Facile and purification free synthesis of peptides utilizing ROMPgel- and ROMPsphere-supported coupling reagents

Article abstract of DOI:10.1016/j.tet.2005.06.120

5-Norbornene-2-carboxaldehyde and norbornadiene were respectively converted into norbornene derivatives functionalized with fluoroformamidinium hexafluorophosphate and 2-bromo-N-methylpyridinium tetrafluoroborate residues. Both these norbornene monomers were ring opening metathesis polymerized or graft copolymerized onto polystyrene cores to produce ROMPgel and ROMPsphere peptide-coupling reagents. These were used to prepare hindered amides, dipeptides and tripeptides with minimal purification in parallel arrays.

Full text of DOI:10.1016/j.tet.2005.06.120

Tetrahedron 61 (2005) 12033–12041
Facile and purification free synthesis of peptides utilizing
ROMPgel- and ROMPsphere-supported coupling reagents
*
¨
Anthony G. M. Barrett, Brigitte Bibal, Brian T. Hopkins, Johannes Kobberling,
Andrew C. Love and Livio Tedeschi
Department of Chemistry, Imperial College London, London SW7 2AZ, UK
Received 16 February 2005; revised 21 June 2005; accepted 21 June 2005
Available online 20 October 2005
Abstract—5-Norbornene-2-carboxaldehyde and norbornadiene were respectively converted into norbornene derivatives functionalized with
fluoroformamidinium hexafluorophosphate and 2-bromo-N-methylpyridinium tetrafluoroborate residues. Both these norbornene monomers
were ring opening metathesis polymerized or graft copolymerized onto polystyrene cores to produce ROMPgel and ROMPsphere peptide-
coupling reagents. These were used to prepare hindered amides, dipeptides and tripeptides with minimal purification in parallel arrays.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
chemistry and parallel synthesis has been the generalization
of synthetic protocols to maximize functional group diversity
through automation. We have sought to address this need by
the introduction of new classes of high-loading polymer-
supported reagents for purification-free (mix, filter and
evaporate) parallel synthesis.
The synthesis of structurally diverse combinatorial oligopep-
tide libraries using purification free processes originated
from the pioneering work of Merrifield and Letsinger.1 Since
the advent of this methodology, an array of techniques
including parallel synthesis,2 tagging,3 split and mix,4 and
indexing5 has been developed for the generation of peptide
and non-peptide libraries on solid supports. The need to
synthesize chemically diverse libraries of small drug-like
entities through automation has resulted in a shift from the
traditional solid support approach to the use of solid
supported reagents.6 This approach significantly facilitates
the process of library synthesis for high throughput assay7
since the undesired by-products are bound to the support
facilitating purification through simple filtration. The use of
polymer-supported reagents was conceived as a practical
solution for simplifying tedious workup procedures associ-
ated with the removal of undesired by-products8 such as
phosphine oxides, sulfonamides and urea type reagents. Over
the past three decades this approach has been further
extended to include transformations such as oxidations,9
reductions,10 halogenations,11 carbon–carbon bond for-
mation12 and also the use of polymer bound catalysts.13
These supported reagents are normally synthesized on cross-
linked polystyrene beads, macroporous ion exchange resins,
or inorganic supports. The major focus of combinatorial
Recently, we have reported the use of ring opening metathesis
(ROM) polymerization for the synthesis of high-loading,
insoluble, polymer-gel supported reagents (ROMPgels).
These reagents have several major advantages. Firstly, alkene
metathesis catalysts are noted for tolerance of diverse
functionalities thereby permitting the production of fully
functionalized (reagent) monomers prior to the polymer-
ization process. Secondly, such monomers are readily
available from inexpensive precursors. Thirdly, ROMPgels
are high-loading reagents, which have been employed for
Horner–Emmons reactions,14 in TOSMIC condensation
reactions,15 in acylation reactions including the preparation
of Mosher amides,16 and in reactions using triphenylpho-
sphine,17 N-hydroxysuccinimide,18 naphthalene and biphe-
nyl,19 Wilkinson’s catalyst,20 allylboronate reagents,21 and
diazoketophosphonates,22 in catalyzing the Stetter reaction23
and as scavengers for amines and hydrazines.24 Hanson and
Flynn,25 Roberts26 and Janda27 have described related
ROMPolymer-supported reagents and supports and the area
of ROMPolymer-supported reagents has been reviewed.28 To
further expand on our current methodologies, we now wish to
provide details for the synthesis and application of immobi-
lized fluoroformamidinium and immobilized 2-bromopyr-
idinium ROMPgel and ROMPsphere reagents for peptide-
coupling reactions and the synthesis of hindered amides.28
Keywords: Acylations; Combinatorial chemistry; Peptides; Parallel
synthesis; Supported reagents.
Corresponding author. Tel.: C44 207 594 5766; fax: C44 207 594 5805;
e-mail: agmb@ic.ac.uk
*
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.06.120

12034
A. G. M. Barrett et al. / Tetrahedron 61 (2005) 12033–12041
Gramicidin,29 an antibiotic first isolated in 1941, was found
to contain a Caa di-substituted amino acid residue. Since
then such amino acid residues have been identified in a
number of natural products30 and their occurrence has led to
significant interest in the development of efficient methods
for their synthesis.31 Traditional peptide-coupling protocols,
using activated esters and anhydrides,32 and carbodimides
with N-hydroxybenzotriazole,33 have been found to be
inadequate for coupling such hindered moieties. The next
real advancement in coupling activity came with
the development of phosphonium salt based reagents such as
(1-benzotriazolyoxy)tris(dimethylamino)-phosphonium hexa-
fluorophosphate (BOP)34 and (1-benzotriazolyoxy)tris(pyrro-
lidino)-phosphonium hexafluorophosphate (PyBOP).35 Due
to toxicity of their side products, they soon were replaced by
uronium reagents such as O-(benzotriazol-1-yl)-1,1,3,3-
tetramethyluronium hexafluorophosphate (HBTU)36 and
O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (HATU).37 Recently an immobilized
version of as O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluro-
nium tetrafluoroborate (TBTU) based on a polystyrene bound
benzotriazole was published.38 These uronium reagents show
a remarkable activity and low racemization in standard
peptide-couplings but are still of limited use for the coupling
of Caa di-substituted amino acid residues, due to the steric
demand of the activating group. Other very active onium type
coupling reagents for hindered amide bonds include thiazo-
lium (2-bromo-3-ethyl-4-methylthiazolium tetrafluoroborate,
BEMT)39 and iminium (benzotriazol-1-yloxy-N,N-dimethyl-
methan-iminium hexachloroantimonate, BOMI)40 type
reagents. Recently, onium type coupling reagents, that
generate acid fluorides or bromides, have been reported to
be effective in the synthesis ofamides derived frommono- and
di-substituted amino acids in acceptable yields, with good
reaction rates and with minimal racemization. The most
promising and synthetically accessible candidates are fluor-
oformamidinium salts (tetramethylfluoro-formamidinium
hexafluorophosphate, TFFH and bis(tetramethylenefluoro-
formam-idinium) hexafluorophosphate, BTFFH)41 and
2-halopyridinium salts (2-bromo-1-ethylpyridinium
tetrafluoroborate, BEP and 2-fluoro-1-ethylpyridinium tetra-
fluoroborate, FEP).42 The inherent problem of all reagents
mentioned, includingthe immobilizedTBTU, isthe formation
of undesired by-product, which may be toxic43 and that
necessitate extensive work-up after peptide-couplings in
solution. Consequently, we sought to prepare related
polymer-supported reagents to simplify work-up and to
minimize the need for chromatographic purification. Herein
we report the synthesis of monomers 4 and 8 (Schemes 1
and 2), their polymerization and graft ROM-polymerization
using starter divinylbenzene cross-linked polystyrene cores
(Scheme 3) and their use in the elaboration of hindered
peptides and amides in the solution phase with minimal
purification (Scheme 4).
