Total Syntheses of All Six Chiral Natural Pyrethrins: Accurate Determination of the Physical Properties, Their Insecticidal Activities, and Evaluation of Synthetic Methods

Article abstract of DOI:10.1021/acs.joc.9b02767

Chiral total syntheses of all six insecticidal natural pyrethrins (three pyrethrin I and three pyrethrin II compounds) contained in the chrysanthemum (pyrethrum) flower were performed. Three common alcohol components [(S)-cinerolone, (S)-jasmololone, and (S)-pyrethrolone] were synthesized: (i) straightforward Sonogashira-type cross-couplings using available (S)-4-hydroxy-3-methyl-2-(2-propynyl)cyclopent-2-en-1-ones (the prallethrin alcohol) for (S)-cinerolone (overall 52% yield, 98% ee) and (S)-pyrethrolone (overall 54% yield, 98% ee) and (ii) traditional decarboxylative-aldol condensation and lipase-catalyzed optical resolution for (S)-jasmololone (overall 16% yield, 96% ee). Two counter acid segments [(1R,3R)-chrysanthemic acid (A) and (1R,3R)-second chrysanthemic acid precursor (B)] were prepared: (i) C(1) epimerization of ethyl (±)-chrysanthemates and optical resolution using (S)-naphthylethylamine to afford A (96% ee) and (ii) concise derivatization of A to B (96% ee). All six pyrethrin esters (cinerin I/II, jasmolin I/II, and pyrethrin I/II) were successfully synthesized utilizing an accessible esterification reagent (TsCl/N-methylimidazole). To investigate the stereostructure-activity relationship, all four chiral stereoisomers of cinerin I were synthesized. Three alternative syntheses of (±)-jasmololone were investigated (methods utilizing Piancatelli rearrangement, furan transformation, and 1-nitropropene transformation). Insecticidal activity assay (KD₅₀ and IC₅₀) against the common mosquito (Culex pipiens pallens) revealed that (i) pyrethrin I > pyrethrin II, (ii) pyrethrin I (II) > cinerin I (II) ? jasmolin I (II), and (iii) "natural" cinerin I ? three "unnatural" cinerin I compounds (apparent chiral discrimination).

Full text of DOI:10.1021/acs.joc.9b02767

Subscriber access provided by Universite du Quebec a Montreal (UQAM)
Article
Total Syntheses of All Six Chiral Natural Pyrethrins:
Accurate Determination of the Physical Properties, Their
Insecticidal Activities, and Evaluation of Synthetic Methods
Momoyo Kawamoto, Mizuki Moriyama, Yuichiro Ashida, Noritada Matsuo, and Yoo Tanabe
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02767 • Publication Date (Web): 08 Jan 2020
Downloaded from pubs.acs.org on January 8, 2020
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 46
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Total Syntheses of All Six Chiral Natural Pyrethrins: Accurate
Determination of the Physical Properties, Their Insecticidal Activities,
and Evaluation of Synthetic Methods
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
Momoyo Kawamoto, Mizuki Moriyama, Yuichiro Ashida, Noritada Matsuo,* Yoo Tanabe*
Department of Chemistry, School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen,
Sanda, Hyogo, 669-1337, Japan
ABSTRACT: Chiral total syntheses of all six insecticidal natural pyrethrins (three pyrethrin-I and three
pyrethrin-II compounds) contained in the chrysanthemum (pyrethrum) flower were performed. Three
common alcohol components [(S)-cinerolone, (S)-jasmololone, (S)-pyrethrolone] were synthesized: (i)
Straightforward Sonogashira-type cross-couplings using available (S)-4-hydroxy-3-methyl-2-(2-
propynyl)cyclopent-2-en-1-ones (the prallethrin alcohol) for (S)-cinerolone (overall 52% yield, 98% ee)
and (S)-pyrethrolone (overall 54% yield, 98% ee) and (ii) traditional decarboxylation-aldol condensation
and lipase-catalyzed optical resolution for (S)-jasmololone (overall 16% yield, 96% ee). Two counter
acid segments of [(1R,3R)-chrysanthemic acid (A) and (1R,3R)-second chrysanthemic acid precursor
(B)] were prepared: (i) C(1)-epimerization of ethyl (±)-chrysanthemates and optical resolution using (S)-
naphthylethylamine to afford A (96% ee) and (ii) concise derivatization of A to B (96% ee). All six
pyrethrin esters (cinerin I/II, jasmolin I/II, pyrethrin I/II) were successfully synthesized utilizing an
accessible esterification reagent (TsCl/N-methylimidazole). To investigate the stereostructure-activity
relationship, all four chiral stereoisomers of cinerin I were synthesized. Three alternative syntheses of
(±)-jasmololone were investigated (methods utilizing Piancattelli-rearrangement, furan-transformation,
and 1-nitropropene-transformation). Insecticidal activity assay (KD50 and IC50) against the common
mosquito (Culex pipiens pallens) revealed that (i) pyrethrin-I > pyrethrin-II, (ii) pyrethrin I(II) > cinerin
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 46
I(II) >> jasmolin I(II), (iii) “natural” cinerin I >> three “unnatural” cinerin I compounds (apparent chiral
discrimination).
1
2
3
4
5
6
7
8
Introduction
9
Natural pyrethrin families are well-recognized lead origins of a variety of synthetic pyrethroid
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
insecticides.1-9 The flowers of pyrethrums (Chrysanthemum cinerariaefolium and C. coccineum)
produce pyrethrins, which comprise three closely related sets of natural products (Figure 1): pyrethrin I
(cinerin I, jasmolin I, pyrethrin I) and pyrethrin II (cinerin II, jasmolin II, pyrethrin II). Since the
discovery of pyrethrins, considerable efforts have been devoted to the research and development of
synthetic pyrethroids originating from natural pyrethrins. Among various commercialized insecticides,
synthetic pyrethroids are currently established as a strong commodity, not only in the agricultural
industry but also as everyday house-hold amenity.
Developments in synthetic chemistry have contributed to the longstanding progress of synthetic
pyrethroids (over 30 commercialized products) from the standpoint of total cost-performance, such as
compound stability, constant supply capacity, chiral switch for environmental demands, etc.9
Nonetheless, the recent trend toward the natural-source pesticides, has attracted considerable attention to
the practical usage of natural pyrethrins as an origin regression. Actually, 10,000 metric tons (dried
flower bases) of natural pyrethrins are still cultivated, mainly in Australia, East Africa, and Southern
China. These crops are widely employed for the biodegradable house-hold product with high
insecticidal activity and with low mammalian toxicity.
O
O
O
R
R
R
CO2
CO2
CO2
Jasmolin I:
Jasmolin II:
Pyrethrin I: R = Me
Pyrethrin II:
R = Me
Cinerin I:
Cinerin II:
R = Me
R = CO2Me
R = R = CO2Me
R = CO2Me
Figure 1. Six natural pyrethrin families.
2
ACS Paragon Plus Environment

Page 3 of 46
The Journal of Organic Chemistry
Because of the structural resemblance of pyrethrin families, practical separation of pure ingredients
1
2
from the natural mixture products is virtually impossible, even using recent elaborate techniques. In
1983, Casida and Ando disclosed the first synthetic approach and structure confirmation of “chiral”
pyrethrin I, based on the analytical data of 90 MHz 1H NMR spectra and optical rotations.10 They used
the starting (S)-4-hydroxy-3-methyl-2-(allyl)cyclopent-2-en-1-one precursor with unknown chemical
and optical purities that was gifted from a certain company. At that time, accurate HPLC analyses and
3
4
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
13
higher resolution H and C NMR measurements had not yet been developed. Moreover, contrary to
general and prevailing brief, the independent insecticidal activities of all six pyrethrin families were not
yet clarified. Taking this background into account, we envisaged chiral total syntheses of all six natural
pyrethrins to accurately accumulate their physical properties and evaluate their unknown insecticidal
activities, consistent with our longstanding studies of cyclopropane transformation chemistries11 and
syntheses of novel pyrethroids.12
Insecticidal activities against the common mosquito (Culex pipiens pallens) of all six highly pure
synthesized pyrethrins were evaluated. In addition, stereostructure-activity-relationship of all four
enantiomers of cinerine I was investigated.
On the other hand, three selected alternative syntheses of jasmololone, the alcohol component of
jasmolin, was investigated to compare the efficiency with the present synthesis.
Results and discussion:
1. Design of total syntheses of all six natural pyrethrin I and II families
Our designed synthetic routes for the chiral syntheses of all six natural pyrethrins are illustrated in
Scheme 1. The starting (S)-4-hydroxy-3-methyl-2-(2-propynyl)cyclopent-2-en-1-one (1), an alcohol
component of prallethrin (ETOC® , was readily prepared from the racemate13 through lipase-catalyzed
)
asymmetric hydrolysis.14 Sonogashira-type cross-coupling and (Z)-stereocontrolled partially reduction
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 46
sequences leading to (S)-cinerolone (3), (S)-jasmorolone (5), and (S)-pyrethrolone (7), are common
1
2
3
strategy for this object.
4
5
6
7
8
9
O
O
O
O
MeO2
C
CO2
Cinerin I
CO2
HO
HO
HO
(S)-Cinerolone (3)
2
Cinerin II
O
O
O
O
O
1
MeO2
C
2
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
HO
CO2
4
3
CO2
HO
1
(S)-Jasmololone (5)
4
Jasmolin I
Jasmolin II
O
O
O
O
MeO2C
HO
HO
CO2
CO2
6
(S)-Pyrethrolone (7)
Pyrethrin I
Pyrethrin II
Scheme 1. Synthetic route for all six natural pyrethrin families.
2. Total syntheses of three natural pyrethrin I families
2. 1. (1R,3R)- and (1S,3S)-Chrysanthemic acids
Commercially available racemic ethyl chrysanthemate [(±)-8] was converted to (±)-trans-8 by C(1)-
epimerization using a NaH catalyst (Scheme 2). Hydrolysis of (±)-trans-8 gave the carboxylic acid (±)-
trans-9 in 86% overall yield (trans/cis = 90:10). A modified optical resolution method15 of (±)-trans-9
using (S)-naphthylethylamine (NEA) produced the desired chiral chrysanthemic acid (1R,3R)-9 in 22%
yield (trans/cis = 98:2) with excellent enantiomeric excess (97%). In a similar manner, antipodal acid
(1S,3S)-9 was provided using (R)-NEA [nearly the same price as (S)-NEA]. Compared with several
recent resolution methods, such as the unique preferential resolution of Rosini’s group using (1R,3R)-9
itself,16 column chromatographic resolutions using chiral BINOL monomethyl ether12c and diol derived
from (+)-carene,17 and solid-liquid resolution using chiral BINOL monoalkyl ethers,18 we consider the
present overall procedures to be the most accessible for synthetic chemists.
4
ACS Paragon Plus Environment

