New chiral amino-phosphite and phosphite-phosphoroamidite ligands for the copper-catalyzed asymmetric 1,4-addition of diethylzinc to cyclohexenone

Article abstract of DOI:10.1016/S0957-4166(01)00512-2

We have designed a series of amino-phosphite and phosphite-phosphoroamidite ligands 1-6 derived from inexpensive D-(+)-xylose. These ligands were screened in the Cu-catalyzed asymmetric 1,4-addition of diethylzinc to cyclohexenone. High reaction rates (TO

Full text of DOI:10.1016/S0957-4166(01)00512-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 2861–2866
New chiral amino-phosphite and phosphite-phosphoroamidite
ligands for the copper-catalyzed asymmetric 1,4-addition of
diethylzinc to cyclohexenone
Montserrat Di e´ guez,* Aurora Ruiz and Carmen Claver
Departament de Qu ´ı mica F ´ı sica i Inorg a` nica, Universitat Rovira i Virgili, Pl. Imperial T a` rraco 1, 43005 Tarragona, Spain
Received 18 October 2001; accepted 7 November 2001
Abstract—We have designed a series of amino-phosphite and phosphite-phosphoroamidite ligands 1–6 derived from inexpensive
D
-(+)-xylose. These ligands were screened in the Cu-catalyzed asymmetric 1,4-addition of diethylzinc to cyclohexenone. High
−1
reaction rates (TOF >1200 h ) and moderate enantioselectivities (up to 63% e.e.) were obtained. The results showed that the
configuration of the stereogenic carbon atom C(3) at the ligand backbone and the different substituents at the amino group had
remarkable effects on the activity and enantioselectivity. © 2001 Elsevier Science Ltd. All rights reserved.
1
. Introduction
However, further study is needed to understand how
efficient enantiocontrol can be achieved. In this context,
the rational design of new ligands is still a highly
significant field of research. For this purpose, carbohy-
drates are particularly advantageous because their mod-
ular construction means that structural diversity is easy
Catalytic asymmetric synthesis using organometallic
reagents is currently one of the most prominent areas of
research in organic chemistry. The 1,4-addition of
1
organometallic reagents to a,b-unsaturated carbonyl
compounds is an important process for CꢀC bond
5
to achieve, so enantioselectivity can be maximized.
2
formation
in
organic
synthesis.
Although
organocuprates and the copper-catalyzed 1,4-additions
of Grignard reagents are most frequently employed, a
number of alternative reagents, based on other metal
catalysts (i.e. Ni and Mn) and other organometallic
Following our interest in using carbohydrates as an
5,6
available chiral source for preparing ligands
and
4b,4g
encouraged by the success of some bidentate P,N-
4d–f,4k,4p
and phosphoroamidite
ligands in conjugate 1,4-
reagents (i.e. ZnR2 and AlR ), have recently been
3
additions, we have designed a series of amino-phosphite
and phosphite-phosphoroamidite ligands 1–6 with a
furanoside backbone (Fig. 1). We also report the use of
these ligands in the enantioselective copper-catalyzed
3
developed.
Several successful methods for enantioselective 1,4-
addition have been described. These have mainly been
based on chiral auxiliaries or stoichiometric
organometallic reagents, whereas only a few have been
1
,4-addition of diethylzinc to 2-cyclohexenone.
3
The advantage of these ligands is that many structural
variations can be made. These variations can provide
information about the effects of the different stereo-
genic centres in the ligand on the enantioselectivity of
the reaction. This study may also provide some insight
into the origin of the stereochemistry of the reaction.
The effect of the amino group was investigated by
introducing different substituents at the nitrogen atom.
We have also investigated the effects of the configura-
tion of the C(3) stereogenic centre in the ligand back-
bone and the substituents at the para positions of the
bisphenol moiety.
based on highly enantioselective catalytic processes. A
prominent position in the rapid development of the
latter field is occupied by the copper-catalyzed, ligand-
4
accelerated, 1,4-addition of organozinc reagents. Thus,
excellent enantioselectivities have been obtained using
4
d–f,4k,4p
4c,4h–j,4l,4m
phosphites,
4n,4o
chiral phosphoroamidites,
bidentate P,N-ligands
4b,4g
and Schiff base ligands.
*
0
Corresponding author. Fax: +34-977559563; e-mail: dieguez@
quimica.urv.es
957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00512-2

2
862
M. Di e´ guez et al. / Tetrahedron: Asymmetry 12 (2001) 2861–2866
t-Bu
OMe
t-Bu
t-Bu
t-Bu
t-Bu
O
O
t-Bu
O
O
OMe
O
O
t-Bu
O
O
O
P
O O
P
O O
P
O O
HN
HN
HN
t-Bu
t-Bu
t-Bu
O
O
O
1
2
3
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu t-Bu
t-Bu
HN
t-Bu
O
O
O
O
t-Bu
t-Bu
O
O
O
t-Bu
O
O
P
HN
t-Bu
P
P
O
O
HN
O
O O
O
O
P
O
t-Bu
t-Bu
O
O
O
t-Bu
4
5
6
t-Bu
Figure 1.
