Pheromone synthesis. Part 260: Synthesis of (±)-(anti-1,2-dimethyl-3-methylenecyclopentyl)acetaldehyde, the racemate of the female-produced sex pheromone of the pineapple mealybug (Dysmicoccus brevipes), and its syn-isomer

Article abstract of DOI:10.1016/j.tet.2016.08.072

(±)-(anti-1,2-Dimethyl-3-methylenecyclopentyl)acetaldehyde, the racemate of the female-produced sex pheromone of the pineapple mealybug, was synthesized in four different ways. Ireland–Claisen rearrangement or conjugate addition was employed for the const

Full text of DOI:10.1016/j.tet.2016.08.072

Tetrahedron 72 (2016) 6578e6588
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Pheromone synthesis. Part 260: Synthesis of (ꢀ)-(anti-1,2-dimethyl-
3-methylenecyclopentyl)acetaldehyde, the racemate of the
female-produced sex pheromone of the pineapple mealybug
q
(
Dysmicoccus brevipes), and its syn-isomer
Kenji Mori *
Photosensitive Materials Research Center, Toyo Gosei Co., Ltd, 4-2-1 Wakahagi, Inzai-shi, Chiba, 270-1609, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 July 2016
Received in revised form 23 August 2016
Accepted 24 August 2016
Available online 25 August 2016
(ꢀ)-(anti-1,2-Dimethyl-3-methylenecyclopentyl)acetaldehyde, the racemate of the female-produced sex
pheromone of the pineapple mealybug, was synthesized in four different ways. IrelandeClaisen re-
arrangement or conjugate addition was employed for the construction of the quaternary carbon center,
while ring-closing olefin metathesis or cationic cyclization was used for the construction of the five-
membered carbocycle.
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Dysmicoccus brevipes
IrelandeClaisen rearrangement
Monoterpene aldehyde
Pheromone
Ring-closing metathesis
1. Introduction
Recent studies by Millar and co-workers culminated in the
identifications of three monoterpenes A, B and C (Fig. 1) with
a five-membered carbocycle as the sex pheromones of the
mealybugs.2 In 2005, A was identified as the pheromone of the
3
obscure mealybug (Pseudococcus viburni). Then in 2007, the
pheromone of the grape mealybug (Pseudococcus maritimus) was
4
shown to be B. Finally in 2009, C was proved to be the pheromone
of the longtailed mealybug (Pseudococcus longispinus).5 Their
unique structures including stereochemistry were all confirmed
by syntheses.2
In Japan, Tabata et al. are working on the identification of the
female produced sex pheromone of the pineapple mealybug
Fig. 1. Structures of the mealybug pheromones. A: the obscure mealybug (Pseudo-
coccus viburni); B: the grape mealybug (Pseudococcus maritimus); C: the longtailed
mealybug (Pseudococcus longispinus); 1: the pineapple mealybug (Dysmicoccus bre-
vipes). The structures depicted for anti- and syn-1 show relative configuration.
[
Dysmicoccus brevipes (Cockerell), Homoptera: Pseudococcidae],
6
which is a pest infesting pineapples in Okinawa. Dr. Tabata asked
me to synthesize samples with the proposed structure 1 of the
pheromone (Tabata, J. personal communication). My synthesis
provided both (ꢀ)-anti- and syn-1. Their NMR and GCeMS com-
parisons with the natural pheromone as well as their bioassay
established the structure of the pheromone as anti-1, although its
7
q
absolute configuration still remains unknown.
For Part 259, see Ref. 1. This work was orally reported by K.M. as a part of his
lecture at International Chemical Ecology Conference 2016 (July 5, 2016) in Iguassu
Falls, Brazil.
This paper describes in detail the synthesis of (ꢀ)-anti- and syn-
1
as achieved by several different approaches.
*
Fax: þ81 3 3816 6889; e-mail address: kjk-mori@arion.ocn.ne.jp.
http://dx.doi.org/10.1016/j.tet.2016.08.072
0
040-4020/Ó 2016 Elsevier Ltd. All rights reserved.

K. Mori / Tetrahedron 72 (2016) 6578e6588
6579
2
2
. Results and discussion
first reported by J a€ ger and co-workers in their polycyclopentanoid
12
synthesis, and then Zou and Millar in their synthesis of the
13
.1. Retrosynthetic analyses of 1
pheromone C.
The rest of the present paper details the realization of these
three retrosynthetic analyses to achieve three different syntheses
of 1 as well as a formal synthesis of 1 via K.
Fig. 2 shows the retrosynthetic analyses of 1, all of which could
be realized later to give (ꢀ)-1. The most direct route to 1 is route (a),
making the ring first and then generating the quaternary carbon
8
center. Conjugate addition of allylsilane is employed as the key
2.2. First synthesis of the pheromone 1
step for conversion of the known E to 1 via D. This route was ex-
amined first, and gave both (ꢀ)-anti- and syn-1 used for the iden-
The first synthesis of 1 was accomplished as shown in Scheme 1.
7
tification of the natural pheromone.
Synthesis of the starting material, 2,3-dimethyl-2-cyclopenten-1-
14e18
one (2) have been reported repeatedly.
Polyphosphoric acid
(
PPA)-mediated cyclization of 4-methyl-4-hexenoic acid was most
12,14
reliable to give over 10 g of 2.
of 2-methyl-1,3-cyclopentanedione with Me
method to prepare 2. Isopropylmagnesium chloride-promoted
Methylation of the enol phosphate
CuLi was also a good
2
15
unilateral addition of MeMgBr to 2-methyl-1,3-cyclopentanedione
19
according to Yuan et al. afforded 2, but in a low yield of 14% af-
ter distillation.
Scheme 1. First synthesis of (ꢀ)-anti-1. Reagents: (a) CH
2
]CHCH
, NMO, t-BuOH, Me
O; then SiO chromatography
2
TMS, TiCl
4
, CH
2 2
Cl ,
2
O
ꢂ
ꢁ
78 to ꢁ30 C; then SiO
2
chromatography (12%); (b) OsO
4
2
CO,H
(
58%); (c) Tebbe reagent, toluene, THF; (d) NaIO
4
, THF, H
2
2
(
18%, two steps); (e) AgNO /SiO chromatography.
3
2
Conjugate addition of allyltrimethylsilane to 2 was achieved
8
according to Hosomi and Sakurai, employing TiCl
The desired allylated ketone 3 (diastereomer ratio¼ca. 1:1) was
obtained in 12% yield after SiO chromatography. Although the
4
as the catalyst.
2
yield was quite unsatisfactory, 3 could be obtained repeatedly,
confirming the reproducibility of the reaction. An attempt was
2
0
3
made to increase the yield by employing InCl as the catalyst,
Fig. 2. Retrosynthetic analyses of 1.
which unfortunately did not work at all. Additional unsuccessful
attempts were made to construct the quaternary carbon center by
means of copper(I)-catalyzed conjugate addition to 2 of allyl
Practical difficulties encountered in the course of the realization
of route (a) forced me to adopt route (b) as the more reliable one.
2
Grignard reagent in the presence of conventional CuI or CuBr/Me S,
LiCl and TMSCl. Conjugate addition of dimethyl malonate to 2 in
the presence of NaOMe in MeOH was not fruitful, either.
9
21
Ireland’s ester-enolate Claisen rearrangement and Grubbs’s ring-
10,11
closing olefin metathesis
serve as the two key reactions. The
five-membered ring is to be closed by olefin metathesis (G/F), and
the quaternary carbon center is to be constructed by Ire-
landeClaisen rearrangement (I/H/G). Ester J will give I in two
steps.
In future it will be necessary to prepare both the enantiomers of
anti-1 so as to determine the absolute configuration of the natural
pheromone. Route (c) can be used for that purpose, because the
resolution of N may be feasible to give the enantiomers of N. The
IrelandeClaisen rearrangement of acetate M via L gives K, which is
structurally equivalent to F in route (b). Accordingly, K can readily
be converted to 1. It must be mentioned that the construction of the
quaternary center in cyclopentanoids by means of route (c) was
Dihydroxylation of the allylated ketone 3 with OsO
4
and N-
2
2
methylmorpholine N-oxide (NMO) yielded dihydroxy ketone 4,
2
3
which was treated with excess Tebbe reagent to give methylen-
ated diol 5. Finally, cleavage of the glycol system of 5 with NaIO
afforded a crude oil (540 mg), which was purified by SiO chro-
4
2
matography to give 132 mg of 1 (44.4% GC purity) as a stereoiso-
meric mixture. The overall yield of 1 was 0.6% based on 2 (four
steps).
3 2
The mixture could be further purified by AgNO /SiO chroma-
2
4
tography to separate (ꢀ)-anti-1 from its syn-isomer. After the
1
separation, the H NMR spectra of the two isomers were compared,
and the relative configuration of the two methyl groups was

6580
K. Mori / Tetrahedron 72 (2016) 6578e6588
studied by NOESY to find out NOE in the case of the later eluting
isomer. Accordingly, the later eluting one must be (ꢀ)-syn-1, while
facile enolization rendered conventional methylenation with
Ph P]CH impractical. Accordingly, attempts were made to em-
3
2
the earlier eluting one was (ꢀ)-anti-1. The retention time (t
R
) of
ploy Ando’s new olefination reagent [1-methyl-2-(methyl-
1
25
(
ꢀ)-anti-1 was identical to that of the natural pheromone. The H,
sulfonyl)benzimidazole (14)] for the methylenation.
1
3
C NMR and MS spectra of (ꢀ)-anti- and (ꢀ)-syn-1 were different
from each other (see 4.6), and the spectra of (ꢀ)-anti-1 was iden-
tical to those of the natural pheromone. The structure and the
relative configuration of the natural pheromone was therefore
determined as anti-1.
Field bioassay of the synthetic (ꢀ)-anti- and (ꢀ)-syn-1 as well as
their mixture was carried out by Dr. J. Tabata at National Agriculture
and Food Research Organization, Japan. The racemic anti-1 was
bioactive as the pheromone of D. brevipes, while syn-1 was devoid
of bioactivity. Fortunately, syn-1 did not inhibit the pheromone
7
activity of (ꢀ)-anti-1. Therefore, a stereoisomeric mixture 1 of the
two isomers can be used sufficiently for the practical purpose of
population monitoring or communication disruption.
2
.3. Construction of the quaternary carbon center by means
of IrelandeClaisen rearrangement
Since it was difficult to improve the miserable 10e12% yield of
the conjugate allylation step (2/3, Scheme 1), efforts were made
to employ IrelandeClaisen rearrangement for the construction of
the quaternary carbon center (Scheme 2).
Scheme 3. Second synthesis of (ꢀ)-1. Reagents: (a) Grubbs II (0.3 mol %), CH
flux, 2 h (76%); (b) BH $SMe , Et O; then Jones CrO , Me CO (47%); (c) 14, NaHMDS,
DMF (27%; 51% based on the consumed 13); (d) LiAlH , Et O (quant.); (e) NaOCl$5H O,
Bu NHSO4, azadol, H O, CH Cl (63% after distillation); (f) 3,5-dinitrobenzoyl chloride,
DMAP, C N; then recrystallization from EtOAc/hexane.
