Fluorinated organocatalysts for the enantioselective epoxidation of enals: Molecular preorganisation by the fluorine-iminium ion Gauche effect

Article abstract of DOI:10.1002/chem.201201316

The fluorine-iminium ion gauche effect is triggered upon union of a secondary β-fluoroamine and an α,β-unsaturated aldehyde, providing a useful strategy for controlling the molecular topology of intermediates that are central to organocatalytic processes. The β-fluoroamine (S)-2-(fluorodiphenylmethyl)pyrrolidine (1) is an effective catalyst for the enantioselective epoxidation of α,β-unsaturated aldehydes. A process of structural editing has revealed that the efficiency of this catalyst is due to the (fluorodiphenyl)methyl group when it is embedded in a β-fluoroiminium motif. Epoxidations of challenging cyclic α,β-disubstituted, β,β-disubstituted and α,β,β-trisubstituted enals catalysed by 1 proceed with excellent levels of enantiocontrol (up to 98 % ee). Fluorine finesse. The β-fluoroamine (S)-2-(fluorodiphenylmethyl)pyrrolidine (1) is an effective catalyst for the enantioselective epoxidation of α,β-unsaturated aldehydes (see scheme). Application of this catalyst to challenging cyclic α,β-disubstituted enals, β,β-disubstituted enals, and an α,β,β-trisubstituted enal proceeds in a highly enantioselective fashion (up to 98 % ee). Copyright

Full text of DOI:10.1002/chem.201201316

FULL PAPER
DOI: 10.1002/chem.201201316
Fluorinated Organocatalysts for the Enantioselective Epoxidation of Enals:
Molecular Preorganisation by the Fluorine-Iminium Ion Gauche Effect
Eva-Maria Tanzer, Lucie E. Zimmer, W. Bernd Schweizer, and Ryan Gilmour*[a]
Dedicated to Professor Dr. Alois Fꢀrstner on the occasion of his 50th birthday.
Abstract: The fluorine-iminium ion
gauche effect is triggered upon union
of a secondary b-fluoroamine and an
a,b-unsaturated aldehyde, providing
a useful strategy for controlling the
molecular topology of intermediates
that are central to organocatalytic pro-
cesses. The b-fluoroamine (S)-2-(fluo-
rodiphenylmethyl)pyrrolidine (1) is an
effective catalyst for the enantioselec-
tive epoxidation of a,b-unsaturated al-
dehydes. A process of structural editing
has revealed that the efficiency of this
catalyst is due to the (fluorodiphenyl)-
methyl group when it is embedded in
a b-fluoroiminium motif. Epoxidations
of challenging cyclic a,b-disubstituted,
b,b-disubstituted and a,b,b-trisubstitut-
ed enals catalysed by 1 proceed with
excellent levels of enantiocontrol (up
to 98% ee).
Keywords: conformation analysis ·
enantioselectivity
· epoxidation ·
fluorine · reaction intermediates
Introduction
Fluorine conformational effects are emerging as powerful
strategies for the preorganisation of transient intermediates
that are central to organocatalytic processes.[1–3] Stabilising
hyperconjugative interactions involving the low-lying s*Cꢀ
F
[4]
orbital with adjacent s-bonds (e.g., sCꢀH!s*Cꢀ
)
manifest
F
themselves in the gauche conformational preference of fluo-
rinated molecules bearing vicinal electron-withdrawing
groups (F-CH2-CH2-X).[5] Furthermore, the polarised nature
of the Cd+
bond evokes stabilising electrostatic/charge-
dꢀ
ꢀ
F
dipole interactions with electropositive centres (Scheme 1;
for example, Fdꢀ-Cb-Ca-N+).[6] Hence, gauche conformers
are often preferentially populated over the corresponding
anti conformers in the absence of superseding steric limita-
tions. Further conformational refinement to discriminate be-
tween the two possible conformers (gauche1 and gauche2)
can be achieved by introducing additional structural features
that allow for stabilising (e.g., p-stacking or CH-p interac-
tions)[3e] or destabilising interactions (e.g., A1,3-strain). A
logical process of molecular design can therefore lead to
pronounced energy differences between conformers in the
Scheme 1. The fluorine-iminium ion gauche effect for molecular pre-or-
ganisation.
dictably positioned in an area of molecular space and, in the
case of enantioselective organocatalysis, exploited as shield-
ing groups to direct incoming nucleophiles to one of two
faces of a planar electrophile (Scheme 1, lower). Fluorineꢀs
small steric footprint, coupled with its high bond strength to
ꢀ
rotational profile of a key Ca Cb bond. Consequently, sub-
stituents attached to the fluorine-bearing carbon can be pre-
ꢀ
carbon, render the C F bond a unique conformational steer-
ing group when appropriately embedded in a molecular
[a] E.-M. Tanzer, Dr. L. E. Zimmer, Dr. W. B. Schweizer,
Prof. Dr. R. Gilmour
scaffold proximal to an electropositive centre.[7]
The iminium ion activation mode[8] provides an excellent
platform from which to exploit fluorine effects in reaction
design by creating small, conformationally dynamic ensem-
bles that emulate the quintessential aspect of enzymatic cat-
alysts, the induced fit concept.[9] To that end, this laboratory
has employed (S)-2-(fluorodiphenylmethyl)pyrrolidine (1)[3b]
for the catalytic, enantioselective epoxidation of a,b-unsatu-
Laboratory for Organic Chemistry
Swiss Federal Institute of Technology (ETH) Zꢁrich
8093 Zꢁrich (Switzerland)
Fax : (+41)44-632-79-34
E-mail: ryan.gilmour@org.chem.ethz.ch
Homepage: http://www.gilmour.ethz.ch
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201316.
