Approach to Tertiary-Type β-Hydroxyl Carboxamides through Sc(OTf)3-Catalyzed Addition of Ynamides and Ketones

Article abstract of DOI:10.1021/acs.joc.9b02854

An efficient approach to access functionalized tertiary-type β-hydroxyl carboxamides has been developed through Sc(OTf)₃-catalyzed addition of ynamides and substituted ketones. Water was found to be an important reaction substrate, and the solvent was not needed in this process. A broad range of substituted ynamides and ketones was well applicable to the reaction with excellent chemical selectivities. Moreover, several chiral β-hydroxyl carboxamides 3j-3r were prepared with excellent regioselectivities and outstanding diastereoselectivities.

Full text of DOI:10.1021/acs.joc.9b02854

Subscriber access provided by University of Winnipeg Library
Article
An Approach to Tertiary Type #-Hydroxyl Carboxamides
Through Sc(OTf)3-Catalyzed Addition of Ynamides and Ketones
Yi-Wen Liu, Zhuo-Ya Mao, Xiao-Di Nie, Chang-Mei Si, Bang-Guo Wei, and Guo-Qiang Lin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02854 • Publication Date (Web): 28 Nov 2019
Downloaded from pubs.acs.org on November 28, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
An Approach to Tertiary Type β-Hydroxyl Carboxamides Through
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Sc(OTf)3-Catalyzed Addition of Ynamides and Ketones
Yi-Wen Liu,† Zhuo-Ya Mao,† Xiao-Di Nie,† Chang-Mei Si,† Bang-Guo Wei*,† and Guo-
Qiang Lin‡
† Institutes of Biomedical Sciences and School of Pharmacy, Fudan University, 220 Handan Road,
Shanghai, 200433, China
‡ Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai,
200032, China
Supporting Information Placeholder
O
O
OH
R
R
X
N
*
Sc(OTf)3
H2O
*
+
N
R1
X
R1
O
O
31 examples, dr up to 99:1
3aa~3ia, 3j~3r
1a~1r
2a~2n
ABSTRACT
An efficient approach to access functionalized tertiary type β-hydroxyl carboxamides has
been developed through Sc(OTf)3-catalyzed addition of ynamides and substituted
ketones. Water was found to be an important reaction substrate and solvent is no needed
in this process. A broad range of substituted ynamides and ketones were well applicable
to the reaction with excellent chemical selectivities. Moreover, several chiral β-hydroxyl
carboxamides 3j-3r were prepared with excellent regioselectivities and outstanding
diastereoselectivities.
INTRODUCTION
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 33
1
2
3
4
5
6
7
8
9
The exploration of advanced methodology to access privileged structural motifs is one of
the most important and urgent requirement for modern organic chemistry.1 As a prime
instance, β-hydroxy α-substituted carboxamides serve as versatile and useful subunits for
numerous biologically pharmaceutical agents.2 In particular, β-hydroxy α-substituted
carboxamides can be applied to form skeletons such as oxazolines,3 oxazoles,4
pyrrolidines5 and azetidines,6 which are also used as important building blocks in
synthetic chemistry7 and flexible ligands in asymmetric organic transformations.8 In past
decades, tremendous efforts have been devoted to the development of novel synthetic
approach, and several important processes including aldol reactions of aldehyde or ketone
and carboxamide9 or acylsilane,10 hydrogenation of β-keto carboxamide precursors11 or
β-ketonitriles,12 and ring-opening of α,β-epoxy carboxamides13 have been established.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Recent years, ynamide has undoubtedly become one of the most fascinating building
blocks in synthetic chemistry and many important chemical conversions of ynamides
have been successfully achieved.14 Among them, reactions of ynamides with ketones
were reported to afford different products including acrylic amides,15 γ-
hydroxyenamides,16 and α-halo-γ-hydroxyenamides17 under the promotion of different
Lewis acids (Figure 1). As a continuation of our interest in synthetic application of
ynamides, we have reported an effective approach to access functionalized pyrido and
pyrrolo[1,2-c][1,3]oxazin-1-ones through nucleophilic addition-cyclization process of
N,O-acetal with ynamides.18 Encouraged by these positive results, we envisioned that
certain mild Lewis acids could promote, in spite of known difficulty,19 the addition of
ynamides with ketones to give β-hydroxyl carboxamides.
ACS Paragon Plus Environment

Page 3 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
BF3.Et2O-catalyzed metathesis of ynamides and cyclobutanones (Xu)15
R3
R3
R1
R2
EWG
R4
R1
R2
.
R4
N
BF3 Et2O
+
EWG
R5
(1)
R5
O
50 oC
N
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Pd-trifluoropyruvate-catalyzed [2 + 2] cycloaddition (Mikami)16
Bn
O
Ts
N
+
Bn
N
Pd Cat* 2SbF6
-78oC
Ts
OEt
O
(2)
Ph
F3C
CF3
O
Ph
CO2Et
TiCl4-catalyzed addition of ynamides and ketones (Matsuo)17
HO
O
Ts
Cl
TiCl4
H
N
+
(3)
(4)
-78oC
Bn
Ts N
Bn
Sc(OTf)3-catalyzed addition of ynamides and ketones (This Work)
R3 R4
R2
HO
O
O
N
Sc(OTf)3
H2O
R
R1
+
R3 R4
N
R1 R2
3aa~3ia, 3j~3r
R
1a~1r
2a~2n
Figure 1. Lewis acid-promoted additions of ynamides with ketones.
RESULTS AND DISCUSSION
Our investigation started with the addition reaction of ynamide 1a and ketone 2a. First,
.
similar conditions (TiCl4 and BF3 Et2O) used by Matsuo17 and Xu15 failed to promote this
addition process (Table 1, entries 1-2). Initial trials with Sc(OTf)3 in several solvents also
turned out to be fruitless (Table 1, entries 3-5). Encouragingly, when 1 equiv. water was
added, the product of carbonyl addition 3a was obtained in 53% yield, along with the
hydration product 4 in 35% yield (Table 1, entry 6). However, the replacement of water
with MeOH did not produce any product (Table 1, entry 7). Notably, the neat reaction of
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 33
1
2
3
4
5
6
7
8
9
ynamide 1a, Sc(OTf)3, acetone and water significantly improved the yield of desired 3a
to 93% yield (Table 1, entry 8). Other Lewis acids including scandium salt ScF3, ScCl3
were screened, and the results showed that most Lewis acids gave the hydration product 4
(Table 1, entries 9-20).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1. Optimization of Reaction Conditions. a-e
OH
Ts
O
O
O
Ph
N
Ph
conditions
+
+
Bn
N
N
Bn
Ts
Bn
3a
Ts
Ph
1a
2a
4
Entrya Lewis Acid
Solventb Additive Yc 3a/4(%)
1d
2d
3d
4d
5d
6
TiCl4
THF
THF
THF
DMF
PhMe
PhMe
PhMe
--
--
--
BF3•Et2O
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
ScF3
--
Complex
Complex
--
--
--
--
--
H2O
53/35
7
MeOHe --
8
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
93/0
9
--
--
.
10
11
12
13
14
15
16
Sc(AcO)3 xH2O --
--
.
Sc(NO3)3 xH2O --
20/-
--
.
ScCl3 6H2O
--
--
--
--
--
In(OTf)3
10/75
-/89
-/85
-/86
La(OTf)3
Nd(OTf)3
Bi(OTf)3
ACS Paragon Plus Environment

