Keywords

14.1 Introduction

Carbohydrates, along with nucleic acids and proteins, are major biopolymers and are abundant in many living organisms. They perform crucial functions in a variety of biological processes, including cell adhesion, proliferation, and pathogenic infection because of their structural diversity. Therefore, elucidation of the biological functions of these carbohydrates is essential. Carbohydrates are also found in numerous biologically useful natural compounds, pharmaceuticals, and materials with high functionalities [1,2,3,4]. Hence, the development of lead compounds for new pharmaceuticals and materials is highly desired, especially in the era of Sustainable Development Goals (SDGs). To this end, many stereoselective and efficient chemical glycosylation methods have been developed [5, 6], and studies on the synthesis and functional evaluation of useful carbohydrates with complex structures are becoming more prevalent. In particular, the stereoselective synthesis of 1,2-trans-glycosidic bonds, represented by β-glucoside and α-mannoside, is easily achieved by utilizing the participation from the neighboring acyl protecting group in the C2 position of the glycosyl donor, enabling the synthesis of complex polysaccharides. However, the stereoselective synthesis of 1,2-cis-glycosidic bonds, represented by α-glucoside and β-mannoside, remains a challenging endeavor owing to the absence of participation from neighboring functional groups (Fig. 14.1). Therefore, the development of comprehensive 1,2-cis-stereoselective glycosylation reactions with high generality is in great demand.

Fig. 14.1
Seven molecular structures of Kanamycin A, alpha Galactosyl ceramide, alpha-cyclodextrin, L L B M 78 2 alpha 1, fondaparinux, mannosyl erythritol lipid, and branched alpha glucan from P dot boydii.

Chemical structures of various carbohydrates containing a 1,2-cis glycoside

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Conventional chemical synthetic tactics for glycosides have so far relied heavily on protecting group strategies with the main objective of controlling α/β-stereoselectivity. This decreases the overall synthetic efficiency, since the introduction and removal of protecting groups are complicated and require multiple steps. Therefore, to create a new synthetic tactic, a novel method for controlling both the 1,2-cis-stereoselectivity and regioselectivity in the glycosylation of unprotected or partially protected glycosyl acceptors, by chemical means, has been eagerly anticipated. In this context, we have proposed and developed a conceptually new regioselective and 1,2-cis-stereospecific glycosylation using an organoboron catalyst and a 1,2-anhydro sugar, namely boron-mediated aglycon delivery (BMAD) [7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22]. As shown in Fig. 14.2, in this reaction, boronic ester 3 with moderate Lewis acidity, which is prepared from 1,3- and/or cis-1,2-diol glycosyl acceptor 1 and boronic acid 2 under mild conditions in the absence of other reagents, activates the 1,2-anhydro sugar 4. Next, the generated anionic boronate ester 5 enhances the nucleophilicity of the oxygen atom bound to boron. Intramolecular glycosylation then occurs from the favorable transition state via a SNi-type reaction mechanism, providing the 1,2-cis glycoside 7 via boronic ester 6 with high regioselectivity and full stereoselectivity. A major feature of this reaction is that the diol exchange between boronic ester 6 and acceptor 1 occurs quickly and the reaction proceeds catalytically. An example of the BMAD reaction is shown in Scheme 14.1 [7]. Initially, boronic ester 10 was prepared from 4,6-diol sugar acceptor 8 and boronic acid 9 under toluene reflux conditions. 1,2-anhydroglucose 11 [23] was subsequently introduced to the reaction mixture to examine the BMAD reaction. It was found that excellent α-stereoselectivity developed and α(1,4)-glucoside 12 was obtained as a single isomeric compound in 82% yield. In this chapter, we introduce the extension of the substrate generality of the developed BMAD reaction for glycosyl donors and glycosyl acceptors, as well as some examples of applying this method to synthesize useful glycosides with complex structures.

Fig. 14.2
A chemical reaction of the S N i type mechanism of diol exchange with a boronic acid catalyst, glycosyl acceptor, and glycosyl donor leads to the formation of 1, 2 cis glycoside.

Boron-mediated aglycon delivery (BMAD) using boronic acid catalysts

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Scheme 14.1
A chemical reaction of the B M A D reaction of compounds 8 and 11 to form compound 12, including intermediary compound 10 and the conditions required for each step.

