[1,2] Boc migration during pyroglutamate alkylations

Article abstract of DOI:10.1016/j.tet.2005.05.003

Treatment of N-Boc protected pyroglutamates with strong bases lead to a Boc migration from the N-atom to the C2 position when no or poor electrophiles are being used.

Full text of DOI:10.1016/j.tet.2005.05.003

Tetrahedron 61 (2005) 6749–6756
[1,2] Boc migration during pyroglutamate alkylations
*
Nicolai Dieltiens, Christian V. Stevens, Kurt G. R. Masschelein and Thomas Rammeloo
Research group SynBioC, Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure links 653,
B-9000 Ghent, Belgium
Received 22 February 2005; revised 22 April 2005; accepted 2 May 2005
Abstract—Treatment of N-Boc protected pyroglutamates with strong bases lead to a Boc migration from the N-atom to the C2 position when
no or poor electrophiles are being used.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
pyroglutamates occurs at the 2-position, resulting in 6
and 7.8
Pyroglutamates and their syntheses have received a lot of
attention over the years because of their importance in
several domains. Pyroglutamic acid is a very useful and
versatile starting material for the synthesis of both natural
and unnatural products. Intensive study of glutamate
analogues resulted in specific inhibitors of different receptor
types of the mammalian central nervous system.1 It has also
been used for the synthesis of pyrrolidine alkaloids,2
kainoids,3 (K)-bulgecinine,4 (K)-domoic acid,5 enantio-
merically pure glycine and proline derivatives,6 a wide
variety of non-proteinogenic amino acids,7 etc.
The regioselectivity of the alkylation of N-Boc protected
pyroglutamates was explained by the formation of a
stabilized Li-salt 4 which directs the alkylation to the
4-position. This stabilized intermediate cannot be formed in
N-benzyl or N-unprotected derivatives, thus resulting in
alkylation at the 2-position.
This proves that the Boc protecting group plays a crucial
role in pyroglutamate chemistry. The reactivity of this
carbamate group, however, is often an underestimated
feature. There are numerous reports of cases where the Boc
group reacts as an electrophile or a nucleophile, resulting in
unexpected and often undesired side reactions.9
Alkylation of pyroglutamates has therefore been essential in
order to expand the range of glutamate analogues and to
study their biological properties. The attractiveness of
pyroglutamates as a building block lies in the fact that the
site of alkylation can be directed by changing the protecting
group on N (Scheme 1). Alkylation of N-Boc protected
pyroglutamates 1 results in C4 functionalized derivatives 5
whereas alkylation of N-benzyl 2 or N-unprotected 3
2. Results and discussion
During an ongoing project on the synthesis of 2,4-
methanoproline 9,10 pyroglutamate derivative 8 was
Scheme 1.
Keywords: Boc migration; Pyroglutamate; Alkylation; Carbamates.
*
Corresponding author. Tel.: C32 9 2645957; fax: C32 9 264643; e-mail: chris.stevens@ugent.be
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.05.003

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N. Dieltiens et al. / Tetrahedron 61 (2005) 6749–6756
Scheme 4.
Scheme 2.
derivatives were synthesized and subjected to the same
reaction conditions (Table 1). In this way, we found that
esters with a varying substitution pattern underwent the
same reaction. Although deprotonation of the pyrogluta-
mates in entries b and h could result in theory in
intramolecular substitution of the chloride with formation
of a six-membered ring, only the [1,2] Boc migrated product
was observed. When there is no or only one substituent
present on the C4 position, a double amount of base is
needed since the first equivalent is consumed in deprotonat-
ing this position. In this case, the Boc migration occurs via a
dianion. Some of the Boc migrated products proved to be
quite unstable on silica gel during purification (e.g., entries g
and h), leading to a substantial loss of material.
synthesized,11 as a possible precursor for this interesting
amino acid (Scheme 2).
It was observed however, that treating 8 with 1.5 equiv of
LiHMDS did not lead to the envisaged 2-azabicyclo[2.1.1]-
hexane skeleton, although the starting material was
completely converted to a new product. In the 1H-spectrum,
the CH proton at the C2-position had disappeared and the
remaining CH2 of the ring was reduced from a ABX-system
to a AB-system. Furthermore a broad singlet appeared
around 6.41 ppm, which is typical for a NH proton of an
amide. In the 13C-spectrum the carbonyl of the Boc group,
which is normally around 150 ppm was missing, but two
t-Butyl groups were still present. Taking all this information
into account, structure 10 was deduced, proving that the
Boc-group migrated from the N-atom to the C2 position.
When no substituent is present on the C4 position (entries i
and j), no Boc migration was observed. Instead, the ring-
opened products were isolated. Apparently, in these cases,
the formed dianions are unstable and the esters fragment
with formation of alkoxide anions. These anions in turn
attack another pyroglutamate molecule and induce ring-
opening with formation of racemic glutamate derivatives
15i, j (no optical rotation). In this fashion, the yield is
limited to 50% and explains the low yield of the isolated
products.
The proposed mechanism is depicted in Scheme 3. The
formed anion at the 2-position is unreactive towards the
chloromethyl group, probably because of the high ring
strain involved in the formation of a four-membered ring
within a five-membered ring, combined with the planar
character of the lactam functionality. However, at room
temperature the anion is reactive enough to attack the
adjacent N-Boc group. The formed bicyclic intermediate 11
is not stable and opens again to form 10 upon work up.
In summary, we have shown that deprotonation of N-Boc
protected pyroglutamates at the C2 position can result in the
[1,2] Boc migration in the absence of good electrophiles
resulting in the formation of functionalized g-lactam gem
dicarboxylates. This is the first example of an intra-
molecular nucleophilic attack of an ester enolate onto a
Boc-protecting group. Not only should this side reaction be
taken into account when working with pyroglutamates,
g-lactam gem dicarboxylates are useful intermediates in
organic synthesis.14
Although there are reports of the Boc moiety reacting as an
electrophile, these reactions are usually limited to intra-
molecular attacks by oxygen or nitrogen nucleophiles.9 In
the literature, only two cases of intramolecular attack on a
Boc group by a carbon nucleophile followed by Boc
migration were reported. Snieckus mentioned the migration
of the Boc group from N to the ortho carbon atom of aniline
derivatives after directed ortho metallation leading to
anthranilate esters.12 Kise et al. described that the reaction
of N,N-di-Boc-protected benzylamines 12 with KDA/
t-BuOLi at K78 8C gave N-Boc protected t-Butyl phenyl-
glycines 13 (Scheme 4).13
3. Experimental
High-resolution 1H NMR (270 MHz) and 13C NMR
(68 MHz) spectra were run with a Jeol JNM-EX 270
NMR spectrometer or on a Jeol JNM-EX 300 NMR. Peak
assignments were obtained with the aid of DEPT, 2D-
HETCOR, 2D-COSY spectra. The compounds were diluted
in deuterated solvents and the used solvent is indicated for
each compound. Mass spectra were recorded on a Varian
These examples show the Boc migration under quite
extreme reaction conditions, whereas in the case of
pyroglutamate alkylation, the Boc migration can really
compete with the alkylation reaction. In order to investigate
the generality of this reaction, a number of pyroglutamate
Scheme 3.

