Asymmetric α-Allylation of α-Substituted β-Ketoesters with Allyl Alcohols

Article abstract of DOI:10.1021/acs.joc.7b02188

Enantioselective α-allylation of α-substituted β-ketoesters with simple allyl alcohols was successfully performed by synergistic catalysis with the catalyst combination of a chiral primary amino acid and an achiral palladium complex without additional promotors like acids or bases. The allylation reaction and generation of a chiral quaternary carbon stereocenter proceeded smoothly to produce α,α-disubstituted β-ketoesters in high yields (91-99%) with high enantioselectivities (90-99% ee).

Full text of DOI:10.1021/acs.joc.7b02188

Subscriber access provided by University of Florida | Smathers Libraries
Note
Asymmetric #-Allylation of #-Substituted #-Ketoesters with Allyl Alcohols
Masanori Yoshida
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02188 • Publication Date (Web): 19 Oct 2017
Downloaded from http://pubs.acs.org on October 19, 2017
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 free 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 accessible to all
readers and 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.
The Journal of Organic Chemistry 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 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
Asymmetric αꢀAllylation of αꢀSubstituted βꢀKetoesters with Allyl Alcohols
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
Masanori Yoshida*
Faculty of Mathematics and Science, National Institute of Technology, Asahikawa College,
Shunkodai 2 jo 2ꢀ1ꢀ6, Asahikawa, Hokkaido 071ꢀ8142 Japan
yoshida@edu.asahikawaꢀnct.ac.jp
Abstract
Enantioselective αꢀallylation of αꢀsubstituted βꢀketoesters with simple allyl alcohols was successfully performed by
synergistic catalysis with the catalyst combination of a chiral primary amino acid and an achiral palladium complex
without additional promotors like acids or bases. The allylation reaction and generation of a chiral quaternary carbon
stereocenter proceeded smoothly to produce α,αꢀdisubstituted βꢀketoesters in high yields (91–99%) with high
enantioselectivities (90–99% ee).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 20
1
2
3
4
5
6
7
8
9
Chiral quaternary carbon stereocenters can be found in many natural organic compounds with useful biological
activity as pharmaceuticals and agrochemicals. Since the biological properties are often affected by the configuration of
the chiral carbon atoms, the enantioselective synthesis of quaternary carbon stereocenters is critical in medicinal
chemistry. Although various methodologies for the enantioselective synthesis of quaternary carbon stereocenters have
been recently developed, an enantioselective catalytic method remains challenging in organic synthesis.1,2 Carbon–
carbon bond formation at the tertiary carbon atom is a simple method to obtain the quaternary carbon atom; however,
steric repulsion between the two reactants often makes this carbon–carbon bond formation difficult. Activation of both
reactants is an approach to establish a carbon–carbon bond between the reactants and overcome this problem. In recent
years, synergistic catalysis for the activation of both an electrophile and a nucleophile to produce a carbon–carbon bond
has attracted the attention of synthetic organic chemists.3 The corporative catalysis consisted with organocatalysis and
transitionꢀmetal catalysis, which were investigated individually in the past, led to a new era of enantioselective catalysis
in organic synthesis.3 From the successful Tsuji–Trost allylation of aldehydes and ketones using an organic–
transitionꢀmetal synergistic catalysis by Cόrdova’s group in 2006,4,5a several types of synergistic catalysis using the
combination of an organocatalyst and a palladiumꢀcomplex have been developed for enantioselective Tsuji–Trost
allylation reaction.5,6 We recently reported that the catalyst combination of a chiral primary amino acid and an achiral
palladium complex was effective for the enantioselective synthesis of a quaternary carbon stereocenter by Tsuji–Trost
αꢀallylation of αꢀbranched aldehydes.7 In our related research, αꢀbranched ketones, such as 2ꢀoxocycloalkanecarboxylates,
were also found to be good substrates for the enantioselective synthesis of a quaternary carbon stereocenter. However,
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
ACS Paragon Plus Environment

Page 3 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
most of the substrates required a long reaction time to complete the allylation reaction; for example, allylation of
2ꢀoxocycloheptanecarboxylate required 5 days to consume the substrate completely.8–10
7
8
9
Tsuji–Trost allylation reaction is typically performed with a reactive allyl compound such as an allyl ester and
an allyl halide; therefore, the reaction produces a stoichiometric amount of acid as a byproduct. Although allyl alcohols
are less reactive than allyl esters and allyl halides in Tsuji–Trost allylation reaction, the use of allyl alcohols directly for
the allylation reaction has two advantages: 1) no requirement of the transformation of allyl alcohols to reactive allyl
compounds before carrying out the allylation reaction and 2) the production of water instead of an acid as a waste
byproduct after the reaction.11 In continued efforts to improve the reaction conditions for the enantioselective Tsuji–Trost
allylation of αꢀsubstituted βꢀketoesters,8 the allylation reaction and generation of a chiral quaternary carbon stereocenter
were achieved by the direct use of simple allyl alcohols, and various α,αꢀdisubstituted βꢀketoesters were obtained in high
yields with high enantioselectivities. Details of direct asymmetric αꢀallylation of αꢀsubstituted βꢀketoesters with allyl
alcohols are described in this report.
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
Allylation of ethyl 2ꢀoxocyclopentancarboxylate (1a) was performed for investigation of the reactivity of allyl
alcohol (2a) and its acetate (2aꢀAc) in the presence of a catalytic amount of Oꢀ(tertꢀbutyldiphenylsilyl)ꢀLꢀthreonine (3a)
and tetrakis(triphenylphosphine)palladium(0) [Pd(PPh3)4, 4a] (Table 1). The allylation reaction of 1a with 2aꢀAc
proceeded readily at 25 °C to give αꢀallylated product 5a in 86% yield with 78% ee,8 while the reaction using 2a instead
of 2aꢀAc hardly proceeded under the same reaction conditions to give only a trace amount of 5a (Table 1, Entries 1 and
2). Fortunately, the low reactivity of 2a in the allylation reaction was overcome by carrying out the reaction under gentle
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 20
1
2
3
4
5
6
7
8
9
heating (40 °C), and 5a was obtained in 95% yield with moderate enantioselectivity (Table 1, Entry 3). When the
reaction temperature of the allylation reaction with 2aꢀAc was increased to 40 °C, the enantioselectivity was decreased
(Table 1, Entry 4). By using a reduced amount of allyl compound, enantioselectivity of the allylation reaction with 2a
was improved to 90% ee, while no improvement of the enantioselectivity was observed in the case of the reaction with
2aꢀAc (Table 1, Entries 5 and 6). Thus, the allylation reaction with 2a provided better results than that with 2aꢀAc. When
an increased amount of solvent was used for the reaction of 1a with 2a in the presence of 3a and 4a, slightly better yield
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
and enantioselectivity were obtained (Table 1, Entry 7).
