Synthetic studies on the solanacol ABC ring system by cation-initiated cascade cyclization: Implications for strigolactone biosynthesis

Article abstract of DOI:10.1039/c1ob05751k

We report a new method for constructing the ABC ring system of strigolactones, in a single step from a simple linear precursor by acid-catalyzed double cyclization. The reaction proceeds with a high degree of stereochemical control, which can be qualitatively rationalized using DFT calculations. Our concise synthetic approach offers a new model for thinking about the (as yet) unknown chemistry that is employed in the biosynthetic pathways leading to this class of plant hormones.

Full text of DOI:10.1039/c1ob05751k

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Synthetic studies on the solanacol ABC ring system by cation-initiated
cascade cyclization: implications for strigolactone biosynthesis†
Kinga Chojnacka,a Stefano Santoro,b Radi Awartani,c Nigel G. J. Richards,a Fahmi Himob and Aaron Aponick*a
Received 12th May 2011, Accepted 7th June 2011
DOI: 10.1039/c1ob05751k
We report a new method for constructing the ABC ring
system of strigolactones, in a single step from a simple linear
precursor by acid-catalyzed double cyclization. The reaction
proceeds with a high degree of stereochemical control, which
can be qualitatively rationalized using DFT calculations. Our
concise synthetic approach offers a new model for thinking
about the (as yet) unknown chemistry that is employed in the
biosynthetic pathways leading to this class of plant hormones.
Strigol 1 (Fig. 1) was isolated in 1966 from cotton root exudates,1
and a relatively large family of related strigolactones has subse-
quently been characterized.2 These compounds were originally
identified as germination stimulants for parasitic weeds and later
as chemical signaling agents for root colonization by symbiotic
arbuscular mycorrhizal fungi.3 The recent discovery that strigolac-
tones are a new class of plant hormones that function to regulate
Fig. 1 Select examples of strigolactone natural products.
shoot branching4 has renewed biochemical interest in this family
of natural products.2,5 Little is known about the biosynthesis
The structural complexity of these carotenoid-derived natural
of strigolactones other than that they are likely derived from
carotenoid precursors.6 In part, this is because (i) genetic studies
suggest that only a small number of enzymes are involved in the
pathway,7 and (ii) technical problems have been encountered in
feeding studies employing suitably labeled precursors.5d
Our interest in these molecules stems from this lack of biosyn-
thetic information, coupled with the unique structural diversity
found in this family of natural products. As can be seen in
Fig. 1, simple strigol congeners have been identified such as
orobanchol 2 with the allylic alcohol transposed from the A- to
B-ring.8 However, a much more interesting structural difference
is observed in the epoxy-derivative fabacyl acetate 39 and the
aromatic congener solanacol 4,10 whose core stereochemistries are
enantiomeric with the ostensible parent compound strigol 1 or
orobanchol 2.
products, notably the ABC tricyclic ring system, has generated
considerable synthetic interest and several strategies have been
developed for their construction.10a,11 To date, however, there seem
to have been no efforts to employ a “biomimetic” strategy to
build the ABC ring system, such as cation-initiated cyclization,
which is widely employed by enzymes such as sesquiterpene and
diterpene cyclases.12 We have examined the feasibility of obtaining
the tricyclic skeleton by formation of the B- and C-rings in a single
step via a cascade cyclization from a linear precursor (Scheme 1),
and now report conditions under which this reaction proceeds
with high yield and excellent stereocontrol.
aDepartment of Chemistry, University of Florida, P.O. Box 117200,
Gainesville, FL 32611, USA. E-mail: aponick@chem.ufl.edu; Fax: +1-352-
846-0296; Tel: +1-352-392-3484
bDepartment of Organic Chemistry, Stockholm University, SE-106 91 Stock-
holm, Sweden. E-mail: himo@organ.su.se; Fax: +46-8-154908; Tel: +46-8-
162476
Scheme 1 Cascade-based route to the B/C ring system of strigolactones.
Given that many strigolactones, such as orobranchol 2,8
fabacyl acetate 3,9 and solanacol 410 are oxygenated at C4 (see
Fig. 1 for numbering), we examined the reactivity of cations
such as 5 (R = OH, Scheme 1) formed by protonation of an
aldehyde in the precursor. Accordingly, the methyl esters 12
cPetra Research, Inc., 12775 Rachael Boulevard, Alachua, FL 32615, USA.
