Enantioselective Synthesis of Non-Natural Aromatic α-Amino Acids

Article abstract of DOI:10.1002/chem.200305421

We present two complementary methods for the stereoselective synthesis of non-natural α-amino acids with aromatic or heteroaromatic side chains. One approach is based on the chemical transformation of methionine, whereas the other applies the stereoselective Myers alkylation of glycine. The resulting product types differ in the linker length between glycine and the aromatic substituent. Since methionine and pseudoephedrine are available in both absolute configurations, R- or S-configured enantiopure amino acids with either C₂ or C₃ linkers can be obtained on gram scales. In each case the key step of the synthesis is hydroboration of the unsaturated building blocks 9 and 17, followed by palladium-catalyzed Suzuki cross-coupling with aryl halides. Attention must in certain cases be paid to the stereochemical integrity when basic Suzuki conditions are applied. Our initial difficulties are reported as well as the final "racemization-proof" procedures. The protecting groups chosen for the α-amino acids should be compatible with solid-phase peptide synthesis. This was confirmed by the successful synthesis of a series of tripeptides.

Full text of DOI:10.1002/chem.200305421

FULL PAPER
Enantioselective Synthesis of Non-Natural Aromatic a-Amino Acids
Andreas Krebs, Verena Ludwig, Josÿ Pfizer, Gerd D¸rner, and Michael W. Gˆbel*[a]
Abstract: We present two complemen-
tary methods for the stereoselective
synthesis of non-natural a-amino acids
with aromatic or heteroaromatic side
chains. One approach is based on the
chemical transformation of methionine,
whereas the other applies the stereose-
lective Myers alkylation of glycine. The
resulting product types differ in the
linker length between glycine and the
aromatic substituent. Since methionine
and pseudoephedrine are available in
both absolute configurations, R- or S-
configured enantiopure amino acids
with either C2 or C3 linkers can be ob-
tained on gram scales. In each case the
key step of the synthesis is hydrobora-
tion of the unsaturated building blocks
9 and 17, followed by palladium-cata-
lyzed Suzuki cross-coupling with aryl
halides. Attention must in certain cases
be paid to the stereochemical integrity
when basic Suzuki conditions are ap-
plied. Our initial difficulties are report-
ed as well as the final ™racemization-
proof∫ procedures. The protecting
groups chosen for the a-amino acids
should be compatible with solid-phase
peptide synthesis. This was confirmed
by the successful synthesis of a series
of tripeptides.
Keywords: amino acids
¥
chiral
auxiliaries ¥ chiral pool ¥ peptides ¥
Suzuki reaction
Introduction
™racemization-proof∫ reactions. Derivatives of vinyl- or al-
lylglycine should fulfil the criteria for such central inter-
mediates, since various aryl residues could be introduced by
Over the last few years, combinatorial libraries of synthetic
peptides have seen numerous applications in protein bio-
chemistry.[1] More recently, synthetic libraries have also al-
lowed promising peptide ligands for DNAand RNAto be
identified.[2] Apart from charge effects and hydrogen bonds,
molecular recognition of nucleic acids is often dominated by
stacking interactions.[3] Being interested in RNAligands and
artificial nucleases,[4] we felt that, of the different classes of
amino acids, those carrying positive charge or aromatic rings
are the preferable building blocks. To enhance chemical di-
versity, it would be desirable not to restrict library design to
Arg, Lys, His, Phe, Tyr, and Trp alone, but also to include
non-natural aromatic or heteroaromatic amino acids.
8]
a Suzuki cross-coupling reaction.[6 Allylglycine is readily
available through Myers alkylation of glycine with pseudoe-
phedrine as auxiliary.[9] The conversion of serine into deriva-
tives of vinylglycine has also been reported.[10] For the ex-
tension of the side chain, however, the corresponding amino
aldehyde is required,[11] an intermediate known for its ten-
dency to racemize. The alternative approach described here
involves methionine as starting material. This is transformed
into a vinylglycine derivative ready for use in Suzuki cou-
pling.
Several methods for the synthesis of non-natural a-amino
acids exist.[5] Often the complete side chain is attached to a
prochiral precursor molecule in a stereoselective reaction.
This approach, while successful in many cases, creates the
need to determine the enantiomeric purity of each newly
synthesized batch of amino acids scrupulously and, if neces-
sary, to purify to high levels of ee. We preferred a different
strategy, of transforming an easily accessible, enantiopure,
common intermediate into a variety of final products by
Results and Discussion
Synthesis by transformation of methionine: Initially we tried
to keep the oxidation level of the carboxy group unchanged.
Thus, (S)-l-methionine (1) was converted into the carboxy-
benzoxy(Cbz)-protected methyl ester and oxidized to form
sulfoxide 2 (Scheme 1). Athermal syn elimination then led
to the vinylglycine derivative 3.[12] This step turned out to be
troublesome, temperatures around 1608C being insufficient
for complete conversion. Higher temperatures, on the other
hand, produced large amounts of the achiral products 4a
and 4b, making the purification of 3 laborious (HPLC). On
larger scales, yields of 3 rarely exceeded 20%. Performing
the reaction under solvent-free conditions in a Kugelrohr[13]
did not give reliable results in our hands. Even worse, the
[a] A. Krebs, V. Ludwig, J. Pfizer, Dr. G. D¸rner, Prof. Dr. M. W. Gˆbel
Institute of Organic Chemistry and Chemical Biology
Marie-Curie Strasse 11, 60439 Frankfurt/Main (Germany)
Fax : (+49)697-982-9464
E-mail: M.Goebel@chemie.uni-frankfurt.de
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¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/chem.200305421
Chem. Eur. J. 2004, 10, 544 553

544 553
dicated that the normal hydroboration conditions[6c] were
not appropriate in this case. Attempts to improve the yield
of 7 by promoting the 9-borabicyclo[3.3.1]nonane (9-BBN)
addition with Wilkinson×s catalyst failed.[14] The use of 1,4-
dioxane as solvent and higher temperatures,[15] however, re-
sulted in a smooth hydroboration. The cross-coupling was
found to give satisfying yields (Table 1) in the presence of
CsF[7] as base and [Pd(PPh3)4] as catalyst. Further optimiza-
tion of the cross-coupling conditions showed a correlation of
yields with increasing strength of the base (Table 2). Un-
fortunately, when the ee of product 7 was determined, a cor-
relation with partial racemization was also observed
(Table 2), consistent with the ability of strong bases such as
FÀ to deprotonate the a-position of the amino acid esters.
Scheme 1. a) MeOH, SOCl2, 95%; b) Cbz-Cl, KHCO3, 92%; c) NaIO4,
84%; d) o-dichlorobenzene, 1608C, 20%.
enantiomeric purity of the vinylglycine intermediate 3 drop-
ped below 95% ee in the pyrolysis, incompatibly with our
strategy described above. Nevertheless, cross-coupling stud-
ies were initiated with compound 3.
Initial attempts to hydroborate 3 with 9-BBN and to
cross-couple the intermediate alkyl borane under Suzuki
conditions led to surprisingly low yields of compound 7
(Scheme 2; Table 1). Furthermore, the modest yield of lac-
tone 6, obtained by oxidation of the borane intermediate, in-
Table 2. ee-Determination of compound 7.[a]
Base [3 equiv]
Yield [%]
ee [%]
K3PO4
CaCO3
Cs2CO3
K2CO3
CsF
60
6
61
64
85
85
n.d.
40
52
32
[a] Hydroboration with 1.1 equivalents of 9-BBN in 1,4-dioxane at 858C;
cross-coupling at 808C overnight with [Pd(PPh3)4] as catalyst.
At this stage we changed our tactics and converted me-
thionine into the amino alcohol. Through these additional
reduction and oxidation steps, all the previous problems
could be circumvented while not complicating the syntheses
significantly (Scheme 3).
After LiAlH4 reduction of the carboxy group in boiling
THF overnight[16] followed by Cbz- and tert-butyldimethylsil-
yl (TBS)-protection, periodate oxidation led to the sulfoxide
8. Successive pyrolysis afforded the desired unsaturated de-
rivative 9 as a stable compound in scales above 30 g. Com-
pound 9, unlike the carbonyl analogue 3, has no tendency
towards migration of the double bond, so the elimination
temperature could be increased to 1808C, improving the
yield of 9 to 88% (Scheme 3). Clean hydroboration of com-
pound 9 was observed under the previously established con-
ditions. Replacement of [Pd(PPh3)4] by [Pd(dppf)Cl2] in the
cross-coupling step then allowed all products 10a f to be
obtained reproducibly and in high yields. While the desilyla-
tion with TBAF in THF was a straightforward reaction, re-
moval of Cbz under normal hy-
Scheme 2. a) H2O2, THF; b) Suzuki reaction.
drogenolysis conditions (Pd-C/
H2) was found to cause partial
Table 1. Hydroboration of the protected vinylglycine 3.
Solvent
9-BBN
[equiv]
T
Catalyst 1
Catalyst 2
Base
Yield
[%][e]
reduction of some aromatic
side chains. To avoid this draw-
back we utilized a transfer hy-
drogenation procedure with 1,4-
cyclohexadiene and Pd(OH)2 in
refluxing ethanol.[17] Fmoc pro-
tection and oxidation of the hy-
droxy group completed the syn-
theses of building blocks 13a e,
ready for peptide coupling. For
amino alcohol 12 f, substituted
[8C][a]
[3 mol%][b]
[3 mol%][c]
[3 equiv][d]
THF
THF
THF
THF
THF
toluene
dioxane
dioxane
1
2
2
2
3
2
1.1
1.1
RT
66
RT
66
66
85
85
85
[Pd(dppf)]
[Pd(dppf)]
[Pd(dppf)]
[Pd(dppf)]
[Pd(dppf)]
[Pd(dppf)]
[Pd(PPh3)4]
[Pd(PPh3)4]
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
CsF
15
15
18
18
20
30
60
85
[Rh(Ph3P)3Cl]
[Rh(Ph3P)3Cl]
[Rh(Ph3P)3Cl]
[a] Temperature of the hydroboration step (overnight). [b] Hydroboration catalyst. [c] Cross-coupling catalyst.