N. Dieltiens et al. / Tetrahedron 61 (2005) 6749–6756
6751
Table 1. [1,2] Boc migration observed for different N-Boc protected pyroglutamates upon treatment with LiHMDS in THF
Entry
Substrate
LiHMDS (equiv)
Product
Conversiona
100%
Yieldb
61%
a
1.5
b
1.5
91%
64%
c
d
e
f
3
3
3
3
3
90%
82%
86%
81%
79%
72%
56%
62%
69%
c
g
c
h
1.5
91%
i
j
3
3
77%
71%
36%
32%
a Conversion determined by 1H NMR on the crude reaction mixture.
b Yield after purification by flash chromatography.
c The product could not be obtained in sufficient purity.
MAT 112 spectrometer (70 eV), using either GC–MS
coupling or a direct inlet system. Some volatile samples
were recorded on an HP 6890 GC coupled with a HP 5973
MSD (Mass selective detector; quadrupole). Mass spectra of
molecules with a high molecular weight were recorded on
an Agilent 1100 Series VS (ES, 4000 V) mass spectrometer.
IR-spectra were obtained from a Perkin–Elmer Spectrum
One infrared spectrometer. For liquid samples, the spectra
were collected by preparing a thin film of compound
between two sodium chloride plates. The crystalline

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N. Dieltiens et al. / Tetrahedron 61 (2005) 6749–6756
compounds were mixed with potassium bromide and
pressed until a transparent potassium bromide plate was
obtained. Melting points of crystalline compounds were
measured with a Bu¨chi 540 apparatus and are uncorrected.
The elemental analysis was performed on a Perkin–Elmer
2400 Elemental Analyzer. The purification of reaction
mixtures was performed by flash chromatography using a
glass column with silica gel (Across, particle size 0.035–
0.070 mm, Pore diameter ca. 6 nm).
C23H30ClNO7: C 59.03%, H 6.46%, N 2.99%; found: C
58.89%, H 6.56%, N 3.10%.
3.1.2. 2-Benzyl 1,4-di-t-Butyl 4-(3-chloropropyl)-5-oxo-
1,2,4-pyrrolidinetricarboxylate (14b). The reaction was
performed on 2.3 mmol of starting material. 3-Bromo-1-
chloro-propane was used as electrophile (yield Z82%,
major/minor 54/46). The product was obtained as a white
powder.
1
Major. H NMR (270 MHz, CDCl3) d: 1.44 (9H, s t-Bu),
4-Alkoxycarbonyl-2-alkyl-1-t-butyl 5-oxo-1,2,4-pyrrolidine-
tricarboxylates (14c, 14d, 14e, 14f, 14g) were prepared
following the literature procedure.11
1.45 (9H, s, t-Bu), 1.37–1.5 (2H, m, CH2CH2CH2Cl), 1.79–
1.88 (2H, m, CH2CHaHbCH2ClCCHaHb ring), 2.05–2.14
(1H, m, CH2CHaHbCH2Cl), 2.76 (1H, dd, JZ13.5, 8.9 Hz,
CHaHb ring), 3.46 (2H, t, JZ5.9 Hz, CH2Cl), 4.64 (1H, dd,
JZ8.9, 7.3 Hz, CH ring), 5.19 (1H, d, JZ12.0 Hz, CHaHb-
Ph), 5.22 (1H, d, JZ12.0 Hz, CHaHbPh), 7.37 (5H, s, Ph).
13C NMR (68 MHz, CDCl3) d: 27.60 (CH2CH2CH2), 27.78
(t-Bu), 30.67 (CH2CH2CH2), 31.18 (CH2 ring), 44.64
(CH2Cl), 56.85 (CH, C2), 56.99 (Cquat., C4), 67.51
(CH2Ph), 83.22 (Cquat., t-Bu), 84.15 (Cquat., t-Bu), 128.71
(CH), 128.77 (CH), 134.86 (Cquat., Ph), 149.09 (C]O,
Boc), 168.68 (C]O), 170.58 (C]O), 170.92 (C]O). IR
(cmK1) nmax: 1793, 1724. MS: m/z (%): (ES, Pos) no MC,
342 (17), 340 (50), 91 (100). Chromatography: Hex/EtOAc
80/20 RfZ0.27. Mp 79.2–83.1 8C. Anal. Calcd
C25H34ClNO7: C 60.54%, H 6.91%, N 2.82%; found: C
60.40%, H 6.99%, N 2.89%.
3.1. General procedure for the alkylation of 2,4-dialkyl
1-t-butyl 5-oxo-1,2,4-pyrrolidinetricarboxylate at the
4-position
In a classical experiment, 1 g of 2-benzyl 1,4-di-t-butyl
5-oxo-1,2,4-pyrrolidinetricarboxylate (2.3 mmol) was dis-
solved in 10 ml of dry THF and kept under a positive N2-
pressure. 0.29 g of KOtBu (1.1 equiv) was added and the
mixture was stirred for 30 min after which the electrophile
(2 equiv) was added. The reaction mixture was subsequently
refluxed overnight. After cooling, the solution was poured in
water and extracted with diethyl ether. The organic layers
were combined and dried with MgSO4. Filtering off the
drying agent and evaporating the solvent led to a mixture
which was purified by chromatography to remove the excess
of electrophile.
