A convenient synthesis of functionalized α-methylidenebutano-4- lactams

Article abstract of DOI:10.1002/hlca.201100070

A concise synthetic approach to functionalized α- methylidenebutanolactams has been developed. The synthetic strategy is based on the preliminary assembly of the lactam template equipped with appropriate functionalities. Subsequent installation of the methylidene by a metalation/alkylation/elimination sequence completed the elaboration of the racemic title compounds. Copyright

Full text of DOI:10.1002/hlca.201100070

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A Convenient Synthesis of Functionalized a-Methylidenebutano-4-lactams
by Gwenae¨lle Libergea)b), Ste´phane Lebruna)b), Axel Couture*a)c), and Pierre Grandclaudona)b)
a
´
) Universite Lille Nord de France, F-59000 Lille
b
ˆ
) USTL, Laboratoire de Chimie Organique Physique, EA CMF 4478, Batiment C3(2),
F-59655 Villeneuve dꢀAscq
c) CNRS, UMR 8181 ꢁUCCSꢀ, F-59655 Villeneuve dꢀAscq (e-mail: axel.couture@univ-lille1.fr)
A concise synthetic approach to functionalized a-methylidenebutanolactams has been developed.
The synthetic strategy is based on the preliminary assembly of the lactam template equipped with
appropriate functionalities. Subsequent installation of the methylidene by a metalation/alkylation/
elimination sequence completed the elaboration of the racemic title compounds.
Introduction. – a-Alkylidene-g-lactams 1 (Fig.) are the active constituents of many
natural and synthetic compounds exhibiting pronounced biological properties [1][2].
In particular the a-methylidenebutano-4-lactams exhibit cytotoxicity [2] but with less
toxic activity than the corresponding lactones [2g][3], rendering them promising
compounds as potential anticancer [2a] and anti-inflammatory agents [2]. They are
able to act as Michael acceptors in the reaction with thiol groups of bionucleophiles [2]
or can readily form [2 þ 2] cycloadducts with the DNA bases [4]. Additionally, they can
be partners in ring-closing metathesis (RCM) reactions [5] and can serve as key
building blocks for the synthesis of multifarious natural and/or bioactive compounds
[6]. Paradoxically, these lactams, less common in nature [7] than their oxo analogues 2
(Fig.), have not elicited much synthetic efforts. Metal-promoted syntheses
[1f][1h][1l][8] as well as radical [1g] or anionic methodologies [9] have been used
with varying degrees of success, but most synthetic procedures leading to a-
methylidenebutano-4-lactams utilize the base-promoted reaction of nitro alkanes with
the acetates of BaylisꢀHillman adducts [1j], with bromomethyl fumarates [1k] and
functionalized acrylates [1i], followed by reductive or sonochemically induced [1r]
cyclization. They can also be accessed by ring opening of N-tosylaziridines [1a] and
from aldimines by exposure to b-functional crotyl-Zn reagents [1f] or In-promoted
addition to (bromomethyl)acrylic acid derivatives [1b][1s]. The required methylidene
unit can be incorporated early in the synthetic sequence or can be ultimately accessed
by HornerꢀEmmons or Peterson olefination on preliminarily assembled phosphory-
lated [1i][1n][2g] or silylated lactams [1c]. All these methods are of procedural
simplicity, but they can hardly accommodate additional functional groups and,
particularly, carboxylic acid functions at C(3) of the lactam. This is rather worrying,
since structurally sophisticated models, as e.g., by 3 (Fig.), have been designed and
developed for the treatment of immunopathy [10]. Furthermore, their formation is
invariably accompanied by an undesirable isomerization leading to the corresponding
ꢂ 2011 Verlag Helvetica Chimica Acta AG, Zꢃrich

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Figure. a-Alkylidenebutano-4-lactams and -lactones 1 and 2, respectively, and Biologically Active a-
Methylidenebutano-4-lactam 3
endocyclic unsaturated analogs. As a consequence, for the construction of structurally
diverse models the development of general synthetic methodologies providing
molecular complexity in a highly efficient manner is an area of current interest.
In this context, we aimed to develop a synthetic approach to rapidly achieve
molecular diversity, and, for this purpose, we targeted some exemplary functionalized
and C(3)-disubstituted models 4 and 5 that fulfil the above-mentioned structural
criteria. In particular, we speculated that the carboxylate function may serve as a
handle or key branching point for alternative functionalization.
Results and Discussion. – The first facet of the synthesis, depicted in the Scheme,
was the preliminary elaboration of the C-methylated keto diesters 6 and 7. These
precursors were readily assembled from keto esters 8 and 9, respectively, by two
sequential metalation/alkylation processes involving ethyl bromoacetate and MeI as
alkylating agents. Compounds 6 and 7 were obtained in moderate yields, probably due
to the steric congestion of the final compounds. Subsequent reductive amination
reaction under forcing conditions by making use of AcONH4/NaBH3CN in refluxing
MeOH triggered the preliminary conversion of the keto diesters 6 and 7 to the primary
amine 10, followed by spontaneous intramolecular regioselective aminolysis leading to
the lactam unit. The resulting lactams 11 and 12, respectively, were obtained in
satisfactory yields as almost equimolecular mixtures of easily separable diastereoisom-
ers (Table). The cis-isomer was predominant by a small margin for 11 and the trans-
isomer for 12, probably due to the presence of the bulkier vicinal pentyl group.
