Screening of a modular sugar-based phosphite ligand library in the asymmetric nickel-catalyzed trialkylaluminum addition to aldehydes

Article abstract of DOI:10.1021/jo0613535

We synthesized a modular sugar-based phosphite ligand library for the Ni-catalyzed trialkylaluminum addition to aldehydes. This library has been designed to rapidly screen the ligands to uncover their important structure features and determine the scope of the phosphite ligands in this catalytic reaction. After systematic variation of the sugar backbone, the substituents at the phosphite moieties, and the flexibility of the ligand backbone, the monophosphite ligand 1,2:5,6-di-O-isopropylidene-3-O-((3,3′;5,5′- tetra-tert-butyl-1,1′-biphenyl-2,2′-diyl)phosphite) -α-D-glucofuranose 1c was found to be optimal, yielding high activities and enantioselectivities (ee's up to 94%) for several aryl aldehydes.

Full text of DOI:10.1021/jo0613535

Screening of a Modular Sugar-Based Phosphite Ligand Library
in the Asymmetric Nickel-Catalyzed Trialkylaluminum Addition
to Aldehydes
†
,†
,†
,‡
Yvette Mata, Montserrat Di e´ guez,* Oscar P a` mies,* and Simon Woodward*
Departament de Qu ´ı mica F ´ı sica i Inorg a` nica, UniVersitat RoVira i Virgili, Campus Sescelades,
C/Marcel‚l ´ı Domingo, s/n. 43007 Tarragona, Spain and School of Chemistry, The UniVersity of
Nottingham, Nottingham NG7 2RD, United Kingdom
montserrat.dieguez@urV.net; oscar.pamies@urV.net; simon.woodward@nottingham.ac.uk
ReceiVed June 30, 2006
We synthesized a modular sugar-based phosphite ligand library for the Ni-catalyzed trialkylaluminum
addition to aldehydes. This library has been designed to rapidly screen the ligands to uncover their important
structure features and determine the scope of the phosphite ligands in this catalytic reaction. After systematic
variation of the sugar backbone, the substituents at the phosphite moieties, and the flexibility of the
ligand backbone, the monophosphite ligand 1,2:5,6-di-O-isopropylidene-3-O-((3,3′;5,5′-tetra-tert-butyl-
1
,1′-biphenyl-2,2′-diyl)phosphite)-R-D-glucofuranose 1c was found to be optimal, yielding high activities
and enantioselectivities (ee’s up to 94%) for several aryl aldehydes.
Introduction
or N-sulfonylated amino alcohols as ligands.3 However, the
a-d
4
high catalyst loadings needed and the slow turnover rate ham-
Catalytic asymmetric carbon-carbon bond formation is one
of the most actively pursued areas of research in the field of
asymmetric catalysis. In this context, catalytic addition of
dialkylzincs to aldehydes as a route to chiral alcohols has
attracted much attention since many chiral alcohols are highly
valuable intermediates for preparing chiral pharmaceutical and
per the potential utility of these catalytic systems. Recently,
Woodward and co-workers reported the first report of the asym-
metric addition of a trialkylaluminum to aldehydes employing
a nickel catalyst, containing a phosphoroamidite ligand. Excel-
3e
lent enantioselectivities with low catalyst loadings were attained.
To further expand the range of ligands and performance of
this asymmetric nickel-catalyzed addition of organoaluminum
reagents to the aldehydes process, we designed a library of chiral
monophosphite ligands 1-5 (Figure 1). These ligands are
derived from natural D-glucose, D-galactose, and D-fructose and
have the advantage of carbohydrate and phosphite ligands, such
1
agricultural products. For alkylation reagents, trialkylaluminum
compounds are more interesting than other organometallic
reagents because they are economically obtained on an industrial
2
scale from aluminum hydride and olefins. Despite this advan-
3
tage, their use is rare. In this respect, the few most successful
catalysts for the enantioselective addition of trialkylaluminum
to aldehydes have been titanium complexes bearing chiral diols
(
3) (a) Chan, A. S. C.; Zhang, F.-Y.; Yip, C.-W. J. Am. Chem. Soc. 1997,
1
3
19, 4080. (b) Pagenkopf, B. L.; Carreira, E. M. Tetrahedron Lett. 1998,
9, 9593. (c) Lu, J.-F.; You, J.-S.; Gau, H.-M. Tetrahedron: Asymmetry
†
Universitat Rovira i Virgili.
The University of Nottingham.
2000, 11, 2531. (d) You, J.-S.; Hsieh, S.-H.; Gau, H.-M. Chem. Commun.
2001, 1546. (e) Biswas, K.; Prieto, O.; Goldsmith, P. J.; Woodward, S.
Angew. Chem., Int. Ed. 2005, 44, 2232.
(4) Addition reactions of AlR3 to an aldehyde normally require catalyst
loadings of 10-20%, see refs 3a-d.
‡
(
1) Pu, L.; Yu, H. B. Chem. ReV. 2001, 101, 757.
(2) Cotton, F. A.; Wilkinson, G. AdVanced Inorganic Chemistry, 5th ed.;
Wiley: New York, 1988; p 224.
1
0.1021/jo0613535 CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/15/2006
J. Org. Chem. 2006, 71, 8159-8165
8159

Mata et al.
FIGURE 1. Carbohydrate-based phosphite ligands 1-5.
as availability at a low price from readily available alcohols
and facile modular constructions. In addition, they are less
hydroxyl group. Several phosphoric acid biaryl esters (a-f) were
attached to these basic frameworks (Figure 1).
5
sensitive to air than typical phosphines, widely used as ligands
in asymmetric catalysis. All these favorable features enable
series of chiral ligands to be synthesized and screened in the
The influence of the different groups attached to the ortho
and para positions of the biphenyl moieties on enantioselectivity
was investigated using ligands 1a-d, which have the same
configuration on carbon atom C-3. To determine whether there
is a cooperative effect between the stereocenters of the ligand
backbone and the configuration of the biaryl phosphite moieties,
we prepared a series of enantiomerically pure binaphthol-based
ligands 1e,f and 2e,f.
5
search for high activity and selectivity. Although carbohydrate-
based bidentate ligands have been successfully used in some
enantioselective reactions (mainly hydrogenation and allylic
5
alkylation), few good monodentate chiral ligands have been
6
reported based on carbohydrates.
We report here the design of a library of 60 potential sugar-
based chiral phosphite ligands and screen their use in the nickel-
catalyzed addition of organoaluminum reagents to aldehydes.
