Synthesis of the bifunctional BINOL ligands and their applications in the asymmetric additions to carbonyl compounds

Article abstract of DOI:10.1016/j.tet.2006.06.049

Efficient one-step syntheses of the bifunctional BINOL and H₈BINOL ligands (S)-6 and (S)-8 have been developed from the reaction of BINOL and H₈BINOL with morpholinomethanol, respectively. The X-ray analyses of these compounds have revealed their structural similarity and difference. The bifunctional H₈BINOL (S)-8 is found to be highly enantioselective for the reaction of diphenylzinc with many aliphatic and aromatic aldehydes and especially is the most enantioselective catalyst for linear aliphatic aldehydes. Unlike other catalysts developed for the diphenylzinc addition which often require the addition of a significant amount of diethylzinc with cooling (or heating) the reaction mixture in order to achieve high enantioselectivity, using (S)-8 needs no additive and gives excellent results at room temperature. (S)-8 in combination with diethylzinc and Ti(OⁱPr)₄ can catalyze the highly enantioselective phenylacetylene addition to aromatic aldehydes. It can also promote the phenylacetylene addition to acetophenone at room temperature though the enantioselectivity is not very high yet. Without using Ti(OⁱPr)₄ and a Lewis base additive, (S)-8 in combination with diethylzinc can catalyze the reaction of methyl propiolate with an aldehyde to form the highly functional γ-hydroxy-α,β-acetylenic esters except that the enantioselectivity is low at this stage. The bifunctional BINOL ligand (S)-6 in combination with Me₂AlCl is found to be a highly enantioselective catalyst for the addition of TMSCN to both aromatic and aliphatic aldehydes.

Full text of DOI:10.1016/j.tet.2006.06.049

Tetrahedron 62 (2006) 9335–9348
Synthesis of the bifunctional BINOL ligands and their applications
in the asymmetric additions to carbonyl compounds
*
Ying-Chuan Qin, Lan Liu, Michal Sabat and Lin Pu
Department of Chemistry, University of Virginia, Charlottesville, VA 22904-4319, USA
Received 26 April 2006; revised 13 June 2006; accepted 14 June 2006
Available online 14 August 2006
Abstract—Efficient one-step syntheses of the bifunctional BINOL and H8BINOL ligands (S)-6 and (S)-8 have been developed from the
reaction of BINOL and H8BINOL with morpholinomethanol, respectively. The X-ray analyses of these compounds have revealed their struc-
tural similarity and difference. The bifunctional H8BINOL (S)-8 is found to be highly enantioselective for the reaction of diphenylzinc with
many aliphatic and aromatic aldehydes and especially is the most enantioselective catalyst for linear aliphatic aldehydes. Unlike other catalysts
developed for the diphenylzinc addition which often require the addition of a significant amount of diethylzinc with cooling (or heating) the
reaction mixture in order to achieve high enantioselectivity, using (S)-8 needs no additive and gives excellent results at room temperature.
(S)-8 in combination with diethylzinc and Ti(OiPr)4 can catalyze the highly enantioselective phenylacetylene addition to aromatic aldehydes.
It can also promote the phenylacetylene addition to acetophenone at room temperature though the enantioselectivity is not very high yet. With-
out using Ti(OiPr)4 and a Lewis base additive, (S)-8 in combination with diethylzinc can catalyze the reaction of methyl propiolate with an
aldehyde to form the highly functional g-hydroxy-a,b-acetylenic esters except that the enantioselectivity is low at this stage. The bifunctional
BINOL ligand (S)-6 in combination with Me2AlCl is found to be a highly enantioselective catalyst for the addition of TMSCN to both aromatic
and aliphatic aldehydes.
Ó 2006 Published by Elsevier Ltd.
1. Introduction
Development of catalysts containing both Lewis acidic sites
and Lewis basic sites has attracted significant attention in the
field of asymmetric catalysis.1 Such bifunctional chiral cata-
lysts can simultaneously activate both the electrophile and
nucleophile in a chemical reaction and control the stereo-
O
PPh2
NEt2
NEt2
chemistry of the reaction course to provide efficient chiral
induction. We are particularly interested in the study of the
1,10-bi-2-naphthol (BINOL)-based bifunctional catalysts.
The chiral Lewis acid catalysts prepared from the combina-
tion of BINOL with a metal complex have been used in
many asymmetric organic reactions.2 Recently, additional
Lewis basic functional groups are also incorporated into
BINOL to construct various bifunctional BINOL ligands
for asymmetric catalysis.3 Figure 1 gives a few examples of
the bifunctional BINOL ligands. The aluminum complexes
of the chiral ligands 14 and 25 have been used to catalyze
the enantioselective reaction of aldehydes with trimethyl-
silylcyanide (TMSCN) to generate the synthetically useful
chiral cyanohydrins. The zinc complexes of 36 and 47 were
used to carry out the alkyne addition to aldehydes and the
Simmons–Smith reaction, respectively. Ligand 5 catalyzed
the aza-Morita–Baylis–Hillman reaction in the absence of a
metal.8 These ligands have exhibited high enantioselectivity
in the corresponding reactions.
OMe
OH
OH
OMe
OH
OH
OH
OH
PPh2
O
1
2
3
O
NEt2
NEt2
N
OH
OH
OH
OH
N
O
4
5
* Corresponding author. Tel.: +1 434 924 6953; fax: +1 434 924 3710;
e-mail: lp6n@virginia.edu
Figure 1. Examples of the bifunctional BINOL ligands.
0040–4020/$ - see front matter Ó 2006 Published by Elsevier Ltd.
doi:10.1016/j.tet.2006.06.049

