New synthesis of A-ring aromatic strigolactone analogues and their evaluation as plant hormones in pea (pisum sativum)

Article abstract of DOI:10.1002/chem.201203585

A new general access to A-ring aromatic strigolactones, a new class of plant hormones, has been developed. The key transformations include in sequence ring-closing metathesis, enzymatic kinetic resolution and a radical cyclization with atom transfer to install the tricyclic ABC-ring system. The activity as plant hormones for the inhibition of shoot branching in pea of various analogues synthesized by this strategy is reported. Inhibiting shoot branching: A new general access to A-ring aromatic strigolactones (see scheme), a new class of plant hormones, has been developed. The biological activity of various analogues synthesized by this strategy for inhibiting bud outgrowth in pea was evaluated. Copyright

Full text of DOI:10.1002/chem.201203585

FULL PAPER
DOI: 10.1002/chem.201203585
New Synthesis of A-Ring Aromatic Strigolactone Analogues
and Their Evaluation as Plant Hormones in Pea (Pisum sativum)
Victor X. Chen,[a] FranÅois-Didier Boyer,*[a] Catherine Rameau,[c] Jean-Paul Pillot,[c]
Jean-Pierre Vors,[d] and Jean-Marie Beau*[a, b]
Abstract: A new general access to A-ring aromatic strigolactones, a new class of
plant hormones, has been developed. The key transformations include in sequence
ring-closing metathesis, enzymatic kinetic resolution and a radical cyclization with
atom transfer to install the tricyclic ABC-ring system. The activity as plant hor-
mones for the inhibition of shoot branching in pea of various analogues synthe-
sized by this strategy is reported.
Keywords: lactones
· plant hor-
mones radical reactions
·
·
·
structure–activity relationships
total synthesis
Introduction
found to have an effect on phytopathogenic fungi.[10] In
these AMF symbioses, plants receive water and mineral nu-
trients from their fungal partners, hence promoting optimal
plant growth conditions. SLs belong to a class of compounds,
the g-butyrolactone, known as pheromones or allelochemi-
cals:[11] Recently, one of us[12] demonstrated that SLs regu-
late protonema branching and act as a quorum sensing-like
signal in the moss Physcomitrella patens emphasizing their
roles in both plant development and communications be-
tween organisms. The structural core of SLs is a tricyclic lac-
tone (ABC rings) with various substitution patterns on AB
rings. It is connected via an enol ether linkage to an invaria-
ble a,b-unsaturated furanone moiety (D-ring) (Scheme 1).
To date, at least 15 naturally occurring SLs have been
completely identified and characterized in root exudates. It
is expected that many other SLs or derivatives will be iden-
tified in the future.[1] They are derived from the carotenoid
pathway, involving isomerization of b-carotene 1 by a b-car-
otene isomerase (D27), and cleavage at the C9’,C10’ posi-
tion by Carotenoid Cleavage Dioxygenases 7 (CCD7) to
form 9-cis-b-apo-10’-carotenal. Introduction of oxygens and
intramolecular rearrangement by CCD8 lead to carlactone
2.[13] Bioactive carlactone 2, very recently isolated, is central
for understanding the biosynthesis of SLs but also for con-
ceiving SL analogues. It implies that the BC rings are
formed after the D ring to give 5-deoxystrigol (3) contrary
to a previous hypothesis.[14] This required cyclization was re-
cently rationalized[15] by synthetic studies based on a simple
linear precursor by an acid-catalyzed double cyclization.
Further hydroxylations, epoxidation/oxidation and methyl
transfer or acetylation from 3 would lead to hydroxy-SLs or
acetylated-SLs: strigol (4), strigyl acetate (4-Ac), orobanchol
(5),[16] orobanchyl acetate (5-Ac), solanacol (6) and fabacyl
acetate (7), six major hydroxylated and acetylated-SLs
found in Nature. Although the synthetic aromatic SL ana-
logue GR24 has been known for a long time[17] as a refer-
ence compound in bioassays on seed germination of parasit-
ic weeds, solanacol (6), the first natural SL containing a
Strigolactones (SLs), the most recent class of hormones
identified in plants,[1] are especially studied in pea, Arabi-
dopsis, petunia and rice. Formed mainly in the lower parts
of the stem and roots and transported presumably to the
aerial parts,[2] they suppress shoot branching[3] and are in-
volved in nodule formation,[4] root architecture[5] and the
stimulation of cambium activity.[6] Their production would
be inversely correlated with the concentration of phosphate
and nitrogen available for the plants.[7] SLs belong to a class
of compounds first identified in 1966 as stimulants of the
seed germination of parasitic weeds Orobanche and Striga.[8]
They are produced in trace concentrations and are partly ex-
creted in the rhizosphere. These molecules, recently identi-
fied as stimulants for spore germination and hyphal prolifer-
ation of arbuscular mycorrhizal fungi (AMF),[9] were also
[a] Dr. V. X. Chen, Dr. F.-D. Boyer, Prof. J.-M. Beau
Centre de Recherche de Gif
Institut de Chimie des Substances Naturelles
CNRS, INRA, 1 avenue de la Terrasse, 91198 Gif-sur-Yvette (France)
Fax : (+33)1-6907-7247
E-mail: boyer@icsn.cnrs-gif.fr
jean-marie.beau@icsn.cnrs-gif.fr
[b] Prof. J.-M. Beau
Universitꢀ Paris-Sud and CNRS
Laboratoire de Synthꢁse de Biomolꢀcules
Institut de Chimie Molꢀculaire et des Matꢀriaux
91405 Orsay (France)
Fax : (+33)1-6985-3715
E-mail: jean-marie.beau@u-psud.fr
[c] Dr. C. Rameau, J.-P. Pillot
IJPB UMR1318 INRA-AgroParisTech
RD10, 78126 Versailles Cedex (France)
[d] Dr. J.-P. Vors
Bayer SAS, 14-20 rue Pierre Baizet
BP 99163, 69263 Lyon Cedex 09 (France)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203585; contains experimen-
tal details of all building blocks.
Chem. Eur. J. 2013, 19, 4849 – 4857
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4849

method to access SL analogues bearing substituents at this
position. We[25] recently reported the first total synthesis of
(À)-solanacol and the first SAR study on pea as a plant hor-
mone.[26] We established that the presence of a Michael ac-
ceptor and a methylbutenolide or a dimethylbutenolide
motif in the same molecule is essential. We demonstrated
that SLs show potent activity for the control of shoot
branching in a structure dependent manner but with low
specificity. Herein, we present a full report concerning our
strategy for the enantioselective synthesis of the natural aro-
matic SL solanacol and epimers useful for our very recently
published SAR study. We also report a detailed diastereose-
lective synthesis for A-ring aromatic derivatives and helpful
complementary information on our SAR study in pea,[26]
confirming our first findings. This class of SL derivatives
bearing a hydroxy group at C4 were only tested for the ger-
mination of parasitic weeds[27] for which they showed great
differences in bioactivity from one species to another.
Results and Discussion
Our retrosynthetic analysis is outlined in Scheme 2. Con-
struction of aromatic SLs 8 was envisioned from tricyclic
lactones 10a–b with the correct relative stereochemistry by
coupling with bromofuranone 9 as the D-ring precursor,
using well-known procedures.[28] The stereoselective intro-
duction of a C4-hydroxyl group[29] could be achieved from
trichlorides 11a–b by a substitution with retention of config-
uration at this benzylic position. Compounds 10a–b could in
turn be derived from enantiopure esters 12a–b by an atom
transfer radical cyclization (ATRC),[30] which would origi-
nate from a ring closing metathesis (RCM)/kinetic resolu-
tion sequence on dienes 13a–b. These aromatic dienes
would be prepared from inexpensive and commercially
available 2-bromostyrene and 3,4-dimethyl phenol.