BMAD reaction of 8 and 11

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14.2 Development of Regioselective and 1,2-cis-β-Stereospecific BMAD Reaction and Its Use in the Synthesis of Oligosaccharides Found in Pathogenic Bacteria

We investigated the regioselective and stereospecific 1,2-cis-β-glycosylation, which is a more challenging linkage to construct, using an organoboron catalyst and a 1,2-anhydro donor. The β-mannoside and β-rhamnoside structures, which are typical examples for 1,2-cis-β-glycosides, are contained in the antigenic oligosaccharides of various pathogens, including Escherichia coli (E. coli) and Streptococcus pneumoniae (S. pneumoniae). Thus, the development of efficient synthetic methods for 1,2-cis-β-glycosides is required for the development of highly safe glycoconjugate vaccines.

14.2.1 Development of Regioselective and β-Stereospecific Mannosylation and Its Use in the Synthesis of Oligosaccharides Found in E. coli O75 [8]

Initially, the BMAD reaction of 4,6-diol 8 and 1,2-anhydromannose 15 [24] was investigated using various boronic acid catalysts. When boronic ester 14, prepared from 8 and catalyst 13 having an electron-withdrawing nitro group, was employed, the reaction went smoothly and β(1,6)-mannoside 16 was afforded in good yield as a single-isomeric compound. On the other hand, when boronic acid 9 having an electron-donating methoxy group was employed, the chemical yield of 16 reduced, and little β-stereoselectivity was observed. These results suggested that the reactivity of catalyst 13 is higher than that of 9 and the SN2 reaction from α-face of 1,2-anhydro donor 15 proceeds when the donor activation is weakened by a decrease in the Lewis acidity of the corresponding boronic ester. Subsequent optimization of the reaction solvent and temperature achieved a 90% yield of 16 (Scheme 14.2a). Interestingly, omitting the toluene reflux and subsequent concentration and simply mixing the three substrates afforded 16 in almost the same 85% yield (Scheme 14.2b). These results indicate that the formation of the boronic ester proceeds effectively in organic solvents and that the formation of a small amount of water in the reaction system does not significantly affect the chemical yield or regio and stereoselectivities. This finding was an important hint for the development of the late-stage glycosylation method for unprotected glycosides, which will be introduced later. The glycosylation reaction of the galactose-type 4,6-diol 17 with 15 took place with complete reversal of regioselectivity and β(1,4)-mannoside 18 was afforded as a single-isomeric compound in 86% yield (Scheme 14.2c). The reasons for the reversal of regioselectivity can be explained using the predictive model of regioselectivity based on the transition state (TS) models shown in Fig. 14.3. Specifically, the glycosylation of Glc-type 4,6-diol 8 with 1,2-anhydromannose donor 15 is expected to proceed at the 6-position because TS-β(1,6), where the donor moiety does not overlap with the acceptor moiety, is energetically advantageous over TS-β(1,4). On the other hand, in the case of Gal-type 4,6-diol 17, TS-β(1,4) is energetically favored over TS-β(1,6) due to the opposite C4 stereochemistry.

Scheme 14.2
Three distinct chemical reactions involving multiple compounds and their transformations.

BMAD reaction of 8 and 15 a with and b without preformation of 14. c BMAD reaction of 17 and 15 without preformation of the boronic ester

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Fig. 14.3
A 2 by 2 matrix. The column header is 1, 2, Anhydromannose donor 15. The row headers are Glc type acceptor 8, and gal type acceptor 17. a. T S beta 1, 4 disfavored. b. T S beta 1, 6 favored. c. T S beta 1, 4 favored. d. T S beta 1, 6 disfavored.

Predictive model for regioselectivity in the BMAD reaction of Glc-type 4,6-diol 8 (a, b) and Gal-type 4,6-diol 17 (c, d) with 1,2-anhydromannose donor 15

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Since the β-mannoside bond was efficiently constructed at the 4-position of galactose, this reaction was applied to the synthesis of glycan 19 derived from pathogenic E. coli O75 [25, 26]. In recent years, the appearance of multidrug-resistant E. coli O75, the cause of urinary tract infections [27], has become a problem [28, 29]. Scheme 14.3 shows the retrosynthetic analysis of 19. The main feature of this synthesis is the sequential introduction of disaccharide unit 21 and monosaccharide unit 15 into 3,4,6-triol acceptor 22 in a regio and stereoselective manner. The target tetrasaccharide 19 could be synthesized by regioselective and β-stereospecific BMAD reaction of 4,6-diol 20 with 15, followed by conversion and deprotection of the protecting groups. The trisaccharide 20 could be synthesized through the regioselective glycosylation of triol 22 with thioglycoside 21 with stoichiometric amounts of boronic acid 9 as a temporary protecting group for the 4,6-diol [30].