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Y.-C. Qin et al. / Tetrahedron 62 (2006) 9335–9348
Since the bifunctional BINOL ligands often require a signifi-
cant number of steps to prepare, we are interested in develop-
ing more efficient synthetic methods in order to make these
ligands more practically applicable. We have conducted the
one-step Mannich-type reaction of BINOL or its partially
hydrogenated compound H8BINOL to synthesize the 3,30-
amino methyl substituted BINOL derivatives.9 Herein, we
report our detailed study of the synthesis of these ligands
and their use in the asymmetric organozinc and TMSCN
additions to aldehydes and ketones.
We further explored the reaction conditions and the results
are summarized in Table 1. At 90 ꢀC, various additives
such as NaBH4, P2O5, and Et2Zn were used, but no product
was obtained (entries 3–5). The best condition was at
110ꢂ2 ꢀC, which gave (S)-6 in 55% yield and 75% ee (entry
8). From this reaction, (S)-7 was also isolated in 30% yield
and >87% ee. We explored the addition of Lewis acid com-
plexes such as CeCl3, Zn(OTf)2, TbCl3, InCl3, ZnI2, LiCl,
and VO(acac)2, but no improvement was observed.
Table 1. Reaction of (S)-BINOL with morpholinomethanol under various
conditions (under 30 psi nitrogen)
Entry Temperature Additive
(ꢀC)
Time Yield of ee of (S)-6
(h)
OH
OH
OH
OH
(S)-6 (%) (%)
1
2
3
4
5
6
7
8
160
95–100
90
90
90
130
120
110
None
None
24
60
94
w5
w0
w0
w0
90
0
>99
—
NaBH4 (1 equiv) 24
P2O5 (1 equiv) 24
Et2Zn (4–6 equiv) 24
None
None
None
—
—
(S)-BINOL
(S)-H8BINOL
48
72
72
<30
<50
75
63
55
2. Results and discussion
2.1. One-step synthesis of the 3,30-bismorpholinomethyl
substituted BINOL and H8BINOL compounds
Compound (S)-6 obtained in entry 8 of Table 1 was purified
by recrystallization to give the optically pure product. It was
first dissolved in a hot CH2Cl2/CH3OH (3:1) mixture, which
upon cooling gave white needle-like racemic crystals. After
this process was repeated a couple of more times, the com-
pound in the mother liquor was found to be the optically
pure (S)-6. It was isolated as an off-white solid in 37% yield
based on (S)-BINOL and the optical purity of this compound
was over 99% ee. The specific optical rotation of (S)-6 was
[a]D ꢁ152.1 (c 1.0, CH2Cl2). The side product (S)-7 could
be converted to (S)-6 by further treatment with morpholino-
methanol under the reaction conditions. We also obtained the
optically pure (R)-6 and (R)-7 by starting from (R)-BINOL.
2.1.1. Reaction of BINOL. Previously, Cram reported the
reaction of racemic BINOL with a-alkoxyamines at 160 ꢀC
to prepare the 3,30-bisaminomethyl substituted BINOLs.10
We examined this reaction by using the optically pure (S)-
BINOL to react with the in situ generated morpholino-
methanol at 160 ꢀC under nitrogen (Scheme 1). The resulting
6 was converted to its diacetate, and the subsequent analysis
by using HPLC Chiralcel-OD column showed a racemic
product. Thus, a complete racemization took place during
this reaction.
O
N
O
HO
N
2.1.2. Reaction of H8BINOL. Like BINOL, the partially
hydrogenated derivative H8BINOL is also very useful in
asymmetric catalysis.11,12 In a few reactions, the Lewis
acid complexes based on H8BINOL showed enhanced chiral
induction over BINOL. This was attributed to the increased
size of the partially hydrogenated rings in H8BINOL. Al-
though it should be very interesting to study the application
of the bifunctional H8BINOLs in asymmetric catalysis, very
few functional H8BINOL compounds have been prepared
and studied.12b–d
OH
OH
OH
OH
160 ºC, 24 h/N2
O
N
(S)-BINOL
rac-6
>90% yield, 0% ee
Scheme 1. Reaction of (S)-BINOL with morpholinomethanol at 160 ꢀC.
When the reaction of (S)-BINOL with morpholinomethanol
was conducted at 95–100 ꢀC, the mono-morpholinomethyl
substituted compound (S)-7 was obtained in 3 d as the major
product in 60% yield and >99% ee. The specific optical
rotation of (S)-7 was [a]D ꢁ35.1 (c 1.0, CH2Cl2). The opti-
cally pure (S)-6 was isolated only in 5% yield.
We conducted the reaction of (S)-H8BINOL with morpholi-
nomethanol (Scheme 2). We expected that (S)-H8BINOL
should be more reactive in the Mannich-type reaction than
(S)-BINOL because of its electron-donating alkyl groups
on the phenol rings. Thus, the high-temperature condition
employed in the reaction of BINOL that caused the partial
racemization might not be necessary for H8BINOL. In addi-
tion, it was previously reported that 2,20-biphenol reacted
with the in situ generated morpholinomethanol at 60 ꢀC to
give the 3,30-bismorpholinomethyl substituted 2,20-biphenol
product in 50% yield.13 Therefore, we treated the optically
pure (S)-H8BINOL with morpholinomethanol in dioxane
at 60 ꢀC. To our delight, the desired (S)-3,30-bimorpholino-
methyl H8BINOL, (S)-8, was obtained in 95% yield and
OH
OH
N
O
(S)-7

Y.-C. Qin et al. / Tetrahedron 62 (2006) 9335–9348
9337
over 99% ee. The specific optical rotation of (S)-8 was [a]D
ꢁ35.4 (c 1.04, THF).
in Figures 2 and 3. The most characteristic feature of these
structures is the torsion angle C(2)–C(1)–C(10)–C(20) be-
tween the two binaphthyl moieties, which measures
113.7(2)ꢀ in (S)-6 and 100.0(1)ꢀ in (S)-8. The 13.7ꢀ differ-
ence between the biaryl angles can be attributed to the in-
creased steric interactions of the partially hydrogenated
aryl rings, forcing the biaryl unit of (S)-8 to move closer to
the orthogonal (90ꢀ) conformation.
N
O
O
HO
N
OH
OH
OH
OH
60 °C, 12 h
dioxane
O
N
The molecules are stabilized by strong intramolecular hy-
drogen bonds O–H/N involving the alcohol groups and
the morpholine ring N atoms. The O/N donor acceptor
(S)-H8BINOL
(S)-8
95% yield, >99% ee
˚
Scheme 2. Reaction of (S)-H8BINOL with morpholinomethanol.
separations which are 2.681 and 2.732 A in (S)-6 become
˚
slightly shorter (2.650 and 2.671 A) in (S)-8. The O–H/N
angles in these bonds range from 147.3ꢀ to 157.4ꢀ.
2.2. X-ray structures of (S)-6 and (S)-8
2.3. Asymmetric diphenylzinc additions catalyzed by the
bifunctional ligands9c
The bifunctional BINOL ligand (S)-6 was crystallized by
slow evaporation from a CH2Cl2/methanol (1:1) solution,
whereas the X-ray quality crystals of the bifunctional
H8BINOL ligand (S)-8 were obtained from its ethanol solu-
tion. The molecular structures of these compounds are shown
The asymmetric diphenylzinc addition to aldehydes can gen-
erate the synthetically useful chiral a-substituted benzyl
alcohols. In 1999, we found that compound 9 showed high
θ
θ
'
O1
d1
H
N1
O1' H' N1'
d2'
d2
d1'
D'
D
d1' = 0.765 Å
d2' = 1.969 Å
D' = 2.681 Å
d1 = 0.794 Å
d2 = 2.031 Å
D = 2.732 Å
θ
' = 154.7 º
θ
= 147.3 º
Figure 2. ORTEP drawing (30% probability ellipsoids) of (S)-6.
θ
θ
'
O1
d1
H
N1
O1'
H
d1'
N1'
d2'
d2
D
D'
d1' = 0.850 Å
d2' = 1.898 Å
D' = 2.671 Å
d1 = 0.771 Å
d2 = 1.922 Å
D = 2.650 Å
θ
' = 150.6 º
θ
= 157.4 º
Figure 3. ORTEP drawing (30% probability ellipsoids) of (S)-8.

