A general asymmetric synthesis of phenylglycinols

Article abstract of DOI:10.1016/j.tetasy.2011.01.011

Hydride reduction and deprotection of siloxymethyl sulfinimines 2 reliably furnished chiral phenylglycinols 1 or 10 in high overall yield and enantiomeric purity.

Full text of DOI:10.1016/j.tetasy.2011.01.011

Tetrahedron: Asymmetry 22 (2011) 329–337
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A general asymmetric synthesis of phenylglycinols
Xingang Pan a, Liangbin Jia a, Xuejian Liu a, Haikuo Ma a, Wenqian Yang a, , Jacob B. Schwarz b,
⇑
⇑
a Shanghai Chempartner Co., Ltd, Building 1, 998 Halei Road, Zhangjiang Hi-Tech Park, Pudong New Area, Shanghai 201203, China
b Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Hydride reduction and deprotection of siloxymethyl sulfinimines 2 reliably furnished chiral phenylglyci-
nols 1 or 10 in high overall yield and enantiomeric purity.
Received 5 January 2011
Accepted 12 January 2011
Available online 15 February 2011
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
spontaneously cyclized to 2-aryl-pyrrolidines.9 Inspired by this
work, we herein report the highly selective hydride reduction of
For decades, enantiomerically pure phenylglycinol has been
exploited as a key building block for asymmetric reaction methodol-
ogy.1 Of the general asymmetric approaches to phenylglycinols re-
ported to date, only moderate efficiencies have been obtained.
Hence, the ability to electronically or sterically tune such motifs in
a systematic manner, for instance in the design of novel catalysts,
has been somewhat limited. One innovative approach toward solv-
ing this problem involved the addition of methyl lithium p-tolyl sulf-
a-silyloxy-sulfinimines to afford chiral phenylglycinols, which
constitutes an improvement over existing methods10 for generating
these valuable structures.
2. Results and discussion
Fluorine is known to impart unique properties to organic sub-
stances, and a search of the literature revealed several recent
reports exploiting 4-fluorophenylglycinol in various contexts.11
As a result, this target was selected for an initial evaluation of
the approach. In order to access the sulfinimine precursor 2a,
we envisioned that the requisite acetophenone 7a could be
obtained through aryl Grignard addition to the readily available
Weinreb amide 6.12 This proved to be the case as the addition of
4-fluorophenylmagnesium bromide to 6 smoothly furnished ketone
7a (Scheme 1). Standard conditions for sulfinimine formation were
employed,13 providing an acceptable overall yield of the reduction
precursor 2a on a 10-g scale. It is noteworthy that hydroxyl protec-
tion was required to carry out conversion of the ketone 7a to the
sulfinimine.
oxide to N-PMP imines followed by a Pummerer-type reaction.2
A
more general asymmetric route to phenylglycinols was based on
the addition of an aryl organometallic species to a chiral sulfinimine
3.3–7 A potential limitation of this method is that high levels of
selectivity in the addition of 4 were achieved using benzyl
ethers, but in the limited number of cases tested, the ratios were
diminished for the more synthetically versatile silyl ethers. Alter-
nately, the hydride reduction of O-alkylated enamides 5 afforded
the desired framework, although hydrolysis of the resultant acetam-
ide to provide the free amine would require harsh conditions.8 More
recently an article appeared wherein a chloralkylated sulfinimine
underwent selective hydride reduction, and on auxiliary cleavage
S
H
M
X
Y
N
O
Refs 4,5
Ref 6
+
F
MgBr
BnO
O
TBSO
OMe
N
3
4
THF, 0 oC
91%
1
NHAc
6
MOMO
H2, cat*
+
Y
O
(R)-tBuS(O)NH2
Ti(OiPr)4
5
TBSO
2a
THF, reflux, 16 h
71%
⇑
F
Corresponding authors. Tel.: +86 21 5132 0662, fax: +86 21 5137 1359 (W.Y.),
tel.: +1 650 225 7732, fax: +1 650 742 4943 (J.B.S.).
E-mail addresses: wqyang@chempartner.cn (W. Yang), schwarz.jacob@gene.com
(J.B. Schwarz).
7a
Scheme 1. Preparation of sulfinimine 2a from 6.
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.01.011

330
X. Pan et al. / Tetrahedron: Asymmetry 22 (2011) 329–337
Table 1
Table 2
Reagent optimization in the reduction of sulfinimine 2a
Optimization of solvent in the reduction of 2a
Entry
Hydridea
Solvent
Ratio 8a:9ab
1
2
3
4
5
6
BH3ꢁTHF
BH3ꢁTHF
BH3ꢁTHF
DIBALH
DIBALH
DIBALH
Toluene
CH2Cl2
THF
Toluene
CH2Cl2
THF
95:5
94:6
97:3
97:3
96:4
95:5
S
S
HN
O
HN
O
TBSO
+
F
TBSO
2a
F
a
8a
9a
All reactions were performed on a 0.2 mmol scale at ꢀ78 °C for 2 h with
3.0 equiv of hydride.
b
Entry
Hydridea
Conversionb (%)
Ratio 8a:9ac
Diastereomeric ratio determined by LC/MS analysis of crude reaction mixture.
1
2
3
4
5
6
NaBH4
LiBH4
NaBH3CN
Red-Al
LiAlH4
62
95
<5
>99
>99
>99
89:11
91:9
ND
78:22
80:20
61:39
and in the case of 8j was unambiguously assigned after deprotec-
tion and comparison to the literature data for 1j. Similar results
were obtained for the
a- and b-naphthyl examples 2m and 2n.
Virtually no selectivity was obtained for the ortho-substituted
2m, but this was completely rescued by shifting the point of ring
fusion as in 2n (entries 11 and 12). Importantly, in each case
involving ortho-substitution we observed a diminished E/Z ratio
of the sulfinimine 2 by 1H NMR, which was then manifested in
the reduction selectivity (vide infra). As the amino alcohols 1k
and 1m were in fact novel structures, their stereochemical assign-
ments were based on analogy of the behavior of 8, 9j on HPLC.
In an attempt to explain the origin of the reduced stereoselectiv-
ities, a NOESY experiment of 2f was conducted which suggested that
thesulfinyl group was proximalto the aryl group in the majorisomer
present in the solution. This result is consistent with the previous re-
ports that the N-sulfinyl imines predominantly exist as E isomers.13
One possible model to explain the selectivity based on work from
Davis14 is showninFigure 1. In thismodel, coordination ofthereduc-
tant (B or Al) to the sulfinimine oxygen leads to an open transition
state in which attack by a second equivalent of hydride would fur-
nish the major isomer. The inclusion of an ortho-substituent on the
aromatic ring would serve to block access of the hydride to the less
hindered face, thereby reducing the chemical yield and selectivity.
Alternately, the ortho-substituent was shown to disrupt the prefer-
ence of the sulfinimine 2 for the E geometry, which is able to adopt
a chairlike transition state in which the metal is bound to both oxy-
gen atoms.5 Consistent with these observations, it was recently re-
ported that benzophenone sulfinimines containing an ortho-alkyl
substituent afforded only marginal selectivity upon reduction with
either borane or DIBALH.15
L
-Selectride
7
8
9
10
11
LiBHEt3
BH3ꢁiTHF
DIBAꢁLH
9-BBN
>99
>99
>99
37
67:33
97:3
95:5
99:1
88:12
Catecholborane
>99
a
All reactions were performed on a 0.2 mmol scale at ꢀ78 °C for 2 h in anhydrous
THF with 3.0 equiv of hydride.
b
Conversion determined by LC/MS analysis of consumption of sulfinimine.
Diastereomeric ratio determined by LC/MS analysis of the crude reaction
mixture.
c
With the chiral sulfinimine 2a in hand, we set out to explore the
effect of a number of reducing agents on the substrate (Table 1).
Lithium borohydride proved to be more efficient than sodium
borohydride, although the diastereoselectivities were similar (en-
tries 1 and 2). Aluminum reagents Red-Al and lithium aluminum
hydride afforded the sulfinamides with very good conversion, but
only with modest selectivity (ca. 4:1, entries 4 and 5). We exam-
ined bulkier reducing agents such as L-Selectride and lithium tri-
ethylborohydride, which in the previous report9 exclusively
afforded the diastereomer corresponding to 9a. Although further
deterioration of the selectivity was observed, 8a was still predom-
inant in these cases (entries 6 and 7). Excellent results were ob-
tained when either borane–THF or diisobutylaluminum hydride
was used, affording very high conversion and diastereoselectivity
(entries 8 and 9). The use of 9-BBN retained the high selectivity
but diminished the yield, and while catecholborane retained high
conversion, it was less selective (entries 10 and 11).
Finally, deprotection of the auxiliary and TBS ether was evalu-
ated. Treatment of sulfinamides 8 with HCl/MeOH afforded the de-
Next, the effect of solvent on the sulfinimine reduction reaction
was investigated using the two best performing reductants
(Table 2). To our delight, very little reliance of the selectivity on
the solvent was observed. Optimal conditions involved the addi-
tion of 3.0 equiv of borane–THF or DIBALH to the sulfinimine in
either toluene, CH2Cl2 or THF at ꢀ78 °C. Unfortunately, deprotec-
tion of the silyloxy sulfinimine 2a with TBAF resulted in extensive
decomposition, and hence we were unable to test the influence of
the free hydroxyl on the reduction conversion or selectivity.