Scheme 1. Synthesis of the fluoroformamidinium monomer 4.
Scheme 2. Synthesis of the 2-bromopyridinium monomer 8.
2. Results and discussion
2.1. Synthesis of monomers
The fluoroformamidinium monomer 4 was synthesized in
four steps from commercially available 5-norbornene-2-
carboxaldehyde (1) (Scheme 1). Reductive amination of
Scheme 3. Synthesis of the ROMPgel reagent 10.

A. G. M. Barrett et al. / Tetrahedron 61 (2005) 12033–12041
12035
Scheme 5. Parallel synthesis of hindered amides using the ROMPgel 10.
2,5-dibromopyridine.
Selective
bromine–lithium
exchange,46 upon treatment of the dibromide 5 with
n-butyllithium at K78 8C and iodination using 1,2-
diiodoethane gave 2-bromo-5-iodopyridine 6 (69%). Palla-
dium catalyzed exo-hydroarylation47 of iodide 6 gave the
bromide 7 (66%). Subsequent ethylation using triethylox-
onium tetrafluoroborate48 gave the norbornene pyridinium
salt 8 (81%).
2.2. Ring opening metathesis polymerization: synthesis
of ROMPgel and ROMPsphere coupling reagents
With monomers 4 and 8 in hand, the stage was set for both
ROM-polymerization in the presence of a crosslink to pro-
vide the ROMPgel reagent 10 and graft ROM-polymer-
ization reactions onto polystyrene beads to provide the
corresponding ROMPsphere49 reagents 14 and 15. ROMP-
sphere reagents are analogous to functionalized Hodges
Rasta resins50 due to the fact that both types of polymers are
derived from living polymerization reactions to increase the
mass and loading of core divinylbenzene cross-linked
polystyrene beads. ROM polymerization of monomer 4 in
the presence of catalyst 1151 (1 mol%) and cross-linker 922
gave the fluoroformamidinium ROMPgel 10 (Scheme 3).
This was isolated in excellent yield (98%) after quenching
with ethyl vinyl ether and extensive washing with
dichloromethane and diethyl ether.
Scheme 4. Synthesis of the ROMPsphere reagents 14 and 15.
aldehyde 1 gave amine 244 which was allowed to react with
dimethylcarbamoyl chloride to afford the urea derivative 3
in 89% yield. Formation of the formamidinium salt 4 was
achieved using a one-pot phosgene-free procedure
´
45
described by Najera et al. Thus, reaction of the amide 3
with oxalyl chloride and DMF in dichloromethane afforded
the formamidinium chloride salt. Subsequent treatment with
potassium hexafluorophosphate and potassium fluoride in
acetonitrile gave the formamidinium hexafluorophosphate 4
as a crystalline solid.
Secondly, Merrifield resin 12 (0.9 mmol/gK1) was allowed
to react with excess 2-norbornene-5-methanol in DMF
under basic conditions for 24 h at reflux (Scheme 4). The
polymer was sequentially washed with dichloromethane and
methanol and dried. The loading of the norbornene 13 was
The second coupling reagent prepared was an immobilized
variant of the 2-bromo-1-ethylpyridinium tetrafluoroborate
(BEP) coupling reagent (Scheme 2). Monomer 8
was synthesized in 3 steps from the commercially available
Table 1. Parallel synthesis of hindered amides using the ROMPgel 10
Entry
R1CO2H (16)
R1CONR2R3 (17)
Yield %
(purity %)a
1
16a
17a
87 (88)
2
3
16b
16c
17b
17c
98 (97)
73 (88)
4
5
16d
16e
17d
17e
95 (90)
81 (88)
a Yields refer to isolated products; the purities were estimated by 1H and 13C NMR spectra and, for volatile acids and amides, also by GC–S analysis.

12036
A. G. M. Barrett et al. / Tetrahedron 61 (2005) 12033–12041
dichloromethane at room temperature and allowed to react
with ethyldiisopropylamine and the acid component. After
ten minutes, a secondary amine was added and the resulting
mixture stirred at room temperature for 12 h. Pre-washed
Amberlite MB1 ion exchange resin was added and the
mixture shaken for a further 2 h. The suspension was
filtered, and the ROMPgel washed alternatively with
CH2Cl2 and MeOH. Evaporation of the solvent afforded
the desired amides in reasonable yields and high purities
(Table 1, entries 1–5).
Scheme 6. Peptide—coupling reactions using ROMPsphere reagents 14
and 15.
The ROMPsphere reagents 14 and 15 were suspended in
dichloromethane at K10 8C, and allowed to react with
ethyldiisopropylamine (3 equiv), an N-protected amino acid
18 (0.5 equiv) and an amino ester hydrochloride 19
(0.5 equiv) at 25 8C for 12 h. Pre-washed Amberlite MB11
ion exchange resin was added and the mixture shaken for a
further 2 h. The suspension was simply filtered, washed with
dichloromethane and methanol to afford the corresponding
di- and tri-peptides 20 (Scheme 6, Table 2). The reactions
could also be very effectively performed in Bohdan
Miniblocks: the peptide-coupling was performed in one
block and afterwards the liquid reaction components were
transferred in parallel into a second block containing the ion
exchange resin. After agitating the resin for further 1 h, the
solution was free of salt by-products and the pure dipeptides
20 were released into a deep well Miniblock and evaporated.
The preparation of Caa-disubstituted peptides was shown to
be extremely effective in terms of reaction time, yields and
purities, as exemplified in by 20b, 20c, 20d, 20g and 20h.
The results in Table 2 indicate that there is little difference
in term of yield and purity when using the ROMPsphere
reagents 14 or 15. In several cases the Anteunis test was
conducted at K78 8C using ethyldiisopropylamine as the
base and samples were taken after 10 min, 1 h and finally
12 h and the DL values were determined by HPLC using a
protocol described by Li and Xu.42 Unfortunately, complete
epimerization was observed after only 10 min reaction using
the ROMPsphere reagents 14 and 15 (Table 2, entries 9 and
10). Changing the base for the peptide-coupling from
ethyldiisopropylamine to a weaker base such as 2,6-lutidine
or N-methylmorpholine failed to suppress complete
epimerization. Our optical rotation values for the coupling
of Z-Gly and PheOEt wereshown tobezero(Table2, entries 1
and 2). These unexpected results were possibly due to slow
estimated by an increase in mass and by elemental analysis.
The supported norbornene 13 (0.65 mmol/gK1) was allowed
to react with carbene 11 (3 mol%) in dichloromethane to
afford a red colored polymer, which was subsequently
washed with dichloromethane and 2-propanol. The resin
was immediately treated separately with the monomers 4 or
8 for 2 h and the polymerization reactions terminated with
ethyl vinyl ether, and the beads were washed with dichloro-
methane and diethyl ether. Both ROMPsphere reagents 14
and 15 were obtained with loadings of 1.45 and 1.80 mmol/gK1
respectively as determined by an increase in mass and by
elemental analysis. We investigated the swelling properties
of the ROMPsphere salts 14 and 15 in a range of solvents
and observed significant swelling for both ROMPspheres in
dichloromethane, THF and DMF. Dichloromethane, as the
most volatile, was selected for amide and peptide synthesis.
