Oxaziridine-mediated enantioselective aminohydroxylation of styrenes catalyzed by copper(II) bis(oxazoline) complexes

Article abstract of DOI:10.1016/j.tet.2009.03.012

We report an oxaziridine-mediated enantioselective aminohydroxylation of olefins catalyzed by a chiral copper(II) bis(oxazoline) complex. A variety of styrenic olefins undergo efficient aminohydroxylation with excellent regioselectivity and synthetically

Full text of DOI:10.1016/j.tet.2009.03.012

Tetrahedron 65 (2009) 5118–5124
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Oxaziridine-mediated enantioselective aminohydroxylation of styrenes
catalyzed by copper(II) bis(oxazoline) complexes
*
David J. Michaelis, Kevin S. Williamson, Tehshik P. Yoon
Department of Chemistry, University of Wisconsin, 1101 University Avenue, Madison, WI 53706, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
We report an oxaziridine-mediated enantioselective aminohydroxylation of olefins catalyzed by a chiral
copper(II) bis(oxazoline) complex. A variety of styrenic olefins undergo efficient aminohydroxylation
with excellent regioselectivity and synthetically useful levels of enantioselectivity (up to 84% ee). The
reaction can be conducted on multi-gram scale with as little as 2 mol % of the copper(II) catalyst. Hy-
drolysis of the resulting 1,3-oxazolines under acidic conditions produces N-sulfonyl amino alcohols that
can be purified by recrystallization to afford very high levels of enantioselectivity.
Received 28 January 2009
Received in revised form 1 March 2009
Accepted 2 March 2009
Available online 9 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
Over the past several years, our group has been investigating the
unique reactivity observed when N-sulfonyl oxaziridines (Davis’
Vicinal amino alcohols are substructures found frequently in
a diverse range of natural products and other biologically active
compounds. In addition, many of the most frequently utilized chiral
reagents for asymmetric synthesis employ 1,2-amino alcohols as
key stereocontrolling structural elements. Due to the importance of
this valuable structural motif, a great number of methods have been
developed for the synthesis of enantiopure chiral 1,2-amino alco-
hols.1 Among the most powerful of these methods is the osmium-
catalyzed asymmetric aminohydroxylation reported by Sharpless
in 1996,2 which enables the direct oxidative functionalization of
a variety of structurally diverse alkenes. The utility of this reaction
has become widely recognized,3 and numerous enantioselective
total syntheses have been reported that feature this method.4
Nevertheless, several research groups have continued to in-
vestigate alternative methods for the addition of nitrogen- and
oxygen-containing moieties across carbon–carbon double bonds.5
This interest has been motivated in part by the cost and toxicity
associated with the use of osmium catalysts as well as by the rel-
atively modest regioselectivities observed when styrenes and other
non-polarized alkenes are subjected to aminohydroxylation using
Sharpless methodology.3 A key advance has recently reported by
Chemler and co-workers, who have developed a method for the
asymmetric synthesis of pyrrolidines and indolines using an
intramolecular oxyamination of olefins catalyzed by a chiral cop-
per(II) bis(oxazoline) complex.6 However, to the best of our
knowledge, enantioselective intermolecular oxyaminations under
osmium-free conditions have not yet been reported.
oxaziridines)7 are used in oxidative transformations of organic
substrates in the presence of various transition metal catalysts.8
A
particular focus of our research has been the development of
a novel strategy for copper(II)-catalyzed aminohydroxylation of
olefins that utilize oxaziridines as the terminal oxidant.8a,c Given
the broad range of styrenes, dienes, and electron-rich olefins that
successfully undergo aminohydroxylation using our methodology,
the excellent regioselectivity we observe in this process, and the
ability to perform these reactions on reasonably large scales, we
reasoned that an enantioselective variant of this new reaction using
a chiral copper(II) catalyst could be a valuable supplement to the
well-established Sharpless methodology. Herein, we report that
synthetically useful levels of enantioselectivity can be achieved in
oxaziridine-mediated aminohydroxylations of styrenes in the
presence of a copper(II) bis(oxazoline) catalyst.
2. Results and discussion
We began our investigations by studying the reaction between
N-sulfonyloxaziridine 1 and 4-methylstyrene in the presence of
various chiral copper salts (Table 1). A screen of chiral ligands
commonly utilized in copper(II)-catalyzed asymmetric reactions
(entries 1–4) indicated that the complex formed in situ from
Cu(TFA)2 and (R,R)-isopropylidene bis(4-phenyloxazoline) (Ph-box,
2a) afforded modest levels of enantioselectivity for both di-
astereomers of the 1,3-oxazolidine product (entry 1). Importantly,
although the relative diastereoselectivity was poor (2:1 cis:trans),
the reaction proceeded with exclusive regioselectivity, and the
major enantiomer of each diastereomer formed in this reaction
possesses S stereochemistry at the stereogenic benzylic carbon.
* Corresponding author. Tel.: þ1 608 262 2268; fax: þ1 608 265 4534.
E-mail address: tyoon@chem.wisc.edu (T.P. Yoon).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.03.012

D.J. Michaelis et al. / Tetrahedron 65 (2009) 5118–5124
5119
therefore, that additional experiments to control the diaster-
eoselectivity and improve the overall reactivity of this system will
be necessary to further improve the enantioselectivity of this
process.
Table 1
Optimization studiesa,b
Although the enantioselectivities of aminohydroxylations per-
formed using the (Ph-box) copper(II) catalyst are not as high as
those observed under Sharpless conditions, they are nevertheless
synthetically useful, and the regioselectivites observed are sig-
nificantly higher than those typically observed in osmium-cata-
lyzed oxyaminations of styrenes. Given these considerations and
the attractiveness of an osmium-free asymmetric amino-
hydroxylation protocol, we next elected to investigate the scope of
the oxaziridine-mediated asymmetric aminohydroxylation in
greater detail.
Entry
X
Ligand
Solvent
Yieldc
d.r. (cis:trans)
% eed,e
The results of experiments that probe the effect of substrate
modification on the yield and selectivity of the aminohydroxylation
under our optimized conditions are summarized in Table 2. Sub-
stitutions at the para (entry 2) and meta (entries 3 and 4) positions
are tolerated; however, substitution at the ortho position signifi-
cantly reduces both the efficiency and selectivity of the reaction
(entry 5). Sterically bulky (entries 5 and 6) and electron-with-
drawing groups (entries 7–10) can be incorporated at the para
position, although in the latter case the enantioselectivity of the
reaction is somewhat diminished. Strongly electron-donating
groups at the para position, on the other hand, are not tolerated and
result in a dramatic decrease in selectivity (entry 11). The sensitivity
of the aminohydroxylation reaction to substituents at the meta po-
sition is less pronounced; substrates bearing both electron-donating
(entry 12) and electron-withdrawing (entry 13) substituents at the
meta position on the aryl ring are aminohydroxylated with good
levels of enantioselectivity. Finally, we were delighted to observe
that reactions can be performed on gram scale without any
significant impact on the yield or selectivity of the process; the
aminohydroxylation of 4-methylstyrene conducted on 20 mmol
scale, using 2 mol % of Cu(F6acac)2 and 6 mol % of Ph-box,
afforded the desired 1,3-oxazoline in essentially the same yield
and enantiomeric excess as small-scale reactions with higher
catalyst loading (entry 14).