Page 5 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
17
18
19
20
Y(OTf)3
Zn(OTf)2
Ni(OTf)2
Er(OTf)3
--
--
--
--
H2O
H2O
H2O
H2O
-/90
18/76
--
--
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a
The reactions were performed with ynamide 1a (0.25 mmol), Sc(OTf)3 (30 mg, 0.05 mmol), H2O
(4.5 μL, 0.25 mmol) and acetone 2a (2.50 mmol) at rt for 2 h. b Solvent (1.0 mL). Isolated yield.
c
d
Without H2O. e MeOH (10.0 μL, 0.25 mmol).
Next, we turned to investigate the scope and limitation of the addition of ynamides 1a-1i
with different ketones 2a-2n (Scheme 1). First, different substituted ynamides 1a-1i were
surveyed to react with acetone under the optimal condition, as summarized in Scheme 1.
In general, most substituted ynamides 1a-1h could smoothly react with acetone to give
desired products 3aa-3ha in excellent yields, except that 4-Cl-Ts substituted ynamide 1i
afforded low yield (3ia, 41%). Various aromatic ketones 2b-2n were also examined
under the optimal condition. The reactions of most aromatic ketones with ynamide 1a
could lead to the desired addition products 3ab-3an in moderate yields. The steric
hindered β-acetonaphthone 2m also worked well to give 3am in 75% yield. It is worth
mentioning that cyclopentanone 2n was also a suitable substrate, albeit with low yield
(3an, 23%). However, the reaction with cyclohexanone turned out to be messy and did
not generate any desired product. The structure of 3aa-3ia was unambiguously confirmed
by X-ray crystallographic analysis of compound 3ab (see Supporting Information).
Scheme 1. Substrate Scope of Ynamides and Ketones. a-d
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 33
1
2
3
4
5
6
7
8
9
EWG
N
R3
R2
O
R4
EWG
HO
Sc(OTf)3
+ R3 R4
N
R1
R2
Solvent-free
H2O
R1
O
1a~1i
2a~2n
3aa~3ia
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
OH
OH
Ts
N
Ts
N
Bn
Bn
R1
O
S
3ea
O
99%
OH
1
3aa
R =H, 93%
1
3ba
R =4-F-, 92%
Ts
3ca
3da
R1=4-Me-, 84%
R =4-n-C4H9-, 82%
N
R2
1
O
2
3fa
R =Me-, 99%
R3
2
OH
Ts
3ga
R =n-C4H9-, 91%
OH
Ms
N
Bn
H
O
N
Bn
O
3
3ab
3ac
3ad
R = H, 65%
3ha
85%
3
R = 4-Br-, 75%
OH
3
R = 4-Cl-, 77%
Bn
3
3ae
3af
R = 4-CF3-, 79%
O
S
N
3
R = 4-Me-, 72%
O
O
3
3ag
3ah
3ai
R = 2-MeO-, 61%
Cl
3
R = 2-F-, 78%
3ia
41%
OH
3
R = 3-CF3-, 72%
3
3aj
3ak
3al
R = 3-F-, 80%
3
Ts
N
R = 3-Me-, 66%
3
R = 3-Cl-, 73%
Bn
H
O
c
3am
75%
Ts
N
HO
Bn
O
3ab
3an
23%
ACS Paragon Plus Environment

Page 7 of 33
The Journal of Organic Chemistry
1
2
3
4
a The reactions were performed with ynamides 1a-1i (0.25 mmol), Sc(OTf)3 (30 mg, 0.05 mmol), H2O
5
6
c
(4.5 μL, 0.25 mmol) and ketones 2a-2n (2.50 mmol) at rt for 2 h. b Isolated yield. The reaction was
7
8
performed in PhMe (1.0 mL). d dr > 99:1 and dr was determined by 1H NMR of crude product.
9
Then, we turned our attention to investigate this transformation with chiral ynamides 1j-
1r, which were prepared according to similar known approach20 (Scheme 2). When (R)-
4-benzyloxazolidin-2-one substituted ynamide 1j was used, the desired product could be
generated in 63% yield with high diastereoselectivity (dr > 99:1). The alkyl chain
substituted ynamide 1k also led to excellent diastereoselectivity (dr > 99:1), along with
slightly lower yield (3k, 42%). Other chiral auxiliary derived ynamides also worked well.
Ynamides 1l–1r bearing (R)-4-phenyloxazolidin-2-one, (R)-4-isopropyloxazolidin-2-one,
(4S,5R)-4-methyl-5-phenyloxazolidin-2-one, all offered the desired products in moderate
yields with outstanding diastereoselectivities. The absolute configuration of newly
generated chiral centre was fully controlled by chiral auxiliaries. Ynamides 1j–1o
provided αR-carboxamide products, while ynamides 1p–1r bearing (4S,5R)-4-methyl-5-
phenyloxazolidin-2-one afforded the desired products 3p-3r with αS-configuration. The
stereochemistry of compounds 3j-3r was unambiguously assigned by X-ray
crystallographic analysis of compound 3o (see Supporting Information).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 2. Substrate Scope of Chiral Substituted Ynamides. a-c
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 33
1
2
3
4
5
6
7
8
9
O
N
OH
R
O
Sc(OTf)3
*
R
+
*
N
R1
Solvent-free
R1
H2O
O
3j~3r
O
1j~1r
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
OH
O
O
N
Bn
O
Cl
3o
OH
3j
68%, dr > 99:1
OH
O
O
O
O
N
N
C6H13
Bn
O
O
3k
42%, dr > 99:1
3o
59%, dr > 99:1
OH
O
OH
O
O
N
O
Ph
N
R1
R1
Ph
O
O
1
1
3p
3q
3r
R = H, 41%, dr > 99:1
3l
R = H, 63%, dr > 99:1
1
1
R = 4-MeO-, 70%, dr > 99:1
3m
3n
R = 4-MeO-, 82%, dr > 99:1
R = 4-Br-, 52%, dr > 99:1
1
1
R = 4-Br-, 40%, dr > 99:1
a The reactions were performed with ynamides 1j-1r (0.25 mmol), Sc(OTf)3 (30 mg, 0.05 mmol), H2O
(4.5 μL, 0.25 mmol) and acetone (2.50 mmol) at rt for 2 h. b Isolated yield. c dr was determined by 1H
NMR of crude product.
According to previous work9b, 14f, 19 and our results, a possible mechanism was illustrated
for this addition reaction of ynamides with ketones (Figure 2). First, scandium(III)
triflate coordinated with the acetylene bond of 1a to give anti-allene-type Sc(III)
intermediate 5. Such a metal species 5 would attack Sc-activated keto-carbonyl group to
give preferred conformation intermediate 6, which subsequently form the enol
ACS Paragon Plus Environment

Page 9 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
intermediate 7. On the other hand, slight 5 produced the hydration product 4. Finally,
isomerization of unstable enol 7 led to 3ab.
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
OH
Bn
Tf
H
Ph
Ph
Ts
H
O
Ts
N
N
OTf
Ph
Ph
Sc
O
OTf
O
Bn
6
OH
7
O
Ph
Bn
Sc(OTf)3
Ph
O
OH
H
N Ts
Ph
Ts
N
4
Ph
Ts
Bn
Ph
1a
Bn
N
H
O
3ab
OTf
(OTf)2
OSc
5
H2O
Figure 2. Proposed mechanism of the reaction.
18
To verify this process, 1a was subjected to the standard reaction conditions with H2 O,
the desired isotope substituted products 3ab-18O was isolated (Scheme 3). This showed
that water was attended the reaction process.
Scheme 3. Mechanistic studies of the reaction. a, b
Ts
N
OH
H
O
Bn
Sc(OTf)3
H218O
+
18O
+
N
Bn
3ab-18O
Ts
1a
2b
The reaction was performed with ynamide 1a (0.25 mmol), Sc(OTf)3 (30 mg, 0.05 mmol), H218O
a
(4.5 μL, 0.50 mmol) and ketone 2b (2.50 mmol) at rt for 2 h. b The result was based on HRMS (see
Supporting Information).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 33
1
2
3
4
CONCLUSION
5
6
7
8
9
In summary, we established a novel and efficient approach for highly regioselective
synthesis of functionalized tertiary type β-hydroxyl carboxamides 3aa-3ia through a
Sc(OTf)3-catalyzed addition of ynamides and ketones. It is worth mentioning that water
was found to be an important reaction substrate. Moreover, a series of chiral
carboxamides 3j-3r were synthesized through this approach in excellent regio-
selectivities and outstanding diastereoselectivities.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
EXPERIMENTAL SECTION
General Methods. Reactions were monitored by thin layer chromatography (TLC) on
glass plates coated with silica gel with fluorescent indicator. Flash chromatography was
performed on silica gel (300−400) with Petroleum/EtOAc as eluent. Optical rotations
were measured on a polarimeter with a sodium lamp. HRMS were measured on a
LCMSIT apparatus. IR spectra were recorded using film on a Fourier Transform Infrared
Spectrometer. NMR spectra were recorded at 400 or 600 MHz, and chemical shifts are
1
reported in δ (ppm) referenced to an internal TMS standard for H NMR and CDCl3
(77.16 ppm) for 13C{1H} NMR.
General procedure for synthesis of (3). To a solution of compound 1 (0.25 mmol，
1.0 equiv), Sc(OTf)3 (30 mg, 0.05 mmol, 0.2 equiv) and 2 (2.50 mmol, 10.0 equiv) at rt
for 2 h. The residue was purified by flash chromatography on silica gel (PE/EA) to give
3.
N-benzyl-3-hydroxy-3-methyl-2-phenyl-N-tosylbutanamide (3aa). Colorless oil.
(102 mg, 93%, PE/EA = 4:1); IR (film): νmax 3502, 2976, 1674, 1357, 1167, 1088, 701,
ACS Paragon Plus Environment

