Multigram Synthesis of Well-Defined Extended Bifunctional Polyethylene Glycol (PEG) Chains

Article abstract of DOI:10.1021/jo035042v

A series of novel, well-defined, unsymmetrical poly(ethylene glycol) chains of the type X(OCH₂-CH₂)_nY (where X = protecting group; Y = nucleofuge or a different protecting group; n = 3, 6, 9, 12, 15, 18, and 24) were prepared in high yields by applying orthogonal protecting groups. The purity of the compounds was fully verified by elemental and high-resolution mass spectrometry analyses.

Full text of DOI:10.1021/jo035042v

Mu ltigr a m Syn th esis of Well-Defin ed Exten d ed Bifu n ction a l
P olyeth ylen e Glycol (P EG) Ch a in s
Franc¸ois A. Loiseau, King Kuok (Mimi) Hii,* and Alison M. Hill†
Department of Chemistry, King’s College London, Strand, London WC2R 2LS, UK, and
School of Chemistry, University of Exeter, Stocker Road, Exeter EX4 4QD, UK
mimi.hii@imperial.ac.uk
Received J uly 18, 2003
A series of novel, well-defined, unsymmetrical poly(ethylene glycol) chains of the type X(OCH2-
CH2)nY (where X ) protecting group; Y ) nucleofuge or a different protecting group; n ) 3, 6, 9,
12, 15, 18, and 24) were prepared in high yields by applying orthogonal protecting groups. The
purity of the compounds was fully verified by elemental and high-resolution mass spectrometry
analyses.
SCHEME 1. Rep or ted Syn th esis of Exten d ed
Sym m etr ica l P EG Ch a in sa
In tr od u ction
The incorporation of hydrophilic poly(ethylene glycol)
(PEG) units into peptides, proteins, and biopolymers
often transforms their physical properties and biological
activities.1 Exploited extensively in the design and syn-
thesis of biomolecules, the efficacy of these modified
compounds are often dependent on the length of the PEG
chains attached. Nevertheless, the synthesis of long
monodisperse PEGn chains H(OCH2CH2)nOH (where n
g 12) is rare and remains a synthetic challenge. Ex-
tended homologues are most commonly prepared from
shorter, commercially available PEG chains from mono-
or difunctionalized derivatives 1 and 2 (Scheme 1). This
strategy is limited by the availability of monoprotected
and bifunctional PEGs (1 and 3).2,3 As an excess of one
of the reactants is needed to maximize the yield of these
unsymmetrical PEGs,4 further extension of the chain
length becomes an impractical and expensive exercise.
To date, examples of long PEGs are limited to no more
than a handful of symmetrical diols H(OCH2CH2)nOH,
where n ) 12,5,6 13,7 14,8 18,9 28,6 and 42.9 Purification
a
Key: (i) Monoprotection; (ii) ditosylation; (iii) coupling.
procedures for these compounds were rarely reported,
and characterization data were often poor or nonexistent.
Unsymmetrical PEGn chains were prepared by Will-
iamson reaction between a monoprotected diol with a
monoprotected halide (Scheme 2). PEGs with up to 12
ethylenoxy units were obtained by this method with
yields between 16 and 80%.10 However, due to the forcing
conditions required for the ether synthesis (>100 °C for
3 days), the formation of side products becomes a
significant issue for certain chain lengths.11 In a different
approach, 2-(benzyloxy)ethanol and potassium hydride
were used, as initiator and base, respectively, in a
controlled anionic polymerization of ethylene oxide, to
* Corresponding author. Current address: Department of Chemis-
try, Imperial College London, South Kensington SW7 9AY, UK. This
work was conducted at King’s College London.
† Exeter University.
(1) Recent articles in the area: (a) Luxon, B. A.; Grace, M.; Brassard,
D.; Bordens, R. Clin. Ther. 2002, 24, 1363-1383. (b) Roberts, M. J .;
Bentley, M. D.; Harris, J . M. Adv. Drug Delivery Rev. 2002, 54, 459-
476. (c) Hinds, K. D.; Kim, S. W. Adv. Drug Delivery Rev. 2002, 54,
505-530. (d) Youngster, S.; Wang, Y. S.; Grace, M.; Bausch, J .;
Bordens, R.; Wyss, D. F. Curr. Pharm. Design 2002, 8, 2139-2157.
(e) Otsuka, H.; Nagasaki, Y.; Kataoka, K. Curr. Opin. Coll. Interface
Sci. 2001, 6, 3-10. (f) Torchilin, V. P. J . Controlled Release 2001, 73,
137-172. (g) Lentz, B. R.; Lee, J . K. Mol. Membrane Biol. 1999, 16,
279-296.
(6) Harada, A.; Li, J .; Kamachi, M. J . Am. Chem. Soc. 1994, 116,
3192-3196.
(2) Herve´, G.; Hahn, D. U.; Herve´, A.-C.; Goodworth, K. J .; Hill, A.
M.; Hailes, H. C. Org. Biomol. Chem. 2003, 1, 427-435.
(3) An example of an amine-azide derivative prepared from HO-
PEG3-OH was reported: Schwabacher, A. W.; Lane, J . W.; Schiesher,
M. W.; Leigh, K. M.; J ohnson, C. W. J . Org. Chem. 1998, 63, 1727-
1729.
(4) Svedhem, S.; Hollander, C.; Shi, J .; Konradsson, P.; Liedberg,
B.; Svensson, S. C. T. J . Org. Chem. 2001, 66, 4494-4503.
(5) Keegstra, E. M. D.; Zwikker, J . W.; Roest, M. R.; J enneskens, L.
W. J . Org. Chem. 1992, 57, 6678-6680.
(7) Andrus, M. B.; Turner, T. M.; Updegraff, E. P.; Sauna, Z. E.;
Ambudkar, S. V. Tetrahedron Lett. 2001, 42, 3819-3822.
(8) Chen, Y.; Baker, G. L. J . Org. Chem. 1999, 64, 6870-6873.
(9) Fordyce, R.; Lovell, E. L.; Hibbert, H. J . Am. Chem. Soc. 1939,
61, 1905-1910.
(10) Burns, C. J .; Field, L. D.; Hashimoto, K.; Petteys, B. J .; Ridley,
D. D.; Sadanayake, K. R. A. S. Synth. Commun. 1999, 29, 2337-2347
and references therein.
(11) Boden, N.; Bushby, R. J .; Clarkson, S.; Evans, S. D.; Knowles,
P. F.; Marsh, A. Tetrahedron 1997, 53, 10939-10952.
10.1021/jo035042v CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/14/2004
J . Org. Chem. 2004, 69, 639-647
639

Loiseau et al.
SCHEME 2. Rep or ted Syn th esis of Exten d ed
SCHEME 3. P r op osed Rou te for th e P r ep a r a tion
of Lon g P EG Ch a in sa
Un sym m etr ica l P EG Ch a in s (X ) Nu cleofu ge)a
a
PG ) CPh3, CH2Ph, THP.
F IGURE 1.
give PEG monobenzyl ethers with molecular weights of
1000, 2000, and 4500 amu with polydispersities (Mw/Mn)
of 1.04 or less. However, the procedures are technically
demanding, as the purity of the reagents and solvents
were found to be critical for reproducible results.12
As part of our ongoing study of hydrophilic and
functionalized calix-[8]-arenes 5 (Figure 1),2 we required
access to extended unsymmetrical bifunctional PEGns
(particularly those with n g 12). In this paper, we report
the development of a general procedure for the prepara-
tion of unsymmetrical PEGn chains of the type X(OCH2-
CH2)nY (where X ) protecting group; Y ) nucleofuge or
a different protecting group; n ) 3, 6, 9, 12, 15, 18, and
24), by the introduction of orthogonal protecting groups
in a specific sequence. Successive chain extensions may
then be achieved using these unsymmetrical PEGs
(Scheme 3).
a
Key: (i) Desymmetrization; (ii) tosylation; (iii) extension; (iv)
deprotection.
SCHEME 4. Desym m etr iza tion of P EG-d iolsa
Resu lts a n d Discu ssion
Mon ofu n ction a liza tion of P oly(eth ylen e glycol)
Diols (Scheme 4). Using substoichiometric amounts of
dihydropyran (Method A), the introduction of a THP
protecting group furnished products 6 and 7 only in low
to moderate yields (e55%). Coupled this with known
problems of THP transfer during subsequent ether
synthesis,10 the use of this fragile protecting group was
generally not used in this initial step.
In contrast, monotosylation (Method B) and benzyla-
tion (Method C) of symmetrical diols may be achieved in
the presence of freshly prepared silver(I) oxide, using
stoichiometric amounts of the reagents.13 The presence
of potassium iodide is not always necessary, e.g., for the
preparation of 8, a very high yield (92%) can be achieved
without the presence of the additive. Commercially
available PEG3 and PEG6 diols can thus be desymme-
trized, furnishing monofunctionalized tosylate and ben-
zyl-protected PEGs 8-11 in good to excellent yields and
high purity.
a
Method A: dihydropyran, p-TsOH, 2 h, room temperature.
