Oxidation of 3,5-di-C-(per-O-acetylglucopyranosyl)phloroacetophenone in the synthesis of hydroxysafflor yellow A

Accepted Manuscript Oxidation of 3,5-di-C-(per-O-acetylglucopyranosyl)phloroacetophenone in the synthesis of hydroxysafflor yellow A Toshiyuki Suzuki, Mitsuo Ishida, Toshihiro Kumazawa, Shingo Sato PII:

S0008-6215(17)30327-0

DOI:

10.1016/j.carres.2017.05.009

Reference:

CAR 7383

To appear in:

Carbohydrate Research

Received Date: 29 April 2017 Revised Date:

12 May 2017

Accepted Date: 12 May 2017

Please cite this article as: T. Suzuki, M. Ishida, T. Kumazawa, S. Sato, Oxidation of 3,5-di-C-(per-Oacetylglucopyranosyl)phloroacetophenone in the synthesis of hydroxysafflor yellow A, Carbohydrate Research (2017), doi: 10.1016/j.carres.2017.05.009. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Graphical Abstracts

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Oxidation

of

3,5-di-C-(per-O-acetylglucopyranosyl)phloroacetophenone

in

the

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synthesis of hydroxysafflor yellow A Toshiyuki Suzuki, Mitsuo Ishida, Toshihiro Kumazawa, Shingo Sato*

Graduate School of Science and Engineering, Yamagata University, Jonan 4-3-16,

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Yonezawa-shi, Yamagata 992-8510, Japan

that

is

present

in

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Abstract: In the synthesis of the main yellow pigment hydroxysafflor yellow A (HSYA), safflower

petals,

the

key

compound

4-(S)-2-acetyl-4,6-di-C-(per-O-acetyl-β-D-glucosyl)-3,4-dihydroxy-5-methoxycyclohex a-2,5-dienone (11b) was diastereoselectively synthesized in an overall yield of 18 %

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from di-C-β-D-glucosylphloroacetophenone per-O-acetate (8).

Keywords: safflower petal; hydroxysafflor yellow A; C-glycosylquinochalcone;

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intramolecular condensation; oxidation; diastereoselectivity

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1. Introduction

Safflomin A is one of the main yellow components of the petals of the safflower

plant and was first isolated and structurally characterized as 1 by our group in 1981 (Fig. 1).1 In 1982, Takahashi et al.2 proposed structure 2 for this compound and named it safflor yellow A. A decade later, Meselhy and coworkers performed a detailed NMR analysis and proposed structure 3 and called it hydroxysafflor yellow A (HSYA).3−8 In 1997, Goda et al. performed detailed HPLC and NMR analyses and concluded that the -1-

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structure of safflomin A was not 1 but instead 3.9 Furthermore, it has been found that the yellow and red pigments present in safflower petals all have the C-glycosyl quinochalcone structure in common.5,7,8 The other C-glycoside in the yellow component (3)

is

present

between

the

1,3-diketone

on

the

A-ring

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HSYA

of

C-glycosylquinochalcone. It has been previously reported10 that this glycoside is unstable and the hydroxyl group at position 2 of the glycoside readily undergoes

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condensation with the neighboring enol. This reaction is followed by the opening of the pyranose ring due to the strain effect and subsequently, recyclization takes place to form oxofuro[3,2-d]benzofuran

ring.11

Recently,

the

spiro

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the

derivatives

of

3,

saffloquinosides A (4), and C (5) have been isolated from safflower petals and their structures have been determined by Jiang et al.12 The abovementioned compound safflor

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yellow A (2) is also a oxopyrano[3,2-b]benzofuran derivative of 3.

Fig. 1.

Results and Discussion

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2.

For the total synthesis of the main yellow component in safflower petals, HSYA (3,

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safflomin A), a retrosynthetic strategy was developed by taking into consideration the aforementioned changes in its structure. Therefore, it was expected that the oxidation of di-C-glucosylphloroacetophenone (7)13 would result in the formation of the key compound di-C-glycosylquinol (6), which could be directly transformed into 3, as illustrated in Scheme 1.

