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Synlett 2024; 35(13): 1561-1564
DOI: 10.1055/s-0042-1751547
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Stereoselective Synthesis of Volicitin and 9-D 1-Volicitin

Shunki Mamada
a   Department of Applied Chemistry, Meiji University, 1-1-1 Higashimita, Tama-ku, Kawasaki, Kanagawa214-8571, Japan
,
Kosuke Niwa
a   Department of Applied Chemistry, Meiji University, 1-1-1 Higashimita, Tama-ku, Kawasaki, Kanagawa214-8571, Japan
,
Shoya Toyoshima
a   Department of Applied Chemistry, Meiji University, 1-1-1 Higashimita, Tama-ku, Kawasaki, Kanagawa214-8571, Japan
,
Yoshiya Seto
b   Department of Agricultural Chemistry, Meiji University, 1-1-1 Higashimita, Tama-ku, Kawasaki, Kanagawa 214-8571, Japan
,
Narihito Ogawa  ∗
a   Department of Applied Chemistry, Meiji University, 1-1-1 Higashimita, Tama-ku, Kawasaki, Kanagawa214-8571, Japan
› Author Affiliations

This work was supported by Research Project Grant B from the Institute of Science and Technology, Meiji University, and Meiji University Graduate School Joint Research Project (MU-GS-JRP2023-04).
› Further Information
 
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Abstract

The synthesis of volicitin involved the condensation of l-(+)-glutamine with 17(S)-hydroxylinolenoic acid, derived from a Wittig reaction between the C10–C18 phosphonium salt and the C1–C9 aldehyde. The phosphonium salt was prepared through the alkynylation of a (Z)-allylic phosphate with an alkyne derived from (2S)-but-3-yn-2-ol. The deuterated aldehyde was derived with a 96% deuteration ratio by reduction of the C1–C9 methyl ester with NaBD4, followed by oxidation. Subsequently, 9-D 1-volicitin was synthesized from the monodeuterated aldehyde by using the Wittig reaction and condensation with l-(+)-glutamine.


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Key words

volicitin - deuteration - alkynylation - Wittig reaction - condensation

N-(17S-Hydroxylinolenoyl)-l-glutamine, also known as volicitin (1), is a biochemical elicitor that plays a crucial role in triggering defense responses in plants (Scheme [1a]).[1] It is recognized for its ability to activate volatile-component-biosynthesis genes and the production of indoles and terpenes in plants.[2] Volicitin has been synthesized by several groups,[1a] [3] by using the condensation of 17-hydroxylinolenic acid (2) with l-(+)-glutamine as the final step in each synthesis process. The syntheses of 2 were primarily achieved through either a Wittig reaction and/or a coupling reaction of a propargylic bromide derivative with an alkyne, followed by catalytic hydrogenation to form an unconjugated double bond (Scheme [1b]). In addition, we have synthesized 1,4-dienes of various lipid mediators by using a Wittig reaction as the key reaction.[4]

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Scheme 1 Structure of volicitin (1) and strategies for synthesis of the 1,4-diene part in 1

Recently, we reported an alkynylation of allylic phosphates with copper reagents, which can be used for the synthesis of lipid mediators.[5] In contrast, previously reported synthetic methods for 1,4-enyne structures were limited to specific substrates and could not be used for the synthesis of lipid mediators. In this study, we planned a synthesis of 1 by regioselective alkynylation of a (Z)-allylic phosphate with an acetylene–copper reagent, and stereoselective reduction.

The deuteration of lipid metabolites plays a pivotal role in determinations of the molecular mechanisms of metabolism, pharmacokinetics, and physiological events.[6] Therefore, the synthesis of deuterated lipid mediators is important for biological research. However, deuterium-labeled volicitin had not been synthesized. In this paper, we also report the synthesis of monodeuterated volicitin.

Our strategy for the synthesis of volicitin (1) is shown in Scheme [2]. We aimed to produce volicitin (1) by the Wittig reaction of phosphonium salt 3 with aldehyde 4, followed by conversion into 2 in a few steps and subsequent condensation with l-(+)-glutamine. Phosphonium salt 3 could be prepared by the alkynylation[5] of allylic phosphate 6 with alkyne 5,[7] derived from commercially available (2S)-but-3-yn-2-ol (98% ee). 9-D 1-volicitin (1-d 1 ) could be synthesized by a similar synthetic method from aldehyde 4-d 1 .

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Scheme 2 Synthetic plan

Our synthesis began with the preparation of the phosphonium salt 3 (Scheme [3]). Protection of the hydroxy group of but-3-yn-1-ol (7) with TBSCl afforded the silyl ether 8, the anion of which was coupled with paraformaldehyde to produce the propargylic alcohol 9.[8] A Z-selective hydrogenation of 9 with P2-Ni (borohydride-reduced nickel)[9] afforded allylic alcohol 10 [10] in a 99% yield. The E-isomer was not observed in this reduction. Alcohol 10 was then converted into the allylic phosphate 6 and subjected to our reported alkynylation[5] with alkyne 5. At 0 °C, the ratio of the SN2 product 11 and the SN2′ product was 75:25. The reaction was therefore carried out at –10 °C to improve the selectivity. When the reaction temperature was further decreased to –30 °C, the selectivity remained the same as that at –10 °C [see the Supporting Information (SI)]. Isomerization of the Z-olefin was not observed in the alkynylation. Deprotection of the SN2 product 11 with PPTS in MeOH afforded alcohol 12 in a 65% yield from 6 via alkynylation at –30 °C. The acetylene moiety in 12 was stereoselectively reduced with P2-Ni to afford diene 13 in an 80% yield. Iodination of the hydroxy group in 13 and the reaction of the resulting iodide with PPh3 resulted in the formation of phosphonium salt 3 in a good yield.

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Scheme 3 Synthesis of phosphonium salt 3

The synthesis of volicitin (1) is shown in Scheme [4]. The Wittig reaction of phosphonium salt 3 with aldehyde 4,[11] derived from nonane-1,9-diol (15) by a two-step reaction via 16, proceeded smoothly to give disilyl ether 17.[12] Deprotection of 17 with PPTS afforded alcohol 18 in a 71% yield from phosphonium salt 3. Carboxylic acid 20 was produced in a 64% yield from 18 by a two-step oxidation. After the deprotection of the TBDPS group in 20 with TBAF, the resultant carboxylic acid 2 was converted into volicitin (1) in a 69% yield by condensation with l-(+)-glutamine. The 1H and 13C NMR spectral data for 1 were in good agreement with the reported data for volicitin.[3a] [c]

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Scheme 4 Synthesis of volicitin (1). IBX = 2-iodoxybenzoic acid.
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Scheme 5 Synthesis of 9-D 1-volicitin (1-d 1 )

We synthesized 9-D 1-volicitin (1-d 1 ) according to the procedure shown in Scheme [5]. Oxidation of the aldehyde 4, followed by esterification of the resulting carboxylic acid 21 [13] with MeI and K2CO3, gave methyl ester 22.[14] The reduction of the methyl ester 22 with NaBD4 afforded an alcohol that was converted into the monodeuterated aldehyde 4-d 1 in a 43% yield by oxidation with SO3·py. The deuteration ratio of 4-d 1 was confirmed to be 96% by 1H NMR analysis (see SI). The deuteration was also confirmed by 13C NMR spectroscopy. As in Scheme [4], the Wittig reaction of 3 with 4-d 1 afforded 17-d 1 , which was converted into 18-d 1 in a 67% yield. The two-step oxidation of 18-d 1 afforded 20-d 1 in a good yield. Finally, after the deprotection of the TBDPS group in 20-d 1 , condensation with l-(+)-glutamine gave 9-D 1-volicitin (1-d 1 ). The deuterated ratio in 1-d 1 was 96%, which was consistent with that of 4-d 1 (see SI).

In summary, we have synthesized volicitin (1)[15] and 9-D 1-volicitin (1-d 1 ). The C10–C18 phosphonium salt 3 was obtained in a few steps through alkynylation of an alkyne with allylic phosphate 6. The Wittig reaction of phosphonium salt 3 with the C1–C9 aldehyde 4 gave 17, which was subjected to construction of the carboxylic acid and deprotection of the TBDPS group to give 17(S)-hydroxylinolenic acid (2). Finally, condensation of 2 with l-(+)-glutamine produced volicitin (1). Spectral analyses of synthetic 1 showed good agreement with the reported data. The 9-D 1-volicitin (1-d 1 ) was derived by the same synthetic method. The reduction of the methyl ester 22 with NaBD4 produced the desired aldehyde 4-d 1 in a deuterated ratio of 96%. Subsequently, the aldehyde was converted into 1-d 1 while maintaining the deuteration ratio. We are currently studying plant chemical biology by using volicitin and its deuterated derivative.


