Design, Synthesis, and Biological Activity of Boron-Bearing Sugar Derivatives for Boron Neutron Capture Therapy (BNCT)

Abstract

Radiotherapy is one of the conventional methods for the treatment of cancers. Boron neutron capture therapy (BNCT) has emerged as a promising and well-recognized modality for treating certain types of cancers. BNCT is a binary radiotherapy that largely depends on neutron beams and ¹⁰B carriers. Although an “ideal” boron carrier should fulfill multiple criteria, high tumor/normal tissue ratio (T/N > 5) and high tumor uptake of boron (>20 μg/g) are critically important. First-generation (boric acid and derivatives) and second-generation (BPA and BSH) boron carriers suffer from poor T/N and extremely high dose in clinical use (500 mg/kg and usually >30 g for each patient). Glucose transporter 1 (GLUT1) is overexpressed on the membrane surface of multiple tumors and is a potential target for third-generation boron carrier to achieve high T/N and high tumor uptake of boron. However, the boron-bearing sugar derivatives designed in the last few decades have suffered from suboptimal T/N values and significant cytotoxicity. In the present study, a total of two categories comprising 6 series (28 in total) of boron-bearing sugar derivatives were designed and synthesized and their cellular boron uptake, T/N, and cytotoxicity were evaluated. The structure–activity relationship (SAR) of these target compounds was analyzed, and one of the target compounds, B3, a phenyl C-mannoside with an o-carborane moiety, exhibited the best boron-carrying profile, which featured 10.6-fold higher boron uptake by the SCC-9 cell line and a largely improved T/N (3.3 for B3 vs. 1.4 for BPA) compared with the current clinical gold standard BPA. Therefore, the chemical structure of B3 represents a privileged candidate structure for the future design of “ideal” boron carriers for BNCT.

1. Introduction

Cancer is one of the leading causes of death in the world. Radiotherapy is one of the conventional methods for the treatment of cancers. Boron neutron capture therapy (BNCT) has emerged as a promising and well-recognized modality for the treatment of certain types of cancers, including melanoma, glioma, and head and neck cancers [1]. BNCT is a binary cancer radiotherapy. A carrier that contains non-radioactive ¹⁰B is first administered to patients, which is selectively absorbed by and accumulated in cancer cells; subsequently, the cancer cells with ¹⁰B are irradiated with a thermal or epithermal neutron beam to induce neutron capture and fission reaction (¹⁰B + ¹n → [¹¹B]* → ⁴He + ⁷Li) and the generated α particles (⁴He) and γ rays from the de-excitation of recoiling ⁷Li ion cause DNA damage and cancer cell death. The α particle has a travel distance of <10 μm, approximately the diameter of one single cancer cell, and therefore BNCT therapy can selectively kill cancer cells, sparing the adjacent normal tissues [2]. Historically, the neutron beam used in BNCT came from a fission reactor, which was profoundly inconvenient for treatment; recently, clinical BNCT in hospital was mainly performed using accelerator-based sources, which are easier to install and more cost-effective [2].

The ¹⁰B carrier compound has remained the mainstay of BNCT therapy. An “ideal” ¹⁰B carrier compound should fulfill multiple criteria, such as rational water solubility, low systemic toxicity, high tumor/normal tissue ratio (T/N > 5), high tumor/blood ratio (T/B > 3.5), high tumor uptake of ¹⁰B (>20 μg/g), long retention of ¹⁰B in tumor cells (several hours), and rapid clearance from the body after therapy [3,4]. Among these criteria, high tumor specificity (T/N and T/B ratios) and high ¹⁰B tumor uptake are of crucial importance for a ¹⁰B carrier compound to achieve highly selective uptake by tumor cells and then accumulation in tumor tissues compared with normal adjacent tissues. [¹⁰B] boric acid and its derivatives, as the “first-generation” ¹⁰B carrier compounds, were studied from the 1950s to the 1960s with moderate efficacy, but they lacked tumor selectivity and therefore were discontinued later [1]. The “second-generation” carriers were then developed and became popular in clinical use in the 1960s, including sodium borocaptate (BSH, Na₂B₁₂H₁₁SH) and (L)-4-boronophenylalanine (BPA) (Figure 1). BSH features good water solubility, high capacity for transporting ¹⁰B atoms (12 ¹⁰B atoms for each BSH molecule), and low systemic toxicity but suffers from no tumor selectivity and being expensive; it is now rarely available in the clinical setting [5]. BPA is the only well-recognized and widely used BNCT carrier today, which is highlighted by its tumor selectivity (T/N = 2.5–3.3) and being relatively cheap, it but suffers from low water solubility and low capacity for transporting ¹⁰B atoms (only one ¹⁰B atom for each BPA molecule). BPA has proven to be efficacious in the treatment of melanoma and head and neck cancers (among others); however, its low T/N and low ¹⁰B-carrying capacity necessitate an extremely high dose in clinical use (500 mg/kg and usually >30 g for each patient depending on body weight) [6,7].

To overcome the shortcomings associated with “second-generation” ¹⁰B carriers, the last few decades have witnessed substantial efforts to develop “third-generation” carriers to enhance their tumor targeting ability, which are based on a variety of modalities, including new chemical entities (nanotechnology-based delivery systems) and cancer-specific biochemical and physiological processes (boron-bearing sugar derivatives, polyamines, peptides, DNA intercalators and monoclonal antibodies) [8,9,10,11]. Among these, boron-bearing sugar derivatives constitute an important class of boron carriers because they are the potential substrates of glucose transporter 1 (GLUT1) due to their structural similarity to the natural substrate of GLUT1 (D-glucose). GLUT1 is a key rate-limiting transporter in the transportation of glucose in cancer cells for energy supply, and it is overexpressed on the membrane surface of multiple tumors [12,13,14]. Furthermore, incorporation of sugar moiety can dramatically increase water solubility. Some representative boron-bearing sugar derivatives as potential BNCT carriers reported in earlier work are summarized in Figure 2 [15,16,17,18,19,20,21,22,23,24,25,26]. Despite some advantages, such as high capacity for transporting boron [15,16,17,20,22,25] mainly due to the incorporation of o-carborane or closo-dodecaborane moiety and enhanced water solubility [16,23] compared with BSH and BPA, most of the reported boron-bearing sugar derivatives are associated with multiple unfavorable properties required for BNCT, such as high plasma protein binding [15], suboptimal T/N or T/B values [15,16,17,18,19,20,21,22,23,24], and pronounced cytotoxicity, particularly at high concentrations [17,18,20,23]. Inspired by these observations, we designed and synthesized a total of two categories comprising 6 series (28 in total) of boron-bearing sugars (Figure 3) to explore novel chemical structures for enhanced tumor-targeting ability and evaluated their cellular boron uptake in normal and high GLUT1-expressing cancer cells as well as their cytotoxicity. The structure–activity relationship (SAR) of the target compounds was analyzed, and one of the target compounds, B3, displayed the best boron-carrying profile, with 10.6-fold higher boron uptake by the SCC-9 cell line and a largely improved T/N (3.3 for B3 vs. 1.4 for BPA) compared with BPA. The findings in the present study, especially the chemical structure of B3, should be helpful for the future design of “ideal” boron carriers for BNCT.

2. Results and Discussion

2.1. Chemistry

2.1.1. Synthesis of Intermediates

The synthetic routes to some intermediates are shown in Scheme 1. Treatment of commercially available D-glucono-δ-lactone (1) with trimethylsilyl chloride (TMSCl) in the presence of 4-dimethylaminopyridine (DMAP) and N-methylmorpholine (NMM) in THF afforded pertrimethylsilylated lactone 2 [26]. Treatment of commercially available 4-bromo-1,2-dimethylbenzene (3) with N-bromosuccinimide (NBS) in the presence of 2,2′-azobisisobutyronitrile (AIBN) as an initiator in refluxing CCl₄ produced bisbenzyl bromide 4 through free radical substitution [27]. Commercially available tetrabenzylated D-glucose lactol 5 was oxidized to corresponding lactone 6 with DMSO/Ac₂O at room temperature [28]. 1,4-Diiodobenzene was treated with 1 eq of n-BuLi to undergo iodine–lithium exchange to furnish 4-iodophenyl lithium, and the latter was trapped with lactone 6 to give a 1-C-aryl lactol intermediate, which gave corresponding 1-C-aryl methyl glucopyranoside 7 upon treatment with MeOH in the presence of MeSO₃H; BF₃·Et₂O-mediated reduction of 7 with Et₃SiH produced C-aryl glucopyranoside 8 [29]. Perbenzylation of commercially available methyl α-D-galactopyranoside (9) with BnBr in the presence of NaH afforded 10. Selective acidic hydrolysis of the anomeric methyl galactoside moiety with 5 M HCl in AcOH at 80 °C liberated the anomeric OH to give lactol 11 [30], which was oxidized to corresponding lactone 12 with DMSO/Ac₂O. Following the procedure identical to the conversion of 6 to 8 discussed above, 12 was converted to 14. Following the same procedure as the conversion of 9 to 14, commercially available methyl α-D-mannopyranoside (15) was converted to C-aryl mannoside 20. Commercially available glycal 21 was perbenzylated to 22 through treatment with BnBr in the presence of NaH and tetra-n-butylammonium iodide (TBAI) in THF. Treatment of 22 with 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2]octane bis(tetrafluoroborate) (selectfluor^®) in DMF/H₂O at 50 °C afforded 2-deoxy-2-F-glucose lactol 23 [31], which was converted to F-bearing intermediate 26, as described above.

2.1.2. Synthesis of Series A

The synthetic route to target compound A1 is shown in Scheme 2. Commercially available o-carborane 27 was deprotonated with 1 eq of n-BuLi and then treated with tert-butyldimethylsilyl chloride (TBDMSCl) to give 28 with TBDMS at one of its two carbon atoms [32]. Deprotonation of 28 with 1 eq of n-BuLi followed by treatment with 4-iodobenzyl bromide gave 29 with the incoming 4-iodobenzyl group attached to the other carbon atom of o-carborane [33]. Treatment of 29 with n-BuLi followed by trapping of the generated aryl lithium with lactone 2 afforded a 1-C-aryl lactol intermediate, which was further converted to corresponding 1-C-aryl methyl glucopyranoside 30 upon treatment with MeSO₃H/MeOH. Peracetylation of 30 with Ac₂O in the presence of DMAP in pyridine afforded 31, which was reduced to 32 with Et₃SiH in the presence of BF₃·Et₂O, as discussed above. The TBDMS group in 32 was cleaved with tetra-n-butylammonium fluoride (TBAF) to give 33 [32]. Zemplén deacetylation of 33 through treatment with MeONa in MeOH to remove all of the acetyl groups yielded target compound A1.

The synthetic routes to target compounds A2 and A3 are shown in Scheme 3. Following an identical procedure described above, aryl iodide 29 underwent iodine–lithium exchange upon treatment with n-BuLi, and the aryl lithium intermediate generated subsequently was trapped with 12 followed by treatment with MeSO₃H/MeOH to give 34, which was then reduced to 35 with Et₃SiH/BF₃·Et₂O. TBAF-mediated cleavage of TBDMS in 35 produced 36. Concomitant debenzylation and acetylation of 36 to give 37 was achieved by treatment with Ac₂O in the presence of BF₃·Et₂O [34]. Zemplén deacetylation of 37 through treatment with MeONa in MeOH afforded target compound A2. Following the procedure for the synthesis of A2, the target compound A3 with a mannose moiety was produced starting from 29 and a mannopyranose lactone 18.

2.1.3. Synthesis of Series B

The synthetic routes to target compounds B1–B4 are summarized in Scheme 4. Thus, o-carborane 27 was deprotonated with 1 eq of n-BuLi to generate a carbanion intermediate, which underwent cross coupling with aryl iodides 8, 14, 20, and 26 mediated by Pd[P(t-Bu)₃]₂ and tricyclohexylphosphine (PCy₃) to give 42, 44, 46, and 48, respectively [35]. Following the identical procedure discussed above for the conversion of 36 to A2, 42, 44, 46, and 48 were converted to target compounds B1–B4, respectively.

2.1.4. Synthesis of Series C

The synthetic routes to target compounds C1 and C2 are depicted in Scheme 5. Thus, treatment of o-carborane (27) with 2 eq of n-BuLi led to deprotonation at its two carbon atoms, and the carbanion generated then reacted with bisbenzyl bromide 4 to form a cyclized product 50 [36]. Following a similar procedure discussed above, aryl bromide 50 underwent bromine–lithium exchange upon treatment with n-BuLi to generate an aryl lithium intermediate, which was trapped with pertrimethylsilyl-protected lactone 2 followed by removal of all of the TMS-protecting group with strongly acidic resin (H⁺ form) to give 1-C-aryl lactol 51. The latter was reduced to 52 with Et₃SiH/BF₃·Et₂O. Compound 52 was actually the target compound C1, but it was rather impure and hard to purify through conventional silica gel column chromatography; instead of directly purifying 52 through preparative HPLC, it was first peracetylated with Ac₂O in the presence of DMAP in pyridine to afford 53, which was purified through conventional column chromatography and then subjected to Zemplén deacetylation through treatment with MeONa/MeOH to give pure target compound C1. Following a similar procedure as the synthesis of A2 from 29 and 12, the target compound C2 was prepared from 50 and 12.

2.1.5. Synthesis of Series D

The synthetic routes to the target compounds D1–D6 are shown in Scheme 6. Thus, deprotonation of o-carborane (27) with 1 eq of n-BuLi generated a carbanion at one of its two carbon atoms, which then underwent SN2 nucleophilic substitution with diethylene glycol di(p-toluenesulfonate) and triethylene glycol bis(p-toluenesulfonate) to produce 57-1 and 57-2, respectively. Treatment of tosylates 57-1 and 57-2 with NaI in the presence of TBAI in toluene at 100 °C gave corresponding iodides 58-1 and 58-2, respectively; the latter were first converted to their corresponding acetates through SN2 nucleophilic substitution with AcONa in DMF at 80 °C and then hydrolyzed with NaOH in MeOH to alcohols 59-1 and 59-2, respectively. Primary alcohol 59 (including 59-1 and 59-2) was reacted with β-D-glucose pentaacetate, β-D-galactose pentaacetate, and α-D-mannose pentaacetate in the presence of BF₃·Et₂O to afford O-glucosides 60-1 and 60-2, O-galactosides 61-1 and 61-2, and O-mannosides 62-1 and 62-2, respectively [37]. Zemplén deacetylation of these compounds with MeONa in MeOH as described above gave target compounds D1–D6.

2.1.6. Synthesis of Series E

The synthetic routes to the target compounds E1–E4 are shown in Scheme 7. Following the procedure for the synthesis of 32 from 29 and 2, 65 was prepared from 1,4-diiodobenzene and 2. Cross coupling of aryl iodide 65 and bis(pinacolato)diboron (B₂Pin₂) in the presence of Pd(dppf)Cl₂ and KOAc in DMSO at 87 °C gave 66. Zemplén deacetylation of 66 with MeONa in MeOH gave target compound E1; oxidative cleavage of the pinacol ester functionality in 66 with NaIO₄ in the presence of NH₄OAc in acetone/H₂O afforded phenylboronic acid 67, and Zemplén deacetylation of the latter with MeONa in MeOH gave the target compound E2. Following the same procedures for the synthesis of E1 and E2 described above, E3 and E4 were prepared from 1,3-diiodobenzene and 2.

The synthetic routes to the target compounds E5–E8 are shown in Scheme 8. Following the procedure for the synthesis of 8 from 6 and 1,4-diiodobenzene, 77 was prepared from 18 and 1,3-diiodobenzene. Perbenzylated mannosides 20 and 77 were treated with Ac₂O/BF₃·Et₂O as described above to give peracetylated counterparts 73 and 78, respectively. Following the procedure from 65 for the synthesis of E1 and E2, 73 and 78 were converted to E5/E6 and E7/E8, respectively.

The synthetic route to the target compound E9 is shown in Scheme 9. E9 was prepared from 26 following the procedure for the synthesis of E5 from 20.

2.1.7. Synthesis of Series F

The synthetic routes to the target compounds F1 and F2 are shown in Scheme 10. Following the procedure for the synthesis of E7 and E8 from 18, F1 and F2 were prepared from 6 and 1,3,5-tribromobenzene.

The synthetic routes to the target compounds F3 and F4 are shown in Scheme 11. Following the procedure for the synthesis of F1 and F2 from 6 and 1,3,5-tribromobenzene, the mannose-bearing target compounds F3 and F4 were prepared from mannose lactone 18 and 1,3,5-tribromobenzene.

It should be noted that the compounds in series E and F were found to be slightly unstable after prolonged storage at 0 °C to room temperature.

The anomeric configurations of the sugar ring in all of the target compounds were found to be β, as evidenced by the coupling constants of H1-H2 in their peracetylated derivatives. Specifically, for all of the target compounds with a glucopyranose or galactopyranose moiety, the H1-H2 coupling constants were in the range of 8.0–10.0 Hz, while for those with a mannopyranose moiety the H1-H2 coupling constants were in the range of 0–2.0 Hz. For B4 and E9, both with a 2-deoxy-2-fluoro-D-glucopyranose moiety, the anomeric configuration was hard to determine directly due to the complication of signal splitting given the presence of an F atom and signal overlapping in the ¹H NMR spectra; however, a similar synthetic procedure reported earlier led to the formation of the same 2-deoxy-2-fluoro-D-glucopyranose with an anomeric β configuration [38], supporting the anomeric β configuration in B4 and E9.

2.2. Cytotoxicity Assay

As discussed above, low systemic toxicity is one of the criteria for “ideal” boron carriers. Thus, a 24 h cytotoxicity assay was conducted to determine the anti-proliferative activity of the target compounds against two selected cell lines, SCC-9 human tongue squamous cell carcinoma cells and HaCaT immortalized human keratinocytes, and the results were expressed as the half-maximal inhibitory concentration (IC₅₀) and are summarized in

Table 1. Cytotoxicity of target compounds and BPA against SCC-9 and HaCaT cell lines.

Compd	IC50 (mM)		Compd	IC50 (mM)
	SCC-9	HaCaT		SCC-9	HaCaT
A1	0.71	0.60	E1	>1	>1
A2	0.64	0.61	E2	>1	>1
A3	0.56	0.46	E3	>1	>1
B1	0.52	0.52	E4	>1	>1
B2	0.50	0.52	E5	>1	>1
B3	>0.2	>0.2	E6	>1	>1
B4	0.25	0.38	E7	>1	>1
C1	0.50	0.53	E8	>1	>1
C2	0.51	0.53	E9	>1	>1
D1	0.30	0.26	F1	>1	>1
D2	0.22	0.21	F2	>1	>1
D3	0.35	0.31	F3	>1	>1
D4	0.63	0.49	F4	>1	>1
D5	0.31	0.28	BPA	>1	>1
D6	0.40	0.34

. As will be discussed in the next section, SCC-9 and HaCaT cell lines were selected to represent GLUT1 high expressing tumor and normal cell lines, respectively, for the determination of selective cellular boron uptake (T/N). As shown in Table 1, the IC₅₀ values of the target compounds in series A–D against SCC-9 and HaCaT cell lines were in the range of 0.20–0.71 mM, indicating that their cytotoxicity was relatively small and acceptable compared with the boron-bearing compounds reported earlier [17,18,20,23]; the IC₅₀ values of the target compounds in series E–F were >1 mM, indicating that those compounds in series E–F exhibited smaller cytotoxicity than those in series A–D. BPA was used as a reference compound and was found to exhibit no significant cytotoxicity toward either cell line within the tested concentration range, comparable to the target compounds in series E–F (IC₅₀ values > 1 mM).

2.3. Cellular Boron Uptake Assay

As discussed above, among the criteria for an “ideal” boron carrier, high tumor specificity (T/N and T/B ratios) and high boron tumor uptake are of crucial importance for a boron carrier compound to achieve highly selective uptake by tumor cells and then accumulation in tumor tissues compared with normal adjacent tissues. In order to determine these two factors for the target compounds in the present study, we selected the SCC-9 cell line, a kind of human tongue squamous cell carcinoma cell, and the HaCaT cell line, a kind of human keratinocyte, to represent tumor cells and normal cells, respectively. It should be noted that the GLUT1 high expressing SCC-9 cell line was selected to represent tumor cells because the target compounds in the present study were designed to target GLUT1 [39]. Thus, the SCC-9 and HaCaT cells were incubated with a solution of target compounds at specific concentrations for 3 h, and the boron taken up by the cells was quantified through inductively coupled plasma–mass spectrometry (ICP-MS) and expressed as μg/10⁶ cell; the T/N was calculated as [boron taken up by SCC-9 cell line (μg/10⁶ cell)]/[boron taken up by HaCaT cell (μg/10⁶ cell)].

The designed six series of target compounds in the present study fall into two categories: category I includes series A–D, with each target compound having one o-carborane moiety, while category II includes series E–F, with each target compound having one or two boronic acid or its pinacol ester moieties (Figure 3). The boron uptake results for target compounds series A–D (category I) and series E–F (category II) are summarized in

Table 2. Summary of boron uptake by SCC-9 and HaCaT cell lines for target compounds in series A–D.

Compd	B Uptake (μg/106 cell)				Compd	B Uptake (μg/106 cell)
	SCC-9		HaCaT			SCC-9		HaCaT
	0.1 mM	0.05 mM	0.1 mM	0.05 mM		0.1 mM	0.05 mM	0.1 mM	0.05 mM
A1	1.28	0.84	0.53	0.33	C2	0.91	0.67	0.55	0.29
A2	0.88	0.72	0.54	0.30	D1	0.13	0.1	0.09	0.05
A3	1.42	1.34	0.60	0.63	D2	0.17	0.07	0.07	0.04
B1	1.66	0.85	1.02	0.38	D3	0.25	0.23	0.15	0.16
B2	1.25	0.82	0.65	0.38	D4	0.21	0.21	0.22	0.10
B3	2.22	1.17	0.68	0.51	D5	0.23	0.23	0.10	0.06
B4	1.62	1.03	0.88	0.48	D6	0.21	0.13	0.13	0.08
C1	0.87	0.81	0.42	0.33

and

Table 3. Summary of boron uptake by SCC-9 and HaCaT cell lines for target compounds in series E–F and BPA.

Compd	B Uptake (μg/106 cell)
	SCC-9			HaCaT
	5 mM	2.5 mM	1 mM	5 mM	2.5 mM	1 mM
E1		0.08	0.01		0.01	0
E2		0	0		0	0
E3		0.01	0		0.01	0
E4		0	0		0.01	0
E5		0.06	0.02		0.02	0.01
E6		0.02	0.01		0.01	0
E7		0.06	0.03		0.07	0.03
E8		0.10	0.04		0.02	0.01
E9		0.09	0.02		0.05	0.01
F1		0	0		0	0
F2		0.02	0		0.01	0
F3		0.03	0		0	0
F4		0.05	0.01		0	0
BPA	0.21	0.07		0.15	0.05

, respectively, and their calculated T/N ratios are summarized in

Table 4. Summary of T/N values for target compounds in series A–D.

Compd	T/N a		Compd	T/N a
	0.1 mM	0.05 mM		0.1 mM	0.05 mM
A1	2.4	2.5	C2	1.7	2.3
A2	1.6	2.4	D1	1.4	2
A3	2.4	2.1	D2	2.4	1.8
B1	1.6	2.2	D3	1.7	1.4
B2	1.9	2.2	D4	1.0	2.1
B3	3.3	2.3	D5	2.3	3.8
B4	1.8	2.1	D6	1.6	1.6
C1	2.1	2.5

^a T/N = boron uptake by SCC-9 cell (μg/10⁶ cell)/boron uptake by HaCaT cell (μg/10⁶ cell).

and

Table 5. Summary of T/N values for target compounds in series E–F and BPA.

Compd	T/N a		Compd	T/N a
	2.5 mM	1 mM		5 mM	2.5 mM	1 mM
E1	8		E8		5	4
E2			E9		1.8	2
E3	1		F1
E4			F2		2
E5	3	2	F3
E6	2		F4
E7	0.86	1	BPA	1.4	1.50

^a T/N = boron uptake by SCC-9 cell (μg/10⁶ cell)/boron uptake by HaCaT cell (μg/10⁶ cell).

