Towards simplifying the chemistry of N-acyliminium ions: A one-pot protocol for the preparation of 5-acetoxy pyrrolidin-2-ones and 2-acetoxy N-alkoxycarbonyl pyrrolidines from imides

Article abstract of DOI:10.1055/s-2006-926318

A new one-step protocol for the synthesis of acetoxy lactams starting from imides has been developed. This method involves regiospecific reduction of the imide with LiEt₃BH, then capture of the transient lithium alkoxide by acetic anhydride. Ge

Full text of DOI:10.1055/s-2006-926318

PAPER
875
Towards Simplifying the Chemistry of N-Acyliminium Ions: A One-Pot
Protocol for the Preparation of 5-Acetoxy Pyrrolidin-2-ones and 2-Acetoxy
N-Alkoxycarbonyl Pyrrolidines from Imides
Acetoxy
N
-A
l
r
koxycarb
i
onyl
P
d
yrrolidines
f
r
rom Imid
i
es ch Szemes, Jr., Anthony Fousse, Raja Ben Othman, Till Bousquet, Mohamed Othman, Vincent Dalla*
Unité de Recherche en Chimie Organique et Macromoléculaire, Faculté des Sciences et Techniques de l’Université du Havre,
25 rue Philippe Lebon, BP 540, 76058 Le Havre CEDEX, France
Fax +33(2)32744391; E-mail: vincent.dalla@univ-lehavre.fr
Received 24 August 2005
Such tandem reactions are known in the ester5 and lactone
series6 for the preparation of mixed acetals, and also in the
conversion of acyclic imides to amino acetals.7 However,
reports dealing with the preparation of acetoxy lactams
using a similar strategy were not known.8
Abstract: A new one-step protocol for the synthesis of acetoxy lac-
tams starting from imides has been developed. This method in-
volves regiospecific reduction of the imide with LiEt3BH, then
capture of the transient lithium alkoxide by acetic anhydride.
Key words: N-acyliminium ion precursors, imide reduction,
LiEt3BH, one-pot process
Herein we report some preliminary results demonstrating
the feasibility of the hypothesis described above.
Reactions between N-acyliminium ions and enoxy silanes
(the so-called Mannich reaction) have recently emerged
as one of the more useful processes in the field of N-
acyliminium chemistry.1 Of particular interest are reac-
tions involving chiral N-acyliminium ions, which undergo
C–C bond formation providing highly substituted adducts
bearing at least two controlled stereogenic centers.
Ac2O
M-H
OM
O
N
R
O
O
N
R
OAc
O
N
R
Scheme 1
As part of a new research programme towards the total
synthesis of polyhydroxylated alkaloids based on the
Mannich reaction, we needed a straightforward access to
enantiopure precursors of endocyclic N-acyliminium
ions. Although alkoxy lactams can successfully serve this
purpose,2 a literature survey revealed that acetoxy lactams
are in general more convenient synthons in such situa-
tions.3 Previous reports have shown that formation of
acetoxy lactams from either malic acid,3a–d tartaric ac-
id,3b,3c,3e or pyroglutamic acid3j,3k invariably involves two
distinct steps: reduction of the imide with a hydride
reagent3a–f,3j,3k or cyclization of an amino aldehyde3g,3i fol-
lowed by acetylation of the resulting hydroxy lactam.
Even if the more usual reduction–acetylation sequence is
high-yielding, it suffers from some drawbacks. For in-
stance, the reduction step has to be conducted very care-
fully in order to avoid ring-opening due to over reduction
of the hydroxy lactam.4 Moreover, the latter generally
needs purification in order to ensure an efficient acylation
process. We realized that the preparation of such acetoxy
lactams could be improved upon development of a one-
pot protocol. Our idea capitalized on the possibility of re-
duction of the imide by a strong hydride in aprotic medi-
um, and subsequent trapping of the transient metal
alkoxide ion in situ with acetic anhydride (Scheme 1).
Our first experiments focused on the well-known (3S)-
acetoxy imide 1a derived from L-malic acid.3a–d In a re-
cent report dealing with a similar one-pot preparation of
medium-sized ring N-acyliminium ion precursors using
DIBAL-H as the reductant, it was shown that acetic anhy-
dride was unreactive towards the alkoxide ion intermedi-
ate.8 Also, other unsuccessful attempts made by our group
in relation to ester reduction (DIBAL-H) followed by in
situ tosylation prompted us to use LiEt3BH as the reduc-
tant.9 We expected that the transient lithium alkoxide
would be more nucleophilic toward acetic anhydride
(Scheme 2).