[d] Conditions of the cross-coupling step: THF 668C, toluene or dioxane 808C (each overnight). [e] Isolated
yield of the Suzuki product.
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Michael W. Gˆbel et al.
FULL PAPER
Scheme 3. a) LiAlH4, THF, 76%; b) Cbz-Cl; c) TBS-Cl, imidazole; d) NaIO4, 94% (over three steps); e) o-dichlorobenzene, 1808C, 88%; f) 1. 9-BBN,
2. Aryl-Br, CsF, [Pd(dppf)Cl2], 83 97%; g) TBAF, 68 84%; h) 1,4-cyclohexadiene, Pd(OH)2; i) Fmoc-Suc, 57 84% (over two steps); j) PDC, DMF, 56
86%.
with anthracene, no sufficient oxidation to the carboxylic
acid could be achieved. The starting material disappeared,
but the oxidized product could not be isolated. Perhaps the
poor solubility led to co-precipitation with the inorganic
solid formed in the reaction.
The described approach was found to be universal for
both configurations and we were able to synthesize the d
derivative ent-13d by using (R)-d-methionine as starting ma-
terial. The availability of the two enantiomers allowed the
enantiomeric purity to be determined rigorously by HPLC
on chiral columns. Enantiomers 13d and ent-13d both exhib-
ited >99% ee.
Synthesis by stereoselective alkylation of glycine: The chiral
glycine amide 14 (Scheme 4), available from pseudoephe-
drine and glycine methyl ester, was introduced by Myers
and applied for the synthesis of a broad scope of a-amino
acids. In this procedure, a dianion of 14 is alkylated at
carbon with high diastereoselectivity. We adopted the Myers
protocol as a convenient route to the allyl glycine derivative
Scheme 4. a) LiCl, THF, LiHMDS, then allyl bromide, 68%; b1) Boc2O, NaHCO3, ultrasound, 85%; b2) Cbz-Cl, Et3N, CHCl3, 87%; c) 9-BBN (0.5m
THF) 2.4 equiv, 5 mol% catalyst, base, aryl halide, see Table 3; d) MeOH, Pd/C, H2; e) H2O, reflux, 50 60% over two steps; f) DCM, TMS-Cl, DIPEA,
Fmoc-Cl, 70%.
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Chem. Eur. J. 2004, 10, 544 553

Non-Natural Aromatic a-Amino Acids
544 553
Table 3. Suzuki coupling of the Boc- and Cbz-protected derivatives 16
and 17.[a]
tion is a rather critical step. Acid-induced removal of sulfon-
ic acids such as Mtr or Pmc requires drastic conditions and
forms electrophilic intermediates that might endanger aro-
matic rings. If the arginine-rich tripeptide could be prepared
from a certain building block, we argued, its incorporation
into other sequences would be less challenging. Scheme 5
summarizes the structures of tripeptides 22 32. Two pepti-
des, 31 and 32, however, proved to be troublesome. After
cleavage from the resin and deprotection under standard
conditions (Table 5, entry 1), the mass spectra did not reveal
the expected peaks, thus indicating the formation of undesir-
able adducts ([M+138]+). To overcome this problem, vari-
ous cleaving conditions for peptide 32 were tested (Table 5).
Ar-Halide
Product
Yield [%]
2-Br-pyridine
3-Br-pyridine
2-Br-pyrimidine
5-Br-pyrimidine
Cl-pyrazine
18a/19a
18b/19b
18c/19c
18d/19d
18e/19e
76[b]/90[c]
20[b]/38[c]
68[b]/88[c]
0[b]/27[c]
75[b]/86[c]
[a] All coupling reactions were carried out with 2.4 equivalents of 9-BBN
(0.5m in THF), [Pd(PPh3)4] as catalyst and K3PO4 as base at room tem-
perature for 16 h reaction time. [b] Boc-protected. [c] Cbz-protected.
15.[9,18] First cross-coupling experiments started from com-
pound 16. As described above, the unsaturated side chain
was hydroborated with 9-BBN and coupled with aryl halides
in a Suzuki reaction. Because of the presence of the hydrox-
yl group, hydroboration required at least 2 and worked best
with 2.4 equivalents of 9-BBN. Three cross-coupling prod-
ucts (18a, 18c, 18e) could be obtained in good, and one in
moderate, yield (18b) (Table 3). In all cases, however, the
purification was found to be troublesome and required prep-
arative HPLC. Compound 18d remained inaccessible even
after several attempts (Table 4).
Superior results were obtained with the Cbz-protected
compound 17 (Scheme 4, Table 3). The Suzuki reaction was
found to be highly efficient even with an aryl chloride, a
species generally known for low coupling rates.[6a] We were
able to synthesize pyrazine derivative 19e (86% yield) and
also the pyrimidine 19d. Furthermore, the products could be
isolated by simple column chromatography. Replacement of
the catalyst [Pd(PPh3)4] by [Pd(dppf)Cl2] did not raise the
yields but again imposed the need to purify products by
HPLC. After removal of Cbz, pseudoephedrine was cleaved
off by boiling in neutral H2O to avoid the risk of base-in-
duced racemization and to isolate products not contaminat-
ed with salts. The chiral purity of the Fmoc-protected d-
amino acid 21e was determined by HPLC as 99% ee. Fur-
thermore, when (R,R)-(À)-pseudoephedrine was used as
auxiliary, the corresponding l derivative ent-21e could be
obtained in high yield and with more than 99% ee.
Table 5. Cleavage of tripeptide 32 under various conditions.
Entry
1
Cleaving conditions
Time
5 h
Result
[M+138]+
TFA/PhSCH3/PhOH/H2O/EDT
82.5:5:5:5:2.5
2
3
TFA/TIS/H2O
92.5:5:2.5
TFA/TIS/H2O
4.5 h
4.5 h
[M]+/[M+138]+
1:1
[M]+/[M+138]+
60:39:1
1:1
4
TFA/PhSCH3/PhOH/H2O/EDT/TIS
81.5:5:5:5:2.5:1
TFA/PhSCH3/PhOH/H2O/TIS
84:5:5:5:1
4.5 h
[M]+/[M+138]+
2:1
5
4.5 h
[M]+/[M+138]+
1:2
6
TFA/TES/H2O
4.5 h
[M]+/[M+138]+
92.5:5:2.5
TMSBr/EDT/PhOH/H2O
84:1:5:10
1:1
0
7
15 min
8[a]
CH2Cl2/TFA30 min
70:30
[
M]+/[M+61]+
4:5
[a] The sample also contained protected tripeptide.
Established reagents such as trimethylsilyl bromide
(TMSBr) or trifluoroacetic acid/triisopropylsilane (TFA/
TIS) were not successful either. Standard conditions in the
presence of TIS (Table 5, entry 4) gave best results and fa-
vored the desired tripeptide peak in a ratio of 2:1 relative to
the [M+138]+ product. The 5-indolyl and the 5-pyrimidinyl
amino acids are thus not suitable as building blocks for com-
binatorial libraries.
Application in solid-phase peptide synthesis: To demon-
strate the practical use of the Fmoc building blocks 13a e
and 21a e for peptide synthesis, we assembled the tripepti-
des 22 32 by standard methods on solid support. In each
compound, one of the synthetic amino acids is flanked by
two D-arginines. Arginine was chosen because its deprotec-
Conclusions
Here we report an efficient, easy to handle and cost-effec-
tive synthesis of non-natural aromatic amino acids, starting
from vinylglycine or allylglycine
as useful precursors for Suzuki
Table 4. Attempts to prepare the Boc-protected derivative 18d (room temperature, 16 h, various catalysts and
bases).
couplings with aryl halides.
Both configurations were acces-
sible in 99% enantiomeric ex-
cesses after elimination of ini-
tial problems due to base-cata-
lyzed racemization. The applic-
ability of the new building
blocks was tested in the solid-
phase synthesis of tripeptides.
Some aromatic systems formed
Ar halide
Catalyst
Base
Yield [%]
[Pd(PPh3)4], 5 mol%
[Pd(PPh3)4], 5 mol%
Pd(OAc)2, 10 mol%
Pd (polymer-bound)
[Pd(PPh3)4], 5 mol%
[Pd(dppf)Cl2], 5 mol%
NaOH (10%), 3 equiv
Ag2O, 2 equiv
5-Br-Pyrimidine
Na2CO3, 2 equiv
[b]
K3PO4
CsF, 3 equiv
K2CO3, 3 equiv
[a] All coupling reactions were carried out with 2.4 equivalents of 9-BBN (0.5m in THF). [b] 2-Propanol/H2O
1:1.[21] [c] 9-BBN solid 1.5 equiv.
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Michael W. Gˆbel et al.
FULL PAPER
Scheme 5. Tripeptides prepared from the building blocks 13a e, 21a e, and ent-21e by standard Fmoc solid-phase synthesis (C terminus: carbox-
amide)[19]
by-products upon acid-induced deprotection. Isolation of
pure peptides would require purification steps, and so the
use of such building blocks in combinatorial libraries is not
recommended. Most tripeptides, however, could easily be
obtained, thus demonstrating the applicability of the new
building blocks in peptide chemistry.
LiHMDS, LiAlH4 or 9-BBN were carried out in oven-dried glassware
under inert argon atmosphere. DCM: dichloromethane. DIC: diisopro-
pylcarbodiimide. DIPEA: N,N-diisopropylethylamine. EDT: ethanedi-
thiol. HOBt: N-hydroxybenzotriazole. PDC: pyridinium dichromate.
Methioninol: LiAlH4 (11.0 g, 290 mmol) was suspended in dry THF
(400 mL), and l-methionine (20.0 g, 134 mmol) was then added in small
portions. The gray suspension was heated at reflux overnight. To quench
the reaction, H2O (11 mL), NaOH (15%, 11 mL) and H2O (33 mL) were
added successively. The precipitate was filtered off and the solvent was
removed in vacuo. The residual oil was further purified by distillation in
the Kugelrohr (1808C, 0.3 mbar) to give methioninol (13.75 g, 76%) as a
colorless oil. Rf = 0.1 (MeOH/AcOEt 1:9) staining yellow with KMnO4;
[a]D20À16.18 (c = 1.2, MeOH), literature: À148 (c = 1, EtOH);[16b] 1H
NMR (250 MHz, CDCl3): d = 3.63 (dd, J = 10.7/3.9 Hz, 1H), 3.35 (dd,
J = 10.7/0.7 Hz, 1H), 3.03 2.99 (m, 1H), 2.64 2.58 (m, 2H), 2.27 (brs,
3H), 2.14 (s, 3H), 1.78 1.72 (m, 1H), 1.64 1.58 (m, 1H) ppm; IR (KBr):
n˜ = 3346, 2917, 2856, 2592, 1435, 1366, 1318, 1056, 958, 860, 755 cmÀ1; el-
emental analysis calcd (%) for C5H13NOS (135.23): C 44.41, H 9.69, N
10.36; found: C 44.22, H 9.69, N 10.15.