Although the 1H- and 13C-NMR chemical shifts were different for the diastereoisomers,
stereochemical assignments were made on the basis of nuclear Overhauser effect
(NOE). For the NOE experiments, the singlet resonance of MeꢀC(3) of either isomer
was irradiated under identical conditions. For one isomer (cis-11 and cis-12, resp.), the
intensity of the signal of the HꢀC(2) was enhanced significantly, whereas this
enhancement was reduced for the other isomer (trans-11 and trans-12, resp.). These
results are interpreted in terms of the spatial proximity of HꢀC(2) to the irradiated Me
group, and the spectrum displaying the enhancement can be unambiguously assigned to
the isomer having a trans-configuration for the two alkyl groups, i.e., cis-11 and cis-12.
The ultimate installation of the exocyclic methylidene unit by a carbanionic process
required the preliminary protection of the lactam N-atom. For this purpose, the isolated
lactams cis- and trans-11, and cis- and trans-12 were N-Boc-protected (Boc ¼ (tert-

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butoxy)carbonyl), since we anticipated that deprotection of the resulting N-acyl
carbamates at a later stage of the process would spare the latent functionalities within
the lactam framework. This operation was easily performed under standard conditions
to afford excellent yields of the desired N-Boc-protected lactams cis- and trans-13, and
cis- and trans-14 (Scheme and Table). For the creation of the methylidene unit, a
metalation/electrophilic attack/elimination sequence precluding the use of paraform-
aldehyde was preferred. In this regard, compounds 13 and 14 were initially exposed to
lithium hexamethyldisilazide (LHMDS) at low temperature, and the transient enolates
were captured with iodomethyl methyl ether to afford excellent yields of the C(4)-
substituted lactams cis- and trans-15, and cis- and trans-16 (Table). At this stage,
configurational considerations about the configuration at C(4) were not crucial for the
outcome of the synthetic process, because conversion of the alkoxylated appendage to
the mandatory methylidene moiety was planned behind in the sequence. The creation
of the exocyclic unsaturated moiety was secured by treatment of the MeOCH2-
substituted precursors cis- and trans-15, and cis- and trans-16 with 1,8-diazabicy-
clo[5.5.0]undec-7-ene (DBU) in toluene and, gratifyingly, this protocol afforded the
methylidene compounds cis- and trans-17, and cis- and trans-18. With these compounds
in hand, we were only one step away from the targeted compounds. Treatment of 17
and 18 with CF3COOH (TFA) in CH2Cl2 for a short period triggered release of the N-
Boc protection to provide the N-unsubstituted functionalized lactams cis- and trans-4,
and cis- and trans-5 in fairly good yields (Table).
Table. Diastereoisomeric Ratio and Yields for the Synthesis of Compounds 4, 5, and 11 – 18
R
Compound
Yield [%]
(cis/trans ratio)
Diastereo-
isomer
Butano-4-lactams (Yield [%])
Me
11
12
43 (56 : 44)
40 (40 : 60)
cis
trans
cis
13 (71)
13 (75)
14 (79)
14 (75)
15 (52)
15 (64)
16 (65)
16 (75)
17 (74)
17 (57)
18 (70)
18 (65)
4 (95)
4 (97)
5 (93)
5 (98)
C5H11
trans
Conclusions. – We have devised a concise and efficient method to synthesize
functionalized a-methylidene-g-butyrolactams. The notable advantages of this method
are operational simplicity, mild reaction conditions, and ease of isolation of racemic cis-
and trans-products. This simple protocol developed in this study paves the way for
further biological studies, and we believe that this work provides a strong incentive for
the elaboration of structurally modified models.
´
This research was supported by ADIR (Laboratoires Servier) and by the Program PRIM (Region
Nord-Pas-de-Calais). We thank also E. Deniau (UST Lille 1) for helpful discussions.
Experimental Part
1. General. Abbreviations: Boc: (tert-butoxy)carbonyl; DBU: 1,8-diazabicyclo[5.5.0]undec-7-ene;
DMAP: 4-(dimethylamino)pyridine; LHMDS: lithium hexamethyldisilazide. All solvents were dried
and distilled according to standard procedures. Glassware was dried in oven and assembled under dry Ar.

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Scheme. Synthesis of Functionalized a-Methylidenebutano-4-lactams

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Helvetica Chimica Acta – Vol. 94 (2011)
The glassware was equipped with rubber septa and reagent transfer was performed by syringe techniques.
