Wang-aldehyde resin as a recyclable support for the synthesis of α,α-disubstituted amino acid derivatives

Article abstract of DOI:10.1039/b505881c

Merrifield resin was functionalised with hydroxybenzaldehyde under microwave irradiation. The resultant resin was used as a means for immobilisation and activation of α-amino acid esters for alkylation reactions. α,α-Disubstituted and cyclic amino acid esters were prepared in good yields. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b505881c

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A R T I C L E
Wang-aldehyde resin as a recyclable support for the synthesis of
a,a-disubstituted amino acid derivatives
Meritxell Guino´a and King Kuok (Mimi) Hii*b
a Department of Chemistry, King’s College London, Strand, London, UK WC2R 2LS
b Department of Chemistry, Imperial College London, Exhibition Road, South Kensington,
London, UK SW7 2AZ. E-mail: mimi.hii@imperial.ac.uk; Fax: +44 (0)20 7594 5804;
Tel: +44 (0)20 7594 1142
Received 27th April 2005, Accepted 29th June 2005
First published as an Advance Article on the web 27th July 2005
Merrifield resin was functionalised with hydroxybenzaldehyde under microwave irradiation. The resultant resin was
used as a means for immobilisation and activation of a-amino acid esters for alkylation reactions. a,a-Disubstituted
and cyclic amino acid esters were prepared in good yields.
Introduction
Schiff base esters are widely employed as precursors in the
synthesis of unnatural a,a-disubstituted amino acids.1 Trans-
position of these reactions on to the solid-phase has since been
achieved, notably by O’Donnell, who developed a methodology
for unnatural peptide synthesis (UPS) using polymer supports
(Scheme 1).2,3 In these reactions, N-Boc protected amino acids
are tethered onto the support via the C-terminus (ester linkage).
Hence, removal of the N-protecting group and activation of
the a-carbon by the formation of a benzophenone imine is
necessary prior to reaction. Following a-alkylation, removal
of the activating group and cleavage of the product from the
support required two separate steps.
Scheme 2 Proposed route for the synthesis of a,a-disubstituted amino
acid esters: (i) imine formation (activation/immobilisation); (ii) alkyla-
tion; (iii) acid hydrolysis/regeneration of resin.
Result and discussion
Functionalisation of polymer resins7
The required functionalised polymer was prepared by treating
HL Merrifield resin (1.3 mmol g−1, 100–200 mesh, 1% cross-link)
with 4-hydroxybenzaldehyde and K2CO3 in the presence of KI
at 80 ◦C. The substitution was slow under thermal conditions—
two treatments (lasting three days each) were required to achieve
total displacement of the Cl from the resin (%Cl analysis).
To speed up this transformation, a mixture of the Mer-
rifield resin, 4-hydroxybenzaldehyde, Cs2CO3 and NMP was
subjected to microwave-irradiation. Employing a temperature of
150 ◦C, total Cl displacement can be reduced to just 5 minutes
(Scheme 3).
Scheme 1 O’Donnell’s tandem UPS methodology: (i) immobilisation;
(ii) deprotect and activate; (iii) alkylation; (iv) hydrolysis; (v) N-acylation
and cleavage.
Wang-aldehyde resin has been widely used as an efficient
scavenger for primary amines through the formation of aldimine
4
=
(CH N) bonds. We envisaged that such a linkage may also be
used to temporarily immobilise and activate amino acid residues,
such that a-alkylation may be achieved. Product cleavage can be
accomplished by acid hydrolysis, to regenerate the functionalised
resin (Scheme 2). Recently, Park et al. have reported the use of
Wang-aldehyde polymer resin to support glycineimine tert-butyl
ester, for the synthesis of racemic and optically active a-amino
acids by monoalkylation of the supported glycine derivative.5,6
In light of these reports, we wish to disclose our work on the
synthesis of ( )-a,a-disubstituted amino acid residues using this
methodology. The regeneration and reuse of the polymer resin
will also be demonstrated.
Scheme 3 Preparation of benzaldehyde-functionalised resin 1 by MW
irradiation.
3 1 8 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 1 8 8 – 3 1 9 3
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
©

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Resins prepared by either methods are identical in their
physical and chemical properties, and have similar loadings
of ca. 1.10 mmol g−1, corresponding to 95% yield. They
are characterised by on-bead techniques—aldehyde absorption
bands were observed in the transmittance FTIR spectrum (2734,
1685 cm−1), further verified by the characteristic aldehydric
resonance at 9.8 ppm in the 1H MAS-NMR spectrum.
the reaction was unsuitable for the attachment of glycine—
the product resin showed an unusually high %N content,
accompanied by the observation of an unexpected IR (amide)
absorption peak at 1689 cm−1, corresponding to the formation
of polymerised products. This competitive reaction may be
eliminated by conducting the reaction at room temperature in
an orbital shaker. Using these procedures, immobilisation of
glycine and alanine proceeded with good to excellent yields,
while phenylalanine gave a lower yield of 77%.
Attempts to employ microwave irradiation for the immobil-
isation of the amino acids were unsuccessful. Treatment of a
mixture of 1 with phenylalanine and trimethyl orthoformate
gave either very low yield (CH2Cl2, 140 ◦C, 30 minutes, 40%), or
led to uncontrollable polymerisation (NMP, 200 ◦C, 30 minutes).
