Structure-activity relationship of novel juvenile hormone, JHSB 3, isolated from the stink bug, Plautia stali

Article abstract of DOI:10.1016/j.tet.2011.10.080

The structure-activity relationship of JHSB₃ isolated from the pentatomid bug, Plautia stali, was studied. Various synthetic analogs were synthesized and subjected to the juvenilizing activity tests using the last instar nymphs of P. stali. These studies indicated that the coexistence of the ester carbonyl group, two epoxides at C2,3 and C10,11 were proved to be crucial for the potent juvenilizing activity. Among the tested analogs, we found highly potent analogs in which the C6,7 double bond of JHSB₃ was saturated (0.1 μg/insect). The methoxy analogs in which the epoxide moiety at C10,11 was substituted with a methoxy group exerted a moderate juvenilizing activity.

Full text of DOI:10.1016/j.tet.2011.10.080

Tetrahedron 68 (2012) 106e113
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Structureeactivity relationship of novel juvenile hormone, JHSB3, isolated from
the stink bug, Plautia stali
,
Kanako Kaihara a, Toyomi Kotaki b, Hideharu Numata c, Yasufumi Ohfune a, Tetsuro Shinada a
*
a Graduate School of Science, Osaka City University, Sugimoto, Sumiyoshi, Osaka 558-8585, Japan
b National Institute of Agrobiological Sciences, Division of Insect Sciences, 1-2, Ohwashi, Tsukuba, Ibaraki 305-8634, Japan
c Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 October 2011
Received in revised form 22 October 2011
Accepted 24 October 2011
Available online 31 October 2011
The structureeactivity relationship of JHSB3 isolated from the pentatomid bug, Plautia stali, was studied.
Various synthetic analogs were synthesized and subjected to the juvenilizing activity tests using the last
instar nymphs of P. stali. These studies indicated that the coexistence of the ester carbonyl group, two
epoxides at C2,3 and C10,11 were proved to be crucial for the potent juvenilizing activity. Among the
tested analogs, we found highly potent analogs in which the C6,7 double bond of JHSB3 was saturated
(0.1
mg/insect). The methoxy analogs in which the epoxide moiety at C10,11 was substituted with a me-
Keywords:
thoxy group exerted a moderate juvenilizing activity.
Juvenile hormone
Structureeactivity relationship
Juvenilizing effect
Heteropteran insect
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
R1
O
R2
R3
O
O
OMe
OMe
Juvenile hormone (JH) is an important insect hormone that
plays a key role in insect development.1e7 In 1934, Wigglesworth
found a humoral factor controlling the metamorphosis and re-
production in Rhodonius prolixus. The humoral factor has been re-
ferred to ‘an inhibitory hormone’ and later as JH.8,9 The structure
determination of JH was extensively examined due to its significant
role in insects. In 1967, the structure of JH I (1) isolated from the
cecropia silkworm, Hyalophora cecropia, was determined.1,2,10,11
Since the first structure determination, several JHs 2e5 have been
reported (Fig. 1).5 In contrast to these extensive studies, the struc-
ture of JH in heteropteran insects has remained to be a challenging
task to be solved.12
O
JH I : R1 = R2 = Et, R3 = Me ( )
JH II : R1 = Et, R2 = R3 = Me (2)
JH III : R1 = R2 = R3 = Me (3a)
4
4-Me-JH I: ( )
1
JH 0 : R1 = R2 = R3 = Et
(3b)
O
O
OMe
OMe
O
O
O
O
JHB3 (5)
6
JHSB3 ( )
Fig. 1. Structure of juvenile hormones (1e6).
We have recently reported the structure determination of JHSB3
(6) isolated from the pentatomid bug, Plautia stali.13,14 This is the
first example of the JH isolated from heteropterans, bearing the
skipped bisepoxide arrangement in the farnesene skeleton. The
structure determination of JHSB3 (6) was achieved by the un-
precedented JH library-screening approach (Fig. 2). The molecular
library including 32 candidates was initially generated via the
Darzens reaction, which was subjected to the juvenilizing activity
test using P. stali and chiral HPLC separation to screen the target JH.
Along this line, the candidates were focused on 6, 12, 13, and 14.
NMR analysis of these candidates indicated the presence of a skip-
ped bisepoxide structure of trans-methyl farnesoate. Since the
relative and absolute stereochemistries could not be determined by
the NMR studies, the four stereoisomers were stereoselectively
synthesized in an optically active form. Among them, two analogs
(2R,3S,6E,10R)-6 and (2R,3S,6E,10S)-12 exerted potent juvenilizing
activities. The structure of the natural JH was determined to be 6 by
chiral GC/MS analysis of the natural JH obtained from P. stali, and
the synthetic candidates 6 and 12.
Our study provided not only
a successful structure de-
termination of the novel JH, but also several structureeactivity
relationship (SAR) information of JHSB3. First, the skipped bisep-
oxides and 2E,6E-farnesol skeleton are crucial for the juvenilizing
* Corresponding author. E-mail address: shinada@sci.osaka-cu.ac.jp (T. Shinada).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.10.080

K. Kaihara et al. / Tetrahedron 68 (2012) 106e113
107
prepared in a few steps via the condensation of the commercially
available 15 and an HWE reagent 16. We hypothesized that the
C10,11-epoxide of JHSB3 could be symmetrized into a methoxy
moiety the same as the successful analog design. We have reported
that JHSB3 and its stereoisomer (10S)-12 exerted the same potency.
These observations supported our hypothetical molecular design.
Along this line, a series of methoxy analogs 18aeg in which the
ester moiety was derivatized with more hindered esters, amide,
ketone, and ethenyl group was produced. We expected that the role
of the C1 ester methyl group in the juvenilizing effects would be
systematically assessed by this SAR. In this study, these analogs
were used as a mixture of stereoisomers from the commercially
available racemic aldehyde 15. Therefore, (2R,3S,7S)-18a that pos-
sesses the same chiral epoxy moiety of JHSB3 was synthesized as
a single stereoisomer to evaluate the effect of the left half moiety of
18a for the juvenilizing effect. In addition, analogs 19, 20, 21a, and
21b were prepared to assess the role of the epoxide moieties at C2,3
and C10,11, and the olefin at C6,7 of JHSB3, respectively (Fig. 3).
Fig. 2. Structure determination of JHSB3 (6) and JH activity for P. stali.13
effects. On the other hand, the other stereoisomers are much less
potent. Second, comparison of the biological activities of 6, 12e14
indicated that the 2R,3S-stereogenic centers are crucial. It is in-
teresting to note that natural product (2R,3S,10R)-6 and its 10S-
stereoisomer (2R,3S,10S)-12 exhibited the same potency, indicating
that the stereochemical arrangement at C10 did not affect the
juvenilizing activities.
JH was expected to be a prime lead molecule for developing
a ‘third-generation pesticide’, because of the significant insect
growth regulation effects.1,2 In fact, the discovery of JHs 1e4 trig-
gered extensive synthetic studies of JH analogs for the development
of potent insecticides.1e3 Heteroptera includes many agricultural
and medical pests. The development of Heteroptera-specific in-
secticide poses a pivotal subject in this field.15 Therefore, JHSB3 is
expected to be a lead for developing Heteroptera-specific in-
secticides. In this study, we would like to report the SAR of JHSB3.
Various JHSB3 analogs 18aeg,19, 20, 21a, and 21b were synthesized
and subjected to juvenilizing activity tests to gain insights into the
key functional groups of JHSB3.
Fig. 3. JHSB3 analogs (18aeg, 19, 20, 21a and b).
