Catalytic asymmetric allylation of aldehydes and related reactions with bis(((S)-binaphthoxy)(isopropoxy)titanium) oxide as a μ-oxo-type chiral Lewis acid

Article abstract of DOI:10.1002/chem.200305078

A new, chiral bis-Ti^IV of type 3 has been designed and can be utilized for strong activation of aldehyde carbonyls, thereby allowing a new catalytic enantioselective allylation of aldehydes with allyltributyltin. The chiral bis-Ti^IV catalyst (S,S)-3 can be readily prepared either by treatment of bis(triisopropoxy)titanium oxide with (S)-BINOL or by treatment of ((S)-binaphthoxy)isopropoxytitanium chloride with silver(I) oxide. Treatment of hydrocinnamaldehyde with allyltributyltin under the influence of chiral bis-Ti^IV oxide (S,S)-3 generated in situ (10 mol%) in CH ₂Cl₂ afforded an allylation product in 84% yield and with 99% ee. This asymmetric allylation with non-racemic bis-Ti^IV oxide 3 and partially resolved (S)-BINOL shows a positive nonlinear effect in correlation of the enantiopurity of the allylation product with the ee of the (S)-BINOL. Chiral bis-Ti^IV oxide (S,S)-3 can also be utilized for related reactions such as asymmetric methallylation and propargylation of aldehydes with high enantioselectivity. This asymmetric approach provides a very useful way of obtaining high reactivity and selectivity through the simple introduction of the M-O-M unit into the design of chiral Lewis acid catalysts.

Full text of DOI:10.1002/chem.200305078

FULL PAPER
Catalytic Asymmetric Allylation of Aldehydes and Related Reactions with
Bis(((S)-binaphthoxy)(isopropoxy)titanium) Oxide as a m-Oxo-Type Chiral
Lewis Acid
Hideo Hanawa,Daisuke Uraguchi,Shunsuke Konishi,Takuya Hashimoto,
and Keiji Maruoka*[a]
Abstract: A new, chiral bis-TiIV oxide of
type 3 has been designed and can be
utilized for strong activation of aldehyde
carbonyls, thereby allowing a new cata-
lytic enantioselective allylation of alde-
hydes with allyltributyltin. The chiral
bis-TiIV catalyst (S,S)-3 can be readily
prepared either by treatment of bis(trii-
sopropoxy)titaniumoxide with ( S)-BI-
NOL or by treatment of ((S)-binaph-
thoxy)isopropoxytitaniumchloride with
silver(i) oxide. Treatment of hydrocinna-
maldehyde with allyltributyltin under
the influence of chiral bis-TiIV oxide
(S,S)-3 generated in situ (10 mol%) in
CH2Cl2 afforded an allylation product in
84% yield and with 99% ee. This asym-
metric allylation with non-racemic bis-
TiIV oxide 3 and partially resolved (S)-
BINOL shows a positive nonlinear ef-
fect in correlation of the enantiopurity
of the allylation product with the ee of
the (S)-BINOL. Chiral bis-TiIV oxide
(S,S)-3 can also be utilized for related
reactions such as asymmetric methally-
lation and propargylation of aldehydes
with high enantioselectivity. This asym-
metric approach provides a very useful
way of obtaining high reactivity and
selectivity through the simple introduc-
À À
tion of the M O M unit into the design
Keywords: aldehydes ¥ allylation ¥
asymmetric synthesis ¥ Lewis acids ¥
titanium
of chiral Lewis acid catalysts.
Introduction
Asymmetric allylation of carbonyl compounds is currently an
important transformation in asymmetric synthesis, and a
number of chiral Lewis acids possessing various chiral
auxiliaries, in combination with allylsilane or allyltin com-
pounds, have been elaborated for this purpose.[1] Among
these, BINOL/TiIV complexes have been most extensively
studied as effective chiral Lewis acid catalysts in view of
several characteristics, including: 1) the commercial availabil-
ity of both optically pure BINOL and TiIV compounds, 2) the
easy generation of these TiIV complexes, and 3) their versa-
tility and general applicability in terms of substrates and
allylmetal compounds.[2] Indeed, catalytic asymmetric allyla-
tion of aldehydes and allyltributyltin can be effected by use of
BINOL/[Ti(OiPr)4] or BINOL/[TiCl2(OiPr)2] complexes
(Scheme 1), although the nature of these useful chiral
catalysts remains elusive.[3] By mixing (R)-BINOL and
[TiCl2(OiPr)2] in the presence of molecular sieves (4 ä) the
chiral TiIV m-oxo complex (R,R)-1 was obtained accidentally,
and shown to be an efficient catalyst for the glyoxylate ene
reaction.[4] In addition, Mikami and Corey disclosed that
Scheme 1. Asymmetric allylation of aldehydes with chiral (R)-BINOL/TiIV
complexes.
active catalysts, obtained by treatment of [((R)-binaphthoxy)-
Ti(OiPr)2] ((R)-2) with hydrated molecular sieves (4 ä),
might be chiral TiIV m-oxo clusters for effecting asymmetric
ene and Diels Alder reactions.[5] Other chiral TiIV m-oxo
clusters were also prepared by hydrolysis of (R)-2.[6] In this
context, we are interested in investigating the reactivity and
enantioselectivity of certain structurally defined, chiral TiIV m-
oxo complexes for the activation of the carbonyl moiety.
À À
Recently we reported that the Al O Al unit in MAO
(methylalumoxane) and bis(dimethylaluminium) oxide, as
effective Lewis acids, is crucially important for the strong
activation of carbonyl and epoxide oxygens.[7] This observa-
tion led us to design a new, chiral TiIV Lewis acid possessing
[a] Prof. K. Maruoka, H. Hanawa, D. Uraguchi, S. Konishi, T. Hashimoto
Department of Chemistry, Graduate School of Science
Kyoto University, Kyoto 606-8502 (Japan)
Fax : (‡81)75-753-4041
À À
E-mail: maruoka@kuchem.kyoto-u.ac.jp
the key M O M unit (M: metal) including a particular chiral
Chem. Eur. J. 2003, 9, 4405 4413
DOI: 10.1002/chem.200305078
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4405

K. Maruoka et al.
FULL PAPER
auxiliary. Accordingly, we prepared a new, binaphthoxyl-
modified bis-TiIV oxide of type 3 for the enantioselective
activation of carbonyl moieties. The reactivity and the chiral
efficiency of bis-TiIV oxide (S,S)-3 as a chiral Lewis acid were
examined by the use of the catalytic asymmetric allylation of
aldehydes with allyltributyltin, together with the analogous
methallylation and propargylation reactions (Scheme 2).[8]
and subsequently with Ag2O (Method B).[11] Positive ESI-
‡
MS clearly showed an m/z peak at 943 ([M ¥ 2THF‡H] ),
indicating the formation of the (S,S)-3 ¥ 2THF coordination
complex by comparison with the theoretical molecular ion
peak.[12]
À À
In addition, the formation of the Ti O Ti unit by Method-
s A and B was confirmed by treatment of cis-[TiCl2(h2-
guaiacolato)2] (2 equiv) with Ag2O (1 equiv) in CH2Cl2 to
furnish [Ti2(m-O)Cl2(h2-guaiacolato)4] 8, which is spectroscop-
ically identical with that produced by the reported procedure
with use of H2O (Scheme 5).[13] Thus, the Ag2O-mediated
approach seems to provide a simple, yet reliable method for
the controllable formation of the desired mono-m-oxo
[9f]
À À
Ti O Ti bridge.