2
Cl2, re-
3
2
2
3
2
4
2
2
4
2
2
2
Scheme 2. Synthesis of 11. Reagents: (a) (EtO)
LiAlH , Et O; (c) Ac O, DMAP, C N (94%, two steps); (d) LiN(i-Pr)
at 70 C, 4 h; MeOH; then dil HCl (86%); (e) K CO , MeI, DMF (66%).
2
P(O)CHMeCO
2
Et, NaH, THF (95%); (b)
5 5
H
4
ꢂ
2
2
H
5 5
2
, TMSCl, THF; heat
2
3
When sodium hexamethyldisilazide (NaHMDS) was added to
a solution of 13 and 14 in DMF, the desired 15 was obtained. The
yield, however, was only 27% (or 51% based on the consumed 13)
with a substantial amount of the recovered 13, reflecting the large
extent of enolization prior to the nucleophilic addition of the anion
derived from 14. When t-BuOK was used as the base instead of
The required substrate 9 for the rearrangement was synthesized
from commercially available 5-hexen-2-one (6). Treatment of 6
with triethyl 2-phosphonopropanoate and NaH in THF furnished 7
as an E/Z mixture. The dienoic ester 7 was reduced with LiAlH
give 8, which was acetylated to afford 9. The acetate 9 was treated
with LiN(i-Pr) and TMSCl to give TMS-enolate (H in Fig. 2), which
4
to
2
5
2
NaHMDS, the product (28% yield) was not 15 but the corre-
sponding tert-butyl ester generated by the nucleophilic attack of t-
ꢂ
9
was heated at 70 C for 4 h to effect the rearrangement. The TMS
ꢁ
group was removed by methanolysis, and the resulting acid 10
BuO to the ester CO group.
could be isolated in 86% yield. Methylation of 10 with K
MeI afforded methyl ester 11 in 66% yield. Its H NMR spectrum was
consistent with the structure 11, exhibiting three 3H singlets at
2
CO
3
and
Reduction of the ester 15 with LiAlH4 furnished alcohol 16,
1
26
which was oxidized with sodium hypochlorite pentahydrate and
2
7
azadol to give a stereoisomeric mixture of 1 [anti/syn¼1:1.3;
669 mg (78% GC purity)]. The overall yield of 1 was 2.4% based on 6
(10 steps). The present route enabled the preparation of 1 useful for
further field bioassays.
d
¼1.19, 2.07 and 3.62 together with signals due to five olefinic
protons. The overall yield of the acid 10 was 77% based on 6 (four
steps).
Since the separation of (ꢀ)-anti-1 from (ꢀ)-syn-1 by AgNO
3 2
/SiO
2
.4. Second synthesis of the pheromone 1
chromatography was rather tedious, separation of (ꢀ)-anti- and
(
ꢀ)-syn-16 was attempted. 3,5-Dinitrobenzoate 17 of the stereo-
The next thing to do was to execute the ring-closing olefin
isomeric mixture 16 was first prepared. Unfortunately, its fractional
crystallization failed, and neither pure (ꢀ)-anti-17 nor (ꢀ)-syn-17
metathesis of 11 and subsequent conversion of the product 12 to 1
(
Scheme 3). Treatment of 11 with 0.3 mol % of the second gener-
2
could be secured. Chromatographic separation over SiO of a ste-
10,11
ation Grubbs catalyst (Grubbs II)
in refluxing CH
¼5.31) in 76% yield. Hydro-
borationeoxidation of the double bond of 12 with BH $SMe
followed by Jones CrO afforded 13 in 47% yield. The next step,
methylenation of the CO group of 13, was problematic, because its
2
Cl
2
gave 12
reoisomeric mixture of the alcohol 16 was more fruitful, and almost
pure (ꢀ)-anti-16 (anti/syn¼97:3) and (ꢀ)-syn-16 (anti/syn¼4:96)
could be obtained. Their separate derivatizations to the corre-
sponding 3,5-dinitrobenzoates gave (ꢀ)-anti-17 as leaflets, mp
with a single olefinic proton (
d
3
2
3
ꢂ
ꢂ
13
55e56 C, and (ꢀ)-syn-17 as prisms, mp 58e59 C. Their C NMR

K. Mori / Tetrahedron 72 (2016) 6578e6588
6581
spectra confirmed their high purities (see 4.17.3 and 4.17.4), and
Deprotection of 23 was effected in 65% yield with 2,3-dichloro-
31
their mixture melting point determination resulted in the de-
5,6-dicyano-1,4-benzoquinone (DDQ) and water in CH
2
Cl
2
to give
ꢂ
pression of the mp (mmp 41e46 C). It became clear that pure
16. Purification of 16 by SiO chromatography gave 456 mg of anti-
2
(
ꢀ)-anti- and (ꢀ)-syn-16 would be obtained, if we couple SiO
2
rich 16 (anti/syn¼81.3:15.4) and 397 mg of ca. 1:1 mixture of anti-
and syn-16. By adding another batch of syn-rich 16, 1.67 g of syn-
rich 16 (anti/syn¼2:3) was secured. These were separately oxidized
chromatography of 16 with recrystallization of the corresponding
1
7. Hydrolysis of the pure 3,5-dinitrobenzoates (ꢀ)-anti- and syn-17
2
7
would give pure (ꢀ)-anti- and syn-16, whose separate oxidation
would furnish pure (ꢀ)-anti- and syn-1. However, as reported in 2.2,
there is no practical need to secure pure (ꢀ)-anti-1, because
with azadol and diacetoxyiodobenzene (DAIB) to give (ꢀ)-anti-
rich 1 (243 mg, 99.6% GC purity, anti/syn¼85.6:14.0) and (ꢀ)-syn-
rich 1 (1.19 g, 99.6% GC purity, anti/syn¼38.0:61.6). The amounts
obtained were sufficient for future field bioassay. The overall yield
of 1 was 12% based on 6 (12 steps), in comparison to 0.6% in the case
of the first synthesis and 2.4% in the case of the second synthesis.
Accordingly, the present third synthesis was 20 times more effi-
cient than the first one and five times more efficient than the
second one, although the protection/deprotection strategy in the
third synthesis increased the number of the steps from 10 in the
second one to twelve.
(ꢀ)-syn-1 does not inhibit the bioactivity of (ꢀ)-anti-1.
2
.5. Third synthesis of the pheromone 1
The low yield (27%) of the methylenation step (13/15, Scheme
) made me modify the synthetic route as shown in Scheme 4:
3
namely, to reduce the carboxy group of 10 and protect the hydroxy
group of the resulting 18 as p-methoxybenzyl (PMB) ether 19.
2.6. Alternative synthesis of the intermediate 20
It is important to develop a synthetic route applicable to the
preparation of both the enantiomers of anti-1 so as to determine
the absolute configuration of the naturally occurring anti-1. Re-
producibility of the synthesis of 26 as reported by J a€ ger and co-
12
workers in 1984 was therefore examined as shown in Scheme 5.
Alcohol (ꢀ)-24 might possibly be resolved by enzymatic means,
because (ꢀ)-2,4,4-trimethyl-2-cyclohexen-1-ol could be resolved
3
2
by asymmetric hydrolysis of its acetate with pig liver esterase.
The synthesis in Scheme 5 was straightforward. Reduction of 2
with LiAlH gave 24, which was acetylated to give acetate 25. Ire-
landeClaisen rearrangement of the TMS-enol ether of 25 gave 26 in
3% yield. Treatment of 26 with LiAlH in THF gave 27. Of course
4
3
4
resolution of (ꢀ)-26 or (ꢀ)-27 might be another option to obtain
the enantiomers of anti-1. Finally, 27 was treated with PMBCl and t-
1
BuOK to give 20, whose IR, H NMR and MS spectra were identical
with those of 20 obtained by ring-closing metathesis of 19 (Scheme
4). The overall yield of 20 was 9.1% based on 2 (five steps). Since 20
had been converted to (ꢀ)-anti-1 as shown in Scheme 4, the
present route constituted the fourth synthesis of (ꢀ)-anti-1 in
a formal sense.
Scheme 4. Third synthesis of (ꢀ)-1. Reagents: (a) LiAlH
BuOK, THF, DMF (99%); (c) Grubbs II (0.44 mol %), CH
4
, THF (73%); (b) PMBCl, t-
Cl2, reflux, 2 h (87%); (d)
2
BH
3
$SMe
2
, THF; then NaOH, H
2
O
2
(68%); (e) Jones CrO
O, CH
(60% for anti-rich 1; 72% for syn-rich 1).
3
, Me
2
CO (93%); (f) Petasis re-
ꢂ
agent, THF, toluene, 70 C, 25 h (85%); (g) DDQ, H
tography; (i) azadol, PhI(OAc)
2
2
Cl
2
(65%); (h) SiO chroma-
2
2
, CH
2
Cl
2
Scheme 5. Alternative synthesis of 20. Reagents: (a) LiAlH
4
, Et
2
O; (b) Ac
2
O, C
5
H
5
N
Treatment of 10 with LiAlH
9 was subjected to ring-closing metathesis in the presence of
.44 mol % of Grubbs II catalyst. The ring-closure took place in
a satisfactory yield of 87% to give 20. Hydroboration of 20 with
BH $SMe was followed by oxidation with H /NaOH to give 21.
Jones CrO oxidized 21 cleanly to ketone 22. Methylenation was
then executed by treatment of 22 with commercially available
4
in THF yielded 18, and its PMB ether
ꢂ
(
(
40%, 2 steps); (c) LiN(i-Pr)
33%); (d) LiAlH
2
, TMSCl, THF; then heat at 65 C, 2.5 h; MeOH; then dil HCl
, THF (69%); (e) PMBCl t-BuOK, THF, DMF (quant.).
1
0
4
3. Conclusion
3
2
2
O
2
3
Both anti- and syn-isomers of (ꢀ)-(1,2-dimethyl-3-
methylenecyclopentyl)acetaldehyde (1) were synthesized. The
2
8
Petasis reagent (Cp
5%. Methylenation reagents employed so far (i.e., Tebbe, Ando, and
Petasis reagents) are all commercially available and easy to handle.
2
TiMe
2
)
to furnish 23 in an excellent yield of
1
13
8
isomer (ꢀ)-anti-1 showed H, C NMR and MS spectra identical
to those of the female-produced sex pheromone of the pineapple
mealybug, D. brevipes. Synthetic (ꢀ)-anti-1 was pheromonally ac-
tive in the field test in Okinawa. A mixture of (ꢀ)-anti- and syn-1
was also bioactive, while (ꢀ)-syn-1 was biologically inactive.
2
9
2 2 4
Lombardo reagent (Zn/CH Br /TiCl in THF), which must be pre-
3
0
pared prior to use, may also work efficiently, and will be exam-
ined in future to achieve a synthesis of the enantiomers of 1.

6582
K. Mori / Tetrahedron 72 (2016) 6578e6588
þ
Accordingly, (ꢀ)-syn-1 does not inhibit the pheromone activity of
[M ],111 (41),110 (55), 95 (11), 83 (85), 69 (100), 55 (55), 41 (43), 39
(23).
(
ꢀ)-anti-1. The synthesis of 1 was executed in four different ways,
and over 1 g of (ꢀ)-1 was secured for future biological studies.
