Disulfonimide-catalyzed asymmetric vinylogous and bisvinylogous mukaiyama aldol reactions

Article abstract of DOI:10.1002/anie.201005954

Let's talk about six! A new chiral disulfonimide catalyzed vinylogous Mukaiyama aldol addition of crotonic acid derived nucleophiles to aldehydes has been developed and the concept of vinylogy was further expanded to double vinylogous, sorbic acid derived nucleophiles. This reaction is an example of a previously unknown Iμ-selective bisvinylogous Mukaiyama Aldol addition that extends the substrate by six carbon atoms (see scheme). Copyright

Full text of DOI:10.1002/anie.201005954

Communications
DOI: 10.1002/anie.201005954
Vinylogous Aldol Reaction
Disulfonimide-Catalyzed Asymmetric Vinylogous and Bisvinylogous
Mukaiyama Aldol Reactions**
Lars Ratjen, Pilar Garcꢀa-Garcꢀa, Frank Lay, Michael Edmund Beck, and Benjamin List*
The term vinylogy, which describes a unique property of
p systems where the electron density and reactivity is
amplified along conjugated bonds, was proposed 75 years
ago by Fuson.[1] The principle becomes particularly relevant
in the context of the aldol reaction: While metal dienolates
often furnish mixtures of a- and g-addition products,[2] the
corresponding dienolsilanes react with high selectivity at the
remote g position.[3] Asymmetric vinylogous Mukaiyama
aldol reactions furnish structural subunits commonly occur-
ring in natural products, as illustrated by the research groups
of Carreira, Denmark, Kalesse, and others.[4] Several catalytic,
asymmetric versions have been developed over the last few
years.[5] However, general and highly stereoselective methods
that tolerate a wide range of unactivated substrates are still
needed. Moreover, bisvinylogous aldol additions, potentially
furnishing a,b,g,d-unsaturated esters in a single step, have to
our knowledge not been successfully developed to date.[6]
Herein we report asymmetric vinylogous aldol additions,
catalyzed by our recently introduced pre-Lewis acidic disul-
fonimide catalysts 1.[7] We also describe the unprecedented
extension of the Mukaiyama aldol addition towards a
bisvinylogous e-selective and highly enantioselective variant.
Initial computational studies revealed the expected reac-
tivity trends of the extended ketene acetals (Scheme 1). DFT
calculations for attack by an electrophile (fÀ(r)) provided the
corresponding condensed Fukui functions (CFF), and the
electrostatic potentials (ESP).[8] The data obtained for
Scheme 1. Reactivity and calculated nucleophilic properties of vinyl-
ogous nucleophiles for the Mukaiyama aldol reaction. The isosurfaces
nucleophiles of type 3 were in line with those previously
reported, thus suggesting the reaction occurred preferentially
correspond to values of À0.025 a.u. (ESP) and 0.01 and 0.005 a.u. for
in the g position (a = 0.09, g = 0.14).[3f] Interestingly for
Fukui functions. TBS=tert-butyldimethylsilyl.
nucleophiles of type 4, compounds that have been obtained
previously though never studied in terms of their application
in aldol additions,[9] the calculations point to nucleophilic
attack from the terminal position as well (a = 0.07, g = 0.07,
e = 0.11). However, the values for the different positions vary
less than for nucleophiles of type 3, possibly suggesting a less
distinct selectivity. Furthermore, the nature of the aldehyde
should also influence the outcome of the reaction.
Despite the advancements in the asymmetric catalysis of
vinylogous Mukaiyama aldol reactions, organocatalytic sys-
tems proved to be more challenging to establish. Probably the
best system to date was reported by Denmark and co-workers,
who described the Lewis base activation of Lewis acids by
utilizing chiral hexamethylphosphoramide (HMPA) deriva-
tives in combination with SiCl4.[10] However, even this method
has its limitations, either in scope or reactivity, and requires
stoichiometric amounts of the Lewis acid.
As a starting point for our experimental work we explored
our chiral disulfonimide catalyst 1 in the reaction of
2-naphthaldehyde with crotonate-derived nucleophile 3a in
different solvents at different temperatures. These studies
revealed that Et2O at À788C was optimal (see the Supporting
[*] L. Ratjen, Dr. P. Garcꢀa-Garcꢀa, F. Lay, Prof. Dr. B. List
Max-Planck-Institut fꢁr Kohlenforschung
Kaiser-Wilhelm-Platz 1, 45470 Mꢁlheim an der Ruhr (Germany)
Fax: (+49)208-306-2982
E-mail: list@mpi-muelheim.mpg.de
Dr. M. E. Beck
Bayer CropScience AG
Alfred-Nobel-Strasse 50, 40789 Monheim am Rhein (Germany)
[**] We thank Caroline Gawlik for technical support. Furthermore, help
from our analytical departments, especially the NMR, HPLC, and
MS facilities is gratefully acknowledged. We thank Sanofi-Aventis,
the Max-Planck-Society, the DFG (Priority Program Organocatalysis
SPP1179), and the Fonds der Chemischen Industrie for funding.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201005954.
754
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Angew. Chem. Int. Ed. 2011, 50, 754 –758