Catalytic asymmetric allylation of aldehydes with chiral bis-
TiIV oxides: Treatment of hydrocinnamaldehyde 4 (R ˆ
CH2CH2Ph) with allyltributyltin (1.1 equiv) under the influ-
ence of chiral bis-TiIV oxide (S,S)-3 generated in situ
(10 mol%) [prepared by Method A] in CH2Cl2 at 08C for
4 h afforded 1-phenyl-5-hexen-3-ol (5, R ˆ CH2CH2Ph) in
84% yield and with 99% ee (see Scheme 2). The absolute
configuration of the homoallylic alcohol was determined to be
R by correlation to the authentic sample.[2b] The catalyst
loading can be reduced to 5 mol% with some reduction in the
chemical yield, which is improved by use of excess allyltribu-
tyltin (2 equiv). It should be noted that both the reaction rate
and the enantioselectivity of the allylation are greatly lowered
(e.g., 10% yield and 72% ee for hydrocinnamaldehyde) under
similar reaction conditions with a chiral mono-TiIV catalyst
(S)-2 (20 mol%).[14] Alternatively, chiral bis-TiIV oxide (S,S)-3,
prepared by Method B, exhibited reactivity and enantiose-
lectivity (81% yield with 98% ee) similar to that of the
catalyst prepared by Method A. Similar results were obtained
when using the supernatant solution of the chiral bis-TiIV
oxide 3 prepared by Method A or B after removal of the
precipitated AgCl. Moreover, attempted addition of AgCl to
chiral mono-TiIV catalyst (S)-2 also afforded a result com-
parable to those described above. Other examples are listed in
Table 1.
Scheme 2. Asymmetric transformation of aldehydes with chiral bis-TiIV
oxide (S,S)-3.
Results and Discussion
Preparation of mono-m-oxo-type chiral bis-TiIV complexes:
We first attempted to synthesize the requisite mono-m-oxo
À À
Ti O Ti structure by simple hydrolysis of triisopropoxytita-
niumchloride [( iPrO)3TiCl] or titanium(iv) tetraisopropoxide
[Ti(OiPr)4], which gave several reaction products.[9] However,
treatment of (iPrO)3TiCl (2 equiv.) with Ag2O (1 equiv) in
CH2Cl2 at room temperature (Scheme 3) with vigorous
Several characteristic features of this allylation follow:
1) The chiral bis-TiIV oxide (S,S)-3 exhibits uniformly high
asymmetric induction as well as high chemical yields.
Scheme 3. Production of bis(triisopropoxytitanium) oxide (iPrO)3Ti-
À
À
O Ti(OiPr)3.
À À
2) The incorporation of a mono-m-oxo Ti O Ti unit in the
chiral bis-TiIV catalyst (S,S)-3 strongly accelerates the rate
of allylation of aldehyde carbonyls relative to the corre-
sponding monoIV catalyst (R)-2 (Table 1, entries 6 and 8).
stirring and with exclusion of direct light resulted in clean
formation of bis(triisopropoxytitanium) oxide (iPrO)3Ti-
[10]
À À
O Ti(OiPr)3.
With this information to
hand, the requisite binaph-
thoxy-modified bis-TiIV oxide
(S,S)-3 was prepared by initial
treatment of [(iPrO)3TiCl] with
Ag2O as described above, and
subsequent addition of (S)-BI-
NOL (Scheme 4; Method A).
The same bis-TiIV oxide (S,S)-3
was also synthesized by treat-
ment of [(iPrO)3TiCl] with (S)-
Scheme 4. Preparation of chiral bis-TiIV oxide (S,S)-3 by methods A or B.
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BINOL (2 equiv) in CH2Cl2
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Chem. Eur. J. 2003, 9, 4405 4413

Catalytic Asymmetric Allylations
4405 4413
lation step was achieved by
Brown×s method.[17] This proce-
dure required stoichiometric
amount of chiral boron reagent
(1.39 equiv (À)-DIPCl) and
Scheme 5. Preparation of [Ti2(m-O)Cl2(h2-guaiacolato)4] (8).
gave a less satisfactory result
(76% yield and 90% ee). In
contrast, treatment of 3,4-diac-
Table 1. Asymmetric allylation of aldehydes with allyltributyltin catalyzed
etoxybenzaldehyde with allyltributyltin (1.1 equiv) in the
presence of catalytic (S,S)-3 (10 mol%) at 08C for 16 h
afforded the desired homoallylic alcohol 11 in 96% yield and
with 98% ee (Scheme 6). Hence, our method was apparently
far superior in terms of catalyst loading, chemical yield, and
enantioselectivity.
by chiral bis-TiIV oxide (S,S)-3.[a]
Aldehyde
Ti catalyst
[mol%][b]
Reaction
time [h]
Yield
[%]
ee[%][c]
(config)[d]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
PhCH2CH2CHO
(S,S)-3 (10)
(S,S)-3 (10)[e]
(S,S)-3 (10)
(S,S)-3 (5)
(S,S)-3 (5)
(S)-2 (20)
(S,S)-3 (10)
(S)-2 (20)
(S,S)-3 (5)
(S,S)-3 (5)
(S,S)-3 (10)
(S)-2 (20)
(S,S)-3 (10)
(S,S)-3 (10)
(S)-2 (20)
(S,S)-3 (10)
(S)-2 (20)
(S,S)-3 (10)[e]
(S,S)-3 (10)
(S,S)-3 (5)
(S,S)-3 (10)
4
4
16[f]
12
7[g]
4
12
12
24
12[g]
28
28
18[g]
15
15
7
84
81
82
77
95
10
85
14
86
92
71
7
91
70
10
90
12
85
81
94
85
99 (R)
98 (R)
98 (R)
98 (R)
98 (R)
72 (R)
99 (R)[h]
81 (R)[h]
99 (R)[h]
98 (R)[h]
> 99 (S)[i]
85 (S)[i]
99 (S)[i]
95 (S)
83 (S)
96 (S)
73 (S)
96 (S)
96 (S)
97 (S)
98 (S)
CH3(CH2)6CHO
(CH3)2CHCHO
ˆ
PhCH CHCHO
PhCHO
7
7
24[f]
9[g]
15
p-bromo-
benzaldehyde
22
23
24
(S)-2 (20)
(S,S)-3 (10)
(S)-2 (20)
15
18
18
15
96
26
83 (S)
97 (S)
85 (S)
Scheme 6. Synthesis of chiral tetrahydropyrans 9 and 10 through asym-
metric allylation of 3,4-diacetoxyaldehyde with chiral bis-TiIV oxide (S,S)-3.
furfural
[a] Unless otherwise noted, the reaction of aldehyde and Bu3SnCH2-
CH CH2 (1.1 equiv) was carried out in the presence of chiral bis-TiIV oxide
ˆ
Catalytic asymmetric methallylation of aldehydes with chiral
bis-TiIV oxides: We also utilized chiral bis-TiIV oxide (S,S)-3 for
the catalytic asymmetric methallylation of aldehydes.[8b] The
enantioselective methallylation of prochiral aldehydes is an
important asymmetric transformation in organic synthesis,[1]
subsequent oxidative cleavage of the methallyl moiety
providing optically active aldol products equivalent to those
of an asymmetric crossed aldol reaction between aldehydes
and the enolate of acetone (Scheme 7).
