3,3′-diphosphoryl-1,1′-bi-2-naphthol-Zn(II) complexes as conjugate acid-base catalysts for enantioselective dialkylzinc addition to aldehydes

Article abstract of DOI:10.1021/jo060908t

A highly enantioselective dialkylzine (R²₂Zn) addition to a series of aromatic, aliphatic, and heteroaromatic aldehydes (5) was developed based on conjugate Lewis acid-Lewis base catalysis. Bifunctional BINOL ligands bearing phosphine oxides [P(=O)R₂] (7), phosphonates [P(=O)(OR)₂] (8 and 9), or phosphoramides [P(=O)(NR₂) ₂] (10) at the 3,3′-positions were prepared by using a phospho-Fries rearrangement as a key step. The coordination of a NaphO-Zn(II)-R² center as a Lewis acid to a carbonyl group in a substrate and the activation of R²₂Zn(II) with a phosphoryl group (P=O) as a Lewis base in the 3,3′-diphosphoryl-BINOL- Zn(II) catalyst could promote carbon-carbon bond formation with high enantioselectivities (up to >99% ee). Mechanistic studies were performed by X-ray analyses of a free ligand (7) and a tetranuclear Zn(II) cluster (21), a ³¹P NMR experiment on Zn(II) complexes, an absence of nonlinear effect between the ligand (7) and Et-adduct of benzaldehyde, and stoichiometric reactions with some chiral or achiral Zn(II) complexes to propose a transition-state assembly including monomeric active intermediates.

Full text of DOI:10.1021/jo060908t

3,3′-Diphosphoryl-1,1′-bi-2-naphthol-Zn(II) Complexes as
Conjugate Acid-Base Catalysts for Enantioselective Dialkylzinc
Addition to Aldehydes
Manabu Hatano, Takashi Miyamoto, and Kazuaki Ishihara*
Graduate School of Engineering, Nagoya UniVersity, Furo-cho, Chikusa, Nagoya 464-8603, Japan
ishihara@cc.nagoya-u.ac.jp
ReceiVed May 2, 2006
A highly enantioselective dialkylzinc (R2 Zn) addition to a series of aromatic, aliphatic, and heteroaromatic
2
aldehydes (5) was developed based on conjugate Lewis acid-Lewis base catalysis. Bifunctional BINOL
ligands bearing phosphine oxides [P(dO)R2] (7), phosphonates [P(dO)(OR)2] (8 and 9), or phosphoramides
[P(dO)(NR2)2] (10) at the 3,3′-positions were prepared by using a phospho-Fries rearrangement as a key
step. The coordination of a NaphO-Zn(II)-R2 center as a Lewis acid to a carbonyl group in a substrate
and the activation of R2 Zn(II) with a phosphoryl group (PdO) as a Lewis base in the 3,3′-diphosphoryl-
2
BINOL-Zn(II) catalyst could promote carbon-carbon bond formation with high enantioselectivities
(up to >99% ee). Mechanistic studies were performed by X-ray analyses of a free ligand (7) and a
tetranuclear Zn(II) cluster (21), a 31P NMR experiment on Zn(II) complexes, an absence of nonlinear
effect between the ligand (7) and Et-adduct of benzaldehyde, and stoichiometric reactions with some
chiral or achiral Zn(II) complexes to propose a transition-state assembly including monomeric active
intermediates.
Introduction
such as amino alcohols (N,O-ligands), diamines (N,N-ligands),
and diols (O,O-ligands) have been developed.4-8 We can classify
organometal alkylation into three types: (a) double activation
by only Lewis acidic organometal reagents, (b) double activation
Modern advanced asymmetric catalysis demands both maxi-
mum efficiency in terms of yield and enantioselectivity and
minimal waste derived from catalysts, reagents, solvents, salts,
etc.1,2 Catalytic enantioselective dialkylzinc addition to alde-
hydes is one of the most important reactions involving carbon-
carbon bond formation, in which optically active secondary
alcohols are obtained as synthetically and pharmaceutically
useful compounds.3 To date, numerous efficient chiral ligands
(4) Reviews for catalytic enantioselective dialkylzinc additions to alde-
hydes and ketones: (a) Soai, K.; Niwa, S. Chem. ReV. 1992, 92, 833-856.
(b) Pu, L.; Yu, H.-B. Chem. ReV. 2001, 101, 757-824. (c) Bolm, C.;
Hildebrand, J. P.; Mun˜iz, K.; Hermanns, N. Angew. Chem., Int. Ed. 2001,
40, 3284-3308. (d) Pu, L. Tetrahedron 2003, 59, 9873-9886. (e) Hatano,
M.; Miyamoto, T.; Ishihara, K. Curr. Org. Chem. 2006, in press.
(5) (a) Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R. J. Am. Chem.
Soc. 1986, 108, 6071-6072. (b) Noyori, R.; Kitamura, M. Angew. Chem.,
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S.; Kitamura, M.; Oguni, N.; Hayashi, M.; Kaneko, T.; Matsuda, Y. J.
Organomet. Chem. 1990, 382, 19-37.
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99-101. (b) Schmidt, B.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1991,
30, 1321-1323. (c) Seebach, D.; Beck, A. K.; Schmidt, B.; Wang, Y. M.
Tetrahedron 1994, 50, 4363-4384. (d) Weber, B.; Seebach, D.; Tetrahedron
1994, 50, 7473-7484. (e) Seebach, D.; Pichota, A.; Beck, A. K.; Pinkerton,
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(1) (a) Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; ComprehensiVe
Asymmetric Catalysis I-III; Springer: Berlin, 1999. (b) Ahluwalia, V. K.;
Kidwai, M. New Trends in Green Chemistry; Kluwer Academic: Dordrecht,
The Netherlands, 2004.
(2) (a) Trost, B. M. Science 1991, 254, 1471-1477. (b) Trost, B. M.
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(3) (a) Knochel, P.; Singer, R. D. Chem. ReV. 1993, 93, 2117-2188. (b)
Knochel, P.; Jones, P. Organozinc Reagents: A Practical Approach; Oxford
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10.1021/jo060908t CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/21/2006
6474
J. Org. Chem. 2006, 71, 6474-6484

EnantioselectiVe Dialkylzinc Addition to Aldehydes
the use of excess Ti(OiPr)4, can be also classified as a
neighboring acid-base catalytic system, type b.11,12 In brief,
these type b catalyses involve only the terminal acid and base
functions without conjugation inside the ligands.
In contrast, in the present study we explored a conjugate
Lewis acid-Lewis base catalysis with 4 (Figures 1c and 3).
The key to designing the catalysts is a conjugation between a
2-naphthol moiety and a 3-phosphoryl group (PdO) to doubly
activate electrophile and nucleophile.13,14 In particular, we
examined the enantioselective dialkylzinc addition to aldehydes
(5) using BINOL-Zn(II) catalysts bearing phosphine oxides
[P(dO)R2], phosphonates [P(dO)(OR)2], or phosphoramides
[P(dO)(NR2)2] at the 3,3′-positions (Figure 3).15-17
Results and Discussion
Evaluation of Conjugate Acid-Base Catalyst, 3,3′-Diphe-
nylphosphoryl-BINOL-Zn(II). First, 10 mol % of 3,3′-
diphenylphosphoryl-BINOL, (R)-7, was used to catalyze the
addition of diethylzinc (3 equiv) to aldehydes (5) in THF/toluene
(1:1) at room temperature.4-8 The results are summarized in
Table 1. In particular, aromatic aldehydes with electron-donating
or -withdrawing groups showed high enantioselectivities (up
to 95% ee) (entries 1-11). The reactions also proceeded
smoothly for heteroaromatic aldehydes and R,â-unsaturated
aldehydes (entries 12-14 and 21-25). For aliphatic aldehydes,
in which competitive reduction often occurs along with ethy-
lation, the corresponding secondary aliphatic alcohols were
obtained with high enantioselectivities (up to 94% ee) (entries
FIGURE 1. Double activation of aldehyde and organometal reagents
(M-R).
by a Lewis acid-Lewis base, and (c) double activation by a
conjugate Lewis acid-Lewis base (Figure 1). Usually, orga-
nomagnesium and organoaluminum reagents belong to type a.
