Synthesis of 2-Deoxyglycosides Bearing Free Hydroxyl Substituents on the Glycosyl Donor

Abstract

Recent efforts in the field of carbohydrate chemistry have focused on the site- and stereocontrolled synthesis of O-glycosides derived from acceptors bearing multiple hydroxyl substituents. By comparison, there are few examples of the site-selective synthesis of O-glycosides bearing free hydroxyl substituents on the donor reagent. Here, we report the application of an umpolung glycosylation strategy to the synthesis of O-glycosides derived from donors bearing free hydroxyl substituents. The reaction proceeds via prior deprotonation of one or more free hydroxyl groups on a thiophenylglycoside donor, reductive lithiation to generate an anomeric anion intermediate, and addition of this anion to an alkyl 2-(2-methyltetrahydropyranyl) peroxide. By this approach, α-linked glycosides were obtained in 39–84% yields and with >50:1 α/β selectivities. In many instances, β-linked products could be obtained by thermal equilibration of the anomeric anion intermediate (selectivities = 3.8–8:1 β/α; yields = 33–68%). The strategy is applicable to polyhydroxyl donors bearing up to three free hydroxyl groups, N-acylated carbohydrates, and the single-flask syntheses of oligosaccharides.

Graphical Abstract

INTRODUCTION

The site- and stereocontrolled construction of O-glycosides employing carbohydrate acceptors bearing two or more free hydroxyl substituents is a contemporary challenge.¹ Steric,² inductive,³ hydrogen bonding,⁴ and acidity⁵ effects have been exploited to achieve site-selective glycosylation reactions. Augé and Veyrières demonstrated the use of stannylene acetals⁶ in site-selective glycosylations.⁷ Subsequently, the Aoyama,⁸ Taylor,⁹ and Toshima¹⁰ laboratories have recorded significant advances in this area through the use of boron-based reagents to direct site- and stereoselectivities (Figure 1a–d).

Figure 1.

Strategies to achieve the site-selective glycosylation of polyhydroxyl acceptors. (a) Glycosylation of polyhydroxyl acceptors often forms regioisomeric mixtures of products. (b) Boronate-directed glycosylation by Aoyama and co-workers.⁸ (c) Borinate-directed glycosylation by Taylor and co-workers.⁹ (d) Epoxide-directed glycosylation by Toshima and co-workers.¹⁰

By comparison, fewer strategies to form O-glycosides using donors bearing free hydroxyl groups have been reported.^1,11 This undoubtedly is due to the incompatibility between a nucleophilic hydroxyl functionality and the anomeric electrophile in the donor reagent (Figure 2a). A notable exception was reported by Miller and Schepartz,¹² who developed site- and stereoselective glycosylation of sucrose using α-d-glucopyranosyl fluoride as the donor (Figure 2b).

Figure 2.

(a) Classical glycosylations employing donors bearing hydroxyl substituents are challenging owing to the presence of nucleophilic and electrophilic sites in the donor. (b) Site- and stereoselective glycosylation of sucrose by Schepartz and Miller.¹²

We recently reported an umpolung approach to O-glycoside bond formation that is amenable to the stereocontrolled synthesis of 2-deoxy- and 2,6-dideoxyglycosides.¹³ This work was based on studies by Cohen and Rychnovksy, which established that anomeric anions can be reliably generated as either α- or β-diastereomers,¹⁴ and from Dussault and co-workers who established alkyl-(2-tetrahydropyranyl)peroxides as viable alkoxenium-ion equivalents.¹⁵ Reductive lithiation of phenylthioglycosides using lithium 4,4-di-tert-butylbiphenylide (LiDBB)^14c,16 provided an axial (α) anomeric anion as the kinetic product (Figure 3a, top). Addition of an alkyl 2-(2-methyltetrahydropyranyl) (MTHP) peroxide¹⁷ then formed the α-linked glycoside. Alternatively, warming of the α-anion to −20 °C promoted equilibration to the more stable equatorial (β) diastereomer. Cooling to −78 °C followed by addition of an alkyl MTHP peroxide then generated the β-linked glycoside (Figure 3a, bottom). Because the configuration of the anomeric anion can be readily controlled, both α- and β-2-deoxyglycosides are accessible from a single carbohydrate donor (diastereoselectivities are typically >50:1). This strategy is applicable to the synthesis of a broad range of 2-deoxy- and 2,6-dideoxyglycosides, including 2-deoxyglycosides bearing a basic nitrogen.¹⁸

Figure 3.

