A versatile synthetic approach to grandisol monoterpene pheromone

Article abstract of DOI:10.1007/s12272-011-0904-7

A versatile and efficient synthetic procedure for the grandisol pheromone library has been established. The key feature of our synthesis involves a versatile and highly regioselective Pd(0)-catalyzed intramolecular allylic alkylation for the key cyclobutane skeleton of grandisol. In this connection, the concise synthesis of (±)-grandisol as well as mechanism study of Pd(0)-catalyzed regioselective cyclization as a key reaction have also been accomplished.

Full text of DOI:10.1007/s12272-011-0904-7

Arch Pharm Res Vol 34, No 9, 1437-1442, 2011
DOI 10.1007/s12272-011-0904-7
A Versatile Synthetic Approach to Grandisol Monoterpene
Pheromone
Young Taek Han, Nam-Jung Kim, Jong-Wha Jung, Hwayoung Yun, Sujin Lee, and Young-Ger Suh
College of Pharmacy, Seoul National University, Seoul 151-742, Korea
(Received March 31, 2011/Revised May 4, 2011/Accepted May 7, 2011)
A versatile and efficient synthetic procedure for the grandisol pheromone library has been
established. The key feature of our synthesis involves a versatile and highly regioselective
Pd(0)-catalyzed intramolecular allylic alkylation for the key cyclobutane skeleton of grandisol.
In this connection, the concise synthesis of (±)-grandisol as well as mechanism study of Pd(0)-
catalyzed regioselective cyclization as a key reaction have also been accomplished.
Key words: Synthesis, Grandisol, Pheromone, Palladium, Pesticide
pathway to the grandisol via Pd(0)-catalyzed regio-
selective cyclization of allylic carbonate.
Selected by Editors, See page 1399
The Pd(0)-catalyzed intramolecular alkylations of
allylic carbonate have been considered as one of the
effective synthetic methods to prepare carbocycles with
INTRODUCTION
Recently, the use of pesticide has been criticized high chemo-, regio- and stereo-selectivity (Trost, 1989).
because of its harmful effect on the human and Recently, we have been working on regio- and stereo-
wildlife. However, considering that insect pheromone selective synthesis of cyclohexanes and cyclopentanes
analogs just interfere in their communication, an via Pd(0)-catalyzed intramolecular alkylation of the
alternative approach to chemical control by using corresponding allylic carbonates (Suh et al., 2000). In
insect pheromone analogs has been attracting signifi- this connection, we investigated regio- and stereo-
cant interests from the chemists and biologists. In this selective Pd(0)-catalyzed intramolecular allylic alkyla-
sense, grandisol (Fig. 1), which is one of the active tions for the synthesis of biologically and structurally
components of aggregating pheromone isolated from interesting natural products consisting of cyclobutane
male boll weevils (Katzenellenbogen, 1976) and other skeleton.
species (Rosini et al., 1991), has been on focus because
of its latent pesticidal effect (Rosini and Marotta, 1985)
as well as structurally unique cyclobutane skeleton
possessing adjacent two chiral centers. Accordingly a
large number of its synthetic studies were carried out
to date (Narasaka et al., 1991). More recently, we have
also been interested in grandisol pheromone library in
connection with development of insect pheromone
analogs. Thus, we have worked on development of ver-
satile and efficient synthetic procedures for grandisol
pheromone. We herein report an efficient synthetic
Fig 1. Structure of grandisol
MATERIALS AND METHODS
General procedure
Correspondence to: Young-Ger Suh, College of Pharmacy, Seoul
National University, Seoul 151-742, Korea
Tel: 82-2-880-7875, Fax: 82-2-888-0649
E-mail: ygsuh@snu.ac.kr
Unless noted otherwise, all starting materials were
obtained from commercial suppliers and were used
without further purification. Air and moisture sensi-
1437