Flash column chromatography (FCC): Merck silica gel 60 (SiO2; 40 – 63 mm; 230 – 400 mesh ASTM) was
used. M.p.: Reichert-Thermopan apparatus; uncorrected. NMR Spectra: Bruker AM 300 (300 and
75 MHz, for 1H and 13C, resp.), CDCl3 as solvent, TMS as internal standard. Elemental analyses: Carlo-
Erba CHNS-11110 equipment.
2. Synthesis of Keto Diesters 6 and 7. General Procedure. A soln. of 8 or 9 (30 mmol) in THF (10 ml)
was added dropwise to a suspension of NaH (35 mmol) in THF (80 ml) at 08 under Ar. The mixture was
stirred at r.t. for 1 h. Then, BrCH2COOEt (33 mmol) was added dropwise, and the mixture was stirred at
r.t. for an additional h. Aq. sat. NH4Cl soln. (30 ml) was added, THF was evaporated under reduced
pressure, and the remaining aq. layer was extracted with AcOEt (3 ꢁ 50 ml). The combined org. layers
were washed with brine (10 ml) and dried (MgSO4). After concentration under reduced pressure, the
oily residue was purified by FCC (SiO2; AcOEt/hexanes 20 :80) to give the crude intermediate keto
esters, which were methylated with MeI following the same procedure but upon heating the mixture to
reflux for 4 h.
1-Benzyl 4-Ethyl 2-Acetyl-2-methylbutanedioate (6). Yield: 40% over the two steps from 8. Oil.
1H-NMR: 1.16 (t, J ¼ 7.1, 3 H); 1.47 (s, 3 H); 2.14 (s, 3 H); 2.82 (d, J ¼ 16.6, 1 H); 2.93 (d, J ¼ 16.6), 1 H;
4.03 (q, J ¼ 7.1, 2 H); 5.09 – 5.18 (m, 2 H); 7.24 – 7.35 (m, 5 H). 13C-NMR: 14.0 (Me); 20.2 (Me); 26.2
(Me); 39.9 (CH2); 57.5 (C); 60.7 (CH2); 67.4 (CH2); 128.3 (2 CH); 128.4 (CH); 128.6 (2 CH); 135.2 (C);
170.7 (CO); 171.6 (CO), 204.2 (CO). Anal. calc. for C16H20O5 (292.33): C 65.74, H 6.90; found: C 65.48, H
7.02.
1-Benzyl 4-Ethyl 2-Hexanoyl-2-methylbutanedioate (7). Yield: 41% over the two steps from 9. Oil.
1H-NMR: 0.82 (t, J ¼ 7.1, 3 H); 1.09 – 1.24 (m, 7 H); 1.41 – 1.50 (m, 2 H); 1.47 (s, 3 H); 2.37 – 2.49 (m,
2 H); 2.82 (d, J ¼ 16.6, 1 H); 2.92 (d, J ¼ 16.6, 1 H); 4.04 (q, J ¼ 7.1, 2 H); 5.14 (s, 2 H); 7.25 – 7.36 (m,
5 H). 13C-NMR: 13.9 (Me); 14.0 (Me); 20.1 (Me); 22.4 (CH2); 23.2 (CH2); 31.1 (CH2); 38.2 (CH2); 40.0
(CH2); 57.4 (C); 60.7 (CH2); 67.3 (CH2); 128.4 (2 CH); 128.5 (CH); 128.6 (2 CH); 135.2 (C); 170.7 (CO);
171.7 (CO); 206.3 (CO). Anal. calc. for C20H28O5 (348.44): C 68.94, H 8.10; found: C 68.80, H 8.14.
3. Synthesis of Lactams 11 and 12. Ammonium acetate (AcONH4; 15.4 g, 200 mmol) and NaBH3CN
(0.80 g, 12.6 mmol) were added to a soln. of 6 or 7 (20 mmol) in MeOH (70 ml), and the mixture was
heated to reflux for 2 h. The mixture was concentrated under reduced pressure, and the residue was
dissolved in toluene (60 ml). After boiling for 12 h, toluene was evaporated under reduced pressure, and
the residue was dissolved in Et2O (50 ml). The Et2O layer was washed with aq. sat. NaHCO3 soln. (2 ꢁ
30 ml) and brine (20 ml), and then dried (MgSO4). After evaporation of the solvent, the oily residue was
submitted to FCC (SiO2; AcOEt/hexanes 90 :10) to afford the separated cis and trans diastereoisomers of
lactams 11 and 12.
Benzyl (2RS,3RS)-2,3-Dimethyl-5-oxopyrrolidine-3-carboxylate (cis-11). White solid. M.p. 92 – 938.
1H-NMR: 1.19 (d, J ¼ 6.6, 3 H); 1.27 (s, 3 H); 2.20 (d, J ¼ 16.8, 1 H); 2.95 (d, J ¼ 16.8, 1 H); 4.00 – 4.11
(m, 1 H); 5.14 (s, 2 H); 7.20 – 7.40 (m, 5 H). 13C-NMR: 15.7 (Me); 18.6 (Me); 42.3 (CH2); 48.6 (C); 54.9
(CH); 67.0 (CH2); 128.0 (2 CH); 128.4 (CH); 128.7 (2 CH); 135.5 (C); 174.6 (CO); 175.8 (CO). Anal.
calc. for C14H17NO3 (247.29): C 68.00, H 6.93, N 5.66; found: C 67.85, H 7.04, N 5.37.
