Water-based conditions for the microscale parallel synthesis of bicyclic lactams

Article abstract of DOI:10.1016/j.tetlet.2012.11.082

We report efficient miniaturized conditions to prepare arrays of bicyclic lactams for screening. The nature of the solvent is usually an important factor of reactivity. At a small synthesis scale, when automated pipetting devices are required, physical pr

Full text of DOI:10.1016/j.tetlet.2012.11.082

Tetrahedron Letters 54 (2013) 562–567
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Water-based conditions for the microscale parallel synthesis of bicyclic lactams
⇑
Sandra Malaquin, Mouhamad Jida, Justin Courtin, Guillaume Laconde, Nicolas Willand, Benoit Deprez ,
Rebecca Deprez-Poulain
⇑
Biostructures and Drug Discovery, INSERM U761, Institut Pasteur de Lille, Université Lille Nord de France, Lille F-59006, France
PRIM, Lille F-59000, France
a r t i c l e i n f o
a b s t r a c t
Article history:
We report efficient miniaturized conditions to prepare arrays of bicyclic lactams for screening. The nature
of the solvent is usually an important factor of reactivity. At a small synthesis scale, when automated
pipetting devices are required, physical properties of the solvent, such as surface tension and vapor pres-
sure also become very important. After having shown that a complete evaporation of a solution of
reagents in water or a mixture of ethanol and water yields the expected lactams, we exemplified the reac-
tion and procedure with the preparation of a library of 80 members. Our synthesis scheme is validated for
synthesis scales from 1 to 100 mg. Therefore, it can be used both to produce rapidly test samples for HTS
as well as to prepare intermediates for the synthesis of more elaborated nature-inspired compounds.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 27 September 2012
Revised 19 November 2012
Accepted 21 November 2012
Available online 29 November 2012
Keywords:
Water
Library
Lactams
Keto-acids
Meyers’ lactamization1 is a bielectrophile–binucleophile reac-
tion that gives access to complex bicyclic lactams (Scheme 1).2 It
is a well known tool for the synthesis of natural products, espe-
cially alkaloids since it allows the formation of key quaternary cen-
ters in a stereoselective manner.3 It is also used for the synthesis of
chiral amines in drug discovery.4 Moreover, the diversity, complex-
ity, and compactness of products obtained make this reaction
highly attractive to feed libraries for High-throughput Screening.2
In this reaction, a keto-acid reacts with a chiral amino-alcohol.
Amino-alcohols are available at low cost and many derive from the
chiral pool of natural amino acids. A version of this reaction using
other binucleophiles such as diamines has been reported.5 Usually,
Water or
O
HO
water/ethanol
O
+
rac.
N
H
OH
H2N
1
O
O
Scheme 1. Meyers’ lactamization using water media.
templates.9 We have first disclosed a procedure with microwave
solvent-free conditions.10 This procedure allows the synthesis of
compounds on a scale from 20 to 100 mg. A solvent-free reaction
requires a weighing step that is not easily automated and makes
cumbersome the preparation of large arrays of compounds. There-
fore, we considered the use of water or water–ethanol mixtures to
dispense reagents at low scale (microtiter plates). The use of water
as a solvent at lab scale is growing. Indeed, both surface tension
and vapor pressure of water make it much easier to handle in
pipetting devices than most organic solvents. Also, water is inex-
pensive, abundant, and nontoxic11 and water–ethanol mixtures
are environmentally sound12 as opposed to volatile organic sol-
vents. Furthermore, water is already used as a solvent in various
lactamization reactions.13
c
-keto-acids or esters,5 d- or
x-keto-acids constrained or not, are
used.6 Recently, Meyers’ lactams were obtained from furans.7
Historically, Meyers’ lactamization proceeds in toluene, with
either an acid catalyst or molecular sieves.5,8 The synthesis is effi-
cient but reaction times are usually long (12–48 h), and it is usually
performed in a Dean–Stark apparatus. In order to reduce the use of
solvents such as toluene, we decided to explore the use of solvent-
free microwave heating and water-based protocols to access these
compounds. To further lessen the environmental impact of parallel
synthesis, we also wish to down-size the synthesis.
Solvent-free microwave irradiation has proven to be an efficient
environment-friendly procedure for the synthesis of various
We describe in this letter a new water-based synthesis of
Meyers’ bicyclic-lactams and analogues. Eventually, we disclose
the microscale parallel synthesis of a pilot 80-member library com-
patible with subsequent biological screening.
We previously optimized the reaction conditions in aqueous
medium on prototypal compound 1. In an aqueous solution, total
⇑
Corresponding authors. Tel.: +33 320 964 947; fax: +33 320 964 709.
E-mail addresses: benoit.deprez@univ-lille2.fr (B. Deprez), rebecca.deprez@
univ-lille2.fr (R. Deprez-Poulain).
URLs: http://www.deprezlab.fr, http://www.drugdiscoverylille.org (Benoit
Deprez).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.082

