A unified approach to mesityl amino acids based on Sharpless dihydroxylation

Article abstract of DOI:10.1016/j.tetasy.2007.10.041

Enantioselective syntheses of two mesityl (2,4,6-trimethylphenyl) amino acids are described. Starting from ethyl 3-mesityl-2-propenoate both enantiomeric dihydroxy esters 5 were prepared in excellent yield and enantiomeric purity (>99% ee) by Sharpless di

Full text of DOI:10.1016/j.tetasy.2007.10.041

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 18 (2007) 2797–2802
A unified approach to mesityl amino acids based on
Sharpless dihydroxylation
*
`
´
Rosario Ramon, Monica Alonso and Antoni Riera
`
Unitat de Recerca en Sı´ntesi Asimetrica (URSA-PCB), Institute for Research in Biomedicine and Departament de Quımica Organica,
´
`
Universitat de Barcelona, Parc Cientific de Barcelona, Josep Samitier, 1-5, Barcelona 08028, Spain
Received 8 October 2007; accepted 31 October 2007
Abstract—Enantioselective syntheses of two mesityl (2,4,6-trimethylphenyl) amino acids are described. Starting from ethyl 3-mesityl-2-
propenoate both enantiomeric dihydroxy esters 5 were prepared in excellent yield and enantiomeric purity (>99% ee) by Sharpless
dihydroxylation. Each diol was converted into ethyl 3-azido-2-hydroxy-3-mesitylpropanoate 3 which is the common intermediate.
Compound (2S,3S)-3 was transformed into Fmoc-D-mesitylglycine D-1 and Fmoc-L-mesitylalanine L-2 through two four-step-sequences.
ꢀ 2007 Elsevier Ltd. All rights reserved.
NH2
COOH
1. Introduction
COOH
NH2
L-Mesitylalanine L-2
Non-proteinogenic amino acids have become increasingly
important due to the biological and therapeutic properties
of their derivatives as drug intermediates1 or as fragments
of modified peptides.2 One strategy to modify the biologi-
cal activity of a peptide and to increase its bioavailability
is to introduce conformationally restricted residues into
the natural sequence.3 In our group we have been inter-
ested in amino acids with conformational restrictions at
the v1 and v2 angles.4 Some years ago, we found that the
replacement of phenyl by mesityl (2,4,6-trimethylphenyl)
in several amino acids notably increased the rotational bar-
riers without substantially changing the geometry of the
lowest energy conformer.5 Mesityl fragments moreover
would notably increase the lipophilicity of the modified
peptide, thus modifying their biological activity. Several
examples of peptide analogues with mesitylalanine have al-
ready been described, but the synthesis was performed
using racemic mesitylalanine and the final diastereomers
had to be separated by chromatography.6
L-Mesitylglycine L-1
SPPS. Our previous synthesis5 of mesityl amino acids based
on Sharpless epoxidation and Sharpless aminohydroxyl-
ation had important drawbacks that made them impractical
for large scale preparations, as they lead to the Boc-pro-
tected amino acids; furthermore, the Sharpless epoxidation
of mesitylpropenol gives low conversion and the Sharpless
aminohydroxylation affords reaction crudes that need to be
chromatographed to remove the excess of reagents. We
planned to use Sharpless asymmetric dihydroxylation9 as
a chirality source because this reaction is very easy to
perform and usually gives high yields and enantiomeric
excess with aromatic unsaturated esters. We envisaged that
both Fmoc-protected amino acids 1 and 2 could be pre-
pared from the same azido alcohol 3 as a key intermediate.
This compound would arise by regioselective ring-opening
of sulfite 4 derived from dihydroxyester 5. Herein, we
report a practical and reliable preparation of both Fmoc-
protected mesityl amino acids 1 and 2 of any absolute
configuration based on the Sharpless asymmetric di-
hydroxylation (Scheme 1).