Benzyl (2RS,3SR)-2,3-Dimethyl-5-oxopyrrolidine-3-carboxylate (trans-11). White solid. M.p. .84 –
858. 1H-NMR: 1.02 (d, J ¼ 6.4, 3 H); 1.40 (s, 3 H); 2.10 (d, J ¼ 17.0, 1 H); 3.01 (d, J ¼ 17.0, 1 H);
3.50 – 3.56 (m, 1 H); 5.07 – 5.17 (m, 2 H); 7.20 – 7.40 (m, 5 H). 13C-NMR: 17.7 (Me); 23.9 (Me); 40.3
(CH2); 49.3 (C); 58.7 (CH); 66.8 (CH2); 128.2 (2 CH); 128.4 (CH); 128.6 (2 CH); 135.4 (C); 173.3 (CO);
176.3 (CO). Anal. calc. for C14H17NO3 (247.29): C 68.00, H 6.93, N 5.66; found: C 67.96, H 6.69, N 5.71.
Benzyl (2RS,3RS)-3-Methyl-5-oxo-2-pentylpyrrolidine-3-carboxylate (cis-12). Oil. 1H-NMR: 0.83 (t,
J ¼ 6.3, 3 H); 1.10 – 1.60 (m, 11 H); 2.16 (d, J ¼ 16.6, 1 H); 2.92 (d, J ¼ 16.6, 1 H); 3.86 (dd, J ¼ 4.4, 9.0,
1 H); 5.13 (s, 2 H); 7.20 – 7.34 (m, 5 H); 7.52 (br. s, 1 H). 13C-NMR: 14.0 (Me); 18.3 (Me); 22.3 (CH2);
26.2 (CH2); 30.3 (CH2); 31.6 (CH2); 43.1 (CH2); 48.4 (C); 59.9 (CH); 67.0 (CH2); 128.0 (2 CH); 128.4
(CH); 128.6 (2 CH); 135.6 (C); 174.7 (CO); 175.7 (CO). Anal. calc. for C18H25NO3 (303.40): C 71.26, H
8.31, N 4,62; found: C 71.39, H 8.09, N 4.88.
Benzyl (2RS,3SR)-3-Methyl-5-oxo-2-pentylpyrrolidine-3-carboxylate (trans-12). Oil. 1H-NMR: 0.80
(t, J ¼ 6.8, 3 H); 1.10 – 1.30 (m, 8 H); 1.40 (s, 3 H); 2.09 (d, J ¼ 17.0, 1 H); 2.99 (d, J ¼ 17.0, 1 H); 3.30 –
3.34 (m, 1 H); 5.12 (s, 2 H); 7.20 – 7.35 (m, 5 H); 7.66 (br. s, 1 H). 13C-NMR: 14.0 (Me); 22.3 (CH2); 24.3

Helvetica Chimica Acta – Vol. 94 (2011)
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(Me); 25.9 (CH2); 31.4 (CH2); 31.8 (CH2); 40.6 (CH2); 49.2 (C); 63.5 (CH); 66.8 (CH2); 128.4 (2 CH);
128.5 (CH); 128.6 (2 CH); 135.4 (C); 173.3 (CO); 176.5 (CO). Anal. calc. for C18H25NO3 (303.40): C
71.26, H 8.31, N 4.62; found: C 71.14, H 8.58, N 4.87.
4. Synthesis of N-Protected Lactams 13 and 14. A soln. of 11 or 12 (4 mmol), Boc2O (0.95 g,
4.4 mmol), DMAP (0.49 g, 4 mmol), and Et3N (0.56 ml, 4 mmol) in CH2Cl2 (30 ml) was stirred at r.t. for
12 h. The solvent was evaporated under reduced pressure, and the residue was purified by FCC (SiO2;
AcOEt/hexanes 40 :60).
3-Benzyl 1-tert-Butyl (2RS,3RS)-2,3-Dimethyl-5-oxopyrrolidine-1,3-dicarboxylate (cis-13). Oil.
1H-NMR: 1.25 (d, J ¼ 6.6, 3 H); 1.29 (s, 3 H); 1.48 (s, 9 H); 2.42 (d, J ¼ 17.3, 1 H); 2.99 (d, J ¼ 17.3,
1 H); 4.51 (q, J ¼ 6.6, 1 H); 5.09 – 5.20 (m, 2 H); 7.29 – 7.34 (m, 5 H). 13C-NMR: 15.5 (Me); 19.0 (Me);
28.0 (3 Me); 41.4 (CH2); 45.8 (C); 59.2 (CH); 67.4 (CH2); 83.0 (C); 128.0 (2 CH); 128.4 (CH); 128.7
(2 CH); 135.3 (C); 146.4 (C); 171.6 (CO); 174.7 (CO). Anal. calc. for C19H25NO5 (347.41): C 65.69, H
7.25, N 4.03; found: C 65.77, H 7.45, N 3.78.