Synthesis of the enantiomers of anti-1 is in progress, and will be
published in due course.
4.4. 3-(1,2-Dimethyl-3-oxocyclopentyl)propane-1,2-diol (4)
A solution of OsO
0% NMO in H O (2.0 g, 8 mmol) were added to a stirred solution of
(340 mg, 2.2 mmol) in a mixture of t-BuOH (5 mL), acetone
4
in t-BuOH [1%, 2 mL¼20 mg (0.08 mmol)] and
5
3
(
2
4
4
. Experimental
10 mL) and H
2
O (3 mL). The dark mixture was stirred for 3 d at
.1. General
ꢂ
room temperature (22 C) to give a clear solution. Solid Na
2
SO
, and the mixture
was concentrated in vacuo. The residue was diluted with brine, and
extracted with EtOAc. The EtOAc extract was dried (MgSO ), and
concentrated in vacuo to give 240 mg (58%) of crude 4 as an oil,
film): 3421 (br s), 2953 (s), 2871 (s), 1736 (s), 1455 (m), 1249 (m),
3
(
2.0 g) was added to reduce both NMO and OsO
4
Melting points are uncorrected values. Refractive indices were
measured on an Atago DMT-1 refractometer. IR spectra were
measured on a Jasco FT/IR-410 spectrometer. H NMR spectra
1
4
13
n
max
(
400 MHz, TMS at
d
¼0.00 as the internal standard) and C NMR
(
spectra (100 MHz, CDCl
3
at
d
¼77.0 as the internal standard) were
1118 (m), 1072 (m), 1038 (m), 863 (m), 837 (m), 681 (s). This oil was
recorded on a Jeol JNM-ECZ 400S/L1 spectrometer. GCeMS were
measured on Agilent Technologies 5975 inert XL. HRMS were
recorded on Jeol JMS-SX 102A or Waters Synapt G2 HDMS. Column
chromatography was carried out on Merck Kieselgel 60 Art 1.00734.
employed in the next step without further purification.
4.5. 3-(1,2-Dimethyl-3-methylenecyclopentyl)propane-1,2-
diol (5)
4
.2. 2,3-Dimethyl-2-cyclopenten-1-one (2)
A solution of Tebbe reagent in toluene (TCI, 0.5 M, 10 mL) was
added dropwise via syringe to a stirred and ice-cooled solution of 4
Eighty five percent H
and the mixture was stirred for 30 min at 200 C to obtain a viscous
liquid of PPA. 4-Methyl-4-hexenoic acid (20.0 g, 156 mmol) was
added to the hot and stirred PPA in one portion at 110 C, and the
mixture was stirred and heated at 110 C for 2 h. The dark PPA
solution was then poured into ice, saturated with NaCl, and
extracted with hexane/Et
with water and brine, dried (MgSO
3
PO
4
(75 mL) was added to P
2
O
5
(135 g),
ꢂ
(
240 mg, 1.3 mmol) in dry THF (10 mL) at 0e5 C under argon. The
ꢂ
ꢂ
mixture was stirred for 1 h at 0e5 C. It was then quenched with
12
NaOH solution (200 mg in 20 mL H
filtered through Celite. The filtrate was extracted with EtOAc. The
extract was washed with brine, dried (MgSO ), and concentrated in
vacuo to give 0.75 g of the residue containing 5. Its IR [ max at 1654
3.3e4.0) showed the
2
O), diluted with EtOAc, and
ꢂ
ꢂ
4
n
2
O. The extract was washed successively
), and concentrated in vacuo.
1
(
m)] and H NMR spectra (olefinic protons at d
4
presence of the methylene group. This oil was employed in the next
step without further purification.
The above process was repeated twice, and the residue from 40.0 g
of the acid was distilled to give 2 (10.15 g, 30%) as a slightly yellow
ꢂ
oil, bp 105e107 C/56 Torr;
nmax (film): 2919 (m), 2864 (w),1698 (s),
4.6. (1,2-Dimethyl-3-methylenecyclopentyl)acetaldehyde (1)
1
651 (s), 1442 (m), 1388 (m),1330 (m),1302 (w), 1181 (w), 1065 (m),
9
H 3
38 (w), 862 (w), 810 (w), 650 (w); d (CDCl ): 1.69 (3H, s), 2.05
NaIO
4
(2.0 g, 10 mmol) was added to a solution of crude 5
(
3H, s), 2.30e2.40 (2H, m), 2.44e2.54 (2H, m); GCeMS [column:
(
750 mg, ca. 4 mmol) in THF (10 mL) and H
was stirred for 40 min at room temperature (22 C). It was then
2
O (5 mL). The mixture
HP-5MS, 5% phenylmethylsiloxane, 0.25 mm i.d.ꢃ30 m; carrier gas,
ꢂ
ꢂ
ꢂ
He; press 60.7 kPa; temp: 70e230 C (þ10 C/min)]; t
R
3.11 (im-
diluted with water, and extracted with Et
washed successively with water and brine, dried (MgSO
concentrated in vacuo to give 540 mg of the residue, which was
chromatographed over SiO (7.5 g). Elution with hexane/EtOAc
(50:1) gave 132 mg (18%) of crude 1 as a clear oil, max (film); 3074
w), 2956 (s), 2870 (m), 2730 (w), 1721 (s), 1655 (w), 1456 (m), 1380
(m), 880 (m); GCeMS (same conditions as used for 2): t 7.21
(18.0%; identical t with that of the natural pheromone) 7.35 min
2
O. The Et
2
O extract was
þ
purity, 5.1%), 5.56 min (88.4%); MS (70 eV, EI): m/z: 110 (76) [M ],
4
), and
9
5 (25), 81 (11), 67 (100), 54 (8), 39 (21).
2
4
.3. 3-Allyl-2,3-dimethylcyclopentan-1-one (3)
n
(
A solution of TiCl
4
in CH
2
Cl
2
(TCI, 1.0 M, 12 mL, 12 mmol) was
R
added dropwise to a stirred and cooled solution of 2 (1.10 g,
R
1
0 mmol) and CH
2
]CHCH
2
TMS (2.28 g, 20 mmol) in dry CH
2
Cl
2
(26.4%); MS of anti-1 with t
[M ], 109 (33), 108 (100), 93 (76), 91 (30), 79 (24), 77 (24), 67 (52),
55 (21), 53 (24), 41 (55), 39 (33); MS of syn-1 with t
(70 eV, EI): m/z: 152 (<1) [M ], 109 (21), 108 (100), 93 (90), 91 (20),
79 (17), 77 (20), 67 (23), 55 (14), 53 (17), 41 (34), 39 (24). The
mixture 1 could be separated by AgNO
give anti-1 and syn-1. NMR data of anti-1:
R
¼7.21 min (70 eV, EI): m/z: 152 (<1)
ꢂ
þ
(
10 mL) at ꢁ40 to ꢁ30 C under argon. The brown-colored mixture
ꢂ
was stirred for 2 h at ꢁ40 to ꢁ30 C. It was then quenched by
adding NH Cl solution, and extracted with Et O. The extract was
washed successively with water and brine, dried (MgSO ), and
concentrated in vacuo. The residual oil (1.73 g) was chromato-
graphed over SiO (20 g). Careful fractionation was necessary to
R
¼7.35 min
þ
4
2
4
3
/SiO
2
chromatography to
): 0.70
2
d
H
(600 MHz, C D
6 6
obtain 3 as a stereoisomeric mixture (176 mg, 12%) by elution with
hexane/EtOAc (100:1e50:1). The above process was repeated twice
and 347 mg of ca. 86.8% pure 3 (ca. 1:1 mixture of isomers) could be
(3H, d, J¼6.6 Hz), 0.86 (3H, s), 1.06e1.40 (1H, m), 1.56e1.62 (1H, m),
1.60e1.74 (2H, m), 1.74e1.80 (1H, m), 2.06e2.14 (1H, m), 2.16e2.24
(1H, m), 4.77 (1H, m), 4.85 (1H, m), 9.47 (1H, t, J¼2.4 Hz);
d
C
secured as a colorless oil,
874 (m), 2840 (w), 1741 (s), 1638 (m), 1455 (m), 1382 (m), 1250
m), 1145 (m), 1038 (m), 996 (m), 915 (s), 842 (m); (CDCl ): 0.79
1.5H, s), 0.94 (1.5H, d, J¼6.8 Hz), 0.96 (1.5H, d, J¼6.8 Hz), 1.11 (1.5H,
n
max (film): 3070 (w), 2959 (s), 2934 (s),
(150 MHz, C ): 12.06, 24.78, 28.94, 35.52, 43.27, 47.20, 50.36,
6 6
D
2
105.73, 155.76, 201.38. The spectra were identical with those of the
natural pheromone and no NOE was observed between the protons
of the two Me groups. NMR data of syn-1: d (600 MHz, C D ): 0.56
H 6 6
(3H, s), 0.72 (3H, d, J¼7.2 Hz), 1.20e1.29 (1H, m), 1.38e1.44 (1H, m),
1.72 (1H, dd, J¼3, 14 Hz), 1.78e1.84 (1H, m), 2.01 (1H, dd, J¼3.6,
15 Hz), 2.07e2.17 (1H, m), 2.17e2.23 (1H, m), 4.78e4.82 (1H, q-
(
(
d
H
3
s), 1.35e1.56 (1H, m), 1.60e1.80 (2H, m), 1.90e2.06 (2H, m),
.06e2.34 (2H, m), 4.99e5.11 (2H, m), 5.70e5.90 (1H, m); GCeMS
2
(
1
same conditions as those used for 2); t
R
7.37 (44.0%), 7.49 (42.8%),
¼7.37 min (70 eV, EI): m/
1.36 min (impurity, 8.6%); MS of 3 with t
R
like), 4.87e4.89 (1H, q-like), 9.48 (1H, t, J¼3 Hz);
): 11.50, 18.69, 29.28, 36.27, 42.73, 48.52, 54.06, 105.51, 155.10,
200.85. The spectra were different from those of the natural
C
d (150 MHz,
þ
z: 152 (18) [M ],111 (41),110 (44), 95 (12), 83 (88), 69 (100), 55 (55),
1 (43), 39 (24); MS of 3 with t
¼7.49 min (70 eV, EI): m/z: 152 (14)
6 6
C D
4
R

K. Mori / Tetrahedron 72 (2016) 6578e6588
6583
pheromone, and the NOESY spectrum of syn-1 indicated the cis-
relationship of the two Me groups of syn-1.
dried (MgSO
4
), and concentrated at atmospheric pressure. The
residue was distilled to give 31.0 g (94% based on 7, two steps) of 9
ꢂ
21
as a colorless oil, bp 83e90 C/6 Torr; n
(w), 2979 (m), 2927 (m), 2865 (m), 1740 (s), 1666 (w), 1640 (m),
443 (m), 1376 (m), 1232 (s), 1022 (m), 911 (m); (CDCl ): 1.70
D
¼1.4582;
nmax (film): 3078
4
.7. Ethyl (E,Z)-2,3-dimethyl-2,6-heptadienoate (7)
1
d
H
3
A
solution of triethyl 2-phosphonopropanoate (50.1 g,
10 mmol) in dry THF (50 mL) was added dropwise to a stirred and
ice-cooled suspension of 60% NaH in mineral oil (8.42 g, 210 mmol)
in dry THF (100 mL) under argon. After the completion of H evo-
(4.5H, s), 1.74 (1.5H, s), 2.04 (3H, s), 2.02e2.25 (4H, m), 4.58 (2H, d,
J¼5.6 Hz), 4.92e5.06 (2H, m), 5.72e5.86 (1H, m); GCeMS (same
2
conditions as used for 7); t
R
8.53 (48.5%), 8.65 min (46.9%) (total
þ
2
95.4%); MS of 9 with t
R
¼8.53 min (70 eV, EI): m/z: 182 (1) [M ], 164
lution to give a homogeneous solution of the sodio enolate, a so-
lution of 6 (20.5 g, 210 mmol) in dry THF (30 mL) was added
dropwise. No exothermic reaction could be observed. The mixture
was stirred for 3 d at room temperature (20 C). It was then diluted
with ice and water, and extracted with Et
(2), 141 (4), 122 (18), 107 (58), 99 (28), 94 (22), 93 (27), 91 (23), 81
(24), 79 (46), 67 (16), 53 (13), 43 (100). The MS spectrum of 9 with
t
R
¼8.65 min was almost identical with the above data. HRMS calcd
for C11 : 182.1307, found: 182.1326 (short t ), 182.1326 (long
R
t ).