Most of the reported enantioselective dialkylzinc additions to
aldehydes are type b in which the Lewis acid and the Lewis
base are attached each other.4,9 To the best of our knowledge,
there have been no reports on conjugate acid-base catalysis
such as type c in enantioselective dialkylzinc additions, which
involves an electron charge transfer at the ligand interior.4 Thus,
type c catalysis offers an advantage at enhancing catalytic
activity because the direct linkage between the acid and base
in type b may weaken or negate both activities.
In principle, catalysis with N,O-ligands such as Noyori’s
DAIB (1) is based on type b as a neighboring acid-base
catalytic system to activate aldehyde and dialkylzinc, respec-
tively (Figure 2).5 For O,O-ligands, 1,1′-bi-2-naphthol (BINOL)
derivatives are important because of their simple C2-symmetric
structures and synthetic utility. Particularly, Ti(IV)-BINOLate
complex (2) has been developed by using type b catalysis.8b,10
The 3,3′-di(o-alkoxyphenyl)-BINOL (3) described by Pu and
co-workers, which has overcome the problem associated with
(11) (a) Huang, W.-S.; Hu, Q.-S.; Pu, L. J. Org. Chem. 1998, 63, 1364-
1365. (b) Huang, W.-S.; Pu, L. Tetrahedron Lett. 2000, 41, 145-149. (c)
Simomson, D. L.; Kingsbury, K.; Xu, M.-H.; Hu, Q.-S.; Sabat, M.; Pu, L.
Tetrahedron 2002, 58, 8189-8193.
(12) (a) Liu, L.; Pu, L. Tetrahedron 2004, 60, 7427-7430. (b) Qin, Y.-
C.; Pu, L. Angew. Chem., Int. Ed. 2006, 45, 273-277.
(13) Resonance behaviors of conjugate aromatic compounds involving
C(sp2)sPdO/C(sp2)sOsH and C(sp2)dPsOs/C(sp2)dO‚‚‚H+ have been
studied. For an excellent textbook on organophosphorus chemistry see Quin,
L. D. A Guide to Organophosphorus Chemistry; Wiley: New York, 2000,
and the references therein.
(14) (a) Griffin, C. E.; Polsky, R. A. J. Org. Chem. 1961, 26, 4772-
4773. (b) Goetz, H.; Nerdel, F.; Wiechel, K.-H. Liebigs Ann. Chem. 1963,
665, 1-13. (c) Albright, T. A.; Freeman, W. J.; Schweizer, E. E. J. Org.
Chem. 1975, 40, 3437-3441. (d) Symmes, C., Jr.; Quin, L. D. J. Org.
Chem. 1976, 41, 1548-1551. (e) Pacchioni, G.; Bagus, P. S. Inorg. Chem.
1992, 31, 4391-4398. (f) Gilheany, D. G. Chem. ReV. 1994, 94, 1339-
1374.
(15) Bifunctional nonconjugate BINOLs with phosphoryl groups: (a)
Hamasima, Y.; Sawada, D.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc.
1999, 121, 2641-2642. (b) Kanai, M.; Hamashima, Y.; Takamura, M.;
Shibasaki, M. J. Synth. Org. Chem., Jpn. 2001, 59, 766-778. (c) Shibasaki,
M.; Kanai, M.; Funabashi, K. Chem. Commun. 2002, 1989-1999. (d) Kanai,
M.; Kato, N.; Ichikawa, E.; Shibasaki, M. 2005, 1419-1508. (e) Kanai,
M.; Kato, N.; Ichikawa, E.; Shibasaki, M. Pure Appl. Chem. 2005, 77,
2047-2052. (f) Yoshida, T.; Morimoto, H.; Kumagai, N.; Matsunaga, S.;
Shibasaki, M. Angew. Chem., Int. Ed. 2005, 44, 3470-3474.
(16) Precedent chiral ligands bearing PdO moieties: (a) Soai, K.; Hirose,
Y.; Ohno, Y. Tetrahedron: Asymmetry 1993, 4, 1473-1474. (b) Hulst,
R.; Heres, H.; Fitzpatrick, K.; Peter, N. C. M. W.; Kellogg, R. M.
Tetrahedron: Asymmetry 1996, 7, 2755-2760. (c) Shibata, T.; Tabira, H.;
Soai, K. J. Chem. Soc., Perkin Trans. 1 1998, 177-178. (d) Brunel, J.-M.;
Constantieux, T.; Legrand, O.; Buono, G. Tetrahedron Lett. 1998, 39, 2961-
2964. (e) Legrand, O.; Brunel, J.-M.; Buono, G. Tetrahedron Lett. 1998,
39, 9419-9422. (f) Shi, M.; Sui, W.-S. Tetrahedron: Asymmetry 1999,
10, 3319-3325. (g) Legrand, O.; Brunel, J.-M.; Buono, G. Tetrahedron
Lett. 2000, 41, 2105-2109. (h) Shi, M.; Sui, W.-S. Chirality 2000, 12,
574-580.
(7) (a) Ding, K.; Ishii, A.; Mikami, K. Angew. Chem., Int. Ed. Engl.
1999, 38, 497-501. (b) Wu, Y.; Yun, H.; Wu, Y.; Ding, K.; Zhou, Y.
Tetrahedron: Asymmetry 2000, 11, 3543-3552. (c) Shen, X.; Guo, H.;
Ding, K. Tetrahedron: Asymmetry 2000, 11, 4321-4327. (d) Yun, H.; Wu,
Y.; Wu, Y.; Ding, K.; Zhou, Y. Tetrahedron Lett. 2000, 41, 10263-10266.
(e) Mikami, K.; Angeland, R.; Ding, K.; Ishii, A.; Tanaka, A.; Sawada, N.;
Kudo, K.; Senda, M. Chem.sEur. J. 2001, 7, 730-737. (f) Du, H.; Ding,
K. Org. Lett. 2003, 5, 1091-1093. (g) Ding, K.; Du, H.; Yuan, Y.; Long,
J. Chem.sEur. J. 2004, 10, 2872-2884. (h) Du, H.; Zhang, X.; Wang, Z.;
Ding, K. Tetrahedron 2005, 61, 9465-9477.
(8) (a) Costa, A. M.; Jimeno, C.; Gavenonis, J.; Carroll, P. J.; Walsh, P.
J. J. Am. Chem. Soc. 2002, 124, 6929-6941. (b) Balsells, J.; Davis, T. J.;
Carroll, P.; Walsh, P. J. J. Am. Chem. Soc. 2002, 124, 10336-10348. (c)
Garc´ıa, C.; LaRochelle, L. K.; Walsh, P. J. J. Am. Chem. Soc. 2002, 124,
10970-10971. (d) Walsh, P. J. Acc. Chem. Res. 2003, 36, 739-749. (e)
Garc´ıa, C.; Walsh, P. J. Org. Lett. 2003, 5, 3641-3644. (f) Joen, S.-J.; Li,
H.; Garc´ıa, C.; LaRochelle, L. K.; Walsh, P. J. J. Org. Chem. 2005, 70,
448-455. (g) Costa, A. M.; Garc´ıa, C.; Carroll, P. J.; Walsh, P. J.
Tetrahedron 2005, 61, 6442-6446. (h) Jeon, S.-J.; Li, H.; Walsh, P. J. J.
Am. Chem. Soc. 2005, 127, 16416-16425.
(9) Rasmussen, T.; Norrby, P.-O. J. Am. Chem. Soc. 2001, 123, 2464-
2465.
(10) Pioneering BINOL-Ti catalysis: (a) Mori, M.; Nakai, T. Tetra-
hedron Lett. 1997, 38, 6233-6236. (b) Zhang, F.-Y.; Yip, C.-W.; Cao, R.;
Chan, A. S. C. Tetrahedron: Asymmetry 1997, 8, 585-589. (c) Zhang,
F.-Y.; Chan, A. S. C. Tetrahedron: Asymmetry 1997, 8, 3651-3655.
(17) Part of this work has been published as a preliminary communica-
tion: (a) Hatano, M.; Miyamoto, T.; Ishihara, K. AdV. Synth. Catal. 2005,
347, 1561-1568. (b) Hatano, M.; Miyamoto, T.; Ishihara, K. Synlett. 2006,
1762-1764.
