PEG-supported pyridylthioesters for racemization-free amide synthesis: A reagent that allows simultaneous product formation and removal from the polymer

Article abstract of DOI:10.1016/j.tet.2005.07.111

Pyridylthioesters anchored to a modified poly(ethylene glycol) of M _w 5000 Da have been prepared in high yields. The thioesters were employed as a convenient starting material for the liquid-phase synthesis of various enantiomerically pure amid

Full text of DOI:10.1016/j.tet.2005.07.111

Tetrahedron 61 (2005) 12100–12106
PEG-supported pyridylthioesters for racemization-free amide
synthesis: a reagent that allows simultaneous product formation
and removal from the polymer
Maurizio Benaglia, Stefania Guizzetti, Clara Rigamonti and Alessandra Puglisi
*
Centro di Eccellenza CISI and Dipartimento di Chimica Organica e Industriale, Universita’ degli Studi di Milano,
Via Golgi 19-20133 Milano, Italy
Received 20 June 2005; revised 12 July 2005; accepted 12 July 2005
Available online 25 October 2005
Abstract—Pyridylthioesters anchored to a modified poly(ethylene glycol) of M 5000 Da have been prepared in high yields. The thioesters
w
were employed as a convenient starting material for the liquid-phase synthesis of various enantiomerically pure amides. This new
methodology allowed to perform simultaneously the reaction with the poly(ethylene glycol)-supported reagent and the traceless removal of
the final product from the polymer support in a single step. The products were obtained in high yield and purity.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
organic molecules on PEGs have been extensively reported
over the last few years.
7
In the early 1990s the first examples of combinatorial
organic synthesis led to a renaissance of the interest in
Recently our group has been involved in the synthesis and
development of poly(ethylene glycol)-supported catalysts.
1
synthetic methodologies on polymer supports. In the last
8
9
Achiral and chiral organic catalysts, as well as chiral
10
decade the number of publications in the field of
combinatorial synthesis of relatively small organic mol-
ecules has been growing exponentially and today solid-
phase organic synthesis (SPOS) is routinely used for the
preparation of combinatorial libraries of low molecular
1
1
organometallic species have been immobilized on
properly modified PEG derivatives and their catalytic
activity investigated. The synthesis of PEG-anchored
N-aryl imines, their conversion into differently substituted,
2
12
13
weight organic molecules.
supported b-lactams and tetrahydroquinolines, and
finally the traceless removal of these products from the
polymer support have also been studied.
Poly(ethylene glycol)s (PEGs) have emerged as very
convenient supports for the synthesis of a variety of small
3
organic molecules. PEGs are inexpensive and commer-
On the basis of this experience we became convinced that
the success of a polymer-supported synthesis strategically
depends on the development of suitably modified new
polymeric backbones. In particular the choice of the
structural unit which temporarily connects the solid support
and the substrate under manipulation (the so-called ‘linker’)
4
cially available polymers that can readily be functionalized
5
with different spacers and linkers. Provided that their M is
w
O2000 Da, PEGs are soluble in many, mostly polar
solvents (including water) and insoluble in a few nonpolar
solvents (hexanes, diethyl ether, tert-butyl methyl ether).
Because of this solubility profile, PEG-based supports
combine the advantageous features of homogeneous
solution chemistry (high reactivity, lack of diffusion
phenomena, analytical simplicity) and of solid-phase
1
4
is crucial. The ideal linker must tolerate the conditions
employed to elaborate the substrate, but it must cleave under
mild conditions without affecting neither chemically nor
stereo chemically the product’s integrity. For the reversible
attachment of special functional groups, known anchors
have often to be modified and optimized or, when necessary,
6
methods (ready isolation and purification of products).
Consequently, syntheses and immobilization of several
1
5
must be created de novo.
Keywords: Poly(ethylene glycol); Mesylate derivative; Pyridylthioester.
*
Recently an increasing attention has been devoted to the
development of ‘traceless’ linkers to join the desired
Corresponding author. Tel.: C39 250314171; fax: C39 250314159;
e-mail: maurizio.benaglia@unimi.it
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.07.111

M. Benaglia et al. / Tetrahedron 61 (2005) 12100–12106
12101
Scheme 1. Synthesis of functionalized PEG derivatives 1 and 2.
Figure 1. Schematic representation of the synthetic sequence in polymer-
supported organic synthesis.
transformed into the mesylate derivative 2 in 95% overall
yield over three steps (Scheme 1).
1
2
synthetic intermediates to the solid support. With these
linkers the cleavage can be accomplished without leaving a
1
6
residue or trace of the linker on the final product (Fig. 1).
The immobilization of a functionalized pyridine unit onto
the polymer was then attempted. 6-Bromo-2-hydroxy-
methylpyridine 3 was easily prepared starting from the
commercially available 2,6-dibromopyridine by lithiation
with n-butyllithium, formylation with DMF and reduction
with NaBH4 (91% overall yield). Unfortunately, any
attempt to react the sodium salt of alcohol 3 (prepared
Another popular strategy in the very active field of the study
and optimization of novel linkers, is the so-called ‘safety-
1
7
catch’ linking methodology. According to this strategy the
linker employed is stable under different reaction conditions
1
8
until it is activated for the removal of the product. Safety-
catch linkers may facilitate the use of a wider range of
reaction conditions but at the cost of one additional
activation step.
