Reaction of allyl tetraacetyl fDglucopyranoside and phenyl boronic acid2425

Golden root (Roseroot, Rhodiola rosea L., Crassulaceae) has been used for a long time as a resource in Chinese traditional medicine. Phenylpropenoid glu-coside, such as Rosin (cinnamyl O-P-D-glucopyranoside; 118a), was isolated from R. rosea as one of the major active ingredients and reported to be pharmacologically active as antioxidants and neurostimulants. Moreover, some other phenylpropenoid glucoside analogs have been isolated as bioactive substances. For instance, Sachaliside 1 (Triandrin; 4-hydroxycinnamyl O-P-D-glucopyranoside; 118b) and Vimalin (4-methoxycinnamyl O-P-D-glucopyranoside; 118c) have been isolated from the callus cultures of the plant. In addition, Citrusin D (Coniferin; 4-hydroxy-3-methoxycinnamyl O-P-D-glucopyranoside; 118d) has been isolated from Citrus unshiu as an antihypertensive ingredient, and Icariside H1 (3,4,5-trimethoxycinnamyl O-P-D-glucopyranoside; 118e), from Epimedium Sagittatuma (Fig. 24).

Meanwhile, some syntheses of phenylpropenoid glycoside derivatives have been reported. Matsui et al. reported the synthesis of Citrusin D (118d) using silica gel-catalyzed P-O-glucosylation of the 3-methoxy-4-(tetrahydropyra-2-yloxy)cinnamylalcohol and the 1,2-anhydro-3,4,6-tri-O-pivaloyl-P-D-glucopyranose as a key reaction. In order to synthesize the diverse phenylpropenoid glucoside analogs using direct glucosidation methods, many kinds of substituted cinnamylalcohols should be synthesized. On the other hand, cross-metathesis could be a useful method to prepare phenylpropenoid

HOH2C ho-VA^-o

HOH2C ho-VA^-o

X)

XX

Rosin

Sachaliside 1 (Triandrin)

Vimalin

(35=118a)

(47=118b) OMe

(36=118c)

rr

^-^OMe

Citrusin D (Coniferin) Icariside H-,

(48=118d)

(118e)

Figure 24: Structure of naturally occuring phenylpropenoid P-D-glucopyranosides.

glucoside analogs. In fact, Chi-Huey et al. reported the synthesis of some phenylpropenoid galactoside analogs from tetra-O-acetyl-a-D-allyl-galactoside and substituted styrene via cross-metathesis. It was an effective method to synthesize a structurally diverse phenylpropenoid library; however, an excess amount of stylenes was required to avoid the production of self-metathesis of tetra-O-acetyl-a-D-allyl-galactoside as a byproduct. Therefore, other methods to prepare diverse phenylpropenoid analogs including natural ones were expected for investigation of their biological activities. A simple total synthesis of rosin (118a), sachaliside 1 (triandrin; 118b), vimalin (118c), citrusin D (coniferin; 118d) and icariside H (118e) is based on the Mizoroki-Heck (MH)-type reaction between the substituted arylboronic acid congeners and allyl 2,3,4,6-tetra-O-acetyl-P-D-glucopyranoside (119) under Pd(II) condition as the key reaction (Fig. 25, step c).

The MH-type reaction of phenylboronic acids and conjugated olefins, such as butyl acrylate, acrylnitrile, and methyl vinyl ketone under Pd(0)-catalyzed d-Glucose

HOH2C

AcOH2C AcO-V^"^

AcOH2C

120a-m

HOH2C

HO Ar

118a-m

Figure 25: Synthesis of naturally occuring phenylpropenoid P-D-glucopyranosides. (a); allyl alcohol/immobilized P-glucosidase with ENTP-4000, (b); Ac2O/4-dimethylaminopyridine/pyridine, (c); organoboron reagents/Pd(OAc)2/Cu(OAc)2/LiOAc/DMF, (d); K2CO3/MeOH.

condition was shown by Cho and Uemura. Moreover, they reported that pheny-lantimonyl chlorides react smoothly with alkenes in the presence of Pd(II) acetate and Hiyama et al. also reported arylsilanols or aryltin reagents undergo the MH-type reaction under Pd(II) condition. On the other hand, organoboron-mediated MH-type reaction via a Pd(II)-species had been also reported by Mori et al. They disclosed that the phenylboronic acid reacted with several olefins other than enones and enals, such as allyl phenyl ether, to give the corresponding coupling products via the Pd(II)-catalyzed MH-type reaction. However, only one example of the reaction of allyl ether with phenylboronic acid was examined in this literature and no other examples have been reported in the field of carbohydrate chemistry. Furthermore, we synthesized not only naturally occurring but also unnaturally occurring phenylpropenoid analogs to investigate the limitation of this strategy.