(S,S)-3 or chiral mono-TiIV (S)-2 in CH2Cl2 at 08C with the given reaction
time. [b] Unless specified, chiral bis-TiIV oxide (S,S)-3 was prepared by
Method A. [c] Determined by HPLC analysis with Chiralcel OD and OJ.
[d] Determined by comparison of the sign of optical rotation with reported
values. See [2l]. [e] Prepared by method B. [f] At À158C. [g] Use of two
equivalents of allyltributyltin. [h] Determined by GC analysis on a chiral
column (Chrompack CP-CHIRASIL-DEX CB). [i] Determined by GC
analysis (Chrompack CP-CHIRASIL-DEX CB column) after conversion
into its benzoate.
3) The enantioselectivity of this allylation is not sensitive to
the reaction temperature (Table 1, entries 1 versus 3 and 16
versus 19).
4) The amount of chiral bis-TiIV oxide (S,S)-3 can be reduced
to 5 mol% without affecting the enantioselectivity (Ta-
ble 1, entries 4, 5, 9, 10, and 20).
Scheme 7. Synthetic approach to chiral aldols through asymmetric meth-
allylation of aldehydes with chiral bis-TiIV oxide (S,S)-3.
Application to natural products synthesis: Allylation prod-
ucts of aldehydes are useful intermediates for natural product
syntheses.[1g] For example, Willis et al. recently reported the
syntheses of tetrahydropyrans 9 and 10,[15] starting from3,4-
diacetoxybenzaldehyde as shown in Scheme 6. These com-
pounds, isolated fromextracts of Plectranthus sylvestris
(Labiatae), are potent in vitro antioxidants, inhibiting the
Fe2‡-catalyzed autooxidation of linoleic acid, and also possess
anti-inflammatory properties.[16] The crucial asymmetric ally-
In contrast to the numerous examples of catalytic asym-
metric allylation of prochiral aldehydes with allyltributyltin,[2]
the corresponding asymmetric methallylation is rather diffi-
cult.[18] Indeed, compared to the allylic system, both reactivity
and enantioselectivity in the catalytic asymmetric methally-
lation with ordinary chiral Lewis acid catalysts and methallyl-
tributyltin were somewhat low, and did not exhibit broad
applicability. In addition, such transformations required
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K. Maruoka et al.
FULL PAPER
longer reaction times at low temperatures. For example,
catalytic asymmetric methallylation of cinnamaldehyde with
BINOL-TiIV complex at À208C for 12 h gave a 68% yield
with 87% ee,[18a] while catalytic asymmetric methallylation of
hydrocinnamaldehyde with BINAP-AgOTf complex at
À208C for 8 h afforded a 22% yield with 70% ee.[18f]
Table 3. Dilution effect of aldehyde substrate on the asymmetric meth-
allylation of aldehydes with methallyltributyltin catalyzed by chiral bis-TiIV
oxide (S,S)-3.[a]
Aldehyde
Concentration
reaction
Yield ee [%][b]
of substrate [m] condition
[8C, h]
[%]
(config)
1
2
3
4
5
6
7
PhCH2CH2CHO 1.33
À 20, 2
76
76
82 (R)
93 (R)
94 (R)
94 (R)
96 (R)
94 (S)
96 (S)
Treatment of hydrocinnamaldehyde 4 (R ˆ CH2CH2Ph)
with methallyltributyltin (1.1 equiv) under the influence of
chiral bis-TiIV oxide (S,S)-3 generated in situ (10 mol%) in
CH2Cl2 at 08C for 30 min afforded 5-methyl-1-phenyl-5-
hexen-3-ol 6 (R ˆ CH2CH2Ph) in 63% yield with 94% ee.
The absolute configuration of the homomethallylic alcohol
was determined to be R by correlation with the authentic
sample.[18a] It should be noted that both the reaction rate and
the enantioselectivity of the methallylation are greatly
lowered (e.g., 13% and 47% ee for hydrocinnamaldehyde)
under similar reaction conditions with a chiral mono-TiIV
catalyst (S)-2 (20 mol%), derived from [Ti(OiPr)4] and (S)-
BINOL by the literature procedure.[13]
0.67
0.33
0.17
0.083
0, 2
0, 0.75 80
0, 2
0, 5
0, 2
0, 11
73
77
90
90
ˆ
PhCH CHCHO 0.33
0.083
ˆ
[a] The reaction between aldehyde and Bu3SnCH2C(Me) CH2 (1.1 equiv)
was carried out in the presence of chiral bis-TiIV oxide (S,S)-3 (10 mol%) in
CH2Cl2 under the given reaction conditions. [b] Determined by HPLC
analysis on Chiralcel OD, OD-H, and OB-H.
Catalytic asymmetric propargylation of aldehydes with chiral
bis-TiIV oxides: Catalytic asymmetric propargylation of pro-
chiral aldehydes is also a valuable transformation, and the
resulting homopropargylic alcohols are readily converted into
the aldol products upon hydrolysis (Scheme 8). However,
there have been few reports on catalytic asymmetric synthesis
Other selected examples are listed in Table 2. Several
characteristic features of this methallylation follow:
Table 2. Asymmetric methallylation of aldehydes with methallyltributyltin cata-
lyzed by chiral bis-TiIV oxide (S,S)-3.[a]
Aldehyde
Ti catalyst
[mol%]
Reaction
time [h]
Yield
[%]
ee[%][b]
(config)[c]
1
2
3
4
5
6
7
8
9
PhCH2CH2CHO
(S,S)-3 (10)
(S)-2 (20)
(S,S)-3 (10)
(S)-2 (20)
(S,S)-3 (10)
(S)-2 (20)
(S,S)-3 (10)
(S)-2 (20)
(S,S)-3 (10)
0.5
0.5
2
63
13
90
32
94
31
88
45
87
94 (R)
47 (R)
94 (S)
85 (S)
95 (S)
72 (S)
91 (S)
79 (S)
92
ˆ
PhCH CHCHO
2
PhCHO
0.5
0.5
2
2
20
Scheme 8. Synthetic approach to chiral aldols through asymmetric prop-
argylation of aldehydes with chiral bis-TiIV oxide (S,S)-3.
furfural
CH3(CH2)6CHO
of homopropargylic alcohols from prochiral aldehydes by use
[a] Unless otherwise noted, the reaction between aldehyde (0.33m) and of allenyltributyltin,[19] presumably due to its low reactivity
and regiochemical problems. An ordinary BINOL-TiIV com-
ˆ
Bu3SnCH2C(Me) CH2 (1.1 equiv) was carried out in the presence of chiral bis-
TiIV oxide (S,S)-3 or chiral mono-TiIV (S)-2 in CH2Cl2 at 08C for the given reaction
plex for catalytic asymmetric propargylation required 50 or
time. [b] Determined by HPLC analysis on Chiralcel OD, OD-H and OB-H.