The synthesis and screening of the library were performed using
a series of parallel reactors each equipped with 12 different
positions. With this library we fully investigated the effects of
systematically varying the configurations at C-3 and C-4 of the
ligand backbone (1-3), different substituents/configurations in
the biaryl phosphite moiety (a-f), the carbohydrate ring size
We studied the effects of the stereogenic carbon atom C-3
on enantioselectivity by comparing diastereomeric ligands 1 and
, which have opposite configuration at C-3. The influence of
the configuration of carbon atom C-4 on the catalytic perfor-
mance was studied using ligands 1 and 3, which only differ in
the configuration at C-4.
2
The influence of the carbohydrate ring size in the catalytic
performance of the nickel catalysts was studied with ligands 4,
which have a pyranoside backbone and the same configuration
at C-3 as ligand 1. Finally, with ligands 5 we studied how the
flexibility of the ligand backbone may affect the catalytic per-
formance of the nickel catalysts. These ligands have a pyrano-
side backbone like ligands 4 but differ from the rest of the
ligands in the phosphite moiety attached to a primary alcohol,
providing a more flexible ligand.
(
1-4), and the flexibility of the ligand backbone (4, 5). By
carefully selecting these elements we achieved high enantiose-
lectivities and activities in different substrate types. To the best
of our knowledge, this is the first example of phosphite ligands
applied to this process.
Results and Discussions
7
Synthesis of Ligands. Ligands 1-5 were efficiently syn-
thesized in one step by reaction of the corresponding sugar
alcohols (6-10) with 1 equiv of PCl3 and subsequent addition
of the biaryl alcohols (a-f) in the presence of triethylamine
using a series of parallel reactors each equipped with 12
Ligand Design. Ligands 1-5 consist of chiral di-O-protected
either furanoside (ligands 1-3) or pyranoside (ligands 4 and 5)
backbones, which determine their underlying structure, and one
6
c
positions (Scheme 1). Sugar alcohols 6-10 were easily
prepared on a large scale from inexpensive D-(+)-glucose,
D-(+)-galactose, and D-(-)-fructose (Scheme 1). All ligands
were stable during purification on neutral silica under an
atmosphere of argon and isolated in moderate yields as white
(5) See, for instance: (a) Di e´ guez, M.; P a` mies, O.; Claver, C. Chem.
ReV. 2004, 104, 3189. (b) Di e´ guez, M.; P a` mies, O.; Ruiz, A.; D ´ı az, Y.;
Castill o´ n, S.; Claver, C. Coord. Chem. ReV. 2004, 248, 2165. (c) Di e´ guez,
M.; Ruiz, A.; Claver, C. Dalton Trans. 2003, 2957. (d) P a` mies, O.; Di e´ guez,
M.; Ruiz, A.; Claver, C. Chem. Today 2004, 12. (e) Di e´ guez, M.; P a` mies,
O.; Ruiz, A.; Claver, C. In Methodologies in Asymmetric Catalysis;
Malhotra, S. V., Ed.; American Chemical Society: Washington, DC, 2004.
1
31
13
solids. The H, P, and C NMR spectra were as expected for
(
1
f) Di e´ guez, M.; P a` mies, O.; Claver, C. Tetrahedron: Asymmetry 2004,
5, 2113.
6) See, for instance: (a) Reetz, M. T.; Mehler, G. Angew. Chem., Int.
these C1 ligands (see Experimental Section).
Asymmetric Addition of AlR3 to Aldehydes. In a first set of
(
Ed. 2000, 39, 3889. (b) Reet, M. T.; Goossen, L. J.; Meiswinkel, A.;
Paetzold, J.; Jense, J. F. Org. Lett. 2003, 5, 3099. (c) Huang, H.; Zheng,
Z.; Luo, H.; Bai, C.; Hu, X.; Chen, H. Org. Lett. 2003, 5, 4137. (d) Huang,
H.; Liu, X.; Chen, S.; Chen, H.; Zheng, Z. Tetrahedron: Asymmetry 2004,
experiments, we evaluated the phosphite ligand library (Figure 1)
(7) Ligands 1a,c,e,f, 2e,f, and 4e,f have been previously synthesized,
see: (a) Su a´ rez, A.; Pizzano, A.; Fern a´ ndez, I.; Khiar, N. Tetrahedron:
Asymmetry 2001, 12, 633 and refs 6b,c.
1
5, 2011. (e) Huang, H.; Liu, X.; Chen, H.; Zheng, Z. Tetrahedron:
Asymmetry 2005, 16, 693.
8160 J. Org. Chem., Vol. 71, No. 21, 2006

Modular Sugar-Based Phosphite Ligand Library
SCHEME 1. Synthesis of Phosphite Ligands 1-5
8
9
9
+
(
a) Acetone, I2, 6 h. (b) PCC, CH2Cl2, NaOAc, 16 h. (c) NaBH4, EtOH, -20 °C to room temperature overnight. (d) DMF, acetone, Dowex H , reflux
10 11 12 6c
4
8 h. (e) HClO4, dimethoxypropane, 0 °C, 6 h. (f) HClO4, dimethoxypropane, rt, 16 h. (g) PCl3, NEt3, THF, biaryl alcohol (a-f), rt.
in the nickel-catalyzed asymmetric addition of trimethyl-
aluminum to benzaldehyde, which is used as a model substrate
position of the biaryl phosphite moiety are necessary (entries
1, 5, and 6 vs 2-4). Regarding enantioselectivities, these are
better when tert-butyl groups are present in the para position
of the biphenyl phosphite moiety (entries 3 vs 2 and 4). The
best tradeoff between yield and enantioselectivity was therefore
obtained using ligand 1c.
(eq 1). The catalytic system was generated in situ by adding
the corresponding phosphite ligand to a suspension of the cata-
lyst precursor [Ni(acac)2] (acac ) acetylacetonate).
With ligands 2, whose configuration at C-3 is opposite those
of ligands 1, we studied the effect of this configuration on the
product outcome. The results indicated that there is an influence
of this configuration on enantioselectivity (entries 7-12).
Therefore, use of ligands 2 with an R configuration at C-3 pro-
vided lower enantioselectivities than using ligands 1. Concerning
the effect of the biaryl substituents, the results using ligands
The results, which are summarized in Table 1, indicate that
the catalytic performance (activities and enantioselectivities) is
highly affected by the configuration of carbon atoms C-3 and
C-4, the size of the ring of the sugar backbone, and the
substituents of the biaryl moieties.
With ligands 1a-f we studied how the biaryl phosphite
moieties affects the product outcome. We found that the sub-
stituents at the ortho positions of the biaryl phosphite moiety
affected yield, while enantioselectivities were mainly affected
by the substituents at the para positions of the biaryl phosphite
group. Therefore, for high yields bulky substituents in the ortho
2
a-d confirm the previous trends observed with ligands 1.
Therefore, yields and enantioselectivities were best using the
ligand that contains tert-butyl groups at both the ortho and para
positions of the biphenyl phosphite moiety (ligand 2c).
