Silyl-modified analogues of 2-tritylpyrrolidine: Synthesis and applications in asymmetric organocatalysis

Article abstract of DOI:10.1002/chem.201002166

Silicon-based organocatalysts: In an effort to study the effects of substituting carbon by silicon within the catalyst backbone, we developed an efficient synthesis of (S)-2-triphenylsilylpyrrolidine [(S)-2]. The evaluation of (S)-2 against its carbon analogue (S)-1 in two organocatalytic reactions is complemented by computational studies.

Full text of DOI:10.1002/chem.201002166

COMMUNICATION
DOI: 10.1002/chem.201002166
Silyl-Modified Analogues of 2-Tritylpyrrolidine: Synthesis and Applications
in Asymmetric Organocatalysis
Jonathan O. Bauer,[a] Julian Stiller,[b] Eugenia Marquꢀs-Lꢁpez,[b] Katja Strohfeldt,[a]
Mathias Christmann,*[b] and Carsten Strohmann*[a]
The design of efficient catalysts with new structural
motifs[1] is one of the major challenges in the growing field
of asymmetric organocatalysis.[2] Inspired by the dramatic
effect of subtle steric and electronic modifications on cata-
lyst activity,[2f] we set out to investigate the performance of
silicon-based, enantiomerically pure pyrrolidines in organo-
catalytic reactions.[3] A remarkable feature of silicon is its
tolerance of sterically demanding substituents, thus allowing
straightforward access to quaternary silicon centers by nu-
cleophilic substitution reactions of trialkylchlorosilanes
(Scheme 1).[3,4] Hence, a diverse array of novel catalyst scaf-
These results prompted us to render the corresponding sili-
con analogue (S)-2 and related derivatives available for a
direct comparison of their catalytic performance in enamine
catalysis (Scheme 1).[6]
In an accompanying quantum-chemical study, we aimed
to rationalize silicon effects on the new catalytic systems by
studying electronic as well as steric differences between the
carbon and silicon analogues 1 and 2. For this purpose DFT
calculations were performed at the B3LYP/6-31+G(d)
level. Based on the energy-optimized structures A1 and B1
of a meaningful conformer for both catalysts, we studied the
NBO charge (Figure 1) and calculated the electrostatic po-
tential (Figure 2).
The comparison of the decisive bond length between pyr-
rolidine C-2 and silicon or carbon, respectively, revealed a
significant elongation of this bond changing from carbon
(A) to silicon (B), which is clearly visible in the space-filling
models A2 and B2 (Figure 2) and may have an effect on the
stereochemical outcome in catalytic asymmetric reactions.[7]
Due to the overcrowded substitution sphere, the respective
Scheme 1. Silicon analogue (S)-2 of the organocatalyst (S)-1 and general
route to functionalized organosilanes.
À
À
folds should be accessible, which are hitherto unknown for
carbon-based pyrrolidine catalysts. Recently, Maruoka et al.
reported the asymmetric a-benzyloxylation of aldehydes
using (S)-2-tritylpyrrolidine [(S)-1] as organocatalyst.[5] The
synthesis of (S)-1 involves a nucleophilic addition to a ni-
trone followed by hydrogenolysis and resolution of (Æ)-1.
