Total Synthesis and Stereochemical Confirmation of Heliolactone

Article abstract of DOI:10.1021/acs.orglett.9b01402

Until now, the relative stereochemistry of the noncanonical strigolactone, heliolactone, has remained ambiguous. The total synthesis of heliolactone is described, with the key bond-forming event being a Stille cross-coupling that relied upon a reversal of

Full text of DOI:10.1021/acs.orglett.9b01402

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Total Synthesis and Stereochemical Confirmation of Heliolactone
Stone Woo and Christopher S. P. McErlean*
School of Chemistry, University of Sydney, Sydney, NSW 2006, Australia
S
* Supporting Information
ABSTRACT: Until now, the relative stereochemistry of the
noncanonical strigolactone, heliolactone, has remained
ambiguous. The total synthesis of heliolactone is described,
with the key bond-forming event being a Stille cross-coupling
that relied upon a reversal of the nucleophile−electrophile
coupling partners. Spectroscopic analysis of synthetic helio-
lactone (and other stereoisomers) and comparisons with the
isolated material enabled the absolute and relative stereo-
chemistry of heliolactone to be secured.
he knowledge that small organic molecules affect plant
Heliolactone (7) (Figure 1) was isolated from the root
exudates of Helianthus annuus (the common sunflower) by
Sugimoto and co-workers in 2014.4e The molecule presents a
densely packed combination of synthetically challenging
structural features, including a doubly vinylogous stereogenic
center at C-6, and a configurationally defined cross-conjugated
diene system. This renders both C-6 epimerization and
isomerization of the C-7/C-8 alkene likely to occur via acid-
and base-mediated mechanisms. The synthetic challenge is
further magnified by the known sensitivity of the butenolide
ring and the stereodefined C-11 acetal to moisture, acids, and
bases.6 The absolute stereochemistry of the C-11 stereocenter
was based on the conserved stereochemistry across all
strigolactones, and this was confirmed in biosynthetic studies
in 2018.7 In contrast, the absolute stereochemistry at C-6 was
tentatively assigned by deconvolution of absorbance peaks in
the CD spectrum of the isolated material. Due to significant
spectroscopic overlap, that assignment remains ambiguous.
The combination of biological function, stereochemical
ambiguity, and chemical sensitivity make heliolactone (7) an
important and challenging target for total synthesis.
T
growth is less than a century old,1 and in 2008 a family of
plant-derived compounds called strigolactones were identified
as phytohormones that affect important aspects of plant
growth and development (Figure 1).2 In addition to the so-
Our initial synthetic strategy to heliolactone (7) was
inspired by the recent work of De Mesmaeker and co-workers
who reported the first synthesis of a noncanonical
strigolactone, methyl carlactonate (3),6 which employed a
mild Stille cross-coupling as the key bond-forming reaction
(Scheme 1).8 We anticipated that stannane 11 and known
iodide 106 would undergo a similar cross-coupling and provide
access to heliolactone (7).
As depicted in Scheme 2, our work began with the
conversion of α-cyclocitral (12) into the corresponding
dibromo-olefin 13.9 The electron-deficient nature of the olefin
enabled subsequent allylic oxidation to occur on the cyclo-
hexene ring to give enone 14.10 The enone unit was masked11
as the enolate 15 before treatment with excess butyl lithium
Figure 1. Selected strigolactones and abscisic acid.
called “strigol-type” (1) and “orobanchol-type”(2) strigolac-
tones which possess a common tricyclic core,3 a subset of
biosynthetically diverged strigolactones (3−7) have been
isolated which are collectively known as “noncanonical”
strigolactones (Figure 1).4 Our interest was particularly
drawn to heliolactone (7), which possesses the butenolide
ring common to all strigolactones, but which also possesses a
cyclohexenone fragment that is strikingly similar to the
unrelated plant hormone, abscisic acid (8).5 The possibility
that heliolactone (7) functions as a multivalent ligand for both
abscisic acid and strigolactone signaling receptors in planta
offers exciting new directions for plant chemical biology and
necessitates access to the naturally occurring compound.
