Access to benzene-modified 2ndgeneration strigolactams and GR24 by merging C-H olefination with decarboxylative Giese cyclization

Article abstract of DOI:10.1039/d1ob01234g

Herein, we reported an efficient and general synthetic route to assemble benzene-modified 2nd generation strigolactams and GR24. The key features of this synthesis include a palladium-catalyzed ortho-selective olefination of the commercially available substituted N-Boc phenylalanine and a decarboxylative Giese radical cyclization. The bioactivities of these compounds to stimulate the seed germination of Orobanche aegyptiaca parasitic weed were also analysed. 2nd generation strigolactam 15f derived from para-OMe phenylalanine showed superior bioactivity to the original unsubstituted 15b.

Full text of DOI:10.1039/d1ob01234g

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Access to benzene-modified 2nd generation strigo-
lactams and GR24 by merging C–H olefination
with decarboxylative Giese cyclization†
Cite this: Org. Biomol. Chem., 2021,
19, 7141
Received 25th June 2021,
Accepted 27th July 2021
Yuhua Ge, *a Xingyue Chen,a Yi Dong,b Hua-Nan Wang,b Yangyan Lib,c and
b
DOI: 10.1039/d1ob01234g
Gang Chen
*
rsc.li/obc
Herein, we reported an efficient and general synthetic route to the optimization and modification of the chemical structure of
assemble benzene-modified 2nd generation strigolactams and such molecules are crucial for further studies.
GR24. The key features of this synthesis include a palladium-cata-
lyzed ortho-selective olefination of the commercially available lactones are non-benzenoid gem-dimethyl cyclohexenes, such
substituted N-Boc phenylalanine and decarboxylative Giese as strigol and 5-deoxystrigol (5DS), as shown in Fig. 1. To sim-
The 6-membered A rings of most naturally occurring strigo-
a
radical cyclization. The bioactivities of these compounds to stimu- plify the skeleton structure and speed up the organic syn-
late the seed germination of Orobanche aegyptiaca parasitic weed thesis, some unnatural strigolactones, such as GR24, which
were also analysed. 2nd generation strigolactam 15f derived from retain the biological activity were subsequently developed;5
para-OMe phenylalanine showed superior bioactivity to the orig- these mimicked strigolactones are employed with a simplified
inal unsubstituted 15b.
aromatic benzene ring to replace multi-substituted cyclohex-
enes (Fig. 1). The newly developed strigolactams6a (the 1st
generation), lactam analogues of the artificial strigolactone
GR24, are another subclass of this family which can durably
exert their activity due to the relatively better stability to hydro-
lysis in moist soil compared to strigolactones; thus they seem
to have more potential for agronomical applications. Recently,
a novel type of strigolactam (hereinafter referred to as the 2nd
generation strigolactam) which possesses a different B/C ring
fused bond was developed by Syngenta. Compared to the
diverse synthetic routes to GR24 and the 1st generation strigo-
Strigolactones,1 as a novel family of phytohormones, refer to a
class of naturally occurring or artificially synthesized com-
pounds that typically contain the same basic tricyclic skeleton
system and a furan-2(5H)-one unit which tethers to the
α-carbon of the γ-lactone through a methylene ether bridge
(Fig. 1). Since the natural molecules were isolated and identi-
fied,2 their biological activities in plants, identification of the
protein targets and mode of actions, and organic synthesis
have attracted considerable interest from various areas. It has
been confirmed that strigolactones can not only stimulate the
germination of seeds of parasitic weeds, control the growth of
plants, and increase the yield of crops, but can also improve
the tolerance to abiotic stress.3 Recent medical research has
also indicated that artificial strigolactones, such as GR24,
exhibit bioactivities, such as anti-inflammation4a and activity
against breast cancer cells.4b Due to the diverse bioactivities,
aSchool of Chemistry and Chemical Engineering, Southeast University, Nanjing
211189, People’s Republic of China. E-mail: geyuhua@seu.edu.cn
bShanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of
Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai
200240, People’s Republic of China. E-mail: gchen2018@sjtu.edu.cn
cCollege of Chemistry and Bioengineering, Hunan University of Science and
Engineering, Yongzhou 425199, People’s Republic of China
†Electronic supplementary information (ESI) available. CCDC 2082705 and
2087617. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/d1ob01234g
Fig. 1 Structures of natural and simplified strigolactones and
strigolactams.
