An efficient synthetic route to functionalized δ-lactams

Article abstract of DOI:10.1016/j.tet.2008.07.057

This paper describes a convenient synthesis of disubstituted functionalized δ-lactams based on Michael addition of primary amines to dimethyl-E-2-alkylidene glutarates 2 followed by an intramolecular cyclisation.

Full text of DOI:10.1016/j.tet.2008.07.057

Tetrahedron 64 (2008) 9540–9543
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An efficient synthetic route to functionalized
d
-lactams
*
`
¨
¨
Ali Samarat, Jihene Ben Kraıem, Taıcir Ben Ayed, Hassen Amri
Laboratoire de Chimie Organique & Organome´tallique, Faculte´ des Sciences, Campus Universitaire, 2092-Tunis, Tunisia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 May 2008
Received in revised form 7 July 2008
Accepted 17 July 2008
Available online 22 July 2008
This paper describes a convenient synthesis of disubstituted functionalized d-lactams based on Michael
addition of primary amines to dimethyl-E-2-alkylidene glutarates 2 followed by an intramolecular
cyclisation.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Aza-Michael addition
Primary amines
2-Alkylidene glutarates
d-Lactams
1. Introduction
bromination–dehydrobromination of dimethyl-2-methylene glu-
tarate 2a.32
Six-membered nitrogen-containing heterocycles are common
skeletons in many natural products and exhibit diverse and im-
portant biological properties.1,2 Alkaloids that contain the piperi-
dine ring are targets for medicinal chemistry.3–7 Accordingly,
As summarized in Scheme 2, we have recently demonstrated
that glutarates 2 represent a useful building block for the enan-
tioselective synthesis of functionalized
g-butyrolactones by the
utilisation of the Sharpless asymmetric dihydroxylation (AD) and
aminohydroxylation (AA) processes,33 while the silylcupration of
the same Michael acceptors 2, followed by oxidation of the carbon–
silicon bond and cyclisation provide the corresponding function-
functionalized
d
-lactams have been generally used as precursors of
the corresponding piperidines.8–10 Functionalized
d-lactams and
structurally related compounds have attracted considerable at-
tention because of various biological activities, including anti-tu-
mour compounds,11 enzyme inhibitors12–14 and anti-HIV agents.15
Over the last few years, there is an increasing interest in the de-
velopment of general methods for their preparation and several
syntheses of these heterocycles, using different approaches, have
alized
We now report the use of dimethyl (E)-2-alkylidene glutarates 2
as intermediates in the synthesis of functionalized -lactams. In our
d
-lactones.34
d
approach, the construction of the nitrogen-containing heterocycle
is based on an efficient coupling of primary amines to Michael ac-
ceptors 2. In fact, the condensation of glutarates 2 with primary
amines in methanol, as solvent, at reflux proceeds via a two-step
sequence: a nucleophilic conjugate addition of amine to the acti-
been reported.16–24 Our interest in the synthesis of poly-
25–30
functionalized heterocyclic compounds
has led us to the de-
-lactams using
sign of a rapid access to these functionalized
d
dimethyl (E)-2-alkylidene glutarates 2 as key intermediates.
vate ethylenic carbon leading to the
b-amino-ester intermediate,
which spontaneously undergoes an intramolecular cyclisation
35
through a 6-exo-trig process
functionalized -lactam 3 (Scheme 3).
It is interesting to notice that spontaneous lactamization of the
resulting -aminoester intermediate was completely regioselective
in the examined cases; only -lactams were obtained in moderate
and good yields. The disubstituted -lactams 3e–g were obtained as
to provide the corresponding
2. Results and discussion
d
We have previously described a highly stereoselective synthesis
of dimethyl (E)-2-alkylidene glutarates 2 by nucleophilic sub-
stitution of the vinylic bromine atom in the diester 1, by using
cuprates as nucleophilic reagents generated in situ at low tem-
perature (Scheme 1).31 The dimethyl (E)-2-bromomethylene glu-
b
d
d
a mixture of two isomers with good diatereoselectivity and satis-
factory yields (Table 1). A small coupling constant (4–5 Hz) for the
two protons at C-2 (d 4.2–3.9) and C-3 (d 2.9–3.1) suggested a cis
tarate
1 was prepared through a simple tandem-process:
configuration for the major isomer of the disubstituted lactams
3e–g. This result allowed us to establish the configuration of the
* Corresponding author.
