Hexafluoroacetone as protecting and activating reagent: An efficient strategy for activation of pyroglutamic acid and homologues

Article abstract of DOI:10.3987/com-03-s34

Hexafluoroacetone-protected glutamic acid on treatment with thionyl chloride is transformed into a carboxy-activated pyroglutamic acid derivative. Likewise, the reaction sequence can be applied to aminoadipic acid and homologues.

Full text of DOI:10.3987/com-03-s34

HETEROCYCLES, Vol. 61, 2003
259
HETEROCYCLES, Vol. 61, 2003, pp. 259 - 269
Received, 26th June, 2003, Accepted, 1st August, 2003, Published online, 4th August, 2003
HEXAFLUOROACETONE AS PROTECTING AND
ACTIVATING REAGENT: AN EFFICIENT STRATE-
GY FOR ACTIVATION OF PYROGLUTAMIC ACID
AND HOMOLOGUES
Ksenia Pumpor, Christoph Böttcher, Susanna Fehn, and Klaus Burger*
Department of Organic Chemistry, University of Leipzig, Johannisallee 29, D-04103 Leipzig,
Germany
Abstract - Hexafluoroacetone-protected glutamic acid on treatment with thionyl chloride is
transformed into a carboxy-activated pyroglutamic acid derivative. Likewise, the reaction
sequence can be applied to aminoadipic acid and homologues.
INTRODUCTION
Pyroglutamic acid and its derivatives are important amino acids, since they are constituents of many
bioactive compounds like azaprostaglandin analogues,1 monocyclic thienyl-γ-lactam2 and thioliberin
(TRH).3 Pyroglutamic acid and substituted pyroglutamic acid derivatives are interesting targets as they
confer unique structural constraints in peptide chains4 and hence may play a major role in protein folding.
Furthermore, glutamic acid which can be derived from pyroglutamic acid acts as one of the major
neurotransmitters at excitatory synapses in the mammalian central nervous system (CNS).5
Substituted 2-pyrrolidinones are an important class of nitrogen-containing heterocycles.6 They exhibit a
variety of biological activities,7 i.a. they have been applied for treatment of brain and cognitive
problems,8 as anticonvulsant agents,9 and as inhibitors for HIV-1 replication.10
Furthermore, they have been used as intermediates in the synthesis of alkaloids,11 α-amino12 and γ-
amino acids.13 Therefore, the development of new methodology for incorporation of pyroglutamic
___________________
* Corresponding author. Tel. + 49 (0)341 9736529; fax + 49 (0)341 9736599; e-mail: burger@organik.chemie.
uni-leipzig.de
** Dedicated to Prof. J. Sieler on the occasion of his 65th birthday.

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HETEROCYCLES, Vol. 61, 2003
acid into target molecules is of current interest, especially when the reaction sequence is suitable for
generation of combinatorial libraries.
RESULTS AND DISCUSSION
Hexafluoroacetone (HFA) (2 equivalents) reacts readily with (S)- and (R)-glutamic acids in DMSO at
room temperature to give 2,2-bis(trifluoromethyl)-1,3-oxazolidin-5-one (2).14,15 The second equivalent of
19
hexafluoroacetone is necessary to trap the water which is eliminated during lactone formation. F NMR
spectral control of the reaction indicates that the five-membered lactone is formed quantitatively, but
there is some loss during work-up, because of the water solubility of 2. Hexafluoroacetone hydrate is
formed as the only by-product. With the formation of the five-membered heterocyclic ring system, amino
group protection and selective activation of the α-carboxy group are achieved in one step. The ω-carboxy
group remains unaffected and can be derivatized regioselectively after separate activation.16
H
H
O
O
HO2C
HO2C
CO2H
(CF3)2CO
SOCl2
HN
O
N
O
H2N H
O
F3C CF3
F3C CF3
1
2
3
Scheme 1
There exist two fundamentally different strategies for the incorporation of the pGlu moiety into peptides:
Incorporation of Glu into the peptide chain and construction of the 2-pyr-
rolidinone ring in a consecutive step,17 or incorporation of the complete pGlu moiety. When we tried to
activate the ω-carboxy group of HFA-protected Glu selectively on treatment with thionyl chloride we
obtained the HFA-protected pGlu (3) in almost quantitative yield. The presence of a lactone as well as a
lactam function can be identified by IR absorptions at ν = 1855 and 1755 cm-1, respectively. The two
diastereotopic trifluoromethyl groups bound to the C-(2) atom of the oxazolidin-5-one ring resonate at δ =
19
-1.99 (q, J = 8.3 Hz, 3F) and 5.76 (q, J = 8.3 Hz, 3F) ppm in the F NMR spectrum. 3 is a crystalline
compound, easy to handle. It can be stored without decomposition in a fridge for months on exclusion of
water.