C C distance (1.589 ꢀ) is slightly longer than endocyclic C
À
C bonds, while the C Si length (1.915 ꢀ) lies in the normal
[8]
À
range for carbon silicon bonds in aminoalkyl silanes. Fur-
thermore, the NBO analysis of B1 indicates a high positive
charge of 1.818 at the silicon center and a definite negative
charge at the carbon atoms (À0.516 to À0.542) directly at-
tached to silicon (Figure 1). By contrast, the carbon ana-
logue A1 shows a well-balanced negative charge distribution
across the carbon-atom backbone. Consequently, the elec-
tronic structure causes a more negatively charged electro-
static potential around the phenyl-substituted silyl moiety
when compared to 2-tritylpyrrolidine, shown at the fast sur-
face models A3 and B3 (Figure 2). In view of polar transi-
tion states in enamine and iminium catalysis, these electron-
ic features possibly contribute to a deeper insight into the
activity of novel catalytic systems.[9]
[a] Dipl.-Chem. J. O. Bauer, Dr. K. Strohfeldt, Prof. Dr. C. Strohmann
Anorganische Chemie, Technische Universitꢁt Dortmund
Otto-Hahn-Strasse 6, 44227 Dortmund (Germany)
Fax : (+49)231-755-7062
E-mail: mail@carsten-strohmann.de
[b] Dipl.-Chem. J. Stiller, Dr. E. Marquꢂs-Lꢃpez,
Prof. Dr. M. Christmann
Organische Chemie, Technische Universitꢁt Dortmund
Otto-Hahn-Strasse 6, 44227 Dortmund (Germany)
Fax : (+49)231-755-5363
As part of our studies on aminoalkyl silanes[8] and with re-
spect to the lack of applications in amine catalysis, we next
disclosed a convenient asymmetric route to enantiopure 2-
E-mail: mathias.christmann@tu-dortmund.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002166.
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the presence of (À)-spar-
teine,[10] a method introduced
by Beak and co-workers.[11]
Subsequent reaction with meth-
yldiphenylchlorosilane gave the
desired silyl-substituted N-boc-
pyrrolidine (S)-4 in 81% yield
with an e.r. of 94:6.[12] The de-
protection of enantiomerically
enriched (S)-4 was carried out
effectively according to a litera-
ture procedure[13] using acetyl
chloride in ethanol to provide
the respective hydrochloric salt
(S)-5·HCl (Scheme 2). After re-
crystallization from 2-propanol,
(S)-5·HCl was obtained as a
single enantiomer in 62% yield.
The enantiomeric ratio was de-
termined by HPLC analysis on
the basis of the boc-protected
compound 4.
Figure 1. Molekel plot of pyrrolidines 1 (A1) and 2 (B1) including selected NBO charges and bond lengths;
B3LYP/6-31+G(d).
X-ray crystallographic analy-
sis of the HCl-salt (S)-5·HCl al-
lowed the determination of its
absolute configuration. The
asymmetric unit contains two
molecules of (S)-5, which are
involved in hydrogen bond in-
teractions (Figure 3).
An attempt to synthesize the
triphenylsilyl-substituted pyrro-
lidine (S)-7 (Scheme 3) in
a
similar manner by conversion
of the enantiomerically en-
riched, lithiated N-boc-pyrroli-
dine with chlorotriphenylsilane
was unsuccessful. Continuative
exploratory studies were based
on the consideration that the
silane component has to be re-
active enough at low tempera-
tures to guarantee a high con-
figurative stability of the chiral
alkyllithium reagent[15] used in
the course of the substitution
reaction. In a following step the
third phenyl group should be
introduced again by nucleophil-
ic attack at the silicon center.
Initially, we focused on dialkox-
ysilanes as electrophiles of
choice[16] for the generation of
Figure 2. Space-filling models A2 and B2 and fast surfaces with mapped electrostatic potential (A3, B3) for
the pyrrolidines 1 (left) and 2 (right).
silyl-substituted pyrrolidines as a conceptionally new class of
potent organocatalysts. The generation of the stereogenic
center adjacent to the nitrogen atom was achieved by asym-
metric deprotonation of N-boc-pyrrolidine 3 with sBuLi in
adequate alkoxy-functionalized N-boc-pyrrolidines, which
are useful intermediates for further transformation reac-
tions. Indeed, for the first time we examined synthetic
access to triphenylsilyl-N-boc-pyrrolidine [(S)-7] via the
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Chem. Eur. J. 2010, 16, 12553 – 12558

Silyl-Modified Analogues of 2-Tritylpyrrolidine
COMMUNICATION
ings led us to a simple asymmetric one-pot synthesis of (S)-7
in overall 50% yield without the need for isolation and
enantiomeric enrichment of the methoxysilylpyrrolidine 6
before further conversion to (S)-7 (Scheme 3).
The absolute configuration of (S)-7 was determined by X-
ray crystallographic analysis (Figure 4).
