Synthesis of (3S,3S′,4S,4S′)-1,1′-ethylenedipyrrolidine- 3,3′,4,4′-tetraol and related diamino diols: Donor-acceptor hydrogen-bonding motifs of the C2 symmetric 3,4-dihydroxypyrrolidine unit

Article abstract of DOI:10.1016/j.tetasy.2005.07.024

Enantiopure 1,1′-ethylenedipyrrolidines possessing 3,4-disubstitution have been prepared from esters of l-(+)-tartaric acid. Although diacylation routes via the diacetoxypyrrolidin-2,5-diones were problematic, N,N-dialkylation protocols proved to be reliable and led to the synthesis of (3S,3S′,4S,4S′)-1,1′-ethylenedipyrrolidine-3,3′,4, 4′-tetraol, (3R,3′S,4R,4′S)-3,4-diamino-1,1′- ethylenedipyrrolidine-3′,4′-diol and (3R,3′R,4S,4′S)-3, 3′-diamino-1,1′-ethylenedipyrrolidine-4,4′-diol. The tetraol possesses a crystal structure that exhibits an unusual zig-zag intermolecular pattern comprising a network of hydrogen bonds involving the terminal hydroxyl groups and a nitrogen atom of one of the pyrrolidine rings.

Full text of DOI:10.1016/j.tetasy.2005.07.024

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 2799–2809
Synthesis of (3S,3S0,4S,4S0)-1,10-ethylenedipyrrolidine-3,30,4,40-
tetraol and related diamino diols: donor–acceptor hydrogen-bonding
motifs of the C2 symmetric 3,4-dihydroxypyrrolidine unit
Charles M. Marson,a,* Robert C. Melling,b Simon J. Colesc and Michael B. Hursthousec
aDepartment of Chemistry, University College London, Christopher Ingold Laboratories, 20 Gordon Street, London WC1H 0AJ, UK
bDepartment of Chemistry, Queen Mary and Westfield College, University of London, London E1 4NS, UK
cDepartment of Chemistry, The University of Southampton, Highfield, Southampton SO17 1BJ, UK
Received 24 June 2005; accepted 25 July 2005
Available online 16 August 2005
Abstract—Enantiopure 1,10-ethylenedipyrrolidines possessing 3,4-disubstitution have been prepared from esters of L-(+)-tartaric
acid. Although diacylation routes via the diacetoxypyrrolidin-2,5-diones were problematic, N,N-dialkylation protocols proved to
be reliable and led to the synthesis of (3S,3S0,4S,4S0)-1,10-ethylenedipyrrolidine-3,30,4,40-tetraol, (3R,30S,4R,40S)-3,4-diamino-
1,10-ethylenedipyrrolidine-30,40-diol and (3R,30R,4S,40S)-3,30-diamino-1,10-ethylenedipyrrolidine-4,40-diol. The tetraol possesses a
crystal structure that exhibits an unusual zig-zag intermolecular pattern comprising a network of hydrogen bonds involving the
terminal hydroxyl groups and a nitrogen atom of one of the pyrrolidine rings.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
tion by Koga et al.10 Given the distinctive features of
such linked trans-3,4-dihydroxypyrrolidines, we sought
to devise routes to systems such as 1 and their related
diamino diols (Fig. 1).
Hydroxylated pyrrolidines and their related fused sys-
tems form an important group of natural products,1
many possessing significant pharmacological properties,
including the inhibition of glycosidases.2 The proximity
of stereochemically defined oxygen and nitrogen atoms
would be expected to give rise to specific patterns of
hydrogen bonding3,4 that could be involved with biolo-
gical molecular recognition.5,6 Such is the case for race-
mic trans-1,2-cyclohexanediol, which gives a crystalline
1:1 adduct when heated with (1R,2R)-(ꢀ)-cyclohexane-
1,2-diamine.7,8
O
O
X
X
AcO
AcO
X
OAc
OAc
N
N
N
N
X
O
1a X=OH
1b X=OAc
O
2
Figure 1.
Within this class, trans-3,4-dihydroxypyrrolidines have
found several uses including the formation of dendri-
mers,9a the assembly of oligomeric macrocycles9b and
their action as catalysts in enantioselective alkylations,9c
functions that make use of their C2 symmetry. The link-
ing of trans-3,4-disubstituted pyrrolidines by an ethylene
unit permits the coordination of a metal to both nitro-
gen atoms, and trans-3,4-disubstituted pyrrolidines have
been studied as catalysts for asymmetric dihydroxyla-
2. Results and discussion
A succinct route to 1,10-ethylenedipyrrolidines 1 could
involve reduction of the imide 2 derived by N,N0-dialkyl-
ation of (3R,4R)-diacetoxypyrrolidin-2,5-dione, itself
available from L-(+)-tartaric acid by reaction with acetic
anhydride followed by treatment with ammonia and
cyclisation with acetyl chloride.11 However, (3R,4R)-
diacetoxypyrrolidin-2,5-dione did not furnish any imide
2 when heated with 1,2-dibromoethane in DMF at up to
100 ꢁC. (3R,4R)-Diacetoxypyrrolidin-2,5-dione reacted
*
Corresponding author. Tel.: +44 20 76794712; fax: +44 20
76797463; e-mail: c.m.marson@ucl.ac.uk
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.07.024

2800
C. M. Marson et al. / Tetrahedron: Asymmetry 16 (2005) 2799–2809
MOMO
OH
O
MOMO
O
ii
i
HO
EtO
EtO
OH
OEt
OEt
OMOM
O
OH
O
OMOM
3
5
4
MOMO
MOMO
OMOM
OMOM
iv
iii
N
MsO
OMs
N
MOMO
OMOM
1c
6
HO
v
OH
OH
N
N
HO
1a
Scheme 1. Reagents and conditions: (i) dimethoxymethane, P2O5, CHCl3; (ii) LiAlH4, Et2O, reflux; work-up with aq NaOH (4 M) 0–20 ꢁC; (iii)
MeSO2Cl, Et3N, CH2Cl2; (iv) ethylenediamine, K2CO3, KI (cat.), 18-crown-6 in DMF at 100 ꢁC; (v) 1:1 hydrochloric acid (10 M)/methanol, 20 ꢁC;
then Me2NEt, ꢀ20 to 20 ꢁC.
with ethylene glycol under Mitsunobu conditions (Ph3P,
diethyl diazocarboxylate) to give the imide 2 (17%), but
attempted reduction to give either 1a (X = OH) or 1b
(X = Ac) by either THFÆBH3 or NaBH4–I2 in THF12
was unsuccessful. A dialkylation approach was therefore
considered (Scheme 1).
for 48 h, giving diazide 14 (56%), which was hydro-
genated over 10% palladium on carbon in ethanol to
give diamine 15 (73%). The MOM groups of 15 were
cleaved with concd hydrochloric acid and methanol
prior to neutralisation with Me2NEt, furnishing diami-
no diol 16 in 10% yield.
Reaction of (+)-diethyl L-tartrate
3
with 2,2-di-
It was also of interest to prepare ethylene-linked pyrrol-
idines that contain an amino alcohol unit on each ring
(Scheme 3). The approach to amino alcohol 22
employed the attack of an azide on the cyclic sulfate
19, a protocol developed by Gao and Sharpless.14 Mak-
ing use of known procedures,15–17 L-(+)-tartaric acid
was converted into diol 17, which upon treatment with
SOCl2 and a catalytic amount of DMF in dichlorometh-
ane afforded the sulfite 18. Oxidation of 18 using NaIO4
in the presence of a catalytic amount of RuO2 in 2:1 ace-
tonitrile/water afforded the desired cyclic sulfate 19
(43%), which with NaN3 (5 equiv) in 1:1 aqueous ace-
tone at 25 ꢁC afforded azido dimesylate 20 (67%) after
careful acidification. Condensation of dimesylate 20
with ethylenediamine, in the presence of KHCO3 and
a catalytic amount of 18-crown-6 in DMF at 100 ꢁC
afforded diazide 21 (12%), which on treatment with
hydrogen at 1 atm over 10% palladium on carbon in eth-
anol afforded diamino diol 22 in 23% yield. Other routes
were unsuccessful, including an attempt to proceed via
23, obtained from (+)-dimethyl L-tartrate via the Gao-
Sharpless procedure,14 but which could not be reduced
satisfactorily by LiAlH4 in THF at reflux to give the
key amine intermediate 24.
methoxymethane and P2O5 in chloroform (Scheme 1)
afforded the bis-MOM derivative 4 (74%),13 which was
reduced with LiAlH4 at reflux in diethyl ether to give
diol 5, which was converted into dimesylate 6 in 49%
yield by reaction with methanesulfonyl chloride
(2.5 equiv) and Et3N (2.5 equiv). Reaction of dimesylate
6 with ethylenediamine and K2CO3 in the presence
of catalytic amounts of KI and 18-crown-6 in DMF
at 100 ꢁC afforded the 1,10-ethylenedipyrrolidine 1c
(22%), which was deprotected using 1:1 hydrochloric
acid (10 M)/methanol at 20 ꢁC followed by Me2NEt
and then continuous extraction with 1:3 THF/chloro-
form to give diamino diol 1a in 55% yield.
