Total synthesis of (±)-3-hydroxy-β-ionone through a ring-closing enyne metathesis

Article abstract of DOI:10.1055/s-0031-1290353

The total synthesis of (±)-3-hydroxy - ionone, a bisnor-sesquiterpene having allelopathic activity, has been accomplished employing an enyne metathesis for the construction of the C1-C8 segment and two-carbon elongation via a nitrile oxide-alkene [3+2] cycloaddition as the key steps. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290353

LETTER
577
Total Synthesis of ( )-3-Hydroxy-b-ionone through a Ring-Closing Enyne
Metathesis
Total
S
ynthesis of
a
(
)-3-Hydr
i
oxy-
b
-
s
ionone uke Kikuchi, Masahiro Yoshida, Kozo Shishido*
Graduate School of Pharmaceutical Sciences, The University of Tokushima, 1-78-1 Sho-machi, Tokushima 770-8505, Japan
Fax +81(88)6337287; E-mail: shishido@ph.tokushima-u.ac.jp
Received 6 December 2011
ment 3 would be assembled through a ring-closing enyne
metathesis of the acyclic precursor 5, which can be pre-
pared from 3,3-dimethylpent-4-ynal (6)8 and (2-methyl-
allyl)magnesium chloride (7). The C1–C7 aldehyde
segment 4 might be derived from 3 by oxidation. Since a
ring-closing enyne metathesis directed toward the synthe-
sis of the vinylcyclohexenes employing the substrate pos-
sessing the 1,1-disubstituted alkene and the acetylene with
a quaternary carbon center at the propargylic position has
never been reported so far,9 the reaction of 5 would be
synthetically challenging (Scheme 1).
Abstract: The total synthesis of ( )-3-hydroxy-b-ionone, a bisnor-
sesquiterpene having allelopathic activity, has been accomplished
employing an enyne metathesis for the construction of the C1–C8
segment and two-carbon elongation via a nitrile oxide–alkene [3+2]
cycloaddition as the key steps.
Key words: enyne metathesis, total synthesis, ionones, nitrile ox-
ide, cycloaddition
The ionone-type bisnorsesquiterpenes, a widely distribut-
ed class of natural products, are known as natural aroma
constituents. In 2010, 3-hydroxy-b-ionone (1)1,2d and 3-
oxo-a-ionol (2),2 two representatives of ionone-type natu-
ral products, were isolated from an aqueous extracts of
rattail fescue (Vulpia myuros) by Fujii et al. and identified
as growth inhibitors against lettuce, alfalfa, timothy, D.
sanguinalis, and L. multiflorum, namely, allelochemi-
cals.3 During the course of our synthetic studies on natural
products having allelopathic activity,4 we have concen-
trated on developing efficient methods focused on the ion-
one-type bisnorsesquiterpenes. In our previous paper, we
reported the first enantioselective total synthesis of 3-oxo-
a-ionol (2).5 Herein we describe a total synthesis of ( )-3-
hydroxy-b-ionone (1), employing as the key step an enyne
metathesis6 of 5 for the construction of 3,5,5-trimethyl-4-
vinylcyclohex-3-en-1-ol (3, R = H), the C1–C8 segment
of 1. Although several reports on the total syntheses of 1
have been published,7 the syntheses starting from acyclic
precursors are very few. We therefore wanted to develop
a flexible synthetic method, which would enable us to as-
semble a library of diverse compounds analogous to 1 for
biological evaluations (Figure 1).
( )-1
two or three carbons elongation
enyne
metathesis
X
RO
RO
5
3: X = CH2
4: X = O
+
ClMg
O
H
7
6
Scheme 1 Retrosynthetic analysis
Reaction of 6 with the Grignard reagent 7 provided the al-
cohol 5a and the alcohol moiety of which was protected
as the TBS ether to give 5b. Enyne metathesis of 5a,b was
examined with 10 mol% of catalyst and ethylene gas10 in
a toluene solution at 80 °C. Treatment of 5a with the
Grubbs second-generation catalyst 8 or the Hoveyda–
Grubbs second-generation catalyst 9 resulted in decompo-
sition of the starting 5a; none of the cyclized products was
found in the reaction mixture. When a solution of a mix-
ture of 5b and 8 in toluene was heated at 80 °C for four
hours under an atmosphere of argon, the substrate 5b was
recovered. Fortunately, prolonged heating of the solution
for eight hours with ethylene gas resulted in quantitative
formation of the desired vinylcyclohexene 3b along with
the seven-membered diene 10b as an inseparable 2.3:1
mixture. The reaction with the catalyst 9 provided a 3:1
mixture of the cyclized products in 73% yield (Table 1).