The generality of the process using a variety of aryl substitu-
tions was then investigated (Table 3). When the fluoro group of
2a was relocated to the meta-position as in 2b or alternately com-
bined with a chloro substituent in a 3,4-arrangement, the effi-
ciency of the process was high and the sulfinimine reduction was
completely diastereoselective (entries 1–4). No deterioration in
yield or selectivity was observed when switching the fluoro in 2a
to methoxy in 2e or methyl in 2f (entries 5 and 6). Similarly, the
3- and 4-trifluoromethyl derivatives were excellent substrates
(entries 7 and 8). However, when the fluoro or methyl substituent
was located at the ortho-position, both the conversion and the
selectivity significantly decreased (entries 9 and 10). In both cases,
the major diastereomer could be separated by chromatography,
sired free phenylglycinols
1 with no detectable loss in the
stereochemical integrity. Table 4 summarizes the results for full
deblocking of 8a–n. Importantly, a modification to the optimized
conditions in which diethyl ether was included in the reaction mix-
ture served to liberate the amine hydrochloride with the silyl ether
still intact in excellent yield as demonstrated for 8c (Scheme 2). This
complementary mono-deprotection would obviate the need for
reprotection in situations where further synthetic manipulation is
required (Table 5).
3. Conclusion
In summary, an efficient process has been developed wherein
the readily available Weinreb amide 6 is converted in a few short
steps to the chiral phenylglycinols 1. Excellent selectivities were
observed in the sulfinimine reduction step where aryl substitu-
tions were located at the 3- or 4-positions (or both). Although de-
creases in yield and selectivity were observed for ortho-substituted
cases, the reduction products could still be chromatographically
separated and converted to the corresponding enantiomerically
pure amino alcohols. Noteworthy is the fact that
a simple

X. Pan et al. / Tetrahedron: Asymmetry 22 (2011) 329–337
331
Table 3
Isolated yields of 7, 2, and 8, and diastereomer ratio 8:9
Entry
Aryl
Yield of 7a
Yield of 2a
Reduction product
Yieldb
Ratio of 8:9c
1
2
4-F-Ph
91
86
85
88
93
86
90
91
45
86
60
73
71
61
81
65
75
78
86
70
36
61
61
57
8a
8b
8c
8d
8e
8f
70d
>98:2
65d
3-F-Ph
97:3
3
3-Cl-4-F-Ph
3-F-4-Cl-Ph
3-MeO-Ph
3-Me-Ph
3-CF3-Ph
4-CF3-Ph
2-F-Ph
80e
>98:2
79e
4
>98:2
5
70e
>98:2
79e
6
>98:2
7
8g
8h
8j
76e
>98:2
81e
8
>98:2
9
33e
70:30
25e
10
11
12
2-Me-Ph
1-Naphthyl
2-Naphthyl
8k
8m
8n
80:20
30e
40:60
74e
>98:2
a
b
c
Isolated yield.
Isolated yield of diastereomer 8.
Determined by LC/MS of crude reaction mixture as before.
Using BH3ꢁTHF in THF at ꢀ78 °C.
d
e
Using DIBALH in THF at ꢀ78 °C.
8c
SiO
SiO
HCl/MeOH/Et2O
HCl/MeOH
97%
R
94%
H
M
H
M
O
O
NH2
NH2
M
M
N
N
TBSO
Cl
F
HO
Cl
F
10c
1c
HCl/MeOH
99%
H
Scheme 2. Differential deprotection of 8c.
tBuS(O)HN
TBSO
reduced yield,
selectivity
(S)
Table 5
Yields of phenylglycinol ethers 10 from sulfinamides 8a
Entry
Sulfinamide 8
Silyl Ether 10
Yield (%)
Figure 1. Proposed model for the reduction of sulfinimines 2.
1
2
3
4
8c
8d
8f
10c
10d
10f
94
86
79
90
8n
10n
a
Table 4
Conditions: HCl, MeOH, Et2O, room temperature.
Yields of phenylglycinols 1 from sulfinamides 8a
adjustment of the conditions used to effect deprotection of the
auxiliary could in fact spare the silyl ether moiety to afford 10,
which could be of considerable advantage in the context of effect-
ing subsequent transformations. Finally, should the enantiomeric
(unnatural) phenylglycinol products be desired, the (S)-antipode
of the chiral auxiliary could be employed.
Entry
Sulfinamide 8
Phenylglycinol 1
Yield (%)
1
2
3
4
5
6
7
8
9
8a
8b
8c
8d
8e
8f
8g
8h
8j
1a
1b
1c
1d
1e
1f
1g
1h
1j
93
85
97
93
80
89
91
93
92
90
97
99
4. Experimental
10
11
12
8k
8m
8n
1k
1m
1n
4.1. General methods
All chemicals were purchased from commercial sources and
used immediately upon arrival. THF was distilled from sodium/
a
Conditions: HCl, MeOH, room temperature.

332
X. Pan et al. / Tetrahedron: Asymmetry 22 (2011) 329–337
benzophenone. All 1H, 13C NMR, NOESY spectrawere recorded witha
Bruker AVANCE III 500 or 400 MHz UltraShield-PlusTM Digital NMR
spectrometer. LC–MS was recorded with an Agilent 1200 HPLC/6110
4.82 (s, 2H), 0.92 (s, 9H), 0.11 (s, 6H); 13C NMR (125 MHz, CDCl3) d
195.59 (d, J = 2.6 Hz), 158.08 (d, J = 312.4 Hz), 134.96 (d, J = 8.0 Hz),
130.89, 126.62 (d, J = 22.4 Hz), 124.53 (d, J = 4.2 Hz), 116.23
(d, J = 27.2 Hz), 67.63, 25.73, 18.37, ꢀ5.39; IR (thin film) 2953,
2929, 2893, 2856, 1710, 1578, 1250, 1143, 1067 cmꢀ1; HRMS
(ESI) m/z calcd for C14H21ClFO2Si 303.0983, found 303.0980 (M+H).
SQD system (Method: column: XBridge C18, 4.6 ꢂ 150 mm, 3.5
lm;
mobile phase: A water (0.01% ammonia), B CH3CN; gradient:
5–95% B in 8.0 min; flow rate: 1.2 mL/min; oven temperature 40 °C),
monitored at 210 and 254 nm and scanned between 110 and
800 amu in ESI ionization mode. Chiral HPLC analyses were recorded
with a SHIMADZU 20A system. Melting points were obtained with
DSC Q2000(v 24.4, Build 116). Optical rotationswere measured with
an Autopol V polarimeter. ESI HRMS analyses were performed by the
Facility of Shanghai Institute of Organic Chemistry.
4.2.5. 2-(tert-Butyldimethylsilyloxy)-1-(3-methoxyphenyl)
ethanone 7e
Yield: 93%; 1H NMR (500 MHz, CDCl3) d 7.47 (m, 2H), 7.35
(m, 1H), 7.11 (m, 1H), 4.91 (s, 2H), 3.85 (s, 3H), 0.94 (s, 9H), 0.13
(s, 6H); 13C NMR (125 MHz, CDCl3) d 197.19, 159.83, 136.12,
129.61, 120.26, 119.76, 112.19, 67.46, 55.40, 25.83, 18.51, ꢀ5.30;
IR (thin film) 2955, 2930, 2893, 2857, 1711, 1591, 1252, 1151,
839 cmꢀ1; HRMS (ESI) m/z calcd for C15H24NaO3Si 303.1392, found
303.1387 (M+Na).
4.2. Representative procedure for the preparation of TBS-
a-
hydroxyacetophenone
4.2.1. 2-(tert-Butyldimethylsilyloxy)-1-(4-fluorophenyl)etha
none 7a
4.2.6. 2-(tert-Butyldimethylsilyloxy)-1-m-tolylethanone 7f
Yield: 86%; 1H NMR (500 MHz, CD3OD) d 7.78 (s, 1H), 7.74
(d, J = 8.0 Hz, 1H), 7.44 (m, 1H), 7.38 (m, 1H), 5.00 (s, 2H), 2.41
(s, 3H), 0.94 (s, 3H), 0.13 (s, 6H); 13C NMR (100 MHz, CDCl3) d
196.59, 137.39, 133.84, 133.01, 127.46, 127.34, 123.97, 66.42,
24.81, 20.31, 17.49, ꢀ6.33; IR (thin film) 2953, 2930, 2891, 2857,
1707, 1587, 1254, 1145, 839 cmꢀ1; HRMS (ESI) m/z calcd for
To a 250 mL three-necked flask was added magnesium turnings
(3.60 g, 150 mmol) and anhydrous THF (150 mL) under argon. A
few drops of 1,2-dibromoethane were added followed by the slow
addition of 1-bromo-4-fluorobenzene (13.1 g, 75.0 mmol). The
solution was stirred at ambient temperature for 40 min, then
cooled to 0 °C, at which time the solution was added slowly to 2-
(tert-butyldimethylsilyloxy)-N-methoxy-N-methylacetamide 6
(10.0 g, 42.8 mmol) in THF (150 mL). The resultant mixture was
stirred at 0 °C for 3 h, then quenched with saturated NH4Cl
(100 mL). The mixture was extracted with CH2Cl2 (3 ꢂ 100 mL)
and the combined organic phases washed with water
(3 ꢂ 100 mL), dried (Na2SO4), and concentrated. The residue was
purified by column chromatography (1:20 EtOAc/petroleum ether)
to afford 10 g (91%) of 2-(tert-butyldimethylsilyloxy)-1-(4-fluoro-
C15H24NaO2Si 287.1439, found 287.1438 (M+Na).
