Practical and efficient enantioselective synthesis of α-amino acids in aqueous media

Article abstract of DOI:10.1039/b413017k

Enantiomerically pure natural and unnatural α-amino acids have been synthesized from a chiral melhyleneoxazolidinone by means of a highly diastereoselective 1,4-conjugate addition of alkyl iodides in aqueous media. The zinc-copper conjugate addition reaction exhibits high chemoselectivity, with the possibility of using functionalized iodides, to afford a single diastereomer in short reaction times and with good yields.

Full text of DOI:10.1039/b413017k

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A R T I C L E
Practical and efficient enantioselective synthesis of a-amino acids in
aqueous media
Rosa M. Sua´rez, Jose´ Pe´rez Sestelo* and Luis A. Sarandeses*
Departamento de Qu´ımica Fundamental, Universidade da Corun˜a, E-15071, A Corun˜a, Spain.
E-mail: sestelo@udc.es; Tel: +34 981 167 000; Fax: +34 981 167 065
Received 25th August 2004, Accepted 7th October 2004
First published as an Advance Article on the web 9th November 2004
Enantiomerically pure natural and unnatural a-amino acids have been synthesized from a chiral
methyleneoxazolidinone by means of a highly diastereoselective 1,4-conjugate addition of alkyl iodides in aqueous
media. The zinc–copper conjugate addition reaction exhibits high chemoselectivity, with the possibility of using
functionalized iodides, to afford a single diastereomer in short reaction times and with good yields.
We recently used this methodology to achieve the stere-
Introduction
oselective synthesis of vitamin D3 metabolites and various
analogs.9 In the work described here, we demonstrated that
the conjugate addition products resulting from 1,4-addition
to methyleneoxazolidinones can be efficiently transformed into
enantiopure a-amino acids. Although several new procedures
for the synthesis of racemic a-amino acids in water have recently
been developed,10 the stereoselective synthesis of a-amino acids
in aqueous media has not been reported to date.
a-Amino acids are the fundamental building blocks of pep-
tides and proteins and their physiological importance ensures
sustained interest in their chemistry.1 In addition, unnatural a-
amino acids are expected to play key roles in improving the
original properties and functions of proteins. The development
of efficient methods for the preparation of various types of a-
amino acids is desired not only in the field of organic chemistry
but also in many biologically related areas. The synthesis of
a-amino acids can be achieved by several general methods,
the most common of which are the alkylation of a-halo acids,
cyanide addition to imines (Strecker reaction) and the reduction
of amino acrylates.2 Indeed, asymmetric synthesis based on these
methodologies represents a field of great importance.3
In recent decades organic chemists have been interested in
developing organic synthesis in aqueous media.4 The use of
water as a solvent has particular advantages and these include
low cost, safety and environmental compatibility. Moreover, the
study of organic reactions in water may also contribute to our
understanding of the basic mechanisms of life. A significant
number of organic reactions have so far been performed under
aqueous conditions, although the stereoselective control of these
organic transformations is an issue of current interest.5
Results and discussion
7b
In previous studies we found that the conjugate addition of
alkyl iodides to (2S)-N-benzoyl-5-methyleneoxazolidinone (1)
generally proceeds with good yields (up to 94%) but with variable
diastereoselectivity (20–82% de, Scheme 2). The stereochemistry
of the major diastereomer (cis) was explained in terms of
diastereoselective protonation of the intermediate enolate, which
occurs anti with respect to the bulky tert-butyl group. Unfortu-
nately, the synthesis of enantiomerically pure amino acids was a
laborious process since the separation of diastereomers required
the use of HPLC techniques. For this reason we explored the
possibility of increasing the diastereoselectivity of the reaction
by changing the N-protecting group. Some years ago, Beckwith
reported that, in radical conjugate addition reactions, the nature
of the N-protecting group in methyleneoxazolidinones has a
significant influence on the stereoselectivity.11
We recently became interested in studying the stereoselectivity
of the aqueous conjugate addition reaction developed by Luche
in 1986 (Scheme 1).6 This methodology allows the 1,4-addition
of alkyl halides to a,b-unsaturated carbonyl systems and has
several advantages when compared to other methods, including
simplicity, mild reaction conditions and high chemoselectivity.
Scheme 2 Conjugate addition reaction to N-Bz methyleneoxazolidi-
none 1.
Scheme 1 Luche’s conjugate addition.