Table 1. Initial study of the allylation reaction of 1a with 2a or 2aꢀAc in the presence of 3a and 4aa
Entry Allyl compound Temp.
Yield
(%)b
86
ee
(equiv)
(°C)
25
25
40
40
40
40
40
(%)c
78
nd
81
75
90
72
92
1
2
3
4
5
6
7d
2aꢀAc (2.0)
2a (2.0)
trace
95
2a (2.0)
2aꢀAc (2.0)
2a (1.1)
92
86
2aꢀAc (1.1)
2a (1.1)
81
91
a Unless otherwise mentioned, the reaction was carried out with 1a (0.5 mmol), 2 (0.55 mmol), 3a (0.1 mmol), 4a
(0.025 mmol) in toluene (0.6 mL) for 16 h under N2 atmosphere. b Yield of 5a based on 1a. c Determined by chiral HPLC
analysis. nd = not determined d The amount of toluene was increased to 1.0 mL.
ACS Paragon Plus Environment

Page 5 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
A catalyst screen of palladium complexes for the allylation reaction of 1a with 2a in the presence of 3a was
then performed (Table 2). The use of palladium(II) acetate [Pd(OAc)2, 4b] with triphenylphosphine (PPh3) gave results
similar to those obtained with 4a, and the use of three equivalents of PPh3 to 4b was optimal (Table 2, Entries 1–4). After
screening of various monodentate and bidentate ligands with 4b, tris(4ꢀfluorophenyl)phosphine [P(4ꢀFC6H4)3] was found
to be the most effective ligand to give allylated compound 5a in high yield with high enantioselectivity (Table 2, Entries
5–15).
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 2. Screening of palladium complexes for the allylation reaction of 1a with 2a in the presence of 3aa
Entry Ligand
Yield (%)b ee (%)c
1d
none
91
92
91
91
92
77
97
nd
nd
nd
nd
nd
nd
nd
88
71
2
PPh3 (20)
86
3
PPh3 (15)
88
4
PPh3 (10)
43
5
P(2ꢀfuryl)3 (15)
P(4ꢀFC6H4)3 (15)
P(C6F5)3 (15)
81
6
92
7
trace
8
P(2ꢀCH3C6H4)3 (15) nr
P(cyclohexyl)3 (15) nr
9
10
11
12
13
14
15
P(nꢀbutyl)3 (15)
dppee (10)
nr
trace
trace
trace
81
dpppf (10)
dppbg (10)
dppfh (10)
(±)ꢀBINAPi (10)
83
a Unless otherwise mentioned, the reaction was carried out with 1a (0.5 mmol), 2a (0.55 mmol), 3a (0.1 mmol), and
Pd(OAc)2 (4b, 0.025 mmol) in toluene (1.0 mL) at 40 °C for 16 h. b Yield of 5a based on 1a. nr = no reaction c
Determined by chiral HPLC analysis. nd = not determined d Pd(PPh3)4 (4a) was used instead of Pd(OAc)2. e
1,2ꢀBis(diphenylphosphino)ethane f 1,3ꢀBis(diphenylphosphino)propane g 1,4ꢀBis(diphenylphosphino)buthane h
1,1'ꢀBis(diphenylphosphino)ferrocene i 2,2'ꢀBis(diphenylphosphino)ꢀ1,1'ꢀbinaphthyl
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 20
1
2
3
4
5
6
7
8
9
Next, the screening of catalysts with amino acids 3 was examined in the presence of 4b and P(4ꢀFC6H4)3, and
Table 3 summarizes the results obtained. When lipophilic primary amino acids, Oꢀsilylated threonines 3a,b and
βꢀhomoserine 3c, were used as catalysts, the allylation reaction proceeded readily to give 5a in high yield with high
enantioselectivity.12,13 Common primary and secondary amino acids 3d–g could not promote the allylation reaction due
to low solubility in the solvent, and a large amount of 1a was recovered after the experiments. Using amino ester 3h, a
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
methyl ester of 3a, as a catalyst, Nꢀ(2ꢀethoxycarbonylcyclopentꢀ1ꢀenyl) OꢀTBDPSꢀL
ꢀthreonine methyl ester (6),14 an
enamine generated from 1a and 3h, was obtained in 12% yield and no allylated product was generated. Addition of a
catalytic amount of acetic acid to the allylation reaction with 3h gave the same result, and enamine 6 was obtained
instead of the allylated product 5a. These results indicated that the carboxylic acid group of an amino acid catalyst was
pivotal to the allylation reaction. It was confirmed that the allylation reaction does not proceed in the absence of an
amino acid catalyst 3. Since the synthesis of 3a can be performed in shorter steps from a commercially available amino
acid than that of 3c, 3a was chosen as the amino acid catalyst.
a
Table 3. Screening of 3 for the allylation reaction of 1a with 2a in the presence of 4b and P(4ꢀFC6H4)3
Amino acid catalysts 3, Yield of 5a,b eec
3a, 92%, 97% ee 3b, 82%, 98% ee 3c, 92%, 98% eed
3d, trace, nd
3e, no reaction
3f, 11%, 6% ee
none
ACS Paragon Plus Environment

Page 7 of 20
The Journal of Organic Chemistry
1
2
3
4
3g, trace, nd
3h, 0%e
no reaction
5
6
7
8
a Unless otherwise mentioned, the reaction was carried out with 1a (0.5 mmol), 2a (0.55 mmol), 3 (0.1 mmol), 4b
(0.025 mmol) and P(4ꢀFC6H4)3 (0.075 mmol) in toluene (1 mL) at 40 °C for 16 h under N2 atmosphere. b Yield of 5a
based on 1a. c Determined by chiral HPLC analysis. nd = not determined d Ee of (S)ꢀenantiomer e Enamine 6 was
obtained in 12% yield.
