Syntheses of novel chiral sulfinamido ligands and their applications in diethylzinc additions to aldehydes

Article abstract of DOI:10.1021/jo062249q

(Chemical Equation Presented) A novel class of sulfinamido alcohol ligands 1-6 was synthesized from (S)-tert-butanesulfinamide. These ligands showed excellent catalytic activities and enantiomeric selectivities in asymmetric additions of diethylzinc to aromatic aldehydes.

Full text of DOI:10.1021/jo062249q

Syntheses of Novel Chiral Sulfinamido Ligands and Their
Applications in Diethylzinc Additions to Aldehydes†
Zhiyan Huang, Hongshan Lai, and Yong Qin*
Department of Chemistry of Medicinal Natural Products and Key Laboratory of Drug Targeting,
West China School of Pharmacy, and State Key Laboratory of Biotherapy, Sichuan UniVersity,
Chengdu 610041, P. R. China
yongqin@scu.edu.cn
ReceiVed October 30, 2006
A novel class of sulfinamido alcohol ligands 1-6 was synthesized from (S)-tert-butanesulfinamide. These
ligands showed excellent catalytic activities and enantiomeric selectivities in asymmetric additions of
diethylzinc to aromatic aldehydes.
Introduction
Over the last two decades, the asymmetric addition of
dialkylzinc to aldehyde has been well developed since the initial
report of Oguni.1 Most of the ligands are based upon chiral
amino alcohols, amino thiols, amino disulfides, amino dis-
elenides, diamines, or diols.2 Ligands possessing carbon atomic
chirality or axial chirality with two coordinating heteroatoms
feature the most common frameworks for the successful chiral
ligands. However, chiral ligands with a stereogenic heteroatom
that can effectively catalyze the diethylzinc addition with high
levels of enantioselectivity are scarcely reported.3 Therefore,
research on asymmetric addition of diethylzinc to aldehydes
FIGURE 1. Structures of sulfinamido ligands 1-6.
† Dedicated to Prof. Yaozhong Jiang on the occasion of his 70th birthday.
(1) (a) Oguni, N.; Omi, T. Tetrahedron Lett. 1984, 25, 2823. (b) Oguni,
N.; Omi, T.; Yamamoto, Y.; Nakamura, A. Chem. Lett. 1983, 841.
(2) For comprehensive reviews, see: (a) Pu, L.; Yu, H.-B. Chem. ReV.
2001, 101, 757. (b) Soai, K.; Niwa, S. Chem. ReV. 1992, 92, 833. (c) Noyori,
R.; Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991, 30, 49.
(3) (a) Bolm, C.; Mu¨ller, J. Tetrahedron 1994, 50, 4355. (b) Bolm, C.;
Mu¨ller, J.; Schlingloff, G.; Zehnder, M.; Neuburger, M. J. Chem. Soc.,
Chem. Commun. 1993, 182.
(4) (a) Qin, Y.; Wang, C.; Huang, Zh.; Xiao, X.; Jiang, Y. J. Org. Chem.
2004, 69, 8533. (b) Liao, J.; Sun, X.-X.; Cui, X.; Yu, K.-B.; Zhu, J.; Deng,
J.-G. Chem. Eur. J. 2003, 9, 2611. (c) Weix, D. J.; Ellman, J. A. Org. Lett.
2003, 5, 1317. (d) Han, Zh.-X.; Krishnamurthy, D.; Grover, P.; Fang,
Q. K.; Senanayake, C. H. J. Am. Chem. Soc. 2002, 124, 7880. (e) Cogan,
D. A.; Liu, G.-Ch.; Kim, K.; Backes, B. J.; Ellman, J. A. J. Am. Chem.
Soc. 1998, 120, 8011.
catalyzed by chiral ligands with a stereogenic heteroatom
remains an interesting topic in asymmetric synthesis.
Chiral tert-butanesulfinamide (TBSA)4 has been extensively
used as a chiral auxiliary in recent years,5 but few studies have
focused on the applications of its derivatives as chiral catalysts.6
To extend our studies on TBSA chemistry,7 herein we report
on the synthesis of a novel class of sulfinamido alcohol ligands
(6) (a) Pei, D.; Wang, Zh.; Wei, S.; Zhang, Y.; Sun, J. Org. Lett. 2006,
8, 5913. (b) Schenkel, L. B.; Ellman, J. A. J. Org. Chem. 2004, 69, 1800.
(c) Schenkel, L. B.; Ellman, J. A. Org. Lett. 2003, 5, 545. (d) Owens,
T. D.; Souers, A. J.; Ellman, J. A. J. Org. Chem. 2003, 68, 3.
(5) For reviews on the application of chiral tert-butanesulfinamide as a
chiral auxiliary in asymmetric synthesis, see: (a) Zhou, P.; Chen, B.-Ch.;
Davis, F. A. Tetrahedron 2004, 60, 8003. (b) Ellman, J. A. Pure Appl.
Chem. 2003, 75, 39. (c) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc.
Chem. Res. 2002, 35, 984.
(7) (a) Wang, Y.; He, Q.; Wang, H.; Zhou, X.; Huang, Zh.; Qin, Y.
J. Org. Chem. 2006, 71, 1588. (b) Xiao, X.; Wang, H.; Huang, Zh.; Yang,
J.; Bian, X.; Qin, Y. Org. Lett. 2006, 8, 139. (c) Huang, Zh.; Zhang, M.;
Wang, Y.; Qin, Y. Synlett 2005, 1334. (d) Ke, B.; Qin, Y.; He, Q.; Huang,
Zh.; Wang, F. P. Tetrahedron Lett. 2005, 46, 1751.
10.1021/jo062249q CCC: $37.00 © 2007 American Chemical Society
Published on Web 01/19/2007
J. Org. Chem. 2007, 72, 1373-1378
1373

Huang et al.
SCHEME 1a
SCHEME 3a
a
Reagents and conditions: (a) LiNH2 in liquid NH3; (b) Pd(PPh3)4,
NaBH4, THF, 90% yield, 90% er, 99% er after twice recrystallization.
a
Reagents and conditions: (a) KHSO4, toluene, 45 °C; (b) NaBH4,
two steps, 70-92% overall yields.