2.3. Parallel synthesis of hindered amides and peptides
As previously discussed, both fluoroformamidinium and
2-bromopyridinium salts have proven to be effective coup-
ling reagents for formation of peptides from a,a-dialkylated
amino acids with minimal racemization. Thus we evaluated
the effectiveness of the ROMPgel 10 (Scheme 5, Table 1)
and the ROMPsphere reagents 14 and 15 (Scheme 6,
Table 2) in the purification-minimized parallel synthesis of
hindered amides and di-peptides containing the sterically
hindered Aib (a-aminoisobutyric acid). In several examples
of dipeptide synthesis, the degree of racemization was
determined using both the Anteunis test52 and Young’s
test.53 ROMPgel reagent 10 was suspended in
Table 2. Yields and purities of dipeptides 20 synthesized using ROMPspheres 14 or 15
Entry
Dipeptide
18
19
ROMPsphere
% Yielda
% Purityb
1
2
3
4
5
6
7
8
20a
20a
20b
20c
20c
20d
20e
20e
20f
Z-Gly
Z-Gly
Boc-Aib
Z-Gly
Z-Gly
Boc-Aib
Z-(L)-Leu
Z-(L)-Leu
Z-Gly-(L)-Phe
Z-Gly-(L)-Phe
N-Fmoc-Aib
N-Fmoc-Aib
(L)-Phe-OEt $HCl
(L)-Phe-OEt $HCl
Gly-OEt $HCl
Aib-OMe$HCl
Aib-OMe$HCl
Aib-OMe$HCl
Gly-OEt$HCl
14
15
14
14
15
14
14
15
14
15
15
15
96
86
97
97
84
90
89
92
95
87
85
80
95c
87c
98
98
96
98
92d
94d
90c
87c
88
Gly-OEt$HCl
9
(L)-Val-OMe$HCl
(L)-Val-OMe$HCl
Gly-OEt$HCl
10
11
12
20f
20g
20h
(L)-Ala-OEt$HCl
89d
a Isolated yields.
1
b Purity as determined by H NMR.54
c Product completely racemized (epimerized).
d Extent of racemization not determined.

A. G. M. Barrett et al. / Tetrahedron 61 (2005) 12033–12041
12037
diffusion of the amine to the ROMPsphere immobilized
activated acid thereby facilitating racemization. In spite of
this limitation, the ROMPsphere coupling reagents 14 and
15 are valuable in the parallel synthesis of hindered peptides
containing a,a-disubstituted amino acid residues (Table 2,
entries 3–6 and 11).
m/z 138 (MCH)C; HRMS (CI, NH3) calcd for C9H16N
(MCH)C, 138.1283; found: (MCH)C, 138.1280.
4.1.2. N-(Bicyclo[2.2.1]hept-5-en-2-ylmethyl)-N,N0,N0-
trimethylurea (3). Dimethyl-carbamoyl chloride (4.7 g
44 mmol) was added slowly with stirring to amine 2
(6.0 g, 44 mmol) in THF (250 mL) and Et3N (12.2 mL,
88 mmol) at 25 8C. After 3 h, the reaction mixture was
filtered through Celite and silica gel and rotary evaporated
to afford a residue. Chromatography (hexane/Et2O 2:1) gave
urea 3 (8.2 g, 89%) as a yellow oil: Rf 0.14 (EtOAc/hexanes
2:3); IR (thin film) 1644, 1495, 1461, 1382, 1343, 1260,
3. Conclusions
We have demonstrated the utility of a ROMPgel-supported
fluoroformamidinium hexafluorophosphate, a ROMP-
sphere-supported fluoroformamidinium hexafluoro-phos-
phate and a ROMPsphere-supported N-ethylpyridinium
tetrafluoroborate for the parallel synthesis of hindered
amides with minimal purification. The approach, whilst
useful for hindered peptides containing a,a-disubstituted
amino acid residues, it is unsatisfactory for standard
peptide-coupling reactions on account of racemization.
1
1123, 1112, 1063, 782, 719 cmK1; H NMR (300 MHz,
CDCl3) d 6.09 (dd, JZ5.3, 2.8 Hz, 1H), 5.84 (dd, JZ5.3,
2.8 Hz, 1H), 3.20 (m, 1H), 2.85 (dd, JZ2.6, 7.7 Hz, 2H),
2.75 (br s, 3H), 2.74 (br s, 6H), 2.36 (m, 1H), 1.76 (m, 1H),
1.36 (m, 1H), 1.29–1.18 (m, 2H), 0.48 (m, 1H); 13C NMR
(75 MHz, CDCl3) d 165.4, 137.3, 132.3, 54.1, 49.5, 44.4,
42.2, 38.6, 37.4, 37.3, 30.0; MS (CI, NH3) m/z 209 (MC
H)C; HRMS (CI, NH3) calcd for C12H21N2O (MC
H)C209.1654; found: (MCH)C, 209.1645. Anal. calcd
for C12H20N2O: C, 69.19; H, 9.68; N, 13.45. Found: C,
69.39; H, 9.84; N, 13.12.
4. Experimental
4.1. General
4.1.3. N-(Bicyclo[2.2.1]hept-5-en-2-ylmethyl)-N,N0,N0-
trimethylfluoroform-amidinium hexafluorophosphate
(4). Oxalyl chloride (1.0 mL, 11.5 mmol) was added
dropwise to the urea 3 (2.1 g, 10 mmol) and DMF (75 mL)
in CH2Cl2 (10 mL) at 25 8C. After 1 h, the solution was
heated to reflux for 4 h when rotary evaporation gave the
crude chloroformamidinium salt. KPF6 (2.2 g, 12.0 mmol)
and KF (0.56 g, 10.0 mmol) in MeCN (10 mL) were added
and the mixture was stirred for 48 h. The suspension was
filtered and the filtrate was concentrated in vacuo to afford a
residue. Recrystallization from CH3CN and Et2O gave the
salt 4 (2.3 g, 64%) as a white solid: mp 91–93 8C; IR (solid)
All reactions were carried out in an atmosphere of dry
nitrogen or argon at room temperature unless otherwise
stated. Reaction temperatures other than room temperature
were recorded as bath temperatures unless otherwise stated.
Flash chromatography was carried out on BDH silica 60,
230–400 mesh ASTM (eluants are quoted in parenthesis).
Analytical thin-layer chromatography (TLC) was per-
formed on Merck precoated silica 60 F254 plates. Hexanes
refers to redistilled alkanes with bp 40–60 8C. Dichloro-
methane (CH2Cl2) and tetrahydrofuran (THF) were purified
by distillation under N2 respectively from CaH2 and Ph2CO/
K, All other organic solvents and reagents were obtained
from commercial sources and used without further
purification. Organic extracts were concentrated using a
rotary evaporator at !40 8C bath temperature. Non volatile
oils and solids were vacuum dried at !2 mm Hg. Bohdan
miniblocks with 8 mL glass reactors with bottom filtration
and the option for transfer from one block to the other were
used for parallel reactions.