OAc
OAc
1) LiEt3BH, solvent
2) Ac2O
O
OAc
N
O
O
N
Ph
Ph
1a
2a
Scheme 2
A series of feasibility experiments were conducted on a
100 mg scale and we found the overall process quite effec-
tive using a small excess of LiEt3BH (1.15 equiv), fol-
lowed by immediate addition of acetic anhydride (1.35
equiv). Dichloromethane appeared to be superior to THF
as solvent and the best yields (90%) were achieved when
both reduction and acylation were performed at –78 °C.
We also found that the majority of residues could be re-
moved by addition of charcoal to the reaction mixture and
SYNTHESIS 2006, No. 5, pp 0875–0879
x
x
.
x
x
.2
0
0
6
Advanced online publication: 07.02.2006
DOI: 10.1055/s-2006-926318; Art ID: P13005SS
© Georg Thieme Verlag Stuttgart · New York

876
F. Szemes Jr. et al.
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subsequent filtration through a Celite pad, thus avoiding from (R) and (S)-pyroglutamic acid (3a–e)15–18 were also
hydrolysis of the water-sensitive acetoxy lactams. Under evaluated.
these conditions, only trace amounts of acetic anhydride
Reaction of 1d (1 g scale) under the optimized conditions
gave the expected amide 2d as a single stereomer in good
yield (Table 1, entry 3), demonstrating that a trialkylsilyl
were observed in the crude products by 1H NMR spectros-
copy, making 2a ready for further synthetic manipulations
without the need for purification. Importantly, the reac-
protecting group is tolerated. It is noteworthy that the re-
tion could be successfully scaled up to 15 g without loss
action could not be extrapolated as well as in the case of
of efficiency, further demonstrating the synthetic rele-
the acetate 1a, since a decreased yield was observed when
vance of our protocol.
the reaction was scaled up.19 Steric effects seem then to be
1
The H NMR spectrum of the crude product proved that a limiting factor in this reaction. Both PMB and allyl pro-
the reaction occurred with complete stereoselectivity. The tecting groups are well tolerated, as demonstrated by the
values of the chemical shifts and coupling constants were good yields obtained for the acetoxy lactams 2b, 2c, and
in accordance with a cis relationship between the two ace- 2e (Table 1, entries 1, 2, and 4).
tate groups.3a
Table 1 Reduction–Acetylation of Chiral Imides under Optimized
Having demonstrated that our process rivaled Spec-
kamp’s two-step method3a–e in terms of both yield and ste-
reoselectivity, we focused on extending its scope. Other
chiral and achiral cyclic imides 1b–q (Figure 1) were syn-
thesized according to known procedures either from L-
malic acid (1b–e),10,11 L-tartaric acid (1f–h),12–14 phthal-
amide anhydride (1i–k), or succinic anhydride (1l–p).
Various N-alkoxycarbonyl pyrrolidines, readily available
Reaction Conditionsa
Entry
Imides
Acetoxy lactams
(isolated yield)
trans/cis
1b
2c
1b
1c
1d
1e
1f
2b (88%)
2c (79%)
2d (75%)
2e (76%)
2f (95%)
2g (80%)
2h (30%)
2i (50%)
2j (81%)
2k (83%)
2l (60%)
see text
0:100
0:100
3b
4b
5b
6b
7
0:100
8:92
OAc
O
OTBS
O
AcO
OAc
O
100:0
O
O
O
1g
1h
1i
100:0
N
N
N
GP
GP
GP
100:0
GP = Bn 1d
PMB 1e
GP = Bn 1a
GP = Bn 1f
allyl 1g
8
–
–
–
–
–
–
–
–
–
–
–
–
–
–
PMB
allyl
1b
1c
9
1j
10
11
12
13
14
15
16
17
18
19
20
21
1k
1l
TBSO
OTBS
O
O
O
N
1m
1n
1o
1p
1q
3a
3b
3c
3d
3e
O
N
O
N
O
GP
2n (60%)
see text
GP
Ph
1h
GP = Bn 1i
vinyl 1j
allyl 1k
GP = Bn
propenyl
allyl
1m
1n
1o
2p (0%)
2q (0%)
propenyl
1l
4a (100%)c,d,e
4b (96%)c,d,e
4c (77%)c
see text
O
O
CO2Me
O
CO
2R
O
N
N
N
Cbz
Boc
Ph
R
R = Me 1p
R = Me 3a
t-Bu 3b
3c
CH2OMe 1q
see text
a The reaction was carried out on a 1 mmol scale unless otherwise in-
dicated.
