Asymmetric synthesis of 2-substituted butane-1,4-diols by hydrogenation of homochiral fumaramide derivatives

Article abstract of DOI:10.1016/j.tetasy.2004.11.023

Diastereoselective hydrogenation of homochiral fumaramides 1 derived from (2R)-Oppolzer's sultam was observed by analysis of the ¹H NMR spectra of the succinamide mixtures with de's of 77-88%. Reduction of these succinamides using LiAlH₄ gave the corresponding (2S)-butane-1,4- diols and established that addition of hydrogen takes place selectively on the re-face of fumaramides 1. The stereoselectivity was confirmed by estimating the ee's from the ¹⁹F NMR spectra of the Mosher's diesters of the diols. This methodology was applied to the synthesis of selected pyrrolidine natural products in homochiral form.

Full text of DOI:10.1016/j.tetasy.2004.11.023

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 3979–3988
Asymmetric synthesis of 2-substituted butane-1,4-diols
by hydrogenation of homochiral fumaramide derivatives
Samaila Jawaid, Louis J. Farrugia and David J. Robins*
Department of Chemistry, The Joseph Black Building, University of Glasgow, Glasgow G12 8QQ, UK
Received 1 November 2004; accepted 15 November 2004
Abstract—Diastereoselective hydrogenation of homochiral fumaramides 1 derived from (2R)-OppolzerÕs sultam was observed by
1
analysis of the H NMR spectra of the succinamide mixtures with deÕs of 77–88%. Reduction of these succinamides using LiAlH4
gave the corresponding (2S)-butane-1,4-diols and established that addition of hydrogen takes place selectively on the re-face of
fumaramides 1. The stereoselectivity was confirmed by estimating the eeÕs from the 19F NMR spectra of the MosherÕs diesters of
the diols. This methodology was applied to the synthesis of selected pyrrolidine natural products in homochiral form.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Butane-1,4-diols are important four-carbon building
blocks in organic chemistry and they are precursors
for the synthesis of a number of pyrrolidine natural
products.1 OppolzerÕs camphorsultam2 was introduced
in 1984 and ranks today among the most useful chiral
auxiliaries available for asymmetric synthesis. In the
synthesis of chiral compounds, the reduction of prochi-
ral unsaturated reactants has great importance. The dia-
stereoselective hydrogenation of N-enoylsultams has
previously been reported by Oppolzer et al.3
Synthesis of the novel fumaramide derivatives 1a–j
required the corresponding 2-substituted fumaric acids
as starting materials. These were synthesised according
to known literature procedures.6,7 Modification of a
literature procedure6 improved yields by 10–20%. Cou-
pling of the acids to commercially available (2R)-(ꢀ)-
2,10-camphorsultam was carried out either by treating
the acid chloride with the camphorsultam in the pres-
ence of sodium hydride or by using DCC and DMAP
as coupling reagents with the diacid and camphorsul-
tam. Optimisation of the conditions for the catalytic
hydrogenation using 1a involved the investigation of
solvent, catalyst, temperature and pressure effects. The
use of dry toluene and 10% Pd/C catalyst under 7 bar
pressure at 25 ꢁC was found to be the best set of condi-
tions. More polar solvents gave lower deÕs. Under the
best conditions catalytic hydrogenation produced dia-
stereomerically enriched mixtures of succinamides 2
and 3 (a–g) (Scheme 1) in near quantitative yields (Table
The diastereoselective conjugate addition of a series
of Grignard reagents has recently been carried out
using N,N0-bis[(2R)-bornane-10,2-sultam]-fumaramide.4
This occurred with moderate to high levels of
diastereoselectivity.
We report the diastereoselective hydrogenation of a
number of novel fumaramide derivatives 1a–i containing
N,N0-bis[(2R)-bornane-10,2-sultam]-fumaramide. Some
of the products were reduced using LiAlH4 to produce
2-substituted butane-1,4-diols 4a–e. The enantiomer of
the methyl derivative 4a was used in the synthesis of a
series of pyrrolidine natural products.5
1
1). H NMR spectra were used to determine deÕs. The
ABX system of the succinamide protons resonated at
different chemical shifts for each pair of diastereomers.
The ABX system of the minor diastereomer was consis-
tently at a lower d value than the major diastereomer.
Integration of the signals gave an estimate of the diaste-
reomeric excess.
The length of time to reach completion for the hydroge-
nation varied with the R group. The hexyl and octyl
derivatives 1d and 1e took 2 and 7 days, respectively,
*
Corresponding author. Tel.: +44 1413304378; fax: +44
1413304888; e-mail: d.robins@chem.gla.ac.uk
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.11.023

3980
S. Jawaid et al. / Tetrahedron: Asymmetry 15 (2004) 3979–3988
O2
S
a R=Me
b R=Et
O
c R=Pr
N
d R=hexyl
octyl
e R=
N
R
phenylethyl
isopentyl
f R=
S
O
O2
g R=
h R=
1
isopropyl
H2
Pd/ C
isobutyl
i R=
j R=
cyclohexylethyl
O2
S
O
N
N
R
S
O
O2
3
O2
S
O
N
N
R
S
O
O2
LiAlH4
2
OH
Figure 1. ORTEP diagram of compound 1b. The view is normal to the
olefin plane, with 50% probability ellipsoids for the non-H atoms and
arbitrary sized spheres for the H-atoms.
HO
R
4
Scheme 1.
The succinamide mixtures 2 and 3 (a–g) were separated
by column chromatography leading to single diastereo-
1
mers 2 and 3 (a–g) by analysis of H NMR spectra.
to reach completion compared with 1a–c, which were
complete overnight. The isopropyl 1h and isobutyl 1g
derivatives could only be hydrogenated partially even
after two weeks and the cyclohexylethyl derivative did
not hydrogenate at all. This may be due to steric effects.
The reduction of succinamides 2a–e produced 2-substi-
tuted butane-1,4-diols 4a–e. A small amount of each
diol was converted into its MosherÕs diesters. Estimation
of deÕs by analysis of the 19F NMR spectra of the
MosherÕs diesters provided figures that correlated well
with the initial values (Table 1).
X-ray crystal structures were determined for the ethyl
derivative 1b (Fig. 1) and the corresponding succina-
mide 2b (Fig. 2). From a consideration of the space-fill-
ing views of 1b shown in Figure 3, it can been seen that
the olefinic carbon atom C(15) is less sterically hindered
from the re-face than from the si-face. Moreover, the
olefinic H-atom is also more accessible from this face.
Given the caveat that the solution conformation may
differ from that in the solid phase, it is reasonable to
assume that this sterically less crowded re-face interacts
more easily with the catalyst surface, and hence explains
the formation of the major product 2b.
3. Natural product synthesis
We have applied our methodology towards the synthesis
of a number of pyrrolidine natural products. In 1995,
Veith et al. reported8 the isolation of five N-alkylated
3-methylpyrrolidines. Methods for the preparation of
enantiomerically pure pyrrolidines substituted exclu-
sively at the 3-position are scarce. We have synthesised
Table 1. Hydrogenation of fumaramides 1 to the corresponding succinamides 2 and 3
Entry
R
Yield (%)
Dra (major/minor)
Dea (%) (1H NMR)
Deb (%) (19F NMR)
1
2
Methyl (1a)
Ethyl (1b)
Propyl (1c)
100
96
89:11 (2a/3a)
94:6 (2b/3b)
90:10 (2c/3c)
93:7 (2d/3d)
89:11 (2e/3e)
90:10 (2f/3f)
90:10 (2g/3g)
74:26d
77
88
80
85
78
80
79
—
—
—
81c
78
75
85
75
—
—
—
—
—
3
98
98
4
Hexyl (1d)
Octyl (1e)
5
94
100
6
Phenylethyl (1f)
Isopentyl (1g)
Isopropyl (1h)
Isobutyl (1i)
Cyclohexylethyl (1j)
7
100
50
8
9
10
30
No product
84:16d
—
a Diastereomeric ratios were determined by 1H 400 MHz NMR spectra of the crude reaction mixtures.
b Both (R)- and (S)-bis MosherÕs esters of each diol were synthesised and analysed by 19F NMR spectra.
c Determined from HPLC analysis of the dianilide.
d Incomplete reaction.