Immobilisation/activation of amino acid esters
Glycine, alanine and phenylalanine ethyl esters were immo-
bilised and activated in one synthetic step, by treating 1 with an
excess of the corresponding amino acid ester in the presence of
trimethyl orthoformate (Scheme 4). The progress of the reaction
was monitored on-bead using transmittance FTIR spectroscopy,
by observing the disappearance of the aldehyde (1685 cm−1)
and concurrent emergence of the imine and ester (1640 and
Synthesis of a,a-disubstituted amino acid esters
1
1740 cm−1) absorption bands. The H MAS-NMR spectrum
The alkylation of supported glycine 2a was examined initially,
using benzyl bromide as the electrophile in the presence of
different bases (Table 1, entries 1–5). Neutral phosphazene bases
such as BEMP and BTPP, previously employed in the UPS
methodology,2 were assessed along with weak bases (K2CO3,
NEt3, pyridine) and strong, non-nucleophilic bases (LDA and
LHMDS). After a suitable period of time (14 h), the resin was
filtered off and washed repeatedly with several organic solvents
and water. Finally, by treating the resin with 2 M aq. HCl (5 h),
the product was collected in the aqueous phase and isolated as
their HCl salts. These were subsequently analysed by 1H NMR
spectroscopy and mass spectrometry.
=
of the final product resin showed a distinctive imine CH N
resonance at 8.3 ppm. The amount of the immobilised amino
acid on the beads was calculated from %N analysis, verified by
the amount of amino acid recovered from the beads upon acid
hydrolysis. The reaction is dependent on the steric nature of
the substituent on the amino acid. Whilst the immobilisation of
alanine and phenylalanine were achieved at 50 ◦C in three days,
Unsurprisingly, weak bases were found to be totally ineffective
for the alkylation (entries 1–3)—only starting material was re-
covered. In contrast, reactions employing phosphazene reagents
gave a mixture of mono- and di-alkylated products. Interestingly,
different product distributions were observed—BTPP, the more
basic and slightly less sterically bulky, gave dialkylated amino
acid as the major product, whereas the opposite was observed
with BEMP (entries 4 and 5).
Scheme 4 Immobilisation of amino acid esters: R = H (2a), rt, 5 days,
91% (0.96 mmol g−1); R = Me (2b), 50 ◦C, 3 days, 89% (0.93 mmol g−1);
R = CH2Ph (2c), 50 ◦C, 3 days, 77% (0.75 mmol g−1).
Table 1 Alkylation of 2a, 2b and 2c employing different basesa
Entry
R1 (resin)
Baseb
R2X
Product
Yield (%)c
1
2
3
4
5
6
7
H (2a)
Pyridine (5)
NEt3 (5)
PhCH2Br (5)
PhCH2Br (5)
PhCH2Br (5)
PhCH2Br (5)
PhCH2Br (5)
3a
3a
3a
3a
3a
3b
3b
3b
3c
3b
3c
3d
3d
3e
3d
3e
3d
3b
3b
3b
3e
3e
3e
3d
3d
3d
—
—
—
K2CO3 (5)
BEMP (5)
BTPP (5)
75 (25)d
10 (90)d
—
LDAe(5)
CH2 CHCH2Br (5)
=
Me (2b)
LHMDSe (5)
BEMP (5)
CH2 CHCH2Br (5)
90
25
50
90
90
20
75
15
25
85
90
90
90
90
70
85
=
=
10
11
12
13
14
15
18
19
20
21
22
23
24
25
26
27
28
29
30
CH2 CHCH2Br (5)
PhCH2Br (5)
=
BTPP (5)
CH2 CHCH2Br (5)
PhCH2Br (5)
PhCH2Br (5)
PhCH2Br (5)
PhCH2 (2c)
LDAe (5)
LHMDSe (5)
BEMP (5)
=
CH2 CHCH2Br (5)
PhCH2Br (5)
=
BTPP (5)
CH2 CHCH2Br (5)
PhCH2Br (5)
=
Me (2b)
BTPP (2)
BTPP (5)
BTPP (10)
BTPP (2)
BTPP (5)
BTPP (10)
BTPP (2)
BTPP (5)
BTPP (10)
CH2 CHCH2Br (2)
=
CH2 CHCH2Br (5)
=
CH2 CHCH2Br (10)
=
PhCH2 (2c)
CH2 CHCH2Br (2)
=
CH2 CHCH2Br (5)
=
CH2 CHCH2Br (10)
90
70
90
85
PhCH2Br (2)
PhCH2Br (5)
PhCH2Br (10)
a Typical reaction conditions: The resin, base and electrophile were allowed to react in anhydrous NMP, at room temperature for 14 h. Equivalents
of reagents given in parentheses. LDA = lithium diisopropylamide, LHMDS = lithium hexamethyldisilazane, BEMP = 2-tert-butylimino-2-
diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine, BTPP = tert-butylimino-tri(pyrrolidino)phosphorane. b H NMR integration of product
mixture obtained after hydrolysis. c Value in parentheses corresponds to yield of dialkylated product 3c. d Reaction was performed in anhydrous THF
at −78 ◦C, then warmed to room temperature and stirred for 14 h.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 1 8 8 – 3 1 9 3
3 1 8 9

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Table 2 Synthesis of a,a-disubstituted amino acid esters (Scheme 2)a
Entry
R1 (resin)
R2X
Product
Additive (equiv.)