1
9
from 3 with NaH) with mesylate 1 or 2 were unsuccesfull.
On the contrary, reaction of the mesylate 4, obtained in 98%
2
0
yield from 3, with MeOPEG carried out in the presence of
potassium t-butoxide in dry toluene allowed to obtain the
poly(ethylene glycol)-supported 6-bromopyridyl derivative
Here, we report a new methodology that allows to perform
simultaneously a chemical transformation of the polymer
supported substrate and the traceless cleavage of the product
5
in 91% yield (Scheme 2).
(
Fig. 2). A single synthesis-removal step delivers the
The most straightforward transformation of a 2-bromopyr-
idine into the corresponding thioester involves lithiation at
position 2 by lithium–halogen exchange followed by
quenching with sulphur and in situ reaction with an acyl
chloride. However, when this sequence was performed on
bromide 5 in ethereal solvents the very low solubility of
PEG in these reaction media prevented any product
product in solution while leaving the polymer ready for
recycling after an activation step.
2
. Results and discussion
2
1
formation. Therefore, on the base of Peterson’s work,
The functionalization of the polymeric support was
performed as follows. The monomethylether of PEG with
a Mw of 5000 Da (MeOPEG) was easily converted into
mesylate 1 that was reacted with the cesium salt of the
commercially available 3-(4-hydroxyphenyl)-1-propanol
we decided to employ dichloromethane as reaction solvent.
We were very pleased to find that reaction of 5 with
butyllithium in dry CH Cl at K78 8C, followed by
2
2
(3 mol equiv, N,N-dimethylformammide, 48 h) to afford
the corresponding polymer supported alcohol. This was
Figure 2. Schematic representation of the novel methodology.
Scheme 2. Synthesis of poly(ethylene glycol)-supported pyridyl unit 5.

12102
M. Benaglia et al. / Tetrahedron 61 (2005) 12100–12106
were obtained in the condensation between the same
aminoesters and pyridylthio-2-benzyloxyacetate 9; in this
case the reaction with 10, 11 and 12 afforded the
corresponding products 16, 17 and 18 in 84, 51 and 71%
yield, respectively.
The same reaction starting from the PEG-supported
pyridylthioesters were then studied (Scheme 5). The
dimethylaluminum amide of (S)-phenylalanine methylester
Scheme 3. Synthesis of poly(ethylene glycol)-supported pyridylthioesters 6
and 7.
(
2 mol/equiv) reacted with the poly(ethylene glycol)-
quenching with sulfur and trapping of the intermediate
thiolate with butanoyl chloride afforded the PEG-supported
supported pyridylthioester 6 (1 mol/equiv) in dichloro-
methane to afford, after 24 h at room temperature, the
product 13 in 63% yield. After the work up, the organic
phase was concentrated and poured into a diethyl ether
solution. The precipitated polymer was filtered off, and the
organic solvent simply evaporated to give the reaction
2
-pyridylthiobutanoate 6 in an excellent 87% overall yield.
Scheme 3). Similarly, by lithiation of 5, reaction first with
(
sulfur and then with benzyloxyacetyl chloride, polymer-
supported pyridylthioester 7 was synthesized in 91%
yield.
2
2
28
product. Starting always from 6, a similar procedure
allowed to obtain the amide 14 and 15, derived from
reaction of (S)-phenylglycine and (S)-serine derivatives, in
33 and 19% yield.
The availability of the PEG-supported thioesters 6 and 7
allowed us to investigate the possibility of performing in a
2
3
single step a synthesis/removal process. Thioesters are
activated carboxylic acid derivatives that have found
widespread application as acylating agents in synthetic
chemistry acting as precursors of carbonyl compounds,
acids, esters, lactones, amides, lactams, and
PEG-anchored thioester 7 gave better results than 6, exactly
like the nonimmobilized thioester 9 did in comparison with
8. Compound 16, the product of the reaction of 7 with
phenylalanine derivative, was isolated in 77% yield, that
was only marginally lower than that obtained starting from
the nonsupported derivative 9 (84% yield). Analogously,
starting from 7 compounds 17 and 18 were synthesized in 35
and 43% yield, respectively. It is worth mentioning that
these are highly functionalized molecules; for example
different functional groups as an amide, an ester, a free
primary alcohol and another primary but protected alcohol
are all present in 18. Noteworthy, all the products 13-18
were obtained as enantiomerically pure compounds, in a
2
4,25
heterocycles.
We decided to employ our PEG-supported thioesters in
some amide bond forming reactions, where it is essential to
prevent base-catalysed racemization during the coupling
process. In particular, the reaction of PEG-supported
pyridylthioesters 6 and 7 with differently substituted chiral
2
6,27
a-amino esters in the presence of Me Al was studied.