OTBS
O
N
b The reaction was carried out on a 1 g scale.
c The reaction was carried out on a 5 g scale.
d A mixture of stereomers and/or N-invertomers was detected in the
1H NMR spectrum; the stereochemistry was not determined.
e Crude yield is given.
GP
GP = Boc 3d
Cbz 3e
Figure 1
Synthesis 2006, No. 5, 875–879 © Thieme Stuttgart · New York

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Acetoxy N-Alkoxycarbonyl Pyrrolidines from Imides
877
The easy access to acetates 2f–h (Table 1, entries 5–7) entry 19). On the other hand, reduction and acetylation of
proves that our protocol can be applied to tartarimides both the N-Boc and N-Cbz protected alcohols 3d and 3e
bearing different protecting groups. The reaction occurred gave troublesome results, with formation of at least three
with high to complete diastereoselectivity. Based on the products (TLC, Table 1, entries 20 and 21). Examination
1
J4,5 coupling constant values (1.5–2.3 Hz), and in contrast of the H NMR spectra of the crude mixtures revealed
to the malic acid series, the hydride delivery seems to small integration values for the proton adjacent to the
have proceeded with trans stereoselectivity with respect newly formed acetate group (d = 6 ppm) and the related
to the neighboring hydrogen. The moderate yield obtained methyl group (d = 2 ppm), suggesting the formation of
by starting from the bis-OTBS compound 1h confirms competitive ring-opening products.4
that sterics can limit the scope of the process (Table 1, en-
try 7).20 Not unexpectedly taking steric considerations
OSiMe3
i
into account, imides 1p–q bearing chiral auxiliaries at ni-
trogen proceeded unfavorably in the reduction–acetyla-
tion process, affording hydroxy lactams exclusively,
instead of the desired acetoxy lactams after work-up
(Table 1, entries 15 and 16).21 The presence of an addi-
tional oxygen atom in 1q significantly retarded the reduc-
tion step, for which 2.5 equivalents of reductant was
necessary to ensure complete reaction.
AcO
+
CO2R
N
CO2R
t-Bu
N
Boc
Boc
O
t-Bu
R = Me
t-Bu
4a
4b
5a (55%)
5b (45%)
Scheme 3 Reagents and conditions: (i) BF3·OEt2 (1.2 equiv),
CH2Cl2, –65 °C to –50 °C, work-up.
Succimide and glutarimide derivatives bearing no substit-
uent on their carbon framework are known to be prone to
competitive ring-opening during reduction.4,22
Similar results were obtained with N-Cbz pyrrolidine and
piperidine (results not shown). In these cases, even the
usual two-step strategy failed to produce the desired ace-
toxy lactams probably due to their instability. In light of
these results, we recommend the use of 2-methoxy or 2-
ethoxy derivatives as N-acyliminium ion precursors for
pyrrolidines and piperidines bearing no substituent on
their C3 and C4 (pyrolidine) or C3–C5 (piperidine) frag-
ment and lacking an alkoxycarbonyl substituent at C5 and
C6.
Accordingly, the reduction–acetylation of N-allyl and N-
benzyl succinimides 1m and 1o furnished complex reac-
tion mixtures containing recovered starting material, hy-
droxy lactams, and the linear amido acetates (Table 1,
entries 12 and 14). On the other hand, the N-propenyl suc-
cinimide 1n, in which the lone pair of electrons on the ni-
trogen is conjugated with the pendant double bond, gave
the desired acyloxy lactam 2n in good yield (Table 1, en-
try 13). As expected, the analogous and less sensitive ph-
thalimides were readily reduced and acetylated to afford
acetates 2i–l in fair to good yields (Table 1, entries 8–11).
In summary, we have developed a new protocol for ac-
cessing 2-acetoxy pyrrolidin-5-ones from parent cyclic
imides. These are useful precursors of N-acyliminium
ions. Our one-pot procedure provides a shortened alterna-
tive to known methodologies and is especially relevant for
chiral compounds derived from malic and tartaric acids.
This process proved to be competitive with the usual two-
step procedure in terms of efficiency, rapidity, generality,
and stereochemistry and could also be applied to esters of
pyrroglutamic acid.