J. Org. Chem, Vol. 71, No. 17, 2006 6475

Hatano et al.
FIGURE 2. Precedent acid-base catalytic systems by type b.
TABLE 1. Enantioselective Diethylzinc Addition to Aldehydes
with (R)-7a
FIGURE 3. Expected conjugate acid-base catalysis using 3,3′-
diphosphoryl-BINOL-Zn(II) complexes.
15-20). An increase in the catalytic activity of (R)-7 was
observed at 50 °C with a bit loss of enantioselectivity, and the
catalyst loading could be decreased to 5 mol % (brackets in
Table 1).
entry
R1CHO (5)
time (h)
yield (%)b
ee (%)c
1
PhCHO
3 [2]
18 [7]
8 [3]
4 [2]
9
3 [1]
1 [0.5]
0.5 [0.1]
6
4 [1.5]
4 [1]
1
24
24
95 [84]
89 [95]
>99 [96]
>99 [98]
89
94 [98]
98 [92]
>99 [98]
82
95 [92]
95 [93]
86
82
63
95 [88]
89 [85]
93 [88]
93 [85]
86
94 [90]
94 [90]
94 [90]
80
95 [93]
95 [89]
86
75
81
2
4-MeOC6H4CHO
4-MeC6H4CHO
4-PhC6H4CHO
2-FC6H4CHO
3
4
BINOL-Zn(II) Catalysts Bearing Phosphonates [P(dO)-
(OR)2] or Phosphoramides [P(dO)(NR2)2]. To achieve strong
Lewis basicity for PdO, chiral ligands ((R)-8 and (R)-9), which
had electron-donating P-substitutions, were examined (Table 2).
The reaction with 3 mol % of (R)-7 proceeded with high
enantioselectivity (93% ee), but was slow. However, even
3 mol % of (R)-8 or (R)-9 was more effective than (R)-7 for
the enantioselective addition of diethylzinc (1.5 equiv) to
benzaldehyde in THF/toluene at room temperature (Table 2,
entries 1-3). This preference for (R)-9 to (R)-8 was probably
because of the strong electron-donation and compact structure
required by a fixed ring conformation. For a promising ligand
with strong Lewis basicity, we next examined the BINOL-
Zn(II) catalyst bearing conjugate phosphoramide [Pd(O)(NR2)2]
moieties. The reaction proceeded smoothly with 3 mol % of
(R)-10 and 1.5 equiv of Et2Zn at room temperature for 24 h
to give the product in 98% yield and 97% ee (entry 4).
Therefore, the catalytic activity of (R)-10 was higher than those
of 7, 8, and 9, and the order of reactivity was 10 > 9 > 8 > 7,
according to their electron-donating abilities to PdO moieties.18
By using 8-10, a warm temperature (50 °C) increased the
reactivity with almost the same enantioselectivity (within 0-2%
ee) (entries 6-8). Particularly for (R)-10, the Et-adduct was
obtained in quantitative yield with 95% ee after only 4 h (entry
8).
5
6
4-FC6H4CHO
7
4-ClC6H4CHO
4-CF3C6H4CHO
1-naphthylCHO
2-naphthylCHO
3,4-(OCH2O)C6H3CHO
PhCtCCHO
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
trans-PhCHdCHCHO
trans-MeCHdCMeCHO
PhCH2CH2CHO
n-C5H11CHO
6 [4]
12
73 [50]
71
82 [86]
94
c-C6H11CHO
12
55
91
n-C7H15CHO
12
69
80
n-C9H19CHO
12
72
90
n-C11H23CHO
6
66
93
2-furylCHO
3-furylCHO
3 [1.5]
3
90 [93]
90
84 [80]
73
3-thienylCHO
3-pyridylCHO
4-pyridylCHO
2 [1.5]
0.5
0.5
94 [95]
30
41
92 [83]
81
79
a An amount of 10 mol % of (R)-7 and 3 equiv of Et2Zn were used at
room temperature, while 5 mol % of (R)-7 and 3 equiv of Et2Zn were used
at 50 °C (data in brackets). b Isolated yield. c Absolute configurations of 6
were R. The ee values were determined by chiral GC analysis or chiral
HPLC (see Supporting Information).
2-naphthaldehyde, high enantioselectivities and high yields were
observed under optimized reaction conditions with 3 mol % of
(R)-10 and 1.5 equiv of Et2Zn (entries 1-11). The general
reactivities were higher with electron-withdrawing aromatic
aldehydes than electron-donating ones, although high enanti-
oselectivities were not affected by the type of substitution or
its position. Heteroaromatic aldehyde, R,â-unsaturated aldehyde,
and aliphatic aldehydes were also effective (entries 12-14). It
should be noted that (R)-9 was also useful because (R)-9 showed
high enantioselectivities and was easily prepared in two steps,
in contrast to the more elaborate preparation of (R)-10. In some
cases, however, the reactivities with (R)-9 were not as high as
with (R)-10 (brackets in Table 3).
Encouraged by the high efficiency of (R)-10-Zn(II) catalyst
in the enantioselective ethylation of benzaldehyde, we next
examined the generality of this method for other aldehydes
(Table 3). For mono- or disubstituted aromatic aldehydes and
(18) The PdO bond in P(dO)Ph2 has been known to be less basic than
that of P(dO)(OR)2 or P(dO)(NMe2)2. While the greater electronegitivity
of the oxygen in P-OR over the carbon in P-Ph will decrease the basicity
of the PdO in some extents, resonance donation of the OR or NMe2 lone
pair to P makes the PdO more basic effectively. See Arnett, E. M.; Mitchell,
E. J.; Murty, T. S. S. R. J. Am. Chem. Soc. 1974, 96, 3875-3891.
6476 J. Org. Chem., Vol. 71, No. 17, 2006

EnantioselectiVe Dialkylzinc Addition to Aldehydes
TABLE 2. Enantioselective Diethylzinc Addition to Benzaldehyde
with Conjugate Acid-Base BINOL-Zn(II) Catalysts
TABLE 4. Highly Enantioselective Dialkylzinc Addition to
Aromatic Aldehydes with (R)-10 [or (R)-9]a
entry
R1CHO (5)
PhCHO
4-MeC6H4CHO
3-ClC6H4CHO
4-ClC6H4CHO
4-CF3C6H4CHO
4-CF3C6H4CHO
3-thienylCHO
R2
time (h)
yield (%)b
ee (%)c
1
2
3
4
5
6d
7
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
24 [48]
72
48
24 [48]
12 [24]
48
94 [92]
78
87
94 [89]
91 [98]
92
96 [93]
95
92
90 [95]
97 [93]
92
36
83
89
8
9
10
11
12
13e
PhCHO
Me
Me
Me
Me
Me
Me
72
72
72
48
24 [48]
48
82
80
84
90
88 [60]
84
96
90
87
95
91 [82]
86
entry
ligand
temp
rt
rt
rt
rt
time (h)
yield (%)a
ee (%)b
4-MeC6H4CHO
3-ClC6H4CHO
4-ClC6H4CHO
4-CF3C6H4CHO
4-CF3C6H4CHO
1
2
3
4
(R)-7
(R)-8
(R)-9
(R)-10
72
48
48
24
77
70
81
98
93
94
97
97
5
6
7
8
(R)-7
(R)-8
(R)-9
(R)-10
50 °C
50 °C
50 °C
50 °C
12
12
12
4
60
65
76
91
94
96
95
a Unless otherwise noted, 5 mol % of (R)-10 and 2 equiv of R2 Zn were
2
used in THF/toluene for methylation and in THF/heptane for butylation.
An amount of 5 mol % of (R)-9 was used instead of (R)-10 (data in brackets).
b Isolated yield. c Absolute configulations of products were R. The ee values
were determined by chiral GC or HPLC analyses (see Supporting Informa-
tion). d An amount of 3 mol % of (R)-10 and 1.5 equiv of n-Bu2Zn were
used. e An amount of 3 mol % of (R)-10 and 2 equiv of Me2Zn were used.
>99
a Isolated yield. b Absolute configulation of product was R. The ee values
were determined by chiral GC analysis.
