Diastereoselective conjugate addition of Grignard reagents to a homochiral fumaramide derived from Oppolzer's sultam

Article abstract of DOI:10.1016/j.tetasy.2003.12.010

Conjugate addition of Grignard reagents to N,N′-fumaroylbis[(2R)- bornane-10,2-sultam] 1 occurred with moderate to high levels of diastereoselectivity. Diastereomeric excesses were estimated by analysis of the ¹H NMR spectra of the succinamide mixtures and enantiomeric excesses from ¹⁹F NMR spectra of the bis Mosher esters of the diols produced by reductive cleavage of the succinamides. Saponification of the succinamides gave the corresponding (R)-succinic acids with ees up to 92% showing that addition of the Grignard reagents takes place selectively on the re-face of 1.

Full text of DOI:10.1016/j.tetasy.2003.12.010

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 793–801
Diastereoselective conjugate addition of Grignard reagents to a
homochiral fumaramide derived from Oppolzerꢀs sultam
Gary P. Reid, Kieron W. Brear and David J. Robins*
Department of Chemistry, The Joseph Black Building, University of Glasgow, Glasgow G12 8QQ, UK
Received 14 November 2003; accepted 2 December 2003
Dedicated to Professor David Crout, University of Warwick, UK, to mark the occasion of his retirement
Abstract—Conjugate addition of Grignard reagents to N,N0-fumaroylbis[(2R)-bornane-10,2-sultam] 1 occurred with moderate to
1
high levels of diastereoselectivity. Diastereomeric excesses were estimated by analysis of the H NMR spectra of the succinamide
mixtures and enantiomeric excesses from 19F NMR spectra of the bis Mosher esters of the diols produced by reductive cleavage of
the succinamides. Saponification of the succinamides gave the corresponding (R)-succinic acids with ees up to 92% showing that
addition of the Grignard reagents takes place selectively on the re-face of 1.
ꢀ 2003 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Asymmetric conjugate addition reactions to a,b-unsat-
urated organic compounds are one of the most useful
methods for producing b-substituted products stereo-
selectively.1 The introduction of chirality using a chiral
auxiliary is a useful way of producing a wide variety of
optically active organic compounds. Oppolzer et al.
reported the diastereoselective conjugate addition of
Grignard reagents to N-enoylsultams.2 N,N0-Fuma-
roylbis[(2R)-bornane-10,2-sultam] 1,3 is readily avail-
able from Oppolzerꢀs (2R)-bornane-10,2-sultam.4 The
C2 symmetrical fumaramide 1 containing two of Op-
polzerꢀs camphorsultam moieties has previously been
used in cycloaddition and dihydroxylation reactions.3;5;6
However no examples of conjugate additions to 1 have
been reported.
The fumaramide 1 was prepared from fumaroyl chloride
and commercially available (2R)-())-2,10-camphorsul-
tam.3 We first established that 3.5 equiv of Grignard
reagents were required for successful conjugate addition.
Using these conditions the fumaramide 1 was treated
with a series of Grignard reagents derived from alkyl
bromides and chlorides to produce a mixture of diaste-
reomers 2 and 3 (Scheme 1 and Table 1). The extent of
diastereofacial differentiation was determined in all
cases except for the benzyl derivative 19 by analysis of
the 1H NMR spectra of the crude reaction mixtures. The
ABX system of the succinamide protons resonated at
different chemical shifts for each pair of diastereomers
(except for the benzylsuccinamide). The ABX system of
the major diastereomer was consistently at a lower
We report the diastereoselective conjugate addition of a
series of Grignard reagents to fumaramide 1. It was
intended to hydrolyse the succinamide products 2 and 3
to yield the corresponding enantiomerically enriched
substituted succinic acids. Substituted succinic acids 6
are important intermediates in organic synthesis. They
are building blocks for the synthesis of enantiomerically
pure b-substituted b-amino acids.7 They also have a role
as structural components of natural products.8
O2S
N
O
N
O
S
O2
1
RMgX, THF, -78 oC.
O2S
O
O2S
N
O
R
N
N
N
R
O
O
S
S
O2
O2
2
3
* Corresponding author. Tel.: +44-141-330-4378; fax: +44-141-330-
4888; e-mail: d.robins@chem.gla.ac.uk
Scheme 1.
0957-4166/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.12.010

794
G. P. Reid et al. / Tetrahedron: Asymmetry 15 (2004) 793–801
Table 1. Conjugate addition to fumaramide 1
Entry
RMgX
Isolated yield (%)
Dra (major/minor)
De (%)
1
2
R ¼ ethyl
76
89
69
76
87
62
78
87
80
75
81:19 (7/8)
62
32
R ¼ isopropyl
R ¼ propyl
66:34 (9/10)
68:32 (11/12)
77:23 (13/14)
66:34 (15/16)
76:24 (17/18)
N/A (19)
3
36
54
4
R ¼ butyl
5
R ¼ cyclohexyl
R ¼ octyl
34
52
6
7
R ¼ benzyl
N/A
44
8
R ¼ isobutyl
R ¼ hexyl
72:28 (20/21)
76:24 (22/23)
69:31 (24/25)
9
10
53
38
R ¼ cyclohexyl methyl
a Diastereomeric ratios were determined by 1H 400 MHz NMR spectra of the crude reaction mixtures.
d value than the minor diastereomer. Integration of the
signals gave an estimate of the diastereomeric excess.
The moderate diastereoselectivity observed did permit
the separation and characterisation of individual dia-
stereomers 2, 3 (except for benzyl derivative 19). The
methyl, phenyl and allyl Grignard reagents reacted with
1 to produce the direct 1,2-addition products. Oppolzer
et al. observed the same result with the methyl Grignard
reagent on N-enoylsultams.2
excesses estimated from 1H NMR spectra of compounds
2 and 3 showed moderate diastereoselectivity. The
existence of these other conformations could explain the
moderate values obtained.
In order to confirm the results obtained from the NMR
spectra of the products from the conjugate addition we
decided to make the 2-substituted diols 5 by reduction of
the succinamides with lithium aluminium hydride
(Scheme 2). This reaction produced the diols 5 and
camphorsultam 4, which were separated by column
chromatography. The camphorsultam 4 was recovered
in 90–95% yield and showed no loss of enantiomeric
excess. The absolute configuration of each of the diols
26, 27, 28 and 30 was determined to be (R) by com-
parison of the specific rotations with those reported in
the literature. This agrees with the postulated model
system with attack on the re-face of 1.
The number of equivalents of Grignard reagent appears
to have a considerable effect on the reaction outcome.
This is due to the importance of chelation by magnesium
as discussed by Oppolzer et al.2 More than 3 equiv of
Grignard reagent are required to effect the addition to
fumaramide 1. One is required for chelation to the O
atoms of the C@O and SO2 groups at each end and the
C@O adopts a cis-conformation with the C@C. This
forces the camphor rings to block the si-face. The third
equivalent then delivers its alkyl group in a 1,4-manner
from the re-face and the addition proceeds via a six-
membered cyclic mechanism.2 There was no difference in
the reactivity of Grignard reagents prepared from alkyl
bromides or chlorides.
A more accurate method than specific rotations was
desirable for determining the enantiomeric excesses of
the diols produced. GC on chiral columns was not
possible as the diols were not volatile enough. Attempts
O2S
O
If chelation of the magnesium does not occur, compar-
ative semi-empirical PM3 and ab initio STO 3 21G
calculations suggest that at 193 K four conformations of
1 can exist.9 There are two symmetrical and two
unsymmetrical species with the symmetrical conforma-
tions making up 96% and the nonsymmetrical confor-
mations 4% of the total. The initial diastereomeric
N
NH
N
HO
OH
R
O
S
S
LiAlH4, THF,
R
O2
O2
0 °C, 38-85%.
2 + 3
4
5
Scheme 2.
