Direct synthesis of Fmoc-protected amino acids using organozinc chemistry: Application to polymethoxylated phenylalanines and 4-oxoamino acids

Article abstract of DOI:10.1039/b103832j

The newN-Fmoc 3-iodoalaninetert-butyl ester derived organozinc reagent1, obtained in 7 steps from optically pure 3-serine, was coupled to a range of electrophiles under palladium catalysis to give substituted phenylalanines and 4-oxoamino acids in variabl

Full text of DOI:10.1039/b103832j

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Direct synthesis of Fmoc-protected amino acids using organozinc
chemistry: application to polymethoxylated phenylalanines and
4-oxoamino acids†
1
Hervé J. C. Deboves,a Christian A. G. N. Montalbettia and Richard F. W. Jackson*b
a Department of Chemistry, Bedson Building, The University of Newcastle,
Newcastle upon Tyne, UK NE1 7RU
b Department of Chemistry, Dainton Building, The University of Sheffield, Sheffield,
UK S3 7HF
Received (in Cambridge, UK) 27th April 2001, Accepted 21st June 2001
First published as an Advance Article on the web 19th July 2001
The new N-Fmoc 3-iodoalanine tert-butyl ester derived organozinc reagent 1, obtained in 7 steps from optically pure
-serine, was coupled to a range of electrophiles under palladium catalysis to give substituted phenylalanines and 4-
oxoamino acids in variable yields (21–59%). Transformation into the organocopper reagent 13 allowed coupling with
allyl chloride and ethyl oxalyl chloride. Removal of the tert-butyl group gives Fmoc-protected amino acids (63–95%),
suitable for use in automated solid phase peptide synthesis.
The synthesis of nonproteinogenic amino acids continues to
provide a challenge for organic chemists. We have developed
effective methods for the conversion of readily available enantio-
merically pure natural amino acids (serine, aspartic acid,
glutamic acid) into unnatural amino acids using organometallic
chemistry without loss of stereochemical integrity.1–5 Since N-
Fmoc protected amino acids are routinely used in automated
solid phase peptide synthesis (SPPS),6–8 it was of interest to
establish whether these methods could be applied to N-Fmoc
protected starting materials. One unoptimised example of the
coupling of the corresponding Fmoc methyl ester iodoalanine-
derived zinc reagent has been reported,9 and although con-
ditions were reported for the selective hydrolysis of the methyl
ester of the product in the presence of the Fmoc-protecting
group, the use of a carboxylic acid protecting group more
obviously orthogonal to the methyl ester was desirable. We have
therefore synthesised the new N-Fmoc protected serine-derived
organozinc reagent 1, from the corresponding iodide precursor
2, and studied the palladium catalysed coupling of 1 with
aromatic iodides and acid chlorides, and the copper mediated
coupling reactions of 1. Furthermore, in the case of the phenyl-
alanine derivatives, we have targeted polyoxygenated analogues
as most of these derivatives, to our knowledge, have not
been reported previously in the literature. Biologically active
molecules containing polyoxygenated phenylalanine fragments
include angiotensin-converting enzyme (ACE) inhibitors such
as 3,10 HIV-1 protease inhibitors,11 the antibiotic puromycin,
sweeteners 4,12 tunichromes 513 and 3,4-dihydroxyphenyl-
alanine (DOPA), a prodrug for the neurotransmitter dopamine,
which has been prescribed in the treatment of Parkinson’s
disease.
thesis of protected 3-iodoalanines1 proved unsuccessful in the
case of intermediate 2 due to the instability of the latter during
Results and discussion
the final chromatographic purification. The following method
starting from the known β-chloroalanine 6 hydrochloride was
therefore developed (Scheme 1).
The iodide precursor 2 was synthesised from commercially
available -serine. The approach used previously for the syn-
Treatment of 6 under Paquet’s conditions14 gave the N-Fmoc
protected derivative 7 in good yield (78%) which was used with-
out further purification. For the esterification, the tert-butyl
cation was generated using isobutene under acidic conditions
(sulfuric acid), in dichloromethane as reported by Andreson.15
† Electronic supplementary information (ESI) available: details of the
preparation and spectral properties of 3-iodobenzophenone, 2,3,4-
trimethoxyiodobenzene, 2,4-dimethoxyiodobenzene, 3,4-dimethoxy-
iodobenzene, 3,4,5-trimethoxyiodobenzene and 3,5-dimethoxyiodo-
benzene. See http://www.rsc.org/suppdata/p1/b1/b103832j/
1876
J. Chem. Soc., Perkin Trans. 1, 2001, 1876–1884
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b103832j

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Using the conditions developed for p-iodonitrobenzene,
several phenylalanine analogues 10a–n were synthesised with
yields ranging from good to moderate (21–59%, Table 1). The
yield obtained for the coupling of 1 with 4-iodonitrobenzene
(59%) was almost identical to that obtained with the analogous
N-Boc protected methyl ester zinc reagent3 so the Fmoc pro-
tection is not a limiting factor in the coupling process.
The yields of the coupling reaction with electron rich
aromatic iodides (entries 10e–m) were generally slightly lower
than for the electron poor ones (entries 10a–e) as expected,
with the exception of entries 10c (21%) and 10l (59%). We were
however surprised by the higher yields obtained for the tri-
substituted derivatives (47 and 59%, entries 10k and 10l). While
the yields are moderate (45% on average), these results never-
theless show the utility of organozinc reagents in the synthesis
of various polyoxygenated phenylalanine derivatives.
Removal of the tert-butyl protecting group to give the Fmoc-
protected amino acids 11 was efficiently achieved using tri-
fluoroacetic acid in the presence of triethylsilane (Scheme 3), a
Scheme 1 Reagents and conditions: i, FmocOsuccinimide, NaHCO3,
H2O–acetone mixture (1 : 1) (78%); ii, isobutene, H2SO4, CH2Cl2,
Ϫ78 ЊC (84%); iii, NaI, acetone (99%).
This step gave the ester 8 in good yield (84%) as a nice crystal-
line material after purification. The iodide 2 was finally
obtained in near-quantitative yield by Finkelstein reaction.
The N-Fmoc protected organozinc reagent 1 was formed by
direct insertion of activated zinc powder into the carbon–iodine
bond of iodide 2, the zinc powder being previously activated by
treatment with chlorotrimethylsilane in DMF at room tem-
perature for 30 min. This activation method appears to be at
least as reliable as the method for zinc activation16 which
included a pre-treatment with 1,2-dibromoethane, but it has the
advantage that the use of carcinogenic 1,2-dibromoethane is
avoided. The organozinc reagent 1 was shown to be formed
quantitatively by quenching the reaction either with water,
giving N-Fmoc-protected alanine tert-butyl ester 9, or with
iodine regenerating the starting iodide 2.
Scheme 3 Reagents and conditions: i, TFA, Et3SiH (2.5 equiv.),
CH2Cl2, 4 h.
scavenger of the tert-butyl cation, which has been described by
Douglas and co-workers17 to limit side reactions in this process
(Table 2).
The specific rotation of our sample of N-Fmoc-4-methoxy-
phenylalanine 11g compared favourably with that reported
by Motawia and co-workers18 for the same material prepared
from 4-O-Me--tyrosine. We have previously established that
the palladium catalysed coupling of organozinc reagents with
aromatic iodides proceeds without affecting the chiral integrity
of the α-carbon,4 and we are therefore confident that all the
examples are enantiomerically pure.
Due to the success of the new N-Fmoc protected organozinc
reagent 1 in the palladium catalysed coupling reaction with
aromatic iodides, we decided to investigate the coupling pro-
cedure with acid chlorides.1 The organozinc reagent 1 was pre-
pared using zinc–copper couple in a mixture of toluene–DMA
(93 : 7), which avoids the incompatibility of DMF and acid
chlorides. While zinc insertion is very slow in this solvent below
40 ЊC, it takes less than 5 minutes at 70 ЊC but is accompanied
by significant decomposition. At 50 ЊC, insertion is complete
within 20 minutes with less than 5% decomposition being
detected. The conditions for the coupling reaction were opti-
mised using acetoxyacetyl chloride. The best yield (47%)
was obtained when bis(triphenylphosphine)dichloropalladium
was used as catalyst and the reaction carried out for 4 hours
(Scheme 4). The coupling reaction was then carried out
using these optimised conditions with a range of acid chlorides
(Table 3) to give the corresponding 4-oxo derivatives 12 in
moderate yields (42–52%)
The optimisation of the conditions for the palladium
catalysed coupling reaction between organozinc reagent 1
and aryl iodides was carried out using p-nitroiodobenzene.
The optimum result was obtained at 50 ЊC, using Pd2dba3
(2.5 mol%) and P(o-tol)3 (10 mol%) as the catalytic system
(Scheme 2). The main difference between the behaviour of the
Conversion of the organozinc reagent 1 into the more
reactive zinc–copper reagent 13 was achieved by treatment with
CuCNؒ2LiCl (Scheme 5). Treatment with allyl chloride gave the
adduct 14a (60%), a similar yield to that obtained with the
N-Boc protection (52%)2 which shows that the Fmoc group is
not a limiting factor in such reactions. Treatment with ethyl
oxalyl chloride gave the corresponding adduct 14b (30%).
Scheme 2 Reagents and conditions: i, Zn* (prepared from zinc dust
using Me3SiCl, in DMF), DMF, rt, 1 h; ii, Pd2dba3 (2.5 mol%), P(o-tol)3
(10 mol%), DMF, ArI, 50 ЊC, 4 h.
Conclusions
N-Fmoc 3-iodoalanine tert-butyl ester 2 is easily prepared in
good overall yield via a six step sequence to give a crystalline
compound which can be stored in the fridge without decom-
position for months. It gives access to organozinc reagent 1
zinc reagent 1 and other analogous protected serine-derived
zinc reagents is the higher temperature required for effective
cross-coupling of reagent 1.
J. Chem. Soc., Perkin Trans. 1, 2001, 1876–1884
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Table 1 Preparation of phenylalanine derivatives 10a–l
Aryl iodide
Ar
Yield (%)a
10a
10b
10c
10d
10e
10f
10g
10h
10i
4-Nitroiodobenzene
4-Nitrophenyl
2-Bromophenyl
2-Methoxycarbonylphenyl
3-Benzoylphenyl
2-Methoxyphenyl
3-Methoxyphenyl
4-Methoxyphenyl
2,4-Dimethoxyphenyl
3,4-Dimethoxyphenyl
3,5-Dimethoxyphenyl
2,3,4-Trimethoxyphenyl
3,4,5-Trimethoxyphenyl
59
47
21
55
31
48
34
24
41
47
47
59
2-Bromoiodobenzene
2-Methoxycarbonyliodobenzene
3-Iodobenzophenone
2-Iodoanisole
3-Iodoanisole
4-Iodoanisole
2,4-Dimethoxyiodobenzene
3,4-Dimethoxyiodobenzene
3,5-Dimethoxyiodobenzene
2,3,4-Trimethoxyiodobenzene
3,4,5-Trimethoxyiodobenzene
10j
10k
10l
a Based on N-Fmoc-3-iodoalanine tert-butyl ester 2.
