A simple synthesis of the metabotropic receptor ligand (2S)-α-(hydroxymethyl)-glutamic acid and its Fmoc protected derivatives

Article abstract of DOI:10.1016/j.tetasy.2007.03.028

The highly enantioselective synthesis of (2S)-α-(hydroxymethyl)-glutamic acid 2, a potent metabotropic receptor ligand, was accomplished using the improved Schoellkopf methodology for the construction of quaternary α-amino acids and β-lactams. This was converted to a derivative suitably protected for direct use in Fmoc solid phase peptide synthesis.

Full text of DOI:10.1016/j.tetasy.2007.03.028

Tetrahedron: Asymmetry 18 (2007) 873–877
A simple synthesis of the metabotropic receptor ligand (2S)-a-
(hydroxymethyl)-glutamic acid and its Fmoc protected derivatives
Athanasios Yiotakis,a Plato A. Magriotisb and Stamatia Vassilioua,*
aDepartment of Chemistry, Laboratory of Organic Chemistry, University of Athens, Panepistimiopolis Zofrafou, 15771 Athens, Greece
bDepartment of Pharmacy, University of Patars, Rio, 26500 Patras, Greece
Received 26 February 2007; accepted 27 March 2007
Available online 25 April 2007
Abstract—The highly enantioselective synthesis of (2S)-a-(hydroxymethyl)-glutamic acid 2, a potent metabotropic receptor ligand, was
accomplished using the improved Scho¨llkopf methodology for the construction of quaternary a-amino acids and b-lactams. This was
converted to a derivative suitably protected for direct use in Fmoc solid phase peptide synthesis.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
efforts have been devoted to the discovery of selective ago-
nists and antagonists of the glutamate receptors. To date,
numerous (S)-glutamic acid analogues have been synthe-
sized some of which displayed great subtype-selectivity.
The commonly used concept for designing these molecules
is the synthesis of conformationally constrained analogues
of (S)-glutamic acid.1,4
(S)-Glutamic acid 1 (Fig. 1), which is the main excitatory
neurotransmitter in the central nervous system, plays a cen-
tral role in memory and learning as well as in the pathogen-
esis of neuron damage to cause various neuronal diseases.1
Its association with many acute and chronic neurodegener-
ative disorders such as cerebral ischemia, epilepsy, Parkin-
son’s, and Alzheimer’s diseases is well established.2 In fact,
1 represents an endogenous ligand for more than 40 gluta-
mate receptors, which are subdivided into ionotro-
pic (iGluRs) and metabotropic glutamate receptors
(mGluRs).3
Among the synthetic ligands disclosed so far, (2S)-a-
(hydroxymethyl)glutamic acid 2 (Fig. 1) has been recog-
nized as one of the most useful ligands;5 compound 2
is able to act as a relatively potent agonist of the group
2 receptor mGluR3, while functioning as a weak antago-
nist of mGluR2. This compound has, in contrast, little
or no effect on the group 1 and group 3 mGluRs.
Since this initial report, Langlois,6 Park and Jew,7
and Casiraghi8 have also disclosed syntheses of enantio-
pure 2.
To study the functions of these receptors and their modu-
lation mechanism in the nervous system, considerable
O
O
We have recently reported an efficient enantioselective syn-
thesis of orthogonally protected (R)-a-alkylserines.9 In
continuation of our studies on the syntheses of a,a-disub-
stituted (quaternary) a-amino acids, our attention was
focused on the a-hydroxymethyl derivative 2, which is
not only a useful ligand for glutamate receptors, but can
also be viewed as a synthetic precursor to various types
of natural products,10 such as (ꢀ)-deoxydysibetaine11 and
(ꢀ)-kaitocepahalin.12 Herein we report a simple synthesis
of enantiomerically pure 2 and its conversion to an appro-
priately protected derivative for use in Fmoc-based solid-
phase peptide synthesis.
H2N
H2N
OH
OH
O
OH
O
HO
OH
1
2
Figure 1.