Page 11 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
587, 547 cm-1; H NMR (400 MHz, CDCl3) δ 7.62-7.52 (m, 2H), 7.40-7.33 (m, 2H),
7.33-7.30 (m, 3H), 7.29-7.26 (m, 1H), 7.25-7.20 (m, 4H), 7.04-6.87 (m, 2H), 5.22 (d, J =
16.8 Hz, 1H), 6.67 (d, J = 16.8 Hz, 1H), 3.91 (s, 1H), 3.86 (brs, 1H), 2.44 (s, 3H), 1.06 (s,
13
3H), 0.82 (s, 3H) ppm; C{1H} NMR (100 MHz, CDCl3) δ 174.9, 145.1, 136.6, 136.0,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
133.3, 129.9, 129.6, 129.0, 128.5, 128.3, 128.0, 127. 9, 126.9, 72.5, 59.2, 49.5, 29.4,
27.2, 21.8 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for C25H28NO4S+: 438.1734,
found: 438.1739.
(2S, 3S)-N-Benzyl-3-hydroxy-2,3-diphenyl-N-tosylbutanamide (3ab). White solid.
(81 mg, 65%, PE/EA = 8:1); M.P. 117-119oC; IR (film): νmax 3473, 2929, 1779, 1674,
1495, 1356, 1168, 1087, 701 cm-1; H NMR (400 MHz, CDCl3) δ 7.37-7.27 (m, 5H),
1
7.26-7.17 (m, 9H), 7.16-7.09 (m, 3H), 6.97-6.83 (m, 2H), 5.01 (s, 1H), 4.98-4.86 (m,
1H), 4.41 (d, J = 15.2 Hz, 1H), 2.41 (s, 3H), 1.11 (s, 3H) ppm; 13C{1H} NMR (100 MHz,
CDCl3) δ 174.5, 147.5, 144.9, 135.9, 135.5, 133.0, 130.5, 129.6, 128.8, 128.6, 128.4,
128.1, 128.1, 127.6, 126.8, 126.7, 124.9, 76.3, 58.9, 49.2, 28.7, 21.7 ppm; HRMS (ESI-
Orbitrap) m/z: [M + H]+ Calcd for C30H30NO4S+: 500.1890, found: 500.1892.
(2S,
3S)-N-Benzyl-3-(4-bromophenyl)-3-hydroxy-2-phenyl-N-tosylbutanamide
(3ac). White solid. (108 mg, 75%, PE/EA = 8:1); M.P. 134-136oC; IR (film): νmax 3483,
2974, 1688, 1363, 1167, 1087, 995, 750, 588 cm-1; H NMR (400 MHz, CDCl3) δ 7.37-
1
7.22 (m, 10H), 7.21-7.12 (m, 4H), 7.10-6.97 (m, 2H), 6.96-6.82 (m, 2H), 5.05 (s, 1H),
5.01-4.84 (m, 1H), 4.41 (d, J = 16.4 Hz, 1H), 2.42 (s, 3H), 1.08 (s, 3H) ppm; C{1H}
13
NMR (100 MHz, CDCl3) δ 174.3, 146.6, 145.0, 135.6, 135.3, 132.5, 131.2, 130.4, 129.5,
128.8, 128.6, 128.1, 128.0, 127.7, 126.8, 126.7, 120.6, 76.0, 58.5, 49.1, 28.5, 21.7 ppm;
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 33
1
2
3
4
HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for C30H29BrNO4S+: 578.0995, 580.0975,
5
6
found: 578.0996, 580.0983.
7
8
9
(2S,
3S)-N-Benzyl-3-(4-chlorophenyl)-3-hydroxy-2-phenyl-N-tosylbutanamide
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(3ad). White solid. (103 mg, 77%, PE/EA = 8:1); M.P. 110-112oC; IR (film): νmax 3425,
1
1655, 1493, 1356, 1167, 1088, 813, 753, 585 cm-1; H NMR (400 MHz, CDCl3) δ 7.39-
7.24 (m, 8H), 7.22-7.03 (m, 8H), 7.02-6.87 (m, 2H), 5.04 (s, 1H), 4.94 (brs, 1H), 4.40 (d,
13
J = 16.4 Hz, 1H), 2.42 (s, 3H), 1.08 (s, 3H) ppm; C{1H} NMR (100 MHz, CDCl3) δ
174.4, 146.1, 145.1, 135.8, 135.4, 132.6, 132.5, 130.5, 129.6, 128.8, 128.7, 128.4, 128.2,
128.1, 127.8, 126.9, 126.4, 76.1, 58.6, 49.2, 28.6, 21.8 ppm; HRMS (ESI-Orbitrap) m/z:
[M + H]+ Calcd for C30H29ClNO4S+: 534.1500, found: 534.1503.
(2S,
3S)-N-Benzyl-3-hydroxy-2-phenyl-N-tosyl-3-(4-
(trifluoromethyl)phenyl)butanamide (3ae). White solid. (112 mg, 79%, PE/EA = 8:1);
M.P. 139-141oC; IR (film): νmax 3454, 2924, 1666, 1327, 1165, 1121, 1083, 700, 587 cm-
1
1; H NMR (400 MHz, CDCl3) δ 7.43-7.35 (m, 4H), 7.35-7.28 (m, 4H), 7.28-7.24 (m,
2H), 7.24-7.15 (m, 4H), 7.15-7.08 (m, 2H), 7.05-6.85 (m, 2H), 5.16 (s, 1H), 4.94 (brs,
1H), 4.40 (d, J = 16.4 Hz, 1H), 2.41 (s, 3H), 1.09 (s, 3H) ppm; 13C{1H} NMR (100 MHz,
CDCl3) δ 174.3, 151.6, 145.2, 135.3, 132.4, 130.7 (q, J = 670.4, 331.4 Hz), 130.5, 129.6,
128.8, 128.8, 128.3, 128.1, 127.9, 126.9, 125.4, 125.3, 125.2, 123.0, 76.3, 58.5, 49.2,
28.7, 21.7 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for C31H29F3NO4S+:
568.1764, found: 568.1767.
(2S,
3S)-N-Benzyl-3-hydroxy-2-phenyl-3-(p-tolyl)-N-tosylbutanamide
(3af).
White solid. (96 mg, 72%, PE/EA = 8:1); M.P. 112-114oC; IR (film): νmax 3448, 2924,
ACS Paragon Plus Environment

Page 13 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1638, 1454, 1357, 1167, 1085, 699, 588 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.47-7.24
(m, 7H), 7.23-7.04 (m, 7H), 7.03-6.98 (m, 2H), 6.97-6.85 (m, 2H), 4.98 (s, 1H), 4.97-
4.83 (m, 1H), 4.42 (d, J = 16.8 Hz, 1H), 2.41 (s, 3H), 2.35 (s, 3H), 1.09 (s, 3H) ppm;
13C{1H} NMR (100 MHz, CDCl3) δ 174.5, 144.9, 144.6, 136.0, 135.9, 135.5, 133.1,
130.6, 129.5, 129.1, 128.7, 128.6, 128.1, 128.0, 127.6, 126.9, 124.8, 76.2, 58.9, 49.2,
28.8, 21.7, 21.2 ppm; HRMS (ESI-Orbitrap) m/z: [M + Na]+ Calcd for C31H31NO4SNa+:
536.1866, found: 536.1863.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(2S, 3S)-N-Benzyl-3-hydroxy-3-(2-methoxyphenyl)-2-phenyl-N-tosylbutanamide
(3ag). White solid. (84 mg, 61%, PE/EA = 8:1); M.P. 141-143oC; IR (film): νmax 3458,
1
2924, 2854, 1666, 1455, 1359, 1167, 1082, 755 cm-1; H NMR (400 MHz, CDCl3) δ
7.54-7.47 (m, 1H), 7.33-7.20 (m, 6H), 7.18-7.12 (m, 4H), 7.12-7.05 (m, 3H), 6.90-6.83
(m, 1H), 6.82-6.75 (m, 3H), 5.54 (brs, 1H), 5.45 (s, 1H), 4.79 (d, J = 16.4 Hz, 1H), 4.54
(d, J = 16.0 Hz, 1H), 3.68 (s, 3H), 2.39 (s, 3H), 1.22 (s, 3H) ppm; 13C{1H} NMR (100
MHz, CDCl3) δ 175.3, 155.2, 144.6, 136.0, 135.6, 134.6, 133.7, 130.8, 129.5, 128.6,
128.5, 128.4, 128.0, 127.7, 127.2, 126.3, 120.9, 111.1, 76.0, 55.2, 55.1, 49.1, 25.1, 21.7
ppm; HRMS (ESI-Orbitrap) m/z: [M + Na]+ Calcd for C31H31NO5SNa+: 552.1815, found:
552.1821.
(2S,
3S)-N-Benzyl-3-(2-fluorophenyl)-3-hydroxy-2-phenyl-N-tosylbutanamide
(3ah). White solid. (101 mg, 78%, PE/EA = 8:1); M.P. 118-120oC; IR (film): νmax 3434,
1
2924, 2854, 1638, 1458, 1364, 1168, 1083, 580 cm-1; H NMR (400 MHz, CDCl3) δ
7.54-7.47 (m, 1H), 7.43-7.30 (m, 3H), 7.29-7.23 (m, 3H), 7.22-7.17 (m, 3H), 7.17-7.10
(m, 4H), 7.05-6.99 (m, 1H), 6.96-6.79 (m, 3H), 5.52 (s, 1H), 4.92 (d, J = 16.8 Hz, 1H),
4.58 (d, J = 16.8 Hz, 1H), 2.42 (s, 3H), 1.17 (s, 3H) ppm; 13C{1H} NMR (100 MHz,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 33
1
2
3
4
5
6
7
8
9
CDCl3) δ 174.9, 158.8 (d, J = 242.8 Hz), 144.8, 135.8, 135.6, 133.7 (d, J = 12.2 Hz),
132.7, 130.6, 129.4, 128.9 (d, J = 8.6 Hz), 128.8, 128.6, 128.3 (d, J = 4.3 Hz), 128.2,
128.1, 127.5, 126.3, 124.3, 116.1 (d, J = 24.2 Hz), 75.0, 74.9, 56.6, 49.3, 26.0, 25.9, 21.7
ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for C30H29FNO4S+: 518.1796, found:
518.1799.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(2S,
3S)-N-Benzyl-3-hydroxy-2-phenyl-N-tosyl-3-(3-
(trifluoromethyl)phenyl)butanamide (3ai). White solid. (102 mg, 72%, PE/EA = 8:1);
M.P. 128-130oC; IR (film): νmax 3451, 2924, 1702, 1459, 1328, 1164, 1083, 702, 544 cm-
1
1; H NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 7.47-7.42 (m, 1H), 7.41-7.28 (m, 5H),
7.27-7.23 (m, 3H), 7.22-7.14 (m, 4H), 7.13-7.07 (m, 2H), 7.03-6.85 (m, 2H), 5.04 (s,
1H), 4.94-4.81 (m, 1H), 4.41 (d, J = 16.4 Hz, 1H), 2.39 (s, 3H), 1.12 (s, 3H) ppm;
13C{1H} NMR (100 MHz, CDCl3) δ 174.3, 148.8, 145.1, 135.7, 135.4, 132.6, 130.6,
129.6, 128.8, 128.7, 128.2, 128.0, 127.8, 126.8, 125.6, 123.7 (d, J = 4.3 Hz), 122.9, 122.0
(d, J = 3.5 Hz), 76.3, 58.5, 49.3, 28.8, 21.7 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+
Calcd for C31H29F3NO4S+: 568.1764, found: 568.1767.
(2S,
3S)-N-Benzyl-3-(3-fluorophenyl)-3-hydroxy-2-phenyl-N-tosylbutanamide
(3aj). White solid. (104 mg, 80%, PE/EA = 8:1); M.P. 116-118oC; IR (film): νmax 3447,
2960, 1638, 1493, 1358, 1167, 1084, 699, 457 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.42-
7.22 (m, 9H), 7.20-7.10 (m, 5H), 7.01-6.92 (m, 2H), 6.91-6.82 (m, 2H), 5.05 (s, 1H),
5.03-4.86 (m, 1H), 4.42 (d, J = 16.4 Hz, 1H), 2.41 (s, 3H), 1.07 (s, 3H) ppm; 13C{1H}
NMR (100 MHz, CDCl3) δ 174.3, 162.8 (d, J = 244.2 Hz), 150.5 (d, J = 5.8 Hz), 145.1,
135.8, 135.4, 132.6, 130.5, 129.8 (d, J = 8.0 Hz), 129.6, 128.9, 128.7, 128.2, 128.1,
127.8, 126.8, 120.4, 113.6 (d, J = 21.0 Hz), 112.4 (d, J = 22.6 Hz), 76.1, 58.6, 49.2, 28.7,
ACS Paragon Plus Environment