ꢂ
H
18
O
2
R
2
O. The Et
2
O extract was
) and
washed successively with water and brine, dried (MgSO
4
concentrated in vacuo. The residue was distilled to give 36.2 g (95%)
4.10. 3-Isopropenyl-3-methyl-6-heptenoic acid (10)
of 7 [an almost 1:1 mixture of its (E)- and (Z)-isomers] as a colorless
ꢂ
18
oil, bp 85e95 C/7 Torr; n
m), 2932 (m), 2871 (w), 1714 (s), 1640 (m), 1446 (m), 1365 (m),
277 (s), 1210 (s), 1101 (s), 911 (m), 772 (m); (CDCl ): 1.297 (1.5H,
D
¼1.4618;
n
max (film): 3078 (w), 2980
TMSCl (37.0 g¼42 mL, 340 mmol) was added to a stirred and
ꢂ
(
1
cooled solution of 9 (15.5 g, 85 mmol) in dry THF (60 mL) at ꢁ78 C
d
H
3
2
under argon. A solution of LiN(i-Pr) in THF/PhEt/heptane (TCI,
t, J¼6.8 Hz),1.303 (1.5H, t, J¼6.8 Hz),1.78 (1.5H, s), 1.85 (1.5H, s),1.87
1.5 M, 100 mL, 150 mmol) was added dropwise over 15 min to the
ꢂ
(
1.5H, s), 1.98 (1.5H, s), 2.12e2.28 (3H, m), 2.43 (1H, t, J¼7.2 Hz), 4.18
1H, q, J¼7.2 Hz), 4.20 (1H, q, J¼7.2 Hz), 4.90e5.10 (2H, m),
stirred solution at ꢁ78 to ꢁ60 C. Then the dry ice/acetone bath was
(
removed, and the mixture was allowed to reach room temperature
ꢂ
5
.77e5.90 (1H, m); GCeMS [column: HP-5MS, 0.25 mm i.d.ꢃ30 m;
over 1 h. The mixture was stirred and heated at 70 C (bath tem-
ꢂ
ꢂ
carrier gas, He; press 61 kPa; temp: 70e230 C (þ10 C/min)]: t
R
perature) for 4 h. After cooling, MeOH (40 mL) was added to the
mixture, which was stirred for 10 min at room temperature. The
mixture was then transferred to a separatory funnel, and extracted
with 5% NaOH aqueous solution (60 mLꢃ3). The aqueous extract
was transferred into another separatory funnel, and washed with
8
.32 (49.3%), 8.69 min (47.4%) (total 96.7%); MS of 7 with
þ
t
(
(
(
R
¼8.32 min (70 eV, EI): m/z: 182 (5) [M ], 167 (2), 153 (38), 137
33), 113 (65), 109 (100), 95 (26), 93 (23), 81 (18), 79 (14), 67 (38), 43
27); MS of 7 with t
3), 153 (40), 137 (59), 125 (22), 113 (92), 109 (100), 95 (27), 93 (25),
þ
R
¼8.69 min (70 eV, EI): m/z: 182 (6) [M ], 167
Et
with dil. HCl with ice-cooling, and the separated oily 10 was
extracted with Et O. The Et O extract was washed successively with
water and brine, dried (MgSO ), and concentrated in vacuo to give
3.3 g (86%) of 10 as an oil, max (film): 3078 (w), 2976 (s), 2939 (s),
2684 (br w), 1708 (s), 1640 (m), 1447 (m), 1410 (m), 1380 (m), 1309
m), 1227 (m), 898 (s); (CDCl ): 1.22 (3H, s), 1.44e1.66 (2H, m),
2
O to remove neutral impurities. The aqueous layer was acidified
8
1 (22), 79 (16), 67 (58), 55 (18), 53 (17), 43 (33). HRMS calcd for
C
11
18
H O
2
R
: 182.1307, found: 182.1305 (short t ) and 182.1322 (long
2
2
t
R
).
4
1
n
4
.8. (EZ)-2,3-Dimethyl-2,6-heptadien-1-ol (8)
A solution of 7 (33.0 g, 181 mmol) in dry Et O (50 mL) was added
(
d
H
3
2
1.74 (3H, s), 1.82e2.00 (2H, m), 2.36 (1H, d, J¼13.6 Hz), 2.48 (1H, d,
J¼13.6 Hz), 4.75 (1H, s), 4.88 (1H, t-like, J¼1.6 Hz), 4.91e5.02 (2H,
m), 5.74e5.84 (1H, m); This oil was used in the next step without
further purification.
dropwise to a stirred and ice-cooled suspension of LiAlH
4
(4.00 g,
ꢂ
105 mmol) in dry Et
2
O (200 mL) at 10e15 C. After the addition, the
ꢂ
4
mixture was stirred for 2 h at 0e5 C. Then excess LiAlH was
destroyed by slowly adding water to the stirred mixture with ice-
cooling. The mixture was acidified with ice and dil. HCl, and
4.11. Methyl 3-isopropenyl-3-methyl-6-heptenoate (11)
extracted with Et
2
O. The Et
2
O extract was washed successively with
), and concentrated
water, NaHCO solution and brine, dried (MgSO
3
4
2 3
K CO (34.5 g, 250 mmol) and MeI (54.0 g 380 mmol) were
in vacuo to give 28.4 g (quant.) of 8 as a colorless oil. An analytical
added to a stirred solution of 10 (24.3 g, 134 mmol) in dry DMF
ꢂ
sample of 8 was obtained by distillation, bp 81e82 C/6 Torr;
(160 mL). After the initial exothermic reaction, the mixture was
2
0
ꢂ
n
2
D
¼1.4755;
n
max (film): 3326 (br m), 3077 (w), 2978 (m), 2925 (s),
(CDCl ):
stirred for 3 d at room temperature (21 C). It was then diluted with
864 (m), 1663 (w), 1640 (m), 1442 (m), 996 (s), 910 (s);
d
H
3
ice and water, and extracted with Et
washed successively with water and brine, dried (MgSO
concentrated in vacuo. The residue was distilled to give 17.4 g (66%)
2
O. The Et
2
O extract was
1
.37 (1H, br s), 1.67 (1.5H, s), 1.72 (1.5H, s), 1.74 (3H, s), 2.08e2.25
4H, m), 4.10 (2H, d, J¼14 Hz), 4.90e5.08 (2H, m), 5.72e5.88 (1H,
m); GCeMS (same conditions as used for 7); t 6.67 (48.6%),
¼6.67 min (70 eV, EI):
4
), and
(
ꢂ
24
R
of 11 as a colorless oil, bp 93e96 C/8 Torr; n
D
¼1.4532;
nmax (film):
6
.81 min (47.5%) (total 96.1%); MS of 8 with t
R
3079 (w), 2975 (m), 2950 (m), 1739 (s), 1639 (m), 1436 (m), 1379
(m), 1337 (m), 1311 (m), 1252 (m), 1196 (s), 1120 (m), 1015 (m), 898
þ
m/z: 140 (<1) [M ], 125 (10), 109 (40), 107 (29), 93 (16), 91 (18), 85
(
18), 81 (21), 79 (28), 67 (16), 57 (8), 55 (23), 43 (100). The MS
spectrum of 8 with t
¼6.81 min was almost identical with the
above described one. HRMS calcd for C 16O: 140.1201, found:
H 3
(s), 845 (w); d (CDCl ): 1.19 (3H, s), 1.41e1.49 (1H, m), 1.54e1.66
R
(1H, m), 2.07 (3H, s), 1.81e1.98 (2H, m), 2.34 (1H, d, J¼14 Hz), 2.47
(1H, d, J¼14 Hz), 3.62 (3H, s), 4.72 (1H, s), 4.86 (1H, s-like),
4.90e5.04 (2H, m), 5.74e5.86 (1H, m); GCeMS (same conditions as
9
H
1
40.1218 (short t
R
), 140.1220 (long t
R
).
used for 7); t
R
9.03 min (87.1%); MS (70 eV, EI): m/z: 197 (<1)
þ
4
.9. (EZ)-2,3-Dimethyl-2,6-heptadienyl acetate (9)
[(MþH) ], 181 (20), 142 (42), 122 (54), 110 (42), 109 (39), 107 (42),
99 (19), 95 (43), 82 (81), 81(100), 67 (41), 59 (19), 55 (35), 41 (38).
Ac
2
O (60 mL¼78 g, 765 mmol) and DMAP (0.2 g) were added to
HRMS calcd for C12 : 196.1463, found: 196.1491.
20 2
H O
a stirred solution of 8 (28.3 g, 180 mmol) in dry C
5 5
H
N (100 mL).
When the exothermic reaction subsided, the mixture was stirred
and heated at 80 C for 30 min. After cooling, the mixture was di-
4.12. Methyl (1,2-dimethyl-2-cyclopentenyl)acetate (12)
ꢂ
luted with ice and water, and extracted with Et
was washed successively with dil HCl, NaHCO
2
O. The Et
solution and brine,
2
O extract
Grubbs II catalyst (190 mg, 0.22 mmol, 0.4 mol %) was added to
a solution of 11 (17.3 g, 88 mmol) in CH Cl (400 mL) under argon.
