Straightforward Access to a Great Diversity of Complex Biorelevant γ-Lactams Thanks to a Tunable Cascade Multicomponent Process

Article abstract of DOI:10.1021/acs.oprd.9b00438

This reviews surveys the preparation of a great diversity of complex biorelevant γ-lactam backbones thanks to scalable copper(I)-catalyzed cascade multicomponent processes.

Full text of DOI:10.1021/acs.oprd.9b00438

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Review
Straightforward Access To a Great Diversity of Complex Biorelevant
#-Lactams Thanks To a Tunable Cascade Multicomponent Process
Muhammad Idham Darussalam Mardjan, Atef Mayooufi, Jean-
Luc Parrain, Jérôme Thibonnet, and Laurent Commeiras
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.9b00438 • Publication Date (Web): 10 Feb 2020
Downloaded from pubs.acs.org on February 18, 2020
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Straightforward Access To a Great Diversity of
Complex Biorelevant γ-Lactams Thanks To a
Tunable Cascade Multicomponent Process
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a,c
Muhammad Idham Darussalam Mardjan, Atef Mayooufi, Jean-Luc Parrain, , Jérôme
b
a
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Thibonnet, * and Laurent Commeiras, *
a
a) Aix Marseille Univ, CNRS, Centrale Marseille, iSm2, Marseille, France
b) Laboratoire SIMBA, EA7502, Université de Tours, Faculté des Sciences et Techniques, Parc
de Grandmont, 32 Av. Monge, 37200 Tours, France
c) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah
Mada, Bulaksumur POS BLS 21, Yogyakarta 55281, Indonesia.
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TABLE OF CONTENTS
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ABSTRACT. The current article reviews the preparation of a great diversity of complex
biorelevant γ-lactams backbones thanks to scalable copper(I)-catalyzed cascade multicomponent
processes.
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KEYWORDS. Lactams, Copper Catalysis, Heterocyclic Compounds, Multicomponent
Reaction, g-Hydroxybutyrolactams, Spirolactams
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1. INTRODUCTION
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1H-Pyrrol-2(5H)-ones 1 represent important heterocycles found in many natural products and
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molecules with a variety of pharmaceutical uses. Several examples possessing interesting
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structural and biological activities include codinaeopsin 2, axinellamide 3, pulchellalactam 4,
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pandamarine 5, and erysotramidine 6 (Figure 1). Among them, 5-hydroxy-1H-pyrrol-2(5H)-ones
7, also known as γ-hydroxy-γ-lactams, have gained a lot of interests due to their versatility in
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organic synthesis and medicinal chemistry. As a consequence, numbers of synthetic strategies
have been devised to access these heterocycles including intra- and intermolecular routes as well
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as oxidation reactions of heterocyclic compounds. More specifically, several groups have
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designed efficient and attractive routes, based on multicomponent reactions (MCRs), to address a
modular preparation of these γ-hydroxy-γ-lactams 7.
H
N
R3
R2
R4
H
H
O
HO
O
N
H
O
R1
N
N
H
HO
R4
O
1H-pyrrol-2(5H)-ones 1,
5-hydroxy-1H-pyrrol-2(5H)-ones 7
if R1 or R2 = OH
codinaeopsin (2)
anti-plasmodium
axinellamide (3)
MeO
MeO
O
N
N
HN
O
HN
N
H
O
O
MeO
erysotramidine (6)
Anti-convulsant
pandamarine (5)
flavouring
pulchellalactam (4)
CD45 protein tyrosine
phosphatase inhibitor
Figure 1. Natural product containing the γ-lactam moiety
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These MCRs mainly involve a three-component reaction between aldehydes, 1,3-dicarbonyl
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compounds and isocyanides, or dialkylacetylenedicarboxylates, benzoyl chlorides and
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isocyanides, or primary amines, dimethylacetylenedicarboxylate and oxalyl chloride, or
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dibenzoylacetylene, aryl sulfonyl isocyanates and amines. More recently, an elegant
enantioselective MCR between ketones, carboxylic acids and a nitroalkenes, catalyzed by a chiral
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proline ester derivative, has been also reported by Cossío and co-workers.
