Asymmetric organocatalytic cyclopropanation of cinnamone derivatives with stabilized sulfonium ylides

Article abstract of DOI:10.1021/jo400743b

A simple chiral diamine catalyst 1h was successfully applied in the asymmetric cyclopropanation of cinnamone derivatives with stabilized sulfur ylides. The desired cyclopropanation adducts were obtained in moderate yields (up to 68%) with good enantioselectivities (67-93% ee) and excellent diastereoselectivities (>95:5) under mild conditions.

Full text of DOI:10.1021/jo400743b

Subscriber access provided by Caltech Library Services
Note
Asymmetric Organocatalytic Cyclopropanation of
Cinnamone Derivatives with Stabilized Sulfonium Ylides
Jing Wang, Xiaohua Liu, Shunxi Dong, Lili Lin, and Xiaoming Feng
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400743b • Publication Date (Web): 29 May 2013
Downloaded from http://pubs.acs.org on June 5, 2013
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 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
Asymmetric Organocatalytic Cyclopropanation of Cinnamone Derivatives with
Stabilized Sulfonium Ylides
8
9
Jing Wang, Xiaohua Liu,* Shunxi Dong, Lili Lin and Xiaoming Feng*
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan
University, Chengdu 610064, P. R. China
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
*E-mail: liuxh@scuh.edu.cn; xmfeng@scu.edu.cn
ABSTRACT: A simple chiral diamine catalyst 1h was successfully applied in the asymmetric
cyclopropanation of cinnamone derivatives with stabilized sulfur ylides. The desired cyclopropanation
adducts were obtained in moderate yields (up to 68%) with good enantioselectivities (67–93% ees) and
excellent diastereoselectivities (>95:5) under mild conditions.
Cyclopropanes and their derivatives are common units presented in a large number of biologically active
pharmaceutical agents and natural products. They could serve as versatile and important building blocks in
organic synthesis because of their unique combination of reactivity and structural properties.1 Therefore,
enormous effort has been invested in diastereo- and enantioselective synthesis of functionalized cyclopropanes.
The carbenoid-mediated reactions, such as Lewis acid catalyzed Simmons-Smith type cyclopropanation, and
metallocarbenoid-mediated cyclopropanation from diazo compounds, are the most often used.2 On the other
hand, catalytic-ylide-based cyclopropanation has also been employed successfully for this purpose, which
could date back to work by Corey in 1965.3 A variety of ylide species as cyclopropanation reagents has been
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 19
1
2
3
4
5
6
7
8
9
developed to construct substituted three-membered carboncyclic rings. Of the methods developed, the
catalytic asymmetric cyclopropanation of electron-deficient olefins with ylides is less. The first catalytic
asymmetric cyclopropanation of α,β-unsaturated aldehydes with stabilized sulfonium ylides was reported by
the MacMillan group based on iminium catalysis.5a Chiral dihydroindol derivative was also proven useful.5b
Zhao’s group utilized a diphenylprolinol silyl ether to promote the cyclopropanation between α,β-unsaturated
aldehydes and arsonium ylides.5c Later, the Shibasaki group successfully accomplished asymmetric
cyclopropanation of enones with dimethyloxosulfonium methylide catalyzed by a La-Li(biphenyldiolate)3/NaI
complex.6 Recently, Xiao’s group reported C2-symmetric ureas-catalyzed asymmetric cyclopropanation of
β,γ-unsaturated α-ketoesters via a cooperative effect of the hydrogen-bond catalysis.7 Chiral amine catalysis8
offers a powerful strategy in useful organocatalysis based on the selective activation of aldehyde. Despite
these achievements, little progress has been achieved in the corresponding organocatalytic transformations of
cinnamone derivatives, mainly because of the inherent difficulties in generating congested covalent
intermediates from amines and ketones. 6, 9 In the mechanism study by Aggarwal’s group, it showed that the
reactions of stabilized sulfonium ylides with acyclic enones unexpectedly gave low ee. Following addition of a
stabilized ylide to the Michael acceptor, rapid and reversible intramolecular proton transfer within the betaine
intermediate, prior to ring closure, results in an erosion of ee.10 In addition, The activation of α,β-unsaturated
ketones with primary amine catalyst toward an iminium-enamine sequence11 might afford a formal [4+1]
addition/cyclization byproduct.12 Therefore, developing for an efficient catalytic system to generate
trisubstituted cyclopropanes in high stereoselectivity is still challenging and interesting. Herein, we describe
the first example of organocatalytic asymmetric cyclopropanation of cinnamone derivatives with stabilized
sulfonium ylides. In the presence of an easily available chiral primary-secondary diamine catalyst, a series of
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 19
The Journal of Organic Chemistry
1
2
3
4
5
1,2,3-trisubstituted cyclopropanes was obtained with good results (up to 65% yield, 93% ee, >95:5 dr),
6
7
meanwhile, a byproduct of 3,4-disubstituted cyclopentanone derivative was detected.
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
Figure1. Chiral Organocatalysts Used for the Reaction
Table 1. Optimization of the Reaction Conditions
entrya catalyst
additive
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
--
yieldb(%)
eec(%)
49
--
drd
>95:5
--
1
2
1a
1b
1c
1d
1e
1f
60
No reaction
3
15
8
44
73
--
>95:5
>95:5
--
4
5
trace
40
6
50
46
85
--
>95:5
>95:5
>95:5
--
7
1g
1h
1h
1h
1h
1h
1h
1h
1h
24
8
61
9
trace
8
10
11
12
13
14e
15e,f
TsOH
0
--
AcOH
22
75
55
47
90
90
>95:5
>95:5
>95:5
>95:5
>95:5
HCOOH
salicylic acid
PhCO2H/5 Å MS
PhCO2H/5 Å MS
55
64
62
68
a Unless otherwise noted, reactions were carried out with 2a (0.10 mmol), 3a
(0.12 mmol), diamine (20 mol %) and acidic additive (20 mol %) in CHCl3 (1.0 mL)
at 30 oC for 2 days. b Isolated yield of the product 4aa. c Determined by chiral HPLC.
d Determined by 1H NMR. e 5 Å MS (15.0 mg) was added. f Reaction time was 3 days.