Page 15 of 33
The Journal of Organic Chemistry
1
2
3
4
21.7 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for C30H29FNO4S+: 518.1796,
5
6
found: 518.1793.
7
8
9
(2S,
3S)-N-Benzyl-3-hydroxy-2-phenyl-3-(m-tolyl)-N-tosylbutanamide
(3ak).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
White solid. (88 mg, 66%, PE/EA = 8:1); M.P. 130-132oC; IR (film): νmax 3449, 2924,
1
2854, 1638, 1460, 1376, 1167, 749, 420 cm-1; H NMR (400 MHz, CDCl3) δ 7.37-7.26
(m, 5H), 7.24-7.14 (m, 5H), 7.13-7.06 (m, 3H), 7.04-7.00 (m, 1H), 6.96-6.81 (m, 2H),
4.97 (s, 1H), 4.89 (d, J = 16.0 Hz, 1H), 4.41 (d, J = 16.8 Hz, 1H), 2.40 (s, 3H), 2.28 (s,
3H), 1.11 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 174.5, 147.6, 144.9, 137.9,
135.8, 135.6, 133.2, 130.6, 129.6, 128.8, 128.6, 128.3, 128.0, 127.5, 126.7, 125.7, 122.0,
76.3, 58.8, 49.2, 28.8, 21.8, 21.7 ppm; HRMS (ESI-Orbitrap) m/z: [M + Na]+ Calcd for
C31H31NO4SNa+: 536.1866, found: 536.1867.
(2S,
3S)-N-Benzyl-3-(3-chlorophenyl)-3-hydroxy-2-phenyl-N-tosylbutanamide
(3al). White solid. (97 mg, 73%, PE/EA = 8:1); M.P. 132-134oC; IR (film): νmax 3424,
2960, 1655, 1494, 1356, 1166, 1084, 700, 546 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.56-
7.21 (m, 10H), 7.20-7.11 (m, 5H), 7.10-7.05 (m, 1H), 7.02-6.91 (m, 2H), 5.02 (s, 1H),
4.98-4.83 (m, 1H), 4.41 (d, J = 16.4 Hz, 1H), 2.41 (s, 3H), 1.08 (s, 3H) ppm; 13C{1H}
NMR (100 MHz, CDCl3) δ 174.3, 149.9, 145.1, 135.7, 135.4, 134.4, 132.6, 130.5, 129.6,
128.9, 128.7, 128.2, 128.1, 127.8, 127.0, 126.8, 125.4, 123.1, 76.1, 58.5, 49.2, 28.8, 21.8
ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for C30H29ClNO4S+: 534.1500, found:
534.1506.
(2S,
3S)-N-Benzyl-3-hydroxy-3-(naphthalen-2-yl)-2-phenyl-N-tosylbutanamide
(3am). White solid. (107 mg, 75%, PE/EA = 8:1); M.P. 136-138oC; IR (film): νmax 3447,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 33
1
2
3
4
1
1638, 1494, 1359, 1166, 1084, 750, 582, 457 cm-1; H NMR (400 MHz, CDCl3) δ 7.87-
5
6
7
8
7.82 (m, 1H), 7.82-7.60 (m, 3H), 7.55-7.47 (m, 2H), 7.42-7.31 (m, 4H), 7.30-7.24 (m,
2H), 7.23-7.04 (m, 3H), 7.00-6.60 (m, 5H), 5.20 (s, 1H), 4.86 (brs, 1H), 4.39 (d, J = 16.0
Hz, 1H), 2.31 (s, 3H), 1.21 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 174.5,
145.0, 144.8, 135.6, 135.4, 133.3, 133.0, 132.4, 130.6, 129.5, 128.7, 128.6, 128.1, 127.8,
127.6, 126.6, 126.1, 125.9, 123.8, 123.4, 76.6, 58.7, 49.1, 28.7, 21.7 ppm; HRMS (ESI-
Orbitrap) m/z: [M + Na]+ Calcd for C34H31NO4SNa+: 572.1866, found: 572.1866.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N-Benzyl-2-(1-hydroxycyclopentyl)-2-phenyl-N-tosylacetamide (3an). Colorless
oil. (27 mg, 23%, PE/EA = 8:1); IR (film): νmax 3483, 2926, 1688, 1587, 1363, 1167,
1
1014, 750, 588 cm-1; H NMR (400 MHz, CDCl3) δ 7.60-7.52 (m, 2H), 7.39-7.34 (m,
2H), 7.34-7.28 (m, 3H), 7.26-7.19 (m, 5H), 7.01-6.97 (m, 2H), 5.22 (d, J = 16.8 Hz, 1H),
4.62 (d, J = 16.8 Hz, 1H), 3.86 (s, 1H), 3.73 (s, 1H), 2.43 (s, 3H), 1.75-1.56 (m, 3H),
1.42-1.30 (m, 2H), 1.29-1.20 (m, 2H), 1.18-1.10 (m, 1H) ppm; 13C{1H} NMR (100 MHz,
CDCl3) δ 175.0, 145.0, 136.6, 136.0, 133.9, 129.5, 129.5, 129.1, 128.5, 128.3, 128.0,
127.8, 126.8, 83.2, 58.4, 49.4, 40.0, 37.7, 23.5, 23.1, 21.8 ppm; HRMS (ESI-Orbitrap)
m/z: [M + H]+ Calcd for C27H30NO4S+: 464.1890, found: 464.1893.
N-Benzyl-2-(4-fluorophenyl)-3-hydroxy-3-methyl-N-tosylbutanamide
(3ba).
Corlorless oil. (105 mg, 92%, PE/EA = 4:1); IR (film): νmax 3451, 1674, 1508, 1355,
1167, 1088, 811, 577, 546 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.61-7.52 (m, 2H), 7.38-
7.28 (m, 5H), 7.26-7.21 (m, 2H), 7.04-6.96 (m, 2H), 6.95-6.85 (m, 2H), 5.19 (d, J = 16.4
Hz, 1H), 4.72 (d, J = 16.4 Hz, 1H), 3.94 (brs, 1H), 3.84 (s, 1H), 2.44 (s, 3H), 1.04 (s, 3H),
0.81 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 174.9, 162.5 (d, J = 245.6 Hz),
145.2, 136.4, 136.1, 131.6 (d, J = 7.9 Hz), 129.7, 129.2 (d, J = 2.8 Hz), 128.1, 128.0,
ACS Paragon Plus Environment