In addition, it has been reported in 2009 that the palladium-free Sonogashira coupling between
(Z)-3-iodoacrylic acids 8 and terminal alkynes 9, followed by a 5-exo-dig oxa-cyclisation offered
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a convenient access to γ-alkylidenebutenolides 10 (scheme 1a). It is also generally known and
commonly used, that treatment of γ-alkylidenebutenolides 10 with primary amines 11 lead to the
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formation of γ-hydroxy-γ-butyrolactams 7 (Scheme 1a). Moreover, the treatment of γ-
hydroxybutyrolactams 7 with acid sources results in the formation of the corresponding N-
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acyliminium ions 12 which can evolve either to γ-alkylidene-γ-butyrolactams 13 or γ-
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functionalized lactams 14 (Scheme 1a). By taking advantage of these transformations, Commeiras
and co-workers proposed new multicomponent synthetic strategies between readily or
commercially available (Z)-3-iodoacrylic acids, as well as (E)-2,3-dihalogenoacrylic acids 8,
terminal alkynes 9, and primary amines 11 in the presence of copper(I) catalyst providing either
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γ-hydroxy-γ-butyrolactams 7 or various γ-lactam motifs 13-16. In this review, we provide a
comprehensive survey of this copper(I)-mediated multicomponent process, which could be
compared to a (3+1+1) ring construction cyclization approach, able to prepare, in a simple and
atom economic transformation, a great diversity of complex biorelevant γ-hydroxy-γ-
butyrolactams 7 and their one-pot post-functionalization (Scheme 1b).
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R1
ref. 19
a) Previous reports
O
N
R3
R2
R1
R1
R1
R1
HO
R3
X
9
NH2
11
R2
X
13
HX
CuI
+
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X
O
ref. 15,16
ref.17, 18
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O
N
R3
N
R3
O
CO2H
R2
R1
R2
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R2
7
12
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R2
O
Nu
N
ref. 20
R3
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b) This review
R1
X
R1
R1
R1
R1
X
X
"one-pot" Copper-Catalyzed-
Multicomponent Process
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HO
X
COOH
R2
R2
Nu
or
or
or
O
O
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O
O
N
N
N
N
H2N
R3
Nu
R2
R2
R3
R3
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13
16
R2
R3
9
11
R3
Scheme 1. The proposed cascade strategies for direct synthesis of various γ-lactam motifs
g
2. SYNTHESIS OF -HYDROXYBUTYROLACTAMS 7. Initially, the authors have shown
that the optimum reaction conditions were obtained when the process was conducted in degassed
i-PrOH at 50 °C for 12 h using 1 equiv. of the acrylic acid (((Z)-3-iodobut-2-enoic acid 8a), 2
equiv. of the terminal alkyne (phenylacetylene 9a ) and 2 equiv. of primary amine (butylamine
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11a), 2 equiv. of K2CO3 and 20 mol% of CuI. Under these conditions, the γ-hydroxy-γ-
butyrolactam 7a was obtained in excellent 84% isolated yield on a 2 mmol scale (Scheme 1). It is
worth noting that the γ-hydroxy-γ-butyrolactam 7a was prepared thanks to one-pot-cascade
reactions involving palladium free Sonogashira coupling-heterocyclization-nucleophilic addition,
in which one C-C, one C-O and two C-N bonds were created, without the formation of side
products arising from the potential reactions such as Ullmann coupling as well as 1,4- and 1,6-
conjugate addition between the lactone intermediate 10a and primary amine. In addition, the scale-
up to 20 mmol of (Z)-3-iodobut-2-enoic acid 8a was readily accomplished without requiring the
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optimization of the previous reaction conditions. The γ-hydroxy-γ-butyrolactam 7a was isolated
with the same excellent yield (82%, 4.27 g).
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The applicability and the generality of this process has been demonstrated by the preparation of
a large library, more than 60 examples, of γ-hydroxybutyrolactams 7 (Schemes 2 and 3). Indeed,
diversely substituted and functionalized starting materials are tolerated and have been converted
to the desired targets 7.
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R1
R1
8
CuI
K2CO3 (2 eq.)
