Synthesis of non-natural amino acids based on the ruthenium-catalysed oxidation of a phenyl group to carboxylic acid

Article abstract of DOI:10.1055/s-2005-861812

An efficient method for the synthesis of enantiopure β-, β-, and δ-amino acids with proteinogenic side chains, starting from natural α-amino acids, was developed. The method is based on the ruthenium-catalyzed oxidation of a phenyl group to a carboxylic a

Full text of DOI:10.1055/s-2005-861812

PAPER
933
Synthesis of Non-Natural Amino Acids Based on the Ruthenium-Catalysed
Oxidation of a Phenyl Group to Carboxylic Acid
Synthesis of
N
a
on-Natural
n
A
mino
A
cid
a
s
giota Moutevelis-Minakakis, Charalambos Sinanoglou, Vassilios Loukas, George Kokotos*
Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Panepistimiopolis, Athens 15771, Greece
Fax +30(210)7274761; E-mail: gkokotos@cc.uoa.gr
Received 27 July 2004; revised 12 September 2004
tively inert benzene rings, such as phenyl, since the
discovery by Djerassi in 1953.11 Although a stoichiomet-
ric amount of RuO4, readily prepared by the reaction of
RuCl3 or RuO2 with NaIO4, has been used for the oxida-
Abstract: An efficient method for the synthesis of enantiopure b-,
g-, and d-amino acids with proteinogenic side chains, starting from
natural a-amino acids, was developed. The method is based on the
ruthenium-catalyzed oxidation of a phenyl group to a carboxylic ac-
id. b-Amino acids may be prepared starting from Boc-phenylalani- tions, the reactions can be conveniently performed in a bi-
nol. The route described for the synthesis of g- and d-amino acids
permits the insertion of any chain length between the amino and car-
boxy functionalities as a result of the original choice of the starting
ylide chain length.
phasic system using a catalytic amount of RuCl3 with a
combined use of oxidants,12 such as NaIO4.13 As shown by
Sharpless14 and others,15 RuO4-catalyzed oxidations were
remarkably improved by employing a solvent system con-
taining MeCN, for example CCl4–MeCN–H2O. Although
RuO4-catalyzed oxidations have found some applications
in peptide chemistry,16,17 no systematic studies for its use
in the synthesis of non-natural amino acids have been per-
formed.
Key words: amino acids, amino alcohols, Wittig reaction, oxida-
tions, ruthenium
The development of new synthetic approaches to non-nat-
ural amino acids is a blossoming area of research since
such compounds find applications in the synthesis of
pharmacologically relevant molecules, analogues of bio-
active peptides and peptide mimetics.1–3 Recently, new
bioorganic methodologies have enabled the incorporation
of unnatural amino acids into protein frameworks.4 In ad-
dition, oligopeptides containing unnatural amino acids are
able to form well-defined secondary structures. Recent in-
vestigations have shown that short chain peptides com-
prising b- or g-amino acids can adopt helix sheets or
reverse turn conformations in solution or solid state as ev-
idenced by NMR, X-ray and modelling studies.5,6 The sur-
prising difference between the natural a- and the
analogous b- and g-peptides is that the helix stability in-
creases upon homologation of the residues.7 As recently
demonstrated,8 b- and g-peptides are completely stable to
common proteases, without inhibiting their normal activ-
ity. This is of considerable importance as it suggests that
b- and g-peptides may be suitable for pharmaceutical ap-
plications. The aim of this work was to develop new, effi-
cient methods for the synthesis of b-, g- and d-amino
acids.
Our approach for the synthesis of b-amino acids is depict-
ed in Scheme 1. Boc-L-phenylalaninol (1) was prepared
from Boc-Phe-OH by the mixed anhydride-NaBH4
method18 and was oxidized to the corresponding aldehyde
by NaOCl in the presence of a catalytic amount of 4-ace-
tamido-2,2,6,6-tetramethylpiperidine-1-yloxy free radical
(AcNH-TEMPO).19 The aldehyde, without any purifica-
tion, was treated with non-stabilized, stabilized and semi-
stabilized ylides to produce the unsaturated derivatives 2
(yield 75%), 3, 4a (yield 95%) and 4b (yield 50%), re-
spectively. As indicated by 1H NMR analysis, the geome-
try of the double bonds of 2 and 3 were Z and E,
respectively. Compound 4a was obtained mainly as the E-
isomer and 4b mainly as the Z-isomer. After hydrogena-
tion of the double bond, the aromatic ring of the saturated
amines 5, 6 and 7 was oxidized to carboxylic acid by
RuCl3·3H2O using NaIO4 in a biphasic system (EtOAc or
CCl4, MeCN, H2O).20,21 Thus, Boc-protected derivatives
of b-D-norleucine 8 (yield: 58%) and b-D-glutamic acid 9
(yield: 55%) were obtained. Oxidation of compounds
7a,b containing two phenyl groups led to the dicarboxylic
acids 10a (yield: 50%) and 10b (yield: 59%).