With ligands 1e, 1f, 2e and 2f, we studied the possibility of
a cooperative effect between the stereocenters of the ligand
backbone and the configuration of the biaryl phosphite moieties
(entries 5, 6, 11, and 12). The results indicated that the matched
(
8) Kartha, K. P. R. Tetrahedron Lett. 1986, 27, 3415.
(11) Tu, Y.; Frohn, M.; Wang, Z.-X.; Shi, Y. In Organic Synthesis; Wolf,
S., Ed.; 2003; p 1.
(9) Hollenberg, D. H.; Klein, R. S.; Fox, J. J. Carbohydr. Res. 1978, 67,
4
91.
10) Wang, H.; Ning, J. J. Org. Chem. 2003, 68, 2521.
(12) Beksan, E.; Schieberle, P.; Robert, F.; Blank, I.; Fay, L. B.;
Schlichtherle-Cerny, H.; Hofmann, T. J. Agric. Food Chem. 2003, 51, 5428.
(
J. Org. Chem, Vol. 71, No. 21, 2006 8161

Mata et al.
TABLE 1. Selected Results for the Nickel-Catalyzed Asymmetric a
TABLE 3. Selected Results for the Nickel-Catalyzed Asymmetric
Addition of DABAL-Me3 to Benzaldehydea
Addition of AlMe3 to Benzaldehyde Using Phosphite Library (1-5)
entry
ligand
L*/Ni
t (h)
% conv.b
% yieldc
% eed
entry ligand L*/Ni DABAL (equiv) t (h) % conv.b % yieldc % eed
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
2a
2b
2c
2d
2e
2f
3c
4b
4c
5c
1c
1c
1c
1c
2c
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2.5
1
1
1
1
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
1
1
1
16
89
100
100
14
17
15
98
100
100
29
12
100
99
15
80
85
87
11
12
12
95
100
86
22
3
60
58
64
52
68
100
100
96
95
27 (R)
82 (S)
89 (S)
52 (S)
41 (R)
10 (R)
5 (R)
41 (R)
44 (R)
17 (R)
6 (R)
5 (S)
70 (R)
9 (S)
52 (S)
36 (R)
88 (S)
89 (S)
90 (S)
88 (S)
45 (R)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1a
1b
1c
1d
1e
1f
2a
2b
2c
2d
2e
2f
2
2
2
2
2
2
2
2
2
2
2
2
2
1
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
0.6
1.3
3
3
3
3
3
3
3
3
3
3
3
3
3
1.5
75
63
85
73
59
60
74
90
90
70
88
83
61
97
36
35
40
60
37
5
43
51
27
38
38
29
40
78
18 (R)
86 (S)
87 (S)
46 (S)
47 (R)
0
5 (S)
47 (S)
58 (S)
17 (S)
11 (S)
4 (S)
10
11
12
13
14
15
16
17
18
19
20
21
1c
1c
84 (S)
88 (S)
100
83
a
Reaction conditions: T ) 5 °C, Ni(acac)2 (1 mol %), substrate (0.25
b
mmol), solvent THF (2 mL). Percent conversion determined by GC.
Percent yield determined by GC using dodecane as internal standard.
Enantiomeric excess measured by GC using Cyclodex-B column.
100
100
100
100
100
c
d
TABLE 4. Selected Results for the Nickel-Catalyzed Asymmetric
Addition of DABAL-Me3 to Aldehydes Using Ligand 1c
a
a
Reaction conditions: T ) -20 °C, [Ni(acac)2] (1 mol %), AlMe3 (2
equiv), substrate (0.25 mmol), solvent THF (2 mL). Percent conversion
determined by GC. Percent yield determined by GC using dodecane as
internal standard. Enantiomeric excess measured by GC using Cyclodex-B
b
c
d
column.
TABLE 2. Selected Results for the Nickel-Catalyzed Asymmetric
% conv.b
yieldc
% eed
entry
R
Addition of AlR′3 (R′ ) Me or Et) to Aldehydes Using Ligand 1ca
1
2
3
4
5
6
7
8
C6H5
85
99
92
100
93
96
90
90
86
78
64
25
53
69
68
58
62
22
88 (S)
91 (S)
78 (S)
82 (S)
90 (S)
88 (S)
67 (S)
35 (R)
30 (R)
4-Cl-C6H4
4-OMe-C6H4
4-CF3-C6H4
4-Br-C6H4
4-Me- C6H4
3-Cl-C6H4
2-Cl-C6H4
PhCHdCH
entry
R
R′
% conv.b
yieldc
% eed
1
2
3
4
5
6
7
8
9
C6H5
C6H5
Me
Et
Me
Et
Me
Me
Et
Me
Et
Me
Me
Me
Me
Me
100
100
100
100
93
100
100
94
98
98
95
97
100
96
82
83
53
95
96
84
85
86
73
85
89
44
90 (S)
88 (S)
91 (S)
90 (S)
94 (S)
93 (S)
94 (S)
91 (S)
88 (S)
92 (S)
74 (S)
41 (R)
25 (S)
25 (R)
e
9
a
4-Cl-C6H4
4-Cl-C6H4
4-OMe-C6H4
4-CF3-C6H4
4-CF3-C6H4
4-Me- C6H4
4-Me- C6H4
4-Br-C6H4
3-Cl-C6H4
2-Cl-C6H4
PhCH2CH2
PhCHdCH
Reaction conditions: T ) 5 °C, Ni(acac) (1 mol %), 1c (1mol %),
2
DABAL-Me3 (1.3 equiv), substrate (0.25 mmol), solvent THF (2 mL).
b
Percent conversion determined by GC after 1.5 h. c Percent yield
d
determined by GC using dodecane as internal standard. Enantiomeric
excess measured by GC using Cyclodex-B column. e 1c (2mol %).
1
1
1
1
1
0
1
2
3
4
Finally, the most flexible ligand 5, which has the phosphite
moiety attached to a primary carbon, provided the lowest
enantioselectivities (entry 16 vs 3, 9, 13, and 15).
With the ligand that provided the best results (ligand 1c) we
next studied the effect of the ligand-to-nickel ratio in the product
outcome. Our results show that no excess of ligand is needed
for high yields and enantioselectivities (entry 17 vs 3 and 16).
Finally, we optimized the reaction time and found complete
reaction after 1 h (entry 18 vs 3).
e
f
100
97
a
Reaction conditions: T ) -20 °C, [Ni(acac)2] (1 mol %), 1c (1mol
b
%
), AlR′3 (2 equiv), substrate (0.25 mmol), solvent THF (2 mL). Percent
conversion determined by GC after 1 h. Percent yield determined by GC
using dodecane as internal standard. Enantiomeric excess measured by
GC using Cyclodex-B column. 1c (2 mol %), reaction time 6 h. 1c
2 mol %), reaction time 5 h.
c
13
d
e
f
(
To further investigate the catalytic efficiency of these Ni/
1
-5 systems, we then tested them in the nickel-catalyzed
combination is achieved with ligand 1e, which has an S config-
uration at carbon atom C-3 and in the biaryl phosphite moiety.