Scheme 1. Biosynthetic precursors of SLs, selected natural SLs and syn-
thetic analogue GR24. D27=Dwarf 27=b-carotene isomerase); CCD=
Carotenoid Cleavage Dioxygenase.
phenyl ring was recently isolated from tobacco and tomato
root exudates.[18,19] GR24 presents high germination activity
and increased stability compared to natural SLs, which are
sensitive in a natural media resulting from a Michael addi-
tion of water on the enol ether linkage. The bioactiphore for
the germination of parasitic weeds has been extensively
studied since its discovery in the 1970s and was found reside
in the CD part.[20] Essential structural features for AM fungi
branching appear to be similar, but important SL structure
variations seem to affect bioactivity.[21] Contrary to the ger-
mination of parasitic weeds, the oxygenation pattern of the
SL and the replacement of the enol ether link between rings
C and D by an alkoxy or an imino ether have little effect in
activity. Also, the presence of the ABC-rings is essential.
The great importance of SLs in many plant chemical biol-
ogy areas with opposite effects (repression of cell division in
axillary bud and stimulation of cambial activity or hyphal
proliferation) depending on the target, their intriguing
origin in green lineage,[22] and their extremely low bio-avail-
ability prompted us to develop a new strategy for the syn-
thesis of this class of compounds to perform structure-activi-
ty relationship studies as a plant hormone. Indeed, contrary
to the germination activity,[1] few studies have been descri-
bed for the hormonal function of SLs.[3b,23] Due to the fact
that compounds active on the parasitic seed germination[24]
possess a hydroxyl group at the C4 position and are the
most difficult to synthesize, we focused on developing a
Alcohol 13a was easily prepared in two steps from 2-bro-
mostyrene by formylation and alkylation with vinylmagnesi-
um bromide in an 89% overall yield (Scheme 3). Because of
the aromatic o-dimethyl substitution, the preparation of
Scheme 2. Retrosynthesis of A-ring aromatic SLs for SAR studies target-
ed in this study.
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Aromatic Strigolactone Analogues
FULL PAPER
Table 1. Synthesis of the tricyclic lactones 20a,b.
diene 13b needed a more elaborated route requir-
ing nine steps from the starting 3,4-dimethylphe-
nol. It started by a selective o-bromation at posi-
tion 6 of 3,4-dimethylphenol. This step suitably es-
tablished a temporary protection at this position in
the following sequence. Thus, alkylation of the
phenol with allyl bromide and Lewis acid catalyzed
Claisen rearrangement were completely regioselec-
tive providing bromide 14 in a 90% overall yield.
À
Isomerization of the terminal C C double bond in
14 (90% yield) and ozonolysis furnished aldehyde
15 (79% yield). It was quantitatively debrominated
by catalytic hydrogenolysis using hydrogen and Pd/
C in the presence of an excess of triethylamine.
The vinylation conditions of the trisubstituted
phenol were obtained by triflation under standard
conditions to triflate 16, and cross-coupling with
vinyl trifluoroborate[31] under Suzuki–Miyaura con-
ditions to furnish aldehyde 17 (98% yield). Vinyla-
tion with the vinylic Grignard reagent completed
the sequence to diene 13b in an 89% overall yield
from 16.
Entry
Starting
material
Conditions
Product
ACHTUNGTRENNUNG(yield [%])
1
2
3
4
5
6
13a
13a
13b
13b
13b
13b
CCl3COCl[a]
19 (78)
Grubbs[b]
18a (84)
18b (88)
12b (88)
12a (50)
12a (34)
Grubbs[b]
1) Grubbs, 2) (CCl3CO)2O[c]
1) Grubbs, 2) (CCl3CO)2O, 3) Grubbs[d]
1) Grubbs, 2) (CCl3CO)2O, 3) CuCl;
one-pot procedure[e]
7
8
13b
13a
1) Grubbs, 2) (CCl3CO)2O, one-pot procedure,[c]
3) CuCl[f]
11a (65)
11b (66)
1) Grubbs, 2) (CCl3CO)2O, one-pot procedure,[c]
3) CuCl[f]
[a] CCl3COCl, Et3N, Et2O, 0 8C, 15 min. [b] Grubbs I catalyst, 5 mol%, CH2Cl2, RT,
12 h. [c] 1) Grubbs I catalyst, 5 mol%, toluene, RT, 12 h, 2) (CCl3CO)2O, pyr, 08C,
Elaboration of the B- and C-ring was studied
using ruthenium-catalyzed RCM and ATRC reac-
tions on dienes 13a and 13b as shown in Table 1.
Not surprisingly, direct trichloroacetylation of alco-
hol 13a led to the quantitative formation of 19
(entry 1, Table 1) via a [3,3]-sigmatropic rearrange-
ment. This result impeded a possible RCM/ATRC
tandem version to the ABC-tricyclic structure.
one-pot procedure. [d] 1) Grubbs
I catalyst, 5 mol%, toluene, RT, 12 h, 2)
(CCl3CO)2O, pyr, 08C, 3) Grubbs I catalyst, 5 mol%, one-pot procedure. [e] 1)
Grubbs I catalyst, 5 mol%, toluene, RT, 12 h, 2) (CCl3CO)2O, pyr, 08C, 3) CuCl/
dHBipy catalyst, 5 mol%, one-pot procedure. [f] CuCl/dHBipy catalyst, 5 mol%,
DCE, 908C, 12 h.
Elaboration of the B-ring was performed using a ruthenium-
catalyzed RCM reaction on dienes 13a,b furnishing racemic
indenols (Æ)-18a,b in high yields (entries 2–3, Table 1).
RCM followed by trichloroacetylation of indenol could be
done in a one-pot procedure (entry 4, Table 1) but any at-
tempt of ATRC by Grubbs I[30] or copper(I) catalysts in the
same medium failed to furnish the tricyclic lactone 11a (en-
tries 5–6, Table 1). The best way to synthesize 11a, 11b was
ultimately to proceed via isolation of trichloroesters 12a,
12b and cyclization to lactones 11a, 11b in a next step using
catalytic copper(I) coordinated to 4,4’-di-n-heptylbipyridine
(dHbipy)[32] (entries 7–8, Table 1). The stereoselective lacto-
nization to the ABC-tricyclic system 11a (11b) was best ob-
tained in a 78% (77%) yield, for the ATRC step.[30,32] Steri-
cally-controlled halogen transfer to benzylic radical 20 from
the CuII complex generated in the catalytic process, proceed-
ed stereoselectively anti to ring C. The stereochemistry was
unambiguously established by X-ray analysis of 11b.[25]
Access to enantiomerically pure indenol derivatives was
conveniently performed by enzymatic kinetic resolution. Al-
cohols (Æ)-18a and 18b were acetylated to esters (Æ)-21a
and (Æ)-21b, respectively (Scheme 4). Their kinetic resolu-
tion with immobilized Candida antarctica lipase[33] was par-
ticularly efficient in producing both enantiomerically pure
alcohols (R)-18a,b (>99% ee), and the enantiomeric esters
(S)-21a,b (>99% ee).[33] Direct kinetic resolution of allylic
trichloroester (Æ)-12b unfortunately failed as the Candida
antarctica lipase was completely inactive on this substrate.
