The syntheses of new camphorsulfonylated ligands derived from 2-amino-2'-hydroxy-1,1'-binaphthyl and their enantioselectivities in the addition of dialkylzinc reagents to aldehydes

Article abstract of DOI:10.1002/chir.22078

A series of new camphorsulfonylated ligands derived from chiral 2-amino-2'-hydroxy-1,1'-binaphthyl (NOBIN) and (+)-camphorsulfonic acid were synthesized by a short and simple synthetic sequence, and their enantioselective catalytic activities were assessed in the nucleophilic addition reaction of dialkylzinc reagents to aldehydes in the presence of titanium tetraisopropoxide. The most efficient ligand, N-hydroxycamphorsulfonylated (S)-NOBIN, gave (S)-addition products with good yields and up to 87% of ee value. The ¹H nuclear magnetic resonance (NMR) and ¹³C NMR results of the titanium titration experiments on this ligand indicate that the most likely catalytic reactive species involved in this catalytic asymmetric addition is a bimetallic titanium complex. A possible catalytic reaction mechanism is proposed. Copyright

Full text of DOI:10.1002/chir.22078

CHIRALITY (2012)
The Syntheses of new Camphorsulfonylated Ligands Derived from
0
0
2
-Amino-2 -Hydroxy-1,1 -Binaphthyl and Their Enantioselectivities in
the Addition of Dialkylzinc Reagents to Aldehydes
1,2
1,2
1,2
1,2
GUANGLING BIAN, HUAYIN HUANG, HUA ZONG, AND LING SONG
*
1
The Key Laboratory of Coal to Ethylene Glycol and Its Related Technology, Chinese Academy of Sciences, Fuzhou, Fujian, China
2
The State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou,
Fujian, China
0
ABSTRACT
A series of new camphorsulfonylated ligands derived from chiral 2-amino-2 -
0
hydroxy-1,1 -binaphthyl (NOBIN) and (+)-camphorsulfonic acid were synthesized by a short
and simple synthetic sequence, and their enantioselective catalytic activities were assessed in
the nucleophilic addition reaction of dialkylzinc reagents to aldehydes in the presence of tita-
nium tetraisopropoxide. The most efficient ligand, N-hydroxycamphorsulfonylated (S)-NOBIN,
1
gave (S)-addition products with good yields and up to 87% of ee value. The H nuclear magnetic
1
3
resonance (NMR) and C NMR results of the titanium titration experiments on this ligand indi-
cate that the most likely catalytic reactive species involved in this catalytic asymmetric addition is
a bimetallic titanium complex. A possible catalytic reaction mechanism is proposed. Chirality
0
0:000–000, 2012. © 2012 Wiley Periodicals, Inc.
KEY WORDS: camphorsulfonamide; titanium complex; asymmetric catalysis; dialkylzinc addition
INTRODUCTION
structure could be expected to give higher enantioselectivity.
With the use of the synergistic coordination of phenolate
The stereoselective nucleophilic addition of organometallic
reagents to aldehydes or ketones is an efficient and versatile
method to generate chiral alcohols. These alcohols are not
only components of many naturally occurring biologically
active compounds but also valuable intermediates for the
syntheses of other functionalities, such as halides, amides,
0
0
oxygen atom with titanium, 2-amino-2 -hydroxy-1,1 -binaphthyl
NOBIN) may replace the flexible alkoxide bridge and gener-
(
ate a more rigid catalyst structure. To verify our assumption,
we report our investigation on the syntheses of new chiral
camphorsulfonamides derived from NOBIN and the studies of
their enantioselective catalytic activities in the addition of
dialkylzinc reagents to aldehydes.
1
esters, and ethers. Concerning this subject, the asymmetric
addition of organozinc reagents to carbonyl groups has been
extensively investigated, and numerous chiral ligands2
containing a variety of structures have been developed.
Despite significant efforts so far, the development of new
high efficient catalytic system remains as enduring interest.
Since Ramón and Yus firstly reported several camphorsul-
fonamide ligands promoting addition of dialkylzincs to alde-
EXPERIMENTAL
General Information
Rotations were measured on SGW-1 automatic polarimeter (Precision
1
Scientific Instrument Co., Ltd., Shanghai, China). The H nuclear magnetic
1
3
resonance (NMR) and C NMR spectra were recorded on a Bruker Avance
00 MHz spectrometer (Switzerland). Elemental analyses were performed
3
–5
4
hydes and ketones in the presence of titanium alkoxide,
on Vario MICRO CHONS analyzer (Germany ELEMENTAR). Electrospray
ionization mass spectrometry (ESI-MS) spectra were obtained at 70 eV on a
Thermo Finnigan DECAX-30000 LCQ Deca XP spectrometer (Switzerland)
giving fragment ions in m/z with relative intensities (%) in parentheses. Gas
chromatography (GC) analyses were performed on 9790 II chromatograph
many camphorsulfonamide ligands derived from various
aliphatic and aromatic monoamines and diamines have been
tested in the addition of dialkylzinc reagents to carbonyl
groups with varying success in the presence of titanium
6
–28
alkoxide.
hydroxycamphorsulfonamide) ligand derived from (R,R)-
,2-cyclohexyl diamine, has been shown to be the best one
Among these ligands, Walsh’s HOCSAC, a bis
(Fuli Analytical Instrument Co., Ltd., Zhejiang, China) by using a Varian CP-
(
1
Chirasil Dex CB column (25 m ꢀ 0.32 mm) (USA). All solvents used were
dried and purified by using standard, published methods. All aldehydes,
so far to give excellent results with up to 99% ee value using
only 2% catalyst loading. Compared with the diverse camphor-
sulfonamides derived from monoamines and diamines, the
camphorsulfonamide ligands derived from amino alcohols
4
NaBH , and diethylzinc (1.5 M solution in toluene) were purchased from
Acros and were used directly. Dimethylzinc (1.0 M solution in toluene) and
Additional Supporting Information may be found in the online version of this
article.
Contract grant sponsor: Natural Science Foundation of Fujian Province,
China; Contract grant number: 2010J01055.
Contract grant sponsor: State Key Lab of Structural Chemistry, Fujian Insti-
tute of Research on the Structure of Matter, Chinese Academy of Sciences.
Contract grant sponsor: The Scientific Research Foundation for the Returned
Overseas Chinese Scholars, State Education Ministry.
2
9–31
have rarely emerged.
According to the investigations by others, the design of
camphorsulfonamide ligand has been based on the mecha-
nism that the bimetallic titanium complexes are the active
5
,18,28
catalytic species,
which have both a highly electrophilic,
*
Correspondence to: Ling Song, The State Key Lab of Structural Chemistry,
pentacoordinated, positively charged titanium center and a
highly nucleophilic, hexacoordinated, negatively charged
titanium center.32 The two titanium centers are bridged with
the flexible alkoxide, whose flexibility is likely to decrease
enantioselectivity. We assume that a more rigid catalyst
Fujian Institute of Research on the Structure of Matter, Chinese Academy of
Sciences, Fuzhou, Fujian 350002, China. E-mail: songling@fjirsm.ac.cn
Received for publication 14 December 2011; Accepted 09 May 2012
DOI: 10.1002/chir.22078
Published online in Wiley Online Library
(wileyonlinelibrary.com).
©
2012 Wiley Periodicals, Inc.

BIAN ET AL.
