Organocatalytic conjugate addition of malonates to α,β- unsaturated aldehydes: Asymmetric formal synthesis of (-)-paroxetine, chiral lactams, and lactones

Article abstract of DOI:10.1002/anie.200601025

(Chemical Equation Presented) In addition: The scope of the title reaction is demonstrated by the synthesis of chiral lactones and lactams. The latter class of compounds is very important for the preparation of the pharmaceutical compounds such as (-)-par

Full text of DOI:10.1002/anie.200601025

Angewandte
Chemie
Organocatalysis
DOI: 10.1002/anie.200601025
Organocatalytic Conjugate Addition of
Malonates to a,b-Unsaturated Aldehydes:
Asymmetric Formal Synthesis of (À)-Paroxetine,
Chiral Lactams, and Lactones**
Sven Brandau, Aitor Landa, Johan FranzØn,
Mauro Marigo, and Karl Anker Jørgensen*
Chiral lactones and lactams are endowed with a large
spectrum of biological properties[1] including very important
pharmaceutical activities.[2] The chiral piperidines (À)-
paroxetine hydrochloride 1, marketed as paxil/seroxat, and
(+)-femoxetine 2 are selective serotonin reuptake inhibitors
and are used in the treatment of depression, obsessive-
compulsive disorder, and panic (Figure 1).[3] The nonpeptide
Figure 1. Antidepressants (À)-paroxetine 1, (+)-femoxetine 2, and
peptidomimetic inhibitor Roche-1 3.
peptidomimetic type III inhibitor of renin, the piperidine
Roche-1 3, was found to stabilize an enzyme conformation
not previously observed for this enzyme.[4] All these com-
pounds consist of a phenyl piperidine core structure with two
trans-related substituents at C3 and C4. However, (À)-
paroxetine 1 possesses the opposite enantiomeric configura-
tion relative to (+)-femoxetine 2 and Roche-1 3.
The synthesis of the antidepressants (À)-paroxetine 1 and
(+)-femoxetine 2 is focused on enzymatic asymmetric desym-
metrization,[3a,5] chiral auxiliary-assisted,[6] or asymmetric
[*] Dr. S. Brandau, Dr. A. Landa, Dr. J. FranzØn, Dr. M. Marigo,
Prof. Dr. K. A. Jørgensen
The Danish National Research Foundation: Center for Catalysis
Department of Chemistry
Aarhus University
8000 Aarhus C (Denmark)
Fax: (+45)8919-6199
E-mail: kaj@chem.au.dk
[**] This work was made possible by a grant from The Danish National
Research Foundation. A.L. thanks Eusko Jaurlaritza/Gobierno Vasco
for financial support (postdoctoral fellowship). J.F. thanks The
Wenner–Gren Foundation for a grant. Thanks are expressed to Dr.
JacobOvergaard from the Department of Chemistry, Aarhus
University for performing the X-ray crystal structure analysis.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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4305

Communications
deprotonation[7] reactions. The total synthesis of these chiral
Table 1: Solvent screening for the addition of dibenzyl malonate 8a to
cinnamaldehyde 7a.
compounds consists of approximately 12–14 steps. Herein we
present a novel approach, based on organocatalysis employ-
ing chiral proline-derived catalysts, for a new, short, and
simple methodology for the synthesis of chiral lactams and
lactones of which the former can be converted to the phenyl
piperidine serotonin reuptake inhibitors.
