A synthesis of 5-hydroxysedamine using hydroformylation

Article abstract of DOI:10.1016/j.tet.2014.02.001

A synthesis of 5-hydroxysedamine, a Sedum alkaloid, has been completed using N,O-heterocycle chemistry to establish the aminoalcohol structure, hydroformylation to form the piperidine ring and diastereoselective dihydroxylation to introduce the 5-hydroxy group.

Full text of DOI:10.1016/j.tet.2014.02.001

Tetrahedron 70 (2014) 2134e2140
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A synthesis of 5-hydroxysedamine using hydroformylation
,
a,
Roderick W. Bates a , Nur Filza bte Mohamed Aslam b, Chi H. Tang a, Oliver Simon b
*
a Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link,
Singapore 637371, Singapore
b Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, Singapore 138670, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
A synthesis of 5-hydroxysedamine, a Sedum alkaloid, has been completed using N,O-heterocycle
chemistry to establish the aminoalcohol structure, hydroformylation to form the piperidine ring and
diastereoselective dihydroxylation to introduce the 5-hydroxy group.
Received 21 November 2013
Received in revised form 28 January 2014
Accepted 3 February 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Available online 7 February 2014
1. Introduction
2. Results and discussion
We have recently shown that the combination of tandem
hydroformylation-condensation of N-tosyl homoallylic amines,
followed by diastereoselective dihydroxylation, provides an effi-
cient route to the synthesis of 3-hydroxypiperidines. This strategy
was employed for the synthesis of pseudoconhydrine 11 and azimic
acid 2.2 We have earlier shown that cyclofunctionalisation of O-
homoallyl and allenyl hydroxylamine derivatives stereoselectively
provides isoxazolidines,3 which are useful intermediates for the
synthesis of 1,3-aminoalcohols and their derivatives, such as
monomorine,4 porantheridine5 and the Sedum alkaloids, sed-
amine6 and sedinine.7
The homoallylic alcohol 411 was converted to the N-tosyl hy-
droxylamine 7 through a Mitsunobu reaction12 with N-hydrox-
yphthalimide, dephthaloylation and reprotection (Scheme 1).
While our previous studies of the Sakurai reaction used carbamate
protecting groups on nitrogen, we selected a tosyl group due to its
greater robustness, the higher possibility of obtaining crystalline
intermediates and to avoid issues with rotamer formation. Ozo-
nolysis of hydroxylamine 7 in acidic methanol, followed by a di-
methyl sulfide work up, gave 3-methoxyisoxazolidine 8 as an
inconsequential 1.5:1 mixture of stereoisomers. Tosic acid mono-
hydrate was used as the acid catalyst as amberlyst-15, which we
used previously, did not result in complete conversion to the
methoxy compound. Treatment of 3-methoxyisoxazolidine 8 with
allyltrimethylsilane in the presence of boron trifluoride at ꢀ78 ꢁC
with slow warming to room temperature gave the allyl iso-
xazolidine 9 as a 7.5:1 mixture of stereoisomers. Pleasingly, this
ratio is distinctly better than that obtained with carbamate pro-
tecting groups (3:1e4:1). The major isomer proved to be crystalline
and was confirmed to be the trans isomer by X-ray crystallography
(Fig. 1).13 Cleavage of the NeO bond was achieved in the usual way
with molybdenum hexacarbonyl in wet acetonitrile14 to give the
protected aminoalcohol 10a, which would be the intended hydro-
formylation substrate.15
Me
HO
OH
HO
Me
OH
HN
N
CO2H
n-Pr
N
H
Ph
3
1
2
We speculated that we could combine both of these methods in
the synthesis of 5-hydroxysedamine 3.8 Originally isolated from
Sedum acre, this alkaloid is both a Sedum alkaloid,9 therefore con-
taining a 1,3-aminoalcohol moiety, and a 3-hydroxypiperidine. The
use of hydroformylation to construct the piperidine ring would
require the synthesis of an allyl isoxazolidine. We have recently
shown that these compounds are readily available by Sakurai re-
action of the corresponding 3-methoxyisoxazolidines.10 This re-
action favours formation of the trans isomer, corresponding to the
anti-aminoalcohol. As 5-hydroxysedamine possesses syn stereo-
chemistry, an inversion of the alcohol group must be included in
the synthetic pathway.
Hydroformylation of aminoalcohol 10a derivatives can, in
principle, give rise to four products (Table 1). Ene-sulfonamide 11a
is the desired product. N,O-Hemiaminal 1216 is the precursor of
ene-sulfonamide 11a by dehydration. Bicyclic N,O-aminal 13 can
arise by cyclisation of the benzylic alcohol group onto the ene-
sulfonamide 11a.17 The structure of bicyclic N,O-aminal 13 was
also confirmed by X-ray crystallography (Fig. 2).12 The pyrrolidines
14, the products of branched hydroformylation, can exist as a mix-
ture of stereoisomers.
* Corresponding author. E-mail address: roderick@ntu.edu.sg (R.W. Bates).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.02.001

R.W. Bates et al. / Tetrahedron 70 (2014) 2134e2140
2135
Table 1
5 X = ONPhth
6 X = ONH2
Hydroformylation of alkene 10aa
H2NNH2, CH2Cl2
100%
TsCl, Na2CO3
98%
PhthNOH,
X
OH
DIAD, PPh3
Ph
Ts
Entry
Ligand (L)
L:Rh ratio
Solvent
Yields, %
Ph
90%
7 X = ONHTs
4
11a
12
13
14
Ts
N
SiMe3
O3, MeOH, H+,
Me2S
O
N
O
1
2
3
4
5
P(OPh)3
P(OPh)3
P(OPh)3
BIPHEPHOS
BIPHEPHOS
3:1
THF
THF
THF
THF
2
19
48
75
45
35
27
0
0
0
18
12
20
29
18
23
0
BF3•OEt2
Ph
60% + 8%, 7.5:1
10:1
20:1
1:1
Ph
OMe
90%
8
9
Mo(CO)6,
NaBH4,
0
0
1:1
Toluene
0
CH3CN, H2O
Et3SiCl,
Et3N
91%
HO
Ph
NHTs
10a
TESO
Ph
NHTs
a
66%
All reactions used Rh2(OAc)4 as the source of rhodium and were run for 22 h at
65 ꢁC under 60 psi of 1:1 CO/H2.
10b
Rh2(OAc)4,
BIPHEPHOS
91%
CO, H2 (60 psi)
Rh2(OAc)4,
Ts
BIPHEPHOS
TESO
N
CO, H2 (60 psi)
see table 1
11b
Ph
NaOH
96%
N
MeOH
OH
OH
H
Ts
Ts
Ph
Ts
O
N
Ts
HO
Ph
N
H
HO
Ph
N
H
HO
Ph
11a
12
13
14
H
Ac2O,
amberlyst-15
70%
Ts
DIAD, PPh3,
ClCH2CO2H
K2CO3,
MeOH
100%
AcO
Ph
N
17% + 70%
11c
O
O
OR
Ts
K2OsO4, NMO,
MeSO2NH2
Ts
Ts
Cl
Cl
OR
O
N
N
O
N
100%, 4.6:1
Ph
Ph
Ph
15b
15a
16 R = H
Ac2O,
K2CO3
71%
17 R = Ac
R
Ts
OH
OR'
Et3SiH,
HO
Ph
N
RO
N
Fig. 2. The X-ray structure of bicyclic N,O-aminal 13.
CF3CO2H
Mg, MeOH, )))
49% + 12%
Ph
18 R = ClCH2CO, R' = Ac
19 R = R' = H
20 R = H
3 R = Me
K2CO3,
MeOH
100%
HCO2H,
(CH2O)n
When the bulky, bidentate phosphite ligand BIPHEPHOS18 was
employed, as expected, formation of the branched products 14 was
not observed. A somewhat higher yield of the desired ene-
sulfonamide 11a could be obtained in THF. This was accompanied
by some formation of the bicyclic N,O-aminal 13. We did experience
some variability in yield and product distribution depending on the
batch of BIPHEPHOS employed. The reaction in toluene proved
lower yielding, but more reproducible.