The enantiomerically pure ABC-tricyclic trichlorides
(+)-11a,b and (À)-11a,b were elaborated from (+)-18a,b
and (À)-18a,b following the steps (RCM, trichloroacetyla-
Scheme 3. Formation of the B-ring precursors 13a and 13b. a) nBuLi, N-
formylpiperidine, THF, À788C to RT, 18 h, 94%; b) CH2=CHMgBr,
THF, RT, 3 h, 95%; c) 1) Br2, CH2Cl2, 08C, 1 h, 90%; d) allyl bromide,
K2CO3, acetone, reflux, 3 h, quant.; e) Et2AlCl, hexane, RT, 6 h, quant.;
f) tBuOK, THF, RT, 48 h, 90%; g) O3, CH2Cl2, À788C; Me2S, À788C to
RT, 12 h, 79%; h) Pd/C, H2, NEt3, MeOH, RT, 2 h, quant.; i) Pyr, Tf2O,
CH2Cl2, 08C to RT, 1 h, 74%; j) CH2=CHBF3K, PdCl2, Cs2CO3, PPh3,
THF/H2O 9:1, 858C, 12 h, 98%; k) CH2=CHMgBr, THF, RT, 3 h, 91%.
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F.-D. Boyer, J.-M. Beau et al.
Scheme 4. Enzymatic kinetic resolution of (Æ)-18a,b. a) Ac2O, pyr, THF,
08C, 15 min, 21a: 78% from 13a, 21b: 95%; b) immobilized Candida
antarctica lipase, CH3CN, H2O, 24 h, 50% of (R)-18a,b, 50% of (S)-
21a,b.
Scheme 6. Presumed intermediates in the formation of the C4-hydroxy
ABC tricyclic compounds 23–25. HFIP=hexafluoroisopropanol.
Table 2. Formation of the C4-hydroxy ABC tricyclic compounds 23–25.
tion and ATRC) reported above (Table 1) for the
racemic substrates.
No enantioselective synthesis of GR24 has been
reported until now and the only preparation of the
(+)- and (À)-GR24 we are aware of was establish-
ed by chromatographic resolution of lactone 22.[34]
With (+)- and (À)-11a in hand, a novel access to
(+)- and (À)-GR24 was easily achieved by dech-
lorination leading to (+)- and (À)-22 with Bu3SnH
in high yield (97%). Unfortunately, dechlorination
with zinc dust was not compatible with the pres-
ence of a chlorine atom at C4. Enantiopure (+)-
and (À)-22 are the precursors to (+)- and (À)-
GR24 via formylation and coupling with D-ring
precursor 9 (Scheme 5) as was early described.[34]
Entry
1
Starting material
Conditions
Product (yield [%])
11a
MeONa (1.1 equiv),
MeOH/H2O 9:1, RT, 4 h
MeONa (1.1 equiv),
MeOH/H2O 9:1, RT, 4 h
H2O/HFIP 1:1, 908C, 1 h
H2O/HFIP 1:1, 908C, 4 h
23a (82)
2
11b
23b/24[a] 1:1 (64)
3
4
11b
(+)-11a
25b/23b[a] 9:1 (quant.)
(Æ)-23a (82)
[a] Inseparable mixture.
The substitution with retention of configuration of the
benzylic chlorine atom in (+)-, (À)- and (Æ)-11b (entry 3,
Table 2) by a hydroxyl group was achieved with good stereo-
control (9:1, anti/syn to ring C) under SN1 conditions, by
heating a solution of 11b in a 1:1 mixture of water/hexa-
fluoroisopropanol.[35] The same conditions applied on
(+)-11a, however, gave racemic (Æ)-23a because of the
above opening/closure of the lactone precluding the use of
this strategy to prepare enantiopure 4-hydroxy-GR24 deriv-
atives (entry 4, Table 2). This last result emphasizes the im-
portance of the aromatic dimethyl substitution in 11b to fa-
cilitate the formation of the presumed benzylic cationic in-
termediate 26, trapped by water anti to ring C in a SN1 fash-
ion. This provided an enantioselective access to (+)- or (À)-
solanacol starting from (+)-25b or (À)-25b (Scheme 6).
At this stage, the synthesis was pursued with (Æ)-23a and
(Æ)-25b as well as with the enantiopure compounds (+)-
and (À)-25b. Dechlorination of the gem-dichloro motif with
zinc dust afforded tricyclic lactone 28a (10b) in a 95%
(91%) overall yield from 23a (25b/23b) (Scheme 7).
Scheme 5. Enantioselective access to GR24. a) Bu3SnH, AIBN, toluene,
908C, 15 min, 22: 97%; b) see reference [34].
The following substitution of the benzylic chlorine atom
in 11a and 11b by a hydroxyl group was achieved with good
stereocontrol under conditions varying according to the sub-
strate (Table 2). Under basic conditions (NaOH generated
from MeONa in a mixture of MeOH/H2O), chloride 11a led
to alcohol 10a with inversion of configuration at C4
(entry 1, Table 2). Under the same conditions 11b gave an
equimolar mixture of 25b and 24 (entry 2, Table 2). This in-
dicated that, in both cases, the displacement of the chlorine
atom was followed by the opening of the lactone and re-clo-
sure on either hydroxyl groups through undetected diol 27
(Scheme 6). This event was hidden with 11a, which only
gave product 23a because of the symmetry in the open in-
termediate 27 (R1 =R2 =H).
To allow[28c] coupling with the D-ring, inversion of the
stereochemistry of the hydroxy group at C4 (28a to 10a)
was performed in high yield (90%) under Mitsunobu condi-
tions. Derivative 29a bearing a fluorine atom at C4 could
easily be prepared from alcohol 28a using Deoxo-Fluor at
À788C. Careful formylation, by controlling the temperature,
of 10a, 10b, and 29a followed by coupling (in the same pot
in the case of 10b) with D-ring precursor 9 completed the
synthesis to provide the same proportions of compound 6
identified as (À)-solanacol[25] and (À)-2’-epi-solanacol 30b
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Aromatic Strigolactone Analogues
FULL PAPER
ed us to examine the effect of the substitution at C4 on the
biological activity by synthesis of esters 34/35, 36/37, 38/39
and 40 from alcohols 30a/31a using standard procedures
(Scheme 7).
Pea (Pisum sativum) is an excellent model for physiologi-
cal studies, and in particular, to study the control of branch-
ing. Its simple architecture is particularly suitable for precise
exogenous hormone applications directly onto the bud at
the axil of leaf. One major advantage of our bioassay with
direct bud application is the small quantity (less than 1 mg)
of molecule needed contrary to the relatively large amount
of samples required in rice where a hydroponic culture has
to be used.[3b,23] The evaluation of hormonal activity in in-
hibiting bud outgrowth with our synthesized compounds was
performed and compared to the active synthetic SL ana-
logue (Æ)-GR24 commonly used for this bioassay.[3a] Appli-
cation of the solution to be tested (10 mL per plant) was car-
ried out directly onto the axillary bud at node 3 or 4 of
10 day-old SL-deficient rms1/ccd8 plants.[3a]
At a concentration of 1 mm, a significant effect in bud out-
growth repression was observed for the new compounds of
the solanacol series in comparison with control 0 (Figure 1).