*
Corresponding author. Tel.: +30 210 7274292; fax: +30 210 7274761;
e-mail: svassiliou@chem.uoa.gr
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.03.028

874
A. Yiotakis et al. / Tetrahedron: Asymmetry 18 (2007) 873–877
2. Results and discussion
the free hydroxyl function with Ac2O, the fully protected
amino acid 6 was readily obtained. The Sharpless RuCl3/
NaIO4 mediated degradative oxidation of the phenyl group
proceeded smoothly affording acid 7 in very good yield
(72%).16 Treatment of acid 7 with 6 M HCl followed by
ion exchange chromatography (Dowex 50Wx8-200, 5%
aq NH3) finally afforded (2S)-a-(hydroxymethyl)glutamic
acid 2 as a white solid.
The key features of our proposed syntheses involve (i)
enantioselective construction of the quaternary carbon cen-
ter of 2 employing a highly improved Scho¨llkopf protocol
we have developed,9,13 (ii) utilization of the phenyl group
as a masked carboxylic acid group. As shown in Scheme
1, the lithiated (R)-bislactim ether 3 was treated with 2-iodo-
ethylbenezene to generate the monoalkylated Scho¨llkopf
adduct in 89% yield. The diastereomeric ratio (>10:1) of
this step is irrelevant, since the stereochemical outcome of
the overall sequence is determined by the second alkyl-
ation. Therefore, while the minor isomer, cis with reference
to the isopropyl group, can be removed by column chroma-
tography, separation is not necessary. Next, lithiation of
the monoalkylated product was carried out using tert-BuLi
instead of n-BuLi to exploit its more basic action toward
the less hindered C-3 hydrogen, as well as its negligible
nucleophilicity toward the imino esters.9,13 Alkylation with
chloromethyl benzyl ether,14 afforded 4 in good yield and
high stereoselectivity (>95%), which is generally the rule
as we and previous workers have found on a number of
occasions.13,15 The benzyl ether and the isopropyl group
have a trans relationship in this product and hence the
(S)-configuration was generated at the C-3 position. It
should be stressed that changing the order of the stepwise
alkylation, in order to obtain the (3R)-stereoisomer is not
feasible since tiny amounts of the desired dialkylated prod-
uct ent-4 were obtained when we attempted this procedure.
With monoacid 7 in hand, we next attempted to transform
it to a corresponding derivative, which was suitably pro-
tected for direct use in Fmoc solid-phase peptide synthesis
by careful manipulation of the protecting groups of the
four functionalities present in the molecule. After some
experimentation, we found that the following reaction
sequence is the most efficient for this conversion (Scheme
2): (1) careful treatment of 7 with K2CO3 in MeOH to
remove the acetyl group while the methyl ester remains
intact; (2) introduction of the tert-butyl group to both the
carboxyl and the hydroxyl side chains by treating 8 with
tert-butyl tricloroacetimidate. Initial attempts to react 8
with isobutylene and catalytic sulfuric acid or boron triflu-
oride etherate proved unsuccessful; (3) hydrolysis of 9 with
aqueous NaOH to generate the free acid 10; (4) removal of
N-Boc protecting group while retaining both the tert-butyl
ester and ether was achieved by treating 10 with a 1 M
solution of HCl in diethyl ether.17 Reaction of the precipi-
tated internal salt with Fmoc-Cl/Na2CO3 gave rise to the
desired compound 11 in excellent ee (ꢁ95%), confirmed
by chiral HPLC.
H2N
CO2CH3
O
a
H3CO
c
OCH3
H3CO
N
N
6
N 3
BocHN
HOOC
CO2CH3
OH
BocHN
CO2CH3
OtBu
b
a
b
N
7
c
OCH3
O
ButO2C
8
9
3
4
5
BocHN
CO2H
OtBu
FmocHN
ButO2C
CO2H
OtBu
d,e
d,e,f
ButO2C
H2N
COOH
OH
BocHN
HOOC
CO2CH3
OAc
BocHN
CO2CH3
OAc
g
h
10
11
HOOC
Scheme 2. Reagents and conditions: (a) K2CO3, MeOH, rt, 40 min, 92%;
(b) tert-butyl trichloroacetimidate, cat. BF3ÆEt2O, cyclohexane, rt, 24 h,
61%; (c) NaOH, MeOH, rt, 16 h, 89%; (d) 1 M HCl Et2O, rt, 3 h; (e)
Fmoc-Cl, Na2CO3, dioxane, rt, 10 h, 67%.