The cyclopropanation between stabilized sulfonium ylide 3a with a ketone unit and cinnamone 2a was
used as the model reaction to screen the optimal conditions. We envisioned that the iminium catalysis and
hydrogen activation of the two substrates in concert would provide access to the desired products. Firstly,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 19
1
2
3
4
5
6
7
8
9
various chiral diamine catalysts assisted with identical equivalence of benzoic acid were selected for the
reaction. Chiral primary diamine catalysts bearing different backbones were investigated. The desired product
4aa was obtained in 60% yield, 49% ee, and >95:5 dr when (S,S)-cyclohexylenediamine 1a was used as the
catalyst (Table 1, entry 1). Trace amount of five-membered carboncyclic rings product 5aa was detected as a
racemate. Axial chiral binaphthyl diamine 1b was inert to the cyclopropanation (Table 1, entry 2). The use of
chiral amino alcohol 1c as the catalyst resulted in 15% yield, 44% ee, and >95:5 dr (Table 1, entry 3).
Excitingly, (S,S)-1,2-diphenylethylenediamine (Dpen) 1d showed superior in enantioselectivity (73% ee)
(Table 1, entry 4). To further improve the reactivity of the reaction, diamine catalysts 1e−h, formed by
modification of the primary diamine were introduced. Trace amount of cyclopropanation product was obtained
in the presence of secondary diamine 1e. Primary-secondary diamine catalyst 1h containing one cyclohexyl
substituent showed the best results in both the yield and the enantioselectivity (Table 1, entry 8 vs entries 5–7).
Additionally, in the absence of the acidic additive, the product was generated in extremely low yield, which
indicated that the acid was crucial in the activation process (Table 1, entry 9 vs entry 8). Other reaction
conditions to improve the yield were examined.13 The acidity of the additive affected the yield and
enantioselectivity greatly, and enhancing the acidity led to the loss of the enantiomeric excess (Table 1, entries
10–13). Pleasingly, the addition of 5 Å molecular sieves (MS) improved the ee value to 90% ee (Table 1, entry
14). Finally, a slight higher yield was achieved when the reaction time was prolonged to 3 days (Table 1, entry
15). It should be noteworthy that in all cases high diastereoselectivity (up to 95:5) was achieved.
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. Asymmetric Cyclopropanations of Sulfonium Ylides with Various Cinnamone Derivatives
ACS Paragon Plus Environment

Page 5 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
entrya R1
R2
Ph
Ph
Ph
Ph
4
yieldb (%) eec(%)
drd
1
2e
3e
4e
5
Ph
4aa 68(40)
4ba 63(40)
90(98)f >95:5
90(99) f >95:5
90(98) f >95:5
90(99) f >95:5
92(98) f >95:5
92(98) f >95:5
93(98) f >95:5
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
4-FC6H4
4-ClC6H4
4-BrC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
3-CF3C6H4
4-PhC6H4
4ca
56(34)
4da 53(31)
4-FC6H4 4bb 60(38)
4-FC6H4 4cb 57(35)
4-FC6H4 4db 52(30)
4-FC6H4 4eb 60
6e
7e
8
89
>95:5
9
4-FC6H4 4fb
61(39)
90(98) f >95:5
10
11
12
13
14
15
3-MeOC6H4 4-FC6H4 4gb 65
4-FC6H4 4hb 51
91
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
86
2-naphthyl
2-furyl
n-Pr
4-FC6H4 4ib
4-FC6H4 4jb
55(33)
50
88(98)
90
4-FC6H4 4kb 67
4-FC6H4 4lb 57
71
i-Pr
67
a Unless otherwise noted, reactions were carried out with 2 (0.20 mmol), 3 (0.24 mmol),
1h/PhCO2H (1/1, 20 mol %), and 5 Å MS (30.0 mg) in CHCl3 (2.0 mL) at 30 oC for
3 days. b Isolated yield of the product 4, and the yield in parenthesis was that after
recrystallization. c Determined by chiral HPLC. d Determined by 1H NMR. e The yield
of 4 was determined by 1H NMR analysis of the isolated mixture of 4 and 5 which
could not be separated. f The data in parenthesis was determined after recrystallization.
The optimized reaction conditions were applicable to a variety of cinnamone derivatives with sulfonium
ylides 3a and 3b. The corresponding cyclopropanation products were gained in moderate yields, good ee
values and excellent diastereoselectivites (>95:5). In general, moderate yields (51–68%) and good ee values
(86–93%) were obtained, regardless of the electronic properties of substituents at the aryl group of enones
(Table 2, entries 1–11). Notably, a disubstituted cinnamone derivative 2h was also tolerated in the reaction,
although the enantioselectivity of the adduct 4hb was slightly reduced (86% ee, Table 2, entry 11). Optical
pure products could be afforded (up to 98% ee) after recrystallization procedure. A fused-ring
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 19
1
2
3
4
5
6
7
8
9
aromatic-substituted enone, such as 2i, could also be employed successfully in this transformation, giving the
corresponding product 4ib with 88% ee (Table 2, entry 12). Heteroaromatic enone 2j was a suitable substrate
to generate the desired product 4jb with 90% ee (Table 2, entry 13). In addition, β-alkyl substituted enones 2k
and 2l were also investigated, and underwent the reaction well in moderate yields with 71% ee and 67% ee,
respectively (Table 2, entries 14–15).
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 3. Asymmetric Cyclopropanations of Cinnamone 2a with Various Sulfonium Ylides
entrya R2
4
yieldb (%) eec(%)
drd
1
2e
3e
4
4-FC6H4
4ab 65(41)
4ac 62(40)
4ad 63(40)
90(99) f >95:5
91(98) f >95:5
90(98) f >95:5
89(98) f >95:5
4-ClC6H4
4-BrC6H4
4-CH3C6H4 4ae 55(32)
4af
2-naphthyl 65
5
89
>95:5
a Unless otherwise noted, reactions were carried out with 2a (0.20 mmol), 3
(0.24 mmol, 1.2 equiv), 1h/PhCO2H (1/1, 20 mol %), and 5 Å MS (30.0 mg)
in CHCl3 (2.0 mL) at 30 oC for 3 days. b Isolated yield of the product 4, and
the yield in parenthesis was that after recrystallization. c Determined by chiral
HPLC. d Determined by 1H NMR. e The yield of 4 was determined by 1H NMR
analysis of the isolated mixture of 4 and 5. f The data in parenthesis was determined
after recrystallization.
Significantly, structural variation in the sulfonium ylide components can also be tolerated in the reaction.
