Catalytic transfer hydrogenation reactions of PEG-bound succinyl esters

Article abstract of DOI:10.1016/j.tetlet.2005.03.031

Various substrates bound to polyethylene glycol (PEG) through succinyl ester linkages were cleaved under catalytic transfer hydrogenation conditions. The substrates with unsaturated functions also underwent hydrogenation. The protocol was found to be suit

Full text of DOI:10.1016/j.tetlet.2005.03.031

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3591–3593
Catalytic transfer hydrogenation reactions of PEG-bound
I
succinyl esters
a,b,
a
Pawan Chakravarthy, Sanghapal D. Sawant,
b
*
H. M. Sampath Kumar,
b
a
Parvinder Pal Singh, M. Shesha Rao and J. S. Yadav
a
a
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
b
Regional Research Laboratory, Canal Road, Jammu-Tawi 180 001, India
Received 27 September 2004; revised 1 March 2005; accepted 7 March 2005
Available online 1 April 2005
Abstract—Various substrates bound to polyethylene glycol (PEG) through succinyl ester linkages were cleaved under catalytic trans-
fer hydrogenation conditions. The substrates with unsaturated functions also underwent hydrogenation. The protocol was found to
be suitable for substrates having acid and base labile functional groups.
Ó 2005 Published by Elsevier Ltd.
1
. Introduction
free radical initiated cleavage, viz. thioethers and (v)
TFA cleavage through acid-catalyzed hydrolysis.
Saponification or nucleophilic cleavage involves bases
and neither is suitable for base-sensitive substrates.
TFA cleavage methods are not suitable for substrates
bearing acid-sensitive functions. Hydrogenolysis meth-
ods often involve heterogeneous catalysts in the presence
of molecular hydrogen.
Combinatorial synthesis is a relatively new paradigm for
1
modern day molecular research. Despite several advan-
tages associated with solid-phase reactions, the hetero-
geneous nature of the reaction conditions can be a
major problem in applications to some classical organic
reactions. As alternatives, soluble polymers such as
2
,3
polyethylene glycol (PEG) were developed as attrac-
tive substitutes to solid-phase synthesis by virtue of their
ability to be used under familiar reaction conditions of
classical organic chemistry. One such advantage is the
possibility of utilizing heterogeneous catalysts, which
can be readily separated from the polymer support by
simple filtration. Of particular interest in the context
of our research would be the cleavage of the product
from soluble polymers (PEG). A variety of linkers and
Even though several heterogeneous reactions including
the hydrogenolysis of PEG-bound substrates have been
reported, to our knowledge there has been no report on
the application of catalytic transfer hydrogenation reac-
tions (CTH) to PEG-bound substrates. Arising from our
continued interest in the development of new methodol-
ogies for combinatorial synthesis, we report herein a
new cleavage protocol for PEG-bound substrates under
catalytic transfer hydrogenation conditions.
5
4
numerous cleavage methods for particular linkers have
evolved for reactions involving PEG-bound substrates.
Important cleavage protocols are, (i) heterogeneous
hydrogenolysis employing Raney nickel or NaBH4,
reductive cleavage via desulfurization using Na–Hg/
Na HPO ; (ii) saponification/base catalyzed alcoholysis
Several substrates with –OH functions were anchored to
PEG through succinyl ester linkages and subjected to
catalytic transfer hydrogenation. The cleavage was
effected by heating the PEG-bound substrates to reflux
in methanol with 10% Pd/C in the presence of ammo-
nium formate as hydrogen source. The cleaved products
were isolated from the solvent after precipitation of
PEG by addition of diethyl ether. Unsaturated sub-
strates underwent partial or complete hydrogenation,
for example, compounds with a double bond or keto
functions were transformed into alkanes and alcohols.
The cleavage was found to be general for various
2
4
or hydrolysis with dilute aqueous NaOH; (iii) nucleo-
philic cleavage reactions involving KCN/MeOH; (iv)
Keywords: PEG-Succinyl ester; CHT; Cleavage.
q
IICT Communication No. 040611.
Corresponding author. Tel.: +91 2580604; fax: +91 2547850/
573765; e-mail: hmskumar@yahoo.com
*
2
0
040-4039/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.03.031