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Y.-C. Qin et al. / Tetrahedron 62 (2006) 9335–9348
enantioselectivity for this reaction.14 At a similar time, Bolm
reported good results with the use of 10.15 Other chiral
ligands were also developed for the asymmetric diphenyl-
zinc addition.14–20 A few of these compounds are able to cat-
alyze the diphenylzinc addition to aromatic and a-branched
aliphatic aldehydes with high enantioselectivity (>90% ee).
However, the enantioselectivity for the reaction of linear
aliphatic aldehydes is generally lower, and no catalyst has
been reported to give over 90% ee for the reaction of di-
phenylzinc with a linear aliphatic aldehyde. In addition,
the catalysts for the asymmetric diphenylzinc addition often
require the use of a significant amount of the diethylzinc
additive while cooling (or heating) the reaction mixtures.
Table 2. Results for the diphenylzinc addition to valeraldehyde under vari-
ous conditions catalyzed by (S)-6 and (S)-8a
Entry
Ligand
Solvent
Ph2Zn (equiv)
ee (%)e,f
1
2
3
4
(S)-8 (10 mol %)
(S)-8 (10 mol %)
(S)-8 (10 mol %)
(S)-8 (10 mol %)
(S)-6 (10 mol %)
(S)-8 (10 mol %)
(S)-8 (10 mol %)
(S)-8 (10 mol %)
(S)-8 (10 mol %)
(S)-8 (5 mol %)
(S)-8 (20 mol %)
CH2Cl2
Toluene
Et2O
THF
THF
THF
THF
THF
THF
THF
1.2
1.2
1.2
1.2
1.2
1.2
1.0
1.6
1.6
1.2
1.4
35
38
39
92
87
93
91
89
91
84
87
5
6b
7c
8d
9c,d
10
11
THF
a
Unlessindicatedotherwise,thefollowingprocedurewasused:Undernitro-
gen to a flask containing (S)-8 (12.3 mg, 0.025 mmol) and diphenylzinc
(66.0 mg, 0.3 mmol), a solvent (2 mL, dried) was added and the solution
was stirred at room temperature for 1 h. Valeraldehyde (0.25 mmol) was
then added and the resulting solution was stirred for 12 h. Aqueous work
up and column chromatography on silica gel gave 1-phenyl-1-pentanol.
Valeraldehyde was added dropwise over 2 h.
(S)-8 was pretreated with diethylzinc (20 mol %) for 1 h followed by the
addition of diphenylzinc and aldehyde.
MeOH (40 mol %) was added after (S)-8 was treated with diphenylzinc or
diethylzinc.
Isolated yields of all these reactions were 82–89%.
OR
O
N
OR
b
c
OH
CPh2OH
Fe
OH
d
OR
e
f
ee’s were determined by HPLC-chiral OD column.
OR
10
9
Since the bifunctional BINOL and H8BINOL ligands (S)-6
and (S)-8 are structurally analogous to 9, we have examined
their catalytic properties for the asymmetric diphenylzinc
addition to aldehydes. We first studied the reaction of diphe-
nylzinc with valeraldehydes in the presence of (S)-6 and (S)-
8 (Scheme 3). Table 2 summarizes the results of this reaction
under various conditions. In solvents such as methylene
chloride, toluene, and diethyl ether, (S)-8 showed very low
enantioselectivity (35–39% ee, entries 1–3). However, a dra-
matic increase in enantioselectivity was observed when the
reaction was carried out in THF (92% ee, entry 4). The ab-
solute configuration of the alcohol product was determined
to be R by comparing its optical rotation with that in litera-
ture.21,22 The enantioselectivity using the BINOL derivative
(S)-6 is lower than that using the H8BINOL derivative (S)-8
(entry 5). Slow addition of the aldehyde did not significantly
change the ee (entry 6). Using diethylzinc and/or methanol
as the additive slightly reduced the enantioselectivity (en-
tries 7–9). Both decreasing and increasing the amount of
the chiral ligand gave lower ee (entries 10 and 11).
Table 3. Asymmetric diphenylzinc addition to aliphatic aldehydes catalyzed
by (S)-8
Entry
Aldehyde
Product
Time Yield ee
(h)
(%)a
(%)b,c
OH
3
CHO
3
1
12
87
92
OH
6
CHO
6
2
3
4
5
6
12
12
8
78
75
96
93
82
93
92
98
98
92
OH
OH
OH
OH
OH
CHO
CHO
CHO
CHO
6
OH
(S)-6 or (S)-8
O
Zn
+
R
2
solvent, rt
H
16
Scheme 3. Asymmetric diphenylzinc addition to valeraldehyde.
We then used (S)-8 to catalyze the reaction of diphenylzinc
with various aliphatic aldehydes by applying the conditions
of entry 4 in Table 2. The results are summarized in Table 3.
For the reactions of linear (entries 1–3), a-branched (entries
4 and 5) and b-branched (entry 6) aliphatic aldehydes, ee’s
were observed in the range of 92–98%. For the aldehyde
containing an ester group (entry 7), 81% ee was observed.
The yields for the reactions were in the range of 75–96%.
CHO
7
12
80
81
CO2Me
CO2Me
a
Isolated yield.
Determined by HPLC-chiral column or GC-chiral column.
All racemic compounds were prepared by mixing the aldehydes with
diphenylzinc.
b
c

Y.-C. Qin et al. / Tetrahedron 62 (2006) 9335–9348
9339
These results demonstrate that (S)-8 is generally enantio-
selective for the reaction of diphenylzinc with both linear
and branched aliphatic aldehydes. Optical rotation measure-
ments showed that the absolute configurations of the alcohol
products from the addition to the aliphatic aldehydes were R
(entries 1 and 5).21,22
The reaction of 2-naphthyl aldehyde gave 89% ee (entry 6).
Moderate ee’s were observed for the ortho and meta
substituted benzaldehydes (51–78% ee, entries 7–10). The
isolated yields for all the reactions were 75–97%. Optical
rotation measurements showed that the addition to aromatic
aldehydes gave (S)-alcohols (entries 3 and 4).14a,23
We also used (S)-8 to catalyze the reaction of diphenylzinc
with various aromatic aldehydes by applying the conditions
of entry 4 in Table 2. The results are summarized in Table 4.
High enantioselectivity was observed for the reaction of
para substituted benzaldehydes (89–96% ee, entries 1–5).
We further studied the reaction of a,b-unsaturated aldehydes
with diphenylzinc in the presence of (S)-8. The results are
summarized in Table 5. By using the conditions of entry 4
in Table 2, the reaction of 2-methyl-but-2-enal with di-
phenylzinc in the presence of (S)-8 showed very high enan-
tioselectivity and high yield (96% ee and 88% yield, entry 1).
However, the reaction of cinnamaldehyde gave a signifi-
cantly lower ee under the same conditions (77% ee, entry 2).
Various reaction conditions were examined for the reaction
of cinnamaldehyde, including lowering the reaction temper-
ature (entry 3); increasing the amount of (S)-8 and diphenyl-
zinc (entry 4); using additives (entries 5 and 6); and changing
the reaction concentration (entries 7 and 8), but no further
improvement was observed. Apparently, an a-substituent
is important for the high enantioselectivity in the reaction
of the a,b-unsaturated aldehydes.
Table 4. Diphenylzinc addition to various aromatic aldehydes catalyzed by
(S)-8
Entry
Aldehyde
Product
Time Yield ee
(h)
(%)a (%)b,c
OH
CHO
1
16
90
91
89
89
OH
OH
OH
OH
CHO
CHO
CHO
CHO
CHO
2
3
4
5
16
16
16
16
A linear relationship between the enantiomeric composition
of the chiral ligand (S)-8 and those of the diphenylzinc addi-
tion products was observed.9c This suggests that the catalysis
for the diphenylzinc addition to either aliphatic or aromatic
aldehydes might be catalyzed by a monomeric H8BINOL
catalyst. We also studied the mechanism of the diphenylzinc
addition catalyzed by (S)-8 by using NMR spectroscopy and
Br
Cl
F
Br
Cl
F
90
92
91
89
94
91
Table 5. Reaction of diphenylzinc with a,b-unsaturated aldehydes in the
presence of (S)-8
Entry
Aldehyde
(S)-8
(mol %)
Additive
T
rt
rt
THF Ph2Zn ee
(mL) (equiv) (%)
CHO
O
96
O
1
2
10
10
None
2
2
1.2
1.2
(88)a
OH
OH
OH
CHO
77
6
7
16
16
97
80
89
78
None
(98)a
CHO
CHO
CHO
CHO
CHO
CHO
3
4
5
6
7
10
20
20
10
10
10
None
None
0 ꢀC 2
1.2
2.4
2.4
1.2
1.2
1.0
70
78
73
78
75
78
CHO
rt
rt
rt
rt
rt
2
2
2
5
1
CHO
Cl
8
9
16
16
95
94
51
60
40 mol %
MeOH
Cl
OMe OH
CHO
20 mol %
Et2Zn
OCH3
OH
CHO
None
None
10
16
78
68
Br
Isolated yield.
Determined by HPLC-chiral column or GC-chiral column.
All racemic compounds were prepared by mixing the aldehydes with
diphenylzinc.
Br
8
a
b
c
a
The isolated yield is given in the parentheses and the reaction time was
12 h.

