1
Copyright WILEY-VCH Verlag GmbH, 69451 Weinheim, 2000
Angew. Chem. 2000
SUPPLEMENTARY MATERIAL
A Practical Asymmetric Synthesis of Enantiomerically Pure 3Substituted Pyroglutamic Acids and Related Compounds [**]
Vadim A. Soloshonok,* Chaozhong Cai and Victor J. Hruby*
Department of Chemistry, University of Arizona, Tucson, AZ 85721, U.S.A.
1H, 13C and 19F NMR were performed on Varian Unity-300
General.
(299.94 MHz) and Gemini-200 (199.98 MHz) spectrometers using TMS, CDCl3
and CCl3F as internal standards.
were
recorded
measured
on
on
a
a
JASCO
JEOL
High Resolution Mass Spectra (HRMS)
HX110A
P-1010
instrument.
polarimeter.
Optical
Melting
rotations
points
uncorrected and were obtained in open capillaries.
were
(mp)
are
All reagents and
solvents, unless otherwise stated, are commercially available and were
used as received.
Synthesis of the Ni(II)-complex of the Schiff base of
(S)-BPB and glycine (S)-1 was accomplished by the procedure given in
ref. 17.
Unless otherwise stated, yields refer to isolated yields of
products of greater than 95% purity as estimated by 1H, 19F and 13C NMR
pectrometry.
All new compounds were characterized by 1H, 19F, 13C NMR
and HRMS.
General procedure for the reactions of glycine complex (S)-1 with
(S)- or (R)-N-(E-enoyl)-5-phenyl-3-oxazoline-2-ones.
To a suspension of
complex (S)-1 (0.25 g, 0.50 mmol) in DMF (1.5 mL), (S)- or (R)-N-(Eenoyl)-5-phenyl-3-oxazoline-2-ones
stirring.
The
mixture
homogeneous
solution,
was
and
(2a-f)
stirred
then
DBU
at
(0.53
rt
(0.011
mmol)
for
g,
was
10-15
0.072
min
mmol)
added
to
was
with
get
a
added
2
dropwise.
The course of reaction was monitored by TLC (SiO2).
Each
sample was quenched with 5% aqueous acetic acid and the products were
extracted
with
chloroform
before
being
applied
to
the
plate.
Upon
disappearance of the starting (S)-1, the reaction mixture was poured
into icy 5% aqueous acetic acid (80 mL) and stirred with a glass bar to
initiate crystallization of the product.
The crystalline product was
filtered off, thoroughly washed with water and dried in vacuo to afford
addition products 3 or 4.
Ni(II) complex of Schiff base of (S)-BPB and (2S,3S,4'S)-3-methyl5-[3'-(4'-phenyl-2'-oxazolidinonyl)]glutamic
acid
(3a).
m.p.
157.0-
158.0 °C, [α]D25 +2576, (c 0.0103, CHCl3).
1H-NMR (CDCl ) δ 1.77 (3H,
3
d, J=6.9 Hz), 2.02-2.08 (2H, m), 2.46-2.55 (2H, m), 2.76-2.85 (3H, m),
3.45-3.48 (3H, m), 3.57, 4.42 (2H, AB, J=12.9 Hz), 4.02 (1H, d, J=6.0
Hz), 4.15, 5.21 (2H, ABX, J=8.7, 3.4 Hz), 4.48 (1H, t, J=8.7 Hz), 6.63
(2H, d, J=3.9 Hz), 6.93 (1H, a part of AB, J=7.2 Hz), 7.09-7.52 (13H,
m), 8.02 (2H, a part of AB, J=6.9 Hz), 8.23 (1H, a part of AB, J=8.7
Hz).
13C-NMR (CDCl ) δ 16.6, 23.2, 30.6, 33.9, 38.9, 56.7, 57.4, 63.2,
3
69.9,
70.4,
73.2,
120.6,
123.1,
125.9,
126.2,
127.1,
128.2,
128.5,
128.8, 128.9, 129.0, 129.6, 131.5, 132.3, 133.2, 133.7, 133.8, 139.2,
142.4, 153.4, 170.4, 171.6, 177.6, 180.2.
HRMS(FAB) [M+H]+ calcd. for
C40H39N4NiO6 729.2223, found 729.2216.
Ni(II)
complex
of
Schiff
base
of
(S)-BPB
and
(2S,3S,4'S)-3-
isopropyl-5-[3'-(4'-phenyl-2'-oxazolidinonyl)]glutamic acid (3b).
147.0-148.0 °C, [α]D25 +2813, (c 0.0114, CHCl3).
m.p.
