One-pot synthesis of chiral N-protected-4-amino functionalized but-2-enoates from α-amino acids mediated by 1-hydroxybenzotriazole

Article abstract of DOI:10.1246/bcsj.75.2691

A novel one-pot synthetic route to 4-acetylamino-2-cyano-3-hydroxybut-2-enoates in good yields (63-71%) is reported. An HPLC analysis of these compounds showed very good enantiomeric excesses (90-94%), justifying the success of our methodology to maintain the stereochemical integrity of the starting materials used.

Full text of DOI:10.1246/bcsj.75.2691

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Bull. Chem. Soc. Jpn., 75, 2691–2692 (2002) 2691
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using a variety of C-acylation reagents, we recently managed
to synthesize a series of 4-amino-2-cyano-3-hydroxybut-2-
enoates 4–7 (Scheme 1) in good yields and very good enantio-
meric ratios (better than previously reported10) (Table 1). The
high optical purities of these compounds confirm that neither
the N-hydroxybenzotriazole esterification nor the C-acylation
reaction cause detectable racemization. Moreover, the synthe-
sized butenoates 4–7 could serve as precursors of the statine
family series (Fig. 1) under asymmetric hydrogenation condi-
tions.11
One-Pot Synthesis of Chiral N-Pro-
tected-4-amino Functionalized But-
α
2-enoates from -Amino Acids Medi-
ated by 1-Hydroxybenzotriazole
02
91
92
SJA8
09-2673
2721
Giorgos Athanasellis, Efstathios Gavrielatos, and
Olga Igglessi-Markopoulou*
The proposed synthesis comprises a C-acylation reaction
between an active methylene compound and the N-hydroxy-
benzotriazole ester of the appropriate optically active amino
acid. The N-hydroxybenzotriazole ester was synthesized by
treatment of the appropriate optically active N-acetyl α-amino
acid 1 (10 mmol) with 1-hydroxybenzotriazole (10 mmol) and
DCC (10 mmol) in anhydrous THF (40 mL) at 0 °C. The reac-
tion mixture was filtered off and the filtrate was added into a
thick slurry mixture containing the sodium salt of the active
methylene compound [prepared from the addition of NaH
(20 mmol) in anhydrous THF (80 mL) and ethyl cyanoacetate
(10 mmol)]. After stirring for 2.5 h, the solvent was removed
under reduced pressure. The residue was diluted with water,
and washed with diethyl ether, and the aqueous layer was acid-
ified with 10% HCl to give products 4–7 as white solids. One
first remark concerning our methodology is that the molar ratio
between the amino acid 1 and ethyl cyanoacetate 3 does not af-
fect the product of the reaction, in contrast to what was previ-
ously reported.9 Thus, when ethyl cyanoacetate 3 was used in
stoichiometric ratio (1:1) or in molar excess (2:1) to the N-
acetyl α-amino acid 1, compounds 4–7 were obtained, and not
the corresponding cyclized compounds. In addition, the treat-
ment of compounds 4–7 under basic conditions (EtONa/EtOH,
rt) did not afford the corresponding cyclized compounds. Nev-
ertheless, these compounds can be afforded by the treatment of
compounds 4–7 with 10% HCl in MeOH.10 The merits of the
proposed synthetic route in contrast to the previously de-
scribed methodology10 are as follows. Because there is no
need for isolating the intermediates N-hydroxybenzotriazole
esters of the chiral α-amino acids, the products are obtained in
a one-step reaction. This fact reduces the time for synthesizing
the desired products, and is beneficial for the overall yield of
the reaction (63–71%). Moreover, an HPLC analysis of opti-
cally active products 5–7 indicates the success of the proposed
methodology to maintain the stereochemical integrity of the
corresponding α-amino acids. The reaction is simple, inex-
pensive, easily scaled-up and proceeds with low racemiza-
tion. Finaly, in contrast to the N-hydroxysuccinimide esters of
α-amino acids, the use of N-hydroxybenzotriazole esters as
Laboratory of Organic Chemistry, Department of Chemical
Engineering, National Technical University of Athens,
Zografou Campus, 15773 Athens, Greece
02
02
(Received May 2, 2002)
A novel one-pot synthetic route to 4-acetylamino-2-cy-
ano-3-hydroxybut-2-enoates in good yields (63–71%) is re-
ported. An HPLC analysis of these compounds showed very
good enantiomeric excesses (90–94%), justifying the success
of our methodology to maintain the stereochemical integrity
of the starting materials used.
.4
0.3
3-Hydroxy-4-amino acids, homologues of statine, are
achieving increased pharmacological significance due to their
participation in the bioactivity of peptides and their ability to
act as selective renin inhibitors.1–3 Especially, the functional-
ized enols of type Ⅰ (Fig. 1) have been reported to possess topo-
graphical similarities with Boc-statine; therefore, they can be
effective as inhibitors of HIV-1 protease.4,5
In continuation of our studies on the use of “active esters” of
N-substituted α-amino acids as precursors for the synthesis of
optically active tetramic acids and other heterocyclic com-
pounds,6–8 we developed a new ‘one-pot’ method for the syn-
thesis of optically active 3-substituted tetramic acids using
N-hydroxybenzotriazole esters of α-amino acids as chiral pre-
cursors.9 During our attempts to expand this methodology by
Fig. 1. Compounds of the statine family series.
Scheme 1. Synthesis of compounds 4–7.