The retrosynthetic analysis of (À)-paroxetine 1 and (+)-
femoxetine 2 leads to the phenyl piperidinone core structure
5, which can be synthesized by a reductive amination
sequence, starting from the optically active aldehyde 6
(Scheme 1). Moreover, compound 6 is also a precursor for
Entry
Solvent
Conversion [%][b]
Yield [%][c]
ee [%][d]
1
2
CH2Cl2
Et2O
0
0
–
–
-
-
3
4
5
6
CH3CN
DMSO
n-hexane
H2O
45
46
26
12
–
–
81
–
28[e]
–
–
–
7
8
9
10
11
(CH3)2CO
MeOH
EtOH
nPrOH
iPrOH
<5
70
100
48
–
–
46[e]
80
24[e]
–
92
91
86
–
<5
[a] All reactions were performed on
a 0.25 mmol scale. [b] The
1
conversion of 7a into 6a was estimated by H NMR spectroscopy after
4 days at 08C. [c] Yield of the isolated product. [d] Determined by chiral
HPLC after oxidation to the corresponding methyl ester. [e] Yield after
oxidation.
Scheme 1. Retrosynthetic analysis.
The screening of the reaction conditions in Table 1 shows
that the reaction is very solvent dependent. Primary alcohols
are the optimal solvent and the best results are obtained in
MeOH and EtOH; in the latter solvent, full conversion is
found after 4 days giving an 80% yield of the addition product
6a with an enantiomeric excess of 91% ee (Table 1, entry 9).
A slightly higher enantioselectivity (92% ee) is obtained in
MeOH (Table 1, entry 8); however, the conversion is much
lower compared to EtOH. In nPrOH, a high enantioselectiv-
ity is also found (86% ee) (Table 1, entry 10), but in this
solvent a low conversion and yield have also been observed. It
is notable that in all the other solvents, with the exception of
dimethylsulfoxide (DMSO; Table 1, entry 4), no or low
conversion is observed.
The reaction proceeds especially well for malonate
derivatives with benzyl and methyl esters, 8a,b (Table 2,
entry 1, 2). For the ethyl ester 8c, a lower yield is obtained
(Table 2, entry 3), whereas no conversion is observed for the
isopropyl ester 8d (Table 2, entry 4). For the unsymmetrical
malonate 8e in Table 2, entry 5, a nondiastereoselective
reaction takes place. The scope of the organocatalytic
enantioselective addition of the dibenzyl 8a and dimethyl
malonates 8b to a number of different aromatic a,b-
unsaturated aldehydes 7a–k catalyzed by (S)-10 and (R)-10
is presented in Table 3.
the formation of chiral lactones 9, which are accessible
through a reductive cyclization sequence. The formation of
optically active 6 is derived from a conjugate addition
reaction of malonates 8 to a,b-unsaturated aldehydes 7. To
date, no asymmetric organocatalytic reaction is reported for
the conjugate addition of malonates to a,b-unsaturated
aldehydes.[8,9]
The field of organocatalysis is a rapidly progressing area[10]
and a large number of new asymmetric reactions have been
developed. For the addition of nucleophiles to a,b-unsatu-
rated compounds, a variety of different nucleophiles have
been added to, for example, a,b-unsaturated aldehydes.[11]
However, according to our knowledge, nucleophiles such as
malonates that use iminium ion activation have only been
added enantioselectively to a,b-unsaturated ketones.[12]
Herein we will present the development of the first organo-
catalytic enantioselective addition of malonates to aromatic
a,b-unsaturated aldehydes[13] with the purpose of creating a
simple approach to optically active lactams and lactones, and
also to show the potential of this new reaction for the
formation of very important pharmaceutical compounds.
The organocatalytic enantioselective addition of malo-
nates to aromatic a,b-unsaturated aldehydes was initially
developed by reaction of cinnamaldehyde 7a with dibenzyl
malonate 8a in different solvents at 08C by using the l-
proline derivative (S)-2-[bis(3,5-bistrifluoromethylphenyl)tri-
methylsilanyloxymethyl]pyrrolidine (S)-10[11c,d,m,14] as the cat-
alyst (Table 1).