The ability of amines to form adducts with alcohols7,8
suggested that the terminal groups of diamino diol 16
could lead to interesting non-covalent interactions, and
a synthesis was devised (Scheme 2). Dimesylate 6 under-
went cyclisation with ethanolamine in the presence of
KHCO3 to give 1-(2-hydroxyethyl)pyrrolidine 7 in 57%
yield, which was converted into the unstable mesylate
8 (50%) with methanesulfonyl chloride (1.5 equiv) and
Et3N (1.5 equiv) in dichloromethane at ꢀ30 ꢁC. Mesyl-
ate 8 was treated with NaN3 (2 equiv) in DMF at
80 ꢁC for 16 h, giving azide 9 (54%), which was hydroge-
nated over 10% palladium on carbon in ethanol to give
amine 10 (82%). Deprotection using 1:1 10 M HCl/
MeOH afforded 11 (51%), which was condensed with
dimesylate 6 using KHCO3 as the base and in the pres-
ence of catalytic amounts of KI and 18-crown-6 in DMF
at 100 ꢁC to give diol 12 (31%). Mesylation of 12 with
methanesulfonyl chloride (3 equiv) and Et3N (3 equiv)
in dichloromethane from 0 to 20 ꢁC proceeded in 46%
yield to give dimesylate 13, which underwent twofold
displacement with LiN3 (10 equiv) in DMF at 80 ꢁC
2.1. Crystallisation studies
After Kawashima and Hirayamaꢀs discovery that heat-
ing (1R,2R)-(ꢀ)-cyclohexane-1,2-diamine with racemic
trans-1,2-cyclohexanediol gave a crystalline adduct of
1:1 stoichiometry,1 Hanessian et al. showed that such
adducts possess remarkable ordering as triple helicate
systems with a polar core and hydrophobic periphery.8
The mode of helicity depends upon the absolute
configuration of the diamine. Such molecular recogni-
tion of a primary amine by an alcohol is consistent with

C. M. Marson et al. / Tetrahedron: Asymmetry 16 (2005) 2799–2809
2801
OMOM
OMOM
HO
i
ii,iii
vi
MsO
RO
OMs
N
OMOM
OMOM
OR
6
7
OMOM
OMOM
H2N
iv,v
N
N
OR
8 R = Ms
9 R = N3
10 R = MOM
11 R = H
MOMO
MOMO
MOMO
OMs
OMs
OH
OH
ii
N
N
N
N
MOMO
13
12
MOMO
N3
N3
vii
viii
N
N
MOMO
14
HO
HO
MOMO
NH2
NH2
v, ix
N
N
N
N
MOMO
NH2
NH2
16
15
HO
HO
OMOM
OH
OH
NH2
NH2
H2N
N
MsO
+
N
N
OMs
OMOM
Scheme 2. Reagents and conditions: (i) H2NCH2CH2OH, KI (cat.), K2CO3, 18-crown-6, in DMF, 100 ꢁC, 48 h; (ii) MeSO2Cl, Et3N, in
dichloromethane, 0 ꢁC, 1 h to give 8; 20 ꢁC, 45 min for 13; (iii) NaN3, DMF, 80 ꢁC, 16 h for 9; 100 ꢁC for 14; (iv) H2 10% Pd–C, EtOH, 20 ꢁC; (v) 1:1
10 M HCl/MeOH, 20 ꢁC, 16 h; (vi) 6, KHCO3, KI (cat.), 18-crown-6 (cat.) in DMF, 100 ꢁC, 48 h; (vii) LiN3, DMF, 80 ꢁC, 48 h; (viii) H2 (1 atm),
10% Pd–C, ethanol, 20 ꢁC; (ix) 1:1 hydrochloric acid (10 M)/methanol, 20 ꢁC; then Me2NEt, ꢀ20 to 20 ꢁC.
the lone pair of the amino group acting as an acceptor,
the two hydrogen atoms being available as donors;
whereas for an alcohol, the two lone pairs can be
acceptors but only one donor (the hydrogen atom) is
available.3,8 Thus, in a 1:1 stoichiometry of the cyclo-
hexane-1,2-diamine with trans-1,2-cyclohexanediol, the
donor–acceptor ratio is balanced, and a stable adduct
could be expected in the absence of other factors, includ-
ing adverse stereochemistry.
of extended zig-zag (or herring-bone) sheets, with the
sheets being stacked in parallel layers, which are
bound by means of two weaker, inter-layer, hydrogen
˚
bonds (O2ꢁ ꢁ ꢁC1, C7ꢁ ꢁ ꢁO4 = 2.4209(3) and 2.5442(2) A,
respectively).
The above considerations of donor:acceptor ratios
imply that the 1:1 amine/alcohol complementarity exists
in diamino diol 16, assuming that the tertiary nitrogen
atoms are not engaged in hydrogen bonding. Such com-
plementarity is observed in the 1:1 adduct of racemic
trans-1,2-cyclohexanediol with (1R,2R)-(ꢀ)-cyclohex-
ane-1,2-diamine,7,8 and by analogy the diamino diol 16
might align in a head-to-tail assembly. However, 16
was obtained as an oil, which resisted several attempts
at crystallisation. The cis-3,4-amino alcohol units of 22
could also participate in an ordered network of hydro-
gen bonding;20 but again, 22 could not be obtained in
crystalline form.
Such analysis would be expedited by the knowledge of
the tertiary amine–alcohol interactions in the symmetri-
cal tetraol 1a. Crystallisation of 1a from methanol–chlo-
roform by slow diffusion afforded rhombic needles
whose structure was determined by single crystal X-ray
diffraction18 (Fig. 2). The trans-disposition of the two
hydroxy groups appended to pyrrolidine rings in enve-
lope conformations is apparent.
An interesting supramolecular architecture was observed
(Fig. 3), in which a strong hydrogen-bonding array19
is formed between the alcohol moieties [O1ꢁ ꢁ ꢁO2,
3. Conclusions
˚
and O3ꢁ ꢁ ꢁO4 = 1.9514(4) A] in addition to a single,
slightly weaker, alcohol–amine interaction [O1ꢁ ꢁ ꢁN1 =
Enantiopure 1,10-ethylenedipyrrolidines possessing 3,4-
disubstitution have been prepared from esters of
˚
2.0031(5) A]. This produces a two-dimensional network

2802
C. M. Marson et al. / Tetrahedron: Asymmetry 16 (2005) 2799–2809
OH
O
OMs
i
ii
MsO
O
S
OMs
OMs
O
OH
17
19
18
N3
O
O
O
O
iv
iii
OMs
MsO
S
OMs
OMs
OH
20
HO
HO
N3
NH2
OH
v
N
N
N
N
N3
H2N
OH
22
21
N3
O
NH2
MeO
HO
OMe
OH
O
OMEM
OMEM
23
24
Scheme 3. Reagents and conditions: (i) SOCl2, cat. DMF in dichloromethane, 20 ꢁC; (ii) NaIO4, cat. RuO2 in 2:1 MeCN/H2O; (iii) NaN3, acetone,
25 ꢁC; subsequent addition of 1:1 2 M aq H2SO4/ether; (iv) ethylenediamine, KHCO3, 18-crown-6 (cat.) in DMF, 100 ꢁC; (v) H2 (1 atm), 10% Pd–C,
ethanol, 20 ꢁC.
Figure 2. ORTEP structure of (3S,3S0,4S,4S0)-1,10-ethylenedipyrrolidine-3,30,4,40-tetraol 1a.
L-(+)-tartaric acid. Diacylation routes via the diacetoxy-
pyrrolidin-2,5-diones were problematic, but N,N-dialky-
lation protocols proved to be reliable and enabled the
synthesis of one tetraol and two diamino diol systems,
each containing the 1,10-ethylenedipyrrolidine frame-
work. Previous studies have shown that molecular
recognition between amino and hydroxy groups in
different compounds is possible. Herein, an unusual
example of pre-organisation between amino and hydroxy
groups in the same molecule has been presented. Such
studies suggest that other non-planar and hydroxylated
N-heterocycles may possess interesting features of
pre-organisation, and of possible relevance to related
natural products and transformations by enzymes.
ium-backed silica gel plates, visualised by UV illumina-
tion or iodine vapour, or developed by charring with
one of: (a) 5% anisaldehyde in ethanol/acetic acid/sulfu-
ric acid (95:5:1 by volume), (b) 2% vanillin in ethanol/
sulfuric acid (98:2), (c) 1% potassium permanganate in
aqueous 0.5 M potassium carbonate or (d) 2.0 M sulfu-
ric acid saturated with cerium(IV) sulfate. Flash column
chromatography was performed on alumina (Merck 90,
63–200 lm; 60G neutral type E) or silica gel (Merck 40–
63 lm, 230–400 mesh). Melting points were determined
on a Reichert hot stage apparatus and are uncorrected.
