Sequential stereoselective catalysis: Two single-flask reactions of a substrate in the presence of a bifunctional chiral ligand and different transition metals

Article abstract of DOI:10.1002/ejoc.200390201

A new bifunctional ligand capable of promoting different stereoselective catalytic transformations in combination with different transition metals has been prepared by connecting with a spacer a bis(oxazoline) to dihydroquinidine; this ligand was employed in a one-flask procedure in which methyl (E)-3-(4-vinylphenyl)propenoate underwent first cyclopropanation at the electron-rich double bond and then dihydroxylation at the electron-poor alkene to afford a product containing four stereocenters with complete regiocontrol and high stereoselectivity. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200390201

FULL PAPER
Sequential Stereoselective Catalysis: Two Single-Flask Reactions of a
Substrate in the Presence of a Bifunctional Chiral Ligand and Different
Transition Metals
Rita Annunziata,[a] Maurizio Benaglia,*[a] Mauro Cinquini,[a,b] Franco Cozzi,[a,b] and
Alessandra Puglisi[a]
Keywords: Stereoselective catalysis / Bifunctional ligand / Chiral ligands / Cyclopropanation / Dihydroxylation
A new bifunctional ligand capable of promoting different
stereoselective catalytic transformations in combination with
different transition metals has been prepared by connecting
with a spacer a bis(oxazoline) to dihydroquinidine; this li-
gand was employed in a one-flask procedure in which
cyclopropanation at the electron-rich double bond and then
dihydroxylation at the electron-poor alkene to afford a prod-
uct containing four stereocenters with complete regiocontrol
and high stereoselectivity.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
methyl (E)-3-(4-vinylphenyl)propenoate underwent first Germany, 2003)
Introduction
and stereo-controlled fashion, two one-flask reactions on a
single substrate would further demonstrate its applica-
bility.[3,4] Here, we report the results of this study.
The possibility of performing highly stereoselective cata-
lytic transformations at different sites of a given substrate
in a sequential fashion and in a single reaction flask rep-
resents an important result, which can further improve the
widespread applications of catalytic processes.[1]
Results and Discussion
In this context, we have recently reported the synthesis
of the bifunctional ligand 1 (Scheme 1) containing a bis(ox-
azoline) moiety connected to a dihydroquinidine residue.
This ligand was employed in the presence of CuI and OsVIII
species to promote the cyclopropanation and the dihydrox-
ylation of different molecules of styrene in a single reaction
flask. Both processes occurred with good levels of stereo-
control to afford adducts 2 and 3 in 79 and 70% ee, respec-
tively.[2]
First, we decided to synthesize a bifunctional ligand simi-
lar to 1 by a new, shorter, and more practical reaction se-
quence than the one previously employed.[2] We performed
the synthesis of the new bis(oxazoline)-dihydroquinidine
adduct 9 as described in Scheme 2.
Scheme 1. Structure of ligand 1 and adducts 2 and 3
Although this result showed the feasibility of this ap-
proach toward sequential stereoselective catalysis, we
thought that the possibility of performing, in a highly regio-
[a]
Dipartimento di Chimica Organica e Industriale, Universita’
degli Studi di Milano
Via Golgi 19, 20133 Milano, Italy
[b]
CNR-ISTM, Universita’ degli Studi di Milano
Via Golgi 19, 20133 Milano, Italy
Scheme 2. Synthesis of bifunctional ligand 9
1428
 2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0408Ϫ1428 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2003, 1428Ϫ1432

Sequential Stereoselective Catalysis
FULL PAPER
Commercially available tert-butyl-substituted bis(oxazo-
line) 4 was metallated with MeLi (2.2 mol-equiv., Ϫ55 °C
in THF for 1 h),[5] and alkylated first with 4-allyloxybenzyl
[6]
bromide 5 (1 mol-equiv., 40 min at Ϫ10 °C)
then with
MeI (3 mol-equiv., 15 h from Ϫ10 °C to room temp.). From
this reaction, bis(oxazoline) 6 was obtained in 40% isolated
yield. It must be noted that this one-pot procedure afforded
6 in better yield and a shorter time than procedures involv-
ing either methylation (or benzylation) of 4, isolation of the
monoalkylated product by chromatography, and further
benzylation (or methylation). It also greatly shortened the
synthesis of 6 from diethyl methylmalonate that we have
recently described en route to poly(ethylene glycol)-sup-
ported bis(oxazoline)s.[6]
Deallylation of compound 6, carried out at 90 °C with
Pd(OAc)2 and PPh3 in EtOH in the presence of SiO2, gave
phenol 7 in 78% yield. This was then O-alkylated with di-
hydroquinidine 6-bromohexanoate (8)[2] in the presence of
Cs2CO3 (DMF, 4 d, 50 °C) to afford ligand 9 in 60% yield.