E-mail address: hassen.amri@fst.rnu.tn (H. Amri).
b-amino-ester precursor. The major isomer was found to possess
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.07.057

A. Samarat et al. / Tetrahedron 64 (2008) 9540–9543
9541
CO2Me
CO2Me
CO2Me
R
Br
RMgX, LiCuBr2 (cat.)
THF, -20 °C
1) Br2 / CCl4, reflux
2) TBAF, HMPT
CO2Me
2(b-d)
CO2Me
2a
CO2Me
1
Scheme 1.
Table 1
the syn-relative configuration (Scheme 3). The configuration of the
-amino-ester intermediate is determined during protonation in
Functionalized d-lactams 3a–g prepared
b
the aza-Michael addition of primary amines on the alkylidene
glutarates 2b–d. It is well recognized that aza-Michael addition on
unsaturated esters is the most direct method used in the prepara-
d-lactams
R
R0
Cis/transa
Yield (%)b
3a
3b
3c
3d
3e
3f
H
H
H
H
Me
Et
Pr
PhCH2
d
82
92
80
65
55
63
59
p-MeOC6H4-CH2
p-FC6H4-CH2
iPr
PhCH2
PhCH2
d
b
-aminoesters.36–40 However, this reaction is limited by
d
tion of
steric factors imposed by the presence of
d
a
and/or b-substituents, as
78:22
84:16
92:8
evidenced by Pfau’s pioneering results.41 Interestingly, we found
that diastereoselectivity increases with the size of R group in 2b–d,
consequently we examined two transition state conformations
TS-1 and TS-2, in which Hþ would approach the enolate face anti-
relative to the bulky amino group (Scheme 4).
3g
PhCH2
a
Calculated by integration of the OMe signals in 3e–g.
Yields referred to isolated pure product.
b
TS-2 shows an increasingly important A1,2-allylic strain when
the size of R group becomes larger and, therefore it will be dis-
favoured relatively to TS-1 in which this interaction is minimised.
The diastereocontrol then improves with large R groups and the
relative syn-diastereomer being largely predominant, which is
corroborated by the experiment (Table 1).
expressed in parts per million and hertz. IR spectra were recorded
with a Perkin–Elmer paragon 1000 FT-IR spectrophotometer. Mass
spectra MS were recorded on a Hewlett–Packard 5989A apparatus
(EI with 70 eV ionisation potential). Elemental analyses were car-
ried out with a Perkin–Elmer 240 B microanalyser. Merck silica gel
60 (70–230 mesh) and (0.063–0.200 mm) were used for flash
chromatography. All reactions involving anhydrous conditions
were conducted in dry glassware under a nitrogen atmosphere.
Solvents were distilled under nitrogen immediately prior to use.
Grignard reagents were prepared by known methods and stored
under inert atmosphere. They were titrated prior to use with a 1 M
solution of benzyl alcohol in anhydrous toluene and in the presence
of 2,20-bipyridil as indicator.42
3. Conclusion
In summary, an efficient and rapid method for the synthesis of
functionalized disubstituted d-lactams 3 has been developed by an
effective coupling between dimethyl-2-alkylidene glutarates 2 and
primary amines. The advantages of this method include using
readily inexpensive available starting materials and operational
simplicity. Extension of this method to a more functionalised Mi-
chael acceptor and its application to the synthesis of alkaloids
skeletons of biological relevance is in progress.
4.2. Synthesis of (E)-dimethyl 2-alkylidene glutarates 2b–d:
general procedure
An ether or THF solution of alkylmagnesium halide RMgX (2–
3 M) was added dropwise over a period of 20–30 min to a stirred
mixture of dimethyl (E)-2-bromomethylene glutarate 1 (1.25 g,
5 mmol) and a 1 M solution of LiCuBr2 (0.15 mL, 3 mol %) diluted in
dry THF (20 mL) at ꢀ20 ꢁC under nitrogen atmosphere. After a few
minutes (TLC), the reaction mixture was quenched with a saturated
aqueous NH4Cl solution (10 mL) then extracted with ether
(3ꢂ20 mL). The combined organic layers were dried over MgSO4,
filtered and concentrated under reduced pressure. The crude
4. Experimental
4.1. General
1H and 13C NMR spectra were recorded on Bruker AC-300 FT
(1H: 300 MHz, 13C: 75 MHz) with CDCl3 as internal reference. The
chemical shifts (
d
) and coupling constants (J) are, respectively,
CO2Me
R
ref. 34
ref. 33
H+
OMe
MeO2C
MeO2C
OMe
CO2Me
H2
2
R'
N
H
O
R
O
H
O
O
O
H+
R' NH2
R
A1,2
O
R
O
O
MeO2C
R
TS-2
TS-1
MeO2C
R
NHR'
OH
CO2Me
Syn β-amino-ester
Scheme 4.