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lactams, there has been only one route to this 2nd generation adopt carboxylate rather than amine as the directing group to
strigolactam to date which utilized indene as the starting avoid the switching of the N-protecting group.11 Therefore, the
material and hardly introduced substituents at the benzene commercially available N-Boc protected phenylalanine deriva-
ring (Fig. 2(a)).7 Therefore, the development of an innovative tives and/or O-protected phenyllactic acid could be used as the
and universal synthetic route8 which could easily introduce a starting materials straightforwardly without any additional
substituent group in the benzene ring is highly desirable. functional group transformations. However, the low reactivity
More importantly, as the exact function of the A ring of this is the major challenge of this strategy. On one hand, the un-
novel class of 2nd generation strigolactam analogues has not precedented 7-membered transition state (the 6-membered
been well elaborated yet, the modification of the benzene ring transition state in Yu’s work10a) may not be strong and stable
will undoubtedly help in unveiling the structure–activity enough to assist the C–H cleavage; moreover, the carboxylate
relationship.
is inherently a weak coordinating group to palladium. On the
Recently, we reported the biomimetic total syntheses of fes- other hand, the substrate itself could function as a ligand
tuclavine and pyroclavine by 4-nitrobenzenesulfonyl (Ns)-NH- (mono-protected amino acid (MPAA) ligand10a,b) to chelate
directed C4–H olefination of tryptophan to introduce the with the palladium catalyst, which would hamper the inter-
indole C4 component9 followed by an intramolecular decar- action between the metal centre and the ortho-carbon and
boxylative Giese reaction to form the central C ring (Fig. 2(b)). therefore reduce the reactivity.
Encouraged by the precedent successful experiences, we envi-
Despite the anticipated challenge, the direct installment of
sioned a rapid synthetic route to acquire phenyl-substituted an ethyl acrylate group on the benzene ring of the N-Boc
2nd generation strigolactams and/or GR24 as depicted in phenylalanine or O-Piv phenyllactic acid is worth trying.
Fig. 2(c) which employed sequential C–H olefination and dec- Initially, the p-methylphenylalanine 1a 12 was chosen as the
arboxylative Giese radical cyclization as the key steps for con- model substrate to investigate the reactivity (Table 1 and
structing the A/B ring in two steps. Slightly different from the
above case, we referred to Yu’s research work in 2015 on free
Table 1 Evaluation and optimization of the reaction conditions for the
ortho-C–H olefinationa
carboxylic acid directed C–H olefination of O-pivaloyl (Piv)
mandelic acid (or N-Piv phenylglycine)10a and decided to
Entry Solvent
Ligand
Base
Yieldb (%) Mono : di
1
2
3
4
5
6
7
8
t-AmylOH
Toluene
DCE
—
—
—
—
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
34
11
11
5
16 : 1
3 : 1
10 : 1
16 : 1
>20 : 1
15 : 1
>20 : 1
12 : 1
16 : 1
>20 : 1
17 : 1
6 : 1
MeCN
t-AmylOH Ac-L-Ala-OH
t-AmylOH Ac-L-Leu-OH
t-AmylOH Ac-L-Phe-OH
t-AmylOH Ac-L-Val-OH
t-AmylOH Ac-L-Gly-OH
t-AmylOH Fmoc-L-Ala-OH NaOAc
t-AmylOH Boc-L-Ala-OH
t-AmylOH Pyridine
t-AmylOH 2-Picoline
t-AmylOH Ac-L-Ala-OH
t-AmylOH Ac-L-Ala-OH
t-AmylOH Ac-L-Ala-OH
t-AmylOH Ac-L-Ala-OH
t-AmylOH Ac-L-Ala-OH
t-AmylOH Ac-L-Ala-OH
t-AmylOH Ac-L-Ala-OH
t-AmylOH Ac-L-Ala-OH
37
32
31
25
34
25
27
10
20
33
32
51
25
38
51
17
9
10
11
12
13
14
15
16
17
18
19
20
21
NaOAc
NaOAc
NaOAc
NaOMe
NaOH
Na2CO3
KOH
K2CO3
KHCO3
Cs2CO3
9 : 1
11 : 1
11 : 1
10 : 1
8 : 1
19 : 1
7 : 1
>20 : 1
>20 : 1
LiOH·H2O 10
a Reaction conditions unless otherwise noted: N-Boc phenylalanine
(0.1 mmol), ethyl acrylate (0.5 mmol), Pd(OAc)2 (0.01 mmol), ligand
(0.02 mmol), AgOAc (0.2 mmol), base (0.2 mmol), solvent (0.5 mL),
100 °C, 12 h. b Yields refer to the overall yields of mono- and di-olefi-
nated products which were determined by 1H NMR analysis of the
crude product using 1,3,5-trimethoxybenzene as an internal standard.
t-AmylOH = 2-methyl-2-butanol; DCE = 1,2-dichloroethane; THF =
tetrahydrofuran.