As a suitable substrate for testing ligand 9, methyl (E)-
3-(4-vinylphenyl)propenoate (10) (Scheme 2) was selected,
with the aim of exploiting the different electronic properties
of its two double bonds to secure high regioselectivity in
the first transformation. In a control experiment, it was
shown that the cyclopropanation of an equimolecular mix-
Scheme 3. Stereoselective synthesis of adducts 11, 12, and 13; L*:
dihydroquinidine 4-chlorobenzoate or 9
ture of styrene and methyl cinnamate with ethyl diazoacet- 83:17. The ee of the major diastereoisomer, made of 12 and
ate catalyzed by a CuOTf/bis(oxazoline) complex occurred ent-12, was determined to be 95%; that of the minor dia-
exclusively on styrene, whereas the unsaturated ester could stereoisomer (13 ϩ ent-13) was found to be 99% (ee estab-
be quantitatively recovered. Therefore, compound 10 was lished by HPLC). It must be noted that from the reaction
prepared in 77% yield by olefination of 4-vinylbenzaldehyde mixture it was possible to recover the unchanged mixture
under HornerϪWadsworthϪEmmons conditions followed of (R,R)-11 and (S,S)-11 in 42% yield, enriched from the
by flash-chromatographic separation to obtain the pure originally observed 91:9 ratio (see above) up to a 96:4 ratio.
(E) isomer.
These results can be interpreted as follows. The osmyl-
With adduct 10 in hand, we performed experiments to ation reaction proceeds with kinetic resolution,[11] with
assess the stereoselectivity of the cyclopropanation and di- (S,S)-11 reacting with the Os/chiral ligand complex faster
hydroxylation reactions carried out in the presence of metal and more stereoselectively than (R,R)-11. The fact that 13
complexes of conventional ligands (Scheme 3). Thus, the was obtained in higher ee than 12 supports this hypothesis,
cyclopropanation of 10 under Evans’ conditions (excess and suggests that the stereochemical preference of the os-
ethyl diazoacetate, 0.05 mol-equiv. of CuOTf/6, CH2Cl2, mium catalyst matched that of the (S,S) substrate.[12] On
[7]
room temp., 24 h) afforded a trans/cis (70:30) mixture of the basis of this reasoning and of the known stereochemical
1
isomers in 75% yield, as determined by H NMR analysis preference of the osmylation reaction of cinnamate esters
of the crude reaction product. The trans isomer 11, isolated promoted by dihydroquinidine-derived ligands,[9] the 12 and
in the pure form by flash chromatography, was shown to be ent-13 configurations were assigned to the largely major en-
constituted of a 91:9 mixture of enantiomers, to which the antiomers of the two diastereoisomers.[13]
(R,R) and (S,S) configurations, respectively, were as-
We then repeated the two reactions, working sequentially
in one flask using compound 9 as the ligand. In this case,
signed.[8]
We then subjected the mixture of the diastereoiso- the order of addition of the metal species was crucial, since
merically pure adducts 11 to a dihydroxylation reaction un- the basic sites of 9 can compete for the different cations
der Sharpless’ conditions (0.1 mol-equiv. of K2OsO4/chiral involved in the process. Thus, potassium osmate was added
ligand complex, 3 mol-equiv. of [K3Fe(CN)6] and K2CO3, to a solution of 9 in CH2Cl2, followed, after 10 min of stir-
tBuOH/water, 0 °C to room temp., 15 h)[9] using dihydro- ring, by CuOTf.[14] As previously described,[2] this pro-
quinidine 4-chlorobenzoate as the ligand.[10] From this reac- cedure allowed selective complexation of copper and os-
tion we isolated a diol mixture in 53% yield
mium ions by the bis(oxazoline) and dihydroquinidine moi-
In principle, this mixture could be composed of four ster- ety of ligand 9, respectively. The substrate 10 and ethyl di-
eoisomers, namely the two diastereoisomeric diols 12 and azoacetate were then added and the cyclopropanation
13, arising from the major cyclopropane (R,R)-11, and their reaction allowed to proceed for 48 h at room temperature.