We have recently presented methods for the synthesis of
g- and w-amino acids, which were based on the Wittig ole-
fination reaction of protected a-amino aldehydes with
suitable ylides.9,10 Our strategy presented here is based on
the ruthenium-catalyzed oxidation of a phenyl group to a
carboxylic acid.
The synthetic route to g- and d-amino acids is presented in
Scheme 2. Na,Ne-di(tert-butoxycarbonyl)lysine (11a) and
N-(tert-butoxycarbonyl)leucine (11b) were converted to
alcohols and subsequently into aldehydes, as previously
described. Wittig olefination of the aldehydes with ylides
of the general structure Br–Ph3P+(CH2)n+1Ph produced the
unsaturated amines 13a (yield: 60%), 13b (yield: 71%)
and 13c (yield: 52%). After hydrogenation, the aromatic
ring of 14a, 14b and 14c was converted into a carboxylic
group by oxidation with NaIO4/RuCl3·3H2O leading to
Boc-protected g-leucine, 15b (yield 62%) and d-leucine,
Ruthenium tetraoxide (RuO4) has found a number of ap-
plications in the synthesis of carboxylic acids from rela-
SYNTHESIS 2005, No. 6, pp 0933–0938
x
x
.
x
x
.2
0
0
5
Advanced online publication: 21.02.2005
DOI: 10.1055/s-2005-861812; Art ID: T08804ST
© Georg Thieme Verlag Stuttgart · New York

934
P. Moutevelis-Minakakis et al.
PAPER
Ph
OH
NHBoc
1
a, b
a, d
Ph
a, c
O
Ph
( )n
Ph
Ph
OMe
Ph
NHBoc
NHBoc
e
NHBoc
3
2, 75%
4a, 95%
4b, 50%
e
e
O
Ph
( )n+1
OMe
Ph
Ph
NHBoc
NHBoc
NHBoc
6, 87%
5, 88%
7a, 81%
7b, 98%
f
f
f'
O
O
HO
HO
HO
OMe
9, 55%
( )n+1
OH
O
NHBoc
O
NHBoc
O
NHBoc
8, 56%
10a, 50%
10b, 59%
4,7,10
a
b
n
0
1
Scheme
1
Reagents and conditions: (a) NaOCl, AcNH-TEMPO, NaBr, NaHCO3, EtOAc–toluene–H2O (3:3:0.5), –5 °C;
(b) Ph3P+(CH2)2CH3Br–, KHMDS, toluene, –78 °C, overnight at r.t.; (c) Ph3P=CHCO2Me, THF, reflux; (d) Ph3P+CH2PhBr–, KHMDS, toluene,
0 °C, overnight at r.t.; Ph3P+CH2CH2PhBr–, KHMDS, toluene, –78 °C, overnight at r.t.; (e) H2, 10% Pd/C; (f) NaIO4 (29 equiv), 5%
RuCl3·3H2O, EtOAc–MeCN–H2O (1:1:8); (f¢) NaIO4 (29 equiv), 4.5% RuCl3·3H2O, CCl4–MeCN–H2O (1:1:2), 3 d.
15c (yield 48%) and Boc-protected d-lysine, 15a (yield
Ph
b,c1
O
57%).
NHBoc
a
R
R
The yields of the oxidation step are not quantitative, pre-
sumably because some partial removal of the Boc group
and oxidation of the secondary amide occur. The pro-
posed method produced optically pure amino acids as in-
dicated by comparison of their specific rotation values
with those reported in the literature. For example, for 15b:
[a]D –10.2 (c = 0.6, CH2Cl2) {Lit.22 [a]D –10.3 (c = 0.77,
CH2Cl2)}. In full agreement with our previous observa-
tions,9,10 in the 1H NMR (CDCl3) spectra of b-, g- and d-
Boc-protected amino acids, two signals correspond to the
carbamate NH proton, attributed to the existence of rota-
mers.
OH
OH
NHBoc
13b, 71%
b,c2
NHBoc
R
Ph
12a,b
11a,b
NHBoc
13a, 60%
13c, 52%
R
( )
d
R
OH
( )
e
n
Ph
n
13a-c
NHBoc
NHBoc
O
14a, 99%
14b, 85%
14c, 96%
15a, 57%
15b, 62%
15c, 48%
The oxidative degradation of the benzene ring of methyl
N-(tert-butoxycarbonyl)phenylalaninate (16) was also
studied. As shown in Scheme 3, a-methyl N-(tert-butoxy-
carbonyl)aspartate (17) (yield 45%) was readily obtained
from 16 by treatment with RuCl3·3H2O/NaIO4. This trans-
formation constitutes an extremely practical one-step syn-
R
n
11a, 12a, 13a BocHN(CH2)4
11b, 12b, 13c (CH3)2CHCH2
14a, 15a
14b, 15b
14c, 15c
BocHN(CH2)4
(CH3)2CHCH2
(CH3)2CHCH2
1
0
1
Scheme 2 Reagents and conditions: (a) i. ClCO2Et, NMM, THF, thesis of the aspartate derivative 17. It should be noted
–10 °C, ii. NaBH4, MeOH; (b) NaOCl, AcNH-TEMPO, NaBr,
that this commercially available amino acid derivative can
be traditionally synthesized from aspartic acid by a multi-
NaHCO3, EtOAc–toluene–H2O (3:3:0.5), –5 °C; (c1) Ph3P+CH2-
PhBr–, KHMDS, toluene at 0 °C, then overnight at r.t.; (c2)
step procedure involving selective protection-deprotec-
tion steps. The comparison of the specific rotation of 17
[a]D –21.4 (c = 1.0, MeOH) with that reported in the liter-
ature [a]D –17.9 (c = 1.45, MeOH),23 shows that the oxi-
dative transformation does not influence the optical
integrity.