Scheme 14.3
Two complex chemical reactions. The first one is a regioselective and beta stereospecific B I M A D reaction, and the second one is a regioselective glycosylation using a boronic acid as a transient masking group.

Retrosynthetic analysis of a tetrasaccharide repeating unit of LPS derived from E. coli O75

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Scheme 14.4 shows the synthetic scheme of 19. 4,6-diol-protected boronic acid ester 23 was obtained by acetone reflux of triol 22 and boronic acid 9, followed by concentration. The glycosylation reaction of 23 with thioglycoside 21 using NIS/TfOH as an activator in DCE/toluene at − 30 °C provided trisaccharide 24 in high yield with excellent regio and 1,2-trans-stereoselectivities. The BMAD reaction of the trisaccharide acceptor 24 with 1,2-anhydromannose 15 using boronic acid 13 was investigated in MeCN at 0 °C. As expected, the reaction proceeded β(1,4) selectively and the desired tetrasaccharide 25 was obtained as a single isomeric compound in 91% yield. Efficient synthesis of 19 was completed by conversion and deprotection of the protecting groups.

Scheme 14.4
A complex chemical reaction sequence with the transformation of various molecules through different steps.

Synthesis of tetrasaccharide 19

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14.2.2 Development of Regioselective and β-Stereospecific Rhamnosylation and Its Use in the Synthesis of Oligosaccharides Found in E. coli O1 [10, 14]

We next developed regioselective and stereospecific β-rhamnosylation. Specifically, we examined the BMAD reaction of 4,6-diols with 1,2-anhydrorhamnose donor 26 [31] using catalytic amounts of boronic acid 13 at 0 °C in MeCN. The reaction went efficiently to afford β(1,4)-rhamnoside 27 with high regio and complete stereoselectivities in 87% yield, indicating that the regioselectivity of the β-rhamnosylation of 4,6-diols is the same as that of the α-glucosylation. In addition, the glycosylations with 26 were examined using three different 4,6-diol acceptors, glucal, N-acetyl-glucosaminide, and mannoside, under the same reaction conditions. In all cases, the reaction gave the corresponding β(1,4)-rhamnosides 28–30 in high yields and with high regio and stereoselectivities, indicating the high substrate generality of this reaction (Fig. 14.4).

Fig. 14.4
A complex B M A D reaction of several 4, 6 diols with 26. The image provides a detailed and organized representation of the chemical structures and reactions involved in this process.

BMAD reaction of several 4,6-diols with 26

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To demonstrate the utility of this reaction, we focused on avian pathogenic E. coli (APEC), which is a bacterial pathogen that infects chickens and causes economic damage to poultry farmers [32, 33]. The APEC O1 strain is especially problematic due to its high genomic similarity to the human pathogenic E. coli O1 strain and its potential for zoonotic transmission [34,35,36]. The detailed structure of the O-antigen of the APEC O1 strain is still unknown, hampering the development of effective and safe vaccines against APEC O1. Thus, we focused on the O1A antigen which is the pentasaccharide repeat unit of the LPS from pathogenic E. coli O1 [37]. In this study, we first synthesized O1A pentasaccharide 31 as a glycotope candidate of APEC O1 for vaccine development (Fig. 14.5).

Fig. 14.5
Two molecular structures of O 1 A antigen as a repeating unit of L P S derived from E dot coli O 1, with labeled atoms and bonds.

Chemical structures of O1A antigen as a repeating unit of LPS derived from E. coli O1 and pentasaccharide 31

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Scheme 14.5 shows the synthetic scheme of 31. The BMAD reaction of 4,6-diol 32 and 1,2-anhydrorhamnose 33 was investigated using catalytic amounts of boronic acid 13 at room temperature in THF. The reaction cleanly provided the desired β(1,4)-rhamnoside 34 as a single isomeric compound in 92% yield. Protecting the two hydroxyl groups in 34 with Bz groups, followed by removing the PMB group under acidic conditions, afforded 35. α-stereoselective rhamnosylation of 35 and known donor 36 gave the trisaccharide as a single isomeric compound in high yield. The removal of the PMB group provided the trisaccharide acceptor 37. Next, the [2 + 3] glycosylation with 38 [14] using TfOH as an activator in toluene at − 40 °C gave protected pentasaccharide 39 in 80% yield. Transformation of the azido and N-Troc groups to acetamide groups, followed by global deprotection, furnished 31. Subsequently, we synthesized a glycoconjugate of 31 with a carrier protein and evaluated its immunogenicity by ELISA assay, which showed that the glycoconjugate is a lead compound for vaccine development against APEC O1 [16].

