An oxidatively-activated safety catch linker for solid phase synthesis

Article abstract of DOI:10.1039/b802204f

A N-benzyl-4-amino-2,2-dimethylbutanoic acid-based system has been developed as a new oxidatively activated safety catch linker for reaction monitoring and optimisation on solid support. The CAN promoted oxidative debenzylation of the tertiary N-benzylamine moiety, followed by concomitant cyclisation and release of alcohols and amines has been demonstrated both in solution phase model studies and on the solid phase. The linker system has been applied to the solid phase synthesis of a collection of phenol derivatives, and to the demonstration of the attachment and release of a chiral auxiliary from a solid support. The Royal Society of Chemistry 2008.

Full text of DOI:10.1039/b802204f

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www.rsc.org/obc | Organic & Biomolecular Chemistry
An oxidatively-activated safety catch linker for solid phase synthesis†
Stephen G. Davies,* Duncan A. B. Mortimer, Andrew W. Mulvaney, Angela J. Russell, Hjalmar Skarphedinsson,
Andrew D. Smith and Richard J. Vickers
Received 7th February 2008, Accepted 21st February 2008
First published as an Advance Article on the web 14th March 2008
DOI: 10.1039/b802204f
A N-benzyl-4-amino-2,2-dimethylbutanoic acid-based system has been developed as a new oxidatively
activated safety catch linker for reaction monitoring and optimisation on solid support. The CAN
promoted oxidative debenzylation of the tertiary N-benzylamine moiety, followed by concomitant
cyclisation and release of alcohols and amines has been demonstrated both in solution phase model
studies and on the solid phase. The linker system has been applied to the solid phase synthesis of a
collection of phenol derivatives, and to the demonstration of the attachment and release of a chiral
auxiliary from a solid support.
Introduction
Solid phase organic synthesis is an important strategy that has
been widely applied to the parallel synthesis of large arrays of
structurally similar molecules for high throughput screening in
pharmacological assays.1 The advancement of simple, selective
and high yielding cleavage strategies is of paramount importance
for the success of this approach.2,3 Within this field, the safety
catch principle, first introduced by Kenner et al.,4 describes a linker
that is stable to a derivatisation sequence before being selectively
activated and subsequently releasing the desired product into
solution. Numerous safety catch linkers have been developed and
used to release a variety of functional groups into solution.3,5–7
This strategy has been applied to a range of systems,7 and even
to the development of in vivo drug delivery systems that require
Fig. 1 Proposed oxidatively activated safety catch linker system.
enzyme activation.8 Although a wide range of simple linkers
and cleavage strategies for alcohols9 and amines10,11 have been
nol derivatives, and preliminary investigations into its evaluation
developed, relatively few safety catch linkers have been described
for the anchoring and release of alcohols.
as an analytical tool in solid phase asymmetric synthesis.
We have previously shown that N-benzyl tertiary amines are
susceptible to chemoselective N-debenzylation with CAN,11 and
considered this reaction ideal for the development of a novel
oxidatively cleavable linker system for applications in solid phase
synthesis. At the onset of these investigations, a number of
features were incorporated into the linker design to enhance
its stability under a range of reaction conditions yet facilitate
cleavage and release from the resin. gem-Dimethyl substitution a-
to the carbonyl group was incorporated to simultaneously protect
against nucleophilic attack, render the carbonyl non-enolisable
and promote 5-exo-trig cyclisation after oxidative cleavage using
the Thorpe–Ingold effect,12 giving the solid phase bound c-lactam
and releasing the product into solution (Fig. 1).
Results and discussion
Model solution phase studies
Initial studies focused upon the demonstration of this oxidatively
cleavable linker strategy on a model solution phase system.
Dihydrofuranone 1 was identified as a key intermediate in this
sequence, and was prepared in two steps following literature
protocols from commercially available iso-butyronitrile, reliably
giving 1 in multi-gram quantitities. Installation of the oxidatively
activated linker section was achieved by reductive amination of
dihydrofuranone 1 with N-benzyl-N-phenylethylamine, affording
acid 2 in good yield. Coupling of acid 2 with benzyl alcohol and
2-phenyl-propan-1-ol 7 using EDCI and HOBt gave the esters
3 and 4 in 72% and 71% yield respectively. The oxidative N-
debenzylation and cyclisation of 3 with CAN, followed by heating
at reflux gave quantitative conversion to lactam 6 after removal
of benzyl alcohol in vacuo. N-Debenzylation of ester 4 with CAN
followed by aqueous NaOH afforded amino ester 5. Subsequent
reflux in toluene to promote cyclisation and alcohol release gave
a 50 : 50 mixture of 6 and 7, with chromatographic purification
giving lactam 6 in 74% yield and alcohol 7 in 53% yield (Scheme 1).
In this manuscript we demonstrate model studies in solution
towards this goal, describe the realisation of this strategy on solid
phase, its application to the parallel synthesis of a number of phe-
Department of Chemistry, Chemistry Research Laboratory, University of
Oxford, Mansfield Road, Oxford, OX1 3TA, UK. E-mail: steve.davies@
chem.ox.ac.uk
† Electronic supplementary information (ESI) available: Further experi-
mental details. See DOI: 10.1039/b802204f
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As a final solution phase model, the introduction of a reaction
step capable of introducing diversity in a subsequent solid phase
library was investigated. To this end, esterification of acid 2 to
the corresponding 4-iodophenyl ester was investigated, as it was
envisaged that derivatisation could be achieved by Suzuki cou-
pling. Activation and esterification of acid 2 was achieved through
treatment with EDCI and HOBt with excess 4-iodophenol, giving
the desired 4-iodophenyl ester 22 in 82% yield. Suzuki coupling of
ester 22 with phenylboronic acid using 20 mol% of Pd2(dba)3 gave
the biaryl ester 23 (vmax 1748 cm−1) with complete conversion;
the identity of biaryl ester 23 was unambiguously confirmed
by treatment of acid 2 with excess 4-phenylphenol 24 under
standard coupling conditions, giving 23 in 71% isolated yield after
chromatography. To complete the model solution phase studies,
N-debenzylation of ester 23 was accomplished by treatment with
CAN (5 eq.) in THF : H2O (8 : 1) and subsequent treatment with
neutral alumina promoted spontaneous cyclisation in this case
affording a 50 : 50 mixture of the lactam 6 and 4-phenylphenol 24.
Chromatographic purification facilitated their separation, giving
lactam 6 (vmax 1682 cm−1) in 96% yield and 4-phenylphenol 24 in
92% yield (Scheme 3).