+)-(S)-10-camphorsulfonic acid were purchased from J&Kchemical and were
(
(d, J = 8.1 Hz, 1H, ArH), 7.80 (d, J = 9.0 Hz, 1H, ArH), 7.56–7.52 (t, 1H, ArH),
.45–7.36 (m, 2H, ArH), 7.33–7.26 (m, 2H, ArH), 7.09 (d, J= 8.4 Hz, 1H,
ArH), 6.84 (s, 1H, NH), 3.52 (d, J = 14.9 Hz, 1H, CH S), 3.01
S), 2.42
, CH), 0.96, 0.81, 0.72,
) d (ppm): 214.73, 213.12,
i
used directly. Ti(O Pr)
4
purchased from Aldrich was freshly distilled prior
7
to use. (R)-NOBIN and (S)-NOBIN were prepared according to literature
2
33
procedures. Unless otherwise noted, all reactions were carried out under
nitrogen atmosphere by using standard Schlenk and vacuum line techniques.
(
(
d, J= 14.9Hz, 1H, CH
d, J = 14.9Hz, 1H, CH S), 2.28–1.24 (m, 14H, CH
2 2
S), 2.72 (d, J = 14.9 Hz, 1H, CH
2
2
1
3
0
1
1
1
2
3 3
.57 (s, 12H, CH ); C NMR (100 MHz, CDCl
Preparation of Bisketocamphorsulfonylated NOBIN 1–2
General procedure of synthesis of the investigated sulfonamides is shown
in Scheme 1. Initially, the (+)-(S)-10-camphorsulfonyl chloride was prepared
46.05, 134.37, 133.03, 132.43, 131.25, 130.73, 130.30, 128.52, 128.08,
27.91, 127.40, 126.78, 125.95, 125.70, 125.44, 123.95, 121.86, 120.18,
19.92, 58.57, 57.63, 50.98, 49.03, 48.07, 47.71, 42.75, 42.72, 42.40, 42.25,
from (+)-(S)-10-camphorsulfonic acid by reflux in SOCl
bisketocamphorsulfonylated NOBIN were obtained as follows: 17.5mmol
of Et and 0.2 mmol of 4-(dimethylamino)pyridine (DMAP) were
2
. The investigated
6.80, 26.75, 25.45, 24.87, 19.72, 19.62, 19.37, 19.31; ESI-MS calce for
+
3
N
[C40
H43NO S
7 2
+ Na] 736.24, found 736.5; Anal. Calcd for C40
7 2
H43NO S :
added to the solution of (R)-NOBIN and (S)-NOBIN (3.5mmol) in tetrahy-
drofuran (THF) (20 ml) at room temperature, respectively, then (+)-(S)-10-
camphorsulfonyl chloride (10.5 mmol) was added in portions at 0 C and
C, 67.30, H, 6.07, N, 1.96, O, 15.69, S, 8.98, Found: C, 67.14, H, 5.97, N,
1.90, O, 16.05, S, 9.02.
ꢁ
the reaction mixture was stirred for 2.5 h at room temperature. The reaction
mixturewas subsequentlyquenched byadding 100ml of water, extracted by
EtOAc (3 ꢀ 50ml), washed by brine (50ml), dried over anhydrous sodium
sulfate, and filtered. The filtrate was concentrated in vacuo to give a residue,
which was purified by column chromatography (eluting with n-hexane/
EtOAc = 4/1) to provide the titled products correspondingly.
Preparation of Mono-N-ketocamphorsulfonylated NOBIN 3–4
The general procedure of hydrolysis of 1–2 to give 3–4 is as follows: 4 ml
of 3 M sodium hydroxide solution was added to the solution of bisketocam-
phorsulfonylated NOBIN 1–2 (1mmol) in EtOH (10ml) and THF (10ml),
respectively, then the reaction mixture was refluxed for 24 h. After comple-
tion, the reaction mixture was cooled to room temperature, quenched by
adding 12 ml of 1 M hydrochloric acid, extracted with EtOAc (3ꢀ 30 ml),
washed by brine (30ml), dried over anhydrous sodium sulfate, and filtered.
The filtrate was concentrated in vacuo to give a residue, which was purified
by column chromatography (eluting with n-hexane/EtOAc = 4/1) to give
the corresponding titled products.
(R
a
)-1-[2-({[(1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-
yl]methane}sulfonamido))naphthalen - 1- yl])naphthalen - 2 - yl
(1S,4R)-7,7-dimethyl -2-oxobicyclo[2.2.1]heptan-1-yl]methane-
[
sulfonate (1). Colorless solid (90%); [a]3
400 MHz, CDCl ) d (ppm): 8.21 (d, J= 9.0 Hz, 1H, ArH), 8.12–8.06 (m, 2H,
ArH), 8.00 (d, J= 8.2 Hz, 1H, ArH), 7.91 (d, J= 8.1 Hz, 1H, ArH), 7.79
d, J= 9.0 Hz, 1H, ArH), 7.56–7.52 (t, 1H, ArH), 7.43–7.34 (m, 2H, ArH),
.30–7.24 (m, 2H, ArH), 7.06 (d, J= 8.5 Hz, 1H, ArH), 6.87 (s, 1H, NH), 3.34
d, J= 14.8 Hz, 1H, CH S), 3.18 (d, J= 14.9 Hz, 1H, CH S), 2.92
d, J=14.8Hz, 1H, CH S), 2.34–2.18 (m, 4H, CH S, CH ), 2.06–1.71 (m, 8H,
CH , CH), 1.39–1.17 (m, 3H, CH ), 0.96, 0.63, 0.59, 0.48 (s, 12H, CH
NMR (100 MHz, CDCl ) d (ppm): 214.65, 213.05, 145.87, 134.53, 133.10,
33.05, 132.43, 131.24, 130.68, 130.32, 128.55, 128.11, 127.96, 127.23, 126.81,
0
= +16.7 (c 0.6, THF); H NMR
1
D
(
3
(R )-1-[(1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl]-
a
(
7
(
(
N-[1-(2-hydroxynaphthalen-1-yl)naphthalen-2-yl]methanesul-
3
0
1
fonamide (3). Colorless solid (96%); [a]
D
=ꢂ18.2 (c 1.1, THF); H NMR
(400 MHz, CDCl
3
) d (ppm): 8.15–8.08 (m, 2H, ArH), 7.99–7.95 (m, 2H,
2
2
ArH), 7.91 (d, J= 8.0 Hz, 1H, ArH), 7.50–7.46 (t, 1H, ArH), 7.40–7.28 (m, 4H,
ArH), 7.19 (d, J= 8.5 Hz, 1H, ArH), 7.03 (d, J= 8.4 Hz, 1H, ArH), 6.79 (s, 1H,
2
2
2
13
2
2
3
);
C
NH), 5.56 (s, 1H, OH), 3.36 (d, J= 14.8 Hz, 1H, CH
1H, CH S), 2.30–1.27 (m, 7H, CH , CH), 0.98, 0.64 (s, 6H, CH
(100 MHz, CDCl ) d (ppm): 215.52, 152.01, 134.86, 133.42, 133.23, 131.47,
2
S), 2.82 (d, J=14.8Hz,
3
13
1
1
4
1
2
2
3
); C NMR
25.95, 125.79, 125.29, 124.01, 121.91, 119.79, 119.77, 58.64, 57.56, 50.91,
9.16, 48.12, 47.57, 42.70, 42.58, 42.44, 42.18, 26.88, 26.73, 25.54, 24.50,
9.61, 19.50, 19.17, 19.13; ESI-MS calce for [C40
3
131.28, 130.59, 129.47, 128.55, 128.37, 127.61, 127.43, 125.70, 125.52, 124.08,
124.00, 120.79, 120.18, 118.24, 113.22, 58.75, 50.49, 48.05, 42.75, 42.37, 26.79,
+
H
43NO
7
S
2
+Na] 736.24,
25.44, 19.66, 19.52; ESI-MS calce for [C30
522.3; Anal. Calcd for C30 29NO S: C, 72.12, H, 5.85, N, 2.80, O, 12.81, S,
.42, Found: C, 71.99, H, 5.90, N, 2.68, O, 13.03, S, 6.32.