Scheme 14.5
A complex chemical process of synthesizing pentasaccharide 31, exhibits a series of chemical reactions and structures.

Synthesis of pentasaccharide 31

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14.3 Development of Regioselective and 1,2-cis-Stereospecific BMAD Reaction of Unprotected Glycosides and Its Use in the Synthesis of the Oligosaccharide Found in P. boydii [9]

The development of chemical methods capable of regio and stereoselective glycosylation to specific hydroxyl groups in the presence of many free hydroxyl groups would significantly reduce protection and deprotection steps. Furthermore, this method could be employed for late-stage glycosylations of unprotected natural products and pharmaceutical compounds to facilitate the creation of prodrugs and conduct structure–activity relationship studies. We therefore investigated the development of regioselective and 1,2-cis-stereospecific BMAD reactions for unprotected glycosides with several free hydroxyl groups.

Initially, we selected 1,2-anhydroglucose 11 as a glycosyl donor and d-glucal (40) as an unprotected sugar acceptor and examined the glycosylation using boronic acid catalyst 13. Specifically, the reaction was initiated by adding donor 11 after preparation of boronic ester 41 by toluene refluxing of 13 and 40 followed by concentration. The desired α(1,4)-glycoside 42 was obtained in 49% yield, in addition to the trisaccharides 44 and 45, which are considered products of over-reaction, in 8% and 15% yields, respectively (Table 14.1, entry 1). It was considered that the 9-membered boronic ester intermediate 46 was generated after the first BMAD reaction activated donor 11, which caused the second BMAD reaction to produce 44 and 45 (Fig. 14.6). Here, as mentioned above, this reaction proceeded effectively even in the presence of a small amount of water, and we hypothesized that the addition of an excess amount of water to the reaction mixture might inhibit the progress of the over-reaction and improve the yield of the target disaccharide 42. In other words, we considered that the addition of water to the reaction mixture would quickly allow the hydrolysis of the unstable 9-membered ring boronic ester 46 and inhibit the activation of 11 by 46. Thus, we found for the first time that when 5.0 equiv. of water was added, the desired 42 was afforded with high regio and complete stereoselectivities in a high yield of 92%, without producing trisaccharides 44 and 45 (Table 14.1, entry 2). Furthermore, to improve the efficiency, the reaction was carried out without preformation of 41 and only with the addition of catalyst 13. The desired 42 was obtained in similar yields (Table 14.1, entry 3).

Table 14.1 BMAD reaction of 11 and 40
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Fig. 14.6
A chemical reaction process involving the transformation of a 6-membered boronic ester into disaccharides and trisaccharides exhibits the steps and intermediate compounds formed during the reactions.

Proposed mechanism for the generation of trisaccharides 44 and 45

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Next, several unprotected sugars were used to examine the substrate generality with respect to the glycosyl acceptors (Fig. 14.7). The BMAD reaction using 1,2-anhydroglucose 11 and catalytic amounts of boronic acid 13 proceeded highly regioselectively with complete 1,2-cis-stereoselectivity even for a glucoside with four free hydroxyl groups, yielding α(1,4)-glycoside 47 in a high yield of 88%. The corresponding α(1,4)-glycosides 48–50 were similarly afforded in high yields when using a glucoside with different substituents at the anomeric position, a thioglucoside with a leaving group at the anomeric position, and a glucosaminide, respectively.

Fig. 14.7
A B M A D reaction of several unprotected sugars with compound 11, exhibits the chemical structures and resulting alpha Glucosides with their respective yields.

BMAD reactions of several unprotected sugars with 11

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The BMAD reaction of unprotected natural glycosides was investigated to clarify the usefulness of this reaction as a late-stage glycosylation method. Specifically, daidzin (51), which has five free hydroxyl groups, including a phenolic hydroxyl group, was selected as a natural glycoside. Its glycosylation reaction with 52 using catalyst 13 afforded the desired α(1,4)-glycoside 53 with good regio and complete stereoselectivities in 70% yield. The synthesis of isoflavone glycoside 54 was easily achieved by removing the protecting groups of the resulting glycoside 53 (Scheme 14.6a). Paeoniflorin (55), which has five free hydroxyl groups and hemiketal and acetal moieties considered acid labile, was glycosylated with 11 to afford the desired α(1,4) glucoside 56 in 73% yield, followed by the removal of the protecting groups to afford the corresponding glycoside 57 in only two steps (Scheme 14.6b). Thus, the BMAD method is a practical technique for the chemical modification of natural glycosides and pharmaceuticals with complex structures.

Scheme 14.6
A detailed chemical diagram showing B M A D reaction of unprotected natural glycosides, specifically for Daidzin 51 and Paeoniflorin 55, with the resulting chemical structures and conditions for the reactions noted.

BMAD reactions of unprotected natural glycosides

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To demonstrate additional applications of this method, we synthesized the branched α-glucan oligosaccharide found in P. boydii. Scheme 14.7 shows the synthetic scheme of 64. The BMAD reaction of the unprotected sugar 58 with 52 using boronic acid catalyst 13 gave the desired α(1,4) glucoside 59 as a single isomeric compound in 72% yield. The BMAD reaction of 59 and 11 using borinic acid catalyst 60 was then conducted. This reaction is a glycosylation reaction in which borinic acid and the alcohol in the sugar acceptor form a borinic ester, which then activates a 1,2-anhydro donor and proceeds by a SNi-type reaction mechanism, similar to the boronic acid-catalyzed BMAD reaction [38, 39]. The desired trisaccharide 61 was glycosylated only at the 6-position, a primary hydroxyl group, in a regio and stereoselective manner. PMB group selective deprotection of 61 gave 62 with seven free hydroxyl groups. The BMAD reaction of trisaccharide 62 and 11 with boronic acid catalyst 13 also proceeded in a regio and stereoselective manner to provide the desired α(1,4)-glycoside 63 in good yield. Finally, by the removal of the Bn groups in 63, efficient synthesis of the branched α-glucan tetrasaccharide 64 with minimal protecting groups was achieved, demonstrating the usefulness of this method.

Scheme 14.7
A complex chemical synthesis process of branched alpha glucan tetrasaccharide 64, showcases the intricate steps and reactions involved in creating this specific compound.

Synthesis of branched α-glucan tetrasaccharide 64

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14.4 Development of Diastereoselective Desymmetric BMAD Reaction of meso-Diols and Its Use in the Synthesis of the Common Structure of the LLBM-782 Series [11]

In natural and pharmaceutical products, there are many glycosides glycosylated to meso-diols with a symmetrical face, such as 2-deoxystreptamin and myo-inositol. However, to synthesize these glycosides, it is necessary to introduce a sugar unit into the desired hydroxyl group of two equivalent hydroxyl groups of the meso-diol, and multiple steps are required to control the glycosylation site. Reducing the number of synthetic steps is a major challenge. The conventionally used synthetic tactic of myo-inositol glycosides is illustrated with an example (Fig. 14.8). First, the meso-diol 65 prepared from myo-inositol is desymmetrized utilizing a chiral auxiliary group 66, resulting in a mixture of diastereomers 67 and 68 [40, 41]. Next, one of the desired diastereomers 68 is separated and purified as a glycosyl acceptor, and then the desired myo-inositol glycoside 71 can be synthesized by stereoselective glycosylation with glycosyl donor 69, followed by removal of the chiral auxiliary in the resulting 70. However, this conventional synthetic tactic is inefficient due to the low yield and regioselectivity of the desymmetrization reaction with the chiral auxiliary group and the multiple steps required. We hypothesized that the BMAD reaction of a meso-diol with 1,2-anhydro donor 72 and boronic acid catalyst 73 would proceed regio and stereoselectively with desymmetrization to yield the targeted myo-inositol glycoside 71 in a single step.

Fig. 14.8
Two different chemical synthesis tactics, the diastereoselective desymmetric glycosylation tactic, and the conventional synthetic tactic, exhibit the transformation of chemical compounds through various stages.