HO
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5
6
X
COOH
O
+
N
i-PrOH
H2N
R2
9
R2
11
R3
7
R3
T (°C)
7
8
HO
HO
HO
HO
HO
HO
HO
HO
HO
HO
HO
O
O
O
O
O
O
O
O
O
O
O
N
N
N
N
N
N
N
N
N
N
N
9
2
5
BnO
O
EtO
TBSO
TBSO
OMe
OEt
O
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7a, 84%a
7b, 59%a
7c, 69%a
7d, 68%a
7e, 93%a
7g, 77%a
7h, 44%b
7i, 50%b
7j, 83%a
7k, 84%a
7f, 60%a
HN
N
HO
HO
HO
HO
HO
HO
HO
HO
HO
HO
HO
O
O
O
N
O
N
O
O
O
O
O
O
O
N
N
N
N
N
N
N
N
H
OCH3
4
OMe
OH
MeO
7p, 61%,a 73%c
OMe
7l, 75%a
7m, 41%a
7n, 71%c
7o, 77%c
7q, 58%,a 87%c
7r, 38%c
7u, 7%c
7v, 51%a
OMe
7s, 25%d
7t, 45%e
O
TMS
HO
O
HO
HO
HO
HO
HO
HO
HO
HO
HO
HO
O
O
O
O
O
O
O
TBSO
O
N
O
O
O
N
N
N
N
N
N
N
N
N
N
BnO
TBSO
TBSO
OH
7w, 16%,a 25%c
7x, 24%c
7y, 72%a
7z, 78%a
7aa, 40%a
7ab, 9%f
7ac, 49%f
7ad, 59%a
7ae, 56%a
7af, 45%a
7ag, 74%a
O
O
HO
N
HO
HO
N
HO
HO
HO
HO
HO
HO
HO
N
HO
N
O
O
N
O
N
O
O
O
O
N
O
N
O
O
O
N
N
N
BnO
BnO
TBSO
BnO
BnO
BnO
TBSO
HN
HN
HN
HN
HN
HN
MeO
7ak, 74%c
7am, 85%a
7an, 84%a
7ao, 64%a
7ar, 81%a
7ah, 69%a
7aj
84%a
7al, 77%c
7ap, 63%a
7ai, 38%a
OMe
HO
7aq, 38%a
O
HO
HO
N
HO
HO
HO
HO
HO
HO
HO
O
O
O
O
O
O
O
O
O
O
N
N
N
N
N
3
2
N
2
N
2
2
N
2
3
N
N
N
N
N
N
EtO
OEt
2
NH
NH
OMe
OMe
F
HN
HN
HN
7at, 50%a
7as, 73%a
7au, 89%g
7av, 60%g
7aw, 64%g
7ax, 47%g
7ay, 53%g
7az, 55%g
7ba, 43%b
7bb, 42%b
(a) 1 eq. of 8, 2 eq. of 9, 2 eq. of 11, 20 mol% of CuI, 50 °C, 12 h.; (b) 1 eq. of 8, 2 eq. of 9, 4 eq. of 11, 20 mol% of CuI, 45 °C,12 h.; (c) 1 eq. of 8, 2 eq. of 9, 3 eq. of 11, 20 mol% of CuI, 50 °C, 12 h.; (d) 1 eq. of 8, 2 eq. of 9, 10 eq. of 11,
20 mol% of CuI, 50 °C, 48 h.; (e) 1 eq. of 8, 2 eq. of 9, 3 eq. of 11, 20 mol% of CuI, 6 eq. of NEt3, 50 °C, 72 h.; (f) 1 eq. of 8, 2 eq. of 9, 2 eq. of 11, 1 eq. of CuI, 50 °C, 12 h.; (g) 1 eq. of 8, 2 eq. of 9, 3 eq. of 11, 1 eq. of CuI, 50 °C, 12 h.