Ph3P+CH2CH2PhBr–, KHMDS, toluene, –78 °C, overnight at r.t.;
(d) H2, 10% Pd/C; (e) NaIO4 (29 equiv), 5% RuCl3·3H2O, EtOAc–
MeCN–H2O (1:1:8).
Synthesis 2005, No. 6, 933–938 © Thieme Stuttgart · New York

PAPER
Synthesis of Non-Natural Amino Acids
935
(Na2SO4). The solvent was removed, and the residue was purified
by column chromatography [EtOAc–petroleum ether (bp 40–60
°C), 1:9].
O
O
HO
Ph
OMe
NHBoc
OMe
NHBoc
O
16
17, 45%
Compounds 2, 4b, and 13a,c
For the synthesis of compounds 2, 4b, 13a,c the procedure was as
described above with the following differences:
The non-stabilized ylides Br–Ph3P+(CH2)2CH3 (2.40 mmol) and Br–
Ph3P+(CH2)2Ph (2.40 mmol) were used, and the base KHMDS (2.40
mmol) was added at –20 °C, followed by the addition of aldehyde
at –78 °C.
Scheme 3 Reagents and conditions: NaIO4 (29 equiv), 5%
RuCl3·3H2O, EtOAc–MeCN–H2O (1:1:8).
In conclusion, a new method for the synthesis of Boc-pro-
tected b-, g- and a- amino acids with proteinogenic side
chains based on the ruthenium-catalyzed oxidation of a
phenyl group to carboxylic acid was developed. The route
described for the synthesis of g- and d-amino acids per-
mits the insertion of any chain length between the amino
and carboxy functionalities as a result of the original
choice of the starting ylide chain length.
[(S,Z)-1-Benzylpent-2-enyl]carbamic Acid tert-Butyl Ester (2)
Yield: 0.41 g (75%); white solid; mp 57–59 °C; [a]D –2.5 (c = 1,
CHCl3).
1H NMR: d = 0.82 (t, J = 7.8 Hz, 3 H, CH3), 1.46 [s, 9 H, C(CH3)3],
2.00 (m, 2 H, CH2CH3), 2.72 (dd, J = 13.2, 7.4 Hz, 1 H, C6H5CHH),
2.95 (dd, J = 13.2, 5.2 Hz, 1 H, C6H5CHH), 4.40–4.72 (m, 2 H, NH,
CH), 5.23 (dd, J = 10.6, 9.6 Hz, 1 H, CH=CHCH2), 5.43 (dt,
J = 10.6, 7.2 Hz, 1 H, CHCH=CH2), 7.17–7.37 (m, 5 H, C6H5).
Mps were determined on a mp apparatus and are uncorrected. Spe-
cific rotations were measured at 25 °C on a polarimeter using a 10
cm cell. NMR spectra were recorded in CDCl3 on a 200 Mz spec-
trometer, unless otherwise indicated. All amino acid derivatives
were of L-configuration and were purchased from Fluka Chemical
Co. TLC plates (silica gel 60 F254) and silica gel 60 (70–230 or 230–
400 mesh) for column chromatography were purchased from Merck
and RuCl3·3H2O from Fluka. Visualization of spots was effected
with UV light and/or phosphomolybdic acid and/or ninhydrin, both
in EtOH stain. THF, toluene and Et2O were dried by standard pro-
cedures and stored over molecular sieves or Na. All other solvents
and chemicals were of reagent grade and used without further puri-
fication. The phosphonium salts were prepared by refluxing PPh3
and (2-bromoethyl)benzene or 1-bromopropane or bromomethyl-
benzene in anhyd MeCN and were used in the Wittig reaction with-
out purification. Compound 3 was prepared as previously
described.10 All new compounds gave satisfactory elemental analy-
sis: C 0.35, H 0.27, and N 0.19.
13C NMR: d = 13.5 (CH3), 20.6 (CH3CH2), 28.0 [C(CH3)3], 41.8
(CH2C6H5), 48.9 (CH), 78.9 [C(CH3)3], 125.9, 127.8, 128.1, 129.3,
133.9, 137.3 (C6H5, CH=CH), 154.7 (OCONH).
[(S,E)-1-Benzyl-3-phenylallyl]carbamic Acid tert-Butyl Ester
(4a)
Yield: 0.61 g (95%); white solid; mp 100–101 °C; [a]D +3.1 (c =
0.9, EtOH).