H29NO
4
S+Na]+ 522.17, found
found 736.3; Anal. Calcd for C40
H
43NO
7
S
2
: C, 67.30, H, 6.07, N, 1.96, O,
15.69, S, 8.98, Found: C, 66.88, H, 6.01, N, 1.87, O, 16.30, S, 8.69.
H
4
6
(S
a
)-1-[2-({[(1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl]
methane}sulfonamido))naphthalen-1-yl])naphthalen-2-yl[(1S,4R)-
,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl]methanesulfonate
a
(S )-1-[(1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl]-N-
7
(
[1-(2-hydroxynaphthalen-1-yl)naphthalen-2-yl]methanesulfo-
2). Colorless solid (89%); [a]3
0
= +51.7 (c 0.7, THF); H NMR (400MHz,
1
namide (4). Colorless solid (94%); [a]
30
1
D
D
= +69.3 (c 0.7, THF); H NMR
3
CDCl ) d (ppm): 8.19–8.05 (m, 3H, ArH), 8.01 (d, J = 8.2 Hz, 1H, ArH), 7.92
(400MHz, CDCl ) d (ppm): 8.15 (d, J = 9.0Hz, 1H, ArH), 8.07 (d, J = 9.1Hz,
3
0
0
Scheme 1. Preparation of camphorsulfonamides derived from 2-amino-2 -hydroxy-1,1 -binaphthyl.
Chirality DOI 10.1002/chir

DIALKYLZINCS ASYMMETRIC ADDITION TO ALDEHYDES
1
H, ArH), 7.98–7.90 (m, 3H, ArH), 7.48–7.27 (m, 5H, ArH), 7.18 (d,
Preparation of Mono-N-hydroxycamphorsulfonylated
NOBIN 7–8
J= 8.5 Hz, 1H, ArH), 7.05 (d, J = 8.4 Hz, 1H, ArH), 6.76 (s, 1H, NH), 5.70 (s,
1
2
H, OH), 3.46 (d, J= 14.9 Hz, 1H, CH
.30–1.26 (m, 7H, CH , CH), 0.97, 0.72 (s, 6H, CH
) d (ppm): 215.67, 151.96, 135.20, 133.24, 133.14, 131.38, 131.26,
30.67, 129.52, 128.53, 128.37, 127.62, 127.56, 125.63, 125.29, 124.13,
23.99, 119.85, 118.86, 118.07, 112.95, 58.67, 50.42, 48.23, 42.68, 42.43,
2
S), 2.83 (d, J= 14.9Hz, 1H, CH
2
S),
The general procedure of reduction of 1–2 to give 7–8 is as follows: NaBH
4
13
ꢁ
2
3
); C NMR (100 MHz,
(10 mmol) was slowly added in portions at ꢂ20 C to the solution of bisketo-
CDCl
3
camphorsulfonylated NOBIN 1–2 (1 mmol) in EtOH (20 ml), respectively.
1
1
2
The mixture was stirred at this temperature for 2 h and then continued to stir
ꢁ
for 3 h at 25 C. The mixture was quenched by adding 10 ml of saturated
+
ammonium chloride, extracted with EtOAc (3 ꢀ 30 ml), washed by brine
6.82, 25.22, 19.69, 19.62; ESI-MS calce for [C30
29NO S: C, 72.12, H, 5.85, N, 2.80, O,
2.81, S, 6.42, Found: C, 72.05, H, 5.75, N, 2.88, O, 12.70, S, 6.52.
4
H29NO S+ Na] 522.17,
(
30 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was
found 522.3; Anal. Calcd for C30
1
H
4
concentrated in vacuo to give a residue, which was purified by column
chromatography (eluting with n-hexane/EtOAc= 4/1) to give the titled
products correspondingly.
Preparation of Bishydroxycamphorsulfonylated NOBIN 5–6
a
(R )-1-[(1S,2R,4R)-2-hydroxy-7,7-dimethylbicyclo[2.2.1]heptan-
The general procedure of reduction of 1–2 to give 5–6 is as follows:
1
-yl]-N-[1-(2-hydroxynaphthalen-1-yl)naphthalen-2-yl]methanesulfo-
ꢁ
NaBH
4
(10 mmol) was slowly added in portions at ꢂ20 C to the solution
30
1
namide (7). Colorless solid (80%); [a]
D
=ꢂ76.7 (c 1.0, THF); H NMR
of bisketocamphorsulfonylated NOBIN 1–2 (1 mmol) in EtOH (20 ml),
respectively, then the reaction mixture was stirred at this temperature
for 12 h and quenched by adding 10 ml of saturated ammonium chloride.
The mixture was allowed to warm up to room temperature, extracted with
EtOAc (3 ꢀ 30 ml), washed by brine (30 ml), dried over anhydrous
sodium sulfate, and filtered. The filtrate was concentrated in vacuo to give
a residue, which was purified by column chromatography (eluting with
n-hexane/EtOAc = 4/1) to give the titled products correspondingly.
(
3
400 MHz, CDCl ) d (ppm): 8.17 (d, J= 9.0 Hz, 1H, ArH), 8.06–7.93 (m, 4H,
ArH), 7.54–7.50 (t, 1H, ArH), 7.43–7.32 (m, 4H, ArH), 7.27 (d, J= 8.6 Hz, 1H,
ArH), 7.02 (d, J= 8.3 Hz, 1H, ArH), 6.14 (s, 2H, NH, ArOH), 3.25–3.21 (m,
1H, CHO), 3.17 (d, J=13.6Hz, 1H, CH
2
S), 2.37 (d, J= 13.6 Hz, 1H, CH
, CH), 0.81, 0.64 (s, 6H,
CH3); C NMR (100 MHz, CDCl ) d (ppm): 152.20, 152.17, 134.20, 133.24,
2
S),
2.24 (d, J= 3.5 Hz, 1H, OH), 1.61–0.87 (m, 7H, CH
2
13
3
1
1
4
33.10, 132.05, 132.03, 131.37, 131.07, 129.23, 128.81, 128.51, 128.01, 127.60,
26.16, 125.63, 124.20, 123.34, 118.33, 112.96, 76.47, 52.36, 50.28, 48.65,
ꢂ
4.07, 38.17, 30.39, 27.17, 20.32, 19.52; ESI-MS calce for [C30
H
31NO
4
Sꢂ H]
(R
a
)-1-[2-({[(1S,2R,4R)-2-hydroxy-7,7-dimethylbicyclo[2.2.1]
heptan-1-yl]methane}sulfonamido))naphthalen-1-yl])naphthalen-
-yl[(1S,2R,4R)-2-hydroxy-7,7-dimethylbicyclo[2.2.1]heptan-1-yl]
500.20, found 500.4; Anal. Calcd for C30
H
31NO
4
S: C, 71.83, H, 6.23, N, 2.79,
2
O, 12.76, S, 6.39, Found: C, 71.74, H, 6.24, N, 2.68, O, 12.86, S, 6.43.