3-Benzyl 1-tert-Butyl (2RS,3SR)-2,3-Dimethyl-5-oxopyrrolidine-1,3-dicarboxylate (trans-13). White
1
solid. M.p. 67 – 688. H-NMR: 1.11 (d, J ¼ 6.4, 3 H); 1.42 (s, 3 H); 1.49 (s, 9 H); 2.23 (d, J ¼ 17.6, 1 H);
3.23 (d, J ¼ 17.6, 1 H); 3,99 (q, J ¼ 6.4, 1 H); 5.09 – 5.19 (m, 2 H); 7.25 – 7.40 (m, 5 H). 13C-NMR: 16.2
(Me); 24.3 (Me); 28.0 (3 Me); 40.8 (CH2); 46.2 (C); 61.5 (CH); 67.2 (CH2); 83.2 (C); 128.4 (2 CH); 128.6
(CH); 128.7 (2 CH); 135.1 (C); 146.6 (C); 171.4 (CO); 172,5 (CO). Anal. calc. for C19H25NO5 (347.41): C
65.69, H 7.25, N 4.03; found: C 65.94, H 7.37, N 4.24.
3-Benzyl 1-tert-Butyl (2RS,3RS)-3-Methyl-5-oxo-2-pentylpyrrolidine-1,3-dicarboxylate (cis-14). Oil.
1H-NMR: 0.83 (t, J ¼ 6.5, 3 H); 1.20 – 1.70 (m, 11 H); 1.42 (s, 9 H); 2.40 (d, J ¼ 17.3, 1 H); 2.92 (d, J ¼
17.3, 1 H); 4.43 (t, J ¼ 6.2, 1 H); 5.03 – 5.15 (m, 2 H); 7.23 – 7.31 (m, 5 H). 13C-NMR: 13.9 (Me); 18.8
(Me); 22.5 (CH2); 26.0 (CH2); 27.9 (3 Me); 31.0 (CH2); 32.0 (CH2); 41.8 (CH2); 46.7 (C); 62.8 (CH); 67.4
(CH2); 82.8 (C); 128.0 (2 CH); 128.4 (CH); 128.6 (2 CH); 135.3 (C); 149.6 (C); 171.9 (CO); 174.8 (CO).
Anal. calc. for C23H33NO5 (403.52): C 68.46, H 8.24, N 3.47, found: C 68.54, H 7.94, N 3.32.
3-Benzyl 1-tert-Butyl (2RS,3SR)-3-Methyl-5-oxo-2-pentylpyrrolidine-1,3-dicarboxylate (trans-14).
1
Oil. H-NMR: 0.79 (t, J ¼ 6.9, 3 H); 1.10 – 1.55 (m, 8 H); 1.41 (s, 3 H); 1.48 (s, 9 H); 2.21 (d, J ¼ 17.6,
1 H); 3.22 (d, J ¼ 17.6, 1 H); 3.97 (t, J ¼ 5.6, 1 H); 5.09 – 5.18 (m, 2 H); 7.20 – 7.40 (m, 5 H). 13C-NMR:
13.9 (Me); 22.4 (Me); 24.9 (CH2); 25.5 (CH2); 28.0 (3 Me); 31.8 (CH2); 31.9 (CH2); 41.6 (CH2); 46.5 (C);
65.4 (CH); 67.2 (CH2); 82.8 (C); 128.5 (2 CH); 128.6 (CH); 128.7 (2 CH); 135.3 (C); 149.6 (C); 171.9
(CO); 174.8 (CO). Anal. calc. for C23H33NO5 (403.52): C 68.46, H 8.24, N 3.47; found: C 68.68, H 8.01, N
3.59.
5. Synthesis of Methoxymethylated Lactams 15 and 16. LHMDS (3.85 ml, 1m soln. in THF, 3.9 mmol)
was added dropwise to a soln. of 13 or 14 (3.5 mmol) in THF at ꢀ 788 under Ar. The mixture was stirred
at ꢀ 788 for 1 h, then 1.5 equiv. of MeOCH2I (0.45 ml, 5.25 mmol) was added. The mixture was stirred at
ꢀ 788 for 1 h, and then the reaction was quenched with aq. sat. NH4Cl soln. (10 ml). The temp. was raised
to r.t., and the mixture was extracted with AcOEt (3 ꢁ 20 ml). The combined extracts were washed with
brine (10 ml) and dried (MgSO4). The solvent was evaporated under reduced pressure, and the residue
was purified by FCC (SiO2; AcOEt/hexanes 30 :70).
