Efficient enantioselective synthesis of condensed and aromatic-ring- substituted tyrosine derivatives

Article abstract of DOI:10.1021/jo060704c

An efficient access to both condensed and conjugated tyrosine analogues of high enantiomeric purity is described. Novel ring-substituted tyrosines were synthesized by Suzuki cross couplings of appropriately protected L-3-iodotyrosine with a series of activated and deactivated boronic acid derivatives to achieve the target compounds in high yields. D- and L-4-hydroxy-1-naphthylalanines were readily prepared from the corresponding α-enamide in two different approaches, by asymmetric hydrogenation as well as by unselective hydrogenation and enzymatic resolution of the racemic mixture.

Full text of DOI:10.1021/jo060704c

Efficient Enantioselective Synthesis of Condensed and
Aromatic-Ring-Substituted Tyrosine Derivatives
Sebastian Kno¨r, Burkhardt Laufer, and Horst Kessler*
Lehrstuhl II fu¨r Organische Chemie, Department Chemie, Technische UniVersita¨t Mu¨nchen,
Lichtenbergstrasse 4, Garching D-85747, Germany
Horst.Kessler@ch.tum.de
ReceiVed April 3, 2006
An efficient access to both condensed and conjugated tyrosine analogues of high enantiomeric purity is
described. Novel ring-substituted tyrosines were synthesized by Suzuki cross couplings of appropriately
protected L-3-iodotyrosine with a series of activated and deactivated boronic acid derivatives to achieve
the target compounds in high yields. D- and L-4-hydroxy-1-naphthylalanines were readily prepared from
the corresponding R-enamide in two different approaches, by asymmetric hydrogenation as well as by
unselective hydrogenation and enzymatic resolution of the racemic mixture.
Introduction
pharmaceutical research. Thus, there is a great demand for
methods allowing the synthesis of a variety of derivatives in a
short time. In the past few years several groups have reported
strategies for the synthesis of aromatic substituted phenyl-
alanines,4-9 tryptophans,7,8 and naphthylalanines.4,7,8 However,
to the best of our knowledge, methods for the synthesis of the
corresponding tyrosine derivatives have not been reported in
the literature yet.
In contrast to phenylalanine, tyrosine provides an additional
hydroxyl group in the side chain which may be crucial for the
activity or selectivity of biologically active compounds, e.g.,
by acting as a hydrogen bond donor or acceptor. To enable
systematic studies of structure-activity relationships going along
with the tyrosine residue, an efficient access to a wide range of
substituted tyrosine analogues is required.
Nonproteinogenic amino acids play an important role in drug
development. While proteinogenic amino acids provide limited
variation in size and shape, the introduction of unusual substit-
uents allows a systematic study of the structure-activity
relationship (SAR). Consequently, nonproteinogenic amino acids
have been found to significantly improve the biological proper-
ties of numerous biologically active peptides and peptidomi-
metics, e.g., by limiting conformational flexibility, enhancing
enzymatic stability, and improving pharmacodynamics or
bioavailability.1-3 Especially modified aromatic amino acids are
important structural features in various pharmaceuticals which
are currently under development or have already been introduced
into the market. Among the latter are, for example, the broad-
spectrum antibiotics Ampicillin and Amoxicillin, which contain
a D-phenylglycine and a D-4-hydroxyphenylglycine moiety,
respectively, and Nafarelin, a luteinizing hormone releasing
hormone (LHRH) analogue for treatment of endometrioses
comprising a D-2-naphthylalanine residue. It is evident that such
unnatural aromatic amino acids are indispensable tools in
In our approach toward tyrosine analogues with extended
aromatic side chain residues, we focused on strategies that allow
an easy and short access to a variety of compounds in a few
(4) Wang, W.; Zhang, J.; Xiong, C.; Hruby, V. J. Tetrahedron Lett. 2002,
43, 2137-2140.
(5) Burk, M. J.; Lee, J. R.; Martinez, J. P. J. Am. Chem. Soc. 1994, 116,
10847-10848.
(6) Burk, M. J.; Gross, M. F.; Harper, T. G. P.; Kalberg, C. S.; Lee, J.
R.; Martinez, J. P. Pure Appl. Chem. 1996, 68, 37-44.
(7) Wang, W.; Xiong, C.; Zhang, J.; Hruby, V. J. Tetrahedron 2002,
58, 3101-3110.
(8) Wang, W.; Cai, M.; Xiong, C.; Zhang, J.; Trivedi, D.; Hruby, V. J.
Tetrahedron 2002, 58, 7365-7374.
(9) Kotha, S.; Lahiri, K. Biopolymers 2003, 69, 517-528.
* To whom correspondence should be addressed. Phone: +49-089-289-13300.
Fax: +49-089-289 13210.
(1) Jeng, A. Y.; Savage, P.; Beil, M. E.; Bruseo, C. W.; Hoyer, D.; Fink,
C. A.; Trapani, A. J. Clin. Sci. 2002, 103, 98S-101S.
(2) Goodman, M.; Shao, H. Pure Appl. Chem. 1996, 68, 1303-1308.
(3) Dechantsreiter, M. A.; Planker, E.; Matha¨, B.; Lohof, E.; Ho¨lzemann,
G.; Jonezyk, A.; Goodman, S. L.; Kessler, H. J. Med. Chem. 1999, 42,
3033-3040.
10.1021/jo060704c CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/22/2006
J. Org. Chem. 2006, 71, 5625-5630
5625

Kno¨r et al.
To demonstrate the further procedure and to verify the optical
purity of our products, we deprotected samples of 7a and 7d to
apply them in solid-phase peptide synthesis. The benzyl ester
in both compounds could be cleaved chemoselectively using
lithium hydroxide to give the free acids 8a and 8b in 86% and
83% yield, respectively (Scheme 2). Alternatively, simultaneous
cleavage of both benzyl groups can be achieved by hydrogena-
tion with palladium on charcoal, yielding 9a and 9b in 95%
and 87%, respectively.
The latter compounds were coupled to the amino free resin
bound L-valine using 1.8 equiv of the amino acids 9a and 9b,
respectively, TBTU, and HOBt in NMP for 30 min. After
cleavage from the resin and deprotection, the resulting dipeptides
H-m-(phenyl)Tyr-Val-OH (10a) and H-m-(o-tolyl)Tyr-Val-OH
(10b) were isolated in high purity (Scheme 3). A formation of
side products due to the free phenolic side chain was not
observed.
FIGURE 1. Structures of condensed and aromatic-ring-substituted
tyrosine derivatives.
steps, avoiding complicated protecting group chemistry. Herein
we report a general three-step procedure for the synthesis of
enantiomerically pure 3-aryl-substituted L-tyrosine analogues of
types 1 and 2 via a Suzuki-type cross coupling reaction (Figure
1). To extend the aromatic residue, we used a second approach
in which we synthesized the condensed 2-naphthylalanine
analogue of tyrosine 3 via an asymmetric hydrogenation of the
corresponding R-enamide as a key step. In an alternative
approach we hydrogenated the R-enamide unselectively and split
the racemic mixture using acylase I.10 This procedure provides
a much cheaper approach in cases where both enantiomers are
desired.
The corresponding diastereomeric dipeptides H-m-(phenyl)-
Tyr-D-Val-OH (10c) and H-m-(o-tolyl)Tyr-D-Val-OH (10d),
respectively, were synthesized in an analogous way by coupling
to D-valine. NMR and HPLC analyses of 10a-d showed the
formation of only one single isomer, proving that no reasonable
racemization occurred during our synthesis.
Enantioselecive Synthesis of 4-Hydroxy-1-naphthylalanine
Derivatives. A synthesis of 4-hydroxy-1-naphthylalanine has
already been reported by Vela et al.12 By their procedure,
4-hydroxynaphthalene-1-carbaldehyde (11) was condensed with
hippuric acid to form the (Z)-oxazolone, which was subsequently
opened using ethoxide and hydrogenated to give the N-benzoyl-
protected 4-hydroxy-1-naphthylalanine ethyl ester. The cleavage
of the amino protection group was accomplished by refluxing
in 6 N hydrochloric acid in dioxane. Obviously, their procedure
requires harsh conditions, and it is not stereoselective. Therefore,
we developed a more efficient access to achieve the compound
in high enantiomeric purity via Horner-Emmons olefination
and hydrogenation, applying protection groups which can be
cleaved under mild conditions to conserve the enantiomeric
purity.
In our synthesis we also started from commercially available
11 whose hydroxy group was protected as a tert-butyldimeth-
ylsilyl (TBS) ether in 88% yield (Scheme 4). In our initial
experiments, we used a benzyl protection group instead;
however, the final cleavage by catalytic hydrogenation led to a
partial hydrogenation of the naphthalene residue. This was
circumvented by the use of the TBS group. The Horner-
Emmons olefination of aldehyde 12 with Schmidt’s Boc-R-
phosphonoglycine trimethyl ester gave the dehydroamino acid
13 with the Z-configuration as the major product13 (Z:E ) 93:
7)14 in 91% yield.15,16 The TBS group in this system was found
to be quite acid sensible. For that reason, triethylamine had to
be added to the eluent for column chromatography to avoid
decomposition and great losses in yield.
Results and Discussion
Synthesis of Aromatic-Ring-Substituted Tyrosine Deriva-
tives. Our synthesis of 3-aryl-substituted L-tyrosine derivatives
started with commercially available L-3-iodotyrosine (4). The
amino function was protected with a tert-butyloxycarbonyl group
(Boc) to ensure stability under Suzuki coupling conditions
(Scheme 1). As expected, attempts to use compound 4 or 5
directly for Suzuki couplings failed, probably due to complex-
ation of palladium after insertion into the carbon-iodine bond
by the neighboring free phenolic hydroxyl group, which made
a side chain protection necessary. Since for standard peptide
coupling purposes, in both solution and the solid phase, a
protection of the phenolic side chain is not crucial,11 we
protected both the phenolic side chain and the carboxylic acid
in one step as a benzyl ether and a benzyl ester, respectively.
This procedure avoids an additional protection and deprotection
step as both groups can be removed simultaneously by
hydrogenation, but offers the opportunity of a selective saponi-
fication of the benzyl ester when a side chain protection is
needed. The benzyl protection was performed under mild
conditions using sodium carbonate as the base to give the fully
protected amino acid 6 in 93% yield and without loss of
enantiomeric purity as shown below.
For Suzuki cross couplings we used PdOAc2/P(o-tolyl)3 as
the catalyst and sodium carbonate as the base, a system which
has proven to give good results in similar systems.4-8 Thus, a
series of 3-aryl-substituted tyrosine derivatives were synthesized
in moderate to high yields using a variety of activated and
deactivated phenylboronic acids as well as heteroaromatic
boronic acids (Table 1). The formation of the dimeric homo-
coupling product was generally less than 2% as measured by
HPLC-MS, except for the 3-chlorophenylboronic acid, with
which greater amounts of this side product were formed.
For the asymmetric hydrogenation of 13 we chose Burk’s
[1,2-bis((2S,5S)-2,5-diethylphospholano)benzene](cyclooctadiene)-
rhodium(I) trifluoromethanesulfonate [(S,S)-Et-DuPHOS-(COD)-
RhI]OTf, which gives high yields (>95%) and high enantiomeric
(12) Vela, M. A.; Fronczek, F. R.; Horn, G. W.; McLaughlin, M. L. J.
Org. Chem. 1990, 55, 2913-2918.
(13) The Z configuration was assigned by NOESY.
(10) Birnbaum, S. M.; Levintow, L.; Kingsley, R. B.; Greenstein, J. P.
J. Biol. Chem. 1952, 194, 455-470.
(11) Following our procedure for peptide coupling, side-chain-unprotected
tyrosine and its analogues can be coupled without side reactions.
(14) The Z:E ratio was determined by HPLC.
(15) Schmidt, U.; Lieberknecht, A.; Wild, J. Synthesis 1984, 53-60.
(16) Schmidt, U.; Griesser, H.; Leitenberger, V.; Lieberknecht, A.;
Mangold, R.; Meyer, R.; Riedl, B. Synthesis 1992, 487-490.
5626 J. Org. Chem., Vol. 71, No. 15, 2006

EnantioselectiVe Synthesis of Tyrosine DeriVatiVes
SCHEME 1. Synthesis of 3-Aryl-Substituted Tyrosine Derivativesa
a Reagents and conditions: (a) Boc2O, dioxane/H2O, 0 °C, 18 h, 96%; (b) BnBr, Na2CO3, acetone, rt, 5 h, 93%; (c) ArB(OH)2, Na2CO3, Pd(OAc)2,
P(o-tolyl)3, DME/H2O, 80 °C, 4-6 h, 39-99%.
TABLE 1. Suzuki Cross Coupling of 6 with Arylboronic Acids
SCHEME 3. Solid-Phase Peptide Synthesis Applying
Side-Chain-Unprotected Tyrosine Analoguesa
a Reagents and conditions: (a) (i) TBTU, HOBt, NMP, rt, 30 min; (ii)
TFA/DCM/H2O (50:40:10, v/v/v), rt, 1 h, >98% purity.
enantiomer in similar enantiomeric purities.5,6,17 Thus, a preced-
ing separation of the two isomers is not essential. In our first
attempts, however, working in MeOH4-8 as solvent, we
observed no conversion even at high pressures (1-50 bar).
Therefore, we scanned various solvents and found the highest
conversion rates when using DCM or THF (Table 2), but to
our surprise, in both solvents, working at 1 bar of pressure, we
were not able to reach complete conversion even at prolonged
reaction times and/or by addition of fresh catalyst. Separation
and analysis of the unreacted starting material gave pure E
isomer of the dehydroamino acid 13, indicating a much slower
reaction rate for this isomer. For complete conversion of the
obtained Z/E mixture of 13 the pressure had to be raised to 40
bar using DCM as the solvent. The pure Z isomer, which could
be isolated in 75% yield from 12, proved to react to completion
at 1 bar of pressure.
Working under 40 bar of hydrogen pressure in DCM, the
S,S catalyst gave the amino acid derivative 14 with an absolute
S configuration on the basis of the selectivity of the (S,S)-Et-
DuPHOS ligand5,6,17 in 95% yield. The enantiomeric purity was
determined after subsequent cleavage of the TBS group and
the methyl ester. The resulting free acid (S)-15 was coupled to
amino free resin bound L-valine using the conditions described
in Scheme 3 above. Cleavage from the resin and deprotection
gave the dipeptide H-(4-hydroxy)Nal-Val-OH (16) as a single
diastereomer, as proven by HPLC and NMR analysis. As a
reference, we synthesized the diastereomeric mixture H-(D/L)-
(4-hydroxy)Nal-Val-OH (17), which was obtained by unselec-
tive hydrogenation of 13 with palladium on charcoal and
subsequent deprotection and coupling to L-valine. The enan-
tiomeric purity of 14 and (S)-15 was assigned to be greater than
95%. In addition, the catalyst proved to work very efficiently
(we worked with a catalyst-to-substrate ratio of 1:500), and we
were able to synthesize the (S)-4-hydroxy-1-naphthylalanine
derivative 14 in a high overall yield of 76% using three steps.
a Yields refer to isolated pure products.
SCHEME 2. Regioselective Deprotection of
3-Aryl-Substituted Tyrosine Derivativesa
a Reagents and conditions: (a) LiOH, THF/H2O, 0 °C f rt, 18 h, 86%
(8a), 83% (8b); (b) H2, Pd/C, MeOH/AcN(Me)2, 6 h, 95% (9a), 87% (9b).
access (97% ee) when applied to hydrogenation of dehy-
droamino acids. Furthermore, using this type of catalyst, both
diastereomers, Z and E, are hydrogenated to give the same
(17) Burk, M. J.; Feaster, J. E.; Nugent, W. A.; Harlow, R. L. J. Am.
Chem. Soc. 1993, 115, 10125-10138.
J. Org. Chem, Vol. 71, No. 15, 2006 5627

Kno¨r et al.
SCHEME 4. Enantionselective Synthesis of 4-Hydroxynaphthylalanine Derivativesa
a Reagents and conditions: (a) (TBS)Cl, imidazole, THF, 0 °C f rt, 18 h, 88%; (b) (MeO)2P(O)CH(NHBoc)CO2Me, DBU, THF, 0 °C f rt, 18 h, 91%;
(c) H2, [(S,S)-Et-DuPHOS-(COD)-RhI]OTf, DCM, 40 bar, 6 h, 95%; (d) (i) TBAF, THF, 0 °C, 15 min; (ii) LiOH, THF/H2O, rt, 3 h, 89% (two steps); (e)
(MeO)2P(O)CH(NHCbz)CO2Me, DBU, THF, 0 °C f rt, 18 h, 87%; (f) (i) H2, Pd/C, MeOH, 1 bar, 2 h; (ii) Ac2O, NEt3, DCM, rt, 18 h, 76% (two steps);
(g) (i) TBAF, THF, 0 °C, 15 min; (ii) LiOH, THF/H2O, rt, 3 h; (iii) acylase I, H2O (pH 7-8), 3 h, 40 °C, 46% (21, three steps); (iv) SOCl2, MeOH, rt, 18h,
41% (22, four steps).
TABLE 2. Asymmetric Hydrogenation of Dehydroamino Acid 13
Prolonged reaction times (18 h) led to partial hydrogenation of
the naphthalene residue. The resulting racemic mixture was
directly acetylated by treatment with acetic acid anhydride in
the presence of triethylamine to yield 19 in 76% yield over two
steps. Applying the fully protected compound 19 to the
enzymatic resolution led to an unseparable product mixture due
to a partial loss of the TBS group and partial cleavage of the
methyl ester. Thus, both protecting groups were removed prior
to the resolution, improving the solubility in aqueous conditions.
To avoid additional separation steps, a one-pot procedure was
developed: the TBS ether and the methyl ester were subse-
quently cleaved, and the racemic mixture was resolved using
acylase I to give the L isomer 20 as a free amine, while the D
isomer 21 remained in the N-acetylated form, which was easily
separated by extraction in high purity (93% by HPLC analy-
sis).10 As the isolation of the free L-amino acid 20 by
crystallization failed, it was converted to the corresponding
methyl ester 22 and also isolated by extraction (90% purity by
HPLC analysis). Further purification by column chromatography
gave the pure enantiomer 2210 and 21 (96% ee)18 in high yields
(41% over four steps and 46% over three steps, respectively).
Z:E ratio
of 13
pressure
(bar)
time
(h)
conversion
(%)
yielda
(%)
solvent
93:7
93:7
93:7
93:7
93:7
99:1
93:7
MeOH
MeOH
benzene
THF
DCM
DCM
1
50
1
1
1
24
24
24
24
24
24
4
0
0
<10
93
93
99
100
b
b
91
b
95
1
40
DCM
a Yields refer to isolated pure products. b Yield not determined.
The 1H NMR analysis of several N-Boc-protected compounds,
e.g., 14 and 15, showed two groups of proton signals which
can be referred to the existence of two rotamers as we have
already reported more than three decades ago.19 As usual, for
N-acetyl-protected or unprotected compounds the existence of
rotamers has not been observed.
Nevertheless, the high costs for the catalyst limit this
procedure, especially if both enantiomers, the L and the D forms,
are needed. Therefore, we used a second approach offering a
concurrent synthesis of both enantiomers. Here we condensed
the aldehyde 12 in a way analogous to that described above
with Cbz-R-phosphonoglycine trimethyl ester to give the (Z)-
dehydroamino acid 1813 (Z:E > 95:5)14 in 87% yield. Again,
triethylamine had to be added to the eluent for column
chromatography to avoid decomposition. This time, the hydro-
genation was carried out using palladium on charcoal as the
catalyst, leading to a simultaneous hydrogenation of the double
bond and cleavage of the Cbz protection group. The reaction
was monitored by TLC and mass spectroscopy and quenched
after complete conversion to the saturated free amine (4 h).
Conclusion
The sequences described above provide high-yielding ste-
reoselective access to a variety of tyrosine analogues. We
developed a convenient route for the synthesis of aromatic-ring-
substituted tyrosine derivatives via a Suzuki cross coupling
reaction, thereby introducing a variety of substituted and
unsubstituted aromatic as well as heteroaromatic residues in high
yield. Even heavily deactivated boronic acids could be coupled
in moderate yields. To provide a structural alternative, methods
for the asymmetric synthesis of the ring-condensed tyrosine
analogue 4-hydroxynaphthylalanine are described. For the
preparation, two alternative methologies were explored to offer
the most economical access if only one or both enantiomers
are desired. In the latter case, the unselective hydrogenation of
(18) The enantiomeric purity of 21 was determined by chiral HPLC
analyses after conversion to the corresponding methyl ester.
(19) Kessler, H.; Molter, M. Angew. Chem., Int Ed. Engl. 1973, 12,
1011-1012.
5628 J. Org. Chem., Vol. 71, No. 15, 2006

EnantioselectiVe Synthesis of Tyrosine DeriVatiVes
Hz, 2H), 7.35 (dd, J ) 7.2, 7.2 Hz, 2H), 7.31-7.22 (m, 6H), 7.22-
7.10 (m, 2H), 7.02 (d, J ) 8.3 Hz, 1H), 5.02 (s, 2H), 4.36 (dd, J
) 8.2, 5.1 Hz, 1H), 3.15 (dd, J ) 13.9, 4.8 Hz, 1H), 2.91 (dd, J )
13.8, 8.7 Hz, 1H), 1.36 (s, 9H); 13C NMR (90 MHz, MeOH-d4) δ
175.4, 157.7, 155.9, 140.0, 138.8, 132.9, 132.5, 131.3, 130.7, 130.4,
129.3, 128.8, 128.6, 128.2, 127.8, 114.8, 80.5, 71.7, 56.3, 37.9,
28.7; HRMS (EI) m/z calcd for C27H29NO5 447.20456, found
447.20400.
the corresponding dehydroamino acid and enzymatic separation
of the racemic mixture is the most cost efficient access, as
acylase I is cheap and both enantiomers are obtained simulta-
neously. In contrast, if only one single enantiomer is required,
the racemic synthesis is associated with 50% loss of substance
due to the undesired second enantiomer. The asymmetric
hydrogenation of the dehydroamino acid provides a high-
yielding access to a single enantiomer. Although the catalyst is
quite expensive, its great efficiency and the high yields make
this procedure the most economic when only one enatiomer is
desired.
(S)-Nr-tert-Butyloxycarbonyl-m-phenyltyrosine (9a). Palla-
dium on charcoal (5% Pd/C, 0.23 g, 10 mol % Pd) was added to
a degassed solution of 7a (0.60 g, 1.11 mmol) in N,N-dimethylac-
etamide/MeOH (1:1, 30 mL). Hydrogenation was carried out at 1
bar of hydrogen pressure for 6 h. The catalyst was removed by
filtration, the solvent removed under reduced pressure, and the
residue purified by flash chromatography on silica gel (EtOAc/
hexane, 1:2; 1% AcOH), yielding 9a (373 mg, 95%) as a colorless
solid: Rf ) 0.26 (EtOAc/hexane, 1:1; 1% AcOH); [R]23D +17.9 (c
Experimental Section
(S)-Nr-tert-Butyloxycarbonyl-O-benzyl-m-iodotyrosine Benzyl
Ester (6). To a solution of 5 (2.74 g, 6.73 mmol, 1.0 equiv) in
acetone (20 mL) were added K2CO3 (2.90 g, 21.0 mmol, 3.0 equiv)
and benzyl bromide (1.38 mL, 14.4 mmol, 2.2 equiv), and the
mixture was heated under reflux for 5 h. After the solvent was
evaporated, the residue was taken up in CHCl3 (240 mL), washed
with saturated aqueous NaHCO3 (3 × 80 mL), dried over Na2SO4,
and evaporated. Flash chromatography on silica gel (EtOAc/hexane,
1:4) yielded 6 (3.30 g, 83%) as a colorless solid: Rf ) 0.20 (EtOAc/
hexane, 1:4); [R]23D +2.4 (c 6.1, CHCl3); mp 68-70 °C; 1H NMR
(360 MHz, CDCl3) δ 7.55 (d, J ) 1.1 Hz, 1H), 7.51 (m, 2H), 7.36
(m, 8H), 6.94 (d, J ) 7.9 Hz, 1H), 6.69 (d, J ) 8.4 Hz, 1H), 5.17
(d, J ) 12.2 Hz, 1H), 5.11 (d, J ) 12.2 Hz, 1H), 5.10 (s, 2H), 5.02
(d, J ) 7.6 Hz, 1H), 4.57 (m, 1H), 3.08-2.88 (m, 2H), 1.44 (s,
9H); 13C NMR (90 MHz, CDCl3) δ 171.4, 156.3, 154.9, 140.2,
136.5, 135.1, 130.5, 130.2, 128.6, 128.52, 128.49, 128.47, 127.9,
126.9, 112.5, 86.8, 80.0, 70.9, 67.2, 54.5, 36.9, 28.3; HRMS (EI)
m/z calcd for C28H30INO5 587.11687, found 587.11707.
1
10.5, MeOH); mp 80-82 °C; H NMR (360 MHz, acetone-d6) δ
7.61 (dd, J ) 8.1, 1.0 Hz, 2H), 7.39 (dd, J ) 7.5, 7.5 Hz, 2H),
7.29 (dd, J ) 7.4, 7.4 Hz, 1H), 7.22 (d, J ) 1.6 Hz, 1H), 7.09 (dd,
J ) 8.1, 1.7 Hz, 1H), 6.92 (d, J ) 8.2 Hz, 1H), 4.43 (m, 1H), 3.17
(dd, J ) 14.0, 4.8 Hz, 1H), 2.99 (dd, J ) 13.8, 8.4 Hz, 1H), 1.36
(s, 9H); 13C NMR (90 MHz, acetone-d6) δ 174.5, 157.1, 154.7,
140.7, 133.5, 131.1, 130.5, 129.9, 129.8, 129.7, 128.4, 117.8, 80.2,
56.6, 38.3, 21.4; HRMS (EI) m/z calcd for C20H23NO5 357,15762,
found 357.15622.
(Z)-Methyl 2-(tert-Butyloxycarbonyl)amino-3-(1-(tert-butyldim-
ethylsilyloxy)naphthalen-4 -yl)acrylate (13). To a solution of
(MeO)2P(O)CH(NHBoc)CO2Me15 (1.47 g, 4.95 mmol, 1.5 equiv)
in dry CH2Cl2 (3 mL) was added DBU (583 µL, 3.9 mmol, 1.3
equiv), and the mixture was stirred for 10 min at 0 °C. A solution
of 12 (945 mg, 3.30 mmol, 1.0 equiv) in dry CH2Cl2 (3 mL) was
added slowly via syringe, and the reaction mixture was warmed to
room temperature over 18 h. After the solvent was removed under
reduced pressure, the residue was dissolved in EtOAc (50 mL),
quickly washed with saturated aqueous NH4Cl (2 × 20 mL) and
brine (20 mL), and dried over Na2SO4. The solvent was evaporated
and the crude product purified by flash chromatography on silica
gel (EtOAc/hexane, 1:4; 1% NEt3), yielding 13 (Z:E > 90:10, 1.37
g, 91%) as a pale yellow solid. Pure Z isomer was separated under
the same conditions as the pale yellow solid (75% yield): Rf )
0.43 (EtOAc/hexane, 1:2); mp 116-120 °C; 1H NMR (360 MHz,
CDCl3) δ 8.24 (dd, J ) 7.3, 2.3 Hz, 1H), 7.95 (dd, J ) 7.3, 1.9
Hz, 1H), 7.69 (s, 1H), 7.59 (d, J ) 8.0 Hz, 1H), 7.56-7.46 (m,
2H), 6.86 (d, J ) 8.0 Hz, 1H), 6.08 (s, 1H), 3.90 (s, 3H), 1.31 (s,
9H), 1.10 (s, 9H), 0.31 (s, 6H); 13C NMR (63 MHz, CDCl3) δ
165.9, 152.7, 132.9, 127.8, 127.1, 126.9, 126.1, 125.8, 125.3, 124.0,
123.7, 123.1, 112.0, 80.7, 52.4, 27.9, 25.8, 18.4, -4.2; HRMS (EI)
m/z calcd for C25H35NO5Si 457.22845, found 457.22828.
(S)-Nr-tert-Butyloxycarbonyl-1-(4-tert-butyldimethylsilyloxy)-
naphthylalanine Methyl Ester (14). [(S,S)-Et-DuPHOS-(COD)-
RhI]OTf (0.38 mg, 0.52 µmol) was added to a solution of 13 (120
mg, 262 µmol, 1.0 equiv) in degassed DCM (3 mL). Hydrogenation
was carried out at 40 bar of hydrogen pressure for 4 h. The catalyst
was removed by flash chromatography on silica gel (EtOAc/hexane,
1:10), yielding 14 (114 mg, 95%) as a colorless oil: two rotamers
(ca. 4:1 ratio); Rf ) 0.31 (EtOAc/hexane, 1:4); [R]23D +20.5 (c 3.7,
CHCl3); 1H NMR (360 MHz, CDCl3) δ 8.24 (d, J ) 8.1 Hz, 1H),
8.01 (d, J ) 8.2 Hz, 1H), 7.54 (ddd, J ) 7.0, 6.8, 1.3 Hz, 1H),
7.48 (ddd, J ) 7.3, 7.0, 0.8 Hz, 1H), 7.12 (d, J ) 7.7 Hz, 1H),
6.78 (d, J ) 7.7 Hz, 1H), 5.06 (d, J ) 7.3 Hz, 1H (80%)), 4.86 (s,
1H (20%)), 4.68 (d, J ) 6.9 Hz, 1H (80%)), 4.57 (s, 1H (20%)),
3.66 (s, 3H (20%)), 3.61 (s, 3H (80%)), 3.50 (dd, J ) 14.0, 6.3
Hz, 1H), 3.39 (dd, J ) 13.7, 6.6 Hz, 1H), 3.15 (s, 1H), 1.41 (s, 9H
(80%)), 1.17 (s, 9H (20%)), 1.10 (s, 9H), 0.29 (s, 6H); 13C NMR
(90 MHz, CDCl3) δ 172.7, 154.9, 151.2, 133.4, 128.2, 127.3, 126.4,
124.9, 124.8, 123.4, 123.2, 111.8, 79.7, 54.4, 52.0, 35.3, 28.2, 25.8,
18.4, -4.2; HRMS (EI) m/z calcd for C25H37NO5Si 459.24411,
found 459.24438.
(S)-Nr-tert-Butyloxycarbonyl-O-benzyl-m-phenyltyrosine Ben-
zyl Ester (7a). To a solution of 6 (3.30 g, 5.62 mmol, 1.0 equiv)
in degassed DME/H2O (6:1, 40 mL) were added the appropriate
phenylboronic acid (1.03 g, 8.43 mmol, 1.5 equiv) and Na2CO3
(1.20 g, 11.2 mmol, 2.0 equiv). After five vacuum/argon cycles
Pd(OAc)2 (63 mg, 281 µmol, 5 mol %) and P(o-tolyl)3 (171 mg,
562 µmol, 10 mol %) were added, and the mixture was heated to
80 °C until complete conversion (3-8 h). After the reaction mixture
was cooled to room temperature, it was passed through a short
column with a bottom layer of silica gel (40-63 µm) and a top
layer of NaHCO3 using EtOAc as the eluent. The solvent was
removed under reduce pressure and the crude product purified by
flash chromatography (EtOAc/hexane, 1:4) to achieve 7a (2.75 g,
91%) as a pale yellow solid: Rf ) 0.25 (EtOAc/hexane, 1:4); [R]23
D
+2.6 (c 0.6, CHCl3); mp 111-113 °C; 1H NMR (360 MHz, CDCl3)
δ 7.54 (d, J ) 7.5 Hz, 2H), 7.40 (dd, J ) 7.4, 7.4 Hz, 2H), 7.38-
7.26 (m, 11H), 7.09 (s, 1H), 6.94 (d, J ) 7.4 Hz, 1H), 6.87 (d, J
) 8.1 Hz, 1H), 5.15 (d, J ) 12.3, 1H), 5.10 (d, J ) 12.3, 1H),
5.06-5.00 (m, 3H), 4.67-4.61 (m, 1H), 3.13-3.02 (m, 2H), 1.41
(s, 9H); 13C NMR (63 MHz, CDCl3) δ 171.7, 155.1, 154.6, 138.1,
137.1, 135.0, 132.0, 131.2, 130.3, 129.5, 129.2, 128.5, 128.43,
128.40, 128.37, 127.8, 127.5, 126.9, 126.7, 113.4, 80.0, 70.4, 67.1,
54.5, 37.3, 28.2; HRMS (EI) m/z calcd for C34H35NO5 537.25153,
found 537.25207.
(S)-Nr-tert-Butyloxycarbonyl-O-benzyl-m-phenyltyrosine (8a).
A solution of lithium hydroxide (1.8 mg, 74 µmol, 1.0 equiv) in
H2O (0.11 mL) was added to a solution of 7a (40 mg, 74 µmol,
1.0 equiv) in 2 mL of THF at 0 °C. After the resulting solution
was stirred for 18 h, a 10% aqueous solution of citric acid (50 mL)
was added, and the aqueous layer was extracted with EtOAc (3 ×
30 mL). The combined organic layers were dried (Na2SO4), the
solvent removed under reduced pressure, and the residue purified
by flash chromatography on silica gel (EtOAc/hexane, 1:1; 1%
AcOH), yielding 8a (28.6 mg, 86%) as a colorless solid: Rf ) 0.30
(EtOAc/hexane, 1:1; 1% AcOH); [R]23D +11.3 (c 1.7, MeOH); mp
1
108-110 °C; H NMR (250 MHz, MeOH-d4) δ 7.53 (d, J ) 7.0
J. Org. Chem, Vol. 71, No. 15, 2006 5629

Kno¨r et al.