1647, 1473, 1457, 1412, 1398, 1245, 1058, 833, 726 cmK1
;
1H NMR (300 MHz, CDCl3) d 6.32 (m, 1H), 5.92 (m, 1H),
3.80–3.60 (m, 1H), 3.42 (br s, 3H), 3.41 (br s, 6H), 2.91 (br
s, 1H), 2.84 (br s, 1H), 2.54 (m, 1H), 2.00–1.98 (m, 1H),
1.59–1.55 (m, 1H), 1.38–1.36 (m, 1H), 1.24–1.16 (m, 1H),
0.60–0.56 (m, 1H); 13C NMR (75 MHz, CDCl3) d 159.4,
139.5, 131.0, 61.1, 49.9, 44.6, 44.5, 43.2, 42.4, 37.4, 30.1;
MS (FAB C) m/z 211 (MC); HRMS (FAB C) m/z calcd for
C12H20FN2 (MC), 211.1611; found: (MC), 211.1614.
4.1.1. 5-(Methylaminomethyl)bicyclo[2.2.1]hept-2-ene
(2).55 MeNH2 in THF (2.0 M; 65 mL, 132 mmol) was
added to aldehyde 1 (8.0 g, 66 mmol), Et2–O (50 mL) and
4.1.4. 2-Bromo-5-iodopyridine (6). n-BuLi in hexanes
(2.5 M; 7.00 mL, 17.5 mmol) was added dropwise to 2,5-
dibromopyridine 5 (3.76 g, 15.9 mmol) in THF (190 mL) at
K78 8C and the mixture stirred for 40 min. ICH2CH2I
(5.78 g, 20.5 mmol) in THF (25 mL) was added and the
mixture was allowed to warm up to 25 8C over 12 h. The
solution was diluted with H2O and Et2O (1:1, 300 mL) and
the aqueous phase was extracted with additional Et–2O (4!
50 mL). The combined organic phases were washed with
Na2S2O4 (100 mL) and brine (100 mL), dried (Na2SO4) and
rotary evaporated to afford a yellow solid. Chromatography
(hexanes/CH2Cl2 4:1) gave iodide 6 (3.2 g, 69%) as a white
solid: mp 119 8C (EtOH); IR (film) 1544, 1439, 1354, 1278,
˚
4 A molecular sieves (8.0 g) at 0 8C. The mixture was stirred
for 2 h, filtered and rotary evaporated to afford the imine as
an oil, which was dissolved in MeOH (100 mL) and NaBH4
(3.7 g, 99 mmol) was added in portions at 0 8C. After
stirring at 25 8C for 4 h, the mixture was rotary evaporated
to afford a residue, which was portioned between CH2Cl2
and hydrochloric acid (2 M; 66 mL). The aqueous solution
was basified to a pH 8–9 and extracted with CH2Cl2. The
combined organic phases were dried (Na2SO4) and rotary
evaporated to afford 2 (8.1 g, 90%) as a pale yellow oil; IR
(thin film) 3291, 1623, 1468, 1447, 1341, 1150, 718 cmK1
.
1H NMR (300 MHz, CDCl3) d 6.08–5.88 (m, 2H), 2.80–
2.74 (m, 2H), 2.57–2.54 (m, 1H), 2.41–2.36 (m, 3H),
2.34–2.14 (m, 2H), 1.85–1.77 (m, 1H), 1.28–1.10 (m, 3H),
0.50–0.46 (m, 1H); 13C NMR (75 MHz, CDCl3) d 137.2,
132.1, 56.7, 49.5, 44.3, 42.3, 39.1, 36.8, 30.6; MS (CI, NH3)
1
1141, 1086, 994, 911, 828, 716, 666, 624 cmK1; H NMR
(300 MHz, CDCl3) d 8.60 (d, JZ2.0 Hz, 1H), 7.82 (dd, JZ
2.0, 8.3 Hz, 1H), 7.28 (d, JZ8.3 Hz, 1H); 13C NMR
(75 MHz, CDCl3) d 156.2, 146.6, 145.5, 130.0, 91.8; MS

12038
A. G. M. Barrett et al. / Tetrahedron 61 (2005) 12033–12041
(EI, m/z) 283 (M%C), 237, 204, 156, 127; calcd for
C5H3BrIN: (MC%), 282.8494; found: (MC%), 282.8497.
Anal. calcd for C5H3BrIN: C, 21.15; H, 1.06; N, 4.93.
Found: C, 21.14; H, 0.95; N, 4.87.
4.1.8. Polystyrene-supported norbornene (13). endo/exo-
Bicyclo[2.2.1]hept-5-en-2-ylmethanol (12) (2.5 g, 20 mmol)
and KH (0.8 g, 20 mmol) were added to Merrifield resin
(Polymer Labs, 75–150 mm, 0.9 mmol/gK1; 10 g) in DMF
(100 mL). The mixture was heated at 60 8C for 16 h,
quenched with MeOH and filtered, washed with DMF (3!
30 mL), CH2Cl2 (3!30 mL) and MeOH (3!30 mL) and
dried to afford resin beads 13 (10.6 g, 76%, 0.65 mmol/gK1);
IR (film) 1094, 1017, 857, 819 cmK1. Anal. calcd: C, 89.96,
H; 7.82. Found C, 89.99; H, 7.98.
4.1.5. 2-Bromo-5-(exo-bicyclo[2.2.1]hept-2-en-5-yl)pyri-
dine (7). Norbornadiene (3.0 mL, 28 mmol), (Ph3P)2-
Pd(OAc)2 (266 mg, 0.35 mmol), piperidine (2.1 mL,
21 mmol) and HCO2H (0.6 g, 0.5 mL, 14 mmol) were
added to 2-bromo-5-iodopyridine 6 (2.0 g, 7.0 mmol) in
DMF (5 mL) and the suspension was slowly heated to 55 8C
and maintained at that temperature for 12 h. The solution
was diluted with H2O (100 mL) and extracted with Et2O
(3!50 mL). The combined organic phases were washed
with brine (200 mL), dried (Na2SO4), rotary evaporated and
chromatographed (hexane/EtOAc 97:3) to afford 7 (1.84 g,
66%) as a clear oil; IR (film) 1573, 1555, 1451, 1384, 1331,
1316, 1285, 1251, 1200, 1133, 1088, 1020, 1003, 947, 904,
827, 776, 733, 714, 650 cmK1; 1H NMR (300 MHz, CDCl3)
d 8.29 (s, 1H), 7.44 (m, 2H), 6.23 (m, 2H), 3.02 (s, 1H), 2.89
(s, 1H), 2.67 (t, JZ6.7 Hz, 1H), 1.68 (dd, JZ1.8. 6.7 Hz,
2H), 1.48 (s, 2H); 13C NMR (75 MHz, CDCl3) d 149.8,
140.8, 139.0, 137.6, 136.8, 127.5, 47.9, 45.6, 42.4, 40.9,
33.6; MS (EI) m/z 250 (M%C), 184, 104. Anal. calcd for
C12H12BrN: C, 57.63; H, 4.83, N, 5.60. Found: C, 57.71, H,
4.71, N, 5.58.