2
. Results and discussion
isolated in good yields (75–85%) as solids by purification
on neutral alumina under an atmosphere of argon. They
1
13
2
.1. Ligand synthesis
are stable at room temperature. The H and C NMR
spectra agree with those expected for these C ligands.
1
31
The amino-phosphite ligands 1–5 were prepared in two7
steps, starting from the corresponding monotosylates 7
One singlet was observed in the P NMR spectrum.
Rapid ring inversions (atropisomerization) in the bisphe-
nol moieties occurred on the NMR time scale since the
expected diastereoisomers were not detected by low-tem-
8
and 8, which are easily prepared on a large scale from
inexpensive
7
D
-(+)-xylose (Scheme 1). Treating tosylates
10
and 8 with tert-butylamine, aniline and isopropylamine
perature phosphorus NMR.
in propan-2-ol at reflux afforded the corresponding
amino alcohols 9, 10, 11 and 12, which are stable to air
at room temperature. The desired amino-phosphite lig-
ands 1–5 were obtained by reaction of the corresponding
amino alcohol and either (3,3%,5,5%-tetra-tert-butyl-1,1%-
Phosphite-phosphoroamidite 6 was synthesized accord-
11
ing to our previously reported procedure. The reaction
of the tosylate 7 with sodium azide followed by treatment
with triphenylphosphine afforded the corresponding
amino alcohol. This reacted readily with two equiva-
lents of phosphorochloridite to produce ligand 6 in good
yield.
9
biphenyl-2,2%-diyl)phosporochloridite or (5,5%-bis-tert-
butyl-3,3%-bis-methoxy-1,1%-biphenyl-2,2%-diyl)phosporo-
9
chloridite in the presence of base. Compounds 1–5 were
TsO
O
RHN
O
c)
d)
OH
OH
1-4
O
O
O
O
a)
7
9
R = t-Bu
D-(+)-xylose
b)
10 R = i-Pr
1 R = Ph
1
TsO
O
RHN
O
c)
d)
5
O
O
OH O
OH O
8
12 R = Ph
Scheme 1. Synthesis of ligands 1–5. (a) Ref. 7. (b) Ref. 8. (c) RNH , propan-2-ol, reflux. (d) (RO) PCl, py, toluene, 100°C.
2
2

M. Di e´ guez et al. / Tetrahedron: Asymmetry 12 (2001) 2861–2866
2863
2
2
.2. Asymmetric 1,4-addition of diethylzinc to
-cyclohexenone
The effect of the ligand aminoalkyl substituent on the
performance of the catalyst was investigated by using
ligands 1, 3 and 4. Our results showed that both the
reaction rate and enantioselectivity depended on the
nature of the substituent (entries 2, 8 and 9); conver-
sions and enantioselectivities were higher for the cata-
lyst precursor containing ligand 4, and with a phenyl
substituent at the amino group. Interestingly, the sense
of enantioselectivity was also affected; ligand 1, con-
taining a bulky tert-butyl substituent in the amino
group, gave the (R)-product (entry 2), while the less
sterically hindered ligands 3 and 4 gave the (S)-enan-
tiomer preferentially (entries 8 and 9). Ligand 5, whose
configuration of carbon atom C(3) is opposite to that
of ligand 4 (Fig. 1), proceeded at a similar reaction rate,
but the enantioselectivity dropped considerably (entry 9
versus 10). Ligand 6, which contains a bulky phospho-
roamidite moiety at carbon atom C(5) rather than the
alkylated amino group in ligands 1–5, proceeded at
We tested ligands 1–6 in the copper-catalyzed conjugate
addition of diethylzinc to 2-cyclohexenone. The latter
was chosen as a substrate because this reaction has
been performed with a wide range of ligands having
several donor groups enabling the direct comparison of
the efficiency of the different ligand systems.
catalytic system was generated in situ by adding the
3
c–e
The
corresponding ligand to a suspension of Cu(OTf) . The
2
results are shown in Table 1. In general, good reaction
rates were found for all ligands. No 1,2-product was
observed by gas chromatographic analysis.
In a first set of experiments, we studied the effect of the
reaction temperature and solvent using ligand 1. The
results showed that the efficiency of the process
depended on the nature of the solvent (entries 1–3). The
best catalyst performance (activity and selectivity) was
achieved when dichloromethane was used as a solvent
−
1
high reaction rates (TOF >1200 h ) but the enantiose-
lectivity was lower (30% e.e., entry 11).