4.2.7. 2-(tert-Butyldimethylsilyloxy)-1-(3-(trifluoromethyl)
phenyl)ethanone 7g
Yield: 90%; 1H NMR (500 MHz, CDCl3) d 8.23 (s, 1H), 8.13
(d, J = 8.0 Hz, 1H), 7.84 (d, J = 7.5 Hz, 1H), 7.61 (t, J = 8.0 Hz, 1H),
4.88 (s, 2H), 0.92 (s, 9H), 0.12 (s, 6H); 13C NMR (125 MHz, CDCl3)
d 196.65, 135.42, 131.35, 131.17 (q, J = 157.6 Hz), 129.65 (q,
J = 3.8 Hz), 129.24, 125.24 (q, J = 3.6 Hz), 123.66 (q, J = 270.8 Hz),
67.78, 25.72, 18.37, ꢀ5.39; IR (thin film) 2955, 2932, 2858, 1714,
1333, 1163, 839 cmꢀ1; HRMS (ESI) m/z calcd for C15H21F3NaO2Si
341.1161, found 341.1162 (M+Na).
phenyl)ethanone as
a
white solid, mp = 37–38 °C: 1H NMR
(500 MHz, CDCl3) d 7.97 (m, 2H), 7.13 (m, 2H), 4.86 (s, 2H), 0.92
(s, 9H), 0.12 (s, 6H); 13C NMR (125 MHz, CDCl3) d 196.13, 165.80
(d, J = 254 Hz), 131.34 (d, J = 2.2 Hz), 130.77 (d, J = 9.3 Hz), 115.74
(d, J = 21.5 Hz), 67.51, 25.81, 18.46, ꢀ5.33; IR (thin film) 2954,
2929, 2893, 2856, 1705, 1598, 1255, 1151, 980 cmꢀ1; HRMS (ESI)
m/z calcd for C14H21FNaO2Si 291.1193, found 291.1189 (M+Na).
4.2.8. 2-(tert-Butyldimethylsilyloxy)-1-(4-(trifluoromethyl)
phenyl)ethanone 7h
Yield: 91%; mp = 44–47 °C; 1H NMR (500 MHz, CDCl3) d 8.05
(d, J = 8.5 Hz, 2H), 7.73 (d, J = 8.0 Hz, 2H), 4.90 (s, 2H), 0.92
(s, 9H), 0.12 (s, 6H); 13C NMR (125 MHz, CDCl3) d 196.88, 137.66,
134.58 (q, J = 32.5 Hz), 128.51, 125.66 (q, J = 4.6 Hz), 123.58 (q,
J = 270.88 Hz), 67.76, 25.74, 18.467, ꢀ5.33; IR (thin film) 2932,
2895, 2858, 1703, 1325, 1163, 835 cmꢀ1; HRMS (ESI) m/z calcd
for C15H21F3NaO2Si 341.1161, found 341.1166 (M+Na).
4.2.2. 2-(tert-Butyldimethylsilyloxy)-1-(3-fluorophenyl)ethanone
7b
Yield: 86%; 1H NMR (500 MHz, CDCl3) d 7.59 (m, 1H), 7.50
(m, 1H), 7.32 (m, 1H), 7.14 (m, 1H), 4.75 (s, 2H), 0.81 (s, 9H), 0.00
(s, 6H); 13C NMR (125 MHz, CDCl3) d 196.39, 162.78 (d, J = 246 Hz),
136.92 (d, J = 6.0 Hz), 130.27 (d, J = 7.8 Hz), 123.70, 120.26
(d, J = 22.2 Hz), 114.88 (d, J = 22.2 Hz), 67.60, 25.77, 18.44, ꢀ5.36;
IR (thin film) 2955, 2929, 2857, 1710, 839 cmꢀ1; HRMS (ESI) m/z
calcd for C14H21FNaO2Si 291.1189, found 291.1187 (M+Na).
4.2.9. 2-(tert-Butyldimethylsilyloxy)-1-(2-fluorophenyl)
ethanone 7j
Yield: 45%; 1H NMR (500 MHz, CDCl3) d 7.86 (m, 1H), 7.47
(m, 1H), 7.18 (m, 1H), 7.06 (m, 1H), 4.78 (s, 2H), 0.86 (s, 9H), 0.57
(s, 6H); 13C NMR (100 MHz, CDCl3) d 195.33, 160.98 (d, J = 252 Hz),
136.29, 129.64 (d, J = 3.9 Hz), 125.75, 122.34 (d, J = 15.9 Hz),
115.42 (d, J = 23.7 Hz), 60.82, 24.79, 17.50, ꢀ6.4; IR (thin film)
2955, 2930, 2855, 1705, 1255, 839 cmꢀ1; HRMS (ESI) m/z calcd
for C14H21FNaO2Si 291.1186, found 291.1187 (M+Na).
4.2.3. 2-(tert-Butyldimethylsilyloxy)-1-(3-chloro-4-fluorophenyl)
ethanone 7c
Yield: 85%; 1H NMR (500 MHz, CDCl3) d 8.13 (d, J = 5.5 Hz, 1H),
7.94 (m, 1H), 7.56 (m, 1H), 5.02 (s, 2H), 0.88 (s, 9H), 0.06 (s, 6H);
13C NMR (125 MHz, DMSO-d6) d 195.24, 155.06 (d, J = 253 Hz),
132.15, 130.42, 128.94, 120.20 (d, J = 17.9 Hz), 117.26 (d, J =
22.3 Hz), 66.87, 25.62, 18.01, ꢀ5.56; IR (thin film) 2955, 2930,
2893, 2857, 1711, 1591, 1252, 1151, 839 cmꢀ1; HRMS (ESI) m/z
calcd for C14H20ClFNaO2Si 325.0803, found 325.0800 (M+Na).
4.2.10. 2-(tert-Butyldimethylsilyloxy)-1-o-tolylethanone 7k
Yield: 86%; 1H NMR (500 MHz, CDCl3) d 7.44 (d, J = 7.5 Hz, 1H),
7.28 (m, 1H), 7.15 (m, 2H), 4.67 (s, 2H), 2.41 (s, 3H), 0.83 (s, 9H),
0.04 (s, 6H); 13C NMR (100 MHz, CDCl3) d 201.97, 138.08, 135.73,
131.81, 128.01, 125.49, 68.78, 25.81, 20.87, 18.48, ꢀ5.31; IR (thin
film) 2953, 2930, 2857, 1707, 1157, 839 cmꢀ1; HRMS (ESI) m/z
calcd for C15H24NaO2Si 287.1437, found 287.1438 (M+Na).
4.2.4. 2-(tert-Butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)
ethanone 7d
Yield: 88%; mp = 31–34 °C; 1H NMR (500 MHz, CDCl3) d 7.75
(d, J = 9.5 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.50 (t, J = 7.7 Hz, 1H),

X. Pan et al. / Tetrahedron: Asymmetry 22 (2011) 329–337
333
4.2.11. 2-(tert-Butyldimethylsilyloxy)-1-(naphthalen-1-yl)etha
none 7m
Yield: 60%; 1H NMR (500 MHz, CDCl3) d 8.54 (d, J = 8.5 Hz, 1H),
4.3.4. (Rs)-N-(2-(tert-Butyldimethylsilyloxy)-1-(4-chloro-3-
fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide 2d
Yield: 65%; 1H NMR (500 MHz, CDCl3) d 7.67 (d, J = 10.5 Hz, 1H),
7.61 (d, J = 5.5 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 5.28 (d, J = 14 Hz,
1H), 4.99 (d, J = 14 Hz, 1H), 1.31 (s, 9H), 0.82 (s, 9H), 0.1 (s, 3H),
8.00 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz,
1H), 7.55 (m, 3H), 4.91 (s, 2H), 0.93 (s, 9H), 0.15 (s, 6H); 13C NMR
(125 MHz, CDCl3)
d
202.08, 133.89, 133.45, 132.65, 130.29,
0.06 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 174.80, 157.75
128.41, 127.90, 127.23, 126.49, 125.55, 124.19, 68.93, 25.86,
18.58, ꢀ5.36; IR (thin film) 3049, 2953, 2857, 1703, 1465, 1253,
939, 839 cmꢀ1; HRMS (ESI) m/z calcd for C18H24NaO2Si 323.1437,
found 323.1438 (M+Na).
(d, J = 247.1 Hz), 137.21, 130.17, 125.05, 124.15, 116.62
(d, J = 23.4 Hz), 60.17, 58.69, 25.64, 22.82, 18.06, ꢀ5.37, ꢀ5.38; IR
(thin film) 2955, 2928, 2857, 1710, 1568, 1257, 1082, 839 cmꢀ1
;
HRMS (ESI) m/z calcd for
C18H30ClFNO2SSi 406.1439, found
406.1450 (M+H).
4.2.12. 2-(tert-Butyldimethylsilyloxy)-1-(naphthalen-2-yl)
ethanone 7n
4.3.5. (Rs)-N-(2-(tert-Butyldimethylsilyloxy)-1-(3-methoxy
phenyl)ethylidene)-2-methylpropane-2-sulfinamide 2e
Yield: 73%; 1H NMR (500 MHz, CDCl3) d 8.33 (s, 1H), 7.85
(m, 1H), 7.76 (m, 1H), 7.71 (m, 2H), 7.41 (m, 2H), 4.90 (s, 2H), 0.82
(s, 9H), 0.02 (s, 6H); 13C NMR (500 MHz, CDCl3) d 196.33, 134.58,
131.36, 131.09, 128.49, 128.43, 127.43, 126.72, 125.73, 122.64,
66.58, 24.81, 17.45, ꢀ6.31; IR (thin film) 3059, 2953, 2928, 2885,
2854, 1701, 1469, 1256, 1149, 1121, 839 cmꢀ1; HRMS (ESI) m/z
calcd for C18H24NaO2Si 323.1439, found 323.1438 (M+Na).
Yield: 75%; 1H NMR (500 MHz, CDCl3) d 7.43 (m, 2H), 7.31
(m, 1H), 7.01 (m, 1H), 5.25 (s, 1H), 5.02 (s, 1H), 2.83 (s, 3H), 1.31
(s, 9H), 0.83 (s, 9H), 0.10 (s, 3H), 0.07 (s, 3H); 13C NMR (125 MHz,
CDCl3) d 176.93, 159.19, 128.91, 121.14, 120.14, 119.76, 117.02,
113.55, 67.58, 60.42, 58.17, 55.28, 25.69, 22.75, 17.98, ꢀ5.31; IR
(thin film) 2954, 2930, 2857, 1607, 1576, 1464, 1256, 1080,
839 cmꢀ1; HRMS (ESI) m/z calcd for C19H34NO3SSi 384.2029, found
384.2022 (M+H).