Anti β-amino-ester
Scheme 2.
O
R'
R
H
N
CO2Me
R'
R
N
OMe
O
R
R' NH2
MeOH, reflux
- MeOH
2
3
(Major)
CO2Me
2(a-d)
CO2Me
CO2Me
3(a-g)
Scheme 3.

9542
A. Samarat et al. / Tetrahedron 64 (2008) 9540–9543
product was purified by flash chromatography on silica gel (AcOEt/
hexane, 1:9) to produce (E)-dimethyl-2-alkylidene glutarates 2b–d.
4.3.3. 1-(4-Fluoro-benzyl)-6-oxo-piperidine-3-carboxylic acid
methyl ester 3c
Colourless oil. IR (film) nmax 1734, 1692 cmꢀ1. 1H NMR (300 MHz,
4.2.1. (E)-2-Ethylidene pentanedioic acid dimethyl ester 2b
CDCl3)
d
7.2 (dd, 2H, J¼8.3, 5.5 Hz, aromatic H), 7.0 (t, 2H, J¼8.4 Hz,
Colourless oil. IR (film) nmax 1704, 1697, 1642 cmꢀ1
.
1H NMR
aromatic H), 4.6 (AB, 2H, JAB¼14.7 Hz, CH2), 3.6 (s, 3H, CH3), 3.4 (t,
2H, J¼8.5 Hz, CH2), 2.85–2.64 (m,1H, CH), 2.5–2.3 (m, 2H, CH2), 2.1–
(300 MHz, CDCl3)
d
6.91 (q, 1H, J¼7.0 Hz, CH), 3.70 (s, 3H, CH3), 3.64
(s, 3H, CH3), 2.66–2.48 (m, 2H, CH2), 2.47–2.32 (m, 2H, CH2), 1.81 (d,
1.9 (m, 2H, CH2). 13C NMR (75 MHz, CDCl3)
d 172.5 (C]O), 168.8
3H, J¼7.0 Hz, CH3). 13C NMR (75 MHz, CDCl3)
d
173.4 (C]O), 167.7
(C]O), 163.8 (aromatic C, JC–F¼245.7 Hz), 132.7 (aromatic C), 129.9
(aromatic CH), 115.5 (aromatic CH), 52.1 (CH3), 49.5 (CH2), 48.0
(CH2), 39.0 (CH), 30.6 (CH2), 23.8 (CH2).
(C]O), 139.2 (CH), 131.2 (C), 51.7 (CH3), 51.5 (CH3), 33.1 (CH2), 21.9
(CH2), 14.2 (CH3). MS (EI, 70 eV) m/z (%) 186 (Mþ, 2), 171 (48), 154
(100), 127 (72), 113 (64), 99 (30).
4.3.4. 1-Isopropyl-6-oxo-piperidine-3-carboxylic acid methyl
4.2.2. (E)-2-Propylidene pentanedioic acid dimethyl ester 2c
ester 3d
Colourless oil. IR (film) nmax 1716, 1702, 1651 cmꢀ1
.
1H NMR
Viscous oil. IR (film) nmax 1704, 1697, 1642 cmꢀ1 1H NMR
.