1
Minor. H NMR (270 MHz, CDCl3) d: 1.36–1.50 (1H, m,
CHaHbCH2CH2Cl), 1.41 (9H, s, t-Bu), 1.42 (9H, s, t-Bu),
1.64–1.87 (2H, m, CHaHbCH2CH2ClCCH2CHaHbCH2Cl),
2.13–2.25 (1H, m, CH2CHaHbCH2Cl), 2.17 (1H, dd, JZ
13.5, 9.9 Hz, CHaHb ring), 2.82 (1H, dd, JZ13.5, 2.0 Hz,
CHaHb ring), 3.52 (2H, t, JZ5.8 Hz, CH2Cl), 4.61 (1H, dd,
JZ9.9, 2.0 Hz, CH ring), 5.12 (1H, d, JZ12.0 Hz, CHaHb-
Ph), 5.24 (1H, d, JZ12.0 Hz, CHaHbPh), 7.34–7.38 (5H, m,
CH, Ph). 13C NMR (68 MHz, CDCl3) d: 27.69 (t-Bu), 27.74
(t-Bu), 27.92 (CH2CH2CH2), 30.98 (CH2 ring), 33.24
(CH2CH2CH2), 44.47 (CH2Cl), 56.24 (CH, C2), 56.73
(Cquat., C4), 67.42 (CH2Ph), 83.16 (Cquat., t-Bu), 83.83
(Cquat., t-Bu), 128.48 (CH), 128.54 (CH), 128.61 (CH),
135.09 (Cquat., Ph), 149.09 (C]O, Boc), 167.94 (C]O),
170.19 (C]O), 170.22 (C]O). IR (cmK1) nmax: 1792,
1725. MS: m/z (%): (ES, Pos) no MC, 342 (15), 340 (45), 91
(100). Chromatography: Hex/EtOAc 80/20 RfZ0.19. Mp
91.5–93.0 8C. Anal. Calcd C25H34ClNO7: C 60.54%, H
6.91%, N 2.82%; found: C 60.42%, H 7.11%, N 2.88%.
3.1.1. 2-Benzyl 1,4-di-t-butyl 4-(chloromethyl)-5-oxo-
1,2,4-pyrrolidinetricarboxylate (14a). The reaction was
performed on 2.3 mmol of starting material. Chloroiodo-
methane was used as electrophile (yieldZ58%, major/
minor 53/47). The product was obtained as a white powder.
1H NMR (270 MHz, CDCl3) d: major: 1.41 (9H, s, t-Bu),
1.42 (9H, s, t-Bu), 2.54 (1H, dd, JZ13.9, 10.2 Hz, CHaHb
ring), 2.81 (1H, dd, JZ13.9, 2.6 Hz, CHaHb ring), 3.83 (1H,
d, JZ11.2 Hz, CHaHbCl), 3.96 (1H, d, JZ11.2 Hz, CHa-
HbCl), 4.69 (1H, dd, JZ10.2, 2.6 Hz, CH ring), 5.15 (1H, d,
JZ12.2 Hz, CHaHbPh), 5.26 (1H, d, JZ12.2 Hz, CHaHb-
Ph), 7.35K7.38 (5H, m, CH, Ph). Minor: 1.43 (9H, s, t-Bu),
1.47 (9H, s, t-Bu), 2.22 (1H, dd, JZ13.3, 6.9 Hz, CHaHb
ring), 2.87 (1H, dd, JZ13.9, 8.9 Hz, CHaHb ring), 3.80 (1H,
d, JZ11.3 Hz, CHaHbCl), 3.99 (1H, d, JZ11.3 Hz, CHa-
HbCl), 4.69 (1H, dd, JZ9.0, 6.9 Hz, CH ring), 5.21 (1H, d,
JZ12.5 Hz, CHaHbPh), 5.23 (1H, d, JZ12.5 Hz, CHaHb-
Ph), 7.35–7.38 (5H, m, CH, Ph). 13C NMR (68 MHz,
CDCl3) d: major, minor, not assigned: 27.64 (t-Bu), 27.73
(t-Bu), 28.77 (CH2 ring), 29.29 (CH2 ring), 45.30 (CH2Cl),
47.08 (CH2Cl), 56.39 (CH, ring), 56.78 (CH, ring), 59.19
(Cquat., C4), 59.55 (Cquat., C4), 67.46 (CH2Ph), 67.55
(CH2Ph), 84.06 (Cquat., t-Bu), 84.15 (Cquat., t-Bu), 84.47
(Cquat., t-Bu), 128.50 (CH), 128.53 (CH), 128.61 (CH),
128.71 (CH), 134.82 (Cquat., Ph), 135.09 (Cquat., Ph), 148.80
(C]O, Boc), 165.87 (C]O), 166.50 (C]O), 167.92
3.1.3. 1,4-Di-t-Butyl 4-(3-chloropropyl) 2-ethyl 5-oxo-
1,2,4-pyrrolidinetricarboxylate (14h). The reaction was
performed on the diastereoisomeric mixture of 14g. 3-
Bromo-1-chloro-propane was used as electrophile (yieldZ
80%, major/minor 52/48). The product was obtained as a
brown oil.
1H NMR (300 MHz, CDCl3) d: major, minor, not assigned:
1.41–1.55 (1H, m, CHAHBCH2CH2Cl); 1.45 (9H, s, t-Bu);
1.46 (9H, s, t-Bu); 1.50 (9H, s, t-Bu); 1.71–1.80 (2H, m,
CHAHBCH2CH2ClCCH2CHAHBCH2Cl); 1.82–1.91 (2H,
m, CH2CHAHBCH2ClCCH-AHB ring); 2.11–2.25 (1H, m,
CH2CHAHBCH2Cl); 2.11–2.25 (2H, m, CH2CHAHBCH2-
ClCCH-AHB ring); 2.78 (1H, dd, JZ13.5, 8.5 Hz, CHAHB
(C]O), 169.93 (C]O), 170.71 (C]O). IR (cmK1) nmax
:
(KBr) 1782, 1742. MS: m/z (%): (ES, Pos) no MC, 314 (12),
312 (28), 91 (100). Chromatography: Hex/EtOAc 80/20
RfZ0.22 and 0.19. Mp 89.2–90.3 8C. Anal. Calcd

N. Dieltiens et al. / Tetrahedron 61 (2005) 6749–6756
6753
ring); 2.80 (1H, dd, JZ14.1, 2.5 Hz, CH-AHB ring); 3.53
(2H, t, JZ6.1 Hz, CH2Cl); 3.53 (2H, t, JZ6.0 Hz, CH2Cl);
4.13–4.29 (2H, m, CH2CH3); 4.13–4.29 (2H, m, CH2CH3);
4.55 (1H, dd, JZ10.0, 2.1 Hz, CH ring); 4.59 (1H, dd, JZ
8.6 Hz, JZ7.7 Hz, CH ring). 13C NMR (75 MHz, CDCl3) d:
major, minor, not assigned: 14.13 (CH2CH3–); 14.13
(CH2CH3–); 27.72 (t-Bu); 27.84 (t-Bu); 27.95 (CH2CH2-
CH2); 28.29 (CH-2CH2CH2); 30.97 (CH2CH2CH2); 31.16
(CH2 ring, C3); 31.29 (CH2 ring, C3); 33.32 (CH2CH2CH2);
44.47 (CH-2Cl); 44.70 (CH2Cl); 56.21 (CH ring, C2); 56.71
(Cquat, C4); 56.96 (CH ring, C2); 57.04 (Cquat, C4); 61.69
(CH2CH3); 61.81 (CH2CH3); 83.02 (Cquat, t-Bu); 83.19
(Cquat, t-Bu); 83.68 (Cquat, t-Bu); 84.03 (Cquat, t-Bu); 149.15
(C]O, N-Boc); 149.15 (C]O, N-Boc); 167.94 (C]O);
168.74 (C]O); 170.25 (C]O); 170.32 (C]O); 170.65
(C]O); 171.12 (C]O). IR (cmK1) nmax: 1725 (C]O);
1794 (C]O). MS: m/z (%): (ES, pos) no MC; 366 (13); 325
(7); 280 (41); 279 (14); 278 (100); 234 (6); 232 (11); 202
(16); 158 (9). Anal. Calcd C20H32ClNO7: C 55.36%, H
7.43%, N 3.23%; found: C 55.18%, H 7.62%, N 3.46%.