In a project devoted to the synthesis of analogues of pep-
tidic natural hormones, we became interested in the prepa-
ration of multigram amounts of Fmoc-mesitylglycine 1 and
Fmoc-mesitylalanine 2. Although several preparations of
these amino acids have been described5,7,8 none of them
report the Fmoc protection, which is very convenient for
2. Results and discussion
*
According to our retrosynthetic analysis, the synthesis
Corresponding author. Tel.: +34 934037093; fax: +34 934037095;
e-mail: ariera@pcb.ub.es
started from unsaturated ester 6, which was easily available
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.10.041

2798
R. Ramo´n et al. / Tetrahedron: Asymmetry 18 (2007) 2797–2802
NHFmoc
COOH
N3
OH
Fmoc-D-1
COOEt
OH
COOEt
OH
3
COOH
NHFmoc
5
6
COOEt
Fmoc-L-2
Scheme 1. Retrosynthetic analysis.
in multigram scale by Horner–Wadsworth–Emmons reac-
tion of mesityl aldehyde. The Sharpless asymmetric dihydr-
oxylation (AD) afforded nearly quantitative yields of both
dihydroxy esters 5 in enantiomerically pure forms (>99% ee
by chiral HPLC) using either (DHQ)2PHAL or
(DHQD)2PHAL as ligands.9 The absolute configuration
of the dihydroxylated products 5 was assigned by the
mnemonic device for predicting stereoselectivities reported
by Sharpless.10 The absolute configuration was later con-
firmed by the specific rotation of the hydrochloride of 11.
Although compound 5 was obtained as very dense oil,
the reaction crude was pure enough to be used in the next
step without any purification. The preparation of the corre-
sponding sulfate was unsuccessful on this substrate. Conse-
quently, we introduced the amino functionality through
sulfite 4, which was prepared by treatment with thionyl
chloride in methylene chloride in quantitative yield.11 The
crude reaction of sulfite 4 without any purification was dis-
solved in DMF and treated with sodium azide at 100 ꢁC.
The ring-opening was completely regioselective, affording
azido alcohol 3 in good yield as an oil. Using this proce-
dure, several grams of either enantiomer of the key inter-
mediate 3 could be easily prepared (Scheme 2).
tions to give 8. Fmoc-protected aminodiol 8 was
subsequently oxidized to the desired amino acid D-1 in
excellent yield. The enantiomeric purity was checked by
chiral HPLC (>99% ee) (Scheme 3).
The synthesis of Fmoc-mesitylalanine 2 from the common
intermediate 3 required the rearrangement of the amino
function from C3 to C2. Following our previous work in
which we used N-Boc aziridines in the preparation of aryl
alanines,12 we planned to use aziridines as intermediates,
as we predicted that their hydrogenation would be regio-
selective at the benzylic position. Since our aim was to pro-
tect the amino group with Fmoc, the unprotected aziridine
would be the most suitable for our purpose. Thus, by treat-
ing azido alcohol 3 with triphenylphosphine under Stau-
dinger13 conditions, aziridine 9 was obtained in moderate
yield but in enantiomerically pure form (>99% ee by chiral
HPLC). After some experimentation, hydrogenation of 9
took place in quantitative yield with complete regioselectiv-
ity using Pd/C as a catalyst. The best reaction conditions
included the addition of acetic acid and working at high
hydrogen pressure. The amino acid could be obtained by
hydrolysis of ester 10 either in basic or acidic media.
Hydrolysis of the ester was carefully studied to minimize
racemization (Table 1, Scheme 4).
The synthesis of Fmoc-mesitylglycine D-1 was performed
as follows. The ester was reduced with LiBH4 in THF to
give azido diol 7 in excellent yield. Then, the azido group
was hydrogenated with Pd/C in ethyl acetate to the pri-
mary amine which was protected under standard condi-
The hydrolysis in acidic media (Table 1, entry 1) provided
the hydrochloride of 11 but with some loss of enantiomeric
purity {[a]D = +51.8 (c 1.0, CH3OH); lit.8a [a]D = +64.6 (c
OH
COOEt
SOCl2
COOEt
AD
OH
Et3N, CH2Cl2
(DHQ)2PHAL cat.
97%,
(2R,3S)-5 (99% ee)
6
O
S
O
N3
O
NaN3,
COOEt
OH
DMF, 100 °C
78% (two steps)
COOEt
3
4
Scheme 2. Preparation of the key intermediate.

R. Ramo´n et al. / Tetrahedron: Asymmetry 18 (2007) 2797–2802
N3 N3
2799
COOEt
1. H2, Pd/C cat, AcOEt
OH
LiBH4
THF
2. FmocOSu, Na2CO3
dioxane
OH
OH
3
7
62%
88%
NHFmoc
OH
NHFmoc
COOH
1. NaIO4, THF:H2O
2. NaClO2,NaH2PO4,
THF:ButOH
OH
67%
8
D-1
Scheme 3. Synthesis of Fmoc-mesitylglycine from 3.