Experimental Section
General: Melting points: Kofler hot plate microscope, uncorrected. Opti-
cal rotations: Perkin Elmer 241 polarimeter, temperature control by
H2O bath. 1H NMR: Bruker Avance DPX 250 MHz, TMS as external
standard; chemical shifts (d) are given in ppm (* denotes rotamer peaks).
Analytical thin layer chromatography: alumina plates precoated with
silica gel 60 F254 (Merck); viewing with the aid of UV light or aqueous
KMnO4 solution. Flash chromatography: silica gel Merck-60 (0.040
¾
0.063 mm). Filtration: Celite 535 (Fluka). FT-IR: Perkin Elmer 1600
Benzyl [1-(tert-butyldimethylsilanyloxymethyl)-3-methanesulfinylpropyl]-
carbamate (8): Methioninol (13.75 g, 92 mmol) was dissolved in AcOEt
(300 mL). KHCO3 (27.6 g, 276 mmol) in H2O (300 mL) was added to the
organic phase and the mixture was cooled to 08C. Small portions of Cbz-
Cl (15.7 mL, 112 mmol) were added to the vigorously stirred mixture.
Series. Elemental analysis: Heraeus CHN Rapid. Mass spectroscopy: low
resolution: Fisons CG Platform II; high resolution: Applied Biosystems
Mariner System 5033, spray voltage +700 V. All reagents were obtained
from commercial suppliers and were used without further purification.
THF was distilled from sodium/benzophenone. All reactions involving
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Non-Natural Aromatic a-Amino Acids
544 553
After 30 min the ice bath was removed, the mixture was stirred for a fur-
ther 3 h at room temperature, and the basic aqueous phase was separat-
ed. The organic phase was then washed with HCl (1n), H2O and brine.
After the mixture had been dried over MgSO4 the solvent was evaporat-
ed in vacuo. The crude product was dissolved in DCM (400 mL) contain-
ing imidazole (7.61 g, 112 mmol). The solution was cooled to 08C and
tert-butyldimethylsilyl chloride (TBDMS-Cl) (16.85 g, 112 mmol) was
added in small portions. After 30 min the ice bath was removed. The re-
action mixture was stirred at room temperature overnight. The organic
phase was extracted several times with H2O. After evaporation of the or-
ganic solvent, the crude protected amino alcohol was dissolved in MeOH
(300 mL). An aqueous solution (300 mL) of NaIO4 (23.9 g, 112 mmol)
was added dropwise to the MeOH solution over a period of 30 min. A
thick, colorless precipitate was produced. After the mixture had been
stirred for 2 h at room temperature all starting material was consumed.
The solid was filtered off, and after evaporation of MeOH the aqueous
solution was extracted three times with DCM. Finally the organic solvent
was removed, and the remaining oil was purified by column chromatog-
raphy (AcOEt) to give 8 (38.04 g, 94% over three steps) as a colorless
7.8 Hz, 1H), 8.80 (d, J = 5.8 Hz, 1H), 8.16 (d, J = 7.5 Hz, 1H), 7.86 (d,
J = 6.3 Hz, 1H), 7.72 7.61 (m, 5H), 7.41 7.30 (m, 6H), 5.09 (s, 2H),
3.64 3.51 (m, 3H), 2.36 2.31 (m, 1H), 2.05 2.00 (m, 1H), 1.78 1.73 (m,
2H), 0.83 (s, 9H), 0.00 (s, 6H) ppm; IR (KBr): n˜ = 3338, 3066, 3032,
2926, 2855, 2366, 1698, 1506, 1453, 1252, 1064, 838, 778, 778, 747, 726,
696 cmÀ1; elemental analysis calcd (%) for C32H39NO3Si (513.74): C
74.81, H 7.65, N 2.73; found: C 74.68, H 7.92, N 2.78.
Compound 10d: yield: 95%; Rf = 0.2 (AcOEt/hex 1:10); [a]2D0 À25.08 (c
= 0.9, MeOH); 1H NMR (250 MHz, [D6]DMSO): d = 8.06 (d, J =
6.2 Hz, 1H), 7.94 7.90 (m, 1H), 7.76 (d, J = 7.9 Hz, 2H), 7.54 7.50 (m,
2H), 7.42 7.28 (m, 7H), 5.05 (s, 2H), 3.61 3.45 (m, 3H), 3.25 2.92 (m,
2H), 1.74 1.50 (m, 2H), 0.87 (s, 9H), 0.00 (s, 6H) ppm; IR (KBr): n˜ =
3341, 2954, 2857, 1715, 1635, 1607, 1506, 1464, 1390, 1262, 1230, 1120,
878, 778 cmÀ1; elemental analysis calcd (%) for C28H37NO3Si (463.68): C
72.53, H 8.04, N 3.02; found: C 72.26, H 8.14, N 3.14.
Compound 10e: yield: 93%; Rf = 0.1 (AcOEt/hex 1:10); [a]2D0 À23.48 (c
= 0.9, MeOH); 1H NMR (250 MHz, [D6]DMSO): d = 7.91 (d, J =
8.5 Hz, 1H), 7.60 (d, J = 3.7 Hz, 2H), 7.37 7.35 (brs, 5H), 7.12 (m, 2H),
6.61 (d, J = 3.6 Hz, 1H), 5.03 (s, 2H), 3.57 3.44 (m, 3H), 2.75 2.63 (m,
2H), 1.87 1.72 (m, 2H), 1.62 (s, 9H), 0.83 (s, 9H), 0.00 (s, 6H) ppm; IR
(KBr): n˜ = 3358, 2956, 2856, 1706, 1506, 1470, 1348, 1250, 1160, 847, 766,
670 cmÀ1; elemental analysis calcd (%) for C31H44N2O5Si (552.78): C
67.36, H 8.02, N 5.07; found: C 67.33, H 8.27, N 4.96.
oil. Rf
=
0.4 (AcOEt); [a]2D0 À21.68 (c
=
0.9, MeOH); 1H NMR
(250 MHz, [D6]DMSO): d = 7.27 (s, 5H), 7.12 (d, J = 7.9 Hz, 1H), 4.98
(s, 2H), 3.54 3.45 (m, 2H), 2.70 2.60 (m, 2H), 2.47 (s, 3H), 1.91 1.82 (m,
1H), 1.67 1.58 (m, 1H), 0.83 (s, 9H), 0.00 (s, 6H) ppm; IR (KBr): n˜ =
3252, 3067, 2954, 2856, 1714, 1561, 1472, 1250, 1122, 1022, 837, 699 cmÀ1
;
Compound 10 f: yield: 83%; Rf = 0.5 (AcOEt/hex 1:10); [a]2D0 +1.78 (c
elemental analysis calcd (%) for C19H33NO4SSi (399.62): C 57.11, H 8.32,
N 3.51; found: C 56.95, H 8.35, N 3.65.
1
= 1.1, MeOH); H NMR (250 MHz, [D6]DMSO): d = 8.45 (s, 1H), 8.30
(d, J = 6.7 Hz, 2H), 8.06 (d, J = 4.4 Hz, 2H), 7.50 7.28 (m, 10H), 5.09
(s, 2H), 3.69 3.54 (m, 3H), 2.33 2.28 (m, 1H), 2.00 1.92 (m, 1H), 1.83
1.73 (m, 2H), 0.83 (s, 9H), 0.00 (s, 6H) ppm; IR (KBr): n˜ = 3315, 3059,
2952, 2855, 2366, 1693, 1542, 1470, 1290, 1249, 1122, 1060, 836, 776,
726 cmÀ1; elemental analysis calcd (%) for C32H39NO3Si (513.74): C
74.81, H 7.65, N 2.73; found: C 74.56, H 7.74, N 2.71.
Benzyl [1-(tert-butyldimethylsilanyloxymethyl)allyl]carbamate (9): The
sulfoxide
8 (45.18 g, 113 mmol) was dissolved in o-dichlorobenzene
(300 mL). After addition of powdered CaCO3 (28.6 g, 268 mmol) the stir-
red mixture was heated to reflux at 1808C until total consumption of the
starting material (4 h). The reaction mixture was cooled to room temper-
ature and filtered over celite, and the solvent was removed by vacuum
distillation (508C, 4 mbar). The yellow, viscous residue was purified by
column chromatography (AcOEt/hex 1:10) to give 9 (33.54 g, 88%) as a
colorless oil. Rf = 0.5 (AcOEt/hex 1:10); [a]2D0 À31.78 (c = 3.2, MeOH);
1H NMR (250 MHz, [D6]DMSO): d = 7.32 7.24 (brs, 6H), 5.15 (d, J =
20.6 Hz, 1H), 5.07 (d, J = 12.5 Hz, 1H), 5.00 (s, 2H), 4.09 3.97 (m, 1H),
3.49 (d, J = 6.3 Hz, 2H), 0.82 (s, 9H), 0.00 (s, 6H) ppm; IR (KBr): n˜ =
3445, 3332, 2956, 2857, 1716, 1646, 1505, 1471, 1256, 1115, 992, 921, 836,
General procedure for the synthesis of the alcohols 11a f: preparation of
alcohol 11a: The protected amino alcohol 10a (2.13 g, 4.3 mmol) was dis-
solved in TBAF in THF (1m, 10 mL, 10 mmol) and the mixture was stir-
red for 4 h at room temperature. After addition of H2O, the mixture was
extracted with AcOEt. The crude product was isolated from the organic
phase and purified by column chromatography (AcOEt/hex 1:1) to give
11a (1.26 g, 77%) as a colorless solid. Rf = 0.2 (AcOEt/hex 1:1); m.p.
