Synthesis of azimic acid using hydroformylation

Article abstract of DOI:10.1016/j.tet.2013.01.060

A synthesis of the alkaloid azimic acid has been achieved using double hydroformylation with a single tandem condensation to form the six membered ring. The oxygen substituent was introduced by diastereoselective dihydroxylation, cis to the existing alkyl substituent. The methyl substituent was introduced via an iminium ion intermediate under stereoelectronic control.

Full text of DOI:10.1016/j.tet.2013.01.060

Tetrahedron 69 (2013) 3088e3092
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Tetrahedron
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Synthesis of azimic acid using hydroformylation
*
Roderick W. Bates , Sivarajan Kasinathan
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link,
Singapore 637371, 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 the alkaloid azimic acid has been achieved using double hydroformylation with a single
tandem condensation to form the six membered ring. The oxygen substituent was introduced by dia-
stereoselective dihydroxylation, cis to the existing alkyl substituent. The methyl substituent was in-
troduced via an iminium ion intermediate under stereoelectronic control.
Received 7 November 2012
Received in revised form 2 January 2013
Accepted 21 January 2013
Available online 31 January 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Dedicated, on the occasion of his retirement,
to Professor Willie Motherwell who in-
troduced the corresponding author to the
concept of stereoelectronic control
Keywords:
Piperidine
Alkaloid
Iminium ion
Stereoselectivity
Hydroformylation
O
O
1. Introduction
Azimic acid 1, a hydrolysis product of the alkaloid azimine 3,
isolated from azima tetracantha L., is a trisubstituted piperidine,
with all substituents on the same face of the ring.1,2 Azimic acid has
been the subject of a number of total syntheses. The synthetic
challenge is in the installation of the three stereocentres of the
piperidine ring cis to each other around the ring.3 The most com-
mon approach has been to install the majority of the stereocentres
prior to piperidine ring formation. Brown employed a Henry re-
action to form the 1,2-aminoalcohol moiety prior to cyclisation.4
Hanessian,5 Datta6 and Huang7 employed intramolecular re-
ductive amination reactions. Naito employed a nitrone cycloaddi-
tion.8 In a minority of cases, one or more stereocenters have been
installed after ring formation: Ma employed an enaminone cycli-
sation.9 Both Padwa10 and Zhou11 established the aminoalcohol
system using an aza-Achmatowicz reaction. Natsume constructed
the molecule from pyridine,12 while Gerlach started with
a substituted pyridine.13 Carpamic acid 2, a higher analogue of
azimic acid containing an additional carbon atom in the side chain,
has also been the subject of several syntheses.14e18
HO
Me
Me
N
H
CO2H
n
N
H
H
N
Me
O
1 n = 1: Azimic acid
2 n = 2: Carpamic acid
3: Azimine
O
2. Results and discussion
It has been shown that dihydroxylation of six membered ring
ene-sulfonamides shows good selectivity for the isomer in which
the diol is cis to an a
0-substituent (Scheme 1).19 This selectivity,
which has been attributed to a combination of lipophilic and
electrostatic effects, delivers the correct stereochemistry of the 3
and 6 substituents. We anticipated that replacement of the 2-
hydroxy group of the diol 4 with a methyl group via an iminium
ion20 would deliver the desired stereochemistry under stereo-
electronic control.21 The required ene-sulfonamide 522,23 would, in
* Corresponding author. Tel.: þ65 6316 8907; fax: þ65 6791 1961; e-mail ad-
dress: roderick@ntu.edu.sg (R.W. Bates).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.01.060

R.W. Bates, S. Kasinathan / Tetrahedron 69 (2013) 3088e3092
3089
The desired diene 6 was prepared using the method of Vilaivan
et al. (Scheme 2).30 Condensation of (S)-phenylglycinol with hex-5-
enal generated the oxazolidine 7,31 which reacted with allyl bro-
mide under Barbier conditions using indium to give the amino-
alcohol derivative 6 as a single diastereoisomer after cleavage of the
chiral auxiliary, N-sulfonylation and chromatographic purification,
in 42% yield (from hex-5-enal) and >98% ee. The diaster-
eoselectivity of the allylation was found to be highly dependent on
both the reaction temperature and the rate of addition of the allyl
bromide. Hex-5-enal was prepared by IBX oxidation32 of the
commercially available alcohol. It was found to be important to
employ a precisely measured quantity of the freshly distilled al-
dehyde to achieve a satisfactory Barbier allylation. Use of an excess
of undistilled aldehyde resulted in the formation of a different
allylation product 9 from a 2:1 condensation of the aldehyde with
the phenylglycinol. Compound 9 was formed as a single di-
astereoisomer,33 and is proposed to arise from Barbier allylation of
iminium ion 10. Double hydroformylation of diene 6 using rhodium
acetate and either triphenylphosphite or BIPHEPHOS34 gave the
ene-sulfonamide 11 in 60% and 74% yield, respectively, with the
HO
Me
HO
HO
CO2H
N
H
N
R
Ts
1
4
N
Ts
R
HN
Ts
5
6
Scheme 1. Azimic acid retrosynthesis.