S. Malaquin et al. / Tetrahedron Letters 54 (2013) 562–567
563
conversion of reagents into 1 requires 16 h of heating allowing a
complete evaporation of water.
Most of the selected keto-acids were commercially available,
others were synthesized 3a–d. The tetralone derivatives 3a–b were
synthesized from the corresponding ketones (Scheme 2). Keto-
acids can also be obtained from the corresponding unsaturated car-
Selecting and synthesizing precursors
boxylic acids.14 The
steps from
a
-tetralone derivative 3a was synthesized in 2
a
-tetralone. For the first step, the use of glyoxalic acid in
A diverse set of keto-acids was gathered. It included linear
(Table 1, entries 1, 2, and 6), cyclic (entries 3–5, 7–10), and ali-
phatic (entries 1–2) keto-acids. Among the precursors, three are
d-keto-acids (entries 2, 9–10). Two keto-acids present a phenyl
ring in alpha of the ketone function (entries 6–7) and two other
compounds display a piperidine ring (entries 9–10) among which
3d bears a positive charge. These piperidines are found in many
bioactive compounds and display nitrogen that can be further
derivatized. Interestingly, tetralone template (entries 7–8) is found
in drug candidates such as serotonine receptor ligands.4
acidic conditions15 gave better results than the Knoevenagel reac-
tion in basic conditions. Keto-acid 3a was obtained from 2a by
reduction using classical conditions.16 The b-tetralone derivative
3b could not be obtained by the same procedure as the reduction
step led to degradation of the unsaturated intermediate. b-
Tetralone was thus reacted with tert-butyl bromoacetate in the
presence of NaH. The use of unprotected ester was unsuccessful
and the use of ethyl ester led to the formation of the unsaturated
lactone. The tert-butyl moiety was removed with TFA. Piperidone
Table 1
Scope of the reaction with various keto-acids in reaction with R-phenylglycinol
Entry
Keto-acida
Lactams
Yield (%) water (solvent-free lwave)
O
O
OH
N
O
1
76
O
4
O
O
O
N
O
Ph
Ph
OH
N
3
2
3
4
79c
O
O
5a/5b
O
O
N
97
OH
H
O
O
1
O
N
O
O2N
O2N
OH
86
H
O
O
6
O
O
OH
N
H
5
55
O
O
7
O
OH
OH
O
O
N
6
7
59
O
8
O
O
O
8 (5)
N
H
3a
O
9
(continued on next page)

564
S. Malaquin et al. / Tetrahedron Letters 54 (2013) 562–567
Table 1 (continued)
Entry
Keto-acida
Lactams
Yield (%) water (solvent-free lwave)
O
O
OH
N
H
8
9
73 (5)
O
O
10
3b
ClH
N
ClH
N
Bn N
ClH
O
Bn
Bn
O
O
O
OH
Ph
Ph
Ph
( )2
65b
N
N
H
O
H
O
O
3d
11a/11b
Boc
Boc
Boc
N
H
O
N
O
N
H
OH
Ph
N
N
80c
( )2
10
O
O
O
3c
12a/12b
a
All chiral keto-acids were used as racemic forms, except for 2-nitromethyl5-oxocyclopentaneacetic acid derivative (entry 4).
Ratio of diastereoisomers 90/10 (before separation) measured by LCMS and NMR.
Ratio of diastereoisomers 80/20, measured by LCMS and NMR.
b
c
derivatives 3c–d were also synthesized. Compound 3c was ob-
tained as previously described.17 In 3d, the Boc group that was
used to protect the nitrogen of the piperidone core in 3c was re-
placed by a benzyl group. First, 1-benzyl-3-carbethoxy-4-piperi-
done was reacted with methylacrylate in acetone in the presence
of cesium carbonate to give the alkylated intermediate 2d. Hydro-
lysis and decarboxylation using 6 N HCl gave 3d (Scheme 3).
O
R1
O
H
R1
R2
H
+
N
R
N
OH
R2
H
R
O
O
Figure 1. Expected bicyclic lactam and non-cyclic amide by-product.
O
O
O
acetic acid
Zn, H2O
70 °C, 1 h
glyoxalic acid
H2SO4
OH
OH
O
O
dioxane
110 °C, 1 h
61%
2a
2b
3a
O
O
BrCH2COOtBu
OtBu
O
OH
O
TFA/DCM
r.t., 15 min
NaH, THF
O
77%
3b
Scheme 2. Synthesis of keto-acid from tetralones.
Methyl acrylate
O
Cs2CO3
acetone
reflux, 1.5 h
O
O
O
O
O
HCl 6 N
reflux, 20 h
CO2Et
OH
81%
96%
CO2Et
N
N
N
HCl
HCl
Bn
Bn
2d
Bn
3d
Scheme 3. Synthesis of keto-acid 3d based on the piperidone template.

