Transition metal complexes as linkers for solid phase synthesis: Chromium carbonyl complexes as linkers for arenes

Article abstract of DOI:10.1039/b106582n

Substrates containing aromatic rings have been attached to 'polymer supported triphenylphosphine' using a chromium carbonyl linker, chemically manipulated, and released from the polymer to demonstrate the potential use π-bound ligands in linker chemistry. Immobilisation of the phenylalanine derivative Fmoc-Phe-OtBu via its aromatic ring has been achieved and the resulting resin successfully subjected to standard amino acid deprotection and coupling procedures.

Full text of DOI:10.1039/b106582n

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Transition metal complexes as linkers for solid phase synthesis:
chromium carbonyl complexes as linkers for arenes
Alex C. Comely,a,b Susan E. Gibson (née Thomas),*a,b Neil J. Halesc and Mark A. Peplowb
1
a Department of Chemistry, King’s College London, Strand, London, UK WC2R 2LS
b Department of Chemistry, Imperial College of Science, Technology and Medicine,
South Kensington, London, UK SW7 2AY
c AstraZeneca UK Ltd, Mereside, Alderley Park, Macclesfield, UK SK10 4TG
Received (in Cambridge, UK) 23rd July 2001, Accepted 10th August 2001
First published as an Advance Article on the web 1st October 2001
Substrates containing aromatic rings have been attached to ‘polymer supported triphenylphosphine’ using a
chromium carbonyl linker, chemically manipulated, and released from the polymer to demonstrate the potential
use of π-bound ligands in linker chemistry. Immobilisation of the phenylalanine derivative Fmoc-Phe-OtBu via its
aromatic ring has been achieved and the resulting resin successfully subjected to standard amino acid deprotection
and coupling procedures.
Introduction
Combinatorial chemistry and multiple parallel synthesis are
now established as invaluable approaches to the production of
large numbers of compounds.1 Using polymer supported (or
Scheme 1
‘solid phase’) synthesis, the development of combinatorial
‘linker ligand’ (Scheme 1). Subsequent chemical transform-
chemistry has reached a stage where vast ‘libraries’ of organic
compounds may be stored and processed with relative ease.
The efficiency of solid phase techniques has led to the use of
automation in organic synthesis to an unprecedented degree.
Substrate molecules are generally attached to the polymer via
a covalent bond. Once attached, the immobilised substrate may
be isolated simply by filtration of the polymer from the reaction
mixture. Further organic transformations may then be carried
out while the substrate is bound to the polymer before chemical
cleavage of the final product from the solid support. A legacy of
solid phase peptide synthesis (SPPS) is the release of carboxylic
acid derivatives from an ester or amide-bound substrate. While
entirely appropriate in peptide synthesis, these polar function-
alities are not always desirable in a more general arena. Efforts
to address this problem have, in recent years, stimulated the
evolution of an impressive arsenal of linkers with the ability to
release most functionalities upon cleavage.
ations could then be carried out without cleavage of the sub-
strate and, finally, decomplexation conditions would afford a
transformed organic molecule bearing the intact unsaturated
carbon scaffold. We describe herein experiments that demon-
strate for the first time that this approach to immobilising and
releasing organic molecules is feasible. Part of this work has
been described in a preliminary communication.3
Results and discussion
Ubiquitous in organic chemistry is the unsaturated carbon
scaffold, the arene in particular, and a number of linkers have
been developed which liberate such functionality. An elegant
example is the attachment of aromatic rings to a polymer sup-
port via aryl–silicon bonds that, upon cleavage with anhydrous
HF, afford a product containing an aryl–hydrogen bond.2
We reasoned that a substrate could be attached to a solid
support by a method other than a conventional σ-bond. Many
organic molecules containing an unsaturated moiety may be
complexed with transition metals via a bonding mode described
by the Dewar–Chatt model. Donation of π electrons from the
unsaturated organic molecule into empty dσ orbitals on the
metal is accompanied by donation from filled metal dπ orbitals
into empty π* orbitals on the organic molecule. Futhermore,
decomplexation may often be achieved without any alteration
to the organic species. Examples of compounds which fulfil
these criteria include diene–iron, 1, arene–chromium, 2,
and alkyne–cobalt, 3, complexes. Due to the variety of ligands
which complex with transition metals, it is possible to
bind transition metal species such as 1–3 to a polymer via a
Aromatic rings are one of the most common functionalities in
organic molecules and most may be complexed to chromium
carbonyl moieties.4 Moreover the complexes are resistant to the
conditions of many synthetic reactions, and yet may be decom-
plexed easily under several sets of well-defined conditions.
A
polystyrene-supported phosphine, ‘triphenylphosphine,
polymer-bound’ (PTPP) is commercially available and relatively
inexpensive. As substitution of tricarbonyl(arene)chromium(0)
complexes with phosphines is well established,5 it was envisaged
that the phosphines of this polymer would function as suitable
linker ligands between the polystyrene and the chromium
metal. The phosphorus loading of the commercial polymer
(1.6 mmolP gϪ1) equates to a pendant diphenylphosphine
moiety approximately every 4.2 styrene units. The polystyrene
backbone is cross-linked with 1% divinylbenzene, a percentage
which imparts structural rigidity and strength while also
permitting partial solvation to occur.6 The colourless resin
beads have good swelling properties in widely used solvents
such as THF, DCM and DMF, and poor swelling properties in
aliphatic hydrocarbons and diethyl ether. We thus decided to
2526
J. Chem. Soc., Perkin Trans. 1, 2001, 2526–2531
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b106582n

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attempt to immobilise an (arene)tricarbonylchromium(0) com-
plex onto PTPP, demonstrate that the immobilised organic
molecule could be manipulated whilst bound to the resin via the
metal, and then remove the modified organic product from
the resin.
Commercially available 4-(4-methoxyphenyl)butan-2-one
was heated with hexacarbonylchromium(0) to give the novel
complex 4 as yellow air-stable crystals in 71% yield. Complex 4
(1.1 equivalents) was then irradiated in the presence of PTPP in
THF. Subsequent filtration, washing and drying of the polymer
gave a brown powder that was characterised as predominantly
5 on the basis of its IR and 31P NMR spectra (Scheme 2).
metal–ligand linker with a view to determining whether or not
the arene immobilised amino acid could be manipulated on the
polymer, and products from its reactions subsequently released.