Page 17 of 33
The Journal of Organic Chemistry
1
2
3
4
127.1, 115.4, 115.2, 72.4, 58.3, 49.6, 29.3, 27.1, 21.8 ppm; HRMS (ESI-Orbitrap) m/z:
5
6
[M + H]+ Calcd for C25H27FNO4S+: 456.1639, found: 456.1644.
7
8
9
N-benzyl-3-hydroxy-3-methyl-2-(p-tolyl)-N-tosylbutanamide (3ca). Colorless oil.
(95 mg, 84%, PE/EA = 4:1); IR (film): νmax 3442, 1671, 1454, 1356, 1167, 1117, 804,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
699, 546 cm-1; H NMR (400 MHz, CDCl3) δ 7.65-7.53 (m, 2H), 7.43-7.28 (m, 5H),
7.27-7.20 (m, 2H), 7.07-6.98 (m, 2H), 6.93-6.83 (m, 2H), 5.22 (d, J = 16.8 Hz, 1H),
4.65 (d, J = 16.8 Hz, 1H), 3.88 (s, 1H), 3.76 (brs, 1H), 2.44 (s, 3H), 2.32 (s, 3H), 1.04 (s,
3H), 0.80 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 175.0, 145.0, 137.6, 136.6,
136.1, 130.2, 129.7, 129.5, 129.2, 129.0, 128.3, 127.9, 126.8, 72.4, 58.8, 49.4, 29.4,
27.2, 21.8, 21.2 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for C26H30NO4S+:
452.1890, found: 452.1896.
N-Benzyl-2-(4-butylphenyl)-3-hydroxy-3-methyl-N-tosylbutanamide
(3da).
Colorless oil. (101 mg, 82%, PE/EA = 4:1); IR (film): νmax 3511, 2929, 1675, 1456, 1356,
1167, 1087, 813, 701 cm-1; H NMR (400 MHz, CDCl3) δ 7.62-7.54 (m, 2H), 7.40-7.34
1
(m, 2H), 7.34-7.30 (m, 3H), 7.25-7.20 (m, 2H), 7.05-7.01 (m, 2H), 6.93-6.87 (m, 2H),
5.22 (d, J = 16.8 Hz, 1H), 4.67 (d, J = 16.8 Hz, 1H), 3.92 (s, 1H), 3.79 (brs, 1H), 2.61-
2.56 (m, 2H), 2.44 (s, 3H), 1.60-1.53 (m, 2H), 1.40-1.33 (m, 2H), 1.05 (s, 3H), 0.98-0.92
(m, 3H), 0.81 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 175.1, 145.0, 142.6,
136.7, 136.1, 130.4, 129.8, 129.5, 129.0, 128.6, 128.3, 127.9, 126.9, 72.5, 58.9, 49.5,
35.4, 33.7, 29.4, 27.2, 22.5, 21.8, 14.1 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd
for C29H36NO4S+: 494.2360, found: 494.2358.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 33
1
2
3
4
5
6
7
8
9
N-Benzyl-3-hydroxy-3-methyl-2-(thiophen-2-yl)-N-tosylbutanamide (3ea). White
solid. (110 mg, 99%, PE/EA = 4:1); M.P. 99-101oC; IR (film): νmax 3449, 1656, 1355,
1243, 1167, 1087, 814, 701, 545 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.65-7.54 (m, 2H),
7.37-7.33 (m, 4H), 7.33-7.27 (m, 1H), 7.26-7.17 (m, 3H), 6.87 (dd, J = 4.0, 3.2 Hz, 1H),
6.67 (d, J = 2.8 Hz, 1H), 5.19 (d, J = 16.4 Hz, 1H), 4.84 (d, J = 16.4 Hz, 1H), 4.38 (s,
1H), 3.82 (s, 1H), 2.42 (s, 3H), 1.03 (s, 3H), 0.92 (s, 3H) ppm; 13C{1H} NMR (100 MHz,
CDCl3) δ 174.6, 145.2, 136.4, 136.0, 134.9, 129.7, 128.9, 128.2, 128.0, 127.4, 126.4,
126.1, 72.5, 54.6, 49.7, 28.8, 27.0, 21.8 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
for C23H26NO4S2 : 444.1298, found: 444.1291.
3-Hydroxy-N,3-dimethyl-2-phenyl-N-tosylbutanamide (3fa). Colorless oil. (90 mg,
99%, PE/EA = 4:1); IR (film): νmax 3450, 1656, 1358, 1262, 1167, 1080, 749, 673, 548
cm-1; 1H NMR (400 MHz, CDCl3) δ 7.52-7.45 (m, 2H), 7.31-7.25 (m, 3H), 7.23-7.14 (m,
4H), 4.24 (s, 1H), 3.98 (s, 1H), 3.20 (s, 3H), 2.41 (s, 3H), 1.28 (s, 3H), 0.98 (s, 3H) ppm;
13C{1H} NMR (100 MHz, CDCl3) δ 174.8, 145.0, 135.6, 133.7, 130.2, 129.7, 128.5,
127.8, 72.6, 59.4, 33.3, 29.7, 27.2, 21.7 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd
for C19H24NO4S+: 362.1421, found: 362.1427.
N-Butyl-3-hydroxy-3-methyl-2-phenyl-N-tosylbutanamide (3ga). Colorless oil. (92
mg, 91%, PE/EA = 4:1); IR (film): νmax 3495, 2962, 1668, 1357, 1168, 1085, 909, 701,
548 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.59-7.50 (m, 2H), 7.29-7.20 (m, 5H), 7.17-7.09
(m, 2H), 4.09 (brs, 1H), 4.04 (s, 1H), 3.77 (ddd, J = 14.8, 10.4, 5.6 Hz, 1H), 3.57 (ddd, J
= 14.8, 10.4, 5.2 Hz, 1H), 2.42 (s, 3H), 1.64-1.53 (m, 2H), 1.37-1.28 (m, 2H), 1.26 (s,
3H), 0.96 (s, 3H), 0.95-0.90 (m, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 174.6,
144.9, 136.4, 133.8, 130.1, 129.6, 128.4, 127.9, 127.8, 72.6, 59.2, 46.7, 32.2, 29.7, 27.3,
ACS Paragon Plus Environment

