Diastereoselective synthesis of α-methylpyroglutamates from α,β-didehydro α-amino acids

Article abstract of DOI:10.1002/1099-0690(200212)2002:24<4190::AID-EJOC4190>3.0.CO;2-Q

A new method for the diastereoselective synthesis of α-methylpyroglutamates from α,β-didehydro-N-(diphenylmethylene)glutamates has been developed. Deprotection of the (diphenylmethylene)amino moiety of the starting materials affords pyridazinone derivativ

Full text of DOI:10.1002/1099-0690(200212)2002:24<4190::AID-EJOC4190>3.0.CO;2-Q

FULL PAPER
Diastereoselective Synthesis of α-Methylpyroglutamates from α,β-Didehydro
α-Amino Acids
[a]
[a]
[a]
´
´
¨
Carlos Alvarez-Ibarra,* Aurelio G. Csaky,* and Cristina Gomez de la Oliva
Keywords: Amino acids / Lithiation / Diastereoselectivity / Ring contraction / Lactams
A new method for the diastereoselective synthesis of α-
methylpyroglutamates from α,β-didehydro-N-(diphenylme-
thylene)glutamates has been developed. Deprotection of the
(diphenylmethylene)amino moiety of the starting materials
affords pyridazinone derivatives which can be transformed
into α-methyl-6-oxoperhydropyridazine-3-carboxylates in a
highly diastereoselective fashion. Ring contraction of the lat-
ter induced by LiHMDS affords α-methylpyroglutamates.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2002)
Introduction
double bond, cyclopropanation or DielsϪAlder reaction.[9]
We have recently reported a new procedure which allows
for the diastereoselective transformation of α,β-didehy-
droglutamates into the 6-oxoperhydropyridazine-3-carb-
oxylic acid derivatives 2 and 3 (OPCAs) (Scheme 1).[10] We
report herein our results on the diastereoselective synthesis
of α-methylpyroglutamates using OPCAs 2 and 3 as start-
ing materials[11] (Scheme 1).
The implication of glutamate receptors in Alzheimer’s
disease[1] and the therapeutic potential of substituted glu-
tamic acid derivatives in the treatment of epilepsy[2] and
stroke[3] has paved the way for the asymmetric synthesis of
these unnatural α-amino acids. Pyroglutamates (5-oxoprol-
ines) can be considered glutamic acid derivatives having the
carboxylate group γ to the nitrogen atom internally pro-
tected (Figure 1, R1 ϭ H).[4]
Figure 1. Pyroglutamates (5-oxoprolines)
Scheme 1
The conformational constraints induced by these subun-
its in peptides can lead to their enhanced bioactivity and
stability, which has found pharmacological use.[5] Amino
acids constrained by the introduction of an alkyl chain at
the α position, and in particular α-methyl α-amino acids
(AMAAs), have assumed an important role in bioorganic
chemistry as subunits for the definition of the secondary
structure in de novo designs of peptides and proteins.[6]
However, comparatively to other AMAAs, few efforts have
been directed towards the preparation of cyclic α-substi-
tuted glutamic acid derivatives.[7,8]
α,β-Didehydro α-amino acids (DDAAs) constitute valu-
able synthetic intermediates for the preparation of more
elaborated targets by means of hydrogenation of the CϭC
[a]
´
´
´
Departamento de Quımica Organica, Facultad de Quımica,
Universidad Complutense
28040 Madrid, Spain
Fax: (internat.) ϩ 34-91/394-4103
E-mail: csaky@quim.ucm.es
Scheme 2
4190
 2002 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/02/1224Ϫ4190 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2002, 4190Ϫ4194

Diastereoselective Synthesis of α-Methylpyroglutamates
FULL PAPER
(δ ϭ 2.83 ppm, dd, 2J ϭ 16.0, 3J ϭ 9.0 Hz) upon saturation
of the 4-H signal of compound 5c. The stereochemistry of
the rest of compounds 5 and 6 was supposed to be similar
to that of 5c.[12]
The stereochemistry of the nucleophilic addition to the
CϭN bond was not dependent on the substituent R2 at C-
5, either cis or trans. This was evidenced in the reactions of
compounds 2d (R1, R2 cis) and 3 (R1, R2 trans), which took
place with the same diastereoselectivity as that of com-
pounds 2b, unsubstituted at C-5 (R2 ϭ H).