Table 2. Reduction of succinamides 2+3 yielding diols 5
Entry
2-Substituted diol
Isolated yield (%)
Ee (%)a
Configurationb
1
2
3
4
5
6
7
8
9
Ethyl (26)
44
43
46
56
38
79
75
85
75
73
29
36
56
33
54
90
50
60
(R)11
(R)12
(R)12
Isopropyl (27)
Propyl (28)
Butyl (29)
Cyclohexyl (30)
Octyl (31)
(R)c
Benzyl (32)
Isobutyl (33)
Hexyl (34)
a Enantiomeric excesses were determined by synthesis of both (R)- and (S)-bis Mosherꢀs esters of each diol and were analysed by 19F NMR spectra.
b Compared with specific rotations reported in the literature.
c (S) previously reported with opposite sign.13

G. P. Reid et al. / Tetrahedron: Asymmetry 15 (2004) 793–801
Table 3. Saponification of succinamides 2+3 yielding 2-substituted succinic acids 6
795
Entry
2-Substituted diacid
Isolated yield (%)
Ee (%)a
Configuration
1
2
3
4
5
Ethyl
Propyl
Butyl
65
71
67
71
65
63
(R)14
(R)15
(R)16
(R)17
(R)18
52b
72b
92c
37
Benzyl
Hexyl
a Enantiomeric excesses were determined by chiral HPLC of dianilide derived from diacid.
b Not resolved by chiral HPLC, % ee based on specific rotation of substituted succinic acid compared with literature value.
c Diacid converted into dimethyl ester.
to trifluoroacetylate the diols resulted in mainly mono-
trifluoroacetate products in crude mixtures that could
not be purified. In another approach racemic 2-meth-
ylbutane-1,4-diol was converted into the dibenzoate10
but this could not be resolved on the chiral HPLC col-
umns available. Synthesis of the (R)- and (S)-bis Mosher
esters of the substituted diols 5 was carried out. Inte-
gration of the fluorine signals in the 19F NMR spectra
allowed us to determine the enantiomeric excesses of the
diols (Table 2). The results obtained were generally in
good agreement with the results from the 1H NMR
studies on the initial conjugate addition.
were purchased from commercial suppliers and used
without further purification unless otherwise stated.
Melting points were measured using a Gallenkamp
melting point apparatus and are uncorrected. Nuclear
magnetic resonance spectra were obtained on a Bruker
DPX-400 spectrometer. Chemical shifts are given rela-
tive to residual chloroform (dH ¼ 7:27) and (dC ¼ 77:2)
as internal standards unless otherwise stated. All cou-
pling constants are reported in hertz (Hz). Infrared
spectra were recorded on either a Nicolet Impact 410
FT-IR or Perkin Elmer 500 spectrometer. Combustion
analysis was carried out using an Elemental Analyser
MOD 1106. All of the thin layer chromatography 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 thickness. The plates were
visualised by illumination with UV light, permanganate,
or vanillin solution. Optical rotations were recorded on
Saponification of some of the succinamide products 2
and 3 yielded the corresponding enantiomerically
enriched substituted succinic acids 6 (Scheme 3 and
Table 3). Their absolute configuration was confirmed as
(R) by comparison of the specific rotations with those
reported in the literature.
a Polaar 2000 polarimeter with path length 10 cm. ½aꢀ
D
values are given in 10ꢁ1 deg cm2 gꢁ1
.
O2S
N
O
R
O
4.2. N,N0-Bis[(2R)-bornane-10,2-sultam]fumaramide 13
NH
N
HO
OH
O
S
S
O
R
O2
O2
LiOH.H2O, H2O2,
aq. THF, 0 °C, 65-76%.
This was prepared in 81% yield on a 3.34 mmol scale by
the method of Bauer et al.3 and gave mp 246 ꢁC (lit.3
4
6
2 + 3
247–248 ꢁC); ½aꢀ ¼ )133.5 (c 1.18, CHCl3) [lit.3 )135.6
Scheme 3.
D
(c 1.18, CHCl3)].
3. Conclusion
4.3. General procedure for the 1,4-addition of Grignard
reagents to N,N0-bis[(2R)-bornane-10,2-sultam]fumar-
amides 1 (Table 1)
We have developed methodology for the preparation of
a range of substituted butane-1,4-diols and substituted
succinic acids in moderate enantiomeric excess apart
from (2R)-benzylsuccinic acid, which was obtained in
high 92% ee. (2R)-Benzylsuccinic acid has been shown
to be an inhibitor of carboxypeptidase A.19
The Grignard reagent (3.5 equiv) in diethyl ether was
added dropwise to a stirred solution of N,N0-bis[(2R)-
bornane-10,2-sultam]fumaramide 1 (1 equiv) in dry
THF under N2 at )78 ꢁC. After 3 h at )78 ꢁC the reac-
tion mixture was quenched with satd aq NH4Cl soln and
then poured onto satd aq NH4Cl soln. The product was
extracted with ethyl acetate (2 · 20 mL). The combined
organic extracts were dried (MgSO4) and concentrated
under reduced pressure.
4. Experimental
4.1. General experimental
All reactions were carried out under nitrogen with
anhydrous solvents unless otherwise stated. Tetrahy-
drofuran and diethyl ether were dried by distillation
from sodium and benzophenone immediately before
use. Toluene and dichloromethane were dried by distil-
lation from CaH2 immediately before use. Reagents
4.3.1. (2R)-7 and (2S)-N,N0-Bis[(2R)-bornane-10,2-sul-
tam]-2-ethylsuccinamide 8. . Ethyl magnesium bromide
(7.0 mL of a 2 M solution in Et2O, 14 mmol) was added
dropwise to N,N0-bis[(2R)-bornane-10,2-sultam]fumar-
amide 1 (2.0 g, 4.0 mmol) in dry THF (20 mL) as above
to produce a residue, which was chromatographed

796
G. P. Reid et al. / Tetrahedron: Asymmetry 15 (2004) 793–801
[SiO2, EtOAc–hexane (1:1)] to give (2R)-N,N0-bis[(2R)-
bornane-10,2-sultam]-2-ethylsuccinamide 7 (1.0 g, 56%)
and (2S)-N,N0-bis[(2R)-bornane-10,2-sultam]-2-ethyl-
succinamide 8 (0.35 g, 17%) as plates.
170.3, 173.8; HR-FABMS m=z 555.2565 (Mþ) (calcd for
C27H42N2O6S2: 555.2563).
10 (Minor): mp 256–258 ꢁC; ½aꢀ ¼ )83 (c 0.7, EtOAc);
D
IR (KBr, cmꢁ1) 2965, 1693, 1324, 1137; 1H NMR
(400 MHz, CDCl3) d 0.92–0.96 (9H, m, CH3 and
2 · CH3), 1.00–1.02 (3H, m, CH3), 1.15, 1.26 (3H, s,
CH3), 1.28–1.44 (4H, m), 1.83–1.89 (6H, m), 1.95–2.05
(3H, m), 2.15–2.20 (1H, m), 2.29–2.33 (1H, m,
CH2CHC@O), 2.95 (1H, dd, J ¼ 3.9 and 17.0,
CHHCHC@O), 3.12 (1H, dd, J ¼ 10.0 and 17.0,
CHHCHC@O), 3.31–3.36 (1H, m, CH2CHC@O), 3.39–
3.50 (4H, m, 2 · CH2SO2), 3.82–3.86 (1H, app t, J ¼ 6.3,
CHN), 3.90–3.92 (1H, app t, J ¼ 6.3, CHN); 13C NMR
(100 MHz, CDCl3) d 17.9, 18.8, 20.3, 20.5, 21.0, 21.3,
21.7, 26.8, 26.9, 28.7, 33.2, 33.3, 34.3, 38.5, 38.7, 45.0,
46.4, 48.1, 48.2, 48.8, 48.9, 53.2, 53.5, 65.6, 65.7, 170.5,
173.8; HR-CIMS (isobutane) m=z 555.2563 (calcd for
7 (Major): mp 196–199 ꢁC; ½aꢀ ¼ )98 (c 1.2, EtOAc); IR
D
(KBr, cmꢁ1
)
2965, 1687, 1330, 1164; 1H NMR
(400 MHz, CDCl3) d 0.93–0.96 (9H, m, 2 · CH3 and
CH3CH2), 1.13, 1.15 (3H, s, CH3), 1.24–1.42 (4H, m),
1.61–1.70 (1H, m), 1.78–1.98 (8H, m), 2.05–2.18 (3H,
m), 2.85 (1H, dd, J ¼ 4.4 and 17.0, CHHCHC@O), 3.31
(1H, dd, J ¼ 9.0 and 17.0, CHHCHC@O), 3.40–3.49
(5H, m, 2 · CH2SO2 and CH2CHC@O), 3.86 (1H, t,
J ¼ 8.0, CHN), 3.95 (1H, t, J ¼ 6.3, CHN); 13C NMR
(100 MHz, CDCl3) d 11.4, 20.3 (·2), 21.2, 21.3, 26.0,
26.8 (·2), 33.2, 33.3, 36.0, 38.8, 39.0, 42.7, 45.0, 45.1,
48.1 (·2), 48.7, 48.9, 53.3, 53.4, 65.6, 65.7, 170.0, 174.0;
HR-EIMS m=z 540.2329 (Mþ) (calcd for C26H40N2O6S2:
540.2328). Anal. Calcd for C26H40N2O6S2: C, 57.75; H,
7.5; N, 5.2. Found: C, 57.5; H, 7.4; N, 5.1%.