methanesulfonate (5). Colorless solid (86%); [a]3
0
= ꢂ68.2 (c 0.9,
D
1
(S )-1-[(1S,2R,4R)-2-hydroxy-7,7-dimethylbicyclo[2.2.1]heptan-
THF); H NMR (400 MHz, CDCl
3
) d (ppm): 8.15 (d, J= 9.0 Hz, 1H, ArH),
a
1
-yl]-N-[1-(2-hydroxynaphthalen-1-yl)naphthalen-2-yl]methanesulfo-
8.09–8.03 (m, 3H, ArH), 7.94 (d, J = 8.1Hz, 1H, ArH), 7.77 (d, J= 9.0 Hz,
1H, ArH), 7.61–7.57 (t, 1H, ArH), 7.50–7.41 (m, 2H, ArH), 7.36–7.32 (t,
1H, ArH), 7.26 (s, 1H, ArH), 7.10 (d, J = 8.5Hz, 1H, ArH), 6.47 (s, 1H,
3
0
1
D
namide (8). Colorless solid (87%); [a] = +10.7 (c 1.1, THF); H NMR
(
7
400 MHz, CDCl
.43–7.30 (m, 4H, ArH), 7.21 (d, J= 8.5 Hz, 1H, ArH), 7.03 (d, J= 8.4 Hz, 1H,
ArH), 6.35 (s, 1H, NH), 5.45 (s, 1H, ArOH), 4.00–3.96 (m, 1H, CHO), 3.25
d, J=13.7Hz, 1H, CH S), 2.93 (d, J= 3.8 Hz, 1H, OH), 2.51 (d, J=13.7Hz,
1H, CH S), 1.78–1.00 (m, 7H, CH
100 MHz, CDCl ) d (ppm): 151.83, 134.44, 133.09, 131.62, 130.90, 129.45,
28.76, 128.44, 127.82, 127.75, 126.03, 125.52, 124.25, 123.87, 120.48, 120.36,
3
) d (ppm): 8.09–7.93 (m, 5H, ArH), 7.52–7.48 (t, 1H, ArH),
NH), 4.04–4.01 (q, 1H, OH), 3.68–3.65 (q, 1H, OH), 3.12 (d, J= 13.7 Hz,
1
2
0
1
1
7
3
H, CH
2
S), 3.11 (d, J = 13.9 Hz, 1H, CH
2
S), 2.77 (d, J= 13.7Hz, 1H, CH
, CH), 0.82, 0.78,
3 3
.67, 0.37 (s, 12H, CH ); C NMR (100 MHz, CDCl ) d (ppm): 145.61,
2
S),
(
2
.17 (d, J= 13.9Hz, 1H, CH
2
S), 1.77–0.88 (m, 16H, CH
2
13
13
2
2 3
, CH), 0.90, 0.56(s, 6H, CH ); C NMR
(
1
1
3
33.88, 133.01, 132.88, 132.50, 131.60, 130.98, 130.54, 128.78, 128.25,
27.57, 127.11, 125.84, 125.77, 125.72, 124.15, 121.86, 121.21, 120.38,
6.23, 75.69, 53.56, 51.86, 50.52, 49.55, 48.71, 48.68, 44.36, 44.23, 39.22,
9.09, 30.42, 29.70, 29.57, 27.27, 27.08, 20.42, 20.07, 19.60, 19.48; ESI-MS
18.10, 112.81, 76.28, 52.64, 50.41, 48.76, 44.29, 38.99, 30.31, 27.22, 26.93,
ꢂ
2
1.03, 20.22, 19.73; ESI-MS calce for [C30
H
31NO
4
Sꢂ H] 500.20, found
+ Na]+ 740.27, found 740.3; Anal. Calcd for
7 2
H47NO S
30 4
500.7; Anal. Calcd for C H31NO S: C, 71.83, H, 6.23, N, 2.79, O, 12.76, S,
calce for [C40
47NO : C, 66.92, H, 6.60, N, 1.95, O, 15.60, S, 8.93, Found: C,
6.93, H, 6.33, N, 1.82, O, 15.90, S, 8.98.
6
.39, Found: C, 71.96, H, 6.18, N, 2.73, O, 12.88, S, 6.30.
C
6
40
H
7 2
S
General Procedure for the Catalytic Reactions
Titanium tetraisopropoxide (1.5 mmol) was added via a syringe to the
solution of ligands 1–8 (0.1 mmol) in an appropriate freshly dried solvent
(
S
a
)-1-[2-({[(1S,2R,4R)-2-hydroxy-7,7-dimethylbicyclo[2.2.1]
heptan-1-yl]methane}sulfonamido))naphthalen-1-yl])naphthalen-
-yl[(1S,2R,4R)-2-hydroxy-7,7-dimethylbicyclo[2.2.1]heptan-1-yl]
(3 ml), respectively, and the mixture was stirred for 0.5 h at room temper-
ꢁ
2
ature. Then, the resulting solution was cooled to 0 C, dialkylzinc
methanesulfonate (6). Colorless solid (88%); [a]3
THF); H NMR (400 MHz, CDCl
0
= ꢂ18.6 (c 1.4,
D
(3 mmol) was added via a syringe, and the mixture was stirred for another
1
ꢁ
3
) d (ppm): 8.16 (d, J = 9.0 Hz, 1H,
0.5 h at 0 C, followed by the addition of aldehyde (1 mmol) via a syringe.
ArH), 8.09–8.03 (m, 3H, ArH), 7.94 (d, J = 8.1 Hz, 1H, ArH), 7.77 (d,
J = 9.0 Hz, 1H, ArH), 7.60–7.57 (t, 1H, ArH), 7.50–7.47 (t, 1H, ArH),
The reaction mixture was stirred at the same temperature for 0.5–24 h.
The mixture was quenched by adding 10 ml of 1 M hydrochloric acid,
extracted with EtOAc (3 ꢀ 30 ml), washed by brine (30 ml), dried over an-
hydrous sodium sulfate, and filtered. The filtrate was concentrated in
vacuo to give a residue, which was purified by column chromatography
7
.44–7.40 (t, 1H, ArH), 7.36–7.32 (t, 1H, ArH), 7.25 (d, J = 8.4 Hz, 1H,
ArH), 7.09 (d, J = 8.5 Hz, 1H, ArH), 6.44 (s, 1H, NH), 4.01–3.98 (q, 1H,
OH), 3.73–3.70 (q, 1H, OH), 3.31 (d, J = 13.7 Hz, 1H, CH S), 2.94 (d,
J = 13.8 Hz, 1H, CH S), 2.45 (d, J = 13.7 Hz, 1H, CH S), 2.37 (d,
J = 13.8 Hz, 1H, CH S), 1.77–1.01 (m, 16H, CH , CH), 0.90, 0.71, 0.53,
); C NMR (100 MHz, CDCl ) d (ppm): 145.71,
2
(eluting with n-hexane/EtOAc) to give the titled secondary alcohol. The
2
2
ee values of secondary alcohols were analyzed by GC equipped with a
Varian CP-Chirasil Dex CB column.