(
entry 2). As reported for related Cu-diphosphite cata-
4l,12
lytic systems,
obtained at 0°C (entry 2). These decreased when the
reaction temperature was either lowered or raised
the best enantioselectivities were
The effect of the ligand-to-copper ratio on the outcome
of the reaction was investigated using ligand 4 (entries
9, 12 and 13). Adding a one-fold excess of ligand led to
a higher reaction rate and higher enantioselectivity
(entry 12). However, the outcome of the reaction was
not affected when a greater excess of ligand was added
(entry 13). Within the accuracy of these experiments,
there was no change in the enantioselectivity over time.
This agrees with the presence of the same aggregates
(
entries 2, 4–6). Comparing the results using ligands 1
and 2, which have different substituents in the para
positions of the biphenyl moiety, we can conclude that
the presence of methoxy groups in the para positions of
the biphenyl moiety had a negative effect on the activity
and enantioselectivity (entry 2 versus 7).
a
Table 1. Asymmetric 1,4-addition of diethylzinc to 2-cyclohexenone
O
O
Cu(OTf)2 / L*
*
ZnEt2
Et
Entry
Ligand
Solvent
T (°C)
TOFb
696
720
516
1020
504
% Conv.c
% e.e.d
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
2
3
4
5
6
4
4
Toluene
CH Cl
0
0
0
25
−20
−40
58
60
43
85
18 (R)
20 (R)
11 (R)
15 (R)
17 (R)
12 (R)
15 (R)
42 (S)
48 (S)
8 (R)
2
2
THF
CH Cl
2
2
2
2
2
2
2
2
2
2
2
e
CH Cl
100
2
e
CH Cl
432
660
960
92
2
CH Cl
0
0
0
0
0
0
0
55
80
85
84
100
90
2
CH Cl
2
CH Cl
1020
1008
\1200
1080
1092
2
10
11
12
13
CH Cl
2
CH Cl
30 (S)
63 (S)
63 (S)
2
f
CH Cl
2
g
CH Cl
91
2
a
b
c
d
e
f
Reaction conditions: Cu(OTf) (0.025 mmol), ligand (0.025 mmol), ZnEt2 (3.5 mmol), 2 (2.5 mmol), solvent (6 mL).
2
−1
−1
TOF in mol 4×mol Cu ×h determined after 5 min reaction time by GC.
Conversion determined by GC using undecane as internal standard after 5 min.
%
Enantiomeric excess measured by GC using Lipodex A column.
After 15 min.
0
.05 mmol of ligand used.
g
0
.075 mmol of ligand used.

2
864
M. Di e´ guez et al. / Tetrahedron: Asymmetry 12 (2001) 2861–2866
throughout the reaction. It should be noted that under
the same reaction conditions the activity and enantio-
selectivity (e.e. of up to 63%) of reactions with ligand 4
were much higher than those of the corresponding bulky
ol (4 mL), aniline (0.27 mL, 3 mmol) was added. The
mixture was stirred under reflux for 48 h. The solvent was
then evaporated and the residue was treated with satu-
rated aqueous NaHCO3 and extracted with
dichloromethane (3×20 mL). The organic layers were
3
,5-bis-[(3,3%,5,5%-tetra-t-butyl-1,1%-biphenyl-2,2%-diyl)-
phosphite] - 1,2 - O - isopropylidene - a - - xylofuranose
diphosphite analogue (which induced e.e. up to 24%).
D
dried on Na SO4 and evaporated. The mixture was
2
12
purified by flash chromatography to yield as a pale-yel-
low oil (339 mg, 64%). Anal. calcd for C H NO : C,
1
4
19
4
1
6
3.38; H, 7.22. Found: C, 63.56; H, 7.34%. H NMR, l:
3
. Conclusions
1.38 (s, 3H, CH ), 1.47 (s, 3H, CH ), 2.21 (b, 1H, NH),
3
3
3
2
3
.34 (dd, 1H, H-5, J =13.2 Hz, J =5.6 Hz), 3.50
5-5% 5-4
2 3
A series of amino-phosphite and phosphite-phospho-
(dd, 1H, H-5%, J =13.2 Hz, J5%-4=3.6 Hz), 3.88 (dd,
5%-5
3 3
roamidite ligands 1–6, derived from inexpensive and
1H, H-3, J =8.6 Hz, J =4.8 Hz), 3.97 (m, 1H, H-4),
3-4 3-2
3 3
readily available
D
-(+)-xylose, were screened in the highly
4.57 (dd, 1H, H-2, J =3.6 Hz, J =4.8 Hz), 5.82 (d,
2-1 2-3
3 3
active Cu-catalyzed asymmetric 1,4-addition of diethyl-
1H, H-1, J =3.6 Hz), 6.66 (d, 2H, CHꢁ, JH-H=7.8
1-2
−
1
3
zinc to 2-cyclohexenone (TOF >1200 h and e.e. of up
to 63%). The advantage of these ligands is that their
modular nature allows facile systematic variation in the
configuration of the C(3) stereocentre, at the ligand
bridge and in the amino and biphenyl substituents, so
their effects on the stereoselectivity can be studied. The
results showed that the configuration of the stereogenic
carbon atom C(3) in the ligand backbone and the
different substituents at the amino group had very
marked effects on the activity and enantioselectivity. The
enantioselectivity was best with ligand 4, which has
Hz), 6.72 (t, 1H, CHꢁ, J =7.2 Hz), 7.18 (t, 2H, CHꢁ,
H-H
3
13
J
=7.6 Hz). C NMR, l: 26.6 (CH ), 26.8 (CH ),
3 3
H-H
44.7 (C-5), 73.3 (C-3), 78.8 (C-2), 79.4 (C-4), 104.2 (C-1),
113.0 (CMe ), 113.3 (CHꢁ), 118.0 (CHꢁ), 129.5 (CHꢁ),
148.3 (C).