N-Acyl pyrrolidine esters 3a–c derived from pyroglutam-
ic acid gave clean reduction–acetylation processes as
judged by TLC and the 1H NMR spectra of the crude prod-
ucts 4a–c (Table 1, entries 17–19). The stereochemical as-
signment of the products formed by 1H NMR
spectroscopy proved to be difficult due to the presence of
rotamers. The N-Boc adducts 4a and 4b turned out to be
very sensitive – after purification on silica gel, only the
corresponding hydroxy lactams were obtained. This
stands in sharp contrast with results previously reported
by Barrett, in which related products were synthesized
and successfully purified on silica gel,23 but corroborates
recent observations made by Kobayashi and co-workers
in the piperidine series.24
All melting points were measured on a Boetius micro hotstage ap-
paratus and are uncorrected. 1H and 13C NMR spectra were recorded
at 200 and 50 MHz, respectively, in CDCl3 at 25 °C. IR spectra were
recorded on a Perkin-Elmer FT-IR Paragon 1000 Spectrometer.
TLC were performed with aluminum plates (0.20 mm) precoated
with fluorescent silica gel, using EtOAc–hexanes as eluent. Reac-
tion components were then visualized under UV light and dipped in
Dragendorff solution. Silica gel (230–400 mesh) was used for flash
chromatography. All reactions were performed under an inert atmo-
sphere. MS and elemental analyses were not carried out due to the
Fortunately, our work-up procedure with charcoal and
Celite resulted in the removal of almost all residues origi-
nating from the reagents as evidenced by 1H NMR spec- thermal sensitivity of the acetates. Analytical data of 2a,3a 2b,3a and
2h13 were identical to those reported in the literature.
troscopy (Table 1, entries 17 and 18). Virtually pure
acetoxy lactams 4a and 4b were then obtained without the
One-Pot Reduction–Acetylation Process; Typical Procedure
need for further purification and were easily alkylated as
To a solution of imide 1a (15 g, 60.7 mmol) in anhyd CH2Cl2 (250
mL) was added dropwise at –78 °C a commercially available solu-
tion of LiEt3BH (1 M in THF; 69.8 mL, 69.8 mmol). The solution
was stirred for 15 min and Ac2O (7.75 mL, 81.9 mmol) was added
dropwise at –78 °C. The solution was allowed to slowly warm to r.t.
and stirred for an additional 20 h. Charcoal was added to the solu-
such through their N-acyliminium ions (Scheme 3, yields
unoptimized).
The N-Cbz acetate 4c appeared to be more robust and
could be purified on silica gel without difficulty (Table 1,
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878
F. Szemes Jr. et al.
PAPER
tion, which was then stirred for 15 min and filtered through a Celite
pad. The solvents were carefully removed under vacuum to give
white crystals which were purified by flash chromatography (cyclo-
hexane–EtOAc, 1:1) to give acetoxy lactam 2a1 in 90% yield; mp
83–84 °C; [a]D25 +2.8 (c 0.5, acetone).
13C NMR: d = 20.5, 20.7, 26.8, 43.4, 73.9, 75.9, 83.5, 118.5, 131.1,
167.4, 169.5, 169.7.
2-Benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl Acetate (2i)
White solid; mp 73–75 °C.
IR (CHCl3): 1776, 1740, 1709 cm–1.
1H NMR: d = 1.88 (s, 3 H), 4.56 (d, J = 14.8 Hz, 1 H), 4.84 (d, J =
14.8 Hz, 1 H), 6.86 (s, 1 H), 7.13–7.29 (m, 5 H), 7.40–7.54 (m, 3 H),
7.77–7.97 (m, 1 H).
13C NMR: d = 21.0, 44.5, 81.1, 124.0, 127.9, 128.5, 128.9, 130.5,
132.0, 132.8, 136.9, 141.2, 168.1, 171.2.
(2S,3S)-1-Allyl-5-oxopyrrolidine-2,3-diyl Diacetate (2c)
Colorless oil; [a]D25 –32.9 (c 0.9, EtOH).
IR (CHCl3): 1733, 1673, 1644 cm–1.
1H NMR: d = 2.09 (s, 3 H), 2.11 (s, 3 H), 2.59 (dd, J = 9.4, 16.4 Hz,
1 H), 2.73 (dd, J = 7.8, 16.4 Hz, 1 H), 3.66 (dd, J = 7.0, 15.6 Hz, 1
H), 4.12 (dd, J = 5.4, 15.6 Hz, 1 H), 5.07–5.20 (m, 2 H), 5.30 (ddd,
J = 4.7, 7.8, 9.4 Hz, 1 H), 5.60–5.82 (m, 1 H), 6.27 (d, J = 4.7 Hz,
1 H).
2-Vinyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl Acetate (2j)
White solid; mp 70–72 °C.