Scheme 1 Reagents and conditions: (i) LDA (1 eq.), THF, bromoacetalde-
hyde diethyl acetal (1 eq.), D, 16 h; (ii) HCl : AcOH : H2O (20 : 10 : 5),
D, 16 h; (iii) N-benzyl-N-phenylethylamine, MeOH, TMOF, 2 h rt then
NaBH4, 0 ◦C, 1 h, then rt, 16 h; (iv) Benzyl alcohol (3 eq.), EDCI, HOBt,
DIPEA, CH2Cl2, rt, 16 h; (v) 1-phenyl-propan-2-ol 7 (3 eq.), EDCI, HOBt,
DIPEA, CH2Cl2, rt, 16 h; (vi) CAN (5 eq.), THF : H2O (8 : 1), rt, 16 h,
then NaOH (2 M, aq.); (vii) toluene, D, 16 h.
Solid phase synthesis: model studies
Having successfully demonstrated the concept of an oxidatively
activated cleavage system in a model solution phase system,
efforts were directed towards its adaptation to the solid phase.
An approach designed to allow the loading of the polymer to be
determined unambiguously was followed. Reductive amination of
dihydrofuranone 1 with N-benzyl-N-butenylamine gave acid 25 in
81% yield, with subsequent esterification giving the corresponding
4-phenylphenol ester 26 (vmax 1745 cm−1) in 92% yield. Grafting
of ester 26 to the polymer with bromopolystyrene resin using a
Suzuki–Miyaura cross coupling was next investigated. Treatment
of ester 26 with 9-BBN at 0 ◦C, followed by the addition
of prewashed bromopolystyrene resin (Argonaut Technologies,14
polymer loading: 3.22 mmol g−1) with 9% Pd(OAc)2 and DPPF
gave, after subsequent washing, the solid supported ester 27 (vmax
1748 cm−1). To determine the polymer loading, ester 27 was
saponified by treatment with LiOH in THF : H2O (8 : 1) under
reflux, giving both 4-phenylphenol 24 and polymer supported acid
28 (vmax 1713 cm−1) in quantitative yield, consistent with a polymer
loading of 1.73 mmol g−1 (Scheme 4). The designed enhanced
stability of the ester towards basic hydrolysis, conferred by the
gem-dimethyl substitution a- to the carbonyl, is illustrated by the
forcing conditions necessary for complete saponification.
The ability of 27 to undergo debenzylation and cyclo-release
from the solid support was next investigated. Treatment of 27
with 5 equivalents of CAN in THF : H2O (8 : 1), followed
by washing, gave a yellow resin that was dried in vacuo to a
constant mass. IR investigations of this polymer revealed the
presence of an ester bond (vmax 1746 cm−1), allowing its assignment
as 29. Investigations in the solution phase model system had
demonstrated that intermediates such as 29 undergo cyclisation
under mild conditions and a base promoted cyclisation to lactam
30 at rt was therefore investigated. Treatment of 29 with CH2Cl2 :
NEt3 (5 : 1) gave 4-phenylphenol 24 in 78% yield after work-up,
with IR investigations of the remaining resin indicating complete
conversion of 29 (vmax 1746 cm−1) to the polymer bound lactam 30
To probe the efficiency of this linker system in solution phase
the coupling and subsequent cyclo-release of a range of amines
was investigated. Activation of acid 2 with EDCI and HOBt
and addition of benzylamine 18, (R)-a-methylbenzylamine (R)-19,
N-benzyl-N-methylamine 20 or N-benzylpiperazine 21 gave the
corresponding amides 8–11 in moderate to good yields. However,
treatment of acid 2 with N-benzyl-N-ethylamine under the same
conditions only returned starting acid 2. Treatment of acid 2 with
4-aminopiperidine was observed to give complete conversion to
the secondary amide 13, with none of the corresponding tertiary
amide observed, demonstrating the capability of the linker to
discriminate between primary and secondary amines.
Treatment of 8 with CAN resulted in chemoselective N-
debenzylation, giving amine 14 in 80% isolated yield, with
subsequent reflux in toluene and treatment of the crude product
mixture with HCl, followed by aqueous work-up, allowing the
isolation of benzylamine hydrochloride 18·HCl in 99% yield and
lactam 6 in 97% yield. The application of this protocol to amides
9 and 10 also proved efficient, giving the corresponding amine
hydrochlorides 19·HCl and 20·HCl in excellent yields, with no N-
debenzylation of the intermediate N-methyl-N-benzylamide 16,
consistent with previous observations.11 Treatment of 11 with
CAN allowed the selective mono N-debenzylation of the acyclic
tertiary amino group in the presence of the N-benzylpiperazine
group to give 17, again consistent with previous observations,11
with subsequent reflux in toluene and treatment with HCl
affording N-benzylpiperazine hydrochloride 21·HCl in 69% yield.
This process also proceeds without racemisation of (R)-19, as its
specific rotation {[a]2D2 +2.6 (c 1.0, H2O)}, was identical to an
authentic sample, and consistent with the literature value {lit.13
[a]2D2 +2.3 (c 2.9, H2O)} (Scheme 2).
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Scheme 2 Reagents and conditions: (i) amine (3–4 eq.), EDCI, HOBt, DIPEA, CH2Cl2 or DMF, rt, 16 h; (ii) CAN (5 eq.), THF : H2O (8 : 1), rt 16 h,
then NaOH (2 M, aq.); (iii) D, toluene, 48 h then HCl.
Scheme 3 Reagents and conditions: (i) 4-iodophenol (5 eq.), EDCI (1.5 eq.), HOBt (2 eq.), DIPEA (3 eq.), CH2Cl2, rt, 16 h; (ii) phenylboronic acid
(2 eq.), Pd2(dba)3 (0.2 eq.), K2CO3 (2.5 eq.), DMF, rt, 24 h; (iii) 4-phenylphenol (4 eq.), EDCI (2.5 eq.), HOBt (2 eq.), DIPEA (4 eq.), CH2Cl2, rt, 16 h;
(iv) CAN (5 eq.), THF : H2O (8 : 1), rt, 16 h then Al2O3.
(vmax 1682 cm−1) (Scheme 5). Although base promoted cyclisation
and release from the polymer support incurs another reaction step
in this strategy, this could be beneficial for product purity as it
allows its controlled release into solution. Furthermore, this allows
the inorganic CAN residues to be washed from the polymer matrix
before product release, preventing any undesired side reactions
with the released product.
Having demonstrated the use of the linker system for the release
of 4-phenylphenol 24 from the solid phase, the utility of this
protocol for the attachment and release of benzylamine 18 was
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cyclisation, resulting in complete conversion to lactam 30 (vmax
1682 cm−1). The released amine was subsequently converted to its
hydrochloride salt 18·HCl and isolated in 65% yield (Scheme 6).