3
2
9
For sake of comparison, the condensation between
thioesters 8 and 9 (the nonsupported equivalents of 6 and
racemization-free methodology.
7
) and the chiral a-amino esters, was also performed as test
Another point of interest is the possibility to recover and
recycle the polymer-supported reagent. For example, from
the reaction of 9 with phenylalanine derivative 10, besides
product 16, the PEG-supported 2-mercaptopyridyl deriva-
tive 19 was recovered by filtration in 91% yield (Scheme 6).
reactions (Scheme 4). Condensation of 2-pyridyl-thiobu-
tanoate 8 in the presence of trimethylaluminum in dry
dichloromethane with (S)-phenylalanine methyl ester 10
afforded the corresponding amide 13 in 71% yield.
Analogously, the reactions under the same experimental
conditions of 8 with (S)-phenylglycine methyl ester 11 and
Starting from 19 the poly(ethylene glycol)-anchored
benzyloxy-pyridylthioacetate 7 was easily regenerated by
reaction with benzyloxyacetyl chloride in the presence of a
(
1
S)-serine methylester 12 gave the corresponding products
4 and 15 in 47 and 23% yield, respectively. Better yields
Scheme 4. Reaction of nonsupported pyridylthioesters 8 and 9.
Scheme 5. Reaction of PEG-supported pyridylthioesters 6 and 7.

M. Benaglia et al. / Tetrahedron 61 (2005) 12100–12106
12103
in CDCl . Optical rotations were measured at the Na-D line
3
in a 1 dm cell at 22 8C. IR spectra were recorded on thin film
or as solution in CH Cl .
2
2
All the PEG samples were melted at 80 8C under vacuum for
0 min before use to remove traces of moisture. After
6
reaction, PEG-supported product purification involved
evaporation of the reaction solvent in vacuum and addition
of the residue dissolved in a few mL of CH Cl to
Scheme 6. Recycle of the PEG-supported reagent.
2
2
diethylether (40 mL/g of polymer), which was stirred and
cooled at 0 8C. After 20 min stirring at 0 8C, the obtained
suspension was filtered through a sintered glass filter, and
the solid repeatedly washed on the filter with diethylether
base and employed in a new condensation with 10 that
afforded the product 16 in a comparable yield (75% vs
7
7%).
(
up to 80 mL/g of polymer, overall).
Finally we tested the polymer-supported thioester also in
3
another reaction. We were attracted by Seki’s and
0
Yield and purity determination of PEG-supported com-
pounds. The yield of the PEG-supported compounds were
determined by weight with the assumption that Mw is
3
1
Mukaiyama’s work, where a iodo compound in the
presence of an excess of zinc, under catalysis of nickel
(II) chloride, was coupled to a pyridylthioester to afford a
ketone. We decided to study this reaction with the PEG-
supported pyridylthioester 7 (Scheme 7).
5
000 Da for the PEG fragment. The Mw actually ranged
from 4500 to 5500. The indicated yields were for pure
compounds. The purity of these compounds was determined
by H NMR analysis in CDCl3 at 300 MHz with pre-
1
saturation of the methylene signals of the polymer centered
at dZ3.63. In recording the NMR spectra, a relaxation time
of 6 s and an acquisition time of 4 s were used to ensure
complete relaxation and accuracy of the integration. The
relaxation delay was selected after T measurements. The
1
integration of the signals of the PEG CH OCH fragment at
2
3
dZ3.30 and 3.36 were used as internal standard. The
estimated integration error was C5%.
Scheme 7. Nickel catalysed synthesis of ketones 20 and 21.
3.2. Synthesis of pyridyl derivatives
To the polymer-immobilized thioester 7 in dry N,N-
dimethylformammide (DMF), iodo-butane, zinc and a
catalytic amount of nickel chloride were added; the reaction
mixture was allowed to stir for 20 h at room temperature.
After work up with water and diethyl ether the evaporation
of the organic phase afforded the expected ketone 20 in 81%
yield. Similarly, the long chain-ketone 21 was obtained
from the reaction with iodododecane.
PEG derivative 1 was prepared by a synthesis developed in
our group. Products 3 and 4 are known compounds;
1
2
20
3
2
product 14 is also known; product 14 is known also as
3
3
racemic compound.
3.2.1. Synthesis of PEG-mesylate 2. To a solution of
mesylate 1 (9.00 g, 1.80 mmol) in dry DMF (20 mL) stirred
under nitrogen, Cs CO (1.94 g, 5.94 mmol) and 3-(4-
2
3
In conclusion, a new synthesis of soluble polymer-
supported pyridylthioesters, useful starting materials for
several reactions in liquid phase synthesis has been
developed. A new methodology allowed to perform at the
same time the reaction of the poly(ethylene glycol)-
supported reagent and the traceless removal of the final
product from the polymer support in a single step. This
synthetic procedure was successfully tested in two different
reactions, the synthesis of various enantiomerically pure
amides and a nickel-catalyzed preparation of ketones. The
recovery, the regeneration and the recycle of the polymer-
supported reagent was also realized.
hydroxy-phenyl)-1-propanol (0.82 g, 5.40 mmol) were
added. The mixture was stirred at room temperature for
40 h and concentrated under vacuum to half of the original
volume. Purification by precipitation with diethyl ether
(40 mL/g of polymer) afforded the corresponding alcohol
(8.85 g, 96% yield).