Table 1. Hydrolysis of 10 to 11
4. Experimental
Entry Conditions
Time (h) ee (%) Yield (%)
4.1. General
1
2
3
4
Concd HCl at reflux
6
2
2
93
95
94
99
99a
64
74
80
20% NaOH/EtOH, 65 ꢁC
20% LiOH/EtOH, 65 ꢁC
20% LiOH/dioxane, rt
Optical rotations were measured at room temperature on a
Perkin–Elmer 241MC polarimeter (concentration in g/
100 mL). Infrared spectra were recorded on a Nicolet
510FT-IR instrument using NaCl film or KBr pellet tech-
niques. NMR spectra were acquired on a 400 MHz instru-
24
ee was measured by chiral HPLC.
a The yield corresponds to the hydrochloride.
1
ment. H NMR were obtained at 400 MHz (s = singlet,
d = doublet, t = triplet, dt = double triplet, m = multiplet
and br = broad) 13C NMR were obtained at 100 MHz.
1H chemical shifts are quoted relative to TMS and 13C
shifts relative to solvent signals. Signals marked with an
asterisk correspond to rotamers.
0.5, CH3OH)}. Gratifyingly, basic hydrolysis using 20% aq
LiOH in dioxane (Table 1, entry 4) yielded mesitylalanine
11 in enantiomerically pure form (>99% ee by chiral
HPLC). This result confirmed the absolute configuration
of 11. Finally, protection under standard conditions affor-
ded the desired Fmoc-L-2 (Scheme 4).
4.2. Ethyl (2R,3S)-dihydroxy-3-mesitylpropanoate 5
To a mixture of (DHQ)2PHAL (790 mg, 1.0 mmol),
K3Fe(CN)6 (100 g, 302 mmol), K2CO3 (41.7 g, 302 mmol)
in H2O/tBuOH (1:1, 1 L) was added K2OsO4(OH)4
(149 mg, 0.403 mmol) followed by methanesulfonamide
(9.5 g, 100 mmol). After stirring for 15 min, ethyl 3-mesit-
yl-2-propenoate 6 (22.0 g, 100 mmol) was added in one
portion. The reaction mixture was stirred at room temper-
ature for 48 h and then quenched with sodium sulfite
(180 g). The stirring was continued for 2 h and the aqueous
layer was extracted with CH2Cl2 (3 · 150 mL). The com-
bined organic layer was washed with 2 M KOH, dried over
MgSO4 and evaporated to give (2R,3S)-5 as a yellow oil
(24.3 g, 97% yield). [a]D = À24.7 (c 0.98, CHCl3). IR (film):
3. Conclusion
In conclusion, we have developed enantioselective synthe-
ses of two amino acids with a mesityl (2,4,6-trimethyl-
phenyl) fragment using Sharpless dihydroxylation as a
source of chirality. Starting from ethyl 3-mesityl-2-pro-
penoate, both enantiomeric dihydroxy esters 5 were pre-
pared in excellent yield and enantiomeric purity (>99%
ee). These diols were converted into methyl 3-azido-2-
hydroxy-3-mesitylpropanoate 3, which is the common
intermediate for the synthesis of Fmoc-mesitylglycine 1
and Fmoc-mesitylalanine 2.
H
N
COOEt
H2, Pd/C
COOEt
NH2
PPh3
3
CH3OH, AcOH
CH3CN
67%
9
10
COOH
COOH
LiOH 20% aq
Dioxane
Fmoc-OSu
NH2
NHFmoc
KHCO3,
Dioxane
L-2
80%
11
78%
Scheme 4. Synthesis of Fmoc-mesitylalanine from 3.

2800
R. Ramo´n et al. / Tetrahedron: Asymmetry 18 (2007) 2797–2802
mmax 3441 (b), 2978, 1733, 1611, 1190 cmÀ1
.
1H NMR
(C), 72.1 (CH), 64.1 (CH), 62.4 (CH2), 21.0 (CH3), 20.9
(CH3), 14.2 (CH3). MS (CI–NH3) m/z: 295.3 [(M+18)+,
90%]. HRMS (ESI): calcd for C14H19N3O3Na, 300.1315;
found, 300.1318.