1H-NMR (CDCl ) δ 0.25
3
(3H, d, J=6.8 Hz), 0.86 (3H, d, J=6.8 Hz), 2.02-2.11 (2H, m), 2.37-2.50
(3H, m), 2.94 (1H, dd, J=18.8, 10.3 Hz), 3.00 (1H, m), 3.40, 4.37 (2H,
AB, J=12.5 Hz), 3.41 (1H, m), 3.53-3.56 (2H, m), 3.60-3.67 (2H, m),
3.84, 5.13 (2H, ABX, J=8.8, 2.2 Hz), 3.91 (1H, m), 6.68-6.71 (1H, m),
6.81-6.85 (1H, m), 7.00-7.13 (2H, m), 7.23-7.37 (9H, m), 7.52-7.55 (3H,
m), 8.09 (2H, a part of AB, J=7.0 Hz), 8.35 (1H, a part of AB, J=8.3
Hz).
13C-NMR (CDCl ) δ 15.7, 21.7, 23.7, 27.0, 30.1, 31.2, 45.6, 57.3,
3
3
57.7, 63.6, 70.6, 70.7, 72.2, 120.6, 122.3, 125.2, 125.6, 127.9, 128.4,
128.5, 128.7, 129.1, 129.4, 129.5, 129.9, 131.2, 132.6, 133.9, 134.0,
HRMS(FAB) [M+H]+
134.3, 139.6, 142.4, 153.9, 171.6, 172.1, 178.6, 180.1.
calcd. for C42H43N4NiO6 757.2536, found 757.2529.
Ni(II) complex of Schiff base of (S)-BPB and (2S,3R,4'S)-3-phenyl5-[3'-(4'-phenyl-2'-oxazolidinonyl)]glutamic
acid
(3c).
m.p.
152.0-
153.0 °C, [α]D25 +2299, (c 0.0113, CHCl3).
1H-NMR (CDCl ) δ 1.43-1.55
3
(1H, m), 1.91-2.03 (2H, m), 2.14-2.22 (2H, m), 2.77, 3.98 (2H, ABX,
J=17.7, 9.3, 6.0 Hz), 2.92 (1H, a part of AB, J=10.2, 5.4 Hz), 3.23 (1H,
t, J=8.7 Hz), 3.41, 4.24 (2H, AB, J=12.6 Hz), 3.41 (1H, m), 4.04, 5.15
(2H, ABX, J=8.7, 4.2 Hz), 4.30 (1H, d, J=4.2 Hz), 4.49 (1H, t, J=8.7
Hz), 6.62-6.71 (2H, m), 6.77-6.80 (2H, m), 7.09-7.56 (17H, m), 7.97 (2H,
a part of AB, J=7.2 Hz), 8.27 (1H, a part of AB, J=8.4 Hz).
13C-NMR
(CDCl3) δ 23.1, 30.6, 37.2, 45.6, 57.2, 57.3, 63.4, 69.6, 70.3, 73.7,
120.4, 123.0, 125.2, 125.8, 127.1, 127.8, 128.1, 128.3, 128.6, 128.8,
128.9, 129.0, 129.1, 129.7, 129.8, 131.5, 132.4, 133.2, 133.7, 134.2,
138.4, 138.5, 143.0, 153.2, 170.0, 171.8, 177.2, 180.3.
HRMS(FAB) [M+H]+
calcd. for C45H41N4NiO6 791.2380, found 791.2355.
Ni(II)
complex
of
Schiff
base
of
(S)-BPB
and
(2S,3R,4'S)-3-(p-
methoxyphenyl)-5-[3'-(4'-phenyl-2'-oxazolidinonyl)]glutamic
m.p. 267.0-268.0 °C, [α]D25 +2263, (c 0.0121, CHCl3).
acid
(3e).
1H-NMR (CDCl ) δ
3
1.45-1.55 (1H, m), 1.95-2.09 (2H, m), 2.14-2.22 (2H, m), 2.67, 4.00 (2H,
ABX, J=17.1, 9.4, 5.9 Hz), 2.99 (1H, a part of AB, J=10.5, 5.4 Hz), 3.26
(1H, t, J=8.5 Hz), 3.51 (1H, m), 3.41, 4.25 (2H, AB, J=12.5 Hz), 3.85
(3H, s), 4.01-4.11 (2H, m), 4.27 (1H, d, J=4.0 Hz), 4.50 (1H, t, J=8.7
Hz), 5.17 (1H, a part of AB, J=8.7, 4.1 Hz), 6.62-6.71 (2H, m), 6.80
(2H, a part of AB, J=6.6 Hz), 6.96 (2H, a part of AB, J=8.5 Hz), 7.007.30 (11H, m), 7.40-7.54 (3H, m), 7.99 (2H, a part of AB, J=7.3 Hz),
8.26 (1H, a part of AB, J=8.5 Hz).
