New and expeditious tandem sequence Aza-Michael/intramolecular nucleophilic substitution route to substituted γ-lactams: Synthesis of the tricyclic core of (±)-martinellines

Article abstract of DOI:10.1021/jo702752w

(Chemical Equation Presented) A new and highly diastereoselective tandem reaction azaMichael/intramolecular nucleophilic substitution is presented. This unprecedented tandem reaction between N-substituted α-bromoacetamides and Michael acceptors proceeds with good yields and excellent diastereoselectivity to provide the corresponding trisubstituted γ-lactam systems. An application to the concise synthesis of the tricyclic core of (±)-martinelline alkaloids is also described.

Full text of DOI:10.1021/jo702752w

numerous syntheses2 and constitute also valuable intermediates
for the synthesis of enantiopure γ-amino acids related to
inhibitory neurotransmitter GABA as biologically active com-
pounds in the CNS system of mammals.3
New and Expeditious Tandem Sequence
Aza-Michael/Intramolecular Nucleophilic
Substitution Route to Substituted γ-Lactams:
Synthesis of the Tricyclic Core of
(()-Martinellines
Various synthetic approaches to γ-lactam skeletons have been
reported and the most frequently employed include (i) the
cyclization of nitrogen radicals onto unsaturated systems from
N-haloamides 2,4 (ii) the cycloaddition reaction between imines
3 and cyclic anhydrides 4,5 (iii) the thermal reactions of
π-allyltricarbonyliron lactam complexes 5 obtained from ox-
azines and diiron nonacarbonyl,6 (iv) the transition metal (Rh,
Ru)-catalyzed intramolecular carbenoid C-H insertion by
decomposition of R-diazocarbonyl compounds (6, X ) N2)7 or
Au(I)-catalyzed intramolecular addition of ꢀ-ketoamides to
unactivated alkenes (6, X ) H2 and CdR4 linkage as a double
bond),8 (v) the ring expansion through N1-C4 cleavage of
4-substituted ꢀ-lactams of type 79 and the [3 + 2] annulation
reactions of allylic silanes with chlorosulfonyl isocyanate or
R-sulfonylacetamides with substituted (Z)-2-bromo-2-prope-
noates.10 A plethora of other specific enantioselective and
racemic methods, not presented in Scheme 1, has been outlined
recently by Wang et al.11
Se´bastien Comesse,*,† Morgane Sanselme,‡ and
Adam Da¨ıch†
URCOM, EA 3221, UFR des Sciences & Techniques,
UniVersite´ du HaVre, 25 rue Philippe Lebon, BP 540,
F-76058 Le HaVre Cedex, France, and UPRES-EA
3233-IRCOF, UniVersity of Rouen, 1 rue Tesnie`re, F-76821
Mont-Saint-Aignan Cedex, France
sebastien.comesse@uniV-lehaVre.fr;
adam.daich@uniV-lehaVre.fr
ReceiVed December 26, 2007
To address substrate limitations of existing methods for the
preparation of N-heterocyclic compounds, we have explored the
synthetic potential of R-bromoacetamides of type 9. We have
previously demonstrated their engagement with dimethyl ma-
lonate to provide efficaciously in very good yields symmetrical
and unsymmetrical spiro-bis-imides and corresponding 3-meth-
oxycarbonyl succinimides in a one-pot procedure or two-step
sequence, respectively.12 In this paper, we explore the scope
and limitations of a new and rapid tandem sequence aza-
A new and highly diastereoselective tandem reaction aza-
Michael/intramolecular nucleophilic substitution is presented.
This unprecedented tandem reaction between N-substituted
R-bromoacetamides and Michael acceptors proceeds with
good yields and excellent diastereoselectivity to provide the
corresponding trisubstituted γ-lactam systems. An application
to the concise synthesis of the tricyclic core of (()-
martinelline alkaloids is also described.
