Synthesis of All Eight Stereoisomers of the Germination Stimulant Sorgolactone

Article abstract of DOI:10.1021/jo9718408

The naturally occurring sesquiterpene sorgolactone (2) belongs to the class of "strigolactones", which are highly potent germination stimulants for seeds of the parasitic weeds Striga and Orobanche. The aim of the present work was to synthesize all eight

Full text of DOI:10.1021/jo9718408

J . Org. Chem. 1998, 63, 1259-1267
1259
Syn th esis of All Eigh t Ster eoisom er s of th e Ger m in a tion Stim u la n t
Sor gola cton e
†
Yukihiro Sugimoto, Suzanne C. M. Wigchert, J an Willem J . F. Thuring, and
Binne Zwanenburg*
NSR Center for Molecular Structure, Design and Synthesis, Department of Organic Chemistry,
University of Nijmegen, Toernooiveld, 6525 ED Nijmegen, The Netherlands
Received October 6, 1997
The naturally occurring sesquiterpene sorgolactone (2) belongs to the class of “strigolactones”, which
are highly potent germination stimulants for seeds of the parasitic weeds Striga and Orobanche.
The aim of the present work was to synthesize all eight stereoisomers of sorgolactone and to evaluate
their activities in the stimulation of germination of S. hermontica and O. crenata. Two racemic
diastereomers of the ABC part of sorgolactone, r a c.10a and r a c.10b respectively, were prepared
and coupled with homochiral latent D-ring synthons 12 and en t.12. In this manner, four mixtures
of two separable (protected) sorgolactone diastereomers were obtained. Deprotection gave all eight
target compounds as single isomers. Bioassays revealed that only those isomers possessing the
same stereochemistry as natural sorgolactone at two adjacent chiral centers exhibit high biological
activities.
Parasitic weeds of the genera Striga, Orobanche, and
Alectra have an extremely devastating impact on several
graminaceous and leguminous crops in tropical and
Ch a r t 1
1
,2
semitropical areas of the eastern hemi-sphere.
These
root parasitic weeds specifically interact with their hosts
at four levels: (1) germination of the parasitic seed, (2)
initiation of haustorial development, (3) transfer of water
and minerals, and (4) host responses to infection.3 The
first two events mentioned require host-derived signals
as recognition cues. Especially the stimulation of ger-
mination and the compounds that trigger this process
have attracted much attention. The first naturally
occurring germination stimulant, strigol (1) (Chart 1),
was isolated from the root exudate of the false host cotton
4
(
Gossypium hirsutum L.) and its structure was eluci-
5
dated in 1972. The absolute configuration was unam-
biguously assigned several years later.
tion stimulant produced by maize (Zea mays L.) and proso
millet (Panicum miliaceum L.)9
6
It was not until 1992 that some germination stimulants
closely related to strigol were isolated from the root
The structure of sorgolactone (2) has been tentatively
assigned as depicted in Chart 1. On the basis of
spectroscopic evidence its gross structure was elucidated.
The absolute configuration of the stereogenic centers C3a,
C8b, and C2′ was deduced from the similar circular
dichroic (CD) data by comparison with those of (+)-strigol
7
exudates of true hosts, viz. sorgolactone (2) from sor-
ghum (Sorghum bicolor (L.) Moench) and alectrol (3)8
from cowpea (Vigna unguiculata (L.). Walp) (Chart 1).
Strigol itself was shown to be the major Striga germina-
(1).
*
E-mail: zwanenb@sci.kun.nl. Tel: ++31-24-3653159. Fax: ++31-
2
4-3652929.
Because of lack of spectroscopic detail due to the small
†
On leave from Arid Land Research Center, Tottori University, 1390
Hamasaka, Tottori, 680, J apan.
1) Musselman, L. J ., Ed. Parasitic Weeds in Agriculture. Vol I.
Striga; CRC Press: Boca Raton, FL, 1987; p 317.
2) Parker, C.; Riches, C. R. Parasitic Weeds of the World: Biology
amount of sorgolactone obtained (5 µg from 300 000
sorghum plants) and the extremely laborious isolation
procedure, the proposed structure could not be ascer-
tained. Therefore the total synthesis of 2 was under-
taken10 to verify this tentative structure and to unam-
biguously establish the absolute stereochemical con-
figuration. Very recently the synthesis of four racemic
stereoisomers of sorgolactone was reported, supporting
the gross structure proposed by Hauck.11 Our goal was
(
(
and Control; CAB International Press: Wallingford, Oxon, U.K., 1993;
p 332.
(
3) Press: M. C.; Graves, J . D.; Stewart, G. R. Plant Cell Environ.
984, 13, 91-104.
4) Cook, C. E.; Whichard, L. P.; Turner, B.; Wall, M. E.; Egley, G.
H. Science 1966, 1189-1190.
5) Cook, C. E.; Whichard, L. P.; Wall, M. E.; Egley, G. H.; Coggan,
P.; Luhan, P. A.; McPhail, A. T. J . Am. Chem. Soc. 1972, 94, 6198-
1
(
(
6
1
1
1
199.
(6) Brooks, D. W.; Bevinakatti, H. S.; Powell, D. R. J . Org. Chem.
(9) Siame, B. A.; Weerasuriya, Y.; Wood, K.; Ejeta, G.; Butler, L. G.
J . Agric. Food Chem. 1993, 41, 1486-1491.
(10) Sugimoto, Y.; Wigchert, S. C. M.; Thuring, J . W. J . F.;
Zwanenburg, B. Tetrahedron Lett. 1997, 13, 2321-2324.
(11) Mori, K.; Matsui, J .; Bando, M.; Kido, M.; Takeuchi, Y.
Tetrahedron Lett. 1997, 14, 2507-2510.
985, 50, 3779-3781.
(7) Hauck, C.; M u¨ ller, S.; Schildknecht, H. J . Plant Physiol. 1992,
39, 474-478.
8) M u¨ ller, S.; Hauck, C.; Schildknecht, H. J . Plant Growth Regul.
992, 11, 77-84.
(
S0022-3263(97)01840-9 CCC: $15.00 © 1998 American Chemical Society
Published on Web 02/04/1998

1
260 J . Org. Chem., Vol. 63, No. 4, 1998
Sugimoto et al.
Sch em e 1
Sch em e 2
to develop a strategy that allows the synthesis of all eight
possible sorgolactone diastereoisomers as single isomers.
Evaluation of their respective bioactivities will provide
more insight in the structure-activity relationships of
these germination stimulants. In this paper a full
account of the synthesis and biological evaluation of these
eight sorgolactones is presented.
Sch em e 3
Resu lts a n d Discu ssion
Retrosynthesis of the target compounds involves cou-
pling of the D ring to the ABC part of the molecule
(Scheme 1). Stereoselective coupling of the butenolide
to diastereomerically pure tricyclic ABC lactone 10
furnishes a separable mixture of two protected sorgolac-
tone diastereomers.
A method to introduce the D ring of a strigol analogue
stereoselectively was recently developed in our labora-
tory1
2,13
and applied in the stereoselective synthesis of
1
2
14
strigol analogues GR7 and GR24 and demethylsorgo-
lactone (DMSL), the sorgolactone analogue lacking the
A-ring methyl group.15 Application of this coupling
methodology in the synthesis of 2 necessitates the
preparation of trans and cis tricyclic lactones r a c.10a and
r a c.10b as individual diastereomers.
The cis tricyclic lactone r a c.10b crystallized from the
mixture and could be obtained in 87% de. Reduction of
trans-AB-intermediate 9a with sodium borohydride pro-
ceeded with complete retention of stereochemistry, lead-
ing to the trans-sorgolactone ABC part r a c.10a in a
purity of 93.5%. The contaminant was identified as the
cis-ABC-fragment 10b ; consequently the de of 10a is
87%. Using 2D-NOESY experiments, the relative con-
figurations of r a c.10a and r a c.10b were assigned. The
oily diastereomer r a c.10a showed its characteristic
doublet, which was attributed to H8, at 5.5 ppm, whereas
the corresponding proton of crystalline r a c.10b resonates
at 5.3 ppm.
To this end, acid chloride 6 was prepared via slightly
modified literature procedures,1
6-19
and was then sub-
jected to a Friedel-Crafts reaction in the presence of
trimethylvinylsilane, followed by a Nazarov cyclization
of the in situ formed cyclopentadienyl cation to give AB
fragment 720 (Scheme 2). Thus obtained bicyclopenten-
2
1
one 7 was then converted via standard procedures into
keto acid 9 as a 1:1 mixture of diastereomers from which
the trans isomer 9a remained as a precipitate when 9
was dissolved in diisopropyl ether. Repeated crystalliza-
tions afforded the trans isomer of 9 in a diastereomeric
excess of 87% as was deduced from a detailed analysis
of the 13C NMR spectra. The residue 9b, enriched with
the cis diastereomer, was subjected to a reduction by
employing sodium borohydride in the presence of cerium
trichloride,22 which resulted in a mixture of the sorgo-
lactone ABC fragments 10 (Scheme 3).
To obtain four racemic mixtures of the sorgolactone
stereoisomers, both racemic ABC diastereomers r a c.10a
2
3,24
and r a c.10b were coupled with chlorobutenolide 11.
The reaction of r a c.10a (of which only the 3a(R),8(S),
8b(S) enantiomer is drawn) with 11 gave a mixture of
two diastereomeric racemates of sorgolactone, r a c.2a and
r a c.2b, respectively (yields not optimized), in a ratio of
about 1:1 (Scheme 4). They were readily separated by
flash chromatography. In the same manner r a c.2c and
r a c.2d were obtained starting from r a c.10b, of which
only the 3a(R),8(R),8b(S) enantiomer is depicted (Scheme
(
12) Thuring, J . W. J . F.; Nefkens, G. H. L.; Schaafstra, R.;
Zwanenburg, B. Tetrahedron 1995, 51, 5047-5056.
13) Thuring, J . W. J . F.; Nefkens, G. H. L.; Wegman, M. A.;
Klunder, A. J . H.; Zwanenburg, B. J . Org. Chem. 1996, 61, 6931-6935.
14) Thuring, J . W. J . F.; Nefkens, G. H. L.; Zwanenburg, B. J . Agric.
Food Chem. 1997, 45, 2278-2283.
15) Thuring, J . W. J . F.; Heinsman, N. W. J . T.; J acobs, R. W. A.
W. M.; Nefkens, G. H. L.; Zwanenburg, B. J . Agric. Food Chem. 1997,
5, 507-513.
(
(
(
5
).
4
The chemical shifts of the proton H8b of diastereoiso-
(16) Cox, R. F. B.; Stormont, R. T. Org. Synth. Coll. Vol II 1963, 7.
(17) Linstead, R. P.; Millidge, A. F. J . Chem. Soc. 1936, 478.
(18) Rapson, W. S.; Shuttleworth, R. G. J . Chem. Soc. 1940, 636.
(19) Helferich, B.; Schaefer, W. Org. Synth. Coll. Vol. I, 1964, 147.
(20) Cooke, F.; Moerck, R.; Schwindeman, J .; Magnus P. J . Org.
mers r a c.2a -d were compared with the corresponding
value reported by Hauck.7 In the trans-ABC sorgolactone
diastereomers r a c.2a and r a c.2b the H8b doublet reso-
Chem. 1980, 45, 1046-1053.
21) Mangnus, E. M.; Dommerholt, F. J .; de J ong, R. L. P.; Zwanen-
burg, B. J . Agric. Food Chem. 1992, 40, 1230-1235.
22) Luche, J . L. J . Am. Chem. Soc. 1978, 100, 2226-2227.
(
(23) J ohnson, A. W.; Gowda, G.; Hassanali, A.; Knox, J .; Monaco,
S.; Razavi, Z.; Roseberry, G. J . Chem. Soc., Perkin Trans. 1 1981, 1734.
(24) Burness, D. M. Org. Synth. 1959, 39, 46 and 49.
(

Synthesis of All Stereoisomers of Sorgolactone
J . Org. Chem., Vol. 63, No. 4, 1998 1261
Sch em e 4
Sch em e 6
Sch em e 5
Sch em e 7
nates at the same frequency as in the natural compound,
viz. 5.5 ppm, whereas in the cis-ABC diastereoisomers
r a c.2c and r a c.2d , H8b resonates at 5.3 ppm. This
comparison allows the conclusion that the original tenta-
tive assignment of a trans relationship between the
A-ring methyl moiety and ring C is correct. As was
known from previous syntheses of strigolactone ana-
logues, deduction of the absolute stereochemistry at C2′
is not feasible using NMR techniques.25 Consequently,
the NMR signals that can be distinguished in Hauck’s
Ch a r t 2
1
H NMR spectra match with both diastereomers r a c.2a
and r a c.2b. Circular dichroism spectrometry is neces-
sary for the determination of the absolute configuration
at C2′.
Recently we prepared both enantiopure latent D-ring
synthons 12 and its enantiomer en t.12.1
2,13
Trans tri-
cyclic lactone r a c.10a was coupled via its potassium
enolate with chloro lactone 12 to give diastereomers 13a
and en t.13b, which were separated by flash chromatog-
raphy (Scheme 6). Similarly, r a c.10a was coupled with
chlorolactone en t.12 to give diastereomers 13b and
en t.13a (structures not shown). In the same manner,
reaction of cis-ABC-lactone r a c.10b with 12 provided 13c
and en t.13d , respectively (structures not shown). Iden-
tically, coupling of cis-ABC-lactone r a c.10b with en t.12
provided 13d and en t.13c, respectively (Scheme 7).
These reactions proceeded with complete exo selectivity,
heating the compounds in o-dichlorobenzene. In this way
all single sorgolactone stereoisomers 2a -d and en t.2a -d
were obtained (Chart 2, en t.2a -d not shown). The
results obtained for the cycloreversions are collected in
Table 1. It should be noted that in none of the reactions
any epimerization was observed. Due to the fact that
the de of tricyclic compounds r a c.10a and r a c.10b was
not 100%, sorgolactones 2a -d and en t.2a -d contained
a small diastereomeric impurity, viz. their C8 epimer.
These diastereomeric impurities could be largly removed
by recrystallization and in the case of en t.2a , 2b, and
en t.2b by preparative HPLC.
1
as judged from H NMR analysis.
The thermal retro-Diels-Alder reaction of homochiral
adducts 13a -d and en t.13a -d was accomplished by
The absolute configurations of all eight sorgolactone
1
stereoisomers were determined from their H NMR
spectra in combination with comparison of their CD
spectra (Figures 1-4) with those of the corresponding
isomers of demethylsorgolactone and (+)- and (-)-
(
25) Frischmuth, K.; Wagner, U.; Samson, E.; Weigelt, D.; Koll, P.;
Meuer, H.; Sheldrick, W. S.; Welzel, P. Tetrahedron Asymm. 1993, 4,
51-360.
3

1
262 J . Org. Chem., Vol. 63, No. 4, 1998
Sugimoto et al.
Ta ble 1. Cyclor ever sion of Ad d u cts 13a -d a n d Th eir
En a n tiom er s en t.13A-d
entry adduct product yield (%) purity (%)a ee (%)
[R]D
1
2
3
4
5
6
7
8
13a
en t.13a en t.2a
13b 2b
en t.13b en t.2b
13c 2c
en t.13c en t.2c
13d 2d
en t.13d en t.2d
2a
49
52
77
65
40
46
58
67
>99
97.4
98.6
94.3
>99 +271.2
>99 -278.9
>99 +138.6
>99 -137.5
>99 +283.4
>99 -286.5
>99 +170.8
>99 -167.2
>99
98.9
96.7
97.4
a
The impurities present were identified as diastereomers of the
major products.
F igu r e 4. CD spectra of sorgolactone 2d and its enantiomer
en t.2d .
the CD sign around 270 nm was in all cases in complete
agreement with the expected stereochemistry on the
basis of the chirality of the latent D-ring synthon.
Furthermore, a large Cotton effect around 240 nm in
combination with a small Cotton effect of opposite sign
at 270 nm proved to be indicative of a “transoid” relation-
ship between the C ring and the stereocenter C2′ [i.e.,
3
a(R),8b(S),2′(R) and 3a(S),8b(R),2′(S)]. In contrast, a
small Cotton effect at 240 nm and no change of sign at
70 nm corresponds with a “cisoid” relationship between
2
ring C and C2′ [i.e., 3a(R),8b(S),2′(S)and 3a(S),8b(R),2′(R)].
A positive Cotton effect at 240 nm corresponds with the
F igu r e 1. CD spectra of sorgolactone 2a and its enantiomer
en t.2a .
3
a(R),8b(S) configuration, whereas a negative Cotton
effect at this wavelength indicates 3a(S),8b(R) stereo-
chemistry. In this manner, all absolute configurations
were unambiguously assigned. The CD spectrum of (+)-
sorgolactone (2a ) (Chart 2) was identical with that
reported for the naturally occurring germination stimu-
lant, thus proving that the proposed absolute configura-
tion is indeed correct.
Biologica l Activity
The germination stimulatory activity of all eight ste-
reoisomers of sorgolactone, 2a -d and en t.2a -d , was
2
7
assayed using seeds of S. hermontica and O. crenata.
In preliminary experiments the concentration dependent
activity range (GR 24 and demethylsorgolactone) of seeds
of S. hermontica has been established. Maximal germi-
nation percentages were obtained within the concentra-
tion range of 1 and 0.01 mg/L. Half-maximal activity was
observed at approximately 0.001 mg/L. Assessment of
the relative bioactivity of the individual stereoisomers
of sorgolactone was therefore established at concentra-
tions of 0.01 and 0.001 mg/L and at the sensitive
concentration of 0.0001 mg/L. It was expected that the
lower concentration should exhibit more profound dif-
ferences. Relevant data are collected in Table 2 and
represented in Figure 5.
F igu r e 2. CD spectra of sorgolactone 2b and its enantiomer
en t.2b.
The data presented in Table 2 reveal that there is a
significant difference in germination stimulatory activity
between the eight stereoisomers. For Striga, sorgolac-
tone diastereomer 2a , possessing the “natural” absolute
stereochemistry, is the most active one. For S. hermon-
tica the difference in activity between 2a and most other
diastereomers amounts at least a factor of 100; i.e. that
the activity of about 50%, which is exhibited by all
F igu r e 3. CD spectra of sorgolactone 2c and its enantiomer
en t.2c.
strigol.15,25,26 From these previously reported data it was
inferred that the sign of the Cotton effect around 270 nm
could be directly correlated with the stereochemistry at
C2′, a negative sign corresponding with the C2′(R)
configuration. The configuration at C2′ as deduced from
-
2
sorgolactone isomers at a concentration of 10 mg/L, is
(27) In each bioassay a diastereomeric mixture of the sorgolactone
analogue GR 24 was included as a positive control and an aqueous
solution of 0.1% (v/v) acetone was used as a negative control. This
procedure enables a comparison between results obtained in different
test series.
(
26) Heather, J . B.; Mittal, R. S. D.; Sih, C. J . J . Am. Chem. Soc.
1
976, 98, 3661-3669.

Synthesis of All Stereoisomers of Sorgolactone
J . Org. Chem., Vol. 63, No. 4, 1998 1263
Ta ble 2. Ger m in a tion P er cen ta ges for Seed s of S. Her m on tica a fter Exp osu r e to Solu tion s (0.01, 0.001, a n d 0.0001
m g/L) of Sor gola cton e Dia ster eoisom er s 2a -d a n d en t.2a -d a n d th e Con tr ol GR 24b
a
configuration
at C3aC8C8b
% germination ( SE at a concentration of
2
10-3 mg/L
10-4 mg/L
entry
compound
at C2′
10- mg/L
1
2
3
4
5
6
7
8
9
2a
en t.2a
2b
en t.2b
2c
en t.2c
2d
RSS
SRR
RSS
SRR
RRS
SSR
RRS
SSR
R
S
S
R
R
S
58.1 ( 6.0
47.6 ( 0.5
57.7 ( 2.1
40.5 ( 3.9
57.1 ( 4.6
38.4 ( 4.8
53.3 ( 0.8
50.8 ( 1.1
62.4 ( 2.9
60.6 ( 1.3
16.2 ( 5.3
30.5 ( 1.4
8.9 ( 1.9
50.6 ( 4.1
14.3 ( 3.9
9.2 ( 2.4
22.9 ( 0.4
55.6 ( 2.1
48.6 ( 3.7
c
7.7 ( 3.3
21.1 ( 5.3
0.2 ( 0.2
33.5 ( 6.9
1.4 ( 1.4
0.3 ( 0.3
5.8 ( 1.3
38.8 ( 4.9
c
c
c
c
S
R
en t.2d
GR 24
a,d
racemic
a
-8
-9
-10
-8
-9
3
.16 × 10 mol/L, 3.16 × 10 mol/L, and 3.16 × 10
mol/L respectively for sorgolactone, 3.35 × 10 mol/L, 3.35 × 10 mol/L, and
-
10
b
c
3
.35 × 10
mol/L, respectively, for GR 24. Data presented are the mean ( SE of one representative experiment. Not significantly
d
different from aqueous control (without stimulant). Equimolar mixture of two racemic diastereomers.
comparison, bioassays were also performed with seeds
of O. crenata, using the same concentration range of
stimulant. The results are collected in Table 3 and
Figure 6. These data clearly indicate that the sorgolac-
tones are considerably less active in germinating
Orobanche seeds (however, the dose-response curve for
O. crenata is evidently different from that for S. hermon-
tica). As far as the absolute stereochemistry is concerned,
the trend is the same as for Striga seeds. It should be
noted that sorghum, from which sorgolactone was iso-
lated, is not a natural host for Orobanche crenata.
Con clu sion
We have synthesized all eight stereoisomers of the
germination stimulant sorgolactone. Combination of the
relative trans configuration of the natural sorgolactone
ABC part (determined by NMR) with the absolute
stereochemistry of the C-ring stereogenic centers C8bC3a
and that of C2′ of naturally occurring sorgolactone
(determined by CD spectrometry) leads to the conclusion
that the proposed absolute structure of natural sorgo-
lactone is correct. The bioactivity of all eight stereoiso-
mers was determined, and only those isomers containing
the same absolute stereochemistry as “natural” sorgo-
lactone (2a ) at two adjacent stereocenters exhibit sig-
nificant germination stimulatory activity at sensitive
concentrations.
F igu r e 5. Bar representation of the germination percentages
for seeds of S. hermontica after exposure to different concen-
trations of sorgolactone stereoisomers 2.
at a concentration of 10-4 mg/L only exhibited by com-
pound 2a . At this sensitive concentration, the activity
of almost all other sorgolactones is strongly reduced.
Interestingly 2c, which only differs from 2a in the
configuration at C8, also exhibits a relatively high
germinating activity. Apparently, the absolute configu-
ration at C8 is much less critical for the bioactivity than
that of the stereocenter at C3aC8b. Remarkably, isomer
Exp er im en ta l Section
Gen er a l. For general methods and instrumentation see ref
1
2
5. Final purification of sorgolactone diastereomers en t.2a ,
b, and en t.2b was accomplished by preparative HPLC using
2
b, which is the C2′ epimer of “natural” sorgolactone (2a ),
a Lichrosorb Si60 (7 µm) column (Merck, Hibar, 250 × 25 mm)
and 95/5 hexane/2-propanol as the eluent. Enantiomeric
excesses and purities of stereoisomers 2a -d and en t.2a -d
were determined by analytical HPLC using a Chiralcel OD
(10 µm) cellulose carbamate column (Baker, 250 × 4.6 mm)
and 80/20 hexane/2-propanol as the eluent.
also is appreciably active. The receptor for the germina-
tion stimulant still can accommodate this epimer in such
a manner that induction of germination can take place.
Extended bioassays involving a series of strigolactones
will be needed however to allow the development of a
model for the interaction of receptor and stimulant.
8(S)(R)-Meth yl-3-[[(4′-m eth yl-5′-oxo-2′,5′-d ih yd r ofu r a n -
2′(R)(S)-yl)oxy]m et h ylen e]-3,3a (R)(S),4,5,6,7,8,8b(S)(R)-
oct a h yd r oin d en o[1,2-b]fu r a n -2-on e (r a c.2a ) a n d It s
It is well documented28,29 that seeds of Orobanche also
respond to strigolactones. Therefore, for the sake of
2
′(S)(R) Dia ster eom er : 8(S)(R)-Meth yl-3-[[(4′-m eth yl-5′-
o x o -2′,5′-d ih y d r o fu r a n -2′(S )(R )-y l)o x y ]m e t h y le n e ]-
3,3a(R)(S),4,5,6,7,8,8b(S)(R)-octah ydr oin den o[1,2-b]fu r an -
2-on e (r a c.2b). These products were synthesized in the same
manner as r a c.2c and r a c.2d starting from trans tricyclic
lactone r a c.10a and chlorobutenolide 11. Yields were 27% of
fast moving diastereomer r a c.2a and 22% of slow moving
diastereomer r a c.2b, that were both obtained as colorless
crystals.
(
28) Bergmann, C.; Wegmann, K.; Frischmuth, K.; Samson, E.;
Kranz, A.; Weigelt, D.; Koll, P.; Welzel, P. J . Plant Physiol. 1993, 142,
38-342.
29) Pepperman, A. B.; Dailey, O. D.; Vail, S. L. Biological activity
3
(
of strigol, its precursors and its analogues. In Synthesis and Chemistry
of Agrochemicals; Baker, D. R., Fenyes, J . G., Moberg, W. K., Cross,
B., Eds.; ACS Symposium Series 355; American Chemical Society:
Washington, DC, 1987; pp 445-461.

1
264 J . Org. Chem., Vol. 63, No. 4, 1998
Sugimoto et al.
a
Ta ble 3. Ger m in a tion P er cen ta ges for Seed s of O. Cr en a ta a fter Exp osu r e to Solu tion s (0.1, 0.01, a n d 0.001 m g/L) of
Sor gola cton e Dia ster eoisom er s 2a -d a n d en t.2a -d a n d th e Con tr ol GR 24b
configuration
at C3aC8C8b
% germination ( SE at a concentration of
1
10-2 mg/L
10-3 mg/L
entry
compound
at C2′
10- mg/L
c
1
2
3
4
5
6
7
8
9
2a
en t.2a
2b
en t.2b
2c
en t.2c
2d
RSS
SRR
RSS
SRR
RRS
SSR
RRS
SSR
R
S
S
R
R
S
17.3 ( 0.5
6.7 ( 1.0
10.0 ( 1.1
6.4 ( 0.1
17.4 ( 3.5
8.6 ( 0.6
8.2 ( 0.5
5.9 ( 1.9
27.9 ( 6.3
5.9 ( 1.2c
1.0 ( 1.0
1.5 ( 0.8
c
0
c
c
1.0 ( 0.5
0
0
c
c
0
4.9 ( 2.9c
1.2 ( 0.1
2.0 ( 0.1
1.7 ( 0.5
c
0
0
0
nd
c
S
R
c
c
en t.2d
GR 24
0
d
e
racemic
5.9 ( 1.0
a
-7
-8
-9
-7
-8
3
.16 × 10 mol/L, 3.16 × 10 mol/L, and 3.16 × 10 mol/L, respectively, for sorgolactone, 3.35 × 10 mol/L, 3.35 × 10 mol/L, and
-
9
b
c
3
.35 × 10 mol/L, respectively, for GR 24. Data presented are the mean ( SE of one representative experiment. Not significantly
different from aqueous control (without stimulant). Equimolar mixture of two racemic diastereomers. e Germination percentage not
d
determined.
racemic cis tricyclic lactone r a c.10b (380 mg, 2.0 mmol) in
diethyl ether (10 mL) were added, under a continuous stream
of nitrogen, 3 equiv of ethyl formate (444 mg, 6.0 mmol) and
1
.1 equiv of potassium tert-butoxide (247 mg, 2.2 mmol). The
mixture was stirred overnight at room temperature. Ether
was removed using a stream of nitrogen gas, and the thus
obtained potassium salt of formylated r a c.10b was dissolved
in DMF (15 mL) and cooled to -50 °C. Then a solution of
chlorobutenolide 11 (265 mg, 2 mmol) in DMF (3 mL) was
gradually added at -50 °C under nitrogen. After overnight
stirring at room temperature, the mixture was quenched with
acetic acid (0.5 mL) and the solvent was removed in vacuo.
The residue was dissolved in a mixture of water and ethyl
acetate. The aqueous phase was extracted with ethyl acetate
(
2 times), and the combined organic layers were washed with
brine (2 times), dried (MgSO ), and concentrated under
reduced pressure. The crude product was purified using flash
chromatography (SiO , hexane/ethyl acetate 3/1) to afford two
diastereomeric products. Fast moving diastereomer r a c.2c
253 mg, 41%) and slow moving diastereomer r a c.2d (294 mg,
4
2
(
4
7%) were obtained as colorless crystals.
r a c.2c: mp 142-144 °C. 400 MHz H NMR (CDCl
1
3
): δ 1.13
(
1
d, 3H, J ) 7.0 Hz); 1.34 (m, 1H); 1.54 (m, 1H); 1.72 (m, 2H);
.98 (m, 2H); 2.03 (s, 3H); 2.31 (m, 1H); 2.33 (bd, 1H, J ) 16.9
Hz); 2.71 (ddd, 1H, J ) 3.1 Hz, 9.2 Hz, 16.8 Hz); 3.62 (m, 1H);
5.35 (d, 1H, J ) 7.6 Hz); 6.15 (s, 1H); 6.92 (s, 1H); 7.42 (d, 1H,
F igu r e 6. Bar representation of the germination percentages
for seeds of O. crenata after exposure to different concentra-
tions of sorgolactone stereoisomers 2.
+
J ) 2.5 Hz). MS [EI m/z, rel intensity (%)]: 316 ([M] , 9.8);
+
+
+
219 ([C13
3
H
15
O
3
] , 43.9); 201 ([C13
H
7
13
O
2
] , 67.7); 173 ([C12
H
13O] ,
+
+
6.6); 97 ([C
5
H
5
O
2
] , 100); 91 ([C
H
7
] , 28.7). Anal. Calcd for
1
r a c.2a : mp 114-115 °C. 400 MHz H NMR (CDCl
3
): δ 1.06
18 20 5
C H O : C, 68.34; H, 6.37. Found: C, 68.40; H, 6.37.
1
(
1
d, 3H, J ) 6.9 Hz); 1.25 (m, 1H); 1.55 (m, 1H); 1.70 (m, 1H);
.78 (m, 1H); 1.93 (m, 2H); 2.03 (s, 3H); 2.34 (bd, 1H, J ) 15.9
Hz); 2.36 (m, 1H); 2.75 (dd, 1H, J ) 8.5 Hz, 15.9 Hz); 3.61 (m,
r a c.2d : mp 138-139 °C. 400 MHz H NMR (CDCl ): δ 1.12
3
(d, 3H, J ) 7.0 Hz); 1.36 (m, 1H); 1.54 (m, 1H); 1.72 (m, 2H);
1.95 (m, 2H); 2.03 (s, 3H); 2.31 (m, 1H); 2.33 (bd, 1H, J ) 16.9
Hz); 2.69 (ddd, 1H, J ) 2.9 Hz, 12.1 Hz, 16.9 Hz); 3.61 (m,
1H); 5.35 (d, 1H, J ) 7.7 Hz); 6.13 (s, 1H); 6.93 (s, 1H); 7.42
1
(
6
(
H); 5.49 (d, 1H, J ) 7.6 Hz); 6.15 (s, 1H); 6.93 (s, 1H); 7.43
+
d, 1H, J ) 2.6 Hz). MS [EI m/z, rel intensity (%)]: 316 ([M] ,
+
+
+
.9); 219 ([C13
H
15
O
3
] , 21.8); 201 ([C13
H
13
O
2
] , 52.8); 173
7
(d, 1H, J ) 2.5 Hz). MS [EI m/z, rel intensity (%)]: 316 ([M] ,
+
+
+
+
+
[C12
H
13O] , 24.7); 97 ([C
5
H
5
O
2
] , 92.7); 91 ([C
: C, 68.34; H, 6.37. Found: C, 68.25; H,
7
H
] , 27.2). Anal.
5.7); 219 ([C13
H
15
O
3
] , 43.9); 201 ([C13
H
13
O
2
] , 76.9); 173
+
+
+
Calcd for C18
.37.
H
20
O
5
([C12
H
13O] , 40.2); 97 ([C
5
H
5
O
2
] , 100); 91 ([C
7
H
7
] , 28.9).
6
Elemental analysis was done for the enantiopure compounds,
2d and en t.2d .
1
r a c.2b: mp 112-114 °C. 400 MHz H NMR (CDCl
3
): δ 1.06
(
1
d, 3H, J ) 6.9 Hz); 1.25 (m, 1H); 1.55 (m, 1H); 1.70 (m, 1H);
.77 (m, 1H); 1.93 (m, 2H); 2.03 (s, 3H); 2.33 (bd, 1H, J ) 15.9
Hz); 2.36 (m, 1H); 2.73 (dd, 1H, J ) 8.5 Hz, 15.9 Hz); 3.60 (m,
8(S)-Met h yl-3-[[(4′-m et h yl-5′-oxo-2′,5′-d ih yd r ofu r a n -
2′(R)-yl)oxy]m et h ylen e]-3,3a (R),4,5,6,7,8,8b (S)-oct a h y-
d r oin d en o[1,2-b]fu r a n -2-on e (2a ). Deprotection of Diels-
Alder adduct 13a was accomplished by heating in o-di-
1
(
8
(
H); 5.49 (d, 1H, J ) 7.7 Hz); 6.14 (s, 1H); 6.94 (s, 1H); 7.43
+
15
d, 1H, J ) 2.6 Hz). MS [EI m/z, rel intensity (%)]: 316 ([M] ,
chlorobenzene as described by Thuring et al. Sorgolactone
+
+
.5); 219 ([C13
H
15
O
3
] , 26.7); 201 ([C13
H
13
O
2
] , 55.7); 173
stereoisomer 2a was obtained as off-white crystals in 49%
+
+
+
21
[C12
H
13O] , 22.8); 97 ([C
5
H
5
O
2
] , 100); 91 ([C
: C, 68.34; H, 6.37. Found: C, 68.28;
7
H
7
] , 17.0).
yield: mp 139.5-142 °C, [R]
D
3
) +271.2° (c ) 0.25, CDCl ),
1
Anal. Calcd for C18
H, 6.36.
H
20
O
5
purity 99.7%, ee >99% (determined by HPLC). 400 MHz H
NMR (CDCl ): δ 1.06 (d, 3H, J ) 6.9 Hz); 1.26 (m, 1H); 1.55
3
8
(R)(S)-Meth yl-3-[[(4′-m eth yl-5′-oxo-2′,5′-d ih yd r ofu r a n -
′(R)(S)-yl)oxy]m et h ylen e]-3,3a (R)(S),4,5,6,7,8,8b (S)(R)-
oct a h yd r oin d en o[1,2-b]fu r a n -2-on e (r a c.2c) a n d It s
′(S)(R) Dia ster eom er 8(R)(S)-Meth yl-3-[[(4′-m eth yl-5′-
o x o -2′,5′-d ih y d r o fu r a n -2′(S )(R )-y l)o x y ]m e t h y le n e ]-
(m, 1H); 1.70 (m, 1H); 1.77 (m, 1H); 1.94 (m, 2H); 2.03 (s, 3H);
2.33 (bd, 1H, J ) 15.4 Hz); 2.36 (m, 1H); 2.75 (dd, 1H, J ) 9.0
Hz,15.4 Hz); 3.61 (m, 1H); 5.49 (d, 1H, J ) 7.4 Hz); 6.15 (s,
2
1
3
2
3
1H); 6.92 (s, 1H); 7.41 (d, 1H, J ) 2.6 Hz). C NMR (CDCl ):
δ 10.8; 18.6; 20.7; 26.1; 27.8; 31.2; 36.5; 41.4; 88.0; 100.4; 114.5;
136.0; 137.3; 140.9; 141.3; 150.0; 170.2; 171.8. MS [EI m/z,
3
2
,3a(R)(S),4,5,6,7,8,8b(S)(R)-octah ydr oin den o[1,2-b]fu r an -
-on e (r a c.2d ). To a cooled (0 °C) and stirred solution of
+
+
15 3
H O ] , 25.2); 201
rel intensity (%)]: 316 ([M] , 8.1); 219 ([C13

Synthesis of All Stereoisomers of Sorgolactone
J . Org. Chem., Vol. 63, No. 4, 1998 1265
C, 68.34; H, 6.37. Found: C, 68.26; H, 6.34. CD (CH CN, c )
(
9
[C13
1 ([C
H
7
13
O
2
+
]+, 48.2); 173 ([C12
H
13O] , 18.0); 97 ([C
+
5
H
5
O
2
]+, 100);
: C, 68.34; H, 6.37.
CN, c ) 35.9µM): λmax
3
-1
-1
H
7
] , 14.2). Anal. Calcd for C18
Found: C, 68.15; H, 6.32. CD (CH
30 nm, ∆ꢀ ) +20 L mol cm
(R)-Met h yl-3-[[(4′-m et h yl-5′-oxo-2′,5′-d ih yd r o-fu r a n -
′(S)-yl)oxy]m et h ylen e]-3,3a (S),4,5,6,7,8,8b (R)-oct a h y-
H
20
O
5
33.2 µM): λmax ) 225 nm, ∆ꢀ ) -23 L mol cm .
3
)
8(R)-Met h yl-3-[[(4′-m et h yl-5′-oxo-2′,5′-d ih yd r ofu r a n -
2′(S)-yl)oxy]m et h ylen e]-3,3a (R),4,5,6,7,8,8b (S)-oct a h y-
d r oin d en o[1,2-b]-fu r a n -2-on e (2d ). Sorgolactone stereo-
isomer 2d was prepared in the same manner as described for
isomer 2a starting from adduct 13d . 2d was obtained as
-
1
-1
2
.
8
2
d r oin d en o[1,2-b]fu r a n -2-on e (en t.2a ). Sorgolactone stere-
oisomer en t.2a was prepared in the same manner as reported
for isomer 2a starting from en t.13a . en t.2a was obtained as
a yellowish oil in 52% yield. Final purification by HPLC
2
1
colorless crystals in 58% yield: mp 136-138 °C, [R]
D
)
+170.8° (c ) 0.16, CHCl ), purity 96.7%, ee >99% (determined
by HPLC). H NMR, C, NMR and mass data were identical
3
1
13
2
1
afforded off-white crystals: mp 145-146 °C, [R]
D
) -278.9°
with those of its enantiomer en t .2d . Anal. Calcd for
(
c ) 0.10, CH Cl ), purity 97.4%, ee >99% (determined by
HPLC). H NMR, C NMR, and mass data were identical with
2
2
13
18 20 5
C H O : C, 68.34; H, 6.37. Found: C, 68.52; H, 6.31. CD
1
-1
-1
3
(CH CN, c ) 33.2 µM): λmax ) 243 nm, ∆ꢀ ) +3 L mol cm .
those of its enantiomer 2a . CD (CH
3
CN, c ) 40.5 µM): λmax
8(S)-Met h yl-3-[[(4′-m et h yl-5′-oxo-2′,5′-d ih yd r ofu r a n -
2′(R)-yl)oxy]m et h ylen e]-3,3a (S),4,5,6,7,8,8b (R)-oct a h y-
d r oin d en o[1,2-b]fu r a n -2-on e (en t.2d ). Sorgolactone stere-
oisomer en t.2d was synthesized in the same manner as
reported for isomer 2a starting from en t.13d . en t.2d was
obtained as colorless crystals in 67% yield: mp 135-137 °C,
-
1
-1
)
226 nm, ∆ꢀ ) -13.5 L mol cm
.
8
(S)-Met h yl-3-[[(4′-m et h yl-5′-oxo-2′,5′-d ih yd r ofu r a n -
2
′(S)-yl)oxy]m et h ylen e]-3,3a (R),4,5,6,7,8,8b (S)-oct a h y-
d r oin d en o[1,2-b]fu r a n -2-on e (2b). Sorgolactone stereoiso-
mer 2b was synthesized in the same way as described for
isomer 2a starting from 13b. 2b was obtained as a yellowish
oil in 77% yield. Further purification by HPLC gave off-white
[R]21
) -167.2° (c ) 0.25, CHCl ), purity 97.4%, ee >99%
D
3
1
(determined by HPLC). 400 MHz H NMR (CDCl ): δ 1.12
3
2
1
crystals: mp 111-114 °C, [R]
D
) +138.6° (c ) 0.17, CHCl
3
),
(d, 3H, J ) 7.0 Hz); 1.36 (m, 1H); 1.54 (m, 1H); 1.72 (m, 2H);
1.95 (m, 2H); 2.03 (s, 3H); 2.31 (m, 1H); 2.33 (bd, 1H, J ) 16.9
Hz); 2.69 (ddd, 1H, J ) 2.9 Hz, 12.1 Hz, 16.9 Hz); 3.61 (m,
purity 98.6%, ee >99% (determined by HPLC). H NMR, 13C
NMR, and mass data were identical with those of its enanti-
1
omer en t.2b. CD (CH
3
CN, c ) 31.6µM): λmax ) 243 nm, ∆ꢀ )
1H); 5.35 (d, 1H, J ) 7.7 Hz); 6.13 (s, 1H); 6.93 (s, 1H); 7.42
-
1
-1
13
+
2.5 L mol cm
(R)-Met h yl-3-[[(4′-m et h yl-5′-oxo-2′,5′-d ih yd r ofu r a n -
′(R)-yl)oxy]m et h ylen e]-3,3a (S),4,5,6,7,8,8b (R)-oct a h y-
.
(d, 1H, J ) 2.5 Hz). C NMR (CDCl ): δ 10.8; 20.0; 20.3; 26.2;
3
8
30.2; 31.7; 36.8; 41.5; 90.9; 100.6; 114.6; 135.9; 136.5; 141.0;
2
143.0; 149.9; 170.3; 171.9. MS [EI m/z, rel intensity (%)]: 316
+
+
+
d r oin d en o[1,2-b]fu r a n -2-on e (en t.2b). Sorgolactone stere-
oisomer en t.2b was synthesized in the same manner as
described for isomer 2a starting from en t.13b. en t.2b was
obtained as a yellowish oil in 65% yield. Chromatographic
purification by HPLC afforded off-white crystals: mp 109-
([M] , 7.9); 219 ([C13
H
15
O
3
] , 32.1); 201 ([C13
H
13
O
2
] , 47.7); 173
+
+
+
([C12
H
13O] , 20.2); 97 ([C
5
H
5
O
2
] , 100); 91 ([C
7
H
7
] , 15.5).
Anal. Calcd for C18
20 5
H O : C, 68.34; H, 6.37. Found: C, 68.63;
H, 6.36. CD (CH CN, c ) 31.0 µM): λmax ) 240 nm, ∆ꢀ ) -2.3
3
-
1
-1
L mol cm
.
2
1
1
12 °C; [R]
D
) -137.5° (c ) 0.10, CH
2
Cl
2
), purity 94.3%, ee
2-[(Meth oxycar bon yl)m eth yl]-4-m eth yl-3-oxo-2,3,4,5,6,7-
h exa h yd r o-1H -in d en e-2-ca r b oxylic Acid Met h yl E st er
(8). Diester 8 was prepared starting from 7 analogous to the
procedure described by Mangnus et al.21 Yield: 89%. Mp:
1
>
0
1
99% (determined by HPLC). 400 MHz H NMR (CDCl ): δ
3
.99 (d, 3H, J ) 6.9 Hz); 1.17 (m, 1H); 1.49 (m, 1H; 1.63 (m,
H,); 1.70 (m, 1H); 1.87 (m, 2H); 1.96 (s, 3H); 2.26 (bd, 1H, J
1
)
15.9 Hz); 2.29 (m, 1H); 2.66 (dd, 1H, J ) 8.6 Hz, 15.9 Hz);
53.5-54.5 °C. Bp: 121.5 °C (0.5 mmHg). 400 MHz H NMR
3
1
2
1
.53 (m, 1H); 5.43 (d, 1H, J ) 7.7 Hz); 6.07 (s, 1H); 6.87 (s,
(CDCl ): δ 1.09 (d, 3H, J ) 7.0 Hz); 1.43 (m, 1H); 1.67-1.80
3
1
3
2
H); 7.36 (d, 1H, J ) 2.6 Hz). C NMR (CDCl
3
): δ 10.5; 18.6;
(m, 3H); 2.23-2.55 (m, 3H); 2.46 and 3.25 (AB, 2H, J ) 17.1
2
0.7; 26.0; 27.8; 31.6; 36.5; 41.4; 88.0; 100.6; 114.6; 135.8; 137.2;
Hz); 2.48 and 3.29 (AB, 2H, J ) 17.3 Hz); 3.67 and 3.69 (2 ×
1
3
41.0; 141.5; 150.3; 170.3; 171.8. MS [EI m/z, rel intensity
s, 2 × 3H). C NMR (CDCl
3
): δ 18.4; 19.0; 26.1; 28.7; 30.1;
+
+
+
(%)]: 316 ([M] , 8.9); 219 ([C13
H
15
O
3
] , 29.1); 201 ([C13
H
13
O
H
2
] ,
38.6; 41.6; 51.9; 52.9; 56.2; 139.8; 170.5; 171.6; 173.7; 202.0.
+
+
+
+
+
5
3
3
3.6); 173 ([C12
.1). HRMS/EI: m/z calcd for C18
16.13098 ( 0.00088. CD (CH
H
13O] , 20.2); 97 ([C
5
H
5
O
2
] , 96.4); 91 ([C
7
7
] ,
MS [EI m/z, rel intensity (%)]: 280 ([M] , 40.7); 220 ([C13
H
16
O
H
3
] ,
+
+
+
H
20
O
5
316.13107, found
100); 192 ([C12
19.2); 91 ([C
H, 7.19. Found: C, 64.48; H, 7.11.
H
7
16
+
O
2
] , 47.7); 133 ([C10
] , 35.6). Anal. Calcd for C15
H
13] , 73.6); 105 ([C
8
9
] ,
3
CN, c ) 29.1 µM): λmax ) 240
7
H
H
20
O
5
: C, 64.27;
-
1
-1
nm, ∆ꢀ ) -3 L mol cm
(R)-Met h yl-3-[[(4′-m et h yl-5′-oxo-2′,5′-d ih yd r ofu r a n -
′(R)-yl)oxy]m et h ylen e]-3,3a (R),4,5,6,7,8,8b (S)-oct a h y-
.
8
(4-Meth yl-3-oxo-2,3,4,5,6,7-h exah ydr o-1H-in den -2-yl)ace-
tic Acid (9). Carboxylic acid 9 was synthesized from 8 in 97%
2
2
1
d r oin d en o[1,2-b]fu r a n -2-on e (2c). Sorgolactone stereoiso-
mer 2c was prepared in the same manner as described for
isomer 2a starting from adduct 13c. 2c was obtained as
yield according to the procedure reported by Mangnus et al.
and obtained as 1:1 mixture of cis and trans carboxylic acids
9. Racemic trans acid 9a precipitated when mixture 9 was
dissolved in diisopropyl ether. Recrystallization from diiso-
propyl ether gave acid 9a in 87% de.
colorless crystals in 40% yield: mp 178-181 °C, [R]21
)
D
+
284.4° (c ) 0.21, CHCl
3
), purity >99%, ee >99% (determined
by HPLC). 400 MHz H NMR (CDCl ): δ 1.13 (d, 3H, J ) 7.0
Hz); 1.34 (m, 1H); 1.54 (m, 1H); 1.72 (m, 2H); 1.98 (m, 2H);
.03 (s, 3H); 2.31 (m, 1H); 2.33 (bd, 1H, J ) 16.9 Hz); 2.71
ddd, 1H, J ) 3.1 Hz, 9.2 Hz, 16.8 Hz); 3.62 (m, 1H); 5.35 (d,
H, J ) 7.6 Hz); 6.15 (s, 1H); 6.92 (s, 1H); 7.42 (d, 1H, J ) 2.5
1
9a : mp 111-113 °C, de 87% (determined by 13C NMR). 400
3
1
MHz H NMR (CDCl
3
): δ 1.11 (d, 3H, J ) 7.0 Hz); 1.42 (m,
2
(
1
1H); 1.64-1.81 (m, 3H); 2.21-2.30 (m, 3H); 2.41 (dd, 1H, J )
13
7.8 Hz, 16.3 Hz); 2.52 (m, 1H); 2.74-2.88 (m, 3H). C NMR
(CDCl ): δ 18.5; 19.1; 25.9; 28.8; 30.2; 35.5; 37.2; 41.5; 141.7;
3
1
3
+
Hz). C NMR (CDCl
3
): δ 10.8; 20.0; 20.3; 26.2; 30.1; 31.6;
173.0; 176.0; 209.3. MS [EI m/z, rel intensity (%)]: 208 ([M] ,
38.1); 190 ([C12
+
+
3
1
2
2
6.9; 41.4; 90.9; 100.4; 114.6; 136.0; 136.6; 140.9; 142.8; 149.6;
70.2; 171.8. MS [EI m/z, rel intensity (%)]: 316 ([M] , 7.5);
19 ([C13
0.7); 97 ([C
H
14
O
2
] , 36.7); 163 ([C11
H
15O] , 32.9); 147
+
+
+
+
([C11
H
15] , 22.3); 105 ([C
8
H
9
] , 14.1); 91 ([C
7
H
7
] , 23.3); 28
+
+
+
+
H
15
O
3
] , 32.6); 201 ([C13
H
13
O
2
] , 48.8); 173 ([C12
H
13O] ,
16 3
([CO] , 100). Anal. Calcd for C12H O : C, 69.21; H, 7.74.
+
+
5
H
5
O
2
] , 100); 91 ([C
7
H
7
] , 15.6). Anal. Calcd for
Found: C, 69.24; H, 7.61. The cis diastereomer of 9 could not
be obtained in diastereomerically pure form.
8(S)(R)-Meth yl-3,3a(R)(S),4,5,6,7,8,8b(S)(R)-octah ydr oin -
d en o[1,2-b]fu r a n -2-on e (r a c.10a ). To a solution of trans
carboxylic acid 9a (2.7 g, 13 mmol) in methanol (100 mL) were
18 20 5
C H O : C, 68.34; H, 6.37. Found: C, 68.63; H, 6.36. CD
-
1
-1
(
CH
3
CN, c ) 34.2µM): λmax ) 227 nm, ∆ꢀ ) +22 L mol cm
.
8
(S)-Met h yl-3-[[(4′-m et h yl-5′-oxo-2′,5′-d ih yd r ofu r a n -
2
′(S)-yl)oxy]m et h ylen e]-3,3a (S),4,5,6,7,8,8b (R)-oct a h y-
d r oin d en o[1,2-b]fu r a n -2-on e (en t.2c). Sorgolactone stere-
oisomer en t.2c was synthesized in the same way as described
for isomer 2a starting from en t.13c. en t.2c was obtained as
added 2 equiv of CeCl
methanol (100 mL) and 4 equiv of NaBH
The reaction mixture was stirred at room temperature for 3
h, and conversion was followed by GC. When no further
3
‚7H
2
O (9.7 g, 26 mmol) dissolved in
(2.0 g, 52 mmol).
4
2
1
colorless crystals in 46% yield: mp 177.5-178.5 °C, [R]
D
)
-
286.5° (c ) 0.21, CHCl ), purity 98.9%, ee >99% (determined
3
progress could be detected, another equivalent of CeCl
(4.8 g, 13 mmol) dissolved in methanol (50 mL) and 2 equiv of
NaBH (0.98 g, 26 mmol) were added and stirring was
3
‚7H
2
O
1
13
by HPLC). H NMR, C NMR, and mass data were identical
with those of its enantiomer 2c. Anal. Calcd for C18
H
20
O
5
:
4

1
266 J . Org. Chem., Vol. 63, No. 4, 1998
Sugimoto et al.
): δ 18.6;
continued overnight. Thereafter 1.5 equiv of NaBH
4
was
(2m, 2H); 7.34 (d, 1H, J ) 2.5 Hz). 13C NMR (CDCl
3
added, and the reaction was allowed to stir until all starting
material had disappeared. Methanol was evaporated in vacuo,
and the residue was dissolved in a mixture of diethyl ether
and a 20% aqueous solution of H
extracted with diethyl ether (2 times), and the combined
organic layers were dried (MgSO ) and concentrated in vacuo.
20.7; 22.6; 26.1; 27.8; 31.1; 36.5; 41.4; 45.2; 49.8; 52.0; 53.4;
54.5; 87.8; 103.8; 113.7; 133.5; 137.5; 137.8; 141.1; 151.0; 171.9;
+
178.7. MS [EI m/z, rel intensity (%)]: 382 ([M] , 2.8); 316
+
+
+
2
2
SO
4
. The aqueous phase was
([C18
H
20
O
5
] , 1.6); 202 ([C13
H
14
O
7
2
] , 34.3); 163 ([C10
H
11
O
] ,
+
+
89.2); 97 ([C
5
H
5
O
2
] , 100); 91 ([C
H
7
] , 15.0). Anal. Calcd for
: C, 72.23; H, 6.85. Found: C, 72.14; H, 6.81.
4
C
23
H
26
O
5
Silica gel column chromatography (hexane/ethyl acetate 6/1)
en t.13b: mp 170-171 °C, de 87% (determined by NMR),
[R]21 ) -234.0° (c ) 0.5, CH Cl ). 400 MHz H NMR
1
yielded racemic trans tricyclic lactone r a c.10a as a colorless
D
2
2
3
0
oil (2.0 g, 80%): de 87% (determined by NMR). 400 MHz
(CDCl ): δ 1.05 (d, 3H, J ) 7.0 Hz); 1.22 (m, 1H); 1.55 (m,
3
1
H NMR (CDCl
3
): δ 1,05 (d, 3H, J ) 7.0 Hz); 1.25 (m, 1H);
1H); 1.57 (s, 3H); 1.68 (m, 1H); 1.71 (m, 2H); 1.75 (m, 1H);
1.93 (m, 2H); 2.29 (bd, 1H, J ) 16.5 Hz); 2.36 (m, 1H); 2.70
(dd, 1H, J ) 8.2 Hz, 16.5 Hz); 2.72 (d, 1H, J ) 4.2 Hz); 2.88
(m, 1H); 3.21 (m, 1H); 3.58 (m, 1H); 5.19 (d, 1H, J < 1 Hz);
5.47 (d, 1H, J ) 7.2 Hz); 6.25 (2m, 2H); 7.32 (d, 1H, J ) 2.6
1
.60 (m, 1H); 1.76 (m, 2H); 1.97 (m, 2H); 2.14 (dd, 1H, J ) 1.9
Hz, 16.5 Hz); 2.29 (dd, 1H, J ) 5.7 Hz, 18.4 Hz); 2.36 (m, 1H);
2
1
2
.71 (dd, 1H, J ) 8.2 Hz, 16.6 Hz); 2.83 (dd, 1H, J ) 0.7 Hz,
8.3 Hz); 3.05 (m, 1H); 5.47 (d, 1H, J ) 7.5 Hz). 400 MHz
D-NOESY NMR (CDCl
1
3
3
): δ 5.31 (H8b) cross peak with δ 3.04
Hz). C NMR (CDCl ): δ 18.6; 20.7; 22.5; 26.0; 27.8; 31.2;
3
1
3
(
H3a), δ 1.11 (CH
3
) not with δ 2.32 (H8). C NMR (CDCl
3
):
36.5; 41.1; 45.2; 49.8; 52.0; 53.4; 54.3; 87.8; 103.7; 113.8; 133.5;
137.3; 137.8; 141.3; 151.1; 171.8; 178.8. MS [EI m/z, rel
δ 18.6; 20.7; 26.1; 27.9; 31.2; 34.0; 36.6; 42.6; 89.9; 137.4; 140.9;
1
(
(
+
+
+
5
77.7. MS [EI m/z, rel intensity (%)]: 192 ([M] , 72.8); 148
18 20
intensity (%)]: 382 ([M] , 1.0); 316 ([C H O ] , 1.1); 202
+
+
+
+
+
+
2
[C11
H
9
16] , 49.0); 133 ([C10
H
13] , 100); 108 ([C
8
H
12] , 89.6); 105
13 14 2 10 11 2 5 5
([C H O ] , 29.5); 163 ([C H O ] , 78.2); 97 ([C H O ] , 100);
91 ([C H ] , 13.2). Anal. Calcd for C H O : C, 72.23; H, 6.85.
7 23 26 5
+
+
+
7
[C
8
H
] , 64.3); 91 ([C
7
H
7
] , 76.4).
8
(R)(S)-Meth yl-3,3a(R)(S),4,5,6,7,8,8b(S)(R)-octah ydr oin -
Found: C, 72.16; H, 6.77.
d en o[1,2-b]fu r a n -2-on e (r a c.10b). The reaction was per-
formed as described for compound r a c.10a . The product was
obtained (starting from the 2:1 mixture of cis and trans acids
8(R )-Me t h yl-3-[[(6′(R )-m e t h yl-5′-oxo-4′-oxa t r icyclo-
[5.2.1.02 ]d e c -8′-e n -3′(S )-yl)oxy]m e t h yle n e ]-3,3a (S ),
4,5,6,7,8,8b (R )-o c t a h y d r o -in d e n o [1,2-b ]fu r a n -2-o n e
(en t.13a ) a n d Its 3a (R),8(S),8b(S) Dia ster eom er (13b).
These compounds were prepared in the same way as described
for 13a and en t.13b, starting from tricyclic lactone r a c.10a
and chloro lactone en t.12. Yields were 33% of fast moving
diastereomer en t.13a and 39% of slow moving diastereomer
13b.
′,6′
9
b (5.4 g)) as an oily mixture of cis and trans lactones 10 (4.6
g, 92%) from which cis tricyclic lactone r a c.10b crystallized.
Recrystallization from n-heptane provided r a c.10b in 87% de.
2
8
1
Mp: 54-57 °C, de 87% (determined by NMR). 400 MHz H
NMR (CDCl ): δ 1.11 (d, 3H, J ) 7.1 Hz); 1.35 (m, 1H); 1.55
m, 1H); 1.73 (m, 2H); 1.98 (m, 2H); 2.19 (bd, 1H, J ) 16.5
Hz); 2.32 (m, 1H); 2.35 (dd, 1H, J ) 4.4 Hz, 18.2 Hz); 2.61
ddd, 1H, J ) 3.0 Hz, 8.8 Hz, 16.8 Hz); 2.81 (dd, 1H, J ) 10.4
Hz, 18.0 Hz); 3.04 (m, 1H); 5.31 (d, 1H, J ) 7.3 Hz). 400 MHz
D-NOESY NMR (CDCl
H3a), δ 1.11 (CH ) and δ 2.32 (H8). C NMR (CDCl
0.4; 26.2; 30.1; 31.6; 34.7; 36.2; 42.4; 92.6; 136.9; 142.8; 177.8.
3
(
en t.13a : mp 111-114 °C,31 de 97% (determined by NMR),
[R]21 ) -169.6° (c ) 0.5, CH Cl ). H NMR, C NMR, and
1
13
(
D
2
2
mass data were identical with those of its enantiomer 13a .
2
(
2
3
): δ 5.31 (H8b) cross peak with δ 3.04
Anal. Calcd for C H O : C, 72.23; H, 6.85. Found: C, 72.40;
2
3
26
5
1
3
3
3
): δ 19.9;
H, 6.89.
21
1
3b: mp 172-173 °C, de 95% (determined by NMR), [R]
D
+
MS [EI m/z, rel intensity (%)]: 193 ([M + 1] , 100); 148
1
13
)
2 2
+232.8° (c ) 0.5, CH Cl ). H NMR, C NMR, and mass
data were identical with those of its enantiomer en t.13b.
+
+
+
9
([C11
H
16] , 13.0); 133 ([C10
H
13] , 79.3); 105 ([C
8
H
] , 37.0); 91
192.11503,
+
([C
7
H
7
] , 15.0). HRMS/EI: m/z calcd for C12
H
16
O
2
Anal. Calcd for C23
H, 6.80.
26 5
H O : C, 72.23; H, 6.85. Found: C, 72.09;
found 192.11511 ( 0.00054.
8
(S )-Me t h yl-3-[[(6′(S )-m e t h yl-5′-oxo-4′-oxa t r icyclo-
8(R )-Me t h yl-3-[[(6′(S )-m e t h yl-5′-oxo-4′-oxa t r icyclo-
2
′,6′
2′,6′
[
4
5.2.1.0
]d e c-8′-e n -3′(R )-yl)oxy]m e t h yle n e ]-3,3a (R ),
[5.2.1.0
]d e c-8′-e n -3′(R )-yl)oxy]m e t h yle n e ]-3,3a (R ),
4,5,6,7,8,8b(S)-octa h yd r oin d en o[1,2-b]fu r a n -2-on e (13c)
a n d Its 3a (S),8(S),8b(R) Dia ster eom er (en t.13d ). These
compounds were prepared in the same way as described for
13a and en t.13b, starting from tricyclic lactone r a c.10b and
chloro lactone 12. Yields were 28% of fast moving diastere-
,5,6,7,8,8b(S)-octa h yd r oin d en o[1,2-b]fu r a n -2-on e (13a )
a n d Its 3a (S),8(R),8b(R) Dia ster eom er (en t.13b). To a
cooled (0 °C) and stirred solution of racemic trans tricyclic
lactone r a c.10a (576 mg, 3.0 mmol) in diethyl ether (15 mL)
were added, under a continuous stream of nitrogen, 3 equiv
of ethyl formate (666 mg, 9 mmol) and 1.1 equiv of potassium
tert-butoxide (370 mg, 3.3 mmol). The mixture was stirred
overnight at room temperature. Ether was removed by a
nitrogen flow, and the potassium salt of formylated r a c.10a
omer 13c and 35% of slow moving diastereomer en t.13d .
21
1
3c: mp 240-242 °C, de >99% (determined by NMR), [R]
D
1
)
+182.4° (c ) 0.5, CH
.12 (d, 3H, J ) 7.0 Hz); 1.34 (m, 1H); 1.54 (m, 1H, H6); 1.58
s, 3H); 1.72 (m, 4H); 1.94 (m, 2H); 2.33 (m, 2H); 2.68 (d, 1H,
J ) 4.1 Hz); 2.71 (ddd, 1H, J ) 3.1 Hz, 9.3 Hz, 16.8 Hz); 2.89
m, 1H); 3.22 (m, 1H); 3.60 (m, 1H); 5.20 (d, 1H, J < 1 Hz);
.33 (d, 1H, J ) 7.7 Hz); 6.25 (2m, 2H); 7.33 (d, 1H, J ) 2.4
2 2 3
Cl ). 400 MHz H NMR (CDCl ): δ
1
was dissolved in DMF (20 mL) and cooled to -50 °C.
A
(
solution of chloro lactone 12 (596 mg, 3.0 mmol) in DMF (5
mL) was gradually added at -50 °C under nitrogen. After
being stirred overnight, the mixture was quenched with acetic
acid (0.5 mL) and the solvent was removed under reduced
pressure. The residue was dissolved in a mixture of water
and ethyl acetate. The aqueous phase was extracted with
ethyl acetate (2 times), and the combined organic layers were
(
5
13
Hz). C NMR (CDCl
3
): δ 19.8; 20.3; 22.6; 26.2; 30.1; 31.6;
3
1
6.9; 41.5; 45.2; 49.8; 52.0; 53.4; 54.5; 90.7; 103.8; 113.7; 133.5;
36.8; 137.8; 142.6; 150.7; 171.9; 178.8. MS [EI m/z, rel
+
+
intensity (%)]: 382 ([M] , 0.8); 316 ([C18
H
20
O
5
] , 0.5); 202
washed with brine (2 times), dried (MgSO
in vacuo. The crude product was purified using flash chro-
matography (SiO , hexane/ethyl acetate 4/1) to give fast
moving diastereomer 13a (444 mg, 39%) and slow moving
diastereomer en t.13b (558 mg, 49%) as colorless crystals.
4
), and concentrated
+
+
+
(
9
[C13
H
14
O
2
+
] , 28.3); 163 ([C10
H
11
O
2
] , 80.2); 97 ([C
] , 8.2). Anal. Calcd for C23
Found: C, 72.09; H, 6.80.
5
H
5
O
2
] , 100);
1 ([C
7
H
7
26 5
H O : C, 72.23; H, 6.85.
2
en t.13d : mp 217-218.5 °C, de >99% (determined by NMR),
21
1
[
(
1
2
(
R]
D
) -242.8° (c ) 0.5, CH
): δ 1.12 (d, 3H, J ) 7.0 Hz); 1.37 (m, 1H); 1.54 (m,
H); 1.58 (s, 3H); 1.71 (m, 2H); 1.73 (m, 2H); 1.94 (m, 2H);
.31 (m, 2H); 2.66 (ddd, 1H, J ) 3.2 Hz, 9.0 Hz, 16.8 Hz); 2.73
2 2
Cl ). 400 MHz H NMR
2
1
1
3a : mp 150-152 °C, de 93% (determined by NMR), [R]
D
CDCl
3
1
)
1
4
(
(
2 2 3
+174.8° (c ) 0.5, CH Cl ). 400 MHz H NMR (CDCl ): δ
.06 (d, 3H, J ) 7.0 Hz); 1.26 (m, 1H); 1.56 (m, 4H); 1.74 (m,
H); 1.94 (m, 2H); 2.35 (m, 2H); 2.69 (d, 1H, J ) 4.1 Hz); 2.76
d, 1H, J ) 4.2H); 2.90 (m, 1H); 3.22 (m, 1H); 3.60 (m, 1H);
dd, 1H, J ) 8.8 Hz, 15.6 Hz); 2.90 (m, 1H); 3.22 (m, 1H); 3.60
m, 1H); 5.20 (d, 1H, J < 1 Hz); 5.47 (d, 1H, J ) 7.2 Hz); 6.25
5
7
.20 (d, 1H, J < 1 Hz); 5.35 (d, 1H, J ) 7.8 Hz); 6.25 (2m, 2H);
13
.33 (d, 1H, J ) 2.5 Hz). C NMR (CDCl ): δ 20.0; 20.2; 22.5;
3
(
30) Detailed NMR analysis revealed that the de differed slightly
(31) The difference in melting point as compared to that of its
enantiomer 13a is presumably due to the difference in de.
from that reported in ref 10.

Synthesis of All Stereoisomers of Sorgolactone
J . Org. Chem., Vol. 63, No. 4, 1998 1267
2
1
6.2; 30.1; 31.6; 36.7; 41.1; 45.1; 49.8; 51.9; 53.4; 54.3; 90.7;
03.6; 113.7; 133.5; 136.5; 137.8; 142.7; 150.8; 171.8; 178.8.
(b) P r ep a r a tion of Test Solu tion s. A compound to be
tested was weighed out accurately to the amount of 1 mg,
dissolved in 1 mL acetone p.a., and diluted with demineralized
water to 100 mL. Aliquots of this stock solution were diluted
further with water to obtain test solutions containing 0.1, 0.01,
0.001, and 0.0001 mg/L test compound and 0.01, 0.001, 0.0001,
and 0.00001% (v/v) acetone, respectively.
+
+
MS [EI m/z, rel intensity (%)]: 382 ([M] , 0.9); 316 ([C18
0
H
20
O
5
] ,
+
+
.5); 202 ([C13
H
14
O
2
] , 20.4); 163 ([C10
H
11
O
2
] , 64.1); 97
+
+
([C
5
H
5
O
2
] , 100); 91 ([C
7
H
7
] , 4.1). Anal. Calcd for C23
H
26
O
5
:
C, 72.23; H, 6.85. Found: C, 72.21; H, 6.76.
8
(S )-Me t h yl-3-[[(6′(R )-m e t h yl-5′-oxo-4′-oxa t r icyclo-
2
′,6′
[
5.2.1.0
]d e c -8′-e n -3′(S )-yl)oxy]m e t h yle n e ]-3,3a (S ),
(c) Bioa ssa ys. The sterilization, conditioning, and stimu-
lation of the seeds were performed as described by Mangnus
et al.32 for O. crenata and as described by Kuiper for S.
hermontica. In each test series aqueous solutions with 0.1%
(v/v) acetone were used as the control. Test solutions of the
stimulant GR 24 (concentrations of 0.1, 0.01, 0.001, and 0.0001
mg/L) were used as references, which enables comparison
among results obtained in different test series. These positive
controls are important, since the response of seeds of parasitic
weeds varies considerably from test to test. All tests were
performed at least in duplicate, and in each test the germina-
tion percentages were determined on six disks per treatment.
4
,5,6,7,8,8b(R)-octah ydr oin den o[1,2-b]fu r an -2-on e (en t.13c)
33
a n d Its 3a (R),8(R),8b(S) Ster eoisom er (13d ). These com-
pounds were prepared in the same way as described for 13a
and en t.13b, starting from tricyclic lactone r a c.10b and chloro
lactone en t.12. Yields were 46% of fast moving diastereomer
en t.13c and 40% of slow moving diastereomer 13d .
en t.13c: mp 238-240 °C, de 97% (determined by NMR),
2
1
1
13
[R]
D
2 2
) -187.0° (c ) 0.5, CH Cl ). H NMR, C NMR, and
mass data were identical with those of its enantiomer 13c.
Anal. Calcd for C23
H, 6.79.
H
26
O
5
: C, 72.23; H, 6.85. Found: C, 71.69;
2
1
1
3d : mp 217-219 °C, de 94% (determined by NMR), [R]
D
Ack n ow led gm en t. We thank Dr. Christian Hauck
for supplying us with copies of the original NMR spectra
of naturally occurring sorgolactone. H. Amatdjais, P.
van Galen, and A. Swolfs are acknowledged for conduct-
ing elemental analysis, mass, and 400 MHz NMR
measurements, respectively. We appreciate the coopera-
tion with Dr. E. Kuiper and Dr. J . Verkley from the Free
University of Amsterdam in performing the bioassays.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
r a c.10a , r a c.10b, and 2a (3 pages). This material is contained
in libraries on microfiche, immediately follows this article in
the microfilm version of the journal, and can be ordered from
the ACS; see any current masthead page for ordering
information.
1
13
)
+250.2° (c ) 0.5, CH
2
Cl
2
). H NMR, C NMR, and mass
data were identical with those of its enantiomer en t.13d .
Anal. Calcd for C23
H, 6.84.
26 5
H O : C, 72.23; H, 6.85. Found: C, 72.52;
Biologica l Activity. (a ) Seed s. Seeds of S. hermontica
Del.) Benth. (from Sorghum bicolor (L.) Moench) and O.
(
crenata Forsk. (from Vicia faba L.) were harvested in Burkina
Faso in 1994 and Egypt in 1991, respectively, and were stored
in the dark at room temperature until use in germination tests.
Bioassays were carried out essentially following the procedure
3
2
of Mangnus et al. with minor modifications.
(
32) Mangnus, E. M.; Stommen, P. L. A.; Zwanenburg, B. J . Plant
Growth Regul. 1992, 11, 91-98.
33) Kuiper, E., Thesis Free University Amsterdam, The Nether-
lands, ISBN 90-5651-035-5, 1997.
(
J O9718408