1
2
3
4
TFA
TFA
TFA
TFA
TFA
TFA
TFA
OTf
2a
2b
2c
2d
2a
2a
2a
2a
2a
2a
2a
2a
2a
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
EtOAc
64%
43%
33%
54%
66%
70%
62%
67%
54%
67%
46%
62%
72%
2.0:1
0.5:1
0.8:1
0.3:1
2.1:1
2.0:1
2.3:1
1.0:1
2.0:1
2.1:1
1.7:1
1.7:1
2.4:1
71/68 (70)
30/21 (24)
31/13 (21)
ꢀ11/20 (13)
31/32 (31)
53/47 (51)
75/64 (72)
53/53 (53)
79/18 (59)
75/65 (72)
76/59 (70)
84/47 (70)
87/71 (82)
5f
6g
7h
8
9
Cl
10
11
12
13
F6acac
F6acac
F6acac
F6acac
Acetone
a
Unless otherwise noted, reactions were performed using 5 mol % of the copper
salt, 15 mol % of the ligand, and 2.5 equiv of oxaziridine. Data reported are the av-
erage of two reproducible experiments.
b
Bs¼benzenesulfonyl.
c
Total isolated yield of both diastereomers.
d
ee values reported as: cis:trans (weighted average).
Product ratios determined by chiral SFC analysis.
Ligand: 6 mol %.
Ligand: 10 mol %.
e
f
g
h
Ligand: 20 mol %.
Hydrolysis of both aminals thus affords the same major enantiomer
of the desired 1,2-amino alcohol. In further optimizations of this
reaction, therefore, we found it useful to consider the combined
enantioselectivity for formation of the benzylic stereocenter as
a weighted average of the enantiomer ratios for each diastereomer.
The ratio of ligand to copper was an important variable in the
optimization of this reaction. We found that a 3:1 ratio was opti-
mal; lower ratios led to a dramatic diminution in enantioselectivity
(entries 5 and 6), while higher ratios afforded no significant benefit
to the rate or selectivity of this reaction (entry 7). These results
suggest that the aminohydroxylation is not strongly ligand-accel-
erated, and that competition between free and ligand-bound cop-
per(II) can adversely impact the enantioselectivity of the reaction.
Additional optimization of the copper source (entries 8–10) in-
dicated that reactions performed with copper(II) bis(hexa-
Table 2
Scope of the aminohydroxylationa
Entry
Ar
Time
Yieldb
d.r. (cis:trans)
% eec,d
1
2
3
4
5
6
7
8
Ph
24 h
15 h
18 h
16 h
26 h
17 h
20 h
24 h
24 h
44 h
17 h
18 h
29 h
14 h
81%
72%
78%
65%
44%
67%
71%
61%
70%
57%
70%
77%
51%
67%
1.5:1
2.2:1
1.6:1
1.6:1
0.2:1
2.3:1
1.9:1
1.0:1
0.8:1
1.4:1
0.4:1
1.3:1
0.8:1
2.5:1
85/79 (82)
86/74 (82)
84/72 (79)
85/70 (79)
12/47 (20)
87/78 (84)
87/62 (78)
83/47 (65)
89/45 (69)
83/71 (78)
0/24 (9)
4-MePh
3-MePh
3,5-Me2Ph
2-MePh
4-t-BuPh
4-PhPh
4-BrPh
4-ClPh
fluoroacetylacetonate) enjoyed
a modest increase in yield
compared to our initial lead experiments. Finally, variation of the
solvent (entries 11–13) indicated that the use of acetone increases
the enantioselectivity of this process to synthetically useful levels.
We also examined a variety of other modifications to these re-
action conditions. Other ligands commonly utilized in asymmetric
copper-catalyzed processes9 failed to give comparable levels of
enantioselectivity. Similarly, steric and electronic perturbation
of the oxaziridine also failed to improve the selectivity. In each of
these extensive studies, we observed that structural changes to the
ligand or oxaziridine often had opposing effects on the enantiose-
lectivities of each of the two diastereomers produced in the re-
action. Finally, we found that the efficiency of this process is
dramatically reduced at lower temperatures without a significant
corresponding increase in enantioselectivity. It seems likely,
9
10
11
12
13
14e
4-FPh
4-MeOPh
3-MeOPh
3-ClPh
83/65 (75)
83/39 (60)
86/76 (82)
4-MePh
a
Unless otherwise noted, reactions were performed using 1 mmol olefin, 5 mol %
Cu(F6acac)2, 15 mol % (S)-Ph-box, and 2.5 equiv oxaziridine. Data reported are the
average of two reproducible experiments.
b
Total isolated yield of both diastereomers.
ee values reported as: cis:trans (weighted average).
Product ratios determined by chiral SFC analysis.
Reaction performed using 20 mmol olefin, 2 mol % Cu(F6acac)2, and 6 mol % (S)-
c
d
e
Ph-box.

5120
D.J. Michaelis et al. / Tetrahedron 65 (2009) 5118–5124
The ability to conduct the enantioselective aminohydroxylation
that will improve the reactivity of this system and induce higher
levels of enantioselectivity.
on gram scale is important for practical applications of our new
methodology. The aminal protecting group can be easily removed
from the mixture of diastereomers in high yield under standard
acidic hydrolysis conditions. In all cases, the enantiomeric excess of
the deprotected N-sulfonyl amino alcohol is in agreement with the
calculated weighted average of the two diastereomers, which in-
dicates that the benzylic stereocenter is not racemized under these
acidic conditions and that the rate of hydrolysis for the two di-
astereomers are comparable. In addition, the N-sulfonyl amino al-
cohols are highly crystalline solids, and the enantiopurity of these
compounds can be improved to high levels upon recrystallization.
Examples of this process are summarized in Scheme 1. The 1,3-
oxazolidine products arising from reaction of 4-methylstyrene (3)
and 3,5-dimethylstyrene (5) can be hydrolyzed on gram scale upon
treatment with TFA in aqueous dioxane (86% and 88% yield of 4 and
6, respectively), and a single recrystallization from EtOAc/hexanes
affords the N-sulfonyl amino alcohol products in very high enan-
tiomeric purity (>99% ee and 98% ee, respectively). In a similar
fashion, the 1,3-oxazoline product derived from 4-phenylstyrene
(7) undergoes hydrolysis in 86% yield, and recrystallization affords
3.4 g of the N-sulfonyl amino alcohol 8 in 86% ee.
In summary, we have developed the first enantioselective cop-
per(II)-catalyzed intermolecular aminohydroxylation reaction of
alkenes. This discovery is significant for a number of reasons. First,
this method provides a convenient route to enantioenriched amino
alcohols from styrenes. The ability to perform this amino-
hydroxylation under osmium-free conditions and the very high
levels of regioselectivity obtained make this method an attractive
complement to the well-established Sharpless asymmetric amino-
hydroxylation. We anticipate, therefore, that this method could
find significant utility in the syntheses of enantioenriched vicinal
amino alcohols. In addition, these results provide strong evidence
that the chiral copper(II) catalyst is intimately involved in the ste-
reochemistry-determining step of the aminohydroxylation. Future
efforts in our labs will focus on the discovery of ligands for copper
3. Experimental section
3.1. General methods
Oxaziridine 1 was prepared as described by Davis.10 (R)-Phenyl
bis(oxazoline) was synthesized from (R)-phenylglycinol using the
procedure reported by Garcıa and Pires. Product ratios were de-
11
´
termined by supercritical fluid chromatography (SFC) on a Berger
Analytix instrument equipped with an Agilent 1100 variable
wavelength detector, using chiral columns and methods as noted.