As shown in Table 3, various sulfonium ylides were proven to be suitable for this catalytic asymmetric
cyclopropanation reaction. For example, electron-withdrawing substituents in the benzoyl group of sulfonium
ylides 3b–d proceeded well, generating the corresponding products in moderate yields (62–65%) and
stereoselectivities (89–91% ees, >95:5 dr) (Table 3, entries 1–3). Introducing an electron-donating group (e.g.,
methyl) to the benoyl unit of sulfonium ylide 3e could also give the desired product 4ae in slightly reduced
ACS Paragon Plus Environment

Page 7 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
yield with 89% ee and >95:5 dr (Table 3, entry 4). Moreover, the cyclopropanation of a fused-ring substituted
sulfonium ylide 3f gave the product 4af in 65% yield and 89% ee (Table 3, entry 5). In most cases,
five-membered byproducts 5 were detected as nearly racemates.
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. Gram-Scale Version of Cyclopropanation of Sulfonium Ylide 3a to Cinnamone 2a
In order to show the synthetic utility of the catalytic system, a gram-scale synthesis of 4aa was performed.
As shown in Scheme 1, by treatment of 2a (10.0 mmol) and 3a (12.0 mmol) under the optimal reaction
conditions, the desired product 4aa was obtained in 60% yield with 90% ee and > 95:5 dr. The absolute
configuration of the major enantiomer was established by X-ray crystallography analysis as (1S,2R,3S)
(Scheme 1).14
A bifunctional catalytic model for the cyclopropanation reaction between cinnamone 2a and sulfonium
ylide 3a was proposed. As shown in Figure 2, the primary moiety associating with the Brønsted acid additive
could activate the cinnamone by forming the iminium ion intermediate (Table 1, entry 5). On the other hand,
the secondary amine moiety directed the addition of sulfonium ylide through hydrogen bonding. The
formation of the Michael adduct by approach of the sulfonium ylide 3a from the β-Re-face of the cinnamone
was favored. Finally, the corresponding (1S,2R,3S)-4aa as the major product was afforded after an
intramolecular SN2 displacement and release of dimethylsulfane. When the isolated product 4aa was
resubjected to the catalyst system, the cyclopentanone derivative was not detected, which exclude the
byproduct formation via vinyl cyclopropane rearrangement, following enolization or enamine formation.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 19
1
2
3
4
5
6
7
8
9
Based on the fact that only racemic trans-3,4-disubstituted cyclopentanones were given, we postulated that the
side reaction might undergo a single activation model without facial selectivity. Following the addition of
sulfonium ylide to the iminium-ion of cinnamon, competitive transformation to enamine intermediates TS2
with the terminal methyl group formed. Subsequently, the intermediate underwent an intramolecular SN2
displacement to afford a formal [4+1] ylide annulation product as racemate.
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
Figure 2. Proposed Catalytic Models
In summary, we have developed the first highly enantioselective cyclopropanation of cinnamone
derivatives with stabilized sulfonium ylides catalyzed by an easily available primary-secondary diamine. A
series of cyclopropanation adducts were obtained in moderate yields (up to 68%) with good
enantioselectivities (67–93% ees) and excellent dr values (>95:5) under mind conditions. This strategy
provides a potential method for the formation of 1,2,3-trisubstituted cyclopropane compounds.
EXPERIMENTAL SECTION
1
General Details. Unless otherwise noted, H and 13C NMR spectra are internally referenced to residual
solvent signals (1H 400 MHz, CDCl3; 13C 100 MHz, CDCl3). Spectra were reported as follows: chemical shift
(δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet). Diastereoisomeric ratios
were determined by 1H NMR. Enantiomeric excesses (ee) were determined by HPLC analysis using chiralpak
ACS Paragon Plus Environment

Page 9 of 19
The Journal of Organic Chemistry
1
2
3
4
5
25
columns. Optical rotations were reported as follows: [a]D (c g/100 mL, CH2Cl2). HRMS was recorded on a
6
7
commercial apparatus (ESI Source: TOF).
8
9
Typical Procedure for Asymmetric Cyclopropanation of Cinnamone Derivatives with Stabilized
Sulfonium Ylides. Catalyst 1h (11.8 mg, 0.04 mmol), benzoic acid (4.8 mg, 0.04 mmol), 5 Å (30 mg),
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
o
sulfonium ylide 3a (43.2 mg, 0.24 mmol) were mixed in dry CHCl3 (2 mL). After stirring at 30 C for 0.5 h,
cinnamone 2a (29.2 mg, 0.2 mmol) was added directly. The reaction mixture was stirred at 30 oC for 3 days
and purified by flash column chromatography on silica gel (petroleum ether/ethyl ether (6:1) to give the
corresponding pure product 4aa in 68% yield (35.9 mg) as white solid. The diastereoisomer ratio (>95:5) was
determined by 1H NMR and enantiomeric excesses (ee) were determined by chiral HPLC (Daicel Chirapak IA,
hexane/2-propanol 80/20).
1-(2-benzoyl-3-phenylcyclopropyl)ethanone (4aa) 35.9 mg, 68% yield; 90% ee; >95:5 dr; (After
o
25
recrystallization: 21.1 mg, 40% yield; 98% ee); white solid: 110–112 C; [a]D = +3.77 (c 0.32, CH2Cl2) for
98% ee; HPLC Daicel chiralpack IA, n-hexane/i-PrOH 80/20, 1.0 mL/min, t(major) 9.52 min, t(minor) 10.57 min;
1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 7.8 Hz, 2H), 7.56 (t, J = 7.3 Hz, 1H), 7.45 (t, J = 7.5 Hz, 2H), 7.35
(t, J = 7.3 Hz, 2H), 7.27 (t, J = 7.1 Hz, 1H), 7.22 (d, J = 7.7 Hz, 2H), 3.37 (t, J = 6.1 Hz, 1H), 3.21 (t, J = 7.5
Hz, 1H), 2.88 – 2.73 (m, 1H), 2.31 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 203.1, 194.3, 138.3, 136.9, 133.4,
128.8, 128.7, 128.4, 127.2, 126.4, 39.6, 37.2, 31.1, 30.9, 25.3; HRMS (ESI-TOF) m/z: Calcd for
[C18H16O2+K]+: 303.0782, found: 303.0791.