Hydroxy-SLs were already found less active than their cor-
responding acetates,[26] which was also observed here with
2’-epimer 30b being less active than 33b and GR24 (Fig-
ure 1B). At a concentration of 100 nm, a significant effect
for branching inhibition was observed for GR24 and ace-
tates 32b and 33b (Figure 1A and B). Bud outgrowth activi-
ty was found barely significant at 10 nm for acetate 33b (P=
0.12, Kruskal–Wallis rank sum test) (Figure 1A).[26] The dif-
ference of activity of hydroxyl-SL when compared with the
corresponding acetate, may be attributed to its instability in
an aqueous solution or to its lower lipophilicity making it
difficult for 6 to reach the receptor. This last hypothesis was
reinforced by a molecular bioassay using transcript levels in
axillary buds of the transcription factor PsBRC1, 6 h after
SL application. PsBRC1 is the homologue from pea of the
Arabidopsis BRANCHED1 (BRC1) and TEOSINTE
BRANCHED1 (TB1) from Maize and is transcriptionally
regulated by SL. Transcript levels were found significantly
higher for 33b compared to solanacol 6, 6 h after applica-
tion.[26,36] In contrast to the importance of the absolute con-
figuration of SLs for their germination stimulation activities
in root parasitic weeds[1a,27] and stimulation of hyphal
branching in AM fungi,[21] we observed no significant activi-
ty difference for the (+) and (À)-enantiomers (Figure 1).
At a 1 mm concentration, a significant effect in bud out-
growth repression was observed for the new compounds of
the 4-R-GR24 series except for compound 40 (Figure 2A).
As for the solanacol series, the activity of acetates 32a and
33a is higher than that of the corresponding alcohols 30a
and 31a, especially at low concentrations <1 mm (Fig-
ure 2B). Similar activity was found by replacing the hydroxy
group by a fluorine atom (fluorides 41/42) compared with
the acetates 32a or 33a (Figure 2A). However the esterifica-
tion of 4-OH by N-Boc alanine (40) led to loss of bioactivity
(Figure 2A). Surprisingly, the esters 4-OR-2’-epi-GR24 (33a,
Scheme 7. Final steps in the synthesis of aromatic SL analogues. a) Zn
dust, NH4Cl, MeOH, 08C to reflux, 2 h, (95% for 28a (two steps), 91%
for 10b (two steps)); b) Deoxo-Fluor, CH2Cl2, À788C, 2 h, 91%; c) PPh3,
DEAD, PhCO2H, THF, RT, 12 h; d) K2CO3, MeOH; RT, 2 h, 90% (2
steps), e1) 1) tBuOK, ethyl formate, THF, À108C, 12 h, 83%; 2) 9,
K2CO3, NMP, RT, 3 h, 36% for 30a; 34% for 31a; 52% for the insepara-
ble mixture 36/37 1:1; e1) Ac2O, pyr, RT, 12 h, 92%. e2) tBuOK, ethyl for-
mate, THF, À78 to À408C, 6 h; 9, À608C to RT, 12 h, 38% for 3; 38%
for 43; f) Ac2O, pyr, RT, 12 h, 50% for 32 and 40% for 33 from a mix-
ture (1:1) of 30/31; 37% for 32b and 38% for 33b from a 1:1 mixture of
30b/6; g) DCC, DMAP, n-butyric acid, CH2Cl2, 08C to RT, 3 h, 38% for
34 and 28% for 35 from a 1:1 mixture of 30a/31a; h) DCC, DMAP, octa-
noic acid, CH2Cl2, 08C to RT, 3 h, 43% for 36 and 37% for 37 from a 1:1
mixture of 30a/31a; i) DCC, DMAP, undecanoic acid, CH2Cl2, 08C to
RT, 3 h, 35% for 38 and 26% for 39 from a 1:1 mixture of 30a/31a; j)
DCC, DMAP, Boc-Ala-OH, CH2Cl2, 08C to RT, 3 h, 72% for 40 from
31a.
separated by chromatography on silica gel in a 76% com-
bined yield. The same sequence furnished 4-OH-GR24 30a,
4-OH-2’-epi-GR24 31a and 4-F-GR24 (41/42) as an insepa-
rable mixture of diastereoisomers in the latter case. The
stereochemistry at C2’ relative to the other asymmetric cen-
ters was unambiguously assessed by X-ray analysis of com-
pounds 6[25] and 30b showing an R configuration at C2’ in 6
and an S configuration at this center in 30b. We clearly es-
tablished, in our previous communication, that the natural
product corresponded to the more polar synthetic diaster-
eoisomer (À)-6[25] by comparing the CD and NMR spectra
of (À)-6 with that of the natural product.[17] This first total
synthesis of solanacol (6) and 2’-epi-solanacol (30b) in-
volved 15 linear steps with a 21% overall yield. Our synthe-
sis of 4-OH-GR24 30a and 4-OH-2’-epi-GR24 31a is more
rapid (10 linear steps) but with a similar overall yield
(24%). We previously[25,26] demonstrated that solanacyl ace-
tate 33b is a more active compared with 6 to inhibit the out-
growth of axillary buds into branches. These results prompt-
Chem. Eur. J. 2013, 19, 4849 – 4857
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4853

F.-D. Boyer, J.-M. Beau et al.
Figure 2. Comparative activity in the 4-R-GR24 series. A) Comparative
activity of compounds 32a–33a and 40–42 at 1 mm concentration. B)
Comparative activity of compounds 30a–33a and GR24 at 1 mm to 10 nm
concentrations. Length of axillary bud, 8 days after direct application of a
solution of the tested compound at node 3. Data are means ÆSE (n=
24). * P <0.05, ** P <0.01, *** P <0.001 indicate significant differences
with GR24 at the same concentration (Kruskal–Wallis rank sum test). P
<0.001 indicates significant differences with CTL 0 (Kruskal–Wallis rank
sum test). CTL 0=control 0.
Figure 1. Comparative activity in the solanacol series. A) Length of axil-
lary bud, 10 d after direct application at node 4 for compounds GR24,
(+)-30b, (À)-30b, (Æ)-30b, (Æ)-33b at 1 mm to 10 nm concentrations. B)
Length of axillary bud, 8 d after direct application at node 3 for com-
pounds GR24, (+)-32b, (À)-32b, (+)-33b, (À)-33b, (Æ)-33b at 1 mm to
100 nm concentrations. Data are means ÆSE (n=24). * P < 0.05, *** P
< 0.001 indicate significant differences with GR24 at the same concentra-
tion (Kruskal–Wallis rank sum test). CTL 0=control 0.
35, 37 and 39) bearing a linear alkyl chain from 1 to 10 car-
bons presented similar dose dependent activity (Figure 3).
This result underlines the fact that the ABC-part is not im-
portant for the hormonal activity.
Conclusion
In summary, we have exploited an efficient ring closing
metathesis/enzymatic kinetic resolution/atom transfer radi-
cal cyclization sequence of key transformations to construct
the key ABC-ring system in the first synthesis of the natural
aromatic SL solanacol (6). This firmly established its com-
plete structure. We have demonstrated that this strategy can
be applied to other SL analogues. We have further establish-
ed that solanacyl acetate 33b, a natural SL found in tobac-
co,[37] showed in our bioassay high hormonal activity for
shoot branching but not better than GR24.[26] The hydropho-
bic analogues tested were more active in our bioassays than
the hydroxyl analogues. Our SAR studies of SLs as plant
hormones confirmed that SLs show potent activity in a
structure dependent manner but with low specificity con-
cerning the stereochemistry or the substitution at C4 posi-
Figure 3. Comparative activity of more active 4-OR-2’-epi-GR24 (33a,
35, 37, 39). Length of axillary bud, 10 d after direct application at node 3.