In our investigation we discovered that achiral alkyl iodides
add diastereoselectively to chiral a,b-unsaturated carbonyl com-
pounds in good yields.7 The stereoselectivity can be achieved
using different chiral a,b-unsaturated systems such as methylene-
dioxolanones or methyleneoxazolidinones8 and c-substituted
a,b-unsaturated esters. The stereoselectivity obtained in these
reactions is consistent with the mechanism proposed by Luche:
i.e., single electron transfer (SET) from the metal surface to the
carbon–halogen bond to generate an adsorbed radical, followed
by 1,4-radical addition to the a,b-unsaturated system, which in
turn gives rise to an enolate that is protonated by the solvent.6
In an effort to explore this stereochemical parameter, we
pursued the synthesis of N-Cbz methyleneoxazolidinone 3.
Compound 3 was prepared in a four-step synthetic procedure
from S-methyl-(R)-cysteine according to the literature method.12
It was found that the zinc–copper conjugate addition reaction
of alkyl iodides (4a–f) with N-Cbz oxazolidinone 3 afforded the
conjugate addition products 5a–f in excellent yields with high
diatereoselectivity; only one diastereomer can be detected by 1H
NMR spectroscopy (Table 1). As in the radical conjugate addi-
tions to 3 using organomercuric reagents,11 the stereochemistry
of the products was assigned as cis by NOE experiments. As
3 5 8 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 5 8 4 – 3 5 8 7
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
©

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Table 1 Zinc–copper conjugate addition of iodides 4a–f to N-Cbz
methyleneoxazolidinone 3
Entry
R–I
Yield (%)a
cis : transb
1
2
3
4
5
6
nC5H11I (4a)
96
76
98
99
60
96
>98 : 2
>98 : 2
>98 : 2
>98 : 2
>98 : 2
>98 : 2
iC3H5I (4b)
Scheme 4 Synthesis of 10.
cC6H11I (4c)
MeO2C(CH2)3I (4d)
HO(CH2)3I (4e)
HO(CH2)12I (4f)
induced conjugate addition (>96% de) of alkyl iodides over the
chiral methyleneoxazolidinone 3 in aqueous media. The chiral
auxiliary can be efficiently removed to give enantiomerically
pure functionalized a-amino acids.
a Isolated yield. b cis : trans ratio determined by 1H NMR spectroscopy.
Experimental
shown in Table 1, the reaction exhibited high chemoselectivity
and it was possible to use iodides bearing different functional
groups such as free hydroxy, ester or amino groups. The reaction
also gave high yields in short reaction times (less than 90
minutes).
Melting points were measured on a Stuart Scientific SMP3
melting point apparatus and are uncorrected. Optical rotations
were measured on a Jasco DIP-1000 polarimeter using a sodium
lamp (589 nm) in cells of 10 cm path length. Concentrations are
given in units of 10−2 g cm3. Infrared spectra were recorded on
a Matson FTIR spectrophotometer and the frequencies (m) as
absorption maxima are given in wavenumbers (cm−1) relative
to polystyrene (1603 cm−1). NMR spectra were acquired on a
Bruker AC-200F spectrometer (1H, 200 MHz; 13C, 50 MHz).
Chemical shifts (d) are given in ppm downfield from SiMe4 using
the residual solvent signals as reference. The multiplicities of 1H
signals are designated by the following abbreviations: s = singlet;
d = doublet; t = triplet; q = quartet; dd = doublet of doublets;
Having obtained the conjugate addition products, we turned
our attention to the synthesis of the corresponding enantiomer-
ically pure a-amino acids. The conversion of the oxazolidinone
moiety into the a-amino acid can be performed by acid
hydrolysis in the case of N-Bz oxazolidinones13 or by direct hy-
drogenolysis for N-Cbz oxazolidinones.11 In our case we decided
to employ a recently reported two-step sequence,12 using firstly
LiOH to obtain N-Cbz-a-amino acids, which are suitable for
peptide coupling technology, followed by hydrogenolysis with
Pd/C in aqueous ethanol (Scheme 3). In this way, natural and
unnatural alkylic a-amino acids such as (S)-2-aminooctanoic
acid (7a), (S)-leucine (7b) or (S)-cyclohexyl alanine (7c) were
obtained in good yields (74–94%) as enantiomerically pure
compounds. This experimental procedure was also used to
convert the conjugate addition product 5d into the a-amino
acid 7d (100%), although in this case the ester group was also
hydrolyzed. Unfortunately, we were unable to obtain the a-
amino acids derived from the hydroxy-free conjugate addition
products since the hydrogenolysis reaction was not effective.