IR (CHCl3): 1723, 1643 cm–1.
1H NMR: d = 2.11 (s, 3 H), 4.55 (d, J = 16.4 Hz, 1 H), 4.59 (d, J =
9.4 Hz, 1 H), 7.04 (dd, J = 9.4, 16.4 Hz, 1 H), 7.45–7.60 (m, 3 H),
7.80 (d, J = 6.2 Hz, 1 H).
13C NMR: d = 21.1, 79.5, 95.8, 124.3, 124.4, 127.0, 130.9, 131.2,
133.7, 141.1, 165.8, 171.1.
13C NMR: d = 20.8, 21.0, 34.2, 43.8, 66.3, 81.8, 118.9, 131.9, 170.2,
170.4, 171.6.
(2S,3S)-1-Benzyl-3-{[tert-butyl(dimethyl)silyl]oxy}-5-oxopyrro-
lidin-2-yl Acetate (2d)
Colorless oil; [a]D25 +12 (c 0.098, EtOH).
IR (CHCl3): 1745, 1712, 1246, 730 cm–1.
1H NMR: d = 0.02 (s, 3 H), 0.06 (s, 3 H), 0.85 (s, 9 H), 1.95 (s, 3 H),
2.49 (dd, J = 8.6, 15.7 Hz, 1 H), 2.59 (dd, J = 7.8, 15.7 Hz, 1 H),
4.21 (d, J = 14.9 Hz, 1 H), 4.37 (ddd, J = 4.7, 7.8, 8.6 Hz, 1 H), 4.70
(d, J = 14.9 Hz, 1 H), 6.11 (d, J = 4.7 Hz, 1 H), 7.20–7.40 (m, 5 H).
13C NMR: d = –5.0, –4.9, 18.0, 20.9, 25.7, 37.6, 44.8, 66.4, 83.3,
127.9, 128.6, 128.9, 136.3, 170.5, 173.0.
2-Allyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl Acetate (2k)
White solid; mp 62–63 °C.
IR (CHCl3): 1740, 1712, 1645 cm–1.
1H NMR: d = 2.11 (s, 3 H), 3.91 (ddt, J = 1.5, 6.2, 15.6 Hz, 1 H),
4.35 (ddt, J = 1.5, 6.2, 15.6 Hz, 1 H), 5.15–5.24 (m, 2 H), 5.72–5.91
(m, 1 H), 7.00 (s, 1 H), 7.40–7.76 (m, 3 H), 7.78–7.82 (m, 1 H).
13C NMR: d = 21.2, 43.2, 81.2, 118.1, 123.9, 124.1, 130.5, 132.1,
132.7, 132.8, 141.2, 167.8, 171.2.
(2S,3S)-3-{[tert-Butyl(dimethyl)silyl]oxy}-1-(4-methylbenzyl)-
5-oxopyrrolidin-2-yl Acetate (2e)
White solid; mp 51 °C; cis/trans, 92:8.
IR (CHCl3): 1740, 1709, 1248 cm–1.
2-Propenyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl Acetate (2l)
White solid; mp 57–59 °C.
IR (CHCl3): 1739, 1644 cm–1.
1H NMR: d = 1.78 (dd, J = 1.5, 7.0 Hz, 3 H), 2.16 (s, 3 H), 5.20 (qd,
J = 7.0, 14.8 Hz, 1 H), 6.87 (qd, J = 1.5, 14.8 Hz, 1 H), 7.50–7.64
(m, 3 H), 7.78–7.82 (m, 1 H), 7.81–7.86 (m, 1 H).
13C NMR: d = 15.9, 21.2, 80.1, 108.6, 122.0, 124.2, 124.3, 130.8,
131.5, 133.3, 141.1, 165.5, 171.2.
1H NMR: d = 0.00 (s, 3 H, cis, 92%), 0.02 (s, 3 H, cis), 0.12 (s, 3 H,
trans, 8%), 0.15 (s, 3 H, trans), 0.81 (s, 9 H, cis), 0.88 (s, 9 H, trans),
1.95 (s, 3 H, cis), 2.02 (s, 3 H, trans), 2.47 (dd, J = 8.6, 15.7 Hz, 1
H, cis/trans), 2.57 (dd, J = 7.8, 15.7 Hz, 1 H, cis/trans), 3.77 (s, 3
H, cis/trans), 4.06 (d, J = 14.9 Hz, 1 H, cis/trans), 4.30 (ddd, J =
4.7, 7.8, 8.6 Hz, 1 H, cis/trans), 4.64 (d, J = 14.9 Hz, 1 H, cis), 4.65
(d, J = 14.9 Hz, 1 H, trans), 5.95 (dd, J = 2.2, 6.3 Hz, 1 H, trans),
6.05 (d, J = 4.7 Hz, 1 H, cis), 6.82 (d, J = 8.6 Hz, 2 H, cis/trans),
7.15 (d, J = 8.6 Hz, 2 H, cis/trans).