Scheme
4 Reagents and conditions: (i) N-benzyl-N-butenylamine,
MeOH, TMOF, NaBH4; (ii) HOC6H4Ph (3 eq.), EDCI (2 eq.), HOBT
(2 eq.), CH2Cl2, rt; (iii) phenylboronic acid (5 eq.), Pd(OAc)2 (9 mol%),
DPPF (0.11 eq.), K2CO3 (5 eq.), DMF, 70 ◦C, 48 h; (iv) LiOH (10 eq.),
THF : H2O (8 : 1), D.
Scheme 6 Reagents and conditions: (i) benzylamine 18 (6 eq.), DIC (3 eq.),
HOBt (3 eq.), DIPEA (6 eq.), CH2Cl2, rt, 16 h; (ii) CAN (5 eq.), THF :
H2O (8 : 1), rt, 16 h, then NaOH (2 M, aq.); (iii) D, toluene, 48 h.
Cross-coupling reactions and cyclo-release on solid phase: library
synthesis
Further studies focused upon the performance of cross coupling
reactions on the solid phase to prepare 4-phenylphenol 24.
Treatment of polymer bound carboxylic acid 28 with DIC–HOBt
and 4-iodophenol (10 eq.) gave quantitative conversion by mass
to the desired 4-iodophenyl ester resin 33 (vmax 1749 cm−1). Suzuki
coupling of 4-iodophenyl ester resin 33 with phenylboronic acid
at 70 ◦C and subsequent treatment of the product resin 27
with 5 equivalents of CAN afforded 4-phenylphenol 24 in 55%
isolated yield. Significantly, under these optimised conditions, no
4-iodophenol was detected upon cyclorelease indicating complete
conversion, with IR analysis of the residual resin indicating the
presence of the polymer-supported lactam 30 (vmax 1682 cm−1)
(Scheme 7).
Scheme 5 Reagents and conditions: (i) CAN (5 eq.), THF : H2O (8 : 1),
Following these successful solid phase transformations, at-
tention turned to the preparation of a small pilot library of
phenols including biphenols 42 and 43 and terphenol 39 that
have been evaluated as ligands for the b-estrogen receptor in an
analogous library synthesis of 4-hydroxy biphenyls.15 A diverse
range of arylboronic acids incorporating electron donating and
withdrawing substituents were chosen for this Suzuki coupling
strategy, whose products were anticipated to be tolerant towards
oxidative debenzylation with CAN and subsequent cyclo-release
rt, 16 h; (ii) CH2Cl2 : NEt3 (5 : 1), rt, 30 min.
investigated. Solid supported carboxylic acid 28 was activated
with DIC–HOBt and treated with excess benzylamine 18 (6 eq.)
to afford the polymer supported N-benzylamide 31 that exhibited
similar IR properties (vmax 1634 cm−1, 1529 cm−1) to the solution
phase analog 8 (vmax 1643 cm−1, 1529 cm−1). Treatment of 31
with CAN followed by aqueous NaOH gave a polymer 32 (vmax
1635 cm−1, 1529 cm−1), which was heated in toluene to promote
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Scheme 7 Reagents and conditions: (i) 4-iodophenol (10 eq.), DIC (3 eq.),
HOBt (4 eq.), DIPEA (8 eq.), CH2Cl2, rt, 16 h; (ii) phenylboronic acid
(5 eq.), Pd2(dba)3 (0.2 eq.), K2CO3 (5 eq.), DMF, 70 ◦C, 48 h; (iii) CAN
(5 eq.), THF : H2O (8 : 1), rt, 16 h, then CH2Cl2 : NEt3 (5 : 1), rt, 30 min.
from the safety catch linker. Under standard conditions, treatment
of resin 33 with a range of arylboronic acids under Pd catalysis
and treatment of the resulting resins 34–38 with CAN gave the
desired phenols 39–43 in 43–92% isolated yield and in generally
high HPLC purity (Scheme 8).
Scheme 8 Reagents and conditions: (i) aryl boronic acid (HO)2BR (5 eq.),
Pd2(dba)3 (0.2 eq.), K2CO3 (5 eq.), DMF, 70 ◦C, 48 h; (ii) CAN (5 eq.),
THF : H2O (8 : 1), rt, 16 h, then CH2Cl2 : NEt3 (5 : 1), rt, 30 min.
could be used to allow cleavage of a chiral auxiliary attached to
the solid phase at any point in the reaction sequence, allowing
simple and straightforward reaction monitoring, thus facilitating
optimisation.21 This concept has contemporaneously been applied
by us,22 and recently by Bull et al.23 to the development of a
labile linker for an oxazolidinone derived solid-supported chiral
auxiliary. The safety catch linker described herein was also
proposed to be a suitable system for application in the optimisation
of such solid phase asymmetric transformations.
Tyrosine derived SuperQuat 5,5-dimethyloxazolidinone 45 was
therefore prepared following our established literature procedure
in 73% yield.24 O-Silylation of 45 gave 46 in 90% yield after
recrystallisation, with subsequent deprotonation with n-BuLi and
acylation with propanoyl chloride affording O-TBDMS protected
47 in 97% yield (88% over two steps). Silyl deprotection of 47 with
TBAF in THF subsequently afforded the N-propanoyl SuperQuat
48 in 93% yield. SuperQuat 48 was next readily attached to the solid
supported carboxylic acid 28 using standard protocols, with IR
analysis of the resin 49 revealing three bands in the carbonyl region
{mmax 1778 cm−1 (endocyclic), 1749 cm−1 (ester) and 1701 cm−1
(exocyclic)}. The debenzylation and cyclorelease protocol was
Towards an oxidatively cleavable solid supported chiral auxiliary
system
Having demonstrated the applicability of this safety catch protocol
to the solid phase synthesis of a small number of phenol deriva-
tives, subsequent studies were directed towards the incorporation
of a chiral auxiliary into the safety catch linker. Oxazolidin-2-one
based chiral auxiliaries have found widespread use in solution
phase asymmetric synthesis due to their efficiency in a broad
range of stereoselective manipulations16 and their accessibility
from readily available a-amino acids.17 Much effort has been
made to immobilise oxazolidine-2-one based chiral auxiliaries on
polymer supports,18 with Burgess having shown that a tyrosine
derived oxazolidinone requires a Wang linker as the optimal
support.19 This tyrosine derived oxazolidinone has since been
applied to a range of stereoselective transformations on solid phase
including aldol reactions, conjugate addition, Diels–Alder and
1,3-dipolar cycloadditions,20 although these reactions are difficult
to optimise due to problems in reaction monitoring.19 Calme`s
et al. first demonstrated in 2001 that a suitable labile linker system
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then examined, with treatment of 49 with CAN (5 eq.), followed
by washing with THF and water to remove inorganic residues.