O
OH
7
1
8
HO
3-hydroxy-β-ionone (1)
O
3-oxo-α-ionol (2)
Figure 1 Structures of ionone-type allelochemicals
Our synthetic strategy is shown in Scheme 1. We envis-
aged the two or three carbons elongation being achieved
in the last stage of the synthesis. The C1–C8 diene seg-
Desilylation of the mixture of 3b and 10b (Table 1, entry
4) provided a mixture of the corresponding alcohols,
which was separated by HPLC to give 3a11 and 10a12 in
54% and 13% yield, respectively. With the requisite key
SYNLETT 2012, 23, 577–580
Advanced online publication: 13.02.2012
DOI: 10.1055/s-0031-1290353; Art ID: U74711ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.
2
0
1
2

578
D. Kikuchi et al.
LETTER
starting material or the decomposition and the expected
12a–d could not be obtained at all. This result is likely due
to the hindered nature of the vinyl group. The Wittig13 and
the aldol reactions14 of the aldehyde 13a and 13b (pre-
pared from 3a and 3b by oxidative cleavage of the vinyl
group) for obtaining 12a and 1 were also unsuccessful
(Scheme 2).
Table 1 Preparation and Enyne Metathesis of 5a,b
1) 7, THF, 0 °C
2 h, 58%
6
2) TBSOTf, 2,6-lutidine
RO
r.t., 94%
5a: R = H
5b: R = TBS
catalyst
For the carbon chain elongation, it was thought that a ni-
trile oxide–alkene [3+2] cycloaddition15 would be suit-
able. Thus, treatment of 3b with nitroethane, a nitrile
oxide precursor, in the presence of p-chlorophenylisocy-
anate and triethylamine in refluxing benzene for three
hours provided the isoxazoline 14 and the recovered 3b in
19% and 77% yield, respectively (Table 2, entry 1). A
higher yield of 14 was obtained under prolonged reaction
time (Table 2, entry 2). When the reaction was conducted
using N-hydroxyacetimidoyl chloride (15)16 as the nitrile
oxide precursor and triethylamine in benzene at room
temperature, 14 was obtained in 61% yield along with 3b
(39%). The best result was realized by treatment of a so-
lution of 15 in dichloromethane with triethylamine at
room temperature for ten hours, which provided 14 in
75% yield (Table 2, entry 5).
(10 mol%)
+
RO
toluene, 80 °C
ethylene gas
RO
3a: R = H
10a: R = H
10b: R = TBS
3b: R = TBS
Entry
Precursor Catalyst
Time (h) Yield (%)
3/10a
–
1
5a
5a
5b
5b
5b
8
9
8
8
9
2
decomp.
decomp.
recovered
quant.
2
0.5
4
–
3b
4
–
8
2.3:1
3:1
5
3
73
a Determined by 1H NMR spectroscopy.
b Under argon atmosphere instead of ethylene gas.
Table 2 Nitrile Oxide–Alkene [3+2] Cycloaddition
O
N
MesN
Cl
NMes
conditions
3b
MesN
Cl
NMes
Ru
O
Cl
TBSO
14
Ru
Ph
Cl
PCy3
Entry Conditions
Yield of 14 Yield of 3b
(%)a
(%)
8
9
1
2
EtNO2, 4-ClC6H4NCO, Et3N,
benzene, reflux, 3 h
19
77
intermediates 3a,b in hand, we next examined the forma-
tion of the enone part of the natural product. Attempted
cross metathesis of 3a and 3b, derived by resilylation of
3a, with the alkenes 11a–d using catalysts 8 or 9 under
various reaction conditions resulted in the recovery of the
EtNO2, 4-ClC6H4NCO, Et3N,
benzene, reflux, 8 h
52
34
3
4
5
15, Et3N, benzene, r.t., 15 h
15, NaHCO3, EtOAc, r.t., 15 h
15, Et3N, CH2Cl2, r.t., 10 h
61
63
75
39
–
b
a
3b/10b
(Table 1, entry 4)
3b
3a + 10a
–
54% 13%
a Mixture of diastereoisomers (1:1 to 1:5).
