10.4, 16.9 Hz, CH=), 5.38 (1 H, d, J = 16.9 Hz, =CH2),
5.25 (2 H, s, PhCH2), 5.21 (1 H, d, J = 10.4 Hz, =CH2), 4.92 (1 H,
dd, J = 6.2, 10.0 Hz, PhCH), 4.87 (1 H, m, CHN), 2.89 (1 H, ddd,
J = 6.2, 8.5, 12.5 Hz, CH2), 2.15 (1 H, ddd, J = 7.0, 10.0, 12.5 Hz,
CH2).
13C NMR (75 MHz, CDCl3): d = 158.0, 137.7, 137.0, 136.4, 129.1,
129.0, 128.9, 128.7, 128.5, 127.3, 116.4, 83.8, 68.4, 63.1, 44.1.
MS (CI): m/z (%) = 310 (M+, 39), 266 (34), 107 (30), 91 (92).
HRMS: m/z calcd for C19H20NO3 (MH+): 310.1443; found:
HRMS: m/z calcd for C11H14NO (MH+): 176.1075; found:
176.1082.
310.1441.
N-(1-tert-Butoxycarbonyl)-O-(2-hexa-4,5-dienyl)hydroxyl-
amine (7)
Prepared from the methyl-substituted substrate corresponding to the
allenic alcohol 2a by the method described for allene 3a in 81%
yield (two steps) as a colourless oil.
(3R,5S)-(–)-2-But-3-enyl-5-phenyl-3-vinylisoxazolidine (11)
1-Bromobut-3-ene (390 mL, 3.83 mmol) was added to a solution of
the isoxazolidine 10 (558 mg, 3.19 mmol) and NaHCO3 (452 mg,
5.38 mmol) in DMF (16 mL) and the mixture was stirred at 50 °C
for 14 h. An additional amount of 1-bromobut-3-ene (195 mL, 1.92
mmol) was added to the mixture, which was stirred for a further 20
h at 55 °C. The DMF was removed by cold-finger distillation. The
residue was then neutralised with aq sat. NH4Cl (5 mL) and extract-
ed with Et2O (3 × 10 mL). The combined organic extracts were
washed with H2O (10 mL) and brine (5 mL), dried (MgSO4), and the
solvent removed in vacuo. Purification of the product and separa-
tion of the two diastereomers, by flash chromatography (1:25
EtOAc–PE) on silica gel (16 g) gave the title compound (407 mg,
56%) as a colourless oil; [a]D32 –134.4 (c = 0.9, CHCl3).
IR (neat): 3304, 2979, 1957, 1721 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.98 (1 H, br s, NH), 5.13 (1 H app
quint, J = 8 Hz, =CH), 4.66 (2 H, dt, J = 6.7, 2.9 Hz, =CH2), 3.94 (1
H, app quint, J = 6.2 Hz, CHO), 2.36 (1 H, m, CH), 2.20 (1 H, m,
CH), 1.48 (9 H, s, t-C4H9), 1.24 (3 H, d, J = 6.3 Hz).
13C NMR (75 MHz, CDCl3): d = 209.7, 157.5, 86.1, 81.6, 81.3, 74.9,
32.9, 28.2, 18.3.
HRMS: m/z calcd for C11H19O3N (M+): 213.1365; found 213.1365.
IR (neat): 3078, 3028, 2978, 2831, 1642 cm–1 (C=C).
2-tert-Butoxycarbonyl-5-methyl-3-vinylisoxazolidine (8)
Prepared from 7 by the method described for isoxazolidine 6a in
83% yield as a colourless oil (4:1 mixture of isomers).
IR (neat): 2979, 2935, 1731, 1705, 1645 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.84 (1 H, ddd, J = 17, 10.2, 7
Hz, =CH), 5.24 (1 H, dt, J = 17, 1.1 Hz, =CH), 5.10 (1 H, dt, J =
1H NMR: (400 MHz, CDCl3): d = 7.27–7.42 (5 H, m, ArH), 5.90 (1
H, dt, J = 6.8, 10.2, 17.1 Hz, CH=CH2), 5.75–5.90 (1 H, m), 5.30 (1
H, d, J = 17.1 Hz, =CH), 5.1–5.3 (2 H, m, =CH, OCH) 5.11 (1 H,
dd, J = 1.2 12.8 Hz, =CH), 5.03 (1 H, dd, J = 7.7, 1.2 Hz, =CH),
3.35–3.45 (1 H, m, CHN), 2.8–3.05 (1 H, m, CH), 2.8–2.9 (2 H, m,
CH2), 2.4–2.55 (2 H, m, CH2), 2.19 (1 H, dt, J = 8.6, 12.3 Hz, CH).