, respectively. For the target compounds in series A–D (category I), their boron uptakes were determined at two concentrations (0.1 mM and 0.05 mM), both lower than their cytotoxicity IC₅₀ values. Three compounds in series A, A1–A3, were initially designed by connecting three individual phenyl C-glycoside moieties to o-carborane by a CH₂ linker. All three compounds could be efficiently taken up by both cell lines, with boron uptake at 0.88–1.42 μg/10⁶ cell by the SCC-9 cell line and 0.53–0.60 μg/10⁶ cell by the HaCaT cell line at 0.1 mM (T/N = 1.6–2.4), which were significantly higher than those for BPA, with boron uptake at 0.21 μg/10⁶ cell by the SCC-9 cell line and 0.15 μg/10⁶ cell by the HaCaT cell line at 5 mM (T/N = 1.4). Considering A3, a phenyl C-mannoside, exhibited the highest boron uptake and the largest T/N value (2.4) in series A, we moved on with the phenyl C-mannoside moiety to further design series B by removing the CH₂ linker in series A. Overall, the compounds in series B exhibited higher boron uptake and larger T/N value than those in series A, with B3, also a phenyl C-mannoside, being the best (T/N = 3.3 at 0.1 mM). Series C was then designed by adding one more CH₂ linker to series A to form a fused tricycle system, but it was associated with decreased boron uptake and a comparable T/N value. Although the exact reason remains unknown, it was observed that cellular boron uptake across series A–C depended on the rigidity of aglycons, and reasonable rigidity seemed beneficial to cellular boron uptake (rigidity increased in this order: series A < series B < series C). Series D was designed by connecting three individual O-glycosides to o-carborane with two long hydrophilic poly ethylene glycol (PEG) linkers with an aim to improve aqueous solubility; unfortunately, although the T/N values were comparable to those in series A–C, series D was associated with dramatically decreased boron uptake. Finally, we designed series E by incorporating boronic acid or its pinacol ester moiety with the benzene ring of two phenyl C-glycosides and series F by incorporating two boronic acid or its pinacol ester moieties on the base of series E. The boron uptakes for both series were determined at 1 mM and 2.5 mM for these two series; disappointingly, almost no boron uptake was observed in both series by SCC-9 and HaCaT (no more than 0.1 μg/10⁶ cell) and, in this case, the calculated T/N values were of little value, indicating that the structures of target compounds in series E–F are not favorable for BNCT. As discussed above, category I was significantly better than category II in terms of cellular boron uptake. The exact reason for this significant difference is unknown but can be partially explained by the following two factors. (1) The o-carborane moiety in category I has a 10-fold boron-carrying capacity compared to the boronic acid and its pinacol ester moieties in category II. (2) The compounds in category I could be transported more efficiently than those in category II, probably due to the difference between their structures and physicochemical properties, such as lipophilicity and water solubility. In summary, compounds in series A–C (category I) were associated with higher cellular boron uptake by SCC-9 and HaCaT cell lines and larger T/N values. Notably, compound B3 was the best one and demonstrated 10.6-fold higher boron uptake by the SCC-9 cell line and a superior T/N (3.3 for B3 vs. 1.4 for BPA) compared with BPA. The chemical structure of B3 represents a privileged candidate structure for the future design of “ideal” boron carriers for BNCT. Further SAR exploration around the structure of B3 is promising to discover an “ideal” boron carrier for BNCT and will be conducted in the future because the T/N of B3 still falls short of that for an “ideal” boron carrier (T/N = 3.3 for B3 vs. T/N > 5 for “ideal” boron carriers).

3. Materials and Methods

3.1. Chemistry

Unless stated otherwise, all of the chemical reagents were obtained commercially and used without further purification. All of the dried solvents were prepared through standard methods. Reaction progress was monitored through thin-layer chromatography (TLC) on commercially available precoated TLC silica gel plates, and separation and purification on flash column chromatography were performed through silica gel column (200–300 or 300–400 mesh) eluting with EtOAc/petroleum ether (PE, b.p. 60–90 °C) or MeOH/CH₂Cl₂ (by v/v). Melting points were measured in open capillaries with an SGW X-4A microscopic melting point apparatus (Shanghai INESA Physico-Optical Instrument Co., Ltd., Shanghai, China) and are uncorrected. Optical rotations were determined on an Anton Paar MCP 4100 polarimeter (Anton Paar OptoTec, Seelze, Germany) at 20 °C in MeOH, DMSO, or H₂O as solvent. NMR spectra were recorded on a Bruker Ascend 500 or 600 NMR spectrometer (Bruker Switzerland AG, Fällanden, Switzerland) using CDCl₃, DMSO-d₆, CD₃OD, or D₂O as the solvent and TMS (for ¹H NMR) or known chemical shifts of carbon signals of deuterated solvents (for ¹³C NMR) as the internal standard. High-resolution mass spectra (HR-MS) were determined with a Thermo Scientific Exactive Plus mass spectrometer (Thermo Fisher Scientific, Bremen, Germany) equipped with electrospray ionization (ESI) and an Orbitrap mass analyzer. The purities were determined with a Waters Arc HPLC instrument equipped with a UV detector (Waters Corporation, Singapore); Column, chromcore C₁₈ (Nanochrom), 4.6 × 150 mm, 3 μm; eluent, H₂O/MeOH = 20/80; flow rate, 0.7 min/min; column temperature, room temperature; wavelength, 201 nm for C1 and C2, 220 nm for the others.

The copies of ¹H NMR, ¹³C NMR, ¹⁹F NMR, ¹¹B NMR and HR-MS spectra of the synthesized intermediates and target compounds can be seen in Supplementary Materials.

General synthetic procedure 1: To a stirred solution of sugar lactol (1.0 eq) in DMSO (about 10 mL/g of sugar derivative) cooled at 0 °C under N₂ was added dropwise Ac₂O (5 mL/g of sugar derivative) and, after addition, the reaction mixture was stirred at room temperature overnight when TLC analysis indicated completion of the reaction. The reaction mixture was poured into stirred ice water, and the resulting mixture was extracted with EtOAc in three portions (3×). The combined extracts were washed successively with saturated aqueous NaHCO₃ and brine, dried (MgSO₄), and evaporated on a rotary evaporator to afford a residue, which was purified through column chromatography to obtain the product sugar lactone.

General synthetic procedure 2: To a stirred solution of aryl halide (1.0–1.2 eq) in dried THF (about 10 mL/g of aryl halide) cooled at −78 °C under N₂ was added dropwise a solution of n-BuLi in THF (1.0–1.2 eq) and, after addition, the resulting mixture was stirred at this temperature for 1 h followed by dropwise addition of a solution of sugar lactone in dried THF. After addition, the resulting mixture was stirred at this temperature for 1 h followed by dropwise addition of a solution of MeSO₃H (5.0 eq) in MeOH. After that, the reaction mixture was stirred at room temperature overnight when TLC analysis indicated completion of the reaction and poured into ice water, and the mixture thus obtained was extracted with EtOAc in three portions (3×). The combined extracts were washed successively with saturated aqueous NaHCO₃ and brine, dried (MgSO₄), and evaporated on a rotary evaporator to afford a crude methyl glycopyranoside, which was used in the next step without further purification or characterization.

General synthetic procedure 3: To a stirred solution of the crude methyl glycopyranoside prepared above in general synthetic procedure 2 (1.0 eq, calculated by assuming the sample was pure) in dried CH₂Cl₂ (about 10 mL/g of crude methyl glycopyranoside) cooled at −35 °C under N₂ were added successively Et₃SiH (2.0–3.0 eq) and BF₃·Et₂O (1.2–5.2 eq) each in a dropwise manner, and, after additions, the reaction mixture was stirred at room temperature overnight when TLC analysis indicated completion of the reaction. The reaction mixture was poured into ice water, and the mixture thus obtained was extracted with CH₂Cl₂ in three portions (3×). The combined extracts were washed successively with saturated aqueous NaHCO₃ and brine, dried (MgSO₄), and evaporated on a rotary evaporator to afford a residue, which was purified through column chromatography to obtain the desired product.

General synthetic procedure 4: To a stirred solution of o-carborane (1.0 eq) in dried THF (about 8 mL/g of o-carborane) cooled at 0 °C under N₂ was added dropwise a solution of n-BuLi in THF (1.5 eq) and, after addition, the resulting mixture was stirred at room temperature for 1 h followed by the addition of bis(tri-tert-butylphosphine)palladium(0) (Pd[P(t-Bu)₃]₂) (0.1–1.0 eq) and tricyclohexylphosphine (PCy₃) (0.1–1.0 eq). After that, stirring was continued for 0.5 h, and a solution of aryl iodide in dried m-xylene (20 mL/g of aryl iodide) was added. The reaction mixture was then stirred at 130 °C overnight when TLC analysis indicated completion of the reaction. Upon cooling to room temperature, the reaction mixture was quenched with saturated aqueous NH₄Cl, and the mixture thus obtained was extracted with EtOAc in three portions (3×). The combined extracts were washed with brine, dried (MgSO₄), and evaporated on a rotary evaporator to afford a residue, which was purified through column chromatography to obtain the desired product.

General synthetic procedure 5: To a stirred dried MeOH (about 20 mL/g of substrate) cooled at 0 °C under N₂ was added portion-wise freshly cut sodium (3.0–12.0 eq), and the mixture was stirred until the sodium was consumed completely. The substrate to be deacetylated was added, and stirring was continued at room temperature until completion, as indicated by TLC analysis (typically within 0.5 h). Strongly acidic cation exchange resin (Amberlite 732) was added to neutralize the OH⁻ and absorb the Na⁺ until pH = 7. The mixture was filtered off, and the filtrate was evaporated on a rotary evaporator to afford a residue, which was purified through column chromatography to obtain the desired product.

General synthetic procedure 6: To a stirred solution of alcohol (1.0 eq) and β-D-glucose pentaacetate (2.0 eq) in dried CH₂Cl₂ cooled at 0 °C under N₂ was added dropwise BF₃·Et₂O (4.0 eq) and, after addition, the reaction mixture was stirred at room temperature when TLC analysis indicated completion of the reaction. The reaction mixture was poured into ice water, and the resulting mixture was extracted with CH₂Cl₂ in three portions (3×). The combined extracts were washed successively with saturated aqueous NaHCO₃ and brine, dried (MgSO₄), and evaporated on a rotary evaporator to afford a residue, which was purified through column chromatography to obtain the desired product.

General synthetic procedure 7: A mixture of aryl halide (1.0 eq), B₂Pin₂ (1.0–3.0 eq), KOAc (3.0 eq), and Pd(dppf)Cl₂ (0.2–0.3 eq) in dried DMSO under N₂ was stirred at 87 °C until completion of the reaction, as indicated by TLC analysis (typically within 5–6 h). Upon cooling to room temperature, the reaction mixture was poured into ice water, and the resulting mixture was filtered off through celite. The filtrate was extracted with EtOAc in three portions (3×), and the combined extracts were washed with brine, dried (MgSO₄), and evaporated on a rotary evaporator to afford a residue, which was purified through column chromatography to obtain the desired product.

General synthetic procedure 8: To a stirred solution of phenylboronic acid pinacol ester (1.0 eq) in a mixed solvent of acetone/H₂O (8/2 by v/v; in total 10 mL/g of phenylboronic acid pinacol ester) at room temperature were added NaIO₄ (2.5 eq) and NH₄OAc (1.5 eq) and, after addition, the reaction mixture was stirred at room temperature overnight when TLC indicated completion of the reaction. The reaction mixture was then brought to pH = 3 with 1 M HCl and extracted with CH₂Cl₂ in three portions (3×), and the combined extracts were washed with brine, dried (MgSO₄), and evaporated on a rotary evaporator to afford a residue, which was purified through column chromatography to obtain the desired product.

Synthesis of (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (2): To a stirred mixture of D-glucono-δ-lactone (1, 30.00 g, 0.168 mol) in dried THF (300 mL) cooled at 0 °C under N₂ were added NMM (136.27 g, 1.35 mol) and DMAP (2.06 g, 16.8 mmol), followed by dropwise addition of TMSCl (109.77 g, 1.01 mol), and, after addition, the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water (300 mL), and the resulting mixture was extracted with n-hexane (b.p., 60–90 °C; 200 mL × 3). The combined extracts were washed with brine, dried (MgSO₄), and evaporated on a rotary evaporator to afford a residue, which was purified through column chromatography (PE) to give 2. Colorless oil, 53.15 g (68%). ¹H NMR (500 MHz, CDCl₃) δ 4.19–4.16 (m, 1H), 4.00 (d, J = 8.0 Hz, 1H), 3.90 (t, J = 7.5 Hz, 1H), 3.83–3.74 (m, 3H), 0.20–0.13 (m, 36H). The ¹H NMR data were consistent with those reported [40].

Synthesis of 4-bromo-1,2-bis(bromomethyl)benzene (4): To a stirred mixture of 4-bromo-1,2-dimethylbenzene (3, 10.00 g, 54.0 mmol) and NBS (19.23 g, 0.108 mol) in dried CCl₄ (100 mL) heated at 60 °C under N₂ was added AIBN (0.89 g, 5.40 mmol) portion-wise, and, after addition, the reaction mixture was refluxed (caution: violent exotherm may occur) until completion of the reaction, as indicated by TLC analysis (typically within 1 h). Upon cooling to room temperature, the reaction mixture was filtered off through celite, and the filtrate was evaporated on a rotary evaporator to afford a residue, which was purified through column chromatography (PE) to give 4. Colorless oil, 5.90 g (37%). ¹H NMR (500 MHz, CDCl₃) δ 7.52 (d, J = 2.0 Hz, 1H), 7.43 (dd, J = 8.0, 2.0 Hz, 1H), 7.25–7.23 (m, 1H), 4.59 (s, 2H), 4.58 (s, 2H). The ¹H NMR data were consistent with those reported [41].

Synthesis of (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-one (6): Following the general synthetic procedure 1, 6 was prepared from 5 (25.00 g, 46.2 mmol) using Ac₂O (125 mL) and DMSO (250 mL). The crude 5 was purified through column chromatography (EtOAc/PE = 1/5 by v/v) to give 6. Yellow oil, 23.59 g (95%). ¹H NMR (500 MHz, CDCl₃) δ 7.39–7.37 (m, 2H), 7.35–7.28 (m, 14H), 7.26–7.24 (m, 2H), 7.18–7.16 (m, 2H), 4.99 (d, J = 11.5 Hz, 1H), 4.74–4.69 (m, 2H), 4.65–4.49 (m, 5H), 4.46–4.44 (m, 1H), 4.12 (d, J = 6.5 Hz, 1H), 3.97–3.89 (m, 2H), 3.74–3.65 (m, 2H). The ¹H NMR data were consistent with those reported [42].

Synthesis of (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)-2-(4-iodophenyl)-2-methoxytetrahydro-2H-pyran (7): Following the general synthetic procedure 2, 7 was prepared from 6 (24.00 g, 44.6 mmol) and 1,4-diiodobenzene (17.64 g, 53.5 mmol) using n-BuLi (33 mL, 1.6 M in THF, 52.8 mmol), MeSO₃H (21.40 g, 0.223 mol), MeOH (107 mL), and dried THF (240 mL). The crude compound 7 was isolated as a brown oil, 41.50 g. This sample was used directly in the next step without further purification or characterization.

Synthesis of (2R,3R,4R,5S,6S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-6-(4-iodophenyl)tetrahydro-2H-pyran (8): Following the general synthetic procedure 3, 8 was prepared from crude 7 prepared above (41.50 g, deemed to be 54.8 mmol) using Et₃SiH (12.75 g, 0.110 mol) and BF₃·Et₂O (9.34 g, 65.8 mmol) in dried CH₂Cl₂ (415 mL). The crude 8 was purified through column chromatography (EtOAc/PE = 1/5 by v/v) to give 8. White solid, 8.90 g (27% overall for 6 to 8). m.p. 102.4–104.9 °C. ¹H NMR (500 MHz, CDCl₃) δ 7.68–7.66 (m, 2H), 7.34–7.27 (m, 13H), 7.22–7.16 (m, 7H), 6.93–6.91 (m, 2H), 4.95–4.85 (m, 3H), 4.64–4.61 (m, 2H), 4.56–4.54 (m, 1H), 4.44 (d, J = 10.5 Hz, 1H), 4.18 (d, J = 9.5 Hz, 1H), 3.88 (d, J = 10.0 Hz, 1H), 3.81–3.73 (m, 4H), 3.59–3.56 (m, 1H), 3.43 (t, J = 9.0 Hz, 1H). The ¹H NMR data were consistent with those reported [43].

Synthesis of (2R,3S,4S,5R,6S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-6-methoxytetrahydro-2H-pyran (10): To a stirred mixture of methyl α-D-galactopyranoside (9, 50.00 g, 0.257 mol) and BnBr (264.00 g, 1.54 mol) in a mixture of dried DMF (400 mL) and dried THF (100 mL) cooled at 0 °C under N₂ was added portion-wise NaH (61.80 g, 60%, 1.54 mol), and, after addition, the reaction mixture was stirred at room temperature until completion of the reaction, as indicated by TLC analysis (typically within 2 h), and then slowly poured into stirred ice water (1000 mL). The resulting mixture was extracted with EtOAc (250 mL × 3), and the combined extracts were washed with brine, dried (MgSO₄), and evaporated on a rotary evaporator to afford a residue, which was purified through column chromatography (EtOAc/PE = 1/5 by v/v) to give 10. Yellow oil, 130.64 g (91%). ¹H NMR (500 MHz, CDCl₃) δ 7.40–7.27 (m, 20H), 4.95 (d, J = 11.5 Hz, 1H), 4.86–4.82 (m, 2H), 4.75–4.68 (m, 3H), 4.57 (d, J = 11.5 Hz, 1H), 4.50–4.47 (m, 1H), 4.41–4.39 (m, 1H), 4.05–4.02 (m, 1H), 3.95–3.89 (m, 3H), 3.53 (d, J = 6.5 Hz, 2H), 3.37 (s, 3H). The ¹H NMR data were consistent with those reported [44].

Synthesis of (3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-ol (11): To a stirred solution of 10 (130.64 g, 0.236 mol) in AcOH (784 mL) heated at 80 °C was added dropwise 5 M HCl (130 mL), and, after addition, the reaction mixture was stirred at this temperature until completion of the reaction as indicated by TLC (typically within 1 h). Upon completion, the reaction mixture was quickly poured into ice water (700 mL), and the resulting mixture was extracted with EtOAc (600 mL × 3). The combined extracts were washed successively with saturated aqueous NaHCO₃ (until pH > 7) and brine, dried (MgSO₄), and evaporated on a rotary evaporator to afford a residue, which was purified through column chromatography (EtOAc/PE = 1/6 by v/v) to give 11. Yellow oil, 74.66 g. This sample was used directly in the next step without characterization.

Synthesis of (3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-one (12): Following general synthetic procedure 1, 12 was prepared from 11 (74.66 g, 0.138 mmol) using Ac₂O (373 mL) and DMSO (750 mL). Column chromatography purification (EtOAc/PE = 1/10 by v/v) gave 12. Colorless oil, 38.00 g (30% overall for 10 to 12). ¹H NMR (500 MHz, CDCl₃) δ 7.42–7.41 (m, 2H), 7.34–7.27 (m, 16H), 7.24–7.22 (m, 2H), 5.18 (d, J = 11.0 Hz, 1H), 4.93 (d, J = 11.0 Hz, 1H), 4.79–4.75 (m, 2H), 4.70–4.68 (m, 1H), 4.61 (d, J = 11.5 Hz, 1H), 4.52–4.44 (m, 3H), 4.35–4.32 (m, 1H), 4.16 (t, J = 2.0 Hz, 1H), 3.88 (dd, J = 9.5, 2.0 Hz, 1H), 3.72–3.64 (m, 2H). The ¹H NMR data were consistent with those reported [45].

Synthesis of (3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)-2-(4-iodophenyl)-2-methoxytetrahydro-2H-pyran (13): Following the general synthetic procedure 2, 13 was prepared from 12 (25.00 g, 46.4 mmol) and 1,4-diiodobenzene (18.37 g, 55.7 mmol) using n-BuLi (34.8 mL, 1.6 M in THF, 55.68 mmol), MeSO₃H (22.30 g, 0.232 mol), MeOH (112 mL), and dried THF (250 mL). The crude 13 was isolated as a brown oil, 48.41 g, which was used in the next step without further purification or characterization.

Synthesis of (2R,3S,4R,5S,6S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-6-(4-iodophenyl)tetrahydro-2H-pyran (14): Following the general synthetic procedure 3, 14 was prepared from crude 13 prepared above (48.41 g, deemed to be 64.0 mmol) using Et₃SiH (14.88 g, 0.128 mol) and BF₃·Et₂O (10.90 g, 76.8 mmol) in dried CH₂Cl₂ (480 mL). Column chromatography purification (EtOAc/PE = 1/10 by v/v) gave 14. Brown oil, 16.20 g (48% overall for 12 to 14). ¹H NMR (500 MHz, CDCl₃) δ 7.64–7.62 (m, 2H), 7.37–7.27 (m, 14H), 7.24–7.16 (m, 6H), 6.94–6.92 (m, 2H), 5.00 (d, J = 11.5 Hz, 1H), 4.78–4.72 (m, 2H), 4.63 (d, J = 12.0 Hz, 1H), 4.51 (d, J = 10.5 Hz, 1H), 4.47–4.40 (m, 2H), 4.13 (d, J = 9.0 Hz, 1H), 4.04 (d, J = 3.0 Hz, 1H), 3.94 (d, J = 10.5 Hz, 1H), 3.84 (t, J = 9.5 Hz, 1H), 3.69–3.67 (m, 2H), 3.64–3.57 (m, 2H). ¹³C NMR (151 MHz, CDCl₃) δ 139.46, 139.13, 138.57, 137.99, 137.92, 137.31, 129.96, 128.57, 128.55, 128.44, 128.39, 128.36, 128.10, 127.93, 127.91, 127.77, 127.74, 127.63, 93.78, 84.44, 81.60, 80.43, 75.33, 74.70, 74.36, 73.67, 72.67, 68.94. HR-MS (ESI): m/z [M+H]⁺ calcd for C₄₀H₄₀IO₅⁺: 727.1915, found: 727.1923.

Synthesis of (2R,3R,4S,5S,6S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-6-methoxytetrahydro-2H-pyran (16): Following the procedure for the synthesis of 10 from 9, 16 was prepared from 15 (50.00 g, 0.257 mol) using NaH (61.80 g, 60%, 1.54 mol) and BnBr (264.00 g, 1.54 mol) in a mixture of dried DMF (400 mL) and dried THF (100 mL). Column chromatography purification (EtOAc/PE = 1/8 by v/v) gave 16. Yellow oil, 109.46 g (77%). ¹H NMR (500 MHz, CDCl₃) δ 7.38–7.26 (m, 16H), 7.24–7.23 (m, 2H), 7.17–7.15 (m, 2H), 4.88 (d, J = 11.0 Hz, 1H), 4.77–4.76 (m, 1H), 4.74–4.70 (m, 2H), 4.66 (d, J = 12.0 Hz, 1H), 4.61 (s, 2H), 4.57–4.50 (m, 2H), 3.97 (t, J = 9.3 Hz, 1H), 3.89–3.87 (m, 1H), 3.79–3.72 (m, 4H), 3.32 (s, 3H). The ¹H NMR data were consistent with those reported [46].

Synthesis of (3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-ol (17): Following the procedure for the synthesis of 11 from 10, 17 was prepared from 16 (109.46 g, 0.197 mol) using 5 M HCl (110 mL) in AcOH (660 mL). Column chromatography purification (EtOAc/PE = 1/6 by v/v) gave 17. Yellow oil, 42.23 g. This sample was used directly in the next step without characterization.

Synthesis of (3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-one (18): Following the general synthetic procedure 1, 18 was prepared from 17 (42.23 g, 78.1 mmol) using Ac₂O (211 mL) and DMSO (422 mL). Column chromatography purification (EtOAc/PE = 1/8 by v/v) gave 18. Colorless oil, 37.00 g (35% overall for 16 to 18). ¹H NMR (500 MHz, CDCl₃) δ 7.40–7.29 (m, 18H), 7.10–7.08 (m, 2H), 5.06 (d, J = 12.0 Hz, 1H), 4.83 (d, J = 12.0 Hz, 1H), 4.65–4.58 (m, 2H), 4.56–4.51 (m, 2H), 4.35–4.32 (m, 2H), 4.26–4.22 (m, 2H), 4.05–4.04 (m, 1H), 3.79–3.77 (m, 1H), 3.63 (d, J = 4.5 Hz, 2H). The ¹H NMR data were consistent with those reported [47].

Synthesis of (3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)-2-(4-iodophenyl)-2-methoxytetrahydro-2H-pyran (19): Following the general synthetic procedure 2, 19 was prepared from 18 (22.00 g, 40.8 mmol) and 1,4-diiodobenzene (16.17 g, 49.0 mmol) using n-BuLi (30.6 mL, 1.6 M in THF, 48.96 mmol), MeSO₃H (19.63 g, 0.204 mol), MeOH (98 mL), and dried THF (220 mL). The crude product was isolated as a brown oil, 33.68 g, and used directly in the next step without further purification or characterization.

Synthesis of (2R,3R,4R,5R,6S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-6-(4-iodophenyl)tetrahydro-2H-pyran (20): Following the general synthetic procedure 3, 20 was prepared from crude 19 prepared above (33.68 g, deemed to be 44.5 mmol) using Et₃SiH (10.35 g, 89.0 mmol) and BF₃·Et₂O (7.58 g, 53.4 mmol) in dried CH₂Cl₂ (337 mL). Column chromatography purification (EtOAc/PE = 1/15 by v/v) gave 20. Yellow oil, 7.74 g (26% overall for 18 to 20). ¹H NMR (500 MHz, CDCl₃) δ 7.61–7.58 (m, 2H), 7.38–7.27 (m, 13H), 7.23–7.14 (m, 5H), 7.08–7.07 (m, 2H), 6.90–6.89 (m, 2H), 4.91 (d, J = 10.5 Hz, 1H), 4.76–4.69 (m, 3H), 4.62–4.54 (m, 3H), 4.40 (s, 1H), 4.22 (d, J = 11.5 Hz, 1H), 4.01 (t, J = 9.5 Hz, 1H), 3.89–3.88 (m, 1H), 3.82–3.77 (m, 3H), 3.61–3.58 (m, 1H). ¹³C NMR (151 MHz, CDCl₃) δ 138.84, 138.56, 138.46, 138.42, 138.08, 137.10, 128.66, 128.61, 128.51, 128.47, 128.23, 128.20, 128.17, 128.02, 127.85, 127.83, 127.67, 127.50, 92.84, 85.02, 80.03, 79.41, 75.43, 75.07, 74.57, 73.65, 72.52, 69.71. HR-MS (ESI): m/z [M+Na]⁺ calcd for C₄₀H₃₉INaO₅⁺: 749.1734, found: 749.1732.