(a) Reductive lithiation of thiophenylglycosides followed by addition of an alkyl MTHP peroxide provides access to α- or β-linked 2-deoxyglycosides, including 2-deoxyaminoglycosides bearing a basic nitrogen. (b) Umpolung glycosylation of thiophenyl glycosides bearing free hydroxyl groups studied herein.

In our earlier work,¹³ we found that this glycosylation strategy was compatible with thiophenylglycosides bearing a free C6-hydroxyl substituent, provided the acidic proton was removed by treatment with methyllithium before reductive lithiation. We sought to evaluate the generality of this strategy for the construction of glycosides bearing free hydroxyl substituents at other positions because this is inherently challenging using classical glycosylation strategies (vide supra). At the outset, it was unclear if a C3 or C4 alkoxide would have a detrimental effect on the reductive lithiation step. Additionally, the influence of the alkoxide substituent on the rates of equilibration and relative energies of the α- and β-anions was not known. Because α-glycosylations do not require an intermediate warming step, we anticipated that these would proceed more efficiently and focused our initial efforts on these transformations, as detailed below.

RESULTS AND DISCUSSION

The α-selective glycosylation reaction proved general for 2-deoxyglycosides bearing free hydroxyl substituents at the C3-, C4-, and C6-positions with minimal modification of our reported reaction conditions (Table 1). In a typical experiment, a solution of the hydroxythiophenyglycoside in tetrahydrofuran and pentane (1:1 v/v) was cooled to −78 °C and treated sequentially with methyllithium (1.00 equiv) and LiDBB (nominally 0.4 M).¹⁶ An alkyl MTHP peroxide was then added, to furnish an α-disaccharide. By this approach, the 3-hydroxythiophenyl 2-deoxy-glucose derivatives 5 and 6 were transformed into the 3-hydroxyglycosides 13α and 14α in 71 and 74% yields, respectively, when the primary MTHP peroxide 11 was used as an electrophile. The same starting 3-hydroxythiophenylglycosides provided the α-disaccharides 16α and 17α in 39 and 59% yields, respectively, when the secondary MTHP peroxide 12α was employed. The diminished yields using the secondary peroxide 12α relative to the primary peroxide 11 are consistent with our earlier studies.^13,18 We attribute this to a slower rate of bimolecular displacement arising from increased steric hindrance, which allows non-productive pathways, such as reduction of the peroxide or proton abstraction by the anomeric anion from solvent, to compete. Although the yields were somewhat diminished, the stereoselectivity of the reaction remained high (>50:1 α/β selectivity). The 3-hydroxygalactosyl derivative 7 was converted to the disaccharide 15α in 84% yield and >50:1 α/β selectivity when the alkyl MTHP peroxide 11 was employed as the electrophile.

Table 1.

α-Selective Glycosylation Reactions of 3-, 4-, or 6-Hydroxy Thiophenylglycosides

4-Hydroxyphenylthioglycosides also underwent efficient α-glycosylations. The 4-hydroxyolivosyl disaccharide 18α was isolated in 83% yield and >50:1 α/β selectivity following addition of the alkyl MTHP peroxide 11 to the dianion derived from 1. Alternatively, the silyl-protected olivoside 2α provided the disaccharide 19α in 47% yield and >50:1 α/β selectivity. The 4-hydroxyoliosyl derivatives 20α and 22α were obtained in 77 and 55% yields, respectively, and with >50:1 α/β selectivity, following addition of the alkyl MTHP peroxides 11 or 12α to the dianion derived from the d-oliose derivative 4α. We isolated 20α in 72% yield (>50:1 α/β selectivity) when the reaction was conducted using 1 mmol of the electrophile 11. By using the rhodinose thioglycoside 3α as a donor, the α-disaccharides 21α and 23α were obtained in 80 and 72% yields, respectively (>50:1 α/β selectivity). The hydroxy disaccharide 24α was obtained in 55% yield and with >50:1 α/β selectivity upon treatment of the secondary electrophile 12α with the dianion derived From the l-oliosyl thioglycoside 8α. The 6-hydroxy-α-disaccharides 25α and 26α were isolated in 77 and 64% yields and >50:1 α/β selectivities by addition of the 3,4-(butane 2,3-bisacetal)-protected thiophenylglycoside 9 to the alkyl MTHP peroxides 11 or 12α. The 6-hydroxy-α-disaccharide 27α was obtained in 75% yield when the dianion derived from the acetonide-protected 2-deoxy-galactosyl thioglycoside 10α was treated with the alkyl MTHP peroxide 12α (>50:1 α/β selectivity).