Method B: TsCl, Ag2O, KI (needed only for PEG6), CH2Cl2, 15-
20 min, 0 °C. Method C: BnBr, Ag2O, KI, CH2Cl2, 2 h, room
temperature. Method D: PMBCl, Ag2O, KI, toluene, reflux (2 h,
room temperature for PEG3). Method E: TrCl, Ag2O, KI, CH2Cl2,
reflux.
surprisingly (Table 1), the introduction of the PMB group
onto the PEG6 diol was considerably slower than the
corresponding benzylation reaction, requiring elevated
temperatures for a respectable yield of the monoprotected
diol 13 (Method D, 67%).
With slight modifications, the procedure is applicable
for the introduction of a p-methoxybenzyl (PMB) group,
furnishing 12 and 13 in reasonably good yields. Rather
Using similar reaction conditions, the bulky trityl
protecting group may also be introduced onto PEG6 diol
to furnish 14 in a fairly good yield (Method E).
(12) Reed, N. N.; J anda, K. D. J . Org. Chem. 2000, 65, 5843-5845.
(13) Bouzide, A.; Sauve´, G. Org. Lett. 2002, 4, 2329-2332.
640 J . Org. Chem., Vol. 69, No. 3, 2004

Extended Bifunctional Polyethylene Glycol Chains
TABLE 1. Rea ction Op tim iza tion for th e Syn th esis of
13 by Meth od D (Sch em e 4)a
SCHEME 6. F ir st Exten sion for th e Syn th esis of
Un sym m etr ica l P EG9 a n d P EG12 Ch a in s
reaction time/h KI/equiv solvent
temperature % yieldb
2
15
15
16
17
17
0.2
0.2
0.2
0.5
0.6
0.8
CH2Cl2
CH2Cl2
toluene
toluene
toluene
toluene
ambient
reflux
reflux
reflux
reflux
reflux
36
51
58
66
67
64
a
Typical reaction conditions: PEG6 diol (1 equiv), PMBCl (1.1
b
equiv), Ag2O (1.5 equiv). Isolated yields after purification.
SCHEME 5. Bifu n ction a l P EG3 a n d P EG6 Un itsa
TABLE 3. Syn th esis of Un sym m etr ica lly P r otected
P EG9 to P EG12 Ch a in sa
entry PG1 (m) PG2 (n)
product
% yieldb
1
2
3
4
5
6
7
8
9
PMB (6) THP (3) PMB(OCH2CH2)9OTHP (21) 80 (11)
Bn (3) THP (6) Bn(OCH2CH2)9OTHP (22)
Bn (6) THP (3)
Bn (3) PMB (6) Bn(OCH2CH2)9OPMB (23)
84 (6)
81 (7)
83 (8)
87 (3)
PMB (6)
Bn (3)
PMB (6) THP (6) PMB(OCH2CH2)12OTHP(24) 86 (4)
PMB (6)
Bn (6) PMB (6)
Bn (6) THP (6) Bn(OCH2CH2)12OTHP (26)
Bn (6) Bn(OCH2CH2)12OPMB (25)
84 (9)
83 (5)
85 (6)
a
Key: (i) protection; (ii) tosylation.
TABLE 2. P r ep a r a tion of TsO(CH2CH2O)m P G
(Sch em e 5)a
a
Reaction conditions: the alcohol was stirred with 1.8 equiv of
NaH in THF for 20 to 24 h, prior to the addition of the tosylate,
and reacted further for 3 days. Isolated yields after purification.
Value in parentheses correspond to % yield of the vinyl ether side
product 27.
entry
m
product
method
% yieldb
b
1
2
3
4
5
6
7
8
9
3
TsO(CH2CH2O)3Bn (15)
A
B
A
B
A
B
A
B
A
B
A
B
66 (61)
90 (81)
83 (71)
91 (76)
74 (68)
81 (60)
67 (57)
74 (50)
98 (90)
79 (43)
96 (82)
85 (37)
6
3
6
3
6
TsO(CH2CH2O)6Bn (16)
TsO(CH2CH2O)3PMB (17)
TsO(CH2CH2O)6PMB (18)
TsO(CH2CH2O)3THP (19)
TsO(CH2CH2O)6THP (20)
MS analysis of the crude reaction mixture revealed the
presence of the desired product Bn(OCH2CH2)6Cl (36%),
accompanied by a significant amount of the truncated
Bn(OCH2CH2)4Cl (34%), which corresponded to a loss of
two ethylenoxy units. Attempted chlorination of Bn-
(OCH2CH2)9OH led similarly to a mixture of Bn(OCH2-
CH2)9Cl (43%) and, interestingly, Bn(OCH2CH2)8Cl (24%),
with a loss of only one ethylenoxy unit in this instance.
Indeed, the reaction between polyethylenoxy alcohols and
thionyl chloride is known to be prone to competitive
“depolymerization” reactions, as was reported previously
by Bushby et al.11 As a result, only the tosylates 15-20
were utilized as electrophilic precursors in our subse-
quent work on PEG chain extensions.
F ir st E xt en sion -Syn t h esis of Un sym m et r ica l
P EG9 a n d P EG12 Ch a in s (Scheme 6, Table 3). Reaction
of the bifunctional PEG chains 15-20 with the mono-
protected alcohols 10-13 led to orthogonally protected
PEGs containing up to 12 ethylenoxy units. Provided that
the alcohol component was allowed to react with the base
up to 24 h prior to the addition of the electrophilic
component, very little vinyl ether side product 27 (result-
ing from elimination of the tosylate11) was formed, which
can be easily removed by column chromatography, fur-
nishing the requisite extended chains in good yields
(>80%).
10
11
12
a
Method A: protection of monotosylate. Method B: tosylation
b
of monoprotected diol. Isolated yields after purification. Value
in parentheses is the overall yield over two steps from the
commercially available diol.
These desymmetrization reactions were not applicable
to the longer PEG diols. Attempted monotosylation of
PEG12 and PEG18 diols (prepared earlier through the
nondirectional route, described in Scheme 1) led to a
mixture of the starting material, as well as mono- and
ditosylated products in roughly statistical ratios.
Mon op r otected P EG3 a n d P EG6 Tosyla tes (Scheme
5, Table 2). The desymmetrized diols may either be
subjected to protection (8 and 9, Method A, with THP,
Bn, or PMB) or tosylation (6, 7, 10-13, Method B) to
furnish bifunctional PEGs in high yields. The synthesis
of tosylates 15-20 can be accomplished in moderate to
good yields (57-90%) from the corresponding diols over
two steps. To the best of our knowledge, this represents
the shortest, highest yielding synthesis of these bifunc-
tional molecules.
Select ive (Mon o-) Dep r ot ect ion a n d Tosyla t ion
(Scheme 7). The protecting groups were selectively
removed, furnishing a hydroxyl site for further chain
extension. Compatibility issues between the three dif-
ferent protecting groups needed to be taken into account
at this stage. For example, the benzylic protecting groups
were stable under the acidic conditions required for the
deprotection of the THP group, but not vice versa.
Likewise, PMB may be oxidatively cleaved in the pres-
In contrast, we failed repeatedly in our attempts to
chlorinate the monobenzyl-protected 11 using thionyl
chloride (with or without pyridine), even though it has
been previously reported to proceed in high yields.14 GC-
(14) Gartiser, T.; Selve, C.; Mansuy, L.; Robert, A.; Delpuech, J .-J .
J . Chem. Res., Synop. 1984, 292-293.
J . Org. Chem, Vol. 69, No. 3, 2004 641

Loiseau et al.