Page 5 of 46
The Journal of Organic Chemistry
KOH (5.0 eq.)
3
1
NaH (10 mol%)
/ neat, 130 – 135 °C, 3 h
1
CO2Et
CO2Et
CO2H
(±)-
2
(±)-
(±)-
/ EtOH – H2O (5:1),
130 – 135 °C, 3 h
2
3
-8
(±)
9
(±)-trans-
8
(±)-trans-
93% trans / cis = 90 : 10
trans / cis = 65 : 35
86% trans / cis = 90 : 10
4
5
NH2
NH2
6
7
8
9
10
11
12
(R)-NEA
(S)-NEA
CO2H
CO2H
9
9
(±)-trans-
(±)-trans-
/ EtOH, rt, 16 h
/ EtOH, rt, 16 h
9
9
(1S,3S)-
22% trans / cis = 98 : 2
(1R,3R)-
22% trans / cis = 98 : 2
Two times
recrystallization
Two times
recrystallization
96% ee
99% ee
Scheme 2. Preparation of (1R,3R)-chrysanthemic acid.
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
2. 2. Cinerin I
Sonogashira-type cross-coupling of (S)-prallethrin alcohol (1) with MeI using Pd(II) / Cu(II) /
ItBu•HBF4 catalysis, developed by Fu and Eckhardt,19 was successfully applied to afford the methylated
intermediate 2 in 46% yield (Scheme 3). Lindlar catalytic hydrogeneation of 2 under standard
conditions furnished (S)-cinerolone (3) in an overall yield of 52% and an excellent enantiomeric excess
(98%). Finally, TsCl / N-methylimidazole (NMI)–mediated esterification20 of 4 with chiral trans-
chrysanthemic acid (1R,3R)-9 successfully produced the desired cinerin-I in a yield of 76%. It should
be noted that the conventional EDCI esterification method resulted in 35% inferior yield under identical
conditions (20–25 ºC, 2 h). Thus, throughout this study, esterification reaction utilized the high velocity
method using TsCl / NMI (/ i-Pr2NEt).
MeI (2.0 eq.), ItBu·HBF4 (5 mol%),
[(p-allyl)Pd]Cl2 (2.5 mol%),
CuI (7.5 mol%), Cs2CO3 (1.4 eq.)
H2 balloon
Pd-BaSO4 (5 mol%)
quinoline (6.0 eq.)
O
O
1
/ AcOEt
20 – 25 °C, 1.5 h
/ DMF - Et2O (1:2), 40 – 45 °C, 3 h
HO
HO
2
(S)-Cinerolone (3)
tBu
56%
N
93%, 98% ee
BF
·
=
ItBu·HBF4
4
N
tBu
O
TsCl (1.2 eq.), NMI (3.0 eq.)
/ CH3CN, 20 – 25 °C, 2 h
+
3
CO2H
CO2
9
(1R,3R)-
Cinerin I
76%
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 46
Scheme 3. Synthetic route for natural cinerin I.
1
2
3
4
5
6
2. 3. Jasmolin I
7
8
9
A similar Sonogashira-type cross-coupling of (S)-prallethrin alcohol (1) with EtI instead of MeI was
examined (Scheme 4). Among various reaction conditions screened, including the use of 5 equiv of
EtI, the desired product 4 was obtained in a maximum yield of 10% (SI, Table S1) probably due to the
β-hydride elomination of Et group.
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
although Lindler reduction of 4 proceeded smoothly to afford (S)-jasmololone (5) in 88% yield.
This dissapointed result turned our attention to an alternative synthetic route. The dianion of methyl
acetoacetate was treated with readily available (Z)-1-bromo-2-pentene to afford β-ketoester 10 in 75%
yield. Traditional decarboxylative aldol condensation of 10 with methyl glyoxal afforded the aldol
(±)-11 in 64% yield. Transformation of (±)-11 to the desired 4-hydroxy-3-cyclopent-2-en-1-one was
performed by the reported method,21 followed by acetylation to provide acetate precursor (±)-12 in
overall 46% yield.
An accessible lipase-catalyzed optical resolution method14 was successfully applied to acetate (±)-12
to produce the desired highly optically pure acetate (S)-12 (40%, 96% ee) with the remaining (R)-
jasmololone [5’ (R)] (42%, 96% ee). The mixture of (S)-14 and 6’ (R) was easily separated by column
chromatography, and successive deacetylation of (S)-12 furnished the desired (S)-jasmorolone (5).
Finally, esterification of 5 with (1R,3R)-chrysanthemic acid (9) afforded jasmolin I in a yield of 60%.
6
ACS Paragon Plus Environment

Page 7 of 46
The Journal of Organic Chemistry
EtI (5 eq.), ItBu·HBF4 (5 mol%),
[(p-allyl)Pd]Cl2 (2.5 mol%),
CuI (7.5 mol%), Cs2CO3 (1.4 eq.)
H2 balloon
Pd-BaSO4 (5 mol%)
quinoline (6.0 eq.)
O
O
O
1
2
3
4
/ AcOEt
20 – 25 °C, 1.5 h
HO
HO
(S)-Jasmololone (5)
88%
/ DMF - Et2O (1:2), 40 – 45 °C, 3 h
HO
1
4
10%
5
6
7
8
OHC
(1.1 eq.)
(1.2 eq.)
Br
O
NaHCO3 (30 mol%)
Na2S2O4 (30 %w/w)
O
OH
O
O
NaH (1.1 eq.), nBuLi (1.1 eq.)
NaOH (1.0 eq.)
CO2Me
CO2Me
9
O
/ toluene, 35 – 40 C, 16 h
/ THF, 0 – 5 °C, 2 h
/ H2O, 30 – 35 C, 5 h
10
11
(±)-
75%
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
64%
O
O
O
NaOH (4.0 eq.)
Ac2O (2.4 eq.), DMAP (5 mol%)
/ pyridine, 20 – 25 °C, 2.5 h
Lipase
+
/ pH 6.86 buffer,
20 – 25 °C, 16 h
/ H2O-toluene (2:1), –10 C, 2.5 h
AcO
AcO
HO
12
(±)-
(R)-Jasmololone (5')
(S)-12
46%
40%,
96% ee
42%,
96% ee
O
O
K2CO3 (2.0 eq.)
(S)-12
TsCl (1.2 eq.), NMI (3.0 eq.)
/ CH3CN, 20 – 25 °C, 2 h
/ MeOH
20 – 25 °C, 1 h
+
5
CO2
CO2H
HO
Jasmolin I
(S)-Jasmololone (5)
9
(1R,3R)-
60%
85%
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 4. Two synthetic routes to natural jasmolin I.
2. 4. Pyrethrin I
Chiral synthesis of (S)-pyrethrolne (7) was performed (Scheme 5). (S)-Prallethrin alcohol (1) was
subjected to a Sonogashira-type direct vinylation-cross-coupling reaction with vinyl bromide using
Pd(Ph3)4 / CuI / Et3N catalysis to afford ene-yne alcohol 6 in 70% yield. Z-Stereocontrolled Zn-
mediated partial reduction22 of the triple bond in 6 furnished (S)-pyrethrolone (7) in 77% yield (98% ee).
Esterification between 7 and (1R,3R)-chrysanthemic acid (9) produced pyrethrin I in a yield of 74%
yield.
Br
(1.5 eq.)
O
O
O
Pd(PPh3)4 (5 mol%)
Zn (165 eq.), HCl aq
CuI (10 mol%), Et3N (2.0 eq.)
/ EtOH-H2O (1:1)
75 – 80 °C, 16 h
/ toluene, 20 – 25 °C, 16 h
HO
HO
HO
6
(S)-Pyrethrolone (7)
1
70%
77%
O
TsCl (1.2 eq.), NMI (3.0 eq.)
/ CH3CN, 20 – 25 °C, 2 h
7
+
CO2
CO2H
Pyrethrin I
10
(1R,3R)-
74%
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 46
Scheme 5. Synthetic route to natural pyrethrin I.
1
2
3
4
5
6
7
3. Total syntheses of three natural pyrethrin II families
8
9
3. 1. (1R,3R)-Second chrysanthemic acid precursor (1R,3R)-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
Pyrethrins II contain a common ester moiety of methoxycarbonylated (1R,3R)-chrysanthemic acid
[so-called (1R,3R)-second chrysanthemic acid] instead of chrysanthemic acid (1R,3R)-9 in pyrethrins I
(Figure 1 and Scheme 1). Following the reported method, methyl (1R,3R)-3-formylchrysanthemate
(caronaldehyde) (13) was prepared from (1R,3R)-9 in two steps (Scheme 6),23 i.e., methyl esterification
and successive ozonolysis. Linear derivatization of natural (+)-carene is an alternative method for
preparing (1R,3R)-13 in several steps idependently developed by Dev’s group24 and Kitahara’s group.25
Crossed aldol condensation of propanal with (1R,3R)-13 afforded α,β-unsaturated aldehyde precursor
(1R,3R)-14.26
KOH-hydrolysis of the methyl ester group of (1R,3R)-14 proceeded smoothly to afford the desired
carboxylic acid (1R,3R)-15 as a crude solid, which was recrystallized from 2-propanol to provide highly
pure acid (1R,3R)-15 in 59% yield. Notably, the labile aldehyde functional group of (1R,3R)-14
tolerated the KOH-hydrolytic conditions without any protection.27
i) MeOH, H+
CHO
OHC
OHC
OHC
cat. pyrollidine
KOH
ii) O3
CO2H
CO2Me
CO2Me
14
CO2H
15
/ MeOH - H2O
(5:1)
/ 60 °C, 1 h
13
(1R,3R)-
9
(1R,3R)-
20 – 25 °C, 16 h
(1R,3R)-
(1R,3R)-
59%
mp 113 – 114 °C
Scheme 6. Preparation of (1R,3R)-second chrysanthemic acid precursor.
3. 2. Cinerin II, jasmolin II, and pyrethrin II
Syntheses of three sets of pyrethrins II are depicted in Scheme 7. (1R,3R)-Second chrysanthemic acid
precursor (15) was coupled with (S)-cinerolone (3), (S)-jasmololone (5), and pyrethrolone (7) to afford
8
ACS Paragon Plus Environment

