Multicomponent reactions for the synthesis of complex piperidine scaffolds

Article abstract of DOI:10.1002/anie.200806065

Creating diversity: Multicomponent reactions for the synthesis of complex piperidine scaffolds lead to high levels of skeletal, functional, and stereochemical diversity in an efficient way (see scheme, X=OR, NR₂). Connecting the acid chloride c

Full text of DOI:10.1002/anie.200806065

Communications
DOI: 10.1002/anie.200806065
Synthetic Methods
Multicomponent Reactions for the Synthesis of Complex Piperidine
Scaffolds**
Wei Zhu, Marisa Mena, Eric Jnoff, Na Sun, Patrick Pasau, and Lꢀon Ghosez*
The structures of small natural molecules have been opti-
mized by evolution and are therefore tailored to interact with
natural macromolecules to induce a biological response.[1]
They represent an invaluable resource in the discovery
process of new therapeutic agents. Since the natural product
is usually not endowed with the biological properties desired
for a chemotherapeutic agent, a series of skeletal and
stereochemical analogues have to be generated by using
synthesis. A promising strategy (diverted total synthesis,
DTS)[1g] involves the production of a set of advanced
intermediate scaffolds by using a multicomponent reaction
(MCR)[2] and subsequent transformations to additionally
increase the molecular complexity and diversity. Polysubsti-
tuted piperidines are common subunits in natural alkaloids
and many biologically relevant molecules, representing
attractive scaffolds for the production of natural product
analogues having interesting biological profiles. To the best of
our knowledge there are only a few MCRs for the con-
struction of structurally and stereochemically diverse poly-
substituted piperidine derivatives.[3] Some years ago we
reported a new synthesis of polysubstituted piperidines by
using the Diels–Alder reactions of 3-trialkylsilyloxy-2-aza-
dienes with electron-poor olefins (Scheme 1).[4] These dienes
were prepared from the reaction of acid chlorides with N-
trialkylsilylimines derived from non-enolizable aldehydes.[5]
The drawback of the method resulted from the thermal
instability of the azadienes, which are very reactive towards
electrophilic reagents and either cyclize[6] or decompose upon
distillation. This instability resulted in severe limitations of
the type of functional groups that could be introduced into the
cycloadducts.
Scheme 1. Sequence of five reactions leading to piperidone scaffolds.
TMS=trimethylsilyl, X=alkoxy, amide.
We envisioned the synthesis of the diene and the cyclo-
addition reaction in a single operation.[7] This four-component
process[2b] involving the combination of readily available
reactants (aldehyde, equivalent of ammonia, acyl chloride,
and dienophile) should allow the incorporation of high levels
of skeletal, functional, and stereochemical diversity in the
piperidone products (Table 1).
To establish the experimental conditions of this MCR we
first prepared piperidone 1a (Table 1, entry 1), which we had
previously[4b] synthesized by reacting the purified 2-azadiene
with trans-methyl crotonate. The sequential addition of
benzaldehyde, LiHMDS, and propionyl chloride in the
presence of triethylamine in toluene generated the inter-
mediate azadiene in situ. Then the cycloaddition, with
moderately active dienophiles like trans-methyl crotonate,
proceeded in refluxing toluene for a few hours, after which the
triethylamine hydrochloride had to be filtered off to avoid
competitive decomposition of the basic azadiene. Therefore,
petroleum ether was first added to the precipitate triethyl-
amine hydrochloride and then the filtrate was treated with
trans-methyl crotonate and heated to reflux, and then the
addition of methanol gave piperidone 1a. This simple
procedure gave a much better yield (75%) than the earlier
method using a purified azadiene (33% yield).[4b] When the
MCR involved a more reactive dienophile (Table 1, entries 5
and 6), the reaction was conducted in one pot without the
addition of petroleum ether and filtration of the triethylamine
salt.
[*] Dr. W. Zhu, Dr. M. Mena, Dr. N. Sun, Prof. Dr. L. Ghosez
Institut Europꢀen de Chimie et Biologie
Universitꢀ de Bordeaux CNRS UMR 5248 2,
Rue Robert Escarpit, 33607 Pessac (France)
Fax: (+33)5-4000-2215
E-mail: l.ghosez@iecb.u-bordeaux.fr
Dr. E. Jnoff
Department of Chemistry, University of Louvain
Place L. Pasteur, 1, 1348 Louvain-la-Neuve (Belgium)
Dr. P. Pasau
UCB S.A., Chemin du Foriest
1420 Braine l’Alleud (Belgium)
There are interesting aspects to this one-pot four-compo-
nent piperidone synthesis (Table 1). The scope of the method
was considerably expanded by making possible the introduc-
tion of functional groups or substituents which would have
prevented the isolation and purification of the corresponding
2-azadienes. A variety of functional groups were tolerated at
C4 (Table 1, entries 4–6) and C5 (Table 1, entries 5 and 6).
[**] This work was generously supported by UCB S.A. and IECB. We
thank K. Bathany (mass spectra), A. Grelard (NMR), and B.
Kauffmann (X-ray diffraction analyses) for their assistance and P.
Talaga for his support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200806065.
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Table 1: Four-component synthesis of piperidone scaffolds involving an intermolecular Diels–Alder
reaction.
substituent which was readily trans-
formed into a ketone by ozonolysis
(Scheme 2). This additionally
increases the power of the method
for the construction of complex
heterocyclic molecular skeleton as
shown by the formation of the
tetracyclic molecule 3 when the
MCR is used in combination with
three additional steps.
The MCR also allowed the cre-