TABLE 4. Syn th esis of Un sym m etr ica lly P r otected
P EG12 to P EG24 Ch a in sa
SCHEME 7. Selective Mon od ep r otection of
Bifu n ction a l P EGsa
entry PG1 (p) PG2 (m)
product
% yieldb
1
2
3
4
5
6
7
8
9
10
11
12
13
PMB (9)
Bn (9) PMB (3) Bn(OCH2CH2)12OPMB (25)
THP (3) PMB(OCH2CH2)12OTHP (24) 81 (9)
88 (0)
84 (5)
83 (7)
87 (4)
81 (0)
88 (0)
81 (7)
80 (7)
85 (8)
91 (3)
PMB (9)
Bn (9)
Bn (3)
THP (3) Bn(OCH2CH2)12OTHP (26)
Bn (9) PMB (6) Bn(OCH2CH2)15OPMB (37)
PMB (12)
Bn (9)
Bn (9)
Bn (3)
THP (6) Bn(OCH2CH2)15OTHP (38)
THP (9) Bn(OCH2CH2)18OTHP (39)
Bn (12) THP (6)
Bn (9) PMB (9) Bn(OCH2CH2)18OPMB (40)
Bn (12) PMB (6)
PMB (9)
THP (9) PMB(OCH2CH2)18OTHP (41) 90 (4)
83 (0)
Bn (12) PMB (12) Bn(OCH2CH2)24OPMB (42)
a
Reaction conditions: same as before (Table 3). b Isolated yields
after purification. Value in parentheses corresponds to isolated
yield of the vinyl ether side product 43.
previously described reaction procedure, unsymmetrical
elongated PEG chains up to 24 ethylenoxy units (PEG24)
may be prepared in high yields. Concomitant formation
of a small amount of the vinyl ether product 43 was once
again observed, which may be removed by column chro-
matography.
a
Key: (i) H+, MeOH/CH2Cl2, rt; (ii) 10% Pd(OH)2/C, EtOH,
cyclohexene, reflux; (iii) CAN, CH3CN/H2O, rt.
SCHEME 8. Tosyla tion of Com p ou n d s 28-31
Due to the relatively high molecular weight and
fragility of these molecules, the veracity of all the
compounds prepared above was validated by high-resolu-
tion ES or FAB mass spectrometry, in addition to
microanalysis data (Table 5).11 In all cases, the HRMS
revealed the presence of a monodispersed species with
the predicted molecular weight (Figure 2). In all but one
of the samples analyzed, the [M + Na+] ion was observed
as the predominant ion.
SCHEME 9. Secon d Exten sion for th e Syn th esis of
Un sym m etr ica l P EGp+m , Wh er e p + m ) 12-24
Con clu sion
In summary, we have developed a viable and high-
yielding strategy for the preparation of elongated, mono-
dispersed PEGs. A series of novel unsymmetrical PEG3,
PEG6, PEG9, PEG12, PEG15, PEG18, and PEG24 of distinct
chain lengths were synthesized from commercially avail-
able PEG3 and PEG6 diols. The methodology is used
routinely in our laboratory for the synthesis of these
elongated PEGs on a multigram scale (>10 g demon-
strated in a few cases). Proof of purity is provided by
comprehensive microanalytical data, as well as high-
resolution MS data.
ence of Bn in high yields.15 These trends dictate that
selective monodeprotection of these bifunctional mol-
ecules has to be performed in the following order: THP
> PMB > Bn.
Exp er im en ta l Section
Tosylation of the monoprotected 28-31 diols using
TsCl/pyridine led to persistent, inseparable mixtures of
the tosylate PG(OCH2CH2)nOTs and chloride PG(OCH2-
CH2)nCl derivatives. This problem was overcome by
adopting the silver(I) oxide-mediated tosylation described
previously, which furnished the desired bifunctional
PEG9 and PEG12 chains 33-36 in high yields (Scheme
8).
Secon d Ch a in Exten sion -Syn th esis of High er
Hom ologu es (Scheme 9, Table 4). These unsymmetrical
bifunctional PEGs 33-36 were subjected to further chain
extensions to access higher homologues. Adopting the
Sp ecia l Note on Nom en cla tu r e. To avoid excessive use
of a long series of numbers, the mathematical shorthand for
expressing arithmetic progressions is used to denote the
positions of oxygen atoms in the elongated PEG chains, e.g.,
35-benzyloxy-3n333-undecaoxapentatriacontan-1-ol (compound
31) refers to 35-benzyloxy-3,6,9,12,15,18,21,24,27,30,33-unde-
caoxapentatriacontan-1-ol.
Gen er a l P r oced u r es for th e Mon op r otection of P oly-
(eth ylen e glycol)s (Scheme 4): Meth od A. To an ice-cold (0
°C) solution of the diol (1 equiv) and 2,3-dihydro-2H-pyran (1.1
equiv) in DCM was added p-toluenesulfonic acid monohydrate
(0.2 equiv). The mixture was stirred for 10 min and then
warmed gradually to room temperature and stirred for an
additional 2 h. H2O was then added to the mixture and the
solution extracted with DCM. The combined organic extracts
were washed with water and brine, dried over MgSO4, filtered,
(15) Wright, J . A.; Yu, J .; Spencer, J . B. Tetrahedron Lett. 2001,
42, 4033-4036.
642 J . Org. Chem., Vol. 69, No. 3, 2004

Extended Bifunctional Polyethylene Glycol Chains
TABLE 5. Elem en ta l a n d HRMS Da ta for All P r ep a r ed P EG Ch a in s
microanalysis/%a
compd (molecular formula)
C
H
HRMSb
6 (C11H22O5)
7 (C17H34O8)
56.57 (56.39)
55.70 (55.72)
51.18 (51.30)
52.19 (52.28)
65.03 (64.98)
61.47 (61.27)
62.17 (62.20)
59.59 (59.68)
70.85 (70.97)
60.90 (60.89)
59.25 (59.30)
59.49 (59.42)
58.29 (58.26)
55.77 (55.65)
55.49 (55.37)
60.30 (60.17)
61.26 (61.20)
63.41 (63.44)
59.09 (59.18)
61.74 (61.89)
59.82 (59.98)
58.39 (58.41)
57.76 (57.64)
59.65 (59.51)
58.37 (58.47)
55.32 (55.40)
57.36 (57.54)
56.97 (57.06)
58.21 (58.34)
57.84 (57.70)
60.62 (60.79)
59.06 (59.14)
58.39 (58.52)
60.18 (59.98)
57.81 (57.97)
58.74 (58.86)
9.39 (9.46)
9.38 (9.35)
6.52 (6.62)
7.47 (7.39)
8.46 (8.39)
8.68 (8.66)
8.18 (8.20)
8.71 (8.51)
7.59 (7.68)
6.71 (6.64)
7.21 (7.27)
6.73 (6.65)
7.40 (7.24)
7.41 (7.27)
7.67 (7.74)
8.72 (8.80)
8.82 (8.90)
8.34 (8.39)
8.84 (8.86)
8.63 (8.52)
8.85 (8.95)
8.79 (8.67)
8.91 (8.77)
8.61 (8.79)
8.89 (8.86)
9.34 (9.30)
7.57 (7.61)
7.79 (7.86)
7.76 (7.65)
8.07 (7.90)
8.78 (8.62)
9.02 (8.98)
8.96 (9.00)
8.55 (8.69)
9.04 (8.94)
8.96 (8.78)
257.1346 (257.1365, M + Na+)
389.2187 (389.2151, M + Na+)
305.1054c (305.1059, MH+)
8 (C13H20O6S)
9 (C19H32O9S)
10 (C13H20O4)
11 (C19H32O7)
12 (C14H22O5)
13 (C20H34O8)
14 (C31H40O7)
15 (C20H26O6S)
16 (C26H38O9S)
17 (C21H28O7S)
18 (C27H40O10S)
19 (C18H28O7S)
20 (C24H40O10S)
459.1624 (459.1665, M + Na+)
263.1246c (263.1259, M + Na+)
395.2051c (395.2046, M + Na+)
293.1376c (293.1365, M + Na+)
425.2164c (425.2151, M + Na+)
547.2620 (547.2672, M + Na+)
417.1343c (417.1348, M + Na+)
549.2105 (549.2134, M + Na+)
447.1489 (447.1453, M + Na+)
579.2194 (579.2240, M + Na+)
411.1450 (411.1453, M + Na+)
543.2289 (543.2240, M + Na+)
641.3443 (641.3513, M + Na+)
611.3343 (611.3407, M + Na+)
647.3430c (647.3407, M + Na+)
773.4300 (773.4299, M + Na+)
779.4124 (779.4194, M + Na+)
743.4120 (743.4194, M + Na+)
557.2866 (557.2938, M + Na+)
689.3663 (689.3724, M + Na+)
527.2774 (527.2832, M + Na+)
659.3622 (659.3619, M + Na+)
521.2856 (521.2938, M + Na+)
711.2915 (711.3026, M + Na+)
843.3845 (843.3813, M + Na+)
681.2870 (681.2921, M + Na+)
813.3478 (813.3707, M + Na+)
911.4876 (911.4980, M + Na+)
875.4961 (875.4980, M + Na+)
1007.5746 (1007.5767, M + Na+)
1043.5641 (1043.5767, M + Na+)
1037.5761 (1037.5872, M + Na+)
1307.7168 (1307.7340, M + Na+)
21 (C31H54O12
22 (C30H52O11
23 (C33H52O11
24 (C37H66O15
25 (C39H64O14
26 (C36H64O14
28 (C26H46O11
29 (C32H58O14
30 (C25H44O10
31 (C31H56O13
32 (C23H46O11
)
)
)
)
)
)
)
)
)
)
)
33 (C33H52O13S)
34 (C39H64O16S)
35 (C32H50O12S)
36 (C38H62O15S)
37 (C45H76O17
38 (C42H76O17
39 (C48H88O20
40 (C51H88O20
41 (C49H90O21
42 (C63H112O26
)
)
)
)
)
)
a
b
Calculated values are in parentheses (%). Observed values (expected values and assignments are in parentheses), ES ionization
unless otherwise specified. c FAB ionization.