br. s, CH2Ph), 6.39 (1H, br. s, NHC]O), 7.36 (5H, m, CH,
Ph). 13C NMR (68 MHz, CDCl3) d: 27.61 (t-Bu), 27.78
(t-Bu), 27.78 (CH2CH2CH2Cl), 31.75 (CH2CH2CH2Cl),
36.39 (CH2 ring), 44.80 (CH2Cl), 55.20 (Cquat., C4), 66.39
(Cquat., C2), 68.11 (COOCH2Ph), 82.79 (Cquat., t-Bu), 84.44
(Cquat., t-Bu), 128.77 (CH), 129.22 (CH), 134.86 (Cquat., Ph),
166.97 (C]O), 168.35 (C]O), 169.36 (C]O), 173.70
(C]O). IR (cmK1) nmax: 1742, 2978. MS: m/z (%): (ES,
Pos) no MC, 386 (20), 384 (57), 91 (100). Chromatography:
Hex/EtOAc 70/30 RfZ0.21. Anal. Calcd C25H34ClNO7: C
60.54%, H 6.91%, N 2.82%; found: C 60.38%, H 7.09%, N
3.02%.
3.1.6. 2,4-Dibenzyl 1-t-butyl-5-oxo-1,2,4-pyrrolidine-
tricarboxylate (14c). Yield 83% (major/minor 80/20), the
product is obtained as a brown oil.
1H NMR (270 MHz, CDCl3) d: major: 1.43 (9H, s, t-Bu),
2.23 (1H, dd, JZ13.4, 2.3 Hz), 2.71 (1H, ddd, JZ13.5, 9.1,
10.2 Hz, CHaHb ring), 3.71 (1H, dd, JZ10.7 Hz, JZ9.1 Hz,
CH, C4), 4.70 (1H, dd, JZ9.6, 2.3 Hz, NCH). Minor: 1.41
(9H, s, t-Bu), 2.52–2.59 (2H, m, CHaHb ring), 3.58 (1H, dd,
JZ8.9, 5.6 Hz, CH, C4) 4.64 (1H, dd, JZ8.6, 5.0 Hz,
NCH), not assigned 5.07–5.26 (4H, m, CH2Ph), 7.33–7.39
(10H, m, Ph). 13C NMR (68 MHz, CDCl3) d: major, minor,
not assigned: 24.65 (CH2), 25.3 (CH2), 27.31 (tBu), 27.71
(tBu), 48.44 (CH, C4), 48.75 (CH, C4), 57.19 (NCH), 57.63
(NCH), 67.35 (CH2Ph), 67.49 (CH2Ph), 67.62 (CH2Ph),
83.99 (Cquat), 84.15 (Cquat), 128.15 (CH), 128.3 (CH),
128.37 (CH), 128.49 (CH), 128.57 (CH), 128.67 (CH),
134.89 (Cquat, Ph), 135.11 (Cquat, Ph), 148.85 (C]O, Boc),
148.94 (C]O, Boc), 167.74 (C]O), 167.81 (C]O),
3.1.4. 2-Benzyl 2,4-di-t-butyl 4-(chloromethyl)-5-oxo-
2,2,4-pyrrolidinetricarboxylate (15a). To a solution of
0.1 g (0.2 mmol) of the major diastereoisomer of 14a in
2 ml of dry THF, 0.32 ml (1.5 equiv) of a LiHMDS solution
(1 M in hexanes) was added at K78 8C and under a N2-
atmosphere. The mixture was stirred for 30 min at this
temperature. After allowing the reaction to warm up
overnight to room temperature, it was quenched with a
saturated NH4Cl/NH4OH solution and extracted with
EtOAc. The organic phase was washed with water and
dried with MgSO4. Filtering off the MgSO4 and evaporating
the filtrate gave the crude product that was purified by
column chromatography which led to 0.061 g of 15a as a
clear oil (yield Z61%).
170.17 (C]O, Boc), 170.65 (C]O, Boc). IR (cmK1
)
nmax: 1795, 1733. MS: m/z (%): no MC, 353 (23), 219 (19),
200 (32), 180 (18), 107 (38), 92 (38), 91 (100), 65 (22), 57
(93). Chromatography: Hex/EtOAc 80/20 RfZ0.12. Anal.
Calcd C25H27NO7: C 66.21%, H 6.00%, N 3.09%; found: C
65.92%, H 6.12%, N 3.25%.
1H NMR (270 MHz, CDCl3) d: 1.34 (9H, s, t-Bu), 1.42 (9H,
s, t-Bu), 2.90 (1H, d, JZ14.5 Hz, CHaHb ring), 3.23 (1H, d,
JZ14.5 Hz, CHaHb ring), 3.86 (1H, d, JZ11.4 Hz, CHa-
HbCl), 3.90 (1H, d, JZ11.4 Hz, CHaHbCl), 5.22 (1H, d, JZ
11.9 Hz, CHaHbPh), 5.26 (1H, d, JZ11.9 Hz, CHaHbPh),
6.41 (1H, br. s, NHCO), 7.36 (5H, s, Ph). 13C NMR
(68 MHz, CDCl3) d: 27.53 (t-Bu), 27.66 (t-Bu), 34.44 (CH2
ring), 45.48 (CH2Cl), 57.68 (Cquat., C4), 66.31 (Cquat., C2),
68.18 (CHC]O2Ph), 83.74 (Cquat., Ph), 84.46 (Cquat., t-Bu),
128.70 (CH), 128.79 (CH), 128.88 (CH), 134.72 (Cquat., Ph),
3.1.7. 2,4-Dibenzyl 2-t-butyl 5-oxo-2,2,4-pyrrolidine-
tricarboxylate (15c). The reaction is similar to that of the
conversion of 14a–15a.The reaction was performed on the
diastereoisomeric mixture of 14c and gave 15c as a clear oil.
(Major/minor 54/46).
1H NMR (270 MHz, CDCl3) d: major, minor, not assigned:
1.32 (9H, s, t-Bu), 1.34 (9H, s, t-Bu), 2.82–2.94 (2H, m,
CH2), 3.57–3.64 (1H, m, CHCH2), 5.13–5.26 (4H, m,
COOCH2Ph), 6.54 (1H, NH), 7.26–7.37 (10H, m, CH, Ph).
