Download PDF
Synthesis 2014; 46(02): 170-174
DOI: 10.1055/s-0033-1338559
paper
© Georg Thieme Verlag Stuttgart · New York

The First Synthesis of Uralenol, 5′-Prenylated Quercetin, via Palladium-Catalyzed­ O-Dimethylallylation Reaction with Concurrent Acetyl Migration

Tomoyuki Kawamura
a   Department of Pharmaceutical Chemistry, Division of Heath Biosciences, Graduate School of the University of Tokushima, 1-78-1, Sho-machi, Tokushima 770-8505, Japan   Fax: +81(88)6337284   Email: nem@ph.tokushima-u.ac.jp
,
Moemi Hayashi
a   Department of Pharmaceutical Chemistry, Division of Heath Biosciences, Graduate School of the University of Tokushima, 1-78-1, Sho-machi, Tokushima 770-8505, Japan   Fax: +81(88)6337284   Email: nem@ph.tokushima-u.ac.jp
,
Rie Mukai
b   Department of Food Science, Institute of Health Biosciences, Graduate School of the University of Tokushima, 3-18-15, Kuramoto-cho, Tokushima 770-8503, Japan
,
Junji Terao
b   Department of Food Science, Institute of Health Biosciences, Graduate School of the University of Tokushima, 3-18-15, Kuramoto-cho, Tokushima 770-8503, Japan
,
Hisao Nemoto*
a   Department of Pharmaceutical Chemistry, Division of Heath Biosciences, Graduate School of the University of Tokushima, 1-78-1, Sho-machi, Tokushima 770-8505, Japan   Fax: +81(88)6337284   Email: nem@ph.tokushima-u.ac.jp
› Author Affiliations
Further Information

Publication History

Received: 18 September 2013

Accepted after revision: 25 October 2013

Publication Date:
22 November 2013 (online)

 
 PDF Download Permissions and Reprints All articles of this category


Abstract

The first synthesis of uralenol, 5′-prenylated quercetin, is described. The key step is a palladium-catalyzed O-1,1-dimethylallylation reaction, with concurrent acetyl migration to afford the desired intermediate as a major isomer, which was purified by recrystallization. Finally, Claisen rearrangement, followed by deprotection of all phenolic protecting groups, afforded uralenol in excellent yield.


#

Key words

palladium - prenylation - quercetin - flavonoids - rearrangement

The bioactivity of prenylated flavonoids is more attractive than that of unmodified flavonoids, since the changed conformation resulting from prenylation can have effects such as slowing down metabolism.[1] One such prenylated flavonoids, uralenol (1), which was first isolated from the leaves of Glycyrrhiza uralensis Fisch by Wang et al.,[1h] displays many types of biological activity[2] (Scheme [1]).

In this paper, we report the first synthesis of uralenol. The key step was based on our recently reported procedure,[3] palladium-catalyzed 1,1-dimethylallylation (Kaiho’s method,[4] step A) at O-4′ on the B ring, followed by prenylation at C-5′ via Claisen rearrangement in acetic anhydride[5] (step B). Although it was difficult to prepare an appropriate synthetic intermediate for uralenol as a single isomer due to the low energy gap for acetyl migration between the 3′- and 4′-positions, a combination of palladium-catalyzed O-dimethylallylation and acetyl migration predominantly afforded the desired synthetic intermediate for uralenol.

The synthetic strategy was as follows. Compound 4, whose hydroxyl groups were protected except the one at 4′-position, is an important precursor. Once 4 can be prepared, our procedure for obtaining 2 from 4 via 3 is easily applicable to the introduction of a prenyl group at C-5′. Therefore, the most reactive acetyl group at C-7, the para-position of carbonyl functionality of the peracetylquercetin (5) can be deprotected, after which the resulting hydroxyl group is reprotected with an orthogonal protecting group to afford the compound such as 7 (Scheme [2]). Because of a dipole moment interaction with the neighboring carbonyl group, deprotection of the acetyl groups at C-3 and C-5 proceeds more slowly than at the other acetyl groups. Accordingly, the key step is the discrimination of deprotection between the 4′- and 3′-acetyl group. Unfortunately, no appropriate method of discrimination was available[6] at the beginning of this synthetic study. However, we were ultimately successful in this regard by virtue of careful observation.