The orthogonally protected phenylalanine derivative Fmoc-
Phe-OtBu 8 was prepared by treatment of -phenylalanine
tert-butyl ester hydrochloride with N-[(fluoren-9-ylmethoxy-
carbonyl)oxy]succinimide, FmocOSu (Scheme 3).10 The Fmoc
protecting group was attractive not only as perhaps the most
widely used protocol for SPPS, but also for the ease with which
the carbamate is cleaved non-hydrolytically using simple
amines, releasing the protected amine as its free base. After
disappointing preliminary results with other Phe derivatives,
these attractions were seen to outweigh any complications that
might arise from the aromatic nature of the Fmoc group in the
complexation step.
As anticipated, direct complexation of Fmoc-Phe-OtBu 8
with hexacarbonylchromium(0) gave the desired complex 9
in 31% yield accompanied by the tricarbonyl(η6-dibenzo-
fulvene)chromium(0) 10 in 16% yield. The photolytic loading
of the Fmoc-protected derivative 9 onto polymer-bound tri-
phenylphosphine was effected by irradiation in THF followed
by filtration, washing and drying of the polymer beads.
Analysis of the resulting resin by 31P NMR and IR spectro-
scopy revealed that the desired resin-bound arene species 11
was found to occupy 70% of the phosphine sites, equating to a
loading of 0.69 mmol[Fmoc-Phe-OtBu] gϪ1. [The remaining
phosphine sites were either unreacted phosphine (10%),
phosphine oxide (15%), polymer–(PPh2)2Cr(CO)4 (5%) or
polymer–PPh2Cr(CO)5.]
Having successfully immobilised a phenylalanine derivative
with an orthogonal protecting set, experiments were under-
taken to assess the stability of the carbonylchromium(0)
linker in the context of established peptide chemistries. Our
efforts were directed towards deprotection of, and subsequent
coupling at, the N-terminus. Hence to the resin beads 11 sus-
pended in DCM under constant nitrogen agitation was added
piperidine (Scheme 4). After 20 minutes the beads were filtered
and washed, and the process repeated. Resin 12 bearing the free
amine was resuspended in DCM and acetylated with excess
triethylamine and acetic anhydride to give resin-bound Ac-Phe-
OtBu 13. 31P NMR spectroscopy of the resin revealed an 8%
loss in occupancy of phosphine sites by the (η6-Ac-Phe-
OtBu)dicarbonyl(phosphine)chromium(0) linker equating to a
loading of 0.71 mmol[Ac-Phe-OtBu] gϪ1. IR spectroscopy data
were consistent with the integrity of the linker and with for-
mation of the amide, identified by an additional absorption at
1677 cmϪ1.
Scheme 2
The former contained strong absorptions at 1870, 1802 cmϪ1
[Cr(CO)2PPh3C6H5OMe7 strongly absorbs at 1886 and 1827
cmϪ1] and 1710 cmϪ1, whilst the latter contained a resonance at
δ 90 [Cr(CO)2PPh3C6H5OMe resonates at δ 91.97]. The 31P
NMR spectrum revealed that the polymer coverage with the
arene chromium dicarbonyl complex was ∼40%, the remainder
of the sites being made up of polymer–PPh2Cr(CO)5 (δ = 56,
20%), polymer–P(O)Ph2 (δ = 29, 10%) and polymer–PPh2
(δ = Ϫ5, 30%) [PPh3Cr(CO)5, δP = 55.3;8 polymer–P(O)Ph2,
δP = 28.8;9 polymer–PPh2, δP = Ϫ6.39]. Polymer 5 was then
reduced with LiAlH4 giving, after work-up, a dark yellow
powder that did not absorb at 1710 cmϪ1. The 31P NMR
spectrum of the reduced material revealed that the loading of 6
on the polymer was 25% indicating some loss of material from
the polymer, perhaps as a result of complex decomposition
resulting from nucleophilic addition at the metal carbonyl
ligands, and representing a yield for this step of 62%. The
reduction product was released from the polymer by heating in
pyridine for 2 h. Filtration, washing the polymer with THF and
diethyl ether, and concentration of the washings gave alcohol 7
of у95% purity. The yield for the release of 7 from the polymer
was 92%.
The above experiments demonstrate that an organic molecule
containing an aromatic ring can be attached to a solid support
via a transition metal–ligand linker, manipulated and sub-
sequently released. Each step in the sequence proceeded
in tolerably good yield (unoptimised). Most encouraging at
this stage, however, was the usefulness of IR and 31P NMR
spectroscopy for obtaining direct information about the
structure and loading of polymer-bound complexes 5 and 6.
We next turned out attention to the immobilisation of the
biologically important molecule phenylalanine via a transition
Cleavage of the linker to liberate the product Ac-Phe-OtBu
1411 was effected by stirring the resin 13, ground to a fine yellow
powder, in DCM in air under white light for 48 h. Filtration of
the mixture through Celite to remove the resulting green–brown
polymeric residue gave a colourless filtrate containing, as indi-
1
cated by H NMR spectroscopy, 14 and minor unidentified
hydrocarbon and aromatic contaminants, possibly fragments of
the polystyrene resin. Peaks characteristic of Fmoc-Phe-OtBu 8
were absent from the spectrum confirming that deprotection
of the amine of 11 is complete under the conditions used.
The crude mixture was purified by chromatography and 14 was
isolated in 77% yield (68% overall from resin 11). The optical
rotation of released 14 was within 2Њ of that quoted in the
literature, demonstrating that the linker methodology did not
affect the optical purity of the amino acid.