3592
H. M. S. Kumar et al. / Tetrahedron Letters 46 (2005) 3591–3593
O
O
O
O
O
NH O CH, Pd-C(10%)
4 2
O
1
HO
MeO-PEG-O
MeOH, reflux
O
O
O
O
O
O
O
f
2f (86%)
Scheme 1.
1
PEG-bound substrates such as phenols, saturated alco-
hols, benzylic and allylic alcohols and protected sugars.
Cleavage was found to be nearly quantitative as deter-
mined by GC analysis of the crude residue obtained
after hydrolysis with 2 N NaOH and this was confirmed
by IR and H NMR analysis of the PEG obtained dur-
ing post cleavage work-up. The protocol was found to
be suitable for the base-sensitive substrate, 6-hydroxy-
coumarin, which was found to retain its lactone struc-
ture (entry g) but showed partial reduction of the
Table 1. Catalytic transfer hydrogenation of PEG-bound succinyl esters
a
b
Entry
Substrate (1)
Product (2)
Time (h)
Yield (%)
O
O
OH
a
MeO-PEG-O
8
78
O
HO
O
O
O
b
c
7.5
81
OH
MeO-PEG-O
MeO-PEG-O
O
OH
OH
3
2
O
+
7
O
O
57
84
80
O
O
O
d
e
7
8
7
OH
MeO-PEG-O
MeO-PEG-O
O
O
OTBDMS
O
8.5
HO
OTBDMS
O
O
O
O
f
O
O
8
86
O
O
HO
HO
O
O
MeO-PEG-O
MeO-PEG-O
O
O
O
O
O
O
64
O
O
O
O
g
12
+
HO
O
O
22
a
1
The structures of all the products after CTH were determined by H NMR and mass spectroscopy and also by comparison with authentic
compounds.
Yields based on GC analysis of the crude product obtained after the hydrogen transfer reaction.
b