1438
Y. T. Han et al.
tive reactions were performed under an argon atmos- 1448, 1324, 1148; HRMS (FAB+) calcd for C13H17O4S
phere. Flash column chromatography was performed (M+H+): 269.0848, found 269.0844.
using silica gel 60 (230-400 mesh, Merck) with indi-
cated solvents. Thin-layer chromatography was per-
formed using 0.25 mm silica gel F254 plates (Merck).
Ethyl (2-methylallyl) carbonate (7)
To a solution of 1-methylpropenol (2.4 g, 33.28
Tetrahydrofuran (THF) was distilled from sodium mmol) and pyridine (4 mL, 49.9 mmol) in benzene
benzophenone ketyl. N,N-dimethyl formamide (DMF) (100 mL), ethyl chloroformate (4.2 mL, 43.26 mmol)
and dimethyl sulfoxide (DMSO) were distilled under was added slowly over 10 min at 0oC. The reaction
reduced pressure from calcium hydride and stored mixture was stirred for 3 h at room temperature and
over 4 Å molecular sieves under argon. Dichloromethane quenched with aq. NH4Cl. The mixture was diluted
was distilled from calcium hydride. All solvents used with ethyl acetate and the combined organic phase
for routine isolation of products and chromatography was washed with water and brine, dried over MgSO4,
were reagent grade and distilled. Reaction flasks were and concentrated in vacuo. Flash column chromatog-
oven dried at 120oC. 1H- and 13C-NMR spectra were re- raphy (EtOAc-Hexane = 1 : 3) of the residue afforded
corded on a JEOL LNM-LA 300 (300 MHz), Brucker FT-
NMR AVANCE 400 (400 MHz), or FT-NMR AVANCE MHz)
500 (500 MHz) spectrometer as solutions in deuterio- 4.05 (q, 2H,
chloroform (CDCl3). Chemical shifts were expressed in 7.14 Hz); 13C-NMR (CDCl3, 500MHz)
parts per million (ppm, ) and tetramethylsilane (TMS) 112.9, 70.4, 63.5, 18.9, 13.9.
7
(4.37 g, 91%) as yellowish oil. 1H-NMR (CDCl3, 300
4.86 (s, 1H), 4.80-4.78 (m, 1H), 4.38 (s, 2H),
= 7.1 Hz), 1.62 (s, 3H), 1.57 (t, 3H,
154.7, 139.2,
δ
J
J =
δ
δ
1
was use as an internal standard. H-NMR data were
reported in the order of chemical shift, multiplicity (s,
singlet; d, doublet; t, triplet; q, quartet; m, multiplet
and/or multiple resonance), number of protons and
coupling constant in herz (Hz). Infrared spectra were
Methyl 7-((ethoxycarbonyl)oxy)-6-methyl-2-
(phenylsulfonyl)hept-5-enoate (3)
A solution of methyl 2-(phenylsulfonyl)hex-5-enoate
5
(156 mg, 0.58 mmol), allylic carbonate
7
(504 mg,
(25
recorded on Jasco FT/IR-4200 or Perkin-Elmer 1710 3.49 mmol) and Grubbs’ 2nd generation catalyst
8
FT-IR spectrometer. Low resolution mass spectra mg, 0.03 mmol) in CH2Cl2 (10 mL) was refluxed for 10
were obtained on VG Trio-2 GC-MS. High resolution h. After the reaction mixture was cooled to room