E-mail: petra@petraresearch.com; Fax: +1-386-462-0602; Tel: +1-386-
462-0414
† Electronic supplementary information (ESI) available: Experimental
procedures and spectra for new compounds, additional DFT calculation
details. See DOI: 10.1039/c1ob05751k
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and 13 were prepared in three steps from known precursors
(Scheme 2). Thus, the functionalized benzaldehyde 7 was pre-
pared from phthalic anhydride by reduction with lithium alu-
minium hydride, monoprotection using sodium hydride and
tert-butyldimethylsilyl chloride, and oxidation with manganese
dioxide.13 The linear cyclization precursors could then be obtained
in a straightforward manner by introduction of the ester moiety
using a Wittig reaction with 814 followed by deprotection of both
the ortho-ester and silylether with methanolic sulfuric acid.14,15
This gave alcohols 10 and 11 as a 1 : 1 mixture, which were
separated by flash column chromatography. Subsequent oxidation
using pyridinium chlorochromate (PCC) then gave the desired
aldehydes 12 and 13 in high yields.16
lyltriflate (TMSOTf), in dichloromethane at 0 ◦C, the cyclized
products 14 and 15 were produced in an 80 : 20 diastereomeric
ratio (60% combined yield) together with 7% of 16, which was
presumably formed via a single cyclization event and subsequent
deprotonation (entry 1, Table 1). Interestingly, these compounds
were produced as methyl ethers by transfer of the methyl group
to the C4 hydroxyl, presumably from the methyl ester moiety. The
conditions were improved by using catalytic amounts of a protic
acid. Thus, when 12 was treated with 0.1 equivalents of TfOH in
dichloromethane, 14 and 15 were isolated as a 99 : 1 diastereomeric
ratio in 68% combined yield (entry 2). This high ratio favoring the
B-ring methyl ether trans to the C-ring initially suggested that the
products might equilibrate to the most stable diastereomer under
the reaction conditions. As a control experiment, diastereomers
14 and 15 were treated under the reaction conditions in both
entries 1 and 2 to determine if epimerization of the C4 stere-
ocenter was possible. Even with super-stoichiometric amounts
of TMSOTf and TfOH, compounds 14 and 15 were recovered
in high yield with no detectable interconversion. Interestingly,
when stoichiometric amounts of TMSOTf or TfOH were used
to catalyze the cyclization of 12, the yields were lower than those
observed in entries 1 and 2, likely due to decomposition of the
substrate.
The cis-olefin 13 was also subjected to the cyclization conditions
(Table 1, entries 3–5). The reaction was unexpectedly much slower
than that of 12 requiring a minimum of 1 equivalent of catalyst
to attain a reasonable reaction rate at 0 ◦C. While the reaction is
slower, 13 exclusively gives the cis-diastereomer 15 when TMSOTf
is employed, albeit in 46% yield along with 2% of 16 (entry 3).
With TfOH (entry 4), a 48% yield of 14 and 15, again favoring
15 in a 13 : 87 diastereomeric ratio, was obtained. When catalytic
TMSOTf was used (entry 5), the reaction was slow, even at room
temperature, but a mixture of 14 and 15 in a 30 : 70 ratio was
obtained in a higher yield (68%).
A probable reaction mechanism is shown in Scheme 3. In this
model, oxocarbenium ion 17 is formed by protonation of the
aldehyde oxygen. At this stage, the substrate may form both the
B- and C-rings in a single concerted step (17→19), but a stepwise
mechanism is necessary to explain the formation of 16. Cyclization
of the olefin in 17 by addition to the C4 oxocarbenium ion produces
the benzylic cation 18 which could further cyclize forming the C-
ring (path a) or eliminate to form 20 (path b). Demethylation
Scheme 2 Synthesis of cyclization precursors. Reagents: (a) LHMDS,
THF, 97%, E : Z = 1 : 1; (b) 0.2 M H2SO4/MeOH, 66%; (c) PCC, CH2Cl2,
93%; (d) PCC, CH2Cl2, 93%.
With these two aldehydes in hand, we set out to test the
cyclization hypothesis under chemical conditions using both Lewis
and Brønsted acids to initiate the cyclization event. When the
trans-olefin 12 was treated with catalytic Lewis acid, trimethylsi-
Table 1 Cyclization studies
Entry
Substrate
Conditions
Yielda 14+15 (Ratiob 14 : 15)
Yield 16a (%)
1
2
3
4
5
12
12
13
13
13
TMSOTf (0.2 eq.), DCM, 0 ◦C, 2 h
60 (80 : 20)
68 (99 : 1)
46 (0 : 100)
48 (13 : 87)
68 (30 : 70)
7
2
2
0
3
TfOH (0.1 eq.), DCM, -78 ◦C, 1 h then 0 ◦C, 3 h
TMSOTf (1 eq.), DCM, 0 ◦C, 10 min then rt, 6.5 h
TfOH (1.1 eq.), DCM, -78 ◦C, 1 h then 0 ◦C, 2.5 h
TMSOTf (0.2 eq.), DCM, 0 ◦C, 3 h then rt 22h
a Isolated yield. b The ratio was determined by 1H NMR.