101 1038C; [a]2D0 À17.48 (c
=
0.5, MeOH); 1H NMR (250 MHz,
778, 696, 699 cmÀ1
; elemental analysis calcd (%) for C18H29NO3Si
[D6]DMSO): d = 7.73 (d, J = 7.1 Hz, 2H), 7.59 (s, 1H), 7.39 7.27 (m,
7H), 7.12 (d, J = 6.4 Hz, 2H), 5.05 (s, 2H), 4.66 (t, J = 5.5 Hz, 1H),
3.87 (s, 3H), 3.50 3.25 (m, 3H), 2.84 2.60 (m, 2H), 1.93 1.89 (m, 1H),
1.71 1.66 (m, 1H) ppm; IR (KBr): n˜ = 3449, 3311, 3061, 2939, 2911,
2370, 1684, 1606, 1541, 1483, 1389, 1265, 1232, 1175, 852, 697 cmÀ1; ele-
mental analysis calcd (%) for C23H25NO4 (379.45): C 72.80, H 6.64, N
3.69; found: C 72.88, H 6.68, N 3.71.
(335.51): C 64.44, H 8.71, N 4.17; found: C 64.18 H 8.78 N 4.38.
General procedure for the synthesis of Suzuki products 10a f: prepara-
tion of Suzuki product 10a: Compound 9 (1.5 g, 4.5 mmol) was dissolved
in dry 1,4-dioxane (15 mL). After addition of 9-BBN (0.6 g, 5.0 mmol),
the stirred mixture was heated to 808C and kept at this temperature for
about 20 min until TLC showed complete hydroboration. After the addi-
tion of CsF (2.04 g, 13.4 mmol), Pd[dppf]Cl2 (110 mg, 0.13 mmol) and 2-
bromo-6-methoxy-naphthalene (1.33 g, 5.6 mmol), the resulting heteroge-
neous mixture was stirred overnight at 808C. For the isolation of the cou-
pling product the mixture was extracted with H2O and AcOEt. The or-
ganic phase was then evaporated and the residue was adsorbed on SiO2.
The crude product was purified by chromatography (AcOEt/hex 1:10) to
give 10a (2.14 g, 97%) as a colorless oil. Rf = 0.4 (AcOEt/hex 1:10);
[a]2D0 À26.28 (c = 0.9, MeOH); 1H NMR (250 MHz, [D6]DMSO): d =
7.94 7.71 (m, 2H), 7.61 (s, 1H), 7.56 7.26 (m, 7H), 7.17 7.10 (m, 2H),
5.04 (s, 2H), 3.87 (s, 3H), 3.57 3.46 (m, 3H), 2.79 2.66 (m, 2H), 1.99
1.87 (m, 1H), 1.70 1.67 (m, 1H), 0.86 (s, 9H), 0.00 (s, 6H) ppm; IR
(KBr): n˜ = 2954, 2857, 1728, 1714, 1607, 1505, 1470, 1470, 1392, 1229,
Compound 11b: yield: 84%; Rf = 0.3 (AcOEt); m.p. 102 1048C; [a]D20
1
À20.38 (c = 0.6, MeOH); H NMR (250 MHz, [D6]DMSO): d = 8.81 (s,
1H), 8.13 (s, 1H), 8.02 (d, J = 8.3 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H),
7.70 (t, J = 5.4/1.5 Hz, 1H), 7.61 (t, J = 6.9 Hz, 1H), 7.42 7.35 (brs,
5H), 7.20 (d, J = 8.3 Hz, 1H), 5.07 (s, 2H), 4.74 (t, J = 5.5 Hz, 1H),
3.54 3.32 (m, 3H), 2.90 2.78 (m, 2H), 2.03 1.73 (m, 2H) ppm; IR (KBr):
n˜ = 3322, 3206, 3035, 2953, 1959, 1680, 1528, 1467, 1331, 1308, 1253,
1073, 1051, 961, 880, 782, 732 cmÀ1; elemental analysis calcd (%) for
C21H22N2O3 (350.41): C 71.98, H 6.33, N 7.99; found: C 71.72, H 6.32, N
7.82.
Compound 11c: yield: 75%; Rf = 0.6 (AcOEt/hex 1:1); m.p. 1568C;
[a]2D0 À6.78 (c = 0.7, MeOH); 1H NMR (250 MHz, [D6]DMSO): d =
8.89 (d, J = 7.1 Hz, 1H), 8.81 (d, J = 6.7 Hz, 1H), 8.18 (d, J = 6.9 Hz,
1H), 7.92 7.88 (m, 1H), 7.76 7.64 (m, 5H), 7.43 7.28 (m, 6H), 5.11 (s,
2H), 4.73 (t, J = 5.5 Hz, 1H), 3.66 (m, 1H), 3.52 3.38 (m, 2H), 3.22 3.06
(m, 2H), 2.06 1.86 (m, 2H) ppm; IR (KBr): n˜ = 3328, 3063, 2851, 1685,
1534, 1451, 1258, 1069, 1025, 959, 869, 744, 722 cmÀ1; elemental analysis
calcd (%) for C26H25NO3 (399.48): C 78.17, H 6.31, N 3.51; found: C
77.98, H 6.31, N 3.70.
1118, 836, 777 cmÀ1
; elemental analysis calcd (%) for C29H39NO4Si
(493.71): C 70.55, H 7.96, N 2.84; found: C 70.31, N 8.03, H 3.04.
Compound 10b: yield: 88%; Rf = 0.2 (AcOEt/hex 1:3); [a]2D0 À28.88 (c
1
= 1.1, MeOH); H NMR (250 MHz, [D6]DMSO): d = 8.92 (s, 1H), 8.08
(s, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.88 (d, J = 7.9 Hz, 1H), 7.70 (t, J =
6.8/1.4 Hz, 1H), 7.54 (t, J = 7.9/7.0 Hz, 1H), 7.36 (brs, 5H), 7.22 (d, J =
8.6 Hz, 1H), 5.03 (s, 2H), 3.56 3.51 (m, 3H), 2.88 2.70 (m, 2H), 2.00
1.74 (m, 2H), 0.82 (s, 9H), 0.00 (s, 6H) ppm; IR (KBr): n˜ = 3326, 3034,
2953, 2857, 1716, 1540, 1497, 1463, 1388, 1330, 1251, 1116, 1058, 836, 778,
752, 697 cmÀ1; elemental analysis calcd (%) for C27H36N2O3Si (464.67): C
69.79, H 7.81, N 6.03; found: C 69.52, H 7.98, N 5.96.
Compound 11d: yield: 69%; Rf = 0.4 (AcOEt/hex 1:1); m.p. 96 1058C;
[a]2D0 À6.28 (c = 0.9, MeOH); 1H NMR (250 MHz, [D6]DMSO): d =
8.11 (t, J = 5.1/4.0 Hz, 1H), 7.95 (m, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.55
(m, 2H), 7.48 7.33 (m, 7H), 7.27 (d, J = 8.5 Hz, 1H), 5.10 (s, 2H), 4.71
(t, J = 5.5 Hz, 1H), 3.61 3.49 (m, 1H), 3.47 3.39 (m, 2H), 3.20 3.00 (m,
Compound 10c: yield: 95%; Rf = 0.5 (AcOEt/hex 1:10); [a]2D0 À16.08 (c
= 1.1, MeOH); 1H NMR (250 MHz, [D6]DMSO): d = 8.86 (d, J =
549
Chem. Eur. J. 2004, 10, 544 553
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Michael W. Gˆbel et al.
FULL PAPER
2H), 1.95 1.78 (m, 2H) ppm; IR (KBr): n˜ = 3293, 3061, 2934, 1953,
1730, 1596, 1509, 1478, 1454, 1411, 1244, 1026, 940, 800, 737 cmÀ1; ele-
mental analysis calcd (%) for C22H23NO3 (349.42): C 75.62, H 6.63, N
4.01; found 75.39, H 6.86, N 4.21.
2863, 2364, 1813, 1793, 1734, 1689, 1541, 1472, 1374, 1350, 1257, 1220,
1165, 1131, 1085, 1032, 760, 739 cmÀ1; elemental analysis calcd (%) for
C32H34N2O5¥1H2O (544.64): C 70.57, H 6.66, N 5.14; found: C 70.57, H
6.69, N 5.20.
Compound 11e: yield: 83%; Rf = 0.2 (AcOEt/hex 1:1); m.p. 101 1038C;
[a]2D0 À16.18 (c = 1.2, MeOH); 1H NMR (250 MHz, [D6]DMSO): d =
7.94 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 3.7 Hz, 1H), 7.40 7.32 (brs, 6H),
7.13 (t, J = 10.3/9.0 Hz, 1H), 6.64 (d, J = 3.6 Hz, 1H), 5.04 (s, 2H), 4.65
(t, J = 5.5 Hz, 1H), 3.46 3.23 (m, 2H), 2.77 2.55 (m, 2H), 1.88 1.84 (m,
2H), 1.80 1.70 (brs, 10H) ppm; IR (KBr): n˜ = 3332, 2959, 2860, 1949,
1732, 1690, 1534, 1470, 1384, 1328, 1257, 1130, 1054, 891, 841, 765, 726,
697 cmÀ1; elemental analysis calcd (%) for C25H30N2O5¥0.5H2O (447.53):
C 67.10, H 6.98, N 6.26; found: C 67.17, H 6.79, N 6.38.
Compound 12 f: yield: 68%; Rf = 0.3 (AcOEt/hex 1:1); m.p. 2218C;
1
[a]2D0 À30.78 (c = 0.4, DMF); H NMR (250 MHz, [D6]DMSO): d = 8.48
(s, 1H), 8.36 8.32 (m, 2H), 8.10 8.07 (m, 2H), 7.93 7.88 (m, 2H), 7.82
(d, J = 7.2 Hz, 2H), 7.54 7.50 (m, 4H), 7.45 7.29 (m, 5H), 4.75 (t, J =
5.5 Hz, 1H), 4.50 4.28 (m, 3H), 3.79 (brs, 1H), 3.60 3.38 (m, 4H), 2.00
1.82 (m, 2H) ppm; IR (KBr): n˜ = 3307, 3060, 2955, 2372, 1695, 1547,
1450, 1286, 1249, 1149, 1039, 879, 736 cmÀ1; elemental analysis calcd (%)
for C33H29NO3¥0.75H2O (501.11): C 79.04, H 6.13, N 2.80; found 78.94, H
6.09, N 2.80.