m = multiplet. All coupling constants, J, are reported in Hz. 13
C
NMRspectra were acquiredonbroad banddecoupledmodeand
the carbon types were assigned using DEPT sequences. Mass
spectra were recorded on a Fisons VG-Quattro spectrometer
using electron ionization (EI) at 70 eV or FAB. FAB spectra
were recorded using thioglycerol as a matrix. Flash column
chromatography was performed on Merck silica gel 60 (230–
400 mesh) by Still’s method.16 Thin layer chromatography was
carried out on Merck silica gel 60 F254 (layer thickness 0.2 mm)
and components were located by observation under UV light
and/or by treating the plates with a phosphomolybdic acid
or p-anisaldehyde reagent followed by heating. Unless stated
otherwise, all reactions were conducted in flame-dried glassware
under a positive pressure of argon. Reaction temperatures refer
to external bath temperatures. All dry solvents were distilled
under argon immediately prior to use. Absolute MeOH and
EtOH were distilled from Mg turnings. For conjugate addition
reactions, Milli-Q water was used and the solvent mixture
EtOH : H2O was deoxygenated by bubbling through a positive
pressure of argon during 10 min. Zinc dust (325 mesh) was
used without purification and copper iodide was purified by
recrystallization from saturated potassium iodide solution.17 All
other reagents were commercial products and were used as
received. Sonications were carried out in a Selecta SE3000513
(50 kHz, 150 W) cleaning bath, which was filled with water
and the temperature controlled (18–20 ◦C) by running tap water
through a stainless steel coil.
Scheme 3 Synthesis of enantiopure a-amino acids 7a–d.
As part of this study we also exploited the synthetic utility
of this methodology by using more complex iodides, such
as D-serine iodide derivative 8 (Scheme 4).14 Interestingly, the
reaction of iodide 8 with oxazolidinone 3 afforded the conjugate
addition product 9 as the only diastereomer, as detected by 1H
NMR spectroscopy, in 76% yield. Basic hydrolysis followed by
hydrogenolysis led to the synthesis of N-Boc-protected diacid
10, which is an interesting nor-analog of meso-diaminopimelic
acid. The latter compound is a naturally occurring amino acid
biosynthesized in bacteria and higher plants and is of interest as
a target for antibiotic design.15
General procedure for conjugate addition of alkyl iodides (4a–f)
to chiral oxazolidinone 3
To a sonicated solution of oxazolidinone 3 (1 equiv.) and alkyl
iodide (4a–f, 2 equiv.) in aqueous EtOH (3 cm3, 70% v/v) was
added CuI (2 equiv.) and Zn (6 equiv.). After a few minutes, more
aqueous EtOH (5 cm3, 70% v/v) was added and sonication was
continued for 45–90 min. The mixture was diluted with Et2O
(25 cm3), sonicated for 10 min, and filtered through a short
In conclusion, a-amino acids can be synthesized in aqueous
media, at room temperature and in short reaction times to
give high yields using a short synthetic sequence. The key
step of the synthesis is the highly diastereoselective ultrasound-
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 5 8 4 – 3 5 8 7
3 5 8 5

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pad of Celite, washing the solids with EtOAc (3 × 30 cm3).
The combined organic phases were washed with brine (30 cm3),
dried (Na2SO4 anhydrous), filtered, and concentrated under
reduced pressure (20–30 mmHg). The residue was purified by
flash chromatography to afford, after concentration, the desired
1,4-addition product (76–99% yield).
chromatography (hexanes : EtOAc, 9 : 1), 5d (80 mg, 99%) as
the only diastereomer (colorless oil). Rf 0.50 (hexanes : EtOAc,
7 : 3); [a]2D1 +43.0 (c 0.1 in CHCl3); mmax (film)/cm−1 2872–2958
=
=
(CH), 1792, 1723 (C O), 1482, 1457 (C C), 1197; dH (200 MHz,
CDCl3) 0.97 (9 H, s, Me3C), 1.52–2.05 (6 H, m, 3 × CH2), 2.28
(2 H, dd, J 7.3 and 6.8, CH2CO2), 3.67 (3 H, s, OCH3), 4.26
(1 H, dd, J 7.3 and 6.8, NCHCO), 5.18 (2 H, s, CH2Ar), 5.56
(1 H, s, NCHO), 7.37 (5 H, s, ArH); dC (50 MHz, CDCl3) 24.4
(CH2), 24.9 (3 × CH3), 25.8 (CH2), 33.0 (CH2), 33.7 (CH2), 36.9
(C), 51.5 (CH), 56.9 (CH3), 68.3 (CH2), 96.3 (CH), 128.5 (2 ×
CH), 128.6 (CH), 128.7 (2 × CH), 135.2 (C), 156.0 (C), 172.6
(C), 173.7 (C); m/z (EI) 391 (3%, M+), 334 (16, M+ − C4H9), 91
(100).