The desired cyclisation was promoted by treatment with NEt3 in
CH2Cl2, affording N-propanoyl SuperQuat 48 in 84% yield, thus
demonstrating that the ester linkage may be selectively cleaved
in the presence of the N-acyloxazolidinone to release the chiral
auxiliary into solution (Scheme 9).
using standard vacuum line techniques and glassware that was
flame dried and cooled under nitrogen or argon before use.
Solvents were dried according to the procedure outlined by
R
Grubbs and co-workers.25 Water was purified by an Elixꢀ UV-
10 system. All other solvents were used as supplied (analytical
or HPLC grade) without prior purification. Organic layers were
dried over MgSO4 or Na2SO4 as stated. Thin layer chromatography
was performed on aluminium plates coated with 60 F254 silica.
Plates were visualised using UV light (254 nm), iodine, 1% aq.
KMnO4, or 10% ethanolic phosphomolybdic acid. Flash column
chromatography was performed on Kieselgel 60 silica.
Elemental analyses were recorded by the microanalysis service
of the Inorganic Chemistry Laboratory, University of Oxford,
UK. Melting points were recorded on a Gallenkamp Hot Stage
apparatus and are uncorrected. Optical rotations were recorded
on a Perkin-Elmer 241 polarimeter with a water-jacketed 10 cm
cell. Specific rotations are reported in 10−1 deg cm2 g−1 and
concentrations in g per 100 mL. IR spectra were recorded on
either a Perkin-Elmer Paragon 1000 FT-IR spectrometer or a
Bruker Tensor 27 FT-IR spectrometer as either a thin film on NaCl
plates (film) or a KBr disc (KBr), as stated. Selected characteristic
peaks are reported in cm−1. Nuclear magnetic resonance (NMR)
spectra were recorded on Bruker DPX 400 (1H: 400 MHz and
13C: 100.6 MHz), AMX 500 (1H: 500 MHz and 13C: 125.3 MHz),
Bruker DPX 250 (1H: 250 MHz) or Varian 200 (1H: 200 MHz)
spectrometers in the deuterated solvent stated. All chemical shifts
(d) are quoted in ppm and coupling constants (J) in Hz. Coupling
constants are quoted twice, each being recorded as observed
in the spectrum without averaging. The field was locked by
external referencing to the relevant deuteron resonance. Residual
signals from the solvents were used as an internal reference. 13C
multiplicities were assigned using a DEPT sequence. Reverse-
phase HPLC was carried out on a Gilson instrument comprising
of Gilson 306 pumps, Gilson 811C dynamic mixer, Gilson 806
manomeric module with automated injection on a Gilson 215
liquid handler, configured with a Gilson 819 valve actuator.
R
Separations were performed on a Hypersilꢀ Elite C18 column
(5 lm particle size, 150 × 4.6 mm). All experiments were performed
under gradient elution with deionised H2O (containing 0.1% TFA)
and MeCN, starting from 95% H2O, 5% MeCN to 5% H2O,
95% MeCN over 8 minutes then isocratic for 4 minutes. The
flow rate was 1.0 mL min−1. Detection was at k 220, 254 and
290 nm with a Gilson 170 Diode Array Detector with equipment
control and data collection managed by Gilson Unipoint LC
software version 3.01. Low-resolution mass spectra were recorded
on either a VG MassLab 20–250 or a Micromass Platform 1
spectrometer. Accurate mass measurements were run on either a
Bruker MicroTOF and were internally calibrated with polyaniline
in positive and negative modes, or a Micromass GCT instrument
fitted with a Scientific Glass Instruments BPX5 column (15 m ×
0.25 mm) using amyl acetate as a lock mass.
Scheme 9 Reagents and conditions: (i) SOCl2, MeOH, D then Boc2O,
NaHCO3, EtOH, rt; (ii) MeMgBr (5 eq.), THF, −78 ◦C to rt; (iii) tBuOK,
THF, D; (iv) TBDMSCl, imidazole, CH2Cl2, rt, 24 h; (v) n-BuLi, −78 ◦C,
THF, then CH3CH2COCl; (vi) TBAF, THF, 1 h; (vii) 28, EDCI, HOBt,
DIPEA, CH2Cl2, 20 h; (viii) CAN (5 eq.), THF : H2O (8 : 1), rt, 5 h; (ix)
CH2Cl2 : NEt3 (5 : 1), rt, 30 min.
In conclusion, we have developed a novel, oxidatively activated
safety catch linker system that has been applied to the solid phase
synthesis of a range of phenols. The attachment and release of a
chiral auxiliary from the solid phase using this linker system has
also been demonstrated. Current studies are underway to apply
this methodology to a range of asymmetric protocols on the solid
phase.
General experimental procedures
Experimental
Representative Procedure 1: carbodiimide coupling reactions in
solution. To a solution of the requisite carboxylic acid in CH2Cl2
or DMF was added DIPEA, nucleophile (amine or alcohol),
HOBt and coupling reagent (EDCI, TBTU or DIC). The reaction
mixture was stirred at room temperature for 16 hours. The
General experimental
All reactions involving organometallic or other moisture-sensitive
reagents were carried out under a nitrogen or argon atmosphere
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N-(2ꢀ-Phenylethyl)-3,3-dimethyl-pyrrolidin-2-one
resulting solution was partitioned with 10% aqueous HCl and
then 2 M aqueous NaOH. The organic layer was dried (Na2SO4),
concentrated in vacuo before purification as described.
6
and 2-
phenylpropan-1-ol (7). Following Representative Procedure 2,
CAN (494 mg, 0.903 mmol, 5.0 eq.) was added to a stirred solution
of 4 (80 mg, 0.181 mmol, 1.0 eq.) in THF : H2O (8 : 1) (6 mL).
After 3 hours the mixture was partitioned with 2 M aqueous
NaOH solution (5 mL) and ether (20 mL). The aqueous layer was
extracted with ether (20 mL). The combined organic layers were
dried (MgSO4) and concentrated in vacuo to afford 2ꢀꢀ-phenylprop-
1ꢀꢀ-yl 2,2-dimethyl-4-[N-(2ꢀ-phenylethyl)amino]butanoate 5. The
crude residue was refluxed in toluene for 16 hours. The solvent
was removed and separation by column chromatography on
silica gel (EtOAc : petrol, 1 : 9–4 : 6, stepwise elution) afforded
2-phenylpropan-1-ol 7 (13 mg, 53%) as a colourless oil; dH
(200 MHz, CDCl3) 1.30 (3H, d, J 6.9, CH3CHPh), 2.93–3.01 (1H,
m, CH3CHPh), 3.72 (2H, d, J 6.8, CH2OH), 7.20–7.40 (5H, m,
Ph); further elution afforded 6 as a colourless oil (29 mg, 74%);
Representative Procedure 2: CAN oxidation in solution. CAN
(5.0 eq.) was added to a stirred solution of the requisite tertiary
amine (1.0 eq.) in THF : H2O (8 : 1) or MeCN : H2O (5 :
1) and stirred for 16 hours at room temperature. The reaction
was quenched with either a 2 M aqueous solution of NaOH or
saturated aqueous bicarbonate solution (NaHCO3) and extracted
into ether or CH2Cl2. The organic extracts were dried (MgSO4),
filtered and concentrated in vacuo and the resulting crude product
purified as described.
