Enantioselective Synthesis of Dialkylated α-Hydroxy Carboxylic Acids through Asymmetric Phase-Transfer Catalysis

Article abstract of DOI:10.1021/acs.joc.5b01081

In the presence of an L-tert-leucine-derived urea-ammonium salt as phase-transfer catalyst, a highly enantioselective alkylation of 5H-oxazol-4-ones with various benzyl bromides and allylic bromides has been developed to furnish catalytic asymmetric synthesis of biologically important dialkylated α-hydroxy carboxylic acids with a broad scope. This is the first example of an L-amino acid-derived urea-ammonium salt being used as a phase-transfer catalyst with excellent catalytic efficiency.

Full text of DOI:10.1021/acs.joc.5b01081

Note
pubs.acs.org/joc
Enantioselective Synthesis of Dialkylated α‑Hydroxy Carboxylic Acids
through Asymmetric Phase-Transfer Catalysis
Shaobo Duan,†,¶ Sanliang Li,†,¶ Xinyi Ye,‡ Nuan-Nuan Du,† Choon-Hong Tan,†,‡ and Zhiyong Jiang*,†
†Key Laboratory of Natural Medicine and Immuno-Engineering of Henan Province, Henan University, Kaifeng, Henan 475004, P. R.
China
‡Division of Chemistry and Biological Chemistry, Nanyang Technological University, 21 Nanyang Link 637371, Singapore
S
* Supporting Information
ABSTRACT: In the presence of an L-tert-leucine-derived urea−ammonium salt as phase-transfer catalyst, a highly
enantioselective alkylation of 5H-oxazol-4-ones with various benzyl bromides and allylic bromides has been developed to
furnish catalytic asymmetric synthesis of biologically important dialkylated α-hydroxy carboxylic acids with a broad scope. This is
the first example of an L-amino acid-derived urea−ammonium salt being used as a phase-transfer catalyst with excellent catalytic
efficiency.
I,1a and α-ethyl-α-benzyl HCA has been demonstrated as a
nantiomeric pure dialkylated α-hydroxy carboxylic acids
E(HCAs), containing a tertiary hydroxy stereogenic center precursor to produce compound II with significant hypolidemic
activity.1b α-Methyl-α-allyl HCA has been successfully
and an easily modified carboxylic acid, are versatile and
employed as a key motif to accomplish asymmetric total
synthesis of alkaloid (−)-aphanorphine (III).1c Furthermore,
α,α-dibenzyl HCAs are found as the main frameworks of
bioactive non-natural products IV and V and the side chain of
natural product VI (cephalotaxine ester).1d−f In this context,
stereoselective construction of these valuable entities has
attracted numerous interest of chemists over the past few
decades. To date, several efficient protocols,1b,c,2,3 including
kinetic resolution2 and the employment of chiral auxiliaries,1c,3
have been described. However, a catalytic asymmetric variant
still remains elusive.1b
powerful intermediates to access various chiral molecules with
biological importance.1 For example (Figure 1), α-methyl-α-
benzyl HCA can be conveniently transformed to microbicide
In 2004, the Trost group4 creatively introduced 5H-oxazol-4-
ones as α-alkyl-α-hydroxy ester surrogates in an asymmetric
allylic alkylation, leading to a convenient pathway to furnish
asymmetric synthesis of HCAs. Since then, 5H-oxazol-4-ones
have been utilized as nucleophiles in a variety of asymmetric
reactions to provide various HCA derivatives with biological
targets. For instance, in 2010, Misaki, Sugimura, and co-workers
presented a chiral guanidine-catalyzed aldol reaction of 5H-
Received: May 13, 2015
Figure 1. Representative dialkylated HCAs.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b01081
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The Journal of Organic Chemistry
Note
oxazol-4-ones to afford α-methyl-α,β-dihydroxy esters.5a
Subsequently, the same research group described an asym-
metric 1,4-addition of 5H-oxazol-4-ones to alkynyl carbonyl
compounds, and the obtained adducts could be conveniently
converted to γ,γ-disubstituted butenolides.5b Ye et al. revealed
an asymmetric Michael addition of 5H-oxazol-4-ones to α,β-
unsaturated ketones.6 To achieve highly stereoselective syn-
thesis of α-alkylisoserine derivatives, Wang7a and our7b groups
individually accomplished asymmetric Mannich reactions of
5H-oxazol-4-ones.6 Other well-established examples include
1,4-conjugate addition to nitroolefins,8a,b vinyl sulfones8c and
enones,8d transition metal-catalyzed allylic alkylation,8e and α-
sulfenylation.8f Nevertheless, to the best of our knowledge,
asymmetric phase-transfer alkylation and allylic alkylation of
5H-oxazol-4-ones, which can produce the desirable chiral
dialkylated HCAs, has never been reported and represents a
formidable task for their easily hydrolyzed imide groups under
basic conditions. As an extension of our recent interest in
developing organocatalytic asymmetric methodologies to
construct chiral tertiary alcohols,7b,8b,c,f,9 especially through
exploring 5H-oxazol-4-one paticipating highly stereoselective
asymmetric reactions,7b,8b,c,f we report here an unprecedented
enantioselective alkylation of 5H-oxazol-4-ones through asym-
metric phase-transfer catalysis to provide chiral dialkylated
HCAs in satisfactory yields.
In our initial study, alkylation of 5H-oxazol-4-one 1a and
benzyl bromide 2a was chosen as the model reaction to probe
the feasible reaction conditions (Table 1). First, the reaction
was carried out at 25 °C with 5.0 equiv of Cs2CO3 as base and
employing 10 mol % of L-tert-leucine-derived thiourea−tertiary
amine A (Figure 2) as catalyst, whose efficacy has been verified
by our group and others.8b,9,10 It was discovered that the
desired alkylation product 3a was obtained in 33% yield after
35 h with 40% ee (entry 1). In 2013, Zhao and co-workers
developed L-α-amino acid-derived thiourea−ammonium salts
as novel phase-transfer catalysts (PTCs) to successively address
asymmetric aza-Henry reactions and the addition of mercaptans
to imines in high enantioselectivities.11 These achievements
prompted us to attempt thiourea−ammonium B as PTC, but
product 3a with only 5% ee was achieved (entry 2). Although
no success has yet been established utilizing L-amino acid-
derived thiourea−ammonium salts as a catalyst, we still looked
forward to improving the enantioselectivity through modifying
the brønsted acid moiety of the catalyst. Thus, urea−
ammonium salt C was evaluated, and to our delight, the
enantioselectivity was dramatically improved (75% ee, entry 3).
Subsequently, we evaluated urea−ammonium salts D and E
derived from other L-α-amino acids, but their distinct side
chains could not give better results (entries 4 and 5). Catalyst
F, featuring a pyrrolidine-formed ammonium salt, could slightly
improve the ee value of 3a to 77% (entry 6). A screening of
solvents (entries 7−10) proved that cyclopentyl methyl ether
(CPME) was the best (entry 10). When K3PO4 was utilized as
base, 3a with 81% ee was achieved (entry 11). The lower
temperature was found to improve the enantioselectivity
(entries 12−13), and the ee value of 3a reached 87% when
the temperature was 0 °C (entry 13).
a
Table 1. Optimization of Reaction Conditions
b
c
d
entry
1
cat.
solvent
T (h)
yield (%)
ee (%)
1
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
A
B
C
D
E
F
F
F
F
F
F
F
F
F
F
F
F
G
H
I
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
Et2O
35
35
35
35
35
35
35
35
35
35
35
72
72
72
48
24
24
24
24
24
17
48
17
24
24
33
54
47
48
42
50
37
32
55
51
56
48
43
40
34
63
71
67
60
63
60
71
63
50
57
40
5
2
3
75
73
70
77
62
69
79
80
81
85
87
90
88
88
85
79
86
86
91
91
67
81
85
4
5
6
7
8
9
MTBE
CPME
CPME
CPME
CPME
CPME
CPME
CPME
CPME
CPME
CPME
CPME
CPME
CPME
CPME
CPME
CPME
10
11
12
13
14
e
15
f
16
g
17
f
18
f
19
f
20
f
21
J
f
22
K
L
M
N
f
23
f
24
f
25
a
Unless otherwise noted, the reaction was carried out with 0.05 mmol
of 1, 0.25 mmol of 2a (5.0 equiv), 0.25 mmol of base, and 0.005 mol of
catalyst in 0.5 mL of solvent. Entries 1−10, Cs2CO3 was used as base;
entries 11−26, K3PO4 was used as base. Entries 1−11, T = 25 °C;
entry 12, T = 10 °C; entries 13−26 T = 0 °C. Entries 1−13, 3a was
product; entries 14−26, 3b was product. The reaction time was
determined on TLC analysis until 1 was exhausted. Isolated yield after
b
c
d
silica gel column chromatography. Determined by HPLC analysis.
Used 10.0 equiv of 2a. Used 15.0 equiv of 2a. Used 20.0 equiv of 2a.
e
f
g
group at the meta position of the phenyl ring, could be obtained
with the best enantioselectivity (90% ee, entry 14). Although
excellent enantioselectivity was obtained, 40% yield of 3b
prompted us to improve the reactivity by increasing the amount
of 2a (entries 15−17). The survey indicated that 15.0 equiv of
benzyl bromide 2a could produce 3b in moderate yield with
slightly decreased ee value (entry 16). We then examined other
PTCs (entries 18−24), such as G−I bearing different benzyl
groups on ammonium moieties (entries 18−20) and J−M with
different urea substituents (entries 21−24); catalyst K was
observed to present the best results, affording product 3a in
71% yield with 91% ee within 48 h (entry 22). Disappointingly,
urea−tertiary amine N, the precursor of K, could not contribute
a better enantioselective result than K (entry 26), representing
an opposite stereoselective tendency compared to thiourea−
tertiary amine A and thiourea−ammonium salt B (entries 1−2).
With the optimized reaction conditions in hand, we
examined the reaction scope, and the results are summarized
in Table 2. First, we attempted enantioselective alkylation of
5H-oxazol-4-one 1b with a variety of benzyl bromides in the
presence of 10 mol % of catalyst K at 0 °C and in CPME as
Our previous investigations indicated that the aryl group on
the 2-position of 5H-oxazol-4-ones often affects the enantio-
selective outcomes.8b,f Therefore, a series of 5H-oxazol-4-ones
were tested under the established reaction conditions (see the
Supporting Information for details). It was found that the
alkylation product 3b, from 5H-oxazol-4-one 1b with a fluoro
B
DOI: 10.1021/acs.joc.5b01081
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The Journal of Organic Chemistry
Note
Table 2. Asymmetric Alkylation of 5H-oxazol-4-ones 1 to
a
Various Benzyl Bromides 2
Figure 2. Structures of catalysts (A−N) and 5H-oxazol-4-ones (1a−
g).
solvent (Table 2, entries 1−14). The corresponding products
3b−o were obtained in 62−80% yield with 87−93% ee within
44−72 h. Next, 5H-oxazol-4-ones 1c−e were subjected to
alkylation with benzyl bromide 2a, producing adducts 3p−r
with slightly decreased ee values (entry 15, 83−87% ee),
probably due to less steric hindrance of methyl, ethyl, and n-
butyl on the 5-position of 5H-oxazol-4-ones.
Subsequently, we engaged in surveying alkylations of 5-
benzyl-substituted 5H-oxazol-4-one 1f to several benzyl
bromides to access the intriguing but challenging chiral
dibenzylated HCAs (Table 2, entries 16−22). It was found
that the corresponding products 3s−y were achieved in 71−
82% yields with good to excellent enantioselectivities.