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Y.-C. Qin et al. / Tetrahedron 62 (2006) 9335–9348
O
O
O
N
N
N
Ph
Zn
ZnPh
O
Zn
Ph2Zn
O
O
O
ZnPh2
Ph
(excess)
tBuCHO
ZnPh2
ZnPh2
Ph
O
ZnPh
Zn
H
Zn
O
N
O
Ph
2
Zn
tBu
N
O
11
Ph
N
O
12
13
O
Ph
Ph2Zn
H
Ph Zn
O
tBu
oligomers or clusters
Scheme 4. A proposed mechanism for the catalytic diphenylzinc addition.
the detailed experiments were reported.9c The NMR study
showed that 2 equiv of (S)-8 reacted with 3 equiv of diphe-
nylzinc to form a stable (2+3) complex with a proposed
structure of 11 (Scheme 4). This complex then reacted
with excess diphenylzinc to form a C2-symmetric complex
like 12. Complex 12 might be the catalytically active spe-
cies, which can activate an aldehyde and produce the phenyl
addition product via the proposed transition state 13.
Table 6. Asymmetric reactions of phenylacetylene with aromatic aldehydes
in the presence of (S)-8, Et2Zn, and Ti(OiPr)4
a
Entry
Aldehyde
Product
Isolated
yield (%) (%)
ee
H
HO
HO
HO
HO
HO
HO
CHO
1
93
88
76
83
88
62
84
68
83
97
93
92
89
98
97
H
2.4. Asymmetric alkyne addition to aldehydes catalyzed
by (S)-89b
CHO
Cl
2
Cl
H
The bifunctional H8BINOL ligand (S)-8 was used to cata-
lyze the asymmetric alkynylzinc addition to aldehydes to
generate chiral propargylic alcohols that are of great utility
in organic synthesis.24–26 The results for the reactions of
phenylacetylene with various aldehydes in the presence of
(S)-8 (Scheme 5) are summarized in Table 6. The reactions
were completed in 4 h by mixing (S)-8 (20 mol %), diethyl-
zinc (4 equiv), Ti(OiPr)4 (100 mol %), 4 equiv of phenylace-
tylene (4 equiv), and benzaldehyde (1 equiv) at room
temperature in THF. In the case of benzaldehyde, the product
was (R)-1,3-diphenyl-prop-2-yn-1-ol obtained in 95% yield
and 84% ee.
CHO
OMe
3
OMe
H
CHO
OEt
4
OEt
H
CHO
Me
5
OH
Me
H
(S)-8
H
RCHO
+
Et2Zn, Ti(OiPr)4
THF, rt, 4 h
R
CHO
NO2
6b
Scheme 5. Reaction of phenylacetylene with aldehydes catalyzed by (S)-8.
NO2
H
HO
As shown in Table 6, (S)-8 was highly enantioselective for
the reaction of the alkyne with aromatic aldehydes. Earlier,
Chan and co-workers found that H8BINOL in combination
with Ti(OiPr)4 and Me2Zn catalyzed the reaction of phenyl-
acetylene with certain aromatic aldehydes with high enantio-
selectivity at 0 ꢀC.27 Under these conditions, however, the
reaction of an ortho-substituted benzaldehyde was not very
good. Using H8BINOL could give only 76% ee for the reac-
tion of phenylacetylene with o-chlorobenzaldehyde. In con-
trast, the bifunctional H8BINOL ligand (S)-8 catalyzed the
CHO
Br
7
Br
H
HO
Me
Me
CHO
Me
Me
8
96
Me
Me
(continued)

Y.-C. Qin et al. / Tetrahedron 62 (2006) 9335–9348
9341
Table 6. (continued)
Entry Aldehyde
Although significant progress has been made on the asym-
metric alkyne addition to aldehydes, not many good cata-
lysts have been obtained for the asymmetric alkyne
addition to ketones.28 The lower reactivity of ketones re-
quires more active catalysts than those for aldehydes. We
also found that (S)-8 was an active catalyst for the reaction
of phenylacetylene with acetophenone at room temperature
(Scheme 6). Table 7 summarizes the results under various
reaction conditions. Generally, the reaction was conducted
by mixing (S)-8 (10 mol %), Et2Zn (4 equiv), and phenyl-
acetylene (4 equiv) at room temperature for 2 h in a solvent
(1 mL) followed by the addition of Ti(OiPr)4 (100 mol %)
and acetophenone. After 36 h, the reaction was quenched
and the ee was determined by HPLC-chiral column. Less
than 34% ee was observed for the reactions in toluene,
methylene chloride, and diethyl ether (entries 1–3). A sig-
nificant increase of the enantioselectivity was observed in
THF (63% ee and 60% yield, entry 4). Reducing the amount
of Ti(OiPr)4 or increasing the amount of THF decreased the
enantioselectivity (entries 5 and 6). Changing the solvent
from THF to 1,4-dioxane increased the ee to 69% (entry 7).
Product
Isolated ee
yield (%) (%)
H
HO
CHO
9
93
86
OMe
OMe
H
HO
CHO
CHO
10
11
86
50
87
86
Br
F
Br
F
H
HO
H
HO
CHO
12
98
91
O
OH
Me
(S)-8
Me
H
+
Et2Zn, Ti(OiPr)4
solvent, rt
H
HO
CHO
CHO
13
14
86
99
83
85
Me
Scheme 6. Reaction of phenylacetylene with acetophenone catalyzed by
(S)-8.
Me
H
HO
Table 7. Reaction of phenylacetylene with acetophenone in the presence of
(S)-8 under various conditions
MeO
Entry (S)-8 (mol %) Ti(OiPr)4 (mol %) Solvent
ee (%)
MeO
1
2
3
4
5
6
7
10
10
10
10
10
10
10
100
100
100
100
40
Toluene
CH2Cl2
Et2O
0
34
19
H
H
HO
CHO
THF
THF
63 (60)a
60
56
15
85
83
100
40
THFb
1,4-Dioxane 69
HO
Cl
a
Isolated yield in the parentheses.
3 mL THF was used.
Cl
b
16c
62
76
86
67
CHO
Cl
We recently reported that the unfunctionalized BINOL in
combination with Et2Zn, Ti(OiPr)4, and HMPA can catalyze
the highly enantioselective reaction of methyl propiolate
with aldehydes to generate g-hydroxy-a,b-acetylenic es-
ters.29 These compounds are used extensively in the synthe-
sis of complex organic compounds.30 We also studied the
use of (S)-8 to catalyze the reaction of methyl propiolate
with valeraldehyde. It was found that (S)-8 in combination
with Et2Zn was highly active at room temperature without
the need for Ti(OiPr)4 and a Lewis base additive (Scheme 7).
However, the enantioselectivity was low in various solvents
such as Et2O, CH2Cl2, and toluene. The highest enantio-
selectivity at room temperature was only 28% ee though
the reaction was generally completed in 3–6 h (Table 8,
entry 1). Other reaction conditions were examined and the
results are shown in Table 8. In diethyl ether, decreasing
the reaction temperature to ꢁ20 ꢀC led to a significantly in-
creased enantioselectivity (70% ee, entry 4). At ꢁ20 ꢀC, all
the reactions were completed in high yields in 16 h (entries
2–4). Further decreasing the temperature to ꢁ40 ꢀC made
the reaction sluggish and reduced both the yield and ee
Cl
H
HO
17d
CH3(CH2)6CHO
n
H15C7
a
Unless indicated otherwise, reactions were conducted by stirring (S)-8/
Et2Zn/PhCCH/Ti(OiPr)4/RCHO¼0.1:4:4:1:1 at room temperature in
THF for 4 h.
2 equiv of Et2Zn and 2 equiv of PhCCH were used.
The reaction time was 6 h.
20 mol % (S)-8 was used.
b
c
d
same reaction with 97% ee (entry 2). This ligand was found
to be good for the asymmetric reaction of a variety of ortho-
substituted benzaldehydes with ee’s in the range of 89–98%
(entries 2–8). In addition, (S)-8 was also generally good
for other aromatic aldehydes (entries 9–16). The enantio-
selectivity for a linear aliphatic aldehyde was lower (67%
ee, entry 17).