Representative Procedure 3: carbodiimide coupling reactions on
polymer support. To a suspension of the requisite carboxylic acid
in CH2Cl2 was added DIPEA, nucleophile (amine or alcohol),
HOBt and coupling reagent (EDCI, TBTU or DIC). The reaction
mixture was stirred at room temperature for 16 hours. The resin
was transferred to a sintered funnel, washed repeatedly with DMF,
MeOH and CH2Cl2 then dried to a constant mass in vacuo.
v
max/cm−1 (film) 1685; dH (400 MHz, CDCl3) 1.08 (6H, s, CMe2),
1.77 (2H, t, J 6.8, C(4)H2), 2.85 (2H, t, J 7.4, C(2ꢀ)H2), 3.12 (2H,
t, J 6.8, C(5)H2), 3.54 (2H, t, J 7.4, C(1ꢀ)H2), 7.20–7.32 (5H, m,
Ph); dC (100 MHz, CDCl3) 24.5, 33.7, 34.2, 40.5, 43.9, 44.1, 126.4,
128.4, 128.7, 138.8, 179.4; m/z (ESI+) 218 (MH+, 100%); HRMS
C14H20NO (MH+) requires 218.1545; found 218.1548.
Representative Procedure 4: Suzuki couplings on polymer support.
To a stirred suspension of the polymer supported 4-iodophenyl
ester (1.0 eq.) in DMF, boronic acid (4.0 eq.) and K2CO3 (5.0 eq.)
was a◦dded Pd2dba3 (0.20 eq.) in 2 or 3 portions over 36 hours
at 70 C. The resin was transferred to a sintered funnel, washed
repeatedly with DMF, water, THF and CH2Cl2 and then dried to
a constant mass in vacuo.
N-Benzyl-2,2-dimethyl-4-[N-benzyl-N-(2ꢀ -phenylethyl)amino]-
butanamide (8). Following Representative Procedure 1, to a
stirred solution of 2 (3.20 g, 9.83 mmol, 1.0 eq.), benzylamine 18
(3.22 mL, 29.5 mmol, 3.0 eq.), HOBt (2.66 g, 19.7 mmol, 2.0 eq.)
and DIPEA (6.88 mL, 39.3 mmol, 4.0 eq.) in CH2Cl2 (100 mL)
was added EDCI (2.45 g, 12.8 mmol, 1.3 eq.). The resulting
solution was stirred for 16 hours then washed with 10% aqueous
HCl (150 mL) and 2 M aqueous NaOH solution (150 mL), then
dried (Na2SO4) and concentrated in vacuo. Purification by column
chromatography on silica gel (MeOH : CHCl3, 2 : 98) afforded the
title compound 8 as a yellow viscous oil (4.08 g, 100%); vmax/cm−1
(film) 3351, 1643, 1529; dH (400 MHz, CDCl3) 1.20 (6H, s, CMe2),
1.76 (2H, t, J 7.4, C(3)H2), 2.55 (2H, t, J 7.4, C(4)H2), 2.65–2.76
(4H, m, C(1ꢀ)H2 and C(2ꢀ)H2), 3.63 (2H, s, NCH2Ph), 4.40 (2H, d,
J 5.4, NHCH2Ph), 6.65 (1H, t, J 5.4, NHCH2Ph), 7.12–7.47 (15H,
m, Ph); dC (100 MHz, CDCl3) 26.1, 33.1, 37.6, 41.5, 43.5, 49.6, 55.4,
58.4, 125.9, 126.9, 127.4, 127.8, 128.2, 128.3, 128.7, 128.7, 129.0,
138.8, 139.1, 140.4, 177.3; m/z (ESI+) 415 (MH+, 100%); HRMS
C35H35N2O (MH+) requires 415.2749; found 415.2754.
Representative Procedure 5: CAN oxidation on polymer support.
CAN (5.0 eq.) was added to a stirred suspension of the requisite
resin (1.0 eq.) in THF : H2O (8 : 1). After stirring for 16 hours the
resin was transferred to a sintered funnel and washed repeatedly
with THF, water, THF and CH2Cl2. The resin was then treated
with CH2Cl2 : NEt3 (5 : 1) and the filtrate was concentrated in
vacuo. The resulting residue was filtered through a plug of silica
(EtOAc eluent) and the solvent removed in vacuo. The resin was
dried in vacuo to a constant mass.
2ꢀꢀ-Phenylprop-1ꢀꢀ-yl
2,2-dimethyl-4-[N-benzyl-N-(2ꢀ-phenyl-
ethyl)amino]butanoate (4). Following Representative Procedure
1, to a stirred solution of 2 (544 mg, 1.67 mmol, 1.0 eq.),
2-phenylpropan-1-ol 7 (0.701 mL, 5.02 mmol, 3.0 eq.), HOBt
(452 mg, 3.35 mmol, 2.0 eq.) and DIPEA (0.878 mL, 5.02 mmol,
3.0 eq.) in CH2Cl2 (20 mL) was added EDCI (481 mg, 2.51 mmol,
1.5 eq.). The resulting solution was stirred for 16 hours and
washed with 10% aqueous HCl (30 mL) and 2 M aqueous
NaOH solution (30 mL). The solution was dried (Na2SO4) and
concentrated in vacuo. Purification by column chromatography on
silica gel (EtOAc : petrol, 1 : 9) afforded the title compound 4 as a
colourless oil (525 mg, 71%); vmax/cm−1 (film) 1726; dH (400 MHz,
CDCl3) 1.12 (6H, s, CMe2), 1.31 (3H, d, J 7.0, C(3ꢀꢀ)H3), 1.71–1.75
(2H, m, C(3)H2), 2.44–2.48 (2H, m, C(4)H2), 2.64–2.79 (4H, m,
C(1ꢀ)H2 and C(2ꢀ)H2), 3.04–3.13 (1H, m, C(2ꢀꢀ)H), 3.62 (2H, s,
NCH2Ph), 4.06–4.22 (2H, m, C(1ꢀꢀ)H2), 7.16–7.47 (15H, m, Ph);
dC (100 MHz, CDCl3) 18.1, 25.3, 33.5, 37.2, 39.0, 41.3, 49.5, 55.4,
58.4, 69.2, 125.9, 126.6, 126.8, 127.3, 128.2, 128.3, 128.4, 128.8,
139.5, 140.6, 143.2, 177.5; m/z (ESI+) 444 (MH+, 100%); HRMS
C30H38NO2 (MH+) requires 444.2903; found 444.2905.