1
3
H NMR: 1.83 (m, 2H, CH –CH –CH ), 2.67 (t, JH,HZ
2
2
2
7.4 Hz, 2H, Ar-CH –CH –CH ), 3.38 (s, 3H, OMe), 4.10 (t,
JH,HZ5.0 Hz, 2H, Ar-O–CH –CH –PEG), 6.82 (B part of
2
2
2
3
2
2
3
a AB system, J Z8.5 Hz, 2H, H ortho to O in aromatic
ring), 7.07 (A part of a AB system, J Z8.5 Hz, 2H, H
H,H
3
H,H
1
2
meta to O in aromatic ring). This intermediate was then
converted into mesylate 2. To a solution of the PEG-alcohol
(6.00 g, 1.2 mmol) in dichloromethane (30 mL), mesyl
chloride (3.6 mmol, 0.29 mL) and trioctylamine
(3.96 mmol, 1.72 mL) were added. The mixture was stirred
at room temperature for 24 h. Purification by precipitation
with diethyl ether (40 mL/g of polymer) afforded the
corresponding mesylate 2 (6.01 g, 99% yield). 2.73 g,
3
. Experimental
3
.1. General methods
1
H NMR spectra were recorded at 300 MHz in chloroform-d
CDCl ) unless otherwise stated, and were referenced to
tetramethylsilane (TMS) at 0.00 ppm. C NMR spectra
were recorded at 75 MHz and were referenced to 77.0 ppm
(
3
1
3
1
yield 91%). H NMR: 1.93 (m, 2H, CH –CH –CH ), 2.60
2
2
2
3
(t, J Z7.5 Hz, 2H, Ar-CH –CH –CH ), 3.07 (s, 3H,
H,H
2
2
2

12104
M. Benaglia et al. / Tetrahedron 61 (2005) 12100–12106
3
OSO Me), 3.35 (s, 3H, OMe), 4.05 (t, JH,HZ5.0 Hz, 2H,
1–6 h. t-Butanol (a few drops) was added, then the reaction
solution was acidified by addition of 5% HCl to pH 4–5.
Water was added, the phases separated and the aqueous
phase extracted twice with CH Cl . The combined organic
phases were washed with water, dried over sodium sulfate,
filtered, concentrated under vacuum, to give the crude
product that was purified by flash chromatography with
hexanes:AcOEt mixtures as eluant.
2
3
Ar-O–CH –CH –PEG), 4.25 (t, J Z5.2 Hz, 2H, –CH –
2
2
H,H
2
3
OSO Me), 6.87 (B part of a AB system, JH,HZ8.0 Hz, 2H,
2
H ortho to O in aromatic ring), 7.15 (A part of a AB system,
JH,HZ8.0 Hz, 2H, H meta to O in aromatic ring).
2
2
3
3
.2.2. Synthesis of PEG-derivative 5. To a solution of
poly(ethylene glycol) monomethylether (3.00 g, 0.60 mmol)
in dry toluene (20 mL) stirred under nitrogen, potassium
t-butoxide (80 mg, 0.72 mmol) was added. The mixture was
warmed up to 60 8C and stirred at that temperature for 3 h. A
solution of mesylate 4 (479 mg, 1.8 mmol) in toluene
With supported reagents 6 and 7. To a solution of PEG-
supported pyridylthioester (0.4 mmol) in dry dichloro-
methane (4 mL) at 0 8C, the amino-ester (0.8 mmol) was
added. After a few minutes a 2 M toluene solution of
trimethylaluminum (1.6 mmol) was added and the reaction
mixture was allowed to stir at 0 8C for 3–12 h. t-Butanol (a
few drops) was added, then the reaction solution was
acidified by addition of 5% HCl to pH 4–5. Water was
added, the phases separated and the aqueous phase extracted
(
3 mL) was then added and all the reaction mixture was
allowed to stir at 65 8C for 48 h. The solvent was then
evaporated under vacuum, and the residue was solved into
CH Cl (30 mL). This organic phase was washed with
water, dried over sodium sulfate, filtered, concentrated
under vacuum, and precipitated with diethyl ether (see
above). The product was isolated by filtration. (2.73 g, yield
1%). H NMR: 3.38 (s, 3H, OMe), 3.80 (t, JH,HZ6 Hz,
H, CH –O–EG–Me), 4.68 (s, 2H, Py-CH –O), 7.31 (d,
JH,HZ9 Hz, 1H, H Py), 7.46 (d, J Z9 Hz, 1H, H Py),
2
2
twice with CH Cl . The combined organic phases were
2 2
1
3
9
washed with water, dried over sodium sulfate, filtered,
concentrated under vacuum, and poured into diethyl ether
(100 mL). The PEG-derivative 19 was recovered by
filtration, while the evaporation of the organic phase
afforded the crude product that was purified by a filtration
onto a short plug of silica gel with hexanes:AcOEt mixtures
as eluant.