13C NMR (68 MHz, CDCl3) d: MAJOR, MINOR, not
assigned: 27.51 (t-Bu), 27.55 (t-Bu), 31.21 (CH2 ring),
31.32 (CH2 ring), 47.12 (CH, C4), 47.19 (CH, C4), 66.88
(Cquat., C2), 67.21 (Cquat., C2), 67.49 (COOCH2Ph), 67.53
(COOCH2Ph), 68.03 (COOCH2Ph), 68.21 (COOCH2Ph),
84.17 (Cquat., t-Bu), 84.31 (Cquat., t-Bu), 128.30 (CH),
128.34 (CH), 128.43 (CH), 128.55 (CH), 128.66 (CH),
128.69 (CH), 134.55 (Cquat., Ph), 134.70 (Cquat., Ph), 135.27
(Cquat., Ph), 135.33 (Cquat., Ph), 166.41 (C]O), 166.75
(C]O), 167.98 (C]O), 168.35 (C]O), 170.83 (C]O). 1H
NMR (270 MHz, C6D6) d: 1.18 (9H, s, t-Bu), 1.21 (9H, s,
t-Bu), 2.62 (1H, dd, JZ13.9, 9.2 Hz, CHaHb), 2.68 (1H, dd,
JZ13.7, 9.6 Hz, CHaHb), 3.04 (1H, dd, JZ13.7, 10.6 Hz,
CHaHb), 3.06 (1H, dd, JZ13.9, 11.2 Hz, CHaHb), 3.39–3.46
167.33 (C]O), 167.96 (C]O), 170.83 (C]O). IR (cmK1
)
nmax: 1739. MS: m/z (%): (ES, Pos) no MC, 358 (10), 356
(20), 91 (100). Chromatography: 80/20 Hex/EtOAc RfZ
0.30. Anal. Calcd C23H30ClNO7: C 59.03%, H 6.46%, N
2.99%; found: C 59.10%, H 6.39%, N 3.08%.
3.1.5. 2-Benzyl 2,4-di-t-butyl 4-(3-chloropropyl)-5-oxo-
2,2,4-pyrrolidinetricarboxylate (15b). The reaction is
similar to that of the conversion of 14a–15a. The reaction
was performed on the major diastereoisomer of 14b. The
product was obtained as a clear oil.
1H NMR (270 MHz, CDCl3) d: 1.33 (9H, s, t-Bu), 1.42 (9H,
s, t-Bu), 1.39–1.47 (2H, m, CH2CH2CH2Cl), 1.78–1.87 (1H,
m, CH2CHaHbCH2Cl), 2.05–2.12 (1H, m, CH2CHaHbCH2-
Cl), 2.53 (1H, d, JZ14.3 Hz, CHaHb ring), 3.16 (1H, d, JZ
14.3 Hz, CHaHb ring), 3.53–3.55 (2H, m, CH2Cl), 5.22 (2H,

6754
N. Dieltiens et al. / Tetrahedron 61 (2005) 6749–6756
(1H, m, CH), 4.86–4.99 (4H, m, CH2Ph), 7.04–7.24 (10H,
m, CH, Ph), 8.07(1H, br. s, NH), 8.10 (1H, br. s, NH). 13C
NMR (68 MHz, C6D6) d: 27.39 (t-Bu), 27.46 (t-Bu), 31.59
(CH2 ring), 31.46 (CH2 ring), 47.69 (CH, C4), 47.76 (CH,
C4), 67.24 (CH2Ph), 67.31 (CH2Ph), 67.67 (CH2Ph), 67.74
3.1.10. 2-Benzyl 1,4-di-t-butyl 5-oxo-1,2,4-pyrrolidine-
tricarboxylate (14e). Di-t-butyldicarbonate (1.5 equiv) was
used as electrophile and once it was added the reaction was
allowed to warm to room temperature. The product
crystallizes as a white powder (major/minor 78/22).
(CH2Ph), 67.82 (Cquat., C2), 68.00 (Cquat., C2), 83.36 (Cquat.
,
t-Bu), 83.49 (Cquat., t-Bu), 128.21 (CH), 128.25 (CH),
128.39 (CH), 128.66 (CH), 128.75 (CH), 135.56 (Cquat., Ph),
135.70 (Cquat., Ph), 136.15 (Cquat., Ph), 136.21 (Cquat., Ph),
167.04 (C]O), 167.36 (C]O), 168.51 (C]O), 168.75
(C]O), 168.78 (C]O), 168.87 (C]O), 171.79 (C]O),
171.86 (C]O). IR (cmK1) nmax: 3032, 1610, 1495, 1454,
1741, 1714. MS: m/z (%): (ES, Pos) 454 (MCHC, 25), 398
(100), 181 (34), 91 (35). Chromatography: Hex/EtOAc
70/30 RfZ0.19. Anal. Calcd C25H27NO7: C 66.21%, H
6.00%, N 3.09%; found: C 65.99%, H 6.10%, N 3.18%.
1H NMR (270 MHz, CDCl3) d: major, minor, not assigned:
1.40 (9H, s, t-Bu), 1.42 (9H, s, t-Bu), 1.45 (9H, s, t-Bu), 1.47
(9H, s, t-Bu), 2.18 (1H, ddd, JZ13.4, JZ9.0, 2.3 Hz,
CHaHb), 2.47–2.53 (2H, m, CH2 ring), 2.67 (1H, ddd, JZ
13.5, 10.1, 9.9 Hz, CHaHb), 3.42 (1H, dd, JZ6.4, 8.4 Hz,
CH), 3.53 (1H, dd, JZ10.4, 9.1 Hz, CH), 4.61 (1H, dd, JZ
5.9, 7.9 Hz, NCH), 4.68 (1H, dd, JZ9.6, 2.3 Hz, NCH),
5.13–5.28 (2H, m, COOCH2Ph), 7.26–7.45 (5H, m, CH,
Ph). 13C NMR (68 MHz, CDCl3) d: major, minor, not
assigned: 24.71 (CH2 ring), 25.23 (CH2 ring), 27.67 (t-Bu),
27.76 (t-Bu), 27.85 (t-Bu), 28.23 (t-Bu), 49.29 (CH, C4),
49.67 (CH, C4), 57.18 (NCH), 57.56 (NCH), 67.24
(COOCH2Ph), 67.38 (COOCH2Ph), 82.59 (Cquat., t-Bu),
83.63 (Cquat., t-Bu), 83.84 (Cquat., t-Bu), 128.44 (CH),
128.50 (CH), 128.55 (CH), 128.66 (CH), 135.02 (Cquat., Ph),
135.16 (Cquat., t-Bu), 148.93 (C]O, Boc), 148.98 (C]O,
Boc), 156.6 (C]O), 166.45 (C]O), 167.09 (C]O),
168.14 (C]O), 168.43 (C]O), 170.42 (C]O), 170.83
(C]O). IR (cmK1) nmax: 1703, 1726. MS: m/z (%): (direct
inlet) no MC, 308 (7), 264 (25), 129 (19), 128 (98), 110
(37), 91 (87), 57 (100). Chromatography: Hex/EtOAc 70/30
RfZ0.31 Mp 84–86.5 8C (yield Z77%). Anal. Calcd
C22H29NO7: C 62.99%, H 6.97%, N 3.34%; found: C
62.71%, H 7.25%, N 3.25%.