ation of four stereogenic centers
with the same stereochemical
Entry
Product 1[a]
Yield exo/endo[c]
Components[d]
[%][b]
A
C
D
dichotomy
that
had
been
observed[4] for related reactions
involving pure 2-azadienes: cyclic
dienophiles yielded endo adducts
(Table 1, entries 6 and Scheme 2,
product 1g) whereas acyclic dieno-
philes gave exo adducts (Table 1,
entries 1–4) as major stereoisomers.
However, when the diene carried a
large substituent at C5, the major
isomer resulted from an exo addi-
tion even with a cyclic dienophile
(Table 1, entry 5). In all cases the
configurations of both the diene
and dienophile were retained in
the adducts.
The four-component reaction
was applied to the preparation of
the spirolactam 6 in 50% yield by
reacting aldehyde 4, LiHMDS,
acetyl chloride, and dienophile 5
(Scheme 3). By using a subsequent
mesylation of the alcohol and intra-
molecular alkylation of the spiro-
lactam nitrogen atom, the molecu-
lar complexity of the product
increased; pentacyclic compound 7
(81% for 2 steps), which is an
advanced intermediate for the
diverted synthesis of analogues of
aspidosperma alkaloids,[8] was iso-
lated.
1
1a
1b
1c
1d
75
75
65
42
>99:1
EtCOCl
EtCOCl
EtCOCl
EtCOCl
2
3
4
10:1
>99:1
>99:1
5
6
1e
1 f
65[e]
1.9:1
60[e]
<1:99
AcOCH2COCl
Connecting the carboxylic acid
chloride component to the dieno-
phile[9] resulted in two rings by
virtue of an intramolecular Diels–
Alder reaction of the in situ gener-
ated azadienes (Table 2). In all
cases the cycloaddition reaction
[a] Only the major product is shown. [b] Combined yields of exo and endo products. [c] Ratios
determined by H NMR analysis based on the crude products. [d] Component B was LiHMDS in all
cases. [e] The reaction was run at room temperature. HMDS=hexamethyldisilazide, X=alkoxy, amide.
1
The presence of an ortho-functionalized phenyl group (e.g., a
nitro group, Table 1, entry 2) or a reactive heterocycle (e.g.,
an indole ring, Table 1, entry 3) at C2 permitted the con-
struction of an additional ring. In contrast alkyl groups at C2
were not accessible because the MCR failed using an
aldehyde having an a-hydrogen atom. This limitation could
be overcome by the introduction of an (E)-2-alkyl-cinnamyl
was extremely fast and could be conducted in one pot. The
scope of the reaction sequence was very broad, allowing the
preparation of diversely functionalized piperidine rings fused
to a five- or six-membered ring. As expected, the absolute
configurations of the diene and dienophile substituents were
maintained in the products. Two NMR features permitted the
establishment of the endo or exo configurations of the
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Table 2: Three-component synthesis of polycyclic piperidine scaffolds
involving an intramolecular Diels–Alder reaction.
Entry
Product 1[a]
Yield exo/
Components[d]
[%][b] endo[c]
A
C
1
1h 73 <1:99
Scheme 2. Sequential MCR/ozonolysis/aromatization/condensation.
2
3
1i
92 <1:99
1j
85 <1:99
Scheme 3. Synthesis of an advanced intermediate for diverted syn-
thesis of aspidosperma alkaloid analogues. TBS=tert-butyldimethyl-
silyl, Ts=4-methyltoluenesulfonyl, TBAF=n-tetrabutylammonium fluo-
ride, Ms=methanesulfonyl.
4
5
1k 50
1.6:1
3:1
products: 1) the NMR chemical shifts of the vicinal protons at
C2 and C3, which are shielded in the exo isomers, and 2) the
coupling constant between these protons, which are larger for
the exo products. The structural and stereochemical assign-
ments were confirmed by X-ray diffraction analyses of
products 1h and 1k.[10]
1l
30
[a] Only the major product is shown. [b] Combined yields of exo and
endo products. [c] Ratios determined by H NMR analysis based on the
crude products. [d] Component B was LiHMDS in all cases. X=alkoxy.
1
The stereochemical outcome of the cycloaddition step
varied with the nature of the aldehyde. Combining o-nitro-
benzaldehyde or N-tosyl-2-indole aldehyde with a trans-
unsaturated ethyl ester led to a high endo selectivity (Table 2,
entries 1–3) and a trans fusion of the two rings. In contrast, the
combination of 2-chlorocinnamaldehyde with a trans-unsatu-
rated ester (Table 2, entries 4 and 5) gave the exo adduct as
the major isomer and a cis fusion of the two rings. Given the
limited number of cases, it would be premature to propose a
rational for these stereochemical differences. However, the
results are quite promising in terms of the possible incorpo-
ration of stereochemical diversity into the products 1. Entry l
of Table 2 shows that the MCR could be applied to the
synthesis of an advanced scaffold for producing analogues of
dendrobatid alkaloid 251F.[11]
In summary, we have demonstrated that the MCR for
making piperidine scaffolds is considerably expanded in scope
compared to the earlier method involving the isolation of 2-
azadienes. Attractive features of this MCR are its versatility,
convenience (it uses simple and often commercially available
material), and efficiency in creating skeletal, functional, and
stereochemical complexity in a single operation. Awide range
of piperidine scaffolds can be prepared having a substitution
pattern controlled by the selection of the reactants. A variety
of functionalities are tolerated, making possible additional
transformations into diverse mono-and polycyclic piperidine
derivatives. The stereochemical course of the reaction can be
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Received: December 12, 2008
Revised: February 17, 2009
Published online: March 23, 2009
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Keywords: cycloadditions · diversity-oriented synthesis ·
multicomponent reactions · heterocycles
.
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