1H NMR: d = 1.42 [s, 9 H, C(CH3)3], 2.93 (m, 2 H, CH2), 4.48–4.62
(m, 2 H, CH, NH), 6.12 (dd, J = 15.8, 6.3 Hz, 1 H, CHCH=CH),
6.49 (d, J = 15.8 Hz, 1 H, CH=CHC6H5), 7.23–7.31 (m, 10 H, 2
C6H5).
13C NMR: d = 28.3 [C(CH3)3], 41.9 (CH2C6H5), 53.6 (CH), 79.5
[C(CH3)3], 126.0, 126.4, 126.5, 127.5, 128.4, 128.5, 128.6, 129.6,
130.1, 137.3 (C6H5, CH=CH), 155.1 (OCONH).
[(S,Z)-1-Benzyl-4-phenylbut-2-enyl]carbamic Acid tert-Butyl
Ester (4b)
Yield: 0.34 g (50%); yellow oil; [a]D –3.3 (c = 1, MeOH).
1H NMR: d = 1.44 [s, 9 H, C(CH3)3], 2.75 (dd, J = 13.2, 7.4 Hz, 1
Compounds 2, 4a,b, 13a–c; General Procedure10,19
To a solution of N-protected 2-amino alcohol 1 or 12a,b (2.00
mmol) in a mixture of toluene–EtOAc (1:1; 12 mL) was added a so-
lution of NaBr (0.22 g, 2.1 mmol) in H2O (1 mL) and subsequently
AcNH-TEMPO (4 mg, 0.02 mmol) in H2O (1 mL). To the resulting
biphasic system, which was cooled to –5 °C, an aq 0.35 M solution
of NaOCl (6.3 mL, 2.2 mmol) containing NaHCO3 (0.50 g, 6 mmol)
was added dropwise under vigorous stirring at –5 °C over 1 h. After
the mixture was stirred for an additional 15 min at 0 °C, EtOAc (12
mL) and H2O (4 mL) were added. The aqueous layer was separated
and washed with EtOAc (12 mL). The combined organic layers
were washed with aq 5% citric acid (12 mL) containing KI (0.07 g),
aq 10% Na2S2O3 (12 mL) and brine and dried (Na2SO4). The sol-
vents were evaporated under reduced pressure and the obtained
crude aldehyde was immediately used in the next step as given be-
low separately for compounds 4a and 13b and compounds 2, 4b and
13a,c.
H, NCHCHHC6H5), 2.99 (dd, J = 13.2, 5.6 Hz,
NCHCHHC6H5), 3.20 (dd, J = 15.8, 7.2 Hz,
CH=CHCHHC6H5), 3.37 (dd, J = 15.8, 7.8 Hz,
1
1
1
H,
H,
H,
CH=CHCHHC6H5), 4.54 (d, J = 6.4 Hz, 1 H, NH), 4.74 (m, 1 H,
CHNH), 5.34 (dd, J = 10.8, 9.2 Hz, 1 H, CHCH=CH), 5.60 (dt,
J = 10.8, 7.8 Hz, 1 H, CH=CHCH2), 6.95–7.33 (m, 10 H, 2 C6H5).
13C NMR: d = 28.3 [C(CH3)3], 33.8 (CH=CHCH2C6H5), 42.1
(CH2C6H5), 49.3 (CH), 79.4 [C(CH3)3], 125.1, 125.9, 126.4, 128.3,
128.4, 129.7, 131.0, 131.3, 137.6, 140.2 (C6H5, CH=CH), 155.0
(OCONH).
[(S,Z)-5-(tert-Butoxycarbonylamino)-8-phenyloct-6-enyl]car-
bamic Acid tert-Butyl Ester (13a)
Yield: 0.50 g (60%); white solid; mp 87–90 °C; [a]D –3.9 (c = 1.1,
CHCl3).
Compounds 4a and 13b
To a stirred suspension of the phosphonium salt Br–Ph3P+CH2C6H5
(2.40 mmol) in anhyd toluene (10 mL) was added a 0.5 M solution
of KHMDS (4.8 mL, 2.40 mmol) in toluene dropwise over a period
of 15 min at 0 °C under argon. The bright red solution was stirred
for another 15 min at 0 °C, when a solution of the above prepared
aldehyde in anhyd toluene (4 mL) was instantly added, and the tem-
perature was left to rise from 0 °C to r.t. The light yellow mixture
was stirred at r.t. for 20 h. The reaction mixture was quenched with
sat. aq NH4Cl (20 mL) and extracted with Et2O (3 × 6 mL). The
combined organic phases were washed with brine and dried
1H NMR: d = 1.23–1.39 (m, 4 H, 2 CH2), 1.45 [s, 18 H, 2 C(CH3)3],
1.61 (m, 2 H, CH2), 3.08 (m, 2 H, CH2C6H5), 3.50 (m, 2 H, CH2NH),
4.42–4.58 (m, 3 H, CH, 2 NH), 5.29 (dd, J = 10.2, 9.6 Hz, 1 H,
CHCH=CH), 5.66 (dt, J = 10.2, 7.6 Hz, 1 H, CH=CHCH2), 7.18–
7.33 (m, 5 H, C6H5).