Synthesis was carried out as illustrated in Scheme [2]. First, commercially available quercetin was acetylated to afford the peracetylated derivative 5, which was transformed to mono-deacetylated compound 6 in 84% yield via a known procedure.[7] Treatment of 6 with chloromethyl methyl ether afforded 7 in 95% yield.

Next, the conversion of 7 into 8a was examined using thiophenol with imidazole in N-methylpyrrolidone (NMP) by reference to a previous paper[8] to afford a mixture of 8a and 8b (ca. 76:24) in 92% combined yield without deacetylation at either the 3- or 5-position. The mixture of 8a and 8b [9] was treated with the carbonate 9 in the presence of a catalytic amount of tetrakis(triphenylphosphine)palladium to afford a mixture of 10a and 10b in reproducibly 92% yield. However, the molar ratio of 10a and 10b was irreproducible (approximately 70–80:30–20). It was concluded that the reason for this irreproducibility was the low-energy-gap equilibrium between 8a and 8b via 1,2-acetyl migration, although it is well known that the palladium-catalyzed reactions with carbonates, similar to that in step A, proceed under essentially neutral conditions.

We eventually noticed that the irreproducibility was due to the presence of trace amounts of residual imidazole, which had been used in the previous step. Therefore, we examined the reaction in the presence of 0.01 equivalent of various additives (Table [1]).

Zoom Image
Scheme 1

Table 1 Molar Ratio of 10a and 10b after Pd-Catalyzed O-Dimethylallylation from a Mixture of 8a and 8b (76:24) with Additives (0.01 equiv)

Entry

Additive

Molar ratio of 10a and 10b

1

–

71:29

2

DMAP

–

3

2,6-lutidine

–

4

p-TsOH·H2O

79:21

5

pyridine

87:13

6

i-Pr2NEt

84:17

As shown in entry 1, 10a and 10b were reproducibly obtained with a molar ratio of 71:29 when the imidazole was exhaustively removed.[10] When either 2,6-lutidine or 4-(dimethylamino)pyridine (DMAP) was used, the palladium-catalyzed reaction was disrupted (Table [1], entries 2 and 3). In the presence of 4-toluenesulfonic acid monohydrate (p-TsOH·H2O), the resulting molar ratio of 10a and 10b was 79:21 (entry 4). The most suitable ratio for the synthesis of uralenol was achieved using pyridine (entry 5) and diisopropylethylamine (i-Pr2NEt) (entry 6). Because of the chemical yield, we chose pyridine as the most appropriate base, obtaining a mixture of 10a and 10b with a molar ratio of 87:13 in 92% yield. After a single recrystallization, pure 10a was isolated in 79% overall yield from a mixture of 8a and 8b.

Claisen rearrangement of purified 10a smoothly proceeded in acetic anhydride[3] to afford the desired 5′-prenylated product 11 in 95% isolated yield. Finally, the methoxymethyl group was deprotected using carbon tetrabromide in isopropyl alcohol,[11] followed by deprotection of the other four acetyl groups by ammonium acetate to give uralenol (1) in 96% overall yield from 11.

In conclusion, the first synthesis of uralenol (1) was accomplished in 8 steps and in 53% overall yield from quercetin. It is noted that even the mild palladium-catalyzed reaction with carbonates under essentially neutral conditions could not prevent the 1,2-acetyl migration between the ortho-phenolic groups. However, this disadvantage was finally utilized to increase the selectivity and overall chemical yield of the reaction via the newly examined concerted acetyl migration and palladium-catalyzed O-1,1-dimethylallylation using an amine purposely added as a base.