Compound (3) represents an activated ester and reacts readily with nucleophiles like water, alcohols and
amines to give the corresponding acid, esters and amides in very good yields (56-90%), respectively.

HETEROCYCLES, Vol. 61, 2003
261
O
H
NH2
R1
NH
O
H
H
O
OR2
O
H
N
5
COOH
NH
H
H
R1
NH
O
NH3
R2O2C
NH2
H2O
6 a-e
O
4
3
H CO2CH2C6H5
CO2CH2Ph
O
H
N
H
H
H2NNHCO2CH3
N
O
H
N
H
NH
CH
3
OCH3
HN
CO2CH 3
N
H
O
7
NH
O
O
H
O
OCH3
O
9
N
NH
CH3
O
8
R1
R2
6a
6b
6c
6d
6e
CH3
CH(CH3)2
CH2C6H5
C2H5
CH3
CH3
CH3
C2H5
p-HOC6H4CH2
CH2CO2C2H5
Scheme 2
Dipeptides and dipeptide surrogates are obtainable in high yields on reaction with amino acid esters, N-
alkylamino acid esters and N-protected amino acid hydrazides, respectively. Dipeptide (8) formed on
reaction of 3 with sarcosine methyl ester exists in solution (CDCl3) at room temperature as a mixture of
rotamers (ratio 5:1).
H
O
H
O
HO2C
CO2H
HO2C
(CF3)2CO
SOCl2
HN
O
N
O
H2N H
10
O
F3C CF3
F3C CF3
11
12
Scheme 3

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HETEROCYCLES, Vol. 61, 2003
α-Aminoadipic acid (10) and hexafluoroacetone react analogously to give a 2,2-bis(trifluoromethyl)-1,3-
oxazolidin-5-one (11). On treatment with thionyl chloride 11 is converted into an acid chloride which
spontaneously undergoes ring closure to give a bicyclic six-membered lactam (12). The chemistry of 11
and 12 parallels that of 2 and 3. Best yields are obtained, when appropriate solvents are used where the
products crystallize spontaneously. In general the products are analytically pure after careful trituration
with dry diethyl ether.
H
CO2CH3
O
H
O
H
CH2C6H5
OCH2C6H5
H
N
CO2CH3
H
N
NH
H
N
H
NH
O
O
H
14
CH2Ph
NH2
O
13
PhCH2O2C
12
CH
3
HN
CO2CH 3
H2NNHCO2CH2Ph
O
H
OCH3
O
H
N
N
H
OCH2C6H5
NH CH3
O
N
H
NH
O
O
15
O
16
Scheme 4
EXPERIMENTAL
Melting points were determined on a Boetius heating table. IR spectra were obtained with a FTIR
1
spectrometer (Genesis ATI Mattson/Unicam). H NMR spectra were recorded with VARIAN Gemini
2000 spectrometers at 200 and 300 MHz. Chemical shifts were reported in ppm relative to
13
tetramethylsilane (TMS, δ = 0 ppm); J values are given in Hertz (Hz). C NMR spectroscopy was
performed at 50 and 75 MHz. 19F NMR spectra were recorded at 188 and 282 Hz with trifluoroacetic acid
(TFA, δ = 0 ppm) as external standard. Optical rotations ([α]D) were measured using a Polarotronic
polarometer (Schmidt & Haensch) in a 5 cm cell. For C, H, N analyses a CHNO-Rapid-Elemental-
Analyzer (Heraeus) was used. For flash chromatography, silica gel (32-63 µm) was used with solvent
systems given in the text. Organic solvents were dried and distilled prior to use.

HETEROCYCLES, Vol. 61, 2003
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(S)-[2,2-Bis(trifluoromethyl)-5-oxo-1,3-oxazolidin-4-yl]propionic acid (2). (S)-Glutamic acid (1)
(14.71 g, 100 mmol) was reacted for 6-8 h in DMSO (50 mL) with an excess of hexafluoroacetone at rt in
a glass apparatus sealed with a dry-ice condenser. When the reaction was complete, water (500 mL) was
added and the reaction mixture was extracted with CH2Cl2 (4 x 50 mL). The organic phase was extracted
with water (3 x 50 mL), dried with MgSO4 and evaporated to dryness. Yield 19.78 g (67%), mp 117 - 118
1
oC (CH2Cl2), [α]D = +6.4° (c = 1.1, DMSO). IR (KBr) ν 3355, 1810, 1700 cm-1. H NMR (acetone-d6) δ
13
1.91 (1H, m), 2.17 (1H, m), 2.46 - 2.61 (2H, m), 4.30 (1H, m), 5.31 (1H, d, J = 6.5 Hz). C NMR
(acetone-d6) δ 29.0, 29.6, 54.3, 89.3 (qq, J = 34.0 Hz, J = 34.0 Hz), 121.5 (q, J = 285.0 Hz), 122.4 (q, J =
288.0 Hz), 172.3, 174.0. 19F NMR (acetone-d6) δ -2.02 (3F, q, J = 9.0 Hz), -2.96 (3F, q, J = 9.0 Hz). MS
m/z = 295 [M]+, 277 [M - H2O]+, 249 [M - H2O, - CO]+, 235 [M - H2O, - CO, - CH2]+, 180 [M - H2O, -
CO, - CF3]+, 166 [M - H2O, - CO, - CH2, - CF3]+, 152 [M - H2O, - CO, - CH2, - CF3, - CH2]+, 136 [M -
H2O, - CO, - CF3, - CO2]+, 85 [CH2CH2CHCO2]+, 69 [CF3]+. Anal. Calcd for C8H7NO4F6: C, 32.56; H,
2.39; N, 4.75. Found: C, 32.64; H, 2.54; N, 4.78.