C27H42N2O6S2:
555.2563).
Anal.
Calcd
for
C27H42N2O6S2: C, 58.5; H, 7.6; N, 5.05. Found: C,
58.45; H, 7.5; N, 5.0%.
8 (Minor): mp 115–117 ꢁC; ½aꢀ ¼ )104 (c 1.2, EtOAc);
D
IR (KBr, cmꢁ1) 2962, 1693, 1333, 1134; 1H NMR
(400 MHz, CDCl3) d 0.94–0.98 (12H, m, 3 · CH3 and
CH3CH2), 1.15 (3H, s, CH3), 1.31–1.44 (4H, m), 1.51–
1.58 (1H, m), 1.84–2.16 (11H, m), 3.00 (1H, dd, J ¼ 5.0
and 17.0, CHHCHC@O), 3.14 (1H, dd, J ¼ 8.7 and
17.0, CHHCHC@O), 3.35–3.51 (5H, m, 2 · CH2SO2 and
CH2CHC@O), 3.82–3.92 (2H, m, 2 · CHN); 13C NMR
(100 MHz, CDCl3) d 11.8, 20.3, 20.4, 21.0, 21.2, 24.5,
26.8, 26.9, 33.2, 33.3, 38.2, 38.4, 38.7, 42.8, 45.0 (·2),
48.1, 48.2, 48.8, 48.9, 53.2, 53.5, 65.5, 65.7, 170.2, 174.2;
HR-FABMS m=z 541.2405 (Mþ) (calcd for
4.3.3. (2R)-11 and (2S)-N,N0-Bis[(2R)-bornane-10,2-sul-
tam]-2-propylsuccinamide 12.. Propyl magnesium bro-
mide (3.5 mL of a 1 M solution in Et2O, 3.4 mmol) was
added dropwise to N,N0-bis[(2R)-bornane-10,2-sul-
tam]fumaramide 1 (0.5 g, 1.0 mmol) in dry THF (20 mL)
as above to produce a residue, which was chromato-
graphed [SiO2, EtOAc–hexane (1:1)] to give (2R)-N,N0-
bis[(2R)-bornane-10,2-sultam]-2-propylsuccinamide 11
(0.23 g, 43%) and (2S)-N,N0-bis[(2R)-bornane-10,2-sul-
tam]-2-propylsuccinamide 12 (0.14 g, 26%) as plates.
C26H40N2O6S2:
541.2406).
Anal.
Calcd
for
C26H40N2O6S2: C, 57.75; H, 7.5; N, 5.2. Found: C, 57.6;
H, 7.45; N, 5.2%.
11 (Major): mp 198–200 ꢁC; ½aꢀ ¼ )90 (c 1.0, EtOAc);
D
IR (KBr, cmꢁ1) 2960, 1685, 1335, 1133; 1H NMR
(400 MHz, CDCl3) d 0.90 (3H, t, J ¼ 7.2, CH2CH3),
0.96, 0.98 (3H, s, CH3), 1.16, 1.17 (3H, s, CH3), 1.31–
1.43 (6H, m), 1.55–1.60 (3H, m), 1.73–1.77 (1H, m),
1.86–1.89 (5H, m), 2.07–2.19 (3H, m), 2.86 (1H, dd,
J ¼ 4.5 and 17.2, CHHCHC@O), 3.32 (1H, dd, J ¼ 8.9
and 17.2, CHHCHC@O), 3.41–3.51 (5H, m, 2 · CH2SO2
and CH2CHC@O), 3.87 (1H, t, J ¼ 7.4, CHN), 3.95
(1H, t, J ¼ 6.2, CHN); 13C NMR (100 MHz, CDCl3)
d 13.9, 19.9 (·2), 19.9, 20.8, 20.9, 26.4 (·2), 32.8, 32.9,
34.5, 36.0, 38.4, 38.6, 41.1, 44.7 (·2), 47.7 (·2), 48.3,
48.5, 52.9, 53.0, 65.2 (·2), 169.6, 173.8; HR-FABMS
m=z 577.2380 (M+Na)þ (calcd for C27H42N2O6S2Na:
577.2382). Anal. Calcd for C27H42N2O6S2: C, 58.5; H,
7.6; N, 5.05. Found: C, 58.2; H, 7.6; N, 5.0%.
4.3.2. (2R)-9 and (2S)-N,N0-Bis[(2R)-bornane-10,2-sul-
tam]-2-isopropylsuccinamide 10.. Isopropyl magnesium
chloride (2.7 mL of a 2 M solution in Et2O, 5.5 mmol)
was added dropwise to N,N0-bis[(2R)-bornane-10,2-sul-
tam]fumaramide 1 (0.8 g, 1.6 mmol) in dry THF (20 mL)
as above. A portion of the residue (0.14 g) was
chromatographed [SiO2, EtOAc–hexane (1:1)] to give
(2R)-N,N0-bis[(2R)-bornane-10,2-sultam]-2-isopropyl-
succinamide 9 (81 mg, 58%) and (2S)-N,N0-bis[(2R)-
bornane-10,2-sultam]-2-isopropylsuccinamide 10 (43 mg,
31%) as plates.
9 (Major): mp 74–78 ꢁC; ½aꢀ ¼ )142 (c 0.7, EtOAc); IR
D
(KBr, cmꢁ1
)
2962, 1691, 1330, 1134; 1H NMR
12 (Minor): mp 187–189 ꢁC; ½aꢀ ¼ )88 (c 1.0, EtOAc);
D
(400 MHz, CDCl3) d 0.86 (3H, d, J ¼ 7.0, CH3CHCH3),
0.92, 0.96 (3H, s, CH3), 1.02 (3H, d, J ¼ 6.8,
CH3CHCH3), 1.15 (6H, s, 2 · CH3), 1.24–1.42 (4H, m),
1.83–1.89 (6H, m), 2.00–2.18 (4H, m), 2.27–2.31 (1H, m,
CH2CHC@O), 2.80 (1H, dd, J ¼ 3.7 and 17.0,
CHHCHC@O), 3.26 (1H, dd, J ¼ 9.6 and 17.0,
CHHCHC@O), 3.40–3.49 (4H, m, 2 · CH2SO2), 3.86
(1H, t, J ¼ 5.0, CHN), 3.95 (1H, t, J ¼ 5.4, CHN); 13C
NMR (100 MHz, CDCl3) d 17.9, 20.3 (·2), 21.2 (·2),
21.3, 26.9 (·2), 30.6, 32.1, 33.2, 33.3, 38.7, 39.1, 45.0
(·2), 47.1, 48.1 (·2), 48.6, 48.9, 53.3, 53.5, 65.7 (·2),
IR (KBr, cmꢁ1) 2960, 1687, 1336, 1136; 1H NMR
(400 MHz, CDCl3) d 0.90 (3H, t, J ¼ 7.2, CH2CH3),
0.95–0.97 (6H, m, 2 · CH3), 1.15, 1.25 (3H, s, CH3),
1.31–1.51 (7H, m), 1.78–1.93 (7H, m), 1.96–2.16 (4H,
m), 3.00 (1H, dd, J ¼ 5.2 and 17.0, CHHCHC@O), 3.13
(1H, dd, J ¼ 8.6 and 17.0, CHHCHC@O), 3.39–3.51
(5H, m, 2 · CH2SO2 and CH2CHC@O), 3.83–3.86 (1H,
app t, J ¼ 6.3, CHN), 3.88–3.91 (1H, app t, J ¼ 6.3,
CHN); 13C NMR (100 MHz, CDCl3) d 14.3, 20.3, 20.4,
20.5, 21.0, 21.2, 26.8, 26.9, 33.2 (·2), 33.3, 33.4, 38.5,
38.7, 41.2, 45.0 (·2), 48.1, 48.2, 48.8, 48.9, 53.2, 53.5,

G. P. Reid et al. / Tetrahedron: Asymmetry 15 (2004) 793–801
797
65.5, 65.7, 170.1, 174.4; HR-FABMS m=z 555.2563
(M+H)þ (calcd for C27H42N2O6S2: 555.2563). Anal.