Zoom Image
Scheme 2

Melting points were obtained on a Yanagimoto-model 20 melting point apparatus and were uncorrected. IR spectra were recorded on a Jasco FT-IR 6200 spectrophotometer. 1H NMR spectra were recorded in CDCl3 or CD3OD and referenced to TMS using Jeol JNM-AL 300 (300 MHz), Jeol JNM-AL 400 (400 MHz), or Bruker AV400N (400 MHz) spectrometers. 13C NMR were recorded in CDCl3 or acetone-d 6 and referenced to CDCl3 (δ = 77.0) or CD3OD (δ = 49.9) using a Jeol JNM-AL 300 (75 MHz) spectrometer. Column chromatography was performed on silica gel (Kanto Kagaku N-60). TLC was performed on precoated plates (0.25 mm, silica gel Merck Kieselgel 60F254). All reactions were performed in oven-dried glassware under positive pressure of argon, unless otherwise noted. Reaction mixtures were stirred magnetically. MeOH was distilled over Mg. NMP was distilled over CaH2. Anhydrous THF and Ac2O were purchased from Wako Chemicals Co. Inc.


#

4-[3,5-Diacetoxy-7-(methoxymethoxy)-4-oxo-4H-chromen-2-yl]-1,2-phenylene Diacetate (7)

To a solution of tetraacetylated quercetin 6 [6] (10.0 g, 21.3 mmol, 1.00 equiv) and i-Pr2NEt (5.6 mL, 31.9 mmol, 1.50 equiv) in acetone (85 mL, 0.25 M) was added chloromethyl methyl ether (1.9 mL, 25.5 mmol, 1.2 equiv) at 0 °C, and the mixture was stirred for 2 h at r.t. The resulting mixture was diluted with EtOAc (1.0 L), and the EtOAc layer was washed with aq 1 M HCl (300 mL) and brine (300 mL). The organic phase was dried (Na2SO4) and concentrated in vacuo. The residue was recrystallized from EtOAc–hexane (2:1) to give 7 as a white powder; yield: 10.4 g (20.2 mmol, 95%); mp 173–174 °C.

FT-IR (KBr): 3503, 2943, 1773, 1636, 1506, 1442, 1372, 1264, 1201, 1083, 1023, 936, 871, 847, 814, 793, 676, 601, 552, 498, 468 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.73 (dd, J = 8.4, 2.0 Hz, 1 H), 7.69 (d, J = 2.0 Hz, 1 H), 7.34 (d, J = 8.4 Hz, 1 H), 7.06 (d, J = 2.4 Hz, 1 H), 6.74 (d, J = 2.4 Hz, 1 H), 5.26 (s, 2 H), 3.50 (s, 3 H), 2.43 (s, 3 H), 2.34 (s, 9 H).

13C NMR (75 MHz, CDCl3): δ = 170.1 (C), 169.5 (C), 168.0 (C), 167.8 (C), 167.7 (C), 161.4 (C), 157.8 (C), 153.2 (C), 150.6 (C), 144.2 (C), 142.1 (C), 133.8 (C), 128.0 (C), 126.4 (CH), 123.8 (CH), 123.7 (CH), 111.7 (C), 109.9 (CH), 101.5 (CH), 94.5 (CH2), 56.5 (CH3), 21.1 (CH3), 20.7 (2 × CH3), 20.5 (CH3).


#

2-(3-Acetoxy-4-hydroxyphenyl)-7-(methoxymethoxy)-4-oxo-4H-chromene-3,5-diyl Diacetate (8a)/2-(4-Acetoxy-3-hydroxyphenyl)-7-(methoxymethoxy)-4-oxo-4H-chromene-3,5-diyl Diacetate (8b)

To a suspension of 7 (10.0 g, 19.4 mmol, 1.00 equiv) in NMP (40 mL, 0.50 M) were added imidazole (0.528 g, 7.76 mmol, 0.400 equiv) and thiophenol (2.8 mL, 27.2 mmol, 1.40 equiv) at –20 °C, and the mixture was stirred for 20 h at the same temperature. The resulting mixture was diluted with EtOAc (1.0 L) and washed with aq 1 M HCl (0.50 L), H2O (0.50 L), and brine (0.50 L). The organic phase was dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chlomatography (silica gel, hexane–EtOAc, 2:3) to give a mixture of 8a and 8b (8.43 g, 17.8 mmol, 92%, 76:24) as a pale yellow amorphous powder. Although pure 8a was obtained by recrystallization of the mixture of 8a and 8b, it was difficult to record the spectral data of 8a because 8a was converted into a mixture of 8a and 8b within a short time. Only 1H NMR was available.

