A simple reaction to produce small structurally complex and diverse molecules

Article abstract of DOI:10.1016/j.tetlet.2004.05.008

In order to mimic the complexity of natural products, we designed and obtained with simple synthetic methods, building blocks with 'quaternary chiral centers'. These tricyclic lactams resulted from the reaction of a functional γ-keto-acid and various comm

Full text of DOI:10.1016/j.tetlet.2004.05.008

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5287–5290
A simple reaction to produce small structurally complex
and diverse moleculesq
Rebecca Deprez-Poulain,a Nicolas Willand,b Christophe Boutillon,b Guy Nowogrocki,c
Nathalie Azarouald and Benoit Depreza,*
aLaboratoire de Chimie Gꢀenꢀerale (UMR8525), Facultꢀe des Sciences Pharmaceutiques et Biologiques de Lille, 3 rue du Pr Laguesse,
F-59006 Lille cedex, France
bLaboratoire de Chimie Organique (UMR8525), Facultꢀe des Sciences Pharmaceutiques et Biologiques de Lille, 3 rue du Pr Laguesse,
F-59006 Lille cedex, France
cLaboratoire de Cristallochimie et Physicochimie du Solide, CNRS UMR 8012, USTL, Citꢀe Scientifique F-59655,
Villeneuve d’Ascq cedex, France
dLaboratoire de Biophysique (UMR8009), Facultꢀe des Sciences Pharmaceutiques et Biologiques de Lille, 3 rue du Pr Laguesse,
F-59006 Lille cedex, France
Received 22 January 2004; revised 3 May 2004; accepted 4 May 2004
Abstract—In order to mimic the complexity of natural products, we designed and obtained with simple synthetic methods, building
blocks with ‘quaternary chiral centers’. These tricyclic lactams resulted from the reaction of a functional c-keto-acid and various
commercially available bi-nucleophiles.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
building blocks. In particular, we focused on bi- and tri-
cyclic lactams obtained from c-keto-acid and bi-nucleo-
philes. The reaction proceeds in a condensation of
various chiral b-amino-alcohols with a linear or cyclic
nonchiral or racemic c-keto-acid. Thanks to the
deracemization of the tertiary carbon atom in a-position
relative to the keto group, the reaction produces only
one diastereoisomer, in a very stereoselective manner.7
Meyers and other groups have extensively developed the
use of bi-cyclic lactams as useful intermediates to gen-
erate highly stereoselective heterocycles, like chiral
pyrrolidines.7–12
Nature has always provided valuable leads for the
development of new drugs.1 Since 1980, the develop-
ment of combinatorial and parallel synthesis has led to
the accumulation of chemical libraries, either diverse or
focused. These libraries usually lack natural templates,
whose complex synthesis cannot be achieved using
simple automated reactions. In order to enhance the
value of hit-seeking libraries for biological screening,
many groups are developing strategies for parallel syn-
thesis of ‘natural privileged structures’.2–6
In our on-going interest to incorporate more value into
chemical libraries made in parallel, we investigate the
design and synthesis of complex, chiral and reactive
We used the commercially available chiral c-keto-acid 1
(Fig. 1).13 This precursor presents several advantages.
(1) It displays three functional groups: ketone, carboxy-
lic acid, nitromethyl; (2) it is a pure enantiomer available
in bulk at low price; (3) it has a low molecular
weight. To our knowledge, only one group has used
chiral cyclic c-keto-acids to obtain complex fused
heterocycles.14;15
Keywords: Building blocks; Tricyclic lactams; c-Keto-acid.
q Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2004.05.008
From compound 1, we thus synthesized 7 nitromethyl-
lactams and validated their conversion into amine
*Corresponding author. Tel.: +33-3-2096-4024; fax: +33-3-2096-4709;
e-mail: bdeprez@pharma.univ-lille2.fr
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.008