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rated aldehydes.[3a,10] Fundamental to the approach was the
notion that union of a secondary b-fluoroamine with an a,b-
unsaturated aldehyde would reversibly generate an iminium
intermediate in which the fluorine atom is positioned vicinal
to an electropositive nitrogen centre (F-Cb-Ca-N+). To satis-
ꢀ
fy the stereoelectronic gauche effect, the C H (donor) and
ꢀ
C F (acceptor) bonds would be antiperiplanar (sCꢀ
!
H
s*CꢀF), such that the syn clinal-endo conformer is favoured.
A density functional theory (DFT) analysis of this effect es-
tablished that the gauche conformation is preferred over the
anti conformation by 16.5 and 18.1 kJmolꢀ1 for the E- and
Z-configured iminium ions, respectively. The substituents on
the fluorine-bearing carbon are thus positioned in a predicta-
ble region of space, such that the upper Re face of the pend-
ant iminium chain is shielded (Scheme 2). Consequently, ad-
Figure 1. Target catalyst scaffolds used in this study.
carbinol precursor of 11 are commercially available,[11]
whilst the syntheses of 3,[3a,12] 8,[13] 10 and 11[2d] have previ-
ously been reported. As indicated in Scheme 3, the synthe-
ses of 9 and 10 commenced from l-proline (12) by esterifica-
tion and subsequent benzylation of the secondary amine to
Scheme 2. Exploiting the fluorine-iminium ion gauche effect for molecu-
lar pre-organisation in the enantioselective, organocatalytic epoxidation
of a,b-unsaturated aldehydes.[3c]
dition of hydrogen peroxide occurs to the Si face of the E-
iminium system[3c] with concomitant trapping of the inter-
mediate enamine to form the trans-epoxide as the major re-
action product (96% ee, R=Ph). Importantly, performing the
same reaction using the non-fluorinated catalyst (CHPh2)
resulted in a 10% erosion of enantioselectivity, indicating
that the fluoro substituent is important to achieve optimal
enantioinduction.
Scheme 3. The synthesis of catalyst scaffolds from l-proline (12).
DAST=diethylaminosulfur trifluoride.
Results and Discussion
With a view to establishing the role of the fluorine atom,
both in the framework of the b-fluoro iminium motif and
also as a component of the C2 fluorodiphenylmethyl sub-
furnish 13. Independent treatment of this common inter-
mediate with the relevant Grignard reagent furnished the
expected carbinols in good yield (90 and 87% for R=4-
tBuPh and 4-biPh, 14 and 15, respectively). Hydrogenolysis
(Pd/C), followed by deoxyfluorination using diethylamino-
sulfur trifluoride (DAST), furnished the desired catalysts 9
and 10 (55 and 60% yield for R=4-tBuPh, 4-biPh, respecti-
vely).[3b] The deoxyfluorination protocol was finally applied
to commercially available carbinol 18 to generate 11 (65%),
thus completing this stage of the target syntheses.
stituent,
a process of structural editing was initiated
(Figure 1).
Starting from catalyst 1, a systematic process of molecular
deletions gave rise to scaffolds 2–5, thus allowing the signifi-
cance of the fluorodiphenylmethyl groupꢀs components to
be assessed. Catalysts 6 and 8 would act as structural, and in
the case of 6, electronic, extremes of 1, whilst 7 is the non-
fluorinated congener. Finally, it was envisaged that by modi-
fying the aromatic groups, improved levels of diastereocon-
trol could be attained; thus scaffolds 9, 10 and 11 were con-
ceived. Conveniently, the proline derivatives 2, 6, 7 and the
The synthesis of the configurationally defined fluorides 4
and 5 posed somewhat more of a challenge. However, in-
spired by Bachꢀs elegant work on the diastereoselective ad-
dition of nucleophiles to chiral benzylic cations,[14] together
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Enantioselective Epoxidation of Enals
FULL PAPER
with the SN1-like character of benzylic deoxyfluorination re-
actions using DAST, it was envisaged that the fluorination
selectivity of precursor 22 might be tuned by appropriate
substitution at nitrogen.[3e] To that end, compound 22 was
prepared from l-proline by following the procedure report-
ed by Chemla and co-workers.[15] Although the final addition
of phenylmagnesium bromide to N-tritylprolinal (21) pro-
ceeded in a highly diastereoselective manner (d.r.>95:<5),
this stereochemical information would prove inconsequen-
tial at the fluorination stage. Treatment of 22 with DAST in
CH2Cl2, followed by cleavage of the trityl group, furnished
the (S,R)-diastereomer 4 with configurational retention (d.r.
