Synthesis of new chiral aryl diphosphite ligands derived from pyranoside backbone of monosacharides and their application in copper-catalyzed asymmetric conjugate addition of diethylzinc to cyclic enones

Article abstract of DOI:10.1002/adsc.200404053

New chiral aryl diphosphite ligands based on the pyranoside backbones of glucose and galactose were prepared. These ligands were tested in the Cu-catalyzed asymmetric conjugate addition of diethyl-zinc to cyclic enones with up to 88% ee. The stereoselecti

Full text of DOI:10.1002/adsc.200404053

FULL PAPERS
Synthesis of New Chiral Aryl Diphosphite Ligands Derived from
Pyranoside Backbone of Monosacharides and Their Application
in Copper-Catalyzed Asymmetric Conjugate Addition of
Diethylzinc to Cyclic Enones
Lailai Wang,a, b Yue-Ming Li,a Chiu-wing Yip,a,* Liqin Qiu,a Zhongyuan Zhou,a
Albert S. C. Chana,*
a
Open Laboratory of Chirotechnology of the Institute of Molecular Technology for Drug Discovery and Synthesis, and
Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom,
Kowloon, Hong Kong, People×s Republicof China
Fax: (þ852)-2364-9932, e-mail: bcachan@polyu.edu.hk
b
State Key Laboratory for Oxo Synthesis & Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese
Academy of Sciences, Lanzhou 730000, People×s Republic of China
Received: February 21,2004; Accepted: June 15, 2004
Abstract: New chiral aryl diphosphite ligands based figuration of the C-4 stereogeniccenter of the ligand
on the pyranoside backbones of glucose and galactose backbone, while the sense of enantioselectivity is
were prepared. These ligands were tested in the Cu- mainly controlled by the configuration of the bi-
catalyzed asymmetric conjugate addition of diethyl- naphthyl phosphite moieties.
zincto cyclicenones with up to 88% ee. The stereose-
lectivity was found to be dependent on the ring size of
the substrate as well as the ligand and copper source. Keywords: asymmetric; C C bond formation; conju-
The enantioselectivity depends on the absolute con- gate addition; copper salt; P ligands; zinc
À
Introduction
and are readily available; 2) the multifunctional proper-
ty makes it possible to design various structures through
The asymmetric conjugate addition of carbon nucleo- a series of modifications. Spescha reported the use of
philes to a,b-unsaturated carbonyl compounds is a use- sulphur ligands derived from glucose in the addition of
ful method for the formation of new carbon-carbon Grignard reagents to enones,[6] Selke et al. reported
bonds and the synthesis of chiral compounds. Recently, the use of a series of chiral phosphinite ligands derived
conjugate additions of nucleophiles to cyclic enones from glucose in the Rh-catalyzed asymmetric hydroge-
have been extensively studied as the products may be nation of dehydroamino acid derivatives to give good
useful for the synthesis of biologically active com- to excellent results.[7] Further improvements of ligands
pounds.[1] Several successful chiral ligands such as P,N li- of this type were achieved by Rajanbabu et al.[8] Recent-
gands,[2] phosphoramidites,[3] phosphites[4] and aryl di- ly, new chelating chiral aryl diphosphite ligands, based
phosphites[5] have been synthesized and employed in on a furanoside backbone of glucose, were synthesized.
asymmetric conjugate addition reactions, and good re- These ligands gave good results in the Rh-catalyzed
[9]
sults have been obtained. One of the main problems re- asymmetrichydroformylation of styrene,
vealed in these investigations is the dynamicbehaviour
Rh-cata-
lyzed asymmetrichydrogenation, [10] as well as Pd-cata-
with equilibria between several species of organocopper lyzed asymmetricallylicsubstitution, [11] and up to 63%
compounds in solution. If the more reactive cuprates ee was obtained when these chiral ligands were used in
lead to the racemic product, a loss of enantioselectivity the Cu-catalyzed asymmetric conjugate addition of di-
is unavoidable. It is therefore desirable to design and ethylzincto cyclicenones. [12] In this paper, we describe
synthesize new chiral catalysts which can react rapidly the synthesis of new chiral aryl diphosphite ligands
with the substrate and therefore suppress the formation based on the pyranoside backbones of glucose and gal-
of the undesired competing reactions.
actose. These ligands have been applied to the Cu-cata-
Using carbohydrates (and derivatives) as starting ma- lyzed asymmetricconjugate addition of diethylzincto
terials for the synthesis of chiral ligands has several ad- cyclic enones to give the desired products with good
vantages: 1) the raw materials are of high optical purity ees and yields.
Adv. Synth. Catal. 2004, 346, 947 953
DOI: 10.1002/adsc.200404053
¹ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Lailai Wang et al.