1-(2-benzoyl-3-(4-fluorophenyl)cyclopropyl)ethanone (4ba) 35.6 mg, 63% yield; 90% ee; >95:5 dr;
(After recrystallization: 22.6 mg, 40% yield; 99% ee); white solid: 136–138 oC; [a]D25 = +7.14 (c 0.18, CH2Cl2)
for 99% ee; HPLC Daicel chiralpack ID, n-hexane/i-PrOH 80/20, 1.0 mL/min, t(major) 19.98 min, t(minor) 24.40
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 19
1
2
3
4
1
min; H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.8 Hz, 2H), 7.58 (t, J = 7.3 Hz, 1H), 7.52 – 7.40 (m, 4H),
7.09 (d, J = 8.2 Hz, 2H), 3.33 (t, J = 6.1 Hz, 1H), 3.16 (dd, J = 9.3, 6.4 Hz, 1H), 2.77 (dd, J = 9.2, 6.2 Hz, 1H),
2.30 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 202.5, 193.8, 137.4, 136.8, 133.5, 131.9, 128.7, 128.4, 128.2,
121.0, 39.4, 37.1, 30.9, 30.3; HRMS (ESI-TOF) m/z: Calcd for [C18H15FO2+K]+: 321.0688, found: 321.0675.
1-(2-benzoyl-3-(4-chlorophenyl)cyclopropyl)ethanone (4ca) 33.5 mg, 56% yield; 90% ee; >95:5 dr;
(After recrystallization: 20.3 mg, 34% yield; 98% ee); white solid: 164–166 oC; [a]D25 = +9.06 (c 0.28, CH2Cl2)
for 98% ee; HPLC Daicel chiralpack ID, n-hexane/i-PrOH 80/20, 1.0 mL/min, t(major) 21.40 min, t(minor) 29.94
min.; 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 7.7 Hz, 1H), 7.60 (t, J = 7.2 Hz, 0H), 7.49 (t, J = 7.5 Hz, 1H),
7.34 (d, J = 8.2 Hz, 1H), 7.17 (d, J = 8.2 Hz, 1H), 3.37 (t, J = 6.1 Hz, 0H), 3.18 (dd, J = 9.2, 6.4 Hz, 0H), 2.79
(dd, J = 9.2, 6.2 Hz, 0H), 2.48 (s, 0H), 2.32 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 202.5, 193.8, 136.8, 136.8,
133.5, 133.0, 129.0, 128.7, 128.4, 127.8, 39.5, 37.1, 30.9, 30.24; HRMS (ESI-TOF) m/z: Calcd for
[C18H1534.9689ClO2+Na]+: 321.0653, found: 321.0664.
5
6
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
1-(2-benzoyl-3-(4-bromophenyl)cyclopropyl)ethanone (4da) 36.4 mg, 53% yield; 90% ee; >95:5 dr;
(After recrystallization: 21.3 mg, 31% yield; 99% ee); white solid: 186–188 oC; [a]D25 = +7.93 (c 0.29, CH2Cl2)
for 99% ee; HPLC Daicel chiralpack ID, n-hexane/i-PrOH 80/20, 1.0 mL/min, t(major) 21.40 min, t(minor) 29.94
1
min; H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.8 Hz, 2H), 7.58 (t, J = 7.3 Hz, 1H), 7.52 – 7.40 (m, 4H),
7.09 (d, J = 8.2 Hz, 2H), 3.33 (t, J = 6.1 Hz, 1H), 3.16 (dd, J = 9.3, 6.4 Hz, 1H), 2.77 (dd, J = 9.2, 6.2 Hz, 1H),
2.30 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 202.5, 193.8, 137.4, 136.8, 133.5, 131.9, 128.7, 128.4, 128.2,
121.0, 39.4, 37.1, 30.9, 30.3; HRMS (ESI-TOF) m/z: Calcd for [C18H1578.9183BrO2+Na]+: 365.0148, found:
365.0151.
ACS Paragon Plus Environment

Page 11 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1-(2-(4-fluorobenzoyl)-3-(4-fluorophenyl)cyclopropyl)ethanone (4bb) 36.0 mg, 60% yield; 92%
ee; >95:5 dr; (After recrystallization: 22.8 mg, 38% yield; 98% ee); white solid: 132–134 oC; [a]D25 = +5.29 (c
0.45, CH2Cl2) for 98% ee; HPLC Daicel chiralpack ID, n-hexane/i-PrOH 80/20, 1.0 mL/min, t(major) 16.38 min,
t(minor) 18.50 min; 1H NMR (400 MHz, CDCl3) δ 8.01 (dd, J = 8.6, 5.5 Hz, 2H), 7.22 – 7.09 (m, 4H), 7.04 (t, J
= 8.6 Hz, 2H), 3.34 (t, J = 6.2 Hz, 1H), 3.08 (dd, J = 9.3, 6.4 Hz, 1H), 2.76 (dd, J = 9.3, 6.1 Hz, 1H), 2.30 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 202.7, 192.4, 131.0, 130.9, 128.1, 128.0, 116.0, 115.869, 115.8, 115.657,
39.4, 36.9, 30.9, 30.3; HRMS (ESI-TOF) m/z: Calcd for [C18H14F2O2+Na]+: 323.0854, found: 323.0858.
1-(2-(4-chlorophenyl)-3-(4-fluorobenzoyl)cyclopropyl)ethanone (4cb) 36.1 mg, 57% yield; 92%
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
25
ee; >95:5 dr; (After recrystallization: 22.2 mg, 35% yield; 98% ee); white solid: 174–176 oC; [a]D = −11.35
(c 0.52, CH2Cl2) for 98% ee; HPLC Daicel chiralpack ID, n-hexane/i-PrOH 80/20, 1.0 mL/min, t(major) 18.53
min, t(minor) 21.01 min.; 1H NMR (400 MHz, CDCl3) δ 8.04 – 7.95 (m, 2H), 7.32 (d, J = 8.4 Hz, 2H), 7.13 (t, J
= 8.5 Hz, 4H), 3.32 (t, J = 6.2 Hz, 1H), 3.09 (dd, J = 9.4, 6.3 Hz, 1H), 2.76 (dd, J = 9.4, 6.1 Hz, 1H), 2.30 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 202.5, 192.2, 136.6, 133.1, 131.0, 130.9, 129.0, 127.8, 116.0, 115.8, 39.3,
37.0, 30.9, 30.3; HRMS (ESI-TOF) m/z: Calcd for [C18H1434.9689ClFO2+Na]+: 339.0559, found: 339.0562.