2
2
2
3
3
5
H,H
3
3
7
.53 (t, J Z9 Hz, 1H, H Py).
H,H 4
3
.2.3. Synthesis of PEG-supported pyridylthioesters 6
and 7. To a solution of poly(ethylene glycol) monomethyl-
ether (2.5 g, 0.48 mmol) in dry CH Cl (20 mL) stirred
2
2
under nitrogen and cooled to K78 8C, butyllithium
0.39 mL of a 1.5 M solution of butyllithium in hexanes,
.58 mmol) was slowly added by syringe. The suspension
was allowed to stir at K78 8C for 45 min, then sulfur
0.186 g, 5.8 mmol) was added; the reaction mixture was
stirred at that temperature for 15 min, then at 0 8C for other
5 min and finally at room temperature for other 90 min.
Then a solution of the acyl chloride (0.97 mmol in 5 mL of
dichloromethane) was added and the reaction mixture was
allowed to stir overnight at room temperature. Na HCO3
satd sol was added and the phases separated. The organic
phase was dried over sodium sulfate, filtered, concentrated
under vacuum, and precipitated with diethyl ether (see
above). The product was isolated by filtration.
3.3.1. N-Butanoyl-(S)-phenylalanine methylester 13.
2
2
(
0
Thick oil; [a]
D
65.6 (c 1.2 in CHCl
3
). IR: 3408, 1747,
1686 cm . H NMR: 0.90 (t, JH,HZ7 Hz, 3H, CH –CH
CH –CO), 1.55 (m, 2H, CH –CH –CH –CO), 2.05 (t,
H,HZ7 Hz, 2H, CH –CH –CH –CO), 3.0–3.08 (m, 2H,
CH -Ph), 3.65 (s, 3H, OMe), 4.85 (dd, JH,HZ6, 8 Hz, 1H,
CH–NHCO), 5.90 (bs, 1H, NH), 7.01 (m, 2H, phenyl), 7.11–
K1 1
3
–
2
3
2
3
2
2
3
(
J
3
2
2
3
2
1
1
3
7.31 (m, 3H, phenyl). C NMR: d 172.6, 172.2, 135.95,
129.2, 128.5, 127.0, 52.9, 52.2, 38.5, 38.0, 18.9, 13.6. M
w
249.31 Da. Anal. Calcd for C14H19NO . C, 67.45; H, 7.68;
3
N, 5.62. Found: C, 67.29; H, 7.79; N, 5.71.
3
2,33
3.3.2. N-Butanoyl-(S)-phenylglycine methylester 14.
Thick oil; [a]
2
D
2
86.7 (c 0.2 in CHCl
). IR: 3408, 1744,
3
K1 1
3
1
CH
666 cm . H NMR: 0.91 (t, J Z8 Hz, 3H, CH –CH –
H,H 3 2
1
3
Product 6. (2.3 g, yield 87%). H NMR: 1.10 (t, JH,HZ
2
–CO), 1.60 (m, 2H, CH
3
–CH
2
–CH –CO), 2.20 (t,
2
JH,HZ8 Hz, 2H, CH –CH –CH –CO), 3.70 (s, 3H, OMe),
3 2 2
3
5.60 (d, JH,HZ6 Hz, 1H, CH–NHCO), 7.01–7.40 (m, 5H,
3
3
7
Hz, 3H, CH –CH CO), 2.35 (q, J Z7 Hz, 2H, CH –
CH CO), 3.38 (s, 3H, OMe), 3.80 (t, J Z6 Hz, 2H,
CH –O–EG–Me), 4.65 (s, 2H, Py-CH –O), 7.31 (d, JH,HZ
Hz, 1H, H Py), 7.41 (d, J Z8 Hz, 1H, H Py), 7.49 (t,
3
2
H,H
3
3
2
H,H
3
phenyl).
2
2
3
8
5
H,H
3
3
JH,HZ8 Hz, 1H, H Py).
3.3.3. N-Butanoyl-(S)-threonine methylester 15. Thick
4
K1
1
3
oil; IR: 3408, 1747, 1686 cm . H NMR: 0.98 (t, JH,HZ
7 Hz, 3H, CH –CH –CH –CO), 1.65 (m, 2H, CH –CH –
1
Product 7. (2.41 g, yield 91%). H NMR: 3.38 (s, 3H, OMe),
3
2
2
3
2
3
3
3
CO–CH –O), 4.60 (s, 2H, Ph-CH –O), 4.70 (s, 2H, Py-
.80 (t, J Z6 Hz, 2H, CH –O–EG–Me), 4.10 (s, 2H,
CH –CO), 2.15 (t, J Z7 Hz, 2H, CH –CH –CH –CO),
H,H
2
2 H,H 3 2 2
3.65 (s, 3H, OMe), 3.95 (m, 2H, CH OH), 4.70 (m, 1H, CH–
2
2
2
3
13
NHCO), 7.45 (bs, 1H, NH). C NMR: d 173.7, 171.0, 63.8,
CH –O), 7.25–7.35 (m, 5H, phenyl), 7.31 (d, JH,HZ8 Hz,
H, H Py), 7.43 (d, J Z8 Hz, 1H, H Py), 7.53 (t,
JH,HZ8 Hz, 1H, H Py).