27:1), consistent with minimisation of allylic strain in the
transient benzylic cation (I, Scheme 4). Formation of an azir-
idinium intermediate seems unlikely on steric grounds. Syn-
the syn clinal-exo conformation of the hydrochloride salt of
5 (5·HCl) was observed (fNCCF =54.38).[16] In both cases, the
phenyl ring is distal from the nitrogen centre, signifying
that, in this case, the gauche conformer selection is influ-
enced by minimisation of non-bonding interactions. These
observations are consistent with previous structural studies
on fluorinated imidazolidinone scaffolds.[3e]
With amines 1–11 in hand, efforts focussed on preparing,
isolating and characterising the iminium salts derived from
their condensation with trans-cinnamaldehyde.[17] A general
procedure was developed that involved the treatment of the
secondary amines (2–8) with trans-cinnamaldehyde and
HSbF6 in MeOH (Scheme 5). Isolation often proved capri-
cious, however, in many cases (24, 26, 27 and 29), it was pos-
sible to grow crystals of the hexafluoroantimonic salts that
Scheme 4. Diastereoselective syntheses of catalysts 4 and 5.
thesis of the (S,S)-diastereomer 5 was achieved by first
cleaving the trityl group (5N HCl), to form amino alcohol
23. Deoxyfluorination using DAST, this time in the absence
of Hꢁnigs base, furnished the desired compound with a dia-
stereomeric ratio of 20:1 (Scheme 4).
Structural analysis of the ammonium salts of 4 and 5 by
single crystal X-ray diffraction crystallography not only con-
firmed the relative configuration of the two centres, but re-
vealed which of the two possible gauche conformations were
favoured in the solid state (Figure 2). The perchlorate salt of
4 (4·HClO4) preferentially resides in the syn clinal-endo con-
formation, with two symmetry-independent molecules in the
asymmetric unit (fNCCF =ꢀ63.58 and ꢀ55.58). Interestingly,
Scheme 5. Synthesis of b-fluoroiminium salts 24–30. Reagents and condi-
tions: a) trans-cinnamaldehyde, HSbF6, MeOH. b) trans-cinnamaldehyde,
MeOH, 308C.
were suitable for X-ray diffraction analysis (Figure 3). In the
case of 30, it was necessary to start from the perchlorate salt
of 9 to prepare single crystals that were suitable for this
analysis. It is important to note that the iminium salts 25
and 28 have been reported elsewhere,[3a] nevertheless, their
inclusion in Scheme 5 is helpful for completeness. In the
solid state, the (E)-geometry of the iminium functionalities
was generally observed even with the simplest case (2!24),
thus minimising 1,3-allylic strain. This structural study also
Figure 2. X-ray crystallographic analysis of catalysts 4·HClO4 (left) and
5·HCl (right). The counterions have been omitted for clarity. Structure
4·HClO4: two symmetry-independent molecules in the asymmetric unit,
fNCCF =ꢀ63.58 and ꢀ55.58 (structure with fNCCF =ꢀ63.58 shown). Struc-
ture 5·HCl: fNCCF =54.38. Thermal ellipsoids set at the 50% probability
level.
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R. Gilmour et al.
poles. Introduction of a phenyl group to the fluorine-bearing
carbon (26) causes a switch to the syn clinal-endo arrange-
ment (fNCCF =65.48) with the fluorine atom positioned over
the five-membered ring. Intriguingly, inverting the configu-
ration of the fluorine centre does not cause a spacial reposi-
tioning of the pendant phenyl ring, with the epimer (27) this
time adopting a syn clinal-exo conformation. These results
are particularly noteworthy when compared with the analo-
gous fluorinated imidazolidinone systems (1st generation
MacMillan catalyst), for which union with trans-cinnamalde-
hyde elicits a conformational change (sc-endo ! sc-exo and
vice versa) on account of stabilising features that develop
upon condensation (CH-p, p-p, see the conclusions).[3e]
These structural attributes are notably absent in the simpler
pyrrolidine scaffolds.