(2S,4S)-2-(1,1-Dimethylethyl)-4-hexyl-5-oxo-3-oxazolidinecarb-
oxylic acid phenylmethyl ester (5a)
Following the general experimental procedure, a mixture of
oxazolidinone 3 (100 mg, 0.345 mmol) and 1-iodopentane
(0.090 cm3, 0.69 mmol) was treated with CuI (131 mg,
0.69 mmol) and Zn (135 mg, 2.07 mmol) to give, after column
chromatography (hexanes : EtOAc, 9 : 1), 5a (120 mg, 96%) as the
only diastereomer (colorless oil). Rf 0.57 (hexanes : EtOAc, 7 : 3);
[a]D20 +31.6 (c 0.1 in CHCl3); mmax (film)/cm−1 2859–2958 (CH),
(2S,4S)-2-(1,1-Dimethylethyl)-4-(4-hydroxybutyl)-5-oxo-3-oxa-
zolidinecarboxylic acid phenylmethyl ester (5e)
=
1794 (CO), 1721, 1482 (C C), 1466; dH (200 MHz, CDCl3) 0.88
Following the general experimental procedure, a mixture of
oxazolidinone 3 (56 mg, 0.193 mmol) and 3-iodopropanol
(0.040 cm3, 0.415 mmol) was treated with CuI (79 mg,
0.415 mmol) and Zn (81 mg, 1.244 mmol) to give, after column
chromatography (hexanes : EtOAc, 9 : 1), 5e (40 mg, 60%) as the
only diastereomer (colorless oil). Rf 0.1 (hexanes : EtOAc, 7 : 3);
(3 H, t, J 6.8, CH3), 0.97 (9 H, s, Me3C), 1.23–1.95 (10 H, m, 5 ×
CH2), 4.26 (1 H, t, J 7.3, NCHCO), 5.18 (2 H, s, CH2Ar), 5.56
(1 H, s, NCHO), 7.37 (5 H, s, ArH); dC (50 MHz, CDCl3) 14.0
(CH3), 22.5 (CH2), 24.9 (3 × CH3), 26.3 (CH2), 28.9 (CH2), 31.5
(CH2), 33.4 (CH2), 36.9 (C), 57.2 (CH), 68.2 (CH2), 96.3 (CH),
128.4 (2 × CH), 128.59 (CH), 128.64 (2 × CH), 135.3 (C), 156.0
(C), 172.8 (C); m/z (EI) 361 (1%, M+), 304 (23 M+ − C4H9), 91
(100).
mmax (film)/cm−1 3441 (OH), 2872–2959 (CH), 1719, 1790 (C O),
=
=
1457, 1482 (C C), 1326, 1198, 1040; dH (200 MHz, CDCl3) 0.96
(9 H, s, Me3C), 1.55–1.98 (6 H, m, 3 × CH2), 3.59 (2 H, dd, J 6.3
and 5.8, CH2OH), 4.28 (1 H, dd, J 7.3 and 6.8, NCHCO), 5.17
(2 H, s, CH2Ar), 5.55 (1 H, s, NCHO), 7.37 (5 H, s, ArH); dC
(50 MHz, CDCl3) 22.6 (CH2), 24.9 (3 × CH3), 32.1 (CH2), 33.0
(CH2), 36.9 (C), 57.0 (CH), 62.4 (CH2), 68.4 (CH2), 96.4 (CH),
128.5 (2 × CH), 128.7 (3 × CH), 135.2 (C), 156.0 (C), 172.7 (C).
