Total synthesis of (±)-heliannuol D, an allelochemical from Helianthus annuus

Article abstract of DOI:10.1016/S0040-4039(99)02284-4

The total synthesis of (±)-heliannuol D and its epimer has been completed in 9 steps and 12% overall yield from 2-methylanisole. The benzoxepane moiety of the title compound, a common structural feature in the heliannuol family of natural products, is pre

Full text of DOI:10.1016/S0040-4039(99)02284-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1151–1154
Total synthesis of (±)-heliannuol D, an allelochemical from
Helianthus annuus
James R. Vyvyan ∗ and Ryan E. Looper
Department of Chemistry, Western Washington University, Bellingham, WA 98225, USA
Received 19 October 1999; revised 8 December 1999; accepted 9 December 1999
Abstract
The total synthesis of (±)-heliannuol D and its epimer has been completed in 9 steps and 12% overall yield from
2-methylanisole. The benzoxepane moiety of the title compound, a common structural feature in the heliannuol
family of natural products, is prepared by a biomimetic opening of an epoxide by a phenol. © 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: allelopathy; biomimetic reactions; phenols; herbicides.
Maximizing the world’s agricultural efficiency depends on controlling unwanted pests, especially
weeds. A wide variety of synthetic herbicides have met the weed control needs of industrialized
nations for over 50 years. Mounting ecological and human health concerns, however, are continuing
to shift attention to alternative weed control technology based on cues from nature.1,2 Allelopathy, the
chemical interaction between plants and/or microorganisms, has been known for thousands of years.3
Allelochemicals that suppress or eliminate competing plant species near the source plant have received
special attention due to the potential of these compounds to serve as natural herbicides.4 Indeed, this
agricultural potential and the synthetic challenges to be found in the skeletons of allelopathic natural
products are now beginning to attract the attention of organic chemists.5
The cultivated sunflower Helianthus annuus is allelopathic and shows activity against such trou-
blesome weeds as morning glory, velvetleaf, pigweed, jimson weed, wild mustard, and others.6 The
heliannuols (1–5, Fig. 1) are a promising group of phenolic allelochemicals isolated from H. annuus that
exhibit activity against dicotyledon plant species.7 In addition to their value as natural herbicide models,
the unusual structures of the heliannuols, comprised of previously unknown benzo-fused 6-, 7- and 8-
membered cyclic ether skeletons, make them challenging synthetic targets.8 Herein we report the total
synthesis of (±)-heliannuol D (4) and its epimer 14.9
We chose 2-methylanisole (6) as our starting material for the preparation of the differentially protected
methylhydroquinone core (cf. 9) that is common to all of the heliannuols (Scheme 1). Bromination of
∗
Corresponding author. E-mail: vyvyan@chem.wwu.edu (J. R. Vyvyan)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02284-4
tetl 16212

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Fig. 1. Structures of the heliannuols
6 provided 4-bromo-2-methylanisole (7)10 in excellent yield. The aryl lithium species prepared from
7 was reacted with triisopropylborate followed by oxidation of the resultant aryl borate ester with tert-
butylhydroperoxide (TBHP) to provide 4-methoxy-3-methylphenol11 in essentially quantitative yield. We
have found the use of TBHP as the oxidant under very weakly acidic aqueous conditions (satd NH4Cl
solution) to be superior to H2O2 and dilute acetic or hydrochloric acids as previously described.12 In the
present case, for example, use of H2O2 and dilute HCl provided the phenol in only ∼50% yield.
Scheme 1. Reagents and conditions: (a) Br2, CHCl3, 0°C. (b) (i) Li metal, Et2O, reflux; (ii) B(OiPr)3, −78°C to rt; (iii)
TBHP, aq. NH4Cl. (c) (i) NaH, THF, 0°C; (ii) BnBr, DMF. (d) (i) tert-BuLi (2.2 equiv.), −78°C; (ii) ZnCl2, THF; (iii)
CH2_C(OTf)CH2CH2CH_C(CH3)2, Pd(PPh3)4 (5 mol%), THF, reflux. (e) Li (6 equiv.), liquid NH3
The crude 4-methoxy-3-methylphenol was immediately brominated at the less hindered ortho position
followed by protection of the phenol as its benzyl ether to yield 8. This sequence provided the aryl halide
needed for attachment of the side chain in 4 steps and 85% yield from 2-methylanisole (6). Bromide 8
was subjected to metal–halogen exchange with tert-butyllithium and transmetallation with zinc chloride
to provide the aryl zinc species, which was coupled to the enol triflate derived from 6-methyl-5-hepten-2-
one13 under palladium catalysis. The crude reaction mixture from the coupling was directly treated with
excess lithium in liquid ammonia to reduce simultaneously the conjugated alkene and the benzyl ether
group to provide aromatic bisabolane derivative 914 in 42% yield for the 2 steps. This coupling–reduction
strategy is a highly efficient method for the preparation of aromatic bisabolane skeletons, but apparently
is sensitive to the triflate:aryl zinc stoichiometry or the quality of the Pd0 catalyst. These issues will be
examined further as we continue our studies in this area.15
Our strategy for the construction of the benzoxepane moiety of heliannuol D (4) mirrors the proposed
biosynthesis of the compound, which involves a phenol-epoxide cyclization.7b The cyclization substrate
was prepared by oxidation of 9 with m-CPBA to furnish a ∼1:1 ratio of diastereomeric epoxides 10 and 11
that were easily separable using flash chromatography (Scheme 2). The relative stereochemistry of these
epoxides and their cyclization products can be reliably assigned based on the magnitude of the coupling
1
constants of the C-10 methine hydrogen resonance in the H NMR spectrum.16 Treatment of 10 with
powdered KOH in warm DMSO resulted in an excellent yield of benzoxepane 12 via regiospecific attack
of the phenoxide at the less hindered proximal position of the epoxide.17 Epoxide 11 also underwent
regiospecific cyclization to provide a good yield of cyclic ether 13 under similar conditions, but required
longer reaction times or higher temperatures to achieve complete conversion of the starting epoxide.
The only remaining step in the synthesis was deprotection of the methyl ether in 11. Reaction of
11 with excess sodium ethanethiolate in refluxing DMF18 provided (±)-heliannuol D (4) in 90% yield
1
after purification by flash chromatography. The IR, H and 13C NMR, and mass spectra of synthetic 4