2.2. Synthesis of JHSB3 analogs
Analogs 18aeg, 19, and 20 were synthesized starting from the
commercially available 7-methoxy-3,7-dimethyloctanal (15) and
geranyl acetone (7) (Scheme 1). The aldehyde 15 was converted to
the known ketone 22.16 The Darzens reaction of 22 with methyl
chloroacetate afforded 18a as a mixture of eight stereoisomers with
respect to the stereogenic centers at C2, C3, and C7. Other analogs
18bed bearing sterically bulkier esters (ethyl, allyl, and propargyl
ester) were prepared by the mild K2HPO4-mediated trans-
esterification reaction.17 Analogs 18eeg were synthesized from 22
as the common intermediate. The Darzens reaction of 22 with N-
chloro-N-methylacetamide afforded the epoxy amide 18e in good
yield (88%, based on recovered starting material).18 The treatment
of 18e with MeMgBr gave the ketone 18f. The alkyne analog 18g
was synthesized by the addition of an organozinc reagent prepared
from 3-chloro-1-trimethylsilylpropyne19 followed by desilylation
of the TMS group.20 The analog 19 was prepared by the reduction of
22, followed by the OH insertion reaction of the resulting alcohol in
2. Results and discussion
2.1. Analog design
Methoprene (17) is a representative of the JH structure-based
insecticide.1,3 The features of this analog design are summarized
as follows: (i) the 10,11-epoxide is successfully substituted with
a symmetrical methoxy group, (ii) the installation of an isopropyl
ester contributes to the enhancement of the inhibitory effects of the
metabolic methyl esterases, (iii) the saturation of the 6,7-olefin
resulted in maintaining the biological activity, and (iv) 17 was

108
K. Kaihara et al. / Tetrahedron 68 (2012) 106e113
O
O
a, b
c
OMe
OMe
11
d
3
a
CO2Me
15
CHO
R
7R
O
S
7
OMe
OH
2
O
18a
22
24
23
(+)-citronellal (
(7R)-
)
a mixture of 8 stereoisomers
O
c
d
i, j
18g
k, l
OMe
b
g
e
18c
f
18d
(7R)-27
7R
(2Z,7R)-25: R = OTs
(2E,7R)-26: R = Me
19
18e
18f
18b
h
O
O
f
3S
R
2S
OMe
O
O
30
m, n
H
(2S,3S,7R)-28: R = CH2OH (dr = 95 : 5)
11
3
7
e
CO2Me
29
O
(2R,3S,7R)- : R = CHO
g
h
2
O
20
a mixture of 8 stereoisomers
7
O
3S
7R
10R/S
3S
7S
OMe
OMe
OMe
Scheme 1. Synthesis of JHSB3 analogs (18aeg, 19, and 20). Reagents and conditions: (a)
L-proline, acetone, H2O, 70 ꢁC, 74%. (b) Pd/C, H2, AcOEt, 88%. (c) Methyl chloroacetate,
t-BuOK, t-BuOH/THF, 30%. (d) K2HPO4, EtOH, 60 ꢁC, 85%. (e) K2HPO4, allyl alcohol, 75 ꢁC,
O
O
O
2R
OMe
O
2R
18a
(2R,3S,7S)-
(2R,3S,7R,10R/ S)-21a
ꢀ
88%. (f) K2HPO4, 4 A MS, propargyl alcohol, 93%. (g) N-Chloro-N-methylacetamide,
O
LHMDS, THF, ꢀ78 ꢁC to rt, 86%. (h) MeMgBr, THF,
0
ꢁC, 79%. (i) 3-Chloro-1-
7S
10R/S
a-g
O
O
3S
7S
trimethylsilylpropyne, ZnBr2, LDA, THF, ꢀ80 to ꢀ20 ꢁC, 74%, (j) K2CO3, MeOH, 99%. (k)
NaBH4, MeOH/THF, 0 ꢁC,100%. (l) N2CHCO2Et, Rh2(OAc)4, CHCl3, 98%. (m) Pd/C, H2, MeOH,
95%. (n) Methyl chloroacetate, t-BuOK, t-BuOH/THF, 42%. MS, molecular sieves; LHMDS,
lithium bis(trimethylsilyl)amide; LDA, lithium diisopropylamide.
O
OMe
2R
21b
(7S)-24
(2R,3S,7S,10R/ S)-
Scheme 2. Synthesis of JHSB3 analogs (21a,b and (2R,3S,7S)-18a). Reagents and condi-
tions: (a) TsCl, LiCl, Et3N, NMI, toluene, 0 ꢁC to rt, 98% (E/Z¼2:98). (b) Me2Zn, PdCl2(PPh3)2,
THF, 0 ꢁC to rt, 99% (E/Z¼>95:5). (c) DIBAL, toluene, ꢀ78 ꢁC, 98%. (d) (þ)-DIPT, Ti(Oi-Pr)4,
the presence of Rh2(OAc)4. In a manner similar to the synthesis of
18a, the analog 20 was synthesized from geranyl acetone (7). These
analogs 18aeg and 20 possess three stereogenic centers at C2, C3,
and C7. These were obtained as a mixture of eight stereoisomers
with the stereogenic centers. The analog 19 having two stereogenic
centers was obtained as a mixture of eight stereoisomers.
3 A MS, t-BuOOH, CH2Cl2, ꢀ45 ꢁC, 95% (dr¼95:5). (e) SO3 pyridine, DMSO, i-Pr2NEt,
ꢀ
CH2Cl2, 0 ꢁC, 99%. (f) (i) NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH/H2O; (ii) CH2N2,
Et2O, 0 ꢁC, 66%. (g) m-CPBA, CH2Cl2, 0 ꢁC, 97%. (h) MeOH, Hg(OAc)2, 72%. TsCl, p-tolue-
nesulfonyl chloride; NMI, N-methylimidazole; DIBAL, diisobutylaluminum hydride; DIPT,
diisopropyl tartrate; MS, molecular sieves; DMSO, dimethyl sulfoxide; m-CPBA,
m-chloroperbenzoic acid.
The syntheses of 6,7-dihydro JHSB3 analogs (2R,3S,7R,10R/S)-21a
and (2R,3S,7S,10R/S)-21b, and optically active (2R,3S,7S)-18a were
started with the commercially available chiral citronellal 23
(Scheme 2). (þ)-Citronellal (23) was converted into the
b-keto ester
24,21e23 which was transformed into 21a by a series of sequential
transformations: (i) stereoselective formation of (Z)-tosylate 25
using Tanabe’s protocol with a high selectivity (E/Z¼2:98, 98%),24,25
(ii) stereoselective construction of the E-trisubstituted olefin by the
Negishi cross-coupling reaction using PdCl2(PPh3)2 and Me2Zn (E/
Z¼>95:5, 99%).26 After reduction of the
a,b-unsaturated ester 26,
the resulting allyl alcohol 27 was subjected to the Shar-
plesseKatsuki asymmetric epoxidation reaction13 to secure the
chiral stereocenters at C2 and C3 to provide the optically active
(2S,3S)-epoxide 28 (dr¼95:5).27 The chiral epoxide 28 was con-
verted into the corresponding methyl ester 30 by a conventional
protocol in three steps to give a 1:1 mixture of bisepoxide 21a. In
a similar manner, the analog 21b was synthesized from (ꢀ)-citro-
nellal. Compound (2R,3S,7S)-18a was synthesized from 30 by the
treatment with MeOH in the presence of Hg(OAc)2.
Fig. 4. Juvenilizing effects in P. stali. (A): an adult, (B): a last instar nymph, (C):
a nympheadult intermediate generated by application of JHSB3 to the last instar
nymph (B).
juvenilizing activities (0.1 mg/insect). Compound (7R)-21a was
slightly more potent than (7S)-21b. As already mentioned, JHSB3 and
its 10S-isomer exhibited the same potency. In this context, the dif-
ference in the juvenilizing activity between them would be ascribed
to the stereochemical arrangement of the methyl groups at C7.
Analogs 18aeg in which the epoxide at C10,11 was substituted
by a methyl ether showed moderate juvenilizing activities in
2.3. Juvenilizing effects of analogs
The synthetic analogs were subjected to the juvenilizing activity
test reported by Kotaki et al. (Fig. 4).12e14 The analog sample solu-
tion (1 mL aliquot of a hexane solution) was topically applied to the
last instar nymphs of the P. stali in four different concentrations
(Fig. 4, B). Under the control conditions, the last instar nymphs (B)
of P. stali metamorphose to the adult insect (A) after the molting.
The inhibitory effect of the analogs would result in a nympheadult
intermediate (C) that retains the nymphal characteristics (B). The
inhibitory effects were classified into five categories according to
the degree of juvenilization (Table 1).
a range of effective doses in 1e10 mg/insect. The ester analogs
18aed are more potent than the other analogs 18eeg, and 19, in-
dicating the significant role of the ester moiety in the juvenilizing
effect for P. stali. Analogs 18aed are a mixture of eight stereoiso-
mers. A previous SAR study of JHSB3 indicated that the (2R,3S)-
stereoisomers are more potent than the other stereoisomers.13,14
Moreover, the C7-stereoisomers of 21a and 21b exerted almost
the same biological activities. These facts indicated that the (2R,3S)-
stereoisomers of 18aed could be possible biologically active prin-
ciples. Indeed, the chiral (2R,3S,7S)-18a (Ej1) was more potent
than 18a (1<E<10, as a mixture of eight stereoisomer). The potency
of (2R,3S,7R)-18a, the C7-stereoisomer, was not assessed in this
study. We speculated that the potency of its C7-stereoisomer would
be the same as that of (2R,3S,7S)-18a due to the fact that the C7-
stereoisomers of 21a and 21b exerted almost the same biological
activities. Although the potencies of 18aed were moderate, these
The dose response ‘þ’ depicted in Table 1 refers to the effective
dose (E: mg/insect). The potency of the synthetic analogs was esti-
mated as follows: E<0.01: JHSB3 (6); E<0.1: 21a; Ej0.1: 21b; Ej1:
18bed, (2R,3S,7S)-18a; 1<E<10: 18a; Ej10: R-JH III (3a), JHB3 (5),
18f; E>10: S-JH III,17,18e,18g,19, and 20. Among them, 21a and 21b
that possesses the skipped bisepoxide motif maintained potent

K. Kaihara et al. / Tetrahedron 68 (2012) 106e113
109
Table 1
provided valuable information regarding the development of
a Heteroptera-specific insecticide based on the JHSB3 as a lead.
Further synthetic studies to explore the more potent JHSB3 analogs
are underway.
