Design and synthesis of optically active esters of γ-amino-β-oxo acids as precursors for the synthesis of tetramic acids derived from L-serine, L -tyrosine, and L-threonine

Article abstract of DOI:10.1002/ejoc.201000700

Tetramic acids bearing a hydroxyalkyl or hydroxybenzyl group at C-5 of the heterocyclic ring were successfully prepared. α-Amino acids appropriately protected and activated were used as acylating agents for the C-acylation of active methylene compounds. T

Full text of DOI:10.1002/ejoc.201000700

FULL PAPER
DOI: 10.1002/ejoc.201000700
Design and Synthesis of Optically Active Esters of γ-Amino-β-oxo Acids as
Precursors for the Synthesis of Tetramic Acids Derived from -Serine,
L
L
-Tyrosine, and -Threonine
L
Dimitris Matiadis[a] and Olga Igglessi-Markopoulou*[a]
Keywords: Cyclization / Nitrogen heterocycles / Acylation / Amino acids
Tetramic acids bearing a hydroxyalkyl or hydroxybenzyl
group at C-5 of the heterocyclic ring were successfully pre-
pared. α-Amino acids appropriately protected and activated
were used as acylating agents for the C-acylation of active
methylene compounds. These novel synthesized intermedi-
ates, substituted γ-amino acids, were isolated in excellent
yields and enantiomeric purities. Cyclization under basic
conditions afforded the desired products in high yields and
enantiomeric purity.
domonas aeruginosa, produces the antibiotic (S)-3-(1-
hydroxydecylidene)-5-(2-hydroxyethyl)pyrrolidine-2,4-dione
derived from a Claisen-like condensation reaction from one
of the quorum sensing molecules.[13]
Introduction
Tetramic acid derivatives constitute an important class
of nitrogen heterocycles containing the pyrrolidine-2,4-di-
one ring system. They are commonly found in many natural
products exhibiting distinct pharmaceutical and biological
activities, including antibiotic, antifungal, cytotoxic, and
anti-HIV.[1] Over 100 natural products containing the tet-
ramic acid moiety have been isolated to date from a variety
of marine and terrestrial species such as sponges, cyanobac-
teria, bacteria, and fungi. The natural products tenuazonic
acid,[2] melophlins,[3] and reutericyclin[4] are representative
examples of the structurally diverse family of acyl-
tetramic acids.
Recently, peptide analogues incorporating the pyrrol-
idine-2,4-dione ring have been prepared.[5] This motif is
found in many natural products displaying interesting bio-
logical activities such as dolastatin 15[6] and althiomycin.[7]
Many natural products such as equisetin[8] and trichose-
tin,[9] paecilosetin[10] and virgineone[11] (Figure 1) include
the tetramic acid structural unit derived from -serine, -
tyrosine, and -threonine.[12] Equisetin was first isolated in
1974 from the white mould Fusarium equiseti and shows
remarkable antibiotic and HIV inhibitory activities, cytoto-
xicity, phytotoxicity, and mammalian DNA binding. Both
trichosetin and paecilosetin, structurally related to equise-
tin, are well known for exhibiting antimicrobial activity,
whereas virgineone possesses antifungal activity. Recently,
it was discovered that the Gram-negative bacterium Pseu-
[a] National Technical University of Athens, Department of
Chemical Engineering, Laboratory of Organic Chemistry,
Zografou Campus, Athens 15773, Greece
Figure 1. Naturally occurring tetramic acids.
Fax: +30-210-7723-072
E-mail: ojmark@orfeas.chemeng.ntua.gr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000700.
Although much information concerning the synthesis of
tetramic acids and congeners is available in the litera-
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D. Matiadis, O. Igglessi-Markopoulou
FULL PAPER
ture,[14,3b,4b] the generation of functionalized tetramic acids intermediates easier to handle. It is well known that the
containing a polar substituent at the 5-position is still a high polarity of tetramic acids make them difficult to han-
challenging problem. Our research group has contributed dle, and the fact that they exist in various tautomeric forms
noteworthy to the synthesis and study of many heterocyclic (Figure 2) makes the interpretation of their spectra a chal-
compounds in solution[15] and in the solid phase,[16] includ- lenge.
ing functionalized tetramic acids.[17] In the present study,
we describe the synthesis of optically active tetramic acids
bearing
a
hydrophilic group (hydroxyalkyl or hy-
droxybenzyl) in the side arm attached to the C-5 position
of the pyrrolidine-2,4-dione moiety by using suitably pro-
tected O-benzyl--serine, -tyrosine, and -threonine as
scaffolds.
Of note is the isolation in excellent purity, yields, and
ee values of the intermediate γ-amino-β-oxopentanoates 1,
attractive precursors of β-hydroxy-γ-amino acids. The latter
are found in several natural products as relevant statin sub-
structures.[18] Moreover, in two recent studies,[19] they have
been reported as important intermediates to the synthesis
of a novel peptide lactone melleumin A and its seco acid
methyl ester melleumin B, natural products isolated from
cultured plasmodium of the myxomycete Physarium mel-
leum.[20]
Results and Discussion
The synthetic course for tetramic acids 3a–f is outlined
in Scheme 1. The N-Boc-protected tetramic acids were pre-
pared in just three steps from the appropriate commercially
Figure 2. Enol–enol tautomers of the tetramic acids.
Coupling of the active methylene compound with the
available N-hydroxy succinimide esters[21] of O-benzyl-pro- free hydroxy N-Boc-protected -serine or -tyrosine under
tected N-Boc amino acids. Benzyl protection of the hydroxy the reaction conditions was unsuccessful and did not pro-
group was chosen because of the mild conditions involved vide the desired products. The C-acylation reaction of an
in its removal by catalytic hydrogenolysis and for the com- active methylene compound with the activated amino acids
patibility with the Boc protecting group attached to the provided intermediates 1a–f in almost quantitative yield
amine at the deprotection step.[22] Moreover, etherification (93–99%) and high purities. Formation of 1a–f was best
of the starting material made the final products and the achieved when 1 equiv. of the active methylene compound
Scheme 1. Synthetic protocol methodology. Reagents and conditions: (i) NaH, dry THF, 1 h, 0 °C Ǟ r.t, 10% HCl; (ii) 2  NaOH, MeOH
or EtOH, 2 h, r.t., 10% HCl; (iii) H2, Pd/C (10%), 1 h, r.t., 1 atm.