(300 MHz, CDCl3)
d
6.84 (t, 1H, J¼7.3 Hz, CH), 3.78 (s, 3H, CH3), 3.65
(300 MHz, CDCl3)
d
3.8 (qt, 1H, J¼7.3 Hz, CH), 3.6 (s, 3H, CH3), 3.5
(s, 3H, CH3), 2.71–2.60 (m, 2H, CH2), 2.58–2.35 (m, 2H, CH2), 2.28
(AB, 2H, JAB¼14.7 Hz, CH2), 2.9–2.7 (m, 1H, CH), 2.45–2.26 (m, 2H,
(qt, 2H, J¼7.6, 7.2 Hz CH2), 1.08 (t, 3H, J¼7.6 Hz, CH3). 13C NMR
CH2), 2.2–1.85 (m, 2H, CH2), 1.3 (d, 6H, J¼7.3 Hz, 2CH3). 13C NMR
(75 MHz, CDCl3)
d
173.3 (C]O), 167.9 (C]O), 146.2 (CH), 129.7 (C),
(75 MHz, CDCl3) d 175.6 (C]O),172.5 (C]O), 55.2 (CH3), 49.5 (CH2),
51.9 (CH3), 51.3 (CH3), 33.4 (CH2), 23.0 (CH2), 20.4 (CH2), 13.9 (CH3).
MS (EI, 70 eV) m/z (%) 200 (Mþ, 4), 171 (62), 168 (100), 141 (74), 140
(42), 127 (39).
44.2 (CH), 43.8 (CH), 33.9 (CH2), 28.0 (CH2), 22.5 (2CH3).
4.3.5. 1-Benzyl-2-methyl-6-oxo-piperidine-3-carboxylic acid
methyl ester 3e (major isomer)
4.2.3. (E)-2-Butylidene pentanedioic acid dimethyl ester 2d
Viscous yellow oil. IR (film) nmax 1728, 1704, 1642 cmꢀ1. 1H NMR
Yellow oil. IR (film) nmax 1733, 1692 cmꢀ1 1H NMR (300 MHz,
.
CDCl3)
d
7.8–6.8 (m, 5H, aromatic H), 4.4 (AB, 2H, JAB¼15.8 Hz, CH2),
(300 MHz, CDCl3)
(s, 3H, CH3), 2.79–2.57 (m, 2H, CH2), 2.54–2.33 (m, 2H, CH2), 2.23 (q,
d
6.81 (q, 1H, J¼7.6 Hz, CH), 3.71 (s, 3H, CH3), 3.65
3.9 (dq, 1H, J¼6.9, 5.7 Hz, CH), 3.7 (s, 3H, CH3), 3.1–2.75 (m, 1H, CH),
2.72–2.56 (m, 2H, CH2), 2.48–2.22 (m, 2H, CH2), 1.9 (d, 3H, J¼6.9 Hz,
2H, J¼7.4 Hz, CH2), 1.42–1.28 (m, 2H, CH2), 0.96 (t, 3H, J¼6.8 Hz,
CH3). 13C NMR (75 MHz, CDCl3)
d 172.3 (C]O), 168.1 (C]O), 139.0
CH3). 13C NMR (75 MHz, CDCl3)
d
175.4 (C]O), 167.2 (C]O), 139.2
(aromatic C), 131.5 (aromatic C), 128.7 (aromatic CH), 126.4 (aro-
matic CH), 51.7 (CH2), 50.2 (CH3), 46.1 (CH), 43.5 (CH), 30.7 (CH2),
23.9 (CH2), 15.8 (CH3). Anal. Calcd for C15H19NO3: C, 68.94; H, 7.33;
N, 5.36. Found: C, 68.99; H, 7.34; N, 5.42.
(CH), 131.2 (C), 51.5 (CH3), 51.3 (CH3), 31.7 (CH2), 28.8 (CH2), 24.1
(CH2), 23.2 (CH2), 14.2 (CH3). MS (EI, 70 eV) m/z (%) 214 (Mþ, 2), 185
(50), 182 (100), 155 (39), 141 (61), 73 (54), 59 (68).
4.3.6. 1-Benzyl-2-ethyl-6-oxo-piperidine-3-carboxylic acid methyl
ester 3f (major isomer)
4.3. Preparation of
d
-lactams 3a–g: general procedure
Colourless oil. IR (film) nmax 1746, 1712 cmꢀ1. 1H NMR (300 MHz,
CDCl3)
d
7.4–7.2 (m, 5H, aromatic H), 4.6 (AB, 2H, JAB¼15.7 Hz, CH2),
A solution of (E)-dimethyl-2-alkyldiene glutarate 2 (3 mmol)
and an excess of primary amine (9 mmol, 3 equiv) in methanol
(7 mL) was stirred at reflux for 48–72 h. The reaction mixture was
concentrated under reduced pressure to remove methanol, then
the crude product was purified by flash chromatography on silica
4.2 (dt, 1H, J¼7.3, 4.5 Hz, CH), 3.6 (s, 3H, CH3), 3.3–2.9 (m, 1H, CH),
2.28–2.25 (m, 2H, CH2), 2.2–1.9 (m, 2H, CH2), 1.75–1.4 (m, 2H, CH2),
0.8 (t, 3H, J¼7.6 Hz, CH3). 13C NMR (75 MHz, CDCl3)
d 176.4 (C]O),
171.9 (C]O), 138.3 (aromatic C), 132.7 (aromatic C), 129.8 (aromatic
CH),127.1 (aromatic CH), 51.8 (CH), 51.3 (CH3), 49.7 (CH2), 45.7 (CH),
34.9 (CH2), 25.6 (CH2), 23.0 (CH2), 17.8 (CH3). Anal. Calcd for
gel (AcOEt/hexane, 1:1) to afford the corresponding d-lactam 3.
