Organocatalytic asymmetric wittig reactions: Generation of enantioenriched axially chiral olefins breaking a symmetry plane

Article abstract of DOI:10.1055/s-0031-1289516

The first catalytic asymmetric Wittig reaction is presented. Hydrogen-bond donors catalyze the [2+2] cycloaddition reaction between stabilized phosphorus ylides and 4-substituted cyclohexanones, breaking their symmetry plane and furnishing axially chiral

Full text of DOI:10.1055/s-0031-1289516

LETTER
2745
Organocatalytic Asymmetric Wittig Reactions: Generation of
Enantioenriched Axially Chiral Olefins Breaking a Symmetry Plane
O
rganocatalytic
u
A
symmetric
c
Wittig
R
e
i
Luca Bernardi*a
a
Department of Organic Chemistry ‘A. Mangini’, University of Bologna, Viale Risorgimento 4, 40136 Bologna, Italy
Fax +39(051)2093654; E-mail: luca.bernardi2@unibo.it
Departamento de Química Orgánica, Universidad Autónoma de Madrid, Cantoblanco 28049, Madrid, Spain
b
Received 16 May 2011
This article is dedicated to Professor Alfredo Ricci on the occasion of his retirement, for his invaluable mentorship and support
methods for C=C bond formation have found ubiquitous
applications in organic synthesis,11 including preparations
of axially chiral olefins.12
Abstract: The first catalytic asymmetric Wittig reaction is present-
ed. Hydrogen-bond donors catalyze the [2+2] cycloaddition reac-
tion between stabilized phosphorus ylides and 4-substituted
cyclohexanones, breaking their symmetry plane and furnishing ax-
ially chiral olefins with moderate stereoselectivities.
symmetry
breaking
symmetry plane
(no axis)
chirality
axis
Key words: asymmetric catalysis, chirality, olefination, Wittig
reaction, ylides
EWG
H
R
H
chiral H-bond-
donor catalyst
O
R
H
H
(Ra)-3
(Sa)-3
Asymmetric organocatalysis has witnessed spectacular
advances over the last few years.1 Transmission of the
chiral information from catalyst to substrate has been
achieved with high fidelity in an impressive range of
chemical transformations. In most cases, the result of
these efficient asymmetric protocols is the stereocon-
trolled formation of a chiral center, typically a tetrahedral
carbon atom bearing four different substituents. Also ki-
netic resolutions, wherein the catalyst distinguishes two
enantiomeric substrates and desymmetrization processes,
wherein the catalyst recognizes local asymmetry, discrim-
inating two enantiotopic moieties, have been studied in
detail. In these latter cases, substrate/product asymmetry
is again mostly due to tetrahedral carbon atoms. However,
chirality is not restricted to the presence of a chiral center.2
Compounds featuring a chirality axis or plane are in fact
of tremendous importance. Axial/planar chirality is show-
cased in many natural compounds,3 ligands or catalysts
for asymmetric synthesis,4 synthetic intermediates,5 and
molecular switches/motors.6 Use of organocatalysis for
the stereocontrolled generation of chiral axes or planes
has, however, been largely ignored.7
EWG
+
1
H
R
PAr3
EWG
2
Scheme 1 Asymmetric olefination of ketones 1
Olefination of a ketone featuring a symmetry plane but
lacking a symmetry axis leads in fact to an axially chiral
alkene, as exemplified in Scheme 1 for the benchmark re-
action for asymmetric Wittig-type processes, with 4-sub-
stituted cyclohexanones 1.13 Stereoselectivity in this class
of symmetry-breaking transformations has been achieved
in the past using Wittig and related olefinations, exploit-
ing stoichiometric chiral auxiliaries and reagents.13,14
A
single example instead made use of a chiral catalyst.15,16
Horner–Wadsworth–Emmons olefination of 4-tert-butyl-
cyclohexanone (1a), performed under phase-transfer-
catalysis conditions, gave the corresponding olefin in only
moderate enantioselectivity (<57% ee). We tentatively as-
cribed this moderate stereocontrol to the reversibility of
the first step in Horner–Wadsworth–Emmons reac-
tions.11a We thus set our focus on the Wittig reaction with
stabilized phosphorus ylides 2, which is known to proceed
irreversibly through an asynchronous [2+2]-cycloaddition
pathway.17 To achieve enantioenrichment in the resulting
alkenes 3, we envisioned the use of chiral hydrogen-bond
donors18 as catalysts, to coordinate the cyclohexanone
carbonyl which bears a partial negative charge during the
cycloaddition (Scheme 2). Applying a simplified working
model, selectivity in the prochiral face of the ylide 2 at-
tacking in the [2+2]-cycloaddition step results in the pre-
dominant formation of one of the two enantiomeric
products (Sa)-3 and (Ra)-3. Stereospecificity in the elimi-
nation of phosphine oxide should in fact ensure full cen-
tral-to-axial chirality transfer. This model assumed a high
Herein, we present the first example of a catalytic asym-
metric Wittig reaction (Scheme 1). The reaction furnishes
enantioenriched axially chiral olefins 3 and is catalyzed
by hydrogen-bond donors. The Wittig8 olefination be-
tween carbonyl compounds and phosphorus ylides, to-
gether with its related counterparts (Horner9 involving
phosphine oxides and Horner–Wadsworth–Emmons10 in-
volving phosphonates), is amongst the most venerable
transformations of organic chemistry. These powerful
SYNLETT 2011, No. 18, pp 2745–2749
Advanced online publication: 06.10.2011
DOI: 10.1055/s-0031-1289516; Art ID: S04211ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
1
1