Table 2 Cleavage of the tert-butyl protecting group
Table 3 Preparation of 4-oxo derivatives 12a–e
Ar
Yield (%)
R
Yield (%)a
11d
11g
11h
11j
11k
11l
3-Benzophenyl
4-Methoxyphenyl
2,4-Dimethoxyphenyl
3,5-Dimethoxyphenyl
2,3,4-Trimethoxyphenyl
3,4,5-Trimethoxyphenyl
73
64
74
63
81
95
12a
12b
12c
12d
12e
AcOCH2
CH3CH2
(S)-N-Trifluoroacetylpyrrolidin-2-yl
PhthNCH2
47
47
46
43
42
b
CH2᎐᎐CH
a Based on N-Fmoc-3-iodoalanine tert-butyl ester 2. b Phth = 1,3-
phthaloyl.
Scheme 4 Reagents and conditions: i, Zn–Cu couple, toluene–DMA
(93 : 7), 50 ЊC, 20 min; ii, RCOCl, Pd(PPh3)2Cl2, toluene–DMA (93 : 7),
50 ЊC, 4 h.
which can be converted into N-Fmoc tert-butyl protected
phenylalanine derivatives 10a–l in moderate yields (21–59%).
The ester derivatives obtained can be easily converted into the
corresponding acids 11 which are ready for use in solid phase
peptide synthesis. Organozinc reagent 1 can also be used in the
preparation of 4-oxoamino acids (12a–e and 14b) as well as in
the preparation of amino acids bearing an unsaturated side
chain 14a.
Scheme 5 Reagents and conditions: i, CuCNؒ2LiCl, THF, Ϫ10 ЊC;
ii, allyl chloride, Ϫ25 ЊC, overnight; iii, ethyl oxalyl chloride, Ϫ25 ЊC,
overnight.
been reported.25 J Values are given in Hz and optical rotations
in 10Ϫ1 deg cm2 gϪ1
.
(2R)-Amino-3-chloropropionic acid hydrochloride (I-(ꢀ-Cl)-Ala)
Experimental
626,27
For general experimental procedures, see our previous paper.19
Methyl (2R)-2-amino-3-chloropropionate hydrochloride was
prepared from serine using the literature method.20 3-Iodo-
benzophenone was prepared from 3-iodobenzoic acid.21 Poly-
oxygenated aromatic iodides containing ortho- and para-
substituents with respect to the iodine were synthesised in good
yields (79–83%) following a method described by Orito and
co-workers.22 The meta substituted iodides were prepared in
moderate yields (38–72%) via the corresponding diazonium
salts following procedures described by Pavia23 and Erdtman.24
Procedures and full characterisation data for these aryl iodides
are reported in the supplementary information.† The procedure
for the preparation of 12c, and the characterisation data, have
Methyl (2R)-2-amino-3-chloropropionate hydrochloride (9.0 g,
51.7 mmol) was dissolved in aqueous HCl 20% solution (90 ml,
520 mmol, 10 equiv.). The solution was refluxed for 1.5 hours
followed by overnight stirring at room temperature. The solvent
was evaporated to yield a pale yellow powder which was dis-
solved in dry methanol (30 ml) and precipitated by the addition
of diethyl ether (9 ml) to yield (2R)-2-amino-3-chloropropionic
acid hydrochloride 6 (6.6 g, 80%) as white crystals. Mp 180–
185 ЊC (Found Mϩ 124.0167; C3H7NO2Cl requires 124.0165);
[α]1D7 ϩ1.0 (c 1.0 in H2O) (Found: C, 22.6; H, 4.5; N, 8.8%.
C3H7NO2Cl requires C, 22.6; H, 4.4 and N, 8.8%); νmax (KBr
disc)/cmϪ1 3200–2700 (s), 1984 (m), 1960 (m), 1744 (s), 1496 (s),
1878
J. Chem. Soc., Perkin Trans. 1, 2001, 1876–1884

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1230 (s), 1200 (s) and 794 (m); δH (CD3OD) 4.25 (1H, dd, J 3.5,
12.5, C(3)H), 4.39 (1H, dd, J 4.5, 12.5, C(3)HЈ), 4.87 (1H, dd,
J 3.5, 4.5, C(2)H); δC(CD3OD) 44.36 (C(3)), 56.07 (C(2)),
169.61 (C(1)); m/z (EI) Mϩ 126 (0.42), 124 (0.3), 104 (0.2), 102
(0.1), 80 (33), 78 (100%).
155.57 (C᎐O, Fmoc), 167.64 (C(1)); m/z (EI) Mϩ 403 (0.07), 401
(0.2), 300 (5.5), 178 (100), 165 (13), 57 (17%).
᎐
(2R)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-iodopropionic
acid tert-butyl ester 2
(2R)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-chloro-
propionic acid tert-butyl ester 8 (7.84 g, 19.5 mmol) was dis-
solved in acetone (500 ml). NaI (11.8 g, 79.2 mmol, 4.0 equiv.)
was added in a single portion. The yellow solution was refluxed
(2R)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-chloro-
propionic acid 7
(2R)-2-Amino-3-chloropropionic acid hydrochloride (6.5 g,
40.6 mmol) was dissolved in a 1 : 1 water–acetone mixture
(150 ml). NaHCO3 (6.82 g, 81.2 mmol, 2 equiv.) was added
in portions. When carbon dioxide evolution had stopped
Fmoc succinimide (14.4 g, 42.7 mmol, 1.05 equiv.) was added.
The “milky” solution was stirred at ambient temperature for
the following two days. The acetone was evaporated and the
resulting solution acidified to pH 1 with 5 M HCl. The acidic
solution was extracted with ethyl acetate (3 × 50 ml) and the
combined organic phases were washed with saturated Na-
HCO3 (50 ml). The aqueous phase was collected and acidified
to pH 1 with 5 M HCl and then extracted with ethyl acetate
(3 × 50 ml). The combined organic phases were dried and
evaporated to yield (2R)-2-(9H-fluoren-9-ylmethoxycarbonyl-
amino)-3-chloropropionic acid 7 (11.0 g, 78%) as white crystals.
Mp 155–157 ЊC (Found: Mϩ 345.0769; C18H16NO4Cl requires
345.0768); [α]1D7 ϩ28.2 (c 0.5 in CHCl3) (Found C, 62.5; H, 4.6;
N, 4.1%. C18H16NO4Cl requires C, 62.5; H, 4.65 and N, 4.05%);
νmax (KBr disc)/cmϪ1 3316 (s), 3039 (m), 2964 (m), 2926 (s), 1703
(s), 1537 (s) and 794 (s); δH (CD3OD) 3.91 (2H, d, J 5.0,
C(3)H2), 4.22 (1H, t, J 7.0, CH Fmoc), 4.34 (1H, d, J 7.0, CH2
Fmoc), 4.56 (1H, t, J 5.0, C(2)H), 7.30 (2H, dt, J 7.5, 1.0, ArH
Fmoc), 7.37 (2H, t, J 7.5, ArH Fmoc), 7.64–7.68 (2H, m, ArH
Fmoc), 7.78 (2H, d, J 7.5, ArH Fmoc); δC (CD3OD) 45.53
(C(3)), 51.50 (CH Fmoc), 57.00 (C(2)), 68.40 (CH2 Fmoc),
121.08 (Ar Fmoc), 126.44 (Ar Fmoc), 128.33 (Ar Fmoc),
128.96 (Ar Fmoc), 142.72 (Ar Fmoc), 145.30 (Ar Fmoc),
1
for 3 days (the extent of reaction was checked by H NMR).
Acetone was removed under vacuum giving a yellow oil which
was dissolved in CHCl3 (500 ml). The solution was washed
with water (500 ml), sodium thiosulfate (1 M, 250 ml), water
(500 ml), dried and evaporated to give a pale yellow oil which
was triturated with petrol (25 ml) to give (2R)-2-(9H-fluoren-
9-ylmethoxycarbonylamino)-3-iodopropionic acid tert-butyl
ester 2 (9.4 g, 99%) as a pale yellow powder. Mp 78–81 ЊC
(Found Mϩ 493.0768; C22H24NO4I requires 493.0750); [α]D23
ϩ16.3 (c 1.05 in CHCl3) (Found: C, 53.7; H, 4.9; N, 2.9%.
C22H24NO4I requires C, 53.6; H, 4.9 and N, 2.8%); νmax (KBr
disc)/cmϪ1 3387 (m), 3011 (m), 2968 (m), 1723 (s), 1720 (s), 1513
(s), 1242 (m) and 471 (w); δH (CDCl3) 1.51 (9H, s, But), 3.58
(1H, dd, J 3.5, 10.5, C(3)H), 3.61 (1H, dd, J 3.5, 10.5, C(3)HЈ),
4.24 (1H, t, J 7.5, CH Fmoc), 4.32–4.43 (3H, m, C(2)H and
OCH2 Fmoc), 5.72 (1H, d, J 6.5, NH), 7.29–7.33 (2H, m, ArH
Fmoc), 7.39 (2H, t, J 7.5, ArH Fmoc), 7.61 (2H, d, J 7.5, ArH
Fmoc), 7.75 (2H, d, J 7.5, ArH Fmoc); δC (CDCl3) 8.43 (C(3)),
27.97 (C(CH3)3), 47.05 (CH Fmoc), 55.04 (C(2)), 67.29 (CH2
Fmoc), 83.60 (C(CH3)3), 119.99 (Ar Fmoc), 125.18 (Ar Fmoc),
127.07 (Ar Fmoc), 127.73 (Ar Fmoc), 141.27 (Ar Fmoc),
143.66 (Ar Fmoc), 155.37 (C᎐O, Fmoc), 168.16 (C(1)); m/z (EI)
᎐
Mϩ 493 (0.1), 392 (0.7), 178 (100), 165 (17), 57 (17%).
General procedure for the coupling reaction between zinc reagent
1 and aromatic iodides
158.48 (C᎐O, Fmoc), 169.61 (C(1)); m/z (EI) Mϩ 345 (0.30),
᎐
Zinc dust (325 mesh, 0.150 g, 2.25 mmol, 3.0 equivalents) was
weighed into a 50 ml round-bottomed flask with side arm which
was repeatedly evacuated (with heating using a hot air gun) and
flushed with nitrogen. Dry DMF (0.3 ml) and trimethylsilyl
chloride (30 µL, 0.375 mmol) were added, and the resultant
mixture was allowed to stir for a further 30 min under nitrogen.
N-(Fluoren-9-ylmethoxycarbonyl)-3-iodo--alanine tert-butyl
ester 2 (0.370 g, 0.75 mmol) in dry DMF (0.5 ml under nitro-
gen) was added to the flask and stirred at room temperature
until no starting material remained as judged by TLC (4 : 1,
petroleum ether–ethyl acetate). The aromatic iodide (1.0 mmol,
1.3 equivalents), tri-o-tolylphosphine (31 mg, 0.1 mmol,
0.13 equivalents), and tris(dibenzylideneacetone)dipalladium
(23 mg, 0.025 mmol, 6.6 mol%), were added sequentially to the
reaction mixture. Stirring was continued for 4 h at 50 ЊC. The
reaction mixture was diluted with ethyl acetate (50 ml), and the
organic layer was washed with aq. sodium thiosulfate (1 M,
20 ml), water (2 × 20 ml), and brine (40 ml), dried and con-
centrated under reduced pressure to give the crude product as
an oil. Purification by flash column chromatography over silica
with a suitable petroleum ether–ethyl acetate gradient furnished
the pure protected products. In each case, varying amounts of
the protonated zinc reagent 9 were isolated.