Data are means ÆSE (n=24). P < 0.001 indicates significant differences
with CTL 0 (Kruskal–Wallis rank sum test). CTL 0=control 0.
tion. These results confirm our previous ones demonstrating
the low specificity of the SL receptor[38] for shoot branching
inhibition[26] contrary to other models (AM fungi[21] and par-
asitic plants[20]). A mechanism for the SL mode of action in-
volving the hydrolysis of the butenolide D ring,[39] very re-
cently proposed, is in accordance with our last SAR data.[26]
4854
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Chem. Eur. J. 2013, 19, 4849 – 4857

Aromatic Strigolactone Analogues
FULL PAPER
analysis (%) calcd for C13H11Cl3O: C 51.10, H 3.63, O 10.47; found: C
51.05, H 3.56, O 10.32.
Experimental Section
(3aS*,4S*,8bS*,E)-4-Hydroxy-3-((((R*)-4-methyl-5-oxo-2,5-dihydrofur-
an-2-yl)oxy)methylene)-3,3a,4,8b-tetrahydro-2H-indeno-[1,2-b]furan-2-
one (30a) and (3aS*,4S*,8bS*,E)-4-hydroxy-3-((((S*)-4-methyl-5-oxo-
2,5-dihydrofuran-2-yl)oxy)methylene)-3,3a,4,8b-tetrahydro-2H-indeno-
All non-aqueous reactions were run under an inert atmosphere (argon),
by using standard techniques for manipulating air-sensitive compounds.
All glassware was stored in the oven and/or was flame-dried prior to use.
THF was purified by distillation, under nitrogen, from sodium/benzophe-
none. CH2Cl2 was dried by distillation under nitrogen from P2O5. All re-
agents and solvents were commercially available and were used without
further purification. Chiral HPLC analyses were performed using a Chir-
alcel AD-H column (4.6ꢃ250 mm) with UV detection at 254 nm. Analyt-
ical thin-layer chromatography (TLC) was performed on plates precoated
with silica gel layers (PLC silica gel 60 F254, 0.5 mm). Visualization of
the developed chromatogram was followed by UV absorbance and/or by
staining with vanillin or 5% ethanolic phosphomolybdic acid and heat as
developing agent. Flash column chromatography was performed using
35–70 mesh silica. NMR spectra (1H; 13C) were recorded respectively at
(300; 75) MHz. Chemical shifts are reported in parts per million relative
[1,2-b]furan-2-one (31a): To
a solution of lactone 10a (312 mg,
1.64 mmol, 1 equiv) and freshly distilled ethyl formate (1.33 mL,
16.40 mmol, 10 equiv) in THF (25 mL) was added tBuOK (405 mg,
3.61 mmol, 2.2 equiv) in small portions at À108C under argon. After 6 h,
the reaction was quenched with 1n HCl and the product was extracted
with EtOAc. The crude product was then purified by flash chromatogra-
phy (heptane/EtOAc 100:0, then 50:50). The pure enol was obtained as a
white solid (295 mg, 1.35 mmol, 83%) in a mixture of diastereoisomers.
Major diastereoisomer: 1H NMR (300 MHz, [D6]acetone): d = 9.99 (brs,
1H, 9OH), 7.65 (d, 1H, J9,3a =2.4 Hz, H9), 7.50–7.39 (m, 4H, Har), 6.02
(d, 1H, J8b,3a =7.5 Hz, H8b), 5.36 (s, 1H, H4), 3.81 (m, 1H, H3), 2.93 ppm
(brs, 1H, 4OH); 13C NMR (75 MHz, [D6]acetone): d = 172.3 (C2), 154.5
(C9), 146.5 (C4a or C8a), 141.5 (C4a or C8a), 130.7 (Car), 130.0 (Car),
126.9 (2 Car), 105.6 (C3), 84.1 (C8b), 79.4 (C4), 51.1 ppm (C3a); IR
(film): n =3176, 2948, 1712, 1651, 1462, 1196, 986 cmÀ1; MS (ESI): m/z:
273.1 [M+Na+MeOH]+, 241.1 [M+Na]+; HRMS (ESI): m/z: calcd for
C12H10O4Na [M+Na]+: 241.0477; found: 241.0470.
1
to an internal standard of residual chloroform (d=7.24 ppm for H NMR
and 77.23 ppm for 13C NMR). For the 1H spectra, data were reported as
follows: chemical shift, multiplicity (s=singlet, d=doublet, t=triplet, q=
quartet, m=multiplet, brs=broad singulet), coupling constant in Hz, in-
tegration, and assignments. Assignments were obtained using DEPT 135,
1H-1H COSY, 1H-13C HMQC and 1H,13C HMBC experiments. IR spectra
were reported in reciprocal centimeters (cmÀ1). Mass spectra (MS) were
determined either by electrospray ionization (ESI) or chemical ionization
with ammonia (CI, NH3) and high-resolution mass spectra (HRMS) were
determined by electrospray ionization (ESI) or atmospheric pressure
chemical ionization (APCI). Optical rotations were determined using a
cell of 1 dm-length path. Data are reported as follows: [a]TD, concentra-
tion (c in g per 100 mL) and solvent.
To a solution of enol (100.0 mg, 0.46 mmol, 1 equiv) in freshly distilled
N-methylpyrrolidone (2 mL) was added K2CO3 (129.9 mg, 0.94 mmol,
2.05 equiv) at room temperature under argon. To this mixture was added
a solution of 9[28] (166.4 mg, 0.94 mmol, 2.05 equiv) in N-methylpyrroli-
done (2 mL). After 3 h, the reaction was quenched with a solution of 1m
HCl and the product was extracted with EtOAc. The organic layer was
washed with water, brine and dried on MgSO4. The crude product was
purified by preparative TLC (heptane/EtOAc 70:30) to afford the two di-
astereoisomers as two pure fractions (F1=30a: 63.6 mg, 0.20 mmol,
44%; F2=31a: 59.3 mg, 0.19 mmol, 41%) as amorphous white solids.
(3aR*,4S*,8bS*)-3,3,4-Trichloro-3,3a,4,8b-tetrahydro-2H-indeno-[1,2-
b]furan-2-one (11a): A solution of commercial CuCl (54 mg, 0.54 mmol,
0.05 equiv) and dHbipy (191 mg, 0.54 mmol, 0.05 equiv) in degassed
DCE (10 mL) was prepared and stirred at room temperature under
argon. The solution turned into dark brown after 10 min and a solution
of trichloroester 12a (3.00 g, 10.81 mmol, 1 equiv) in degassed DCE
(30 mL) was added to it. The mixture was heated at 908C for 12 h. The
solvent was evaporated and the crude product was directly purified on
silica gel (heptane/EtOAc 95:5). The product 11a (2.34 g, 8.43 mmol,
78%) was obtained as a very pale yellow solid. (+)-(3aR,4S,8bS)-11a:
[a]2D4 = +113.9 (c = 1, CHCl3); (À)-(3aS,4R,8bR)-11a: [a]2D6 = À115.2 (c
= 1, CHCl3); 1H NMR (300 MHz, CDCl3): d = 7.58–7.42 (M, 4H, Har),
5.96 (d, 1H, J8b,3a = 6.0 Hz, H8b), 5.43 (d, 1H, J4,3a = 6.0 Hz, H4),
4.02 ppm (t, 1H, J3a,4 = J3a,8b = 6.0 Hz, H3a); 13C NMR (75 MHz, CDCl3):
d = 167 (C2), 143 (C8), 135 (C4a), 132 (Car), 131 (Car), 127 (Car), 126
(Car), 83 (C8b), 79 (C3), 66 (C3a), 60 ppm (C4); IR (film): n = 2929,
1798, 1466, 1249, 1162, 1151, 955, 909, 726 cmÀ1; MS (IE): m/z: 278
[M+2H]+, 276.0 [M]+, 241 [MÀCl]+; elemental analysis (%) calcd for
C11H13BrO: C 47.60, H 2.54, O 11.53; found: C 47.46, H 2.50, O 11.61.
1
30a: H NMR (300 MHz, [D6]acetone): d = 7.52–7.49 (m, 2H, Har, H6’),
7.43–7.39 (m, 3H, Har), 6.97 (t, 1H, J3’,2’ =J3’,7’ =1.5 Hz, H3’), 6.21 (t, 1H,
J
2’,3’ =1.5 Hz, H2’), 6.05 (d, 1H, J8b,3a =7.3 Hz, H8b), 5.29 (brs, 1H, OH),
5.27 (s, 1H, H4), 3.79 (dt, 1H, J3a,8b =7.3, J3a,6’ =2.6 Hz, H3a), 2.01 ppm (t,
3H, J7’,3’ =1.5 Hz, H7’); 13C NMR (75 MHz, [D6]acetone): d = 170.9 (C2),
170.3 (C5’), 151.9 (C6’), 144.0 (C8a), 141.0 (C3’), 139.4 (C4a), 136.5 (C4’),
130.9 (Car), 130.4 (Car), 126.8 (Car), 125.8 (Car), 110.4 (C3), 100.7 (C2’),
84.4 (C8b), 79.9 (C4), 50.7 (C3a), 11.0 ppm (C7’); IR (film): n = 3417,
3076, 2927, 1778, 1745, 1674, 1330, 1183, 733 cmÀ1; MS (ESI): m/z: 337.1
[M+Na]+; HRMS (ESI): m/z: calcd for C17H14O6Na [M+Na]+: 337.0688;
found: 337.0685.
1
31a: H NMR (300 MHz, [D6]acetone): d = 7.53–7.47 (m, 2H, Har, H6’),
7.42–7.38 (m, 3H, Har), 6.97 (t, 1H, J3’,2’ =J3’,7’ =1.5 Hz, H3’), 6.20 (t, 1H,
J
2’,3’ =1.5 Hz, H2’), 6.05 (d, 1H, J8b,3a =7.3 Hz, H8b), 5.27 (s, 1H, H4),
3.79 (dt, 1H, J3a,8b =7.3, J3a,6’ =2.6 Hz, H3a), 2.01 ppm (t, 3H, J7’,3’
=
1.5 Hz, H7’); 13C NMR (75 MHz, [D6]acetone): d = 171.0 (C2), 170.4
(C5’), 152.3 (C6’), 144.0 (C8a), 141.2 (C3’), 139.4 (C4a), 136.3 (C4’), 131.0
(Car), 130.3 (Car), 126.7 (Car), 125.9 (Car), 110.3 (C3), 101.0 (C2’), 84.4
(C8b), 79.8 (C4), 50.6 (C3a), 11.0 ppm (C7’); IR (film): n = 3415, 3078,
2925, 1776, 1747, 1672, 1332, 1181, 733 cmÀ1; MS (ESI): m/z: 337.1
[M+Na]+; HRMS (ESI): m/z: calcd for C17H14O6Na [M+Na]+: 337.0688;
found: 337.0680.
(À)-(3aR,4R,8bR)-7,8-Dimethyl-3,3,4-trichloro-3,3a,4,8b-
tetrahydroindenoACHTUNGTRENNUNG[1,2-b]furan-2-one (11b): A solution of commercial
CuCl (5.0 mg, 0.05 mmol, 0.05 equiv) and dHbipy (19.0 mg, 0.05 mmol,
0.05 equiv) in degassed dichloroethane (2 mL) was prepared and stirred
at room temperature under argon. The solution turned to dark brown
after 10 min and a solution of trichloroester 12b (328.0 mg, 1.07 mmol,
1 equiv) in degassed dichloroethane (4 mL) was added. The mixture was
heated at 908C for 6 h, cooled to RT and the solvent evaporated under
reduced pressure. The crude product was directly purified on silica gel
(heptane/ethyl acetate 95:5). Product 11b (271 mg, 0.89 mmol, 83%) was
obtained as a white solid. M.p. 135–1378C; [a]2D6 =À130.5 (c = 1.03,
(3aS*,4S*,8bS*,E)-3-((((R*)-4-Methyl-5-oxo-2,5-dihydrofuran-2-yl)oxy)-
methylene)-3,3a,4,8b-tetrahydro-2H-indeno-[1,2-b]furan-4-yl
acetate
(32a) and (3aS*,4S*,8bS*,E)-3-((((S*)-4-methyl-5-oxo-2,5-dihydrofuran-
2-yl)oxy)methylene)-3,3a,4,8b-tetrahydro-2H-indeno-[1,2-b]furan-4-yl
acetate (33a): Pyridine (500 mL, excess) was added to a equimolar solu-
tion of 30a and 31a (30.0 mg, 0.10 mmol, 1 equiv) in acetic anhydride
(500 mL, excess) at room temperature under argon. After 12 h, the reac-
tion mixture was evaporated to dryness and the obtained residue was pu-
rified on silica gel (heptane/EtOAc 70:30) to afford the two diaster-
eoisomers as two pure fractions (F1=32a: 17.7 mg, 0.05 mmol, 52%;
F2=33a: 13.6 mg, 0.04 mmol, 40%) as amorphous white solids.
1
CHCl3); H NMR (300 MHz, CDCl3): d = 7.31 (d, J6,5 = 7.9 Hz, 1H, H6),
7.20 (d, J5,6 = 7.9 Hz, 1H, H5), 6.03 (d, J8b,3a = 5.8 Hz, 1H, H8b), 5.40 (d,
J4,3a = 5.8 Hz, 1H, H4), 3.98 (t, J3a,4 = 5.8, J3a,8b = 5.8 Hz, 1H, H1), 2.34
(s, 3H, H10), 2.31 ppm (s, 3H, H9); 13C NMR (75 MHz, CDCl3): d =
167.1 (C2), 140.3 (C4a), 139.1 (C7), 135.2 (C8), 133.9 (C8a), 133.8 (C6),
122.7 (C5), 82.3 (C8b), 78.9 (C3), 66.0 (C3a), 60.6 (C4), 19.6 (C9),
15.4 ppm (C10); IR (film): n = 1794, 1481, 1161, 955, 825 cmÀ1; elemental
32a: 1H NMR (300 MHz, CDCl3): d = 7.59–7.39 (m, 5H, Har and H6’),
6.99 (t, 1H, J3’,2’ =J3’,7’ =1.5 Hz, H3’), 6.43 (s, 1H, H4), 6.16 (t, 1H, J2’,3’
=
Chem. Eur. J. 2013, 19, 4849 – 4857
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4855

F.-D. Boyer, J.-M. Beau et al.
1.5 Hz, H2’), 6.10 (d, 1H, J8b,3a =7.5 Hz, H8b), 3.85 (dq, 1H, J3a,8b =7.5,
3a,6’ =2.6 Hz, H3a), 2.05 (s, 3H, H4c), 2.01 ppm (t, 3H, J7’,3’ =1.5 Hz,
was added acetic anhydride (0.5 mL). The mixture was stirred overnight.
After 12 h, the solvent was evaporated and the crude product was puri-
fied on silica gel (heptane/EtOAc 70:30). Two fractions corresponding to
the 2 epimers were collected in pure form (F1=32b: 27.0 mg, 0.07 mmol,
48%; F2=33b: 25.3 mg, 0.07 mmol, 45%) as amorphous white solids.
(+)-32b: [a]2D6 = +99.6 (c = 2.34, CHCl3); (À)-32b: [a]2D6 = À88.4 (c =
0.7, CHCl3); 1H NMR (300 MHz, CDCl3): d = 7.59 (d, 1H, J6’,3a =2.6 Hz,
H6’), 7.20 (d, 1H, Jar,ar =7.7 Hz, Har), 7.11 (d, 1H, Jar,ar =7.7 Hz, Har),
6.99 (t, 1H, J3’,2’ =J3’,7’ =1.3 Hz, H3’), 6.40 (brs, 1H, H4), 6.16 (d, 1H,
J
H7’); 13C NMR (75 MHz, CDCl3): d = 170.4 (C2 or C4b or C5’), 170.3
(C2 or C4b or C5’), 170.2 (C2 or C4b or C5’), 153.1 (C6’), 141.2 (C3’),
140.7 (C4a or 8a), 140.6 (C4a or C8a), 136.0 (C4’), 130.9 (Car), 130.8
(Car), 126.8 (Car), 126.7 (Car), 109.0 (C3), 100.8 (C2’), 83.9 (C8b), 79.1
(C4), 47.5 (C3a), 21.4 (C4c), 11.0 ppm (C7’); IR (film): n = 2972, 2899,
1781, 1748, 1679, 1372, 1329, 1228, 1080, 863, 744 cmÀ1; MS (ESI): m/z:
379.1 [M+Na]+; HRMS (ESI): m/z: calcd for C19H16O7Na [M+Na]+:
379.0794; found: 379.0806.
J
8b,3a =7.5 Hz, H8b), 6.15 (d, 1H, J2’,3’ =1.3 Hz, H2’), 3.84 (dt, 1H, J3a,8b =
33a: 1H NMR (300 MHz, CDCl3): d = 7.53–7.37 (m, 5H, Har, H6’), 6.96
7.5 Hz, J3a,4 =J3a,6’ =2.6 Hz, H3a), 2.35 (s, 3H, H7a or H8c), 2.28 (s, 3H,
H7a or H8c), 2.03 (brs, 3H, H4c), 2.02 ppm (d, 3H, J7’,3’ =1.3 Hz, H7’);
13C NMR (75 MHz, CDCl3): d = 170.4 (C2, C4b or C5’), 170.3 (C2, C4b
or C5’), 170.1 (C2, C4b or C5’), 152.8 (C6’), 141.2 (C3’), 139.6 (C4’, C4a,
C7, C8 or C8a), 139.5 (C4’, C4a, C7, C8 or C8a), 138.6 (C4’, C4a, C7, C8
or C8a), 135.9 (C4’, C4a, C7, C8 or C8a), 135.7 (C4’, C4a, C7, C8 or
C8a), 132.8 (C5 or C6), 123.5 (C5 or C6), 109.5 (C3), 100.8 (C2’), 83.9
(C8b), 79.6 (C4), 47.4 (C3a), 21.5 (C4c), 19.8 (C7a or C8c), 15.9 (C7a or
C8c), 10.9 ppm (C7’); IR (film): n = 2926, 1785, 1745, 1681, 1372, 1233,
1014, 751 cmÀ1; MS (ESI): m/z: 385.1 [M+H]+; HRMS (ESI): m/z: calcd
for C21H21O7 [M+H]+: 385.1287; found: 385.1287;
(s, 1H, H3’), 6.37 (s, 1H, H4), 6.19 (s, 1H, H2’), 6.09 (d, 1H, J8b,3a
=
7.3 Hz, H8b), 3.86 (brd, 1H, J3a,8b =7.3 Hz, H3a), 2.03 ppm (s, 6H, H4c,
H7’); 13C NMR (75 MHz, CDCl3): d = 170.4 (C2 or C4b or C5’), 170.2
(C2 or C4b or C5’), 170.1 (C2 or C4b or C5’), 151.9 (C6’), 141.0 (C3’),
140.7 (C4a or 8a), 140.6 (C4a or C8a), 136.6 (C4’), 130.8 (Car), 130.7
(Car), 126.9 (Car), 126.5 (Car), 109.2 (C3), 100.2 (C2’), 83.9 (C8b), 79.1
(C4), 47.6 (C3a), 21.3 (C4c), 11.0 ppm (C7’); IR (film): n = 2970, 2900,
1780, 1747, 1680, 1371, 1330, 1227, 1081, 862, 746 cmÀ1; MS (ESI): m/z:
379.1 [M+Na]+; HRMS (ESI): m/z: calcd for C19H16O7Na [M+Na]+:
379.0794; found: 379.0802.
(+)-33b: [a]2D7 = +52.1 (c = 3.11, CHCl3); (À)-33b: [a]2D7 = À52.8 (c =
1.1, CHCl3); 1H NMR (300 MHz, CDCl3): d = 7.48 (d, 1H, J6’,3a =2.4 Hz,
H6’), 7.17 (d, 1H, Jar,ar =7.7 Hz, Har), 7.10 (d, 1H, Jar,ar =7.7 Hz, Har),
Solanacol (6) and 2’-epi-solanacol (30b): Potassium tert-butoxide
(67.9 mg, 0.61 mmol, 2.2 equiv) was added to a mixture of lactone 10b
(60.0 mg, 0.28 mmol, 1 equiv) and ethyl formate (0.23 mL, 2.80 mmol,
10 equiv) in THF (1 mL) at À788C under argon. It was then warmed to
À408C and was stirred for 6 h at this temperature. The mixture was then
cooled to À608C and 9[28] (99.8 mg, 0.56 mmol, 2.05 equiv) was gradually
added. The mixture was then warmed to room temperature. The reaction
was quenched with AcOH (1 mL) after 12 h at this temperature. The sol-
vent was evaporated and the crude product was purified on preparative
TLC (heptane/ethyl acetate 50:50) to afford the two diastereomers as
two pure fractions (F1=30b: 36.0 mg, 0.11 mmol, 38%; F2=6: 36.0 mg,
6.96 (s, 1H, H3’), 6.32 (s, 1H, H4), 6.19 (s, 1H, H2’), 6.14 (d, 1H, J8b,3a
=
7.5 Hz, H8b), 3.84 (d, 1H, J3a,8b =7.5 Hz, H3a), 2.33 (s, 3H, H7a or H8c),
2.26 (s, 3H, H7a or H8c), 2.01 (brs, 3H, H7’), 2.00 ppm (s, 3H, H4c);
13C NMR (75 MHz, CDCl3): d = 170.6 (C2, C4b or C5’), 170.3 (C2, C4b
or C5’), 170.1 (C2, C4b or C5’), 151.5 (C6’), 141.1 (C3’), 139.4 (C4’, C4a,
C7, C8 or C8a), 139.3 (C4’, C4a, C7, C8 or C8a), 138.5 (C4’, C4a, C7, C8
or C8a), 136.4 (C4’, C4a, C7, C8 or C8a), 135.5 (C4’, C4a, C7, C8 or
C8a), 132.7 (C5 or C6), 123.6 (C5 or C6), 109.7 (C3), 100.1 (C2’), 83.9
(C8b), 79.6 (C4), 47.5 (C3a), 21.3 (C4c), 19.8 (C7a or C8c), 15.8 (C7a or
C8c), 11.0 ppm (C7’); IR (film): n = 2924, 1783, 1747, 1682, 1372, 1231,
1015, 750 cmÀ1; MS (ESI): m/z: 385.1 [M+H]+; HRMS (ESI): m/z: calcd
for C21H21O7 [M+H]+: 385.1287; found: 385.1289.