Juvenilizing activity of JHs, its analog and synthetic JHSB3 analogs against P. stali
4. Experimental
4.1. Materials and methods
All reagents and solvents were purchased from SigmaeAldrich,
Nacalai Tesque or Tokyo Chemical Industry, and used without fur-
ther purification unless otherwise indicated. Solvents of anhydrous
grade were used without distillation. All reactions were generally
monitored by thin layer chromatography using 0.25 mm E. Merck
silica gel plates (60 F254). Visualization was accomplished by irra-
diation with a UV lamp (254 nm) and/or a charring solution of
ethanoic phosphomolybdic acid or KMnO4 aqueous. Flash column
chromatography was performed with the indicated solvents and
silica gel, Daisogel IR-60 1002W (particle size 0.040e0.063 mm).
Yields refer to chromatographically pure compounds and spectro-
scopically pure compounds, except as otherwise indicated. Optical
rotations ([a]D) were taken using a JASCO P-1030 polarimeter with
a sodium lamp (D line). The FTIR spectra were measured by a JASCO
FT/IR-420 infrared spectrophotometer. 1H NMR spectra were recor-
ded by either a JEOL JNM-LA 300 (300 MHz), Brucker BioSpin
AVANCE III Nanobay (300 MHz) or JEOL JNM-LA 400 (400 MHz).
Chemical shifts of the 1H NMR were reported in parts per million
To evaluate the biological activities of the synthesized analogs, a 1 mL aliquot of
a hexane solution of the analog was topically applied to the last instar nymphs of P.
stali (Fig. 4B). After the final molt, the test insects were classified into five categories
according to the degree of metamorphosis inhibition; þþþ: nymph-looking in-
termediates with metamorphosis fully inhibited (Fig. 4C), þþ: intermediates with
some characteristics of adult, þ: adult-looking intermediates with green-colored
pronotum and scutellum, ꢃ: adults with nymphal type, 4-segmented antennae,
and d: adults having normal 5-segmented antennae (Fig. 4A).
(ppm,
d
) relative to the residual solvent peak in CDCl3 (
d
¼7.26). The
13C NMR spectra were recorded by a Brucker BioSpin AVANCE III
Nanobay (75 MHz) or a JEOL JNM-LA 400 (100 MHz). The chemical
shifts of the 13C NMR were reported in ppm (
d) relative to CDCl3
(d¼77.0). Low resolution mass spectra (LRMS) and high resolution
mass spectra (HRMS) were obtained using a JEOL JMX-AX500 for fast
atom bombardment ionization (FAB) and chemical ionization (CI).
A stock culture of P. stali was established from adults collected in
Joso (formerly Mitsukaido), Ibaraki, Japan (36.18 N, 140.08E), in
2001, and kept for more than 30 generations under long-day con-
ditions (16 h light:8 h dark) at 25 ꢁC in the laboratory. The insects
were reared on raw peanuts and dry soybeans with water sup-
methoxy analogs could not be metabolized by enzymes, such as the
epoxide (C10,11) hydroxylase. The lifetime of these analogs in in-
sects may be prolonged to enhance the juvenilizing activity.28 Re-
search toward the development of the advanced analogs having the
methoxy group at C11 is now in progress.
The above SAR studies coupled with the experimental results
obtained from methoprene (17) and the demethoxy analog 20
clearly showed that the coexistence of the ester carbonyl group at
C1, the chiral epoxide at C2,3, and the epoxide at C10,11 or the
methyl ether at C11 are essential for the juvenilizing effects. A
comparison of the juvenilizing effects of JH III (3a), JHB3 (5), and
JHSB3 (6) substantiated the facts that the skipped bisepoxide ar-
rangement is a crucial structural element in JHSB3.
plemented with 0.05% sodium L-ascorbate and 0.025% L-cysteine.
Diapausing insects were obtained by rearing them under short-day
conditions (12 h light:12 h dark) at 20 ꢁC.12,14
4.2. Synthesis of JHSB3 analogs
Analogs 18aeg, 19, and 20 were synthesized as a mixture of
stereoisomers listed in Table 1.
Among the tested analogs, we found 21a and 21b as potent
JHSB3 mimics. The potencies of 21a and 21b were almost the same,
ensuring that 21a and 21b can serve as the JHSB3 mimics as
a mixture. The synthesis of the mixture has several practical merits
as the starting racemic citronellal is much cheaper than that of the
enantiomeric pure citronellal.29 In addition, the overall synthetic
efficiency is much improved in comparison to that of JHSB3 due to
the lack of the double bond at C6,7 in 21a and 21b. For example, the
undesired side reactions observed in the synthesis of JHSB3, such as
the excessive dihydroxylation at C6,7 during the asymmetric
dihydroxylation step and the undesired quenching of the HCl with
the double bond at C6,7 during the Pinnick oxidation step,13 could
be excluded in the synthesis of 21a and 21b.
4.2.1. Analog 18a. To a solution of ketone 2216 (500 mg, 2.2 mmol)
in t-BuOH (5.5 mL) and THF (0.5 mL) was added t-BuOK (370 mg,
1.5 mmol) portion wise. The mixture was stirred for 30 min. Methyl
chloroacetate (230 mL, 1.2 mmol) was added to the mixture. The
mixture was stirred for 15 h, quenched with saturated NH4Cl, and
extracted with hexane/AcOEt (1/1ꢂ2). The combined organic layers
were washed with brine, dried over anhydrous MgSO4, and fil-
trated. The filtrate was concentrated under reduced pressure. The
residue was purified by flash column chromatography on silica gel
(elution with hexane/AcOEt¼25/1, 20/1, then 15/1) to give 18a
(198 mg, 33%, based on recovered starting material) as yellow oil. Rf
0.59 (hexane/AcOEt 5/1); FTIR (neat) 2939, 1759, 1462, 1441, 1410,
1381, 1363, 1290, 1203, 1082, 1032, 914, 739 cmꢀ1
;
1H NMR
3. Summary
(400 MHz, CDCl3) 3.79, 3.78 (each s, 3H), 3.34, 3.33 (each s, 1H),
d
3.17 (s, 3H), 1.70e1.51 (m, 4H), 1.48e1.36 (m, 3H), 1.40, 1.35 (each s,
3H), 1.32e1.22 (m, 4H), 1.17e1.03 (m, 2H), 1.13 (s, 6H), 0.87, 0.85
In this study, the crucial structural elements of JHSB3 have been
identified. The present study coupled with the SAR study per-
formed during the course of the structure determination of JHSB3
(each d, J¼6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 168.9, 168.8,
74.4, 62.9, 62.7, 59.3, 58.4, 52.0, 48.9, 40.0, 37.9, 37.4, 37.4, 37.4, 37.3,

110
K. Kaihara et al. / Tetrahedron 68 (2012) 106e113
36.7, 36.7, 36.6, 32.5, 32.4, 32.3, 32.2, 24.8, 22.8, 22.8, 22.3, 22.3,
21.4, 21.1, 19.4, 19.4, 19.3, 16.0, 16.0; HRMS (FAB) m/z [MþH]þ calcd
for [C17H32O4þH]þ 301.2379, found 301.2381.
and filtered. The filtrate was concentrated under reduced pressure.
The residue was purified by flash column chromatography on silica
gel (elution with hexane/AcOEt¼15/1, 10/1, 6/1 then 3/1) to give 18e
(847 mg, 88%, based on recovered starting material) as pale yellow
oil. Rf 0.44 (hexane/AcOEt 2/1); FTIR (neat) 2937, 1680, 1464, 1379,
1309,1250,1184,1082, 993, 928, 823, 754 cmꢀ1; 1H NMR (400 MHz,
4.2.2. Transesterification of 18a to 18b. To a stirred solution of 18a
(67.1 mg, 0.223 mmol) in EtOH (2.0 mL) was added K2HPO4
(20.1 mg, 0.115 mmol). The mixture was stirred for 1 week at 60 ꢁC,
then cooled to room temperature, diluted with hexane, and filtered
through a short silica gel pad. The filtrate was concentrated under
reduced pressure. The residue was purified by flash column chro-
matography on silica gel (elution with hexane/AcOEt¼25/1, then
20/1) to give analog 18b (59.6 mg, 85%) as colorless oil. Rf 0.66
(hexane/AcOEt 5/1); FTIR (neat) 2947, 1753, 1456, 1282, 1215, 1080,
CDCl3) d 3.74, 3.73 (each s, 3H), 3.64, 3.62 (each br s, 1H), 3.24, 3.22
(each s, 3H), 3.17 (s, 3H), 1.71e1.52 (m, 4H), 1.50e1.35 (m, 3H), 1.43,
1.31 (each s, 3H), 1.33e1.21 (m, 4H), 1.19e1.05 (m, 2H), 1.13 (s, 3H),
1.13 (s, 3H), 0.87, 0.85, 0.84 (each d, J¼6.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 168.6, 74.5, 74.5, 62.4, 62.2, 61.5, 60.1, 59.2, 59.2,
49.0, 40.1, 40.1, 38.1, 37.5, 37.5, 37.4, 36.9, 36.8, 32.6, 32.6, 32.6, 32.5,
24.9, 22.8, 22.8, 22.5, 22.4, 21.4, 21.2, 19.5, 19.4, 19.4, 19.3, 16.4;
HRMS (CI) m/z [MþH]þ calcd for [C18H35NO4þH]þ 330.2644, found
330.2638.