SCHEME 2a
-20 °C to afford compound 11 in 95% yield. Deprotection of
10
the allyl group with NaBH4 catalyzed by 2 mol % of Pd(PPh3)4
provided ligand 2 in 90% yield and >99% er. However,
methylation of 10 resulted in about 1.5% racemization of
compound 11 with a diminished er of 97% when NaH was
employed as base rather than KH. Similar racemization was
also observed in the acylation of TBSA 8 with NaH as base.11
The addition of PhMgBr to sulfimine 9 in CH2Cl2 at -48 °C
provided compound 12 in 92% yield and 99:1 dr.12 Deprotection
of the allyl group in 12 with Pd(PPh3)4 and NaBH4 gave ligand
(SS,R)-3 in 95% yield. The absolute configuration of the major
isomer was secured by the X-ray crystallographic analysis
of 3.13
Ligand 4 was prepared from O-protected 2-aminophenol 1314
and enantiomeric rich (SS)-thiosulfinate 144c,e (Scheme 3).
Ammonolysis of (SS)-14 (93% er) with the lithium salts of 13a
(R ) Me) and 13b (R ) allyl), generated in situ by the reaction
of 13 with LiNH2 in liquid ammonia, afforded (SS)-5 in 83%
(90% er) and (SS)-15 in 75% yields, respectively. After twice
recrystallization from a mixture of petroleum and ethyl acetate
(10:1), an enantiopure sample of 5 was obtained. The efforts to
remove the O-methyl group in 5 were unsuccessful with use of
the common demethylation reagents such as BF3, AlCl3, and
Me3SiI. In all cases, a dark-colored mixture was obtained
probably because the TBSA moiety in 5 is highly sensitive to
Lewis acids and the phenol group tends to be easily oxidized
in the system. Fortunately, deallylation of 15 was successful
with Pd(PPh3)4 and NaBH4, which generated 4 in 90% yield
and 90% er. The enantiomeric purity of 4 was greatly enhanced
to 99.4% after twice recrystallization from a degassed mixture
of hexane and ethyl ether (4:1). Notably, when exposed to air
at room temperature, ligand 4 is prone to be oxidized. Therefore,
storage of 4 in an inert atmosphere at -30 °C is strongly
recommended.
a
Reagents and conditions: (a) allyl bromide, K2CO3; (b) 8, KHSO4,
two steps, 93% overall yield; (c) NaBH4, 95% yield; (d) KH, MeI, 95%
yield; (e) Pd(PPh3)4, NaBH4, 90% yield; (f) PhMgBr, CH2Cl2, -48 °C,
92% yield, 98% dr; (g) Pd(PPh3)4, NaBH4, 95% yield.
1-6 incorporating a (S)-TBSA moiety and their applications
in asymmetric additions of diethylzinc to aldehydes.
Results and Discussion
Syntheses of Ligands 1-6. Our efforts to prepare ligands
1-6 incorporating a (S)-TBSA moiety began with the syntheses
of ligands 1a-g.8 Ligands 1a-g were readily prepared by a
two-step reaction in 70-92% yield from corresponding alde-
hydes 7 and (S)-TBSA 8 (Figure 1). Condensation of 7 with 8
was performed without racemization using our previous protocol
for sulfimine formation.7c Reduction of the resulting sulfimine
Ligand 6 was prepared from methyl dimethoxyacetate 16 by
a four-step reaction shown in Scheme 4. Grignard addition of
9
with NaBH4 afforded ligands 1a-g (Scheme 1).
Ligand 2 with a methyl substituent on nitrogen and ligand 3
with a phenyl substituent on the tertiary carbon were both
prepared from O-allyl protected (S)-sulfimine 9 by using the
procedure presented in Scheme 2. After reduction of the CdN
double bond in 9 with NaBH4, the resulting compound 10 was
treated with MeI in the presence of 2 equiv of KH in THF at
(10) Beugelmans, R.; Bourdet, S.; Bigot, A.; Zhu, J. Tetrahedron Lett.
1994, 35, 4349.
(11) Backes, B. J.; Dragoli, D. R.; Ellman, J. A. J. Org. Chem. 1999,
64, 5472.
(12) (a) Davis, F. A.; McCoull, W. J. Org. Chem. 1999, 64, 3396. (b)
Cogan, D. A.; Liu, G.; Ellman, J. A. Tetrahedron 1999, 55, 8883.
(13) A colorless crystal of 3 (C17H21N1O2S1, mp 215-216 °C) for X-ray
analysis was obtained by recrystallization from MeOH. The crystallographic
data have been deposited with the Cambridge Crystallographic Data Centre,
CCDC 620263, and are also available in the Supporting Information (the
ORTEP/X-ray figure of 3 is shown in the Supporting Information).
(14) Morel, G.; Marchand, E.; Benjelloun, A. T.; Sinbandhit, S.; Guillou,
O.; Gall, P. Eur. J. Org. Chem. 1998, 11, 2631.
(8) Chiral o-hydroxybenzylamines have been reported as catalysts for
the asymmetric additions of diethylzinc to aldehydes with moderate to high
er values, see: Palmieri, G. Tetrahedron: Asymmetry 2000, 11, 3361.
(9) Borg, G.; Cogan, D. A.; Ellman, J. A. Tetrahedron Lett. 1999, 40,
6709.
1374 J. Org. Chem., Vol. 72, No. 4, 2007

Syntheses of NoVel Chiral Sulfinamido Ligands
SCHEME 4a
TABLE 1. Screening of Ligands 1-6 in Asymmertic Addition of
Diethylzinc to Benzaldehyde
entry L* R1
R2
R3 time (h) yield (%) er %a (config)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1a
H
H
H
H
Me
OMe
NO2
H
H
H
H
H
H
H
Me
18
18
18
18
24
18
13
24
24
16
18
18
18
24
18
18
89
90
67
87
15
66
47
36
40
70
78
80
93
89
95
58
94 (R)
94 (R)
79 (R)
94 (R)
78 (R)
84 (R)
33 (S)b
0
17 (R)
40 (R)
0
75 (R)
96 (R)c
94 (R)d
96 (R)e
96 (R)f
1b Me
1c tBu
1d
1e
1f
1g
2
3
4
5
6
1a
1a
1a
1a
H
H
H
H
a
Reagents and conditions: (a) p-TolMgBr, 83% yield; (b) I2, acetone;
(c) 8, KHSO4, toluene, 87% yield; (d) NaBH4, 92% yield.
p-tolMgBr to 16 provided alcohol 17 in 83% yield. Hydrolysis
of 17 with I2 in acetone15 was followed by condensation with
(S)-8 to give sulfimine 18 in 87% yield. Reduction of 18
provided ligand 6 in 92% yield.