Calcd for C27H42N2O6S2: C, 58.5; H, 7.6; N, 5.05.
Found: C, 58.2; H, 7.7; N, 5.0%.
15 (Major): mp 180–183 ꢁC; ½aꢀ ¼ )80 (c 1.0, EtOAc);
D
IR (KBr, cmꢁ1) 2927, 1686, 1333, 1134; 1H NMR
(400 MHz, CDCl3) d 0.86–1.42 (20H, m), 1.60–1.73 (6H,
m), 1.84–1.89 (7H, m), 2.00–2.18 (4H, m), 2.83 (1H, dd,
J ¼ 4.0 and 17.0, CHHCHC@O), 3.25 (1H, dd, J ¼ 9.3
and 17.0, CHHCHC@O), 3.39–3.55 (5H, m, 2 · CH2SO2
and CH2CHC@O), 3.86 (1H, app t, J ¼ 6.3, CHN), 3.94
(1H, t, J ¼ 6.2, CHN); 13C NMR (100 MHz, CDCl3) d
20.3 (·2), 21.0, 21.2, 26.4, 26.8 (·2), 27.0, 28.7, 31.4,
33.1, 33.3, 38.8, 39.0 (·2), 40.8, 45.0, 48.1, 48.6 (·2), 48.8
(·2), 53.3, 53.4, 65.6, 65.7, 170.2, 173.6. Anal. Calcd for
C30H46N2O6S2: C, 60.6; H, 7.8; N, 4.7. Found: C, 60.4;
H, 7.9; N, 4.7%.
4.3.4. (2R)-13 and (2S)-N,N0-Bis[(2R)-bornane-10,2-sul-
tam]-2-butylsuccinamide 14.. Butyl magnesium chloride
(1.7 mL of a 2 M solution in Et2O, 3.43 mmol) was
added dropwise to N,N0-bis[(2R)-bornane-10,2-sultam]-
fumaramide 1 (0.5 g, 1 mmol) in dry THF (20 mL) as
above to produce a residue, which was chromato-
graphed [SiO2, EtOAc–hexane (1:1)] to give (2R)-N,N0-
bis[(2R)-bornane-10,2-sultam]-2-butylsuccinamide
13
(0.28 g, 56%) and (2S)-N,N0-bis[(2R)-bornane-10,2-sul-
tam]-2-butylsuccinamide 14 (0.1 g, 20%) as plates.
16 (Minor): mp 244–246 ꢁC; ½aꢀ ¼ )84 (c 1.0, EtOAc);
D
IR (KBr, cmꢁ1) 2929, 1684, 1327, 1136; 1H NMR
(400 MHz, CDCl3) d 0.96–1.43 (21H, m), 1.56–2.19
(16H, m), 2.97 (1H, dd, J ¼ 4.1 and 17.0,
CHHCHC@O), 3.11 (1H, dd, J ¼ 9.7 and 16.8,
CHHCHC@O), 3.29–3.31 (1H, m, CH2CHC@O), 3.39–
3.51 (4H, m, 2 · CH2SO2), 3.84 (1H, app t, J ¼ 6.2,
CHN), 3.92 (1H, app t, J ¼ 6.2, CHN); 13C NMR
(100 MHz, CDCl3) d 20.3, 20.5, 21.0, 21.3, 26.6, 26.7,
26.8 (·2), 27.1, 28.7, 32.1, 33.2, 33.4, 35.2, 38.6, 38.7,
38.9, 45.0, 45.1, 46.4, 48.1 (·2), 48.7, 48.9, 53.2, 53.5,
65.6, 65.8, 170.4, 173.6; HR-FABMS m=z 595.2878
(M+H)þ (calcd for C30H46N2O6S2 595.2876). Anal.
Calcd for C30H46N2O6S2: C, 60.6; H, 7.8; N, 4.7. Found:
C, 60.65; H, 7.9; N, 4.8%.
13 (Major): mp 73–75 ꢁC; ½aꢀ ¼ )75 (c 0.88, EtOAc); IR
D
(KBr, cmꢁ1
)
2960, 1690, 1333, 1135; 1H NMR
(400 MHz, CDCl3) d 0.86 (3H, t, J ¼ 7.2, CH2CH3),
0.95, 0.96 (3H, s, CH3), 1.15, 1.16 (3H, s, CH3), 1.23–
1.42 (8H, m), 1.52–1.62 (1H, m), 1.72–1.76 (1H, m),
1.85–1.88 (6H, m), 2.05–2.18 (4H, m), 2.85 (1H, dd,
J ¼ 2.3 and 17.2, CHHCHC@O), 3.31 (1H, dd, J ¼ 9.0
and 17.2, CHHCHC@O), 3.40–3.50 (5H, m, 2 · CH2SO2
and CH2CHC@O), 3.84–3.88 (1H, app t, J ¼ 6.3, CHN),
3.94 (1H, t, J ¼ 6.3, CHN); 13C NMR (100 MHz,
CDCl3) d 14.2, 20.3 (·2), 21.2, 21.3, 22.9, 26.8 (·2), 29.1,
32.5, 33.2 (·2), 36.4, 38.8, 39.0, 41.6, 45.0 (·2), 48.1 (·2),
48.7, 48.8, 53.3 (·2), 65.6 (·2), 170.0, 174.2; HR-
FABMS m=z 591.2535 (M+Na)þ (calcd for
C28H44N2O6S2Na: 591.2539). Anal. Calcd for
C28H44N2O6S2: C, 59.1; H, 7.5; N, 4.9. Found: C, 59.0;
H, 7.7; N, 4.95%.
4.3.6. (2R)-17 and (2S)-N,N0-Bis[(2R)-bornane-10,2-sul-
tam]-2-octylsuccinamide 18.. Octyl magnesium bromide
(6.8 mL of a 2 M solution in Et2O, 13.7 mmol) was
added dropwise to N,N0-bis[(2R)-bornane-10,2-sultam]-
fumaramide 1 (2.0 g, 3.9 mmol) in dry THF (20 mL) as
above to produce a crude mixture of diastereoisomers. A
portion (0.5 g) was chromatographed [SiO2, EtOAc–
hexane (1:1)] to give (2R)-N,N0-bis[(2R)-bornane-10,2-
sultam]-2-octylsuccinamide 17 (0.39 g, 78%) and (2S)-
N,N0-bis[(2R)-bornane-10,2-sultam]-2-octylsuccinamide
18 (93 mg, 19%) as plates.