100 mol% catalyst and very long reaction times (72 or
100 h).[19a] Recently, Yu et al. reported an improved method
[c] Determined by comparison of the sign of optical rotation with reported values.
See ref. [18a].
by the addition of a stoichiometric amount of Et2BSiPr as a
synergetic accelerator.[19b,c]
We also succeeded in carrying out asymmetric propargyla-
1) The chiral bis-TiIV oxide (S,S)-3 is applicable to various
types of aldehydes and exhibits uniformly high asymmetric
induction as well as high chemical yields.
tion through the use of a catalytic amount of chiral bis-TiIV
oxide (S,S)-3.[8b] With 10 20 mol% catalyst and longer
reaction times, our method afforded the desired homopro-
pargyl alcohol 7 in moderate yield and with high enantiose-
lectivity, accompanied by a small amount of allenyl alcohol 12,
as indicated in Table 4.
IV
À À
2) The incorporation of the Ti O Ti unit in the chiral bis-Ti
catalyst (S,S)-3 strongly accelerates the rate of methally-
lation of aldehyde carbonyls compared to the correspond-
ing mono-TiIV catalyst (S)-2.
Nonlinear effect with chiral bis-TiIV oxides: Nonlinear behav-
ior in asymmetric catalysis is typically reported as product
enantioselectivity (eeprod) versus catalyst enantiomeric excess
3) The absolute configuration of the homomethallylic alcohol
5 is predictable based on the use of either (S,S)-3 or (R,R)-
3.
In the asymmetric methallylation of aldehydes with (S,S)-3,
we found some effect of the concentration of the solvent.
Selected results are summarized in Table 3, which clearly
shows a high-dilution effect in correlation of the enantiopurity
(eecat), where a positive deviation fromthe linear relationship
[20]
is termed an asymmetric amplification of eeprod
.
Non-
enantiopure chiral auxiliaries may be worthy of consideration
in stoichiometric or catalytic enantioselective synthesis when
they are associated with an asymmetric amplification.[21]
ˆ
of methallylation products 6 (R ˆ CH2CH2Ph, CH CHPh).
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Chem. Eur. J. 2003, 9, 4405 4413

Catalytic Asymmetric Allylations
4405 4413
Table 4. Asymmetric propargylation of aldehydes with allenyltributyltin cata-
lyzed by chiral bis-TiIV oxide (S,S)-3.[a]
Table 5. Chiral Amplification in asymmetric allylation catalyzed by non-
racemic bis-TiIV oxide 3.[a]
Aldehyde
Ti catalyst
(mol%)
Reaction
time [h]
Yield
[%]
ee[%][c]
ee[%] of 3[b]
Method C[c]
Yield [%]
Method D[c]
Yield[%]
ee[%][d]
(config)[d]
ee[%][d]
(ratio)[b]
0
38
50
63
69
84
0
64
87
96
99
70
74
75
75
84
3
23
52
75
99
1
2
PhCH2CH2CHO
PhCHO
(S,S)-3 (10)
0, 18
0, 18
25, 6
0, 18
0, 18
25, 6
50 (10:1)
64 (15:1)
92 (R)
92 (R)
25
50
75
100
(S,S)-3 (10)[e]
3
4
(S,S)-3 (10)
(S,S)-3 (20)[e]
28 (10:1)
69 (10:1)
95 (S)
92 (S)
[a] Reaction between aldehyde 4 (R ˆ CH2CH2Ph) (0.33m) and allyltribu-
tyltin (1.1 equiv) was carried out in the presence of non-racemic bis-TiIV
oxide 3 (10 mol%) in CH2Cl2 at 08C for 4 h. [b] In the non-racemic
BINOL, (S)-BINOL was in excess. [c] See Experimental Section for
methods C and D. [d] Determined by HPLC analysis on Chiralcel OD.
[a] Unless otherwise noted, the reaction between aldehyde (0.33m) and
Bu3SnCH C CH2 (1.1 equiv) was carried out in the presence of chiral bis-TiIV
ˆ ˆ
oxide (S,S)-3 in CH2Cl2 under the given reaction conditions. [b] Isomeric ratio of
homopropargyl alcohol 7 and allenyl alcohol 12. [c] Determined for major 7 by
HPLC analysis on Chiralcel OD, OD-H, and AD-H. [d] Determined by compar-
ison of the sign of optical rotation with reported values. See [19b]. [e] Use of
ˆ ˆ
excess Bu3SnCH C CH2 (3 equiv).
derived fromoptically pure ( S)-BINOL is ca. 4 times greater
than that of heterochiral (S,R)-3 derived from rac-BINOL
under the same reaction conditions (Figure 3).
When we used partially resolved (S)-BINOL as chiral
auxiliary for the preparation of non-racemic bis-TiIV oxide 3
(Method C), we observed a positive nonlinear effect in
correlation of the enantiopurity of allylation product 5 (R ˆ
CH2CH2Ph) with the ee of (S)-BINOL, as shown in Table 5
and Figure 1. With such partially resolved (S)-BINOL, three
kinds of bis-TiIV oxides exist: major (S,S)-3, minor (S,R)-3, and
very minor (R,R)-3 (Scheme 9). The big difference in the
(S,S)-3/(R,R)-3 catalyst ratio is assumed to be the reason for
the positive nonlinear effect observed in these asymmetric
allylation reactions. In marked contrast, however, optically
pure bis-TiIV oxides (S,S)-3 and (R,R)-3 were prepared
independently by starting fromoptically pure ( S)- and (R)-
BINOL, and asymmetric allylation by mixing them in a
different ratio with the condition that (S,S)-3 > (R,R)-3
(Method D) gave rise to product 5 (R ˆ CH2CH2Ph) in rather
high yield without any chiral amplification (Table 5 and
Figure 2). These results imply the following important points:
Figure 1. Reactivity and selectivity profile of chiral bis-TiIV oxide prepared
by method C.
1) Symmetric
(S,S)-3
and
(R,R)-3 are more reactive
than meso-(S,R)-3 catalyst.
2) Bis-TiIV oxide 3 exists in
solution as
a monomeric
species rather than as a di-
meric one,[22]
3) Bis-TiIV oxide 3 is coordina-
tively stable, and no scram-
bling between (S,S)-3 and
(R,R)-3 was observed under
these allylation conditions.
Kinetic information may also
help in the development of
efficient synthetic strategies us-
ing non-enantiopure systems.