turn, be available by tandem hydroformylation-condensation,24e27
as in our recent synthesis of pseudoconhydrine,19 building on the
work of Ojima.25,28 Given that the long side chain of azimic acid
terminates with a carboxylic acid, we planned to employ a double
hydroformylation of diene 6.29
Ph
Ph
NH2
Ph
HO
NH
Br
In
MgSO4
HO
N
O
O
66%
8
7
Ts
11 X = CHO
Ag2O, NaOH 95%
H2, CO, Rh2(OAc)4,
1. Pb(OAc)4; NH2OH
2. TsCl, Et3N, DMAP
(PhO)3P or
BIPHEPHOS
X
12 X = CO2H
HN
Ts
N
Ts
64%
60%
MeI, DBU 91%
6
13 X = CO2Me
RO
RO
AcO
Me
OsO4, NMO,
MeSO2NH2
AlMe3
CO2Me
CO2Me
87%
73%
N
Ts
N
Ts
16
14 R = H
Ac2O, K2CO3
15 R = Ac
97%
HO
Me
19 R = Ts
KOH, MeOH
97%
CO2H
Mg, MeOH, )))
59%
N
R
1
R = H
Ph
N
Ph
N
AcO
Me
O
O
CO2Me
10
9
N
Ts
17
(CH2)5CO2Me
Ts
(CH2)5CO2Me
AcO
N
N
Ts
AcO
18a
18b
Scheme 2. Azimic acid synthesis.

3090
R.W. Bates, S. Kasinathan / Tetrahedron 69 (2013) 3088e3092
tandem condensation occurring exclusively at the nearer of the two
aldehydes. Oxidation of the remaining aldehyde and esterification
then yielded the methyl ester 13 in 86% yield. Dihydroxylation of
the alkene following the Upjohn procedure with the addition of
methane sulfonamide proceeded in 87% yield and gave an in-
separable 5.8:1 mixture of diols 14. Based upon our previous
work19 and that of Harrity,35 the major diol was assigned the all-cis
stereochemistry. The rather labile diol mixture36 was acetylated to
give the diacetates 15 in 97% yield as a 5.8:1 mixture, still in-
separable. Treatment of the diacetates 15 with trimethylalumi-
nium, serving as both a methyl source and as a Lewis acid, gave the
all cis methylated product 16 in 73% yield. The minor product of this
reaction, isolated in 5% yield and separated by column chroma-
tography, was found by X-ray crystallography to be 17, with the 2-
and 6-substituents cis diaxial.37 This product arises by methylation
of the minor diacetate diastereoisomer. The stereochemistry of
both products is consistent with axial attack by a methyl nucleo-
phile on the corresponding iminium ions 18ab in conformations
t, J¼7.0 Hz, 0.5H), 4.38 (app. t, J¼7.5 Hz, 0.5H), 4.29 (app. t, J¼7.9 Hz,
0.5H), 4.12 (app. t, J¼7.7 Hz, 0.5H), 3.68 (app. t, J¼7.6 Hz, 0.5H), 3.60
(dd, J¼8.2, 6.6 Hz, 0.5H), 2.21e2.04 (m, 2H), 1.95e1.45 (m, 4H).
3.1.2. (S)-2-((R)-Nona-1,8-dien-4-ylamino)-2-phenylethanol (8). Allyl
bromide (0.53 mL, 6.07 mmol) was added slowly via syringe pump
over 3 h to a mixture of indium powder (465 mg, 4.05 mmol) and
oxazolidine 7 (440 mg, 2.02 mmol) in methanol (10 mL) at ꢁ10 ꢀC
and the mixture was stirred for another 6 h. The mixture was di-
luted with 10% aqueous NaHCO3 (10 mL), extracted with ethyl ac-
etate (15 mLꢂ3), dried (MgSO4), filtered and evaporated. The
residue was purified by flash chromatography on silica gel eluting
with 20% ethyl acetate/hexane to give homoallylic amine 8 (350 mg,
66%) as a yellowish oil: FTIR (neat, cmꢁ1): vmax 3326, 1639; 1H NMR
(400 MHz, CDCl3)
d 7.39e7.22 (m, 5H), 5.88e5.62 (m, 2H),
5.14e5.03 (m, 2H), 4.98e4.86 (m, 2H), 3.88 (dd, J¼8.6, 4.6 Hz, 1H),
3.66 (dd, J¼10.6, 4.5 Hz, 1H), 3.47 (dd, J¼10.6, 8.7 Hz, 1H), 2.60e2.47
(m, 1H), 2.26e2.12 (m, 2H), 1.96e1.84 (m, 2H), 1.45e1.20 (m, 4H);
such that the existing
a
-side chain is axial.38 Hydrolysis of the two
13C NMR (100 MHz, CDCl3)
d 141.2, 138.7, 135.1, 128.6, 127.6, 127.4,
ester groups of piperidine 16 and reductive detosylation of the
known10 sulfonamide 19 using magnesium in methanol,39 pro-
moted by ultrasound, yielded the natural product 1, which was
purified by carefully optimised ion exchange chromatography, in
59% yield. The 1H NMR10 and 13C NMR10,13 spectroscopic data and
the chiroptical data5e9,11 were in good agreement with those re-
ported for the natural product.