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Design and Synthesis of Optically Active Esters of γ-Amino-β-oxo Acids
was treated with 1 equiv. of the amino acid ester in the pres-
ence of an excess amount (2 equiv.) of NaH in THF for
1 h. The resulting salt after careful acidification with 10%
hydrochloric acid gave the pure γ-amino-β-oxopentanoates
as solids or colorless oils without the need for further puri-
fication.
Cyclization of 1a–f under basic conditions gave the O-
benzyl-protected tetramic acids. Hydrogenolytic removal of
the benzyl group of the tetramic acid was accomplished
over 10% Pd/C and led to the formation of the N-protected
tetramic acids in an overall yield of up to 92% over three
steps.
Table 1 shows the resulting yields for the synthesized tet-
ramic acids and the intermediates. All the products are
1
newly synthesized and fully characterized by H and 13C
NMR spectroscopy, melting point, specific rotation, FTIR
spectroscopy, and HRMS. The target molecules could be
approached in a two-step synthesis, apart from the depro-
tection step. Our procedure enables us to obtain tetramic
acids bearing a hydrophilic group in the C-5 position in
very good yields, with mild reaction conditions, short reac-
tion times, and great purities without the need for
chromatography or recrystallization as no side products are
formed. The activation of the chiral α-amino acids as the
N-hydroxysuccinimide esters as building blocks is beneficial
for the maintenance of the stereochemical integrity of the
corresponding molecules.
Figure 3. 1H and 13C NMR chemical shifts (ppm) and multiplicities
for compound 3c as observed for the two tautomeric forms existing
in CDCl3 solution at 26 °C.
Table 1. Synthesized γ-amino-β-oxopentanoates and tetramic acids.
The IR spectra of the prepared compounds further sup-
port their suggested molecular structures. Intermediate es-
ters 1 are characterized mainly by bands at 1734–1718 cm–1
corresponding to the β-dicarbonyl system.[24] Cyclized tet-
ramic acids 2 are characterized by the appearance of the
absorption band at 1649–1645 cm–1, indicating a lactam
carbonyl moiety. The appearance of the bands at 2996–
2948 cm–1, characteristic of a free hydroxy group, strongly
verifies the deprotection of the hydroxy group at C-5.
The enantiomeric excess of some representative deriva-
tives were determined by chiral HPLC and were found to
be over 98% for the intermediate pentanoates and 95% in
the case of the final products.
Yield [%]
Entry
X
Y
1
2
3
a
b
c
d
e
f
CH2
CH2
CH2C6H4
CH2C6H4
CH(CH3)
CH(CH3)
Me
Et
Me
Et
Me
Et
96
94
96
99
93
94
82
98
90
99
89
80
99
92
96
94
86
82
1
The H NMR spectra of the deprotected tetramic acids
showed in the case of serine and threonine derivatives ab-
normal broadening in [D6]DMSO, whereas in nonpolar sol-
vents (CDCl3) it was not possible to obtain satisfactory
spectra. Moreover, the 13C NMR spectra showed weak sig-
nals for the carbonyl moieties. This phenomenon is proba-
bly due to a dynamic tautomerization that occurs at room
temperature.[8b,10]
Conclusions
In summary, we have demonstrated that the O-protected
Intermediates 1a–f exist as keto/enol tautomers (Fig- activated esters of -serine, -tyrosine, and -threonine may
ure 3) as observed by 1H NMR spectroscopy in CDCl3 be transformed into γ-amino-β-oxopentanoates, important
(keto/enol, 80:20) and in [D6]DMSO (keto/enol, 40:60). The statin precursors, in high yields and enantiopurities. These
tetramic acids, similarly, exist in two enolic tautomers products may be cyclized and deprotected to afford 5-hy-
(80:20) in chloroform (Figure 2), as no peaks assignable to droxyalkyl and 5-hydroxybenzyl tetramic acids. The key
H-3 or methine C-3 (keto form) were detected, whereas in step of our proposed work was the use of a benzyl group
DMSO only one form is observable. The NMR spectro- for protection of the hydroxy group of the amino acids. This
scopic data are in full accordance with the structural in- protection, apart from blocking the reactive hydroxy group
vestigations that have been previously published.[23] The thus preventing unwanted reactions, lowered the polarity of
products derived from -threonine, thus having two asym- the products. Therefore, we were able to adapt these chal-
metric carbon atoms, were diastereomerically pure as deter- lenging target molecules to the methodology developed
1
mined by H NMR spectroscopy.
from our group.
Eur. J. Org. Chem. 2010, 5989–5995
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D. Matiadis, O. Igglessi-Markopoulou
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3 H, CO2CH2CH3), 1.44 (s, 9 H, 3 CH3), 3.65 (dd, J = 4.8, 9.9 Hz,
1.5 H, CH2CH, keto), 3.75 (d, 0.5 H, CH2CH, enol), 3.94 (dd, J =
The synthesis of more complex molecules with polar
groups on the side arm of the tetramic acid skeleton, from
different amino acid analogues as precursors, and the pos-
sibility of the application of this methodology to natural
products containing the pyrrolidine-2,4-dione nucleus with
specific side chain arms is part of our future plans.