—
Yield (%)b
=
1
2
3
4
5
6
7
8
Me (2b)
CH2 CHCH2Br
3b
3b
3c
3c
90 (100)
80c
30
=
CH2 CHCH2Cl
—
TBAI (5)
—
85
PhCH2Br
PhCH2Cl
90 (100)
90c
—
TBAI (5)
45
80
9
MeI
n-C6H13I
—
3f
—
—
—(100)
95 (97d)
90c
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
naphthCH2Cl
CH2 CHCH2CH2Br
3g
—
—
3e
TBAI (5)
90 (98)
—(5)
—
=
—
—
—
tert-C4H9Br
=
PhCH2(2c)
CH2 CHCH2Br
85 (96)
85c
=
CH2 CHCH2Cl
3e
3d
3d
—
TBAI (5)
—
50
90
PhCH2Br
PhCH2Cl
90 (100)
90c
—
TBAI (5)
—
—
55
90
5 (98)
95 (75d)
95c
MeI
n-C6H13I
3c
3h
naphthCH2Cl
3i
TBAI (5)
—
—
—
TBAI (5)
—
—
95 (99)
—(2)
—
=
CH2 CHCH2CH2Br
—
—
3j
tert-C4H9Br
=
H (2a)
CH2 CHCH2Br
20 [80]e
15 [85]
10 [90]
35 [55]f
5 [95]
=
CH2 CHCH2Cl
3j
3a
3a
PhCH2Br
PhCH2Cl
TBAI (5)
a Typical reaction conditions: the resin was reacted with 5 equiv. of BTPP and 5 equiv. of electrophile in anhydrous NMP, at room temperature for
14 h. TBAI = tetra-n-butyl ammonium iodide, equivalents given in parentheses. b 1H integration of product mixture obtained after hydrolysis. Value
in parentheses (x) refers to that reported by using the UPS methodology.8 Value in square brackets [x] refers to yield of the dialkylated product.
c Yield obtained with recovered resin. d Value obtained with n-octyl iodide. e Diallylated product = 3k. f 10% glycine ester recovered.
Alkylation of 2b and 2c gives amino acid derivatives with
a quaternary a-carbon centre. For this part of the study, allyl
bromide was also used as an electrophile. LHMDS is better than
LDA for the reaction (entries 6, 7, 14 and 15), but the depro-
tonation has to be performed at low temperatures. In contrast,
the phosphazene bases may be employed at room temperature.
This is more practical as this enables the deployment of parallel
synthesiser (Argonaut QUEST 210) for the latter part of our
investigations. Again, the structure of the phosphazene base
was observed to have a dramatic effect. The use of BTPP gave
cleaner and higher yield of products (entries 10–13, 18–19).
For the alkylation of 2b containing the less sterically de-
manding alanine, the amount of reagents may be reduced to
2 equivalents (entries 22–24), but at least 5 equivalents of each
reagent were required for the alkylation of 2c, whilst the use
of 10 equivalents did not lead to any noticeable improvement
(entries 25–30).
The optimal reaction conditions established were subse-
quently adopted to prepare a number of a,a-dialkylated amino
acid derivatives from alanine and phenylalanine (Table 2). In
general, yields comparable to those obtained using the UPS
methodology were achieved (entries 1, 5, 9, 10, 12, 15, 19, 24
and 26).
The nature of the electrophile is important in the alkylation
step. Activated benzyl and allyl bromides afforded good yields
of products (entries 1, 5, 15 and 19), whereas the corresponding
chlorides gave much lower yield of the same products without
the assistance of iodide (entries 3 vs. 4, 7 vs. 8, 17 vs. 18, and 19
vs. 20). Methyl iodide gave very little or no product (entries
9 and 23), which is in contrast to the good yields obtained
with n-hexyl iodide (entries 10 and 24). We attribute this to the
volatility of the methyl iodide (bp 41–3 ◦C), which is clearly not
compatible with deployment of the parallel reaction synthesiser
(Argonaut Quest 210). As was observed earlier in the UPS
method, the reaction of 1-bromobut-3-ene gave little or no
products (entries 13 and 27). This could be due to the slow rate
of alkylation, which allowed base-induced elimination of the
electrophile (to butadiene) to become competitive under these
conditions.
The reaction is also clearly sensitive to steric and electronic
effects-tert-butyl bromide is unreactive (entries 14 and 28),
whereas 1-naphthylmethyl chloride–TBAI gave a good yield of
products (entries 12 and 26).
As was observed before, the alkylation of immobilised glycine
derivative 2a is susceptible to competitive formation of dialky-
lated products. Attempts to alkylate glycine led to the formation
of dialkylated products in all our attempts (entries 29–33). On
the other hand, employment of reduced amounts of base and/or
electrophile, mixtures of products and starting material were
obtained.
Regeneration and recycling
One of the major impetuses for the development of the current
strategy is the potential recovery of 1 for subsequent reuse.
Following acid-cleavage of the product, the resins were washed
1
repeatedly with organic solvents. Transmittance FTIR and H
NMR spectra of the recovered polymer beads showed the
restoration of the aldehyde functional group, with a loading
similar to the original value.
The recovered beads were subsequently used to immo-
bilise/activate amino acid esters for further alkylation reactions.
3 1 9 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 1 8 8 – 3 1 9 3

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In all cases, the product yields obtained with the recovered beads
were similar, if not identical, to the results obtained with freshly
prepared beads (Table 2, entries 1/2, 5/6, 10/11, 15/16, 19/20
and 24/25). The products obtained were of high purity—no
cross-contamination was detectable (by H and MS) when the
recovered beads were used in the support of a different amino
acid ester and/or reacted with a different electrophile.
using the Mass Spectrometry Service within the Department of
Chemistry (Imperial College). CI-MS were run in a Micromass
Platform II. This instrument is a single quadrupole, and is used
to provide the nominal mass EI and CI service for masses up
to 800 Da. Infra-red spectra and single bead FT-IR spectra
(transmittance) were recorded on a Perkin Elmer Spectrum One
spectrometer with a beam-condensing accessory (BCA), using a
diamond compressor to flatten the bead.