Results and Discussion
The addition of MeMgBr to 2a (R1, R2 ϭ H) was consid-
ered first (Scheme 2) in order to optimize the chemoselectiv-
ity of the addition of the organomagnesium reagent to the
CϭN or the ester groups. The results are given in Table 1.
Table 1. Reactions of 2 and 3 with MeMgBr
Entry 6, 7 Solvent T [°C] Lewis acid[a] 5,6/7,8[b]
5, 6 (%)[c]
Treatment of compounds 5 and 6 with an excess of
LiHMDS (4 equiv., THF) gave rise to compounds 9
(Scheme 4). The results are given in Table 2.
1
2
3
4
5
6
7
8
9
2a THF
2a THF
2a Et2O
2a Et2O
2a toluene Ϫ50
2a toluene Ϫ50
2a toluene
Ϫ78
Ϫ50
Ϫ50
0
BF3
BF3
BF3
BF3
Ϫ
Ϫ
5a/7a ϭ 5:3 5a (40)
Ϫ
Ϫ
5a/7a ϭ 6:2 5a (50)
5a/7a ϭ 1:0 5a (10)
5a/7a ϭ 5:1 5a (70)
5a/7a ϭ 7:3 5a (60)
5b/7b ϭ 7:1 5b (70)
5c/7c ϭ 7:1 5c (70)
5d/7d ϭ 1:0 5d (75)
BF3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
0
2b toluene Ϫ50
2c toluene Ϫ50
2d toluene Ϫ50
10
11
3
toluene Ϫ50
6/8 ϭ 5:1
6 (65)
[a]
[b]
1 equiv.
Determined by integration of the 1H NMR
[c]
(200 MHz) spectrum of the crude reaction products.
yield after chromatography.
Isolated
No reaction was observed when the addition of MeMgBr
was carried out in a THF solution at Ϫ78 °C using BF3 as
catalyst (Entry 1), and the reaction at Ϫ50 °C was unselect-
ive (Entry 2). Similar results were observed with Et2O as
solvent (Entries 3, 4). On the other hand, the reaction in
toluene took place with low yield but good chemoselectivity
(Entry 5). Best results were observed when Yb(OTf)3 was
used as catalyst in a toluene solution (Entries 6Ϫ7). The
reaction conditions given in Entry 6 were used for the syn-
thesis of the rest of compounds 5 and 6 (Entries 8Ϫ11).
Compounds 5 and 6 were isolated as single diastereo-
mers. The stereochemical outcome of the addition was con-
trolled by the substituent at C-4, giving rise to a trans relat-
ive disposition between the CH3 group at C-3 and the R1
group at C-4. This relative stereochemistry was determined
1
by the NOE effects observed in the H NMR spectrum of
compound 5c (Scheme 3). Thus, saturation of the 4-H sig-
Scheme 4
3
3
nal of compound 5c (δ ϭ 3.07 ppm, dd, J ϭ 9.0, J ϭ
5.5 Hz, 1 H) gave rise to a 5% enhancement of the signal
of the CH3 group at C-3 (δ ϭ 1.26 ppm, s, 3 H) and a 3%
enhancement of the pseudo-equatorial hydrogen signal at
Table 2. Synthesis of compounds 9 and 4
2
3
C-5 (δ ϭ 2.63 ppm, dd, J ϭ 16.0, J ϭ 5.5 Hz). No NOE
Entry
5, 6
9 (%)[a]
4 (%)[a]
was observed with the pseudo-axial hydrogen atom at C-5
1
2
3
4
5
5a
5b
5c
5d
6
9a (85)
9b (80)
9c (75)
9d (75)
9d (80)
4a (90)
4b (85)
4c (85)
4d (85)
4d (85)
[a]
Isolated yield after chromatography
The ring contraction of compounds 5 and 6 into 9 may
be understood on the basis of proton abstraction by
LiHMDS from the α carbon atom of the carbonyl group
and N-1, followed by formation of a ketene, thus planariz-
Scheme 3
Eur. J. Org. Chem. 2002, 4190Ϫ4194
4191

´
´
C. Alvarez-Ibarra, A. G. Csaky¨, C. Gomez de la Oliva
FULL PAPER
2
CDCl3): δ ϭ 7.36Ϫ7.28 (m, 5 H), 4.75 (AB, 1 H, J ϭ 14.0 Hz),
ing the stereogenic center. Intramolecular cyclization would
then explain the formation of compounds 9. It is worth
mentioning that ring contraction did not take place by us-
ing LDA as the base.