3-Benzyl 1-tert-Butyl (2RS,3RS)-4-(Methoxymethyl)-2,3-dimethyl-5-oxopyrrolidine-1,3-dicarboxy-
late (cis-15). Oil. 1H-NMR: 1.11 (d, J ¼ 6.6, 3 H); 1.24 (s, 3 H); 1.31 (s, 9 H); 2.61 (dd, J ¼ 3.9, 6.5, 1 H);
3.05 (s, 3 H); 3.39 (dd, J ¼ 6.5, 10.0, 1 H); 3.60 (dd, J ¼ 3.9, 10.0, 1 H); 4.14 (q, J ¼ 6.6, 1 H); 4.89 – 5.05
(m, 2 H); 7.15 – 7.20 (m, 5 H). 13C-NMR: 15.4 (Me); 18.2 (Me); 27.8 (3 Me); 48.1 (C); 51.3 (CH); 57.8
(CH); 59.1 (Me); 66.8 (CH2); 68.7 (CH2); 82.6 (C); 127.9 (2 CH); 128.2 (CH); 128.5 (2 CH); 135.4 (C);
149.5 (C); 171.0 (C); 173.3 (C). Anal. calc. for C21H29NO6 (391.47): C 64.43, H 7.47, N 3.58; found: C
64.25, H 7.69, N 3.61.
3-Benzyl 1-tert-Butyl (2RS,3SR)-4-(Methoxymethyl)-2,3-dimethyl-5-oxopyrrolidine-1,3-dicarboxy-
late (trans-15). Oil. 1H-NMR: 1.19 (d, J ¼ 6.4, 3 H); 1.40 (s, 3 H); 1.47 (s, 9 H); 2.66 (dd, J ¼ 5.1, 7.8, 1 H);
3.11 (s, 3 H); 3.34 (dd, J ¼ 7.8, 10.0, 1 H); 3.70 – 3.80 (m, 2 H); 5.07 – 5.19 (m, 2 H); 7.25 – 7.30 (m, 5 H).
13C-NMR: 14.4 (Me); 21.4 (Me); 28.0 (3 Me); 49.9 (C); 52.6 (CH); 58.9 (Me); 60.5 (CH); 66.5 (CH2);
69.5 (CH2); 82.9 (C); 128.3 (2 CH); 128.4 (CH); 128.5 (2 CH); 135.2 (C); 150.0 (C); 171.5 (CO); 172.2
(CO). Anal. calc. for C21H29NO6 (391.47): C 64.43, H 7.47, N 3.58; found: C 64.57, H 7.73, N 3.39.

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3-Benzyl 1-tert-Butyl (2RS,3RS)-4-(Methoxymethyl)-3-methyl-5-oxo-2-pentylpyrrolidine-1,3-dicar-
boxylate (cis-16). Oil. 1H-NMR: 0.70 – 0.90 (m, 3 H); 1.10 – 1.80 (m, 20 H); 2.72 – 2.76 (m, 1 H); 3.16 (s,
3 H); 3.44 (dd, J ¼ 6.7, 10.2, 1 H); 3.70 (dd, J ¼ 4.1, 10.2, 1 H); 4.17 (t, J ¼ 6.1, 1 H); 5.05 – 5.11 (m, 2 H);
7.26 – 7.29 (m, 5 H). 13C-NMR: 13.9 (Me); 18.0 (Me); 22.4 (CH2); 26.1 (CH2); 27.9 (3 Me); 31.1 (CH2);
32.0 (CH2); 49.3 (C); 51.7 (CH); 59.0 (Me); 61.4 (CH); 67.0 (CH2); 68.9 (CH2); 82.7 (C); 128.1 (2 CH);
128.3 (CH); 128.6 (2 CH); 135.3 (C); 149.9 (C); 171.6 (CO); 173.6 (CO). Anal. calc. for C25H37NO6
(447.58): C 67.09, H 8.33, N 3.13; found: C 67.38, H 8.24, N 3.02.
3-Benzyl 1-tert-Butyl (2RS,3SR)-4-(Methoxymethyl)-3-methyl-5-oxo-2-pentylpyrrolidine-1,3-dicar-
boxylate (trans-16). Oil. 1H-NMR: 0.79 – 0.84 (m, 3 H); 1.00 – 1.55 (m, 11 H); 1.50 (s, 9 H); 2.65 (dd, J ¼
5.0, 7.6, 1 H); 3.14 (s, 3 H); 3.33 (dd, J ¼ 7.6, 10.0, 1 H); 3.67 – 3.70 (m, 1 H); 3.75 (dd, J ¼ 5.0, 10.0, 1 H);
5.10 – 5.19 (m, 2 H); 7.25 – 7.32 (m, 5 H). 13C-NMR: 14.0 (Me); 22.4 (CH2); 23.1 (Me); 26.5 (CH2); 28.0
(3 Me); 30.6 (CH2); 32.0 (CH2); 49.9 (C); 53.4 (CH); 58.9 (Me); 65.0 (CH); 66.6 (CH2); 69.5 (CH2); 83.0
(C); 128.4 (2 CH); 128.5 (CH); 128.6 (2 CH); 135.2 (C); 150.3 (C); 171.9 (CO); 172.1 (CO). Anal. calc.
for C25H37NO6 (447.58): C 67.09, H 8.33, N 3.13; found: C 67.14, H 8.50, N 3.03.
