Contact ion pair directed Lewis acid catalysis: Asymmetric synthesis of trans-configured β-lactones

Article abstract of DOI:10.1002/anie.200801143

Opposites attract. A novel concept for dual-activation catalysis takes advantage of the cooperative action of aprotic contact ion pair catalysis and Lewis acid catalysis. This strategy was used for the first trans-selective catalytic asymmetric [2+2] cycl

Full text of DOI:10.1002/anie.200801143

Angewandte
Chemie
DOI: 10.1002/anie.200801143
Dual-Activation Catalysis
Contact Ion Pair Directed Lewis Acid Catalysis: Asymmetric Synthesis
of trans-Configured b-Lactones**
Thomas Kull and RenØ Peters*
Dedicated to Professor Sir Jack Baldwin
b-Lactones readily undergo nucleophilic ring-opening reac-
tions as a result of their intrinsic ring strain and thus behave as
activated aldol equivalents.[1] Various hard nucleophiles such
as metal alcoholates, amines, and C nucleophiles can regio-
selectively cleave the acyl–oxygen bond providing the corre-
sponding aldol adducts.[1,2] Consequently, the development of
catalytic asymmetric [2+2] cycloadditions of ketenes[3] and
aldehydes[4–7] offers an alternative to catalytic asymmetric
ester and amide aldol reactions, which in most cases require
the preformation and isolation of enolate equivalents such as
silyl ketene acetals.[8]
process was based upon the initial idea that if enolate 5, and
not ketene 4, represents the reactive intermediate, the trans-
configured product would be expected to be formed in
preference (Scheme 1). The enolate would undergo an
b-Lactones are not only very useful building blocks, but
also represent a structural motif in a number of important
natural and synthetic bioactive products such as the anti-
obesity drug tetrahydrolipstatin (Xenical, F. Hoffmann-La
Roche). The majority of these bioactive compounds have a
trans configuration about the heterocyclic system.[9] Unfortu-
nately, almost all of the known catalytic asymmetric [2+2]
cycloadditions using substituted ketene substrates provide
preferentially the cis isomers. To our knowledge, there is only
one [2+2] cycloaddition available for the catalytic enantiose-
lective formation of trans-configured b-lactones.[7b] This
conversion is limited though to the use of aromatic aldehydes,
whereas most bioactive systems such as Xenical contain an
aliphatic chain at the 4-position of the 3,4-disubstituted
oxetanone.[10–13]
Scheme 1. Initial working hypothesis for the trans-selective catalytic
asymmetric formation of b-lactones (LA=Lewis acid).
enantioselective aldol addition to the aldehyde, which is
activated by coordination to a chiral Lewis acid. The resulting
acyl halide alcoholate 6 would subsequently experience a
dehydrohalogenation to give the hydroxyalkyl-substituted
ketene 7, which in turn could cyclize to form the thermody-
namically more stable trans-configured product. The key
aspect is then that the enolate, which should be present at
least in small quantities in equilibrium with ketene 4,[15] would
have to react faster than the ketene intermediate 4 itself.
Since this preference is usually not observed, the enolate
would have to be further activated and/or generated by the
catalyst.
To realize this idea, the anionic nucleophile might be
directed by the formation of a contact ion pair (CIP) with a
positively charged aprotic functionality within the ligand
system, for example, by a quaternary ammonium moiety
(Figure 1). In contrast, protic cations might quench either the
anionic nucleophile or the Lewis acid after deprotonation by a
base, which is required to generate the enolate intermedi-
ate.[16] The new concept would thus have the principal
The aim of the present work was to develop a trans-
selective catalytic asymmetric [2+2] cyclocondensation of
acyl halides 1 and aliphatic aldehydes 2 which would thus
represent a surrogate for the rare type of catalytic enantio-
selective anti-aldol additions.[14] The development of this
[*] T. Kull, Prof. Dr. R. Peters
ETH Zürich, Laboratory of Organic Chemistry
Wolfgang-Pauli-Strasse 10, Hönggerberg HCI E 111
8093 Zürich (Switzerland)
Fax: (+41)446-331-226
E-mail: peters@org.chem.ethz.ch
Homepage: http://www.peters.ethz.ch
[**] This work was financially supported by F. Hoffmann-La Roche and
TH research grants TH-30/04-2 and TH-0107-1. We thank Priv.-
Doz. Dr. Martin Karpf and Dr. Paul Spurr (both F. Hoffmann-La
Roche, Synthesis and Process Research) for carefully reading this
manuscript and Reuter Chemische Apparatebau KG (Freiburg,
Germany) for the generous donation of enantiomerically pure 1,2-
diaminocyclohexane.
Supporting information for this article (including experimental
procedures) is available on the WWW under http://dx.doi.org/10.
1002/anie.200801143.
Figure 1. The concept of contact ion pair directed Lewis acid catalysis.
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advantage—over bifunctional Lewis acid/Lewis base cataly-
reactivity. Moreover, the enantioselectivity was significantly
improved, and the major enantiomer displays an inverted
absolute configuration. Most strikingly, the cationic ammoni-
um or heterocyclic functionalities provided high trans selec-
tivities (entries 4–8, Table 1). As a general trend, the enan-
tioselectivity was slightly reduced with increased steric bulk of
the cationic moiety. The planar pyridinium system 8g
possessing an sp2-hybridized N atom was the most selective
catalyst so far. One explanation may be that formation of the
contact ion pair with 8g might be more efficient than with
ammonium functionalities. Imidazolium derivative 8h, in