F IGURE 2. High-resolution ESMS of Bn(OCH2CH2)24OPMB, 42 (C63H112O26). Inset: Isotopic distribution of the [M + Na+] ion
peak. The asterisk indicates the [M + H2O + Na+] peak.
J . Org. Chem, Vol. 69, No. 3, 2004 643

Loiseau et al.
and concentrated under vacuum. The remaining oil was
purified by column chromatography.
concentrated to give a yellow oil. The crude product was
purified by column chromatography.
Meth od B. To a chilled (0 °C) and stirred solution of tri- or
hexa-ethylene glycol (1 equiv) in DCM were added Ag2O (1.5
equiv), TsCl (1.1 equiv), and KI (0.2 equiv, for PEG6 only). After
stirring for 15 to 20 min., the precipitated silver salts were
removed by filtration through a pad of Celite, which was
washed thoroughly with EtOAc. The combined filtrate was
concentrated under vacuum, and the residue was purified by
column chromatography.
Meth od C. At ambient temperature, the corresponding diol
(1 equiv) was added dropwise to a solution of Ag2O (1.5 equiv)
and KI (0.4 equiv, for PEG6 only) in DCM. BnBr (1.1 equiv)
was then added over 5 min, and the mixture was stirred for 2
h. After this time, the suspension was filtered through a pad
of Celite, which was thoroughly washed with DCM. The
combined filtrate was concentrated under reduced pressure,
and the residue was purified by column chromatography.
Meth od D. To a solution of diol (1 equiv), Ag2O (1.5 equiv),
and KI (0.2 equiv for PEG3, 0.6 equiv for PEG6) in toluene was
added PMBCl (1.1 equiv) in a dropwise manner at room
temperature. The mixture was subsequently stirred at room
temperature for 2 h (PEG3) or heated at reflux for 17 h (PEG6).
After cooling to room temperature, the salts were removed by
filtration through a pad of Celite, which was rinsed thoroughly
with EtOAc. The combined filtrate was evaporated and the
residue purified by column chromatography.
P r otection of Mon otosyla te w ith Bn or P MB. The
monotosylated glycol (8, 9) (1 equiv) was dissolved in THF.
Pyridine (1.5 equiv) and benzyl bromide or p-methoxybenzyl
chloride (1.3 equiv) were added, and the solution was refluxed
for 16 h. After this time, the mixture was concentrated under
reduced pressure. The residue was dissolved in EtOAc, washed
with water and brine, dried (MgSO4), filtered, and concen-
trated. The crude product was purified by column chromatog-
raphy.
Meth od B. Tosyla tion of Mon op r otected Glycol. The
monoprotected glycol (6, 7, 10-13, 1 equiv) was dissolved in
pyridine at 0 °C and stirred for 30 min. A solution of TsCl (1.5
equiv) in pyridine was then added dropwise via cannula. The
reaction mixture was then stirred for 5-17 h at room tem-
perature before it was poured into ice-water and extracted
with diethyl ether. The pH of the aqueous layer was neutral-
ized with 2 M HCl (pH paper) and re-extracted with ether.
The combined ether extracts were then washed with water and
brine, dried (MgSO4), filtered, and concentrated under vacuum.
The desired product was purified by chromatography.
1-(p -Met h oxyb en zyloxy)-8-t osyloxy-3n 63-d ioxa oct a n e
(17). Meth od A (Table 2, entry 5) yielded a colorless oil (4.50
g, 74%) from 8 (4.36 g, 14.3 mmol), while Meth od B (Table 2,
entry 6) yielded a colorless oil (2.89 g, 81%) from PMBO-
PEG3-OH 12 (2.27 g, 8.40 mmol), EtOAc, Rf 0.58: 1H NMR
(CDCl3) δ 2.39 (s, 3H), 3.51-3.64 (m, 10H), 3.71 (s, 3H), 4.08-
4.09 (m, 2H), 4.47 (s, 2H), 6.75 (d, J ) 8.7 Hz, 2H), 7.16 (d, J
) 8.7 Hz, 2H), 7.26 (d, J ) 8.2 Hz, 2H), 7.72 (d, J ) 8.2 Hz,
2H); 13C NMR (CDCl3) δ 22.0 (CH3), 55.7 (CH3), 69.0 (CH2),
69.5 (CH2), 70.8 (CH2), 70.9 (CH2), 71.1 (CH2), 73.2 (CH2), 114.1
(CH), 128.4 (CH), 129.7 (CH), 130.2 (CH), 130.7 (C), 133.4 (C),
145.2 (C), 159.5 (C); LR-MS (FAB) 447 (M + Na+, 35), 424
(M+, 2), 243 (16), 121 (100); IR (υ, cm-1) 1354.9, 1188.3, 1098.7.
Meth od E. To a solution of diol (1.81 g, 6.41 mmol) in DCM
(40 mL) were added Ag2O (2.23 g, 9.62 mmol), KI (0.43 g, 2.59
mmol), and TrCl (1.97 g, 7.06 mmol). The resulting mixture
was heated at reflux for 14 h. After this time, the silver salts
were removed by filtration through a pad of Celite, which was
thoroughly washed with EtOAc. The combined filtrate was
concentrated under reduced pressure, and the residue was
purified by column chromatography.
8-(2H -Tet r a h yd r op yr a n -2-yloxy)-3n 63-d ioxa oct a n -1-
ol (6): colorless oil (3.49 g, 55%, Meth od A) from tri-ethylene
glycol HO-PEG3-OH (4.07 g, 27.1 mmol), EtOAc/hexane 1:1,
Rf 0.23; 1H NMR (CDCl3) δ 1.48-1.81 (m, 6H), 2.75 (t, J ) 6.1
Hz, 1H, OH), 3.50-3.87 (m, 14H), 4.61-4.63 (m, 1H); 13C NMR
(CDCl3) δ 19.8 (CH2), 25.8 (CH2), 30.9 (CH2), 62.1 (CH2), 62.6
(CH2), 66.9 (CH2), 70.7 (CH2), 70.9 (CH2), 71.0 (CH2), 72.9
(CH2), 99.3 (CH); LR-MS (EI) 235 (MH+, 9), 151 (100), 121 (21),
98 (58); IR (υ, cm-1) 3459.0, 1125.3, 1076.0.
1-(p -Met h oxyb en zyloxy)-17-t osyloxy-3n 153-p en t a oxa -
h ep ta d eca n e (18). Meth od A (Table 2, entry 7) yielded a
yellow oil (2.38 g, 67%) from 9 (2.78 g, 6.37 mmol), while
Meth od B (Table 2, entry 8) yielded a yellow oil (8.54 g, 74%)
from 13 (8.35 g, 20.7 mmol), EtOAc/acetone 4:1, Rf 0.44: 1H
NMR (CDCl3) δ 2.37 (s, 3H), 3.50-3.61 (m, 22H), 3.72 (s, 3H),
4.07-4.09 (m, 2H), 4.41 (s, 2H), 6.78 (d, J ) 8.7 Hz, 2H), 7.18
(d, J ) 8.7 Hz, 2H), 7.26 (d, J ) 8.2 Hz, 2H), 7.72 (d, J ) 8.2
Hz, 2H); 13C NMR (CDCl3) δ 22.0 (CH3), 55.6 (CH3), 69.0 (CH2),
69.5 (CH2), 69.6 (CH2), 70.8 (CH2), 70.9 (CH2), 70.95 (CH2),
71.0 (CH2), 71.1 (CH2), 73.2 (CH2), 114.1 (CH), 128.4 (CH),
129.7 (CH), 130.2 (CH), 130.7 (C), 133.4 (C), 145.2 (C), 159.5
(C); LR-MS (EI, 70 eV) 556 (M+, 9), 287 (5), 243 (10), 199 (62),
155 (21), 121 (100); IR (υ, cm-1) 1355.5, 1097.9.
8-(p-Meth oxyben zyloxy)-3n 63-d ioxa octa n -1-ol (12): yel-
low oil (9.43 g, 74%, Meth od D) from tri-ethylene glycol HO-
PEG3-OH (7.08 g, 47.1 mmol), EtOAc, Rf 0.38; 1H NMR
(CDCl3) δ 2.81 (s, 1H, OH), 3.47-3.68 (m, 12H), 3.71 (s, 3H),
4.41 (s, 2H), 6.79 (d, J ) 8.7 Hz, 2H), 7.19 (d, J ) 8.7 Hz, 2H);
13C NMR (CDCl3) δ 55.1 (CH3), 61.6 (CH2), 68.9 (CH2), 70.7
(CH2), 71.5 (CH2), 72.5 (CH2), 72.8 (CH2), 113.6 (CH), 129.3
(CH), 130.1 (C), 159.1 (C); LR-MS (EI) 293 (M + Na+, 13), 208
(7), 132 (9), 121 (100); IR (υ, cm-1) 3464.3, 1107.1, 821.7.