309 (0.5), 265 (0.2), 178 (100), 165 (40%).
(2R)-2-(Fluoren-9-ylmethoxycarbonylamino)-3-chloropropionic
acid tert-butyl ester 8
(2R)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-chloro-
propionic acid 7 (11.0 g, 31.8 mmol) was dissolved in CH2Cl2
(500 ml). The solution was cooled to Ϫ78 ЊC then 2-methyl-
propene (110 ml) was condensed into the solution. The mixture
was allowed to warm to room temperature and H2SO4 (2.9 ml,
52.6 mmol, 1.7 equiv.) was added (solution became purple). The
solution was stirred for 19 hours (checked regularly by TLC:
EtOAc). The 2-methylpropene was removed under vacuum
then the solution was washed with saturated NaHCO3 (160 ml).
The solution was neutralised (pH 6–7) by adding solid
NaHCO3 then was washed with brine (2 × 100 ml), dried and
evaporated to yield a yellow oil. The oil was purified by flash
chromatography (petroleum ether–ethyl acetate, 9 : 1) to give
(2R)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-chloroprop-
ionic acid tert-butyl ester 8 (10.7 g, 84%) as white crystals.
Mp 89–91 ЊC (Found Mϩ 401.1393; C22H24NO4Cl requires
401.1394); [α]2D1 ϩ 18.1 (c 1.05 in CHCl3) (Found: C, 65.2; H,
6.2; N, 3.3%. C22H24NO4Cl requires C, 65.7; H, 6.0 and N,
3.5%); νmax (KBr disc)/cmϪ1 3347 (s), 3003 (m), 2969 (m), 1703
(s), 1694 (s) and 738 (s); δH (CDCl3) 1.51 (9H, s, But), 3.89
(1H, dd, J 3.0, 11.5, C(3)H), 3.97 (1H, dd, J 3.0, 11.5, C(3)HЈ),
4.24 (1H, t, J 7.0, CH Fmoc), 4.36–4.42 (1H, m, OCH Fmoc),
4.63–4.66 (2H, m, C(2)H and OCHЈ Fmoc), 5.73 (1H, d, J 7.5,
NH), 7.30–7.34 (2H, m, ArH Fmoc), 7.39–7.42 (2H, m, ArH
Fmoc), 7.61 (2H, d, J 7.5, ArH Fmoc), 7.76 (2H, d, J 7.5, ArH
Fmoc); δC (CDCl3) 27.92 (C(CH3)3), 45.66 (C(3)), 47.05 (CH
Fmoc), 55.08 (C(2)), 67.29 (CH2 Fmoc), 83.49 (C(CH3)3),
119.99 (Ar Fmoc), 125.10 (Ar Fmoc), 127.07 (Ar Fmoc),
127.73 (Ar Fmoc), 141.27 (Ar Fmoc), 143.64 (Ar Fmoc),
(2S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)propionic
acid tert-butyl ester 9. The compound was isolated as white
crystals, mp 78–80 ЊC (Found Mϩ, 367.1798; C22H25NO4
requires 367.1784); [α]2D5 ϩ0.3 (c 0.95 in CH2Cl2); νmax (KBr
disc)/cmϪ1 3336, 1724 and 1696; δH (CDCl3) 1.37 (3H, d, J 7.0,
CH3), 1.46 (9H, s, C(CH3)3), 4.20 (1H, t, J 7.5, CH Fmoc),
4.26–4.31 (1H, m, C(2)H), 4.35–4.39 (2H, m, OCH2 Fmoc),
5.48 (1H, d, J 7.5, NH), 7.29 (2H, t, J 7.5, ArH Fmoc), 7.36
(2H, t, J 7.5, ArH Fmoc), 7.59 (2H, d, J 7.5, ArH Fmoc), 7.73
(2H, d, J 7.5, ArH Fmoc); δC (CDCl3) 18.85 (CH3), 27.95
J. Chem. Soc., Perkin Trans. 1, 2001, 1876–1884
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(CH3), 47.17 (CH), 50.14 (CH), 66.88 (CH2), 81.92 (quat.),
119.94 (Ar), 125.11 (Ar), 127.03 (Ar), 127.65 (Ar), 141.27 (Ar),
143.84 (Ar), 143.96 (Ar), 155.62 (CO), 172.30 (CO); m/z (EI)
367 (Mϩ, 3), 266 (23), 178 (100), 165 (64), 57 (78%).
(2S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-(3Ј-benzo-
ylphenyl)propionic acid tert-butyl ester 10d. Following the pro-
cedure described for the coupling reaction, treatment with
3-iodobenzophenone (308 mg, 1.0 mmol) gave (2S)-2-(9H-
fluoren-9-ylmethoxycarbonylamino)-3-(3Ј-benzoylphenyl)prop-
ionic acid tert-butyl ester 10d (226 mg, 55%) as colourless
crystals. Mp 56–60 ЊC; [α]2D5 ϩ49.7 (c 1.0 in CHCl3) (Found: C,
76.8; H, 6.0; N, 2.6%. C35H33NO5 requires C, 76.8; H, 6.1 and
N, 2.6%); νmax (KBr disc)/cmϪ1 3425 (m), 1723 (s), 1657 (s), 1508
(s), 1250 (s) and 1153 (s); δH (CDCl3) 1.40 (9H, s, But), 3.15 (1H,
dd, J 6.0, 14.0, C(3)H), 3.21 (1H, dd, J 6.0, 14.0, C(3)HЈ), 4.18
(1H, t, J 7.4, CH Fmoc), 4.33 (1H, dd, J 7.4, 10.6, CH2 Fmoc),
4.40 (1H, dd, J 7.4, 10.6, CHЈ2 Fmoc), 4.57 (1H, m, C(2)H),
5.34 (1H, d, J 8.0, NH), 7.27–7.78 (17H, m, Ar Fmoc and
benzoylphenyl); δC (CDCl3) 27.95 (C(CH3)3), 38.24 (C(3)),
47.16 (CH Fmoc), 55.03 (C(2)), 66.98 (CH2 Fmoc), 82.81
(C(CH3)3), 119.99 (Ar Fmoc), 124.81 (Ar), 125.14 (Ar Fmoc),
127.08 (Ar Fmoc), 127.72 (Ar Fmoc), 128.32 (Ar), 128.89 (Ar),
130.00 (Ar), 131.04 (Ar), 132.44 (Ar), 133.69 (Ar), 136.59 (Ar),
137.53 (Ar), 137.70 (Ar), 141.30 (Ar Fmoc), 143.79 (Ar Fmoc),
155.53 (C᎐O, Fmoc), 170.29 (C(1)); m/z (EI) Mϩ Ϫ C H O
(2S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-(4-nitro-
phenyl)propionic acid tert-butyl ester 10a. Following the pro-
cedure described for the coupling reaction, treatment with
1-iodo-4-nitrobenzene (249 mg, 1.0 mmol) gave (2S)-2-(9H-
fluoren-9-ylmethoxycarbonylamino)-3-(4-nitrophenyl)propionic
acid tert-butyl ester 10a (216 mg, 59%) isolated as yellow
needles, mp 122–123 ЊC (Found Mϩ, 488.1943; C28H28N2O6
requires 488.1947); [α]2D5 ϩ31.4 (c 0.82 in CH2Cl2); νmax (KBr
disc)/cmϪ1 3500, 1721, 1521, 1346 and 739; δH (CDCl3) 1.42
(9H, s, C(CH3)3), 3.13 (1H, dd, J 13.5, 5.5, C(3)H), 3.21 (1H,
dd, J 13.5, 6.0, C(3)HЈ), 4.19 (1H, t, J 6.5, CH), 4.38 (1H, dd,
J 10.5, 6.5, OCH Fmoc), 4.40 (1H, dd, J 10.5, 7.0, OCHЉ
Fmoc), 4.56 (2H, m, C(2)H), 5.36 (1H, d, J 7.0, NH), 7.27 (2H,
d, J 8.5, ArH), 7.31 (2H, d, J 7.5, ArH Fmoc), 7.40 (2H, d,
J 7.5, ArH Fmoc), 7.54–7.57 (2H, m, ArH Fmoc), 7.77 (2H, d,
J 7.5, ArH Fmoc), 8.12 (2H, d, J 8.5, ArH); δC (CDCl3) 27.98
(CH3), 38.20 (CH2), 47.17 (CH), 54.77 (CH), 66.78 (CH2), 83.10
(quat.), 120.02 (Ar), 120.04 (Ar), 123.50 (Ar), 124.90 (Ar),
124.98 (Ar), 127.06 (Ar), 127.78 (Ar), 130.39 (Ar), 141.32 (Ar),
141.37 (Ar), 143.60 (Ar), 143.77 (Ar), 144.10 (Ar), 147.04
(Ar), 155.47 (CO), 169.88 (CO); m/z (EI) 488 (Mϩ, 0.1), 415 (6),
387 (7), 178 (95), 165 (100%).
᎐
21 15
264 (0.18), 178 (100), 165 (23), 105 (14), 77 (8), 57 (14%).
(2S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-(2Ј-meth-
oxyphenyl)propionic acid tert-butyl ester 10e. Following the
procedure described for the coupling reaction, treatment with
2-iodoanisole (234 mg, 1.0 mmol) gave (2S)-2-(9H-fluoren-
9-ylmethoxycarbonylamino)-3-(2Ј-methoxyphenyl)propionic
acid tert-butyl ester 10e (110 mg, 31%) as a clear yellow
oil (Found Mϩ Ϫ C5H9O2 372.1604; C24H22NO3 requires
372.1600); [α]2D3 ϩ16.0 (c 1.0 in CH2Cl2) (Found: C, 73.7; H,
6.9; N, 3.0%. C29H31NO5 requires C, 73.6; H, 6.6 and N, 3.0%);
νmax (KBr disc)/cmϪ1 3338 (m), 3065 (m), 2977 (m), 2837 (m),
1724 (s), 1516 (s), 1156 (s) and 740 (s); δH (CDCl3) 1.40 (9H, s,
But), 3.03–3.12 (2H, m, C(3)H2), 3.83 (3H, s, OCH3), 4.18 (1H,
t, J 7.0, CH Fmoc), 4.28–4.33 (2H, m, OCH2 Fmoc), 4.48–4.54
(1H, m, C(2)H), 5.59 (1H, d, J 8.0, NH), 6.86 (1H, d, J 8.0,
ArH), 6.89 (1H, t, J 7.5, ArH), 7.14 (1H, d, J 7.5, ArH), 7.23
(1H, dd, J 7.5, 8.0, ArH), 7.26–7.32 (2H, m, ArH Fmoc), 7.39
(2H, t, J 7.5, ArH Fmoc), 7.51–7.57 (2H, m, ArH Fmoc), 7.75
(2H, d, J 7.5, ArH Fmoc); δC (CDCl3) 27.94 (C(CH3)3), 33.13
(C(3)), 47.15 (CH Fmoc), 55.04 (OCH3), 55.28 (C(2)), 66.78
(CH2 Fmoc), 81.74 (C(CH3)3), 110.40 (Ar), 119.92 (Ar Fmoc),
120.65 (Ar), 125.07 (Ar), 125.17 (Ar Fmoc), 127.00 (Ar Fmoc),
127.62 (Ar Fmoc), 128.41 (Ar), 131.28 (Ar), 141.27 (Ar Fmoc),
(2S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-(2Ј-bromo-
phenyl)propionic acid tert-butyl ester 10b. Following the pro-
cedure described for the coupling reaction, treatment with
1-iodo-2-bromobenzene (283 mg, 1.0 mmol) gave (2S)-2-(9H-
fluoren-9-ylmethoxycarbonylamino)-3-(2Ј-bromophenyl)prop-
ionic acid tert-butyl ester 10b (246 mg, 47%) as a colourless
oil (Found Mϩ 521.1211; C28H28NO4Br requires 521.1202);
[α]2D0 ϩ18.4 (c 1.0 in CHCl3) (Found: C, 64.4; H, 5.3; N, 2.6%.