(2) Ordo´n˜ez, M.; Cativiela, C. Tetrahedron: Asymmetry 2007, 18, 3–99.
(3) (a) Coppola, G. M.; Schuster, H. F. In Asymmetric Synthesis. Construction
of Chiral Molecules Using Amino Acids; John Wiley: New York, 1987. (b)
Na´jera, C.; Yus, M. Tetrahedron: Asymmetry 1999, 10, 2245–2303.
(4) For free radical cyclizations involving nitrogen, see: (a) Fallis, A. G.;
Brinza, I. M. Tetrahedron 1997, 53, 17543–17594.
(5) (a) Ng, P. Y.; Masse, C. E.; Shaw, J. T. Org. Lett. 2006, 8, 3999–4002.
For a recent one-pot, four-component synthesis of γ-lactams, see: (b) Wei, J.;
Shaw, J. T. Org. Lett. 2007, 9, 4077–4080. (c) Masse, C. E.; Ng, P. Y.; Fukase,
Y.; Sanchez-Rosello, M.; Shaw, J. T. J. Comb. Chem. 2006, 8, 293–296. (d)
Piwowarczyk, K.; Zawadzka, A.; Roszkowski, P.; Szawkało, J.; Leniewski, A.;
Maurin, J. K.; Kranza, D.; Czarnockia, Z. Tetrahedron: Asymmetry 2008, 19,
309–317.
Nitrogen heterocycles are of considerable interest in a number
of areas, ranging from drug discovery to the polymer industry.
γ-Lactams and their reduced forms, belonging to this family,
are very attractive cyclic systems because they are present in
wide range of natural and non-natural biologically active
molecules and drug candidates.1 Especially, functionalized chiral
γ-lactams have proven to serve as crucial building blocks of
(6) For uses of π-allyltricarbonyliron lactam complexes in organic synthesis,
see: (a) Ley, S. V.; Cox, L. R.; Meek, G. Chem. ReV. 1996, 96, 423–442.
(7) For recent examples, see: (a) Choi, M. K.-W.; Yu, W.-Y.; Che, C.-M.
Org. Lett. 2005, 7, 1081–1084. (b) Wee, A. G. H.; Duncan, S. C.; Fan, G.-J.
Tetrahedron: Asymmetry 2006, 17, 297–307.
(8) Zhou, C.-Y.; Che, C.-M. J. Am. Chem. Soc. 2007, 129, 5828–5829.
(9) (a) Van Brabandt, W.; De Kimpe, N. J. Org. Chem. 2005, 70, 3369–
3374. (b) Alcaide, B.; Almendros, P.; Cabrero, G.; Ruiz, M. P. Org. Lett. 2005,
7, 3981–3984. (c) Park, J.-H.; Ha, J.-R.; Oh, S.-J.; Kim, J.-A.; Shin, D.-S.; Won,
T.-J.; Lam, Y.-F.; Ahn, C. Tetrahedron Lett. 2005, 46, 1755–1757.
(10) For examples of [3 + 2] annulations, see: (a) Roberson, C. W.; Woerpel,
K. A. J. Org. Chem. 1999, 64, 1434–1435. (b) Romero, A.; Woerpel, K. A.
Org. Lett. 2006, 8, 2127–2130. (c) Sun, P.-P.; Chang, M.-Y.; Chiang, M. Y.;
Chang, N.-C. Org. Lett. 2003, 5, 1761–1763.
† URCOM, EA 3221 at the University of Le Havre.
‡ UPRES-EA 3233-IRCOF at the University of Rouen.
(1) For recent representative examples, see: (a) Roberson, C. W.; Woerpel,
K. A. J. Org. Chem. 1999, 64, 1434–1435. (b) Gandon, V.; Bertus, P.;
Szymoniak, J. Synthesis 2002, 1115–1120. (c) Tye, H.; Whittaker, M. Org.