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
The substrate scope of the allylation reaction was investigated with various βꢀketoesters 1 and allyl alcohols 2
(Table 4). By using a reduced amount of solvent, the allylation reaction of 1a with 2a in the presence of a catalyst
combination of 3a, 4b and P(4ꢀFC6H4)3 gave 5a with an improved yield without reducing the enantioselectivity (Table 4,
Entry 1). The effect of the alkoxycarbonyl group of ketoesters on the allylation reaction was investigated with 1a–c, and
the results indicated that the bulkiness of the alkoxycarbonyl group did not significantly affect the yields and
enantioselectivities of the allylated products 5a–c (Table 4, Entries 1–3). The allylation reaction of
2ꢀoxocyclohexanonecarboxylate (1d) and 2ꢀoxocycloheptanonecarboxylate (1e) with 2a also readily proceeded to give
the allylated products 5d and 5e, respectively, in high yields with high enantioselectivities (Table 4, Entries 4 and 5).
Although acyclic αꢀsubstituted βꢀketoesters, 2ꢀmethylꢀ3ꢀoxobutanoate (1f) and 2ꢀbenzylꢀ3ꢀoxobutanoate (1g), required a
longer reaction time, the allylation reactions with 2a were completed within 24 h to give the allylated products 5f and 5g
(Table 4, Entries 6 and 7). The allylation reaction of 2ꢀphenylꢀ3ꢀoxobutanoate (1h) did not proceed due to the steric
hindrance of the phenyl group (Table 4, Entry 8).8 2ꢀBenzoyl propionate (1i) was also resulted in no reaction, since the
reaction of aromatic ketones with the amino acid catalyst probably did not produce a sufficient amount of a
corresponding enamine, which is a possible intermediate in allylation (Table 4, Entry 9).13c,d Substituted allyl alcohols
like βꢀmethallyl alcohol (2b), transꢀcinnamyl alcohol (2c), and crotyl alcohol (2d) were also good allyl substrates for the
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 20
1
2
3
4
5
6
allylation reaction of 1a, and the corresponding allylated products 5h–j were obtained in high yields with high
enantioselectivities (Table 4, Entries 10–12). The allylation reactions with 1g or 2b–d required an increased amount of
7
8
9
palladium catalyst 4b and P(4ꢀFC6H4)3 to prevent prolonging the reaction time.
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 4. Substrate scopea
O
OH
CO2R3
R2
O
R4
R5
CO2R3
R1
R1
+
R2
R5
R4
1
2
5
1a: R1,R2 = (CH2)3, R3 = Et
1b: R1,R2 = (CH2)3, R3 = Me
1c: R1,R2 = (CH2)3, R3 = Bn
1d: R1,R2 = (CH2)4, R3 = Et
1e: R1,R2 = (CH2)5, R3 = Et
1f: R1 = R2 = Me, R3 = Et
2a: R4 = R5 = H
2b: R4 = Me, R5 = H
2c: R4 = H, R5 = Ph
2d: R4 = H, R5 = Me
1g: R1 = Me, R2 = Bn, R3 = Et
1h: R1 = Me, R2 = Ph, R3 = Et
1i: R1 = Ph, R2 = Me, R3 = Et
Entry
1
2
5
Yield
(%)b
96
Ee
(%)c
97
97
97
97
99
90
96
nd
nd
97
98
97
1
1a
1b
1c
1d
1e
1f
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
5a
5b
5c
5d
5e
5f
5g
–
2
96
3
97
4
96
5
92
6d
7e
8e
9e
10e
11e
12e
91
96
1g
1h
1i
nr
–
nr
96
1a
1a
1a
5h
5i
99
96
5j
a Unless otherwise mentioned, the reaction was carried out with 1 (0.5 mmol), 2 (0.55 mmol), 3a (0.1 mmol), 4b
(0.025 mmol) and P(4ꢀFC6H4)3 (0.075 mmol) in toluene (0.6 mL) at 40 °C for 16 h under N2 atmosphere. b Yield of 5
based on 1. nr = no reaction c Determined by chiral HPLC analysis. nd = not determined d The reaction was carried out
ACS Paragon Plus Environment

Page 9 of 20
The Journal of Organic Chemistry
1
2
3
4
for 24 h. e The reaction was carried out with an increased amount of 4b (0.035 mmol) and P(4ꢀFC6H4)3 (0.105 mmol) for
5
6
24 h.
7
8
9
By comparing the spectroscopic data with those previously reported, it was found that both the cyclic and
acyclic allylated products, 5a and 5f, were Rꢀenantiomers. Plausible mechanisms for the allylation reaction and its
stereocontrol are proposed in Scheme 1. By formation of an intramolecular hydrogen bond between NH and CO,
enamine Imꢀ1, generated from βꢀketoester 1 and amino acid 3a, would be a Zꢀisomer [Scheme 1 (a)].15 Then, the
carboxylic acid group of the amino acid moiety assisted dehydration from the palladium olefin complex, which was
generated from allyl alcohol 2a, Pd(OAc)2 4b and P(4ꢀFC6H4)3, to afford Imꢀ2, which can proceed to a rapid
intramolecular allylation between the enamine and πꢀallylpalladium moiety.11b,16 A plausible mechanism of the
stereocontrol is depicted in Scheme 1 (b). To avoid the steric repulsion between R1ꢀsubstituent of the enamine moiety and
the carboxylate group, the large amino acid side chain (Y) comes perpendicular to the Siꢀface of the αꢀcarbon atom of the
enamine moiety. Therefore, the Reꢀface of the αꢀcarbon atom approached the πꢀallylpalladium moiety rather than the
Siꢀface to furnish an Rꢀenantiomer of allylated product 5 [Scheme 1 (b)]. Since amino ester 3h contained no carboxylic
acid groups to promote a rapid intramolecular allylation, the experiment with 3h would give an enamine instead of the
allylated product as described in Table 3.11b
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
In conclusion, the asymmetric αꢀallylation of αꢀsubstituted βꢀketoesters with allyl alcohols was successfully
carried out by a synergistic catalysis using the catalyst combination of a chiral primary amino acid,
OꢀTBDPSꢀLꢀthreonine, and an achiral palladium complex, Pd(OAc)2–P(4ꢀFC6H4)3. The allylation reaction and
generation of a chiral quaternary carbon stereocenter proceeded readily without additional promotors or harsh conditions
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 20
1
2
3
4
5
6
7
8
9
to give α,αꢀdisubstituted βꢀketoesters in high yields with high enantioselectivity. By using allyl alcohols directly instead
of allyl esters or allyl halides, the allylation reaction could be performed without generation of a stoichiometric amount
of an acid waste byproduct.