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Y.-C. Qin et al. / Tetrahedron 62 (2006) 9335–9348
(entry 5). Replacing diethylzinc with dimethylzinc decreased
the enantioselectivity (entry 6). Increasing the amount of
(S)-8 and diethylzinc could not improve the reaction
(entry 7). The ee of the product was determined by analyzing
the 1H NMR spectrum of the (R)-O–Ac mandelate derivative
(Scheme 8).
from the optically active BINOL32 or an optical resolution
in a multi-step synthesis from a naphthalene derivative.5
This makes the use of the bifunctional BINOL and H8BINOL
ligands (S)-6 and (S)-8 very attractive because of their one-
step synthesis.
We studied the use of the ligands (S)-6, (S)-7, and (S)-8 in
combination with Me2AlCl to catalyze the reaction of
TMSCN with benzaldehyde (Scheme 9). The reaction con-
ditions employed were similar to those using 1 and 2. The
catalyst was prepared by stirring Me2AlCl (10 mol %) with
ligand (10 mol %) in a solvent (1 mL) at room temperature
OH
(S)-8
nBuCHO
+
MeO2C
MeO2C
H
Et2Zn
nBu
Scheme 7. Asymmetric reaction of methyl propiolate with valeraldehyde.
˚
for 1 h over 4 A MS. Then Ph3PO was added and the mixture
was cooled down to ꢁ20 ꢀC. Benzaldehyde and TMSCN
were both added in one portion. After 48 h, the reaction
was quenched with HCl (2 N), the product was converted
to O-acetyl cyanohydrin. The ee of the acetate was analyzed
by GC-chiral column. The results are summarized in Table 9.
Table 8. Results for the reaction of methyl propiolate with valeraldehyde in
the presence of (S)-8
Entry (S)-8 (mol %) Solvent R2Zn
T (ꢀC) ee (%)
1
2
3
4
5
6
7
10
10
10
10
10
10
20
Toluene 1.2 equiv Et2Zn
Toluene 1.2 equiv Et2Zn
CH2Cl2 1.2 equiv Et2Zn
25
ꢁ20
ꢁ20
ꢁ20
ꢁ40
28
43
28
70
62
50
69
As shown in Table 9, toluene was found to be the best solvent.
The bifunctional BINOL ligand (S)-6 was highly enantio-
selective for this reaction in toluene (96% ee, entry 2). The
monosubstituted ligand (S)-7 gave very low enantioselectiv-
ity (entries 5–7). The H8BINOL ligand (S)-8 showed signifi-
cantly lower enantioselectivity than (S)-6 (53% ee, entry 8).
Et2O
Et2O
Et2O
Et2O
1.2 equiv Et2Zn
1.2 equiv Et2Zn
1.2 equiv Me2Zn ꢁ40
2.4 equiv Et2Zn
ꢁ20
2.5. Asymmetric alkylzinc addition to aldehydes
catalyzed by (S)-8
We also tested the use of Ti(OiPr)4 in place of Me2AlCl in
combination with the chiral ligands but only obtained mod-
erate ee’s. We found that switching the Ph3P]O additive to
HMPA led to a shorter reaction time and a slightly higher
yield. Thus the optimized conditions involved the use of
The use of (S)-8 to catalyze the classical dimethylzinc and
diethylzinc addition to aldehydes was tested.25a,b To our sur-
prise, (S)-8 could not give the desired product for the reac-
tion of diethylzinc or dimethylzinc with valeraldehyde in
THF at room temperature in spite of its high enantioselectiv-
ity for the diphenylzinc addition. For the reaction of diethyl-
zinc with benzaldehyde in THF at room temperature, (S)-8
produced 1-phenyl-propyl-1-ol in 78% yield and 73% ee.
˚
(S)-6 in combination with Me2AlCl, HMPA, 4 A MS in tolu-
ene at ꢁ20 ꢀC. It gave 92% yield and 94% ee in 24 h for the
TMSCN addition to benzaldehyde. The optimized condi-
tions were applied for the reactions of TMSCN with various
aromatic aldehydes and the results are summarized in
Table 10. In general, good enantioselectivity was observed.
2.6. Asymmetric TMSCN addition to aldehydes
catalyzed by the bifunctional ligands
Table 9. Results for the TMSCN addition to benzaldehyde in the presence of
the bifunctional ligands
The asymmetric syntheses of cyanohydrins have attracted
considerable research activity because these compounds are
versatile starting materials for manyfunctional organic mole-
cules such as a-hydroxyacids, a-hydroxyketones, a-amino
acids, and b-amino alcohols.31 Previously, the aluminum
complexes of the bifunctional ligands 14 and 25 have been
used to catalyze the reaction of aldehydes with TMSCN to
generatethechiral cyanohydrinswithgoodenantioselectivity.
These bifunctional ligands require either a six-step synthesis
Entry
Ligand
Solvent
ee (%)
1
2
3
4
5
6
7
8
(S)-6
(S)-6
(S)-6
(S)-7
(S)-7
(S)-7
(S)-7
(S)-8
THF
72
96
73
7
20
11
7
Toluene
Et2O
THF
Toluene
Et2O
CH2Cl2
Toluene
53
OAc
OAc
OH
O
DCC, DMAP
CH2Cl2, rt
CO2H
MeO2C
R
+
MeO2C
O
nBu
nBu
Scheme 8. Preparation of the O-Ac Mandelate derivative for NMR analysis.
Ligand (10 mol%)
Me2AlCl (10 mol%)
Ph3PO (40 mol%)
OTMS
CN
O
OAc
CN
1. 2N HCl
2. Ac2O,
H
TMSCN
+
4Å MS, -20 ºC,
36 - 48 h
pyridine
Scheme 9. Catalytic reaction of benzaldehyde with TMSCN.

Y.-C. Qin et al. / Tetrahedron 62 (2006) 9335–9348
9343
Table 10. Results of TMSCN addition to aromatic aldehydes
Table 11. Asymmetric addition of TMSCN to octyl aldehyde in the presence
of (S)-6 and Me2AlCla
Entry
Aldehyde
CHO
Product
OAc
CN
Yield (%) ee (%)
˚
4 A MS (mg)
Entry
Solvent
Time (h)
ee (%)
1
2
Toluene
THF
Et2O
Toluene
Toluene
Et2O
5
5
5
24
24
24
24
24
3
91
87
97
82
46
76
31
6
1
92
90
94
93
3
4b
5
5
OAc
CN
None
5
15
5
CHO
CHO
6c
7c,d
8c
2
3
Et2O
Hexane
4
24
a
The following procedure was used unless otherwise indicated: (S)-6
˚
(0.025 mmol, 10 mol %), 4 A molecular sieves, and Me2AlCl
OAc
CN
(10 mol %, 1 M in hexanes) in a solvent (1 mL) were stirred under nitro-
gen at room temperature for 3 h. It was then combined with the additive
HMPA (40 mol %) and cooled down to ꢁ20 ꢀC. TMSCN (3.0 equiv)
and an aldehyde were added.
No additive.
Reaction at rt.
20 mol % (S)-6 and 20 mol % Me2AlCl.
77
88
82
94
82
80
Cl
Cl
b
c
d
OAc
CN
CHO
CHO
4
5
Br
various conditions are summarized. In toluene solution,
(S)-6 showed up to 91% ee for this reaction (entry 1). Chang-
ing the solvent to THF reduced the ee (entry 2). In diethyl
ether, however, a significant enhancement in ee was ob-
served (97% ee, entry 3). Without the additive HMPA, a
somewhat lower ee was observed (entry 4). Absence of
molecular sieves led to a large reduction in enantioselectiv-
ity (entry 5). The room temperature reaction gave a lower
but still significant ee (entry 6). Increasing the amount of
molecular sieves at room temperature greatly decreased
the enantioselectivity even with the increased amount
of the chiral catalyst (entry 7). Changing the solvent to hex-
anes at room temperature diminished the enantioselectivity
(entry 8).
Br
OAc
CN
OMe
OMe
OAc
CN
CHO
6
7
86
85
75
90
OAc
CN
CHO
F
F
We applied the optimized conditions of entry 3 in Table 11 to
the reaction of a variety of aliphatic aldehydes with TMSCN.
As the results summarized in Table 12 show, in the presence
of (S)-6 (10 mol %) and Me2AlCl (10 mol %), high enantio-
selectivities were achieved for the reactions of TMSCN with
diverse aliphatic aldehydes including linear (entries 1–3),
branched (entries 4–7), a,b-unsaturated (entries 8 and 9),
and functionalized substrates (entries 10 and 11). The
absolute configurations of the products from hydrocinnam-
aldehyde and cinnamaldehyde were determined to be R
by comparing their optical rotations with those in the
literature.
OAc
CN
CHO
8
80
80
MeO
MeO
OAc
CN
O
O
CHO
9
70
94
74
80
Cl
Cl
OAc
CN
CHO
10
A large positive nonlinear effect was observed for the re-
action of octyl aldehyde with TMSCN in the presence of
(S)-6 and Me2AlCl.9a A chiral ligand of only 40% ee could
generate the product of the same high ee as that by the ligand
of high optical purity. The remarkable nonlinear effect indi-
cates that the catalytic process may involve intermolecularly
aggregated Al complexes. When (S)-6 was treated with
Me2AlClintoluene-d8, the1HNMRspectrumshowedacom-
plete disappearance of all the signals of the ligand. A singlet
at d 0.16 appeared in the spectrum, which was attributed
to methane generated from the protonation of Me2AlCl by
the chiral ligand. A white precipitate was produced in the
toluene-d8 solution, indicating the aggregation of the alumi-
num complexes. Octyl aldehyde and TMSCN were added to
the NMR tube at room temperature. A triplet at d 4.10
Although ligand 2 was reported to be highly enantioselective
for the reaction of aromatic aldehydes with TMSCN, it gave
much lower ee’s for the reaction of aliphatic aldehydes.5 For
example, even at ꢁ40 ꢀC, (S)-2 catalyzed the addition of
TMSCN to heptaldehyde with only 66% ee. In general,
very few catalysts could give consistently good results
for the asymmetric reaction of aliphatic aldehydes with
TMSCN in spite of a good number of highly enantioselective
catalysts for the reaction of aromatic aldehydes.31 Therefore,
we explored the application of (S)-6 for the asymmetric
reaction of aliphatic aldehydes with TMSCN.
In Table 11, the results for the reaction of octyl aldehyde
with TMSCN in the presence of (S)-6 and Me2AlCl under