Information). The desired product was obtained in almost
quantitative yield and g selectivity, with an excellent e.r. value
of 97:3 using 5 mol% of the catalyst. In line with previous
studies,[11] the E/Z geometry of the starting dienolate had only
a small influence on the stereochemical outcome of the
reaction as shown in control experiments with the chromato-
graphically separated geometrical isomers of 3a (see the
Supporting Information), and therefore 3a was used as a
mixture.
Next, we also explored other nucleophiles (see Table 1).
Studying the influence of the silyl group and the ester
substituent in nucleophiles 3b–3 f revealed that the silyl group
had only a small influence on the reaction outcome, while the
ester substituent proved to be important in terms of reactivity.
The methyl ester showed high reactivity and delivered
products in high yields, while increasing the ester bulkiness,
for example, with a tert-butyl group, significantly reduced the
yields (Table 1, entries 4–6).
The introduction of substituents, such as in nucleophiles
3g–3i, revealed that a substituent in the b position is well
tolerated (Table 1, entries 7 and 9). A substituent in the
a position furnished the product with somewhat decreased
enantioselectivity (Table 1, entry 8), a trend that comple-
ments the Denmark approach, where a substituents are
better tolerated than b substituents.[10b] Ketene acetal 3i, a
preferred and especially reactive substrate in previous
studies,[5] also gave the product with decreased enantioselec-
tivity.
The reaction of nucleophile 3a with different aldehydes
was also explored (Table 2). In general, electron-rich or
-neutral aromatic aldehydes provide superior results, but
electron-poor aromatic substrates still enable the reaction to
occur with promising enantioselectivities and yields for
products not accessible by previous methods. Branched and
unbranched aliphatic aldehydes can be utilized as well;
however, the products are obtained with lower enantioselec-
tivities and yields.
Table 1: Nucleophile scope of the disulfonimide-catalyzed vinylogous
Mukaiyama aldol reaction.[a]
After demonstrating the suitability of our catalytic system
for asymmetric vinylogous Mukaiyama aldol reactions, we
turned our focus on the previously unexplored bisvinylogous
version. The products that are potentially accessible by this
method can otherwise only be synthesized directly by using
aluminum-mediated mixed crossed aldol condensations of
aldehydes with conjugated esters, as shown by Yamamoto and
co-workers.[12] The required ketene acetal nucleophiles 4 are
easily accessible as E/Z mixtures from inexpensive sorbic acid
derivatives, which are naturally occurring bulk chemicals.[13]
We were pleased to find that compound 4a reacted
smoothly under the same reaction conditions evaluated for its
congener 3a with various aldehydes in good conversions and
high enantioselectivity (Table 3). To the best of our knowl-
edge, this is the first report of a regio-, highly enantio-, and
e-selective vinylogous Mukaiyama aldol reaction of double
vinylogous silyl ketene acetals with aldehydes.
Entry
1
Product
Yield [%]
96
e.r.[b]
97:3[c]
2
3
4
5
6
7
67[d]
73
96:4
95:5
96:4
95:5
94:6
94:6
71
61[e]
30[e]
60[d]
As predicted by our DFT calculations, the terminal,
e selectivity proved to be less distinct in these transforma-
tions. For example, product 6a was obtained in a e/a ratio of
5:1. The g product remained entirely undetectable as proven
1
spectroscopically by analyses of the H, 13C, DEPT-135, and
1H-1H-COSY spectra (see the Supporting Information). The
data also confirmed an all-E-configuration of e product 6a.
While pronounced structural and electronic variations of the
aldehyde were tolerated, the moderate e/a ratio proved to be
true for other substrates as well, thus diminishing the yields of
the isolated products somewhat.
8
9
78
80
81:19
92:8[f]
Our catalyst system was particularly suited for aromatic
and cinnamaldehyde derivatives, with the desired products
obtained in high enantioselectivities and good yields. Ali-
phatic aldehydes, such as pivaldehyde, could be used, which
led to the product with promising regioselectivity and yield,
but poor enantioselectivity. The introduction of a methyl
group to the silyl enol ether, as in nucleophile 4b (Table 3,
entries 10 and 11) gave products with good enantioselectivites
but somewhat lower yields.
[a] Typical reaction conditions: 0.2 mmol of aldehyde, 0.3 mmol of
corresponding nucleophile 3, and 5 mol% of 1 were stirred in Et2O
[0.2m] for 3 days at À788C; the yields refer to isolated products.