1H and 13C NMR spectra were obtained using Bruker AC-300 and
Varian Unity-300 spectrometers and were referenced to TMS
(0.00 ppm) or CDCl3 (77.23 ppm), respectively. Mass spectrometry
was performed with a Micromass LCT (electrospray ionization,
time-of-flight analyzer). Optical rotations were obtained using
a Rudolph Autopol III polarimeter. Isolated yields refer to the
combined yields of both diastereomers obtained upon chroma-
tography; characterization data were obtained from analytically
pure samples isolated by further chromatography or selective
crystallization.
3.2. Asymmetric aminohydroxylations
3.2.1. General procedure for enantioselective aminohydroxylation
of styrenes (Table 2)
A
flame-dried 2 dram vial containing (R,R)-2,20-isopropy-
lidenebis(4-phenyl-2-oxazoline) (0.15 mmol), copper(II) hexa-
fluoroacetylacetonate (0.05 mmol), and a stir bar was charged with
acetone (2.0 ml). The reaction vial was then capped with a septum
and flushed with nitrogen, and the solution was stirred for 30 min.
N-Benzenesulfonyl-3-phenyloxaziridine (1, 2.5 mmol) was then
added, followed by the styrene substrate (1.0 mmol). The reaction
was stirred under positive pressure of nitrogen for 14–44 h and
then quenched by the addition of 200 mL dimethylsulfide to destroy
remaining excess oxaziridine. The solvent was removed by rotary
evaporation, and the residue was dissolved in 2 ml toluene and
loaded directly onto a silica gel column. Elution with 5:1 hexanes/
ethyl acetate with 3% triethylamine co-solvent afforded the 1,3-
oxazolidine products.
3.2.2. N-Benzenesulfonyl-2,4-diphenyl-1,3-oxazolane (Table 2,
entry 1)
Prepared according to the general procedure using 104 mg
styrene. Yield 1: 298 mg, 80%, 1.6:1 cis:trans, 85/79% ee cis/trans
(82% ee combined); yield 2: 293 mg, 79%, 1.44:1 cis:trans, 83/76% ee
cis/trans (80% ee combined). Spectral data were in agreement with
previously reported values.8a cis Diastereomer: 85% ee [Daicel
Chiracel OJ-H column, 10% MeOH 6 min, then 17% MeOH 10 min,
22
2.5 ml/min, 210 nm; t1¼5.37 min (major), t2¼6.38 min], [
a]
þ57.4
D
(c 0.93, CH2Cl2). trans Diastereomer: >99% ee [t1¼12.62 min (ma-
22
jor), t2¼16.01 min], [
a
]
þ114.2 (c 0.55, CH2Cl2).
D
3.2.3. N-Benzenesulfonyl-2-phenyl-4-(4-methylphenyl)-1,3-
oxazolane (Table 2, entry 2)
Yield 1: 0.264 g, 70%, 2.2:1 cis:trans, 86/65% ee cis/trans (82% ee
combined); yield 2: 0.281 g, 74%, 2.2:1 cis:trans, 86/65% ee cis/trans
(82% ee combined). cis Diastereomer: 86% ee [Daicel Chiracel OJ-H
column, 3% MeOH 18 min, then 20% MeOH 6 min, 2.5 ml/min,
22
210 nm; t1¼16.81 min (major), t2¼18.41 min], [
a
]
þ76.5 (c 2.00,
D
CH2Cl2); 1H NMR (300 MHz, CDCl3):
d
7.72–7.84 (–SO2PhH, m, 2H),
7.55–7.67 (ArH, m, 3H), 7.44–7.54 (ArH, m, 2H), 7.29–7.43 (ArH, m,
3H), 7.02–7.18 (ArH, m, 4H), 6.34 (Haminal, s, 1H), 4.82 (CH-CH2, t,
J¼7.0 Hz, 1H), 4.15 (CH2, dd, J¼9.0, 7.1 Hz, 1H), 3.87 (CH2, dd, J¼9.0,
Scheme 1. Large-scale hydrolysis of the diastereomeric 1,3-oxazolidine products and
recrystallization to high enantiopurity.

D.J. Michaelis et al. / Tetrahedron 65 (2009) 5118–5124
5121
6.9 Hz,1H), 2.30 (ArCH3, s, 3H); 13C NMR (75.4 MHz, CDCl3):
d
138.2,
3.2.7. N-Benzenesulfonyl-2-phenyl-4-(4-tert-butylphenyl)-1,3-
oxazolane (Table 2, entry 6)
137.9, 137.6, 135.6, 133.4, 129.5, 129.3, 129.0, 128.6, 128.2, 127.4,
127.3, 92.7, 73.4, 63.3, 21.3; HRMS (EIþ) calcd for [C22H21NO3SH]þ
requires m/z 380.1315, found m/z 380.1313. Isolated as a white solid
Prepared according to the general procedure using 161 mg 4-
tert-butylstyrene. Yield 1: 0.283 g, 67%, 2.1:1 cis:trans, 87/73% ee
cis/trans (83% ee combined); yield 2: 0.291 g, 67%, 2.4:1 cis:trans,
87/79% ee cis/trans (84% ee combined). cis Diastereomer: 85% ee
[Daicel Chiralpak AD column,10% MeOH ramp (0.75 ml/min) to 25%
(mp¼178–180 ꢁC). trans Diastereomer: 99% ee [t1¼25.44 min
22
(major), t2¼26.52 min], [
a]
þ135.9 (c 0.69, CH2Cl2); 1H NMR
D
(300 MHz, CDCl3): d 7.48–7.56 (–SO2PhH, m, 2H), 7.31–7.43 (ArH, m,
4H), 7.08–7.20 (ArH, m, 6H), 6.95 (ArH, d, J¼7.9 Hz, 2H), 6.35
(Haminal, s, 1H), 5.06 (CH–CH2, dd, J¼6.4, 2.2 Hz, 1H), 4.38 (CH2, dd,
J¼8.8, 6.4 Hz, 1H), 3.98 (CH2, dd, J¼8.8, 2.2 Hz, 1H), 2.31 (ArCH3, s,
MeOH, 2.0 ml/min, 210 nm; t1¼5.01 min, t2¼6.48 min (major)],
22
[a
]
þ41.8 (c 1.10, CH2Cl2); 1H NMR (300 MHz, CDCl3):
d 7.69–7.80
D
(–SO2PhH, m, 2H), 7.53–7.67 (ArH, m, 3H), 7.31–7.52 (ArH, m, 5H),
7.22–7.30 (ArH, m, 2H), 7.08–7.19 (ArH, m, 2H), 6.37 (Haminal, s, 1H),
4.83 (CH–CH2, t, J¼7.1 Hz, 1H), 4.17 (CH2, dd, J¼9.0, 7.1 Hz, 1H), 3.87
(CH2, dd, J¼9.0, 7.1 Hz, 1H), 1.28 (t-BuH, s, 9H); 13C NMR (75.4 MHz,
3H); 13C NMR (75.4 MHz, CDCl3):