Scheme 1. -2-

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The condensation-recyclization step could be prevented after oxidation by transforming the di-C-glycoside 7 into di-C-(per-O-acetylglucosyl)phloroacetophenone

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(9). Selective de-O-acetylation of the three phenolic acetyl groups of per-O-acetate of 7 (8) was achieved by treatment with BF3·2AcOH at room temperature (r.t.) for 5 h to give the desired compound 9 in 83% yield.14 The phenolic hydroxyl-free glycoside 9

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was then subjected to oxidation to obtain the desired quinol 10.

The oxidation of the model compound, 3,5-dimethylphloroacetophenone, gives

the

desired

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reportedly

compound

2-acetyl-3,4,5-trihydroxy-4,6-dimethyl-2,5-cyclohexadienone in either 50% yield when oxidized under air in the presence of pyridine (1.0 equiv.) with MeOH solvent at r.t. or 60%

yield

using

lead(II)

acetate

in

MeOH.15−17

Air-oxidation

of

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3-methyl-5-C-β-D-glucopyranosylphloroacetophenone did not take place in the presence of lead(II) acetate, but could be carried out in the presence of 2 equiv. of pyridine. However, the desired oxidized product underwent intramolecular condensation to give

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the oxofuro[3,2-b]benzofuran derivatives in 20% yield.10 Since the oxidation of 9 with O2 under the aforementioned conditions did not take place, the amount of pyridine

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added was gradually increased. After optimization of the amount of pyridine (11 equiv.), the desired oxidized product 10 could be obtained with a maximum yield of 52% (10a:10b = 1:3.35) by vigorously stirring the reaction mixture in MeOH at r.t. for 25 h. Owing to the instability of 10 under such basic conditions, the enol form of 10 was protected as a methyl enol ether for the next aldol reaction. Therefore, a solution of diazomethane in ether was added dropwise at 0 °C to both 10a and 10b in ethyl acetate in order to obtain the stable methyl ethers 11a and 11b in 60% and 54% yields, -3-

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respectively.

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Scheme 2.

The circular dichroism spectra of 11a and 11b were both symmetric (Fig. S11). It was observed that 11a showed a positive Cotton effect at 268 and 298 nm and a

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negative Cotton effect at 353 nm, while 11b displayed a negative Cotton effect at 264 and 299 nm and a positive Cotton effect at 366 nm. Based on these observations, it

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could be concluded that the chiral carbon at position 4 of 11a had R configuration while that in 11b could be assigned the S configuration when compared with the previously reported data.10,12,18,19 Although diastereoselectivity could not be observed in the oxidation of 3-C-β-D-glucopyranosyl-5-methylphloroacetophenone (R:S = 1.6:1),10 in

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this work the selectivity toward the S configuration in the product was overridden and a

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maximum diastereomeric excess of 64% could be achieved in the oxidation of 9.

Table 1.

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As summarized in Table 1 (runs 1−3), there was no change in the overall yield

when the oxidation of 9 was carried out under air instead of O2, although the diastereomeric ratio was reversed. Addition of 0.1 equiv. of CuCl or CuI increased the rate of the reaction which was finished after 5 h. The diastereomeric ratio in these reactions increased in favor of the desired compound 10b until a maximum amount was reached, that of 4.56 times the amount of 10a (runs 4−6, 8). Due to the instability of 10, longer reaction times resulted in its conversion to more polar compounds and thus lower -4-

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yields (runs 2 and 9). In conclusion, the key compound in the total synthesis of HSYA 3 is 4-(S)-2-acetyl-4,5-dihydroxy-4,6-di-C-β-D-glucosyl-3-methoxycyclohexa-2,5-dienone

di-C-glucosylphloroacetophenone per-O-acetate (8).

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3. Experimental

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(11b) and it was synthesized diastereoselectively in an overall yield of 18% from

3.1 General

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All solvents used in this work are commercially available. The reaction progress was monitored by thin layer chromatography (TLC) on 0.25 mm silica gel F254 plates (E. Merck, Japan). UV light (λ = 254 and 365 nm), 5% ferric chloride solution in ethanol, and 7% phosphomolybdic acid solution in ethanol with application of heat were

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used as TLC coloring agents. The separation and purification of the reaction products was performed by flash column chromatography on silica gel 60 (40−50 µm, Kanto Reagents Co. Ltd., Japan). Melting points were determined using an ASONE

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micro-melting point apparatus and are uncorrected. IR spectra were recorded on a Horiba FT-720 IR spectrometer using a KBr disk and the NMR spectra were recorded

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on the Varian Inova 500 and JEOL ECX-500 spectrometers using Me4Si as the internal standard. Circular dichroism (CD) spectra were recorded on a JASCO J-720WI spectropolarimeter, while high-resolution mass spectra (HRMS) were obtained under electrospray ionization (ESI) conditions on a JEOL JMS-T100LP spectrometer.