910, 858, 758 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d 4.26, 4.25, 4.24
(each q, J¼7.2 Hz, 2H), 3.32, 3.31 (each s, 1H), 3.17 (s, 3H), 1.70e1.52
(m, 4H), 1.50e1.37 (m, 3H), 1.40, 1.35 (each s, 3H), 1.34e1.21 (m, 4H),
1.31,1.30 (each t, J¼7.2 Hz, 3H),1.17e1.05 (m, 2H),1.14 (s, 3H),1.13 (s,
3H), 0.87, 0.85 (each d, J¼6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
4.2.6. Analog 18f. To a solution of analog 18e (236 mg, 0.72 mmol)
in THF (3 mL) was added dropwise methyl magnesium bromide
d
168.5, 168.4, 74.5, 62.9, 62.6, 61.2, 59.5, 58.5, 49.0, 40.1, 38.0, 37.5,
(620 m
L of a 1.4 M solution in toluene/THF, 3/1, 0.87 mmol) at 0 ꢁC.
37.4, 36.9, 36.8, 36.7, 32.7, 32.6, 32.6, 32.4, 32.3, 24.9, 23.0, 22.9,
22.4, 22.4, 21.5, 21.2, 19.5, 19.4, 19.4, 16.0, 16.0, 14.2; HRMS (CI) m/z
[MþH]þ calcd for [C18H34O4þH]þ 315.2535, found 315.2533.
The mixture was stirred for 30 min at 0 ꢁC, quenched by saturated
NH4Cl, and extracted with hexane (ꢂ3). The combined organic
layers were dried over anhydrous MgSO4 and filtered. The filtrate
was concentrated under reduced pressure. The residue was purified
by flash column chromatography on silica gel (elution with hexane/
AcOEt¼15/1) to give 18f (161.6 mg, 79%) as pale yellow oil. Rf 0.74
(hexane/AcOEt 2/1); FTIR (neat) 3429, 2937, 1722, 1462, 1406, 1381,
1362, 1240, 1213, 1186, 1082, 966, 926, 877, 843, 756 cmꢀ1; 1H NMR
4.2.3. Transesterification of 18a to 18c. According to the same
procedure described above, 18a (50.0 mg, 0.166 mmol) was treated
with allyl alcohol (2.0 mL) in the presence of K2HPO4 (30.0 mg,
0.172 mmol) at 70 ꢁC for 7 days to give analog 18c (48.0 mg, 95%,
based on recovered starting material) as colorless oil. TLC Rf 0.40
(hexane/AcOEt 7/1); FTIR (neat) 2943, 1755, 1597, 1462, 1414, 1279,
(400 MHz, CDCl3)
d 3.38, 3.37 (each s, 1H), 3.17 (s, 3H), 2.23, 2.22
(each s, 3H), 1.72e1.52 (m, 3H), 1.48e1.33 (m, 4H), 1.41, 1.25 (each s,
3H), 1.31e1.21 (m, 4H), 1.18e1.05 (m, 2H), 1.13 (s, 3H), 1.13 (s, 3H),
0.87, 0.85, 0.84 (each d, J¼6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
1194, 1080, 991, 931, 762 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
5.99e5.85 (m, 1H), 5.36 (dd, J¼16.8, 1.4 Hz, 1H), 5.28 (d, J¼10.4 Hz,
1H), 4.73e4.63 (m, 2H), 3.35, 3.34 (each s, 1H), 3.17 (s, 3H),
1.70e1.52 (m, 3H), 1.49e1.35 (m, 4H), 1.40, 1.35 (each s, 3H),
1.32e1.25 (m, 4H), 1.13 (s, 6H), 1.13e1.06 (m, 2H), 0.86, 0.85 (each d,
d 203.4, 203.3, 73.8, 65.1, 64.1, 63.2, 63.2, 62.6, 48.3, 39.6, 39.5, 37.8,
37.8, 36.9, 36.8, 36.4, 36.3, 36.3, 36.1, 34.3, 32.1, 32.0, 31.9, 31.9, 29.6,
28.6, 27.5, 27.5, 27.3, 24.5, 24.4, 24.4, 22.8, 22.5, 22.3, 22.1, 22.0, 21.9,
21.6, 21.4, 20.6, 20.6, 20.5, 19.0, 19.0, 19.0, 18.8, 15.6, 15.6; HRMS (CI)
m/z [MþH]þ calcd for [C17H32O3þH]þ 285.2429, found 285.2434.
J¼6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 168.3,168.2,131.6,131.5,
120.9, 119.3, 119.1, 74.6, 65.9, 65.8, 63.2, 62.9, 59.5, 58.5, 49.1, 40.1,
38.0, 37.5, 36.9, 36.9, 36.7, 32.7, 32.7, 32.4, 32.4, 25.0, 23.1, 23.0, 22.5,
21.6, 21.3, 19.5, 19.4, 16.1; HRMS (CI) m/z [MþH]þ calcd for
[C19H34O4þH]þ 327.2535, found 327.2533.
4.2.7. Analog 18g. To a solution of ZnBr2 (1.01 g, 4.48 mmol) in THF
(3 mL) at ꢀ20 ꢁC was added 3-chloro-1-trimethylsilylpropyne
(208 mg, 1.42 mmol) in THF (1.5 mL). The mixture was cooled to
ꢀ80 ꢁC. LDA (3.0 mmol) in THF (3 mL) was added to the mixture
and stirred for 1 h. A solution of 22 (320 mg, 1.40 mmol) in THF
(3 mL) was added to the mixture and the mixture was stirred for 3 h
at ꢀ80 ꢁC. The mixture was allowed to warm to ꢀ20 ꢁC, stirred for
1 h, then quenched with a 2/1 mixture of saturated NH4Cl aqueous
NH3, and extracted with Et2O (ꢂ3). The combined organic layers
were washed with H2O (ꢂ2) and brine, dried over anhydrous
MgSO4, and filtered. The filtrate was concentrated under reduced
pressure. The residue was purified by flash column chromatogra-
phy on silica gel (elution with hexane/AcOEt¼35/1, then 20/1) to
give the corresponding chlorohydrin (282.3 mg, 74%, based on re-
covered starting material) as pale yellow oil. Rf 0.55 (hexane/AcOEt
5/1); FTIR (neat) 3801, 2942, 2902, 2242, 2178, 1463, 1379, 1364,
4.2.4. Transesterification of 18a to 18d. According to the same
procedure described above, 18a (50.0 mg, 0.166 mmol) was treated
with propargyl alcohol (2.0 mL) in the presence of K2HPO4
ꢀ
(30.0 mg, 0.172 mmol) and powdered molecular sieves 4 A (5 mg)
at room temperature for 5 days to give analog 18d (51.1 mg, 95%) as
pale yellow oil. Rf 0.31 (hexane/AcOEt 7/1); FTIR (neat) 3282, 2939,
2129, 1761, 1464, 1414, 1381, 1275, 1184, 1082, 1038, 999, 939,
760 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
4.79, 4.78 (each d, J¼2.6 Hz,
2H), 3.37, 3.36 (each s, 1H), 3.17 (s, 3H), 2.50 (t, J¼2.6 Hz, 1H),
1.70e1.48 (m, 4H),1.47e1.38 (m, 3H),1.41,1.36 (s, 3H),1.33e1.22 (m,
4H), 1.18e1.02 (m, 2H), 1.13 (s, 6H), 0.86, 0.85 (each d, J¼6.4 Hz, 3H);
13C NMR (100 MHz, CDCl2)
d 167.7, 75.4, 74.6, 63.5, 63.2, 59.2, 58.2,
52.6, 52.5, 49.1, 40.1, 38.0, 37.5, 36.7, 32.7, 25.0, 23.0, 22.4, 21.6, 21.3,
19.5, 16.1; HRMS (CI) m/z [MþH]þ calcd for [C19H32O4þH]þ
325.2379, found 325.2384.
1251, 1156, 1044, 914, 842, 790, 760 cmꢀ1
;
1H NMR (400 MHz,
CDCl3) 4.55, 4.54, 4.51 (each s, 1H), 3.17 (s, 3H), 1.74e1.61 (m, 3H),
d
1.46e1.38 (m, 4H), 1.35 (s, 3H) 1.33e1.21 (m, 4H), 1.14 (s, 6H),
1.14e1.08 (m, 2H), 0.88 (d, J¼6.4 Hz, 3H), 0.19 (s, 9H); 13C NMR
4.2.5. Analog 18e. To a solution of N-chloro-N-methylacetamide
(495 mg, 3.60 mmol) in THF (3.5 mL) at ꢀ78 ꢁC was added drop-
wise LHMDS (freshly prepared from hexamethyldisilyl amine,
(100 MHz, CDCl3)
d 100.8, 100.7, 100.7, 93.4, 93.4, 74.8, 74.7, 74.7,
74.6, 60.3, 59.2, 59.2, 58.2, 58.1, 49.0, 40.1, 38.8, 38.8, 37.7, 37.7, 37.6,
37.4, 37.4, 37.3, 32.7, 32.7, 32.7, 32.7, 32.6, 25.0, 23.0, 23.0, 22.8, 22.7,
21.3, 21.3, 21.2, 21.0, 20.9, 20.8, 19.6, 19.5, 14.2; HRMS (FAB) m/z
[MþH]þ calcd for [C20H3935ClO2SiþH]þ 375.2486, found 375.2480
and [C20H3937ClO2SiþH]þ 377.2456, found 377.2453.