6. Synthesis of a-Methylidenebutano-4-lactams 17 and 18. A soln. of 15 or 16 (5 mmol) and DBU
(0.75 ml, 5 mmol) in toluene (30 ml) was heated at reflux for 4 h. After cooling, the solvent was
evaporated under reduced pressure, and the residue was purified by FCC (SiO2; AcOEt/hexanes 30 :70).
3-Benzyl 1-tert-Butyl (2RS,3RS)-2,3-Dimethyl-4-methylidene-5-oxopyrrolidine-1,3-dicarboxylate
1
(cis-17). Oil. H-NMR: 1.08 (d, J ¼ 6.6, 3 H); 1.33 (s, 3 H); 1.40 (s, 9 H); 4.52 (q, J ¼ 6.6, 1 H); 4.93 –
5.03 (m, 2 H); 5.50 (s, 1 H); 6.24 (s, 1 H); 7.13 – 7.22 (m, 5 H). 13C-NMR: 16.6 (Me); 17.4 (Me); 27.9
(3 Me); 50.0 (C); 57.5 (CH); 67.3 (CH2); 82.9 (C); 121.9 (CH2); 127.6 (2 CH); 128.2 (CH); 128.5 (2 CH);
135.2 (C); 142.9 (C); 149.8 (C); 164.6 (CO); 172.5 (CO). Anal. calc. for C20H25NO5 (359.43): C 66.83, H
7.01, N 3.90; found: C 66.61, H 6.87, N 3.64.
3-Benzyl 1-tert-Butyl (2RS,3SR)-2,3-Dimethyl-4-methylidene-5-oxopyrrolidine-1,3-dicarboxylate
1
(trans-17). H-NMR: 1.06 (d, J ¼ 6.4, 3 H); 1.14 (s, 3 H); 1.45 (s, 9 H); 3.90 (q, J ¼ 6.4, 1 H); 5.09 (s,
2 H); 5.67 (s, 1 H); 6.27 (s, 1 H); 7.15 – 7.35 (m, 5 H). 13C-NMR: 17.0 (Me); 25.4 (Me); 28.0 (3 Me); 50.4
(C); 60.2 (CH); 66.9 (CH2); 83.2 (C); 122.6 (CH2); 128.3 (2 CH); 128.4 (CH); 128.6 (2 CH); 135.1 (C);
142.5 (C); 150.1 (C); 164.8 (CO); 171.2 (CO). Anal. calc. for C20H25NO5 (359.43): C 66.83, H 7.01, N 3.90;
found: C 66.94, H 7.20, N 4.06.
3-Benzyl 1-tert-Butyl (2RS,3RS)-3-Methyl-4-methylidene-5-oxo-2-pentylpyrrolidine-1,3-dicarboxy-
late (cis-18). Oil. 1H-NMR: 0.83 (t, J ¼ 6.5, 3 H); 1.12 – 1.76 (m, 11 H); 1.46 (s, 9 H); 4.55 (t, J ¼ 5.7, 1 H);
5.06 (s, 2 H); 5.53 (s, 1 H); 6.30 (s, 1 H); 7.21 – 7.31 (m, 5 H). 13C-NMR: 13.9 (Me); 17.4 (Me); 22.4 (CH2);
25.2 (CH2); 27.9 (3 Me); 31.6 (CH2); 31.9 (CH2); 50.7 (C); 61.0 (CH); 67.5 (CH2); 83.0 (C); 121.1 (CH2);
127.7 (2 CH); 128.3 (CH); 128.6 (2 CH); 135.2 (C); 143.5 (C); 150.1 (C); 165.1 (CO); 172.8 (CO). Anal.
calc. for C24H33NO5 (415.53): C 69.37, H 8.00, N 3.37; found: C 69.26, H 7.73, N 3.16.
3-Benzyl 1-tert-Butyl (2RS,3SR)-3-Methyl-4-methylidene-5-oxo-2-pentylpyrrolidine-1,3-dicarboxy-
late (trans-18). Oil. 1H-NMR: 0.79 (t, J ¼ 6.7, 3 H); 0.99 – 1.54 (m, 8 H); 1.49 (s, 3 H); 1.51 (s, 9 H); 3.99 (t,
J ¼ 5.5, 1 H); 5.17 (s, 2 H); 5.76 (s, 1 H); 6.32 (s, 1 H); 7.33 (s, 5 H). 13C-NMR: 13.9 (Me); 22.3 (CH2);
24.6 (CH2); 27.3 (Me); 28.0 (3 Me); 31.7 (CH2); 32.4 (CH2); 50.5 (C); 64.1 (CH); 67.1 (CH2); 83.3 (C);
122.5 (CH2); 128.5 (2 CH); 128.6 (CH); 128.7 (2 CH); 135.0 (C); 143.0 (C); 150.4 (C); 165.1 (CO); 171.5
(CO). Anal. calc. for C24H33NO5 (415.53): C 69.37, H 8.00, N 3.37; found: C 69.51, H 7.82, N 3.60.