Scheme 2. Scope of the MCR process
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Terminal alkynes bearing both aromatic and heteroaromatic rings and terminal alkynes
substituted with different functional groups, such as methyl ester, diethyl acetal and benzyl as well
as silicon-protected-propargyl alcohol, are tolerated in the multicomponent reaction. Application
of alkynes containing longer aliphatic chain such as TBS-protected but-4-ynol and oct-1-yne,
produced the corresponding lactams 7h-i but in lower yield (up to 50%) due to the formation of 6-
membered-lactones (13% and 10%, respectively as the thermodynamic products generated from
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6-endo-heterocyclization step). Unfortunately, these 6-membered-lactones are unreactive towards
primary amine. For these non-activated alkynes, the optimization of the reaction conditions
revealed that it is necessary to perform the reaction at 45 °C in the presence of 4 equiv. of primary
amines to obtain better results. The authors found that this reaction was dependent on the
nucleophilicity of the primary amines 11. Compared to nucleophilic amines, such as butylamine,
tryptamine, homoallylamine and propylamine for which only 2 equivalents are required, 3 equiv.
of amines possessing less nucleophilic character (for instance, allyl and benzylamine) were
necessary to completely convert the lactones intermediates 10 into the γ-hydroxy-γ-lactams. In the
case of 2-methoxybenzylamine and 4-methoxybenzylamine, the reaction could be conducted by
using 2 equiv. of the corresponding primary amine to give the desired products 7p-q but in lower
yield (61 and 58% yields respectively) compared with the use of 3 equiv. of 11. The major
limitation of the reaction was obtained with low-nucleophilic aniline derivatives (aniline and 4-
methoxyaniline) since the hydroxylactams 7 were not detected. The low-nucleophilic behavior of
non-alkyl primary amine was also observed with ammonia. The resulting scaffold 7s was isolated
in moderate yield (25%) even by using 10 equiv. of NH3 solution (2M in i-PrOH) for 48h. It is
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worth mentioning that beneficial alpha-effect occurred starting from methoxyamine
hydrochloride; 7t was isolated in better yield (45%).
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The chemoselectivity of the multicomponent process was also assessed by using alkynylamine
substrates such as propargylamine and hex-5-ynylamine. While low isolated yield of
hydroxylactam 7u (7%) was observed by using propargylamine (even with 3 equiv.),
hydroxylactam 7v was obtained in moderate yield (51%) starting from hex-5-ynylamine. This
result demonstrated that the Sonogashira coupling exclusively favored the triple bond of terminal
aromatic alkynes compared to that of alkynylamines. The steric effect on the efficiency of the
cascade process was also evaluated. When iso-propylamine was used as primary amine under
standard otherwise conditions, a 1:0.5 mixture of the desired lactam 7w and the residual
alkylidenebutenolide 10w was formed. Compared to hydroxylactam isomer 7l which was isolated
in 75% yield, 7w was isolated in 16% yield. The presence of lactone 10w would indicate that the
steric hindrance may inhibit the nucleophilic addition reaction of primary amine. Increasing the
amount of primary amine to 3 equiv. gave full conversion to the hydroxylactam 7w, unfortunately
with a slight increase of the yield (25%). It has been also shown that various substituents can be
installed on the b-position of iodoacrylic acids to effectively produce the desired γ-hydrolactams.
It should be noted that α,β-unsubstituted-γ-hydroxy-γ-lactam moiety 7ab couldn’t be generated
in good yield (9%) starting from (Z)-3-iodo-propenoic acid. This low isolated yield could be
explained by the formation of side products arising from 1,4-conjugate addition reaction and from
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the low stability of the lactam. As an alternative pathway, the γ-lactam 7ab could be obtained in
a two-step procedure by installing a temporary disposable trimethylsilyl group on the β-position.
Indeed, the reaction was conducted from (Z)-3-iodo-3-(trimethylsilyl)propenoic acid with 1 equiv.
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of copper(I) iodide to give the β-silylated-hydroxylactam 7ac in 49% yield, which in turn
underwent the desylilation reaction using NaF to furnish 7ab in 57%.