1-Propenyl-5-oxo-2,5-dihydro-1H-pyrrol-2-yl Acetate (2n)
Colorless oil.
IR (CHCl3): 1707, 1674 cm–1.
13C NMR: d = –4.8, –4.7, 18.2, 21.2, 25.8, 37.8, 44.2, 55.6, 66.6,
83.4, 114.4, 128.5, 130.2, 159.5, 170.7, 173.0.
1H NMR: d = 1.68 (dd, J = 1.5, 6.2 Hz, 3 H), 2.08 (s, 3 H), 2.23–
2.80 (m, 4 H), 5.12 (qd, J = 7.0, 14.0 Hz, 1 H), 6.45 (d, J = 5.5 Hz,
1 H), 6.62 (dd, J = 1.5, 14.0 Hz, 1 H).
13C NMR: d = 15.7, 21.3, 26.6, 28.9, 83.12, 109.45, 122.2, 170.7,
173.4.
(2S,3R,4R)-1-Benzyl-5-oxopyrrolidine-2,3,4-triyl Triacetate
(2f)
Colorless oil; [a]D25 +22.9 (c 0.11, EtOH).
IR (CHCl3): 2252, 1753, 1731, 1371 cm–1.
1H NMR: d = 1.90 (s, 3 H), 2.09 (s, 3 H), 2.20 (s, 3 H), 4.36 (d, J =
14.9 Hz, 1 H), 4.67 (d, J = 14.9 Hz, 1 H), 5.22 (dd, J = 1.6, 3.9 Hz,
1 H), 5.37 (d, J = 3.9 Hz, 1 H), 6.06 (d, J = 1.5 Hz, 1 H), 7.20–7.40
(m, 5 H).
13C NMR: d = 20.6, 20.7, 45.0, 73.3, 76.0, 83.6, 128.1, 128.3, 128.9,
135.3, 167.9, 169.7, 169.8, 169.9.
(5R)-2-Acetoxy-1,5-pyrrolidinedicarboxylic Acid 5-Methyl 1-
tert-Butyl Diester (4a)
Colorless oil.
IR (CHCl3): 2253, 1734, 1707, 1380 cm–1.
1H NMR: d = 1.43 (s, 9 H), 1.95–2.15 (m, 3 H), 2.08 (s, 3 H), 2.30–
2.40 (m, 1 H), 3.77 (s, 3 H), 4.20–4.35 (m, 1 H), 6.48 (br s, 1 H).
13C NMR: d = 22.3, 27.2, 27.9, 28.3, 32.2, 32.7, 52.3, 59.6, 60.2,
81.5, 83.4, 84.0, 152.7, 153.0, 166.6, 170.5, 170.7, 172.6, 172.9.
(2S,3R,4R)-1-Allyl-5-oxopyrrolidine-2,3,4-triyl Triacetate (2g)
White solid; mp 48–49 °C; trans (2S,3R)/cis (2R,3R), 86:14.
IR (CHCl3): 1732, 1675, 1646 cm–1.
1H NMR: d = 2.09 (s, 3 H), 2.11 (s, 3 H), 2.15 (s, 3 H), 3.45 (dd,
J = 7.0, 15.7 Hz, 1 H), 4.11 (dd, J = 5.5, 15.7 Hz, 1 H, cis, 14%),
5.14–5.36 (m, 4 H), 5.62–5.82 (m, 1 H), 6.11 (d, J = 1.5 Hz, 1 H),
6.31 (d, J = 4.7 Hz, 1 H, cis).
(5R)-2-Acetoxy-1,5-pyrrolidinedicarboxylic Acid 1,5-di-tert-
Butyl Diester (4b)
White solid; mp 74–76 °C.
Synthesis 2006, No. 5, 875–879 © Thieme Stuttgart · New York

PAPER
Acetoxy N-Alkoxycarbonyl Pyrrolidines from Imides
879
IR (CHCl3): 2973, 1728, 1707, 1394, 1369 cm–1.
(5) (a) Dahanukar, V. H.; Rychnowski, S. D. J. Org. Chem.