Synthesis 2008, No. 7, 1033–1038 © Thieme Stuttgart · New York

PAPER
Cycloisomerisation of Allenic Hydroxylamines
1037
13C NMR (75 MHz, CDCl3): d = 142.0, 137.5, 136.9, 128.8, 127.8,
126.4, 118.4, 116.1, 78.1, 71.7, 56.9, 45.9, 33.2.
(3S,4aR)-(+)-3-Phenyl-4,4a,7,8-tetrahydropyrido[1,2-c][1,3]ox-
azin-1(3H)-one (15)
Grubbs’ first-generation catalyst (11.5 mg, 0.014 mmol) was added
to a solution of the diene 14 (91 mg, 0.35 mmol) in CH2Cl2 (2 mL)
under N2 and the mixture was stirred for 3 h. The solvent was then
removed in vacuo. The crude product was purified by flash chroma-
tography on silica gel (3 g), eluting with EtOAc–PE (3:10) to give
the title compound (65 mg, 81%) as a colourless crystalline solid;
mp 178–180 °C; [a]D32 +72.50 (c 0.80, CHCl3).
1H NMR (300 MHz, CDCl3): d = 7.25–7.40 (5 H, m, ArH), 5.94 (1
H, m, CH=CH), 5.58 (1 H, dt, J = 1.1, 10.0 Hz, CH=CH), 5.25 (1 H,
dd, J = 1.9, 11.7 Hz, PhCH), 4.56 (1 H, dd, J = 5.8, 13.2 Hz, CHN),
4.27 (1 H, m, NCH2), 2.92 (1 H, td, J = 3.8, 11.9 Hz, NCH2), 2.38–
2.47 (1 H, m, CH2), 2.32 (1 H, ddd, J = 2.1, 4.9, 13.9 Hz), 2.06 (1
H, m, CH2), 1.83 (1 H, dt, J = 11.9, 13.7 Hz, CH2).
MS (CI): m/z = 230 (MH+, 91), 229 (27), 188 (100), 126 (48).
HRMS: m/z calcd for C15H20NO (MH+): 230.1545; found:
230.1553.
2-(But-3-enyl)-2-methyl-5-phenyl-3-vinylisoxazolidin-2-ium
Tosylate (12)
A mixture of the isoxazolidine 11 (47 mg, 0.21 mmol) and methyl
tosylate (39 mg, 0.21 mmol) was stirred at 70 °C for 2 days. The
mixture was then dissolved in MeOH (5 mL) and partitioned with
hexane (5 mL) to form two organic layers. The MeOH layer was
evaporated in vacuo to give the title compound as a viscous oil,
which was used without further purification.
1H NMR (400 MHz, CDCl3): d (major isomer) = 7.76 (2 H, d, J =
8.1 Hz, tosyl ArH), 7.25–7.4 (5 H, m, ArH), 7.10 (2 H, d, J = 7.9
Hz, tosyl ArH), 6.14 (1 H, ddd, J = 8.3, 9.8, 17.1 Hz, CHCH=CH2),
5.8–5.9 (2 H, m), 5.60–5.74 (3 H, m, =CH2, CHN), 5.12 (1 H, d, J =
12 Hz, =CH), 5.00 (1 H, d, J = 10.2 Hz, =CH), 3.98–4.10 (1 H, m,
CH), 3.75–3.88 (1 H, m, CH), 3.30 (3 H, s, NCH3), 2.85–3.05 (1 H,
m, CH2), 2.55–2.70 (3 H, m, CH2), 2.24 (3 H, m, ArCH3).
13C NMR (75 MHz, CDCl3): d = 153.5, 139.2, 131.3, 129.2, 129.0,
127.3, 126.3, 77.1, 52.8, 41.3, 37.5, 25.0.
MS (CI): m/z (%) = 230 (MH+, 11), 154 (20), 126 (100), 82 (9).
HRMS: m/z calcd for C14H16NO2 (MH+): 230.1267; found:
230.1235.