(2S,4S)-2-(1,1-Dimethylethyl)-4-(2-methylpropyl)-5-oxo-3-oxa-
zolidinecarboxylic acid phenylmethyl ester (5b)
Following the general experimental procedure, a mixture of oxa-
zolidinone 3 (100 mg, 0.345 mmol) and 2-iodopropane (0.07 cm3,
0.691 mmol) was treated with CuI (131 mg, 0.69 mmol) and
Zn (135 mg, 2.07 mmol) to give, after column chromatography
(hexanes : EtOAc, 9 : 1), 5b (87 mg, 76%) as the only diastereomer
(colorless oil). Rf 0.56 (hexanes : EtOAc, 7 : 3); [a]2D2 +53.0 (c 0.1
in CHCl3); mmax (film)/cm−1 2872–959 (CH), 1793 (CO), 1721,
(2S,4S)-2-(1,1-Dimethylethyl)-4-(4-hydroxytridecyl)-5-oxo-3-
oxazolidinecarboxylic acid phenylmethyl ester (5f)
Following the general experimental procedure, a mixture of
oxazolidinone 3 (60 mg, 0.207 mmol) and 12-iodododecanol
(129 mg, 0.415 mmol) was treated with CuI (79 mg, 0.415 mmol)
and Zn (81 mg, 1.244 mmol) to give, after column chromatog-
raphy (hexanes : EtOAc, 9 : 1), 5f (95 mg, 96%) as the only
diastereomer (colorless oil). Rf 0.35 (hexanes : EtOAc, 7 : 3);
[a]D25 +26.4 (c 0.1 in CHCl3); mmax (film)/cm−1 3440 (OH), 2854–
=
1497 (C C), 1467; dH (200 MHz, CDCl3) 0.92 (6 H, d, J 6.3,
2 × CH3), 0.97 (9 H, s, Me3C), 1.58–2.07 (3 H, m, CHCH2), 4.33
(1 H, dd, J 7.8 and 6.3, NCHCO), 5.17 (2 H, s, CH2Ar), 5.56
(1 H, s, NCHO), 7.37 (5 H, s, ArH); dC (50 MHz, CDCl3) 21.9
(CH3), 22.7 (CH3), 24.9 (3 × CH3), 36.9 (C), 42.4 (CH2), 55.5
(CH), 68.3 (CH2), 96.3 (CH), 128.6 (5 × CH), 135. 2 (C), 156.0
(C), 173.0 (C), 198.5 (C); m/z (EI) 333 (1%, M+), 276 (49, M+ −
C4H9), 91 (100).
=
=
2925 (CH), 1721, 1794 (C O), 1482 (C C), 1465, 1325, 1198,
1041; dH (200 MHz, CDCl3) 0.97 (9 H, s, Me3C), 1.26–1.98 (24
H, m, 12 × CH2), 3.64 (2 H, m, CH2OH), 4.26 (1 H, t, J 7.3,
NCHCO), 5.18 (2 H, s, CH2Ar), 5.55 (1 H, s, NCHO), 7.37 (5
H, s, ArH); dC (50 MHz, CDCl3) 24.9 (3 × CH3), 25.7 (CH2),
26.4 (CH2), 29.2 (CH2), 29.3 (CH2), 29.4 (CH2), 29.5 (CH2), 29.6
(CH2), 32.8 (CH2), 33.4 (CH2), 36.9 (C), 57.2 (CH), 63.1 (CH2),
63.1 (CH2), 68.2 (CH2), 96.3 (CH), 128.4 (2 × CH), 128.6 (CH),
128.6 (2 × CH), 135.3 (C), 156.0 (C), 172.8 (C); m/z (FAB) 476
(10%, M+ + H).
(2S,4S)-4-(Cyclohexylmethyl)-2-(1,1-dimethylethyl)-5-oxo-3-
oxazolidinecarboxylic acid phenylmethyl ester (5c)
Following the general experimental procedure, a mixture of
oxazolidinone 3 (60 mg, 0.207 mmol) and iodocyclohexane
(0.054 cm3, 0.415 mmol) was treated with CuI (79 mg,
0.415 mmol) and Zn (81 mg, 1.244 mmol) to give, after column
chromatography (hexanes : EtOAc, 9 : 1), 5c (75 mg, 98%) as the
only diastereomer (colorless oil). Rf 0.57 (hexanes : EtOAc, 7 : 3);
[a]D23 +54.9 (c 0.07 in CH3Cl); mmax (film)/cm−1 2851–2924 (CH),
(aR,2S,4S)-a-{[(1,1-Dimethylethoxy)carbonyl]amino}-2-(1,1-
dimethylethyl)-5-oxo-3-[(phenylmethoxy)carbonyl]-4-
oxazolidinebutanoic acid methyl ester (9)
=
=
1793 (C O), 1721, 1481 (C C), 1448; dH (200 MHz, CDCl3)
0.97 (9 H, s, Me3C), 0.89–1.82 (13 H, m, cC6H11CH2), 4.37 (1
H, dd, J 7.8 and 5.4, NCHCO), 5.17 (2 H, dd, J 12.2 and 15.6,
CH2Ar), 5.56 (1 H, s, NCHO), 7.37 (5 H, s, ArH); dC (50 MHz,
CDCl3) 24.9 (3 × CH3), 25.9 (2 × CH2), 26.4 (2 × CH2), 32.8
(CH2), 33.4 (CH2), 34.2 (CH), 36.9 (C), 41.1 (CH2), 54.9 (CH),
96.3 (CH), 128.6 (5 × CH), 135.2 (C), 156.0 (C), 173.1 (C); m/z
(EI) 316 (5%, M+ − C4H9), 91 (100).