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 1. Plausible mechanisms for the allylation reaction and its stereocontrol
Experimental Section
Materials. βꢀKetoesters 1a,b,d,f–i were purchased and used after distillation; other ketoesters 1c17a and 1e17b were
synthesized according to the literature procedures. Allyl alcohols 2a–d were purchased and used without purification.
ACS Paragon Plus Environment

Page 11 of 20
The Journal of Organic Chemistry
1
2
3
4
OꢀSilylated
L
ꢀthreonines (3a and 3b)12 and βꢀhomoserine 3c13 were synthesized according to the literature procedures;
5
6
7
8
9
other amino acids 3d–g were purchased and used without purification. Palladium catalysts 4 and phosphine ligands were
purchased and were used without purification. Purification of the products was accomlished by column chromatography
on Kanto Chemical Co., Inc. Silicagel 60N (spherical, neutral; 63–210ꢁm). Proton NMR (1H NMR) and
protonꢀdecoupled carbon NMR [13C{1H} NMR] spectra were recorded on a JNMꢀECS400 FT NMR. Chemical shifts, δ
are referred to TMS. Specific rotation was measured by a HORIBA SEPAꢀ500 polarimeter. HPLC was carried out using
a JASCO PUꢀ2089 Plus intelligent pump and a UVꢀ2075 Plus UV detector. HRMS was mesured by a Hitach
HighꢀTechnologies NanoFrontier eLD.
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
Typical procedure for the allylation reaction. In a 7 mL vial, Pd(OAc)2 (4b, 5.6 mg, 0.025 mmol), P(4ꢀFꢀC6H4)3
(23.7 mg, 0.075 mmol), OꢀTBDPSꢀLꢀthreonine (3a, 35.7 mg, 0.1 mmol) and toluene (0.6 mL) were placed, and the
atmosphere in the vial was replaced with nitrogen. To the reaction mixture, allyl alcohol (1a, 32 mg, 0.55 mmol) and
ethyl 2ꢀoxocyclopentanecarboxylate (2a, 78 mg, 0.5 mmol) were added with stirring. The reaction mixture was then
stirred for 16 h at 40 °C. The resulting mixture was filtered through a small plug of silica gel, eluted with Et2O (1 mL ×
4) and concentrated under reduced pressure. Ethyl (R)ꢀ1ꢀ(propꢀ2ꢀenyl)ꢀ2ꢀoxocyclopentanecarboxylate (5a) was isolated
by column chromatography (silica gel, hexane–Et2O 9:1) in 96% yield (93.7 mg) as colorless oil. The enantioselectivity
was determined by chiral HPLC analysis (97% ee). The absolute configuration was determined by comparison of the
specific rotation with that of the literature.18a Spectroscopic data are in agreement with the published data.18b Colorless
oil; [α]58924.9 = –38.2 (c 1.0, CHCl3); Rf = 0.43 (nꢀhexane–EtOAc, 4:1). 1H NMR (400 MHz, CDCl3) 1.25 (3H, t, J 7.2 Hz),
1.88–2.06 (3H, m), 2.20–2.29 (1H, m), 2.34–2.50 (3H, m), 2.64–2.70 (1H, m), 4.13–4.20 (2H, m), 5.09–5.13 (2H, m),
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 20
1
2
3
4
5
6
7
8
9
5.64–5.75 (1H, m); 13C{1H} NMR (100 MHz, CDCl3) 14.1, 19.5, 32.1, 37.8, 38.1, 59.9, 61.4, 119.0, 133.0, 170.9, 214.7.;
ν(neat)/cm–1 1749 (C=O of CO2Et), 1720 (C=O of ketone), 1640 (C=C); HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C11H16O3Na 219.0992; Found 219.0997.
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
Methyl (R)ꢀ1ꢀ(propꢀ2ꢀenyl)ꢀ2ꢀoxocyclopentanecarboxylate (5b)
Spectroscopic data are in agreement with the published data.18c
25.0
96% yield (87.0 mg). Colorless oil; [α]589 = –51.9 (c 1.0, CHCl3); Rf = 0.46 (nꢀhexane–EtOAc, 4:1). 1H NMR (400
MHz, CDCl3) 1.85–2.04 (3H, m), 2.18–2.27 (1H, m), 2.32–2.49 (3H, m), 2.62–2.68 (1H, m), 3.69 (3H, s), 5.06–5.11 (2H,
m), 5.61–5.71 (1H, m); 13C{1H} NMR (100 MHz, CDCl3) 19.6, 32.2, 38.0, 38.2, 52.7, 60.1, 119.3, 133.0, 171.4, 214.7.;
ν(neat)/cm–1 1750 (C=O of CO2Me), 1724 (C=O of ketone), 1639 (C=C); HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C10H14O3Na 205.0835; Found 205.0835.
Benzyl 1ꢀ(propꢀ2ꢀenyl)ꢀ2ꢀoxocyclopentanecarboxylate (5c)
Spectroscopic data are in agreement with the published data.11c
97% yield (125.0 mg). Colorless oil; [α]58925.3 = –27.3 (c 1.0, CHCl3); Rf = 0.51 (nꢀhexane–EtOAc, 4:1). 1H NMR (400
MHz, CDCl3) 1.84–2.03 (3H, m), 2.18–2.27 (1H, m), 2.32–2.49 (3H, m), 2.65–2.70 (1H, m), 5.04–5.09 (2H, m), 5.13
(2H, s), 5.60–5.71 (1H, m), 7.28–7.37 (5H, m); 13C{1H} NMR (100 MHz, CDCl3) 19.6, 32.2, 37.9, 38.2, 60.0, 67.2,
119.3, 128.0, 128.4, 128.7, 133.0, 135.7, 170.9, 214.5.; ν(neat)/cm–1 1750 (C=O of CO2Bn), 1724 (C=O of ketone), 1639
(C=C); HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C16H18O3Na 281.1148; Found 281.1147.