Page 9 of 46
The Journal of Organic Chemistry
the corresponding esters 16, 17, and 18 in good to excellent yield. Pinnick oxidation and successive
methylation using MeI/K2CO3 of 16 and 17 produced the desired cinerin II and jasmolin II, respectively.
In the case of pyrethrin II, the MeI/K2CO3 system caused undesirable side-chain double bond migration
in pyrethrin II, and therefore, a milder methylation reagent, TMSCHN2, was adopted for the
esterification.
1
2
3
4
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
TsCl (1.4 eq.)
/ NMI (1.2 eq.)
/ iPr2NEt (2.4 eq.)
i) NaClO2 (3.0 eq.), NaH2PO4 (5.0 eq.)
2-methyl-2-butene (10.0 eq.)
O
O
O
/
t-BuOH – H2O (2:1), 20 – 25 °C, 5 h
MeO2C
OHC
+
+
+
/ CH3CN,
20 – 25 °C, 2 h
ii) MeI, K2CO3
/ DMF, 20 – 25 °C, 16 h
HO
HO
HO
CO2
CO2
16
(S)-Cinerolone (3)
Cinerin II
42%
91%
TsCl (1.4 eq.)
/ NMI (1.2 eq.)
/ iPr2NEt (2.4 eq.)
i) NaClO2 (3.0 eq.), NaH2PO4 (5.0 eq.)
2-methyl-2-butene (10.0 eq.)
O
O
O
15
MeO2C
(1R,3R)-
/
t-BuOH – H2O (2:1), 20 – 25 °C, 5 h
OHC
/ CH3CN,
20 – 25 °C, 2 h
CO2
CO2
ii) MeI, K2CO3
/ DMF, 20 – 25 °C, 16 h
(S)-Jasmololone (5)
Jasmolin II
17
42%
96%
O
TsCl (1.4 eq.)
/ NMI (1.2 eq.)
/ iPr2NEt (2.4 eq.)
O
O
MeO2C
OHC
ii) Instead of MeI, K2CO3,
TMSCHN2, / toluene – MeOH (3:1),
20 – 25 °C, 16 h
CO2
/ CH3CN,
20 – 25 °C, 2 h
CO2
(S)-Pyrethrolone (7)
18
Pyrethrin II
30%
99%
Scheme 7. Syntheses of all three natural pyrethrins II.
4. Syntheses of all four chiral stereoisomers of cinerin I
To investigate the stereostructure-activity relationship, all four chiral stereoisomers of cinerin I were
synthesized (Scheme 8). A literature survey (SciFinder®) indicated that the three unnatural cinerine (α),
(β), and (γ), comprising antipodal (unnatural) chrysanthemic acid (1S,3S)-9 and/or (R)-cinerolone (3’),
have not yet been reported. Following a similar optical resolution procedure for (1R,3R)-9, (1S,3S)-9
was obtained using (R)-NEA. (R)-Cinerolone (3’) was obtained from (S)-cinerolone (3) using standard
Mitsunobu reaction with an excellent 99% ee (Method A). Alternatively, using a mild but highly
reactive TsCl / Et3N / Me3N+H•Cl- reagent,28 3 was converted to tosylate 19, which was subjected to SN2
inversion to afford desired product 3’ in 82% yield with 87% ee (Method B). With (1S,3S)-9 and 3’(R)
in hands, three other cinerine I chiral stereoisomers I(α), I(β), and I(γ) were successfully synthesized.
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 46
i) DEAD (2.0 eq.), PPh3 (2.0 eq.)
4-Nitrobenzoic acid (2.0 eq.)
/ toluene, 20 – 25 °C, 6 h
<Method A>
1
O
O
ii) K2CO3 (1.2 eq.)
2
/ MeOH, 20 – 25 °C, 10 min
NH2
3
HO
HO
4
5
6
7
(S)-Cinerolone (3)
(R)-Cinerolone (3')
(R)-NEA
CO2H
9
(±)-trans-
82%, 99% ee
<Method B>
9
(1S,3S)-
31% 99% ee
TsCl (2.0 equiv) / Et3N (2.5 equiv) /
Me3N+HCl- (0.1 equiv)
O
NaHCO3
/ H2O
3
3'
8
/
MeCN, 0 – 5 °C, 1 h
TsO
82%, 87% ee
9
19
82%
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
O
O
TsCl (1.2 eq.), NMI (3.0 eq.)
/ CH3CN, 20 – 25 °C, 2 h
3
(S)
+
9
(1R,3R)-
9
+
3 (S)
(1S,3S)-
CO2
CO2
Cinerin I
Cinerin I ()
76%
76%
O
+
3'
(R)
9
(1R,3R)-
+
9
(1S,3S)-
3'
(R)
CO2
CO2
Cinerin I ()
61%
Cinerin I ()
76%
Scheme 8. Syntheses of all four chiral stereoisomers of cinerin I.
5. Alternative syntheses of (±)-jasmololone (6)
Three accessible syntheses of (±)-jasmololone (6) were evaluated as the 4-hydroxycyclopent-2-en-1-
one probe to compare the efficiency described in section 2.3.
5.1. Piancattelli rearrangement method
This approach is representative to be applied for the synthesis of relevant prostaglandin intermediates
as well as the syntheses of pyrethroid alcohols.27 Grignard and Barbier-type reactions of (Z)-1-bromo-
2-pentene with commercially available 5-methyl-2-furfral, however, gave disappointing results (Scheme
9); all our trials examined, such as Mg/AlCl3-,28 Zn-,29 Sn-,29 In-29 mediated α-regioselective addition
reactions yielded not the desired α-adduct 20 but exclusivey the isomeric γ-adduct 21, otherwise,
polymeric byproducts. A related Sn / TMSCl / NaI-mediated reaction30 using (Z)-2-penten-1-ol instead
of (Z)-1-bromo-2-pentene did not proceeded (no reaction).
To overcome the problem Barbier-type reaction of 1-bromo-2-pentyne was examined and produced
the desired adduct 22(α) as a relatively minor product with the undesirable isomeric allene product 22(γ).
10
ACS Paragon Plus Environment

Page 11 of 46
The Journal of Organic Chemistry
Lindlar reduction of the separated isomer 22(α) afforded the Z-olefin 23 in 90% yield. Finally, 23 was
1
2
3
subjected to Piancattelli rearrangement using sequential aqueous AcOH/AcONa buffer solvents to
4
5
6
7
8
9
furnish the desired (±)-jasmorolone (5) in 27% yield through the tertiary alcohol intermediate 24.
M (Mg/AlCl3,
Zn, Sn, In)
Br
or
+
+
+
polymer
O
CHO
O
O
OH
20
OH
HO
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
Sn / TMSCl / NaI
21
Zn
Br
+
+
CHO
O
O
O
/ THF, sat. NH4Cl aq.,
20 – 25 °C, 1.5 h
OH
22( )
OH

22(
)
24%

29%
H2
O
AcOH / AcONa
pH ~ 5
Pd-BaSO4 (5 mol%)
quinoline (6.0 eq.)
O
pH ~ 8
/ H2O, 100 °C, 2 h
22(
)

O
/
H2O, 100 °C, 12 h
/ MeOH
HO
OH
23
OH
Jasmololone
5
(±)-
20 – 25 °C, 0.5 h
24
27%
69%
Scheme 9. Synthesis of (±)-jasmorolone (5) utilizing Piancattelli rearrangement.
5.2. Method utilizing oxidation of furan and aldol condensation
This approach was a previous candidate applied for the synthesis of prallethrin alcohol (1) (Scheme
10).31 Alkylation of mesityl oxide with 1-bromo-2-pentyne using LHMDS gave β,γ-unsaturated ketone
25 in 43% yield.32 Chemoselective mCPBA olefin-oxidation of 25 afforded epoxide 26 in 52% yield.
Base-catalyzed transformation of allylic alcohol intermediate 27 afforded tri-substituted furan 28 in 33%
yield, wherein PhSH catalyzed E → Z isomerization to facilitate the desired furan-formation.
Unfortunately, Lindler reduction of 28 leading to 29 did not proceed probably due to the prevention
caused by PhSH. Eventually, we abandoned this approach.
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 46
O
O
1
O
O
mCPBA
LHMDS (1.0 eq.)
Na2CO3
2
3
4
5
+
/ CH2Cl2
– 78 °C ~ rt, 16 h
/ THF
– 78 °C ~ rt, 2.5 h
/ MeCN – H2O (1:1)
70 – 75 °C, 16 h
Br
O
OH
25
26
43%
52%
27
6
7
8
H2
Pd-BaSO4 (5 mol%)
quinoline (6.0 eq.)
Br2, base
/ MeOH
PhSH
9
Jasmololone
5
(±)-
MeO
OMe
O
O
O
/ MeCN – H2O (1:1)
70 – 75 °C, 2 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
/ MeOH
20 – 25 °C
28
29
30
33%
Scheme 10. Synthetic trial of (±)-jasmololone (5) utilizing furan-oxidation and successive aldol
condensation.
5.3. Utilization of 1-nitropropene as an enolium ion synthon
This approach involves three key C-C bond formation steps (Scheme 11).33 (i) Alkylation of 1-
(phenylthio)propan-2-one (31) with (Z)-1-bromo-2-pentene under phase-transfer conditions afforded α-
disubstituted ketone 32 in 80% yield. (ii) NaHMDS-mediated conjugate addition of 32 with 1-
nitropropene (33) furnished 4-keto-1-nitro compound 34 in 93% excellent yield. (iii) After the
conversion of nitro compound 34 to aldehyde 36 through bis(methoxy)acetal 35 (Nef-type reaction),34
afforded key 4-keto-1-aldehyde 36 in 61% yield. The intramolecular aldol addition of 36, concomitant
with elimination of PhS- group, produced the desired (±)-jasmololone (5) in 60% yield.
NO2
33
50% NaOH
aq., cat. TBAB
O
O
O
SPh
NaHMDS
SPh
+
Br
30 – 35 °C, 1 h
/ THF
O2N
SPh
32
31
– 78 °C, 1 h
34
93%
i) NaOMe / MeOH, rt
ii) H2SO4 / MeOH, 0 °C,
0.5 h
O
1M HCl aq. / MeCN,
rt , 1 h
NaOEt / EtOH
rt, 1 h
MeO
SPh
SPh
Jasmololone
5
(±)-
(±)-
O
H
O
60%
MeO
36
35
61%
Scheme 11. Synthesis of (±)-jasmorolone (5) utilizing conjugate addition to 1-nitropropene and
successive aldol addition concomitant with elimination.
12
ACS Paragon Plus Environment