2
3
1
54.8, 52.9, 38.5, 19.1, 13.8. M 189.21 Da. Anal. Calcd for
w
5
H,H
3
3
C H NO . C, 50.78; H, 7.99; N, 7.40. Found: C, 50.79; H,
8
4
15
4
7
.89; N, 7.71.
3
.3. Synthesis of amides 13-18
3
.3.4. N-Benzyloxyacetyl-(S)-phenylalanine methylester
2
2
With nonsupported reagents. To a solution of pyridylthio-
ester (1 mmol) in dry dichloromethane (5 mL) at 0 8C, the
amino-ester (2 mmol) was added. After a few minutes a 2 M
toluene solution of trimethylaluminum (4 mmol) was added
and the reaction mixture was allowed to stir at 0 8C for
16. Thick oil; [a] 8.476 (c 1.15 in CHCl ). IR: 3412, 1744,
D 3
K1
1681 cm . H NMR: 3.0–3.08 (m, 2H, CH -Ph), 3.65 (s,
1
2
3H, OMe), 3.90 (s, 2H, CO–CH –O), 4.55 (B part of an AB
2
3
system, J Z12 Hz, 1H, O–CH Ph), 4.60 (A part of an
H,H
2
3
AB system, JH,HZ12 Hz, 1H, O–CH Ph), 4.85 (dd,
2

M. Benaglia et al. / Tetrahedron 61 (2005) 12100–12106
12105
3
JH,HZ6, 8 Hz, 1H, CH–NHCO), 5.90 (bs, 1H, NH), 7.05–
3.5.2. 1-Benzyloxy-tetradecan-2-one 21. Oil; IR:
1
3
K1
1
3
7
1
5
.35 (m, 10H, phenyl). C NMR: d 171.5, 169.2, 136.6,
35.6, 129.1, 128.5, 128.4, 128.0, 127.7, 127.0, 73.3, 68.0,
2.3, 52.2, 37.8. Mw 327.37 Da. Anal. Calcd for
1721 cm
CH –), 1.30–1.55 (m, 20H, alifatic chain CH –), 2.25 (m,
. H NMR: 1.02 (t, JH,HZ8 Hz, 3H, CH3–
2
2
2H, –CH –CO), 4.10 (s, 2H, CO–CH –O), 4.65 (s, 2H,
2
2
C H NO . C, 69.71; H, 6.47; N, 4.28. Found: C, 69.79;
1
O–CH Ph), 7.30–7.45 (m, 5H, phenyl).
2
9
21
4
H, 6.49; N, 4.31.
3
1
1
.3.5. N-Benzyloxyacetyl-(S)-phenylglycine methylester
2
2
Acknowledgements
7. Thick oil; [a] 81.6 (c 1.1 in CHCl ). IR: 3410, 1734,
3
D
K1 1
671 cm . H NMR: 3.70 (s, 3H, OMe), 3.92 (s, 2H, CO–
3
This work was supported by MIUR (Rome) within the
national project ‘Stereoselezione in Sintesi Organica.
Metodologie e Applicazioni’. We thank Dr. Antonio Zara
for his collaboration and Prof. Franco Cozzi and Prof.
Mauro Cinquini-Universit a` degli Studi di Milano-Italy, for
very helpful suggestions.
CH –O), 4.50 (B part of an AB system, JH,HZ11 Hz, 1H,
O–CH Ph), 4.55 (A part of an AB system, JZ11 Hz, 1H,
O–CH Ph), 5.55 (d, J Z8 Hz, 1H, CH–NHCO), 7.10–
2
2
3
2
H,H
3
13
7
.35 (m, 10H, phenyl); 7.50 (d, JH,HZ8 Hz, 1H, NH).
NMR: d 171.2, 169.2, 136.8, 136.4, 129.1, 128.7, 128.4,
28.1, 73.8, 69.4, 55.9, 52.9. M 313.35 Da. Anal. Calcd for
C
1
w
C H NO . C, 68.99; H, 6.11; N, 4.47. Found: C, 68.91; H,
4
1
8
19
6
.10; N, 4.51.
3.3.6. N-Benzyloxyacetyl-(S)-threonine methylester 18.
Thick oil; [a] 11.95 (c 0.4 in CHCl ). IR: 3410, 1737,
2
D
2
References and notes
3
K1
686 cm . H NMR: 3.70 (s, 3H, OMe), 3.90 (m, 2H,
1
1
CH OH), 3.98 (s, 2H, CO–CH –O), 4.51 (B part of an AB
2
2
1. For reviews see: Senkan, S. Angew. Chem., Int. Ed. 2001, 40,
312–337. Reetz, M. T. Angew. Chem., Int. Ed. 2001, 40,
284–311. Shuttleworth, S. J.; Allin, S. M.; Wilson, R. D.;
Nasturica, D. Synthesis 2000, 8, 1035–1047.
system, JZ10 Hz, 1H, O–CH Ph), 4.56 (A part of an AB
2
system, JZ10 Hz, 1H, O–CH Ph), 4.80 (m, 1H, CH–
2
1
3
NHCO), 7.21–7.31 (m, 5H, phenyl), 7.50 (bs, 1H, NH).