FULL PAPERS
Results and Discussion
Synthesis of Chiral Diphosphite Ligands
Diphosphite ligands 1 4, based on pyranoside back-
bones of glucose and galactose, were synthesized stereo-
specifically in three steps from phenyl b-d-galactopyra-
noside (7) and phenyl b-d-glucopyranoside (10) as
shown in Scheme 1. Ligands 1 and 2 have the same con-
figuration at the stereogenic center C-4, which is oppo-
site to that of ligands 3 and 4 (Figures 1 and 2). The bi-
naphthyl phosphite moieties of ligands 1 and 3 have
the same configuration which is opposite to that of li-
gands 2 and 4 (Figure 1). Tosylation of compounds 7
and 10 produced the expected 6-tosyl derivatives 8 and
11 in low to moderate yields.[13] Treating the tosylated
compounds with sodium hydroxide in ethanol at 80
858C produced colourless syrups 9 and 12.[14] Mixing
with ether induced crystallization and after recrystalli-
Figure 2. ORTEP diagram of phenyl 3,6-anhydro-b-d-gluco-
pyranoside (C12 H14 O5). Selected bond lengths [ä] and an-
À
À
gles [8]: O(1) C(5), 1.444(2); O(1) C(1), 1.401(2);
C(2) C(3), 1.527(3); C(3) C(4), 1.518(2); O(3) C(4),
À
À
À
À
À
À
1.407(2); O(2) C(2), 1.420(2); O(3) C(4) C(3), 116.14(14);
O(2) C(2) C(3), 111.51(15); O(1) C(1) O(5), 115.4(14);
O(5) C(1) C(2), 105.42(12); C(3) O(4) C(6), 107.48(12);
O(4) C(6) C(5), 105.16(13); C(4) C(5) C(6), 100.49(13).
À
À
À
À
À
À
À
À
À
À
À
À
zation from ether, the colourless crystals were obtained gen. The white solid ligands 1 4 were air-stable at
in moderate to good yields. An ORTEP drawing of phe- room temperature.
nyl 3,6-anhydro-b-d-glucopyranoside (12) is shown in
The 1H and 13 C NMR spectra were consistent with the
Figure 2. The bond angles (8) of O(3) C(4) C(3) and expectation for these ligands. The 31P NMR spectra of li-
À
À
À
À
O(2) C(2) C(3) are 116.18 and 111.58, respectively gands 1 and 2 displayed two singlets, one for each phos-
(Figure 2). The reaction of 9 and 12 with 2.2 equivalents phorus moiety. For ligands 3 and 4, two doublets, one for
of a suitable chlorodiarylphosphine afforded the corre- each phosphorus, were observed. The coupling con-
sponding ligands 1 4. All the ligands were stable during stants for ligands 3 and 4 were consistent with other
purification on silica gel under an atmosphere of nitro- phosphorus-phosphorus coupling constants in similar
diphosphites ligands [J(P,P) ¼12 Hz].[15]
Enantioselective Copper-Catalyzed 1,4-Addition of
Diethylzinc to Cyclic Enones
c]
Based on the experience from previous studies,[3a,5a
Cu(OTf)2 was chosen as the Cu source for the prepara-
tion of the active catalysts. In the first set of experiments,
2-cyclohexenone (5b) was treated with diethyzincin the
presence of Cu(OTf)2 and ligands 1 4 in toluene, re-
spectively (Table 1, entries 1 4). No 1,2-addition prod-
uct was observed from the gas chromatographic analy-
sis. It was found that the catalyst prepared in situ from
Cu(OTf)2 and ligand 3 was more effective than that
Figure 1. The chiral diphosphite ligands with the pyranoside
backbone of galactose (L1 and L2) and glucose (L3 and L4).
Scheme 1. Preparation of ligands L1 L4.
948
¹ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Adv. Synth. Catal. 2004, 346, 947 953

Chiral Aryl Diphosphite Ligands Derived from Pyranoside Backbone
Table 1. Cu-catalyzed enantioselective addition of diethylzinc reagents to cyclic enones using ligands 1 4.[a]
FULL PAPERS
Entry
Substrate
L
Copper salts
T [ 8C]
t [h]
Conversion [%][b]
Yield [%][b]
ee [%][b]
1
2
3
4
5
6
7
8
5b
5b
5b
5b
5a
5c
5a
5b
L1
L2
L3
L4
L3
L3
L3
L3
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
(CuOTf)2 ¥C6H6
(CuOTf)2 ¥C6H6
À30
À40
À30
À30
À30
À30
À40
À40
19
13
19
17
17
17
17
17
>99%
>99%
>99%
66%
>99%
97%
86%
94%
83%
72%
18%
12%
36%
94%
2%(S)
9%(S)
59%(R)
13%(S)
35%(R)
11%(R)
64%(R)
74%(R)
>99%
>99%
[a]
Reaction conditions: Cu(OTf)2 (0.01 mmol), ligand (0.02 mmol), ZnEt2 (1.2 mmol), substrate (0.5 mmol), toluene (4 mL).
The data on conversion and yield were determined by GC-MS using dodecane as an internal standard on an HPG 1800C
GCD system with a Bexs column (30 mꢀ0.25 mm I. D.). The enantiomeric excess of the product was determined by GC
using an HP5890 gas chromatograph equipped with a Chiraldex A-TA column (50 mꢀ0.25 mm I. D.). The absolute con-
figuration of the product 3-ethylcyclohexenone was determined by comparison with authentic materials.