820 mL, 3.9 mmol and n-BuLi (a 2.6 M solution in hexane, 1.7 mL,
4.5 mmol)) under argon. The reaction mixture was stirred for an
additional 20 min at ꢀ78 ꢁC. A solution of 22 (685 mg, 3.0 mmol) in
THF (4.5 mL) was added to the mixture via cannula. The reaction
mixture was warmed to room temperature, stirred for 17 h, then
quenched with saturated NH4Cl, and extracted with AcOEt (ꢂ3).
The combined organic layers were dried over anhydrous MgSO4
To a stirred solution of the chlorohydrin (160 mg, 0.427 mmol)
in MeOH (1 mL) at room temperature was added K2CO3 (88.0 mg,
0.637 mmol). The mixture was stirred for 2.5 h, then quenched

K. Kaihara et al. / Tetrahedron 68 (2012) 106e113
111
with saturated NH4Cl, and extracted with hexane (ꢂ3). The com-
bined organic layers were dried over anhydrous MgSO4 and fil-
tered. The filtrate was concentrated under reduced pressure. The
residue was purified by flash column chromatography on silica gel
(elution with hexane/AcOEt¼30/1) to give 18g (113.0 mg, 99%) as
colorless oil. Rf 0.64 (hexane/AcOEt 5/1); FTIR (neat) 3311, 2937,
2345, 2318, 2121, 1461, 1381, 1365, 1309, 1248, 1213, 1188, 1147,
warmed to room temperature for 26 h, quenched with H2O
(50 mL), and extracted with AcOEt (ꢂ3). The combined organic
layers were dried over anhydrous MgSO4 and filtered. The filtrate
was concentrated under reduced pressure. The residue was purified
by flash column chromatography on silica gel (gradient elution with
hexane/AcOEt¼1/0 to 4/1) to give (2Z,7R)-tosylate 25 (15.6 g, 98%)
as yellow oil. Rf 0.24 (hexane/Et2O 4/1); ½a D24
þ2.0 (c 1.79, CHCl3);
ꢄ
1080, 976, 889, 756 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
3.20 (d,
FTIR (neat) 2954, 2912, 1732, 1670, 1599, 1435, 1377, 1358, 1288,
J¼2.0 Hz, 1H), 3.17 (s, 3H), 2.37, 2.36 (each d, J¼2.0 Hz, 1H),
1.76e1.52 (m, 2H), 1.50e1.39 (m, 6H), 1.43, 1.33 (each s, 3H),
1.36e1.21 (m, 3H), 1.19e1.03 (m, 2H), 1.13 (s, 6H), 0.88, 0.86 (each
1207, 1173, 1092, 1024, 928, 904 cmꢀ1 1H NMR (400 MHz, CDCl3)
;
d
7.90 (d, J¼8.2 Hz, 2H), 7.36 (d, J¼8.2 Hz, 2H), 5.53 (s, 1H),
5.09e5.05 (m, 1H), 3.59 (s, 3H), 2.46 (s, 3H), 2.37e2.35 (m, 2H),
1.96e1.88 (m, 2H), 1.68 (s, 3H), 1.59 (s, 3H), 1.56e1.43 (m, 2H),
1.36e1.31 (m, 1H), 1.31e1.21 (m, 2H), 1.14e1.05 (m, 2H), 0.83 (d,
d, J¼6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 79.7, 79.6, 74.6, 73.5,
73.4, 62.8, 51.3, 50.4, 49.0, 40.1, 37.5, 37.5, 37.4, 37.3, 37.0, 36.8, 34.4,
34.3, 32.7, 32.7, 32.6, 24.9, 22.6, 22.5, 21.2, 21.2, 20.6, 19.6, 19.6,
19.5, 17.9; HRMS (CI) m/z [MþH]þ calcd for [C17H30O2þH]þ
267.2324, found 267.2323.
J¼6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 163.0, 159.9, 145.1,
133.3, 130.7, 129.4, 128.0, 124.5, 109.7, 51.0, 36.6, 35.6, 35.1, 31.7,
25.4, 25.2, 23.5, 21.3, 19.0, 17.3; HRMS (CI) m/z [MþH]þ calcd for
[C22H32O5þH]þ 409.2049, found 409.2054.
4.2.8. Analog 19. Ketone 22 was reduced with NaBH4 to give the
known alcohol.30 N2CHCO2Et (105
mL, 1.0 mmol) was added drop-
4.2.11. (2Z,7S)-Tosylate 25. According to the same procedure de-
scribed above, the titled compound was synthesized from (ꢀ)-23.
Analytical data of (2Z,7S)-tosylate 25 were identical with those of
wise to a solution of this alcohol (23 mg, 0.10 mmol) and Rh2(OAc)4
(6.6 mg, 0.015 mmol) in CHCl3 (2 mL) for 5 min at room tempera-
ture. The mixture was stirred for 1 h, diluted with Et2O, and washed
with 10% HCl (ꢂ2) and H2O (ꢂ1). The combined organic layers were
dried over anhydrous MgSO4 and filtered. The filtrate was con-
centrated under reduced pressure. The residue was purified by
flash column chromatography on silica gel (elution with hexane/
AcOEt¼35/1, 30/1 then 20/1) to give 19 (31.0 mg, 98%) as colorless
oil. Rf 0.93 (hexane/AcOEt 3/1); FTIR (neat) 3379, 2937, 1757, 1608,
a 24
(2Z,7R)-tosylate 25 except for the sign of optical rotation: ½ ꢄD ꢀ1.8
(c 1.65, CHCl3).
4.2.12. (2E,7R)-Ester 26. To a suspension of PdCl2(PPh3)2 (420 mg,
0.6 mmol) in THF (20 mL) was added (2Z,7R)-tosylate 25 (2.46 g,
6.0 mmol) in THF (30 mL) at 0 ꢁC under argon. Me2Zn (12.0 mmol in
Et2O) was added dropwise to the mixture. The mixture was
warmed to room temperature, stirred for 45 min, quenched by
saturated NH4Cl, and extracted with Et2O (ꢂ3). The combined or-
ganic layers were dried over anhydrous MgSO4 and filtered. The
filtrate was concentrated under reduced pressure. The residue was
purified by flash column chromatography on silica gel (elution with
hexane/AcOEt¼45/1) to give (2E,7R)-ester 26 (1.50 g, 99%) as pale
1462, 1381, 1213, 1130, 768 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 4.21
(q, J¼7.2 Hz, 2H), 4.07, 4.06 (each s, 2H), 3.48 (sextet, J¼6.0 Hz, 1H),
3.16 (s, 3H), 1.63e1.54 (m, 2H), 1.47e1.32 (m, 4H), 1.30e1.19 (m, 4H),
1.28 (t, J¼7.2 Hz, 3H), 1.16 (d, J¼6.0 Hz, 3H), 1.14e1.06 (m, 3H), 1.13
(s, 6H), 0.85 (d, J¼6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 171.0,
74.7, 66.2, 60.8, 49.1, 40.2, 37.7, 37.7, 37.2, 36.8, 36.7, 32.8, 25.1, 23.0,
23.0, 21.4,19.7, 19.7,19.4,19.3,14.3; HRMS (CI) m/z [MþH]þ calcd for
[C18H36O4þH]þ 317.2692, found 317.2695.
yellow oil. Rf 0.80 (hexane/AcOEt 5/1); ½a D28
þ4.3 (c 2.40, CHCl3);
ꢄ
FTIR (neat) 2914, 1720, 1649, 1435, 1377, 1358, 1223, 1147,
1039 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
5.66 (dd, J¼2.4, 1.2 Hz, 1H),
4.2.9. Analog 20. According to the literature, 6,10-dimethyl-2-
undecanone31 was prepared from 7. To a solution of this ketone
(958 mg, 4.8 mmol) in t-BuOH (10 mL) and THF (1 mL) was added
t-BuOK (808 mg, 7.2 mmol). The mixture was stirred for 30 min,
5.11e5.07 (m, 1H), 3.68 (s, 3H), 2.15 (d, J¼1.2 Hz, 3H), 2.11 (t,
J¼7.6 Hz, 2H), 2.00e1.91 (m, 2H), 1.68 (d, J¼1.2 Hz, 3H), 1.60 (s, 3H),
1.53e1.39 (m, 3H), 1.36e1.25 (m, 2H), 1.18e1.08 (m, 2H), 0.87 (d,
J¼6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 167.3, 160.7, 131.1, 124.9,
then added methyl chloroacetate (470
mL, 5.3 mmol). The mixture
115.0, 50.7, 41.2, 37.0, 36.4, 32.2, 25.7, 25.5, 24.8, 19.5, 18.7, 17.6;
HRMS (CI) m/z [MþH]þ calcd for [C16H28O2þH]þ 253.2167, found
253.2170.
was stirred for 23 h, quenched by saturated NH4Cl, and extracted
with hexane/AcOEt (1/1). The combined organic layers were
washed with brine, dried over anhydrous MgSO4, and filtrated. The
filtrate was concentrated under reduced pressure. The residue was
purified by flash column chromatography on silica gel (elution with
hexane/AcOEt¼65/1) to give 20 (544 mg, 66%, based on recovered
starting material) as pale yellow oil. Rf 0.70 (hexane/AcOEt 7/1);
FTIR (neat) 2954, 2927, 2868, 1759, 1462, 1439, 1410, 1385, 1290,
4.2.13. (2E,7S)-Ester 26. According to the procedure described
above, (2E,7S)-ester 26 was synthesized from (2Z,7S)-25. Analytical
data of (2E,7S)-ester 26 were identical with those of (2E,7R)-ester
26 except for the sign of optical rotation: ½a D28
ꢀ3.9 (c 2.32, CHCl3).