17-(p-Meth oxyben zyloxy)-3n 153-p en ta oxa h ep ta d eca n -
1-ol (13): yellow oil (11.8 g, 67%, Meth od D) from hexa-
ethylene glycol HO-PEG6-OH (12.3 g, 43.6 mmol), EtOAc/
acetone 3:2, Rf 0.31; 1H NMR (CDCl3) δ 2.93 (s, 1H, OH), 3.59-
3.87 (m, 24H), 3.81 (s, 3H), 4.50 (s, 2H), 6.87 (d, J ) 8.7 Hz,
2H), 7.27 (d, J ) 8.7 Hz, 2H); 13C NMR (CDCl3) δ 55.6 (CH3),
62.1 (CH2), 69.4 (CH2), 70.7 (CH2), 70.9 (CH2), 71.0 (CH2), 72.9
(CH2), 73.2 (CH2), 114.1 (CH), 129.8 (CH), 130.7 (C), 159.5 (C);
LR-MS (FAB) 425 (M + Na+, 21), 164 (9), 121 (100); IR (υ,
cm-1) 3468.7, 1102.7, 823.1.
1-(2H-Tetr a h yd r op yr a n -2-yloxy)-8-tosyloxy-3n 63-d ioxa -
octa n e (19). Meth od A (Table 2, entry 9) yielded a yellow oil
(22.0 g, 98%) from 8 (17.6 g, 57.8 mmol), while Meth od B
(Table 2, entry 10) yielded a yellow oil (7.32 g, 79%) from 6
(5.59 g, 23.9 mmol), EtOAc/hexane 4:1, Rf 0.58: 1H NMR
(CDCl3) δ 1.49-1.81 (m, 6H), 2.45 (s, 3H), 3.50-3.71 (m, 10H),
3.82-3.87 (m, 2H), 4.13-4.17 (m, 2H), 4.61-4.63 (m, 1H), 7.34
(d, J ) 8.2 Hz, 2H), 7.80 (d, J ) 8.2 Hz, 2H); 13C NMR (CDCl3)
δ 19.9 (CH2), 22.0 (CH3), 23.8 (CH2), 31.0 (CH2), 62.7 (CH2),
67.0 (CH2), 69.1 (CH2), 69.6 (CH2), 70.9 (CH2), 70.95 (CH2),
71.2 (CH2), 99.4 (CH), 128.4 (CH), 130.2 (CH), 133.4 (C), 145.2
(C); LR-MS (EI) 387 (M - H+, 1), 229 (20), 199 (100), 172 (45),
155 (85), 85 (37); IR (υ, cm-1) 1358.9, 1176.7, 1034.4, 776.3,
664.4.
Gen er a l P r oced u r es for t h e Syn t h esis of TsO(CH2-
CH2O)m P G (Sch em e 5, Ta ble 2). Meth od A: P r otection
of Mon otosyla te w ith THP . To a solution of monotosylated
glycol (8, 9) (1 equiv) in DCM were added pyridinium tolu-
enesulfonate (0.2 equiv) and 2,3-dihydro-2H-pyran (1.5 equiv).
The resulting mixture was refluxed for 3 h. The solution was
then concentrated under vacuum, poured into ice-water, and
extracted with DCM. The combined organic layers were
washed with water and brine, dried over MgSO4, filtered, and
1-(2H-Tetr a h yd r op yr a n -2-yloxy)-17-tosyloxy-3n 153-p en -
ta oxa h ep ta d eca n e (20). Meth od A (Table 2, entry 11)
yielded a colorless oil (4.00 g, 96%) from 9 (3.49 g, 8.00 mmol),
while Meth od B (Table 2, entry 12) yielded a colorless oil (3.59
g, 85%) from 7 (2.97 g, 8.10 mmol), EtOAc/hexane 4:1, Rf
0.51: 1H NMR (CDCl3) δ 1.41-1.65 (m, 6H), 2.38 (s, 3H), 3.44-
3.63 (m, 22H), 3.76-3.80 (m, 2H), 4.07-4.09 (m, 2H), 4.54-
4.57 (m, 1H), 7.26 (d, J ) 8.2 Hz, 2H), 7.72 (d, J ) 8.2 Hz,
2H); 13C NMR (CDCl3) δ 19.9 (CH2), 22.0 (CH3), 25.8 (CH2),
644 J . Org. Chem., Vol. 69, No. 3, 2004

Extended Bifunctional Polyethylene Glycol Chains
30.9 (CH2), 62.6 (CH2), 67.0 (CH2), 69.0 (CH2), 69.6 (CH2), 70.8
(CH2), 70.9 (CH2), 71.0 (CH2), 71.1 (CH2), 99.3 (CH), 128.4
(CH), 130.2 (CH), 133.3 (C), 145.2 (C); LR-MS (CI) 538 (M +
NH4+, 34), 520 (M+, 2), 454 (100), 410 (7), 366 (62), 322 (7),
282 (34), 278 (10), 234 (4), 85 (57); IR (υ, cm-1) 1356.3, 1177.5,
1034.6, 776.7, 664.3.
1-Ben zyloxy-35-(p -m et h oxyb en zyloxy)-3n 333-u n d eca -
oxa p en ta tr ia con ta n e (25) (Table 3, Entry 7): yellow oil (3.17
g, 84%) from 13 (2.01 g, 4.99 mmol) and 16 (2.63 g, 4.99 mmol),
EtOAc/Acetone 4:1, Rf 0.58; 1H NMR (CDCl3) δ 3.58-3.71 (m,
48H), 3.79 (s, 3H), 4.49 (s, 2H), 4.56 (s, 2H), 6.86 (d, J ) 8.7
Hz, 2H), 7.26 (d, J ) 8.7 Hz, 2H), 7.29-7.34 (m, 5H); 13C NMR
(CDCl3) δ 55.6 (CH3), 69.5 (CH2), 69.8 (CH2), 70.9 (CH2), 71.0
(CH2), 73.3 (CH2), 73.6 (CH2), 114.1 (CH), 128.0 (CH), 128.1
(CH), 128.7 (CH), 129.7 (CH), 130.7 (C), 138.7 (C), 159.6 (C);
LR-MS (EI) 756 (M+, 2), 665 (100), 635 (13), 621 (13), 177 (32),
Gen er a l P r oced u r e for th e Syn th esis of Un sym m etr i-
ca l Elon ga ted P oly(eth ylen e glycol)s (Scheme 6, Table 3).
NaH (60% in mineral oil, 1.8 equiv) was placed in a three-
neck round-bottom flask and washed with n-pentane. The
residue was dried under vacuum, and THF was added to form
a suspension. A solution of the monoprotected glycol (1 equiv)
in THF was added dropwise, and the reaction mixture was
stirred at room temperature for between 20 and 24 h. A
solution of the monoprotected tosylate (1 equiv) in THF was
then added to the solution via cannula. The resulting mixture
was stirred at room temperature for 70 h to 76 h. The excess
of NaH was carefully destroyed by the addition of MeOH at 0
°C. The solution was then concentrated under vacuum, and
the resulting precipitate was partitioned between EtOAc/H2O
(1:1 v/v). The aqueous layer was then extracted with EtOAc.
The combined organic layers were washed with water and
brine, dried on MgSO4, filtered, and concentrated under
reduced pressure. The remaining oil was purified by column
chromatography.
133 (65), 121 (33), 89 (33); IR (υ, cm-1) 1103.1, 743.0, 700.2.
3
1-Ben zyloxy-35-(2H -t et r a h yd r op yr a n -2-yloxy)-3n 33
-
u n d eca oxa p en ta tr ia con ta n e (26) (Table 3, Entry 9): yellow
oil (11.4 g, 85%) from 20 (9.68 g, 18.6 mmol) and 11 (6.91 g,
18.6 mmol), EtOAc/Acetone 3:2, Rf 0.23; 1H NMR (CDCl3) δ
1.42-1.65 (m, 6H), 3.44-3.82 (m, 50H), 4.49 (s, 2H), 4.55-
4.57 (m, 1H), 7.19-7.27 (m, 5H); 13C NMR (CDCl3) δ 19.9
(CH2), 25.8 (CH2), 30.9 (CH2), 62.6 (CH2), 67.0 (CH2), 69.8
(CH2), 70.9 (CH2), 70.95 (CH2), 71.0 (CH2), 71.05 (CH2), 73.6
(CH2), 99.3 (CH), 128.0 (CH), 128.1 (CH), 128.8 (CH), 138.6
(C); IR (υ, cm-1) 1122.8, 1035.4, 740.4, 669.5.