S. Jawaid et al. / Tetrahedron: Asymmetry 15 (2004) 3979–3988
3981
SO2
N
O
N
O
O2S
5a
LiAlH4
THF
74%
OH
OMs
MsO
MsCl
79%
HO
7
6
RNH2
Et2O
64 - 71%
N
N
N
8
9
10
Scheme 2.
Figure 2. ORTEP diagram of compound 2b. Ellipsoids are plotted at
the 50% probability level, with H atoms shown as arbitrary spheres.
the minor enantiomer. Reduction of 5a produced diol
6, which was mesylated in good yield. The mesylate 7
was stirred over 2–4 days with the appropriate amine
and the homochiral final products 8–10 were isolated
by column chromatography.
4. Conclusions
An asymmetric heterogeneous hydrogenation method
has been developed for the synthesis of enantiomerically
pure 2-substituted butane-1,4-diols and succinic acids.
This methodology has been applied to natural product
synthesis of pyrrolidine alkaloids.
5. Experimental
5.1. General experimental
All reactions were carried out under nitrogen with anhy-
drous solvents unless otherwise stated. Tetrahydrofuran
and diethyl ether were dried by distillation from sodium
benzophenone immediately before use. Toluene and
dichloromethane were dried by distillation from CaH2
immediately before use. Reagents were purchased from
commercial suppliers and used without further purifica-
tion unless otherwise stated. Melting points were mea-
sured using a Gallenkamp melting point apparatus
and are uncorrected. Nuclear magnetic resonance spec-
tra were obtained on a Bruker DPX-400 spectrometer.
Chemical shifts are given relative to chloroform
(dH = 7.27) and (dC = 77.0) as internal standards unless
otherwise stated. All coupling constants are reported
in Hertz (Hz). Infra red spectra were recorded on either
a Nicolet Impact 410 FT-IR or Perkin–Elmer 500 spec-
trometer. Mass spectra were obtained on a Jeol JMS700
or a VG updated MS902 spectrometer, using the
Figure 3. Space filling plot of compound 1b. Viewed normal to the re-
face of the olefin (topview) and the si-face (bottom view). The olefinic
C@C bond is vertical in both views.
three of these alkaloids from the antipode of methyl
derivative 2a (Scheme 2). Column chromatography or
crystallisation provided succinamide 5a in good yield
1
with >98% diastereomeric excess by H NMR spectra
analysis. To confirm this the diastereomer was hydroly-
sed to 2-methylsuccinic acid. This was converted into the
dianilide and chiral HPLC analysis showed no trace of

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S. Jawaid et al. / Tetrahedron: Asymmetry 15 (2004) 3979–3988
electron impact method unless otherwise stated. Com-
bustion analysis was carried out using an Elemental
Analyser MOD 1106. All of the thin layer chromatogra-
phy plates used were Merck aluminium oxide 60 F254
neutral (type E) with layers of 0.2 mm thickness or
Merck silica gel 60 F254 with layers of 0.25 mm thick-
ness. The plates were visualised by illumination with
UV light or permanganate solution. Optical rotations
were recorded on a Polaar 2000 polarimeter with path
24.1, 29.0, 30.7 (·2), 30.8, 31.1, 33.4, 128.2, 149.8,
169.3, 170.5; HR-CIMS m/z 229.1441 (M+H)+ (calcd
for C12H21O4: 229.1440). Anal. Calcd for C12H20O4:
C, 63.1; H, 8.8. Found: C, 63.1; H, 8.8.
5.3. Diethyl cyclohexylethylfumarate
This was prepared in 43% yield on a 20 mmol scale by
1
the method of Cooke.7 IR (KBr, cmꢀ1) 2952, 1721; H
length 10 cm. [a]D Values are given in 10ꢀ1 deg cm2 gꢀ1
.
NMR (400 MHz, CDCl3) d 0.86–0.96 (2H, m, 2 · cyclo-
hexane-H), 1.10–1.35 (11H, m, 5 · cyclohexane-H,
2 · CH3CH2O), 1.61–1.76 (6H, m, 4 · cyclohexane-H,
CH2CH), 2.76–2.80 (2H, m, CH2C@C), 4.17–4.26 (4H,
m, 2 · CH3CH2O), 6.69 (1H, s, CH@C); 13C NMR
(100 MHz, CDCl3) d 14.1, 14.2, 25.6, 26.3, 26.6, 33.1,
36.7, 38.0, 60.5, 61.4, 125.9, 148.9, 165.7, 167.0;
HR-EIMS m/z 282.1829 M+ (calcd for C16H26O4:
282.1831).
5.2. Substituted fumaric acids
Isopentyl-, cyclohexylethyl- and phenylethyl-fumaric
esters were prepared as described.7 The remaining
substituted fumaric acids were made by modification
of the route of Akhtar et al.6
Sodium (1.1 equiv) was dissolved in dry ethanol. Ethyl
acetoacetate (1.0 equiv) was added dropwise over
10 min, the solution stirred for an additional 5 min
and, after addition of KI (0.1 equiv), the appropriate
alkyl bromide (1.3 equiv) was added slowly dropwise.
Following the addition, the reaction was heated at reflux
overnight and was then allowed to cool. The solution
was poured into water and extracted with diethyl ether
(5 · 200 mL). The combined organic extracts were
washed with water and dried over MgSO4. The solvent
was removed in vacuo and the resultant oil purified by
distillation. To a vigorously stirred solution of the
appropriate ester (1.0 equiv) in dry diethyl ether was
slowly added bromine (2.0 equiv) and the solution was
heated at reflux for 3 h. The mixture was washed with
10% sodium thiosulfate and then with brine. The solvent
was removed under pressure to give the dibromide as a
pale yellow oil. The dibromide was added slowly to a
solution of ethanol containing potassium hydroxide
(5.7 equiv) with rapid stirring. The mixture was heated
at reflux for 30 min and the solvent removed in vacuo.
After addition of water, the solution was acidified to
pH 1 using concd HCl and extracted with diethyl ether
(4 · 200 mL). The organic extracts were dried over
MgSO4 and the solvent removed in vacuo. The products
were purified by recrystallisation.
5.4. General procedure for the hydrolysis of isopentyl-,
cyclohexylethyl- and phenylethyl-fumarate into 2-substi-
tuted fumaric acids
A solution of KOH (4 equiv) in ethanol/water (1:1) was
added to the appropriate diethyl ester (1 equiv) and the
mixture heated at reflux overnight. The reaction mixture
was concentrated, taken upin water (30 mL) and ex-
tracted with diethyl ether (2 · 20 mL). The aqueous
layer was acidified to pH 1 using concd HCl and ex-
tracted with diethyl ether (3 · 50 mL). The combined
organic extracts were dried over Na2SO4 and concen-
trated in vacuo.
5.5. General procedure 1 for the synthesis of 2-substituted
fumaramides
(1S,2R)-(ꢀ)-2,10-Camphorsultam (2 equiv) in toluene
was added dropwise to a suspension of NaH (60% in
mineral oil, 3 equiv) in dry toluene and the mixture
was stirred at 0 ꢁC for 2 h. The appropriate fumaric acid
(1 equiv) was heated at reflux with thionyl chloride
(6 equiv) overnight and the excess thionyl chloride was
removed in vacuo. The resultant acid chloride was taken
upin dry toluene (15 mL) and added to the camphorsul-
tam mixture dropwise at 0 ꢁC. The mixture was stirred
at room temperature overnight. Saturated aqueous
ammonium chloride was added and the mixture poured
into saturated aqueous ammonium chloride, extracted
with toluene (3 · 100 mL) and the organic layers washed
with brine. The combined organic layers were dried over
MgSO4 and concentrated in vacuo.