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Y.-C. Qin et al. / Tetrahedron 62 (2006) 9335–9348
Table 12. Asymmetric addition of TMSCN to aliphatic aldehydes in the
presence of (S)-6 and Me2AlCl
TMSO
CN
O
(S)-6 or (S)-8 (10 mol%)
Me2AlCl (10 mol%)
Aldehydea
Product
Yield (%) ee (%)
+
TMSCN
Entry
1
4Å MS, Additive
OAc
O
N
CHO
6
91
92
87
97
98
96
Additive: Ph3P=O,
HMPA,
CN
6
O
OAc
CHO
7
2
3
CN
Scheme 10. Reaction of acetophenone with TMSCN.
7
3
OAc
CHO
3
CN
3. Summary
OAc
CHO
CHO
CHO
In summary, we have developed the efficient one-step syn-
thesis of the bifunctional BINOL and H8BINOL ligands
(S)-6 and (S)-8 from the reaction of BINOL and H8BINOL
with morpholinomethanol, respectively. The X-ray analyses
of these compounds have revealed their structural similarity
and difference. The bifunctional H8BINOL (S)-8 is found to
be highly enantioselective for the reaction of diphenylzinc
with many aliphatic and aromatic aldehydes and especially
is the most enantioselective catalyst for linear aliphatic alde-
hydes. Unlike other catalysts developed for the diphenylzinc
addition which often require the addition of a significant
amount of diethylzinc with cooling (or heating) the reaction
mixtures in order to achieve high enantioselectivity, using
(S)-8 needs no additive and gives excellent results at room
temperature. (S)-8 in combination with diethylzinc and
Ti(OiPr)4 can catalyze the highly enantioselective phenyl-
actylene addition to aromatic aldehydes. It can also promote
the phenylacetylene addition to acetophenone at room tem-
perature though the enantioselectivity is not very high yet.
Without using Ti(OiPr)4 and a Lewis base additive, (S)-8
in combination with diethylzinc can catalyze the reaction
of methyl propiolate with an aldehyde to form the highly
functional g-hydroxy-a,b-acetylenic esters except that the
enantioselectivity is low at this stage. The bifunctional
BINOL ligand (S)-6 in combination with Me2AlCl is found
to be a highly enantioselective catalyst for the addition of
TMSCN to both aromatic and aliphatic aldehydes.
4
90
99
CN
OAc
5
6
65
72
97
96
CN
OAc
CN
OAc
CN
CHO
7
8
86
70
95
98
OAc
CN
CHO
OAc
CN
CHO
9
74
67
90
94
96
92
OAc
CN
CHO
10
OAc
CN
CHO
CO2Me
Freshly distilled.
11
CO2Me
a
4. Experimental
(J¼6.4 Hz) appeared, which was attributed to –CH(CN)O-
Si(CH3)3. Complicated aromatic signals were also observed,
which were assigned to the aluminum complexes of the
ligand. After the complete conversion of the aldehyde to
the product, a C2-symmetric complex might be generated
because of the greatly simplified aromatic signals. However,
the structure of this complex could not be determined yet.
4.1. Preparation and characterization of (S)-3,30-
morpholinomethyl-1,10-bi-2-naphthol, (S)-6
To a 250 mL round bottom flask containing paraformalde-
hyde (30.0 g, 1.0 mol), morpholine (88 mL, 1.0 mol) was
added dropwise at 0 ꢀC over 1 h with rigorous stirring. (Cau-
tion: this was a highly exothermic reaction.) The reaction
mixture was allowed to warm up to room temperature. After
4 h, the mixture was slowly heated to 60 ꢀC and maintained
at the temperature for 10 h. This led to the formation of mor-
pholinomethanol as a clear syrup-like liquid. Morpholino-
methanol (60 mL) was combined with (S)-BINOL (3.0 g,
0.0106 mol) and degassed by bubbling with N2. The mixture
was placed in a Parr Non-Stirred Pressure Vessel (Series
4750 1.50 Inch Inside diameter, 125 mL) under 25–30 psi
N2 and heated at 110ꢂ2 ꢀC for 72 h. Diethyl ether was
then added after the reaction, and part of the product (S)-6
precipitated out as a white solid. The white solid was washed
twice with diethyl ether. The diethyl ether solutions were
We also used (S)-6 and (S)-8 to catalyze the cyanosilylation
of acetophenone (Scheme 10).33 The same amounts of
˚
ligands, Me2AlCl, and 4 A molecular sieves as used in the
cyanosilylation of benzaldehyde were applied to this reac-
tion. Various additives were examined. Using Ph3P]O
(40 mol %) or HMPA (40 mol %) as the additive gave very
low yield of the product with no enantioselectivity at
ꢁ20 ꢀC, 0 ꢀC or room temperature. We also tested the use
of N-methylmorpholine N-oxide (10, 20 or 40 mol %) as
the additive at 0 ꢀC or room temperature. Despite the high
yield, only the racemic product was obtained.