71%
(two steps)
Scheme 1. The synthesis of 5-hydroxysedamine.
Some of the undesired products could be converted to the de-
sired ene-sulfonamide. Thus, treatment of the bicyclic N,O-aminal
13 with acetic anhydride in the presence of amberlyst-15 gave ac-
etate 11c. It is notable that amberlyst-15 proved effective for this
ring opening while a series of Lewis acids were ineffective.19 Ace-
tate 11c could be converted to ene-sulfonamide 11a by treatment
with methanolic potassium carbonate. N,O-Hemiaminal 12 could
be converted to the desired ene-sulfonamide 11a by resubjecting
this material to the hydroformylation conditions.
The rather complex results of hydroformylation of substrate 10a
stand in contrast to our previous experience. It is apparent that the
hydroxy group in the aminoalcohol substrate introduces significant
complication and is capable of interfering with the usual smooth
running of the hydroformylation reaction. Accordingly, a cleaner
hydroformylation was achieved when the original substrate 10a
was protected as its triethylsilyl ether 10b.20 With this substrate,
hydroformylation proved less complex, however, to ensure that
dehydration went to completion, a higher temperature (85 ꢁC) was
required. Under these conditions, ene-sulfonamide 11b was ob-
tained in 90% yield. At 65 ꢁC, only a 30% yield was obtained, ac-
companied by a 58% yield of the corresponding hemiaminal.
Deprotection of ene-sulfonamide 11b then gave the desired ene-
sulfonamide 11a.
Fig. 1. The X-ray structure of allyl isoxazolidine 9.
As expected, when triphenylphosphite was used as the ligand,
appreciable amounts of the branched isomers 14 were formed. In
addition, increasing the amount of this ligand caused an increase in
the formation of the desired ene-sulfonamide 11a at the expense of
the N,O-hemiaminal 12. At the highest phosphite loading
employed, some of the bicyclic N,O-aminal 13 was also isolated.

2136
R.W. Bates et al. / Tetrahedron 70 (2014) 2134e2140
The ene-sulfonamide 11a represents the opportunity to carry
acquired on a Waters Q-ToF Premier mass spectrometer in positive
ion mode.
out the necessary inversion of the alcohol to give the syn stereo-
chemistry. Disappointingly, a Mitsunobu reaction with acetic acid
in THF gave a substantial amount of the eliminated product 15b
(30% yield), alongside the desired acetate (37%) and recovered
starting material (16%). The formation of this alkene may be at-
tributed to the steric hindrance around the reaction site. It is known
that the balance of reactivity will be tipped in favour of substitution
if a more acidic partner is employed.21 Gratifyingly, the use of
chloroacetic acid22 (pKa¼2.86) in place of acetic acid gave an im-
proved yield, 50%, of the desired substitution product 15a. A further
improvement to 70% was achieved by changing the solvent to tol-
uene. Dihydroxylation of chloroacetate 15a then gave the diols 16
as an inseparable 4.6:1 mixture of stereoisomers and, based on our
previous work, it was assumed that the cis isomer was the major
product. This was subsequently confirmed by completion of the
3.1.1. (R)-2-((1-Phenylbut-3-en-1-yl)oxy)isoindoline-1,3-dione
(5). A stirred mixture of homoallylic alcohol 4 (8.00 g, 54.0 mmol),
PPh3 (17.0 g, 64.8 mmol) and N-hydroxyphthalimide (10.6 g,
64.8 mmol) in anhydrous THF (100 mL) was cooled to 0 ꢁC in an ice-
water bath. A solution of DIAD (12.8 mL, 64.8 mmol) in anhydrous
THF (20 mL) was added dropwise. The mixture was stirred at 0 ꢁC
for 1 h and then stirred at room temperature overnight. The mix-
ture was concentrated in vacuo. The residue was dissolved in CH2Cl2
and absorbed onto silica. The residue was purified by flash chro-
matography with gradual elution (5e20% Ethyl Acetate/Hexane) to
give the desired N-hydroxyphthalimide 5 derivative as a colourless
solid (14.2 g, 90%); mp 85e86 ꢁC; Rf 0.35 (20% Ethyl Acetate/Hex-
22
ane); [
a
]
þ197.1 (c 0.11, CH2Cl2); nmax (Nujol) 3404, 1728, 1643,
synthesis. Acetylation then allowed selective removal of the
a
-
698 cmꢀ1D
; dH (396 MHz, CDCl3): 7.59e7.78 (4H, m), 7.46 (2H, dd, J
acetoxy group under KursanoveParnes conditions.23 Diester 18
could be obtained as a single diastereoisomer after careful column
chromatography. Removal of all of the acyl groups and detosylation
then gave des-methyl 5-hydroxysedamine 20. This compound was
then methylated to give 5-hydroxysedamine 3 in 71% yield over
two steps using the EschweilereClarke reaction: reductive amina-
tion with a combination of formaldehyde and formic acid. It was
notable that this reaction was much more effective using para-
formaldehyde rather than formalin as the source of formaldehyde.
We attribute this to the higher concentration of formaldehyde be-
ing generated in the absence of water, as it will not be lost due to
hydrate formation. The spectroscopic data for our synthetic mate-
7.5, 2.0 Hz), 7.26e7.39 (3H, m), 5.78 (1H, ddt, J 17.0, 10.3, 7.0 Hz),
5.39 (1H, t, J 7.0 Hz), 4.99e5.22 (2H, m), 2.95 (1H, dt, J 14.4, 7.1 Hz),
2.72 (1H, dt, J 14.3, 6.9 Hz); dC (100 MHz, CDCl3): 163.6, 137.4, 134.2,
133.0, 129.1, 128.8, 128.3, 128.1, 123.3, 118.0, 88.3, 39.2; MS (ESI þve)
m/z 131.5 (MþꢀC8H4NO3, 100); HRMS (ESI) m/z calculated for
C
18H16O [MþH]þ 294.1130, found 294.1128.
3.1.2. (R)-O-(1-Phenylbut-3-en-1-yl)hydroxylamine (6). Hydrazine
monohydrate (8.6 mL, 177 mmol) was added dropwise to a stirred
solution of N-hydroxyphthalimide 5 (13.0 g, 44.3 mmol) in CH2Cl2
(350 mL) at room temperature. The mixture was stirred for 2 h,
then filtered through a pad of Celite, washing with Et2O (100 mL).
The filtrate was concentrated in vacuo to give the desired hydrox-
ylamine 6 (7.41 g, 100%) as a clear oil that was used without further
rial was in excellent agreement with that reported. In addition, the
22
specific rotation recorded for our material, [
a
]
ꢀ55.3 (c 0.15,
D
22
MeOH), is in good agreement with previous reports: [
a
]
ꢀ40 (c
purification; Rf 0.15 (20% Ethyl Acetate/Hexane); [
a
]
22 þ68.3 (c 0.13,
D
D
22
22
0.3, MeOH),8a
[
a
]
ꢀ53 (c 0.3, MeOH),8b,d
[
a
]
D
ꢀ51 (c 2.5
CH2Cl2); nmax (neat) 3420, 3317, 3075, 3030, 2905, 1641, 1585, 1454,
D
22
MeOH),8c
[
a
]
ꢀ53.4 (c 0.5, MeOH)8e The completion of the syn-
1184 cmꢀ1
; dH (400 MHz, CDCl3): 7.27e7.41 (5H, m), 5.76 (1H, ddt, J
D
thesis illustrates how these disparate synthetic methods, de-
veloped in this laboratory and elsewhere, can be brought together
to synthesise complex alkaloids.