13C NMR: d = 22.9 (CH2), 28.4 [C(CH3)3], 29.8 (CH2), 34.0 (CH2),
35.7 (CH2), 40.3 (CH2C6H5), 47.6 (CH), 79.0 [C(CH3)3], 112.0,
126.0, 128.4, 131.2, 140.5 (C6H5, CH = CH), 155.1 (OCONH),
155.6 (OCONH).
Synthesis 2005, No. 6, 933–938 © Thieme Stuttgart · New York

936
P. Moutevelis-Minakakis et al.
PAPER
[(S,E)-3-Methyl-1-styrylbutyl]carbamic Acid tert-Butyl Ester
(13b)
Yield: 0.41 g (71%); yellow solid; mp 61–62 °C; [a]D –46.7 (c = 1,
CHCl3).
1H NMR: d = 0.95 [d, J = 6.2 Hz, 6 H, CH(CH3)2], 1.45 [s, 9 H,
C(CH3)3], 1.67–1.76 [m, 3 H, CH(CH3)2, CH2], 4.18–4.55 (m, 2 H,
NH, CHCH2), 6.06 (dd, J = 15.8, 6.4 Hz, 1 H, CHCH=CH), 6.51 (d,
J = 15.8 Hz, 1 H, CHCH=CH), 7.17–7.39 (m, 5 H, C6H5).
1H NMR: d = 1.41 [s, 9 H, C(CH3)3], 1.78 (m, 2 H, CHCH2CH2),
2.60–2.82 (m, 4 H, 2 CH2C6H5), 3.89 (m, 1 H, CH), 4.35 (m, 1 H,
NH), 7.16–7.27 (m, 10 H, 2 C6H5).
13C NMR:
d = 28.3 [C(CH3)3], 32.5 (CHCH2CH2), 36.1
(CH2CH2C6H5), 41.4 (CH2C6H5), 51.4 (CH), 79.0 [C(CH3)3], 125.8,
126.3, 128.3, 128.4, 129.5, 138.0, 141.8 (C6H5), 155.4 (OCONH).
[(R)-1-Benzyl-4-phenylbutyl]carbamic Acid tert-Butyl Ester
(7b)
13C NMR: d = 22.4 [CH(CH3)2], 24.5 [CH(CH3)2], 28.2 [C(CH3)3],
44.6 [CH2CH(CH3)2], 50.6 (CH), 79.1 [C(CH3)3], 126.1, 127.2,
128.3, 129.5, 130.8, 136.7 (C6H5, CH=CH), 155.1 (OCONH).
Yield: 0.66 g (98%); white solid; mp 83–85 °C; [a]D +6.3 (c = 1,
CHCl3).
1H NMR: d = 1.40 [s, 9 H, C(CH3)3], 1.58–1.78 (m, 4 H, 2 CH2),
2.59 (m, 2 H, CH2CH2C6H5), 2.75 (m, 2 H, CHCH2C6H5), 3.85 (m,
1 H, CH), 4.28 (m, 1 H, NH), 7.16–7.29 (m, 10 H, 2 C6H5).
[(S,Z)-1-Isobutyl-4-phenylbut-2-enyl]carbamic Acid tert-Butyl
Ester (13c)
Yield: 0.32 g (52%); white solid; mp 48–49 °C; [a]D +2.1 (c = 1,
13C NMR: d = 27.8 (CH2CH2C6H5), 28.3 [C(CH3)3], 33.7
(CHCH2CH2), 35.5 (CH2C6H5), 41.3 (CHCH2C6H5), 51.3 (CH),
79.4 [C(CH3)3], 125.7, 126.2, 128.3, 128.4, 129.5, 138.2, 142.2
(C6H5), 155.5 (OCONH).
CHCl3).
1H NMR: d = 0.92 [d, J = 6.6 Hz, 6 H, CH(CH3)2], 1.20–1.70 [m, 12
H, C(CH3)3, CH2CHNH, CH(CH3)2], 3.50 (m, 2 H, CH2C6H5),
4.38–4.65 (m, 2 H, CH, NH), 5.28 (dd, J = 10.6, 9.2 Hz, 1 H,
CHCH=CH), 5.61 (dt, J = 10.6, 7.4 Hz, 1 H, CH=CHCH2), 7.17–
7.30 (m, 5 H, C6H5).
[(R)-5-(tert-Butoxycarbonylamino)-8-phenyloctyl]carbamic
Acid tert-Butyl Ester (14a)
Yield: 0.83 g (99%); white solid; mp 52–53 °C; [a]D –2.0 (c = 1,
13C NMR: d = 22.6 [CH(CH3)2], 24.7 [CH(CH3)2], 28.4 [C(CH3)3],
34.0 (CH2C6H5), 45.3 [CH2CH(CH3)2], 46.2 (CH), 79.1 [C(CH3)3],
125.9, 128.3, 128.4, 130.2, 131.7, 140.5 (C6H5, CH=CH), 155.1
(OCONH).
CHCl3).