4.59 (d, 1 H, 2J ϭ 14.0 Hz), 4.57 (s, 1 H), 2.48Ϫ2.21 (m, 3 H),
1.87Ϫ1.76 (m, 1 H), 1.46 (s, 9 H), 1.19 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ ϭ 173.2, 171.6, 137.2, 128.6, 128.5, 127.5,
82.2, 60.2, 52.1, 33.9, 29.2, 27.9, 23.4 ppm. C17H24N2O3 (304.18):
calcd. C 67.08, H 7.95, N 9.20; found C 67.21, H 7.79, N 9.23.
The trans relative stereochemistry between R1 and the
CH3 group α to the carboxyl group of the starting materials
5 and 6 was conserved in the reaction, as evidenced by the
tert-Butyl (3S*,4R*)-1-Benzyl-3,4-dimethyl-6-oxoperhydropyridaz-
ine-3-carboxylate (5b): White solid (70 mg, 70%); m.p. 95Ϫ97 °C
1
NOE effects observed in the H NMR spectrum of com-
pound 9c (Scheme 3). Thus, saturation of the signal of the
CH3 group at C-2 (δ ϭ 1.72 ppm, s, 3 H) gave rise to a 3%
(hexane). IR (CHCl3): ν˜ ϭ 3298, 1718, 1630 cmϪ1
.
1H NMR
2
(200 MHz): δ ϭ 7.28Ϫ7.21 (m, 5 H), 4.75 (s, 1 H), 4.69 (AB, J ϭ
2
2
14.0 Hz, 1 H), 4.48 (AB, J ϭ 14.0 Hz, 1 H), 2.42 (dd, J ϭ 16.0,
3J ϭ 5.5 Hz, 1 H), 2.25 (dd, 2J ϭ 16.0, 3J ϭ 8.5 Hz, 1 H),
1.99Ϫ1.82 (m, 1 H), 1.38 (s, 9 H), 1.10 (s, 3 H), 0.91 (d, 3J ϭ
7.0 Hz, 3 H) ppm. 13C NMR (50.5 MHz): δ ϭ 171.7, 170.9, 137.1,
128.8, 128.5, 127.5, 82.5, 63.1, 52.1, 38.6, 36.7, 28.0, 22.4,
16.8 ppm. C18H26N2O3 (318.19): calcd. C 67.90, H 8.23, N 8.80;
found C 68.00, H 8.18, N 8.83.
3
enhancement of the signal of 3-H (δ ϭ 3.49 ppm, dd, J ϭ
3
11.5, J ϭ 8.5 Hz, 1 H). On the other hand, either 5d (R1,
R2 cis) or 6 (R1, R2 trans) gave rise to the same ring con-
traction product 9c, which showed a cis relative disposition
between R1 and R2. Therefore, the ring contraction process
took place with epimerization at C-5 of compounds 5 or
6.[13,14]
tert-Butyl
(3S*,4S*)-1-Benzyl-3-methyl-4-phenyl-6-oxoperhydro-
Treatment of compound 9a with hydrazine afforded 10.
However, the NϪN linkage in compounds 9 could be re-
duced with Raney Ni to afford the corresponding pyroglut-
amates 4 (Scheme 4). The results are given in Table 2.
pyridazine-3-carboxylate (5c): Colorless oil (70%). IR (CHCl3): ν˜ ϭ
3352, 1708, 1630 cmϪ1. H NMR (300 MHz): δ ϭ 7.24Ϫ6.96 (m,
1
2
2
10 H), 4.98 (s, 1 H), 4.89 (AB, J ϭ 14.0 Hz, 1 H), 4.41 (AB, J ϭ
14.0 Hz, 1 H), 3.07 (dd, 3J ϭ 9.0, 3J ϭ 5.5 Hz, 1 H), 2.83 (dd, 2J ϭ
16.0, 3J ϭ 9.0 Hz, 1 H), 2.63 (dd, 2J ϭ 16.0, 3J ϭ 5.5 Hz, 1 H),
1.26 (s, 3 H), 1.17 (s, 9 H) ppm. 13C NMR (75 MHz): δ ϭ 171.3,
170.7, 139.0, 137.0, 129.1, 128.6, 128.5, 128.0, 127.6, 127.5, 82.3,
64.2, 52.3, 49.8, 34.9, 27.5, 23.2 ppm. C23H28N2O3 (380.21): calcd.