Having demonstrated that deprotection and chemical
manipulation of the N-terminus is feasible, peptide coupling
conditions were investigated next. Amine deprotection of
resin 11 and isolation of resin 12 were carried out as described
above. Of the wide variety of peptide coupling conditions
available, it was decided to use the in situ activating agent
benzotriazolyloxytripyrrolidinophosphonium
hexafluoro-
phosphate, PyBOP12. Developed as a substitute to the widely-
J. Chem. Soc., Perkin Trans. 1, 2001, 2526–2531
2527

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used and highly efficient benzotriazolyloxytris(dimethylamino)-
phosphonium hexafluorophosphate (BOP), PyBOP reacts
without the generation of carcinogenic HMPA. Hence, to a
suspension of 12 in DCM was added a solution of diisopropyl-
ethylamine and Fmoc-Val-OH in DCM. Following addition of
PyBOP, the mixture was left under constant nitrogen agitation
for 6 h, then filtered and washed in the usual way. 31P NMR
spectroscopic analysis of the resulting resin-bound dipeptide 15
revealed a 63% phosphorus site occupany, equating to a
10% loss over two steps and a substrate loading of 0.60 mmol-
[Fmoc-Val-Phe-OtBu] gϪ1. Aerial oxidative cleavage of the
chromium(0) linker effected release of the protected dipeptide
of both materials (values within 4Њ) supports retention, to a
large extent, of optical purity.
The experiments described above demonstrate that transition
metal π-complexes may be used as linkers in solid phase syn-
thesis. Although the focus of our first experiments in this area
has been the attachment of arene groups to a phosphine-
containing polymer via a chromium carbonyl linker, several
other possibilities exist, including those indicated by structures
1 and 3, for the immobilisation of common organic motifs via
this approach. Further support for the use of transition metal
linkers has recently been provided by Maiorana et al. who have
developed an attractive chromium(0) linker using a tethered
isocyanide, a ligand electronically very similar to carbon
monoxide. The SNAr reaction between a dicarbonyl(fluoro-
arene)(polymer-bound isocyanide)chromium(0) complex and a
variety of nitrogen nucleophiles was effected with high yields.13
1
Fmoc-Val-Phe-OtBu 16 in 90% yield. Comparison of IR, H
and 13C NMR and mass spectroscopic data with those from 16
prepared by conventional solution phase chemistry confirms
the product’s identity and a comparison of the optical rotations
Scheme 3
Scheme 4
2528
J. Chem. Soc., Perkin Trans. 1, 2001, 2526–2531

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MHz, CDCl3) 27.5 (CH3CO), 30.4 (CH2CO), 45.3 (ArCH2),
56.1 (MeO), 78.2 (MeOCCHCH), 96.3 (MeOCCH), 105.5
Experimental
Reactions under nitrogen were performed using standard
vacuum line and Schlenk tube techniques.14 Diethyl ether,
toluene and hexane were dried over sodium wire. THF was dis-
tilled from sodium benzophenone ketyl. DCM and 1,4-dioxane
were distilled from calcium hydride. All solvents intended for use
in chromatography were used as bought. SiO2 refers to chroma-
tography grade silica of particle size 40–63 µm. Irradiation
was carried out with a 125 W Hg vapour lamp (Cathodeon).
Melting points, which are uncorrected, were determined using a
Gallenkamp capillary melting point apparatus. IR spectra were
obtained on a Perkin-Elmer 1710FTIR spectrometer. NMR
spectra were recorded at room temperature on Bruker DRX300
(300.0 MHz 1H, 75.5 MHz 13C), Bruker DRX500 (500.0 MHz,
1H, 202.4 MHz 31P) (Imperial College) and Bruker AM360
(360.0 MHz 1H, 90.6 MHz 13C, 145.8 MHz 31P), Bruker
AMX400 (400.0 MHz 1H, 100.6 MHz 13C) (King’s College) and
Bruker DPX300 (300.0 MHz 1H, 75.5 MHz 13C) (AstraZeneca
UK Ltd.). Resin samples for NMR were prepared under N2,
were swollen in deoxygenated THF and were scanned with a
D2O capillary lock. Longitudinal relaxation times of the 31P
nuclei were determined using the inverse recovery technique.
Phosphine oxide and transition metal-complexed phosphines
were found to have similar relaxation times of ∼0.07 seconds.
The free phosphine was generally too weak to be measured
accurately but, by inspection, appeared to have a slightly
longer relaxation time of 0.10–0.15 seconds. Based on these
figures, a 90Њ pulse was applied with a relaxation delay of
0.3 seconds. Because resin signals can be broad the FID (free
induction decay) decays rapidly and only a short acquisition
time is required, achieved by data set reduction to between
64 and 1024 words (depending on the sample). As a means
to reduce ‘ringing’ in the spectra, a trapezoidal window
function was used to reduce the last third of the FID to
zero and the remaining data set (4 K words) was ‘zero filled’.
Mass spectra were recorded on VG Micromass 7070E and
AutoSpec-Q instruments at Imperial College, on a VG 70/250
SE spectrometer at AstraZeneca UK Ltd. and on Kratos
MS890MS and JEOL AX505W instruments at King’s College
London. Microanalyses were conducted by the Imperial
College of Science, Technology and Medicine microanalytical
service, by Steven Boyer (S.A.C.S.) at the University of North
London and by MEDAC Ltd., Analytical and chemical con-
sultancy services, Brunel Science Centre. Optical rotation
values were measured at 589 nm on a Perkin-Elmer 241 polar-
imeter using a cell of 1 dm pathlength and are reported in
10Ϫ1 deg cm2 gϪ1.
(MeOCCHCHC), 142.8 (MeOC), 207.1 (C᎐O) and 233.8
᎐
ϩ
᎐
(C᎐O); m/z (E.I.) 314 (M , 5%), 286 (M Ϫ CO, 7), 258
᎐
(M Ϫ 2CO, 3), 230 (M Ϫ 3CO, 100), 215 (M Ϫ 3CO Ϫ Me, 20),
178 [M Ϫ Cr(CO)3, 15], and 121 (MeOC7H6, 80).