4.2, 9.6 Hz, 0.75 H, CH2CH, keto), 4.17-4.27 (m,
4 H,
CO2CH2CH3), 4.51 (s, 1.5 H, CH2Ph, keto), 4.54 (s, 0.5 H, CH2Ph,
enol), 4.62 (m, 0.75 H, CH2CH, keto), 4.83 [s, 0.75 H,
CH(CO2CH2CH3)2, keto], 5.07 (m, 0.25 H, CH2CH, enol), 5.26 (d,
0.25 H, NH, enol), 5.42 (d, 0.75 H, NH, keto), 7.28-7.34 (m, 5 H,
Ph), 13.86 (s, 0.25 H, OH, enol) ppm. 13C NMR (75 MHz, CDCl3):
δ = 13.8, 13.9, 14.0, 14.0, 28.2, 29.6, 53.6, 59.3, 61.1, 61.4, 61.7,
62.3, 62.7, 69.1, 69.8, 72.9, 73.2, 80.0, 80.4, 99.8, 127.5, 127.7,
128.3, 137.2, 137.4, 155.2, 155.5, 164.1, 165.1, 171.3, 173.5, 179.1,
Experimental Section
General: All reagents were purchased from Aldrich, Fluka, and
Acros and used without further purification. Dry THF was distilled
from Na/Ph2CO. Flash column chromatography was carried out
on silica gel Macherey–Nagel 0.063-0.2 mm/70-230 mesh. Melting
points were determined with a Gallenkamp MFB-595 melting
point apparatus. HRMS were carried out in the department of
Chemistry & Biochemistry of the University of Notre Dame, IN,
USA, with an ESI instrument. NMR spectra were recorded with a
Varian Gemini-2000 300 MHz spectrometer operating at 300 MHz
(1H) and 75 MHz (13C). Chemical shifts are reported in ppm rela-
tive to [D6]DMSO (1H: δ = 2.50 ppm, 13C: δ = 39.52 ppm) and
CDCl3 (1H: δ = 7.26 ppm, 13C: δ = 77.16 ppm). HPLC separations
197.9 ppm. IR (ATR): ν= 3648–3846 (m), 1718 (s, CO-CH-CO,
˜
ester), 1686 (s, urethane), 1508 (s, aromatics), 1457, 1364 (CO2Et),
1250 (s, tBu) cm–1. HRMS: calcd. for C22H32NO8 438.2122; found
438.2101.
(S)-Methyl 5-[4-(Benzyloxy)phenyl]-4-tert-butoxycarbonylamino-2-
met-hoxycarbonyl-3-oxopentanoate (1c): White solid; yield 116 mg,
96%; m.p. 94–95 °C (ether). [α]2D0 = +4.2 (c = 1.6, CHCl3). Rf =
0.24 (petroleum ether/AcOEt, 8:2). 1H NMR (300 MHz, CDCl3;
keto/enol, 80:20): δ = 1.38 (s, 7.2 H, 3 CH3, keto), 1.42 (s. 1.8 H,
3 CH3, enol), 2.90 (m, 1 H, CH2CH), 3.16 (dd, J = 13.5, 4.8 Hz, 1
H, CH2CH), 3.77 (s, 4.8 H, 2 CO2CH3, keto), 3.83 (s, 1.2 H, 2
CO2CH3, enol), 4.58 (m, 0.2 H, CH2CH, enol), 4.71 [s, 0.8 H,
CH(CO2Me)2, keto], 4.86 (br., 0.8 H, CH2CH, keto), 5.04 (s, 2 H,
OCH2Ph), 6.91 (d, J = 8.1 Hz, 2 H, CHCH2C6H4), 7.09 (d, J =
8.1 Hz, 2 H, CHCH2C6H4), 7.32–7.41 (m, 5 H, Ph), 13.72 (s, 0.2
H, OH, enol) ppm. 13C NMR (75 MHz, CDCl3): δ = 28.3, 29.8,
35.9, 39.0, 52.3, 52.7, 53.2, 60.5, 62.5, 70.1, 79.9, 80.6, 98.9, 115.0,
127.5, 128.0, 128.6, 130.4, 130.5, 137.1, 154.9, 155.4, 157.9, 164.8,
were performed by using
a DAICEL CHIRALPAK AS
(4.6ϫ250 mm) column incorporated in an HPLC system con-
sisting of a Varian 2510 HPLC pump, Varian 2510 variable λ detec-
tor, and a SRI Model 203 Peaksimple chromatography data system
using n-hexane/ethanol as eluent. Optical rotations were measured
with a Perkin–Elmer 241 polarimeter.
Typical Procedure for the Synthesis of Compounds 1a–f: To a sus-
pension of NaH (60% in mineral oil, 20 mg, 0.50 mmol) in dry
THF (1.5 mL) at 0 °C and under an atmosphere of argon was
added dropwise dimethyl malonate (33 mg, 0.25 mmol). After stir-
ring for 30 min, the hydroxysuccinimide ester of the appropriate
Boc-O-benzyl--amino acid was added (0.25 mmol), and the reac-
tion mixture was stirred for 1 h at room temperature. The mixture
was concentrated, and the residue was diluted with water (0.5 mL).
The suspension was washed with diethyl ether and acidified with
10% hydrochloric acid. The precipitated solid was filtered, washed
with water (2ϫ) and dried to afford the desired product as white
solid or colorless oil.
165.6, 171.9, 174.8, 180.8, 198.7 ppm. IR (ATR): ν = 3648–3847
˜
(m), 1734 (s, CO-CH-CO, ester), 1685 (s, urethane), 1510 (s, aro-
matics), 1456, 1369 (s, CO2Me), 1248 (s, tBu) cm–1. HPLC (n-hex-
ane/ethanol/TFA, 65:35:0.1; flow rate: 1.00 mL/min; 254 nm): tR
=
5.13 (99%; S, major enantiomer), 6.77 min (1%; R, minor enanti-
omer). HRMS: calcd. for C26H32NO8 486.2122; found 486.2097.