The use of the hydroformylationedihydroxylation sequence for
the stereoselective synthesis of 2,3,6-trisubstituted piperidines has
been demonstrated. The synthesis of azimic acid has been achieved
in a 10-step sequence from phenylglycinol, employing the less
common strategy of installing the majority of the substituents after
ring formation. The synthesis further illustrates the utility of
hydroformylation as a tool for CeC bond formation in organic
synthesis, and the value of ene-sulfonamides as synthetic
intermediates.
117.4, 114.6, 66.9, 61.7, 53.6, 37.6, 34.2, 33.7, 25.1; MS (ESIþ) m/z 259
([MþH]þ, 100); HRMS calcd for C17H25NO ([MþH]þ) 260.2014,
found 260.2025; [
a
]
D
21 þ82.3 (c 1.1, CHCl3).
3.1.3. (R)-N-Tosylnona-1,8-dienyl-4-amine (6). Lead tetraacetate
(1.46 g, 3.29 mmol) was added to a solution of aminoalcohol 8
(711 mg, 2.74 mmol) in dry CH2Cl2/MeOH (1:1, 20 mL) at 0 ꢀC and
the mixture was stirred until confirmed complete by TLC (30 min).
Hydroxylamine hydrochloride (1.90 g, 27.4 mmol) was added to the
mixture and it was stirred for another 30 min at 0 ꢀC. The solvents
were evaporated under reduced pressure. The residue was washed
with hexane (15 mLꢂ3), then suspended in CH2Cl2 (20 mL) and
filtered. The filtrate was concentrated in vacuo. The residue was
taken up in dry CH2Cl2 (20 mL), Et3N (0.76 mL, 5.48 mmol), TsCl
(575 mg, 3.02 mmol) and DMAP (33 mg, 0.274 mmol) were added
and the mixture was stirred overnight. The reaction mixture was
then diluted with satd aq ammonium chloride (20 mL), extracted
with ethyl acetate (20 mLꢂ3), dried over MgSO4, filtered and
evaporated. The crude product was purified by flash chromatog-
raphy on silica gel eluting with 10% ethyl acetate/hexane to give
sulfonamide 6 (510 mg, 64% yield) as a colourless oil: FTIR (neat,
3. Experimental section
3.1. General
All reactions requiring anhydrous conditions were carried out
under a nitrogen atmosphere using oven-dried glassware (120 ꢀC),
which was cooled under vacuum. Anhydrous tetrahydrofuran was
distilled from sodium metal and benzophenone under nitrogen.
Anhydrous dichloromethane and acetonitrile were dried by distil-
lation from CaH2 immediately prior to use under nitrogen. Anhy-
drous methanol was distilled from activated magnesium under
nitrogen. All other solvents and reagents were used as received.
Flash chromatography was carried out on silica gel, 230e400 mesh.
1H NMR spectra were recorded at 300, 400 or 500 MHz in CDCl3
solutions. 13C NMR spectra were recorded at the corresponding
frequency on the same instruments at 75, 100 or 125 MHz.
Chemical shifts are recorded in parts per million and coupling
constants are recorded in Hertz. Optical rotations are given with
cmꢁ1): vmax 3279, 1641,1322,1156; 1H NMR (400 MHz, CDCl3)
d 7.74
(d, J¼8.1 Hz, 2H), 7.29 (d, J¼8.1 Hz, 2H), 5.68 (ddt, J¼16.1,11.1, 6.7 Hz,
1H), 5.55 (ddt, J¼17.3, 10.1, 7.3 Hz, 1H), 5.16e4.79 (m, 4H), 4.32 (d,
J¼7.9 Hz, 1H), 3.33e3.24 (m, 1H), 2.43 (s, 3H), 2.10 (app. t, J¼6.4 Hz,
2H), 1.93 (app. q, J¼6.9 Hz, 2H), 1.52e1.17 (m, 4H); 13C NMR
(100 MHz, CDCl3)
d 143.3, 138.3, 138.3, 133.4, 129.7, 127.2, 118.9,
114.8, 53.3, 39.2, 34.0, 33.3, 24.7, 21.6; MS (ESIþ) m/z 293 ([MþH]þ,
100), 316 ([MþþNa], 71); HRMS Calcd for C16H23NO2S ([MþH]þ)
294.1528, found 294.1537; [
a
]
22 þ3.0 (c 1.35, CHCl3).