Importantly, ee values of 3t−w and 3y could be improved to
90 to >99% ee after a single recrystallzation.
Then, 5H-oxazol-4-one 1g, bearing a meta-methyl-substituted
phenyl group on the 2-position was reacted respectively with
allylic bromide, crotyl bromide, and 3-methylcrotyl bromide
under the established reaction conditions (Scheme 1); three
corresponding allylic alkylation products 5a−c were obtained in
61−87% yields with 87−91% ee within 41−78 h. The absolute
configurations of alkylation products 3 and allylic alkylation
products 5 were assigned based on X-ray crystallographic
analysis of a single crystal of 3t (Table 2, entry 17).12
To elucidate the enantioselective outcome of this asymmetric
alkylation, a favored transition-state model is proposed as
shown in Figure 3 (left). After abstraction of 5-hydrogen from
5H-oxazol-4-ones, the formed enolates of 5H-oxazol-4-ones
should bind to the R4N+ arm of the catalyst via electrostatic
interaction. The better enantioselectivity of urea catalyst than
thiourea catalyst indicates that urea would simultaneously
interact with the enolate of 5H-oxazol-4-one via hydrogen
bonding for its higher acidity and the reasonably longer N−H
bond. Then, the tert-butyl group of the catalyst would produce
steric hindrance to the 5-substituent of 5H-oxazol-4-one (see
disfavored transition state, Figure 2, right), which finally affords
the obtained alkylated products with the observed enantiose-
lective results. In light of bulkier substituents on the 5-position
a
All reactions were carried out with 0.1 mmol of 1, 1.5 mmol of 2, 0.5
mmol of K3PO4, and 0.01 mmol of catalyst K in 1.0 mL of CPME at 0
°C. Isolated yields. Ee values were determined by chiral HPLC
analysis. Used 10 mol % of catalyst F. The ee values were obtained
after a single recrystallization. Initial data: 3t: ee = 85%; 3u: ee = 85%;
3v: ee = 89%; 3w: ee = 85%; 3y: ee = 84%.
b
c
of 5H-oxazol-4-ones yielding better enantioselective results, the
devised transition-state model can be further demonstrated.
To exhibit the synthetic utility of this work, we explored
several transformations from alkylation products (Scheme 2).
First, the hydrolysis of 3s employing NaOH as the base
smoothly afforded amide 6 in 86% yield (Scheme 2, eq 1).
Then, amide 6 was able to be reduced to amine 7 in 81% yield
without compromising the ee value. It is worth mentioning that
both chiral dibenzylated α-hydroxyl amides and dibenzylated α-
hydroxyl amines are significant structural motifs presenting in
C
DOI: 10.1021/acs.joc.5b01081
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The Journal of Organic Chemistry
Note
Scheme 1. Enantioselective Allylic Alkylation of 5H-oxazol-
Scheme 2. Transformations of Alkylation Products
4-one 1g
many biologically active molecules.13 Subsequently, through the
sequence of hydroxylation by NaOH, acidification, and
esterification, adduct 3x was transformed to ester 9 in 67%
yield with maintained enantiomeric purity (Scheme 2, eq 2).
Obviously, this strategy could be readily adopted in asymmetric
synthesis of fungicide IV.
In summary, we have developed a highly enantioselective
catalytic synthesis of dialkylated HCAs with a broad scope. By
employing an L-tert-leucine-derived urea−ammonium salt as
phase-transfer catalyst, 5H-oxazol-4-ones could work with
various benzyl bromides and allylic bromides to afford the
biologically important alkylated and allylic alkylated adducts
with 83 to >99% ee. This is the first successful example
demonstrating the excellent catalytic efficiency of L-amino acid-
derived urea−ammonium salts. We believe that this work
should help to further develop novel L-amino acid-based
bifunctional PTCs to deal with challenging and unprecedented
reactions.
(S)-1-Benzyl-1-(2-(3-(3,5-bis(trifluoromethyl)phenyl)thioureido)-
3,3-dimethylbutyl)piperidin-1-ium Bromide (B). White powder; mp
179.0−181.3 °C; 204 mg (0.5 mmol), 65.3% yield (final step); H
1
NMR (400 MHz, CDCl3) δ 9.49 (s, 1H), 7.51−7.49 (m, 3H), 7.31 (t,
J = 7.4 Hz, 2H), 7.23 (d, J = 7.3 Hz, 1H), 7.12 (s, 2H), 6.55 (d, J = 9.5
Hz, 1H), 4.79 (d, J = 14.1 Hz, 1H), 4.61 (s, 1H), 4.39 (d, J = 14.1 Hz,
1H), 4.08 (d, J = 12.8 Hz, 1H), 3.73 (d, J = 12.0 Hz, 1H), 3.59 (s, 1H),
2.84 (s, 1H), 2.72 (d, J = 10.7 Hz, 2H), 2.45 (d, J = 12.3 Hz, 1H), 1.98
(d, J = 8.0 Hz, 4H), 1.50 (s, 1H), 0.82 (s, 9H); 13C NMR (75 MHz,
CDCl3) δ 182.0, 155.4, 150.7, 140.9, 135.8, 132.6, 132.2, 131.8, 131.3,
128.9 (two peaks), 127.7, 125.2, 122.7, 122.4, 121.6, 117.9 (two
peaks), 116.0, 57.7, 56.1, 55.3, 53.9, 35.7, 35.4, 26.6, 26.2, 23.3, 22.1,
21.7; HRMS (ESI) m/z 546.2372 (M − Br−), calcd for C27H34F6N3S
546.2378.
EXPERIMENTAL SECTION
■
General Procedure. 5H-Oxazol-4-ones 1 (0.1 mmol, 1.0 equiv),
urea−ammonium salt K (6.2 mg, 0.01 mmol, 0.1 equiv) and K3PO4
(0.5 mmol, 5.0 equiv) were dissolved in CPME (1.0 mL) in a 4.0 mL
sample vial and stirred at 0 °C for 30 min. Then, benzyl bromide 2
(1.5 mmol, 15.0 equiv) was added. The reaction mixtures were stirred
and maintained at 0 °C, and the reaction progress was monitored by
TLC. Upon complete consumption of 1, the reaction mixtures were
directly loaded onto a short silica gel column, followed by separation
with flash chromatography using gradient elution with petroleum
ether/ethyl acetate (15:1 to 8:1). After removal of solvent under
vacuum, corresponding adducts 3 were obtained.
(S)-1-Benzyl-1-(2-(3-(3,5-bis(trifluoromethyl)phenyl)ureido)-3,3-
dimethylbutyl)piperidin-1-ium Bromide (C). White powder; mp
1
129.8−131.2 °C; 233 mg (0.5 mmol), 76.5% yield (final step); H
NMR (300 MHz, CDCl3) δ 9.64 (s, 1H), 8.07 (s, 2H), 7.87 (d, J = 9.8
Hz, 1H), 7.55−7.41 (m, 6H), 4.89 (d, J = 13.0 Hz, 1H), 4.80 (d, J =
13.0 Hz, 1H), 4.26 (t, J = 9.7 Hz, 1H), 4.08−4.00 (m, 2H), 3.83−3.68
Figure 3. Proposed reaction mechanism.
D
DOI: 10.1021/acs.joc.5b01081
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The Journal of Organic Chemistry
Note
(m, 2H), 3.24−3.07 (m, 2H), 2.16 (s, 3H), 1.92 (s, 3H), 1.09 (s, 9H);
13C NMR (75 MHz, CDCl3) δ 155.7, 141.3, 133.5, 132.0, 131.6, 131.1
8.15 (s, 2H), 8.04 (s, 2H), 8.01 (s, 1H), 7.72 (d, J = 9.8 Hz, 1H), 7.42
(s, 1H), 5.21 (d, J = 13.4 Hz, 1H), 5.10 (d, J = 13.4 Hz, 1H), 4.38−
4.32 (m, 1H), 4.26−4.13 (m, 2H), 4.09−4.00 (m, 1H), 3.69−3.65 (m,
1H), 3.47−3.38 (m, 2H), 2.50−2.33 (m, 2H), 2.29−2.17 (m, 2H),
1.09 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 155.9, 141.0, 133.9,
133.4, 133.1 (three peaks), 132.6, 132.1, 131.7, 131.2, 130.1, 125.0
(two peaks), 124.3, 121.5, 120.7, 118.0, 115.4, 62.5, 61.6, 61.0, 60.5,
53.4, 36.3, 26.4 (two peaks), 21.1, 20.6; HRMS (ESI) m/z 652.2194
(M − Br−), calcd for C28H30F12N3O 652.2197.
(d, J = 10.5 Hz), 129.4, 128.8, 126.4, 125.2, 121.6, 118.0, 115.1, 66.7,
60.2, 57.3 (two peaks), 52.4, 36.7, 26.5, 20.8, 20.3 (two peaks); HRMS
(ESI) m/z 530.2601 (M − Br−), calcd for C27H34F6N3O 530.2606.
(S)-1-Benzyl-1-(2-(3-(3,5-bis(trifluoromethyl)phenyl)ureido)-3-
methylbutyl)piperidin-1-ium Bromide (D). White powder; mp
1
203.5−205.9 °C; 245 mg (0.5 mmol), 82.3% yield (final step); H
NMR (300 MHz, CDCl3) δ 9.64 (s, 1H), 8.06 (s, 2H), 7.86 (d, J = 9.7
Hz, 1H), 7.52−7.41 (m, 6H), 4.87 (d, J = 13.1 Hz, 1H), 4.79 (d, J =
13.1 Hz, 1H), 4.46−4.43 (m, 1H), 3.99−3.82 (m, 3H), 3.43−3.22 (m,
3H), 2.14 (d, J = 13.4 Hz, 2H), 1.94 (s, 4H), 1.52−1.40 (m, 1H), 1.06
(t, J = 6.2 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 155.7, 141.2, 133.2,
132.3, 131.9, 131.6, 131.2 (d, J = 37.2 Hz), 129.4, 128.7, 126.2, 125.1,
121.5, 117.9, 114.9, 65.7, 60.8, 58.5, 58.0, 48.8, 33.38, 20.7, 20.2 (two
peaks), 19.5, 17.1; HRMS (ESI) m/z 516.2446 (M − Br−), calcd for
C26H32F6N3O 516.2449.
(S)-1-Benzyl-1-(2-(3-(3,5-dichlorophenyl)ureido)-3,3-
dimethylbutyl)pyrrolidin-1-ium Bromide (J). White powder; mp
1
207.0−209.2 °C; 176 mg (0.5 mmol), 66.8% yield (final step); H
NMR (300 MHz, CD3OD_SPE) δ 7.91 (s, 1H), 7.65−7.63 (m, 2H),
7.57−7.53 (m, 3H), 7.49 (d, J = 1.8 Hz, 2H), 7.03 (t, J = 1.7 Hz, 1H),
4.72 (d, J = 13.3 Hz, 1H), 4.65 (d, J = 13.3 Hz, 1H), 4.35 (d, J = 9.3
Hz, 1H), 3.71−3.45 (m, 6H), 2.21−2.01 (m, 4H), 1.03 (s, 9H); 13C
NMR (75 MHz, CD3OD_SPE) δ 155.6, 141.7, 134.8, 132.7, 130.5,
129.2, 128.0, 121.6, 116.4, 78.1, 62.9, 61.8, 61.1, 60.8, 52.9, 35.9, 25.0,
21.2, 20.5; HRMS (ESI) m/z 448.1918 (M − Br−), calcd for
C24H32Cl2N3O 448.1922.