1H NMR (400 MHz, CDCl3): δ = 7.59–7.55 (m, 2 H), 7.00 (d, J = 3.2 Hz, 1 H), 6.97 (d, J = 11.2 Hz, 1 H), 6.72 (d, J = 3.2 Hz, 1 H), 6.50 (s, phenolic OH, 1 H), 5.27 (s, 2 H), 3.51 (s, 3 H), 2.44 (s, 3 H), 2.35 (s, 3 H), 2.33 (s, 3 H).


#

2-{3-Acetoxy-4-[(2-methylbut-3-en-2-yl)oxy]phenyl}-7-(meth­oxymethoxy)-4-oxo-4H-chromene-3,5-diyl Diacetate (10a)

To a solution of 8a/8b (8.00 g, 16.9 mmol, 1.00 equiv) in THF (170 mL, 0.10 M) were added pyridine (14 mL, 0.169 mmol, 0.01 equiv), the mixed carbonate 9 (90 wt%, 10.5 g, 50.7 mmol, 3.00 equiv), and Pd(PPh3)4 (0.976 g, 0.845 mmol, 0.05 equiv) at 0–5 °C, and the mixture was stirred for 20 h at the same temperature. The resulting mixture was filtered through a Celite pad, and the residue was then washed with EtOAc (3 × 100 mL). The combined eluents were concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane–EtOAc, 1:1) to give a mixture of 10a and 10b (8.40 g, 15.5 mmol, 92%, 10a/10b = 87:13) as a pale yellow amorphous powder. The mixture was recrystallized from EtOAc–hexane (1:1) to give the single isomer 10a as a white powder; yield: 7.22 g (13.4 mmol, 79% from 8a/8b); mp 124–125 °C.

FT-IR (KBr): 3446, 2987, 1773, 1633, 1506, 1434, 1365, 1286, 1203, 1076, 1021, 948, 858, 793, 697, 600 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.60 (dd, J = 8.8, 2.0 Hz, 1 H), 7.54 (d, J = 2.0 Hz, 1 H), 7.22 (d, J = 8.8 Hz, 1 H), 7.05 (d, J = 2.4 Hz, 1 H), 6.72 (d, J = 2.4 Hz, 1 H), 6.13 (dd, J = 17.6, 10.8 Hz, 1 H), 5.27 (d, J = 17.6 Hz, 1 H), 5.26 (s, 2 H), 5.22 (d, J = 10.8 Hz, 1 H), 3.50 (s, 3 H), 2.43 (s, 3 H), 2.34 (s, 3 H), 2.33 (s, 3 H), 1.52 (s, 6 H).

13C NMR (75 MHz, CDCl3): δ = 170.3 (C), 169.7 (C), 168.7 (C), 168.1 (C), 161.3 (C), 157.9 (C), 154.0 (C), 150.8 (C), 150.7 (C), 143.4 (CH), 142.4 (C), 133.3 (C), 126.3 (CH), 122.8 (CH), 122.6 (C), 119.5 (CH), 114.4 (CH2), 111.7 (C), 109.7 (CH), 101.5 (CH), 94.5 (CH2), 81.6 (C), 56.4 (CH3), 26.9 (2 × CH3), 21.0 (CH3), 20.5 (2 × CH3).


#

2-[3,4-Diacetoxy-5-(3-methylbut-2-enyl)phenyl]-7-(methoxymethoxy)-4-oxo-4H-chromene-3,5-diyl Diacetate (11)

A solution of 10a (7.00 g, 13.0 mmol, 1.00 equiv) in Ac2O (130 mL, 0.10 M) and pyridine (3.2 mL, 39.0 mmol, 3.00 equiv) was heated to 120–130 °C and stirred for 5 h at the same temperature. After cooling to r.t., the resulting mixture was concentrated in vacuo. The residue was recrystallized from EtOAc and hexane (2:1) to give 11 as a white powder; yield: 7.19 g (12.4 mmol, 95%); mp 152–154 °C).