(S)-Ethyl
5-[4-(Benzyloxy)phenyl]-4-tert-butoxycarbonylamino-2-
ethoxycarbonyl-3-oxopentanoate (1d): White solid; yield 127 mg,
99%; m.p. 95–98 °C. [α]2D0 = +1.2 (c = 0.9, CHCl3). Rf = 0.45 (petro-
1
leum ether/AcOEt, 90:10). H NMR (300 MHz, CDCl3; keto/enol,
75:25): δ = 1.24–1.35 (m, 3 H, CO2CH2CH3), 1.38 (s, 9 H, 3 CH3),
2.93 (dd, J = 7.8, 14.1 Hz, 1 H, CH2CH), 3.18 (dd, J = 6.0, 13.8 Hz,
1 H, 1 H, CH2CH), 4.18–4.30 (m, 4 H, CO2CH2CH3), 4.62 (m, 0.2
H, CH2CH, enol), 4.67 [s, 0.8 H, CH(CO2CH2CH3)2, keto], 4.92
(m, 0.8 H, CH2CH, keto), 5.04 (s, 2 H, OCH2Ph), 6.90 (d, J =
(S)-Methyl 5-Benzyloxy-4-tert-butoxycarbonylamino-2-methoxycar-
bonyl-3-oxopentanoate (1a): Colorless oil; yield 98 mg, 96%. [α]2D0
=
+1.0 (c = 1.8, CHCl3); Rf = 0.46 (petroleum ether/AcOEt, 8:2). 1H
NMR (300 MHz, CDCl3; keto/enol, 80:20): δ = 1.44 (s, 9 H, 3
CH3), 3.64 (dd, J = 4.8, 9.9 Hz, 0.8 H, CH2CH, keto), 3.70 (d, 0.4
H, CH2CH, enol), 3.75 (s, 4.8 H, CO2CH3, keto), 3.83 (s, 1.2 H,
CO2CH3, enol), 3.94 (dd, J = 3.6, 9.6 Hz, 0.8 H, CH2CH, keto),
4.50 (s, 1.6 H, CH2Ph, keto), 4.54 (s, 0.4 H, CH2Ph, enol), 4.60 (m,
0.8 H, CH2CH, keto), 4.88 [s, 0.8 H, CH(CO2CH3)2, keto], 5.06
(m, 0.2 H, CH2CH, enol), 5.25 (d, 0.2 H, NH, enol), 5.42 (d, 0.8
H, NH, keto), 7.27- 7.37 (m, 5 H, Ph), 13.8 (s, 0.2 H, OH) ppm.
13C NMR (75 MHz, CDCl3): δ = 28.3, 29.7, 52.4, 52.7, 53.2, 53.8,
59.5, 62.5, 69.3, 69.9, 70.6, 73.1, 73.5, 80.1, 80.6, 99.4, 127.6, 127.8,
127.8, 127.9, 128.0, 128.4, 128.5, 137.3, 137.7, 155.2, 155.7, 164.7,
8.4 Hz,
2 H, CHCH2C6H4), 7.10 (d, J = 8.4 Hz, 2 H,
CHCH2C6H4), 7.31–7.43 (m, 5 H, Ph), 13.70 (s, 0.2 H, OH,
enol) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.0, 14.2, 28.3, 29.8,
36.0, 39.1, 60.5, 61.3, 61.8, 62.5, 62.9, 70.1, 80.5, 99.0, 115.0, 115.1,
127.5, 128.1, 128.6, 128.7, 130.5, 137.1, 153.9, 155.3, 157.9, 158.0,
164.5, 164.6, 171.5, 174.8, 198.9 ppm. IR (ATR): ν = 3648–3837
˜
(m), 1734 (s, CO-CH-CO, ester), 1689 (s, urethane), 1516 (s, aro-
matics), 1456, 1367 (s, CO2Et), 1244 (s, tBu) cm–1. HRMS: calcd.
for C28H36NO8 514.2435; found 514.2416.
(3S,4R)-Methyl 5-Benzyloxy-4-tert-butoxycarbonylamino-2-meth-
oxy-carbonyl-3-oxohexanoate(1e): Colorless oil after column
chromatography (petroleum ether/AcOEt, 8:2); yield 98 mg, 93%.
[α]2D0 = –0.4 (c = 1.8, CHCl3). Rf = 0.53 (petroleum ether/AcOEt,
165.6, 171.8, 173.6, 179.8, 197.9 ppm. IR (ATR): ν= 3648–3837
˜
(m), 1718 (s, CO-CH-CO, ester), 1689 (s, urethane), 1508 (s, aro-
matics), 1454, 1367 (CO2Me), 1250 (s, tBu) cm–1. HRMS: calcd.
for C20H28NO8 410.1809; found 410.1798.
1
8:2). H NMR (300 MHz, CDCl3; keto/enol, 80:20): δ = 1.19 (d, J
(S)-Ethyl
5-Benzyloxy-4-tert-butoxycarbonylamino-2-ethoxycar-
= 6.3 Hz, 3 H, CH3CH), 1.27 (dd, J = 3.0, 6.3 Hz, 3 H, CH3CH),
1.45 (s, 9 H, 3 CH3), 3.75 (s, 4.8 H, CO2CH3, keto), 3.83 (s, 1.2 H,
CO2CH3, enol), 3.99 (m, 0.2 H, CH3CHCH, enol), 4.18 (m, 0.2 H,
bonyl-3-oxopentanoate (1b): Colorless oil; yield 103 mg, 94%. [α]2D0
= +8.0 (c = 1.8, CHCl3); Rf = 0.47 (petroleum ether/AcOEt, 8:2).