4.3. Representative procedure for the preparation of tert-
butylsulfinimines
4.3.6. (Rs)-N-(2-(tert-Butyldimethylsilyloxy)-1-m-tolylethy
lidene)-2-methylpropane-2-sulfinamide 2f
4.3.1. (Rs)-N-(2-(tert-Butyldimethylsilyloxy)-1-(4-fluorophenyl)
ethylidene)-2-methylpropane-2-sulfinamide 2a
Yield: 78%; 1H NMR (500 MHz, CDCl3) d 7.66 (m, 2H), 7.26
(m, 2H), 5.22 (m, 1H), 5.03 (m, 1H), 2.37 (s, 3H), 1.30 (s, 9H),
0.81 (s, 9H), 0.08 (s, 3H), 0.06 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 176.58, 136.57, 135.89, 130.89, 128.20, 126.93, 124.73, 59.56,
56.80, 24.64, 21.70, 20.15, 16.85, ꢀ6.66; IR (thin film) 2955,
2859, 2856, 1711, 1499, 1256, 1078, 837 cmꢀ1; HRMS (ESI) m/z
calcd for C19H34NO2SSi 368.2076, found 368.2074 (M+H).
At first, 2-(tert-butyldimethylsilyloxy)-1-(4-fluorophenyl)etha-
none 7a (5.00 g, 18.6 mmol), (R)-2-methylpropane-2-sulfinamide
(2.71 g, 22.4 mmol), and Ti(OiPr)4 (13.2 g, 46.5 mmol) were dis-
solved in anhydrous THF (40 mL) and the mixture was refluxed
overnight under nitrogen. The reaction was cooled and quenched
with brine (50 mL). The solids were filtered off and the filtrate
was concentrated by vacuum. The residue was purified by column
chromatography (1:15 EtOAc/petroleum ether) to provide 4.9 g
(71%) of (Rs)-N-(2-(tert-butyldimethylsilyloxy)-1-(4-fluoro-
phenyl)ethylidene)-2-methylpropane-2-sulfinamide as a colorless
oil. 1H NMR (500 MHz, CDCl3) d 7.88 (br, 2H), 7.07 (m, 2H), 5.26
(m, 1H), 5.01 (m, 1H), 1.30 (s, 9H), 0.80 (s, 9H), 0.09 (s, 3H),
4.3.7. (Rs)-N-(2-(tert-Butyldimethylsilyloxy)-1-(3-(trifluoro
methyl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide 2g
Yield: 86%; 1H NMR (500 MHz, CDCl3) d 8.10 (s, 1H), 8.02
(d, J = 6.5 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H),
5.31 (d, J = 14.5 Hz, 1H), 5.06 (d, J = 14.0 Hz, 1H), 1.29 (s, 9H),
0.77 (s, 9H), 0.07 (s, 3H), 0.05 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 175.93, 137.66, 131.75, 130.06 (q, J = 32.5 Hz), 128.64, 127.50,
125.68, 123.95 (q, J = 270.6 Hz), 60.40, 58.66, 25.57, 22.83, 18.02,
ꢀ5.44; IR (thin film) 2957, 2930, 2858, 1610, 1335, 1130,
839 cmꢀ1; HRMS (ESI) m/z calcd for C19H31F3NO2SSi 422.1797,
found 422.1797 (M+H).
0.06 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 176.13, 164.53
(d, J = 251.8 Hz), 133.06, 130.97 (d, J = 4.6 Hz), 115.12 (d, J = 21.5 Hz),
60.41, 58.17, 25.65, 22.72, 18.07, ꢀ5.36, ꢀ5.38; IR (thin film)
2954, 2929, 2858, 1600, 1581, 1508, 1469, 1296 cmꢀ1; HRMS
(ESI) m/z calcd for C18H31FNO2SSi 372.1823, found 372.1830
(M+H).
4.3.2. (Rs)-N-(2-(tert-Butyldimethylsilyloxy)-1-(3-fluorophenyl)
ethylidene)-2-methylpropane-2-sulfinamide 2b
4.3.8. (Rs)-N-(2-(tert-Butyldimethylsilyloxy)-1-(4-(trifluoro
methyl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide 2h
Yield: 70%; 1H NMR (500 MHz, CDCl3) d 7.93 (br, 2H), 7.65
(d, J = 8.5 Hz, 2H), 5.30 (br, 1H), 5.05 (br, 1H), 1.31 (s, 9H), 0.80
(s, 9H), 0.08 (s, 3H), 0.05 (s, 3H); 13C NMR (125 MHz, CDCl3) d
176.12 140.17, 132.40 (q, J = 34.3 Hz), 128.86, 124.93, 123.80 (q,
J = 270.75 Hz), 60.34, 58.60, 25.55, 22.74, 18.00, ꢀ5.48; IR (thin
film) 2957, 2930, 2858, 1618, 1327, 1130, 837 cmꢀ1; HRMS (ESI)
m/z calcd for C19H31F3NO2SSi 422.1797, found 422.1797 (M+H).
Yield: 61%; 1H NMR (500 MHz, CDCl3) d 7.56 (m, 1H), 7.50 (m,
1H), 7.29 (m, 1H), 7.06 (m, 1H), 5.20 (m, 1H), 4.93 (m, 1H), 1.24
(s, 9H), 0.75 (s, 9H), 0.027 (s, 3H), 0.00 (s, 3H); 13C NMR
(125 MHz, CDCl3) d 194.95, 161.49 (d, J = 238 Hz), 138.165, 128.51
(d, J = 7.3 Hz), 123.32, 116.97 (d, J = 20.5 Hz), 114.38 (d, J = 22.6 Hz),
59.32, 57.43, 24.60, 21.76, 17.03, ꢀ6.39; IR (thin film) 2955,
2930, 2859, 839 cmꢀ1; HRMS (ESI) m/z calcd for C18H31FNO2SSi
372.1822, found 372.1823 (M+H).
4.3.3. (Rs)-N-(2-(tert-Butyldimethylsilyloxy)-1-(3-chloro-4-fluo
rophenyl)ethylidene)-2-methylpropane-2-sulfinamide 2c
ield:81%;1HNMR(500 MHz, DMSO-d6)d 7.96(s, 1H), 7.81(s, 1H),
7.52 (m, 1H), 5.17 (s, 1H), 5.14 (s, 1H), 1.21 (s, 9H), 0.75 (s, 9H), 0.03
(s, 3H), 0.025 (s, 3H); 13C NMR (100 MHz, CDCl3) d 173.87, 158.68
(d, J = 254 Hz), 132.89, 130.36, 127.86, 120.04, 119.86, 115.30,
115.09, 59.33, 57.50, 24.60, 21.77, 17.02, ꢀ6.42; IR (thin film)
2955, 2859, 2856, 1711, 1499, 1256, 1078, 837 cmꢀ1; HRMS (ESI)
m/z calcd for C18H30ClFNO2SSi 406.1439, found 406.1445 (M+H).
4.3.9. (Rs)-N-(2-(tert-Butyldimethylsilyloxy)-1-(2-fluoro
phenyl)ethylidene)-2-methylpropane-2-sulfinamide 2j
Yield: 36%; 1H NMR (500 MHz, CDCl3) d 7.86 (m, 1H), 7.37
(m, 1H), 7.17 (m, 1H), 7.06 (m, 1H), 5.04 (m, 1H), 4.58 (m, 1H),
1.30 (s, 9H), 0.82 (s, 9H), 0.027 (m, 6H); 13C NMR (125 MHz, CDCl3)
d 179.28, 160.01 (d, J = 238 Hz), 131.664, 128.79, 123.83, 115.09
(d, J = 6.8 Hz), 68.72, 57.93, 25.51, 22.30, 17.91, ꢀ5.61; IR (thin
film) 2955, 2930, 2857, 1705, 1254, 839 cmꢀ1; HRMS (ESI) m/z
calcd for C18H31FNO2SSi 372.1830, found 372.1823 (M+H).

334
X. Pan et al. / Tetrahedron: Asymmetry 22 (2011) 329–337
4.3.10. (Rs)-N-(2-(tert-Butyldimethylsilyloxy)-1-o-tolylethy
lidene)-2-methylpropane-2-sulfinamide 2k
837 cmꢀ1; HRMS (ESI) m/z calcd for C18H33FNO2SSi 374.1977,
found 374.1980 (M+H).
Yield: 61%; 1H NMR (500 MHz, CDCl3) d 7.33 (m, 2H), 7.26
(m, 2H), 6.00 (m, 1H), 5.93 (m, 1H), 2.43 (s, 3H), 1.29 (s, 9H),
0.90 (s, 9H), 0.09 (s, 3H), 0.06 (s, 3H). 13C NMR (125 MHz, CDCl3)
d 184.83, 136.65, 135.82, 130.07, 129.04, 125.64, 125.21, 68.85,
56.34, 25.64, 22.20, 20.06, 18.26, ꢀ5.55. IR (thin film) 2955,
2930, 2855, 1255, 841 cmꢀ1; HRMS (ESI) m/z calcd for C19H34NO2S-
Si 368.2074, found 368.2074 (M+H).