enantiomers ent-12 and ent-13, deriving from (S,S)-11. The The solvent and the excess diazoacetate were then removed
diastereoisomeric ratio, as determined by 1H NMR, was under reduced pressure, and potassium hexacyanoferrate
Eur. J. Org. Chem. 2003, 1428Ϫ1432
1429

R. Annunziata, M. Benaglia, M. Cinquini, F. Cozzi, A. Puglisi
FULL PAPER
with 10 mL of CH2Cl2. The combined organic phases were dried
with Na2SO4 and concentrated under vacuum. The residue was
purified by flash chromatography with CH2Cl2/EtOAc (9:1) as elu-
ent to afford the product (0.064 g, 0.15 mmol, 40% yield) as a vis-
cous pale-yellow oil. The product had optical rotation and spectro-
scopic data identical to those reported in the literature.[6]
and potassium carbonate were added to the residue, dis-
solved in tBuOH/water, to perform the dihydroxylation re-
action.[9] After overnight reaction from 0 °C to room tem-
perature and workup, the mixture of diols featuring the
trans-cyclopropane residue was separated from the other di-
[15]
ols by flash chromatography and isolated in 20% yield
Synthesis of 2,2-Bis{2-[(4S)-4-(1,1-dimethylethyl)-1,3-oxazolin-2-yl]-
as a 75:25 mixture of (12 ϩ ent-12): (13 ϩ ent-13) dia-
stereoisomers.[16] Their ee values were established by HPLC
as 95 and 99% in favor of 12 and ent-13, respectively. Thus,
while the diastereoselectivity of the two-flask process and
of the sequential reaction were different, the ee in which the
products have been obtained were identical, showing that
the high stereocontrol characteristic of the individual bi-
s(oxazoline) and dihydroquinidine ligands were maintained
in the bifunctional ligand 9. Remarkably, this compound
1-(4-hydroxyphenyl)propane (7):
A solution of compound 6
(0.426 g, 1 mmol) in ethanol (10 mL), containing Pd(OAc)2
(0.023 g, 0.1 mmol) and PPh3 (0.115 g, 0.44 mmol), was refluxed
for 90 min. The resulting mixture was cooled to room temp., and
SiO2 (1 g) was added in one portion. After 40 min of stirring at
room temp., the mixture was filtered through a Celite plug, the
solvent was evaporated under vacuum, and the residue was purified
by flash chromatography with CH2Cl2/EtOAc (6:4) as eluent to give
the product (0.301 g, 0.78 mmol, 78% yield). The product had op-
could be recovered unchanged in 91% yield in the chroma- tical rotation, m.p., and spectroscopic data identical to those re-
ported in the literature.[6]
tographic purification of the products.
Synthesis of Compound 9: To a stirred solution of compound 7
(0.041 g, 0.107 mmol) in dry DMF (2 mL), warmed to 50 °C, ces-
ium carbonate (0.244 g, 0.749 mmol) was added, followed, after
Conclusions
30 min, by bromide 8 (0.054 g, 0.107 mmol), dissolved in DMF
A bifunctional ligand capable of promoting different ster-
eoselective catalytic transformations when coordinated to
different transition metal atoms has been prepared in a sim-
ple and straightforward fashion by connecting a bis(oxazo-
line) to dihydroquinidine with a spacer. This ligand was em-
ployed in a one-flask procedure in which methyl (E)-3-(4-
vinylphenyl)propenoate underwent first cyclopropanation
at the electron-rich double bond and then dihydroxylation
at the electron-poor alkene to afford a product containing
four stereocenters with complete regiocontrol and high
stereoselectivity. These results showed that multifunctional
ligands can conveniently be exploited to perform a new type
of stereoselective process called sequential stereoselective
catalysis.
(2 mL). The resulting mixture was stirred at 50 °C for 4 d, and the
solvent was then removed under vacuum. The residue was taken
up in CH2Cl2 (10 mL), the mixture was filtered, and the filtrate
was concentrated under vacuum to give the crude product, which
was purified by flash chromatography with CH2Cl2/MeOH (98:2,
then 95:5, and finally 85:15) as eluent to give the product (0.052 g,
0.064 mmol, 60% yield) as a yellow viscous oil that solidified on
standing in the freezer. [α]2D3 ϭ Ϫ14.3 (c ϭ 0.48, chloroform). IR:
1
ν˜ ϭ 1741, 1658 cmϪ1. H NMR: δ ϭ 0.85 (s, 9 H, CMe3), 0.88 (s,
3
9 H, CMe3), 0.95 (t, JH,H ϭ 4.0 Hz, 3 H, CH2CH3), 1.42 (s, 3 H,
CH2CCH3), 1.51 (m, 5 H, CH, CH2CH3 and OCH2CH2CH2), 1.53
(m, 1 H, A part of an AB system, NCHCH2CH), 1.76 (m, 5 H,
OCHCH2CH2CH2 and CHCHCH2CH3), 1.80 (m, 1 H, B part of
3
an AB system, NCHCH2CH), 2.44 (t, JH,H ϭ 7.5 Hz, 2 H,
CH2COOCH), 2.73 (m, 3 H, NCH2CH2CH and A part of an AB
3
2
system in NCH2CHCH2CH3), 2.90 (dd, JH,H ϭ 7.0 and JH,H
ϭ
9.0 Hz, 1 H, B part of an AB system, NCH2CHCH2CH3), 3.15 (A
2
part of an AB system, JH,H ϭ 13.7 Hz, 1 H, ArCH2CCH3), 3.31
Experimental Section
2
(m, 1 H, NCHCHOCO), 3.33 (A part of an AB system, JH,H
ϭ
13.7 Hz, 1 H, ArCH2CCH3), 3.83 (m, 2 H, CH2CHCMe3), 3.88 (t,
General: 1H NMR spectra were recorded at 300 MHz and are refer-
enced to tetramethylsilane (TMS) at δ ϭ 0.00 ppm. 13C NMR spec-
tra were recorded at 75 MHz and are referenced to δ ϭ 77.0 ppm
in [D]chloroform (CDCl3). IR spectra were recorded on thin films.
Optical rotations were measured at the Na-D line in a 1-dm cell at
23 °C.
3JH,H ϭ 6.0 Hz, 2 H, OCH2CH2CH2), 3.98 (s, 3 H, OCH3), 4.17
3
(m, 4 H, CH2CHCMe3), 6.58 (d, JH,H ϭ 6.8 Hz, 1 H, CHOCO),
3
6.74 (A part of an AB system, JH,H ϭ 9.0 Hz, 2 H, aromatic hy-
3
drogen atoms), 7.08 (B part of an AB system, JH,H ϭ 9.0 Hz, 2
3
H, aromatic hydrogen atoms), 7.34 (d, JH,H ϭ 4.7 Hz, 1 H, 3-H
3
4
of quinoline), 7.10 (dd, JH,H ϭ 9.2 and JH,H ϭ 2.6 Hz, 1 H, 7-H
of quinoline), 7.45 (d, 4JH,H ϭ 2.6 Hz, 1 H, 5-H of quinoline), 8.02
(d, 3JH,H ϭ 9.2 Hz, 1 H, 8-H of quinoline), 8.74 (d, 3JH,H ϭ 4.7 Hz,
1 H, 2-H of quinoline) ppm. 13C NMR: δ ϭ 12.0, 21.05, 23.3, 24.6,
25.4, 25.7, 25.8, 26.0, 27.1, 28.9, -33.8, 33.9, 34.4, 37.3, 41.15, 43.5,
49.9, 50.7, 55.6, 59.1, 67.4, 68.7, 73.3, 75.4, 75.6, 101.4, 113.9,
118.6, 121.9, 127.0, 128.85, 131.5, 131.8, 143.9, 144.7, 147.4, 157.7,
157.9, 167.2, 167.8, 172.5 ppm. C49H68N4O6 (808.53): calcd. C
72.74, H 8.47, N 6.92; found C 72.48, H 8.39, N 7.03.
Synthesis of Ligand 9: This compound was obtained by a stepwise
synthesis starting from bis(oxazoline) 4.
Synthesis of 2,2-Bis{[(4S)-4-(1,1-dimethylethyl)-1,3-oxazolin-2-yl]-1-
[4-(2-propenyl)oxyphenyl]propane (6): A 1.6  solution of MeLi in
Et2O (0.520 mL, 0.826 mmol) was added dropwise to a stirred solu-
tion of bis(oxazoline) 4 (0.100 g, 0.375 mmol) in dry THF (5 mL),
cooled to Ϫ 55 °C under nitrogen. After stirring at Ϫ55 °C for 1 h,
4-allyloxybenzyl bromide 5 (0.085 g, 0.375 mmol) in THF (3 mL)
was added dropwise and the reaction mixture was stirred at
Ϫ10 °C for 40 min. MeI (0.070 mL, 1.125 mmol) in THF (1 mL)
was then added and the reaction mixture was allowed to warm to
room temp. and stirred at that temperature overnight. The reaction
was quenched by the addition of a saturated aqueous solution of
NH4Cl (10 mL) and the resulting mixture was extracted three times
Synthesis of Methyl (E)-3-(4-Vinylphenyl)propenoate (10): Trimeth-
ylphosphonoacetate (1.11 mL, 6.87 mmol) in THF (3 mL) was
slowly added to a stirred suspension of oil-free NaH (0.165 g,
6.87 mmol) in THF (5 mL), cooled to Ϫ30 °C. After 30 min of
stirring at Ϫ30 °C, 4-vinylbenzaldehyde (0.818 g, 6.2 mmol) in
THF (2 mL) was added and the reaction mixture was stirred at
1430
Eur. J. Org. Chem. 2003, 1428Ϫ1432

Sequential Stereoselective Catalysis
FULL PAPER
Ϫ30 °C for 1 h. The reaction was quenched by the addition of
a saturated aqueous solution of ammonium chloride (10 mL), the
organic phase was separated, and the aqueous phase was extracted of the major diastereoisomer: δ ϭ 1.32 (t, JH,H ϭ 7.2 Hz, 3 H,
yield as an 83:17 mixture of diastereoisomers (see text). [α]2D3
ϭ
Ϫ34.0 (c ϭ 0.42, chloroform). IR: ν˜ ϭ 3350, 1742 cmϪ1. 1H NMR
3
with EtOAc (3 ϫ 5 mL). The combined organic phases were dried
with sodium sulfate, and the solvent was removed under vacuum. propane), 1.62 (dt, JH,H ϭ 5.8, 8.7 Hz, 1 H, one hydrogen atom
The residue was purified by flash chromatography with hexanes/
COOCH2CH3), 1.33 (m, 1 H, one hydrogen atom of CH2 of cyclo-
3
of CH2 of cyclopropane), 1.95 (ddd, 3JH,H ϭ 4.2, 5.8, 8.3 Hz, 1 H,
3
EtOAc (95:5) as eluent to afford the pure (E) isomer in 77% yield
CHAr of cyclopropane), 2.56 (ddd, JH,H ϭ 4.2, 6.2, 8.7 Hz, 1 H,
(0.897 g, 4.77 mmol) as a white solid, m.p. 73Ϫ74 °C (ref.[17] CHCOOEt of cyclopropane), 2.67 (d, JH,H ϭ 7.2 Hz, 1 H, HO-
3
74.5Ϫ75 °C). IR: ν˜ ϭ 1711 cmϪ1
.
1H NMR: δ ϭ 3.78 (s, 3 H,
CHAr), 3.08 (d, JH,H ϭ 6.2 Hz, 1 H, HOCHCOOMe), 3.85 (s, 3
3
3
MeO), 5.29 (d, JH,H ϭ 8.4 Hz, 1 H, one hydrogen atom of CHϭ
H, OCH3), 4.21 (q, 2 H, 3JH,H ϭ 7.2 Hz, 2 H, COOCH2CH3), 4.38
3
3
CH2), 5.78 (d, JH,H ϭ 15.0 Hz, 1 H, one hydrogen atom of CHϭ
(dd, JH,H ϭ 2.8 and 6.2 Hz, 1 H, HOCHCOOMe), 5.02 (dd,
3
CH2), 6.41 (d, JH,H ϭ 16.0 Hz, 1 H, HCϭCHCOOMe), 6.69 (dd, 3JH,H ϭ 2.8 and 7.2 Hz, 1 H, HOCHAr), 7.13 (A part of an AB
3JH,H ϭ 15.0, 8.4 Hz, 1 H, CHϭCH2), 7.38 (A part of AB system,
system, JH,H ϭ 8.2 Hz, 2 H, aromatic hydrogen atoms), 7.34 (B
3
3JH,H ϭ 8.3 Hz, 2 H, aromatic hydrogen atoms), 7.46 (B part of part of an AB system, JH,H ϭ 8.2 Hz, 2 H, aromatic hydrogen
3
3
AB system, JH,H ϭ 8.3 Hz, 2 H, aromatic hydrogen atoms), 7.66
atoms) ppm. 13C NMR of the major diastereoisomer: δ ϭ 14.4,
17.5, 22.2, 27.1, 53.4, 61.1, 74.2, 75.0, 126.7, 129.9, 138.5, 142.0,
171.5, 174.2 ppm. 1H NMR of the minor diastereoisomer: δ ϭ 1.03
(t, 3JH,H ϭ 7.1 Hz, 3 H, COOCH2CH3), 1.33 (m, 1 H, one hydrogen
3
(d, JH,H ϭ 16.0 Hz, 1 H, HCϭCHCOOMe) ppm. 13C NMR: δ ϭ
52.3, 112.3, 117.0, 126.2, 126.6, 135.8, 137.1, 144.0, 146.1, 170.2
ppm.
3
atom of CH2 of cyclopropane), 1.71 (dt, JH,H ϭ 5.8, 7.4 Hz, 1 H,
3
Synthesis of trans-Cyclopropane 11: A solution of bis(oxazoline) 6
(0.0217 g, 0.051 mmol) and CuOTf·0.5PhH (0.0126 g, 0.05 mmol)
in CH2Cl2 (3 mL), kept under nitrogen, was stirred for 1 h at room
temp. Ester 10 (0.188 g, 1 mmol) in CH2Cl2 (3 mL) was added to
this mixture. A solution of ethyl diazoacetate (0.525 mL, 5 mmol)
in CH2Cl2 was slowly added by means of a syringe pump. After a
total of 24 h of stirring at room temp., the low-boiling materials
one hydrogen atom of CH2 of cyclopropane), 2.10 (ddd, JH,H
ϭ
3
4.2, 5.8, 8.3 Hz, 1 H, CHAr of cyclopropane), 2.53 (ddd, JH,H
ϭ
4.2, 6.2, 7.4 Hz, 1 H, CHCOOEt of cyclopropane), 2.67 (br. s, 1 H,
one OH), 3.10 (br. s, 1 H, other OH), 3.84 (s, 3 H, OCH3), 3.91 (q,
3JH,H ϭ 7.1 Hz, 2 H, COOCH2CH3), 4.37 (br. s, 1 H, HOCH-
COOMe), 5.00 (br. s, 1 H, HOCHAr), 7.14 (A part of an AB sys-
3
tem, JH,H ϭ 8.2 Hz, 2 H, aromatic hydrogen atoms), 7.33 (B part
1
3
were removed under vacuum and the residue was analyzed by H
of an AB system, JH,H ϭ 8.2 Hz, 2 H, aromatic hydrogen atoms)
ppm. 13C NMR of the minor diastereoisomer: δ ϭ 14.4, 17.5, 24.2,
26.4, 53.3, 60.6, 74.1, 74.7, 126.2, 126.7, 137.1, 142.5, 170.0,
173.5 ppm. C16H20O6 (308.16): calcd. C 62.33, H 6.54; found C
62.69, H 6.48. The ee was determined by HPLC [DAICEL Chiral-
pack AD, hexane/iPrOH (80:20), flow rate 0.8 mL/min, λ ϭ
220 nm; for the major diastereoisomer: tR of 12 (major) ϭ
18.36 min; tR of ent-12 (minor) ϭ 17.29 min; for the minor
diastereoisomer: tR of ent-13 ϭ 14.43 min (only enantiomer de-
tected].
NMR to assess the trans/cis diastereoisomeric ratio. The residue
was then purified by flash chromatography with hexanes/EtOAc
(95:5 and then 80:20) as eluent to afford the pure trans isomer as
a colorless liquid in 52.5% yield (0.144 g, 0.525 mmol). [α]2D3
ϭ
Ϫ195.2 (c ϭ 0.42, chloroform). IR: ν˜ ϭ 1723, 1712 cmϪ1
.
1H
3
NMR: δ ϭ 1.30 (t, JH,H ؍ 7.2 Hz, 3 H, COOCH2CH3), 1.34 (A
part of an AB system, JH,H ؍ 5.2, JH,H ϭ 6.2, 9.7 Hz, 1 H, one
hydrogen atom of CH2 of cyclopropane), 1.66 (B part of an AB
2
3
2
3
system, JH,H ؍ 5.2, JH,H ؍ 5.2, 9.3 Hz, 1 H, one hydrogen atom
of CH2 of cyclopropane), 1.95 (ddd, 3JH,H ؍ 4.2, 5.2, 9.7 Hz, 1 H,
3
ArCH of cyclopropane), 2.54 (ddd, JH,H ؍ 4.2, 6.2, 9.3 Hz, 1 H,
Synthesis of Diols 12 and 13. One-Flask Reaction: K2OsO4 dihy-
drate (0.0188 g, 0.051 mmol) was added to a stirred solution of
ligand 9 (0.041 g, 0.051 mmol) in CH2Cl2 (2.5 mL). After 10 min
of stirring at room temp., CuOTf·0.5C6H6 (0.0126 g, 0.05 mmol)
was added, and stirring was continued for 30 min. Compound 10
(0.094 g, 0.5 mmol), dissolved in CH2Cl2 (1 mL), was then added,
followed by ethyl diazoacetate (0.263 mL, 2.5 mmol) in CH2Cl2
(1 mL), the latter being slowly added by a syringe pump over a
period of 12 h. After 48 h of stirring at room temp., the solvent
was evaporated under vacuum, the residue was dissolved in a 1:1
mixture of tert-butanol (2 mL) and water (2 mL), and the resulting
suspension was cooled to 0 °C. K3Fe(CN)6 (0.493 g, 1.5 mmol) and
K2CO3 (0.207 g, 1.5 mmol) were then added, and the mixture was
stirred at 0 °C for 6 h and at room temp. 9 h. Excess solid sodium
sulfite was then added, and the mixture was stirred for 30 min.
The organic solvent was removed under vacuum, and the aqueous
solution was extracted with CH2Cl2 (3 ϫ 5 mL) and EtOAc (2 ϫ
5 mL). The combined organic phases were dried and concentrated
under vacuum, and the residue was purified by flash chromatogra-
phy with hexanes/EtOAc (90:10, then 70:30, and finally 50:50) as
eluent. The diols featuring the trans-configured cyclopropane resi-
due were isolated in 20% yield (0.031 g, 0.1 mmol) as a 75:25 mix-
ture of diastereoisomers (see text). These were analyzed for ee de-
termination as described above and mentioned in the text. Further
CHCOOEt of cyclopropane), 4.9 (s, 3 H, OCH3), 4.18 (q, 2 H,
3JH,H ϭ 7.2 Hz, 2 H, COOCH2CH3), 6.42 (d, 3JH,H ϭ 16.0 Hz, 1 H,
HCϭCHCOOEt), 7.27 (A part of an AB system, 3JH,H ϭ 8.3 Hz, 2
H, aromatic hydrogen atoms), 7.46 (B part of an AB system,
3
3JH,H ϭ 8.3 Hz, 2 H, aromatic hydrogen atoms), 7.67 (d, JH,H
ϭ
16.0 Hz, 1 H, HCϭCHCOOEt) ppm. 13C NMR: δ ϭ 14.2, 17.6,
24.5, 26.0, 51.7, 60.8, 117.3, 126.6, 128.2, 130.0, 143.0, 144.3,
168.0 ppm. C16H18O4 (274.16): calcd. C 70.05, H 6.61; found C
69.89, H 6.71. The ee was determined by HPLC as 93:7 [DAICEL
Chiralpack OD-H, hexane/iPrOH (85:15), flow rate 0.8 mL/min,
λ ϭ 210 nm, tR ϭ 7.38 min (minor) and 8.57 min (major)].
Synthesis of Diols 12 and 13. Two-Flask Reaction: Quinidine 4-chlo-
robenzoate (0.024 g, 0.051 mmol), dissolved in tBuOH/water (1:1,
2 mL), was added to a cooled (0 °C) and stirred solution of cyclo-
propane 11 (0.139 g, 0.51 mmol) in the same solvent (3 mL), fol-
lowed by K2OsO4 dihydrate (0.019 g, 0.051 mmol), [K3Fe(CN)6]
(0.504 g, 1.53 mmol), and K2CO3 (0.211 g, 1.53 mmol). The mix-
ture was stirred at 0 °C for 6 h and then at room temp. for 9 h.
Excess solid sodium sulfite was then added, and the mixture was
stirred for 30 min. The organic solvent was removed under vacuum,
and the aqueous solution was extracted with CH2Cl2 (3 ϫ 5 mL)
and EtOAc (2 ϫ 5 mL). The combined organic phases were dried
and concentrated under vacuum, and the residue was purified by
flash chromatography with hexanes/EtOAc (70:30 and then 50:50) elution of the crude reaction product with CH2Cl2/MeOH (90:10)
as eluent. The product, a white viscous oil, was isolated in 53%
as eluent allowed us to recover the ligand 9 in 91% yield.
Eur. J. Org. Chem. 2003, 1428Ϫ1432
1431

R. Annunziata, M. Benaglia, M. Cinquini, F. Cozzi, A. Puglisi
FULL PAPER
[10]
[11]
We are well aware of the fact that other ligands (e.g. PHAL-
DHQD) secure higher stereoselectivity in this reaction. Never-
theless, we considered dihydroquinidine 4-chlorobenzoate a
good structural analog of ligand 9.
Acknowledgments
We thank MURST (Progetto Nazionale Stereoselezione in Sintesi
Organica. Metodologie e Applicazioni) and CNR for financial sup-
port.
For previous examples of asymmetric dihydroxylation reac-
[11a]
tions proceeding with kinetic resolution see:
R. Annunzi-
ata, M. Benaglia, M. Cinquini, F. Cozzi, F. Ponzini, Biorg.
[1]
[11b]
Review: Comprehensive Asymmetric Catalysis, vol. IϪIV (Eds.:
E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer, Berlin,
Med. Chem. Lett. 1993, 11, 2397Ϫ2402.
M. S. Van-
Nieuwenhze, K. B. Sharpless, J. Am. Chem. Soc. 1993, 115,
[11c]
1999.
7864Ϫ7865.
E. J. Corey, M. C. Noe, A. Guzman-Perez, J.
[2]
R. Annunziata, M. Benaglia, M. Cinquini, F. Cozzi, Eur. J.
Am. Chem. Soc. 1995, 117, 10817Ϫ10824.
[12]
[13]
Org. Chem. 2001, 1045Ϫ1048.
The possibility of performing sequential stereoselective cata-
For a general treatment of double stereoselection and the defi-
nition of matched and mismatched pairs see: S. Masamune, W.
Choy, J. S. Petersen, L. R. Sita, Angew. Chem. Int. Ed. Engl.
1985, 24, 1Ϫ30.
[3]
lytic processes was reported for the first time using a copoly-
meric catalyst by: [3a] H.-B. Yu, Q.-S. Hu, L. Pu, J. Am. Chem.
Soc. 2000, 122, 6500Ϫ6501. For more recent results obtained
On the basis of these stereochemical results it could be antici-
pated that a ligand such as 9 prepared starting from either
bis(oxazoline) 4 and dihydroquinine or (less practically) from
ent-4 and dihydroquinidine would provide a more stereoselec-
tive overall process in which the stereochemical preference of
the osmylation reaction matches that of the cyclopropane sub-
strate 11.
The possibility that CuOTf is oxidized to catalytically inactive
CuII species by the OsVI salt has previously been considered
and found to be negligible (see ref.[2]).
This yield is only slightly lower than that calculated for the
mixture of the trans-cyclopropanediols obtained performing
the reactions separately (27.8%). In a control experiment the
reactions were repeated sequentially in one flask, operating as
described in the case of 9, and using bis(oxazoline) 6 and di-
hydroquinidine 4-chlorobenzoate as the ligands. From this
experiment the trans-cyclopropanediols were isolated in 21%
yield as an 80:20 mixture of diastereoisomers.
As suggested by one referee, in the cyclopropanation reaction
the active catalyst may bind to a molecule of substrate via the
osmate, and it would be cleaved on addition of water in the
second step.
[3b]
with supported ligands see:
B. M. Choudary, N. S. Chow-
dary, S. Madhi, M. N. Kantam, Angew. Chem. Int. Ed. 2001,
[3c]
40, 4620Ϫ4623.
B. M. Choudary, N. S. Chowdary, K.
Jyothi, N. S. Kumar, M. N. Kantam, Chem. Commun. 2002,
586Ϫ587; and references therein.
For reviews describing related approaches see:
[4]
[5]
[4a]
M. Shiba-
[14]
[15]
saki, M. Kanai, K. Funabashi, Chem. Commun. 2002,
1989Ϫ1999 (‘‘asymmetric two-center catalysis’’). [4b] G. J. Rowl-
ands, Tetrahedron 2001, 57, 1865Ϫ1882 (‘‘ambifunctional co-
operative catalysis’’).
M. I. Burguete, J. M. Fraile, J. I. Garcia, E. Garcia-Verdugo,
C. I. Herrerias, S. V. Luis, J. A. Mayoral, J. Org. Chem. 2001,
66, 8893Ϫ8901,
R. Annunziata, M. Benaglia, M. Cinquini, F. Cozzi, M. Pitillo,
J. Org. Chem. 2001, 66, 3160Ϫ3166.
D. A. Evans, K. A. Worpel, M. M. Hinman, M. M. Faul, J.
Am. Chem. Soc. 1991, 113, 726Ϫ728.
The assignment was tentatively based on the assumption that
the enantiofacial preference of the Evans’ cyclopropanation re-
action was the same for 10 and styrene; it must be noted that
(R,R)-11 and the major trans adduct obtained from styrene
both had strong negative optical rotations.
H. Kwong, C. Sorato, Y. Ogino, H. Chen, K. B. Sharpless,
Tetrahedron Lett. 1990, 31, 2999Ϫ3002.
[6]
[7]
[8]
[16]
[17]
DE Patent 2340601, 1973, Chem. Abstr. 1973, 80, 145713.
[9]
Received November 25, 2002
[O02661]
1432
Eur. J. Org. Chem. 2003, 1428Ϫ1432