C28H28NO4Br requires C, 64.4; H, 5.4 and N, 2.7%); νmax (KBr
disc)/cmϪ1 3420 (m), 3064 (m), 2976 (m), 1734 (s), 1717 (s), 1506
(m), 1154 (s), 1046 (m) and 759 (m); δH (CDCl3) 1.41 (9H, s,
But), 3.14 (1H, dd, J 8.5, 14.0, C(3)H), 3.29 (1H, dd, J 6.5, 14.0,
C(3)HЈ), 4.17 (1H, t, J 7.5, CH Fmoc), 4.20–4.29 (1H, m, CH2
Fmoc), 4.31–4.38 (1H, m, CHЈ2 Fmoc), 4.66 (1H, dt, J 6.5, 8.5,
C(2)H), 5.39 (1H, d, J 8.5, NH), 7.09 (1H, t, J 8.0, ArH), 7.21
(1H, t, J 7.5, ArH), 7.25 (1H, d, J 7.0, ArH), 7.28–7.32 (2H, m,
ArH Fmoc), 7.39 (2H, t, J 7.5, ArH Fmoc), 7.56 (2H, t, J 7.5,
ArH Fmoc), 7.60 (1H, d, J 7.5, ArH Fmoc), 7.75 (2H, d, J 7.5,
ArH Fmoc); δC (CDCl3) 27.98 (C(CH3)3), 38.88 (C(3)), 47.19
(CH Fmoc), 54.45 (C(2)), 67.01 (CH2 Fmoc), 82.40 (Ar),
119.95 (Ar Fmoc), 125.14 (Ar), 125.19 (Ar Fmoc), 127.04 (Ar
Fmoc), 127.41 (Ar), 127.67 (Ar Fmoc), 128.61 (Ar), 131.40
(Ar), 132.95 (Ar), 136.27 (Ar), 141.27 (Ar Fmoc), 143.84 (Ar
Fmoc), 155.58 (C(4)), 170.76 (C(1)); m/z (EI) Mϩ 521 (1.2), 466
(1.0), 420 (32), 368 (98), 313 (15), 198 (35), 178 (100), 165 (12),
57 (28%).
143.93 (Ar Fmoc), 155.70 (C᎐O, Fmoc), 157.68 (Ar), 171.33
᎐
(C(1)); m/z (EI) Mϩ Ϫ C5H9O2 372 (0.8), 328 (9.0), 267 (0.6),
178 (100), 165 (6), 121 (10), 57 (5.0%).
(2S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-(3Ј-meth-
oxyphenyl)propionic acid tert-butyl ester 10f. Following the
procedure described for the coupling reaction, treatment with
3-iodoanisole (234 mg, 1.0 mmol) gave (2S)-2-(9H-fluoren-
9-ylmethoxycarbonylamino)-3-(3Ј-methoxyphenyl)propionic
acid tert-butyl ester 10f (170 mg, 48%) as a clear yellow oil
(Found Mϩ 473.2187; C29H31NO5 requires 473.2202); [α]D23
ϩ18.4 (c 1.05 in CH2Cl2) (Found: C, 73.7; H, 6.7; N, 2.8%.
C29H31NO5 requires C, 73.6; H, 6.6 and N, 3.0%); νmax (KBr
disc)/cmϪ1 3339 (m), 3065 (m), 2977 (m), 2835 (m), 1723 (s),
1511 (s), 1155 (s), 886 (w) and 760 (s); δH (CDCl3) 1.43 (9H, s,
But), 3.04–3.11 (2H, m, C(3)H2), 3.76 (3H, s, OCH3), 4.21 (1H,
t, J 7.0, CH Fmoc), 4.33 (1H, dd, J 7.0, 10.5, OCH Fmoc), 4.41
(1H, dd, J 7.0, 10.5, OCHЈ Fmoc), 4.52–4.58 (1H, m, C(2)H),
5.31 (1H, d, J 8.0, NH), 6.73 (1H, br s, ArH), 6.76 (1H, d, J 8.0,
ArH), 6.79 (1H, dd, J 8.0, 2.5, ArH), 7.20 (1H, t, J 8.0, ArH),
7.28–7.34 (2H, m, ArH Fmoc), 7.40 (2H, t, J 7.5, ArH Fmoc),
7.57 (2H, t, J 8.5, ArH Fmoc), 7.76 (2H, d, J 7.5, ArH Fmoc);
δC (CDCl3) 27.99 (C(CH3)3), 38.43 (C(3)), 47.17 (CH Fmoc),
55.00 (OCH3), 55.15 (C(2)), 67.00 (CH2 Fmoc), 82.40
(2S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-(2Ј-meth-
oxycarbonylphenyl)propionic acid tert-butyl ester 10c. Following
the procedure described for the coupling reaction, treatment
with 2-methoxycarbonyliodobenzene (263 mg, 1.0 mmol) gave
(2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(2Ј-methoxy-
carbonylphenyl)propionic acid tert-butyl ester 10c (80 mg,
21%) as a yellow oil; [α]D21 ϩ19.0 (c 1.0 in CHCl3); δH (200 MHz,
CDCl3) 1.44 (9H, s, But), 3.37–3.39 (1H, m, C(3)H), 3.40–3.43
(1H, m, C(3)HЈ), 3.94 (3H, s, OMe), 4.10–4.25 (3H, m, CH2
Fmoc and CH Fmoc), 4.48–4.59 (1H, m, C(2)H), 6.07 (1H, d,
J 8.0, NH), 7.20–7.60 (9H, m, ArH), 7.75 (2H, d, J 7.5, Ar
FmocH), 7.92 (1H, d, J 7.5, ArH); m/z (EI) (Found Mϩ
501.2152; C30H31NO6 requires 501.2151) Mϩ Ϫ H 500 (1.5), 469
(0.5), 444 (1.6), 412 (1.1), 337 (3.1), 322 (2.7), 178 (100), 165
(37), 146 (73), 118 (10), 57 (30%).
1880
J. Chem. Soc., Perkin Trans. 1, 2001, 1876–1884

View Article Online
(C(CH3)3), 112.35 (Ar), 115.30 (Ar), 119.98 (Ar Fmoc), 121.91
(Ar), 125.18 (Ar Fmoc), 127.05 (Ar Fmoc), 127.69 (Ar Fmoc),
129.40 (Ar), 137.58 (Ar), 141.29 (Ar Fmoc), 143.90 (Ar Fmoc),
(3H, s, OCH3), 3.85 (3H, s, OCH3), 4.21 (1H, t, J 7.0, CH
Fmoc), 4.35 (1H, dd, J 7.0, 11.0, OCH Fmoc), 4.39 (1H, dd,
J 7.0, 11.0, OCHЈ Fmoc), 4.51–4.80 (1H, m, C(2)H), 5.29 (1H,
d, J 8.0, NH), 6.68–6.71 (2H, m, 2 × ArH), 6.77 (1H, d, J 7.0,
ArH), 7.30 (2H, d, J 7.5, ArH Fmoc), 7.40 (2H, t, J 7.5, ArH
Fmoc), 7.54–7.59 (2H, m, ArH Fmoc), 7.76 (2H, d, J 7.5, ArH
Fmoc); δC (CDCl3) 28.02 (C(CH3)3), 37.98 (C(3)), 47.15
(CH Fmoc), 55.11 (C(2)), 55.83 (OCH3), 55.88 (OCH3), 66.96
(CH2 Fmoc), 82.30 (C(CH3)3), 111.12 (Ar), 112.58 (Ar), 119.99
(Ar Fmoc), 121.71 (Ar), 125.09 (Ar Fmoc), 127.04 (Ar Fmoc),
127.70 (Ar Fmoc), 128.49 (Ar), 141.29 (Ar Fmoc), 143.78 (Ar
155.56 (C᎐O, Fmoc), 159.63 (Ar), 170.60 (C(1)); m/z (EI)
᎐
Mϩ 473 (0.2), 372 (0.5), 295 (0.5), 267 (1.6), 235 (3.2), 178 (100),
165 (17), 121 (16), 57 (20%).
(2S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-(4Ј-meth-
oxyphenyl)propionic acid tert-butyl ester 10g. Following the
procedure described for the coupling reaction, treatment with
4-iodoanisole (234 mg, 1.0 mmol) gave (2S)-2-(9H-fluoren-
9-ylmethoxycarbonylamino)-3-(4Ј-methoxyphenyl)propionic
acid tert-butyl ester 10g (120 mg, 34%) as an orange oil (Found
Mϩ 473.2209; C29H31NO5 requires 473.2202); [α]2D3 ϩ17.5 (c 0.99
in CH2Cl2) (Found: C, 73.6; H, 6.9; N, 2.9%. C29H31NO5
requires C, 73.6; H, 6.6 and N, 3.0%); νmax (KBr disc)/cmϪ1 3337
(m), 3065 (m), 2975 (m), 2934 (m), 2835 (m), 1723 (s), 1612 (s),
1511 (s), 1155 (s) and 845 (s); δH (CDCl3) 1.43 (9H, s, But), 3.02
(1H, dd, J 6.0, 14.0, C(3)H), 3.06 (1H, dd, J 6.0, 14.0, C(3)HЈ),
3.77 (3H, s, OCH3), 4.21 (1H, t, J 7.0, CH Fmoc), 4.32 (1H, dd,
J 7.0, 10.5, OCH Fmoc), 4.44 (1H, dd, J 7.0, 10.5, OCHЈ
Fmoc), 4.48–4.52 (1H, m, C(2)H), 5.26 (1H, d, J 8.0, NH), 6.81
(2H, d, J 8.0, ArH), 7.06 (1H, d, J 8.0, ArH), 7.31 (2H, dt, J 7.5,
2.5, ArH Fmoc), 7.31 (2H, t, J 7.0, ArH Fmoc), 7.56–7.59 (2H,
m, ArH Fmoc), 7.76 (2H, d, J 7.5, ArH Fmoc); δC (CDCl3)
28.01 (C(CH3)3), 37.46 (C(3)), 47.20 (CH Fmoc), 55.22 (C(2)),
56.63 (OCH3), 66.86 (CH2 Fmoc), 82.33 (C(CH3)3), 113.83
(Ar), 119.98 (Ar Fmoc), 125.18 (Ar Fmoc), 127.04 (Ar Fmoc),
127.69 (Ar Fmoc), 128.01 (Ar), 130.55 (Ar), 141.31 (Ar Fmoc),
Fmoc), 148.08 (Ar), 148.81 (Ar), 155.59 (C᎐O, Fmoc), 170.76
᎐
(C(1)); m/z (EI) Mϩ 503 (4.8), 325 (4), 178 (35), 165 (16), 151
(100), 57 (9%).