Following the general experimental procedure, a mixture of
oxazolidinone 3 (100 mg, 0.346 mmol) and iodide 8 (220 mg,
0.691 mmol) was treated with CuI (132 mg, 0.691 mmol) and
Zn (135 mg, 2.074 mmol) to give, after column chromatography
(hexanes : EtOAc, 8 : 2), 9 (132 mg, 78%) as the only diastereomer
(colorless oil). Rf 0.23 (hexanes : EtOAc, 7 : 3); mmax (film)/cm−1
=
3372 (NH), 2974–2875 (CH), 1791, 1719 (C O), 1500, 1455
=
(C C), 1319, 1170, 1040; dH (200 MHz, CDCl3) 0.95 (9 H, s,
(2S,4S)-2-(1,1-Dimethylethyl)-4-(methoxycarbonylbutyl)-5-oxo-
3-oxazolidinecarboxylic acid phenylmethyl ester (5d)
Me3CC), 1.44 (9 H, s, Me3CO), 1.97 (4 H, m, 2 × CH2), 3.74 (3
H, s, OCH3), 4.24–4.31 (2 H, m, 2 × NCHCO), 5.06 (1 H, br
m, NH), 5.18 (2 H, s, CH2Ar), 5.55 (1 H, s, O2CH), 7.33–7.41
(5 H, m, ArH); dC (50 MHz, CDCl3) 24.9 (3 × CH3), 28.3 (3 ×
CH3), 29.2 (CH2), 29.6 (CH2), 36.8 (C), 52.4 (CH), 53.1 (CH),
56.7 (CH3), 68.5 (CH2), 80.0 (C), 96.5 (CH), 128.5 (2 × CH),
Following the general experimental procedure, a mixture of
oxazolidinone 3 (60 mg, 0.207 mmol) and methyl 4-iodobutyrate
(0.056 cm3, 0.415 mmol) was treated with CuI (79 mg,
0.415 mmol) and Zn (81 mg, 1.244 mmol) to give, after column
3 5 8 6
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 5 8 4 – 3 5 8 7

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128.7 (CH), 128.7 (2 CH), 135.2 (C), 155.3 (C), 155.9 (C), 172.2
(2S,5R)-2-Amino-5-{[(1,1-dimethylethoxy)carbonyl]amino}
(C), 172.6 (C); m/z (EI) 391 (5%, M+ − C5H9O2), 91 (100).
hexanedioic acid (10)
Following the general experimental procedure, reaction of 9
(100 mg, 0.203 mmol) with LiOH (34 mg, 0.812 mmol) afforded a
white solid, which was stirred in a H2 atmosphere in the presence
of Pd/C (10%, 19 mg, 0.018 mmol) for 2 h to give 10 (35 mg,
66%) as a white solid. [a]D24 −8.9 (c 0.3 in EtOH); dH (200 MHz,
D2O) 1.27 (9 H, s, Me3CO), 1.58–1.87 (4 H, m, 2 × CH2), 3.63
(1 H, t, J 5.5, NCHCO), 3.92 (1 H, m, NCHCO); dC (50 MHz,
D2O) 28.0 (2 × CH2), 28.7 (3 × CH3), 30.7 (2 × CH), 55.2
General experimental procedure for the preparation of a-amino
acids
◦
To a cooled (0 C) solution of the conjugate addition product
5a–d or 9 (50–100 mg, 1 equiv.) in THF : H2O (3 : 1, 8–15 cm3)
was added LiOH (2 equiv.). After 1 h stirring, water (5–8 cm3)
was added and the organic phase was evaporated under reduced
pressure. The aqueous layer was neutralized and extracted with
EtOAc (3 × 25 cm3). The combined organic phases were dried,
filtered and the solvent evaporated under reduced pressure. The
protected amino acid was dissolved in deoxygenated aqueous
EtOH (5–10 cm3, 70% v/v), Pd/C (10%, 0.1 equiv.) was added,
and the mixture was stirred at rt under a H2 atmosphere
(balloon) for 1 h. The resulting mixture was filtered through a
short pad of Celite washing the solids with aqueous EtOH (3 ×
10 cm3, 70% v/v). The filtrate was concentrated under vacuum
to afford the a-amino acids as white solids (74–100% yield).
(C), 82.6 (C), 158.7 (C), 174.8 (C); m/z (EI) 219 (1%, M+
−
C4H9), 203 (20, M+ − C4H9O), 68 (100); m/z (FAB) 277 (25%,
M+ + H).