Incorporation of the second Ph substituent on the fluo-
rine-bearing carbon leads to the syn clinal-endo arrange-
ment (7!28, fNCCF =56.68),[19] placing a shielding group
over the iminium system. Efficient shielding of the p-system
is also observed with the more sterically demanding C2-
trityl derivative (8!29).[20] Finally, introducing a bulky tBu
substituent at the 4-position of the aromatic groups of cata-
lyst 1 led to b-fluoroamine 9. A gauche conformation (syn
clinal-endo, fNCCF =56.28) was also observed in the corre-
sponding iminium salt 30. It was anticipated that the modi-
fied shielding group would improve levels of geometric con-
trol during iminium ion formation (E/Z ratio).[21]
This crystallographic analysis also proved helpful in iden-
tifying systems in which the iminium functionality deviates
from planarity. As noted by Seebach,[22] the consequence of
nucleophilic addition to the trigonal iminium carbon is a pyr-
amidalisation of the nitrogen syn to the approaching nucleo-
phile, consistent with the alternation of orbital parity.[23] It
was envisaged that a structural survey might expose candi-
dates that show a predisposition towards re-hybridisation in
the solid state. However, no discernible correlation could be
drawn between the C2 substituent and the degree of pyra-
midalisation of the iminium nitrogen (Figure 3, d=0.003–
0.08 ꢃ).[24] Furthermore, no clear relationship between the
C2 group and the internal C2-C3-C4-C5 torsion angle [f(ring)
]
could be established. The iminium salt derived from pyrroli-
dine (R=H) and trans-cinnamaldehyde (31) was used as
a control (d=0.024 ꢃ).[25]
To establish the effect of structural editing on catalyst per-
formance, the epoxidation of trans-cinnamaldehyde with
H2O2 in CHCl3 at ambient temperature was studied
(Table 1). Amines 1–11 were employed as organocatalysts at
a loading of 10 mol% and compared to (S)-2-(fluorodiphe-
nylmethyl)pyrrolidine (1; 91%, 82:18 d.r., 96% ee; Table 1,
entry 1).
Figure 3. X-ray crystallographic analyses of the iminium salts 24–31.
Thermal ellipsoids set at the 50% probability level; the counterions have
been omitted for clarity. N.B. the X-ray of iminium salt 28 is derived
from (R)-1 and has a (Z)-configured iminium moiety. For 25 and 29, only
one of the two symmetry-independent molecules in the asymmetric unit
is shown.[24]
The simplest amine, (R)-(ꢀ)-2-methylpyrrolidine (2;
Table 1, entry 2) proved to be a perfectly competent catalyst
for this transformation, furnishing the desired epoxide in
85% yield after 2 h and with a d.r. of 84:16. The enantio-
meric excess of the reaction was, however, only 16%. Intri-
guingly, introduction of the fluoro substituent (catalyst 3;
Table 1, entry 3) resulted in a notable 9% enhancement in
confirmed the gauche preference of the b-fluoroiminium
moiety (fNCCF) in 26, 27 and 30. Intriguingly, iminium salt
25[18] adopts a syn clinal-exo conformation (fNCCF =688 and
77.88, for the two symmetry-independent molecules in the
ꢀ
asymmetric unit), thus opposing the iminium and C F di-
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Enantioselective Epoxidation of Enals
FULL PAPER
Table 1. Enantioselective, catalytic epoxidation of trans-cinnamaldehy-
tion of the benzylic fluoro substituent is inconsequential
(82:18 d.r., 53% ee; Table 1, entry 5). The least effective cat-
alyst in this study proved to be the 2-(trifluoromethyl)pyr-
de.[a]
AHCTUNGTREGrNNNU olidine 6 (Table 1, entry 6), which delivered the product in
low yield (38%) after extended reaction times (15 h). As
previously reported, using the non-fluorinated congener of
b-fluoroamine 1 (7; Table 1, entry 7) gave lower levels of
enantiocontrol (84% ee) and a reduction in yield. The trityl
catalyst 8 also delivered the product in a lower yield (78%)
after 6.5 h, but with 93% ee (Table 1, entry 8). Catalyst 9
gave superior levels of diastereoselectivity compared with 8,
a consequence of introducing tBu groups at the 4-position of
the Ph rings, but the overall performance (yield and enantio-
selectivity) did not exceed that of 1. Comparable performan-
ces were observed for catalysts 10 and 11, which, although
being competent catalysts for this transformation, did not
supersede 1.
Thus far, the substrate scope of this enantioselective epox-
idation catalysed by 1 has been mainly restricted to simple
b-substituted enals. With a view to extending the synthetic
utility of the method, attention turned to the epoxidation of
a,b-disubstituted enals, and, in particular, to cyclic scaffolds
(Table 2).[3a,10r,26] The substrate choice was also motivated by
the dearth of synthetic precedence for synthesising these
valuable intermediates, and the challenges associated with
functionalising medium rings. Whereas cyclohexene-1-car-
boxaldehyde 33 (Table 2, entry 2) is commercially available,
the corresponding 5-, 7-, 8- and 15-membered ring systems
(32, 34, 35 and 36; Table 2, entries 1, 3, 4 and 5, respectively)
can be prepared following established literature proce-
dures.[27]
To facilitate isolation, the epoxy aldehydes were reduced
in situ (NaBH4, MeOH, 08C, 0.5 h) to furnish the corre-
sponding epoxy alcohols, hence, the isolated yields refer to
the two step epoxidation/reduction sequence. However, the
enantioselectivities were measured prior to reduction. To
our delight, treatment of 32 with H2O2 in CHCl3 in the pres-
ence of 10 mol% 1 furnished the desired epoxide in quanti-
tative yield and with good levels of enantiocontrol
(83% ee). Likewise, the six-membered ring system 33 was
also smoothly epoxidised with an exceptional 97% ee, albeit
with a reduction in yield (68%).[3a] Although the seven- and
eight-membered enals 34 and 35 required an increased cata-
lyst loading of 30 mol% 1 and an elevated temperature
(408C), the products could be isolated with excellent levels
of enantiocontrol (88 and 94% ee respectively; for the X-
ray structure of a dinitrobenzoate derivative of 34 see
Figure 4, left).[28] Epoxidation of the 15-membered ring 36
was also performed at 408C using 30 mol% catalyst loading.