TABLE 3. Highly Enantioselective Diethylzinc Addition to
Aldehydes with (R)-10 [or (R)-9]a
observed in aromatic aldehydes without competitive reductions
into ArCH2OH. Particularly, dialkylzinc addition to benzalde-
hyde with 5 mol % of (R)-10 showed high enantioselectivities
(96% ee, entries 1 and 8).21 Instead of (R)-10, 5 mol % of (R)-9
was also effective for both n-butylation and methylation of
aldehydes to give the products with high enantioselectivities
(82-95% ee), although longer reaction times were necessary
(brackets in Table 4).
Enantioselective Ph2Zn Addition to Aldehydes. Enanti-
oselective phenylation to aldehydes (5) with 1 equiv of Ph2Zn
was examined in the presence of conjugate Lewis acid-Lewis
base BINOL-Zn(II) catalyst and 10 mol % of Et2Zn.12b,22,23
Unexpectedly, low yield and low enantioselectivity were
observed in phenylation of 4-chlorobenzaldehyde by using (R)-
entry
R1CHO (5)
PhCHO
time (h)
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
24 [48]
48
24
24
24
12[24]
8 [24]
12 [36]
1 [3]
12 [24]
24 [48]
12 [24]
24
98 [81]
91
90
90
85
92 [92]
95 [96]
93 [98]
95 [95]
94 [87]
87 [86]
70 [98]
85
97 [97]
94
96
96
93
94 [91]
98 [96]
95 [93]
97 [97]
>99 [97]
95 [90]
79 [90]
77
4-MeOC6H4CHO
2-MeC6H4CHO
4-MeC6H4CHO
4-PhC6H4CHO
2-ClC6H4CHO
3-ClC6H4CHO
4-ClC6H4CHO
4-CF3C6H4CHO
2-naphthylCHO
3,4-(OCH2O)C6H3CHO
PhC≡CCHO
9
10
11
12
13
14
(20) Recent Me2Zn addition: (a) Lurain, A. E.; Maestri, A.; Kelly, A.
R.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2004, 126, 13608-13609.
(b) Garc`ıa-Delgado, N.; Fontes, M.; Perica`s, M. A.; Riera, A.; Verdaguer,
X. Tetrahedron: Asymmetry 2004, 15, 2085-2090. (c) Sprout, C. M.;
Richmond, M. L.; Seto, C. T. J. Org. Chem. 2004, 69, 6666-6673. (d)
Garc´ıa-Delgado, N.; Fontes, M.; Perica`s, M. A.; Riera, A.; Verdaguer, X.
Tetrahedron: Asymmetry 2004, 15, 2085-2090. (e) Blay, G.; Ferna´ndez,
I.; Herna´ndez-Olmos, V.; Marco-Aleixandre, A.; Pedro, J. R. Tetrahe-
dron: Asymmetry 2005, 16, 1953-1958. (f) Cozzi, P. G.; Rudolph, J.; Bolm,
C.; Norrby, P.-O.; Tomasini, C. J. Org. Chem. 2005, 70, 5733-5736. (g)
Wieland, L. C.; Deng, H.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem.
Soc. 2005, 127, 15453-15456. (h) Cozzi, P. G.; Kotrusz, P. J. Am. Chem.
Soc. 2006, 128, 4940-4941.
(21) As much as 10 mol % of (R)-7 and 3 equiv of Me2Zn to
benzaldehyde gave low conversion (29% yield) and moderate enantiose-
lectivity (71% ee) for 120 h.
(22) Pioneering work of Ph2Zn transfer: (a) Bolm, C.; Hermanns, N.;
Hildebrand, J. P.; Mun˜iz, K. Angew. Chem., Int. Ed. 2000, 39, 3465-3467.
(b) Bolm, C.; Kesselgruber, M.; Hermanns, N.; Hildebrand, J. P.; Raabe,
G. Angew. Chem., Int. Ed. 2001, 40, 1488-1490. (c) Bolm, C.; Hildebrand,
J. P.; Mun˜iz, K.; Hermanns, N. Angew. Chem., Int. Ed. 2001, 40, 3284-
3308. (d) Rudolph, J.; Rasmussen, T.; Bolm, C.; Norrby, P.-O. Angew.
Chem., Int. Ed. 2003, 42, 3002-3005.
n-C5H11CHO
3-thienylCHO
12 [48]
94 [86]
95 [95]
a An amount of 3 mol % of (R)-9 was used instesd of (R)-10 (data in
brackets). b Isolated yield. c Absolute configulations of 6 were R. The ee
values were determined by chiral GC or HPLC analyses (see Supporting
Information).
Enantioselective n-Bu2Zn and Me2Zn Addition to Alde-
hydes. Other catalytic enantioselective additions of dialkylzinc
to aldehydes were examined (Table 4). Despite the general
difficulties in n-Bu- or Me-addition reactions,19,20 (R)-10 (3-5
mol %) and 1.5-2 equiv of n-Bu2Zn or Me2Zn gave smooth
conversion at room temperature. High enantioselectivities were
(19) Examples of catalytic enantioselective n-Bu2Zn or Me2Zn addition
to aldehydes have been limited with or without Ti(OiPr)4. Pioneering works
of dialkylzinc transfer can be found in the following examples: (a) Noyori,
R.; Suga, S.; Kawai, K.; Okada, S.; Kitamura, M.; Oguni, N.; Hayashi, M.;
Kaneko, T.; Matsuda, Y. J. Organomet. Chem. 1990, 382, 19-37. (b) Soai,
K.; Yokoyama, S.; Hayasaka, T. J. Org. Chem. 1991, 56, 4264-4268. (c)
Jones, G. B.; Heaton, S. B. Tetrahedron: Asymmetry 1993, 4, 261-272.
(23) Recent progress in Ph2Zn transfer: (a) Fontes, M.; Verdaguer, X.;
Sola`, L.; Perica`s, M. A.; Riera, A. J. Org. Chem. 2004, 60, 2532-2543.
(b) Castellnou, D.; Fonte, M.; Jimeno, C.; Font, D.; Sola`, L.; Verdaguer,
X.; Perica`s, M. A. Tetrahedron 2005, 61, 12111-12120. Also see ref 12b.
J. Org. Chem, Vol. 71, No. 17, 2006 6477

Hatano et al.
TABLE 5. Highly Enantioselective Diphenylzinc Addition to
6). (R)-BINOL, (R)-BINAP, and (R)-BINAPO were ineffective
under our reaction conditions even though they have the same
C2-symmetric binaphthyl structures (entries 2-4). Medium
enantioselectivities and reactivities were observed with the use
of 14 and 15, which have bulky substituents at the 3,3′-positions
but lack the key PdO units (entries 5 and 6). These results mean
that mere bulkiness at the 3,3′-positions is insufficient to
improve the enantioselectivity. Hydroxycarbonyl groups as
conjugate moieties at the 3,3′-positions (16) were also ineffective
because of weaker basicity of CdO than that of PdO (entry
7). Furthermore, two C2-symmetric PdO moieties at the 3,3′-
positions in the BINOL skeleton are necessary to achieve high
catalytic activity, since 17, which has a diphenylphosphine oxide
on only one side, was ineffective for this catalysis (entry 8). A
low reactivity of 18, which has OH and PdO moieties at the
2- and 2′-positions in a binaphthyl backbone, was also attribut-
able to the lack of a C2-symmetric structure (entry 9). The low
performance of 17 and 18 with respect to 7 is probably due not
only to the rigidity of the chelation network, but also to the
fact that the missing second P(dO)Ph2 moiety in the appropriate
position induces a competing chelation mode. H8-19 with
a 5,5′,6,6′,7,7′,8,8′-H8-BINOL backbone and 20 bearing 3,3′-
[P(dS)Ph2]2 moieties in BINOL backbone could catalyze the
reaction, but the yield and enantioselectivity were inferior to
those with the original 7 (entries 10 and 11).