d 140.7, 138.5, 138.1, 135.8, 131.9,
129.3, 128.5, 128.4, 128.0, 127.6, 127.1, 92.4, 73.2, 62.8, 21.3; HRMS
(EIþ) calcd for [C22H21NO3SH]þ requires m/z 380.1315, found m/z
380.1315. Isolated as a colorless oil.
CDCl3):
d 151.1, 138.3, 137.7, 135.4, 133.3, 129.3, 129.0, 128.6, 128.2,
127.4, 127.1, 125.7, 92.6, 73.4, 63.3, 34.7, 31.5; HRMS (EIþ) calcd for
3.2.4. N-Benzenesulfonyl-2-phenyl-4-(3-methylphenyl)-1,3-
oxazolane (Table 2, entry 3)
[C25H27NO3SH]þ requires m/z 422.1785, found m/z 422.1786. Iso-
lated as a colorless oil. trans Diastereomer: 66% ee [t1¼8.97 min
22
Prepared according to the general procedure using 119 mg 3-
methylstyrene. Yield 1: 290 mg, 76%, 1.6:1 cis:trans, 84/72% ee cis/
trans (79% ee combined); yield 2: 296 mg, 78%, 1.6:1 cis:trans, 82/
71% ee cis/trans (78% ee combined). Spectral data were in agree-
ment with previously reported values.8a cis Diastereomer: 84% ee
(major), t2¼10.93 min], [
a]
þ33.0 (c 1.06, CH2Cl2); 1H NMR
D
(300 MHz, CDCl3): d 7.49–7.62 (–SO2PhH, m, 2H), 7.29–7.47 (ArH, m,
4H), 7.05–7.22 (ArH, m, 8H), 6.36 (Haminal, s, 1H), 5.09 (CH–CH2, dd,
J¼6.3, 2.1 Hz, 1H), 4.37 (CH2, dd, J¼8.8, 6.3 Hz, 1H), 3.99 (CH2, dd,
J¼8.8, 2.1 Hz, 1H), 1.30 (t-BuH, s, 9H); 13C NMR (75.4 MHz, CDCl3):
[Daicel Chiracel OJ-H column, 12% MeOH, 2.5 ml/min, 210 nm;
d 151.3, 140.7, 138.8, 135.4, 132.0, 129.3, 128.6, 128.4, 127.9, 127.5,
22
t1¼3.88 min (major), t2¼4.26 min], [
a
]
þ61.6 (c 1.34, CH2Cl2).
127.1, 125.5, 92.2, 73.0, 62.7, 34.7, 31.6; HRMS (EIþ) calcd for
[C25H27NO3SH]þ requires m/z 422.1785, found m/z 422.1789. Iso-
lated as a white solid (mp¼158–160 ꢁC).
D
trans Diastereomer: 73% ee [t1¼9.59 min, t2¼11.05 min (major)],
22
[
a]
þ93.1 (c 1.66, CH2Cl2).
D
3.2.5. N-Benzenesulfonyl-2-phenyl-4-(3,5-dimethylphenyl)-1,3-
oxazolane (Table 2, entry 4)
3.2.8. N-Benzenesulfonyl-2-phenyl-4-(4-biphenyl)-1,3-oxazolane
(Table 2, entry 7)
Prepared according to the general procedure using 140 mg 3,5-
dimethylstyrene. Yield 1: 0.276 g, 66%, 1.5:1 cis:trans, 83/70% ee cis/
trans (78% ee combined); yield 2: 0.253 g, 69%, 1.6:1 cis:trans, 85/
70% ee cis/trans (79% ee combined). cis Diastereomer: 80% ee
[Daicel Chiracel OJ-H column, 3% MeOH 12 min then 20% MeOH
Prepared according to the general procedure using 180 mg 4-
vinylbiphenyl. Yield 1: 0.326 g, 71%, 1.9:1 cis:trans, 86/62% ee cis/
trans (78% ee combined); yield 2: 0.311 g, 71%, 1.9:1 cis:trans, 87/
62% ee cis/trans (78% ee combined). cis Diastereomer: 96% ee
[Daicel Chiracel OD-H column, 5% MeOH 10 min then 15% MeOH
7 min, 2.5 ml/min, 210 nm; t1¼8.76 min (major), t2¼11.52 min],
10 min, 3.0 ml/min, 210 nm; t1¼20.25 min, t2¼21.71 min (major)],
22
22
[
a]
þ67.8 (c 1.19, CH2Cl2); 1H NMR (300 MHz, CDCl3):
d
7.74–7.82
[a
]
þ101.8 (c 1.07, CH2Cl2); 1H NMR (300 MHz, CDCl3):
d 7.73–7.85
D
D
(–SO2PhH, m, 2H), 7.56–7.66 (ArH, m, 3H), 7.44–7.54 (ArH, m, 2H),
7.31–7.42 (ArH, m, 3H), 6.85 (ArH, br s, 1H), 6.79 (ArH, br s, 2H), 6.37
(Haminal, s, 1H), 4.81 (CH–CH2, t, J¼6.9 Hz, 1H), 4.14 (CH2, dd, J¼8.9,
(–SO2PhH, m, 2H), 7.27–7.68 (ArH, m, 17H), 6.38 (Haminal, s, 1H), 4.92
(CH–CH2, t, J¼6.9 Hz, 1H), 4.21 (CH2, dd, J¼9.0, 7.1 Hz, 1H), 3.94
(CH2, dd, J¼9.0, 6.8 Hz, 1H); 13C NMR (75.4 MHz, CDCl3):
d 141.1,
7.2 Hz, 1H), 3.86 (CH2, dd, J¼8.9, 6.7 Hz, 1H), 2.20 (ArCH3, s, 6H); 13
C
140.8, 138.1,137.6, 133.5,129.4,129.1, 129.0, 128.7,128.3, 127.8,127.6,
127.5, 127.4, 127.3, 92.8, 73.3, 63.2; HRMS (EIþ) calcd for
[C27H23NO3SNa]þ requires m/z 464.1291, found m/z 464.1292. Iso-
NMR (75.4 MHz, CDCl3):
d 138.5, 138.2, 138.2, 137.8, 133.4, 129.7,
129.3, 129.0, 128.6, 128.3, 127.4, 125.2, 92.6, 73.5, 63.4, 21.4; HRMS
(EIþ) calcd for [C23H23NO3SNa]þ requires m/z 416.1291, found m/z
lated as a white solid (mp¼131–133 ꢁC). trans Diastereomer: 98% ee
22
416.1308. Isolated as a white solid (mp¼121–124 ꢁC). trans Di-
[t1¼25.43 min (major), t2¼28.51 min], [
a
]
þ59.2 (c 0.61, CH2Cl2);
D
22
astereomer: 70% ee [t1¼21.90 min, t2¼23.21 min (major)], [
a
]
1H NMR (300 MHz, CDCl3):
d 7.18–7.62 (ArH, m, 17H), 7.07–7.17
D
þ93.3 (c 1.20, CH2Cl2); 1H NMR (300 MHz, CDCl3):
d
7.51–7.62
(ArH, m, 2H), 6.42 (Haminal, s, 1H), 5.14 (CH–CH2, dd, J¼6.2, 1.9 Hz,
(–SO2PhH, m, 2H), 7.30–7.47 (ArH, m, 4H), 7.09–7.24 (ArH, m, 4H),
6.82 (ArH, br s, 1H), 6.78 (ArH, br s, 2H), 6.37 (Haminal, s, 1H), 5.01
(CH–CH2, dd, J¼6.4, 2.0 Hz, 1H), 4.34 (CH2, dd, J¼8.8, 6.4 Hz, 1H),
3.94 (CH2, dd, J¼8.8, 2.0 Hz, 1H), 2.15 (ArCH3, s, 6H); 13C NMR
1H), 4.42 (CH2, dd, J¼9.0, 6.2 Hz, 1H), 4.04 (CH2, dd, J¼9.0, 1.9 Hz,
1H); 13C NMR (75.4 MHz, CDCl3):
d 141.3, 140.9, 140.7, 138.6, 137.7,
132.0, 129.4, 129.1, 128.6, 128.5, 127.7, 127.5, 127.4, 127.2, 127.1, 92.5,
73.0, 62.7; HRMS (EIþ) calcd for [C27H23NO3SH]þ requires m/z
442.1472, found m/z 442.1461. Isolated as a white solid (mp¼195–
197 ꢁC).
