Synthesis of new enantiopure proton-ionizable crown ethers containing a dialkylhydrogenphosphate moiety

Article abstract of DOI:10.1016/j.tetasy.2006.09.018

Seven new enantiopure proton-ionizable crown ethers containing a dialkylhydrogenphosphate moiety were prepared starting from optically active dialkyl-substituted oligoethylene glycols and phosphorus oxychloride followed by mild hydrolysis of the resulting macrocyclic chlorophosphates. Pentaethylene glycols having primary hydroxyl groups gave good yields of 17-crown-6 type ethers. Pentaethylene glycols with secondary hydroxyl groups rendered about the same amount of 17-crown-6 ethers and open chain dihydrogenphosphates in low yields. Tetraethylene glycols are reluctant to undergo macrocyclization with phosphorus oxychloride, especially the ones which contain secondary hydroxyl groups.

Full text of DOI:10.1016/j.tetasy.2006.09.018

Tetrahedron: Asymmetry 17 (2006) 2538–2547
Synthesis of new enantiopure proton-ionizable crown ethers
containing a dialkylhydrogenphosphate moietyI
a,b
a,
a
b
*
´
´
´
Ilona Kovacs, Peter Huszthy, Ferenc Bertha and Denes Sziebert
aInstitute for Organic Chemistry, Budapest University of Technology and Economics and Research Group for Alkaloid
Chemistry of the Hungarian Academy of Sciences, H-1521 Budapest, Hungary
bDepartment of Inorganic Chemistry, Budapest University of Technology and Economics, H-1521 Budapest, Hungary
Received 4 August 2006; accepted 12 September 2006
Abstract—Seven new enantiopure proton-ionizable crown ethers containing a dialkylhydrogenphosphate moiety were prepared starting
from optically active dialkyl-substituted oligoethylene glycols and phosphorus oxychloride followed by mild hydrolysis of the resulting
macrocyclic chlorophosphates. Pentaethylene glycols having primary hydroxyl groups gave good yields of 17-crown-6 type ethers. Pen-
taethylene glycols with secondary hydroxyl groups rendered about the same amount of 17-crown-6 ethers and open chain dihydrogen-
phosphates in low yields. Tetraethylene glycols are reluctant to undergo macrocyclization with phosphorus oxychloride, especially the
ones which contain secondary hydroxyl groups.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
ers, because at pH values higher than their pKa, they are
mostly ionized to ligand anions, which increase the cat-
ion–ligand complex stability with enhancement of selectiv-
ity, and avoid the need for a counteranion in a cation
transport through various membrane systems or in solvent
extraction.4–12 The latter factor is of immense importance
for practical applications in separations involving hydro-
philic aqueous phase anions, such as chloride, nitrate and
sulfate.5 The transport of cations in most of these cases is
pH dependent, so the transport can be turned on and off
by adjusting the pH. Proton-ionizable macrocyclic carriers
should have lipophilic substituents to ensure that they re-
main in the organic membrane. Without a lipophilic substi-
tuent, no transport occurs, because the crown ether leaks
into the aqueous phase and is thus unavailable as a carrier.
In order for an ion carrier (e.g., a crown ether) to perform a
practically useful so-called ‘active transport’ (i.e., transport
against a concentration gradient) across the membrane of
an aqueous source phase/lipophilic membrane/aqueous
receiving phase system, it should possess a relatively strong
ion-binding ability at the source phase/membrane inter-
face, and a relatively weak ion-binding ability at the mem-
brane/receiving phase interface.
A solution for this seemingly contradictory requirement is
to engineer into the ion carrier a so-called ‘switching mech-
anism’, which enables alternation between strong and weak
binding states. These two states can be reversibly intercon-
verted by external forces, such as redox,1 light,2 tempera-
ture3 and pH4 gradients.
We have been interested for several years in proton-ioniz-
able crown ethers, in which the proton dissociable group
is incorporated into the macroring. In such pH switching
ligands, after deprotonation, the negatively charged hetero-
atom (e.g., oxygen or nitrogen) is in the coordination
sphere of the complexed cation.7–12
Proton-ionizable crown ethers having a pH switching
mechanism have attracted the attention of many research-
q Presented at the XXIX International Symposium on Macrocyclic
Chemistry, July 4–8, 2004 Cairns, Australia.
There has always been a strong demand for proton-ioniz-
able macrocyclic ligands with pKa values, which would
allow the transport of cations at relatively low pH values.
Such more acidic pH-switched ligands can also be used
*
Corresponding author. Tel.: +36 1 463 1071; fax: +36 1 463 3297; e-mail:
huszthy@mail.bme.hu
URL: http://www.och.bme.hu/org
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.09.018

I. Kova´cs et al. / Tetrahedron: Asymmetry 17 (2006) 2538–2547
2539
As an extension of our research for the purpose of finding
enantiopure chiral host molecules having enhanced selec-
tivity for both metal ions and the enantiomers of chiral
protonated primary amines in binding,18–20 solvent extrac-
tion,21 membrane transport,8,9,12 potentiometric22 and
other studies, we prepared macrocycles (S,S)-7–(S,S)-13
(see Fig. 1).
O
R3
R3
R2
O
P
O
*
*
*
OH
2
R
O
O
*
1
O
R2
n
Note that to the best of our knowledge, no enantiopure
chiral proton-ionizable crown ethers containing a dial-
kylhydrogenphosphate moiety have been reported.
1: n=1, R1=R2=R3=H
rac-2: n=1, R1=octyl, R2=R3=H
3: n=2, R1=R2=R3=H
rac-4: n=2, R1=octyl, R2=R3=H
rac-5: n=2, R1=decyl, R2=R3=H
rac-6: n=2, R1=hexadecyl, R2=R3=H
(S,S)-7: n=1, R1=R3=H, R2= iBu
(S,S)-8: n=2, R1=R3=H, R2= Me
(S,S)-9: n=2, R1=R2=H, R3= Me
(S,S)-10: n=2, R1=R3=H, R2= iBu
(S,S)-11: n=2, R1=R2=H, R3= iBu
(S,S)-12: n=2, R1=R3=H, R2= octyl
(S,S)-13: n=2, R1=R2=H, R3= octyl
Application studies on these new ligands will be reported
when that work is finished.
2. Results and discussion
For the preparation of the new enantiopure macrocycles
(S,S)-7–(S,S)-13, the reported procedure for obtaining
the crown ethers 1–rac-611 has been thoroughly modified.
The intermediate chlorophosphates were obtained by react-
ing phosphorus oxychloride with the appropriate enantio-
pure oligoethylene glycols using a high dilution technique
which provided higher yields than the reported11 proce-
dure. Also yields increased when the reaction temperature
was raised from the reported ꢀ7011 to ꢀ15 ꢁC.
Figure 1. Schematics of proton ionizable crown ethers containing a
dialkylhydrogenphosphate moiety.
to transport certain heavy metal cations, ammonium and
primary organic ammonium ions at relatively low aqueous
source phase pH.10–12
Our optimized general procedure (see Section 4) for macro-
cyclization was followed by the smooth hydrolysis of the
resulting chlorophosphates to the desired crown ethers
(S,S)-7–(S,S)-13 using a water–dioxane mixture at room
temperature (see Scheme 1 and Table 1). Starting from
enantiopure pentaethylene glycols (S,S)-20, (S,S)-22 and
(S,S)-24 with primary hydroxyl groups, only crown ethers
could be isolated in good yields (see Table 1, entries 7, 9
and 11). Starting from pentaethylene glycols having sec-
ondary hydroxyl groups (S,S)-21, (S,S)-23 and (S,S)-25,
about the same amounts of crown ethers and open chain
dihydrogenphosphates could be isolated in low yields (see
Table 1, entries 8, 10 and 12). Using tetraethylene glycols
(S,S)-14–(S,S)-19 as starting materials, except for (S,S)-
16, only open chain dihydrogenphosphates could be iso-
lated in low yields (see Table 1, entries 1–6). Starting from
tetraethylene glycol (S,S)-16, having primary hydroxyl
groups, 3% of crown ether (S,S)-7 could be obtained (see
Table 1, entry 3).