mass spectra were obtained on a JEOL JMS-AX 505 temperature, DMSO (1 mL) was added. The reaction
wA and JEOL JMSHX/HX 110A spectrometer. Energy mixture was stirred overnight and then concentrated
minimizations were calculated using Gasteiger-Hückel in vacuo. Flash column chromatography (EtOAc-
charge and Tripos force field by the SYBYL 6.4 software. Hexane = 1 : 5) of the residue afforded
3
(185 mg,
83%) as yellowish oil. H-NMR (CDCl3, 300 MHz)
7.82-7.79 (m, 2H), 7.66-7.62 (m, 1H), 7.55-7.50 (m, 2H),
1
δ
Methyl 2-(phenylsulfonyl)hex-5-enoate (5)
To a solution of 60% sodium hydride (in mineral oil, 5.31 (m, 1H), 4.41 (s, 2H), 4.16-4.07 (m, 2H), 3.92-3.87
440 mg, 11.48 mmol) in DMF (10 mL), a solution of (m, 1H), 3.63 (s, 3H), 2.03-1.98 (m, 4H), 1.54 (s, 3H),
methyl benzenesulfonylacetate
4 δ 166.1,
(2 g, 9.35 mmol) in 1.27-1.70 (m, 3H); 13C-NMR (CDCl3, 400 MHz)
DMF (10 mL) was added slowly over 10 min at 0oC. 154.9, 136.9, 134.2, 132.1, 129.1, 129.0, 126.5, 72.6,
The reaction mixture was stirred for 1 h at room tem- 70.0, 63.8, 52.8, 26.5, 24.8, 14.1, 13.7; IR (neat) cm−1:
perature and cooled below 0oC. A solution of 4-bromo- 1743, 1447, 1325, 1260, 1149; LRMS (FAB) m/z 385
1-butene
6
(1.40 mL, 13.18 mmol) in DMF (10 mL) (M+H+).
was added dropwise to the reaction mixture for 30
min and stirred for 1 h at 70oC. The reaction mixture
was quenched with aq. NH4Cl, and diluted with ethyl
acetate. The combined organic phase was washed with
Methyl 1-(phenylsulfonyl)-2-isoprophenylcyclo-
butanecarboxlate (9)
A solution of allylic carbonate
3 (33 mg, 85.9 mmol)
water and brine, dried over MgSO4, and concentrated and Pd(PPh3)4 (5.0 mg, 4.3 mmol) in DMSO (1.7 mL)
in vacuo. Flash column chromatography (EtOAc- was stirred for 3 h at room temperature. The reaction
Hexane = 1 : 5) of the residue afforded
5
(2.13 g, 85%) mixture was diluted with ethyl acetate (5 mL) and
as yellowish oil. H-NMR (CDCl3, 300 MHz) 7.83- filtrated through silica gel plug. The filtrate was con-
7.79 (m, 2H), 7.66-7.61 (m, 1H), 7.55-7.50 (m, 2H), 5.69- centrated in vacuo. Column chromatography (EtOAc-
1
δ
5.55 (m, 1H), 4.97-4.89 (m, 2H), 3.96-3.87 (m, 1H), 3.55 Hexane = 1 : 5) of the residue afforded
9
along with
' (20.0 mg) and 10. Major di-
7.86-7.80
(s, 3H), 2.15-1.90 (m, 4H); 13C-NMR (CDCl3, 400 MHz) minor diastereomer
9
1
δ
166.2, 154.9, 136.9, 135.5, 134.2, 129.1, 128.9, 128.3, astereomer
9
: H-NMR (CDCl3, 300 MHz)
δ
116.7, 69.9, 52.8, 30.6, 25.7; IR (neat) cm−1: 1741, (m, 2H), 7.64-7.56 (m, 1H), 7.54-7.47 (m, 2H), 4.90 (s,