0.11 mmol, 38%) as colorless oils. (À)-(2’S,3aR,4R,8bR,E)-30b: [a]D26
=
À176.4 (c = 1.7, CHCl3); (+)-(2’R,3aS,4S,8bS,E)-30b: [a]2D6 = +178.6 (c
1
= 1, CHCl3); H NMR (300 MHz, CDCl3): d = 7.54 (d, J9,3a =2.6 Hz, 1H,
H9), 7.25 (d, J6,5 =7.7 Hz, 1H, H6), 7.17 (d, J5,6 =7.7 Hz, 1H, H5), 7.00 (t,
Plant assays: Pea rms1 mutant plants (allele rms1–10 identified in the
line Tꢀrꢁse)[40] deficient in SLs were used for the bioassay. The com-
pound to be tested was applied directly to the bud with a micropipette as
10 mL of solution containing 0.1% acetone with 2% polyethylene glycol
1450, 50% ethanol and 0.4% DMSO. 24 plants were sown per treatment
in trays. The treatment was generally done 10 days after sowing, on the
axillary bud at node 4 (or 3). The branches at nodes 1 to 2 were removed
to encourage the outgrowth of axillary buds at nodes above. Nodes were
numbered acropetally from the first scale leaf as node 1 and cotyledonary
node as node 0. Bud growth at node 4 (node 3) was measured 8 to 10
days after treatment with an electronic calliper.
J
3’,2’ =1.5, J3’,7’ =1.5 Hz, 1H, H3’), 6.24 (t, J2’,3’ =1.5, J2’,7’ =1.5 Hz, 1H,
H2’), 6.15 (d, J8b,3a =7.5 Hz, 1H, H8b), 5.27 (d, J4,3a =5.8 Hz, 1H, H4),
3.81 (ddd, J3a,8b =7.5, J3a,4 =5.8, J3a,9 =2.6 Hz, 1H, H3a), 2.37 (s, 3H, H10),
2.31 (s, 3H, H9), 2.08 (d, 1H, OH), 2.05 ppm (t, J7’,2’ =1.5, J7’,3’ =1.5 Hz,
3H, H7’); 13C NMR (75 MHz, CDCl3): d = 171.0 (C2), 170.2 (C5’), 151.5
(C6’), 141.9 (C4a or C8), 141.0 (C3’), 139.0 (C7 or C8a), 138.4 (C7 or
C8a), 136.6 (C4’), 135.7 (C4), 132.9 (C6), 122.5 (C5), 110.9 (C3), 100.7
(C2’), 84.2 (C8b), 80.3 (C4), 50.8 (C3a), 19.8 (C9), 15.8 (C10), 11.1 ppm
(C7’); IR (film): n = 3437, 1780, 1740,1677, 1334, 1186, 1092, 1016,
957 cmÀ1; MS: m/z (%): 365 (100) [M+Na]+, 343 (75) [M+H]+; HRMS
(ESI): m/z: calcd for C19H18NaO6 [M+Na]+: 365.1001; found: 365.1010.
Statistical analyses: Because deviations from normality were observed
for axillary bud length after SL treatment, the Kruskal-Wallis test was
used to assess the significance of treatment in comparison to the control
treatment (0 nm) or to GR24 treatment at the same concentration using
R Commander version 1.7-3.[41]
(À)-(2’R,3aR,4R,8bR,E)-6: [a]D26
=
À164.2 (c
=
2.2, CHCl3); (À)-
(2’S,3aS,4S,8bS,E)-3: [a]D26 = +162.7 (c = 1, CHCl3); H NMR (300 MHz,
CDCl3): d = 7.55 (d, J9,3a =2.6 Hz, 1H, H6’), 7.23 (d, J6,5 =7.7 Hz, 1H,
H6), 7.16 (d, J5,6 =7.7 Hz, 1H, H5), 6.99 (t, J3’,2’ =1.5, J3’,7’ =1.5 Hz, 1H,
H3’), 6.22 (t, J2’,3’ =1.5, J2’,7’ =1.5 Hz, 1H, H2’), 6.15 (d, J8b,3a =7.5 Hz, 1H,
H8b), 5.25 (d, J4,3a =5.8 Hz, 1H, H4), 3.81 (ddd, J3a,8b =7.5, J3a,4 =5.8,
1
J
3a,9 =2.6 Hz, 1H, H3a), 2.37 (s, 3H, H10), 2.30 (s, 3H, H9), 2.06 (d, 1H,
OH), 2.05 ppm (t, J7’,2’ =1.5, J7’,3’ =1.5 Hz, 3H, H6’); 13C NMR (75 MHz,
CDCl3): d = 171.0 (C2), 170.3 (C5’), 151.8 (C6’), 141.9 (C4a or C8), 141.1
(C3’), 138.9 (C7 or C8a), 138.3 (C7 or C8a), 136.4 (C4’), 135.6 (C4), 132.9
(C6), 122.6 (C5), 110.8 (C3), 100.9 (C2’), 84.3 (C8b), 80.2 (C4), 50.6
(C3a), 19.8 (C9), 15.8 (C10), 11.0 ppm (C7’); IR (film): n = 3333, 1781,
1737,1675, 1329, 1183, 953 cmÀ1; MS: m/z (%): 365 (100) [M+Na]+, 343
(75) [M+H]+; HRMS (ESI): m/z: calcd for C19H18NaO6 [M+Na]+:
365.1001; found: 365.1015.
Acknowledgements
The authors thank R. Beau for her comments on the manuscript. We are
grateful to Bayer CropScience (contract no. 08H0120RD), the Institut
Universitaire de France (IUF) and the Centre National de la Recherche
Agronomique (INRA) for the financial support of this study.
(+)-(3aS,4S,8bS,E)-7,8-Dimethyl-3-((((R)-4-methyl-5-oxo-2,5-dihydrofur-
an-2-yl)oxy)methylene)-3,3a,4,8b-tetrahydro-2H-indeno-[1,2-b]furan-4-yl
acetate (32b) and (+)-(3aS,4S,8bS,E)-7,8-dimethyl-3-((((S)-4-methyl-5-
oxo-2,5-dihydrofuran-2-yl)oxy)methylene)-3,3a,4,8b-tetrahydro-2H-
indeno-[1,2-b]furan-4-yl acetate (33b): To a mixture of solanacol 6 and
2’-epi-solanacol 30b (50.0 mg, 0.15 mmol, 1 equiv) in dry pyridine (1 mL)
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Received: October 8, 2012
Published online: February 18, 2013
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ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4857