Bradshaw et al. synthesized fairly acidic proton-ionizable
crown ethers containing a dialkylhydrogenphosphate moi-
ety 1–rac-6 (see Fig. 1). These ligands were either achiral 1
and 3 or racemic rac-2, rac-4, rac-5 and rac-6.11 The water-
insoluble macrocycles rac-2, rac-4, rac-5 and rac-6 showed
an appreciable transport of alkali, alkaline earth and sev-
eral transition metal cations in a H2O–CH2Cl2–H2O liquid
membrane system.12
It is known that natural ion carriers (ionophores), such as
valinomycin, monensin, lasalocid, monactin, dinactin, sal-
inomycin, narasin, and nigericin, are optically active com-
pounds and their stereostructure plays a very important
role in the selective transport of metal cations through bio-
membranes.13,14 Other studies have shown that the chiral-
ity of the synthetic host molecules is also an important
factor in binding, solvent extraction and transport of metal
cations.15–17
O
R3
R3
O
P
O
*
*
R3
R3
*
*
R2
R2
R2
O
R3
R2
O
R3
1) POCl3 / CH2Cl2
2) H2O / dioxane
O
OH
*
*
*
*
*
*
*
*
R2
+
O
O
R2
P
OH
HO
O
O
OH
HO
O
O
O
n
n
OH
O
n
oligoetylene glycols
*
dihydrogenphosphates
crown ethers
(S,S)-7 - (S,S)-13
(S,S)-14 - (S,S)-25
(S,S)-26 - (S,S)-34
Scheme 1. Formation of new enantiopure chiral crown ethers containing a dialkylhydrogenphosphate moiety and open chain dihydrogenphosphates (see
also Table 1).

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I. Kova´cs et al. / Tetrahedron: Asymmetry 17 (2006) 2538–2547
Table 1. Isolated yields (in per cent) of crown ethers and open chain dihydrogenphosphates (see also Scheme 1)
Entry
n
R2
R3
Starting oligoethylene glycol
Crown ether
Yield (%)
Dihydrogenphosphate
Yield (%)
1
2
3
4
5
6
7
8
1
1
1
1
1
1
2
2
2
2
2
2
Me
H
i-Bu
H
Octyl
H
Me
H
i-Bu
H
Octyl
H
H
Me
H
i-Bu
H
Octyl
H
Me
H
i-Bu
H
(S,S)-14
(S,S)-15
(S,S)-16
(S,S)-17
(R,R)-18
(S,S)-19
(S,S)-20
(S,S)-21
(S,S)-22
(S,S)-23
(S,S)-24
(S,S)-25
—
—
(S,S)-7
—
—
—
—
3
—
—
—
61
14
59
8
(S,S)-26
(S,S)-27
(S,S)-28
(S,S)-29
(R,R)-30
(S,S)-31
—
(S,S)-32
—
(S,S)-33
—
40
36
31
22
36
31
—
16
—
10
—
15
—
(S,S)-8
(S,S)-9
(S,S)-10
(S,S)-11
(S,S)-12
(S,S)-13
9
10
11
12
63
15
Octyl
(S,S)-34
Based on these experimental facts, it can be concluded that
the fastest macrocyclization reaction leading to the forma-
tion of a 17-membered ring takes place when pentaethylene
glycols with primary hydroxyl groups are used. In these
cases, only a small amount of by-products is formed. Using
pentaethylene glycols with secondary hydroxyl groups,
macrocyclization reaction becomes slower. In the studied
cases, the formation of a 14-membered ring is very unfa-
vourable, especially when involving secondary hydroxyl
groups. As it can be seen from Table 1, entries 2, 4 and
6, no crown ethers, but only open chain dihydrogenphos-
phates could be isolated, indicating a reluctance for ring
closure of the open chain dichloro intermediates.
than the others (eight conformations in the case of 1 and
six in the case of 35) were further optimized at the ab initio
B3LYP/6-31+G* level of theory. For conformers having
energies within 2 kcal/mol from the most stable one (five
in the case of 1 and four in the case of 35) vibrational fre-
quencies and IR intensities were calculated with the help of
second derivative calculations carried out at the same level
of theory. As illustrated in Figure 2, the most stable confor-
mations of both 1 and 35 seem to be stabilized by intramo-
lecular hydrogen bonds. These provide a way to interpret
the IR spectra of the two structures. According to the cal-
culations in the case of 1, the P–O–H bending motion of
the single hydrogen bridge appears as a sharp peak between
1290 and 1310 cmꢀ1 in the vibrational spectra of all stable
conformers. The open chain dihydrogenphosphate 35 con-
taining three OH groups has far more possibilities for
hydrogen bonding compared to 1, so the bands corre-
sponding to the OH bending motions appear smeared over
the 1100–1400 cmꢀ1 region. This finding is in good agree-
ment with the observed IR spectra of the methyl-substi-
tuted analogues (S,S)-9 and (S,S)-32, while the IR
spectra of (S,S)-9 exhibit a narrow band at 1280 cmꢀ1, in
the case of (S,S)-32 the vibration bands appearing in the
1200–1400 cmꢀ1 region are merged.
A close inspection of the IR spectra of our crown ethers
and of the open chain dihydrogenphosphates revealed
some general differences, which prompted us to obtain a
deeper insight into this phenomenon.
Quantum chemical calculations enabled us to interpret the
differences between the vibrational spectra of the open
chain dihydrogenphosphates and the crown ethers.
Due to the flexible nature of structures 1 and 35 (see
Fig. 2), the investigation of only a single conformer is not
sufficient. Therefore, a conformational search was carried
out using the Monte Carlo technique with the MM3 force
field. Conformations having significantly lower energies
It should be mentioned that with the exception of (S,S)-11,
the acidic proton of P–O–H could not be located in the 1H
NMR spectra of crown ethers (S,S)-7–(S,S)-13. In the case
of crown ether (S,S)-11, a very broad proton signal centred
at 5.05 could be observed.
Except for (S,S)-14,23 (S,S)-15,24,25 (S,S)-1726 and (S,S)-
21,24 the enantiopure oligoethylene glycols needed for the
preparation of crown ethers (S,S)-7–(S,S)-13 have, to the
best of our knowledge, not been reported, although some
of them, rac,meso-18,27 rac,meso-1928 and rac,meso-24,27
have been prepared as mixtures of rac and meso com-
pounds. The above mentioned oligoethylene glycols have
been synthesized by different procedures than the ones we
reported here. Note that the antipodes of (S,S)-15 and
(S,S)-17, that is, (R,R)-1525 and (R,R)-17,29 are also
known, but the latter tetraethylene glycols were prepared
using procedures different from ours.
Figure 2. The most stable conformations of 1-hydroxy-2,5,8,11,14-penta-
Herein we report two general procedures for preparing
enantiopure oligoethylene glycols. One was applied to ob-
oxa-1-phosphacyclotetradecane-1-oxide
oxy]ethoxy}ethoxy)ethan-2-yl dihydrogenphosphate 35.
1 and 2-(2-{2-[2-hydroxyeth-

I. Kova´cs et al. / Tetrahedron: Asymmetry 17 (2006) 2538–2547
2541
tain the oligoethylene glycols with two secondary hydroxyl
groups (Scheme 2, procedure A), and the other one for oli-
goethylene glycols with two primary hydroxyl groups
(Scheme 2, procedure B). In both cases, optically active
2-tetrahydropyranyloxy-alkane-1-ols (S)-36,24 (S)-37,26,30
(R)-38 and (S)-38 were used as key intermediates. In the
case of procedure A the THP-blocked glycols were first
deprotonated using a strong base (sodium hydride), after
which two moles of the resulting sodium salts were reacted
with one mole of diethylene glycol ditosylate 39 or triethyl-
ene glycol ditosylate 40 to obtain the bis-tetrahydropyranyl
derivatives of the desired oligoethylene glycols. The latter
were deblocked by an acidic ion-exchange resin in
methanol.
hydride. The resulting sodium salts (2 mol) were
reacted with 1 mol of ditosylates 39 or 40 to obtain the
bis-benzyl derivatives of the desired oligoethylene glycols.
The benzyl protecting groups were removed by cata-
lytic hydrogenation. Although the synthesis of (S)-3624
and (S)-3726,30 has been reported, (R)-38 and (S)-38 are
new.
The starting materials for (R)-38 and (S)-38, that is, (R)-
and (S)-2-hydroxydecanoic acids (R)-44 and (S)-44
(Scheme 3) were obtained by resolution of racemic 2-
hydroxydecanoic acid rac-44 with the help of (R)- and
(S)-1-phenylethylamine, respectively, as reported for the
R enantiomer only.31 Hydroxy acids (R)-44 and (S)-44
were first treated with thionyl chloride in methanol to give
methyl esters (R)-45 and (S)-45 (see Scheme 3). The esters
were reacted with an excess of dihydropyran (DHP) in the
presence of pyridinium p-toluenesulfonate (PPTS) catalyst
to give the 2-tetrahydropyranyloxy esters (R)-46 and
(S)-46, which were then reduced to give the THP-blocked
glycols (R)-38 and (S)-38.