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R. Deprez-Poulain et al. / Tetrahedron Letters 45 (2004) 5287–5290
2. Synthesis of tri-cyclic lactams
O
HO
O
The complex lactams are synthesized in a one-step
procedure as described in Scheme 1 (step a). Tables 1–3
summarize the results of syntheses achieved and
attempted.
NO2
1
Compound 1 reacted with chiral amino-alcohols with
good to high yields (68–85%) to give the desired tri-
cyclic lactams (2a–5a, Table 1). The b-amino-alcohols
were selected for (1) their availability and (2) the posi-
tion and orientation of the aromatic group relative to
both the semi-rigid lactam skeleton and the masked
amino function (NO2). Other b-amino-alcohols readily
obtained from natural a-amino-acids could also be used,
to access a chemically diverse platform. To further
explore the scope of this reaction, we investigated other
bi-nucleophiles that would allow the synthesis of ana-
logues. In particular, two derivatives of a-amino-acids
were tested, in order to introduce in the compounds
another chemical function (here a methyl ester) for
Figure 1.
building blocks. Central rigidity has been recognized as
a key feature controlling the bioavailability of drug
molecules.16 In this series, the diverse substituents are
projected in the three directions of space in a conform-
ationally restricted manner around the rigid cyclopen-
tane core. Moreover, the nitro group of the precursor
can easily be reduced to yield a primary amine that can
be reacted with diverse electrophiles. This makes them
suitable building blocks for parallel synthesis of complex
chemical libraries.
further derivatization (Table 2). While L-serine methyl
O
O
O
HO
NO2
O
NO2
NH2
H
H
NH2
N
N
a
b,c
*
*
*
*
*
R
+
*
*
R
R
X
X
XH
X = O,S
2a-7a
1
2b-6b
Scheme 1. (a) Molecular sieves, toluene, reflux, 2–6 h; (b) 5 eq Pd/C, ammonium formate, methanol, reflux, 2–4 h or Fe/HCl; (c) 5 eq HCl conc, THF,
reflux 2–4 h.
Table 1. Tri-cyclic lactam and amine building blocks synthesized from chiral b-amino-alcohols
Entry
b-Amino-alcohol
Tri-cyclic lactam
Amine building
block yield (%)
Structure
Yield (%)
68
O
O
H
NO2
1
(R)-Phenylglycinol
2a
––
N
O
O
H
NO2
2
(S)-Phenylglycinol
3a
84
3b 87a
N
H
O
NO2
N
3
4
(1R,2S) Norephedrine
4a
5a
O
80
85
4b 90b
O
H
NO2
L
(-)-3-Phenyl-2-amino-propan-l-ol
––
N
O
a As the chlorhydrate salt (two steps).
b As the free amine.