NMR: d 170.5, 170.0, 136.5, 128.6, 128.3, 128.0, 73.7, 69.2,
3.3, 54.3, 52.8. Mw 267.28 Da. Anal. Calcd for
C H NO . C, 58.42; H, 6.41; N, 5.24. Found: C, 58.39;
C
2. Eames, J.; Watkinson, M. Eur. J. Org. Chem. 2001, 7,
1213–1235. Bhattacharyya, S. Comb. Chem. High Throughput
Screen. 2000, 3, 65–73.
6
1
3
17
5
H, 6.39; N, 5.21.
3. Reviews: Gravert, D. J.; Janda, K. D. Chem. Rev. 1997, 97,
489–509. Wenthworth, P., Jr.; Janda, K. D. J. Chem. Soc.,
Chem. Commun. 1999, 1917–1924.
3
.4. Regeneration of 7 starting from 19
4
. For a report on the synthesis of monoprotected PEGs see:
Reed, N. N.; Janda, K. D. J. Org. Chem. 2000, 65, 5843–5845.
To a solution of the PEG-derivative 19 recovered from a
previous reaction (0.4 mmol) in dichloromethane (5 mL)
trioctylamine (1 mmol) and then benzyloxyacetyl chloride
5. For a discussion on the linkers connecting small organic
molecules to PEGs see: Grether, U.; Waldmann, H. Chem.
Eur. J. 2001, 7, 959–971.
(
0.8 mmol) were added at room temperature. The reaction
mixture was allowed to stir overnight, then it was
concentrated and poured into a diethyl ether solution. The
precipitated polymer was recovered by filtration and
showed NMR spectra identical to those of product 7,
previously prepared starting from 5.
6. Fr u¨ chtel, J. S.; Jung, G. Angew. Chem., Int. Ed. 1996, 35,
17–42. Thompson, L. A.; Ellman, J. A. Chem. Rev. 1996, 96,
555–600.
7. Dickerson, T. J.; Reed, N. N.; Janda, K. D. Chem. Rev. 2002,
102, 3325–3344.
8
. See Ref. 7; for the use of other soluble polymer-supported
catalysts see: Bergbreiter, D. E. Chem. Rev. 2002, 102,
3
.5. Synthesis of ketones 20 and 21
3
345–3384. For a recent review on polymer-supported organic
In typical procedure, to a solution of PEG-supported
pyridylthioester (0.2 mmol) in dry dimethylformammide
catalysts see: Benaglia, M.; Puglisi, A.; Cozzi, F. Chem. Rev.
2003, 103, 3401–3429.
(
(
2 mL) at room temperature, zinc (3 mmol), nickel chloride
0.2 mmol) and the iodoalkane (2 mmol) were added. Then
9. Annunziata, R.; Benaglia, M.; Cinquini, M.; Cozzi, F.; Tocco,
G. Org. Lett. 2000, 2, 1737–1739. Benaglia, M.; Danelli, T.;
Fabris, F.; Sperandio, D.; Pozzi, G. Org. Lett. 2002, 4,
4229–4233. Benaglia, M.; Dell’ Anna, G.; Cavazzini, M.;
Quci, S. Org. Lett. 2004, 6, 441–443.
the reaction mixture was allowed to stir at room temperature
overnight, then it was filtered and water and diethyl ether
were added. The organic phase was separated, dried over
sodium sulfate, filtered, concentrated under vacuum to
afford the crude product that was purified by a filtration onto
a short plug of silica gel with hexanes:AcOEt mixtures as
eluant.
10. Benaglia, M.; Celentano, G.; Cozzi, F. Adv. Synth. Catal.
2001, 343, 171–173. Benaglia, M.; Cinquini, M.; Cozzi, F.;
Puglisi, A.; Celentano, G. Adv. Synth. Catal. 2002, 344,
533–542 and references therein. Danelli, T.; Annunziata, R.;
Benaglia, M.; Cinquini, M.; Cozzi, F.; Tocco, G. Tetrahedron:
Asymmetry 2003, 14, 461–467. Puglisi, A.; Benaglia, M.;
Cinquini, M.; Cozzi, F.; Celentano, G. Eur. J. Org. Chem.
2004, 567–573 and references therein.
K1
3
.5.1. 1-Benzyloxy-hexan-2-one 20. Oil; IR: 1724 cm
.