Optical rotations were recorded on an Optical activity
AA-100 digital polarimeter using the sodium-D line.
1H NMR spectra were recorded at 250 MHz while 13C
NMR spectra were recorded at 62 MHz, both in CDCl3
and on a Bruker AM 250 instrument unless otherwise
stated, using tetramethylsilane as the internal standard.
19F NMR spectra were observed on 1H channel de-tune
(heteronuclear probe) and were recorded at 565 MHz on
4. Experimental
4.1. General
1
a Bruker AMX 600 instrument, or were assigned as H
Analytical thin-layer chromatography (TLC) was
performed on Merck 0.25 mm thick pre-coated, alumin-
coupled or 1H decoupled at 376 MHz. 19F chemical shift
values are expressed in parts per million relative to inter-

C. M. Marson et al. / Tetrahedron: Asymmetry 16 (2005) 2799–2809
2803
stirring continued at that temperature for 48 h under
an atmosphere of dry nitrogen. Addition of 40–60 ꢁC
petroleum ether (100 mL), filtration and evaporation
gave a residue that was adsorbed onto silica gel and
the impregnated dispersion was applied to the top of a
pre-packed column of silica gel, which was eluted with
1:1 ethyl acetate/40–60 ꢁC petroleum ether to give 2
(1.48 g, 17%) as a buff solid, mp 154–158 ꢁC. An analyt-
ical sample crystallised from benzene as colourless
30
needles, mp 163–164 ꢁC; ½aꢂD ¼ þ70.1 (c 0.95, chloro-
form); IR mmax (KBr) 3020, 2970, 2930, 1750, 1730
1
(C@O) cmꢀ1; H NMR d 5.55 (4H, s, CHOAc), 3.86
(4H, dt, J 18.0, 9.0 Hz, CH2CH2) 2.19 (12H, s, OAc);
13C NMR d 169.7 (COCH3), 169.6 (NCO), 72.5
(CHOAc), 37.2 (CH2CH2), 20.3 (COCH3); LRMSFAB
m/e (rel. intensity %; +ve m-NO2C6H5CO2H MATRIX)
457 ([M+H]+, 19), 415 (27), 397 (22), 373 (28), 331 (19),
218 (100), 204 (30). HRMSFAB Calcd for C18H21N2O12
[M+H]+ 457.1094. Found: 457.1088. Anal. Calcd for
C18H20N2O12: C, 47.37; H, 4.42; N, 6.14. Found: C,
47.26; H, 4.22; N, 6.01.
4.1.2. General procedure A: (2S,3S)-2,3-bis(methoxy-
methyloxy)-4-methylsulfonyloxy-butylmethanesulfonate 6.
To a stirred solution of (2R,3R)-2,3-bis(methoxymethyl-
oxy)butane-1,4-diol 58 (15.0 g, 71.4 mmol) and triethyl-
amine (18.1 g, 179 mmol) in dry dichloromethane
(200 mL) at 0 ꢁC under an atmosphere of dry nitrogen
was added dropwise a solution of methanesulfonyl chlo-
ride (20.5 g, 179 mol) in dry dichloromethane (45 mL),
using a double-tipped stainless steel needle. The mixture
was stirred at 0 ꢁC under an atmosphere of dry nitrogen
for 1 h, then quenched by addition of water (50 mL),
and the organic layer was separated and retained. The
aqueous layer was extracted with dichloromethane
(3·40 mL). The combined dichloromethane extracts
were washed sequentially with 50 mL portions of water,
4 M hydrochloric acid and lastly saturated aqueous so-
dium hydrogen carbonate. The original organic layer
was combined with the dichloromethane extracts and
the whole washed with brine (2·50 mL) and dried over
MgSO4. The solution was filtered through a sintered
glass funnel and the filtrate evaporated. The residue
was adsorbed onto neutral alumina and the impregnated
dispersion was applied to the top of a pre-packed column
of silica gel and eluted with ethyl acetate/40–60 ꢁC petro-
leum ether (gradient elution: 1:1 to 1:0). The appropriate
fractions were combined, filtered through a glass wool
plug and evaporated to give 6 (12.8 g, 49%) as a pale
yellow oil. An analytical sample was obtained by low-
Figure 3. The hydrogen bonded supramolecular architecture of
(3S,3S0,4S,4S0)-1,10-ethylenedipyrrolidine-3,30,4,40-tetraol 1a.
nal trichlorofluoromethane. Infra red spectra were re-
corded as KBr plates, chloroform solution or neat as li-
quid films. Mass spectra were obtained either as electron
impact (HRMSEI) or fast atom bombardment
(HRMSFAB) in a m-nitrobenzoic acid (+Na) matrix.
All reactions were performed under an atmosphere of
dry nitrogen except for those reactions conducted in
aqueous media. Solvents were rigorously dried and puri-
fied prior to use. Solvents were transferred via cannula-
tion (stainless steel double-tipped needle) under positive
atmospheric pressure. Evaporation of solvent refers to
removal under reduced pressure.
The following compounds were prepared according to
the literature procedures: (3R,4R)-3,4-diacetoxypyrrol-
idin-2,5-dione;11 diethyl (2R,3R)-2,3-bis(methoxymeth-
yloxy)butanedioate 4;13 (2S,3S)-2,3-bis(methoxymeth-
yloxy)butane-1,4-diol 5;13 (2S,3S)-1,4-bis(methanesul-
fonyloxy)butane-2,3-diol 17;17 (4S,5S)-4,5-bis[methyl-
(methanesulfonyloxy)]-2-oxo-1,2,3-thiolane 18.16
temperature recrystallisation (ꢀ35 ꢁC) from chloroform
27
giving 6 as needles, mp 89.5–90 ꢁC; ½aꢂD ¼ þ10.4 (c
0.25, chloroform); IR mmax (KBr) 2940, 2900, 1350
1
4.1.1. (3R,30R,4R,40R)-3,30,4,40-Tetrakis(acetoxy)-1,10-
(S@O) cmꢀ1; H NMR d 4.74 (2H, d, J 7.0 Hz, OCH-
ethylenedipyrrolidine-2,20,5,50-dione 2. To
a
stirred
HO), 4.70 (2H, d, J 7.0 Hz, OCHHO), 4.41 (2H, dd, J
10.0, 5.0 Hz, CHHOMs), 4.30 (2H, dd, J 10.0, 5.0 Hz,
CHHOMs), 4.02 (2H, t, J 5.0 Hz, OCH), 3.38 (6H, s,
OMe), 3.04 (6H, s, SO2Me); 13C NMR d 97.4 (OCH2O),
75.0 (CH2OMs), 68.1 (CH), 56.2 (OMe), 37.5 (SO2Me);
LRMSEI m/e (rel. intensity %) 289 [C7H13O8S2,
M+ꢀC3H9O2, (3)], 289 (4), 185 (5), 151 (8), 98 (7), 85
(47) and 45 (100); HRMSEI Calcd for C7H13O8S2
(M+ꢀC3H9O2) 289.0052. Found: 289.0038.
solution of (3R,4R)-3,4-diacetoxypyrrolidin-2,5-dione11
(8.0 g, 37.2 mmol), triphenylphosphine (12.2 g, 46.5
mmol) and ethylene glycol (1.15 g, 18.6 mmol) in dry
benzene (100 mL) at 0 ꢁC under an atmosphere of dry
nitrogen was added dropwise a solution of diethylazido
dicarboxylate, (9.71 g, 55.8 mmol) in dry benzene
(15 mL) using a stainless steel, double-tipped needle.
The mixture was allowed to warm slowly to 20 ꢁC and

2804
C. M. Marson et al. / Tetrahedron: Asymmetry 16 (2005) 2799–2809
4.1.3. General procedure B: (3S,3S0,4S,4S0)-3,30,4,40-tetra-
kis(methoxymethyloxy)-1,10-ethylenedipyrrolidine 1c. To
a stirred suspension of the methanesulfonate 6 (10.0 g,
27.3 mmol), potassium carbonate (11.3 g, 82.0 mmol),
18-crown-6 (0.72 g, 2.73 mmol) and potassium iodide
(0.45 g, 2.73 mmol) in dry DMF (150 mL) at ꢀ10 ꢁC
under an atmosphere of dry nitrogen was added via a
syringe a solution of ethylenediamine (0.91 mL, 0.82 g,
13.7 mmol) in dry triethylamine (3 mL). The mixture
was heated slowly to 100 ꢁC and stirred at that temper-
ature for 48 h under an atmosphere of dry nitrogen. The
DMF was removed by distillation under reduced pres-
sure and the residue was suspended in saturated aqueous
ammonium chloride (150 mL) and the mixture continu-
ously extracted with 3:1 ethyl acetate/2-butanone for
80 h. The organic layer was dried over K2CO3, filtered
through a sintered glass funnel and the filtrate evapo-
rated. The residue was adsorbed onto neutral alumina
and the impregnated dispersion was applied to the top
of a pre-packed silica gel column and eluted with 99:1
chloroform/methanol to give 1c (2.4 g, 22%) as a colour-
less syrup. An analytical sample was obtained by pre-
parative silica plate thin-layer chromatography (two
plate elutions at 20 ꢁC with 99:1 chloroform/acetoni-
trile). The appropriate band was excised and extracted
with methanol, filtered through a sintered glass micro-
funnel and the filtrate was evaporated under reduced
pressure and the residue redissolved in chloroform. This
solution was filtered through a fluted paper and the fil-
methanol/0.880 aqueous ammonia. The appropriate
fractions were filtered and evaporated to give 1a
(0.70 g, 55%) as a yellow oil that slowly solidified upon
standing. An analytical sample was obtained by prepara-
tive silica plate thin-layer chromatography (three plate
elutions with 9:1 methanol/acetonitrile at 5 ꢁC in the
dark; extraction and isolation as in General procedure
B) to give 1a as a white amorphous solid, mp 164–
166 ꢁC. Recrystallisation from methanol by the slow dif-
fusion of chloroform vapour at 5 ꢁC gave 1a as long
30
white needles, mp 168 ꢁC; ½aꢂD ¼ þ15.4 (c 0.35, metha-
1
nol); IR mmax (KBr) 3320 (OH), 2930, 2820 cmꢀ1; H
NMR (CD3OD) d 4.79 (4H, s, CHOH), 3.98 (4H, t, J
6.0, 4.5 Hz, CHOH), 2.93 (4H, dd, J 10.0, 6.0 Hz,
NCHH), 2.58 (4H, m, CH2CH2), 2.50 (4H, dd, J
10.0, 4.5 Hz, NCHH); 13C NMR (CD3OD) d 79.0
(CHOH), 61.9 (NCH2), 56.0 (CH2CH2); LRMSEI m/e
(rel. intensity %) 119 (24), 117 (87), 116 (100). HRMSEI
Calcd for C10H17N2O2 (M+ꢀH3O2) 197.1290. Found:
197.1279.
4.1.5. (3S,4S)-1-(2-Hydroxyethyl)-3,4-bis(methoxymeth-
yloxy)pyrrolidine 7. To a stirred suspension of the
methanesulfonate 6 (13.0 g, 35.5 mmol), potassium car-
bonate (14.7 g, 107 mmol), 18-crown-6 (0.89 mg,
3.5 mmol) and potassium iodide (0.59 g, 3.5 mmol) in
dry DMF (120 mL) at ꢀ10 ꢁC under an atmosphere of
dry nitrogen was added via a syringe a solution of etha-
nolamine (2.14 mL, 2.16 g, 35.5 mmol) in dry triethyl-
amine (3 mL). The mixture was slowly heated with
stirring to 100 ꢁC and maintained at that temperature
for 48 h under an atmosphere of dry nitrogen. Removal
of DMF, extraction and work-up as in General proce-
dure B gave a gum that was purified by short-path dis-
tillation (bp 190–196 ꢁC/1.2 mmHg). The resulting
glassy solid was adsorbed onto neutral alumina and
the impregnated dispersion applied to the top of a pre-
packed silica gel column and eluted with 49:1 chloro-
form/methanol to give 7 (4.76 g, 57%) as a yellow
gum. An analytical sample was obtained by preparative
silica plate thin-layer chromatography (two plate elu-
trate was evaporated to give 1c as a colourless syrup;
30
½aꢂD ¼ ꢀ10.6 (c 0.15, chloroform); IR mmax (film) 2940,
2890, 2825, 1450 cmꢀ1 1H NMR d 4.70 (4H, d, J
;
6.5 Hz, OCHH), 4.64 (4H, d, J 6.5 Hz, OCHH), 4.13
(4H, t, J 5.0 Hz, OCH), 3.39 (12H, s, OMe), 3.00 (4H,
m, NCHH), 2.67 (4H, s, CH2CH2) and 2.62 (4H, m,
NCHH); 13C NMR d 95.8 (OCH2O), 81.2 (OCH),
59.2 (NCH2), 55.6 (OMe), 54.6 (CH2CH2); LRMSEI
m/e (rel. intensity %) 233 [C17H33N2O7, M+ꢀCH3O
(3)], 285 (15), 204 (85), 82 (7.6), 45 (100), 145 (66), 137
(33), 117 (46). HRMSEI Calcd for C17H33N2O7
(M+ꢀCH3O) 377.2288. Found: 377.2278.
4.1.4. (3S,3S0,4S,4S0)-1,10-Ethylenedipyrrolidine-3,30,4,40-
tetraol 1a. To a stirred suspension of pyrrolidine 1c
(2.20 g, 5.45 mmol) in methanol (10 mL) at 0 ꢁC under
an atmosphere of nitrogen was added dropwise concen-
trated hydrochloric acid (10 mL, 10 M). The mixture
was allowed to warm slowly to 20 ꢁC and stirred at that
temperature for 48 h under an atmosphere of dry nitro-
gen. Evaporation gave a residue that was made basic
by the addition of N,N-dimethylethylamine (CAU-
TION) at ꢀ20 ꢁC under an atmosphere of nitrogen with
stirring. The mixture was allowed to warm slowly to
20 ꢁC and the digestion continued for 2 h under an atmo-
sphere of nitrogen. Evaporation gave a residue that was
suspended in saturated aqueous ammonium chloride
(70 mL) and the mixture continuously extracted with
3:1 chloroform/THF for 80 h under an atmosphere of
nitrogen. The organic layer was dried over K2CO3, fil-
tered through a sintered glass funnel and the filtrate evap-
orated. The residue was adsorbed onto neutral alumina
and the impregnated dispersion was applied to the top
of a pre-packed silica gel column and eluted with 99:1
tions with chloroform and isolation as described in Gen-
31
eral procedure B) to give 7 as a viscous oil; ½aꢂD ¼ ꢀ0.8
(c 0.5, methanol); IR mmax (film) 3420 (OH), 2940,
2890 cmꢀ1; 1H NMR d 4.64 (2H, d, J 7.5 Hz, OCHHO),
4.58 (2H, d, J 7.5 Hz, OCHHO), 4.07 (2H, J 4.0 Hz,
OCH), 3.56 (2H, t, J 5.5 Hz, NCH2CH2), 3.30 (6H, s,
OMe), 2.92 (2H, dd, J 10.0, 7.0 Hz, NCHH), 2.7 (1H,
br, CH2OH), 2.56 (2H, m, NCH2CH2 and 2H, dd, J
11.0, 5.0 Hz, NCHH); 13C NMR d 95.8 (OCH2O),
81.5 (OCH), 59.7 (NCH2CH2), 58.7 (NCH2CHO), 57.8
(NCH2CH2), 55.5 (OMe); LRMSEI m/e (rel. intensity
%) 235 (M+, 1.1), 206 (10), 204 (100), 160 (4), 86 (5),
45 (65). HRMSEI exact mass calcd for C10H21NO5
(M+) 235.1420. Found: 235.1420.
4.1.6. Procedure C: (3S,4S)-1-[2-(methanesulfonyloxy)-
ethyl]-3,4-bis(methoxymethyloxy)pyrrolidine 8. To
a
stirred solution of pyrrolidine 7 (25.6 g, 109 mmol) and
triethylamine (16.6 g, 164 mmol) in 200 mL of anhy-
drous dichloromethane at ꢀ30 ꢁC under an atmosphere
of dry nitrogen was added dropwise a solution of meth-
anesulfonyl chloride (18.8 g, 164 mmol) in 50 mL of dry

C. M. Marson et al. / Tetrahedron: Asymmetry 16 (2005) 2799–2809
2805
dichloromethane using a stainless steel double-tipped
needle. The mixture was allowed to warm slowly to
0 ꢁC and stirring continued at that temperature for 1 h
under an atmosphere of dry nitrogen. The mixture was
quenched by addition of water (100 mL) and the organic
layer was separated and retained. The aqueous layer was
extracted with dichloromethane (2·50 mL). The com-
bined dichloromethane extracts were washed sequen-
tially with 50 mL portions of water, aqueous 2 M citric
acid and then saturated aqueous sodium hydrogen car-
bonate. The original organic layer was combined with
the dichloromethane extracts and the solution was
washed with brine (2·50 mL) and dried over MgSO4.