Page 13 of 46
The Journal of Organic Chemistry
1
2
3
These three alternative methods require rather longer steps and/or result in lower yields (Experimentals
4
5
6
are described in SI) compared with the aforementioned chiral syntheses of jasmololone (5).
7
8
9
6. Insecticidal activity and structure-activity relationship
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 insecticidal activity of all six natural pyrethrins (synthetic specimen), i.e., cinerin I/II, jasmolin I/II, and
pyrethrin I/II against the common mosquito (Culex pipiens pallens was assessed. Table 1 lists the results of
median knock down (KD50) and insect control (IC50) values. The salient features are as follows. (i) Pyrethrin I
exhibited the strongest activity among all six pyrethrins. (ii) The activity order of type-I was pyrethrin I > cinerin
I >> jasmolin I, and that of type-II was pyrethrin II > cinerin II >> jasmolin II. (iii) Type-I was consistently more
active than type-II with regard to both the KD50 and IC50. Notably, subtle side-chain differences in the alcohol
segment caused significant changes of the insecticidal activity: prop-1,3-dienyl (pyrethrin) > but-2-enyl (cinerin)
>> prop-2-enyl (jasmolin).
Table 1. Insecticidal activity of six natural pyrethrins (synthetic specimen).a)
Compound
KD50
LD50
KD50
LD50
(30 min)b) (24 h)b)
(30 min)b) (24 h)b)
O
O
O
Cinerin I
Cinerin
0.036 II
MeO2C
0.015
0.105
0.016
0.218
0.051
0.254
CO2
CO2
O
Jasmolin I
Jasmolin
0.218 II
MeO2C
CO2
CO2
O
O
Pyrethrin Ic)
Allethrind)
Pyrethrin
MeO2C
0.006
0.013
0.024 II
0.034
0.029
0.061
CO2
CO2
O
CO2
a) The bioassay method of is described in the Experimental section.
b) μg / one mosquito.
c) Containing 10% 4-tert-butylcatechol (TBC) as a polymerization inhibitor.
d) A relevant synthetic pyrethroid (dl, d-T80).
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 46
On the other hand, Table 2 lists the results of insecticidal activities of all four chiral stereoisomers of cinerin I.
As expected, the activity was clearly concentrated not to “unnatural” α, β, γ-isomers but to “natural” cinerin I.
Notably, the β-isomer with the antipodal (R)-cinerolone (3’) exhibited slightly, but not significantly, higher KD50
and IC50 values (pyrethrin I level), whereas the α and γ-isomers with the antipodal chrysanthemic acid (1S,3S)-9
were completely inactive. This apparent chiral discrimination indicates that the solid cyclopropane conformation
of unnatural (antipodal) chrysanthemic acid may inhibit flexible-induced fitting for a conceivable “pyrethroid
receptor”.
1
2
3
4
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
Table 2. Insecticidal activity of four enantiomers of cinerin I (synthetic specimen).a)
Compound
KD50
LD50
KD50
LD50
(30 min)b) (24 h)b)
(30 min)b) (24 h)b)
O
O
O
Cinerin I
(natural)
#
Cinerin I(α)
Cinerin I(γ)
0.015
0.104
0.040
0.116
>1.0
>1.0
>1.0
>1.0
CO2
CO2
O
Cinerin I(β)
#
CO2
CO2
a) The bioassay method is described in Experimental section.
b) μg / one mosquito.
Conclusion:
We achieved chiral total syntheses of all six insecticidal natural pyrethrins (cinerin I/II, jasmolin I/II, pyrethrin
I/II), which are contained in the flowers of pyrethrums. Three common chiral alcohol components [(S)-
cinerolone, (S)-jasmololone, (S)-pyrethrolone] and two counter acid segments of [(1R,3R)-chrysanthemic acid
and (1R,3R)-second chrysanthemic acid] were successfully synthesized by using readily available starting
materials, reagents, and accessible reaction sequences. To investigate the stereostructure-activity relationship, all
four chiral stereoisomers of cinerin I were also synthesized. Three other alternative synthetic methods of (±)-
jasmololone were investigated
The physical properties (1H and 13C NMRs, HRMS, optical purities by HPLC analyses, optical rotations) of the
chiral alcohol components and two acid segments were accurately determined.
14
ACS Paragon Plus Environment

Page 15 of 46
The Journal of Organic Chemistry
Insecticidal activity assays (KD50 and IC50) against the common mosquito revealed that (i) consistent
1
2
3
4
5
pyrethrins-I > pyrethrins-II, (ii) pyrethrin I/II > cinerin I/II >> jasmolin I/II, (iii) “natural” cinerin I >> three
“unnatural” cinerin I, in which apparent chiral discrimination was observed.
6
7
8
9
The present document provides one of the significant and progressive solutions regarding the missing link in
long-standing and future pyrethroid chemistries.
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
(S)-4-Hydroxy-3-methyl-2-(prop-2-yn-1-yl)cyclopent-2-en-1-one [(S)-prallethrin alcohol] (1) was prepared by the
reported method.14
(S)-4-hydroxy-3-methyl-2-(but-2-yn-1-yl)cyclopent-2-en-1-one (2)35
O
HO
(S)-4-hydroxy-3-methyl-2-(prop-2-yn-1-yl)cyclopent-2-en-1-one [(S)-prallethrin alcohol] (1; 450 mg, 3.0
mmol) in DMF – Et2O (1:2) (3 mL) and MeI (028 mL, 4.5 mmol) was successively added to a stirred suspension
of ItBuHBF4 (40 mg, 0.15 mmol), CuI (43 mg, 0.23 mmol), [(η-allyl)Pd(II)]Cl2 (27 mg, 0.075 mmol), and
Cs2CO3 (1.37 g, 4.2 mmol) in DMF – Et2O (1:2) (3 mL) at 20 – 25 °C under an Ar atmosphere, followed by being
stirred at 40 – 45 °C for 1.5 h. Et2O was added to the mixture, which was filtered through Celite®. Water was
added to the obtained filtrate, which was extracted twice with AcOEt. The aqueous layer was saturated with
NaCl, and the was extracted twice with AcOEt. The combined organic phase was washed with brine, dried
(Na2SO4) and concentrated. The obtained crude oil was purified by silica-gel column chromatography (hexane /
AcOEt = 1:1) to give the desired product 2 (277 mg, 56%).
1
Yellow colored oil; H NMR (500 MHz, CDCl3) δ 1.75 (t, J = 2.9 Hz, 3H), 2.21 (s, 3H), 2.30 (dd, J = 2.3 Hz,
18.3 Hz, 1H), 2.81 (dd, J = 6.3 Hz, 18.3 Hz, 1H), 3.01 – 3.10 (m, 2H), 4.74 – 4.75 (m, 1H). 13C{1H} NMR (125
MHz): δ = 3.33, 12.5, 13.7, 43.9, 71.3, 74.3, 76.0, 137.3, 171.0, 204.4.
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 46
(S,Z)-2-(But-2-en-1-yl)-4-hydroxy-3-methylcyclopent-2-en-1-one: (S)-cinerolone [(S)-3]10,21,36
1
2
3
O
4
5
6
HO
7
8
9
A mixture of alcohol 2 (445 mg, 2.71 mmol), quinoline (1.93 mL, 16.3 mmol), 5 % Pd-BaSO4 on carbon (288
mg, 0.14 mmol) in AcOEt (27 mL) was stirred at 20 – 25 °C under an H2 atmosphere for 1 h. AcOEt was added
to the mixture, which was filtered through Celite®. The obtained filtrate was washed three times with 1 M HCl
aq. solution. brine, dried (Na2SO4) and concentrated. The aqueous layer was saturated with NaCl, and the was
extracted twice with AcOEt. The obtained crude oil was purified by silica-gel column chromatography (hexane /
AcOEt = 5:1) to give the desired product (S)-3 (416 mg, 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
Pale yellow oil; 98% ee: HPLC analysis (Daicel Chiralcel AD-3 column, hexane/2-propanol = 30:1, 1.0
mL/min, 254 nm UV detector), tR = 15.6 min for (major) and tR = 18.58 min for (minor); [α]D22 +21.2 (c 0.41,
23
CHCl3) [(lit.10 [α]D +16.3 (c 1.3, CHCl3)]. 1H NMR (500 MHz, CDCl3) δ 1.71 (dd, J = 1.7 Hz, 6.9 Hz, 3H),
2.10 (s, 3H), 2.28 (dd, J = 1.7 Hz, 18.3 Hz, 1H), 2.79 (dd, J = 6.3 Hz, 18.3 Hz, 1H), 2.96 (d, J = 7.5 Hz, 2H), 4.73
(d, J = 6.3 Hz, 1H), 5.26 – 5.32 (m, 1H), 5.47 – 5.53 (m, 1H). 13C{1H} NMR (125 MHz): 12.7, 13.7, 20.7, 44.1,
71.3, 125.1, 125.7, 140.5, 169.7, 205.6.
(S)-4-hydroxy-3-methyl-2-(pent-2-yn-1-yl)cyclopent-2-en-1-one (4)
O
HO
Following a similar procedure for the synthesis of 2, the reaction using 1 (451 mg, 3.0 mmol), EtI (1.21 mL,
15.0 mmol), ItBuHBF4 (40 mg, 0.15 mmol), CuI (42 mg, 0.23 mmol), [(η-allyl)Pd(II)]Cl2 (27 mg, 0.075 mmol),
and Cs2CO3 (1.37 g, 4.2 mmol) gave the desired product 4 (53 mg, 10%).
Pale yellow oil; 1H NMR (500 MHz, CDCl3): 1.10 (t, J = 7.5 Hz, 3H), 2.13 (qt, J = 2.3 Hz, 7.5 Hz, 2H), 2.22 (s,
3H), 2.30 (dd, J = 2.3 Hz, 18.3 Hz, 1H), 2.80 (dd, J = 6.3 Hz, 18.3 Hz, 1H), 3.04 – 3.12 (m, 2H), 4.74 (m, 1H).
13C{1H} NMR (125 MHz, CDCl3): δ = 12.2, 12.5, 13.8, 13.9, 43.9, 71.2, 74.5, 82.1, 137.1, 171.4, 204.6. IR
16
ACS Paragon Plus Environment