[b]
from either ligands 1, 2, or 4 (Table 1, entries 1, 2, and 4 strate 5b gave 94% yield and 74% ee (Table 1, entry 8),
vs. entry 3). The use of ligand 3 gave 3-ethylcyclohexe- while substrate 5a gave 36% yield and 64% ee (Table 1,
none (6b) in 83% yield and 59% ee (Table 1, entry 3). entry 7). These results (Table 1, entries 3, 5, 7, and 8)
In contrast, the use of other diastereomeric ligands suggested that the matched combination of (CuOTf)2 ¥
gave substantially lower ees (entries 1, 2, and 4). The C6H6, and ligand 3 under the reaction conditions gave
use of ligand 4, which was based on the same pyranoside better enantioselectivity and chemical yield of the prod-
backbone of glucose as ligand 3 and an oppositely con- uct 6b (Table 1, entry 7).
figurated binaphthyl moiety, gave 72% yield and 13%
A profound solvent effect on enantioselectivity was
ee (Table 1, entry 4). Ligand 2, bearing the same config- observed and the results are summarized in Table 2.
uration of the binaphthyl phosphite moieties as ligand 4, Contrary to the common notion that the use of a coordi-
in which the configuration at the stereogenic center C-4 nating solvent is detrimental to either the yield or the ee
is opposite to that of ligand 3, gave 94% yield and 8.6% values in most asymmetric catalytic reactions involving
ee (Table 1, entry 2). The above-mentioned comparison the use of diethylzincas a reagent, Alexakis et al. have
of entries 1 4 clearly shows the synergistic effects of the shown that asymmetricconjugate addition of diethyl-
different chiral elements of ligands on the enantioselec- zinc to enones gave higher ees compared to reactions
tivity of the reactions: one between the backbone stereo- carried out in other reaction media.[16] In our cases, we
centers C-2 and C-4 (Figure 2); another between the also found that ethereal solvents (ether and THF, Ta-
stereocenters of the ligand backbone and the configura- ble 2, entries 6, 7) proved to be more effective than the
tion of the binaphthyl phosphite moieties (Figure 1). non-coordinating toluene and dichloromethane sol-
The value of the enantiomericexcess is controlled by
vents (Table 2, entries 4, 5). When the reaction was car-
all chiral elements, whereas the sense of enantioselectiv- ried out in THF, higher enantioselectivity (84% ee) was
ity is mainly controlled by the configuration of the bi- observed (Table 2, entry 7).
naphthyl phosphite moieties.
The effect of reaction temperature on enantioselectiv-
2-Cyclopentenone (5a) and 2-cycloheptenone (5c) ity was also investigated. Like many similar reactions,
were also reacted with diethylzinc in the presence of li- higher enantioselectivity was obtained at a lower reac-
gand 3 and Cu(OTf)2, respectively. A significant de- tion temperature (Table 2). When the reaction temper-
pendence of the stereoselectivity on the ring size of ature was lowered from 0 0C to À78 0C, enantioselectiv-
the substrate was observed: 35% ee for 2-cyclopente- ity increased from 82% ee to 88% ee in THF (Table 2,
none (Table 1, entry 5), 59% ee for 2-cyclohexenone entries 2, 7, and 8). When the reaction temperature
(Table 1, entry 3), and 11% ee for 2-cycloheptenone was lowered from 0 0C to À40 0C, enantioselectivity
(Table 1, entry 6).
rose from 63% ee to 74% ee in toluene (Table 2, en-
When (CuOTf)2 ¥C6H6 was used as the source of cop- tries 3 and 4). This finding is consistent with that ob-
per ion, it was interesting to find enhanced yield and tained by Alexakis et al.
enantioselectivity for both substrates 5a and 5b. Sub-
Adv. Synth. Catal. 2004, 346, 947 953
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Lailai Wang et al.
FULL PAPERS
Table 2. The effect of reaction temperature on the conjugate addition of diethylzinc to 2-cyclohexenone catalyzed by
(CuOTf)2 ¥C6H6-L3 complex.[a]
Entry
Solvent
T [0C]
t [h]
Conversion [%][b]
Yield [%][b]
ee [%][b]
1
2
3
4
5
6
7
THF
0
0
3
3
96%
>99%
>99%
>99%
>99%
>99%
64%
76%
96%
94%
82%
80%
95%
54%
82% (R)
63% (R)
74% (R)
67% (R)
81% (R)
84% (R)
88% (R)
toluene
toluene
CH2Cl2
ether
THF
THF
À40
À40
À40
À40
À78
17
17
17
17
5
[a]
Reaction conditions: (CuOTf)2 ¥C6H6 (0.01 mmol), L3 (0.02 mmol), ZnEt2 (1.2 mmol), 2-cyclohexenone (0.5 mmol),
solvent (4 mL).
[b]
[c]
The data on yield, and the enantiomeric excess of the product were determined using the same conditions as noted in
Table 1.