The product was isolated as a 6:1 mixture of diastereoiso-
mers (43% isolated product yield, 62% conversion by
1H NMR spectroscopic analysis) with 98% ee recorded for
the major product. Reduction of this epoxy aldehyde to the
corresponding alcohol furnished a clear oil that solidified at
low temperature (ꢀ208C). Gratifyingly, it was possible to
isolate a single crystal that was suitable for X-ray analysis,
thus unambiguously establishing its structure and facilitating
Entry
Organocatalyst
t
Yield
[%][b]
d.r.[c]
82:18
84:16
82:18
85:15
82:18
74:26
77:23
80:20
90:10
85:15
80:20
ee[d]
96[3a]
16
[h]
1
2
2
91
85
91
91
95
38
82
78
86
89
85
2
3[e]
5.5
25
4
1.5
1.5
55
5
53
6
15
66[f]
84[3a]
93
7
2.5
6.5
2
8
9
88
10
11
2
87
2
92
[a] Reactions performed with aldehyde (500 mmol) and H2O2 (1.3 equiv)
in CHCl3 at RT for the specified time. (S)-1 was prepared from l-proline
(98% ee by HPLC) according to reference [3b]. [b] Yield of the isolated
product. [c] Diastereomeric ratio determined by 1H NMR spectroscopic
analysis of the crude reaction mixture. [d] GC measurements performed
on a Supelco b-DEX 120 column (1208C isotherm). [e] Reaction per-
formed in CH2Cl2. [f] Opposite enantiomer isolated.
enantioselectivity (25% ee) and an improved yield (91%).
Although this reaction proved sluggish (5.5 h), a substantial
acceleration was achieved by the addition of a phenyl group
to the fluorine-bearing carbon (1.5 h). In the case of the
(S,R)-diastereomer 4, the product epoxide was formed in ex-
cellent yield (91%) and with appreciable levels of diastereo-
and enantiocontrol (85:15 d.r. and 55% ee, respectively;
Table 1, entry 4). Notably, the (S,S)-diastereomer 5 dis-
played comparable behaviour, signifying that the configura-
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R. Gilmour et al.
Table 2. Enantioselective, catalytic epoxidation of cyclic a,b-disubstituted
enals using catalyst (S)-1.[a]
Finally, to establish the limitations of the method, b,b-dis-
ubstituted enals (37, 38 and 39) and the challenging a,b,b-
trisubstituted enal 40 were exposed to the reaction condi-
tions developed in this study (Table 3). Gratifyingly, the ep-
Entry Substrate
Conditions
Yield
[%][b]
d.r.[c]
ee[d]
1
T
t
AHCTUNGTREGUN[NN mol%] [8C] [d]
1
2
10
10
0
0.5
98 >20:1
83
Table 3. Enantioselective, catalytic epoxidation of b,b-disubstituted enals
and an a,b,b-disubstituted enal using catalyst (S)-1.[a]
Entry
Substrate
Conditions
Yield
[%][b]
ee[c]
1
T
t
RT 3.5
68 >20:1 97[3a]
A
[8C]
[h]
1
2
10
10
ꢀ20
22
96
78
81
83
69
3
4
30
30
40 2.5 56 (70) >20:1
88
94
0
40 2.5 64 (87) >20:1
3
4
10
30
ꢀ20
24
22
56[d]
89
96
5
30
40 2.5 43 (62)
6:1
98
37
64[d]
[a] Reactions were performed in CHCl3. (S)-1 was prepared from l-pro-
line (98% ee by HPLC) according to reference [3b]. [b] Yield of the iso-
lated product following the two-step epoxidation and reduction sequence
(NaBH4, MeOH, 0.5 h, 08C). Numbers in parentheses refer to conversion
by 1H NMR spectroscopy. [c] Diastereomeric ratio determined by
1H NMR spectroscopic analysis of the crude reaction mixture. [d] ee of
the major epoxy aldehyde prior to reduction. GC measurements per-
formed on a Supelco b-DEX 120 column.