R. Deprez-Poulain et al. / Tetrahedron Letters 45 (2004) 5287–5290
Table 2. Tri-cyclic lactam and amine building block synthesized from a-amino-acids
5289
Entry
a-Amino-acid
Tri-cyclic lactam
Yield (%) (diastereoisomer ratio)
Amine building block yield (%)
Structure
––
1
L
L
-Serine
35 (two diastereoisomersa (50:50))
O
H
NO2
62 (one diastereoisomer)b
6b 98c
N
O
O
2
-Cysteine
6a
S
a In view of 1H NMR spectrum.
b Absolute stereochemistry determined by X-ray crystal analysis.
c As the chlorhydrate salt (one step).
Table 3. Tri-cyclic lactam synthesized from other bi-nucleophiles
lactam ring (Fig. 2). Noteworthy, this nucleophile leads
to a single diastereoisomer (7a), as o-amino-thiophenol
in a lesser extend.
A
B
O
O
NO2
H
NO2
H
N
N
These results demonstrate that it is possible to rapidly
obtain related tri-cyclic lactams and expand the chemi-
cal and stereochemical diversity of this series.
R
( )n
X
R
( )n
X
X = N; O; S and n = 1 or 2
Bi-nucleophile
Tri-cyclic
lactams A:B
ratioa
Yield (%)
3. Structure elucidation
1
2
3
4
5
6
(R)-2-Amino-1-phenylethanol
2-Amino-benzylalcohol
o-Amino-phenol
50:50
50:50
50:50
50:50
90:10
100:0
85
90
30
20
32
38
The absolute stereochemistry of compound 6a was
determined using X-ray crystal analysis, thanks to the
presence of the sulfur atom. The relative stereochemistry
of compounds 2a, 3a, and 7a was established by NMR-
ROESY experiments and X-ray crystal analysis. In
particular, the presence (dotted arrows) or absence of
NOE cross-peaks from the hydrogen atoms at C1, C2,
C3, and C8 (Fig. 3), have confirmed a relative stereo-
chemistry in agreement with Meyers’ observations for
compounds 2a and 3a. Relative stereochemistry of
compounds 4a and 5a (Table 1) were assigned from
these preceding results.
o-Phenylenediamine
o-Amino-thiophenol
2-Amino-benzylamine
O
NO2
H
N
N
H
7ab
a In view of 1H NMR spectrum and/or LCMS.
b Relative stereochemistry determined by X-ray crystal analysis.
ester gave two diastereoisomers, the reaction of L-cys-
4. Synthesis of the building blocks
teine methyl ester with compound 1 gave only lactam 6a
in a good yield. We hypothesized that the Ca of the
amino-acid function racemizes at different rates in serine
and cysteine.
The conversion of the nitromethyl group into a reactive
aminomethyl group was validated for three tricyclic
lactams (Scheme 1). The reduction proceeds easily with
Experiments with other nonchiral bi-nucleophiles (Table
3) led most of the time to the expected mixture of di-
asteroisomers. Interestingly, the reaction with 2-amino-
benzylamine is regioselective since the tri-cyclic lactam
(7a) displays the benzylamine moiety involved in the
O
7
6
H
1
N
H
5
8
2
CH2 NO2
O
4
3
H
9
2a
O
O
NO2
H
O
NO2
N
H
*
6
7
N
*
*
H
1
*
N
N
H
8
H
5
O
N
2
CH2 NO2
H
3
H
4
not observed
9
3a
Figure 2. Possible regioisomers resulting for the reaction of 1 with
2-amino-benzylamine.
Figure 3.

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R. Deprez-Poulain et al. / Tetrahedron Letters 45 (2004) 5287–5290
ꢀ
We are grateful to Fabien Fecourt and Axelle Moine for
technical assistance.
Pd/C and ammonium formate, except for the sulfur-
containing derivative 6a for which, expectedly, the
reaction is not complete. Compound 6b was thus
obtained via a reduction with Fe and HCl in methanol,
yielding the desired compound as a HCl salt. Compound
4b was stored as a free base, whereas compound 3b was
transformed into a HCl salt.
References and notes
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5. Conclusion
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We developed a procedure to obtain complex tricylic
building blocks useful as reactants in parallel synthesis
of chemical libraries. The key precursor is the c-keto-
acid 1 that is accessible in large quantities. The synthesis
is versatile enough to allow the use of a variety of
b-amino-alcohols (symmetrical or chiral), as well as
adequate derivatives of natural and other, non-chiral,
bi-nucleophiles. We are now focusing on synthesizing
b-amino-alcohols from chiral a-amino-acids to improve
the diversity of the final building blocks. Compound 6a
is of particular interest since it displays two functional
groups (amine and methyl ester), for a moderate
molecular weight. We are currently investigating its
incorporation into complex chemical libraries.
Material
13. For synthesis of close analogues that are precursors of
prostaglandines, see works at Hoffmann–La Roche: (a)
Kienzle, F.; Holland, G. W.; Jernow, J. L.; Kwoh, S.;
Rosen, P. J. Org. Chem. 1973, 38, 3440–3442; (b) Coffen,
D. L.; Holland, G. W.; Rosen, P.; Wong, F. U.S. Patent
4558140, 1985.
Supplemental material contains the chemical procedures
and the characterization of all the compounds synthe-
sized. The crystallographic data for compounds 2a, 3a,
6a, and 7a is also given (.cif).
ꢀ
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ꢀ
The authors would like to thank Pr. Andre Tartar and
Pr. Jean-Claude Gesquiere for thoughtful discussions.
ꢁ