[4-(4-Methoxyphenyl)butan-2-one]dicarbonyl(triphenylphos-
phine polymer)chromium(0) 5
Triphenylphosphine polymer (3 mmol gϪ1, 1.59 g, 4.77 mmol)
was stirred in THF (350 cm3) for 1 h before addition of [4-(4-
methoxyphenyl)butan-2-one]tricarbonylchromium(0) 4 (1.65 g,
5.25 mmol). The mixture was irradiated for 3 h, and then
allowed to react in the dark for a further 1 h. The reaction
mixture was transferred by cannula into a 1 dm3 round-
bottomed flask, and the solid allowed to settle. The supernatant
solvent was removed by cannula, and the residual solid washed
with THF (2 × 100 cm3). The solid was then dried in vacuo,
and the title polymer 5 isolated as a brown powder (2.3 g);
νmax(Nujol)/cmϪ1 [polymer–PPh2Cr(CO)2Ar] 1870s, 1802s
᎐
[Cr(C᎐O) ] and 1710s (C᎐O); [polymer–PPhCr(CO) ] 2059m,
᎐
᎐
᎐
3
5
1
1984w and 1933s [Cr(C᎐O) ]; δ { H}(202.4 MHz, CDCl )
᎐
3
P
3
Ϫ5 (30%, polymer–PPh ), 29 (10%, polymer–PPh ᎐O), 56 [20%,
᎐
2
2
polymer–PPh2Cr(CO)5], 90 [40%, polymer–PPh2Cr(CO)2Ar].
31P NMR analysis determined polymer loading with Ar(CO)2-
Cr as 1.20 mmol gϪ1.
[4-(4-Methoxyphenyl)butan-2-ol]dicarbonyl(triphenylphosphine
polymer)chromium(0) 6
[4-(4-Methoxyphenyl)butan-2-one]dicarbonyl(triphenylphos-
phine polymer)chromium(0) 5 (1.2 mmol gϪ1, 40% load), 1 g,
1.2 mmol] was stirred in THF (80 cm3) for 1 h, and then cooled
to 0 ЊC. Lithium aluminium hydride (137 mg, 3.61 mmol) was
dissolved in THF (10 cm3), and the solution added dropwise to
the polymer suspension via a cannula. The mixture was allowed
to warm to room temperature, and stirred for 16 h. Ethyl
acetate (10 cm3) was cautiously added, followed by water
(10 cm3), and the mixture allowed to settle. The supernatant
liquid was removed by cannula, and the remaining solid washed
with THF (2 × 20 cm3) and diethyl ether (20 cm3). The solid was
dried in vacuo, and the title polymer 6 isolated as a dark yellow
powder (0.93 g); νmax(Nujol)/cmϪ1 [polymer–PPh2Cr(CO)2Ar]
᎐
1876s, 1814s [Cr(C᎐O) ], complete absence of ketone absorp-
᎐
3
tion at 1710 cmϪ1; [polymer–PPh2Cr(CO)5] 2060vw and 1929vw
1
᎐
[Cr(C᎐O) ]; δ { H}(202.4 MHz, CDCl ) Ϫ21 (55%, polymer–
᎐
3
P
3
PPh2), 22 (20%, polymer–PPh ᎐O), 54 [trace, polymer–
᎐
2
PPh2Cr(CO)5], 86 [25%, polymer–PPh2Cr(CO)2Ar]. 31P NMR
analysis determined polymer loading with Ar(CO)2Cr as 0.72
mmol gϪ1.
[4-(4-Methoxyphenyl)butan-2-one]tricarbonylchromium(0) 4
Hexacarbonylchromium(0) (2.50 g, 11.4 mmol) was dissolved
in degassed dibutyl ether (80 cm3), and to this mixture was
added 4-(4-methoxyphenyl)butan-2-one (3.03 g, 17.0 mmol) in
degassed THF (8 cm3). The reaction vessel was fitted with an air
condenser below a water condenser. The reaction mixture was
then heated to 140 ЊC for 48 h with complete exclusion of light,
after which time solvents were removed in vacuo. The residual
green sludge was filtered through deactivated alumina (diethyl
ether). The yellow oil obtained was preabsorbed onto silica gel
and purified by column chromatography [SiO2; petrol–diethyl
ether (1 : 1), then diethyl ether], which yielded a yellow solid.
This was subsequently recrystallised [hexane–diethyl ether
(10 : 1)] to yield the title complex 4 as yellow crystals (2.54 g,
71%); mp 54–55 ЊC (Found: C, 53.7; H, 4.5. C14H14CrO5
4-(4-Methoxylphenyl)butan-2-ol 7
[4-(4-Methoxyphenyl)butan-2-ol]dicarbonyl(triphenylphosphine
polymer)chromium(0) 6 [0.72 mmol gϪ1, 25% load, 500 mg, 0.36
mmol] was added to pyridine (10 cm3), the mixture degassed
and subsequently refluxed under a nitrogen atmosphere
for 2 h, during which time the solution became bright red. The
mixture was allowed to cool, and the solid to settle out.
Supernatant liquid was removed via a cannula, and the residual
solid was washed successively with THF (2 × 20 cm3) and
diethyl ether (20 cm3). The organic washings were reduced in
vacuo and filtered through a short pad of silica (diethyl ether).
Diethyl ether was removed in vacuo to afford the title com-
pound 715 as a colourless oil of у95% purity (60 mg, 0.33
mmol, 92%); δH(270.0 MHz, CDCl3) 1.24 [3 H, d, J 6, CH(O-
H)CH3], 1.68–178 [3H, m, CH2CH(OH) and OH], 2.58–2.76
(2H, m, ArCH2), 3.81 (3H, s, OCH3), 3.82–3.86 (1H, m,
CHOH), 6.85 (2H, d, J 8.5, MeOCCH), and 7.14 (2H, d, J 8.5,
MeOCCHCH).