ZnEt2 (1.2 mmol) in 0.5 mL THF.
were obtained by geometrical analysis with 1740 Friedel pairs,
Conclusion
and Flack parameter¼0.8(9). Programs used were SHELXS97
(Sheldrick, 1997) andSHELXTL-NT forstructuresolution, re-
finement and molecular graphics.
New chiral aryl diphosphite ligands, based on the pyra-
noside backbones of glucose and galactose, have been
synthesized. Their copper complexes are efficient cata-
lysts for the asymmetricconjugate addition of diethyl-
zinc to cyclic enones. Two cooperative effects of the ster-
eochemistry of ligands on the enantioselectivity were
observed in the reactions: one between the backbone
stereocenters C-2 and C-4; another between the stereo-
centers of the ligand backbone and the configuration of
the binaphthyl phosphite moieties.
Phenyl 6-O-p-Tolylsulphonyl-b-d-galactopyranoside
(8) and Phenyl 6-O-p-Tolylsulphonyl-b-d-
glucopyranoside (11)
Phenyl b-d-galactopyranoside (7; 0.996 g, 3.89 mmol) was dis-
solved in 20 mL of dry pyridine, and mixed at À158C with tol-
uene-p-sulphonyl chloride (0.744 g, 3.92 mmol) in10 mL of dry
pyridine. The reaction mixture was kept for 30 min. at À158C
and 12 h at 208C, and the pyridine was distilled off under re-
duced pressure at 408C. The residue was dissolved in chloro-
form. The chloroform solution was washed with saturated po-
tassium hydrogen sulphate solution, saturated sodium hydro-
gen carbonate solution, and dried with anhydrous sodium sul-
phate. Since the solution had a tendency to gel, all these oper-
ations were conducted at 508C. After the removal of
chloroform, the dry powder was dissolved in 200 mL of toluene
under reflux, and the solution was left to crystallize. Compound
8 was obtained as a colourless crystal; yield: 0.407 g (25%).
1H NMR (500 MHz, CD3OD): d¼2.34 (s, 3H, CH3), 3.50 (dd,
1H, C3-H, J(3,4) ¼3.5 Hz, J(2,3) ¼10 Hz), 3.67 (m, 1H, C5-H),
Experimental Section
Reagents and Materials
All experiments were carried out under a nitrogen atmosphere.
(CuOTf)2 ¥C6H6, Cu(OTf)2 and Et2Zn (neat) were purchased
from Aldrich and were used without further purification. 2-Cy-
clohexenone, 2-cyclopentenone and 2- cycloheptenone were
dried with anhydrous sodium sulphate, distilled and degassed
with dry nitrogen before use. Toluene, ether and THF were dis-
tilled from sodium. Dichloromethane was distilled over calci-
um hydride. The other commercially available reagents were
used as received without further purification. 1H NMR,
13C NMR, and 31P NMR were recorded on a Varian AS 500
3.77 (d, 1H, C4-H, J(3,4) ¼3.5 Hz), 3.88 (dd, 1H, C6-H, J(5,6)
¼
3.5 Hz, J(6,6) ¼8.0 Hz), 4.12 (dd, 1H, C6-H, J(5,6) ¼10.5 Hz,
1
at room temperature. H NMR spectra are reported in ppm
J(6,6) ¼8.0 Hz), 4.22 (dd, 1H, C2-H, J(2,3) ¼10 Hz, J(1,2) ¼
with TMS as an internal standard (d¼0 ppm). 31P NMR spec-
tra are reported in ppm with 85% H3PO4 as an external refer-
ence. Mass spectrometry was performed using a Finnigan
MAT 95S model spectrometer.
7.5 Hz), 4.76 (d, 1H, C1-H, J(1,2) ¼7.5 Hz), 6.97 7.67 (m, 9H,
Ar-H); anal. calcd. for C19H22O8S: C 55.6, H 5.4, S, 7.8.; found:
C 55.0, H 5.7, S 7.5.
Treatment of phenyl b-d-glucopyranoside (10) and toluene-
p-sulphonyl chloride as described for compound 8 afforded
compound 11 as a colourless crystal; yield: 0.65 g (41%).
1H NMR (500 MHz, DMSO): d¼2.36 (s, 3H, CH3), 3.60 (t,
1H, C3-H), 4.04 (dd, 1H, C5-H, J(4,5) ¼10.5 Hz, J(5,6) ¼5.5 Hz),
The crystals of phenyl 3,6-anhydro-b-d-glucopyranoside
were coated in an inert oil prior to transfer to a cold nitrogen
gas stream on a Bruker CCD area-detector diffractomer sys-
tem equipped with Mo Ka radiation (l¼0.71073E). Data
were collected with narrow (R(int) ¼0.0175) frame exposures.