1
1H and 13C NMR spectra were recorded using JEOL 270,
Bruker AM 360 and AVANCE 400 spectrometers. High res-
olution magic angle spinning (HR-MAS) NMR spectra were
recorded using a Bruker AVANCE 400 spectrometer with special
HR-MAS probe and the resin was placed in a 4 mm rotor. Chem-
ical shifts were recorded in parts per million (d: ppm) referenced
to TMS (d:0) as an internal standard. Coupling constants (J)
are given in Hertz (Hz). The following abbreviations are used
to describe multiplicity: br—broad, s—singlet, d—doublet, t—
triplet, q—quartet, m—multiplet, dd—double doublet.
Synthesis of cyclic amino esters
Given the propensity of the glycine residue to form dialkylated
products under these reaction conditions, we investigated the
use of 2a for the synthesis of cyclic amino esters by the reaction
with dielectrophiles. Reactions of 2a with 1,4-dibromobutane,
ꢀ
1,5-dibromopentane and a,a -dibromo-o-xylene furnished the
required amino acid esters 4, 5 and 6 respectively (Scheme 5).
The formation of the 1-aminopentanecarboxylate ring 4 was the
most facile, the reaction was completed by a single treatment
with the base and dielectrophile (absence of %Br in the
resin). The corresponding reactions with 1,5-dibromopentane
and 1,2-dibromomethylbenzene were slower. In these cases, a
second treatment with the base were needed for the complete
displacement of Br.
Synthesis of Wang-aldehyde resin 1 by thermal heating
4-Hydroxybenzaldehyde (1.5 equiv.), K2CO3 (5 equiv.) and KI
(2 equiv.) were placed in an oven-dried three-neck round bottom
flask equipped with an overhead stirrer and a condenser and
purged with N2, containing Merrifield resin HL resin (1 equiv.,
1.3 mmol g−1). Anhydrous DMF (200 mL) was added via s◦yringe
and the mixture was stirred (60 rpm) and heated at 80 C for
3 days. After cooling to room temperature, the beads were
transferred to a sintered tube and washed successively with
acetone–CH3OH–H2O (1 : 1 : 1) (5 mL × 5), acetone–CH3OH
(1 : 1) (5 mL × 5), acetone (5 mL × 5), ethyl acetate (5 mL ×
5), CH2Cl2 (3 mL × 5) and HPLC-grade pentane (5 mL × 5). A
second treatment for 3 more days was carried out to bring the
reaction to completion. After cooling to room temperature, the
beads were transferred to a sintered tube and washed as before,
then dried under vacuum at 50 ◦C for 2 hours to give pale
yellow–white beads. After two treatments, %Cl = 0% (100% Cl
displacement). Theoretical loading = 1.1 mmol g−1. mmax/cm−1
Scheme 5 Synthesis of cyclic amino acid derivatives: (i) dielectrophile,
BTPP, rt; (ii) 2 M aq. HCl.
Following acid hydrolysis, the cyclic amino acid residues 4 and
5 were obtained in quantitative yields, whereas the yield of the
cyclohexyl derivative 6 was lower.
In summary, we demonstrate that a number of unnatural a,a-
disubstituted amino acid derivatives can be synthesised using
the Wang aldehyde resin 1 as a solid support, with good to
excellent yields. The current methodology reduces immobili-
sation/activation and deprotection/recovery into single-steps.
Additionally, resin 1 is reusable, hence the overall atom and
economic efficiency of the process can be improved significantly.
New ways of improving and extending the synthetic scope of
the methodology, either through the modification of polymer
support and/or reaction conditions are currently under investi-
gation.
=
=
2734 (O C-H), 1685 (C O); dH (400 MHz, CDCl3) 9.82 (1H, s,
CHO), 7.76 (2H, br s, H-Ar), 7.00 (br s, PS), 6.55 (br s, PS), 4.91
(2H, br s, OCH2), 1.60 (br s, PS), 1.35 (br s, PS).
Synthesis of Wang-aldehyde resin 1 using microwave irradiation
Merrifield resin HL (100 mg, 1.3 mmol g−1, 0.13 mmol)
was placed in a reaction vessel and allowed to swell in dry
NMP (0.5 mL) under N2. 4-Hydroxybenzaldehyde (24 mg,
0.195 mmol) and Cs2CO3 (85 mg, 0.26 mmol) were dissolved
in dry NMP (2.5 mL) and added via syringe to the reaction
vessel. The mixture was stirred and heated in the microwave at
150 ◦C for 5 minutes. After cooling to room temperature, the
beads were transferred to a sintered tube and washed as above.
%Cl = 0% (100% Cl displacement).
Experimental
Merrifield resin HL (1.3 mmol g−1, 1% cross-linked, 100–200
mesh) was purchased from Novabiochem. Anhydrous DMF,
trimethyl orthoformate and NMP were bought from Aldrich
(in Sure Seal bottles) and dichloromethane was freshly distilled
from calcium hydride under nitrogen. Commercially available
chemicals were purchased from Aldrich, Avocado, Fluka or
Lancaster, and were used as received, unless otherwise stated.