14 (Minor): mp 131–133 ꢁC; ½aꢀ ¼ )82 (c 1.0, EtOAc);
D
IR (KBr, cmꢁ1) 2960, 1695, 1331, 1134; 1H NMR
(400 MHz, CDCl3) d 0.91 (3H, t, J ¼ 6.6, CH2CH3),
0.97, 0.98, 1.17 (3H, s, CH3), 1.24–1.50 (13H, m), 1.86–
1.90 (6H, m), 1.98–2.18 (4H, m), 3.01 (1H, dd, J ¼ 5.0
and 17.0, CHHCHC@O), 3.15 (1H, dd, J ¼ 8.5 and
17.0, CHHCHC@O), 3.41–3.53 (5H, m, 2 · CH2SO2 and
CH2CHC@O), 3.86 (1H, t, J ¼ 7.1, CHN), 3.91 (1H, t,
J ¼ 7.3, CHN); 13C NMR (100 MHz, CDCl3) d 14.2,
20.3, 20.4, 20, 21.2, 23.0, 26.8, 26.9, 29.4, 31.0, 33.2,
33.3, 38.4, 38.5, 38.7, 41.5, 45.0 (·2), 48.1, 48.2, 48.8,
48.9, 53.3, 53.5, 65.5, 65.7, 170.1, 174.4; HR-FABMS
m=z 569.2717 (M+H)þ (calcd for C28H44N2O6S2:
569.2719). Anal. Calcd for C28H44N2O6S2: C, 59.1; H,
7.8; N, 4.9. Found: C, 58.9; H, 8.0; N, 4.75%.
17 (Major): mp 160–163 ꢁC; ½aꢀ ¼ )76 (c 1.2, EtOAc);
D
IR (KBr, cmꢁ1) 2923, 1683, 1331, 1134; 1H NMR
(400 MHz, CDCl3) d 0.87 (3H, t, J ¼ 7.1, CH2CH3),
0.95, 0.96 (3H, s, CH3), 1.15, 1.16 (3H, s, CH3), 1.23–
1.42 (19H, m), 1.73–1.79 (1H, m), 1.85–1.88 (5H, m),
2.05–2.15 (3H, m), 2.85 (1H, dd, J ¼ 4.6 and 17.1,
CHHCHC@O), 3.30 (1H, dd, J ¼ 9.0 and 17.1,
CHHCHC@O), 3.44–3.50 (5H, m, 2 · CH2SO2 and
CH2CHC@O), 3.84–3.87 (1H, app t, J ¼ 6.3, CHN),
3.94 (1H, t, J ¼ 6.3, CHN); 13C NMR (100 MHz,
CDCl3) d 14.5, 20.3 (·2), 21.2, 21.3, 23.0, 26.8 (·2), 26.9,
29.6, 29.7, 29.9, 32.2, 32.9, 33.2, 33.3, 36.4, 38.8, 38.9,
41.7 (·2), 45.1, 48.1 (·2), 48.7, 48.8, 53.3, 53.4, 65.6,
65.7, 170.0, 174.2; HR-EIMS m=z 624.3260 (Mþ) (calcd
for C32H52N2O6S2: 624.3267). Anal. Calcd for
C33H52N2O6S2: C, 61.5; H, 8.4; N, 4.5. Found: C, 61.5;
H, 8.3; N, 4.5%.
4.3.5. (2R)-15 and (2S)-N,N0-Bis[(2R)-bornane-10,2-sul-
tam]-2-cyclohexylsuccinamide 16.. Cyclohexyl magne-
sium chloride (6.8 mL of a 2 M solution in Et2O,
13.7 mmol) was added dropwise to N,N0-bis[(2R)-bor-
nane-10,2-sultam]fumaramide 1 (2.0 g, 3.9 mmol) in dry
THF (20 mL) as above to produce a crude mixture of
diastereoisomers. A portion (0.5 g) was chromato-
graphed [SiO2, EtOAc–hexane (1:1)] to give (2R)-N,N0-
bis[(2R)-bornane-10,2-sultam]-2-cyclohexylsuccinamide
15 (0.28 g, 56%) and (2S)-N,N0-bis[(2R)-bornane-10,2-
sultam]-2-cyclohexylsuccinamide 16 (0.11 g, 22%) as
plates.
18 (Minor): ½aꢀ ¼ )83 (c 1.2, EtOAc); IR (KBr, cmꢁ1
)
2932, 1678, 1332, 1134; H NMR (400 MHz, CDCl3)
D
1

798
G. P. Reid et al. / Tetrahedron: Asymmetry 15 (2004) 793–801
d 0.87 (3H, t, J ¼ 7.0, CH2CH3), 0.96, 0.97 (3H, s, CH3),
1.16 (3H, s, CH3), 1.26–1.49 (21H, m), 1.85–2.18 (10H,
m), 3.00 (1H, dd, J ¼ 5.1 and 17.0, CHHCHC@O), 3.14
(1H, dd, J ¼ 8.5 and 17.0, CHHCHC@O), 3.40–3.52
(5H, m, 2 · CH2SO2 and CH2CHC@O), 3.85 (1H, app t,
J ¼ 6.2, CHN), 3.90 (1H, app t, J ¼ 6.2, CHN); 13C
NMR (100 MHz, CDCl3) d 14.1, 19.9, 20.0, 20.5, 20.8,
22.6, 26.4, 26.5, 26.9, 29.2, 29.3, 29.5, 30.9, 31.8, 32.8,
32.9, 38.0, 38.1, 38.3, 41.1, 44.6 (·2), 47.7, 47.8, 48.4,
48.5, 52.9, 53.1, 65.1, 65.3, 169.8, 174.0; HR-FABMS
m=z 647.3166 (M+Na)þ (calcd for C32H52N2O6S2Na:
647.3165).
(·2), 48.7, 48.8, 53.3, 53.4, 65.7 (·2), 170.0, 174.6; HR-
FABMS m=z 591.2536 (M+Na)þ (calcd for
C28H44N2O6S2Na: 591.2539). Anal. Calcd for
C28H44N2O6S2: C, 59.1; H, 7.8; N, 4.9. Found: C, 59.1;
H, 7.75; N, 4.9%.
21 (Minor): mp 208–210 ꢁC; ½aꢀ ¼ )80 (c 1.0, EtOAc);
D
1
IR (KBr, cmꢁ1) 2960, 1685, 1336; H NMR (400 MHz,
CDCl3) d 0.89–0.97 (12H, m), 1.15, 1.25 (3H, s, CH3),
1.29–1.43 (5H, m), 1.61–1.68 (2H, m), 1.73–1.80 (1H,
m), 1.84–1.89 (6H, m), 1.94–2.16 (4H, m), 3.00 (1H, dd,
J ¼ 5.5 and 17.0, CHHCHC@O), 3.09 (1H, dd, J ¼ 7.9
and 17.0, CHHCHC@O), 3.39–3.54 (5H, m, 2 · CH2SO2
and CH2CHC@O), 3.84 (1H, app t, J ¼ 6.2, CHN), 3.88
(1H, app t, J ¼ 6.2, CHN); 13C NMR (100 MHz, CDCl3)
d 20.3, 20.4, 20.9, 21.2, 22.0, 23.5, 26.0, 26.8, 26.9, 33.2,
33.3, 38.4, 38.5, 38.7, 39.7, 40.0, 45.0 (·2), 48.1, 48.2,
48.8, 48.9, 53.3, 53.5, 65.6, 65.7, 170.1, 174.5; HR-
FABMS m=z 591.2540 (M+Na)þ (calcd for C28H44N2-
O6S2Na: 591.2539). Anal. Calcd for C28H44N2O6S2: C,
59.1; H, 7.8; N, 4.9. Found: C, 59.05; H, 7.9; N, 4.9%.