2
2
1
3
0
1
1
1
3
.52 (s, 12H, CH
3
3
33.72, 132.96, 132.92, 132.47, 131.54, 131.04, 130.63, 128.77, 128.29,
28.24, 127.71, 127.05, 125.98, 125.80, 125.68, 124.19, 121.93, 121.34,
20.21, 76.21, 75.70, 53.22, 51.82, 50.46, 49.65, 48.72, 48.69, 44.31, 44.30,
9.16, 38.99, 30.32, 29.87, 29.70, 27.23, 27.17, 20.19, 19.76, 19.48; ESI-
(1S)-1-phenylpropan-1-ol. Colorless liquid; 1H NMR (400 MHz,
CDCl
3
) d (ppm): 7.36–7.29 (m, 5H, ArH), 4.56–4.53 (t, 1H, CH), 3.05
13
(s, 1H, OH), 1.84–1.73 (m, 2H, CH
2
3
), 0.95–0.91 (t, 3H, CH ); C NMR
(100 MHz, CDCl
3
) d (ppm): 144.7, 128.4, 128.1, 127.6, 127.4, 126.4,
+ Na]+ 740.27, found 740.3; Anal. Calcd for
126.1, 75.9, 31.9, 10.2; (GC, T = 125 C):
ꢁ
t
= 9.4 min,
t
= 9.7 min;
MS calce for [C40
47NO : C, 66.92, H, 6.60, N, 1.95, O, 15.60, S, 8.93, Found: C,
6.79, H, 6.52, N, 1.93, O, 15.66, S, 8.90.
H
47NO
7
S
2
R
20
S
2
5
34
C
6
40
H
7
S
2
[a]
D
= ꢂ38.5 (c 1.0, CCl
3
) for 87% ee, {Lit [a]
D
= ꢂ33.5 (c 2.3, CCl
3
)
for 86% ee (S)}.
Chirality DOI 10.1002/chir

BIAN ET AL.
1S)-1-(4-chlorophenyl)propan-1-ol. Colorless liquid; 1H NMR
400 MHz, CDCl ) d (ppm): 7.32–7.24 (m, 4H, ArH), 4.55 (t, 1H, CH),
.38 (s, 1H, OH), 1.80–1.68 (m, 2H, CH
ꢁ
S
(ppm): 43.1, 29.3, 27.8, 26.7, 26.5, 26.4, 26.2, 10.2; (GC, T = 105 C): t = 16.9
(
2
5
36
25
(
2
3
min, t = 17.9 min; [a] = ꢂ8.6 (c 1.1, CCl ) for 84% ee, {Lit [a] D = +6.6
R
D
3
1
3
2
), 0.92–0.88 (t, 3H, CH
3
);
C
3
(c 0.65, CCl ) for 68% ee (R)}.
NMR (100 MHz, CDCl
3
) d (ppm): 143.0, 133.0, 128.5, 127.4, 75.2, 31.9,
(1S)-1-phenylethan-1-ol. Colorless liquid; 1H NMR (400MHz,
ꢁ
25
1
CCl
0.0; (GC, T = 150 C): t
R
= 8.6 min, t
S
= 9.1 min; [a]
D
= ꢂ32.5 (c 1.1,
3
4
20
CDCl ) d (ppm): 7.21–7.10 (m, 5H, ArH), 4.72–4.67 (q, 1H, CH), 2.46
) for 85% ee, {Lit [a]
D
= ꢂ25.5 (c 2.0, CCl ) for 72% ee (S)}.
3
3
3
1
3
(
s, 1H, OH), 1.33 (d, J = 6.5Hz, 3H, CH
d (ppm): 145.9, 128.5, 127.4, 125.5, 70.3, 25.1; (GC, T = 130 C): t
= 5.0 min; [a]
c 2.8, CCl ) for 88% ee (S)}.
3
); C NMR (100 MHz, CDCl
3
)
(
1S)-1-(4-methoxyphenyl)propan-1-ol. Colorless liquid; 1H NMR
400 MHz, CDCl ) d (ppm): 7.20 (d, J= 8.4 Hz, 2H, ArH), 6.86 (d, J=8.5Hz,
H, ArH), 4.51–4.47 (m, 1H, CH), 3.78 (s, 3H, OCH ), 2.36 (s, 1H, OH),
ꢁ
S
= 5.2min,
(
3
25
34
20
t
R
D
= ꢂ20.1 (c 1.1, CCl
3
) for 44% ee, {Lit [a]
D
= ꢂ37.5
2
1
3
(
3
13
2
.85–1.63 (m, 2H, CH ), 0.92–0.88 (t, 3H, CH
3
); C NMR (100 MHz, CDCl
3
)
=
ꢁ
24
(1S)-1-(2-methylphenyl)ethan-1-ol. Colorless liquid; 1H NMR
d (ppm): 158.9, 134.9, 128.3, 113.6, 79.2, 55.2, 31.3, 10.6; (GC, T= 150 C): t
R
2
5
35
8
.4 min, t
S
=8.6min; [a]
D
=ꢂ30.1 (c 0.9, CCl
3
) for 83% ee, {Lit [a]
D
=ꢂ23.4
(400MHz, CDCl ) d (ppm): 7.55 (d, J = 7.9 Hz, 1H, ArH), 7.30–7.17(m. 3H,
3
(
c 0.3, CCl
3
) for 65% ee (S)}.
ArH), 5.13–5.08 (q, 1H, CH), 2.80 (s, 1H, OH), 2.38(s, 3H, ArCH ), 1.49
3
1
3
(
d, J = 6.5 Hz, 3H, CH
3
); C NMR (100 MHz, CDCl
3
) d (ppm): 144.0, 134.2,
(
1S)-1-[4-(trifluoromethyl)phenyl]propan-1-ol. Colorless liquid;
H NMR (400 MHz, CDCl ) d (ppm): 7.61 (d, J = 8.2 Hz, 2H, ArH), 7.45
d, J = 8.2 Hz, 2H, ArH), 4.68–4.65 (t, 1H, CH), 2.33 (s, 1H, OH), 1.85–1.72
ꢁ
34
1
130.3, 127.1, 126.4, 124.6, 66.7, 23.9, 18.9; (GC, T = 130 C): t
R
= 8.9min,
= ꢂ35.0
3
2
5
20
t
S
= 10.6 min; [a]
D
= ꢂ7.2 (c 1.2, CCl
3
) for 11% ee, {Lit [a]
D
(
(
1
3
(c 3.4, CCl ) for 53% ee (S)}.
3
m, 2H, CH
2
), 0.95–0.91 (t, 3H, CH
3
); C NMR (100MHz, CDCl
3
)
ꢁ
d (ppm): 148.5, 126.2, 125.3, 75.3, 32.0, 9.9; (GC, T = 150 C): t
R
= 4.6 min,
1S)-1-[4-(trifluoromethyl)phenyl]ethan-1-ol. Yellow liquid; 1H
NMR (400MHz, CDCl ) d (ppm): 7.62 (d, J = 8.2 Hz, 2H, ArH), 7.49
d, J = 8.6Hz, 2H, ArH), 4.99–4.95(q, 1H, CH), 2.18 (s, 1H, OH), 1.50
(
2
5
36
25
t
(
S
= 4.9min; [a]
D
= ꢂ19.00 (c 1.00, CCl
3
) for 84% ee, {Lit [a]
D
= +15.8
3
c 1.3, CCl ) for 72% ee (R)}.