H
H
H
H
H
H
H
H
H
H
H
H
Ligand Screening. Ligands 1-6 were roughly divided into
two types, namely the R-sulfinamido alcohol ligands and the
â-sulfinamido alcohol ligands. We sought to compare the
coordinating abilities of the two types as well as the catalytic
performance of the corresponding zinc complexes formed from
the ligands. The ligands were evaluated for their catalytic
activities in the asymmetric addition of diethylzinc to benzal-
dehyde. Unless otherwise stated, all the reactions were carried
out in toluene with 10 mol % of individual ligand, using 1.5
equiv of diethylzinc at room temperature. The results are shown
in Table 1. The initial experiment provided a promising result
that the addition reaction catalyzed by ligand 1a proceeded
smoothly to afford (R)-1-phenyl-1-propanol in 89% yield and
94% er (Table 1, entry 1). The enantioselectivity of the reaction
was unambiguously induced by the stereogenic heteroatom of
sulfur in 1a. The results of the reactions with ligands 1a-f
demonstrated the steric and electronic effects of a variety of
comparable substituents at the ortho and para positions of the
hydroxy group. Increasing the substituent size at the adjacent
position from the smallest hydrogen (1a) to the bulky tert-butyl
group (1c) resulted in decreased yield and enantiomeric excess
(Table 1, entries 1-3). Ligand 1d with a methyl group at the
para position showed the same catalytic activity as ligand 1a.
Replacement of the hydrogen (1a) with an electron-donating
group (1e) or an electron-withdrawing group (1f) at the para
position resulted in critically diminished catalytic activity (Table
1, entries 5 and 6). Methylation of the hydroxy group (ligand
1g) provided the product in a low yield (47%) with an inverse
configuration (Table 1, entry 7).
a Determined by chiral stationary phase HPLC, Chiralcel OD. b The
inverse (R)-configuration (32% er) and similar yield (52%) of adduct were
observed when the enantiomer of 1g with the opposite (R)-TBSA moiety
was employed. c Toluene/hexane 1:1, 10% mol of 1a. d Toluene/hexane 1:1,
5% mol of 1a. e Toluene/hexane 1:1, 20% mol of 1a. f Toluene/hexane 1:1,
10% mol of 1a, at 0 °C.
1a, the disappointing result indicated that the crowded phenyl
substituent between the sulfinamido group and the hydroxy
group might have shielded the coordination of aldehyde to the
catalytically active zinc complex.
The R-sulfinamido alcohol ligands 4 and 6 showed inferior
catalytic activity to ligand 1a of the â-sulfinamido alcohol type.
The former achieved but moderate yields and enantiomeric
excess (Table 1, entries 10 and 12). Surprisingly, the addition
reaction catalyzed by ligand 5 with a methoxy group on the
phenyl ring provided a racemic product (Table 1, entry 11).
According to the above results, ligand 1a was the best catalyst
among those tested. We subsequently found that the use of a
mixture solvent of toluene and n-hexane (1:1) slightly increased
the yield and er (93% yield, 96% er) relative to the use of toluene
alone (89% yield, 94% er) for benzaldehyde addition (Table 1,
entries 1 and 13). Further changes in the loading amount of 1a,
by either increasing or decreasing it (20 and 5 mol %), had
little effect on the yield and er (Table 1, entries 14 and 15).
Lowering the reaction temperature from 25 to 0 °C failed to
bring up the er value and cut down the yield by 35% (Table 1,
entry 16).
Asymmetric Additions of Diethylzinc to Aldehydes. The
performance of ligand 1a was examined in the asymmetric
additions of diethylzinc to a variety of aldehydes under the
optimal condition (10 mol % of 1a in a mixture of toluene and
n-hexane (1:1) and 1.5 equiv of Et2Zn at room temperature).
The results are shown in Table 2. Similar to the results for
benzaldehyde, all the additions to aromatic aldehydes provided
the corresponding R-configuration alcohols as the major isomer
with excellent enantioselectivities (93-97% er) and in moderate
to high yields (Table 2, entries 1-6). Under the same condition,
the additions of diethylzinc to phenylpropionaldehyde and trans-
cinnamaldehyde afforded the (R)-configuration alcohols in
moderate yields and enantioselectivities (Table 2, entries 7
and 8).
It was reported that R-amino alcohol ligands with tertiary
amine generally provided better enantioselectivities than the
ligands with secondary amine in the additions of dialkylzinc to
aldehydes.16 In contrast to these observations, the addition
reaction catalyzed by ligand 2 with a tertiary sulfinamido
functionality gave racemic 1-phenylpropanol in 36% yield
(Table 1, entry 8). Addition reaction catalyzed by ligand 3 also
provided a low yield and poor enantioselectivity (Table 1, entry
9). Although ligand 3 has the same structural motif as ligand
(15) Sun, J. W.; Dong, Y. M.; Cao, L. Y.; Wang, X. Y.; Wang, Sh. Zh.;
Hu, Y. F. J. Org. Chem. 2004, 69, 8932.
(16) (a) Liu, D.-X.; Zhang, L.-Ch.; Wang, Q.; Da, Chapter-Sh.; Xin,
Zh.-Q.; Wang, R.; Choi, M. C. K.; Chan, A. S. C. Org. Lett. 2001, 3, 2733.
(b) Wilken, J.; GrO¨ ger, H.; Kossenjans, M.; Martens, J. Tetrahedron:
Asymmetry 1997, 8, 2761.
J. Org. Chem, Vol. 72, No. 4, 2007 1375

Huang et al.