Gen er a l P r oced u r es for Selective Dep r otection of
Bifu n ction a l P EGs (Scheme 7): Rem ova l of THP Gr ou p .
The glycol (21, 22, 24, 26) was deprotected according to a
previously reported procedure.4
Rem ova l of Bn Gr ou p . Pearlman’s catalyst (10% Pd, 0.27
g) was added to a solution of glycol 22 (1.12 g, 1.90 mmol) in
a mixture of EtOH/cyclohexene (40 mL, 5:3, v/v), and the
solution was heated at reflux for 17 h. After this time, the
reaction mixture was filtered through a pad of Celite, which
was washed with EtOAc (100 mL). The combined filtrate was
concentrated under vacuum, and the remaining oil was puri-
fied by column chromatography.
Rem ova l of P MB Gr ou p . The glycol (21, 23, 25) was
dissolved in a mixture of MeCN/H2O (9:1, v/v) and cooled to 0
°C. CAN (3 equiv) was added in three portions over 1.5 h, and
the solution was stirred at room temperature for 2.5 h. The
resulting mixture was extracted with DCM, and the combined
extracts were washed with water and brine, dried (MgSO4),
filtered, and concentrated under reduced pressure. The crude
product was purified by column chromatography.
1-(p -Met h oxyb en zyloxy)-26-(2H -t et r a h yd r op yr a n -2-
yloxy)-3n 243-octa oxa h exa cosa n e (21) (Table 3, Entry 1):
yellow oil (8.46 g, 80%) from 13 (6.88 g, 17.1 mmol) and 19
(6.64 g, 17.1 mmol), EtOAc/acetone 3:2, Rf 0.47; 1H NMR
(CDCl3) δ 1.49-1.88 (m, 6H), 3.48-3.69 (m, 36H), 3.80 (s, 3H),
3.83-3.88 (m, 2H), 4.49 (s, 2H), 4.62 (t, J ) 3.2 Hz, 1H), 6.86
(d, J ) 8.7 Hz, 2H), 7.25 (d, J ) 8.7 Hz, 2H); 13C NMR (CDCl3)
δ 19.9 (CH2), 25.8 (CH2), 30.9 (CH2), 55.7 (CH3), 62.6 (CH2),
67.0 (CH2), 69.4 (CH2), 70.9 (CH2), 70.95 (CH2), 71.0 (CH2),
73.3 (CH2), 99.3 (CH), 114.1 (CH), 129.8 (CH), 130.7 (C), 159.5
(C); LR-MS (EI) 618 (M+, 1), 533 (100), 489 (10), 340 (7), 283
(7), 221 (10), 177 (21), 133 (53), 121 (37), 89 (69); IR (υ, cm-1
)
1121.8.
1-Ben zyloxy-26-(2H-tetr a h yd r op yr a n -2-yloxy)-3n 243-oc-
ta oxa h exa cosa n e (22) (Table 3, entry 3): yellow oil (10.0 g,
81%) from 11 (7.83 g, 21.0 mmol) and 19 (8.17 g, 21.0 mmol),
EtOAc/acetone 3:2, Rf 0.45; 1H NMR (CDCl3) δ 1.42-1.76 (m,
6H), 3.42-3.63 (m, 36H), 3.76-3.82 (m, 2H), 4.49 (s, 2H), 4.56
(t, J ) 3.3 Hz, 1H), 7.19-7.27 (m, 5H); 13C NMR (CDCl3) δ
19.9 (CH2), 25.8 (CH2), 30.9 (CH2), 62.6 (CH2), 67.0 (CH2), 69.8
(CH2), 70.9 (CH2), 70.95 (CH2), 70.97 (CH2), 71.0 (CH2), 73.6
(CH2), 99.3 (CH), 128.0 (CH), 128.1 (CH), 128.7 (CH), 138.6
(C); LR-MS (EI) 588 (M+, 2), 503 (54), 398 (8), 354 (11), 310
(12), 265 (12), 221 (25), 177 (58), 133 (100); IR (υ, cm-1) 1119.6,
740.6, 699.6.
26-(p -Met h oxyb en zyloxy)-3n 243-oct a oxa h exa cosa n -1-
ol (28): yellow oil (2.94 g, 92%) from 21 (3.68 g, 5.95 mmol),
EtOAc/Acetone 1:1, Rf 0.27; 1H NMR (CDCl3) δ 2.62 (s, 1H,
OH), 3.58-3.72 (m, 36H), 3.80 (s, 3H), 4.50 (s, 2H), 6.87 (d, J
) 8.7 Hz, 2H), 7.26 (d, J ) 8.7 Hz, 2H); 13C NMR (CDCl3) δ
55.7 (CH3), 62.1 (CH2), 69.4 (CH2), 70.7 (CH2), 70.95 (CH2),
71.05 (CH2), 72.9 (CH2), 73.3 (CH2), 114.1 (CH), 129.8 (CH),
130.7 (C), 159.5 (C); LR-MS (EI) 534 (M+, 36), 489 (5), 283
(12), 221 (19), 177 (47), 133 (94), 121 (68), 89 (100); IR (υ, cm-1
3479.9, 1103.2.
)
1-Ben zyloxy-26-(p -m et h oxyb en zyloxy)-3n 243-oct a oxa -
h exa cosa n e (23) (Table 3, Entry 5): yellow oil (10.3 g, 87%)
from 13 (7.64 g, 19.0 mmol) and 15 (7.47 g, 18.9 mmol), DCM/
35-(p -Met h oxyb en zyloxy)-3n 333-u n d eca oxa p en t a t r ia -
con ta n -1-ol (29): yellow oil (1.14 g, 94%) from 24 (1.37 g, 1.82
mmol), EtOAc/acetone 4:1, Rf 0.32. 1H NMR (CDCl3) δ 2.60 (s,
1H, OH), 3.51-3.70 (m, 48H), 3.73 (s, 3H), 4.42 (s, 2H), 6.80
(d, J ) 8.7 Hz, 2H), 7.19 (d, J ) 8.7 Hz, 2H); 13C NMR (CDCl3)
δ 55.7 (CH3), 62.1 (CH2), 69.5 (CH2), 70.7 (CH2), 70.9 (CH2),
71.0 (CH2), 71.05 (CH2), 73.0 (CH2), 73.3 (CH2), 114.1 (CH),
129.8 (CH), 130.7 (C), 159.6 (C); IR (υ, cm-1) 3465.0, 1106.9,
820.3.
1
EtOAc 4:1, Rf 0.20; H NMR (CDCl3) δ 3.58-3.75 (m, 36H),
3.80 (s, 3H), 4.49 (s, 2H), 4.57 (s, 2H), 6.87 (d, J ) 8.7 Hz,
2H), 7.26 (d, J ) 8.7 Hz, 2H), 7.29-7.35 (m, 5H); 13C NMR
(CDCl3) δ 55.6 (CH3), 69.5 (CH2), 69.8 (CH2), 70.9 (CH2), 71.0
(CH2), 73.3 (CH2), 73.6 (CH2), 114.1 (CH), 127.9 (CH), 128.1
(CH), 128.7 (CH), 129.8 (CH), 130.7 (C), 138.7 (C), 159.5 (C);
LR-MS (FAB) 647 (M + Na+, 100), 623 (22), 533 (32), 239 (47);
IR (υ, cm-1) 1122.7.
26-Ben zyloxy-3n 243-octa oxa h exa cosa n -1-ol (30): color-
less oil from 22 (3.98 g, 6.76 mmol) in 95% yield (3.24 g) or 23
(9.57 g, 16.3 mmol) in 88% yield (7.22 g), EtOAc/acetone 1:1,
Rf 0.28; 1H NMR (CDCl3) δ 2.64 (t, J ) 6.2 Hz, 1H, OH), 3.52-
3.67 (m, 36H), 4.49 (s, 2H), 7.19-7.27 (m, 5H); 13C NMR
(CDCl3) δ 62.1 (CH2), 69.8 (CH2), 70.7 (CH2), 70.9 (CH2), 70.95
(CH2), 71.0 (CH2), 72.9 (CH2), 73.6 (CH2), 128.0 (CH), 128.1
(CH), 128.7 (CH), 138.6 (C); LR-MS (EI) 504 (M+, 7), 372 (2),
208 (8), 147 (10), 133 (23), 91 (100); IR (υ, cm-1) 3479.6, 1104.2.