1H NMR (300 MHz, CDCl3; keto/enol, 75:25): δ = 1.24–1.32 (m, CH3CHCH, enol), 4.26 (pseudoq, 0.8 H, CH3CHCH, keto), 4.38
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Design and Synthesis of Optically Active Esters of γ-Amino-β-oxo Acids
(br., 0.2 H, CH3CHCH), 4.47 (m, 0.8 H, CH3CHCH), 4.58 (dd, J 1 H, OH) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.1, 28.0, 29.6,
= 11.7, 7.2 Hz, 2 H, CH2Ph), 4.83 (m, 0.2 H, CH3CHCH), 4.90 [s,
0.8 H, CH(CO2CH3)2, keto], 5.33 (d, J = 8.7 Hz, 0.2 H, NH, enol),
5.41 (d, J = 8.7 Hz, 0.8 H, NH, keto), 7.29-7.36 (m, 5 H, Ph), 14.03
(s, 0.2 H, OH, enol) ppm. 13C NMR (75 MHz, CDCl3): δ = 16.1,
16.2, 17.2, 28.4, 29.8, 41.2, 52.3, 52.6, 53.2, 56.6, 57.8, 63.0, 63.8,
59.3, 61.6, 65.5, 69.8, 73.3, 73.4, 80.0, 83.2, 99.6, 126.9, 127.4,
127.5, 127.7, 127.9, 128.1, 128.3, 128.3, 137.3, 137.4, 149.7, 155.6,
162.8, 167.1, 173.5, 185.7 ppm. IR (ATR): ν = 3648–3837 (m), 1731
˜
(s, ester), 1676 (s, urethane), 1645 (s, C-2), 1571 (s, aromatics), 1456,
1365 (s, CO2Et), 1255 (s, tBu) cm–1. HRMS: calcd. for C20H26NO7
71.4, 71.7, 74.1, 74.6, 76.1, 77.1, 80.0, 80.2, 80.6, 98.9, 127.7, 127.8, 392.1704; found 392.1687.
128.0, 128.4, 128.5, 137.7, 138.1, 155.8, 156.3, 164.5, 164.9, 165.8,
(S)-N-tert-Butoxycarbonyl-5-[4-(benzyloxy)benzyl]-3-methoxy-
167.1, 174.0, 180.8, 198.9 ppm. IR (ATR): ν = 3648–3846 (m), 1723
˜
carbonyltetramicAcid (2c): White solid; yield 95 mg, 90 %, m.p.
(s, CO-CH-CO, ester), 1686 (s, urethane), 1508 (s, aromatics), 1457,
1366 (CO2Me), 1250 (s, tBu) cm–1. HRMS: calcd. for C21H30NO8
424.1966; found 424.1948.
188–191 °C. [α]2D0 = +3.2 (c = 0.7, CHCl3). Rf = 0.47 (DCM/MeOH/
1
AcOH, 95:5:0.5). H NMR (300 MHz, [D6]DMSO): δ = 1.46 (s, 3
H, 3 CH3), 3.09 (br. dd, 2 H, CH2CH), 3.50 (s, 3 H, CO2CH3),
(3S,4R)-Ethyl 5-Benzyloxy-4-tert-butoxycarbonylamino-2-ethoxy- 4.00 (s, 1 H, CH2CH), 4.96 (s, 2 H, CH2Ph), 6.76 (d, J = 8.1 Hz,
carbo-nyl-3-oxohexanoate (1f): Colorless oil after column
2 H, CHCH2C6H4), 6.91 (d, J = 8.1 Hz, 2 H, CHCH2C6H4), 7.30–
7.42 (m, 5 H, OCH2Ph) ppm. 13C NMR (75 MHz, [D6]DMSO): δ
= 27.9, 34.2, 49.7, 61.9, 69.1, 79.7, 90.3, 113.9, 127.5, 127.8, 128.3,
chromatography (petroleum ether/AcOEt, 8:2); yield 106 mg, 94%.
[α]2D0 = –6.5 (c = 1.8, CHCl3). Rf = 0.49 (petroleum ether/AcOEt,
1
8:2). H NMR (300 MHz, CDCl3; keto/enol, 80:20): δ = 1.18 (t, J 128.5, 130.6, 134.5, 137.2, 150.0, 156.8, 164.9, 169.4, 189.0 ppm.
= 6.6 Hz, 3 H, CH3), 1.24 (t, J = 6.9 Hz, 6 H, CO2CH2CH3), 1.43 IR (ATR): ν = 3648–3847 (m), 1754 (s, ester), 1694 (s, urethane),
˜
(s, 9 H, 3 CH3), 4.20 (q, J = 6.9 Hz, 4 H, CO2CH2CH3), 4.44–4.57 1649 (s, C-2), 1522 (s, aromatics), 1460, 1362 (s, CO2Me), 1253 (s,
(m, 3 H, CH3CHCH, CH2Ph), 4.66 (s, 1 H, CH2Ph), 4.83 (m, 0.2
H, CH3CHCH, enol), 4.85 [s, 0.8 H, CH(CO2CH2CH3)2, keto],
5.33 (d, J = 9.3 Hz, 0.2 H, NH, keto), 5.42 (d, J = 9.3 Hz, 0.8 H,
NH, keto) 7.26-7.33 (m, 5 H, Ph) ppm. 13C NMR (75 MHz,
CDCl3): δ = 13.9, 14.1, 16.1, 17.1, 28.2, 29.7, 58.0, 61.1, 61.6, 61.8,
62.3, 63.3, 63.7, 71.3, 71.5, 74.1, 74.7, 80.2, 80.4, 99.3, 127.7, 127.8,
127.9, 128.0, 128.1, 128.3, 128.4, 137.8, 138.2, 155.8, 156.3, 164.2,
tBu) cm–1. HRMS: calcd. for C25H28NO7 454.1860; found
454.1838.
(S)-N-tert-Butoxycarbonyl-5-[4-(benzyloxy)benzyl]-3-ethoxy-
carbonyltetramicAcid (2d): White solid; yield 114 mg, 99%; m.p.