With the scope of the α-glycosylation established, we then evaluated the synthesis of β-linked glycosides by thermal equilibration of the anomeric anion intermediate (Table 2). As anticipated, the efficiency of the α-to-β equilibration was variable, and slightly higher temperatures (−65 °C) were required to promote coupling of the less reactive β-dianions with the alkyl MTHP electrophiles.^13,18 We hypothesize that β-anions are less nucleophilic than their α-counterparts owing to the reduced repulsive interactions with the non-bonding electrons on the adjacent oxygen. Consistent with this, we previously calculated the energies of both α- and β-anions and found that for both the 2-deoxy- and 2,6-dideoxyglycoside series, the β-anions were lower in energy in a C-PCM solvation model (ε = 7.43) and in the gas phase [MP2/6-311+G(d,p)].¹³ Thus, the β-disaccharide 25β was obtained in 68% yield with 8:1 β/α selectivity following sequential treatment of the 6-hydroxythiophenylglycoside 9 with methyllithium, addition of LiDBB at −78 °C, warming to −20 °C for 1 h to promote equilibration, re-cooling to −78 °C, introduction of the alkyl MTHP peroxide 11, and warming to −65 °C (entry 1). Based on prior studies by Rychnovsky^14c and Zhu,¹⁹ as well as our own work,¹⁸ we anticipated that the β-selectivity could be enhanced by using tetrahydrofuran exclusively as a solvent. However, under these conditions, the yield of 25β decreased to 43% and the stereoselectivity was diminished (5.4:1 α/β; entry 2). An increase in β-selectivity (10 → 50:1 β/α) was observed as the equilibration temperature was raised to 0 °C; however, the yield of the disaccharide 25β was reduced (11–34%, entries 3–5). The results in entries 3–5 suggest that the rate of equilibration to the β-anomeric anion is competitive with proton transfer from the solvent to the more reactive dianionic intermediate. We hypothesized that changing the structure of the dianion, by the addition of inert salts (such as lithium bromide) or the use of a different counterion, might alter the rate of equilibration. However, the addition of lithium bromide (as a methyl lithium–lithium bromide complex, entry 6) did not provide a meaningful improvement over the conditions in entry 1 (54% yield of 25β, 7.8:1 β/α selectivity). To probe the effects of variation of the alkoxide counterion, we attempted an α-glycosylation using sodium hydride as the base. However, the disaccharide 25α was obtained in only 20% yield (entry 7). While α-selective reactions were broad in scope and provided α-disaccharides in yields typically >70% and selectivities of >50:1 α/β, the β-selective glycosylation was less general. Thus, the β-glucosyl disaccharides 13β–26β were obtained in 33–68% yields and with selectivities ranging from 3.8 to 8:1 β/α (Figure 4).

Table 2.

Optimization of the β-selective Glycosylation Reaction

entry	equiv 9	Solvent	T (°C)a	t (min)b	yield of 25β (%)c	selectivity
1	2.0	THF–pentane	−20	60	68d	8:1 β/α
2	2.0	THF	−20	60	43	5.4:1 β/α
3	2.0	THF–pentane	−10	60	34	13:1 β/α
4	2.0	THF	−10	60	21	10:1 β/α
5	2.0	THF	0	60	11	>50:1 β/α
6e	2.0	THF–pentane	−20	60	54	7.8:1 β/α
7f	2.0	THF–pentane	N/A	N/A	20 (25α)	>50:1 α/β

^aTemperature of α-to-β equilibration.