2
4.3. 5-Deoxy-5-N-phenylamino-1,2-O-isopropylidene-a-
D
-xylofuranose 11
Treatment of tosylate 7 (689 mg, 2 mmol) and aniline
(0.27 mL, 3 mmol) as described for compound 12
afforded amino alcohol 11, which was purified by flash
chromatography to produce a pale-yellow powder (323
mg, 61%). Anal. calcd for C H NO : C, 63.38; H, 7.22.
Found: C, 63.17; H, 6.99. H NMR, l: 1.34 (s, 3H, CH ),
1.51 (s, 3H, CH ), 3.60 (d, 2H, H-5, H-5%, J =4.2 Hz),
(
R)-configuration at C(3) and a phenyl substituent on the
amino group. Also, the presence of methoxy groups in
the para positions of the biphenyl moiety had a negative
effect on both the activity and enantioselectivity of the
ligand. Exploiting the fact that these sugar ligands can
be easily modified, further research is now in progress.
14
19
4
1
3
3
3
5-4
3
4
.09 (m, 1H, NH), 4.32 (d, 1H, H-3, J =2.6 Hz), 4.40
3-4
3 3
(
dd, 1H, H-4, J =4.2 Hz, J =2.6 Hz), 4.55 (d, 1H,
4-5 4-3
3 3
4. Experimental
H-2, J =3.6 Hz), 6.02 (d, 1H, H-1, J =3.6 Hz), 6.76
2-1 1-2
3 3
(
d, 2H, CHꢁ, J =7.8 Hz), 6.85 (t, 1H, CHꢁ, JH-H=
H-H
3 13
H-H
4
.1. General comments
7.2 Hz), 7.18 (t, 2H, CHꢁ, J =7.6 Hz). C NMR, l:
2
6.4 (CH ), 27.0 (CH ), 43.9 (C-5), 77.4 (C-3), 77.6 (C-4),
3 3
All syntheses were performed using standard Schlenk
techniques under an argon atmosphere. Solvents were
purified by standard procedures. 1,2-O-Isopropylidene-
85.8 (C-2), 105.2 (C-1), 111.9 (CMe ), 115.4 (CHꢁ), 120.1
2
(CHꢁ), 129.5 (CHꢁ), 147.3 (C).
7
5
-O-p-tolylsulfonyl-a-
propylidene-5-O-p-tolylsulfonyl-a-
were prepared by tosylation of the corresponding diols
D
-xylofuranose 7 and 1,2-O-iso-
8
D
-ribofuranose
8
4.4. 3-[(3,3%,5,5%-Tetra-t-butyl-1,1%-biphenyl-2,2%-
diyl)phosphite]-5-deoxy-5-N-tert-butylamino-1,2-O-
isopropylidene-a-D-xylofuranose 1
1
1
13
13
using standards procedures. Compounds 6, 9, 10
9
and phosphorochloridites were prepared by previously
described methods. All other reagents were used as
commercially available. Elemental analyses were per-
In situ formed (3,3%,5,5%-tetra-tert-butyl-1,1%-biphenyl-
2,2%-diyl)-phosphorochloridite (1.2 mmol) was dissolved
in toluene (5 mL) to which pyridine (0.36 mL, 4.6
mmol) was added. 1,2-O-Isopropylidene-5-desoxy-5-N-
1
formed on a Carlo Erba EA-1108 instrument. H,
C{ H} and P{ H} NMR spectra were recorded on a
Varian Gemini 400 MHz spectrometer. Chemical shifts
are relative to SiMe ( H and C) as internal standard
or H PO ( P) as external standard. All assignments in
1
3
1
31
1
tert-butylamino-a- -xylofuranose 9 (245.3 mg, 1 mmol)
D
1
13
was azeotropically dried with toluene (3×1 mL) and
dissolved in toluene (10 mL) to which pyridine (0.18
mL, 2.3 mmol) was added. The diol solution was
transferred slowly over 30 min to a solution of phos-
phorochloridite at room temperature. 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 over alumina (eluent: toluene/NEt3
4
3
1
3
4
NMR spectra were determined by COSY and HETCOR
spectra. Gas chromatographic analyses were run on a
Hewlett–Packard HP 5890A instrument equipped with a
Hewlett–Packard HP 3396 series II integrator.