D
3.1.4. 6-((R)-1,2,3,4-Tetrahydro-1-tosylpyridin-2-yl)hexanal
(11). Sulfonamide 6 (440 mg, 1.50 mmol), Rh2(OAc)4 (7 mg,
15.0ꢂ10ꢁ3 mmol) and P(OPh)3 (98
mL, 0.375 mmol) were dissolved
in THF (15 mL) in a FisherePorter tube. The FisherePorter tube was
purged (three times) with H2/CO (1:1) and finally charged with H2
(30 psi)/CO (30 psi). The reaction mixture was stirred vigorously at
65 ꢀC for 18 h. The solvent was removed under reduced pressure
and the residue was purified by flash chromatography on silica gel
eluting with 2% ethyl acetate/hexane to give ene-sulfonamide 11
(300 mg, 60% yield) as a colourless oil: FTIR (neat, cmꢁ1): vmax 1721,
units of 10ꢁ1 deg cm2 ꢁ1. Rotations were measured at a wave-
g
length of 589 nm. Enantiomeric excess was determined by chiral
HPLC analysis, using a Diacel IC column, eluting with IPA/hexane.
3.1.1. (4S)-2-(Pent-4-en-1-yl)-4-phenyloxazolidine (7). Hex-5-enal
(0.16 g, 1.60 mmol) was added to a mixture of (S)-phenylglycinol
(0.2 g, 1.46 mmol) and MgSO4 (1.75 g, 14.60 mmol) in dry CH2Cl2
(15 mL). The reaction mixture was stirred overnight, filtered,
evaporated to give the crude oxazolidine 7 (0.32 g, quant.) as
a mixture of diastereoisomers and as a yellowish oil. 1H NMR
1645, 1339, 1164; 1H NMR (400 MHz, CDCl3)
7.66 (d, J¼8.1 Hz, 2H), 7.29 (d, J¼8.1 Hz, 4H), 6.57 (d, J¼8.3 Hz, 1H),
5.09e4.97 (m, 1H), 3.89 (br s, 1H), 2.48e2.38 (m, 2H), 2.41 (s, 3H),
2.01e1.07 (m, 10H), 1.02e0.71 (m, 2H); 13C NMR (100 MHz, CDCl3)
d
9.77 (t, J¼1.6 Hz, 1H),
(400 MHz, CDCl3)
J¼17.4 Hz, 1H), 4.97 (d, J¼10.1 Hz, 1H), 4.60e4.54 (m, 1H), 4.51 (app.
d
7.43e7.20 (m, 5H), 5.88e5.76 (m, 1H), 5.03 (d,
d 203.0, 143.4, 136.1, 129.7, 127.0, 123.5, 109.7, 52.8, 43.8, 31.3, 28.9,
25.6, 23.0, 22.0, 21.6, 17.3; MS (ESIþ) m/z 336 ([MþH]þ, 100); HRMS

R.W. Bates, S. Kasinathan / Tetrahedron 69 (2013) 3088e3092
3091
22
calcd for C18H25NO3S ([MþH]þ) 336.1633, found 336.1634; [
ꢁ265.8 (c 1.0, CHCl3).
a
]
CH2Cl2 (10 mL). The mixture was stirred for 3 h. The reaction
mixture was diluted with satd aq NH4Cl (20 mL), extracted with
CH2Cl2 (15 mLꢂ3), washed with water (20 mL) dried over MgSO4,
filtered and evaporated. The residue was purified by flash chro-
matography on silica gel eluting with 25% ethyl acetate/hexane to
give diacetates 15 (280 mg, 97% yield) as a colourless oil and as
an inseparable mixture of diastereoisomers: FTIR (neat, cmꢁ1):
nmax 1738, 1346, 1240, 1162; 1H NMR (400 MHz, CDCl3, major
D
3.1.5. 6-((R)-1,2,3,4-Tetrahydro-1-tosylpyridin-2-yl)hexanoic
acid
(12). NaOH (137 mg, 3.43 mmol) was added to a suspension of
Ag2O (175 mg, 0.754 mmol) in H2O (5 mL). Aldehyde 11 (230 mg,
0.686 mmol) dissolved in diethyl ether (3 mL) was added and the
mixture was stirred overnight. The reaction mixture was acidified
with 2 M HCl (15 mL), extracted with Et2O (20 mLꢂ3), washed with
water (20 mL) and brine (20 mL), and dried (MgSO4), filtered and
evaporated to give carboxylic acid 12 (228 mg, 95% yield) as a pale
yellowish oil: FTIR (neat, cmꢁ1): vmax 2930, 1705, 1646, 1339, 1163;
diastereoisomer)
d
7.71 (d, J¼8.3 Hz, 1H), 7.29 (d, J¼8.3 Hz, 1H),
6.78 (d, J¼3.8 Hz, 1H), 4.59 (dt, J¼12.1, 4.2 Hz, 1H), 3.96e3.87 (m,
1H), 3.66 (s, 3H), 2.41 (s, 3H), 2.29 (t, J¼7.5 Hz, 2H), 2.02 (s, 3H),
1.96 (s, 3H), 1.80e1.13 (m, 12H); 13C NMR (100 MHz, CDCl3, major
1H NMR (400 MHz, CDCl3)
d
7.66 (d, J¼8.1 Hz, 2H), 7.29 (d, J¼8.1 Hz,
diastereoisomer) d 174.2, 170.0, 169.2, 143.9, 137.8, 129.9, 127.2,
2H), 6.58 (d, J¼8.2 Hz,1H), 5.08e4.98 (m,1H), 3.89 (br s,1H), 2.41 (s,
76.0, 69.7, 52.6, 51.6, 34.1, 33.2, 29.1, 26.9, 26.4, 24.9, 21.7, 21.1,
20.9, 19.3. MS (ESIþ) m/z 424 ([MþꢁOac], 100), 506 ([MþNa]þ,
54); HRMS calcd for C23H33NO8S ([MþNa]þ) 506.1825 found
506.1824.