The solution was filtered through a sintered glass funnel
and the filtrate evaporated. The residue was adsorbed
onto neutral alumina and the impregnated dispersion
was applied to the top of a pre-packed column of silica
gel and eluted in the dark with 9:1 ethyl acetate/40–
60 ꢁC petroleum ether pre-cooled to 5 ꢁC. The appropri-
ate fractions were combined, filtered through a glass
wool plug and the eluent evaporated to give 8 (15.7 g,
46%) as a dark solid. An analytical sample was obtained
by preparative silica plate thin-layer chromatography
(with toluene at 5 ꢁC in the dark followed by extraction
and isolation as in General procedure B) to give 8 as
an oil. For spectral analysis, this material was dissolved
with diethyl ether (3·50 mL). The combined organic
layers were washed with brine (2·50 mL) and dried over
MgSO4. The solution was filtered through a sintered
glass funnel and the filtrate was evaporated. The residue
was adsorbed onto neutral alumina and the impregnated
dispersion was applied to the top of a pre-packed
column of silica gel and eluted with 1:1 diethyl ether/
40–60 ꢁC petroleum ether. The appropriate fractions
were combined, filtered through a glass wool plug and
the eluent was evaporated under reduced pressure to
32
give 9 (7.0 g, 54%); ½aꢂD ¼ þ1.9 (c 2.1, chloroform); IR
mmax (film) 2935, 2890, 2800, 2100 (azide), 1470 cmꢀ1
;
1H NMR d 4.72 (2H, d, J 6.5 Hz, OCHHO), 4.65 (2H,
d, J 6.5 Hz, OCHHO), 4.15 (2H, dt, J 4.5, 1.5 Hz,
OCH), 3.39 (6H, s, OMe), 3.39 (2H, t, J 2.5 Hz,
NCH2CH2), 3.01 (2H, dd, J 9.5, 5.5 Hz, NCHH), 2.71
(2H, m, NCH2CH2), 2.63 (2H, dd, J 9.5, 4.5 Hz,
NCHH); 13C NMR d 95.8 (OCH2O), 81.4 (OCH),
59.0 (NCH2CHO), 55.5 (OMe), 54.8 (NCH2CH2), 49.8
(NCH2CH2); LRMSEI m/e (rel. intensity %) 261
([M+H]+, 12), 261 (M+, 3), 204 (100), 160 (10), 99
(24), 82 (50). HRMSEI Calcd for C10H20N4O4 (M+)
260.1485. Found: 260.1494.
4.1.8. Procedure D: (3S,4S)-1-(2-aminoethyl)-3,4-bis-
(methoxymethyloxy)pyrrolidine 10. To a three-necked
100 mL flask equipped with a two-way vacuum tap,
rubber septum and magnetic stirring bar were added
pyrrolidine 9 (6.88 g, 26.5 mmol), ethanol (50 mL) and
10% palladium on carbon (2.0 g). The vessel was cooled
to 0 ꢁC, evacuated to 15 mmHg and purged with a
hydrogen at positive atmospheric pressure. Following
three successive cycles of evacuation-purging the vessel
was allowed to warm to 20 ꢁC and stirring was contin-
ued for 16 h at that temperature under fresh hydrogen
at positive atmospheric pressure. (Monitoring by IR
spectroscopy showed the absence of mmax 2100 cmꢀ1
azide stretch). The mixture was filtered through a fluted
paper and washed with ethanol (4·5 mL). The filtrates
were evaporated and the residue was adsorbed onto neu-
tral alumina. The impregnated dispersion was applied to
the top of a pre-packed flash column of silica gel and
eluted with 199:1 methanol/0.880 aqueous ammonia.
The appropriate fractions were combined, filtered
through a fluted paper and the eluent was evaporated.
The residue was dissolved in THF (50 mL) and dried
over K2CO3. The solution was filtered through a fluted
paper and evaporated to give 10 (5.1 g, 82%) as a pale
yellow oil. An analytical sample was obtained by pre-
parative silica plate thin-layer chromatography (with
99:1 acetonitrile/0.880 aqueous ammonia followed by
in C6D6 and passed rapidly through a Pasteur pipette
30
containing 2 cm of alumina; ½aꢂD ¼ þ10.8 (c 0.5,
C6D6); IR mmax (film) 2940, 2900, 2830, 1445, 1350 (asym-
1
metric S@O), (symmetric S@O) 1150 cmꢀ1; H NMR
(C6D6) d 4.59 (2H, d, J 6.5 Hz, OCHHO), 4.49 (2H, d,
J 6.5 Hz, OCHHO), 4.14 (2H, q, J 11.0, 5.0 Hz, OCH),
3.22 (6H, s, OMe), 2.89 (2H, dd, J 11.0, 5.0 Hz, NCHH),
2.81 (2H, t, NCH2CH2), 2.66 (3H, s, SO2Me), 2.61 (2H,
m, NCHH), 2.54 (2H, m, NCH2CH2); 13C NMR (C6D6)
d 96.6 (OCH2O), 82.1 (OCH), 72.6 (NCH2CH2), 68.6
(NCH2CH2), 59.4 (NCH2CHO), 55.9 (OMe), 37.9
(SO2Me); LRMSEI m/e (rel. intensity %) 313 (M+, 3),
303 (13), 218 (100), 204 (39), 188 (7), 174 (15), 160 (7)
and 130 (7).
CAUTION: All reactions employing azides were con-
ducted in a fume-hood with a lowered sash and a rein-
forced blast-shield. Where it was necessary to conduct
certain azide displacements on a multigram scale, the
appropriate precautions necessary for large scale work-
ing with explosive reagents were observed. Caution must
also be exercised when recording melting points because
detonation sometimes occurs.
4.1.7. (3S,4S)-1-(2-Azidoethyl)-3,4-bis(methoxymethyloxy)-
pyrrolidine 9. To a stirred solution of pyrrolidine 8
(15.6 g, 49.8 mmol) in dry dimethylformamide (60 mL)
at 20 ꢁC under an atmosphere of dry nitrogen was added
sodium azide (6.47 g, 99.6 mmol; CAUTION) using a
solid-addition funnel equipped with a side-arm. The
mixture was slowly heated (CAUTION) to 80 ꢁC and
stirring continued for 16 h at 80 ꢁC (CAUTION) under
an atmosphere of dry nitrogen. DMF was then removed
by co-evaporation under reduced pressure with toluene
(50 mL, repeated twice) at 20 ꢁC. The residue was parti-
tioned with water (90 mL) and ethyl acetate (100 mL),
the layers separated and the aqueous layer extracted
extraction and isolation as in General procedure B) to
33
give 10 as an oil; ½aꢂD ¼ þ2.0 (c 1.4, chloroform); IR
mmax (film) 3420 (NH), 2935, 2895, 2825 cmꢀ1 1H
;
NMR d 4.74 (2H, d, J 6.5 Hz, OCHHO), 4.65 (2H, d,
J 6.5 Hz, OCHHO), 4.13 (2H, t, J 4.2 Hz, OCH), 3.38
(6H, s, OMe), 2.95 (2H, dd, J 9.5, 6.0 Hz, NCHH),
2.81 (2H, t, J 6.5 Hz, NCH2CH2), 2.57 (2H, dd, J
10.0, 4.5 Hz, NCHH), 2.56 (2H, m, NCH2CH2), 1.90
(2H, br s, CH2NH2); 13C NMR d 95.7 (OCH2O), 81.5
(OCH), 58.9 (OCHCH2N and NCH2CH2), 55.4
(OMe), 40.2 (NCH2CH2); LRMSEI m/e (rel. intensity
%) 235 ([M+H]+, 14), 218 (6), 204 (100), 160 (9), 111

2806
C. M. Marson et al. / Tetrahedron: Asymmetry 16 (2005) 2799–2809
(6), 98 (15), 82 (27), 68 (15). HRMSEI Calcd for
C10H22N2O4 (M+) 234.1580. Found: 234.1588.
neutral alumina and the impregnated dispersion applied
to the top of a pre-packed flash column of silica gel and
eluted with 7:3 chloroform/methanol. The appropriate
fractions were combined, filtered and evaporated. To
the residue was added dichloromethane and the solution
was filtered through a fluted paper and evaporated to
give 12 (1.05 g, 31%) as an oil. An analytical sample
was obtained by preparative silica plate thin-layer chro-
matography (five plate elutions with 19:1 chloroform/
methanol followed by extraction and isolation as in
4.1.9. (3S,4S)-1-(2-Aminoethyl)pyrrolidine-3,4-diol 11.
Hydrochloric acid (25 mL, 10 M) was added dropwise
to a stirred solution of 10 (5.0 g, 21.4 mmol) in methanol
(25 mL) at 0 ꢁC under an atmosphere of nitrogen. The
mixture was allowed to warm slowly to 20 ꢁC with stir-
ring for 16 h under an atmosphere of nitrogen. Evapora-
tion gave a residue that was made alkaline with 4 M
potassium hydroxide in methanol (4 M, CAUTION)
at 0 ꢁC while stirring under an atmosphere of nitrogen.