2746
L. Gramigna et al.
LETTER
prevalence of the equatorial conformer in the parent cy- for a representative set of results, there is not a clear cor-
clohexanone 1, as well as exclusive attack at the equatori- relation between catalyst acidity and activity. Amongst
al face of the ketone19 by the bulky ylide 2 nucleophile. the (thio)urea catalysts 4a–d tested, 4a seemed to be the
However, competing reaction pathways cannot be exclud- most efficient (Table 1, entries 1–4). Bifunctional cata-
ed.
lysts 4k,l bearing a basic tertiary amino group were in-
stead found to be unsuitable (Table 1, entries 11 and 12).
The same holds for the rather acidic triflimide catalysts
4e,f, as well as for the binaphthols 4h–j (Table 1, entries
5, 6, 8–10). In contrast, a-amino and a-hydroxy acid de-
rivatives 4m,n catalyzed the reaction to some extent; ste-
reoselectivity was, however, very poor (Table 1, entries
13 and 14). The most efficient catalyst in terms of enan-
tioinduction was found to be the (R,R)-TADDOL (4g),
We started our investigations studying the asymmetric
Wittig reaction between 4-tert-butylcyclohexanone (1a)
and phosphorus ylide 2a, bearing a methyl ester as stabi-
lizing group (Table 1). Confident in that weak hydrogen-
bond donors, such as alcohols, phenols, (thio)ureas, and
aliphatic carboxylic acids, would not protonate the ylide
leading to catalyst deactivation,20,21 we screened a number
of such compounds18 in the reaction. As shown in Table 1
Table 1 Representative Results from the Screening of the Different Catalysts 4a–n in the Wittig Reaction between 1a and 2aa
X
N
X
N
O
S
N
N
Ar
t-Bu
4a–n (20 mol%)
toluene (0.20 M)
r.t., 60 h
N
H
N
H
H
Ar
H
H
Ar
Y
X
CO2Me
1a
H
H
4a: X = S, Ar = 3,5-(F3C)2C6H3
4b: X = O, Ar = 3,5-(F3C)2C6H3 4d: X = H, Y = OH, Ar = 3,5-(F3C)2C6H3
4c: X = OH, Y = H, Ar = 3,5-(F3C)2C6H3
+
t-Bu
CO2Me
3a
R
N
R
N
Ph
R
Ph
PPh3
2a
O
O
OH
Tf
Tf
OH
OH
Ar
N
OH
Ph
H
H
Ph
S
H
4e: R = Ph
4f: R = -(CH2)4-
H
H
4g: (R,R)-TADDOL
HO
N
N
N
H
R
4h: R = H
4i: R = Ph
MeO
OH
MeO
CO2H
4j: R = 4-PhC6H4
Ph
CO2H
NHBoc
N
N
N
H
4k
4l: Ar = 3,5-(F3C)2C6H3
4m
4n
Entry
1
Catalyst
4a
Conversion (%)b
ee (%)c
45
25
20
17
–
20
11
7
2
4b
4c
3
4
4d
4e
10
<5
<5
6
5
6
4f
–
7
4g
53
2
8
4h
4i
15
4
9
11
0
10
11
12
13
14
4j
5
4k
4l
<5
7
–
3
4m
4n
11
14
16
14
a Conditions: ketone 1a (0.05 mmol), catalyst 4a–n (0.010 mmol, 20 mol%), ylide 2a (0.0625 mmol, 1.25 equiv), toluene (0.25 mL), 60 h, r.t.
b Determined by 1H NMR spectroscopy.
c Determined by chiral stationary phase HPLC.
Synlett 2011, No. 18, 2745–2749 © Thieme Stuttgart · New York