13C-NMR (CDCl ) δ 23.0, 30.6, 37.2,
3
45.1, 55.2, 57.3, 63.5, 69.6, 70.4, 73.9, 114.2, 120.4, 123.0, 125.2,
125.8, 127.0, 128.1, 128.3, 128.2, 128.6, 128.8, 129.0, 129.1, 129.7,
4
130.2, 130.8, 131.5, 132.4, 133.2, 133.7, 134.1, 138.4, 142.9, 153.2,
159.4,
170.1,
171.6,
177.2,
180.3.
[M+H]+
HRMS(FAB)
calcd.
for
C46H43N4NiO7 821.2485, found 821.2495.
Ni(II)
complex
of
Schiff
base
of
(S)-BPB
and
(2S,3R,4'S)-3-(p-
trifluoromethylphenyl)-5-[3'-(4'-phenyl-2'-oxazolidinonyl)]glutamic
(3f).
m.p. 270.0-271.0 °C, [α]D25 +1979, (c 0.0212, CHCl3).
acid
1H-NMR
(CDCl3) δ 1.45-1.58 (1H, m), 1.83-2.93 (2H, m), 2.11-2.23 (2H, m), 2.57
(1H, a part of ABX, J=17.7, 5.0 Hz), 2.89 (1H, m), 3.24 (1H, dd, J=9.4,
7.7 Hz), 3.42 (1H, a part of AB, J=12.5 Hz), 3.51 (1H, m), 4.03-4.13
(2H, m), 4.21-4.26 (2H, m), 4.52 (1H, t, J=8.7 Hz), 5.15 (1H, a part of
AB, J=8.8, 4.4 Hz), 6.64-6.72 (2H, m), 6.82 (2H, a part of AB, J=7.1
Hz), 7.15-7.65 (16H, m), 7.95 (2H, a part of AB, J=7.6 Hz), 8.29 (1H, a
part of AB, J=8.8 Hz).
22.8,
30.6,
37.3,
19F-NMR (CDCl ) δ -63.50 (s).
3
45.7,
57.0,
57.4,
63.4,
69.6,
13C-NMR (CDCl ) δ
3
70.2,
73.6,
120.6,
123.1, 125.3, 125.6 (q, J=3.0 Hz), 127.0, 128.2, 128.4, 128.7, 128.8,
129.1, 129.3, 129.9, 130.0, 131.4, 132.8, 133.2, 133.8, 134.1, 138.1,
142.7, 143.0, 153.2, 169.7, 172.3, 176.8, 180.3; two signals of aromatic
carbons having 1JCF and 2JCF and are obscured due to low intensity.
HRMS(FAB) [M+H]+ calcd. for C46H40F3N4NiO6 859.2253, found 859.2265.
Ni(II) complex of Schiff base of (S)-BPB and (2R,3R,4'R)-3-methyl5-[3'-(4'-phenyl-2'-oxazolidinonyl)]glutamic
acid
(4a).
m.p.
146.0-
147.5 °C, [α]D25 -1277, (c 0.0199, CHCl3).
1H-NMR (CDCl ) δ 1.67 (3H,
3
d, J=6.8 Hz), 1.71-1.90 (2H, m), 2.11-2.17 (1H, m), 2.43-2.63 (3H, m),
2.80, 2.90 (2H, ABX, J=18.1, 7.6, 6.6 Hz),
3.64 (1H, dd, J=9.6, 4.0
Hz), 3.95-3.98 (1H, m), 4.04 (1H, d, J=4.9 Hz), 4.07, 4.93 (2H, AB,
J=13.5 Hz), 4.18, 5.27 (2H, ABX, J=8.8, 3.7 Hz), 4.56 (1H, t, J=8.8 Hz),
6.72-6.80 (2H, m), 7.04-7.63 (16H, m), 8.54 (1H, a part of AB, J=8.7
Hz).
13C-NMR (CDCl ) δ 16.2, 23.5, 30.9, 34.6, 38.9, 56.2, 57.4, 60.9,
3
68.3,
69.8,
73.4,
120.7,
123.4,
125.9,
126.8,
128.5,
128.2,
128.8,
128.9, 129.1, 129.5, 131.8, 132.0, 132.5, 133.9, 134.1, 139.1, 142.8,
5
153.3,
170.4,
172.1,
177.9,
182.2.