TABLE 2. Asymmertic Additions of Diethylzinc to Aldehydes
Catalyzed by 1aa
the coordination with zinc (Figure 2). In this way, the transfer
of ethyl to the Si-face affords S-configuration alcohol. Methyl-
ation of the sulfonamide (ligand 2) totally rules out the possible
formation of a chelating zinc complex. Therefore, the diethylzinc
addition to benzaldehyde catalyzed by ligand 2 affords a racemic
product. The proposed transition states may well explain our
experimental observations that the substituents on the phenyl
ring and the sulfinamide have considerable effects on the
catalytic activities of ligands 1-3 and the configuration of the
resulting adducts.
entry
aldehydes
C6H5CHO
time (h) yieldb (%) er %c (config)
1
2
3
4
5
6
7
8
18
20
24
24
15
20
24
15
93
90
77
58
71
78
70
82
96 (R)
96 (R)
94 (R)
97 (R)
93 (R)
94 (R)
70 (R)
54 (R)
p-ClC6H4CHO
p-CH3OC6H4CHO
p-(CH3)2NC6H4CHO
3-furaldehyde
2-thiophenealdehyde
PhCH2CH2CHO
Conclusion
trans-PhCHdCHCHO
In summary, a novel class of sulfinamido alcohol ligands
possessing the stereogenic heteroatom rather than the carbon
atomic chirality was synthesized from commercially available
(S)-tert-butanesulfinamide. These ligands were evaluated in the
asymmetric additions of diethylzinc to aldehydes and showed
excellent enantiomerically catalytic activities for aromatic
aldehydes. Further efforts will be focused on the applications
of these ligands toward different asymmetric reactions and the
exploration of new ligands based on chiral tert-butanesulfin-
amide.
a Unless otherwise noted, reactions were carried out in the presence of
10 mol % of ligand, 1.5 equiv of Et2Zn at rt. b Isolated yield. c Determined
by chiral stationary phase HPLC, Chiralcel OD.
Experimental Section
Synthesis of Ligand (S)-1 (a representative procedure for
ligand 1a). To a stirred solution of 8 (121 mg, 1.0 mmol) in dry
toluene (5 mL) at 45 °C was added anhydrous KHSO4 (272 mg,
2.0 mmol) and salicylaldehyde 7 (213 µL, 2.0 mmol). After 24 h,
The reaction mixture was filtered and concentrated in vacuum to
afford sulfimine as a white solid. The solid was dissolved in THF
(10 mL), and NaBH4 (38 mg, 1.0 mmol) was added at 0 °C. Once
the addition was complete, the mixture became yellow and was
stirred for additional 2 h at 0 °C. The solution turned colorless
before saturated aqueous NH4Cl was added to quench the reaction.
The resulting mixture was extracted with CH2Cl2 (3 × 10 mL).
The combined organic layers were dried (Na2SO4), filtered, and
concentrated. (S)-1a (198 mg, 87% yield for two steps) was obtained
as a white solid after purification by column chromatography (1:2
ethyl acetate/hexanes). The enantiomeric excess was determined
to be >99.9% by HPLC analysis on a Diacel Chiralcel OD column
(95:5 hexanes/IPA, 1.0 mL/min; 227 nm; (R)-1a, tR ) 14.2 min,
(S)-1a, tR ) 16.0 min). A needle crystal of 1a was obtained by
FIGURE 2. Proposed transition states.
Mechanistic Considerations. On the basis of the stereo-
chemical outcome of the adducts and the structure-activity
relationship of ligands 1-3 revealed in the addition of dieth-
ylzinc to benzaldehyde, the canonical anti transition states17 are
proposed in Figure 2. Accordingly, both the nitrogen atom and
the oxygen atom of the sulfinamido group, along with the
oxygen atom of hydroxy group, participate in the coordination
with zinc to form O,N,O-chelating six/four bicyclic transition
states Ts-1 and Ts-2 as the catalytically active species. Ts-1 is
the dynamically favorable transition state except for the case
that the bulky R3 group (ligand 3, R3 ) Ph) faces upward to
have an interaction with the R group and to shield the
coordination of aldehyde to zinc. The transfer of the ethyl group
from diethylzinc to the Re-face of aldehyde in Ts-1 results in
the formation of R-configuration alcohol. The unfavorable
transition state Ts-2 is responsible for the formation of S-
configuration alcohol, in which a strongly steric interaction of
the tert-butyl group with R takes place. Methylation of either
the hydroxy group or the sulfinamido group undoubtedly
precludes the formation of transition states Ts-1 and Ts-2. When
the hydroxyl group on the phenyl ring is replaced with a
methoxy group (ligand 1g), the addition reaction may proceed
with a different transition state Ts-3, in which only the nitrogen
atom and oxygen atom of the sulfinamido moiety participate in
recrystallization from a mixture solvent of ethyl acetate and hexanes
1
(1:4): mp 116-117 °C; [R]20 +48.3 (c 1.18, CHCl3); H NMR
D
(400 MHz, CDCl3) δ 8.20 (s, 1Η), 7.20-7.12 (m, 2Η), 6.88-6.81
(m, 2H), 4.30 (d, J ) 5.6 Hz, 2H), 3.91 (t, J ) 5.6 Hz, 1H), 1.26
(s, 9H) ppm; 13C NMR (50 MHz, CDCl3) δ 22.5 (3C), 46.9, 56.1,
115.9, 119.3, 124.2, 129.2, 129.4, 155.5 ppm; IR (KBr) 3267, 3178,
1458, 1245, 1035, 757 cm-1; HRMS-ESI calcd for C11H17NNaO2S
(M + Na)+ 250.0872, found 250.0866.
Ligand (S)-1b. (S)-1b was purified by column chromatography
(1:2 ethyl acetate/ hexanes) as a white powder (89% yield). The
enantiomeric excess was determined to be >99.9% by HPLC
analysis on a Diacel Chiralcel OD column (95:5 hexanes/IPA, 1.0
mL/min; 227 nm; (R)-1b, tR ) 11.3 min, (S)-1b, tR ) 8.7 min).