S. Malaquin et al. / Tetrahedron Letters 54 (2013) 562–567
565
Table 2
Scope of the reaction with various binucleophilesa
Entry
Binucleophile
Lactams
Yield (%) water (lwave)
O
N
1
R-Phenylglycinol
1
97
H
O
O
N
2
3
R-Phenylalaninol
13
14
80
H
O
S
COOMe
27b (97)
N
L
-Cysteine methyl ester
H
O
O
N
4
15
55 (0c)
D-Alaninol
O
H
N
O
16a
N
H
O
5
85d
L
-Tryptophanol
HN
16b
N
H
OH
H
O
O
N
6
7
o-Aminobenzylaminee
17
18
73
66
N
H
O
N
Diaminopyrimidinee
N
N
H
N
a
Compound 1, 13–14, 16 obtained with 2-oxocyclopentane acetic acid; compound 15 obtained with 3-benzoylpropionic acid; compound 17–18 obtained with 4-
acetylbutyric acid.
b
Partial hydrolysis of methyl ester into carboxylic acid was observed.
Only the amide by-product was observed.
Ratio 16a/16b 67/33 measured by LCMS and NMR.
Solubilized in ethanol.
c
d
e
1
O
O
O
O
H
H
N
Me
NH
13
1
N
Me
N
Me
N
N
N
Me
N
H
N
N
H
N
H
H
13 H
N
regioisomer not observed
Figure 2. Structure of 17.
regioisomer not observed
17
18
Figure 3. Structure of 18.