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A special attention was paid to introduce an indole moiety in order to have a rapid access to
biorelevant γ-hydroxybutyrolactam/indole hybrids scaffolds. For this purpose, the indole nucleus
could be incorporated either on the primary amines (starting from tryptamine) or terminal alkynes
(starting from N-propargylindole or 3-(buty-3-yn-1yl)-1H-indole). Whatever the nature of the
starting materials, the desired hybrid scaffolds 7am-7bb were successfully prepared up to 89%
yield. It is worth noting that when N-propargylindole was applied as starting material, 1 equiv. of
CuI and 3 equiv. of primary amine were required to have a complete conversion of lactone
intermediate. As previously discussed, in the case of non-activated 3-(buty-3-yn-1yl)-1H-indoles,
the desired γ-hydroxybuterolactams 7ba and 7bb were prepared in moderates yields (43 and 42%,
respectively) together with the non-desired pyran-2-ones (ratio of 1:0.22 and 1:0.22, respectively).
Finally, in order to increase the molecular complexity of γ-hydroxybutyrolactams, this process
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was also assessed starting from a,b-dihalogenoacrylic acid (Scheme 3). In this case, the copper-
mediated MCR would furnish a-halogeno-γ-hydroxybutyrolactams allowing a-post-
functionalization by exploiting the reactivity of the resultant halogen atom. The utilization of a,b-
dibromobutenoic acid or a,b-diiodobutenoic acid required a slight modification of the reaction
conditions. The best results were observed when the reaction was conducted with 40 mol% of CuI
at 55 °C. Under these conditions, several a-halogeno-γ-hydroxybutyrolactams were prepared in
moderate yield (up to 60%) by varying both the nature of terminal alkynes and primary amines.
As previously, the reaction has been scale-up to 20 mmol without loss of efficiency. 7bc was
isolated in 52% yield. Interestingly, when 7bp is exposed to p-methoxyphenylboronic acid, the
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Pd-catalyzed Suzuki-Miyaura coupling reaction led to the formation of a-substituted γ-
hydroxybutyrolactam 7bq in 74% yield (Scheme 4).
7
8
R1
8
R1
HO
X2
CuI (40 mol%)
K2CO3 (2 eq.)
9
X
COOH
10
11
12
13
14
15
16
17
18
19
20
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47
48
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50
51
52
53
54
55
56
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59
60
+
O
N
11
R3
i-PrOH, 12 h
H2N
R2
9
R2
R3
7
50 °C
Br
Br
I
Br
I
Br
HO
HO
HO
HO
HO
HO
O
O
O
O
O
O
N
N
N
N
N
N
MeO
HO
F
7bc, 60%a
7bd, 49%a
7bg, 50%a
7bh, 46%a
7be, 52%a
7bf, 50%a
Br
Br
I
Br
I
I
HO
HO
HO
HO
HO
O
O
O
O
N
O
O
N
N
N
N
N
7bi, 51%b
7bk, 53%b
Br
7bl, 54%b
7bj, 47%b
7bm, 51%b
7bn, 59%b
Br
HO
HO
O
O
N
N
7bp, 55%d
7bo, 56%c
(a) 1 eq. of 8, 2 eq. of 9 and 2 eq. of 11; (b) 1 eq. of 8, 2 eq. of 9 and 3 eq. of 11,(c) 1 eq. of 8, 2 eq. of 9 and 3eq. of 11 (d) 1 eq. of 8,
5 eq. of 9 and 3 eq. of 11.
Scheme 3. Preparation of a-halogeno-γ-hydroxybutyrolactams.
OMe
Pd(PPh3)4, 5 mol%
NEt3 (2 eq.)
Br
OMe
HO
+
O
HO
N
TBAI (10 mol%)
EtOH/toluene (1/1)
70 °C, 8 h.
(HO)2B
O
N
74%
7bp
7bq
Scheme 4. Preparation of a-substituted γ-hydroxybutyrolactam 7bq
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Two mechanistic scenarios could be considered for this copper-mediated multicomponent
process. The first one would involve a Castro-Stephens type coupling whereas the second one a
Sonogashira type coupling (without palladium). The Castro-Stephens type coupling is disregarded
because when the reaction of the formation of the lactone 10 is performed with one equivalent of
phenylethynyl cooper reagent and (Z)-3-iodobut-2-enoic acid 8a, no lactone 10a was observed in
the crude mixture. Therefore, a plausible mechanism, based on a Sonogashira type coupling
without palladium, is depicted in Scheme 5. The first step is likely to be an oxidative addition of
the copper(I) into the C–I bond of A to give copper(III) intermediate B. The next steps would
involve a p-coordination of the alkyne reagent followed by the formation of complex D thanks to
a base-mediated-deprotonation of terminal acetylenic proton. Next, the reductive elimination of
the intermediate D followed by a 5-exo-dig cyclisation assisted by copper(I) would lead vinyl
copper intermediate F which would give lactone G via protodemetalation. Finally, the nucleophilic
addition of the primary amine onto the lactone G would furnish the desired hydroxylactams I via
the intermediate H.