101–102 °C. [α]2D0 = +22.7 (c = 0.3, CHCl3). Rf = 0.50 (DCM/
MeOH/AcOH, 95:5:1). 1H NMR (300 MHz, CDCl3): δ = 1.27 (br.,
3 H, CO2CH2CH3), 1.40 (s, 2.25 H, 3 CH3), 1.53 (s, 6.75 H, 3
CH3), 3.17 (d, J = 12.3 Hz, 1 H, CH2CH), 3.30 (br., 1 H, CH2CH),
4.27 (br., 2 H, CO2CH2CH3), 4.50 (br., 1 H, CH2CH), 4.96 (s, 1.5
H, CH2Ph), 5.03 (s, 0.5 H, CH2Ph), 6.78 (d, J = 7.8 Hz, 1.5 H,
C6H4), 6.85 (d, J = 7.8 Hz, 0.5 H, C6H4), 6.97 (d, J = 7.8 Hz, 1.5
H, C6H4), 7.07 (d, J = 7.8 Hz, 0.25 H, C6H4), 7.32-7.38 (m, 5 H,
Ph) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.4, 28.3, 29.8, 34.7,
61.1, 70.1, 83.1, 89.0, 100.3, 114.8, 115.0, 127.6, 128.0, 128.7, 130.6,
130.8, 137.2, 150.4, 156.8, 158.0, 166.7, 174.0, 182.8 ppm. IR
164.5, 174.4, 176.1, 181.4, 198.9 ppm. IR (ATR): ν = 3648–3847
˜
(m), 1724 (s, CO-CH-CO, ester), 1690 (s, urethane), 1510 (s, aro-
matics), 1457, 1366 (CO2Et), 1247 (s, tBu) cm–1. HRMS: calcd. for
C23H34NO8 452.2279; found 452.2264.
Typical Procedure for the Synthesis of Compounds 2a–f: To a solu-
tion of 1 (≈0.25 mmol) in MeOH or EtOH (0.5 mL) was dropwise
added a sodium hydroxide solution (0.4 mL, 2 ). The resulting
suspension was stirred for 3 h. ROH was evaporated at room tem-
perature, and the aqueous suspension was carefully acidified with
10% hydrochloric acid at 0 °C. The precipitated solid was filtered,
washed with water (2ϫ) and petroleum ether (3ϫ) and dried to
afford the desired product as white solid.
(ATR): ν = 3648–3846 (m), 1753 (s, ester), 1701 (s, urethane), 1646
˜
(s, C-2), 1521 (s, aromatics), 1460, 1358 (s, CO2Et), 1256 (s, tBu)
cm–1. HRMS: calcd. for C26H30NO7 468.2017; found 468.1993.
(S)-N-tert-Butoxycarbonyl-5-[(R)-1-(benzyloxy)ethyl]-3-methoxy-
(S)-N-tert-Butoxycarbonyl-5-benzyloxymethyl-3-methoxycarbonyl- carbonyltetramic Acid (2e): White solid; yield 81 mg, 89%; m.p.
tetramic Acid (2a): White solid; yield 74 mg, 82%; m.p. 114 °C.
[α]2D0 = +38.5 (c = 0.8, CHCl3). Rf = 0.24 (DCM/MeOH/AcOH,
95:5:0.1). 1H NMR (300 MHz, CDCl3): δ = 1.44 (s, 2.25 H, 3 CH3),
175–177 °C. [α]2D0 = +46.4 (c = 0.1, CHCl3). Rf = (DCM/MeOH/
AcOH, 95:5:1). 1H NMR (300 MHz, [D6]DMSO; keto/enol, 80:20):
δ = 1.09 (d, J = 6.3 Hz, 3 H, CH3CH), 1.41 (s, 9 H, 3 CH3), 3.54
1.50 (s, 6.75 H, 3 CH3), 3.56 (dd, J = 3.0, 9.3 Hz, 0.25 H, CH2CH), (s, 3 H, CO2CH3), 3.92 (br., 1 H, CH3CH), 4.08 (br., 1 H,
3.71 (dd, J = 3.0, 9.3 Hz, 1 H, CH2CH), 3.91 (s, 3 H, CO2CH3), CH3CHCH), 4.48 (s, 2 H, CH2Ph), 7.28 (br., 5 H, Ph), 14.00 (s, 1
4.08 (dd, J = 3.0, 9.3 Hz, 0.75 H, CH2CH), 4.49 (s, 1.5 H, CH2Ph),
H, OH, enol) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 16.6,
4.53 (s, 0.25 H, CH2Ph), 4.57 (dd, 1 H, CH2CH), 7.21–7.33 (m, 5 27.8, 49.4, 63.2, 70.5, 74.7, 78.5, 78.9, 79.2, 79.4, 80.3, 127.0, 127.1,
H, Ph), 9.80 (br., 1 H, OH) ppm. 13C NMR (75 MHz, CDCl3): δ 127.3, 128.0, 138.8, 150.0, 168.7 ppm. IR (ATR): ν = 3648–3837
˜
= 28.2, 29.8, 52.4, 59.5, 65.8, 69, 9, 73.5, 73.6, 80.3, 83.4, 99.7, (m), 1759 (s, ester), 1699 (s, urethane), 1649 (s, C-2), 1521 (s, aro-
127.6, 127.7, 127.9, 128.1, 128.5, 137.5, 149.8, 155.8, 163.2, 167.5,
matics), 1458, 1354 (s, CO2Me), 1253 (s, tBu) cm–1. HRMS: calcd.
173.9, 185.9 ppm. IR (ATR): ν = 3648–3837 (m), 1753 (s, ester),
for C20H26NO7 392.1704; found 392.1697.
˜
1699 (s, urethane), 1649 (s, C-2), 1521 (s, aromatics), 1460, 1354 (s,
CO2Me), 1253 (s, tBu) cm–1. HRMS: calcd. for C19H24NO7
378.1547; found 378.1532.
(S)-N-tert-Butoxycarbonyl-5-[(R)-1-(benzyloxy)ethyl]-3-ethoxy-
carbonyltetramic Acid (2f): White solid; yield 76 mg, 80 %; m.p.