1H NMR: d = 1.24–1.74 [m, 28 H, 2 C(CH3)3, 5 CH2], 2.63 (m, 2 H,
CH2C6H5), 3.11 (m, 2 H, CH2NH), 3.58 (m, 1 H, CH), 4.24 (d,
J = 8.8 Hz, 1 H, CHNH), 4.57 (m, 1 H, CH2NH), 7.15–7.32 (m, 5
H, C6H5).
Compounds 5–7a,b, 14a–c; General Procedure
To a solution of compound 2, 3, 4a,b, or 13a–c (2.00 mmol) in
MeOH (20 ml) was added 10% Pd/C (22 mg, 0.02 mmol). The mix-
ture was stirred overnight under H2 at r.t. The catalyst was removed
by filtration through a pad of Celite and the solvent was evaporated
under reduced pressure. The product was purified by recrystalliza-
tion from Et2O–petroleum ether.
13C NMR: d = 22.9 (CH2), 27.6 (CH2), 28.3 [C(CH3)3], 29.6 (CH2),
35.0 (CH2), 35.1 (CH2), 35.5 (CH2), 40.2 (CH2C6H5), 50.0 (CH),
78.8 [C(CH3)3], 125.6, 128.1, 128.2, 142.1 (C6H5), 155.8
(OCONH), 156.0 (OCONH).
[(R)-3-Methyl-1-phenethylbutyl]carbamic Acid tert-Butyl Ester
(14b)
[(R)-1-Benzylpentyl]carbamic Acid tert-Butyl Ester (5)
Yield: 0.40 g (88%); white solid; mp 76–78 °C; [a]D +12.2 (c = 1,
CH2Cl2) {for the (S)-enantiomer: Lit24 mp 74–75 °C; [a]D –9.5 (c =
1.05, CH2Cl2}.
1H NMR: d = 0.88 (t, J = 6.2 Hz, 3 H, CH3), 1.19–1.58 [m, 15 H, 3
CH2, C(CH3)3], 2.77 (m, 2 H, CH2C6H5), 3.82 (m, 1 H, CH), 4.31
(d, J = 8.4 Hz, 1 H, NH), 7.15–7.35 (m, 5 H, C6H5).
13C NMR: d = 14.0 (CH3), 22.5 (CH2CH3), 28.1 (CH2CH2CH3),
28.4 [C(CH3)3], 33.8 (CHCH2CH2), 41.4 (CH2C6H5), 51.5 (CH),
79.0 [C(CH3)3], 126.2, 128.2, 129.5, 138.3 (C6H5), 155.5
(OCONH).
Yield: 0.49 g (85%); white solid; mp 72–74 °C; [a]D –18.1 (c = 1.2,
CHCl3).
1H NMR: d = 0.99 [d, J = 6.6 Hz, 6 H, CH(CH3)2], 1.30–1.95 [m, 14
H, C(CH3)3, CH(CH3)2, 2 CH2], 2.75 (m, 2 H, CH2C6H5), 3.80 (m,
1 H, CH), 4.35 (d, J = 8.4 Hz, 1 H, NH), 7.23–7.43 (m, 5 H, C6H5).
13C NMR: d = 22.2 [CH(CH3)2], 24.8 [CH(CH3)2], 28.4 [C(CH3)3],
32.2 (CH2C6H5), 38.2 (CH2), 45.1 [CH2CH(CH3)2], 48.7 (CH), 78.8
[C(CH3)3], 125.7, 128.3, 142.2 (C6H5), 155.6 (OCONH).
[(R)-3-Methyl-1-(3-phenylpropyl)butyl]carbamic Acid tert-Bu-
tyl Ester (14c)
Yield: 0.58 g (96%); pale yellow oil; [a]D –10.8 (c = 1.1, CHCl3).
(R)-4-(tert-Butoxycarbonylamino)-5-phenylpentanoic Acid
Methyl Ester (6)
Yield: 0.54 g (87%); white solid; mp 81–83 °C; [a]D +3.7 (c = 1,
CHCl3).
1H NMR: d = 0.89 [d, J = 6.6 Hz, 6 H, CH(CH3)2], 1.20–1.95 [m, 16
H, C(CH3)3, CH(CH3)2, 3 CH2], 2.62 (m, 2 H, CH2C6H5), 3.66 (m,
1 H, CH), 4.19 (d, J = 8.4 Hz, 1 H, NH), 7.16–7.38 (m, 5 H, C6H5).
13C NMR: d = 22.2 [CH(CH3)2], 23.2 (CH2CH2C6H5), 24.8
[CH(CH3)2], 27.6 (CHCH2CH2), 28.4 [C(CH3)3], 35.7 (CH2C6H5),
45.1 [CH2CH(CH3)2], 48.5 (CH), 78.8 [C(CH3)3], 125.6, 128.2,
128.4, 142.4 (C6H5), 155.6 (OCONH).