Y.-C. Qin et al. / Tetrahedron 62 (2006) 9335–9348
9345
combined with ethyl acetate (100 mL) and washed three
times with 3% NaHCO3. The organic phase was then con-
centrated under vacuum and the residue was purified by
column chromatography on silica gel (size: 36 mm ID and
30 cm L) eluted with CH2Cl2/ethyl acetate (8:1) to give
(S)-6 and (S)-7. The combined yield of (S)-6 was 55%
(2.8 g). The optical purity of (S)-6 was determined by
HPLC analysis (vide infra) to be 75% ee. Yield of (S)-7
was 30% (1.2 g). The optical purity of this (S)-7 was deter-
mined by optical rotation measurement to be >87% ee [[a]D
ꢁ30.8 (c 1.0, CH2Cl2)]. For the preparation of the optically
pure (S)-7, see below. The product (S)-6 of 75% ee was dis-
solved in hot CH2Cl2/MeOH (3:1). The solution was cooled
to room temperature and needle-shaped crystals appeared,
which were found to be predominantly the racemic com-
pound [[a]D ꢁ1.9 to ꢁ4.5 (c 1.0, CH2Cl2)]. After separation
of the racemic crystals, the solution was concentrated under
vacuum and redissolved in hot CH2Cl2/MeOH (3:1). Cool-
ing again allowed the separation of the racemic crystals. Af-
ter this process was conducted for 3–4 times, removal of the
solvent from the mother liquor gave the optically pure (S)-6
(>99% ee, determined by HPLC vide infra). Sometimes,
a simple column chromatography on silica gel (size:
36 mm ID and 30 cm L; eluent: 6:1 CH2Cl2/ethyl acetate)
may be needed to remove impurities in the mother liquor af-
ter the crystallization. Mp 309–310 ꢀC. 1H NMR (500 MHz,
CDCl3) d 11.04 (s, 2H), 7.80 (m, 2H), 7.67 (s, 2H), 7.28 (m,
2H), 7.21 (m, 2H), 7.16 (m, 2H), 4.13 (m, 2H), 3.90 (m, 2H),
3.70 (m, 8H), 2.66 (m, 8H). 13C NMR (125 MHz, CDCl3)
d 153.4, 134.0, 128.5, 127.9, 126.3, 125.0, 123.4, 123.3,
116.8, 66.8, 62.6, 53.1. [a]D ꢁ152.1 (c 1.0, CH2Cl2).
Anal. Calcd for C30H32N2O4: C, 74.36; H, 6.66; N, 5.78.
Found: C, 74.60; H, 6.82; N, 6.05. High-resolution mass
analysis: calcd for C30H32N2O4: 484.2362. Found:
484.2350.
chromatography on silica gel (size: 36 mm ID and
30 cm L) eluted with CH2Cl2/ethyl acetate (12:1) to give
(S)-7 in 52% yield (1.9 g) and (S)-6 in 10% yield (0.46 g,
>99% ee by HPLC). (S)-7 as a white solid from this reaction
was considered to be optically pure since the optical purity of
(S)-6 obtained from this reaction was found to be >99%
ee by HPLC. In addition, the optical purity of (S)-7
(>97% ee) was supported by the 1H NMR studies of (S)-7,
(R)-7, and racemic-7 in the presence of 10 mol % chiral
shift reagent Eu(hfc)3 {Europium tris[3-(heptafluoropropyl-
hydroxymethylene)-(+)-camphorate]} (vide infra). Mp
1
215.5–216.5 ꢀC. H NMR (300 MHz, CDCl3) d 7.74–7.93
(m, 4H), 7.10–7.39 (m, 7H), 4.015 (s, 2H), 3.71 (m, 4H),
2.66 (m, 4H). 13C NMR (75 MHz, CDCl3) d 154.8, 151.6,
134.1, 133.8, 130.2, 129.7, 129.5, 128.7, 128.6, 128.0,
127.3, 126.7, 125.0, 124.8, 124.1, 123.7, 123.5, 117.8,
115.2, 113.1, 66.7, 62.5, 53.1. [a]D ꢁ35.1 (c 1.0, CH2Cl2).
Anal. Calcd for C25H23NO3: C, 77.90; H, 6.01; N, 3.63.
Found: C, 78.16; H, 5.99; N, 3.80. High-resolution mass
analysis: calcd for C25H23NO3: 385.1677. Found: 385.1662.
1
Determination of the optical purity of (S)-7 and (R)-7. H
NMR spectrums of (S)-7, (R)-7, and racemic-7 in the pres-
ence of 10 mol % chiral shift reagent Eu(hfc)3 {Europium
tris[3-(heptafluoropropylhydroxyl methylene)-(+)-camphor-
ate]} were studied. Before the addition of the chiral shifting
reagent, there was no signal at d 7.39–7.73. After the samples
were treated with Eu(hfc)3 (10 mol %), new peaks appeared
at d 7.63 and/or 7.53 as summarized in Table 13. These data
support the high optical purity of (S)-7 and (R)-7.
Table 13. Resolution of the 1H NMR signals of the enantiomers of 7 in the
presence of the chiral shift reagent
Sample
1H NMR signals
d¼7.63 d¼7.53
The enantiomeric purity of (S)-6 was determined by HPLC
analysis of its acetate derivative: To a CH2Cl2 (5 mL) solu-
tion of (S)-6(13 mg) were added Ac2O (250 mL) and pyridine
(250 mL). After the solution was stirred at room temperature
for 6 h, thevolatiles were removed under vacuum. The result-
ing acetate of (S)-6 as a white solid was purified by column
chromatography on aluminum oxide (size: 12 mm ID and
10 cm L) eluted with petroleum ether/ethyl acetate (4:1).
1H NMR (300 MHz, CDCl3) d 8.02 (s, 2H), 7.88 (m, 2H),
7.44 (m, 2H), 7.24 (m, 2H), 7.14 (m, 2H), 3.52–3.76 (m,
12H), 2.50 (m, 8H), 1.80 (s, 6H). HPLC (CHIRALCEL
AD) was used to measure the ee% of the acetate. Solvent:
hexane/isopropanol (98:2). Flow rate: 1.0 mL/min. Reten-
tion times: tR¼31.0 min and tS¼35.5 min.
(S)- or (R)- or Rac-7
0H
1H
0H
1H
0H
1H
1H
0H
Rac-7+10 mol % Eu(hfc)3
(S)-7+10 mol % Eu(hfc)3
(R)-7+10 mol % Eu(hfc)3
4.3. Preparation and characterization of (S)-3,30-bis-
morpholinomethyl-5,50,6,60,7,70,8,80-octahydro-1,10-
bi-2-naphthol, (S)-8
To a 250 mL round bottom flask containing 1,4-dioxane
(30 mL) solution of (S)-H8BINOL (5.0 g, 0.017 mol) was
added morpholinomethanol (50 mL) at room temperature.
After the mixture was heated at 60 ꢀC for 12 h with stirring,
it was cooled down to room temperature and combined with
ethyl acetate (150 mL) in a separation funnel. The organic
layer was then washed with saturated NaHCO3 (3ꢃ
100 mL) and water (2ꢃ100 mL). Removal of ethyl acetate
gave (S)-8 as a white solid (8.0 g, 95% yield). Recrystalliza-
tion of this compound from ethanol gave white needle crys-
4.2. Preparation and characterization of (S)-3-morpho-
linomethyl-1,10-bi-2-naphthol, (S)-7
A mixture of (S)-BINOL (3.0 g, 0.0106 mol) and morpholi-
nomethanol (50 mL) in a Parr Non-Stirred Pressure Vessel
(Series 4750 1.50 Inch Inside diameter, 125 mL) was de-
gassed with nitrogen and then sealed under 30 psi nitrogen.
After being heated at 95–100 ꢀC for 48 h, the reaction
mixture was diluted with ethyl acetate (150 mL) at room
temperature, and washed with 3% sodium bicarbonate
(2ꢃ60 mL) and water (100 mL). After rotoevaporation of
the organic solution, the residue was purified by column
1
tals. H NMR (500 MHz, toluene-d8) d 9.99 (s, 2H), 6.62
(s, 2H), 3.20–3.36 (m, 12H), 2.75 (m, 6H), 2.42 (m, 2H),
2.07 (m, 8H), 1.63–1.72 (m, 8H). 13C NMR (125 MHz, tolu-
ene-d8) d 153.14, 136.44, 128.54, 127.19, 125.031, 118.26,
66.72, 62.19, 53.04, 29.91, 27.61, 24.04, 23.91. [a]D25
ꢁ35.4 (c 1.04, THF). Anal. Calcd for C30H40N2O4: C,