4
.2. 5-Deoxy-5-N-phenylamino-1,2-O-isopropylidene-a-
D
-ribofuranose 12
1
00/1, R 0.9) to produce a white powder (0.60 g, 88%).
f
To a solution of 1,2-O-isopropylidene-5-O-p-tolylsul-
fonyl-a- -ribofuranose 8 (689 mg, 2 mmol) in propan-2-
Anal. calcd for C H NO P: C, 70.25; H, 9.14. Found:
40 62 6
31 1
D
C, 70.01; H, 9.02%. P NMR, l: 144.3 (s, 1P). H

M. Di e´ guez et al. / Tetrahedron: Asymmetry 12 (2001) 2861–2866
2865
NMR, l: 0.94 (s, 9H, CH , t-Bu-N), 1.21 (s, 3H, CH ),
(m, 1H, H-4), 4.38 (m, 1H, H-2), 4.65 (dd, 1H, H-3,
3 3
3
3
1
3
.33 (s, 9H, CH , t-Bu), 1.34 (s, 9H, CH t-Bu), 1.43 (s,
J3-4=2.8 Hz, J3-P=10.0 Hz), 5.75 (d, 1H, H-1, J =
1-2
13
3
3
H, CH ), 1.47 (s, 9H, CH t-Bu), 1.48 (s, 9H, CH ,
3.6 Hz), 7.1–7.4 (m, 4H, CHꢁ). C NMR, l: 22.6 (CH3
i-Pr), 22.8 (CH i-Pr), 26.3 (CH ), 26.6 (CH ), 31.1
3
3
3
2
3
t-Bu), 2.65 (dd, 1H, H-5, J =11.2 Hz, J =6.8 Hz),
5
-5%
5-4
3
3
3
2
3
2
.80 (dd, 1H, H-5%, J5 =11.2 Hz, J5%-4=7.6 Hz), 4.27
(CH , t-Bu), 31.2 (CH , t-Bu), 31.4 (CH , t-Bu), 31.5
%-5
3 3 3
(
m, 1H, H-4), 4.39 (m, 1H, H-2), 4.66 (dd, 1H, H-3,
(CH , t-Bu), 34.6 (C, t-Bu), 35.3 (C, t-Bu), 35.4 (C,
3
t-Bu), 45.9 (CH, i-Pr), 48.8 (C-5), 76.9 (d, C-3, JC-P=
3
3
J =2.8 Hz, J =9.2 Hz), 5.75 (d, 1H, H-1, J =3.2
3
-4
3-P
1-2
Hz), 7.14 (m, 1H, CHꢁ), 7.17 (m, 2H, CHꢁ), 7.43 (m,
2.0 Hz), 84.3 (d, C-4, JC-P=3.8 Hz), 84.3 (C-2), 104.6
1
3
1
H, CHꢁ). C NMR, l: 26.3 (CH ), 26.7 (CH ), 28.8
(C-1), 111.7 (CMe ), 124.1 (CHꢁ), 124.3 (CHꢁ), 125.3
3
3
2
(
CH , t-Bu-N), 31.2 (CH , t-Bu), 31.3 (CH , t-Bu), 31.5
(CHꢁ), 132.4 (C), 132.8 (C), 139.8 (C), 140.0 (C), 146.5
3
3
3
(CH , t-Bu), 34.6 (C, t-Bu), 34.7 (C, t-Bu), 35.4 (C,
(C), 146.9 (C).
3
t-Bu), 35.5 (C, t-Bu), 41.3 (C-5), 77.3 (m, C-3), 80.3 (d,
C-4, JC-P=3.8 Hz), 84.4 (d, C-2, JC-P=11.4 Hz), 104.6
4.7. 3-[(3,3%,5,5%-Tetra-t-butyl-1,1%-biphenyl-2,2%-
diyl)phosphite]-5-deoxy-5-N-phenylamino-1,2-O-
isopropylidene-a-D-xylofuranose 4
(
(
(
C-1), 111.7 (CMe ), 124.2 (CHꢁ), 124.3 (CHꢁ), 125.3
2
CHꢁ), 133.5 (C), 132.9 (C), 139.9 (C), 140.0 (C), 146.5
C), 146.8 (C).