(S)-1-Benzyl-1-(2-(3-(3,5-bis(trifluoromethyl)phenyl)ureido)-2-
cyclohexylethyl)piperidin-1-ium Bromide (E). White powder; mp
1
101.9−103.2 °C; 199 mg (0.5 mmol), 62.5% yield (final step); H
NMR (300 MHz, CDCl3) δ 9.60 (s, 1H), 8.00 (s, 2H), 7.77 (d, J = 9.6
Hz, 1H), 7.46−7.34 (m, 6H), 4.82 (d, J = 13.1 Hz, 1H), 4.71 (d, J =
13.1 Hz, 1H), 4.37−4.35 (m, 1H), 3.92 (dd, J = 13.9, 10.3 Hz, 1H),
3.76 (d, J = 9.3 Hz, 2H), 3.36 (d, J = 14.2 Hz, 1H), 3.23−3.16 (m,
2H), 2.10−2.06 (m, 1H), 1.86 (s, 3H), 1.75−1.65 (m,5H), 1.54−1.51
(m, 2H), 1.37−1.24 (m, 2H), 1.17−1.00 (m, 4H); 13C NMR (75
MHz, CDCl3) δ 155.6, 141.3, 133.3, 132.5, 132.0, 131.6, 131.1, 129.5,
126.3, 125.2, 121.6, 118.0, 115.0, 65.8, 61.1, 58.2 (two peaks), 48.8,
43.4, 29.8, 27.6, 25.9 (two peaks), 20.8, 20.2 (two peaks); HRMS
(ESI) m/z 556.2758 (M − Br−), calcd for C29H36F6N3O 556.2762.
(S)-1-benzyl-1-(2-(3-(3,5-bis(trifluoromethyl)phenyl)ureido)-3,3-
dimethylbutyl)pyrrolidin-1-ium bromide (F). White powder; mp
(S)-1-Benzyl-1-(2-(3-(3,5-dibromophenyl)ureido)-3,3-
dimethylbutyl)pyrrolidin-1-ium Bromide (K). White powder; mp
1
205.9−208.2 °C; 237 mg (0.5 mmol), 76.9% yield (final step); H
NMR (300 MHz, CDCl3) δ 9.34 (s, 1H), 7.84 (d, J = 10.0 Hz, 1H),
7.75 (s, 2H), 7.57−7.43 (m, 5H), 7.22 (s, 1H), 4.79 (d, J = 13.3 Hz,
1H), 4.58 (d, J = 13.3 Hz, 1H), 4.38 (t, J = 9.7 Hz, 1H), 4.07 (s, 1H),
3.92−3.70 (m, 2H), 3.62−3.41 (m, 3H), 2.44−2.18 (m, 2H), 2.07 (s,
2H), 1.05 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 155.7, 142.0, 132.7,
131.2, 129.7, 127.3, 127.0, 122.7, 119.9, 62.2 (two peaks), 61.7, 61.1,
53.0, 36.3, 26.6, 21.5, 20.5; HRMS (ESI) m/z 536.0908 (M − Br−),
calcd for C24H3279Br2N3O 536.0912.
(S)-1-Benzyl-1-(2-(3-(3,5-dimethoxyphenyl)ureido)-3,3-
dimethylbutyl)pyrrolidin-1-ium Bromide (L). White powder; mp
83.5−85.9 °C; 199 mg (0.5 mmol), 76.9% yield (final step); 1H NMR
(300 MHz, CDCl3) δ 8.94 (s, 1H), 7.71 (d, J = 10.0 Hz, 1H), 7.47 (dt,
J = 13.4, 6.9 Hz, 5H), 6.83 (d, J = 2.2 Hz, 2H), 6.09 (t, J = 2.2 Hz,
1H), 4.81 (d, J = 13.3 Hz, 1H), 4.60 (d, J = 13.3 Hz, 1H), 4.38 (t, J =
9.8 Hz, 1H), 4.11−3.98 (m, 1H), 3.91−3.80 (m, 1H), 3.78−3.66 (m,
7H), 3.58−3.45 (m, 3H), 2.34 (s, 1H), 2.18 (s, 1H), 2.08−1.95 (m,
1H), 1.05 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 161.0, 156.0, 141.5,
132.8, 131.0, 129.5, 127.2, 96.8, 95.1, 62.5, 62.1, 61.2 (two peaks),
55.4, 52.9, 36.3, 26.6, 21.5, 20.6; HRMS (ESI) m/z 440.2908 (M −
Br−), calcd for C26H38N3O3 440.2913.
1
102.3−104.5 °C; 212 mg (0.5 mmol), 71.4% yield (final step); H
NMR (300 MHz, CDCl3) δ 9.67 (s, 1H), 8.08 (s, 2H), 7.80 (d, J = 9.3
Hz, 1H), 7.52−7.41 (m, 6H), 4.80 (d, J = 12.8 Hz, 1H), 4.62 (d, J =
12.8 Hz, 1H), 4.47−4.31 (m, 1H), 4.15−4.02 (m, 1H), 3.98−3.74 (m,
2H), 3.67−3.42 (m, 3H), 2.38 (s, 2H), 2.05 (s, 2H), 1.06 (s, 9H); 13C
NMR (75 MHz, CDCl3) δ 155.8, 141.3, 132.8, 132.6 (two peaks),
132.0, 131.6, 131.2, 129.6, 127.0, 125.2, 121.6, 118.0, 115.1, 62.3 (two
peaks), 61.4, 61.0, 53.1, 36.3, 26.5, 21.5, 20.6; HRMS (ESI) m/z
516.2446 (M − Br−), calcd for C26H32F6N3O 516.2449.
(S)-1-(2-(3-(3,5-Bis(trifluoromethyl)phenyl)ureido)-3,3-dimethyl-
butyl)-1-(4-(trifluoromethyl)benzyl)pyrrolidin-1-ium Bromide (G).
White powder; mp 115.3−117.1 °C; 241 mg (0.5 mmol), 72.8%
yield (final step); 1H NMR (300 MHz, CDCl3) δ 9.64 (s, 1H), 8.00 (s,
2H), 7.71−7.62 (m, 5H), 7.37 (s, 1H), 4.91−4.80 (m, 2H), 4.27 (t, J =
10.0 Hz, 1H), 4.03−3.86 (m, 3H), 3.54−3.40 (m, 3H), 2.30−2.23 (m,
1H), 2.20−2.14 (m, 1H), 2.02 (s, 2H), 1.01 (s, 9H); 13C NMR (75
MHz, CDCl3) δ 155.8, 141.2, 133.5, 133.0, 132.5, 132.1, 131.6, 131.1
(two peaks), 126.4 (two peaks), 125.1, 121.5, 117.9, 115.2, 62.2, 61.8,
61.5, 60.4, 53.3, 36.3, 26.4, 21.2, 20.6; HRMS (ESI) m/z 584.2320 (M
− Br−), calcd for C27H31F9N3O 584.2323.
(S)-1-(2-(3-(3,5-Bis(trifluoromethyl)phenyl)ureido)-3,3-dimethyl-
butyl)-1-(2-(trifluoromethyl)benzyl)pyrrolidin-1-ium Bromide (H).
White powder; mp 96.8−98.4 °C; 251 mg (0.5 mmol), 75.6% yield
(final step); 1H NMR (300 MHz, CDCl3) δ 9.55 (s, 1H), 8.05 (d, J =
11.5 Hz, 3H), 7.85 (d, J = 6.2 Hz, 1H), 7.80−7.77 (m, 1H), 7.63 (p, J
= 8.0 Hz, 2H), 7.43 (s, 1H), 5.21 (d, J = 14.2 Hz, 1H), 5.11 (d, J =
14.2 Hz, 1H), 4.33−4.21 (m, 2H), 4.16−4.11 (m, 1H), 4.04−3.96 (m,
1H), 3.69 (d, J = 13.7 Hz, 1H), 3.29−3.22 (m, 1H), 3.16−3.10 (m,
1H), 2.44−2.37 (m, 1H), 2.25−2.15 (m, 1H), 2.08−1.95 (m, 2H),
1.13 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 155.6, 141.2, 136.1, 132.6
(two peaks), 132.0, 131.5 (two peaks), 128.0 (two peaks), 125.2 (three
peaks), 118.1, 63.7, 60.5 (two peaks), 53.3, 36.4, 26.4, 20.8 (two
peaks); HRMS (ESI) m/z 584.2319 (M − Br−), calcd for
C27H31F9N3O 584.2323.
(S)-1-Benzyl-1-(2-(3-(3,5-di-tert-butylphenyl)ureido)-3,3-
dimethylbutyl)pyrrolidin-1-ium Bromide (M). White powder; mp
1
198.4−201.2 °C; 161 mg (0.5 mmol), 56.5% yield (final step); H
NMR (300 MHz, CDCl3) δ 8.60 (s, 1H), 7.76 (d, J = 9.6 Hz, 1H),
7.52 (t, J = 7.2 Hz, 2H), 7.45−7.39 (m, 5H), 7.05 (s, 1H), 4.82 (d, J =
13.2 Hz, 1H), 4.65 (d, J = 13.2 Hz, 1H), 4.43−4.36 (m, 1H), 4.11 (s,
1H), 3.88−3.80 (m, 2H), 3.63−3.50 (m, 3H), 2.37 (s, 1H), 2.21 (s,
1H), 1.99 (s, 2H), 1.29 (s, 18H), 1.07 (s, 9H); 13C NMR (75 MHz,
CDCl3) δ 156.1, 151.2, 139.0, 132.9, 131.0, 129.5, 127.3, 116.5, 113.5,
62.4, 60.9 (two peaks), 52.8, 36.3, 34.9, 31.9, 31.5, 29.7, 29.4, 26.6,
22.7, 21.5, 20.7, 14.1; HRMS (ESI) m/z 492.3951 (M − Br−), calcd
for C32H50N3O 492.3954.
(S)-1-(3,5-Dibromophenyl)-3-(3,3-dimethyl-1-(pyrrolidin-1-yl)-
butan-2-yl)urea (N). White powder; mp 175.5−177.5 °C; 154 mg
1
(0.5 mmol), 68.9% yield (final step); H NMR (300 MHz, CDCl3) δ
7.47 (s, 2H), 7.19 (s, 1H), 5.11 (s, 1H), δ 3.46 (s, 1H), 3.28 (s, 1H),
2.80−2.56 (m, 6H), 1.86 (s, 4H), 0.98 (s, 9H); 13C NMR (75 MHz,
CDCl3) δ 156.8, 142.6, 127.1, 122.8, 120.4, 59.4, 54.4, 34.0, 26.6, 23.6;
HRMS (ESI) m/z 446.0438 (M + H+), calcd for C17H2679Br2N3O
446.0443.