5.2.1. Hexylfumaric acid. This was prepared in 10%
yield on a 76 mmol scale by the above method and gave
1
mp172–174 ꢁC; IR (KBr, cmꢀ1) 2930, 1712; H NMR
(400 MHz, DMSO-d6) d 0.85 (3H, t, J = 7.0, CH3CH2),
1.16–1.34 (6H, m), 1.34–1.38 (2H, m), 2.64 (2H, t,
J = 7.3, CH2C@C), 6.57 (1H, s, CH@C); 13C NMR
(100 MHz, DMSO-d6) d 14.2, 22.3, 27.4, 28.9, 28.9,
31.3, 127.1, 147.4, 167.1, 168.4; HR-CIMS m/z
201.1128 (M+H)+ (calcd for C10H17O4 requires
201.1127).
5.6. General procedure 2 for the synthesis of 2-substituted
fumaramides
To
a
solution of (1S,2R)-(ꢀ)-2,10-camphorsultam
5.2.2. Octylfumaric acid. This was prepared in 10%
yield on a 76 mmol scale by the above method and gave
(2 equiv) in dry DCM (15 mL) were added DCC
(2.4 equiv), DMAP (0.3 equiv) and the appropriate
fumaric acid (1 equiv) at 0 ꢁC. The mixture was stirred
at 0 ꢁC for 3 h, then allowed to warm to room tempera-
ture overnight. The separated dicyclohexylurea was
removed by filtration and washed with cold DCM.
The filtrate was washed sequentially with 4% NaOH
1
mp125–128 ꢁC; IR (KBr, cmꢀ1) 2927, 1710; H NMR
(400 MHz, MeOH-d4) d 0.80 (3H, t, J = 7.0, CH3CH2),
1.10–1.30 (10H, m), 1.32–1.42 (2H, m), 2.64 (2H, t,
J = 7.5, CH2C@C), 4.79 (2H, br s, 2 · OH), 6.60 (1H,
s, CH@C); 13C NMR (100 MHz, MeOH-d4) d 14.8,

S. Jawaid et al. / Tetrahedron: Asymmetry 15 (2004) 3979–3988
3983
(2 · 15 mL), 3% HCl (30 mL) and water (until neutral).
The organic layer was dried over Na2SO4 and concen-
trated in vacuo.
1.53–1.60 (2H, m, CH2CH3), 1.89–1.98 (6H, m), 2.04–
2.19 (4H, m), 2.69–2.84 (2H, m, CH2CH2CH3), 3.38–
3.52 (4H, m, 2 · CH2SO2), 3.93 (1H, dd, J = 5.0, 7.7,
CHN), 4.02 (1H, app t, J = 6.2, CHN), 6.90 (1H, s,
CH@C); 13C NMR (100 MHz, CDCl3) d 14.3, 19.8,
19.9, 20.8, 21.0, 21.8, 26.5 (·2), 31.8, 32.8, 33.0, 38.3,
38.5, 44.7, 44.9, 47.8, 48.3, 48.5, 52.9, 53.4, 64.9, 65.4,
125.3, 151.9, 162.9, 170.0; HR-FABMS m/z 553.2407
(M+H)+ (calcd for C27H41O6N2S2: 553.2406). Anal.
Calcd for C27H41O6N2S2: C, 58.5; H, 7.4; N, 5.1. Found:
C, 58.6; H, 7.3; N, 5.1.
5.6.1. N,N0-Bis[(2R)-bornane-10,2-sultam]-2-methyl-fumar-
amide 1a. Mesaconic acid (0.50 g, 3.84 mmol) was
treated following general procedure 2 to produce a
beige foam, which was triturated using ethanol to
give 1a (1.57 g, 50%) as
a beige powder; mp
239–240 ꢁC; [a]D = ꢀ117 (c 1.18, CHCl3); IR (KBr,
cmꢀ1) 2970, 1678, 1331, 1138; 1H NMR (400 MHz,
CDCl3) d 0.97 (3H, s, CH3), 0.99 (3H, s, CH3), 1.19
(3H, s, CH3), 1.25 (3H, s, CH3), 1.34–1.46 (4H, m),
1.57 (3H, s, CH3C@C), 1.89–1.97 (6H, m), 2.02–
2.29 (4H, m), 3.38–3.54 (4H, m, 2 · CH2SO2), 3.93
(1H, dd, J = 4.9, 7.6, CHN), 4.01 (1H, app t, J = 6.6,
CHN), 6.88 (1H, s, CH@C); 13C NMR (100 MHz,
CDCl3) d 19.7, 19.8, 20.7, 21.0, 21.1, 26.4, 26.5,
32.7, 33.0, 38.1, 38.5, 44.6, 45.0, 47.7, 48.4, 48.5,
52.9, 53.2, 64.8, 65.2, 124.5 147.8, 162.8, 170.3;
HR-FABMS m/z 525.2094 (M+H)+ (calcd for
C25H37N2O6S2: 525.2093). Anal. Calcd for C25H37-
N2O6S2: C, 57.1; H, 6.7; N, 5.3. Found: C, 57.1; H,
6.8; N, 5.4.
5.6.5. N,N0-Bis[(2R)-bornane-10,2-sultam]-2-hexyl-fuma-
ramide 1d. Hexylfumaric acid (0.50 g, 2.50 mmol) was
treated following the general procedure 2 and the resul-
tant mixture chromatographed [SiO2, ethyl acetate/hex-
ane (2:3)] to produce 1d (0.35 g, 23%) as a white powder;
mp85–88 ꢁC; [a]D = ꢀ103 (c 1.18, CHCl3); IR (KBr,
cmꢀ1) 2958, 1682, 1338, 1134; 1H NMR (400 MHz,
CDCl3) d 0.86 (3H, t, J = 6.8, CH3CH2), 0.96 (3H, s,
CH3), 0.98 (3H, s, CH3), 1.18 (3H, s, CH3), 1.24 (3H,
s, CH3), 1.25–1.36 (3H, m), 1.37–1.60 (9H, m), 1.88–
1.98 (6H, m), 2.04–2.18 (4H, m), 2.71 (1H, dt, J = 5.2,
12.6, CHHC@C), 2.83 (1H, dt, J = 5.2, 12.6,
CHHC@C), 3.38–3.52 (4H, m, 2 · CH2SO2), 3.92 (1H,
dd, J = 5.0, 7.6, CHN), 4.02 (1H, app t, J = 6.2,
CHN), 6.88 (1H, s, CH@C); 13C NMR (100 MHz,
CDCl3) d 14.1, 19.8, 19.9, 20.8, 21.0, 22.5, 26.5 (·2),
28.3, 29.6, 29.9, 31.5, 32.8, 32.9, 38.2, 38.5, 44.7, 44.9,
47.8, 48.3, 48.5, 52.9, 53.4, 64.8, 65.4, 125.0, 152.1,
162.7, 170.0; HR-FABMS m/z 595.2870 (M+H)+ (calcd
for C30H46N2O6S2: 595.2876). Found: C, 60.5; H, 7.9;
N, 4.7. Found C, 60.6; H, 7.8; N, 4.7.
5.6.2. N,N0-Bis[(2S)-bornane-10,2-sultam]-2-methyl-fum-
aramide. Mesaconic acid (1.30 g, 10 mmol) and
(1R,2S)-camphorsultam (4.31 g, 20 mmol) were treated
following general procedure 1 to produce a beige foam,
which was triturated using ethanol to produce N,N0-
bis[(2S)-bornane-10,2-sultam]-2-methylfumaramide
(2.67 g, 51%) as a beige powder; mp 214–216 ꢁC. Spec-
tral data were identical to 1a.