Aromatic Aldehydes with (R)-7-10
entry
ligand
R1CHO (5)
yield (%)a
ee (%)b
1c
2c
3
4
5
6
7
8
9
10
9
8
7
7
7
7
7
7
7
7
4-ClC6H4CHO
4-ClC6H4CHO
4-ClC6H4CHO
4-ClC6H4CHO
4-FC6H4CHO
4-CF3C6H4CHO
4-MeC6H4CHO
4-PhC6H4CHO
4-MeOC6H4CHO
1-naphthylCHO
2-naphthylCHO
65
62
78
96
>99
93
86
93
77
97
49
52
87
88
86
88
85
82
73
77
81
10
11
95
a Isolated yield. b Absolute configurations of 13 were R. The ee values
were determined by chiral GC or HPLC analysis (see Supporting Informa-
tion). c Reaction time was 48 h.
10, (R)-9, and (R)-8 (Table 5, entries 1-3). However, (R)-7
bearing conjugate phosphine oxide moieties showed good
reactivities, and the corresponding Ph-adduct was obtained in
96% yield and 88% ee (entry 4). For other aromatic aldehydes
bearing electron-donating or -withdrawing groups, (R)-7 was
so effective that the reactions proceeded smoothly to give the
corresponding 1,1-diarylcarbinols with 73-88% ee. The unex-
pected reversal of catalytic activity between phenylation (7 >
8 > 9 > 10) and alkylations (10 > 9 > 8 > 7) has not been
clear and further examinations are necessary, but for one reason
a steric factor involving π-π interactions among the catalysts
and Ph2Zn cannot be denied completely.24 Eventually, our Lewis
acid-Lewis base BINOL-Zn(II) catalysts (i.e., (R)-7 and (R)-
10) gave complementary results in enantioselective phenylation
and alkylation, respectively.
Characteristics of Zn(II) Cluster and Dinuclaer Zn(II)
Complexes through Stoichiometric Reaction. We should
address the association between the characteristics of the Zn-
(II) catalysts and mechanistic aspects. The first key to studying
this catalysis should be to clarify whether the PdO moiety
coordinates to the Zn(II) center as a Lewis base. Fortunately, a
single crystal was obtained for X-ray analysis from a mixture
of (R)-7 and Et2Zn (1 equiv each) in CH2Cl2-hexane at room
temperature for 24 h under open air conditions. The ORTEP
drawings are shown in Figure 4. The structure of the obtained
Zn(II) cluster {Zn4[(R)-3,3’-bis(diphenyphosphinoyl)-BINO-
Late]3(µ4-O)}‚(CH2Cl2)3 (21) was self-assembled from four Zn-
(II) metals and three units of (R)-7. At the center of this cluster,
Effects of Phosphoryl Groups in the Binaphthyl Backbone.
The presence of PdO in the BINOL structure was critical (Table
TABLE 6. Diethylzinc Addition to Benzaldehyde Catalyzed by Chiral Binaphthyl Ligand-Zn(II) Complexa
entry
ligand
X
X′
Y
Y′
yield (%)b
ee (%)c
confign
1d
2
3
7
OH
OH
PPh2
P(dO)Ph2
OH
OH
OH
OH
OH
OH
OH
PPh2
P(dO)Ph2
OH
OH
OH
OH
P(dO)Ph2
OH
P(dO)Ph2
H
H
H
PPh2
Ph
CO2H
P(dO)Ph2
H
P(dO)Ph2
P(dS)Ph2
P(dO)Ph2
H
H
H
PPh2
Ph
CO2H
H
95
17
21
67
76
87
18
34
44
72
85
95
39
0
R
R
BINOL
BINAP
BINAPO
14
15
16
17
18
H8-19
20
4
2
R
R
R
5
66
49
0
21
41
87
83
6e
7
8
9
R
R
R
R
H
10f
11
OH
OH
P(dO)Ph2
P(dS)Ph2
OH
a Unless otherwise noted, 10 mol % of (R)-binaphthyl ligand and 3 equiv of Et2Zn were used for bezaldehyde in THF/toluene (1:1) at room temperature
for 24 h. b Isolated yield. c The ee values were determined by chiral GC analysis. d Reaction time was 3 h. e Solvent was THF/hexane (1:1). f H8-19 is
5,5′,6,6′,7,7′,8,8′-H8-BINOL derivative.
6478 J. Org. Chem., Vol. 71, No. 17, 2006

EnantioselectiVe Dialkylzinc Addition to Aldehydes
FIGURE 4. ORTEP drawings of self-assembled Zn(II) cluster 21 (hydrogen atoms are omitted for clarity).
FIGURE 5. Postulated oligonuclear and dinuclear BINOL-Zn(II) complexes.
µ4-O, which might be derived from adventitious water during
recrystallization, coordinates to four Zn(II) centers.25 The Zn-
(II) center in the top position coordinates to µ4-O (1.93 Å) and
three PdO (1.92-1.95 Å) in three different units of 7. Each of
the other three Zn(II) centers at bottom positions coordinates
to µ4-O (1.94-1.96 Å), Naph-O (1.87-1.88 Å), and OdPsCd
CsO (1.98-2.01 Å and 1.94-1.95 Å, respectively) through
chelation. The position of PdO was not in extension of the
naphthyl plane, and the torsion angles of OdPsC(3)sC(2) were
50.9-58.1°. The R*O2Zn [R*(OH)2 ) (R)-7] chelation to the
Zn(II) center did not exist in 21.
quantitatively with the partial release of (R)-7 for 24 h under
open air conditions. Complex 22 with one singlet peak with
large downfield shifts in the NMR study suggested a sym-
metrical structure with two PdO units coordinating to Zn(II)
centers, namely oligomeric [-OR*O-Zn-]n (n g 2) besides
Zn‚‚‚OdP coordination but without R*O2Zn chelation.26 This
postulated structure of 22 was also supported by X-ray analysis
of 21. Moreover, the addition of another 1 equiv of Et2Zn to
22 caused no release of gas to provide a probable C2-symmetric
dinuclear Zn(II) complex 23 [R*(OZnEt)2] with two independent
NaphO-ZnEt‚‚‚OdP chelations. The optical rotation ([R]21.0
D
in toluene) of 23 (-39.5°, c ) 3.22) changed from that of 22
(-94.6°, c ) 2.61), although 23 showed one major singlet peak
at 43.5 ppm with almost no changes from 22. The addition of
benzaldehyde (1 equiv) to dinuclear 23 (1 equiv), which was
prepared by adding either directly two or one then 1 equiv Et2Zn
to 7, showed no reactivity, and therefore 23 was the inactive
species.
Absence of Nonlinear Effect. The relation between the ee
values of (R)-7 and those of the Et-adduct of benzaldehyde,
(R)-1-phenylpropanol, provided additional information. For
benzaldehyde, 10 mol % of (R)-7 (0-100% ee) and 3 equiv of
Et2Zn were used in THF/toluene at room temperature for 3-5
h to give (R)-1-phenylpropanol in >95% yield, and a linear
relationship was observed between the ee values of (R)-7 and
those of (R)-1-phenylpropanol (Figure 6 and Supporting Infor-
mation).
As expected, this Zn(II) cluster (21) was not an active species;
ethylation of benzaldehyde proceeded with 3.3 mol % of isolated
crystal 21 under the typical reaction conditions at room
temperature for 24 h to give (R)-1-phenylpropanol in 38% yield
and 20% ee. In fact, in a 31P NMR study in CDCl3 under
anhydrous conditions, the addition of 1 equiv of Et2Zn to (R)-7
led to a new complex (22) with a singlet peak at 43.3 ppm
(major, >98%), with downfield shifts from 39.0 ppm for (R)-7
(Figure 5). In this case, 2 equiv of ethane gas were trapped,
and Zn(II) cluster 21 was also obtained as a minor product at
39.3 and 40.3 ppm (<2%). Complex 22 was highly moisture
sensitive and decomposed to the inactive cluster 21 almost
(24) Uncatalyzed background reaction of diphenylzinc should occur. See
refs 22 and 23. For another reason, particularly in 10, the steric hiderance
around the catalyst might interrupt the central coordination such as R*O2-
ZnPh2 [R*(OH)2 ) 10]. As discussed later in this paper, that central
coordination should be critical for a transition-state assembly in diethylzinc
addition (i.e., 37).