(R)-(+)-5-Benzyl-2-(3-fluorophenyl)-5-isopropyloxazol-4(5H)-one
(3b). Colorless oil; 22 mg (0.1 mmol), 71% yield; 91% ee; [α]D22
1
+39.23 (c 0.50, CHCl3); H NMR (300 MHz, CDCl3) δ 7.86 (d, J =
7.7 Hz, 1H), 7.75−7.71 (m, 1H), 7.46 (td, J = 8.0, 5.5 Hz, 1H), 7.34
(ddd, J = 10.1, 5.5, 1.7 Hz, 3H), 7.15−7.11 (m, 5H), 3.32 (d, J = 13.9
Hz, 1H), 3.20 (d, J = 13.9 Hz, 1H), 2.37−2.28 (m, 1H), 1.14 (d, J =
6.9 Hz, 3H), 1.05 (d, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
(S)-1-(3,5-Bis(trifluoromethyl)benzyl)-1-(2-(3-(3,5-bis-
(trifluoromethyl)phenyl)ureido)-3,3-dimethylbutyl)pyrrolidin-1-ium
Bromide (I). White powder; mp 214.5−216.2 °C; 300 mg (0.5 mmol),
82.1% yield (final step); 1H NMR (300 MHz, CDCl3) δ 9.66 (s, 1H),
E
DOI: 10.1021/acs.joc.5b01081
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
192.5, 184.3, 164.2, 160.9, 133.4, 130.6 (d, J = 7.9 Hz), 130.0, 128.3,
127.7 (d, J = 8.2 Hz), 127.3, 125.6 (d, J = 3.1 Hz), 122.0, 121.7, 116.5,
116.2, 94.3, 39.8, 34.0, 16.6 (d, J = 2.4 Hz); HRMS (ESI) m/z
312.1408 (M + H+), calcd for C19H19FNO2 312.1400. The ee was
determined by HPLC analysis. CHIRALPAK IC (4.6 mm i.d. × 250
mm); hexane/2-propanol = 90:10; flow rate 1.0 mL/min; 25 °C; 254
nm; retention time, 11.0 min (major) and 13.0 min (minor).
(R)-(−)-5-(2-Bromobenzyl)-2-(3-fluorophenyl)-5-isopropyloxazol-
4(5H)-one (3c). Colorless oil; 24.5 mg (0.1 mmol), 63% yield; 93% ee;
[α]2D2 −41.41 (c 1.50, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.88 (d,
J = 7.8 Hz, 1H), 7.77−7.74 (m, 1H), 7.43 (td, J = 8.0, 5.5 Hz, 1H),
7.37 (d, J = 7.3 Hz, 1H), 7.31 (td, J = 8.3, 1.9 Hz, 1H), 7.19 (dd, J =
7.7, 1.5 Hz, 1H), 7.11 (dd, J = 10.8, 4.2 Hz, 1H), 6.94 (td, J = 7.8, 1.6
Hz, 1H), 3.81 (d, J = 13.8 Hz, 1H), 3.28 (d, J = 13.8 Hz, 1H), 2.42−
2.32 (m, 1H), 1.20 (d, J = 6.8 Hz, 3H), 1.06 (d, J = 6.9 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 192.9, 184.6, 163.7, 161.2, 133.3, 132.8,
131.5, 130.5 (d, J = 7.9 Hz), 129.0, 127.6, 127.4, 125.8, 122.2, 122.0
(d, J = 21.3 Hz), 116.7, 116.5, 94.3, 39.2, 34.3, 16.6; HRMS (ESI) m/z
392.0493 (M + H+), calcd for C19H1881BrFNO2 392.0484. The ee was
determined by HPLC analysis. CHIRALPAK IC (4.6 mm i.d. × 250
mm); hexane/2-propanol = 90:10; flow rate 1.0 mL/min; 25 °C; 254
nm; retention time, 9.0 min (major) and 11.2 min (minor).
(R)-(+)-2-(3-Fluorophenyl)-5-isopropyl-5-(2-(trifluoromethyl)-
benzyl)oxazol-4(5H)-one (3g). Colorless oil; 24 mg (0.1 mmol), 62%
yield; 93% ee; [α]2D2 +28.37 (c 1.00, CHCl3); H NMR (400 MHz,
1
CDCl3) δ 7.76 (t, J = 6.4 Hz, 1H), 7.65−7.62 (m, 1H), 7.50 (d, J = 7.9
Hz, 1H), 7.41 (td, J = 8.0, 5.5 Hz, 1H) 7.35−7.27 (m, 3H), 7.20 (t, J =
7.3 Hz, 1H), 3.81−3.78 (m, 1H), 3.36 (d, J = 14.4 Hz, 1H), 2.40−2.30
(m, 1H), 1.14 (d, J = 6.8 Hz, 3H), 1.06 (d, J = 6.9 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 193.4, 184.8, 163.7, 161.2, 132.0 (d, J = 15.1
Hz), 131.6, 130.6 (d, J = 7.8 Hz), 129.8, 129.5, 127.5, 127.2 (d, J = 8.2
Hz), 126.3 (d, J = 5.7 Hz), 125.5 (d, J = 3.1 Hz), 123.0, 122.2, 122.0,
116.6, 116.3, 93.7, 36.1, 34.8, 16.5 (d, J = 9.8 Hz); HRMS (ESI) m/z
402.1082 (M + Na+), calcd for C20H17F4NO2Na 402.1093. The ee was
determined by HPLC analysis. CHIRALPAK IC (4.6 mm i.d. × 250
mm); hexane/2-propanol = 90:10; flow rate 1.0 mL/min; 25 °C; 254
nm; retention time, 6.5 min (major) and 7.5 min (minor).
(R)-(+)-5-(3-Chlorobenzyl)-2-(3-fluorophenyl)-5-isopropyloxazol-
4(5H)-one (3h). Colorless oil; 27 mg (0.1 mmol), 77% yield; 90% ee;
[α]2D2 +73.47 (c 1.50, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.88 (d,
J = 7.8 Hz, 1H), 7.77−7.73 (m, 1H), 7.48 (td, J = 8.0, 5.5 Hz, 1H),
7.38−7.33 (m, 1H), 7.14 (s, 1H), 7.09 (td, J = 5.4, 2.2 Hz, 2H), 7.05−
7.01 (m, 1H), 3.30 (d, J = 13.9 Hz, 1H), 3.16 (d, J = 13.9 Hz, 1H),
2.31 (dq, J = 13.7, 6.9 Hz, 1H), 1.14 (d, J = 6.9 Hz, 3H), 1.04 (d, J =
6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 192.2, 184.3, 163.8,
161.3, 135.3, 134.0, 130.7 (d, J = 7.8 Hz), 130.2, 129.6, 128.1, 127.5,
125.6 (d, J = 3.1 Hz), 122.2, 122.1 (d, J = 21.3 Hz), 116.5, 116.3, 93.8,
39.4, 34.0, 16.6 (d, J = 2.9 Hz); HRMS (ESI) m/z 346.1012 (M + H+),
calcd for C19H18ClFNO2 346.1010. The ee was determined by HPLC
analysis. CHIRALPAK IA (4.6 mm i.d. × 250 mm); hexane/2-
propanol = 95:5; flow rate 0.5 mL/min; 25 °C; 254 nm; retention
time, 17.7 min (minor) and 19.1 min (major).
(R)-(+)-5-(3-Bromobenzyl)-2-(3-fluorophenyl)-5-isopropyloxazol-
4(5H)-one (3d). Colorless oil; 28 mg (0.1 mmol), 73% yield; 90% ee;
1
[α]2D2 +53.41 (c 1.50, CHCl3); H NMR (400 MHz, CDCl3) δ 7.89−
7.87 (m, 1H), 7.75 (ddd, J = 9.0, 2.4, 1.5 Hz, 1H), 7.49 (td, J = 8.0, 5.5
Hz, 1H), 7.36 (tdd, J = 8.3, 2.6, 0.9 Hz, 1H), 7.30 (d, J = 1.6 Hz, 1H),
7.26−7.25 (m, 1H), 7.24−7.22 (m, 1H), 7.04 (dt, J = 15.4, 7.7 Hz,
2H), 3.29 (d, J = 13.9 Hz, 1H), 3.15 (d, J = 13.9 Hz, 1H), 2.32 (dt, J =
13.7, 6.8 Hz, 1H), 1.14 (d, J = 6.9 Hz, 3H), 1.04 (d, J = 6.9 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 192.2, 184.3, 163.8, 161.38, 135.68,
(R)-(+)-2-(3-Fluorophenyl)-5-isopropyl-5-(4-(trifluoromethyl)-
benzyl)oxazol-4(5H)-one (3i). Colorless oil; 27 mg (0.1 mmol), 70%
133.1, 130.6, 129.9, 128.5, 127.5 (d, J = 8.2 Hz), 125.6 (d, J = 3.2 Hz),
122.1, 116.5, 116.3, 93.8, 39.4, 33.9, 16.6 (d, J = 2.3 Hz); HRMS (ESI)
m/z 390.0508 (M + H+), calcd for C19H18BrFNO2 390.0505. The ee
was determined by HPLC analysis. CHIRALPAK IA (4.6 mm i.d. ×
250 mm); hexane/2-propanol = 95:5; flow rate 0.5 mL/min; 25 °C;
254 nm; retention time, 17.3 min (minor) and 19.1 min (major).
(R)-(+)5-(4-Bromobenzyl)-2-(3-fluorophenyl)-5-isopropyloxazol-
4(5H)-one (3e). Colorless oil; 29 mg (0.1 mmol), 76% yield; 88% ee;
yield; 91% ee; [α]2D2 +111.60 (c 1.50, CHCl3); H NMR (400 MHz,
1
CDCl3) δ 7.86 (d, J = 7.7 Hz, 1H), 7.73 (d, J = 8.9 Hz, 1H), 7.48 (m,
1H), 7.37 (m, 3H), 7.28 (s, 2H), 3.38 (d, J = 13.8 Hz, 1H), 3.25 (d, J =
13.8 Hz, 1H), 2.38−2.26 (m, 1H), 1.16 (d, J = 6.8 Hz, 3H), 1.05 (d, J
= 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 192.1, 184.4, 163.8,
161.3, 137.6, 130.8 (d, J = 7.8 Hz), 130.4, 129.8, 129.5, 127.4 (d, J =
8.2 Hz), 125.8, 125.4 (dd, J = 37.0, 3.4 Hz), 122.6, 122.3, 122.1, 116.4,
116, 93.8, 39.5, 34.2, 16.6 (d, J = 1.9 Hz); HRMS (EI) m/z 379.1198
(M+), calcd for C20H17F4NO2 379.1195. The ee was determined by
HPLC analysis. CHIRALPAK IC (4.6 mm i.d. × 250 mm); hexane/2-
propanol = 95:5; flow rate 0.5 mL/min; 25 °C; 254 nm; retention
time, 21.4 min (minor) and 23.0 min (major).
(R)-(+)-2-(3-Fluorophenyl)-5-isopropyl-5-(2-methylbenzyl)oxazol-
4(5H)-one (3j). Colorless oil; 22 mg (0.1 mmol), 68% yield; 91% ee;
[α]2D2 +67.91 (c 1.50, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.81 (d,
J = 7.7 Hz, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.44 (td, J = 8.0, 5.5 Hz,
1H), 7.32 (td, J = 8.3, 2.0 Hz, 1H), 7.08 (d, J = 6.9 Hz, 1H), 7.02−6.92
(m, 3H), 3.44 (d, J = 14.1 Hz, 1H), 3.25 (d, J = 14.1 Hz, 1H), 2.44−
2.29 (m, 4H), 1.19 (d, J = 6.8 Hz, 3H), 1.05 (d, J = 6.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 192.9, 184.2, 163.7, 161.2, 137.0, 131.8,
130.5 (dd, J = 19.0, 9.4 Hz), 127.7 (d, J = 8.4 Hz), 127.4, 125.9, 125.4
(d, J = 3.1 Hz), 121.9, 121.7, 116.4, 116.1, 94.7, 36.3, 34.4, 19.8, 16.7
(d, J = 2.0 Hz); HRMS (ESI) m/z 326.1566 (M + H+), calcd for
C20H21FNO2 326.1556. The ee was determined by HPLC analysis.