5.6.3. N,N0-Bis[(2R)-bornane-10,2-sultam]-2-ethyl-fumar-
amide 1b. Ethylfumaric acid (0.27 g, 1.87 mmol) was
treated following general procedure 2 and recrystallised
from ethanol to produce 1b (1.33 g, 32%) as cream nee-
dles; mp194–195 ꢁC; [a]D = ꢀ103 (c 1.18, CHCl3); IR
(KBr, cmꢀ1) 2959, 1684, 1337, 1135; 1H NMR
(400 MHz, CDCl3) d 0.96 (3H, s, CH3), 0.97 (3H, s,
CH3), 1.13 (3H, t, J = 7.5, CH3CH2), 1.17 (3H, s,
CH3), 1.24 (3H, s, CH3), 1.33–1.46 (4H, m), 1.85–1.97
(6H, m), 2.04–2.21 (4H, m), 2.73 (1H, dq, J = 7.4,
14.7, CH3CHH), 2.88 (1H, dq, J = 7.5, 15.0, CH3CHH),
3.34–3.49 (4H, m, 2 · CH2SO2), 3.93 (1H, dd, J = 4.9,
7.7, CHN), 4.02 (1H, app t, J = 6.2, CHN), 6.87 (1H,
s, CH@C); 13C NMR (100 MHz, CDCl3) d 12.6, 19.8
(·2), 20.8, 21.0, 23.2, 26.4, 26.5, 32.8, 32.9, 38.2, 38.5,
44.6, 44.9, 47.8, 48.2, 48.5, 52.9, 53.4, 64.8, 65.3, 124.8,
153.1, 162.7, 169.9; HR-FABMS m/z 539.2247
(M+H)+ (calcd for C26H39O6N2S2: 539.2250). Anal.
Calcd for C26H39O6N2S2: C, 57.9; H, 7.1; N, 5.2. Found:
C, 58.1; H, 7.1; N, 4.9.
5.6.6. N,N0-Bis[(2R)-bornane-10,2-sultam]-2-octyl-fumar-
amide 1e. Octylfumaric acid (0.50 g, 2.19 mmol) was
treated following general procedure 2 and the resultant
mixture chromatographed [SiO2, ethyl acetate/hexane
(1:2)] to produce 1e (1.13 g, 41%) as a white powder;
mp68–70 ꢁC; [a]D = ꢀ91.5 (c 1.18, CHCl3); IR (KBr,
cmꢀ1) 2927, 1682, 1338, 1134; 1H NMR (400 MHz,
CDCl3) d 0.87 (3H, t, J = 6.4, CH3CH2), 0.96 (3H, s,
CH3), 0.98 (3H, s, CH3), 1.18 (3H, s, CH3), 1.24–1.54
(19H, m), 1.89–1.98 (6H, m), 2.04–2.19 (4H, m), 2.72
(1H, dt, J = 5.6, 12.6, CHHC@C), 2.83 (1H, dt,
J = 5.6, 12.6, CHHC@C), 3.38–3.52 (4H, m,
2 · CH2SO2), 3.93 (1H, dd, J = 4.9, 7.5, CHN), 4.02
(1H, app t, J = 6.2, CHN), 6.89 (1H, s, CH@C); 13C
NMR (100 MHz, CDCl3) d 14.1, 19.8, 19.9, 20.8, 21.0,
22.6, 26.4, 26.5, 28.3, 29.2, 29.9, 31.8, 32.8, 32.9, 38.2,
38.5, 44.6, 44.9, 47.8, 48.2, 48.5, 52.9, 53.4, 64.8, 65.4,
125.0, 152.1, 162.7, 170.0; HR-FABMS m/z 623.3192
(M+H)+ (calcd for C30H46N2O6S2: 623.3189). Anal.
Calcd for C30H46N2O6S2: C, 61.7; H, 8.1; N, 4.5. Found:
C, 61.8; H, 8.1; N, 4.7.
5.6.4. N,N0-Bis[(2R)-bornane-10,2-sultam]-2-propyl-fum-
aramide 1c. Propylfumaric acid (1.0 g, 6.20 mmol) was
treated following general procedure 1 and recrystallised
from ethanol to produce 1c (0.76 g, 24%) as beige plates;
mp190–193 ꢁC; [a]D = ꢀ88 (c 1.18, CHCl3); IR (KBr,
cmꢀ1) 2961, 1683, 1340, 1135; 1H NMR (400 MHz;
CDCl3) d 0.94–0.98 (9H, m, CH3CH2, 2 · CH3), 1.18
(3H, s, CH3), 1.24 (3H, s, CH3), 1.33–1.43 (4H, m),
5.6.7. N,N0-Bis[(2R)-bornane-10,2-sultam]-2-phenyl-eth-
ylfumaramide 1f. Phenylethylfumaric acid (0.50 g,
2.3 mmol) was treated following general procedure 2
to produce a beige foam, which was chromatographed
[SiO2, ethyl acetate/hexane (1:2)] to produce 1f (0.61 g,
44%) as an off-white powder; mp 179–180 ꢁC;
[a]D = ꢀ102 (c 1.18, CHCl3); IR (KBr, cmꢀ1) 2963,

3984
S. Jawaid et al. / Tetrahedron: Asymmetry 15 (2004) 3979–3988
1
1688, 1329, 1163; H NMR (400 MHz, CDCl3) d 0.96
(3H, s, CH3), 0.98 (3H, s, CH3), 1.18 (3H, s, CH3),
1.25 (3H, s, CH3), 1.27–1.47 (4H, m), 1.82–1.98 (6H,
m), 2.04–2.19 (4H, m), 2.78 (1H, dt, J = 4.4, 12.4,
CHHC@C), 2.92 (1H, dt, J = 4.8, 12.8, CHHC@C),
2.98–3.14 (2H, m), 3.39–3.54 (4H, m, 2 · CH2SO2),
3.93 (1H, dd, J = 5.2, 7.2, CHN), 4.05 (1H, app t,
J = 6.0, CHN), 6.96 (1H, s, CH@C), 7.15–7.18 (1H, m,
Ar), 7.24–7.26 (4H, m, Ar); 13C NMR (100 MHz,
CDCl3) d 19.8 (·2), 20.8, 21.0, 26.4, 26.5, 32.1, 32.8,
32.9, 34.5, 38.2, 38.5, 44.7, 44.9, 47.8, 48.3, 48.5, 52.9,
53.4, 64.8, 65.4, 125.6, 125.8, 128.2, 128.5, 138.1,
141.6, 162.5, 169.9; HR-FABMS m/z 615.2562
(M+H)+ (calcd for C32H43N2O6S2: 615.2563). Anal.
Calcd for C32H42N2O6S2: C, 62.5; H, 6.9; N, 4.6. Found:
C, 62.4; H, 7.0; N, 4.6.
to produce an off-white powder, which was crystallised
from ethanol to give 1i (1.49 g, 45%) as white needles;
mp193–195 ꢁC; [a]D = ꢀ103 (c 1.18, CHCl3); IR (KBr,
cmꢀ1) 2962, 1682, 1336, 1167; 1H NMR (400 MHz,
CDCl3) d 0.94–1.02 (12H, m, (CH3)2CH, 2 · CH3),
1.18 (3H, s, CH3), 1.24 (3H, s, CH3), 1.32–1.47 (4H,
m), 1.86–1.98 (7H, m), 2.03–2.20 (4H, m), 2.74 (2 H,
d, J = 7.1, CH2CH), 3.38–3.52 (4H, m, 2 · CH2SO2),
3.87 (1H, dd, J = 5.0, 7.6, CHN), 3.92 (1H, app t,
J = 6.2, CHN), 6.96 (1 H, s, CH@C); 13C NMR
(100 MHz, CDCl3) d 19.8, 19.9, 20.8, 20.9, 22.4, 23.0,
26.5, 28.2, 32.8, 32.9, 38.0, 38.2, 38.5, 44.7, 44.8, 47.8
(·2), 48.2, 48.5, 52.9, 53.4, 64.9, 65.5, 126.6, 151.1,
162.8, 170.0; HR-FABMS m/z 567.2564 (M+H)+ (calcd
for C28H43N2O6S2: 567.2563). Anal. Calcd for
C28H43N2O6S2: C, 59.3; H, 7.5; N, 4.9. Found: C,
59.3; H, 7.3; N, 5.0.