which the positive charge is delocalized over two N atoms, led
to significantly lower enantio- and diastereoselectivity as a
consequence of a less stable contact ion pair.
sis[17]—that the cationic functionality does not deactivate the
Lewis acid by a self-quenching process, and the strategy
would implement a cooperative combination of the two
concepts of phase-transfer catalysis[18] and Lewis acid catal-
ysis.
To establish proof of principle, we selected readily
available enantiopure aluminum–salen complexes[19,20] 8 dif-
fering in the substituent X at the 6-position of the phenol ring
(Table 1).[21] The transformation of propionyl bromide with
dihydrocinnamaldehyde was investigated as model reaction.
Table 1: Development of a contact ion pair/Lewis acid catalyst.[a]
To attain synthetically useful enantioselectivities, the
reaction temperature had to be further decreased. While the
reaction catalyzed by trimethylammonium system 8d was
extremely slow at À508C as a result of poor catalyst solubility,
the pyridinium catalyst 8g, prepared in four steps from 2-
hydroxy-5-tert-butylbenzaldehyde with an overall yield of
87% (see the Supporting Information), was significantly
more reactive (entry 10, Table 1) and gave high enantiose-
lectivity and trans selectivity and good yield at À708C.
The reaction generally provided high trans selectivities
with aliphatic aldehydes (Table 2). The enantioselectivity did
not significantly depend on the aldehyde, and almost identical
Entry
8
X
T [8C] Yield [%][b] e.r.[c]
trans/cis[d]
1
2
3
8a
8b iBu
8c tBu
H
À20
À20
À20
42
28
0
56:44
38.5:61.5 25:75
–
21:79
–
Table 2: Application of the optimized bifunctional catalyst system 8g.
4
8d
À20
59
79.5:20.5 91:9
5
8e
À20
68
70:30
75:25
85:15
92:8
6
8 f
À20
69
7
8
9
8g
8h
8g
À20
À20
À50
65
83:17
80:20
90:10
90:10
86:14
92:8
51
72[f]
10[e]
8g
À70
82[g]
94:6
97:3
Entry
3
R1
R2
Yield [%][a] ee [%][b] trans/cis[c]
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3 f
3g
Me (CH2)2Ph
82[d]
77
88
87
88
87
87
93
89
87
94
95
94
95
93
94
97:3
96:4
96:4
94:6
95:5
97:3
97:3
94:6
98:2
98:2
97:3
98:2
96:4
96:4
[a] The catalyst was prepared in situ if not mentioned otherwise; reaction
time 2 h. [b] Yield determined by 1H NMR spectroscopy using aceto-
phenone as an internal standard. [c] Enantiomer ratios determined by
HPLC on a chiral support. [d] Ratio determined by 1H NMR spectros-
copy. [e] Preformed catalyst was used. [f] Reaction time 5 h. [g] Reaction
time 24 h.
Me nHept
Me (CH2)3CH CH2 74[d]
=
=
Me (CH2)8CH CH2 62
Me Et
Me nPr
Me nBu
76[d]
67
64
3h Me iBu
76[d]
91
9
3i
3j
3k
3l
nPr (CH2)2Ph
nPr (CH2)3CH CH2 96
nPr Et
nPr nPr
The most simple catalyst system 8a (X = H) produced b-
lactone 3a with moderate cis selectivity in almost racemic
form (entry 1, Table 1). For the more bulky salen 8b carrying
isobutyl substituents, both reduced reactivity and cis selec-
tivity were noted, while tert-butyl substituents in 8c com-
pletely impeded any product formation, presumably for steric
reasons.
=
10
11
12
13
14
63
93
92
76
3m nPr nBu
3n nPr iBu
[a] Yield of isolated product if not indicated otherwise. [b] Determined by
HPLC or GC on a chiral support (see the Supporting Information).
[c] Ratio determined by 1H NMR spectroscopy. [d] Determined by
1H NMR spectroscopy.
In contrast, all catalysts 8d–h possessing a positively
charged substituent at the phenol 6-position led to enhanced
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results were obtained with substrates possessing long aliphatic
side chains (entries 2–4, and 10, Table 2) with or without a
cooperative action of aprotic contact ion pair and Lewis acid
catalysis. This concept has allowed us to develop the first
trans-selective catalytic asymmetric [2+2] cyclocondensation
of acyl bromides with aliphatic aldehydes, furnishing 3,4-
disubstituted b-lactones; thus it represents an alternative to
asymmetric anti-aldol additions. The described and related
catalyst systems should also be attractive for alternative
reactions that rely on contact ion pair catalysis. Studies
directed towards developing our catalyst systems further in
this direction are underway.
=
C C bond, with b-branched aldehydes such as isovaleralde-
hyde (entries 8 and 14, Table 2),[22] and with sterically
undemanding aldehydes like propanal, butanal or pentanal
(entries 5–7, 11—13, Table 2). In particular these latter results
are remarkable, since high enantioselectivities have previ-
ously never been reported for very small aliphatic aldehydes
in other catalytic asymmetric cycloadditions with acyl halides
or ketenes.
Both yields and enantioselectivities were further
increased when valeroyl bromide was used instead of
propionyl bromide (entries 9—14, Table 2). It is expected
that the corresponding ketene with a bulkier substituent is
less reactive and hence a background reaction, in which the
pyridinium moiety is not involved, should be less favorable
when a larger acyl bromide is used.
The proposed reaction mechanism is depicted in
Scheme 2. The aldehyde is assumed to bind with its sterically
more accessible lone pair to the free Al coordination site to
Received: March 9, 2008
Published online: June 9, 2008
Keywords: aluminum · bifunctional catalysis · contact ion pairs ·
.
lactones · salen ligands
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À
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Angew. Chem. Int. Ed. 2008, 47, 5461 –5464
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5463

Communications
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