(400 MHz, CDCl3): 6.80 (s, 2H), 5.18 (d, 1H,
d
J = 6.4 Hz), 4.51 (d, 1H, J = 6.4 Hz), 4.04 (q, 2H,
J = 7 Hz), 3.18 (br, 1H), 2.86 (br, 1H), 2.40 (s, 6H), 2.24
(s, 3H), 1.00 (t, 3H, J = 7 Hz). 13C NMR (100MHz,
CDCl3): d 173.0 (CO), 137.4 (C), 136.8 (C), 131.8 (C),
130.3 (CH), 73.8 (CH), 73.7 (CH), 61.9 (CH2), 21.0
(CH3), 20.9 (CH3), 13.7 (CH3). MS (CI–NH3) m/z: 270.1
[(M+18)+, 100%], 252.1 [(M)+, 60%]. HRMS (CI+): calcd
for C14H20O4, 252.1361; found, 252.1357. HPLC: Chiral-
pack-AD. Hexane/i-PrOH 98:2, 1 mL/min, k = 254 nm,
tR (S,R) = 44 min and tR (R,S) = 41 min. The same proce-
dure using (DHQD)2PHAL as catalyst gave (2S,3R)-5 in
95% yield. The enantiomeric purity of (2R,3S)-5 and
(2S,3R)-5 was >99% ee.
4.5. (2R,3R)-3-Azido-3-mesitylpropane-1,2-diol 75
To a solution of 3 (10.0 g, 36.06 mmol) in dry THF
(100 mL) was added LiBH4 (1.1 g, 50.48 mmol) in por-
tions. The mixture was stirred 2.5 h at room temperature,
quenched with ammonium chloride and 2 M HCl (1:1,
326 mL) and extracted with ethyl acetate (3 · 150 mL).
The combined organic layers were dried over MgSO4 and
evaporated to give 7 (7.5 g, 88% yield) as a yellow solid.
Mp 72–74 ꢁC. [a]D = À183 (c 1, CHCl3). IR (film): mmax
3392, 2956, 2101, 1760 cmÀ1. 1H NMR (400 MHz, CDCl3):
d 6.89 (s, 2H), 5.20 (d, 1H, J = 10 Hz), 4.04 (m, 1H), 3.94
(m, 1H), 3.78 (m, 1H), 2.42 (s, 6H), 2.27 (s, 3H). 13C
NMR (100 MHz, CDCl3): d 138.6 (C), 138.1 (C), 130.8
(C), 128.8 (CH), 128.6 (C), 72.0 (CH), 64.1 (CH2), 62.1
(CH), 21.3 (CH3), 21.0 (CH3). MS (CI–NH3) m/z: 253
[(M+18)+, 100%]. Anal. Calcd for C12H17N3O2: C, 61.26;
H, 7.28; N 17.86. Found C, 61.59; H, 7.61; N 17.45.
4.3. (4R,5S)-4-Ethoxycarbonyl-5-mesityl-1,3,2-dioxathio-
lane-2-oxide 4
To a solution of diol 5 (23.5 g, 93 mmol) in CH2Cl2 (1.4 L)
was added NEt3 (38.9 mL, 279 mmol). The reaction mix-
ture was cooled at 0 ꢁC and stirred for 5 min. SOCl2
(9.5 mL, 130.4 mmol) was added dropwise, and after stir-
ring for 15 min at 0 ꢁC, Et2O (370 mL) and water
(370 mL) were added. The aqueous layer was extracted
with Et2O (3 · 150 mL) and the combined organic layer
washed with brine, dried over MgSO4 and evaporated,
yielding 27.0 g of 4 (quantitative yield) as an oil.