A Versatile Synthesis for Grandisol
1439
1H), 4.74 (s, 1H), 3.83 (t, 1H,
J
= 9.3 Hz), 3.58 (s, 3H), 174.4, 146.8, 144.8, 110.6, 108.9, 51.6, 51.2, 45.1, 44.2,
2.85-2.75 (m, 1H), 2.51-2.42 (m, 1H), 2.28-2.04 (m, 2H), 44.0, 42.9, 23.6, 23.4, 21.3, 21.0, 20.1, 20.0; IR (neat)
1.71 (s, 3H); 13C-NMR (CDCl3, 400M Hz) 166.72, cm−1: 1734, 1649, 1169, 892.
δ
143.00, 137.28, 133.98, 129.54, 128.84, 113.98, 53.50,
52.51, 45.58, 24.00, 21.13, 19.75 ; IR 1735, 1647, 1446,
1310, 1215, 1153; HRMS (FAB+) calcd for C15H19O4S
RESULTS AND DISCUSSION
(M+H+): 295.1004, found 295.1033; minor diastereomer
Our synthetic plan shown in Scheme 1 involves an
1
9': H-NMR (CDCl3, 300 MHz)
δ
7.82-7.80 (m, 2H), effective construction of the known synthetic interme-
(Mori and Fukamatsu, 1992) possessing the
= 10.3 Hz), 2.77- key cyclobutane skeleton of grandisol. It can be syn-
2.48 (m, 3H), 1.94-1.84 (m, 1H), 1.80 (s, 3H); HRMS thesized by a sequence of alkylation of the starting
(FAB+) calcd for C15H19O4S (M+H+): 295.1004, found benzenesulfonyl acetate
, olefin cross metathesis and
Pd(0)-catalyzed intramolecular allylic alkylation of the
7.62-7.60 (m, 1H), 7.52-7.50 (m, 2H), 5.13 (s, 1H), 5.07 diate
(s, 1H), 3.68 (s, 3H), 3.50 (t, 1H,
2
J
4
295.0994.
resulting allylic carbonate
lation.
3 followed by desulfony-
Methyl 1-(phenylsulfonyl)-cyclohex-3-enecar-
boxylate (10)
A solution of propenyl cyclobutane
Our synthesis commenced with preparation of the
as shown in Scheme 2. Alkyla-
mmol) and Pd(PPh3)4 (1.2 mg, 1.0 mmol) in CH2Cl2 (0.4 tion of commercially available methyl benzenesulfony-
mL) was refluxed for 30 min. The reaction mixture lacetate with 4-bromo-1-butene and coupling of
was filtrated through silica gel plug and the filtrate the resulting methyl hexanoate with known allyl
was concentrated in vacuo. Column chromatography carbonate (Deska and Kazmaier, 2007) in the pre-
(EtOAc-Hexane = 1 : 9) of the residue afforded 10. 1H- sence of Grubbs’ 2nd generation catalyst
(Scholl et
NMR (CDCl3, 300 MHz) 7.81-7.77 (m, 2H), 7.69-7.60 al., 1999) afforded
(m, 1H), 7.57-7.51 (m, 2H), 5.30 (s, 1H), 3.63 (s, 3H), We initially examined the reaction conditions for the
2.62 (s, 2H), 2.42-2.33 (m, 1H), 2.13-2.90 (m, 3H), 1.66 requisite cyclization of . Unfortunately, upon cycliza-
(s, 3H); 13C-NMR (CDCl3, 400 MHz)
167.8, 135.6, tion of in the presence of Pd(0) and PPh3 in CH2Cl2,
9 (6 mg, 20.4 cyclization precursor 3
4
6
5
7
8
δ
3.
3
δ
3
134.2, 130.7, 130.14, 128.8, 122.8, 72.7, 53.0, 31.6, 24.5, we obtained cyclohexene 10 as a sole product (entry
23.5, 22.8; HRMS (FAB+) calcd for C15H19O4S (M+H+): 1). This result was likely due to the preferred 6-endo-
295.1004, found 295.1019.
trig cyclization rather than the desired 4-exo-trig
cyclization (Trost, 1989) leading to the purposed cyclo-
butane
regioselctivity is summarized in Table I. Cyclization of
in the presence of Pd(PPh3)4 in DMSO for 3 h pro-
9. Our effort for the improved results including
Methyl 2-isoprophenylcyclobutanecarboxlate
(2)
To a solution of cyclobutane
9
(45 mg, 0.15 mmol)
3
and Na2HPO4 (218 mg, 1.53 mmol) in anhydrous vided the best results in terms of yield and efficiency
methanol (1 mL), 6% Na/Hg amalgam (490 mg, 1.3 (entry 7). Notably, reactions in CH2Cl2 at room tem-
mmol) was added at room temperature. The reaction perature afforded the undesirable cyclohexene 10
mixture was stirred for 2 h. The resultant mixture was instead of cyclobutane
diluted with ethyl acetate and separated by decanta- solvents, formation of cyclohexene 10 was suppressed
tion. The organic layer was concentrated in vacuo although the reactions were not completed (entry 5
Column chromatography (Ether-Pentane = 1 : 20) of and 6). Cyclizaton in the presence of Pd(PPh3)4 pro-
the residue afforded
(18 mg). 1H-NMR (CDCl3, 500 vided the best yield compared to that in the presence
MHz) 4.82, 4.74, 4.70 (each s, total 2H), 3.67, 3.60 of Pd(dppe)2, Pd2(dba)3 (entry 8, 9 and 10). However,
9 (entry 2, 3 and 4). In polar
.
9
δ
(each s, total 3H), 3.35-2.94 (m, 2H), 2.14-1.80 (m, 4H), diastereoselectivity of cyclobutane
9 in all cases was
1.66 (s, 3H); 13C-NMR (CDCl3, 300 MHz)
δ 175.0, higher than 25:1.
Scheme 1. Retrosynthetic scheme