Accordingly, we performed ki-
netic studies of these TiIV cata-
lysts for the asymmetric allyla-
tion of hydrocinnamaldehyde.
As expected, the catalytic ac-
tivity of the homochiral (S,S)-3
Scheme 9. Preparation of non-racemic bis-TiIV oxide (S,S)-3 by methods C or D.
www.chemeurj.org ¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2003, 9, 4405 4413
4409

K. Maruoka et al.
FULL PAPER
philic activation of the pyrone carbonyl by (S,S)-3. Further-
more, addition of one more equivalent of 2,6-dimethyl-g-
pyrone to the 1:1 pyrone/(S,S)-3 complex produced 13C NMR
chemical shifts at d ˆ 166.22 ppm. Hence, two pyrone carbon-
yls coordinate separately to two TiIV centers of (S,S)-3 in the
2:1 pyrone/(S,S)-3 mixture.
Elucidation of possible reaction pathways: Several possible
reaction pathways to account for the activation phenomenon
with chiral bis-TiIV oxide 3 have been considered. First, chiral
bis-TiIV oxide (S,S)-3 might exist as an equilibrium mixture of
(S)-binaphthoxytitaniumoxide ( S)-13[23] and (S)-binaphthox-
ytitaniumdiisopropoxide ( S)-2.[13] However, this possibility
has been excluded by independent preparation of (S)-13 and
(S)-2, and subsequent carrying out of the asymmetric
allylation of hydrocinnamaldehyde with allyltributyltin in
the presence of a mixture of (S)-13 and (S)-2 (each 10 mol%)
at 08C for 4 h to furnish homoallylic alcohol 5 (R ˆ
CH2CH2Ph) in 31% yield and with 88% ee. Since the use
solely of (S)-13 gave product 5 (R ˆ CH2CH2Ph) in 20% yield
with 5% ee, mixing of (S)-13 and (S)-2 seems partially to
generate bis-TiIV oxide (S,S)-3. Indeed, on heating a mixture
of (S)-13 and (S)-2 at reflux in CH2Cl2 for 3 h, we observed
higher reactivity and selectivity (78% yield with 94% ee) in
this allylation under similar conditions (Scheme 10).
Figure 2. Reactivity and selectivity profile of chiral bis-TiIV oxide prepared
by method D.
It should be noted that (S)-binaphthoxytitanium m-oxo
complex (S,S)-1 showed only low reactivity and selectivity
under similar allylation condition (14%, 25% ee).[4] In
addition, Keck×s mono-TiIV reagent (20 mol%) derived from
[Ti(OiPr)4] (20 mol%) and (S)-BINOL (40 mol%) was also
examined for the asymmetric allylation of hydrocinnamalde-
hyde (53% yield (93% ee) at 08C for 4 h), again excluding the
possibility of the generation of Keck×s reagent by Methods A
or B.[2d, 18b] Therefore, the high reactivity and selectivity of the
chiral bis-TiIV oxide (S,S)-3 might be attributable to the
intramolecular coordination of one isopropoxy oxygen to the
other titanium, thereby enhancing the otherwise weak Lewis
acidity of the original titanium(iv) center for the carbonyl
activation as shown in 14. Alternatively, a carbonyl oxygen
atommay coordinate simultaneously to two Ti centers as an
intermediate or as a dynamic species, thereby producing
strong activation of aldehyde carbonyls, such as depicted in
Figure 3. Catalytic activity of homochiral (S,S)-3 vs. heterochiral (S,R)-3.
NMR study of carbonyl/TiIV Lewis acid complexes: The high
reactivity of chiral TiIV complex (S,S)-3 toward aldehyde
carbonyls is attributed to the strong coordination of the
À À
mono-m-oxo Ti O Ti structure to a carbonyl oxygen atom,
thereby allowing strong activation of the aldehyde carbonyls.
Such activation is also observed by 13C NMR spectroscopy
with 2,6-dimethyl-g-pyrone as carbonyl substrate. Thus,
75 MHz 13C NMR examination of the 1:1 2,6-dimethyl-g-
pyrone/mono-TiIV 2 complex in
15.[20, 24] In both cases, the mono-m-oxo Ti O Ti bridge plays a
À À
key role in the activation of aldehyde carbonyl.
CDCl3 at 208C showed that the
original signal of the b-carbon
atoms of the free pyrone at d ˆ
165.41 ppmshifted only slightly,
to d ˆ 166.07 ppm, suggesting
feeble Lewis acidity of 2. In
contrast, the 1:1 2,6-dimethyl-g-
pyrone/(S,S)-3 chelation com-
plex under similar conditions
shows a further downfield shift
for the b-carbon atoms of the
pyrone (d ˆ 167.90 ppm). This
Scheme 10. Apparent partial generation of bis-TiIV oxide (S,S)-3 by mixing of (S)-13 and (S)-2.
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.chemeurj.org Chem. Eur. J. 2003, 9, 4405 4413
result implies strong electro-
4410

Catalytic Asymmetric Allylations
4405 4413
3 mmol) in CH2Cl2 (25 mL). After stirring for 1 h at that temperature, the
reaction mixture was azeotroped until the volume of the solution had been
reduced to 10 mL. Further concentration was continued under reduced
pressure. The resulting orange residue was dissolved in diethyl ether
(20 mL) and allowed to stand for several hours at 08C. The resulting
needle-crystalline material was decanted and the supernatant solution was
removed by syringe. The ether solvent was removed under reduced
pressure to give ((S)-binaphthoxy)Ti(OiPr)2 (S)-2 (2.0 g, 4.3 mmol, 72%)
as yellowish orange crystals: 1H NMR (CD2Cl2): d ˆ 7.93 (d, J ˆ 8.1 Hz, 2H;
À
À
Ar H), 7.54 (d, J ˆ 8.7 Hz, 2H; Ar H), 7.40 (ddd, J ˆ 3.1, 4.9, 8.1 Hz, 2H;
À
À
À
Ar H), 7.14 7.24 (m, 4H; Ar H), 6.79 (d, J ˆ 8.7 Hz, 2H; Ar H), 4.55
Conclusion
À
(sept, J ˆ 6.0 Hz, 2H; O CH), 1.15 (d, J ˆ 6.0 Hz, 6H; CH3), 1.09 (d, J ˆ
6.0 Hz, 6H; CH3) ppm; 13C NMR (CD2Cl2): d ˆ 158.75, 132.80, 129.88,
In conclusion, a new chiral bis-TiIV complex (S,S)-3 has been
designed and can be utilized for the precise enantiofacial
discrimination of aldehyde carbonyls for a new catalytic,
practical, and enantioselective allylation of aldehydes with
allyltributyltin and for similar reactions. This asymmetric
approach provides a very useful way of obtaining high
reactivity and selectivity by the simple incorporation of the
128.90, 127.96, 126.35, 125.27, 123.17, 120.96, 118.57, 80.84, 25.02, 24.79 ppm.