(75.4 MHz, CDCl3):
d 140.6, 138.8, 138.3, 138.2, 132.0, 129.9, 129.3,
128.6, 128.3, 127.5, 127.1, 126.0, 92.4, 73.0, 63.0, 21.3; HRMS (EIþ)
calcd for [C23H23NO3SH]þ requires m/z 394.1472, found m/z
394.1469. Isolated as a white solid (mp¼94–95 ꢁC).
3.2.9. N-Benzenesulfonyl-2-phenyl-4-(4-bromophenyl)-1,3-
oxazolane (Table 2, entry 8)
3.2.6. N-Benzenesulfonyl-2-phenyl-4-(2-methylphenyl)-1,3-
oxazolane (Table 2, entry 5)
Prepared according to the general procedure using 184 mg
4-bromostyrene. Yield 1: 0.279 g, 63%, 1.0:1 cis:trans, 83/46% ee cis/
trans (65% ee combined); yield 2: 0.275 g, 62%, 1.0:1 cis:trans, 83/
47% ee cis/trans (65% ee combined). cis Diastereomer: >99% ee
Prepared according to the general procedure using 59 mg 2-
methylstyrene. Yield 1: 81 mg, 43%, 6.3:1 cis:trans, 11/50% ee cis/
trans (16% ee combined); yield 2: 84 mg, 44%, 6.3:1 cis:trans, 12/
47% ee cis/trans (17% ee combined). Spectral data were in agree-
ment with previously reported values.8a cis Diastereomer: 48% ee
[Daicel Chiracel OJ-H column, 5% MeOH 15 min, then 20% MeOH
[Daicel Chiralpak AD column, 15% MeOH, 2.0 ml/min, 210 nm;
22
t1¼9.24 min, t2¼13.11 min (major)], [
a]
þ80.2 (c 1.00, CH2Cl2); 1H
D
NMR (300 MHz, CDCl3):
d
7.71–7.82 (–SO2PhH, m, 2H), 7.45–7.67
(ArH, m, 5H), 7.30–7.44 (ArH, m, 5H), 7.04–7.17 (ArH, m, 2H), 6.34
(Haminal, s, 1H), 4.83 (CH–CH2, t, J¼6.8 Hz, 1H), 4.17 (CH2, dd, J¼9.0,
6.8 Hz, 1H), 3.86 (CH2, dd, J¼9.0, 6.8 Hz, 1H); 13C NMR (75.4 MHz,
10 min, 2.0 ml/min, 210 nm; t1¼7.61 min (major), t2¼8.74 min],
22
[
a]
þ23.2 (c 0.50, CH2Cl2). trans Diastereomer: 8% ee
D
22
[t1¼20.57 min (major), t2¼22.35 min], [
a
]
þ8.4 (c 2.25, CH2Cl2).
CDCl3): d 137.9, 137.8, 137.5, 133.6, 131.9, 129.4, 129.2, 129.1, 128.7,
D

5122
D.J. Michaelis et al. / Tetrahedron 65 (2009) 5118–5124
128.2, 127.3, 122.2, 92.8, 73.1, 62.8; HRMS (EIþ) calcd for
3.2.12. Benzenesulfonyl-2-phenyl-4-(4-methoxyphenyl)-1,3-
oxazolane (Table 2, entry 11)
[C21H18BrNO3SNa]þ requires m/z 466.0083, found m/z 466.0084.
Isolated as a white solid (mp¼149–150 ꢁC). trans Diastereomer:
Prepared according to the general procedure using 67 mg 4-
vinylanisole. Yield 1: 0.140 g, 71%, 0.4:1 cis:trans, 24/0% ee cis/
trans (9% ee combined); yield 2: 0.133 g, 69%, 0.4:1 cis:trans, 25/
0% ee cis/trans (9% ee combined). Spectral data were in agree-
ment with previously reported values.8a cis Diastereomer: 28%
22
99% ee [t1¼11.21 min (major), t2¼16.90 min], [
a
]
D
þ94.0 (c 1.23,
CH2Cl2); 1H NMR (300 MHz, CDCl3):
d 7.47–7.57 (–SO2PhH, m, 2H),
7.34–7.45 (ArH, m, 4H), 7.06–7.30 (ArH, m, 8H), 6.37 (Haminal, s, 1H),
5.04 (CH–CH2, dd, J¼6.3, 1.8 Hz, 1H), 4.37 (CH2, dd, J¼9.0, 6.3 Hz,
1H), 3.94 (CH2, dd, J¼9.0, 1.8 Hz, 1H); 13C NMR (75.4 MHz, CDCl3):
ee [Daicel Chiracel OJ-H column, 15% MeOH, 2.5 ml/min, 210 nm;
22
d
140.6, 138.3, 137.9, 132.3, 131.8, 129.8, 129.4, 128.7, 128.6, 127.5,
t1¼5.26 min (major), t2¼5.96 min], [
a
]
þ15.8 (c 0.77, CH2Cl2).
D
127.0, 122.5, 92.5, 72.8, 62.3; HRMS (EIþ) calcd for
[C21H18BrNO3SH]þ requires m/z 466.0083, found m/z 466.0090.
Isolated as a white solid (mp¼163–164 ꢁC).
trans Diastereomer: 0% ee [t1¼11.14 min, t2¼12.29 min].
3.2.13. N-Benzenesulfonyl-2-phenyl-4-(3-methoxyphenyl)-1,3-
oxazolane (Table 2, entry 12)
3.2.10. N-Benzenesulfonyl-2-phenyl-4-(4-chlorophenyl)-1,3-
oxazolane (Table 2, entry 9)
Prepared according to the general procedure using 138 mg 4-
chlorostyrene. Yield 1: 0.280 g, 70%, 0.9:1 cis:trans, 89/45% ee cis/
trans (69% ee combined); yield 2: 0.280 g, 67%, 0.8:1 cis:trans, 89/
45% ee cis/trans (69% ee combined). cis Diastereomer: >99% ee
Prepared according to the general procedure using 137 mg 4-
vinylanisole. Yield 1: 0.306 g, 76%, 1.3:1 cis:trans, 87/65% ee cis/
trans (77% ee combined); yield 2: 0.317 g, 78%, 1.3:1 cis:trans, 87/
64% ee cis/trans (77% ee combined). cis Diastereomer: 90% ee
[Daicel Chiralpak AD column, 12% MeOH, 2.5 ml/min, 210 nm;
22
t1¼5.43 min, t2¼6.08 min (major)], [
a
]
þ69.6 (c 1.81, CH2Cl2);
D
[Daicel Chiralpak AD column, 12% MeOH, 2.5 ml/min, 210 nm;
1H NMR (300 MHz, CDCl3):
d 7.73–7.83 (–SO2PhH, m, 2H), 7.55–
22
t1¼7.55 min, t2¼9.36 min (major)], [
a]
þ77.9 (c 1.53, CH2Cl2); 1H
7.67 (ArH, m, 3H), 7.44–7.54 (ArH, m, 2H), 7.29–7.43 (ArH, m, 3H),
7.16 (ArH, t, J¼8.0 Hz, 1H), 6.64–8.85 (ArH, m, 3H), 6.40 (Haminal, s,
1H), 4.85 (CH–CH2, t, J¼7.0 Hz, 1H), 4.19 (CH2, dd, J¼9.0, 7.2 Hz,
1H), 3.88 (CH2, dd, J¼9.0, 6.8 Hz, 1H), 3.62 (Ar–OCH3, s, 3H); 13C
D
NMR (300 MHz, CDCl3):
d
7.70–7.84 (–SO2PhH, m, 2H), 7.44–7.66
(ArH, m, 5H), 7.30–7.43 (ArH, 1, 3H), 7.10–7.28 (ArH, m, 4H), 6.34
(Haminal, m, 1H), 4.85 (CH–CH2, t, J¼6.8 Hz, 1H), 4.07 (CH2, dd,
J¼9.1, 7.2 Hz, 1H), 3.78 (CH2, dd, J¼9.1, 6.5 Hz, 1H); 13C NMR
NMR (75.4 MHz, CDCl3):
d 160.0, 140.3, 138.2, 137.7, 133.5, 129.7,
(75.4 MHz, CDCl3):
d
137.8, 137.4, 137.3, 134.0, 133.6, 129.4, 129.2,
129.4, 129.0, 128.7, 128.3, 127.3, 119.6, 114.4, 112.2, 92.7, 73.5, 63.4,
129.0, 128.7, 128.2, 127.3, 92.7, 73.2, 62.7; HRMS (EIþ) calcd for
55.3; HRMS (EIþ) calcd for [C22H21NO4SNa]þ requires m/z
[C21H18ClNO3SNa]þ requires m/z 422.0589, found m/z 422.0592.