Page 17 of 46
The Journal of Organic Chemistry
(neat): νmax = 3420, 2974, 2320, 1697, 1647, 1381, 1049, 1011. HRMS (ESI-TOF): m/z Calcd for C11H14O2 [M +
1
2
3
Na]+ 201.0891; Found: 201.0906.
4
5
6
Methyl (Z)-3-oxonon-6-enoate (10)38
7
8
O
CO2Me
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
Methyl acetoacetate (1.51 mL, 14.1 mmol) and nBuLi (1.55 M, 10.0 mL, 15.5 mmol) was successively added
to a stirred suspension of NaH (60% dispersion in paraffin, 620 mg, 15.5 mmol) in THF (25 mL) at 0 – 5 °C
under an Ar atmosphere, and the mixture was stirred at the same temperature for 0.5 h. (Z)-1-Bromo-2-pentene
(2.52 g, 16.9 mmol) in THF (3 mL) was added to the mixuture at 0 – 5 °C, and the mixture was stirred at the
same temperature for 2 h. 1 M HCl aqueous solution was added to the mixture, which was extracted twice with
AcOEt. The combined organic phase was washed with water, brine, dried (Na2SO4) and concentrated. The
obtained crude oil was purified by SiO2-column chromatography (hexane/AcOEt = 7:1) to give the desired
product 10 (1.93 g, 75%).
1
Pale yellow oil; H NMR (500 MHz, CDCl3): 0.96 (t, J = 7.5 Hz, 3H), 2.05 (quin, J = 7.5 Hz, 2H), 2.33 (q, J =
7.5 Hz, 2H), 2.59 (t, J = 7.5 Hz, 3H), 3.45 (s, 2H), 3.74 (s, 3H), 5.24 – 5.32 (m, 1H), 5.37 – 5.45 (m, 1H).
13C{1H} NMR (125 MHz, CDCl3): δ = 14.1, 20.4, 21.2, 42.8, 49.0, 52.2, 126.5, 133.1, 167.5, 202.0.
(Z)-3-Hydroxyundec-8-ene-2,5-dione (11)38
O
OH
O
Methyl (Z)-3-oxonon-6-enoate (10; 1.48 g, 8.0 mmol) in 10% NaOH aqueous solution (3.0 g) was stirred at 30
– 35 °C for 5 h. 1 M HCl aqueous solution was added to the mixture at 0 – 5 °C to adjust pH 6 – 7. NaHCO3
(0.19 g, 2.2 mmol) and Na2S2O4 (0.44 g, 2.6 mmol) was successively added to the stirred solution. Then, methyl
glyoxal (40% in H2O, 1.48 mL, 9.7 mmol) was added to the stirred mixture at 0 – 5 °C for 10 min, and the
mixture was stirred at 20 – 25 °C for 16 h. The mixture was saturated with NaCl (ca. 5 g), and the solution was
extracted twice with AcOEt. The combined organic phase was washed with brine, dried (Na2SO4), and
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 46
concentrated. The obtained crude oil was purified by silica-gel column chromatography (hexane/AcOEt = 2:1) to
1
2
3
give the desired product 11 (1.01 g, 64 %).
4
5
6
7
8
Pale yellow oil; 1H NMR (500 MHz, CDCl3): 0.96 (t, J = 7.5 Hz, 3H), 2.04 (quin, J = 7.5 Hz, 2H), 2.26 (s, 3H),
2.31 (q, J = 7.5 Hz, 2H), 2.52 (t, J = 7.5 Hz, 2H), 2.83 (dd, J = 6.3 Hz, 17.2 Hz, 1H), 2.95 (dd, J = 3.4 Hz, 17.2
Hz, 1H) , 3.70 (d, J = 5.2 Hz, 1H), 4.33 – 4.36 (m, 1H), 5.23 – 5.28 (m, 1H), 5.38 – 5.43 (m, 1H).. 13C{1H} NMR
(125 MHz, CDCl3): 14.1, 20.4, 21.1, 25.3, 43.6, 45.3, 73.7, 126.6, 133.1, 208.8, 209.2.
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
(Z)-3-(But-2-yn-1-yl)-2-methyl-4-oxocyclopent-2-en-1-yl acetate [(±)-12]38,39
O
AcO
(Z)-3-Hydroxyundec-8-ene-2,5-dione (11; 1.01 g, 5.1 mmol) in toluene (2.5 mL) was added to a stirred 10%
NaOH aqueous solution (8.15 g, 20 mmol) and toluene (1 mL) at –10 °C under an Ar atmosphere, followed by
being stirred at the same temperature for 2.5 h. 6 M HCl aqueous solution (ca. 10 mL) was added to the mixture,
which was extracted with AcOEt. The aqueous layer was saturated with NaCl (ca. 3 g), and the solution was re-
extracted twice with AcOEt. The combined organic phase was washed with brine, dried (Na2SO4) and
concentrated. The obtained crude oil was purified by silica-gel column chromatography (hexane/AcOEt = 2:1) to
give the desired alcohol intermediate38,39 (467 mg, 51 %).
Pale yellow oil; 1H NMR (500 MHz, CDCl3): 0.99 (t, J = 7.5 Hz, 3H), 2.10 (s, 3H), 2.15 (quin, J = 7.5 Hz, 2H),
2.27 (dd, J = 1.7 Hz, 18.3 Hz, 1H), 2.79 (dd, J = 6.3 Hz, 18.3 Hz, 1H) , 2.95 (d, J = 7.5 Hz, 2H), 4.71 – 4.73 (m,
1H), 5.21 – 5.26 (m, 1H), 5.38 – 5.44 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3): 13.7, 14.0, 20.5, 21.0, 44.2,
124.1, 132.9, 140.7, 169.1, 205.2.
Ac2O (2.27 mL, 24 mmol) was added to a stirred solution of the alcohol (1.50 g, 10 mmol) and DMAP (61 mg,
0.5 mmol) in pyridine (5 mL) at 20 – 25 °C under an Ar atmosphere, and the mixture was stirred at the same
temperature for 2.5 h. The mixture was slowly added to 1 M HCl aqueous solution. solution at 0 – 5 °C, which
was extracted twice with AcOEt. The combined organic phase was washed with 1 M HCl aqueous solution.
18
ACS Paragon Plus Environment

Page 19 of 46
The Journal of Organic Chemistry
solution three times, brine, dried (Na2SO4) and concentrated. The obtained crude product was purified by SiO2-
1
2
3
column chromatography (hexane/Et2O = 4:1) to give the desired product (±)-12 (1.73 g, 90%).
4
5
6
7
8
Pale yellow oil; 1H NMR (500 MHz, CDCl3): 0.99 (t, J = 7.5 Hz, 3H), 2.03 (s, 3H), 2.11 (s, 3H), 2.15 (quin, J =
7.5 Hz, 2H), 2.25 (dd, J = 2.3 Hz, 18.9 Hz, 1H), 2.86 (dd, J = 6.3 Hz, 18.9 Hz, 1H) , 2.98 (d, J = 7.5 Hz, 2H),
5.21– 5.26 (m, 1H), 5.40 – 5.46 (m, 1H), 5.67 – 5.69 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ = 13.8, 14.0,
20.5, 20.8, 21.1, 41.5, 72.9, 123.7, 133.1, 142.8, 163.3, 170.6, 203.6.
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
(S,Z)-3-(But-2-yn-1-yl)-2-methyl-4-oxocyclopent-2-en-1-yl acetate [(S)-12]10 and
(R,Z)-2-(Pent-2-en-1-yl)-4-hydroxy-3-methylcyclopent-2-en-1-one: [(R)-Jasmololone] [(R)-5’]
O
O
+
(R)-5'
AcO
(S)-12
HO
A mixture of acetate (±)-12 (386 mg, 1.74 mmol), Lipase AK Amano (36 mg) in pH 6.86 buffer (10 mL) was
stirred at 20 – 25 °C for 16 h. The solution was extracted twice with AcOEt. The combined organic phase was
washed with brine, dried (Na2SO4), and concentrated. The obtained crude oil was purified by silica-gel column
chromatography (hexane/AcOEt = 7:1 to 2:1) to give the desired acetate (S)-12 (155 mg, 40 %) and alcohol (R)-
5’ (133 mg, 42 %).
(S)-12: Pale yellow oil; [α]D17 +33.7 (c 1.39, CHCl3) [lit.10 [α]D23 +29.2 (c 1.7, CHCl3)].
(R)-5’: Pale yellow oil; 96% ee: HPLC analysis (Daicel Chiralcel AD-3 column, hexane/2-propanol = 30:1, 1.0
mL/min, 254 nm UV detector), tR = 15.38 min for (major) and tR = 17.36 min for (minor); [α]D17 –17.2 (c 0.37,
CHCl3) [(S)-5 form: lit.10 [α]D23 +15.6 (c 1.3, CHCl3)].
(S,Z)-2-(Pent-2-en-1-yl)-4-hydroxy-3-methylcyclopent-2-en-1-one [(S)-Jasmololone] [(S)-5]10,37
O
HO
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 46
Acetate (S)-12 (132 mg, 0.59 mmol) in MeOH (1 mL) was added to a stirred solution of K2CO3 (396 mg, 2.86
mmol) in MeOH (2 mL) at 20 – 25 °C under an Ar atmosphere, followed by being stirred at the same temperature
for 1 h. 1 M HCl aqueous solution (ca. 7 mL) was added to the mixture, which was extracted with a large amount
of AcOEt. The aqueous layer was saturated with NaCl, and the solution was extracted twice with AcOEt. The
combined organic phase was washed with brine, dried (Na2SO4), and concentrated. The obtained crude oil was
purified by silica-gel column chromatography (hexane / AcOEt = 2:1) to give the desired product (S)-5 (203 mg,
85 %).
1
2
3
4
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
Pale yellow oil; 96% ee: HPLC analysis (Daicel Chiralcel AD-3 column, hexane/2-propanol = 30:1, 1.0 mL/min,
254 nm UV detector), tR = 17.02 min for (major) and tR = 15.63 min for (minor); [α]D17 +18.4 (c 1.17, CHCl3)
[lit.10 [α]D23 +15.6 (c 1.3, CHCl3)].
As the key alternative method, following a similar procedure for the synthesis of (S)-cinerolone [(S)-3], the
reaction using 4 (278 mg, 1.56 mmol), quinoline (1.11 mL, 9.36 mmol), 5 % Pd-BaSO4 on carbon (166 mg, 0.078
mmol) gave the desired product (S)-5 (248 mg, 96 %).
(S)-4-hydroxy-3-methyl-2-(pent-4-en-2-yn-1-yl)cyclopent-2-en-1-one [(S)-6]
O
HO
CuI (57 mg, 0.30 mmol), Pd(PPh3)4 (173 mg, 0.15 mmol) and vinyl bromide (1.0 M in Et2O, 4.5 mL, 4.5
mmol) was successively added to a stirred solution of (S)-prallethrin alcohol (1; 451 mg, 3.0 mmol) and Et3N
(0.83 mL, 6.0 mmol) in toluene (4.5 mL) at 20 – 25 °C under an Ar atmosphere, followed by being stirred at the
same temperature for 16 h. 1 M HCl aqueous solution was added to the mixture, which was extracted twice with
AcOEt. The combined organic phase was washed with water (twice), brine, dried (Na2SO4) and concentrated.
The obtained crude oil was purified by silica-gel column chromatography (hexane / AcOEt = 1:1) to give the
desired product (S)-6 (369 mg, 70%).
20
ACS Paragon Plus Environment