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Conflict of Interest

The authors declare no conflict of interest.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/s-0042-1751547.
  • Supporting Information

  • References and Notes

  • 5 Mamada S, Ogawa N. Eur. J. Org. Chem. 2023; e202300056
    Crossref
  • 7 Raghavan S, Patel JS, Ramakrishna KV. S. RSC Adv. 2016; 6: 72877
    CrossrefSearch in Google Scholar
  • 8 Gagestein B, von Hegedus JH, Kwekkeboom JC, Heijink M, Blomberg N, van der Wel T, Florea BI, van den Elst H, Wals K, Overkleeft HS, Giera M, Toes RE. M, Ioan-Facsinay A, van der Stelt M. J. Am. Chem. Soc. 2022; 144: 18938
    CrossrefPubMedSearch in Google Scholar
  • 10 Schulthoff S, Hamilton JY, Heinrich M, Kwon Y, Wirtz C, Fürstner A. Angew. Chem. Int. Ed. 2021; 60: 446
    CrossrefPubMedSearch in Google Scholar
  • 11 Tonoi T, Inohana T, Kawahara R, Sato T, Ikeda M, Akutsu M, Murata T, Shiina I. ACS Omega 2021; 6: 3571
    CrossrefPubMedSearch in Google Scholar
  • 12 The 1H and 13C NMR spectra of the Wittig product indicated a high Z-selectivity for the Wittig reaction.
  • 13 Ishiwata H, Sone H, Kigoshi H, Yamada K. Tetrahedron 1994; 50: 12853
    CrossrefSearch in Google Scholar
  • 14 Fortunati T, D’Acunto M, Caruso T, Spinella A. Tetrahedron 2015; 71: 2357
    CrossrefSearch in Google Scholar
  • 15 Volicitin (1) To an ice-cold solution of carboxylic acid 2 (83.1 mg 0.282 mmol) in THF (2.8 mL) was added Et3N (0.047 mL, 0.34 mmol). After 1 h at 0 °C, ClCO2Et (0.032 mL, 0.034 mmol) was added to the mixture. After a further 1 h at 0 °C, a solution of l-(+)-glutamine (53.5 mg, 0.367 mmol) in aq NaOH was added to the mixture. After 1.5 h at r.t., the mixture was diluted with 3 N aq HCl and extracted with EtOAc (×3). The combined extracts were dried (MgSO4) and concentrated. The residue was semi-purified by chromatography (silica gel, EtOAc to EtOAc–MeOH) to give crude 1. The crude 1 was purified by chromatography (Wakosil 50C18, MeCN–H2O) to give a white amorphous solid; yield: 81.8 mg (69%); Rf = 0.09 (EtOAc–MeOH, 2:1); [α]D 27 +8 (c 0.095, MeOH), [α]D 26 +2 (c 0.26, CH2Cl2) [Lit.3a [α]D 22 +3 (c 0.83, CH2Cl2)]. IR (neat): 3472, 1715, 1670, 1450, 670 cm–1. 1H NMR (400 MHz, CD3OD): δ = 1.11 (d, J = 6.4 Hz, 3 H), 1.21–1.31 (m, 8 H), 1.54 (t, J = 7.2 Hz, 2 H), 1.81–1.90 (m, 1 H), 1.99 (q, J = 6.4 Hz, 2 H), 2.03–2.13 (m, 1 H), 2.16 (t, J = 7.6 Hz, 2 H), 2.18–2.23 (m, 2 H), 2.73 (t, J = 6.0 Hz, 2 H), 2.78 (t, J = 6.0 Hz, 2 H), 4.26 (dd, J = 8.8, 5.2 Hz, 1 H), 4.54 (quint, J = 6.4 Hz, 1 H), 5.20–5.36 (m, 6 H). 13C NMR (100 MHz, CD3OD): δ = 24.0, 26.5, 26.8, 26.9, 28.1, 28.8, 30.21, 30.26, 30.32, 30.7, 32.8, 36.9, 53.6, 64.3, 128.6, 129.1, 129.6, 131.2, 135.4, 175.6, 176.2, 177.8. HRMS (FD): m/z [M+] calcd for C23H38N2O5: 422.27807; found: 422.27801.