ꢄ
1201, 1030, 914, 739 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
3.79, 3.78
4.2.14. (7R)-Allyl alcohol 27. To a solution of (2E,7R)-ester 26 (1.4 g,
5.55 mmol) in toluene (19 mL) was added dropwise DIBAL-H
(16.4 mL, 1.02 M in hexane solution, 16.7 mmol) at ꢀ78 ꢁC under
argon. The mixture was stirred for 10 min, quenched by MeOH at
ꢀ78 ꢁC, and warmed to room temperature. 1 N HCl (50 mL) was
added to the mixture. The mixture was extracted with Et2O (ꢂ3).
The combined organic layers were dried over anhydrous MgSO4
and filtered. The filtrate was concentrated under reduced pressure.
The residue was purified by flash column chromatography on silica
gel (elution with hexane/AcOEt¼30/1, then 15/1) to give (7R)-27
(each s, 3H), 3.34, 3.33 (each s, 1H), 1.71e1.48 (m, 4H), 1.47e1.35 (m,
2H), 1.40, 1.35 (each s, 3H), 1.32e1.19 (m, 4H), 1.16e1.03 (m, 4H),
0.86 (d, J¼6.4 Hz, 9H); 13C NMR (100 MHz, CDCl3)
d 168.5, 168.4,
62.4, 62.1, 58.9, 58.0, 51.5, 38.9, 37.7, 36.8, 36.8, 36.7, 36.6, 36.5,
36.4, 36.4, 32.4, 32.3, 32.2, 32.1, 32.0, 31.9, 31.2, 27.6, 27.5, 24.4, 22.8,
22.5, 22.3, 22.2, 22.2, 22.1, 22.1, 21.1, 19.2, 19.0, 15.7, 15.6, 13.7; HRMS
(CI) m/z [MþH]þ calcd for [C16H30O3þH]þ 271.2273, found
271.2265.
4.2.10. (2Z,7R)-Tosylate 25. To
a
suspension of LiCl (8.31 g,
-keto
(1.23 g, 98%) as colorless oil. Rf 0.24 (hexane/AcOEt 7/1); ½a D28
þ2.5
ꢄ
194 mmol) in toluene (30 mL) were added a solution of (7R)-
b
(c 2.10, CHCl3); FTIR (neat) 3338, 2925, 1668, 1452, 1378, 1232, 1178,
ester 2422 (9.86 g, 38.8 mmol) in toluene (60 mL), a solution of p-
toluenesulfonyl chloride (11.0 g, 58.1 mmol) in toluene (60 mL),
NMI (4.6 mL, 58.1 mmol), and Et3N (8.1 mL, 58.1 mmol) at 0 ꢁC
under argon, successively. The mixture was stirred at 0 ꢁC for 1 h,
1082,1003 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
5.41 (td, J¼6.8,1.2 Hz,
1H), 5.11e5.08 (m, 1H), 4.15 (d, J¼6.8 Hz, 2H), 1.99 (t, J¼7.4 Hz, 2H),
2.01e1.90 (m, 2H), 1.68 (s, 3H), 1.67 (s, 3H), 1.60 (s, 3H), 1.50e1.23
(m, 6H), 1.17e1.04 (m, 2H), 0.86 (d, J¼6.4 Hz, 3H); 13C NMR

112
K. Kaihara et al. / Tetrahedron 68 (2012) 106e113
(100 MHz, CDCl3)
d
140.2, 131.1, 125.0, 123.1, 59.4, 39.8, 37.1, 36.6,
mixture was stirred for 1.5 h, diluted with Et2O (50 mL), and
washed with saturated CuSO4 (ꢂ3) and H2O (ꢂ2). The combined
organic layers were dried over anhydrous MgSO4 and filtered.
The filtrate was concentrated under reduced pressure. The resi-
due was purified by flash column chromatography on silica gel
(gradient elution with hexane/AcOEt¼99/1 to 99/5) to give
(2R,3S,7R)-29 (0.98 g, 99%) as colorless oil. Rf 0.83 (hexane/AcOEt
32.3, 25.7, 25.6, 25.1, 19.6, 17.6, 16.2; HRMS (CI) m/z [M]þ calcd for
[C15H28O]þ 224.2140, found 224.2146.
4.2.15. (7S)-Allyl alcohol 27. According to the procedure described
above, (7S)-27 was synthesized from (2E,7S)-26. Analytical data of
(7S)-27 was identical with those of (7R)-27 except for the sign of
optical rotation: ½a D28
ꢄ
ꢀ2.3 (c 2.04, CHCl3).
5/1); ½a 2D8
þ28.4 (c 2.32, CHCl3); FTIR (neat) 3429, 2912, 2860,
ꢄ
2727, 1722, 1454, 1381, 1238, 1103, 1072, 984, 947, 914, 798,
4.2.16. (2S,3S,7R)-Epoxy alcohol 28. To a suspension of
L
-(þ)-di-
isopropyl tartrate and powdered molecular sieves 3 A (540 mg) in
CH2Cl2 (5.5 mL) was added Ti(Oi-Pr)4 (785 L, 2.68 mmol, distilled)
756 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
9.47 (d, J¼5.2 Hz, 1H),
ꢀ
5.11e5.07 (m, 1H), 3.17 (d, J¼5.2 Hz, 1H), 2.04e1.88 (m, 2H), 1.68
(s, 3H), 1.66e1.60 (m, 1H), 1.60 (s, 3H), 1.57e1.48 (m, 1H),
1.48e1.26 (m, 5H), 1.44 (s, 3H), 1.18e1.09 (m, 2H), 0.87 (d,
m
at ꢀ20 ꢁC. TBHP (1.5 mL, 8.0 mmol, 5.5 M in decane) was added to
the mixture at ꢀ50 ꢁC. The mixture was stirred for 30 min. (7R)-
Allyl alcohol 27 (1.20 g, 5.35 mmol) was added to the mixture. The
mixture was stirred for 2 h at ꢀ50 ꢁC and quenched with 10%
aqueous tartaric acid solution (25 mL). The mixture was warmed to
room temperature, stirred for 1 h, and extracted with CH2Cl2 (ꢂ4).
The combined organic layers were washed with H2O, dried over
anhydrous MgSO4, and filtered. The filtrate was concentrated under
reduced pressure. Aqueous 10% NaOH (30 mL) was added to a so-
lution of the residue in Et2O (50 mL). The mixture was stirred for
30 min at 0 ꢁC and extracted with Et2O (ꢂ3). The organic layers
were dried over anhydrous MgSO4 and filtered. The filtrate was
concentrated under reduced pressure. The residue was purified by
flash column chromatography on silica gel (elution with hexane/
AcOEt¼20/1, 10/1 then 6/1) to give (2S,3S,7R)-28 (1.22 g, 95%) as
J¼6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 199.5, 130.9, 124.7,
64.2, 63.4, 38.5, 36.8, 36.5, 32.2, 25.6, 25.4, 22.2, 19.3, 17.5, 17.0;
HRMS (CI) m/z [MþH]þ calcd for [C15H26O2þH]þ 239.2007, found
239.2011.
4.2.19. (2R,3S,7S)-Epoxy aldehyde 29. According to the procedure
described above, (7S)-29 was synthesized from (7S)-28. Rf 0.83
(hexane/AcOEt 5/1); ½a D28
ꢄ
þ60.7 (c 2.29, CHCl3); FTIR (neat) 2922,
2862, 1724, 1460, 1408, 1383, 1240, 1105, 1072, 802, 760 cmꢀ1
;
1H
NMR (400 MHz, CDCl3)
d
9.47 (d, J¼5.2 Hz, 1H), 5.09 (br t, J¼6.8 Hz,
1H), 3.17 (d, J¼5.2 Hz, 1H), 2.04e1.88 (m, 2H), 1.68 (s, 3H), 1.66e1.60
(m, 1H), 1.60 (s, 3H), 1.54e1.47 (m, 1H), 1.48 (m, 5H), 1.44 (s, 3H),
1.18e1.07 (m, 2H), 0.87 (d, J¼6.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3)
d 199.6, 131.1, 124.7, 64.3, 63.5, 38.5, 36.9, 36.6, 32.2, 25.6,
colorless oil. Rf 0.36 (hexane/AcOEt 2/1); ½a D28
ꢄ
ꢀ4.1 (c 1.88, CHCl3);
25.4, 22.2, 19.4, 17.6, 17.1; HRMS (CI) m/z [MþH]þ calcd for
FTIR (neat) 3431, 2914, 2729, 1454, 1379, 1230, 1030, 953, 912, 868,
[C15H26O2þH]þ 239.2011, found 239.2015.