3
(
(
1
1S)-1-(2-methoxyphenyl)propan-1-ol. Colorless liquid; 1H NMR
400 MHz, CDCl ) d (ppm): 7.34 (d, J= 7.5 Hz, 1H, ArH), 7.29–7.25
t, 1H, ArH), 7.00–6.97 (t, 1H, ArH), 6.90 (d, J= 8.2 Hz, 1H, ArH), 4.85–
13
d, J = 6.5 Hz, 3H, CH
3
); C NMR (100 MHz, CDCl
3
) d (ppm): 149.8, 129.9,
(
ꢁ
29.5, 125.7, 125.5, 125.4, 122.3, 69.8, 25.4; (GC, T = 145 C): t
R
= 4.3min,
(
(
3
2
5
34
20
t
S
= 4.7min; [a]
D
= ꢂ7.2 (c 1.0, CCl
3 D
) for 29% ee, {Lit [a]
= ꢂ29.0 (c 2.0,
CCl ) for 88% ee (S)}.
3
4
1
.80 (q, 1H, ArCH), 3.86 (s, 3H, OCH
.87–1.80 (m, 2H, CH ), 1.0–0.97 (t, 3H, CH
) d (ppm): 156.5, 132.3, 128.1, 127.0, 120.6, 110.4, 72.2, 55.2, 30.1,
3
), 2.82 (d, J= 6.1 Hz, 1H, OH),
13
2
3
); C NMR (100 MHz,
1S)-1-(naphthalen-1-yl)ethan-1-ol. Colorless liquid; 1H NMR
400MHz, CDCl ) d (ppm): 7.92–7.90 (m, 1H, ArH), 7.72–7.70 (m, 1H,
ArH), 7.60 (d, J= 8.2 Hz, 1H, ArH), 7.48 (d, J = 7.1Hz, 1H, ArH), 7.36–7.27
m, 3H, ArH), 5.45–5.40 (q, 1H, CH), 2.26 (s, 1H, OH), 1.47 (d, J= 6.5 Hz,
(
CDCl
0.4; (GC, T= 150 C): t
3
25
(
3
ꢁ
1
S
= 6.5 min, t
R
= 7.4 min; [a]
D
= ꢂ35.5 (c 0.8,
3
6
25
CCl
3
) for 64% ee, {Lit [a]
D
= +40.5 (c 0.45, CCl ) for 70% ee (R)}.
3
(
1S)-1-(naphthalen-2-yl)propan-1-ol. Colorless liquid; 1H NMR
400 MHz, CDCl ) d (ppm): 7.89–7.48 (m, 7H, ArH), 4.75–4.72 (t, 1H, CH),
.64 (s, 1H, OH), 1.97–1.83 (m, 2H, CH
13
(
3H, CH3); C NMR (100 MHz, CDCl ) d (ppm): 141.5, 133.6, 130.3, 128.9,
3
ꢁ
(
2
3
127.9, 126.0, 125.6, 123.2, 122.1, 67.0, 24.4; (GC, T= 165 C): t = 13.1min,
S
1
3
25
35
24
2
), 0.99–0.95 (t, 3H, CH
3
);
C
tR = 14.2min; [a]D = ꢂ23.5 (c 0.9, CCl ) for 36% ee, {Lit [a] D = ꢂ41.7
3
NMR (100 MHz, CDCl
3
) d (ppm): 142.0, 133.3, 133.0, 128.2, 128.0, 127.7,
(c 0.57, CCl ) for 78% ee (S)}.
3
ꢁ
1
26.1, 125.8, 124.8, 124.3, 76.1, 31.8, 10.2; (GC, T= 165 C): t
R
= 15.7min, t
= +28.6 (c 0.77,
S
=
2
5
36
25
1
6.2min; [a]
CCl ) for 81% ee (R)}.
1S)-1-(naphthalen-1-yl)propan-1-ol. Colorless liquid; 1H NMR
400 MHz, CDCl ) d (ppm): 8.14–7.49 (m, 7H, ArH), 5.36–5.33 (t, 1H, CH),
D
= ꢂ28.0 (c 0.8, CCl
3
) for 78% ee, {Lit [a]
D
RESULTS AND DISCUSSION
3
Ligand Synthesis
Ligands bisketocamphorsulfonylated NOBIN 1–2 were
easily synthesized from the (R)-NOBIN and (S)-NOBIN by
sulfonation with (+)-(S)-10-camphorsulfonyl chloride in the
presence of triethylamine and a catalytic amount of DMAP
at room temperature in excellent yields. The further selective
hydrolysis of the sulfonate ester of ligands 1–2 by 3 M NaOH
in THF gave corresponding mono-N-ketocamphorsulfony-
lated NOBIN 3–4. Bishydroxycamphorsulfonylated NOBIN
(
(
3
1
3
2.97 (s, 1H, OH), 2.07–1.89 (m, 2H, CH
2
), 1.07–1.04 (t, 3H, CH
3
);
C
NMR (100 MHz, CDCl
3
) d (ppm): 140.4, 133.9, 130.6, 129.0, 127.9, 125.9,
ꢁ
1
1
CCl
25.5, 125.5, 123.4, 123.1, 72.4, 31.2, 10.6; (GC, T= 170 C): t
S
25
= 12.6min, t
= ꢂ41.7 (c 0.57,
R
=
2
5
35
3.6min; [a]
D
= ꢂ40.5 (c 0.9, CCl
3
) for 77% ee, {Lit [a]
D
3
) for 78% ee (S)}.
(
1S)-1-(2-methylphenyl)propan-1-ol. Colorless liquid; 1H NMR
400 MHz, CDCl ) d (ppm): 7.49–7.16 (m, 4H, ArH), 4.88–4.85(t, 1H,
CH), 2.37 (s, 3H, ArCH ), 2.19 (s, 1H, OH), 1.82–1.75 (m, 2H, CH ),
) d (ppm): 142.8,
5
–6 were obtained by the reduction of ligands 1–2 using
(
3
ꢁ
excess of NaBH at ꢂ20 C, whereas using excess of NaBH
4
4
ꢁ
3
2
at 25 C resulted in the reduction followed by hydrolysis of
ligands 1–2 to give mono-N-hydroxycamphorsulfonylated
NOBIN 7–8 (Scheme 1). In all cases, the main products of
ligands 5–8 are the corresponding exo isomers confirmed
by rotating frame Overhauser effect spectroscopy (ROESY)
spectroscopic study, which were easily isolated by chroma-
tography on silica gel. The crystal structure of 8 was deter-
mined by X-ray diffraction.37
1
3
1
.03–0.99(t, 3H, CH
3 3
); C NMR (100 MHz, CDCl
ꢁ
1
5
34.6, 130.3, 127.1, 126.2, 125.3, 72.0, 30.9, 19.1, 10.4; (GC, T = 150 C): t
R
=
= 5.3 min; [a] 2
5
= ꢂ12.8(c 0.6, CCl
36
.1 min, t
= +40.5 (c 0.45, CCl
S
D
3
) for 22% ee, {Lit [a]
2
5
D
3
) for 70% ee (R)}.