Mp 74-75 °C; [R]20D +54.0 (c 1.01, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 7.63 (s, 1H), 7.12 (d, J ) 7.2 Hz, 1H), 6.97 (dd, J ) 7.6,
1.2 Hz, 1H), 6.77 (t, J ) 7.6 Hz, 1H), 4.38 (dd, J ) 13.2, 7.2 Hz,
1H), 4.35 (dd, J ) 13.2, 4.0 Hz, 1H), 3.59 (dd, J ) 7.2, 4.0 Hz,
1H), 2.24 (s, 3H), 1.26 (s, 9H) ppm; 13C NMR (50 MHz, CDCl3)
δ 16.0, 22.6 (3C), 46.9, 56.1, 119.7, 123.4, 126.0, 127.5, 131.0,
(17) (a) Huang, J.; Lanni, J. C.; Antoline, J. E.; Hsung, R. P.; Kozlowski,
M. C. Org. Lett. 2006, 8, 1565. (b) Rasmussen, T.; Norrby, P.-O. J. Am.
Chem. Soc. 2003, 125, 5130. (c) Vazquez, J.; Pericas, M. A.; Maseras, F.;
Lledos, A. J. Org. Chem. 2000, 65, 7303. (d) Yamakawa, M.; Noyori, R.
Organometallics 1999, 18, 128. (e) Goldfuss, B.; Houk, K. N. J. Org. Chem.
1998, 63, 8998. (f) Yamakawa, M.; Noyori, R. J. Am. Chem. Soc. 1995,
117, 6327.
153.7 ppm; IR (KBr) 3302, 2960, 1473, 1210, 1052, 752 cm-1
;
HRMS-ESI calcd for C12H19NNaO2S (M + Na)+ 264.1029, found
264.1018.
1376 J. Org. Chem., Vol. 72, No. 4, 2007

Syntheses of NoVel Chiral Sulfinamido Ligands
Ligand (S)-1c. (S)-1c was purified by flash chromatography (1:4
ethyl acetate/hexanes) as a colorless liquid (87% yield). The
enantiomeric excess was determined to be >99.9% by HPLC
analysis on a Diacel Chiralcel OD column (95:5 hexanes/IPA, 1.0
concentrated in vacuum. The residue was diluted with ethyl acetate
(10 mL), filtered, and concentrated to afford the crude O-allyl
salicylaldehyde, which was then condensed directly with 0.61 g
(5 mmol) of (S)-TBSA to afford 1.33 g of sulfimine 9 in 93% yield.
1H NMR (400 MHz, CDCl3) δ 9.13 (s, 1H), 8.01 (dd, J ) 8.0, 1.6
Hz, 1H), 7.46 (td, J ) 7.2, 1.6 Hz, 1H), 7.03 (t, J ) 7.6 Hz, 2H),
6.97 (d, J ) 8.4 Hz, 1H), 6.13-6.03 (m, 1Η), 5.47-5.42 (m, 1Η),
5.34-5.31 (m, 1Η), 4.67-4.65 (m, 2Η), 1.29 (s, 9Η) ppm.
Crude compound 10 obtained by reducing sulfimine 9 (530 mg,
2.0 mmol) dissolved in THF (20 mL). KH (35% in oil, 450 mg,
4.0 mmol) was added slowly at -20 °C. After being stirred for 20
min, MeI (187 µL, 3.0 mmol) was added. The mixture was stirred
for an additional 4 h at -20 °C and quenched with saturated
aqueous NH4Cl. Following the extraction with ethyl acetate
(3 × 15 mL), the combined organic layers were dried (Na2SO4),
concentrated, and purified by flash chromatography (1:8 ethyl
acetate/hexanes) to give 506 mg (90% yield for two steps) of 11
as a yellow liquid. 1H NMR (400 MHz, CDCl3) δ 7.32 (d, J ) 7.2
Hz, 1H), 7.23 (t, J ) 8.0 Hz, 1H), 6.94 (t, J ) 7.2 Hz, 1H), 6.85
(d, J ) 8.4 Hz, 1H), 6.10-6.00 (m, 1H), 5.33 (dd, J ) 43.2, 28.0
Hz, 2H), 4.54 (d, J ) 4.4 Hz, 2H), 4.29 (dd, J ) 43.2, 28.0 Ηz,
2Η), 2.63 (s, 3Η), 1.19 (s, 9Η) ppm.
Compound 11 (470 mg, 1.70 mmol) and Pd(PPh3)4 (42 mg, 0.03
mmol) were dissolved in 10 mL of dry THF at 0 °C. After the
mixture was stirred for 5 min at 0 °C, NaBH4 (95 mg, 2.50 mmol)
was slowly added. The stirring was continued for an additional 2
h at room temperature and the reaction was quenched with saturated
aqueous NH4Cl at 0 °C. Following the extraction with CH2Cl2
(3 × 10 mL), the combined organic layers were dried (Na2SO4),
concentrated, and purified by flash chromatography (1:10 ethyl
acetate/hexanes) to afford 367 mg (90% yield) of ligand (S)-2 as a
light yellow liquid. The enantiomeric excess was determined to be
>99.9% by HPLC analysis on a Diacel Chiralcel OD column (98:2
hexanes/IPA, 0.5 mL/min; 227 nm; (R)-2, tR ) 38.9 min, (S)-2,
tR ) 41.1 min). [R]20D +102.2 (c 0.96, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 8.66 (s, 1H), 7.22 (td, J ) 8.0, 1.6 Hz, 1H), 7.04 (dd,
J ) 7.6, 1.6 Hz, 1H), 6.69 (d, J ) 8.0 Hz, 1H), 6.80 (td, J ) 7.6,
1.2 Hz, 1H), 4.86 (d, J ) 14.0 Hz, 1H), 3.67 (d, J ) 14.0 Hz, 1H),
2.70 (s, 3H), 1.26 (s, 9H) ppm; 13C NMR (50 MHz, CDCl3) δ 23.3
(3C), 36.2, 46.2, 59.6, 117.6, 119.1, 120.4, 130.4, 143.3, 156.1 ppm;
IR (KBr) 3192, 1457, 1037, 912, 755 cm-1; HRMS-ESI calcd for
C12H19NNaO2S (M + Na)+ 264.1029, found 264.1027.
Synthesis of Ligand (SS,R)-3. To a solution of 9 (3.00 g, 11.3
mmol) in 50 mL of dry CH2Cl2 was added phenylmagnesium
bromide (19 mL, 1.2 M in THF, 22.8 mmol) at -48 °C. After
being stirred for 5 h at -48 °C, the reaction was quenched with
saturated aqueous NH4Cl and extracted with CH2Cl2 (3 × 50 mL).
