Chemical and Pharmaceutical Bulletin
Online ISSN : 1347-5223
Print ISSN : 0009-2363
ISSN-L : 0009-2363
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Total Synthesis of (+)-Silybin A
Makoto Inai Hiroto SagaraYoshinori UenoHitoshi OuchiFumihiko YoshimuraTomohiro AsakawaYoshitaka Hamashima Toshiyuki Kan
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2024 年 72 巻 6 号 p. 570-573

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Abstract

We report the first total synthesis of silybin A (1). Key synthetic steps include the construction of the 1,4-benzodioxane neolignan skeleton, a modified Julia–Kocienski olefination reaction between m-nitrophenyltetrazole sulfone (m-NPT sulfone) 10 and aldehyde 21, the formation of the flavanol lignan skeleton 28 via a quinomethide intermediate under acidic conditions, and stepwise oxidation of the benzylic position of flavanol 29.

Introduction

Silybin, the first member of a new family of natural compounds referred to as flavonolignans, was isolated as a secondary metabolite from the seeds of the blessed milk thistle (Silybum marianum) in 1960.1) Natural silybin, a roughly 1 : 1 mixture of silybins A (1) and B (2),212) exhibits diverse bioactivities, including anti-viral (against hepatitis C virus (HCV) and human immunodeficiency virus-type 1 (HIV-1)), hepato-protective, antifibrotic, antioxidant, membrane-stabilizing, anti-cholestatic, anti-atherogenic, anti-inflammatory and anticarcinogenic activities.1319) Structurally, silybins 1 and 2 belong to a class of hybrid natural polyphenols consisting of a flavanonol skeleton and a 7′,8′-trans-configured 1,4-benzodioxane neolignan skeleton. Each fragment features two contiguous stereogenic centers and highly electron-rich aromatic rings. In 2015, Scheidt and colleagues accomplished a total synthesis of a related compound, (−)-isosilybin A (3), via a biomimetic chalcone cyclization reaction.20) In 2022, we reported a total synthesis of (−)-isosilybin B (4), in which the key step was the construction of the flavanol skeleton through the formation of a quinomethide intermediate under acidic conditions.21) To our knowledge, however, total syntheses of silybin A (1) and B (2) have not yet been reported (Fig. 1).

Fig. 1. Structures of Silybins (1 and 2) and Isosilybins (3 and 4)

During our investigation of the synthesis of hybrid natural polyphenols, we established an efficient method for the construction of the enantiomeric (7′R,8′R) and (7′S,8′S)-1,4-benzodioxane frameworks, and applied to total syntheses of princepin and isoprincepin.22) In this paper, we present the first total synthesis of (+)-silybin A (1) using this key methodology.

Results and Discussion

Our retrosynthetic analysis of (+)-silybin A (1) is illustrated in Chart 1. The flavanonol framework would be formed through benzylic oxidation at the C-4 position of flavanol 5 in the final stage of the total synthesis. In our previous synthetic study of hybrid polyphenol and catechin derivatives, we established an efficient method for the construction of a flavanol framework from a diol precursor.2325) We expected that the same approach would be applicable for the synthesis of the flavanol skeleton of 5, in which the benzopyran ring would be formed by an acid-promoted cyclization reaction via the quinomethide intermediate 6. The required diol precursor 7 could be obtained through a reaction sequence consisting of modified Julia–Kocienski olefination reaction between aldehyde 9 and m-nitrophenyltetrazole sulfone (m-NPT sulfone, 10)26,27) and Sharpless dihydroxylation of alkene 8.28) The (7′R,8′R)-1,4-benzodioxane 922) and m-NPT sulfone 1021) would be synthesized according to our reported procedures.

Chart 1. Retrosynthetic Analysis

Our synthesis commenced with the construction of (7′R,8′R)-1,4-benzodioxane neolignan 21 (Chart 2). Mitsunobu reaction between the p-hydroxybenzaldehyde 1129) and protected glycerol 1230) afforded ether 13 in 91% yield. Conversion of 13 to the corresponding pinacol acetal, removal of the TIPS group, and Dess-Martin periodinane (DMP) oxidation provided aldehyde 15. Halogen–lithium exchange reaction of readily available 1631) with t-butyl lithium and subsequent nucleophilic addition to 15 gave benzyl alcohol 17 in 81% yield (dr = 5 : 4). After selective deprotection of the benzyl phenol ether of 17 in the presence of Pd/C in EtOAc under an H2 balloon, the resulting 18 was treated with 10% aqueous HCl at 60 °C.22) Hydrolysis of the MOM ether and pinacol acetal and six-membered ring formation via quinomethide 19 proceeded smoothly in one pot, affording 1,4-benzodioxane 20 with moderate diastereoselectivity (dr = 4 : 1). Epimerization of 20 (dr = 4 : 1) at the C-7′ position with KHCO3 in N,N-dimethylformamide (DMF) proceeded via a putative ring-opening/closing equilibrium to afford the thermodynamically more stable trans-isomer 20 with an excellent diastereomeric ratio (dr=>20 : 1). The phenolic alcohol of 20 (dr=>20 : 1) was protected with a MOM group to afford (7′R,8′R)-1,4-benzodioxane 21 in 82% yield (four steps). The minor isomer was removed during chromatographic purification.