Biomol. Chem. 2004, 2, 813–815. (d) Freifeld, I.; Armbrust, H.; Langer, P.
Synthesis 2006, 1807–1808. (e) Candeias, N. R.; Gois, P. M. P.; Afonso, C. A. M.
J. Org. Chem. 2006, 71, 5489–5497. (f) Rhee, J. U.; Krische, M. J. J. Am. Chem.
Soc. 2006, 128, 10674–10675.
(11) Dong, C.; Mo, F.; Wang, J. J. Org. Chem. 2008, 73, 1971–1974,
references therein.
(12) Allous, A.; Comesse, S.; Da¨ıch, A. Lett. Org. Chem. 2008, 5, 73–78.
5566 J. Org. Chem. 2008, 73, 5566–5569
10.1021/jo702752w CCC: $40.75 2008 American Chemical Society
Published on Web 06/13/2008

TABLE 1. Reaction of N-Benzyl-r-bromoacetamide (9d) with
Michael Acceptors 8a-e in the Presence of Basea
SCHEME 1. Representative Strategies Used for the
Synthesis of γ-Lactam Skeletons
SCHEME 2. Mechanistic Aspect of the Tandem Sequence
a Isolated yield. b 2.5 equiv of K2CO3 was used in refluxing CH3CN.
c 1.5 equiv of base was used in THF at rt. d No reaction.
acceptors 8a-e in the presence of different base, and the results
Michael/intramolecular nucleophilic substitution between N-
substituted R-bromoacetamides 9 and various Michael acceptors.
We also demonstrate its synthetic utility with the tricyclic core
13 of both (()-martinelline and (()-martinellic acid alkaloids.
As highlighted in Scheme 2, two possible disconnections a/b
could be considered to reach these architectures. Either by an
intramolecular 1,4-addition of an amide in basic medium to an
R,ꢀ-unsaturated system via A13 or by an intramolecular nu-
cleophilic substitution of the stabilized anion onto the acetamide
carbon bearing a good leaving group via B.14 We anticipated
that it would be possible to perform this sequence in a one-step
fashion using a new tandem reaction from Michael acceptor 8
and N-substituted R-bromoacetamide 9. The amidate anion
derived from 9 in basic medium would lead to concomitant aza-
Michael addition into species B and its spontaneous intramo-
lecular nucleophilic substitution by displacement of the leaving
group X, providing directly compound 1 in a single synthetic
operation. While a recent study by Tu and co-workers15 for the
syntheses of (()-3-demethoxyerythratidinone and (()-erysotra-
midine has highlighted the use of N-alkyl-R-halogenoacetamides
for the formation of numerous γ-lactams, no examples of this
tandem reaction have been described.
are shown in Table 1.16
To our surprise, however, reaction of N-benzyl-R-bromo-
acetamide (9d) with the Knoevenagel substrate 8a in dry
acetonitrile in the presence of K2CO3 produced none of the
desired γ-lactam 1d (entry 1). The starting materials were
recovered in all cases regardless of changes in the reaction
temperature and time. Numerous other bases (entries 2-4),
which have wide usages, were investigated. Most gratifyingly,
good yields (63%) were obtained when the reaction was carried
out with 1.5 equiv of NaH in THF at room temperature for
12 h (entry 3). Replacement of NaH with t-BuOK or KHMDS
was also successful, albeit in low yield (23% (entry 2) or 24%
(entry 4)). We hypothesized that, due to the low nucleophilicity
of amides, with the optimized conditions found above no
reaction would occur with R,ꢀ-unsaturated systems bearing only
one electron-withdrawing group. This was tested by using
different Michael acceptors, and indeed we never observed the
expected product 1 (entries 5-7). When diene 8e was used
under the same conditions, the expected γ-lactam product 1l
was obtained in only 35% yield. The remaining alkene
introduces also another point of the molecular diversity.