4.1.9. ROMPsphere-supported fluoroformamidium hexa-
fluorophosphate (14). Resin 13 (1.00 g) was suspended in
CH2Cl2 (9 mL) and agitated for 15 min, the solvent was
removed by decantation and catalyst 11 (255 mg, 3 mmol)
in CH2Cl2 (1.5 mL) was added and agitation continued for
45 min. The resin was thoroughly washed with CH2Cl2 and
2-PrOH, suspended in CH2Cl2 (10 mL) and monomer 4
(3.00 g, 14 mmol) in CH2Cl2 (15 mL) was added. After
agitating for 3 h, the resin was washed with CH2Cl2 and
Et2O (3!3 mL) and dried to yield the ROMPsphere
supported reagent 14 (2.0 g, 1.45 mmol). Anal. calcd C,
62.36; H, 6.70, N, 3.93. Found C, 62.7; H, 6.86; N, 3.52.
4.1.10. ROMPsphere-supported 2-Bromo-1-ethylpyridi-
nium tetrafluoroborate (15). The resin 13 (200 mg) was
suspended in CH2Cl2 (6 mL) and agitated for 15 min, the
solvent was removed by decantation and catalyst 11 (60 mg,
0.6 mmol) in CH2Cl2 (1.5 mL) was added and agitation
continued. After 15 min, the resin was further diluted with
CH2Cl2 (6 mL) and agitated for an additional 1 h, and
thoroughly washed with CH2Cl2. Monomer 8 (600 mg,
1.6 mmol) in CH2Cl2 (3 mL) was added to the resin and
agitation continued for 12 h. The resin was washed with
CH2Cl2 and Et2O (3!3 mL) and dried to yield the
ROMPsphere reagent 15 (636 mg, 1.8 mmol/gK1); IR
(film) 1733, 1499, 1288, 1052, 864 cmK1. Anal. calcd C,
57.95; H, 5.54; N, 2.75. Found C, 58.37; H, 5.93; N, 2.31.
4.1.6. 2-Bromo-5-(exo-bicyclo[2.2.1]hept-2-en-5-yl)-1-
ethylpyridinium tetrafluoroborate (8). Et3OBF4 (874 mg,
4.60 mmol) in CH2Cl2 (3 mL) was added dropwise to pyri-
dine 7 (1.1 g, 4.4 mmol) in CH2Cl2 (3 mL) at 0 8C. After 3 h
at 25 8C, the solution was heated to reflux for 30 min. The
salt was precipitated upon the addition of Et2O (12 mL) at
0 8C, filtered and dried to afford salt 8 (1,36 g, 81%) as a
white solid: mp 174–176 8C (Et2O); IR (film) 1617, 1571,
1507, 1468, 1391, 1332, 1287, 1213, 1163, 1053, 903, 836,
1
797, 734, 713, 664 cmK1; H NMR (300 MHz, CDCl3) d
8.94 (s, 1H), 8.22 (m, 2H), 6.22 (m, 2H), 4.87 (q, JZ7.2 Hz,
2H), 3.04 (s, 2H), 2.89 (t, JZ6.7 Hz, 1H), 1.77 (m, 2H),
1.64 (t, JZ7.2 Hz, 3H), 1.46 (s, 2H); 13C NMR (75 MHz,
CDCl3) d 148.0, 147.1, 145.4, 138.1, 136.7, 133.7, 133.3,
59.4, 47.9, 45.6, 42.7, 41.5, 33.7, 15.5; MS (FABC) m/z 278
(MC), 212, 89, 77; calcd for C14H17BrN: (MC), 278.0554;
found: (MC), 278.0544. Anal. calcd for C14H17BBrF4N: C,
45.94; H, 4.68; N, 3.83. Found: C, 45.87, H, 4.68; N, 3.78.
4.2. General procedure for amide synthesis using
ROMPgel reagent 10
i-Pr2NEt (3 equiv) was added to acid 16 (0.07–0.11 mmol)
and ROMPgel 10 (2 equiv) in CH2Cl2 (0.5 mL). After 0.5 h,
piperidine (6.9–11.0 mL; 1 equiv) was added and the
mixture shaken for 12 h. Amberlite MB1 ion exchange
resin was added and the mixture shaken for a further 3.5 h.
Filtration and rotary evaporation gave amide 17e56
(22.2 mg, 81% yield, 88% purity): mp 85.5–87.5.0 8C;
lit56 86–87 8C.
4.1.7. N,N0,N0-Trimethylfluoroformamidinium hexafluor-
ophosphate functionalized ROMPgel (10). Catalyst 11
(2.7 mg, 3.17 mmol) in ClCH2CH2Cl (0.25 mL) was added
to monomer 4 (225.8 mg, 0.63 mmol) and cross-linker 9
(24.9 mg, 0.09 mmol) in ClCH2CH2Cl (1 mL). The mixture
was heated at 50 8C for 0.5 h and allowed to cool to 25 8C.
After 16 h, CH2Cl2 (1 mL), CH3CN (0.5 mL) and ethyl vinyl
ether (0.5 mL) were added and the mixture heated to 50 8C for
1.5 h. After cooling, the mixture was cooled to 25 8C, filtered
and the ROMPgel extracted with CH2Cl2 (3!20 mL), THF
(2!20 mL) and Et2O (3!20 mL) followed by concentration
in vacuo to give ROMPgel 10 (252.4 mg, 100%) as a white
4.2.1. 12-Isopropyl-2,6-dimethyltricyclo[8.4.0.0]tetra-
deca-1(14),10,12-trien-6-yl-piperidinomethanone (17a).
(24.0 mg, 87% yield, 88% purity) as a clear yellow oil: Rf
0.60 (EtOAc/hexanes 1:1); IR (CHCl3) 1625, 1457, 1409,
1247, 1120, 1012, 910 cmK1; 1H NMR (300 MHz, CDCl3)
d 7.17 (d, JZ8.0 Hz, 1H), 7.00 (d, JZ7.6 Hz, 1H), 6.91 (s,
1H), 3.66–3.52 (m, 4H), 3.03–2.94 (m, 1H), 2.91–2.79 (m,
2H), 2.35–2.26 (m, 2H), 1.84–1.30 (m, 13H), 1.33 (s, 3H),
1.24 (s, 3H), 1.23 (s, 3H), 1.21 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 176.9, 147.1, 145.5, 135.2, 127.0, 124.1, 123.6,
47.0, 46.7, 45.2, 44.7, 37.6, 37.5, 35.2, 33.4, 30.7, 26.2,
25.5, 24.7, 23.9, 22.1, 18.9, 15.7; MS (CI, NH3) m/z 368
solid; IR (solid) 1640, 1457, 1407, 1250, 1099, 834 cmK1
.
Anal. calcd for C13.04H20.26P0.87F6.09N1.74: C, 45.53; H, 5.94;
N, 7.08. Found: C, 45.43; H, 5.80; N, 6.95.

A. G. M. Barrett et al. / Tetrahedron 61 (2005) 12033–12041
12039
(MCH)C; HRMS (CI, NH3) calcd for C25H38NO (MC
H)C, 368.2953; found: (MCH)C, 368.2952.
67.3, 56.6, 52.7, 44.6, 24.7; HRMS (CIC, NH4) calcd for
C15H21N2O5: (MCH)C, 309.1458; found: (MCH)C,
309.1451.
4.2.2. 1-[(1-Methylcyclohexyl)carbonyl]piperidine (17b).