C 72.60, H 7.42, N 7.36; found C 72.57, H 7.53, N 7.24.
Conclusion
In conclusion, a new method for the diastereoselective
synthesis of α-methylpyroglutamates has been developed
tert-Butyl (3S*,4R*,5S*)-1-Benzyl-3,4,5-trimethyl-6-oxoperhydro-
making use of α,β-didehydroglutamates as starting mat- pyridazine-3-carboxylate (5d): Colorless oil (85 mg, 70%). IR
(CHCl3): ν˜ ϭ 3313, 1714, 1627 cmϪ1
.
1H NMR (300 MHz): δ ϭ
erials.[15]
2
2
7.38Ϫ7.29 (m, 5 H), 4.80 (AB, J ϭ 13.5 Hz, 1 H), 4.73 (AB, J ϭ
13.5 Hz, 1 H), 2.72Ϫ65 (m, 1 H), 2.15Ϫ2.03 (m, 1 H), 1.48 (s, 9
3
3
H), 1.26 (d, J ϭ 7.0 Hz, 3 H), 1.23 (s, 3 H), 0.86 (d, J ϭ 7.0 Hz,
3 H) ppm. 13C NMR (75 MHz): δ ϭ 172.3, 172.3, 128.6, 128.5,
127.4, 82.1, 62.7, 52.0, 41.1, 41.1, 28.0, 22.2, 12.6, 11.7 ppm.
C19H28N2O3 (332.21): C 68.65, H 8.49, N 8.43; found C 68.70, H
8.48, N 8.53.
Experimental Section
General Remarks: Toluene, THF, and Et2O were distilled after re-
fluxing in the presence of Na/benzophenone. Silica gel 60 F254 was
used for TLC, and the spots were detected with UV. Flash column
chromatography was carried out on silica gel 60. IR spectra were
recorded as CHCl3 solutions. 1H NMR spectra were recorded at
200 or 300 MHz in CDCl3 solution with TMS as internal reference.
13C NMR spectra were recorded at 75 or 50 MHz in CDCl3 solu-
tion with CHCl3 (δ ϭ 77.0 ppm) as internal reference. Melting
points are uncorrected. The starting materials 1 were prepared as
described previously.[10]
tert-Butyl (3S*,4R*,5R*)-1-Benzyl-3,4,5-trimethyl-6-oxoperhydro-
pyridazine-3-carboxylate (6): Colorless oil (70 mg, 65%). IR
(CHCl3): ν˜ ϭ 3303, 1713, 1624 cmϪ1
.
1H NMR (200 MHz): δ ϭ
2
2
7.28Ϫ7.19 (m, 5 H), 4.96 (AB, J ϭ 10.0 Hz, 1 H), 4.75 (AB, J ϭ
10.0 Hz, 1 H), 2.46Ϫ2.35 (m, 2 H), 1.32 (s, 9 H), 1.19 (s, 3 H), 1.11
3
3
(d, J ϭ 7.0 Hz, 3 H), 1.05 (d, J ϭ 7.0 Hz, 3 H) ppm. 13C NMR
(50.5 MHz): δ ϭ 170.2, 169.8, 128.7, 128.3, 128.0, 127.3, 82.4, 60.8,
52.2, 39.4, 40.2, 27.8, 22.1, 16.4, 15.8 ppm. C19H28N2O3 (332.21):
calcd. C 68.65, H 8.49, N 8.43; found C 68.75, H 8.37, N 8.49.
Addition of Methylmagnesium Bromide. General Procedure: A solu-
tion of compounds 2 or 3 (0.32 mmol) in toluene (1.5 mL) was
added to a solution of Yb(OTf)3 (0.32 mmol, 200 mg) in toluene
(1 mL) at Ϫ50 °C and the mixture was stirred for 15 min. Methyl-
magnesium bromide (3  in Et2O, 0.64 mmol, 0.21 mL) was added
dropwise, and the reaction mixture was stirred for 24 h. The tem-
perature of the mixture was raised to room temp. and a solution
of saturated NaHCO3 (15 mL) was added. The organic layer was
decanted, the aqueous layer was extracted with EtOAc (3 ϫ
15 mL), and the combined organic extracts were dried with
MgSO4. Evaporation of the solvent under reduced pressure af-
forded a residue, which was purified by column chromatography
(hexane/EtOAc, 70:30).