Chart 2. Synthesis of trans-1,4-Benzodioxane 21

With the requisite aldehyde 21 in hand, we next examined olefination reaction to obtain alkene 22. Based on our previous finding that the modified Julia–Kocienski reaction with m-nitrophenyltetrazole sulfone m-NPT sulfone proceeded smoothly to afford the corresponding alkene in good yield with excellent geometric control,21,26,27) we expected that this reaction would also be applicable to the present case. To our delight, upon treatment of a mixture of m-NPT sulfone 10 and aldehyde 21 with lithium bis(trimethylsilyl)amide (LiHMDS) in tetrahydrofuran (THF), the desired alkene 22 was formed in 83% yield with an E/Z ratio of >30 : 1. Next, the phenolic protecting group was switched from a tert-butyldimethylsilyl (TBS) group to a mesyl group, and the resulting alkene 23 was subjected to Sharpless dihydroxylation,28) affording the desired diol 24 in 89% yield as a single diastereomer. Since the TBS ether 22 was insufficiently soluble in the standard aqueous solvent system, we had to perform the Sharpless dihydroxylation after changing the protecting group. The reaction of the corresponding phenol, which was obtained upon treatment of 22 with tetrabutylammonium fluoride (TBAF), did not give the desired diol.

Removal of the mesyl group with LiHMDS,32) followed by treatment with pyridinium p-toluenesulfonate (PPTS) in the presence of triethyl orthoformate in (CH2Cl)2 led to the construction of the benzopyran ring through the ortho ester 26 and the quinomethide intermediate 27. Subsequent methanolysis of the remaining formate of the secondary alcohol under basic conditions furnished flavanol 28 as a single diastereomer in 64% yield (two steps).33) Benzylic oxidation of the TBS-protected 29 with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) was carried out without difficulty and then Iwabuchi oxidation with the combination of nor-AZADO and PhI(OAc)2 gave flavanonol 31.34) Finally, simultaneous deprotection of the MOM and benzyl groups with 10% aqueous HCl in the presence of pentamethylbenzene at 60 °C,35) followed by hydrogenolysis with Pd(OH)2/C, completed the total synthesis of (+)-silybin A (1) in 68% yield (two steps). All spectroscopic data of our synthetic (+)-silybin A (1) were consistent with the literature data9,10) (Chart 3).

Chart 3. Total Synthesis of (+)-Silybin A (1)

Conclusion

We have achieved the first total synthesis of silybin A (1) starting from the known phenol 11 and m-NPT sulfone 10. Several key steps, including modified Julia–Kocienski olefination reaction and Sharpless dihydroxylation, enabled the highly stereocontrolled synthesis. In particular, acid-promoted generation of two types of quinomethide intermediates led to the biomimetic construction of both the 1,4-benzodioxane neolignane and the flavanol lignan core skeletons within 1. Our methodology offers high generality and should be applicable to the syntheses of various structurally related silybins, isosilybins, and other hybrid polyphenols. Further synthetic studies are underway in our laboratory.

This paper is dedicated to the memory of Prof. Toshiyuki Kan, deceased on July 24, 2021.

Acknowledgments

We thank Prof. Mitsuru Kondo (Shizuoka University, Research Institute of Green Science and Technology) for his invaluable support in structural elucidation. This work was financially supported by MEXT/JSPS KAKENHI Grant Numbers: JP17H03973 and JP17K15424, Grants-in-Aid for Scientific Research on Priority Areas JP16H01160 and JP17H06402 from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, and Platform Project for Supporting Drug Discovery and Life Science Research [Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)] from AMED under Grant Number JP19am0101099.

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

This article contains supplementary materials.

Notes

This paper is dedicated to the memory of Prof. Toshiyuki Kan, deceased on July 24, 2021.

References
 
© 2024 Author(s)
Published by The Pharmaceutical Society of Japan

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