17.0, 10.1, 7.0 Hz), 5.24 (2H, br s), 4.99e5.13 (2H, m), 4.56 (1H, t, J
6.9 Hz), 2.59 (1H, dt, J 14.6, 7.3 Hz), 2.42 (1H, dt, J 14.0, 7.0 Hz); dC
(100 MHz, CDCl3): 141.3, 134.4, 128.4, 127.8, 126.7, 117.0, 86.6, 40.5;
MS (ESI ꢀve) m/z 163.4 (Mꢀ, 100); HRMS (ESI) m/z calculated for
3. Experimental section
3.1. General
C
10H14O [MþH]þ 164.1075, found 164.1075.
3.1.3. (R)-4-Methyl-N-((1-phenylbut-3-en-1-yl)oxy)benzenesulfona-
mide (7). Anhydrous sodium carbonate (4.88 g, 46.0 mmol) and
tosyl chloride (8.77 g, 46.0 mmol) were added sequentially to
a stirred solution of hydroxylamine 6 (5.00 g, 30.6 mmol) in CH2Cl2
(50 mL) and water (50 mL) at room temperature. The mixture was
stirred overnight. The organic layer was separated, dried over
MgSO4, filtered and concentrated in vacuo. The residue was purified
by flash chromatography with gradual elution (5e20% Ethyl Ace-
tate/Hexane) to give the desired N-tosyl hydroxylamine 7 (9.48 g,
Unless otherwise indicated, all starting materials were obtained
from commercial suppliers, and were used without further purifi-
cation. Each reaction with air- and moisture-sensitive components
was carried out under a nitrogen atmosphere unless otherwise
indicated. Tetrahydrofuran was distilled from sodium/benzophe-
none, and dichloromethane was distilled from calcium hydride.
Analytical thin-layer chromatography (TLC) was performed on
Merck DC pre coated TLC plates with 0.25 mm Kieselgel 60 F254
.
98%) as a clear oil; Rf 0.32 (20% Ethyl Acetate/Hexane); [
a
]
22 þ102.8
D
Visualization was performed with a 254 nm UV lamp, or stained
with ammonium molybdate or potassium permanganate solution.
Flash chromatography was performed using silica gel 60 (particle
size 0.040e0.063) purchased from Merck. All melting points were
measured on a Stanford Research Systems OptiMelt apparatus and
are uncorrected. Optical rotations were measured on a Jasco P-1030
(c 0.34, CH2Cl2); nmax (neat) 3435, 3225, 3066, 3032, 2924, 1714,
1643, 1597, 1454, 1339, 1183 cmꢀ1
; dH (400 MHz, CDCl3): 7.82 (2H, d,
J 8.2 Hz), 7.23e7.40 (7H, m), 6.67 (1H, s), 5.77 (1H, ddt, J 17.2, 9.9,
7.0 Hz), 4.98e5.15 (3H, m), 2.65 (1H, dt, J 14.8, 7.5 Hz), 2.41e2.54
(4H, m); dC (100 MHz, CDCl3) 144.8, 139.6, 133.8, 133.7, 129.6, 128.7,
128.4, 128.3, 127.1, 117.6, 88.0, 39.6, 21.7; MS (ESI þve) m/z 131.5
(MþꢀC7H8NO3S, 100), 148.6 (MþꢀC7H7NO2S, 10); HRMS (ESI) m/z
calculated for C17H20NO3S [MþH]þ 318.1164, found 318.1185.
polarimeter using a 10 mm path-length cell at 589 nm. 1H and 13
C
NMR spectra were recorded on a JEOL 400 MHz or JEOL 396 MHz
spectrometer in CDCl3. Chemical shifts are expressed in parts per
million (
d
) with solvent (
d
7.26 for 1H,
d
77.0 for 13C) or Me4Si
3.1.4. (5R)-3-Methoxy-5-phenyl-2-tosylisoxazolidine (8). p-Tolue-
nesulfonic acid monohydrate (230 mg, 1.2 mmol) was added to
a solution of N-tosyl hydroxylamine 7 (7.66 g, 24.1 mmol) in MeOH
(100 mL). The mixture was cooled to ꢀ78 ꢁC and a stream of O3/O2
was passed through the mixture until the solution turned blue in
colour. The flask was then purged with O2 until the blue colour
dissipated. Me2S (2.4 mL, 28.9 mmol) was added and the reaction
(
d
¼0.00 ppm) as internal standards. Coupling constants (J) are re-
ported in Hertz. IR spectra were obtained on a Jasco FT/IR-4100
spectrometer or Shimadzu IR Prestige-21 spectrometer and are
reported in frequency of absorption (cmꢀ1). Low resolution mass
spectrometry was obtained on a Waters Acquity UPLC PDA with
ZQ2000 system. High-resolution mass spectra (HRMS) were

R.W. Bates et al. / Tetrahedron 70 (2014) 2134e2140
2137
mixture was warmed to room temperature and stirred for a further
48 h. The reaction solvent was removed with a rotary evaporator
and the residue was taken up in CH2Cl2 (100 mL) and washed with
water (2ꢂ50 mL). The organic phase was dried over MgSO4, filtered
and concentrated in vacuo. The crude product was purified by flash
chromatography with gradual elution (5e25% Ethyl Acetate/Hex-
ane) to give methoxyisoxazolidine 8 (7.22 g, 90%) as a mixture of
diastereomers (ratio¼1.5:1) and as a clear oil; Rf 0.38, 0.33 (20%
Ethyl Acetate/Hexane); nmax (neat) 3500, 2957, 1635, 1597, 1456,
1368, 1333, 1224, 1183 cmꢀ1; MS (ESI þve) m/z 302.9 (MþꢀOCH3,
the resulting mixture was filtered through a pad of Celite, washing
with Et2O (2ꢂ20 mL). The filtrate was concentrated in vacuo. The
residue was purified by flash chromatography with gradual elution
(5e30% Ethyl Acetate/Hexane) to give the desired 1,3-aminoalcohol
10a (2.00 g, 66%) as a colourless solid; mp 92e93 ꢁC; Rf 0.13 (20%
22
Ethyl Acetate/Hexane); [
a
]
þ30.6 (c 0.12, CH2Cl2); nmax (Nujol
D
mull) 3446, 1638, 1597, 1317, 1155 cmꢀ1
; dH (396 MHz, CDCl3):
7.70e7.91 (2H, m), 7.11e7.45 (7H, m), 5.40e5.54 (1H, m), 4.71e5.07
(4H, m), 3.61e3.72 (1H, m), 2.87 (1H, br s), 2.45 (3H, s), 1.97e2.18
(2H, m), 1.70e1.82 (1H, m), 1.54e1.68 (1H, m); dC (100 MHz, CDCl3):
144.1, 143.5, 137.7, 132.9, 129.7, 128.4, 127.3, 127.2, 125.5, 119.1, 70.0,
50.5, 43.9, 39.4, 21.5; MS (ESI ꢀve) m/z, 345.00 (MꢀꢀH, 100); HRMS
(ESI) m/z calculated for C19H24NO3S [MþH]þ 346.1477, found
346.1468.
28); HRMS (ESI) m/z calculated for
C
17H19NO4SNa [MþNa]þ
356.0932, found 356.0930.
Minor diastereomer: dH (400 MHz, CDCl3): 7.89 (2H, d, J 8.2 Hz),
7.22e7.44 (7H, m), 5.71 (1H, dd, J 6.8, 2.7 Hz), 5.46 (1H, t, J 8.2 Hz),
3.54 (3H, s), 2.98 (1H, ddd, J 13.4, 8.4, 6.8 Hz), 2.42 (3H, s), 2.33 (1H,
ddd, J 13.1, 8.2, 2.7 Hz); dC (100 MHz, CDCl3): 145.1, 137.6, 133.6,
129.7, 129.0, 128.7, 128.6, 127.5, 91.7, 84.7, 56.6, 44.0, 21.7.