(5S)-2,2-Bis(trifluoromethyl)-1-aza-3-oxabicyclo[3.3.0]octan-4,8-dione (3). To a solution of (4S)-3-
[2,2-bis(trifluoromethyl)-5-oxo-1,3-oxazolidin-4-yl]propionate (2) (10.44 g, 35.4 mmol) in CH2Cl2 (100
o
mL) four drops of dimethyl formamide were added. After cooling to 0 C to the stirred reaction mixture
thionyl chloride (5.95 g, 50 mmol) was added dropwise. Stirring was continued at rt for 16 - 24 h. The
progress of the reaction was monitored by 19F NMR spectroscopy. Then the excess of the thionyl chloride
and of the solvent was evaporated in vacuo, the remaining solid was recrystallized from hexane. Yield
o
9.66 g (99%), mp 85 - 86 C (hexane), [α]D = +24.0° (c = 1.0, CHCl3). IR (KBr) ν 1855, 1755 cm-1. 1H
NMR (CDCl3) δ 2.28 (1H, m), 2.60 - 2.72 (2H, m), 2.87 (1H, ddd, J = 17.2 Hz, J = 12.9 Hz, J = 8.3 Hz),
13
4.68 (1H, dd, J = 10.1 Hz, J = 7.3 Hz). C NMR (CDCl3) δ 24.9, 34.2, 57.7, 88.0 (qq, J = 36.0 Hz, J =
36.0 Hz), 118.8 (q, J = 289.0 Hz), 120.0 (q, J = 288.0 Hz), 166.5, 172.1. 19F NMR (CDCl3) δ -1.99 (3F, q,
J = 8.3 Hz), 5.76 (3F, q, J = 8.3 Hz). MS m/z = 277 [M]+, 233 [M - CO2]+, 208 [M - CF3]+, 180 [M - CO,
- CF3]+, 152 [M - CO, - CF3, - CO]+, 83 [M - CO, - (CF3)2CO]+, 69 [CF3]+, 55 [M - CO, - (CF3)2CO, -
CO]+. Anal. Calcd for C8H5NO3F6: C, 34.67; H, 1.81; N, 5.05. Found: C, 34.74; H, 1.94; N, 5.10.
(S)-2-Pyrrolidinone-5-carboxylate (4). A solution of 3 (2.77 g, 10 mmol) in 2-propanol/ water (40 mL,
1:1) was stirred at rt until the starting material was consumed (19F NMR analysis). The solvent was
evaporated in vacuo, then the crystalline residue was carefully triturated with dry ether and filtered off.
Yield 1.12 g (87%), mp 158 - 159 oC (ether) (lit.,18 mp 155-157 oC), [α]D = -15.0° (c = 1.0, H2O), [α]D =
1
-12.5° (c = 2.0, H2O) (lit.,19 [α]D = -10.1° (c = 5.0, H2O)). IR (KBr) ν 3410, 1725, 1650, 1235 cm-1. H

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NMR (DMSO-d6) δ 1.97 (1H, m), 2.06 - 2.21 (2H, m), 2.33 (1H, m), 4.67 (1H, dd, J = 8.9 Hz, J = 4.3
Hz), 7.93 (1H, s, NH). 13C NMR (DMSO-d6) δ 24.7, 29.2, 54.9, 174.6, 177.3. MS m/z = 129 [M]+, 84 [M
- COOH]+, 56 [M - COOH, - CO]+, 41 [M - COOH, - CO, - NH]. Anal. Calcd for C5H7NO3: C, 46.51: H,
5.46; N, 10.85. Found: C, 46.10; H, 5.76; N, 10.78.