Synthesis of (2R,3S,4R)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-3,4-dihydro-2H-pyran (22): To a stirred mixture of 21 (33.00 g, 0.226 mol) in dried THF (462 mL) cooled at 0 °C under N₂ were added NaH (32.5 g, 60%, 0.813 mol) portion-wise and TBAI (5.00 g, 13.5 mmol) in one portion, and, after additions, stirring was continued for 0.5 h, followed by dropwise addition of BnBr (139.06 g, 0.813 mol). After that, the reaction mixture was stirred at room temperature overnight, when TLC analysis indicated completion of the reaction, and then poured slowly into stirred ice water (1000 mL). The resulting mixture was extracted with EtOAc (300 mL × 3), and the combined extracts were washed with brine, dried (MgSO₄), and evaporated on a rotary evaporator to afford a residue, which was purified through column chromatography (EtOAc/PE = 1/12 by v/v) to give 22. White solid, 48.00 g (51%). m.p. 52.8–55.2 °C. ¹H NMR (500 MHz, CDCl₃) δ 7.33–7.27 (m, 13H), 7.25–7.23 (m, 2H), 6.42 (d, J = 6.0 Hz, 1H), 4.87 (dd, J = 6.3, 2.8 Hz, 1H), 4.83 (d, J = 11.5 Hz, 1H), 4.65–4.62 (m, 2H), 4.61–4.54 (m, 3H), 4.21 (d, J = 5.5 Hz, 1H), 4.08–4.05 (m, 1H), 3.87–3.84 (m, 1H), 3.82–3.75 (m, 2H). The ¹H NMR data were consistent with those reported [48].

Synthesis of (3R,4S,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-3-fluorotetrahydro-2H-pyran-2-ol (23): A mixture of 22 (7.70 g, 18.5 mmol) and selectfluor^® (26.20 g, 73.9 mmol) in a mixture of DMF (39 mL) and H₂O (39 mL) was stirred at 50 °C overnight when TLC analysis indicated completion of the reaction. Upon cooling to room temperature, the reaction mixture was poured into ice water (90 mL), and the resulting mixture was extracted with EtOAc (80 mL × 3). The combined extracts were washed with brine, dried (MgSO₄), and evaporated on a rotary evaporator to afford crude 23 as a yellow oil, 10.90 g, which was used directly in the next step without further purification or characterization.

Synthesis of (3R,4S,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-3-fluorotetrahydro-2H-pyran-2-one (24): Following the general synthetic procedure 1, 24 was prepared from crude 23 prepared above (10.90 g, deemed to be 24.1 mmol) using Ac₂O (55 mL) and DMSO (109 mL). Column chromatography purification (EtOAc/PE = 1/6 by v/v) gave 24. White solid, 1.39 g (17% overall for 22 to 24). m.p. 58.8–60.2 °C. ¹H NMR (600 MHz, DMSO-d₆) δ 7.35–7.29 (m, 13H), 7.23–7.22 (m, 2H), 5.38 (dd, J = 46.8, 8.4 Hz, 1H), 4.76–4.71 (m, 3H), 4.57–4.53 (m, 3H), 4.51–4.49 (m, 1H), 4.26–4.21 (m, 1H), 3.98 (t, J = 7.8 Hz, 1H), 3.70 (d, J = 3.6 Hz, 2H). The m.p. and ¹H NMR were consistent with those reported [38].

Synthesis of (3R,4S,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-3-fluoro-2-(4-iodophenyl)-2-methoxytetrahydro-2H-pyran (25): Following the general synthetic procedure 2, 25 was prepared from 24 (0.50 g, 1.11 mmol) and 1,4-diiodobenzene (0.44 g, 1.33 mmol) using n-BuLi (0.83 mL, 1.6 M in THF, 1.328 mmol), MeSO₃H (0.53 g, 5.55 mmol), MeOH (2.7 mL), and dried THF (5 mL). The crude 25 was isolated as a yellow oil, 0.24 g, which was used directly in the next step without further purification or characterization.

Synthesis of (2R,3R,4S,5S,6S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-fluoro-6-(4-iodophenyl)tetrahydro-2H-pyran (26): Following the general synthetic procedure 3, 26 was prepared from crude 25 prepared above (0.24 g, deemed to be 0.359 mmol) using Et₃SiH (83 mg, 0.718 mmol) and BF₃·Et₂O (61 mg, 0.431 mmol) in dried CH₂Cl₂ (2.4 mL). Column chromatography purification (EtOAc/PE = 1/20 by v/v) gave 26. Yellow oil, 94 mg (13% overall for 24 to 26). ¹H NMR (500 MHz, CDCl₃) δ 7.76 (d, J = 8.0 Hz, 2H), 7.41–7.27 (m, 15H), 7.21 (d, J = 8.0 Hz, 2H), 4.96 (t, J = 10.3 Hz, 2H), 4.85–4.82 (m, 1H), 4.67–4.65 (m, 2H), 4.60–4.58 (m, 1H), 4.50–4.39 (m, 1H), 4.35–4.32 (m, 1H), 3.98–3.92 (m, 1H), 3.82–3.79 (m, 3H), 3.68–3.65 (m, 1H). ¹³C NMR (151 MHz, CDCl₃) δ 138.25, 138.19, 138.11, 137.57, 137.48, 129.03, 128.52, 128.51, 128.49, 128.10, 127.94, 127.89, 127.81, 127.76, 95.57, 94.32 (d, J = 5.1 Hz), 84.6 (d, J = 16.3 Hz), 79.39, 78.74 (d, J = 23.2 Hz), 75.34, 75.00 (d, J = 3.0 Hz), 73.56, 68.93. HR-MS (ESI): m/z [M+H]⁺ calcd for C₃₃H₃₃FIO₄⁺: 639.1402, found: 639.1407.

Synthesis of 1-(tert-butyldimethylsilyl)-1,2-dicarba-closo-dodecaborane (28): To a stirred solution of o-carborane (27, 0.20 g, 1.39 mmol) in dried THF (1.6 mL) cooled at 0 °C under N₂ was added n-BuLi (1 mL, 1.6 M in THF, 1.6 mmol), and, after addition, the reaction mixture was stirred at room temperature for 1 h and cooled back to 0 °C again, followed by the addition of a solution of TBDMSCl (0.27 g, 1.80 mmol) in dried THF (0.4 mL). After that, the reaction mixture was stirred at room temperature overnight, when TLC analysis indicated completion of the reaction, and then poured into ice water (20 mL). The mixture thus obtained was extracted with EtOAc (30 mL × 3), and the combined extracts were washed with brine, dried (MgSO₄), and evaporated on a rotary evaporator to afford a residue, which was purified through column chromatography (PE) to give 28. White solid, 0.29 g (81%). m.p. 60.8–62.2 °C. ¹H NMR (500 MHz, CDCl₃) δ 3.44 (s, 1H), 2.85–1.50 (m, 10H), 1.02 (s, 9H), 0.23 (s, 6H). The m.p. and ¹H NMR were consistent with those reported [49].

Synthesis of 1-tert-butyl-2-[(4-iodophenyl)methyl]-1,2-dicarba-closo-dodecaborane (29): To a stirred solution of 28 (0.50 g, 1.93 mmol) in dried THF (5 mL) cooled at 0 °C under N₂ was added dropwise n-BuLi (1.5 mL, 1.6 M in THF, 2.4 mmol), and, after addition, the reaction mixture was stirred at room temperature for 1 h and cooled back to 0 °C again, followed by dropwise addition of 4-iodobenzyl bromide (0.69 g, 2.32 mmol) in dried THF. After that, the reaction mixture was stirred at room temperature overnight, when TLC analysis indicated completion of the reaction, and then poured into ice water (30 mL). The resulting mixture was extracted with EtOAc (30 mL × 3), and the combined extracts were washed with brine, dried (MgSO₄), and evaporated on a rotary evaporator to afford a residue, which was purified through column chromatography (PE) to give 29. White solid, 0.28 g (31%). m.p. 124.0–125.8 °C. ¹H NMR (500 MHz, CDCl₃) δ 7.68–7.65 (m, 2H), 6.91–6.89 (m, 2H), 3.40 (s, 2H), 2.68–1.81 (m, 10H), 1.13 (s, 9H), 0.42 (s, 6H). ¹³C NMR (151 MHz, CDCl₃) δ 137.94, 135.47, 131.84, 93.95, 80.54, 75.25, 75.24, 75.22, 43.12, 27.84, 20.66, −2.02. HR-MS (ESI): m/z [M+H]⁺ calcd for C₁₅H₃₂B₁₀ISi⁺: 477.2243, found: 477.2267.

Synthesis of (3R,4S,5S,6R)-6-(hydroxymethyl)-2-methoxy-2-(4-((2-tert-butyldimethylsilyl-1,2-dicarba-closo-dodecaboran-1-yl)methyl)phenyl)tetrahydro-2H-pyran-3,4,5-triol (30): To a stirred solution of 29 (4.27 g, 9.00 mmol) in dried THF (43 mL) cooled at −78 °C under N₂ was added dropwise n-BuLi (6.7 mL, 1.6 M in THF, 10.72 mmol), and, after addition, the reaction mixture was stirred at this temperature for 1 h, followed by dropwise addition of a solution of 2 (8.40 g, 18.0 mmol) in dried THF (10 mL). After that, the reaction mixture was stirred at this temperature for 1 h, followed by dropwise addition of a solution of MeSO₃H (4.32 g, 45.0 mmol) in MeOH (22 mL). After that, the reaction mixture was stirred at room temperature overnight, when TLC analysis indicated completion of the reaction, and then poured into ice water (150 mL). The resulting mixture was extracted with EtOAc (50 mL × 3), and the combined extracts were washed with brine, dried (MgSO₄), and evaporated on a rotary evaporator to afford crude 30 as a brown foam, 5.80 g, which was used directly in the next step without further purification.

Synthesis of (3R,4S,5R,6R)-6-(acetoxymethyl)-2-methoxy-2-(4-((2-tert-butyldimethylsilyl-1,2-dicarba-closo-dodecaboran-1-yl)methyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (31): To a stirred mixture of crude 30 prepared above (5.80 g, deemed to be 10.7 mmol) and DMAP (1.31 g, 10.7 mmol) in pyridine (58 mL) cooled at 0 °C was added dropwise Ac₂O (29 mL), and, after addition, the reaction mixture was stirred at room temperature overnight, when TLC analysis indicated completion of the reaction, and then poured into ice water (70 mL). The resulting mixture was extracted with EtOAc (80 mL × 3), and the combined extracts were washed successively with 1 M HCl (until pH = 5–6) and brine, dried (MgSO₄), and evaporated on a rotary evaporator to afford crude 31 as a brown oil, 7.06 g, which was used directly in the next step without further purification or characterization.

Synthesis of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-((2-tert-butyldimethylsilyl-1,2-dicarba-closo-dodecaboran-1-yl)methyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (32): Following the general synthetic procedure 3, 32 was prepared from crude 31 prepared above (7.06 g, deemed to be 9.96 mmol) using Et₃SiH (3.47 g, 29.9 mmol) and BF₃·Et₂O (7.35 g, 51.8 mmol) in dried CH₂Cl₂ (70 mL). Column chromatography purification (EtOAc/PE = 1/3 by v/v) gave 32. White foam, 1.50 g (25% overall for 29 to 32). ¹H NMR (500 MHz, CDCl₃) δ 7.31 (d, J = 8.5 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 5.35–5.30 (m, 1H), 5.23 (t, J = 9.8 Hz, 1H), 5.10 (t, J = 9.8 Hz, 1H), 4.40 (d, J = 10.0 Hz, 1H), 4.32–4.28 (m, 1H), 4.19–4.11 (m, 1H), 3.86–3.83 (m, 1H), 3.45 (s, 2H), 2.89–1.51 (m, 10H), 2.10 (s, 3H), 2.06 (s, 3H), 2.00 (s, 3H), 1.79 (s, 3H), 1.14 (s, 9H), 0.43 (s, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 170.86, 170.47, 169.64, 168.92, 136.57, 136.32, 130.03, 127.56, 80.99, 80.00, 77.36, 76.34, 75.22, 74.21, 72.74, 68.70, 62.43, 43.31, 27.82, 20.91, 20.76, 20.62, 20.43, −2.04, −2.07. HR-MS (ESI): m/z [M+H]⁺ calcd for C₂₉H₅₁B₁₀O₉Si⁺: 681.4227, found: 681.4238.

Synthesis of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-((1,2-dicarba-closo-dodecaboran-1-yl)methyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (33): To a stirred solution of 32 (0.75 g, 1.10 mmol) in dried THF (7.5 mL) cooled at −78 °C under N₂ was added dropwise a solution of TBAF in THF (1.7 mL, 1.0 M in THF, 1.7 mmol), and, after addition, the reaction mixture was stirred at room temperature for 1 h, when TLC analysis indicated completion of the reaction, and then poured into ice water (30 mL). The resulting mixture was extracted with EtOAc (30 mL × 3), and the combined extracts were washed with brine, dried (MgSO₄), and evaporated on a rotary evaporator to afford a residue, which was purified through column chromatography (EtOAc/PE = 1/2 by v/v) to obtain 33. White solid, 0.44 g (71%). m.p. 192.2–195.9 °C. ¹H NMR (500 MHz, CDCl₃) δ 7.34 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 5.34 (t, J = 9.5 Hz, 1H), 5.22 (t, J = 9.7 Hz, 1H), 5.02 (t, J = 9.8 Hz, 1H), 4.39 (d, J = 9.5 Hz, 1H), 4.32–4.29 (m, 1H), 4.21–4.18 (m, 1H), 3.87–3.84 (m, 1H), 3.51 (s, 2H), 3.13 (s, 1H), 2.76–1.63 (m, 10H), 2.10 (s, 3H), 2.06 (s, 3H), 2.00 (s, 3H), 1.79 (s, 3H). ¹³C NMR (151 MHz, CDCl₃) δ 170.87, 170.45, 169.67, 168.92, 137.04, 135.03, 130.00, 127.84, 79.92, 76.39, 74.31, 73.93, 73.03, 68.68, 62.38, 59.46, 43.26, 20.94, 20.78, 20.48. HR-MS (ESI): m/z [M+H]⁺ calcd for C₂₃H₃₇B₁₀O₉⁺: 567.3363, found: 567.3361.

Synthesis of (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(4-((1,2-dicarba-closo-dodecaboran-1-yl)methyl)phenyl)tetrahydro-2H-pyran-3,4,5-triol (A1): Following the general synthetic procedure 5, A1 was prepared from 33 (0.40 g, 0.708 mmol) using Na (98 mg, 4.25 mmol) in MeOH (8 mL). Column chromatography purification (MeOH/CH₂Cl₂ = 1/10 by v/v) gave A1. White foam, 0.25 g (89%). [α]_D²⁰ = +10.2° (c = 10.4, MeOH). ¹H NMR (500 MHz, CD₃OD) δ 7.43 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 7.5 Hz, 2H), 4.24 (s, 1H), 4.15 (d, J = 9.5 Hz, 1H), 3.90–3.88 (m, 1H), 3.72–3.69 (m, 1H), 3.58 (s, 2H), 3.50–3.47 (m, 1H), 3.42–3.41 (m, 2H), 3.38–3.35 (m, 1H), 2.57–1.63 (m, 10H). ¹³C NMR (151 MHz, CD₃OD) δ 140.94, 136.23, 130.85, 129.35, 83.18, 82.27, 79.81, 76.92, 76.41, 71.91, 63.13, 62.71, 43.98. ¹¹B NMR (161 MHz, CD₃OD) δ −2.35, −3.27, −5.39, −6.31,−8.90, −9.83, −10.57, −11.59, −12.56, −13.40. HR-MS (ESI): m/z [M-H]⁻ calcd for C₁₅H₂₇B₁₀O₅⁻: 397.2795, found: 397.2776. HPLC purity, 97.84%.

Synthesis of (3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)-2-methoxy-2-(4-((2-tert-butyldimethylsilyl-1,2-dicarba-closo-dodecaboran-1-yl)methyl)phenyl)tetrahydro-2H-pyran (34): Following the general synthetic procedure 2, 34 was prepared from 29 (3.78 g, 7.97 mmol) and 12 (6.44 g, 11.9 mmol) using n-BuLi (5.5 mL, 1.6 M in THF, 8.8 mmol), MeSO₃H (3.83 g, 39.8 mmol), MeOH (19.2 mL), and dried THF (38 mL) as a crude sample. Brown oil, 10.22 g. This sample was used directly in the next step without further purification or characterization.

Synthesis of (2R,3S,4R,5S,6S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-6-(4-((2-tert-butyldimethylsilyl-1,2-dicarba-closo-dodecaboran-1-yl)methyl)phenyl)tetrahydro-2H-pyran (35): Following the general synthetic procedure 3, 35 was prepared from crude 34 prepared above (10.22 g, deemed to be 11.3 mmol) using Et₃SiH (2.64 g, 22.7 mmol) and BF₃·Et₂O (1.93 g, 13.6 mmol) in dried CH₂Cl₂ (102 mL). Column chromatography purification (EtOAc/PE = 1/10 by v/v) gave 35. White foam, 2.83 g (41%, 29 to 35). ¹H NMR (500 MHz, CDCl₃) δ 7.45–7.43 (m, 2H), 7.39–7.27 (m, 15H), 7.21–7.19 (m, 3H), 7.15–7.13 (m, 2H), 6.99–6.97 (m, 2H), 5.03 (d, J = 12.0 Hz, 1H), 4.79 (s, 2H), 4.65 (d, J = 11.5 Hz, 1H), 4.51–4.48 (m, 1H), 4.46–4.42 (m, 2H), 4.21 (d, J = 9.5 Hz, 1H), 4.07–4.06 (m, 1H), 3.90 (t, J = 9.3 Hz, 1H), 3.81 (d, J = 10.0 Hz, 1H), 3.72–3.70 (m, 2H), 3.68–3.61 (m, 2H), 3.47 (s, 2H), 2.98–1.71 (m, 10H), 1.14 (s, 9H), 0.44 (s, 6H). ¹³C NMR (151 MHz, CDCl₃) δ 139.78, 139.22, 138.70, 138.04, 135.73, 129.73, 128.56, 128.42, 128.37, 128.36, 128.33, 128.10, 127.91, 127.73, 127.69, 127.61, 127.56, 84.29, 81.84, 81.34, 80.95, 75.40, 75.23, 74.73, 74.54, 73.67, 72.74, 68.96, 43.43, 27.87, 20.66, −1.95, −2.04. HR-MS (ESI): m/z [M+H]⁺ calcd for C₄₉H₆₇B₁₀O₅Si⁺: 873.5683, found: 873.5743.

Synthesis of (2R,3S,4R,5S,6S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-6-(4-((1,2-dicarba-closo-dodecaboran-1-yl)methyl)phenyl)tetrahydro-2H-pyran (36): Following the procedure for the synthesis of 33 from 32, 36 was prepared from 35 (0.59 g, 0.677 mmol) using TBAF (1 mL, 1.0 M in THF) in dried THF (5.9 mL). Column chromatography purification (EtOAc/PE = 1/8 by v/v) gave 36. Pale yellow oil, 0.29 g (57%). ¹H NMR (500 MHz, CDCl₃) δ 7.47 (d, J = 8.0 Hz, 2H), 7.38–7.33 (m, 8H), 7.32–7.27 (m, 7H), 7.21–7.18 (m, 3H), 7.11 (d, J = 8.0 Hz, 2H), 6.94–6.92 (m, 2H), 5.02 (d, J = 11.5 Hz, 1H), 4.80–4.74 (m, 2H), 4.65 (d, J = 11.5 Hz, 1H), 4.53 (d, J = 10.5 Hz, 1H), 4.49–4.42 (m, 2H), 4.22 (d, J = 9.0 Hz, 1H), 4.08–4.07 m, 1H), 3.89 (t, J = 9.5 Hz, 1H), 3.80 (d, J = 10.0 Hz, 1H), 3.73–3.70 (m, 2H), 3.66–3.60 (m, 2H), 3.52 (s, 2H), 3.17 (s, 1H), 2.60–1.70 (m, 10H). ¹³C NMR (151 MHz, CDCl₃) δ 140.20, 139.13, 138.58, 137.97, 137.95, 134.14, 129.70, 128.78, 128.57, 128.40, 128.36, 128.15, 128.11, 127.97, 127.93, 127.78, 127.63, 84.28, 81.70, 80.75, 77.42, 75.33, 74.76, 74.53, 74.42, 73.68, 72.69, 68.87, 59.37, 43.40. HR-MS (ESI): m/z [M+H]⁺ calcd for C₄₃H₅₃B₁₀O₅⁺: 759.4818, found: 759.4868.

Synthesis of (2R,3S,4R,5S,6S)-2-(acetoxymethyl)-6-(4-((1,2-dicarba-closo-dodecaboran-1-yl)methyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (37): To a stirred solution of 36 (1.16 g, 1.53 mmol) in Ac₂O (11.6 mL) cooled at 0 °C under N₂ was added dropwise BF₃·Et₂O (11.6 mL), and, after addition, the reaction mixture was stirred at 50 °C overnight, when TLC analysis indicated completion of the reaction. Upon cooling to room temperature, the reaction mixture was poured into ice water (50 mL), and the resulting mixture was extracted with EtOAc (70 mL × 3). The combined extracts were washed with brine, dried (MgSO₄), and evaporated on a rotary evaporator to afford a residue, which was purified through column chromatography (EtOAc/PE = 1/4 by v/v) to give 37. Yellow foam, 0.36 g (42%). ¹H NMR (500 MHz, CDCl₃) δ 7.38 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 8.0 Hz, 2H), 5.54–5.53 (m, 1H), 5.24–5.17 (m, 2H), 4.35 (d, J = 8.5 Hz, 1H), 4.23–4.16 (m, 2H), 4.10–4.06 (m, 1H), 3.55–3.49 (m, 2H), 3.13 (s, 1H), 2.86–1.64 (m, 10H), 2.21 (s, 3H), 2.04 (s, 3H), 1.98 (s, 3H), 1.79 (s, 3H). ¹³C NMR (151 MHz, CDCl₃) δ 170.59, 170.37, 170.27, 169.06, 137.38, 134.92, 129.87, 127.97, 80.46, 74.83, 74.36, 71.81, 70.44, 67.84, 61.82, 59.48, 43.19, 20.84, 20.73, 20.57. HR-MS (ESI): m/z [M+H]⁺ calcd for C₂₃H₃₇B₁₀O₉⁺: 567.3363, found: 567.3369.

Synthesis of (2R,3R,4R,5R,6S)-2-(hydroxymethyl)-6-(4-((1,2-dicarba-closo-dodecaboran-1-yl)methyl)phenyl)tetrahydro-2H-pyran-3,4,5-triol (A2): Following the general synthetic procedure 5, A2 was prepared from 37 (0.36 g, 0.638 mmol) using Na (59 mg, 2.55 mmol) in dried MeOH (7.2 mL). Column chromatography purification (MeOH/CH₂Cl₂ = 1/10 by v/v) gave A2. White solid, 0.22 g (87%). m.p. 108.6–110.9 °C. [α]_D²⁰ = +20.0° (c = 10, MeOH). ¹H NMR (500 MHz, DMSO-d₆) δ 7.34–7.32 (m, 2H), 7.16–7.14 (m, 2H), 5.11 (s, 1H), 4.71 (d, J = 5.5 Hz, 1H), 4.61–4.60 (m, 1H), 4.57 (t, J = 5.3 Hz, 1H), 4.41–4.40 (m, 1H), 3.96 (d, J = 9.5 Hz, 1H), 3.77–3.75 (m, 1H), 3.57 (s, 2H), 3.56–3.47 (m, 4H), 3.42–3.38 (m, 1H), 2.85–1.47 (m, 10H). ¹³C NMR (151 MHz, DMSO-d₆) δ 140.33, 134.53, 129.28, 127.99, 81.70, 79.38, 76.59, 75.03, 71.53, 68.90, 62.83, 60.89, 41.80. ¹¹B NMR (161 MHz, DMSO-d₆) δ −2.75, −3.68, −7.18, −9.32, −9.40, −10.22, −10.27, −12.10. HR-MS (ESI): m/z [M+Na]⁺ calcd for C₁₅H₂₈B₁₀NaO₅⁺: 421.2760, found: 421.2742. HPLC purity, 97.90%.

Synthesis of (3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)-2-methoxy-2-(4-((2-tert-butyldimethylsilyl-1,2-dicarba-closo-dodecaboran-1-yl)methyl)phenyl)tetrahydro-2H-pyran (38): Following the general synthetic procedure 2, 38 was prepared from 29 (3.00 g, 6.32 mmol) and 18 (5.11 g, 9.48 mmol) using n-BuLi (4.3 mL, 1.6 M in THF, 6.88 mmol), MeSO₃H (3.04 g, 31.6 mmol), MeOH (15.2 mL), and dried THF (30 mL) as a crude sample. Yellow oil, 7.75 g. This sample was used directly in the next step without further purification or characterization.