CHIRALPAK IC (4.6 mm i.d. × 250 mm); hexane/2-propanol =
90:10; flow rate 1.0 mL/min; 25 °C; 254 nm; retention time, 9.5 min
(major) and 13.1 min (minor).
[α]2D2 +121.45 (c 1.00, CHCl3); H NMR (400 MHz, CDCl3) δ 7.88
1
(d, J = 7.7 Hz, 1H), 7.77−7.74 (m, 1H), 7.49 (td, J = 8.0, 5.5 Hz, 1H),
7.37 (ddd, J = 8.3, 5.0, 1.8 Hz, 1H), 7.28 (dd, J = 4.8, 3.1 Hz, 2H), 7.02
(d, J = 8.4 Hz, 2H), 3.28 (d, J = 14.0 Hz, 1H), 3.16 (d, J = 14.0 Hz,
1H), 2.31 (m, 1H), 1.14 (d, J = 6.8 Hz, 3H), 1.03 (d, J = 6.9 Hz, 3H);
13C NMR (101 MHz, CDCl3) δ 192.3, 184.3, 163.8, 161.3, 132.4,
131.5 (d, J = 16.5 Hz), 130.7 (d, J = 7.9 Hz), 127.4, 125.7, 122.5, 122.2
(d, J = 21.3 Hz), 121.5, 116.5, 116.2, 93.9, 39.1, 34.1, 16.56; HRMS
(ESI) m/z 392.0485 (M + H+), calcd for C19H1881BrFNO2 392.0484.
The ee was determined by HPLC analysis. CHIRALPAK IA (4.6 mm
i.d. × 250 mm); hexane/2-propanol = 90:10; flow rate 1.0 mL/min; 25
°C; 254 nm; retention time, 6.8 min (minor) and 8.0 min (major).
(R)-(+)-5-(2-Fluorobenzyl)-2-(3-fluorophenyl)-5-isopropyloxazol-
4(5H)-one (3f). Colorless oil; 23 mg (0.1 mmol), 72% yield; 92% ee;
[α]2D2 +69.20 (c 1.50, CHCl3); H NMR (400 MHz, CDCl3) δ 7.87−
1
7.85 (m, 1H), 7.74 (ddd, J = 9.0, 2.4, 1.5 Hz, 1H), 7.45 (td, J = 8.0, 5.5
Hz, 1H), 7.33 (tdd, J = 8.3, 2.6, 0.9 Hz, 1H), 7.15 (td, J = 7.5, 1.6 Hz,
1H), 7.09 (tdd, J = 7.3, 5.3, 1.7 Hz, 1H), 6.94 (td, J = 7.5, 1.0 Hz, 1H),
6.86 (t, J = 9.1 Hz, 1H), 3.58 (d, J = 13.9 Hz, 1H), 3.13 (dd, J = 13.9,
1.2 Hz, 1H), 2.35 (dt, J = 13.7, 6.9 Hz, 1H), 1.15 (d, J = 6.8 Hz, 3H),
1.06 (d, J = 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 192.6, 184.5,
163.7, 162.5, 161.2, 160.0, 131.9 (d, J = 3.7 Hz), 130.6 (d, J = 7.8 Hz),
129.3 (d, J = 8.3 Hz), 127.6 (d, J = 8.2 Hz), 125.6 (d, J = 3.2 Hz),
124.2 (d, J = 3.6 Hz), 122.1, 121.9 (d, J = 21.3 Hz), 120.6 (d, J = 15.4
Hz), 116.5, 116.3, 115.3, 115.1, 93.9, 34.0, 32.7 (d, J = 2.0 Hz), 16.6
(d, J = 3.2 Hz); HRMS (ESI) m/z 330.1317 (M + H+), calcd for
C19H18F2NO2 330.1306. The ee was determined by HPLC analysis.
CHIRALPAK IC (4.6 mm i.d. × 250 mm); hexane/2-propanol =
90:10; flow rate 1.0 mL/min; 25 °C; 254 nm; retention time, 10.4 min
(major) and 12.4 min (minor).
(R)-(+)-2-(3-Fluorophenyl)-5-isopropyl-5-(3-methylbenzyl)oxazol-
4(5H)-one (3k). Colorless oil; 23 mg (0.1 mmol), 71% yield; 90% ee;
[α]2D2 +80.11 (c 1.50, CHCl3); H NMR (400 MHz, CDCl3) δ 7.89−
1
7.85 (m, 1H), 7.76−7.73 (m, 1H), 7.49−7.44 (m, 1H), 7.36−7.32 (m,
1H), 7.01 (t, J = 7.4 Hz, 1H), 6.94−6.92 (m, 3H), 3.29 (d, J = 13.8 Hz,
1H), 3.14 (d, J = 13.8 Hz, 1H), 2.36−2.28 (m, 1H), 2.14 (s, 3H), 1.14
(d, J = 6.8 Hz, 3H), 1.04 (d, J = 6.9 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 192.5, 184.2, 163.7, 161.3, 137.7, 133.2, 130.8, 130.6 (d, J =
7.9 Hz), 128.0 (dd, J = 25.2, 11.4 Hz), 126.9, 125.5 (d, J = 3.1 Hz),
121.9, 121.7, 116.4, 116.2, 94.3, 39.8, 33.9, 21.1, 16.6; HRMS (ESI)
m/z 326.1563 (M + H+), calcd for C20H21FNO2 326.1556. The ee was
F
DOI: 10.1021/acs.joc.5b01081
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
determined by HPLC analysis. CHIRALPAK IC (4.6 mm i.d. × 250
mm); hexane/2-propanol = 90:10; flow rate 1.0 mL/min; 25 °C; 254
nm; retention time, 10.6 min (major) and 12.6 min (minor).
(R)-(+)-2-(3-Fluorophenyl)-5-isopropyl-5-(4-methylbenzyl)oxazol-
4(5H)-one (3l). Colorless oil; 25 mg (0.1 mmol), 76% yield; 90% ee;
(d, J = 3.1 Hz), 122.1, 121.9, 116.6, 116.4, 88.5, 42.9, 21.8; HRMS
(ESI) m/z 306.0911 (M + Na+), calcd for C17H14FNO2Na 306.0906.
The ee was determined by HPLC analysis. CHIRALPAK IC (4.6 mm
i.d. × 250 mm); hexane/2-propanol = 90:10; flow rate 1.0 mL/min; 25
°C; 254 nm; retention time, 19.5 min (major) and 26.6 min (minor).
(S)-(+)-5-benzyl-5-ethyl-2-(3-fluorophenyl)oxazol-4(5H)-one (3q).
Colorless oil; 19 mg (0.1 mmol), 64% yield; 86% ee; [α]2D2 +44.26 (c
1
[α]2D2 +108.77 (c 1.50, CHCl3); H NMR (400 MHz, CDCl3) δ 7.88
(d, J = 7.8 Hz, 1H), 7.77−7.73 (m, 1H), 7.47 (td, J = 8.0, 5.5 Hz, 1H),
7.34 (ddd, J = 10.1, 7.9, 2.2 Hz, 1H), 7.02 (d, J = 8.0 Hz, 2H), 6.93 (d,
J = 7.9 Hz, 2H), 3.28 (d, J = 14.0 Hz, 1H), 3.15 (d, J = 14.0 Hz, 1H),
2.31 (dt, J = 13.7, 6.8 Hz, 1H), 2.19 (s, 3H), 1.13 (d, J = 6.8 Hz, 3H),
1.03 (d, J = 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 192.6, 184.2,
163.7, 161.3, 136.8, 130.6 (d, J = 7.8 Hz), 130.1 (d, J = 15.9 Hz),
129.8, 129.0, 127.8 (d, J = 8.3 Hz), 125.6 (d, J = 3.1 Hz), 121.9, 121.7
116.5, 116.2, 94.4, 39.4, 33.9, 20.9, 16.6; HRMS (ESI) m/z 326.1562
(M + H+), calcd for C20H21FNO2 326.1556. The ee was determined by
HPLC analysis. CHIRALPAK IA (4.6 mm i.d. × 250 mm); hexane/2-
propanol = 90:10; flow rate 1.0 mL/min; 25 °C; 254 nm; retention
time, 6.1 min (minor) and 7.3 min (major).
1
1.50, CHCl3); H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 7.8 Hz,
1H), 7.79−7.77 (m, 1H), 7.48 (td, J = 8.0, 5.5 Hz, 1H), 7.35 (ddd, J =
8.3, 5.0, 1.8 Hz, 2H), 7.22−7.08 (m, 5H), 3.20 (s, 2H), 2.13−1.98 (m,
2H), 0.89 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 192.8,
184.4, 163.8, 161.3, 133.4, 130.6 (d, J = 7.9 Hz), 130.0, 128.4, 127.8,
127.4, 125.7 (d, J = 3.1 Hz), 122.2, 122.0 (d, J = 21.3 Hz), 116.6,
116.3, 92.2, 42.0, 28.9, 7.4; HRMS (ESI) m/z 298.1244 (M + H+),
calcd for C18H17FNO2 298.1243. The ee was determined by HPLC
analysis. CHIRALPAK IC (4.6 mm i.d. × 250 mm); hexane/2-
propanol = 90:10; flow rate 1.0 mL/min; 25 °C; 254 nm; retention
time, 14.9 min (major) and 17.9 min (minor).
(R)-(+)-2-(3-Fluorophenyl)-5-isopropyl-5-(4-isopropylbenzyl)-
oxazol-4(5H)-one (3m). Colorless oil; 24 mg (0.1 mmol), 67% yield;
87% ee; [α]2D2 +105.57 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 7.85 (d, J = 7.7 Hz, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.46 (td, J = 8.0,
5.6 Hz, 1H), 7.34 (td, J = 8.3, 1.9 Hz, 1H), 7.05 (d, J = 8.1 Hz, 2H),
6.98 (d, J = 8.0 Hz, 2H), 3.28 (d, J = 13.9 Hz, 1H), 3.16 (d, J = 13.9
Hz, 1H), 2.74 (dt, J = 13.8, 6.9 Hz, 1H), 2.32 (dt, J = 13.7, 6.8 Hz,
1H), 1.09 (ddd, J = 19.2, 13.7, 6.9 Hz, 12H); 13C NMR (100 MHz,
CDCl3) δ 192.7, 184.2, 163.7, 161.2, 147.9, 130.5 (d, J = 10.4 Hz),
129.9, 127.9, 126.3, 125.5 (d, J = 3.1 Hz), 121.9, 121.7, 116.4, 116.2,
94.4, 39.5, 33.8, 33.6, 23.8, 16.6 (d, J = 3.8 Hz); HRMS (ESI) m/z
354.1871 (M + H+), calcd for C22H25FNO2 354.1869. The ee was
determined by HPLC analysis. CHIRALPAK IA (4.6 mm i.d. × 250
mm); hexane/2-propanol = 95:5; flow rate 0.5 mL/min; 25 °C; 254
nm; retention time, 13.7 min (minor) and 15.2 min (major).