Scheme 2. Asymmetric synthesis of enantiomerically pure (S)-2-(methyl-
diphenylsilyl)pyrrolidine·HCl [(S)-5·HCl].
Figure 4. ORTEP plot of the molecular structure of (S)-2-(triphenylsilyl)-
N-boc-pyrrolidine [(S)-7].[14] Displacement ellipsoids drawn at the 50%
probability level.
Deprotection of (S)-7 gave the enantiopure hydrochloride
(S)-2·HCl in 70% yield (Scheme 3), which could be crystal-
lized from chloroform affording single crystals suitable for
X-ray structure determination analysis (Figure 5). For com-
parison, Figure 5 shows the molecular structure of the hy-
drochloric salt of (S)-2-tritylpyrrolidine [(S)-1·HCl]. The
Figure 3. ORTEP plot of the molecular structure of (S)-2-(methyldiphe-
nylsilyl)pyrrolidine·HCl [(S)-5·HCl].[14] Displacement ellipsoids drawn at
the 50% probability level.
À
À
measured C1 C20 and C19 Si bond lengths of 1.573(2) ꢀ
and 1.904(3) ꢀ, respectively, are slightly shortened com-
pared with the corresponding distances in the calculated
structures of the free amines A1 and B1.[17] However, these
results support the validity of our computational conclusions
(Figure 5).
To benchmark the performance of (S)-1 and (S)-2, both
catalysts were tested in organocatalytic alkylations of enam-
ines. As the first test reaction, we investigated the a-alkyla-
tion[18,19] of n-octanal (9) with bis[4-(dimethylamino)phenyl]-
methanol (10),[20] recently developed by Cozzi and co-work-
ers.[18c] Interestingly, in their studies only MacMillanꢅs imida-
zolidinone catalysts[21] showed significant activity, whereas
pyrrolidine-based catalysts[22] failed to catalyze the reaction
with useful enantiomeric excess. In light of their observa-
tions, it is even more remarkable that both the trityl- and
triphenylsilyl-substituted pyrrolidines (S)-1 and (S)-2 cata-
lyze the SN1-type reaction of 9 and 10 to the a-alkylated al-
dehydes (R)-11 and (S)-11, respectively, albeit with moder-
ate enantiomeric ratios and yields (Scheme 4). Attempts to
optimize the reaction conditions are ongoing in our labora-
tories.
Scheme 3. Asymmetric synthetic route to enantiomerically pure (S)-2-
(triphenylsilyl)pyrrolidine·HCl [(S)-2·HCl].
enantiomerically enriched methoxysilylpyrrolidine 6 and
therefore to an appropriate precursor for the promising sili-
con analogue of the already known carbon catalyst 1. As we
found out, (S)-7 was accessible in enantiomerically pure
form by recrystallization from acetone. The enantiomeric
ratio of (S)-7 was determined by HPLC analysis. These find-
We also tested (S)-1 and (S)-2 in the conjugate addition[23]
of propanal (12) to nitrostyrene (13).[1c,24,25] With (S)-2-trityl-
Chem. Eur. J. 2010, 16, 12553 – 12558
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12555

C. Strohmann, M. Christmann, et al.
enantiomeric ratio (97:3). Low-
ering the temperature to
À208C raised the diastereo-
meric ratio to 95:5 without
changing the enantioselectivity
(Table 1, entry 3). However, the
reaction rate was lowered. Most
importantly, exchanging one
phenyl group with
a methyl
group [(S)-2 vs. (S)-5] had a
negative impact on the enantio-
selectivity (Table 1, entries 4
and 5). These preliminary re-
sults suggest that a bulky sub-
stituent at C-2 on the pyrroli-
dine is essential for high enan-
À
Figure 5. ORTEP plot of the molecular structures of (S)-tritylpyrrolidine [(S)-1·HCl] (left) and (S)-2-(triphe-
nylsilyl)pyrrolidine·HCl [(S)-2·HCl] (right).[14] Displacement ellipsoids drawn at the 50% probability level.
tioselectivity. Moreover, the longer Si C distance between
the pyrrolidine C-2 and the triphenylsilyl group might be
the critical factor for retaining the catalystꢅs reactivity, as
the comparable sterically demanding trityl substitutent clear-
ly lowers the reactivity of the pyrrolidine catalyst.
