Fluoro-organocatalysts: Conformer equivalents as a tool for mechanistic studies

Article abstract of DOI:10.1002/anie.201003734

Fluorine in charge! The fluorine-iminium ion gauche effect has been exploited in the design of conformational probes for organocatalysis (see scheme). Stabilizing hyperconjugative [σC H→σ ^*C F] and/or electrostatic [N+ Fσ-] interactions render the C F bond an excellent steering group for controlling molecular topology without introducing additional steric constraints.

Full text of DOI:10.1002/anie.201003734

Communications
DOI: 10.1002/anie.201003734
Conformational Analysis
Fluoro-Organocatalysts: Conformer Equivalents as a Tool for
Mechanistic Studies**
Christof Sparr and Ryan Gilmour*
Dedicated to Professor Albert Eschenmoser on the occasion of his 85th birthday
Enantioselective organocatalysis has revolutionized the field
of asymmetric synthesis, transforming rudimentary consider-
ations of enamine and iminium ion reactivity into powerful
strategies for stereoselective reaction design. This renaissance
of catalysis mediated by low-molecular-weight organic amine
derivatives not only compliments existing organometallic and
enzymatic strategies for enantioinduction, but confers a
number of advantages ranging from ease of catalyst prepa-
ration through to simplicity of reaction execution. Unsurpris-
ingly a colossal number of innovative, often bioinspired,
organocatalytic processes have been reported.[1] While this
constantly expanding repertoire is impetus enough for further
Scheme 1. Iminium ion conformer equivalents.
development, interplay between preparative and mechanistic
studies is imperative in order to sustain innovation. The
improvement of existing catalyst topologies and the de novo
design of unique architectures require an intimate apprecia-
tion of the decisive interactions involved in orchestrating
asymmetric amplification. Conformational analysis is there-
fore of fundamental importance.
described.[2–5] However, to the best of our knowledge no
“tool” to study the contributions of individual conformations,
separated by minimal steric bias, has been described. We
therefore envisaged that the fluorine–iminium ion gauche
effect[6] reported earlier by our research group could be
exploited in the design of conformational probes for organo-
catalysis. Stabilizing hyperconjugative [sCꢀH!s*CꢀF] and/or
MacMillanꢀs seminal reports of Diels–Alder,[2] 1,3-dipolar
cycloaddition,[3] and Friedel–Crafts reactions[4] of a,b-unsatu-
rated aldehydes catalyzed by imidazolidinone 1 remain
landmark developments in this field. Catalytic efficiency is
principally due to several design features that take effect upon
intramolecularization to form a transient iminium ion inter-
mediate (2; Scheme 1). In particular the three sp2 hybridized
centers create a highly strained core, while the gem-dimethyl
motif imparts geometric control by virtue of 1,3-allylic (A1,3)
strain. Enantioinduction is conferred by a directing phenyl
group, however, the prevailing conformation responsible for
amplification of chirality has yet to be firmly established.
Models incorporating p–p interactions, CH–p interactions,
and the oscillatory motion of the phenyl ring have been
electrostatic [N+···Fdꢀ] interactions render the C F bond an
ꢀ
excellent steering group for controlling molecular topology
without introducing additional steric constraints. The prede-
termined configuration of the benzylic fluorine center would
encode for a given topology, hence diastereoisomers 3 and 4
were envisioned to be “conformer equivalents” of I and II,
respectively (Scheme 1).
Synthesis of iminium salt 3 commenced with the methyl-
ation and subsequent amidation of l-threo-phenylserine 5
(Scheme 2). Diastereoselective fluorination by treatment
with DAST in CH2Cl2 proceeded with retention of config-
uration to furnish the desired fluoride 8 in good yield (d.r. =
4.2:1). The stereoselectivity observed in this transformation
may be rationalized by minimization of 1,3-allylic strain in the
transient chiral benzylic cation in accordance with the models
proposed by Bach and co-workers.[7] Subsequent formation of
the imidazolidinone ring system furnished the target R,R-
catalyst structure 9 which was then processed to the iminium
ion 3 for conformational analysis and mechanistic studies.
Iminium salt 4 was prepared from the fluorophenylalanine
derivative 11 by an analogous reaction sequence.[8] Again, the
diastereoselectivity of the fluorination reaction is dictated by
A1,3 strain, to furnish the R,S-diastereoisomer 11 in a concise,
highly selective manner (d.r. = 120:1).