(R)-(+)-5-(4-(tert-Butyl)benzyl)-2-(3-fluorophenyl)-5-isopropylox-
azol-4(5H)-one (3n). Colorless oil; 22 mg (0.1 mmol), 61% yield; 88%
ee; [α]2D2 +7.25 (c 0.80, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.84
(d, J = 7.7 Hz, 1H), 7.72 (dd, J = 8.7, 1.9 Hz, 1H), 7.46 (td, J = 8.0, 5.5
Hz, 1H), 7.36−7.33 (m, 1H), 7.13 (d, J = 8.3 Hz, 2H), 7.06 (d, J = 8.3
Hz, 2H), 3.29 (d, J = 13.9 Hz, 1H), 3.16 (d, J = 13.9 Hz, 1H), 2.32 (dt,
J = 13.7, 6.8 Hz, 1H), 1.16 (s, 9H), 1.13 (d, J = 6.8 Hz, 3H), 1.05 (d, J
= 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 192.7, 184.3, 163.7,
161.2, 150.1, 130.5 (d, J = 7.8 Hz), 130.2, 129.7, 127.9 (d, J = 8.2 Hz),
125.5 (d, J = 3.1 Hz), 125.1, 121.8, 121.6, 116.4, 116.2, 94.4, 39.5, 34.3,
33.8, 31.1, 16.6 (d, J = 5.0 Hz); HRMS (ESI) m/z 368.2029 (M + H+),
calcd for C23H27FNO2 368.2026. The ee was determined by HPLC
analysis. CHIRALPAK IE (4.6 mm i.d. × 250 mm); hexane/2-
propanol = 90:10; flow rate 1.0 mL/min; 25 °C; 254 nm; retention
time, 12.4 min (major) and 13.8 min (minor).
(S)-(+)-5-Benzyl-5-butyl-2-(3-fluorophenyl)oxazol-4(5H)-one (3r).
Colorless oil; 20 mg (0.1 mmol), 63% yield; 83% ee; [α]2D2 +42.65 (c
1
1.00, CHCl3); H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 7.7 Hz,
1H), 7.79−7.76 (m, 1H), 7.48 (td, J = 8.0, 5.5 Hz, 1H), 7.36 (td, J =
8.3, 1.8 Hz, 1H), 7.18−7.15 (m, 5H), 3.24−3.17 (m, 2H), 2.07−1.94
(m, 2H), 1.34−1.18 (m, 5H), 0.85 (t, J = 7.1 Hz, 3H); 13C NMR (101
MHz, CDCl3) δ 192.9, 184.2, 163.8, 161.3, 133.3, 130.6 (d, J = 7.8
Hz), 123.0, 128.3, 127.8, 127.4, 125.7 (d, J = 3.1 Hz), 122.1, 121.9,
116.6, 116.3, 91.8, 42.3, 35.5, 25.0, 22.5, 13.7; HRMS (ESI) m/z
326.1554 (M + H+), calcd for C20H21FNO2 326.1556. The ee was
determined by HPLC analysis. CHIRALPAK IC (4.6 mm i.d. × 250
mm); hexane/2-propanol = 90:10; flow rate 1.0 mL/min; 25 °C; 254
nm; retention time, 11.1 min (major) and 13.0 min (minor).
(S)-(−)-5-Benzyl-5-(2-bromobenzyl)-2-(3-fluorophenyl)oxazol-
4(5H)-one (3s). White crystal; mp 83.8−85.1 °C; 33 mg (0.1 mmol),
76% yield; 90% ee; [α]2D2 −97.20 (c 1.5, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 7.81−7.78 (m, 1H), 7.67 (ddd, J = 9.0, 2.5, 1.5 Hz, 1H),
7.46−7.38 (m, 2H), 7.32−7.25 (m, 2H), 7.25−7.13 (m, 6H), 7.02 (td,
J = 7.8, 1.7 Hz, 1H), 3.70 (d, J = 14.2 Hz, 1H), 3.41−3.28 (m, 3H);
13C NMR (100 MHz, CDCl3) δ 192.3, 184.1 (d, J = 3.0 Hz), 163.6,
161.1, 133.3, 133.0 (d, J = 5.5 Hz), 131.8, 130.5 (d, J = 7.8 Hz), 130.0,
129.2, 128.4, 127.5 (dd, J = 16.2, 11.8 Hz), 125.7, 122.1, 121.9, 116.6,
116.4, 91.4, 77.3, 77.0, 76.7, 41.8, 40.9; HRMS (ESI) m/z 438.0506
(M + H+), calcd for C23H18BrFNO2 438.0505. The ee was determined
by HPLC analysis. CHIRALPAK IE (4.6 mm i.d. × 250 mm); hexane/
2-propanol = 90:10; flow rate 1.0 mL/min; 25 °C; 254 nm; retention
time, 24.9 min (major) and 32.0 min (minor).
(S)-(+)-5-Benzyl-5-(3-bromobenzyl)-2-(3-fluorophenyl)oxazol-
4(5H)-one (3t). White crystal; mp 95.0−96.3 °C; 32 mg (0.1 mmol),
73% yield; 85% ee (>99% ee after a single recrystallization); [α]D22
+12.9 (c 1.50, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.71 (d, J = 7.7
Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.38 (td, J = 8.0, 5.7 Hz, 1H), 7.29
(d, J = 1.9 Hz, 1H), 7.22 (d, J = 7.7 Hz, 1H), 7.19 (s, 1H), 7.12 (s,
5H), 7.02 (dt, J = 15.1, 7.6 Hz, 2H), 3.27−3.12 (m, 4H); 13C NMR
(75 MHz, CDCl3) δ 191.8, 184.1 (d, J = 3.1 Hz), 164.2, 160.9, 135.4,
133.1 (d, J = 10.4 Hz), 130.7 (d, J = 6.0 Hz), 130.1 (d, J = 3.6 Hz),
128.6 (d, J = 6.0 Hz), 127.5, 125.5 (d, J = 3.1 Hz), 122.3, 122.0, 116.5,
116.2, 91.0, 41.9, 41.3; HRMS (ESI) m/z 438.0504 (M + H+), calcd
for C23H18BrFNO2 438.0505. The ee was determined by HPLC
analysis. CHIRALPAK IE (4.6 mm i.d. × 250 mm); hexane/2-
propanol = 90:10; flow rate 1.0 mL/min; 25 °C; 254 nm; retention
time, 29.2 min (major) and 30.8 min (minor).
(R)-(+)-2-(3-Fluorophenyl)-5-isopropyl-5-(naphthalen-2-
ylmethyl)oxazol-4(5H)-one (3o). Colorless oil; 29 mg (0.1 mmol),
80% yield; 90% ee; [α]2D2 +136.14 (c 1.50, CHCl3); H NMR (400
1
MHz, CDCl3) δ 7.83 (d, J = 7.8 Hz, 1H), 7.74−7.60 (m, 5H), 7.41−
7.26 (m, 5H), 3.50 (d, J = 13.9 Hz, 1H), 3.37 (d, J = 13.9 Hz, 1H),
2.37 (dq, J = 13.7, 6.9 Hz, 1H), 1.18 (d, J = 6.8 Hz, 3H), 1.08 (d, J =
6.9 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 192.5, 184.3 (d, J = 3.1
Hz), 163.7, 161.2, 133.1, 132.4, 130.9, 130.5 (d, J = 7.9 Hz), 129.0,
127.7, 125.9, 125.6, 122.0, 121.8, 116.4, 116.2, 94.3, 39.9, 34.1, 16.6 (d,
J = 4.1 Hz); HRMS (ESI) m/z 362.1563 (M + H+), calcd for
C23H21FNO2 362.1556. The ee was determined by HPLC analysis.
CHIRALPAK IA (4.6 mm i.d. × 250 mm); hexane/2-propanol =
90:10; flow rate 1.0 mL/min; 25 °C; 254 nm; retention time, 8.6 min
(minor) and 11.0 min (major).
(S)-(+)-5-Benzyl-5-(4-bromobenzyl)-2-(3-fluorophenyl)oxazol-
4(5H)-one (3u). White crystal; mp 138.8−140.5 °C; 36 mg (0.1
mmol), 82% yield; 85% ee (90% ee after a single recrystallization);
(S)-(+)-5-Benzyl-2-(3-fluorophenyl)-5-methyloxazol-4(5H)-one
(3p). Colorless oil; 15 mg (0.1 mmol), 54% yield; 87% ee; [α]D22
1
[α]2D2 +26.25 (c 1.00, CHCl3); H NMR (300 MHz, CDCl3) δ 7.78−
1
+46.03 (c 1.50, CHCl3); H NMR (400 MHz, CDCl3) δ 7.93−7.90
7.75 (m, 1H), 7.66−7.62 (m, 1H), 7.47−7.40 (m, 1H), 7.36−7.29 (m,
3H), 7.21−7.12 (m, 5H), 7.06−7.02 (m, 2H), 3.33−3.18 (m, 4H); 13C
NMR (75 MHz, CDCl3) δ 191.8, 184.0 (d, J = 3.1 Hz), 164.1, 160.8,
132.9, 132.2, 131.6 (d, J = 4.5 Hz), 130.7 (d, J = 7.9 Hz), 123.0, 128.5,
127.4, 125.5 (d, J = 3.1 Hz), 122.3, 122.0, 121.7, 116.4, 116.1, 91.1,
42.0, 41.0; HRMS (ESI) m/z 438.0523 (M + H+), calcd for
(m, 1H), 7.78 (ddd, J = 9.0, 2.4, 1.6 Hz, 1H), 7.48 (td, J = 8.0, 5.5 Hz,
1H), 7.36 (tdd, J = 8.3, 2.6, 0.9 Hz, 1H), 7.23−7.17 (m, 5H), 3.22 (d, J
= 14.2 Hz, 1H), 3.18 (d, J = 14.2 Hz, 1H), 1.62 (s, 3H); 13C NMR
(101 MHz, CDCl3) δ 193.2, 183.8 (d, J = 3.0 Hz), 163.7, 161.3, 133.4,
130.6 (d, J = 7.8 Hz), 123.0, 128.4, 127.9 (d, J = 8.2 Hz), 127.5, 125.7
G
DOI: 10.1021/acs.joc.5b01081
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
C23H18BrFNO2 438.0505. The ee was determined by HPLC analysis.
CHIRALPAK IC (4.6 mm i.d. × 250 mm); hexane/2-propanol =
90:10; flow rate 1.0 mL/min; 25 °C; 254 nm; retention time, 16.5 min
(minor) and 18.8 min (major).
CHIRALPAK IC (4.6 mm i.d. × 250 mm); hexane/2-propanol =
90:10; flow rate 1.0 mL/min; 25 °C; 254 nm; retention time, 17.1 min
(major) and 19.4 min (minor).
(R, E)-(+)-5-(But-2-en-1-yl)-5-isopropyl-2-(m-tolyl)oxazol-4(5H)-
one (5b). Colorless oil; 18 mg (0.1 mmol), 67% yield; 91% ee;
(S)-(−)-5-Benzyl-2-(3-fluorophenyl)-5-(2-methylbenzyl)oxazol-
4(5H)-one (3v). White crystal; mp 89.3−91.2 °C; 29 mg (0.1 mmol),
78% yield; 89% ee (94% ee after a single recrystallization); [α]D22
[α]2D2 +61.01 (c 1.50, CHCl3); H NMR (400 MHz, CDCl3) δ 8.04−
1
7.96 (m, 2H), 7.49 (d, J = 7.6 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 5.58
(dq, J = 12.9, 6.4 Hz, 1H), 5.23 (dtd, J = 8.8, 7.2, 1.6 Hz, 1H), 2.66
(dd, J = 14.2, 7.3 Hz, 1H), 2.56 (dd, J = 14.2, 7.1 Hz, 1H), 2.44 (s,
3H), 2.21 (dt, J = 13.7, 6.9 Hz, 1H), 1.52 (d, J = 6.2 Hz, 3H), 1.05 (d,
J = 6.9 Hz, 3H), 0.95 (d, J = 6.9 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 193.4, 185.8, 138.9, 135.8, 131.5, 130.5, 128.9, 127.1, 125.8,
122.0, 93.4, 36.9, 33.5, 21.3, 18.0, 16.4; HRMS (ESI) m/z 272.1645
(M + H+), calcd for C17H22NO2 272.1651. The ee was determined by
HPLC analysis. CHIRALPAK IC (4.6 mm i.d. × 250 mm); hexane/2-
propanol = 95:5; flow rate 0.5 mL/min; 25 °C; 254 nm; retention
time, 48.8 min (major) and 54.0 min (minor).