^bTime of α-to-β equilibration.

^cCombined yield of both diastereomers as determined by ¹H NMR analysis using trimethoxybenzene as an internal standard.

^dIsolated yields.

^eMethyllithium–LiBr used as the base.

^fNaH used as the base.

Figure 4.

Scope of the β-selective glycosylation.

One explanation for the lower selectivity in the β-glycosylation reaction might be that the α-to-β equilibration is slower for the dianionic intermediates. To probe this, the experiments shown in Figure 5 were carried out. The 3-hydroxy-β-disaccharide 14β was obtained in 56% yield and with 4.8:1 β/α selectivity when the 3-hydroxythiophenylglycoside 6 was employed (Figure 5a). By comparison, the 3-methoxy-β-disaccharide 29β was obtained in 66% yield and >50:1 β/α selectivity when the 3-methoxythiophenylglycoside 28 was subjected to the same reaction conditions. Additionally, the α-linked products 21α and 31α were obtained with >10:1 α/β selectivity when the d-rhodinosyl and d-forosaminyl derivatives 3α and 30α were employed, and equilibration to the β-dianion was attempted (−20 °C, 1 h; Figure 5b). These observations are consistent with a slower rate of equilibration. However, the presence of the additional alkoxide may also render the α-anion more thermodynamically favorable. Unfortunately, we have not been able to test this hypothesis because the employment of higher temperatures (to ensure the reaction is under thermodynamic control) has been shown to lead to greatly diminished yields (see entries 4 and 5, Table 2), consistent with prior studies of monoanionic anomeric anion intermediates.^13,14c,18,19 Regardless of the precise basis, the β-selective glycosylation is not as general as the α-selective pathway.

Figure 5.

(a) Comparison of the β-glycosylation for the substrates 6 and 28, which bear a free and protected C3 hydroxyl substituent, respectively. (b) Attempted formation of β-linked products derived from the thiophenylglycosides 3α and 30α.

Notwithstanding the limited scope of the β-selective glycosylations, this strategy is also amenable to the synthesis of α-glycosides bearing other acidic functional groups or fully deprotected 2,6-dideoxyglycosides (Table 3). For example, we previously showed the N-acylated disaccharides 31α, 35α, and 36α are accessible in 60–80% yields and with >50:1 α/β selectivity. Attempts to form the β-product 35β were less successful (56%, 2.6:1 β/α). Treatment of the 3,4-dihydroxy l-olivose thioglycoside 33 with two equivalents of methyllithium, followed by sequential addition of LiDBB and the primary or secondary alkyl MTHP peroxides 11 and 12α provided the products 37α and 38α in a 44% and 48% yields and in >50:1 α/β selectivity. Subjecting this thioglycoside to the β-selective conditions provided the β-glycoside 37β in 8% yield and 7:1 β/α selectivity. Finally, this strategy was taken a step further by employing the 3,4,6-trihydroxy thioglycoside 34. Treatment with methyllithium (3.00 equiv) followed by reductive lithiation and addition of the MTHP peroxide 11 provided the α-disaccharide 39α in 42% yield and >50:1 α/β selectivity. To probe the nature of the anionic intermediate, we subjected 34 to 2.50 equiv of methyllithium prior to the reductive lithiation and addition of 11. However, the yield of 39α was reduced to 17% (by quantitative NMR analysis). This suggests that the removal of each of the three hydroxyl protons in 34 is necessary for optimal yields.

Table 3.

Anionic Glycosylations for N-Acylated or Fully Unprotected 2-Deoxyglycosides

The products shown in Figure 6 were prepared to highlight the applicability of this strategy toward the one-flask syntheses of oligosaccharides. Thus, the trisaccharides 40, 41, and 42 were obtained in 36, 52, and 64% yields, respectively, by sequential deprotonation and reductive lithiation of the appropriate hydroxythioglycoside (3α, 6, or 9) followed by addition of the peroxy thiophenyl glycoside 12α, further reductive lithiation, and addition of the primary MTHP peroxide 11. In this way, each trisaccharide was formed as a single detectable diastereomer (¹H NMR analysis of the unpurified product mixture).