The mixture was allowed to warm slowly to 20 ꢁC with
stirring for 2 h under an atmosphere of nitrogen. Evap-
oration gave a residue that was suspended in saturated
aqueous ammonium chloride (45 mL) and then continu-
ously extracted with chloroform for 96 h under an atmo-
sphere of nitrogen. The organic layer was dried over
K2CO3, filtered and evaporated. Fractional distillation
of the residue at 160–180 ꢁC/2.0 mmHg gave an oil that
was adsorbed onto neutral alumina and the impregnated
dispersion applied to the top of a pre-packed flash col-
umn of silica gel and eluted with 1:49 0.880 ammonia/
methanol. The appropriate fractions were combined, fil-
tered and evaporated. The residue was dissolved in THF
(45 mL) and dried over K2CO3. Filtration and evapora-
tion gave 11 (1.59 g, 10.9 mmol, 51%) as an oil. An
analytical sample was obtained by preparative alumina
thin-layer chromatography (with methanol at 5 ꢁC in the
dark over 16 h followed by extraction and isolation as
General procedure B) to give 12 as a clear oil;
32
½aꢂD ¼ þ14.7 (c 0.18, chloroform); IR mmax (film) 3365
(OH), 2900, 2825 cmꢀ1 1H NMR d 4.72 (2H, d, J
;
6.5 Hz, OCHHO), 4.65 (2H, d, J 6.5 Hz, OCHHO),
4.22 (2H, m, CHOMOM), 4.15 (2H, m, CHOH), 3.82
(2H, br s, CHOH), 3.39 (6H, s, OMe), 3.19 (2H, dd, J
10.0, 5.0 Hz, NCHH), 3.02 (2H, dd, J 10.0, 5.0 Hz,
NCHH), 2.70 (8H, br m, N0CH2·2 and NCH2CH2N0);
13C NMR d 95.8 (OCH2), 81.0 (CHOH), 77.3 (CHO-
MOM), 60.2 (MOM/CH2N), 59.0 (HO/CH2N), 55.7
(OMe), 53.8 (CH2CH2); LRMSFAB m/e (rel. intensity
%; +ve m-NO2C6H5CO2H MATRIX) 321 ([M+H]+,
100), 303 (46), 278 (83), 218 (46), 204 (35) 174 (10),
130 (66), 116 (31). HRMSFAB Calcd for C14H29N2O6
[M+H]+ 321.2026. Found: 321.2032.
4.1.11. (3S,30S,4S,40S)-3,4-Bis(methanesulfonyloxy)-30,40-
bis-(methoxymethyloxy)-1,10-ethylenedipyrrolidine 13. To
a stirred solution of pyrrolidine-3,4-diol 12 (1.02 g,
3.19 mmol) and triethylamine (0.97 g, 9.6 mmol) in dry
dichloromethane (40 mL) at 0 ꢁC under an atmosphere
of dry nitrogen was added dropwise a solution of meth-
anesulfonyl chloride (1.10 g, 9.57 mmol) in dichloro-
methane (15 mL) using a stainless steel double-tipped
needle. The mixture was allowed to warm slowly to
20 ꢁC and stirring was continued for 45 min at that tem-
perature under an atmosphere of dry nitrogen. The mix-
ture was quenched by the addition of water (35 mL),
and worked up and the residue purified by column chro-
matography as in General procedure C but using 19:1
chloroform/methanol to give 13 (0.70 g, 46%) as a
wax. An analytical sample was obtained by preparative
silica plate thin-layer chromatography (four plate elu-
in General procedure B) to give 11 as an opaque, waxy
33
solid; ½aꢂD ¼ þ22.2 (c 7.1, methanol); IR mmax (film)
1
3298, 2935, 2820 cmꢀ1; H NMR (250 MHz, CD3OD)
d 4.82 (4H, br s, CHOH·2, CH2NH2), 4.00 (2H, m,
CHOH), 2.93 (2H, dd, J 10.5, 6.0 Hz, NCHH), 2.70
(2H, t, J 6.5 Hz, CH2NH2), 2.53 (2H, m, NCH2CH2-
NH2), 2.47 (2H, dd, J 10.5, 5.0 Hz, NCHH); 13C
NMR d 79.1 (CHOH), 61.8 (NCH2CHOH), 53.7
(NCH2CH2NH2), 40.8 (NCH2CH2NH2); LRMSEI m/e
(rel. intensity %) 147 (75), 130 (44), 116 (100), 104
(20), 98 (10), 85 (8), 72 (12), 58 (14). LRMSFAB m/e
(rel. intensity %; +ve m-NO2C6H5CO2H MATRIX)
147 ([M+H]+, 100), 146 (M+, 4), 145 (45), 133 (5), 130
(21), 116 (41). HRMSFAB Calcd for C6H15N2O2
[M+H]+ 147.1134. Found: 147.1129.
tions with 199:1 chloroform/methanol at 20 ꢁC in the
33
dark) to give 13 as a clear wax; ½aꢂD ¼ þ26.2 (c 0.93,
4.1.10. (3S,30S,4S,40S)-30,40-Bis(methoxymethyloxy)-1,10-
ethylenedipyrrolidine-3,4-diol 12. To a stirred suspen-
chloroform); IR mmax (film) 2940, 2895, 2820, 1360
(asymmetric S@O), 1175 (symmetric S@O) cmꢀ1 1H
;
NMR d 5.14 (2H, t, J 3.5 Hz, MsOCH), 4.70 (2H, d, J
7.3 Hz, OCHHO), 4.64 (2H, d, J 7.3 Hz, OCHHO),
4.12 (2H, t, J 4.0 Hz, MOMOCH), 3.39 (6H, s, OMe),
3.15 (2H, dd, J 10.0, 6.0 Hz, Ms/CHHN), 3.10 (6H, s,
SO2Me), 2.96 (2H, dd, J 10.0, 6.0 Hz, MsCHHN),
2.82 (2H, dd, J 10.0, 4.0 Hz, MOM/CHHN), 2.62
(4H, m, CH2CH2), 2.57 (2H, dd, J 10.0, 4.0 Hz,
sion of methanesulfonate
6
(3.89 g, 10.6 mmol),
potassium hydrogen carbonate (3.19 g, 31.9 mmol), 18-
crown-6 (0.28 g, 1.1 mmol) and potassium iodide
(0.18 g, 1.1 mmol) in dry dimethylformamide (40 mL)
at 0 ꢁC under an atmosphere of dry nitrogen was added
via a syringe a solution of pyrrolidinediol 11 (1.55 g,
10.6 mmol) in dry triethylamine (2 mL) in one portion.
The mixture was allowed to warm slowly to 100 ꢁC
and stirring was continued for 48 h at that temperature
under an atmosphere of dry nitrogen. Removal of DMF
by vacuum distillation (45–60 ꢁC/2–3 mmHg), addition
of saturated aqueous ammonium chloride (35 mL) and
continuous extraction with ethyl acetate for 48 h gave
an organic layer that was dried over K2CO3, filtered
and evaporated to give a residue that was adsorbed onto
MOMCHHN); 13C NMR
d 95.8 (OCH2O), 82.4
(MsOCH), 81.4 (MOMOCH), 59.3 (Ms/CH2N), 58.6
(MOM/CH2N), 55.6 (OMe), 54.4 (NCH2CH2N0), 53.8
(NCH2CH2N0), 38.5 (SO2Me); LRMSFAB m/e (rel.
intensity %; +ve m-NO2C6H5CO2H MATRIX) 477
([M+H]+, 34), 476 (M+, 3), 286 (24), 272 (6), 218 (28)
204 (100), 174 (9). HRMSFAB Calcd for C16H33N2O10S2
[M+H]+ 477.1577. Found: 477.1569.

C. M. Marson et al. / Tetrahedron: Asymmetry 16 (2005) 2799–2809
2807
4.1.12. (3R,30S,4R,40S)-3,4-Diazido-30,40-bis(methoxy-
methyloxy)-1,10-ethylenedipyrrolidine 14. To a stirred
solution of dipyrrolidine 13 (0.69 g, 1.45 mmol) in dry
DMF (7 mL) at 20 ꢁC under an atmosphere of dry nitro-
gen was added portionwise lithium azide (0.706 g,
14.4 mmol; CAUTION) using a solid-addition funnel
equipped with a side-arm. The mixture was slowly
heated to 80 ꢁC (CAUTION) and stirring continued
for 48 h at 80 ꢁC (CAUTION) under an atmosphere of
dry nitrogen. Aqueous lithium chloride (25 mL, 2 M)
was added and the mixture was continuously extracted
with diethyl ether for 96 h. The organic layer was dried
over MgSO4, filtered and evaporated The crude product
was adsorbed onto silica gel and the impregnated disper-
sion applied to the top of a pre-packed flash column.
This material was purified by flash column chromatog-
raphy over silica gel (9:1 ethyl acetate/40–60 ꢁC petro-
leum ether) to give 14 (0.30 g, 56%) as a white powder,
mp 43 ꢁC. An analytical sample was obtained by pre-
parative silica plate thin-layer chromatography (three
plate elutions with 4:1 ethyl acetate/40–60 ꢁC petroleum
ether) to give a grey powder that was recrystallised from
Calcd for C14H30N4O4 [M+H]+ 319.2345. Found:
319.2335.
4.1.14. (3R,30S,4R,40S)-3,4-Diamino-1,10-ethylenedipyr-
rolidine-30,40-diol 16. To a stirred solution of 15
(0.152 g, 0.48 mmol) in methanol (2 mL) at 0 ꢁC concd
hydrochloric acid (2 mL, 10 M) was added dropwise.
