Synthesis of γ-lactam lignans via aza-Michael addition

Article abstract of DOI:10.1055/s-2006-932485

The synthesis of γ-lactam lignans from thuriferic acid via Michael addition of substituted anilines under basic conditions, followed by lactam ring closure, is described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-932485

LETTER
591
Synthesis of g-Lactam Lignans via Aza-Michael Addition
g
-Lacta
m
Lignans via
aza-Michatt
tion hieu Dorbec,a Jean-Claude Florent,*a Claude Monneret,a Marie-Noëlle Rager,b Emmanuel Bertounesque*a
a
UMR 176 CNRS-Institut Curie, Section de Recherche, 26 rue d’Ulm, 75248 Paris Cedex 05, France
Fax +33(1)2346631; E-mail: Emmanuel.Bertounesque@curie.fr
b
Département de RMN, Ecole Nationale Supérieure de Chimie de Paris, 11 rue P. et M. Curie, 75231 Paris Cedex 05, France
Received 20 December 2005
combination of 1 with g-lactam rings was carried out by
Kadow and co-workers17 with the synthesis of antitumor
lactams from the anticancer drug etoposide, a glucoside
derivative of the cytotoxic 1-aryltetralin lignan podophyl-
lotoxin. We chose thuriferic acid 2,18,19 a lignan isolated
from Juniperus thurifera leaves,20 which encompasses the
1-aryltetralin scaffold 1, and whose chemical reactivity
has been the subject of a few studies18,19a (Figure 1). In
this paper we present the synthesis of g-lactam lignans 3,
which were synthesized by the conjugate addition of sub-
stituted anilines to the methyl ester of thuriferic acid 5,
followed by intramolecular cyclization of the correspond-
ing b-amino ketones. To our knowledge there is only one
example21 of a Michael addition to a related substrate of 2,
namely 3-carboxy-2-methylene-4-(3¢,4¢,5¢-trimethoxy-
phenyl)-6,7-dimethoxy-1-tetralone, which was prepared
from morpholine.
Abstract: The synthesis of g-lactam lignans from thuriferic acid via
Michael addition of substituted anilines under basic conditions,
followed by lactam ring closure, is described.
Key words: lignans, lactams, Michael additions, thuriferic acid,
privileged structure
g-Lactams are important molecules with numerous phar-
macological properties such as, psychotropic agents,1
muscarinic acid agonists,2 antihypertensive agents,3
peptide mimics,4 b-turn peptidomimetics,5 non-peptide
mimics of somatostatin/sandostatin,6 serine protease
inhibitors,7 and anti-asthma drug rolipram.8 Unlike b-lac-
tams, to date g-lactams have been found as components of
only a few natural products such as fischerellin B,9 the an-
tibiotic lactonamycin,10 and the alkaloid gelsemine.11 Re-
ports regarding the construction of g-lactam libraries have
been published.12 Within this context, and in the search for
ligands for a range of biological targets, we initiated a pro-
gram to synthesize g-lactam libraries based on the concept
of privileged structure.13 The 1-aryltetralin system 114 rep-
resents a privileged structure which remains to be exploit-
ed by combinatorial chemistry. Indeed, lignans of the type
1-aryltetralin are the constituents of plants or their syn-
thetic derivatives and present a wide range of biological
activities15 including inhibition of the polymerization of
tubulin, inhibition of DNA topoisomerase II, immunosup-
pressive activity, and anti-HIV activity. Recently, cyclo-
lignans as inhibitors of the insulin-like growth factor-1
receptor (IGF-1R) have been reported.16 Interestingly, the
O
O
O
O
O
O
NAr
CO2H
OMe
O
MeO
MeO
OMe
1
OMe
OMe
2
3
Figure 1
O
O
O
O
11
3
Ar
O
O
O
O
O
O
O
O
4
1
N
H
d
a
c
O
NAr
O
2
CO2R
OMe
CO2Me
O
6'
2'
MeO
OMe
MeO
b
MeO
OMe
MeO
OMe
OMe
OMe
OMe
OMe
3a–i
4
2 R = H
6a–i
5 R = Me
Scheme 1 Reagents and conditions: (a) t-BuOK, t-BuOH, reflux; (b) MeI, NaHCO3, DMF, r.t.; (c) ArNH2, Et3N, THF, reflux; (d) t-BuOK
(cat.), t-BuOH, DMF, r.t.
SYNLETT 2006, No. 4, pp 0591–0594
0
2.
0
3.
2
0
0
6
Advanced online publication: 20.02.2006
DOI: 10.1055/s-2006-932485; Art ID: G40705ST
© Georg Thieme Verlag Stuttgart · New York