ESI-MS analysis of chiral bis-TiIV oxide (S,S)-3: [Ti(OiPr)4] (88 mL,
0.3 mmol) was added under argon at 08C to a stirred solution of TiCl4
(0.1 mmol) in CH2Cl2 (2 mL), and the mixture was then allowed to warm to
roomtemperature. After 1 h, Ag 2O (46.4 mg, 0.2 mmol) was added at room
temperature, and the mixture was stirred for 5 h with exclusion of direct
light. The mixture was diluted with CH2Cl2 (4 mL), and treated at room
temperature with (S)-BINOL (114.5 mg, 0.4 mmol) for 2 h to furnish chiral
bis-TiIV oxide (S,S)-3 in CH2Cl2. This mixture was filtered to remove AgCl,
and THF (2 mL) was then added to the resulting CH2Cl2 solution at room
temperature. An electrospray ionization mass spectrum (ESI-MS) was
recorded on an Applied Biosystems Mariner ESI-TOF mass spectrometer.
Experimental conditions were as follows: direct infusion by syringe pump;
sample concentration, 50 mm in CH3CN; flow rate, 5 mLminÀ1; nebulizing
gas, N2; spray tip voltage, 3.5 kV; API interface nozzle potential, 80 V; API
interface quad RF voltage, 300 V; API interface nozzle temperature, 808C;
À À
M O M unit into the design of chiral Lewis acid catalysts.
Experimental Section
General: For thin layer chromatography (TLC) analysis, Merck precoated
TLC plates (silica gel 60 GF254, 0.25 mm) were used throughout this work.
The products were purified by preparative column chromatography on
silica gel 60 (Merck 1.09385.9025, 230 400 mesh). Infrared (IR) spectra
were recorded on a Shimadzu FT-IR 8200A spectrometer. 1H NMR spectra
were measured on a JEOL JNM-FX400 (400 MHz) spectrometer. Chem-
‡
‡
found: 943 [M‡2THF‡H] ; [C54H55O9Ti2] calcd 943.
Synthesis of [Ti2(m-O)Cl2(h2-guaiacolato)4] (8) with Ag2O: 2-Methoxyphe-
nol (660 mL, 6 mmol) was added under argon at room temperature to a
stirred solution of TiCl4 (329 mL, 3 mmol) in toluene (20 mL). After 24 h,
the solution was concentrated to about 12 mL, and the reddish-brown
precipitate was filtered off, washed with toluene, and dried under vacuum.
Recrystallization fromtoluene afforded cis-[TiCl2(h2-guaiacolato)2];[13]
1
ical shifts of H NMR spectra were reported relative to tetramethylsilane
(d ˆ 0 ppm). Splitting patterns were designated as follows: s, singlet; d,
doublet; t, triplet; q, quartet; m, multiplet; br, broad. 13C NMR spectra
were measured on a JEOL JNM-FX400 (100 MHz) spectrometer. Chem-
ical shifts of 13C NMR spectra were reported relative to CDCl3 (d ˆ 77.0).
Analytical high performance liquid chromatography (HPLC) was per-
formed on a Shimadzu LC-10A instrument with columns of Daicel
Chiralcel OD, OJ, OD-H, OB-H, and AD-H (l ˆ 210 or 254 nm).
Analytical gas liquid phase chromatography (GC) was performed on a
Shimadzu Model 14B instrument with a flame-ionization detector and a
capillary column (Chrompack CP-Chirasil-Dex CB). Optical rotations
were measured on a JASCO DIP-1000 digital polarimeter. Electrospray
ionization mass spectra (ESI-MS) were recorded on an Applied Biosystems
Mariner ESI-TOF Mass spectrometer.
1H NMR (400 MHz, CDCl3): d ˆ 7.39 7.26 (m, 5H; Ph H), 5.89 5.75
À
À
ˆ
ˆ
(m, 1H; C CH C), 5.22 5.13 (m, 2H; C CH2), 4.77 4.72 (m, 1H;
À
À ˆ
O CH), 2.60 2.45 (m, 2H; CH2 C C), 2.02 ppm(d, J ˆ 3.3 Hz, 1H; OH).
Ag2O (46.4 mg, 0.2 mmol) was added at room temperature to a stirred
solution of cis-[TiCl2(h2-guaiacolato)2] (146.0 mg, 0.4 mmol) in freshly
distilled CH2Cl2 (5 mL), and the mixture was stirred for 5 h with exclusion
of direct light. After removal of AgCl by filtration, the red solution was
concentrated under vacuum. The residue was dissolved in CDCl3. The
solution was then transferred by cannula to a NMR tube, which was capped
with a rubber septumand filled with argon. The 1H NMR spectrumwas
recorded at roomtemperature, and was spectroscopically identical with
that of [Ti2(m-O)Cl2(h2-guaiacolato)4] (8) prepared by the reported
procedure by use of H2O;[13] 1H NMR (400 MHz, C6D6): d ˆ 6.84 (m, 4H;
4 Â 4-HAr), 6.61 (m, 8H; 4 Â 3,6-HAr), 6.14 (m, 4H; 4 Â 5-HAr), 3.42 ppm
(s, 12H; 4 Â OCH3).
All experimental work was carried out under an atmosphere of argon.
CH2Cl2 was freshly distilled fromcalciumhydride. Toluene was freshly
distilled fromsodiummetal. THF was freshly distilled fromsodium
benzophenone ketyl. Aldehydes were distilled under reduced pressure.
Other simple chemicals were purchased and used as such.
Synthesis of chiral bis-TiIV oxide (S,S)-3 by Method A: Dried [Ti(OiPr)4]
(88 mL, 0.3 mmol) was added under argon at 08C to a stirred solution of
TiCl4 (0.1 mmol) in CH2Cl2 (2 mL). The solution was allowed to warm to
roomtemperature. After 1 h, silver( i) oxide (46.4 mg, 0.2 mmol) was added
at room temperature, and the whole mixture was stirred for 5 h with
exclusion of direct light. The mixture was diluted with CH2Cl2 (4 mL), and
treated with (S)-BINOL (114.5 mg, 0.4 mmol) at room temperature for 2 h
to furnish chiral bis-TiIV oxide (S,S)-3 in CH2Cl2 solvent.
Synthesis of chiral bis-TiIV oxide (S,S)-3 by method B: Dried [Ti(OiPr)4]
(88 mL, 0.3 mmol) was added under argon at 08C to a stirred solution of
TiCl4 (0.1 mmol) in CH2Cl2 (2 mL). The solution was allowed to warm to
roomtemperature. After 1 h, ( S)-BINOL (114.5 mg, 0.4 mmol) was added
at room temperature, and the solution was stirred for 2 h. The mixture was
cooled to 08C, and treated at 08C with silver(i) oxide (46.4 mg, 0.2 mmol).
The mixture was allowed to warm to room temperature, and stirred for 5 h
with exclusion of direct light to furnish chiral bis-TiIV oxide (S,S)-3, which
was diluted with CH2Cl2 (4 mL) before use.