2
7
6
Scheme 1. Reagents and conditions: (a) n-BuLi, THF, ꢀ78 ꢁC; then 2-
iodoethyl-benzene, ꢀ78 ꢁC, 3 h, 81%; (b) tert-BuLi, THF, ꢀ78 ꢁC; then
chloromethyl benzyl ether, ꢀ78 ꢁC, 8 h, 87%; (c) TFA, CH3CN–H2O, rt,
10 h; (d) (Boc)2O, dioxane, rt, 91%; (e) H2, Pd/C, MeOH, rt, quant.; (f)
(Ac)2O, DIEA, DMAP, CH2Cl2, rt, 14 h, 96%; (g) NaIO4, RuCl3, AcOEt,
CH3CN, H2O, rt, 3 h, 72%; (h) 6 M HCl, reflux 14 h, 86%.
3. Conclusions
In conclusion, we have developed an efficient enantioselec-
tive synthesis of the potent mGluR3 agonist (2S)-a-
(hydroxymethyl)-glutamic acid 2. The synthesis was
accomplished in 38% overall yield from commercially
available (R)-Scho¨llkopf chiral auxiliary 3. The other enan-
tiomer can be accessed by using ent-3. To the best of our
knowledge, this report has described the first synthetic pro-
tocol to obtain orthogonally protected (2S)-a-(hydroxy-
Mild acid hydrolysis using TFA in aqueous acetonitrile
was used to effect the hydrolytic cleavage of the pyrazine
ring providing the aminoacid ester 5. Upon treatment with
Boc2O followed by catalytic hydrogenolysis using H2/10%
Pd–C to remove the benzyl group and final reprotection of

A. Yiotakis et al. / Tetrahedron: Asymmetry 18 (2007) 873–877
875
methyl)-glutamic acid, suitable for Fmoc-solid phase
peptide syntheses.
2H), 2.20–2.60 (m, 3H), 3.38 (d, 1H, J = 8.8 Hz), 3.68,
4.03 (AB, 2H, JAB = 9.1 Hz), 3.73, 3.75 (s, 6H), 4.47 (s,
2H), 7.13–7.33 (m, 10H); 13C NMR (50 MHz, CDCl3): d
17.1, 19.8, 30.6, 30.9, 37.7, 52.5, 61.0, 63.2, 97.0, 125.9,
127.5, 127.6, 128.5, 128.6, 138.9, 142.7, 162.5, 164.5; MS
(EI): 409.3 (M+).
4. Experimental
4.1. General
4.3. Methyl (2S)-2-amino-2-[(benzyloxy)methyl]-4-phenyl-
butanoate 5
All of the compounds for which analytical and spectro-
scopic data are quoted were homogeneous by TLC. TLC
analyses were performed using silica gel plates (E. Merck
silica gel 60 F-254) and components were visualized by
the following methods: ultraviolet light absorbance, phos-
phomolybdic acid and ninhydrin spray. Column chroma-
tography was carried out on silica gel (E. Merck, 70-230
To a solution of compound 4 (0.72 g, 1.76 mmol) in aceto-
nitrile–water 3:1 (8 ml), trifluoroacetic acid (0.9 ml) was
added and the resulting solution stirred at ambient temper-
ature for 10 h. After this time the solvents were evaporated
and the residue was diluted with ethyl acetate and water.
The aqueous layer was neutralized with NaHCO3 5% solu-
tion and extracted with CH2Cl2. The organic layer was
dried over Na2SO4. After removal of the solvent under
reduced pressure, the residue was purified by column chro-
1
mesh). All the compounds were characterized by H and
13C NMR spectroscopy. 1H and 13C NMR spectra were re-
corded on a 200 MHz Mercury Varian spectrometer. Elec-
tron spray mass spectroscopy (ESMS) was performed on a
Surveyor MSQ instrument. Optical rotations were
recorded on a Perkin Elmer 349 Polarimeter (k = 589 nm,
1 dm cell). Dry THF was distilled from sodium and benzo-
phenone. HPLC analysis was carried out on an analytical
column Chiradex LichroCART-250-4 at a flow rate of
0.5 ml/min using 30% CH3CN and 70% CH3COOH/
CH3COONa buffer pH 4.4.
matography (silica gel, CH2Cl2/MeOH = 9.7/0.3) to afford
25
5 as semisolid (0.47 g, 85%); ½aꢂD ¼ ꢀ17:1 (c 1, CH2Cl2);
(C19H23NO3 requires C, 72.82; H, 7.40. Found: C, 72.48;
H, 7.31); 1H (200 MHz, CDCl3): d 1.70–2.18 (m, 4H),
2.45–2.67 (m, 2H), 3.45, 3.78 (AB, 2H, JAB = 8.7 Hz),
3.68 (s, 3H), 4.51 (s, 2H), 7.15–7.32 (m, 10H); 13C NMR
(50 MHz, CDCl3): d 30.1, 38.4, 52.5, 62.2, 73.5, 97.0,
126.2, 127.1, 127.7, 128.5, 128.6, 138.1, 141.4, 176.2; MS
(EI): 314.0 (M+).