[a]D = À18.8 (c 1.00, CHCl3). IR (film): mmax 2979, 1742,
4.6. (2R,3R)-3-Fmoc-amino-3-mesitylpropan-1,2-diol 8
To a solution of 7 (3.18 g; 13.55 mmol) in ethyl acetate
(260 mL) was added Pd–C (318 mg, 10% Pd) and the stir-
red suspension was hydrogenated at atmospheric pressure
(balloon) for 3 h at room temperature. The catalyst was fil-
tered off, and the filtrate was concentrated in vacuo to give
2.83 g (quantitative yield) of amino diol as yellow solid that
was directly used in the next step. To a solution of this oil
in 10% Na2CO3 (36 mL), cooled to 0 ꢁC, a solution of
Fmoc-OSu (6.07 g, 18.0 mmol) in dioxane (36 mL) was
slowly added. The reaction was stirred for 36 h. Then,
water was added and extracted with ethyl acetate
(3 · 20 mL). The combined organic layers were dried over
MgSO4 and the solvent was evaporated at reduced pres-
sure. The crude was purified by flash chromatography (hex-
anes/AcOEt) yielding 1.72 g (62% yield) of 8 as a brown
oil. [a]D = À14.5 (c 1.02, CHCl3). IR (film): mmax 3419
1
1216, 1030 cmÀ1. H NMR (400 MHz, CDCl3): d 6.90 (s,
2H), 6.89* (s, 2H), 6.61 (d, 1H, J = 8 Hz), 5.95* (d, 1H,
J = 10 Hz), 5.35* (d, 1H, J = 10 Hz), 4.96 (d, 1H,
J = 8 Hz), 4.30 (dq, 2H, J = 20 and 7 Hz), 4.22* (m, 2H),
2.45* (s, 6H), 2.37* (s, 6H), 2.28 (s, 6H), 1.31 (t, 3H,
J = 7 Hz), 1.22* (t, 3H, J = 7 Hz). 13C NMR (100MHz,
CDCl3): d 168.0 (CO), 166.2 (CO), 139.9 (C), 139.8 (C),
138.4 (C), 138.2 (C), 131.0 (CH), 130.9 (CH), 125.6 (C),
122.6 (C), 84.9 (CH), 80.6 (CH), 80.3 (CH), 76.0 (CH),
62.8 (CH2), 21.07 (CH3), 21.06 (CH3), 20.5 (CH3), 20.2
(CH3), 14.2 (CH3), 14.0 (CH3). MS (CI–NH3) m/z: 315.6
[(M+17)+, 100%]. HRMS (CI+): calcd for C14H18O5S,
298.0875; found, 298.0876.
(b), 2949, 2916, 1703, 1450, 1254 cmÀ1
.
1H NMR
4.4. Ethyl (2S,3S)-3-azido-2-hydroxy-3-mesitylpropanoate 3
(400 MHz, CDCl3): d 7.74 (d, 2H, J = 8 Hz), 7.54 (d, 2H,
J = 6 Hz), 7.38 (m, 2H), 7.29 (m, 2H), 6.86 (s, 2H), 5.28
(m, 2H), 4.48 (dd, 1H, J = 4 and 7 Hz), 4.38 (dd, 1H,
J = 4 and 6 Hz), 4.17 (t, 1H, J = 7 Hz), 4.02 (m, 1H),
3.73 (m, 2H), 3.21 (m, 1H), 2.41 (s, 6H), 2.24 (s, 3H) 2.05
(m, 1H). 13C NMR (100 MHz, CDCl3): d 157.0 (CO),
143.6 (C), 141.3 (C), 137.5 (C), 131.7 (CH), 127.7 (CH),
127.0 (CH), 124.8 (CH), 119.9 (CH), 72.8 (CH), 67.0
(CH2), 63.3 (CH2), 52.3 (CH), 47.2 (CH), 21.2 (CH3),
21.0 (CH3), 20.7 (CH3). MS (CI–CH4) m/z: 432.4
[(M+1)+, 1%], 178.1 [(M-235)+, 100%]. HRMS: calcd for
C27H30N2O4, 432.2175; found, 432.2183.
To a solution of 4 (18.6 g, 62.95 mmol) in DMF (386 mL),
NaN3 (8.2 g, 125.9 mmol) was added and heated at 100 ꢁC
for 18h. The solvent was removed and the crude was dis-
solved in Et2O (310 mL) and 20% H2SO4 (310 mL) and
stirred at room temperature overnight. An excess of satu-
rated NaHCO3 was added and the aqueous layer was ex-
tracted with Et2O (3 · 150 mL). The combined organic
layer was dried over MgSO4 and evaporated. The crude
was purified by flash chromatography (hexanes/AcOEt)
yielding 13.6 g (78% yield) of
3 as a yellow oil.