The combined organic layers were dried (MgSO4) and concentrated
in vacuum. The dr value (99:1) of the crude product was determined
by 1H NMR spectrum. The major isomer 12 as a white solid (92%
yield) was obtained by flash chromatography (1:5 ethyl acetate/
hexanes). Mp 67-68 °C; [R]20D +70.0 (c 1.01, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 7.48 (d, J ) 7.6 Hz, 1H), 7.46 (d, J ) 7.6
Hz, 1H), 7.29 (t, J ) 7.2 Hz, 2H), 7.24-7.20 (m, 1H), 6.97 (t, J
) 7.6 Hz, 1H), 6.83 (d, J ) 8.0 Hz, 1H), 6.02 (d, J ) 4.4 Hz, 1H),
5.95-5.88 (m, 1Η), 5.29-5.19 (m, 2Η), 4.47-4.46 (m, 2H), 3.88
(d, J ) 3.6 Hz, 1H), 1.12 (s, 9H) ppm; 13C NMR (50 MHz, CDCl3)
δ 22.5 (3C), 55.6, 57.1, 68.8, 112.1, 117.3, 120.6, 127.2, 127.3
(2C), 128.0, 128.1, 128.3 (2C), 128.4, 130.2, 142.4, 155.7 ppm.
mL/min; 227 nm; (R)-1c, tR ) 9.6 min, (S)-1c, tR ) 6.1 min). [R]20
D
1
+34.8 (c 0.54, CHCl3); H NMR (400 MHz, CDCl3) δ 7.71 (s,
1H), 7.27 (dd, J ) 8.0, 1.6 Hz, 1H), 7.01 (dd, J ) 7.6, 1.6 Hz,
1H), 6.81 (t, J ) 7.6 Hz, 1H), 4.39 (dd, J ) 13.2, 7.2 Hz, 1H),
4.28 (dd, J ) 13.2, 3.6 Hz, 1H), 3.59 (dd, J ) 7.2, 3.6 Hz, 1H),
1.40 (s, 9H), 1.27 (s, 9H) ppm; 13C NMR (50 MHz, CDCl3) δ 22.6
(3C), 29.6 (3C), 34.8, 45.9, 56.1, 119.6, 123.4, 127.3, 128.0, 136.0,
154.6 ppm; IR (KBr) 3485, 3140, 1440, 1229, 1027, 750 cm-1
;
HRMS-ESI calcd for C15H25NNaO2S (M + Na)+ 306.1498, found
306.1488.
Ligand (S)-1d. (S)-1d was purified by flash chromatography (1:2
ethyl acetate/ hexanes) as a white solid (90% yield). The enantio-
meric excess was determined to be >99.9% by HPLC analysis on
a Diacel Chiralcel AS column (90:10 hexanes/IPA, 1.2 mL/min;
227 nm; (R)-1d, tR ) 30.4 min, (S)-1d, tR ) 24.0 min). Mp 136-
137 °C; [R]20D +53.5 (c 1.05, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 7.59 (s, 1H), 7.02 (dd, J ) 8.4, 2.0 Hz, 1H), 6.93 (d, J ) 2.4 Hz,
1H), 6.80 (d, J ) 8.0 Hz, 1H), 4.30 (dd, J ) 13.6, 6.8 Hz, 1H),
4.24 (dd, J ) 13.6, 4.4 Hz, 1H), 3.67 (t, J ) 4.8 Hz, 1H), 2.26 (s,
3H), 1.26 (s, 9H) ppm; 13C NMR (50 MHz, CDCl3) δ 20.3, 22.6
(3C), 47.0, 56.1, 115.9, 123.6, 126.5, 129.6, 130.1, 153.3 ppm; IR
(KBr) 3261, 3160, 1512, 1268, 1027, 818 cm-1; HRMS-ESI calcd
for C12H19NNaO2S (M + Na)+ 264.1029, found 264.1025.
Ligand (S)-1e. (S)-1e was purified by flash chromatography (1:2
ethyl acetate/hexanes) as a white solid (89% yield). The enantio-
meric excess was determined to be >99.9% by HPLC analysis on
a Diacel Chiralcel AS column (85:15 hexanes/IPA, 1.2 mL/min;
227 nm; (R)-1e, tR ) 27.2 min, (S)-1e, tR ) 20.1 min). Mp 145-
146 °C; [R]20D +70.6 (c 0.96, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 7.63 (s, 1H), 6.82 (d, J ) 8.8 Hz, 1H), 6.75 (dd, J ) 8.8, 2.8 Hz,
1H), 6.69 (d, J ) 2.8 Hz, 1H), 4.26 (d, J ) 5.6 Hz, 2H), 3.83 (t,
J ) 5.6 Hz, 1H), 3.74 (s, 3H), 1.25 (s, 9H) ppm; 13C NMR (50
MHz, CDCl3) δ 22.6 (3C), 46.7, 55.6, 56.1, 114.2, 115.1, 117.1,
124.6, 149.3, 152.7 ppm; IR (KBr) 3249, 3164, 1512, 1223, 1021,
823 cm-1; HRMS-ESI calcd for C12H19NNaO3S (M + Na)+
280.0978, found 280.0971.
Ligand (S)-1f. (S)-1f was purified by recrystallization from the
mixture solvent (1:1 ethyl acetate/hexanes) to afford a yellow solid
(70% yield for two steps). The enantiomeric excess was determined
to be >99.9% by HPLC analysis on a Diacel Chiralcel AS column
(85:15 hexanes/IPA, 1.2 mL/min; 227 nm; (R)-1f, tR ) 34.8 min,
(S)-1f, tR ) 21.8 min). Mp 146-147 °C; [R]20 +48.4 (c 1.00,
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 10.5 (s, 1H), 8.10 (d, J )
2.8 Hz, 1H), 7.95 (dd, J ) 8.8, 2.8 Hz, 1H), 6.75 (d, J ) 8.8 Hz,
1H), 4.40-4.34 (m, 1Η), 4.29-4.22 (m, 2Η), 1.29 (s, 9Η) ppm;
13C NMR (50 MHz, DMSO-d6) δ 22.6 (3C), 42.5, 55.6, 115.2,
124.6, 124.6, 127.7, 139.6, 161.4 ppm; IR (KBr) 3183, 3108, 1597,
1503, 1342, 1292, 1030, 799 cm-1; HRMS-ESI calcd for C11H16N2-
NaO4S (M + Na)+ 295.0723, found 295.0717.