(2S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-(3Ј,5Ј-di-
methoxyphenyl)propionic acid tert-butyl ester 10j. Following the
procedure described for the coupling reaction, treatment with
3,5-dimethoxyiodobenzene (264 mg, 1.0 mmol) gave (2S)-
2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(3Ј,5Ј-dimethoxy-
phenyl)propionic acid tert-butyl ester 10j (177 mg, 47%) as a
white powder. Mp 48–50 ЊC (Found Mϩ 503.2325; C30H33NO6
requires 503.2308); [α]1D7 ϩ7.5 (c 0.99 in CHCl3) (Found: C, 71.1;
H, 6.6; N, 3.0%. C30H33NO6 requires C, 71.5; H, 6.6 and N,
2.8%); νmax (KBr disc)/cmϪ1 3340 (m), 3065 (m), 2975 (m), 2837
(m), 1724 (s), 1511 (s), 1152 (s), 843 (m) and 741 (s); δH (CDCl3)
1.44 (9H, s, But), 3.04–3.09 (2H, m, C(3)H2), 3.74 (6H, s,
OCH3), 4.18–4.24 (1H, m, CH Fmoc), 4.33 (1H, dd, J 7.5, 10.5,
OCH Fmoc), 4.38 (1H, dd, J 7.5, 10.5, OCHЈ Fmoc), 4.52–4.58
(1H, m, C(2)H), 5.30 (1H, d, J 8.0, NH), 6.32–6.36 (3H, m,
ArH), 7.28–7.33 (2H, m, ArH Fmoc), 7.36–7.42 (2H, m, ArH
Fmoc), 7.54–7.60 (2H, m, ArH Fmoc), 7.76 (2H, d, J 7.5, ArH
Fmoc); δC (CDCl3) 28.01 (C(CH3)3), 38.63 (C(3)), 47.14 (CH
Fmoc), 54.90 (C(2)), 55.28 (OCH3), 67.06 (CH2 Fmoc), 82.38
(C(CH3)3), 98.95 (Ar), 107.59 (Ar), 119.98 (Ar Fmoc), 125.18
(Ar Fmoc), 127.07 (Ar Fmoc), 127.69 (Ar Fmoc), 138.25 (Ar),
143.91 (Ar Fmoc), 155.52 (C᎐O, Fmoc), 158.63 (Ar), 170.66
᎐
(C(1)); m/z (EI) Mϩ 473 (0.1), 372 (1.0), 328 (0.3), 178 (100), 165
(10), 121 (49), 57 (70%).
(2S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-(2Ј,4Ј-di-
methoxyphenyl)propionic acid tert-butyl ester 10h. Following the
procedure described for the coupling reaction, treatment with
2,4-dimethoxyiodobenzene (264 mg, 1.0 mmol) gave (2S)-2-
(9H-fluoren-9-ylmethoxycarbonylamino)-3-(2Ј,4Ј-dimethoxy-
phenyl)propionic acid tert-butyl ester 10h (91 mg, 24%) as a
clear oil. [α]1D6 ϩ8.2 (c 1.01 in CHCl3) (Found: C, 71.2; H, 6.4; N,
2.6%. C30H33NO6 requires C, 71.5; H, 6.6 and N, 2.8%); νmax
(KBr disc)/cmϪ1 3342 (s), 3065 (s), 2976 (s), 2836 (m), 1724 (vs),
1508 (s), 1157 (vs), 877 (m), 837 (m) and 740 (s); δH (CDCl3)
1.41 (9H, s, But), 2.90–3.10 (2H, m, C(3)H), 3.76 (3H, s, OCH3),
3.78 (3H, s, OCH3), 4.15–4.20 (1H, m, CH Fmoc), 4.27–4.33
(2H, m, OCH Fmoc), 4.42–4.48 (1H, m, C(2)H), 5.59 (1H, d,
J 7.5, NH), 6.40 (1H, d, J 7.5, ArH), 6.44 (1H, s, ArH), 6.53
(1H, d, J 7.5, ArH), 7.29 (2H, d, J 7.5, ArH Fmoc), 7.38 (2H, t,
J 7.5, ArH Fmoc), 7.50–7.60 (2H, m, ArH Fmoc), 7.74 (2H, d,
J 7.5, ArH Fmoc); δC (CDCl3) 28.02 (C(CH3)3), 32.38 (C(3)),
47.15 (CH Fmoc), 55.22 (C(2)), 55.33 (OCH3), 55.65 (OCH3),
66.76 (CH2 Fmoc), 81.65 (C(CH3)3), 98.55 (Ar), 104.14 (Ar),
117.31 (Ar), 119.90 (Ar Fmoc), 125.17 (Ar Fmoc), 127.07 (Ar
Fmoc), 127.69 (Ar Fmoc), 131.56 (Ar), 141.26 (Ar Fmoc),
141.27 (Ar Fmoc), 143.82 (Ar Fmoc), 155.59 (C᎐O, Fmoc),
᎐
160.79 (Ar), 170.61 (C(1)); m/z (EI) Mϩ 503 (1.2), 325 (27), 269
(32), 178 (100), 165 (23), 151 (25), 57 (25%).
(2S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-(2Ј,3Ј,4Ј-
trimethoxyphenyl)propionic acid tert-butyl ester 10k. Following
the procedure described for the coupling reaction, treatment
with 2,3,4-trimethoxyiodobenzene (294 mg, 1.0 mmol) gave
(2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(2Ј,3Ј,4Ј-tri-
methoxyphenyl)propionic acid tert-butyl ester 10k (188 mg,
47%) as a clear oil (Found Mϩ 533.2395; C31H35NO7 requires
533.2414); [α]2D3 ϩ5.0 (c 1.0 in CH2Cl2) (Found: C, 69.8; H, 6.7;
N, 2.6%. C31H35NO7 requires C, 69.8; H, 6.6 and N, 2.6%); νmax
(KBr disc)/cmϪ1 3064 (m), 2835 (m), 1724 (s), 1495 (s), 1100 (s)
and 741 (s); δH (CDCl3) 1.43 (9H, s, But), 2.98 (1H, dd, J 6.0,
14.0, C(3)H), 3.20 (1H, dd, J 6.0, 14.0, C(3)HЈ), 3.82 (3H,
s, OCH3), 3.86 (3H, s, OCH3), 3.92 (3H, s, OCH3), 4.19 (1H, t,
J 6.5, CH Fmoc), 4.29 (1H, dd, J 6.5, 10.0, OCH Fmoc), 4.31
(1H, dd, J 6.5, 10.0, OCHЈ Fmoc), 4.39–4.46 (1H, m, C(2)H),
5.67 (1H, d, J 8.0, NH), 6.58 (1H, d, J 6.0, ArH), 6.84 (1H, d,
J 6.0, ArH), 7.28–7.31 (2H, m, ArH Fmoc), 7.39 (2H, t, J 7.5,
ArH Fmoc), 7.57 (2H, t, J 7.5, ArH Fmoc), 7.75 (2H, d, J 7.5,
ArH Fmoc); δC (CDCl3) 27.98 (C(CH3)3), 32.75 (C(3)), 47.18
(CH Fmoc), 55.56 (C(2)), 56.00 (OCH3), 60.74 (OCH3), 60.89
(OCH3), 66.90 (CH2 Fmoc), 81.83 (C(CH3)3), 107.20 (Ar),
119.92 (Ar Fmoc), 122.38 (Ar), 125.15 (Ar), 125.19 (Ar Fmoc),
127.03 (Ar Fmoc), 127.64 (Ar Fmoc), 141.27 (Ar Fmoc),
142.10 (Ar), 143.92 (Ar Fmoc), 144.04 (Ar), 153.01 (Ar), 155.82
143.92 (Ar Fmoc), 155.77 (C᎐O, Fmoc), 158.56 (Ar), 160.08
᎐
(Ar), 171.34 (C(1)); m/z (EI) Mϩ 503 (4.5), 325 (42), 178 (100),
165 (19), 151 (46), 121 (11), 57 (3%).
(2S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-(3Ј,4Ј-di-
methoxyphenyl)propionic acid tert-butyl ester 10i. Following the
procedure described for the coupling reaction, treatment with
3,4-dimethoxyiodobenzene (264 mg, 1.0 mmol) gave (2S)-2-
(9H-fluoren-9-ylmethoxycarbonylamino)-3-(3Ј,4Ј-dimethoxy-
phenyl)propionic acid tert-butyl ester 10i (155 mg, 41%) as a
white powder. Mp 98–100 ЊC (Found Mϩ 503.2318; C30H33NO6
requires 503.2308); [α]1D6 ϩ25.1 (c 1.0 in CHCl3) (Found: C, 71.0;
H, 6.9; N, 2.8%. C30H33NO6 requires C, 71.5; H, 6.6 and N,
2.8%); νmax (KBr disc)/cmϪ1 3344 (m), 3065 (m), 2973 (m), 2833
(m), 1723 (s), 1700 (s), 1541 (s), 1154 (s), 815 (m) and 736 (s); δH
(CDCl3) 1.44 (9H, s, But), 3.01–3.09 (2H, m, C(3)H2), 3.82
(C᎐O, Fmoc), 171.21 (C(1)); m/z (EI) Mϩ 533 (1.4), 355 (3.1),
᎐
181 (100), 178 (46), 166 (62), 57 (12%).
