Facile synthesis of versatile functionalized amino caprolactams using RCM reactions of α-amino acrylamide

Article abstract of DOI:10.1016/j.tetlet.2006.03.022

We report an efficient synthetic methodology allowing access to functionalized α-amino caprolactams using ring-closing metathesis (RCM). A very high tolerance of α-amino acrylamide RCM precursors toward functional groups is demonstrated. The synthetic pat

Full text of DOI:10.1016/j.tetlet.2006.03.022

Tetrahedron Letters 47 (2006) 3295–3298
Facile synthesis of versatile functionalized amino caprolactams
using RCM reactions of a-amino acrylamide
Gang Liu,a Wan-Yi Tai,b Yu-Lin Lia and Fa-Jun Nanb,*
aState Key Laboratory of Applied Organic Chemistry and Institute of Organic Chemistry, Lanzhou University, Lanzhou 730000, China
bChinese National Center for Drug Screening, Shanghai Institute of Materia Medica, Shanghai Institutes of Biological Sciences,
Graduate School of the Chinese Academy of Sciences, Shanghai 201203, China
Received 20 January 2006; revised 3 March 2006; accepted 6 March 2006
Available online 22 March 2006
Abstract—We report an efficient synthetic methodology allowing access to functionalized a-amino caprolactams using ring-closing
metathesis (RCM). A very high tolerance of a-amino acrylamide RCM precursors toward functional groups is demonstrated. The
synthetic pathway is facile, and can be extended to prepare a variety of substituted amino caprolactams in good to excellent yields.
These compounds serve as versatile building blocks for the synthesis of some important natural products and their analogues.
Ó 2006 Elsevier Ltd. All rights reserved.
Medium-sized lactams, especially the seven-membered
ones, are of considerable interest in drug discovery and
pharmaceutical research, as some natural products (or
their analogues) and small molecules bearing such units
show potent biological activity. As shown in Figure 1,
bengamide B and one of its analogues LAF389 display
an activity with IC50 values at the nanomolar level for
in vitro growth inhibition.1 New vasopeptidase inhibi-
tors containing hydroxamic acid-derived azepinones
(caprolactams) have been found to have selective angio-
tensin-converting enzyme (ACE) and neutral endopepti-
dase (NEP) inhibition.2 Lately, BN 83253 compounds
have been shown to act as powerful anti-inflammatory
agents in vivo at the doses of 1 mg/kg.3 Another novel
class of orally active factor Xa (FXa) inhibitors has also
been developed.4 On the other hand, the development of
small molecular weight scaffolds containing a high
degree of diversity has become a focus in modern drug
discovery.5 In this regard, the efficient synthesis of
multiply substituted amino caprolactams is of great
importance. However, the synthetic methods that have
been used seem to be either too long (usually involving
complex transformation6), or lack flexibility (where
limited functional groups are modified at the amide
nitrogen7 or are difficult to functionalize at position 7).
Following our successful construction methodology for
the ring-closing metathesis (RCM) reaction of a-amino
acrylamide8 to substituted amino caprolactams, in this
work, we extend the scope of this methodology to
diverse substitution at the amide nitrogen, and have con-
structed 1-, 6-, 7-position functionalized a-amino capro-
lactams 3 (Scheme 1), which can be easily transformed to
caprolactams by hydrogenation.
O
R1
R2
OH OMe
R3
H
O
N
N
HS
N
N
OH OH
Bengamide B: R1=Me, R3=H
R2=OC(=O)(CH2)12CH3
LAF 389: R1= H, R3=CH3
R2=
O
H
OR1
O
Vasopeptidase inhibitors
O
O
O
O
N
O
H
H
H
N
N
NH
N
( )
( )
n2
O
N
n1
H
O
Y
X
BN 83253
FXa inhibitors
Figure 1. Some bioactive natural products (or analogues) and small
molecules containing amino caprolactam units.
Keywords: Ring-closing metathesis; Functionalized lactams; Natural
products; a-Amino acrylamide; a-Amino a,b-unsaturated capro-
lactams.
Our method therefore provides an easy access to all of
the above-mentioned natural products and their versa-
tile analogues with potentially interesting properties.
*
Corresponding author. Tel./fax: +86 21 50800954; e-mail: fjnan@
mail.shcnc.ac.cn
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.022