Intensities were corrected empirically for absorption, based
on the SADABS (Sheldrick, 1996) program, Tmin ¼0.9670,
Tmax ¼0.9888, and 3777 measured reflections. The structure
was refined on F2 values for all unique data. All H atoms
4.30 (d, 1H, C4-H, J(4,5) ¼10.5 Hz), 4.90 (d, 1H, C6-H, J(6,6)
¼
7.5 Hz), 5.20 (d, 1H, C6-H, J(5,6) ¼5.5 Hz), 5.30 (d, 1H, C2-H,
J(2,1) ¼5 Hz), 5.40 (d, 1H, C1-H, J(2,1) ¼5 Hz), 6.96 7.71 (m,
9H, Ar-H); anal. calcd. for C19H22O8S: C 55.6, H 5.4, S 7.8;
found: C 55.1, H 5.6, S, 7.7.
950
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Adv. Synth. Catal. 2004, 346, 947 953

Chiral Aryl Diphosphite Ligands Derived from Pyranoside Backbone
FULL PAPERS
Phenyl 3,6-Anhydro-b-d-galactopyranoside (9) and
Phenyl 3,6-Anhydro-b-d-glucopyranoside (12)
2,4-Bis{[(S)-1,1’-binaphthyl-2,2’-diyl] Phosphite}-
phenyl 3,6-Anhydro-b-d-galactopyranoside (2)
Phenyl 6-O-p-tolylsulphonyl-b-d-galactopyranoside (8; 0.65 g,
1.585 mmol) in ethanol (20 mL) was converted by a solution of
sodium hydroxide (20 mL, 1 N) at 80 858C in 2 h into com-
pound 9, which was extracted with ether-acetone (1:1, v/v).
Evaporation of the extract yielded a colourless syrup. Tritura-
tion with ether induced crystallization and a colourless powder
was obtained after recrystallization from ether; yield: 0.372 g
Treatment of in situ formed[17] (S)-(1,1’-binaphthyl-2,2’-dioxy)-
chlorophosphine (2.2 mmol) and compound 9 as described for
compound 1 afforded diphosphite 2, which was purified by
flash chromatography (toluene, Rf ¼0.64) to produce a white
powder; yield: 0.405 g (47%). 31P NMR (202 MHz, CDCl3):
1
d¼137.1 (s, 1P), 140.5 (s, 1P); H NMR (500 MHz, CDCl3):
d¼3.86 (dd, 1H, C2-H, J(1,2) ¼3 Hz, J(2,3) ¼9.5 Hz), 4.11 (d,
1H, C3-H, J(2,3) ¼9.5 Hz), 4.35 (s, 1H, C4-H), 4.38 (d, H, C6-
1
(94%). H NMR (500 MHz, CD3OD): d¼3.80 (dd, 1H, C5-
H, J(5,6) ¼10 Hz, J(4,5) ¼3 Hz), 4.35 (d, 1H, C4-H, J(4,5) ¼3 Hz),
4.15 (m, 4H, C2-H, C3-H, C6-H), 5.24 (s, 1H, C1-H), 6.89
7.22 (m, 5H, Ar-H); anal. calcd. for C12H14O5: C 60.5, H
5.9%; found: C 60.4, H 5.5%.
H, J(6,6) ¼5.0 Hz), 4.46 (dd, 1H, C6-H, J(5,6) ¼10 Hz, J(6,6)
¼
5.0 Hz), 4.88 (dd, C5-H, J(6,5) ¼2 Hz, J(6,5) ¼9.5 Hz), 5.22 (s,
1H, C1-H), 6.73 7.93 (m, 29H, Ar-H); 13C NMR (125 MHz,
CDCl3): d¼71.0 (s, C6), 73.8 (d, C4), 75.8 (s, C3), 77.9 (d,
¼
¼
Treatment of phenyl 6-O-p-tolylsulphonyl-b-d-glucopyra-
noside (11) as described for compound 9 afforded compound
12 as colourless crystals; yield: 0.210 g (53%). 1H NMR
(500 MHz, CD3OD): d¼3.80 (m, 2H, C2-H, C4-H), 4.07 (t,
1H, C5-H), 4.13 (m, 3H, C6-H, C3-H), 5.50 (s, 1H, C1-H),
6.66 7.22 ( m, 5H, Ar-H); anal. calcd. for C12H14O5: C 60.5,
H 5.9; found: C 60.2, H 5.8.
C5), 79.9 (d, C2), 90.4 (s, C1), 118.8 (CH ), 120.5 (CH ),
¼
¼
¼
¼
121.5 (CH ), 121.6 (CH ), 121.9 (CH ), 122.3 (CH ), 122.6
¼
¼
¼
¼
(CH ), 123.7 (CH ), 123.9 (CH ), 124.2 (CH ), 124.9
(CH ), 125.0 (CH ), 125.2 (CH ), 125.3 (CH ), 125.4
(CH ), 126.2 (CH ), 126.3 (CH ), 126.4 (CH ), 126.5
(CH ), 126.8 (CH ), 127.7 (CH ), 128.2 (CH ), 128.3
(CH ), 128.4 (CH ), 128.5 (CH ), 129.1 (CH ), 129.5
(CH ), 130.1 (CH ), 130.5 (CH ), 130.7 (CH ), 130.9
¼
¼
¼
¼
¼
¼
¼
¼
¼
¼
¼
¼
¼
¼
¼
¼
¼
¼
¼
¼
¼
¼
¼
¼
(CH ), 131.2 (CH ), 131.6 (C), 131.7 (CH ), 132.5 (CH ),
¼
¼
132.7 (CH ), 132.8 (CH ), 137.8 (C), 146.8 (C), 147.3 (C),
147.6 (C), 147.7 (C), 147.8 (C), 147.9 (C), 150.4 (C); MS
(5.34ꢀ104 eV): m/e (int (%)¼867 (2.2) [Mþ1], 889 (1.9)
[MþNa], 317 (100), 235 (23), 285 (34).