The results in Table 3 show the generality of this conjugate
addition reaction with regard to aromatic a,b-unsaturated
aldehydes. Very good to excellent enantioselectivities were
obtained for all the addition products 6 ranging from 86–95%
ee. The addition of malonates to the aromatic a,b-unsaturated
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Table 2: Screening of various malonates for the organocatalytic addition
to cinnamaldehyde 7a.[a]
tional aldehydes are tolerated well in this reaction giving the
addition products in high yields up to 95% and enantiose-
lectivities up to 92% ee (Table 3, entry 12, 15). Use of the
catalyst (R)-10 for the addition of dibenzyl malonate 8a to
cinnamaldeyde 7a afforded the enantiomeric (S)-configu-
rated product 6a in 75% yield and with an enantiomeric
excess of 90% ee (Table 3).
The absolute configuration of the addition products 6 was
confirmed by a single-crystal X-ray analysis of the methyl
ester 11k obtained by oxidation of 6k (Figure 2).[15] The
Entry
R1
R2
Yield [%][b]
d.r.[c]
ee [%][d]
1
2
3
4
5
Bn
Me
Et
iPr
Bn
Bn—8a
Me—8b
Et—8c
iPr—8d
Me—8e
6a—80
6b—85
6c—42
6d—0
–
–
–
–
91
94
89
–
6e—nd[e]
1:1
nd
[a] All reactions were performed on a 0.25 mmol scale. [b] Yield of the
isolated product. [c] Estimated by 1H NMR spectroscopy. [d] Determined
by chiral HPLC after oxidation to the corresponding methyl ester. [e] No
full conversion after 96 h.
Table 3: Reaction of dibenzyl 8a and dimethyl malonates 8b with
different aromatic aldehydes 7a-k catalyzed by (S)- and (R)-10.[a]
Figure 2. X-ray crystal structure of (R)-2-benzyloxycarbonyl-3-(4-chloro-
phenyl)petanedioic acid 5-benzyl ester 1-methyl ester, 11k.
optically active compounds 6, which are formed by the
organocatalytic addition of dimethyl malonate 8b to a,b-
unsaturated aldehydes 7, are valuable precursors for the
formation of chiral lactones 9 (Scheme 1). In a reduction–
cyclization procedure, the aldehyde function is reduced with
NaCNBH3 to the alcohol and then, in the presence of silica, a
stereoselective cyclization reaction to the desired lactone
takes place (Scheme 2).[16] We obtained the diastereomeri-
Entry
R1
R2
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Ph—7a
Ph—7a
Ph—7a
Bn—8a
Bn—8a
Me—8b
Bn—8a
Me—8b
Bn—8a
Bn—8a
Me—8b
Bn—8a
Bn—8a
Bn—8a
Bn—8a
Bn—8a
Bn—8a
Bn—8a
6a—80
6a—75
6b—85
6 f—84
6g—31
6h—34
6i—93
6j—73
6k—85
6l—76
6m—72
6n—95
6o—95
6p—69
6q—83
91
(À)90[d]
94
p-BrPh—7b
p-BrPh—7b
o-BrPh—7c
p-MeOPh—7d
p-MeOPh—7d
p-ClPh—7e
p-PhPh—7 f
p-FPh—7g
p-CHOPh—7h
p-CH3Ph—7i
2-Np—7j
90
95
88
92
90
86
89
86
86
88
88
92
Scheme 2. Synthesis of chiral lactones 9. Reagents: a) NaCNBH3,
AcOH, THF; b) SiO2, CH2Cl2.
2-Thiophene—7k
cally pure trans-lactones 9 in good yields and excellent
enantioselectivities of up to 93% ee. However, we observed a
minor loss of chirality of up to 2% ee during these reactions.
The trans relationship of the substituents at C2 and C3 was
[a] All reactions were performed on a 0.25 mmol scale. [b] Yield of the
isolated product. [c] Determined by chiral HPLC after oxidation to the
corresponding methyl ester. [d] (R)-2-[bis(3,5-bistrifluoromethylphenyl)-
trimethylsilanyloxymethyl]pyrrolidine (R)-10 used as the catalyst.