General procedure for the synthesis of the carboxylic acids 13a f: prepa-
ration of acid 13a: The Fmoc-protected alcohol 12a (649.4 mg, 1.4 mmol)
was dissolved in DMF (20 mL). PDC (3.13 g, 8.3 mmol) was added to
this clear solution, which was stirred overnight at room temperature.
After completion of the reaction the dark solution was extracted with
H2O and AcOEt. The combined organic phases were washed with aque-
ous Na2S2O5. The organic phase was evaporated and the residue was ad-
sorbed onto SiO2. The crude product was purified by column chromatog-
Compound 11 f: yield: 68%; Rf = 0.4 (AcOEt/hex 1:1); m.p. 1358C;
[a]2D0 +19.78 (c = 0.8, MeOH); 1H NMR (250 MHz, [D6]DMSO): d =
8.50 (s, 1H), 8.38 8.34 (m, 2H), 8.13 8.09 (m, 2H), 7.59 7.35 (m, 10H),
5.20 (s, 2H), 4.77 (t, J = 5.6, 1H), 3.80 (brs, 1H), 3.67 3.41 (m, 4H),
2.02 1.95 (m, 2H) ppm; IR (KBr): n˜ = 3319, 3057, 2946, 1694, 1540,
1452, 1349, 1286, 1243, 1149, 1067, 1038, 879, 836, 729, 696 cmÀ1; elemen-
tal analysis calcd (%) for C26H25NO3 (399.48): C 78.17, H 6.31, N 3.51;
found: C 77.97, H 6.42, N 3.70.
raphy (MeOH/AcOEt 1:9) to give 13a (390 mg, 58%) as a solid. Rf
=
General procedure for the synthesis of the alcohols 12a f: preparation of
alcohol 12a: The Cbz-protected alcohol 11a (707.8 mg, 1.9 mmol), 1.4-cy-
clohexadiene (873 mL, 9.3 mmol) and Pd(OH)2 (53 mg, 0.38 mmol) were
heated at reflux in ethanol (25 mL). After complete conversion of the
starting material (TLC monitoring), the catalyst was removed by filtra-
tion over celite. The filtrate was concentrated in vacuo and redissolved in
AcOEt (25 mL) and EtOH (15 mL). The addition of Fmoc-Suc (705 mg,
2.1 mmol) followed and the clear solution was stirred at room tempera-
ture. After 30 min a colorless precipitate of 12a was produced. The solid
was isolated by filtration to give the Fmoc-protected amino alcohol 12a
0.3 (MeOH/AcOEt 1:9); m.p. 190 1958C; [a]2D0 +19.58 (c = 0.6, DMF/
MeOH/AcOEt 1:3:6); 1H NMR (250 MHz, [D6]DMSO): d = 7.91 (d, J
= 6.2 Hz, 2H), 7.71 7.67 (m, 4H), 7.55 (s, 1H), 7.41 7.32 (m, 6H), 7.10
(m, 2H), 4.35 4.23 (m, 4H), 3.85 (s, 3H), 2.2 1.9 (m, 2H) ppm; IR
(KBr): n˜ = 3422, 3062, 2934, 2370, 1701, 1607, 1578, 1543, 1508, 1458,
1450, 1420, 1390, 1340, 1264, 1229, 1081, 1033, 740 cmÀ1; MS (ESI) m/z
(%): 480.3 (100) [MÀH]+, 227.8 (83) [MÀHÀFmoc]+ ; C30H27NO5 calcd
481.54; elemental analysis calcd (%) for C30H27NO5¥1.75H2O (513.04): C
70.23, H 5.99, N 2.73; found 69.94, H 5.70, N 3.03.
(699.7 mg, 80%). Rf
=
0.3 (AcOEt/hex 1:1); m.p. 196 1978C; [a]D20
Compound 13b: yield: 79%; Rf = 0.3 (MeOH/AcOEt 1:2); m.p. 181
1848C; [a]2D0 +11.88 (c = 0.3, MeOH/AcOEt 1:2); 1H NMR (250 MHz,
[D6]DMSO): d = 9.19 (s, 1H), 8.89 (s, 1H), 8.38 (m, 2H), 8.22 (d, J =
7.7 Hz, 1H), 8.03 (m, 1H), 7.92 7.74 (m, 5H), 7.42 7.34 (m, 4H), 4.32
4.22 (m, 3H), 4.02 (m, 1H), 3.17 (m, 2H), 2.21 1.99 (m, 2H) ppm; IR
(KBr): n˜ = 3400, 3062, 2947, 2368, 1702, 1604, 1498, 1450, 1420, 1332,
À10.58 (c = 0.7, DMF); 1H NMR (250 MHz, [D6]DMSO): d = 7.93 (d,
J = 7.3 Hz, 2H), 7.79 7.73 (m, 4H), 7.62 (s, 1H), 7.48 7.29 (m, 6H), 7.16
(t, J = 6.5/2.4 Hz, 2H), 4.69 (t, J = 5.5 Hz, 1H), 4.41 4.27 (m, 3H), 3.89
(s, 3H), 3.51 3.31 (m, 3H), 2.80 2.68 (m, 2H), 1.94 1.73 (m, 2H) ppm;
IR (KBr): n˜ = 3327, 3052, 2933, 1957, 1913, 1689, 1607, 1538, 1451, 1390,
1291, 1264, 1158, 1087, 1032, 966, 901, 851, 760 cmÀ1; elemental analysis
calcd (%) for C30H29NO4 (467.56): C 77.06, H 6.25, N 3.00; found: C
76.92, H 6.22, N 3.21.
1254, 1130, 1053, 740, 670 cmÀ1; MS (ESI) m/z (%): 453.3 (100) [M+H]+
C28H24N2O4 calcd 452.2.
;
Compound 13c: yield: 86%; Rf = 0.3 (MeOH/AcOEt 1:9); m.p. 135
1408C; [a]2D0 +16.68 (c = 0.7, MeOH/AcOEt 1:2); 1H NMR (250 MHz,
[D6]DMSO): d = 8.88 (d, J = 9.3 Hz, 1H), 8.80 (d, J = 8.7 Hz, 1H),
8.20 (d, J = 9.2 Hz, 1H), 7.96 7.87 (m, 6H), 7.81 7.59 (m, 5H), 7.46
7.35 (m, 4H), 4.37 4.32 (m, 3H), 4.13 (m, 1H), 3.24 3.17 (m, 2H), 2.16
(m, 2H) ppm; IR (KBr): n˜ = 3403, 3063, 2931, 2372, 1953, 1718, 1663,
1596, 1496, 1449, 1414, 1330, 1246, 1146, 1050, 741 cmÀ1; MS (ESI) m/z
= 524.1896 [M+Na]+ ; C33H27NO4Na calcd 524.1838.
Compound 12b: yield: 84%; Rf = 0.3 (AcOEt), m.p. 158 1598C; [a]D20
1
À11.38 (c = 0.7, MeOH); H NMR (250 MHz, [D6]DMSO): d = 8.78 (s,
1H), 8.11 7.18 (m, 15H), 4.70 (brs, 1H), 4.42 4.21 (m, 3H), 3.43 3.39
(m, 2H), 2.85 2.67 (m, 2H), 1.95 1.71 (m, 2H) ppm; IR (KBr): n˜
=
3333, 2931, 1959, 1702, 1676, 1531, 1450, 1254, 1048, 739 cmÀ1; elemental
analysis calcd (%) for C28H26N2O3¥0.3AcOEt (464.95): C 75.43, H 6.16, N
6.02; found: C 75.20, H 6.18, N 6.20.
Compound 13d: yield: 56%; Rf = 0.3 (AcOEt); m.p. 156 1578C; [a]D20
+19.48 (c = 0.2, MeOH/AcOEt 1:4); 1H NMR (250 MHz, [D6]DMSO):
d = 8.10 (s, 1H), 7.96 (s, 1H), 7.91 (d, J = 8.6 Hz, 2H), 7.76 (d, J =
7.6 Hz, 2H), 7.51 7.31 (m, 10H), 4.38 4.26 (m, 3H), 3.95 (m, 1H), 3.06
(m, 2H), 2.07 (m, 2H) ppm; IR (KBr): n˜ = 3407, 3063, 2934, 2368, 1718,
1664, 1596, 1510, 1450, 1417, 1334, 1247, 1080, 1054, 740 cmÀ1; MS (ESI)
m/z (%): 450.3 (50) [MÀH]+, 227.8 (100) [MÀHÀFmoc]+ ; C29H25NO4
calcd 451.2; elemental analysis calcd (%) for C29H25NO4¥1.25-
H2O¥0.25DMF (492.28): C 72.58, H 5.99, N 3.56; found 72.53, H 5.62, N 3.71.
Compound 12c: yield: 74%; Rf = 0.3 (AcOEt/hex 1:1); m.p. 195 1968C;
1
[a]2D0 +5.98 (c = 0.5, DMF); H NMR (250 MHz, [D6]DMSO): d = 8.73
(d, J = 7.3 Hz, 1H), 8.64 (d, J = 6.8 Hz, 1H), 8.03 (d, J = 7.0 Hz, 1H),
7.78 7.72 (m, 3H), 7.64 7.46 (m, 7H), 7.29 7.15 (5H), 4.55 (brs, 1H),
4.28 4.13 (m, 4H), 3.48 2.87 (m, 4H), 1.88 1.85 (m, 2H) ppm; IR (KBr):
n˜ = 3313, 3063, 2947, 2870, 2364, 1918, 1692, 1542, 1450, 1334, 1291,
1246, 886, 738 cmÀ1; elemental analysis calcd (%) for C33H29NO3 (487.59):
C 81.29, H 5.99, N 2.87; found: C 81.04, H 5.95, N 3.05.