[b] Determined by HPLC on a chiral stationary phase. [c] g/a ratio >50:1
determined by GC-MS analysis. [d] In these cases small amounts of side
product evident by TLC led to decreased yields of the isolated product.
[e] Starting material recovered. [f] The absolute stereochemistry of 5i
was assigned by optical rotation measurements and comparison with
literature values. The other compounds were assigned following analogy
(see the Supporting Information). TIPS=triisopropylsilyl.
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Table 2: Aldehyde scope of the disulfonimide-catalyzed vinylogous
Mukaiyama aldol reaction.[a]
Table 3: Development of
a
disulfonimide-catalyzed bisvinylogous
Mukaiyama aldol reaction.[a]
Entry
1
Product
Yield [%]
80
e.r.[b]
Entry Product
1
Yield [%][b] e.r.[c] e/a[d]
98:2[c]
75
65
54
95:5
89:11
93:7
5:1
9:1
2:1
2
3
89
67
92:8[c]
93:7[c]
2
3
96:4[c]
4
49[e]
91:9
5:1
4
81
5
6
7
76
65
80
84:16
82:18
78:22
5
6
7
46
57
37
87:13 8.4:1
96:4 7.7:1
81:19 1.2:1
8
9
61
62
65
45
81:19
61:39
65:35
72:28
8
9
42
76:24 1.4:1
54:46 3.2:1
90:10 0.6:1
90:10 1.4:1
47
10
11
55[f]
49
10
11
[a] Typical reaction conditions: 0.2 mmol of aldehyde, 0.3 mmol of
corresponding nucleophile 4, and 5 mol% of 1 were stirred in Et2O
[0.2m] for 3 days at À788C. [b] The yields refer to isolated e product. The
side products were isolated and characterized by NMR spectroscopy
where possible (see the Supporting Information). [c] Determined by
HPLC on a chiral stationary phase. The stereochemistry was assigned by
12
33
72:28
[a] Experiments conducted under the conditions mentioned in Table 1;
the yields refer to isolated products. [b] Determined by HPLC on a chiral
stationary phase. [c] All g/a ratios >40:1, as determined by GC-MS.
1
analogy. [d] Determined by integration of the H NMR spectrum of the
crude products or by GC-MS. [e] Starting material recovered: 70% conv.
[f] Product 6j was inseparable from a regioisomer by column chroma-
tography and a virtually pure sample was obtained by preparative TLC.
Having a,b,g,d-unsaturated esters 6 readily available, we
envisioned their implementation in
a straightforward
approach towards z-lactones (Scheme 2). This structural
motif occurs in a variety of natural products,[14] and our
bisvinylogous aldol products would be ideal starting points for
their synthesis. Accordingly, deprotected product 7 was
converted into lactone 8 in reasonable yield by a hydro-
genation, ester cleavage, Yamaguchi lactonization
sequence.[15]
ogous Mukaiyama aldol additions. These extended aldoliza-
tions display good to excellent enantioselectivity and have a
remarkably broad ketene acetal scope. Highly enantioselec-
tive catalytic asymmetric bisvinylogous aldol reactions of any
type were previously unknown and, similar to the Mukaiyama
aldol reaction itself and its vinylogous variation, offer
excellent potential in natural product synthesis. Future
In summary we have developed efficient and easily
applicable, disulfonimide-catalyzed vinylogous and bisvinyl-
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With regard to the scope and applicability towards a wider
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laboratories.
Experimental Section
A septum-capped vial with a stirring bar was charged with the
corresponding aldehyde (0.2 mmol), catalyst 1 (5 mol%), and dry
Et2O (1 mL). The resulting mixture was cooled to À788C in an
acetone/dry ice bath, before the silyl enolate (0.3 mmol) was added
dropwise by syringe. The resulting reaction mixture was stirred at
À788C for 3 days. A saturated NaHCO3 solution (0.5 mL) was then
added at À788C and the reaction mixture was allowed to reach room
temperature. Subsequently, the reaction was diluted with Et2O
(25 mL) and dried with MgSO4. The solvent was removed in vacuo
and the resulting crude material purified by column chromatography
on silica gel (hexanes/ethyl acetate 8:1) to afford the desired products
as colorless oily liquids. For further details see the Supporting
Information.
[7] P. Garcꢀa-Garcꢀa, F. Lay, P. Garcꢀa-Garcꢀa, C. Rabalakos, B. List,
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[8] For detailed descriptions of the DFT calculations see the
Supporting Information and a) M. E. Beck, J. Chem. Inf.
Model. 2005, 45, 273 – 282; b) M. E. Beck, M. Schindler, Chem.
Phys. 2009, 356, 121 – 130.
Received: September 22, 2010
Revised: October 18, 2010
Published online: December 17, 2010
Keywords: aldol reactions · organocatalysis · regioselectivity ·
.
synthetic methods · vinylogy
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