10
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16
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7
R1
X
X
R1
O
X
11
H2N R3
R1
8
X
COOH
O
R2
HN
O
K2CO3
H2O + CO2
O
R2
R3
G
H
8
9
R1
X
R1
HO
X
X
COO
A
10
11
12
13
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15
16
17
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K
CuI
protodemetalation
O
N
oxidative
addition
R2
I
R1
X
R3
R1
X
CuI
X
CuIII
O
O
O
R2
O
F
B
R2
H
5-exo-dig
9
R1
X
R1
CuIII
X
E
C
CuI
X
O
O
R2
O
O
R2
H
reductive
elimination
D
R1
X
K2CO3
KX + H2O + CO2
CuIII
O
R2
O
Scheme 5. Plausible mechanism for the preparation of 7.
3. ONE-POT POST-FUNCTIONALIZATION OF 7. Encouraged by the excellent results
obtained with this copper(I)-catalyzed cascade multicomponent process, Commeiras and co-
workers then investigated the synthetic application of γ-hydroxy-γ-lactams 7 by exploiting their
24,26,27
reactivity as N-acyliminium ion (NAI) precursors 12.
Indeed, NAI are highly reactive
electrophilic intermediates and they are therefore excellent candidates for the creation of both
carbon-carbon or carbon-heteroatom bonds. The purpose was to extend the previously
multicomponent process by adding the formation and the post-functionalization of NAI in a one-
pot fashion. The incorporation of the NAI chemistry into the cascade process has been simply
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carried out by quenching the copper(I)-catalyzed multicomponent reaction with an HCl acidic
aqueous solution instead of a saturated aqueous NH4Cl solution.
7
8
9
In the absence of any potential nucleophiles, the NAI intermediates 12 underwent to β-elimination
reaction to give the corresponding γ-alkylidene-γ-lactams 13 as an inseparable mixture of
diastereomers and in good yields (Scheme 6). Importantly, this strategy allowed to obtain the γ-
methylidenebutyrolactam 13f (54% brsm) in a very convergent way compared to those described
10
11
12
13
14
15
16
17
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59
60
28
in the literature for such scaffolds. In this case, ethynyltrimethylsilane has played the role of an
acetylene equivalent. It is worth noting that the moderate yield observed is presumably due to a
low conversion rate (50%) of the reaction.
R1
X
R1
R1
1)
2)
8
X
X
Cu
X
COOH
O
O
N
R3
N
H2N
9
R2
R2
HCl (6M, 20 eq.)
50 °C, 1-2 h
R3
R3
R2
13
12
11
Br
O
O
O
O
O
O
N
N
N
N
N
N
13c
13b
13d
13a
13e
60%c
(Z):(E) = 1:1
13f
66%a
74%a
76%a
70%b
27%d
(Z):(E) = 1:0.4
(Z):(E) = 1:0.5
(Z):(E) = 1:0.5
(Z):(E) = 1:0.5
(a) 1 eq. of 8, 2 eq. of 9, 2 eq. of 11, 20 mol% of CuI, 50 °C; (b) 1 eq. of 8, 2 eq. of 9, 3 eq. of 11, 20 mol% of CuI; (c) 1 eq. of 8, 5 eq. of
9 and 3 eq. of 11; 20 mol% of CuI; (d) 1) 1 eq. of 8, 5 eq. of 9, 2 eq. of 11, 100 mol% of CuI, 75 °C, 12 h.; 2) HCl, (6M, 20 eq., 75 °C)
Scheme 6. Cascade multicomponent process towards the synthesis of γ-alkylidene-γ-lactams 13
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On contrary, in presence of nucleophiles, the NAI intermediates 12 could be trapped by these later.