1996, 61, 8317. (b) Kopecky, D. J.; Rychnowski, S. D. J.
Org. Chem. 2000, 65, 191.
1H NMR: d = 1.45 (s, 9 H), 1.49 (s, 9 H), 1.52–1.67 (m, 1 H), 1.75–
1.95 (m, 1 H), 1.90–2.10 (m, 1 H), 2.07 (s, 3 H), 2.23–2.37 (m, 1 H),
4.05–4.3 (m, 1 H), 6.40–6.50 (br s, 1 H).
13C NMR (50 MHz, CDCl3): d = 21.4, 21.5, 21.7, 27.2, 28.1, 28.2,
28.4, 32.1, 32.7, 60.1, 60.2, 60.5, 60.7, 60.8, 81.3, 83.5, 84.3, 88.6,
88.9, 89.5, 93.3, 170.5, 170.7, 171.2, 171.5, 171.9.
(6) Shaw, J. T.; Woerpel, K. A. Tetrahedron 1999, 55, 8747; see
also reference 5a.
(7) Suh, Y.-G.; Shin, D.-Y.; Jung, J.-K.; Kim, S.-H. Chem.
Commun. 2002, 1064.
(8) As our study was in progress a publication dealing with the
one-pot synthesis of 7–9-membered ring N,O-acetal TMS
ethers from the parent imides was reported: Suh, Y.-G.;
Shin, D.-Y.; Jung, J.-K.; Kim, S.-H. Tetrahedron Lett. 2002,
43, 3165.
(9) For the conversion of imides into hydroxy lactams by
LiEt3BH, see: (a) Zanardi, P.; Battistini, L.; Nespi, M.;
Rassu, G.; Spanu, P.; Cornia, M.; Casiraghi, G.
Tetrahedron: Asymmetry 1996, 7, 1167. (b) Vittoria-
Chiesa, M.; Manzoni, L.; Scholastico, C. Synlett 1996, 441.
(c) Kim, Y. K.; Kitahara, T. Tetrahedron Lett. 1997, 38,
3423. (d) Collado, I.; Ezquerra, J.; Pedregal, C. J. Org.
Chem. 1995, 60, 5011; see also references 2d and 3i.
(10) (a) Wistrand, L. G.; Thaning, M. J. Org. Chem. 1990, 55,
1406. (b) Keum, G.; Kim, G. Bull. Korean Chem. Soc. 1994,
15, 278.
(5R)-2-Acetoxy-1,5-pyrrolidinedicarboxylic Acid 1-Benzyl 5-
Methyl Diester (4c)
Colorless oil.
IR (CHCl3): 3153, 2253, 1740, 1713 cm–1.
1H NMR: d = 1.95–2.15 (m, 3 H), 2,04 (s, 3 H), 2.28–2.34 (m, 1 H),
3.58 (s, 0.5 H, N-invertomer), 3.75 (s, 0.5 H, N-invertomer), 4.26–
4.35 (m, 1 H), 5.00–5.18 (m, 2 H), 6.51 (br s, 1 H).
13C NMR: d = 21.0, 24.4, 26.7, 27.6, 31.5, 31.7, 32.3, 52.1, 59.5,
67.3, 83.0, 84.0, 127.5, 127.5, 127.7, 127.7, 127.9, 128.2, 135.7,
170.1, 170.1, 171.3, 171.8, 172, 174.3.
References
(11) Chamberlin, A. R.; Chung, J.-Y.-L. J. Am. Chem. Soc. 1983,
105, 3653.
(12) Dener, J. M.; Hart, D. J.; Ramesh, S. J. Org. Chem. 1988, 53,
6022.
(1) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56,
3817.
(2) (a) Lennartz, M.; Sadakane, M.; Stekhan, E. Tetrahedron
1999, 55, 14407. (b) deKoning, H.; Hiemstra, H.;
Speckamp, W. N.; Moolenaar, M. J. Eur. J. Org. Chem.
1998, 1729. (c) Pilli, R. A.; Diaz, C. C.; Maldaner, A. O. J.
Org. Chem. 1995, 60, 717. (d) Dhimane, H.; Vanucci-
Bacque, C.; Hamon, L.; Lhommet, G. Eur. J. Org. Chem.
1998, 1555. (e) Shono, T.; Matsumara, Y.; Tsubata, K. J.