LETTER
Organocatalytic Asymmetric Wittig Reactions
2747
Ar
Ar
H
H
*A
*A
Ar
Ar
Ar
H
equatorial
O
O
H
Ar
P
EWG
ylide Re
conformer of 1
P
face attacks
equatorial
favored
R
R
R
R
EWG
attack favored
R
R
H
EWG
O
(Sa)-3
(Ra)-3
Ar
Ar
Ar
EWG
H
R
ylide Si
face attacks
Ar
Ar
Ar
O
P
O
P
EWG
H
R
EWG
cat. (HA*)
H
EWG
P(Ar)3
2
stereospecific
elimination, central
to axial chirality
transfer
transition-state
stabilization by the
chiral H-bond-donor
catalyst (HA*)
O
Scheme 2 Simplified working model for the asymmetric Wittig reaction catalyzed by hydrogen-bond donors (HA*)
which produced the axially chiral alkene 3a with a prom-
ising 53% ee, despite the very low conversion (Table 1,
entry 7).
Table 2 Representative Results from the Screening of the Different
Ylides 2a–j in the Wittig Reactiona
4a or 4g (20 mol%)
toluene (0.20 M)
r.t., 60 h
H
EWG
O
The effect of stereoelectronic variations at the ylide 2 was
studied next, using the most promising catalysts 4a22 and
4g23 (Table 2). Whereas the steric bulk of the ester group
did not influence the enantioinduction to a great extent, in-
creasing electron density at the ester did improve the con-
version, with both 4a and 4g as catalysts (Table 2, entries
1–6). The tert-butyl derivative 2c gave the best results in
terms of conversion. Enantioselectivity was instead
slightly better with the benzyl ester ylide 2b, but only
when 4g was used (Table 2, entry 4). We somehow ex-
pected ketone-, cyano-, and thioester-derived ylides 2d–f
to be less reactive, due to the strong electron-withdrawing
properties of these stabilizing groups suppressing nucleo-
philicity. Indeed, only the cyano-derived ylide 2f fur-
nished the corresponding olefin 3f (Table 2, entries 7–10).
Stereoselectivity was similar or lower compared to the es-
ter-derived ylides 2a–c (Table 2, entries 1–6). This stabi-
lizing group was thus discarded. The lack of reactivity
displayed by p-nitrophenyl24 and amide-derived ylides
2g,h was instead much more surprising (Table 2, entries
11 and 12). At this point, an extensive screening of sol-
vents and reaction dilutions was undertaken, without giv-
ing notable improvements. Similarly, variation of the
catalyst structure, using TADDOL derivatives bearing
different aromatic groups (1-naphthyl and 2-naphthyl),
and a series of 1,2-cyclohexanediamine-derived thio-
ureas, did not improve the results obtained with the lead
catalysts 4a and 4g.
EWG
t-Bu
t-Bu
+
PAr3
2a–j
1a
3a–h
Entry Cat. 4 Ylide 2EWG
Ar
Conv. of 3 ee
(%)b
(%)c
1
2
4a
4g
4a
4g
4a
4g
4a
4a
4a
4g
4a
4a
4a
4g
4g
4g
4g
2a
2a
2b
2b
2c
2c
2d
2e
2f
CO2Me
CO2Me
CO2Bn
CO2Bn
CO2t-Bu
CO2t-Bu
COMe
COSBn
CN
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3a 20
3a 6
45
53
37
68
48
64
–
3
3b 30
3b 10
3c 52
3c 22
3d <5d
3e <5d
3f 32
3f 18
3g <5d
3h <5d
3c 82
3c 55
3b 41
3c 72
3c 50
4
5
6
7
8
–
9
48
27
–
10
11
12
13
14
15
2f
CN
2g
2h
2i
4-O2NC6H5 Ph
CONMe2 Ph
–
CO2t-Bu
CO2t-Bu
CO2Bn
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
22
60
68
70
75
2i
2j
Therefore we turned again our attention to a fine tuning of
the ylide structure, with the aim of increasing its nucleo- 16e
2i
CO2t-Bu
CO2Bn
philicity in order to perform the reaction at lower temper-
17e
2j
atures. To this end, 2i and 2j – bearing electron-rich aryl
groups at phosphorus25 – were prepared and tested in the
reaction. Indeed, these species showed enhanced reactivi-
ty (Table 2, entries 13–15). Enantioselectivity was, how-
a Conditions: ketone 1a (0.05 mmol), catalyst 4a or 4g (0.010 mmol,
20 mol%), ylide 2a–j (0.0625 mmol, 1.25 equiv), toluene (0.25 mL),
60 h, r.t.
b Determined by 1H NMR spectroscopy.
ever, not compromised only when TADDOL 4g was used
as catalyst. Using these electron-rich ylides 2i and 2j, and
swapping reaction stoichiometry, it was finally possible to
cool the reaction to 0 °C, with a beneficial effect on the
enantioselectivity (Table 2, entries 16 and 17). Good lev-
c Determined by chiral stationary phase HPLC.
d Same result with catalyst 4g.
e Reaction performed at 0 °C, using 3 equiv of 1a.
Synlett 2011, No. 18, 2745–2749 © Thieme Stuttgart · New York