Compound 12d: yield: 57%; Rf = 0.3 (AcOEt/hex 1:1); m.p. 196 1978C;
[a]2D0 +0.78 (c
=
0.8, MeOH/AcOEt 1:9); 1H NMR (250 MHz,
Compound ent-13d: yield: 53%; Rf = 0.3 (AcOEt); m.p. 154 1558C;
[a]2D0 À19.18 (c = 0.4, MeOH/AcOEt 1:4); NMR and IR spectra are iden-
tical with those of compound 13d.
[D6]DMSO): d = 8.11 8.08 (m, 1H), 7.94 7.89 (m, 3H), 7.77 (d, J =
7.5 Hz, 3H), 7.56 7.27 (m, 9H), 4.68 (t, J = 5.5 Hz, 1H), 4.42 4.27 (m,
3H), 3.60 (brs, 1H), 3.48 3.33 (m, 2H), 3.13 2.98 (m, 2H), 1.92 1.76 (m,
2H) ppm; IR (KBr): n˜ = 3482, 3336, 3066, 2947, 2873, 2366, 1677, 1546,
Determination of ee: Column: Daicel Chiralcel OJ-R 150î4.6 mm;
eluent: aqueous 0.1% trifluoroacetic acid/acetonitrile 40:60, flow rate
0.5 mLminÀ1; detection: UV, 254 nm; Rt 13d: 9.03 min, Rt ent-13d :
11.52 min.
1451, 1399, 1342, 1286, 1259, 1286, 1259, 1142, 1088, 1070, 779, 739 cmÀ1
;
elemental analysis calcd (%) for C29H27NO3 î0.5H2O (446.53): C 78.00,
Compound 13e: yield: 79%; Rf = 0.3 (AcOEt); m.p. 158 1608C; [a]D20
+18.68 (c = 1, MeOH/AcOEt 1:4); H NMR (250 MHz, [D6]DMSO): d
= 7.96 7.90 (m, 4H), 7.70 (s, 1H), 7.57 (d, J = 3.3 Hz, 2H), 7.39 7.33
(m, 5H), 7.11 7.08 (d, J = 7.9 Hz, 4H), 6.57 (s, 1H), 4.34 4.21 (m, 3H),
3.85 (m, 1H), 2.64 (m, 2H), 1.92 (m, 2H), 1.59 (9H) ppm; IR (KBr): n˜
= 3405, 2977, 2931, 1729, 1665, 1590, 1508, 1450, 1374, 1256, 1164, 1131,
1023, 740 cmÀ1; MS (ESI) m/z (%): 539.2 (50) [MÀH]+, 317.3 (100)
H 6.32, N 3.14; found: C 78.12, H 6.25, N 3.13.
Compound 12e: yield: 58%; Rf = 0.3 (AcOEt/hex 1:1); m.p. 648C; [a]D20
À4.98 (c = 0.4, AcOEt); 1H NMR (250 MHz, [D6]DMSO): d = 7.96 (t,
J = 9.2/8.8 Hz, 3H), 7.77 (d, J = 7.0 Hz, 2H), 7.65 (d, J = 3.6 Hz, 1H),
7.48 7.34 (m, 5H), 7.17 (t, J = 8.2/7.4 Hz, 2H), 6.66 (d, J = 3.6 Hz, 1H),
4.67 (t, J = 5.5/5.1 Hz, 1H), 4.40 4.28 (m, 3H), 3.46 3.26 (m, 3H), 2.75
2.66 (m, 2H), 2.02 1.90 (m, 11H) ppm; IR (KBr): n˜ = 3329, 2977, 2928,
1
550
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 544 553

Non-Natural Aromatic a-Amino Acids
544 553
[MÀHÀFmoc]+ ; C32H32N2O6 calcd 540.2; elemental analysis calcd (%)
for C32H32N2O6¥1.2H2O¥0.4DMF (591.44): C 67.42, H 6.34, N 5.68; found
67.25, H 5.94, N 6.00.
Compound 19e: yield: 86%; Rf = 0.5 (DCM/MeOH 20:1); [a]2D0 +58.28
(c = 0.5, MeOH); 1H NMR (250 MHz, [D6]DMSO): d = 8.60 8.50 (m,
2H, J = 2.5 Hz), 8.48 (d, 1H, J = 2.5 Hz), 7.60 7.25 (m, 12H), 5.50 (d,
1H, J = 3.7 Hz), 5.35 4.90 (m, 2H), 4.75 4.45 (m, 2H), 4.20 4.05 (m,
N-Cbz-(S,S)-Pseudoephedrine-allylglycine
compound
(17):
Et3N
1H), 2.90 2.65 (m, 5H), 1.85 1.40 (m, 4H), 0.83 (d*, 3H,
J =
(9.56 mL, 69 mmol) was added dropwise by syringe to a solution of the
allylglycine derivative 15[9b] (15.0 g, 57 mmol) in CHCl3 (250 mL, argon
atmosphere). After the mixture had been stirred at room temperature for
30 min, Cbz-Cl (9.67 mL, 69 mmol) was added slowly at 08C. The reac-
tion mixture was allowed to warm up to room temperature and stirred
for 18 h. At this point saturated aqueous NaHCO3 solution was added
(100 mL) and the mixture was stirred for 20 min. The organic phase was
separated and washed with saturated NaHCO3 solution (100 mL). After
reextraction of the combined aqueous layers (twice with 100 mL DCM),
the combined organic layers were evaporated in vacuo. The resulting
yellow oil was purified by gradient column chromatography (AcOEt/hex
1:1, AcOEt), providing 17 as a pale yellow oil in 96% yield (21.68 g). Rf
6.5 Hz) ppm; IR (KBr): n˜ = 3407, 3062, 2934, 1718, 1636, 1526, 1497,
1476, 1456, 1405, 1245, 1120, 1050, 1017, 912, 836, 757, 700, 610 cmÀ1; ele-
mental analysis calcd (%) for C27H32N4O4¥0.45H2O (484.34): C 66.91, H
6.84, N 11.56; found: C 66.95, H 6.75, N 11.36.
General procedure for the deprotection of amino acids: preparation of
20a: Aflask filled with argon was charged with MeOH (20 mL), 19a
(5.9 g, 12.4 mmol) and Pd/C (10%, 700 mg). After replacement of argon
by hydrogen (normal pressure), the mixture was vigorously stirred for
16 24 h (depending on the activity of the catalyst) at room temperature
until total consumption of the starting material. The reaction mixture
¾
was then filtrated over celite and washed with MeOH, and the resulting
=
0.5 (AcOEt/hex 1:1); [a]2D0 +53.98 (c 0.3, MeOH); 1H NMR
=
organic layer was concentrated in vacuo. The oily residue was suspended
in H2O (40 mL) and heated at reflux for 24 h to remove the chiral auxili-
ary. After cooling to room temperature, the mixture was extracted five
times with DCM. The aqueous solution was concentrated in vacuo and
the resulting oily residue crystallized from MeOH/AcOEt/hexanes/Et2O
to yield a colorless solid (1.5 g, 62% over two steps). Rf = 0.2 (H2O);
(250 MHz, [D6]DMSO): d = 7.54 (d, J = 8.8 Hz, 1H), 7.53 7.23 (m, 10H),
5.91 5.69 (m, 1H), 5.26 4.94 (m, 4H), 4.69 4.46 (m, 2H), 4.17 4.00 (m,
1H), 2.82 (s*, 3H), 2.46 2.24 (m, 2H), 0.83 (d*, J = 6.6 Hz, 3H) ppm;
IR (KBr): n˜ = 3416, 3032, 1717, 1630, 1508, 1455, 1411, 1253, 1112, 1049,
919, 756, 700 cmÀ1
; elemental analysis calcd: (%) for C23H28N2O4
m.p. 1928C; [a]2D0 +7.08 (c
=
0.4, MeOH); 1H NMR (250 MHz,
(396.47): C 69.67, H 7.12, N 7.07; found: C 69.42, H 7.01, N 6.92.
[D6]DMSO): d = 8.39 8.33 (m, 1H), 7.76 7.69 (m, 1H), 7.39 7.19 (m,
2H), 3.73 3.64 (m, 1H), 2.84 2.70 (m, 2H), 1.87 1.66 (m, 4H) ppm; IR
(KBr): n˜ = 3017, 2934, 2862, 2594, 2112, 1631, 1587, 1520, 1477, 1459,
1439, 1406, 1352, 1308, 1232, 1201, 1157, 1129, 1065, 1050, 1015, 998, 882,
846, 827, 784, 755, 737, 671, 634, 605 cmÀ1; elemental analysis calcd (%)
for C10H14N2O2¥0.3MeOH (203.72): C 60.69, H 7.52, N 13.74; found: C
60.81, H 6.75, N 13.68.
General procedure for Suzuki cross-coupling reactions of compound 17:
preparation of the 2-pyridyl derivative (19a): Athree-necked, round-bot-
tomed flask was charged with 17 (2.0 g, 5.1 mmol) under argon atmos-
phere. 9-BBN (24.3 mL of 0.5m in THF, 12.2 mmol) was added and the
mixture was stirred at room temperature. After total consumption of the
starting material (15 min), [Pd(PPh3)4] (291 mg, 5 mol%) was added, fol-
lowed by aqueous K3PO4 solution (3m, 5 mL) and 2-bromopyridine
(517 mL, 5.3 mmol). The resulting mixture was stirred for another 16 h at
room temperature. The mixture was diluted with Et2O (10 mL) and ex-
tracted four times with saturated NaHCO3 solution. The combined aque-
ous solutions were extracted twice with Et2O (20 mL). The organic layers
were combined and concentrated in vacuo. The resulting viscous residue
was purified by column chromatography on silica gel eluting with a gradi-
ent (AcOEt/hex 1:1, AcOEt) to afford product 19a as a colorless foam
Compound 20e: yield: 63% (over two steps); Rf
= 0.4 (H2O);
m.p. 2468C; [a]2D0 +3.98 (c 0.3, MeOH); 1H NMR (250 MHz,
=
[D6]DMSO): d = 8.49 (d, J = 3.6H, 2H), 8.41 (d, J = 2.6 Hz, 1H),
3.40 3.35 (m, 1H), 2.79 2.74 (m, 2H), 1.80 1.61 (m, 4H) ppm; IR (KBr):
n˜ = 3444, 3042, 2956, 2602, 2133, 1584, 1519, 1407, 1355, 1355, 1327,
1161, 1134, 1062, 1019, 828, 670 cmÀ1; elemental analysis calcd (%) for
C9H13N3O2 (195.10): C 55.37, H 6.71, N 21.52; found: C 55.41, H 6.72, N
21.33.