Received: April 22, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01402
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
olefin 19 into the alkyne 20.14 Hydrostannylation of 20 gave
the E-configured stannane 21 in moderate yield and set the
stage for the projected Stille cross-coupling. Frustratingly,
subjecting 21 to De Mesmaeker’s cross-coupling conditions
with the known racemic iodide 106 gave low yields (<20%) of
the desired product 22 contaminated with a substantial
Scheme 1. Initial Retrosynthetic Analysis of Heliolactone
(7)
1
proportion (40−50% by H NMR analysis) of inseparable
impurities resulting from decomposition of the D-ring
(determined by characteristic aldehydic resonances in the
chromatographically homogeneous material). Attempted mild
in situ deprotection of the acetal and alkene isomerization of
the product mixture containing 22 led to decomposition, and
heliolactone (7) was not detected in the reaction mixture.
Given the difficulties in generating the desired stannane 11
and the inability to successfully perform the Stille reaction−
deprotection sequence with the protected variant 21, we
revised our synthetic strategy to invert the polarity of the
coupling partners for the projected Stille reaction, which
necessitated iodide 23 and alkenyl-stannane 24 (Scheme 4).
Scheme 2. Attempted Synthesis of Stannane 11
Scheme 4. Revised Retrosynthetic Analysis of Heliolactone
(7)
The total synthesis of racemic heliolactone ( )-7 (as a
mixture of diastereomers) is shown in Scheme 5. While α-
cyclocitral (12) resisted all attempts at Takai olefination,15 the
previously generated dibromo-olefin 13 was converted into the
volatile alkyne 25, which was immediately subjected to
hydrostannylation and titration with iodine to give vinyl
iodide 27 in good yield and high diastereoselectivity (E/Z
12:1) over the three-step sequence.16 Our fears that the vinyl
iodide would not be suitably electron-deficient to facilitate
regioselective allylic oxidation proved unfounded and 27 was
converted into the desired coupling partner 23, with only a
minor loss of diastereomeric integrity (E/Z 8.4:1). Similarly,
conversion of the known vinyl iodide 106 into the desired
stannane 24 proceeded uneventfully.
With both coupling partners 23 and 24 in hand, the Stille
cross-coupling reaction was optimized, and under room
temperature conditions, racemic heliolactone ( )-(7) was
isolated in good yield. It is noteworthy that only the desired E-
configured olefin 27 participated in the palladium-catalyzed
coupling, while the Z-isomer was not consumed.
delivered the unstable alkyne 16 as the minor product in an
inseparable mixture containing allene 17. This proved
inconsequential, as the mixture of 16 and 17 resisted
hydrostannylation under a range of radical and palladium-
catalyzed reaction conditions.6,12
To temper the deleterious reactivity of the enone system and
doubly allylic methine proton, compound 14 was converted
into the corresponding acetal 19 (Scheme 3). The 4,5-
dimethyl-1,3-dioxolane acetal was chosen following reports
from Frackenpohl and co-workers that less substituted acetals
(such as 1,3-dioxolane) were unstable on similar systems.13
Acetal formation was accompanied by isomerization of the C-
4/C-5 alkene into conjugation. The action of cesium carbonate
in wet dimethyl sulfoxide effected conversion of the dibromo-
Scheme 3. Attempted Synthesis of Heliolactone (7) Using
an Acetal Protected Strategy
Comparison of the NMR spectra of synthesized heliolactone
( )-(7) (a 1:1 mixture of C-6/C-11 syn and anti
diastereomers) against authentic spectra of the isolated
material confirmed the atom connectivity of the natural
compound. Enantioselective HPLC separation of the mixture
was only partially successful, with resolution occurring at the
C-6 stereocenter to give two fractions, 7a and 7b. The
chromatographically slower moving fraction exhibited a
circular dichroism (CD) spectrum that closely aligned with
the reported values for the isolated natural product. However,
attempts to chromatographically separate the C-11 diaster-
eomers or unambiguously assign the C-6 absolute stereo-
chemistry proved unsuccessful. Therefore, the enantioselective
total synthesis of heliolactone was undertaken.
B
DOI: 10.1021/acs.orglett.9b01402
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Organic Letters
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Scheme 5. Total Synthesis of ( )-Heliolactone ( )-(7)
a
Scheme 6. Enantioselective Synthesis of Heliolactone (7)
a
NHPI = N-hydroxyphthalimide, DCC = dicyclohexylcarbodiimide, DMAP = 4-N,N-dimethylaminopyridine, B2pin2 = bis(pinacolato)diboron,
TBHP = tert-butylhydroperoxide, MS = molecular sieves, Pd2dba3 = tris(dibenzylideneacetone)dipalladium(0), NMP = N-methylpyrrolidinone.