3H), 2.36 (t, J¼7.4 Hz, 2H), 1.99e1.16 (m, 11H), 0.97e0.77 (m, 1H);
13C NMR (100 MHz, CDCl3)
d 180.1, 143.4, 136.1, 129.7, 127.0, 123.6,
109.7, 52.9, 34.1, 31.3, 28.9, 25.5, 24.6, 23.0, 21.6, 17.3; MS (ESIþ) m/z
352 ([MþH]þ, 100); HRMS calcd for C18H25NO4S ([MþH]þ)
352.1583, found 352.1583; [
a
]
23 ꢁ260.2 (c 0.25, CHCl3).
3.1.9. Methyl 6-((2R,5S,6S)-5-acetoxy-6-methyl-1-tosylpiperidin-2-
yl)hexanoate (16). Trimethylaluminium (0.22 mL of a 2 M solu-
tion in toluene, 0.447 mmol) was added dropwise to a solution of
diacetates 15 (180 mg, 0.372 mmol) in CH2Cl2 (5 mL) at 0 ꢀC. The
mixture was allowed to warm to room temperature and stirred
for a further 1 h. The reaction was quenched with water (10 mL),
extracted with CH2Cl2 (15 mLꢂ3), washed with water (20 mL),
dried over MgSO4, filtered and evaporated. The crude product
was purified by flash chromatography on silica gel eluting with
15% ethyl acetate/hexane to give acetate 16 (120 mg, 73% yield)
as a pale yellowish oil: FTIR (neat, cmꢁ1): nmax 1736, 1337, 1238,
D
3.1.6. Methyl
6-((R)-1,2,3,4-tetrahydro-1-tosylpyridin-2-yl)-hex-
L, 1.25 mmol) dissolved in toluene
anoate (13). Methyl iodide (78
m
(10 mL) was added to a solution of carboxylic acid 12 (200 mg,
0.569 mmol) and DBU (0.10 mL, 0.683 mmol) in toluene. The
mixture was heated at reflux with vigorous stirring for 3 h. The
mixture was filtered, washing with Et2O (20 mL). The organic layer
was washed with water (10 mL), 2 M HCl (10 mL), satd aq NaHCO3
(10 mL), water (10 mL) and brine (10 mL), and dried (MgSO4), fil-
tered and evaporated. The crude product was purified by flash
chromatography on silica gel eluting with 20% ethyl acetate/hexane
to give ene-sulfonamide 13 (189 mg, 91% yield) as a colourless oil:
FTIR (neat, cmꢁ1): vmax 1734, 1645, 1340, 1163; 1H NMR (400 MHz,
1164; 1H NMR (400 MHz, CDCl3)
d
7.72 (d, J¼8.2 Hz, 2H), 7.28 (d,
J¼8.2 Hz, 2H), 4.44e4.24 (m, 2H), 3.91 (app. q, J¼6.8 Hz, 1H),
3.66 (s, 3H), 2.40 (s, 3H), 2.31 (t, J¼7.5 Hz, 2H), 2.00 (s, 3H),
1.81e1.30 (m, 12H), 1.25 (d, J¼6.9 Hz, 3H); 13C NMR (100 MHz,
CDCl3)
d
7.65 (d, J¼8.3 Hz, 2H), 7.28 (d, J¼8.3 Hz, 2H), 6.57 (dd, J¼8.2,
0.8 Hz, 1H), 5.06e4.98 (m, 1H), 3.89 (br s, 1H), 3.67 (s, 3H), 2.41 (s,
3H), 2.31 (t, J¼7.5 Hz, 2H), 1.98e1.21 (m, 11H), 0.96e0.77 (m, 1H);
CDCl3) d 174.4, 170.2, 143.2, 138.7, 129.9, 126.8, 70.8, 52.1, 51.6,
49.6, 35.1, 34.1, 29.1, 27.0, 26.9, 24.9, 21.7, 21.2, 19.6, 15.8; MS
13C NMR (100 MHz, CDCl3)
d
174.4, 143.4, 136.3, 129.8, 127.1, 123.7,
(ESIþ) m/z 440 ([MþþH], 100), 462 ([MþþNa], 13); HRMS calcd
23
109.7, 53.0, 51.6, 34.2, 31.4, 29.1, 25.6, 25.0, 23.1, 21.7, 17.4; MS (ESIþ)
for C18H25NO4S ([MþH]þ) 440.2107, found 440.2109; [
(c 0.3, CHCl3).