Ligands 3, whose configuration at C-4 is opposite those of
ligands 1, afforded lower enantioselectivity than the catalytic
system Ni/1 (entry 3 vs 13) but higher than the catalytic system
Ni/2 (entry 9 vs 13). From these results we can conclude that
the effect of the configuration of carbon C-3 is more important
than the effect of C-4 on the catalytic performance.
addition of trialkylaluminum (AlR′ ; R′ ) Me or Et) to other
benchmark aldehydes with different steric and electronic proper-
ties. The results are summarized in Table 2.
We found that enantioselectivity for AlMe3 addition is hardly
affected by the presence of electron-withdrawing or electron-
donating groups at the para position of the phenyl group (entries
3
1
, 3, 5, 6, 8, and 10). However, the best yield was achieved
using benzaldehyde as substrate, while substrate 4-OMe-Ph gave
Ligands 4, which have a pyranoside backbone, provided lower
yields and enantioselectivities (up to 52% (S)) than their related
furanoside ligands 1 (entries 2 and 3 vs 14 and 15).
(
13) At high ligand-to-nickel ratio the disproportionation of benzaldehyde
to benzoic acid and benzyl alcohol takes place.
8162 J. Org. Chem., Vol. 71, No. 21, 2006

Modular Sugar-Based Phosphite Ligand Library
prepared by previously described methods.8 Ligands 1a,c,e,f, 2e,f,
-12
the poorest (entry 1 vs 5). Enantioselectivity of the reaction is
also significantly influenced by steric factors. Therefore, enantio-
selectivities are better when para-substituted aryl aldehydes were
used as substrates (entries 3, 11, and 12). We also found that
enantioselectivity was more difficulty to control when a more
flexible substrate is used (entries 13 and 14).
The results of using triethylaluminum as alkylating reagent
indicated that the catalytic performance followed the same trend
as for the trimethylaluminum addition (entries 1, 3, 6, and 8 vs
7
and 4e,f have been previously synthesized. All other reagents were
1
13
1
31
1
used as commercially available. H, C{ H}, and P{ H} NMR
spectra were recorded on a Varian Gemini 400 MHz spectrometer.
The chemical shifts are referenced to tetramethylsilane ( H and C)
1
13
31
1
as internal standard or H
3
PO
4
( P) as external standard. The H
13
1
1
and C NMR spectral assignments were determined by H- H
and H- C correlation spectra.
,2:5,6-Di-O-isopropylidene-3-O-((3,3′-di-tert-butyl-5,5′-
dimethoxy-1,1′-biphenyl-2,2′-diyl)phosphite)-R-D-glucofuran-
ose (1b). To a stirred solution of 1,2:5,6-di-O-isopropylidene-R-
D-glucofuranose 6 (390 mg, 1.5 mmol) in THF (5 mL) was slowly
1
13
1
2, 4, 7, and 9).
Asymmetric Addition of DABAL-Me3 to Aldehydes.
Recently, Woodward and co-workers reported for the first time
the advantages of using DABAL-Me3 as air-stable methylating
added PCl
the resulting mixture was stirred for 1 h at room temperature. The
reaction mixture was then cooled to -10 °C, and NEt (1.07 mL,
3
(132 µL, 1.5 mmol) as a solution in THF (4 mL), and
3e
reagent in the nickel-catalyzed additions to aldehydes. Encour-
aged by the excellent results obtained using trialkylaluminum
reagents to aldehydes, we decided to also test the phosphite
library 1-5 in the nickel-catalyzed addition of DABAL-Me3
to aldehydes (eq 2).
3
4
.5 mmol) was slowly added. The reaction mixture was allowed to
warm to room temperature, maintained under these conditions for
.25 h, and then cooled to 0 °C. Solid 3,3′-di-tert-butyl-5,5′-
0
dimethoxy-1,1′-biphenyl-2,2′-diol (0.54 g, 1.5 mmol) was added,
and the resulting mixture was allowed to warm to room temperature
and stirred overnight. Diethyl ether was added; then the solid was
removed by filtration through a pad of Celite, the solvent was
removed in vacuo, and the residue was purified by flash chroma-
tography (eluent CH
white solid. 31P NMR (400 MHz, C
400 MHz, C ) δ 1.03 (s, 3H, CH
H, CH ,), 1.39 (s, 3H, CH ), 1.49 (s, 18H, CH
3
2 2 f
Cl , R : 0.32) to produce 100 mg (11%) of a
1
D
6 6
) δ 145.2 ppm. H NMR
), 1.26 (s, 3H, CH ), 1.34 (s,
, Bu), 3.31 (s, 6H,
(
3
6
D
6
3
3
t
3
3
2
OMe), 4.01 (dd, 1H, H-6′, 2J6′-6 ) 8.4 Hz, J6′-5 ) 6.0 Hz), 4.10
2
3
(
4
dd, 1H, H-6, J6-6′ ) 8.4 Hz, J6-5 ) 5.2 Hz), 4.27 (m, 1H, H-2),
3
3
.44 (dd, 1H, H-4, J4-3 ) 2.4 Hz, J4-5 ) 8.0 Hz), 4.57 (m, 1H,
The results, which are summarized in Tables 3 and 4, indicate
that the catalytic performance (activities and enantioselectivities)
follows the same trend as for the trialkylaluminum addition to
aldehydes, which is not unexpected because the reactions have
a similar mechanism. However, the yields were lower than in
trimethylaluminum addition. Again, the catalytic precursor
containing the phosphite ligand 1c provided the best enantio-
selectivity (87% ee). It is worth noting that in this case the
negative effect on yields in the presence of an excess of ligand
is more pronounced than when trimethylaluminum was used.
Therefore, yields increased almost 100% by reducing the ligand-
to-nickel ratio from 2 to 1 (entries 3 vs 14).