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with the aromatic ring. In the energetically favored transition states
(TS12→14 and TS13→15), small deviations from planarity are observed
(~35◦). On the other hand, in order to reduce steric repulsion
between the protonated aldehyde oxygen and the attacking olefin,
the formation of the cis isomer 15 from the trans-olefin 12 (TS12→15
)
and of the trans isomer 14 from the cis-olefin 13 (TS13→14) requires
a higher deviation from co-planarity in the transition states with
the aldehyde nearly perpendicular to the aromatic ring (~85◦ and
~75◦ dihedral angles, respectively).
In order to estimate the energetic contribution of this deviation
to the increased activation energy barrier, the rotational barrier of
protonated benzaldehyde was calculated (Fig. 3). Although previ-
ous computational work was reported by Setia and Formosinho in
1988,19a for consistency the barrier was calculated using identical
methods to those used in locating the cyclization transition states.
In this case, the barrier to rotation was found to be quite high
(24 and 21 kcal mol-1 in gas phase and in dichloromethane,
respectively), which is consistent with the differences in the energies
obtained for the cyclization transition states.
Scheme 3 Mechanistic hypothesis for the cyclization reaction.
of 19 may occur by alkylation of a variety of nucleophilic species
present in solution such as alcohols 20 or 21. Under these catalytic
conditions, the methylated tricyclic strigolactone core 14 is thus
obtained and the acid catalyst regenerated.
Standard density functional theory (DFT) calculations using
the B3LYP functional17 as implemented in the Gaussian03 software
package18 were employed to investigate the origin of the stereose-
lectivity observed in the acid-catalyzed cascade cyclization (see the
ESI for computational details†). Transition states associated with
attack of the double bond on the protonated aldehyde moiety were
located as these define the relative stereochemistry of the product
if the reaction is under kinetic control. It was found that for both
trans-olefin 12 and cis-olefin 13 the cyclization could be either
concerted (with the formation of both the B and the C rings at the
same time) or stepwise. The difference in the energy between the
two mechanisms is quite small.
The four lowest-lying transition states corresponding to those
for cyclization of either the trans-olefin 12 or the cis-olefin 13 to
each of the two possible diastereomeric products are shown in
Fig. 2. The relative energies of these transition states provide a
qualitative explanation of the observed cyclization stereoselectiv-
ity. The origin of the selectivity appears to arise from the degree
of deviation of the protonated aldehyde moiety from co-planarity
Fig. 3 Calculated rotational barriers for protonated benzaldehyde.
The successful demonstration of the cation-induced cascade
cyclization outlined here not only represents a novel approach
for constructing a similar ABC tricyclic ring system to that found
in solanacol (4) from simple aldehyde precursors, but also raises
the possibility that a similar reaction might be catalyzed by a single
cyclase in the biosynthetic pathway leading to strigolactones. In-
deed, such a hypothesis would greatly simplify literature proposals
for the biosynthetic origins of strigolactones, which have invoked
highly reactive intermediates or unusual chemical transformations
in order to rationalize experimental observations.6,20 Although
Fig. 2 Calculated transition states and relative energies for the cyclization of 12 and 13 initiated by protonation.
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there is no direct evidence to rule out complicated chemical trans-
formations in strigolactone biosynthesis, the chemical feasibility
of constructing the ABC ring system from a linear aldehyde
precursor makes new predictions for intermediates that might be
tested in future feeding experiments and in vitro screening studies
of recombinant enzymes that are implicated in strigolactone
biosynthesis. Efforts to utilize this method in the synthesis of the
ABC ring system of aliphatic strigolactones, such as orobanchol
(2), are currently underway and will be reported in due course.
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Acknowledgements
This work was supported in part by grants from (i) the National
Science Foundation to Harry Klee and Donald McCarty (DBI-
0211875), (ii) the Herman Frasch Foundation (647-HF07) and
(iii) the Swedish Research Council (Grants 621-2009-4736 and
622-2009-371 to F.H.). Petra Research Inc. (Alachua, FL) is also
acknowledged for the generous gift of starting materials. Stefano
Santoro thanks the Wenner–Gren Foundation for a postdoctoral
fellowship. Computer time was generously provided by the PDC
Center for High Performance Computing.
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