Major diastereomer: dH (400 MHz, CDCl3): 7.82 (2H, d, J 8.2 Hz),
7.22e7.44 (7H, m), 5.51 (1H, d, J 5.4 Hz), 5.30 (1H, dd, J 11.9, 5.0 Hz),
3.54 (3H, s), 2.40e2.50 (4H, m), 2.08 (1H, ddd, J 12.3, 5.2 Hz); dC
(100 MHz, CDCl3): 145.2, 136.4, 132.6, 129.6, 129.4, 128.8, 128.5,
127.4, 91.9, 83.2, 55.7, 43.0, 21.7.
3.1.7. 4-Methyl-N-((1R,3S)-1-phenyl-1-((triethylsilyl)oxy)hex-5-en-
3-yl)benzenesulfonamide (10b). Triethylamine (380
was added dropwise to a solution of aminoalcohol 10a (1.00 g,
2.9 mmol) and chlorotriethylsilane (420 L, 3.5 mmol) in CH2Cl2
mL, 4.1 mmol)
m
(15 mL) at 0 ꢁC. Once addition was complete, the mixture was
warmed to room temperature and stirred overnight. The mixture
was diluted with CH2Cl2 (20 mL) and washed with saturated
aqueous NH4Cl (20 mL). The organic phase was washed with brine
(10 mL), dried over MgSO4, filtered and concentrated in vacuo. The
residue was purified by flash chromatography (10% Ethyl Acetate/
Hexane) to give the desired silyl ether 10b (1.22 g, 91%) as a clear
3.1.5. (3S,5R)-3-Allyl-5-phenyl-2-tosylisoxazolidine
(4.4 mL, 36.0 mmol) was added dropwise to a stirred solution of
methoxyisoxazolidine (6.00 g, 18.0 mmol) and allyl-
(9). BF3$Et2O
8
trimethylsilane (11.4 mL, 72.0 mmol) in anhydrous CH2Cl2 (60 mL)
at ꢀ78 ꢁC. The mixture was gradually warmed to room temperature
and stirred until the reaction was shown to be complete by TLC
analysis. The reaction mixture was cooled to ꢀ78 ꢁC and quenched
with Et3N (2.5 mL,18.0 mmol). The mixture was allowed to warm to
room temperature and was washed with water (100 mL). The or-
ganic phase was dried over MgSO4, filtered and concentrated in
vacuo. The residue was purified by flash chromatography (5e20%
Ethyl Acetate/Hexane) to give the trans isomer 9 (3.73 g, 60%) as
a crystalline solid and the cis isomer (517 mg, 8%) as a pale yellow
oil.
oil; Rf 0.43 (20% Ethyl Acetate/Hexane); [
a
]
22 þ28.7 (c 0.25, CH2Cl2);
D
nmax (film) 3284, 2954, 2911, 2876, 1454, 1415, 1329, 1160,
1092 cmꢀ1
; dH (396 MHz, CDCl3): 7.72 (2H, d, J 8.2 Hz), 7.29 (2H, d, J
8.2 Hz), 7.18e7.23 (3H, m), 7.03e7.09 (2H, m), 5.51e5.69 (2H, m),
4.93e5.07 (2H, m), 4.87 (1H, dd, J 7.7, 4.1 Hz), 3.28e3.38 (1H, m),
2.44 (3H, s), 2.18e2.38 (2H, m), 1.58e1.79 (2H, m), 0.83e0.92 (9H,
m), 0.42e0.60 (6H, m); dC (100 MHz, CDCl3): 143.9, 143.1, 138.2,
133.8, 129.6, 128.2, 127.4, 127.2, 125.7, 118.2, 73.0, 51.2, 42.8, 38.9,
21.5, 6.7, 4.7; MS (ESI ꢀve) m/z 459.1 (MꢀꢀH, 88), 345.0 (30), 171.6
(44), 117.3 (100); HRMS (ESI) m/z calculated for C25H38NO3SSi
[MþH]þ 460.2342, found 460.2328.
Major diastereomer: mp 72e77 ꢁC; Rf 0.40 (20% Ethyl Acetate/
Hexane); [
a]
22 þ85.7 (c 0.25, CH2Cl2); nmax (neat) 3439, 2922, 2852,
3.1.8. (S)-2-((R)-2-Phenyl-2-((triethylsilyl)oxy)ethyl)-1-tosyl-1,2,3,4-
tetrahydropyridine (11b). In a FisherePorter tube, silyl ether 10b
(500 mg, 1.09 mmol), Rh2(OAc)4 (4 mg, 0.01 mmol) and BIPHEPHOS
(17 mg, 0.02 mmol) were dissolved in anhydrous toluene (20 mL).
The mixture was purged with H2/CO (1:1) three times and then
charged with H2 (30 psi) and CO (30 psi). The mixture was stirred at
85 ꢁC for 22 h. The mixture was allowed to cool to room temper-
ature, the pressure was vented and the mixture was concentrated in
vacuo. The residue was purified by flash chromatography with
gradual elution (5e15% Ethyl Acetate/Hexane) to give the desired
D
1636, 1456, 1377 cmꢀ1
;
dH (400 MHz, CDCl3): 7.80 (2H, d, J 8.2 Hz),
7.23e7.37 (7H, m), 5.90 (1H, ddt, J 17.1, 10.1, 7.0 Hz), 5.13e5.25 (3H,
m), 4.39 (1H, q, J 7.0 Hz), 2.63 (1H, dt, J 14.2, 6.4 Hz), 2.39e2.48 (4H,
m), 2.29e2.38 (1H, m), 2.19 (1H, td, J 11.8, 8.0 Hz); dC (100 MHz,
CDCl3): 144.9, 137.1, 133.7, 132.1, 129.6, 129.5, 128.5, 128.4, 127.2,
118.3, 82.9, 61.1, 40.5, 39.1, 21.7; MS (ESI þve) m/z, 345.0 (MþþH,
100), 367.0 (MþþNa,10); HRMS (ESI) m/z calculated for C19H22NO3S
[MþH]þ 344.1320, found 344.1311.
22
Minor diastereomer: Rf 0.46 (20% Ethyl Acetate/Hexane); [a]
D
ꢀ68.0 (c 0.20, CH2Cl2); nmax (film) 3065, 2981, 2852, 1598, 1357,
ene-sulfonamide 11b (466 mg, 91%) as a clear oil; Rf 0.58 (20% Ethyl
1332 cmꢀ1
;
dH (400 MHz, CDCl3): 7.90 (2H, d, J 8.2 Hz), 7.27e7.41
Acetate/Hexane); [
a
]
D
ꢀ218.8 (c 0.18, CH2Cl2); nmax (film) 2952,
22
(7H, m), 5.89 (1H, ddt, J 17.2, 10.2, 6.9 Hz), 5.13e5.21 (3H, m), 4.45
(1H, qd, J 7.8, 5.5 Hz), 2.64e2.83 (2H, m), 2.42e2.55 (4H, m), 2.08
(1H, ddd, J 12.5, 10.2, 7.5 Hz); dC (100 MHz, CDCl3): 144.9, 136.9,
133.7, 133.2, 129.7, 129.2, 128.6, 128.5, 127.8, 126.8, 118.2, 83.2, 60.0,
42.4, 40.4, 21.7; MS (ESI þve) m/z, 345.0 (MþþH, 100), 240.8 (40),
173.6 (64), 155.5 (70); HRMS (ESI) m/z calculated for C19H22NO3S
[MþH]þ 344.1320, found 344.1319.