4.4.3. (Rs,2S)-N-((tert-Butyldimethylsilyloxy)-1-(4-chloro-3-
fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide 8c
To a solution of (Rs)-N-(2-(tert-butyldimethylsilyloxy)-1-(3-
chloro-4-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinam-
ide 2c (3.30 g, 8.13 mmol) in THF (120 mL) at ꢀ78 °C was added DI-
BALH (1.0 M in toluene, 20.3 mL), and the mixture stirred at ꢀ78 °C
for 1 h. The reaction was quenched with water (8.0 mL), warmed to
room temperature, and extracted with EtOAc (3 ꢂ 150 mL). The
combined organic phases were washed with brine (3 ꢂ 30 mL),
dried (Na2SO4), and concentrated. The residue was purified by col-
umn chromatography (1:6 EtOAc/petroleum ether) to give 2.7 g
(80%) of (Rs,2S)-N-((tert-butyldimethylsilyloxy)-1-(3-chloro-4-
4.3.11. (Rs)-N-(2-(tert-Butyldimethylsilyloxy)-1-(naphthalen-1-
yl)ethylidene)-2-methylpropane-2-sulfinamide 2m
Yield: 61%; 1H NMR (500 MHz, CDCl3) d 7.87 (m, 3H), 7.52
(m, 4H), 4.67 (m, 2H), 1.01 (s, 9H), 0.79 (s, 9H), 0.23 (s, 3H), 0.21
(s, 3H); 13C NMR (125 MHz, CDCl3) d 183.98, 133.929, 129.41,
128.79, 128.22, 127.33, 126.87, 126.24, 125.84, 125.21, 124.39,
69.08, 55.45, 25.72, 22.18, 18.08, ꢀ5.50; IR (thin film) 2953,
2929, 2858, 1625, 1078, 840, 779 cmꢀ1; HRMS (ESI) m/z calcd for
fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide as
a white
solid, mp = 101–104 °C: 1H NMR (500 MHz, DMSO-d6) d 7.71 (d,
J = 7.5 Hz, 1H), 7.47 (m, 2H), 5.80 (d, J = 9.0 Hz, 1H), 4.36 (m, 1H),
3.82 (m, 1H), 3.71 (m, 1H), 1.19 (s, 9H), 0.85 (s, 9H), ꢀ0.01
(s, 3H), ꢀ0.03 (s, 3H); 13C NMR (125 MHz, DMSO-d6) d 156.30
(d, J = 244.8 Hz), 139.58, 129.79, 128.32 (d, J = 7.1 Hz), 118.76
(d, J = 17.0 Hz), 116.11 (d, J = 21.0 Hz), 66.56, 59.85, 55.59, 25.58,
22.40, 11.73, ꢀ5.73; IR (thin film) 3246, 2951, 2859, 1599, 1503,
1252, 1119, 1047, 839 cmꢀ1; HRMS (ESI) m/z calcd for C18H31ClFN-
NaO2SSi 430.1415, found 430.1405 (M+Na).
C22H34NOSSi 404.2074, found 404.2074 (M+H).
4.3.12. (Rs)-N-(2-(tert-Butyldimethylsilyloxy)-1-(naphthalen-2-
yl)ethylidene)-2-methylpropane-2-sulfinamide 2n
Yield: 57%; 1H NMR (500 MHz, CDCl3) d 8.42 (s, 1H), 7.86
(m, 4H), 7.53 (m, 2H), 5.37 (s, 1H), 5.15 (s, 1H), 1.34 (s, 9H), 0.02
(s, 9H), 0.13 (s, 3H), 0.09 (s, 3H); 13C NMR (125 MHz, CDCl3) d
176.64, 134.61, 134.15, 132.65, 129.83, 129.15, 127.68, 127.64,
126.43, 124.94, 60.52, 58.00, 25.56, 22.99, 17.82, ꢀ5.45; IR (thin
film) 2955, 2930, 2886, 1701, 1593, 1464, 1362, 1254, 1076,
841 cmꢀ1; HRMS (ESI) m/z calcd for C22H34NO2SSi 404.2073, found
404.2074 (M+H).
4.4.4. (Rs,2S)-N-((tert-Butyldimethylsilyloxy)-1-(4-chloro-3-
fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide 8d
Yield: 79%; mp = 102–103 °C; 1H NMR (500 MHz, CDCl3) d 7.35
(t, J = 8.0 Hz, 1H), 7.19 (dd, J = 2.0 Hz, J = 10 Hz, 1H), 7.10 (dd,
J = 1.75 Hz, J = 8.25 Hz, 1H), 4.41 (q, J = 5.0 Hz, 1H), 4.05
(d, J = 5.5 Hz, 1H), 3.84–3.77 (m, 2H), 1.21 (s, 9H), 0.83 (s, 9H), ꢀ0.05
(s, 3H), ꢀ0.06 (s, 3H); 13C NMR (CDCl3, 125 MHz) d 157.98 (d,
J = 247.3 Hz), 141.51 (d, J = 6.7 Hz), 130.47, 124.06 (d, J = 3.4 Hz),
120.22 (d, J = 16.7 Hz), 115.97 (d, J = 21.6 Hz), 67.04, 58.86, 56.49,
25.76, 22.55, 18.17, ꢀ5.59, ꢀ5.62; IR (thin film) 3250, 2955,
4.4. Representative procedure for asymmetric reduction of tert-
butylsulfinimines
4.4.1. (Rs,2S)-N-((tert-Butyldimethylsilyloxy)-1-(4-
fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide 8a
2929, 2856, 1043, 847 cmꢀ1
;
HRMS (ESI) m/z calcd for
To a solution of (Rs)-N-(2-(tert-butyldimethylsilyloxy)-1-(4-
fluorophenyl)-ethylidene)-2-methylpropane-2-sulfinamide 2a
(1.00 g, 2.69 mmol) in THF (7 mL) at ꢀ78 °C was added BH3ꢁTHF
(1.0 M in THF, 8.1 mL) and the mixture stirred at ꢀ78 °C for 3 h.
The reaction was quenched with water (20 mL), then warmed to
room temperature, and extracted with EtOAc (3 ꢂ 50 mL). The
combined organic phases were washed with brine (3 ꢂ 20 mL),
dried (Na2SO4), and concentrated. The residue was purified by col-
umn chromatography (1:8 EtOAc/petroleum ether) to yield 0.55 g
(71%) of (Rs,2S)-N-((tert-butyldimethylsilyloxy)-1-(4-fluoro-
phenyl)ethyl)-2-methylpropane-2-sulfinamide as a white solid,
mp = 88–90 °C: 1H NMR (500 MHz, CDCl3) d 7.34 (m, 2H), 7.02
(m, 2H), 4.42 (q, J = 5.0, 5.0 Hz, 1H), 3.99 (d, J = 4.5 Hz, 1H), 3.80
(d, J = 4.5 Hz, 2H), 1.21 (s, 9H), 0.83 (s, 9H), ꢀ0.05 (s, 3H), ꢀ0.06
(s, 3H); 13C NMR (125 MHz, CDCl3) d 162.32 (d, J = 244.9 Hz),
136.04 (d, J = 2.9 Hz), 129.30 (d, J = 8.0 Hz), 115.21 (d, J = 21.2 Hz),
67.32, 59.41, 56.27, 25.76, 22.53, 18.15, ꢀ5.61, ꢀ5.64; IR (thin film)
3240, 2949, 2927, 2858, 1604, 1512, 1467, 1220 cmꢀ1; HRMS (ESI)
m/z calcd for C18H33FNO2SSi 374.1980, found 374.1985 (M+H).
C
18H32ClFNO2SSi 408.1596, found 408.1602 (M+H).
4.4.5. (Rs,2S)-N-((tert-Butyldimethylsilyloxy)-1-(3-methoxy
phenyl)ethyl)-2-methylpropane-2-sulfinamide 8e
Yield: 70%; 1H NMR (500 MHz, CDCl3) d 7.31 (m, 1H), 7.01
(m, 2H), 6.88 (d, J = 10.0 Hz, 1H), 4.46 (m, 1H), 4.10 (d, J = 4.0 Hz,
1H), 3.88 (s, 1H), 3.87 (s, 3H), 1.28 (s, 9H), 0.91 (s, 9H), 0.02
(s, 3H), 0.01 (s, 3H); 13C NMR (125 MHz, CDCl3) d 159.80, 141.95,
129.94, 120.11, 113.40, 113.27, 67.51, 59.69, 55.93, 54.99, 25.65,
22.79, 18.34, ꢀ6.1; IR (thin film) 3221, 2955, 2928, 2857, 1603,
1491, 1389, 1258, 1117, 1057, 837 cmꢀ1; HRMS (ESI) m/z calcd
for C19H36NO3SSi 386.2185, found 386.2176 (M+H).
4.4.6. (Rs,2S)-N-((tert-Butyldimethylsilyloxy)-1-m-tolylethyl)-2-
methylpropane-2-sulfinamide 8f
Yield: 79%; mp = 67–70 °C; 1H NMR (500 MHz, CDCl3) d 7.18
(m, 3H), 7.09 (m, 1H), 4.38 (m, 1H), 4.00 (d, J = 3.5 Hz, 1H), 3.80
(d, J = 5.5 Hz, 2H), 2.35 (s, 3H), 1.22 (s, 9H), 0.84 (s, 9H), ꢀ0.06
(s, 6H); 13C NMR (125 MHz, CDCl3) d 139.96, 138.01, 128.60,
128.42, 128.34, 124.63, 67.52, 60.20, 56.28, 25.79, 22.58, 21.44,
18.19, ꢀ5.61; IR (thin film) 3275, 2949, 2857, 1608, 1465, 1260,
1102, 1047, 845 cmꢀ1; HRMS (ESI) m/z calcd for C19H36NO2SSi
370.2245, found 370.2231 (M+H).