In procedure B the sodium salts of alcohols (S)-36–(S)-38
were generated, which were then treated with benzyl
chloride. On removal of the THP protecting group
from the diblocked glycols in the same way as above, the
benzyl protected glycols (S)-41–(S)-43 were obtained. The
latter compounds were deprotonated using also sodium
Procedure A
1) NaH (THF)
2) TsOCH2(CH2OCH2)nCH2OTs
(39: n=1, 40: n=2)
R3
R3
R3
*
*
*
2 mol
3) Ion-exchange resin H+
(MeOH)
n
O
THPO OH
HO
O
O
OH
(S,S)-15: R3 =Me, n=1
(S,S)-17: R3 =iBu, n=1
(S,S)-19: R3 =octyl, n=1
(S,S)-21: R3 =Me, n=2
(S,S)-23: R3 =iBu, n=2
(S,S)-25: R3 =octyl, n=2
(S)-36: R3 =Me
(S)-37: R3 =iBu
(S)-38: R3 =octyl
Procedure B
R2
O
R2
*
O
1) NaH (THF)
(S)-41−(S)-43
*
2) TsOCH2(CH2OCH2)nCH2OTs
(39: n=1, 40: n=2)
(2 mol)
n
OH
HO
O
3) H2/Pd/C (MeOH)
(S,S)-14:R2 =Me, n=1
(S,S)-16:R2 =iBu, n=1
(R,R)-18:R2 =octyl, n=1
(S,S)-20:R2 =Me, n=2
(S,S)-22:R2 =iBu, n=2
(S,S)-24: R2 =octyl, n=2
R2
*
THPO OH
R2
1) NaH (THF)
2) BnCl
*
3) Ion-exchange resin H+
(MeOH)
HO OBn
(S)-36: R2 =Me
(S)-37: R2 =iBu
(R)-38: R2 =octyl
(S)-38: R2 =octyl
(S)-41: R2 =Me
(S)-42: R2 =iBu
(R)-43: R2 =octyl
(S)-43: R2 =octyl
Note: THP = tetrahydropyranyl, Ts = tosyl, Bn = benzyl
Scheme 2. Preparation of enantiopure chiral oligoethylene glycols.

2542
I. Kova´cs et al. / Tetrahedron: Asymmetry 17 (2006) 2538–2547
octyl
octyl
O
O
octyl
SOCl2
DHP
O
*
*
*
(MeOH)
HO OH
HO OMe
PPTS, CH2Cl2
THPO OMe
(R)-44
(S)-44
(R)-45
(S)-45
(R)-46
(S)-46
LiAlH4
ether
(R)-38
(S)-38
(R)-46
(S)-46
Note: DHP = 3,4-dihydro-2H-pyran, PPTS = pyridinium p-toluenesulfonate
Scheme 3. Preparation of (R)- and (S)-2-tetrahydropyranyloxy-decane-1-ol (R)-38 and (S)-38.
3. Conclusions
The Monte-Carlo conformational searches were carried
out with the help of the Tinker33 package. For ab initio
geometry optimizations and second derivative calculations,
the Gaussian98 package was used.34
The rate of macrocyclization reaction of optically active
alkyl-substituted tetra- and pentaethylene glycols, respec-
tively, with phosphorus oxychloride using a high dilution
technique depends very much on the constitution of the oli-
goethylene glycols. The fastest macrocyclization reaction
takes place when alkyl-substituted pentaethylene glycols
with primary hydroxyl groups are used. Macrocyclization
becomes slower when the alkyl-substituted pentaethylene
glycols contain secondary hydroxyl groups. Using alkyl-
substituted tetraethylene glycols for macrocyclization,
especially the ones which have secondary hydroxyl groups,
the reaction slows down by a large extent. It has also been
shown that general procedures for obtaining enantiopure
alkyl-substituted oligoethylene glycols with primary and
secondary hydroxyl groups, respectively, could be devel-
oped by starting from commercially available and rela-
tively cheap materials.
4.2. General procedure for the preparation of crown ethers
(S,S)-7–(S,S)-13 and open chain dihydrogenphosphates
(S,S)-26–(S,S)-34 (see also Fig. 1, Scheme 1 and Table 1)
To a vigorously stirred, dry and pure CH2Cl2 (200 mL)
were simultaneously added a solution of the appropriate
oligoethylene glycol (S,S)-14–(S,S)-25 (5 mmol) in CH2Cl2
(10 mL) and
a solution of phosphorus oxychloride
(76.6 mg, 5 mmol) in CH2Cl2 (10 mL) at ꢀ15 ꢁC under
Ar in 30 min. After the addition of the two solutions, the
resulting reaction mixture was stirred for 1 h at ꢀ15 ꢁC,
then allowed to warm up to room temperature (rt) and stir-
red for another 20 h. The solvent was removed and the
chlorophosphate was dissolved in dioxane (10 mL). The
latter solution was added dropwise to a vigorously stirred
mixture of dioxane (10 mL) and water (5 mL) at rt. This
was then stirred at room temperature for 10 h. The solvent
was removed and the crude product purified by column
chromatography on silica gel. Eluents are given for each
compound (see below). For yields see also Table 1.
4. Experimental
4.1. General
Infrared spectra (neat unless otherwise indicated) were re-
corded on a Zeiss Specord IR 75 spectrometer. Optical
rotations were taken on a Perkin–Elmer 241 polarimeter
that was calibrated by measuring the optical rotations of
both enantiomers of menthol. NMR spectra were recorded
in CDCl3 on a Bruker DRX-500 Avance spectrometer (at
4.2.1. (4S,12S)-1-Hydroxy-4,12-diisobutyl-2,5,8,11,14-pen-
taoxa-1-phosphacyclotetradecane 1-oxide (S,S)-7. Eluent
for chromatography: EtOAc/MeOH/H2O (10:2:1.3); yield:
23
23
3%; ½aꢁD ¼ ꢀ8:5, ½aꢁ436 ¼ ꢀ18:1 (c 1.52, CH2Cl2); 1H NMR
0.83 (d, J = 6.3 Hz, 12H), 1.11–1.26 (m, 2H), 1.28–1.46 (m,
2H), 1.55–1.75 (m, 2H), 3.40–3.72 (m, 6H), 3.72–4.00 (m,
8H); 13C NMR 22.69, 23.29, 24.60, 40.55, 68.06, 69.11,
70.98, 77.29; 31P NMR 0.35; IR mmax 3296, 2872, 1468,
1368, 1244, 1096, 952, 856 cmꢀ1; MS: 369 (M+1)+. Anal.
Calcd for C16H33O7P: C, 52.16; H, 9.03. Found: C, 52.06;
H, 9.24.
1
500 MHz for H, 125 MHz for 13C and 202 MHz for 31P
spectra). Mass spectra were recorded on a ZQ2000 MS
instrument (Waters Corp.) using ESI method. Elemental
analyses were performed in the Microanalytical Labora-
tory of the Department of Organic Chemistry, Institute
for Chemistry, L. Eo¨tvo¨s University, Budapest, Hungary.
Melting points were taken on a Boetius micro-melting
point apparatus and were uncorrected. Starting materials
were purchased from Aldrich Chemical Company unless
otherwise noted. Silica gel 60 F254 (Merck) plates were used
for TLC and silica gel 60 (70–230 mesh, Merck) were used
for column chromatography. Ratios of the solvents for the
eluents are given in volumes (mL/mL). Romil Ltd (Cam-
bridge UK) SuperPurity Solvent grade THF stored under
argon was used as purchased. All other solvents were dried
and purified according to the well established methods.32
Evaporations were carried out under reduced pressure.
4.2.2.
(4S,15S)-1-Hydroxy-4,15-dimethyl-2,5,8,11,14,17-
hexaoxa-1-phosphacycloheptadecane-1-oxide (S,S)-8. Elu-
ent for chromatography: EtOAc/MeOH/H2O (10:5:2);
24
24
yield: 61%; ½aꢁD ¼ þ26:8, ½aꢁ436 ¼ þ52:3 (c 1.77, CH2Cl2);
1H NMR 1.13 (d, J = 6.0 Hz, 6H), 3.55–3.92 (m, 16H),
3.95–4.08 (m, 2H); 13C NMR 15.23, 66.70, 68.44,
69.14, 69.90, 75.04 (d, J = 6.8 Hz); 31P NMR 0.85; IR
mmax 3392, 2872, 1460, 1376, 1360, 1248, 1104, 968,
856 cmꢀ1; MS: 329 (M+1)+. Anal. Calcd for C12H25O8P:
C, 43.94; H, 7.67. Found: C, 43.83; H, 7.79.

I. Kova´cs et al. / Tetrahedron: Asymmetry 17 (2006) 2538–2547
2543
4.2.3.