N-Benzyl-2,2-dimethyl-4-[N-(2ꢀ-phenylethyl)amino]butanamide
(14). Following Representative Procedure 2, CAN (6.15 g,
11.2 mmol, 5.0 eq.) was added to a stirred solution of 8 (929 mg,
2.24 mmol, 1.0 eq.) in THF : H2O (8 : 1) (90 mL). After
16 hours the mixture was partitioned between 2 M aqueous NaOH
solution (100 mL) and ether (200 mL). The aqueous layer was
extracted with ether (200 mL). The combined organic layers were
dried (MgSO4) and concentrated in vacuo. Purification by column
chromatography on silica gel (MeOH : CHCl3, 2 : 98–3 : 7, stepwise
elution) afforded the title compound 14 as a colourless oil (579 mg,
80%); vmax/cm−1 (film) 3339, 1641, 1532; dH (400 MHz, CDCl3)
1.20 (6H, s, CMe2), 1.72 (2H, t, J 7.4, C(3)H2), 2.21 (1H, br s,
NH), 2.62 (2H, t, J 7.4, C(4)H2), 2.69–2.82 (4H, m, C(1ꢀ)H2
and C(2ꢀ)H2), 4.40 (2H, d, J 5.6, NHCH2Ph), 6.97 (1H, t, J 5.6,
NHCH2Ph), 6.97–7.34 (10H, m, Ph); dC (100 MHz, CDCl3) 26.2,
36.0, 40.3, 41.5, 43.6, 45.6, 50.9, 126.2, 127.3, 127.7, 128.5, 128.6,
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128.7, 138.7, 139.6, 177.5; m/z (ESI+) 325 (MH+, 100%); HRMS
Method B. To a stirred solution of 22 (393 mg, 0.746 mmol,
1.0 eq.), K2CO3 (257 mg, 1.86 mmol, 2.5 eq.) and phenylboronic
acid (182 mg, 1.49 mmol, 2.0 eq.) in DMF (20 mL) was added
portionwise over 20 hours Pd2(dba)3 (136 mg, 0.149 mmol,
0.20 eq.). After 24 hours the solvent was removed in vacuo and
the resulting residue partitioned between water (40 mL) and
CH2Cl2 (80 mL). The aqueous layer was extracted with CH2Cl2
(80 mL). The combined organic extracts were dried (Na2SO4) and
concentrated in vacuo to afford a yellow oil (247 mg). Attempted
purification by column chromatography (EtOAc : petrol, 1 : 9–2 :
8) afforded a mixture, inseparable by column chromatography,
of dibenzylideneacetone and 23, with identical physical and
spectroscopic properties to those described above.
C21H29N2O (MH+) requires 325.2280; found 325.2278.
N-(2ꢀ-Phenylethyl)-3,3-dimethyl-pyrrolidin-2-one (6) and benzy-
lamine hydrochloride (18·HCl). 14 (210 mg, 0.648 mmol, 1.0 eq.)
was refluxed in toluene (20 mL) for 16 hours. The organic layer
was washed with 10% aqueous HCl (10 mL). The organic layer
was concentrated in vacuo. The resultant residue was partitioned
between CH2Cl2 (20 mL) and the retained aqueous layer. The
organic layer was washed with 10% aqueous HCl (10 mL, 2×),
dried (Na2SO4) and concentrated in vacuo to afford 6 (136 mg,
97%) with identical physical and spectroscopic properties to those
described above. The combined aqueous layers were co-evaporated
with MeOH in vacuo to a constant mass to afford benzylamine
hydrochloride 18·HCl as a white crystalline solid (92 mg, 99%);
N-(2ꢀ-Phenylethyl)-3,3-dimethyl-pyrrolidin-2-one (6) and 4-
phenylphenol (24). CAN (419 mg, 0.765 mmol, 5.0 eq.) was
added to a solution of 23 (73 mg, 0.153 mmol, 1.0 eq.) in THF :
H2O (8 : 1) (4 mL) and the resulting mixture stirred for 16 h.
Filtration through a small plug of aluminium oxide (neutral) using
EtOAc as the eluting solvent afforded a ca. 50 : 50 mixture of
6 and 24. Separation by column chromatography on silica gel
(EtOAc : petrol, 2 : 98–8 : 2, stepwise elution) afforded lactam
4 as a colourless oil (32 mg, 96%) with identical physical and
spectroscopic properties to those described above. Further elution
afforded 4-phenylphenol 24 as a white crystalline solid (24 mg,
◦
◦
mp 258–260 C (lit.26 261–262 C); dH (200 MHz, CD3OD) 4.16
(2H, s, NCH2Ph), 7.45–7.52 (5H, m, Ph).
4ꢀꢀ -Iodophenyl 2,2-dimethyl-4-[N-benzyl-N-(2ꢀ -phenylethyl)-
amino]butanoate (22). Following Representative Procedure 1, to
a stirred solution of 2 (1.50 g, 4.61 mmol, 1.0 eq.), 4-iodophenol
(5.08 g, 23.1 mmol, 5.0 eq.), HOBt (1.25 g, 9.23 mmol, 2.0 eq.)
and DIPEA (2.42 mL, 13.8 mmol, 3.0 eq.) in CH2Cl2 (60 mL) was
added EDCI (1.33 g, 6.92 mmol, 1.5 eq.). The resulting solution
was stirred for 16 hours then washed with 10% aqueous HCl
(60 mL) and 2 M aqueous NaOH solution (60 mL). The organic
layer was dried (Na2SO4) and concentrated in vacuo. Purification
by column chromatography on silica gel (MeOH : CHCl3, 2 : 98)
afforded the title compound 22 as a colourless oil (1.99 g, 82%);
◦
◦
92%); mp 158–160 C (lit.27 166–167 C); dH (400 MHz, CDCl3)
4.89 (1H, br s, OH), 6.89–6.96 (2H, m, Ar), 7.27–7.58 (7H, m, Ar).