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Scheme 2. Reagents and conditions: (a) m-CPBA, Na2HPO4, CH2Cl2, 0°C. (b) powdered KOH, DMSO, 70−100°C. (c) NaSEt
(15 equiv.), DMF, reflux
match the tabulated data reported for natural heliannuol D.7b,19 Overall, the synthesis of heliannuol D
(4) required 9 steps from 2-methylanisole (6) and proceeded in 12% yield. epi-Heliannuol D (14) was
obtained in 93% yield (12% overall from 6) after cleavage of the methyl ether in 13 under identical
conditions employed for the preparation of 4.
In summary, we have shown that the palladium-catalyzed coupling of the vinyl triflate derived from
6-methyl-5-hepten-2-one to the aryl zinc species prepared from 8 provides a streamlined approach to the
aromatic bisabolane skeleton, a framework that is frequently encountered in natural products. Regios-
pecific cyclization of epoxides 10 and 11 under basic conditions gives high yields of the corresponding
benzoxepanes 12 and 13. We are currently pursuing syntheses of the other heliannuols based on the
strategy developed above.
Acknowledgements
We thank The Camille and Henry Dreyfus Foundation, Research Corporation, and the Western
Washington University Bureau for Faculty Research for funding our work. Acknowledgement is also
made to the donors of The Petroleum Research Fund, administered by the ACS, for partial support of this
research.
References
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3. (a) Rice, E. L. Pest Control with Nature’s Chemicals; University of Oklahoma Press: Norman, OK, 1983. (b) Rice, E. L.
Allelopathy, 2nd ed.; Academic: New York, 1984.
4. (a) Duke, S. O.; Dayan, F.; Rimando, A. Proceedings of Special Lecture Meeting on ‘Recent Topics of Weed Science and
Weed Technology’, Tokyo, April 3, 1998; 1–11. (b) Duke, S. O.; Dayan, F. E.; Hernandez, A.; Duke, M. V.; Abbas, H. K.
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9. During the preparation of this manuscript, a reported synthesis of heliannuol A and D came to our attention, see: Takabatake,
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15. This somewhat disappointing yield for the coupling and reduction sequence is in stark contrast to similar coupling reactions
of aryl zinc species with the same vinyl triflate that proceed in 85–90% yield for the 2 step sequence: Looper, R. E. M. S.
Thesis, Western Washington University: Bellingham, WA, 1999.
16. For 10: δH10=2.79, app t, J=6.2 Hz; for 11: δH10=2.83, dd, J=9 and 3 Hz; The stereochemical assignment was confirmed
by X-ray diffraction of a model 2-(5-methyl-2H,3H,4H,5H-benzo[f]oxepan-2-yl)propan-2-ol. Details of the stereochemical
correlation will be reported in the full article describing this work.
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19. The melting point of our synthetic 4 is 162–163°C, 100 degrees higher than was reported for the natural material in the
original work (Ref 7b). Professor Macías confirmed via personal communication that an error exists in the original paper,
and that the melting point of natural heliannuol D is 159–161°C.