4.2. (3S,6R)-3-[(Benzyloxy)methyl]-6-isopropyl-1,4-di-
methoxy-3-phenethyl-3,6-dihydropyrazine 4
4.4. Methyl (2S)-2-[(acetyloxy)methyl]-2-[(tert-butoxy-
carbonyl)amino]-4-phenylbutanoate 6
To a solution of (3R)-3-isopropyl-5-methoxy-6-methyl-3,6-
dihydro-2-pyrazinyl methyl ether (0.60 g, 3.04 mmol) in
dry THF (6 ml) under argon at ꢀ78 ꢁC was added n-BuLi
(1.6 M, 1.90 ml, 3.04 mmol) dropwise. The resulting solu-
tion was stirred at ꢀ78 ꢁC for 15 min and treated slowly
with a solution of 2-iodoethylbenzene (0.72 g, 3.10 mmol)
in THF (8 ml). The mixture was stirred at ꢀ78 ꢁC for
3 h, allowed to slowly warm to ambient temperature, and
quenched with saturated NH4Cl. The aqueous layer was
extracted with Et2O twice and the combined organic layers
washed with brine and dried over Na2SO4. After removal
of solvent under reduced pressure, the residue was purified
by column chromatography (silica gel, CH2Cl2) to afford
the monoalkylated pyrazine as oil in 89% yield.
Compound 5 (0.45 g, 1.44 mmol) was dissolved in dioxane
(5 ml) and the mixture cooled in an ice bath for 20 min.
Boc anhydride (0.38 g, 1.73 mmol) was added, and the mix-
ture stirred for 10 h (1 h in an ice bath and overnight at abi-
ent temperature). The reaction was partitioned between
aqueous NaHCO3 5% and Et2O. The organic phase was
washed with citric acid 10%, water, dried over Na2SO4,
concentrated under reduced pressure, and purified by chro-
matography (silica gel, CH2Cl2/MeOH = 9.8/0.2) to afford
the fully protected amino acid as a highly viscous oil
25
1
(0.54 g, 91%); ½aꢂD ¼ ꢀ8:8 (c 1, CH2Cl2); H (200 MHz,
CDCl3): d 1.48 (s, 9H), 1.95–2.75 (m, 4H), 3.65, 3.80
(AB, 2H, JAB = 8.9 Hz), 3.68 (s, 3H), 4.51 (s, 2H), 5.75
(br s, 1H), 7.12–7.33 (m, 10H); 13C NMR (50 MHz,
CDCl3): d 28.6, 30.3, 33.8, 52.9, 64.3, 67.3, 71.5, 73.5,
79.6, 126.3, 127.1, 127.7, 128.5, 128.7, 138.2, 141.3, 154.4,
173.0.
This pyrazine (0.72 g, 2.50 mmol) was dissolved in dry
THF (5.5 ml) under argon, cooled to ꢀ78 ꢁC followed by
the slow addition of tert-BuLi (1.6 M, 1.56 ml, 2.50 mmol).
Stirring was continued for 1 h and then a solution of chlo-
romethyl benzyl ether (0.41 g, 2.70 mmol) in THF (6 ml)
was added slowly. The reaction mixture was stirred for
8 h at ꢀ78 ꢁC, and then allowed to warm to ambient tem-
perature overnight, and quenched with saturated NH4Cl.