3.1.8. 1,4-Di-t-butyl 2-methyl 5-oxo-1,2,4-pyrrolidine-
tricarboxylate (14d). 1H NMR (300 MHz, CDCl3) d:
major, minor, not assigned: 1.47 (9H, s, t-Bu); 1.49 (9H,
s, t-Bu); 1.50 (9H, s, t-Bu); 2.18 (1H, ddd, JZ13.4, 9.0,
2.5 Hz, CHAHB); 2.43–2.59 (2H, m, CH2 ring); 2.68 (1H,
ddd, JZ13.4, 10.2, 9.4 Hz, CHAHB); 3.47 (1H, dd, JZ9.4,
5.8 Hz, CH, C4); 3.56 (1H, dd, JZ10.2, 9.0 Hz, CH, C4);
3.78 (3H, s, OCH3); 3.79 (3H, s, CH3); 4.61 (1H, dd, JZ9.1,
5.0 Hz, CH, C2); 4.67 (1H, dd, JZ9.4, 2.5 Hz, CH, C2). 13C
NMR (75 MHz, CDCl3) d: major, minor, not assigned:
24.81 (CH2 ring); 25.33 (CH2 ring); 27.82 (t-Bu); 27.91
(t-Bu); 49.36 (CH, C4); 49.68 (CH, C4); 52.49 (CH3); 52.67
(OCH3); 57.12 (CH, C2); 57.50 (CH, C2); 82.66 (Cquat
,
t-Bu); 83.71 (Cquat, t-Bu); 83.93 (Cquat, t-Bu); 149.03
(C]O, N-Boc); 149.03 (C]O, N-Boc); 166.38 (C]O);
167.14 (C]O); 168.10 (C]O); 168.41 (C]O); 171.03
(C]O); 171.49 (C]O). IR (cmK1) nmax: 1729 (C]O);
1753 (C]O); 1797 (C]O). MS: m/z (%): (ES, neg) 342
(MKHC, 100). Anal. Calcd C16H25NO7: C 55.97%, H
7.34%, N 4.08%; found: C 56.30%, H 7.52%, N 4.29%.
3.1.11. 2-Benzyl 2,4-di-t-butyl 5-oxo-2,2,4-pyrrolidine-
tricarboxylate (15e). The reaction is similar to that of the
conversion of 14a–15a. The reaction was performed on the
diastereoisomeric mixture of 14e and gave 15e as a clear oil.
(Major/minor 52/48).
1H NMR (300 MHz, CDCl3) d: major, minor, not assigned:
1.33 (9H, s, t-Bu); 1.36 (9H, s, t-Bu); 1.47 (9H, s, t-Bu); 1.47
(9H, s, t-Bu); 2.82–2.87 (2H, m, CH2 ring, C3); 3.41 (1H,
dd, JZ9.4, 2.5 Hz, CH ring, C4); 3.44 (1H, dd, JZ9.1,
3.0 Hz, CH ring, C4); 5.14–5.28 (2H, m, CH2Ph); 6.56 (1H,
br. s, NH); 6.58 (1H, br. s, NH); 7.31–7.36 (5H, m, Ph). 13C
NMR (75 MHz, CDCl3) d: major, minor, not assigned:
27.54 (t-Bu); 27.59 (t-Bu); 27.93 (t-Bu); 31.27 (CH2 ring,
C3); 31.41 (CH2 ring, C3); 48.00 (CH ring, C4); 48.14 (CH
ring, C4); 66.83 (Cquat, C2); 67.15 (Cquat, C2); 68.03
3.1.9. 2,4-Di-t-butyl 2-methyl 5-oxo-2,2,4-pyrrolidine-
tricarboxylate (15d). The reaction is similar to that of the
conversion of 14a–15a. The reaction was performed on the
diastereoisomeric mixture of 14d and gave 15d as a clear oil
(major/minor 53/47).
1H NMR (300 MHz, CDCl3) d: major, minor, not assigned:
1.46 (9H, s, t-Bu); 1.48 (9H, s, t-Bu); 1.49 (9H, s, t-Bu);
2.82–2.88 (2H, m, CH2 ring, C3); 3.43 (1H, dd, JZ8.9,
5.9 Hz, CH ring, C4); 3.45 (1H, dd, JZ9.1, 7.2 Hz, CH ring,
C4); 3.80 (3H, s, CH3); 3.82 (3H, s, CH3); 6.51 (1H, br. s,
NH); 6.53 (1H, br. s, NH). 13C NMR (75 MHz, CDCl3) d:
major, minor, not assigned: 27.71 (t-Bu); 27.74 (t-Bu);
27.91 (t-Bu); 27.94 (t-Bu); 31.38 (CH2 ring, C3); 31.50
(CH2 ring, C3); 48.03 (CH ring, C4); 48.13 (CH ring, C4);
(CH2Ph); 68.16 (CH2Ph); 82.45 (Cquat, t-Bu); 82.49 (Cquat
,
t-Bu); 84.04 (Cquat, t-Bu); 84.20 (Cquat, t-Bu); 126.97 (CH,
Ph); 128.60 (CH, Ph); 128.66 (CH, Ph); 128.71 (CH, Ph);
128.74 (CH, Ph); 128.82 (CH, Ph); 134.62 (Cquat, Ph);
134.77 (Cquat, Ph); 166.53 (C]O); 166.94 (C]O); 167.63
(C]O); 167.67 (C]O); 168.12 (C]O); 168.54 (C]O);
171.51 (C]O). IR (cmK1) nmax:1732 (C]O, br.). MS: m/z
(%): (ES, neg) 418 (MKHC, 100). Chromatography:
Hex/EtOAc (70/30) RfZ0.40. Anal. Calcd C22H29NO7: C
62.99%, H 6.97%, N 3.34%; found: C 62.78%, H 7.26%, N
3.42%.