7. N-Boc Deprotection. Synthesis of the N-Unsubstituted Lactams 4 and 5. A soln. of 17 or 18
(2.8 mmol) and TFA (2 ml) in CH2Cl2 (15 ml) was stirred at r.t. for 45 min. Elimination of the solvents
under vacuum furnished 4 or 5. Compounds trans-4 and trans-5 were recrystallized from Et2O/hexane.
Benzyl (2Rs,3RS)-2,3-Dimethyl-4-methylidene-5-oxopyrrolidine-3-carboxylate (cis-4). Oil.
1H-NMR: 1.12 (d, J ¼ 6.4, 3 H); 1.33 (s, 3 H); 4.25 (q, J ¼ 6.4, 1 H); 5.03 (s, 2 H); 5.56 (s, 1 H); 6.11
(s, 1 H); 7.15 – 7.35 (m, 5 H); 8.38 (br. s, 1 H). 13C-NMR: 16.5 (Me); 19.5 (Me); 51.4 (C); 54.3 (CH); 67.3
(CH2); 119.6 (CH2); 127.9 (2 CH); 128.3 (CH); 128.6 (2 CH); 135.5 (C); 143.9 (C); 169.8 (CO); 172.6
(CO). Anal. calc. for C15H17NO3 (259.31): C 69.48, H 6.61, N 5.40; found: C 69.59, H 6.57, N 5.29.
Benzyl (2RS,3SR)-2,3-Dimethyl-4-methylidene-5-oxopyrrolidine-3-carboxylate (trans-4). White sol-
id. M.p. 124 – 1258. 1H-NMR: 1.10 (d, J ¼ 6.4, 3 H); 1.46 (s, 3 H); 3.53 (q, J ¼ 6.4, 1 H); 5.11 (s, 2 H); 5.31
(s, 1 H); 6.01 (s, 1 H); 7.10 – 7.35 (m, 5 H); 7.91 (br. s, 1 H). 13C-NMR: 16.7 (Me); 22.6 (Me); 52.6 (C);
57.4 (CH); 66.7 (CH2); 116.9 (CH2); 128.0 (2 CH); 128.2 (CH); 128.5 (2 CH); 135.4 (C); 145.1 (C); 169.7

Helvetica Chimica Acta – Vol. 94 (2011)
1669
(CO); 172.0 (CO). Anal. calc. for C15H17NO (259.31): C 69.48, H 6.61, N 5.40; found: C 69.48, H 6.84, N
5.12.
Benzyl (2RS,3RS)-3-Methyl-4-methylidene-5-oxo-2-pentylpyrrolidine-3-carboxylate (cis-5). Oil.
1H-NMR: 0.80 – 0.94 (m, 3 H); 1.15 – 1.70 (m, 8 H); 1.42 (s, 3 H); 4.08 – 4.19 (m, 1 H); 5.18 (s, 2 H);
5.64 (s, 1 H); 6.17 (s, 1 H); 7.20 – 7.40 (m, 5 H); 8.47 (br. s, 1 H). 13C-NMR: 13.3 (Me); 19.3 (Me); 21.8
(CH2); 25.4 (CH2); 30.3 (CH2); 31.0 (CH2); 51.0 (C); 58.9 (CH); 67.2 (CH2); 119.9 (CH2); 127.6 (2 CH);
128.1 (CH); 128.2 (2 ꢁ CH); 134.7 (C); 143.1 (C); 170.1 (CO); 172.0 (CO). Anal. calc. for C19H25NO3
(315.42): C 72.35, H 7.99, N 4.44, found: C 72.20, H 8.15, N 4.57.
Benzyl (2RS,3SR)-3-Methyl-4-methylidene-5-oxo-2-pentylpyrrolidine-3-carboxylate (trans-5). White
1
solid. M.p. 65 – 668. H-NMR: 0.86 (t, J ¼ 6.0, 3 H); 1.10 – 1.60 (m, 8 H); 1.51 (s, 3 H); 3.40 – 3.54 (m,
1 H); 5.16 (s, 2 H); 5.52 (s, 1 H); 6.16 (s, 1 H); 7.25 – 7.40 (m, 5 H); 8.33 (br. s, 1 H). 13C-NMR: 13.9 (Me);
22.3 (CH2); 22.9 (Me); 26.3 (CH2); 31.3 (CH2); 31.5 (CH2); 51.7 (C); 62.4 (CH); 66.8 (CH2); 116.9 (CH2);
128.2 (2 CH); 128.3 (CH); 128.5 (2 CH); 134.6 (C); 143.6 (C); 170.9 (CO); 171.0 (CO). Anal. calc. for
C19H25NO3 (315.42): C 72.35, H 7.99, N 4.44, found: C 72.49, H 8.14, N 4.67.
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Received February 15, 2011