Ethyl (R)ꢀ1ꢀ(propꢀ2ꢀenyl)ꢀ2ꢀoxocyclohexanecarboxylate (5d)
Spectroscopic data are in agreement with the published data.9g
ACS Paragon Plus Environment

Page 13 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
25.4
1
96% yield (100.4 mg). Colorless oil; [α]589 = +126.5 (c 1.0, CHCl3); Rf = 0.31 (nꢀhexane–EtOAc, 9:1). H NMR
(400 MHz, CDCl3) 1.23 (3H, t, J 7.2 Hz), 1.40–1.48 (1H, m), 1.55–1.78 (3H, m), 1.96–2.03 (1H, m), 2.29–2.34 (1H, m),
2.42–2.49 (3H, m), 2.57–2.62 (1H, m), 4.17 (2H, q, J 7.2 Hz), 5.00–5.04 (2H, m), 5.67–5.78 (1H, m); 13C{1H} NMR
(100 MHz, CDCl3) 14.3, 22.6, 27.6, 35.9, 39.4, 41.2, 60.9, 61.3, 118.4, 133.4, 171.6, 207.7.; ν(neat)/cm–1 1745 (C=O of
CO2Et), 1711 (C=O of ketone), 1639 (C=C); HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C12H18O3Na 233.1148; Found
233.1148.
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
Ethyl 1ꢀ(propꢀ2ꢀenyl)ꢀ2ꢀoxocycloheptanecarboxylate (5e)
Spectroscopic data are in agreement with the published data.18d
92% yield (103.2 mg). Colorless oil; [α]58925.4 = +79.7 (c 1.0, CHCl3); Rf = 0.69 (nꢀhexane–EtOAc, 4:1). 1H NMR (400
MHz, CDCl3) 1.23 (3H, t, J 7.2 Hz), 1.34–1.43 (1H, m), 1.58–1.81 (6H, m), 2.04–2.12 (1H, m), 2.29–2.47 (2H, m),
2.61–2.75 (2H, m), 4.15 (2H, q, J 7.2 Hz), 5.02–5.06 (2H, m), 5.65–5.76 (1H, m); 13C{1H} NMR (100 MHz, CDCl3)
14.2, 24.6, 25.6, 30.0, 32.1, 39.7, 42.2, 61.3, 62.9, 118.7, 133.7, 172.1, 209.3.; ν(neat)/cm–1 1732 (C=O of CO2Et), 1708
(C=O of ketone), 1639 (C=C); HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C13H20O3Na 247.1305; Found 247.1313.
(R)ꢀ3ꢀEthoxycarbonylꢀ3ꢀmethylhexꢀ5ꢀenꢀ2ꢀone (5f)
Spectroscopic data are in agreement with the published data.18e,f
25.6
91% yield (83.7 mg). Colorless oil; [α]589 = +24.2 (c 1.0, CHCl3); Rf = 0.37 (nꢀhexane–EtOAc, 9:1). 1H NMR (400
MHz, CDCl3) 1.24 (3H, t, J 7.2 Hz), 1.30 (3H, s), 2.13 (3H, s), 2.45–2.64 (2H, m), 4.17 (2H, q, J 7.2 Hz), 5.05–5.10 (2H,
m), 5.57–5.68 (1H, m); 13C{1H} NMR (100 MHz, CDCl3) 14.2, 19.0, 26.3, 39.4, 59.5, 61.5, 119.1, 132.7, 172.6, 205.2.;
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 20
1
2
3
4
5
6
ν(neat)/cm–1 1740 (C=O of CO2Et), 1711 (C=O of ketone), 1641 (C=C); HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for
C10H17O3 185.1172; Found 185.1174.
7
8
9
3ꢀEthoxycarbonylꢀ3ꢀ(phenylmethyl)hexꢀ5ꢀenꢀ2ꢀone (5g)
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
96% yield (124.7 mg). Colorless oil; [α]58917.9 = –24.1 (c 1.0, CHCl3); Rf = 0.57 (nꢀhexane–EtOAc, 4:1). 1H NMR (400
MHz, CDCl3) 1.23 (3H, t, J 7.2 Hz), 2.11 (3H, s), 2.55–2.57 (2H, m), 3.11–3.24 (2H, m), 4.11–4.21 (2H, m), 5.11–5.15
(2H, m), 5.63–5.74 (1H, m), 7.05–7.08 (2H, m), 7.21–7.26 (3H, m); 13C{1H} NMR (100 MHz, CDCl3) 14.1, 27.6, 36.1,
37.6, 61.5, 64.8, 119.4, 127.0, 128.4, 130.1, 132.4, 136.3, 171.6, 204.6.; ν(neat)/cm–1 1740 (C=O of CO2Et), 1710 (C=O
of ketone), 1640 (C=C); HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C16H21O3 261.1485; Found 261.1471.
Ethyl 1ꢀ(2ꢀmethylpropꢀ2ꢀenyl)ꢀ2ꢀoxocyclopentanecarboxylate (5h)
96% yield (100.6 mg). Colorless oil; [α]58925.5 = –39.8 (c 1.0, CHCl3); Rf = 0.79 (nꢀhexane–EtOAc, 4:1). 1H NMR (400
MHz, CDCl3) 1.26 (3H, t, J 7.2 Hz), 1.65 (3H, s), 1.88–2.06 (3H, m), 2.23–2.32 (2H, m), 2.37–2.45 (1H, m), 2.54–2.61
(1H, m), 2.81–2.84 (1H, m), 4.16 (2H, q, J 7.2 Hz), 4.71 (1H, s), 4.84 (1H, s); 13C{1H} NMR (100 MHz, CDCl3) 14.0,
19.4, 23.4, 31.8, 37.6, 41.4, 60.1, 61.6, 114.8, 141.3, 170.5, 214.4.; ν(neat)/cm–1 1750 (C=O of CO2Et), 1717 (C=O of
ketone), 1645 (C=C); HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C12H19O3 211.1329; Found 211.1339.