2692 Bull. Chem. Soc. Jpn., 75, No. 12 (2002)
© 2002 The Chemical Society of Japan
Table 1. Optical Rotations, Retention Times and Enantiomeric Excesses of Compounds 4–7
Compound Yield/%b) [α]Da) (c 1, MeOH) Retention time/min Enantiomeric excessb)
4
5
6
7
63
—
—
—
68 (50)
68 (45)
71 (65)
+18.2
+88.3
+ 3.2
5.58:6.07
5.12:6.82
5.42:6.13
94 (68)
90 (56)
92 (84)
a) Optical rotations were recorded on a Perkin-Elmer 241 polarimeter. Enantiomeric ratios
were determined by HPLC analysis with a CHIRALPAK AS column (4.6 × 250 mm),
[254 nm, 0.6 mL/min, ethanol-hexane (1:1). b) Numbers in brackets refer to the results of
the previously described methodology.9b
the enantioselective synthesis of tetramic acids,” 17th Internation-
al Symposium “Synthesis in Organic Chemistry”, Oxford, UK,
July 2001, Abstr, No. P20.
10 M. Petroliagi and O. Igglessi-Markopoulou, J. Heterocycl.
Chem., 38, 917 (2001).
11 R. Noyori, in “Asymmetric Catalysis in Organic
Synthesis,” ed by John Wiley and Sons, United States of America
(1994).
building blocks in the C-acylation reaction would also open the
possibility of using bases strong enough to abstract a proton
from different types of carbonyl systems with a functional α-
CH group acting not only as an electron-withdrawing group
(CN), but also as an electron donor. The structures of com-
pounds 4–7 have been elucidated by elemental analyses as
well as NMR and FT-IR Spectroscopy.12
In conclusion, we successfully synthesized N-protected
4-amino functionalized but-2-enoates 4–7 in very good enanti-
omeric ratios by using a series of chiral N-acetyl α-amino ac-
ids and 1-hydroxybenzotriazole, a useful precursor in the syn-
thesis of peptides. Work currently in progress includes appli-
cations of the proposed methodology in the synthesis of func-
tionalized 4-amino-3-hydroxy- and 3,4-dihydroxybut-2-
enoates as well as their cyclization reactions to tetramic and
tetronic acids,13 respectively. Additionaly, the catalytic asym-
metric hydrogenation of the above-reported functionalized
4-hydroxybut-2-enoates to “statine-homologues” is under in-
vestigation.
12 Typical analytical and spectroscopic data: 1H/13C-NMR
spectra (J in Hz; 300 and 75 MHz) were measured in CDCl3. 4:
71% yield; mp 126–127 °C; IR (KBr) 3300 (NH), 2223 (CN),
1656/1581 (CO), and 1544 cm−1 (CwC) ; 1H NMR δ 1.37 (3H, t, J
= 7.5, CH3), 2.08 (3H, s, COCH3), 4.36 (4H, m, COOCH2CH3
and CH2NHCOCH3), 5.99 (1H, s, NH); 13C NMR δ 13.9 (C-7),
22.6 (C-9), 41.6 (C-1), 62.9 (C-6), 80.2 (C-3), 113.6 (C-4), 170.2
(C-5), 170.7 (C-8), 185.9 (C-2); Anal. Calcd for C9H12N2O4: C,
50.94; H, 5.66; N, 13.21%; Found: C, 50.77; H, 5.43; N, 13.43%.
5: 63% yield; mp 111–112 °C; IR (KBr) 3286 (NH), 2221 (CN),
1
1649/1588 (CO), and 1553 cm−1(CwC) ; H NMR δ 1.36 (3H, t,
CH2CH3), 1.48 (3H, d, J = 6.9, CH3), 2.03 (3H, s, COCH3), 4.34
(2H, q, J = 6.9, CH2CH3), 4.91 (1H, q, CH3CH), 5.90 (1H, s,
NH); 13C NMR δ 13.9 (C-7), 18.2 (CH3), 22.6 (C-9), 48.3 (C-1),
62.9 (C-6), 79.3 (C-3), 113.6 (C-4), 170.0 (C-5), 170.5 (C-8),
190.0 (C-2); Anal. Calcd for C10H14N2O4: C, 53.10; H, 6.19; N,
12.39%; Found: C, 53.11; H, 6.22; N, 12.47%. 6: 68% yield; mp
146–147 °C; IR (KBr) 3304 (NH), 2223 (CN), 1654/1592 (CO),
We thank the National Technical University of Athens for fi-
nancial support (project “Archimides”). We also thank Ms. V.
Skouridou (National Technical University of Athens,
Biotechnology Laboratory) for recording the IR spectra.
1
and 1540 cm−1 (CwC) ; H NMR δ 1.35 (3H, t, COOCH2CH3),
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M. Vaillancourt, B. Vanasse, E. Cohen, and G. Sauve,
0.98 (3H, d, J = 6.9, CH3), 0.99 (3H, d, J = 6.9, CH3), 1.36 (3H, t,
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COCH3), 4.32 (2H, q, J = 6.9, COOCH2CH3), 4.89 (1H, q, J =
6.9, CH), 5.83 (1H, d, J = 7.2, NH), 13.9 (1H, br s, OH); 13C-
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