1
−15.04 (c 1.00, CHCl3); H NMR (300 MHz, CDCl3) δ 7.74 (d, J =
7.7 Hz, 1H), 7.62 (dd, J = 8.9, 2.2 Hz, 1H), 7.42 (td, J = 8.0, 5.5 Hz,
1H), 7.32 (dd, J = 8.3, 1.7 Hz, 1H), 7.19−7.14 (m, 6H), 7.03 (dd, J =
9.6, 2.9 Hz, 3H), 3.40−3.25 (m, 4H), 2.32 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 192.5, 183.8 (d, J = 3.1 Hz), 164.0, 137.1, 133.2,
131.7, 130.6, 130.0, 128.4, 127.5 (t, J = 5.3 Hz), 126.0, 125.4 (d, J = 3.2
Hz), 122.1, 121.8, 116.4, 116.0, 91.9, 42.0, 38.2, 19.8; HRMS (ESI) m/
z 374.1562 (M + H+), calcd for C24H21FNO2 374.1556. The ee was
determined by HPLC analysis. CHIRALPAK IC (4.6 mm i.d. × 250
mm); hexane/2-propanol = 90:10; flow rate 1.0 mL/min; 25 °C; 254
nm; retention time, 16.5 min (major) and 17.9 min (minor).
(R)-(+)-5-Isopropyl-5-(3-methylbut-2-en-1-yl)-2-(m-tolyl)oxazol-
(S)-(+)-5-Benzyl-2-(3-fluorophenyl)-5-(3-methylbenzyl)oxazol-
4(5H)-one (3w). White crystal; mp 89.7−91.5 °C; 26 mg (0.1 mmol),
71% yield; 85% ee (90% ee after a single recrystallization); [α]2D2 +7.65
4(5H)-one (5c). Colorless oil; 23 mg (0.1 mmol), 81% yield; 87% ee;
1
[α]2D2 +55.68 (c 1.50, CHCl3); H NMR (400 MHz, CDCl3) δ 8.02−
7.98 (m, 2H), 7.49 (d, J = 7.6 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 4.98−
4.94 (m, 1H), 2.73 (dd, J = 14.6, 7.8 Hz, 1H), 2.57 (dd, J = 14.6, 7.3
Hz, 1H), 2.44 (s, 3H), 2.24 (dt, J = 13.7, 6.9 Hz, 1H), 1.58 (d, J = 17.0
Hz, 6H), 1.07 (d, J = 6.9 Hz, 3H), 0.96 (d, J = 6.9 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 193.5, 185.75, 138.85, 137.5, 135.7, 130.5, 128.8,
127.0, 125.8, 115.2, 93.8, 33.5, 32.4, 25.8, 21.2, 18.0, 16.5; HRMS
(ESI) m/z 286.1808 (M + H+), calcd for C18H24NO2 286.1807. The
ee was determined by HPLC analysis. CHIRALPAK IC (4.6 mm i.d. ×
250 mm); hexane/2-propanol = 90:10; flow rate 1.0 mL/min; 25 °C;
254 nm; retention time, 14.3 min (major) and 16.4 min (minor).
(S)-(−)-2-Benzyl-3-(2-bromophenyl)-2-hydroxypropanamide (6).
To a solution of 3s (87.6 mg, 0.2 mmol) in EtOH (1.0 mL) was added
NaOH aqueous solution (2.0 N, 1.0 mL). The resulting mixture was
stirred for 3 h at 25 °C. Then, the reaction mixture was diluted with
water. The mixture was extracted three times with ethyl acetate (5
mL), and the combined organic phase was washed with brine, dried
(Na2SO4), and concentrated. Then, the reaction mixtures were loaded
onto a short silica gel column, followed by gradient elution with
DCM/MeOH mixture (100:1−50:1 ratio) to afford 6 in 86% yield
(57.4 mg, white powder); mp 148.4−150.0 °C; 90% ee; [α]2D2 −16.93
1
(c 1.00, CHCl3); H NMR (300 MHz, CDCl3) δ 7.77 (d, J = 7.7 Hz,
1H), 7.67−7.63 (m, 1H), 7.43 (td, J = 8.0, 5.5 Hz, 1H), 7.34−7.28 (m,
1H), 7.15 (s, 5H), 7.10−7.04 (m, 1H), 6.97 (d, J = 7.6 Hz, 3H), 3.34−
3.19 (m, 4H), 2.19 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 192.2,
183.9 (d, J = 3.1 Hz), 164.0, 160.8, 137.9, 133.1 (d, J = 15.4 Hz),
130.6, 130.0, 128.3, 127.6, 127.0, 125.4 (d, J = 3.1 Hz), 122.0, 121.7,
116.4, 116.1, 91.4, 41.8, 21.2; HRMS (ESI) m/z 374.1557 (M + H+),
calcd for C24H21FNO2 374.1556. The ee was determined by HPLC
analysis. CHIRALPAK IE (4.6 mm i.d. × 250 mm); hexane/2-
propanol = 95:5; flow rate 0.5 mL/min; 25 °C; 254 nm; retention
time, 102.1 min (minor) and 107.4 min (major).
(S)-(−)-5-Benzyl-5-(2,4-dichlorobenzyl)-2-(3-fluorophenyl)oxazol-
4(5H)-one (3x). White crystal; mp 106.7−108.2 °C; 32 mg (0.1
mmol), 75% yield; 90% ee; [α]2D2 −21.13 (c 2.00, CHCl3); H NMR
1
(300 MHz, CDCl3) δ 7.78 (d, J = 7.7 Hz, 1H), 7.66 (dd, J = 8.7, 1.9
Hz, 1H), 7.43 (td, J = 8.0, 5.5 Hz, 1H), 7.36−7.29 (m, 2H), 7.21−7.11
(m, 7H), 3.63 (d, J = 14.2 Hz, 1H), 3.38−3.25 (m, 3H); 13C NMR (75
MHz, CDCl3) δ 192.0, 184.2 (d, J = 3.1 Hz), 164.1, 160.8, 135.8,
134.2, 132.8 (d, J = 5.6 Hz), 130.7 (d, J = 7.9 Hz), 130.1 (d, J = 9.9
Hz), 129.5, 128.5, 127.4 (dd, J = 16.5, 11.6 Hz), 125.7 (d, J = 3.2 Hz),
122.4, 122.1, 116.6, 116.3, 91.2, 41.9, 37.9; HRMS (EI) m/z 427.0539
(M+), calcd for C23H16NO2FCl2 427.0542. The ee was determined by
HPLC analysis. CHIRALPAK IC (4.6 mm i.d. × 250 mm); hexane/2-
propanol = 90:10; flow rate 1.0 mL/min; 25 °C; 254 nm; retention
time, 12.7 min (major) and 15.5 min (minor).
1
(c 0.60, CHCl3); H NMR (300 MHz, CDCl3) δ 7.45 (d, J = 8.0 Hz,
1H), 7.33 (m, 6H), 7.23 (d, J = 7.7 Hz, 1H), 7.04 (dd, J = 10.9, 4.4 Hz,
1H), 6.31 (s, 1H), 5.45 (s, 1H), 3.30 (dt, J = 14.0, 12.2 Hz, 3H), 2.89
(d, J = 13.5 Hz, 1H), 2.43 (s, 1H); 13C NMR (75 MHz, CDCl3) δ
176.6, 135.7, 135.3, 132.7, 132.4, 130.6, 128.6 (two peaks), 127.6,
127.2, 125.9, 79.9, 45.2, 42.8; HRMS (ESI) m/z 356.0263 (M + Na+),
calcd for C16H16NO2BrNa 356.0262. The ee was determined by
HPLC analysis. CHIRALPAK IA (4.6 mm i.d. × 250 mm); hexane/2-
propanol = 90:10; flow rate 1.0 mL/min; 25 °C; 210 nm; retention
time, 9.3 min (major) and 10.5 min (minor).
(S)-(−)-1-Amino-2-benzyl-3-(2-bromophenyl)propan-2-ol (7). A
solution of 57.4 mg (0.17 mol) of 6 in 1 mL of anhydrous THF was
heated to reflux under N2, and 38.7 mg (0.51 mmol) of borane
dimethyl sulfide complex was added. A gas evolved, and the mixture
was refluxed for 3 h, cooled to room temperature, and treated with
methanol. Then, the solvent was removed, and the residue was
chromatographed on silica gel using 50:1 methanol-DCM as eluent to
afford 7 in 81% yield (44.1 mg, a white crystal); mp 87.8−89.3 °C;
90% ee; [α]2D2 −6.20 (c 1.00, CHCl3); 1H NMR (300 MHz, CDCl3) δ
7.49 (d, J = 8.0 Hz, 1H), 7.42 (dd, J = 7.7, 1.5 Hz, 1H), 7.29−7.17 (m,
6H), 7.03 (td, J = 7.8, 1.6 Hz, 1H), 3.03 (d, J = 13.9 Hz, 1H), 2.92 (d,
J = 13.9 Hz, 1H), 2.81 (s, 2H), 2.68 (d, J = 12.9 Hz, 1H), 2.58 (d, J =
12.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 137.5 (two peaks),
133.1, 132.7, 130.6, 128.1, 127.9, 127.0, 126.4, 125.8, 73.8, 47.3, 45.2,
43.5; HRMS (ESI) m/z 320.0652 (M + H+), calcd for C16H19NOBr
320.0650. The ee was determined by HPLC analysis. CHIRALCEL
OD-H (4.6 mm i.d. × 250 mm); hexane/2-propanol = 90:10; flow rate
1.0 mL/min; 25 °C; 210 nm; retention time, 12.0 min (minor) and
14.7 min (major).
(S)-(+)-5-Benzyl-2-(3-fluorophenyl)-5-(naphthalen-2-ylmethyl)-
oxazol-4(5H)-one (3y). White crystal; mp 134.6−135.1 °C; 34 mg
(0.1 mmol), 82% yield; 84% ee (93% ee after a single
recrystallization); [α]2D2 +28.17 (c 1.00, CHCl3); 1H NMR (300
MHz, CDCl3) δ 7.76−7.61 (m, 6H), 7.44−7.28 (m, 5H), 7.21−7.11
(m, 5H), δ 3.51−3.27 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 192.1,
183.9 (d, J = 3.1 Hz), 164.0, 160.7, 133.2 (d, J = 3.6 Hz), 132.5, 130.6,
130.0, 129.1, 128.4, 127.7, 126.0 (d, J = 14.6 Hz), 125.5 (d, J = 3.1
Hz), 122.1, 121.8, 116.4, 116.1, 91.5, 41.9 (d, J = 4.0 Hz); HRMS
(ESI) m/z 410.1570 (M + H+), calcd for C27H21FNO2 410.1556. The
ee was determined by HPLC analysis. CHIRALPAK IC (4.6 mm i.d. ×
250 mm); hexane/2-propanol = 90:10; flow rate 1.0 mL/min; 25 °C;
254 nm; retention time, 23.0 min (minor) and 24.7 min (major).