1-(2-(4-bromophenyl)-3-(4-fluorobenzoyl)cyclopropyl)ethanone (4db) 37.6 mg, 52% yield; 93%
ee; >95:5 dr; (After recrystallization: 21.7 mg, 30 % yield; 98% ee); white solid: 186–188 oC; [a]D25 = −2.71 (c
0.33, CH2Cl2) for 98% ee; HPLC Daicel chiralpack ID, n-hexane/i-PrOH 80/20, 1.0 mL/min, t(major) 20.24 min,
t(minor) 23.17 min; 1H NMR (400 MHz, CDCl3) δ 8.08 – 7.93 (m, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.19 – 7.03 (m,
4H), 3.30 (t, J = 6.2 Hz, 1H), 3.09 (dd, J = 9.4, 6.3 Hz, 1H), 2.77 (dd, J = 9.4, 6.1 Hz, 1H), 2.30 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 201.4, 191.2, 136.2, 130.9, 130.0, 129.9, 127.1, 120.0, 115.0, 114.8, 38.3, 36.0,
29.9, 29.3; HRMS (ESI-TOF) m/z: Calcd for [C18H1478.9183BrFO2+Na]+: 383.0053, found: 383.0058.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 19
1
2
3
4
5
1-(2-(4-fluorobenzoyl)-3-(3-(trifluoromethyl)phenyl)cyclopropyl)ethanone (4eb) 42.0 mg, 60% yield;
6
7
o
25
89% ee; >95:5 dr; white solid: 62–64 C; [a]D = −15.0 (c 0.10, CH2Cl2); HPLC Daicel chiralpack ADH,
8
9
1
n-hexane/i-PrOH 90/10, 1.0 mL/min, t(minor) 10.60 min, t(major) 13.00 min; H NMR (400 MHz, CDCl3) δ 8.03
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
(dd, J = 8.4, 5.5 Hz, 2H), 7.58 – 7.40 (m, 4H), 7.15 (t, J = 8.5 Hz, 2H), 3.42 (t, J = 6.1 Hz, 1H), 3.18 (dd, J =
9.3, 6.4 Hz, 1H), 2.86 (dd, J = 9.3, 6.2 Hz, 1H), 2.31 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 202.2, 191.9,
139.2, 131.1, 131.0, 130.20, 129.4, 124.1, 124.1, 122.9, 122.9, 116.1, 115.8, 39.4, 36.9, 31.0, 30.2; HRMS
(ESI-TOF) m/z: Calcd for [C19H14F4O2+Na]+: 373.0822, found: 373.0827.
1-(2-([1,1'-biphenyl]-4-yl)-3-(4-fluorobenzoyl)cyclopropyl)ethanone (4fb) 43.7 mg, 61% yield; 90%
ee; >95:5 dr; (After recrystallization: 28.0 mg, 39% yield; 98% ee); white solid: 174–176 oC; [a]D25 = +4.87 (c
0.31, CH2Cl2) for 98% ee; HPLC Daicel chiralpack ID, n-hexane/i-PrOH 80/20, 1.0 mL/min, t(major) 28.12 min,
t(minor) 36.02 min; 1H NMR (400 MHz, CDCl3) δ 8.04 (dd, J = 8.8, 5.4 Hz, 2H), 7.59 (d, J = 7.9 Hz, 4H), 7.45
(t, J = 7.5 Hz, 2H), 7.36 (t, J = 7.3 Hz, 1H), 7.29 (d, J = 8.1 Hz, 2H), 7.14 (t, J = 8.6 Hz, 2H), 3.39 (t, J = 6.2
Hz, 1H), 3.18 (dd, J = 9.3, 6.3 Hz, 1H), 2.84 (dd, J = 9.3, 6.1 Hz, 1H), 2.34 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 203.0, 192.6, 140.5, 140.3, 137.2, 131.1, 131.0, 128.9, 127.6, 127.5, 127.0, 126.8, 116.0, 115.8, 39.5,
37.2, 31.0, 30.9; HRMS (ESI-TOF) m/z: Calcd for [C24H19FO2+Na]+: 381.1261, found: 381.1266.
1-(2-(4-fluorobenzoyl)-3-(3-methoxyphenyl)cyclopropyl)ethanone (4gb) 40.6 mg, 65% yield; 91%
25
ee; >95:5 dr; white solid: 88–90 oC; [a]D = −20.70 (c 0.31, CH2Cl2); HPLC Daicel chiralpack IA,
n-hexane/i-PrOH 70/30, 1.0 mL/min, t(major) 8.10 min, t(minor) 9.34 min; 1H NMR (400 MHz, CDCl3) δ 8.02 (dd,
J = 8.8, 5.4 Hz, 2H), 7.27 (dd, J = 8.7, 7.1 Hz, 1H), 7.13 (t, J = 8.6 Hz, 2H), 6.80 (m, 3H), 3.82 (s, 3H), 3.31 (t,
J = 6.2 Hz, 1H), 3.12 (dd, J = 9.3, 6.3 Hz, 1H), 2.79 (dd, J = 9.3, 6.1 Hz, 1H), 2.31 (s, 3H); 13C NMR (100
ACS Paragon Plus Environment

Page 13 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
MHz, CDCl3) δ 203.0, 192.6, 160.0, 139.8, 131.1, 131.0, 129.90, 118.40, 116.0, 115.7, 112.495, 112.4, 55.3,
39.4, 37.1, 31.1, 31.0; HRMS (ESI-TOF) m/z: Calcd for [C19H17FO3+K]+: 351.0793, found: 351.0792.