Microwave reactions were conducted using a CEM Discover
Synthesis Unit. Reactions were performed in glass vessels
(capacity 10 mL) sealed with a septum. The semi-automated
synthesiser used is a Quest 210 purchased from Argonaut
Technologies and contains twenty reactors with an internal
volume of 5 mL. It is combined with an automated solvent
wash unit, which is usually programmed as follows: acetone–
CH3OH–H2O (1 : 1 : 1) (5 mL × 5), acetone–CH3OH (1 : 1)
(5 mL × 5), acetone (5 mL × 5), ethyl acetate (5 mL × 5),
CH2Cl2 (3 mL × 5) and HPLC-grade pentane (5 mL × 5).
Elemental analysis was carried out by the Elemental Analysis
Services at the University of North London (CHN) or Univer-
sity College London (halides). Mass spectra (MS) were recorded
General procedure for the immobilisation of amino acid esters
Alanine or phenylalanine ethyl ester hydrochloride (10 equiv.)
were respectively dissolved in water (10 mL). 2 M aqueous
NaOH was added until pH between 9 and 10 was obtained.
The solution was extracted with DCM (3 × 10 mL). The
organic extracts were dried over magnesium sulfate, filtered
and concentrated in vacuo to give an oil. Wang-aldehyde resin
1 (1 equiv.) was placed in an oven-dried three-neck round
bottom flask purged with N2 and equipped with an overhead
stirrer and a condenser. Anhydrous dichloromethane (20 mL),
anhydrous trimethyl orthoformate (20 mL) and the alanine or
phenylalanine ethyl ester were added and the flask was stirred
(60 rpm) at 50 ◦C for 3 days. After cooling to room temperature,
the beads were transferred to a sintered tube and washed as
above. The beads were dried under vacuum at 50 ◦C for 2 hours
to give pale yellow beads.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 1 8 8 – 3 1 9 3
3 1 9 1

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Wang alanine ethyl ester resins, 2b. 89% of attachment to the
resin, based on %N analysis of 1.3%. Loading = 0.93 mmol g−1.
(CH3); m/z (EI) 194 ([M − Cl]+, 100%), 177 (28%), 135 (32%),
134 (22%).
mmax/cm−1 1740 (C O), 1640 (C N); dH (400 MHz, CDCl3) 8.27
=
=
Allylalanine ethyl ester hydrochloride, 3b. mmax/cm−1 1739
=
(1H, s, CH N), 7.76 (2H, br s, H-Ar), 7.08 (br s, PS + H-Ar),
=
=
(C O); dH (270 MHz, D2O) 5.67–5.52 (1H, m, CH CH2), 5.19–
5.12 (2H, m, CH CH2), 4.16 (2H, q, J 7.2, CH2CH3), 2.62 (1H,
6.60 (br s, PS), 5.00 (2H, br s, OCH2), 4.23 (2H, br s, CH2CH3),
4.14 (1H, br s, CH), 1.90 (br s, PS), 1.56 (br s, PS + CH3), 1.30
(br s, CH3).
=
dd, J 14.5 Hz and 7.1 Hz, CH2Allyl), 2.45 (1H, dd, J 14.5 Hz
and 8.0 Hz, CH2Allyl), 1.44 (3H, s, CH3), 1.15 (3H, t, J 7.2 Hz,
CH2CH3); dC (90.5 MHz, D2O) 172.8 (C O), 130.2 (CH), 123.6
(CH2), 65.0 (CH2), 60.8 (C), 42.1 (CH2), 22.3 (CH3), 14.3 (CH3);
m/z (CI) 158 ([M − Cl]+, 100%), 159 (14%), 118 (14%), 100
(20%), 90 (32%), 58 (66%).
=
Wang phenylalanine ethyl ester resins, 2c. 77% of attachment
to the resin, based on %N analysis of 1.05%. Loading =
0.75 mmol g−1. mmax/cm−1 1740 (C O), 1640 (C N); dH
=
=
=
(400 MHz, CDCl3) 8.02 (1H, s, CH N), 7.95 (br s, H-Ar), 7.77
Methylphenylalanine ethyl ester hydrochloride, 3c. mmax/cm−1
(br s, H-Ar), 7.18 (br s, PS + H-Ar), 6.71 (br s, PS), 5.11 (2H,
br s, OCH2), 4.32 (3H, br s, CH + CH2CH3), 3.49 (1H, br s,
CH2Ph), 3.28 (1H, br s, CH2Ph), 1.98 (br s, PS), 1.57 (br s, PS),
1.45 (br s, CH3).
=
1743 (C O); dH (270 MHz, D2O) 7.30–7.10 (5H, m, H-Ar), 4.16
(2H, q, J 7.2 Hz, CH2CH3), 3.26 (1H, d, J 14.3 Hz, CH2Ph),
3.02 (1H, d, J 14.3 Hz, CH2Ph), 1.53 (3H, s, CH3), 1.15 (3H, t,
=
J 7.2 Hz, CH2CH3); dC (90.5 MHz, D2O) 171.5 (C O), 130.5
(CH), 129.5 (CH), 128.7 (CH), 64.3 (CH2), 61.3 (C), 42.9 (CH2),
21.9 (CH3), 13.5 (CH3); m/z (CI) 208 ([M − Cl]+, 100%), 209
(44%), 134 (9%), 118 (10%).