(2.16 g, 90%). Rf
= = 0.1,
0.5 (DCM/MeOH 20:1); [a]2D0 +56.58 (c
MeOH); 1H NMR (250 MHz, [D6]DMSO): d = 8.5 7.2 (m, 15H), 5.50
(d, 1H, J = 3.7 Hz), 5.07 4.93 (m, 2H), 4.58 4.47 (m, 2H), 4.14 4.05 (m,
First procedure for Fmoc-protection: preparation of 21a: Compound 20a
(500 mg, 2.57 mmol) was suspended in DCM (15 mL) under argon and
TMS-Cl (651 mL, 5.15 mmol) was added dropwise. Within 30 min the sus-
pension dissolved to form a pale yellow solution. At that point DIPEA
(761 mL, 4.45 mmol) and Fmoc-Cl (665 mg, 2.57 mmol) were added and
the resulting mixture was stirred at room temperature for 16 h. The reac-
tion mixture was diluted with aqueous NaHCO3 solution (2.5%, 15 mL)
and Et2O (15 mL). The aqueous layer was extracted four times with
Et2O. The combined organic layers were extracted with aqueous
NaHCO3 solution (2.5%, 20 mL) followed by H2O (20 mL). All aqueous
layers were combined and acidified to pH 1 with HCl (1m). Upon acidifi-
cation, the solution became turbid. It was then extracted eight times with
AcOEt (50 mL). After concentration in vacuo a slightly brownish foam
remained. It was dissolved in AcOEt with heating. The organic layer was
separated from the brown precipitate. After concentration in vacuo the
resulting foam was recrystallized with AcOEt/MeOH/hexanes/Et2O to
yield a tan-colored powder (860 mg; 80%). Rf = 0.5 (MeOH); m.p. 108
1H), 2.84 2.65 (m, 5H), 1.77 1.44 (m, 4H), 0.82 (d*, 3H,
J =
6.4 Hz) ppm; IR (KBr): n˜ = 3402, 3287, 3062, 3031, 2935, 2863, 1715,
1630, 1528, 1496, 1477, 1454, 1436, 1409, 1247, 1119, 1050, 1027, 911, 838,
753, 700, 612 cmÀ1; elemental analysis calcd (%) for C28H33N3O4¥0.3H2O
(480.65): C 69.92, H 7.04, N 8.74; found: C 69.97, H 7.11, N 8.39.
Compound 19b: yield: 38%; Rf = 0.5 (DCM/MeOH 20:1); [a]2D0 +53.38
(c = 0.6, MeOH); 1H NMR (250 MHz, [D6]DMSO): d = 8.48 8.37 (m,
1H), 7.66 7.18 (m, 13H), 5.51 (d, 1H, J = 3.7 Hz), 5.09 4.91 (m, 2H),
4.62 4.37 (m, 2H), 4.19 4.07 (m, 1H), 2.88 2.52 (m, 5H), 1.66 1.35 (m,
4H), 0.83 (d*, J = 6.3 Hz, 3H) ppm; IR (KBr): n˜ = 3406, 2933, 1718,
1629, 1528, 1456, 1412, 1351, 1245, 1116, 1049, 755, 700, 611 cmÀ1; ele-
mental analysis calcd (%) for C28H33N3O4¥0.95AcOEt (558.95): C 68.29,
H 7.32, N 7.51; found: C 68.02, H 7.02, N 7.77.
Compound 19c: yield: 88%; Rf = 0.5 (DCM/MeOH 20:1); [a]2D0 +58.18
(c = 0.5, MeOH); 1H NMR (250 MHz, [D6]DMSO): d = 8.72 (dd, 2H,
1108C; [a]2D0 +1.78 (c
=
0.2, methanol); 1H NMR (250 MHz,
J
= 4.9/4.1 Hz), 7.55 7.27 (m, 12H, J = 4.9 Hz), 5.48 (d, 1H, J =
[D6]DMSO): d = 12.8 12.2 (brs, 1H), 8.49 (d, 1H, J = 4.1 Hz), 7.91
7.20 (m, 12H), 4.31 4.23 (m, 3H), 4.15 3.95 (m, 1H), 2.74 (d, 2H, J =
5.9 Hz), 1.50 1.81 (m, 4H) ppm; IR (KBr): n˜ = 3556, 2959, 2490, 1960,
1697, 1599, 1538, 1449, 1334, 1301, 1235, 1155, 1110, 1082, 1055,
1012 cmÀ1; elemental analysis calcd (%) for C25H24N2O4¥1.3H2O (440.57):
C 68.26, H 6.09, N 6.37; found: C 68.21, H 5.83, N 6.55.
3.7 Hz), 5.07 4.93 (m, 2H), 4.75 4.65 (m, 2H), 4.18 4.00 (m, 1H), 2.90
2.78 (m, 5H,), 1.85 1.50 (m, 4H), 0.83 (d*, 3H, J = 6.5 Hz) ppm; IR
(KBr): n˜ = 3336, 3063, 2936, 1711, 1639, 1561, 1529, 1491, 1453, 1423,
1376, 1249, 1199, 1101, 1046, 912, 818, 754, 698, 636, 582 cmÀ1; elemental
analysis calcd (%) for C27H32N4O4¥0.50H2O (485.24): C 66.79, H 6.85, N
11.54; found: C 66.95, H 6.87, N 11.21.
Compound 21e: yield: 68%; Rf = 0.5 (MeOH); m.p. 89 908C; [a]D20
+
Compound 19d: yield: 27%; Rf = 0.5 (DCM/MeOH 20:1); [a]2D0 +61.28
(c = 0.5, MeOH); H NMR (250 MHz, [D6]DMSO): d = 9.04 (d, 1H, J
1
1
1.58 (c = 0.3, MeOH); H NMR (250 MHz, [D6]DMSO): d = 12.53 (brs,
1H), 8.56 (s, 2H), 8.49 (d, J = 2.2 Hz, 1H), 7.91 7.29 (m, 10H), 4.32
4.20 (3H), 4.15 3.85 (m, 1H), 2.85 2.70 (m, 2H), 1.85 1.61 (m, 4H) ppm;
IR (KBr): n˜ = 3320, 3064, 2926, 2863, 2519.4, 1924, 1718, 1691, 1608,
1542, 1476, 1450, 1404, 1372, 1258, 1160, 1050, 9889, 861, 758, 733, 660,
621 cmÀ1; elemental analysis calcd (%) for C24H23N3O4 (416.17): C 69.05,
H 5.55, N 10.07; found: C 68.84, H 5.76, N 9.82.
= 1.9 Hz), 8.66 (m, 2H), 7.42 7.24 (m, 11H), 5.57 (d, 1H, J = 4.1 Hz),
5.08 4.93 (m, 2H), 4.62 4.41 (m, 2H), 4.18 4.00 (m, 1H), 2.88 2.52 (m,
5H), 1.69 1.41 (m, 4H), 0.83 (d*, 3H, J = 6.6 Hz) ppm; IR (KBr): n˜ =
3396, 3291, 3031, 2936, 2866, 1713, 1632, 1563, 1530, 1496, 1454, 1410,
1375, 1250, 1122, 1049, 911, 838, 756, 728, 701, 635, 612 cmÀ1; MS (ESI)
m/z = 477.2345 [M+H]+ ; C27H33N4O4 calcd 477.2502.
551
Chem. Eur. J. 2004, 10, 544 553
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Michael W. Gˆbel et al.
FULL PAPER
Compound ent-21e: yield: 67%; Rf = 0.5 (MeOH); m.p. 87 908C; [a]D20
À1.48 (c = 0.4, MeOH); NMR and IR spectra are identical with those of
compound 21e; elemental analysis calcd (%) for C24H23N3O4¥0.5AcOEt
(460.23): C 67.67, H 5.90, N 9.10; found: C 67.60, H 5.86, N 9.35.
Preparation of compound NH2-d-Arg-l-Phenan-d-Arg-CONH2 (24)
from 13c: yield: 99%; MS (ESI) m/z (%): 591.5 (4) [M+H]+, 296.2 (100)
[M+2H]+ ; C30H42N10O3 calcd 590.3.
Preparation of compound NH2-d-Arg-l-Napht-d-Arg-CONH2 (25) from
13d: yield: 94%; MS (ESI) m/z (%): 541.5 (8) [M+H]+, 271.1 (100)
[M+2H]+ ; C26H40N10O3 calcd 540.3.
Determination of ee: Column: Daicel Chiralcel OJ-R 150î4.6 mm;
eluent: aqueous 0.1% trifluoroacetic acid/acetonitrile 73:27; flow rate
0.5 mLminÀ1; detection: UV, 254 nm; Rt ent-21e: 42.19 min, Rt 21e:
47.73 min.
Preparation of compound NH2-d-Arg-d-2-Pyridyl-d-Arg-CONH2 (26)
from 21a: yield: 74%; MS (ESI) m/z (%): 506.5 (8) [M+H]+, 253.7 (100)
[M+2H]+ ; C22H39N11O3 calcd 505.3.
Second procedure for Cbz removal and Fmoc protection: preparation of
compound 21b: The Cbz group of 19b (2.1 g, 4.39 mmol) was removed
by hydrogenolysis with Pd/C (10%, 300 mg) as described above. The re-
maining oil was suspended in H2O (30 mL) and heated at reflux until re-
moval of the auxiliary was complete (24 h). Pseudoephedrine was isolat-
ed by extraction with DCM. Evaporation of the aqueous phase to dry-
ness gave the amino acid 20b. It was used for Fmoc protection without
further purification according to the general procedure with TMS-Cl
(1.04 mL, 8.24 mmol), DIPEA(1.22 mL, 7.13 mmol) and Fmoc-Cl
(451 mg, 4.12 mmol) to yield a colorless foam (906 mg, 50% over three
Preparation of compound NH2-d-Arg-d-3-Pyridyl-d-Arg-CONH2 (27)
from 21b: yield: 92%; MS (ESI) m/z (%): 506.5 (10) [M+H]+, 253.6
(100) [M+2H]+ ; C22H39N11O3 calcd 505.3.