Synthesis of (2R,3R,4R,5R,6S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-6-(4-((2-tert-butyldimethylsilyl-1,2-dicarba-closo-dodecaboran-1-yl)methyl)phenyl)tetrahydro-2H-pyran (39): Following the general synthetic procedure 3, 39 was prepared from crude 38 prepared above (7.75 g, deemed to be 8.60 mmol) using Et₃SiH (2.00 g, 17.2 mmol) and BF₃·Et₂O (1.46 g, 10.3 mmol) in dried CH₂Cl₂ (78 mL). Column chromatography purification (EtOAc/PE = 1/13 by v/v) gave 39. Yellow oil, 2.13 g (39% overall for 29 to 39). ¹H NMR (500 MHz, CDCl₃) δ 7.38–7.27 (m, 16H), 7.24–7.22 (m, 2H), 7.19–7.17 (m, 2H), 7.11 (d, J = 8.0 Hz, 2H), 7.06–7.04 (m, 2H), 4.93 (d, J = 10.5 Hz, 1H), 4.75–4.69 (m, 3H), 4.62 (t, J = 11.0 Hz, 2H), 4.49–4.45 (m, 2H), 4.08–4.02 (m, 2H), 3.96–3.95 (m, 1H), 3.87–3.79 (m, 3H), 3.63–3.60 (m, 1H), 3.47 (s, 2H), 2.98–1.75 (m, 10H), 1.15 (s, 9H), 0.44 (s, 6H). ¹³C NMR (151 MHz, CDCl₃) δ 139.13, 138.66, 138.55, 138.52, 138.45, 135.04, 129.59, 128.57, 128.50, 128.47, 128.27, 128.15, 128.09, 128.00, 127.80, 127.78, 127.64, 127.40, 126.97, 84.77, 81.40, 80.05, 79.56, 78.15, 75.41, 75.25, 75.02, 74.88, 73.74, 72.26, 69.80, 43.41, 27.88, 20.67, −1.98, −1.99. HR-MS (ESI): m/z [M-H]⁻ calcd for C₄₉H₆₅B₁₀O₅Si⁻: 871.5537, found: 871.5599.

Synthesis of (2R,3R,4R,5R,6S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-6-(4-((1,2-dicarba-closo-dodecaboran-1-yl)methyl)phenyl)tetrahydro-2H-pyran (40): Following the procedure for the synthesis of 36 from 35, 40 was prepared from 39 (2.00 g, 2.30 mmol) using TBAF (3.4 mL, 1.0 M in THF, 3.4 mmol) in dried THF (20 mL). Column chromatography purification (EtOAc/PE = 1/10 by v/v) gave 40. Yellow oil, 1.14 g (66%). ¹H NMR (500 MHz, CDCl₃) δ 7.39–7.28 (m, 12H), 7.27–7.13 (m, 8H), 7.07 (d, J = 8.5 Hz, 2H), 6.97–6.96 (m, 2H), 4.92 (d, J = 10.5 Hz, 1H), 4.76–4.71 (m, 3H), 4.63–4.59 (m, 2H), 4.54–4.49 (m, 2H), 4.09 (d, J = 11.5 Hz, 1H), 4.03 (t, J = 9.5 Hz, 1H), 3.95–3.94 (m, 1H), 3.86–3.79 (m, 3H), 3.64–3.60 (m, 1H), 3.55–3.49 (m, 2H), 3.17 (s, 1H), 2.86–1.64 (m, 10H). ¹³C NMR (151 MHz, CDCl₃) δ 139.60, 138.56, 138.45, 138.43, 138.28, 133.41, 129.52, 128.60, 128.51, 128.48, 128.24, 128.16, 128.05, 127.84, 127.82, 127.69, 127.65, 127.49, 127.39, 84.84, 80.01, 79.44, 77.77, 75.44, 75.02, 74.68, 74.59, 73.70, 72.44, 69.75, 59.37, 43.38. HR-MS (ESI): m/z [M-H]⁻ calcd for C₄₃H₅₁B₁₀O₅⁻: 757.4662, found: 757.4716.

Synthesis of (2R,3R,4R,5R,6S)-2-(acetoxymethyl)-6-(4-((1,2-dicarba-closo-dodecaboran-1-yl)methyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (41): Following the procedure for the synthesis of 37 from 36, 41 was prepared from 40 (1.14 g, 1.51 mmol) using Ac₂O (11.4 mL) and BF₃·Et₂O (11.4 mL). Column chromatography purification (EtOAc/PE = 1/4 by v/v) gave 41. White foam, 0.63 g (74%). ¹H NMR (500 MHz, CDCl₃) δ 7.33 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 7.5 Hz, 2H), 5.51 (d, J = 3.5 Hz, 1H), 5.34 (t, J = 10.0 Hz, 1H), 5.27–5.24 (m, 1H), 4.79 (s, 1H), 4.36–4.33 (m, 1H), 4.27–4.24 (m, 1H), 3.84–3.81 (m, 1H), 3.50 (s, 2H), 3.15 (s, 1H), 2.87–1.63 (m, 10H), 2.12 (s, 3H), 2.09 (s, 3H), 1.99 (s, 3H), 1.89 (s, 3H). ¹³C NMR (151 MHz, CDCl₃) δ 170.91, 170.37, 169.94, 169.91, 136.86, 134.28, 129.80, 126.85, 78.01, 76.67, 74.40, 72.39, 70.79, 66.13, 63.06, 59.44, 43.29, 20.99, 20.90, 20.78, 20.51. HR-MS (ESI): m/z [M+H]⁺ calcd for C₂₃H₃₇B₁₀O₉⁺: 567.3363, found: 567.3378.

Synthesis of (2R,3S,4R,5S,6S)-2-(hydroxymethyl)-6-(4-((1,2-dicarba-closo-dodecaboran-1-yl)methyl)phenyl)tetrahydro-2H-pyran-3,4,5-triol (A3): Following the general synthetic procedure 5, A3 was prepared from 41 (0.54 g, 0.956 mmol) using Na (66 mg, 2.87 mmol) in MeOH (10.8 mL). Column chromatography purification (MeOH/CH₂Cl₂ = 1/10 by v/v) gave A3. White solid, 0.35 g (92%). m.p. 197.8–198.9 °C. [α]_D²⁰ = +30.4° (c = 7.5, MeOH). ¹H NMR (500 MHz, DMSO-d₆) δ 7.37 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 5.09 (s, 1H), 4.78 (d, J = 5.0 Hz, 1H), 4.69 (d, J = 5.5 Hz, 1H), 4.47 (s, 1H), 4.43 (t, J = 5.8 Hz, 1H), 4.16 (d, J = 5.5 Hz, 1H), 3.78–3.74 (m, 2H), 3.56 (s, 2H), 3.53–3.46 (m, 2H), 3.43–3.38 (m, 1H), 3.21–3.17 (m, 1H), 2.90–1.52 (m, 10H). ¹³C NMR (151 MHz, DMSO-d₆) δ 139.82, 133.85, 129.05, 126.91, 81.47, 78.74, 76.68, 75.09, 72.02, 67.11, 62.81, 61.74, 41.83. ¹¹B NMR (160 MHz, CD₃OD) δ −2.36, −3.28, −5.55, −6.38, −8.97, −9.90, −10.64, −11.67, −12.69, −13.54. HR-MS (ESI): m/z [M+Na]⁺ calcd for C₁₅H₂₈B₁₀NaO₅⁺: 421.2760, found: 421.2761. HPLC purity, 95.05%.

Synthesis of (2R,3R,4R,5S,6S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-6-(4-(1,2-dicarba-closo-dodecaboran-1-yl)phenyl)tetrahydro-2H-pyran (42): Following the general synthetic procedure 4, 42 was prepared from o-carborane (0.83 g, 5.75 mmol) and 8 (3.76 g, 5.18 mmol) using 8 (3.76 g, 5.18 mmol), n-BuLi (5.4 mL, 1.6 M in THF, 8.64 mmol), Pd[P(t-Bu)₃]₂ (0.29 g, 0.575 mmol), PCy₃ (0.16 g, 0.575 mmol), dried THF (6.6 mL), and dried m-xylene (16.6 mL). Column chromatography purification (EtOAc/PE = 1/7 by v/v) gave 42. Yellow foam, 0.89 g (21%). ¹H NMR (500 MHz, CDCl₃) δ 7.45–7.43 (m, 2H), 7.38–7.36 (m, 2H), 7.33–7.32 (m, 8H), 7.31–7.28 (m, 6H), 7.20–7.18 (m, 4H), 6.83–6.81 (m, 2H), 4.95–4.93 (m, 2H), 4.86 (d, J = 10.5 Hz, 1H), 4.64–4.60 (m, 2H), 4.55–4.48 (m, 2H), 4.22 (d, J = 9.5 Hz, 1H), 3.96 (s, 1H), 3.83–3.74 (m, 5H), 3.59–3.57 (m, 1H), 3.44 (t, J = 9.0 Hz, 1H), 2.86–1.48 (m, 10H). ¹³C NMR (151 MHz, CDCl₃) δ 141.42, 138.62, 138.33, 138.19, 137.47, 133.44, 128.63, 128.61, 128.54, 128.42, 128.24, 128.22, 128.13, 127.99, 127.86, 127.80, 127.49, 86.97, 83.88, 80.84, 79.54, 78.40, 76.39, 75.86, 75.32, 75.22, 73.64, 69.18, 60.19. HR-MS (ESI): m/z [M-H]⁻ calcd for C₄₂H₄₉B₁₀O₅⁻: 743.4516, found: 743.4540.

Synthesis of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-(1,2-dicarba-closo-dodecaboran-1-yl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (43): Following the procedure for the synthesis of 37 from 36, 43 was prepared from 42 (0.42 g, 0.565 mmol), Ac₂O (4.2 mL), and BF₃·Et₂O (4.2 mL). Column chromatography purification (EtOAc/PE = 1/3 by v/v) gave 43. White solid, 0.20 g (64%). m.p. 186.7–187.9 °C. ¹H NMR (500 MHz, CDCl₃) δ 7.48–7.45 (m, 2H), 7.33–7.31 (m, 2H), 5.32 (t, J = 9.5 Hz, 1H), 5.22 (t, J = 9.5 Hz, 1H), 5.09 (t, J = 9.5 Hz, 1H), 4.42 (d, J = 9.5 Hz, 1H), 4.29–4.25 (m, 1H), 4.17–4.14 (m, 1H), 3.94 (s, 1H), 3.85–3.81 (m, 1H), 2.78–1.62 (m, 10H), 2.08 (s, 3H), 2.06 (s, 3H), 2.01 (s, 3H), 1.83 (s, 3H). ¹³C NMR (151 MHz, CDCl₃) δ 170.81, 170.48, 169.62, 169.00, 138.46, 134.14, 127.91, 127.74, 79.33, 76.44, 76.03, 74.30, 72.48, 68.49, 62.33, 60.29, 20.91, 20.78, 20.76, 20.58. HR-MS (ESI): m/z [M+H]⁺ calcd for C₂₂H₃₅B₁₀O₉⁺: 553.3206, found: 553.3228.

Synthesis of (2R,3R,4R,5S,6S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-6-(4-(1,2-dicarba-closo-dodecaboran-1-yl)phenyl)tetrahydro-2H-pyran (B1): Following the general synthetic procedure 5, B1 was prepared from 43 (0.19 g, 0.345 mmol) using Na (32 mg, 1.38 mmol) in dried MeOH (3.8 mL). Column chromatography purification (MeOH/CH₂Cl₂ = 1/10 by v/v) gave B1. White solid, 0.12 g (91%). m.p. 128.8–130.2 °C. [α]_D²⁰ = +8.2° (c = 7.4, MeOH). ¹H NMR (500 MHz, CD₃OD) δ 7.54–7.52 (m, 2H), 7.45–7.43 (m, 2H), 5.11 (s, 1H), 4.15 (d, J = 9.5 Hz, 1H), 3.89–3.86 (m, 1H), 3.72–3.69 (m, 1H), 3.49–3.39 (m, 3H), 3.30–3.26 (m, 1H), 2.89–1.79 (m, 10H). ¹³C NMR (151 MHz, CD₃OD) δ 143.01, 134.62, 129.25, 128.02, 82.61, 82.17, 79.71, 78.04, 76.44, 71.79, 63.05, 61.71. ¹¹B NMR (160 MHz, CD₃OD) δ −2.39, −3.31, −4.38, −8.61, −9.54, −10.39, −11.46, −13.19. HR-MS (ESI): m/z [M-H]⁻ calcd for C₁₄H₂₅B₁₀O₅⁻: 383.2638, found: 383.2636. HPLC purity, 96.55%.

Synthesis of (2R,3S,4R,5S,6S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-6-(4-(1,2-dicarba-closo-dodecaboran-1-yl)phenyl)tetrahydro-2H-pyran (44): Following the general synthetic procedure 4, 44 was prepared from o-carborane (0.50 g, 3.47 mmol) and 14 (3.02 g, 4.16 mmol) using n-BuLi (3.3 mL, 1.6 M in THF, 5.28 mmol), Pd[P(t-Bu)₃]₂ (1.77 g, 3.47 mmol), PCy₃ (0.97 g, 3.47 mmol), dried THF (4 mL), and dried m-xylene (10 mL). Column chromatography purification (EtOAc/PE = 1/8 by v/v) gave 44. Yellow oil, 1.27 g (49%). ¹H NMR (500 MHz, CDCl₃) δ 7.42–7.30 (m, 17H), 7.25–7.18 (m, 5H), 6.85–6.84 (m, 2H), 5.00 (d, J = 11.5 Hz, 1H), 4.80–4.73 (m, 2H), 4.64 (d, J = 11.5 Hz, 1H), 4.57 (d, J = 10.5 Hz, 1H), 4.48–4.41 (m, 2H), 4.18 (d, J = 9.0 Hz, 1H), 4.07–4.06 (m, 1H), 3.94–3.91 (m, 2H), 3.87 (t, J = 9.3 Hz, 1H), 3.72–3.68 (m, 2H), 3.64–3.56 (m, 2H), 2.77–1.61 (m, 10H). ¹³C NMR (151 MHz, CDCl₃) δ 141.78, 139.08, 138.46, 137.93, 137.84, 133.24, 128.61, 128.57, 128.44, 128.41, 128.34, 128.32, 128.10, 127.97, 127.88, 127.84, 127.66, 127.35, 84.50, 81.25, 80.20, 77.45, 76.49, 75.40, 74.74, 74.29, 73.69, 72.62, 68.85, 60.20. HR-MS (ESI): m/z [M+H]⁺ calcd for C₄₂H₅₁B₁₀O₅⁺: 745.4662, found: 745.4706.

Synthesis of (2R,3S,4R,5S,6S)-2-(acetoxymethyl)-6-(4-(1,2-dicarba-closo-dodecaboran-1-yl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (45): Following the procedure for the synthesis of 37 from 36, 45 was prepared from 44 (0.96 g, 1.29 mmol) using Ac₂O (9.6 mL) and BF₃·Et₂O (9.6 mL). Column chromatography purification (EtOAc/PE = 1/3 by v/v) gave 45. Yellow foam, 0.37 g (52%). ¹H NMR (500 MHz, CDCl₃) δ 7.48–7.46 (m, 2H), 7.37–7.35 (m, 2H), 5.52–5.51 (m, 1H), 5.30 (t, J = 9.8 Hz, 1H), 5.18–5.16 (m, 1H), 4.39 (d, J = 10.0 Hz, 1H), 4.19–4.12 (m, 2H), 4.07–4.05 (m, 1H), 3.94 (s, 1H), 2.76–1.71 (m, 10H), 2.20 (s, 3H), 2.03 (s, 3H), 1.99 (s, 3H), 1.84 (s, 3H). ¹³C NMR (151 MHz, CDCl₃) δ 170.58, 170.34, 170.30, 169.03, 138.77, 134.04, 127.88, 127.81, 79.84, 76.08, 74.92, 72.24, 69.72, 67.85, 61.82, 60.30, 20.85, 20.84, 20.76, 20.65. HR-MS (ESI): m/z [M+H]⁺ calcd for C₂₂H₃₅B₁₀O₉⁺: 553.3206, found: 553.3212.

Synthesis of (2R,3R,4R,5R,6S)-2-(hydroxymethyl)-6-(4-(1,2-dicarba-closo-dodecaboran-1-yl)phenyl)tetrahydro-2H-pyran-3,4,5-triol (B2): Following the general synthetic procedure 5, B2 was prepared from 45 (0.45 g, 0.817 mmol) using Na (56 mg, 2.45 mmol) in dried MeOH (9 mL). Column chromatography purification (MeOH/CH₂Cl₂ = 1/10 by v/v) gave B2. White solid, 0.28 g (90%). m.p. 124.5–126.1 °C. [α]_D²⁰ = +22.2° (c = 12.2, MeOH). ¹H NMR (500 MHz, DMSO-d₆) δ 7.53 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.5 Hz, 2H), 5.78 (s, 1H), 4.72 (t, J = 5.3 Hz, 2H), 4.53 (t, J = 5.3 Hz, 1H), 4.41 (d, J = 5.0 Hz, 1H), 3.98 (d, J = 9.5 Hz, 1H), 3.76–3.74 (m, 1H), 3.54–3.46 (m, 4H), 3.41–3.38 (m, 1H), 2.92–1.64 (m, 10H). ¹³C NMR (151 MHz, DMSO-d₆) δ 142.71, 131.96, 128.28, 126.64, 81.19, 79.45, 77.09, 74.95, 71.38, 68.89, 61.00, 60.86. ¹¹B NMR (160 MHz, CD₃OD) δ −2.35, −3.27, −5.14, −8.57, −9.51, −10.54, −11.44, −13.26. HR-MS (ESI): m/z [M+H]⁺ calcd for C₁₄H₂₇B₁₀O₅⁺: 385.2784, found: 385.2785. HPLC purity, 95.05%.

Synthesis of (2R,3R,4R,5R,6S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-6-(4-(1,2-dicarba-closo-dodecaboran-1-yl)phenyl)tetrahydro-2H-pyran (46): Following the general synthetic procedure 4, 46 was prepared from o-carborane (0.20 g, 1.39 mmol) and 20 (1.01 g, 1.39 mmol) using n-BuLi (1.3 mL, 1.6 M in THF, 2.08 mmol), Pd[P(t-Bu)₃]₂ (0.35 g, 0.693 mmol), PCy₃ (0.19 g, 0.693 mmol), dried THF (1.6 mL), and dried m-xylene (4 mL). Column chromatography purification (EtOAc/PE = 1/10 by v/v) gave 46. Yellow oil, 0.25 g (24%). ¹H NMR (500 MHz, CDCl₃) δ 7.38–7.28 (m, 17H), 7.23–7.11 (m, 5H), 6.81 (d, J = 7.0 Hz, 2H), 4.92 (d, J = 10.5 Hz, 1H), 4.77–4.76 (m, 2H), 4.70–4.68 (m, 1H), 4.64–4.57 (m, 3H), 4.44 (s, 1H), 4.20 (d, J = 12.0 Hz, 1H), 4.03 (t, J = 9.5 Hz, 1H), 3.95 (s, 1H), 3.91–3.90 (m, 1H), 3.82–3.78 (m, 3H), 3.61–3.58 (m, 1H), 2.96–1.64 (m, 10H). ¹³C NMR (151 MHz, CDCl₃) δ 141.22, 138.51, 138.39, 138.35, 138.02, 132.58, 128.65, 128.53, 128.49, 128.22, 128.14, 128.10, 128.01, 127.92, 127.87, 127.71, 127.68, 127.62, 127.15, 127.12, 85.08, 80.07, 79.20, 76.55, 75.47, 75.05, 74.58, 73.70, 72.69, 69.68, 60.22, 29.18. HR-MS (ESI): m/z [M-H]⁻ calcd for C₄₂H₄₉B₁₀O₅⁻: 743.4516, found: 743.4565.

Synthesis of (2R,3R,4R,5R,6S)-2-(acetoxymethyl)-6-(4-(1,2-dicarba-closo-dodecaboran-1-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (47): Following the procedure for the synthesis of 37 from 36, 47 was prepared from 46 (0.68 g, 0.915 mmol) using Ac₂O (6.8 mL) and BF₃·Et₂O (6.8 mL). Column chromatography purification (EtOAc/PE = 1/4 by v/v) gave 47. Yellow foam, 0.37 g (73%). ¹H NMR (500 MHz, CDCl₃) δ 7.45 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 5.56 (d, J = 3.5 Hz, 1H), 5.34–5.30 (m, 1H), 5.24–5.21 (m, 1H), 4.75 (s, 1H), 4.34–4.31 (m, 1H), 4.25–4.22 (m, 1H), 3.94 (s, 1H), 3.83–3.79 (m, 1H), 2.90–1.65 (m, 10H), 2.10 (s, 3H), 2.08 (s, 3H), 1.99 (s, 3H), 1.92 (s, 3H). ¹³C NMR (151 MHz, CDCl₃) δ 170.84, 170.37, 170.04, 169.87, 138.34, 133.39, 127.61, 126.71, 77.58, 76.69, 76.12, 72.47, 70.22, 65.99, 62.98, 60.25, 20.93, 20.87, 20.75, 20.58. HR-MS (ESI): m/z [M+H]⁺ calcd for C₂₂H₃₅B₁₀O₉⁺: 553.3206, found: 553.3213.

Synthesis of (2R,3S,4R,5S,6S)-2-(hydroxymethyl)-6-(4-(1,2-dicarba-closo-dodecaboran-1-yl)tetrahydro-2H-pyran-3,4,5-triol (B3): Following the general synthetic procedure 5, B3 was prepared from 47 (0.37 g, 0.672 mmol) using Na (62 mg, 2.69 mmol) in dried MeOH (7.4 mL). Column chromatography purification (MeOH/CH₂Cl₂ = 1/10 by v/v) gave B3. White solid, 0.14 g (54%). m.p. 222.1–223.5 °C. [α]_D²⁰ = +12.0° (c = 15.2, MeOH). ¹H NMR (500 MHz, DMSO-d₆) δ 7.50 (d, J = 8.5 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 5.78 (s, 1H), 4.79 (d, J = 5.5 Hz, 1H), 4.73 (d, J = 5.5 Hz, 1H), 4.48 (s, 1H), 4.41 (t, J = 5.8 Hz, 1H), 4.27 (d, J = 5.5 Hz, 1H), 3.75–3.72 (m, 2H), 3.52–3.46 (m, 2H), 3.42–3.38 (m, 1H), 3.19–3.15 (m, 1H), 2.90–1.71 (m, 10H). ¹³C NMR (151 MHz, DMSO-d₆) δ 142.30, 131.30, 127.26, 126.32, 81.48, 78.37, 77.18, 74.96, 71.83, 67.04, 61.68, 60.98. ¹¹B NMR (160 MHz, CD₃OD) δ −2.39, −3.31, −5.32, −8.63, −9.57, −10.39, −11.45, −12.44, −13.38. HR-MS (ESI): m/z [M-H]⁻ calcd for C₁₄H₂₅B₁₀O₅⁻: 383.2638, found: 383.2631. HPLC purity, 98.50%.

Synthesis of (2R,3R,4S,5S,6S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-fluoro-6-(4-(1,2-dicarba-closo-dodecaboran-1-yl)tetrahydro-2H-pyran (48): Following the general synthetic procedure 4, 48 was prepared from o-carborane (0.20 g, 1.39 mmol) and 26 (0.80 g, 1.25 mmol) using n-BuLi (1.3 mL, 1.6 M in THF, 2.08 mmol), Pd[P(t-Bu)₃]₂ (0.35 g, 0.693 mmol), PCy₃ (0.19 g, 0.693 mmol), dried THF (1.6 mL), and dried m-xylene (4 mL). Column chromatography purification (EtOAc/PE = 1/12 by v/v) gave 48. Yellow oil, 0.21 g (23%). ¹H NMR (500 MHz, CDCl₃) δ 7.50–7.49 (m, 2H), 7.41–7.30 (m, 15H), 7.22–7.20 (m, 2H), 4.93–4.89 (m, 2H), 4.81–4.78 (m, 1H), 4.61 (d, J = 12.0 Hz, 2H), 4.56–4.53 (m, 1H), 4.46–4.37 (m, 1H), 4.35–4.34 (m, 1H), 3.96 (s, 1H), 3.93–3.89 (m, 1H), 3.78–3.75 (m, 3H), 3.65–3.61 (m, 1H), 2.89–1.77 (m, 10H). ¹³C NMR (151 MHz, CDCl₃) δ 139.85, 138.20, 138.15, 138.06, 133.63, 128.58, 128.56, 128.54, 128.14, 128.02, 127.98, 127.85, 127.76, 127.57, 95.34, 94.30, 84.59 (d, J = 16.3 Hz), 79.46, 78.44 (d, J = 23.1 Hz), 76.27, 75.42, 75.09 (d, J = 2.9 Hz), 73.64, 68.95, 60.23. HR-MS (ESI): m/z [M-H]⁻ calcd for C₃₅H₄₂B₁₀FO₄⁻: 655.4003, found: 655.4020.