2-Benzyl-6-(1-hydroxy-1-methylethyl)-4,5-dihydropyridazin-3(2H)-
one (7a): Colorless oil (8 mg, 10%). IR (CHCl3): ν ϭ 3470, 1665
cmϪ1. 1H NMR (300 MHz, CDCl3): δ ϭ 7.31Ϫ7.26 (m, 5 H), 4.98
(s, 2 H), 3.62 (s, 1 H), 2.52Ϫ2.48 (m, 4 H), 1.38 (s, 6 H) ppm. 13C
NMR (75 MHz, CDCl3): δ ϭ 165.2, 159.4, 137.2, 128.4, 128.3,
127.4, 72.2, 51.9, 27.7, 27.2, 21.3 ppm. C14H18N2O2 (246.14): C
68.27, H 7.37, N 11.37; found C 68.42, H 7.56, N 11.10
˜
2-Benzyl-6-(1-hydroxy-1-methylethyl)-5-methyl-4,5-dihydropy-
ridazin-3(2H)-one (7b): Colorless oil (8 mg, 10%). IR (CHCl3): ν˜ ϭ
3465, 1660 cmϪ1. 1H NMR (300 MHz, CDCl3): δ ϭ 7.24Ϫ7.19 (m,
2
5 H), 5.01 (1 H, B part of AB system, J ϭ 14.5 Hz), 4.78 (1 H, A
2
tert-Butyl
1-Benzyl-3-methyl-6-oxoperhydropyridazine-3-carb-
part of AB system, J ϭ 14.5 Hz), 3.55 (s, 1 H), 2.79Ϫ2.68 (m, 1
3
oxylate (5a): White solid (70 mg, 70%); m.p. 82Ϫ84 °C (hexane).
H), 2.45Ϫ2.25 (m, 2 H), 1.33 (s, 6 H), 1.10 (d, J ϭ 7.0 Hz, 3 H)
IR (CHCl3): ν˜ ϭ 3296, 1716, 1658 cmϪ1
.
1H NMR (300 MHz, ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 164.8, 163.5, 137.2, 128.5,
4192
Eur. J. Org. Chem. 2002, 4190Ϫ4194

Diastereoselective Synthesis of α-Methylpyroglutamates
128.3, 127.4, 72.5, 51.7, 35.2, 28.2, 27.1, 27.0, 15.8 ppm. tert-Butyl (2S*,3R*,4S*)-1-Benzylidenamino-2,3,4-trimethyl-5-oxo-
FULL PAPER
C15H20N2O2 (260.15): calcd. C 69.20, H 7.74, N 10.76; found C
69.44, H 7.81, N 10.55.
pyrrolidine-2-carboxylate (9d): Colorless oil (90 mg, 80%). IR
1
(CHCl3): ν˜ ϭ 1711, 1691cmϪ1. H NMR (200 MHz): δ ϭ 9.62 (s,
1 H), 7.73Ϫ7.39 (m, 5 H), 2.40Ϫ2.32 (m, 2 H), 1.67 (s, 3 H), 1.49
(s, 9 H), 1.43 (d, 3J ϭ 7.0 Hz, 3 H), 1.15 (d, 3J ϭ 7.0 Hz, 3 H)
ppm. 13C NMR (50.5 MHz): δ ϭ 173.6, 170.5, 155.0, 134.8, 130.6,
128.6, 127.5, 82.6, 68.1, 47.1, 31.9, 29.3, 22.7, 14.1, 9.8 ppm.