1
3
H NMR: 0.98 (t, J Z8 Hz, 3H, CH –CH –CH –CH –
H,H
3
2
2
2
CO), 1.35 (m, 2H, CH –CH –CH –CH –CO), 1.65 (m, 2H,
CH –CH –CH –CH –CO), 2.20 (t, JH,HZ7 Hz, 2H,
3
2
2
2
3
11. Annunziata, R.; Benaglia, M.; Cinquini, M.; Cozzi, F.; Pitillo,
M. J. Org. Chem. 2001, 66, 3160–3166. Benaglia, M.; Danelli,
T.; Pozzi, G. Org. Biomol. Chem. 2003, 1, 454–456. Benaglia,
3
2
2
2
CH –CH –CH –CH –CO), 4.02 (s, 2H, CO–CH –O), 4.70
(
3
2
2
2
2
s, 2H, O–CH Ph), 7.20–7.45 (m, 5H, phenyl).
2

12106
M. Benaglia et al. / Tetrahedron 61 (2005) 12100–12106
M.; Cinquini, M.; Cozzi, F.; Celentano, G. Org. Biomol. Chem.
004, 2, 3401–3407.
Hennequin, L. F.; Piva-Le Blanc, S. Tetrahedron Lett. 1999,
40, 3881–3884.
2
1
1
2. Annunziata, R.; Benaglia, M.; Cinquini, M.; Cozzi, F. Chem.
Eur. J. 2000, 6, 133–138.
24. For a few selected examples of their use in synthesis see:
Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G. J. Am.
Chem. Soc. 1996, 118, 4322–4329. Um, P. J.; Drueckhammer,
D. G. J. Am. Chem. Soc. 1998, 120, 5605–5610. Aggarwal,
V. K.; Thomas, A.; Schade, S. Tetrahedron 1997, 53,
3. Annunziata, R.; Benaglia, M.; Cinquini, M.; Cozzi, F. Eur.
J. Org. Chem. 2002, 1184–1190.
1
4. James, I. W. Tetrahedron 1999, 55, 4855–4882.
5. Guillier, F.; Orain, D.; Bradley, M. Chem. Rev. 2000, 100,
16213–16220. White, J. D.; Kim, T. S.; Nambu, M. J. Am.
Chem. Soc. 1997, 119, 103–109.
5. Canne, L. E.; Walker, S. M.; Kent, S. B. H. Tetrahedron Lett.
1
2091–2105.
2
1
1
1
1
2
2
2
2
6. Comely, A. C.; Gibson, S. E. (n e´ e Thomas) Angew. Chem., Int.
Ed. 2001, 40, 1012–1032.
1996, 7, 1217–1221. Kobayashi, S.; Hachiya, I.; Yasuda, M.
Tetrahedron Lett. 1996, 37, 5569–5573.
7. Backes, B. J.; Ellman, J. A. J. Am. Chem. Soc. 1994, 116,
2
6. Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977,
8, 4171–4174.
1
1171–11172.
8. Tai, C.-H.; Wu, H.-C.; Li, W.-R. Org. Lett. 2004, 6,
905–2908 and references cited there.
1
2
7. Kurosu, M. Tetrahedron Lett. 2000, 41, 591–594.
8. The crude reaction product was often pure enough to be
analyzed directly by NMR spectroscopy. However, a filtration
through a short plug of silica gel of the crude reaction mixture
afforded analytical pure products. Low yielding reaction
products, like 14 or 15, were purified by a standard flash
chromatography (hexanes/ethylacetate 60:40 mixture as
eluant).
2
2
9. Extensive degradation of 6-bromo-2-hydroxymethyl-pyridine
was observed, with loss also of bromine atom.
0. Puglisi, A.; Benaglia, M.; Roncan, G.; Eur J. Org. Chem. 2003,
1
552–1558.
1. Peterson, M. A.; Mitchell, J. R. J. Org. Chem. 1997, 62,
237–8239.
8
2. For details on synthesis and purity determination of PEG-
supported molecules see Section 3.
2
9. For example, for product 14 optical rotation was measured and
a [a] Z131 (c 8 in CHCl ) was found (lit. [a] Z136 (c 9 in
D
3
D
3. For other examples where the removal of the compound from
the polymer has been accomplished by realizing a new C–
bond, introducing a further degree of diversity see: (a) Stille
reaction: Nicolau, K. C.; Winssinger, N.; Pastor, J.; Murphy, F.
Angew. Chem., Int. Ed. 1998, 37, 2534–2536. (b) Heck
coupling: Kuhn, H.; Neumann, W. P. Synthesis 1994,
32
3
CHCl ).
3
0. Shimizu, T.; Seki, M. Tetrahedron Lett. 2002, 43, 1039–1042.
1. Onaka, M.; Matsuoka, Y.; Mukaiyama, T. Chem. Lett. 1981,
3
5
2. Orsini, F.; Pelizzoni, F.; Ghioni, C. Amino Acids 1995, 9,
31–534.
3
135–140.
33. Koppen, J.; Matthies, D.; Schewein, H. Liebigs Ann. Chem.
1985, 2383–2389.
123–128. (c) Suzuki coupling: Li, W.; Burgess, K. Tetra-
hedron Lett. 1999, 40, 6527–6530. (d) other reactions: