Synthesis of a bifunctional ligand for the sequential enantioselective catalysis of various reactions

Article abstract of DOI:10.1002/1099-0690(200103)2001:6<1045::AID-EJOC1045>3.0.CO;2-I

A new bifunctional ligand capable of promoting various enantioselective catalytic transformations has been prepared by connecting a bis(oxazoline) to dihydroquinidine via a spacer. This ligand has been employed in a one-pot procedure, in which the asymmetric cyclopropanation and dihydroxylation of styrene were accomplished in a sequential fashion with good enantioselectivity.

Full text of DOI:10.1002/1099-0690(200103)2001:6<1045::AID-EJOC1045>3.0.CO;2-I

SHORT COMMUNICATION
Synthesis of a Bifunctional Ligand for the Sequential Enantioselective
Catalysis of Various Reactions
Rita Annunziata,[a] Maurizio Benaglia,*[a] Mauro Cinquini,[a] and Franco Cozzi[a]
Keywords: Asymmetric catalysis / Bifunctional ligands / Chiral ligands / Cyclopropanations / Dihydroxylations
A new bifunctional ligand capable of promoting various en-
antioselective catalytic transformations has been prepared by
connecting a bis(oxazoline) to dihydroquinidine via a spacer.
This ligand has been employed in a one-pot procedure, in
which the asymmetric cyclopropanation and dihydroxylation
of styrene were accomplished in a sequential fashion with
good enantioselectivity.
Enantioselective catalytic transformations represent in-
valuable tools in modern organic synthesis.[1] Many of these
processes are dependent on the use of chiral ligands that,
in combination with various metals, promote highly stereo-
selective reactions. Some ligands can be employed in a vari-
ety of processes. For instance, metal complexes of chiral
bis(oxazoline)s (box)[1] have been used in enantioselective
DielsϪAlder, hetero DielsϪAlder, and 1,3-dipolar cycload-
ditions, in cyclopropanations and aziridinations, in Mukai-
yama-aldol and MukaiyamaϪMichael additions, in al-
lylations, hydrocyanations, and hydrosilylations of carbonyl
compounds, and in reduction and oxidation reactions.[2]
In principle, further extension of the versatility of box
ligands might be achieved by attaching such species to a
residue capable of exerting stereocontrol over other cata-
lytic transformations. This approach would also provide the
appealing opportunity of using the new bifunctional ligand
in sequential processes.[3Ϫ8]
With this goal in mind, the bis(oxazoline)Ϫ
dihydroquinidine (box-DHQD) adducts 1a,b were synthe-
sized (Scheme 1). Esters and ethers of DHQD 2 have been
shown to be powerful ligands for the asymmetric dihy-
droxylation[9] and aminohydroxylation[10] reactions de-
veloped by Sharpless. Moreover, compounds structurally
related to DHQD have been employed in other enantiose-
lective catalytic processes,[11] including alkylations, epoxida-
tions, Michael additions, and β-lactam syntheses.[12]
Scheme 1. Synthesis of box-DHQD ligands 1a,b
Reagents and conditions: (a) Br(CH2)5COCl, Et3N, CH2Cl2, room
temp., 15 h; (b) metalation of 4a,b: 1.0 mol equiv. of BuLi, 0.5 mol
equiv. of (iPr)2NH, 1.0 mol equiv. of TMEDA, THF/1,3-dimethyl-
3,4,5,6-tetrahydro-2(1H)pyrimidone (DMPU) 1:3, Ϫ50 °C, 30 min;
then 4a or 4b (1.0 mol equiv.); Ϫ50 °C, 2.0 h; alkylation: 1.0 mol
equiv. of 2, Ϫ50 °C to room temp., 15 h; (c) metalation: as in (b)
on 1.0 mol equiv. of 5a,b; alkylation: 1.6 mol equiv. of MeI, Ϫ50
°C to room temp., 56 h
Reaction of 2 with 6-bromohexanoyl chloride in the pres-
ence of triethylamine gave ester 3 in quantitative yield. This
was reacted[13] with the metalated box ligands 4a (R ϭ Ph)
and 4b (R ϭ tBu) to afford compounds 5a,b in yields of
55% and 53%, respectively. Since disubstitution at the
bridging carbon atom of box ligands has proved to be es-
sential to achieve a high degree of stereocontrol in many
box-promoted reactions,[2] 5a,b were methylated to give the
adducts 1a,b in yields of 33% and 30% (47% and 45% based
on recovered 5a,b), respectively.[14] It is important to note
that the bridging carbon atom in box ligands 1a,b is not
stereogenic since it bears two identical residues.
When compounds 1a,b were employed as ligands in the
OsVIII-catalyzed asymmetric dihydroxylation of stilbene
(Scheme 2),[15] 1,2-diphenyl-1,2-ethanediol 6 was obtained
in racemic form. However, when the dihydroxylation reac-
tion was carried out using 1b pre-complexed with an equim-
olar amount of CuBr2, (R,R)-6 was formed in 81% yield
with 90% enantiomeric excess (ee).[15] This result suggested
that the box moiety can compete with the DHQD part of
1 in the osmium complexation, thereby affecting the stereo-
selectivity of the dihydroxylation, and that the undesired
complexation is prevented by providing 1 with a metal for
box ligation.
[a]
Centro CNR and Dipartimento di Chimica Organica
e
`
Industriale, Universita degli Studi di Milano,
Via Golgi 19, 20133 Milano, Italy
Eur. J. Org. Chem. 2001, 1045Ϫ1048
WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001
1434Ϫ193X/01/0306Ϫ1045 $ 17.50ϩ.50/0
1045

R. Annunziata, M. Benaglia, M. Cinquini, F. Cozzi
SHORT COMMUNICATION
Experimental Section
General: 1H NMR spectra were recorded at 300 MHz and were
referenced to tetramethylsilane (TMS; δ ϭ 0.00). Ϫ 13C NMR spec-
tra were recorded at 75 MHz and were referenced to the CDCl3
solvent signal (δ ϭ 77.0). Ϫ IR spectra were recorded from thin
films of the samples. Ϫ Optical rotations were measured with light
of the Na-D line in 1-dm cells at 23 °C.
Synthesis of DHQD 6-Bromohexanoate (3): A solution of 6-bro-
mohexanoyl chloride (0.612 mL, 4 mmol) in dry CH2Cl2 (5 mL)
was added dropwise to a stirred solution of DHQD (1.304 g,
4 mmol) and triethylamine (0.72 mL, 5.2 mmol) in dry CH2Cl2
(20 mL) under nitrogen at room temp. After stirring for 15 h, the
reaction mixture was poured into water and the organic compon-
ents were extracted with CH2Cl2 (3 ϫ 20 mL). The combined or-
ganic extracts were dried with sodium sulfate, the solvent was evap-
orated in vacuo, and the residue was purified by flash chromato-
graphy using CH2Cl2/MeOH (98:2) as the eluent. The product was
obtained in quantitative yield (2.010 g) as a thick yellow oil. It had
[α]2D3 ϭ ϩ80.3 (c ϭ 1.28 in CHCl3). Ϫ IR: ν˜ ϭ 1740, 1230,
Scheme 2. Stereoselective reactions promoted by ligands 1a,b
Reagents and conditions: (a) 1.0 mol equiv. of stilbene, 3.0 mol
equiv. of K3Fe(CN)6 and K2CO3, 0.022 mol equiv. of K2OsO4 dihy-
drate, 0.056 mol equiv. of 1a or 1b, 0.058 mol equiv. of CuBr2,
tBuOH/H2O 1:1, 0 °C to room temp., 15 h; (b) 3.0 mol equiv. of
styrene, 1.0 mol equiv. of ethyl diazoacetate, 0.01 mol equiv. each
of CuOTf, K2OsO4 dihydrate, and 1b, room temp., 48 h; (c) see text
1
1170 cmϪ1. Ϫ H NMR: δ ϭ 8.68 (d, 1 H, J ϭ 4.0 Hz, quinoline
Similarly, the use of ligands 1a,b alone in the CuI-pro- 2-H), 7.95 (d, 1 H, J ϭ 9.2 Hz, quinoline 8-H), 7.28Ϫ7.34 (m, 3
H, remaining aromatic protons), 6.48 (d, 1 H, J ϭ 7.7 Hz,
CHOCO), 3.90 (s, 3 H, MeO), 3.28 (t, 2 H, J ϭ 6.7 Hz, CH2Br),
3.23 (t, 1 H, J ϭ 7.0 Hz, CHN bridgehead), 2.58Ϫ2.87 (m, 4 H,
CH2NCH2), 2.35 (t, 2 H, J ϭ 7.4 Hz, CH2COO), 1.33Ϫ1.80 (m,
14 H, 3 CH2 of the aliphatic chain, 2 CH and 2 CH2 of the bicyclic
ring, CH2 of ethyl group), 0.86 (t, 3 H, J ϭ 7.3 Hz, CH3CH2). Ϫ
13C NMR: δ ϭ 172.1, 157.7, 147.3, 144.6, 143.8, 131.6, 127.0,
121.7, 118.5, 101.4, 73.1, 59.0, 55.5, 50.6, 49.7, 37.1, 34.0, 33.2,
32.2, 27.5, 27.0, 25.9, 25.3, 23.9, 23.2, 11.9. Ϫ C26H35BrN2O3
(503.4): calcd. C 62.02, H 7.01, N 5.56; found C 61.87, H 6.91,
N 5.63.
moted cyclopropanation of styrene with ethyl diazoacet-
ate[16] led to a very poor yield of racemic 7. On the other
hand, the use of 1b pre-complexed with an equimolar
amount of potassium osmate furnished (R,R)-7 in 45%
yield with 80% ee (trans/cis ratio 80:20).[16] As before, it
would seem that the Lewis-basic bridgehead nitrogen atom
of the DHQD part of 1 can interfere with the complexation
of CuI by the box group, thereby affecting the stereoselect-
ivity of the process. Addition of potassium osmate prevents
this phenomenon.[17]
In the light of these results, a one-pot procedure was at-
tempted in which styrene was sequentially subjected to
cyclopropanation and dihydroxylation. To a mixture of 1b
(0.1 mol equiv.), CuOTf (0.1 mol equiv.), K2OsO4 dihydrate
(0.1 mol equiv.), and styrene (2 mol equiv.) in CH2Cl2 at
room temp., ethyl diazoacetate (1 mol equiv.) was added
Synthesis of box-DHQD (5b): A solution of bis(oxazoline) 4b
(0.201 g, 0.756 mmol) in a mixture of dry THF (1 mL) and DMPU
(3 mL) was added dropwise to a stirred solution of BuLi (0.458 mL
of a 1.5  solution in hexanes, 0.687 mmol), diisopropylamine
(0.048 mL, 0.344 mmol), and TMEDA (0.103 mL, 0.687 mmol) in
a mixture of dry THF (3 mL) and DMPU (9 mL) under nitrogen
over a period of 12 h by means of a syringe pump. After at Ϫ50 °C. The mixture was stirred at this temperature for 1.5 h,
in the course of which a pale-yellow solution was formed. There-
after, a solution of bromoester 3 (0.346 g, 0.687 mmol) in a mixture
of dry THF (1 mL) and DMPU (3 mL) was added, and the re-
sulting mixture was allowed to slowly warm to room temp. Stirring
was continued for 15 h. The reaction was then quenched by the
addition of a saturated aqueous ammonium chloride solution. The
mixture was extracted with diethyl ether (20 mL) and the remaining
aqueous phase was further extracted with CH2Cl2 (10 mL). The
combined organic phases were washed with brine (2 ϫ 20 mL),
dried with sodium sulfate, and concentrated in vacuo. Residual
traces of DMPU were removed under high vacuum. The residue
was purified by flash chromatography using CH2Cl2/MeOH (90:10)
as the eluent. The product (0.251 g) was obtained in 53% yield as
a thick yellow oil. It had [α]2D3 ϭ Ϫ3.2 (c ϭ 2.8 in CH2Cl2). Ϫ IR:
stirring for 48 h at this temperature, the solvent was re-
moved, the residue was redissolved in tBuOH/H2O (1:1),
and K3Fe(CN)6 and K2CO3 (3 mol equiv. each) were added
at 0 °C. After stirring for 24 h at room temp., the reaction
was quenched by the addition of NaHSO3. After aqueous
work-up and extraction with CH2Cl2, the crude mixture
was purified by flash chromatography to afford cyclopro-
pane (R,R)-7 in 40% yield with 79% ee along with diol (R)-
8 in 71% yield with 70% ee.[18] Ligand 1b was also recovered
in 50% yield.
This experiment showed the feasibility of the sequential
catalytic process, although it proceeded with levels of ster-
eoselection slightly lower than those observed when the two
reactions were carried out independently using monofunc-
tional ligands.[19]
1
ν˜ ϭ 1739, 1664 cmϪ1. Ϫ H NMR: δ ϭ 8.75 (d, 1 H, J ϭ 4.0 Hz,
quinoline 2-H), 8.02 (d, 1 H, J ϭ 9.0 Hz, quinoline 8-H), 7.33Ϫ7.47
(m, 3 H, remaining aromatic protons), 6.53Ϫ6.63 (m, 1 H,
CHOCO), 4.07Ϫ4.17 (m, 4 H, two CH2O of box), 3.97 (s, 3 H,
MeO), 3.84Ϫ3.90 (m, 2 H, two CHtBu), 3.50 [t, 1 H, J ϭ 8.0 Hz,
CH(CϭN)2], 3.26Ϫ3.33 (m, 1 H, CHN bridgehead), 2.66Ϫ3.00 (m,
4 H, CH2NCH2), 2.38 (t, 2 H, J ϭ 7.4 Hz, CH2COO), 1.27Ϫ2.16
(m, 16 H, 4 CH2 of the aliphatic chain, 2 CH and 2 CH2 of the
In conclusion, the new bifunctional ligand box-DHQD
1b, readily synthesized from commercially available starting
materials, has been successfully applied in a sequential en-
antioselective catalytic process involving two different reac-
tions.
1046
Eur. J. Org. Chem. 2001, 1045Ϫ1048

Bifunctional Ligands for Sequential Enantioselective Catalysis
SHORT COMMUNICATION
bicyclic ring, CH2 of ethyl group), 0.93 (t, 3 H, J ϭ 7.3 Hz,
CH3CH2), 0.90 (s, 9 H, one of two tBu), 0.86 (s, 9 H, one of two
2.80Ϫ3.15 (m, 4 H, CH2NCH2), 2.29Ϫ2.45 (m, 2 H, CH2COO),
2.00Ϫ2.13 [m, 2 H, CH2CH(CϭN)2], 1.25Ϫ1.90 (m, 14 H, 3 CH2
tBu). Ϫ 13C NMR: δ ϭ 172.5, 164.8, 164.7, 157.9, 147.4, 145.0, of the aliphatic chain, 2 CH and 2 CH2 of the bicyclic ring, CH2
144.0, 131.8, 127.0, 121.9, 118.5, 101.4, 75.6, 75.5, 73.3, 68.8, 59.2,
55.6, 50.8, 49.9, 39.7, 37.3, 34.3, 33.7, 29.5, 28.7, 27.1, 27.0, 26.0,
25.7, 25.4, 24.6, 23.4, 12.0. Ϫ C41H60N4O5 (688.9): calcd. C 71.48,
H 8.78, N 8.13; found C 71.67, H 8.65, N 8.29.
of ethyl group), 1.64 [s, 3 H, CH3C(CϭN)2], 0.92 (t, 3 H, J ϭ
7.1 Hz, CH3CH2). Ϫ 13C NMR: δ ϭ 172.0, 169.7, 157.9, 147.2,
144.7, 144.5, 142.4, 131.8, 127.9, 127.6, 126.8, 126.6, 122.3, 118.1,
101.3, 75.3, 75.2, 72.4, 69.6, 69.5, 59.0, 56.0, 50.5, 49.8, 42.6, 36.7,
34.3, 29.3, 29.3, 28.2, 27.1, 26.4, 25.3, 24.6, 24.1, 23.0, 21.6, 11.9.
Ϫ C46H54N4O5 (743.0): calcd. C 74.36, H 7.33, N 7.54; found C
74.18, H 7.52, N 7.39.
Synthesis of box-DHQD (5a): This compound was similarly pre-
pared from bromoester 3 (0.346 g, 0.687 mmol) and bis(oxazoline)
4a (0.231 g, 0.756 mmol). The product (0.401 g) was obtained in
55% yield as a thick yellow oil. It had [α]2D3 ϭ Ϫ1.6 (c ϭ 0.25 in
CH2Cl2). Ϫ IR: ν˜ ϭ 1739, 1655 cmϪ1. Ϫ 1H NMR: δ ϭ 8.73 (d, 1
H, J ϭ 4.0 Hz, quinoline 2-H), 8.00 (d, 1 H, J ϭ 9.0 Hz, quinoline
8-H), 7.20Ϫ7.45 (m, 13 H, remaining aromatic protons), 6.57 (d, 1
H, J ϭ 7.3 Hz, CHOCO), 5.17Ϫ5.26 (m, 2 H, two PhCH),
4.58Ϫ4.72 (m, 2 H, two protons of two CH2O of box), 4.08Ϫ4.25
(m, 2 H, two protons of two CH2O of box), 3.95 (s, 3 H, MeO),
3.67 [t, 1 H, J ϭ 8.0 Hz, CH(CϭN)2], 3.23Ϫ3.33 (m, 1 H, CHN
bridgehead), 2.63Ϫ3.00 (m, 4 H, CH2NCH2), 2.28Ϫ2.45 (m, 2 H,
CH2COO), 2.00Ϫ2.13 [m, 2 H, CH2CH(CϭN)2], 1.25Ϫ1.90 (m,
14, 3 CH2 of the aliphatic chain, 2 CH and 2 CH2 of the bicyclic
ring, CH2 of ethyl group), 0.92 (t, 3 H, J ϭ 7.1 Hz, CH3CH2). Ϫ
13C NMR: δ ϭ 172.5, 166.2, 157.9, 147.3, 144.7, 143.9, 142.1,
131.7, 128.7, 127.6, 126.8, 126.6, 121.9, 118.5, 101.4, 75.1, 73.5,
69.6, 59.1, 55.7, 50.7, 49.9, 39.6, 37.2, 34.3, 29.6, 28.7, 27.1, 26.9,
25.9, 25.4, 24.6, 23.2, 11.9. Ϫ C45H52N4O5 (729.0): calcd. C 74.15,
H 7.19, N 7.67; found C 74.38, H 7.31, N 7.45.
Synthesis of Compounds 7 and 8 by Sequential Cyclopropanation
and Dihydroxylation: K2OsO4 dihydrate (6.6 mg) was added to a
stirred solution of 1b (13 mg, 0.018 mmol) in CH2Cl2 (1 mL) under
nitrogen. After stirring for 10 min at room temp., CuOTf·0.5C6H6
(4.5 mg, 0.018 mmol) was added and stirring was continued for
30 min. Freshly distilled styrene (0.041 mL, 0.36 mmol) was then
added, followed by a solution of ethyl diazoacetate (0.021 mL,
0.18 mmol) in CH2Cl2 (1 mL), the latter being slowly added by
means of a syringe pump over a period of 12 h. After stirring for
48 h at room temp., the solvent was evaporated in vacuo, the res-
idue was taken up in a mixture of tert-butyl alcohol (2 mL) and
water (2 mL), and the resulting suspension was cooled to 0 °C.
K3Fe(CN)6 (178 mg, 0.54 mmol) and K2CO3 (74 mg, 0.54 mmol)
were then added, and the mixture was stirred for 15 h while the
temperature was allowed to rise to ambient. An excess of Na2SO3
was then added and the solvent was evaporated in vacuo. The res-
idue was taken up in CH2Cl2, the organic phase was dried with
sodium sulfate, and the solvent was evaporated in vacuo. The crude
products were separated by flash chromatography using hexanes/
diethyl ether mixtures as eluents (90:10, then 70:30, then 50:50).
Cyclopropane 7 (11 mg) was obtained in 40% yield, diol 8 (15 mg)
in 71% yield. Their 1H NMR spectra were identical to those re-
ported. Their ee’s were determined by comparison of the observed
optical rotations {for 7: [α]2D3 ϭ Ϫ234 (c ϭ 0.10 in CHCl3); for 8:
[α]2D3 ϭ Ϫ38.5 (c ϭ 0.20 in diethyl ether)} with those reported for
samples of known ee {for 7: [α]2D3 ϭ Ϫ296 (c ϭ 0.88 in CHCl3);[16]
for 8: [α]2D3 ϭ Ϫ55.5 (c ϭ 3.0 in diethyl ether)[20]}.
Synthesis of box-DHQD (1b): Bis(oxazoline) 5b (0.097 g,
0.141 mmol) was metalated as described above for the metalation
of 4b. After stirring for 1.5 h at Ϫ50 °C, MeI (0.014 mL,
0.226 mmol) was added, and the mixture was stirred at the same
temperature for 3 h. It was then allowed to slowly warm to room
temp. and stirring was continued for 56 h. Work-up as described
above gave the crude product, which was purified by flash chroma-
tography using CH2Cl2/MeOH (95:5 Ǟ 90:10) as the eluent. The
product (0.030 g) was obtained in 30% yield as a thick yellow oil.
It had [α]2D3 ϭ Ϫ4.0 (c ϭ 0.33 in CH2Cl2). Ϫ IR: ν˜ ϭ 1737,
1
1660 cmϪ1. Ϫ H NMR: δ ϭ 8.75 (d, 1 H, J ϭ 4.6 Hz, quinoline
2-H), 8.02 (d, 1 H, J ϭ 9.2 Hz, quinoline 8-H), 7.33Ϫ7.47 (m, 3
H, remaining aromatic protons), 6.53Ϫ6.63 (m, 1 H, CHOCO),
4.07Ϫ4.17 (m, 4 H, two CH2O of box), 3.98 (s, 3 H, MeO),
3.84Ϫ3.90 (m, 2 H, two CHtBu), 3.26Ϫ3.33 (m, 1 H, CHN bridge-
head), 2.66Ϫ3.00 (m, 4 H, CH2NCH2), 2.38 (t, 2 H, J ϭ 7.4 Hz,
CH2COO), 1.27Ϫ2.16 (m, 16 H, 4 CH2 of the aliphatic chain, 2
CH and 2 CH2 of the bicyclic ring, CH2 of ethyl group), 1.48 [s, 3
H, CH3C(CϭN)2], 0.94 (t, 3 H, J ϭ 7.3 Hz, CH3CH2), 0.90 (s, 9
H, one of two tBu), 0.88 (s, 9 H, one of two tBu). Ϫ 13C NMR:
δ ϭ 172.5, 164.8, 164.7, 157.9, 147.4, 145.0, 144.0, 131.8, 127.0,
121.9, 118.6, 101.4, 75.5, 75.3, 73.5, 68.7, 59.2, 55.6, 50.7, 49.9,
42.0, 37.3, 36.2, 34.4, 33.7, 29.3, 27.0, 26.0, 25.7, 25.4, 24.0, 23.5,
23.4, 21.4, 12.0. Ϫ C42H62N4O5 (703.0): calcd. C 71.76, H 8.89, N
7.97; found C 71.53, H 8.88, N 7.81.
Acknowledgments
We thank the MURST (Progetto Nazionale Stereoselezione in Sin-
tesi Organica: Metodologie e Applicazioni) and the CNR for finan-
cial support.
[1]
Review: Catalytic Asymmetric Synthesis (Ed.: I. Ojima), VCH
Publishers, New York, 1993.
[2]
Review: A. K. Ghosh, P. Mathivanan, J. Cappiello, Tetrahed-
ron: Asymmetry 1998, 9, 1Ϫ45.
[3]
The possibility of performing sequential enantioselective cata-
lytic processes has very recently been reported for the first time:
H.-B. Yu, Q.-S. Hu, L. Pu, J. Am. Chem. Soc. 2000, 122,
6500Ϫ6501. In this case, the chiral ligand was a copolymer
composed of BINOL and BINAP units, which stereocontrolled
the addition of diethylzinc to an aldehyde function and the
Ru-catalyzed hydrogenation of a ketone, both carbonyls being
present within the same molecule. For recent reports on other
bifunctional ligands that have been used to promote a single
reaction, see refs.[4Ϫ7]
Synthesis of box-DHQD (1a): This compound was similarly pre-
pared from bis(oxazoline) 5a (0.146 g, 0.200 mmol). The product
(0.049 g) was obtained in 33% yield as a thick yellow oil. It had
[α]D23 ϭ Ϫ87.6 (c ϭ 0.51 in CH2Cl2). Ϫ IR: ν˜ ϭ 1720, 1650 cmϪ1. Ϫ
1H NMR: δ ϭ 8.72 (d, 1 H, J ϭ 4.4 Hz, quinoline 2-H), 8.02 (d,
1 H, J ϭ 9.2 Hz, quinoline 8-H), 7.20Ϫ7.45 (m, 13 H, remaining
aromatic protons), 6.80 (d, 1 H, J ϭ 7.3 Hz, CHOCO), 5.17Ϫ5.26
(m, 2 H, two PhCH), 4.58Ϫ4.72 (m, 2 H, two protons of two CH2O
of box), 4.08Ϫ4.25 (m, 2 H, two protons of two CH2O of box),
4.01 (s, 3 H, MeO), 3.28Ϫ3.38 (m, 1 H, CHN bridgehead),
[4]
A. P. H. J. Schenning, J. H. Lutje Spelberg, D. H. W. Hubert,
M. C. Feiters, R. J. M. Nolte, Chem. Eur. J. 1998, 4, 871Ϫ880
(epoxidation of alkenes).
[5]
M. P. Sibi, G. R. Cook, P. Liu, Tetrahedron Lett. 1999, 40,
2477Ϫ2480 (reduction of ketones).
Y. Hamashima, M. Kanai, M. Shibasaki, J. Am. Chem. Soc.
2000, 122, 7412Ϫ7413 (hydrocyanation of ketones).
[6]
[7]
For the attachment of two identical ligands to a soluble poly-
Eur. J. Org. Chem. 2001, 1045Ϫ1048
1047

R. Annunziata, M. Benaglia, M. Cinquini, F. Cozzi
SHORT COMMUNICATION
mer support, see: C. Bolm, C. L. Dinter, A. Seger, H. Höcker,
gand, as described in: D. A. Evans, K. A. Worpel, M. M. Hin-
man, M. M. Faul, J. Am. Chem. Soc. 1991, 113, 726Ϫ728. Un-
der these conditions, (R,R)-7 was obtained in 56% yield with
99% ee; the trans/cis ratio was 73:27.
J. Brozio, J. Org. Chem. 1999, 64, 5730Ϫ5731.
[8]
For a recent review on multifunctional asymmetric catalysis,
see: M. Shibasaki, Chemtracts Ϫ Organic Chemistry 1999, 12,
[17]
979Ϫ998.
It is known (T. Aratani, Pure & Appl. Chem. 1985, 57,
1839Ϫ1846) that the active catalyst in the cyclopropanation re-
action is a CuI rather than a CuII species. Our reaction seems
to suggest that the CuI/box species can survive the presence of
OsVI under the experimental conditions. In a control experi-
ment, the cyclopropanation of styrene (ref.[16]) with ethyl diazo-
acetate was carried out in CH2Cl2 with gem-dimethyl 4b as the
ligand in the presence of CuOTf and K2OsO4 dihydrate. This
gave (R,R)-7 in 5% yield with 99% ee. This result suggested
that the OsVI species can indeed decrease the yield of the reac-
tion, most probably by inhibiting the catalytic cycle. This deac-
tivation seems to be less significant in the presence of the Os
ligand DHQD.
[9]
Review: D. J. Berrisford, C. Bolm, K. B. Sharpless, Angew.
Chem. Int. Ed. Engl. 1995, 34, 1059Ϫ1070.
[10]
L. J. Goosen, H. Liu, K. Ruprecht Dress, K. B. Sharpless, An-
gew. Chem. Int. Ed. 1999, 38, 1080Ϫ1083, and references
therein.
[11]
Review: A. Nelson, Angew. Chem. Int. Ed. 1999, 38,
1583Ϫ1585.
[12]
A. E. Taggi, A. M. Hafez, H. Wack, B. Young, W. H. Drury
III, T. Lectka, J. Am. Chem. Soc. 2000, 122, 7831Ϫ7832.
[13]
A modification of a literature procedure has been employed: I.
W. Davies, L. Gerena, L. Castonguay, C. H. Senanayake, R. D.
Larsen, T. R. Verhoeven, P. J. Reider, Chem. Commun. 1996,
1753Ϫ1754.
[18]
[19]
Using DHQD 4-chlorobenzoate as the ligand in the dihy-
droxylation of styrene (see ref.[15]), (R)-8 was obtained with
74% ee.
[14]
These poor yields can be ascribed to the steric hindrance and
relatively low acidity of the trisubstituted bridging carbon
atom. The use of stronger bases or higher temperatures for the
metalation resulted in extensive decomposition of the bis(ox-
azoline)s. Reversal of the alkylation sequence (reaction of 4
first with MeI and then with 3) led to only low yields of 1.
The sequential process was not attempted using a substrate
possessing two double bonds, for instance 1,4-divinylbenzene,
in order to avoid the possibility of the stereocenters generated
in the first reaction ‘‘intramolecularly’’ affecting the stereo-
chemical course of the second reaction. On the contrary, cyclo-
propane 7 would seem unlikely to exert an ‘‘intermolecular’’
effect on the synthesis of diol 8. Moreover, the use of a sub-
strate with two double bonds could give rise to up to eight
stereoisomeric products in the sequential process, thus greatly
complicating the stereochemical analysis of the reaction course.
[15]
This reaction was performed as described by: K. B. Sharpless,
W. Amberg, M. Beller, H. Chen, Y. Kawanami, D. Lübben, E.
Manoury, Y. Ogino, T. Shibata, T. Ukita, J. Org. Chem. 1991,
56, 4585Ϫ4588. Under these conditions, the use of DHQD 4-
chlorobenzoate as a ligand afforded (R,R)-diol 6 with 99% ee.
The use of DHQD acetate (i.e. of an aliphatic ester of DHQD
[20]
`
as 1) under different conditions (E. N. Jacobsen, I. Marko, W.
D. Beer, R. Meuwly, A. Vasella, Helv. Chim. Acta 1982, 65,
S. Mungall, G. Schröder, K. B. Sharpless, J. Am. Chem. Soc.
1988, 110, 1968Ϫ1970) gave the product with 94% ee.
2570Ϫ2582.
Received November 8, 2000
[O00561]
[16]
This reaction was performed with gem-dimethyl 4b as the li-
1048
Eur. J. Org. Chem. 2001, 1045Ϫ1048