1-(2-(benzo[d][1,3]dioxol-5-yl)-3-(4-fluorobenzoyl)cyclopropyl)ethanone (4hb) 33.3 mg, 51% 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
o
25
86% ee; >95:5 dr; white solid: 114–116 C; [a]D = −7.0 (c 0.10, CH2Cl2); HPLC Daicel chiralpack IA,
1
n-hexane/i-PrOH 70/30, 1.0 mL/min, t(major) 10.83 min, t(minor) 15.72 min; H NMR (400 MHz, CDCl3) δ 8.01
(dd, J = 8.7, 5.5 Hz, 2H), 7.13 (t, J = 8.6 Hz, 2H), 6.78 (d, J = 8.0 Hz, 1H), 6.70 (m, 2H), 5.97 (s, 2H), 3.27 (t,
J = 6.2 Hz, 1H), 3.05 (dd, J = 9.3, 6.4 Hz, 1H), 2.72 (dd, J = 9.3, 6.1 Hz, 1H), 2.31 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 202.8, 192.6, 148.2, 146.9, 131.9, 131.1, 131.0, 119.9, 116.0, 115.7, 108.5, 106.7, 101.2, 39.3,
37.0, 31.1, 31.0; HRMS (ESI-TOF) m/z: Calcd for [C19H15FO4+K]+: 365.0586, found: 365.0583.
1-(2-(4-fluorobenzoyl)-3-(naphthalen-2-yl)cyclopropyl)ethanone (4ib) 36.6 mg, 55% yield; 88%
ee; >95:5 dr; (After recrystallization: 21.9 mg, 33% yield; 98% ee); white solid: 148–150 oC; [a]D = −4.0 (c
25
0.10, CH2Cl2) for 98% ee; HPLC Daicel chiralpack IA, n-hexane/i-PrOH 90/10, 1.0 mL/min, t(major) 56.77 min,
t(minor) 61.77 min; 1H NMR (400 MHz, CDCl3) δ 8.04 (dd, J = 8.1, 5.7 Hz, 2H), 7.82 (dd, J = 13.3, 8.2 Hz, 3H),
7.68 (s, 1H), 7.56 – 7.41 (m, 2H), 7.31 (d, J = 8.4 Hz, 1H), 7.13 (t, J = 8.5 Hz, 2H), 3.51 (t, J = 6.1 Hz, 1H),
3.24 (dd, J = 9.1, 6.5 Hz, 1H), 2.92 (dd, J = 9.1, 6.2 Hz, 1H), 2.35 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
202.9, 192.0, 135.5, 133.4, 132.6, 131.1, 131.0, 128.7, 127.7, 127.5, 126.6, 126.0, 125.2, 124.3, 116.0, 115.7,
39.4, 37.2, 31.4, 31.0; HRMS (ESI-TOF) m/z: Calcd for [C22H17FO2+K]+: 371.0844, found: 371.0846.
1-(2-(4-fluorobenzoyl)-3-(furan-2-yl)cyclopropyl)ethanone(4jb) 27.2 mg, 50% yield; 90% ee; >95:5
dr; yellow solid: 112–114 oC; [a]D = +9.84 (c 0.12, CH2Cl2); HPLC Daicel chiralpack ADH,
25
1
n-hexane/i-PrOH 80/20, 1.0 mL/min, t(major) 11.51 min, t(minor) 12.54 min; H NMR (400 MHz, CDCl3) δ 8.03
(dd, J = 8.3, 5.6 Hz, 2H), 7.31 (s, 1H), 7.14 (t, J = 8.5 Hz, 2H), 6.35 (s, 1H), 6.25 (d, J = 2.9 Hz, 1H), 3.34 (t, J
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 19
1
2
3
4
5
6
7
8
9
= 6.0 Hz, 1H), 3.26 (dd, J = 9.2, 6.3 Hz, 1H), 2.90 (dd, J = 9.3, 6.0 Hz, 1H), 2.30 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 202.5, 192.1, 151.2, 141.5, 131.1, 131.0, 116.0, 115.8, 110.9, 106.8, 37.3, 35.0, 30.9, 24.4; HRMS
(ESI-TOF) m/z: Calcd for [C16H13FO3+Na]+: 295.0741, found: 295.0745.
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-(2-(4-fluorobenzoyl)-3-propylcyclopropyl)ethanone (4kb) 33.3 mg, 67% yield; 71% ee; >95:5 dr;
yellow solid: 44–46 oC; [a]D25 = +12.74 (c 0.42, CH2Cl2); HPLC Daicel chiralpack ID, n-hexane/i-PrOH 80/20,
1.0 mL/min, t(minor) 9.98 min, t(major) 11.46 min; 1H NMR (400 MHz, CDCl3) δ 7.99 – 7.89 (m, 2H), 7.10 – 6.99
(m, 2H), 2.58 (dd, J = 8.7, 6.6 Hz, 1H), 2.27 – 2.15 (m, 2H), 2.14 – 2.08 (m, 3H), 1.42 (m, 4H), 0.94 – 0.84 (m,
3H); 13C NMR (100 MHz, CDCl3) δ 203.0, 192.7, 129.8, 129.7, 114.8, 114.6, 37.4, 34.0, 33.5, 29.6, 26.8, 21.0,
12.7; HRMS (ESI-TOF) m/z: Calcd for [C15H17FO2+K]+: 287.0844, found: 287.0846.
1-(2-(4-fluorobenzoyl)-3-isopropylcyclopropyl)ethanone (4lb) 28.3 mg, 57% yield; 67% ee; >95:5 dr;
yellow solid: 46–48 oC; [a]D25 = +8.65 (c 0.21, CH2Cl2); HPLC Daicel chiralpack ID, n-hexane/i-PrOH 80/20,
1.0 mL/min, t(minor) 9.31 min, t(major) 10.28 min; 1H NMR (400 MHz, CDCl3) δ 8.00 – 7.93 (m, 2H), 7.06 (t, J =
8.6 Hz, 2H), 2.63 (dd, J = 9.2, 6.2 Hz, 1H), 2.24 (dd, J = 9.1, 6.4 Hz, 1H), 2.12 (s, 3H), 2.05 (dt, J = 8.3, 6.3
Hz, 1H), 1.34 – 1.23 (m, 1H), 1.00 (s, 3H), 0.98 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 204.0, 193.8, 130.9,
130.8, 115.8, 115.6, 37.7, 35.6, 33.8, 31.6, 30.5, 21.5, 21.4; HRMS (ESI-TOF) m/z: Calcd for [C15H17FO2+K]+:
287.0844, found: 287.0845.