C16H21NO3: C, 69.79; H, 7.69; N, 5.09. Found: C, 69.72; H, 7.73; N,
4.3.1. 1-Benzyl-6-oxo-piperidine-3-carboxylic acid methyl ester 3a
Viscous colourless oil. IR (film) nmax 1735, 1696 cmꢀ1 1H NMR
(300 MHz, CDCl3) 7.81–6.94 (m, 5H, aromatic H), 4.6 (AB, 2H,
JAB¼14.7 Hz, CH2), 3.6 (s, 3H, CH3), 3.4 (t, 2H, J¼8.5 Hz, CH2), 2.89–
2.74 (m, 1H, CH), 2.62–2.48 (m, 2H, CH2), 2.2–1.9 (m, 2H, CH2). 13
NMR (75 MHz, CDCl3) 172.3 (C]O), 168.8 (C]O), 136.8 (aromatic
C), 128.5 (aromatic C), 128.4 (aromatic CH), 128.1 (aromatic CH),
52.0 (CH3), 50.1 (CH2), 47.9 (CH2), 39.0 (CH), 30.6 (CH2), 23.8 (CH2).
Anal. Calcd for C14H17NO3: C, 68.00; H, 6.93; N, 5.66. Found: C,
68.05; H, 6.98; N, 5.59.
5.12.
.
d
4.3.7. 1-Benzyl-2-propyl-6-oxo-piperidine-3-carboxylic acid
methyl ester 3g (major isomer)
C
Viscous oil. IR (film) nmax 1731, 1695 cmꢀ1 1H NMR (300 MHz,
.
d
CDCl3)
d
7.3–7.1 (m, 5H, aromatic H), 4.5 (AB, 2H, JAB¼13.9 Hz, CH2),
3.9 (dt, 1H, J¼7.8, 5.4 Hz, CH), 3.7 (s, 3H, CH3), 3.1–2.8 (m, 1H, CH),
2.45–2.25 (m, 2H, CH2), 2.15–1.72 (m, 2H, CH2), 1.7–1.5 (m, 2H, CH2),
1.45–1.35 (m, 2H, CH2), 0.9 (t, 3H, J¼7.0 Hz, CH3). 13C NMR (75 MHz,
CDCl3)
d 177.0 (C]O), 172.4 (C]O), 144.7 (aromatic C), 138.2 (aro-
matic CH), 130.4 (aromatic CH), 128.7 (aromatic CH), 52.0 (CH3),
50.1 (CH2), 48.9 (CH), 43.0 (CH), 35.6 (CH2), 29.5 (CH2), 24.3 (CH2),
21.0 (CH2), 13.8 (CH3).
4.3.2. 1-(4-Methoxy-benzyl)-6-oxo-piperidine-3-carboxylic acid
methyl ester 3b
Viscous yellow oil. IR (film) nmax 1731, 1695 cmꢀ1 1H NMR
.
(300 MHz, CDCl3)
d
7.1 (d, 2H, J¼8.8 Hz, aromatic H), 6.8 (d, 2H,
References and notes
J¼8.8 Hz, aromatic H), 4.6 (AB, 2H, JAB¼14.9 Hz, CH2), 3.7 (s, 3H,
CH3), 3.6 (s, 3H, CH3), 3.4 (t, 2H, J¼8.5 Hz, CH2), 2.9–2.7 (m, 1H, CH),
2.65–2.45 (m, 2H, CH2), 2.2–1.9 (m, 2H, CH2). 13C NMR (75 MHz,
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