2 2
3

6584
K. Mori / Tetrahedron 72 (2016) 6578e6588
The mixture was stirred and heated under gentle reflux. After 2 h,
when the evolution of ethylene ceased, the mixture was concen-
crude 15. Further elution with the same eluent furnished 2.88 g
(47% recovery) of 13. The crude 15 was purified by distillation to
give 1.65 g (27%; 51% based on the consumed 13) of 15 as a col-
trated in vacuo. The residue was chromatographed over SiO
100 g). Elution with hexane/EtOAc(30:1) gave 15.0 g of crude 12,
which was distilled to furnish 11.3 g (76%) of 12 as a colorless oil, bp
2
ꢂ
24
(
orless oil, bp 83e85 C/7 Torr; n
2961 (m), 2873 (w), 1739 (s), 1656 (w), 1436 (m), 1201 (m), 1124
(m), 1013 (m), 880 (m); (CDCl ): 0.78 (1.8H, s), 0.93 (3H, d,
D
¼1.4590;
nmax (film): 3074 (w),
ꢂ
25
7
(
2e75 C/7 Torr; n
m),1739 (s),1437 (m),1218 (m);
like), 1.66e1.76 (1H, m), 2.06e2.14 (1H, m), 2.16e2.22 (2H, m), 2.28
D
¼1.4542;
n
max (film): 3038 (w), 2953 (m), 2851
d
H
3
d
H
(CDCl ): 1.09 (3H, s),1.63 (3H, s-
3
J¼6.8 Hz), 1.13 (1.2H, s), 1.02e1.44 and 1.86e1.94 (total 1H, m),
1.56e1.70 (2H, m), 2.06e2.20 and 2.30e2.40 (total 2H, m), 2.22
(1H, d, J¼13 Hz), 2.42 (1H, d, J¼13 Hz), 3.65 and 3.66 (total 3H,
each s), 4.78 (1H, s-like), 4.87 (1H, s-like); GCeMS (same con-
(
1H, d, J¼13 Hz), 2.36 (1H, d, J¼13 Hz), 3.64 (3H, s), 5.31 (1H, br s);
GCeMS (same conditions as used for 7): t
R
6.95 min (94.6%); MS
þ
(
70 eV, EI): m/z: 168 (19) [M ], 136 (4), 121 (3), 95 (98), 94 (100), 79
ditions as used for 7); t
82.7%); MS of the minor isomer (70 eV, EI): m/z: 182 (<1) (M ),
R
8.41 (32.7%), 8.58 min (50.0%) (total
þ
(
1
35), 65 (18), 55 (7), 41 (7), 39 (7). HRMS calcd for C10
68.1150, found: 168.1168.
H
16
O
2
:
151 (6), 123 (4), 109 (33), 108 (100), 93 (35), 67 (15), 41 (9); MS of
þ
the major isomer (70 eV, EI): m/z: 183 (<1) [(MþH) ], 151 (4),
4
.13. Methyl (1,2-dimethyl-3-oxocyclopentyl)acetate (13)
BH $Me
109 (53), 108 (100), 93 (58), 91 (12), 67 (14), 41 (10). HRMS calcd
18 2
for C11H O : 182.1307, found: 182.1322 (minor isomer), 182.1323
(major isomer).
3
2
S (7.2 mL¼5.7 g, 75 mmol) was added dropwise to
a stirred and ice-cooled solution of 12 (11.3 g, 88 mmol) in dry
Et
3
When t-BuOK, instead of NaHMDS, was employed as the base,
the products (28% yield) were mainly the two isomeric t-Bu es-
ꢂ
2
O (80 mL) at 5e10 C under argon. The mixture was stirred for
ꢂ
ꢁ
h at room temperature (21 C). Water (30 mL) was slowly
ters generated by the nucleophilic attack of t-BuO to the ester
ꢂ
ꢂ
24
added dropwise to the stirred and ice-cooled mixture at 5e10 C
C]O of 15. The t-Bu esters, bp 93e97 C/7 Torr, n
showed a signal due to t-Bu at
D
¼1.4538,
to destroy excess BH
3
. Subsequently, the mixture was diluted
d
¼1.45, while the signal due to
with acetone (60 mL). Jones CrO
over 20 min to the stirred and ice-cooled mixture at 5e10 C.
3
(50 mL) was added dropwise
CO
2
Me at
d
3.66 was almost absent. Its GCeMS showed two peaks
ꢂ
þ
at t
R
¼10.41 (24.7%) and 10.53 (40.4%) both with M ¼224
After adding MeOH (5 mL) to destroy the excess CrO
ture was concentrated in vacuo. The residue was diluted with
water, and extracted with Et O. The extract was washed suc-
cessively with water, NaHCO solution and brine, dried (MgSO ),
and concentrated in vacuo to give 9.73 g of crude hydroxy ester,
max (film): 3460 (br m), 2956 (s), 2874 (m), 1737 (s), 1438 (m),
348 (m), 1213 (m), 1010 (m). This oil was dissolved in acetone
3
, the mix-
(C14
H
24
O
2
).
2
4.15. 2-(1,2-Dimethyl-3-methylenecyclopentyl)ethanol (16)
3
4
A solution of 15 (1.80 g, 10 mmol) in dry Et
2
O (10 mL) was
n
added dropwise to a stirred and ice-cooled suspension of LiAlH
4
1
(380 mg, 10 mmol) in dry Et
for 1 h at 5e10 C. Then water was added dropwise to the stirred
2
O (10 mL). The mixture was stirred
ꢂ
(
120 mL), and treated with Jones CrO
3
(14 mL) under ice-cooling
ꢂ
at 5e10 C. After 10 min, the mixture was quenched with MeOH
and ice-cooled mixture to destroy excess LiAlH
acidified with dil. HCl and ice, and extracted with Et
extract was washed successively with water, NaHCO
and brine, dried (MgSO ), and concentrated in vacuo to give
1.60 g (quant.) of 16 as a colorless oil, max (film): 3345 (br m),
3073 (w), 2959 (s), 1655 (w), 1454 (m), 1379 (m), 1054 (m), 1037
(m), 1009 (m), 876 (m); (CDCl ): 0.69 (1.9H, s), 0.93 (1.9H, d,
4
. The mixture was
O. The Et
solution
(
5 mL), and concentrated in vacuo. The residue was diluted with
water and extracted with Et O. The Et O extract was washed
successively with water, NaHCO solution and brine, dried
MgSO ), and concentrated in vacuo. The residue was distilled to
give 5.8 g (47%) of 13 as a colorless oil, bp 110e115 C/7 Torr;
2
2
O
2
2
3
3
4
(
4
n
ꢂ
2
4
n
1
(
1
D
¼1.4594;
438 (m), 1239 (m), 1213 (m), 1170 (m), 1119 (m), 1009 (m);
CDCl
): 0.96 (1H, d, J¼7.6 Hz), 0.98 (2H, d, J¼7.6 Hz), 1.26 (3H, s),
n
max (film): 2957 (m), 2876 (m), 1739 (s), 1455 (m),
d
H
3
d
H
J¼6.8 Hz), 0.94 (1.1H, d, J¼6.8 Hz), 1.01 (1.1H, s), 1.20e1.80 (5H,
m), 2.05 (1H, br), 2.15e2.45 (2H, m), 3.65e3.80 (2H, m), 4.77 (1H,
m), 4.84e4.88 (1H, m); GCeMS (same conditions as those used
3
.60e1.74 (2H, m), 1.90e2.40 (5H, m), 3.67 (2H, s), 3.69 (1H, s);
GCeMS (same conditions as used for 7); t
R
9.90 (56.5%),
for 7): t
R
8.33 (30.9%), 8.49 min (48.2%); MS of the minor isomer
þ
1
0.09 min (24.0%) (total 80.5%); MS of the major isomer (70 eV,
(70 eV, EI): m/z: 154 (<1) [M ], 139 (6), 125 (15), 121 (24), 110
(47), 109 (100), 95 (25), 93 (38), 91 (19), 81 (24), 79 (27), 67 (46),
55 (22), 53 (15), 41 (30); MS of the major isomer (70 eV, EI): m/z:
þ
EI): m/z: 184 (7) [M ], 169 (5), 153 (12), 127 (10), 111 (100), 95
11), 83 (12), 74 (11), 69 (24), 55 (17), 41 (17); MS of the minor
isomer (70 eV, EI): m/z: 184 (1), 169 (5), 153 (8), 127 (6), 111 (100),
6 (7), 83 (7), 69 (18), 55 (13), 41 (13). HRMS calcd for C10
84.1099, found: 184.1112 (major isomer), 184.1107 (minor
isomer).
(
þ
155 (<1) [(MþH) ], 139 (4), 121 (13), 109 (100), 93 (25), 81 (12),
9
1
H
16
O
3
:
79 (14), 67 (19), 55 (10), 53 (8), 41 (15). HRMS calcd for C10H18O:
154.1358, found: 154.1374 (minor isomer), 154.1372 (major
isomer).
4
.14. Methyl (1,2-dimethyl-3-methylenecyclopentyl)acetate
4.16. (1,2-Dimethyl-3-methylenecyclopentyl)acetaldehyde (1)
(
15)
Crystalline NaOCl$5H
2
O (TCI, 1.60 g, 10 mmol) was added in one
A solution of NaHMDS in THF (TCI, 1.9 M, 22.6 mL, 43 mmol)
was added over 5 min to a stirred and cooled solution of 13
portion to a stirred and ice-cooled mixture of 16 (1.08 g, 7 mmol),
Bu
4
NHSO
4
(0.12 g, 0.35 mmol), azadol (30 mg, 0.2 mmol) and water
ꢂ
(
ꢁ
6.14 g, 33 mmol) and 14 (8.41 g, 40 mmol) in dry DMF (90 mL) at
(0.3 mL) in CH
2
Cl
2
(30 mL) at 5e10 C. The mixture was stirred for
ꢂ
ꢂ
70 to ꢁ60 C under argon. The mixture was stirred for 10 min at
1 h at 5e10 C, when it became turbid. The mixture was shaken
ꢂ
ꢁ
78 C, and then the cooling bath was removed to raise the
with an aqueous solution of Na
was separated, and the aqueous layer was extracted with Et
combined organic solution was washed with brine, dried (MgSO
2
S
2
O
3
and NaHCO
3
, the organic layer
O. The
),
temperature gradually to room temperature in the course of 1 h.
2
ꢂ
The mixture was stirred for 40 min at room temperature (22 C).
4
The reaction was quenched by adding ice and NH
the mixture was extracted with Et O. The Et
washed successively with water and brine, dried (MgSO
concentrated in vacuo. The residue was chromatographed over
SiO (80 g). Elution with hexane/EtOAc (30:1) gave 2.42 g of
4
Cl solution and
O solution was
), and
and concentrated in vacuo. The residue was distilled to give 1
(669 mg, 63%) as a colorless oil, bp 74e77 C/7 Torr; GCeMS (same
conditions as those used for 7); t 7.02 (33.8%, anti-1), 7.16 min
R
(44.2%, syn-1). Its IR, NMR and MS data were identical to those
ꢂ
2
2
4
2
reported in 4.6 and 4.25.