Treatment of the corresponding in situ formed phos-
phorochloridite (1.2 mmol) and 11 (265.3 mg, 1 mmol)
as described for compound 1 afforded amino-phosphite
4
.5. 3-[(3,3%-Bis-tert-butyl-5,5%-bis-methoxy-1,1%-
biphenyl-2,2%-diyl)phosphite]-5-deoxy-5-N-tert-butyl-
amino-1,2-O-isopropylidene-a- -xylofuranose 2
4
, which was purified by flash chromatography over
D
alumina (eluent: toluene/NEt 100/1, R 0.9) to produce
3
f
a white powder (0.57 g, 81%). Anal. calcd for
C H NO P: C, 71.67; H, 8.31. Found: C, 71.43; H,
Treatment of in situ formed (3,3%-bis-tert-butyl-5,5%-bis-
methoxy - 1,1% - biphenyl - 2,2% - diyl)phosphorochloridite
42
58
6
31
1
8
3
.40%. P NMR, l: 145.6 (s, 1P). H NMR, l: 1.23 (s,
H, CH ), 1.31 (s, 9H, CH t-Bu), 1.36 (s, 9H, CH
3
(
1.2 mmol) and 9 (245.3 mg, 1 mmol) as described for
3
3
compound 1 afforded amino-phosphite 2, which was
purified by flash chromatography over alumina (eluent:
toluene/NEt 100/1, R 0.9) to produce a white powder
t-Bu), 1.42 (s, 3H, CH ), 1.49 (s, 9H, CH t-Bu), 1.51
3
3
(
s, 9H, CH t-Bu), 3.21 (m, 1H, H-5), 3.28 (m, 1H,
3
3
f
H-5%), 3.83 (m, 1H, NH), 4.36 (m, 1H, H-4), 4.42 (m,
(
0.47 g, 75%). Anal. calcd for C H NO P: C, 64.64;
34 50 8
31
3
1
H, H-2), 4.70 (dd, 1H, H-3, J =2.8 Hz, J3-P=9.6
3-4
3
H, 7.98. Found: C, 64.78; H, 7.92%. P NMR, l: 146.0
Hz), 5.79 (d, 1H, H-1, J =3.6 Hz), 6.50 (m, 2H,
1
1-2
(
s, 1P). H NMR, l: 0.96 (s, 9H, CH , t-Bu-N), 1.24 (s,
3
CHꢁ), 6.66 (m, 1H, CHꢁ), 7.2 (m, 4H, CHꢁ), 7.45 (m,
3
H, CH ), 1.46 (b, 21H, CH , CH t-Bu), 2.65 (dd, 1H,
3 3 3
2 3
13
2
(
H, CHꢁ). C NMR, l: 26.2 (CH ), 26.7 (CH ), 31.1
3
3
H-5, J =11.6 Hz, J =5.6 Hz), 2.77 (dd, 1H, H-5%,
5
-5%
5-4
CH , t-Bu), 31.2 (CH , t-Bu), 31.4 (CH , t-Bu), 31.5
3 3 3
2
3
J5%-5=11.6 Hz, J5%-4=7.6 Hz), 3.80 (s, 3H, OMe), 3.81
(
CH , t-Bu), 34.6 (C, t-Bu), 34.7 (C, t-Bu), 35.4 (C,
3
(
4
s, 3H, OMe), 4.28 (m, 1H, H-4), 4.38 (m, 1H, H-2),
t-Bu), 35.5 (C, t-Bu), 42.2 (C-5), 76.6 (d, C-3, JC-P=2.0
Hz), 78.4 (d, C-4, JC-P=3.8 Hz), 84.3 (d, C-2, JC-P=2.2
3
.67 (dd, 1H, H-3, J =3.2 Hz, J3-P=9.6 Hz), 5.78 (d,
3
-4
3
1
H, H-1, J =3.6 Hz), 6.69 (d, 1H, CHꢁ, JH-H=3.2
1
-2
Hz), 104.7 (C-1), 111.8 (CMe ), 112.8 (CHꢁ), 117.4
2
Hz), 6.74 (d, 1H, CHꢁ, J =2.8 Hz), 6.99 (m, 2H,
H-H
(
(
1
1
CHꢁ), 124.2 (CHꢁ), 124.4 (CHꢁ), 125.2 (CHꢁ), 128.2
CHꢁ), 129.0 (CHꢁ), 129.1 (CHꢁ), 132.4 (C), 132.9 (C),
1
3
CHꢁ). C NMR, l: 26.3 (CH ), 26.8 (CH ), 29.0 (CH ,
3
3
3
t-Bu-N), 31.2 (CH , t-Bu), 31.3 (CH , t-Bu), 35.6 (C,
3
3
37.8 (C), 139.9 (C), 140.0 (C), 146.8 (C), 147.0 (C),
47.7 (C).