[a] Reactions were performed in CHCl3. (S)-1 was prepared from l-pro-
line (98% ee by HPLC) according to reference [3b]. [b] Yield of the iso-
lated product. [c] ee of the major epoxy aldehyde prior to reduction. GC
measurements performed on a Supelco b-DEX 120 column. [d] Yield fol-
lowing reduction to the epoxy alcohol (two steps).
oxidation of prenal (37) furnished the expected product
after 22 h at ꢀ208C (83% ee). The more sterically hindered
diphenyl derivative 38 required prolonged reaction times
and an elevated temperature (08C) to reach completion;
these conditions delivered the product in 81% yield
(69% ee). The 2-cyclohexylidene acetaldehyde 39 also
proved amenable to epoxidation under these conditions. To
facilitate isolation, in situ reduction furnished the epoxy al-
cohol in 56% yield over two steps (89% ee).[29] Finally, our
attention turned to 1-methyl-2-formalcyclohexene (40).[30]
A
recent study by List and co-workers noted that this com-
pound was recalcitrant to epoxidation by using H2O2 in the
presence of a cinchona-derived primary amine and chiral
phosphoric acid.[26] By employing catalyst 1 it was possible
to synthesise the desired epoxide (64% yield over two steps
including in situ reduction) with exquisite levels of enantio-
control (96% ee). Reduction of the epoxy aldehyde, with
concomitant esterification to form the dinitrobenzoate de-
rivative, afforded a solid that could be recrystallised, allow-
ing structural confirmation by X-ray crystallography
(Figure 5).[31]
Figure 4. X-ray crystallographic analysis of a dinitrobenzoate derivative
of 34 (left) and the epoxy alcohol derived from 36 (right). Thermal ellip-
soids set at the 50% probability level.[28]
determination of the relative stereochemistry (Figure 4,
right).[28]
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Enantioselective Epoxidation of Enals
FULL PAPER
by iminium ion formation (Scheme 6). The syn clinal-endo
conformation of salt 41 switches to syn clinal-exo in the imi-
nium salt 42 such that the system benefits from a stabilising
C-H!p interaction. Conversely, the syn clinal-exo confor-
Figure 5. X-ray crystallographic analysis of the dinitrobenzoate derivative
of 40. Two symmetry-independent molecules in the asymmetric unit. The
second molecule displayed a different conformation of the six-membered
ring. Thermal ellipsoids set at the 50% probability level.
Conclusion
Having identified (S)-2-(fluorodiphenylmethyl)pyrrolidine
(1) as an effective catalyst for the enantioselective epoxida-
tion of a,b-unsaturated aldehydes, a process of molecular
editing was completed. Fundamental to the reaction design
is the fluorine-iminium ion gauche effect, which is triggered
upon union of a secondary b-fluoroamine with an enal to
generate a transient b-fluoroiminium motif. The syn clinal-
endo conformation (fNCCF =578) positions one of the shield-
ing phenyl groups on the fluorine-bearing carbon over the
pendant iminium chain, thus facilitating enantioinduction.
Structural modifications of the C2 (fluorodiphenyl)methyl
group were generally found to have unfavourable ramifica-
tions on catalytic efficiency in the enantioselective epoxida-
tion of trans-cinnamaldehyde. During the course of prepar-
ing a small catalyst library, it was possible to further exploit
the use of DAST for the synthesis of non-chiral (diarylfluo-
Scheme 6. Comparing the conformations of 4 and 5 with those of imida-
zolidinones 41 and 43, and their respective iminium salts.
ACHTUNGTRENNUNGro)methyl moieties. However, this study presented a notable
synthetic challenge at the outset, namely developing a diaste-
reoselective route to the configurationally defined benzylic
fluorides 4 and 5. By exploiting the partial SN1-like charac-
ter of DAST mediated deoxyfluorinations of benzylic alco-
hols, it was possible to bias the diastereoselectivity of fluori-
nation by appropriate functionalisation of the pyrrolidine ni-
trogen. Moreover, it was possible to convert a number of
the secondary amines used in this study into their corre-
sponding iminium salts by union with trans-cinnamaldehyde.
Crystallographic analysis unambiguously established the
solid state structures of a number of derivatives (see
Figure 3), confirming the (E)-geometry of the iminium
moiety and the expected fluorine-iminium ion gauche effect
in 26, 27 and 30. From this structural survey it was also pos-
sible to determine which of the two possible gauche confor-
mations was present in 25–28 and 30. The conformational
selection of syn clinal-endo versus syn clinal-exo is subtle
and depends on the structural nuances of the entire scaffold.
Intriguingly, no conformational change was observed upon
condensation with trans-cinnamaldehyde in either 4!26 (sc-
endo!sc-endo) or 5!27 (sc-exo!sc-exo). This is particu-
larly noteworthy because the analogous imidazolidinone sys-
tems 41 and 43 (based on the MacMillan 1st generation cat-
alyst) do undergo conformational changes that are triggered
mation present in 43 changes to syn clinal-endo in the imini-
um salt 44. Admittedly, the imidazolidinone scaffold is nota-
bly more complex by virtue of the N-methyl amide and
gem-dimethyl groups, which presumably render the structure
more rigid and allow for stabilising interactions that does
not occur in the conformationally more labile pyrrolidine
system.