182–184 °C. [α]2D0 = +13.1 (c = 0.8, CHCl3). Rf = 0.44 (DCM/
MeOH, 95:5). 1H NMR (300 MHz, CDCl3): δ = 1.27 (d, J =
6.3 Hz, 3 H, CH3CH), 1.28 (t, J = 7.2 Hz, 3 H, CO2CH2CH3), 1.46
(s, 9 H, 3 CH3), 4.21 (q, J = 7.2 Hz, 2 H, CO2CH2CH3), 4.37 (br.
d, J = 8.7 Hz, 1 H, CH3CHCH), 4.52 (dd, J = 11.7, 42.6 Hz, 2 H,
CH2Ph), 5.33 (br. d, J = 8.7 Hz, 1 H, CH3CHCH), 7.27-7.31 (m,
5 H, Ph) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.1, 16.2, 28.4,
(S)-N-tert-Butoxycarbonyl-5-benzyloxymethyl-3-ethoxycarbonyl-
tetramic Acid (2b): White solid; yield 90 mg, 98%; m.p. 114–116 °C.
[α]2D0 = +24.1 (c = 1.1, CHCl3). Rf = 0.54 (DCM/MeOH, 95:5). H
1
NMR (300 MHz, CDCl3 ): δ = 1.22 (t, J = 6.9 Hz, 3 H,
CO2CH2CH3), 1.29 (s, 2.25 H, 3 CH3), 1.35 (s, 6.75 H, 3 CH3),
3.56 (dd, J = 3.0, 9.6 Hz, 0.25 H, CH2CH), 3.74 (dd, J = 1.8,
10.2 Hz, 1 H, CH2CH), 3.92 (dd, J = 3.0, 9.6 Hz, 0.75 H, CH2CH), 34.7, 58.0, 61.7, 71.4, 74.5, 80.4, 127.9, 128.1, 128.6, 137.6, 153.9,
4.23 (q, J = 6.9 Hz, 2 H, CO2CH2CH3), 4.34 (s, 2.5 H, CH2Ph,
CHCH2), 4.38 (s, 0.5 H, CH2Ph), 7.06–7.20 (m, 5 H, Ph), 7.80 (br.,
156.3, 166.8, 175.1 ppm. IR (ATR): ν = 3648–3847 (m), 1747 (s,
ester), 1699 (s, urethane), 1649 (s, C-2), 1602 (s, aromatics), 1452,
˜
Eur. J. Org. Chem. 2010, 5989–5995
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5993

D. Matiadis, O. Igglessi-Markopoulou
FULL PAPER
1363 (s, CO2Et), 1219 (s, tBu) cm–1. HRMS: calcd. for C21H28NO7
1366 (s, CO2Et), 1228 (s, tBu) cm–1. HRMS: calcd. for C19H24NO7
406.1860; found 406.1854.
378.1547; found 378.1546.
Typical Procedure for the Synthesis of Compounds 3a–f: To a solu-
tion of 2 (0.25 mmol) in dry THF (15 mL) was carefully added
10% Pd/C (210 mg, 0.20 mmol). The reaction mixture was placed
under a H2 atmosphere (doubled balloon) and stirred for 1 h. The
reaction was monitored by TLC (DCM/MeOH, 90:10–95:5). The
reaction mixture was then filtered through Celite 545, and washed
with THF (3ϫ), and the filtrate was evaporated in vacuo at room
temperature to give Boc-tetramic acid 3c. For analytical purposes,
the crude product was purified by column chromatography (DCM/
MeOH/AcOH, 95:5:1).
(S)-N-tert-Butoxycarbonyl-5-[(R)-1-hydroxyethyl]-3-methoxy-
carbonyltetramic Acid (3e): White solid; yield 65 mg, 86%; m.p. Ͼ
200 °C (dec.). [α]2D0 = +5.6 (c = 0.8, MeOH). Rf = 0.35 before col-
umn chromatography, 0.31 after column chromatography (DCM/
MeOH/AcOEt, 95:5:1). 1H NMR (300 MHz, [D6]DMSO): δ = 0.93
(br., 3 H, CH3CH), 1.43 (s, 9 H, 3 CH3), 3.55 (s, 3 H, CO2CH3),
3.84 [br., 1 H, CHCH(CH3)OH], 4.12 [br., 1 H, CHCH(CH3)OH],
5.00 (br., 1 H, OH) ppm. 13C NMR (75 MHz, [D6]DMSO): δ =
18.1, 27.8, 49.6, 63.4, 66.4, 80.8, 91.1, 150.0, 165.5, 190.9,
207.2 ppm. IR (ATR): ν = 3648–3847 (m), 2948 (br., OH), 1755 (s,
˜
ester), 1694 (s, urethane), 1646 (s, C-2), 1442, 1361 (s, CO2Me),
1219 (s, tBu) cm–1. HRMS: calcd. for C13H20NO7 302.1234; found
302.1248.
(S)-N-tert-Butoxycarbonyl-5-hydroxymethyl-3-methoxycarbonyl-
tetramic Acid (3a): White solid; yield 71 mg, 99%; m.p. Ͼ300 °C.