(3S,16S)-1-Hydroxy-3,16-dimethyl-2,5,8,11,14,17-
4.2.8. (2S)-2-(2-{2-[(2S)-1-Hydroxypropan-2-yloxy]ethoxy}-
ethoxy)propyl dihydrogenphosphate (S,S)-26. Eluent
for chromatography: EtOAc/MeOH/H2O (10:5:2); yield:
hexaoxa-1-phosphacycloheptadecane 1-oxide (S,S)-9. Elu-
ent for chromatography: EtOAc/MeOH/H2O (10:5:2); yield:
23
23
28
28
14%; ½aꢁD ¼ þ20:1, ½aꢁ436 ¼ þ39:7 (c 2.85, CH2Cl2);
1H NMR 1.23 (d, J = 6.4 Hz, 6H), 3.32–3.74 (m, 16H),
4.36–4.53 (m, 2H); 13C NMR 18.73, 69.62, 69.77, 70.01,
70.93, 75.29; 31P NMR ꢀ0.15; IR mmax 3280, 2872, 1456,
1356, 1244, 1088, 992, 788 cmꢀ1, MS: 329 (M+1)+. Anal.
Calcd for C12H25O8P: C, 43.94; H, 7.67. Found: C, 43.85;
H, 7.88.
40%; ½aꢁD ¼ þ24:2, ½aꢁ436 ¼ þ47:3 (c 2.91, CH2Cl2);1H
NMR 1.07 (d, J = 5.5 Hz, 3H), 1.13 (d, J = 5.0 Hz, 3H),
3.36–3.78 (m, 12H), 3.78–4.03 (m, 2H), 6.65 (br s, 3H,
OH); 13C NMR 15.99, 16.36, 65.95, 67.42, 67.73, 68.73,
70.52 (br probably two carbon 13 signals together),
74.99, 76.47; 31P NMR ꢀ0.04; IR mmax 3392, 2872, 1460,
1376, 1088, 960, 800 cmꢀ1; MS: 303 (M+1)+. Anal. Calcd
for C10H23O8P: C, 39.74; H, 7.67. Found: C, 39.61; H, 7.74.
4.2.4. (4S,15S)-1-Hydroxy-4,15-diisobutyl-2,5,8,11,14,17-
hexaoxa-1-phosphacycloheptadecane
4.2.9.
(2S)-3-(2-{2-[(2S)-2-Hydroxypropoxy]ethoxy}eth-
1-oxide
(S,S)-10.
oxy)propan-2-yl dihydrogenphosphate (S,S)-27. Eluent
for chromatography: EtOAc/MeOH/H2O (10:5:2); yield:
Eluent for chromatography: EtOAc/MeOH/H2O (10:2:1);
26
26
yield: 59%; ½aꢁD ¼ þ10:2, ½aꢁ436 ¼ þ21:3 (c 1.49, CH2Cl2);
1H NMR 0.88 (d, J = 6.6 Hz, 12H), 1.23–1.31 (m, 2H),
1.39–1.47 (m, 2H), 1.61–1.72 (m, 2H), 3.53–3.79 (m,
14H), 3.81–3.91 (m, 2H), 3.98–4.07 (m, 2H); 13C NMR
22.95, 23.15, 24.86, 39.47, 67.31, 67.55, 69.42, 70.29,
77.93; 31P NMR 0.79; IR mmax 3400, 2872, 1468, 1368,
1248, 1104, 948, 848 cmꢀ1; MS: 413 (M+1)+. Anal. Calcd
for C18H37O8P: C, 52.42; H, 9.04. Found: C, 52.33; H, 9.23.
27
27
36%; ½aꢁD ¼ þ11:1, ½aꢁ436 ¼ þ22:6 (c 1.41, CH2Cl2); 1H
NMR 1.14 (d, J = 6.2 Hz, 3H), 1.26 (d, J = 5.8 Hz, 3H),
3.29–3.78 (m, 12H), 3.94–4.08 (m, 1H), 4.38–4.54 (m, 1H),
6.00 (br s, 3H, OH); 13C NMR 18.60, 19.05, 65.87, 69.90
(br probably two carbon 13 signals together), 69.98 (br
probably two carbon 13 signals together), 70.39, 75.24,
77.32; 31P NMR 1.80; IR mmax 3312, 2872, 1456, 1376,
1104, 960, 932, 768 cmꢀ1; MS: 303 (M+1)+. Anal. Calcd
for C10H23O8P: C, 39.74; H, 7.67. Found: C, 39.56; H, 7.71.
4.2.5. (3S,16S)-1-Hydroxy-3,16-diisobutyl-2,5,8,11,14,17-
hexaoxa-1-phosphacycloheptadecane 1-oxide (S,S)-11. Elu-
ent for chromatography: EtOAc/MeOH/H2O (10:2:1.4);
4.2.10. (2S)-2-(2-{2-[(2S)-1-Hydroxy-4-methylpentan-2-yl-
dihydrogenphosphate
oxy]ethoxy}ethoxy)-4-methylpentyl
(S,S)-28. Eluent for chromatography: EtOAc/MeOH/
26
26
yield: 8%; ½aꢁD ¼ þ7:95, ½aꢁ436 ¼ þ16:3 (c 1.59, CH2Cl2);
1H NMR 0.86 (d, J = 7.0 Hz, 6H), 0.88 (d, J = 6.7 Hz,
6H),1.16–1.29 (m, 2H), 1.57–1.67 (m, 2H), 1.68–1.81 (m,
2H), 3.39–3.84 (m, 16H), 4.23–4.41 (m, 2H), 5.05 (very
br,1H, OH); 13C NMR 22.79, 23.01, 24.47, 42.42, 68.91,
69.15, 69.88, 72.85; 75.10; 31P NMR 0.85; IR mmax 3360,
2872, 1472, 1368, 1240, 1096, 964, 784 cmꢀ1; MS: 413
(M+1)+. Anal. Calcd for C18H37O8P: C, 52.42; H, 9.04.
Found: C, 52.28; H, 9.12.
23
23
H2O (10:2:1.3); yield: 31%; ½aꢁD ¼ ꢀ7:3, ½aꢁ436 ¼ ꢀ15:35 (c
1
2.05, CH2Cl2); H NMR 0.83 (d, J = 6.6 Hz, 12H), 1.04–
1.24 (m, 2H), 1.28–1.44 (m, 2H), 1.51–1.79 (m, 2H), 3.37–
3.95 (m, 14H), 6.70 (br s, 3H, OH); 13C NMR 22.51,
22.81, 23.17, 23.43, 24.69, 24.94, 39.91, 39.95, 64.24, 67.53
(br probably two carbon 13 signals together), 68.00, 70.54
(br probably two carbon 13 signals together), 70.88,
79.15; 31P NMR 3.09; IR mmax 3250, 2952, 1464, 1368,
1100, 944, 864, 836 cmꢀ1; MS: 387 (M+1)+. Anal. Calcd
for C16H35O8P: C, 49.73; H, 9.13. Found: C, 49.55; H, 9.22.
4.2.6. (4S,15S)-1-Hydroxy-4,15-dioctyl-2,5,8,11,14,17-hex-
aoxa-1-phosphacycloheptadecane 1-oxide (S,S)-12. Eluent
for chromatography: EtOAc/MeOH/H2O (15:2:1); yield:
4.2.11. (2S)-1-(2-{2-[(2S)-2-Hydroxy-4-methylpentyloxy]-
ethoxy}ethoxy)-4-methylpentan-2-yl dihydrogenphosphate
(S,S)-29. Eluent for chromatography: EtOAc/MeOH/
26
26
63%; ½aꢁD ¼ þ7:0, ½aꢁ436 ¼ þ14:3 (c 2.50, CH2Cl2); 1H
NMR 0.81 (t, J = 6.3 Hz, 6H), 1.12–1.31 (m, 24H), 1.36–
1.50 (m, 4H), 3.41–3.51 (m, 2H), 3.51–3.73 (m, 12H),
3.77–3.89 (m, 2H), 3.89–4.02 (m, 2H); 13C NMR 14.08,
22.66, 25.40, 29.30, 29.59, 29.90, 30.48, 31.87, 67.07,
67.75, 69.53, 70.33, 79.38; 31P NMR 0.28; IR mmax 3400,
2856, 1468, 1352, 1220, 1096, 952, 856 cmꢀ1; MS: 525
(M+1)+. Anal. Calcd for C26H53O8P: C, 59.52; H, 10.18.
Found: C, 59.29; H, 10.25.