R
8 or 9
R
TBSO
Cl
N
12a–d
11a: R = COMe
11b: R = CH(OH)Me
11c: R = CO2Et
11d: R = CN
OH
15
H
Wittig etc.
or aldol
c for 3a
d for 3b
O
3a,b
12a or 1
The isoxazoline 14 thus prepared was exposed to the re-
ductive hydrolysis conditions17 under an atmosphere of
hydrogen in the presence of Raney Ni (W2) and trimethyl
borate in a methanol–dichloromethane–water (10:5:1)
solvent mixture at room temperature for four hours and
provided the b-hydroxy ketone 16 in 74% yield. Dehydra-
tion was realized by acetylation followed by DBU treat-
ment gave the dienone 17, which was converted into ( )-
RO
13a: R = H
13b: R = TBS
Scheme 2 Reagents and conditions: (a) HF·pyridine, THF–pyridine
(4:1), 40 °C, 4 h then separation by HPLC, 54% for 3a, 13% for 10a;
(b) TBSCl, imidazole, 4-DMAP, CH2Cl2, r.t., 2 h, 94%; (c) OsO4 (5
mol%), NMO, acetone–H2O (9:1), r.t. 4 h then NaIO4, MeCN–H2O
(3:2), r.t., 2 h, 66%; (d) OsO4 (2 mol%), NaIO4, MeCN–H2O (3:1),
r.t., 3 h, 72%.
Synlett 2012, 23, 577–580
© Thieme Stuttgart · New York

LETTER
Total Synthesis of ( )-3-Hydroxy-b-ionone
579
3-hydroxy-b-ionone (1)18,19 in 83% yield for the two
steps. All spectral data of the synthetic material were iden-
tical to those published (Scheme 3).7g
(3) Kato-Noguchi, H.; Yamamoto, M.; Tamura, K.; Teruya, T.;
Suenaga, K.; Fujii, Y. Plant Growth Regul. 2010, 60, 127.
(4) For a review, see: (a) Kamei, T.; Morimoto, S.; Shishido, K.
J. Synth. Org. Chem. Jpn. 2006, 64, 1021. For recent
synthetic studies, see: (b) Kanematsu, M.; Soga, K.;
Manabe, Y.; Morimoto, S.; Yoshida, M.; Shishido, K.
Tetrahedron 2011, 67, 4758. (c) Yokoe, H.; Mitsuhashi, C.;
Matsuoka, Y.; Yoshimura, T.; Yoshida, M.; Shishido, K.
J. Am. Chem. Soc. 2011, 133, 8854.
OH
O
H2, Raney Ni (W2), (MeO)3B
MeOH–CH2Cl2–H2O (10:5:1)
r.t., 4 h
14
74%
TBSO
16
(5) Kikuchi, D.; Yoshida, M.; Shishido, K. Tetrahedron Lett.
2012, 53, 145.
(6) For reviews, see: (a) Connon, S. J.; Blechert, S. Angew.
Chem. Int. Ed. 2003, 42, 1900. (b) Poulson, C. S.; Madsen,
R. Synthesis 2003, 1. (c) Diber, S. T.; Giessert, A. Chem.
Rev. 2004, 104, 1317. (d) Mori, M. J. Synth. Org. Chem.
Jpn. 2005, 63, 5.
(7) For the syntheses of racemic 1, see: (a) Loeber, D. E.;
Russell, S. W.; Toube, T. P.; Weedon, C. L. J. Chem. Soc. C
1971, 404. (b) Takazawa, O.; Tamura, H.; Kogami, K.;
Hayashi, K. Bull. Chem. Soc. Jpn. 1982, 55, 1907 . For the
syntheses of optically active 1, see: (c) Mori, K.
Tetrahedron Lett. 1973, 28, 2635. (d) Mayer, H. Helv.
Chim. Acta 1980, 63, 154. (e) Parry, A. D.; Neill, S. J.;
Horgan, R. Phytochemistry 1990, 29, 1033. (f) Ito, M.