The mixture was allowed to warm slowly to 20 ꢁC and
stirring continued at that temperature for 16 h. Evapora-
tion gave a residue that was made basic by the addition
of N,N-dimethylethylamine (CAUTION) at 0 ꢁC, which
was stirred for an additional 30 min under an atmo-
sphere of nitrogen. Evaporation gave a residue that
was adsorbed onto neutral alumina and the impregnated
dispersion then applied to the top of a pre-packed alu-
mina column and eluted with 9:1 water/0.880 aqueous
ammonia. The appropriate fractions were combined, fil-
tered and evaporated to give 16 (11 mg, 10%) as a brown
gum. An analytical sample was obtained by preparative
silica plate thin-layer chromatography (five plate elu-
tions with 19:1 0.880 aqueous ammonia/methanol eluted
at 5 ꢁC in the dark). Bands were continuously extracted
with THF for 24 h in a micro-soxhlet thimble. The or-
ganic extract was dried over KOH pellets, filtered and
evaporated to give 16 as an oil; IR mmax (thin film) 3355
chloroform by the slow diffusion of n-hexane vapour at
34
5 ꢁC to give 14 as prisms, mp 48–49 ꢁC; ½aꢂD ¼ ꢀ6.0 (c
0.2, chloroform); IR mmax (film) 2935, 2800, 2804, 2100
1
1
(azide) cmꢀ1; H NMR d 4.72 (2H, d, J 6.0 Hz, OCH-
(br, NH, OH), 1448, 1379 cmꢀ1; H NMR (250 MHz,
HO), 4.64 (2H, d, J 6.0 Hz, OCHHO), 4.12 (2H, t, J
4.0 Hz, MOMOCH), 3.86 (2H, t, J 3.6 Hz, N3CH),
3.38 (6H, s, OMe), 3.00 (4H, m, MOMOCHCH2),
2.62 (8H, m, N3CHCH2·2 and CH2CH2); 13C NMR
95.8 (OCH2O), 81.4 (MOMOCH), 65.7 (N3CH), 59.3
(MOMOCHCH2), 58.1 (N3CHCH2), 55.6 (OMe), 54.7
D2O) d 4.57 (2H, d, J 3.0 Hz, CHOH), 4.17 (2H, t,
J 5.0 Hz, CHNH2), 3.94 (2H, m, HOCHCHHN),
3.66 (4H, m, HOCHCHHN and N0CH2CH2N), 3.47
(2H, dd, J 10.0, 6.0 Hz, H2NCHCHHN), 3.18 (2H,
m, N0CH2CH2N), 3.00 (2H, dd, J 10.0, 4.0 Hz,
H2NCHCHHN); 13C NMR (150 MHz, D2O) d 77.2
(CHOH), 62.2 (H2NCH), 58.7 (HOCHCH2), 58.0
(H2NCHCH2), 56.2 (HO/NCH2CH2N), 51.4 (HO/
NCH2CH2N); LRMSFAB m/e (rel. intensity %; +ve m-
NO2C6H5CO2H MATRIX) 231 ([M+H]+, 74), 192
(37), 176 (43), 171 (35), 154 (70) 149 (100), 136 (77),
121 (19), 107 (46). HRMSFAB Calcd for C10H23N4O2
[M+H]+ 231.1821. Found: 231.1838.
(NCH2CH2N/MOM),
53.9
(NCH2CH2N/MOM);
LRMSFAB m/e (rel. intensity %; +ve m-NO2C6H5CO2H
MATRIX) 371 ([M+H]+, 100), 285 (18), 218 (28),
204 (67), 180 (15) 154 (17) and 136 (18). HRMSFAB
Calcd for C14H27N8O4 [M+H]+ 371.2155. Found:
371.2142.
4.1.13. (3R,30S,4R,40S)-3,4-Diamino-30,40-bis(methoxy-
methyloxy)-1,10-ethylenedipyrrolidine
15. Prepared
4.1.15. (4S,5S)-4,5-Bis[methyl(methanesulfonyloxy)]-2,2-
dioxo-1,2,3-thiolane 19. To a stirred solution of dime-
thanesulfonate 1816 (2.30 g, 7.10 mmol) and sodium
periodate (2.28 g, 10.7 mmol) in 5:3 acetonitrile/water
(60 mL) at 0 ꢁC was added ruthenium(IV) oxide
(15 mg, 0.11 mmol) followed by the portionwise addi-
tion of water (50 mL, kept near 0 ꢁC with ice) to control
the highly exothermic reaction. Stirring was continued
at 20 ꢁC for 2 h. The mixture was extracted with ethyl
acetate (60 mL), the organic layer separated and kept.
The aqueous layer was further with extracted ethyl ace-
tate (3·50 mL) and the combined organic layers (includ-
ing the originally separated layer) were washed with
brine (2·40 mL) and dried over MgSO4. The solution
was filtered, evaporated and the residue dissolved in
dichloromethane (minimum volume) and applied to
the top a column of silica gel. Flash chromatography
using 1:1 ethyl acetate/40–60 ꢁC petroleum ether affor-
ded 19 (1.04 g, 43%) as a grey powder, mp 89–91 ꢁC.
An analytical sample crystallised from 1:1 ethyl ace-
according to the General procedure D, using dipyrrol-
idine 14 (0.277 g, 0.75 mmol) with purification by flash
column chromatography on silica gel (49:1 methanol/
0.88 aqueous ammonia) to give a residue that was dis-
solved in dry THF (20 mL) and the solution stirred over
KOH pellets, filtered and evaporated to give 14 (0.174 g,
73%) as a yellow oil. An analytical sample was obtained
by preparative silica plate thin-layer chromatography
(three plate elutions with 99:1 methanol/0.88 aqueous
ammonia at 20 ꢁC in the dark) to give 15 as a clear oil
33
that turned cloudy on exposure to air; ½aꢂD ¼ ꢀ9.7 (c
1.1, chloroform); IR mmax (KBr) 3340 (asymmetric
NH), 3290 (symmetric NH), 2930, 2895, 2820 cmꢀ1
;
1H NMR d 4.70 (2H, d, J 6.5 Hz, OCHHO), 4.62 (2H,
d, J 6.5 Hz, OCHHO), 4.11 (2H, m, MOMOCH), 3.35
(6H, s, OMe), 3.20–2.30 (18H, m); 13C NMR
(150 MHz, CDCl3) d 95.6 (OCH2O), 81.2 (MOMOCH),
61.3
(H2NCH),
59.5
(MOMOCHCH2),
59.1
(H2NCHCH2), 55.6 (OMe), 54.5 (NCH2CH2N0), 54.1
(NCH2CH2N0); LRMSFAB m/e (rel. intensity %; +ve
m-NO2C6H5CO2H MATRIX) 319 ([M+H]+, 28), 235
(10), 218 (65), 204 (100), 174 (15), 136 (20). HRMSFAB
tate/40–60 ꢁC petroleum ether as white prisms, mp
30
90–91 ꢁC; ½aꢂD ¼ ꢀ48.3 (c 0.9, acetone); IR mmax (chloro-
form), 1340 (asymmetric S@O), 1180 (symmetric S@O)

2808
C. M. Marson et al. / Tetrahedron: Asymmetry 16 (2005) 2799–2809
cmꢀ1; 1H NMR (DMSO-d6) d 5.41 (2H, m, OSCH), 4.75
(2H, dd, J 12.0, 1.0 Hz, CHHOMs), 4.64 (2H, dd, J 12.0,
6.0 Hz, CHHOMs), 3.29 (6H, s, SO2Me); 13C NMR
(DMSO-d6) d 80.4 (OSCH), 66.7 (CH2OMs), 37.3
(SO2Me); LRMSFAB m/e (rel. intensity %; +ve m-
NO2C6H5CO2H MATRIX) 363 ([M+Na]+, 94), 344
(22), 329 (47), 307 (37), 286 (100), 245 (26), 234 (36),
216 (31), 202 (31). HRMSFAB Calcd for C6H12NaO10S3
[M+Na]+ 362.9490. Found: 362.9465.
was adsorbed onto basic alumina and the impregnated
dispersion was applied to the top of a column of silica
gel that was eluted with 4:1 chloroform/methanol. Evap-
oration of the appropriate fractions gave a residue that
was dissolved in THF (15 mL) and stirred over K2CO3.
The solution was filtered and evaporated to give 21
(61 mg, 12%) as a clear wax. An analytical sample was
obtained by preparative silica plate thin-layer chroma-
tography (three plate elutions with 19:1 chloroform/
methanol eluted at 5 ꢁC in the dark). Extraction and iso-
lation as in General procedure B, but using THF in
4.1.16.
