Stereoselective Synthesis of (–)-Heliannuol E by α-Selective ­Propargyl Substitution

Abstract

This paper describes a stereoselective synthesis of (–)-heliannuol E through intramolecular cyclization of a phenol mesylate. The introduction of the aromatic group was achieved by α-selective propargyl substitution of a propargylic phosphate.

Key words

heliannuol E - propargyl substitution - stereoselectivity - asymmetric synthesis - intramolecular cyclization

The common sunflower Helianthus annuus is a rich source of sesquiterpenoids such as heliannuols, which show allelopathy to suppress or eliminate competing plant species near native plants.[1] [2] To date, 13 types of heliannuol have been isolated. Typically, they have a characteristic bicyclic structure consisting of an aromatic ring fused to a five- to eight-membered ring (Figure [1]).[1] In 1999, Macias et al. isolated heliannuol E from an extract of Helianthus annuus L. cv. SH-222; this compound contains a fused six-membered ring.[3] Because of its unique structure, syntheses of heliannuol E have been reported by many chemists.[4]

Figure 1 The heliannuol family

The syntheses of optically active heliannuol E so far reported were carried out through enzyme-mediated optical resolution[4a] [c] [d] or by asymmetric synthesis with asymmetric auxiliaries[4f] or asymmetric catalysts.[4g–i] Syntheses by optical resolution required separation of the compounds, and the yields were low. In the asymmetric syntheses, the limited range of substrates is disadvantageous for the synthesis of derivatives for structure–activity relationship studies. In addition, the availability of auxiliaries or catalysts is a problem. Recently, we reported a copper-catalyzed α-selective propargyl substitution of the propargylic phosphate 14 with Grignard reagents (Scheme [1]).[5] The reaction proceeds with high regio- and stereoselectivity, irrespective of steric and electronic effects of the nucleophile. Optically active propargylic phosphates can be easily synthesized by the reduction of alkynones with a commercially available ruthenium catalyst.[6] Considering these synthetic advantages, we carried out a stereoselective synthesis of heliannuol E (5).

Scheme 1 α-Selective propargyl substitution

Our retrosynthetic analysis is shown in Scheme [2], where alkyne 17 is proposed to form (–)-heliannuol E (5) through an epoxidation and subsequent cyclization reaction. We surmised that the aromatic ring in 17 could be introduced through an α-selective propargyl substitution reaction between phosphate 18 and a Grignard reagent in the presence of a copper catalyst. Furthermore, d-malic acid (20) was envisaged as a starting compound for the synthesis of phosphate 18 via ketone 19.

Scheme 2 Retrosynthetic analysis of (–)-heliannuol E (5)

Protection of malic acid (20) with cyclohexanone in the presence of PPTS gave carboxylic acid 21 in 62% yield (Scheme [3]).[7] After the reduction of 21 with BH₃·SMe₂, the resulting alcohol was protected with TBDPSCl to give silyl ether 22. Diol 23 was then obtained through a Grignard reaction with MeMgBr in 31% yield over three steps. Subsequently, 23 was protected with cyclohexanone in the presence of PPTS to give acetal 24 in 79% yield, which was deprotected by using TBAF to furnish alcohol 25 in 97% yield. Parikh–Doering oxidation of 25, followed by the addition of (trimethylsilyl)ethyne afforded propargylic alcohols 27 and dia-27 in 91% yield.[8] The stereoselectivity was determined by ¹H NMR spectroscopy (27/dia-27 = 45:55). Oxidation of the mixture with PCC in the presence of NaOAc formed ketone 19, which was converted into the optically active propargylic alcohol 27 [8] by ruthenium-catalyzed asymmetric transfer hydrogenation[6] in 81% yield and >99% de, as determined by ¹H NMR spectroscopy. Finally, the hydroxy group of 27 was protected with diethyl chlorophosphate to give phosphate 18 in 79% yield.

Scheme 3 Synthesis of phosphate 18

The α-selective propargylic substitution of 18 with ­Grignard reagent 28 and CuBr·SMe₂ catalyst produced compound 17, which was deprotected to give diol 29 in 65% yield (Scheme [4]).[5] The regioselectivity of the propargyl substitution was >99%, as determined by ¹H NMR spectroscopy (see the Supporting Information).[5] After removal of the TMS group with K₂CO₃/MeOH, the resulting alkyne was reduced by using Zn[9] to form olefin 31 in 88% yield.

Scheme 4 Synthesis of olefin 31

The final steps of the synthesis are summarized in Scheme [5]. Mesylation of 31, followed by the addition of ­K₂CO₃ to 32, afforded epoxide 33 in 67% yield. Then, 33 was oxidized with CAN to produce quinone 34 as the major product, along with as other unidentified products, which could not be separated from 34 by column chromatography on silica gel. Subsequently, the addition of NaBH₄ to the mixture facilitated reduction to the phenol; this was followed by a cyclization reaction, to give (–)-heliannuol E (5) and (–)-epi-heliannuol E (epi-5) in yields of 8 and 17%, respectively. The ¹H NMR and ¹³C NMR spectra of 5 and epi-5 were consistent with those previously reported.[3] [4a] [b] [f] [h] No seven-membered-ring product was formed in the cyclization reaction of 34. We proposed that epi-5 was produced via a cation generated by ring-opening of the epoxide.