53.32 (CH3); 53.44 (CH3); 66.77 (Cquat, C2); 67.15 (Cquat
C2); 82.48 (Cquat, t-Bu); 82.54 (Cquat, t-Bu); 84.11 (Cquat
,
,
t-Bu); 84.30 (Cquat, t-Bu); 166.68 (C]O); 167.14 (C]O);
167.64 (C]O); 168.88 (C]O); 169.31 (C]O); 171.48
(C]O); 171.51 (C]O). IR (cmK1) nmax:1717 (C]O);
1739 (C]O, br.). MS: m/z (%): (ES, neg) 342 (MKHC,
100). Chromatography: Hex/EtOAc (70/30) Rf Z0.34.
Anal. Calcd C16H25NO7: C 55.97%, H 7.34%, N 4.08%;
found: C 55.85%, H 7.46%, N 4.19%.
3.1.12. 4-Benzyl 1-t-butyl 2-methyl 5-oxo-1,2,4-pyrroli-
dinetricarboxylate (14f). Yield 80% (major/minor 77/23),
the product is obtained as a white powder.

N. Dieltiens et al. / Tetrahedron 61 (2005) 6749–6756
6755
1H NMR (300 MHz, CDCl3) d: major, minor, not assigned:
1.50 (9H, s, t-Bu); 2.25 (1H, ddd, JZ13.5, 8.8, 2.5 Hz,
CHAHB ring, C3); 2.52–2.57 (2H, m, CH2 ring, C3); 2.74
(1H, ddd, JZ13.5, 10.4, 9.4 Hz, CHAHB ring, C3); 3.59
(1H, dd, JZ8.3, 6.6 Hz, CH ring, C4); 3.69 (3H, s, CH3);
3.74 (1H, dd, JZ10.4. 8.8 Hz, CH ring, C4); 3.78 (3H, s,
CH3); 4.61 (1H, dd, JZ7.8, 5.9 Hz, CH ring, C2); 4.68 (1H,
dd, JZ9.4, 2.5 Hz, CH ring, C2); 5.11 (2H, s, CH2Ph); 5.22
(2H, s, CH2Ph); 7.30–7.40 (5H, m, Ph). 13C NMR (75 MHz,
CDCl3) d: major, minor, not assigned: 24.69 (CH2 ring, C3);
25.37 (CH2 ring, C3); 27.85 (t-Bu); 27.85 (t-Bu); 48.53 (CH
ring, C4); 48.82 (CH ring, C4); 52.57 (CH3); 52.77 (CH3);
57.12 (CH ring, C2); 57.57 (CH ring, C2); 66.86 (CH2Ph);
67.75 (CH2Ph); 84.18 (Cquat, Ph); 84.32 (Cquat, Ph); 128.13
(CH, Ph); 128.24(CH, Ph); 128.41(CH, Ph);128.47(CH, Ph);
128.55 (CH, Ph); 128.58 (CH, Ph); 128.62 (CH, Ph); 135.08
(Cquat, Ph); 135.14 (Cquat, Ph); 148.99 (C]O, N-Boc); 148.99
(C]O, N-Boc); 167.76 (C]O); 167.91 (C]O); 170.79
(C]O); 171.37 (C]O). IR (cmK1) nmax:1737 (C]O); 1777
(C]O, br.). MS: m/z (%): (ES, neg) 376 (MKHC, 100).
Chromatography: Hex/EtOAc (70/30) RfZ0.19. Mp 94–
97 8C. Anal. Calcd C19H23NO7: C 60.47%, H 6.14%, N
3.71%; found: C 60.58%, H 6.24%, N 3.88%.
3.56 (1H, dd, JZ10.5, 8.8 Hz, CH ring, C4); 4.19–4.27 (2H,
m, CH2CH3); 4.19–4.27 (2H, m, CH2CH3); 4.56 (1H, dd,
JZ7.2, 6.6 Hz, CH ring, C2); 4.64 (1H, dd, JZ9.6, 2.5 Hz,
CH ring, C2). 13C NMR (75 MHz, CDCl3) d: major, minor,
not assigned: 14.24 (CH2CH3–); 14.24 (CH2CH3–); 24.88
(CH2 ring, C3); 25.46 (CH-2 ring, C3); 27.75 (t-Bu); 27.93
(t-Bu); 28.03 (t-Bu); 28.30 (t-Bu); 49.45 (CH, C4); 49.77
(CH, C4); 57.28 (CH ring, C2); 57.63 (CH ring, C2); 61.81
(CH2CH3); 61.92 (CH2CH3); 82.90 (Cquat, t-Bu); 82.98
(Cquat, t-Bu); 83.95 (Cquat, t-Bu); 84.11 (Cquat, t-Bu); 149.22
(C]O, N-Boc); 149.22 (C]O, N-Boc); 166.40 (C]O);
167.26 (C]O); 168.13 (C]O); 168.46 (C]O); 170.55
(C]O); 172.09 (C]O). IR (cmK1) nmax:1729 (br., C]O);
1796 (C]O). MS: m/z (%): (ES, pos) No MC; 297 (8); 254
(12); 203 (8); 202 (100). Anal. Calcd C17H27NO7: C 57.13%,
H 7.61%, N 3.92%; found: C 57.00%, H 7.89%, N 3.88%.
3.1.15. 2,4-Di-t-butyl 2-ethyl 5-oxo-2,2,4-pyrrolidine-
tricarboxylate (15g). The reaction is similar to that of the
conversion of 14a–15a. The reaction was performed on the
diastereoisomeric mixture of 14g and gave 15g as a brown
oil. (Major/minor 51/49, purity 85%).
1H NMR (300 MHz, CDCl3) d: major, minor, not assigned:
1.29 (3H, t, JZ7.2 Hz, CH-2CH3); 1.31 (3H, t, JZ7.0 Hz,
CH2CH3); 1.46 (9H, s, t-Bu); 1.48 (9H, s, t-Bu); 1.48 (9H, s,
t-Bu); 1.49 (9H, s, t-Bu); 2.82–2.85 (2H, m, CH-2 ring);
3.41–3.48 (1H, m, CH ring); 4.23–4.30 (2H, m, CH2CH3);
4.23–4.30 (2H, m, CH2CH3); 6.30 (1H, br. s, NH); 6.32 (1H,
br. s, NH). 13C NMR (75 MHz, CDCl3) d: major, minor, not
assigned: 13.97 (CH2CH3); 14.01 (CH2CH3); 27.66 (t-Bu);
27.71 (t-Bu); 27.87 (t-Bu); 28.01 (t-Bu); 31.23 (CH-2 ring,
C3); 31.35 (CH-2 ring, C3); 48.12 (CH ring, C4); 48.20 (CH
3.1.13. 4-Benzyl 2-t-butyl 2-methyl 5-oxo-2,2,4-pyrroli-
dinetricarboxylate (15f). The reaction is similar to that of
the conversion of 14a–15a. The reaction was performed on
the diastereoisomeric mixture of 14f and gave 15f as a clear
oil. (Major/minor 51/49).