3.2 2,4,6-Tri-O-acetyl-3,5-di-C-(2',3',4',6'-tetra-O-acetyl-β-D-glucopyranosyl)phloroace -5-

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tophenone (8) Colorless prism (EtOH). [α]D24 -23.8 (c1.02, CHCl3); mp 138 oC; IR v 3380, 2944, 1756, 1619, 1369, 1228, 1151, 1041 cm-1; 1H NMR (CDCl3 at 50 oC) δ 2.67 (s, 3H, Ac),

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1.90, 1.99, 2.05, 2.13 (each s, 6H, OAc x 8), 3.89 (dt 1H, J 9.4, 2.8, 3.0 Hz, H-5), 4.16 (dd, 1H, J 2.1, 12.6 Hz, H-6’a), 4.32 (dd, 1H, J 3.4, 12.8 Hz, H-6’b), 5.22 (d, 1H, J 9.4 Hz, H-1’), 5.26 (t, 1H, J 9.4 Hz, H-4’), 5.3 (br.m, 1H, H-2’), 5.36 (t, 1H, J 9.4 Hz, H-3’),

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8.24, 8.47, 14.3 (each s, 1H, OH x 3). 13C NMR (CDCl3, at 50 oC) δ (sugar moiety) 61.5, 65, 68, 70.1, 73.8, 76, (phloroacetophenone moiety) 101.1, 105.6, 160.2, 169.4, 169.9,

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170.3 (benzene ring) 204.3, 33.1 (ArAc), 169.3 (br.), 169.4, 170.0, 170.4 (each C x 2, OAc x 8). HRESIMS m/z Calcd for C42H50NaO25 [M+Na]+: 977.2539; Found: 977.2523.

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3.3

2-Acetyl-4,6-di-C-(2',3',4',6'-tetra-O-acetyl-β-D-glucopyranosyl)-3,4,5-tri-hydroxy2,5-cyclohexadienone (9)14

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Per-O-acetate 8 (100 mg) was dissolved in 40% BF3·2AcOH (4.2 mL) and the

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solution was stirred at r.t. for 5 h. Subsequently, 100 mL of ice-cold water was added to the reaction mixture, which was extracted three times using ethyl acetate. The organic layer was washed four times with water/brine (5:1) and finally with brine. The organic extract was dried over anhydrous Na2SO4

and filtered. The residue obtained after

evaporating the organic solvent was purified by silica-gel column chromatography using a mixture of hexane and ethyl acetate (2:3) to obtain 9 (72 mg, 83%), which was recrystallized with ether to give colorless prisms. 3.4 -6-

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2-Acetyl-4,6-di-C-[2',3',4',6'-tetra-O-acetyl-β-D-glucopyranosyl]-3,4,5-tri-hydroxy -2,5-cyclohexadienone (10) Pyridine (1.677 mL, 20.74 mmol) was added to a solution of 9 (1.561 g, 1.885

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mmol) in MeOH (20 mL) and the mixture was vigorously stirred at r.t. under O2 atmosphere (balloon) for 24 h. After removing the solvents from the reaction mixture under reduced pressure, the residue was purified by silica-gel column chromatography

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using the solvent mixture of toluene, ethyl acetate, and acetic acid in proportions of

(636 mg, 40.0%), respectively.

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6:1:0.2 and 5:2:0.5 to give both the quinol diastereomers 10a (191 mg, 12.0%) and 10b

10a: colorless prism; [α]D25 -36.0 (c 0.500, CHCl3); mp 106-109 oC; Rf 0.36 (toluene/EtOAc/AcOH = 6:3:1); IR (KBr)ν 3475, 2952, 1754, 1369, 1232, 1103, 1035 cm-1; 1H NMR (CDCl3, 50 oC) δ 2.02, 2.03, 2.04, 2.05, and 2.09 s, (OAc x 8), 2.52 (3H,

