Total Synthesis of (±)-Glabridin

Abstract An efficient formal synthesis of (±)-glabridin was accomplished in 10 steps from resorcinol using Raney Ni to reduce carbon–carbon double bonds in α,β-unsaturated carbonyl compound as the key step. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for the following free supplemental resource(s): Full experimental and spectral details.] GRAPHICAL ABSTRACT


INTRODUCTION
In 1970s, glabridin was first isolated as an isoflavan from the root of a Glycyrrhiza glabra licorice. [1] The extract of the root of licorice is a Chinese herbal medicine that is used as demulcents and expectorants to treat allergic inflammation. Glabridin has been identified as responsible for the antioxidative effect and other activities shown in licorice. [2] Additionally, further research showed that glabridin could be used to efficiently inhibit the tyrosinase-dependent melanin biosynthesis, suggesting that it may serve as candidates for skin-lightening agents. [2e] Although it has attracted considerable attention, only two total syntheses of (AE)-glabridin have been reported, and Nahm by Yoo [3] and by Kenichi and Shingo [4] . In this article, we report our synthetic studies toward (AE)-glabridin using the chemoselective reduction of conjugated olefins in a,b-unsaturated carbonyl compound as the key step. The retrosynthetic sequence is represented in Scheme 1.

RESULTS AND DISCUSSION
At first, we obtained 2,4-dimethoxyphenylacetic acid (3) from resorcinol (2) through a four-step reaction as described in the literature. [5][6][7] In the next step, the preparation of the isoflavone 4 was easily achieved on the basis of the reported using BF 3 Á Et 2 O as the catalyst and solvent [8] (Scheme 2).
With available isoflavone 4 in hand, our next task was to reduce both carbonyl group and carbon-carbon double bonds in 4. Initially, isoflavane 5 could be easily obtained in a single step according to Goto et al.'s method [8] in 87% yield. However, when isoflavane 5 was treated with 3-methyl-2-butenal through methods as described in the literature, [3,9] the major product 7 along with a trace amount of the target product 6 was isolated (Scheme 3).
Therefore, a stepwise reduction of 4 had to be conducted. The chemoselective reduction of conjugated olefins in a,b-unsaturated carbonyl compounds have been reported. [10] After screening several reducing reagents (e.g., Pd=C, Raney Ni, InCl 3 =NaBH 4 , Na 2 S 2 O 4 ), Raney Ni in dimethylformamide (DMF) was found to be a good choice for reducing reagent to produce 8 in a 91% yield (Table 1). Compound 8 was then reacted with 3-methyl-2-butenal in the presence of phenylboronic acid to afford 9 and 10 with a 84% yield and a 15:1 ratio. The isomers 9 and 10 could be isolated by column chromatography (Scheme 3).
In conclusion, we have synthesized (AE)-glabridin from the easily available resorcinol in 10 steps with a 14% overall yield. This procedure provide a practical synthesis of (AE)-glabridin. Efforts to complete an asymmetric synthesis of Glabridin are in progress.

EXPERIMENTAL
NMR spectra were in CDCl 3 or CD 3 SOCD 3 ( 1 H at 600 MHz and 13 C at 125 MHz). Column chromatography was performed on silica gel (300-400 mesh). All chemicals were purchased from Sigma Aldrich. Unless otherwise noted, all reagents were obtained commercially and used without further purification. DMF was dried by CaH 2 . Compounds 4 and 5 were prepared as per reported procedures. [5][6][7][8] Synthesis of 7, 9, and 10: General Procedure A solution of 5 or 8 (0.02 mol), aldehyde (0.03 mol), phenylboronic acid (0.024 mol), and glacial HOAc (130 mL) in anhydrous toluene (100 mL) was refluxed for 12 h under N 2 in an apparatus fitted with a Dean-Stark trap. The mixture was cooled and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to give the major product 7 or 9 and 10.  (AE)-Glabridin (1) A solution of boron tribromide (1.0 M in CH 2 Cl 2 , 0.05 mol) was added to a stirred solution of 6 (3.52 g, 0.01 mol) in CH 2 Cl 2 (200 mL) at À78 C. The reaction mixture was further stirred at room temperature for 2 h. Then the mixture was poured into an aqueous solution of saturated NaHCO 3 (100 mL) and extracted with EtOAc (3 Â 100 mL). The combined organic layers were washed with brine (100 mL) and dried (Na 2 SO 4 ). Removal of the solvent in vacuo followed by purification on silica gel provided (AE)-glabridin (1) (2.72 g, 84%). Mp: 227-229 C. Rf 0.41 (100:9 CH 2 Cl 2 -MeOH). 1

SUPPORTING INFORMATION
Full experimental detail and 1 H and 13 C NMR spectra can be found via the Supplementary Content section of this article's Web page.