t-Bu), 41.4 (C-5), 55.8 (OMe), 76.8 (d, C-3, JC-P=3.4
Hz), 80.7 (d, C-4, JC-P=4.1 Hz), 84.5 (d, C-2, JC-P=2.3
Hz), 104.9 (C-1), 111.9 (CMe ), 113.0 (CHꢁ), 113.2
2
4
.8. 3-[(3,3%,5,5%-Tetra-t-butyl-1,1%-biphenyl-2,2%-
(
CHꢁ), 114.5 (CHꢁ), 133.6 (C), 133.7 (C), 134.1 (C),
diyl)phosphite]-5-deoxy-5-N-phenylamino-1,2-O-
142.7 (C), 142.8 (C), 142.9 (C), 155.9 (C), 156.0 (C).
isopropylidene-a-D-ribofuranose 5
4
.6. 3-[(3,3%,5,5%-Tetra-t-butyl-1,1%-biphenyl-2,2%-
Treatment of the corresponding in situ formed phos-
phorochloridite (1.2 mmol) and 12 (265.3 mg, 1 mmol)
as described for compound 1 afforded amino-phosphite
diyl)phosphite]-5-deoxy-5-N-isopropylamino-1,2-O-
isopropylidene-a-D-xylofuranose 3
5
, which was purified by flash chromatography over
Treatment of the corresponding in situ formed phos-
phorochloridite (1.2 mmol) and 10 (231.3 mg, 1 mmol)
as described for compound 1 afforded amino-phosphite
alumina (eluent: ethyl acetate, R 0.9) to produce a
f
white powder (0.59 g, 84%). Anal. calcd for
C H NO P: C, 71.67; H, 8.31. Found: C, 71.52; H,
4
2
58
6
3
1
1
3
, which was purified by flash chromatography over
alumina (eluent: toluene/NEt 100/1, R 0.9) to produce
8.54%. P NMR, l: 142.3 (s, 1P). H NMR, l: 1.31 (s,
3H, CH ), 1.35 (s, 9H, CH t-Bu), 1.36 (s, 9H, CH
3
3
f
3
3
of a white powder (0.53 g, 79%). Anal. calcd for
C H NO P: C, 69.93; H, 9.03. Found: C, 69.86; H,
t-Bu), 1.47 (s, 9H, CH t-Bu), 1.49 (s, 9H, CH t-Bu),
3
3
1.56 (s, 3H, CH ), 3.05 (m, 1H, H-5), 3.42 (dd, 1H,
3
9
60
6
3
3
1
1
3
2
8
.95%. P NMR, l: 145.2 (s, 1P). H NMR, l: 0.87 (d,
H-5%, JH-P=2.8, J =6.0 Hz, J5%-5=15.2 Hz), 3.83 (m,
5%-4
3
3
H, CH i-Pr, J =5.6 Hz), 0.95 (d, 3H, CH , i-Pr,
JH-H=6.4 Hz), 1.21 (s, 3H, CH ), 1.33 (s, 9H, CH3
1H, NH), 4.18 (m, 1H, H-2), 4.28 (m, 2H, H-3, H-4),
3
H-H
3
3
3
5.58 (d, 1H, H-1, J =3.6 Hz), 6.54 (d, 2H, CHꢁ,
3
1-2
t-Bu), 1.34 (s, 9H, CH t-Bu), 1.42 (s, 3H, CH ), 1.46
J
=8.0 Hz), 6.89 (t, 1H, CHꢁ, J =7.2 Hz), 7.13 (t,
3
3
H-H
H-H
(
s, 9H, CH t-Bu), 1.47 (s, 9H, CH t-Bu), 2.58 (m, 1H,
2H, CHꢁ, J =7.6 Hz), 7.16 (d, 1H, JH-H=2.4 Hz),
3
3
H-H
H-5), 2.67 (m, 1H, H-5%), 2.75 (m 1H, CH i-Pr), 4.27
7.20 (d, 1H, JH-H=2.4 Hz), 7.43 (d, 1H, JH-H=2.4 Hz),

2
866
M. Di e´ guez et al. / Tetrahedron: Asymmetry 12 (2001) 2861–2866
1
3
7
2
(
.45 (d, 1H, JH-H=2.4 Hz). C NMR, l: 26.7 (CH3),
6.9 (CH ), 31.3 (CH , t-Bu), 31.4 (CH , t-Bu), 31.5
4. For example, see: (a) Wendish, V.; Sewald, N. Tetra-
hedron: Asymmetry 1998, 9, 1341; (b) Kn o¨ bel, A. K. H.;
Escher, I. J.; Pfaltz, A. Synlett 1997, 1429; (c) Alexakis,
A.; Vastra, J.; Burton, J.; Benhaim, C.; Mangeney, P.