Synthesis of (2R,3R,4S,5S,6S)-2-(acetoxymethyl)-5-fluoro-6-(4-(1,2-dicarba-closo-dodecaboran-1-yl)tetrahydro-2H-pyran-3,4-diyl diacetate (49): Following the procedure for the synthesis of 37 from 36, 49 was prepared from 48 (0.50 g, 0.764 mmol) using Ac₂O (5 mL) and BF₃·Et₂O (5 mL). Column chromatography purification (EtOAc/PE = 1/4 by v/v) gave 49. White solid, 0.25 g (64%). m.p. 202.8–204.4 °C. ¹H NMR (500 MHz, CDCl₃) δ 7.51 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.5 Hz, 2H), 5.48–5.42 (m, 1H), 5.14 (t, J = 9.8 Hz, 1H), 4.49–4.46 (m, 1H), 4.42–4.30 (m, 1H), 4.29–4.27 (m, 1H), 4.18–4.16 (m, 1H), 3.96 (s, 1H), 3.87–3.84 (m, 1H), 2.98–1.69 (m, 10H), 2.08 (s, 6H), 2.07 (s, 3H). ¹³C NMR (151 MHz, CDCl₃) δ 170.74, 170.23, 169.76, 138.50, 134.10, 127.91, 127.38, 91.50, 90.24, 78.36 (d, J = 22.5 Hz), 76.30, 74.05 (d, J = 19.8 Hz), 68.32 (d, J = 7.6 Hz), 62.24, 60.16, 20.87, 20.81, 20.72. HR-MS (ESI): m/z [M-H]⁻ calcd for C₂₀H₃₀B₁₀FO₇⁻: 511.2912, found: 511.2914.

Synthesis of (2R,3S,4S,5R,6S)-5-fluoro-2-(hydroxymethyl)-6-(4-(1,2-dicarba-closo-dodecaboran-1-yl)tetrahydro-2H-pyran-3,4-diol (B4): Following the general synthetic procedure 5, B4 was prepared from 47 (0.20 g, 0.392 mmol) using Na (54 mg, 2.35 mmol) in dried MeOH (4 mL). White solid, 75 mg (50%). m.p. 220.3–221.2 °C. [α]_D²⁰ = +18.6° (c = 6.2, MeOH). ¹H NMR (500 MHz, DMSO-d₆) δ 7.58 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 5.80 (s, 1H), 5.52 (d, J = 5.0 Hz, 1H), 5.27 (d, J = 5.5 Hz, 1H), 4.54 (s, 1H), 4.42–4.39 (m, 1H), 4.20–4.06 (m, 1H), 3.69 (d, J = 11.5 Hz, 1H), 3.61–3.54 (m, 1H), 3.47–3.44 (m, 1H), 3.34–3.31 (m, 1H), 3.27–3.23 (m, 1H), 2.99–1.66 (m, 10H). ¹³C NMR (151 MHz, DMSO-d₆) δ 140.33, 132.86, 128.04, 127.18, 94.33, 93.12, 81.30, 77.25 (d, J = 23.4 Hz), 76.79, 75.60 (d, J = 16.5 Hz), 70.07 (d, J = 8.3 Hz, 2H), 61.04. ¹¹B NMR (160 MHz, DMSO-d₆) δ −2.80, −3.61, −8.72, −9.66, −11.33. ¹⁹F NMR (471 MHz, DMSO-d₆) δ −193.99. HR-MS (ESI): m/z [M-H]⁻ calcd for C₁₄H₂₄B₁₀FO₄⁻: 385.2595, found: 385.2587. HPLC purity, 95.49%.

Synthesis of 1,2-[4-bromo-1,2-phenylenebis(methylene)]-1,2-dicarba-closo-dodecaborane (50): To a stirred solution of o-carborane (27, 4.00 g, 27.7 mmol) in a mixture of dried toluene (32 mL) and THF (16 mL) cooled at 0 °C under N₂ was added dropwise a solution of n-BuLi in THF (43 mL, 1.6 M in THF, 68.8 mmol), and, after addition, the reaction mixture was stirred at room temperature for 1 h and then cooled back to 0 °C again, followed by dropwise addition of a solution of 4 (14.26 g, 41.6 mmol) in dried toluene (15 mL). After that, the reaction mixture was stirred at 100 °C overnight, when TLC analysis indicated completion of the reaction. Upon cooling to room temperature, the reaction mixture was poured into ice water (100 mL), and the resulting mixture was extracted with EtOAc (70 mL × 3). The combined extracts were washed with brine, dried (MgSO₄), and evaporated on a rotary evaporator to afford a residue, which was purified through column chromatography (PE) to give 50. White solid, 4.50 g (50%). m.p. 140.6–142.3 °C. ¹H NMR (500 MHz, CDCl₃) δ 7.37–7.35 (m, 1H), 7.23 (s, 1H), 6.94 (d, J = 8.5 Hz, 1H), 3.67 (s, 2H), 3.65 (s, 2H), 2.85–1.79 (m, 10H). ¹³C NMR (151 MHz, CDCl₃) δ 131.59, 131.42, 130.90, 130.36, 128.33, 121.35, 70.90, 70.59, 37.34, 37.28. HR-MS (ESI): m/z [M+Na]⁺ calcd for C₁₀H₁₇B₁₀BrNa⁺: 349.1336, found: 349.1360.

Synthesis of (3R,4S,5S,6R)-6-(hydroxymethyl)-2-(1,2-(1,2-dicarba-closo-dodecaboranylene)bis(methylene)benzen-4-yl)tetrahydro-2H-pyran-2,3,4,5-tetraol (51): To a stirred solution of 50 (1.30 g, 4.00 mmol) in dried THF (13 mL) cooled at −78 °C under N₂ was added dropwise a solution of n-BuLi in THF (3 mL, 1.6 M in THF, 4.8 mmol), and, after addition, stirring was continued at this temperature for 1 h, followed by dropwise addition of a solution of 2 (2.80 g, 6.00 mmol) in dried THF (3 mL). After that, the reaction mixture was stirred at this temperature for 1 h and quenched through dropwise addition of saturated aqueous NH₄Cl (10 mL). The resulting mixture was extracted with EtOAc (20 mL × 3), and the combined extracts were washed with brine, dried (MgSO₄), and evaporated on a rotary evaporator to afford a residue. The residue was dissolved in MeOH (10 mL) and strongly acidic cation exchange resin (Amberlite 732) was added to adjust the pH = 5–6. The reaction mixture was stirred for an additional 2 h, adjusted to pH = 7–8 through the addition of Et₃N and evaporated on a rotary evaporator to give crude 51. Yellow oil, 1.00 g. This sample was used directly in the next step without further purification or characterization.

Synthesis of (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(1,2-(1,2-dicarba-closo-dodecaboranylene)bis(methylene)benzen-4-yl)tetrahydro-2H-pyran-3,4,5-triol (52): To a stirred solution of crude 51 prepared above (1.00 g, deemed to be 2.45 mmol) in dried CH₂Cl₂ (10 mL) cooled at −35 °C under N₂ was added Et₃SiH (0.57 g, 4.90 mmol) in one portion, followed by dropwise addition of BF₃·Et₂O (0.52 g, 3.67 mmol). After that, the reaction mixture was stirred at room temperature overnight, when TLC analysis indicated completion of the reaction. Et₃N was added dropwise to the reaction mixture to adjust the pH = 7–8, and the resulting mixture was stirred for another 10 min and then evaporated on a rotary evaporator to dryness to give crude 52. Yellow oil, 1.06 g. This sample was used directly in the next step without further purification or characterization.

Synthesis of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(1,2-(1,2-dicarba-closo-dodecaboranylene)bis(methylene)benzen-4-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (53): Following the procedure for the synthesis of 31 from 30, 53 was prepared from crude 52 prepared above (1.06 g, deemed to be 2.59 mmol) using DMAP (0.48 g, 3.89 mmol) and Ac₂O (5.3 mL) in pyridine (10.6 mL). Column chromatography purification (EtOAc/PE = 1/4 by v/v) gave 53. White solid, 0.15 g (7% overall for 50 to 53). m.p. 226.2–227.8 °C. ¹H NMR (500 MHz, CDCl₃) δ 7.21–7.19 (m, 1H), 7.06–7.03 (m, 2H), 5.32 (t, J = 9.5 Hz, 1H), 5.22 (t, J = 9.8 Hz, 1H), 5.08 (t, J = 9.8 Hz, 1H), 4.36 (d, J = 10.0 Hz, 1H), 4.31–4.28 (m, 1H), 4.17–4.14 (m, 1H), 3.85–3.81 (m, 1H), 3.70–3.65 (m, 4H), 2.89–1.69 (m, 10H), 2.09 (s, 3H), 2.06 (s, 3H), 2.00 (s, 3H), 1.82 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 170.84, 170.49, 169.64, 168.93, 136.09, 130.07, 129.65, 128.94, 127.51, 126.55, 79.71, 76.41, 74.24, 72.65, 71.13, 71.09, 68.59, 62.41, 37.73, 37.55, 20.94, 20.79, 20.77, 20.57. HR-MS (ESI): m/z [M+Na]⁺ calcd for C₂₄H₃₆B₁₀NaO₉⁺: 601.3182, found: 601.3187.

Synthesis of (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(1,2-(1,2-dicarba-closo-dodecaboranylene)bis(methylene)benzen-4-yl)tetrahydro-2H-pyran-3,4,5-triol (C1): Following the general synthetic procedure 5, C1 was prepared from 53 (60 mg, 0.112 mmol) using Na (31 mg, 1.35 mmol) in MeOH (0.8 mL). Column chromatography purification (MeOH/CH₂Cl₂ = 1/10 by v/v) gave C1. White solid, 24 mg (52%). m.p. 119.6–121.4 °C. [α]_D²⁰ = +0.5° (c = 10.0, MeOH). ¹H NMR (600 MHz, DMSO-d₆) δ 7.22–7.11 (m, 3H), 4.96–4.79 (m, 3H), 4.44 (s, 1H), 3.98 (d, J = 7.5 Hz, 1H), 3.82 (s, 4H), 3.69 (d, J = 10.0 Hz, 1H), 3.28–3.12 (m, 5H), 2.77–1.56 (m, 10H). ¹³C NMR (151 MHz, DMSO-d₆) δ 139.65, 128.47, 128.22, 127.98, 127.79, 127.09, 81.25, 80.95, 78.43, 74.61, 72.73, 70.36, 61.40, 36.48, 36.24. ¹¹B NMR (160 MHz, CD₃OD) δ −5.10, −6.01, −9.64, −10.35. HR-MS (ESI): m/z [M+H]⁺ calcd for C₁₆H₂₇B₁₀O₅⁺: 409.2784, found: 409.2763. HPLC purity, 94.68%.

Synthesis of (3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)-2-methoxy-2-(1,2-(1,2-dicarba-closo-dodecaboranylene)bis(methylene)benzen-4-yl)tetrahydro-2H-pyran (54): Following the general synthetic procedure 2, 54 was prepared from 50 (0.37 g, 1.14 mmol) and 12 (0.74 g, 1.37 mmol) using n-BuLi (0.85 mL, 1.6 M in THF, 1.36 mmol), MeSO₃H (0.55 g, 5.69 mmol), dried MeOH (2.8 mL), and dried THF (3.7 mL) as a crude sample. Yellow oil, 0.96 g. This sample was used directly in the next step without further purification or characterization.

Synthesis of (2R,3S,4R,5S,6S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-6-(1,2-(1,2-dicarba-closo-dodecaboranylene)bis(methylene)benzen-4-yl)tetrahydro-2H-pyran (55): Following the general synthetic procedure 3, 55 was prepared from crude 54 prepared above (0.96 g, deemed to be 1.20 mmol) using Et₃SiH (0.28 g, 2.40 mmol) and BF₃·Et₂O (0.26 g, 1.80 mmol) in dried CH₂Cl₂ (9.6 mL) as a crude sample. Yellow oil, 0.20 g. This sample was used directly in the next step without further purification or characterization.

Synthesis of (2R,3S,4R,5S,6S)-2-(acetoxymethyl)-6-(1,2-(1,2-dicarba-closo-dodecaboranylene)bis(methylene)benzen-4-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (56): Following the procedure for the synthesis of 37 from 36, 56 was prepared from crude 55 prepared above (0.20 g, deemed to be 0.764 mmol) using Ac₂O (2 mL) and BF₃·Et₂O (2 mL). Column chromatography purification (EtOAc/PE = 1/4 by v/v) gave 56. White foam, 0.10 g (15% overall 50 to 56). ¹H NMR (500 MHz, CDCl₃) δ 7.23 (d, J = 7.5 Hz, 1H), 7.10 (s, 1H), 7.04 (d, J = 8.0 Hz, 1H), 5.52 (d, J = 3.5 Hz, 1H), 5.28 (t, J = 10.0 Hz, 1H), 5.18–5.15 (m, 1H), 4.32 (d, J = 9.5 Hz, 1H), 4.18–4.14 (m, 2H), 4.07–4.04 (m, 1H), 3.72–3.67 (m, 4H), 2.80–1.67 (m, 10H), 2.21 (s, 3H), 2.04 (s, 3H), 1.99 (s, 3H), 1.82 (s, 3H). ¹³C NMR (151 MHz, CDCl₃) δ 170.60, 170.38, 170.33, 169.02, 136.38, 129.98, 129.60, 128.83, 127.63, 126.76, 80.26, 74.88, 72.18, 71.16, 71.13, 69.94, 67.86, 61.82, 37.74, 37.55, 20.89, 20.86, 20.77, 20.67. HR-MS (ESI): m/z [M+H]⁺ calcd for C₂₄H₃₇B₁₀O₉⁺: 579.3363, found: 579.3380.

Synthesis of (2R,3R,4R,5R,6S)-2-(hydroxymethyl)-6-(1,2-(1,2-dicarba-closo-dodecaboranylene)bis(methylene)benzen-4-yl)tetrahydro-2H-pyran-3,4,5-triol (C2): Following the general synthetic procedure 5, C2 was prepared from 56 (74 mg, 0.128 mmol) using Na (21 mg, 0.898 mmol) in dried MeOH (1.5 mL). Column chromatography purification (MeOH/CH₂Cl₂ = 1/10 by v/v) gave C2. White solid, 42 mg (52%). m.p. 118.3–119.2 °C. [α]_D²⁰ = +4.1° (c = 2.2, MeOH). ¹H NMR (500 MHz, DMSO-d₆) δ 7.23–7.22 (m, 1H), 7.15 (s, 1H), 7.13–7.11 (m, 1H), 4.69 (d, J = 5.5 Hz, 1H), 4.59 (d, J = 5.5 Hz, 1H), 4.54–4.52 (m, 1H), 4.38 (d, J = 5.0 Hz, 1H), 3.91 (d, J = 9.0 Hz, 1H), 3.82 (d, J = 5.0 Hz, 4H), 3.76–3.74 (m, 1H), 3.53–3.45 (m, 4H), 3.39–3.37 (m, 1H), 2.88–1.57 (m, 10H). ¹³C NMR (151 MHz, DMSO-d₆) δ 139.94, 128.35, 128.08, 127.90, 127.85, 127.12, 81.63, 79.43, 75.02, 72.68, 71.35, 68.85, 60.86, 54.91, 36.42, 36.19. ¹¹B NMR (160 MHz, CD₃OD) δ −5.16, −6.09, −9.54, −9.76, −10.46. HR-MS (ESI): m/z [M-H]⁻ calcd for C₁₆H₂₇B₁₀O₅⁻: 409.2795, found: 409.2800. HPLC purity, 95.34%.

Synthesis of 2-(2-(1,2-dicarba-closo-dodecaboran-1-yl)ethoxy)ethyl 4-methylbenzenesulfonate (57-1): To a stirred solution of o-carborane (27, 2.50 g, 17.3 mmol) in dried THF (25 mL) cooled at 0 °C was added a solution of n-BuLi in THF (13 mL, 1.6 M in THF, 20.8 mmol), and, after addition, the reaction mixture was stirred at room temperature for 1 h and then cooled back to 0 °C, followed by dropwise addition of a solution of TsO-(CH₂CH₂O)₂-Ts (8.62 g, 20.8 mmol) in dried THF (25 mL). After that, the reaction mixture was stirred at room temperature overnight, when TLC analysis indicated completion of the reaction, and then poured into ice water (50 mL). The resulting mixture was extracted with EtOAc (50 mL × 3), and the combined extracts were washed with brine, dried (MgSO₄), and evaporated on a rotary evaporator to afford a residue, which was purified through column chromatography (EtOAc/PE = 1/3 by v/v) to give 57-1. Yellow oil, 1.03 g (15%). ¹H NMR (500 MHz, CDCl₃) δ 7.79 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 4.15–4.13 (m, 2H), 3.85 (s, 1H), 3.61–3.59 (m, 2H), 3.51 (t, J = 5.8 Hz, 2H), 2.75–1.68 (m, 10H), 2.47 (s, 3H), 2.46–2.45 (m, 2H). The ¹H NMR data were consistent with those reported [50].

Synthesis of 2-(2-(2-(1,2-dicarba-closo-dodecaboran-1-yl)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (57-2): Following the procedure for the synthesis of 57-1 from 27, 57-2 was prepared from o-carborane (27, 3.0 g, 20.8 mmol) and TsO-(CH₂CH₂O)₃-Ts (11.45 g, 25.0 mmol) using n-BuLi (15.6 mL, 1.6 M in THF, 24.96 mmol) in dried THF (60 mL). Column chromatography purification (EtOAc/PE = 1/5 by v/v) gave 57-2. Yellow oil, 1.94 g (22%). ¹H NMR (500 MHz, CDCl₃) δ 7.80 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 4.14 (t, J = 4.8 Hz, 2H), 4.08 (s, 1H), 3.68 (t, J = 5.0 Hz, 2H), 3.57–3.53 (m, 4H), 3.51–3.49 (m, 2H), 2.85–1.58 (m, 10H), 2.50 (t, J = 5.8 Hz, 2H), 2.46 (s, 3H). The ¹H NMR data were consistent with those reported [50].

Synthesis of 1-(2-(2-iodoethoxy)ethyl)-1,2-dicarba-closo-dodecaborane (58-1): A mixture of 57-1 (1.03 g, 2.66 mmol), NaI (1.60 g, 10.7 mmol), and TBAI (0.30 g, 0.799 mmol) in dried toluene (10.3 mL) was stirred at 100 °C under N₂ overnight, when TLC analysis indicated completion of the reaction. Upon cooling to room temperature, the reaction mixture was poured into ice water (30 mL), and the resulting mixture was extracted with EtOAc (30 mL × 3). The combined extracts were washed with brine, dried (MgSO₄), and evaporated on a rotary evaporator to afford a residue, which was purified through column chromatography (EtOAc/PE = 1/5 by v/v) to give 58-1. Yellow oil, 0.61 g (62%). ¹H NMR (500 MHz, CDCl₃) δ 4.11 (s, 1H), 3.67 (t, J = 6.0 Hz, 2H), 3.58 (t, J = 5.5 Hz, 2H), 3.24 (t, J = 6.0 Hz, 2H), 2.89–1.71 (m, 10H), 2.55 (t, J = 5.8 Hz, 2H). ¹³C NMR (151 MHz, CDCl₃) δ 73.18, 71.44, 68.34, 60.63, 37.72, 2.73. HR-MS (ESI): m/z [M-H]⁻ calcd for C₆H₁₈B₁₀IO⁻: 343.1338, found: 343.1328.

Synthesis of 1-(2-(2-(2-iodoethoxy)ethoxy)ethyl)-1,2-dicarba-closo-dodecaborane (58-2): Following the procedure for the synthesis of 58-1 from 57-1, 58-2 was prepared from 57-2 (0.50 g, 1.16 mmol) using NaI (0.70 g, 4.65 mmol) and TBAI (0.13 g, 0.348 mmol) in dried toluene (5 mL). Column chromatography purification (EtOAc/PE = 1/9 by v/v) gave 58-2. Yellow oil, 0.38 g (89%). ¹H NMR (500 MHz, CDCl₃) δ 4.16 (s, 1H), 3.73 (t, J = 6.8 Hz, 2H), 3.62–3.55 (m, 6H), 3.25 (t, J = 6.8 Hz, 2H), 2.81–1.71 (m, 10H), 2.53 (t, J = 5.5 Hz, 2H). ¹³C NMR (151 MHz, CDCl₃) δ 73.45, 71.99, 70.14, 69.96, 68.75, 60.37, 37.52, 2.70. HR-MS (ESI): m/z [M+H]⁺ calcd for C₈H₂₄B₁₀IO₂⁺: 389.1746, found: 389.1738.

Synthesis of 2-(2-(1,2-dicarba-closo-dodecaboran-1-yl)ethoxy)ethan-1-ol (59-1): A mixture of 58-1 (0.61 g, 1.78 mmol) and AcONa (0.58 g, 7.13 mmol) in dried DMF (6.1 mL) was stirred at 80 °C under N₂ overnight, when TLC analysis indicated completion of the reaction. Upon cooling to room temperature, the reaction mixture was poured into ice water (10 mL), and the resulting mixture was extracted with EtOAc (20 mL × 3). The combined extracts were washed with brine, dried (MgSO₄), and evaporated on a rotary evaporator to afford a residue, which was dissolved in MeOH (6.1 mL), followed by the addition of NaOH (0.14 g, 3.56 mmol). The resulting mixture was stirred at room temperature under N₂ for 1 h, when TLC analysis indicated completion of the reaction, and poured into ice water (10 mL). The mixture thus obtained was extracted with EtOAc (20 mL × 3), and the combined extracts were washed with brine, dried (MgSO₄), and evaporated on a rotary evaporator to give a residue, which was purified through column chromatography (EtOAc/PE = 1/3 by v/v) to give 59-1. Yellow oil, 0.23 g (56%). ¹H NMR (500 MHz, DMSO-d₆) δ 5.12 (s, 1H), 4.62 (t, J = 5.5 Hz, 1H), 3.50–3.46 (m, 4H), 3.38 (t, J = 5.0 Hz, 2H), 2.86–1.64 (m, 10H), 2.53–2.52 (m, 2H). ¹³C NMR (151 MHz, DMSO-d₆) δ 74.29, 71.92, 67.97, 62.47, 60.01, 36.35. HR-MS (ESI): m/z [M-H]⁻ calcd for C₆H₁₉B₁₀O₂⁻: 233.2321, found: 233.2318.

Synthesis of 2-(2-(2-(1,2-dicarba-closo-dodecaboran-1-yl)ethoxy)ethoxy)ethan-1-ol (59-2): Following the procedure for the synthesis of 59-1 from 58-1, 59-2 was prepared from 58-2 (0.36 g, 0.932 mmol) using AcONa (0.31 g, 3.73 mmol), NaOH (75 mg, 1.86 mmol) dried DMF (3.6 mL) and MeOH (3.6 mL). Column chromatography purification (EtOAc/PE = 1/3 by v/v) gave 59-2. Yellow oil, 0.13 g (50%). ¹H NMR (500 MHz, DMSO-d₆) δ 5.07 (s, 1H), 4.57 (t, J = 5.5 Hz, 1H), 3.50–3.46 (m, 8H), 3.41 (t, J = 5.0 Hz, 2H), 2.83–1.59 (m, 10H), 2.53–2.52k (m, 2H). ¹³C NMR (151 MHz, DMSO-d₆) δ 74.27, 72.28, 69.51, 69.39, 67.95, 62.44, 60.20, 36.31. HR-MS (ESI): m/z [M+H]⁺ calcd for C₈H₂₅B₁₀O₃⁺: 279.2729, found: 279.2729.

Synthesis of (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(2-(2-(1,2-dicarba-closo-dodecaboran-1-yl)ethoxy)ethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (60-1): Following the general synthetic procedure 6, 60-1 was prepared from 59-1 (0.23 g, 0.990 mmol) using β-D-glucose pentaacetate (0.77 g, 1.98 mmol) and BF₃·Et₂O (0.56 g, 3.96 mmol) in dried CH₂Cl₂ (2.3 mL). Column chromatography purification (EtOAc/PE = 1/3 by v/v) gave 60-1. White solid, 0.23 g (41%). m.p. 130.6–131.3 °C. ¹H NMR (500 MHz, CDCl₃) δ 5.21 (t, J = 9.5 Hz, 1H), 5.08 (t, J = 9.8 Hz, 1H), 4.99–4.95 (m, 1H), 4.55 (d, J = 8.0 Hz, 1H), 4.29–4.25 (m, 1H), 4.17–4.14 (m, 1H), 4.05 (s, 1H), 3.93–3.89 (m, 1H), 3.72–3.65 (m, 2H), 3.57–3.54 (m, 4H), 2.86–1.60 (m, 10H), 2.50 (t, J = 5.8 Hz, 2H), 2.10 (s, 3H), 2.05 (s, 3H), 2.03 (s, 3H), 2.02 (s, 3H). ¹³C NMR (151 MHz, CDCl₃) δ 170.80, 170.42, 169.53, 169.39, 100.85, 73.30, 72.85, 72.12, 71.32, 69.95, 68.87, 68.75, 68.48, 62.03, 60.40, 37.62, 20.90, 20.85, 20.76, 20.74. HR-MS (ESI): m/z [M+Na]⁺ calcd for C₂₀H₃₈B₁₀NaO₁₁⁺: 587.3237, found: 587.3257.