The aqueous layer was extracted with Et2O twice and the
combined organic layers were washed with brine and dried
over Na2SO4. The solvent was removed in vacuo and the
crude product was purified by column chromatography
To the previous compound (0.50 g, 1.20 mmol) CH3OH
(10 ml) was added followed by 10% Pd/C (50 mg) and
the mixture was stirred under hydrogen (1 atm) for 10 h
at room temperature. The catalyst was filtered over a Celite
pad and washed with CH3OH. After evaporation to dry-
ness, CH2Cl2 (10 ml) was added. The resulting solution
was cooled to 0 ꢁC via an ice bath. Next, acetic anhydride
(340 ll, 3.6 mmol), DIEA (630 ll, 3.6 mmol), and DMAP
(36 mg, 0.3 mmol) were added to the reaction flask. The
reaction solution was stirred for 30 min at 0 ꢁC and at
ambient temperature overnight, quenched with 10% citric
acid and transferred to a separatory funnel with CH2Cl2.
(silica gel, light petroleum–ethyl acetate: 9/1) to afford 4
25
as an oil (0.89 g, 87%); ½aꢂD ¼ ꢀ31:0 (c 1, CH2Cl2);
(C25H32N2O3 requires C, 73.50; H, 7.90. Found: C, 73.39;
H, 7.84); 1H NMR (200 MHz, CDCl3): d 0.71 (d, 3H,
J = 6.60 Hz), 1.14 (d, 3H, J = 6.60 Hz), 1.75–2.10 (m,

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A. Yiotakis et al. / Tetrahedron: Asymmetry 18 (2007) 873–877
1
The resulting organic layer was washed with water, dried
over Na2SO4, concentrated on a rotary evaporator, and
purified by column chromatography (silica gel, CH2Cl2/
49.48; H, 7.27. Found: C, 49.31; H, 7.18); H (200 MHz,
CDCl3): d 1.43 (s, 9H), 2.07–2.45 (m, 4H), 3.77 (s, 3H),
3.80, 4.10 (AB, 2H, JAB = 10.9 Hz), 5.67 (br s, 1H), 9.5
(br s, 1H); 13C NMR (50 MHz, CDCl3): d 27.4, 28.5,
28.7, 53.2, 64.3, 65.5, 79.9, 155.3, 172.9, 177.8; MS (EI):
290.5 (Mꢀ).
MeOH = 9.7/0.3) to provide 6 as an oil (0.42 g, 96%).
25
½aꢂD ¼ ꢀ9:8 (c 1, CH2Cl2); (C19H27NO6 requires C, 62.45;
H, 7.45. Found: C, 62.61; H, 7.57); 1H (200 MHz, CDCl3):
d 1.45 (s, 9H), 2.00 (s, 3H), 1.95–2.78 (m, 4H), 3.69 (s, 3H),
4.27, 4.65 (AB, 2H, JAB = 10.7 Hz), 5.65 (br s, 1H), 7.10–
7.30 (m, 5H); 13C NMR (50 MHz, CDCl3): d 20.9, 28.5,
30.1, 33.6, 53.1, 63.0, 65.3, 79.9, 126.3, 128.6, 140.8,
154.0, 170.5, 172.3; MS (EI): 366.2 (M+).
4.8. 5-(tert-Butyl)-1-methyl (2S)-2-[(tert-butoxycar-
bonyl)amino]-2-(tert-butoxymethyl)pentanedioate 9
To a solution of 8 (0.61 g, 2.00 mmol) in cyclohexane (4 ml)
t-butyl trichloroacetimidate (1.75 g, 8 mmol) was added
followed by a catalytic amount of boron trifluoride ether-
ate (40 ll). The reaction mixture was stirred at ambient
temperature for 24 h and then solid NaHCO3 (0.84 g,
10 mmol) was added. The precipitate was filtered and the
filtrate was concentrated and purified by column chroma-
4.5. (4S)-4-[(Acetyloxy)methyl]-4-[(tert-butoxycar-
bonyl)amino]-5-methoxy-5-oxopentanoic acid 7
To a solution of 6 (1.55 g, 4.24 mmol) in AcOEt (7 ml),
CH3CN (7 ml) and H2O (14 ml), sodium metaperiodate
(2.13 g, 100 mmol) was added. The resulting mixture was
stirred vigorously and ruthenium trichloride (85 mg,
0.42 mmol) was added. The solution was stirred for 3 h
and after the addition of water, it was extracted with
AcOEt (3 · 30 ml). The combined organic layer was
washed with H2O (30 ml), dried over Na2SO4, and concen-
trated in vacuo. The residue was purified by column chro-
tography using light petroleum ether/diethyl ether = 9/1
25
to deliver 9 as a viscous oil (0.49 g, 61%). ½aꢂD ¼ ꢀ6:9 (c
1, CH2Cl2) (C20H37NO7 requires C, 59.53; H, 9.24. Found:
1
C, 59.64; H, 9.32); H (200 MHz, CDCl3): d 1.16 (s, 9H),
1.42 (s, 9H), 1.55 (s, 9H), 2.12–2.50 (m, 4H), 3.79 (s, 3H),
3.67, 4.08 (AB, 2H, JAB = 10.9 Hz), 5.60 (br s, 1H); 13C
NMR (50 MHz, CDCl3): d 27.5, 28.2, 28.4, 28.5, 28.9,
53.5, 64.3, 65.5, 74.7, 79.5, 80.3, 157.0, 172.9, 173.6; MS
(EI): 404.1 (M+).