a
]
þ16.7
D
m/z 366 ([MþH]þ, 100), 388 ([MþNa]þ, 15); HRMS calcd for
23
C18H25NO4S ([MþH]þ) 366.1739, found 366.1735; [
(c 0.4, CHCl3).
a
]
ꢁ173.4
D
3.1.10. Methyl 6-((2R,5R,6S)-5-acetoxy-6-methyl-1-tosylpiperidin-2-
yl)hexanoate (17). Colourless crystalline solid: FTIR (neat, cmꢁ1):
3.1.7. Methyl
6-((2R,5S,6S)-5,6-dihydroxy-1-tosylpiperidin-2-yl)-
nmax 1733, 1329, 1243, 1159; 1H NMR (400 MHz, CDCl3)
d 7.71 (d,
hexanoate (14). Methanesulfonamide (62 mg, 0.657 mmol) was
added to a solution of ene-sulfonamide 13 (240 mg, 0.657 mmol)
in THF (4.50 mL), and the mixture was stirred until it was com-
pletely dissolved. NMO (50% w/w) (0.40 mL, 1.97 mmol), H2O
(0.50 mL) and K2OsO4 (24 mg, 65.7ꢂ10ꢁ3 mmol) were added to
the solution, and the mixture was stirred overnight. The mixture
was quenched with satd aq Na2S2O3 (10 mL), washed with water
(10 mL), brine (10 mL), dried (MgSO4), filtered and evaporated to
give diols 14 (228 mg, 87% yield) as a yellowish oil and as an in-
separable mixture of diastereoisomers: FTIR (neat, cmꢁ1): vmax
3475, 1734, 1327, 1159; 1H NMR (400 MHz, CDCl3, major di-
J¼7.8 Hz, 2H), 7.26 (d, J¼7.8 Hz, 2H), 4.63 (s, 1H), 4.13e3.88 (m, 2H),
3.67 (s, 3H), 2.39 (s, 3H), 2.31 (t, J¼7.7 Hz, 2H), 1.98e1.12 (m, 18H).
13C NMR (100 MHz, CDCl3)
d 174.3, 170.2, 142.7, 139.1, 129.5, 127.2,
70.5, 52.6, 51.9, 51.6, 35.6, 34.1, 29.1, 27.1, 24.9, 21.5, 21.3, 21.0, 20.9,
18.7; MS (ESIþ) m/z 440 ([MþH]þ, 100), 462 ([MþNa]þ, 13); HRMS
Calcd for C18H25NO4S ([MþH]þ) 440.2107, found 440.2101; mp
96e99 ꢀC; [
a]
24 þ7.4 (c 0.79, CHCl3).
D
3.1.11. 6-((2R,5S,6S)-5-Hydroxy-6-methyl-1-tosylpiperidin-2-yl)-
hexanoic acid (19).10 Potassium hydroxide (3 mL of a 2 M aqueous
solution, 6 mmol) solution was added to a solution of acetate 16
(0.1 g, 0.227 mmol) in MeOH (1 mL). The mixture was stirred at
room temperature for 24 h. The volatiles were evaporated. The
remaining aqueous layer was washed with CH2Cl2 (10 mL), acidified
with 2 M HCl (10 mL) and extracted with CH2Cl2 (15 mLꢂ3). The
combined organic layers were washed with brine (20 mL), and
dried (MgSO4), filtered and evaporated to give carboxylic acid 19
(84 mg, 97% yield) as a colourless oil: 1H NMR (400 MHz, CDCl3)
astereoisomer)
d
7.69 (d, J¼8.2 Hz, 2H), 7.29 (d, J¼8.2 Hz, 2H), 5.40
(app. t, J¼3.1 Hz, 1H), 3.92e3.77 (m, 1H), 3.67 (s, 3H), 3.51 (d,
J¼2.8 Hz, 1H), 3.34e3.21 (m, 1H), 2.42 (s, 3H), 2.31 (t, J¼7.5 Hz,
2H), 1.97e1.19 (m, 12H); 13C NMR (100 MHz, CDCl3, major di-
astereoisomer)
d 174.5, 143.6, 138.3, 129.9, 126.9, 78.4, 69.3, 52.5,
51.7, 34.1, 34.1, 29.0, 27.0, 26.6, 24.9, 22.5, 21.6; MS (ESIþ) m/z 382
([MþꢁOH], 100), 422 ([MþNa]þ, 40); HRMS calcd for C19H29NO6S
([MþH]þ) 400.1794 found 400.1803.