20
23
H2O (10:2:1.2); yield: 22%; ½aꢁD ¼ ꢀ9:8, ½aꢁ436 ¼ ꢀ20:5 (c
1.85, CH2Cl2); 1H NMR 0.90 (d, J = 6.4 Hz, 6H), 0.91
(d, J = 6.4 Hz, 6H), 1.09–1.21 (m, 1H), 1.29–1.41 (m,
2H), 1.51–1.64 (m, 1H), 1.70–1.89 (m, 2H), 3.32–3.40 (m,
1H), 3.41–3.49 (m, 1H), 3.50–3.79 (m, 10H), 3.83–3.92
(m, 1H), 4.28–4.42 (m, 1H), 6.36 (br s, 3H, OH); 13C
NMR 22.54, 22.93, 23.43, 23.49, 24.27, 24.53, 42.12,
42.52, 68.10, 69.90 (br probably three carbon 13 signals to-
gether), 70.61, 72.54, 74.12, 75.83; 31P NMR 2.52; IR mmax
3224, 2952, 1472, 1368, 1120, 936, 760 cmꢀ1; MS: 387
(M+1)+. Anal. Calcd for C16H35O8P: C, 49.73; H, 9.13.
Found: C, 49.59; H, 9.26.
4.2.7. (3S,16S)-1-Hydroxy-3,16-dioctyl-2,5,8,11,14,17-hex-
aoxa-1-phosphacycloheptadecane 1-oxide (S,S)-13. Eluent
for chromatography: EtOAc/MeOH/H2O (10:2:1); yield:
24
24
15%; ½aꢁD ¼ þ12:1, ½aꢁ436 ¼ þ23:7 (c 1.93, CH2Cl2); 1H
NMR 0.87 (t, J = 7.2 Hz, 6H), 1.18–1.45 (m, 24H), 1.45–
1.60 (m, 2H), 1.64–1.81 (m, 2H), 3.51–3.72 (m, 12H),
3.72–3.86 (m, 4H), 4.26–4.41 (m, 2H); 13C NMR 14.12,
22.70, 25.52, 29.37, 29.67, 29.85, 30.93, 33.38, 68.81,
69.12, 69.68, 74.32, 74.69; 31P NMR ꢀ0.63; IR mmax 3250,
2856, 1464, 1360, 1248, 1100, 968, 790 cmꢀ1; MS: 525
(M+1)+. Anal. Calcd for C26H53O8P: C, 59.52; H, 10.18.
Found: C, 59.23; H, 10.36.
4.2.12.
(2R)-2-(2-{2-[(2R)-1-Hydroxydecan-2-yloxy]eth-
oxy}ethoxy)decyl dihydrogenphosphate (R,R)-30. Eluent
for chromatography: EtOAc/MeOH/H2O (10:2:1); yield:
27
27
36%; ½aꢁD ¼ ꢀ5:2, ½aꢁ436 ¼ ꢀ10:7 (c 1.74, CH2Cl2); 1H
NMR 0.88 (t, J = 6.5 Hz, 6H), 1.20–1.55 (m, 28H), 3.40–
3.78 (m, 10H), 3.78–4.00 (m, 4H), 6.90 (br s, 3H, OH);
13C NMR 14.28, 14.30, 22.87, 22.90, 25.72, 25.77, 29.58,

2544
I. Kova´cs et al. / Tetrahedron: Asymmetry 17 (2006) 2538–2547
29.66, 29.85, 29.98, 30.20, 30.25, 32.11 (br probably two
carbon 13 signals together), 32.16 (br probably two carbon
13 signals together), 64.19, 64.23, 67.44, 70.60, 70.65, 70.67,
79.43, 81.00; 31P NMR 1.63; IR mmax 3288, 2928, 1464, 1348,
1104, 936, 828 cmꢀ1; MS: 499 (M+1)+. Anal. Calcd for
C24H51O8P: C, 57.81; H, 10.31 . Found: C, 57.64; H, 10.42.
2.10; IR mmax 3400, 2928, 1460, 1352, 1104, 804 cmꢀ1
;
MS: 543 (M+1)+. Anal. Calcd for C26H55O9P: C, 57.54;
H, 10.22. Found: C, 57.40; H, 10.31.
4.3. General procedure for the preparation of oligoethylene
glycols (S,S)-15, (S,S)-17, (S,S)-19, (S,S)-21, (S,S)-23 and
(S,S)-25, procedure A (see also Scheme 2)
4.2.13. (2S)-1-(2-{2-[(2S)-2-Hydroxydecyloxy]ethoxy}eth-
oxy)decan-2-yl dihydrogenphosphate (S,S)-31. Eluent
for chromatography: EtOAc/MeOH/H2O (10:2:1); yield:
To a suspension of NaH (5.6 g, 140 mmol, 60% dispersion
in mineral oil) in THF (30 mL) was added dropwise at 0 ꢁC
under argon, 2-tetrahydropyranyloxy-alkane-1-ols (S)-36–
(S)-38 (100 mmol) dissolved in THF (140 mL). The reac-
tion mixture was stirred at 0 ꢁC for 10 min, at rt for
20 min and at reflux temperature for 3 h. The reaction mix-
ture was cooled to 0 ꢁC and either diethylene glycol ditosy-
late 39 or triethylene glycol ditosylate 40 (45 mmol in both
cases) dissolved in THF (70 mL) was added dropwise. Stir-
ring was continued at 0 ꢁC for 10 min and then at rt for
4 days. The solvent was removed and the residue taken
up in a mixture of ice (50 g), water (100 mL) and ether
(300 mL). The mixture was shaken well and separated.
The aqueous phase was extracted with ether
(2 · 100 mL). The combined organic phase was shaken
with saturated brine (200 mL), dried over MgSO4, filtered
and the solvent evaporated. The residue was dissolved in
MeOH (500 mL) and Amberliteꢂ IR-120 strong acidic
ion-exchange resin (H+ form) (4 g) was added to this solu-
tion. After stirring the mixture at rt for 2 days, the resin
was filtered off and washed with MeOH (3 · 30 mL). The
filtrate and washings were combined and the solvent was
evaporated. The crude product was purified by column
chromatography on silica gel. Eluents are given for each
individual compound (see below).
27
27
31%; ½aꢁD ¼ þ9:8, ½aꢁ436 ¼ þ20:1 (c 2.29, CH2Cl2); 1H
NMR 0.84 (t, J = 6.3 Hz, 6H), 1.13–1.47 (m, 26H), 1.50–
1.68 (m, 2H), 3.18–3.94 (m, 13H), 4.10–4.41 (m, 1H) 6.40
(br s, 3H, OH); 13C NMR 14.23, 14.25, 22.82, 22.86,
25.45, 25.88, 29.54, 29.69, 29.83, 29.96, 30.06, 30.30,
32.08, 32.15, 32.85, 33.66, 69.98, 70.03, 70.07, 73.41,
74.19, 74.22, 75.54 (br probably two carbon 13 signals to-
gether); 31P NMR 1.90; IR mmax 3250, 2928, 1464, 1352,
1108, 800 cmꢀ1; MS: 499 (M+1)+. Anal. Calcd for
C24H51O8P: C, 57.81; H, 10.31. Found: C, 57.62; H,
10.39.
4.2.14. (2S,15S)-15-Hydroxy-4,7,10,13-tetraoxahexadecan-
2-yl dihydrogenphosphate (S,S)-32. Eluent for chromato-
graphy: EtOAc/MeOH/H2O (10:5:2); yield: 16%;
23
23
1
½aꢁD ¼ þ8:75, ½aꢁ436 ¼ þ16:9 (c 4.16, CH2Cl2); H NMR
1.07 (d, J = 6.4 Hz, 3H), 1.19 (d, J = 6.2 Hz, 3H), 3.20–
3.71 (m, 16H), 3.87–4.00 (m, 1H), 4.33–4.49 (m, 1H),
7.14 (br s, 3H, OH); 13C NMR 18.78, 19.09, 66.07, 70.22,
70.28 (br probably three carbon 13 signals together),
70.40, 70.58, 75.26, 75.34, 76.91; 31P NMR 2.58; IR
mmax 3250, 2864, 1456, 1376, 1350, 1248, 1104, 1000, 932
cmꢀ1; MS: 347 (M+1)+. Anal. Calcd for C12H27O9P: C,
41.62; H, 7.86. Found: C, 41.41; H, 7.95.
4.3.1. (2S,20S)-1,10-[Oxybis(ethyleneoxy)]di(propane-2-ol)
(S,S)-15. Tetraethylene glycol (S,S)-15 prepared accord-
ing to procedure A was identical in every respect to the
one obtained by the reported24 method. Eluent for chroma-
tography: EtOAc/EtOH (9:1); yield: 70%.