FT-IR (KBr): 3503, 2913, 1771, 1621, 1488, 1443, 1372, 1290, 1178, 1079, 1012, 950, 842, 788, 680, 604, 521, 472 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.57 (d, J = 2.0 Hz, 1 H), 7.53 (d, J = 2.0 Hz, 1 H), 7.05 (d, J = 2.4 Hz, 1 H), 6.73 (d, J = 2.4 Hz, 1 H), 5.27 (s, 1 H), 5.20–5.25 (m, 1 H), 3.51 (s, 1 H), 3.31 (d, J = 6.8 Hz, 2 H), 2.43 (s, 3 H), 2.34 (s, 3 H), 2.31 (s, 6 H), 1.77 (s, 3 H), 1.71 (s, 3 H).

13C NMR (75 MHz, CDCl3): δ = 170.4 (C), 169.8 (C), 168.3 (2 × C), 168.0 (C), 161.6 (C), 158.1 (C), 153.9 (C), 150.9 (C), 143.0 (C), 142.8 (C), 136.6 (C), 134.9 (C), 134.0 (CH), 127.9 (C), 127.2 (CH), 121.5 (CH), 120.5 (CH), 112.0 (C), 110.0 (CH), 101.8 (CH), 94.7 (CH2), 56.6 (CH3), 28.8 (CH2), 25.8 (CH3), 21.2 (CH3), 20.8 (CH3), 20.5 (CH3), 20.4 (CH3), 17.9 (CH3).


#

Urarenol (1)

To a suspension of 11 (7.00 g, 12.0 mmol, 1.00 equiv) in i-PrOH (120 mL, 0.10 M) was added CBr4 (0.199 g, 0.60 mmol, 0.05 equiv) at r.t. and the mixture was stirred for 5 h at reflux. After cooling to r.t., NH4OAc (9.25 g, 120 mmol, 10.0 equiv) was added to the resulting solution and the mixture was stirred for 5 h at 60 °C. After cooling to r.t., the mixture was concentrated in vacuo, and the residue was recrystallized from MeOH–H2O (85:15) to give 1 as pale yellow needles; yield: 4.27 g (11.5 mmol, 96%); mp 176–178 °C.

FT-IR (KBr): 3462, 1734, 1653, 1559, 1522, 1457, 1339, 1161 cm–1.

1H NMR (400 MHz, CD3OD): δ = 7.61 (d, J = 2.0 Hz, 1 H), 7.55 (d, J = 2.0 Hz, 1 H), 6.36 (d, J = 2.0 Hz, 1 H), 6.18 (d, J = 2.0 Hz, 1 H), 5.34–5.39 (m, 1 H), 3.37 (d, J = 7.6 Hz, 2 H), 1.76 (s, 6 H).

13C NMR (75 MHz, CD3OD): δ = 177.5 (C), 165.7 (C), 162.7 (C), 158.4 (C), 148.5 (C), 146.9 (C), 145.9 (C), 137.3 (C), 133.4 (C), 129.6 (CH), 123.9 (C), 123.3 (C), 122.1 (CH), 113.5 (CH), 104.6 (CH), 99.3 (CH), 94.4 (CH), 29.3 (CH2), 25.9 (CH3), 17.9 (CH3).


#
#

Acknowledgment

This work was supported by the Program for Promotion of Basic and Applied Researches for Innovations in Bio-oriented Industry (Japan).

Supporting Information

    for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/ejournals/toc/synthesis.
  • Supporting Information