4.4.2. (Rs,2S)-N-((tert-Butyldimethylsilyloxy)-1-(3-
fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide 8b
Yield: 65%; mp = 75–78 °C; 1H NMR (500 MHz, CD3OD) d 7.39
(m, 1H), 7.22 (m, 1H), 7.17 (m, 1H), 7.04 (m, 1H), 4.51 (m, 1H),
4.14 (m, 1H), 3.89 (m, 1H), 1.28 (s, 9H), 0.90 (s, 9H), 0.014
(s, 3H), 0.00 (s, 3H); 13C NMR (100 MHz, CD3OD) d 161.77
(d, J = 244 Hz), 141.99 (d, J = 7.6 Hz), 128.86 (d, J = 6.9 Hz), 122.30,
113.63 (d, J = 24.8 Hz), 66.23, 58.30, 55.38, 24.73, 21.53, 17.14,
ꢀ6.65, ꢀ6.68; IR (thin film) 3230, 2957, 2926, 2859, 1593, 1253,
4.4.7. (Rs,2S)-N-((tert-Butyldimethylsilyloxy)-1-(3-(trifluoro
methyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide 8g
Yield: 76%; mp = 52–55 °C; 1H NMR (500 MHz, CDCl3) d 7.63
(s, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.55 (d, J = 7.5 Hz, 1H), 7.46
(t, J = 7.5 Hz, 1H), 4.52 (q, J = 5.0 Hz, 1H), 4.09 (d, J = 5.5 Hz,1H),

X. Pan et al. / Tetrahedron: Asymmetry 22 (2011) 329–337
335
3.88–3.81 (m, 2H), 1.21 (s, 9H), 0.82 (s, 9H), ꢀ0.07 (s, 3H), ꢀ0.10
(s, 3H); 13C NMR (125 MHz, CDCl3) d 141.50, 131.16, 130.68
(q, J = 32.6 Hz), 128.87, 124.63 (q, J = 4.3 Hz), 124.51 (q, J = 3.8 Hz),
124.07 (q, J = 3.6 Hz), 123.66 (q, J = 271.1 Hz), 67.06, 59.21, 56.49,
25.68, 22.55, 18.12, ꢀ5.72, ꢀ5.73; IR (thin film) 3228, 2955,
2933, 2864, 1472, 1132, 835 cmꢀ1; HRMS (ESI) m/z calcd for
4.5. Representative procedure for the selective deprotection of
tert-butyl sulfinamides
4.5.1. (S)-2-(tert-Butyldimethylsilyloxy)-1-(3-chloro-4-fluoro
phenyl)ethanamine 10c
At first, (Rs,2S)-N-((tert-butyldimethylsilyloxy)-1-(3-chloro-
4-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide 8c (2.0 g,
4.9 mmol) was dissolved in ether (240 mL) and then followed by
the addition of HCl in MeOH (5 N, 3.0 mL). The mixture was stirred
at room temperature for 40 min and the white precipitate was
collected by filtration and washed with ether to give 1.6 g of (S)-
2-(tert-butyldimethylsilyloxy)-1-(3-chloro-4-fluorophenyl)eth-
anamine HCl salt as a white solid. The solid was dissolved in MeOH
(20 mL) and the solution was neutralized with saturated NaHCO3
(50 mL). The mixture was extracted with CH2Cl2/MeOH (10:1,
3 ꢂ 150 mL). The organic layer was dried (Na2SO4) and concen-
trated by vacuum to give 1.4 g (94%) of (S)-2-(tert-butyldimethylsi-
lyloxy)-1-(3-chloro-4-fluorophenyl)ethanamine as a yellow oil.
C19H33F3NO2SSi 424.1953, found 424.1953 (M+H).
4.4.8. (Rs,2S)-N-((tert-Butyldimethylsilyloxy)-1-(4-(trifluoro
methyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide 8h
Yield: 81%; mp = 93–95 °C; 1H NMR (500 MHz, CDCl3) d 7.60
(d, J = 8.0 Hz, 2H), 7.50 (d, J = 8.0 Hz, 2H), 4.51–4.50 (m, 1H), 4.13–4.12
(m, 1H), 3.88–3.81 (m, 2H), 1.22 (s, 9H), 0.83 (s, 9H), ꢀ0.06 (s, 3H),
ꢀ0.08 (s, 3H); 13C NMR (125 MHz, CDCl3) d 144.43, 130.03 (q,
J = 19.6 Hz), 128.06, 125.33 (q, J = 3.6 Hz), 124.10 (q, J = 270.6 Hz),
67.20, 59.51, 56.52, 25.73, 22.55, 18.18, ꢀ5.64, ꢀ5.66; IR (thin film)
3258, 2957, 2930, 2858, 1472, 1327, 1043, 835 cmꢀ1; HRMS (ESI)
m/z calcd for C19H33F3NO2SSi 424.1948, found 424.1935 (M+H).
½
a 2D0
ꢃ
¼ þ24 (c 0.50, CHCl3); >98% ee (1.36 min, AD-H, SFC with
CH3OH/0.1% DEA as co-solvent, 5 min); 1H NMR (500 MHz, CDCl3)
d 7.45 (d, J = 9.0 Hz, 1H), 7.22 (m, 1H), 7.09 (m, 1H), 4.04 (m, 1H),
3.67 (m, 1H), 3.48 (m, 1H), 0.89 (s, 9H), 0.02 (s, 6H); 13C NMR
(125 MHz, CDCl3) d 157.36 (d, J = 322 Hz), 139.87, 129.16, 126.61
(d, J = 6.9 Hz), 120.72 (d, J = 17.4 Hz), 116.25 (d, J = 20.8 Hz),
69.11, 56.59, 25.86, 18.28, ꢀ5.43; IR (thin film) 3455, 2953, 2930,
2857, 1631, 1601, 1501, 1256, 1099, 839 cmꢀ1; HRMS (ESI) m/z
calcd for C14H24ClFNOSi 304.1294, found 304.1294 (M+H).
4.4.9. (Rs,2S)-N-((tert-Butyldimethylsilyloxy)-1-(2-fluoro
phenyl)ethyl)-2-methylpropane-2-sulfinamide 8j
Yield: 33%; mp = 99–100 °C; 1H NMR (500 MHz, CD3OD) d 7.50
(m, 1H), 7.30 (m, 1H), 7.16 (m, 1H), 7.07 (m, 1H), 4.75 (d, J = 6.0 Hz,
1H), 3.86 (m, 2H), 1.23 (s, 9H), 0.83 (s, 9H), ꢀ0.03 (s, 3H), ꢀ0.05 (s,
3H); 13C NMR (100 MHz, CD3OD) d 161.77 (d, J = 243 Hz), 130.45
(m), 129.12 (d, J = 23.2 Hz), 125.26 (d, J = 3.2 Hz), 116.16 (d,
J = 22.3 Hz), 67.57, 57.91, 56.25, 26.26, 23.08, 18.95, ꢀ5.43,
ꢀ5.49; IR (thin film) 2949, 2926, 2857, 1616, 1255, 833 cmꢀ1
;
4.5.2. (S)-2-(tert-Butyldimethylsilyloxy)-1-(4-chloro-3-fluoro
HRMS (ESI) m/z calcd for
C18H33FNO2SSi 374.1976, found
phenyl)ethanamine 10d
374.1980 (M+H).
Yield: 86%; ½a 2D0
¼ 21:5 (c 1.00, MeOH); >99% ee (6.42 min, Cel-
ꢃ
lulose-2, SFC with CH3OH/0.1% DEA as co-solvent, 8 min); 1H NMR
(500 MHz, CDCl3) d 7.34 (t, J = 7.75 Hz, 1H), 7.23 (dd, J = 1.5 Hz,
J = 10 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H), 4.09 (m, 1H), 3.73 (m, 1H),
3.54 (m, 1H), 2.21 (br, 2H), 0.88 (s, 9H), 0.02 (s, 3H), 0.01 (s, 3H);
13C NMR (125 MHz, CD3OD) d 160.12 (d, J = 253.6 Hz), 145.44,
132.37, 126.02 (d, J = 2.8 Hz), 121.42 (d, J = 18.5 Hz), 117.40 (d,
J = 21.8 Hz), 114.82 (d, J = 21.0 Hz), 67.76, 56.48; IR (thin film)
2955, 2928, 2857, 1487, 1099, 837 cmꢀ1; HRMS (ESI) m/z calcd
for C14H24ClFNOSi 304.1299, found 304.1298 (M+H).
4.4.10. (Rs,2S)-N-((tert-Butyldimethylsilyloxy)-1-o-tolylethyl)-2-
methylpropane-2-sulfinamide 8k
Yield: 25%; 1H NMR (500 MHz, CDCl3) d 7.39 (m, 1H), 7.16 (m,
3H), 4.70 (m, 1H), 3.96 (m, 1H), 3.85 (m, 1H), 3.78 (m, 1H), 2.37
(s, 3H), 1.20 (s, 9H), 0.83 (s, 9H), ꢀ0.06 (s, 3H), ꢀ0.07 (s, 3H); 13C
NMR (125 MHz, CDCl3) d 137.95, 135.96, 130.44, 127.61, 126.93,
126.15, 66.81, 56.12, 55.46, 25.80, 22.59, 19.47, 18.20, ꢀ5.57,
ꢀ5.64; IR (thin film) 3250, 2953, 2928, 2857, 1256, 1114,
835 cmꢀ1; HRMS (ESI) m/z calcd for C19H36NO2SSi 370.2224, found
370.2231 (M+H).
4.5.3. (S)-2-(tert-Butyldimethylsilyloxy)-1-m-tolylethanamine
10f
Yield: 79%; mp = 67–70 °C; ½a D25
¼ þ15 (c 0.58, EtOAc); >97% ee
ꢃ
4.4.11. (Rs,2S)-N-((tert-Butyldimethylsilyloxy)-1-(naphthalen-1-
yl)ethyl)-2-methylpropane-2-sulfinamide 8m
(1.23 min, OJ-H, SFC with CH3OH/0.1% DEA as co-solvent, 5 min);
1H NMR (500 MHz, CD3OD) d 7.19 (m, 1H), 7.14 (s, 1H), 7.10 (m,
1H), 7.05 (m, 1H), 3.91 (m, 1H), 3.73 (m, 1H), 3.58 (m, 1H), 2.32
(s, 3H), 0.88 (s, 9H), ꢀ0.01 (s, 6H); 13C NMR (125 MHz, CD3OD) d
142.94, 139.14, 129.49, 129.33, 128.81, 125.12, 70.14, 58.55,
26.71, 21.99, 19.34, ꢀ4.89; IR (thin film) 2957, 2926, 2855, 1259,
1099, 839 cmꢀ1; HRMS (ESI) m/z calcd for C15H28NOSi 266.1940,
found 266.1934 (M+H).