418.1085, found m/z 418.1085. Isolated as a colorless oil. trans
22
Isolated as a white solid (mp¼141–143 ꢁC). trans Diastereomer: 87%
Diastereomer: 53% ee [t1¼7.79 min (major), t2¼8.73 min], [
a]
D
22
ee [t1¼8.42 min (major), t2¼12.21 min], [
a]
þ98.1 (c 1.11, CH2Cl2);
þ56.3 (c 0.49, CH2Cl2); 1H NMR (300 MHz, CDCl3):
d 7.51–7.57
D
1H NMR (300 MHz, CDCl3):
d
7.47–7.56 (–SO2PhH, m, 2H), 7.32–7.45
(–SO2PhH, m, 2H), 7.36–7.43 (ArH, m, 4H), 7.07–7.24 (ArH, m, 5H),
6.85–6.90 (ArH, m, 1H), 6.73–6.78 (ArH, m, 1H), 6.67–6.70 (ArH,
m, 1H), 6.36 (Haminal, s, 1H), 5.07 (CH–CH2, dd, J¼6.3, 2.0 Hz, 1H),
4.37 (CH2, dd, J¼8.9, 6.3 Hz, 1H), 3.98 (CH2, dd, J¼8.9, 2.0 Hz, 1H),
(ArH, m, 4H), 7.04–7.24 (ArH, m, 8H), 6.37 (Haminal, s, 1H), 5.06 (CH–
CH2, dd, J¼6.3, 1.8 Hz, 1H), 4.37 (CH2, dd, J¼9.0, 6.3 Hz, 1H), 3.94
(CH2, dd, J¼9.0, 1.8 Hz, 1H); 13C NMR (75.4 MHz, CDCl3):
d 140.6,
138.3, 137.4, 134.3, 132.3, 129.4, 128.8, 128.6, 128.6, 127.5, 127.0, 92.5,
72.9, 62.2; HRMS (EIþ) calcd for [C21H18ClNO3SH]þ requires m/z
400.0769, found m/z 400.0767. Isolated as a white solid (mp¼144–
148 ꢁC).
3.64 (ArOCH3, s, 3H); 13C NMR (75.4 MHz, CDCl3):
d 159.9, 140.6,
140.1, 138.6, 132.1, 129.6, 129.3, 128.6, 128.5, 127.5, 127.1, 120.8,
114.4, 112.8, 92.4, 73.0, 63.0, 55.3; HRMS (EIþ) calcd for
[C22H21NO4SH]þ requires m/z 396.1265, found m/z 396.1268.
Isolated as a colorless oil.
3.2.11. N-Benzenesulfonyl-2-phenyl-4-(4-fluorophenyl)-1,3-
oxazolane (Table 2, entry 10)
3.2.14. N-Benzenesulfonyl-2-phenyl-4-(3-chlorophenyl)-1,3-
oxazolane (Table 2, entry 13)
Prepared according to the general procedure using 139 mg 3-
chlorostyrene. Yield 1: 0.202 g, 50%, 0.8:1 cis:trans, 39/83% ee
cis/trans (60% ee combined); yield 2: 0.208 g, 52%, 0.8:1 cis:
trans, 38/83% ee cis/trans (60% ee combined). cis Diastereomer:
Prepared according to the general procedure using 122 mg 4-
fluorostyrene. Yield 1: 0.261 g, 68%, 1.6:1 cis:trans, 85/71% ee cis/
trans (78% ee combined); yield 2: 0.265 g, 69%, 1.6:1 cis:trans, 85/
71% ee cis/trans (78% ee combined). cis Diastereomer: 84% ee
[Daicel Chiracel OJ-H column, 7% MeOH 15 min then 20% MeOH
10 min, 2.0 ml/min, 210 nm; t1¼8.96 min (major), t2¼13.71 min],
85% ee [Daicel Chiracel OJ-H column, 18% MeOH, 2.5 ml/min,
22
22
[
a
]
þ46.2 (c 4.42, CH2Cl2); 1H NMR: (300 MHz,)
d
7.70–7.81
210 nm; t1¼3.58 min (major), t2¼4.26 min], [
a
]
þ53.5 (c 0.51,
D
D
(–SO2PhH, m, 2H), 7.43–7.65 (ArH, m, 5H), 7.29–7.43 (ArH, m, 3H),
7.14–7.27 (ArH, m, 2H), 6.87–7.01 (ArH, m, 2H), 6.34 (Haminal, s,
1H), 4.86 (CH–CH2, t, J¼6.8 Hz, 1H), 4.16 (CH2, dd, J¼9.0, 7.0 Hz,
1H), 3.87 (CH2, dd, J¼9.0, 6.6 Hz, 1H); 13C NMR (75.4 MHz, CDCl3):
CH2Cl2); 1H NMR (300 MHz, CDCl3):
d 7.74–7.81 (–SO2PhH, m,
2H), 7.45–7.67 (ArH, m, 5H), 7.34–7.44 (ArH, m, 3H), 7.10–7.23
(ArH, m, 4H), 6.36 (Haminal, s, 1H), 4.85 (CH–CH2, t, J¼7.0 Hz, 1H),
4.18 (CH2, dd, J¼9.0, 7.2 Hz, 1H), 3.87 (CH2, dd, J¼9.0, 6.8 Hz,
d
162.6, 161.0, 137.9, 137.5, 134.5, 133.6, 129.4, 129.2, 129.1, 129.1,
1H); 13C NMR (75.4 MHz, CDCl3):
d 140.9, 137.7, 137.5, 134.6,
128.7, 128.2, 127.3, 115.7, 92.7, 73.3, 62.7; HRMS (EIþ) calcd for
133.6, 130.1, 129.4, 129.2, 128.7, 128.3, 128.2, 127.6, 127.3, 125.4,
92.8, 73.2, 62.8; HRMS (EIþ) calcd for [C21H18ClNO3SH]þ re-
quires m/z 400.0769, found m/z 400.0768. Isolated as a colorless
[C21H18FNO3SNa]þ requires m/z 406.0884, found m/z 406.0901.