[M+H]+
HRMS(FAB)
calcd.
for
C40H39N4NiO6 729.2223, found 729.2221.
Ni(II)
complex
of
Schiff
base
of
(S)-BPB
and
(2R,3R,4'R)-3-
isopropyl-5-[3'-(4'-phenyl-2'-oxazolidinonyl)]glutamic acid (4b).
141.0-142.5 °C, [α]D25 -1991, (c 0.0256, CHCl3).
m.p.
1H-NMR (CDCl ) δ 0.23
3
(3H, d, J=6.9 Hz), 0.87 (3H, d, J=6.9 Hz), 1.49-1.60 (2H, m), 1.89-1.93
(1H, m), 2.28-2.41 (2H, m), 2.53 (1H, a part of AB, J=18.6 Hz), 2.652.74 (1H, m), 3.12, 3.75 (2H, ABX, J=10.3, 9.3 Hz), 3.49 (1H, br.t,
J=9.3 Hz), 3.73 (1H, m), 3.84 (1H, m), 3.98-4.03 (2H, m), 4.18, 5.72
(2H, AB, J=13.9 Hz), 5.42 (1H, a part of ABX, J=6.8, 4.3 Hz),
6.75-6.80
(1H, m), 6.93-6.95 (1H, m), 7.19-7.54 (16H, m), 8.68 (1H, a part of AB,
J=8.8 Hz).
13C-NMR (CDCl ) δ 15.7, 21.7, 23.9, 27.4, 31.5, 31.6, 45.5,
3
55.5, 57.6, 60.1, 68.5, 70.5, 72.3, 120.9, 122.7, 125.4, 126.0, 128.0,
128.6, 128.7, 128.8, 129.1, 129.3, 129.4, 129.9, 131.9, 132.3, 132.8,
133.9,
134.6,
139.6,
143.0,
154.9,
171.8,
172.4,
178.9,
182.4.
HRMS(FAB) [M+H]+ calcd. for C42H43N4NiO6 757.2536, found 757.2534.
Ni(II) complex of Schiff base of (S)-BPB and (2R,3S,4'R)-3-phenyl5-[3'-(4'-phenyl-2'-oxazolidinonyl)]glutamic
acid
(4c).
m.p.
150.0-
151.0 °C, [α]D25 -1798, (c 0.0179, CHCl3).
1H-NMR (CDCl ) δ 1.10-1.26
3
(1H, m), 1.27-1.45 (1H, m), 1.75-1.87 (1H, m), 2.00-2.10 (1H, m), 2.442.53 (1H, m), 3.02, 3.97 (2H, ABX, J=17.7, 8.1, 6.9 Hz), 3.31 (1H, dd,
J=9.5, 3.2 Hz), 3.39 (1H, m), 3.42, 3.60 (2H, AB, J=14.1 Hz), 3.79 (1H,
m), 4.10, 5.15 (2H, ABX, J=8.7, 3.9 Hz), 4.36 (1H, d, J=3.9 Hz), 4.55
(1H, t, J=8.7 Hz), 6.70-6.89 (4H, m), 7.15-7.51 (19H, m), 8.43 (1H, a
part of AB, J=8.1 Hz).
13C-NMR (CDCl ) δ 23.7, 31.3, 36.6, 45.8, 55.0,
3
57.4, 59.4, 68.6, 69.6, 73.8, 120.7, 123.4, 125.5, 126.2, 127.1, 128.0,
128.2, 128.3, 128.6, 128.7, 128.9, 129.0, 129.1, 129.7, 130.4, 131.7,
132.7, 134.0, 134.1, 138.5, 138.8, 143.2, 153.2, 170.0, 171.8, 177.0,
181.6.
791.2373.
HRMS(FAB)
[M+H]+
calcd.
for
C45H41N4NiO6
791.2380,
found
6
Ni(II)
complex
of
Schiff
base
of
(S)-BPB
(2R,3S,4'R)-3-(β
β-
and
naphthyl)-5-[3'-(4'-phenyl-2'-oxazolidinonyl)]glutamic acid (4d).
190.0-191.5 °C, [α]D25 -1549, (c 0.0117, CHCl3).
m.p.