Page 19 of 33
The Journal of Organic Chemistry
1
2
3
4
21.7, 20.2, 13.8 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for C22H30NO4S+:
5
6
404.1890, found: 404.1884.
7
8
9
N-benzyl-3-hydroxy-3-methyl-N-(methylsulfonyl)-2-phenylbutanamide
(3ha).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Colorless oil. (76 mg, 85%, PE/EA = 4:1); IR (film): νmax 3449, 2926, 1719, 1656, 1362,
1166, 1086, 814, 662 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.42-7.34 (m, 5H), 7.33-7.28
(m, 5H), 5.05 (d, J = 16.8 Hz, 1H), 4.77 (d, J = 16.8 Hz, 1H), 4.02 (s, 1H), 3.99 (brs, 1H),
3.00 (s, 3H), 1.22 (s, 3H), 0.90 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 176.0,
136.3, 133.6, 130.1, 129.2, 128.9, 128.3, 128.2, 127.1, 72.7, 59.1, 49.0, 42.6, 29.7, 27.3
ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for C19H24NO4S+: 362.1421 found:
362.1425.
N-Benzyl-N-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-methyl-2-phenylbutanamide
(3ia). Colorless oil. (47 mg, 41%, PE/EA = 4:1); IR (film): νmax 3443, 2925, 1767, 1668,
1356, 1164, 1027, 695, 545 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.66-7.59 (m, 2H), 7.43-
7.37 (m, 4H), 7.36-7.27 (m, 4H), 7.26-7.22 (m, 2H), 7.01-6.92 (m, 2H), 5.23 (d, J =
17.2Hz, 1H), 4. 66 (d, J = 17.2 Hz, 1H), 3.79 (s, 1H), 3.76 (s, 1H), 1.08 (s, 3H), 0.82 (s,
3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 174.8, 140.6, 137.3, 136.3, 133.1, 129.9,
129.8, 129.2, 128.7, 128.2, 128.1, 126.8, 72.5, 59.3, 49.5, 29.4, 27.2 ppm; HRMS (ESI-
Orbitrap) m/z: [M + H]+ Calcd for C24H25ClNO4S+: 458.1187, found: 458.1183.
(R)-4-Benzyl-3-((R)-2-(4-chlorophenyl)-3-hydroxy-3-methylbutanoyl)oxazolidin-2-
24
one (3j). Colorless oil. (66 mg, 68%, PE/EA = 2:1); [α]D = 3.1 (c 0.55, CHCl3); IR
1
(film): νmax 3442, 1779, 1635, 1490, 1376, 1212, 1105, 1015, 701 cm-1; H NMR (400
MHz, CDCl3) δ 7.47-7.43 (m, 2H), 7.37-7.32 (m, 2H), 7.25-7.16 (m, 3H), 6.97-6.92 (m,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 33
1
2
3
4
5
6
7
8
9
2H), 5.03 (s, 1H), 4.83-4.76 (m, 1H), 4.23 (dd, J = 9.2, 8.4 Hz, 1H), 4.11 (dd, J = 9.2, 2.8
Hz, 1H), 3.90 (s, 1H), 3.64 (dd, J = 13.6, 3.6 Hz), 2.59 (dd, J = 13.6, 8.8 Hz, 1H), 1.41 (s,
3H), 1.04 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 174.6, 152.7, 134.6, 134.0,
132.9, 132.1, 129.5, 129.0, 128.6, 127.6, 72.4, 66.0, 56.2, 54.8, 37.3, 30.1, 27.2 ppm;
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
HRMS (ESI-Orbitrap) m/z: [M + H]+ C21H23ClNO4 : 388.1310, found: 388.1314.
(R)-4-Benzyl-3-((R)-2-(2-hydroxypropan-2-yl)octanoyl)oxazolidin-2-one
(3k).
25
Colorless oil. (38 mg, 42%, PE/EA = 2:1); [α]D = -3.1 (c 0.50, CHCl3); IR (film): νmax
3436, 2920, 2852, 1655, 1638, 1386, 1052, 670, 575 cm-1; 1H NMR (400 MHz, CDCl3) δ
7.37-7.32 (m, 2H), 7.31-7.28 (m, 1H), 7.27-7.23 (m, 2H), 4.85-4.75 (m, 1H), 4.20-4.13
(m, 2H), 4.10 (dd, J = 11.2, 3.6 Hz, 1H), 3.40 (dd, J = 13.2, 3.2 Hz, 1H), 2.80 (s, 1H),
2.66 (dd, J = 12.8, 10.0 Hz, 1H), 1.98-1.85 (m, 1H), 1.65-1.56 (m, 1H), 1.38-1.32 (m,
2H), 1.30 (s, 3H), 1.29-1.26 (m, 6H), 1.25 (s, 3H), 0.92-0.85 (m, 3H) ppm; 13C{1H}
NMR (150 MHz, CDCl3) δ 176.7, 154.3, 135.4, 129.5, 129.2, 127.5, 72.6, 66.1, 55.7,
52.2, 38.3, 31.8, 30.2, 29.6, 29.3, 28.0, 25.5, 22.7, 14.2 ppm; HRMS (ESI-Orbitrap) m/z:
[M + H]+ Calcd for C21H32NO4 : 362.2326, found: 362.2326.
+
(R)-3-((R)-3-Hydroxy-3-methyl-2-phenylbutanoyl)-4-phenyloxazolidin-2-one (3l).
24
Colorless oil. (54 mg, 63%, PE/EA = 2:1); [α]D = 59.2 (c 0.92, CHCl3); IR (film): νmax
3450, 2309, 1783, 1580, 1438, 1340, 1053, 671, 620 cm-1; 1H NMR (400 MHz, CDCl3) δ
7.31-7.26 (m, 2H), 7.26-7.21 (m, 4H), 7.19-7.13 (m, 2H), 6.93-6.84 (m, 2H), 5.50 (dd, J
= 8.8, 4.8 Hz, 1H), 5.08 (s, 1H), 4.67 (dd, J = 9.6, 8.8 Hz, 1H), 4.07 (dd, J = 8.8, 4.8 Hz,
1H), 3.77 (s, 1H), 1.41 (s, 3H), 1.01 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ
174.2, 152.9, 138.0, 133.8, 130.8, 129.1, 128.8, 128.2, 127.8, 125.7, 72.2, 69.6, 57.7,
ACS Paragon Plus Environment

Page 21 of 33
The Journal of Organic Chemistry
1
2
3
4
+
57.5, 30.1, 27.3 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for C20H22NO4 :
5
6
340.1543, found: 340.1545.
7
8
9
(R)-3-((R)-3-Hydroxy-2-(4-methoxyphenyl)-3-methylbutanoyl)-4-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
phenyloxazolidin-2-one (3m). White solid. (75 mg, 82%, PE/EA = 2:1); M.P. 110-
112oC; [α]D21 = 74.1 (c 2.00, CHCl3); IR (film): νmax 3449, 2083, 1780, 1637, 1511, 1345,
1
1246, 1182, 1120 cm-1; H NMR (400 MHz, CDCl3) δ 7.32-7.21 (m, 3H), 7.11-7.05 (m,
2H), 6.92-6.86 (m, 2H), 6.80-6.74 (m, 2H), 5.49 (dd, J = 9.2, 5.2 Hz, 1H), 5.02 (s, 1H),
4.66 (dd, J = 9.6, 8.8 Hz, 1H), 4.07 (dd, J = 9.2, 5.2 Hz, 1H), 3.80 (s, 3H), 3.73 (brs, 1H),
1.39 (s, 3H), 1.00 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 174.4, 159.3, 152.9,
138.1, 131.8, 129.1, 128.8, 125.9, 125.7, 113.6, 72.2, 69.6, 57.7, 56.7, 55.4, 29.9, 27.2
+
ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for C21H24NO5 : 370.1649, found:
370.1655.
(R)-3-((R)-2-(4-Bromophenyl)-3-hydroxy-3-methylbutanoyl)-4-phenyloxazolidin-
2-one (3n). White solid. (54 mg, 52%, PE/EA = 2:1); M.P. 130-132oC; [α]D24 = 113.3 (c
0.55, CHCl3); IR (film): νmax 3443, 1778, 1637, 1486, 1380, 1202, 1104, 760, 701 cm-1;
1H NMR (400 MHz, CDCl3) δ 7.38-7.28 (m, 3H), 7.27-7.23 (m, 2H), 7.07-7.01 (m, 2H),
6.92-6.88 (m, 2H), 5.48 (dd, J = 8.8, 4.8 Hz, 1H), 5.03 (s, 1H), 4.68 (dd, J = 9.6, 8.8 Hz,
1H), 4.12 (dd, J = 8.8, 4.8 Hz, 1H), 3.70 (s, 1H), 1.40 (s, 3H), 0.99 (s, 3H) ppm; 13C{1H}
NMR (100 MHz, CDCl3) δ 173.8, 152.9, 137.9, 132.9, 132.4, 131.3, 129.2, 129.0, 125.7,
122.1, 72.0, 69.7, 57.8, 56.9, 30.0, 27.3 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd
+
for C20H21BrNO4 : 418.0649, 420.0628, found: 418.0649, 420.0621.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 33
1
2
3
4
(R)-3-((R)-3-Hydroxy-3-methyl-2-phenylbutanoyl)-4-isopropyloxazolidin-2-one
5
6
25
(3o). White solid. (45 mg, 59%, PE/EA = 2:1); M.P. 122-124oC; [α]D = 30.2 (c 0.26,
7
8
9
1
CHCl3); IR (film): νmax 3443, 2967, 1777, 1668, 1373, 1203, 1027, 720, 611 cm-1; H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
NMR (400 MHz, CDCl3) δ 7.45-7.40 (m, 2H), 7.33-7.25 (m, 3H), 5.08 (s, 1H), 4.57-4.50
(m, 1H), 4.30-4.23 (m, 1H), 4.15-4.07 (m, 1H), 4.03 (s, 1H), 2.25-2.15 (m, 1H), 1.41 (s,
3H), 1.03 (s, 3H), 0.85-0.78 (m, 3H), 0.45-0.35 (m, 3H) ppm; 13C{1H} NMR (100 MHz,
CDCl3) δ 175.1, 153.2, 134.6, 130.5, 128.2, 127.8, 72.3, 62.9, 58.0, 57.0, 30.2, 27.8, 27.3,
+
17.9, 14.0 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for C17H24NO4 : 306.1700,
found: 306.1702.
(4S,5R)-3-((S)-3-Hydroxy-3-methyl-2-phenylbutanoyl)-4-methyl-5-
25
phenyloxazolidin-2-one (3p). Colorless oil. (36 mg, 41%, PE/EA = 2:1); [α]D = -78.4
(c 0.86, CHCl3); IR (film): νmax 3504, 2917, 1780, 1676, 1455, 1345, 1233, 1121, 700 cm-
1
1; H NMR (400 MHz, CDCl3) δ 7.46-7.41 (m, 2H), 7.39-7.28 (m, 6H), 7.22-7.15 (m,
2H), 5.67 (d, J = 4.8 Hz, 1H), 5.01 (s, 1H), 4.92-4.82 (m, 1H), 3.93 (s, 1H), 1.44 (s, 3H),
1.06 (s, 3H), 0.75-0.66 (m, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 174.6, 152.3,
134.2, 133.2, 130.6, 129.0, 128.8, 128.3, 127.8, 125.8, 78.9, 72.4, 57.4, 54.7, 30.1, 27.3,
+
14.0 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for C21H24NO4 : 354.1700, found:
354.1698.
(4S,5R)-3-((S)-3-Hydroxy-2-(4-methoxyphenyl)-3-methylbutanoyl)-4-methyl-5-
23
phenyloxazolidin-2-one (3q). Colorless oil. (67 mg, 70%, PE/EA = 2:1); [α]D = -91.6
(c 0.55, CHCl3); IR (film): νmax 3442, 1778, 1638, 1511, 1380, 1246, 1181, 1036, 759 cm-
1
1; H NMR (400 MHz, CDCl3) δ 7.38-7.32 (m, 5H), 7.22-7.17 (m, 2H), 6.88-6.84 (m,
2H), 5.67 (d, J = 7.2 Hz, 1H), 4.94 (s, 1H), 4.90-4.82 (m, 1H), 3.90 (s, 1H), 3.80 (s, 3H),
ACS Paragon Plus Environment