d
7.68 (d, J¼8.2 Hz, 2H), 7.26 (d, J¼8.2 Hz, 2H), 4.17 (app. quin.,
J¼6.9 Hz, 1H), 3.98e3.88 (m, 1H), 3.36 (ddd, J¼11.7, 6.9, 4.4 Hz, 1H),
2.41 (s, 3H), 2.35 (t, J¼7.3 Hz, 2H), 1.75e1.30 (m, 12H), 1.24 (d,
3.1.8. Methyl
6-((2R,5S,6S)-5,6-diacetoxy-1-tosylpiperidin-2-yl)-
hexanoate (15). Acetic anhydride (0.25 mL, 2.64 mmol), triethyl-
amine (0.42 mL, 3.00 mmol) and DMAP (7 mg, 6.01ꢂ10ꢁ2 mmol)
were added to a solution of diols 14 (240 mg, 0.601 mmol) in
J¼6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 14.7, 21.6, 22.9, 24.7,
27.1, 27.3, 29.0, 34.0, 34.9, 51.9, 52.3, 69.0, 126.8, 129.8, 138.8, 143.1,
179.5. MS (ESIþ) m/z 384 ([MþH]þ, 100); HRMS calcd for

3092
R.W. Bates, S. Kasinathan / Tetrahedron 69 (2013) 3088e3092
23
C19H29NO5S ([MþH]þ) 384.1845, found 384.1836; [
a
]
ꢁ5.13 (c
References and notes
D
0.23, EtOAc).
1. Ling, R.; Yoshida, M.; Mariano, P. S. J. Org. Chem. 1996, 61, 4439.
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6417.
3. For reviews on the synthesis of piperidines, see Cossy, J. Chem. Rec. 2005, 5, 70;
Buffat, M. G. P. Tetrahedron 2004, 60, 1701; Laschat, S.; Dickner, T. Synthesis
2000, 1781; Weintraub, P. M.; Sabol, J. S.; Kane, J. M.; Borcherding, D. R. Tet-
rahedron 2003, 59, 2953.
4. Brown, E.; Gahl, R. J. Chem. Soc., Perkin Trans. 1 1975, 2190.
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8. Kiguchi, T.; Shirakawa, M.; Honda, R.; Ninomiya, I.; Naito, T. Tetrahedron 1998,
54, 15589.
3.1.12. Azimic acid (1). Mg turnings (13 mg, 0.52 mmol) were added
to a solution of tosylpiperidinol 19 (20 mg, 0.052 mmol) in MeOH
(3 mL) as the reaction mixture was sonicated (ultrasonic cleaning
bath). The addition of Mg turnings was repeated till complete con-
sumption of the starting material as judged by TLC. The reaction
mixture was quenched with water (10 mL), evaporated to remove
methanol, taken up inwater (10 mL) again and filtered to remove the
insoluble magnesium salts. The resulting aqueous layer was acidi-
fied with 2 M HCl washed with CH2Cl2 (10 mLꢂ3), evaporated till
dryness. The crude product was taken up in water and loaded onto
a column of water washed amberliteÒ CG-50dtype 1 ion exchange
resin (4 g) suspended in water, and further washed with water
(100 mL). The resin column was eluted with 0.5% aq NH4OH col-
lecting the fractions containing azimic acid as identified by LCMS, to
give azimic acid 1 (7 mg, 59% yield) as a yellowish solid: 1H NMR
9. Ma, D.; Ma, N. Tetrahedron Lett. 2003, 44, 3963.
10. Leverett, C. A.; Cassidy, M. P.; Padwa, A. J. Org. Chem. 2006, 71, 8591.
11. Lu, Z.-H.; Zhou, W.-S. Tetrahedron 1993, 49, 4659.
12. Natsume, M.; Ogawa, M. Heterocycles 1980, 14, 169.
13. Hasseberg, H.-A.; Gerlach, H. Liebigs Ann. Chem. 1989, 255.
14. Masuda, Y.; Tasjiro, T.; Mori, K. Tetrahedron: Asymmetry 2006, 17, 3380.
15. Singh, R.; Ghosh, S. K. Tetrahedron Lett. 2002, 43, 7711.
16. Brown, E.; Bourgouin, A. Tetrahedron 1975, 31, 1047.
17. Randl, S.; Blechert, S. Tetrahedron Lett. 2004, 45, 1167.
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1986, 265.
19. Bates, R. W.; Kasinathan, S.; Straub, B. F. J. Org. Chem. 2011, 76, 6844.
20. For recent reviews of iminium ion chemistry Yazici, A.; Pyne, S. G. Synthesis
2009, 339; Yazici, A.; Pyne, S. G. Synthesis 2009, 513; Speckamp, W. N.; Moo-
lenaar, M. J. Tetrahedron 2000, 56, 3817.
21. The long side chain has been introduced via addition to an iminium ion: Refs.
10,11.