3 2
H-5), 5.20 (dd, 1H, H-3, J3-4 ) 2.8 Hz, J3-P ) 8.0 Hz), 5.83 (d,
3
1
H, H-1, J1-2 ) 3.6 Hz), 6.66 (m, 1H, CHd), 6.72 (m, 1H, CHd),
13
7.14 (m, 2H, CHd). C NMR (400 MHz, C D ) δ 25.8 (CH ),
6
6
3
t
t
26.4 (CH
3
), 27.2 (CH
3
), 27.5 (CH
3
), 31.4 (CH
3
, Bu), 31.5 (CH
, Bu), 36.2 (C Bu), 36.3 (C Bu), 55.4 (d, OCH
c-p ) 3.7 Hz), 68.0 (C-6), 73.4 (C-5), 77.6 (C-3), 81.9 (d, C-4,
c-p ) 4.6 Hz), 85.0 (C-2), 106.1 (C-1), 112.2 (C), 113.7 (CHd),
14.0 (CHd), 115.2 (CHd), 143.1 (C), 154.1 (C), 155.6 (C), 157.0
C). Anal. Calcd for C34 10P: C, 63.15; H, 7.33. Found: C,
3
, -
t
t
t
Bu), 31.6 (CH
3
3
,
J
J
1
(
47
H O
6
3.30; H 7.42.
1,2:5,6-Di-O-isopropylidene-3-O-((3,3′-di-trimethylsilyl-1,1′-
biphenyl-2,2′-diyl) phosphite)-R-D-glucofuranose (1d). Treatment
of 3,3′-di-trimethylsilyl-1,1′-biphenyl-2,2′-diol (0.49 g, 1.5 mmol)
and 6 (390 mg, 1.5 mmol), as described for compound 1b, afforded
phosphite 1d, which was purified by flash chromatography (eluent
CH
NMR (400 MHz, C
δ 0.39 (s, 9H, CH -Si), 0.40 (s, 9H, CH
Conclusions
3
1
2 2 f
Cl , R : 0.61) to produce 210 mg (22%) of a white solid. P
A library of readily available monophosphite ligands has been
synthesized and applied for the first time in the Ni-catalyzed
trialkylaluminum addition to several aldehydes. By carefully
designing this library we were able to systematically investigate
the effect of varying the sugar backbone, the configurations at
carbon C-3 and C-4 of the ligand backbone and the type of
substituents/configurations in the biaryl phosphite moiety. By
judicious choice of the ligand components we obtained high
enantioselectivities (ee values up to 94%) and high activities,
in several aryl aldehydes, with low catalyst loading (1 mol %)
and without excess of ligand.
1
6
D
6
) δ 146.0 ppm. H NMR (400 MHz, C
6
D
6
)
3
3
-Si), 0.98 (s, 3H, CH
3
),
1
1
4
1
7
.26 (s, 3H, CH
3
), 1.30 (s, 3H, CH
3
3
), 1.41 (s, 3H, CH ), 4.00 (dd,
2
3
H, H-6′, J6′-6 ) 8.4 Hz, J6′-5 ) 6.0 Hz), 4.10 (m, 2H, H-6, H-2),
.44 (m, 1H, H-4), 4.56 (m, 1H, H-5), 5.13 (m, 1H, H-3), 5.85 (d,
3
H, H-1, J1-2 ) 4.0 Hz), 7.02 (m, 2H, CHd), 7.16 (m, 2H, CHd),
.38 (m, 2H, CHd). C NMR (400 MHz, C
13
6 6
D
) δ 0.4 (CH
3
-Si),
25.8 (CH ), 26.4 (CH ), 27.1 (CH ), 27.5 (CH ), 67.9 (C-6), 73.4
(C-5), 77.4 (C-3), 81.8 (d, C-4, Jc-p ) 4.6 Hz), 84.9 (C-2), 106.0
(C-1), 109.8 (C), 112.2 (C), 125.5 (CHd), 125.6 (CHd), 130.8
3
3
3
3
(
(
C), 132.1 (C), 133.1 (CHd), 133.2 (CHd), 135.7 (CHd), 135.8
CHd). Anal. Calcd for C30 PSi : C, 58.23; H, 7.00. Found:
H
43
O
8
2
To sum up, the combination of high activities and enanti-
oselectivities with low catalyst loading and the low cost of these
phosphite ligands open up a new class of ligands for the
enantioselective Ni-catalyzed addition of trialkylaluminum
reagents to aldehydes that competes favorably with the best
C, 58.43; H, 6.98.
1
,2:5,6-Di-O-isopropylidene-3-O-((1,1′-biphenyl-2,2′-diyl)-
phosphite)-R-D-allofuranose (2a). Treatment of 1,1′-biphenyl-2,2′-
diol (0.28 g, 1.5 mmol) and 7 (390 mg, 1.5 mmol), as described
for compound 1b, afforded phosphite 2a, which was purified by
flash chromatography (eluent CH
mg (22%) of a white solid. P NMR (400 MHz, C
ppm. H NMR (400 MHz, C
CH ), 1.49 (s, 3H, CH ), 1.50 (s, 3H, CH
3.93 (m, 1H, H-6), 4.11 (dd, 1H, H-2, J2-3 ) 4.2 Hz, J2-1 ) 3.6
Hz), 4.17 (m, 1H, H-5), 4.34 (m, 1H, H-4), 4.48 (m, 1H, H-3),
3
ligands designed for this process.
2
Cl
2
, R
f
: 0.45) to produce 150
) δ 139.5
), 1.31 (s, 3H,
), 3.78 (m, 1H, H-6′),
31
6 6
D
Experimental Section
1
6 6 3
D ) δ 1.16 (s, 3H, CH
General Considerations. All syntheses were performed using
standard Schlenk techniques under an argon atmosphere. Solvents
were purified by standard procedures. Compounds 6-10 were
3
3
3
3
3
J. Org. Chem, Vol. 71, No. 21, 2006 8163

Mata et al.
5
.33 (d, 1H, H-1, 3J1-2 ) 3.6 Hz), 6.94-7.07 (m, 4H, CHd), 7.20
ment of 3,3′;5,5′-tetra-tert-butyl-1,1′-biphenyl-2,2′-diol (0.62 g, 0.5
mmol) and 8 (390 mg, 0.5 mmol), as described for compound 1b,
afforded phosphite 3c, which was purified by flash chromatography
13
(
m, 2H, CHd), 7.37 (m, 2H, CHd). C NMR (400 MHz, C
δ 25.9 (CH ), 27.1 (CH ), 27.2 (CH ), 27.3 (CH ), 66.5 (C-6), 75.1
C-3), 76.5 (C-5), 79.4 (C-4), 80.0 (C-2), 104.7 (C-1), 110.6 (CMe
6 6
D )
3
3
3
3
(
2
)
(eluent CH
2
Cl
P NMR (400 MHz, CDCl
CDCl ) δ 1.28 (s, 3H, CH ), 1.31 (s, 3H, CH
3
Bu), 1.37 (s, 3H, CH ), 1.45 (s, 3H, CH ), 1.47 (s, 18H, CH , Bu),
2 f
, R : 0.55) to produce 80 mg (23%) of a white solid.