K. Mori / Tetrahedron 72 (2016) 6578e6588
6585
4
.17. 2-(1,2-Dimethyl-3-methylenecyclopentyl)ethyl 3,5-
4.48e4.62 (2H, m), 4.81 (1H, d, J¼2 Hz), 4.90 (1H, d, J¼2 Hz), 9.16
(2H, d, J¼2 Hz), 9.23 (1H, t, J¼2 Hz); (CDCl ): 11.55, 18.46, 29.27,
6.50, 39.09, 42.69, 48.62, 64.83, 105.22, 122.34, 129.41, 134.12,
148.71, 155.65, 162.56. HRMS calcd for C17 : 348.1321,
dinitrobenzoate (17)
d
C
3
3
4
.17.1. A mixture of anti- and syn-17. Solid 3,5-dinitrobenzoyl
chloride (1.40 g, 6 mmol) was added to a stirred and ice-cooled
solution of 16 (mixture, 910 mg, 5 mmol) in dry C N (2 mL)
20 6 2
H O N
found: 348.1340. Melting point depression was observed when
ꢂ
5
H
5
anti-17 and syn-17 were mixed: mixture mp 41e46 C.
containing DMAP (10 mg). The mixture was stirred for 1.5 h at room
ꢂ
temperature (22 C), then diluted with ice and water, and extracted
4.18. 3-Isopropenyl-3-methyl-6-hepten-1-ol (18)
with Et
NaHCO
2
O. The Et
solution and brine, dried (MgSO
2
O solution was washed successively with dil. HCl,
), and concentrated in
3
4
A solution of 10 (4.47 g, 24.6 mmol) in dry THF (15 mL) was
vacuo to give 2.00 g (97%) of 17 as a slightly yellow-colored oil. This
added dropwise to a stirred and ice-cooled suspension of LiAlH
(1.40 g, 37 mmol) in dry THF (35 mL) at 5e15 C. After the addition,
the mixture was stirred and heated under reflux for 1.5 h. It was
4
ꢂ
ꢂ
was dissolved in Et
2
O/pentane, and left for 2 d at ꢁ20 C. The
separated solid (1.273 g) was collected on a glass filter, and
recrystallized twice from Et
a mixture of anti- and syn-17 as a solid, mp 39e41 C,
2
O/pentane to give 484 mg (23%) of
then ice-cooled, and excess LiAlH
addition of water. The mixture was acidified with dil HCl and ice,
and extracted with Et O. The Et O extract was washed succes-
sively with water, NaHCO solution and brine, dried (MgSO ), and
concentrated in vacuo. The residue was distilled to give 3.03 g
4
was destroyed by dropwise
ꢂ
n
max (film):
3
1
8
104 (w), 2960 (m), 2931 (m), 2872 (m), 1733 (s), 1630 (w), 1548 (s),
462 (m), 1345 (s), 1280 (s), 1167 (m), 1075 (w), 965 (w), 921 (w),
81 (w), 722 (m). The IR spectrum was very similar to that of syn-17.
2
2
3
4
1
ꢂ
24
Its H NMR spectrum was complicated as that of a mixture of anti-
and syn-17, while its C NMR spectrum clearly showed that the
sample was a mixture of anti- and syn-17: (CDCl ): 11.54, 12.07,
(73%) of 18 as a colorless oil, bp 104e107 C/7 Torr, n
max (film): 3328 (br m), 3087 (w), 2972 (s), 2940 (s), 1639 (m),
1447 (m), 1377 (m),1138 (w), 1034 (m), 994 (m), 908 (s), 894 (s);
(CDCl ): 1.08 (3H, s), 1.30e1.40 (1H, m), 1.42 (1H, br s), 1.49e1.59
D
¼1.4742;
13
n
d
C
3
d
H
18.45, 24.73, 29.00, 29.28, 31.60, 35.02, 36.50, 39.09, 42.69, 48.63,
3
5
1
0.51, 60.41, 64.83, 64.88, 105.22, 105.35, 122.34, 129.41, 134.11,
48.69, 155.66, 156.18, 162.57.
(2H, m), 1.72 (3H, s), 1.75e1.86 (2H, m), 1.87e2.00 (1H, m), 3.60
(2H, t, J¼7.2 Hz), 4.73 (1H, d, J¼1.2 Hz), 4.87 (1H, t, J¼1.6 Hz),
4
.90e5.02 (2H, m), 5.74e5.86 (1H, m); GCeMS (same conditions
4
.17.2. Chromatographic separation of the alcohol mixture 16.. The
alcohol mixture 16 (2.42 g) was purified by chromatography over
SiO (80 g). Elution with hexane (300 mL) gave nothing. Further
elution with hexane/EtOAc (20:1) gave the following six fractions
each 300 mL), whose anti-16 (short t )/syn-16 (long t ) ratio was
determined by GCeMS analysis: (1) 303 mg (97:3)þseveral impu-
rities with shorter t s, (2) 424 mg (67:33), (3) 369 mg (34:66), (4)
85 mg (19:81), (5) 181 mg (8:92), (6) 140 mg (4:96). Fraction 1 was
as those used for 7): t
R
8.96 min (94.4%); MS (70 eV, EI): m/z: 169
þ
(<1) [(MþH) ], 153 (22), 135 (7), 124 (16), 114 (26), 95 (94), 83
2
(100), 81 (98), 67 (74), 55 (80), 41 (64). HRMS calcd for C11
168.1514, found; 168.1532.
H20O:
(
R
R
4.19. 3-Isopropenyl-3-methyl-6-heptenyl p-methoxybenzyl
ether (19)
R
2
nearly pure anti-16, and fraction 6 was nearly pure syn-16. These
were converted to the corresponding 3,5-dinitrobenzoates, anti-17
and syn-17, and fractions 2e5 were combined and oxidized to give
t-BuOK (11.0 g, 90 mmol) was added in one portion to a solution
of 18 (12.2 g, 72.6 mmol) in dry DMF (72 mL), and the mixture was
stirred at room temperature to make a homogeneous solution. p-
Methoxybenzyl chloride (PMBCl, 14.1 g, 90 mmol) was added to the
1
as a stereoisomeric mixture.
ꢂ
stirred solution, and stirring was continued for 1 h at 65 C. After
4
.17.3. 2-(anti-1,2-Dimethyl-3-methylenecyclopentyl)ethyl 3,5-
cooling, the mixture was diluted with ice and water, and extracted
dinitrobenzoate (anti-17). Alcohol anti-16 (303 mg, 2 mmol) was
esterified with 3,5-dinitrobenzoyl chloride (500 mg, 2.2 mmol) and
with Et
and brine, dried (MgSO
(26.8 g) was chromatographed over SiO
hexane/EtOAc (30:1) gave 20.6 g (99%) of 19 as a colorless oil,
2
O. The Et
2
O extract was washed successively with water
), and concentrated in vacuo. The residue
(100 g). Elution with
4
dry C
5
H
5
N (4 mL) containing DMAP (10 mg) as described in 4.17.1.
2
The resulting solid (617 mg) was recrystallized from EtOAc/hexane
ꢂ
21
to give 199 mg of anti-17 as leaflets, mp 55e56 C;
nmax (Nujol):
n
D
¼1.5112;
(m),1614 (s), 1586 (w), 1514 (vs),1464 (m),1362 (m),1302 (m), 1248
(vs), 1173 (m), 1096 (m), 1038 (m), 894 (m), 822 (m); (CDCl ):
nmax (film): 3076 (w), 2971 (s), 2937 (s), 2862 (m), 1638
3
(
7
089 (m), 1720 (vs), 1655 (w), 1631 (m), 1598 (w), 1550 (vs), 1463
s), 1351 (s), 1287 (s), 1170 (m), 966 (m), 926 (m), 869 (w), 776 (w),
22 (s); (CDCl
): 1.01 (3H, d, J¼6.8 Hz),1.11 (3H, s), 1.60e1.65 (2H,
m), 1.65e1.72 (1H, m), 1.76e1.84 (1H, m), 2.08e2.16 (1H, br),
.30e2.40 (1H, m), 2.40e2.52 (1H, m), 4.50 (2H, t, J¼7.2 Hz), 4.82
1H, d, J¼2 Hz), 4.89 (1H, d, J¼2 Hz), 9.15 (2H, m), 9.23 (1H, t,
J¼2 Hz); (CDCl ): 12.08, 24.74, 29.00, 31.60, 35.02, 42.69, 50.51,
4.88, 105.36, 122.32, 129.41, 134.12, 148.69, 156.16, 162.56. HRMS
calcd for C17 : 348.1321, found: 348.1344.
d
H
3
d
H
3
1.04 (3H, s), 1.35e1.40 (1H, m), 1.46e1.55 (1H, m), 1.50e1.65 (1H,
m), 1.68 (3H, s), 1.75e1.88 (2H, m), 1.88e1.98 (1H, m), 3.30e3.46
(2H, m), 3.80 (3H, s), 4.39 (2H, s), 4.68 (1H, s), 4.83 (1H, s),
4.89e5.00 (2H, m), 5.75e5.83 (1H, m), 6.87 (2H, d, J¼7 Hz), 7.24
2
(
d
C
3
(2H, d, J¼7 Hz); GCeMS (same conditions as those used for 7); t
R
þ
6
18.53 min (93.5%); MS (70 eV, EI): m/z: 288 (1) [M ], 137 (12), 136
H
20
O
6
N
2
(12), 121 (100), 109 (8), 83 (13), 55 (6). HRMS calcd for C
9 28 2
H O :
288.2089, found; 288.2106.
4
.17.4. 2-(syn-1,2-Dimethyl-3-methylenecyclopentyl)ethyl 3,5-
dinitrobenzoate (syn-17). Similarly, alcohol syn-16 (140 mg,
mmol) was esterified with 3,5-dinitrobenzoyl chloride (250 mg,
N (2 mL) containing DMAP (5 mg) to give
4.20. 2-(1,2-Dimethyl-2-cyclopentenyl)ethyl p-methoxy-
benzyl ether (20)
1
1.1 mmol) and dry C
5
H
5
2
21 mg of a solid. This was recrystallized from EtOAc/hexane to give
Grubbs II catalyst (280 mg, 0.32 mmol, 0.44 mol % for 19) was
added to a solution of 19 (20.6 g, 71.6 mmol) in CH Cl (400 mL)
ꢂ
162 mg of syn-17 as prisms, mp 58e59 C;
n
max (Nujol): 3108 (m),
2
2
1727 (vs), 1655 (w), 1631 (m), 1598 (w), 1547 (vs), 1460 (m), 1380
under argon. The solution was stirred and heated under reflux for
(
(
w), 1344 (vs), 1316 (w), 1279 (s), 1166 (m), 1074 (m), 959 (m), 919
m), 891 (m), 880 (m), 731 (s), 719 (s); The IR spectrum was dif-
2 h. Then the mixture was concentrated in vacuo. The residue
was chromatographed over SiO
2
(100 g). Elution with hexane
ferent from that of anti-17.
J¼6.8 Hz), 1.52e1.66 (2H, m), 1.72e1.82 (1H, m), 1.98e2.06 (1H, m),
.10e2.18 (1H, br), 2.28e2.40 (1H, m), 2.40e2.52 (1H, m),
H 3
d (CDCl ): 0.79 (3H, s), 0.98 (3H, d,
gave 1.33 g of impurities. Further elution with hexane/EtOAc
2
2
(30:1) gave 16.2 g (87%) of 20 as a colorless oil, n
D
¼1.5156;
n
max
2
(film): 3034 (w), 2952 (m), 2932 (m), 2853 (m), 1614 (m), 1586

6586
K. Mori / Tetrahedron 72 (2016) 6578e6588
(
1
w), 1514 (s), 1456 (m), 1362 (m), 1302 (m), 1248 (s), 1173 (m),
096 (s), 1038 (s), 821 (s); (CDCl ): 1.00 (3H, s), 1.58 (3H, s),
4.23. 2-(1,2-Dimethyl-3-methylenecyclopentyl)ethyl p-
methoxybenzyl ether (23)
d
H
3
1.60e1.76 (3H, m), 1.82e1.90 (1H, m), 2.12e2.25 (2H, m),
3
.37e3.49 (2H, m), 3.80 (3H, s), 4.41 (2H, s), 5.25 (1H, br s), 6.87
A solution of dimethyltitanocene (Petasis reagent, TCI, 5 wt %
solution in THF/toluene, 230 g, 56 mmol) was added to 22 (8.80 g,
32 mmol) under argon. The flask was wrapped with aluminum foils
(
2H, d, J¼6.8 Hz), 7.24 (2H, d, J¼6.8 Hz); GCeMS (same conditions
as those used for 7); t
R
17.22 min (90.2%); MS (70 eV, EI): m/z:
59 (<1) [(M-H) ], 231 (2), 163 (2), 137 (4), 121 (100), 97 (8), 77
þ
2
to keep inside dark, and the orange-colored mixture was stirred
ꢂ
(
5), 57 (3), 41 (4). HRMS calcd for C17
H
24
O
2
: 260.1776, found;
and heated at 70 C for 25 h. After cooling, NaHCO
3
(2.4 g,
2
60.1788.