(400 MHz, MeOD)
d
3.83 (br s, 1H), 3.23 (br q, J¼6.9 Hz, 1H),
3.10e3.00 (m,1H), 2.17 (t, J¼7.2 Hz,1H), 2.00e1.90 (m,1H),1.85e1.34
(m, 11H), 1.33 (d, J¼6.5 Hz, 3H). 13C NMR (100 MHz, MeOD)
d
15.9,
23.7, 25.8, 27.0, 30.0, 31.0, 34.5, 38.6, 57.4, 58.5, 65.9,182.5; MS (ESIþ)
m/z 230 ([MþH]þ, 100); HRMS calcd for C12H23NO3 ([MþH]þ)
230.1756, found 230.1758; mp 216e219 ꢀC [lit. 214e215 ꢀC,5
210e214 ꢀC,11 217 ꢀC,8 209e211 ꢀC,6 212e214 ꢀC7]; [
a]
þ7.7 (c
23
D
22. Taber, D. F.; DeMatteo, P. W. J. Org. Chem. 2012, 77, 4235.
23. Gigant, N.; Gillaizeau, I. Org. Lett. 2012, 14, 3304.
24. Breit, B.; Seiche, W. Synthesis 2001, 1.
25. Ojima, I.; Vidal, E. S. J. Org. Chem. 1998, 63, 7999.
26. Arena, G.; Zill, N.; Salvadori, J.; Girard, N.; Mann, A.; Taddei, M. Org. Lett. 2011,
13, 2294.
0.37, MeOH) [lit.þ8 (MeOH),5 þ7.6 (c 1.1, MeOH),9 þ7.9 (c 1,
MeOH),6,11 þ7.4 (c 0.52, MeOH),8 þ7.7 (c 0.5, MeOH)7].
3.1.13. (4S)-3-(Nona-1,8-dien-4-yl)-2-(pent-4-en-1-yl)-4-phenyl-
oxazolidine (9). Pale yellow oil: FTIR (neat, cmꢁ1): nmax 2920, 2851,
27. Spangenberg, T.; Airiau, E.; Thuong, M. B. T.; Donnard, M.; Billet, M.; Mann, A.
1639, 908; 1H NMR (400 MHz, CDCl3)
d 7.35e7.23 (m, 5H), 5.91e5.61
Synlett 2008, 1859.
28. Ojima, I.; Tzamarioudaki, M.; Eguchi, M. J. Organomet. Chem. 1995, 60, 7078.
29. For an example of double hydroformylation, see Airiau, E.; Spangenberg, T.;
Girard, N.; Breit, B.; Mann, A. Org. Lett. 2010, 12, 528.
30. Vilaivan, T.; Winotapan, C.; Banphavichit, V.; Shinada, T.; Ohfune, Y. J. Org.
Chem. 2005, 70, 3464.
31. The reaction is presumed to proceed via the imine although this species is not
detectable in the 400 MHz 1H NMR spectrum of the oxazolidine.
32. Frigerio, M.; Santagostino, M.; Sputore, S.; Palmisano, G. J. Org. Chem. 1995, 60,
7272.
(m, 3H), 5.28 (t, J¼7.2 Hz, 1H), 5.13e4.83 (m, 6H), 3.77 (dd, J¼6.8,
4.7 Hz,1H), 3.69 (dd, J¼10.5, 4.6 Hz, 1H), 3.49 (dd, J¼10.5, 6.9 Hz, 1H),
3.08 (t, J¼6.4 Hz, 1H), 2.25 (t, J¼6.5 Hz, 2H), 2.14e1.77 (m, 10H),
1.50e1.29 (m, 2H). 13C NMR (100 MHz, CDCl3)
d 141.8, 139.9, 138.9,
138.7,135.8,128.6,127.8,127.6,127.3,117.0,114.7,114.6, 65.7, 61.5, 61.4,
38.9, 33.7, 33.6, 29.2, 28.0, 27.2; MS (ESIþ) m/z 340 ([MþH]þ, 100).
33. The substituents on the oxazolidine ring were shown to be cis by a NOESY
experiment. The stereochemistry of the exo-cyclic stereogenic centre was not
determined
Acknowledgements
34. Cuny, G. D.; Buchwald, S. L. J. Am. Chem. Soc. 1993, 115, 2066.
35. Pattenden, L. C.; Wybrow, R. A. J.; Smith, S. A.; Harrity, J. P. A. Org. Lett. 2006, 8,
3089.
36. The diols undergo dehydration to a ketone even during silica gel chromatog-
raphy: see Ref. 19.
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.
37. See Supplementary data. Details have been deposited with the Cambridge
Crystallographic Data Centre and may be obtained at http://www.ccdc.cam.ac.
uk. CCDC deposition number: 886628.
38. Johnson, F. Chem. Rev. 1968, 68, 375; Neipp, C. E.; Martin, S. F. Tetrahedron Lett.
2002, 43, 1779; Hedley, S. J.; Moran, W. J.; Prenzel, A. H. G. P.; Price, D. A.;
Harrity, J. P. A. Synlett 2001, 1596.
Supplementary data
1H NMR and 13C NMR spectra for compounds 1, 6, 8, 9, 11e17
and 19. ORTEP structure for compound 17. Supplementary data
related to this article can be found at http://dx.doi.org/10.1016/
j.tet.2013.01.060.
39. You, H. T.; Grosse, A. C.; Howard, J. K.; Hyland, C. J. T.; Just, J.; Molesworth, P. P.;
Smith, J. A. Org. Biomol. Chem. 2011, 9, 3948.