Page 21 of 46
The Journal of Organic Chemistry
Yellow oil; [α]D25 +23.0 (c 1.0, CHCl3). H NMR (500 MHz, CDCl3): δ = 2.23 (s, 3H), 2.32 (dd, J = 2.3 Hz, 18.3
Hz, 1H), 2.83 (dd, J = 6.3 Hz, 18.3 Hz, 1H), 3.20 – 3.28 (m, 2H), 4.75 – 4.77 (m, 1H), 5.41 (dd, J = 2.3 Hz, 10.9
Hz, 1H), 5.56 (dd, J = 2.3 Hz, 17.8 Hz, 1H), 5.74 (ddt, J = 2.3 Hz, 10.9 Hz, 17.8 Hz, 1H). 13C{1H} NMR (125
MHz, CDCl3): δ = 13.1, 13.8, 43.8, 71.2, 79.5, 85.8, 117.0, 126.3, 136.4, 171.7, 204.3.
1
1
2
3
4
5
6
7
8
9
(S)-Pyrethrolone [(S)-7]10
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
HO
A mixture of alcohol (S)-13 (300 mg, 1.7 mmol) and Zn (18 g, 275 mmol) in EtOH – H2O (1:1) (18 mL) was
refluxed under an Ar atmosphere for 16 h. Et2O was added to the mixture, which was filtered through Celite®.
The filtrate was washed with 1 M HCl aqueous solution, brine, dried (Na2SO4) and concentrated. The obtained
crude oil was purified by silica-gel column chromatography (hexane / AcOEt = 1:1) to give the desired product
(S)-7 (289 mg, 95%).
Pale yellow oil; [α]D24 +16.2 (c 1.1, CHCl3) [lit.10 [α]D22 +15.6 (c 2.0, CHCl3)]. H NMR (500 MHz, CDCl3): δ =
1
1.98 (d, J = 6.3 Hz, 1H), 2.10 (s, 3H), 2.29 (dd, J = 2.3 Hz, 18.3 Hz, 1H), 2.80 (dd, J = 6.3 Hz, 18.3 Hz, 1H), 3.10
(d, J = 8.0 Hz, 2H), 4.71 – 4.74 (m, 1H), 5.18 (d, J = 10.3 Hz, 1H), 5.24 (d, J = 16.6 Hz, 1H), 5.35 (dt, J = 8.0 Hz,
10.9 Hz, 1H), 6.03 (t, J = 10.9 Hz, 1H), 6.73 – 6.81 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ = 13.7, 21.5,
44.1, 71.2, 118.1, 127.0, 130.1, 131.5, 140.0, 170.4, 205.5.
Ethyl (±)-2,2-dimethyl-3-(2-methylprop-1-en-1-yl)cyclopropane-1-carboxylate [(±)-trans-8]
CO2Et
(±)-
A suspension of commercial ethyl ester (±)-8 (9.00 g, 45.9 mmol, trans / cis = 65 : 35) and NaH (60%
dispersion in paraffin, 183 mg, 4.59 mmol) was stirred at 20 – 25 °C for 3 h under an Ar atmosphere. EtOH (ca.
10 mL) was carefully added to the mixture, which was extracted twice with AcOEt. The combined organic phase
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 46
was washed with water, brine, dried (Na2SO4) and concentrated. The obtained product (±)-trans-8 was sufficient
pure without any purification (8.40 g, 93%, trans : cis = 90 : 10) to the use for further reactions.
1
2
3
4
5
6
(±)-trans-2,2-Dimethyl-3-(2-methylprop-1-en-1-yl)cyclopropane-1-carboxylic acid [ (±)-trans-9]
7
8
9
CO2H
(±)-
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
KOH (13.0 g, 0.232 mol) in H2O (14 mL) was added to a stirred solution of trans-(±)-9 (9.09 g, 46.3 mmol,
trans : cis = 90 : 10) in EtOH (70 mL) at 0 – 5 °C, and the resultant mixture was stirred at 40 – 45 °C for 3 h.
After evaporation of EtOH as much as possible, water was added to the mixture, which was washed twice with
AcOEt. 6 M-HCl aq. was added to the separated aqueous phase to adjust pH = ca. 1 and was extracted twice with
AcOEt. The combined organic phase was washed with water, brine, dried (Na2SO4) and concentrated to give the
desired product (±)-trans-9 (6.70 g, 86%, trans : cis = 90 : 10), which was used to next optical resolution step
without any purification. A small amount of the crude product was purified by recrystallization from hexane to
give the desired product (±)-trans-9 (trans : cis = 98 : 2).
1
Colorless solid; mp 55 – 56 °C [lit.40 50 – 51 °C]. H NMR (500 MHz, CDCl3): δ = 1.15 (s, 3H), 1.30 (s, 3H),
1.39 (d, J = 5.2 Hz, 3H), 1.72 (s, 3H), 2.10 (dd, 1H, J = 5.7 Hz, 8.0 Hz), 4.81-4.91 (m, 1H), 11.59 (brs, 1H).
13C{1H} NMR (125 MHz, CDCl3): δ = 18.5, 20.4, 22.2, 25.5, 29.8, 33.6, 34.6, 120.7, 135.8, 179.4.
(1R,3R)-2,2-Dimethyl-3-(2-methylprop-1-en-1-yl)cyclopropane-1-carboxylic acid [(1R,3R)-9]
CO2H
A solution of racemic acid (±)-9 (4.00 g, 23.8 mmol, trans : cis = 90 : 10) and (S)-1-(1-naphthyl)ethylamine
(3.91 g, 22.8 mmol) in EtOH (20 mL) was left at room temperature for 16 h. The first salt (1.50 g) was collected
by filteration. After recrystallization of the first salt from EtOH (5 mL), the collected second salt was decomposed
with 1 M HCl aqueous solution, and extracted with ether. The organic phase was washed with 1 M HCl aqueous
22
ACS Paragon Plus Environment

Page 23 of 46
The Journal of Organic Chemistry
solution, water, brine, dried (Na2SO4) and concentrated to give the desired carboxylic acid (1R,3R)-9 (0.88 g,
22%, trans : cis = 98 : 2).
1
2
3
4
5
6
7
8
Pale yellow colored oil; 96% ee (its benzyl ester): HPLC analysis (Daicel Chiralcel OD-H column, hexane / 2-
propanol = 200 : 1, 1.0 mL/min, 254 nm UV detector), tR = 5.0 min for (minor) and tR = 5.6 min for (major);
[α]D22 +14.2 (c 1.07, EtOH) [lit.10 [α]D22 +14.5 (c 5.008, EtOH)].
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
(1S,3S)-2,2-Dimethyl-3-(2-methylprop-1-en-1-yl)cyclopropane-1-carboxylic acid [(1S,3S)-9]
CO2H
Following a similar procedure for the preparation of (1R,3R)-9, (1S,3S)-9 was obtained using (R)-1-(1-
naphthyl)ethylamine.
Pale yellow colored oil; [α]D23 ‒14.2 (c 1.03, EtOH); 99% ee (its benzyl ester): HPLC analysis (Daicel Chiralcel
OD-H column, hexane / 2-propanol = 200 : 1, 1.0 mL/min, 254 nm UV detector), tR = 4.9 min for (major) and tR
= 5.6 min for (minor). [α]D23 ‒14.2 (c 1.03, EtOH).
(S)-3-((Z)-But-2-en-1-yl)-2-methyl-4-oxocyclopent-2-en-1-yl (1R,3R)-2,2-dimethyl-3-(2-methylprop-1-en-1-
yl)cyclopropane-1-carboxylate (cinerin I)
O
CO2
TsCl (137 mg, 0.80 mmol) in CH3CN (0.8 mL) was added to a stirred solution of (1R,3R)-9 (101 mg, 0.60
mmol) and N-methylimidazole (148 mg, 1.8 mmol) in CH3CN (0.4 mL) at 0 – 5 °C under an Ar atmosphere, and
the mixture was stirred at the same temperature for 30 min. (S)-Cinerolone (5, 100 mg, 0.60 mmol) in CH3CN
(0.6 mL) was added to a stirred solution at the same temperature, and the mixture was stirred at 20 – 25 °C for 2
h. Water was added to the stirred mixture, which was extracted twice with AcOEt. The combined organic phase
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 46
was washed with 1 M HCl aq. solution, brine, dried (Na2SO4) and concentrated. The obtained crude oil was
purified by SiO2-column chromatography (hexane/AcOEt = 20:1) to give the desired product (145 mg, 76%).
1
2
3
4
5
6
7
8
Colorless oil; [α]D –18.5 (c 0.39, CHCl3) [lit.10 [α]D –17.4 (c 1.2, CHCl3)]; 1H NMR (500 MHz, CDCl3): δ =
1.14 (s, 3H), 1.26 (s, 3H), 1.42 (d, J = 5.2 Hz, 1H), 1.71 (dd, J = 1.2 Hz, 4.6 Hz, 3H), 1.72 (s, 3H), 1.73 (s, 3H),
2.04 (s, 3H), 2.09 (dd, J = 5.2 Hz, 7.5 Hz, 1H), 2.23 (dd, J = 1.7 Hz, 18.3 Hz, 1H), 2.86 (dd, J = 6.3 Hz, 18.3 Hz,
1H), 2.99 (d, J = 7.5 Hz, 2H), 4.89 – 4.92 (m, 1H), 5.27 – 5.33 (m, 1H), 5.48 – 5.55 (m, 1H), 5.66 (dd, J = 1.7 Hz,
6.3 Hz, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ = 12.8, 14.0, 18.5, 20.3, 20.9, 22.1, 22.5, 29.1, 32.9, 34.5, 42.0,
72.9, 120.8, 125.4, 125.5, 135.8, 142.7, 164.9, 172.3, 204.0; HRMS (ESI-TOF): m/z Calcd for C20H28O3 [M +
Na]+ 339.1936; Found: 339.1934.
23
22
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
(S)-2-Methyl-4-oxo-3-((Z)-pent-2-en-1-yl)cyclopent-2-en-1-yl (1R,3R)-2,2-dimethyl-3-(2-methylprop-1-en-
1-yl)cyclopropane-1-carboxylate (jasmolin I)
O
CO2
Following a similar procedure for the preparation of cinerin I, the reaction of (1R,3R)-9 (70 mg, 0.42 mmol)
with (S)-jasmololone (5, 76 mg, 0.42 mmol) using TsCl (95 mg, 0.50 mmol) and N-methylimidazole (103 mg,
1.26 mmol) in CH3CN (1.8 mL) gave the desired product (84 mg, 60%).
22
22
Colorless oil; [α]D –18.2 (c 0.25, CHCl3) [lit.10 [α]D –17.1 (c 1.2, CHCl3)]; 1H NMR (500 MHz, CDCl3): δ =
0.99 (t, J = 7.5 Hz, 3H), 1.14 (s, 3H), 1.26 (s, 3H), 1.41 (d, J = 5.7 Hz, 1H), 1.71 (s, 3H), 1.73 (s, 3H), 2.04 (s,
3H), 2.09 (dd, J = 5.7 Hz, 8.0 Hz, 1H), 2.15 (qd, J = 1.7 Hz, 7.5 Hz, 2H), 2.22 (dd, J = 1.7 Hz, 18.9 Hz, 1H), 2.86
(dd, J = 6.3 Hz, 18.9 Hz, 1H), 2.98 (d, J = 7.5 Hz, 2H), 4.89 – 4.92 (m, 1H), 5.21 – 5.27 (m, 1H), 5.40 – 5.45 (m,
1H), 5.66 (m, 1H), 5.66 (d, J = 6.3 Hz, 1H). C{1H} NMR (125 MHz, CDCl3): δ = 14.0, 14.0, 18.4, 20.3, 20.5,
13
21.2, 22.0, 25.5, 29.0, 32.9, 34.5, 42.0, 72.9, 120.8, 123.9, 133.1, 135.8, 142.7, 164.7, 172.3, 203.9. HRMS (ESI-
TOF): m/z Calcd for C22H33O3 [M + Na]+ 353.2093; Found: 353.2089.
24
ACS Paragon Plus Environment