Acknowledgements
We are grateful to the Ministerio de Ciencia y Tecnolog´ıa of
Spain and FEDER (BQU2003-00301) for financial support.
R.S. thanks the Ministerio de Educacio´n, Cultura y Deporte
of Spain for a predoctoral (FPU) fellowship.
(2S)-2-Aminooctanoic acid (7a)18
References
Following the general experimental procedure, reaction of 5a
(100 mg, 0.277 mmol) with LiOH (23 mg, 0.553 mmol) afforded
71 mg of a colorless oil, which was stirred in a H2 atmosphere
in the presence of Pd/C (10%, 25 mg, 0.024 ◦mmol) to give 7a
(34 mg, 94%) as a white solid, mp 254–256 C; [a]3D7 +16.0 (c
0.3 in 1 M HCl) (lit.,18 +21); dH (200 MHz, D2O) 0.70 (3 H, t,
J 6.7, CH3), 1.15 (8 H, m, 4 × CH2), 1.76 (2 H, m, CH2), 3.81
(1 H, m, NCHCO); dC (50 MHz, D2O) 14.3 (CH3), 22.9 (CH2),
25.1 (CH2), 28.9 (CH2), 31.0 (CH2), 31.7 (CH2), 54.7 (CH); m/z
(FAB) 160 (100, M+ + H).
1 Chemistry and Biochemistry of the Amino Acids, ed. G. C. Barrett,
Chapman and Hall, London, 1985.
2 (a) R. M. Williams, Synthesis of Optically Active-Amino Acids,
Pergamon Press, Oxford, 1989; (b) R. M. Williams and J. A. Hendrix,
Chem. Rev., 1992, 92, 889–917; (c) R. O. Duthaler, Tetrahedron, 1994,
50, 1539–1650.
3 (a) M. Arend, Angew. Chem., Int. Ed., 1999, 38, 2873–2874; (b) L.
Yet, Angew. Chem., Int. Ed., 2001, 40, 875–877 and references therein;
(c) M. van der Berg, A. J. Minnaard, E. P. Schudde, J. van Esch,
A. H. M. de Vries, J. G. de Vries and B. L. Feringa, J. Am. Chem.
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4 (a) C.-J. Li and D. Wang, Chemtracts: Org. Chem., 2003, 16, 59–
78; (b) A. Lubineau and J. Auge, in Modern Solvents in Organic
Synthesis, ed. P. Knochel, Springer-Verlag, Berlin, 1999, pp. 1–39;
(c) P. A. Grieco, Organic Synthesis in Water, Blackie Academic &
Professional, London, 1998; (d) C.-J. Li and T.-H. Chan, Organic
Reactions in Aqueous Media, Wiley, New York, 1997; (e) C.-J. Li,
Chem. Rev., 1993, 93, 2023–2035.
5 U. M. Lindstro¨m, Chem. Rev., 2002, 102, 2751–2772.
6 (a) C. Petrier, C. Dupuy and J. L. Luche, Tetrahedron Lett., 1986, 27,
3149–3152; (b) J. L. Luche and C. Allavena, Tetrahedron Lett., 1988,
29, 5369–5372; (c) J. L. Luche, C. Allavena, C. Petrier and C. Dupuy,
Tetrahedron Lett., 1988, 29, 5373–5374.
7 (a) R. M. Sua´rez, J. Pe´rez Sestelo and L. A. Sarandeses, Synlett, 2002,
1435–1438; (b) R. M. Sua´rez, J. Pe´rez Sestelo and L. A. Sarandeses,
Chem.-Eur. J., 2003, 9, 4179–4187.
8 (a) D. Seebach, R. Naef and G. Calderari, Tetrahedron, 1984, 40,
1313–1324; (b) J. Zimmermann and D. Seebach, Helv. Chim. Acta,
1987, 70, 1104–1114.
9 (a) J. Pe´rez Sestelo, I. Cornella, O. de Un˜a, A. Mourin˜o and L. A.
Sarandeses, Chem. Eur. J., 2002, 8, 2747–2752; (b) J. Pe´rez Sestelo, O.
de Un˜a, A. Mourin˜o and L. A. Sarandeses, Synlett, 2002, 715–719;
(c) I. Cornella, R. M. Sua´rez, A. Mourin˜o, J. Pe´rez Sestelo and L. A.
Sarandeses, J. Steroid Biochem. Mol. Biol., 2004, 89–90, 19–23.
10 (a) T.-S. Huang and C.-J. Li, Org. Lett., 2001, 3, 2037–2039; (b) T.