General procedure for the immobilisation of glycine ethyl ester
Glycine ethyl ester hydrochloride (10 equiv.) was dissolved in
water. 2 M aqueous NaOH was added until pH between 9 and
10 was obtained. The solution was extracted with DCM (3 ×
10 mL). The organic extracts were dried over magnesium sulfate,
filtered and concentrated in vacuo to give an oil. Wang-aldehyde
resin 1 (1 equiv.) was placed in an oven-dried three-neck round
bottom flask purged with N2. Anhydrous dichloromethane
(20 mL), anhydrous trimethyl orthoformate (20 mL) and the
glycine ethyl ester were added. The flask was shaken at room
temperature for 5 days. The beads were transferred to a sintered
tube and washed as above. The beads were dried under vacuum
at 50 ◦C for 2 hours to give pale yellow beads.
Diphenylalanine ethyl ester hydrochloride, 3d. mmax/cm−1
=
1737 (C O); dH (270 MHz, D2O) 7.29–7.07 (10H, m, H-Ar), 4.13
(2H, q, J 7.2 Hz, CH2CH3), 3.42 (2H, d, J 14.5 Hz, CH2Ph), 3.05
(2H, d, J 14.5 Hz, CH2Ph), 1.11 (3H, t, J 7.2 Hz, CH2CH3); m/z
(CI) 284 ([M − Cl]+,100%), 285 (57%), 234 (16%), 194 (11%),
192 (18%).
Allylphenylalanine ethyl ester hydrochloride, 3e. mmax/cm−1
=
1737 (C O); dH (270 MHz, D2O) 7.24–7.04 (5H, m, H-Ar), 5.67–
=
=
5.51 (1H, m, CH CH2), 5.18–5.12 (2H, m, CH CH2), 4.13 (2H,
q, J 7.2 Hz, CH2CH3), 3.26 (1H, d, J 14.5 Hz, CH2Ph), 2.98
(1H, d, J 14.5 Hz, CH2Ph), 2.75 (1H, dd, J 14.5 Hz and 6.7 Hz,
CH2Allyl), 2.49 (1H, dd, J 14.5 Hz and 8.1 Hz, CH2Allyl), 1.10
Wang glycine ethyl ester resins, 2a. 91% of attachment to the
resin, based on %N analysis of 1.35%. Loading = 0.96 mmol g−1.
=
(3H, t, J 7.2 Hz, CH2CH3); dC (90.5 MHz, D2O) 168.7 (C O),
mmax/cm−1 1740 (C O), 1645 (C N); dH (400 MHz, CDCl3) 8.18
=
=
130.5 (CH), 129.6 (CH), 129.2 (CH), 128.8 (CH), 123.3 (CH2),
64.4 (CH2), 41.5 (CH2), 40.3 (CH2), 13.5 (CH3); m/z (CI) 234
([M − Cl]+, 100%), 235 (29%), 194 (8%).
=
(1H, s, CH N), 7.72 (2H, br s, H-Ar), 7.04 (br s, PS + H-Ar),
6.56 (br s, PS), 4.95 (2H, br s, OCH2), 4.34 (2H, br s, CH2), 4.22
(2H, br s, CH2), 1.85 (br s, PS), 1.43 (br s, PS), 1.28 (br s, CH3).
n-Hexylalanine ethyl ester hydrochloride, 3f. mmax/cm−1 1738
=
(C O); dH (270 MHz, D2O) 4.17 (2H, q, J 7.2 Hz, CH2CH3),
General procedure for the synthesis of a,a-dialkylated amino
ethyl ester hydrochlorides (using the semi-automated synthesiser)
1.90–1.60 (2H, m, CH2), 1.44 (3H, s, CH3), 1.20–1.00 (11H, m,
4 × CH2 + CH2CH3), 0.71 (3H, t, J 6.8 Hz, CH3); m/z (CI) 202
([M − Cl]+, 100%), 203 (18%), 128 (18%), 118 (14%), 52 (55%).
The appropriate resin-bound amino ester 2a–c (100 mg, 1 equiv.)
was swollen in dry NMP (2–3 mL) in a 5 mL reaction vessel
fitted into the Quest 210 semi-automated synthesiser under N2.
Corresponding RX (5 equiv.) and Bu4NI (5 equiv.) were added,
and the reaction mixture was subjected to magnetic agitation
for 1 hour, before BTPP (5 equiv.) was added. Agitation was
continued at room temperature overnight (14 hours). The resin
was thencollectedby filtration and washed with the programmed
washing rinsing protocol. The resin was then swollen in a mixture
of THF : H2O (2 : 1) (2–3 mL) and aqueous 2 M HCl (5 equiv.)
was added. The mixture was stirred for 5 hours. The resin was
then filtered and rinsed with THF : H2O (2 : 1) (2–3 mL × 3).
The combined filtrate was collected and evaporated to remove
THF from the mixture. The pH of the aqueous solution was
neutralised by the addition of aqueous 2 M NaOH (until pH 5–
6). The solvent was eventually evaporated to give the crude
product as white or pale yellow solids. Yield was calculated
Naphthylalanine ethyl ester hydrochloride, 3g. mmax/cm−1
=
1743 (C O); dH (270 MHz, D2O) 7.91–7.81 (3H, m, H-Ar), 7.52–
7.31 (4H, m, H-Ar), 3.80 (2H, q, J 7.2 Hz, CH2CH3), 3.66 (1H,
d, J 14.7 Hz, CH2Naphth), 3.57 (1H, d, J 14.7 Hz, CH2Naphth),
1.55 (3H, s, CH3), 0.85 (3H, t, J 7.2 Hz, CH2CH3); m/z (EI) 258
([M − Cl]+, 66%), 158 (100%), 141 (19%), 118 (19%), 116 (78%),
85 (20%), 84 (87%).