9346
Y.-C. Qin et al. / Tetrahedron 62 (2006) 9335–9348
73.14; H, 8.18; N, 5.69. Found: C, 73.22; H, 8.20; N, 5.66.
High-resolution mass analysis: calcd for C30H40N2O4:
492.2988. Found. 492.2969.
dimethylamino)pyridine (22 mg, 0.18 mmol), and (R)-ace-
toxyphenylacetic acid (30.0 mg, 0.18 mmol). The reaction
was monitored by TLC and was judged to be completed after
15 min. The reaction mixture was concentrated and purified
by flash column chromatography on silica gel (size:
36 mm ID and 30 cm L) eluted with 20% ether in hexane
to give a clear oil. The NMR integrations of chemical shift
at d 5.96, 5.91, 3.78, and 3.75 were used to determine the
enantiomeric excess.
4.4. A typical procedure for the asymmetric diphenyl-
zinc addition to aldehydes
Under nitrogen to a 10 mL round bottom flask (flame dried
under vacuum) were added diphenylzinc (66 mg, 0.3 mmol,
1.2 equiv), (S)-6 or (S)-8 (0.025 mmol, 0.1 equiv), and a sol-
vent (2.0 mL, anhydrous) sequentially. After the resulting
solution was stirred at room temperature for 1 h, an aldehyde
(0.25 mmol) was added and the reaction was monitored by
TLC. At the completion of the reaction, ammonium chloride
(saturated, aq) was added to quench the reaction. The mixture
was extracted with methylene chloride three times. After
removal of the solvents, the residue was purified by column
chromatography on silica gel (size: 12 mm ID and 15 cm L)
eluted withhexanes/ethyl acetate (12:1) to givetheproduct as
either colorless oil or white solid in 75–97% yield.
4.8. A typical procedure for the catalytic cyanosilylation
of aldehydes in the presence of (S)-6
Under nitrogen, a mixture of (S)-6 (12.1 mg, 0.025 mmol),
ꢀ
˚
4 A molecular sieves(5 mg, activated at 180 C 30 minunder
0.09 mmHg vacuum), and diethyl ether (1 mL, dried) was
stirred for 10 min and Me2AlCl (25 mL, 0.025 mmol, 1 M
hexane solution) was added. After stirred for 3 h, a white sus-
pension formed to which HMPA (16 mL, 0.1 mmol) was
added. The mixture was cooled down to ꢁ20 ꢀC, and
TMSCN (105 mL, 0.75 mmol) was added in one portion. In
5 min, an aldehyde (0.25 mmol, freshly distilled) was also
added in one portion. After the reaction mixture was stirred
at ꢁ20 ꢀC for 24 h, water (1 mL) was added to quench the re-
action at ꢁ20 ꢀC. At room temperature, diethyl ether (2 mL)
was added to dilute the reaction, and the diethyl ether solution
was washed twice with water. (Removal of the solvent
followed by column chromatography on silica gel (size:
12 mm ID and 10 cm L) eluted with hexanes/ethyl acetate
(20:1) would give the pure cyanosilyl ether product.) In order
to prepare the acetate derivative for ee determination, the di-
ethyl ether solution of the crude silyl ether was treated with
2 N HCl (5 mL) and stirred for 2 h to remove the trimethyl-
silyl group. Then, CH2Cl2 (3ꢃ4 mL) was used for extraction.
The organic layers were combined and then treated with ace-
tic anhydride (0.2 mL) and pyridine (50 mL). After stirred for
1 h, the reaction mixture was concentrated by rotoevapora-
tion and the residue was purified by column chromatography
on silica gel (size: 12 mm ID and 10 cm L) eluted with hex-
anes/ethyl acetate (15:1) to give the cyano acetate product.
The enantiomeric purity of O-acetyl cyanohydrin was deter-
mined by GC analysis. Conditions: HP 6890 series GC;
Supelco Beta-Dex 120 Fused silica capillary column (30 m
lengthꢃ0.25 mm IDꢃ0.25 mm film thickness); constant
flow rate at 1.0 mL/min; inlet temperature 250 ꢀC; FID
detector temperature 280 ꢀC.
4.5. General procedure for the phenylacetylene addition
to aromatic aldehydes catalyzed by (S)-8
Under nitrogen to a 10 mL round bottom flask (flame dried
under vacuum) were added phenylacetylene (1.0 mmol,
113 mL), THF (3 mL), Et2Zn (1.0 mmol, 110 mL), Ti(OiPr)4
(74 mL, 0.25 mmol), (S)-8 (12.3 mg, 0.025 mmol), and an
aldehyde (0.25 mmol). After the resulting reaction mix-
ture was stirred at room temperature for 4 h, a saturated
ammonium chloride solution was added to quench the reac-
tion. The mixture was extracted with methylene chloride
(3ꢃ5 mL) and the organic solution was concentrated under
vacuum. The residue was purified by passing through a short
silica gel column (size: 12 mm ID and 10 cm L) eluted with
methylene chloride/hexane (1:1), which afforded the pure
propargylic alcohol product.
4.6. A typical procedure for the asymmetric methyl
propiolate addition to aldehyde in the presence of (S)-8
(S)-8 (12.3 mg, 0.025 mmol, 0.1 equiv) and 3 mL solvent
were added into a 10 mL round bottom flask (flame dried
under vacuum). Then diethylzinc (33 mL, 0.3 mmol,
1.2 equiv) and phenylacetylene (26 mL, 0.3 mmol, 1.2 equiv)
were added sequentially. After the resulting solution was
stirred at room temperature for 1 h, it was cooled down
to ꢁ20 ꢀC. Valeraldehyde (27 mL, 0.25 mmol) was added
and the reaction was monitored by TLC at ꢁ20 ꢀC. At the
completion of the reaction in 6–12 h, ammonium chloride
(saturated, aq) was added to quench the reaction. The mixture
was extracted with methylene chloride three times. After
removal of the solvents, the residue was purified by column
chromatography on silica gel (size: 12 mm ID and 10 cm L)
eluted withhexanes/ethyl acetate (12:1) to givetheproduct as
colorless oil.
4.9. Catalytic cyanosilylation of acetophenone in the
presence of (S)-6 and (S)-8
˚
Under nitrogen, a mixture of (S)-6 or (S)-8 (0.025 mmol), 4 A
molecular sieves (5 mg, activated at 180 ꢀC for 30 min under
0.09 mmHg vacuum), and a solvent (1 mL, dried) was stirred
for 10 min and Me2AlCl (25 mL, 0.025 mmol, 1 M hexane
solution) was added. After stirred for 3 h, a white suspension
formed to which an additive was added. The mixture was
cooled down to ꢁ20 ꢀC (or kept at room temperature), and
TMSCN (105 mL, 0.75 mmol) was added in one portion. In
5 min, acetophenone (30 mL, 0.25 mmol, freshly distilled)
was also added in one portion. After the reaction mixture
was stirred at ꢁ20 ꢀC for 24–48 h, water (1 mL) was added
to quench the reaction. At room temperature, diethyl ether
(2 mL) was added to dilute the reaction, and the diethyl ether
4.7. A typical procedure for preparation of the
derivative of 4-hydroxy-oct-2-ynoic acid methyl ester
To a solution of 4-hydroxy-oct-2-ynoic acid methyl
ester (0.09 mmol) at room temperature was added 1,3-
dicyclohexylcabodiimde (37 mg, 0.18 mmol), 4-(N,N-

Y.-C. Qin et al. / Tetrahedron 62 (2006) 9335–9348
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solution was washed twice with water. Removal of the
solvent followed by column chromatography on silica gel
(size: 12 mm ID and 10 cm L) eluted with hexanes/ethyl ace-
tate (20:1) would give the pure cyanosilyl ether product. The
enantiomeric purity was determined by GC analysis. Condi-
tions: HP 6890 series GC; Supelco Beta-Dex 120 Fused silica
capillary column (30 m lengthꢃ0.25 mm IDꢃ0.25 mm film
thickness); constant flow rate at 1.0 mL/min; inlet tempera-
ture 250 ꢀC; FID detector temperature 280 ꢀC.
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Acknowledgements
Support of this work from the National Institute of Health
(R01GM58454/R01EB002037) is gratefully acknowledged.
Supplementary data
Analytical data for the catalytic addition products. Supple-
mentary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2006.06.049.
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