Finally, with a view to expanding the substrate scope of
this transformation, the enantioselective epoxidation of
cyclic a,b-disubstituted enals was investigated. Excellent
levels of enantiocontrol were achieved (up to 98% ee), pro-
viding facile access to a valuable family of bicyclic inter-
mediates. Furthermore, amine 1 was found to effectively cat-
alyse the epoxidation of b,b-disubstituted enals, such as
prenal, and the a,b,b-trisubstituted enal 40. To the best of
our knowledge, this constitutes the first enantioselective,
catalytic report of the latter transformation.
Experimental Section
General procedures: All reactions using air- or moisture-sensitive com-
pounds were carried out in flame-dried and evacuated glassware under
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R. Gilmour et al.
an atmosphere of argon. Fluorination reactions were performed under an
atmosphere of argon in pre-dried Teflon vessels. Solvents for these reac-
tions were dried according to standard procedures or were taken from
a solvent drying system. All chemicals were reagent grade and used as
supplied unless otherwise stated. Solvents for extractions and chromatog-
raphy were technical grade and distilled prior to use. Extracts were dried
over technical grade Na2SO4 or MgSO4. Analytical thin layer chromatog-
raphy (TLC) was performed on pre-coated Merck silica gel 60 F254 plates
(0.25 mm). Visualisation was accomplished using ultraviolet light (l=
254 nm) or by dipping in cerium ammonium molybdate (CAM) stain
thank Professor Dr. Jack. D. Dunitz and Professor Dr. Dieter Seebach
for valuable discussions and for their continued support.
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12062–12064; Angew. Chem. Int. Ed. 2011, 50, 11860–11871.
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17, 13433–13437; g) For an excellent review, see: L. Hunter, Beil-
stein J. Org. Chem. 2010, 6, DOI: 10.3762/bjoc.6.38.
[(NH4)6Mo7O24·4H2O (50 g), CeACHTUNTRGNEUNG(SO4)2 (10 g) and H2SO4 (100 mL) in
water (900 mL)] or ninhydrine stain, followed by heating. Flash column
chromatography was carried out on Fluka silica gel 60 (230–400 mesh).
Concentration in vacuo was performed at ca. 10 mbar and 408C, drying
at approximately 10ꢀ2 mbar and RT. 1H, 19F and 13C NMR spectra were
recorded with a Varian AVANCE 300 MHz, a Bruker DRX 400 MHz or
a Bruker AV 400 MHz spectrometer at ambient temperature. Some spec-
tra were recorded by the Laboratory for Organic Chemistry (ETH)
NMR service with a Bruker AV 600 MHz, DRX 600 MHz or DRX
500 MHz spectrometer at ambient temperature. Chemical shifts d are re-
ported in ppm relative to the residual solvent. Coupling constants J are
reported in Hz. The multiplicities are reported as: s=singlet, br s=broad
singlet, d=doublet, t=triplet, q=quartet, m=multiplet. Melting points
were measured with a Bꢁchi B540 melting point apparatus and are un-
corrected. IR spectra were measured with a PerkinElmer Spectrum 100
FTIR spectrometer and reported in cmꢀ1; the intensities of the bands are
reported as: w=weak, m=medium, s=strong. Optical rotations were ob-
tained with a JASCO P-2000 polarimeter. HPLC spectra were recorded
with an Agilent 1100 series (DAD, Agilent technologies 1200 series)
using Reprosil Chiral-OM (5 mm, 250ꢄ4.6 mm) or CHIRACEL OJH
(5 mm, 250ꢄ4.6 mm) columns and n-hexane/iso-propanol as the eluent.
HRMS (ESI and EI) were performed by the MS service at the Laborato-
ry for Organic Chemistry, ETH Zurich.
[3] For examples from this laboratory, see: a) C. Sparr, W. B. Schweizer,
H. M. Senn, R. Gilmour, Angew. Chem. 2009, 121, 3111–3114;
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Tanzer, J. Bachmann, R. Gilmour, Synthesis 2010, 1394–1397; c) D.
ˇ
Seebach, R. Gilmour, U. Groselj, G. Deniau, C. Sparr, M.-O. Ebert,
ˇ
ˇ
A. K. Beck, L. B. McCusker, D. Sisak, T. Uchimaru, Helv. Chim.
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2010, 29, 4424–4427.
General procedure for the epoxidation of trans-cinnamaldehyde (Table 1,
entry 1): (S)-2-(Fluorodiphenylmethyl)pyrrolidine 1 (12.8 mg, 50.0 mmol)
and hydrogen peroxide (30% in H2O, 66.4 mL) were added to a solution
of trans-cinnamaldehyde (66 mg, 500 mmol) in CHCl3 (1.0 mL) at RT.