1440
Y. T. Han et al.
Scheme 2. Synthesis of the cyclization precursor
3
Table I. Optimization of Pd(0)-catalyzed intramolecular allylic alkylation
Entry
Ligan (mol%)
Temp (oC)
Solvent
Time
Result (
3
:
9
:
10b c
)
Yield (%)d
1
2
3
4
5
6
7
8
9
PPh3 (5)
PPh3 (5)
PPh3 (5)
PPh3 (5)
PPh3 (5)
PPh3 (5)
PPh3 (5)
dppee (10)
dppe (10)
dbaf (5)
reflux
rt
rt
rt
rt
rt
rt
rt
rt
rt
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
dioxane
DMSO
CH2Cl2
DMSO
DMSO
10 min
only 10
1
3 h
5 h
1.4 : 1 : 0.0
0.4 : 1 : 0.1
0 : 1 : 0.4
2.3 : 1 : 0.0
0.5 : 1 : 0.0
0 : 1 : 0.1
no reaction
2 : 1 : 0.0
10 : 1 : 0.0
32
53
57
21
58
79
1
10 h
1
5 h
3 h
1
13 h
10 h
40 h
24 h
35
-
10
aReactions performed at 0.05 M concentration.
bDiastereomeric ratio was greater than 25:1 in every case, and each diastereomer was characterized by NOEs.
cThe ratio was determined by integrating the singlet hydrogen in 1H-NMR spectrum of the reaction mixture.
dIsolated yield of propenyl cyclobutane
edppe: Bis(diphenylphosphino)ethane
fdba: Dibenzylideneacetone
9.
Scheme 3. Completion of formal synthesis of (±)-grandisol
Finally, desulfonylation of the cyclization product
9
terested in mechanism of regioselectivities (Zucco et
with 6% sodium amalgam furnished the key inter- al., 1995). Interestingly, formation of cyclohexene 10
mediate , which is identical with the reported inter- increased as the reaction time extended. On the basis
mediate in all aspects (Scheme 3). of this observation, it was supposed that cyclohexene
Although the cyclization in the presence of Pd(PPh3)4 10 did not directly form by the 6-endo-trig cyclization
in DMSO provided best result, we were further in- but by interconversion of cyclobutane , which was
2
3
9

A Versatile Synthesis for Grandisol
1441
ACKNOWLEDGEMENTS
This study was supported by grant of the Korea
Healthcare technology R&D Project, Ministry for
Health, Welfare & Family Affairs, Republic of Korea
(A092006).
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9
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In summary, we have achieved formal synthesis of
(±)-grandisol
mediate from commercially available methyl ben-
zenesulfonylacetate via four step sequence in 43.4%
1 by synthesis of the key advanced inter-
2
4
overall yield. The key features of our synthesis involve
high regioselective Pd(0)-catalyzed intramolecular
allylic alkylation for cyclobutane system. In addition,
we elucidated the mechanism of the regioselectivity,
which includes a sequence of Pd(0)-catalyzed facile C-
C bond cleavage of the constrained cyclobutane sys-
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importantly utilized for preparation of the grandisol
chemical library.

1442
Y. T. Han et al.
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