4.2.15. (4S,17S)-17-Hydroxy-2,19-dimethyl-6,9,12,15-tetra-
oxaeicosan-4-yl dihydrogenphosphate (S,S)-33. Eluent for
chromatography: EtOAc/MeOH/H2O (10:2:1.4); yield:
23
23
10%; ½aꢁD ¼ ꢀ11:4, ½aꢁ436 ¼ ꢀ22:3 (c 2.47, CH2Cl2); 1H
NMR 0.88 (d, J = 6.4 Hz, 6H), 0.90 (d, J = 6.9 Hz, 6H),
1.07–1.16 (m, 1H), 1.28–1.45 (m, 2H), 1.46–1.60 (m, 1H),
1.67–1.84 (m, 2H), 3.27–3.38 (m, 1H), 3.40–3.49 (m, 1H),
3.49–3.77 (m, 14H), 3.79–3.89 (m, 1H), 4.24–4.37 (m,
1H), 6.00 (br s, 3H, OH); 13C NMR 22.45, 23.00, 23.40,
23.58, 24.35, 24.58, 42.12, 42.41, 68.13, 70.18, 70.24 (br
probably two carbon 13 signals together), 70.26 (br proba-
bly two carbon 13 signals together), 70.39, 72.58, 74.18,
76.19; 31P NMR 1.99; IR mmax 3384, 2872, 1472, 1368,
1108, 932 cmꢀ1; MS: 431 (M+1)+. Anal. Calcd for
C18H39O9P: C, 50.22; H, 9.13. Found: C, 50.03; H,
9.29.
4.3.2. (2S,20S)-1,10-[Oxybis(ethyleneoxy)]bis(4-methylpen-
tane-2-ol) (S,S)-17. Tetraethylene glycol (S,S)-17 pre-
pared according to procedure A was identical in every
respect to the one obtained by the reported26 method. Elu-
ent for chromatography: EtOAc/hexane (1:1); yield: 72%.
4.3.3.
(2S,20S)-1,10-[Oxybis(ethyleneoxy)]di(decane-2-ol)
(S,S)-19. Eluent for chromatography: toluene/EtOAc
26
(4:1); yield: 73%; mp: 41–43 ꢁC; ½aꢁD ¼ þ14:3,
26
1
½aꢁ436 ¼ þ27:9 (c 1.0, CHCl3); H NMR 0.88 (t, J = 7 Hz,
6H), 1.2–1.55 (m, 28H), 3.31 (dd, Jgem = 10.2 Hz,
Jvic = 8.5 Hz, 2H), 3.54 (dd, Jgem = 10.2 Hz, Jvic = 2.5 Hz,
2H), 3.62–3.72 (m, 8H), 3.75–3.82 (m, 2H), 3.92 (br s,
2H, OH); IR (KBr) mmax 3424, 2920, 2848, 1472,
4.2.16. (9S,22S)-22-Hydroxy-11,14,17,20-tetraoxatriacon-
tan-9-yl dihydrogenphosphate (S,S)-34. Eluent for chro-
matography: EtOAc/MeOH/H2O (10:2:1); yield: 15%;
1152 cmꢀ1
.
24
24
½aꢁD ¼ þ8:1, ½aꢁ436 ¼ þ16:6 (c 1.46, CH2Cl2); 1H NMR
0.88 (t, J = 6.3 Hz, 6H), 1.17–1.49 (m, 26H), 1.53–1.69
(m, 2H), 3.31–3.41 (m, 1H), 3.43–3.85 (m, 16H), 4.15–
4.31 (m, 1H), 5.14 (br s, 3H, OH); 13C NMR 14.12,
14.15, 22.71, 22.74, 25.34, 25.73, 29.40, 29.56, 29.68,
29.83, 29.91, 30.16, 31.95, 32.03, 32.73, 33.47, 69.85,
69.95, 69.99, 70.03, 70.18, 73.41, 74.00, 75.53; 31P NMR
4.3.4.
(2S,15S)-4,7,10,13-Tetraoxahexadecane-2,15-diol
(S,S)-21. Pentaethylene glycol (S,S)-21 prepared accord-
ing to procedure A was identical in every respect to the
one obtained by the reported24 method. Eluent for chroma-
tography: EtOAc/MeOH/H2O (25:2:2); yield: 67%.

I. Kova´cs et al. / Tetrahedron: Asymmetry 17 (2006) 2538–2547
2545
20
20
4.3.5.
(4S,17S)-2,19-Dimethyl-6,9,12,15-tetraoxacosane-
hexane (5:4); yield: 62%; ½aꢁD ¼ ꢀ6:9, ½aꢁ436 ¼ ꢀ10:7 (c
1
4,17-diol (S,S)-23. Eluent for chromatography: EtOAc/
2.34, CH2Cl2); H NMR 0.91 (d, J = 6.4 Hz, 12H), 1.07–
26
hexane/MeOH/H2O (25:5:2:0.5); yield: 51%; ½aꢁD ¼ þ3:3,
26
1.26 (m, 2H), 1.32–1.54 (m, 2H), 1.62–1.82 (m, 2H),
3.38–3.93 (m, 16H), 13C NMR 22.63, 23.10, 24.68, 40.30,
64.91, 68.60, 70.90, 80.22; IR mmax 3408, 2952, 2872,
½aꢁ436 ¼ þ6:3 (c 2.0, CH2Cl2); 1H NMR 0.91 (d,
J = 6.6 Hz, 6H), 0.93 (d, J = 6.6 Hz, 6H), 1.07–1.17 (m,
2H), 1.34–1.45 (m, 2H), 1.73–1.89 (m, 2H), 3.1 (br s, 2H,
OH), 3.29 (dd, Jgem = 9.8 Hz, Jvic = 8.3 Hz, 2H); 3.50
(dd, Jgem = 9.8 Hz, Jvic = 2.7 Hz, 2H), 3.61–3.72 (m,
12H), 3.82–3.92 (m, 2H); 13C NMR 22.11, 23.43, 24.43,
41.90, 68.25, 70.50, 70.51, 70.54, 76.39; IR mmax 3448,
1468, 1368, 1100, 948 cmꢀ1
.
4.4.3.
(2R,20R)-2,20-[Oxybis(ethyleneoxy)]di(decane-1-ol)
(R,R)-18. Eluent for chromatography: hexane/acetone
23
(5:1); yield: 84%; ½aꢁ365 ¼ ꢀ22:3 (c 1.43, CHCl3); 1H
2952, 2872, 1468, 1112 cmꢀ1
.
NMR 0.88 (t, J = 7.0 Hz, 6H), 1.20–1.60 (m, 28H), 3.37–
3.43 (m, 2H), 3.49 (dd, Jgem = 11.7 Hz, Jvic = 7.5 Hz, 2H);
3.60 (dd, Jgem = 11.7 Hz, Jvic = 2.5 Hz, 2H), 3.55–3.82
(m, 8H), 4.1 (br s, 2H, OH); 13C NMR 14.03, 22.60,
25.64, 29.21, 29.48, 29.73, 31.08, 31.82, 64.74, 68.69,
4.3.6. (9S,22S)-11,14,17,20-Tetraoxatriacontane-9,22-diol
(S,S)-25. Eluent for chromatography: EtOAc/hexane/
MeOH/H2O (25:5:2:1); mp: 33–34 ꢁC; yield: 56%;
27
27
½aꢁD ¼ þ7:4, ½aꢁ436 ¼ þ14:7 (c 1.9, CH2Cl2); 1H NMR
0.88 (t, J = 6.5 Hz, 6H), 1.20–1.50 (m, 28H), 3.11 (br s,
2H, OH), 3.31 (dd, Jgem = 9.7 Hz, Jvic = 8.7 Hz, 2H); 3.52
(dd, Jgem = 9.7 Hz, Jvic = 2.2 Hz, 2H), 3.60–3.72 (m,
12H), 3.75–3.82 (m, 2H); 13C NMR 14.31, 22.88, 25.81,
29.49, 29.76, 29.94, 32.09, 33.21, 70.37, 70.71, 70.73,
76.76, 76.18; IR (KBr) mmax 3448, 2928, 2856, 1456, 1368,
70.81, 81.89; IR mmax 3432, 2928, 2856, 1450, 1108 cmꢀ1
.
4.4.4. (2S,13S)-2,13-Dimethyl-3,6,9,12-tetraoxatetradecane-
1,14-diol (S,S)-20. Eluent for chromatography: EtOAc/
25
MeOH/H2O
(10:1:1);
yield:
46%;
½aꢁD ¼ þ29:5,
25
½aꢁ436 ¼ þ57:6 (c 2.38, CH2Cl2); 1H NMR 0.94 (d,
J = 6.5 Hz, 6H), 3.28 (dd, Jgem = 11.5 Hz, Jvic = 7.0 Hz,
2H); 3.37 (dd, Jgem = 11.5 Hz, Jvic = 3.0 Hz, 2H); 3.42–
3.52 (m, 12H); 3.54–3.59 (m, 2H); 3.62 (br s, 2H, OH);
13C NMR 15.99, 65.76, 67.77, 70.11, 70.52, 76.63; IR mmax
1108, 736, 696 cmꢀ1
.