C19H26N2O3 (330.19): calcd. C 69.06, H 7.93, N 8.48; found C
68.97, H 7.96, N 8.50
2-Benzyl-6-(1-hydroxy-1-methylethyl)-5-phenyl-4,5-dihydropy-
ridazin-3(2H)-one (7c): Colorless oil (10 mg, 10%). IR (CHCl3): ν˜ ϭ
3430, 1660 cmϪ1. 1H NMR (200 MHz, CDCl3): δ ϭ 7.29Ϫ6.61 (m,
2
10 H), 5.24 (1 H, B part of AB system, J ϭ 14.5 Hz), 4.63 (1 H,
A part of AB system, 2J ϭ 14.5 Hz), 3.88 (dd, 3J ϭ 7.0, 3J ϭ
2
3
1.5 Hz, 1 H), 3.25 (br. s, 1 H), 2.72 (dd, J ϭ 15.5, J ϭ 7.0 Hz, 1
2
3
H), 2.57 (dd, J ϭ 15.5, J ϭ 1.5 Hz, 1 H), 1.33 (s, 3 H), 1.05 (s, 3
tert-Butyl 1-Benzylamino-2-methyl-5-oxopyrrolidine-2-carboxylate
(10): Hydrazine hydrate (80%, 0.33 mL) and Pd/C (10%) (200 mg)
H) ppm. 13C NMR (50.5 MHz, CDCl3): δ ϭ 163.4, 160.7, 137.1,
136.7, 129.2, 128.4, 127.7, 127.6, 126.9, 72.9, 51.9, 38.6, 36.6, 29.3, were added to a solution of 9a (0.33 mmol, 100 mg) in MeOH
27.6 ppm. C20H22N2O2 (322.17): calcd. C 74.51, H 6.88, N 9.93;
found C 74.70, H 7.02, N 9.71.
(10 mL) . The mixture was stirred at reflux for 24 h. After cooling
to room temp., the mixture was filtered through Celite and the solid
washed with MeOH (5 mL). The solvent was evaporated under re-
duced pressure to give an oil which was purified by chromato-
graphy (hexane/EtOAc, 70:30). Colorless oil (90 mg, 90%). IR
(4R*,5R*)-2-Benzyl-6-(1-hydroxy-1-methylethyl)-4,5-dimethyl-4,5-
dihydropyridazin-3(2H)-one (8): Colorless oil (18 mg, 20%). IR
(CHCl3): ν˜ ϭ 3460, 1660 cmϪ1. 1H NMR (200 MHz, CDCl3): δ ϭ
7.36Ϫ7.27 (m, 5 H), 4.95 (d, 2J ϭ 14.5 Hz, 1 H), 4.73 (d, 2J ϭ
14.5 Hz, 1 H), 2.49Ϫ2.23 (m, 2 H), 1.32 (s, 6 H), 1.02 (d, 3J ϭ
7.0 Hz, 3 H), 1.01 (d, 3J ϭ 7.0 Hz, 3 H) ppm. 13C NMR
(50.5 MHz, CDCl3): δ ϭ 164.6, 163.2, 137.1, 128.4, 128.3, 127.8,
72.8, 51.6, 39.8, 34.2, 27.3, 27.0, 15.8, 15.2 ppm. C16H22N2O2
(274.17): calcd. C 70.04, H 8.08, N 10.21; found C 70.25, H 8.21,
N 10.05.
(CHCl3): ν˜ ϭ 3392, 1685 cmϪ1
.
1H NMR (200 MHz): δ ϭ
7.37Ϫ7.31 (m, 5 H), 4.19 (d, 2J ϭ 12.0 Hz, 1 H), 3.98 (d, 2J ϭ
3
3
12.0 Hz, 1 H), 2.41 (dd, J ϭ 10.0, J ϭ 6.0 Hz), 2.23Ϫ2.11 (m, 1
H), 1.91Ϫ1.75 (m, 1 H), 1.44 (s, 9 H), 1.38 (s, 3 H) ppm. 13C NMR
(50.5 MHz): δ ϭ 175.9, 172.5, 137.6, 129.2, 128.3, 127.5, 81.9, 67.5,
55.2, 29.7, 29.5, 27.9, 21.9 ppm. C17H24N2O3 (304.18): calcd. C
67.08, H 7.95, N 9.20; found C 67.51, H 7.40, N 9.28.
Synthesis of Pyroglutamates 4. General Procedure: Raney Ni (80%
dispersion in H2O, 10 mL) was added to a solution of compounds
9 (0.33 mmol, 100 mg) in EtOH (10 mL) . The reaction mixture
was stirred at reflux for 24 h. At room temp., the solution was
filtered and the remaining solid material was washed with EtOH
(10 mL). The solvent was evaporated, and the residue was purified
by chromatography (hexane/EtOAc, 70:30).