Figure 6.

Single-flask syntheses of oligosaccharides.

CONCLUSIONS

Here, we have demonstrated the successful reductive coupling of hydroxythiophenyl 2-deoxyglycosides bearing one, two, or three free hydroxyl groups with MTHP peroxides. The reaction manifold is relatively general for the synthesis of α-linked glycosides bearing free hydroxyl groups, while the scope of the β-glycosylation is more narrow. Our data suggest that the additional alkoxide residue decreases the rate of α-to-β equilibration of the anomeric anion intermediate, leading to lower yields and selectivities in the β-selective pathway. Nonetheless, most products were formed in synthetically useful yields. We believe this work constitutes a useful strategy to obtain α-linked 2-deoxyglycosides bearing free hydroxyl groups within the donor reagent.

EXPERIMENTAL SECTION

General Experimental Procedures.

All reactions were performed in single-neck flame-dried round-bottomed flasks with rubber septa under a positive pressure of argon, unless otherwise noted. Air- and moisture-sensitive liquids were transferred via a syringe or stainless-steel cannula or were handled in a nitrogen-filled dry box (working oxygen level < 5 ppm). Flash-column chromatography was performed as described by Still et al.,²⁰ employing silica gel (60 Å, 40–63 μm particle size) purchased from SiliCycle. Analytical thin-layered chromatography (TLC) was performed using glass plates pre-coated with silica gel (0.25 mm, 60 Å pore size) impregnated with a fluorescent indicator (254 nm). TLC plates were visualized by exposure to ultraviolet light (UV) and/or submersion in aqueous ceric ammonium molybdate solution (CAM) or aqueous potassium permanganate solution (KMnO₄), followed by brief heating on a hot plate (120 °C, 10–15 s). Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments.

Materials.

Commercial solvents and reagents were used as received with the following exceptions. Dichloromethane, ether, N,N-dimethylformamide, pentane, tetrahydrofuran, and toluene were purified according to the method of Pangborn et al.²¹ Pyridine was distilled from calcium hydride under an atmosphere of nitrogen immediately prior to use. The molarity of solutions of methyllithium in ether were determined by titration against a standard solution of menthol and 1,10-phenanthroline in tetrahydrofuran (average of three determinations).²² Trifluoromethanesulfonic anhydride was purified by vacuum distillation and stored under argon at 4 °C. Tri-O-acetyl-d-glucal and tri-O-acetyl d-galactal were purchased from Alfa Aesar. d-(+)-Galactose, l-rhamnose, and trichlorooxobis(triphenylphosphone) rhenium(V) were purchased from Sigma-Aldrich. The intermediates S1,²³ S2,²⁴ S3,^11a S4,¹⁹ 3α,¹⁸ 4α,¹³ 5,²⁴ 9,¹³ 11,¹³ 12,¹³ 25α,¹³ 25β,¹³ 30α,¹⁸ 31α,¹⁸ 32α,¹⁸ 33,²⁵ 34,²⁶ 35α,¹⁸ 35β,¹⁸ 36β,¹⁸ and oxotrichloro-triphenylphosphine-dimethylsulfoxide-rhenium(V)²⁷ were prepared according to published procedures. 4,4′-Di-tert-butylbiphenyl (DBB) was purchased from Alfa Aesar. Solutions of LiDBB were prepared by a slight modification of the procedure described by Hill et al.:¹³ DBB (3.60 g, 13.5 mmol, 1 equiv) was melted under vacuum in a flame-dried 50 mL round-bottomed flask that had been fused to a Teflon-coated valve. The flask was left to cool under vacuum (200 mTorr) and the cooled flask was backfilled with argon. Lithium wire (938 mg, 135 mmol, 10.0 equiv) was added to the flask under a positive pressure of argon. The flask was evacuated and backfilled with argon twice. Tetrahydrofuran (34 mL) was added, and the resulting mixture was cooled to 0 °C. The solution was stirred for 5 h at 0 °C before use. The concentration of LiDBB was nominally 0.4 M.¹⁶ The LiDBB solution was stored under argon at −20 °C with protection from light when not in use. Solutions of LiDBB prepared in this way were used within 2 months of preparation.