4.3.7. (2R)-N,N0-Bis[(2R)-bornane-10,2-sultam]-2-benzyl-
succinamide 19.. Benzyl magnesium chloride (7.0 mL of
a 2 M solution in Et2O, 14 mmol) was added dropwise to
N,N0-bis[(2R)-bornane-10,2-sultam]fumaramide 1 (2.0 g,
4.0 mmol) in dry THF (20 mL) as above to produce a
mixture, which was chromatographed [SiO2, EtOAc–
hexane (1:1)] to give N,N0-bis[(2R)-bornane-10,2-sul-
tam]-[(2R)-benzyl]succinamide 19 (1.7 g, 71%) as plates,
mp 191–193 ꢁC; ½aꢀ ¼ )70 (c 1.0, EtOAc); IR (KBr,
D
cmꢁ1) 2958, 1685, 1333, 1135; 1H NMR (400 MHz,
CDCl3) d 0.92, 0.93 (3H, s, CH3), 0.98, 1.07 (3H, s,
CH3), 1.22–1.37 (4H, m), 1.80–1.86 (6H, m), 2.00–2.06
(4H, m), 2.67 (1H, dd, J ¼ 9.4 and 13, ArCCHH), 2.74
(1H, dd, J ¼ 5.2 and 17.5 CHHCHC@O), 3.22 (1H, dd,
J ¼ 7.5 and 13, ArCCHH), 3.32 (1H, dd, J ¼ 8.3 and
17.4, CHHCHC@O), 3.42–3.51 (4H, m, 2 · CH2SO2),
3.82–3.87 (3H, m), 7.17–7.37 (5H, m, Ar); 13C NMR
(100 MHz, CDCl3) d 20.3 (·2), 21.2, 21.3, 26.8 (·2),
33.2, 33.3, 36.3, 38.8 (·2), 43.6, 45.0 (·2), 48.1 (·2), 48.7,
48.8, 53.2 (·2), 53.4, 65.5, 65.6, 127.1, 128.9 (·2), 129.8
(·2), 138.2, 169.9, 173.5; HR-EIMS m=z 602.2487 Mþ
(calcd for C31H42N2O6S2: 602.2484). Anal. Calcd for
C31H42N2O6S2: C, 61.8; H, 7.0; N, 4.65. Found: C, 61.6;
H, 7.1; N, 4.6%.
4.3.9. (2R)-22 and (2S)-N,N0-Bis[(2R)-bornane-10,2-sul-
tam]-2-hexylsuccinamide 23.. Hexyl magnesium bromide
(6.8 mL of a 2 M solution in Et2O, 13.7 mmol) was
added dropwise to N,N0-bis[(2R)-bornane-10,2-sultam]-
fumaramide 1 (2.0 g, 3.9 mmol) in dry THF (20 mL) as
above to produce a mixture of diastereoisomers. A
portion (0.5 g) was chromatographed [SiO2, EtOAc–
hexane (1:1)] to give (2R)-N,N0-bis[(2R)-bornane-10,2-
sultam]-2-hexylsuccinamide 22 (0.31 g, 62%) and
(2S)-N,N0-bis[(2R)-bornane-10,2-sultam]-2-hexylsuccin-
amide 23 (89 mg, 18%) as plates.
22 (Major): mp 164–166 ꢁC; ½aꢀ ¼ )60 (c 1.0, EtOAc);
D
IR (KBr, cmꢁ1) 2960, 1685, 1330, 1164; 1H NMR
(400 MHz, CDCl3) d 0.87 (3H, t, J ¼ 7.0, CH2CH3),
0.96, 0.97 (3H, m, CH3), 1.16, 1.17 (3H, s, CH3), 1.24–
1.48 (11H, m), 1.54–1.62 (4H, m), 1.71–1.78 (1H, m),
1.85–1.92 (5H, m), 2.06–2.18 (4H, m), 2.86 (1H, dd,
J ¼ 4.6 and 17.1, CHHCHC@O), 3.31 (1H, dd, J ¼ 9
and 17.1, CHHCHC@O), 3.45–3.55 (4H, m,
2 · CH2SO2), 3.86 (1H, app t, J ¼ 6.3, CHN), 3.95 (1H,
t, J ¼ 6.3, CHN); 13C NMR (100 MHz, CDCl3) d 13.8,
19.7 (·2), 20.6, 20.7, 22.3, 26.2, 26.3, 28.9, 31.4 (·2),
32.3, 32.6, 32.7, 35.8, 38.2, 38.3, 41.1, 44.5 (·2), 47.5
(·2), 48.1, 48.2, 52.7, 52.8, 65.0, 65.1, 169.4, 173.6; HR-
4.3.8. (2R)-20 and (2S)-N,N0-Bis[(2R)-bornane-10,2-sul-
tam]-2-isobutylsuccinamide 21.. Isobutyl magnesium
bromide (6.8 mL of a 2 M solution in Et2O, 13.7 mmol)
was added dropwise to N,N0-bis[(2R)bornane-10,2-sul-
tam]fumaramide 1 (2.0 g, 3.9 mmol) in dry THF (20 mL)
as above to produce a mixture of diastereoisomers. A
portion (0.5 g) was chromatographed [SiO2, EtOAc–
hexane (1:1)] to give (2R)-N,N0-bis[(2R)-bornane-10,2-
sultam]-2-isobutylsuccinamide 20 (0.16 g, 32%) and
(2S)-N,N0-bis[(2R)-bornane-10,2-sultam]-2-isobutylsuc-
cinamide 21 (96 mg, 19%) as plates.
FABMS m=z 597.3033 (M+H)þ
C30H48N2O6S2: 597.3032). Anal.
(calcd for
Calcd for
C30H48N2O6S2: C, 60.4; H, 8.1; N, 4.7. Found: C, 60.2;
H, 8.1; N, 4.7%.
20 (Major): mp 239–241 ꢁC; ½aꢀ ¼ )76 (c 1.0, EtOAc);
D
IR (KBr, cmꢁ1) 2958, 1685, 1333, 1164; 1H NMR
(400 MHz, CDCl3) d 0.90–0.96 (12H, m), 1.15, 1.16 (3H,
s, CH3), 1.20–1.46 (5H, m), 1.59–1.69 (2H, m), 1.84–1.92
(6H, m), 2.05–2.19 (4H, m), 2.86 (1H, dd, J ¼ 5.2 and
17.2, CHHCHC@O), 3.26 (1H, dd, J ¼ 8.4 and 17.2,
CHHCHC@O), 3.40–3.57 (5H, m, 2 · CH2SO2 and
CH2CHC@O), 3.84–3.88 (1H, app t, J ¼ 6.3, CHN),
3.94 (1H, t, J ¼ 6.3, CHN); 13C NMR (100 MHz,
CDCl3) d 20.3 (·2), 21.2, 21.3, 21.9, 23.6, 26.1, 26.8 (·2),
33.2, 33.3, 36.5, 38.8, 38.9, 40.0, 41.6, 45.1 (·2), 48.1
23 (Minor): mp 76–78 ꢁC; ½aꢀ ¼ )66 (c 1.0, EtOAc); IR
D
(KBr, cmꢁ1
)
2958, 1693, 1333, 1134; 1H NMR
(400 MHz, CDCl3) d 0.86 (3H, t, J ¼ 6.9, CH2CH3),
0.95, 0.97 (3H, s, CH3), 1.16 (3H, s, CH3), 1.20–1.48
(14H, m), 1.58 (4H, s), 1.85–1.94 (6H, m), 1.98–2.16
(4H, m), 3.00 (1H, dd, J ¼ 5.1 and 17.0, CHHCHC@O),
3.14 (1H, dd, J ¼ 8.5 and 17.0, CHHCHC@O), 3.39–
3.52 (4H, m, 2 · CH2SO2), 3.85 (1H, t, J ¼ 6.2, CHN),
3.90 (1H, t, J ¼ 6.2, CHN); 13C NMR (100 MHz,
CDCl3) d 14.0, 19.8, 20.0, 20.5, 20.8, 22.5, 26.4 (·2),

G. P. Reid et al. / Tetrahedron: Asymmetry 15 (2004) 793–801
799
26.8, 29.1, 30.9, 31.5, 32.7, 32.8, 37.9, 38.0, 38.2, 41.1,
44.6 (·2), 47.7 (·2), 48.4, 48.5, 52.8, 53.0, 65.1, 65.2,
169.7, 173.9; HR-FABMS m=z 619.2855 (M+Na)þ
(calcd for C30H48N2O6S2Na: 619.2852). Anal. Calcd for
C30H48N2O6S2: C, 60.4; H, 8.1; N, 4.7. Found: C, 60.55;
H, 8.3; N, 4.6%.
reaction mixture was quenched with satd aq NH4Cl soln
(2 mL). The mixture was filtered and concentrated under
reduced pressure.