Tetrahedron Lett. 1998, 39, 7869; (d) Naasz, R.; Arnold,
L. A.; Pineschi, M.; Keller, E.; Feringa, B. L. J. Am.
Chem. Soc. 1999, 121, 1104; (e) de Vries, A. H. M.;
Meetsma, A.; Feringa, B. L. Angew. Chim., Int. Ed. Engl.
1996, 35, 2374; (f) Zhang, F. Y.; Chan, A. S. C. Tetra-
hedron: Asymmetry 1998, 9, 1179; (g) Hu, X.; Chen, H.;
Zhang, X. Angew. Chim., Int. Ed. Engl. 1999, 38, 3518;
(h) Yan, M.; Yang, L. W.; Wong, K. Y.; Chan, A. S. C.
Chem. Commun. 1999, 11; (i) Yan, M.; Chan, A. S. C.
Tetrahedron Lett. 1999, 40, 6645; (j) Yan, M.; Zhou, Z.
Y.; Chan, A. S. C. Chem. Commun. 2000, 115; (k)
Arnold, L. A.; Imbos, R.; Mandoli, A.; de Vries, A. H.
M.; Nassz, R.; Feringa, B. L. Tetrahedron 2000, 56, 2865;
(l) P a` mies, O.; Di e´ guez, M.; Net, G.; Ruiz, A.; Claver, C.
Tetrahedron: Asymmetry 2000, 11, 4377; (m) Alexakis, A.;
Burton, J.; Vastra, J.; Benhaim, C.; Fournioux, X.; van
den Heuvel, A.; Lev eˆ que, J. M.; Maz e´ , F.; Rosset, S. Eur.
J. Org. Chem. 2000, 4011; (n) Chataigner, I.; Gennari, C.;
Piarulli, U.; Ceccarelli, S. Angew. Chem., Int. Ed. 2000,
39, 916; (o) Chataigner, I.; Gennari, C.; Ongeri, S.;
Piarulli, U.; Ceccarelli, S. Chem. Eur. J. 2001, 7, 2628; (p)
Huttenloch, O.; Spieler, J.; Waldmann, H. Chem. Eur. J.
3
3
3
CH , t-Bu), 31.7 (CH , t-Bu), 34.9 (C, t-Bu), 35.6 (C,
t-Bu), 44.8 (C-5), 74.8 (C-3), 77.6 (d, C-4, JC-P=3.9
Hz), 78.7 (d, C-2, JC-P=2.2 Hz), 103.8 (C-1), 113.4
3 3
(
(
(
(
CMe ), 113.5 (CHꢁ), 117.9 (CHꢁ), 124.3 (CHꢁ), 124.5
2
CHꢁ), 126.7 (CHꢁ), 127.0 (CHꢁ), 129.3 (CHꢁ), 132.8
C), 133.0 (C), 140.5 (C), 140.6 (C), 147.0 (C), 148.2
C).
4
.9. General procedure for the catalytic conjugate
addition of diethylzinc to 2-cyclohexenone
In a typical experiment a solution of Cu(OTf) (9 mg,
.025 mmol) and diphosphite ligand (0.025 mmol) in
dichloromethane (3 mL) was stirred for 30 min at room
temperature. After cooling to 0°C, diethylzinc (1 M sol.
in hexanes, 3.5 mL, 3.5 mmol) was added. A solution of
2
0
2
-cyclohexenone (0.24 mL, 2.5 mmol) and undecane as
GC internal standard (0.25 mL) in dichloromethane (3
mL) was then added. The reaction was monitored by
GC. The reaction was quenched with HCl (2 M) and
filtered twice through silica flash. The conversion and
enantiomeric excesses were obtained by GC using a
1
4
Lipodex-A column.
2001, 7, 671.
Acknowledgements
5. Di e´ guez, M.; P a` mies, O.; Ruiz, A.; Castill o´ n, S.; Claver,
C. Chem. Eur. J. 2001, 7, 3086.
6
. See for instance: (a) P a` mies, O.; Di e´ guez, M.; Net, G.;
Ruiz, A.; Claver, C. Organometallics 2000, 19, 1488; (b)
Di e´ guez, M.; P a` mies, O.; Ruiz, A.; Claver, C.; Castill o´ n,
S. Chem. Commun. 2000, 1607; (c) P a` mies, O.; Di e´ guez,
M.; Net, G.; Ruiz, A.; Claver, C. Chem. Commun. 2000,
We thank the Spanish Ministerio de Educaci o´ n, Cul-
tura y Deportes and the Generalitat de Catalunya
(
0
CIRIT) for their financial support (PB97-0407-CO5-
1).
2
383; (d) Di e´ guez, M.; Jansat, S.; Gomez, M.; Ruiz, A.;
Muller, G.; Claver, C. Chem. Commun. 2001, 1132.
7. Lu, Y.; Just, G. Tetrahedron 2001, 57, 1677.
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. (a) Noyori, R. Asymmetric Catalysis in Organic Synthe-
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2
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