Synthesis of (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(2-(2-(2-(1,2-dicarba-closo-dodecaboran-1-yl)ethoxy)ethoxy)ethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (60-2). Following the general synthetic procedure 6, 60-2 was prepared from 59-2 (0.42 g, 1.52 mmol) using β-D-glucose pentaacetate (1.19 g, 3.04 mmol) and BF₃·Et₂O (0.86 g, 6.08 mmol) in dried CH₂Cl₂ (4.2 mL). White solid, 0.29 g (31%). m.p. 93.7–94.8 °C. ¹H NMR (500 MHz, CDCl₃) δ 5.21 (t, J = 9.5 Hz, 1H), 5.09 (t, J = 9.8 Hz, 1H), 5.01–4.98 (m, 1H), 4.58 (d, J = 8.0 Hz, 1H), 4.28–4.25 (m, 1H), 4.18 (s, 1H), 4.16–4.13 (m, 1H), 3.97–3.93 (m, 1H), 3.72–3.68 (m, 2H), 3.63–3.61 (m, 2H), 3.59–3.55 (m, 4H), 3.54–3.51 (m, 2H), 2.86–1.65 (m, 10H), 2.53 (t, J = 5.8 Hz, 2H), 2.09 (s, 3H), 2.04 (s, 3H), 2.03 (s, 3H), 2.01 (s, 3H). ¹³C NMR (151 MHz, CDCl₃) δ 170.82, 170.43, 169.58, 169.47, 101.00, 73.46, 72.94, 72.01, 71.40, 70.48, 70.36, 70.21, 69.24, 68.65, 68.53, 62.08, 60.43, 37.47, 20.89, 20.83, 20.77, 20.75. HR-MS (ESI): m/z [M-H]⁻ calcd for C₂₂H₄₁B₁₀O₁₂⁻: 607.3534, found: 607.3549.

Synthesis of (2R,3S,4S,5R,6R)-2-(acetoxymethyl)-6-(2-(2-(1,2-dicarba-closo-dodecaboran-1-yl)ethoxy)ethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (61-1): Following the general synthetic procedure 6, 61-1 was prepared from 59-1 (0.20 g, 0.861 mmol) using β-D-galactose pentaacetate (0.67 g, 1.72 mmol) and BF₃·Et₂O (0.49 g, 3.44 mmol) in dried CH₂Cl₂ (2 mL). Column chromatography purification (EtOAc/PE = 1/3 by v/v) gave 61-1. Yellow oil, 0.16 g (33%). ¹H NMR (500 MHz, CDCl₃) δ 5.40–5.39 (m, 1H), 5.21–5.17 (m, 1H), 5.04–5.01 (m, 1H), 4.50 (d, J = 8.0 Hz, 1H), 4.22–4.18 (m, 1H), 4.14–4.11 (m, 2H), 3.94–3.89 (m, 2H), 3.69–3.65 (m, 1H), 3.60–3.52 (m, 4H), 2.85–1.63 (m, 10H), 2.51 (t, J = 5.8 Hz, 2H), 2.17 (s, 3H), 2.06 (s, 6H), 1.99 (s, 3H). ¹³C NMR (151 MHz, CDCl₃) δ 170.55, 170.45, 170.31, 169.49, 101.40, 73.38, 70.96, 69.96, 68.84, 68.83, 68.82, 67.08, 61.36, 60.45, 37.60, 29.84, 20.94, 20.84, 20.81, 20.73. HR-MS (ESI): m/z [M-H]⁻ calcd for C₂₀H₃₇B₁₀O₁₁⁻: 563.3272, found: 563.3288.

Synthesis of (2R,3S,4S,5R,6R)-2-(acetoxymethyl)-6-(2-(2-(2-(1,2-dicarba-closo-dodecaboran-1-yl)ethoxy)ethoxy)ethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (61-2): Following the general synthetic procedure 6, 61-2 was prepared from 59-2 (0.40 g, 1.45 mmol) using β-D-galactose pentaacetate (1.13 g, 2.89 mmol) and BF₃·Et₂O (0.82 g, 5.79 mmol) in dried CH₂Cl₂ (4 mL). Column chromatography purification (EtOAc) gave 61-2. Colorless oil, 0.25 g (28%). ¹H NMR (500 MHz, CDCl₃) δ 5.40–5.39 (m, 1H), 5.22–5.19 (m, 1H), 5.03–5.00 (m, 1H), 4.53 (d, J = 8.0 Hz, 1H), 4.20–4.18 (m, 1H), 4.16–4.10 (m, 2H), 3.98–3.94 (m, 1H), 3.93–3.90 (m, 1H), 3.73–3.68 (m, 1H), 3.65–3.62 (m, 2H), 3.59–3.55 (m, 4H), 3.54–3.52 (m, 2H), 2.81–1.62 (m, 10H), 2.53 (t, J = 5.5 Hz, 2H), 2.16 (s, 3H), 2.06 (s, 3H), 2.05 (s, 3H), 1.99 (s, 3H). ¹³C NMR (201 MHz, CDCl₃) δ 170.52, 170.36, 170.27, 169.54, 101.46, 70.99, 70.82, 70.43, 70.30, 70.17, 69.17, 68.87, 68.59, 67.13, 61.37, 60.40, 45.77, 37.42, 20.89, 20.78, 20.77, 20.69. HR-MS (ESI): m/z [M-H]⁻ calcd for C₂₂H₄₁B₁₀O₁₂⁻: 607.3534, found: 607.3525.

Synthesis of (2R,3R,4S,5S,6R)-2-(acetoxymethyl)-6-(2-(2-(1,2-dicarba-closo-dodecaboran-1-yl)ethoxy)ethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (62-1): Following the general synthetic procedure 6, 62-1 was prepared from 59-1 (0.40 g, 1.72 mmol) using α-D-mannose pentaacetate (1.34 g, 3.44 mmol) and BF₃·Et₂O (0.98 g, 6.89 mmol) in dried CH₂Cl₂ (4 mL). Column chromatography purification (EtOAc/PE = 1/4 by v/v) gave 62-1. Colorless oil, 0.38 g (39%). ¹H NMR (500 MHz, CDCl₃) δ 5.34–5.32 (m, 1H), 5.30–5.27 (m, 1H), 5.24–5.23 (m, 1H), 4.85 (d, J = 2.0 Hz, 1H), 4.30–4.26 (m, 1H), 4.13–4.10 (m, 1H), 4.01–3.98 (m, 1H), 3.94 (s, 1H), 3.82–3.78 (m, 1H), 3.63–3.57 (m, 5H), 2.90–1.65 (m, 10H), 2.53 (t, J = 6.0 Hz, 2H), 2.16 (s, 3H), 2.11 (s, 3H), 2.06 (s, 3H), 2.00 (s, 3H). ¹³C NMR (151 MHz, CDCl₃) δ 170.75, 170.22, 170.03, 169.88, 97.79, 73.18, 69.95, 69.61, 69.06, 69.01, 68.72, 67.33, 66.27, 62.65, 60.50, 37.65, 21.01, 20.88, 20.83, 20.80. HR-MS (ESI): m/z [M-H]⁻ calcd for C₂₀H₃₇B₁₀O₁₁⁻: 563.3272, found: 563.3290.

Synthesis of (2R,3R,4S,5S,6R)-2-(acetoxymethyl)-6-(2-(2-(2-(1,2-dicarba-closo-dodecaboran-1-yl)ethoxy)ethoxy)ethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (62-2): Following general synthetic procedure 6, 62-2 was prepared from 59-2 (0.47 g, 1.70 mmol) using α-D-mannose pentaacetate (1.33 g, 3.40 mmol) and BF₃·Et₂O (0.97 g, 6.80 mmol) in dried CH₂Cl₂ (4.7 mL). Column chromatography purification (EtOAc/PE = 1/3 by v/v) gave 62-2. Colorless oil, 0.57 g (55%). ¹H NMR (500 MHz, CDCl₃) δ 5.36–5.33 (m, 1H), 5.30 (t, J = 5.0 Hz, 1H), 5.27–5.26 (m, 1H), 4.87 (d, J = 1.5 Hz, 1H), 4.31–4.27 (m, 1H), 4.15–4.13 (m, 1H), 4.12–4.09 (m, 1H), 4.05–4.01 (m, 1H), 3.82–3.78 (m, 1H), 3.67–3.64 (m, 3H), 3.62–3.60 (m, 2H), 3.59–3.54 (m, 4H), 2.92–1.70 (m, 10H), 2.53 (t, J = 6.0 Hz, 2H), 2.16 (s, 3H), 2.11 (s, 3H), 2.05 (s, 3H), 2.00 (s, 3H). ¹³C NMR (151 MHz, CDCl₃) δ 170.84, 170.23, 170.13, 169.85, 97.91, 73.44, 70.60, 70.21, 70.14, 69.66, 69.19, 68.73, 68.64, 67.60, 66.25, 62.55, 60.47, 37.45, 21.04, 20.90, 20.85, 20.83. HR-MS (ESI): m/z [M-H]⁻ calcd for C₂₂H₄₁B₁₀O₁₂⁻: 607.3534, found: 607.3555.

Synthesis of (2R,3R,4S,5S,6R)-2-(2-(2-(1,2-dicarba-closo-dodecaboran-1-yl)ethoxy)ethoxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (D1): Following the general synthetic procedure 5, D1 was prepared from 60-1 (0.21 g, 0.373 mmol) using Na (43 mg, 1.87 mmol) in dried MeOH (4.2 mL). Column chromatography purification (MeOH/CH₂Cl₂ = 1/10 by v/v) gave D1. White solid, 0.13 g (88%). m.p. 137.5–138.8 °C. [α]_D²⁰ = −8.5° (c = 10.0, MeOH). ¹H NMR (500 MHz, DMSO-d₆) δ 5.07 (s, 1H), 4.95–4.89 (m, 3H), 4.47 (t, J = 5.8 Hz, 1H), 4.14 (d, J = 8.0 Hz, 1H), 3.85–3.81 (m, 1H), 3.70–3.66 (m, 1H), 3.61–3.57 (m, 1H), 3.54–3.48 (m, 4H), 3.44–3.39 (m, 1H), 3.15–3.07 (m, 2H), 3.03–2.99 (m, 1H), 2.96–2.91 (m, 1H), 2.73–1.58 (m, 10H), 2.54–2.50 (m, 2H). ¹³C NMR (151 MHz, DMSO-d₆) δ 103.03, 76.93, 76.74, 74.24, 73.43, 70.14, 69.38, 67.91, 67.76, 62.45, 61.18, 36.33. ¹¹B NMR (160 MHz, CD₃OD) δ −2.25, −3.17, −5.36, −6.29, −9.41, −10.35, −11.41, −12.47, −13.46. HR-MS (ESI): m/z [M+Na]⁺ calcd for C₁₂H₃₀B₁₀NaO₇⁺: 419.2814, found: 419.2812.

Synthesis of (2R,3R,4S,5S,6R)-2-(2-(2-(2-(1,2-dicarba-closo-dodecaboran-1-yl)ethoxy)ethoxy)ethoxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (D2): Following the general synthetic procedure 5, D2 was prepared from 60-2 (0.29 g, 0.478 mmol) using Na (55 mg, 2.39 mmol) in dried MeOH (5.8 mL). Column chromatography purification (MeOH/CH₂Cl₂ = 1/15 by v/v) gave D2. Colorless oil, 0.17 g (81%). [α]_D²⁰ = −8.7° (c = 7.8, MeOH). ¹H NMR (500 MHz, DMSO-d₆) δ 5.06 (s, 1H), 4.95 (d, J = 5.0 Hz, 1H), 4.92 (d, J = 4.5 Hz, 1H), 4.89 (d, J = 5.0 Hz, 1H), 4.47 (t, J = 5.8 Hz, 1H), 4.14 (d, J = 8.0 Hz, 1H), 3.87–3.83 (m, 1H), 3.68–3.64 (m, 1H), 3.60–3.54 (m, 3H), 3.53–3.47 (m, 6H), 3.44–3.41 (m, 1H), 3.13–3.02 (m, 3H), 2.96–2.92 (m, 1H), 2.81–1.62 (m, 10H), 2.53–2.52 (m, 2H). ¹³C NMR (151 MHz, DMSO-d₆) δ 103.01, 76.90, 76.78, 74.25, 73.41, 70.07, 69.71, 69.58, 69.42, 68.02, 67.85, 62.54, 61.10, 36.32. ¹¹B NMR (161 MHz, DMSO-d₆) δ −2.79, −3.71, −6.52, −9.55, −10.54, −11.89, −12.75, −15.04. HR-MS (ESI): m/z [M-H]⁻ calcd for C₁₄H₃₃B₁₀O₈⁻: 439.3111, found: 439.3097.

Synthesis of (2R,3R,4S,5R,6R)-2-(2-(2-(1,2-dicarba-closo-dodecaboran-1-yl)ethoxy)ethoxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (D3): Following the general synthetic procedure 5, D3 was prepared from 61-1 (0.27 g, 0.480 mmol) using Na (55 mg, 2.40 mmol) in dried MeOH (5.4 mL). Column chromatography purification (MeOH/CH₂Cl₂ = 1/15 by v/v) gave D3. Colorless oil, 0.10 g (53%). [α]_D²⁰ = −2.9° (c = 5.2, MeOH). ¹H NMR (500 MHz, DMSO-d₆) δ 5.07 (s, 1H), 4.75 (d, J = 4.0 Hz, 1H), 4.69 (d, J = 5.0 Hz, 1H), 4.54 (t, J = 5.5 Hz, 1H), 4.33 (d, J = 4.0 Hz, 1H), 4.09 (d, J = 6.5 Hz, 1H), 3.81–3.78 (m, 1H), 3.63–3.62 (m, 1H), 3.57–3.46 (m, 7H), 3.32–3.23 (m, 3H), 2.89–1.59 (m, 10H), 2.53–2.52 (m, 2H). ¹³C NMR (151 MHz, DMSO-d₆) δ 103.60, 75.21, 74.18, 73.50, 70.49, 69.44, 68.09, 68.04, 67.63, 62.59, 60.41, 36.31. ¹¹B NMR (161 MHz, DMSO-d₆) δ −2.78, −3.70, −5.65, −6.51, −9.50, −10.45, −11.43, −11.76, −13.20, −13.78. HR-MS (ESI): m/z [M+H]⁺ calcd for C₁₂H₃₁B₁₀O₇⁺: 397.2995, found: 397.2984.

Synthesis of (2R,3R,4S,5R,6R)-2-(2-(2-(2-(1,2-dicarba-closo-dodecaboran-1-yl)ethoxy)ethoxy)ethoxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (D4): Following the general synthetic procedure 5, D4 was prepared from 61-2 (0.22 g, 0.363 mmol) using Na (50 mg, 2.18 mmol) in dried MeOH (4.4 mL). Column chromatography purification (MeOH/CH₂Cl₂ = 1/15 by v/v) gave D4. Colorless oi, 0.11 g (69%). [α]_D²⁰ = −2.7° (c = 6.8, MeOH). ¹H NMR (500 MHz, DMSO-d₆) δ 5.06 (s, 1H), 4.80 (d, J = 4.0 Hz, 1H), 4.68 (d, J = 5.0 Hz, 1H), 4.55 (t, J = 5.8 Hz, 1H), 4.34 (d, J = 4.5 Hz, 1H), 4.09 (d, J = 6.5 Hz, 1H), 3.84–3.80 (m, 1H), 3.63–3.61 (m, 1H), 3.57–3.51 (m, 7H), 3.49–3.46 (m, 4H), 3.31–3.23 (m, 3H), 2.81–1.58 (m, 10H), 2.53–2.52 (m, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 103.62, 75.20, 74.27, 73.50, 70.52, 69.74, 69.58, 69.41, 68.13, 68.01, 67.75, 62.53, 60.41, 36.32. ¹¹B NMR (161 MHz, DMSO-d₆) δ −2.76, −3.69, −5.74, −6.63, −9.50, −10.49, −11.61, −12.38, −13.80. HR-MS (ESI): m/z [M-H]⁻ calcd for C₁₄H₃₃B₁₀O₈⁻: 439.3111, found: 439.3099.

Synthesis of (2R,3S,4S,5S,6R)-2-(2-(2-(1,2-dicarba-closo-dodecaboran-1-yl)ethoxy)ethoxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (D5): Following the general synthetic procedure 5, D5 was prepared from 62-1 (0.35 g, 0.622 mmol) using Na (57 mg, 2.49 mmol) in dried MeOH (7 mL). Column chromatography purification (MeOH/CH₂Cl₂ = 1/10 by v/v) gave D5. Colorless oil, 0.19 g (77%). [α]_D²⁰ = +33.2° (c = 6.6, MeOH). ¹H NMR (500 MHz, DMSO-d₆) δ 5.03 (s, 1H), 4.70 (t, J = 4.8 Hz, 2H), 4.62 (s, 1H), 4.53 (d, J = 6.0 Hz, 1H), 4.42 (t, J = 6.0 Hz, 1H), 3.68–3.62 (m, 2H), 3.60–3.58 (m, 1H), 3.52–3.47 (m, 4H), 3.46–3.41 (m, 3H), 3.39–3.35 (m, 1H), 3.31–3.27 (m, 1H), 2.87–1.60 (m, 10H), 2.53–2.51 (m, 2H). ¹³C NMR (151 MHz, DMSO-d₆) δ 99.92, 74.23, 73.93, 70.99, 70.25, 69.14, 67.98, 67.00, 65.50, 62.40, 61.26, 36.33. ¹¹B NMR (161 MHz, DMSO-d₆) δ −2.56, −3.49, −5.65, −6.50, −9.42, −10.39, −11.43, −12.54, −13.60. HR-MS (ESI): m/z [M-H]⁻ calcd for C₁₂H₂₉B₁₀O₇⁻: 395.2849, found: 395.2838.

Synthesis of (2R,3S,4S,5S,6R)-2-(2-(2-(2-(1,2-dicarba-closo-dodecaboran-1-yl)ethoxy)ethoxy)ethoxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (D6): Following the general synthetic procedure 5, D6 was prepared from 62-2 (0.55 g, 0.907 mmol) using Na (63 mg, 2.72 mmol) in dried MeOH (11 mL). Column chromatography purification (MeOH/CH₂Cl₂ = 1/12 by v/v) gave D6. Colorless oil, 0.30 g (75%). [α]_D²⁰ = +31.1° (c = 8.6, MeOH). ¹H NMR (500 MHz, DMSO-d₆) δ 5.05 (s, 1H), 4.70 (dd, J = 11.0, 4.5 Hz, 2H), 4.62 (s, 1H), 4.53 (d, J = 6.0 Hz, 1H), 4.42 (t, J = 6.0 Hz, 1H), 3.68–3.62 (m, 2H), 3.59–3.58 (m, 1H), 3.55–3.43 (m, 11H), 3.39–3.36 (m, 1H), 3.31–3.28 (m, 1H), 2.85–1.57 (m, 10H), 2.53–2.52 (m, 2H). ¹³C NMR (151 MHz, DMSO-d₆) δ 99.99, 74.27, 73.92, 70.95, 70.29, 69.56, 69.50, 69.39, 68.02, 66.94, 65.72, 62.49, 61.26, 36.30. ¹¹B NMR (161 MHz, DMSO-d₆) δ −2.75, −3.66, −5.62, −6.55, −9.44, −9.57, −10.48, −11.56, −12.45, −13.64. HR-MS (ESI): m/z [M-H]⁻ calcd for C₁₄H₃₃B₁₀O₈⁻: 439.3111, found: 439.3113.

Synthesis of (3R,4S,5S,6R)-6-(hydroxymethyl)-2-(4-iodophenyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (63): Following the general synthetic procedure 2, 63 was prepared from 2 (10.00 g, 21.4 mmol) and 1,4-diiodide (8.48 g, 25.6 mmol) using n-BuLi (16.1 mL, 1.6 M in THF, 25.76 mmol), MeSO₃H (4.12 g, 42.8 mmol), MeOH (21 mL) and dried THF (120 mL) as a crude sample. Brown oil, 8.76 g. This sample was used directly in the next step without further purification or characterization.

Synthesis of (3R,4S,5R,6R)-6-(acetoxymethyl)-2-(4-iodophenyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triyl triacetate (64): Following the procedure for the synthesis of 31 from 30, 64 was prepared from crude 63 prepared above (8.76 g, deemed to be 22.2 mmol) using DMAP (3.24 g, 26.6 mmol), Ac₂O (36 mL), and pyridine (70 mL). Column chromatography purification (EtOAc/PE = 1/3 by v/v) gave 64. Colorless oil, 5.31 g (44% overall for 2 to 64). ¹H NMR (500 MHz, CDCl₃) δ 7.70 (d, J = 8.5 Hz, 2H), 7.18 (d, J = 8.5 Hz, 2H), 5.60 (t, J = 9.8 Hz, 1H), 5.22 (t, J = 10.0 Hz, 1H), 4.95 (d, J = 10.0 Hz, 1H), 4.36 (dd, J = 12.0, 5.0 Hz, 1H), 4.23 (dd, J = 12.3, 2.3 Hz, 1H), 4.07–4.03 (m, 1H), 3.12 (s, 3H), 2.12 (s, 3H), 2.06 (s, 3H), 1.96 (s, 6H) ¹³C NMR (151 MHz, CDCl₃) δ 170.84, 170.31, 169.69, 169.11, 137.73, 135.79, 128.76, 100.29, 95.65, 73.96, 71.43, 69.08, 68.90, 62.27, 49.66, 20.91, 20.80, 20.77, 20.62. HR-MS (ESI): m/z [M+Na]⁺ calcd for C₂₁H₂₅INaO₁₀⁺: 587.0385, found: 587.0387.

Synthesis of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-iodophenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (65): Following the general synthetic procedure 3, 65 was prepared from 64 (1.00 g, 1.77 mmol) using Et₃SiH (0.25 g, 2.13 mmol) and BF₃·Et₂O (0.50 g, 3.54 mmol) in dried CH₂Cl₂ (10 mL). Column chromatography purification (EtOAc/PE = 1/5 by v/v) gave 65. White solid, 0.80 g (84%). m.p. 142.1–143.7 °C. ¹H NMR (500 MHz, CDCl₃) δ 7.69–7.66 (m, 2H), 7.10–7.07 (m, 2H), 5.32 (t, J = 9.5 Hz, 1H), 5.22 (t, J = 9.8 Hz, 1H), 5.09 (t, J = 9.5 Hz, 1H), 4.35 (d, J = 9.5 Hz, 1H), 4.28 (dd, J = 12.5, 5.0 Hz, 1H), 4.17–4.12 (m, 1H), 3.84–3.81 (m, 1H), 2.09 (s, 3H), 2.06 (s, 3H), 2.00 (s, 3H), 1.83 (s, 3H). ¹³C NMR (151 MHz, CDCl₃) δ 170.88, 170.53, 169.65, 169.00, 137.76, 136.11, 129.14, 94.99, 79.82, 74.29, 72.58, 68.65, 62.45, 20.92, 20.80, 20.78, 20.57. HR-MS (ESI): m/z [M+Na]⁺ calcd for C₂₀H₂₃INaO₉⁺: 557.0279, found: 557.0280.

Synthesis of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (66): Following the general synthetic procedure 7, 66 was prepared from 65 (0.80 g, 1.50 mmol) using B₂Pin₂ (0.57 g, 2.25 mmol), KOAc (0.44 g, 4.50 mmol) and Pd(dppf)Cl₂ (0.20 g, 0.300 mmol) in dried DMSO (8 mL). Column chromatography purification (EtOAc/PE = 1/2 by v/v) gave 66. White foam, 0.58 g (72%). m.p. 127.8–133.4 °C. ¹H NMR (500 MHz, CDCl₃) δ 7.77 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 5.33 (t, J = 9.3 Hz, 1H), 5.23 (t, J = 9.8 Hz, 1H), 5.13 (t, J = 9.8 Hz, 1H), 4.41 (d, J = 10.0 Hz, 1H), 4.29 (dd, J = 12.5, 5.0 Hz, 1H), 4.16 (dd, J = 12.3, 2.3 Hz, 1H), 3.85–3.82 (m, 1H), 2.08 (s, 3H), 2.06 (s, 3H), 2.00 (s, 3H), 1.80 (s, 3H), 1.34 (s, 12H). ¹³C NMR (151 MHz, CDCl₃) δ 170.87, 170.52, 169.63, 168.98, 139.27, 134.96, 126.50, 83.99, 80.28, 76.25, 74.42, 72.72, 68.77, 62.53, 25.03, 24.96, 20.89, 20.78, 20.76, 20.53. HR-MS (ESI): m/z [M+NH₄]⁺ calcd for C₂₆H₃₉BNO₁₁⁺: 552.2611, found: 552.2610.

Synthesis of (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydro-2H-pyran-3,4,5-triol (E1): Following the general synthetic procedure 5, E1 was prepared from 66 (0.43 g, 1.17 mmol) using Na (50 mg, 2.17 mmol) in dried MeOH (8.6 mL). Column chromatography purification (MeOH/CH₂Cl₂ = 1/10 by v/v) gave E1. White solid, 0.94 g (32%). m.p. 176.8–180.1 °C. [α]_D²⁰ = +12.9° (c = 10.0, DMSO). ¹H NMR (500 MHz, DMSO-d₆) δ 7.62 (d, J = 7.5 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 4.95–4.93 (m, 2H), 4.78 (d, J = 6.0 Hz, 1H), 4.45 (t, J = 5.5 Hz, 1H), 4.02 (d, J = 9.5 Hz, 1H), 3.73–3.69 (m, 1H), 3.48–3.43 (m, 1H), 3.28–3.26 (m, 1H), 3.24–3.22 (m, 1H), 3.19–3.16 (m, 1H), 3.13–3.08 (m, 1H), 1.29 (s, 12H). ¹³C NMR (151 MHz, DMSO-d₆) δ 143.82, 133.85, 129.01, 127.24, 83.57, 81.32, 81.20, 78.42, 74.92, 70.39, 61.44, 24.72, 24.67. HR-MS (ESI): m/z [M+NH₄]⁺ calcd for C₁₈H₃₁BNO₇⁺: 384.2188, found: 384.2184.