3296
G. Liu et al. / Tetrahedron Letters 47 (2006) 3295–3298
O
in a yield up to 88% after the addition of a little more
O
R1
R1
catalyst. Compounds 2d, 2e, and 2f are very interesting
lactams, which provide an additional reactive group to
construct N-functionalized caprolactam-containing mole-
cules.
N
N
BocHN
BocHN
Pd/C
Cat. B
R3
R3
1atm. H2
R2
R2
2
1
The R2 group can be either an H or acyloxyl group. The
intermediate was produced by the addition of ally mag-
nesium bromide to a range of aldehydes, followed by
N-protection with DMB to afford the substituted sec-
ondary amine. A representative pathway is shown in
Scheme 3. The ring closure of the precursor 14 afforded
2h in a near quantitative yield, while the amount of cat-
alyst used was much less. A number of such 6-position
hydroxy-derived caprolactams have been documented.
The advantage of our strategy resides in the stereo con-
figuration of the 6-position, which can be effectively con-
trolled in the early stage (step a) by the stereoselective
addition of a metalloorganic reagent to the chiral a-ami-
no aldehyde, along with the short reaction path and the
high yield. Using this procedure, we produced 2i in 97%
yield (Table 1).
O
R1
7
1
PCy3
2
Cl
N
N
N
6
3
4
BocHN
Mes
Cl
Mes
Ru
R3
Cl
Ph
PCy3
Ru
Cl
Ph
5
PCy3
R2
A
3
B
Scheme 1. General procedure for the synthesis of 1,6,7-position
functionalized a-amino caprolactams.
The general procedure for the synthesis of functional-
ized a-amino caprolactam 3 is shown in Scheme 1.
The key intermediate is compound 2 (a-amino a,b-
unsaturated caprolactam), and this was achieved from
1 by the RCM of a-amino acrylamide as a key step using
Grubbs’ second-generation catalyst B (B was selected
here, as it is generally considered to be more reactive
than A in olefin metathesis reactions in the conversion
of electron-deficient C–C double bonds9). Compound
1 can be readily produced by a,b-unsaturated amino
acid or its active ester with a substituted secondary
amine. Later on, we found out that R1, R2, and R3 in
compound 1 were able to accommodate diverse func-
tional groups for successful ring closure, which extends
the scope of our former RCM methodology.
The R3 group can be either an H or a benzyl group, and
it can also be diversified by using an amino acid as the
starting material to produce a chiral a-amino aldehyde,
and following the procedure shown in Scheme 4, gener-
ates a stereo (6,7-position)-controlled caprolactam.
In a previous work,8 we have reported that the dimeth-
oxybenzyl group can be used as an amide N-protecting
group for further cyclization. Here, we extend the substi-
tution group to the N atom of caprolactam, and phenyl-
alkyl 2b, 2f, alkoxyl 2c, 2l, heterocycloalkyl 2d, 2e and
alkoxycarbonylalkyl 2g were introduced on the N atom
and underwent successful cyclization. These results fur-
ther demonstrate the high tolerance of our RCM precur-
sors toward functional groups.
The R1 group can be either a benzyl, 2,4-dimethoxyl-
benzyl (DMB), phenylethyl, benzyloxy, furfuryl, pyri-
din-2-yl, or a –CH2COOEt group. This was introduced
by using a conventional reductive amination of various
aldehydes with amine 5, or amino acid ester with pent-
4-enal 8 (Scheme 2, 2a, 2b, 2d–2g). Examples of the syn-
thetic pathway are shown in 2d and 2g, and typical
experimental procedure for RCM is illustrated with
2d.11 Cyclization yields of these compounds were gener-
ally high, with the amount of catalyst used below
10 mol % (Table 1). Compound 2e, with a nucleophilic
nitrogen in its pyridine ring, which is usually thought
to coordinate to the Ru complex, was also synthesized
Hydrogenation of all the RCM products (a-amino a,b-
unsaturated caprolactams 2a–2l) gave a-amino capro-
lactams 3 in near quantitative yields.
The reason for the surprising reaction facility of this
type of RCM precursor is not clear, N-substitution of
NH2
5
O
O
O
a
N
N
BocHN
BocHN
O
O
O
H
N
BocHN
BocHN
O
c
7
6
b
2d
+
OH
O
O
H
N
OEt
NHBoc
N
N
O
4a
O
O
9
d
O
2g
O
10
8
Scheme 2. An illustrative synthesis of 2d and 2g. Reagents and conditions: (a) 2-furaldehyde, Et3N, EtOH, then NaBH4, rt, 50%; (b) EDCÆHCl,
HOBT, CH2Cl2, 4 A M.S., rt, 66% (4a was prepared according to the literature procedure10); (c) see Table 1; (d) H-Gly-OEtÆHCl, Et3N, EtOH, then
˚
NaBH4, rt, 70% from 8.