756 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 5.11e5.07 (m, 1H), 3.84 (dd,
J¼11.2, 4.4 Hz, 1H), 3.70 (dd, J¼11.2, 6.8 Hz, 1H), 2.96 (dd, J¼6.8,
4.4 Hz, 1H), 2.04e1.89 (m, 2H), 1.68 (d, J¼1.2 Hz, 3H), 1.62e1.57 (m,
2H), 1.60 (s, 3H), 1.47e1.36 (m, 3H), 1.34e1.24 (m, 3H), 1.29 (s, 3H),
1.17e1.07 (m, 2H), 0.87 (d, J¼6.4 Hz, 3H); 13C NMR (100 MHz,
4.2.20. (2R,3S,7R)-Epoxy ester 30. To a solution of (2R,3S,7R)-
epoxy aldehyde 29 (950 mg, 3.99 mmol) in t-BuOH/H2O (5/1,
80 mL) were added 2-methyl-2-butene (3.5 mL, 32.0 mmol) and
NaH2PO4$2H2O (1.87 g, 12.0 mmol) at 0 ꢁC. The mixture was
stirred for 30 min and then 80% NaClO2 (545 mg, 4.8 mmol) was
added. The mixture was warmed to room temperature, stirred
for 1.5 h, and extracted with Et2O (ꢂ4). The combined organic
layers were washed with brine (ꢂ2), dried over anhydrous
MgSO4, and filtered. The filtrate was concentrated under reduced
pressure to give the corresponding carboxylic acid. The crude
carboxylic acid was subjected to the next step without further
purification.
CDCl3,)
d 130.9, 124.8, 63.1, 61.4, 61.3, 38.7, 36.9, 36.8, 32.3, 25.6,
25.4, 22.4, 19.4, 17.5, 16.6; HRMS (CI) m/z [MþH]þ calcd for
[C15H28O2þH]þ 241.2167, found 241.2172.
The diastereomeric ratio of (2S,3S,7R)-epoxy alcohol 28 was
determined by Mosher ester. (þ)-MTPACl (32
added to a solution of (2S,3S,7R)-epoxy alcohol 28 (10.0 mg,
0.042 mmol), DMAP (5.0 mg, 0.042 mmol), and Et3N (90 L,
0.63 mmol) in CH2Cl2 (110
L) at 0 ꢁC. The mixture was stirred for
mL, 0.168 mmol) was
m
m
4 h and diluted with hexane. The mixture was directly subjected to
flash column chromatography on silica gel and purified (elution
with hexane/AcOEt¼30/1) to give the corresponding MTPA ester of
(2S,3S,7R)-28. The diastereomeric ratio was analyzed by 1H NMR
analysis to be 95:5.
To a solution of the crude carboxylic acid in Et2O (10 mL) was
added a solution of diazomethane in Et2O generated from N-
nitrosourea in 40% KOH/Et2O at 0 ꢁC until a slightly excess amount
of diazomethane (pale yellow) remained in the solution. The
mixture was stirred for 30 min and concentrated under reduced
pressure. The residue was purified by flash column chromatogra-
phy on silica gel (elution with hexane/AcOEt¼35/1, 32.5/1 then 30/
1) to give (2R,3S,7R)-30 (630.7 mg, 2.63 mmol, 66%, two steps) as
4.2.17. (2S,3S,7S)-Epoxy alcohol 28. According to the procedure
described above, (7S)-28 was synthesized from (7S)-27. Rf 0.36
(hexane/AcOEt 2/1); ½a D28
ꢄ
ꢀ11.4 (c 2.86, CHCl3); FTIR (neat) 3412,
colorless oil. Rf 0.57 (hexane/AcOEt 7/1); ½a D23
ꢀ23.0 (c 1.08, CHCl3);
ꢄ
2925, 2862, 1460, 1381, 1228, 1032, 955, 910, 866, 737 cmꢀ1
;
1H
FTIR (neat) 2914, 2731, 1757, 1439, 1406, 1383, 1288, 1201, 1115,
NMR (400 MHz, CDCl3)
d
5.11e5.07 (m,1H), 3.84 (dd, J¼12.0, 4.4 Hz,
1072, 1028, 928, 864, 825, 754 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
1H), 3.69 (dd, J¼12.0, 6.8 Hz, 1H), 2.96 (dd, J¼6.8, 4.4 Hz, 1H),
2.04e1.88 (m, 2H), 1.68 (s, 3H), 1.65e1.60 (m, 3H), 1.60 (s, 3H),
1.45e1.36 (m, 3H), 1.34e1.25 (m, 2H), 1.29 (s, 3H),1.18e1.07 (m, 2H),
d
5.11e5.07 (m, 1H), 3.79 (s, 3H), 3.34 (s, 1H), 2.00e1.92 (m, 2H),
1.68 (d, J¼1.2 Hz, 3H), 1.66e1.60 (m, 1H), 1.60 (s, 3H), 1.58e1.52 (m,
1H), 1.50e1.27 (m, 5H), 1.35 (s, 3H), 1.18e1.09 (m, 2H), 0.87 (d,
0.87 (d, J¼6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3,)
d
130.7, 124.7,
J¼6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 168.8, 130.7, 124.6, 62.5,
63.1, 61.1, 61.0, 38.6, 36.8, 36.7, 32.1, 25.5, 25.3, 22.2, 19.2, 17.4, 16.5;
HRMS (CI) m/z [MþH]þ calcd for [C15H28O2þH]þ 241.2168, found
241.2171. The diastereomeric ratio was determined by the Mosher
method to be 94:6.
58.3, 51.9, 37.8, 36.8, 36.4, 32.1, 25.5, 25.3, 22.2, 19.3, 17.4, 15.9;
HRMS (CI) m/z [MþH]þ calcd for [C16H28O3þH]þ 269.2119, found
269.2117.
4.2.21. (2R,3S,7S)-Epoxy ester 30. According to the procedure de-
scribed above, (7S)-30 was synthesized from (7S)-29. Rf 0.57
4.2.18. (2R,3S,7R)-Epoxy aldehyde 29. To a mixture of (2S,3S,7R)-
28 (1.0 g, 4.16 mmol) in CH2Cl2 (40 mL) and DMSO (3 mL,
41.6 mmol) were added i-Pr2NEt (3.6 mL, 20.8 mmol) and pyri-
dine sulfate (2.64 g, 16.6 mmol) in several portions at 0 ꢁC. The
(hexane/AcOEt 7/1); ½a D23
ꢀ34.0 (c 1.47, CHCl3); FTIR (neat) 2925,
ꢄ
2731, 1759, 1439, 1408, 1383, 1288, 1201, 1119, 1076, 1030, 928, 864,
827, 756 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d 5.11e5.07 (m, 1H), 3.79

K. Kaihara et al. / Tetrahedron 68 (2012) 106e113
113
(s, 3H), 3.24 (s, 1H), 2.04e1.88 (m, 2H), 1.68 (s, 3H), 1.67e1.63 (m,
1H), 1.60 (s, 3H), 1.54e1.46 (m, 1H), 1.44e1.38 (m, 3H), 1.35 (s, 3H),
1.36e1.28 (m, 2H), 1.17e1.09 (m, 2H), 0.87 (d, J¼6.4 Hz, 3H); 13C
HRMS (FAB) m/z [MþH]þ calcd for [C17H32O4þH]þ 301.2379, found
301.2387.
NMR(100 MHz, CDCl3)
d 168.7, 130.7, 124.6, 62.4, 58.2, 51.8, 37.8,
Acknowledgements
36.7, 36.4, 32.0, 25.4, 25.3, 22.2, 19.2, 17.3, 15.9; HRMS (CI) m/z
[MþH]þ calcd for [C16H28O3þH]þ 269.2117, found 269.2115.
This study was supported by Grants-in-Aid (Nos. 20380038 and
23108523) for Scientific Research from the Japan Society for the
Promotion of Science (JSPS) and the Ministry of Education, Culture,
Sports, Science, and Technology, Japan, and A-STEP, Exploratory
Research (No. AS231Z03024E) from the Japan Science and Tech-
nology Agency (JST).
4.2.22. Analog 21a. To a stirred solution of (2R,3S,7R)-30 (100 mg,
0.373 mmol) in CH2Cl2 was added m-chloroperbenzoic acid (ca.
70%, 97 mg, 0.56 mmol) at 0e5 ꢁC. The mixture was stirred for 2.5 h
and then washed with 5% aqueous NH3 solution (ꢂ3). The com-
bined organic layers were dried over anhydrous MgSO4 and filtered.