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s, Ac), 3.60 (t, 1H, J 9.6 Hz, H-4), 3.70 (m, 1H, H-5), 3.95 (m, 1H, H-5’), 4.06 (br.d, 1H, J 9.2 Hz, H-1’), 4.18 (m, 1H, H-6’a), 4.21 (m, 1H, H-6b), 4.28 (dd, 1H, J 5.1 and 12.2 Hz, H-6b), 4.30 (br.d, 1H, J 12.2 Hz, H-6’b), 4.81 (d, 1H, J 9.8 Hz, H-1), 5.09 (t, 1H, J

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9.2 Hz, H-3’), 5.22 (t, 1H, J 9.4 Hz, H-2), 5.27 (t, 1H, J 9.4 Hz, H-2’), 5.31 (t, 1H, J 9.4 (CDCl3, 50 oC)

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Hz, H-3), 5.70 (t, 1H, J 9.4 Hz, H-2), 18.5 (br. s, 1H, OH). 13C NMR

δ 25.10, 62.18, 62.30, 68.14, 68.49, 69.31, 70.03, 71.62, 74.08, 74.64, 76.09, 76.17, 78.72, 80.98, 106.41, 106.91, 175.08, 190.12, 192.88, 195.653, OAc x 8; 169.38, 169.45, 169.61, 170.08 (x2), 170.50, 170.60, 171.38, 20.461, 20.49, 20.54 (x2), 20.59, 20.64, 20.73, 21.03. HRESIMS m/z Calcd for C36H44NaO23 [M+Na]+: 867.2171; Found: 867.2182.

10b: colorless prism; [α]D25 -28.1 (c 0.385, CHCl3); mp 143-146 oC; Rf 0.24 -7-

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(toluene/EtOAc/AcOH = 6:3:1); IR (KBr)ν 3448, 2949, 1751, 1369, 1232, 1103, 1035 cm-1; 1H NMR (CDCl3, 50 oC) δ 1.95, 1.99, 2.02, 2.05, 2.07 (each s, OAc x 8), 2.41 (s, 3H, Ac), 3.62 (m, 1H, H-5’), 3.76 (m, 1H, H-5), 3.90 (br.d, 1H, J 7.3 Hz, H-1’), 4.00

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(br.d, 1H, J 12.4 Hz, H-6’a), 4.17 (br.d, 1H, H-6b), 4.22 (br.d, 1H, H-6a), 4.24 (br.d, 1H, H-6’b), 4.66 (d, 1H, J 9.8 Hz, H-1), 4.99 (t, 1H, J 8.5 Hz, H-4’), 5.09 (br.d, 1H, J 9.4 Hz, H-3’), 5.14 (t, 1H, J 9.8 Hz, H-4), 5.17 (t, 1H, J 9.4 Hz, H-3), 5.27 (t, 1H, J 9.4 Hz,

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H-2’), 5.91 (br.d, 1H, J 9.4 Hz, H-2), 17.9 (br. s, 1H, OH). 13C NMR (CDCl3) δ 26.23, 62.46, 62.65, 68.26, 68.86, 70.47, 72.84, 74.55, 75.41, 76.18, 76.37, 77.26, 81.95, 83.01,

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99.3 (br), 103.48, 174.3, 186.68, 193.31, 195.84, OAc x 8; 169.45 (x2), 169.58 (x2), 169.96 (x2), 170.27 (x2), 20.88, 20.69 (x2), 20.61 (x2), 20.51 (x2), 20.41. HRESIMS m/z Calcd for C36H44NaO23 [M+Na]+: 867.2171; Found: 867.2177.

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3.5

2-Acetyl-4,6-di-C-[2',3',4',6'-tetra-O-acetyl-β-D-glucopyranosyl]-5-methoxy-3,4-dihydroxy-2,5-cyclohexadienone (11)

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Either quinol 10a (225 mg) or 10b (755 mg) was dissolved in ethyl acetate and

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diazomethane ether solution was added dropwise at 0 °C until the reactants could not be observed on TLC. After removing the solvent, the corresponding diazomethane products were separated by silica-gel column chromatography (toluene/EtOAc/AcOH = 5:2:0.5) to give either 11a (117 mg, 60%) or 11b (349 mg, 54%). 11a:

pale-yellow

powder;

[α]D25

-33.5

(c

1.04,

MeOH);

Rf

0.40

(toluene/EtOAc/AcOH=5:2:0.5); IR (KBr): v 3452, 2956, 1751, 1369, 1230, 1099, 1036 cm-1; CD λext (MeOH) nm (∆ε): 353 (-1.6), 298 (+7.5), 268 (+3.3). 1H NMR (CDCl3 at