As shown in Scheme 6, technical grade α-ionone (28) was
subjected to a haloform reaction to give acid 30. Resolution of
the acid was achieved by formation of the diastereomeric salts
using (S)-phenylethylamine (29) to give the S-configured acid
(−)-30, according to the literature procedure.17 Disappoint-
ingly, compound (−)-30 resisted direct Hunsdiecker reac-
tion,18 necessitating a three-step sequence involving conversion
into the activated ester (−)-31, amine-catalyzed borylation
into (−)-33,19 and iodination to deliver the required vinyl
iodide (−)-27. Allylic oxidation delivered the single
enantiomer coupling partner (−)-23. The second coupling
partner (+)-24 was synthesized from the known chiral iodide
(+)-106 using palladium-catalyzed stannylation,20 which
proceeded with retention of absolute stereochemistry. Stille
cross-coupling of (−)-23 and (+)-24 delivered heliolactone
(7). Comparison of the NMR spectra and CD curves against
the data for the isolated compound unambiguously showed
that naturally occurring helioactone is the (6S,11R) isomer.
In a similar manner, enantiomeric stannane (−)-24 was
coupled with iodide (−)-23 to give 11-epi-heliolactone (34).
CD comparisons demonstrated that the slow moving mixture
of diastereomers (7b) in Scheme 5 contained the (6S,11R) and
(6S,11S) isomers.
C
DOI: 10.1021/acs.orglett.9b01402
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Organic Letters
Letter
(5) Cutler, S. R.; Rodriguez, P. L.; Finkelstein, R. R.; Abrams, S. R.
Abscisic Acid: Emergence of a Core Signaling Network. In Annual
Review of Plant Biology; Merchant, S., Briggs, W. R., Ort, D., Eds.;
Annual Reviews: 2010; Vol. 61, pp 651−679.
In summary, we report the first total synthesis of
heliolactone (7). The racemic synthesis required 6 steps in
the longest linear sequence (LLS), with 3 of those steps
telescoped into a single operation. The enantioselective
synthesis required 7 steps LLS, which included a chiral
resolution. Comparison of the spectroscopic data for naturally
occurring and synthetic heliolactone (7) secures the (6S,11R)
stereochemistry for the natural product. The chemical biology
of this noncanonical strigolactone can now be explored.
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674.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01402.
■
S
(11) Kende, A. S.; Smith, C. A. Tetrahedron Lett. 1988, 29, 4217−
4220.
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(13) Frackenpohl, J.; Grill, E.; Bojack, G.; Baltz, R.; Busch, M.;
Dittgen, J.; Franke, J.; Freigang, J.; Gonzalez, S.; Heinemann, I.;
1
Experimental details, H and 13C NMR spectra, CD
spectra, and HPLC traces (PDF)
̈
Helmke, H.; Hills, M.; Hohmann, S.; von Koskull-Doring, P.;
AUTHOR INFORMATION
■
Kleemann, J.; Lange, G.; Lehr, S.; Muller, T.; Peschel, E.; Poree, F.;
̈
Corresponding Author
*E-mail: christopher.mcerlean@sydney.edu.au.
ORCID
Schmutzler, D.; Schulz, A.; Willms, L.; Wunschel, C. Eur. J. Org.
Chem. 2018, 2018, 1403−1415.
(14) Zhao, M.; Kuang, C.; Yang, Q.; Cheng, X. Tetrahedron Lett.
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Christopher S. P. McErlean: 0000-0001-8930-7495
Notes
(16) Attempted hydrozirconation/iodination of alkyne 25 was
unsuccessful: Hart, D. W.; Schwartz, J. J. Am. Chem. Soc. 1974, 96,
8115−8116.
The authors declare no competing financial interest.
(17) Fang, H.-J.; Shou, X.-A.; Liu, Q.; Gan, C.-C.; Duan, H.-Q.; Qin,
N. Eur. J. Med. Chem. 2015, 101, 245−253.
ACKNOWLEDGMENTS
■
S.W. is grateful for receipt of an Australian Government
Research Training Program (RTP) Scholarship. We are
indebted to Prof Yukihiro Sugimoto (Kobe University) for
providing original spectra and thank Dr. Girish Lakhwani and
Mr. Yun Li (University of Sydney) for assistance with CD
spectroscopy.
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DOI: 10.1021/acs.orglett.9b01402
Org. Lett. XXXX, XXX, XXX−XXX