Huang, C. C. K. Keh and C.-J. Li, Chem. Commun., 2002, 2440–2441.
11 J. R. Axon and A. L. J. Beckwith, J. Chem. Soc., Chem. Commun.,
1995, 549–550.
L-Leucine (7b)19
Following the general experimental procedure, reaction of 5b
(60 mg, 0.180 mmol) with LiOH (15 mg, 0.360 mmol) afforded
65 mg of a colorless oil, which was stirred in a H2 atmosphere
in the presence of Pd/C (10%, 19 mg, 0.018 ◦mmol) to give 7b
(22 mg, 93%) as a white solid, mp 269–271 C; [a]2D2 +14.5 (c
0.7 in 6 M HCl) (lit.,19 +15.5); dH (200 MHz, D2O) 0.79 (6 H,
d, J 3.0, 2 × CH3), 1.46–1.67 (3 H, m, CHCH2), 3.56 (1 H,
m, NCHCO); dC (50 MHz, D2O) 21.9 (CH3), 23.1 (CH3), 25.2
(CH), 40.8 (CH2), 54.5 (CH), 176.5 (C); m/z (FAB) 132 (100%,
M+ + H).
(aS)-a-Aminocyclohexanepropanoic acid (7c)20
Following the general experimental procedure, reaction of 5c
(52 mg, 0.134 mmol) with LiOH (12 mg, 0.278 mmol) afforded
a colorless oil, which was stirred in a H2 atmosphere in the
presence of Pd/C (10%, 15 mg, 0.014 mmol) for 2 days to give
7c (17 mg, 74%) as a white solid. mp 234–237 ◦C; [a]D29 +9.1 (c 0.1
in 1 M HCl) (lit.,20 +12 1); dH (200 MHz, D2O) 0.65–1.69 (13
H, m, cC6H11CH2), 3.60 (1 H, dd, J 8.5 and 6.1, NCHCO); dC
(50 MHz, D2O) 26.5 (CH2), 26.7 (CH2), 26.9 (CH2), 32.9 (CH2),
34.1 (CH2), 34.4 (CH), 39.4 (CH2), 53.8 (CH), 191.5 (C); m/z
(FAB) 172 (100, M+ + H).
12 R. C. F. Jones, D. J. C. Berthelot and J. N. Iley, Tetrahedron, 2001,
57, 6539–6555.
13 D. Seebach and A. Fadel, Helv. Chim. Acta, 1985, 68, 1243–1250.
14 C. S. Dexter, R. F. W. Jackson and J. Elliott, J. Org. Chem., 1999, 64,
7579–7585.
(2S)-Aminoheptanedioic acid (7d)21
Following the general experimental procedure, reaction of 5d
(60 mg, 0.153 mmol) with LiOH (19 mg, 0.460 mmol) afforded
a colorless oil, which was stirred in a H2 atmosphere in the
presence of Pd/C (10%, 16 mg, 0.015 mmol) to give 7d (29 mg,
100%) as a white solid, mp 264–267 ◦C; [a]D25 +19.3 (c 0.5 in 1 M
HCl) (lit.,21 +20.5); dH (200 MHz, D2O) 1.27 (2 H, m, CH2), 1.49
(2 H, m, CH2), 1.70 (2 H, m, CH2), 2.24 (2 H, t, J 7.3, CH2CO2),
3.58 (1 H, t, J 6.1, NCHCO); dC (50 MHz, D2O) 24.9 (CH2),
25.1 (CH2), 31.1 (CH2), 34.8 (CH2), 55.7 (CH), 175.7 (C), 180.2
(C); m/z (EI) 144 (23%, M+ − CO2H), 69 (100).
15 (a) R. M. Williams, M.-N. Im and J. Cao, J. Am. Chem. Soc.,
1991, 113, 6976–6981; (b) A. Sutherland and J. C. Vederas, Chem.
Commun., 2002, 224–225.
16 W. C. Still, M. Kahn and A. Mitra, J. Org. Chem., 1978, 43, 2923–
2925.
17 G. B. Kauffman and L. A. Teter, Inorg. Synth., 1963, 7, 9–12.
18 J. Umezawa, O. Takahashi, K. Furuhashi and H. Nohira, Tetrahe-
dron: Asymmetry, 1994, 5, 491–498.
19 Aldrich Chemical Co. catalog, ref. L60-2.
20 Fluka/Riedel-de Hae¨n catalog, ref. 29290.
21 T. Pham and W. D. Lubell, J. Org. Chem., 1994, 59, 3676–3680.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 5 8 4 – 3 5 8 7
3 5 8 7