4.4. General procedure for the preparation of oligoethylene
glycols (S,S)-14, (S,S)-16, (R,R)-18, (S,S)-20, (S,S)-22 and
(S,S)-24. Procedure B (see also Scheme 2)
3432, 2872, 1460, 1376, 1248, 1096, 1048, 960 cmꢀ1
.
4.4.5.
(2S,13S)-2,13-Diisobutyl-3,6,9,12-tetraoxatetrade-
To a suspension of NaH (8.4 g, 210 mmol, 60% dispersion
in mineral oil) in THF (45 mL) was added dropwise at 0 ꢁC
under argon 1-benzyloxymethyl-alkane-1-ols (S)-41–(S)-43
(150 mmol) dissolved in THF (200 mL). The reaction mix-
ture was stirred at 0 ꢁC for 10 min, at rt for 20 min and at
reflux temperature for 3 h. The reaction mixture was cooled
to 0 ꢁC and diethylene glycol ditosylate 39 or triethylene
glycol ditosylate 40 (70 mmol in both cases) dissolved in
THF (100 mL) was added dropwise. Stirring was continued
at 0 ꢁC for 10 min, then at rt for 4 days. The solvent was
removed and the residue was taken up in a mixture of ice
(70 g), water (150 mL) and ether (450 mL). The mixture
was shaken well and separated. The aqueous phase was
shaken with ether (2 · 150 mL). The combined organic
phase was shaken with saturated brine (300 mL), dried
over MgSO4, filtered and the solvent evaporated. The rele-
vant dibenzyl derivative was dissolved in MeOH (800 mL),
charcoal added and the resulting suspension stirred at rt for
2 h. This was filtered and hydrogenated in the presence of
Pd/C catalyst (3 g, Merck palladium/charcoal; activated,
10% Pd) until the theoretical volume of hydrogen was con-
sumed. After the reaction was completed, the catalyst was
filtered off and the solvent evaporated. The crude product
was purified by column chromatography on silica gel. Elu-
ents are given for each individual compound (see below).
cane-1,14-diol (S,S)-22. Eluent for chromatography:
EtOAc/hexane/MeOH/H2O (20:5:2:0.5); yield: 62%;
26
26
½aꢁD ¼ ꢀ4:55, ½aꢁ436 ¼ ꢀ7:1 (c 2.13, CH2Cl2); 1H NMR
0.92 (d, J = 6.6 Hz, 12H), 1.09–1.25 (m, 2H), 1.39–1.53
(m, 2H), 1.62–1.79 (m, 2H), 3.41–3.53 (m, 4H), 3.56–3.80
(m, 14H), 3.85 (br s, 2H, OH); 13C NMR 22.60, 23.15,
24.61, 40.45, 64.96, 68.93, 70.32, 71.01, 79.77; IR mmax
3400, 2952, 2872, 1472, 1368, 1100, 952 cmꢀ1
.
4.4.6. (2S,13S)-2,13-Dioctyl-3,6,9,12-tetraoxatetradecane-
1,14-diol (S,S)-24. Eluent for chromatography: EtOAc/
27
hexane/MeOH/H2O (25:5:2:0.5); yield: 42%; ½aꢁD ¼ þ4:5,
27
½aꢁ436 ¼ þ9:8 (c 1.76, CH2Cl2); 1H NMR 0.83 (t, J =
7.0 Hz, 6H), 1.13–1.50 (m, 28H), 3.34 (br s, 2H, OH),
3.41–3.44 (m, 2H), 3.5–3.75 (m, 16H); 13C NMR 14.10,
22.67, 25.67, 29.28, 29.56, 29.81, 31.35, 31.89, 64.72,
69.07, 70.38, 70.99, 81.62; IR mmax 3448, 2928, 2856,
1464, 1348, 1104, 948 cmꢀ1
.
4.5. (S)-1-(Benzyloxy)propane-2-ol (S)-41
Benzyl-blocked glycol (S)-41 was prepared in the same way
as described below for (S)-42 (see also Scheme 2) starting
from (S)-3624 (15.54g, 97 mmol). Yield: 12.74 g (79%).
25
Bp: 130–132 ꢁC (14 mmHg); ½aꢁD ¼ þ4:8 (neat). Com-
pound (S)-41 prepared in this way was identical in every
4.4.1. (2S,20S)-2,20-[Oxybis(ethyleneoxy)]di(propane-1-ol)
(S,S)-14. Tetraethylene glycol (S,S)-14 prepared accord-
ing to procedure B was identical in every respect to the one
obtained by the reported23 method. Eluent for chromatogra-
phy: EtOAc/MeOH/H2O (10:1:0.5); yield: 59%.
respect to the one obtained by the reported35 method.
4.6. (S)-1-(Benzyloxy)-4-methylpentane-2-ol (S)-42
To a suspension of NaH (7.03 g, 175 mmol, 60% dispersion
in mineral oil) in THF (50 mL) was added dropwise at 0 ꢁC
under argon a solution of alcohol (S)-3726,30 (19.64 g,
97 mmol) in THF (130 mL). The reaction mixture was
4.4.2. (2S,20S)-2,20-[Oxybis(ethyleneoxy)]bis(4-methylpen-
tane-1-ol) (S,S)-16. Eluent for chromatography: EtOAc/

2546
I. Kova´cs et al. / Tetrahedron: Asymmetry 17 (2006) 2538–2547
stirred at 0 ꢁC for 10 min, then at rt for 20 min and at reflux
temperature for 3 h. The reaction mixture was cooled to
0 ꢁC and benzyl chloride (13.5 mL, 14.79 g, 117 mmol) dis-
solved in THF (20 mL) was added dropwise. The reaction
mixture was stirred at 0 ꢁC for 10 min, at rt for 20 min and
then at 50–55 ꢁC for 16 h. The solvent was removed and the
residue was taken up in a mixture of ice (50 g), water
(100 mL), saturated aqueous NaHCO3 solution (50 mL)
and ether (200 mL). The aqueous phase was extracted with
ether (4 · 50 mL). The combined organic phase was shaken
with saturated brine (100 mL), dried over MgSO4, filtered
and the solvent was evaporated. The residue was dissolved
in MeOH (400 mL) and Amberliteꢂ IR-120 strong acidic
ion-exchange resin (H+ form) (6 g) was added to this solu-
tion. After stirring the mixture at rt for 2 days, the resin
was filtered off and washed with MeOH (3 · 30 mL). The
filtrate and washings were combined and the solvent was
evaporated. The crude product was purified by distilla-
tion to give (S)-42 (15.46 g, 77%); bp: 116–118 ꢁC (0.76
tile materials were removed and the residue was purified by
distillation under reduced pressure to give (R)-45 (48.1 g,
93%) as a colourless oil. Bp: 61–62 ꢁC (0.02 mmHg), 153–
22
156 ꢁC (22 mmHg); ½aꢁD ¼ ꢀ3:07 (neat); n2D5: 1.4370. Re-
ported37 values for its antipode (S)-45: bp: 152–155 ꢁC
22
(22 mmHg); ½aꢁD ¼ þ3:0 (neat); n2D5: 1.4371.
4.10. Methyl (S)-2-hydroxydecanoate (S)-45
Compound (S)-45 was prepared in the same way as
described above for (R)-45 starting from (S)-44 (38.3 g,
0.203 mol). The crude product was purified by distillation
under reduced pressure to give (S)-45 (38.0 g, 92%) as a
colourless oil. Bp: 60–61 ꢁC (0.02 mmHg), 150–153 ꢁC
22
(22 mmHg); ½aꢁD ¼ ꢀ3:0 (neat); n2D5: 1.4368. Reported37
22
values: bp: 152–155 ꢁC (22 mmHg); ½aꢁD ¼ þ3:0 (neat);
n2D5: 1.4371.