(14.9 mg, 98% yield, 97% purity) as a clear colorless oil: Rf
0.50 (EtOAc/hexanes 1:1); IR (CHCl3) 1696, 1629, 1592,
1448, 1127, 1104, 1014 cmK1; 1H NMR (300 MHz, CDCl3)
d 3.56 (m, 4H), 2.04–2.01 (m, 2H), 1.64–1.16 (m, 14H),
1.23 (s, 3H); 13C NMR (75 MHz, CDCl3) d 173.4, 46.4,
44.6, 37.1, 35.1, 26.3, 26.0, 25.6, 24.8, 24.2, 23.1, 22.9,
15.7; MS (CI, NH3) m/z 210 (MCH)C; HRMS (CI, NH3)
calcd for C13H24NO (MCH)C210.1858; found: (MCH)C,
210.1859.
4.3.2. N-Fmoc-Aib-Gly-OEt (20g). (67 mg, 85%); IR
(film) 3343, 1715, 1669, 1524, 1449, 1254, 1191, 1091,
909, 824, 736 cmK1; 1H NMR (300 MHz, CDCl3) d 7.80 (br
d, JZ7.2 Hz, 2H), 7.62 (d, JZ7.2 Hz, 2H), 7.41 (t, JZ
7.2 Hz, 2H), 7.32 (t, JZ7.2 Hz, 2H), 6.10 (br s, 1H), 5.31
(br s, 1H), 4.23 (m, 3H), 4.13 (q, JZ7.1 Hz, 2H), 3.89 (m,
2H), 1.54 (s, 6H), 1.29 (t, JZ7.1 Hz, 3H); 13C NMR
(75 MHz, CDCl3) d 174.8, 170.2, 156.2, 143.7, 140.5,
128.1, 127.4, 123.2, 120.1, 66.9, 61.9, 56.8, 47.6, 42.9, 25.8,
25.5, 14.5; HRMS (CIC, NH4) calcd for C23H26N2O5:
(M%C), 410.1842; found: (M%C), 410.1844.
4.2.3. 1-(3-Methyl-2-phenylbutanoyl)piperidine (17c).
(12.5 mg, 73% yield, 88% purity) as a clear yellow oil; Rf
0.50 (EtOAc/hexanes 1:1); IR (CHCl3) 1639, 1442, 1247,
4.3.3. N-Fmoc-Aib-L-Ala-OEt (20h). (65 mg, 80%); IR
(film) 3343, 1731, 1655, 1522, 1449, 1254, 1153, 1090, 910,
1221, 1138, 1108, 1016, 772, 700 cmK1 1H NMR
;
1
735 cmK1; H NMR (300 MHz, CDCl3) d 7.80 (br d, JZ
(300 MHz, CDCl3) d 7.33–7.18 (m, 5H), 3.53–3.37 (m,
4H), 3.31 (d, JZ10.0 Hz, 1H), 2.51–2.41 (m, 1H), 1.58–
1.35 (m, 5H), 1.10–1.07 (m, 1H), 1.01 (d, JZ6.4 Hz, 3H),
0.66 (d, JZ6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) d
171.3, 139.5, 128.5, 128.4, 126.7, 56.2, 46.8, 43.2, 31.9,
26.3, 25.5, 24.6, 22.3, 20.4; MS (CI, NH3) m/z 263 (MC
NH4)C246 (MCH)C; HRMS (CI, NH3) calcd for C16H24NO
(MCH)C246.1858; found: (MCH)C, 246.1850.
7.2 Hz, 2H), 7.62 (d, JZ7.2 Hz, 2H), 7.41 (t, JZ7.2 Hz,
2H), 7.32 (t, JZ7.2 Hz, 2H), 6.72 (br s, 1H), 5.34 (br s, 1H),
4.55 (m, 1H), 4.43 (m, 2H), 4.23 (m, 3H), 1.55 (s, 6H), 1.41
(d, JZ6.57 Hz, 3H), 1.28 (m, 3H); 13C NMR (75 MHz,
CDCl3) d 174.2, 173.3, 155.4, 144.3, 141.7, 128.1, 127.4,
125.4, 120.1, 66.9, 61.9, 57.2, 47.6, 42.9, 25.5, 18.7, 14.5;
MS (CIC, NH4) 58 (32), 118 (86), 179 (78), 198 (89), 203
(40), 229 (15), 299 (14), 340 (340), 357 (94), 425 (6) HRMS
(CIC, NH4) calcd for C24H28N2O5: (M%*******C), 424.1998;
found: (M%C), 424.2001.
4.2.4. 1-(3,3-Dimethyl-2-phenylbutanoyl)piperidine
(17d). (17.5 mg, 95% yield, 90% purity) as a white solid:
Rf 0.80 (EtOAc/hexanes, 1:1); mp 73.0–75.0 8C; IR
(CHCl3) 1620, 1456, 1437, 1264, 1136, 1016, 850,
1
737 cmK1; H NMR (300 MHz, CDCl3) d 7.35–7.21 (m,
Acknowledgements
5H), 3.64–3.58 (m, 1H), 3.56 (s, 1H), 3.43–3.32 (m, 3H),
1.58–1.35 (m, 6H), 1.04 (s, 9H); 13C NMR (75 MHz,
CDCl3) d 171.0, 137.4, 130.2, 127.8, 126.6, 57.1, 47.3, 42.8,
34.8, 28.3, 26.1, 25.6, 24.6; MS (CI, NH3) m/z 260 (MC
H)C; HRMS (CI, NH3) calcd for C17H26NO (MC
H)C260.2014; found: (MCH)C, 260.2014.
We thank GlaxoSmithKline for the highly-valued endow-
ment (to A.G.M.B.); the EPSRC, the EU (Marie Curie Intra-
European Fellowship to J.K.), Pfizer and Merck KGaA for
generous research support, the Royal Society and the
Wolfson Foundation for a Royal Society-Wolfson Research
Merit Award (to A.G.M.B.) and for establishing the
Wolfson Centre for Organic Chemistry in Medical Sciences
at Imperial College London and Mettler Toledo-Bohdan for
the generous loan of two Miniblocks.
4.3. General procedure for dipeptide synthesis using
ROMPsphere reagents 14 and 15
ROMPspheres 14 or 15 (0.4 mmol) and isoPr2NEt (104 mL,
0.6 mmol) were added to the N-protected a-aminoacid 18
(0.2 mmol) and the hydrochloric salt of the a-aminoester 19
(0.2 mmol) in CH2Cl2 (1 mL) and the mixture was shaken
for 12 h at 25 8C. Amberlite MB11 (ion exchange resin,
0.5 g) was added and shaking continued for 1 h. The
suspension was filtered and the remaining solid was
subsequently washed with CH2Cl2 (2!2 mL) and MeOH
(2!2 mL) and rotary evaporated to afford the desired
peptide 20: N-Cbz-Gly-L-Phe-OEt (20a)57 (71 mg, 96%);
Boc-Aib-Gly-OEt (20b)58 (56 mg, 97%); Boc-Aib-Aib-
OMe (20d)59 (54 mg, 90%); N-Cbz-L-Leu-Gly-OEt
(20e)60 (15 mg, 89%); N-Cbz-Gly-L-Phe-L-Val-OMe
(20f)42 (89 mg, 95%).
References and notes
1. (a) Merrifield, R. B. J. Am. Chem. Soc. 1963, 85, 2149.
(b) Letsinger, R. L.; Kornet, M. J. J. Am. Chem. Soc. 1963, 85,
3045.
2. Geysen, H. M.; Meloen, R. H.; Barteling, S. J. Proc. Natl.
Acad. Sci. USA 1984, 81, 3998.