requires C, 53.51; H, 4.49%); νmax(dichloromethane)/cmϪ1
᎐
1957vs, 1863vs [Cr(C᎐O) ] and 1714s (C᎐O); δ (270.0 MHz,
᎐
᎐
3
H
CDCl3) 2.20 (3 H, s, MeCO), 2.56 (2 H, t, J 7, CH2CO), 2.75
(2 H, t, J 7, ArCH2), 3.70 (3 H, s, MeO), 5.13 (2 H, d, J 7,
MeOCCHCH), and 5.54 (2 H, d, J 7, MeOCCH); δC{1H}(75.4
J. Chem. Soc., Perkin Trans. 1, 2001, 2526–2531
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Fmoc-Phe-OtBu 8
(8 H, m, H-9, H-10, H-11, H-12, H-15, H-16, H-17 and H-18);
δC{1H}(90.6 MHz, CDCl3) 28.1 [C(CH3)3], 38.3 (PhCH2), 47.3
(C-7), 55.2 (NHCHCO2), 66.6 (CO2CH2), 83.5 [C(CH3)3], 90.7,
92.9, 93.4, 93.4 and 93.7 (C-2, C-3, C-4, C-5 and C-6), 107.0
(C-1), 120.0 and 120.1 (C-12 and C-15), 124.9, 125.1, 127.2,
127.9, 127.9 and 128.6 (C-9, C-10, C-11, C-16, C-17 and C-18),
141.4 (C-13 and C-14), 143.6 and 143.8 (C-8 and C-19),
155.4 (NHCO2), 169.7 (NCHCO2) and 232.7 [Cr(CO)3]; m/z
(FAB positive) 579 (Mϩ, 1.4%), 524 (MH Ϫ 2CO, 2.6), 495
(M Ϫ 3CO, 33), 439 [MH Ϫ 3CO Ϫ C(CH3)3, 8], 179 (dibenzo-
fulveneH, 30), 147 (PhCH2CHNH2, 28), 91 (PhCH2, 49) and 73
[OC(CH3)3, 100].
To a mixture of -phenylalanine tert-butyl ester hydrochloride
(3.05 g, 11.9 mmol) and N-[(fluoren-9-ylmethoxycarbonyl)-
oxy]succinimide (4 g, 11.9 mmol) in DCM (60 cm3) was added
triethylamine (2.47 cm3, 17.8 mmol) and the resulting solution
was stirred at room temperature under nitrogen for 24 h. Con-
centration in vacuo to a crusty yellow oil and purification by
flash column chromatography (SiO2; Et2O–hexane, 1 : 9 to 2 : 4
gradient elution) gave the title compound 8 (3.94 g, 8.9 mmol,
75%) as a colourless glassy oil (Found: C, 75.9; H, 6.7; N, 3.1.
C28H29NO4 requires C, 75.82; H, 6.59; N, 3.16%); [α]2D5 ϩ23.5
(c = 0.65, DCM); νmax(DCM)/cmϪ1 3416w (NH), 1720s (C᎐O
᎐
ester and carbamate) and 1506m [NHC(O)]; δH(300.0 MHz,
CDCl3) 1.41 [9 H, s, C(CH3)3], 3.09 (2 H, m, CH2Ph), 4.20 (1 H,
br t, J 7, COOCH2CH), 4.29 (1 H, dd, J 7, 11, COOCHH), 4.44
(1 H, dd, J 7, 11, COOCHH), 4.55 (1 H, m, NCHCO2), 5.28
(1 H, br d, J 8, NH) and 7.14–7.77 (13 H, m, H-2, H-3, H-4,
H-5, H-6, H-9, H-10, H-11, H-12, H-15, H-16, H-17 and H-18);
δC{1H}(75.5 MHz, CDCl3) 26.7 [C(CH3)3], 37.2 (CH2Ph), 45.9
(C-7), 53.8 (NHCHCO2), 65.6 (CO2CH2), 81.2 [C(CH3)3],
118.7 (C-12 and C-15), 123.8 and 123.9 (C-9, C-10, C-17 and
C-18), 125.7, 126.4, 127.2 and 128.3 (C-2, C-3, C-4, C-5, C-6,
C-11 and C-16), 134.8 (C-1), 140.0 (C-13 and C-14), 142.9 (C-8
and C-19), 157.2 (NHCO2) and 168.9 (NCHCO2); m/z (CI,
NH3) 443 (Mϩ, 37%), 388 (M Ϫ C4H8, 3), 222 (H-Phe-OtBuH,
100), 179 (C14H11, 30) and 166 (C13H10, 56).
(S)-Dicarbonyl[N-(fluoren-9-ylmethoxycarbonyl)-ꢀ6-phenyl-
alanine tert-butyl ester](polymer-bound triphenylphosphine)-
chromium(0) 11
To a suspension of polymer-bound triphenylphosphine (450 mg,
0.72 mmolP) at ambient temperature in anhydrous THF
(200 cm3) left under constant nitrogen agitation for 20 min was
added tricarbonyl(Fmoc-Phe-OtBu)chromium(0) 9 (500 mg,
0.86 mmol) and the yellow mixture was subjected to periodic
irradiation (4 × 10 min) over a 48 h period. The resulting
deep red beads were filtered, washed thoroughly with alternate
aliquots of THF and Et2O and dried in vacuo to afford the title
resin (732 mg, 0.69 mmol[Fmoc-Phe-OtBu] gϪ1); νmax(Nujol)/
cmϪ1 2061vw and 1936w [polymer–PPh Cr(C᎐O) ], 2005w
᎐
᎐
2
5
᎐
[polymer–(PPh ) Cr(C᎐O) ], 1874vs and 1828s [polymer–
PPh Cr(C᎐O) (Ar)] and 1718m [C(᎐O)OtBu]; δ { H}(202.4
᎐
2
2
4
1
(S)-Tricarbonyl[N-(fluoren-9-ylmethoxycarbonyl)-ꢀ6-phenyl-
alanine tert-butyl ester]chromium(0) 9
᎐
᎐
᎐
2
2
P
MHz, THF-swollen resin, D2O capillary lock) Ϫ3.3 (10%,
polymer–PPh2), 27.4 [15, polymer–P(O)Ph2], 58.0 [trace,
polymer–PPh2Cr(CO)5], 78.4 [5, polymer–(PPh2)2Cr(CO)4] and
93.2 [70, polymer–PPh2Cr(CO)2(Fmoc-Phe-OtBu)]; m/z (FAB
positive) 444 (Fmoc-Phe-OtBuHϩ, 2%), 388 (Fmoc-Phe-
OH ϩ H, 5), 289 [Ph2P(C6H4)CHCH2, 17], 178 (dibenzo-
fulvene, 29), 136 [Cr(CO)3, 100], 120 (Phe Ϫ CO2H, 23), 107
[P(C6H4), 35] and 91 (C7H7, 24). Characterisation of the resin
species was aided by comparison of the resin 31P NMR and
IR spectra with those of dicarbonyl(triphenylphosphine)(η6-
toluene)chromium(0),7 trans-tetracarbonylbis(triphenylphos-
phine)chromium(0)16 and pentacarbonyl(triphenylphosphine)-
chromium(0).8
Fmoc-Phe-OtBu 8 (2 g, 4.51 mmol), hexacarbonylchromium(0)
(1.04 g, 4.74 mmol), anhydrous dibutyl ether (40 cm3) and
anhydrous THF (10 cm3) were combined, and the mixture was
thoroughly deoxygenated and heated to reflux under nitrogen
for 40 h. The resulting red solution was cooled to ambient tem-
perature and the solvent was evaporated at reduced pressure.