The reaction was stirred at the specified temperature and monitored by
TLC and/or NMR spectroscopy. Upon completion, the reaction was
quenched by addition of saturated aqueous Na2S2O3 followed by extrac-
tion of the aqueous phase with Et2O (3ꢄ5 mL). The combined organic
phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The
crude product was purified by flash column chromatography on SiO2
(Et2O/n-pentane, 1:4) and the solvents were removed under reduced
pressure. The product epoxide was isolated as a light-yellow oil (91%,
96% ee recorded for the major product). Rf = 0.40 (EtOAc/cyclohexane,
1:4); [a]2D5 =ꢀ14.8 (c 0.14, CHCl3); 1H NMR (300 MHz, CHCl3): d=9.20
(d, 3J=6.0 Hz, 1H; CHO), 9.09 (d, 3J=6.1 Hz, 1H; CHO*), 7.20–7.45
[8] D. W. C. MacMillan, Nature 2008, 455, 304–308.
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a small molecule catalyst, see: T. Kawabata, M. Nagato, K. Takasu,
K. Fuji, J. Am. Chem. Soc. 1997, 119, 3169–3170.
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secondary amines, see: a) M. F. A. Adamo, V. K. Aggarwal, M. A.
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11413–11424; i) X. Liu, Y. Li, G. Wang, Z. Chai, Y. Wu, G. Zhao,
Tetrahedron: Asymmetry 2006, 17, 750–755; j) A. Lattanzi, Adv.
Synth. Catal. 2006, 348, 339–346; k) H. Sundꢅn, I. Ibrahem, A. Cꢆr-
dova, Tetrahedron Lett. 2006, 47, 99–103; l) A. Lattanzi, A. Russo,
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Lett. 2010, 12, 5434–5437; s) C. De Fusco, C. Tedesco, A. Lattanzi,
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Zhao, G. Zou, Adv. Synth. Catal. 2011, 353, 3129–3133; v) For
a recent example of enantioselective organocatalytic aziridination
using secondary amines, see: L. Deiana, P. Dziedzic, G.-L. Zhao, J.
Vesely, I. Ibrahim, R. Rios, J. Sun, A. Cꢆrdova, Chem. Eur. J. 2011,
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3
3
(m, 10H; PhH and PhH*), 4.40 (d, J=4.6 Hz, 1H; CHPh*), 4.17 (d, J=
1.8 Hz, 1H; CHPh), 3.45 (dd, 3J=4.5 Hz, 3J=6.1 Hz, 1H; CHCHO*),
3.45 ppm (dd, 3J=1.8 Hz, 3J=6.0 Hz, 1H; CHCHO) (* denotes the
minor 2R,3R isomer). The ee was determined by GC analysis (Supelco b-
DEX 120 column; 958C isotherm): tR =60.6 (2S,3R), 60.9 (2R,3S), 59.4
(2S,3S), 59.6 min (2R,3R).
Full experimental procedures are provided in the Supporting Informa-
tion.
Acknowledgements
We gratefully acknowledge generous financial support from the Alfred
Werner Foundation (assistant professorship to R.G), the Swiss National
Science Foundation (E.M.T, grant number 200021 129498), and the ETH
Zꢁrich (L.E.Z was an ETH Fellow, 2010–1011). Thanks are also due to
Dr. Christof Sparr for his interest in this work, Ms. Deborah Meyer and
Mr. Raphael Frey for preliminary studies on the synthesis of b-fluoroa-
mine 5, and Mr. Michael Solar for collecting X-ray data. Finally, we
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Enantioselective Epoxidation of Enals
FULL PAPER
[11] (R)-(–)-2-methylpyrrolidine (2) CAS number 41720-98-3; (R)-(–)-2-
(trifluoromethyl)pyrrolidine, 97% (6) CAS: 119618-29-0; (S)-2-di-
phenyl methylpyrrolidine (7) CAS: 119237-64-8; (S)-(–)-a,a-di(2-
naphthyl)-2-pyrrolidinemethanol (18; 97%) CAS: 127986-84-9.
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supplementary crystallographic data for this paper. These data can
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20636–20641; j) Also see references.[3a, 3c,3e]
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[18] CCDC-716829 (25) contains the supplementary crystallographic
data for this paper. These data can be obtained free of
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[19] CCDC-716830 (28) contains the supplementary crystallographic
data for this paper. These data can be obtained free of
Received: April 18, 2012
Revised: May 31, 2012
Published online: && &&, 2012
Chem. Eur. J. 2012, 00, 0 – 0
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www.chemeurj.org
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R. Gilmour et al.
Fluorine Finesse! The b-fluoroamine
(S)-2-(fluorodiphenylmethyl)pyrroli-
dine (1) is an effective catalyst for the
enantioselective epoxidation of a,b-
unsaturated aldehydes (see scheme).
Application of this catalyst to challeng-
ing cyclic a,b-disubstituted enals, b,b-
disubstituted enals, and an a,b,b-trisub-
stituted enal proceed in a highly enan-
tioselective fashion (up to 98% ee).
Enantioselective Epoxidation
E.-M. Tanzer, L. E. Zimmer,
W. B. Schweizer,
R. Gilmour* ................... &&&& — &&&&
Fluorinated Organocatalysts for the
Enantioselective Epoxidation of Enals:
Molecular Preorganisation by the
Fluorine-Iminium Ion Gauche Effect
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These are not the final page numbers!