Page 23 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1.42 (s, 3H), 1.05 (s, 3H), 0.72 (d, J = 6.4 Hz, 3H) ppm; 13C{1H} NMR (100 MHz,
CDCl3) δ 174.9, 159.3, 152.3, 133.3, 131.6, 129.0, 128.8, 126.3, 125.8, 113.7, 78.9, 72.5,
56.6, 55.3, 54.7, 30.0, 27.2, 14.0 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for
+
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
C22H26NO5 : 384.1806, found: 384.1814.
(4S,5R)-3-((S)-2-(4-Bromophenyl)-3-hydroxy-3-methylbutanoyl)-4-methyl-5-
24
phenyloxazolidin-2-one (3r). Colorless oil. (43 mg, 40%, PE/EA = 2:1); [α]D = -74.4
(c 0.55, CHCl3); IR (film): νmax 3442, 2076, 1780, 1636, 1366, 1196, 1121 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.49-7.43 (m, 2H), 7.41-7.35 (m, 3H), 7.34-7.30 (m, 2H), 7.23-7.18
(m, 2H), 5.68 (d, J = 7.6 Hz, 1H), 4.95 (s, 1H), 4.90-4.82 (m, 1H), 3.86 (s, 1H), 1.43 (s,
3H), 1.04 (s, 3H), 0.73 (d, J = 6.4 Hz, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ
174.3, 152.3, 133.4, 133.1, 132.3, 131.5, 129.1, 128.9, 125.8, 122.2, 79.0, 72.3, 56.8,
54.8, 30.1, 27.2, 14.0 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for
+
C21H23BrNO4 : 432.0805, 434.0785, found: 432.0810, 434.0759.
Procedure for Synthesis of (3aa) (Gram Scale).
To a solution of compound 1a (1.08 g, 3.0 mmol, 1.0 equiv), Sc(OTf)3 (0.36 g, 0.6 mmol,
0.2 equiv) and 2a (2.2 mL, 30.0 mmol, 10.0 equiv) at rt for 2 h. The residue was purified
by flash chromatography on silica gel (PE/EA = 4:1) to give 3aa as colorless oil (1.16 g,
88%).
General Procedure for Synthesis of (1a-1r).20 To a mixture of an amide (2 mmol),
K3PO4 (4 mmol), CuSO4·5H2O (0.2 mmol), and 1,10-phenanthroline (0.4 mmol,) in
toluene under a N2 atmosphere was added a solution 1-bromoalkyne (2.2 mmol) in
toluene. The reaction was stirred at 75 °C for 24 h under a N2 atmosphere. The reaction
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 33
1
2
3
4
5
6
7
8
9
mixture was cooled to room temperature, diluted with EtOAc, and filtered through Celite,
and the filtrate was concentrated in vacuo. The crude products were purified by flash
chromatography on silica gel (PE/EA) to afford the desired ynamide.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Data for new compounds of Ynamides.
N-benzyl-N-((4-butylphenyl)ethynyl)-4-methylbenzenesulfonamide (1d). White
solid. (635 mg, 76%, PE/EA = 20:1); M.P. 116-118oC; IR (film): νmax 2929, 1779, 1674,
1535, 1356, 1236, 1187, 689, 501 cm-1; 1H NMR (400 MHz, CDCl3) δ7.75-7.60 (m, 2H),
7.38-7.23 (m, 7H), 7.13-7.06 (m, 2H), 7.01-6.84 (m, 2H), 5.08-5.06 (m, 1H), 3.83-3.81
(m, 1H), 2.59-2.52 (m, 2H), 2.43 (s, 3H), 1.61-1.50 (m, 2H), 1.37-1.25 (m, 2H), 0.91 (dd,
J = 7.6, 6.8 Hz, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 171.6, 145.0, 142.0,
136.8, 136.7, 130.4, 129.8, 129.2, 128.8, 128.7, 128.6, 128.1, 127.9, 127.8, 49.8, 42.7,
35.4, 33.7, 22.5, 21.8, 14.1 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for
C26H28NO2S+: 418.1835, found: 418.1840.
(R)-3-((4-Bromophenyl)ethynyl)-4-phenyloxazolidin-2-one (1n). White solid. (468
26
mg, 68%, PE/EA = 10:1); M.P. 130-132oC; [α]D = -178.6 (c 1.00, CHCl3); IR (film):
νmax 2929, 1779, 1574, 1495, 1258, 1168, 1087, 701, 567 cm-1; H NMR (400 MHz,
1
CDCl3) δ 7.50-7.43 (m, 3H), 7.41-7.32 (m, 4H), 7.13-7.08 (m, 2H), 5.14 (dd, J = 7.6, 6.8
Hz, 1H), 4.79 (dd, J = 9.2, 8.4 Hz, 1H), 4.32 (dd, J = 8.8, 7.2 Hz, 1H) ppm; 13C{1H}
NMR (100 MHz, CDCl3) δ 155.5, 136.0, 133.0, 131.6, 129.8, 129.5, 127.0, 122.4, 121.3,
79.2, 72.1, 70.9, 62.3 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for C17H13BrNO2
+:342.0124, 344.0104, found: 342.0120, 343.0108.
ACS Paragon Plus Environment

Page 25 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
(R)-3-((4-Methoxyphenyl)ethynyl)-4-phenyloxazolidin-2-one (1r). White solid. (583
mg, 82%, PE/EA = 10:1); M.P. 110-112oC; [α]D26 = 22.5 (c 1.00, CHCl3); IR (film): νmax
7
8
9
1
3453, 2329, 1779, 1674, 1495, 1356, 968, 687, 501 cm-1; H NMR (400 MHz, CDCl3,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
rotamers) δ 7.52-7.35 (m, 5H), 7.34-7.24 (m, 4H), 5.77 (d, J = 8.0, 1H), 5.71 (d, J = 7.6
Hz, 1H), 4.50-4.42 (m, 0.9H), 4.24-4.16 (m, 0.1H), 1.00 (d, J = 6.4 Hz, 2.7H), 0.80 (d, J
= 6.4 Hz, 0.3H) ppm; 13C{1H} NMR (100 MHz, CDCl3, rotamers) δ 159.0, 155.3, 135.0,
133.8, 133.1, 131.7, 129.2, 128.9, 128.6, 126.1, 122.5, 122.4, 121.4, 81.0, 80.0, 79.3,
71.5, 58.4, 52.4, 17.7, 15.1 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for
+
C18H15BrNO2 : 356.0281, found 356.0281.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
Crystallographic data for 3ab (CIF)
Crystallographic data for 3o (CIF)
HRMS data for 3ab-18O (PDF).
X-ray structures for 3ab and 3o and copies of 1H and 13C spectra (PDF).
Accession Codes
CCDC 1951962, 1951970 contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or
by emailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223
336033.
AUTHOR INFORMATION
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 33
1
2
3
4
Corresponding Author
5
6
*E-mail: bgwei1974@fudan.edu.cn (B.-G. Wei)
7
8
ORCID
9
Bang-Guo Wei: 0000-0003-3470-6741
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank the National Natural Science Foundation of China (21772027, 21472022 to B.-
G. Wei and 21702032 to C.-M. Si) and the Open Research Fund Program of Beijing Key
Lab of Plant Resource Research and Development, BTBU (No. PRRD-2018-ZD1) for
financial support. The authors also thank Dr Han-Qing Dong (Arvinas, Inc.) for helpful
suggestions.
REFERENCES
(1) (a) Blakemore, D. C.; Castro, L.; Churcher, I.; Rees, D. C.; Thomas, A. W.; Wilson,
D. M.; Wood, A. Organic Synthesis Provides Opportunities to Transform Drug
Discovery. Nat. Chem. 2018, 10, 383-394. (b) Bostroem, J.; Brown, D. G.; Young, R. J.;
Keseru, G. M. Expanding the Medicinal Chemistry Synthetic Toolbox. Nat. Rev. Drug
Discovery 2018, 17, 709-727. (c) Ivanenkov, Y. A.; Zagribelnyy, B. A.; Aladinskiy, V.
A. Are We Opening the Door to a New Era of Medicinal Chemistry or Being Collapsed
to a Chemical Singularity? J. Med. Chem. 2019, 10.1021/acs.jmedchem.9b00004.
(2) For selected examples of β-hydroxy α-substituted amides, see: (a) Mahaney, P. E.;
Gavrin, L. K.; Trybulski, E. J.; Stack, G. P.; Vu, A. T.; Cohn, S. T.; Ye, F.; Belardi, J. K.;
Santilli, A. A.; Sabatucci, J. P.; Leiter, J.; Johnston, G. H.; Bray, J. A.; Burroughs, K. D.;
ACS Paragon Plus Environment