2-(1-Methyl-1,2,5,6-tetrahydropyridin-2-yl)-1-phenylethanol
(16)
(1S,3R)-3-But-3¢-enylamino-1-phenylpent-4-en-1-ol (13)
Zn powder (301 mg, 4.60 mmol) was added to a solution of the N-
alkylated isoxazolidine 11 (210 mg, 0.92 mmol) and AcOH (263
mL, 4.6 mmol) in THF (5 mL). The mixture was stirred for 14 h at
r.t. and then neutralised with aq sat. Na2CO3 (10 mL). The solids
were filtered off under suction and the filtrate was extracted with
CHCl3 (2 × 10 mL). The combined extracts were dried (MgSO4) and
the solvent removed in vacuo to give the title compound (199 mg,
94%) as an oil. This compound was used for the next step without
further purification;
1H NMR (300 MHz, CDCl3): d = 7.33 (5 H, m, ArH), 5.81 (1 H, ddt,
J = 3.2, 7.0, 10.0, 17.0 Hz, CH2CH=CH2), 5.61 (1 H, ddd, J = 7.7,
10.4, 17.3 Hz, CHCH=CH2), 4.95–5.2 (4 H, m, 2 × CH=CH2), 4.96
(1 H, dd, J = 2.6, 10.5 Hz, PhCH), 3.37 (1 H, ddd, J = 2.6, 7.7, 10.5
Hz, CHN), 2.89 (1 H, dt, J = 6.9, 11.3 Hz, NCH2), 2.58 (1 H, dt, J =
6.6, 11.3 Hz, NCH2), 2.1–2.3 (2 H, m, CH2), 1.80 (1 H, dt, J = 2.6,
14.3 Hz, PhCHCH2), 1.62 (1 H, dt, J = 10.5, 14.3 Hz, PhCHCH2).
Oxazinone 15 (62 mg, 0.271 mmol) was dissolved in THF (4 mL).
LiAlH4 (51.5 mg, 1.36 mmol) was added to the solution portion-
wise, and the mixture was heated under reflux for 2 h. After the mix-
ture was allowed to cool, H2O was added cautiously and dropwise
until the LiAlH4 was fully destroyed. A small portion of anhyd
Na2SO4 was added, the mixture was filtered under suction with rins-
es of MeOH, and the solvent was then removed in vacuo. The crude
product was purified by flash chromatography (2 g silica gel), with
elution by EtOAc–PE (30:70), then with EtOAc to give the title
compound (33 mg, 56%) as a colourless oil.
IR (neat): 3163, 3061, 3026, 2939, 1433 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.2–7.4 (5 H, m, ArH), 5.83 (1 H,
m, CH=CH), 5.57 (1 H, br d, J = 10.4 Hz, CH=CH), 4.93 (1 H, dd,
J = 2.8, 10.0 Hz, PhCHOH), 3.14–3.24 (2 H, m), 2.73 (1 H, dd, J =
5.6, 13.7 Hz, NCH2), 2.56 (3 H, s, CH3), 2.31 (1 H, dddd, J = 2.6,
5.7, 11.3, 17.9 Hz, NCH2CH2), 1.67–1.86 (4 H, m, CH2, CH2, OH).
13C NMR (75 MHz, CDCl3): d = 145.7, 128.6, 128.0, 127.3, 126.0,
125.5, 75.8, 61.5, 43.8, 41.5, 41.4, 18.9.
(4R,6S)-(–)-3-But-3-enyl-6-phenyl-4-vinyl[1,3]oxazin-2-one
(14)
Carbonyldiimidazole (156 mg, 0.96 mmol) was added to a solution
of the amino alcohol 13 (119 mg, 0.86 mmol) in THF (4 mL) and
the mixture was stirred for 12 h at r.t. The mixture was acidified
with aq 2 M HCl and then extracted with CHCl3 (3 × 10 mL). The
combined extracts were dried (MgSO4), and the solvent evaporated
in vacuo to give the title compound (221 mg, ~100%) as a colourless
oil; [a]D32 –9.52 (c 0.84, CHCl3).
HRMS: m/z calcd for C14H19NO (M+): 217.1467; found: 217.1463.