30 mmol), water (1.5 mL) and MeOH (30 mL) were added to the
mixture, which was stirred overnight at room temperature (22 C).
ꢂ
4
.21. 2-(3-Hydroxy-1,2-dimethylcyclopentyl)ethyl p-
Then the stirring bar was removed from the dark green-colored
methoxybenzyl ether (21)
mixture to which was added SiO
centrated in vacuo to give yellow-colored powder, which was
transferred to the top of a column of SiO (70 g) in hexane. Elution
2
(20 g). The mixture was con-
BH $Me S (10 mL, 8.0 g, 105 mmol) was added dropwise over
3
2
2
1
0 min to a stirred and ice-cooled solution of 20 (14.2 g, 55 mmol)
with hexane gave 0.18 g of hydrocarbon impurities. Further elution
with hexane/EtOAc (30:1) gave 2.45 g of 23 (anti/syn¼66.5:31.2)
and then 3.52 g of 23 (anti/syn¼43.1:55.9). Total yield of 23 was
5.97 g (68%). In another occasion, 85% yield could be observed.
These two fractions were employed separately in the next step.
ꢂ
in dry THF (140 mL) at 0e10 C under argon. The mixture was
stirred for 30 min at 0e5 C and 2.5 h at room temperature. It was
then ice-cooled again, and water (20 mL) was slowly added drop-
ꢂ
wise (H
NaOH (4.6 g, 115 mmol) in water (32 mL) was added dropwise to
the stirred and ice-cooled mixture. Subsequently 34.5% H
40 mL) was slowly added (exothermic), and stirring was continued
2
evolution) to destroy excess borane. Then a solution of
2
0
Properties of 23 (anti/syn¼ca. 1:1): n
D
¼1.5040;
nmax (film): 3071
(w), 2958 (s), 2934 (s), 2866 (m), 1654 (w), 1613 (m), 1586 (w), 1514
(s), 1464 (m), 1363 (m), 1302 (m), 1248 (s), 1173 (m), 1097 (s), 1038
2
O
2
(
ꢂ
for 1 h at 0e5 C. The mixture was diluted with water, and extracted
with Et O. The Et O extract was washed with water and brine, dried
MgSO ), and concentrated in vacuo. The residue (20.3 g) was
chromatographed over SiO (100 g). Elution with hexane and
H 3
(s), 876 (m), 821 (m); d (CDCl ): 0.66 (1.5H, s), 0.91 (1.5H, d,
2
2
J¼6.8 Hz), 0.93 (1.5H, d, J¼6.8 Hz), 0.99 (1.5H, s), 1.25e1.60 (3H, m),
1.66e1.86 (1H, m), 1.95e2.10 (1H, m), 2.21e2.45 (2H, m), 3.45e3.58
(2H, m), 3.80 (3H, s), 4.41 (1H, s), 4.43 (1H, s), 4.75 (1H, s-like),
4.81e4.84 (1H), 6.87 (2H, d, J¼11 Hz), 7.24e7.27 (2H, m); GCeMS
(
4
2
hexane/EtOAc (10:1) gave 2.08 g of impurities. Further elution with
hexane/EtOAc (4:1) furnished 10.4 g (68%) of 21 as a colorless and
(same conditions as those used for 7); t
R
¼18.25 min (43.1%),
¼18.25 min (70 eV,
viscous oil, n2
2
¼1.5060;
n
max (film): 3401 (br m), 2955 (s), 2869 (s),
18.40 min (55.9%) (total 99.0%); MS of 23 with t
D
R
þ
1
1
0
613 (m), 1586 (w), 1514 (s), 1463 (m), 1363 (m), 1302 (m), 1248 (s),
173 (m), 1093 (s), 1037 (s), 821 (m); (CDCl ): 0.76 (1.4H, s),
.93e0.95 (3H, m), 0.98 (1.6H, s), 1.36e1.60 (5H, m), 1.60e1.80 (3H,
m), 1.98e2.10 (1H, m), 3.80 (3H, s), 3.44e3.54 (2H, m), 4.42 (2H, s),
EI): m/z: 274 (<1) [M ],136 (13), 121 (100), 109 (9), 95 (4), 77 (5), 67
d
H
3
(3), 41 (3); MS of 23 with t
(100), 109 (12), 77 (4), 41 (2). HRMS calcd for C18
found: 274.1947 (short t ), 274.1945 (long t ).
R
¼18.40 min (70 eV, EI): m/z: 229 (8), 121
26 2
H O
: 274.1933,
R
R
6
.87 (2H, d, J¼8.6 Hz), 7.25 (2H, d, J¼8.6 Hz); GCeMS (same con-
ditions as those used for 7); t
7.8%); MS of 21 with t
R
19.77 (40.5%),19.84 min (57.3%) (total
4.24. 2-(1,2-Dimethyl-3-methylenecyclopentyl)ethanol (16)
þ
9
R
¼19.77 min (70 eV, EI): m/z: 278 (<1) [M ],
137 (22), 121 (100), 95 (19), 77 (5), 57 (2); MS of 21 with
DDQ (2.95 g, 13 mmol) was added portionwise over 8 min to
þ
t
R
¼19.84 min (70 eV, EI): m/z: 278 (<1) [M ], 137 (4), 121 (100), 95
a stirred and ice-cooled solution of 23 [anti/syn¼66.5:31.2, 2.34 g
ꢂ
(
10), 77 (5), 57 (3). HRMS calcd for C17
H
26
O
3
: 278.1882, found:
(8.5 mmol)] in CH
2
Cl
2
(70 mL) and water (7 mL) at 5e10 C. The
2
78.1899.
dark-colored mixture was stirred for 30 min at room temperature
ꢂ
(
22 C). It was then diluted with NaHCO
3
solution, and extracted
O. The organic solution was washed with brine, dried
), and concentrated in vacuo. The dark-colored residue
was chromatographed over SiO (50 g). Elution with hexane/
4
.22. 2-(1,2-Dimethyl-3-oxocyclopentyl)ethyl p-
with Et
(MgSO
2
methoxybenzyl ether (22)
4
2
Jones chromic acid (8 N, 8 mL, 64 meq) was added dropwise to
EtOAc (50:1e30:1) gave p-methoxybenzaldehyde (ca. 1 g). Further
elution with hexane/EtOAc (20:1) gave 853 mg (65%) of 16 (rich in
anti-16), which comprised of the following three fractions. The
first (456 mg) of these was a mixture of anti-16 and syn-16 in a GC
a stirred and ice-cooled solution of 21 (9.51 g, 34 mmol) in acetone
ꢂ
(
150 mL) at 5e15 C. The mixture was stirred for further 10 min
after the addition. MeOH (5 mL) was added to destroy the excess
CrO , and the mixture was concentrated in vacuo. The residue was
diluted with water, and extracted with Et O. The Et O extract was
washed successively with water, NaHCO solution and brine, dried
MgSO ), and concentrated in vacuo. The residue was sufficiently
pure 22 (8.80 g, 93%) obtained as a colorless oil, n
film): 2956 (m), 2934 (m), 2871 (m), 1737 (m), 1613 (m), 1586 (w),
514 (m), 1463 (m), 1372 (m), 1302 (m), 1248 (s), 1174 (m), 1095 (m),
037 (m), 821 (m); (CDCl
): 0.80 (1.5H, s), 0.94 (1.5H, d, J¼7.6 Hz),
.95 (1.5H, d, J¼7 Hz), 1.12 (1.5H, s), 1.35e1.60 (2H, m), 1.66e1.98
2H, m), 1.98e2.32 (3H, m), 3.49 (1H, t, J¼6.8 Hz), 3.58 (1H, t,
J¼6.8 Hz), 3.80 (3H, s), 4.41 (1H, s), 4.44 (1H, s), 6.85e6.90 (2H, m),
.22e7.27 (2H, m); GCeMS (same conditions as those used for 7): t
2
2
3
ratio of 81.3:15.4, n
D
¼1.4788;
nmax (film): 3227 (br m), 3073 (w),
2
2
2959 (s), 2938 (s), 2871 (m), 1655 (m), 1454 (m), 1379 (m), 1054
(m), 1037 (s), 1008 (m), 876 (s). The second one (278 mg) was
a 56.3:38.4 mixture, and the third one (119 mg) was a 31.8:64.8
mixture. Comparison of the H NMR spectra of these three frac-
tions allowed the assignment of the data to each of the isomers. H
3
(
4
2
0
1
D
¼1.5042;
n
max
1
(
1
1
0
NMR data of anti-16:
1.16e1.21 (1H, br s), 1.30e1.40 (4H, m), 1.68e1.76 (1H, m),
d
H
(CDCl
3
): 0.95 (3H, d, J¼7.6 Hz), 1.01 (3H, s),
d
H
3
2.24e2.44 (2H, m), 3.69 (2H, t, J¼7.6 Hz), 4.77 (1H, m), 4.84 (1H,
1
(
m); H NMR data of syn-16;
d
H
(CDCl
3
): 0.69 (3H, s), 0.93 (3H, d,
J¼6.8 Hz), 1.18e1.30 (1H, br), 1.30e1.56 (4H, m), 1.68e1.83 (1H, m),
7
R
2.24e2.46 (2H, m), 3.66e3.80 (2H, m), 4.77 (1H, m), 4.86 (1H, m);
1
9.69 (48.5%), 19.83 min (46.8%) (total 95.3%); MS of 22 with
GCeMS (same conditions as those used for 7): t
R
8.38 (anti-16),
þ
þ
t
R
¼19.69 min (70 eV, EI): m/z: 276 (2) [M ], 137 (28), 121 (100), 111
8.51 min (syn-16); MS of anti-16 (70 eV, EI): m/z: 154 (1) [M ], 139
(6), 121 (26), 110 (47), 109 (100), 108 (30), 107 (26), 95 (25), 93 (40),
81 (25), 79 (27), 67 (45), 55 (18), 53 (15), 41 (27); MS of syn-16
(
12), 77 (5), 55 (4); MS of 22 with t
R
¼19.83 min (70 eV, EI): m/z: 276
þ
(
1) [M ], 231 (3), 137 (7), 121 (100), 111 (11), 77 (4), 55 (3). HRMS
þ
calcd for C17
H O
24 3
: 276.1725, found: 276.1740 (short t
R
), 276.1740
(70 eV, EI): m/z: 154 (<1) [M ], 139 (4), 121 (13), 110 (10), 109
(
long t ).