3.10.2. Synthesis of phenylpropenoid fi-D-glucopyranoside using MH-type reaction

Some syntheses of allyl 2,3,4,6-tetra-O-acetyl-P-D-glucopyranocide (119) and the direct glucosidation of D-glucose using P-glucosidase (EC 3.2.1.21) from almonds have been reported. As in the previous method (Table 5, entry 5), the allyl P-D-glucopyranoside (49) was prepared from D-glucose and allyl alcohol using the immobilized ^-glucosidase in 68% yield. Acetylation of 49 with acetic anhydride in pyridine afforded allyl 2,3,4,6-tetra-O-acetyl-P-D-glucopyranocide (119) as a key substrate for MH-type reaction. The coupling reaction of various phenylboronic acids with 119 was carried out and the results are shown in Table 6.

The MH-type reaction was carried out using the substrate 119 (1 mmol), substituted phenylboronic acids (1.2 mmol), Cu(OAc)2 (2.0 mmol), LiOAc (3.0 mmol) in the presence of 10 mol% Pd(OAc)2 in DMF (4.0 mL) at 100°C for 2 h. All phenylboronic acids having an electron-donating group (entries 3, 5-8) and an electron-withdrawing group (entries 9-12) underwent MH-type reactions smoothly in reasonable yield. However, 2.5-3.0 equivalents of phenylboronic acid having a non-protected hydroxyl (entries 2, 4) group at the 4-position were needed to carry out the coupling reaction. Moreover, the reaction of 119 and 4-hydroxy-3-methoxyphenyl boronic acid was carried out at 65 °C due to the thermolability of the coupling product 120d (entry 4). In fact, 120d was decomposed rapidly at 100° C under the coupling condition.

Deprotection of substituted cinnamyl 2, 3, 4, 6-tetra-O-acetyl-P-D-glucopyranoside glycopyranocide (120a-120 m) using NaOMe/MeOH or K2CO3/MeOH gave the corresponding desired phenylpropenoid glycoside analogs (118a-118 m) including natural products 118a-e rapidly.

The MH-type reaction of silanols and organotin compounds with olefins via a Pd(II)-mediated pathway has been reported by Hiyama and co-workers. Based on this pathway, a plausible MH-type reaction mechanism with arylboronic acids was presented in Fig. 26. According to this mechanism, the aryl unit migrated to

Table 6

Reaction of arylboronic acid with allyl-2,3,4,6-tetra-O-acetyl-ß-D-glucopyranoside

Entry

Ar-B(OH)2

Product (yield; %)

1

Phenyl

120a (71)

2

4-Hydroxyphenyl

120b (62)

3

4-Methoxyphenyl

120c (72)

4

4-Hydroxy-3-methoxyphenyl

120d (52)

5

3,4,5-Trimethoxyphenyl

120e (67)

6

3-Methoxyphenyl

120f (86)

7

2-Methoxyphenyl

120g (74)

8

3,4-Dimethoxyphenyl

120h (42)

9

4-Chlorophenyl

120i (74)

10

4-Cyanophenyl

120j (75)

11

4-Trifluoromethylphenyl

120k (45)

12

3-Nitrophenyl

1201 (63)

13

ß-Naphtyl

120m (53)

the palladium center from arylboronic acid to furnish an aryl palladium species first and this reactive aryl palladium species was added to an olefin of allyl 2,3,4,6-tetra-O-acetyl-P-D-glucopyranocide (119) to afford an intermediate A. After reductive ^-elimination of the intermediate A, the desired product was obtained along with the release of palladium(O). Finally, the palladium(O) species was oxidized by a combination of copper(II) acetate and lithium acetate to regenerate palladium^) as the key species of this catalytic reaction. Indeed, the treatment of allyl 2,3,4,6-tetra-O-acetyl-P-D-glucopyranocide (119) and phenylboronic acid in the presence of tetrakistriphenylphosphine palladium(O) effected the removal of the allyl group instead of the desired MH-type reaction. In addition, non-protected allyl P-D-glucopyranoside (49) could be reacted with arylboronic acid under the same conditions. However, the chemical yield was poor due to low conversion. For instance, when allyl P-D-glucopyranoside (49) was treated with phenylboronic acid in the presence of LiOAc, Cu(OAc)2 and a catalytic amount of Pd(OAc)2 in DMF at 100°C for 5 h, the desired cinnamyl P-D-glucopyranoside (118a) could be obtained in only 11% yield along with a large amount of the starting material. This phenomenon might be explained by the deactivation of arylboronic acid due to the formation of arylboronic ester from arylboronic acid and allyl P-D-glucopyranoside (49). In fact, the 4-hydroxyphenylboronic acid could be reacted with 119 in 62% yield; however, 4,4,5,5-tetramethyl-2-(4-hydroxyphenyl)-1,3-dioxaborane failed to react under the same conditions. This result suggested that an arylboronic ester was less reactive than an arylboronic acid with the allyl ether 119 in this case.

3.10.3. Synthesis of naturally occurring phenylpropenoid 6-O-glycosyl-P-D-glucopyranosides26

Golden root (Roseroot, R. rosea L., Crassulaceae) has been used for a long time as a resource in Chinese traditional medicine to enhance the body's resistance against fatigue and to extend human life. Rosavin (121) was isolated as one of the chemical constituents of R. rosea by Kurkin et al. and 4-methoxycinnamyl 6-O-(a-L-arabinopyranosyl)-P-D-glucopyranoside (122) and cinnamyl 6-0-(P-d-xylopyranosyl)-P-D-glucopyranoside (123) were also isolated from an aqueous methanol extract of R. rosea by Ari et al. (Fig. 27).

The synthesis of these three natural products has not been reported so far. Meanwhile, we have reported a simple total synthesis of cinnamyl

R1 = OMe, R2 = H, R3 = OH 122 R1 = H, R2 = OH, R3 = H 123

R1 = OMe, R2 = H, R3 = OH 122 R1 = H, R2 = OH, R3 = H 123

P-glucopyranoside (rosin, 118a) and its analogs using the Mizoroki-Heck (MH)-type reaction between the substituted aryl boron reagents and allyl 2, 3, 4, 6-tetra-O-acetyl-P-D-glucopyranoside (119) using a Pd(II) catalyst as the key reaction. The Rosavin framework could be constructed from the coupling reaction of allyl 6-O-glycosyl-P-D-glucosides (126 or 129) and phenylboronic acid reagents using a Pd(II) catalyst as the key reaction. The TBDMS protection of the primary alcohol group in the allyl P-D-glycopyranoside (49) gave a silyl ether (124) in 56% yield, which was subjected to consecutive benzoylation and deprotection of the TBDMS group to afford the desired allyl 2,3,4-tri-O-benzoyl-P-D-glucopyranoside (125) in 71% yield (two steps). Coupling reaction of 125 and 2,3,4-tri-O-benzoyl-P-L-arabinopyranosyl bromide or 2,3,4-tri-O-benzoyl-a-D-xylopyranosyl bromide in the presence of AgOTf and TMU in CH2Cl2 at 0°C to room temperature for 12 h gave the corresponding coupling product (126) or (129) in 93 or 58% yield, respectively. The coupling reaction of allyl P-D-glycopyranoside congener (126) with phenylboronic acid or 4-methoxyphenyl boronic acid using 10 mol% of Pd(OAc)2, 2 equivalents of Cu(OAc)2, and 3 equivalents of LiOAc in DMF at 100° C for 1 h afforded the hexabenzoyl rosavin (127, 82% yield) and its analogs (128, 93% yield), respectively. Finally, treatment of the coupling products (127 and 128) with NaOMe in MeOH/THF provided the synthetic rosavin (121, 86% yield) or 4-methoxycinnamyl 6-O-( a-L-arabinopyranosyl)-P-D-glucopyranoside (122, 78% yield), respectively. On the other hand, the coupling reaction of allyl P-D-glycopyranoside congener (129) with phenylboronic acid using 10 mol% of Pd(OAc)2, 2 equivalents of Cu(OAc)2, and 3 equivalents of LiOAc in DMF at 100°C for 1 hour afforded the cinnamyl 6-O-(P-D-xylopyranosyl)-P-D-glucopyranoside congener (130, 76% yield). Finally, treatment of the coupling products (130) with NaOMe in MeOH/THF provided the synthetic cinnamyl 6-O-(P-D-xylopyranosyl)-P-D-glucopyranoside (123, 75% yield) (Fig. 28).

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