1H NMR: d = 1.40 [s, 9 H, C(CH3)3], 1.73 (m, 2 H, CH2CH2COO),
2.34 (t, J = 7.0 Hz, 2 H, CH2COO), 2.77 (m, 2 H, CH2C6H5), 3.64
(s, 3 H, CO2CH3), 3.80 (m, 1 H, CH), 4.39 (d, J = 9.2 Hz, 1 H, NH),
7.15–7.35 (m, 5 H, C6H5).
13C NMR:
d = 28.3 [C(CH3)3], 29.2 (CHCH2CH2), 30.9
Compounds 8, 9, 15a–c, 17; General Procedure20
(CH2COOMe), 41.7 (CH2C6H5), 51.4, 51.6 (CH, CH2COOCH3),
79.1 [C(CH3)3], 126.3, 128.8, 129.1, 137.8 (C6H5), 155.4
(OCONH), 173.9 (CO2Me).
To a solution of compound 5, 6, 14a–c, or 16 (1.00 mmol) in a mix-
ture of EtOAc–MeCN–H2O (1:1:8, 30 mL) were added NaIO4 (6.2
g, 29.0 mmol) and RuCl3·3H2O (13.07 mg, 0.05 mmol). After stir-
ring at r.t. for 24 h, the mixture was partitioned between H2O (25
mL) and EtOAc (50 mL). For compounds 8, 9 and 15b the organic
layer was separated, washed with H2O (25 mL), dried (Na2SO4),
and filtered through a pad of silica gel 60 (230–400 mesh) and a
short pad of Celite. The filtrate was evaporated under reduced pres-
sure and the residue was purified by column chromatography using
[(R)-1-Benzyl-3-phenylpropyl]carbamic Acid tert-Butyl Ester
(7a)
Yield: 0.53 g (81%); white solid; mp 84–86 °C; [a]D +3.3 (c = 0.9,
CHCl3).
Synthesis 2005, No. 6, 933–938 © Thieme Stuttgart · New York

PAPER
Synthesis of Non-Natural Amino Acids
937
EtOAc as eluent (compounds 8, 9) or a mixture CHCl3–MeOH (9:1)
(compound 15b). For compounds 15a,c and 17, after the removal of
H2O, the organic phase was washed with aq sat. solution of
NaHCO3 (2 × 10 mL). The aqueous extracts were combined, 5%
H2SO4 was added until the pH reached 3, and the mixture was ex-
tracted with EtOAc (3 × 15 mL). The combined organic layers were
washed with H2O, dried (Na2SO4), and filtered through a pad of sil-
ica gel 60 (230–400 mesh) and a short pad of Celite. The filtrate was
evaporated under reduced pressure.
(S)-2-(tert-Butoxycarbonylamino)succinic Acid 1-Methyl Ester
(17)
Yield: 0.11 g (45%); white solid; mp 79–81 °C; (Lit23 mp 89 °C);
[a]D –21.4 (c = 1, MeOH) {Lit23 [a]D –17.9 (c = 1.45, MeOH)}.
1H NMR: d = 1.46 [s, 9 H, C(CH3)3], 2.87 (dd, J = 18.0, 4.4 Hz, 1
H, CHHCOO), 3.07 (dd, J = 18.0, 6.4 Hz, 1 H, CHHCOO), 3.77 (s,
3 H, CO2CH3), 4.59 (m, 1 H, CH), 5.52 (d, J = 8.0 Hz, 7/8 H, NH),
6.28 (m, 1/8 H, NH).
13C NMR: d = 28.2 [C(CH3)3], 36.5 (CH2CO2H), 49.6 (CH), 52.8
(CO2CH3), 80.4 [C(CH3)3], 155.4 (OCONH), 171.4 (CO2Me),
176.1 (CO2H).
(R)-3-(tert-Butoxycarbonylamino)heptanoic Acid (8)
Yield: 0.14 g (56%); colorless oil; [a]D +12.7 (c = 1.1, CHCl3).
1H NMR: d = 0.89 (t, J = 6.6 Hz, 3 H, CH3), 1.21–1.58 [m, 15 H, 3
CH2, C(CH3)3], 2.54 (m, 2 H, CH2COO), 3.88 (m, 1 H, CH), 4.98
(d, J = 8.4 Hz, 4/5 H, NH), 5.85 (m, 1/5 H, NH).
13C NMR: d = 14.0 (CH3), 22.3 (CH3CH2), 27.9 (CH2CH2CH3),
28.3 [C(CH3)3], 34.1 (CHCH2CH2), 39.1 (CH2COOH), 47.3 (CH),
79.4 [C(CH3)3], 155.5 (OCONH), 177.0 (COOH).
Compounds 10a,b; General Procedure21
To a solution of 7a,b (1.00 mmol) in a mixture of CCl4–MeCN–
H2O (1:1:2, 30 mL) were added NaIO4 (6.2 g, 29.0 mmol) and
RuCl3·3H2O (12 mg, 0.045 mmol). The mixture was subsequently
stirred at r.t. for 3 days. The procedure followed for the isolation and
purification products was the same as for compounds 15a,c and 17
described above.