1H-NMR (CDCl ) δ 0.893
1.00 (1H, m), 1.15-1.25 (1H, m), 1.57-1.72 (1H, m), 1.90-2.00 (1H, m),
2.30-2.40 (1H, m), 2.65, 3.05 (2H, AB, J=14.2 Hz), 2.82 (1H, dd, J=9.5,
2.9 Hz), 2.93, 4.22 (2H, ABX, J=17.3, 9.3, 6.1 Hz), 3.39 (1H, m), 3.503.60 (1H, m), 3.72 (1H, m), 4.05, 5.14 (2H, ABX, J=8.8, 4.3 Hz), 4.38
(1H, d, J=3.7 Hz), 4.53 (1H, t, J=8.8 Hz), 6.50 (2H, a part of AB, J=7.1
Hz), 6.68-6.86 (6H, m), 7.00-7.30 (6H, m), 7.41-7.58 (7H, m), 7.87-8.04
(4H, m), 8.43 (1H, a part of AB, J=7.8 Hz).
13C-NMR (CDCl ) δ 23.5,
3
31.3, 36.5, 46.4, 54.8, 57.4, 59.4, 68.6, 69.6, 74.2, 120.7, 123.5,
125.2, 126.2, 126.3, 126.7, 127.1, 127.7, 128.0, 128.1, 128.2, 128.3,
128.4, 128.5, 129.0, 129.2, 129.8, 131.1, 131.6, 132.7, 133.4, 134.0,
134.1, 136.0, 138.2, 143.3, 153.2, 170.1, 171.6, 177.0, 181.5. HRMS(FAB)
[M+H]+ calcd. for C49H43N4NiO6 841.2536, found 841.2531.
Decomposition of complex 3 or 4;
(2S,3R)-3-arylpyroglutamic
acid
8
Isolation of (2S,3S)-3-alkyl-,
or
(2R,3R)-3-alkyl-,
(2R,3S)-3-
arylpyroglutamic acid 9 and recovery of starting chiral auxiliaries (S)5 and (S)-, (R)-10.
A solution of diastereo- and enantiomerically pure
complex 3 or 4 (5.4 mmol) in MeOH (60 mL) was slowly added with stirring
to a mixture of aqueous 3 N HCl and MeOH (60 mL, ratio 1/1) at 70 °C.
Upon
disappearance
of
the
red
color
of
the
starting
reaction mixture was evaporated in vacuo to dryness.
complex,
the
Water (80 mL) was
added and the resultant mixture was treated with excess of NH4OH and
extracted with CHCl3.
The CHCl3 extracts were dried over MgSO4 and
evaporated in vacuo to afford 2.9 g of a 1:1 mixture (98%) of free (S)(5) and (S)- or (R)-10.
The aqueous solution was evaporated in vacuo.
The residue was dissolved in a minimum amount of water and subjected to
cation exchange resin Dowex 50X2 100.
The column was washed with water
and the acidic fraction was collected to give, after evaporation in
vacuo,
pyroglutamic
acid
8
or
9.
Analytically
pure
sample
of
the
7
product was obtained by crystallization of the compound from THF/nhexane.
(2S,3S)-3-methylpyroglutamic acid (8a).
°C, [α]D25 +41.0, (c 1.16, MeOH).
Yield 88%; m.p. 110-111.5
1H-NMR (CD3COCD3) δ 1.28 (3H, d,
J=6.6 Hz), 1.93, 2.48 (2H, ABX, J=15.9 Hz, J=8.5 Hz, J=5.7 Hz), 2.53
(1H, dqdd, J=8.5 Hz, J=6.6 Hz, J=5.7 Hz, J=5.1 Hz), 3.86 (1H, d, J=5.1
Hz), 7.19 (1H, br.s).
174.0,
178.3.
13C-NMR (CD3COCD3) δ 20.1, 34.8, 38.4, 63.1,
HRMS(FAB)
[M+H]+
calcd.
for
C6H10NO3
144.0661,
found
144.0660.
(2S,3R)-3-Phenylpyroglutamic acid (8c).
142.0 °C, [α]D25 +82.8, (c 1.10, MeOH).
Yield 84%;
m.p. 141.0-
1H-NMR (CD3COCD3) δ 2.34, 2.75
(2H, ABX, J=16.8 Hz, J=9.3 Hz, J=6.3 Hz), 3.72 (1H, ddd, J=9.3 Hz, J=6.3
Hz, J=5.1 Hz), 4.25 (1H, d, J=5.1 Hz), 7.25-7.41 (5H, m).
13C-NMR
(CD3COCD3) δ 38.7, 44.9, 63.1, 127.8, 127.9, 129.6, 143.9, 173.5, 176.4.
HRMS(FAB) [M+H]+ calcd. for C11H12NO3 206.0817, found 206.0809.