5.6.8. N,N0-Bis[(2R)-bornane-10,2-sultam]-2-isopentyl-
fumaramide
1g. Isopentylfumaric
acid
(0.50 g,
5.6.11. N,N0-Bis[(2R)-bornane-10,2-sultam]-2-cyclo-hex-
ylethylfumaramide 1j. Cyclohexylethylfumaric acid
(0.50 g, 2.21 mmol) was treated following general proce-
dure 2 to produce a beige foam, which was chromato-
graphed [SiO2, ethyl acetate/hexane (1:1)] to give 1j
(0.91 g, 66%) as an orange syrup; [a]D = ꢀ154 (c 1.18,
CHCl3); IR (KBr, cmꢀ1) 2925, 1684, 1337, 1135; 1H
NMR (400 MHz, CDCl3) d 0.96 (3H, s, CH3), 0.98
(3H, s, CH3), 1.18 (3H, s, CH3), 1.23 (3H, s, CH3),
1.26–1.54 (10H, m), 1.60–1.74 (7H, m), 1.89–1.98 (6H,
m), 2.04–2.17 (4H, m), 2.72 (1H, dt, J = 4.4, 12.0,
CH2CHHC@C), 2.85 (1H, dt, J = 5.2, 12.4,
CH2CHHC@C), 3.38–3.52 (4H, m, 2 · CH2SO2), 3.93
(1H, dd, J = 4.8, 7.2, CHN), 4.02 (1H, app t, J = 6.4,
CHN), 6.87 (1H, s, CH@C); 13C NMR (100 MHz,
CDCl3) d 19.8, 19.9, 20.8, 21.0, 26.3, 26.5 (·2), 26.6,
27.6, 32.8, 33.0 (·2), 35.5, 38.0, 38.2, 38.5, 44.7, 44.9,
47.8, 48.3, 48.5, 52.9, 53.4, 64.8, 65.4, 124.9, 152.6,
162.7, 170.0; HR-FABMS m/z 621.3033 (M+H)+ (calcd
for C32H49N2O6S2: 621.3032).
2.69 mmol) was treated following general procedure 2
to produce a beige foam, which was chromatographed
[SiO2, ethyl acetate/hexane (1:1)] to produce 1g (0.71 g,
46%) as an off-white powder; mp 112–115ꢁC;
[a]D = ꢀ232 (c 1.18, CHCl3); IR (KBr, cmꢀ1) 2925,
1
1682, 1337, 1167; H NMR (400 MHz, CDCl3) d 0.89–
0.91 (6H, m, (CH3)2CH), 0.96 (3H, s, CH3), 0.98 (3H,
s, CH3), 1.18 (3H, s, CH3), 1.24 (3H, s, CH3), 1.30–
1.65 (7H, m), 1.88–1.95 (6H, m), 2.09–2.22 (4H, m),
2.72 (1H, dt, J = 4.8, 12.4, CHHC@C), 2.85 (1H, dt,
J = 5.2, 12.0, CHHC@C), 3.38–3.52 (4H, m,
2 · CH2SO2), 3.93 (1H, dd, J = 4.8, 7.2, CHN), 4.02
(1H, app t, J = 6.0, CHN), 6.88 (1H, s, CHC@C); 13C
NMR (100 MHz, CDCl3) d 19.8, 19.9, 20.8, 21.0, 22.1,
22.4, 26.5 (·2), 28.0, 28.4, 32.8, 33.0, 37.0, 38.2, 38.5,
44.7, 44.9, 47.8, 48.2, 48.5, 52.9, 53.4, 64.8, 65.4, 125.0,
152.3, 162.7, 170.1; HR-CIMS m/z 581.2714 (M+H)+
(calcd for C29H45N2O6S2: 581.2719).
5.6.9. N,N0-Bis[(2R)-bornane-10,2-sultam]-2-isopropyl-
fumaramide
1h. Isopropylfumaric
acid
(2.0 g,
5.7. General procedure for the hydrogenation of 2-
substituted fumaramides
12.7 mmol) was treated following general procedure 1
to produce an orange syrup, which was triturated from
ethanol to give 1h (0.25 g, 4%) as an off-white powder;
mp224–225 ꢁC; [a]D = ꢀ132 (c 1.18, CHCl3); IR (KBr,
cmꢀ1) 2963, 1682, 1335, 1138; 1H NMR (400 MHz,
CDCl3) d 0.97 (3H, s, CH3), 0.98 (3H, s, CH3), 1.15
(3H, d, J = 6.9, CH3CH), 1.18 (3H, s, CH3), 1.24 (3H,
s, CH3), 1.30 (3H, d, J = 7.0, CH3CH), 1.34–1.47 (4H,
m), 1.88–1.98 (6H, m), 2.04–2.18 (4H, m), 3.38–3.53
(4H, m, 2 · CH2SO2), 3.85 (1H, septet, J = 7.0, CH
(CH3)2), 3.95 (1H, dd, J = 4.9, 7.7, CHN), 4.02 (1H,
dd, J = 5.2, CHN), 6.75 (1H, s, CH@C); 13C NMR
(100 MHz, CDCl3) d 19.3, 19.8, 19.9, 20.8, 21.1, 23.3,
26.4, 26.5, 29.0, 32.8, 33.0, 38.4, 38.6, 44.7, 44.9, 47.8
(·2), 48.1, 48.5, 53.0, 53.4, 64.9, 65.3, 123.9, 157.1,
162.7, 168.3; HR-FABMS m/z 553.2403 (M+H)+ (calcd
for C27H41N2O6S2: 553.2406). Anal. Calcd for
C27H40N2O6S2: C, 58.7; H, 7.3; N, 5.1. Found: C,
58.7; H, 7.4; N, 5.1.
A solution of the fumaramide (1 equiv) in dry toluene
(60 mL) containing 10% Pd/C (0.12 equiv) was shaken
under 7 bar H2 at 25 ꢁC using a Baskerville hydrogena-
tor. The mixture was then filtered through Celite and
the solvent removed in vacuo to give a mixture of dia-
stereoisomers, which were separated by column
chromatography.
5.7.1. (2S)-2a and (2R)-N,N0-Bis[(2R)-bornane-10,2-sul-
tam]-2-methylsuccinamide 3a. N,N0-Bis[(2R)-bornane-
10,2-sultam]-2-methylfumaramide 1a (1.00 g, 1.90
mmol) was hydrogenated overnight as above and the
resultant mixture chromatographed [SiO2, ethyl
acetate/hexane (1:1)] to produce 2a (0.94 g, 94%) and
3a (0.06 g, 6%) as white plates.
Compound 2a (major): mp200–202 ꢁC; [a]D = ꢀ119
(c 1.18, CHCl3); IR (KBr, cmꢀ1) 2958, 1684, 1331,
1163; 1H NMR (400 MHz, CDCl3) d 0.96 (3H, s,
CH3), 0.98 (3H, s, CH3), 0.98 (3H, s, CH3), 1.15 (3H,
s, CH3), 1.18 (3H, d, J = 6.8, CH3CH), 1.31–1.44 (4H,
5.6.10. N,N0-Bis[(2R)-bornane-10,2-sultam]-2-isobutyl-
fumaramide
5.81 mmol) was treated following general procedure 1
1i. Isobutylfumaric
acid
(1.00 g,

S. Jawaid et al. / Tetrahedron: Asymmetry 15 (2004) 3979–3988
3985
m), 1.84–1.93 (6H, m), 1.95–2.13 (4H, m), 2.92 (1H, dd,
J = 4.7, 17.3, CHHCHC@O), 3.23 (1H, dd, J = 9.4,
17.3, CHHCHC@O), 3.39–3.55 (5H, m, 2 · CH2SO2,
CH2CHC@O), 3.84 (1H, dd, J = 5.2, 7.5, CHN), 3.90
(1H, dd, J = 5.0, 7.7, CHN); 13C NMR (100 MHz,
CDCl3) d 16.8, 19.9, 20.0, 20.5, 20.8, 26.4, 26.5, 32.7,
32.8, 35.7, 37.9, 38.2, 40.4, 44.6 (·2), 47.7 (·2), 48.5
(·2), 52.8, 53.0, 65.0, 65.2, 169.5, 174.7; HR-FABMS
m/z 527.2222 (M+H)+ (calcd for C25H39N2O6S2:
527.2250). Anal. Calcd for C25H38N2O6S2: C, 56.9; H,
7.3; N, 5.3. Found: C, 56.8; H, 7.2; N, 5.3.
mixture chromatographed [SiO2, ethyl acetate/hexane
(1:1)] to produce 2c (0.36 g, 81%) and 3c (0.01, 3%) as
white plates.