(+)-Sedamine (1)
Pd/C (10%, 4.8 mg) was added to compound 16 (30.0 mg, 0.138
mmol) in MeOH (1.5 mL), and placed under an atmosphere of H2
and stirred for 4 h. The mixture was filtered and the solvent of the
filtrate evaporated in vacuo to give sedamine (30 mg, 100%) as a
slowly crystallising solid; mp 57–59 °C (Lit.4i mp 54–56 °C, Lit.14
IR (neat): 3076, 3034, 1694, 1419 cm–1.
32
mp 59–61 °C); [a]D +82.10 (c = 0.67, EtOH) {Lit.4i [a]D +87.0
1H NMR (300 MHz, CDCl3): d = 7.2–7.4 (5 H, m, ArH), 5.79 (1 H,
ddt, J = 7.0, 10.2, 17.2 Hz, CH2CH=CH2), 5.62 (1 H, ddd, J = 9.1,
9.1, 17.0 Hz, CHCH=CH2), 5.24–5.36 (2 H, dd, J = 10.6, 17.0
Hz, =CH2), 5.20–5.06 (3 H, m, =CH2, PhCH), 4.12 (1 H, ddd, J =
5.7, 9.1, 14.5 Hz, CHN), 3.83 (1 H, ddd, J = 6.8, 8.1, 14.3 Hz,
NCH2), 3.18 (1 H, ddd, J = 5.8, 8.1, 13.9 Hz, NCH2), 2.3–2.5 (1 H,
m, CH2), 2.15–2.3 (2 H, m, CH2), 2.02 (1 H, dt, J = 11.3, 14.1 Hz,
CH2).
(c = 1.1, EtOH)}.
1H NMR (300 MHz, CDCl3): d = 7.2–7.4 (5 H, m, ArH), 5.50 (1 H,
br s, OH), 4.90 (1 H, dd, J = 2.6, 10.5 Hz, PhCH), 3.08 (1 H, ddd,
J = 3.2, 7.9, 11.1 Hz), 2.8–2.9 (1 H, m), 2.5–2.6 (1 H, m), 2.49 (3 H,
s, CH3), 2.11 (1 H, dt, J = 10.4, 14.3 Hz, CH2), 1.26–1.79 (7 H, m).
13C NMR (75 MHz, CDCl3): d = 145.8, 128.5, 127.1, 125.8, 75.0,
61.2, 51.3, 40.1, 39.9, 25.8, 22.5, 20.6.
13C NMR (75 MHz, CDCl3): d = 154.3, 139.0, 138.0, 135.7, 129.0,
128.9, 126.2, 119.3, 117.5, 76.9, 59.6, 45.2, 38.1, 32.4.
Acknowledgment
MS (CI): m/z (%) = 258 (MH+, 66), 182 (31), 172 (47), 154 (100),
143 (40).
We thank Nanyang Technological University for financial support
of this work. R.H.S. thanks Pfizer Central Research for a summer
undergraduate scholarship for support at the University of Exeter.
HRMS: m/z calcd for C16H20NO2 (MH+): 258.1494; found:
258.1493.
Synthesis 2008, No. 7, 1033–1038 © Thieme Stuttgart · New York

1038
R. W. Bates et al.
PAPER
(5) Meth-Cohn, O.; Yu, C.-Y.; Lestage, P.; Lebrun, M.-C.;
Cagniard, D.-H.; Renard, P. European Patent 1050531,
2000.
(6) (a) Grochowski, E.; Jurczak, J. Synthesis 1976, 682.
(b) Iwagami, H.; Yatagai, M.; Nakazawa, M.; Orita, H.;
Honda, Y.; Ohnuki, T.; Yukawa, T. Bull. Chem. Soc. Jpn.
1991, 64, 175.
References
(1) Bates, R. W.; Sa-Ei, K. Org. Lett. 2002, 4, 4225.
(2) Knapp, S. Chem. Soc. Rev. 1999, 28, 61.
(3) (a) Claesson, A.; Sahlberg, C.; Luthman, K. Acta Chem.
Scand. 1979, 33B, 309. (b) Claesson, A.; Olsson, L.-I.
Synthesis 1979, 743. (c) Arseniyadis, S.; Gore, J.