[a]D = À126 (c 0.79, CHCl3). IR (film): mmax 3468 (b),
1
2924, 2105, 1737, 1610, 1257 cmÀ1. H NMR (400 MHz,
4.7. Fmoc-D-mesitylglycine D-1
CDCl3): d 6.88 (s, 2H), 5.19 (d, 1H, J = 8.8 Hz), 4.45
(dd, 1H, J = 7 and 9 Hz), 4.33 (m, 2H), 2.52 (d, 1H,
J = 7 Hz), 2.43 (s, 6H), 2.26 (s, 3H), 1.36 (t, 3H,
J = 7 Hz). 13C NMR (100 MHz, CDCl3): d 173.0 (CO),
138.4 (C), 137.6 (C), 130.66 (CH), 130.56 (CH), 128.6
To a solution of diol 8 (3.2 g, 7.41 mmol) in THF/H2O
(60 mL, 1:3) was added NaIO4 (2.37 g, 11.12 mmol). After
2 h stirring at room temperature, ethyl acetate (20 mL) and
water (20 mL) were added. The aqueous layer was ex-

R. Ramo´n et al. / Tetrahedron: Asymmetry 18 (2007) 2797–2802
2801
tracted with ethyl acetate (3 · 20 mL) and the combined or-
ganic extracts were dried over MgSO4 and evaporated. To
the crude aldehyde dissolved in THF/tBuOH (66 mL; 1:1.5)
were added 2-methyl-2-butene (3.2 mL) and a solution of
NaClO2 (873 mg; 9.64 mmol) and NaH2PO4 (1.1 g;
8.89 mmol) in water (108 mL). The mixture was stirred
24 h at room temperature, the solvent was evaporated
and the aqueous layer was extracted with ethyl acetate
(3 · 150 mL). The combined organic extracts were washed
with brine, dried over MgSO4 and evaporated. The crude
was purified by chromatography (hexanes/AcOEt) yielding
7.3 g of D-1 (67% yield) as a white solid. Mp 97–98 ꢁC.
[a]D = À62.9 (c 0.80, CHCl3). IR (film): mmax 3266 (b),
[a]D = À26.7 (c 1.00, CHCl3). IR (film): mmax 2918, 1742,
1
1612, 1483, 1225. H NMR (400 MHz, CDCl3): d 6.84 (s,
2H), 5.61 (br, 1H), 4.14 (m, 2H), 3.77 (dd, 1H, J = 6.4
and 7.6 Hz), 3.08 (m, 2H), 2.94 (m, 2H), 2.31 (s, 6H),
2.25 (s, 3H), 1.18 (t, 3H, J = 7 Hz). 13C NMR (100 MHz,
CDCl3): d 178.9 (CO), 137.1 (C), 136.3 (C), 131.1 (C),
129.5 (CH), 129.5 (CH), 129.2 (C), 61.4 (CH2), 54.1
(CH), 34.6 (CH2), 24.9 (CH3), 21.0 (CH3), 19.8 (CH3),
14.2 (CH3). MS (ESI+) m/z: 236.2 [(M+H)+, 100%].
HRMS (ESI+): calcd for C14H22NO2, 236.1645; found,
236.1637.
4.10. (2S)-Mesitylalanine 117,8
2956, 1725, 1665, 1450, 1051, 738 cmÀ1
.
1H NMR
(400 MHz, CDCl3): d 7.40–7.55 (m, 3H), 7.38–7.26 (m,
3H), 7.13–7.03 (m, 2H), 6.87 (s, 2H), 5.8 (m, 1H), 4.45–
4.10 (m, 3H), 2.40, 2.43, 2.26 (s, 9H) ppm. 13C NMR
(100MHz, CDCl3): d 175.5 (CO), 173.9 (CO)*, 157.4
(CO), 155.8 (CO)*, 144.0 (C), 143.8 (C)*, 143.6 (C), 141.4
(C), 141.2 (C), 138.3 (C), 137.7 (C)*, 137.1 (C), 131.0 (C),
130.6 (C)*, 130.5 (CH), 130.2 (CH)*, 127.8 (CH), 127.2
(CH)*, 125.2 (CH), 125.1 (CH)*, 124.8 (CH), 120.1 (CH),
68.3 (CH2), 67.3 (CH2)*, 54.1 (CH), 53.5 (CH)*, 47.3
(CH), 47.0 (CH)*, 21.1 (CH3), 20.4 (CH3) ppm. MS (CI–
CH4) m/z: 179.0 [(MÀ236)+, 100%], 192.0 [(M)+, 61%],
416.0 [(M+1)+, 1%]. HRMS: calcd for C26H25NO4,
415.1784; found, 415.1771. HPLC: Chiralpack-AD. Hep-
tane/i-PrOH/TFA 90:10:0.2, 1 mL/min, k = 254 nm, tR
(D) = 14 min and tR (L) = 22 min. The enantiomeric purity
of D-1 was >99% ee.