In summary, we have reported the asymmetric synthesis
of a new and promising class of chiral silicon-based pyrroli-
dine catalysts. Differing from the synthetic route to (S)-2-
(methyldiphenylsilyl)pyrrolidine (S)-5 using a chlorosilane
as electrophile, the synthesis of the enantiomerically pure
triphenylsilyl-substituted pyrrolidine (S)-2 as the silicon ana-
logue of tritylpyrrolidine [(S)-1)] has been employed accord-
ing to a one-pot reaction via an in situ generated methoxysi-
lane. In two model reactions, the enantioselective a-alkyla-
tion and the Michael reaction, (S)-2 showed promising cata-
lytic activity. Quantum-chemical studies as well as structural
analysis provided insight into steric and electronic differen-
ces between the respective carbon- and silicon-substituted
pyrrolidines. Future investigations will be concerned with
the development of a wide variety of silyl-modified pyrroli-
dines with additional groups at the silicon center designated
for bifunctional catalysis.
Scheme 4. Organocatalytic asymmetric a-alkylation of n-octanal (9) with
bis[4-(dimethylamino)phenyl]methanol (10).
pyrrolidine [(S)-1] as the catalyst, the reaction was extreme-
ly sluggish and did not lead to full conversion after 72 h
(Table 1, entry 1). The Michael adduct 14 was obtained in
good yield but only moderate diastereoselectivity. Switching
to the silicon catalyst (S)-2 (Table 1, entry 2), the reaction
was remarkably faster, affording nitroaldehyde 14 within
12 h with good diastereoselectivity (91:9) and an excellent
Table 1. Michael addition of propionaldehyde (12) and trans-b-nitrostyr-
ene (13).[a]
Acknowledgements
We thank the Fonds der Chemischen Industrie (Dozentenstipendium for
M.C., fellowship for K.S.), the Humboldt-Foundation for a postdoctoral
fellowship (E.M.L.), the Studienstiftung des deutschen Volkes (Max
Weber-Programm des Freistaates Bayern) for a fellowship (J.O.B.), the
Stiftung der deutschen Wirtschaft (sdw) for a doctoral fellowship (J.S.)
and Prof. Dr. Albrecht Berkessel for hosting us to separate racemic 2-tri-
tylpyrrolidine by preparative HPLC within his group. Furthermore, we
are grateful to the Mercator Research Center Ruhr (MERCUR) for fi-
nancial support. Finally, we would like to express our gratitude to
Prof. Dr. Carsten Bolm for sharing his unpublished results with us.[26]
Entry
Catalyst
Yield [%]
52[d]
98
97
87
T [8C]
d.r.[b] (syn/anti)
e.r.[c]
1
2
(S)-1
(S)-2
(S)-2
(S)-5
(S)-5
4
4
78:22
91:9
95:5
93:7
84:16
2:98
97:3
97:3
91:9
94:6
3[e]
4
À20
4
5
90
25
[a] Conditions: aldehyde 12 (2 mmol), nitroolefin 13 (0.2 mmol), catalyst
(S)-1, (S)-2, (S)-5 (0.02 mmol), solvent (1 mL), 12 h. [b] Determined by
chiral HPLC. [c] Enantiomeric ratio (2S,3R)-14:ACTHNUTRGNEUG(N 2R,3S)-14 (syn-diaste-
reomers) given. [d] Reaction was stopped after 72 h (incomplete conver-
sion). [e] Reaction time: 48 h.
Keywords: alkylation
organocatalysis · silicon · silylated pyrrolidines
·
asymmetric
synthesis
·
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Silyl-Modified Analogues of 2-Tritylpyrrolidine
COMMUNICATION
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Received: July 28, 2010
Published online: September 28, 2010
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Chem. Eur. J. 2010, 16, 12553 – 12558