Instrumentation.

Proton nuclear magnetic resonance (¹H NMR) spectra were recorded at 400, 500, or 600 MHz at 23 °C, unless otherwise noted. Chemical shifts are expressed in parts per million (ppm, δ scale) downfield from tetramethylsilane and are referenced to residual protons in the NMR solvent (CHCl₃, δ 7.26; C₆D₅H, δ 7.16). Data are represented as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and/or multiple resonances, br = broad, app = apparent), coupling constant in Hertz (Hz), integration, and assignment. Proton-decoupled carbon nuclear magnetic resonance spectra [¹³C{¹H} NMR] were recorded at 101, 126, or 151 MHz at 23 °C, unless otherwise noted. Chemical shifts are expressed in parts per million (ppm, δ scale) downfield from tetramethylsilane and are referenced to the carbon resonances of the solvent (CDCl₃, δ 77.16; C₆D₆, δ 128.06). Heteronuclear single quantum coherence (HSQC) spectra were recorded at 400, 500, or 600 MHz at 23 °C, unless otherwise noted. Two-dimensional nuclear Overhauser effect spectroscopy (2D NOESY) experiments were performed at 500 MHz or 600 MHz at 23 °C, unless otherwise noted. ¹³C NMR and HSQC data are combined and represented as follows: chemical shift and carbon type [obtained from HSQC experiments]. Attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectra were obtained using a Thermo Electron Corporation Nicolet 6700 FTIR spectrometer referenced to a polystyrene standard. Data are represented as follows: frequency of absorption (cm⁻¹) and intensity of absorption (s = strong, m = medium, w = weak, br = broad). High-resolution mass spectrometry (HRMS) were obtained on a Waters UPLC/HRMS instrument equipped with a dual API/ESI high-resolution mass spectrometry detector and photodiode array detector. Unless otherwise noted, samples were eluted over a reverse-phase C18 column (1.7 μm particle size, 2.1 × 50 mm) with a linear gradient of 5% acetonitrile–water containing 0.1% formic acid → 95% acetonitrile–water containing 0.1% formic acid for 1 min, at a flow rate of 600 μL/min. Optical rotations were measured on a Rudolph Research Analytical Autopol IV polarimeter equipped with a sodium (589 nm, D) lamp. Optical rotation data are represented as follows: specific rotation (${\left[\alpha \right]}_{\lambda }^T$), concentration (g/mL), and solvent.

Synthetic Procedures.

Synthesis of the Ether 1.

Dibutyl tin oxide (272 mg, 1.09 mmol, 1.05 equiv) was added in one portion to a solution of the diol 33 (250 mg, 1.04 mmol, 1 equiv) in benzene (6.9 mL) at 23 °C. A reaction vessel was fitted with a Dean–Stark trap. The reaction vessel was placed in an oil bath that had been preheated to 90 °C. The reaction mixture was stirred for 16 h at 90 °C. The reaction mixture was cooled to 23 °C over 15 min. Tetrabutylammonium bromide (671 mg, 2.08 mmol, 2.00 equiv) and para-methoxybenzyl chloride (441 μL, 3.12 mmol, 3.00 equiv) were added sequentially to the reaction mixture. The reaction vessel was placed in an oil bath that had been preheated to 90 °C. The reaction mixture was stirred and heated for 3 h at 90 °C. The product mixture was cooled to 23 °C over 15 min. The product mixture was diluted sequentially with saturated aqueous sodium hydrogen carbonate solution (50 mL) and ethyl acetate (50 mL). The resulting biphasic mixture was transferred to a separatory funnel and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (3 × 35 mL). The organic layers were combined and the combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was purified by flash-column chromatography (eluting with 5% ethyl acetate–hexanes initially, grading to 20% ethyl acetate–hexanes, three steps) to provide the ether 1 as clear colorless oil (324 mg, 87%, 2:1 mixture of α/β diastereomers).

The diastereomers were not separable by flash-column chromatography; consequently, the optical rotation of the product 1 was not determined.