Fig. 2 (a) The already known synthetic route to strigolactam and GR24
analogues, (b) our previous work on the total synthesis of ergot alka-
loids, and (c) proposal for the synthesis of benzene-modified strigolac-
tam/GR24 analogues.
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Table S1†). The desired product mono-olefinated 3a was
formed in about 30% yield along with di-olefinated 4a under
the conditions of 10 mol% of Pd(OAc)2, 2 equiv. of AgOAc, and
2 equiv. of NaOAc in tert-amyl alcohol at 100 °C (Table 1, entry
1). Furthermore, replacing the tert-amyl alcohol with DCE,
toluene, THF or MeCN reduced the reaction yield dramatically
(Table 1, entries 2–4). Although other solvents were used, such
as ethyl acetate and dimethyl sulfoxide (DMSO), no desired
product could be detected. Therefore, tert-amyl alcohol was
adopted as the solvent to evaluate the effect of ligands on the
C–H functionalization. An extensive array of MPAA ligands10a–f
were evaluated, and they did not evidently improve the reac-
tion yield (Table 1, entries 5–11). N-Acetyl-L-alanine was a rela-
tively better ligand as it obviously improved the ratio of mono :
di-olefinated products as well as increased the reaction yield
from 34% to 37% (Table 1, entry 5). In addition, a series of pyr-
idine derivatives that are effective ligands to promote car-
boxylic acid directed C–H activation10e,j,n were also investi-
gated, but they were either even worse or completely inert to
promote the reaction. Further optimization focused on the
examination of bases. It was found that the overall yield could
be increased to 51% when Na2CO3 (Table 1, entry 16) or
KHCO3 (Table 1, entry 19) was employed as the base with 10 : 1
or 7 : 1 mono : di ratio, respectively. Although the yield of this
C–H olefination was moderate, the Giese cyclization precursor
3a could be obtained in one step from commercially available
NH-Boc phenylalanine with this C–H olefination methodology.
Next, the scope of the ortho-selective olefination of N-Boc
phenylalanines was investigated (Scheme 1). To facilitate the
further transformations, all reactions were carried out on a
gram scale once more. para-Substituents with different elec-
tronic properties were compatible in this reaction, providing
the olefinated products in overall yields ranging from 32 to
Scheme 1 Substrate scope of ortho-C–H olefination. Reaction con-
ditions: substrate (0.1 mmol), ethyl acrylate (0.5 mmol), Pd(OAc)2
(0.01 mmol), Ac-L-Ala-OH (0.02 mmol), AgOAc (0.2 mmol),
Na2CO3(0.2 mmol), t-AmylOH (0.7 mL), 100 °C, 12 h. a Using K2CO3/TFE
instead of Na2CO3/t-AmylOH. b Using K2CO3/HFIP instead of Na2CO3/
t-AmylOH. TFE = 2,2,2-trifluoroethanol; HFIP = 1,1,1,3,3,3-hexafluoro-2-
propanol.
52%, with 6 : 1 to 18 : 1 mono : di ratios. Arside from phenyl- After extensive screening of reaction conditions (for more
alanine derivatives, the reactions of the O-Piv protected phenyl- details, please see Table S6†), the dr value could be improved
lactic acids with the ethyl acrylate were carried out as well (for to 1 : 3, in which trans-8b was the major diastereomer.
more details, please see Table S3†), which afforded the corres- Although the major trans product was the key intermediate in
ponding ortho-selective mono-olefinated products 6 and di-ole- the synthesis of other biological molecules15 and was poten-
finated 7 in higher yields (41–59%) with 5 : 1 to 13 : 1 mono : di tially useful in the modification of the 2nd generation strigolac-
ratios.
tam, it is the cis-product that we still focus on in this paper.
With the ortho-olefinated phenylalanine/phenyllactic acid Thence we adopted Condition A to expand the substrate scope
derivatives in hand, we focused our efforts on the formation of of the decarboxylative radical cyclization (Scheme 2). Most of
the B-ring via an intramolecular decarboxylative Giese cycliza- the ortho-olefinated phenylalanines 3 could be smoothly trans-
tion reaction. At first, the Ir-catalyzed photoredox decarboxyla- formed to the desired cyclized product in high yield with a dr
tive coupling13 was carried out with the substrate 3b. value around 1 : 1. However, the photoredox radical cyclization
Gratefully, 5-exo-trig was the favorable ring-closing mode, was not applicable for the ortho-olefinated O-Piv phenyllactic
giving the cyclized indenyl derivative 8b in high yield under acid 6a, as only a trace amount of the target product 9a was
Condition
A ([Ir(dF(CF3)ppy)2(dtbbpy)]PF6 as the catalyst, obtained. The Ni-catalyzed decarboxylative coupling
Cs2CO3 as the base, LiCl as the additive and DMSO as the reaction of the corresponding active ester could successfully
solvent). However, the dr value of product 8b was not good (cis promote the ring-closure process in 77% yield (Condition B).
versus trans is around 1 : 1, and cis-8b is the desired one in the For phenyllactic acids with a substituted methyl (6b) or chlor-
final strigolactam product). Further optimization did not ine group (6c), the indenyl product 9b or 9c was obtained in
improve the cis selectivity (for more details, please see 52% or 59% yield, respectively. It should be mentioned that
Table S5†); then we tried the one pot condensation/Ni-cata- racemization was found in products 8 and 9 from the chiral
lyzed decarboxylative cyclization of N-hydroxyphthalimide intermediates 3 and 6, which is common in this radical coup-
(NHPI) redox-active esters developed by the Baran group.14 ling reaction.
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Scheme 4 Synthesis of the 2nd generation GR24.
concurrent recovery of the uncyclized trans-amino indanyl
esters 10. Reprotection of the amide with –Boc afforded 12 in
excellent to quantitative yields. According to the procedure
reported in the literature,6 formylation of the tricyclic indanyl
lactam 12 is a two-step procedure: firstly, the formation of the
enamine functionality with tert-butoxybis(dimethylamino)
methane (Bredereck’s reagent) followed by hydrolysis. The Boc
protecting group was cleaved meanwhile in the second hydro-
lysis step, which furnished the hydroxymethylene derivatives
13 (the enol was in equilibrium with its aldehyde form) in very
high yields. Finally, the coupling of the deprotonated enol
with the chlorobutenolide 14 gave the racemic 2nd generation
strigolactam 15 and 16 as mixtures of diastereoisomers in 1 : 1
dr. The atomic connection and the relative configuration of
the B/C ring fusion were ambiguously confirmed by the X-ray
single crystal diffraction analysis of the strigolactam analogue
16e 16 that comprises a chlorine atom.
The synthetic route to benzene-decorated GR24 analogues
was similar to the above one as shown in Scheme 4. Hydrolysis
of the pivalate of 9 released the hydroxyl group followed by
automatic cyclization, affording the cyclized indane lactone 18
as the separable cis-diastereoisomer with the simultaneous
recovery of the unchanged trans-2-OH indanyl ethyl acetate 17.
A two-step procedure for formylation followed by coupling
with chlorobutenolide 14 produced the strigolactone GR24
analogues 20 and 21 as a pair of 1 : 1 diastereoisomers. The
atomic connection and the relative configuration of the B/C
ring fusion were ambiguously confirmed by the X-ray single
crystal diffraction analysis of the GR24 analogue 20c that com-
prises a chlorine atom.16
Scheme 2 Substrate scope of the decarboxylative Giese cyclization.
Reaction conditions: Condition A: [Ir(dF(CF3)ppy)2(dtbbpy)]PF6 (1 mol%),
a blue LED, Cs2CO3 (1.0 equiv.), LiCl (2.0 equiv.), DMSO (0.02 M), ambig-
uous temperature. Condition B: (1) NHPI (1.1 equiv.), DIC, (1.1 equiv.),
DCM, rt, 1 h; then (2) Ni(ClO4)2·6H2O (0.2 equiv.), Zn (2.0 equiv.), LiCl
(3.0 equiv.), THF (0.2 M), rt, 12 h. Dr ratio refers to cis versus
trans. Unless otherwise noted, the reactions were carried out on
a
0.1 mmol scale.