4.11. Methyl (R)-2-[(tetrahydro-2H-pyran-2-yl)oxy]decano-
ate (R)-46
26
1
mmHg); ½aꢁ365 ¼ ꢀ2:4 (c 3.79, CH2Cl2); H NMR 0.90 (d,
J = 6.9 Hz, 3H), 0.92 (d, J = 6.9 Hz, 3H), 1.12–1.19 (m,
1H), 1.37–1.44 (m, 1H), 1.73–1.85 (m, 1H), 2.45 (br s,
1H, OH), 3.29 (dd, Jgem = 9.4 Hz, Jvic = 8.2 Hz, 1H); 3.47
(dd, Jgem = 9.4 Hz, Jvic = 3.1 Hz, 1H), 3.85–3.92 (m, 1H),
4.54 (s, 2H), 7.27–7.34 (m, 5H); 13C NMR 22.22, 23.56,
24.57, 42.20, 68.66, 73.46, 75.28, 127.87, 127.89, 128.58,
138.17; IR mmax 3432, 2952, 2888, 2872, 1456, 1368,
To a mixture of methyl ester (R)-45 (33.0 g, 163 mmol) and
dihydropyran (DHP) (22 mL, 20,33 g, 242 mmol) in dry
CH2Cl2 (240 mL) was added pyridinium p-toluenesulfo-
nate (PPTS) catalyst (0.9 g) and one drop of pyridine. After
stirring the reaction mixture at rt for 80 h, it was poured
into
a mixture of CH2Cl2 (200 mL) and ice-water
1104, 736, 696 cmꢀ1
.
(250 mL). The phases were mixed well and separated.
The aqueous phase was extracted with CH2Cl2 (50 mL).
The combined organic phase was shaken with saturated
NaHCO3 (80 mL), water (80 mL), dried over MgSO4, fil-
tered and the solvent was removed. The residue was puri-
fied by distillation under reduced pressure to give (R)-46
4.7. (R)-1-(Benzyloxy)decane-2-ol (R)-43
Benzyl-blocked glycol (R)-43 was prepared in the same way
as described above for (S)-42 (see also Scheme 2) starting
from (R)-38 (20.26 g, 78 mmol). The crude product was
(mixture of two diastereomers) as a colourless oil. Yield:
22
purified by distillation to give (R)-43 (17.84 g, 87%); bp:
43.4 g (93 %), bp: 80–90 ꢁC (0.02 mmHg); ½aꢁ365 ¼ þ85:6
25
1
147–151 ꢁC (0.05 mmHg); ½aꢁD ¼ ꢀ5:29 (c 2.57, CH2Cl2).
(c 2.13, THF); H NMR 0.88 (t, J = 7 Hz, 6H), 1.2–1.9
Compound (R)-43 prepared in this way was identical in
(m, 40H), 3.45–3.91 (m, 4H), 3.73 (s, 6H), 4.00 (dd,
J = 7.3, 5.9 Hz, 1H), 4.32 (dd, J = 6.6, 6.0 Hz 1H), 4.65
(t, J = 3.5 Hz, 1H), 4.66 (t, J = 3.5 Hz, 1H); 13C NMR
14.05, 18.98, 19.24, 22.61, 25.01, 25.21, 25.37, 25.46,
29.15, 29.19, 29.27, 29.28, 29.34, 30.33, 30.34, 31.80,
32.68, 32.99, 51.72, 51.69, 62.50, 62.17, 73.81, 77.59,
97.04, 99.84, 173.57; IR: mmax 2928, 2856, 1752, 1456,
every respect to the one obtained by the reported36 method.
4.8. (S)-1-(Benzyloxy)decane-2-ol (S)-43
Compound (S)-43 was prepared in the same way as de-
scribed above for (S)-42 (see also Scheme 2) starting from
(S)-38 (10.13 g, 39 mmol). The crude product was purified by
1440, 1200, 1128, 1028 cmꢀ1
.
distillation to give (S)-43 (8.51 g, 83%); bp: 146–150 ꢁC
25
(0.05 mmHg); ½aꢁD ¼ þ5:2 (c 2.48, CH2Cl2); 1H NMR
4.12. Methyl (S)-2-[(tetrahydro-2H-pyran-2-yl)oxy]decano-
ate (S)-46
0.88 (t, J = 7.0 Hz, 3H), 1.25–1.49 (m, 14H), 2.44 (br s,
2H, OH), 3.31 (dd, Jgem = 9.5 Hz, Jvic = 8.0 Hz, 1H), 3.49
(dd, Jgem = 9.5 Hz, Jvic = 3.0 Hz, 1H), 3.72–3.82 (m, 1H),
4.54 (s, 2H), 7.27–7.34 (m, 5H); 13C NMR 14.12, 22.68,
25.54, 29.27, 29.54, 29.69, 31.89, 33,18, 70.43, 73.32,
74.71, 127.73, 128.44, 138.05; IR mmax 3448, 2928, 2856,
Compound (S)-46 was prepared in the same way as de-
scribed above for (R)-46 starting from (S)-45 (48 g,
0.237 mol). The crude product was purified by distillation
to give (S)-46 (mixture of two diastereomers) as a colour-
1456, 1368, 1108, 736, 696 cmꢀ1
.
less oil. Yield: 65.0 g (95%), bp: 78–90 ꢁC (0.02 mmHg);
27
½aꢁ365 ¼ ꢀ88:6 (c 1.00, THF).
4.9. Methyl (R)-2-hydroxydecanoate (R)-45
4.13. (R)-2-[(Tetrahydro-2H-pyran-2-yl)oxy]decane-1-ol
(R)-38
To a stirred mixture of (R)-2-hydroxydeconoic acid (R)-44
(47.9 g, 0.254 mol) in dry and pure methanol (210 mL) was
added very slowly at ꢀ10 ꢁC and under Ar, SOCl2 (23 mL).
After the addition of SOCl2, the reaction mixture was stir-
red at ꢀ10 ꢁC for 10 min. It was then allowed to warm up
to rt and stirring was continued for another 4 h. The vola-
To a well stirred suspension of LiAlH4 (7.2 g, 190 mmol) in
ether (280 mL) at 0 ꢁC was slowly added (R)-46 (43 g,
150 mmol) dissolved in ether (60 mL). The mixture was stir-
red at rt for 22 h. When the reduction was completed, the

I. Kova´cs et al. / Tetrahedron: Asymmetry 17 (2006) 2538–2547
2547
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Biernat, J. F.; Koyama, H.; McDaniel, C. W.; Wood, S. A.;
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Christensen, J. J. Studies Org. Chem. 1987, 31, 553–560.
mixture was cooled in an ice–salt bath and saturated NH4Cl
(7 mL), 15% NaOH solution (5 mL) and water (5 mL) were
added very slowly. The resulting mixture was stirred at rt
for 3 h. The precipitate was filtered and washed with ether
(3 · 50 mL).The filtrate and washings were combined and
shaken with saturated brine (50 mL), dried over MgSO4
and the solvent was removed to give crude (R)-38 (38.4 g,
99%) as a mixture of two diastereomers, which was used
´
10. Huszthy, P.; Kertesz, J.; Bradshaw, J. S.; Izatt, R. M.; Redd,
J. T. J. Heterocycl. Chem. 2001, 38, 1259–1264.
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without further purification; Rf = 0.48, 0.34 (silica TLC,
23
hexane/EtOAc 9:3); yield: 38.4 g (99%); ½aꢁ365 ¼ þ45:1
1
(c 1.04, THF); H NMR 0.88 (t, J = 7 Hz, 6H), 1.2–1.9
(m, 40H), 2.31 (t, J = 6.2 Hz, 1H, OH), 3.43–4.04 (m,
10H), 3.96 (dd, J = 9.5, 2.5 Hz, 1H, OH), 4.44–4.48 (m,
1H) 4.73–4.77 (m, 1H); 13C NMR 14.09, 20.15, 21.29,
22.65, 25.03, 25.35, 25.62, 25.63, 29.23, 29.26, 29.49,
29.73, 29.54, 31.13, 31.48, 31.59, 31.86, 31.93, 64.06,
66.24, 63.33, 65.09, 77.76, 83.67, 97.75, 101.77; IR mmax
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3432, 2928, 2856, 1456, 1136, 1076, 1024 cmꢀ1
.
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(S)-38
´
´
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Nogradi, M. Tetrahedron: Asymmetry 2003, 14, 2803–
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Compound (S)-38 was prepared in the same way as de-
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209 mmol). The crude product (S)-38 (50.2 g, 93%, as a
mixture of two diastereomers) was used without further
´
´
´
19. Szalay, L.; Farkas, V.; Vass, E.; Hollosi, M.; Moczar, I.;
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23
10:0.3); ½aꢁ365 ¼ ꢀ50:5 (c 1.00, THF).
Acknowledgements
´
´
´
´
´
´
The authors thank Professor Mihaly Nogradi and Dr. Jo-
zsef Nagy (Institute for Organic Chemistry, BUTE) for
their help. Financial support of the National Scientific
Research Fund of Hungary (OTKA, T-038393 and K
062654) is gratefully acknowledged.
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Chem. 1982, 19, 551–556.
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