Ethyl 1ꢀ(3ꢀphenylpropꢀ2ꢀenyl)ꢀ2ꢀoxocyclopentanecarboxylate (5i)
Spectroscopic data are in agreement with the published data.18b
99% yield (135.3 mg). Colorless oil; [α]58925.5 = –76.8 (c 1.0, CHCl3); Rf = 0.54 (nꢀhexane–EtOAc, 4:1). 1H NMR (400
MHz, CDCl3) 1.25 (3H, t, J 7.2 Hz), 1.86–2.08 (3H, m), 2.19–2.29 (1H, m), 2.39–2.55 (3H, m), 2.78–2.83 (1H, m),
4.14–4.20 (2H, m), 6.08 (1H, dt, J 7.2, 16.0 Hz), 6.44 (1H, d, J 16.0 Hz), 7.18–7.33 (5H, m); 13C{1H} NMR (100 MHz,
ACS Paragon Plus Environment

Page 15 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
CDCl3) 14.2, 19.7, 32.3, 37.1, 38.2, 60.4, 61.6, 124.6, 126.3, 127.5, 128.6, 134.2, 137.1, 171.1, 214.9.; ν(neat)/cm–1 1748
(C=O of CO2Et), 1720 (C=O of ketone); HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C17H20O3Na 295.1305; Found
295.1310.
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
Ethyl 1ꢀ(butꢀ2ꢀenyl)ꢀ2ꢀoxocyclopentanecarboxylate (5j)
Obtained as a mixture of (E)ꢀ and (Z)ꢀisomers. 96% yield (101.3 mg). Colorless oil; [α]58918.0 = –43.6 (c 1.0, CHCl3); Rf
= 0.57 (nꢀhexane–EtOAc, 4:1). 1H NMR (400 MHz, CDCl3) 1.25 (3H, t, J 7.2 Hz), 1.65 (3H, d, J 6.4 Hz), 1.85–2.05 (3H,
m), 2.18–2.33 (2H, m), 2.37–2.45 (2H, m), 2.56–2.62 (1H, m), 4.12–4.20 (2H, m), 5.26–5.34 (1H, m), 5.48–5.57 (1H,
m); 13C{1H} NMR (100 MHz, CDCl3) 14.2, 18.1, 19.6, 32.1, 36.7, 38.3, 60.3, 61.5, 125.4, 129.9, 171.1, 215.0.;
ν(neat)/cm–1 1749 (C=O of CO2Et), 1720 (C=O of ketone), 1667 (C=C); HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C12H18O3Na 233.1148; Found 233.1145.
Synthesis of OꢀTBDPSꢀLꢀthreonine methyl ester (3h). Nꢀbenzyloxycarbonyl OꢀTBDPSꢀLꢀthreonine was synthesized
according to the literature.12 To a DMF solution (17 mL) of Nꢀbenzyloxycarbonyl OꢀTBDPSꢀLꢀthreonine (4.11 g, 8.4
mmol), K2CO3 (1.16 g, 8.4 mmol) and MeI (1.19 g, 8.4 mmol) were added. After stirring for 6 h at room temperature, the
reaction mixture was poured into H2O (100 mL) and extracted with EtOAc (20 mL × 3), washed with brine, dried over
MgSO4 and concentrated under reduced pressure to give Nꢀbenzyloxycarbonyl OꢀTBDPSꢀLꢀthreonine methyl ester. The
obtained Nꢀbenzyloxycarbonyl OꢀTBDPSꢀLꢀthreonine methyl ester was dissolved in MeOH (15 mL), and the solution
was added into a mixture of Pd/C (10%, 1 g) and MeOH (5 mL) under a nitrogen atmosphere in a roundꢀbottomed flask.
After the atmosphere in the flask was replaced with hydrogen, the reaction mixture was stirred for 15 h under a hydrogen
atmosphere at 40 °C. Pd/C was filtered, and the filtrate was concentrated under reduced pressure. OꢀTBDPSꢀLꢀthreonine
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 20
1
2
3
4
methyl ester (3h) was obtained after purification by column chromatography (silica gel, hexane–EtOAc) in 72% yield
5
6
7
8
9
16.4
1
(2 steps, 2.26 g) as colorless oil. [α]589 = –1.1 (c 1.0, CHCl3); Rf = 0.24 (nꢀhexane–EtOAc, 4:1). H NMR (400 MHz,
CDCl3) 1.02 (9H, s), 1.12 (3H, d, J 6.4 Hz), 3.28 (1H, d, J 2.8 Hz), 3.61 (3H, s), 4.34 (1H, dq, J 2.8, 6.4 Hz), 7.36–7.46
(6H, m), 7.62–7.68 (4H, m); 13C{1H} NMR (100 MHz, CDCl3) 19.4, 20.7, 26.9, 52.0, 60.6, 70.9, 127.6, 127.7, 129.7,
129.9, 133.3, 134.2, 135.9, 136.0, 175.1.; ν(neat)/cm–1 1740 (C=O of CO2Me); HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd
for C21H29NSiO3Na 394.1809; Found 394.1798.