Thanks to both an intramolecular reaction and depending the position of the nucleophiles, the
synthesis of different polyheterocyclic lactams 15-16 have been envisaged. Indeed, while the
installation of nucleophilic site into the terminal alkynes provided the corresponding spirolactams
15, nucleophile-substituted-primary amines provided fused heterocycle-lactam derivatives 16. The
authors have shown that (5,6)-spirolactams 15 were generated when non-activated indole-
substituted-terminal alkynes 9, namely 3-(but-3-yn-1-yl)-1H-indole derivatives were subjected
into the process (Scheme 7). The tolerably yield of 15 is generally due to the formation of 20% of
the non-desired and unreactive six-membered lactone 17. Even if the yields of the isolated desired
products are relatively moderate, this useful cascade multicomponent process allows the synthesis
of (5,6)-spirocyclic scaffolds via the construction of 2 C-C and 2 C-N bonds together with a
quaternary center from readily available starting materials.
9
10
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R1
X
R3
8
R1
R3
1)
H
N
Cu
R1
R3
COOH
NH
R2
5
6
NH
O
R3
+
N
R4
R2
O
2) HCl (6M, 20 eq.)
50 °C, 1-4 h
H2N
N
11
9
15
R4
7
8
R4
12
9
F
10
11
12
13
14
15
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Bu
NH
NH
NH
NH
NH
NH
Br
O
O
O
O
O
O
N
N
N
N
N
N
OMe
15a
43%
15b
32%
15c
32%
15d
33%
15e
17%
15f
33%
(14f : 17f = 1 : 0.22)
(14a : 17a = 1 : 0.22)
(14b : 17b = 1 : 0.22)
(14c : 17c = 1 : 0.17)
(14d : 17d = 1 : 0.20)
(14e : 17e = 1 : 0.20)
O
R1
Ph
NH
NH
R2
O
O
N
N
O
O
R3
HN
17
15g
20%
(14g : 17g = 1 : 0.53)
15h
11%
(14h : 18h = 1 : 2.1)
Scheme 7. Cascade multicomponent process towards the synthesis of (5,6)-spirolactams 15
Concerning the mechanism of the formation of the corresponding spirolactams, the nucleophilic
addition of the indole moiety may occur either from C-2 or C-3 positions (Scheme 9). The C-2
addition would produce the carbocation J, which in turn would undergo β-elimination to give the
desired spirolactam 15. On the other hand, the C-3 addition would provide the spiro-compound
intermediate J. The latter would undergo rearrangement to give I, followed by a β-elimination to
furnish the final product 15.
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9
R3
R3
R1
R1
R1
R1
HO
NH
NH
R2
R2
NH
O
C-2 addition
HCl
β-elimination
N
O
2
N
3
3
R4
O
O
R2
N
N
2
R4
J
15
7
R4
12
R4
NH
R2
R3
rearrangement
R3
10
11
12
13
14
15
16
17
18
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59
60
R3
H
N
R1
2
C-3 addition
3
R2
O
N
K
R4
Scheme 8. Plausible mechanism for the formation of spirolactams 15.
Performing the same previous multicomponent process (copper(I)-catalyzed multicomponent
process followed with the sequential addition of aqueous HCl 6M solution), by mixing tryptamine,
different terminal alkynes and (Z)-3-iodoprop-2-enoic acid derivatives, allowed the formation of
polyheterocycles 16a-h containing a tetrahydro-β-carboline moiety, in moderate to very good
yields, through an intramolecular C-2 Friedel-Craft alkylation (Scheme 9). Attempts to improve
the effectiveness of the cascade process were successfully conducted by using a less concentrated
aqueous solution of HCl (1M). Under this condition, the polyheterocyclic compounds were
obtained in better yields (from 53 to 86% yields). It is worth noting that this cascade process has
been scale-up to 20 mmol. Under these conditions, 16a was obtained in 61% yield (4 g). It was
also demonstrated that the application of 3-aminopropanol allowed to obtain another
polyheterocyclic scaffold 16i of oxazinopyrrolone in 37% yield. Moreover, the extended cascade
process could be exploited to directly produce (80% yield) polyheterocycle 16j, scaffold found in
the natural product erysothramidine 6.