(S)-2-Pyrrolidinone-5-carboxamide (5). A solution of 3 (2.77 g, 10 mmol) in 2-propanol (20 mL) was
stirred for 6 d with conc. ammonia (20 mL) at rt until the starting material was consumed (19F NMR
analysis). After evaporation of the solvent in vacuo, the residue was triturated with ethyl acetate and then
recrystallized from methanol. Yield 0.76 g (59%), mp 148 - 150 oC (methanol) (lit.,20 mp 168 oC), [α]D =
-42.5° (c = 1.0, H2O). IR (KBr) ν 3460, 3400, 3210, 1700 - 1665, 1650 cm-1. 1H NMR (DMSO-d6) δ 1.85
(1H, m), 2.01 - 2.29 (3H, m), 3.93 (1H, dd, J = 8.2 Hz, J = 4.5 Hz), 7.07 (1H, s, NH), 7.41 (1H, s, NH),
13
7.77 (1H, s, NH). C NMR (DMSO-d6) δ 25.4, 29.4, 55.7, 174.7, 177.7. MS m/z = 128 [M]+, 84 [M -
CONH2]+, 56 [M - CONH2, - CO]+. Anal. Calcd for C5H8N2O2: C, 46.87; H, 6.29; N, 21.86. Found: C,
46.56; H, 5.89; N, 21.72.
Pyroglutamyldipeptides (6), general procedure. To a stirred solution of 3 in ether (or ethyl acetate)
1 - 1.5 equivalents of the corresponding C-terminal protected amino acid was added. The progress of the
19
reaction is controlled by F NMR spectroscopy. Crystalline products were filtered off and carefully
triturated with dry ether and afterwards dried in vacuo. If the dipeptide does not crystallize from the crude
reaction mixture, the solvent is evaporated in vacuo. The crude products are purified by reversed phase
chromatography.
(S)-Pyroglutamyl-(S)-alanine ethyl ester (6a). 3 (1.00 g, 3.6 mmol) was reacted for 24 h with
(S)-alanine ethyl ester (0.70 g, 6.0 mmol) in ether (20 mL). Yield 0.72 g (88%), mp 113 oC (ether), [α]D
= -76.0° (c = 2.0, H2O). IR (KBr) ν 3310, 1740, 1700, 1670, 1545 cm-1. 1H NMR (CDCl3) δ 1.28 (3H, t, J
= 7.2 Hz), 1.42 (3H, d, J = 7.3 Hz), 2.13 - 2.62 (4H, m), 4.19 (2H, q, J = 7.2 Hz), 4.21 (1H, m), 4.60 (1H,
dq, J = 7.5 Hz, J = 7.3 Hz), 7.45 (1H, br s, NH), 7.56 (1H, d, J = 7.7 Hz, NH). 13C NMR (CDCl3) δ 14.1,
17.9, 25.7, 29.4, 48.0, 57.4, 61.7, 172.3, 173.4, 179.7. MS m/z = 228 [M]+, 183 [M - OC2H5]+, 155 [M -
OCOC2H5]+, 84 [C4H6NO]+; Anal. Calcd for C10H16N2O4: C, 52.62; H, 7.07; N, 12.27 Found: C, 52.38;
H, 7.07; N, 12.25.
(S)-Pyroglutamyl-(S)-valine methyl ester (6b). To a solution of (S)-valine methyl ester (1.27 g, 9.7
mmol) in ethyl acetate (30 mL) a solution of 3 (2.69 g, 9.7 mmol) in ethyl acetate (10 mL) was added.

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The reaction mixture was stirred for 3 d. 6b was purified by reversed phase chromatography (eluent:
water/methanol, 3:1). Yield 1.56 g (66%), mp 99 - 100 oC (water/methanol), [α]D = -45.5° (c = 2.0, H2O).
IR (KBr) ν 3500 - 2900, 1740, 1700 - 1650 cm-1. 1H NMR (CDCl3) δ 0.94 (3H, d, J = 7.0 Hz), 0.95 (3H,
d, J = 7.0 Hz), 2.14 - 2.55 (5H, m), 3.73 (3H, s), 4.29 (1H, dd, J = 8.6 Hz, J = 5.3 Hz), 4.53 (1H, dd, J =
8.8 Hz, J = 5.9 Hz), 7.55 (1H, d, J = 8.8 Hz, NH), 7.66 (1H, s, NH). 13C NMR (CDCl3) δ 17.9, 18.8, 25.5,
29.3, 30.8, 52.0, 57.1, 57.2, 172.6, 172.7, 179.5. MS m/z = 242 [M]+, 211 [M - OCH3]+, 183 [M -
COOCH3]+, 85 [C4H7NO]+, 84 [C4H6NO]+. Anal. Calcd for C11H18N2O4: C, 54.53; H, 7.49; N, 11.56.