(S)-Nr-tert-Butyloxycarbonyl-1-(4-hydroxy)naphthylalanine
(15). To a solution of 14 (50.0 mg, 109 µmol, 1.0 equiv) in dry
THF at 0 °C was added tetrabutylammonium fluoride (36.1 mg,
114 µmol, 1.05 equiv). After the resulting solution was stirred for
15 min, a solution of lithium hydroxide (5.04 mg, 120 µmol, 1.1
equiv) in water (182 µL) was added, and the mixture was stirred
for an additional 3 h at room temperature. The solution was acidified
by addition of a 10% aqueous solution of citric acid (20 mL) and
extracted with EtOAc (2 × 50 mL), and the combined organic layers
were dried over Na2SO4. After the solvent was removed under
reduced pressure, the crude product was purified by flash chroma-
tography on silica gel (MeOH/CHCl3, 1:9; 1% AcOH), yielding
15 (32 mg, 89%) as a colorless solid: two rotamers (ca. 2.5:1 ratio);
127.2, 126.4, 124.9, 124.7, 123.4, 123.2, 111.8, 53.2, 52.1, 34.6,
25.8, 23.0, 18.4, -4.2; HRMS (EI) m/z calcd for C20H23NO5
357.15762, found 357.15622.
(R)-Nr-Acetyl-1-(4-hydroxy)naphthylalanine (21) and (S)-1-
(4-Hydroxy)naphthylalanine Methyl Ester (22). To a solution
of 19 (100 mg, 249 µmol, 1.0 equiv) in dry THF (7 mL) at 0 °C
was added tetrabutylammonium fluoride (82.5 mg, 261 µmol, 1.05
equiv). After the resulting solution was stirred for 15 min, a solution
of lithium hydroxide (41.8 mg, 996 µmol, 4 equiv) in water (1.5
mL) was added, and stirring was continued for an additional 2 h at
room temperature until complete conversion (TLC control). There-
after, the solvent was removed under reduced pressure and the
residue dissolved in water (10 mL) and adjusted to pH 7-8 by
addition of 1 N HCl. Acylase I (50 mg) was added, and the mixture
was stirred at 37 °C until no further conversion was observed (2-3
h, HPLC monitoring). Additional acylase I (50 mg) was added and
stirring continued for 1 h. The mixture was diluted with water (20
mL), acidified to pH 1 by addition of 1 N HCl, and extracted with
EtOAc (5 × 20 mL).
Rf ) 0.18 (MeOH/CHCl3, 1:9; 1% AcOH); [R]23 -25.9 (c 1.6,
D
MeOH); mp 88-92 °C; 1H NMR (500 MHz, MeOH-d4) δ 8.24 (d,
J ) 8.4 Hz, 1H), 8.05 (d, J ) 8.5 Hz, 1H), 7.51 (dd, J ) 7.5, 7.5
Hz, 1H), 7.42 (dd, J ) 7.4, 7.4 Hz, 1H), 7.17 (d, J ) 7.7 Hz, 1H),
6.73 (d, J ) 7.7 Hz, 1H), 4.44 (dd, J ) 8.8, 5.1 Hz, 1H), 3.68 (dd,
J ) 12.2, 2.9 Hz, 1H (30%)), 3.59 (dd, J ) 14.3, 4.9 Hz, 1H (70%)),
3.17 (dd, J ) 14.2, 9.1 Hz, 1H (70%)), 2.99 (dd, J ) 12.0, 12.0
Hz, 1H (30%)), 1.34 (s, 9H (70%)), 0.98 (s, 9H (30%)); 13C NMR
(125 MHz, MeOH-d4) δ 175.9, 157.8, 154.0, 134.4, 129.4, 129.0,
127.4, 126.9, 125.26, 125.20, 124.4, 124.23, 124.19, 124.0, 108.3,
80.5, 56.8, 56.1, 37.4, 35.8, 28.7, 28.1; HRMS (EI) m/z calcd for
C18H21NO5 331.14197, found 331.14097.
The organic phase was dried over Na2SO4, the solvent removed
under reduced pressure, and the residue further purified by a short
column of silica (MeOH/CHCl3, 1:3; 1% AcOH) to give 21 (31
mg, 46%) as a colorless solid.
The aqueous phase was concentrated under reduced pressure and
dried. The residue was suspended in dry MeOH (30 mL), and SOCl2
(1 mL) was added dropwise at 0 °C. After being stirred for 24 h at
room temperature, the mixture was concentrated under reduced
pressure, diluted with 1 N NaOH (30 mL), and extracted with
EtOAc (5 × 20 mL). The organic phase was dried over Na2SO4,
the solvent removed under reduced pressure, and the residue further
purified by a short column of silica (MeOH/CHCl3, 1:9; 1% NEt3)
to obtain a pale yellow oil which was dissolved in Et2O and a
minimum volume of dioxane. Addition of a 1 M solution of HCl
in ether (2 mL) gave 22 as a colorless solid which was filtered off
and dried in vacuo.
(Z)-Methyl 2-(Benzyloxycarbonyl)amino-3-(1-(tert-butyldim-
ethylsilyloxy)naphthalen-4-yl)acrylate (18). To a solution of
(MeO)2P(O)CH(NHCbz)CO2Me15 (1.10 g, 3.33 mmol, 1.5 equiv)
in dry CH2Cl2 (3 mL) was added DBU (432 µL, 2.89 mmol, 1.3
equiv), and the mixture was stirred for 10 min at 0 °C. A solution
of 12 (635 mg, 2.22 mmol, 1.0 equiv) in dry CH2Cl2 (3 mL) was
added slowly via syringe, and the reaction mixture was warmed to
room temperature over 18 h. After the solvent was removed under
reduced pressure, the residue was dissolved in EtOAc (50 mL),
quickly washed with saturated aqueous NH4Cl (2 × 20 mL) and
brine (20 mL), and dried over Na2SO4. The solvent was evaporated
and the crude product purified by flash chromatography on silica
gel (EtOAc/hexane, 1:4; 1% NEt3), yielding 16 (948 mg, 87%) as
Data for 21: Rf ) 0.31 (MeOH/CHCl3, 1:1; 0.1% TFA); [R]23
D
-1.7 (c 0.5, MeOH); mp 130-134 °C; 1H NMR (500 MHz, CDCl3)
δ 8.23 (d, J ) 8.3 Hz, 1H), 8.05 (d, J ) 8.5 Hz, 1H), 7.51 (dd, J
) 7.6, 7.6 Hz, 1H), 7.42 (dd, J ) 7.5, 7.5 Hz, 1H), 7.17 (d, J )
7.7 Hz, 1H), 6.73 (d, J ) 7.7 Hz, 1H), 4.74 (dd, J ) 8.9, 5.2 Hz,
1H), 3.63 (dd, J ) 14.3, 5.1 Hz, 1H), 3.21 (dd, J ) 14.3, 9.0 Hz,
1H), 1.85 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 175.4, 173.1,
154.0, 134.4, 128.8, 127.3, 126.8, 125.2, 125.1, 124.3, 124.0, 108.2,
55.0, 35.5, 22.3; HRMS (EI) m/z calcd for C15H15NO4 273.10010,
found 273.10083.