Encouraged by the feasibility of this tandem sequence, we
next examined its utility to synthesize a range of γ-lactams. In
this sense, a series of N-substituted R-bromoacetamides was
allowed to react with several Knoevenagel substrates using
optimized conditions (Table 1). The results from these screen-
In the outset, the reaction we investigated as the first step of
our strategy uses N-benzyl-R-bromoacetamide (9d, R2 ) Bn
and X ) Br) as a model amide and different activated Michael
(13) Wakabayashi, T.; Saito, M. Tetrahedron Lett. 1977, 18, 93–97.
(14) Tarnchompoo, B.; Thebtaranonth, C.; Thebtaranonth, Y. Tetrahedron
Lett. 1987, 28, 6675–6678.
(16) Synthesis of all starting materials. (a) For R-bromoacetamides 9, see:
Nilsson, B. L.; Kiessling, L. L.; Raines, R. T. Org. Lett. 2000, 2, 1939–1942.
(b) For Michael acceptors 8, see: May, B. C. H.; Zorn, J. A.; Witkop, J.; Sherrill,
J.; Wallace, A. C.; Legname, G.; Prusiner, S. B.; Cohen, F. E. J. Med. Chem.
2007, 50, 65–73. (c) For reagent 8k, see ref 13.
(15) Gao, S.; Tu, Y. Q.; Hu, X.; Wang, S.; Hua, R.; Jiang, Y.; Zhao, Y.;
Fan, X.; Zhang, S. Org. Lett. 2006, 8, 2373–2376.
J. Org. Chem. Vol. 73, No. 14, 2008 5567

TABLE 2. Extension of the Tandem Reaction Aza-Michael
Addition/Intramolecular Nucleophilic Substitutiona
SCHEME 3. Diastereoselectivity Outcome during the
Process
heteroaromatic ring such as a furan. Likewise, varying one
electron-withdrawing substituent of the activated olefin com-
ponent 8, i.e., ester versus nitrile, seems to have no influence
on the reaction profile (compare entries 4 vs 8 and 7 vs 10 vs
11). The use of harsher conditions for the less reactive olefin
8k (compare entries 7 and 11) also has no influence on the
reaction yields. Moreover the use of unsymmetrical olefins led,
in all cases, to the formation of γ-lactams in good yields and
1
excellent diastereoselectivity (95:5) determined by H NMR
spectra of the crude mixture (entries 8-10). In the latter, a syn
relationship between the nitrile group and the aromatic ring has
been established.
The high degree of diastereoselectivity observed during the
process could be explained by the plausible transition states
presented in Scheme 3. In fact, the more stable carbanion,
produced after 1,4-addition onto 8h,i of the amides 9a,d, is the
one in which the aromatic ring and the nitrile function are
adjacent leading to the major syn products 1h-j. The different
conformation (ET1 and ET2) of the same intermediate (ET)
displays a higher steric hindrance between the ester function or
its enolate form and the aromatic system.
Having developed successfully this tandem reaction aza-
Michael/intramolecular nucleophilic substitution for the genera-
tion of γ-lactam scaffolds, we sought to demonstrate its utility
in a rapid and concise synthesis of the tricyclic core of (()-
martinelline alkaloids. The latter, isolated from the root bark
of the tropical plant Martinella iquitosensis by Witherup et al.18
at Merck, possess antibacterial activity and constitute also the
first potent, naturally occurring nonpeptide bradykinin (BK)
receptor antagonists to be reported.19
The scarcity of a partially reduced pyrrolo[3,2-c]quinoline
skeleton as the unique structure present in these alkaloids,
combined with their interesting biological profiles, has led to
continued interest in total synthesis of these structures and
explorations of their derivatives.20,21 Significantly, while the
importance of the impressive advances published in this area is
well established, the latter strategies required in all cases many
a Isolated yield. b Determined by 1H NMR analysis. c No reaction
occurred. d Harsher reaction conditions were used herein; Knoevenagel
substrate 8k (1 equiv) and R-bromoacetamide (9d, 2.2 equiv) were
reacted with 2.4 equiv of NaH in THF for 24 h.