Synthesis of (4-((2S,3S,4R,5R,6R)-3,4,5-triacetoxy-6-(acetoxymethyl)tetrahydro-2H-pyran-2-yl)phenyl)boronic acid (67): Following the general synthetic procedure 8, 67 was prepared from 66 (1.20 g, 2.25 mmol) using NaIO₄ (1.21 g, 5.61 mmol) and NH₄OAc (0.26 g, 3.37 mmol) in a mixture of acetone (9.6 mL) and H₂O(4.5 mL). Column chromatography purification (MeOH/CH₂Cl₂ = 1/10 by v/v) gave 67. White solid, 0.77 g (76%). m.p. 288.8–292.3 °C. ¹H NMR (500 MHz, DMSO-d₆) δ 8.05 (s, 2H), 7.74 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 7.5 Hz, 2H), 5.37 (t, J = 9.5 Hz, 1H), 5.07 (t, J = 9.8 Hz, 1H), 5.00 (t, J = 9.8 Hz, 1H), 4.69 (d, J = 9.5 Hz, 1H), 4.16–4.12 (m, 1H), 4.10–4.06 (m, 2H), 2.02 (s, 3H), 2.01 (s, 3H), 1.93 (s, 3H), 1.75 (s, 3H). ¹³C NMR (151 MHz, DMSO-d₆) δ 170.18, 169.71, 169.48, 168.56, 138.61, 134.50, 134.01, 126.27, 78.24, 74.72, 73.53, 72.36, 68.56, 62.43, 20.57, 20.46, 20.34, 20.14. HR-MS (ESI): m/z [M+NH₄]⁺ calcd for C₂₀H₂₉BNO₁₁⁺: 470.1828, found: 470.1833.

Synthesis of (4-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)phenyl)boronic acid (E2): Following the general synthetic procedure 5, E2 was prepared from 67 (0.64 g, 1.42 mmol) using Na (55 mg, 2.39 mmol) in dried MeOH (12.8 mL). Column chromatography purification (MeOH/CH₂Cl₂ = 1/10 by v/v) gave E2. White solid, 0.30 g (74%). m.p. 330 °C (decomposition). [α]_D²⁰ = +7.9° (c = 3.4, H₂O). ¹H NMR (500 MHz, D₂O) δ 7.78 (d, J = 7.5 Hz, 2H), 7.48 (d, J = 7.5 Hz, 2H), 4.33–4.31 (m, 1H), 3.90 (d, J = 12.5 Hz, 1H), 3.81–3.77 (m, 1H), 3.65–3.59 (m, 4H). ¹³C NMR (151 MHz, D₂O) δ 139.52, 133.62, 129.66, 127.40, 81.87, 80.02, 77.28, 74.01, 69.76, 60.85. HR-MS (ESI): m/z [M+Na]⁺ calcd for C₁₂H₁₇BNaO₇⁺: 307.0960, found: 307.0963.

Synthesis of (3R,4S,5S,6R)-6-(hydroxymethyl)-2-(3-iodophenyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (68): Following the general synthetic procedure 2, 68 was prepared from 2 (10.00 g, 21.4 mmol) and 1,3-diiodobenzene (8.48 g, 25.6 mmol) using n-BuLi (16.1 mL, 1.6 M in THF, 25.76 mmol), MeSO₃H (4.12 g, 42.8mmol), MeOH (21 mL), and dried THF (120 mL) as a crude sample. Yellow oil, 9.86 g. This sample was used directly in the next step without further purification or characterization.

Synthesis of (3R,4S,5R,6R)-6-(acetoxymethyl)-2-(3-iodophenyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triyl triacetate (69): Following the procedure for the synthesis of 31 from 30, 69 was prepared from crude 68 prepared above (9.86 g, deemed to be 24.8 mmol) using DMAP (3.66 g, 29.8 mmol), Ac₂O (40 mL), and pyridine (80 mL). Column chromatography purification (EtOAc/PE = 1/3 by v/v) gave 69. Yellow foam, 6.04 g. This sample was used directly in the next step without characterization.

Synthesis of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-iodophenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (70): Following the general synthetic procedure 3, 70 was prepared from 69 (6.04 g, 10.7 mmol) using Et₃SiH (1.41 g, 12.1 mmol) and BF₃·Et₂O (1.03 g, 7.25 mmol) in dried CH₂Cl₂ (60 mL). Column chromatography purification (EtOAc/PE = 1/5 by v/v) gave 70. White solid, 1.62 g (14% overall for 2 to 70). m.p. 136.4–144.2 °C. ¹H NMR (500 MHz, CDCl₃) δ 7.68–7.65 (m, 2H), 7.34–7.32 (m, 1H), 7.09 (t, J = 7.8 Hz, 1H), 5.32 (t, J = 9.5 Hz, 1H), 5.21 (t, J = 9.8 Hz, 1H), 5.05 (t, J = 9.8 Hz, 1H), 4.34 (d, J = 9.5 Hz, 1H), 4.29 (dd, J = 12.5, 5.0 Hz, 1H), 4.17 (dd, J = 12.3, 2.3 Hz, 1H), 3.84–3.81 (m, 1H), 2.10 (s, 3H), 2.06 (s, 3H), 2.00 (s, 3H), 1.86 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 170.88, 170.50, 169.62, 168.98, 138.70, 138.04, 136.33, 130.38, 126.19, 94.13, 79.37, 76.37, 74.18, 72.73, 68.62, 62.42, 20.93, 20.79, 20.77, 20.58. HR-MS (ESI): m/z [M+H]⁺ calcd for C₂₀H₂₄IO₉⁺: 535.0460, found: 535.0457.

Synthesis of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (71): Following the general synthetic procedure 7, 71 was prepared from 70 (3.55 g, 6.66 mmol) using B₂Pin₂ (3.38 g, 13.3 mmol), KOAc (1.96 g, 20.0 mmol), and Pd(dppf)Cl₂ (1.46 g, 1.20 mmol) in dried DMSO (36 mL). Column chromatography purification (EtOAc/PE = 1/1 by v/v) gave 71. Colorless oil, 1.35 g (38%). ¹H NMR (500 MHz, CDCl₃) δ 7.76–7.74 (m, 2H), 7.49–7.746 (m, 1H), 7.36 (t, J = 7.5 Hz, 1H), 5.33 (t, J = 9.5 Hz, 1H), 5.23 (t, J = 9.8 Hz, 1H), 5.14 (t, J = 9.5 Hz, 1H), 4.42 (d, J = 9.5 Hz, 1H), 4.28 (dd, J = 12.5, 5.0 Hz, 1H), 4.18 (dd, J = 12.5, 2.5 Hz, 1H), 3.85–3.81 (m, 1H), 2.09 (s, 3H), 2.06 (s, 3H), 2.00 (s, 3H), 1.81 (s, 3H), 1.37–1.34 (m, 12H). ¹³C NMR (201 MHz, CDCl₃) δ 170.92, 170.54, 169.65, 169.07, 135.64, 135.42, 133.97, 129.69, 128.59, 128.13, 84.02, 80.32, 76.31, 74.47, 72.76, 68.82, 62.57, 25.04, 24.98, 20.93, 20.81, 20.78, 20.51. HR-MS (ESI): m/z [M+NH₄]⁺ calcd for C₂₆H₃₉BNO₁₁⁺: 552.2611, found: 552.2607.

Synthesis of (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydro-2H-pyran-3,4,5-triol (E3): Following the general synthetic procedure 5, E3 was prepared from 71 (0.22 g, 0.599 mmol) using Na (30 mg, 1.30 mmol) in MeOH (5 mL). Column chromatography purification (MeOH/CH₂Cl₂ = 1/10 by v/v) gave E3. White solid, 73 mg (49%). m.p. 151.7–160.5 °C. [α]_D²⁰ = +4.1° (c = 11.6, DMSO). ¹H NMR (500 MHz, DMSO-d₆) δ 7.66 (s, 1H), 7.58–7.56 (m, 1H), 7.45–7.43 (m, 1H), 7.32 (t, J = 7.3 Hz, 1H), 4.94–4.91 (m, 2H), 4.76 (d, J = 6.0 Hz, 1H), 4.47 (t, J = 5.5 Hz, 1H), 4.02 (d, J = 9.5 Hz, 1H), 3.72–3.68 (m, 1H), 3.46–3.44 (m, 1H), 3.28–3.16 (m, 4H), 1.30 (s, 12H). ¹³C NMR (151 MHz, DMSO-d₆) δ 139.80, 133.70, 133.49, 131.33, 127.85, 127.22, 83.64, 81.54, 81.33, 78.49, 70.46, 67.32, 61.38, 24.75, 24.66. HR-MS (ESI): m/z [M+H]⁺ calcd for C₁₈H₂₈BO₇⁺: 367.1923, found: 367.1918.

Synthesis of (3-((2S,3S,4R,5R,6R)-3,4,5-triacetoxy-6-(acetoxymethyl)tetrahydro-2H-pyran-2-yl)phenyl)boronic acid (72): Following the general synthetic procedure 8, 72 was prepared from 71 (0.63 g, 1.18 mmol) using NaIO₄ (0.64 g, 2.95 mmol) and NH₄OAc (0.14 g, 1.77 mmol) in a mixture of acetone (5.1 mL) and H₂O (1.3 mL). Column chromatography purification (MeOH/CH₂Cl₂ = 1/10 by v/v) gave 72. White solid, 0.32 g (76%). m.p. 214.4–217.3 °C. ¹H NMR (500 MHz, DMSO-d₆) δ 8.07 (s, 2H), 7.76–7.73 (m, 2H), 7.37 (d, J = 8.0 Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H), 5.39 (t, J = 9.3 Hz, 1H),5.06 (t, J = 9.3 Hz, 1H), 4.99 (t, J = 9.8 Hz, 1H), 4.68 (d, J = 10.0 Hz, 1H), 4.15–4.07 (m, 3H), 2.02 (s, 3H), 2.01 (s, 3H), 1.93 (s, 3H), 1.73 (s, 3H). ¹³C NMR (151 MHz, DMSO-d₆) δ 170.18, 169.70, 169.48, 168.54, 135.76, 134.33, 133.98, 133.32, 128.84, 127.30, 78.46, 74.66, 73.50, 72.41, 68.57, 62.43, 20.59, 20.46, 20.35, 20.12. HR-MS (ESI): m/z [M+H]⁺ calcd for C₂₀H₂₆BO₁₁⁺: 453.1563, found: 453.1555.

Synthesis of (3-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)phenyl)boronic acid (E4): Following the general synthetic procedure 5, E4 was prepared from 72 (0.30 g, 0.663 mmol) using Na (50 mg, 2.17 mmol) in MeOH (8 mL). Column chromatography purification (Me/CH₂Cl₂ = 1/10 by v/v) gave E4. White solid, 0.13 g (66%). m.p. 340 °C (decomposition). [α]_D²⁰ = +1.4° (c = 7.8, DMSO). ¹H NMR (500 MHz, DMSO-d₆) δ 8.01 (s, 2H), 7.78 (s, 1H), 7.68 (d, J = 7.5 Hz, 1H), 7.35 (d, J = 7.5 Hz, 1H), 7.26 (t, J = 7.5 Hz, 1H), 4.96–4.94 (m, 2H), 4.73 (d, J = 5.5 Hz, 1H), 4.43 (t, J = 5.8 Hz, 1H), 3.99 (d, J = 9.5 Hz, 1H), 3.72–3.68 (m, 1H), 3.46–3.43 (m, 1H), 3.27–3.26 (m, 1H), 3.23–3.22 (m, 1H), 3.19–3.17 (m, 1H). HR-MS (ESI): m/z [M+K]⁺ calcd for C₁₂H₁₇BKO₇⁺: 323.0699, found: 323.0709.

Synthesis of (2R,3R,4R,5R,6S)-2-(acetoxymethyl)-6-(4-iodophenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (73): Following the procedure for the synthesis of 37 from 36, 73 was prepared from 20 (1.70 g, 2.34 mmol) using Ac₂O (17 mL) and BF₃·Et₂O (17 mL). Column chromatography purification (EtOAc/PE = 1/5 by v/v) gave 73. Yellow oil, 1.00 g (80%). ¹H NMR (500 MHz, CDCl₃) δ 7.65 (d, J = 8.5 Hz, 2H), 7.07 (d, J = 8.0 Hz, 2H), 5.54–5.53 (m, 1H), 5.32 (t, J = 9.8 Hz, 1H), 5.23 (dd, J = 10.3, 3.3 Hz, 1H), 4.71 (s, 1H), 4.33 (dd, J = 12.3, 5.8 Hz, 1H), 4.22 (dd, J = 12.3, 2.3 Hz, 1H), 3.83–3.79 (m, 1H), 2.10 (s, 3H), 2.08 (s, 3H), 1.99 (s, 3H), 1.93 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 170.87, 170.36, 170.03, 169.89, 137.44, 136.01, 128.12, 93.90, 77.87, 76.59, 72.47, 70.38, 66.11, 63.06, 20.94, 20.88, 20.76, 20.58. HR-MS (ESI): m/z [M+H]⁺ calcd for C₂₀H₂₄IO₉⁺: 535.0460, found: 535.0457.

Synthesis of (2R,3R,4R,5R,6S)-2-(acetoxymethyl)-6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (74): Following the general synthetic procedure 7, 74 was prepared from 73 (0.75 g, 1.41 mmol) using B₂Pin₂ (0.54 g, 2.11 mmol), KOAc (0.42 g, 4.23 mmol), and Pd(dppf)Cl₂ (0.21 g, 0.280 mmol) in dried DMSO (7.5 mL). Column chromatography purification (EtOAc/PE = 1/1 by v/v) gave 74. Colorless oil, 0.65 g (87%). ¹H NMR (500 MHz, CDCl₃) δ 7.75 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 7.5 Hz, 2H), 5.57–5.56 (m, 1H), 5.33 (t, J = 10.0 Hz, 1H), 5.25 (dd, J = 10.0, 3.0 Hz, 1H), 4.77 (s, 1H), 4.35 (dd, J = 12.0, 6.0 Hz, 1H), 4.23 (dd, J = 12.3, 2.3 Hz, 1H), 3.84–3.801 (m, 1H), 2.10 (s, 3H), 2.08 (s, 3H), 1.99 (s, 3H), 1.90 (s, 3H), 1.34 (s, 12H). ¹³C NMR (151 MHz, CDCl₃) δ 170.92, 170.39, 170.06, 169.93, 139.25, 134.74, 128.33, 125.47, 83.97, 78.46, 76.55, 72.62, 70.63, 66.34, 63.19, 25.06, 24.93, 20.94, 20.89, 20.77, 20.58. HR-MS (ESI): m/z [M+NH₄]⁺ calcd for C₂₆H₃₉BNO₁₁⁺: 552.2611, found: 552.2611.

Synthesis of (2R,3S,4R,5S,6S)-2-(hydroxymethyl)-6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydro-2H-pyran-3,4,5-triol (E5): Following the general synthetic procedure 5, E5 was prepared from 74 (0.50 g, 0.936 mmol) using Na (50 mg, 2.17 mmol) in dried MeOH (10 mL). Column chromatography purification (MeOH/CH₂Cl₂ = 1/10 by v/v) gave E5. White solid, 0.17 g (49%). m.p. 149.8–155.7 °C. [α]_D²⁰ = +3.2° (c = 12.8, DMSO). ¹H NMR (500 MHz, DMSO-d₆) δ 7.60 (d, J = 7.5 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 4.78 (d, J = 5.5 Hz, 1H), 4.68 (d, J = 5.5 Hz, 1H), 4.49 (s, 1H), 4.44 (t, J = 5.8 Hz, 1H), 4.15 (d, J = 5.5 Hz, 1H), 3.78–3.75 (m, 2H), 3.53–3.47 (m, 2H), 3.43–3.39 (m, 1H), 3.21–3.18 (m, 1H), 1.29 (s, 12H). ¹³C NMR (151 MHz, DMSO-d₆) δ 143.72, 133.61, 127.34, 126.11, 83.49, 81.43, 78.98, 75.09, 72.19, 67.10, 61.70, 24.70, 24.67. HR-MS (ESI): m/z [M+NH₄]⁺ calcd for C₁₈H₃₁BNO₇⁺: 384.2188, found: 384.2187.

Synthesis of (4-((2S,3R,4R,5R,6R)-3,4,5-triacetoxy-6-(acetoxymethyl)tetrahydro-2H-pyran-2-yl)phenyl)boronic acid (75): Following the general synthetic procedure 8, 75 was prepared from 74 (1.32 g, 2.10 mmol) using NaIO₄ (1.34 g, 6.18 mmol) and NH₄OAc (0.29 g, 3.71 mmol) in a mixture of acetone (10.6 mL) and H₂O (2.6 mL). Column chromatography purification (MeOH/CH₂Cl₂ = 1/10 by v/v) gave 75. Colorless oil, 0.66 g (59%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.02 (s, 2H), 7.74–7.72 (m, 2H), 7.27–7.25 (m, 2H), 5.42–5.41 (m, 1H), 5.39–5.36 (m, 1H), 5.15–5.11 (m, 2H), 4.20 (dd, J = 12.3, 5.8 Hz, 1H), 4.14 (dd, J = 12.0, 2.5 Hz, 1H), 4.04–4.00 (m, 1H), 2.05 (s, 3H), 2.04 (s, 3H), 1.92 (s, 3H), 1.86 (s, 3H). ¹³C NMR (151 MHz, DMSO-d₆) δ 170.15, 169.70, 169.57, 169.45, 138.57, 133.77, 133.58, 125.07, 76.78, 74.97, 71.59, 70.65, 65.94, 62.59, 20.60, 20.54, 20.37, 20.18. HR-MS (ESI): m/z [M+NH₄]⁺ calcd for C₂₀H₂₉BNO₁₁⁺: 470.1828, found: 470.1830.

Synthesis of (4-((2S,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)phenyl)boronic acid (E6): Following the general synthetic procedure 5, E6 was prepared from 75 (0.65 g, 1.44 mmol) using Na (50 mg, 2.17 mmol) in dried MeOH (13 mL). White solid, 0.16 g (39%). m.p. 348.9–356.7 °C. [α]_D²⁰ = +60.0° (c = 0.1, H₂O-DMSO (1/1 by v/v)). ¹H NMR (500 MHz, D₂O) δ 7.79 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 4.94–4.90 (m, 1H), 4.14–4.13 (m, 1H), 3.99 (dd, J = 12.5, 2.5 Hz, 1H), 3.89–3.84 (m, 2H), 3.71 (t, J = 9.8 Hz, 1H), 3.56–3.53 (m, 1H). ¹³C NMR (151 MHz, D₂O) δ 140.91, 133.56, 127.79, 125.62, 80.10, 79.12, 74.28, 72.52, 66.91, 61.24. HR-MS (ESI): m/z [M+Na]⁺ calcd for C₁₂H₁₇BNaO₇⁺: 307.0960, found: 307.0960.

Synthesis of (3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)-2-(3-iodophenyl)-2-methoxytetrahydro-2H-pyran (76): Following the general synthetic procedure 2, 76 was prepared from 18 (10.00 g, 18.6 mmol) and 1,3-diiodide (9.20 g, 27.9 mmol) using n-BuLi (17.4 mL, 1.6 M in THF, 27.84 mmol), MeSO₃H (7.50 g, 78.0 mmol), MeOH (38 mL), and dried THF (200 mL) as a crude sample. Brown oil, 16.23 g. This sample was used directly in the next step without further purification or characterization.

Synthesis of (2R,3R,4R,5R,6S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-6-(3-iodophenyl)tetrahydro-2H-pyran (77): Following the general synthetic procedure 3, 77 was prepared from crude 76 prepared above (16.23 g, deemed to be 21.5 mmol) using Et₃SiH (5.00 g, 43.0 mmol) and BF₃·Et₂O (3.66 g, 25.8 mmol) in dried CH₂Cl₂ (163 mL). Column chromatography purification (EtOAc/PE = 1/6 by v/v) gave 77. Pale yellow oil, 2.97 g (22% overall for 18 to 77). ¹H NMR (500 MHz, CDCl₃) δ 7.75 (s, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.38–7.28 (m, 14H), 7.24–7.17 (m, 5H), 7.02 (t, J = 7.8 Hz, 1H), 6.95–6.93 (m, 2H), 4.91 (d, J = 10.5 Hz, 1H), 4.74–4.69 (m, 3H), 4.58 (dd, J = 25.5, 11.5 Hz, 3H), 4.40 (s, 1H), 4.20 (d, J = 11.5 Hz, 1H), 3.99 (t, J = 9.8 Hz, 1H), 3.90–3.89 (m, 1H), 3.81 (d, J = 3.5 Hz, 2H), 3.77 (dd, J = 9.5, 3.0 Hz, 1H), 3.61–3.58 (m, 1H). ¹³C NMR (126 MHz, CDCl₃) δ 141.42, 138.56, 138.43, 138.39, 138.01, 136.47, 135.82, 129.77, 128.58, 128.47, 128.21, 128.18, 127.93, 127.81, 127.78, 127.61, 127.59, 127.54, 125.84, 94.17, 84.93, 80.00, 79.09, 75.38, 75.02, 74.58, 73.50, 72.41, 69.61. HR-MS (ESI): m/z [M+NH₄]⁺ calcd for C₄₀H₄₃INO₅⁺: 744.2180, found: 744.2186.

Synthesis of (2R,3R,4R,5R,6S)-2-(acetoxymethyl)-6-(3-iodophenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (78): Following the procedure for the synthesis of 37 from 36, 78 was prepared from 77 (2.50 g, 3.44 mmol) using Ac₂O (25 mL) and BF₃·Et₂O (25 mL). Column chromatography purification (EtOAc/PE = 1/5 by v/v) gave 78. Yellow oil, 1.23 g (67%). ¹H NMR (500 MHz, CDCl₃) δ 7.73–7.72 (m, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.26–7.24 (m, 1H), 7.05 (t, J = 7.8 Hz, 1H), 5.51–5.50 (m, 1H), 5.35–5.31 (m, 1H), 5.22 (dd, J = 10.3, 3.3 Hz, 1H), 4.71 (s, 1H), 4.33 (dd, J = 12.3, 5.8 Hz, 1H), 4.24 (dd, J = 12.5, 2.5 Hz, 1H), 3.82–3.79 (m, 1H), 2.11 (s, 3H), 2.08 (s, 3H), 1.99 (s, 3H), 1.96 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 170.93, 170.39, 170.04, 169.90, 138.46, 137.37, 135.58, 130.07, 125.48, 94.17, 77.71, 76.66, 72.44, 70.50, 66.10, 63.09, 20.98, 20.89, 20.77, 20.58. HR-MS (ESI): m/z [M+NH₄]⁺ calcd for C₂₀H₂₇INO₉⁺: 552.0725, found: 552.0724.

Synthesis of (2R,3R,4R,5R,6S)-2-(acetoxymethyl)-6-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (79): Following the general synthetic procedure 7, 79 was prepared from 78 (1.94 g, 3.63 mmol) using B₂Pin₂ (1.38 g, 5.45 mmol), KOAc (1.07 g, 10.9 mmol), and Pd(dppf)Cl₂ (0.53 g, 0.726 mmol) in DMSO (19.4 mL). Column chromatography purification (EtOAc/PE = 1/1 by v/v) gave 79. Colorless oil, 0.64 g (33%). ¹H NMR (500 MHz, CDCl₃) δ 7.73–7.70 (m, 2H), 7.46–7.43 (m, 1H), 7.33 (t, J = 7.5 Hz, 1H), 5.52–5.51 (m, 1H), 5.35 (t, J = 9.8 Hz, 1H), 5.23 (dd, J = 10.0, 3.5 Hz, 1H), 4.76 (s, 1H), 4.33 (dd, J = 12.0, 6.0 Hz, 1H), 4.25 (dd, J = 12.0, 2.5 Hz, 1H), 3.83–3.79 (m, 1H), 2.10 (s, 3H), 2.08 (s, 3H), 1.98 (s, 3H), 1.94 (s, 3H), 1.34 (s, 1H), 1.33 (s, 1H). ¹³C NMR (151 MHz, CDCl₃) δ 170.96, 170.38, 170.09, 169.97, 135.59, 134.73, 132.84, 129.39, 128.35, 127.75, 84.02, 78.74, 76.65, 72.69, 70.87, 66.37, 63.27, 25.09, 24.93, 20.97, 20.91, 20.80, 20.61. HR-MS (ESI): m/z [M+H]⁺ calcd for C₂₆H₃₆BO₁₁⁺: 535.2345, found: 535.2346.

Synthesis of (3-((2S,3R,4R,5R,6R)-3,4,5-triacetoxy-6-(acetoxymethyl)tetrahydro-2H-pyran-2-yl)phenyl)boronic acid (80): Following the general synthetic procedure 8, 80 was prepared from 74 (1.36 g, 2.16 mmol) using NaIO₄ (1.38 g, 6.37 mmol) and NH₄OAc (0.30 g, 3.82 mmol) in a mixture of acetone (10.9 mL) and H₂O (2.7 mL). Column chromatography purification (MeOH/CH₂Cl₂ = 1/10 by v/v) gave 80. Colorless oil, 1.26 g (68%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.04 (s, 2H), 7.73–7.69 (m, 2H), 7.71–7.69 (m, 1H), 7.35–7.33 (m, 1H), 7.29 (t, J = 7.5 Hz, 1H), 5.40–5.36 (m, 2H), 5.14 (t, J = 10.0 Hz, 1H), 5.10 (s, 1H),4.20–4.17 (m, 1H), 4.15–4.12 (m, 1H), 4.05–4.02 (m, 1H), 2.06 (s, 3H), 2.03 (s, 3H), 1.92 (s, 3H), 1.88 (s, 3H). ¹³C NMR (151 MHz, DMSO-d₆) δ 170.17, 169.73, 169.61, 169.46, 135.75, 133.80, 133.59, 132.16, 128.04, 127.02, 77.08, 75.04, 71.65, 70.82, 65.98, 62.71, 20.61, 20.54, 20.39, 20.18. HR-MS (ESI): m/z [M+H]⁺ calcd for C₂₀H₂₆BO₁₁⁺: 453.1563, found: 453.1566.