Preparation of compound NH2-d-Arg-d-2-Pyrimidinyl-d-Arg-CONH2
(28) from 21c: yield: 78; MS (ESI) m/z (%): 507.4 (100) [M+H]+ %;
C21H38N12O3 calcd 506.3.
Preparation of compound NH2-d-Arg-d-Pyrazinyl-d-Arg-CONH2 (29)
from 21e: yield: 73%; MS (ESI) m/z (%): 507.4 (3) [M+H]+, 254.2 (100)
[M+2H]+ ; C21H38N12O3 calcd 506.3.
steps): Rf
(250 MHz, [D6]DMSO): d
=
0.5 (MeOH); [a]2D0 +3.48 (c
=
0.3, MeOH); 1H NMR
7.2/
Preparation of compound NH2-d-Arg-l-Pyrazinyl-d-Arg-CONH2 (30)
from ent-21e: yield: 99%; MS (ESI) m/z (%): 507.3 (8) [M+H]+, 254.1
(100) [M+2H]+ ; C21H38N12O3 calcd 506.3.
=
12.8 12.2 (brs, 1H), 8.48 (dd, J
=
2.2 Hz, 1H), 7.90 (brd, 2H), 7.76 7.26 (m, 9H), 4.35 4.18 (m, 3H), 4.05
3.93 (m, 1H), 2.73 2.57 (m, 2H), 1.82 1.52 (m, 4H) ppm; IR (KBr): n˜ =
3323, 3063, 2937, 1718, 1534, 1450, 1400, 1332, 1245, 1048, 761, 740 cmÀ1
;
MS (ESI) m/z: 417.1677 [M+H]+ ; C25H25N2O4 calcd 417.1814.
Compound 21c (second procedure): yield 32% (over three steps); Rf
0.5 (MeOH); m.p. 60 648C; [a]2D0 +1.98 (c = 0.3, MeOH); 1H NMR
(250 MHz, [D6]DMSO): d 12.9 12.2 (brs, 1H), 8.73 (d, 2H, J
=
Acknowledgement
=
=
Financial support of this work by the Deutsche Forschungsgemeinschaft
(SFB 579) is gratefully acknowledged. A. K. would like to thank the
Fonds der chemischen Industrie for a predoctoral fellowship. We also
thank Dr. Christo D. Roussev and Oliver Boden for helpful discussions
and critical reading.
5.1 Hz), 7.92 7.30 (m, 11H), 4.33 4.20 (m, 3H), 4.08 3.93 (m, 1H), 2.92
2.86 (m, 2H), 1.92 1.57 (m, 4H) ppm; IR (KBr): n˜ = 3405, 3039, 2950,
1718, 1561, 1540, 1527, 1450, 1424, 1340, 1247, 1106, 1052, 760, 741 cmÀ1
;
elemental analysis calcd (%) for C24H23N3O4¥1AcOEt (505.56): C 66.52,
H 6.18, N 8.31; found: C 66.57, H 6.12, N 8.46.
Compound 21d (second procedure): yield: 40% (over three steps); Rf
=
0.5 (MeOH); m.p. 78 808C; [a]2D0 +3.5 8 (c = 0.3, MeOH); 1H NMR
(250 MHz, [D6]DMSO): d = 12.5 12.2 (brs, 1H), 9.05 (s, 1H), 8.68 (s,
2H), 7.93 7.25 (m, 10H), 4.34 4.18 (m, 3H), 4.06 3.92 (m, 1H), 2.68
2.56 (m, 2H), 1.76 1.57 (m, 4H) ppm; IR (KBr): n˜ = 3396, 3040, 2948,
2368, 1718, 1522, 1449, 1410, 1321, 1218, 1052, 760, 740, 646 cmÀ1; MS
(ESI) m/z = 418.1716 [M+H]+ ; C25H24N2O4 calcd 418.1767.
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General procedures for solid-phase peptide synthesis: Attachment of N-
Fmoc-amino acids to Rink amide MBHAresin: After swelling of the
resin (150 mg, theoretical loading 0.78 mmolgÀ1, 0.19 mmol) twice with
DCM (2 mL) for 20 min, the solvent was changed to DMF. The Fmoc-
protected resin was then treated three times with a solution of piperidine
in DMF (25%) to liberate the amine (15 min/5 min/2 min). Subsequently,
the resin was washed with DMF (five times). For coupling, the Fmoc-pro-
tected amino acid (2 equiv, 0.38 mmol) was dissolved in DMF (2 mL) to-
gether with HOBt (3 equiv) and DIC (3 equiv). This mixture was added
to the resin. After 3 h of gentle agitation, the resin was again washed
with DMF and tested for complete coupling by the Kaiser test.[20] The
Fmoc-amine was liberated by treatment with piperidine in DMF as de-
scribed before. After washing with DMF (5 times) the following Fmoc-
amino acids were coupled in identical fashion.
Cleavage of the resin and protecting groups: After removal of the last
Fmoc group, the resin was washed with DCM and dried in vacuo. The
resin was then treated with TFA(1650 mL), thioanisole (100 mL), H2O
(100 mL), phenol (50 mg) and EDT (50 mL). The resin turned red and
after 5 h of gentle agitation it was filtered off. Upon trituration with
Et2O, the peptide precipitated from the filtrate. The precipitate was sev-
eral times suspended in Et2O and spun down in a centrifuge. After re-
moval of the organic solvent, the pellet was dissolved in H2O, concentrat-
ed by use of a speedvac to eliminate volatile impurities and finally dis-
solved in H2O.
[6] a) S. J. Danishefsky, S. R. Chemler, D. Trauner, Angew. Chem. 2001,
113, 4676 4701; Angew. Chem. Int. Ed. 2001, 40, 4544 4568; b) N.
Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457 2483; c) N. Miyaura,
T. Ishiyama, H. Sasaki, M. Ishikawa, M. Satoh, A. Suzuki, J. Am.
Chem. Soc. 1989, 111, 314 321.
Preparation of compound NH2-d-Arg-l-NaphtOMe-d-Arg-CONH2 (22)
from 13a: yield: 74%; MS (ESI) m/z (%): 571.4 (5) [M+H]+, 286.1 (100)
[M+2H]+ ; C27H42N10O4 calcd 570.3.
[7] Fluoride as a base in Suzuki reactions: S. W. Wright, D. L. Hage-
man, L. D. McClure, J. Org. Chem. 1994, 59, 6095 6097.
Preparation of compound NH2-d-Arg-l-Quino-d-Arg-CONH2 (23) from
13b: yield: 87%; MS (ESI) m/z (%): 542.5 (9) [M+H]+, 271.7 (100)
[M+2H]+ ; C25H39N11O3 calcd 541.3.
[8] Application of Suzuki reactions to the synthesis of amino acids:
a) P. N. Collier, A. D. Campbell, I. Patel, R. J. K. Taylor, Tetrahedron
Lett. 2000, 41, 7115 7119; b) P. N. Collier, A. D. Campbell, I. Patel,
552
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 544 553

Non-Natural Aromatic a-Amino Acids
544 553
R. J. K. Taylor, Tetrahedron 2002, 58, 6117 6125; c) P. N. Collier,
A. D. Campbell, I. Patell, T. M. Raynham, R. J. K. Taylor, J. Org.
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b) M. J. McKennon, A. I. Meyers, K. Drauz, M. Schwarm, J. Org.
Chem. 1993, 58, 3568 3571.
[17] A. Dondoni, S. Franco, F. Junquera, F. L. Merchµn, P. Merino, T.
Tejero, V. Bertolasi, Chem. Eur. J. 1995, 1, 505 520.
[18] After recrystallization, compound 15 (prepared from (S,S)-(+)-pseu-
doephedrine) was isomerically pure according to NMR. The sub-
stance had a m.p. of 79 838C and an optical rotation [a]2D0 +87.58 (c
[9] a) A. G. Myers, J. L. Gleason, Org. Synth. 1999, 76, 57 76; b) A . G.
Myers, P. Schnider, S. Kwon, D. W. Kung, J. Org. Chem. 1999, 64,
3322 3327; c) A. G. Myers, J. L. Gleason, T. Yoon, D. W. Kung, J.
Am. Chem. Soc. 1997, 119, 656 673.
[10] A. D. Campbell, T. M. Raynham, R. J. K. Taylor, Synthesis 1998,
1707 1709.
[11] A. Dondoni, D. Perrone, Org. Synth. 1999, 77, 64 77.
[12] P. Meffre, L. Vo-Quang, Y. Vo-Quang, F. Le Goffic, Synth.
Commun. 1989, 19, 3457 3468.
[13] A. Afzali-Ardakani, H. Rapoport, J. Org. Chem. 1980, 45, 4817
4820.
=
0.5, MeOH). Compound ent-15 (prepared from (R,R)-(À)-
pseudoephedrine):[a]2D0 À87.38 (c = 0.5, MeOH).
[19] W. C. Chan, P. D. White, Fmoc Solid Phase Peptide Synthesis,
Oxford University Press, 2000, pp. 41 74.
[20] a) E. Kaiser, R. L. Colescott, C. D. Bossinger, P. I. Cook, Anal. Bio-
chem. 1970, 34, 595 598; b) V. K. Sarin, S. B. H. Kent, J. P. Tam,
R. B. Merrifield, Anal. Biochem. 1981, 117, 147 157.
[14] I. Beletskaya, A. Pelter, Tetrahedron 1997, 53, 4957 5026.
[15] M. Sabat, C. R. Johnson, Org. Lett. 2000, 2, 1089 1092.
[16] a) J. V. Allen, S. J. Coote, G. J. Dawson, C. G. Frost, C. J. Martin,
J. M. J. Williams, J. Chem. Soc. Perkin Trans. 1 1994, 15, 2065 2072;
[21] T. Y. Zhang, M. J. Allen, Tetrahedron Lett. 1999, 40, 5813 5816.
Received: August 1, 2003 [F5421]
553
Chem. Eur. J. 2004, 10, 544 553
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¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim