Synthesis of all eight stereoisomers of the germination stimulant strigol

Article abstract of DOI:10.1055/s-2000-8230

(+)-Strigol is a naturally occurring germination stimulant for the seeds of the parasitic weeds Striga and Orobanche. This paper describes the synthesis of all eight stereoisomers of strigol. The absolute configuration of these stereoisomers has been dedu

Full text of DOI:10.1055/s-2000-8230

1944
SPECIAL TOPIC
Synthesis of All Eight Stereoisomers of the Germination Stimulant Strigol
Anat Reizelman, Marc Scheren, Gérard H.L. Nefkens, Binne Zwanenburg*
Department of Organic Chemistry, NSR Institute for Molecular Structure, Design and Synthesis, University of Nymegen, Toernooiveld 1,
6525 ED Nymegen, The Netherlands
Fax +31(24)3653393; E-mail: zwanenb@sci.kun.nl
Received 4 August 2000
O
O
Abstract: (+)-Strigol is a naturally occurring germination stimulant
for the seeds of the parasitic weeds Striga and Orobanche. This pa-
per describes the synthesis of all eight stereoisomers of strigol. The
absolute configuration of these stereoisomers has been deduced
from their CD-spectra.
O
O
8
8b
B
7
C
C
A
A
B
3a
9
6
4
5
O
O
O
D
O
D
O
O
OH
2'
3'
Key words: (+)-strigol, germination stimulants, natural products,
stereoselectivity, lactones
2, (+)-sorgolactone
Me
4'
1, (+)-strigol
Me
O
O
O
O
C
OH
B
Parasitic weeds belonging to the genera Striga,
Orobanche and Alectra cause severe loss of crops in Afri-
ca, Asia and the USA.1,2 The seeds of these parasitic
weeds germinate upon exposure to a chemical substance,
which is present in the root exudate of a potential host
plant. Strigolactones serve as semiochemicals in the
rhizosphere of host plants and some non-host plants that
induce the germination of seeds of root parasitic weeds.
Thus far, four of these germination stimulants have been
isolated viz.: (+)-strigol 1: (+)-sorgolactone 2, alectrol 3
and (+)-orobanchol 4. The first naturally occurring germi-
nation stimulant, (+)-strigol 1, was isolated from the root
exudates of the false host cotton3 (Gossypium hisutum L.)
and its absolute configuration was unambiguously as-
signed by X-ray diffraction.4 The synthesis of all eight ste-
reoisomers of sorgolactone 2,5 which has a structure
closely related to strigol, has been reported by us6a,b and at
about the same time by the Mori group.7 (+)-Orobanchol
3 is an isomer of strigol, which was isolated from root ex-
udates of the host Trifolium pratense.8 It was assumed by
the Mori group that the secondary hydroxy group in orob-
anchol is attached to C-49. Alectrol 4 was isolated for the
first time from the root exudate of Vigna unguiculata10
(host for Striga and Alectra). A structure has been pro-
posed for alectrol, however, it was shown recently, by the
synthesis of the proposed structure, that the spectral data
do not correspond with those of the natural stimulant.11
Strigol itself was shown to be the major Striga germina-
tion stimulant produced by maize (Zea mays L.) and proso
millet (Panicum miliaceum L.).12 This stimulant has been
the target of extensive synthetic studies.4,13-19,25 Thus far,
the synthesis of only four of the conceivable eight stereoi-
somers has been accomplished in an unambiguous man-
ner.18,19
C
A
A
B
O
O
O
O
O
D
OH
D
O
3, alectrol
proposed structure
Me
4, (+)-orobanchol
Me
Retrosynthetically, there is a logical disconnection be-
tween the ABC skeleton and the D-ring. Thus, the synthe-
sis of the ABC-part was undertaken first. The starting
material is compound 5 which is readily available on a
multigram scale following a literature procedure.20 Selec-
tive reduction of 5 using LiAl(OBut)3H gave hydroxy es-
ter 6 as the major isomer in 80% yield. The acid 7 was
obtained from 6 by dehydration and subsequent hydroly-
sis. The corresponding acid chloride of this acid 7 was
subjected to an intermolecular Friedel-Crafts reaction
with vinyl silane, followed by Nazarov cyclization to give
AB-fragment 8.21 This ketone was then converted via a
standard procedure22 to 9, which was subjected to Luche
reduction employing sodium borohydride in the presence
of cerium trichloride.24 The thus obtained hydroxy acid
underwent spontaneous lactonization to give the strigol
ABC-fragment (±)-10 (Scheme 1).
A crucial step in the sequence to the appropriately func-
tionalized ABC-part of strigol is the introduction of the
hydroxy group in the A-ring. A highly regioselective oxi-
dation of (±)-10 employing selenium dioxide in dioxane,
followed by oxidation with PCC furnished the isomeric
ketone mixture (±)-11a and (±)-11b in a ratio of 15:1
(Scheme 2). These ketones could be separated by column
chromatography. This oxidation of the intermediates alco-
hols to the ketones (±)-11a and (±)-11b was necessary to
facilitate the chromatographic separation. Luche
reduction24 of (±)-11a gave (±)-12a and (±)-12b in a ratio
of 1:1. After separation of the hydroxy lactones (±)-12a
and (±)-12b, each isomer was formylated and coupled to
The aim of the research described in this paper is the syn-
thesis of all eight stereoisomers of strigol. Evaluation of
their respective bioactivities towards Striga and
Orobanche seeds will provide more insight in the struc-
ture-activity relationship of these germination stimulants.
Synthesis 2000, No. 13, 1944–1951 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Synthesis of All Eight Stereoisomers of the Germination Stimulant Strigol
1945
pounds were in full accordance with those reported previ-
ously (see Experimental Section).
O
O
LiAl(OBut)3H
1) POCl3, pyridine
2) HCOOH, H2SO4
OMe
OMe
OH
Alternatively, the hydroxylation of the A-ring could be
accomplished after the D-ring had been coupled to the
formylated ABC unit (±)-10 (Scheme 3). The thus ob-
tained mixture of (±)-13a and (±)-13b was separated by
column chromatography. Each isomer was then oxidized
with selenium dioxide to give (±)-1c and (±)-1d, respec-
tively. Inversion of the configuration at C-5 of (±)-1c and
(±)-1d to give (±)-1a and (±)-1b, respectively, could be
accomplished by oxidation with PCC in dichloromethane
followed by Luche reduction.24 This stereoselectivity of
the selenium dioxide oxidation of (±)-13a or (±)-13b is
quite remarkable. This stereochemical outcome can be ex-
plained by assuming that in the first step, which in essence
is an ene-type reaction, the approach of the double bond
to SeO2 is taking place from the opposite side of the lac-
tone ring. Subsequent [2,3]-sigmatropic rearrangement of
the selenic ester intermediate gives the above mentioned
products.
THF,-20 °C
80%
O
65%
5
6
O
O
1) (MeO)2CO, NaH
2) BrCH2COOMe
1) SOCl2
2)
SiMe3
OH
O
3) HCl, HOAc
SnCl4
65%
65-70%
7
8
O
O
C
B
NaBH4, CeCl3
MeOH, 0 °C
A
COOH
80%
9
(±)-10
Scheme 1
the D-ring using bromo butenolide (±)-14.25 Isomer (±)-
12a gave a mixture of epimeric strigol isomers (±)-1a and
(±)-1b, whereas isomer (±)-12b similarly produced a mix-
ture of the racemic epimers (±)-1c and (±)-1d. In this man-
ner, all four racemic diastereoisomers of strigol 1 had
been obtained. The spectral properties of the four com-
In order to obtain enantiopure single stereoisomers, sever-
al strategies have been reported previously. One involves
the use of a homochiral D-ring precursor, 2-8,33 its cou-
pling with the formylated racemic ABC-fragment and
O
O
O
O
O
O
1) SeO2, dioxane
2) PCC/CH2Cl2
O
(4%)
O
(±)-11a
(±)-10
(±)-11b
(60%)
O
O
O
O
NaBH4
CeCl3
+
(±)-11a
OH
OH
(±)-12a (42%)
(±)-12b (49%)
O
O
O
C
B
O
O
O
C
1) NaH,HCOOMe
A
A
B
2)
Br
O
D
O
O
O
D
O
O
D
14
O
O
OH
OH
OH
2'
2'
(±)-12a
(±)-1a
(±)-1b
Me
Me
Me
29%
33%
O
O
O
O
C
O
O
1) NaH,HCOOMe
C
A
B
A
B
2)
O
D
Br
14
O
O
D
O
O
D
O
O
O
OH
OH
OH
2'
2'
(±)-12b
(±)-1c
(±)-1d
Me
Me
Me
25%
35%
Scheme 2
Synthesis 2000, No. 13, 1944–1951 ISSN 0039-7881 © Thieme Stuttgart · New York

1946
A. Reizelman et al.
SPECIAL TOPIC
O
O
O
O
O
O
1) NaH, HCOOMe
2) DBU, CH2Cl2,
+
O
O
O
O
O
O
(±)-10
O
D
Cl
2'
O
2'
(±)-13a
30%
(±)-13b
Me
15
Me
32%
Me
3) separation by column
chromatography
cy. 70%
SeO2, dioxane, 80 °C
O
O
O
O
+
5
5
O
O
O
O
O
O
OH
OH
2'
2'
(±)-1d
(±)-1c
Me
Me
1) PCC, CH2Cl2
2) NaBH4, CeCl3
60-70%
O
O
O
O
+
5
5
O
O
O
O
O
O
OH
OH
2'
2'
(±)-1a
Me
(±)-1b
Me
Scheme 3
separation of the resulting diastereoisomers containing a meric purity (>99% e.e.). In the case of (-)-5-epistrigol
latent D-ring functionality. In the final step, the D-ring (ent-1c), (+)-2¢,5-bisepistrigol (1d) and (-)-2¢,5-bisepist-
had to be demasked to ultimately give the stimulant as sin- rigol (ent-1d), the enantiomeric purity, as determined by
gle stereoisomers. This strategy was followed for the syn- analytical HPLC, was 88-90% e.e. However, recrystalli-
thesis of all eight stereoisomers of sorgolactone.6b The zation and repetitive chromatography afforded these ste-
other strategy involves synthesis of the enantiopure ABC- reoisomers in a high enantiopurity as well (Table). The
fragment and coupling with racemic D-ring precursor. amount of material obtained (10-30 mg) after separation
The thus obtained mixture of diastereoisomers was sepa- was sufficient for a detailed spectral analysis and biologi-
rated by chromatography to furnish two single stereoiso- cal testing. It should be mentioned that (±)-strigol has
mers of the stimulant.13,18,23 This strategy had been used in been previously separated to its enantiomers using a col-
the syntheses of (+)-strigol and its analogues.23 Several umn of cellulose triacetate.29 However, (+)-strigol was
methods have been reported for the preparation of the less pure in that case because of peak tailing of (-)-strigol
ABC-part of strigol (+)-12a in an enantiomerically pure and both isomers had to be rechromatographed to give the
form. Sih and co-workers used chiral resolving agents13 to pure enantiomers. In our case, using a cellulose carbamate
separate (±)-12a into its enantiomers. Alternatively, Mori Chiracel-OD® HPLC column gave directly the enanti-
used enzymatic acetylation of (±)-12a with vinyl acetate omers of strigol and 2¢-epistrigol in a high enantiomerical-
in the presence of lipase AK,19 whereas Welzel and co- ly pure form. Considerable difference in retention time
workers resolved (±)-12a by chromatographic separation was observed between the two enantiomers of strigol and
using a HPLC chiral column of cellulose triacetate.18
epistrigol (Table, entries 1, 2). (-)-Strigol eluted after 7.1
minutes, whereas (+)-strigol eluted after 16.4 minutes.
(-)-2¢-epistrigol eluted after 11.5 minutes and (+)-2¢-epis-
trigol after 9.4 minutes (Table, entries 3, 4). Only three of
the eight stereoisomers, viz. (-)-5-epistrigol (ent-1c), (+)-
2¢,5-bisepistrigol (1d) and (-)-2¢,5-bisepistrigol (ent-1d),
had to be chromatographed repetitively on a HPLC col-
umn because of the presence of the other enantiomer as an
impurity, which resulted in peak tailing. Cellulose car-
In our strategy, direct resolution of the four racemic
strigol diastereoisomers (±)-1a, (±)-1b, (±)-1c and (±)-1d
was accomplished by chromatographic separation using a
semi-preparative cellulose carbamate Chiracel-OD®
HPLC column. (+)-Strigol (1a), (-)-strigol (ent-1a), (+)-
2¢-epistrigol (1b), (-)-2¢-epistrigol (ent-1b) and (+)-5-
epistrigol (1c) were obtained directly in a high enantio-
Synthesis 2000, No. 13, 1944–1951 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Synthesis of All Eight Stereoisomers of the Germination Stimulant Strigol
1947
Table Physical Data of 1a-d and their Enantiomers ent-1a-d
Entry Compound Configuration
Configuration eeb
23
[a]D
Mp
HPLCc
tR (min)
Solvents
at C3, aC5, C8b at C2¢a
(%)
>99
>99
>99
>99
>99
>99
>99
>99
(oC)
1
2
3
4
5
6
7
8
1a
R,S,S
S,R,R
R,S,S
S,R,R
R,S,S
S,R,R
R,S,S
S,R,R
R
S
S
R
S
R
R
S
+260
-261
+144
-142
+311
-308
-166
+168
191-193
192-193
159-160
160-161
141-142
142-143
95-96
16.4
7.1
hexane/i-PrOH
(1:1)
ent-1a
1b
11.5
9.4
hexane/i-PrOH
(1:1)
ent-1b
1c
18.8
20.3
18.5d
16.1
hexane/i-PrOH
(7:3)
ent-1c
1d
hexane/CHCl3
(6:4)
ent-1d
93-94
a Configuration at C¢2 was deduced from CD-spectra.
b Enantiomeric excesses were determined by chiral HPLC.
c Semi-preparative cellulose carbamate Chiracel-OD® HPLC column. Flow rate: 3 mL/min.
d Flow rate: 6 mL/min.
bamate Chiracel-OD® HPLC column showed a broad se-
lectivity in the resolution of strigol analogous like
deshydroxy strigol,30 methyl GR-2431 and sorgolactone.6b
This method involving the separation of enantiomers on a
chiral preparative HPLC column is convenient when
small amounts of material are required for biological test-
ing. In addition, only minimal amount of materials were
lost during this separation, whereas in the previously re-
ported methods two additional steps, protection and
deprotection, are required for the resolution, which reduc-
es the yield of the end product. Finally, the absolute con-
figurations of 1a, (-)-ent-1a, 1b, and ent-1b were
determined by comparison of their physical (mp and [a]D)
and spectral (1H NMR, 13C NMR and CD) properties with
those reported earlier (see Experimental Section). The
data were in full accordance with those reported previous-
ly. In the case of 1c, ent-1c, 1d and ent-1d, deduction of
the absolute stereochemistry at C2¢ is not possible using
NMR techniques. Therefore, circular dichroism spec-
trometry was used to determine the absolute configuration
at C2¢ of 1c, ent-1c, 1d and ent-1d. Figures 1-4 show the
Figure 1 CD-spectra of 1a and ent-1a
CD-spectra of all eight stereoisomers of strigol. Welzel been obtained as single compounds. The results of the
and co-workers32,33 demonstrated that the sign of the Cot- evaluation of the bioassays of all eight stereoisomers to-
ton effect around 270 nm could be directly correlated with wards Striga and Orobanche seeds will be reported else-
the stereochemistry at C2¢, that is, a negative sign at this where in due course.
wavelength corresponds with the C2¢ (R) configuration,
whereas a positive sign corresponds with the C2¢ (S) con-
1H and 13C NMR (300 MHz) spectra were recorded on a Bruker AC
figuration. This rule has proven its value in several series
300 spectrometer, using TMS as internal standard. Mps were mea-
of strigolactones, in particular for GR 28,34 desmethylsor-
sured with a Reichert thermopan microscope and are uncorrected.
golactone,35 and sorgolactone.6b In this manner, the abso-
IR spectra were recorded on a Bio-Rad FTS-25 instrument. For
lute configurations of all eight stereoisomers of strigol
were unambiguously assigned.
mass spectra a double focusing VG7070E mass spectrometer was
used. GC-MS spectra were run on a Varian Saturn 2 GC-MS ion-
trap system. Separations were carried out on a fused-silica capillary
column (DB-5, 30 m ¥ 0.25 mm), He2 was used as the carrier gas
and electron impact (EI) was used as ionization mode. Elemental
analyses were conducted on a Carlo Erba Instrument CHNSO EA
In summary, by a novel synthesis of all four racemic
strigol diastereoisomers and their subsequent separation
on a chiral column, all eight stereoisomers of strigol have
Synthesis 2000, No. 13, 1944–1951 ISSN 0039-7881 © Thieme Stuttgart · New York

1948
A. Reizelman et al.
SPECIAL TOPIC
Figure 2 CD-spectra of 1b and ent-1b
Figure 4 CD-spectra of 1d and ent-1d
were dried using standard methods. Reagents were obtained from
commercial suppliers and were used without further purification.
Methyl (1S*,6R*)-6-Hydroxy-2,2-dimethylcyclohexane-1-car-
boxylate (6)
To a stirred suspension of lithium tri-tert-butoxyaluminum hydride
(50 g, 0.197 mol) in anhyd THF (120 mL) cooled to -20 °C, 520(20
g, 0.1086 mol) in anhyd THF (20 mL) was added and the resulting
mixture was stirred under N2 at -20 °C. After 2 h of stirring at the
same temperature, the solvent was removed in vacuo and the resi-
due was dissolved in a mixture of HCl (6 N) and EtOAc. The aque-
ous layer was extracted with EtOAc (3 ¥ mL) and the combined
organic layers were washed with sat. NaHCO3 and brine, dried
(MgSO4), and concentrated in vacuo to give crude hydroxy ester 6
(yellow oil, 19.2 g, 80%) as a major isomer, which was sufficiently
pure for further reactions.
6,6-Dimethylcyclohex-1-ene-1-carboxylic Acid (7)
Compound 7 was prepared from the corresponding ester following
the procedure described by Sugimoto et al.6b The ester was obtained
as a colorless oil (29.0 g, 75-80%)and was sufficiently pure for fur-
ther reactions. To the solution of the ene ester (29.0 g, 0.188 mol) in
formic acid (300 mL), a catalytic amount of concd H2SO4 was add-
ed and the resulting solution was refluxed for 12 h. After cooling,
H2O (20 mL) was added and the aqueous layer was extracted with
EtOAc (2 ¥ mL). The combined organic layers were washed with
brine, dried (MgSO4), and concentrated in vacuo to give white-yel-
low crystals of the acid 7. Recrystallization from hexane/diisopro-
pyl ether gave colorless crystals (65% yield); mp = 158-160 °C.
Figure 3 CD-spectra of 1c and ent-1c
1108 element analyser. For the determination of optical rotations a
Perkin-Elmer 241 polarimeter was used. TLC was carried out on
Merck precoated silica gel 60 F254 plates (0.25 mm). Column chro-
matography was performed with Merck Kieselgel 60. Preparative
HPLC separation of racemates 1a, 1b, 1c and 1d was carried out on
a semi-preparative Chiralcel OD (10 mm) cellulose carbamate col-
umn (Daicel Chemical Industries Ltd., 1 ¥ 25 cm) using mixtures of
hexane/i-PrOH, 1:1 for (±)-1a and (±)-1b, hexane/i-PrOH, 7:3 for
(±)-1c and hexane/CHCl3, 6:4 for (±)-1d. Products were detected
with a Merck-Hitachi L-4000 UV detector at 240 nm. Enantiomeric
excesses and purities of stereoisomers 1a-d and ent-1a-d were de-
termined by analytical HPLC using a Cyclobond I 2000 RSP col-
umn and CH3CN/0.1% TEAA, pH 4.1 (1:3) as the eluent. CD-
spectra were recorded using a Jasco spectrophotometer. All solvents
1H NMR (100 MHz, CDCl3): d = 1.23 (s, 6H, 2 ¥ Me), 1.46-1.67
(m, 4H, CH2), 2.10-2.25 (m, 2H, CH2-CH=C), 7.01-7.25 (t, 1H,
CH=C), 11.95 (br s, 1H).
Anal. calcd for C9H14O2 (154.209): C, 70.10; H, 9.15. Found: C,
70.24; H, 9.23.
7,7-Dimethyl-2,3,4,5,6,7-hexahydro-1H-1-indenone (8)
This compound was prepared in 65-70% yield from the acid 7 anal-
ogous to the procedure described by Sugimoto et al.6b. An analyti-
cally pure sample was obtained by recrystallization from
Synthesis 2000, No. 13, 1944–1951 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Synthesis of All Eight Stereoisomers of the Germination Stimulant Strigol
1949
diisopropyl ether; mp = 47-49 °C (Lit.25 mp = 45 °C). 1H and 13
C
1H NMR, 13C NMR, MS, and IR spectra for both compounds were
NMR (100 MHz, CDCl3) spectral data were in full accord with
in full accord with those reported in ref.16,25
those reported in ref.25
Determination of the Enantiomeric Purity of 1a, ent-1a, 1b and
ent-1b
HPLC [column: Chiralcel OD, 4.6 mm ¥ 25 cm; solvent: hexane/i-
PrOH (1:1), flow rate: 0.5 mL/min; detector: 240 nm; temperature:
r.t.], tR = 10.7 min [>99, 1a], tR = 22.5 min [>99, ent 1a], tR = 9.2
min [>99, 1b], tR = 11.0 min [>99, ent 1b].
Anal. calcd for C11H16O (164.2): C, 80.44; H 9.82. Found :C, 80.30;
H, 9.84.
8,8-Dimethyl-3,3a,4,5,6,7,8,8b-octahydrohydro-2H-1-inde-
no[1,2-b]furan-2-one [(±)-10]
This compound was prepared from 8 analogous to the procedure de-
scribed by Sugimoto et al.6b Yield: 52%; crude oil (95% pure by
GC). This compound was sufficiently pure for further reaction. 1H
and 13C NMR (300 MHz, CDCl3) spectral data were in full accord
with those reported previously.16
(+)-(3aR,5S,8bS,2¢R)-3-[(E)-2¢,5¢-Dihydro-4¢-methyl-5¢-oxo-2¢-
furanyloxymethylene]-5-hydroxy-8,8-dimethyl-
3,3a,4,5,6,7,8,8b-octahydroindeno[1,2-b]furan-2-one (1a) [(+)-
Strigol]
Yield: 22 mg; mp: 191-193 °C (colorless crystals from pentane/
8,8-Dimethyl-3,3a,4,5,6,7,8,8b-octahydro-2H-indeno[1,2-b]fu-
ran-2,5-dione [(±)-11a]
CH2Cl2) [Lit.18 mp: 191-192 °C)
23
25
A solution of the lactone (±)-10 (0.7 g, 3.4 mmol) and SeO2 (0.45 g,
4.05 mmol) in dioxane (50 mL) was heated for 4 h at 80 °C. After
cooling, the mixture was filtered through Hyflo Super-Cell® and the
filter cake washed several times with Et2O (20 mL). Solvents were
removed in vacuo and the crude orange oil (0.669 g) was used, with-
out purification, for further reactions. To a stirred solution of this
crude mixture in CH2Cl2 (20 mL), pyridinium chlorochromate
(PCC) was added in portions until no starting material was detected
(TLC). Filtration and concentration in vacuo gave a crude mixture,
which was subjected to column chromatography (silica gel; hexane/
EtOAc, 2:1) to give the fast isomer (±)-11a (0.435 g, 60% as color-
less crystals; mp: 86-87 °C (hexane/Et2O) [Lit.19 mp: 85-86 °C]
and the slow isomer (±)-11b (0.026 g, 4%) as colorless crystals; mp:
70-71 °C (hexane/Et2O) [Lit.9,19 mp: 69-71 °C]. 1H and 13C NMR
(300 MHz, CDCl3) spectral data were in full accord with those re-
ported in ref.9,15,19
[a]D +260 (c 0.25, CHCl3) [Lit.7c [a]D +271 (c 0.5, CHCl3)],
[Lit.13 [a]D +293.0 (c 0.15, CHCl3)], [Lit.15 [a]D +270 (c 0.2,
25
CHCl3)], [a]D20 +262.7 (c 0.69, CHCl3)].
1H NMR (400 MHz, CDCl3): d = 1.10 (s, 3H, 8-Me), 1.17 (s, 3H,
8-Me), 1.42-1.49 (ddd, 1H, J = 13.5, 11.3, 2.8 Hz, 7-H), 1.52-1.60
(m, 1H, 7-H¢), 1.64-1.73 (m, 1H, 6-H), 1.95-2.01 (ddd, 1H,
J = 13.4, 7.1, 3.1 Hz, 6-H¢), 2.00-2.03 (t, 3H, J = 1.5 Hz, 4¢-Me),
2.70-2.73 (m, 2H, 4-CH2,), 3.61-3.67 (dtd, 1H, J = 11.9, 4.0, 2.5
Hz, 3a-H), 4.10-4.15 (t, 1H, J = 6.1, 5-H), 5.50-5.53 (d, 1H,
J = 7.5 Hz, 8b-H), 6.14-6.15 (m, 1H, 2¢-H), 6.92-6.94 (m, 1H, 3¢-
H), 7.45-7.46 (d, 1H, J = 2.4 Hz, 9-H).
13C NMR (400 MHz, CDCl3): d = 10.7, 27.5, 27.6, 29.7, 32.4, 36.6,
37.0, 37.8, 67.4, 87.9, 100.6, 113.7, 135.9, 140.9, 142.5, 142.6,
150.6, 170.2, 171.4.
These spectral data were in full accord with those reported in
ref.18,19
5-Hydroxy-8,8-dimethyl-3,3a,4,5,6,7,8,8b-octahydro-2H-inde-
no[1,2-b]furan-2-one [(±)-12a]
HRMS: calcd for C19H22O6: 346.1416. Found: 346.1414.
Brooks’ procedure was used.15 To a stirred solution of a,b-unsatur-
ated lactone (±)-11a (0.24 g, 1.09 mmol) in EtOH (25 mL),
CeCl3◊7H2O (0.46 g, 1.09 mmol) was added, followed by slow ad-
dition of NaBH4 (0.0412 g, 1.09 mmol) at 0 °C. After stirring for 30
min, the mixture was quenched by dropwise addition of 1 N HCl
and then extracted with CH2Cl2. The organic layer was washed with
brine and dried (MgSO4). Evaporation of the solvent gave a crude
product (±)-12a, which recrystallized selectively from the ether so-
lution of the mixture to give colorless needles (0.10 g, 42%); mp:
146 °C [Lit.15 mp: 142-144 °C] and (±)-12b (0.12 g, 49%) as an oil.
1H and 13C NMR (300 MHz, CDCl3) spectral data were in full ac-
cord with those reported in ref.13-17,25
(-)-(3aS,5R,8bR,2¢S)-3-[(E)-2¢,5¢-Dihydro-4¢-methyl-5¢-oxo-2¢-
furanyloxymethylene]-5-hydroxy-8,8-dimethyl-
3,3a,4,5,6,7,8,8b-octahydroindeno[1,2-b]furan-2-one (ent-1a)
[(-)-Strigol]
Yield: 14 mg; mp: 192-193 °C (colorless crystals from pentane/
23
CH2Cl2) [Lit.19 mp: 194-196 °C], [Lit.13 mp: 193-194 °C ]; [a]D
25
-261 (c 0.25, CHCl3) [Lit.19 [a]D -277 (c 0.37, CHCl3)], Lit.13
[a]D25 -279 (c 0.11, CHCl3).
1H and 13C NMR (400 MHz, CDCl3) spectra were identical with
those of (+)-1a
HRMS: calcd for C19H22O6: 346.1416. Found: 346.1409.
(±)-1a and (±)-1b
(+)-(3aR,5S,8bS,2¢S)-3-[(E)-2¢,5¢-Dihydro-4¢-methyl-5¢-oxo-2¢-
furanyloxymethylene]-5-hydroxy-8,8-dimethyl-
3,3a,4,5,6,7,8,8b-octahydroindeno[1,2-b]furan-2-one (1b) [(+)-
2¢-Epistrigol]
According to Brooks’ procedure,15 starting from hydroxylactone
(±)-12a (100 mg, 0.44 mmol), (±)-1a obtained as a white solid.
Yield: 52 mg (33%); mp: 205-206 °C (hexane/EtOAc) [Lit.25 mp:
202-205 °C). Compound (±)-1b was also obtained; yield: 45 mg
Yield: 30 mg; mp: 159-160 °C (colorless crystals from benzene/
(29%); mp: 177-178 °C (Lit.25 mp: 178-180 °C). H NMR, 13C
1
pentane) [Lit.19 mp: 158-159 °C].
NMR, MS, and IR spectra were in full accord with the literature da-
[a]D23 +144 (c 0.3, CHCl3) [Lit.19 [a]D24 +145 (c 1.24, CHCl3)]
ta.15,25
1H NMR (400 MHz, CDCl3): d = 1.08 (s, 3H, 8-Me), 1.14 (s, 3H,
8-Me), 1.39-1.47 (ddd, 1H, J = 13.5, 11.0, 3.5 Hz, 7-H), 1.52-1.60
(m, 1H, 7-H¢), 1.63-1.72 (m, 1H, 6-H), 1.78-1.86 (br s, 1H, OH),
1.92-2.20 (m, 1H, 6-H¢, t, 3H, J = 1.5 Hz, 4¢-Me), 2.62-2.75 (m,
2H, 4-CH2), 3.58-3.66 (m, 1H, 3a-H), 4.04-4.10 (t, 1H, J = 6.5 Hz,
5-H), 5.46-5.52 (d, 1H, J = 8.0 Hz, 8b-H), 6.14-6.15 (m, 1H, 2¢-
H), 6.90-6.93 (m, 1H, 3¢-H), 7.40-7.44 (d, 1H, J = 2.5 Hz, 9-H).
13C NMR (400 MHz, CDCl3): d = 10.7, 27.5, 27.6, 29.6, 32.3, 36.5,
37.0, 37.9, 67.2, 88.0, 100.4, 113.8, 135.8, 141.1, 142.2, 142.8,
150.3, 170.2, 171.5.
(±)-1c and (±)-1d
These compounds were prepared from (±)-12b following the proce-
dure used for the preparation of (±)-1a and (±)-1b.
(±)-1c: Yield 25%; mp: 157-158 °C (colorless crystals from hex-
ane/EtOAc) [Lit.25 mp: 156-158 °C, Lit.16 mp: 150-151 °C).
(±)-1d: Yield 35%; mp: 186-188 °C (colorless crystals from hex-
ane/EtOAc) [Lit.16,25 mp: 188-190 °C).
Synthesis 2000, No. 13, 1944–1951 ISSN 0039-7881 © Thieme Stuttgart · New York

1950
A. Reizelman et al.
SPECIAL TOPIC
HRMS: calcd for C19H22O6: 346.1416. Found: 346.1412.
These spectral data were in full accord with those reported in ref. 19
HRMS: calcd for C19H22O6: 346.1416. Found: 346.1420.
(-)-(3aS,5S,8bR,2¢S)-3-[(E)-2¢,5¢-Dihydro-4¢-methyl-5¢-oxo-2¢-
furanyloxymethylene]-5-hydroxy-8,8-dimethyl-
3,3a,4,5,6,7,8,8b-octahydroindeno[1,2-b]furan-2-one (ent-1d)
[(-)-2,5-Bisepistrigol]
(-)-(3aS,5R,8bR,2¢R)-3-[(E)-2¢,5¢-Dihydro-4¢-methyl-5¢-oxo-2¢-
furanyloxymethylene]-5-hydroxy-8,8-dimethyl-
3,3a,4,5,6,7,8,8b-octahydroindeno[1,2-b]furan-2-one (ent-1b)
[(-)-2¢-Epistrigol]
Yield: 18 mg; mp: 160-161 °C (colorless crystals from CH2Cl2/
pentane [Lit. 19 mp: 146-148 °C (CH2Cl2/pentane), 155-156 °C
(benzene/pentane)], [a]D23 -142 (c 0.25, CHCl3) [Lit.19 [a]D25 -141
(c 1.38, CHCl3).
Yield: 10 mg; mp: 93-94 °C (colorless crystals from pentane/
Et2O), [a]23D +168 (c 0.07, CHCl3).
1H and 13C NMR (400 MHz, CDCl3) spectra were identical with
those of (+)-1d.
HRMS: calcd for C19H22O6: 346.1416. Found: 346.1412.
1H NMR (400 MHz, CDCl3) and 13C NMR (400 MHz, CDCl3) spec-
tra were identical with those of (+)-1b.
(±)-13a and (±)-13b
Compound (±)-10 was formylated with ethyl formate and NaH as
described by Brooks et al.15 A solution of the formylated product
(80 mg, 0.34 mmol) in CH2Cl2 (15 mL), DBU (0.38 mL, 0.37
mmol), chlorobutenolide (54 mg, 41 mmol) in CH2Cl2 (5 mL) was
added dropwise at r.t. The solution was stirred for 2 h and the sol-
vent was evaporated in vacuo to give a crude mixture, which was
readily separated by column chromatography (silica gel; hexane/
EtOAc, 3:1) to give (±)-13a (34 mg, 30%) as colorless crystals; mp:
139-140 °C [Lit.16 mp: 139 °C] and (±)-13b as colorless crystals
(36 mg, 32%); mp: 146-147 °C.
HRMS: calcd for C19H22O6: 346.1416. Found: 346.1410.
Determination of the enantiomeric purity of 1c, ent-1c, 1d and
ent-1d
HPLC [column: cyclobond I 2000 RSP, 4.6 mm ¥ 25 cm; solvent:
CH3CN/0.1%TEAA, pH 4.1 (1:3), flow rate: 0.5 mL/min; detector:
240 nm; temperature; r.t.]; tR = 15.1 min [>99%, 1c], tR = 17.63 min
[99%, ent 1c], tR = 17.7 min [>99%, 1d], tR = 14.4 min [99%, ent
1d].
(+)-(3aR,5R,8bS,2¢S)-3-[(E)-2¢,5¢-Dihydro-4¢-methyl-5¢-oxo-2¢-
furanyloxymethylene]-5-hydroxy-8,8-dimethyl-
3,3a,4,5,6,7,8,8b-octahydroindeno[1,2-b]furan-2-one (1c) [(+)-
5-Epistrigol]
Alternative Method for (±)-1a, (±)-1b, (±)-1c and (±)-1d
A solution of (±)-13a (50 mg, 0.15 mmol) and SeO2 (50 mg, 0.45
mmol) in dioxane (15 mL) was heated for 5 h at 80 °C. After cool-
ing, the mixture was filtered through Hyflo Super-Cell® and the fil-
ter cake washed several times with Et2O (20 mL). Solvents were
removed in vacuo and the crude orange oil subjected to column
chromatography (silica gel; hexane/EtOAc, 3:1) afforded (±)-1c as
colorless crystals (0.37 mg, 70%). Its physical and spectral data
were identical to those obtained previously.
Yield: 10 mg; mp: 141-142 °C (colorless crystals from pentane/
Et2O), [a]D23 +311 (c 0.128, CHCl3)
1H NMR (400 MHz, CDCl3): d = 1.11 (s, 3H, 8-Me), 1.14 (s, 3H,
8-Me), 1.42-1.48 (ddd, 1H, J = 13.5, 8.0, 3.3 Hz, 7-H), 1.51-1.59
(m, 2H, 7-H¢, OH), 1.66-1.73 (m, 1H, 6-H), 1.94-2.00, (m, 1H, 6-
H¢), 2.00 (t, 3H, J = 1.5 Hz, 4¢-Me), 2.35-2.40 (d, 1H, J = 16.0 Hz,
4-CH2), 3.05-3.12 (dd, 1H, J = 17.2, 9.2, 4¢-CH2), 3.61-3.66 (m,
1H, 3a-H) 4.14-4.17 (t, 1H, J = 4.8 Hz, 5-H), 5.52-5.54 (dd, 1H,
J = 7.6, 2.0 Hz, 8b-H), 6.14-6.15 (m, 1H, 2¢-H), 6.91-6.93 (m, 1H,
J = 1.5 Hz, 3¢-H), 7.43-7.44 (d, 1H, J = 2.4 Hz, 9-H).
Compound (±)-1a was obtained from (±)-1c by oxidation using
PCC in CH2Cl2 in the same manner as described for the reduction
of (±)-10. The crude mixture of the a,b-unsaturated ketone was suf-
ficiently pure for further reactions. This ketone was reduced to the
alcohol (±)-1a in the same manner as described for reduction of (±)-
11a to (±)-12a using Luche reduction.24 Yield: 60-70%.
13C NMR (400 MHz, CDCl3): d = 10.7, 27.3, 27.4, 29.4, 32.4, 35.2,
36.6, 38.3, 66.0, 88.1, 100.4, 113.9, 136.1, 140.9, 141.9, 143.05,
150.0, 170.15, 171.4.
Compound (±)-1b was obtained from (±)-13b in the same manner
as (±)-1a from (±)-13b. Its physical and spectral data were identical
to those reported previously.
HRMS: calcd for C19H22O6: 346.1416. Found: 346.1403.
(-)-(3aS,5S,8bR,2¢R)-3-[(E)-2¢,5¢-Dihydro-4¢-methyl-5¢-oxo-2¢-
furanyloxymethylene]-5-hydroxy-8,8-dimethyl-
3,3a,4,5,6,7,8,8b-octahydroindeno[1,2-b]furan-2-one (ent-1c)
[(-)-5-Epistrigol]
Acknowledgement
H. Amatdjais, P. van Galen, and A. Swolfs are acknowledged for
conducting elemental analyses, mass, and NMR (400 MHz) measu-
rements, respectively.
Yield: 12 mg; mp: 142-143 °C (colorless crystals from pentane/
Et2O), [a]23D -308 (c 0.09, CHCl3)
1H and 13C NMR (400 MHz, CDCl3) spectra were identical with
those of (+)-1c
References
HRMS: calcd for C19H22O6: 346.1416. Found: 346.1408.
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Synthesis 2000, No. 13, 1944–1951 ISSN 0039-7881 © Thieme Stuttgart · New York

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Synthesis of All Eight Stereoisomers of the Germination Stimulant Strigol
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Article Identifier:
1437-210X,E;2000,0,13,1944,1951,ftx,en;E11200SS.pdf
Synthesis 2000, No. 13, 1944–1951 ISSN 0039-7881 © Thieme Stuttgart · New York