(2S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-(3Ј,4Ј,5Ј-
trimethoxyphenyl)propionic acid tert-butyl ester 10l. Following
the procedure described for the coupling reaction, treatment
J. Chem. Soc., Perkin Trans. 1, 2001, 1876–1884
1881

View Article Online
with 3,4,5-trimethoxyiodobenzene (294 mg, 1.0 mmol) gave
(2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(3Ј,4Ј,5Ј-tri-
methoxyphenyl)propionic acid tert-butyl ester 10l (235 mg,
59%) as colourless needles. Mp 84–86 ЊC (Found Mϩ 533.2436;
C31H35NO7 requires 533.2414); [α]2D3 ϩ6.2 (c 0.99 in CH2Cl2)
(Found: C, 69.6; H, 6.3; N, 2.4%. C31H35NO7 requires C, 69.8;
H, 6.6 and N, 2.6%); νmax (KBr disc)/cmϪ1 3351 (m), 3065 (m),
2934 (m), 2835 (m), 1724 (s), 1691 (s), 1508 (s), 1128 (s), 846 (w)
and 737 (s); δH (CDCl3) 1.41 (9H, s, But), 3.02 (1H, dd, J 6.5,
14.0, C(3)H), 3.07 (1H, dd, J 6.0, 14.0, C(3)HЈ), 3.80 (6H, s,
OCH3), 3.81 (3H, s, OCH3), 4.21 (1H, t, J 7.0, CH Fmoc), 4.30–
4.50 (2H, m, OCH2 Fmoc), 4.52–4.58 (1H, m, C(2)H), 5.30 (1H,
d, J 6.0, NH), 6.39 (2H, s, ArH), 7.29 (2H, dt, J 1.0, 7.5, ArH
Fmoc), 7.39 (2H, t, J 7.5, ArH Fmoc), 7.52–7.59 (2H, m, ArH
Fmoc), 7.76 (2H, d, J 7.5, ArH Fmoc); δC (CDCl3) 28.08
(C(CH3)3), 38.80 (C(3)), 47.13 (CH Fmoc), 54.98 (C(2)), 56.90
(OCH3), 60.85 (OCH3), 67.05 (CH2 Fmoc), 82.33 (C(CH3)3),
106.46 (Ar), 120.01 (Ar Fmoc), 125.01 (Ar Fmoc), 127.05 (Ar
Fmoc), 127.74 (Ar Fmoc), 131.71 (Ar), 137.04 (Ar), 141.29 (Ar
72.0; H, 5.3; N, 3.2%. C27H27NO7 requires C, 71.9; H, 5.6 and
N, 3.4%); δH (CD3OD) 2.87 (1H, dd, J 9.5, 14.0, C(3)H), 3.13
(1H, dd, J 4.5, 14.0, C(3)HЈ), 3.70 (3H, s, OCH3), 4.13 (1H, t,
J 7.0, OCH Fmoc), 4.19 (1H, dd, J 7.0, 10.5, OCH Fmoc), 4.29
(1H, dd, J 7.0, 10.5, OCHЈ Fmoc), 4.37 (1H, dd, J 5.0, 9.5,
C(2)H), 6.79 (2H, d, J 8.5, ArH), 7.13 (2H, d, J 8.5, ArH), 7.27
(2H, dt, J 3.5, 7.5, ArH Fmoc), 7.37 (2H, t, J 7.5, ArH Fmoc),
7.58 (2H, dd, J 3.5, 7.5, ArH Fmoc), 7.77 (2H, d, J 7.5, ArH
Fmoc); δC (CD3OD) 37.84 (C(3)), 48.34 (CH Fmoc), 55.69
(C(2)), 57.07 (OCH3), 67.96 (CH2 Fmoc), 114.85 (Ar), 120.87
(Ar Fmoc), 126.34 (Ar Fmoc), 128.14 (Ar Fmoc), 128.74 (Ar
Fmoc), 130.58 (Ar), 131.31 (Ar), 142.53 (Ar Fmoc), 145.22
(Ar Fmoc), 158.33 (C᎐O, Fmoc), 159.98 (Ar), 175.40 (C(1));
᎐
m/z (EI) Mϩ 417 (0.2), 402 (1.5), 373 (1.3), 357 (0.8), 178 (100),
165 (30), 121 (96%).
(2S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-(2Ј,4Ј-di-
methoxyphenyl)propionic acid 11h. Following the general
method for the removal of the tert-butyl protecting group,
treatment of (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-
3-(2Ј,4Ј-dimethoxyphenyl)propionic acid tert-butyl ester 10h
(251 mg, 0.5 mmol) gave (2S)-2-(9H-fluoren-9-ylmethoxy-
carbonylamino)-3-(2Ј,4Ј-dimethoxyphenyl)propionic acid 11h
(165 mg, 74%) as a white amorphous powder. Mp 163–164 ЊC
(Found Mϩ 447.1674; C26H25NO6 requires 447.1682); [α]D16
ϩ28.1 (c 1.0 in CHCl3); νmax (KBr disc)/cmϪ1 3500–2700 (m),
3417 (m), 3182 (m), 2956 (m), 2841 (m), 1714 (s), 1691 (s), 1509
(s), 1158 (s), 831 (s), 739 (s); δH (CDCl3) 3.08 (1H, dd, J 8.0,
14.0, C(3)H), 3.14 (1H, dd, J 4.5, 14.0, C(3)HЈ), 3.76 (3H, s,
OCH3), 3.77 (3H, s, OCH3), 4.16–4.20 (1H, m, OCH Fmoc),
4.30–4.40 (2H, m, CH2 Fmoc), 4.49–4.57 (1H, m, C(2)H), 5.70
(1H, d, J 7.0, NH), 6.42 (1H, d, J 8.0, ArH), 6.45 (1H, s, ArH),
7.03 (1H, d, J 8.0, ArH), 7.29 (2H, t, J 7.5, ArH Fmoc), 7.40
(2H, t, J 7.0, ArH Fmoc), 7.47–7.58 (2H, m, ArH Fmoc), 7.75
(2H, d, J 7.0, ArH Fmoc); δC (CDCl3) 32.32 (C(3)), 47.09 (CH
Fmoc), 54.90 (C(2)), 55.22 (OCH3), 55.36 (OCH3), 67.36 (CH2
Fmoc), 98.71 (Ar), 104.57 (Ar), 116.56 (Ar), 119.97 (Ar Fmoc),
125.09 (Ar Fmoc), 127.05 (Ar Fmoc), 127.72 (Ar Fmoc),
131.70 (Ar), 141.30 (Ar Fmoc), 143.72 (Ar Fmoc), 156.27
Fmoc), 143.71 (Ar Fmoc), 153.14 (Ar), 155.62 (C᎐O, Fmoc),
᎐
170.74 (C(1)); m/z (EI) Mϩ 533 (32), 355 (11), 182 (41), 178
(100), 165 (21), 57 (23%).
General method for the removal of the tert-butyl protective group
of N-Fmoc protected substituted phenylalanines
The N-Fmoc protected tert-butyl ester (0.5 mmol) and Et3SiH
(0.2 ml, 1.25 mmol, 2.5 equiv.) were dissolved in dichloro-
methane (5 ml) under nitrogen. TFA (2 ml) was added slowly.
The reaction mixture was stirred at room temperature for
4 hours then solvent and TFA were evaporated. The residue was
dissolved in diethyl ether, and the product was precipitated by
the addition of petroleum ether. The resulting powder was then
triturated with petrol to yield the N-Fmoc protected substituted
phenylalanine derivative, usually as an amorphous powder.
(2S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-(3Ј-benzo-
ylphenyl)propionic acid 11d. Following the general method for
the removal of the tert-butyl protecting group, treatment of
(2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(3Ј-benzoyl-
phenyl)propionic acid tert-butyl ester 10d (200 mg, 0.36 mmol)
(C᎐O, Fmoc), 158.42 (Ar), 160.31 (Ar), 176.64 (C(1)); m/z (EI)
᎐
Mϩ 447 (0.44), 178 (43), 165 (37), 151 (100%).
gave
(2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(3Ј-
benzoylphenyl)propionic acid 11d (131 mg, 73%) as a white
amorphous powder. Mp 122–123 ЊC; [α]1D8 ϩ11.2 (c 1.0 in
CHCl3) (Found: C, 75.4; H, 4.9; N, 2.6%. C31H25NO5 requires
C, 75.8; H, 5.1 and N, 2.6%); νmax (KBr disc)/cmϪ1 3421 (m),
2854 (s), 1654 (s), 1598 (s), 1507 (m), 1207 (m), 840 (w) and 720
(m); δH (CDCl3) 3.15 (1H, dd, J 6.0, 14.0, C(3)H), 3.21 (1H, dd,
J 6.0, 14.0, C(3)HЈ), 4.18 (1H, t, J 6.5, CH Fmoc), 4.33 (1H, dd,
J 6.5, 10.5, OCH Fmoc), 4.40 (1H, dd, J 6.5, 10.5, OCHЈ
Fmoc), 4.47–4.62 (1H, m, C(2)H), 5.34 (1H, d, J 8.0, NH),
7.22–8.10 (17H, m, ArH Fmoc); δC (CDCl3) 37.68 (C(3)), 47.09
(CH Fmoc), 54.53 (C(2)), 67.20 (CH2 Fmoc), 119.99 (Ar
Fmoc), 125.02 (Ar), 125.07 (Ar Fmoc), 127.10 (Ar Fmoc),
127.76 (Ar Fmoc), 128.34 (Ar), 129.49 (Ar), 130.16 (Ar), 131.52
(Ar), 132.67 (Ar), 133.55 (Ar), 136.22 (Ar), 137.26 (Ar), 137.84
(2S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-(3Ј,5Ј-di-
methoxyphenyl)propionic acid 11j. Following the general
method for the removal of the tert-butyl protecting group,
treatment of (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-
3-(3Ј,5Ј-dimethoxyphenyl)propionic acid tert-butyl ester 10j
(251 mg, 0.5 mmol) gave (2S)-2-(9H-fluoren-9-ylmethoxy-
carbonylamino)-3-(3Ј,5Ј-dimethoxyphenyl)propionic acid 11j
(140 mg, 63%) as a white amorphous powder. Mp 145–146 ЊC
(Found Mϩ 447.1677; C26H25NO6 requires 447.1682); [α]D16
ϩ39.5 (c 1.0 in CHCl3); νmax (KBr disc)/cmϪ1 3600–3200 (m),
3333 (m), 3064 (m), 2925 (m), 2856 (m), 1717 (s), 1684 (s), 1533
(s), 1157 (s), 845 (m) and 737 (s); δH (CDCl3) 3.06 (1H, dd, J 6.0,
13.0, C(3)H), 3.14 (1H, dd, J 6.0, 13.0, C(3)HЈ), 3.72 (6H, s,
2 × OCH3), 4.16–4.24 (1H, m, OCH Fmoc), 4.32–4.48 (2H, m,
CH2 Fmoc), 4.65–4.75 (1H, m, C(2)H), 5.35 (1H, d, J 7.5, NH),
6.35 (3H, br s, ArH), 7.25–7.34 (2H, m, ArH Fmoc), 7.35–7.42
(2H, m, ArH Fmoc), 7.47–7.58 (2H, m, ArH Fmoc), 7.75 (2H,
d, J 7.0, ArH Fmoc); δC (CDCl3) 37.98 (C(3)), 47.07 (CH
Fmoc), 54.47 (C(2)), 55.28 (OCH3), 67.33 (CH2 Fmoc), 99.17
(Ar), 107.41 (Ar), 120.01 (Ar Fmoc), 125.11 (Ar Fmoc), 127.11
(Ar Fmoc), 127.75 (Ar Fmoc), 137.81 (Ar), 141.29 (Ar Fmoc),
(Ar), 141.30 (Ar Fmoc), 143.63 (Ar Fmoc), 155.85 (C᎐O,
᎐
Fmoc), 174.61 (C(1)), 196.93 (C᎐O); m/z (EI) Mϩ Ϫ C H 415
᎐
6
4
(0.11), 295 (0.21), 196 (0.07), 178 (100), 165 (25), 76 (8%).