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50 oC): δ 2.49 (s, 3H, ArAc), 4.30 (s, 3H, OMe), 18.4 (s, 1H, chelated OH), glucose moiety: 3.36 (m, 1H, H-5’), 4.11 (br.d, 1H, H-1’), 4.12-4.25 (m, 2H, H-6’ab), 5.14 (t, 2H, J 9.4 Hz, H-3’ and 4’), 5.38 (t, 1H, J 9.4 Hz, H-2’), glucose moiety: 3.36 (m, 1H,

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H-5”), 4.12-4.25 (br.m, 2H, H-6”ab), 4.74 (br.d, 1H, H-1”), 5.12 (brd, 1H, H-4”), 5.24 (t, 1H, J 9.8 Hz, H-3”), 5.39 (br.s, 1H, H-2”). 13C NMR (CDCl3, *ratio of rotamer = 1: 1):

δ (aglycone moiety): 20.62, 24.54, 82.17, 82.65*, 104.60, 105.28*, 108.17, 111.35*,

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172.73, 173.43*, 188.64, 189.24*, 192.23, 192.87*, 195.57, 196.04*, (glucose moiety): 60.82, 61.09*, 61.66, 61.86*, 62.46, 62.83*, 66.85, 67.16, 67.35*, 67.57, 68.02*, 68.79,

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69.78*, 70.17, 71.24*, 73.66, 73.84*, 74.26, 75.01, 75.41, 75.71*, 81.17, 81.42*, OAc: 19.9~20.35, 168.4~169.1, 169.5~170.2. HRESIMS: m/z Calcd for C37H46NaO23 [M+Na]+: 881.2328. Found: 881.2320.

11b: pale-yellow prism; [α]D25 -91.2 (c 1.07, MeOH); mp 143-146 oC; Rf 0.28

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(toluene/EtOAc/AcOH=5:2:0.5); IR (KBr):ν 3430, 2952, 1751, 1369, 1230, 1099, 1036 cm-1; CD λext (MeOH) nm (∆ε): 366 (+0.7), 299 (-14.9), 264 (-1.7); 1H NMR (CDCl3 at

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50 oC): δ 2.36 (s, 3H, ArAc), 4.41 (s, 3H, OMe), 18.1 (s, 1H, chelated OH), C4-glucose moiety: 3.62 (dt, 1H, J 3.8, 2.1, 11.1 Hz, H-5’), 3.98 (d, 1H, J 4.7 Hz, H-6’a), 4.01 (d,

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1H, J 4.7 Hz, H-6’b), 4.35 (d, 1H, H-1’), 4.93 (t, 1H, J 9.4 Hz, H-4’), 5.09 (br.d, 1H, H-3’), 5.34 (br.d, 1H, H-2’), C6-glucose moiety: 3.71 (dt, 1H, J 3.8,3.4, 13.1 Hz, H-5’), 4.12 (d, 1H, J 3.8 Hz, H-6’a), 4.15 (d, 2H, J 3.0 Hz, H-6’b), 4.62 (br.d, 1H, H-1’), 5.12 (t, 1H, J 9.8 Hz, H- 4’), 5.9 (br.d, 1H, H-2’).

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C NMR (CDCl3): δ (aglycone moiety);

20.80, 24.64, 83.88, 106.72, 117.34, 172.49, 189.12, 192.40, 196.41, (glucose moiety); 61.90, 62.13, 63.72, 67.38, 68.37, 70.53, 72.09, 74.29, 74.43, 75.76, 75.95, 80.45, OAc: 20.47, 20.50, 20.57, 20.62, 20.64, 168.89, 169.22, 169.47, 170.19, 170.30, 170.49.

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HRESIMS: m/z Calcd for C37H46NaO23 [M+Na]+: 881.2328. Found: 881.2306.

Acknowledgement

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The authors wish to thank Professor Bunpei Hatano for HRESIMS measurements and are grateful to Mr. Koya Maeda and Mr. Kota Sasaki for technical assistance.

Appendix A. Supplementary data

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The authors report no conflicts of interest.

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Conflicts of interest

Supplementary data related to this article can be found at…………………..