(25) Tetranuclaer Zn(II) cluster with a central µ-O4 structure: Murugavel,
R.; Sathiyendiran, M.; Walawalker, M. G. Inorg. Chem. 2001, 40, 427-
434.
Characteristics of Trinuclear and Tetranuclear Zn(II)
Complexes through Stoichiometric Reactions. This linear
(26) Huang, W.-S.; Hu, Q.-S.; Pu, L. J. Org. Chem. 1999, 64, 7940-
7956.
J. Org. Chem, Vol. 71, No. 17, 2006 6479

Hatano et al.
FIGURE 8. Possible tetranuclear monomeric complexes.
results, trinuclear complexes (24-27) would not be the active
species, and the equilibrium between the trinuclear complex and
another complex such as tetranuclear 28-32 should be consid-
ered (Figure 8). In fact, the stoichiometric reaction with
benzaldehyde (1 equiv) and the expected tetranuclear 28-32
(1 equiv), which was prepared from 7 (1 equiv) and Et2Zn (4
equiv), could proceed and (R)-1-phenylpropanol was obtained
in 94% yield and 91% ee (Chart 1, eq 3). Interestingly, the
reactivity under the stoichiometric conditions in eq 3 was lower
than that under the catalytic conditions (Table 1, entry 1). We
thus ultimately can assume that the active species in the presence
of excess Et2Zn under normal catalytic reaction conditions may
be derived from the tetranuclear complexes (i.e., 28-32) or
likely the C2-symmetric pentanuclear complex (33) (Figure 9).
In two postulated catalytic cycles, (1) less active precursor 23
would be regenerated via 28-32 and (2) likely precursors 28-
FIGURE 6. An absence of nonlinear effect between the ee values of
(R)-7 and those of Et-adduct.
relationship suggests that, for one possibility, monomeric species
such as 24-27 by way of 23 may be involved in the
enantioselective addition of Et2Zn (Figure 7).27 Unexpectedly,
however, these assumed trinuclear complexes (24-27), which
were directly prepared from 7 (1 equiv instead of 10%) and
Et2Zn (3 equiv), showed low reactivity; the stoichiometric
reaction to benzaldehyde (1 equiv) gave the product in 13%
yield and 87% ee after 72 h at room temperature (Chart 1, eq
1). But the stoichiometric reaction with benzaldehyde (1 equiv)
and the complex prepared from 7 (1 equiv) and Et2Zn (3.5 equiv)
resulted in 57% yield and 91% ee (Chart 1, eq 2). From these
FIGURE 7. Possible trinuclear monomeric complexes.
CHART 1
6480 J. Org. Chem., Vol. 71, No. 17, 2006

EnantioselectiVe Dialkylzinc Addition to Aldehydes
CHART 2
32 would be regenerated through 33, after carbon-carbon bond
formation with R1CHO (5).
Effect of Phenol and Biphenol Structures. We next
examined the effect of phenol and biphenol onto the catalytic
activity. Thus, catalytic diethylzinc addition to benzaldehyde
was explored with achiral ligands, such as 34 and 35 (Chart 2,
eqs 4 and 5). The catalytic activity of 34 (20 mol %) bearing a
phenol backbone was low, and 33% of Et-adduct was given
for 24 h (Chart 2, eq 4). Probably, low reactivity of 34 could
be rationalized by a six-membered Zn(II)-chelation as a
stabilized structure. In high contrast, 10 mol % of 35 with a
biphenol backbone could catalyze the reaction smoothly, and
Et-adduct was obtained in 89% for 6 h (Chart 2, eq 5).
Therefore, biphenol moiety might be an essential structure to
enhance the reactivity.28 These results indicated that a new
seven-membered chelation of Et2Zn with R(OZnEt)2 [R(OH)2
) biphenol] could trigger the dissociation of the original six-
membered Zn(II)-chelation to relieve a steric hindrance before
the transition states (Chart 2, eq 5).
FIGURE 9. Proposed catalytic cycle involving monomeric active
species.
Conformation of PdO and NaphO-Zn(II) Moieties and
Crystal Structures of 7. The direction of the PdO bond in
ligand 4 depends on the (bi)naphthyl plane (Figures 10, 11a,
and 11b): either (a) a “flat” conformation which has a π-orbital
network and a six-membered ring by metal-chelation or (b) a
“nonflat” conformation with hyperconjugation through π(2-
naphthol)-σ*(P-O) is possible.29 Therefore, a BINOL moiety
is suitable for controlling the direction of conjugate PdO (Lewis
base), which can be away from the metal ion (Lewis acid)
(Figure 11b). Our design of 4-Zn(II) can be unique to a
phosphoryl moiety and distinctive from 36 with C(dO)NR2,
for example (Figure 10).30 For 36, which was described by
FIGURE 10. 3,3′-Disubstituted BINOL ligands.
Katsuki and co-workers, a catalysis by a nonflat conformation
as Figure 11d is probably disfavored because the σ* orbital of
C-O is smaller than that of P-O. Therefore, the conjugation
in 36-Zn(II) would be stabilized by metal-chelation in the most-
expected conformation like Figure 11c, and eventually the
catalytic activity would be weakened by the neighboring acid-
base.
To assist the proposed conformations such as shown in Figure
11b, an X-ray analysis of (R)-7 is shown in Figure 12. Hydrogen
bonding, which was observed in NaphOsH‚‚‚OdP (1.86 and
1.93 Å) to form a six-membered ring, supports the notion that
the chelation to Zn(II) (instead of H) is in this manner, unlike
as with R*O2Zn [R*(OH)2 ) 7]. This hydrogen bonding in (R)-7
was responsible for the observed large downfield shift, such as
(27) Major population of C2-symmetric trinuclear complexes such as 24
and 25 were estimated because the further addition of Et2Zn to 23 gave a
major singlet peak at 38.0 ppm in 31P NMR.
(28) Certainly 34 and 35 are sterically very different. However, these
results could reflect our assumption described, because a preliminary
examination by using the model compound, a t-Bu group ortho to the OH
in 34, also resulted in poor reactivities (20 mol %, room temperature, 24 h,
48% yield).
(29) For the nonflat model like Figure 11b, considerable interaction
between vacant d-orbital of phosphorous and π-orbital of 2-naphthol is also
possible. See refs 13 and 14.
(30) (a) Kitajima, H.; Ito, K.; Katsuki, T. Chem. Lett. 1996, 343-344.
(b) Kitajima, H.; Ito, K.; Katsuki, T. Bull. Chem. Soc. Jpn. 1997, 70, 207-
217. (c) Ito, K.; Tomita, Y.; Katsuki, T. Tetrahedron Lett. 2005, 46, 6083-
6086.
1
10.57 ppm in H NMR in CDCl3. Interestingly, the positions
of PdO were not in extension of the naphthyl plane, probably
because of the π(2-naphthol)-σ*(P-O) interaction (see also
Figure 11a and b.);13,14 torsion angles were 45.4° for C(2)-
C(3)-P(1)-O(2) and 45.0° for C(12)-C(13)-P(2)-O(4).
Fortunately, another conformation could be observed by X-ray
J. Org. Chem, Vol. 71, No. 17, 2006 6481

Hatano et al.
FIGURE 13. ORTEP drawing of (S)-7 without hydrogen bondings.
FIGURE 11. Conjugate acid-base catalyst bearing PdO or CdO in
a BINOL backbone.
FIGURE 14. Proposed transition-state assembly including conjugate
acid-base activation and catalytic cycle.
7) on reactivity in alkylations based on the strength of Lewis
basicity of PdO, a new plausible mechanism including tetra-
nuclear 28-32, pentanuclear 33, and 37 is shown in Figure
14.17a Compound 37 may provide the conformation as shown
in Figure 11b with π(2-naphthol) orbital interactions to σ*(P-
O) through hyperconjugation. Compound 37 has two conjugate
Lewis acidic NaphO-Zn(II)-Et centers to activate aldehyde
and Lewis basic phosphoryl groups to activate Et2Zn. From the
results of the catalysis by phenol and biphenol (eqs 4 and 5),
tetranuclear complexes 28-32 might change to C2-symmetric
33 with a central chelation of R*O2ZnEt [R*(OH)2 ) 4] and
then a dissociation of PdO‚‚‚Zn in 33 would lead to 37. Because
of the steric hindrance between the aldehyde and two substit-
uents (R) to the phosphoryl moiety at the 3-position in the
binaphthyl backbone, reface attack should be favored exclusively
in 37. Eventually, (R)-products can be obtained with smooth
release from the catalyst along with the regeneration of 28-
32.