G. Liu et al. / Tetrahedron Letters 47 (2006) 3295–3298
3297
Table 1. RCM reaction conditionsa of a-amino a,b-unsaturated
caprolactams
OH
a
BocHN
11
BocHN
OH
O
O
( )-12
R1
R1
N
N
BocHN
BocHN
O
b, c
Cat. B
R3
R3
DMB
N
BocHN
OH
R2
d, e
R2
DMBHN
2
1
OAc
Entry R1
R2
R3
H
Cat. B
(mol %) (%)
Yieldsb
( )-13
( )-14
+
f
O
O
O
N
DMB
OAc
2a
H
5
86
OH
O
BocHN
NHBoc
2b
2c
H
H
H
H
10
10
78
45
4a
( )-2h
O
Scheme 3. An illustrative synthesis of 2h. Reagents and conditions: (a)
DMSO, (COCl)2, Et3N, CH2Cl2, then ally magnesium bromide, Et2O,
0 °C to rt, 48% from 11; (b) HCl/dioxane, rt; (c) Et3N, EtOH, 2,4-
dimethoxybenzaldehyde, then NaBH4, rt, 73%; (d) EDCÆHCl, HOBT,
DMAP, 4 A MS, rt, 62%; (e) Ac2O/pyridine (v/v = 1/1), rt, 95%; (f) see
Table 1.
O
2d
H
H
5
90
˚
2e
2f
H
H
H
H
10
10
88
92
N
OH
O
O
2g
2h
H
H
H
5
5
86
95
a
b
O
H
NHBoc
NHBoc
O
OAc
( )-16
( )-15
O
O
O
OH
DMB
O
O
N
BocHN
2i
H
5
97
c
Ph
O
NHDMB
OAc
O
O
( )-17
2jc
2kc
2l
OAc
5
10
5
70
85
90
( )-18
O
O
+
F
d
O
F
O
O
DMB
O
O
BocHN
N
O
F
Ph
NHBoc
O
O
F
F
H
OAc
( )-2j
4b
a Other conditions: substrate = 1.0–2.0 mM, reaction time = 10–28 h,
solvent 1,2-dichloroethane (DCE) for 2c and dichloromethane
(DCM) for the others, reaction temperature = 90 °C for 2c, rt for 2h,
2i and 40 °C for the others.
Scheme 4. An illustrative synthesis of 2j. Reagents and conditions: (a)
and (b): the same as Scheme 3, 50% from 15, (dr = 5/1); (c) K2CO3,
CH3COCH3, rt, 60% from 17 (4b was used, as it is more selective than
4a12), then Ac2O/pyridine (v/v = 1/1), rt; (d) see Table 1.
b Isolated yields.
c The stereo configuration of 2j and 2k was determined as syns based
on NOESY data, and the reported diastereoselectivity results of 16.13
stitution at amide nitrogen sites. Compared to other
RCM methodologies, the tolerance of the R1, R2, and
R3 groups toward functional groups is high. We are
now using this amino caprolactam scaffold in the
synthesis of some natural product analogues, and are
further extending our RCM methodology to six and
eight-membered rings. The results of these works will
be presented in due course.
the lactam amide induces a conformation change, which
may serve as a factor, as it ensures a sufficient propor-
tion of the cis amide rotamer, which, according to Miller
et al.,14 is necessary for cyclization.
In conclusion, a variety of a-amino caprolactams 3 were
conveniently synthesized in generally good to excellent
yields using RCM of a-amino acrylamide as key step.
The resulting versatile amino caprolactams may serve
as advantageous structural moieties for the construction
of small-molecule libraries with structural features of
some natural products. At the same time, our former
RCM methodology was extended to obtain diverse sub-
Acknowledgements
This work was supported by the National Natural Sci-
ence Foundation of China (Grant 30572242) and the

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G. Liu et al. / Tetrahedron Letters 47 (2006) 3295–3298
M. J. Tetrahedron Lett. 1995, 36, 6379–6382; (g) Xu, Y.;
Miller, M. J. J. Org. Chem. 1998, 63, 4314–4322; (h)
Hoffmann, T.; Waibel, R.; Gmeiner, P. J. Org. Chem.
2003, 68, 62–69.
Shanghai Commission of Science and Technology
(Grant 03dz19228).
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To a 250 mL flask (dry) equipped with a condenser was
added a solution of 0.14 mmol a-amino acrylamide 7 in
80 mL of dry DCM, the solution was deaerated by
bubbling argon through the mixture for 5 min. Second-
generation Grubbs catalyst B (5 mol %) in 30 mL of dry,
degassed DCM was added to the mixture under argon
atmosphere, and the argon bubbling was continued for an
additional 5 min. The mixture was heated and stirred at
40 °C for 10 h until TLC showed the reaction was
complete. The solvent was removed in vacuo and the
residue was purified by silica gel chromatography to give
tert-butyl (E)-1-((furan-2-yl) methyl)-2,5,6,7-tetrahydro-2-
oxo-1H-azepin-3-ylcarbamate (2d, 39.0 mg, 90% yield) as
1
a pale yellow solid: H NMR (300 MHz, CDCl3): d 1.45
(9H, s), 1.74 (2H, quin, J = 6.9 Hz), 2.18 (2H, q,
J = 6.9 Hz), 3.40 (2H, t, J = 6.3 Hz), 4.63 (2H, s), 6.28–
6.29 (1H, m), 6.31–6.33 (1H, m), 6.64 (1H, t, J = 6.0 Hz),
6.76 (1H, br s, NH), 7.35 (1H, s). 13C NMR (300 MHz,
CDCl3): d 23.0, 29.0, 29.9, 43.7, 46.6, 80.3, 108.9, 110.7,
116.4, 131.3, 142.6, 150.9, 153.5, 167.9. HRMS (EI): calcd
for C16H22N2O4 [M+] 306.1580, found 306.1577.
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