Compound 2c (major): mp188–190 ꢁC (lit.4 187–
189 ꢁC); [a]D ꢀ90 (c 1.0, EtOAc) [lit.4 ꢀ88 (c 1.0,
EtOAc)].
Compound 3c (minor): [a]D ꢀ96 (c 1.0, EtOAc) [lit.4
ꢀ90 (c 1.0, EtOAc)].
5.7.5. (2S)-2d and (2R)-N,N0-Bis[(2R)-bornane-10,2-sul-
tam]-2-hexylsuccinamide 3d.4 N,N0-Bis[(2S)-bornane-
10,2-sultam]-2-hexylfumaramide 1d (0.37 g, 0.62 mmol)
was hydrogenated over 2 d as above and the resultant
mixture chromatographed [SiO2, ethyl acetate/hexane
(1:1)] to produce 2d (0.35 g, 94%) and 3d (0.02, 6%) as
white plates.
Compound 3a (minor): mp218–220 ꢁC; [a]D = ꢀ75 (c
1.18, CHCl3); IR (KBr, cmꢀ1) 2960, 1685, 1327, 1165;
1H NMR (400 MHz, CDCl3) d 0.96 (3H, s, CH3), 0.97
(3H, s, CH3), 1.15 (3H, s, CH3), 1.16 (3H, s, CH3),
1.29 (3H, d, J = 7.1, CH3CH), 1.33–1.42 (4H, m),
1.79–1.94 (6H, m), 2.05–2.18 (4H, m), 2.78 (1H, dd,
J = 4.1, 17.2, CHHCHC@O), 3.38–3.56 (6H, m,
2 · CH2SO2, CH2CHC@O, CHHCHC@O), 3.86 (1H,
dd, J = 5.1, 7.7, CHN), 3.95 (1H, app t, J = 6.4,
CHN); 13C NMR (100 MHz, CDCl3) d 18.0, 19.8, 20.8
(·2), 26.4 (·2), 32.7, 32.8, 36.1, 38.1, 38.4, 44.6 (·2),
47.7, 48.3, 48.5, 52.8, 52.9, 65.1, 65.2, 169.3, 174.2;
HR-FABMS m/z 527.2248 (M+H)+ (calcd for
C25H39N2O6S2 527.2250).
Compound 2d (major): mp80–82 ꢁC (lit.4 76–78 ꢁC);
[a]D = ꢀ68 (c 1.0, EtOAc) [lit.4 ꢀ66 (c 1.0, EtOAc)].
Compound 3d (minor): [a]D = ꢀ64 (c 1.0, EtOAc) [lit.4
ꢀ60 (c 1.0, EtOAc)].
5.7.6. (2S)-2e and (2R)-N,N0-Bis[(2R)-bornane-10,2-sul-
tam]-2-octylsuccinamide 3e.4 N,N0-Bis[(2R)-bornane-
10,2-sultam]-2-octylfumaramide 1e (0.22 g, 0.35 mmol)
was hydrogenated over 7 d as above and the resultant
mixture chromatographed [SiO2, ethyl acetate/hexane
(1:1)] to produce 2e (0.18 g, 81%) as white plates and
3e (0.01, 3%) as a colourless oil.
5.7.2. (2R)-5a and (2S)-N,N0-Bis[(2S)-bornane-10,2-sul-
tam]-2-methylsuccinamide 5b. N,N0-Bis[(2S)-bornane-
10,2-sultam]-2-methylfumaramide (1.00 g, 1.90 mmol)
was hydrogenated overnight as above and the resultant
mixture chromatographed [SiO2, ethyl acetate/hexane
(1:1)] to produce 5a (0.70 g, 70%) and 5b (0.03, 3%) as
white plates.
Compound 2e (major): [a]D = ꢀ68 (c 1.0, EtOAc) [lit.4
ꢀ66 (c 1.0, EtOAc)]. New data: mp164–166 ꢁC.
Compound 5a (major): mp202–203 ꢁC; [a]D = +119 (c
1.18, CHCl3). Spectral data were identical to enantiomer
2a.
Compound 3e (minor): [a]D = ꢀ73 (c 1.2, EtOAc) [lit.4
ꢀ76 (c 1.2, EtOAc)].
5.7.7. (2S)-2f and (2R)-N,N0-Bis[(2R)-bornane-10,2-sul-
tam]-2-phenylethylsuccinamide 3f. N,N0-Bis[(2R)-bor-
nane-10,2-sultam]-2-phenylethylfumaramide 1f (0.20 g,
0.33 mmol) was hydrogenated overnight as above and
the resultant mixture chromatographed [SiO2, ethyl ace-
tate/hexane (1:2)] to produce 2f (0.18 g, 86%) and 3f
(0.02 g, 10%) as white plates.
Compound 5b (minor): mp218–219 ꢁC; [a]D = +75 (c
1.18, CHCl3). Spectral data were identical to enantiomer
3a.
5.7.3. (2S)-2b and (2R)-N,N0-Bis[(2R)-bornane-10,2-sul-
tam]-2-ethylsuccinamide 3b.4 N,N0-Bis[(2S)-bornane-
10,2-sultam]-2-ethylfumaramide 1b (0.35 g, 0.65 mmol)
was hydrogenated overnight as above and the resultant
mixture chromatographed [SiO2, ethyl acetate/hexane
(1:1)] to produce 2b (0.27 g, 77%) and 3b (0.01, 3%) as
white plates.
Compound 2f (major): mp154–155 ꢁC; [a]D = ꢀ80 (c
1.18, CHCl3); (Found: C, 62.3; H, 7.2; N, 4.6;
C32H44N2O6S2 requires C, 62.3; H, 7.2; N, 4.5); IR
(KBr, cmꢀ1) 2963, 1688, 1329, 1163; 1H NMR
(400 MHz, CDCl3) d 0.88 (3H, s, CH3), 0.90 (3H, s,
CH3), 1.07 (3H, s, CH3), 1.18 (3H, s, CH3), 1.24–1.38
(4H, m), 1.69–2.14 (12H, m), 2.52–2.67 (2H, m, CH2Ar),
2.99 (1H, dd, J = 5.2, 17.0, CHHC@O), 3.13 (1H, dd,
J = 8.3, 17.0, CHHC@O), 3.32–3.45 (5H, m,
2 · CH2SO2, CHC@O), 3.77 (1H, dd, J = 5.2, 7.2,
CHN), 3.84 (1H, dd, J = 4.8, 7.2, CHN), 7.06–7.13
(3H, m, Ar), 7.16–7.19 (2H, m, Ar); 13C NMR
(100 MHz, CDCl3) d 19.9, 20.0, 20.5, 20.8, 26.4 (·2),
32.7 (·2), 32.9, 33.3, 38.0 (·2), 38.2, 41.1, 44.6, 47.7
(·2), 48.5 (·2), 52.8, 53.0, 62.8, 65.1, 65.2, 125.8,
128.2, 128.4, 141.4, 169.5, 173.5; HR-EIMS m/z
Compound 2b (major): mp114–117 ꢁC (lit.4 115–
117 ꢁC); [a]D = ꢀ103 (c 1.2, EtOAc) [lit.4 ꢀ104 (c 1.2,
EtOAc)].