FIGURE 12. ORTEP drawing of (R)-7 with hydrogen bondings.
analysis of (S)-7 (Figure 13). In that crystal structure, hydrogen
bonding was not observed in NaphOsH‚‚‚OdP. Torsion angles
were 67.9° for C(2)-C(3)-P(1)-O(2) and 66.6° for C(12)-
C(13)-P(2)-O(4), which were larger than those of (R)-7
involving hydrogen bondings. These structures of (R)-7 with
hydrogen bondings and (S)-7 without hydrogen bondings may
support the existence of π(2-naphthol)-σ*(P-O) interaction.
Proposed Transition-State Assembly with Conjugate Acid-
Base BINOL-Zn(II) Catalysts. Finally, we turned our atten-
tion to the mechanistic aspect of the transition-state assembly
which should be regarded as a working model. On the basis of
X-ray analyses of 7 and 21, NMR experiments, and the absence
of a nonlinear relationship between the ee of (R)-7 and the ee
of (R)-1-phenylpropanol, the active Zn(II) complex in our
catalysis is likely to be a tetra- or pentanuclear monomeric
species. Taking advantage of the ligand effect (10 > 9 > 8 >
Preparation of (R)-3,3′-Diphosphoryl-BINOLs. (R)-3,3′-
Bis(diphenyphosphinoyl)-BINOL (7) was prepared almost quan-
titatively from commercially available (R)-BINOL in two steps
via phospho-Fries rearrangement (Scheme 1).31 Our method has
an advantage with regard to yield and purification in comparison
(31) Synthesis of 7 via asymmetric oxidative biaryl coupling. Li, X.;
Hewgley, J.; Mulrooney, C. A.; Yang, J.; Konzlowski, M. C. J. Org. Chem.
2003, 68, 5500-5511.
6482 J. Org. Chem., Vol. 71, No. 17, 2006

EnantioselectiVe Dialkylzinc Addition to Aldehydes
without further purification.32 The rearrangement of (R)-38
proceeded with LDA in THF at - 78 °C for 1 h to give (R)-7
quantitatively as colorless crystals after recrystallization from
toluene/hexane (ca. 1/5).33 Phosphonates [P(dO)(OR)2] ligands
(R)-8 and (R)-9 which had substituents that were more electron-
donating than phenyl groups in (R)-7 were also prepared in a
similar manner via phospho-Fries rearrangement of 39 and 40.
Unfortunately, promising (R)-10 could not be prepared by
the usual simple procedures described above because the key
phospho-Fries rearrangement could not proceed on both sides.
However, protection of 2-naphthol in (R)-43 with a p-meth-
oxybenzyl (PMB) group after the first phospho-Fries rearrange-
ment enabled the second rearrangement to (R)-47, and (R)-10
was obtained after deprotection of the PMB group (Scheme 2).
Other protective groups such as Bn, Piv, and Ac did not work
well. This synthetic method was also effective for preparing
(R)-8, which was obtained in low yield by simple phospho-
Fries rearrangement, as shown in Scheme 1. The total yields of
(R)-8 in Scheme 2 were improved from 26% in Scheme 1 to
59%.
SCHEME 1. Preparation of (R)-3,3′-Disubstituted BINOLs
Bearing PdO Groups
SCHEME 2. Preparation of 3,3′-Disubstituted BINOLs
Bearing Phosphoramides Groups
Conclusion
We have developed a highly efficient enantioselective di-
alkylzinc (R2 Zn) addition to aldehydes (5) by using a conjugate
2
Lewis acid-Lewis base BINOL-Zn(II) catalyst bearing phos-
phine oxides [P(dO)R2], phosphonates [P(dO)(OR)2], or phos-
phoramides [P(dO)(NR2)2] at the 3,3′-positions, namely 7-10.
A series of 3,3-diphosphoryl-BINOL derivatives were synthe-
sized by phospho-Fries rearrangement as a key reaction. The
coordination of an R2Zn(II) moiety as a Lewis acid to a carbonyl
group in a substrate and the activation of R2 Zn with a
2
phosphoryl (PdO) group as a Lewis base in our BINOL-Zn-
(II) catalyst could promote carbon-carbon bond formation. The
reactions proceeded with high enantioselectivities (up to >99%
ee), and showed good reductions in the amounts of both catalysts
and dialkylzinc that had to be loaded, unlike other previous
catalysts that have been examined for dialkylzinc addition to
aldehydes. Detailed mechanistic studies by X-ray analysis of 7
and 21, a 31P NMR experiment of Zn(II) complexes, an absence
of nonlinear effect between ee values of the chiral ligand (7)
and the Et-adduct product (6), and stoichiometric and catalytic
reactions with various complexes could suggest the transition-
state assembly (37) including a pentanuclear monomeric inter-
mediate (33). Further studies for other enantioselective catalyses
are underway by using the conjugate Lewis acid-Lewis base
complexes to develop more efficient reactions.
Experimental Section
Typical Procedure for the Enantioselective Dialkylzinc Ad-
dition to Aldehydes. A solution of (R)-10 (16.6 mg, 0.03 mmol)
in THF (3 mL) was stirred in a well-dried Pyrex Schlenk tube at
room temperature for 5 min under nitrogen atmosphere. To the
solution was added dialkylzinc (1.5 mmol) at -78 °C. This solution
was stirred for 30 min, and aldehyde (5) (1.0 mmol) was added.
The resulting mixture was then gradually warmed to room tem-
perature (or 50 °C), and stirred for 1-72 h. After hydrolysis with
10 mL of saturated NH4Cl aqueous solution, the product was
with a coupling method that uses halide compounds, expensive
diphenylphosphine oxide [Ph2P(dO)H], and palladium or nickel
catalysts. First, (R)-BINOL in THF was treated with NaH.
Subsequent dropwise addition of diphenylphosphinic chloride
gave the corresponding phosphinates (R)-38 quantitatively
(32) Au-Yeung, T.-L.; Chan, K.-Y.; Haynes, R. K.; Williams, I. D.;
Yeung, L. L. Tetrahedron Lett. 2001, 42, 453-456.
(33) (a) Au-Yeung, T.-L.; Chan, K.-Y.; Haynes, R. K.; Williams, I. D.;
Yeung, L. L. Tetrahedron Lett. 2001, 42, 457-460. (b) Taylor, C. M.;
Watson, A. J. Curr. Org. Chem. 2004, 8, 623-636.
J. Org. Chem, Vol. 71, No. 17, 2006 6483

Hatano et al.
extracted with ether (10 mL × 3) and washed by brine (10 mL).
The combined extracts were dried over MgSO4. The organic phase
was concentrated under reduced pressure, and the crude product
was purified by neutral silica gel column chromatography (eluent:
hexane/EtOAc or pentane/ether) to give the desired products. The
enantiomeric purity was determined by GC or HPLC on a chiral
column.
extracts were dried over MgSO4. The organic phase was concen-
trated under reduced pressure, and the crude product was purified
by neutral silica gel column chromatography (eluent: hexane/EtOAc
) 10/1) to give the desired product (100.1 mg, 82%). The
enantiomeric purity was determined by GC on chiral column (96%
1
ee). H NMR (300 MHz, CDCl3): δ 1.46 (d, J ) 6.6 Hz, 3H),
2.03 (br, 1H), 4.86 (q, J ) 6.6 Hz, 1H), 7.22-7.36 (m, 5H). 13C
NMR (75 MHz, CDCl3): δ 25.3 (CH3), 70.6 (CH), 125.4 (CH),
127.5 (CH), 128.5 (CH), 145.9 (C). IR (film): 3358, 2973, 1698,
1558, 1507, 1451, 1369, 1283, 1203, 1077, 1011, 899 cm-1. HRMS-
(FAB): calcd for C8H11O [M + H]+, 123.0810; found; 123.0809.