Page 25 of 46
The Journal of Organic Chemistry
(S)-2-Methyl-4-oxo-3-((Z)-penta-2,4-dien-1-yl)cyclopent-2-en-1-yl (1R,3R)-2,2-dimethyl-3-(2-methylprop-1-
1
2
3
en-1-yl)cyclopropane-1-carboxylate (pyrethrin I)
4
5
O
6
7
8
CO2
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
Following a similar procedure for the preparation of cinerin I, the reaction of (1R,3R)-9 (100 mg, 0.60 mmol)
with (S)-pyrethrolone (7, 107 mg, 0.60 mmol) using TsCl (137 mg, 0.72 mmol) and N-methylimidazole (148 mg,
1.8 mmol) in CH3CN (1.8 mL) gave the desired product (145 mg, 74%).
24
22
Colorless oil; [α]D –14.6 (c 1.23, CHCl3) [lit.10 [α]D –17.5 (c 1.4, CHCl3)]; 1H NMR (500 MHz, CDCl3): δ =
1.14 (s, 3H), 1.26 (s, 3H), 1.41 (d, J = 5.2 Hz, 1H), 1.71 (d, J = 1.2 Hz, 3H), 1.73 (s, 3H), 2.04 (s, 3H), 2.09 (dd, J
= 5.7 Hz, 7.5 Hz, 1H), 2.23 (dd, J = 1.7 Hz, 18.9 Hz, 1H), 2.88 (dd, J = 6.3 Hz, 18.9 Hz, 1H), 3.13 (d, J = 7.5 Hz,
2H), 4.89 – 4.92 (m, 1H), 5.19 (d, J = 9.7 Hz, 1H), 5.25 (d, J = 16.6 Hz, 1H), 5.35 (dt, J = 7.5 Hz, 10.9 Hz, 1H),
13
5.66 (dd, J = 1.7 Hz, 6.3 Hz, 1H), 6.04 (t, J = 10.9 Hz, 1H). C{1H} NMR (125 MHz, CDCl3): δ = 14.1, 18.5,
20.4, 21.7, 22.1, 25.5, 29.1, 32.9, 34.5, 42.0, 72.9, 118.3, 120.7, 126.9, 130.3, 131.5, 135.9, 141.9, 165.4, 172.3,
203.8. HRMS (ESI-TOF): m/z Calcd for C21H28O3 [M + Na]+ 351.1936; Found: 351.1936.
(1R,3R)-2,2-Dimethyl-3-((E)-2-methyl-3-oxoprop-1-en-1-yl)cyclopropane-1-carboxylic acid (1R,3R)-15
OHC
CO2H
A solution of KOH (5.60 g, 0.10 mol) in MeOH – H2O (5:1) (24 mL) was added to a stirred solution of ester
(1R,3R)-1426 (40% in xylene, 9.81 g, 20 mmol) in MeOH – H2O (5:1) (12 mL) at 0 – 5 °C under an Ar
atmosphere, and the mixture was stirred at 20 – 25 °C for 16 h. 6 M HCl aqueous solution (ca. 80 mL) was
slowly added to the mixture at 0 – 5 °C, which was concentrated to remove MeOH. The mixture was extracted
twice with AcOEt. The combined organic phase was washed water, brine, dried (Na2SO4) and concentrated. The
obtained crude solid product was purified by recrystallization from 2-propanol (3 mL) to give the desired product
(1R,3R)-15 (2.15 g, 59%).
25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 46
Pale yellow solid; mp 113 – 114 °C, [α]D22 +116.7 (c 1.0, CHCl3). H NMR (500 MHz, CDCl3): δ = 1.31 (s, 3H),
1.40 (s, 3H), 1.85 –1.86 (m, 4H), 2.43 (dd, J = 5.2 Hz, 9.7 Hz, 1H), 6.15 (dd, J = 1.2 Hz, 9.7 Hz, 1H), 9.38 (s,
1H). 13C{1H} NMR (125 MHz, CDCl3): δ = 9.5, 20.4, 22.4, 31.8, 33.5, 36.6, 141.0, 150.9, 177.1, 194.2.
1
1
2
3
4
5
6
7
8
(S)-3-((Z)-But-2-en-1-yl)-2-methyl-4-oxocyclopent-2-en-1-yl
(1R,3R)-2,2-dimethyl-3-((E)-2-methyl-3-
9
oxoprop-1-en-1-yl)cyclopropane-1-carboxylate (cinerin II)
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
MeO2C
CO2
Following a similar procedure for the preparation of cinerin I, the reaction of acid (1R,3R)-15 (51 mg, 0.28
mmol) with (S)-cinerolone (3, 46 mg, 0.28 mmol) using TsCl (75 mg, 0.39 mmol), N-methylimidazole (28 mg,
0.34 mmol), and iPr2NEt (87 mg, 0.67 mmol) in CH3CN (0.6 mL) gave the aldehyde precursor (16; 84 mg, 91%).
1
Yellow oil; H NMR (500 MHz, CDCl3): δ = 1.30 (s, 3H), 1.35 (s, 3H), 1.71 (d, J = 6.9 Hz, 1H), 1.87 (s, 3H),
1.88 (d, J = 4.6 Hz, 1H), 2.05 (s, 3H), 2.23 (dd, J = 1.7 Hz, 18.3 Hz, 1H), 2.43 (dd, J = 4.6 Hz, 9.7 Hz, 1H), 2.89
(dd, J = 6.3 Hz, 18.3 Hz, 1H), 3.00 (d, J = 6.9 Hz, 2H), 5.27 – 5.32 (m, 1H), 5.49 – 5.56 (m, 1H), 5.67 (dd, J =
1.7 Hz, 6.3 Hz, 1H), 6.15 (dd, J = 1.2 Hz, 9.7 Hz, 1H), 9.38 (s, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ = 9.4,
12.6, 13.9, 20.2, 31.0, 32.8, 36.4, 41.8, 73.5, 125.2, 125.3, 140.8, 142.8, 150.8, 164.1, 170.5, 193.8, 203.5.
NaH2PO4 (210 mg, 1.75 mmol) in H2O (0.6 mL) was added to a stirred solution of aldehyde (16; 116 mg, 0.35
mmol) and 2-methyl-2-butene (245 mg, 3.5 mmol) in tBuOH (2.4 mL) at 20 – 25 °C. NaClO2 (95 mg, 1.05
mmol) in H2O (0.6 mL) was added to the mixture at 0 – 5 °C, and the mixture was stirred at 20 – 25 °C for 5 h. 1
M HCl aqueous solution was added to the mixture, which was extracted twice with AcOEt. The combined
organic phase was washed with water, brine, dried (Na2SO4) and concentrated. The obtained crude oil was
purified by SiO2-column chromatography (hexane/AcOEt = 10:1-2:1) to give the acid precursor (81 mg).
Yellow oil; 1H NMR (500 MHz, CDCl3): δ = 1.25 (s, 3H), 1.32 (s, 3H), 1.71 (dd, J = 1.7 Hz, 6.9 Hz, 3H), 1.80 (d,
J = 5.2 Hz, 1H), 1.96 (d, J = 1.2 Hz, 3H), 2.05 (s, 3H), 2.23 (dd, J = 1.7 Hz, 18.3 Hz, 1H), 2.26 (dd, J = 5.2 Hz,
9.7 Hz, 1H), 2.89 (dd, J = 6.3 Hz, 18.3 Hz, 1H), 2.99 (d, J = 7.5 Hz, 2H), 5.27 – 5.33 (m, 1H), 5.49 – 5.56 (m,
26
ACS Paragon Plus Environment