1-(2-(4-fluorobenzoyl)-3-phenylcyclopropyl)ethanone (4ab) 36.7 mg, 65% yield; 90% ee; >95:5 dr;
(After recrystallization: 23.1 mg, 41% yield; 99% ee); white solid: 102–104 oC; [a]D25 = −6.04 (c 0.49, CH2Cl2)
for 99% ee; HPLC Daicel chiralpack IA, n-hexane/i-PrOH 90/10, 1.0 mL/min, t(major) 18.86 min, t(minor) 20.92
min; 1H NMR (400 MHz, CDCl3) δ 8.02 (t, J = 6.2 Hz, 2H), 7.35 (t, J = 7.2 Hz, 2H), 7.29 (d, J = 7.6 Hz, 1H),
7.21 (d, J = 7.3 Hz, 2H), 7.12 (t, J = 7.9 Hz, 2H), 3.34 (t, J = 6.1 Hz, 1H), 3.13 (t, J = 7.8 Hz, 1H), 2.80 (t, J =
ACS Paragon Plus Environment

Page 15 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
7.6 Hz, 1H), 2.31 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 201.9, 191.6, 137.1, 130.0, 129.9, 127.8, 126.3,
125.35, 114.9, 114.7, 38.4, 36.1, 30.2, 29.9; HRMS (ESI-TOF) m/z: Calcd for [C18H15FO2+K]+: 321.0688,
found: 321.0691.
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-(2-(4-chlorobenzoyl)-3-phenylcyclopropyl)ethanone (4ac) 37.0 mg, 62% yield; 91% ee; >95:5 dr;
o
25
(After recrystallization: 23.9 mg, 40% yield; 98% ee); white solid: 136–138 C; [a]D = −11.48 (c 0.22,
CH2Cl2) for 98% ee; HPLC Daicel chiralpack ADH, n-hexane/i-PrOH 80/20, 1.0 mL/min, t(minor) 17.40 min,
t(major) 18.80 min; 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.3 Hz, 2H), 7.35 (t, J =
7.4 Hz, 2H), 7.29 (d, J = 7.0 Hz, 1H), 7.21 (d, J = 7.6 Hz, 2H), 3.34 (t, J = 6.1 Hz, 1H), 3.12 (dd, J = 9.2, 6.4
Hz, 1H), 2.81 (dd, J = 9.2, 6.2 Hz, 1H), 2.31 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 203.0, 193.1, 139.9,
138.0, 135.2, 129.8, 129.0, 128.9, 127.3, 126.4, 39.5, 37.1, 31.3, 31.0; HRMS (ESI-TOF) m/z: Calcd for
[C18H1534.9689ClO2+Na]+: 321.0653, found: 321.0661.
1-(2-(4-bromobenzoyl)-3-phenylcyclopropyl)ethanone (4ad) 43.2 mg, 63% yield; 90% ee; >95:5 dr;
o
25
(After recrystallization: 27.5 mg, 40% yield; 98% ee); white solid: 152–154 C; [a]D = –17.02 (c 028,
CH2Cl2) for 98% ee; HPLC Daicel chiralpack ID, n-hexane/i-PrOH 80/20, 1.0 mL/min, t(major) 21.36 min, t(minor)
1
25.94 min; H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.5 Hz, 2H), 7.60 (d, J = 8.5 Hz, 2H), 7.35 (t, J = 7.3
Hz, 2H), 7.29 (d, J = 7.1 Hz, 1H), 7.21 (d, J = 7.2 Hz, 2H), 3.33 (t, J = 6.2 Hz, 1H), 3.11 (dd, J = 9.3, 6.4 Hz,
1H), 2.81 (dd, J = 9.3, 6.1 Hz, 1H), 2.31 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 202.9, 193.3, 138.0, 135.7,
132.0, 129.9, 128.9, 128.6, 127.3, 126.4, 39.5, 37.0, 31.3, 31.0; HRMS (ESI-TOF) m/z: Calcd for
[C18H1578.9183BrO2+Na]+: 365.0148, found: 365.0152.
1-(2-(4-methylbenzoyl)-3-phenylcyclopropyl)ethanone (4ae) 30.6 mg, 55% yield; 89% ee; >95:5 dr;
(After recrystallization: 17.8 mg, 32% yield; 98% ee); white solid: 136−138 oC; [a]D25 = −4.00 (c 0.10, CH2Cl2)
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 19
1
2
3
4
5
for 98% ee; HPLC Daicel chiralpack ID, n-hexane/i-PrOH 80/20, 1.0 mL/min, t(major) 27.12 min, t(minor) 32.47
6
7
1
min; H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.1 Hz, 2H), 7.35 (t, J = 7.3 Hz, 2H), 7.30 – 7.18 (m, 5H),
8
9
3.36 (t, J = 6.2 Hz, 1H), 3.18 (dd, J = 9.4, 6.3 Hz, 1H), 2.77 (dd, J = 9.4, 6.2 Hz, 1H), 2.41 (s, 3H), 2.30 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 203.1, 193.8, 144.3, 138.4, 134.4, 129.4, 128.8, 128.5, 127.2, 126.4, 39.5,
37.2, 31.0, 30.9, 21.7; HRMS (ESI-TOF) m/z: Calcd for [C19H18O2+K]+: 317.0938, found: 317.0913.
1-(2-(2-naphthoyl)-3-phenylcyclopropyl)ethanone (4af) 40.9 mg, 65% yield; 89% ee; >95:5 dr; (After
recrystallization: 25.8 mg, 41% yield; 98% ee); white solid: 154–156 oC; [a]D25 = −39.58 (c 0.05, CH2Cl2) for
98% ee; HPLC Daicel chiralpack ID, n-hexane/i-PrOH 80/20, 1.0 mL/min, t(major) 28.02 min, t(minor) 32.75 min;
1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 8.05 (dd, J = 8.6, 1.5 Hz, 1H), 7.98 – 7.84 (m, 3H), 7.58 (dt, J =
23.7, 6.9 Hz, 2H), 7.38 (t, J = 7.3 Hz, 2H), 7.29 (m, 3H), 3.44 (t, J = 6.2 Hz, 1H), 3.34 (dd, J = 9.4, 6.3 Hz,
1H), 2.88 (dd, J = 9.4, 6.2 Hz, 1H), 2.33 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 203.1, 194.1, 138.3, 135.7,
134.3, 132.5, 130.2, 129.6, 128.9, 128.7, 128.6, 127.9, 127.3, 126.9, 126.5, 124.0, 39.6, 37.3, 31.3, 30.9;
HRMS (ESI-TOF) m/z: Calcd for [C22H18O2+K]+: 353.0938, found: 353.0945.