3. Stavenger, R. A.; Schreiber, S. L. Angew. Chem. Int. Ed. 2001,
40, 3417.
´
´
4. (a) Furka, A.; Sebestyen, F.; Asgedom, M.; Dibo, G. Int. J.
Pept. Protein Res. 1991, 37, 487. (b) Lam, K. S.;
Salmon, S. E.; Hersh, E. M.; Hruby, V. J.; Kazmierski,
W. M.; Knapp, R. J. Nature 1991, 354, 82. (c) Houghten,
R. A.; Pinilla, C.; Blondelle, S. E.; Appel, J. R.; Dooley, C. T.;
Cuervo, J. H. Nature 1991, 354, 84. (d) Tan, D. S.; Foley,
M. A.; Shair, M. D.; Schreiber, S. L. J. Am. Chem. Soc. 1998,
120, 8565.
4.3.1. Z-Gly-Aib-OMe (20c). (60 mg, 97%); IR (film)
3331, 1731, 1670, 1533, 1457, 1387, 1274, 1153, 1051, 978,
1
698 cmK1; H NMR (300 MHz, CDCl3) d 7.31 (br s, 5H),
6.71 (br s, 1H), 5.55 (br s, 1H), 5.11 (s, 2H), 3.84 (d, JZ
5.2 Hz, 2H), 3.71 (s, 3H), 1.52 (s, 6H); 13C NMR (75 MHz,
CDCl3) d 174.8, 168.2, 156.6, 136.1, 128.6, 128.2, 128.0,

12040
A. G. M. Barrett et al. / Tetrahedron 61 (2005) 12033–12041
5. (a) Pirrung, M. C.; Chen, J. J. Am. Chem. Soc. 1995, 117, 1240.
(b) Carell, T.; Wintner, E. A.; Bashir-Hashemi, A.; Rebek, J.,
Jr. Angew. Chem. 1994, 33, 2059.
Poon, K. W. C.; Flynn, D. L.; Hanson, P. R. Tetrahedron Lett.
2003, 44, 7187. (c) Flynn, D. L.; Hanson, P. R.; Berk, S. C.;
Makara, G. M. Curr. Opin. Drug Discov. Dev. 2002, 5, 571.
(d) Moore, J. D.; Herpel, R. H.; Lichtsinn, J. R.; Flynn, D. L.;
Hanson, P. R. Org. Lett. 2003, 5, 105. (e) Harned, A. M.;
Mukherjee, S.; Flynn, D. L.; Hanson, P. R. Org. Lett. 2003, 5,
15. (f) Zhang, M.; Vedantham, P.; Flynn, D. L.; Hanson, P. R.
J. Org. Chem. 2004, 69, 8340. (g) Zhang, M.; Moore, J. D.;
Flynn, D. L.; Hanson, P. R. Org. Lett. 2004, 6, 2657.
26. Roberts, R. S. J. Comb. Chem. 2005, 7, 21.
6. (a) Ley, S. V.; Baxendale, I. R.; Bream, R. N.; Jackson, P. S.;
Leach, A. G.; Longbottom, D. A.; Nesi, M.; Scott, J. S.; Storer,
R. I.; Taylor, S. J. J. Chem. Soc., Perkin Trans. 1 2000, 23,
3815. (b) Kirschning, A.; Monenschein, H.; Wittenberg, R.
Angew. Chem. Int. Ed. 2001, 40, 650.
7. (a) Caldarelli, M.; Habermann, J.; Ley, S. V. Bioorg. Med. Chem.
Lett. 1999, 9, 2049. (b) Habermann, J.; Ley, S. V.; Smith, R.
J. Chem. Soc., Perkin Trans. 1999, 2421. (c) Habermann, J.; Ley,
S. V.; Scicinski, J. J.; Scott, J. S.; Smits, R.; Thomas, A. W.
J. Chem. Soc., Perkin Trans. 1 1999, 2425. (d) Cohen, B. J.;
Kraus, M. A.; Patchornik, S. J. Chem. Soc., Chem. Commun.
1982, 1309.
27. Lee, B. S.; Mahajan, S.; Clapham, B.; Janda, K. D. J. Org.
Chem. 2004, 69, 3319.
¨
28. (a) Barrett, A. G. M.; Hopkins, B. T.; Kobberling, J. Chem.
Rev. 2002, 102, 3301. (b) Barrett, A. G. M.; Tedeschi, L.
Special. Chem. Magazine 2003, 23, 42. (c) Harned, A. M.;
Zhang, M.; Vedantham, P.; Mukherjee, S.; Herpel, R. H.;
Flynn, D. L.; Hanson, P. R. Aldrichimica Acta 2005, 38, 3.
(d) For a review of polymer-supported coupling reagents
see Katritzky, A. R.; Suzuky, K.; Singh, S. K. ARKIVOC 2004,
I, 12.
8. Caldarelli, M.; Baxendale, I. R.; Ley, S. V. Green. Chem.
2000, 9, 43.
9. (a) Rademann, J. PCT Int. Appl. 2002, WO 2002074744. (b)
Takemoto, T.; Yasuda, K.; Ley, S. V. Synlett 2001, 10, 1555.
(c) Hinzen, B.; Ley, S. V. J. Chem. Soc., Perkin Trans. 1 1997,
1907. (d) Abraham, S.; Rajan, P. K.; Sreekumar, K. Polym. Int.
1998, 45, 271. (e) Harrison, C. R.; Hodge, P. J. Chem. Soc.,
Perkin Trans. 1 1976, 2252.
29. Sarges, R.; Witkop, B. J. Am. Chem. Soc. 1965, 87, 2011.
30. (a) Pandey, R. C.; Meng, H.; Cook, J. C., Jr.; Rinehart, K. L.,
¨
Jr. J. Am. Chem. Soc. 1977, 99, 5203. (b) Bruckner, H.; Konig,
10. (a) Gibson, H. W.; Bailey, F. C. J. Chem. Soc., Chem.
Commun. 1977, 815. (b) Tamami, B.; Goudarzian, N. J. Chem.
Soc. Chem. Commun. 1994, 1079. (c) Hu, J.-B.; Zhao, G.;
Ding, Z.-D. Angew. Chem. Int. Ed. 2001, 40, 1109.
11. (a) Bongini, A.; Cainelli, G.; Contento, M.; Manescalchi, F.
Synthesis 1980, 143. (b) Esteves, M. A.; Narender, N.;
Gigante, B.; Marcelo-Curto, M. J.; Alvarez, F. Synth.
Commun. 1999, 29, 275.
W. A.; Greiner, M.; Jung, G. Angew. Chem. Int. Ed. 1979, 18,
476. (c) Walker, M. A.; Heathcock, C. H. J. Org. Chem. 1992,
57, 5566. (d) Carmeli, S.; Moore, R. E.; Patterson, G. M. L.;
Corbett, T. H.; Valeriote, F. A. J. Am. Chem. Soc. 1990, 112,
8195.
31. Humphrey, J. M.; Chamberlin, A. R. Chem. Rev. 1997, 97,
2243.
32. Leplawy, M. T.; Jones, D. S.; Kenner, G. W.; Sheppard, R. C.
Tetrahedron 1960, 11, 39.