Diastereoselective desymmetric glycosylation tactic

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To investigate our hypothesis, the desymmetric BMAD reaction of 1,2-anhydroglucose 11 and meso-myo-inositol 74 using boronic acid catalyst 13 was examined in THF at − 20 °C (Scheme 14.8). For the first time, the glycosylation was found to proceed effectively to give α(1,6)-glucoside 75 with complete regio and stereoselectivities in 96% yield. When 1,2-anhydromannose 15 was employed under the same conditions, the regioselectivity was reversed completely and the BMAD reaction of 74 gave β(1,4)-mannoside 76 as a single isomeric compound in 99% yield. These results indicated that the regioselectivity of this reaction is dependent on the configuration of the C2 position of the donor used. Indeed, it was confirmed that when 1,2-anhydrorhamnose 26 having the same R configuration at the C2 position as 11 and 1,2-anhydrofucose 77 having the same S configuration at the C2 position as 15 were employed in the BMAD reactions of 74, corresponding β(1,6)-rhamnoside 78 and α(1,6)-fucoside 79 were obtained, respectively, in high yields with complete diastereoselectivity. These results clearly indicated that chirality transfer from the 1,2-anhydro donor to the meso-diol acceptor occurred.

Scheme 14.8
A two-line desymmetrization B M A D reaction of meso-diol 74, showing the chemical structures and reaction conditions leading to different products.

Desymmetric BMAD reactions of meso-diol 74

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To demonstrate the utility of this desymmetric BMAD reaction, we applied it to the synthesis of mannoside 80 which is the common structure of the antibiotic LLBM-782 series and is a base hydrolysis product of LLBM-782α (Fig. 14.9) [42,43,44]. The anomeric configuration of 80 was assigned as β by the value of its 1JCH coupling constant of 164 Hz. However, α-anomers and β-anomers are usually observed at 1JCH values of about 170 Hz and 160 Hz, respectively, thus the assignment of the β configuration is ambiguous [45, 46].

Fig. 14.9
A chemical reaction of the chemical structures of the L L B M 782 series and a common structure 80 obtained by base hydrolysis of L L B M 78 2 a 1.

Chemical structures of the LLBM-782 series and common structure 80 obtained by base hydrolysis of LLBM-782α1

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Scheme 14.9 shows the synthetic scheme of 80. Initially, diastereoselective desymmetric BMAD reaction of meso-diol 74 with 1,2-anhydro donor 81 possessing a PMB group at the C3 position took place at − 20 °C in THF affording β(1,4)-mannoside 82 as a single isomeric compound in 85% yield. The 1JCH for 82 was 159 Hz and the nOe correlation between H1 and H5 in the mannose moiety was observed, showing that the anomeric configuration of 82 was β. Treatment of 82 with hydrogen chloride to remove TBS and orthoformate groups, followed by protection of the resulting hexanol with Bn groups, gave 83. Removal of the PMB group in 83 under acidic conditions gave 84. Treatment of 84 with DMP, followed by oximation, afforded 85. Treatment of 85 with Ac2O, followed by reduction of the oxime group and carbamoylation of the resulting amine, gave 86. Finally, removal of Bn groups furnished the target mannoside 80 in high yield. The 13C NMR data obtained for 80 were in good agreement with the reported data. These results indicated that the stereochemistry of the anomeric position of LLBM-782 series is indeed in the β configuration.

Scheme 14.9
A detailed chemical synthesis diagram showing the common structure of the L L B M 782 series, with various chemical reactions and compounds illustrated.

Synthesis of common structure of the LLBM-782 series

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14.5 Conclusion

In summary, we have developed regioselective and 1,2-cis-β-stereospecific BMAD reactions. This study found that the preformation of the boronic ester under toluene reflux conditions was not always necessary, which is an important point for future development. Subsequently, we applied this method to synthesize oligosaccharides found in pathogenic bacteria, E. coli O75 and O1. In addition, we developed regioselective and 1,2-cis-stereospecific BMAD reactions of unprotected glycosides. Adding water to the reaction mixture inhibited the over-reaction. We applied this method to the late-stage BMAD reaction of biologically active natural glycosides and the synthesis of an oligosaccharide found in P. boydii. We also developed a diastereoselective desymmetric BMAD reaction of meso-diols and applied this method to synthesize the common structure of the LLBM-782 series, revealing that the anomeric configuration of the LLBM-782 series was β. Therefore, the BMAD reaction will aid in the creation of lead compounds for new pharmaceuticals and functional materials. These methods will contribute to biology, pharmacy, and medicine through the utilization of the developed glycosides.