J. Chem. Soc., Perkin Trans. 1 1998, 2565. (g) Khachik, F.;
Chang, A. N. J. Org. Chem. 2009, 74, 3875. (h) Khachik,
F.; Chang, A. N. Synthesis 2011, 509.
O
Ac2O, pyridine, 4-DMAP
CH2Cl2, r.t., 5 h
then DBU, r.t., 11 h
95%
RO
3 N HCl (aq)
THF, r.t., 3 h
87%
17: R = TBS
1: R = H
Scheme 3 Conversion of 14 into 1
In summary, we have completed the total synthesis of ( )-
3-hydroxy-b-ionone (1) employing a ring-closing enyne
metathesis for the construction of the C1–C8 segment and
a two-carbon elongation via the nitrile oxide–alkene [3+2]
cycloaddition as the key steps in a longest linear sequence
of eight steps from 3,3-dimethylpent-4-ynal with an over-
all yield of 13%. In addition, it should be emphasized that
the enyne metathesis of the substrate with sterically de-
manding alkene and alkyne functional groups was effec-
tive in producing the substituted vinylcyclohexenol in
moderate yield. The synthetic route developed here is
general and flexible and could be applied not only to the
syntheses of other related ionone-type natural products
but also for assembling a library of compounds for biolog-
ical evaluations.
(8) McMurry, J. E.; Mats, J. R.; Kees, K. L. Tetrahedron 1987,
43, 5489.
(9) For the syntheses of five-membered hetero- and carbocyclic
dienes from the precursors with a 1,1-disubstituted alkene
and an acetylene with a quaternary carbon center at the
propargylic position, see: (a) Kitamura, T.; Sato, Y.; Mori,
M. Chem. Commun. 2001, 1258. (b) Kitamura, T.; Sato, Y.;
Mori, M. Adv. Synth. Catal. 2002, 344, 678. (c) Fürstner,
A.; Ackermann, L.; Gabor, B.; Goddard, R.; Lehmann, C.
W.; Mynott, R.; Stelzer, F.; Thiel, O. R. Chem. Eur. J. 2001,
7, 3236.
(10) Mori, M.; Sakakibara, N.; Kinoshita, A. J. Org. Chem. 1998,
63, 6082.
(11) Analytical Data
IR (neat): 3334, 2922, 1460, 1362, 1049, 918 cm–1. 1H NMR
(400 MHz, CDCl3): d = 6.16 (ddd, J = 13.2, 7.2, 1.6 Hz, 1
H), 5.26 (dd, J = 7.2, 2.4 Hz, 1 H), 4.98 (dd, J = 13.2, 2.4 Hz,
1 H), 4.05–3.92 (m, 1 H), 2.35 (dd, J = 16.8, 5.6 Hz, 1 H),
2.01 (dd, J = 16.8, 6.8 Hz, 1 H), 1.75 (ddd, J = 12.0, 3.2, 2.0
Hz, 1 H), 1.71 (s, 3 H), 1.45 (t, J = 12.0 Hz, 1 H), 1.35 (br s,
1 H), 1.05 (s, 3 H), 1.04 (s, 3 H). 13C NMR (100 MHz,
CDCl3): d = 138.1 (Cq), 134.7 (CH), 125.6 (Cq), 118.7
(CH2), 65.1 (CH), 48.3 (CH2), 42.2 (CH2), 36.6 (Cq), 30.0
(CH3), 28.3 (CH3), 21.2 (CH3). ESI-HRMS: m/z calcd for
C11H18ONa [M + Na]+: 189.1255; found: 189.1255.
(12) Analytical Data
Acknowledgment
This work was supported financially by a Grant-in-Aid for the Pro-
gram for Promotion of Basic and Applied Research for Innovation
in the Bio-oriented Industry (BRAIN).
References and Notes
(1) (a) Fujimori, T.; Kasuga, R.; Noguchi, M.; Kaneko, H.
Agric. Biol. Chem. 1974, 38, 891. (b) Shibata, S.;
Katsuyama, A.; Noguchi, M. Agric. Biol. Chem. 1978, 42,
195.