12. (a) Castells, J.; Font, J.; Virgili, A. J. Chem. Soc., Perkin
Trans. 1 1979, 1. (b) Yamato, T.; Hideshima, C.; Prakash,
G. K. S.; Olah, G. A. J. Org. Chem. 1991, 56, 3955.
13. (a) Dai, L.-X. Angew. Chem. Int. Ed. 2004, 43, 5726. (b) McMorn,
P.; Hutchings, G. J. Chem. Soc. Rev. 2004,33,108.(c)Uozumi,Y.;
Danjo, H.; Hayashi, T. J. Org. Chem. 1999, 64, 3384.
14. Barrett, A. G. M.; Cramp, S. M.; Roberts, R. S.; Zecri, F. J.
Org. Lett. 1999, 1, 579.
33. Nagaraj, R.; Balaram, P. Tetrahedron 1981, 37, 1263.
34. Castro, B.; Dormoy, J. R.; Evin, G.; Selve, C. Tetrahedron
Lett. 1975, 1219.
35. Coste, J.; Le-Nguyen, D.; Castro, B. Tetrahedron Lett. 1990,
31, 205.
36. Dourtoglou, V.; Ziegler, J.-C.; Gross, B. Tetrahedron Lett.
1978, 19, 1269.
37. Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397.
15. Barrett, A. G. M.; Cramp, S. M.; Hennessy, A. J.; Procopiou,
P. A.; Roberts, R. S. Org. Lett. 2001, 3, 271.
`
38. (a) Chinchilla, R.; Dodsworth, D. J.; Najera, C.; Soriano, J. M.
16. Arnauld, T.; Barrett, A. G. M.; Hopkins, B. T.; Zecri, F. J.
Tetrahedron Lett. 2001, 42, 8215.
Tetrahedron Lett. 2000, 41, 2463. (b) Donati, D.; Morelli, C.;
Porcheddu, A.; Taddei, M. J. Org. Chem. 2004, 69, 9316.
(c) Crosignani, S.; Gonzalez, J.; Swinnen, D. Org. Lett. 2004,
6, 4579. (d) Convers, E.; Tye, H.; Whittaker, M. Tetrahedron
Lett. 2004, 45, 3401.
˚
¨
17. Arstad, E.; Barrett, A. G. M.; Hopkins, B. T.; Kobberling, J.
Org. Lett. 2002, 4, 1975.
18. (a) Barrett, A. G. M.; Cramp, S. M.; Roberts, R. S.; Zecri, F. J.
Org. Lett. 2000, 2, 261. (b) Barrett, A. G. M.; Cramp, S. M.;
Roberts, R. S.; Zecri, F. J. Comb. Chem. High Throughput
Screening 2000, 3, 131.
39. Li, P.; Xu, J. C. Tetrahedron Lett. 1999, 40, 8301.
40. Li, P.; Xu, J. C. Tetrahedron Lett. 1999, 40, 3605.
41. (a) Carpino, L. A.; El-Faham, A. J. Am. Chem. Soc. 1995, 117,
5401. (b) El-Faham, A. Chem. Lett. 1998, 671.
19. Arnauld, T.; Barrett, A. G. M.; Hopkins, B. T. Tetrahedron
Lett. 2002, 43, 1081.
˚
20. Arstad, E.; Barrett, A. G. M.; Tadeschi, L. Tetrahedron Lett.
42. (a) Li, P.; Xu, J. C. Tetrahedron 2000, 56, 8119. (b) Li, P.; Xu,
J. C. J. Peptide Res. 2001, 58, 129. (c) Saigo, K.; Usui, M.;
Kikuchi, K.; Shimada, E.; Mukaiyama, T. Bull. Chem. Soc.
Jpn 1977, 50, 1863. (d) Shoda, S.; Mukaiyama, T. Chem. Lett.
1980, 391.
2003, 44, 2703.
21. Arnauld, T.; Barrett, A. G. M.; Seifried, R. Tetrahedron Lett.
2001, 42, 7899.
22. Barrett, A. G. M.; Hopkins, B. T.; Love, A. C.; Tedeschi, L.
Org. Lett. 2004, 6, 835.
43. (a) Cros, S.; Moisand, C.; Tollon, Y. Ann. Pharm. Fr. 1972, 30,
585. (b) Stula, E. F.; Krauss, W. C. Toxicol. Appl. Pharmacol.
1977, 41, 35.
23. Barrett, A. G. M.; Love, A. C.; Tedeschi, L. Org. Lett. 2004, 6,
3377.
44. Larroche, C.; Laval, J. P.; Lattes, A.; Basset, J. M. J. Org.
Chem. 1984, 49, 1886.
´ ´
45. Bailen, M. A.; Chinchilla, R.; Dodsworth, D. J.; Najera, C.
24. Arnauld, T.; Barrett, A. G. M.; Cramp, S. M.; Roberts, R. S.;
Zecri, F. Org Lett. 2000, 2, 2663.
25. (a) Moore, J. D.; Byrne, R. J.; Vedantham, P.; Flynn, D. L.;
Hanson, P. R. Org. Lett. 2003, 5, 4241. (b) Mukherjee, S.;
J. Org. Chem. 1999, 64, 8936.
46. Loren, J. C.; Siegel, J. S. Angew. Chem., Int. Ed. 2001, 40, 754.

A. G. M. Barrett et al. / Tetrahedron 61 (2005) 12033–12041
12041
47. Arcadi, A.; Marinelli, F.; Bernocchi, E.; Cacchi, S.; Ortar, G. J.
Organomet. Chem. 1989, 368, 249.
52. Van der Auwera, C.; Van Damme, S.; Anteunis, M. J. O.; Int,
J. Peptide Protein Res. 1987, 29, 464.
48. Balli, H.; Kersling, F. Liebigs Ann. Chem. 1961,
647, 1.
53. Williams, M. W.; Young, G. T. J. Chem. Soc. 1963, 881.
54. Gerritz, S. W.; Selfer, A. M. J. Comb. Chem. 2000, 2, 39.
55. Bowman, W. R.; Clark, D. N.; Marmon, R. J. Tetrahedron
1994, 50, 1275.
49. Barrett, A. G. M.; Cramp, S. M.; Roberts, R. S. Org. Lett.
1999, 1, 1083.
50. (a) Lindsley, C. W.; Hodges, J. C.; Filzen, G. F.;
Watson, B. M.; Geyer, A. G. J. Comb. Chem. 2000, 2, 550.
(b) Hodges, J. C.; Harikrishnan, L. S.; Ault-Justus, S. J. Comb.
Chem. 2000, 2, 80. (c) McAlpine, S. R.; Lindsley, C. W.;
Hodges, J. C.; Leonard, D. M.; Filzen, G. F. J. Comb. Chem.
2001, 3, 1.
56. Klimko, Y. E.; Isaev, S. D.; Yurchenko, A. G.; Russ J. Org.
Chem. 1994, 30, 1776.
57. Shinagawa, S.; Fujino, M.; Wakimasu, M.; Ishii, H.; Kawai, K.
Chem. Pharm. Bull. 1981, 3646.
58. Barton, D. H. R.; Ferreira, J. A. Tetrahedron 1996, 52, 9367.
59. Saha, A. K.; Rapoport, H.; Schultz, P. J. Am. Chem. Soc. 1989,
111, 4856.
51. Bielawski, C. W.; Grubbs, R. H. Angew. Chem. Int. Ed. 2000,
39, 2903.
60. Castro, B.; Dormoy, J. R. Tetrahedron Lett. 1972, 13, 4747.