Am. Chem. Soc. 1981, 103, 1172. For some recent reviews,
see: (f) DeShong, P.; Pilcher, A. S. J. Org. Chem. 1996, 61,
6901. (g) Konno, H.; Toshiro, E.; Hinoda, N. Synthesis
2003, 2161. (h) Satoh, T.; Shimura, T.; Sakai, K.
Heterocycles 2003, 59, 137. (i) Amishiro, N.; Denmark, S.
E. J. Org. Chem. 2003, 68, 6997.
(13) Ryu, Y.; Kim, G. J. Org. Chem. 1995, 60, 103.
(14) (a) Yamada, H.; Aoyagi, S.; Kibayashi, C. J. Am. Chem. Soc.
1996, 118, 1054. (b) Ohwada, J.; Inouye, Y.; Kimura, M.;
Kakisawa, H. Bull. Chem. Soc. Jpn. 1990, 63, 287.
(15) Compound 5a was prepared according to the procedure
described in the following article: Clive, D. L. J.; Yeh, V. S.
C. Tetrahedron Lett. 1998, 39, 4789.
(16) For the preparation of 5c, see: Lee, Y. S.; Cho, D. J.; Kim, S.
N.; Choi, J. H.; Park, H. J. Org. Chem. 1999, 64, 9727.
(17) For preparation of 5b, see: Acevedo, C. M.; Kogut, E. F.;
Lipton, M. A. Tetrahedron 2001, 57, 6353.
(18) Compounds 5d and 5e were prepared from (S)- and (R)-
pyroglutamic acid using typical procedures for functional-
group transformations similar to those employed for 5a–c.
(19) The yield of 2b fell to 63% when 5 g of 1b was used (the
corresponding hydroxy lactam was also isolated in 16%
yield) and to 40% when the reaction was carried out on a 7.5
g scale.
(20) The acetate 2h was obtained in high yield by using a
conventional acetylation procedure: (a) Kim, G.; Ryu, Y. J.
Org. Chem. 1995, 60, 103. (b) Oba, M.; Koguchi, S.;
Nishiyama, K. Tetrahedron 2002, 58, 9359.
(3) (a) Louwrier, S.; Ostendorf, M.; Boom, A.; Hiemstra, H.;
Speckamp, W. N. Tetrahedron 1996, 52, 2603.
(b) Russowski, D.; Pilli, R. A.; Petersen, R. Z.; Godoi, M. N.
Tetrahedron Lett. 2000, 41, 9939. (c) Klitzke, C. F.; Pilli, R.
A. Tetrahedron Lett. 2001, 42, 5605. (d) Russowski, D.;
Pilli, R. A. J. Org. Chem. 1996, 61, 3187. (e) Romagnoli,
R.; Roos, E. C.; Hiemstra, H.; Moolenar, M. J.; Speckamp,
W. N.; Kaptein, B.; Schoenmaker, H. E. Tetrahedron Lett.
1994, 35, 1087. (f) Oba, M.; Koguchi, S.; Nishiyama, K.
Tetrahedron 2002, 58, 9359. (g) MacDonald, S. F. J.;
Spooner, J. E.; Dowle, M. D. Synlett 1998, 1375. (h) Smith,
A. B. III; Salvatore, B. A.; Hull, K. G.; Duan, T. J. W.
Tetrahedron Lett. 1991, 32, 4859. (i) Katsuki, H.; Iwasaki,
M.; Ochi, M. Heterocycles 1994, 38, 17. (j) Rassu, G.;
Pinna, L.; Spanu, P.; Ulgheri, F.; Casiraghi, G. Tetrahedron
Lett. 1994, 35, 4019. (k) Altman, K. H. Tetrahedron Lett.
1993, 34, 7721.
(21) Hydroxy lactams derived from imides 1p–q can be
acetylated under usual acetylation conditions: Ukaji, Y.;
Tsukamoto, K.; Nasada, Y.; Shimizu, M.; Fujisawa, T.
Chem. Lett. 1993, 221.
(22) Hubert, J. C.; Wijnberg, J. B. P. A.; Speckamp, W. N.
Tetrahedron 1975, 31, 1437.
(23) Barrett, A. G. M.; Philipauskas, D. J. Org. Chem. 1991, 56,
2787.
(24) Okitsu, O.; Suzuki, R.; Kobayashi, S. J. Org. Chem. 2001,
66, 809.
(4) Altman, K. H.; Freier, S. M.; Pieles, U.; Winkler, T. Angew.
Chem., Int. Ed. Engl. 1994, 33, 1654; see also references 3i
and 3j.
Synthesis 2006, No. 5, 875–879 © Thieme Stuttgart · New York