4.4.1. (2R)-Ethylbutane-1,4-diol 26.11. Using 7+8 (0.8 g,
1.5 mmol) gave a mixture of diol and chiral sultam
(0.72 g), which was chromatographed [SiO2, acetone–
hexane (1:1)] to give (2R)-ethylbutane-1,4-diol 26
4.3.10. (2R)-24 and (2S)-N,N0-Bis[(2R)-bornane-10,2-sul-
tam]-2-cyclohexylhexylmethylsuccinamide 25.. Cyclo-
hexylmethyl magnesium bromide (6.8 mL of a 2 M
solution in Et2O, 13.7 mmol) was added dropwise to
N,N0-bis[(2R)-bornane-10,2-sultam]fumaramide 1 (2.0 g,
3.9 mmol) in dry THF (20 mL) as above to produce a
mixture of diastereoisomers. A portion (0.5 g) was
chromatographed [SiO2, EtOAc–hexane (1:1)] to give
(2R)-N,N0-bis[(2R)-bornane-10,2-sultam]-2-cyclohexyl-
methylsuccinamide 24 (0.28 g, 56%) and (2S)-N,N0-
bis[(2R)-bornane-10,2-sultam]-2-cyclohexylmethylsucci-
namide 25 (94 mg, 19%) as plates.
(0.08 g, 39%) as a colourless oil. ½aꢀ ¼ +12 (c 1.5,
D
CHCl3) [lit.10 +14.3 (c 1.5, CHCl3)]; IR (NaCl, cmꢁ1
)
1
3332, 2925, 1018; H NMR (400 MHz, CDCl3) d 0.92
(3H, t, J ¼ 7.4, CH2CH3), 1.25–1.43 (2H, m, CH2CH3),
1.55–1.62 (2H, m, CH2CH2OH), 1.67–1.76 (1H, m, CH),
3.00 (2H, br s, OH), 3.49 (1H, dd, J ¼ 6.7 and 10.8,
CHCHHOH), 3.63–3.68 (2H, m, CH2CH2OH), 3.76–
3.81 (1H, m, CHCHHOH).
4.4.2. (2R)-Isopropylbutane-1,4-diol 27.12. Using 9+10
(0.5 g, 0.9 mmol) gave a mixture (0.24 g), which was
chromatographed [SiO2, acetone–hexane (2:3)] to give
(2R)-isopropylbutane-1,4-diol 27 (0.05 g, 43%) as a col-
24 (Major): mp 214–216 ꢁC; ½aꢀ ¼ )60 (c 1.0, EtOAc);
D
ourless oil; ½aꢀ ¼ )3.3 (c 1.0, MeOH) [lit.11 )10 (c 1.0,
IR (KBr, cmꢁ1) 2924, 1685, 1334, 1164; 1H NMR
(400 MHz, CDCl3) d 0.87–0.96 (8H, m), 1.07–1.18 (8H,
m), 1.24–1.42 (6H, m), 1.60–1.76 (7H, m), 1.84–1.93
(5H, m), 2.05–2.19 (5H, m), 2.85 (1H, dd, J ¼ 5.3 and
17.2, CHHCHC@O), 3.25 (1H, dd, J ¼ 8.2 and 17.2,
CHHCHC@O), 3.41–3.50 (4H, m, 2 · CH2SO2), 3.71
(1H, m, CH2CHC@O), 3.87 (1H, app t, J ¼ 6.4, CHN),
3.93 (1H, t, J ¼ 6.3, CHN); 13C NMR (100 MHz,
CDCl3) d 20.3 (·2), 21.3 (·2), 26.4, 26.6, 26.8, 26.9 (·2),
32.6, 33.2, 33.3, 34.1, 35.5, 36.7, 38.8, 38.9, 39.2, 40.4,
45.1 (·2), 48.1 (·2), 48.7, 48.8, 53.3, 53.4, 65.7 (·2),
170.0, 174.8; HR-FABMS m=z 609.3032 (M+H)þ (calcd
for C31H48N2O6S2: 609.3032). Anal. Calcd for
C31H48N2O6S2: C, 61.15; H, 7.95; N, 4.6. Found: C,
61.0; H, 8.2; N, 4.7%.
D
1
MeOH)]; IR (NaCl, cmꢁ1) 3332, 2958, 1466, 1044; H
NMR (400 MHz, CDCl3) d 0.88 (3H, d, J ¼ 7.2,
CHCH3), 0.89 (3H, d, J ¼ 7.2, CHCH3), 1.44–1.61 (2H,
m, CH2CH2OH), 1.68–1.79 (2H, m, CH3CHCH), 3.20
(2H, br s, OH), 3.54 (1H, dd, J ¼ 7.8 and 10.6,
CHCHHOH), 3.60–3.70 (2H, m, CH2CH2OH), 3.77–
3.82 (1H, m, CHCHHOH).
4.4.3. (2R)-propylbutane-1,4-diol 28.12. Using 11+12
(0.5 g, 0.9 mmol) gave a mixture (0.18 g), which was
chromatographed [SiO2, acetone–hexane (1:1)] to give
(2R)-propylbutane-1,4-diol 28 (0.06 g, 46%) as a col-
ourless oil. ½aꢀ ¼ )1 (c 1.1, MeOH) [lit.11 )3.6 (c 2.12,
D
1
MeOH)]; IR (NaCl, cmꢁ1) 3320, 2929, 1466, 1039; H
NMR (400 MHz, CDCl3) d 0.93 (3H, t, J ¼ 6.9,
CH2CH3), 1.21–1.37 (4H, m, CH3CH2CH2), 1.55–1.75
(3H, m, CHCH2CH2OH), 2.63 (2H, br s, OH), 3.49 (1H,
dd, J ¼ 7.0 and 10.8, CHCHHOH), 3.64–3.71 (2H, m,
CH2CH2OH), 3.76–3.81 (1H, m, CHCHHOH).
25 (Minor): mp 101–103 ꢁC; ½aꢀ ¼ )86 (c 1.0, EtOAc);
D
IR (KBr, cmꢁ1) 2935, 1687, 1328, 1136; 1H NMR
(400 MHz, CDCl3) d 0.89 (8H, m), 1.11–1.44 (14H, m)
1.58–1.89 (12H, m), 1.98–2.18 (5H, m), 2.99 (1H, dd,
J ¼ 5.4 and 17.0, CHHCHC@O), 3.10 (1H, dd, J ¼ 7.8
and 17.0, CHHCHC@O), 3.39–3.55 (5H, m, 2 · CH2SO2
and CH2CHC@O), 3.85 (1H, t, J ¼ 6.2, CHN), 3.90
(1H, t, J ¼ 6.2, CHN); 13C NMR (100 MHz, CDCl3)
d 19.8, 20.0, 20.5, 20.7, 26.0, 26.1, 26.4 (·2), 26.5 (·2)
32.3, 32.7, 32.8, 33.7, 34.9, 38.0, 38.1, 38.3 (·2), 38.5,
44.5, 44.6, 47.7, 48.4 (·2), 52.8, 53.0, 65.1, 65.2, 169.6,
174.2; HR-FABMS m=z 609.3031 (M+H)þ (calcd for
4.4.4. (2R)-Butylbutane-1,4-diol 29.. Using 13+14 (0.5 g,
0.9 mmol) gave a mixture (0.17 g), which was chroma-
tographed [SiO2, acetone–hexane (2:3)] to give (2R)-
butylbutane-1,4-diol 29 (73 mg, 56%) as a colourless oil.
½aꢀ ¼ )1 (c 1.5, EtOH); IR (NaCl, cmꢁ1) 3410, 2946,
D
1
1466, 1041; H NMR (400 MHz, CDCl3) d 0.89 (3H, t,
C31H48N2O6S2:
609.3032).
Anal.
Calcd
for
J ¼ 6.8, CH2CH3), 1.21–1.34 (6H, m), 1.52–1.73 (3H, m,
CHCH2CH2OH), 3.39 (2H, br s, OH), 3.45 (1H, dd,
J ¼ 6.8 and 10.4, CHCHHOH), 3.60–3.65 (2H, m,
CH2CH2OH), 3.73–3.78 (1H, m, CHCHHOH); 13C
NMR (100 MHz, CDCl3) d 14.2, 23.1, 29.5, 31.6, 36.0,
39.6, 61.2, 66.5; HR-CIMS m=z (isobutane) 147.1384
(MHþ) (calcd for C8H18O2: 147.1385).