Tetrahedron Lett. 1983, 24, 3997. (d) Arseniyadis, S.;
Sartoretti, J. Tetrahedron Lett. 1985, 26, 729. (e) Lathbury,
D. C.; Shaw, R. W.; Bates, P. A.; Hursthouse, M. B.;
Gallagher, T. J. Chem. Soc., Perkin Trans. 1 1989, 2415.
(f) Marshall, J. A.; Sehon, C. A. J. Org. Chem. 1995, 60,
5966. (g) Amombo, M. O.; Hausherr, A.; Reissig, H.-U.
Synlett 1999, 1871. (h) Kaden, S.; Reissig, H.-U.; Brüdgam,
I.; Hartl, H. Synthesis 2006, 1351. (i) Chowdhury, M. A.;
Reissig, H.-U. Synlett 2006, 2383. (j) For a review of allene
cyclisation, see: Bates, R. W.; Satchareon, V. Chem. Soc.
Rev. 2002, 31, 12.
(7) (a) The alkynol precursor for allene 4 was prepared by a
modification of Lansbury and Pattison: Lansbury, P. T.;
Pattison, V. A. J. Am. Chem. Soc. 1962, 84, 4295. (b) See
also: Hommes, H.; Verkruijsse, H. D.; Brandsma, L. Recl.
Trav. Chim. Pays-Bas 1980, 99, 113. (c) For the allenol
precursor for allene 5, see ref. 9.
(8) (a) Arcadi, A.; di Giuseppe, S. Curr. Org. Chem. 2004, 8,
795. (b) Hoffmann-Röder, A.; Krause, N. Org. Biomol.
Chem. 2005, 3, 387. (c) Hyland, C. J. T.; Hegedus, L. S.
J. Org. Chem. 2006, 71, 8658. (d) Zhang, Z.; Widenhoefer,
R. A. Angew. Chem. Int. Ed. 2007, 46, 283. (e) Yeom, H.-
S.; Lee, E.-S.; Shin, S. Synlett 2007, 2292.
(9) (a) For ring-opening with lithium acetylide, see: Brandsma,
L. Preparative Acetylenic Chemistry, 2nd ed.; Elsevier:
Amsterdam, 1988, 67. (b) For allene formation, see: Searles,
S.; Li, Y.; Nassim, B.; Lopes, M.-T. R.; Tran, P. T.; Crabbé,
P. J. Chem. Soc., Perkin Trans 1 1984, 747.
(10) (a) Felpin, F.-X.; LeBreton, J. Eur. J. Org. Chem. 2003,
3693. (b) Phillips, A. J.; Abell, A. D. Aldrichimica Acta
1999, 32, 75.
(4) (a) For recent syntheses, see: Bates, R. W.; Sa-Ei, K.
Tetrahedron 2002, 58, 5957. (b) Fustero, S.; Jimenez, D.;
Moscardo, J.; Catalan, S.; del Pozo, C. Org. Lett. 2007, 9,
5283. (c) Yadav, J. S.; Sridar Reddy, M.;
Purushothama Rao, P.; Prasad, A. R. Tetrahedron Lett.
2006, 47, 4397. (d) Borah, J. C.; Boruwa, J.; Barua, N. C.
Lett. Org. Chem. 2006, 3, 140. (e) Zheng, G.; Dwoskin, L.
P.; Crooks, P. A. J. Org. Chem. 2004, 69, 8514.
(f) Josephson, N. S.; Snapper, M. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2004, 126, 3734. (g) Angoli, M.; Barilli, A.;
Lesma, G.; Passarella, D.; Riva, S.; Silvani, A.; Danieli, B.
J. Org. Chem. 2003, 68, 9525. (h) Felpin, F.-X.; Lebreton,
J. J. Org. Chem. 2002, 67, 9192. (i) Cossy, J.; Willis, C.;
Bellosta, V.; BouzBouz, S. J. Org. Chem. 2002, 67, 1982.
(11) Fu, G. C.; Nguyen, S. T.; Grubbs, R. H. J. Am. Chem. Soc.
1993, 115, 9856.
(12) Cossy et al. also employed RCM to form the piperidine ring,
but at a different position, see ref. 4i.
(13) Czech, B. P.; Bartsch, R. A. J. Org. Chem. 1984, 49, 4076.
(14) Poerwono, H.; Hagashiyama, K.; Takahashi, H.
Heterocycles 1998, 47, 262.
Synthesis 2008, No. 7, 1033–1038 © Thieme Stuttgart · New York