2912, 2875, 1643, 1449, 1358, 1166, 1095 cmꢀ1
; dH (396 MHz,
CDCl3): 7.64 (2H, d, J 8.2 Hz), 7.20e7.34 (7H, m), 6.58 (1H, d, J
8.2 Hz), 4.99e5.05 (1H, m), 4.96 (1H, dd, J 9.1, 3.2 Hz), 4.12 (1H, m),
2.42 (3H, s), 1.61e1.94 (5H, m), 1.39e1.53 (1H, m), 0.85e0.92 (9H,
m), 0.37e0.73 (6H, m); dC (100 MHz, CDCl3): 145.5, 143.3, 136.0,
129.6, 128.1, 127.2, 127.0, 126.0, 123.7, 110.0, 72.3, 50.6, 44.1, 24.2,
21.5, 17.3, 6.9, 4.9; MS (ESI ꢀve) m/z 341.0 (MꢀꢀOTES, 100), 236.8
(95); HRMS (ESI) m/z calculated for C26H38NO3SSiNa [MþNa]þ
494.2161, found 494.2165.
3.1.6. N-((1R,3S)-1-Hydroxy-1-phenylhex-5-en-3-yl)-4-
methylbenzenesulfonamide (10a). Mo(CO)6 (692 mg, 2.62 mmol)
was added to a solution of isoxazolidine 9 (3.01 g, 8.76 mmol) in
acetonitrile (28 mL) and water (4 mL). The mixture was stirred at
room temperature for 15 min, and NaBH4 (758 mg, 13.1 mmol) was
added in one portion. The reaction mixture was heated at 90 ꢁC
overnight. The mixture was cooled to room temperature and con-
centrated in vacuo. The residue was diluted with Et2O (20 mL) and
3.1.9. (R)-1-Phenyl-2-((S)-1-tosyl-1,2,3,4-tetrahydropyridin-2-yl)
ethanol (11a) by desilylation. A solution of ene-sulfonamide 11b
(465 mg, 0.99 mmol) in 10% methanolic NaOH (10 mL) was stirred
at room temperature overnight. The mixture was diluted with
CH2Cl2 (20 mL) and washed with water (2ꢂ10 mL). The organic
phase was dried over MgSO4, filtered and concentrated in vacuo.

2138
R.W. Bates et al. / Tetrahedron 70 (2014) 2134e2140
The residue was purified by flash chromatography (20% Ethyl Ac-
etate/Hexane) to give the desired alcohol 11a (340 mg, 96%) as
a colourless solid; mp 117e119 ꢁC; Rf 0.24 (20% Ethyl Acetate/
þve) m/z 340.1 (MþꢀOAc, 30); HRMS (ESI) m/z calculated for
C
22H26NO4S [MþH]þ 400.1583, found 400.1592.
Hexane); [
a
]
22 ꢀ213.7 (c 0.35, CH2Cl2); nmax (film) 3443, 1645, 1597,
3.1.13. (S)-1-Phenyl-2-((S)-1-tosyl-1,2,3,4-tetrahydropyridin-2-yl)
ethyl 2-chloroacetate (15a). DIAD (710 L, 3.57 mmol) was added
dropwise to solution of ene-sulfonamide 11a (639 mg,
D
1338, 1163, 1101, 922 cmꢀ1
;
dH (396 MHz, CDCl3): 7.71 (2H, d, J
m
8.6 Hz), 7.23e7.42 (7H, m), 6.66 (1H, d, J 8.2 Hz), 5.12 (1H, t, J 5.9 Hz),
5.02 (1H, dd, J 11.1, 2.0 Hz), 4.30 (1H, d, J 10.9 Hz), 3.63 (1H, d, J
4.5 Hz), 2.44 (3H, s), 1.73e1.98 (3H, m), 1.37e1.53 (1H, m),
0.80e0.99 (2H, m); dC (100 MHz, CDCl3): 144.2, 143.8, 135.1, 129.8,
128.3, 127.2, 127.1, 125.7, 123.1, 110.9, 69.2, 49.7, 41.6, 23.8, 21.6, 17.5;
MS (ESI þve) m/z 381.0 (Mþ þNa, 10), 341.0 (MþꢀOH, 100); HRMS
(ESI) m/z calculated for C20H24NO3S [MþH]þ 358.1477, found
358.1461.
a
1.79 mmol), PPh3 (939 mg, 3.57 mmol) and chloroacetic acid
(338 mg, 3.57 mmol) in toluene at 0 ꢁC. The mixture was stirred at
0
ꢁC for 1 h and then allowed to warm to room temperature and
stirred overnight. The mixture was concentrated in vacuo. The
residue was dissolved in CH2Cl2 and absorbed onto silica, then
purified by flash chromatography with gradual elution (5e15%
Ethyl Acetate/Hexane) to give chloroacetate 15a (540 mg, 70%) as
a clear oil and alkene 15b (100 mg, 17%) as a colourless powder.
22
3.1.10. (R)-1-Phenyl-2-((S)-1-tosyl-1,2,3,4-tetrahydropyridin-2-yl)
ethanol (11a) by saponification. K2CO3 (21 mg, 0.15 mmol) was
added to a solution of acetate 11c (50 mg, 0.13 mmol) in MeOH
(5 mL) and CH2Cl2 (2 mL). The reaction mixture was stirred at room
temperature for 2 h, then concentrated in vacuo. The residue was
taken up in CH2Cl2 (5 mL) and washed with water (3 mL). The or-
ganic phase was dried over MgSO4, filtered and concentrated in
vacuo to give the desired alcohol 11a (46 mg, 100%) as a colourless
solid, identical to that described above.
Chloroacetate 15a: Rf 0.32 (20% Ethyl Acetate/Hexane); [a]
D
ꢀ221.2 (c 0.14, CH2Cl2); nmax (film) 2961, 2926, 1759, 1644, 1340,
1165 cmꢀ1
dH (400 MHz, CDCl3): 7.63 (2H, d, J 8.2 Hz), 7.23e7.44
;
(7H, m), 6.62 (1H, d, J 7.8 Hz), 5.94 (1H, dd, J 9.1, 4.6 Hz), 4.98e5.10
(1H, m), 3.96e4.21 (3H, m), 2.29e2.49 (4H, m), 1.77e1.97 (3H, m),
1.55 (1H, m), 0.82e1.00 (1H, m); dC (100 MHz, CDCl3): 166.6, 143.5,
139.4, 135.8, 129.7, 128.6, 128.5, 126.9, 126.8, 123.6, 109.1, 75.4, 49.8,
41.1, 38.3, 22.8, 21.5, 17.1; MS (ESI þve) m/z 236.8 (100), 341.0
(MþꢀC2H2O2Cl, 90), 435.0/437.0 (MþþH, 23), 457.0/459 (MþþNa,
23); HRMS (ESI) m/z calculated for
C
22H25NO4S35Cl [MþH]þ
3.1.11. (R)-1-Phenyl-2-((S)-1-tosyl-1,2,3,4-tetrahydropyridin-2-yl)
ethanol (11a) and (1S,3S,5S)-3-phenyl-9-tosyl-2-oxa-9-azabicyclo
[3.3.1]nonane (13) by hydroformylation. In a FisherePorter tube,
aminoalcohol 10a (100 mg, 0.29 mmol), Rh2(OAc)4 (1 mg,
0.03 mmol) and BIPHEPHOS (5 mg, 0.06 mmol) was dissolved in
anhydrous toluene (5 mL). The mixture was purged with H2/CO
(1:1) three times and then charged with H2 (30 psi) and CO (30 psi).
The reaction mixture was heated to 65 ꢁC and stirred for 22 h. The
reaction mixture was allowed to cool to room temperature, the
pressure was vented and the mixture was concentrated in vacuo.
The residue was purified by flash chromatography with gradual
elution (5e25% Ethyl Acetate/Hexane) to give two products, the
desired ene-sulfonamide 11a (47 mg, 46%), identical to that de-
scribed above, and bicyclic acetal 13 (36 mg, 35%).
434.1193, found 434.1189.