Yield: 30%; 1H NMR (500 MHz, CDCl3) d 8.11 (d, J = 8.5 Hz, 1H),
7.87 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 7.0 Hz,
1H), 7.51 (m, 3H), 5.30 (m, 1H), 4.34 (m, 1H), 4.02 (d, J = 5.5 Hz,
1H), 1.19 (s, 9H), 0.82 (s, 9H), ꢀ0.11 (s, 3H), ꢀ0.13 (s, 3H); 13C
NMR (125 MHz, CDCl3) d 134.95, 133.84, 131.12, 128.99, 128.43,
126.27, 125.58, 125.44, 125.26, 122.91; IR (thin film) 3253, 2949,
2929, 2855, 1047, 837, 777 cmꢀ1; HRMS (ESI) m/z calcd for
C22H36NO2SSi 406.2241, found 406.2231 (M+H).
4.5.4. (S)-2-(tert-Butyldimethylsilyloxy)-1-(naphthalen-2-
4.4.12. (Rs,2S)-N-((tert-Butyldimethylsilyloxy)-1-(naphthalen-2-
yl)ethyl)-2-methylpropane-2-sulfinamide 8n
yl)ethanamine 10n
Yield: 90%; ½a 2D0
¼ þ25:6 (c 1.00, CHCl3); >99% ee (1.53 min,
ꢃ
Yield: 74%; 1H NMR (500 MHz, CDCl3) d 7.83 (m, 4H), 7.48
(m, 3H), 4.61 (m, 1H), 4.16 (m, 1H), 3.92 (m, 2H), 1.23 (s, 9H),
0.84 (s, 9H), ꢀ0.06 (s, 3H), ꢀ0.07 (s, 3H); 13C NMR (125 MHz,
CDCl3) d 137.53, 133.23, 133.07, 128.20, 128.00, 127.66, 126.73,
126.14, 125.98, 125.61, 67.37, 60.10, 56.38, 25.81, 22.62, 18.20,
ꢀ5.86; IR (thin film) 3240, 2954, 2928, 2857, 1472, 1254, 1115,
OJ-H, SFC with CH3OH/0.1% DEA as co-solvent, 5 min); 1H NMR
(500 MHz, CD3OD) d 7.83 (m, 4H), 7.45 (m, 3H), 4.12 (m, 1H),
3.85 (m, 1H), 3.74 (m, 1H), 0.87 (s, 9H), ꢀ0.03 (s, 6H); 13C NMR
(125 MHz, CD3OD) d 140.94, 134.87, 134.40, 128.98, 128.89,
128.66, 127.11, 126.79, 126.38, 69.94, 58.71, 26.41, 19.17, ꢀ5.61;
IR (thin film) 2953, 2928, 1601, 1467, 1254, 1254, 1092,
839 cmꢀ1; HRMS (ESI) m/z calcd for C18H28NOSi 302.1932, found
302.1935 (M+H).
1042, 837 cmꢀ1
;
HRMS (ESI) m/z calcd for C22H36NO2SSi
406.2237, found 406.2230 (M+H).

336
X. Pan et al. / Tetrahedron: Asymmetry 22 (2011) 329–337
4.6. Representative procedure for the synthesis of aryl glycinol
787 cmꢀ1; HRMS (ESI) m/z calcd for C9H14NO2 168.1018, found
168.1019 (M+H).
4.6.1. (S)-2-Amino-2-(4-fluorophenyl)ethanol 1a
At first, (Rs,2S)-N-((tert-butyldimethylsilyloxy)-1-(4-fluoro-
phenyl)ethyl)-2-methylpropane-2-sulfinamide 8a (0.280 g, 0.749
mmol) was dissolved in MeOH (10 mL) and then HCl/MeOH (4 M,
2.0 mL) was added. The mixture was stirred at room temperature
for3 h. Thesolventwas removedundervacuumand theresidueneu-
tralized with saturated NaHCO3 (20 mL). The mixture was extracted
with CH2Cl2/MeOH (10:1, 3 ꢂ 50 mL) and the organic phases dried
(Na2SO4) and concentrated to give 0.11 g (93%) of (S)-2-amino-2-
(4-fluorophenyl)ethanol as a white solid, mp = 96–98 °C [lit. mp:
4.6.6. (S)-2-Amino-2-m-tolylethanol 1f
Yield: 89%; mp = 85–87 °C; ½a D20
¼ þ25 (c 0.50, MeOH); >99% ee
ꢃ
(1.66 min, AS-H, SFC with CH3OH/0.1% DEA as co-solvent, 5 min);
1H NMR (500 MHz, CD3OD) d 7.19 (m, 2H), 7.10 (m, 2H), 3.88
(m, 1H), 3.65 (m, 1H), 3.51 (m, 1H), 2.32 (s, 3H); 13C NMR
(125 MHz, CD3OD) d 143.37, 139.18, 129.41, 129.06, 128.61,
125.02, 68.87, 58.23, 21.17; IR (thin film) 3552, 3292, 2910,
2862, 1359, 1161, 1053, 883, 781, 698 cmꢀ1; HRMS (ESI) m/z calcd
for C9H14NO 152.1068, found 152.1070 (M+H).
20
20
94–96 °C]: ½aꢃD ¼ þ56:6 (c 0.325, CHCl3) {lit. ½aꢃD ¼ þ47 (c 0.78,
CHCl3)}; >99% ee (2.06 min, AD-H, SFC with CH3OH/0.1% DEA as
co-solvent, 5 min); 1H NMR (500 MHz, CDCl3) d 7.30 (m, 2H), 7.03
(m, 2H), 4.05 (m, 1H), 3.70 (m, 1H), 3.52 (m, 1H), 2.00 (br, 3H); 13C
NMR (125 MHz, CDCl3) d 161.10 (d, J = 244.1 Hz), 137.20, 127.09 (d,
J = 7.6 Hz), 114.40 (d, J = 21.8 Hz), 66.91, 55.65; IR (thin film) 3331,
3111, 1602, 1512, 1261, 1224 cmꢀ1; HRMS (ESI) m/z calcd for
C8H11FNO156.0819, found 156.0474 (M+H).
4.6.7. (S)-2-Amino-2-(3-(trifluoromethyl)phenyl)ethanol 1g
Yield: 91%; mp = 59–62 °C; ½a D20
¼ þ15 (c 0.50, CH3OH); >98%
ꢃ
ee (1.48 min, OD-H, SFC with CH3OH/0.1% DEA as co-solvent,
5 min); 1H NMR (500 MHz, CDCl3) d 7.62 (s, 1H), 7.55–7.54 (m,
2H), 7.48 (m, 1H), 4.14 (m, 1H), 3.78 (m, 1H), 3.57 (m, 1H), 1.73
(br, 3H); 13C NMR (125 MHz, CDCl3) d 143.55, 130.88 (q, J = 39.75 Hz),
130.07, 129.05, 124.35 (q, J = 4.5 Hz), 123.09 (q, J = 338 Hz),
123.41 (q, J = 4.5 Hz), 123.66 (q, J = 271.1 Hz), 67.69, 57.03; IR (thin
film) 2953, 2924, 2855, 1456, 1130 cmꢀ1; HRMS (ESI) m/z calcd for
C9H11F3NO 206.0793, found 206.0792 (M+H).
4.6.2. (S)-2-Amino-2-(3-fluorophenyl)ethanol 1b
Yield: 85%; mp = 101–103 °C; ½a D25
¼ þ17 (c 0.55, MeOH); >99%
ꢃ
ee (1.33 min, OJ-H, SFC with CH3OH/0.1% DEA as co-solvent,
5 min); 1H NMR (500 MHz, CD3OD) d 7.24 (m, 1H), 7.07 (m, 1H),
7.04 (m, 1H), 6.87 (m, 1H), 3.85 (m, 1H), 3.57 (m, 1H), 3.44 (m, 1H);
13C NMR (100 MHz, CD3OD) d 161.95 (d, J = 243 Hz), 146.67
(d, J = 6.6 Hz), 131.15 (d, J = 8.1 Hz), 123.93 (d, J = 2.0 Hz), 66.62,
58.34; IR (thin film) 3331, 3271, 1585, 1037, 954, 897 cmꢀ1; HRMS
(ESI) m/z calcd for C8H11FNO 156.0817, found 156.0819 (M+H).
4.6.8. (S)-2-Amino-2-(4-(trifluoromethyl)phenyl)ethanol 1h
Yield: 93%; mp = 101–104 °C; ½a D20
¼ þ13 (c 0.51, MeOH); >99%
ꢃ
ee (1.71 min, AS-H, SFC with CH3OH/0.1% DEA as co-solvent,
5 min); 1H NMR (500 MHz, CD3OD) d 7.65 (d, J = 8.5 Hz, 2H), 7.58
(d, J = 8.5 Hz, 2H), 4.06 (m, 1H), 3.72 (m, 1H), 3.60 (m, 1H); 13C
NMR (125 MHz, CD3OD) d 149.19, 131.35 (q, J = 31.25 Hz), 129.6,
127.12 (q, J = 4.0 Hz), 126.6 (q, J = 270.1 Hz), 67.39, 59.26; IR (thin
film) 3337, 3113, 2825, 1423, 1330 cmꢀ1; HRMS (ESI) m/z calcd for
C9H11F3NO 206.0787, found 206.0787 (M+H).