3
confirmed by the J coupling constants of the protons at C2
1
and C3 in the H NMR spectra, showing a value of 10.5 Hz
(9a) and 10.9 Hz (9b), respectively.
aldehydes tolerates many functional groups in the p- or o-
position of the aromatic ring, however, owing to steric
interaction of the o-substituent (7c) to the malonate during
the addition, a lower yield of 6h is obtained (Table 3, entry 6).
It is important to notice that aside from halogens, ethers,
phenyl, and alkyl substituents, heteroaromatics and addi-
Compound 6 is also the building block for chiral lactam
12, which can be easily synthesized by a reductive amination–
cyclization sequence (Scheme 3).[17] We applied a tandem
procedure of three reaction steps: imine formation, reduction,
and lactamization, yielding the lactam 12 in 70% overall yield
with an excellent diastereomeric ratio of 13:1 referring to the
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Communications
unsaturated aldehydes resulting in the addition products in
good yields and very good to excellent enantioselectivities.
Furthermore, we developed new procedures for the forma-
tion of chiral lactones and lactams. These reactions proceed in
a highly stereoselective manner leading to a simple synthesis
of (À)-paroxetine in six steps overall and (+)-femoxetine in
seven steps overall.
Experimental Section
General procedure for the organocatalytic addition of malonates to
a,b-unsaturated aldehydes: 10 (15.0 mg, 0.025 mmol, 0.1 equiv) was
added to a stirred ice-cooled (08C) solution of the a,b-unsaturated
aldehyde 6 (0.50 mmol, 2.0 equiv) in solvent (1.0 mL) followed by the
addition of malonate (0.25 mmol, 1.0 equiv). The reaction mixture
was stirred for 96 h at 08C and then filtered through 1–2 cm bed of
silica that was then washed through with Et2O and CH2Cl2. The
solvents were evaporated under vacuum. The crude product was
subjected to flash chromatography on silica gel (Et2O/n-pentane/
CH2Cl2 1:10:0.1) to yield the desired addition product.
Scheme 3. Synthesis of (À)-paroxetine 1. Reagents: a) PhCH2NH2,
NaBH(OAc)3, dioxane, 70%; b) LiAlH4, THF, D, 85%.
trans-lactam. The trans position of the substituents at C3 and
1
C4 was confirmed by H NMR spectroscopy. Lactam 12 has
previously been transformed to (À)-paroxetine hydrochloride
1 in four steps (Scheme 3):[3a,6b,d,7b] Reduction of 12 with
LiAlH4 to give 13 in 85% yield as one diastereomer,
etherification with sesamol, and hydrogenolysis of the
benzyl group furnished (À)-paroxetine hydrochloride 1. The
2-step asymmetric synthesis of 12 leads to (À)-paroxetine
hydrochloride 1 in sixsteps overall.
Received: March 15, 2006
Published online: April 28, 2006
Keywords: asymmetric synthesis · lactams · lactones ·
.
malonates · organocatalysis
Changing the catalyst for the malonate addition from (S)-
2-[bis(3,5-bistrifluoromethylphenyl)trimethylsilanyloxymeth-
yl]pyrrolidine, (S)-10, to (R)-2-[bis(3,5-bistrifluoromethyl-
phenyl)trimethylsilanyloxymethyl]pyrrolidine, (R)-10, yields
the Michael adduct 6a and gives us the opportunity to
synthesize the precursor for the chiral piperidine (+)-
femoxetine 2 (Scheme 4) and (+)-paroxetine hydrochloride
1. For the synthesis of (+)-femoxetine 2, 6a was transformed
in a one-pot procedure to the trans-lactam 14 in 68% overall
yield and with a diastereomeric ratio of 12:1. It has been
reported that (+)-femoxetine 2 can be formed by subsequent
reduction with LiAlH4 in THF to give the piperidine 15 in
75% yield and as one diastereomers that can be converted to
the desired product (+)-femoxetine 2.[3a,7a]
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Scheme 4. Synthesis of (+)-femoxetine 2. Reagents: a) PhCH2NH2,
NaBH(OAc)3, dioxane, 68%; b) LiAlH4, THF, D, 75%.
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