DIC = N,N’-diisopropylcarbodiimide; NHPI =
N-hydroxyphthalimide.
Having constructed the AB-ring skeleton, we directed our
attention to finish the whole synthesis of the 2nd generation
strigolactam in Scheme 3 and GR24 in Scheme 4. The insepar-
able amino indenyl esters (cis- and trans-8) were treated with
trifluoroacetic acid (TFA) in dichloromethane (DCM) solution
followed by automatic cyclization, smoothly furnishing indane
lactam 11 as the cis-diastereoisomer in high yields with the
The germination stimulatory activity of these 2nd generation
strigolactams and GR-24 was assayed using the seeds of the
parasitic weed Orobanche aegyptiaca6b,17 (for detailed data,
please see Table S14 and Fig. S1†). All the tested compounds
exhibited excellent levels of activity at a concentration of
≥1.0 μM L−1, while at the concentration of 1.0 × 10−8 M L−1
,
the germination stimulatory activity of strigolactam analogues
15c and 16c with phenyl substitution reduced dramatically.
However, 15f derived from para-OMe phenylalanine was clearly
Scheme 3 Synthesis of the 2nd generation strigolactam.
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more potent in comparison to the original unsubstituted 15b,
as it still showed good stimulatory activity at the concentration
of 1.0 × 10−9 M L−1, which was superior to that of 15b.
C. A. Beveridge, C. Rameau and S. F. Rochange, Nature,
2008, 455, 189; (d) S. Al-Babili and H. J. Bouwmeester,
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Biol., 2017, 68, 291.
4 For other bioactivities on strigolactone analogues, see:
(a) J. Zheng, Y. Han, J. Wang, H. Yang, H. Kong, K. Liu,
S. Chen, Y. Chen, Y. Chang, W. Chen, J. Guo and P. Sun,
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G. Gowda, A. Hassanali, J. Knox, S. Monaco, Z. Razavi and
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and Y. Takemoto, Angew. Chem., 2020, 59, 13479.
In conclusion, we have established a modular and concise
synthetic route to acquire the benzene-decorated 2nd generation
of strigolactams and GR-24, and it also represents an alternative
synthetic method to prepare the recently developed novel strigo-
lactam. The inexpensive commercially available substituted
N-Boc phenylalanines and O-pivalate phenyllactic acids were
employed as the starting materials, which underwent two key
transformations, the carboxylate directed ortho-selective olefina-
tion followed by decarboxylative Giese radical addition, to assem-
ble the A/B ring subunit. Preliminary biological activity evalu-
ation indicated that it is very necessary to modify the benzene
ring of the original strigolactam analogue, as we found that the
2nd generation strigolactam with methoxy substitution 15f was
more potent than the unsubstituted one. The preparation of
other strigolactam analogues and further studies on the struc-
ture–activity relationship are underway in our laboratory.
Conflicts of interest
6 For selected examples of the synthesis of stigolactams, see:
(a) M. Lachia, H. C. Wolf, P. J. M. Jung, C. Screpanti and
A. D. Mesmaeker, Bioorg. Med. Chem. Lett., 2015, 25, 2184;
(b) K. Ashida, Y. Hoshimoto, N. Tohnai, D. E. Scott,
M. Ohashi, H. Imaizumi, Y. Tsuchiya and S. Ogoshi, J. Am.
Chem. Soc., 2020, 142, 1594.
There are no conflicts to declare.
Acknowledgements
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(b) Syngenta Participations AG, WO. Pat, 145979, 2018.
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This work is supported by the National Natural Science
Foundation of China (NSFC) (Grant No. 22001165 and
21801075), the “Agri-X” Fund of Shanghai Jiao Tong University
(SJTU) (AF1500088/004) and the startup funding from SJTU.
We thank Prof. Yongqing Ma (Northwest Agriculture & Forestry
University) for supplying Orobanche aegyptiaca seeds. We
thank Prof. Zixing Li and Dr Yajie Li (SJTU) for their kind
assistance in biological activity testing.
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16 The X-ray crystallographic coordinates for the structures
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7146 | Org. Biomol. Chem., 2021, 19, 7141–7146
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