[α]2D0 = –4.7 (c = 0.55, MeOH). Rf = 0.29 before column chromatog-
raphy, 0.14 after column chromatography (DCM/MeOH/AcOH,
90:10:1). 1H NMR (300 MHz, [D6]DMSO): δ = 1.44 (s, 3 H, 3
CH3), 3.57 (s, 3 H, CO2CH3), 3.75 (br., 3 H, CHCH2) ppm. 13C
NMR (75 MHz, [D6]DMSO): δ = 27.9, 50.1, 59.4, 63.9, 79.0, 83.6,
(S)-N-tert-Butoxycarbonyl-3-ethoxycarbonyl-5-[(R)-1-hydroxy-
ethyl]tetramic Acid (3f): White solid; yield 65 mg, 82%; m.p. Ͼ
250 °C. [α]2D0 = +7.3 (c = 0.4, MeOH). Rf = 0.56 (DCM/MeOH/
1
AcOEt, 95:5:1). H NMR (300 MHz, [D6]DMSO): δ = 0.92 (d, J
145.3, 169.4, 191.1, 211.6 ppm. IR (ATR): ν = 3648–3847 (m), 2996
˜
= 6.3 Hz, 3 H, CH3CH), 1.16 (t, J = 6.9 Hz, 3 H, CO2CH2CH3),
1.43 (s, 9 H, 3 CH3), 4.01 (q, J = 6.9 Hz, 2 H, CO2CH2CH3), 3.77
[d, 1 H, CHCH(CH3)OH], 4.13 [br., 1 H, CHCH(CH3)OH], 5.04
(br., 1 H, OH) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 14.4,
18.1, 27.9, 57.9, 64.0, 66.7, 79.9, 86.2, 149.8, 167.7, 191.0,
(br., OH), 1744 (s, ester), 1699 (s, urethane), 1647 (s, C-2), 1442,
1361 (s, CO2Me), 1220 (s, tBu) cm–1. HPLC (n-hexane/ethanol/
TFA, 70:30:0.1; flow rate: 0.60 mL/min; 254 nm): tR = 6.32 (97.5%;
S, major enantiomer), 6.90 min (2.5 %; R, minor enantiomer).
HRMS: calcd. for C12H18NO7 288.1078; found 288.1094.
207.4 ppm. IR (ATR): ν = 3648–3847 (m), 2956 (br., OH), 1749 (s,
˜
ester), 1699 (s, urethane), 1647 (s, C-2), 1442, 1361 (s, CO2Et), 1223
(s, tBu) cm–1. HRMS: calcd. for C14H22NO7 316.1391; found
364.1407.
(S)-N-tert-Butoxycarbonyl-3-ethoxycarbonyl-5-hydroxymethyl-
tetramic Acid (3b): White solid; yield 69 mg, 92%; m.p. 122–125 °C.
[α]2D0 = +1.3 (c = 0.3, MeOH). Rf = 0.15 (AcOEt/MeOH, 90:10).
1 H NM R (3 0 0 M H z, [ D 6 ]DMSO ): δ = 1 . 1 7 ( b r. , 3 H ,
CO2CH2CH3), 1.38, 1.44 (s, 9 H, 3 CH3), 3.60 (CH2OH), 3.75
(CHCH2), 4.06 (br., 2 H, CO2CH2CH3), 6.30 (OH) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 14.6, 28.2, 57.7, 62.1, 63.7, 77.8, 84.0,
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra of compounds 1–3b, 1–3c, and 1–
3e.
146.1, 168.9, 192.1 ppm. IR (ATR): ν = 3648–3843 (m), 2966 (br.,
˜
Acknowledgments
OH), 1751 (s, ester), 1690 (s, urethane), 1647 (s, C-2), 1442, 1348
(s, CO2Et), 1220 (s, tBu) cm–1. HRMS: calcd. for C13H20NO7
302.1234; found 302.1256.
D.M. gratefully acknowledges the Committee of Research of the
National Technical University of Athens for a doctoral assis-
tantship.
(S)-N-tert-Butoxycarbonyl-5-(4-hydroxybenzyl)-3-methoxy-
carbonyltetramic Acid (3c): White solid; yield 87 mg, 96%; m.p.
230 °C (dec.). [α]2D0 = –28.4 (c = 0.3, EtOH). Rf = 0.69 before col-
umn chromatography, 0.26 after column chromatography (DCM/
MeOH/AcOH, 9:1:0.05). 1H NMR (300 MHz, [D6]DMSO): δ =
1.47 (s, 3 H, 3 CH3), 3.03 (pseudoq, 2 H, CH2CH), 3.51 (s, 3 H,
CO2CH3), 3.95 (s, 1 H, C-5), 6.54 (d, J = 8.1 Hz, 2 H, Ar), 6.79
(d, J = 8.1 Hz, 2 H, Ar), 9.10 (br., 1 H, ArOH) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 27.9, 34.2, 49.7, 62.1, 80.5, 91.0, 114.7,
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125.8, 130.5, 149.9, 155.7, 166.2, 190.6, 204.0 ppm. IR (ATR): ν =
˜
3648–3847 (m), 2956 (br., OH), 1744 (s, ester), 1679 (s, urethane),
1645 (s, C-2), 1564 (s, aromatics), 1442, 1356 (s, CO2Me), 1223 (s,
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(S)-N-tert-Butoxycarbonyl-3-ethoxycarbonyl-5-(4-hydroxybenzyl)-
tetramic Acid (3d): White solid; yield 89 mg, 94%; m.p. Ͼ 250 °C
(dec.). [α]2D0 = –16.1 (c = 0.5, MeOH). Rf = 0.64 before column
chromatography, 0.18 after column chromatography (AcOEt/
MeOH, 95:5). 1H NMR (300 MHz, [D6]DMSO): δ = 1.13 (br., 3
H, CO2CH2CH3); 1.46 (s, 9 H, 3 CH3); 3.01 (br. dd, 2 H, CH2CH),
3.92 (s, 1 H, C-5), 4.01 (br., 2 H, CO2CH2CH3), 6.53 (pseudod, 2
H, Ar), 6.78 (pseudod, 2 H, Ar), 9.10 (s, 1 H, ArOH) ppm. 13C
NMR (75 MHz,[D6]DMSO): δ = 14.6, 27.9, 34.3, 57.7, 62.0, 80.2,
91.0, 114.6, 126.1, 127.5, 127.8, 130.5, 150.0, 155.6, 165.7,
190.5 ppm. IR (ATR): ν = 3648–3844 (m), 2972 (br., OH), 1752 (s,
˜
ester), 1687 (s, urethane), 1647 (s, C-2), 1566 (s, aromatics), 1444,
5994
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5989–5995

Design and Synthesis of Optically Active Esters of γ-Amino-β-oxo Acids
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Received: May 17, 2010
Published Online: September 10, 2010
Eur. J. Org. Chem. 2010, 5989–5995
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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