Total Synthesis of Hydroxy-α- and Hydroxy-β-sanshool Using Suzuki–Miyaura Coupling

Abstract

Here, we describe the first total synthesis of hydroxyl-α-and hydroxyl-β-sanshool, which involves Suzuki-Miyaura coupling (SMC). Hydroxy-α-sanshool (1) was synthesized by SMC of bromoalkyne 4 with boronate 3 followed by (Z)-selective reduction of the triple bond in the coupling product. Hydroxy-β-sanshool (2) was synthesized by regio-and (E)-selective conversion of 4 to iodoalkene 11 followed by SMC with 3.Key words hydroxy-α-sanshool; hydroxyl-β-sanshool; Suzuki-Miyaura coupling; Zanthoxylum Fruit; Daikenchuto Hydroxy-α-sanshool (1) was originally isolated as an unstable unsaturated aliphatic amide from the dried fruit of the Japanese pepper (Zanthoxylum piperitum).1) This compound elicits several biological effects such as activation of transient receptor potential channels 2) and inhibition of potassium channels.3) Hydroxy-β-sanshool (2), which is a geometric isomer of hydroxyl-α-sanshool (1), can also be isolated from the same dried fruit.4) Zanthoxylum Fruit is one of the crude drugs in Kampo formulae 'Daikenchuto.' Moreover, hydroxyl-α-and hydroxyl-β-sanshool were detected in human plasma and urine after oral administration of Daikenchuto.5,6) Consequently, in terms of delineating the mechanism of action of Daikenchuto, hydroxyl-α-and hydroxyl-β-sanshool are considered key compounds. Total synthesis of hydroxyl-α-and hydroxyl-β-sanshool has not been reported. However, a non-selective Wittig reaction has been used for the synthesis of α-and β-sanshool, which both lack a hydroxyl group. 7) In this paper, we describe the E/Z-selective total synthesis of hydroxyl-α-and hydroxyl-β-sanshool using Suzuki-Miyaura coupling (SMC).Our synthetic strategy is depicted in Chart 1. Both hydroxyl-α-sanshool (1) and hydroxyl-β-sanshool (2) could be synthesized from two common component parts: N-methyliminodiacetic acid (MIDA) boronate 3 and amide 4. After SMC between 4 and 3, (Z)-selective reduction of triple-bond in the resulting coupling product would lead to hydroxyl-α-sanshool (1). However, conversion of 4 to (E)-iodoalkene followed by SMC with 3 would afford hydroxyl-β-sanshool (2). Results and DiscussionHydroxy-α-sanshool (1) was convergently synthesized from three commercially available reagents; 1,2-epoxy-2-methylpropane (5), trans-2-bromovinylboronic acid MIDA ester (7) and 4-pentyn-1-ol (8). The amine fragment 6 8) was prepared by addition of dibenzylamine to 5 followed by deprotection of the benzyl group in 100% and 99% yield, respectively (Chart 2). The diene fragment 3 (MIDA boronate) was prepared from 7 and trans-1-propen-1-ylboronic acid by SMC in 77% yield (Chart 3). 9) Swern oxidation of 8 followed by Wittig reaction with methyl (triphenylphosphoranylidene) acetate was performed in a one-pot reaction in 88% yield. [10][11][12] This was followed by hydrolysis of the resulting ester to afford carboxylic acid 9 in 93% yield. Condensation 13) of the carboxylic acid 9 with the amine 6 followed by bromination 14) of the alkyne moiety in the amide gave bromoalkyne 4 in 73% and 97% yield, respectively. SMC of bromo...

An Improved and Practical Method for Synthesizing of α-Sanshools and Spilanthol

“…The synthesis of 1 has been reported previously by two independent research groups. Igarashi and co-workers developed two stereoselective approaches to hydroxyl-α-sanshool synthesis, both employing several metal reagents and requiring precise operations (Aoki et al, 2012;Igarashi et al, 2012). Toy and co-workers constructed a (6Z,8E,10E)-conjugated triene precursor moiety with moderate selectivity (6Z:6E = 2:1) using the Wittig reaction; a pure stereoisomer was isolated by recrystallization (Wu et al, 2012).…”

Recent Applications of Phosphane-based Palladium Catalysts in Suzuki-Miyaura Reactions Involved in Total Syntheses of Natural Products

“…[232] (Z)-Stereoselective reduction of the triple bond of the cross-coupling product C42 by treatment with Zn dust in water and MeOH, Cu(OAc)2 and AgNO3 at room temperature gave 244 in 84% yield. [222] In the same year, the Pd(OAc)2/SPhos-catalyzed crosscoupling reaction of pinacol boronate A41 with aryl bromide B49 (entry 7, Table 7) was achieved with concomitant translactonization in a similar manner to the reaction of entry 5, Table 7 and to those illustrated in Scheme 71. [223] The reaction of entry 7 gave in 81% yield compound C42, which is the common precursor to naturally-occurring alterlactone (246) and altenusin (245).…”

“…(E,E)-N-Methyliminodiacetic (MIDA) boronate ester A44, which was used in the total synthesis of hydroxy-αsanshool (244) (entry 6, Table 7), [222] was prepared via the reaction sequence illustrated in Scheme 67. [237] Scheme 67.…”

“…[237] The subsequent Pd(OAc)2/S-Phoscatalyzed reaction of 275 with (E)-1-propenylboronic acid (276) gave A44 in 77% yield. [222] MIDA boronate A49, which was used in the total synthesis of (-)-myxalamide A (253) (entry 14, [229] Some reactions reported in Table 7 and/or some total syntheses that have been performed using these crosscouplings deserve comments. Thus, the optimized conditions developed for the S.-M. reaction between boronic acid A40 and aryl iodide B43 (entry 1, Table 7), which was used in the total synthesis of (+)-korupensamine B (239), led to compound C38 with an unprecedented atropodiastereoselectivity (M:P = 11:1).…”

Synthesis of hydroxy-α-sanshool

“…7,8 The process of separating hydroxy-α-sanshool from Zanthoxylum is tedious and gives low yields. 9 Igarashi et al 10 synthesized hydroxy-α-sanshool using a Suzuki-Miyaura coupling (SMC) (see Scheme 1). This SMC-based route involved the synthesis of complex building blocks and involved non-readily available starting materials.…”