Found: C, 54.72; H, 7.40; N, 11.48.
(S)-Pyroglutamyl-(S)-phenylalanine methyl ester (6c). 3 (1.0 g, 3.6 mmol) and (S)-phenylalanine
o
methyl ester (1.12 g, 6.2 mmol) were reacted for 3 d in ether (30 mL). Yield 0.80 g (77%), mp 74 C
(ether), [α]D = -31.0° (c = 2.0, H2O). IR (CHCl3) ν 3340, 1732, 1711, 1658 cm-1. 1H NMR (CDCl3) δ 1.76
- 1.79 (1H, m), 2.16 - 2.34 (3H, m), 3.01 (1H, dd, J = 13.8 Hz, J = 9.1 Hz), 3.28 (1H, dd, J = 13.8 Hz, J =
5.2 Hz), 3.73 (3H, s), 4.08 (1H, m), 4.93 (1H, ddd, J = 9.1 Hz, J = 8.6 Hz, J = 5.2 Hz), 7.18 -7.30 (6H,
13
m), 7.51 (1H, J = 8.6 Hz, NH). C NMR (CDCl3) δ 25.6, 29.0, 37.6, 52.6, 53.0, 57.2, 127.1, 128.5,
129.2, 136.2, 172.6, 172.7, 179.9. MS m/z = 290 [M]+, 246 [M - CO2]+, 162 [M - CO2, - C4H6NO]+, 84
[C4H6NO]+. Anal. Calcd for C15H18N2O4: C, 62.06; H, 6.25; N, 9.65: Found: C, 61.79; H, 6.33; N, 9.42.
(S)-Pyroglutamyl-(S)-tyrosine methyl ester (6d). 3 (0.83 g, 3.0 mmol) and (S)-tyrosine methyl ester
(0.59 g, 3.0 mmol) were reacted for 3 d in ether (30 mL).Yield 0.59 g (64%), mp 236 oC (ether), [α]D = -
1
27.0° (c = 1, H2O). IR (KBr) ν 3600 - 2900, 1725, 1710, 1640, 1520 cm-1. H NMR (DMSO-d6) δ 1.77
(1H, m), 2.01 - 2.08 (2H, m), 2.21 (1H, m), 2.81 (1H, dd, J = 13.8 Hz, J = 9.1 Hz), 2.92 (1H, dd, J = 13.8
Hz, J = 5.5 Hz), 3.59 (3H, s), 3.99 (1H, dd, J = 8.8 Hz, J = 3.8 Hz), 4.40 (1H, m), 6.65 (2H, m), 6.99 (2H,
13
m), 7.75 (1H, s, NH), 8.31 (1H, d, J = 7.8 Hz), 9.23 (1H, br s, NH). C NMR (DMSO-d6) δ 25.3, 29.0,
35.8, 51.9, 53.9, 55.3, 115.1, 127.2, 130.1, 156.1, 172.0, 172.8, 177.6. MS m/z = 306 [M]+, 247 [M -
COOCH3]+, 178 [HOC6H4CHCHCOOCH3]+, 84 [C6H4NO]+. Anal. Calcd for C15H18N2O5 x H2O: C,
55.55; H, 6.22; N, 8.64. Found: C, 55.71; H, 5.99; N, 8.30.
(S)-Pyroglutamyl-(S)-aspartic acid diethyl ester (6e). 3 (1.0 g, 3.6 mmol) and aspartic acid diethyl ester
o
(1.05 g, 5.5 mmol) were reacted for 48 h in ether (20 mL). Yield 0.77 g (71%), mp 74 - 75 C (ether),
[α]D = -35.0° (c = 1.0, H2O). IR (KBr) ν 3320, 2990, 1750 - 1650 cm-1. 1H NMR (CDCl3) δ 1.25 (3H, t, J
= 7.1 Hz), 1.27 (3H, t, J = 7.2 Hz), 2.15 - 2.55 (4H, m), 2.88 (1H, dd, J = 16.8 Hz, J = 4.8 Hz), 2.99 (1H,
dd, J = 16.8 Hz, J = 5.7 Hz), 4.14 (2H, q, J = 7.1 Hz), 4.17 - 4.23 (3H, m), 4.85 - 4.89 (1H, m), 7.14 (1H,

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13
br s), 7.45 (1H, d, J = 8.2 Hz). C NMR (CDCl3) δ 13.9, 14.0, 25.7, 29.2, 36.1, 48.7, 56.9, 61.1, 61.9,
170.6, 170.7, 172.3, 179.3. MS m/z = 300 [M]+, 255 [M - OC2H5]+, 227 [M - OC2H5, - CO]+, 84
[CH2CONHCHCH2]+. Anal. Calcd for C13H20N2O6: C, 51.99; H, 6.71; N, 9.33. Found: C, 51.96; H, 6.74;
N, 9.38.
(S)-Pyroglutamyl-(S)-proline benzyl ester (7). 3 (1.39 g, 5 mmol) and (S)-proline benzyl ester (1.44 g,
o
7.5 mmol) were stirred for 30 min in dry ether (25 mL). Yield 0.89 g (56%), mp 76 C (ether), [α]D =
-131.5° (c = 2, H2O). IR (KBr) ν 3470, 1735, 1675, 1645, 1440 cm1. 1H NMR (CDCl3) δ 1.97 - 2.38 (8H,
m), 3.54 - 3.59 (2H, m), 4.39 (1H, dd, J = 8.6 Hz, J = 5.0 Hz), 4.58 (1H, dd, J = 8.4 Hz, J = 3.7 Hz), 5.07
13
(1H, d, J = 12.3 Hz), 5.20 (1H, d, J = 12.3 Hz), 7.01 (1H, br s, NH), 7.24 - 7.38 (5H, m). C NMR
(CDCl3) δ 24.4, 24.9, 28.6, 29.2, 46.2, 54.8, 59.2, 67.0, 128.2, 128.5, 128.6, 135.5, 170.7, 171.7, 179.0.
MS m/z = 316 [M]+, 209 [M - OCH2C6H5]+, 208 [M - HOCH2C6H5]+, 180 [M - COOCH2C6H5]+, 108
[C6H5CH2OH]+, 107 [C6H5CH2O]+, 91 [C7H7]+, 84 [CH2CONHCHCH2]+, 77 [C6H5]+. Anal. Calcd for
C17H20N2O4 x H2O: C, 61.06; H, 6.63; N, 8.38. Found: C, 60.76; H, 6.75; N, 8.17.
(S)-Pyroglutamylsarcosine methyl ester (8). A solution of 3 (1.52 g, 5.5 mmol) in acetonitrile (40 mL)
was treated for 24 h with sarcosine methyl ester (0.68 g, 6.6 mmol). Compound (8) was purified by flash
chromatography (eluent: methanol/ether, 1:2). Yield 0.99 g (84%), colorless oil; mixture of rotamers,
1
ratio 5:1, [α]D = -21.8° (c = 1.1, CHCl3). IR (KBr) ν 3475 - 3075, 2950, 1745, 1650 cm-1. H NMR
(CDCl3) δ 1.96 - 2.02 (1H, m), 2.14 - 2.21 (2H, m), 2.29 - 2.34 (1H, m), 2.94 / 2.80 (3H, s), 3.55 / 3.61
(3H, s), 3.76 (1H, d, J = 17.2 Hz), 4.15 (1H, d, J = 17.2 Hz), 4.46 (1H, dd, J = 8.0 Hz, J = 4.8 Hz), 6.99 /
6.96 (1H, s, NH). 13C NMR (CDCl3) δ 24.3 / 24.6, 29.0 / 29.2, 35.6 / 35.0, 49.4 / 50.3, 51.9 / 52.4, 53.5 /
53.2, 169.3, 172.3, 178.3. MS m/z = 214 [M]+, 182 [M - CH3OH]+, 142 [C6H10N2O2]+, 84 [C4H6NO]+, 69
[C4H5O]+, 59 [CO2CH3]+, 44 [CONH2]+. Anal. Calcd for C9H14N2O4: C, 50.46; H, 6.59; N, 13.08. Found:
C, 50.43; H, 6.65; N, 13.02.
(S)-Pyroglutamylazaglycine methyl ester (9). 3 (2.77 g, 10 mmol) were treated for 3 h with
methoxycarbonylhydrazine (0.90 g, 10 mmol) in ethyl acetate (50 mL). Yield 1.47 g (73%), mp 148 -
o
149 C (AcOEt), [α]D = -12.0° (c = 1.0, H2O). IR (KBr) ν 3500 - 3100, 1760, 1730 - 1650, 1525, 1255
cm-1. 1H NMR (DMSO-d6) δ 1.88 (1H, m), 2.04 - 2.33 (3H, m), 3.57 (3H, s), 4.01 (1H, dd, J = 8.5 Hz, J =
13
3.6 Hz), 7.86 (1H, s, NH), 9.11 (1H, s, NH), 9.83 (1H, s, NH). C NMR (DMSO-d6) δ 25.3, 29.1, 52.0,
54.2, 156.6, 172.4, 177.5. MS m/z = 201 [M]+, 173 [M - CO]+, 84 [C4H6NO]+. Anal. Calcd for
C7H11N3O4: C, 41.79: H, 5.51; N, 20.89. Found: C, 41.79; H, 5.61; N, 20.90.