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
o
3-benzoyl-4-phenylcyclopentanone (5aa) White solid: 98–100 C; 1H NMR (400 MHz, CDCl3) δ 7.73
(d, J = 7.5 Hz, 2H), 7.45 (t, J = 7.4 Hz, 1H), 7.31 (t, J = 7.7 Hz, 2H), 7.24 – 7.10 (m, 5H), 4.14 (q, J = 8.6 Hz,
1H), 3.79 (dd, J = 18.2, 8.6 Hz, 1H), 2.81 (dd, J = 18.6, 8.3 Hz, 1H), 2.65 (m, 2H), 2.53 (dd, J = 18.6, 10.1 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 213.9, 199.0, 140.5, 135.1, 132.5, 127.9, 127.7, 127.4, 126.2, 126.0, 49.6,
44.3, 44.0, 41.8; HRMS (ESI-TOF) m/z: Calcd for [C18H16O2+Na]+: 287.1043, found: 287.1047.
ACKNOWLEDGMENTS
We appreciate the National Natural Science Foundation of China (Nos, 21021001, 21072133, and
21222206), the National Basic Research Program of China (973 Program: 2010CB833300), and the Ministry
ACS Paragon Plus Environment

Page 17 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
of Education of China (NCET-11-0345) for financial support. We also thank Institute of Chemistry Chinese
Academy Science Analytical & Testing Center for X-ray analysis.
8
9
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
Full optimization details, 1H and 13C NMR spectra, HPLC data and CD data are available. This material is
available free of charge via the Internet at http://pubs.acs.org.
REFERENCES
(1) (a) Taber, D. F. In Comprehensive Organic Sythesis; Trost, B. M., Fleming, I., Eds.; Pergamon: New
York, 1991; Vol. 3, p 1045. (b) Donaldson, W. A. Tetrahedron 2001, 57, 8589. (c) Pietruszka, J. Chem. Rev.
2003, 103, 1051. (d) Reissig, H. U.; Zimmer, R. Chem. Rev. 2003, 103, 1151.
(2) Lebel, H.; Marcoux, J. F.; Molinaro, C.; Charette, A. B. Chem. Rev. 2003, 103, 977.
(3) (a) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353. (b) Payne, G. B. J. Org. Chem.
1967, 32, 3351.
(4) (a) Hanessian, S.; Andreotti, D.; Gomtsyan, A. J. Am. Chem. Soc. 1995, 117, 10393. (b) Ye, S.;
Huang, Y. Z.; Xia, C. A.; Tang, Y.; Dai, L. X. J. Am. Chem. Soc. 2002, 124, 2432. (c) Liao, W. W.; Li, K.;
Tang, Y. J. Am. Chem. Soc. 2003, 125, 13030. (d) Aggarwal, V. K.; Winn, C. L. Acc. Chem. Res. 2004, 37,
611. (e) Papageorgiou, C. D.; Ley, S. V.; Gaunt, M. J. Angew. Chem., Int. Ed. 2004, 42, 7. (f) Papageorgiou, C.
D.; Cubillo de Dios, M. A.; Ley, S. V.; Gaunt, M. J. Angew. Chem., Int. Ed. 2004, 43, 4641.
(5) (a) Kunz, R. K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 3240. (b) Hartikka, A.;
Arvidsson, P. I. J. Org. Chem. 2007, 72, 5874. (c) Zhao, Y. H.; Zhao, G.; Cao, W. G. Tetrahedron Asymmetry.
2007, 10, 7.
(6) Kakei, H.; Sone, T.; Sohtome, Y.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2007, 129, 13410.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 19
1
2
3
4
5
6
7
(7) (a) Cheng Y.; An J.; Lu, L. Q.; Wang, Z. Y.; Chen, J. R.; Xiao, W. J. J. Org. Chem. 2011, 76, 281. (b)
Dou, X. W.; Lu, Y. X. Chem. Eur. J. 2012, 18, 8315.
8
9
(8) For reviews on amine catalysis, see: (a) Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli, G. Angew.
Chem. Int. Ed. 2008, 47, 6138. (b) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107,
5471. (c) r il , A.; Majander, I.; Pihko, P. M. Chem. Rev. 2007, 107, 5416. (d) Xu, L. W.; Luo, J.; Lu, Y. X.
Chem. Commun. 2009, 14, 1807.
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
(9) (a) Ooi, T.; Ohara, D.; Fukumoto, K. Maruoka, K. Org. Lett. 2005, 7, 3195. (b) Almasi, D.; Alonso, D.
A.; Najera, C. Tetrahedron Asymmetry. 2007, 18, 299.
(10) Riches, S. L.; Saha, C.; Filgueira, N. F.; Grange, E.; McGarrigle, E. M.; Aggarwal, V. K. J. Am.
Chem. Soc. 2010, 132, 7626.
(11) For the activation of α,β-unsaturated ketones with primary amine catalyst toward an
iminium-enamine sequence, see: (a) Melchiorre, P.; Jøgensen, K. A. J. Org. Chem. 2003, 68, 4151. (b)
Pulkkinen, J.; Aburel, P. S.; Halland, N.; Jøgensen, K. A. Adv. Synth. Catal. 2004, 346, 1077. (c) Bencivenni,
G.; Wu, L. Y.; Mazzanti, A.; Giannichi, B.; Pesciaioli, F.; Song, M. P.; Bartoli, G.; Melchiorre, P. Angew.
Chem., Int. Ed. 2009, 48, 7200. (d) Wang, M.; Lin, L. L.; Shi, J.; Liu, X. H.; Feng, X. M. Chem. Eur. J. 2011,
17, 2365. (e) Liu, Y. B.; Liu, X. H.; Wang, M.; He, P.; Lin, L. L.; Feng, X. M. J. Org. Chem. 2012, 77, 4136.
(12) For asymmetric [4+1] annulation of sulfur ylides with α,β-unsaturated compounds, see: (a) Zheng, J.
C.; Zhu, C. Y.; Sun, X. L.; Tang, Y.; Dai, L. X. J. Org. Chem. 2008, 73, 6910. (b) Lu, L. Q.; Chen, J. R.; Xiao
W. J. Acc. Chem. Res. 2012, 45, 1278.
(13) See Supporting Information for details.
(14) CCDC 932350 (4aa) contains the supplementary crystallographic data for this paper. The data can
ACS Paragon Plus Environment

Page 19 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
be obtained free of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
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
ACS Paragon Plus Environment