H. M. S. Kumar et al. / Tetrahedron Letters 46 (2005) 3591–3593
3593
double bond. The method is also applicable to acid-sen-
sitive substrates, for example, PEG-bound mannose
diacetonide was released in good yields under the
CTH conditions without deterioration of its molecular
structure (Scheme 1). In conclusion, we have presented
in this paper a new cleavage strategy for various PEG-
bound succinyl esters employing catalytic transfer
hydrogenation. The procedure is suitable for both
base- and acid-sensitive substrates and hence may find
application as an alternative cleavage protocol for
PEG-bound esters (Table 1).
formate, which was then filtered off. The filtrate was
concentrated to one third of its original volume and
cleaved PEG was precipitated by the addition of chilled
diethyl ether (200 mL). The PEG was washed with
diethyl ether (75 mL) and the combined ether extracts
were concentrated in vacuo to afford a crude product,
which was purified by chromatography (silica gel >200
mesh, elution, EtOAc/hexane gradient; n-hexane to 2:1
n-hexane–EtOAc) to afford pure mannose diacetonide
2f (0.065 g, 85%).
Acknowledgements
2. Experimental
The authors thank Dr. G. N. Qazi, Director RRL-
Jammu for his interest and encouragement.
2
.1. Polymer-supported succinyl ester; general procedure
PEG-succinate was prepared by refluxing PEG5000 (2 g)
with succinic anhydride (0.4 g, 4.0 mmol) in the presence
of diisopropylethylamine (DIEA, 1 mL) in dichloro-
methane (15 mL) for 24 h. After completion of the
reaction the solvent was evaporated to reduce the vol-
ume to one third. The PEG-supported succinyl ester
was precipitated by addition of an excess volume of
chilled diethyl ether (150 mL). Filtration and washing
with diethyl ether (50 mL) followed by drying under
vacuum afforded (1.92 g, 95%) of the product as an off
white solid.
References and notes
1
. (a) Hermekens, P. H.; Ottenheijm, H. C. J. Tetrahedron
996, 52, 4527–4529; (b) Hermekens, P. H.; Ottenheijm, H.
C. J.; Rees, D. Tetrahedron 1997, 53, 5643–5646; (c) Shang,
Y. J.; Wang, Y. G. Synthesis 2002, 12, 1663.
2. (a) Jung, K. W.; Zhao, X. Y.; Janda, K. D. Tetrahedron
1997, 53, 6645–6648; (b) Wentworth, P.; Janda, K. D.
Chem. Commun. 1999, 1917–1918; (c) Gravert, D. J.; Janda,
K. D. Chem. Rev. 1997, 97, 489, and references cited
therein; (d) Gravert, J. G.; Datta, A.; Wentworth, P.;
Janda, K. D. J. Am. Chem. Soc. 1998, 120, 9481–9488; (e)
Han, H.; Wolfe, M. M.; Brenner, S.; Janda, K. D. Proc.
Natl. Acad. Sci. U.S.A. 1995, 92, 6419–6423.
1
2.2. Condensation of polymer-supported succinyl ester
with mannose diacetonide general procedure 1f
3
. (a) Park, W. K. C.; Auer, M.; Jaksche, H.; Wong, C. H. J.
Am. Chem. Soc. 1996, 118, 10150–10153; (b) Shemyakin,
M. M.; Ovchinnikov, Yu. A.; Kiryushkin, A. A.; Ozhev-
nikova, I. V. Tetrahedron Lett. 1965, 2323–2326; (c) Mutter,
M.; Hagenmaier, H.; Bayer, E. Angew. Chem., Int. Ed.
Engl. 1971, 10, 811–815; (d) Bayer, E.; Mutter, M. Nature
Mannose diacetonide (1.04 g, 4.0 mmol), dicyclohexyl-
carbodimide (DCC, 2 g, 9.8 mmol) and a catalytic
amount of dimethylaminopyridine (DMAP, 5 mg) were
added to the PEG-supported succinyl ester (1.9 g) in dry
dichloromethane (25 mL) and the resulting mixture stir-
red at rt for 24 h under nitrogen. Excess DCC and dicy-
clohexyl urea formed during the course of reaction
were removed by filtration. The filtrate was then concen-
trated in vacuo. Polymer-supported PEG was precipi-
tated by addition of chilled diethyl ether (200 mL),
then filtered and washed thoroughly with excess diethyl
ether and dried in vacuum to afford the product as a
1972, 237, 512–514; (e) Zhu, J.; Hegedus, L. S. J. Org.
Chem. 1995, 60, 5837–5840.
4
. (a) Nouvet, A.; Binard, M.; Lamaty, F.; Martinez, J.;
Lazaro, R. Tetrahedron 1999, 55, 4685–4698; (b) Zhao, X.
Y.; Janda, K. D. Tetrahedron Lett. 1997, 38, 5437–5440; (c)
Moore, M.; Norris, P. Tetrahedron Lett. 1998, 39, 7027–
7030; (d) Gennari, C.; Nestler, H. P.; Salom, B.; Still, W. C.
Angew. Chem., Int. Ed. Engl. 1995, 34, 1763–1765.
6
white solid (1.8 g, 91%).
5. (a) Kumar, H. M. S.; Chakravarthy, P.; Shesha Rao, M.;
Reddy, S. R.; Yadav, J. S. Tetrahedron Lett. 2002, 43,
7817–7819; (b) Kumar, H. M. S.; Anjaneyulu, S.; Reddy, B.
V. S.; Yadav, J. S. Synlett 2000, 1129–1130; (c) Kumar, H.
M. S.; Chakravarthy, P.; Shesha Rao, M.; Joyasawal, S.;
2.3. Catalytic transfer hydrogenation of PEG-bound
substrates; typical procedure
Yadav, J. S. Chem. Lett. 2004, 33, 888–889.
. PEG-supported mannose diacetonide (1f):
200 MHz, CDCl
Polymer-supported diacetonide (1f, 1.6 g), ammonium
formate (1 g, 16 mmol) and a catalytic amount (5% w/
w) of Pd/C (10%) were suspended in dry methanol
1
6
H NMR
(
3
): d 1.34 (s, 3H), 1.38 (s, 3H), 1.46 (s,
H), 1.47 (s, 3H), 2.73 (m, 4H, –OCCH CH CO–), 3.46–
3
3
–
2
2
(
20 mL). The reaction mixture was heated to reflux for
h under nitrogen. The Pd/C was filtered off and the fil-
.81 (m, PEG), 3.95–4.10 (m, 2H), 4.25 (t, J = 4.2 Hz, 2H,
PEG–OCH CH OCO), 4.30 (m, 2H), 4.60 (d, 1H,
8
2
2
trate was evaporated to afford a residue to which dichlo-
romethane (20 mL) was added to precipitate ammonium
J = 7.4 Hz), 4.80 (t, 1H, J = 7.4 Hz), 6.10 (d, 1H, J =
3.4 Hz).