35-Ben zyloxy-3n 333-u n decaoxapen tatr iacon tan -1-ol (31):
yellow oil from 26 (7.41 g, 10.2 mmol) in 96% yield (6.29 g) or
25 (2.97 g, 3.92 mmol) in 79% yield (1.97 g), EtOAc/acetone
1-(p -Met h oxyb en zyloxy)-35-(2H -t et r a h yd r op yr a n -2-
yloxy)-3n 333-u n d eca oxa p en ta tr ia con ta n e (24) (Table 3,
Entry 6): yellow oil (1.46 g, 86%) from 13 (0.91 g, 2.27 mmol)
and 20 (1.18 g, 2.27 mmol), EtOAc/acetone 4:1, Rf 0.24; 1H
NMR (CDCl3) δ 1.42-1.81 (m, 6H), 3.43-3.63 (m, 48H), 3.73
(s, 3H), 3.77-3.81 (m, 2H), 4.42 (s, 2H), 4.56-4.57 (m, 1H),
6.80 (d, J ) 8.7 Hz, 2H), 7.19 (d, J ) 8.7 Hz, 2H); 13C NMR
(CDCl3) δ 19.9 (CH2), 25.8 (CH2), 30.9 (CH2), 55.6 (CH3), 62.6
(CH2), 67.0 (CH2), 69.5 (CH2), 70.8 (CH2), 70.9 (CH2), 71.0
(CH2), 73.3 (CH2), 99.3 (CH), 114.1 (CH), 129.8 (CH), 130.7
(C), 159.5 (C); IR (υ, cm-1) 1120.9.
J . Org. Chem, Vol. 69, No. 3, 2004 645

Loiseau et al.
1
3:2, Rf (acetone) 0.21; H NMR (CDCl3) δ 2.63 (t, J ) 6.2 Hz,
1-Ben zyloxy-35-(p -m et h oxyb en zyloxy)-3n 333-u n d eca -
oxa p en ta tr ia con ta n e (25) (Table 4, Entry 3): yellow oil (3.94
g, 84%) from 10 (1.49 g, 6.20 mmol) and 33 (4.27 g, 6.20 mmol).
3
1H, OH), 3.60-3.73 (m, 48H), 4.57 (s, 2H), 7.26-7.35 (m, 5H);
13C NMR (CDCl3) δ 62.0 (CH2), 69.8 (CH2), 70.7 (CH2), 70.9
(CH2), 71.0 (CH2), 72.9 (CH2), 73.6 (CH2), 127.9 (CH), 128.1
(CH), 128.7 (CH), 138.7 (C); LR-MS (CI) 655 (M + NH4+, 100),
636 (M+, 36), 514 (14), 339 (13); IR (υ, cm-1) 3502.0, 1107.1.
26-(2H -Tet r a h yd r op yr a n -2-yloxy)-3n 243-oct a oxa h exa -
cosa n -1-ol (32): colorless oil from 22 (1.12 g, 1.90 mmol) in
55% yield (0.52 g) or 21 (1.36 g, 2.20 mmol) in 83% yield (0.91
1-Ben zyloxy-35-(2H -t et r a h yd r op yr a n -2-yloxy)-3n 33
-
u n d eca oxa p en ta tr ia con ta n e (26) (Table 4, Entry 4): yellow
oil (2.91 g, 83%) from 35 (3.20 g, 4.86 mmol) and 6 (1.14 g,
4.87 mmol).
1-Ben zyloxy-44-(p-m eth oxyben zyloxy)-3n 423-tetr a d eca -
oxa tetr a tetr a con ta n e (37) (Table 4, Entry 5): colorless oil
(7.18 g, 87%) from 35 (6.11 g, 9.27 mmol) and 13 (3.72 g, 9.27
1
g), EtOAc/acetone 3:2, Rf 0.45; H NMR (CDCl3) δ 1.49-1.72
(m, 6H), 2.64 (t, J ) 6.2 Hz, 1H, OH), 3.59-3.73 (m, 36H),
3.85-3.87 (m, 2H), 4.62-4.64 (m, 1H); 13C NMR (CDCl3) δ 19.9
(CH2), 25.8 (CH2), 30.9 (CH2), 62.1 (CH2), 62.6 (CH2), 67.0
(CH2), 70.7 (CH2), 70.9 (CH2), 71.0 (CH2), 72.9 (CH2), 99.3 (CH);
IR (υ, cm-1) 3478.9, 1122.5, 1035.0.
1
mmol), EtOAc/acetone 7:3, Rf 0.30; H NMR (CDCl3) δ 3.53-
3.71 (m, 60H), 3.79 (s, 3H), 4.49 (s, 2H), 4.56 (s, 2H), 6.86 (d,
J ) 8.6 Hz, 2H), 7.25-7.34 (m, 7H); 13C NMR (CDCl3) δ 55.6
(CH3), 69.5 (CH2), 69.8 (CH2), 70.9 (CH2), 71.0 (CH2), 73.3
(CH2), 73.6 (CH2), 114.1 (CH), 128.0 (CH), 128.1 (CH), 128.7
(CH), 129.7 (CH), 130.7 (C), 138.7 (C), 159.5 (C); IR (υ, cm-1
)
Gen er a l P r oced u r e for Tosyla tion of Mon op r otected
Oligom er ic Glycols (Scheme 8). To a solution of monopro-
tected glycol (28-31, 1 equiv) in DCM at room temperature
were added successively TsCl (1.5 equiv), KI (0.4 equiv), and
Ag2O (1.5 equiv), and the mixture was heated at reflux for 14-
18 h. After this time, the silver salts were removed by filtration
through a pad of Celite, which was thoroughly washed with
EtOAc. The filtrate was concentrated under vacuum, and the
resulting oil was purified by column chromatography.
1-(p-Meth oxyben zyloxy)-26-tosyloxy-3n 243-octaoxah exa-
cosa n e (33): colorless oil (2.25 g, 85%) from 28 (2.06 g, 3.85
mmol), EtOAc/acetone 3:2, Rf 0.60; 1H NMR (CDCl3) δ 2.43 (s,
3H), 3.57-3.69 (m, 34H), 3.78 (s, 3H), 4.12-4.14 (m, 2H), 4.48
(s, 2H), 6.85 (d, J ) 8.6 Hz, 2H), 7.25 (d, J ) 8.6 Hz, 2H), 7.33
(d, J ) 8.2 Hz, 2H), 7.78 (d, J ) 8.2 Hz, 2H); 13C NMR (CDCl3)
δ 22.0 (CH3), 55.6 (CH3), 69.0 (CH2), 69.5 (CH2), 69.6 (CH2),
70.8 (CH2), 70.9 (CH2), 71.0 (CH2), 71.1 (CH2), 73.2 (CH2), 114.1
(CH), 128.3 (CH), 129.7 (CH), 130.2 (CH), 130.7 (C), 133.4 (C),
145.2 (C), 159.5 (C); LR-MS (EI) 711 (M + Na+, 100), 237 (7),
121 (4); IR (υ, cm-1) 1356.4, 1189.0, 1099.3.
1106.7, 742.4, 700.0.
3
1-Ben zyloxy-44-(2H -t et r a h yd r op yr a n -2-yloxy)-3n 42
-
tetr a d eca oxa tetr a tetr a con ta n e (38) (Table 4, Entry 7):
colorless oil (2.75 g, 88%) from 35 (2.41 g, 3.66 mmol) and 7
(1.34 g, 3.66 mmol), EtOAc/acetone 1:1, Rf 0.28; 1H NMR
(CDCl3) δ 1.49-1.69 (m, 6H), 3.51-3.67 (m, 60H), 3.79-3.82
(m, 2H), 4.53 (s, 2H), 4.60-4.62 (m, 1H), 7.24-7.31 (m, 5H);
13C NMR (CDCl3) δ 19.9 (CH2), 25.8 (CH2), 30.9 (CH2), 62.6
(CH2), 66.9 (CH2), 69.4 (CH2), 70.9 (CH2), 71.0 (CH2), 73.6
(CH2), 99.3 (CH), 128.0 (CH), 128.1 (CH), 128.8 (CH), 130.7
(C); IR (υ, cm-1) 1107.1.
3
1-Ben zyloxy-53-(2H -t et r a h yd r op yr a n -2-yloxy)-3n 51
-
h ep ta d eca oxa tr ip en ta con ta n e (39) (Table 4, Entry 8):
colorless oil (2.80 g, 81%) from 35 (2.31 g, 3.51 mmol) and 32
(1.75 g, 3.51 mmol), EtOAc/MeOH 9:1, Rf 0.30; 1H NMR
(CDCl3) δ 1.39-1.61 (m, 6H), 3.39-3.77 (m, 74H), 4.48 (s, 2H),
4.53-4.56 (m, 1H), 7.17-7.25 (m, 5H); 13C NMR (CDCl3) δ 19.9
(CH2), 25.8 (CH2), 30.8 (CH2), 62.5 (CH2), 67.0 (CH2), 69.8
(CH2), 70.9 (CH2), 71.0 (CH2), 71.05 (CH2), 73.6 (CH2), 99.4
(CH), 128.0 (CH), 128.1 (CH), 128.8 (CH), 138.6 (C); IR (υ,
cm-1) 1122.7, 1034.8, 741.0, 669.6.