Alkene 15b: mp 108e110 ꢁC; Rf 0.45 (20% Ethyl Acetate/Hexane);
22
[a
]
ꢀ188.1 (c 0.09, CH2Cl2); nmax (film) 2927, 2193, 2021, 1648,
D
1596, 1494, 1359, 1339, 1163, 1098 cmꢀ1
;
dH (400 MHz, CDCl3): 7.68
(2H, d, J 7.8 Hz), 7.17e7.32 (7H, m), 6.73 (1H, d, J 8.2 Hz), 6.48 (1H, d,
J 16.0 Hz), 5.93 (1H, dd, J 15.8, 5.7 Hz), 5.02 (1H, t, J 6.9 Hz), 4.74 (1H,
m), 2.36 (3H, s), 1.69e2.09 (4H, m), 1.31e1.47 (2H, m); dC (100 MHz,
CDCl3): 143.4, 136.5, 136.4, 131.4, 129.6, 128.4, 127.5, 127.1, 126.4,
126.2, 123.7, 108.2, 54.4, 25.5, 21.5, 17.5; MS (ESI þve) m/z 341.0 (Mþ
þH, 30), 169.7 (45), 143.6 (100); HRMS (ESI) m/z calculated for
C
20H22NO2S [MþH]þ 340.1371, found 340.1377.
3.1.14. (2S,3S,6S)-6-((S)-2-(2-Chloroacetoxy)-2-phenylethyl)-1-
tosylpiperidine-2,3-diyl diacetat (17). MeSO2NH2 (166 mg,
1.74 mmol) was added to a solution of ene-sulfonamide 15a
(250 mg, 0.58 mmol) in THF (18 mL) with stirring. When the
Bicyclic acetal 13: mp 138e142 ꢁC; Rf 0.31 (20% Ethyl Acetate/
22
Hexane); [
a
]
D
þ3.83 (c 0.37, CH2Cl2); nmax (film) 2921, 1704, 1643,
1598, 1347, 1163 cmꢀ1
;
dH (400 MHz, CDCl3): 7.86 (2H, d, J 8.2 Hz),
MeSO2NH2 had completely dissolved, NMO (410 mL of a 50%
7.33 (2H, d, J 8.2 Hz), 7.12e7.20 (3H, m), 6.72 (2H, dd, J 7.5, 2.1 Hz),
5.74 (1H, m), 5.38 (1H, dd, J 12.4, 4.1 Hz), 4.26 (1H, m), 2.46 (3H, s),
2.13e2.33 (4H, m), 1.87e1.99 (2H, m), 1.77 (1H, td, J 12.8, 5.9 Hz),
1.17e1.26 (1H, m); dC (100 MHz, CDCl3): 143.3, 142.6, 138.7, 129.8,
128.1, 127.9, 127.6, 125.6, 79.0, 73.2, 47.6, 35.6, 30.7, 30.3, 21.5, 20.2;
MS (ESI þve) m/z 381.0 (Mþ þNa, 10), 341.0 (40), 254.8 (100), 236.8
(58); HRMS (ESI) m/z calculated for C20H23NO3S [MþH]þ 358.1477,
found 358.1493.
aqueous solution, 1.74 mmol), H2O (2 mL) and K2OsO4$2H2O
(21 mg, 0.06 mmol) were added. The mixture was stirred at room
temperature for 48 h. The reaction mixture was taken up in EtOAc
(30 mL) and quenched with saturated aqueous Na2S2O3 (15 mL).
The organic phase was dried over MgSO4, filtered and concentrated
in vacuo to give diols 16 (271 mg, 0.58 mmol) as a mixture of di-
astereomers (ratio¼4.6:1) that was used without further
purification.
Ac2O (120 mL, 1.28 mmol), triethylamine (210 mL, 1.45 mmol) and
3.1.12. (S)-1-Phenyl-2-((S)-1-tosyl-1,2,3,4-tetrahydropyridin-2-yl)
DMAP (1 mg, 0.01 mmol) were added to the solution of the crude
diols in anhydrous CH2Cl2 (15 mL). The mixture was stirred at room
temperature for 3 h. The mixture was diluted with saturated
aqueous NH4Cl (15 mL) and CH2Cl2 (10 mL). The organic phase was
dried over MgSO4, filtered and concentrated in vacuo. The crude
residue was purified by flash chromatography (25% Ethyl Acetate/
Hexane) to give the desired diacetates 17 (268 mg, 83%) as a crys-
talline solid and as an inseparable mixture of diastereomers
(ratio¼4.6:1); mp 135e140 ꢁC; Rf 0.27 (40% Ethyl Acetate/Hexane);
ethyl acetate (11c). Amberlyst-A15 (12 mg) and Ac2O (120
mL,
1.21 mmol) were added to a solution of the bicyclic acetal (289 mg,
0.81 mmol) in CH2Cl2 (10 mL). The reaction mixture was stirred at
room temperature overnight. The mixture was filtered and con-
centrated in vacuo. The residue was purified by flash chromatog-
raphy (10e20% Ethyl Acetate/Hexane) to give acetate 11c as
a colourless powder in (224 mg, 70%); mp 171e175 ꢁC; Rf 0.27 (20%
22
Ethyl Acetate/Hexane); [
a]
ꢀ169 (c 0.11, CH2Cl2); nmax (Nujol)
D
3422, 2361, 1738, 1647, 1597, 1365, 1337, 1231, 1161 cmꢀ1
;
dH
nmax (film) 2952, 2373, 2364, 1747, 1362, 1240, 1165 cmꢀ1
.
(396 MHz, CDCl3): 7.62 (2H, d, J 8.2 Hz), 7.35 (4H, m), 7.28e7.31 (3H,
m), 6.60 (1H, d, J 8.6 Hz), 5.82 (1H, dd, J 9.5, 4.5 Hz), 4.95e5.20 (1H,
m), 4.10 (1H, dd, J 7.7, 3.6 Hz), 2.42 (3H, s), 2.08e2.25 (3H, s),
1.76e2.05 (4H, m), 1.40e1.52 (1H, m), 0.83e0.98 (1H, m); dC
(100 MHz, CDCl3): 170.1,143.4,140.6,135.8,129.6,128.5,127.9,127.1,
126.5, 123.5, 109.9, 72.9, 49.5, 38.2, 23.3, 21.5, 21.2, 17.3; MS (ESI
Major diastereomer: dH (396 MHz, CDCl3): 7.72 (2H, d, J 8.6 Hz),
7.27e7.40 (7H, m), 6.82 (1H, d, J 3.6 Hz), 5.82 (1H, dd, J 10.4, 3.6 Hz),
4.66 (1H, dt, J 11.9, 4.2 Hz), 3.98e4.26 (3H, m), 2.44 (3H, s),
2.29e2.41 (1H, m), 2.12e2.28 (1H, m), 1.96 (3H, s), 1.95 (3H, s),
1.78e1.89 (2H, m), 1.59e1.71 (2H, m); dC (100 MHz, CDCl3): 169.8,
168.9, 166.9, 144.1, 139.1, 137.2, 129.9, 128.8, 128.6, 127.3, 126.4, 75.8,

R.W. Bates et al. / Tetrahedron 70 (2014) 2134e2140
2139
75.4, 69.4, 48.9, 41.0, 39.6, 26.0, 21.6, 21.0, 20.7, 19.0; MS (ESI þve)
m/z 575.1/577.1 (MþþNa, 14), 493.0/495.0 (MþꢀOAc, 44), 399.0
(MþꢀC4H4O345Cl, 100), 351.0 (45), 294.9 (90); HRMS (ESI) m/z cal-
culated for C26H30NO8S35Cl [MþH]þ 552.1459, found 552.1474.
dried over MgSO4, filtered and concentrated in vacuo to give
piperidinol 20 as a pale yellow oil, which was used without further
purification.