(18) Witherup, K. M.; Ransom, R. W.; Graham, A. C.; Bernard, A. M.;
Salvatore, M. J.; Lumma, W. C.; Anderson, P. S.; Pitzenberger, S. M.; Varga,
S. L. J. Am. Chem. Soc. 1995, 117, 6682–6685.
ings17 are summarized in Table 2. We have shown that, as
expected, the steric hindrance of the amide, which decrease the
nitrogen atom nucleophilicity, plays a crucial role in the reaction.
Indeed, the yields dramatically dropped from 63% when R2 )
Bn (entry 5) to 0% in the case of R2 ) t-Bu (entry 3). However,
as may be seen in entries 6 and 7, the tandem reaction readily
tolerates both the nitro substituent and the presence of a
(19) Bock, M. G.; Longmore, J. Curr. Opin. Chem. Biol. 2000, 4, 401–406.
(20) For a recent review, see: (a) Nyerges, M. Heterocycles 2004, 63, 1685–
1712.
(21) (a) For representative existing methods, see ref 5a. (b) Nieman, J. A.;
Ennis, M. D. Org. Lett. 2000, 2, 1395–1397. (c) He, Y.; Mahmud, H.; Moningka,
R.; Lovely, C. J.; Dias, H. V. R. Tetrahedron 2006, 62, 8755–8769. (d) Miyata,
O.; Shirai, A.; Yoshino, S.; Nakabayashi, T.; Takeda, Y. Tetrahedron 2007, 63,
10092–10117. For the first asymmetric total synthesis of (-)-martinelline and
the second total synthesis of (-)-martinellic acid, see: (e) Ikeda, S.; Shibuya,
M.; Iwabuchi, Y. Chem. Commun. 2007, 504–507. (f) Badarinarayana, V.;
Lovely, C. J. Tetrahedron Lett. 2007, 48, 2607–2610.
(17) See Experimental Section for the general procedure for the preparation
of γ-lactams 1.
5568 J. Org. Chem. Vol. 73, No. 14, 2008

SCHEME 4. Scheme Leading to Pyrroloquinoline Core 13
In summary, we have developed an unprecedented and
expedient synthesis of original γ-lactams via a new tandem
reaction aza-Michael/intramolecular nucleophilic substitution
from readily available and inexpensive reagents. Although the
process has not yet been generalized to all categories of olefins
(today, three levels to ensure the molecular diversity are
possible), it has enabled us to synthesize successfully the
tricyclic core of martinelline alkaloids with correct relative
stereochemistry. Ultimately, the investigation of the applicability
of this tandem reaction to synthesis of other heterocyclic
compounds with promising biological profiles and its generali-
zation to other alkenes will be the focus of future work.
Experimental Section
Typical Procedure for the Preparation of γ-Lactams 1
(Nitro-diester-γ-lactam 1k as Example). The required Knoev-
enagel substrate 8 (1.0 mmol) and N-alkyl bromo-acetamide 9 (1.1
mmol) were dissolved in freshly distilled THF (10 mL) at 0 °C.