Isolated as a white solid (mp¼90–91 ꢁC). trans Diastereomer: 74%
22
ee [t1¼21.20 min, t2¼22.30 min (major)], [
a
]
þ96.7 (c 0.67,
oil. trans Diastereomer: 45% ee [t1¼7.74 min, t2¼11.88 min
D
CH2Cl2); 1H NMR (300 MHz, CDCl3):
d
7.48–7.58 (–SO2PhH, m,
(major)], [
a
]
þ69.9 (c 1.00, CH2Cl2); 1H NMR (300 MHz,
22
D
2H), 7.35–7.45 (ArH, m, 4H), 7.14–7.28 (ArH, m, 6H), 6.78–6.88
(ArH, m, 2H), 6.37 (Haminal, s, 1H), 5.08 (CH–CH2, dd, J¼6.2, 2.0 Hz,
1H), 4.38 (CH2, dd, J¼9.0, 6.2 Hz, 1H), 3.95 (CH2, dd, J¼9.0, 2.0 Hz,
CDCl3): d 7.48–7.57 (m, 2H, SO2PhH), 7.34–7.45 (m, 4H, ArH),
7.08–7.28 (m, 8H, ArH), 6.39 (s, 1H, Haminal), 5.05 (dd, J¼6.2,
1.7 Hz, 1H, CH–CH2), 4.37 (dd, J¼9.0, 6.2 Hz, 1H, CH2), 3.94 (dd,
1H); 13C NMR (75.4 MHz, CDCl3):
d
162.8, 140.7, 138.4, 134.7,
J¼9.0, 1.7 Hz, 1H, CH2); 13C NMR (75.4 MHz, CDCl3):
d 140.7,
132.3, 129.9, 129.8, 129.4, 128.6, 127.5, 127.0, 115.5, 110.9, 92.4,
140.4, 138.3, 134.8, 132.5, 129.9, 129.4, 128.6, 128.5, 128.0, 127.5,
126.9, 126.5, 92.6, 72.8, 62.4; HRMS (EIþ) calcd for
[C21H18ClNO3SNa]þ requires m/z 422.0589, found m/z 422.0569.
Isolated as a white solid (mp¼126–128 ꢁC).
73.0, 62.2; HRMS (EIþ) calcd for [C21H18FNO3SNa]þ requires m/z
406.0884, found m/z 406.0877. Isolated as
(mp¼140–144 ꢁC).
a white solid

D.J. Michaelis et al. / Tetrahedron 65 (2009) 5118–5124
5123
3.3. Hydrolysis of 1,3-oxazolidines
hexanes to afford 1.33 g, 98% ee. Data: 95% ee [Diacel Chiralpak
AD column, 5% MeOH, 2.5 ml/min; t1¼22.62 min (major), t2¼
22
3.3.1. N-Benzenesulfonyl-2-amino-2-(4-methylphenyl) ethanol
Into a oven dried 250 ml round bottom flask containing a stir bar
was placed the N-benzenesulfonyl-2-phenyl-4-(4-methylphenyl)-
1,3-oxazolane (5.0 g, 13.2 mmol, 82% combined ee) and 48 ml 2:1
dioxane/H2O. Trifluoroacetic acid (4.52 g, 39.6 mmol) was then
added dropwise while stirring at room temperature. The reaction
was then heated to 80 ꢁC and stirred under positive pressure of
nitrogen for 4 h. The mixture was then cooled to room temperature
and 75 ml saturated NaHCO3 was added slowly. The mixture was
then extracted with 3ꢂ100 ml CH2Cl2 and the combined organic
dried over Na2SO4 before solvent removal. The product was purified
by chromatography on silica gel with 1:1 EtOAc/hexanes as eluent.
Yield 1: 3.36 g, 84% yield, 83% ee; yield 2: 3.38 g 88% yield, 82% ee.
The product was then recrystallized from ethyl acetate/hexanes to
25.46 min], [
a
]
þ88.3 (c 1.28, CH2Cl2). 1H NMR: (300 MHz, CDCl3)
D
d
7.65–7.75 (–SO2PhH, m, 2H), 7.40–7.49 (–SO2PhH, m, 1H), 7.28–
7.38 (–SO2PhH, m, 2H), 6.77 (ArH, s, 1H), 6.62 (ArH, s, 2H), 5.80
(–NH, d, J¼6.1 Hz, 1H), 4.40 (–CH–CH2, q, J¼6.1 Hz, 1H), 3.73 (–CH2,
t, J¼6.1 Hz, 2H), 2.57 (–OH, t, J¼6.1 Hz, 1H), 2.14 (–ArCH3, s, 6H); 13
C
NMR: (75.4 MHz, CDCl3)
d 140.5, 138.3, 137.2, 132.6, 129.7, 128.8,
127.3, 124.9, 66.4, 59.9, 21.3; HRMS (EIþ) calcd for [C16H19NO3SH]þ
requires m/z 306.1159, found m/z 306.1152. Isolated as a white solid
(mp¼106–109 ꢁC).
3.4. Determination of absolute stereochemistry
The absolute stereochemistry of N-benzenesulfonyl-2,4-diphenyl-
1,3-oxazolane (Table 2, entry 1), N-benzenesulfonyl-2-phenyl-4-(4-
methylphenyl)-1,3-oxazolane (Table 2, entry 2), and N-benzene-
sulfonyl-2-phenyl-4-(4-tert-butylphenyl)-1,3-oxazolane (Table 2, entry
6) was determined as described below. The configuration of all other
1,3-oxazolidine products in Table 2 was assigned by analogy.
afford 2.54 g, >99% ee. Data: 98% ee [Diacel Chiracel OJ-H column,
22
6% MeOH, 2.0 ml/min; t1¼11.24 min, t2¼14.98 min (major)], [
a]
D
þ109.52 (c 0.94, CH2Cl2). 1H NMR (300 MHz, CDCl3):
d 7.66–7.78
(–SO2PhH, m, 2H), 7.44–7.55 (ArH, m, 1H), 7.32–7.43 (ArH, m, 2H),
6.90–7.05 (ArH, m, 4H), 5.33 (–NH, d, J¼6.1 Hz,1H), 4.38 (CH–CH2, q,
J¼6.1 Hz, 1H), 3.75 (CH2, t, J¼6.1 Hz, 2H), 2.27 (ArCH3, s, 3H), 1.98
3.4.1. N-Benzenesulfonyl-2,4-diphenyl-1,3-oxazolane (Table 2,
entry 1)
(R)-N-Benzenesulfonyl-2-amino-2-phenylethanol was prepared
from (R)-phenylglycinol using a procedure described by Quintard
and co-workers.12 Spectral data were in agreement with previously
reported values;8a 99.8% ee [Daicel Chiracel OJ-H column, 10%
(–OH, t, J¼6.1 Hz, 1H); 13C NMR (75.4 MHz, CDCl3):
d 140.3, 138.1,
134.6, 132.7, 129.6, 129.1, 127.4, 126.9, 66.5, 59.5, 21.2; HRMS (EIþ)
calcd for [C15H17NO3SNa]þ requires m/z 314.0822, found m/z
314.0811. Isolated as a white solid (mp¼151–153 ꢁC).
3.3.2. N-Benzenesulfonyl-2-amino-2-(4-biphenyl)ethanol
MeOH, 2.5 ml/min, 210 nm; t1¼4.74 min (major), t2¼6.71 min],
22
Into a oven dried 250 ml round bottom flask containing a stir bar
was placed the N-benzenesulfonyl-2-phenyl-4-(4-biphenyl)-1,3-
oxazolane (6.2 g, 14.0 mmol, 74% combined ee) and 52 ml 2:1 di-
oxane/H2O. Trifluoroacetic acid (4.81 g, 42.2 mmol) was then added
dropwise while stirring at room temperature. The reaction was
then heated to 80 ꢁC and stirred under positive pressure of nitrogen
for 4 h. The mixture was then cooled to room temperature and
75 ml saturated NaHCO3 was added slowly. The mixture was then
extracted with 3ꢂ100 ml CH2Cl2 and the combined organic dried
over Na2SO4 before solvent removal. The product was purified by
chromatography on silica gel with 1:1 EtOAc/hexanes as eluent.