2,4-Bis{[(R)-1,1’-binaphthyl-2,2’-diyl] Phosphite}-
phenyl 3,6-Anhydro-b-d-galactopyranoside (1)
(R)-(1,1’-Binaphthyl-2,2’-dioxy)-chlorophosphine (2.2 mmol)
was synthesized in situ,[17] dissolved in toluene (5 mL), and pyr-
idine (0.36 mL, 4.6 mmol) was added. Phenyl 3,6-anhydro-b-d-
galactopyranoside (9; 0.238 g, 1 mmol) was azeotropically
dried with toluene (3ꢀ5 mL) and then dissolved in toluene
(10 mL) to which pyridine (0.18 mL, 2.3 mmol) had been add-
ed. The diol solution was transferred slowly at room tempera-
ture to the solution of phosphorochloridite. The reaction mix-
ture was stirred overnight at reflux, and the pyridine salts were
removed by filtration. Evaporation of the solvent gave a white
foam, which was purified by flash chromatography (toluene,
Rf ¼0.68) to produce a white powder; yield: 0.396 g (46%).
31P NMR (202 MHz, CDCl3): d¼133.5 (s, 1P), 146.7 (s, 1P);
2,4-Bis{[(R)-1,1’-binaphthyl-2,2’-diyl] Phosphite}-
phenyl 3,6-Anhydro-b-d-glucopyranoside (3)
Treatment of in situ formed (R)-(1,1’-binaphthyl-2,2’-dioxy)-
chlorophosphine (2.2 mmol) and compound 12 as described
for compound 1 afforded diphosphite 3, which was purified
by flash chromatography (toluene, Rf ¼0.54) to produce a
white powder; yield: 0.324 g (37%). 31P NMR (202 MHz,
CDCl3): d¼109.6 (d, 1P, J(P,P) ¼5.5 Hz), 146.0 (d, 1P, J(P,P)
¼
5.5 Hz ); 1H NMR (500 MHz, CDCl3): d¼3.00 (s, 1H, C3-H),
3.34 (dd, 1H, C2-H, J(2,3) ¼2.5 Hz, J(1,2) ¼10.5 Hz ), 3.65 (t,
1H NMR (500 MHz, CDCl3): d¼3.80 (dd, 1H, C2-H, J(1,2)
¼
3 Hz, J(2,3) ¼20 Hz), 4.09 (d, 1H, C3-H, J(2,3) ¼20 Hz), 4.30 (s,
1H, C4-H), 4.51 (dd, H, C6-H, J(5,6) ¼0.5 Hz, J(6,6) ¼5.0 Hz ),
1H, C5-H), 3.79 (t, 1H, C4-H), 3.90 (d, 1H, C6-H, J(6,6)
¼
10.5 Hz), 3.94 (t, 1H, C6-H), 5.23 (s, 1H, C1-H), 6.44 7.97
(m, 29H, Ar-H); 13C NMR (125 MHz, CDCl3): d¼66.0 (q,
C6), 69.2 (q, C4), 69.5 (s, C3), 71.5 (m, C5), 75.0 (d, C2), 98.7
4.64 (d, 1H, C6-H, J(6,6) ¼5.0 Hz), 4.98 (dd, C5-H, J(6,
¼
5)
2 Hz, J(6,5) ¼8 Hz), 5.24 (s, 1H, C1-H), 6.87 8.04 (m, 29H, Ar-
H); 13C NMR (125 MHz, CDCl3): d¼70.0 (s, C6), 73.5(d,
C4), 74.8 (s, C3), 77.1 (d, C5), 79.0 (d, C2), 97.4 (s, C1), 115.8
¼
¼
¼
(d, C1), 116.3 (CH ), 120.4 (CH ), 120.5 (CH ), 121.3
¼
¼
¼
¼
¼
¼
¼
¼
(CH ), 121.4 (CH ), 121.5 (CH ), 121.9 (CH ), 122.0
(CH ), 120.5 (CH ), 121.4 (CH ), 121.6 (CH ), 122.0
(CH ), 122.1(CH ), 122.6 (CH ), 123.8 (CH ), 123.9
¼
¼
¼
¼
¼
¼
¼
¼
(CH ), 122.1 (CH ), 122.2 (CH ), 122.3 (CH ), 122.8
¼
¼
¼
¼
¼
¼
¼
¼
(CH ), 123.6 (CH ), 124.5 (CH ), 124.6 (CH ), 125.1
(CH ), 124.2 (CH ), 124.3 (CH ), 125.0 (CH ), 125.2
¼
¼
¼
¼
¼
¼
¼
¼
(CH ), 125.2 (CH ), 125.3 (CH ), 125.4 (CH ), 126.3
(CH ), 125.3 (CH ), 125.4 (CH ), 126.2 (CH ), 126.3
¼
¼
¼
¼
¼
¼
¼
¼
(CH ), 126.5 (CH ), 127.3 (CH ), 128.4 (CH ), 128.6
(CH ), 126.4 (CH ), 126.5 (CH ), 126.9 (CH ), 127.0