(2S,3R)-3-Azido-1,4-bis(methanesulfonyloxy)-
butane-2-ol 20. To a stirred solution of sulfone 19
(0.90 g, 2.91 mmol) in 1:1 acetone/water (30 mL) at
0 ꢁC was added sodium azide (0.95 g, 14.6 mmol; CAU-
TION) in one portion. The mixture was allowed to
warm slowly to 20 ꢁC and stirring was continued at that
temperature for 16 h. When the sulfone had been con-
sumed (as shown by KMnO4 staining of TLC plate fol-
lowed by heating) the solution was concentrated and a
1:1 mixture of 4 M sulfuric acid/diethyl ether (30 mL)
was added (CAUTION: any inorganic azide will be con-
verted into hydrazoic acid, which represents a serious
explosion hazard). Stirring was continued at 20 ꢁC for
16 h. The organic layer was separated and kept. The
aqueous layer was extracted with ethyl acetate
(3·30 mL) and the combined organic layers (including
the originally separated layer) were washed with brine
(2·25 mL) and dried over Na2SO4. The solution was fil-
tered, evaporated and the residue was absorbed onto a
small portion of silica gel and applied to the top a col-
umn of silica gel. Flash chromatography using 1:1 ethyl
place of chloroform, afforded 21 as
a
wax;
28
½aꢂD ¼ þ44.7 (c 1.2, methanol); IR mmax (solid film)
3385 (OH), 2930, 2850, 2110 (azide) cmꢀ1; H NMR
1
(CD3OD) 4.77 (2H, s, CHOH), 4.39 (2H, q, J 5.0 Hz,
CHOH), 3.90 (2H, q, J 5.0 Hz, CHN3), 3.05 (4H, m,
0
0
PyrH2;2 ;5;5 -cis), 2.77 (4H, s, CH2CH2), 2.75 (4H, m,
PyrH2;2 ;5;5 -trans); 13C NMR (151 MHz, CD3OD) d 72.6
0
0
0
0
(CHOH), 63.0 (CHN3), 60.4 (PyrC5;5 ), 57.3 (PyrC2;2 ),
55.2 (CH2CH2); LRMSFAB m/e (rel. intensity %; +ve
m-NO2C6H5CO2H MATRIX) 283 ([M+H]+, 100), 251
(97), 172 (26), 163 (10), 155 (37), 149 (18), 141 (79),
136 (36), 122 (33); HRMSFAB Calcd for C10H19N8O2
[M+H]+ 283.1631. Found: 283.1617.
4.1.18. (3R,30R,4S,40S)-3,30-Diamino-1,10-ethylenedipyr-
rolidine-4,40-diol 22. Diazide 21 (48 mg, 0.17 mmol)
was subjected to hydrogenolysis according to General
procedure D. (On completion, IR spectroscopy showed
the absence of mmax 2100 cmꢀ1 azide stretch.) The mix-
ture was filtered through a micro sintered glass funnel
packed with a small quantity of Celite 545 and washed
with ethanol (4·2 mL). The filtrates were evaporated
and the residue adsorbed onto basic alumina and the
impregnated dispersion was applied to the top of a
pre-packed column of alumina and eluted with 9:9:2
methanol/water/0.880 aqueous ammonia. The appropri-
ate fractions were combined, filtered through a fluted
paper and the eluent evaporated. The residue was dis-
solved in 3:1 THF/methanol and dried over K2CO3.
The solution was filtered through a fluted paper and
evaporated to give 22 (9 mg, 23%) as a brown gum.
An analytical sample was obtained by preparative alu-
mina plate thin-layer chromatography (four plate elu-
tions with 19:1 methanol/0.880 ammonia eluted at
5 ꢁC in the dark). The residue was continuously
extracted with THF for 48 h in a micro-soxhlet thimble
under an atmosphere of nitrogen. The organic layer
acetate/40–60 ꢁC petroleum ether afforded 20 (0.59 g,
30
67%) as a clear, mobile liquid; ½aꢂD ¼ ꢀ35.4 (c 0.6, chlo-
roform); IR mmax (film) 3515 (OH), 3030, 2940, 2105
1
(azide) cmꢀ1; H NMR (250 MHz, CDCl3) d 4.61 (1H,
dd, J 12.0, 3.5 Hz, CHHOMs), 4.46 (1H, m, CHOH),
1
4.39 (1H, m, CHN3), 4.36 (1H, dd, J 12.0, 5.0 Hz,
1CHHOMs), 3.90 (1H, m, CHHOMs), 3.83 (1H, m,
CHHOMs), 3.3 (1H, br s, CHOH), 3.11 (6H, s, SO2Me);
13C NMR (CDCl3) d 70.5 (1CH2OMs), 68.4 (CHOH),
68.3 (4CH2OMs), 60.8 (CHN3), 36.7 (SO2Me);
LRMSFAB m/e (rel. intensity %; +ve m-NO2C6H5CO2H
MATRIX) 436 ([M+Cs]+, 100), 326 ([M+Na]+, 30), 304
([M+H]+, 43), 288 (16), 278 (63), 208 (23), 198 (72), 180
(80), 168 (26); HRMSFAB Calcd for C6H14N3O7S2
[M+H]+ 304.0273. Found: 304.0250.
4.1.17. (3R,30R,4S,40S)-3,30-Diazido-1,10-ethylenedipyr-
rolidine-4,40-diol 21. To a stirred suspension of azide
20 (0.55 g, 1.80 mmol), potassium hydrogen carbonate
(0.54 g, 5.4 mmol) and 18-crown-6 (48 mg, 0.18 mmol)
in dry DMF (8 mL) at 0 ꢁC under an atmosphere of
dry nitrogen was added via a syringe a solution of ethy-
lenediamine (60 mg, 0.90 mmol) in dry pyridine
(0.5 mL). The mixture was allowed to warm slowly to
80 ꢁC (CAUTION) and stirring continued for 72 h at
that temperature under an atmosphere of dry nitrogen.
DMF was then removed by co-evaporation under re-
duced pressure with benzene (10 mL, repeated three
times) at 20 ꢁC. The residue was continuously extracted
with THF for 48 h in a micro-soxhlet thimble under an
atmosphere of nitrogen for 48 h. The organic layer was
dried over K2CO3, filtered and evaporated The residue
was dried over KOH pellets, filtered and evaporated to
32
give 22 as light tan solid; ½aꢂD ¼ þ36.3 (c 0.13, metha-
nol); IR mmax (thin film) 3420 (OH), 2960, 2850 cmꢀ1
;
1H NMR (CD3OD) d 4.03 (2H, m, CHOH), 3.27 (2H,
0
m, CHNH2), 3.04 (2H, dd, J 10.0, 5.5 Hz, PyrH5;5 -cis),
0
2.91 (2H, dd, J 10.0, 7.0 Hz, PyrH2;2 -cis), 2.59 (4H, s,
0
CH2CH2), 2.50 (2H, dd, J 10.0, 5.0 Hz, PyrH5;5 -trans),
0
2.35 (2H, dd, J 10.0, 1.0 Hz, PyrH2;2 -trans); NOESY spec-
trum showed correlations of d 4.03 with d 3.27, 3.04 and
2.50; of d 3.27 with d 3.04, 2.91 and 2.35; of d 3.04 with d
2.59 and 2.50; of d 2.91 with d 2.59 and 2.35; of d 2.59
with d 2.50, 2.35; and of d 2.50 with d 2.35; 13C NMR
0
(62 MHz, CD3OD) d 71.7 (CHOH), 62.6 (PyrC5;5 ), 60.8
0
(
PyrC2;2 ), 56.1 (CH2CH2), 54.5 (CHNH2); LRMSFAB
m/e (rel. intensity %; +ve m-NO2C6H5CO2H MATRIX)

C. M. Marson et al. / Tetrahedron: Asymmetry 16 (2005) 2799–2809
2809
231 ([M+H]+, 32), 192 (48), 176 (47), 171 (27), 154 (93),
149 (34), 136 (100), 120 (22) and 107 (57). HRMSFAB
Calcd for C10H23N4O2 [M+H]+ 231.1821. Found:
231.1838.
D. R.; Serra, M. E. S.; Murtinho, D.; Silva, V. E.; Beja, A.
M.; Paixao, J. A.; Silva, M. R.; da Veiga, L. A. J. Mol.
Catal. A 2003, 195, 1–9.
10. Nakajima, M.; Tomioka, Y.; Iitaka, Y.; Koga, K.
Tetrahedron 1993, 43, 10793–10806.
11. Dener, J. M.; Hart, D. J.; Ramesh, S. J. Org. Chem. 1988,
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Acknowledgements
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Support of this work by the Engineering and Physical
Sciences Research Council as a ROPA studentship (to
R.C.M.) is gratefully acknowledged, as is use of the
EPSRC National Crystallography Service.
15. Mash, E. A.; Nelson, K. A.; Van Deusen, S.; Hemperly, S.
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3
˚
˚
c = 13.945(3) A, b = 96.08(3)ꢁ, U = 1137.9(4) A , Z = 4,
Dc = 1.356 g cmꢀ3, l = 0.104 mmꢀ1, F(000) = 504, crystal
size 0.4·0.1·0.1 mm, 1483 unique data were produced
from 8044 measured reflections (Rint = 0.1042), 151
parameters refined to R1 = 0.0652 and wR2 = 0.1982
[I > 2r(I)] (R1 = 0.0761 and wR2 = 0.2563 for all datꢀa3),
˚
with residual electron densities of 0.407 and ꢀ0.395 e A
.
Crystallographic data (excluding structure factors) for the
structure of 1a in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplemen-
tary publication numbers CCDC 218589. 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 e-mail: deposit@ccdc.cam.ac.uk].
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