C31H48N2O6S2: C, 61.15; H, 7.95; N, 4.6. Found: C,
61.3; H, 8.0; N, 4.7%.
4.4. General procedure for the reduction of 2-
substituted succinamides 2 and 3 into 2-substituted
butane-1,4-diols 5 (Table 2)
The 2-substituted succinamide mixture 2 and 3 (0.5 g) in
dry THF (10 mL) was added dropwise to a stirred
solution of lithium aluminium hydride (5 equiv) in dry
THF (50 mL) under N2 at 0 ꢁC. After 3 h at 0 ꢁC the
4.4.5. (2R)-Cyclohexylbutane-1,4-diol 30. Using 15+16
(0.5 g, 0.8 mmol) gave a mixture (0.44 g), which was
chromatographed [SiO2, acetone–hexane (2:3)] to give

800
G. P. Reid et al. / Tetrahedron: Asymmetry 15 (2004) 793–801
(2R)-cyclohexylbutane-1,4-diol 30 (53 mg, 38%) as a
(3H, t, J ¼ 7.0. CH2CH3), 1.27 (10H, br s), 1.52–1.73
(3H, m, CHCH2CH2OH), 3.27 (2H, br s, OH), 3.46 (1H,
dd, J ¼ 7.0 and 10.7, CHCHHOH), 3.61–3.67 (2H, m,
CH2CH2OH), 3.74–3.80 (1H, m, CHCHHOH); 13C
NMR (100 MHz, CDCl3) d 14.5, 23.0, 27.4, 30.0, 32.2
(·2), 36.2, 39.8, 61.5, 66.7; HR-FABMS m=z 175.1697
(MHþ) (calcd for C10H22O2: 175.1698).
colourless oil. ½aꢀ ¼ )7.6 (c 0.5, EtOH); IR (NaCl,
D
cmꢁ1) 3336, 2921, 1448, 1041; 1H NMR (400 MHz,
CDCl3) d 0.95–1.74 (14H, m), 3.52 (1H, dd, J ¼ 6.8 and
17.6, CHCHHOH), 3.56–3.62 (1H, m, CH2CHHOH),
3.66 (1H, dd, J ¼ 4.0 and 10.8, CHCHHOH), 3.73–3.78
(1H, m, CH2CHHOH); 13C NMR (100 MHz, CDCl3)
d 26.6, 26.7 (·2), 30.0, 30.1, 33.4, 40.1, 45.0, 61.7, 64.8;
HR-FABMS m=z 173.1541 (MHþ) (calcd for C10H20O2
173.1542).
4.5. General procedure for the conversion of 2-substituted
butane-1,4-diols 5 into Mosher diesters
4.4.6. (2R)-Octylbutane-1,4-diol 31.. Using 17+18 (0.6 g,
1.0 mmol) gave a mixture (0.45 g), which was chroma-
tographed [SiO2, acetone–hexane (2:3)] to give 2R-oct-
ylhexylbutane-1,4-diol 31 (0.15 g, 79%) as a colourless
EDCI (5 equiv) was added to a mixture of diol (ꢂ20 mg),
(R)- or (S)-Mosher acid (2.5 equiv) and DMAP (1 equiv)
in dry DCM (2 mL) under N2. The mixture was stirred
at room temperature for 24 h, then quenched with 5%
citric acid (2 mL) and extracted with dichloromethane
(3 · 5 mL). The combined extracts were washed with
sodium hydrogen carbonate (10 mL) followed by water
(10 mL) and brine (10 mL), dried (MgSO4) and con-
centrated under reduced pressure.
oil. ½aꢀ ¼ +0.5 (c 0.2, EtOH); IR (NaCl, cmꢁ1) 3328,
D
1
2924, 1465, 1041; H NMR (400 MHz, CDCl3) d 0.89
(3H, t, J ¼ 7.0, CH2CH3), 1.26–1.33 (15H, m), 1.57–1.77
(2H, m, CH2CH2OH), 2.62 (2H, br s, OH), 3.52 (1H, dd,
J ¼ 6.8 and 10.7, CHCHHOH), 3.68–3.73 (2H, m,
CH2CH2OH), 3.79–3.85 (1H, m, CHCHHOH); 13C
NMR (100 MHz, CDCl3) d 14.1, 22.6, 27.1, 29.3, 29.5,
29.9, 31.7, 31.9, 35.8, 39.3, 61.3, 66.4; HR-EIMS m=z
202.1934 (Mþ) (calcd for C12H26O2: 202.1933).
4.6. General procedure for the saponification of
succinamides 2 and 3
4.4.7. (2R)-Benzylbutane-1,4-diol 32.. Using 19 (0.6 g,
1.0 mmol) gave a mixture (0.60 g), which was chroma-
tographed [SiO2, acetone–hexane (2:3)] to give (2R)-
benzylbutane-1,4-diol 32 (0.15 g, 75%) as a colourless
Aqueous (30%) H2O2 (4.8 equiv) and LiOHÆH2O
(2.4 equiv) was added at 0 ꢁC to a solution of substituted
succinamide 2 and 3 (1 mol equiv) in THF/H2O (4:1,
0.15 M). The mixture was stirred at 0 ꢁC for 7 h, satu-
rated aqueous Na2SO3 was added and the mixture was
extracted with ethyl acetate (2 · 10 mL). The extracts
were dried (MgSO4) and concentrated under reduced
pressure to give recovered auxiliary. The aqueous layer
was then acidified with 1 M HCl to pH 1 and extracted
with ethyl acetate (2 · 10 mL). The extracts were dried
(MgSO4) and concentrated under reduced pressure to
produce the diacid (Table 3).
oil. ½aꢀ ¼ +6.6 (c 1.5, EtOAc); IR (NaCl, cmꢁ1) 3348,
D
2927, 1603, 1454, 1043; H NMR (400 MHz, CDCl3)
1
d 1.56–1.75 (2H, m, ArCH2CH), 1.97–2.01 (1H, m,
ArCH2CH), 2.40 (2H, br s, OH), 2.53–2.74 (2H, m,
CH2CH2OH), 3.47–3.52 (1H, m, CHCHHOH), 3.62–
3.68 (2H, m, CH2CH2OH), 3.75–3.80 (1H, m,
CHCHHOH), 7.16–7.30 (5H, m, Ar); 13C NMR
(100 MHz, CDCl3) d 35.6, 38.6, 41.6, 61.5, 66.0, 126.4,
128.8, 129.5, 140.7; HR-EIMS m=z 162.1046 (Mþ) (calcd
for C11H16O2: 162.1045).
References and notes
4.4.8. (2R)-Isobutylbutane-1,4-diol 33.. Using 20+21
(0.5 g, 0.9 mmol) gave a mixture (0.45 g), which was
chromatographed [SiO2, acetone–hexane (2:3)] to give
(2R)-isobutylbutane-1,4-diol 33 (0.11 g, 85%) as a col-
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)
D
1
3334, 2954, 1468, 1039; H NMR (400 MHz, CDCl3)
d 0.88 (6H, t, J ¼ 6.4. CH3CHCH3), 1.04–1.25 (2H, m,
CH3CHCH2), 1.50–1.75 (4H, m), 3.42 (1H, dd, J ¼ 7.2
and 10.8, CHCHHOH), 3.56 (2H, br s, OH), 3.61–3.66
(2H, m, CH2CH2OH), 3.74–3.79 (1H, m, CHCHHOH);
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4.4.9. (2R)-Hexylbutane-1,4-diol 34.. Using 22+23
(0.54 g, 0.9 mmol) gave a mixture (0.38 g), which was
chromatographed [SiO2, EtOAc–hexane (1:1)] to give
(2R)-hexylbutane-1,4-diol 34 (0.12 g, 75%) as a colour-
less oil. ½aꢀ ¼ +2 (c 1.0, EtOAc); IR (NaCl, cmꢁ1) 3320,
9. Chapius, C.; de Saint Laumer, J.; Marty, M. Helv. Chim.
Acta 1997, 80, 146–171.
D
1
2925, 1466, 1043; H NMR (400 MHz, CDCl3) d 0.88

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