R
(100), 108 (16), 107 (12), 95 (9), 93 (35), 81 (12), 79 (15), 67 (26), 55

K. Mori / Tetrahedron 72 (2016) 6578e6588
6587
(
(
11), 41 (16). HRMS calcd for C10
anti-16), 154.1372 (syn-16).
H
18O: 154.1358, found: 154.1374
m), 2.09 (3H, s), 2.81 (2H, m), 6.01 (1H, br s). HRMS calcd for
9 14 2
C H O : 154.0994, found: 154.1012.
4
.25. (1,2-Dimethyl-3-methylenecyclopentyl)acetaldehyde (1)
4.28. 2-(1,2-Dimethyl-2-cyclopentenyl)acetic acid (26)
4
.25.1. anti-Rich 1. Diacetoxyiodobenzene (DAIB, 1.13 g, 3.5 mmol)
A solution of 25 (1.71 g, 11 mmol) in dry THF (5 mL) was added
was added to a stirred solution of 16 (anti/syn¼81.3:15.4, 411 mg,
over 2 min to a stirred solution of LiN(i-Pr)
2
(TCI, 1.5 M in THF, PhEt
2
.7 mmol) and azadol (TCI, 30 mg, 0.2 mmol) in CH
2
Cl
2
(10 mL). The
ꢂ
and heptane, 8.7 mL, 13 mmol) at ꢁ78 C under argon. Then TMSCl
ꢂ
mixture was stirred for 45 min at room temperature (22 C). The
oxidation was slightly exothermic. Then the solution was washed
(
1.5 mL¼1.18 g, 11 mmol) was added in one portion to the stirred
ꢂ
ꢂ
mixture at ꢁ78 C. The mixture was stirred and heated at 65 C for
with an aqueous solution of NaHCO
was separated, and the aqueous layer was extracted with Et
combined organic solution was dried (MgSO ), and concentrated in
vacuo. The residue was chromatographed over SiO (20 g). Elution
with hexane/EtOAc (50:1) gave 332 mg (82%) of anti-rich 1, which
3
and Na S
2 2
O
3
. The CH
2
Cl
2
layer
2
.5 h, and the reaction was quenched by adding MeOH (3 mL). The
2
O. The
ꢂ
mixture was stirred for 10 min at room temperature (20 C), and
4
extracted with 5% NaOH solution (10 mLꢃ3). The aqueous solution
2
2
was washed with Et O, acidified with dil HCl, and extracted with
Et
brine, dried (MgSO
of 26 as an oil, max (film): 3040e2690 (br m), 2961 (m), 2934 (m),
706 (s), 1442 (m), 1408 (m), 1312 (m), 1287 (m), 1235 (m);
CDCl ): 1.13 (3H, s), 1.63 (3H, s), 1.66e1.78 (1H, m), 2.09e2.18 (1H,
m), 2.18e2.26 (2H, m), 2.30 (1H, d, J¼14 Hz), 2.39 (1H, d, J¼14 Hz),
.32 (1H, br s).
2
O. The Et
2
O solution was washed successively with water and
was distilled to give 243 mg (69%) of anti-rich
1
(anti/
4
), and concentrated in vacuo to give 0.56 g (33%)
ꢂ
23
syn¼85.6:14.0) as a colorless oil, bp 70e72 C/6 Torr; n
D
¼1.4708;
n
n
max (film): 3074 (w), 2959 (m), 2873 (m), 2731 (w), 1721 (s), 1655
1
(
d
H
(
w), 1455 (w), 1382 (w), 881 (m). The following NMR data show
signals due to anti-1. (400 MHz, C
): 0.70 (3H, d, J¼7.6 Hz),
.87 (3H, s),1.06e1.15 (1H, m),1.57e1.62 (1H, m),1.68e1.73 (2H, m),
.74e1.84 (1H, m), 2.02e2.26 (2H, m), 4.78 (1H, m), 4.85 (1H, m),
3
d
H
6 6
D
0
1
5
9
.48 (1H, t, J¼2.4 Hz);
C 6 6
d (100 MHz, C D ): 12.06, 24.78, 28.95,
3
5.49, 43.29, 47.15, 50.39, 105.77, 155.77, 201.51; GCeMS (same
4.29. 2-(1,2-Dimethyl-2-cyclopentenyl)ethanol (27)
conditions as those used for 7): t
R
7.04 (85.6%, anti-1), 7.16 min
þ
(
14.0%, syn-1); MS of anti-1 (70 eV, EI): m/z: 152 (<1) [M ], 137 (3),
A solution of 26 (0.56 g, 3.6 mmol) in dry THF (2 mL) was added
134 (2), 123 (3), 119 (7), 109 (32), 108 (100), 95 (19), 93 (63), 92 (18),
4
dropwise to a stirred and ice-cooled suspension of LiAlH (0.25 g,
8
1 (16), 79 (16), 77 (14), 67 (36), 55 (13), 53 (15), 41 (25). HRMS of
16O: 152.1201, found: 152.1212.
6.5 mmol) in dry THF (8 mL). The mixture was stirred and heated
under reflux for 1.5 h. After cooling, the mixture was acidified with
anti-1 calcd for C10
H
ice and dil HCl, and extracted with Et
washed successively with water, NaHCO
(MgSO ), and concentrated in vacuo to give 0.35 g (69%) of 27 as
a colorless oil, n
(s), 2852 (s), 1655 (w), 1453 (m), 1378 (w), 1055 (m), 1012 (m), 797
(w); (CDCl
): 1.02 (3H, s), 1.35e1.50 (1H, br), 1.62 (3H, d, J¼2 Hz),
1.64e1.70 (2H, m), 1.85e1.90 (2H, m), 2.15e2.22 (2H, br m),
2
O. The Et
solution and brine, dried
2
O extract was
4
.25.2. syn-Rich 1. In the same manner, 1.67 g (10.9 mmol) of syn-
3
rich 16 (anti/syn¼2:3) was oxidized with azadol (60 mg, 0.4 mmol)
4
2
2
and DAIB (4.70 g, 14.6 mmol) in CH
2
Cl
2
(30 mL) to give 1.19 g (72%)
D
¼1.4738;
nmax (film): 3236 (br m), 3037 (w), 2952
ꢂ
of syn-rich 1 (anti/syn¼38:0:61.6) as a colorless oil, bp 75e77 C/
Torr; n2
4
¼1.4690;
.19 (1H, s),1.44e1.90 (3H, s), 2.00e2.20 (1H, m), 2.24e2.54 (3H, m),
.80 (1H, m), 4.90 (1H, m), 9.84 (0.4H, m), 9.88 (0.6H, m); GCeMS
d
(CDCl
): 0.83 (2H, s), 0.96 (3H, d, J¼6.8 Hz),
d
7
1
4
D
H
3
H
3
3.60e3.68 (2H, m), 5.28 (1H, d, J¼2 Hz). HRMS calcd for C
9
H16O:
(
(
(
(
same conditions as those used for 7): t
61.6%); MS of syn-rich 1 (70 eV, EI): m/z: 152 (<1) [M ], 119 (2), 109
19), 108 (100), 93 (80), 91 (16), 79 (11), 77 (11), 67 (21), 55 (9), 53
11), 41 (16). HRMS of syn-1 calcd for C10H16O: 152.1201, found:
R
7.04 (38.0%), 7.18 min
140.1201, found: 140.1201.
þ
4.30. 2-(1,2-Dimethyl-2-cyclopentenyl)ethyl PMB ether (20)
from 27
152.1215.
t-BuOK (366 mg, 3 mmol) and p-methoxybenzyl chloride
0.41 mL¼470 mg, 3 mmol) were added to a solution of 27 (350 mg,
4
.26. 2,3-Dimethyl-2-cyclopenten-1-ol (24)
A solution of 2 (3.30 g, 30 mmol) in dry Et
(
2
.5 mmol) in dry THF (5 mL) and dry DMF (1 mL). The mixture was
2
O (10 mL) was added
ꢂ
stirred and heated at 60 C for 1 h. Work-up as reported for 19 in
dropwise over 20 min to a stirred and ice-cooled suspension of
LiAlH
4.19 gave 1.01 g of crude 20, which was chromatographed over SiO
2
ꢂ
4
(570 mg, 15 mmol) in dry Et
2
O (30 mL) at 5e10 C. The
ꢂ
(
2
8 g). Elution with hexane/EtOAc (50:1) afforded 596 mg (quant.) of
0 as a colorless oil. Its IR, H NMR and MS spectra were identical
mixture was stirred for 2 h at 5e10 C. Then excess LiAlH
destroyed by the addition of water. The mixture was acidified with
ice and dil. HCl/NH Cl solution, and extracted with Et O. The Et
solution was washed successively with water, NaHCO solution and
brine, dried (MgSO ), and concentrated in vacuo to give 3.66 g
quant) of crude 24 as an oil, max (film): 3300 (br s), 2964 (s), 2914
4
was
1
with those of 20 obtained by ring-closing metathesis of 19 as de-
scribed in 4.20.
4
2
2
O
3
4
(
(
(
n
Acknowledgements
s), 2855 (s), 1684 (w), 1442 (m), 1380 (m), 1330 (m), 1182 (m), 1063
s), 1029 (s), 993 (s).
I thank Mr. M. Kimura (President, Toyo Gosei Co., Ltd) and Mr. Y.
Kimura (CEO, Toyo Gosei Co., Ltd) for their support. I am indebted to
Dr. J. Tabata (National Agriculture and Food Research Organization,
Tsukuba) for kindly sharing the structure 1 with me prior to pub-
4
.27. 2,3-Dimethyl-2-cyclopentenyl acetate (25)
Acetic anhydride (10 mL) was added to a solution of crude 24
3 2
lication, and also for carrying out the AgNO /SiO chromatography
(
3.60 g, 30 mmol) in dry C
5
H
5
N (25 mL). The mixture was stirred
and bioassay of (ꢀ)-1. Mr. Y. Shikichi and Ms. Y. Yamaguchi (Toyo
Gosei Co., Ltd) are thanked for NMR and GCeMS measurements.
Drs. T. Nakamura and Y. Hongo (RIKEN) kindly carried out the
HRMS analyses. Dr. T. Tashiro (Niigata University of Pharmacy and
Applied Life Sciences) and Mr. K. Kikusato (RIKEN) helped me in
preparing the manuscript.
ꢂ
and heated at 40e50 C for 2 h. Conventional work-up was fol-
lowed by distillation to give 1.85 g (40% based on 2, two steps) of 25
ꢂ
21
as a colorless oil, bp 60e63 C/5 Torr; n
D
¼1.4602;
m), 2917 (m), 2853 (m), 1735 (s), 1441 (m), 1371 (m), 1243 (s), 1015
m), 990 (m), 968 (m), 876 (m); (CDCl ): 1.94 (6H, s), 2.05 (2H,
nmax (film): 2970
(
(
d
H
3

6588
K. Mori / Tetrahedron 72 (2016) 6578e6588
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1
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3
1
1