Compound 3b (minor): [a]D = ꢀ98 (c 1.2, EtOAc) [lit.4
ꢀ98 (c 1.2, EtOAc)].
5.7.4. (2S)-2c and (2R)-N,N0-Bis[(2R)-bornane-10,2-sul-
tam]-2-propylsuccinamide 3c.4 N,N0-Bis[(2S)-bornane-
10,2-sultam]-2-propylfumaramide 1c (0.45 g, 0.81 mmol)
was hydrogenated overnight as above and the resultant

3986
S. Jawaid et al. / Tetrahedron: Asymmetry 15 (2004) 3979–3988
616.2639 M+ (calcd for C32H44N2O6S2: 616.2641). Anal.
Calcd for C32H44N2O6S2: C, 62.3; H, 7.2; N, 4.5. Found:
C, 62.3; H, 7.2; N, 4.6.
0.94 (3H, d, J = 6.9, CH3CH), 1.55–1.67 (2H, m,
OCH2CH2), 1.78–1.86 (1H, m, CH), 2.71 (2H, br s,
2 · OH), 3.42–3.47 (1H, m, CHCHHOH), 3.51 (1H,
dd, J = 7.4, 10.4, CHCHHOH), 3.64–3.81 (2H, m,
CHCH2OH).
Compound 3f (minor): [a]D = ꢀ44 (c 1.18, CHCl3); IR
(KBr, cmꢀ1) 2971, 1688, 1329, 1163; 1H NMR
(400 MHz, CDCl3) d 0.89 (6H, s, 2 · CH3), 1.08 (3H,
s, CH3), 1.09 (3H, s, CH3), 1.16–1.35 (4H, m), 1.76–
1.90 (7H, m), 1.95–2.11 (5H, m), 2.57 (2H, t, J = 8.4,
CH2Ar), 2.88 (1H, dd, J = 5.0, 17.0, CHHC@O), 3.24–
3.43 (6H, m, 2 · CH2SO2, CHHC@O, CHC@O), 3.78
(1H, dd, J = 5.2, 7.6, CHN), 3.85 (1H, app t, J = 6.4,
CHN), 7.07–7.09 (3H, m, Ar), 7.15–7.18 (2H, m, Ar);
13C NMR (100 MHz, CDCl3) d 19.9, 20.9, 26.4 (·2),
32.8, 32.9, 33.0, 34.3, 35.9, 38.4, 38.6, 41.3, 44.6, 47.7,
48.4, 48.5, 52.9, 53.0, 65.3, 125.9, 128.4 (·2), 141.3,
169.4, 173.3; HR-EIMS m/z 616.2643 M+ (calcd for
C32H44N2O6S2: 616.2641).
5.7.10. (2S)-Ethylbutane-1,4-diol 4b.10 This was pre-
pared using the succinamide mixture 2b and 3b in 68%
yield on a 1.50 mmol scale by the method of Reid
et al.4 and gave [a]D = ꢀ0.6 (c 3.5, MeOH) [lit.10 ꢀ0.6,
(c 3.76, MeOH)]; 1H NMR (400 MHz, CDCl3) d
0.89 (3H, t, J = 7.4, CH3CH2), 1.23–1.38 (2H, m,
CH3CH2), 1.50–1.59 (2H, m, CH2CH2OH), 1.62–1.70
(1H, m, CHCH2), 3.42–3.46 (1H, dd, J = 6.9, 10.8,
CHCHHOH), 3.58–3.63 (2H, m, CH2CH2OH), 3.71–
3.76 (1H, m, CHCHH OH).
5.7.11. (2S)-Propylbutane-1,4-diol 4c.10 This was pre-
pared using the succinamide mixture 2c and 3c in 87%
yield on a 1.33 mmol scale by the method of Reid
et al.4 and gave [a]D = ꢀ2.7 (c 3.0, MeOH) [lit.10
5.7.8. (2S)-2g and (2R)-N,N0-Bis[(2R)-bornane-10,2-sul-
tam]-2-isopentylsuccinamide
3g. N,N0-Bis[(2R)-bor-
1
nane-10,2-sultam]-2-isopentylfumaramide 1g (0.35 g,
0.60 mmol) was hydrogenated overnight as above and
the resultant mixture chromatographed [SiO2, ethyl ace-
tate/hexane (1:1)] to produce 2g (0.30 g, 84%) as white
plates and 3g (0.02, 6%) as a colourless oil.
ꢀ3.1, (c 3.18, MeOH)]; H NMR (400 MHz, CDCl3)
d 0.90 (3H, t, J = 6.9, CH3CH2), 1.19–1.37 (4H, m,
CH3CH2H2), 1.54–1.72 (3H, m, CHCH2CH2O), 3.03
(2H, br s, 2 · OH), 3.45 (1H, dd, J = 7.0, 10.7,
CHCHHOH), 3.61–3.67 (2H, m, CH2CH2OH), 3.72–
3.79 (1H, m, CHCHHOH).
Compound 2g (major): mp102–104 ꢁC; [a]D = ꢀ94 (c
1.0, EtOAc); IR (KBr, cmꢀ1) 2959, 1691, 1331, 1135;
1H NMR (400 MHz, CDCl3) d 0.85–0.87 (6H, m,
(CH3)2CH), 0.95 (3H, s, CH3), 0.96 (3H, s, CH3), 1.14
(3H, s, CH3), 1.16–1.56 (12H, m), 1.81–1.88 (6H, m),
1.93–2.15 (4H, m), 2.98 (1H, dd, J = 4.8, 17.2,
CHHC@O), 3.13 (1H, dd, J = 8.4, 17.2, CHHC@O),
3.33–3.51 (5H, m, 2 · CH2SO2, CHC@O), 3.84 (1H,
dd, J = 5.2, 7.6, CHN), 3.90 (1H, dd, J = 5.2, 7.6,
CHN); 13C NMR (100 MHz, CDCl3) d 19.8, 20.0,
20.5, 20.8, 22.3, 22.4, 26.4 (·2), 28.0, 28.8, 32.7, 32.8,
35.9, 38.0, 38.1, 38.2, 41.4, 44.6, 47.7 (·2), 48.4, 48.5,
52.8, 53.0, 65.1, 65.2, 169.7, 173.9; HR-CIMS m/z
583.2873 (M+H)+ (calcd for C29H47N2O6S2: 583.2876).
5.7.12. (2S)-Hexylbutane-1,4-diol 4d.4 This was pre-
pared using the succinamide mixture 2d and 3d in 68%
yield on a 0.60 mmol scale by the method of Reid
et al.4 and gave [a]D = ꢀ2.0 (c 1.0, EtOAc) [lit.4 for
enant. +2, (c 1.0, EtOAc)]; 1H NMR (400 MHz, CDCl3)
d 0.86 (3H, t, J = 5.6, CH3CH2), 1.25 (10H, app br s),
1.50–1.57 (3H, m, CHCH2CH2OH), 3.39–3.43 (1H,
dd, J = 7.0, 10.6, CHCHHOH), 3.57–3.66 (2H, m,
CH2CH2OH), 3.70–3.75 (1H, m, CHCHHOH).
5.7.13. (2S)-Octylbutane-1,4-diol 4e.4 This was pre-
pared using the succinamide mixture 2e and 3e in 58%
yield on a 1.00 mmol scale by the method of Reid
et al.4 and gave [a]D = ꢀ0.8 (c 0.2, EtOH) [lit.4 +0.5,
(c 0.2, EtOH)]; 1H NMR (400 MHz, CDCl3) d 0.88
(3H, t, J = 6.6, CH3CH2), 1.25–1.30 (15H, m), 1.51–
1.72 (2H, m, CH2CH2OH), 3.44 (1H, dd, J = 7.0, 10.7,
CHCHHOH), 3.59–3.64 (2H, m, CH2CH2OH), 3.73–
3.78 (1H, m, CHCHHOH).