(R)-(+)-5-Allyl-5-isopropyl-2-(m-tolyl)oxazol-4(5H)-one (5a). Col-
orless oil; 16 mg (0.1 mmol), 61% yield; 89% ee; [α]2D2 +27.73 (c 1.00,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.04−8.01 (m, 2H), 7.50 (d,
J = 7.6 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 5.61 (ddt, J = 17.2, 10.1, 7.3
Hz, 1H), 5.17 (dd, J = 17.0, 1.3 Hz, 1H), 5.07 (d, J = 10.1 Hz, 1H),
2.75 (dd, J = 14.1, 7.5 Hz, 1H), 2.64 (dd, J = 14.1, 7.0 Hz, 1H), 2.44
(s, 3H), 2.24 (dt, J = 13.7, 6.9 Hz, 1H), 1.07 (d, J = 6.9 Hz, 3H), 0.97
(d, J = 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 193.1, 185.8,
138.9, 135.9, 130.5, 129.7 128.8, 127.1, 125.7, 120.7, 93.0, 38.0, 33.5,
21.2, 16.4; HRMS (ESI) m/z 258.1487 (M + H+), calcd for
C16H20NO2 258.1494. The ee was determined by HPLC analysis.
H
DOI: 10.1021/acs.joc.5b01081
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(S)-(−)-Methyl 2-Benzyl-3-(2,4-dichlorophenyl)-2-hydroxypropa-
noate (9). (a) To a solution of 3x (85.6 mg, 0.2 mmol) in EtOH (1.0
mL) was added NaOH aqueous solution (2.0 N, 1.0 mL). The
resulting mixture was stirred for 3 h at 25 °C. Then, the reaction
mixture was diluted with water. The mixture was extracted three times
with ethyl acetate (5 mL), and the combined organic phase was
washed with brine, dried (Na2SO4), and concentrated. Then, the
reaction mixtures were loaded onto a short silica gel column, followed
by gradient elution with DCM/MeOH mixture (100:1−50:1 ratio) to
afford 2-benzyl-3-(2,4-dichlorophenyl)-2-hydroxypropanamide in 89%
yield (76.2 mg). (b) A solution of 2-benzyl-3-(2,4-dichlorophenyl)-2-
hydroxypropanamide (76.2 mg, 0.18 mmol) was dissolved in 1,4-
dioxane (0.2 mL). HCl (12 N, 4.0 mL) was added dropwise to the
reaction mixture at 0 °C. The reaction mixture was heated at 100 °C
for 48 h. Then, the solution was cooled and extracted three times with
ethyl acetate (5 mL). The combined organic layers were washed with
saturated aqueous NaCl and dried over Na2SO4. After being
concentrated, crude 2-benzyl-3-(2,4-dichlorophenyl)-2-hydroxypropa-
noic acid 8 was obtained. Subsequently, crude 2-benzyl-3-(2,4-
dichlorophenyl)-2-hydroxypropanoic acid 8 was diluted with methanol
(4.0 mL), and H2SO4 ( conc. 0.1 mL) was added to the stirred
solution. After stirring at 70 °C for 12 h, the reaction mixture was
cooled to room temperature and diluted with water. Then, the mixture
was extracted with EtOAc (5 mL × 3), and the combined organic
phase was washed with brine, dried over Na2SO4, and concentrated.
The obtained crude product was purified by SiO2 column
chromatography (hexane/EtOAc = 10:1) to afford 9 in 75% yield
(45.8 mg, white powder); mp 79.1−81.2 °C; 88% ee; [α]2D2 −5.80 (c
MacNaul, K. L.; Zhou, G.; Agrawal, A.; Alvaro, R.; Cai, T.-q.;
Hernandez, M.; Wright, S. D.; M?ller, D. E.; Heck, J. V.; Meinke, P. T.
J. Med. Chem. 2005, 48, 5589. (c) Pansare, S. V.; Kulkarni, K. G. RSC
Adv. 2013, 3, 19127. (d) Erik, R.; Karl Heinz, B.; Wilhelm, B.; Paul, R.
Ger. Offen. 1984, DE 3235935A1 19840329. (e) Braj Bhushan, L.;
Vidya Bhushan, L.; Channaveerappa Bajji, A.; Shivaramayya, K.; Ranga
Madhavan, G.; Ramanujam, R.; Chakrabarti, R. PCT Int. Appl. 2000,
WO 2000066572A1 20001109. (f) Jean-Pierre, R.; Nina, R.; Julie, B.
PCT Int. Appl. 2010, WO 2010103405A2 20100916. (g) Wolf Dieter,
V.; Gerhard, S.; Manfred, H. U.S. 1978, US 4076937A 19780228.
(h) Sitachitta, N.; Williamson, R. T.; Gerwick, W. H. J. Nat. Prod.
2000, 63, 197. For a selected book: (i) Coppola, G. M.; Schuster, H.
F. α-Hydroxy Acids in Enantioselective Synthesis; VCH: Weinheim, 1997.
(2) (a) Moorlag, H.; Kellogg, R. M. J. Org. Chem. 1990, 55, 5878.
(b) Moorlag, H.; Kellogg, R. M. Tetrahedron: Asymmetry 1991, 2, 705.
(c) O’Hagan, D.; Zaidi, N. A. Tetrahedron: Asymmetry 1994, 5, 1111.
(3) (a) Ojima, I.; Miyazawa, Y.; Kumagai, M. J. Chem. Soc., Chem.
Commun. 1976, 927. (b) Terashima, S.; Jew, S.-s. Tetrahedron Lett.
1977, 18, 1005. (c) Díez, E.; Dixon, D. J.; Ley, S. V. Angew. Chem., Int.
Ed. 2001, 40, 2906. (d) Ley, S. V.; Díez, E.; Dixon, D. J.; Guy, R. T.;
Michel, P.; Nattrass, G. L.; Sheppard, T. D. Org. Biomol. Chem. 2004,
2, 3608.
(4) Trost, B. M.; Dogra, K.; Franzini, M. J. Am. Chem. Soc. 2004, 126,
1944.
(5) (a) Misaki, T.; Takimoto, G.; Sugimura, T. J. Am. Chem. Soc.
2010, 132, 6286. (b) Misaki, T.; Kawano, K.; Sugimura, T. J. Am.
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1
1.00, CHCl3); H NMR (300 MHz, CDCl3) δ 7.35 (d, J = 7.8 Hz,
2H), 7.30−7.27 (m, 1H), 7.25−7.23 (m, 2H), 7.21−7.15 (m, 3H),
3.69 (s, 3H), 3.36 (d, J = 14.0 Hz, 1H), 3.25 (s, 1H), 3.20 (s, 1H), 3.09
(s, 1H), 2.98 (d, J = 13.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
175.1, 135.4 (two peaks), 133.3(two peaks), 132.4, 130.2, 129.2, 128.2,
126.9 (two peaks), 78.2, 52.6, 45.0, 40.8; HRMS (EI) m/z 338.0482
(M+), calcd for C17H16O3Cl2 338.0477. The ee was determined by
HPLC analysis. CHIRALPAK IE (4.6 mm i.d. × 250 mm); hexane/2-
propanol = 90:10; flow rate 1.0 mL/min; 25 °C; 210 nm; retention
time, 6.0 min (minor) and 6.8 min (major).
(7) (a) Zhao, D.; Wang, L.; Yang, D.; Zhang, Y.; Wang, R. Angew.
Chem., Int. Ed. 2012, 51, 7523. (b) Han, Z.; Yang, W.; Tan, C.-H.;
Jiang, Z. Adv. Synth. Catal. 2013, 355, 1505.
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6480. (b) Qiao, B.; An, Y.; Liu, Q.; Yang, W.; Liu, H.; Shen, J.; Yan, L.;
Jiang, Z. Org. Lett. 2013, 15, 2358. (c) Liu, Q.; Qiao, B.; Chin, K. F.;
Tan, C.-H.; Jiang, Z. Adv. Synth. Catal. 2014, 356, 3777. (d) Badiola,
́
E.; Fiser, B.; Gomez-Bengoa, E.; Mielgo, A.; Olaizola, I.; Urruzuno, I.;
García, J. M.; Odriozola, J. M.; Razkin, J.; Oiarbide, M.; Palomo, C. J.
Am. Chem. Soc. 2014, 136, 17869. (e) Chen, W.; Hartwig, J. F. J. Am.
Chem. Soc. 2014, 136, 377. (f) Xu, M.; Qiao, B.; Duan, S.; Liu, H.;
Jiang, Z. Tetrahedron 2014, 70, 8696.
ASSOCIATED CONTENT
■
S
* Supporting Information
(9) (a) Zhang, W.; Tan, D.; Lee, R.; Tong, G.; Chen, W.; Qi, B.;
Huang, K.-W.; Tan, C.-H.; Jiang, Z. Angew. Chem., Int. Ed. 2012, 51,
10069. (b) Zhu, B.; Zhang, W.; Lee, R.; Han, Z.; Yang, W.; Tan, D.;
Huang, K.-W.; Jiang, Z. Angew. Chem., Int. Ed. 2013, 52, 6666.
(10) (a) Gao, Y.; Ren, Q.; Wang, L.; Wang, J. Chem. - Eur. J. 2010,
16, 13068. For a selected review, see: (b) Serdyuk, O. V.; Heckel, C.
M.; Tsogoeva, S. B. Org. Biomol. Chem. 2013, 11, 7051.
(11) (a) Wang, H.-Y.; Chai, Z.; Zhao, G. Tetrahedron 2013, 69, 5104.
(b) Wang, H.-Y.; Zhang, J.-X.; Cao, D.-D.; Zhao, G. ACS Catal. 2013,
3, 2218.
General information, optimization of reaction conditions,
specific synthesis of chiral PTC F, copies of HPLC spectra,
crystallographic data of 3t and catalyst K, and copies of NMR
spectra. The Supporting Information is available free of charge
on the ACS Publications website at DOI: 10.1021/
acs.joc.5b01081.
AUTHOR INFORMATION
Corresponding Author
*E-mail: chmjzy@henu.edu.cn.
■
(12) CCDC1057650 (3t) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
Author Contributions
¶S.D. and S.L. made equal contributions to this work
(13) For biologically active molecules containing dibenzylated α-
hydroxyl amides as chiral scaffolds, see: (a) Howard, T. Eur. Pat. Appl.
1988, EP 253503A2 19880120. (b) Wolfgang, S.; Carsten, M.; Anja, S.;
Ulrike, F.; Andrea, R.; Thomas Andrew, K.; Ralf, W. U.S. Pat. Appl.
2009, US 20090075989A1 20090319. For biologically active
molecules containing dibenzylated α-hydroxyl amines as chiral
scaffolds, see: (c) Herve, G.; Jean Francois, G.; Claude, C. F.;
Marcel, C.; Charlotte, D.; Jacques, W. Eur. J. Med. Chem. 1979, 14,
165.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by NSFC (No’s. 21072044,
21202034), the Program for New Century Excellent Talents
in University of Ministry of Education (NCET-11-0938), and
the Program for Innovative Research Team from the University
of Henan Province (14IRTSTHN006).
REFERENCES
■
(1) (a) Riiburi, P. JPS6267069(A), 19870326. (b) Shi, G. Q.;
Dropinski, J. F.; Zhang, Y.; Santini, C.; Sahoo, S. P.; Berger, J. P.;
I
DOI: 10.1021/acs.joc.5b01081
J. Org. Chem. XXXX, XXX, XXX−XXX