n-Hexylphenylalanine ethyl ester hydrochloride, 3h.
mmax/cm−1 1744 (C O); dH (270 MHz, D2O) 7.24–7.03
=
(5H, m, H-Ar), 4.13 (2H, q, J 7.2 Hz, CH2CH3), 3.23 (1H, d, J
14.4 Hz, CH2Ph), 2.97 (1H, d, J 14.4 Hz, CH2Ph), 2.03–1.66
(2H, m, CH2), 1.19 (11H, m, CH2CH3 + 4 × CH2), 0.67 (3H, t,
=
J 6.7 Hz, CH3); dC (90.5 MHz, D2O) 171.7 (C O), 130.5 (CH),
129.5 (CH), 128.7 (CH), 68.2 (CH2), 64.2 (CH2), 54.5 (C), 41.9
(CH2), 30.8 (CH2), 28.5 (CH2), 25.4 (CH2), 22.9 (CH2), 22.1
(CH3), 13.6 (CH3); m/z (CI) 278 ([M − Cl]+, 100%), 279 (20%),
194 (9%), 76 (31%), 59 (46%).
1
as % conversion by H NMR, and product formation further
verified by 13C NMR and MS analysis. The resin was recovered
by filtration and washed using the automated solvent wash unit
and dried in a vacuum oven for 3 hours at 50 ◦C.
Naphthylphenylalanine ethyl ester hydrochloride, 3i.
mmax/cm−1 1746 (C O); dH (360 MHz, pyr-d5) 8.64 (1H,
=
Phenylalanine ethyl ester hydrochloride, 3a. mmax/cm−1 1739
d, J 8.6 Hz, H-Ar), 7.82–7.10 (11H, m, H-Ar), 4.15–3.95
(4H, m, CH2CH3 + CH2Naphth), 3.71–3.62 (2H, m, CH2Ph),
1.05 (3H, t, J 7.2, Hz CH2CH3); dC (90.5 MHz, pyr-d5) 177.0
=
(C O); dH (270 MHz, D2O) 7.25–7.10 (5H, m, H-Ar), 4.21 (1H,
dd, J 7.2 Hz and 6.1 Hz, CH), 4.10 (2H, q, J 7.2 Hz, CH2CH3),
3.16 (1H, dd, J 14.5 Hz and 6.1 Hz, CH2Ph), 3.06 (1H, dd, J
14.5 Hz and 7.3 Hz, CH2Ph), 1.07 (3H, t, J 7.2 Hz, CH2CH3);
=
(C O), 138.2 (C), 135.3 (C), 134.7 (C), 134.5 (C), 131.7 (CH),
129.9 (CH), 129.8 (CH), 129.5 (CH), 128.9 (CH), 128.1 (CH),
126.9 (CH), 126.8 (CH), 126.6 (CH), 126.4 (CH), 64.9 (C),
62.0 (CH2), 47.5 (CH2), 43.2 (CH2), 14.9 (CH3); m/z (EI) 334
=
dC (90.5 MHz, D2O) 169.9 (C O), 134.1 (C), 129.8 (CH), 129.6
(CH), 128.5 (CH), 63.9 (CH2), 54.5 (CH), 36.0 (CH2), 13.5
3 1 9 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 1 8 8 – 3 1 9 3

View Article Online
([M − Cl]+, 4%), 333 (4%), 262 (21%), 261 (63%), 260 (73%),
244 (8%), 243 (38%), 242 (46%), 206 (27%), 205 (33%), 194
(24%), 193 (81%), 192 (100%), 142 (11%), 141 (31%), 119 (19%),
118 (31%), 91 (39%).
1-Amino-cyclopentanecarboxylic acid ethyl ester hydrochlo-
ride, 4. mmax/cm−1 1745 (C O); dH (400 MHz, D2O) 4.10 (2H,
=
q, J 7.0 Hz, CH2CH3), 2.14 (2H, m, CH2), 1.77–1.67 (6H, m,
3 × CH2), 1.09 (3H, t, J 7.0 Hz, CH2CH3); dC (100 MHz, D2O)
=
169.0 (C O), 68.2 (C), 66.5 (CH2), 39.3 (CH2), 28.0 (CH2), 16.0
Diallylglycine ethyl ester hydrochloride, 3k. mmax/cm−1 1741
(CH3); m/z (CI) 158 ([M − Cl]+, 100%), 176 (30%), 90 (17%), 52
=
=
(C O); dH (270 MHz, D2O) 5.68–5.53 (1H, m, CH CH2),
5.21–5.15 (2H, m, CH CH2), 4.19 (2H, q, J 7.2 Hz, CH2CH3),
(34%), 44 (21%).
=
2.67 (1H, dd, J 14.5 Hz and 7.1 Hz, CH2Allyl), 2.50 (1H, dd, J
14.5 Hz and 8.1 Hz, CH2Allyl), 1.16 (3H, t, J 7.2 Hz, CH2CH3);
m/z (CI) 184 ([M − Cl]+, 100%), 185 (13%), 144 (41%), 90 (17%),
52 (31%).