Chiral GC: CP-cyclodextrin-â-2,3,6-M-19 [110 °C, tR(R) ) 10.0
min, tR(S) ) 10.6 min].
1-Phenylpropanol (Table 1, entry 1; Table 2, entries 1-8; Table
3, entry 1). A solution of (R)-10 (16.6 mg, 0.03 mmol) in THF (3
mL) was stirred in a well-dried Pyrex Schlenk tube at room
temperature for 5 min under nitrogen atmosphere. To the solution
was added Et2Zn (1.35 mL of 1.10 M solution in toluene, 1.5 mmol)
at -78 °C. This solution was stirred for 30 min, and benzaldehyde
(106.1 mg, 1.0 mmol) was added. The resulting mixture was then
gradually warmed to room temperature and stirred for 24 h. After
hydrolysis with 10 mL of saturated NH4Cl aqueous solution, the
product was extracted with ether (10 mL × 3) and washed by brine
(10 mL). The combined extracts were dried over MgSO4. The
organic phase was concentrated under reduced pressure, and the
crude product was purified by neutral silica gel column chroma-
tography (eluent: hexane/EtOAc ) 10/1) to give the desired product
(133.4 mg, 98%). The enantiomeric purity was determined by GC
Typical Procedure for the Enantioselective Diphenylzinc
Addition to Aldehydes. A well-dried Pyrex Schlenk tube was
charged with diphenylzinc (43.9 mg, 0.20 mmol) at the room
temperature under nitrogen atmosphere. THF (2 mL) was added
followed by Et2Zn (18.2 µL of 1.10 M solution in toluene, 0.02
mmol). The mixture was stirred for 30 min, and then (R)-7 (13.7
mg, 0.02 mmol) was added. This solution was stirred for 30 min,
and then aldehyde (5) (0.20 mmol) was added. The resulting mixture
was stirred at room temperature for 24 h. After hydrolysis with 10
mL of saturated NH4Cl aqueous solution, the product was extracted
with ether (10 mL × 3) and washed by brine (10 mL). The
combined extracts were dried over MgSO4. The organic phase was
concentrated under reduced pressure, and the crude product was
purified by neutral silica gel column chromatography (eluent:
hexane/EtOAc) to give the desired products. The enantiomeric
purity was determined by GC or HPLC on chiral column.
(4-Chlorophenyl)(phenyl)methanol (Table 5, entries 1-4). A
well-dried Pyrex Schlenk tube was charged with diphenylzinc (43.9
mg, 0.20 mmol) at the room temperature under nitrogen atmosphere.
THF (2 mL) was added followed by Et2Zn (18.2 µL of 1.10 M
solution in toluene, 0.02 mmol). The mixture was stirred for 30
min, and then (R)-7 (13.7 mg, 0.02 mmol) was added. This solution
was stirred for 30 min, and then 4-chlorobenzaldehyde (28.1 mg,
0.20 mmol) was added. The resulting mixture was stirred at room
temperature for 24 h. After hydrolysis with 10 mL of saturated
NH4Cl aqueous solution, the product was extracted with ether (10
mL × 3) and washed by brine (10 mL). The combined extracts
were dried over MgSO4. The organic phase was concentrated under
reduced pressure, and the crude product was purified by neutral
silica gel column chromatography (eluent: hexane/EtOAc ) 10/
1), to give the desired product (41.9 mg, 96%). The enantiomeric
1
on chiral column (97% ee). H NMR (300 MHz, CDCl3): δ 0.91
(t, J ) 7.5 Hz, 3H), 1.69-1.77 (m, 2H), 2.24 (br, 1H), 4.56 (t, J
) 6.9 Hz, 1H), 7.25-7.38 (m, 5H). 13C NMR (75 MHz, CDCl3):
δ 10.2 (CH3), 31.9 (CH2), 75.9 (CH), 126.0 (CH), 127.5 (CH), 128.4
(CH), 144.7 (C). IR (film): 3360, 2963, 1492, 1454, 1377, 1200,
1097, 1013, 974 cm-1. HRMS(FAB): calcd for C9H13O [M + H]+,
137.0966; found, 137.0964. Chiral GC: CP-cyclodextrin-â-2,3,6-
M-19 [115 °C, tR(R) ) 13.3 min, tR(S) ) 13.7 min].
1-Phenylpentanol (Table 4, entry 1). A solution of (R)-10 (27.7
mg, 0.05 mmol) in THF (3 mL) was stirred in a well-dried Pyrex
Schlenk tube at room temperature for 5 min under nitrogen
atmosphere. To the solution was added n-Bu2Zn (2.00 mL of 1.00
M solution in heptane, 2.0 mmol) at -78 °C. This solution was
stirred for 30 min, and benzaldehyde (106.1 mg, 1.0 mmol) was
added. The resulting mixture was then gradually warmed to room
temperature and stirred for 24 h. After hydrolysis with 10 mL of
saturated NH4Cl aqueous solution, the product was extracted with
ether (10 mL × 3) and washed by brine (10 mL). The combined
extracts were dried over MgSO4. The organic phase was concen-
trated under reduced pressure, and the crude product was purified
by neutral silica gel column chromatography (eluent: hexane/EtOAc
) 10/1), to give the desired product (154.3 mg, 94%). The
enantiomeric purity was determined by HPLC on chiral column
1
purity was determined by HPLC on chiral column (88% ee). H
1
(96% ee). H NMR (300 MHz, CDCl3): δ 0.90 (t, J ) 7.5 Hz,
NMR (300 MHz, CDCl3): δ 2.69 (br, 1H), 5.78 (s, 1H), 7.18-
7.40 (m, 9H). 13C NMR (75 MHz, CDCl3): δ 75.6 (CH), 125.4
(CH), 126.6 (CH), 127.9 (CH), 128.6 (CH), 128.7 (CH), 133.3 (C),
142.3 (C), 143.5 (C). IR (KBr): 3358, 3026, 1485, 1453, 1402,
1346, 1189, 1082, 1071, 918 cm-1. HRMS(FAB): calcd for C13H12-
ClO [M + H]+, 219.0577; found, 219.0579. Chiral HPLC (OB-
H; hexane/IPA ) 9/1, 0.5 mL/min) [tR(R) ) 31.5 min, tR(S) )
49.5 min].
3H), 1.22-1.46 (m, 4H), 1.65-1.87 (m, 2H), 2.06 (br, 1H), 4.65
(t, J ) 6.9 Hz, 1H), 7.24-7.38 (m, 5H). 13C NMR (75 MHz,
CDCl3): δ 14.0 (CH3), 22.7 (CH2), 28.0 (CH2), 38.9 (CH2), 74.8
(CH), 126.0 (CH), 127.5 (CH), 128.5 (CH), 145.0 (CH). IR (film):
3360, 2956, 1492, 1455, 1377, 1107, 1041, 1108, 1071, 1044, 1011,
911 cm-1. HRMS(FAB): calcd for C11H17O [M + H]+, 165.1279;
found, 165.1274. Chiral HPLC (OB-H; hexane/IPA ) 80/1, 1 mL/
min) [tR(R) ) 18.4 min, tR(S) ) 13.9 min].
Acknowledgment. Financial support for this project was
provided by the JSPS. KAKENHI (Grant 15205021) and the
21st Century COE Program “Nature-Guided Materials Process-
ing” of MEXT.
1-Phenylethanol (Table 4, entry 8). A solution of (R)-10 (27.7
mg, 0.05 mmol) in THF (3 mL) was stirred in a well-dried Pyrex
Schlenk tube at room temperature for 5 min under nitrogen
atmosphere. To the solution was added Me2Zn (1.00 mL of 2.00
M solution in toluene, 2.0 mmol) at -78 °C. This solution was
stirred for 30 min, and benzaldehyde (106.1 mg, 1.0 mmol) was
added. The resulting mixture was then gradually warmed to room
temperature and stirred for 72 h. After hydrolysis with 10 mL of
saturated NH4Cl aqueous solution, the product was extracted with
ether (10 mL × 3) and washed by brine (10 mL). The combined
Supporting Information Available: General information,
1
characterization data, and copies of H and 13C NMR spectra for
ligands and products. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO060908T
6484 J. Org. Chem., Vol. 71, No. 17, 2006