To a solution of 10 (2.0 g; 8.50 mmol) in dioxane (57 mL)
was added 20% aq LiOH (70 mL). The mixture was stirred
at room temperature for 24 h. Then, the solvent was evap-
orated and the remaining aqueous phase was cooled and
acidified to pH 7 with hydrochloric acid 1 M. The resulting
crystals were collected by filtration and dried in vacuo. The
product was obtained as an off-white solid (1.3g, 80%). Mp
318–320 ꢁC. [a]D = À80 (c 1.00, CH3OH). IR (film): mmax
1
3300, 2973, 1730, 1608, 1409 cmÀ1. H NMR (400 MHz,
CDCl3): d 6.75 (s, 2H), 3.27 (t, 1H, J = 7.2 Hz), 2.88 (m,
1H), 2.65 (m, 1H), 2.12 (s, 6H), 2.05 (s, 3H). 13C NMR
(100 MHz, CDCl3): d 181.8 (CO), 137.8 (C), 136.4 (C),
132.2 (C), 128.9 (CH), 56.2 (CH), 34.3 (CH2), 19.9
(CH3), 19.4 (CH3). MS (CI+) m/z: 208.3 [(M+H)+,
100%]. HRMS (CI+): calcd for C12H18NO2, 208.1337;
found, 208.1330. Anal. Calcd for C27H27NO4: C, 71.46;
H, 8.99; N, 5.95. Found: C, 71.36; H, 8.69; N, 6.39.
4.8. Ethyl (2R,3S)-3-mesityl-aziridine-2-carboxylate 9
4.11. Fmoc-L-mesitylalanine L-2
To a solution of 3 (13.0 g, 46.72 mmol) in acetonitrile
(282 mL), PPh3 (12.2 g, 46.72 mmol) was added. The mix-
ture was stirred 1 h at room temperature and refluxed for
6 h. Then, the solvent was evaporated and the crude was
purified by flash chromatography (hexanes/AcOEt) yield-
ing 7.32 g (67% yield) of 9 as a yellow oil. [a]D = À131 (c
0.79, CHCl3). IR (film): mmax 3281, 2978, 2922, 1726,
To a suspension of 11 (1.08 g, 5.22 mmol) in 16 mL of 10%
Na2CO3 was added at 0 ꢁC a solution of Fmoc-OSu
(2.64 g, 7.83 mmol) in 24 mL of dioxane. The mixture
was stirred for 20 h at room temperature, diluted with
water (20 mL) and extracted with hexane (3 · 20 mL).
The remaining aqueous phase was cooled and acidified to
pH 2 with 1 M hydrochloric acid and extracted with ethyl
acetate (3 · 20 mL). The combined organic layers were
dried over MgSO4 and evaporated. The crude was purified
by chromatography (hexanes/AcOEt) yielding 1.5 g (68%
yield) of L-2 as a white solid. Mp 187–188 ꢁC. [a]D =
À26.0 (c 1.00, CHCl3). IR (film): mmax 3321, 2962, 1713,
1
1218, 1201 cmÀ1. H NMR (400 MHz, CDCl3): d 6.82 (s,
2H), 4.31 (m, 2H), 3.16 (d, 1H, J = 2 Hz), 2.57 (d, 1H,
J = 2 Hz), 2.39 (s, 6H), 2.26 (s, 3H), 1.78 (br, 1H), 1.36
(t, 3H, J = 7 Hz). 13C NMR (100MHz, CDCl3): d 172.8
(CO), 137.8 (C), 137.3 (C), 129.0 (CH), 61.8 (CH2), 38.9
(CH), 37.8 (CH), 20.9 (CH3), 20.0 (CH3), 14.4 (CH3). MS
(CI–NH3) m/z: 233.0 [(M)+, 25%], 146.0 [(MÀ87)+,
100%]. HRMS (CI+): calcd for C14H19NO2, 233.1416;
found, 233.1418. HPLC: Chiralpack-IA. Heptane/i-PrOH
95:5, 1 mL/min, k = 254 nm, tR (S,R) = 19 min and tR
(R,S) = 14 min. The enantiomeric purity of (2R,3S)-9 was
>99% ee. The same sequence starting from (2S,3R)-5 affor-
ded (2S,3R)-9 also in >99% ee.