1H
(1E,3S)-1-phenylpent-1-en-3-ol. Colorless
liquid;
NMR
(
400 MHz, CDCl
3
) d (ppm): 7.43–7.25 (m, 5H, ArH), 6.59 (d, J= 15.9 Hz, 1H,
ArCH), 6.27–6.21 (m, 1H, C = CH), 4.25–4.20 (q, 1H, CH), 1.89 (s, 1H, OH),
13
2 3 3
1.75–1.62 (m, 2H, CH ), 1.01–0.97(t, 3H, CH ); C NMR (100 MHz, CDCl )
Catalytic Asymmetric Alkylation of Aldehyde with
Dialkylzinc
d (ppm): 136.8, 132.2, 130.4, 128.6, 127.6, 126.5, 74.4, 30.2, 9.8; (GC,
ꢁ
25
T= 130 C): t
R
= 22.0 min, t
S
= 22.9 min; [a]
D
=ꢂ5.0 (c 0.9, CCl
3
) for 55% ee,
3
5
24
Eight new camphorsulfonylated NOBIN ligands were ap-
plied in the asymmetric addition of diethylzinc to benzaldehyde
in the presence of titanium tetraisopropoxide, and the results
are summarized in Table 1. The data show that both the cata-
lytic activities and enantioselectivities of (S)-NOBIN derived
{
Lit [a]
D
=ꢂ5.25 (c 0.45, CCl
3
) for 55% ee (S)}.
1
(
1S)-1-cyclohexylpropan-1-ol. Colorless liquid; H NMR (400 MHz,
CDCl ) d (ppm): 3.24–3.20 (m, 1H, OCH), 2.02 (s, 1H, OH), 1.80–0.94 (m,
3H, CH2, CH), 0.93–0.89 (t, 3H, CH
Chirality DOI 10.1002/chir
3
13
1
3 3
); C NMR (100 MHz, CDCl ) d

DIALKYLZINCS ASYMMETRIC ADDITION TO ALDEHYDES
ligands (2, 4, 6, 8) were generally better than those of the
(R)-NOBIN and (S)-NOBIN’s binaphthyl skeleton with (S)-
camphor’s isoborneol backbone. Furthermore, the single
sulfonyl derivatives of (S)-NOBIN (4, 8) gave better enanotios-
electivities than double sulfonyl derivatives (2, 6), which
indicated that NOBIN’s hydroxyl group improves the perfor-
mance of the ligands both on the conversion of benzaldehyde
and the ee value of the addition product. Compared with keto-
camphorsulfonylated NOBIN ligand 4, the corresponding
hydroxycamphorsulfonylated NOBIN ligand 8 gave better
enantioselectivity and offered the addition product with oppo-
site configuration possibly because of the use of different spatial
arrangement of the complex catalyst. The asymmetric addition
of diethylzinc to benzaldehyde catalyzed by ligand 8 could be
corresponding (R)-NOBIN derivatives (1, 3, 5, 7), which
should be attributed to the different chiral matching effects of
TABLE 1. Chiral ligand-catalyzed additions of diethylzinc to
a
benzaldehyde
1
-Phenylpropan-1-ol.
b
c
ꢁ
t
Yield
(%)
ee
(%)
completed within half an hour in toluene at 0 C to give (S)-1-
d
Entry Ligand
Solvent
(h)
Configuration
phenylpropanol with 96% yield and 85% ee value. Next, the
influence of the solvent for the asymmetric reaction catalyzed
by ligand 8 was examined by performing the reaction in n-
hexane, toluene, dichloromethane, and THF respectively. The
results show that the yields and ee values were higher in
reactions carried out in toluene than other solvents (Table 1,
entries 8–11). The effect of the sequence of metal addition
(Ti/Zn or Zn/Ti) on the addition of diethylzinc to benzaldehyde
was also investigated. The result shows that the sequence of
adding the metal compounds had no significant effect on the
yield and enantiomeric excess (Table 1, entries 8, 12). Finally,
by increasing the amount of ligand 8 to 0.3 eq, the ee value of
1
2
3
4
5
6
7
8
9
1
1
1
2
3
4
5
6
7
8
8
8
8
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
THF
10
10
10
2
10
10
5
0.5
24
10
24
42
81
50
94
50
48
70
96
0
4
7
7
R
R
S
R
R
S
64
11
77
30
85
—
40
—
R
S
—
0
1
DCM
30
0
S
—
n-
Hexane
Toluene
Toluene
Toluene
e
product increased slightly to 87% (Table 1, entriy 13), decreas-
1 f
2
8
8
8
1
1
24
95
95
30
85
87
40
S
S
S
i
ing the amount of Ti(O Pr) to 0.2 eq, and the yield and ee value
1
1
3g
4
4
of product declined significantly (Table 1, entry 14).
Once the mono-N-hydroxycamphorsulfonylated (S)-NOBIN,
was found to be the best ligand and toluene as the appropriate
a
Reaction conditions: 1 mmol of benzaldehyde, 0.1 mmol of ligand, 1.5 mmol of
8
i
Ti(O Pr)
4
, 3 mmol of Et
2
Zn, and in 3 ml of solvent.
solvent for the enantioselective addition of diethylzinc to benzal-
dehyde; other aldehydes were submitted to the enantioselective
addition of diethylzinc (Table 2). From the results presented
in Table 2, it was found that the position of substituents has
significant influence on the enantioselectivity. The orthosubsti-
tuted benzaldehydes resulted in the decrease of corresponding
ee values (Table 2, entries 6 and 8), which indicates that
the catalyst is quite sensitive to steric hindrance. However,
b
Isolated yields.
c
Determined by gas chromatography analysis using a Varian CP-Chirasil Dex
CB column.
d
The configuration was determined by comparing the sign of specific rotation
34
value with the literature value
.
e
ꢁ
Firstly, diethylzinc was added and then stirred for 0.5 h at 0 C, followed by
the addition of titanium tetraisopropoxide.
f
0
0
.3 mmol of ligand was used.
.2 mmol of Ti(O Pr) was used.
4
g
i
a
TABLE 2. Enantioselective additions of dialkylzinc reagents to aldehydes catalyzed by titanium complex of ligand 8
b
c
d
0
Entry
RCHO
CHO
R
2
Zn
Yield (%)
ee (%)
Configuration
1
2
3
4
5
6
7
8
9
4–ClC
4–CH
4–CF
6
H
4
Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
Me
Me
Me
Me
2
2
2
2
2
2
2
2
2
Zn
Zn
Zn
Zn
Zn
Zn
Zn
Zn
Zn
98
96
95
93
90
96
75
97
90
95
98
98
97
97
85
83
84
78
77
22
55
64
84
44
31
11
36
29
S
S
S
S
S
S
S
S
S
S
S
S
S
S
3
OC
H
6
H
4
CHO
3
C
6
4
CHO
2–Naphthaldehyde
1–Naphthaldehyde
2–CH
(E)–PhCHCHCHO
2–CH OC CHO
3 6 4
C H CHO
3
6 4
H
cyclohexanecarbaldehyde
PhCHO
1
1
1
1
1
0e
2
Zn
2
Zn
2
Zn
2
Zn
2
Zn
1
PhCHO
2
2–CH
1–Naphthaldehyde
4–CF CHO
3 6 4
C H CHO
3
4
3 6 4
C H
a
i
0
Reaction conditions: 1 mmol of aldehyde, 0.1 mmol of ligand 8, 1.5 mmol of Ti(O Pr)
4
, 3 mmol of R
2
Zn, and in 3 ml of solvent.
b
Isolated yields.
c
Determined by gas chromatography analysis using a Varian CP-Chirasil Dex CB column.