IR (neat): 3345, 2965, 2925, 1041, 892 cm–1. 1H NMR (400
MHz, CDCl3): d = 5.99 (s, 1 H), 4.98 (s, 1 H), 4.79 (s, 1 H),
3.99–3.92 (m, 1 H), 2.37 (dd, J = 16.4, 3.2 Hz, 1 H), 2.30
(dd, J = 16.4, 9.6 Hz, 1 H), 1.84 (ddd, J = 13.2, 3.6, 1.6 Hz,
1 H), 1.81 (s, 3 H), 1.70 (dd, J = 13.2, 9.6 Hz, 1 H), 1.45 (br
s, 1 H), 1.15 (s, 3 H), 1.14 (s, 3 H). 13C NMR (100 MHz,
CDCl3): d = 153.5 (Cq), 133.1 (Cq), 127.9 (CH), 111.7
(CH2), 67.7 (CH), 52.0 (CH2), 43.9 (CH2), 37.2 (Cq), 31.8
(CH3), 29.4 (CH3), 26.7 (CH3). ESI-HRMS: m/z calcd for
C11H18ONa [M + Na]+: 189.1255; found: 189.1258.
(13) The Wittig and Horner–Wadsworth–Emmons reactions of
13a,b were examined under various conditions; however,
only starting aldehyde was recovered.
(2) (a) Aasen, A. J.; Kimland, B.; Enzell, C. R. Acta Chem.
Scand. 1971, 25, 1481. (b) Kimland, B.; Aasen, A. J.;
Enzell, C. R. Acta Chem. Scand. 1972, 26, 2177. (c) Aasen,
A. J.; Kimland, B.; Enzell, C. R. Acta Chem. Scand. 1973,
27, 2107. (d) Fujimori, T.; Kasuga, R.; Matsushita, H.;
Kaneko, H.; Noguchi, M. Agric. Biol. Chem. 1976, 40, 303.
(e) Behr, D.; Wahlberg, I.; Nishida, T.; Enzell, C. R. Acta
Chem. Scand. 1978, 32, 391. (f) D’Abrosca, B.;
DellaGreca, M.; Fiorentino, A.; Monaco, P.; Oriano, P.;
Temussi, F. Phytochemistry 2004, 65, 497. (g) Park, J. H.;
Lee, D. G.; Yeon, S. W.; Kwon, H. S.; Ko, J. H.; Shin, D. J.;
Park, H. S.; Kim, Y. S.; Bang, M. H.; Baek, N. I. Arch.
Pharm. Res. 2011, 34, 533.
© Thieme Stuttgart · New York
Synlett 2012, 23, 577–580

580
D. Kikuchi et al.
LETTER
(14) It has been reported that the aldol reaction of 13a with
acetone provided 1; however, the yield was not described.7e
When the reaction was attempted under the same conditions
as reported, 1 was not produced at all.
(15) Kozikowski, A. P. Acc. Chem. Res. 1984, 17, 410.
(16) Zhang, Z.; Curran, D. P. J. Chem. Soc., Perkin Trans. 1
1991, 2627.
1 H), 6.11 (d, J = 16.4 Hz, 1 H), 4.06–3.95 (m, 1 H), 2.44
(dd, J = 17.6, 5.2 Hz, 1 H), 2.30 (s, 3 H), 2.09 (dd, J = 17.6,
9.6, 1 H), 1.80 (ddd, J = 12.4, 3.2, 2.0 Hz, 1 H), 1.78 (s, 3 H),
1.49 (t, J = 12.4 Hz, 1 H), 1.25 (br s, 1 H), 1.12 (s, 3 H), 1.11
(s, 3 H). 13C NMR (100 MHz, CDCl3): d = 198.5 (Cq), 142.3
(CH), 135.7 (Cq), 132.4 (CH), 132.2 (Cq), 64.5 (CH), 48.4
(CH2), 42.8 (CH2), 36.9 (Cq), 30.1 (CH3), 28.6 (CH3), 27.3
(CH3), 21.5 (CH3). ESI-HRMS: m/z calcd for C13H21O2
[M + H]+: 209.1542; found: 209.1539.
(17) Curran, D. P. J. Am. Chem. Soc. 1982, 104, 4042.
(18) Analytical Data
IR (neat): 3409, 2960, 2926, 1672, 1606, 1363, 1257, 1051
(19) The optical resolution has been successfully achieved by
cm–1. 1H NMR (400 MHz, CDCl3): d = 7.21 (d, J = 16.4 Hz,
Khachik et al.7h
Synlett 2012, 23, 577–580
© Thieme Stuttgart · New York

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Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
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