Scheme 5 Attempted synthesis of (–)-heliannuol E (5) via epoxide 33

Next, we examined the cyclization of mesylate 35 without the formation of epoxide 33 (Scheme [6]). Mesylation of diol 31 followed by oxidation with CAN and subsequent reduction with Na₂S₂O₄ resulted in 35, which was unstable[9] and was therefore immediately used for the next reaction. K₂CO₃ was added, and the mixture was allowed to react for 15 hours to give 5 as the sole product in 11% yield. Because the cyclization was slow, the yield was reduced due to the decomposition of 35 over time. Therefore, the hydroxy group was protected to form the stable silyl ether 36 in 34% yield over four steps.[10] [11] Finally, cyclization of 36 in the presence of K₂CO₃ resulted in the formation of 5 as the sole product in 67% yield. In this reaction, the TBS group was removed after the cyclization, as monitored by TLC, and the yield of 5 was thereby improved (23% yield from 31).

Scheme 6 Synthesis of (–)-heliannuol E (5)

In conclusion, we have successfully synthesized (–)-heliannuol E (5) through an α-selective propargyl substitution as the key step. Propargylic phosphate 18 was synthesized from d-malic acid (20) and subjected to copper-catalyzed α-selective propargyl substitution to produce alkyne 17 efficiently and with high selectivity. In the final steps of the synthesis, cyclization of silyl ether 36 led to the formation of 5 as the sole product. This synthesis was achieved in a total of 20 steps, with a yield of 1.5% from 20. By using the present method, various heliannuol E derivatives could be synthesized by changing the Grignard reagents.

Conflict of Interest

The authors declare no conflict of interest.

• References and Notes

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• 1e El Marsni Z, Torres A, Varela RM, Molinillo JM. G, Casas L, Mantell C, Martinez de la Ossa EJ, Macias FA. J. Agric. Food Chem. 2015; 63: 6410
• 2 Macías FA, Varela RM, Torres A, Molinillo JM. G. J. Chem. Ecol. 2000; 26: 2173
• 3 Macías FA, Varela RM, Torres A, Molinillo JM. G. Tetrahedron Lett. 1999; 40: 4725
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• 5 Kobayashi Y, Takashima Y, Motoyama Y, Isogawa Y, Katagiri K, Tsuboi A, Ogawa N. Chem. Eur. J. 2021; 27: 3779
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• 8 The stereochemistry of propargylic alcohols 27 and dia-27 was tentatively assigned by the catalyst selectivity for the reduction of ketone 19 to 27, and unambiguously determined from the optical rotation of the synthesized (–)-heliannuol E (5).
• 9 Aerssens MH. P. J, van der Heiden R, Heus M, Brandsma L. Synth. Commun. 1990; 20: 3421
• 10 Osaka M, Kanematsu M, Yoshida M, Shishido K. Tetrahedron: Asymmetry 2010; 21: 2319
• 11 The reaction of 35 with TBSCl resulted only in production of compound 36, and the disilyl ether was not formed. The regioisomer was not formed because of steric hindrance.
• 12 (–)-Heliannuol E (5) K₂CO₃ (73.9 mg, 0.535 mmol) was added to an ice-cold solution of olefin 36 (58.3 mg, 0.127 mmol) in MeOH (10 mL). The mixture was stirred at 0 °C for 1 h, then heated and stirred at 45 °C for 15 h. The mixture was then diluted with 3 N aq HCl to pH 5–6 and extracted with Et₂O (×3). The combined extracts were dried (MgSO₄) and concentrated. The residue was purified by recycling HPLC [LC-Forte/R equipped with YMC-Pack SIL-60, hexane–EtOAc (4:1), 25 mL/min] to give a colorless oil; yield: 22.7 mg (67%); R_f = 0.33 (hexane–EtOAc, 3:1); [α]_D ²⁶ –69 (c 0.33, CHCl₃) [Lit.³ –68.6 (c 0.1, CHCl₃)]. IR (neat): 3379, 1635, 1196 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.24 (s, 3 H), 1.30 (s, 3 H), 1.82–1.97 (m, 2 H), 2.20 (s, 3 H), 2.33–2.38 (br s, 1 H), 3.43–3.52 (m, 1 H), 3.74 (dd, J = 10.4, 3.6 Hz, 1 H), 4.35 (s, 1 H), 4.91 (dd, J = 16.8, 1.6 Hz, 1 H), 5.11 (dd, J = 10.4, 1.6 Hz, 1 H), 6.08 (ddd, J = 16.8, 10.4, 6.4 Hz, 1 H), 6.49 (s, 1 H), 6.66 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 15.8, 24.3, 26.0, 27.6, 38.0, 72.1, 77.6, 115.9, 116.0, 118.6, 120.7, 124.2, 142.2, 147.5, 148.3. HRMS (FD): m/z [M]⁺ calcd for C₁₅H₂₀O₃: 248.14124; found: 248.14106.

Publication History

Received: 10 September 2021

Accepted after revision: 28 September 2021

Article published online:
19 October 2021