4.6.3. (S)-2-Amino-2-(3-chloro-4-fluorophenyl)ethanol 1c
Yield: 97%; ½a 2D0
¼ þ19:6 (c 0.730, MeOH); >99% ee (3.27 min,
ꢃ
AD-H, SFC with CH3OH/0.1% DEA as co-solvent, 5 min); 1H NMR
(500 MHz, DMSO-d6) d 7.56 (m, 1H), 7.34 (m, 2H), 4.82 (s, 1H),
3.85 (m, 1H), 3.40 (m, 1H), 3.31 (m, 1H), 1.92 (s, 2H); 13C NMR
(125 MHz, DMSO-d6) d 155.89 (d, J = 242.5 Hz), 142.57, 128.78,
127.5 (d, J = 7.4 Hz), 118.72 (d, J = 18 Hz), 116.10 (d, J = 20.1 Hz),
67.51, 56.24; IR (thin film) 3356, 3296, 2908, 2870, 2851, 1500,
1356, 1246, 1053, 912 cmꢀ1; HRMS (ESI) m/z calcd for C8H10ClFNO
190.0435, found 190.0432 (M+H).
4.6.9. (S)-2-Amino-2-(2-fluorophenyl)ethanol 1j
Yield: 92%; mp = 84–85 °C; [lit. mp: 154–157 °C]: ½a D20
¼ þ23
ꢃ
(c 0.24, MeOH); {lit.
½
a 2D0
ꢃ
¼ þ22 (c 0.21, MeOH)}; >99% ee
(1.32 min, AS-H, SFC with CH3OH/0.1% DEA as co-solvent, 5 min);
1H NMR (500 MHz, CD3OD) d 7.46 (m, 1H), 7.28 (m, 1H), 7.17
(m, 1H), 7.06 (m, 1H), 4.26 (m, 1H), 3.72 (m, 1H), 3.56 (m, 1H);
13C NMR (100 MHz, CD3OD) d 161.95 (d, J = 243 Hz), 130.26
(d, J = 13.6 Hz), 130.00 (d, J = 8.5 Hz), 129.30 (d, J = 4.6 Hz), 125.47
(d, J = 2.9 Hz), 116.24 (d, J = 22.8 Hz), 67.73, 52.42; IR (thin film)
3339, 3279, 1614, 1492, 1452, 829 cmꢀ1; HRMS (ESI) m/z calcd
for C8H11FNO 156.0816, found 156.0819 (M+H).
4.6.4. (S)-2-Amino-2-(4-chloro-3-fluorophenyl)ethanol 1d
Yield: 93%; mp = 72–74 °C; ½a D20
¼ þ35 (c 0.25, CHCl3); >99% ee
ꢃ
(2.46 min, AD-H, SFC with CH3OH/0.1% DEA as co-solvent, 5 min);
1H NMR (500 MHz, CDCl3) d 7.36 (t, J = 7.75 Hz, 1H), 7.17 (dd,
J = 1.75 Hz, J = 10 Hz, 1H), 7.07 (dd, J = 1.75 Hz, J = 8.25 Hz, 1H),
4.06 (m, 1H), 3.74 (m, 1H), 3.52 (m, 1H), 1.82 (br, 3H); 13C NMR
(125 MHz, CDCl3) d 158.17 (d, J = 248.13 Hz), 143.72 (d, J = 5.6 Hz),
130.66, 122.94 (d, J = 3.8 Hz), 119.79 (d, J = 17.8 Hz), 114.82
(d, J = 21.0 Hz), 67.76, 56.48; IR (thin film) 2918, 1583, 1051,
818 cmꢀ1; HRMS (ESI) m/z calcd for C8H10ClFNO 190.0435, found
190.0435 (M+H).
4.6.10. (S)-2-Amino-2-o-tolylethanol 1k
Yield: 90%; ½a 2D0
¼ þ36 (c 0.40, MeOH); >98% ee (1.51 min,
ꢃ
OD-H, SFC with CH3OH/0.1% DEA as co-solvent, 5 min); 1H NMR
(500 MHz, CD3OD) d 7.33 (m, 1H), 7.19 (m, 1H), 7.14 (m, 2H),
4.25 (m, 1H), 3.66 (m, 1H), 3.47 (m, 1H), 2.35 (s, 3H); 13C NMR
(125 MHz, CD3OD) d 140.39, 136.72, 131.75, 128.56, 127.60,
126.53, 67.92, 54.27, 20.01; IR (thin film) 3354, 3288, 2918,
1382, 1047, 748 cmꢀ1
; HRMS (ESI) m/z calcd for C9H14NO
152.1068, found 152.1070 (M+H).
4.6.5. (S)-2-Amino-2-(3-methoxyphenyl)ethanol 1e
Yield: 80%; ½a 2D0
¼ þ36 (c 0.60, CHCl3); >99% ee (2.18 min,
ꢃ
4.6.11. (S)-2-Amino-2-(naphthalen-1-yl)ethanol 1m
Yield: 97%; mp = 130–132 °C; ½a D20
¼ þ83 (c 0.50, MeOH); >99%
ꢃ
AD-H, SFC with CH3OH/0.1% DEA as co-solvent, 5 min); 1H
ee (3.70 min, AD-H, SFC with CH3OH/0.1% DEA as co-solvent,
5 min); 1H NMR (500 MHz, CD3OD) d 8.16 (d, J = 8.0 Hz, 1H), 7.90
(d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 7.0 Hz, 1H),
7.54 (m, 3H), 4.87 (m, 1H), 3.91 (dd, J = 11.0 Hz, 9.0 Hz, 1H), 3.60
(m, 1H); 13C NMR (100 MHz, CD3OD) d 138.82, 135.36, 132.47,
130.02, 128.81, 127.25, 126.61, 126.51, 124.21, 123.70, 68.61,
53.81 cmꢀ1; IR (thin film) 3354, 2854, 935, 785 cmꢀ1; HRMS (ESI)
m/z calcd for C12H14NO 188.1071, found 188.1070 (M+H).
NMR (500 MHz, CDCl3)
d 7.27 (m, 1H), 6.90 (m, 2H), 6.82
(d, J = 13.0 Hz, 1H), 4.02 (m, 1H), 3.76 (s, 1H), 3.73 (m, 1H), 3.55
(m, 3H), 1.85 (s, 3H); 13C NMR (125 MHz, CDCl3) d 158.81,
143.33, 128.64, 117.76, 111.70, 111.28, 67.01, 56.34, 54.22; IR
(thin film) 3356, 3296, 2956, 1603, 1587, 1489, 1261, 1041,
The first four authors all contributed equally to this work.

X. Pan et al. / Tetrahedron: Asymmetry 22 (2011) 329–337
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M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010, 110, 3600.
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9. Reddy, L. R.; Das, S. G.; Liu, Y.; Prashad, M. J. Org. Chem. 2010, 75, 2236.
10. Other methods to generate chiral phenylglycinols include addition of
organometallic reagents to chiral oximes: Cooper, T. S.; Larigo, A. S.; Laurent,
P.; Moody, C. J.; Takle, A. K. Synlett 2002, 1730; Cooper, T. S.; Larigo, A. S.;
Laurent, P.; Moody, C. J.; Takle, A. K. Org. Biomol. Chem. 2005, 3, 1252; From
chiral hydrazones: Youn, S. W.; Choi, J. Y.; Kim, Y. H. Chirality 2000, 12, 404.
4.6.12. (S)-2-Amino-2-(naphthalen-2-yl)ethanol 1n
Yield: 99%; ½a 1D6
ꢃ
¼ þ37:7 (c 1.40, CHCl3) {lit.1
½
a 1D6
ꢃ
¼ þ31:0 (c
1.41, CHCl3)}; >99% ee (2.51 min, OJ-H, SFC with CH3OH/0.1%
DEA as co-solvent, 5 min); 1H NMR (500 MHz, CDCl3) d 7.83 (m,
4H), 7.46 (m, 3H), 4.22 (m, 1H), 3.84 (m, 1H), 3.65 (m, 1H); 13C
NMR (125 MHz, CD3OD) d 140.02, 134.86, 134.39, 129.44, 129.03,
128.78, 127.36, 127.07, 126.77, 126.12, 66.58, 58.80; IR (thin film)
3360, 3321, 3184, 3053, 2897, 2853, 1595, 1566, 1460, 1342, 1060,
821 cmꢀ1; HRMS (ESI) m/z calcd for C12H14NO 188.1071, found
188.1070 (M+H).
Acknowledgments
The authors thank Professor Scott Denmark for helpful discus-
sions, and Emily Hanan for critically reviewing the manuscript.
Bing-Yan Zhu from Genentech and Wei Deng and Hancheng Zhang
from Shanghai Chempartner are also acknowledged for their
encouragement and support.
11. Use in the design of c-secretase modulators: Huang, X.; Aslanian, R.; Zhou, W.;
Zhu, X.; Qin, J.; Greenlee, W.; Zhu, Z.; Zhang, L.; Hyde, L.; Chu, I.; Cohen-
Williams, M.; Palani, A. ACS Med. Chem. Lett. 2010, 1, 184; use in the design of
BACE inhibitors: Hamada, Y.; Ohta, H.; Miyamoto, N.; Sarma, D.; Hamada, T.;
Nakanishi, T.; Yamasaki, M.; Yamani, A.; Ishiura, S.; Kiso, Y. Bioorg. Med. Chem.
Lett. 2009, 19, 2435; use in the design of Trk kinase inhibitors: Wang, T.; Lamb,
M. L.; Scott, D. A.; Wang, H.; Block, M. H.; Lyne, P. D.; Lee, J. W.; Davies, A. R.;
Zhang, H.-J.; Zhu, Y.; Gu, F.; Han, Y.; Wang, B.; Mohr, P. J.; Kaus, R. J.; Josey, J. A.;
Hoffmann, E.; Thress, K.; MacIntyre, T.; Wang, H.; Omer, C. A.; Yu, D. J. Med.
Chem. 2008, 51, 4672.
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