31
1
1
1
17.4 (CHd), 122.0 (C), 122.6 (C), 123.0 (CHd), 123.1 (CHd),
25.7 (CHd), 127.8 (CHd), 129.7 (CHd), 130.0 (CHd), 130.3
3
) δ 137.6 ppm. H NMR (400 MHz,
3
3
3
), 1.34 (s, 18H, CH ,
3
t
t
(
C
C), 130.5 (CHd), 132.3 (CHd), 132.7 (C). Anal. Calcd for
P: C, 60.76; H, 5.74. Found: C, 60.82; H, 5.89.
,2:5,6-Di-O-isopropylidene-3-O-((3,3′-di-tert-butyl-5,5′-
3
3
24
H O
27 8
3.47 (m, 1H, H-6′), 3.91 (m, 2H, H-5, H-6), 4.19 (d, 1H, H-4,
3
3
1
J
4-3 ) 8 Hz), 4.27 (dd, 1H, H-2, J2-1 ) 5.2 Hz, J2-P ) 4.8 Hz),
3
dimethoxy-1,1′-biphenyl-2,2′-diyl)phosphite)-R-D-allofuranose (2b).
Treatment of 3,3′-di-tert-butyl-5,5′-dimethoxy-1,1′-biphenyl-2,2′-
diol (0.54 g, 1.5 mmol) and 7 (390 mg, 1.5 mmol), as described
for compound 1b, afforded phosphite 2b, which was purified by
4.55 (dd, 1H, H-3, J3-4 ) 8 Hz, J3-P ) 5.2 Hz), 5.47 (d, 1H, H-2,
2
13
J
2-1 ) 5.2 Hz), 7.14 (m, 2H, CHd), 7.41 (m, 2H, CHd).
C
NMR (400 MHz, CDCl ) δ 24.6 (CH ), 25.1 (CH ), 26.2 (CH
3
3
3
3
),
, Bu), 31.8
3
(CH , Bu), 34.8 (C), 35.5 (C), 35.6 (C), 62.9 (d, C-6, Jc-p ) 2.2
t
t
t
3 3 3 3
26.3 (CH ), 31.2 (CH , Bu), 31.3 (CH , Bu), 31.7 (CH
t
flash chromatography (eluent CH
2
Cl
2
, R
f
: 0.30) to produce 180 mg
) δ 144.1 ppm.
), 1.29 (s, 3H, CH ),
, Bu), 1.56
, Bu), 3.33 (s, 3H, OMe), 3.36 (s, 3H, OMe), 3.76 (m,
H, H-6′), 3.82 (m, 1H, H-6), 4.03 (m, 1H, H-2), 4.17 (m, 1H,
(
19%) of a white solid. 31P NMR (400 MHz, C
H NMR (400 MHz, C
D
6 6
Hz), 67.2 (d, C-5, Jc-p ) 2.3 Hz), 70.6 (C-4), 70.7 (C-2), 70.8
(C-3), 96.4 (C-1), 108.8 (C), 109.6 (C), 124.4 (CHd), 124.4 (CHd),
125.5 (CHd), 126.7 (CHd), 128.5 (C), 129.2 (C), 129.3 (C), 133.3
(C), 138.3 (C), 140.0 (C), 140.1 (C), 146.5 (C), 146.6 (C). Anal.
1
6
D
6
) δ 1.14 (s, 3H, CH
3
3
t
1
.42 (s, 3H, CH ,), 1.49 (s, 3H, CH
3
3
), 1.54 (s, 9H, CH
3
t
(s, 9H, CH
3
1
59 8
Calcd for C40H O P: C, 68.74; H, 8.51. Found: C, 68.98; H, 8.62.
H-5), 4.41 (m, 1H, H-4), 4.46 (m, 1H, H-3), 5.42 (d, 1H, H-1,
2,3:5,6-Di-O-isopropylidene-4-O-((3,3′-di-tert-butyl-5,5′-
dimethoxy-1,1′-biphenyl-2,2′-diyl)phosphite)-â-D-fructopyran-
ose (4b). Treatment of 3,3′-di-tert-butyl-5,5′-dimethoxy-1,1′-
biphenyl-2,2′-diol (0.54 g, 1.5 mmol) and 9 (390 mg, 1.5 mmol),
as described for compound 1b, afforded phosphite 4b, which was
3
13
J
1-2 ) 3.6 Hz), 6.71 (m, 2H, CHd), 7.15 (m, 2H, CHd).
NMR (400 MHz, C ) δ 26.1 (CH ), 27.1 (CH ), 27.2 (CH
7.4 (CH ), 31.6 (CH , Bu), 35.9 (C), 36.0 (C), 55.4 (OCH ), 55.5
OCH ), 66.0 (C-6), 75.3 (C-3), 76.7 (C-5), 79.4 (d, C-4, Jc-p
.1 Hz), 79.6 (C-2), 104.8 (C-1), 110.1 (C), 113.4 (CHd), 113.6
C
3
),
6
D
3
6
3
3
t
2
(
3
3
3
3
)
purified by flash chromatography (eluent CH
produce 270 mg (29%) of a white solid. P NMR (400 MHz, C D )
2
Cl
2 f
, R : 0.55) to
31
(
C), 114.0 (CHd), 115.0 (CHd), 142.8 (C), 143.7 (C), 143.8 (C),
56.9 (C). Anal. Calcd for C34 10P: C, 63.15; H, 7.33. Found:
C, 63.08; H, 7.42.