(R)-3-(tert-Butoxycarbonylamino)hexanedioic Acid 6-Methyl
Ester (9)
(R)-3-(tert-Butoxycarbonylamino)hexanedioic Acid (10a)
Yield: 0.13 g (50%); white solid; mp 162–163 °C (Lit.26 mp 162–
164 °C) ; [a]D +7.1 (c = 0.99, EtOH) {Lit.26 [a]D +7.7 (c =2.6,
EtOH)}.
1H NMR (DMSO-d6): d = 1.36 [s, 9 H, C(CH3)3], 2.16 (m, 2 H,
CH2CH2CO2H), 2.30 (d, J = 6.6 Hz, 2 H, HO2CCH2CH), 3.72 (m, 1
H, CH), 6.72 (d, J = 10.0 Hz, 1 H, NH).
Yield: 0.15 g (55%); white solid; mp 90–91 °C (Lit.25 mp 92 °C);
[a]D +12.5 (c = 0.5, CHCl3).
1H NMR: d = 1.43 [s, 9 H, C(CH3)3], 1.88 (m, 2 H,
CH2CH2CO2CH3), 2.41 (t, J = 7.6 Hz, 2 H, CH2CO2CH3), 2.59 (m,
2 H, CH2CO2H), 3.68 (s, 3 H, CO2CH3), 3.93 (m, 1 H, CH), 5.07 (d,
J = 9.4 Hz, 4/5 H, NH), 5.95 (m, 1/5 H, NH).
13C NMR:
d
=
28.3 [C(CH3)3], 29.3 (CHCH2CH2), 30.9
13C NMR:
d = 28.2 [C(CH3)3], 29.6 (CHCH2CH2), 30.3
(CH2CO2Me), 39.1 (CH2CO2H), 46.9 (CH), 51.8 (CO2CH3), 79.7
[C(CH3)3], 155.5 (OCONH), 173.8 (CO2Me), 176.3 (CO2H).
(CH2CO2H), 30.4 (CH2CO2H), 46.9 (CH), 77.6 [C(CH3)3], 155.1
(OCONH), 172.4 (CO2H), 174.2 (CO2H).
(S)-5,9-bis-(tert-Butoxycarbonylamino)nonanoic Acid (15a)
Yield: 0.22 g (57%); yellow oil; [a]D –1.5 (c = 0.9, CHCl3)
1H NMR: d = 1.26 (m, 2 H, CH2), 1.44 [s, 18 H, 2 C(CH3)3], 1.54–
1.78 (m, 8 H, 4 CH2), 2.32–2.46 (m, 4 H, 2 CH2), 3.43–3.64 (m, 2
H, CH2NH, CH), 4.44 (d, J = 9.2 Hz, 5/8 H, CHNH), 6.01 (m, 3/8
H, CHNH).
13C NMR: d = 20.9 (CH2), 28.0 (CH2), 28.4 [C(CH3)3], 33.6 (CH2),
34.4 (CH2), 49.8 (CH2CO2H), 51.3 (CH), 79.4 [C(CH3)3], 155.8
(OCONH), 179.1 (CO2H).
(R)-3-(tert-Butoxycarbonylamino)heptanedioic Acid (10b)
Yield: 0.16 g (59%); yellow oil.
1H NMR (DMSO-d6): d = 1.36–1.79 [m, 13 H, C(CH3)3, 2 CH2],
2.18 (m, 2 H, CH2CO2H), 2.30 (m, 2 H, CH2CO2H), 3.72 (m, 1 H,
CH), 6.72 (d, J = 10.0 Hz, 1 H, NH).
13C NMR: d = 21.1 (CH2CH2CO2H), 27.5 (CHCH2), 28.3
[C(CH3)3], 33.4 (CH2CO2H), 33.9 (CH2CO2H), 47.2 (CH), 77.4
[C(CH3)3], 155.3 (C=O), 172.5 (CO2H), 174.3 (CO2H).
Acknowledgment
(R)-4-(tert-Butoxycarbonylamino)-6-methylheptanoic Acid
(15b)
Financial support from the Special Research Account of the Univer-
sity of Athens is highly appreciated.
Yield: 0.16 g (62%); white solid; mp 106–107 °C; [a]D –10.2 (c =
0.6, CH2Cl2) {Lit.22 [a]D –10.3 (c = 0.77, CH2Cl2)}.
1H NMR: d = 0.91 [d, J = 6.6 Hz, 6 H, CH(CH3)2], 1.20–1.95 [m, 14
H, C(CH3)3, CH(CH3)2, 2 CH2], 2.41 (m, 2 H, CH2CO2H), 3.65 (m,
1 H, CH), 4.30 (d, J = 9.2 Hz, 2/3 H, NH), 5.60 (m, 1/3 H, NH).
13C NMR: d = 22.1 [CH(CH3)2], 24.8 [CH(CH3)2], 28.3 [C(CH3)3],
29.6 (CH2CH2CO2H), 30.8 (CH2CO2H), 44.9 [CH2CH(CH3)2], 49.7
(CH), 79.4 [C(CH3)3], 155.9 (OCONH), 178.6 (CO2H).
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Synthesis 2005, No. 6, 933–938 © Thieme Stuttgart · New York