4ꢀꢀꢀ-Biphenyl 2,2-dimethyl-4-{N-benzyl-N-[4ꢀ-(4ꢀꢀ-polystyrenyl)-
butyl]amino}butanoate (27).
v
max/cm−1 (film) 1752; dH (400 MHz, CDCl3) 1.31 (6H, s, CMe2),
1.88–1.92 (2H, m, C(3)H2), 2.58–2.62 (2H, m, C(4)H2), 2.75–2.84
(4H, m, C(1ꢀ)H2 and C(2ꢀ)H2), 3.66 (2H, s, NCH2Ph), 6.65–6.68
(2H, m, Ar), 7.16–7.57 (10H, m, Ph), 7.70–7.72 (2H, m, Ar); dC
(100 MHz, CDCl3) 25.4, 33.5, 37.3, 41.6, 49.4, 55.6, 58.5, 89.5,
123.8, 125.9, 126.9, 128.3, 128.8, 128.8, 138.4, 139.4, 140.5, 150.8,
175.9; m/z (ESI+) 528 (MH+, 100%); HRMS C27H31NO2 (MH+)
requires 528.1400; found 528.1403.
Method A. A solution of 9-BBN (42.5 mL, 21.3 mmol, 0.5 M
in THF, 2.2 eq.) was added dropwise to a stirred solution of 26
(8.28 g, 19.3 mmol, 2.0 eq.) in THF (25 mL) at 0 ◦C. Stirring
was continued for 1 hour at 0 ◦C and 4 hours at room tem-
perature. Bromopolystyrene resin (3.00 g, 9.66 mmol, Argonout
Technologies,14 3.22 mmol g−1, 106 lm, 1.0 eq.) was washed
repeatedly with DMF, THF and CH2Cl2 and dried in vacuo for
3 hours. The catalyst was prepared separately by the following
procedure: DPPF (589 mg, 1.06 mmol, 0.11 eq.) was dissolved in
DMF (20 mL), Pd(OAc)2 (195 mg, 0.869 mmol, 0.090 eq.) was
then added and the solution degassed before heating at 60 ◦C
for 30 min. The hydroboration mixture was concentrated under
reduced pressure to 5 ml and transferred to the flask containing
the prewashed bromopolystyrene resin via cannula followed by
K2CO3 (3.34 g, 24.2 mmol, 2.5 eq.). The catalyst was transferred to
the resin suspension via cannula and the resulting mixture heated
under nitrogen at 60 ◦C for 18 hours. The resin was transferred to
a sintered funnel in DMF and washed with DMF, water, 0.2 M
aqueous HCl, NEt3, DMF, MeOH, THF, CH2Cl2, ether, THF and
CH2Cl2. The resin was transferred to a round bottom flask, dried
in vacuo to a constant mass (6.50 g) to afford 27; vmax/cm−1 (KBr)
1748.
4ꢀꢀ-Biphenyl 2,2-dimethyl-4-[N-benzyl-N-(2ꢀ-phenylethyl)amino]-
butanoate (23).
Method A. Following Representative Procedure 1, to a stirred
solution of 2 (326 mg, 1.00 mmol, 1.0 eq.), 4-phenylphenol 24
(683 mg, 4.00 mmol, 4.0 eq.), HOBt (271 mg, 2.00 mmol, 2.0 eq.)
and DIPEA (0.702 mL, 4.00 mmol, 4.0 eq.) in CH2Cl2 (25 mL)
was added EDCI (481 mg, 2.50 mmol, 2.5 eq.) portionwise
over 24 hours. The resulting solution was washed with 10%
aqueous HCl (25 mL) and 2 M aqueous NaOH solution (25 mL).
The solution was dried (Na2SO4) and concentrated in vacuo.
Purification by column chromatography on silica gel (EtOAc :
petrol, 1 : 9–2 : 8, stepwise elution) afforded the title compound
23 as a white waxy solid (341 mg, 71%); vmax/cm−1 (film) 1748;
dH (400 MHz, CDCl3) 1.37 (6H, s, CMe2), 1.95–1.99 (2H, m,
C(3)H2), 2.67–2.71 (2H, m, C(4)H2), 2.79–2.88 (4H, m, C(1ꢀ)H2
and C(2ꢀ)H2), 3.75 (2H, s, NCH2Ph), 7.03–7.05 (2H, m, Ar), 7.21–
7.62 (17 H, m, Ph); dC (100 MHz, CDCl3) 25.4, 33.3, 37.2, 41.5,
49.4, 55.5, 58.4, 121.7, 125.4, 125.9, 126.9, 127.1, 127.2, 128.0,
128.2, 128.2, 128.7, 128.8, 138.7, 139.3, 140.3, 140.4, 150.2, 176.2;
m/z (ESI+) 478 (MH+, 100%); HRMS C33H36NO2 requires (MH+)
478.2746; found 478.2740.
Method B. Following Representative Procedure 4, to a stirred
suspension of 33 (100 mg, 0.141 mmol, 1.0 eq.), K2CO3 (97 mg,
0.705 mmol, 5◦.0 eq.) and phenylboronic acid (69 mg, 0.56 mmol,
4.0 eq.) at 70 C in DMF (3 mL) was added, Pd2(dba)3 (26 mg,
0.028 mmol, 0.20 eq.). The resin was repeatedly washed with DMF,
water, THF and CH2Cl2. The resin was dried in vacuo to a constant
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mass to afford 27 (94 mg) with identical spectroscopic properties
After 16 hours the resin was transferred to a sintered funnel
and washed repeatedly with DMF, 2 M aqueous NaOH solution,
water, MeOH and CH2Cl2. The resin was dried to a constant mass
in vacuo to afford 32 as a pale brown powder (304 mg); vmax/cm−1
(KBr) 3371, 1635, 1529; loading 1.98 mmol g−1.
to those described above; loading 1.52 mmol g−1.
Loading determination of 2,2-dimethyl-4-{N-benzyl-N-[4ꢀ-(4ꢀꢀ-
polystyrenyl)butyl]amino}butanoic acid (28)
The resin 27 (6.50 g, 9.66 mmol, 1.0 eq.), as a suspension in THF :
H2O (8 : 1) (100 ml), was stirred at reflux with LiOH·H2O (4.05 g,
17.1 mmol, 10.0 eq.) for 4 hours. The resulting resin was washed
repeatedly with water and THF. The washings were collected and
the THF removed in vacuo. The water layer was acidified with
10% aqueous HCl and repeatedly extracted with CH2Cl2 (3×).
Evaporation of the solvent in vacuo afforded 4-phenylphenol 24
(1.65 g, 9.69 mmol) with identical physical and spectroscopic
properties to those described above. The resin was further washed
repeatedly with THF, DMF and 10% aqueous HCl, the pH was
then adjusted to neutral with aqueous 2 M NaOH solution and
again repeatedly washed with DMF, water and THF. The resin
was dried in vacuo to a constant mass to afford 28 as a dark
brown powder (5.60 g); vmax/cm−1 (KBr) 1713; determined loading
1.73 mmol g−1.
N-[4ꢀ-(4ꢀꢀ-Polystyrenyl)butyl]-3,3-dimethyl-pyrrolidin-2-one (30)
and benzylamine hydrochloride (18·HCl)
The resin 32 (300 mg, 0.585 mmol) was stirred as a suspension in
toluene (10 ml) and refluxed for 48 hours. The resin was transferred
to a sintered funnel and washed repeatedly with toluene. To the
combined organic washings was added 10% aqueous HCl. The
solvents were removed in vacuo and the residue co-evaporated
with MeOH to afford benzylamine hydrochloride 18·HCl as a
white crystalline solid (55 mg, 65%) with identical physical and
spectroscopic properties to those described above. The resin was
washed repeatedly with MeOH, THF and CH2Cl2. The resin was
dried in vacuo to a constant mass to afford 30 as a dark brown
powder (243 mg) with identical spectroscopic properties to those
described above.
(S)-[4ꢀꢀꢀ-(2ꢀꢀꢀ-oxo-3ꢀꢀꢀ-Propanoyl-5ꢀꢀꢀ,5ꢀꢀꢀ-dimethyl-oxazolidin-4ꢀꢀꢀ-yl)-
benzyl] 2,2-dimethyl-4-{N-benzyl-N-[4ꢀ-(4ꢀꢀ-
N-[4ꢀ-(4ꢀꢀ-Polystyrenyl)butyl]-3,3-dimethyl-pyrrolidin-2-one (30)
and 4-phenylphenol (24)
polystyrenyl)butyl]amino}butanoate (49)
CAN (1.25 g, 2.28 mmol, 5.0 eq.) was added to a stirred suspension
of 27 (300 mg, ∼0.456 mmol, 1.0 eq.) in THF : H2O (8 : 1)
(3 mL). After 16 hours reaction time the resin was transferred to
a sintered funnel and washed repeatedly with CH2Cl2, THF and
water. The resin was dried in vacuo to a constant mass to afford
the debenzylated product 29 as a pale yellow powder (315 mg);
To a stirred suspension of 28 (500 mg, 0.865 mmol, 1.0 eq.), (S)-
N-propanoyl SuperQuat 48 (959 mg, 3.46 mmol, 4.0 eq.), HOBt
(467 mg, 3.46 mmol, 4.0 eq.) and DIPEA (0.603 mL, 6.92 mmol,
4.0 eq.) in CH2Cl2 (10 mL) was added EDCI (1.82 mL, 2.60 mmol,
3.0 eq.). After 20 hours the resin was transferred to a sintered
funnel and washed repeatedly with CH2Cl2 and MeOH. The
washings were collected and the solvent removed in vacuo, the
resulting residue was partitioned between CH2Cl2 (50 ml) and 10%
aqueous HCl (50 mL). The organic layer was washed with 10%
aqueous HCl (50 mL). The organic layer was dried with Na2SO4
and the solvent removed in vacuo to afford recovered 48 (780 mg).
The resin was further washed repeatedly with DMF, THF and
CH2Cl2 and re-subjected to the same reaction protocol and work-
up. The resin was dried in vacuo to a constant mass to afford 49 as
a pale brown powder (659 mg). vmax/cm−1 (KBr) 1778, 1749, 1701;
loading 1.31 mmol g−1.
v
max/cm−1 (KBr) 1746. Subsequently the resin (271 mg, ∼0.392
mmol) was stirred in a mixture of CH2Cl2 : NEt3 (5 : 1) (5 mL)
for one hour and washed repeatedly with CH2Cl2 (20 mL, 3×).
The combined organic layers were repeatedly washed with 10%
aqueous HCl (50 mL, 3 ×). The organic layer was concentrated in
vacuo to afford the desired 4-phenylphenol 24 (52 mg, 78%) with
identical physical and spectroscopic properties to those described
above; HPLC (MeCN–H2O, 254 nm) >99%. The resin was dried
in vacuo to a constant mass to afford 30 as a pale brown powder
(209 mg); vmax/cm−1 (KBr) 1682.
N-Benzyl-2,2-dimethyl-4-{N-benzyl-N-[4ꢀ-(4ꢀꢀ-
polystyrenyl)butyl]amino}butanamide (31)
N-[4ꢀ-(4ꢀꢀ-Polystyrenyl)butyl]-3,3-dimethyl-pyrrolidin-2-one (30)
and (S)-3-propanoyl-4-(4ꢀ-hydroxybenzyl)-5,5-
dimethyloxazolidin-2-one (48)
Following Representative Procedure 3, to a stirred suspension of
28 (500 mg, 0.865 mmol, 1.0 eq.), benzylamine 14 (0.566 mL,
5.19 mmol, 6.0 eq.), HOBt (351 mg, 2.56 mmol, 3.0 eq.) and
DIPEA (0.904 mL, 5.19 mmol, 6.0 eq.) in CH2Cl2 (10 mL) was
added DIC (0.406 ml, 2.56 mmol, 3.0 eq.). After 16 hours the
resin was transferred to a sintered funnel and washed repeatedly
with DMF, MeOH and CH2Cl2. The resin was dried in vacuo to
a constant mass to afford 31 as a pale brown powder (518 mg);
CAN (538 mg, 0.983 mmol, 5.0 eq.) was added to a stirred
suspension of 49 (150 mg, 0.197 mmol, 1.0 eq.) in THF : H2O
(8 : 1) (2 mL). After stirring for 5 hours the resin was transferred
to a sintered funnel and washed repeatedly with THF, water, THF
and CH2Cl2. The resin was then treated with CH2Cl2 : NEt3 (5 : 1)
(12 mL) and the filtrate was concentrated in vacuo. The resulting
residue was partitioned between CH2Cl2 (10 ml) and 10% aqueous
HCl (5 mL). The organic layer was washed with 10% aqueous HCl
(5 mL), water (5 mL), dried (Na2SO4) and concentrated in vacuo to
afford 48 (46 mg, 84%); [a]D22 −45.0 (c 1.0, CHCl3); other physical
and spectroscopic data was identical to that reported above. The
resin was dried to a constant mass in vacuo (90 mg) to afford 30
with identical spectroscopic properties to those described above.
v
max/cm−1 (KBr) 3368, 1634, 1529; loading 1.68 mmol g−1.
N-Benzyl-2,2-dimethyl-4-{N-[4ꢀ-(4ꢀꢀ-
polystyrenyl)butyl]amino}butanamide (32)
CAN (1.63 g, 2.96 mmol, 5.0 eq.) was added to a stirred suspension
of 31 (355 mg, 0.593 mmol, 1.0 eq.) in THF : H2O (8 : 1) (13 mL).
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Acknowledgements
The authors would like to thank the British Chevening Scholarship
programme (H. S.) and New College, Oxford for a Junior Research
Fellowship (A. D. S.).
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1634 | Org. Biomol. Chem., 2008, 6, 1625–1634
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