Column chromatography (SiO2; hexane–Et2O 49 : 1 to 0 : 1
gradient elution) effected purification of the following products.
(i) Tricarbonyl(ꢀ6-dibenzofulvene)chromium(0) 10 (hexane–
Et2O 19 : 1). As a red solid (225 mg, 0.72 mmol, 16%), mp
135 ЊC dec. [Found: m/z (M) 314.0037, C17CrH10O3 requires
314.0035]; νmax(Et2O)/cmϪ1 1969vs, 1904s [Cr(C᎐O) ]; δ (300.0
᎐
(S)-Dicarbonyl(ꢀ6-phenylalanine tert-butyl ester)(polymer-
bound triphenylphosphine)chromium(0) 12
᎐
3
H
MHz, CDCl3) 5.41 (1 H, t, J 6, H-3 or H-4), 5.52 (1 H, t, J 6,
H-3 or H-4), 5.93 (1 H, s, CHH), 5.97 (1 H, d, J 6, H-2 or H-5),
6.08 (1 H, s, CHH), 6.11 (1 H, d, J 6, H-2 or H-5), 7.36–7.41
(2 H, m, H-9 and H-10), 7.53–7.55 (1 H, m, H-8 or H-11) and
7.66–6.68 (1 H, m, H-8 or H-11); δC{1H}(90.6 MHz, CDCl3)
85.3, 87.4, 90.1 and 91.7 (C-2, C-3, C-4 and C-5), 104.0 and
To a suspension of dicarbonyl(Fmoc-Phe-OtBu)(polymer–
PPh2)chromium(0) 11 (250 mg, 0.17 mmol[Fmoc-Phe-OtBu])
in anhydrous DCM (8 cm3) at ambient temperature was added
piperidine (2 cm3). After 20 mins under constant nitrogen
agitation, the beads were filtered and washed with alternate
aliquots of DCM and Et2O. The process was repeated: re-
suspension in 20% piperidine–DCM (10 cm3) for 10 mins,
filtration and washing as before afforded red beads of the
title compound resin, taken directly to the next coupling step;
νmax(Nujol)/cmϪ1 2061vw and 1936w [polymer–PPh2Cr-
108.4 (C-1 and C-6), 108.5 (C᎐CH ), 120.2, 121.3, 128.9
᎐
2
and 129.3 (C-8, C-9, C-10 and C-11), 127.6 (C᎐CH ), 137.5 and
᎐
2
141.8 (C-7 and C-12) and 233.2 [Cr(CO)3]; m/z (FAB positive)
314 (Mϩ, 65%), 286 (M Ϫ CO, 23), 258 (M Ϫ 2CO, 68),
230 (M Ϫ 3CO, 31), 178 (M Ϫ Cr Ϫ 3CO, 36) and 121
(M Ϫ Cr Ϫ 3CO Ϫ C4H9, 100).
᎐
᎐
(C᎐O) ], 2005w [polymer–(PPh ) Cr(C᎐O) ], 1883vs and 1832s
᎐
᎐
5
2
2
4
᎐
[polymer–PPh Cr(C᎐O) (Ar)] and 1720m [C(᎐O)OtBu].
᎐
᎐
2
2
(ii) Fmoc-Phe-OtBu 8 (hexane–Et2O 19 : 1 to 4 : 1). As a
yellow stained oil (340 mg, 0.77 mmol, 17%).
(S)-(ꢀ6-N-Acetylphenylalanine tert-butyl ester)dicarbonyl-
(polymer-bound triphenylphosphine)chromium(0) 13
(iii) Title complex 9 (hexane–Et2O 0 : 1). As a solid yellow
foam (820 mg, 1.42 mmol, 31%), mp 82–84 ЊC (Found: C,
64.1; H, 5.0; N, 2.2. C31H29CrNO7 requires C, 64.24; H, 5.04;
To
a
suspension of dicarbonyl(H-Phe-OtBu)(polymer–
PPh2)chromium(0) 12 [derived from dicarbonyl(Fmoc-Phe-
OtBu)(polymer–PPh2)chromium(0) 11 (250 mg, 0.17 mmol-
[Fmoc-Phe-OtBu]) as described above] in anhydrous DCM
(8 cm3) at ambient temperature was added first triethylamine
(2 cm3) then acetic anhydride (1 cm3) and the mixture was left
under constant nitrogen agitation for 3 h. The resulting red
beads were filtered, washed thoroughly with alternate aliquots
of DCM and Et2O and dried in vacuo to afford the title resin
N, 2.42%); [α]D20 ϩ16.9 (c = 1.0, DCM); νmax(DCM)/cmϪ1
᎐
1969vs, 1892vs [Cr(C᎐O) ], 1723br (C᎐O ester and carbamate)
᎐
᎐
3
and 1504m [NH(CO)]; δH(300.0 MHz, CDCl3) 1.46 [9 H, s,
C(CH3)3], 2.65 (1 H, dd, J 6, 14, CHHPh), 2.81 (1 H, dd, J 5, 14,
CHHPh), 4.18 (1 H, br t, J 7, COOCH2CH), 4.33–4.44 (2 H, m,
COOCH2), 4.58 (1 H, m, NCHCO2), 4.92 (1 H, d, J 6, NH),
5.09–5.41 (5 H, m, H-2, H-3, H-4, H-5 and H-6) and 7.30–7.79
2530
J. Chem. Soc., Perkin Trans. 1, 2001, 2526–2531

View Online
13 (230 mg, 0.71 mmol[Ac-Phe-OtBu] gϪ1); νmax(Nujol)/cmϪ1
sion was filtered through Celite and the polymeric residue was
᎐
2061vw and 1936w [polymer–PPh Cr(C᎐O) ], 2005w [polymer–
washed with DCM. The combined filtrate and washings were
concentrated at reduced pressure to afford the colourless title
dipeptide (29 mg, 0.054 mmol, 90%); the optical rotation,
᎐
2
5
᎐
(PPh ) Cr(C᎐O) ], 1883vs and 1831s [polymer–PPh2Cr-
᎐
2
2
4
᎐
(C᎐O) (Ar)], 1727m [C(᎐O)OtBu] and 1677m [C(᎐O)N];
᎐
᎐
᎐
2
δP{1H}(202.4 MHz, THF-swollen resin, D2O capillary lock)
Ϫ6.2 (10%, polymer–PPh2), 24.7 [20, polymer–P(O)Ph2], 56.3
[5, polymer–PPh2Cr(CO)5], 73.6 [5, polymer–(PPh2)2Cr(CO)4]
and 90.1 [60, polymer–PPh2Cr(CO)2(Ac-Phe-OtBu)].