Ligand (S)-1g. (S)-1g was purified by flash chromatography (1:4
ethyl acetate/hexanes) as a colorless liquid. The enantiomeric excess
was determined to be >99.9% by HPLC analysis on a Diacel
Chiralcel OD column (95:5 hexanes/IPA, 1.0 mL/min; 227 nm;
(R)-1g, tR ) 14.4 min, (S)-1g, tR ) 17.4 min). [R]20 +20.4 (c
D
0.85, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.29-7.25 (m, 2H),
6.93 (t, J ) 7.2 Hz, 1H), 6.87 (t, J ) 4.0 Hz, 1H), 4.42 (dd, J )
14.0, 5.2 Hz, 1H), 4.16 (dd, J ) 14.0, 8.0 Hz, 1H), 3.84 (s, 3H),
3.69 (t, J ) 5.2 Hz, 1H), 1.20 (s, 9H) ppm; 13C NMR (50 MHz,
CDCl3) δ 22.5 (3C), 45.4, 55.2, 55.7, 110.3, 120.5, 127.0, 128.8,
Similar to the synthesis of ligand 2, the O-allyl protecting group
in 12 was also removed with NaBH4 catalyzed by Pd(PPh3)4 to
give crude 3, which was purified by flash chromatography (1:5
acetone/hexanes) to afford pure (SS,R)-3 in 95% yield as a white
solid. A colorless crystal of 3 was obtained by recrystallization from
MeOH. Mp 215-216 °C; [R]20D +46.7 (c 0.24, MeOH); 1H NMR
(400 MHz, CDCl3) δ 8.29 (s, 1H), 7.39 (d, J ) 7.6 Hz, 2H), 7.34
(t, J ) 8.0 Hz, 2H), 7.28 (d, J ) 7.2 Hz, 1H), 7.18 (d, J ) 7.2 Hz,
1H), 7.01 (d, J ) 8.0 Hz, 1H), 6.91 (d, J ) 8.0 Hz, 1H), 6.81 (t,
129.3, 157.3 ppm; IR (KBr) 3249, 1526, 1215, 1037, 758 cm-1
;
HRMS-ESI calcd for C12H19NNaO2S 264.1029, found 264.1028.
Synthesis of Ligand (S)-2. To a solution of salicylaldehyde 7
(1.20 g, 10 mmol) in dry acetone (20 mL) was added allyl bromide
(1.3 mL, 15 mmol) and anhydrous potassium carbonate (4.20 g,
30 mmol). After stirring for 2 h at rt, the resulting mixture was
J. Org. Chem, Vol. 72, No. 4, 2007 1377

Huang et al.
J ) 7.6 Hz, 1H), 5.90 (d, J ) 4.0 Hz, 1H), 4.05 (d, J ) 4.0 Hz,
1H), 1.24 (s, 9H) ppm; 13C NMR (50 MHz, DMSO-d6) δ 22.6 (3C),
55.6, 56.8, 115.3, 119.1, 126.6, 127.6 (2C), 128.0, 128.2 (2C),
128.5, 129.3, 143.6, 154.2 ppm; IR (KBr) 3176, 1456, 1356, 1265,
1032, 754 cm-1; HRMS-ESI calcd for C17H21NNaO2S (M + Na)+
326.1185, found 326.1185.
THF) at 0 °C. The solution was stirred at 25 °C for 36 h and
quenched with saturated aqueous NH4Cl at 0 °C. The resulting
mixture was extracted with CH2Cl2 (3 × 15 mL). The combined
organic layers were dried (Na2SO4) and concentrated in vacuum.
The residue was purified by chromatography (1:15 ethyl acetate/
hexanes) to give 1.216 g (83% yield) of 17 as a yellow liquid. 1H
NMR (400 MHz, CDCl3) δ 7.40-7.09 (m, 8Η), 4.72 (s, 1Η), 3.73
(s, 6Η), 2.31 (s, 6Η) ppm.
A mixture of 17 (572 mg, 2.0 mm) and a catalytic amount of I2
(51 mg, 0.2 mmol) in acetone (10 mL) was stirred for 5 min to
afford crude aldehyde for the next step. After the aldehyde was
condensed with (S)-TBSA (121 mg, 1.0 mmol), sulfimine (S)-18
(298 mg) was obtained as a white solid in 87% yield (for two steps).
To a THF (10 mL) solution of 18 (343 mg, 1.0 mmol) was added
NaBH4 (19 mg, 0.5 mmol) at 0 °C. After being stirred for 2 h at 0
°C, the reaction was quenched with saturated aqueous NH4Cl and
extracted with CH2Cl2 (3 × 15 mL). The combined organic layers
were dried (Na2SO4) and concentrated in vacuum. The residue was
purified by recrystallization from a mixture of ethyl acetate and
hexanes (1:3) to give 317 mg (92% yield) of ligand 6 as a white
solid. The enantiomeric excess of 6 was determined to be >99.9%
by HPLC analysis on a Diacel Chiralcel AS column (90:10 hexanes/
Synthesis of Ligand (S)-4. To a solution of ammonia (20 mL)
was added a catalytic crystal of Fe(NO3)3 at -78 °C, and the
solution became yellow immediately. Lithium bars (0.172 g, 24.0
mmol) were added. The resulting blue solution was slowly warmed
to -40 °C until it turned gray. The resulting LiNH2 mixture was
chilled to -78 °C, and 2-allyloxyphenylamine 13b (3.870 g, 26.0
mmol) was added slowly. After being stirred for 3 h, a solution of
(SS)-thiosulfinate 14 (1.540 g, 8.0 mmol, 92% er) in 4 mL of dry
THF was added slowly to the light pink lithium anilide solution.