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8
R1
R1
I
8
1)
Cu
R1
R2
COOH
O
N
R2
O
Nu
11
9
N
2. HCl, 50 °C, 1-4 h
NuH
NH2
R2
12
16
HNu
n= 1,2
9
O
O
O
10
11
12
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15
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BnO
F
Ph
NH
Ph
NH
NH
NH
NH
O
O
N
O
O
O
N
N
N
N
16a
16c
16e
32%a / 65%b
16b
16d
82%a / 86%b
36%a / 53%b
85%a,c
52%a / 65%b
BnO
BnO
BnO
Ph
Bu
BnO
BnO
MeO
NH
NH
NH
O
O
O
N
O
O
O
N
N
N
N
MeO
16f
39%a / 56%b
16g
58%b
16h
62%b
16i
16j
37%a
80%a
(a)HCl 6M, 20 eq., (b)HCl 1M, 7 eq., (c) 3 equiv. of triptamine and 1 eq. of CuI
Scheme 9. Cascade multicomponent process towards polyheterocyclic lactam derivatives 16
Lastly, in addition to these systematic studies, the utility of the copper(I)-mediated MCR process
was nicely illustrated by the total synthesis of a natural product namely (Z)-pulchellalactam (4),
4
which is an inhibitor of the CD45 protein tyrosine phosphatase, in a two-step procedure (γ-
hydroxybutyrolactam formation followed by a dehydration reactions) from (Z)-3-iodobut-2-enoic
acid, iso-propylacetylene and N-p-methoxybenzylamine (Scheme 10). Indeed, using slightly
modified conditions (4 equiv. of iso-propylacetylene and 3 equiv. p-methoxybenzyl amine), the γ-
hydroxybutyrolactam 7br was obtained in 41% yields. The γ-hydroxybutyrolactam 7br was then
subjected to TFA to give a 9:1 separable mixture of (Z)- and (E)-pulchellalactam 4 in which the
natural product was isolated in 77% yield.
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7
CuI (20 mol%)
I
COOH
NH2
HO
TFA
O
K2CO3, i-PrOH
N
O
N
H
reflux
45 °C, 12 h
41%
77%
8
9
OMe
OMe
(Z)-puchellalactam
(4)
7br
10
11
12
13
14
15
16
17
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48
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60
Scheme 10. Total synthesis of (Z)-puchellalactam (4)
4. SUMMARY
Several methods to synthesize g-hydroxy-g-butyrolactams have been reported in the literature.
However, strategies based on multicomponent reactions (MCRs) to address a modular preparation
of these scaffolds are the most suitable. In this context, a scalable and tunable cascade
multicomponent process, starting from the readily available (Z)-3-iodoacrylic acids, as well as (E)-
2,3-dihalogenoacrylic acids, terminal alkynes, and primary amines in the presence of copper(I)
catalyst, was developed allowing the preparation of large library of the hydroxylactams. It was
also demonstrated that the cascade reaction can be extended by exploiting the chemistry of γ-
hydroxy-γ-lactams as the equivalent of N-acyliminium ions. A high diversity of γ-alkylidene-γ-
lactams, spirolactams and polyheterocyclic lactams can be simply accessed in a single operation.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI:
1 13
Synthesis procedures, H and C NMR spectra of each compound.
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AUTHOR INFORMATION
Corresponding Author
7
8
9
laurent.commeiras@univ-amu.fr
jerome.thibonnet@univ-tours.fr
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ACKNOWLEDGMENT
M.I.D.M. thanks The Ministry of Research, Technology and Higher Education (Republic of
Indonesia), the CNRS and Aix Marseille Université (UMR 7313) for financial support. A.M.
thanks Dr. Frédéric Montigny (Analysis Department, Tours University) for HRMS analysis.
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10. Fan, M.-J.; Qian, B.; Zhao, L.-B.; Liang, Y.-M. A facile reaction involving zwitterionic
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