,2:5,6-Di-O-isopropylidene-3-O-((3,3′-5,5′-tetra-tert-butyl-
,1′-biphenyl-2,2′-diyl) phosphite)-R-D-allofuranose (2c). Treat-
6 6
1
1
47
H O
δ 149.8 ppm. H NMR (400 MHz, C
6
D
6
) δ 1.13 (s, 3H, CH
, Bu), 1.45 (s, 3H, CH ), 1.60
Bu), 3.32 (s, 3H, OMe), 3.33 (s, 3H, OMe),
3.80 (m, 1H, H-2), 3.94 (m, 2H, H-1, H-1′), 4.15 (d, 1H, H-6′,
3
),
t
1.24 (s, 3H, CH
(s, 12H,, CH , CH
3
), 1.40 (s, 9H, CH
3
3
t
1
3
3
1
2
ment of 3,3′;5,5′-tetra-tert-butyl-1,1′-biphenyl-2,2′-diol (0.62 g, 1.5
mmol) and 7 (390 mg, 1.5 mmol), as described for compound 1b,
afforded phosphite 2c, which was purified by flash chromatography
J6′-6 ) 11.2 Hz), 4.48 (m, 1H, H-3), 4.56 (m, 1H, H-4), 4.65 (d,
2
1H, H-6, J6-6′ ) 11.6 Hz), 6.68 (m, 2H, CHd), 7.14 (m, 2H,
CHd). 13C NMR (400 MHz, C
D
) δ 26.1 (CH
), 26.8 (CH
, Bu), 31.9 (CH
), 55.5 (OCH ), 60.7 (C-1), 71.8
(C-6), 72.9 (d, C-4, Jc-p ) 9.2 Hz), 74.8 (C-2), 77.2 (C-3), 104.9
(C-5), 109.9 (CMe ), 112.9 (CMe ), 113.5 (CHd), 113.7 (CHd),
6
6
3
3
), 27.8
t
t
t
(
eluent CH
2
Cl
solid. P NMR (400 MHz, CDCl
MHz, CDCl ) δ 1.29 (s, 3H, CH ), 1.31 (s, 3H, CH
3
2
, R
f
: 0.41) to produce 110 mg (12%) of a white
(CH
3
), 28.9 (CH
3
), 31.3 (CH
3
, Bu), 31.4 (CH
3
3
, Bu),
31
1
) δ 143.2 ppm. H NMR (400
), 1.33 (s, 3H,
, Bu), 1.49 (s, 9H,
), 3.62 (m, 1H, H-6′), 3.77 (m, 1H,
35.8 (C), 36.1 (C), 55.4 (OCH
3
3
3
3
3
t
t
CH
CH
3
), 1.35 (s, 18H, CH
3
, Bu), 1.48 (s, 9H, CH
3
2
2
t
3
, Bu), 1.54 (s, 3H, CH
3
115.1 (CHd), 115.3 (CHd), 126.0 (C), 129.6 (C), 134.2 (C), 135.6
H-6), 3.95 (m, 1H, H-2), 4.09 (m, 1H, H-4), 4.14 (m, 1H, H-5),
(C), 140.0 (C), 143.1 (C), 156.6 (C), 157.0 (C). Anal. Calcd for
3
4
.33 (m, 1H, H-3), 5.54 (d, 1H, H-1, J1-2 ) 3.2 Hz), 7.12 (m, 1H,
C
34
H
47
O10P: C, 63.15; H, 7.33. Found: C, 63.44; H, 7.51.
13
CHd), 7.18 (m, 1H, CHd), 7.43 (m, 2H, CHd). C NMR (400
2,3:5,6-Di-O-isopropylidene-4-O-((3,3′-5,5′-tetra-tert-butyl-
MHz, CDCl
3
) δ 25.6 (CH
3
), 26.4 (CH
, Bu), 31.4 (CH
3
), 26.6 (CH
3
), 26.7 (CH
3
),
1,1′-biphenyl-2,2′-diyl) phosphite)-â-D-fructopyranose (4c). Treat-
ment of 3,3′;5,5′-tetra-tert-butyl-1,1′-biphenyl-2,2′-diol (0.62 g, 1.5
mmol) and 9 (390 mg, 1.5 mmol), as described for compound 1b,
afforded phosphite 4c, which was purified by flash chromatography
(eluent CH Cl , R : 0.43) to produce 290 mg (28%) of a white
t
t
t
t
3
3
7
1
1.1 (CH
3
, Bu), 31.2 (CH
3
3
, Bu), 31.5 (CH
3
, Bu),
4.6 (C), 34.7 (C), 35.4 (C), 65.1 (C-6), 73.5 (C-3), 75.3 (C-5),
7.7 (d, C-4, Jc-p ) 3.9 Hz), 78.5 (C-2), 103.6 (C-1), 109.6 (C),
13.1 (C), 124.0 (CHd), 124.2 (CHd), 125.3 (CHd), 126.2
2
2
f
solid. 31P NMR (400 MHz, C D ) δ 151.7 ppm. H NMR (400
1
(
CHd), 126.8 (CHd), 128.2 (CHd), 129.0 (CHd), 140.2 (C),
40.4 (C), 133.5 (C), 133.7 (C), 146.6 (C), 146.7 (C). Anal. Calcd
for C40 P: C, 68.74; H, 8.51. Found: C, 68.89; H, 8.63.
,2:5,6-Di-O-isopropylidene-3-O-((3,3′-di-trimethylsilyl-1,1′-
6 6
1
MHz, C D ) δ 1.05 (s, 3H, CH ), 1.24 (s, 3H, CH ), 1.27 (s, 9H,
6
6
3
3
t
t
t
H
59
O
8
CH , Bu), 1.28 (s, 9H, CH , Bu), 1.46 (s, 9H, CH , Bu), 1.60 (s,
3
3
3
t
1
3H, CH
3
), 1.64 (s, 12H, CH
3
, CH
3
Bu), 3.80 (m, 1H, H-2), 3.94
2
biphenyl-2,2′-diyl) phosphite)-R-D-allofuranose (2d). Treatment
of 3,3′-di-trimethylsilyl-1,1′-biphenyl-2,2′-diol (0.49 g, 1.5 mmol)
and 7 (390 mg, 1.5 mmol), as described for compound 1b, afforded
phosphite 2d, which was purified by flash chromatography (eluent
(m, 2H, H-1, H-1′), 4.12 (d, 1H, H-6′, J6′-6 ) 9.6 Hz), 4.50 (m,
2
1H, H-3), 4.54 (m, 1H, H-4), 5.58 (d, 1H, H-6, J6-6′ ) 9.6 Hz),
1
3
7.28 (m, 1H, CHd), 7.33 (m, 1H, CHd), 7.55 (m, 2H, CHd). C
NMR (400 MHz, C
6
D
6
) δ 26.2 (CH
3
), 26.8 (CH
3
), 28.0 (CH
3
),
3
1
t
t
t
CH
NMR (400 MHz, C
δ 0.43 (s, 9H, CH -Si), 0.45 (s, 9H, CH
2
Cl
2
, R
f
: 0.68) to produce 180 mg (20%) of a white solid.
P
29.0 (CH ), 31.5 (CH
3
3
, Bu), 31.6 (CH
, Bu), 34.9 (C), 35.0 (C), 35.9 (C), 36.1 (C),
3
, Bu), 31.9 (CH
3
, Bu), 32.0
1
t
t
6
6
D ) δ 143.4 ppm. H NMR (400 MHz, C
6
D
6
)
(CH
3
, Bu), 32.1 (CH
3
3
3
-Si), 1.11 (s, 3H, CH
3
),
60.6 (C-1), 71.8 (C-6), 72.8 (d, C-4, Jc-p ) 8.3 Hz), 74.8 (C-2),
1
2
2
.30 (s, 3H, CH
3
), 1.43 (s, 3H, CH
3
), 1.47 (s, 3H, CH
3
), 3.66 (m,
77.2 (C-3), 104.9 (C-5), 109.9 (CMe ), 112.9 (CMe ), 124.5 (CHd),
2
2
H, H-6′, H-2), 3.76 (m, 1H, H-6), 4.12 (m, 1H, H-5), 4.37 (m,
H, H-3, H-4), 5.33 (d, 1H, H-1, J1-2 ) 3.6 Hz), 7.02 (m, 2H,
124.9 (CHd), 126.0 (C), 127.3 (CHd), 127.6 (CHd), 133.7 (C),
134.9 (C), 138.2 (C), 140.9 (C), 141.0 (C), 146.8 (C), 147.3 (C).