Addition of Lithium Bis(trimethylsilyl)amide to 5 and 6. General
Procedure: BuLi (1.6  in hexane, 2.64 mmol, 1.14 mL) was added
to a solution of HMDS (1.32 mmol, 0.28 mL) in THF (1 mL) at 0
°C and the solution was stirred for 1 h. A solution of 5 or 6
(0.33 mmol) in THF (1 mL) was added at Ϫ78 °C, and the temper-
ature was slowly raised (3 h) to room temp. and stirred for a further
24 h. After addition of H2O (3 mL), the organic layer was decanted.
The aqueous layer was extracted with EtOAc (3 ϫ 3 mL), and the
combined organic extracts were dried with MgSO4. Solvent evap-
oration under reduced pressure afforded a residue, which was puri-
fied by column chromatography (hexane/EtOAc, 80:20).
tert-Butyl 2-Methyl-5-oxopyrrolidine-2-carboxylate (4a): Colorless
oil (62 mg, 95%). IR (CHCl3): ν˜ ϭ 3430, 1700 cmϪ1 1H NMR
.
(300 MHz): δ ϭ 5.90 (s, 1 H), 2.52Ϫ2.32 (m, 3 H), 2.04Ϫ1.97 (m,
1 H), 1.48 (s, 9 H), 1.26 (s, 3 H) ppm. 13C NMR (75 MHz): δ ϭ
176.8, 172.9, 82.3, 62.6, 27.9, 25.9, 22.7, 14.1 ppm. C10H17NO3
(199.12): calcd. C 60.28, H 8.60, N 7.03; found C 60.30, H 8.54,
N 7.10.
tert-Butyl
1-Benzylidenamino-2-methyl-5-oxopyrrolidine-2-carb-
oxylate (9a): Colorless oil (85 mg, 85%). IR (CHCl3): ν˜ ϭ 1734,
1691 cmϪ1. 1H NMR (200 MHz): δ ϭ 9.35 (s, 1 H), 7.64Ϫ7.29 (m,
5 H), 2.54Ϫ2.45 (m, 2 H), 2.24Ϫ2.20 (m, 1 H), 1.96Ϫ1.85 (m, 1
tert-Butyl (2S*,3R*)-2,3-Dimethyl-5-oxopyrrolidine-2-carboxylate
H), 1.54 (s, 3 H), 1.37 (s, 9 H) ppm. 13C NMR (50.5 MHz): δ ϭ (4b): Colorless oil (63 mg, 90%). IR (CHCl3): ν˜ ϭ 3440, 1705 cmϪ1
.
172.3, 172.0, 154.1, 135.0, 130.3, 128.5, 127.4, 81.9, 68.2, 29.8, 29.1,
1H NMR (200 MHz): δ ϭ 5.13 (s, 1 H), 2.39Ϫ1.29 (m, 3 H), 1.38
3
27.9, 22.9 ppm. C17H22N2O3 (286.18): calcd. C 67.53, H 7.33, N (s, 9 H), 1.25 (s, 3 H), 1.15 (d, J ϭ 7.0 Hz, 3 H) ppm. 13C NMR
9.26; found C 67.51, H 7.40, N 9.28.
(50.5 MHz): δ ϭ ϭ 176.7, 172.8, 82.4, 61.9, 41.2, 30.2, 28.0, 22.7,
13.8 ppm. C11H19NO3 (213.14): calcd. C 61.95, H 8.98, N 6.57;
found C 62.05, H 7.09, N 6.49.
tert-Butyl (2S*,3R*)-1-Benzylidenamino-2,3-dimethyl-5-oxopyrroli-
dine-2-carboxylate (9b): Colorless oil (90 mg, 85%). IR (CHCl3):
ν˜ ϭ 1732, 1712 cmϪ1
.