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
Synthesis of enamine (6), Nꢀ(2ꢀethoxycarbonylcyclopentꢀ1ꢀenyl) OꢀTBDPSꢀLꢀthreonine methyl ester. To a
solution of OꢀTBDPSꢀLꢀthreonine methyl ester (3h, 74.2 mg, 0.2 mmol) in toluene (1 mL), ethyl
2ꢀoxocyclopentanecarboxylate (1a, 31.2 mg, 0.2 mmol), MgSO4 (24 mg, 0.2 mmol) and AcOH (6.0 mg, 0.1 mmol) were
added. After stirring for 24 h at 40 °C, the resulting mixture was filtered through a small plug of silica gel, eluted with
Et2O (1 mL × 4) and concentrated under reduced pressure. Nꢀ(2ꢀethoxycarbonylcyclopentꢀ1ꢀenyl) OꢀTBDPSꢀLꢀthreonine
methyl ester (6) was isolated by column chromatography (silica gel, hexane–Et2O 9:1) in 95% yield (96.8 mg) as
15.0
1
colorless oil. [α]589 = –43.8 (c 1.0, CHCl3); Rf = 0.59 (nꢀhexane–EtOAc, 4:1). H NMR (400 MHz, CDCl3) 1.03 (9H,
s), 1.07 (3H, d, J 6.4 Hz), 1.27–1.30 (3H, m), 1.72–1.83 (2H, m), 2.23–2.38 (2H, m), 2.52–2.56 (2H, m), 3.67 (3H, s),
3.82 (1H, dd, J 3.2, 10.8 Hz), 4.16–4.24 (2H, m), 4.32 (1H, dq, J 3.2, 6.4 Hz), 7.36–7.46 (6H, m), 7.66–7.71 (4H, m),
7.85 (1H, br); 13C{1H} NMR (100 MHz, CDCl3) 14.9, 19.3, 20.2, 20.7, 26.8, 29.6, 32.3, 52.4, 58.7, 63.4, 70.7, 95.3,
127.6, 127.8, 129.8, 129.9, 133.1, 133.9, 136.0, 136.1, 161.8, 167.9, 171.7.; ν(neat)/cm–1 3310 (NꢀH), 1750 (C=O of
CO2Me), 1663 (C=O of CO2Et), 1604 (C=C of enamine); HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C29H39NSiO5Na
532.2490; Found 532.2486.
ACS Paragon Plus Environment

Page 17 of 20
The Journal of Organic Chemistry
1
2
3
4
Acknowledgment
5
6
7
8
9
This work was partially supported by JSPS KAKENHI Grant Number JP17K05872. The author thanks Mr Hiroaki
Akutsu (Center for Advanced Research and Education, Asahikawa Medical University) for the measurements of HRMS.
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
Supporting Information Available
HPLC data of 5, 1H and 13C{1H} NMR spectra of 5, 3h and 6. This material is available free of charge via the Internet
at http://pubs.acs.org.
References and Notes
(1) (a) Quasdorf, K. W.; Overman, L. E. Nature 2014, 516, 181. (b) Shimizu, M. Angew. Chem. Int. Ed. 2011, 50,
5998. (c) Denissova, I.; Barriault, L. Tetrahedron 2003, 59, 10105. (d) Christoffers, J.; Mann, A. Angew. Chem. Int. Ed.
2001, 40, 4591. (e) Corey, E. J.; GuzmanꢀPerez, A. Angew. Chem. Int. Ed. 1998, 37, 388. (f) Fuji, K. Chem. Rev. 1993,
93, 2037. (g) Martin, S. F. Tetrahedron 1980, 36, 419.
(2) Qaternary Stereocenters; Christoffers, J.; Baro, A. Eds.; WileyꢀVCH: Weinheim, 2005.
(3) Book and reviews on catalysis by combination use of catalysts: (a) Cooperative Catalysis: Designing Efficient
Catalysts for Synthesis; Peters, R. Ed.; WileyꢀVCH: Weinheim, 2015. (b) Afewerki, S.; Cόrdova, A. Chem. Rev. 2016,
116, 13512. (c) Allen, A. E.; MacMillan, D. W. C. Chem. Sci. 2012, 3, 633. (d) Zhong, C.; Shi, X. Eur. J. Org. Chem.
2010, 2999. (e) Shao, Z.; Zhang, H. Chem. Soc. Rev. 2009, 38, 2745. (f) Loh, C. C. J.; Enders, D. Chem. Eur. J. 2012, 18,
10212. (g) Zhou, J.; Chem. Asian J. 2010, 5, 422.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 20
1
2
3
4
(4) Books and selected reviews on Tsuji–Trost allylation reaction: (a) Palladium reagents and catalysts : new
5
6
7
8
9
perspectives for the 21st century; Tsuji, J. Ed.; John Wiley & Sons: Chichester, 2004. (b) Godleski, S. A. In
Comprehensive organic synthesis; Trost, B. M.; Fleming, I. Eds.; Pergamon Press: Oxford, 1991, Vol. 4, 585. (c) Trost,
B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921. (d) Trost, B. M. Chem. Rev. 1996, 96, 395. (e) Hong, A. Y.; Stoltz,
B. M. Eur. J. Org. Chem. 2013, 2745 and references therein.
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
(5) (a) Ibrahem, I.; Cόrdova, A. Angew. Chem. Int. Ed. 2006, 45, 1952. (b) Mukherjee, S.; List, B. J. Am. Chem. Soc.
2007, 129, 11336. (c) Jiang, G.; List, B. Angew. Chem. Int. Ed. 2011, 50, 9471.
(6) Enantioselective allylation of enamines: (a) Weix, D. J.; Hartwig, J. F. J. Am. Chem. Soc. 2007, 129, 7720. (b)
Zhao, X.; Liu, D.; Xie, F.; Zhang, W. Tetrahedron 2009, 65, 512. (c) Chiarucci, M.; Lillo, M. d.; Romaniello, A.; Cozzi,
P. G.; Cera, G.; Bandini, M. Chem. Sci. 2012, 3, 2859. (d) Xu, L.ꢀW.; Gao, G.; Gu, F.ꢀL.; Sheng, H.; Li, L.; Lai, G.ꢀQ.;
Jiang, J.ꢀX. Adv. Synth. Catal. 2010, 352, 1441. (e) Yasuda, S.; Kumagai, N.; Shibasaki, M. Heterocycles 2012, 86, 745.
(f) Krautwald, S.; Salah, D.; Schafroth, M. A.; Carreira, E. M. Science (Washington, D.C.) 2013, 340, 1065.
(7) (a) Yoshida, M.; Terumine, T.; Masaki, E.; Hara, S. J. Org. Chem. 2013, 78, 10853. (b) Yoshida, M.; Masaki, E.;
Terumine, T.; Hara, S. Synthesis 2014, 46, 1367.
(8) Yoshida, M.; Yano, S.; Hara, S. Synthesis 2017, 49, 1295.
(9) Highly enantioselective catalytic asymmetric allylation of 2ꢀoxocycloalkanecarboxylates: (a) Liu, W.ꢀB.; Reeves, C.