R_f = 0.79 (50% ethyl acetate–hexanes; UV, CAM). ¹H NMR (600 MHz, CDCl₃, α-diastereomer only): δ 7.45 (d, J = 8.3 Hz, 2H, Ar), 7.33–7.27 (m, 4H, Ar), 7.25–7.22 (m, 1H, Ar), 6.91 (d, J = 8.6 Hz, 2H, Ar), 5.61 (d, J = 5.6 Hz, 1H, H₁), 4.63 (d, J = 11.2 Hz, 1H, CH₂Ar), 4.46 (d, J = 11.2 Hz, 1H, CH₂Ar), 4.18 (dq, J = 9.0, 6.3 Hz, 1H, H₅), 3.82 (s, 3H, OCH₃), 3.72 (ddd, J = 11.5, 8.9, 4.7 Hz, 1H, H₃), 3.24 (td, J = 9.1, 2.0 Hz, 1H, H₄), 2.46 (ddd, J = 13.2, 4.7, 1.3 Hz, 1H, H₂), 2.43 (d, J = 2.1 Hz, 1H, OH), 2.02 (ddd, J = 13.2, 11.7, 5.7 Hz, 1H, H₂), 1.29 (d, J = 6.2 Hz, 3H, H₆). ¹³C{¹H} NMR (151 MHz, CDCl₃, α-diastereomer only): δ 159.4 (C), 135.1 (C), 131.1 (2 × CH), 130.1 (C), 129.5 (2 × CH), 128.9 (2 × CH), 127.1 (CH), 114.0 (2 × CH), 84.0 (CH), 77.0 (CH), 76.3 (CH), 70.9 (CH₂), 68.6 (CH), 55.3 (CH₃), 35.7 (CH₂), 17.7 (CH₃). IR (ATR-FTIR) (cm⁻¹): 3463 (br, m), 2914 (m), 2362 (w), 1613 (m), 1513 (s). HRMS-ESI (m/z): [M + Na]⁺ calcd for [C₂₀H₂₄O₄SNa]⁺, 383.1293; found, 383.1288.

Synthesis of the Thioglycoside 2α.

Oxotrichloro-triphenylphosphine-dimethylsulfoxide-rhenium-(V) [ReOCl₃(PPh₃)(Me₂SO)] (13.0 mg, 20.0 μmol, 0.01 equiv) was added in one portion to a solution of (2S,3S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-methyl-3,4-dihydro-2H-pyran-3-ol (S1, 489 mg, 2.00 mmol, 1 equiv) and thiophenol (306 μL, 3.00 mmol, 1.50 equiv) in toluene (5.0 mL) at 23 °C. The reaction mixture was stirred for 12 h at 23 °C. The product mixture was transferred directly to a silica gel column and purified by flash-column chromatography (eluting with 2% ether–hexanes initially, grading to 5% ether–hexanes, three steps) to provide the thioglycoside 2α as a white solid [595 mg, 84%, α diastereomer only (¹H NMR analysis)].

R_f = 0.38 (10% ethyl acetate–hexanes; UV, CAM). ¹H NMR (500 MHz, CDCl₃): δ 7.45 (d, J = 7.3 Hz, 2H, Ar), 7.30 (t, J = 7.4 Hz, 2H, Ar), 7.24 (t, J = 7.3 Hz, 1H, Ar), 5.56 (d, J = 5.5 Hz, 1H, H₁), 4.18 (dq, J = 9.4, 6.2 Hz, 1H, H₅), 3.92 (ddd, J = 11.5, 8.6, 4.8 Hz, 1H, H₃), 3.15 (td, J = 9.0, 2.4 Hz, 1H, H₄), 2.26 (d, J = 2.3 Hz, 1H, OH), 2.23 (ddd, J = 13.3, 4.9, 1.1 Hz, 1H, H₂), 2.10 (ddd, J = 13.3, 11.5, 5.6 Hz, 1H, H₂), 1.30 (d, J = 6.2 Hz, 3H, H₆), 0.92 (s, 9H, tBu), 0.15 (s, 3H, CH₃), 0.13 (s, 3H, CH₃). ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 135.3 (C), 131.1 (2 × CH), 128.9 (2 × CH), 127.0 (CH), 84.1 (CH), 78.1 (CH), 71.1 (CH), 68.5 (CH), 39.4 (CH₂), 25.8 (3 × CH₃), 18.0 (C), 17.7 (CH₃), −4.3 (CH₃), −4.6 (CH₃). IR (ATR-FTIR) (cm⁻¹): 3478 (br, m), 2957 (m), 2858 (m), 2363 (m), 1473 (m). HRMS-ESI (m/z): [M + H]⁺ calcd for [C₁₈H₃₁O₃SSi]⁺, 355.1763; found, 355.1758. ${\left[\alpha \right]}_{\text{D}}^{21}-173.1$ (c 1.0, CHCl₃).