1
1450, 1265 cmÀ1. H NMR (400MHz, CDCl3): d 7.74 (d,
2H, J = 7.6 Hz), 7.51 (t, 2H, J = 7.6 Hz), 7.40 (t, 2H,
J = 7.6 Hz), 7.30 (t, 2H, J = 7.6 Hz), 6.83 (s, 2H), 5.25
(d, 1H, J = 8 Hz), 4.60 (dd, 1H, J = 8.0 and 8.4 Hz), 4.30
(m, 1H), 4.14 (m, 1H), 3.18 (m, 2H), 2.32 (s, 6H), 2.21 (s,
6H). 13C NMR (100 MHz, CDCl3): d 176.7 (CO), 156.08
(CO), 144.0 (C), 141.5 (C), 137.2 (C), 136.6 (C), 130.0
(C), 129.6 (C), 129.5 (CH), 127.9 (CH), 127.3 (CH), 125.3
(CH), 120.2 (CH), 67.4 (CH2), 53.7 (CH2), 47.3 (CH),
32.5 (CH2), 21.3 (CH3), 20.4 (CH3). MS (CI–NH3) m/z:
206.09 [(MÀ233)+, 82%], 430.2 [(M+H)+, 5%]. HRMS
(CI+): calcd for C27H28NO4, 430.2029; found, 430.2018.
Anal. Calcd for C27H27NO4: C, 75.50; H, 6.34; N, 3.26.
Found: C, 74.94; H, 6.21; N, 3.41. Chiralcel-AD. Hep-
tane/EtOH/TFA 95:5:0.2, 1 mL/min, k = 254 nm, tR
(D) = 20 min and tR (L) = 26 min. The enantiomeric purity
4.9. (2S)-Mesitylalanine ethyl ester 10
Aziridine 9 (9.9 g; 42.42 mmol) was hydrogenated at 40 bar
of hydrogen over a catalytic amount of Pd–C (990 mg, 10%
Pd/C) in methanol (300 mL) and acetic acid (10 mL,
84.84 mmol) for 48 h. The catalyst was filtered off, and
the filtrate was concentrated in vacuo to give 10.0 g (quan-
titative yield) of 10 as a yellow solid. Mp 81–83 ꢁC.

2802
R. Ramo´n et al. / Tetrahedron: Asymmetry 18 (2007) 2797–2802
6. (a) Nestor, J. J. J.; Ho, T. L.; Simpson, R. A.; Horner, B. L.;
Jones, G. H.; McRae, G. I.; Vickery, B. H. J. Med. Chem.
1982, 25, 795; (b) Porter, J.; Dykert, J.; Rivier, J. Int. J.
Peptide Protein Res. 1987, 30, 13; (c) Zertova, M.; Prochazka,
Z.; Slaninova, J.; Barth, T.; Majer, P.; Lebl, M. Collect.
Czech. Chem. Commun. 1993, 58, 2751; (d) Hlavacek, J.;
Pirkova, J.; Zertova, M.; Pospisek, J.; Maletinska, L.;
Slaninova, J. Collect. Czech. Chem. Commun. 1993, 58, 2761.
of L-2 was >99% ee. The same sequence starting from
(2S,3R)-5 afforded D-2 also in >99% ee.
Acknowledgements
We thank MEC (CTQ2005-000623) and Enantia, S. L. for
financial support. M.A. and R.R. thank MEC for a
fellowship.
´
´
7. Peter, A.; Vekes, E.; Gera, L.; Stewart, J. M.; Armstrong, D.
W. Cromatographia 2002, 56, S79–S89.
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Dygos, J. H.; Yonan, E. E.; Scaros, M. G.; Goodmonson, O.
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