1
a pale yellow oil: Rf ) 0.33 (EtOAc/hexane, 1:2); H NMR (360
MHz, CDCl3) δ 8.28-8.20 (m, 1H), 7.95-7.88 (m, 1H), 7.81 (s,
1H), 7.56-7.47 (m, 3H), 7.34-7.27 (m, 3H), 7.27-7.20 (m, 2H),
6.81 (d, J ) 8.0 Hz, 1H), 6.25 (s, 1H), 5.06 (s, 2H), 3.86 (s, 3H),
1.11 (s, 9H), 0.32 (s, 6H); 13C NMR (90 MHz, CDCl3) δ 165.6,
153.9, 153.0, 135.85, 133.0, 128.4, 128.1, 128.1, 128.1, 127.9,
127.3, 127.0, 125.5, 125.4, 123.9, 123.2, 123.2, 111.9, 67.3, 52.6,
25.8, 18.4, -4.2; HRMS (EI) m/z calcd for C28H33NO5Si 491.21280,
found 491.21264.
Data for 22: Rf ) 0.50 (MeOH/CHCl3, 1:9; 1% NEt3); [R]23
D
+5.2 (c 0.6, MeOH); mp(22‚HCl) > 240 °C; 1H NMR (250 MHz,
CDCl3) δ 8.30 (d, J ) 8.3 Hz, 1H), 7.94 (d, J ) 8.3 Hz, 1H), 7.59
(dd, J ) 7.5, 7.5 Hz, 1H), 7.48 (dd, J ) 7.4, 7.4 Hz, 1H), 7.21 (d,
J ) 7.6 Hz, 1H), 6.80 (d, J ) 7.6 Hz, 1H), 4.31 (dd, J ) 7.4, 7.4
(R/S)-Nr-Acetyl-1-(4-tert-butyldimethylsilyloxy)naphthy-
lalanine Methyl Ester (19). To a solution of 18 (0.28 g, 0.57 mmol,
1 equiv) in degassed MeOH (30 mL) was added palladium on
charcoal (5% Pd/C, 0.12 g, 10 mol % Pd). Hydrogenation was
carried out at 1 bar of hydrogen pressure for 2 h. After the catalyst
was removed by filtration, the solvent was removed under reduced
pressure and the residue dissolved in dry DCM (10 mL). Ac2O (60
µL, 0.68 mmol, 1.2 equiv) and NEt3 (0.12 mL, 0.85 mmol, 1.5
equiv) were added, and the mixture was stirred for an additional
18 h. The solvent was removed under reduced pressure and the
residue taken up with EtOAc (50 mL), subsequently washed with
saturated aqueous NaHCO3 (2 × 50 mL) and brine (50 mL), and
dried over Na2SO4. After the solvent was removed under reduced
pressure, the crude product was purified by flash chromatography
on silica gel (EtOAc/hexane, 1:1; 1% NEt3), yielding 18 (194 mg,
76%) as a colorless solid: Rf ) 0.16 (EtOAc/hexane, 1:1; 1% NEt3);
mp 50-55 °C; 1H NMR (250 MHz, CDCl3) δ 8.24 (d, J ) 7.9 Hz,
1H), 8.01 (d, J ) 7.8 Hz, 1H), 7.57-7.43 (m, 2H), 7.08 (d, J )
7.8 Hz, 1H), 6.77 (d, J ) 7.7 Hz, 1H), 5.99 (d, J ) 7.7 Hz, 1H),
4.97 (m, 1H), 3.61 (s, 3H), 3.45 (dd, J ) 13.9, 6.8 Hz, 1H), 3.45
(dd, J ) 14.4, 6.1 Hz, 1H), 1.93 (s, 3H), 1.09 (s, 9H), 0.28 (s, 6H);
13C NMR (63 MHz, CDCl3) δ 172.4, 169.6, 151.2, 133.4, 128.1,
Hz, 1H), 3.80-3.63 (m, 4H), 3.41 (dd, J ) 14.5, 8.5 Hz, 1H); 13
C
NMR (226 MHz, CDCl3) δ 175.8, 154.4, 134.3, 129.2, 127.5, 125.5,
124.2, 108.3, 56.1, 52.6, 38.3; HRMS (EI) m/z calcd for C14H15-
NO3 245.10519, found 245.10519.
Acknowledgment. We thank Philipp Gradicsky, Mona
Wolff, Burghard Cordes, and Helmut Krause for their technical
assistance. Financial support by the Deutsche Forschungsge-
meinschaft and the Fonds der Chemischen Industrie is gratefully
acknowledged.
Supporting Information Available: Synthesis and compound
characterization of 5, 8b, 9b, and 12, general procedure for the
synthesis of 3-aryl-substituted tyrosine analogues 7b-j by Suzuki
cross coupling, compound characterization of 7b-j, general
1
procedure for the synthesis of dipeptides 10a-d, 16, and 17, H
and 13C NMR spectra of all synthesized compounds, NOESY
spectra of 13 and 18, and HPLC analyses of 10a-d, 16, and 17.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO060704C
5630 J. Org. Chem., Vol. 71, No. 15, 2006