matography using CH2Cl2/MeOH = 9.5/0.5 as eluent to
25
give 7 as a semisolid (1.02 g, 72%). ½aꢂD ¼ þ2:5 (c 1,
CH2Cl2); (C14H23NO8 requires C, 50.44; H, 6.95. Found:
1
C, 50.65; H, 7.02); H (200 MHz, CDCl3): d 1.43 (s, 9H),
4.9. (2S)-5-(tert-Butoxy)-2-[(tert-butoxycarbonyl)amino]-2-
(tert-butoxymethyl)-5-oxopentanoic acid 10
2.03 (s, 3H), 2.05–2.61 (m, 4H), 3.74 (s, 3H), 4.29, 4.70
(AB, 2H, JAB = 9.5 Hz), 5.60 (br s, 1H), 9.5 (br s, 1H);
13C NMR (50 MHz, CDCl3): d 20.9, 28.5, 28.6, 30.1,
53.4, 62.2, 65.0, 79.8, 154.0, 170.5, 171.9, 177.8; MS (EI):
355.9 (M+Na+).
To a solution of 9 (0.42 g, 1.04 mmol) in MeOH (3 ml), 4 N
NaOH (0.37 ml, 1.50 mmol) was added and the mixture
was stirred at ambient temperature for 10 h. After concen-
tration under reduced pressure, the residue was partitioned
between 5% citric acid and Et2O. The organic layer was
washed with H2O, dried over Na2SO4, concentrated under
reduced pressure, and purified by column chromatography
4.6. (2S)-2-Hydroxymethylglutamic acid 2
A solution of compound 7 (0.10 g, 0.30 mmol) in 6 M HCl
(4 ml) was stirred at reflux overnight. After cooling to rt,
AcOEt was added and the aqueous phase was selected,
concentrated in vacuo, and purified by ion exchange col-
using diethyl ether to give 10 as a highly viscous oil (0.36 g,
25
89%). ½aꢂD ¼ ꢀ3:8 (c 1, CH2Cl2) (C19H35NO7 requires C,
1
58.59; H, 9.06. Found: C, 58.83; H, 9.18); H (200 MHz,
umn chromatography (Dowex 50Wx8-200; 5% aq NH3)
CDCl3): d 1.16 (s, 9H), 1.42 (s, 9H), 1.55 (s, 9H), 2.17–
2.48 (m, 4H), 3.49, 3.78 (AB, 2H, JAB = 10.5 Hz), 5.50
(br s, 1H); 13C NMR (50 MHz, CDCl3): d 27.4, 28.5,
28.6, 28.9, 64.3, 65.5, 74.4, 79.8, 80.3, 155.7, 172.8, 179.4;
MS (EI): 411.5 (M+Na+).
25
giving 2 as a white solid (46 mg, 86%). ½aꢂD ¼ þ4:5 (c 1,
H2O); (200 MHz, D2O): 2.05–2.25 (m, 2H), 2.30–2.45 (m,
2H), 3.73 (d, 1H, J = 11.8 Hz), 3.92 (d, 1H, J = 11.8 Hz);
13C NMR (50 MHz, D2O): 175.2, 171.0, 63.9, 63.0, 27.82,
26.12; MS (EI): 176.0 (Mꢀ).