(2S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-(4Ј-meth-
oxyphenyl)propionic acid 11g. Following the general method for
the removal of the tert-butyl protecting group, treatment of
(2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(4Ј-methoxy-
phenyl)propionic acid tert-butyl ester 10g (75 mg, 0.16 mmol)
143.66 (Ar Fmoc), 155.98 (C᎐O, Fmoc), 160.94 (Ar), 175.74
᎐
(C(1)); m/z (EI) Mϩ 447 (0.74), 269 (28), 178 (100), 165 (75), 151
gave
(2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(4Ј-
(60%).
methoxyphenyl)propionic acid 11g (43 mg, 64%) as a beige
amorphous powder. Mp 154–156 ЊC (lit.18 158–158.3 ЊC)
(Found Mϩ 402.1342; C24H20NO5 requires 402.1341); [α]2D1 Ϫ3.5
(c 1.0 in H2O) (lit.18 [α]D20 Ϫ2.94 (c 1.0 in H2O)) (Found: C,
(2S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-(2Ј,3Ј,4Ј-
trimethoxyphenyl)propionic acid 11k. Following the general
method for the removal of the tert-butyl protecting group,
1882
J. Chem. Soc., Perkin Trans. 1, 2001, 1876–1884

View Article Online
treatment of (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-
3-(2Ј,3Ј,4Ј-trimethoxyphenyl)propionic acid tert-butyl ester 10k
(266 mg, 0.5 mmol) gave (2S)-2-(9H-fluoren-9-ylmethoxy-
carbonylamino)-3-(2Ј,3Ј,4Ј-trimethoxyphenyl)propionic acid
11k (193 mg, 81%) as a white amorphous powder. Mp 69–71 ЊC
(Found Mϩ 477.1772; C27H27NO7 requires 477.1788); [α]D16
ϩ47.1 (c 1.0 in CHCl3) (Found: C, 68.3; H, 5.7; N, 2.8%.
C27H27NO7 requires C, 67.9; H, 5.7 and N, 2.9%); νmax (KBr
disc)/cmϪ1 3450–3250 (m), 3065 (m), 2835 (m), 1723 (s), 1496
(s), 1099 (s) and 740 (s); δH (CDCl3) 3.05 (1H, dd, J 4.0, 13.5,
C(3)H), 3.14 (1H, dd, J 4.0, 13.5, C(3)HЈ), 3.81 (3H, s, OCH3),
3.84 (3H, s, OCH3), 3.93 (3H, s, OCH3), 4.18 (1H, t, J 7.0, OCH
Fmoc), 4.28–4.38 (2H, m, CH2 Fmoc), 4.45–4.55 (1H, m,
C(2)H), 5.86 (1H, d, J 7.0, NH), 6.59 (1H, d, J 8.5, ArH), 6.85
(1H, d, J 8.5, ArH), 7.25–7.32 (2H, m, ArH Fmoc), 7.38 (2H, t,
J 7.5, ArH Fmoc), 7.54 (2H, t, J 7.0, ArH Fmoc), 7.74 (2H, d,
J 7.5, ArH Fmoc); δC (CDCl3) 32.00 (C(3)), 47.11 (CH Fmoc),
55.28 (C(2)), 55.97 (OCH3), 60.77 (OCH3), 60.98 (OCH3),
67.17 (CH2 Fmoc), 107.54 (Ar), 119.96 (Ar Fmoc), 121.70 (Ar),
125.18 (Ar Fmoc), 127.05 (Ar Fmoc), 127.71 (Ar Fmoc),
132.20 (Ar), 141.29 (Ar Fmoc), 142.06 (Ar), 143.76 (Ar
was added and stirring was continued for a further 10 min. The
reaction mixture was transferred to a separating funnel and a
further aliquot of ethyl acetate (30 ml) was added. The organic
phase was washed successively with 1 M Na2S2O3 (20 ml), water
(2 × 20 ml) and brine (40 ml), dried and evaporated. The
residue was then purified by flash chromatography on silica gel
using a suitable ethyl acetate–petroleum ether gradient.
(2S)-5-Acetoxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-
oxopentanoic acid tert-butyl ester 12a. Following the general
procedure for coupling with acid chlorides using acetoxyacetyl
chloride (0.137 g, 0.108 ml, 1 mmol), (2S)-5-acetoxy-2-(9H-
fluoren-9-ylmethoxycarbonylamino)-4-oxopentanoic acid tert-
butyl ester 12a was isolated as a yellow oil (0.165 g, 47%)
(Found Mϩ, 467.1980; C26H29NO7 requires 467.1944); [α]2D5 ϩ8.9
(c 1.09 in CH2Cl2); νmax (KBr disc)/cmϪ1 3354, 1733 and 1510;
δH (CDCl3) 1.46 (9H, s, C(CH3)3), 2.18 (3H, s, OCOCH3), 2.99
(1H, dd, J 18.0, 4.5, C(3)H), 3.13 (1H, dd, J 18.0, 4.5, C(3)HЈ),
4.22–4.40 (3H, m, OCH2 Fmoc, CH Fmoc), 4.49–4.55 (1H, m,
C(2)H), AB system (δA 4.62, δB 4.65, JAB 7.0, CH2OAc), 5.75
(1H, d, J 7.5, NH), 7.31 (2H, t, J 6.5, ArH Fmoc), 7.35 (2H, t,
J 6.5, ArH Fmoc), 7.59 (2H, d, J 8.0, ArH Fmoc), 7.77 (2H, d,
J 7.0, ArH Fmoc); δC (CDCl3) 20.37 (CH3), 27.81 (CH3), 41.00
(CH2), 47.12 (CH), 50.20 (CH), 67.22 (CH2), 67.82 (CH2), 82.89
(quat.), 119.97 (Ar), 125.17 (Ar), 127.67 (Ar), 127.72 (Ar),
141.20 (Ar), 147.75 (Ar), 147.87 (Ar), 156.02 (CO), 169.43
(CO), 170.18 (CO), 202.11 (CO); m/z (EI) 467 (Mϩ, 0.1), 366
(1.5), 178 (100), 165 (26), 57 (24), 43 (8%).
Fmoc), 143.89 (Ar), 153.22 (Ar), 156.28 (C᎐O, Fmoc), 176.18
᎐
(C(1)); m/z (EI) Mϩ 477 (0.94), 299 (4), 181 (100), 178 (30),
166 (4%).
(2S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-(3Ј,4Ј,5Ј-
trimethoxyphenyl)propionic acid 11l. Following the general
method for the removal of the tert-butyl protecting group,
treatment of (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-
3-(3Ј,4Ј,5Ј-trimethoxyphenyl)propionic acid tert-butyl ester 10l
(266 mg, 0.5 mmol) gave (2S)-2-(9H-fluoren-9-ylmethoxy-
carbonylamino)-3-(3Ј,4Ј,5Ј-trimethoxyphenyl)propionic acid
11l (226 mg, 95%) as a white amorphous powder. Mp 142–
143 ЊC (Found Mϩ 477.1801; C27H27NO7 requires 477.1788);
[α]D16 ϩ38.5 (c 1.0 in CHCl3); νmax (KBr disc)/cmϪ1 3500–3400
(m), 3065 (m), 2936 (m), 2837 (m), 1717 (s), 1689 (s), 1509 (s),
1129 (s), 823 (w) and 738 (s); δH (CDCl3) 3.04 (1H, dd, J 6.5,
13.5, C(3)H), 3.16 (1H, dd, J 6.5, 13.5, C(3)HЈ), 3.77 (6H, s,
OCH3), 3.81 (3H, s, OCH3), 4.19 (1H, t, J 6.5, OCH Fmoc),
4.32–4.46 (2H, m, CH2 Fmoc), 4.70–4.80 (1H, m, C(2)H), 5.45
(1H, d, J 8.0, NH), 6.41 (2H, s, ArH), 7.27 (2H, t, J 7.5, ArH
Fmoc), 7.38 (2H, t, J 7.5, ArH Fmoc), 7.48–7.57 (2H, m, ArH
Fmoc), 7.75 (2H, d, J 7.5, ArH Fmoc), 9.11 (1H, br s, CO2H);
δC (CDCl3) 38.10 (C(3)), 47.04 (CH Fmoc), 54.67 (C(2)), 56.10
(OCH3), 60.85 (OCH3), 67.33 (CH2 Fmoc), 106.33 (Ar), 120.07
(Ar Fmoc), 124.98 (Ar Fmoc), 127.11 (Ar Fmoc), 127.83 (Ar
Fmoc), 131.46 (Ar), 137.06 (Ar), 141.31 (Ar Fmoc), 143.54
(2S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-4-oxo-
hexanoic acid tert-butyl ester 12b. Following the general
procedure for coupling with acid chlorides using propanoyl
chloride (0.093 g, 0.087 ml, 1 mmol) gave (2S)-2-(9H-fluoren-9-
ylmethoxycarbonylamino)-4-oxohexanoic acid tert-butyl ester
12b isolated as a brown oil (0.149 g, 47%) (Found Mϩ 423.2053;
C25H29NO5 requires 423.2046); νmax (KBr disc)/cmϪ1 3339 and
1720; δH (CDCl3) 1.06 (3H, t, J 7.0, C(5)H3), 1.45 (9H, s,
C(CH3)3), 2.36–2.49 (2H, m, CH2), 2.92 (1H, dd, J 4.5, 18.0,
C(3)H), 3.13 (1H, dd, J 4.5, 18.0, C(3)HЈ), 4.21 (1H, t, J 7.0,
CH Fmoc), 4.31 (1H, dd, J 7.5, 10.5, OCHЈ Fmoc), 4.40 (1H,
dd, J 7.5, 10.5, OCHЉ Fmoc), 4.45–4.48 (1H, m, C(2)H), 5.41
(1H, br s, NH), 7.20 (2H, t, J 7.5, ArH Fmoc), 7.39 (2H, t, J 7.5,
ArH Fmoc), 7.58–7.60 (2H, m, ArH Fmoc), 7.75 (2H, d, J 7.0,
ArH Fmoc); δC (CDCl3) 27.85 (CH3), 35.95 (CH2), 44.04 (CH2),
47.12 (CH), 50.59 (CH), 67.09 (CH2), 82.29 (quat.), 119.96
(Ar), 125.14 (Ar), 127.04 (Ar), 127.69 (Ar), 141.28 (Ar), 143.72
(Ar), 143.92 (Ar), 156.08 (CO), 169.98 (CO), 209.26 (CO);
m/z (EI) 423 (Mϩ, 0.1), 322 (7), 178 (100), 165 (11), 57 (12%).
(Ar Fmoc), 153.26 (Ar), 156.07 (C᎐O, Fmoc), 175.67 (C(1));
᎐
m/z (EI) Mϩ 477 (1), 299 (0.5), 252 (5), 181 (100), 178 (23), 165
(32%).