Chirality DOI 10.1002/chir
d
The configuration was determined by comparing the sign of specific rotation value with the literature value34–36.
e
ꢁ
Reaction temperature: ꢂ15 C.

BIAN ET AL.
the electronic effect of substituents on the reaction yield and
at 87.6 ppm of 13C NMR spectrum, which belongs to the
tertiary carbon of complex II’s bridging isopropoxy (the ter-
enantioselectivity is not obvious (Table 2, entries 1, 2, 3,
and 9). Instead of diethylzinc, dimethylzinc gave significantly
declined ee values of the addition products (Table 2, entries
i
tiary carbon signal of Ti(O Pr) at 76.2, the tertiary carbon sig-
4
nal of isopropanol at 64),40 was observed (Fig. 2C). Therefore,
the possible catalyst structure of ligand 8-catalyzed asymmet-
ric addition of dialkylzincs to aldehydes is dinucear titanium.
From the results presented in Table 1, entries 14 and 8, it
was found that the more complex II the solution has, the
higher yield and enantioselectivity the reaction has. That
means that complex II has better catalytic activity and enan-
tioselectivity than complex I.
1
0–14).
Possible Catalytic Transition State and Mechanism
Detailed studies on catalytic reaction mechanism of the
asymmetric additions of dialkylzinc reagents to aldehydes
i
and ketones in the presence of a chiral ligand and Ti(O Pr)4
have shown that the possible structure for the catalyst is a
2
8,32,38,39
bimetallic titanium complex.
To investigate if the
The transition state of ligand 8-titanium complex II-cata-
lyzed asymmetry addition of dialkylzincs to aldehydes was
proposed as shown in Figure 3. Aldehyde approaches the
top titanium in a way that the aldehyde’s R group is point-
ing toward the other side of the bridging oxygen donor of
enantioselective addition of dialkylzinc reagents to aldehydes
catalyzed by our ligand 8 is also governed by this mechanism
i
or not, a titration of ligand 8 with Ti(O Pr) was undertaken.
4
Thus, to
a CDCl3 or D -toluene solution of ligand
8
i
8
(150 mM), 0.5 and 15 eq amounts of Ti(O Pr) were added,
4
1 13
respectively, and the H NMR and C NMR spectra of the
resulting solutions were recorded accordingly.
As shown in Figures 1 and 2, we identified two ligand
-titanium complexes I and II by comparing our titration data.
8
At low titanium/ligand 8 ratios, complex I, recognized as a 1:1
i
mononuclear TiL*(O Pr) (L* = 8)complex, was dominant
2
(
Figs. 1B and 2B), whereas complex II, recognized as a 2:1
i
dinuclear Ti L*(O Pr) complex, was dominant in the pres-
2
5
i
ence of 15 eq of Ti(O Pr) (Figs. 1C and 2C) because of the
4
i
equilibrium shifting from I to II driven by excess Ti(O Pr) ,
which was also observed previously for 1,1 -bi-2-naphthol-
4
0
based ligands4
0,41
and Sharpless’ tartrate esters. The aro-
42
matic proton signals and aromatic ipsocarbon signals for both
species I and II were shifted to downfield with respect to free
ligand 8 as a consequence of titanium complexation by oxy-
4
3,44
gen or nitrogen donor ligands.
An important resonance
1
3
Fig. 2. i C nuclear magnetic resonance spectra in CDCl
3
at room temperature
of 8/Ti(O Pr) at different ratios.
4
1
Fig. 1. H nuclear magnetic resonance spectra in D
8
-toluene at room tem-
Fig. 3. Proposed transition state for ligand 8-titanium complex II-catalyzed
asymmetry addition of dialkylzincs to aldehydes.
i
perature of 8/Ti(O Pr)
4
at different ratios.
Chirality DOI 10.1002/chir

DIALKYLZINCS ASYMMETRIC ADDITION TO ALDEHYDES
1
4. Zhou ZQ, Guo YJ. Enantioselective addition of diethylzinc to aromatic
aldehydes with novel chiral hydroxysulfonamide as ligands. Modern
Chemical Industry 2005;25:37–39.
NOBIN because the steric effect of bulky camphor moiety
causes positioning of the aldehyde’s R group away from
the camphor moiety. Then, the alkyl group coming from
dialkylzinc and attaching to the bottom titanium attacks
the carbonyl carbon of aldehyde from Si face to obtain
the (S)-addition product.
1
5. Jeon SJ, Li HM, García C, LaRochelle LK, Walsh PJ. Catalytic asymmetric
addition of alkylzinc and functionalized alkylzinc reagents to ketones. J
Org Chem 2004;70:448–455.
16. Forrat VJ, Ramón DJ, Yus M. Chiral tertiary alcohols from a trans-1-arene-
sulfonyl-amino-2-isoborneolsulfonylaminocyclohexane-catalyzed addition
of organozincs to ketones. Tetrahedron: Asymmetry 2005;16:3341–3344.
CONCLUSIONS
1
7. Hui AL, Zhang JT, Wang ZY. Substituent effect of camphor sulfonamide
ligand on the asymmetric addition of diethylzinc to aldehyde. Arkivoc
2006;xiii:41–56.
In conclusion, we have synthesized a series of new cam-
phorsulfonylated ligands derived from both (R)-NOBIN
and (S)-NOBIN and assessed their enantioselectivities in
the addition of dialkylzinc reagents to aldehydes in the
presence of titanium tetraisopropoxide. The highest catalytic
efficiency was obtained with mono-N-hydroxycamphorsulfo-
nylated (S)-NOBIN 8 in toluene, which gave (S)-addition
products with high yields and ee values up to 87%. On the
18. Forrat VJ, Prieto O, Ramón DJ, Yus M. trans-1-Sulfonylamino-2-isobor-
neolsulfonylaminocyclohexane derivatives: excellent chiral ligands for
the catalytic enantioselective addition of organozinc reagents to ketones.
Chem Eur J 2006;12:4431–4445.
1
2
2
9. Forrat VJ, Ramón DJ, Yus M. Polymer supported trans-1-phenylsulfony-
lamino-2-isoborneolsulfonylaminocyclohexane ligand for the titanium
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006;17:2054–2058.
basis of the H NMR and C NMR spectroscopic studies on
the possible catalyst structure, a binuclear titanium complex
is proposed, and a catalytic mechanistic explanation is also
provided.
0. Hui AL, Zhang JT, Fan JM, Wang ZY. A new chiral sulfonamide ligand
based on tartaric acid: synthesis and application in the enantioselective ad-
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2
-symmetrical
ACKNOWLEDGMENTS
J
This work was supported financially by the Natural Science
Foundation of Fujian Province, China, (Grant No. 2010J01055)
the State Key Lab of Structural Chemistry, Fujian Institute of
Research on the Structure of Matter, Chinese Academy of
Sciences, and the Scientific Research Foundation for the
Returned Overseas Chinese Scholars, State Education Ministry.
2
2
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chiral tertiary alcohols by enantioselective addition of organozinc
reagents to ketones using nanosize isoborneol ligands. Tetrahedron:
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