3
1
3
CHd), 7.18 (m, 2H, CHd), 7.40 (m, 2H, CHd). C NMR (400
Anal. Calcd for C40
H, 8.62.
59 8
H O P: C, 68.74; H, 8.51. Found: C, 68.69;
MHz, C
5.4 (C-6), 74.6 (d, C-4, Jc-p ) 8.4 Hz), 76.4 (C-5), 78.5 (d, C-3,
c-p ) 3.0 Hz), 78.9 (C-2), 104.2 (C-1), 113.2 (C), 124.9 (CHd),
25.0 (CHd), 130.3 (C), 130.5 (C), 132.2 (CHd),132.8 (CHd),
6 6
D ) δ -0.1 (CH
3
-Si), 25.7 (CH
3 3 3
), 26.7 (CH ), 26.9 (CH ),
6
J
2,3:4,5-Di-O-isopropylidene-6-O-((3,3′-5,5′-tetra-tert-butyl-
1,1′-biphenyl-2,2′-diyl)phosphite)-â-D-fructopyranose (5c). Treat-
ment of 3,3′;5,5′-tetra-tert-butyl-1,1′-biphenyl-2,2′-diol (0.62 g, 1.5
mmol) and 10 (390 mg, 1.5 mmol), as described for compound
1b, afforded phosphite 5c, which was purified by flash chroma-
1
1
5
43 8 2
35.1 (CHd),135.3 (CHd). Anal. Calcd for C30H O PSi : C,
8.23; H, 7.00. Found: C, 58.84; H, 7.17.
1
,2:5,6-Di-O-isopropylidene-3-O-((3,3′-5,5′-tetra-tert-butyl-
tography (eluent toluene/NEt
mg (15%) of a white solid. 31P NMR (400 MHz, C
D
6 6
3
(100:1), R
f
: 0.55) to produce 140
1
,1′-biphenyl-2,2′-diyl)phosphite)-R-D-galactofuranose (3c). Treat-
) δ 135.9
8164 J. Org. Chem., Vol. 71, No. 21, 2006

Modular Sugar-Based Phosphite Ligand Library
1
ppm. H NMR (400 MHz, C
6
D
6
) δ 0.70 (s, 3H, CH
3
), 0.83 (s, 9H,
), 0.97 (s, 3H,
3
, Bu), 1.21 (s, 9H, CH ,
mixture was extracted with Et
dried over MgSO and analyzed by GC.
General Procedure for the Ni-Catalyzed Enantioselective 1,2-
Addition of DABAL-Me to Aldehydes. [Ni(acac) ] (0.6 mg, 2.33
µmol, 1 mol %) and ligand (2.33 µmol, 1 mol %) were stirred in
dry THF (2 mL) under an argon atmosphere at 5 °C for 10 min.
Neat aldehyde (0.25 mmol) was then added, and trialkylaluminum
2
O (10 mL). The organic layer was
t
t
CH
3
, Bu), 0.86 (s, 9H, CH
3
, Bu), 0.95 (s, 3H, CH
3
4
t
CH
3
), 1.02 (s, 3H, CH ), 1.20 (s, 9H, CH
3
3
t
1
Bu), 3.14 (d, 1H, H-6′, J6′-6 ) 16.8 Hz), 3.31 (m, 2H, H-6, H-4),
3
2
3
3
1
.60 (m, 1H, H-1′), 3.94 (m, 1H, H-1), 4.00 (dd, 1H, H-3, J3-2 )
3
2
4.0 Hz, J3-4 ) 3.6 Hz), 4.18 (d, 1H, H-2, J2-1 ) 3.6 Hz), 6.80
13
(
d, 1H, CHd), 6.90 (d, 2H, CHd), 7.16 (m, 1H, CHd). C NMR
400 MHz, C ) δ 24.7 (CH ), 26.1 (CH ), 26.6 (CH ), 27.1 (CH ),
, Bu),
4.9 (C), 35.0 (C), 36.0 (C), 61.8 (C-6), 64.9 (C-1), 70.4 (C-2),
1.0 (C-3), 71.8 (C-4), 102.9 (C-5), 109.0 (CMe ), 109.3 (CMe ),
24.7 (CHd), 124.8 (CHd), 126.0 (C), 127.3 (CHd), 128.6
(
D
6 6
3
3
3
3
(
84 mg, 0.325 mmol, 1.3 equiv) was added after a further 10 min.
After the desired reaction time, the reaction was quenched with
M HCl (2 mL). Then dodecane (20 µL) was added, and the
mixture was extracted with Et O (10 mL). The organic layer was
dried over MgSO and analyzed by GC.
t
t
t
t
3
3
7
1
3 3 3 3
1.5 (CH , Bu), 31.6 (CH , Bu), 31.9 (CH , Bu), 32.0 (CH
2
2
2
2
4
(
(
CHd), 128.9 (C), 129.6 (C),133.9 (C), 140.6 (C), 140.8 (C), 147.1
C), 147.3 (C). Anal. Calcd for C40 P: C, 68.74; H, 8.51.
59 8
H O
Acknowledgment. We thank the European Union (FP6-
05267-1, LigBank, and the COST D24 Action of the ESF),
Found: C, 68.99; H, 8.71.
General Procedure for the Ni-Catalyzed Enantioselective 1,2-
Addition of Trialkylaluminum Reagents to Aldehydes. [Ni(acac)
0.6 mg, 2.33 µmol, 1 mol %) and ligand (2.33 µmol, 1 mol %)
were stirred in dry THF (2 mL) under an argon atmosphere at -20
C for 10 min. Neat aldehyde (0.25 mmol) was then added, and
trialkylaluminum (0.5 mmol) was added dropwise after a further
0 min. After the desired reaction time, the reaction was quenched
with 2 M HCl (2 mL). Then dodecane (20 µL) was added, and the
5
Consolider Ingenio 2010 (Grant CSD2006-0003), the Spanish
Ministerio de Educaci o´ n, Cultura y Deporte (CTQ2004-04412/
BQU), the Spanish Ministerio de Ciencia y Tecnologia (Ramon
y Cajal fellowship to O.P.), and the Generalitat de Catalunya
2
]
(
°
(Distinction to M.D.)
1
JO0613535
J. Org. Chem, Vol. 71, No. 21, 2006 8165