¼
¼
¼
¼
¼
¼
¼
¼
(CH ), 129.8 (C), 129.9 (CH ), 130.0 (CH ), 130.4 (CH ),
(CH ), 128.2 (CH ), 128.3 (CH ), 128.4 (CH ), 128.5
¼
¼
¼
¼
¼
¼
¼
¼
130.5 (CH ), 130.8 (CH ), 131.1 (CH ), 131.4 (CH ), 131.8
(CH ), 129.0 (CH ), 129.5 (CH ), 130.1 (CH ), 130.5
¼
¼
¼
¼
¼
¼
(CH ), 132.6 (CH ), 133.0 (C), 134.2 (C), 134.5 (C), 138.2
(C), 147.3 (C), 147.8 (C), 147.9 (C), 148.3 (C), 148.4 (C),
148.9 (C), 149.0 (C), 156.8.4 (C); MS (5.07ꢀ104 eV): m/e (int
(%)¼867 (3.2) [Mþ1], 889 (1.1) [MþNa], 317 (100), 235
(19), 285 (50).
(CH ), 130.7 (CH ), 130.9 (CH ), 131.2 (CH ), 131.6 (C),
¼
¼
¼
¼
131.7 (CH ), 132.5 (CH ), 132.7 (CH ), 132.8 (CH ), 137.8
(C), 146.8 (C), 147.1 (C), 147.6 (C), 147.7 (C), 147.8 (C),
147.9 (C), 156.4 (C); MS (5.48ꢀ104 eV): m/e (int (%)¼867
(1.9) [Mþ1], 889 (1.1) [MþNa], 317 (100), 235 (19), 285 (24).
Adv. Synth. Catal. 2004, 346, 947 953
asc.wiley-vch.de
¹ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
951

Lailai Wang et al.
FULL PAPERS
2,4-Bis{[(S)-1,1’-binaphthyl-2,2’-diyl] Phosphite}-
phenyl 3,6-Anhydro-b-d-glucopyranoside (4)
References and Notes
[1] For recent reviews on asymmetric conjugate addition:
see: a) M. P. Sibi, S. Manyem, Tetrahedron 2000, 56,
8033 8061; b) N. Krause, A. A. Hoffmann-Rˆder Syn-
thesis 2001, 171 196; c) A. Alexakis, C. Benhaim Eur.
J. Org. Chem. 2002, 3221 3236.
Treatment of in situ formed (S)-(1,1’-binaphthyl-2,2’-dioxy)-
chlorophosphine (2.2 mmol) and compound 12 as described
for compound 1 afforded diphosphite 4, which was purified
by flash chromatography (toluene, Rf ¼0.41) to produce a
white powder; yield: 0.224 g (26%); 31P NMR (202 MHz,
[2] a) A. W. Hird, A. H. Hoveyda, Angew Chem. Int. Ed.
2003, 43, 1276 1279; b) H. Mizutani, S. J. Degrado,
A. H. Hoveyda, J. Am. Chem. Soc. 2002, 124, 779 781;
c) C. A. Luchaco-Cullis, A. H. Hoveyda, J. Am. Chem.
Soc. 2002, 124, 8192 8193; d) G. Helmchen, A. Pfaltz,
Acc. Chem. Res. 2000, 33, 336 345; e) I. H. Escher, A.
Pfaltz, Tetrahedron 2000, 56, 2879 2888.
[3] a) B. L. Feringa, Acc. Chem. Res. 2000, 33, 346 353;
b) R. Naasz, L. A. Arnold, M. Pineschi, E. Keller, B. L.
Feringa, J. Am. Chem. Soc. 1999, 121, 1104 1105;
c) B. L. Feringa, M. Pineschi, L. A. Arnold, R. Imbos,
A. H. M. de Vries, Angew. Chem. Int. Ed. Engl. 1997,
36, 2620 2623.
[4] a) A. Alexakis, J. Burton, J. Vastra, C. Benhaim, X. Four-
nioux, A. van den Heuvel, J. M. Leveque, F. Maze, S.
Rosset, Eur. J. Org. Chem. 2000, 4011 4027; b) A. Alex-
akis, J. Vastra, J. Burton, C. Benhaim, P. Mangency, Ter-
ahedron Lett. 1998, 39, 7869 7872.
[5] a) M.Yan, L. W. Yang, A. S. C. Chan, Chem. Commun.
1999, 11 12; b) M. Yan, A. S. C. Chan, Tetrahedron
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[6] M. Spescha, Helv. Chim. Acta 1993, 76, 1832 1846.