(2S)-5-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)-2-(9H-fluoren-9-
ylmethoxycarbonylamino)-4-oxopentanoic acid tert-butyl ester
12d. Following the general procedure for coupling with acid
chlorides using phthalimidoglycine chloride (0.224 g, 1 mmol),
(2S)-5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-2-(9H-fluoren-9-yl-
methoxycarbonylamino)-4-oxopentanoic acid tert-butyl ester
12d was isolated as light yellow crystals (0.179 g, 43%), mp 115–
116 ЊC (Found (M Ϫ CO2But)ϩ 453.1431; C32H30N2O7 requires
453.1451); [α]D25 ϩ36.1 (c 1.02 in CH2Cl2); νmax (KBr disc)/cmϪ1
3360 and 1720; δH (CDCl3) 1.45 (9H, s, C(CH3)3), 3.10 (1H, dd,
J 4.0, 18.0, C(3)H), 3.25 (1H, dd, J 4.0, 18.0, C(3)HЈ), 4.22
(1H, t, J 7.0, CH Fmoc), 4.36 (2H, d, J 7.0, OCH2 Fmoc), 4.49
(2H, s, C(16)H2), 4.52–4.55 (1H, m, C(2)H), 5.81 (1H, d, J 7.9,
NH), 7.29–7.32 (2H, m, ArH Fmoc), 7.38 (2H, t, ArH Fmoc),
7.60 (2H, d, J 7.3, ArH Fmoc), 7.69–7.75 (4H, m, ArH Fmoc,
ArH), 7.84–7.87 (2H, m, ArH); δC (CDCl3) 27.84 (CH3), 41.93
(CH2), 46.97 (CH2), 47.08 (CH), 50.23 (CH), 67.29 (CH2), 82.96
(quat.), 119.93 (Ar), 123.58 (Ar), 125.21 (Ar), 127.10 (Ar),
127.68 (Ar), 131.97 (Ar), 134.23 (Ar), 141.25 (Ar), 143.80 (Ar),
156.08 (CO), 167.45 (CO), 169.26 (CO), 200.57 (CO); m/z (EI)
453 (M Ϫ COOBut, 0.3)ϩ, 178 (100), 165 (10), 160 (15%).
General procedure for the coupling reaction of zinc reagent 1 with
acid chlorides
Zinc–copper couple (0.294 g, 4.5 mmol, 6.0 equiv.) was placed
in a 50 ml round-bottomed flask with side arm which was
repeatedly evacuated (with heating using a hot air gun) and
flushed with nitrogen. Toluene–DMA (93 : 7, 0.3 ml) was
added, and the resultant mixture was allowed to stir for a
further 30 min under nitrogen. N-(9-9H-Fluorenylmethoxy-
carbonyl)-3-iodo--alanine-tert-butyl ester 2 (0.370 g, 0.75
mmol) in toluene–DMA (93 : 7, 0.5 ml under nitrogen) was
added to the flask and stirred at 50 ЊC until no starting material
remained as judged by TLC (4 : 1, petroleum ether–ethyl
acetate). The supernatant was carefully removed via a syringe
(care to be taken to avoid transferring too much zinc powder)
and added dropwise to a solution of the acid chloride (1.0
mmol) in toluene–DMA (93 : 7, 1 ml) and Pd(PPh3)2Cl2 (53 mg,
10 mol%) in a dried round-bottomed flask under nitrogen, and
the mixture was heated at 50 ЊC for 4 hours. The solution was
allowed to cool to room temperature and ethyl acetate (20 ml)
J. Chem. Soc., Perkin Trans. 1, 2001, 1876–1884
1883

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(2S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-4-oxohex-5-
enoic acid tert-butyl ester 12e. Following the general procedure
for coupling with acid chlorides using acryloyl chloride (0.091 g,
0.081 ml, 1 mmol), (2S)-2-(9H-fluoren-9-ylmethoxycarbonyl-
amino)-4-oxohex-5-enoic acid tert-butyl ester 12e was isolated
as a colourless oil (0.133 g, 42%) (Found Mϩ 421.1886;
C25H27NO5 requires 421.1889); [α]2D5 ϩ13.6 (c 1.195 in CH2Cl2);
νmax (KBr disc)/cmϪ1 3334, 1723 and 1508; δH (CDCl3) 1.45 (9H,
s, C(CH3)3), 3.14 (1H, dd, J 4.5, 18.0, C(3)H), 3.33 (1H, dd,
J 4.5, 18.0, C(3)HЈ), 4.12 (1H, t, J 7.0, CH Fmoc), 4.30–4.34
(1H, m, C(5)H), 4.37–4.41 (1H, m, C(5)HЈ), 4.51–4.56 (1H, m,
C(2)H), 5.81 (1H, d, J 8.0, NH), 5.92 (1H, d, J 10.5, C(6)Hcis),
6.26 (1H, d, J 18.0, C(6)Htrans), 6.35 (1H, dd, J 10.4, 18.0,
C(5)H), 7.30 (2H, t, J 7.5, ArH), 7.39 (2H, t, J 7.5, ArH), 7.59
(2H, d, J 7.0, ArH), 7.75 (2H, d, J 7.0, ArH); δC (CDCl3) 27.85
(CH3), 41.42 (CH2), 47.15 (CH), 50.53 (CH), 67.15 (CH2), 82.43
(quat.), 119.96 (Ar), 125.17 (Ar), 127.06 (Ar), 127.68 (Ar),
129.50 (CH2), 136.18 (CH), 141.27 (Ar), 143.76 (Ar), 143.92
(Ar), 156.08 (CO), 169.85 (CO), 198.16 (CO); m/z (EI) 421 (Mϩ,
0.4), 320 (1), 196 (3), 178 (100), 165 (15), 57 (10%).
ylmethoxycarbonylamino)-4-oxopentane-1,5-dioic acid 1-tert-
butyl ester 5-ethyl ester 14b was isolated as a colourless oil
(0.105 g, 30%) (Found Mϩ, 467.1923; C26H29NO7 requires
467.1944); νmax (KBr disc)/cmϪ1 3372 and 1729; δH (CDCl3) 1.38
(3H, t, J 7, OCH2CH3), 1.46 (9H, s, C(CH3)3), 3.40–3.45 (2H,
m, C(3)H2), 4.20–4.42 (5H, m, CH Fmoc, OCH2 Fmoc,
OCH2CH3), 4.60–4.65 (1H, m, C(2)H), 5.68 (1H, d, J 8, NH),
7.31 (2H, t, J 7.5, ArH Fmoc), 7.40 (2H, m, ArH Fmoc), 7.58
(2H, d, J 7.5, ArH Fmoc), 7.76 (2H, d, J 7.5, ArH Fmoc);
δC (CDCl3) 13.97 (CH3), 27.84 (CH3), 42.03 (CH2), 50.37 (CH),
59.95 (CH), 62.80 (CH2), 67.25 (CH2), 83.20 (quat.), 120.00
(Ar), 125.12 (Ar), 127.08 (Ar), 127.73 (Ar), 141.31 (Ar), 143.72
(Ar), 155.89 (CO), 160.11 (CO), 169.25 (CO), 191.70 (CO);
m/z (EI) 467 (Mϩ, 0.1), 368 (1), 178 (100), 165 (8), 57 (15%).
Acknowledgements
We thank Medivir (UK) for partial funding of a studentship
(H. J. C. D.) and the European Union for a fellowship under the
TMR Network FMRX-CT 96-0011 project (C. A. G. N. M.).
We also thank Dr Jonathan Clark for useful discussions and
Mr E. Hart for his invaluable technical assistance.
(2S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)hex-5-enoic
acid tert-butyl ester 14a
N-(9H-Fluoren-9-ylmethoxycarbonyl)-3-iodo--alanine tert-
butyl ester 2 (370 mg, 0.75 mmol) dissolved in dry THF (0.5 ml)
was added dropwise, via a syringe, to a slurry of activated zinc
(150 mg in 0.3 ml of THF, prepared as described previously)
previously cooled at 0 ЊC. The reaction mixture was then
allowed to warm up to room temperature and stirred for one
hour to give a solution of the organozinc reagent 1. Stirring of
the organozinc reagent solution was stopped to allow the zinc
powder to settle. The supernatant was carefully removed via a
syringe (care to be taken to avoid transferring too much zinc
powder) and added dropwise to a solution of CuCNؒ2LiCl
(0.75 mmol, 1 equiv.) in THF (1 ml) at Ϫ10 ЊC. The solution
was stirred for 15 min, and allyl chloride (0.077 g, 0.083 ml,
1 mmol) was added dropwise. The cooling bath was removed
and the solution was stirred at room temperature overnight.
Ethyl acetate (20 ml) was added and stirring was continued for
a further 10 min. The reaction mixture was transferred to a
separating funnel and a further aliquot of ethyl acetate (30 ml)
was added. The organic phase was washed successively with
1 M Na2S2O3 (20 ml), water (2 × 20 ml) and brine (40 ml), dried
and evaporated. The residue was then purified by flash chroma-
tography on silica gel using a suitable ethyl acetate–petroleum
ether gradient. (2S)-2-(9H-Fluoren-9-ylmethoxycarbonyl-
amino)hex-5-enoic acid tert-butyl ester was isolated as a colour-
less oil (0.183 g, 60%) (Found Mϩ, 407.2067; C25H29NO4
requires 407.2096); νmax (KBr disc)/cmϪ1 3338, 1722 and 1520;
δH (CDCl3) 1.48 (9H, s, C(CH3)3), 1.73–1.78 (1H, m, C(3)H),
1.91–1.97 (1H, m, C(3)HЈ), 2.04–2.15 (2H, m, C(4)H2), 4.23
(1H, t, J 7.0, CH Fmoc), 4.28–4.31 (1H, m, C(2)H), 4.38–4.40
(2H, m, OCH2 Fmoc), 5.01 (1H, d, J 17.0, C(6)Htrans), 5.06 (1H,
d, J 10.0, C(6)Hcis), 5.32 (1H, d, J 8.0, NH), 5.77–5.85 (1H, m,
C(5)H), 7.31 (2H, t, J 7.5, ArH Fmoc), 7.39 (2H, t, J 7.5, ArH
Fmoc), 7.60 (2H, d, J 7.5, ArH Fmoc), 7.76 (2H, d, J 7.5, ArH
Fmoc); δC (CDCl3) 28.04 (CH3), 29.36 (CH2), 32.18 (CH2),
47.26 (CH), 53.99 (CH), 66.92 (CH2), 82.19 (quat.), 115.59
(CH2), 119.99 (Ar), 125.11 (Ar), 127.06 (Ar), 127.70 (Ar),
137.21 (CH), 141.33 (Ar), 143.85 (Ar), 143.99 (Ar), 155.83
(CO), 171.59 (CO); m/z (EI) 407 (Mϩ, 1.5), 306 (11), 179 (100),
165 (50), 57 (63), 41 (10%).
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1884
J. Chem. Soc., Perkin Trans. 1, 2001, 1876–1884