Formic acid (20 mL, 0.50 mmol) and paraformaldehyde (15 mg,
0.50 mmol) were added to a solution of piperidinol 20 (11 mg,
0.05 mmol) in dioxane (3 mL). The reaction mixture was heated and
stirred at 100 ꢁC overnight. The mixture was cooled to room tem-
perature, filtered and concentrated in vacuo. The residue was dis-
3.1.15. (S)-2-((2S,5S)-5-Acetoxy-1-tosylpiperidin-2-yl)-1-phenylethyl
2-chloroacetate (18). Et3SiH (580
mL, 3.63 mmol) and trifluoroacetic
acid (30 L, 0.36 mmol) were added to a solution of diacetates 17
m
(200 mg, 0.36 mmol) in anhydrous CH2Cl2 (10 mL). The mixture was
stirred at room temperature overnight. The mixture was diluted
with water (5 mL) and extracted with CH2Cl2 (5 mL). The organic
phase was dried over MgSO4, filtered and concentrated in vacuo.
The crude product was purified by flash chromatography (10e20%
Ethyl Acetate/Hexane) to give the two isomers as clear oils: major
isomer 18 (75 mg, 42%), minor isomer (33 mg, 18%).
solved in MeOH (5 mL) and Et3N (110 mL, 0.80 mmol) was added.
The mixture was stirred for 2 h at room temperature. The reaction
mixture was concentrated in vacuo and the crude product was
purified by flash chromatography (10% MeOH/CHCl3 with 1% Et3N)
to give 5-hydroxysedamine 3 as a yellow oil (8.3 mg, 71%); Rf 0.04
22
(10% MeOH/CHCl3 with 1% Et3N); [
a
]
ꢀ55.3 (c 0.15, MeOH); nmax
D
(film) 3343, 2934, 2802, 1600, 1451, 1253, 1058 cmꢀ1
; dH (396 MHz,
Major isomer: Rf 0.36 (40% Ethyl Acetate/Hexane); [
a]
22 ꢀ44.5 (c
CDCl3): 7.19e7.43 (5H, m), 4.87 (1H, dd, J 10.4, 2.3 Hz), 3.88 (1H, tt, J
7.5, 3.6 Hz), 2.88 (1H, dd, J 12.7, 7.7 Hz), 2.66e2.74 (1H, m), 2.59 (1H,
dd, J 13.1, 3.6 Hz), 2.48 (3H, s), 2.17 (1H, ddd, J 14.2, 10.3, 8.2 Hz), 1.91
(1H, ddt, J 13.4, 8.9, 4.5 Hz), 1.67e1.76 (1H, m), 1.53e1.66 (2H, m),
1.49 (1H, ddd, J 14.2, 5.5, 2.8 Hz); dC (100 MHz, CDCl3): 145.0, 128.2,
127.2, 125.4, 73.3, 63.6, 59.7, 57.5, 42.4, 39.6, 30.1, 24.0; MS (ESI þve)
m/z 236.9 (MþþH, 80), 114.4 (100); HRMS (ESI) m/z calculated for
D
0.38, CH2Cl2); nmax (film) 3449, 2594, 1759, 1732, 1597, 1494, 1454,
1342, 1242, 1161 cmꢀ1
; dH (396 MHz, CDCl3): 7.67 (2H, d, J 8.2 Hz),
7.21e7.32 (7H, m), 5.77 (1H, dd, J 8.6, 5.0 Hz), 4.31 (1H, tt, J 10.3,
4.9 Hz), 3.89e4.13 (4H, m), 2.86 (1H, dd, J 14.0, 11.3 Hz), 2.36 (3H, s),
2.24e2.33 (1H, m), 1.94 (3H, s), 1.87 (1H, ddd, J 14.5, 6.8, 5.0 Hz),
1.69e1.79 (1H, m), 1.34e1.45 (3H, m); dC (100 MHz, CDCl3): 169.9,
166.6, 143.6, 139.0, 137.9, 129.9, 128.7, 128.6, 127.0, 126.7, 76.0, 67.4,
49.1, 43.3, 41.1, 36.3, 26.1, 24.5, 21.5, 21.0; MS (ESI þve) m/z 399.0
(MþꢀC2H2O2Cl, 15), 269.9 (100), 236.8 (15); HRMS (ESI) m/z cal-
C
14H22NO2 [MþH]þ 236.1651, found 236.1642.
Acknowledgements
culated for C24H29NO6S35Cl [MþH]þ 494.1404, found 494.1397.
22
Minor isomer: Rf 0.40 (40% Ethyl Acetate/Hexane); [
a
]
ꢀ87.33
D
We thank Nanyang Technological University and the Singapore
Ministry of Education Academic Research Fund Tier 1 (grant RG62/
10) for financial support of this work. NFMA thanks the Economic
Development Board and Novartis for an EDB IPP Scholarship.
(c 0.21, CH2Cl2); nmax (film) 2962, 1758, 1347, 1213, 1163 cmꢀ1
; dH
(396 MHz, CDCl3): 7.64 (2H, d, J 8.2 Hz), 7.28e7.45 (7H, m), 6.62 (1H,
s), 5.95 (1H, dd, J 8.6, 5.0 Hz), 4.16 (1H, d, J 16.0 Hz), 4.05 (1H, d, J
12.0 Hz), 3.91e4.00 (1H, m), 2.36e2.48 (4H, m), 2.10e2.29 (4H, m),
1.82e1.96 (2H, m), 1.51 (1H, dd, J 13.8, 6.6 Hz), 0.80e1.00 (3H, m); dC
(100 MHz, CDCl3): 169.5, 166.5, 143.9, 139.1, 137.0, 135.0, 129.8,
128.6, 128.5, 127.1, 126.8, 115.9, 75.4, 49.6, 41.1, 37.9, 22.5, 21.5, 20.7,
20.4; MS (ESI þve) m/z 399.0 (MþꢀC2H2O325Cl, 100), 357.0 (36),
294.9 (42); HRMS (ESI) m/z calculated for C24H29NO6S35Cl [MþH]þ
494.1404, found 494.1409.
References and notes
1. Bates, R. W.; Kasinathan, S.; Straub, B. F. J. Org. Chem. 2011, 76, 6844.
2. Bates, R. W.; Kasinathan, S. Tetrahedron 2013, 69, 3088.
3. Bates, R. W.; Boonsombat, J.; Lu, Y.; Nemeth, J. A.; Sa-Ei, K.; Song, P.; Cai, M. P.;
Cranwell, P. B.; Winbush, S. Pure Appl. Chem. 2008, 80, 681.
4. Bates, R. W.; Song, P. Synthesis 2009, 655.
5. Bates, R. W.; Lu, Y. J. Org. Chem. 2009, 74, 9460.
6. (a) Bates, R. W.; Boonsombat, J. Org. Biomol. Chem. 2005, 3, 520; (b) Bates, R. W.;
Nemeth, J.; Snell, R. Synthesis 2008, 1033.
3.1.16. (3S,6S)-6-((S)-2-Hydroxy-2-phenylethyl)-1-tosylpiperidin-3-
ol (19). K2CO3 (31 mg, 0.23 mmol) was added to a stirred solution
of piperidine 18 (45 mg, 0.09 mmol) in methanol (5 mL). The
mixture was stirred at room temperature for 2 h. The reaction
mixture was concentrated in vacuo. The residue was taken up in
EtOAc (5 mL) and washed with water (3 mL). The organic phase was
dried over MgSO4, filtered and concentrated in vacuo to give
piperidinol 19 as a colourless oil (34 mg, 100%), which was used
7. Bates, R. W.; Lu, Y. Org. Lett. 2010, 12, 3938.
ꢀ
8. (a) Ibebeke-Bomangwa, W.; Hootele, C. Tetrahedron 1987, 43, 935 For previous
ꢀ
syntheses of this alkaloid, see: (b) Plehiers, M.; Hootele, C. Tetrahedron Lett.