Compound 3g (minor): [a]D = ꢀ86 (c 1.0, EtOAc); IR
(KBr, cmꢀ1) 2959, 1691, 1331, 1135; 1H NMR
(400 MHz, CDCl3) d 0.83–0.86 (6H, m, (CH3)2CH),
0.96 (3H, s, CH3), 0.97 (3H, s, CH3), 1.09 (3H, s,
CH3), 1.16 (3H, s, CH3), 1.18–1.51 (7H, m), 1.52–1.79
(2H, m), 1.85–1.93 (6H, m), 2.05–2.18 (4H, m), 2.84
(1H, dd, J = 4.4, 17.2, CHHC@O), 3.31 (1H, dd,
J = 9.2, 17.2, CHHC@O), 3.37–3.52 (5H, m,
2 · CH2SO2, CHC@O), 3.86 (1H, dd, J = 5.2, 7.6,
CHN), 3.94 (1H, app t, J = 6.4, CHN); 13C NMR
(100 MHz, CDCl3) d 19.9, 20.7, 20.9, 22.3, 22.4, 26.4,
28.0, 30.3, 32.7, 32.9, 35.4, 36.0, 38.4, 38.5, 41.4, 44.6,
47.7 (·2), 48.3, 48.4, 52.9, 53.0, 65.2, 65.3, 169.6,
173.7; HR-CIMS m/z 583.2874 (M+H)+ (calcd for
C29H47N2O6S2: 583.2876).
5.7.14. (2R)-Methylbutane-1,4-diol 6.11 This was pre-
pared using (2R)-N,N0-bis[(2R)-bornane-10,2-sultam]-
2-methyl-succinamide 5 in 74% yield on a 2.27 mmol
scale by the method of Reid et al.4 and gave
[a]D = +14 (c 1.0, MeOH) [lit.14 +13.2 (c 1.0, MeOH)].
Spectral data were identical to enantiomer 4a.
5.7.15. (2R)-Methyl-1,4-bis[(methoxysulfonyloxy)]butane
7.12 This was prepared in 79% yield on a 4.61 mmol
scale by the method of Feringa et al.12 1H NMR
(400 MHz, CDCl3) d 1.06 (3H, d, J = 6.8, CH3CH),
1.64–1.72 (1H, m, CHHCH2O), 1.90–1.98 (1H, m,
CHHCH2O), 2.08–2.16 (1H, m, CHCH3), 3.02 (6H, s,
2 · CH3S), 4.07–4.16 (2H, m, CHCH2O), 4.25–4.36
(2H, m, CH2CH2O).
5.7.9. (2S)-Methylbutane-1,4-diol 4a.9 This was pre-
pared using the succinamide mixture 2a and 3a in 91%
yield on a 1.44 mmol scale by the method of Reid
et al.4 and gave [a]D = ꢀ11.4 (c 0.7, MeOH) [lit.9
1
ꢀ13.4, (c 0.7, MeOH)]; H NMR (400 MHz, CDCl3) d

S. Jawaid et al. / Tetrahedron: Asymmetry 15 (2004) 3979–3988
3987
5.7.16. (R)-3-Methyl-N-(2-phenylethyl)-pyrrolidine 8.5
This was prepared in 67% yield on a 4.15 mmol scale
by the method of Zheng et al.5 and gave [a]D = ꢀ2.0 (c
1.0, EtOH) [lit.5 ꢀ1.87 (c 1.0, EtOH)]; 1H NMR
(400 MHz, CDCl3) d 0.97 (3H, d, J = 6.8, 6-CH3),
1.26–1.36 (1H, m, 3-CH), 1.95–2.04 (2H, m, 4-CH2),
2.15–2.26 (1H, m, 5-CHH), 2.42–2.48 (1H, m, 5-
CHH), 2.57–2.78 (5H, m, 20-CH2, 10-CH2, 2-CHH),
2.83–2.87 (1H, m, 2-CHH), 7.07–7.22 (5H, m, Ar);
HR-CIMS m/z 190.1597 (M+H)+ (calcd for C13H19N:
190.1596).
were integrated using Denzo(SMN)13 and the resultant
raw intensity files processed using a locally modified ver-
sion of DENZOX.14 Absorption corrections, either by
gaussian quadrature,15 based on the measured crystal
faces, or by a semi-empirical correction16 were applied
to the data sets. Data were then sorted and merged using
SORTAV,17 and structures were solved by direct meth-
ods (SIR92).18 Solvent molecules were present, water in
the case of 1b, and ethanol for 2b. Refinement with
SHELXL97–219 using full-matrix least-squares on F2
and all the unique data converged without problems
for both structures. All non-H atoms were allowed
anisotropic thermal motion. Aliphatic C–H hydrogen
atoms were included at calculated positions, with C–
5.7.17. (R)-3-Methyl-N-(3-methylbutyl)-pyrrolidine 9.5
This was prepared in 71% yield on a 7.30 mmol
scale by the method of Zheng et al.5 and gave
˚
H = 0.96 A, and were refined with a riding model and
1
[a]D = ꢀ2.0 (c 1.0, EtOH) [lit.5 ꢀ1.8 (c 1.0, EtOH)]; H
with Uiso set to 1.2 times that of the attached C-atom.
Absolute configurations were confirmed by the refine-
ment of the Flack absolute structure parameter, which
refined to zero within error. Thermal ellipsoid plots were
obtained using the program ORTEP-3 for Windows20
All calculations were carried out using the WinGX
package21,22 of crystallographic programs.
NMR (400 MHz, CDCl3) d 0.90 (6H, d, J = 6.4,
40- and 50-CH3), 1.02 (3H, d, J = 6.8, 6-CH3), 1.09–
1.44 (3H, m, 30-CH, 20-CH2), 1.49–1.63 (1H, m,
3-CH), 1.93–2.05 (2H, m, 4-CH2), 2.20–2.29 (1H, m,
5-CHH), 2.33–2.47 (3H, m, 5-CHH, 10-CH2), 2.66–
2.71 (1H, m, 2-CH2), 2.83 (1H, dd, J = 7.6, 8.8, 2-
CH2); HR-CIMS m/z 156.1749 (M+H)+ (calcd for
C10H21N: 156.1752).
Crystallographic data (excluding structure factors) for
both structures have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publica-
tion numbers CCDC 250740 and 250741. Copies of the
data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK
[fax: +44-(0)1223–336033 or email: deposit@ccdc.cam.
ac.uk].
5.7.18. (3R,20S)-3-Methyl-N-(2-methylbutyl)-pyrrolidine
10.5 This was prepared in 64% yield on a 5.76 mmol
scale by the method of Zheng et al.5 and gave
[a]D = +22 (c 1.0, EtOH) [lit.5 +17.5 (c 0.94, EtOH)];
1H NMR (400 MHz, CDCl3) d 0.83–0.91 (6H, m, 40-
and 50-CH3), 1.01 (3H, d, J = 6.8, 6-CH3), 1.26–1.31
(2H, m, 3-CH, 30-CHH), 1.50–1.55 (2H, m, 30-CHH,
20-CH), 1.92–2.03 (2H, m, 4-CH2), 2.18–2.27 (3H, m,
5-CH2, 10-CHH), 2.32–2.38 (1H, m, 10-CHH), 2.61–
2.67 (1H, m, 2-CHH), 2.76 (1H, dd, J = 7.6, 8.8,
2-CHH); HR-CIMS m/z 155.1677 (M+) (calcd for
C10H21N: 155.1674).
References
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1997, 391–394.
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5.8. General procedure for the conversion of 2-substituted
butane-1,4-diols into Mosher diesters
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combined organic extracts were washed with sodium
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gia, L. J. and Muir, K. W. (2001).
˚
(k = 0.71073 A). Data sets were collected at tempera-
tures of 150 and 100 K, respectively, for 1b and 2b. Typ-
ically scan angles of 1–2ꢁ were used, with integration
times of 50–100 s per image. Precise unit cell dimensions
were determined by post-refinement of the setting angles
of a large proportion of the data set. The frame images

3988
S. Jawaid et al. / Tetrahedron: Asymmetry 15 (2004) 3979–3988
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