The mixture was stirred for 5 h at -78 °C, and then NH4Cl crystals
were carefully added. The volatile material was removed by
warming the solution slowly. After the residue was diluted with
ethyl acetate (80 mL) and water (40 mL), the resulting mixture
was extracted with ethyl acetate (3 × 50 mL). The combined
organic layers were dried (Na2SO4), concentrated, and purified by
flash chromatography (1:10 ethyl acetate/hexanes) to afford 1.520
1
g of (S)-15 (75% yield) as a pink liquid. H NMR (400 MHz,
IPA, 1.0 mL/min; 227 nm; (R)-6, tR ) 20.4 min, (S)-6, tR ) 9.5
1
min). Mp 160-161 °C; [R]20 +59.8 (c 0.99, CHCl3); H NMR
CDCl3) δ 7.22-7.20 (m, 1Η), 6.95-6.92 (m, 2Η), 6.89-6.86 (m,
1Η), 6.11-6.02 (m, 1Η), 6.10 (s, 1Η), 5.44-5.30 (m, 2Η), 4.60-
4.58 (m, 2Η), 1.35 (s, 9Η) ppm.
D
(400 MHz, CDCl3) δ 7.33-7.28 (m, 4Η), 7.16-7.10 (m, 4H), 4.45
(s, 1H), 3.96 (dd, J ) 14.0, 5.2 Hz, 1H), 3.84 (dd, J ) 14.0, 8.0
Hz, 1H), 3.46 (dd, J ) 8.0, 5.2 Hz, 1H), 2.32 (s, 3H), 2.30 (s, 3H),
1.11 (s, 9H) ppm; 13C NMR (50 MHz, CDCl3) δ 20.6, 22.5 (3C),
55.9, 56.4, 77.2, 125.9 (2C), 126.2 (2C), 128.9 (2C), 129.0 (2C),
136.6, 136.7, 141.2, 141.6 ppm; IR (KBr) 3471, 3187, 1510, 1047,
824 cm-1; HRMS-ESI calcd for C20H27NNaO2S (M + Na)+
368.1655, found 368.1668.
The O-allyl protecting group in 15 (1.260 g, 5.0 mmol) was
removed by NaBH4 (0.285 g, 7.5 mmol) in the presence of Pd-
(PPh3)4 (0.125 g, 0.1 mmol) in THF. The crude product was purified
by chromatography (1:2 ethyl acetate/hexanes) to afford 0.960 g
(90% yield) of ligand (S)-4 as a yellow solid with 90% er. After
twice recrystallization from degassed ethyl ether/hexanes (1:4), (S)-4
was obtained with 99.4% er (HPLC, Diacel Chiralcel OD column
90:10 hexanes/IPA, 1 mL/min; 227 nm; (R)-4, tR ) 12.8 min, (S)-
4, tR ) 16.3 min). Mp 132-134 °C; [R]20D +48.2 (c 0.38, MeOH);
1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 7.02 (dd, J ) 7.2, 2.0
Asymmetric Addition of Diethylzinc to Benzaldehyde Cata-
lyzed by Ligand 1a (a representative procedure). To a solution
of 1a (11 mg, 0.05 mmol) in dry hexanes/toluene (1 mL/0.5 mL)
was added diethylzinc (1.5 M in toluene, 0.5 mL, 0.75 mmol) at
room temperature under N2. The resulting mixture was stirred for
30 min and benzaldehyde (53 mg, 0.50 mmol) was added. After
being stirred for an additional 18 h, the reaction was quenched with
saturated aqueous NH4Cl at 0 °C and the resulting mixture was
extracted with CH2Cl2 (3 × 10 mL). The combined organic layers
were dried (Na2SO4) and concentrated in vacuum. The residue was
purified by chromatography (1:15 ethyl acetate/hexanes) to afford
63 mg (93% yield) of (R)-1-phenyl-1-propanol (96% er).
The absolute configuration of adducts in Table 2 was determined
by rotation and the enantiomeric excess was determined by chiral
stationary phase HPLC analysis (Chiralcel OD column).18
Hz, 1H), 6.78-6.66 (m, 3Η), 5.89 (s, 1Η), 1.37 (s, 9Η) ppm; 13
C
NMR (50 MHz, CDCl3) δ 22.5 (3C), 56.5, 116.2, 119.6, 120.2,
124.6, 129.1, 146.1 ppm; IR (KBr) 3084, 1545, 1454, 1284, 1038,
767 cm-1; HRMS-ESI calcd for C10H15NNaO2S (M + Na)+
236.0721, found 236.0726.
Synthesis of Ligand (S)-5. By using the same procedure as the
preparation of compound 15, ligand 5 was prepared from o-anisidine
13a in 83% yield and with 90% er as a brown solid. After twice
recrystallization from a mixture of petroleum and ethyl acetate (10:
1), (S)-5 was obtained with 99% er (HPLC, Diacel Chiralcel OD
column 90:10 hexanes /IPA, 1.0 mL/min; 227 nm; (R)-5, tR ) 8.5
min, (S)-5, tR ) 11.2 min). Mp 112-113 °C; [R]20D +35.6 (c 1.05,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.16 (dd, J ) 7.6, 1.6 Hz,
1H), 6.98-6.88 (m, 1H), 6.85 (dd, J ) 7.6, 1.6 Hz, 1H), 3.85 (s,
3H), 1.28 (s, 9H) ppm; 13C NMR (50 MHz, CDCl3) δ 22.3 (3C),
55.7, 56.4, 110.7, 116.5, 121.1, 122.5, 131.6, 146.5 ppm; IR (KBr)
2959, 1500, 1459, 1248, 1082, 744 cm-1; HRMS-ESI calcd for
C11H17NNaO2S (M + Na)+ 250.0872, found 250.0862.
Acknowledgment. This work was supported by NSFC (No.
20572072), Ministry of Education (NCET and RFDP), and
Sichuan Province Government (Nos. 04ZQ026-011 and 05SG022-
030).
Supporting Information Available: Chiral HPLC analysis of
Synthesis of Ligand (S)-6. Under N2, to a solution of methyl
dimethoxyacetate 16 (0.686 g, 5.1 mmol) in THF (14 mL) was
added p-tolylmagnesium bromide (14 mL, 21.0 mmol, 1.5 M in
1
ligands, data of H and 13C NMR spectra of new compounds, er
determination of adducts, and X-ray crystallographic data for 3 as
a CIF file. This material is available free of charge via the Internet
at http://pubs.acs.org.
(18) Dai, W.-M.; Zhua, H.-J.; Hao, X.-J. Tetrahedron: Asymmetry 2000,
11, 2315.
JO062249Q
1378 J. Org. Chem., Vol. 72, No. 4, 2007