592
M. Dorbec et al.
LETTER
Two protocols have been described18a,c for the synthesis of Table 1 Synthesis of b-Amino Ketones and g-Lactams
thuriferic acid 2 from podophyllotoxone 4. On a large
Michael addition of anilines
5 → 6a–i
g-Lactams
6a–i → 3a–i
scale, 2 was synthesized using the procedure of Höfert and
Matusch.18a To facilitate the purification step the crude
acid thus obtained, after evaporation of t-BuOH, was
converted into methyl ester 5 (Scheme 1).
Entry Aniline
1c
Producta Yield (%)b Producta Yield (%)b
6a
94
3a
63
Br
The Michael addition of substituted anilines to 5 in the
presence of Et3N in THF at reflux afforded b-amino
ketones 6a–i, which were characterized by H NMR
H2N
1
2c
6b
6c
95
78
3b
3c
69
67
spectroscopy22 (Table 1). For halogenoanilines (Table 1,
entries 1–4) and activated anilines (Table 1, entries 5 and
6), the reaction with 5 catalyzed by Et3N (4 equiv) provid-
ed 6a–f after 24 hours at reflux in THF in 78–95% yields.
Intramolecular cyclization of these b-amino ketones was
never observed when an excess of reactants and/or base
were used. Importantly, treatment of 5 with the more basic
4-aminopyridine instead of Et3N led to naphthoic acid
methyl ester 7.23 3-Nitroaniline gave compound 6g in
43% yield after heating for 48 hours (Table 1, entry 7). 4-
Trifluoroaniline provided 6h in 53% yield, regardless of
the reaction time (Table 1, entry 8). Attempts to optimize
the reaction with 4-nitroaniline were unsuccessful
(Table 1, entries 9 and 10). The stereochemistry of 6a–i
was assigned on the basis of the J1,2 (8–11 Hz) and J2,3 (9–
13 Hz) coupling constants which were in agreement with
the 1,2 antidiaxial and 2,3 antidiaxial configurations
previously reported for 11-chloro-3,11-dihydrothuriferic
acid.18b,c
H2N
Br
I
3c
H2N
4c
6d
6e
78
90
3d
3e
72
65
F
H2N
5c
OMe
Me
H2N
6c
6f
93
43
53
3f
64
45
53
H2N
7d
6g
6h
3g
3h
H2N
NO2
CF3
8c,d
As expected, the b-amino ketone 6a proved sensitive to
retro-Michael reaction, for example, the conversion of
the carbonyl group at C-4 into the corresponding
methyloxime24 was attempted under two different condi-
tions and failed (MeONH2·HCl, NaOAc in MeOH–THF,
reflux25a or MeONH2·HCl, pyridine·HCl, EtOH,
reflux25b). Addition of arylhydrazines26 to 6a gave the
same result. Finally, cyclization of 6a–i into the desired
g-lactam lignans 3a–i27,28 occurred under base catalysis29
(t-BuOK) in 45–72% yields (Table 1). Surprisingly, while
picropodophyllone (C-2 epimer of 4) reacted at C-4 with
O-methylhydroxylamine as described,30 the correspond-
ing 4-oxime derivatives of 3a failed to form under the
same reaction conditions.
H2N
9d,e
6i
6i
23
31
3i
3i
65
65
NO2
10f
H2N
a All products were characterized by 1H NMR, 13C NMR, IR, and mass
spectroscopy.
b All yields reported are isolated yields of compounds, estimated to be
95% pure by 1H NMR spectroscopy.
c Et3N (4 equiv), aniline (4 equiv), 24 h.
d Et3N (4 equiv), aniline (4 equiv), 48 h.
e Et3N (4 equiv), aniline (4 equiv), 5 d.
f Et3N (10 equiv), aniline (10 equiv), 5 d.
In summary, the synthesis of g-lactam lignans 3 was References and Notes
achieved from thuriferic acid 2 via Michael addition of
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Acknowledgment
This work was financially supported by the Centre National de la
Recherche Scientifique, the Institut Curie and the Ligue Nationale
contre le Cancer. We thank Dr. Nohad Gresh (CNRS, FRE 2718
INSERM, U648) for molecular modeling.
Synlett 2006, No. 4, 591–594 © Thieme Stuttgart · New York