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b) A. Kumar, G. Oehme, J. P. Roque, M. Schwartze, R.
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2199.
[8] O. Pamies, S. Van, P. F. Gino, M. Dieguez, S. Deeeren-
berg, G. Net, T. V. Rajanbabu, T. A. Ayers, G. A. Halli-
day, K. K. You, J. C. Calabrese, J. Org. Chem. 1997, 62,
6012 6028.
[9] M. Dieguez, O. Pamies, A. Ruiz, C. Claver, New J. Chem.
2002, 26, 827 833.
[10] E. Guiu, B. Munoz, S. Castillon, C. Claver, Adv. Synth.
Catal. 2003, 345, 169 171.
CDCl3): d¼110.0 (d, 1P, J(P,P) ¼3.7 Hz), 146.8 (d, 1P, J(P,P)
¼
1
3.7 Hz); H NMR (500 MHz, CDCl3): d¼3.20 (s, 1H, C3-H),
3.39 (dd, 1H, C2-H, J(2,3) ¼2.0 Hz, J(1,2) ¼10 Hz ), 3.41 (t, 1H,
C5-H), 3.68 (t, 1H, C4-H), 3.75 (d, 1H, C6-H, J(6,6) ¼10 Hz),
3.94 (t, 1H, C6-H), 5.23 (s, 1H, C1-H), 6.12 8.03 (m, 29H,
Ar-H); 13C NMR (125 MHz, CDCl3): d¼62.0 (q, C6), 64.2 (q,
C4), 68.5 (s, C3), 70.5 (m, C5), 74.0 (d, C2), 92.7 (d, C1),
¼
¼
¼
¼
116.3 (CH ), 120.4 (CH ), 120.5 (CH ), 121.3 (CH ), 121.4
(CH ), 121.5 (CH ), 121.9 (CH ), 122.0 (CH ), 122.1
¼
¼
¼
¼
¼
¼
¼
¼
(CH ), 122.2 (CH ), 122.3 (CH ), 122.8 (CH ), 123.6
(CH ), 124.5 (CH ), 124.6 (CH ), 125.1 (CH ), 125.2
(CH ), 125.3 (CH ), 125.4 (CH ), 126.3 (CH ), 126.5
¼
¼
¼
¼
¼
¼
¼
¼
¼
¼
¼
¼
(CH ), 127.3 (CH ), 128.4 (CH ), 128.6 (CH ), 129.8 (C),
¼
¼
¼
¼
129.9 (CH ), 130.0 (CH ), 130.4 (CH ), 130.5 (CH ), 130.8
¼
¼
¼
¼
(CH ), 131.1 (CH ), 131.4 (CH ), 131.8 (CH ), 132.6
¼
(CH ), 133.0 (C), 134.2 (C), 134.5 (C), 138.2 (C), 147.3 (C),
147.8 (C), 147.9 (C), 148.3 (C), 148.4 (C), 148.9 (C), 149.0
(C), 156.8 (C); MS (5.17ꢀ104 eV): m/e (int (%)¼867 (4.2)
[Mþ1], 889 (2.1) [MþNa], 317 (100), 235 (18), 285 (40).
Typical Procedure for the Conjugate Addition of
Diethylzinc to 2-Cyclohexenone
A solution of (CuOTf )2 ¥C6H6 (2.52 mg, 0.01 mmol) and L3
(17.3 mg, 0.02 mmol) in 4 mL THF was stirred for 1.0 hour.
The solution was cooled to À408C, and 2-cyclohexenone
(48 mL, 0.5 mmol) and diethylzinc(123 mL, 1.2 mmol) were
added. After stirring for 17.0 hours at À408C, the solution
was mixed with 2.0 mL water and 2.0 mL of hydrochloric
acid solution (2.0 M), and the product was extracted with 3ꢀ
5.0 mL ethyl acetate. The combined organic layer was washed
with saturated sodium hydrogen carbonate solution, brine, and
then dried over anhydrous sodium sulphate. Most of the sol-
vent was removed at reduced pressure. The crude product, 3-
ethylcyclohexenone, was obtained. The conversion and yield
were determined by GC-MS using dodecane as an internal
standard on an HPG 1800C GCD system with a Bexs column
(30 mꢀ0.25 mm I. D.). The enantiomeric excess of the product
was determined by GC using an HP5890 gas chromatograph
equipped with a Chiraldex A-TA column (50 mꢀ0.25 mm
I. D.). The absolute configuration of the product 3-ethylcyclo-
hexenone was determined by comparison with authentic sam-
ples.
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39; b) D. D. Pastor, S. P. Shum, R. K. Rodebaugh, A. D.
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914.
Acknowledgements
We thank the HongKongResearch Grants Council (Project No.
PolyU 5185/00P), and The HongKongPolytechnic University
ASD Fund for financial support of this study.
952
¹ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2004, 346, 947 953

Chiral Aryl Diphosphite Ligands Derived from Pyranoside Backbone
FULL PAPERS
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Adv. Synth. Catal. 2004, 346, 947 953
asc.wiley-vch.de
¹ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
953