M.; Virgil, S. C.; Stoltz, B. M. J. Am. Chem. Soc. 2013, 135, 10626. (b) Liu, W.ꢀB.; Reeves, C. M.; Stoltz, B. M. J. Am.
Chem. Soc. 2013, 135, 17298. (c) Nemoto, T.; Masuda, T.; Matsumoto, T.; Hamada, Y. J. Org. Chem. 2005, 70, 7172.
(d) Nemoto, T.; Matsumoto, T.; Masuda, T.; Hitomi, T.; Hatano, K.; Hamada, Y. J. Am. Chem. Soc. 2004, 126, 3690. (e)
ACS Paragon Plus Environment

Page 19 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Park, E. J.; Kim, M. H.; Kim, D. Y. J. Org. Chem. 2004, 69, 6897. (f) Brunel, J. M.; Tenaglia, A.; Buono, G.
Tetrahedron: Asymmetry 2000, 11, 3585. (g) Trost, B. M.; Radinov, R.; Grenzer, E. M. J. Am. Chem. Soc. 1997, 119,
7879. (h) Zhou, H.; Zhang, L.; Xu, C.; Luo, S. Angew, Chem. Int. Ed. 2015, 54, 12645.
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) Decarboxylative allylation for synthesis of a quaternary carbon atom: (a) Weaver, J. D.; Recio, A., III; Grenning,
A. J.; Tunge, J. A. Chem. Rev. 2011, 111, 1846. (b) Akula, R.; Guiry, P. J. Org. Lett. 2016, 18, 5472. (c) Franckevičius,
V.; Cuthbertson, J. D.; Pickworth, M.; Pugh, D. S.; Taylor, R. J. K. Org. Lett. 2011, 13, 4264. (d) Trost, B. M.; Xu, J.;
Schmidt, T. J. Am. Chem. Soc. 2009, 131, 18343. (e) Trost, B. M.; Xu, J. J. Am. Chem. Soc. 2005, 127, 2846. (f) Behenna,
D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 15044.
(11) (a) Butt, N. A.; Zhang, W. Chem. Soc. Rev. 2015, 44, 7929. (b) Usui, I.; Schmidt, S.; Breit, B. Org. Lett. 2009, 11,
1453. (c) Manabe, K.; Kobayashi, S. Org. Lett. 2003, 5, 3241.
(12) OꢀSilylated Lꢀthreonines: (a)Teo, Y.ꢀC.; Lau, J.ꢀJ.; Wu, M.ꢀC. Tetrahedron: Asymmetry 2008, 19, 186. (b) Teo,
Y.ꢀC.; Chua, G.ꢀL. Tetrahedron Lett. 2008, 49, 4235. (c) Wu, X.; Jiang, Z.; Shen, H.ꢀM.; Lu, Y. Adv. Synth. Catal. 2007,
349, 812. (d) Cheng, L.; Wu, X.; Lu, Y. Org. Biomol. Chem. 2007, 5, 1018. (e) Yoshida, M.; Narita, M.; Hirama, K.;
Hara, S. Tetrahedron Lett. 2009, 50, 7297.
(13) OꢀSilylated βꢀhomoserine: (a) Yoshida, M.; Narita, M.; Hara, S. J. Org. Chem. 2011, 76, 8513. (b) Yoshida, M.;
Nagasawa, Y.; Kubara, A.; Hara, S.; Yamanaka, M.; Tetrahedron 2013, 69, 10003. (c) Yoshida, M.; Kubara, A.; Hara, S.
Chem. Lett. 2013, 42, 180. (d) Yoshida, M.; Kubara, A.; Nagasawa, Y.; Hara, S.; Yamanaka, M. Asian J. Org. Chem.
2014, 3, 523.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 20
1
2
3
4
5
6
(14) Spectroscopic data of the enamine 6 were compared with those of the authentic sample obtained by the
condensation reaction of 1a with 3h. See the experimental section.
7
8
9
(15) NMR study was performed to observe the formation of the enamine Imꢀ1 intermediate by mixing ketoester 1a and
3a in C6D6; however, no evidence of the formation of the enamine was observed.
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
(16) Intramolecular Tsuji–Trost allylation: (a) Hiroi, K.; Hidaka, A.; Sezaki, R.; Imamura, Y. Chem. Pharm. Bull. 1997,
45, 769. (b) Hiroi, K.; Abe, J.; Suya, K.; Sato, S.; Koyama, T. J. Org. Chem. 1994, 59, 203. (c) Hiroi, K.; Haraguchi, M.;
Masuda, Y.; Abe, J. Chem. Lett. 1992, 2409. (d) Hiroi, K.; Abe, J. Chem. Pharm. Bull. 1991, 39, 616. (e) Hiroi, K.; Abe,
J. Tetrahedron Lett. 1990, 31, 3623. (f) Hiroi, K.; Koyama, T.; Anzai, K. Chem. Lett. 1990, 235.
(17) (a) Suginome, H.; Orito, K.; Yorita, K.; Ishikawa, M.; Shimoyama, N.; Sasaki, T. J. Org. Chem. 1995, 60, 3052.
(b) Darses, B.; Michaelides, I. N.; Sladojevich, F.; Ward, J. W.; Rzepa, P. R.; Dixon, D. J. Org. Lett. 2012, 14, 1684.
(18) (a) Han, Z.; Wang, Z.; Ding, K. Adv. Synth. Catal. 2011, 353, 1584. (b) Punirun, T.; Peewasan, K.; Kuhakarn, C.;
Soorukram, D.; Tuchinda, P.; Reutrakul, V.; Kongsaeree, P.; Prabpai, S.; Pohmakotr, M. Org. Lett. 2012, 14, 1820. (c)
Uyeda, C.; Rötheli, A. R.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2010, 49, 9753. (d) Hodgson, A.; Marshall, J.; Hallett,
P.; Gallagher, T. J. Chem. Soc., Perkin Trans. 1 1992, 2169. (e) Tomioka, K; Ando, K.; Takemasa, Y.; Koga, K. J. Am.
Chem. Soc. 1984, 106, 2718. (f) Hwu, J. R.; Chen, C. N.; Shiao, S.ꢀS. J. Org. Chem. 1995, 60, 856.
ACS Paragon Plus Environment