2748
L. Gramigna et al.
LETTER
els of conversion were obtained, even at this reduced tem-
perature, with the more electron-rich tert-butyl ester
derived ylide 2i.
Acknowledgment
We acknowledge financial support from University of Bologna.
S. D. thanks Universidad Autónoma de Madrid and Comunidad
Autónoma de Madrid for a fellowship. We thank Prof. B. Bonini for
stimulating discussion.
Using these latter reaction conditions, and prolonging
reaction time to 144 hours, the effect of variations in the
cyclohexanone 4-substituent was briefly explored. As
shown in Table 3, results comparable with the parent 4-
tert-butyl-substituted cyclohexanone 1a were obtained
using a range of 4-alkyl-substituted cyclohexanones 1b–d
(Table 3, entries 1–4), as well as 4-phenyl-substituted 1e
(Table 3, entry 6), using ylide 2i. As we were not able to
determine the enantiomeric excess of the olefin 3k de-
rived from 4-methyl cyclohexanone 1d, the reaction was
also performed with the corresponding benzyl ester ylide
2j (Table 3, entry 5). Lower yield of the olefin 3l was ob-
tained, as expected.
References and Notes
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Table 3 Variation of the Cyclohexanone 1a
4g (20 mol%)
toluene (0.20 M)
0 °C, 144 h
H
EWG
O
R
+ 2i,j
R
3c,i–k,m: EWG = CO2t-Bu
3l: EWG = CO2Bn
1a–e
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Entry
1
R
3
Yield (%)b ee (%)c
1
1a
1b
1c
1d
1d
1e
t-Bu
i-Pr
n-Pr
Me
Me
Ph
3c
3i
74
76
76
83
41
93
70
59
64
n.d.
56
67
2
3
3j
3k
3l
4
5d
6
3m
a Conditions: ketone 1a–e (0.45 mmol), catalyst 4g (0.030 mmol),
ylide 2i (0.15 mmol), toluene (0.75 mL), 0 °C, 144 h.
b Isolated yield after chromatography on silica gel.
c Determined by chiral stationary phase HPLC.
d Ylide 2j was used, in a toluene–n-hexane (1:3) solvent mixture.
In conclusion, the present work unequivocally demon-
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reactions can be controlled using hydrogen-bond donors
as catalysts. Coordination and stabilization of the transi-
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aphosphoethane intermediate carrying the chiral
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Synlett 2011, No. 18, 2745–2749 © Thieme Stuttgart · New York

LETTER
Organocatalytic Asymmetric Wittig Reactions
2749
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4-substituted cyclohexanones, giving the corresponding
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Information for details.
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organocatalysis, see: (a) Albrecht, Ł.; Albrecht, A.;
Synlett 2011, No. 18, 2745–2749 © Thieme Stuttgart · New York

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