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References

[1] J. Onodera, H. Obara, M. Osone, Y. Maruyama, S. Sato, Chem. Lett., 1981, 433-436. [2] Y. Takahashi, N. Miyasaka, S. Tasaka, I. Miura, S. Urano, M. Ikura, K. Kikuchi, T.

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Matsumoto, M. Wada, Tetrahedron Lett., 1982, 23, 5163-5166. [3] M.-R., Meselhy, S. Kadota, Y. Momose, M. Hattori, T. Namba, Chem. Pharm. Bull.,

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1992, 40, 3355-3357.

[4] M.-R., Meselhy, S. Kadota, Y. Momose, A. Kusai, M. Hattori, T. Namba, Chem. Pharm. Bull., 1993, 41, 1796-1802. [5] S. Yue, Y. Tang, S. li, J.-A. Duan, Molecules, 2013, 18 15220-15254. [6] Z.-M. Feng, J. He, J.-S. Jiang, Z. Chen, Y.-N. Yang, P.C. Zhang, J. Nat. Prod. 2013, 76, 270-274. [7] S. Yue, Y. Tang, S. Li, J.-A. Duan, Molecules, 2013, 18, 15220-15254. - 10 -

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[8] S. Yue, Y. Tang, C. Xu, S. Li, Y. Zhu, J.-A. Duan, Int. J. Mol. Sci., 2014, 15, 16760-16771. [9] Y. Goda, J. Suzuki, T. Maitani, Jpn. J. Food Chem., 1997, 4, 54-58.

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[10] S. Sato, T. Nojiri, J. Onodera, Carbohydr. Res., 2005, 340, 389-393

[11] S. Sato, M. Miura, T. Sekito, T. Kumazawa, J. Carbohydr. Chem., 2006, 27, 86-102.

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[12] J.-S. Jiang, J. H. Z.-M. Feng, P.-C. Zhang, Org. Lett., 2010, 12, 1196-1199.

[13] S. Sato, T. Akiya, T. Suzuki, J. Onodera, Carbohydr. Res., 2004, 339, 2611-2614.

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[14] T. Kumazawa, M. Ishida, S. Matsuba, S. Sato, and J. Onodera, Carbohydr. Res., 1997, 297, 379-383.

[15] T. W. Champbell, G. M. Coppinger, J. Am. Chem. Soc., 1951, 73, 1849-1850. [16] H. Obara, Y. Machida, S. Namai, J. Onodera, Chem. Lett., 1985, 1393-1394.

65, 452-457.

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[17] S. Sato, H. Obara, J. Onodera, A. Endo, S. Matsuba, Bull. Chem. Soc. Jpn., 1992,

833-834.

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[18] S. Sato, H. Obara, T. Kumazawa, J. Onodera, K. Furuhata, Chem. Lett., 1996,

[19] S. Sato, T. Kumazawa, H. Watanabe, K. Takayanagi, S. Matsuba, J. Onodera, H.

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Obara, K. Furuhata, Chem. Lett., 2001, 1318-1319.

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AcO AcO AcO

OAc OAc OAc

O

O2 / pyridine (11 eq) in MeOH

OH

O AcO H

AcO AcO AcO

OH O

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AcO H HO

OAc OAc

O AcO HO H HO OH * O

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AcO

AcO H

O

O

10a,b

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9

Table 1. Synthesis of 10a and 10b by oxidation of 9. Run Additive (equiv.) Atmosphere Time (h) none

O2

2

none

O2

3

none

10a : 10b

12

46

1 : 1.63

48

41

1 : 1.70

air

12

42

O2

5

30

1 : 1.56

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1

Yield (%)

1.5 : 1

CuCl (0.1)

5

CuCl (0.1)

O2

24

42

1 : 3.0

6

CuCl (1.0)

O2

5

30

1 : 4.56

7

CuCl (1.0)

air

5

43

1 : 1.63

8

CuI (0.1)

O2

5

52

1 : 3.35

9

CuI (0.1)

O2

24

38

1 : 2.03

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Highlights The structure of the main yellow component in safflower petals has been discussed.

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The compound di-C-glycoside HSYA undergoes an intramolecular condensation. A key compound in the synthesis of HSYA is a 4-(S)-di-C-glucosylquinol.

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4-(S)-di-C-glucosylquinol was synthesized via diastereoselective oxidation.

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Configuration of the new stereocenter was determined by circular dichroism.