LETTER
g-Lactam Lignans via Aza-Michael Addition
593
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OH
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O
O
CO2R
OMe
MeO
OMe
7 R = Me
Figure 2
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(27) Synthesis of 6 and 3; General Procedure
To a solution of the methyl ester of thuriferic acid 5 (50 mg,
0.117 mmol) in anhyd THF (2 mL) were added Et3N and the
aniline at r.t. (Table 1). The reaction mixture was then heated
at 65 °C for the reaction time indicated, concentrated under
reduced pressure, and the crude product was purified by
chromatography on silica gel (cyclohexane–EtOAc, 5:2) to
give the desired b-amino ketones 6. This compound (0.165
mmol, 1 equiv) was diluted in DMF (2.5 mL) and a 1 M
solution of t-BuOK in t-BuOH (1 M; 16.5 mL, 0.1 equiv) was
added at r.t. The mixture was stirred for 20 min then the pH
was adjusted to 7 by the addition of aq NH4Cl. The mixture
was extracted with EtOAc (3 ꢀ 20 mL), the combined
organic phases were dried over MgSO4, and concentrated
under reduced pressure. The crude product was purified by
chromatography on silica gel (cyclohexane–EtOAc, 3:1) to
furnish the g-lactam lignans 3.
(19) (a) For the synthesis of analogues of thuriferic acid with the
benzodioxole system replaced by different heterocyclic
moieties, see: Madrigal, B.; Puebla, P.; Ramos, A.; Peláez,
Compound 6i: Yellow powder; yield: 31%; mp 194 °C;
[a]D20 –84 (c 0.19, CHCl3). IR: 3400–3300, 2940, 1734,
1671, 1601, 1506, 1480 cm–1. 1H NMR (300 MHz, CDCl3):
Synlett 2006, No. 4, 591–594 © Thieme Stuttgart · New York

594
M. Dorbec et al.
LETTER
d = 8.07 (d, 2 H, J = 9.2 Hz, H3¢¢, H5¢¢), 7.47 (s, 1 H, H5), 6.55
(d, 2 H, J = 9.2 Hz, H2¢¢, H6¢¢), 6.33 (s, 2 H, H2¢, H6¢), 6.29 (s,
1 H, H8), 6.00 (m, 2 H, OCH2O), 5.19 (br s, 1 H, NH), 4.36
(d, 1 H, J = 10.7 Hz, H1), 3.86 (s, 3 H, OMe4¢), 3.80 (s, 6 H,
OMe3¢,5¢), 3.63 (m, 1 H, H11a), 3.49 (s, 3 H, CO2Me), 3.48
(m, 1 H, H11b), 3.24 (dd, 1 H, J = 12.9, 10.7 Hz, H2), 3.19 (m,
1 H, H3). 13C NMR (75 MHz, acetone-d6): d = 195.8, 174.0,
155.8, 155.5, 154.4, 149.2, 143.7, 139.6, 139.1, 138.5,
128.4, 127.7, 112.9, 110.0, 108.6, 106.7, 104.1, 61.5, 57.4,
54.0, 53.1, 50.9, 50.0, 43.7. MS (DCI, NH3): m/z = 565
[M + H]+.
Compound 3i: Yellow powder; yield: 65%; mp 235–240 °C;
[a]D20 –110 (c 0.34, CHCl3). IR: 2940, 1716, 1670, 1597,
1521, 1481 cm–1. 1H NMR (400 MHz, CDCl3): d = 8.22 (d,
J = 9.3 Hz, 2 H, H3¢¢, H5¢¢), 7.79 (d, J = 9.3 Hz, 2 H, H2¢¢, H6¢¢),
7.48 (s, 1 H, H5), 6.73 (s, 1 H, H8), 6.27 (s, 2 H, H2¢, H6¢), 6.04
(m, 2 H, OCH2O), 4.81 (d, J = 1.7 Hz, 1 H, H1), 4.38 (d, J =
9.7 Hz, 1 H, H11a), 4.01 (m, 1 H, H11b), 3.81 (s, 3 H, OMe4¢),
3.76 (s, 6 H, OMe3¢,5¢), 3.40 (dd, J = 7.6, 1.7 Hz, 1 H, H2),
3.29 (m, 1 H, H3). 13C NMR (75 MHz, CDCl3): d = 193.9,
172.3, 153.7, 153.5, 144.1, 143.6, 139.6, 138.1, 137.0,
126.9, 124.5, 118.6, 109.3, 105.8, 104.6, 102.0, 60.6, 56.0,
50.5, 43.3, 42.9, 39.5. MS (DCI, NH3): m/z = 533 [M + H]+,
550 [M + NH4]+.
Figure 3
Discover, MD simulations (300 K), cff 91, e = 4.8 for
CDCl3] provided a unique global minimum conformation for
3i which fitted the NOE data (Figure 3).
(29) Uneyama, K.; Watanabe, H. Tetrahedron Lett. 1991, 32,
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(28) The 2,3-cis stereochemistry of 3a–i was deduced from the
J1,2 and J2,3 coupling constants (1.7 and 7.6 Hz, respectively
for 3i) and was confirmed from NOESY correlations of H2/
H3, H2/H2¢,6¢, and H3/H2¢,6¢. Molecular modeling [Insight II,
Synlett 2006, No. 4, 591–594 © Thieme Stuttgart · New York