1-(p-Meth oxyben zyloxy)-35-tosyloxy-3n 333-u n d eca oxa -
p en ta tr ia con ta n e (34): colorless oil (2.63 g, 80%) from 29
(2.67 g, 4.00 mmol), EtOAc/acetone 1:1, Rf 0.39; 1H NMR
(CDCl3) δ 2.42 (s, 3H), 3.58-3.70 (m, 46H), 3.76 (s, 3H), 4.12-
4.14 (m, 2H), 4.49 (s, 2H), 6.86 (d, J ) 8.6 Hz, 2H), 7.26 (d, J
) 8.6 Hz, 2H), 7.34 (d, J ) 8.2 Hz, 2H), 7.78 (d, J ) 8.2 Hz,
2H); 13C NMR (CDCl3) δ 22.0 (CH3), 55.7 (CH3), 69.0 (CH2),
69.5 (CH2), 69.6 (CH2), 70.9 (CH2), 70.95 (CH2), 71.0 (CH2),
71.1 (CH2), 73.3 (CH2), 114.1 (CH), 128.3 (CH), 129.8 (CH),
130.2 (CH), 130.7 (C), 133.4 (C), 145.2 (C), 159.6 (C); IR (υ,
cm-1) 1355.7, 1100.3.
1-Ben zyloxy-26-tosyloxy-3n 243-octa oxa h exa cosa n e (35):
colorless oil (6.18 g, 84%) from 30 (5.62 g, 11.1 mmol), EtOAc/
acetone 4:1, Rf 0.63; 1H NMR (CDCl3) δ 2.38 (s, 3H), 3.51-
3.64 (m, 34H), 4.07-4.10 (m, 2H), 4.49 (s, 2H), 7.19-7.28 (m,
7H), 7.72 (d, J ) 8.3 Hz, 2H); 13C NMR (CDCl3) δ 22.0 (CH3),
69.0 (CH2), 69.6 (CH2), 69.8 (CH2), 70.9 (CH2), 70.95 (CH2),
71.0 (CH2), 71.05 (CH2), 71.1 (CH2), 73.6 (CH2), 128.0 (CH),
128.1 (CH), 128.4 (CH), 128.7 (CH), 130.2 (CH), 133.4 (C),
138.7 (C), 145.2 (C); IR (υ, cm-1) 1356.1, 1103.3.
1-Ben zyloxy-53-(p-m eth oxyben zyloxy)-3n 513-h ep ta d e-
ca oxa tr ip en ta con ta n e (40) (Table 4, Entry 11): yellow oil
(4.19 g, 91%) from 36 (3.60 g, 4.54 mmol) and 13 (1.83 g, 4.53
mmol), EtOAc/MeOH 9:1, Rf 0.59: 1H NMR (CDCl3) δ 3.54-
3.70 (m, 72H), 3.80 (s, 3H), 4.50 (s, 2H), 4.57 (s, 2H), 6.87 (d,
J ) 8.6 Hz, 2H), 7.26-7.35 (m, 7H); 13C NMR (CDCl3) δ 55.7
(CH3), 69.5 (CH2), 69.8 (CH2), 70.9 (CH2), 71.0 (CH2), 73.3
(CH2), 73.6 (CH2), 114.1 (CH), 128.0 (CH), 128.2 (CH), 128.8
(CH), 129.8 (CH), 130.7 (C), 138.7 (C), 159.6 (C); IR (υ, cm-1
1104.3, 742.8, 700.4.
)
1-(p -Met h oxyb en zyloxy)-53-(2H -t et r a h yd r op yr a n -2-
yloxy)-3n 513-h ep ta d eca oxa tr ip en ta con ta n e (41) (Table 4,
Entry 12): colorless oil (2.99 g, 90%) from 33 (2.03 g, 2.95
mmol) and 32 (1.47 g, 2.95 mmol), EtOAc/MeOH 9:1, Rf 0.18;
1H NMR (CDCl3) δ 1.52-1.82 (m, 6H), 3.59-3.70 (m, 72H),
3.80 (s, 3H), 3.84-3.88 (m, 2H), 4.50 (s, 2H), 4.62-4.64 (m,
1H), 6.87 (d, J ) 8.6 Hz, 2H), 7.27 (d, J ) 8.6 Hz, 2H); 13C
NMR (CDCl3) δ 19.9 (CH2), 25.8 (CH2), 30.9 (CH2), 55.7 (CH3),
62.6 (CH2), 67.0 (CH2), 69.5 (CH2), 70.9 (CH2), 71.0 (CH2), 73.3
(CH2), 99.3 (CH), 114.1 (CH), 129.8 (CH), 130.7 (C), 159.6 (C);
IR (υ, cm-1) 1107.1, 740.3, 699.8.
1-Ben zyloxy-71-(p-m eth oxyben zyloxy)-3n 693-tr icosa ox-
a h en h ep ta con ta n e (42) (Table 4, Entry 13): waxy white
solid (1.65 g, 83%) from 36 (1.23 g, 1.55 mmol) and 29 (1.04 g,
1.56 mmol), EtOAc/MeOH 7:1, Rf 0.21; mp 26-27 °C; 1H NMR
(CDCl3) δ 3.55-3.75 (m, 96H), 3.81 (s, 3H), 4.50 (s, 2H), 4.57
(s, 2H), 6.87-6.89 (m, 2H), 7.26-7.35 (m, 7H); 13C NMR
(CDCl3) δ 55.7 (CH3), 69.5 (CH2), 69.8 (CH2), 70.9 (CH2), 71.0
(CH2), 73.3 (CH2), 73.6 (CH2), 114.1 (CH), 128.0 (CH), 128.1
(CH), 128.7 (CH), 129.8 (CH), 130.7 (C), 138.7 (C), 159.6 (C);
IR (υ, cm-1) 1104.6, 741.9, 702.1.
1-Ben zyloxy-35-tosyloxy-3n 333-u n decaoxapen tatr iacon -
ta n e (36): colorless oil (4.39 g, 78%) from 31 (4.52 g, 7.10
mmol), EtOAc/acetone 1:1, Rf 0.23; 1H NMR (CDCl3) δ 2.37 (s,
3H), 3.51-3.63 (m, 46H), 4.07-4.10 (m, 2H), 4.49 (s, 2H),
7.20-7.28 (m, 7H), 7.72 (d, J ) 8.3 Hz, 2H); 13C NMR (CDCl3)
δ 22.0 (CH3), 69.0 (CH2), 69.6 (CH2), 69.8 (CH2), 70.9 (CH2),
71.0 (CH2), 73.6 (CH2), 128.0 (CH), 128.1 (CH), 128.4 (CH),
128.7 (CH), 130.2 (CH), 133.4 (C), 138.7 (C), 145.2 (C); IR (υ,
cm-1) 1354.4, 1100.0.
Gen er a l P r oced u r e for th e Syn th esis of Elon ga ted
P E Gs. Secon d E xt en sion (Scheme 9, Table 4). The same
synthetic procedure described previously for Scheme 6 was
applied to the synthesis of the higher homologues.
1-(p -Met h oxyb en zyloxy)-35-(2H -t et r a h yd r op yr a n -2-
yloxy)-3n 333-u n d eca oxa p en ta tr ia con ta n e (24) (Table 4,
Entry 1): yellow oil (5.22 g, 81%) from 6 (2.01 g, 8.58 mmol)
and 33 (5.91 g, 8.58 mmol).
Isola tion of Vin yl P oly(eth ylen e glycol) Eth er . The
vinyl ether side products (27, 43) were isolated by column
chromatography following the extension reactions (Schemes
646 J . Org. Chem., Vol. 69, No. 3, 2004

Extended Bifunctional Polyethylene Glycol Chains
6 and 9). Characterization data for these compounds are
provided as Supporting Information.
Su p p or tin g In for m a tion Ava ila ble: Full characteriza-
tion data for compounds 7-11 and 14-16 (data were previ-
ously reported, but preparation/characterization data are
inadequate); also included are characterization data for vinyl
Ack n ow led gm en t. The authors thank King’s Col-
lege London for studentship support (F.A.L.) and Johnson
Matthey, PLC, for generous gifts of silver nitrate and
Pearlman’s catalyst. We thank Mr. Andy Cakebread and
Roger Tye for help with HRMS experiments. Microana-
lytical Service was provided by London Metropolitan
University.
1
side products 27 and 43, as well as selected H, 13C, and HR-
ESMS spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
J O035042V
J . Org. Chem, Vol. 69, No. 3, 2004 647