4.10. (2S)-5-(tert-Butoxy)-2-(tert-butoxymethyl)-2-[(9H-flu-
oren-9-ylmethoxy)carbonyl]amino-5-oxopentanoic acid 11
4.7. (4S)-4-[(tert-Butoxycarbonyl)amino]-4-(hydroxy-
methyl)-5-methoxy-5-oxopentanoic acid 8
The N-Boc amino acid 10 (0.32 g, 0.82 mmol) was dis-
solved in 1 M HCl in Et2O (5 ml) and the reaction mixture
stirred at rt for 3 h. After this time, the precipitate was iso-
lated by filtration, dissolved in dioxane (3 ml) and 10%
Na2CO3 (2 ml) and cooled in an ice bath. Fmoc-Cl
(0.26 g, 1.00 mmol) in dioxane (1 ml) was added dropwise
and the reaction mixture was stirred at 0 ꢁC for 1 h and
at ambient temperature for 10 h. After careful acidification
with 3 N HCl to pH 2 at 0 ꢁC, the aqueous phase was ex-
tracted with Et2O, the organic layer was washed with
H2O, dried over Na2SO4, concentrated under reduced pres-
A solution of acetate 7 (0.80 g, 2.40 mmol) in MeOH
(62 ml) was treated with K2CO3 (0.49 g, 3.59 mmol) at
25 ꢁC. After stirring for 40 min, the mixture was concen-
trated under reduced pressure in a water bath not exceed-
ing 25 ꢁC to half of the original volume. The mixture was
poured into AcOEt and washed with 5% citric acid then
the aqueous layer was extracted twice with AcOEt. The
combined organic layer was washed with H2O (20 ml),
brine (30 ml), dried over Na2SO4, and evaporated to a res-
idue. Purification by column chromatography using
CH2Cl2/MeOH = 9.3/0.7 as eluent furnished 8 (0.67 g,
92%) ½aꢂD ¼ ꢀ22:5 (c 1, CH2Cl2) (C12H21NO7 requires C,
sure, and purified by column chromatography using diethyl
ether to yield 11 as a semisolid (0.28 g, 67%). ½aꢂD ¼ ꢀ4:1
25
25

A. Yiotakis et al. / Tetrahedron: Asymmetry 18 (2007) 873–877
877
5. Zhang, J.; Flippen-Anderson, J. L.; Kozikowski, A. P. J. Org.
Chem. 2001, 66, 7555–7559.
(c 1, CH2Cl2) (C29H37NO7 requires C, 68.08; H, 7.29.
Found: C, 68.32; H, 7.37); H (200 MHz, CDCl3): d 1.18
1
6. (a) Choudhury, P. K.; Le Nguyen, B. K.; Langlois, N.
Tetrahedron Lett. 2002, 43, 463–464; (b) Langlois, N.; Le
Nguyen, B. K. J. Org. Chem. 2004, 69, 7558–7564.
7. Lee, Y.-J.; Lee, J.; Kim, M.-J.; Jeong, B.-S.; Lee, J.-H.; Kim,
T.-S.; Lee, J.; Ku, J.-M.; Jew, S.-S.; Park, H.-G. Org. Lett.
2005, 7, 3207–3209.
8. Battistini, L.; Curti, C.; Zanardi, F.; Rassu, G.; Auzzas, L.;
Casiraghi, G. J. Org. Chem. 2004, 69, 2611–2613.
9. Vassiliou, S.; Yiotakis, A.; Magriotis, P. A. Tetrahedron Lett.
2006, 47, 7339–7341.
(s, 9H), 1.57 (s, 9H), 2.16–2.50 (m, 4H), 3.46, 3.75 (AB,
2H, JAB = 11.1 Hz), 4.17 (t, 1H, J = 7.1 Hz), 4.28 (d, 2H,
J = 7.1 Hz), 5.57 (br s, 1H), 7.23–7.38 (m, 4H), 7.65 (d,
1H, J = 8.8 Hz), 7.75 (d, 1H, J = 8.8 Hz) 13C NMR
(50 MHz, CDCl3): d 27.4, 28.6, 28.9, 47.3, 64.3, 65.5,
67.1, 74.4, 79.8, 80.3, 120.2, 125.3, 127.3, 127.9, 141.5,
144.1, 155.0, 176.5; MS (EI): 534.6 (M+Na+). HPLC:
Chiradex LichroCART-250-4, 30% CH3CN and 70%
CH3COOH/CH3COONa buffer pH 4.4. tR = 16.4 min.
10. Shinada, T.; Ohfune, Y. Eur. J. Org. Chem. 2005, 24, 5127–
5143.
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