1H NMR (200 MHz): δ ϭ 9.41 (s, 1 H),
tert-Butyl
(2S*,3S*)-2-Methyl-5-oxo-3-phenylpyrrolidine-2-carb-
7.66Ϫ7.32 (m, 5 H), 2.01Ϫ1.99 (m, 3 H), 1.34 (s, 9 H), 1.19 (s, 3 oxylate (4c): Colorless oil (82 mg, 90%). IR (CHCl3): ν˜ ϭ 3430,
H), 1.17 (d, J ϭ 7.0 Hz, 3 H) ppm. 13C NMR (50.5 MHz): δ ϭ
1700 cmϪ1 1H NMR (200 MHz): δ ϭ 7.32Ϫ7.29 (m, 5 H), 3.79
.
3
171.7, 170.3, 155.1, 134.6, 130.7, 128.6, 27.6, 82.7, 69.9, 44.6, 29.7, (dd, 3J ϭ 10, 3J ϭ 8.0 Hz, 1 H), 3.00Ϫ2.87 (m, 2 H), 1.22 (s, 3 H),
28.0, 21.9, 12.2 ppm. C18H24N2O3 (316.18): calcd. C 68.33, H 7.65,
N 8.85; found C 68.40, H 7.70, N 8.78.
1.16 (s, 9 H) ppm. 13C NMR (50.5 MHz): δ ϭ 177.1, 172.4, 130.0,
128.7, 128.4, 128.0, 127.6, 82.1, 64.2, 43.7, 31.3, 27.8, 22.2 ppm.
C16H21NO3 (275.15): calcd. C 69.79, H 7.69, N 5.09; found C
69.89, H 7.78, N 5.01.
tert-Butyl (2S*,3S*)-1-Benzylidenamino-2-methyl-5-oxo-3-phenyl-
pyrrolidine-2-carboxylate (9c): Colorless oil (100 mg, 80%). IR
1
(CHCl3): ν˜ ϭ 1635 cmϪ1. H NMR (200 MHz): δ ϭ 9.41 (s, 1 H), tert-Butyl (2S*,3R*,4S*)-2,3,4-Trimethyl-5-oxopyrrolidine-2-carb-
3
3
7.93Ϫ7.35 (m, 10 H), 3.49 (dd, J ϭ 11.5, J ϭ 8.5 Hz, 1 H), 3.21 oxylate (4d): Colorless oil (30 mg, 90%). IR (CHCl3): ν˜ ϭ 3435,
(dd, 2J ϭ 16.5, 3J ϭ 11.5 Hz, 1 H), 3.81 (dd, 2J ϭ 16.5, 3J ϭ 8.5 Hz,
1 H), 1.72 (s, 3 H), 1.25 (s, 9 H) ppm. 13C NMR: δ (50.5 MHz):
1705 cmϪ1. 1H NMR (200 MHz): δ ϭ 2.26Ϫ2.13 (m, 2 H), 1.41 (9
H,s), 1.38 (d, 3J ϭ 7.0 Hz, 3 H), 1.20 (s, 3 H), 1.10 (d, 3J ϭ 7.0 Hz,
δ ϭ 169.9, 154.8, 135.5, 134.4, 130.4, 130.0, 128.6, 128.5, 128.0, 3 H) ppm. 13C NMR (50.5 MHz): δ ϭ 176.6, 173.2, 82.4, 61.5,
127.5, 82.2, 73.3, 46.9, 35.3, 27.8, 22.7 ppm. C23H26N2O3 (378.19): 43.2, 30.4, 28.9, 22.4, 14.1, 11.4 ppm. C12H21NO3 (227.15): calcd.
calcd. C 72.99, H 6.92, N 7.40; found C 73.07, H 6.87, N 7.37.
C 63.41, H 9.31, N 6.16; found C 63.47, H 9.27, N 6.15.
Eur. J. Org. Chem. 2002, 4190Ϫ4194
4193

´
´
C. Alvarez-Ibarra, A. G. Csaky¨, C. Gomez de la Oliva
FULL PAPER
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Mico, C. Najera, J. Ezquerra, C. Pedregal, An. Quim. Int. Ed.
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Acknowledgments
DGICYT (project BQU 2000-0792) is gratefully acknowledged for
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The creation of asymmetric quaternary centres is one of the
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C. Alvarez Ibarra, A. G. Csaky¨, C. Gomez de la Oliva, J. Org.
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See: C. Najera, M. Yus, Tetrahedron: Asymmetry 1999, 10, 2245
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[6c]
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Received May 27, 2002
[O02284]
4194
Eur. J. Org. Chem. 2002, 4190Ϫ4194