€
1993, 34, 7569; (c) Herdeis, C.; Held, W. A.; Kirfel, A.; Schwabenlander, F. Liebigs
ꢀ
Ann. Chem. 1995, 1295; (d) Plehiers, M.; Hootele, C. Can. J. Chem. 1996, 74, 2444;
(e) Liu, G.; Meng, J.; Feng, C. G.; Huang, P. Q. Tetrahedron: Asymmetry 2008, 19,
1297.
9. Bates, R. W.; Sa-Ei, K. Tetrahedron 2002, 58, 5957.
10. (a) Bates, R. W.; Tang, C. H.; Tan, Y.; bte Buang, S. N. Synlett 2012, 2266 For
reviews of the use of iminium ions, see: (b) Yazici, A.; Pyne, S. G. Synthesis 2009,
339; (c) Yazici, A.; Pyne, S. G. Synthesis 2009, 513; (d) Speckamp, W. N.; Moo-
lenaar, M. J. Tetrahedron 2000, 56, 3817.
without further purification; Rf 0.06 (40% Ethyl Acetate/Hexane);
22
[
a]
ꢀ56.2 (c 0.10, CH2Cl2); nmax (film) 3451, 2925, 2854, 1598,
D
1454, 1330, 1154 cmꢀ1
; dH (400 MHz, CDCl3): 7.73 (2H, d, J 8.2 Hz),
7.26e7.37 (7H, m), 4.71 (1H, dd, J 8.9, 4.3 Hz), 4.20e4.30 (1H, m),
3.92 (1H, ddd, J 14.0, 4.3, 0.9 Hz), 3.36e3.54 (1H, m), 2.77 (1H, dd, J
13.7, 11.0 Hz), 2.42 (3H, s), 2.27 (1H, d, J 5.5 Hz), 1.93e2.03 (1H, m),
1.75e1.90 (2H, m), 1.30e1.51 (3H, m); dC (100 MHz, CDCl3): 144.2,
143.4, 137.9, 129.8, 128.6, 127.7, 127.1, 125.8, 72.3, 66.1, 49.6, 46.6,
38.9, 28.2, 26.5, 21.5; MS (ESI þve) m/z 399.0 (MþþNa, 10), 254.8
(100), 114.3 (68); HRMS (ESI) m/z calculated for C20H25NO4SNa
[MþNa]þ 398.1402, found 398.1430.
11. (R)-Styrene oxide, prepared by the method of Jacobsen (Schaus, S. E.; Brandes,
B. D; Larrow, J. F.; Tokunaga, M.; Hansen, K. B.; Gould, A. E.; Furrow, M. E.; Ja-
cobsen, E.N. J. Am. Chem. Soc. 2002, 124, 1307), was subjected to ring opening
with lithium acetylide ethylene diamine complex, followed by partial reduction
using Lindlar’s catalyst. Lindlar’s catalyst prepared by the reported procedure
(Lindlar, H.; Dubuis, R. Organic Syntheses; Wiley & Sons: New York, NY, 1973;
Collect. Vol. 5., p 880) gave superior and more reproducible results compared to
commercial material.
12. Grochowski, E.; Jurczak, J. Synthesis 1976, 682.
13. Details of the X-ray structure determinations for compounds 9 and 13 have
been deposited with the Cambridge Crystallographic Database, CCDC 949998
and CCDC 967456, respectively, and may be obtained at http://www.ccdc.cam.
ac.uk.
3.1.17. (ꢀ)-5-Hydroxysedamine (3). Activated Mg turnings (24 mg,
1.00 mmol) were added in 5 mg portions every hour to a solution of
N-tosylpiperidinol 19 (19 mg, 0.05 mmol) in anhydrous MeOH
(4 mL) as the mixture was being sonicated in an ultrasonic cleaning
bath. Once the reaction was complete as determined by TLC anal-
ysis, the reaction mixture was acidified with 2 M HCl and washed
with CH2Cl2 (5 mL). The aqueous layer was neutralized with 2 M
NaOH and extracted with CH2Cl2 (2ꢂ5 mL). The organic layer was
14. (a) Cicchi, S.; Got, A.; Brandi, A.; Guarna, A.; Sarlos, F. D. Tetrahedron Lett. 1990,
€
31, 3351; (b) Zhang, D.; Suling, C.; Miller, M. J. J. Org. Chem. 1998, 63, 885; (c)
Mulvihill, M. J.; Gage, J. L.; Miller, M. J. J. Org. Chem. 1998, 63, 3357; (d) Li, F.;
Brogan, J. B.; Gage, J. L.; Zhang, D.; Miller, M. J. J. Org. Chem. 2004, 69, 4538; (e)
Yang, Y.-K.; Choi, J.-H.; Tae, J. J. Org. Chem. 2005, 70, 6995; (f) Calvet, G.; Blan-
chard, N.; Kouklovsky, C. Synthesis 2005, 19, 3346.
15. For reviews of hydroformylation, see: (a) Hydroformylation for Organic Synthe-
sis; Taddei, M., Ed.; Springer: Berlin, Germany, 2013; (b) Franke, R.; Selent, D.;
€
Borner, A. Chem. Rev. 2012, 112, 5675; (c) Breit, B.; Seiche, W. Synthesis 2001, 1

2140
R.W. Bates et al. / Tetrahedron 70 (2014) 2134e2140
For a recent application to sedum alkaloids, see: (d) Spangenberg, T.; Airiau, A.;
17. Such compounds can be useful intermediates in their own right: see Ref. 5
18. Cuny, G. D.; Buchwald, S. L. J. Am. Chem. Soc. 1993, 115, 2066.
Thuong, M. B. T.; Donnard, M.; Billet, M.; Mann, A. Synlett 2008, 2859.
16. Piperidine 12: mp 139e140 ꢁC; Rf 0.13 (20% Ethyl Acetate/Hexane); nmax (film)
19. Some acetate 11c could be observed by TLC when BiCl3 was used; no product
was observed using several lanthanide triflates, Sc(OTf)3 or In(OTf)3.
20. We were unable to protect the alcohol as a TBS ether using TBS chloride,
presumably due to steric hindrance, and considered the TMS ether as poten-
tially too labile. As Kocienski has pointed out, the ‘ratio of pleasure to pain is
quite favourable with TES ethers’. Prot. Groups, Kocienski, P. J. Thieme, p 195.
21. Martin, S. F.; Dodge, J. A. Tetrahedron Lett. 1991, 32, 3017.
3519, 2947, 1598, 1491, 1325, 1158 cmꢀ1
; dH (396 MHz, CDCl3): 7.68e7.74 (2H,
m), 7.39e7.45 (2H, m), 7.21e7.30 (5H, m), 5.53e5.59 (1H, m), 4.99e5.08 (1H,
m), 4.25e4.37 (1H, m), 3.78 (1H, d, J 4.1 Hz), 2.92 (1H, br s), 2.64 (1H, ddd, J 14.
0, 11.6, 2.5 Hz), 2.44 (3H, s), 1.79e1.98 (2H, m), 1.52e1.69 (4H, m), 1.16e1.44 (2H,
m); dC (100 MHz, CDCl3): 144.3, 143.7, 137.7, 130.0, 128.3, 126.9, 126.5, 125.6, 69.
9, 69.8, 50.0, 45.2, 30.1, 28.8, 21.5, 13.1; MS (ESI þve) m/z 399.0 (MþþNa, 18),
341.0 (26), 254.8 (100), 236.8 (44), 155.5 (40); HRMS (ESI) m/z calculated for
22. Saïah, M.; Bessodes, M.; Antonakis, K. Tetrahedron Lett. 1992, 33, 4317.
23. Kursanov, D. N.; Parnes, Z. N.; Loim, N. M. Synthesis 1974, 633.
C
20H26NO4S [MþH]þ 376.1583, found 376.1578.