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4-[2,2-Bis(trifluoromethyl)-5-oxo-1,3-oxazolidin-4-yl]butanoate (11). A vigorously stirred solution of
(4S)-α-aminoadipic acid (10) (10.0 g, 61.7 mmol) in dry DMSO (30 mL) was treated with an excess of
hexafluoroacetone. Procedure see under compound (2). Yield 16.0 g (90%), mp 60-62 oC (CH2Cl2), [α]D
1
= -6.0° (c = 2.1, CHCl3). IR (KBr) ν 3385 br, 1815, 1705 cm-1. H NMR (acetone-d6) δ 1.71 - 2.02 (4H,
13
m), 2.43 (2H, t, J = 7.0 Hz), 4.26 (1H, m), 5.29 (1H, d, J = 6.5 Hz, NH). C NMR (acetone-d6) δ 22.1,
33.9, 34.1, 55.5, 90.0 (sept., J = 34.0 Hz), 122.2 (q, J = 284.0 Hz), 123.2 (q, J = 288.0 Hz), 173.1, 175.3.
19F NMR (acetone-d6) δ -2.91 (3F, q, J = 9.0 Hz), -2.00 (3F, q, J = 9.0 Hz). MS m/z = 309 [M]+, 291 [M -
H2O]+, 263 [M - H2O, -CO]+, 235 [M - H2O, - CH3CHCO]+, 166 [(CF3)2CO]+. Anal. Calcd for
C9H9NO4F6: C, 34.96; H, 2.93; N, 4.53. Found: C, 34.90; H, 2.99; N, 4.56.
(6S)-1-Aza-9,9-bis(trifluoromethyl)-8-oxabicyclo[4.3.0]nonane-2,7-dione (12). 11 (3.09 g, 10 mmol)
was stirred with an excess of thionyl chloride (5.95 g, 50 mmol) due to protocol applied for compound
(3). Yield 2.05 g (70%), mp 51-52 oC (CHCl3/hexane), [α]D = +4.0° (c = 1.4, CH2Cl2). IR (KBr) ν 1855,
1710 cm-1. 1H NMR (CDCl3) δ 1.68 - 1.80 (1H, m), 1.88 - 2.04 (1H, m), 2.06 - 2.18 (1H, m), 2.41 - 2.50
13
(1H, m), 2.53 - 2.62 (2H, m), 4.25 (1H, dd, J = 11.5 Hz, J = 4.0 Hz). C NMR (CDCl3) δ 19.5, 25.2,
19
31.7, 55.4, 90.3 (sept., J = 33.0 Hz), 119.5 (q, J = 289.0 Hz), 120.6 (q, J = 290.0 Hz), 166.7, 167.0. F
NMR (CDCl3) δ 0.05 (3F, m), 5.99 (3F, m). MS m/z = 291 [M]+, 222 [M - CF3]+, 194 [M - CF3, -CO]+,
55 [C4H7]+. Anal. Calcd for C9H7NO3F6: C, 37.13, H, 2.40; N, 4.81. Found: C, 37.19; H, 2.74; N, 4.71.
(S)-6-Oxopipecolyl-(S)-phenylalanine benzyl ester (13). A solution of 12 (1.46 g, 5.0 mmol) in dry
acetonitrile (40 mL) was treated with (S)-phenylalanine benzyl ester (1.53 g, 6.0 mmol). Compound (13)
was purified by column chromatography (eluent: methanol/ether, 1:2). Yield: 1.32 g (69%), colorless oil;
[α]D = -4.5° (c = 1.1, DMSO). IR (Film) ν 3450 - 3060, 1740, 1680, 1655 cm-1. 1H NMR (CDCl3) δ 1.45 -
1.49 (2H, m), 1.73 - 1.87 (2H, m), 2.18 - 2.24 (2H, m), 3.03 (1H, dd, J = 14.0 Hz, J = 9.5 Hz), 3.21 (1H,
dd, J = 14.0 Hz, J = 5.5 Hz), 3.91 (1H, m), 4.90 - 4.94 (1H, m), 5.11 (2H, s), 7.00 - 7.32 (11H, m), 7.88
(1H, d, J = 8.5 Hz, NH). 13C NMR (CDCl3) δ 18.9, 26.3, 31.8, 37.5, 54.5, 55.4, 66.9, 127.0, 127.1, 128.5,
128.6, 129.2, 129.3, 136.0, 136.5, 171.2, 171.8, 172.6. MS (FAB) m/z = 381 [M + H]+, 289 [M - C7H7]+.
Anal. Calcd for C22H24N2O4: C, 69.46; H, 6.36; N, 7.36. Found: C, 69.41; H, 6.45; N, 7.39.
(S)-6-Oxopipecolyl-(S)-proline methyl ester (14). 12 (1.46 g, 5.0 mmol) and (S)-proline methyl ester
(0.77 g, 6.0 mmol) were reacted for 2 d in acetonitrile (40 mL). Compound (14) was purified by column
chromatography (eluent: methanol/ether, 1:2). Yield: 0.83 g (65%), colorless oil; [α]D = -120.9° (c = 1.1,
1
CHCl3). IR (Film) ν 3490-3305, 1745, 1680, 1630, 1440 cm-1. H NMR (CDCl3) δ 1.71-1.80 (2H, m),

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1.81-1.95 (3H, m), 1.98-2.02 (3H, m), 2.28-2.32 (2H, m), 3.53-3.60 / 3.45-3.52 (2H, m), 3.66 / 3.74 (3H,
13
s), 4.25 (1H, m), 4.50 / 4.42 (1H, dd, J = 5.0 Hz, J = 8.5 Hz), 6.76 / 6.62 (1H, s). C NMR (CDCl3) δ
18.8 / 19.1, 24.8 / 25.0, 25.4 / 25.1, 28.9 / 29.0, 31.1 / 31.1, 46.9 / 47.0, 52.5 / 52.5, 54.0 / 54.3, 59.4 /
59.6, 170.3 / 170.2, 172.7 / 172.4, 172.8 / 172.8. MS m/z = 254 [M]+, 222 [M - CH3OH]+, 156 [M -
C5H8NO]+, 128 [M - C5H8NO, - CO]+, 113 [M - C5H8NO, - CO, - CH3]+, 98 [C5H8NO]+, 70 [C4H8N]+, 59
[CO2CH3]+, 43 [CONH]+. Anal. Calcd for C12H18N2O4: C, 56.68; H, 7.13; N, 11.02. Found: C, 56.73; H,
6.98; N, 11.16.
(S)-6-Oxopipecolylsarcosine methyl ester (15). A solution of 12 (1.46 g, 5.0 mmol) in dry acetonitrile
(40 mL) was treated for 24 h with sarcosine methyl ester (0.84 g, 6.0 mmol). Compound (15) was purified
by flash chromatography (eluent: methanol/ether, 1:2). Yield: 0.86 g (75%), colorless oil; mixture of
rotamers, ratio 4:1; [α]D = 3.0° (c = 1.0, CHCl3). IR (Film) ν 3370-3250, 2955, 1750, 1670 cm-1. 1H NMR
(CDCl3) δ 1.68-1.98 (4H, m), 2.25 (2H, m), 3.00 / 2.86 (3H, s), 3.62 / 3.68 (3H, s), 3.81 (1H, d, J = 17.5
Hz), 4.21 (1H, d, J = 17.0 Hz), 4.39 (1H, m), 6.51 (1H, br s). 13C NMR (CDCl3) δ 18.7, 24.8, 30.8, 36.2,
49.9, 52.0, 52.4, 169.3, 171.7, 172.1. MS m/z = 228 [M]+, 197 [M - OCH3]+, 169 [M - OCH3, - CO]+, 130
[M - C5H8NO]+, 98 [C5H8NO]+. Anal. Calcd for C10H16N2O4: C, 52.62; H, 7.07; N, 12.27. Found: C,
52.91; H, 7.13; N, 11.98.
N'-Benzyloxycarbonyl-(S)-6-oxopipecolylhydrazide (16). 12 (1.46 g, 5.0 mmol) and
N-benzyloxycarbonylhydrazine (1.25 g, 7.5 mmol) were stirred for 6 h in dry ether (30 mL). Yield: 0.99 g
(68 %), mp 182 °C (ether), white crystals; [α]D = 9.3° (c = 1.0, MeOH). IR (KBr) ν 3530-3350, 3330-
3120, 1745, 1680, 1635 cm-1. 1H NMR (DMSO-d6) δ 1.60 - 1.79 (4H, m), 2.07 - 2.09 (2H, m), 3.88 (1H,
m), 5.05 (2H, s), 7.34 (5H, m), 7.50 (1H, s, NH), 9.23 (1H, s, NH), 9.80 (1H, s, NH). 13C NMR (DMSO-
d6) δ 17.9, 25.8, 31.1, 53.2, 65.9, 127.8, 128.0, 128.4, 136.6, 156.0, 170.5, 171.8. MS m/z = 291 [M]+, 263
[M - CO]+, 247 [M - CHNO]+, 184 [M - OCH2Ph]+, 107 [OCH2Ph]+, 98 [C5H8NO]+, 91 [CH2Ph]+, 77
[C6H5]+. Anal. Calcd for C14H17N3O4: C, 57.72; H, 5.88; N, 14.42. Found: C, 58.00; H, 5.75; N, 14.10.
ACKNOWLEDGEMENTS
We are grateful to Stiftung Volkswagenwerk, Hannover, for financial support.
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