The filtrate was concentrated under reduced pressure. The residue
was purified by flash column chromatography on silica gel (elution
with hexane/AcOEt¼30/1 then 15/1) to give 21a (103.2 mg, 97%) as
colorless oil. Rf 0.21 (hexane/AcOEt 7/1); FTIR (neat) 2956, 2870,
1755,1460,1439,1408,1381, 1290,1250,1201,1120, 1082, 1028, 864,
References and notes
1. The Juvenile Hormone; Gilbert, L. I., Ed.; Plenum: New York, NY, 1976.
2. Insect Juvenile Hormones, Chemistry and Action; Menn, J. J., Beroza, M., Eds.;
Academic: New York, NY, 1972.
756 cmꢀ1 1H NMR (300 MHz, CDCl3)
; d 3.79 (s, 3H), 3.34 (s, 1H),
3. Menn, J. J.; Pallow, F. M. Environ. Lett. 1975, 8, 71e88.
4. Goodman, W. G.; Granger, N. A. In Comprehensive Molecular Insect Science; Gil-
bert, L. I., Iatrou, K., Gill, S. S., Eds.; Elsevier: Oxford, 2005; Vol. 3, pp 319e408.
5. Morgan, E. D.; Wilson, I. D.; Mori, K. Comprehensive Natural Products Chemistry;
Barton, D. H. R., Nakanishi, K., Eds. Miscellaneous Natural Products Including
Marine Natural Products, Pheromones, Plant Hormones, and Aspects of Ecol-
ogy; Pergamon: Oxford, 1999; Vol. 8, pp 263e369.
6. Riddiford, L. M. J. Insect Physiol. 2008, 54, 895e901.
7. Davey, K. J. Insect Physiol. 2007, 53, 208e215.
8. Wigglesworth, V. B. In Comprehensive Insect Physiology, Biochemistry and Phar-
macology; Kerkut, G. A., Gilbert, L. I., Eds.; Pergamon:Oxford,1985;Vol. 7, pp1e24.
9. Wigglesworth, V. B. Q. J. Microsc. Sci. 1934, 77, 191e222.
2.69 (t, J¼8.0 Hz, 1H), 1.72e1.60 (m, 1H), 1.58e1.24 (m, 8H), 1.35 (s,
3H), 1.31 (s, 3H), 1.26 (s, 3H), 1.22e1.10 (m, 2H), 0.90 (d, J¼8.4 Hz,
3H); 13C NMR (100 MHz, CDCl3)
d 168.9, 64.5, 64.4, 62.6, 58.4, 58.4,
58.1, 58.0, 52.0, 37.8, 36.5, 36.3, 33.4, 33.3, 32.5, 32.4, 26.4, 26.2,
24.8, 22.3, 22.2, 19.3, 19.3, 18.6, 18.5, 16.0, 16.0; LRMS (CI) m/z 285
[MþH]þ, 267, 235, 197.
4.2.23. Analog 21b. According to the procedure described above,
21b was synthesized from (7S)-30. Rf 0.21 (hexane/AcOEt 7/1); FTIR
(neat) 2954, 2870, 1757, 1460, 1441, 1408, 1383, 1290, 1250, 1203,
10. Williams, C. M. Nature 1956, 178, 212e213.
€
11. Roller, H.; Dahm, K. H.; Sweely, C. C.; Trost, B. M. Angew. Chem., Int. Ed. Engl.
1967, 6, 179e180.
12. Kotaki, T. J. Insect Physiol. 1996, 42, 279e286.
13. Kotaki, T.; Shinada, T.; Kaihara, K.; Ohfune, Y.; Numata, H. Org. Lett. 2009, 11,
1122, 1080, 1030, 866, 756 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d 3.79
(s, 3H), 3.33 (s, 1H), 2.69 (t, J¼8.0 Hz, 1H), 1.72e1.29 (m, 9H), 1.35 (s,
5234e5237.
3H), 1.31 (s, 3H), 1.26 (s, 3H), 1.22e1.08 (m, 2H), 0.90 (d, J¼8.4 Hz,
14. Kotaki, T.; Shinada, T.; Kaihara, K.; Ohfune, Y.; Numata, H. J. Insect Physiol. 2011,
57, 147e152.
3H); 13C NMR (100 MHz, CDCl3)
d 169.0, 64.6, 64.5, 62.7, 58.4, 58.2,
58.1, 52.1, 37.9, 37.9, 36.6, 36.4, 33.4, 33.4, 32.5, 32.5, 26.4, 26.3, 24.8,
22.3, 22.3, 19.4, 19.3, 18.6, 18.6, 16.1, 16.1; LRMS (CI) m/z 285
[MþH]þ, 267, 235, 197.
15. Heteroptera of Economic Importance; Schaefer, C. W., Panizzi, A. R., Eds.; CRC:
Boca Raton, 2000.
16. Baker, B. A.; Boskovic, Z. V.; Lipshutz, B. H. Org. Lett. 2008, 10, 289e292. Al-
ternatively, 22 was prepared by the aldol condensation reaction of acetone and
aldehyde 15 in the presence of proline followed by the reduction of the re-
sulting double bond.
17. Shinada, T.; Hamada, M.; Miyoshi, K.; Higashino, M.; Umezawa, T.; Ohfune, Y.
Synlett 2010, 2141e2145.
18. Molander, G. A.; Losada, C. P. J. Org. Chem. 1997, 62, 2935e2943.
19. Verkruijsse, H. D.; Brandsma, L. Synth. Commun. 1990, 20, 3375e3378.
20. (a) Chemla, F.; Bernard, N.; Ferreira, F.; Normant, J. F. Eur. J. Org. Chem. 2001,
3295e3300; (b) Baker, J. R.; Thominet, O.; Britton, H.; Caddick, S. Org. Lett. 2007,
45e48.
21. Belani, J. D.; Rychnovsky, S. D. J. Org. Chem. 2008, 73, 2768e2773.
22. Taber, D. F.; Krewson, K. R.; Raman, K.; Rheingold, A. L. Tetrahedron Lett. 1984,
25, 5283e5286.
23. Jin, Y.; Roberts, G. F.; Coates, M. R. Org. Synth. 2007, 84, 43e57.
24. Nishikado, H.; Nakatsuji, H.; Ueno, K.; Nagase, R.; Tanabe, Y. Synlett 2010,
2087e2092.
4.2.24. (2R,3S,7S)-18a. To
a stirred solution of (2R,3S,7R)-30
(50 mg, 0.186 mmol) in dry MeOH (1 mL) at room temperature was
added Hg(OAc)2 (61.2 mg, 0.192 mmol). The reaction was moni-
tored by 1H NMR. The mixture was stirred for 1 h and cooled to 0 ꢁC.
10% NaOH aqueous (0.2 mL) and NaBH4 (4.9 mg, 0.13 mmol) were
added to the mixture. The color of the reaction mixture instantly
changed to gray suspension from yellow suspension. The slurry was
filtered. The filtrate was diluted with brine. The mixture was
extracted with Et2O (ꢂ3). The combined organic layers were dried
over anhydrous MgSO4 and filtered. The filtrate was concentrated
under reduced pressure. The residue was purified by flush column
chromatography on silica gel (elution with hexane/AcOEt¼30/1 to
15/1) to give (2R,3S,7S)-18a (40.0 mg, 72%) as colorless oil. Rf 0.31
25. Nakatsuji, H.; Nishikado, H.; Ueno, K.; Tanabe, Y. Org. Lett. 2009, 11, 4258e4261.
26. Other reaction conditions resulted in low yields with moderate stereo-
selectivities: MeMgBr, PdCl2(PPh3)2 (no reaction); Me2Zn, NiBr2(PPh3)2 (92%
yield, E/Z¼6/4); Me2CuLi,23 (90%, E/Z¼4/1).
(hexane/AcOEt 7/1); ½a D23
ꢀ23.1 (c 3.70, CHCl3); FTIR (neat) 2938,
ꢄ
27. The diastereomeric ratio was determined by NMR study of the corresponding
MTPA ester.
1758, 1736, 1460, 1439, 1407, 1381, 1364, 1288, 1251, 1200, 1082,
1031, 915, 865, 735 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 3.79 (s, 3H),
28. Seino, A.; Ogura, T.; Tsubota, T.; Shimomura, M.; Nakakura, T.; Tan, A.; Mita, K.;
Shinoda, T.; Nakagawa, Y.; Shiotsuki, T. Biosci. Biotechnol. Biochem. 2010, 74,
1421e1429.
29. Racemic citronellal was ca. 1/100 cheaper than (þ)- or (ꢀ)-citronellal.
30. Szykula, J.; Zabza, A. Liebigs Ann. Chem. 1987, 709e710.
31. Bluthe, N.; Gore, J.; Malacria, M. Tetrahedron 1986, 42, 1333e1344.
3.34 (s, 1H), 3.17 (s, 3H), 1.67e1.51 (m, 4H), 1.50e1.35 (m, 3H), 1.33
(s, 3H), 1.32e1.22 (m, 2H), 1.19e1.07 (m, 4H), 1.13 (s, 6H), 0.87 (d,
J¼6.4 Hz, 3H); 13C NMR (75 MHz, CDCl3,)
d 169.3, 74.5, 62.8, 58.5,
52.1, 49.0, 40.1, 38.0, 37.5, 36.7, 32.6, 24.9, 24.9, 22.4, 21.2, 19.5, 16.1;