Synthesis of (3-((2S,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)phenyl)boronic acid (E7): Following the general synthetic procedure 5, E7 was prepared from 80 (0.21 g, 0.465 mmol) using Na (30 mg, 1.30 mmol) in dried MeOH (4.2 mL). Column chromatography purification (MeOH/CH₂Cl₂ = 1/10 by v/v) gave E7. White solid. 44 mg (36%). m.p. 105.4–110.3 °C. [α]_D²⁰ = +24.6° (c = 2.8, H₂O). ¹H NMR (500 MHz, D₂O) δ 7.80 (s, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H), 4.81 (s, 1H), 4.13 (d, J = 3.5 Hz, 1H), 4.01–3.98 (m, 1H), 3.90–3.84 (m, 2H), 3.71 (t, J = 9.8 Hz, 1H), 3.57–3.53 (m, 1H). ¹³C NMR (151 MHz, D₂O) δ 137.59, 132.86, 131.98, 131.17, 128.69, 127.94, 80.06, 79.07, 74.30, 72.53, 66.92, 61.26. HR-MS (ESI): m/z [M+NH₄]⁺ calcd for C₁₂H₂₁BNO₇⁺: 302.1406, found: 302.1408.

Synthesis of (2R,3S,4R,5S,6S)-2-(hydroxymethyl)-6-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydro-2H-pyran-3,4,5-triol (E8): Following the general synthetic procedure 5, E8 was prepared from 79 (0.50 g, 1.11 mmol) using Na (50 mg, 2.17 mmol) in dried MeOH (10 mL). Column chromatography purification (MeOH/CH₂Cl₂ = 1/10 by v/v) gave E8. White solid. 0.18 g (53%). m.p. 277.6–286.3 °C. [α]_D²⁰ = +11.8° (c = 11.8, DMSO). ¹H NMR (500 MHz, DMSO-d₆) δ 7.72 (s, 1H), 7.53 (d, J = 7.0 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.30 (t, J = 7.5 Hz, 1H), 4.78 (d, J = 5.5 Hz, 1H), 4.68 (d, J = 5.5 Hz, 1H), 4.48 (s, 1H), 4.45 (t, J = 5.8 Hz, 1H), 4.19 (d, J = 5.5 Hz, 1H), 3.79–3.76 (m, 1H), 3.73–3.71 (m, 1H), 3.54–3.48 (m, 2H), 3.43–3.39 (m, 1H), 3.21–3.18 (m, 1H), 1.30 (s, 12H). ¹³C NMR (151 MHz, DMSO-d₆) δ 139.67, 133.08, 132.82, 132.42, 129.97, 126.95, 83.58, 81.65, 79.20, 75.11, 72.28, 67.17, 61.69, 24.74, 24.71. HR-MS (ESI): m/z [M+NH₄]⁺ calcd for C₁₈H₃₁BNO₇⁺: 384.2188, found: 384.2190.

Synthesis of (2R,3R,4S,5S,6S)-2-(acetoxymethyl)-5-fluoro-6-(4-iodophenyl)tetrahydro-2H-pyran-3,4-diyl diacetate (81): Following the procedure for the synthesis of 37 from 36, 81 was prepared from 26 (0.40 g, 0.627 mmol) using Ac₂O (4 mL) and BF₃·Et₂O (4 mL). Column chromatography purification (EtOAc/PE = 1/6 by v/v) gave 81. Colorless oil, 0.25 g (80%). ¹H NMR (500 MHz, CDCl₃) δ 7.74–7.71 (m, 2H), 7.14–7.13 (m, 2H), 5.45–5.40 (m, 1H), 5.14 (t, J = 9.8 Hz, 1H), 4.42–4.41 (m, 1H), 4.40–4.30 (m, 1H), 4.30–4.27 (m, 1H), 4.16 (dd, J = 12.3, 2.3 Hz, 1H), 3.86–3.83 (m, 1H), 2.08 (s, 6H), 2.06 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 170.79, 170.28, 169.78, 137.83, 136.20, 128.85, 90.93 (d, J = 189.6 Hz), 78.82 (d, J = 22.6 Hz), 74.16 (d, J = 19.8 Hz), 68.45 (d, J = 7. 6 Hz), 20.90, 20.85, 20.75. HR-MS (ESI): m/z [M+NH₄]⁺ calcd for C₁₈H₂₄FINO₇⁺: 512.0576, found: 512.0583.

Synthesis of (2R,3R,4S,5S,6S)-2-(acetoxymethyl)-5-fluoro-6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydro-2H-pyran-3,4-diyl diacetate (82): Following the general synthetic procedure 7, 81 was prepared from 81 (0.24 g, 0.486 mmol) using B₂Pin₂ (0.19 g, 0.729 mmol), KOAc (0.14 g, 1.458 mmol) and Pd(dppf)Cl₂ (0.07 g, 0.097 mmol) in dried DMSO (2.4 mL). Column chromatography purification (EtOAc/PE = 1/2 by v/v) gave 82. Colorless oil, 0.82 g (34%). ¹H NMR (500 MHz, CDCl₃) δ 7.84–7.82 (m, 2H), 7.40–7.38 (m, 2H), 5.48–5.43 (m, 1H), 5.17–5.13 (m, 1H), 4.48–4.47 (m, 1H), 4.46–4.36 (m, 1H), 4.30 (dd, J = 12.3, 5.3 Hz, 1H), 4.16 (dd, J = 12.5, 2.5 Hz, 1H), 3.88–3.84 (m, 1H), 2.08 (s, 6H), 2.07 (s, 3H), 1.34 (s, 12H). ¹³C NMR (201 MHz, CDCl₃) δ 170.85, 170.33, 169.82, 139.37, 135.12, 128.73, 126.38, 90.95 (d, J = 188.9 Hz), 84.04, 79.51, 79.40, 76.20, 74.36 (d, J = 19.7 Hz), 68.61 (d, J = 7.4 Hz), 62.47, 25.03, 24.96, 20.91, 20.88, 20.78. HR-MS (ESI): m/z [M+NH₄]⁺ calcd for C₂₄H₃₆BFNO₉⁺: 512.2462, found: 512.2469.

Synthesis of (2R,3S,4S,5R,6S)-5-fluoro-2-(hydroxymethyl)-6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydro-2H-pyran-3,4-diol (E9): Following the general synthetic procedure 5, E9 was prepared from 82 (0.30 g, 0.607 mmol) using Na (50 mg, 2.17 mmol) in dried MeOH (3 mL). Column chromatography purification (MeOH/CH₂Cl₂ = 1/10 by v/v) gave E9. White solid, 34 mg (15%). m.p. 145.8–153.7 °C. [α]_D²⁰ = +9.5° (c = 5.8, DMSO). ¹H NMR (500 MHz, DMSO-d₆) δ 7.67 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 5.49–5.48 (m, 1H), 5.26–5.25 (m, 1H), 4.56 (t, J = 6.0 Hz, 1H), 4.38 (dd, J = 9.5, 3.0 Hz, 1H), 4.14–4.00 (m, 1H), 3.74–3.70 (m, 1H), 3.62–3.58 (m, 1H), 3.57–3.49 (m, 1H), 3.48–3.44 (m, 1H), 3.28–3.25 (m, 1H), 1.29 (s, 12H). ¹⁹F NMR (471 MHz, DMSO-d₆) δ −193.80. HR-MS (ESI): m/z [M+H]⁺ calcd for C₁₈H₂₇BFO₆⁺: 369.1879, found: 369.1880.

Synthesis of (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)-2-(3,5-dibromophenyl)-2-methoxytetrahydro-2H-pyran (83): Following the general synthetic procedure 2, 83 was prepared from 6 (10.00 g, 18.6 mmol) and 1,3,5-tribromobenzene (14.6 g, 46.4 mmol) using n-BuLi (23.2 mL, 1.6 M in THF, 37.12 mmol), MeSO₃H (8.94 g, 0.093 mol), MeOH (45 mL), and dried THF (200 mL) as a crude sample. Brown oil, 18.33 g. This sample was used directly in the next step without further purification or characterization.

Synthesis of (2R,3R,4R,5S,6S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-6-(3,5-dibromophenyl)tetrahydro-2H-pyran (84): Following the general synthetic procedure 3, 84 was prepared from crude 83 prepared above (18.33 g, deemed to be 23.2 mmol) using Et₃SiH (5.40 g, 46.4 mmol) and BF₃·Et₂O (3.95 g, 27.8 mmol) in dried CH₂Cl₂ (183 mL). Column chromatography purification (EtOAc/PE = 1/5 by v/v) gave 84. Colorless oil, 3.10 g. This sample was used directly in the next step without characterization.

Synthesis of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3,5-dibromophenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (85): Following the procedure for the synthesis of 37 from 36, 85 was prepared from 84 (3.10 g, 4.07 mmol) using Ac₂O (31 mL) and BF₃·Et₂O (31 mL). Column chromatography purification (EtOAc/PE = 1/3 by v/v) gave 85. Yellow oil, 1.41 g (11% overall for 6 to 85). ¹H NMR (500 MHz, CDCl₃) δ 7.63–7.62 (m, 1H), 7.43 (d, J = 1.5 Hz, 2H), 5.31–5.29 (m, 1H), 5.20 (t, J = 9.8 Hz, 1H), 4.99 (t, J = 9.8 Hz, 1H), 4.34 (d, J = 9.5 Hz, 1H), 4.29 (dd, J = 12.5, 5.0 Hz, 1H), 4.17 (dd, J = 12.5, 2.5 Hz, 1H), 3.84–3.81 (m, 1H), 2.11 (s, 3H), 2.06 (s, 3H), 2.00 (s, 3H), 1.91 (s, 3H). ¹³C NMR (151 MHz, CDCl₃) δ 170.86, 170.46, 169.58, 168.96, 140.30, 134.58, 128.88, 123.06, 78.70, 76.45, 74.00, 72.69, 68.47, 62.34, 20.93, 20.77, 20.75, 20.57. HR-MS (ESI): m/z [M+Na]⁺ calcd for C₂₀H₂₂Br₂NaO₉⁺: 586.9523, found: 586.9535.

Synthesis of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3,5-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (86): Following the general synthetic procedure 7, 86 was prepared from 85 (0.78 g, 1.38 mmol) using B₂Pin₂ (1.05 g, 4.14 mmol), KOAc (0.82 g, 8.28 mmol), and Pd(dppf)Cl₂ (0.40 g, 0.552 mmol) in dried DMSO (7.8 mL). Column chromatography purification (EtOAc/PE = 1/2 by v/v) gave 86. Colorless oil, 0.37 g (41%). ¹H NMR (500 MHz, CDCl₃) δ 8.22 (s, 1H), 7.88–7.86 (m, 2H), 5.31 (d, J = 9.5 Hz, 1H), 5.23 (t, J = 9.5 Hz, 1H), 5.14 (t, J = 9.8 Hz, 1H), 4.44 (d, J = 10.0 Hz, 1H), 4.27 (dd, J = 12.5, 5.0 Hz, 1H), 4.20 (dd, J = 12.3, 2.3 Hz, 1H), 3.84–3.80 (m, 1H), 2.10 (s, 3H), 2.06 (s, 3H), 1.99 (s, 3H), 1.80 (s, 3H), 1.34 (s, 12H), 1.33 (s, 12H) ¹³C NMR (151 MHz, CDCl₃) δ 171.02, 170.61, 169.67, 169.08, 141.93, 136.39, 134.96, 84.01, 80.37, 76.38, 74.58, 72.91, 68.90, 62.68, 25.04, 25.02, 20.97, 20.83, 20.80, 20.51. HR-MS (ESI): m/z [M+H]⁺ calcd for C₃₂H₄₇B₂O₁₃⁺: 661.3197, found: 661.3214.

Synthesis of (5-((2S,3S,4R,5R,6R)-3,4,5-triacetoxy-6-(acetoxymethyl)tetrahydro-2H-pyran-2-yl)-1,3-phenylene)diboronic acid (87): Following the general synthetic procedure 8, 87 was prepared from 86 (0.40 g, 0.806 mmol) using NaIO₄ (0.86 g, 4.03 mmol) and NH₄OAc (0.19 g, 2.42 mmol) in a mixture of acetone (3.2 mL) and H₂O (0.80 mL). Column chromatography purification (MeOH/CH₂Cl₂ = 1/10 by v/v) gave 87. Colorless oil, 0.16 g. This sample was used directly in the next step without characterization.

Synthesis of (5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-1,3-phenylene)diboronic acid (F1): Following the general synthetic procedure 5, F1 was prepared from 87 (0.16 g, 0.323 mmol) using Na (30 mg, 1.74 mmol) in dried MeOH (3.2 mL). Column chromatography purification (MeOH/CH₂Cl₂ = 1/10 by v/v) gave F1. White solid, 34 mg (17% overall for 86 to F1). m.p. 362.2–378.9 °C. [α]_D²⁰ = +5.3° (c = 4.0, H₂O). ¹H NMR (500 MHz, D₂O) δ 8.12 (s, 1H), 7.90 (s, 2H), 4.36–4.35 (m, 1H), 3.91–3.88 (m, 1H), 3.80–3.75 (m, 2H), 3.65–3.60 (m, 3H). ¹³C NMR (151 MHz, D₂O) δ 139.21, 136.63, 135.53, 81.84, 79.92, 77.25, 74.06, 69.71, 60.82. HR-MS (ESI): m/z [M+Na]⁺ calcd for C₁₂H₁₈B₂NaO₉⁺: 351.1029, found: 351.1028.

Synthesis of (2S,3R,4R,5S,6R)-2-(3,5-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (F2): Following the general synthetic procedure 5, F2 was prepared from 86 (0.40 g, 0.606 mmol) using Na (50 mg, 2.17 mmol) in dried MeOH (8 mL). Column chromatography purification (MeOH/CH₂Cl₂ = 1/10 by v/v) gave F2. White solid, 0.15 g (49%). m.p. 175.7–181.3 °C. [α]_D²⁰ = +2.4° (c = 14.0, MeOH). ¹H NMR (500 MHz, DMSO-d₆) δ 7.96–7.95 (m, 1H), 7.73–7.72 (m, 2H), 4.94–4.93 (m, 1H), 4.91–4.90 (m, 1H), 4.77–4.75 (m, 1H), 4.49 (t, J = 5.5 Hz, 1H), 4.04 (d, J = 9.5 Hz, 1H), 3.71–3.68 (m, 1H), 3.48–3.46 (m, 1H), 3.27–3.20 (m, 3H), 3.14–3.11 (m, 1H), 1.30 (s, 24H). ¹³C NMR (151 MHz, DMSO-d₆) δ 140.20, 139.23, 136.82, 127.14, 83.72, 81.53, 81.39, 78.47, 70.47, 67.30, 61.30, 24.75, 24.63. HR-MS (ESI): m/z [M-H]⁻ calcd for C₂₄H₃₉B₂O₉⁻: 493.2786, found: 493.2773.

Synthesis of (3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)-2-(3,5-dibromophenyl)-2-methoxytetrahydro-2H-pyran (88): Following the general synthetic procedure 2, 88 was prepared from 18 (10.00 g, 18.6 mmol) and 1,3,5-tribromobenzene (8.78 g, 27.9 mmol) using n-BuLi (14 mL, 1.6 M in THF, 22.4 mmol), MeSO₃H (8.94 g, 93 mmol), MeOH (45 mL), and dried THF (200 mL) as a crude sample. Brown oil, 15.65 g. This sample was used directly in the next step without further purification or characterization.

Synthesis of (2R,3R,4R,5R,6S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-6-(3,5-dibromophenyl)tetrahydro-2H-pyran (89): Following the general synthetic procedure 3, 89 was prepared from crude 88 prepared above (15.65 g, deemed to be 19.9 mmol) using Et₃SiH (4.63 g, 39.8 mmol) and BF₃·Et₂O (3.39 g, 23.9 mmol) in dried CH₂Cl₂ (157 mL). Column chromatography purification (EtOAc/PE = 1/5 by v/v) gave 89. Colorless oil, 2.25 g. This sample was used directly in the next step without characterization.

Synthesis of (2R,3R,4R,5R,6S)-2-(acetoxymethyl)-6-(3,5-dibromophenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (90): Following the procedure for the synthesis of 37 from 36, 90 was prepared from 89 (2.25 g, 2.97 mmol) using Ac₂O (23 mL) and BF₃·Et₂O (23 mL). Column chromatography purification (EtOAc/PE = 1/3 by v/v) gave 90. Brown oil, 1.08 g (11% overall for 18 to 90). ¹H NMR (500 MHz, CDCl₃) δ 7.59–7.57 (m, 1H), 7.45–7.42 (s, 2H), 5.48–5.47 (m, 1H), 5.31–5.29 (m, 1H), 5.19 (dd, J = 10.0, 3.5 Hz, 1H), 4.69 (s, 1H), 4.31 (dd, J = 12.3, 5.8 Hz, 1H), 4.23–4.20 (m, m, 1H), 3.81–3.78 (m, 1H), 2.11 (s, 3H), 2.07 (s, 3H), 1.98 (s, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 170.85, 170.30, 169.91, 169.82, 140.05, 133.98, 128.39, 122.89, 77.24, 76.72, 72.28, 70.28, 65.88, 62.98, 20.94, 20.85, 20.73, 20.53. HR-MS (ESI): m/z [M+H]⁺ calcd for C₂₀H₂₃Br₂O₉⁺: 564.9703, found: 564.9712.

Synthesis of (2R,3R,4R,5R,6S)-2-(acetoxymethyl)-6-(3,5-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (91): Following the general synthetic procedure 7, 91 was prepared from 90 (0.85 g, 1.50 mmol) using B₂Pin₂ (1.14 g, 4.50 mmol), KOAc (0.88 g, 9.00 mmol), and Pd(dppf)Cl₂ (0.44 g, 0.60 mmol) in dried DMSO (8.5 mL). Column chromatography purification (EtOAc/PE = 1/2 by v/v) gave 91. Colorless oil, 0.39 g (39%). ¹H NMR (500 MHz, CDCl₃) δ 8.19 (s, 1H), 7.86–7.85 (m, 2H), 5.45–5.44 (m, 1H), 5.35 (t, J = 10.0, 1H), 5.22 (dd, J = 10.0, 3.5 Hz, 1H), 4.74 (s, 1H), 4.29–4.28 (m, 1H), 3.82–3.79 (m, 1H), 3.74–3.70 (m, 1H), 2.10 (s, 3H), 2.08 (s, 3H), 1.98 (s, 6H), 1.34 (s, 12H), 1.32 (s, 12H). ¹³C NMR (201 MHz, CDCl₃) δ 171.00, 170.36, 170.10, 170.00, 141.41, 136.11, 134.83, 83.97, 79.11, 76.78, 72.69, 70.94, 66.48, 63.43, 25.12, 24.91, 20.99, 20.92, 20.81, 20.58. HR-MS (ESI): m/z [M+H]⁺ calcd for C₃₂H₄₇B₂O₁₃⁺: 661.3197, found: 661.3211.

Synthesis of (5-((2S,3R,4R,5R,6R)-3,4,5-triacetoxy-6-(acetoxymethyl)tetrahydro-2H-pyran-2-yl)-1,3-phenylene)diboronic acid (92): Following the general synthetic procedure 8, 92 was prepared from 91 (0.48 g, 0.727 mmol) using NaIO₄ (0.78 g, 3.64 mmol) and NH₄OAc (0.17 g, 2.18 mmol) in a mixture of acetone (3.8 mL) and H₂O (1 mL). Column chromatography purification (MeOH/CH₂Cl₂ = 1/10 by v/v) gave 92. Colorless oil, 0.18 g. This sample was used directly in the next step without characterization.

Synthesis of (5-((2S,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-1,3-phenylene)diboronic acid (F3): Following the general synthetic procedure 5, F3 was prepared from 92 (0.18 g, 0.363 mmol) using Na (30 mg, 1.74 mmol) in MeOH (3.2 mL). Column chromatography purification (MeOH/CH₂Cl₂ = 1/10 by v/v) gave F3. White solid, 26 mg (11% overall for 91 to F3). m.p. 348.9–350.7 °C. [α]_D²⁰ = +12.8° (c = 3.6, H₂O). ¹H NMR (500 MHz, D₂O) δ 8.06 (s, 1H), 7.90 (s, 2H), 4.96 (s, 1H), 4.15–4.14 (m, 1H), 4.01–3.99 (m, 1H), 3.90–3.84 (m, 2H), 3.71 (t, J = 9.8 Hz, 1H), 3.57–3.53 (m, 1H). ¹³C NMR (151 MHz, D₂O) δ 138.01, 137.01, 133.66, 80.03, 78.97, 74.31, 72.44, 66.93, 61.31. HR-MS (ESI): m/z [M+NH₄]⁺ calcd for C₁₂H₂₂B₂NO₉⁺: 346.1475, found: 346.1474.

Synthesis of (2S,3S,4R,5S,6R)-2-(3,5-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (F4): Following the general synthetic procedure 5, F4 was prepared from 91 (0.14 g, 0.212 mmol) using Na (30 mg, 1.74 mmol) in dried MeOH (2.8 mL). Column chromatography purification (MeOH/CH₂Cl₂ = 1/10 by v/v) gave F4. White solid, 43 mg (41%). m.p. 157.8–166.1 °C. [α]_D²⁰ = +1.9° (c = 10.6, MeOH). ¹H NMR (500 MHz, DMSO-d₆) δ 7.92 (s, 1H), 7.79–7.78 (m, 2H), 4.77 (d, J = 5.5 Hz, 1H), 4.66 (d, J = 5.5 Hz, 1H), 4.52 (s, 1H), 4.48 (t, J = 5.5 Hz, 1H), 4.21 (d, J = 5.5 Hz, 1H), 3.80–3.76 (m, 1H), 3.69–3.68 (m, 1H), 3.52–3.49 (m, 2H), 3.42–3.38 (m, 1H), 3.21–3.17 (m, 1H), 1.30 (s, 24H). ¹³C NMR (151 MHz, DMSO-d₆) δ 139.63, 139.19, 135.93, 126.76, 83.67, 81.76, 79.19, 75.00, 72.36, 67.16, 61.64, 24.73, 24.69. HR-MS (ESI): m/z [M+NH₄]⁺ calcd for C₂₄H₄₂B₂NO₉⁺: 510.3140, found: 510.3043.

3.2. Cytotoxicity Assay

Cell culture: SCC-9 human tongue squamous cell carcinoma cells were cultured in Dulbecco’s modified eagle medium (DMEM)/Ham’s F-12 nutrient mixture (1/1) medium supplemented with 10% fetal bovine serum (FBS), 0.5 mM sodium pyruvate, and 400 ng/mL of hydrocortisone. HaCaT immortalized human keratinocytes were maintained in DMEM medium containing 10% FBS. All cells were maintained at 37 °C with 5% CO₂.

Cell viability assay: Cells were seeded in 96-well plates at 5 × 10³ cells per well (SCC-9) and 6.5 × 10³ cells per well (HaCaT) and treated with the indicated concentrations of compounds. After 24 h, cell viability was assayed using the CCK-8 reagent according to the manufacturer’s instructions. Absorbance was measured at 450 nm using a microplate reader. The IC₅₀ values were calculated through nonlinear regression analysis using a four-parameter logistic model.

3.3. Cellular Boron Uptake Assay

Determination of intracellular boron content by ICP-MS: SCC-9 and HaCaT cells were seeded in 6-well plates and incubated overnight. Cells were subsequently treated with the indicated concentrations of the test compounds for 3 h. After treatment, cells were gathered and washed with ice-cold PBS and then digested with HNO₃ until complete clarification was achieved. The digested samples were then diluted with ultrapure water to the appropriate volume for analysis. Boron concentrations were quantified using ICP-MS (Agilent 7850, Agilent Technologies, Singapore). Quantification was performed based on an external standard calibration curve.

4. Conclusions

Based on the strategy of glucose transporter 1 (GLUT1), we designed and synthesized a total of two categories comprising 6 series (28 boron-bearing sugars in total). Their boron-carrying abilities were determined by boron uptake by the SCC-9 and HaCaT cell lines, and their T/N values were calculated. Among the target compounds, almost no boron uptake was observed for series E–F (category II); higher boron uptake and larger T/N values were observed for series A–C (category I) compared with BPA. Notably, compound B3 exhibited the best profile, with 10.6-fold higher boron uptake by the SCC-9 cell line and a largely improved T/N (3.3 for B3 vs. 1.4 for BPA) compared with BPA. The chemical structure of B3 represents a privileged candidate structure for the future design of “ideal” boron carriers for BNCT. Considering that the T/N of B3 still falls short of that for an “ideal” boron carrier (T/N = 3.3 for B3 vs. T/N > 5 for “ideal” boron carriers), further SAR exploration based on B3 will be conducted in the future.