Sodium hydride (48 mg, 60% suspension in mineral oil, 1.2 mmol)
was then added in one portion, and the mixture was stirred at room
temperature for 12 h. The solution was cooled to 0 °C, and the
reaction was quenched by careful addition of an aqueous saturated
solution of NH4Cl (10 mL). The aqueous layer was extracted with
EtOAc (3 × 10 mL), and the organic layers were combined, dried
over MgSO4, and evaporated. The residue was purified by chro-
matography on silica gel column to provide the desired γ-lactam
1. (()-Diethyl 1-benzyl-2-(2-nitrophenyl)-5-oxo-pyrrolidine-3,3-
dicarboxylate (1k) was isolated as a white solid that melted at
101-103 °C (recrystallized from EtOAc) in 53% yield (AcOEt/
cyclohexane, 30:70). IR (KBr): 2985, 1737, 1691, 1534, 1447, 1424
steps and consequently there is a need for the development of
flexible strategies that will accommodate a range of structure
types.22
In this sense, with both nitrile-ester lactam 1j and diester
lactam 1k in hand, two different objectives were pursued:
the chemical confirmation of the reaction diastereoselection
observed and the synthesis of substituted pyrrolo[3,2-c]-
quinoline 13 as the key for (()-martinelline alkaloids
(Scheme 4). So, when compound 1j was treated with iron in
glacial acetic acid at 80 °C for 3 h, only the iminoamine
product 10 was isolated in nearly quantitative yield.23 This
result demonstrated the diastereoselective outcome during the
tandem process, i.e., the syn relationship between the aromatic
system and the nitrile function to the detriment of the ester
group. Following the same protocol, γ-lactam 1k provided
the tricyclic lactam 11 in yield of 93%, and its structure was
secured by a single X-ray analysis (see Supporting Informa-
tion for CIF file and ORTEP drawing of product 11). This
product was also obtained in 93% yield from iminoamine
10 by hydrolysis in a mixture of water/acetic acid. Finally,
the ester function of 11 was been removed in a two-step
sequence, by classical saponification (11 f 12) followed by
decarboxylation, providing the tricyclic system 13 already
described by Shaw et al.5a Importantly, the same authors have
converted an ester analogous of this system 13 to the
complete carbon framework of martinelline alkaloids in three
steps.
1
cm-1. H NMR (300 MHz, CDCl3): δ 7.91 (d, J ) 7.2 Hz, 1H),
7.57 (t, J ) 7.2 Hz, 1H), 7.48 (t, J ) 7.2 Hz, 1H), 7.29-7.22 (m,
4H), 7.17-7.14 (m, 2H), 6.29 (s, 1H), 4.97 (d, J ) 14.6 Hz, 1H),
4.20 (q, J ) 7.1 Hz, 2H), 3.85 (dq, J ) 10.7 and 7.1 Hz, 1H), 3.75
(d, J ) 18.0 Hz, 1H), 3.58 (dq, J ) 10.7 and 7.1 Hz, 1H), 2.96 (d,
J ) 18.0 Hz, 1H), 1.20 (t, J ) 7.0 Hz, 3H), 0.92 (t, J ) 7.0 Hz,
3H). 13C NMR (75 MHz, CDCl3): δ 171.5, 169.0, 167.0, 150.1,
135.0, 133.2, 130.7, 129.7, 128.8, 128.7, 128.6, 128.0, 125.1, 62.8,
62.5, 59.2, 59.1, 45.8, 37.6, 13.9, 13.4. Anal. Calcd for C23H24N2O7:
C, 62.72; H, 5.49; N, 6.36. Found: C, 62.51; H, 5.86; N, 6.39.
Acknowledgment. The authors would like to thank Miss
Charlotte Mazot for the preparation of starting material.
Supporting Information Available: Experimental proce-
dures, product characterization for all new compounds synthe-
sized and the ORTEP plot of compound 11, as well as its CIF
file. This material is available free of charge via the Internet at
http://pubs.acs.org.
(22) During the preparation of this paper, an interesting strategy based on a
SnCl4-mediated domino reaction of 2-(cyanomethyl)-3-oxo-N-arylbutanamides
was published. See: (a) Zhang, Z.; Zhang, Q.; Yan, Z.; Liu, Q. J. Org. Chem.
2007, 72, 9808–9810.
(23) Suzuki, M.; Kaneko, T.; Kamiyama, H.; Ohuchi, Y.; Yokomori, S.
Heterocycles 2000, 53, 2471–2485.
JO702752W
J. Org. Chem. Vol. 73, No. 14, 2008 5569