IR, H, 13C NMR and mass spectrum of 16 were in excellent
1
agreement with data obtained from a sample of 16 obtained by
solution phase coupling: mp 133–134 ЊC (Found: C, 73.2; H,
7.2; N, 5.3. C33H38N2O5 requires C, 73.04; H, 7.06; N, 5.16%),
[α]2D5 ϩ15.0 (c = 0.8, CHCl3); νmax(neat)/cmϪ1 1732vs (C᎐O
᎐
(S)-N-Acetylphenylalanine tert-butyl ester (Ac-Phe-OtBu) 149
ester), 1692vs (C᎐O amide), 1657vs (C᎐O carbamate) and
᎐
᎐
1538vs [NHC(O)]; δH(360.0 MHz, CDCl3) 0.94 [6 H, m, CH-
(CH3)2], 1.39 [9 H, s, C(CH3)3], 2.10 [1 H, m, CH(CH3)2], 3.08
(2 H, m, CH2Ph), 4.06 (1 H, m, Val-αH), 4.23 (1 H, brt, J 7,
OCH2CH), 4.33 (1 H, dd, J 7, 10, OCHH), 4.46 (1 H, dd, J 7,
10, OCHH), 4.78 (1 H, m, Phe-αH), 5.51 (1 H, d, J 9, NH),
6.43 (1 H, d, J 8, NH) and 7.14–7.78 (13 H, m, H-2 to H-6, H-9
to H-12 and H-15 to H-18); δC{1H}(90.6 MHz, CDCl3) 17.9
and 19.2 [CH(CH3)2], 28.0 [C(CH3)3], 31.4 [CH(CH3)2], 38.2
(PhCH2), 47.2 (C-7), 53.7 (Phe-αC), 60.3 (Val-αC), 67.1
(CO2CH2), 82.5 [C(CH3)3], 120.0 (C-12 and C-15), 125.2, 125.2,
127.1, 127.1, 127.8, 128.5 and 129.5 (C-2 to C-6, C-9 to
C-11 and C-16 to C-18), 136.0 (C- 1), 141.4 (C-13 and C-14),
143.9 (C-8 and C-19), 156.4 (NCOO) and 170.3 and 170.8
(Val NCO, Phe NCO); m/z (FAB positive) 543 (MHϩ, 11%), 487
(Fmoc-Val-Phe-OH ϩ H, 36), 265 (H-Phe-Val-OH ϩ 2H, 22),
179 (dibenzofulvene ϩ H, 100), 136 [Cr(CO)3, 13] and 120
(Phe Ϫ CO2H, 28).
Dicarbonyl(Ac-Phe-OtBu)(polymer–PPh2)chromium(0) 13 (90
mg, 0.064 mmol [Ac-Phe-OtBu]) was ground to a fine yellow
powder with a pestle and mortar, and suspended in DCM
(30 cm3) in a 50 cm3 round-bottomed flask equipped with a
condenser and CaCl2 drying tube and was stirred at ambient
temperature in air under white light (100 W) for 48 h. The
resulting brown suspension was filtered through Celite and
the polymeric residue was washed with DCM. The combined
filtrate and washings were concentrated in vacuo and purified by
flash column chromatography (SiO2; DCM–hexane 0 : 1 to 1 : 4
gradient elution) to afford the colourless title compound 14
(13 mg, 0.049 mmol, 77%), [α]2D5 ϩ58.2 (c = 1.0, CHCl3) [lit.16
[α]2D0 ϩ60 (c = 1.0, CHCl3)]; νmax(neat)/cmϪ1 3300br (NH),
1734vs (C᎐O ester), 1653vs (C᎐O amide) and 1540s [NHC(O)];
᎐
᎐
δH(360.0 MHz, CDCl3) 1.41 [9 H, s, C(CH3)3], 1.99 [3 H,
s, C(O)CH3], 3.06–3.12 (2 H, m, PhCH2), 4.73–4.79 (1 H, m,
NCHCO2), 5.92 (1 H, d, J 8, NH) and 7.13–7.31 (5 H, m,
Ar-H); δC{1H}(90.6 MHz, CDCl3) 23.3 [C(O)CH3], 28.0
[C(CH3)3], 38.1 (PhCH2), 53.5 (NCHCO2), 82.5 [C(CH3)3],
127.0 (Cpara), 128.4 and 129.6 (Cmeta and Cortho), 136.2 (Cipso),
169.5 and 170.9 (NHCO2 and NCHCO2).
Acknowledgements
The authors gratefully acknowledge AstraZeneca UK Ltd for
providing a fully-funded studentship (to ACC).