  • References

  • 3 Kawamura T, Hayashi M, Mukai R, Terao J, Nemoto H. Synthesis 2012; 44: 1308
    Thieme ConnectSearch in Google Scholar
    • 4a Kaiho T, Miyamoto M, Nobori T, Katakami T. Yuki Gosei Kagaku Kyokaishi 2004; 62: 27
      CrossrefSearch in Google Scholar
    • 4b Kaiho T, Yokoyama T, Mori H, Fujiwara J, Nobori T, Odaka H, Kamiya J, Maruyama M, Sugawara T. Japanese Patent JP 06-128238, 1994 ; Chem. Abstr. 1995, 123, 55900.
  • 5 When acetic anhydride was used as the solvent, the chemical yield and chemoselectivity of Claisen rearrangement were dramatically improved; see ref. 3.
  • 6 Differentiation of C-4′ from C-3′ with migratory group such as acetyl group has not been reported prior to our result reported herein. In contrast, selective O-methylation of C-4′ of quercetin via six steps was reported: Li N.-G, Shi Z.-H, Tang Y.-P, Yang J.-P, Duan J.-A. Beilstein J. Org. Chem. 2009; 5: No. 60
    PubMedSearch in Google Scholar
  • 8 Peng W, Li Y, Zhu C, Han X, Yu B. Carbohydr. Res. 2005; 340: 1682
    CrossrefPubMedSearch in Google Scholar
  • 9 In fact, pure 8a was isolated from a mixture of 8a and 8b by recrystallization. Unfortunately, however, the purified 8a reverted to a mixture of 8a and 8b after a short time. Furthermore, even when Pd-catalyzed O-dimethylallylation was carried out immediately after isolation of pure 8a, a mixture of 10a and 10b was obtained. Incidentally, isomerization from 8b to 8a was also observed during recrystallization, because recrystallization of a mixture of 8a and 8b (76:24) afforded pure 8a in 84% (which is greater than 76%) yield. Accordingly, the best purification point in the synthesis of uralenol was after obtaining a mixture of 10a and 10b because 10 has no phenolic proton.
  • 10 Pd-catalyzed O-dimethylallylation at the 7-position of tetraacetylated quercetin was reported in our recent paper (see, ref. 3). During the reaction, no acetyl migration was detected probably because the phenolic hydroxide was not located at the ortho-position of any of the acetoxy groups in the starting materials.
  • 11 Shinozuka T, Yamamoto Y, Hasegawa T, Saito K, Naito S. Tetrahedron Lett. 2008; 49: 1619
    CrossrefSearch in Google Scholar

  • References

  • 3 Kawamura T, Hayashi M, Mukai R, Terao J, Nemoto H. Synthesis 2012; 44: 1308
    Thieme ConnectSearch in Google Scholar
    • 4a Kaiho T, Miyamoto M, Nobori T, Katakami T. Yuki Gosei Kagaku Kyokaishi 2004; 62: 27
      CrossrefSearch in Google Scholar
    • 4b Kaiho T, Yokoyama T, Mori H, Fujiwara J, Nobori T, Odaka H, Kamiya J, Maruyama M, Sugawara T. Japanese Patent JP 06-128238, 1994 ; Chem. Abstr. 1995, 123, 55900.
  • 5 When acetic anhydride was used as the solvent, the chemical yield and chemoselectivity of Claisen rearrangement were dramatically improved; see ref. 3.
  • 6 Differentiation of C-4′ from C-3′ with migratory group such as acetyl group has not been reported prior to our result reported herein. In contrast, selective O-methylation of C-4′ of quercetin via six steps was reported: Li N.-G, Shi Z.-H, Tang Y.-P, Yang J.-P, Duan J.-A. Beilstein J. Org. Chem. 2009; 5: No. 60
    PubMedSearch in Google Scholar
  • 8 Peng W, Li Y, Zhu C, Han X, Yu B. Carbohydr. Res. 2005; 340: 1682
    CrossrefPubMedSearch in Google Scholar
  • 9 In fact, pure 8a was isolated from a mixture of 8a and 8b by recrystallization. Unfortunately, however, the purified 8a reverted to a mixture of 8a and 8b after a short time. Furthermore, even when Pd-catalyzed O-dimethylallylation was carried out immediately after isolation of pure 8a, a mixture of 10a and 10b was obtained. Incidentally, isomerization from 8b to 8a was also observed during recrystallization, because recrystallization of a mixture of 8a and 8b (76:24) afforded pure 8a in 84% (which is greater than 76%) yield. Accordingly, the best purification point in the synthesis of uralenol was after obtaining a mixture of 10a and 10b because 10 has no phenolic proton.
  • 10 Pd-catalyzed O-dimethylallylation at the 7-position of tetraacetylated quercetin was reported in our recent paper (see, ref. 3). During the reaction, no acetyl migration was detected probably because the phenolic hydroxide was not located at the ortho-position of any of the acetoxy groups in the starting materials.
  • 11 Shinozuka T, Yamamoto Y, Hasegawa T, Saito K, Naito S. Tetrahedron Lett. 2008; 49: 1619
    CrossrefSearch in Google Scholar

   Permissions and Reprints All articles of this category
Zoom Image
Scheme 1
Zoom Image
Scheme 2