Page 27 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Cosmi, S. A.; Leventhal, L.; Koury, E. J.; Zhang, Y.; Mugford, C. A.; Ho, D. M.;
Rosenzweig-Lipson, S. J.; Platt, B.; Smith, V. A.; Deecher, D. C. Structure-Activity
Relationships of the Cycloalkanol Ethylamine Scaffold: Discovery of Selective
Norepinephrine Reuptake Inhibitors. J. Med. Chem. 2008, 51, 4038-4049. (b) Noda, H.;
Amemiya, F.; Weidner, K.; Kumagai, N.; Shibasaki, M., Catalytic Asymmetric Synthesis
of CF3-Substituted Tertiary Propargylic Alcohols via Direct Aldol Reaction of alpha-N3
Amide. Chem. Sci., 2017, 8, 3260-3269. (c) Shimada, N.; Hirata, M.; Koshizuka, M.;
Ohse, N.; Kaito, R.; Makino, K. Diboronic Acid Anhydrides as Effective Catalysts for
the Hydroxy-Directed Dehydrative Amidation of Carboxylic Acids. Org. Lett. 2019, 21,
4303-4308. For selected reviews, see: (d) McDaniel, R.; Welch, M.; Hutchinson, C. R.
Genetic Approaches to Polyketide Antibiotics. 1. Chem. Rev. 2005, 105, 543-558. (e)
Eppe, G.; Didier, D.; Marek, I. Stereocontrolled Formation of Several Carbon-Carbon
Bonds in Acyclic Systems. Chem. Rev. 2015, 115, 9175-9206. (f) Yamashita, Y.;
Yasukawa, T.; Yoo, W. J.; Kitanosono, T.; Kobayashi, S., Catalytic Enantioselective
Aldol Reactions. Chem. Soc. Rev. 2018, 47, 4388-4480.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(3) (a) Moraski, G. C.; Chang, M.; Villegas-Estrada, A.; Franzblau, S. G.; Mollmann,
U.; Miller, M. J. Structure-Activity Relationship of New anti-Tuberculosis Agents
Derived from Oxazoline and Oxazole Benzyl Esters. Eur. J. Med. Chem. 2010, 45, 1703–
1716. (b) Li, B.; Wang, S. Q.; Liu, B.; Shi, B. F. Synthesis of Oxazolines from Amides
via Palladium-Catalyzed Functionalization of Unactivated C(sp(3))-H bond. Org. Lett.
2015, 17, 1200–1203. (c) Brandstatter, M.; Roth, F.; Luedtke, N. W. Synthesis of 2-
Oxazolines by in Situ Desilylation and Cyclodehydration of beta-Hydroxyamides. J. Org.
Chem. 2015, 80, 40–51.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 33
1
2
3
4
5
6
7
8
9
(4) Moraski, G. C.; Franzblau, S. G.; Miller, M. J. Utilization of the Suzuki Coupling to
Enhance the Antituberculosis Activity of Aryloxazoles. Heterocycles, 2010, 80, 977–988.
(5) (a) Lall, M. S.; Hoge, G.; Tran, T. P.; Kissel, W.; Murphy, S. T.; Taylor, C.;
Hutchings, K.; Samas, B.; Ellsworth, E. L.; Curran, T.; Showalter, H. D. Stereoselective
Synthesis of (S)-3-(Methylamino)-3-((R)-pyrrolidin-3-yl)propanenitrile. J. Org. Chem.
2012, 77, 4732–4739. (b) Magnus, N. A.; Astleford, B. A.; Laird, D. L.; Maloney, T. D.;
McFarland, A. D.; Rizzo, J. R.; Ruble, J. C.; Stephenson, G. A.; Wepsiec, J. P. Additives
Promote Noyori-Type Reductions of a beta-Keto-gamma-Lactam: Asymmetric Syntheses
of Serotonin Norepinephrine Reuptake Inhibitors. J. Org. Chem. 2013, 78, 5768–5774.
(6) Kern, N.; Hoffmann, M.; Weibel, J.-M.; Pale, P.; Blanc, A. Short and Efficient
Route toward α-Substituted N-Arylazetidines from Acetanilides via Mitsunobu Reaction.
Tetrahedron 2014, 70, 5519–5531.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(7) (a) Jerhaoui, S.; Poutrel, P.; Djukic, J. P.; Wencel-Delord, J.; Colobert, F.
Stereospecific C-H Activation as a Key Step for the Asymmetric Synthesis of Various
Biologically Active Cyclopropanes. Org. Chem. Front. 2018, 5, 409-414. (b) Gholami,
H.; Kulshrestha, A.; Favor, O. K.; Staples, R. J.; Borhan, B. Total Synthesis of (-)-
Salinosporamide A via a Late Stage C-H Insertion. Angew. Chem. Int. Ed. 2019, 58,
10110-10113.
(8) Geoghegan, P.; O’Leary, P. Hydroxyamide-Based Ligands and Their Use in the
Asymmetric Catalysis of Key Organic Transformations. ACS Catal. 2012, 2, 573–591.
(9) For selected recent examples and references cited therein, see: (a) Weidner, K.;
Kumagai, N.; Shibasaki, M. Designed Amide as an Aldol Donor in the Direct Catalytic
Asymmetric Aldol Reaction. Angew. Chem. Int. Ed. 2014, 53, 6150-6154. (b) Jadhav, A.
ACS Paragon Plus Environment

Page 29 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
M.; Pagar, V. V.; Huple, D. B.; Liu, R. S., Zinc(II)-Catalyzed Intermolecular Hydrative
Aldol Reactions of 2-en-1-Ynamides with Aldehydes and Water to form Branched Aldol
Products Regio- and Stereoselectively. Angew. Chem. Int. Ed., 2015, 54, 3812-3816. (c)
Weidner, K.; Sun, Z.; Kumagai, N.; Shibasaki, M. Direct Catalytic Asymmetric Aldol
Reaction of an α-Azido Amide. Angew. Chem. Int. Ed. 2015, 54, 6236-6240. (d)
Tallmadge, E. H.; Jermaks, J.; Collum, D. B. Structure-Reactivity Relationships in
Lithiated Evans Enolates: Influence of Aggregation and Solvation on the Stereochemistry
and Mechanism of Aldol Additions. J. Am. Chem. Soc. 2016, 138, 345-55. (e)
Matsuzawa, A.; Noda, H.; Kumagai, N.; Shibasaki, M. Direct Catalytic Asymmetric
Aldol Addition of an α-CF3 Amide to Arylglyoxal Hydrates. J. Org. Chem. 2017, 82,
8304-8308. (f) Liu, Z.; Takeuchi, T.; Pluta, R.; Arteaga, F. A.; Kumagai, N.; Shibasaki,
M. Direct Catalytic Asymmetric Aldol Reaction of α-Alkylamides. Org. Lett. 2017, 19,
710-713. (g) Takeuchi, T.; Kumagai, N.; Shibasaki, M. Direct Catalytic Asymmetric
Aldol Reaction of α-Vinyl Acetamide. J. Org. Chem. 2018, 83, 5851-5858.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(10) (a) Lettan II, R. B.; Reynolds, T. E.; Galliford, C. V.; Scheidt, K. A. Synthesis of
Tertiary β-Hydroxy Amides by Enolate Additions to Acylsilanes. J. Am. Chem. Soc.
2006, 128, 15566-15567. (b) Lettan II, R. B.; Galliford, C. V.; Woodward, C. C.; Scheidt,
K. A. Amide Enolate Additions to Acylsilanes: In Situ Generation of Unusual and
Stereoselective Homoenolate Equivalents. J. Am. Chem. Soc. 2009, 131, 8805-8814. (c)
Lin, C.-Y.; Ma, P.-J.; Sun, Z.; Lu, C.-D.; Xu, Y.-J. Carbamoyl Anion-Initiated Cascade
Reaction for Stereoselective Synthesis of Substituted α-Hydroxy-β-Amino Amides.
Chem. Commun. 2016, 52, 912-915.
ACS Paragon Plus Environment