(S,S)-Dicarbonyl[N-(fluoren-9-ylmethoxycarbonyl)valine-ꢀ6-
phenylalanine tert-butyl ester](polymer-bound triphenylphos-
phine)chromium(0) 15
References
A solution of diisopropylethylamine (0.152 cm3, 0.87 mmol)
and Fmoc-Val-OH (148 mg, 0.44 mmol) in anhydrous DCM
(2 cm3) was added to a suspension of dicarbonyl(H-Phe-
OtBu)(polymer–PPh2)chromium(0) 12 (derived from resin 11,
250 mg, 0.17 mmol [Fmoc-Phe-OtBu]) in anhydrous DCM
(2 cm3) at ambient temperature. PyBOP (227 mg, 0.44 mmol)
was added immediately and the mixture was left under constant
nitrogen agitation for 6 h. The resulting red beads were filtered,
washed thoroughly with alternate aliquots of DCM, methanol
and Et2O and dried in vacuo to afford the title resin 15 (265 mg,
1 (a) A. C. Comely and S. E. Gibson (née Thomas), Angew. Chem.,
Int. Ed., 2001, 40, 1012 and references therein; (b) R. E. Sammelson
and M. J. Kurth, Chem. Rev., 2001, 101, 137 and references therein;
(c) M. T. Reetz, Angew. Chem., Int. Ed., 2001, 40, 284 and references
therein; (d ) I. W. James, Tetrahedron, 1999, 55, 4855 and references
therein.
2 (a) M. J. Plunkett and J. A. Ellman, J. Org. Chem., 1995, 60, 6006;
(b) M. J. Plunkett and J. A. Ellman, J. Org. Chem., 1997, 62, 2885.
3 S. E. Gibson (née Thomas), N. J. Hales and M. A. Peplow,
Tetrahedron Lett., 1999, 40, 1417.
4 (a) M. F. Semmelhack, in Comprehensive Organometallic Chemistry
II, eds. E. W. Abel, F. G. A. Stone and G. Wilkinson, Pergamon,
Oxford, 1995, vol. 12, pp. 979–1038; (b) S. G. Davies, in
Comprehensive Organometallic Chemistry II, eds. E. W. Abel,
F. G. A. Stone and G. Wilkinson, Pergamon, Oxford, 1995, vol. 12,
pp. 1497–1504.
5 M. J. Morris, in Comprehensive Organometallic Chemistry II,
eds. E. W. Abel, F. G. A. Stone and G. Wilkinson, Pergamon,
Oxford, 1995, vol. 5, pp. 506–507.
6 P. Hodge, Chem. Soc. Rev., 1997, 26, 417.
7 T. E. Bitterwolf, Polyhedron, 1988, 7, 1377.
8 S. O. Grim, D. A. Wheatland and W. McFarlane, J. Am. Chem. Soc.,
1967, 89, 5573.
9 M. Bernard and W. T. Ford, J. Org. Chem., 1983, 48, 326.
10 A. Paquet, Can. J. Chem., 1982, 60, 976.
11 D. Merricks, P. G. Sammes, E. R. H. Walker, K. Henrick and
M. M. McPartlin, J. Chem. Soc., Perkin Trans. 1, 1991, 2169.
12 J. Coste, D. Le-Nguyen and B. Castro, Tetrahedron Lett., 1990, 31,
205.
13 S. Maiorana, C. Baldoli, E. Licandro, L. Casiraghi, E. de Magistris,
A. Paio, S. Provera and P. Seneci, Tetrahedron Lett., 2000, 41, 7271.
14 D. F. Shriver and M. A. Drezdzon, The Manipulation of Air-
Sensitive Compounds, Wiley, Chichester, 1986.
15 F. Bracker and T. Litz, Arch. Pharm., 1995, 3, 328.
16 (a) V. C. Zybill, D. L Wilkinson, C. Leis and G. Muller, Angew.
Chem., 1989, 101, 206; (b) F. A. Cotton and C. S. Kraihanzel,
J. Am. Chem. Soc., 1962, 84, 4432.
0.60 mmol[Fmoc-Val-Phe-OtBu] gϪ1); νmax(Nujol)/cmϪ1 2061vw
᎐
and 1936w [polymer–PPh Cr(C᎐O) ], 2005w [polymer–(PPh ) -
᎐
2
5
2 2
᎐
᎐
Cr(C᎐O) ], 1883vs and 1832s [polymer–PPh Cr(C᎐O) (Ar)],
᎐
᎐
4
2
2
1724m [C(᎐O)OtBu and OC(᎐O)N] and 1680m [C(᎐O)N] and
᎐
᎐
᎐
1494m [NHC(O)]; δP{1H}(202.4 MHz, THF-swollen resin, D2O
capillary lock) Ϫ4.8 (10%, polymer–PPh2,), 26.2 [20, polymer–
P(O)Ph2], 57.8 [trace, polymer–PPh2Cr(CO)5], 75.1 [5,
polymer–(PPh2)2Cr(CO)4] and 91.8 [65, polymer–PPh2Cr-
(CO)2(Fmoc-Val-Phe-OtBu)]; m/z (FAB positive) 543 (Fmoc-
Val-Phe-OtBuHϩ, 4%), 487 (Fmoc-Val-Phe-OH ϩ H, 10), 289
[Ph P(C H )CH᎐CH , 19], 179 (dibenzofulvene ϩ H, 56), 136
᎐
2
6
4
2
[Cr(CO)3, 100], 120 (Phe Ϫ CO2H, 28), 107 [P(C6H4), 36] and
91 (C7H7, 39).
Fmoc-Val-Phe-OtBu 16
Dicarbonyl(Fmoc-Val-Phe-OtBu)(polymer–PPh2)chromium(0)
15 (100 mg, 0.06 mmol [Fmoc-Val-Phe-OtBu]) was ground to a
fine yellow powder and suspended in DCM (15 cm3) in a 25 cm3
round-bottomed flask equipped with a condenser and CaCl2
drying tube and stirred at ambient temperature in air under
white light (100 W) for 48 h. The resulting fine brown suspen-
J. Chem. Soc., Perkin Trans. 1, 2001, 2526–2531
2531