566
S. Malaquin et al. / Tetrahedron Letters 54 (2013) 562–567
Table 3
Quality control of a representative sample of the librarya
Binucleophile
Keto-acid
MH+
Purity (%)
R-Phenylglycinol
S-Phenylglycinol
(1R,2S)-1-Amino-2-indanol
(1S,2R)-1-Amino-2-indanol
4-Acetylbutyric acid
4-Acetylbutyric acid
4-Acetylbutyric acid
4-Acetylbutyric acid
3-Benzoylpropionic acid
232
232
244
244
218
85
85
93
91
95
D-Alaninol (R)
(S)-2-Amino-3-methyl-1-butanol
R-2-Amino-3-phenyl-1-propanol
R-2-Amino-3-phenylmethoxy-1-propanol
3-Benzoylpropionic acid
4-Acetylbutyric acid
4-Acetylbutyric acid
4-Acetylbutyric acid
246
246
276
354
86
85
95
85
L-Tyrosinol(benzyl) (S)
2-Aminophenol
4-Acetylbutyric acid
4-Acetylbutyric acid
4-Acetylbutyric acid
4-Acetylbutyric acid
Levulinic acid
2-Oxocyclopentaneacetic acid
3-Benzoylpropionic acid
3b
204
203
205
217
218
244
280
317
80
88
80
92
98
83
95
91
o-Phenylenediamine
Diaminopyrimidine
o-Aminobenzylamine
R-Phenylglycinol
R-Phenylglycinol
R-Phenylglycinol
R-Phenylglycinol
a
Purity is determined by LC/MS at 215 nm.
In the case of 18, the structure, established by the X-ray crystal
analysis (Fig. 3 and Supplementary data) is consistent with the
previously published results.19
Scope of the reaction
In order to evaluate the scope of the reaction in water, the ten
selected keto-acids were reacted with R-phenylglycinol (Table 1).
All compounds derived from c-keto-acids gave the pure diastereo-
Library synthesis
isomer as expected.10 Like other d-keto-acids,18 piperidine-based
bicyclic lactams 11 and 12 were obtained with good yields (65–
80%) as mixtures of 2 diastereoisomers (entries 9 and 10 vs entry
2), with a diastereoisomeric excess of 60%. Bicyclic lactams 4–8
(Table 1) were obtained with yields similar to those obtained using
the microwave solvent-free procedure. Tetralone 3a (entry 7)
which ketone is deactivated by the adjacent phenyl is far less reac-
tive than its linear analogue (entry 6). Surprisingly, tetralone 3b
gave the expected compound in water while the solvent-free
microwave heating gave mainly the non-cyclic amide by-product
(Fig. 1).
According to the scope of the reaction (Table 1 and 2), five keto-
acids and 16 binucleophiles (Supplementary data) were selected
for the parallel synthesis under aqueous conditions of a 80-lactam
library. In that case, as reagents are first solubilized in the solvent
to be distributed by the liquid handling system, we used either
pure water or water/ethanol mixtures (Supplementary data).20
Binucleophiles were selected among commercially available
compounds on the basis of several criteria: (1) price and availabil-
ity; (2) solubility in water or water/ethanol mixtures; (3) reactivity
(assessed by lmol scale); and (4) chemical diversity. The chemical
To further explore the scope of the reaction, chiral amino-
alcohols and more unusual binucleophiles were selected to react
with various keto-acids (Table 2). 2-Oxocyclopentanacetic acid
reacted with R-phenylglycinol and R-phenylalaninol (entries 1–2)
to give the corresponding lactams in very good yields (80–97%).
On the opposite, lactam 14 (entry 3) was obtained from cysteine
methyl ester in a low yield due to partial hydrolysis of the methyl
diversity was assessed by sorting compounds according to the nat-
ure of the R group (Fig. 1), the nature of the second nucleophilic
function, the presence of cycles, and the configuration of the C in
the alpha of nitrogen (Supplementary data).
The five ketoacids were selected on the basis of several criteria:
(1) reactivity (assessed at lmol scale by reaction with R-phenylgly-
cinol); and (2) solubility in water or water/ethanol mixtures
ester function. Lactam 15 from D-alaninol and 3-benzoylpropionic
(Supplementary data).
acid (entry 4) was obtained in only 55% yield using the aqueous
protocol because of the lower reactivity of the keto-acid (already
exemplified in Table 2, entry 6). Interestingly, under microwaves,
only the amide by-product was obtained. As expected from previ-
All structures were generated using Pipeline Pilot from Accelrys.
(Supplementary data). The completion of the reaction was checked
by LCMS and the purity of the ready-to-screen library was found to
be 80% of compounds above 85% purity (Table 3). The lowest con-
versions were observed for 2-amino-phenol due to the formation
of the amide as a side product (Fig. 1).
In conclusion, we have successfully developed a method useful
for the parallel synthesis of bicyclic lactams as water is well suited
for the synthesis by the micromole scale using liquid-handling sys-
tems. As an example, we synthesized a 80-member library, con-
taining 67% new structures,21 that can be used for the direct
in situ screening, in addition to the new compounds in Table 1.
ous results,10
L-tryptophanol (entry 5) can give along with the ex-
pected lactam 16a, compound 16b resulting from cyclization at the
C-2 of the indolyl ring to produce the corresponding tetrahydro-
b-carboline. Surprisingly, whereas the Pictet–Spengler product 16b
is the major compound (98%) under microwave conditions,10 it is
the minor compound (37%) using water. In all reactions using
chiral amino-alcohols, the expected single diastereoisomer was ob-
tained. With diamines (entries 6–7), bicyclic lactams 17–18 were
obtained in good yields (66–73%) as racemic mixtures. Two regioi-
somers could be expected from each of the diamine precursors
(Figs. 2 and 3, and Supplementary data). Interestingly, only one reg-
ioisomer was isolated in each case. A long distance correlation pro-
ton–carbon (HMBC NMR experiment) was observed between the
hydrogen atoms at C13 in the benzylic position and C1 from the lac-
tams function. This allowed assigning the structure of 17 (Fig. 2).5
Acknowledgments
We are grateful to the institutions that support our laboratory
(Inserm, Université de Lille2, Institut Pasteur de Lille, USTL). This
project was supported by Conseil Régional Nord-Pas de Calais,
DRRT PRIM 2008-07 PRIM-SP.

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567
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Supplementary data
Supplementary data (detailed synthesis and spectral data for all
compounds) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.tetlet.2012.11.082.
10. Jida, M.; Deprez-Poulain, R.; Malaquin, S.; Roussel, P.; Agbossou-Niedercorn, F.;
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References and notes
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20. Library synthesis (15 lmol-scale). After checking the solubility of reagents,
0.25 M solutions of keto-acids and binucleophiles are prepared in water or in a
mixture of water and ethanol (50/50). The drying-oven is preheated and the
reagents stock-solutions are placed on the liquid-handling system. In each
well, 60 lL (15 lmol) of the solution of binucleophiles are deposited by the
liquid-handling system. CAUTION: It is necessary to change the value of the
dispense speed between the solution of water and the solution with ethanol to
avoid projections. Tips are then washed. In each well, 60 lL (15 lmol) of the
solution of keto-acids are deposited by the liquid-handling system. Then, the
96-well plate is placed on the stove at 100 °C. After 16 h, the plate is removed
from the stove. The completion of the reaction is checked by LCMS.
21. Based on a search in Reaxys database as of November 2012. See Supplementary
data.