Page 27 of 46
The Journal of Organic Chemistry
1H), 5.66 (dd, J = 1.7 Hz, 6.3 Hz, 1H), 6.60 (dd, J = 1.7 Hz, 9.7 Hz, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ =
12.4, 12.8, 14.0, 20.4, 20.9, 22.2, 30.8, 32.9, 36.0, 41.9, 73.5, 125.3, 125.5, 129.0, 141.6, 143.0, 164.5, 171.0,
172.9, 203.9.
1
2
3
4
5
6
7
8
9
K2CO3 (192 mg, 1.0 mmol) and MeI (0.02 mL, 0.28 mmol) was successively added to a stirred solution of acid
precursor (81 mg, 0.23 mmol) in DMF (0.7 mL) at 0 – 5 °C under an Ar atmosphere, and the mixture was stirred
at 20 – 25 °C for 16 h. Water was added to the stirred mixture, which was extracted twice with AcOEt. The
combined organic phase was washed with 1 M HCl aq. solution, brine, dried (Na2SO4) and concentrated. The
obtained crude oil was purified by SiO2-column chromatography (hexane/AcOEt = 7:1) to give cinerin II (52 mg,
63%).
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
21
Colorless oil; [α]D +11.9 (c 0.21, CHCl3); 1H NMR (500 MHz, CDCl3): δ = 1.24 (s, 3H), 1.31 (s, 3H), 1.71 (d,
3H, J = 7.5 Hz), 1.75 (d, 1H, J = 5.7 Hz),1.95 (d, 3H, J = 1.7 Hz), 2.04 (s, 3H), 2.23 (dd, 1H, J = 2.3 Hz, 18.3
Hz), 2.24 (dd, 1H, J = 5.7 Hz, 9.7 Hz), 2.88 (dd, 1H, J = 6.3 Hz, 18.3 Hz), 2.99 (d, 2H, J = 7.5 Hz), 3.74 (s, 3H),
13
5.27 – 5.33 (m, 1H), 5.49 – 5.56 (m, 1H), 5.66 (d, 1H, J = 6.3 Hz), 6.47 (dd, 1H, J = 1.7 Hz, 9.7 Hz). C{1H}
NMR (125 MHz, CDCl3): δ = 12.8, 12.8, 14.0, 20.4, 20.9, 22.3, 30.5, 32.8, 35.7, 42.0, 51.8, 73.4, 125.4, 125.5,
129.7, 139.0, 142.9, 164.4, 168.1, 171.2, 203.7. HRMS (ESI-TOF): m/z Calcd for C21H28O5 [M + Na]+ 383.1834;
Found: 383.1834.
(S)-2-Methyl-4-oxo-3-((Z)-pent-2-en-1-yl)cyclopent-2-en-1-yl
(1R,3R)-3-((E)-3-methoxy-2-methyl-3-
oxoprop-1-en-1-yl)-2,2-dimethylcyclopropane-1-carboxylate (jasmoline II)
O
MeO2C
CO2
Following a similar procedure for the preparation of cinerin I, the reaction of acid (1R,3R)-15 (194 mg, 1.06
mmol) with (S)-jasmololone (5, 192 mg, 1.06 mmol) using TsCl (282 mg, 1.48 mmol), N-methylimidazole (104
i
mg, 1.27 mmol), and Pr2NEt (329 mg, 2.54 mmol) in CH3CN (2 mL) gave the desired aldehyde precursor (17;
365 mg, 96%).
27
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 46
Colorless oil; 1H NMR (500 MHz, CDCl3): δ = 1.00 (t, J = 7.5 Hz, 3H), 1.29 (s, 3H), 1.35 (s, 3H), 1.87– 1.88 (m,
4H), 2.05 (s, 3H), 2.16 (quint, J = 7.5 Hz, 1H), 2.23 (dd, J = 1.7 Hz, 18.9 Hz, 1H), 2.43 (dd, J = 5.2 Hz, 9.7 Hz,
1H), 2.89 (dd, J = 6.3 Hz, 18.9 Hz, 1H), 2.99 (d, J = 6.9 Hz, 2H), 5.21 – 5.27 (m, 1H), 5.41 – 5.46 (m, 1H), 5.67
(dd, J = 1.7 Hz, 6.3 Hz, 1H), 6.15 (dd, J = 1.2 Hz, 9.7 Hz, 1H), 9.38 (s, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ
= 9.4, 13.8, 13.9, 20.2, 20.3, 21.0, 22.0, 31.0, 32.7, 36.4, 41.7, 73.5, 123.5, 133.0, 140.8, 142.8, 150.7, 164.0,
170.5, 193.7, 203.3.
1
2
3
4
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
Following a similar procedure for preparing the acid precursor of cinerin II, the reaction of aldehyde 17 (365
mg, 1.06 mmol) using NaClO2 (288 mg, 3.2 mmol), NaH2PO4 (636 mg, 5.3 mmol), 2-methyl-2-butene (743 mg,
10.6 mmol) in tBuOH – H2O (2:1, 10 mL) gave the desired acid precursor (282 mg, 74%).
Colorless oil; 1H NMR (500 MHz, CDCl3): δ = 1.00 (t, J = 7.5 Hz, 3H), 1.25 (s, 3H), 1.32 (s, 3H), 1.80 (d, J = 5.2
Hz, 1H), 1.96 (s, 3H), 2.05 (s, 3H), 2.16 (quint, J = 7.5 Hz, 1H), 2.23 (dd, J = 1.7 Hz, 18.9 Hz, 1H), 2.26 (dd, J =
5.2 Hz, 9.7 Hz, 1H), 2.89 (dd, J = 6.3 Hz, 18.9 Hz, 1H), 2.99 (d, J = 6.9 Hz, 2H), 5.21 – 5.27 (m, 1H), 5.41 – 5.46
(m, 1H), 5.66 (d, J = 6.3 Hz, 1H), 6.60 (dd, J = 1.7 Hz, 9.7 Hz, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ = 12.3,
13.9, 13.9, 20.3, 20.4, 21.0, 22.1, 30.7, 32.8, 123.6, 129.0, 133.1, 141.4, 142.8, 164.5, 171.0, 172.6, 203.8.
Following a similar procedure for the preparation of cinerin II, the reaction of the acid precursor (194 mg, 1.06
mmol) using K2CO3 (129 mg, 1.0 mmol) and MeI (133 mg, 0.94 mmol) in DMF (2.4 mL) gave the desired
product (167 mg, 57%).
Colorless oil; 1H NMR (500 MHz, CDCl3): δ = 1.00 (t, J = 7.5 Hz, 3H), 1.24 (s, 3H), 1.31 (s, 3H), 1.75 (d, J = 5.2
Hz, 1H), 1.95 (d, J = 1.2 Hz, 3H), 2.04 (s, 3H), 2.16 (quint, J = 1.2 Hz, 7.5 Hz, 1H), 2.22 (dd, J = 1.7 Hz, 18.3
Hz, 1H), 2.23 (dd, J = 5.2 Hz, 9.7 Hz, 1H), 2.87 (dd, J = 6.3 Hz, 18.3 Hz, 1H), 2.99 (d, J = 7.5 Hz, 2H), 3.74 (s,
3H), 5.21 – 5.27 (m, 1H), 5.40 – 5.46 (m, 1H), 5.65 (d, J = 6.3 Hz, 1H), 6.45 – 6.48 (m, 1H). 13C{1H} NMR (125
MHz, CDCl3): δ = 12.8, 14.0, 14.0, 20.3, 20.5, 21.2, 22.3, 30.5, 32.8, 35.7, 41.9, 51.7, 73.4, 123.7, 129.7, 133.2,
138.9, 142.9, 164.3, 168.0, 172.2, 203.6. HRMS (ESI-TOF): m/z Calcd for C22H30O5 [M + Na]+ 397.1982;
Found: 397.1991.
28
ACS Paragon Plus Environment

Page 29 of 46
The Journal of Organic Chemistry
(S)-2-Methyl-4-oxo-3-((Z)-penta-2,4-dien-1-yl)cyclopent-2-en-1-yl
(1R,3R)-3-((E)-3-methoxy-2-methyl-3-
1
2
3
oxoprop-1-en-1-yl)-2,2-dimethylcyclopropane-1-carboxylate (pyrethrin II)
4
5
O
6
MeO2C
7
CO2
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
Following a similar procedure for the preparation of cinerin I, the reaction of acid (1R,3R)-15 (102 mg, 0.56
mmol) with (S)-pyrethrolone (S)-7 (100 mg, 0.56 mmol) using TsCl (149 mg, 0.78 mmol), N-methylimidazole
i
(55 mg, 0.67 mmol), and Pr2NEt (174 mg, 1.34 mmol) in CH3CN (1 mL) gave the desired aldehyde precursor
(18; 194 mg).
Yellow colored oil; 1H NMR (500 MHz, CDCl3): δ = 1.30 (s, 3H), 1.35 (s, 3H), 1.87 – 1.88 (m, 4H), 2.05 (s, 3H),
2.24 (dd, J = 1.7 Hz, 18.9 Hz, 1H), 2.43 (dd, J = 5.2 Hz, 9.7 Hz, 1H), 2.90 (dd, J = 6.3 Hz, 18.3 Hz, 1H), 3.14 (d,
J = 7.5 Hz, 2H), 5.20 (d, J = 10.3 Hz, 1H), 5.25 (d, J = 16.6 Hz, 1H), 5.35 (dt, J = 7.5 Hz, 10.9 Hz, 1H), 5.67 (d, J
= 6.3 Hz, 1H), 6.05 (t, J = 10.9 Hz, 1H), 6.15 (dd, J = 1.2 Hz, 9.7 Hz, 1H), 6.73 – 6.81 (m, 1H), 9.38 (s, 1H).
13C{1H} NMR (125 MHz, CDCl3): δ = 9.4, 13.9, 20.2, 21.5, 22.1, 31.0, 32.8, 36.4, 41.7, 73.4, 118.2, 126.5,
130.2, 131.3, 140.8, 142.1, 150.7, 164.6, 170.5, 193.8, 203.2.
Following a similar procedure for preparing the acid precursor of cinerin II, the reaction of aldehyde 18 (177
mg, 0.51 mmol) using NaClO2 (134 mg, 1.5 mmol), NaH2PO4 (294 mg, 2.5 mmol), 2-methyl-2-butene (344 mg,
4.9 mmol) in tBuOH – H2O (2:1, 5 mL) gave the desired acid precursor (122 mg, 66%).
Pale yellow colored oil; 1H NMR (500 MHz, CDCl3): δ = 1.22 (s, 3H), 1.29 (s, 3H), 1.77 (d, J = 5.2 Hz, 1H), 1.93
(d, J = 1.2 Hz, 3H), 2.03 (s, 3H), 2.21 (dd, J = 1.7 Hz, 18.9 Hz, 1H), 2.24 (dd, J = 5.2 Hz, 9.7 Hz, 1H), 2.87 (dd, J
= 6.3 Hz, 18.9 Hz, 1H), 3.11 (d, J = 8.0 Hz, 2H), 5.16 (d, J = 10.3 Hz, 1H), 5.22 (d, J = 16.6 Hz, 1H), 5.32 (dt, J
= 8.0 Hz, 10.9 Hz, 1H), 5.64 (d, J = 6.3 Hz, 1H), 6.02 (t, J = 10.9 Hz, 1H), 6.58 (dd, J = 1.2 Hz, 9.7 Hz, 1H), 6.70
13
– 6.78 (m, 1H). C{1H} NMR (125 MHz, CDCl3): δ = 12.4, 14.1, 20.3, 21.6, 22.2, 30.8, 32.9, 35.9, 41.9, 73.4,
118.3, 126.6, 129.0, 130.4, 131.4, 141.5, 142.2, 165.0, 171.0, 172.8, 203.6.
29
ACS Paragon Plus Environment