[*] C. Sparr, Prof. Dr. R. Gilmour
Swiss Federal Institute of Technology (ETH) Zurich
Laboratory for Organic Chemistry
Department of Chemistry and Applied Biosciences
Wolfgang-Pauli-Strasse 10, 8093 Zurich (Switzerland)
E-mail: ryan.gilmour@org.chem.ethz.ch
Homepage: http://www.gilmour.ethz.ch
[**] We gratefully acknowledge generous financial support from the
Alfred Werner Foundation (assistant professorship to R.G.), the
Roche Research Foundation and Novartis AG (doctoral fellowships
to C.S.), and the ETH Zurich. We thank Dr. W. B. Schweizer for X-ray
analysis, Dr. M.-O. Ebert for assistance with NMR spectroscopy, and
Profs D. Seebach and E. M. Carreira for helpful discussions.
Initially, fluoroimidazolidinone salts 9 and 13 were
analyzed by H NMR spectroscopy and single-crystal X-ray
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201003734.
1
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Figure 1. Solid-state analysis of b-fluoroiminium salt 3, and fluoroimi-
dazolidinones 9 and 13. Thermal ellipsoids are drawn at the 50%
Scheme 2. Synthesis of fluoroiminium ions (R,R)-3 and (R,S)-4.
Reagents and conditions: a) SOCl2, MeOH; b) MeNH2, EtOH (12,
70%, 2 steps); c) DAST, CH2Cl2 (8, 43%, 3 steps); d) Me2CO, p-TsOH
(9, 68%; 13, 79%), e) 1. HSbF6, MeOH, 2. (E)-cinnamaldehyde, Et3N,
EtOH (3, 73%; 4, 70%). Alloc=allyloxycarbonyl, Boc=tert-butoxycar-
bonyl, DAST=diethylaminosulfur trifluoride, p-TsOH=para-toluenesul-
fonic acid.
probability level. The counterions have been omitted for clarity.[9]
exo conformer predominates (an equivalent of conformer II)
in solution by virtue of the significant up-field shift of the syn-
methyl group (dH = 0.57 ppm, Me’; DdH(4Me’’-4Me’) =
1.08 ppm).[10]
Further validation came from 13C NMR studies as shown
in Figure 2 (upper). The spectrum of iminium salt 3 shows a
weak scalar coupling (“through-space”) between the fluorine
atom and the syn-methyl group (Me’; 5JCF = 6.7 Hz). This
effect is only possible if the carbon and fluorine atoms are
within van der Waals contact:[11] this distance is around 3 ꢁ in
the solid state. Furthermore, the 13C NMR spectrum of
iminium ion 4 also showed a clear scalar coupling with the
b carbon of the pendant iminium chain (5JCF = 15.3 Hz).
Collectively, these NMR data indicate that the iminium ion
conformers present in the solid state are also dominant in
solution.
diffraction methods to determine which of two possible
gauche conformations was favored (syn-clinal endo vs. syn-
clinal exo).[9] In both cases, an open gauche conformation was
established with the phenyl ring being positioned away from
the catalyst core (Figure 1). While the R-configured fluoride 9
adopted a syn-clinal exo topology (fNCCF = 53.38), the analo-
gous S-configured system 13 resided in the syn-clinal endo
conformation (fNCCF = ꢀ73.08).
Intriguingly, intramolecularization with trans-cinnamal-
dehyde elicited a conformational response with the R,R-
configured fluoroiminium ion 3 selecting the syn-clinal endo
topology in which the phenyl ring is placed over the p system.
X-ray analysis of this material revealed a dihedral angle of
Having completed this conformational study we inves-
tigated the potential usefulness of “conformer equivalents” in
understanding enantioinduction in organocatalytic transfor-
mations. As a representative reaction, we initially elected to
study Friedel–Crafts-type addition reactions to trans-cinna-
maldehyde under MacMillanꢀs previously reported conditions
using 1, 9, and 13.[4a] However, in some reactions mediated by
9 and 13, inversion of the sense of enantioselectivity was
observed. We attribute these findings to selective formation
of the Z-iminium ion as the kinetic product,[12] and under
these conditions addition of the nucleophile occurs prior to
preequilibration to the E-iminium ion. Optimistic that these
initial findings might give an insight into the conformational
requirements of the phenyl group for efficient geometric
control during iminium ion formation, the thermodynamically
more stable E-iminium ions (3 and 4) were preformed and
fNCCF = ꢀ60.98 (an equivalent of conformer I). The dynamic
nature of this topological change triggered by intramolecula-
rization was confirmed by 1H and 13C NMR spectroscopy.