Yield 1: 4.35 g, 88% yield, 72% ee; yield 2: 4.00 g, 84% yield, 72% ee.
The product was then recrystallized from ethyl acetate/hexanes to
[a
]
ꢀ96.6 (c 0.55, CH2Cl2). For comparison, N-benzenesulfonyl-
D
2,4-diphenyl-1,3-oxazolane synthesized according to the general
procedure was subjected to hydrolysis using 3 equiv of trifluoro-
acetic acid in 2:1 dioxane/H2O at 80 ꢁC. The optical rotation of the
resulting (S)-N-benzenesulfonyl amino alcohol was measured: 80%
22
ee, [
a]
þ79.2 (c 0.72, CH2Cl2).
D
3.4.2. N-Benzenesulfonyl-2-phenyl-4-(4-methylphenyl)-1,3-
oxazolane (Table 2, entry 2)
The aminal was subjected to hydrolysis using 3 equiv of tri-
fluoroacetic acid in 2:1 dioxane/H2O at 80 ꢁC. The resulting N-sul-
fonyl amino alcohol was deprotected using the method of Martin.13
The N-sulfonyl amino alcohol (762 mg, 2.61 mmol) in a flame-dried
50 ml round-bottomed flask along with 4,40-di-tert-butylbiphenyl
(69 mg, 0.26 mmol). The flask was charged with 24 ml THF, and to
this solution was added 106 mg (15.3 mmol, 6 equiv) lithium wire
cut into small pieces. After sealing the flask with a septum and
flushing with argon, the reaction vessel was placed into a sonicat-
ing bath and stirred while sonicating over 4 h. After removal of the
remaining lithium metal, the resulting orange mixture was
quenched by the addition of 2 ml ethanol and 1.0 g solid NH4Cl. This
mixture was stirred for 5 min before the solids were removed by
filtration and the filtrate concentrated by rotary evaporation. The
resulting thick oil was dissolved in EtOH (3 ml) and passed through
a short plug of silica gel using EtOH as eluent. The solvent was re-
moved by rotary evaporation, and the residue was diluted with
25 ml CH2Cl2. The precipitate was isolated by vacuum filtration,
affording 0.44 g (2.34 mmol, 90% yield) of (S)-2-amino-2-(4-
methylphenyl)ethanol hydrochloride salt. An analytically pure
afford 3.40 g, 86% ee. Data: 86% ee [Diacel Chiralpak AD column,12%
22
MeOH, 3.0 ml/min; t1¼28.61 min (major), t2¼30.65 min], [
a]
D
þ129.6 (c 0.38, CH2Cl2). 1H NMR (300 MHz, CDCl3):
d 7.67–7.79
(–SO2PhH, m, 2H), 7.30–7.57 (ArH, m, 10H), 7.15 (ArH, m, 2H), 5.38
(–NH, d, J¼6.4 Hz, 1H), 4.45–4.55 (–CH–CH2, m, 1H), 3.74–3.87 (CH2,
m, 2H), 1.93 (–OH, t, J¼6.1 Hz, 1H); 13C NMR (75.4 MHz, CDCl3):
d
141.3, 140.6, 140.4, 136.5, 132.8, 129.1, 129.0, 127.7, 127.6, 127.5,
127.4, 127.2, 66.4, 59.4; HRMS (EIþ) calcd for [C20H19NO3SNa]þ re-
quires m/z 376.0978, found m/z 376.0996. Isolated as a white solid
(mp¼173–174 ꢁC).
3.3.3. N-Benzenesulfonyl-2-amino-2-(3,5-dimethylphenyl)ethanol
Into a oven dried 250 ml round bottom flask containing a stir bar
was placed the N-benzenesulfonyl-2-phenyl-4-(3,5-dimethyl-
phenyl)-1,3-oxazolane (3.0 g, 7.9 mmol, 81% combined ee) and
29 ml 2:1 dioxane/H2O. Trifluoroacetic acid (2.7 g, 23.6 mmol) was
then added dropwise while stirring at room temperature. The re-
action was then heated to 80 ꢁC and stirred under positive pressure
of nitrogen for 4 h. The mixture was then cooled to room temper-
ature and 40 ml saturated NaHCO3 was added slowly. The mixture
was then extracted with 3ꢂ100 ml CH2Cl2 and the combined or-
ganic dried over Na2SO4 before solvent removal. The product was
purified by chromatography on silica gel with 1:1 EtOAc/hexanes as
eluent. Yield 1: 2.06 g, 88% yield, 81% ee; yield 2: 1.99 g, 88% yield,
81% ee. The product was then recrystallized from ethyl acetate/
sample of the free base was generated by the treatment with 6 N
22
KOH, and the optical rotation was measured. [
abs. EtOH) [lit. [a]
D
a
]
þ22.9 (c 0.68,
D
þ26 (c 1.0, abs. EtOH)].14
22
3.4.3. N-Benzenesulfonyl-2-phenyl-4-(4-tert-butylphenyl)-1,3-
oxazolane (Table 2, entry 6)
The1,3-oxazolidine(.223 g, .67 mmol)wasconvertedto2-amino-
2-(4-tert-butylphenyl)ethanol using the procedure described for
N-benzenesulfonyl-2-phenyl-4-(4-methylphenyl)-1,3-oxazolane.

5124
D.J. Michaelis et al. / Tetrahedron 65 (2009) 5118–5124
22
22
520–521; (d) Crowley, B. M.; Mori, Y.; McComas, C. C.; Tang, D.; Boger, D. L.
J. Am. Chem. Soc. 2004, 126, 4310–4317.
5. (a) Noack, M.; Go¨ttlich, R. Chem. Commun. 2002, 536–537; (b) Chikkanna, D.;
Han, H. Synlett 2004, 2311–2314; (c) Mahoney, J. M.; Smith, C. R.; Johnston, J. N.
J. Am. Chem. Soc. 2005, 127, 1354–1355; (d) Alexanian, E. J.; Lee, C.; Sorensen, E. J.
J. Am. Chem. Soc. 2005, 127, 7690–7691; (e) Szolcsa´nyi, P.; Gracza, T. Chem.
Yield: 0.088 g, 68%. [
a
]
þ22.8 (c 1.85, CHCl3) [lit. [
a
]
þ37.5 (c
D
D
0.47, CHCl3)].15
Acknowledgements
´
Commun. 2005, 3948–3950; (f) Correa, A.; Tellitu, I.; Domınguez, E.; SanMartin,
This paper is dedicated to Prof. Michael Krische, recipient of this
year’s Tetrahedron Young Investigator Award, in recognition of his
many creative contributions to synthetic methodology. Funding for
this research has been provided by the NIH (National Institute of
General Medical Sciences: R01-GM084022). D.J.M. was supported
by fellowships from the NIH (CBI Training Grant GM08505) and the
American Chemical Society. The NMR spectroscopy facility at UW–
Madison is funded by the NIH (S10-RR04981-01) and NSF (CHE-
9629688).
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References and notes
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