Representative procedure for asymmetric allylation of aldehydes (by
method A): Compound (S,S)-3 (0.2 mmol) [prepared by Method A],
generated in situ in CH2Cl2 (6 mL), was cooled to À158C, and treated
sequentially at À158C with hydrocinnamaldehyde (263 mL, 2.0 mmol) and
allyltributyltin (682 mL, 2.2 mmol). The mixture was allowed to warm to
08C and stirred for 4 h. The reaction mixture was quenched with saturated
NaHCO3, and extracted with ether. The organic extracts were dried over
Na2SO4. Evaporation of solvents and purification of the residue by column
chromatography on silica gel (ether/hexane 1:4 as eluent) gave (R)-1-
phenyl-5-hexen-3-ol 5 (R ˆ CH2CH2Ph) as a colorless oil (296.1 mg, 84%
yield): 1H NMR (CDCl3): d ˆ 7.32 7.17 (m, 5H; Ar H) , 5.81 (m, 1H;
À
À
ˆ
ˆ
À
C CH C), 5.14 (dd, J ˆ 1.2, 13.2 Hz, 2H; C CH2), 3.68 (m, 1H; O CH),
À ˆ
2.81 (m, 1H; PhCH2), 2.69 (m, 1H; PhCH2), 2.32 (m, 1H; CH2 C C), 2.18
À ˆ
À À
(m, 1H; CH2 C C), 1.80 (m, 2H; Ph C CH2), 1.61 (d, J ˆ 4.4 Hz, 1H;
OH) ppm. The absolute configuration and enantiomeric purity of the
product were determined as R and 99% ee by analytical HPLC analysis
[Daicel Chiralcel OD, iPrOH/hexane 1:20, flow rate ˆ 0.5 mLminÀ1, tR ˆ
18.86 min (S isomer), tR ˆ 29.17 min (R isomer)] by comparison with the
racemic and authentic samples.
((S)-Binaphthoxy)Ti(OiPr)2 (S)-2: Dried [Ti(OiPr)4] (886 mL, 3 mmol) was
added at roomtemperature to a suspension of dried ( S)-BINOL (858 mg,
Chem. Eur. J. 2003, 9, 4405 4413
www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4411

K. Maruoka et al.
FULL PAPER
Asymmetric allylation of 3,4-diacetoxybenzaldehyde: A solution of chiral
bis-TiIV oxide (S,S)-3 (prepared by Method A) was cooled to À158C, and
treated sequentially at À158C with 3,4-diacetoxybenzaldehyde (2 mmol)
and allyltributyltin (682 mL, 2.2 mmol). The mixture was allowed to warm
to 08C and stirred for 16 h. The reaction mixture was quenched with
saturated NaHCO3, and extracted with ether. The organic extracts were
dried over Na2SO4. Evaporation of solvents and purification of the residue
by column chromatography on silica gel (EtOAc/hexane 1:3) gave (S)-1-
and they were mixed in different ratios [(S,S)-3 (y mmol) and (R,R)-3
(z mmol), y ‡ z ˆ 0.4, ˆ 250(y À z)] before the asymmetric allylation.
General procedure for kinetic studies: A solution of chiral TiVI catalyst
(prepared in CDCl3 by Method A, 0.1 or 0.2 mmol) was cooled to À158C,
and was treated sequentially at À158C with aldehyde (1 mmol) and
allyltributyltin (341 mL, 1.1 mmol). The resulting solution was transferred
by cannula to a NMR tube capped with a rubber septum, placed under
argon, and cooled to 08C, and the 1H NMR spectrumwas recorded at 0 8C.
(3,4-diacetoxyphenyl)-3-buten-1-ol
5
(R ˆ 3,4-diacetoxyphenyl)[15] as
a
General procedure for NMR studies on the 1:1 Lewis acid carbonyl
complexes: 2,6-Dimethyl-g-pyrone (47.2 mg, 0.38 mmol) was added at
roomtemperature under argon to a solution of ( S,S)-3 (0.4 mmol, prepared
by Method A) in degassed CDCl3 (1.5 mL). After being stirred for 0.5 h at
that temperature, the resultant solution was transferred by cannula to a
NMR tube, which was capped with a rubber septumand filled with argon.
colorless oil (499.6 mg, 95% yield): [a]2D2 ˆ À35.5 (c ˆ 1.25 in CHCl3);
1H NMR (CDCl3): d ˆ 7.26 7.15 (m, 3H; Ar H), 5.81 (m, 1H; CH CH2),
À
ˆ
ˆ
ˆ
À
5.19 (m, 1H; C CH2), 5.15 (m, 1H; C CH2), 4.74 (m, 1H; O CH), 2.48 (m,
À ˆ
2H; CH2 C C), 2.29 (d, J ˆ 1.2 Hz, 6H; 2  CH3), 2.11 (d, J ˆ 3.2 Hz, 1H;
OH) ppm.
1
The H and 13C NMR were recorded at roomtemperature.
The absolute configuration and enantiomeric purity of the product were
determined as S and 98% ee by HPLC analysis (Daicel Chiralcel OD-H,
hexane/iPrOH 4:1, flow rate ˆ 0.5 mLminÀ1, l ˆ 210 nm), tR ˆ 16.13 min (S
isomer), tR ˆ 17.73 min (R isomer) in comparison with the authentic sample.
Representative procedure for asymmetric methallylation of aldehydes:
Compound (S,S)-3 (0.2 mmol) [prepared by Method A], generated in situ
in CH2Cl2 (6 mL), was cooled to À158C, and treated sequentially at À158C
with hydrocinnamaldehyde (263 mL, 2.0 mmol) and methallyltributyltin
(759.3 mg, 2.2 mmol). The mixture was allowed to warm to 08C and was
stirred for 30 min. The reaction mixture was quenched with saturated
NaHCO3, and extracted with ether. The organic extracts were dried over
Na2SO4. Evaporation of solvents and purification of the residue by column
chromatography on silica gel (EtOAc/hexane 1:12 as eluent) gave (R)-5-
Synthesis of chiral (Binaphthoxy)Ti O (S)-13:[23] A solution of H2O (36 mL,
ˆ
2 mmol) in isopropanol (0.8 mL) was added at 08C under argon to a stirred
solution of Ti(OiPr)4 (590 mL, 2 mmol) in isopropanol (2 mL). The mixture
was then allowed to warmto roomtemperature. It was then concentrated
ˆ
under reduced pressure, and the (iPrO)2Ti O residue was diluted with
ˆ
CH2Cl2 (as a 0.5m solution). A CH2Cl2 solution of (iPrO)2Ti O (0.5m,
1.6 mL, 0.8 mmol) was added under argon at room temperature to a stirred
solution of (S)-BINOL (229.1 mg, 0.8 mmol) in toluene (4 mL). The
mixture was stirred at room temperature for 1 h and was then heated at
reflux for azeotropic removal of isopropanol, followed by complete
removal of toluene under reduced pressure to furnish [(S)-
ˆ
binaphthoxy]Ti O (S)-13.