2-Amino-indan-2-carboxylic acid ethyl ester hydrochloride, 5.
mmax/cm−1 1751 (C O); dH (400 MHz, D2O) 7.27 (4H, m, H-Ar),
=
4.23 (2H, q, J 7.1 Hz, CH2CH3), 3.67 (2H, d, J 17.4 Hz, CH2Ar),
3.26 (2H, d, J 17.4 Hz, CH2Ar), 1.18 (3H, t, J 7.1 Hz, CH2CH3);
=
dC (100 MHz, D2O) 174.8 (C O), 138.2 (C), 128.3 (CH), 125.2
General procedure for the synthesis of a,a-dialkylated amino
ethyl ester hydrochlorides using lithiated bases
(CH), 65.2 (C), 64.4 (CH2), 42.6 (CH2), 13.5 (CH3); m/z (CI)
206 ([M − Cl]+, 100%), 207 (15%), 132 (9%), 100 (4%), 52 (7%).
The appropriate resin-bound amino ester (100 mg, 1 equiv.) was
washed with anhydrous THF and placed in a two-neck flask
under N2. Anhydrous THF (2 mL)◦was added to the resin and
the flask was cooled down to −40 C. LHMDS (1 M in THF,
5 equiv.) or LDA (2 M in THF–pentane, 5 equiv.) was added
dropwise. After 45 minutes, corresponding RX (5 equiv.) and
anhydrous THF (1 mL) were◦added. The◦reaction mixture was
1-Amino-cyclohexanecarboxylic acid ethyl ester hydrochloride,
6. mmax/cm−1 1747 (C O); dH (400 MHz, D2O) 4.14 (2H, q, J
=
7.1 Hz, CH2CH3), 1.90–1.20 (10H, m, 5 × CH2), 1.14 (3H, t, J
=
7.1 Hz, CH2CH3); dC (100 MHz, D2O) 173.3 (C O), 62.8 (C),
66.4 (CH2), 32.4 (CH2), 26.6 (CH2), 23.1 (CH2), 16.2 (CH3); m/z
(CI) 172 ([M − Cl]+, 100%), 208 (24%), 190 (14%), 173 (10%),
98 (8%), 52 (9%).
◦
stirred at −40 C (1 h), −20 C (1 h), 0 C (1 h) and then left
at room temperature and stirred overnight (14 h). The resin was
then filtered off and washed, following same procedure described
above.
Acknowledgements
We thank King’s College London (KCL) for a studentship (to
MG), Mr Jon Cobb for assistance with MAS NMR experiments
and Dr Yolanda de Miguel (LABEIN Technological Centre,
Bizkaia, Spain) for the contribution of the QUEST 210 parallel
solid-phase synthesiser, procured through an instrument grant
from The Royal Society.
General procedure for the synthesis of cyclic amino ethyl ester
hydrochlorides (using the semi-automated synthesiser)
Immobilised glycine ethyl ester (100 mg, 1 equiv.) was swollen in
dry NMP (2–3 mL) in a reaction flask under N2. Corresponding
RX (5 equiv.) was added. The reaction mixture was subjected
to magnetic agitation for 1 hour. BTPP (5 equiv.) was then
added and the agitation was continued at room temperature
overnight (14 h). The resin was then collected by filtration and
washed in the automated washing unit using the usual program.
A second treatment, if required, was carried out by swelling the
beads in anhydrous NMP (2–3 mL) and adding BTPP (5 equiv.).
The reaction mixture was stirred for further 5 hours. The resin
was filtered off and washed. The resin was finally swollen in
a mixture of THF : H2O (2 : 1) (2–3 mL), to which aqueous
2 M HCl (5 equiv.) was added and the mixture was stirred at
room temperature for 5 hours. The resin was then filtered off
and rinsed with THF : H2O (2 : 1) (2–3 mL × 3). The combined
filtrate was then evaporated to remove THF from the mixture.
To the aqueous solution was added aq. 2 M NaOH to adjust
the pH to 5–6 (pH meter). The solvent was evaporated to give
the crude product as a white or pale yellow residue, which was
analysed by IR, 1H NMR spectroscopy and MS.
References
1 M. J. O’Donnell, Acc. Chem. Res., 2004, 37, 506 and references therein.
2 M. J. O’Donnell, Aldrichimica Acta, 2001, 34, 3 and references therein.
3 B. Sauvagnat, K. Kulig, F. Lamaty, R. Lazaro and J. Martinez,
J. Comb. Chem., 2000, 2, 134.
4 M. Guino´, E. Brule and Y. R. de Miguel, J. Comb. Chem., 2003, 5,
161.
5 H.-G. Park, M.-J. Kim, M.-K. Park, H.-J. Jung, J. Lee, Y.-J. Lee, B.-S.
Jeong, J.-H. Lee, M. S. Yoo, J.-M. Ku and S.-S. Jew, Tetrahedron Lett.,
2005, 46, 93.
6 H.-G. Park, M.-J. Kim, M.-K. Park, H.-J. Jung, J. Lee, Y.-J. Lee, S.
Choi, Y.-J. Lee, B.-S. Jeong, J.-H. Lee, M.-S. Yoo, J.-M. Ku and S.-S.
Jew, J. Org. Chem., 2005, 70, 1904.
7 Commercial samples of Wang-aldehyde resins (Novabiochem) were
found to contain unspecified amounts of impurities and up to 0.8% of
Cl (elemental analysis), which gave rise to unidentifiable side-products
in the alkylation reactions.
8 D. L. Griffith, M. J. O’Donnell, R. S. Pottorf, W. L. Scott and J. A.
Porco, Tetrahedron Lett., 1997, 38, 8821.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 1 8 8 – 3 1 9 3
3 1 9 3