Corresponding Author

Narihito Ogawa
Department of Applied Chemistry, Meiji University
1-1-1 Higashimita, Tama-ku, Kawasaki, Kanagawa 214-8571
Japan   

Publication History

Received: 07 November 2023

Accepted after revision: 04 December 2023

Article published online:
15 January 2024

© 2024. Thieme. All rights reserved

Georg Thieme Verlag KG
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  • References and Notes

  • 5 Mamada S, Ogawa N. Eur. J. Org. Chem. 2023; e202300056
    Crossref
  • 7 Raghavan S, Patel JS, Ramakrishna KV. S. RSC Adv. 2016; 6: 72877
    CrossrefSearch in Google Scholar
  • 8 Gagestein B, von Hegedus JH, Kwekkeboom JC, Heijink M, Blomberg N, van der Wel T, Florea BI, van den Elst H, Wals K, Overkleeft HS, Giera M, Toes RE. M, Ioan-Facsinay A, van der Stelt M. J. Am. Chem. Soc. 2022; 144: 18938
    CrossrefPubMedSearch in Google Scholar
  • 10 Schulthoff S, Hamilton JY, Heinrich M, Kwon Y, Wirtz C, Fürstner A. Angew. Chem. Int. Ed. 2021; 60: 446
    CrossrefPubMedSearch in Google Scholar
  • 11 Tonoi T, Inohana T, Kawahara R, Sato T, Ikeda M, Akutsu M, Murata T, Shiina I. ACS Omega 2021; 6: 3571
    CrossrefPubMedSearch in Google Scholar
  • 12 The 1H and 13C NMR spectra of the Wittig product indicated a high Z-selectivity for the Wittig reaction.
  • 13 Ishiwata H, Sone H, Kigoshi H, Yamada K. Tetrahedron 1994; 50: 12853
    CrossrefSearch in Google Scholar
  • 14 Fortunati T, D’Acunto M, Caruso T, Spinella A. Tetrahedron 2015; 71: 2357
    CrossrefSearch in Google Scholar
  • 15 Volicitin (1) To an ice-cold solution of carboxylic acid 2 (83.1 mg 0.282 mmol) in THF (2.8 mL) was added Et3N (0.047 mL, 0.34 mmol). After 1 h at 0 °C, ClCO2Et (0.032 mL, 0.034 mmol) was added to the mixture. After a further 1 h at 0 °C, a solution of l-(+)-glutamine (53.5 mg, 0.367 mmol) in aq NaOH was added to the mixture. After 1.5 h at r.t., the mixture was diluted with 3 N aq HCl and extracted with EtOAc (×3). The combined extracts were dried (MgSO4) and concentrated. The residue was semi-purified by chromatography (silica gel, EtOAc to EtOAc–MeOH) to give crude 1. The crude 1 was purified by chromatography (Wakosil 50C18, MeCN–H2O) to give a white amorphous solid; yield: 81.8 mg (69%); Rf = 0.09 (EtOAc–MeOH, 2:1); [α]D 27 +8 (c 0.095, MeOH), [α]D 26 +2 (c 0.26, CH2Cl2) [Lit.3a [α]D 22 +3 (c 0.83, CH2Cl2)]. IR (neat): 3472, 1715, 1670, 1450, 670 cm–1. 1H NMR (400 MHz, CD3OD): δ = 1.11 (d, J = 6.4 Hz, 3 H), 1.21–1.31 (m, 8 H), 1.54 (t, J = 7.2 Hz, 2 H), 1.81–1.90 (m, 1 H), 1.99 (q, J = 6.4 Hz, 2 H), 2.03–2.13 (m, 1 H), 2.16 (t, J = 7.6 Hz, 2 H), 2.18–2.23 (m, 2 H), 2.73 (t, J = 6.0 Hz, 2 H), 2.78 (t, J = 6.0 Hz, 2 H), 4.26 (dd, J = 8.8, 5.2 Hz, 1 H), 4.54 (quint, J = 6.4 Hz, 1 H), 5.20–5.36 (m, 6 H). 13C NMR (100 MHz, CD3OD): δ = 24.0, 26.5, 26.8, 26.9, 28.1, 28.8, 30.21, 30.26, 30.32, 30.7, 32.8, 36.9, 53.6, 64.3, 128.6, 129.1, 129.6, 131.2, 135.4, 175.6, 176.2, 177.8. HRMS (FD): m/z [M+] calcd for C23H38N2O5: 422.27807; found: 422.27801.

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Zoom Image
Scheme 1 Structure of volicitin (1) and strategies for synthesis of the 1,4-diene part in 1
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Scheme 2 Synthetic plan
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Scheme 3 Synthesis of phosphonium salt 3
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Scheme 4 Synthesis of volicitin (1). IBX = 2-iodoxybenzoic acid.
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Scheme 5 Synthesis of 9-D 1-volicitin (1-d 1 )