Figure 2 shows the upfield shift of the b-iminium proton of 3
(dH = 5.80 ppm vs. dH = 7.50 ppm for 4) consistent with the
shielding influence exerted by the proximal phenyl ring.[5d,e]
The noticeable shifts of the a and g protons, albeit to a lesser
extent, are also attributable to this conformation (DdH(4a-
3a) = 0.19 ppm; DdH(4g-3g) = 0.55 ppm). A conformational
change was also observed when the R,S-configured fluoro-
imidazolidinone 13 was converted into iminium ion 4 with the
phenyl ring being placed in proximity to the adjacent methyl
group. Although this compound proved to be recalcitrant to
crystallization, it was possible to grow microcrystalline
material: frustratingly, this was unsuitable for X-ray analysis.
However, 1H NMR studies confirmed that the syn-clinal
1
isolated prior to conjugate addition. From H and 19F NMR
analyses of these iminium ions, we measured similar E/Z
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Communications
experiencing opposing steric stress from both the gem-
ꢀ
dimethyl motif and the freely rotating C C(Phipso) bond
which is placed in proximity as a result of the gauche effect.
From these findings, we conclude that conformer II
(Scheme 1) contributes to efficient catalysis by minimizing
A1,3 strain, thus allowing high levels of geometric control in
reactions with preequilibrating conditions. It seems rational
that while conformer II benefits from a stabilizing CH–p
interaction it is also likely to be at least a partial manifestation
of minimized nonbonding interactions.
Subsequently, we compared the selectivities of conjugate
additions of N-methylpyrrole to iminium ions 3, 4, and 14
(Scheme 3). We observed enhanced levels of enantioinduc-
Scheme 3. Conjugate addition reactions of iminium ions 3, 4, and 14
to N-methylpyrrole: Addition reactions were performed at ambient
temperature in methanol for a period of 1.5 hours. In situ reduction of
the aldehyde to the corresponding primary alcohol facilitated HPLC
analysis.
tion with iminium ion 3 (conformer equivalent of I) as
compared to 4 (conformer equivalent of II; e.r. = 64:36 vs.
racemic). Taking into consideration the lower E/Z ratio of 3
relative to 14 and 4, this result is in agreement with
MacMillanꢀs original model for stereoinduction via confor-
mation I. By exploiting the fluorine–iminium ion gauche
effect in the design of mechanistic probes, it has been possible
to “freeze out” the two iminium ion conformations that are
widely accepted to be important for the remarkable catalytic
activity of MacMillanꢀs first-generation catalyst. From this
preliminary study, we hope to have provided independent
evidence that the topology of the benzyl shielding group is not
only responsible for translation of chirality, but also in
influencing the E/Z ratio of the transient iminium ions upon
condensation. This conformational symbiosis suggests that
conformation II (equivalent 4) is likely responsible for
assuring high levels of geometric control with conformation I
(equivalent 3) imparting high levels of enantioinduction
(Scheme 4). Clearly bond rotation (II!I) prior to an addition
reaction occurs faster than E/Z isomerization[5f] and is there-
fore inconsequential to the pre-set iminium ion ratio encoded
by conformation II.
Figure 2. Selected regions of the 1H and 13C NMR spectra of iminium
salts 3 (red) and 4 (black). Measurements were conducted in CD2Cl2.
Conformations in black are observed by NMR and X-ray methods;
conformations in blue are not observed.
ratios for 3 and 4, but a consistently lower E/Z ratio for 3. This
observation is consistent with conformer equivalent I (3)
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In summary, the concept of conformer equivalents as a
tool to investigate noncovalent interactions in catalysis is
disclosed. The diastereoselective syntheses of two, novel
imidazolidinones are described together with the dynamic
conformational behavior of these materials when condensed
to form iminium ions. We have gained a preliminary insight
into some of the noncovalent interactions that are important
for further catalyst development. Namely, that the phenyl
group functions both in controlling iminium ion geometry and
conferring enantioinduction in the conjugate addition of N-
methylpyrrole to 3, 4, and 14. Efforts to expand upon the
concept of conformer equivalents are currently on-going in
our laboratory.
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[7] F. Mꢃhlthau, O. Schuster, T. Bach, J. Am. Chem. Soc. 2005, 127,
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[8] K. Okuda, T. Hirota, D. A. Kingery, H. Nagasawa, J. Org. Chem.
2009, 74, 2609 – 2612. Crystal structure analysis of the catalyst
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the original paper. This assignment is in agreement with Bachꢀs
model for diastereoselective SN1 processes via chiral benzylic
cations.[7]
[9] For full experimental details see the Supporting Information.
CCDC 777914 (3), 777913 (5), and 777912 (6) contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[10] Measurements were performed in CD2Cl2. Analogous confor-
mational behavior was observed when these studies were
repeated in MeOD.
Received: June 18, 2010
Published online: August 2, 2010
Keywords: conformational analysis · gauche effect ·
.
organocatalysis · organofluorine chemistry ·
reaction mechanisms
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