1H NMR (300 MHz, CDCl3) d: major, minor, not assigned:
1.45 (9H, s, t-Bu); 1.47 (9H, s, t-Bu); 2.89 (2H, m, CH2 ring,
C3); 3.58–3.66 (1H, m, CH ring, C4); 3.76 (3H, s, CH3);
3.79 (3H, s, CH3); 5.16–5.27 (2H, m, CH2Ph); 6.62 (1H, br.
s, NH); 7.28–7.40 (5H, m, Ph). 13C13C NMR (75 MHz,
CDCl3) d: major, minor, not assigned: 27.70 (t-Bu); 31.31
(CH2 ring, C3); 31.42 (CH2 ring, C3); 47.13 (CH ring, C4);
47.19 (CH ring, C4); 53.35 (CH3); 53.51 (CH3); 66.80
(Cquat, C2); 67.18 (Cquat, C2); 67.56 (CH2Ph); 67.61
(CH2Ph); 84.29 (Cquat, t-Bu); 84.45 (Cquat, t-Bu); 128.16
(CH, Ph); 128.27 (CH, Ph); 128.34 (CH, Ph); 128.39 (CH,
Ph); 128.57 (CH, Ph); 128.66 (CH, Ph); 128.72 (CH, Ph);
128.86 (CH, Ph); 135.24 (Cquat, Ph); 135.31 (Cquat, Ph);
166.57 (C]O); 166.96 (C]O); 168.36 (C]O); 168.71
(C]O); 169.11 (C]O); 170.80 (C]O); 170.83 (C]O). IR
(cmK1) nmax:1740 (C]O, br.). MS: m/z (%): (ES, Pos) 378
(MCHC, 43); 323(17); 322 (100). Chromatography:
Hex/EtOAc (70/30) RfZ0.09 and 0.17. Anal. Calcd
C19H23NO7: C 60.47%, H 6.14%, N 3.71%; found: C
60.35%, H 6.53%, N 3.86%.
ring, C4); 62.41 (CH2CH3); 62.59 (CH2CH3); 66.93 (Cquat
C2); 67.23 (Cquat, C2); 82.27 (Cquat, t-Bu); 82.32 (Cquat
,
,
t-Bu); 83.77 (Cquat, t-Bu); 83.98 (Cquat, t-Bu); 166.80
(C]O); 167.27 (C]O); 167.74 (C]O); 167.74 (C]O);
168.32 (C]O); 168.80 (C]O); 171.82 (C]O); 171.82
(C]O). IR (cmK1) nmax: 1736 (br.); 1793 (C]O). MS: m/z
(%): (ES, pos) No MC; 247 (15); 246 (100); 202 (11).
3.1.16. 1,5-Diethyl-2-[(t-butoxycarbonyl)amino]pentane-
dioate (15i). The reaction is similar to that of the conversion
of 14a–15a.
1H NMR (300 MHz, CDCl3) d: 1.26 (3H, t, JZ7.2 Hz,
CH2CH3); 1.28 (3H, t, JZ7.2 Hz, CH2CH3); 1.44 (9H, s,
t-Bu); 1.88–2.01 (1H, m, COCH2CHAHB); 2.12–2.24 (1H,
m, COCH2CHAHB); 2.36–2.43 (2H, m, COCH2); 4.14 (2H,
q, JZ7.2 Hz, CH2CH3); 4.20 (2H, q, JZ7.2 Hz, CH2CH3);
4.31 (1H, dd, JZ13.1 Hz, JZ8.4 Hz, COCH); 5.19 (1H, br.
s, NH). 13C NMR (75 MHz, CDCl3) d: 14.16 (CH2CH3);
14.19 (CH2CH3); 27.84 (COCH2CH2); 28.29 (t-Bu); 30.37
(COCH2); 52.98 (CH); 60.65 (CH2CH3); 61.52 (CH2CH3);
79.96 (Cquat, t-Bu); 155.39 (C]O, NH-Boc); 172.26
(C]O); 172.79 (C]O). IR (cmK1) nmax:1719 (C]O);
1737 (C]O). MS: m/z (%): (ES, pos) no MC; 204 (MK
BocCHC, 100). Chromatography: Hex/EtOAc (70/30) Rf
Z0.43.
3.1.14. 1,4-Di-t-butyl 2-ethyl 5-oxo-1,2,4-pyrrolidine-
tricarboxylate (14g). Di-t-butyldicarbonate (1.5 equiv)
was used as electrophile and once it was added the reaction
was allowed to warm to room temperature. 14g is obtained
(yield 80% major/minor 70/30) as a brown oil.
H NMR (300 MHz, CDCl3) d: major, minor, not assigned:
1.30 (3H, t, JZ7.2 Hz, CH2CH3); 1.45 (9H, s, t-Bu); 1.47
(9H, s, t-Bu); 1.49 (9H, s, t-Bu); 1.50 (9H, s, t-Bu); .2.20
(1H, ddd, JZ13.5, 8.8, 2.5 Hz, CHAHB ring); 2.48–2.53
(2H, m, CH2 ring); 2.68 (1H, ddd, JZ13.5, 10.5, 9.6 Hz,
CHAHB ring); 3.44 (1H, dd, JZ7.7, 7.4 Hz, CH ring, C4);
3.1.17. 1,5-Dimethyl-2-[(t-butoxycarbonyl)amino]penta-
nedioate (15j). The reaction is similar to that of the
conversion of 14a–15a.

6756
N. Dieltiens et al. / Tetrahedron 61 (2005) 6749–6756
1H NMR (300 MHz, CDCl3) d: 1.44 (9H, s, t-Bu); 1.99–2.02
(1H, m, COCH2CHAHB); 2.13–2.25 (1H, m, COCH2CHA-
HB); 2.39–2.45 (2H, m, COCH2); 3.68 (3H, s, CH3); 3.75
(3H, s, CH3); 4.30–4.37 (1H, m, COCH); 5.19 (1H, br. s,
NH). 13C NMR (75 MHz, CDCl3) d: 27.78 (COCH2CH2);
28.32 (t-Bu); 30.09 (COCH2); 51.81 (CH3); 52.44 (CH3);
52.91 (CH); 80.04 (Cquat, t-Bu); 155.42 (C]O, NH-Boc);
172.72 (C]O); 173.21 (C]O). IR (cmK1) nmax: 1714
(C]O); 1736 (C]O); 1793 (C]O). MS: m/z (%): (ES,
pos) no MC; 176 (MKBocCHC, 100); 144 (24).
Chromatography: Hex/EtOAc (70/30) RfZ0.31.
´ ´
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We thank the BOF (Research Fund, Ghent University) and
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