methyl-1-phenyl-5-hexen-3-ol
6
(R ˆ CH2CH2Ph) as
a colorless oil
ˆ
Asymmetric allylation with ((S)-binaphthoxy)Ti O (S)-13 and (S)-binaph-
thoxytitanium diisopropoxide (S)-2: ((S)-Binaphthoxy)Ti O (S)-13 and
(239.2 mg, 63% yield): 1H NMR (CDCl3): d ˆ 7.31 7.20 (m, 5H; Ar H),
À
[23]
ˆ
ˆ
ˆ
À
4.89 (s, 1H; C CH2), 4.80 (s, 1H; C CH2), 3.75 (m, 1H; O CH), 2.82 (m,
(S)-binaphthoxytitaniumdiisopropoxide ( S)-2[14] were prepared independ-
ently as described above, and asymmetric allylation of hydrocinnamalde-
hyde with allyltributyltin by mixing of (S)-13 and (S)-2 (each 10 mol%) at
08C for 4 h then afforded homoallylic alcohol 5 (R ˆ CH2CH2Ph) in 31%
yield and with 88% ee. Since the use solely of 3 gave product 5 (R ˆ
CH2CH2Ph) in 20% yield with 5% ee, the mixing of (S)-13 and (S)-2
seems partially to generate bis-TiIV oxide (S,S)-3. Indeed, on heating a
mixture of (S)-13 and (S)-2 at reflux in CH2Cl2 for 3 h, we observed higher
reactivity and selectivity (78% yield with 94% ee) in this allylation under
similar conditions.
À
ˆ
1H; PhCH2), 2.71 (m, 1H; PhCH2), 2.15 (m, 2H; CH2 CMe C), 1.81 (m,
À À
2H; Ph C CH2), 1.74 (s, 3H; CH3), 1.72 (d, J ˆ 2.8 Hz, 1H; OH) ppm. The
absolute configuration and enantiomeric purity of the product were
determined as
R and 94% ee by analytical HPLC analysis [Daicel
Chiralcel OD-H, iPrOH/hexane 1:30; flow rate ˆ 0.5 mLminÀ1
,
l ˆ
254 nm), tR ˆ 19.07 min (S isomer), tR ˆ 29.46 min (R isomer)] by compar-
ison with the racemic and authentic samples.
Representative procedure for asymmetric propargylation of aldehydes:
Compound (S,S)-3 (0.2 mmol) [prepared by Method A], generated in situ
in CH2Cl2 (6 mL), was cooled to À158C, and treated sequentially at À158C
with hydrocinnamaldehyde (263 mL, 2.0 mmol) and allenyltributyltin
(724 mg, 2.2 mmol). The mixture was allowed to warm to 08C and was
stirred for 18 h. The reaction mixture was quenched with saturated
NaHCO3, and extracted with ether. The organic extracts were dried over
Na2SO4. Evaporation of solvents and purification of the residue by column
chromatography on silica gel (EtOAc/hexane 1:10 as eluent) gave (R)-1-
phenyl-5-hexyn-3-ol 7 (R ˆ CH2CH2Ph) as a colorless oil (158.7 mg, 45.5%
yield) accompanied by (R)-1-phenyl-4,5-hexadien-3-ol 12 (R ˆ
CH2CH2Ph) (15.6 mg, 4.5% yield). The absolute configuration and
Synthesis of chiral bis-m-oxo Ti(iv) catalyst (S,S)-1:[4] [Ti(OiPr)4] (118 mL,
0.4 mmol) and then H2O (7.2 mL, 0.4 mmol) were added under argon at
roomtemperature to a stirred solution of ( S)-BINOL (114.5 mg, 0.4 mmol)
in toluene (4 mL). The mixture was heated at reflux for 2 h. Azeotropic
removal of 2-propanol followed by complete removal of toluene under
reduced pressure afforded chiral bis m-oxo TiIV catalyst (S,S)-1.
Asymmetric allylation with chiral bis-m-oxo TiIV catalyst (S,S)-1: Asym-
metric allylation of hydrocinnamaldehyde with allyltributyltin in the
presence of (S)-binaphthoxytitanium m-oxo complex (S,S)-1 at 08C for
4 h afforded homoallylic alcohol 5 (R ˆ CH2CH2Ph) in 14% yield and with
25% ee.[4]
Asymmetric allylation with modified Keck×s reagent. Keck×s mono-TiIV
reagent (20 mol%), derived from [Ti(OiPr)4] (20 mol%) and (S)-BINOL
(40 mol%), was utilized for the asymmetric allylation of hydrocinnamal-
dehyde with allyltributyltin at 08C for 4 h to furnish homoallylic alcohol 5
(R ˆ CH2CH2Ph) in 53% yield and with 93% ee.[2d]
enantiomeric purity of the major product
7
(R ˆ CH2CH2Ph) were
determined as R and 92% ee by analytical HPLC analysis [Daicel
Chiralcel OD-H, iPrOH/hexane 1:30, flow rate ˆ 0.5 mLminÀ1
,
tR
ˆ
26.42 min (S isomer), tR ˆ 42.71 min (R isomer)] by comparison with the
racemic and authentic samples.
(R)-1-Phenyl-5-hexyn-3-ol: 1H NMR (CDCl3): d ˆ 7.31 7.19 (m, 5H;
À
À
Ar H), 3.78 (m, 1H; O CH), 2.80 (m, 1H; PhCH2), 2.70 (m, 1H; PhCH2),
2.40 (m, 2H; CH2CCH), 2.06 (t, J ˆ 2.4 Hz, 1H; CH2CCH), 1.95 (brs, 1H;
OH), 1.88 (m, 2H; PhCH2CH2) ppm.
(R)-1-Phenyl-4,5-hexadien-3-ol: 1H NMR (CDCl3): d ˆ 7.31 7.17 (m, 5H;
Acknowledgements
À
Ar H), 5.26 (dd, J ˆ 6.0, 12.8 Hz, 1H; CHCCH2), 4.88 (dt, J ˆ 2.4, 6.0 Hz,
À
2H; CHCCH2), 4.26 (m, 1H; O CH), 2.77 2.55 (m, 2H; PhCH2), 1.97 (m,
This work was supported by a Grant-in-Aid for Scientific Research (No.
13853003) fromthe Ministry of Education, Culture, Sports, Science and
Technology, Japan. H. H. thanks the Japan Society for the Promotion of
Science for Young Scientists for Research Fellowships.
2H; PhCH2CH2), 1.84 (brs, 1H; OH) ppm.
Linear versus positive nonlinear effects: preparation of catalyst solution by
method C: The catalyst solution (x% ee) for 2 mmol scale reaction was
prepared by Method A by the use of partially resolved (S)-BINOL, which
was prepared by mixing (S)-BINOL (y mmol) and rac-BINOL (2 mmol, y
‡ z ˆ 0.4, x ˆ 250y).
Preparation of catalyst solution by method D: The catalyst solution (x%
ee) for a 2 mmol scale reaction was prepared as follows; optically pure
(S,S)-3 and (R,R)-3 solutions were prepared independently by Method A,
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Received: April 28, 2003 [F5078]
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