Synthesis of the Acetonide 6.

para-Toluenesulfonic acid (223 mg, 1.17 mmol, 0.30 equiv) was added to a solution of phenyl 2-deoxy-1-thio-d-glucopyranoside (S2, 1.00 g, 3.90 mmol, 1 equiv, 2:1 mixture of α/β diastereomers) and 2,2-dimethoxypropane (959 μL, 7.80 mmol, 2.00 equiv) in N,N-dimethylformamide (20 mL) at 23 °C. The reaction mixture was stirred for 6 h at 23 °C. The product mixture was diluted sequentially with saturated aqueous sodium hydrogen carbonate solution (150 mL) and ethyl acetate (50 mL). The resulting biphasic mixture was transferred to a separatory funnel and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (3 × 50 mL). The organic layers were combined and the combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was purified by flash-column chromatography (eluting with 5% ethyl acetate–hexanes initially, grading to 25% ethyl acetate–hexanes, three steps) to provide the acetonide 6 as clear, colorless oil (1.01 g, 87%, 2:1 mixture of α/β diastereomers).

The diastereomers were not separable by flash-column chromatography; consequently the optical rotation of the product 6 was not determined.

R_f = 0.54 (50% ethyl acetate–hexanes; UV, CAM). ¹H NMR (600 MHz, C₆D₆, α-diastereomer only): δ 7.37 (d, J = 8.2 Hz, 2H, Ar), 6.99 (d, J = 7.7 Hz, 2H, Ar), 6.97–6.91 (m, 1H, Ar), 5.34 (d, J = 6.0 Hz, 1H, H₁), 4.34 (td, J = 10.1, 5.2 Hz, 1H, H₅), 4.14–4.00 (m, 1H, H₃), 3.81–3.74 (m, 1H, H₆), 3.65 (t, J = 10.5 Hz, 1H, H₆), 3.45 (t, J = 9.2 Hz, 1H, H₄), 2.33–2.22 (m, 2H, OH, H₂), 1.98 (ddd, J = 13.5, 11.5, 6.0 Hz, 1H, H₂), 1.47 (s, 3H, CH₃), 1.23 (s, 3H, CH₃). ¹³C{¹H} NMR (151 MHz, C₆D₆, α-diastereomer only): δ 132.1 (C), 131.6 (2 × CH), 129.2 (2 × CH), 127.3 (CH), 100.0 (C), 84.6 (CH), 77.3 (CH), 67.1 (CH), 65.1 (CH), 62.3 (CH₂), 38.6 (CH₂), 29.5 (CH₃), 19.1 (CH₃).

IR (ATR-FTIR) (cm⁻¹): 3456 (br, m), 2995 (w), 2888 (w), 2363 (m), 1381 (m). HRMS-ESI (m/z): [M + Na]⁺ calcd for [C₁₅H₂₀O₄SNa]⁺, 319.0980; found, 319.0975.

Synthesis of the Acetal 7.

para-Toluenesulfonic acid (66.8 mg, 351 μmol, 0.30 equiv) was added to a solution of phenyl 2-deoxy-1-thio-d-galactopyranoside (34, 300 mg, 1.17 mmol, 1 equiv, 2:1 mixture of α/β diastereomers) and para-anisaldehyde dimethyl acetal (315 μL, 1.76 mmol, 1.50 equiv) in N,N-dimethylformamide (4.2 mL) at 23 °C. The reaction mixture was stirred for 12 h at 23 °C. The product mixture was diluted sequentially with saturated aqueous sodium hydrogen carbonate solution (50 mL) and ethyl acetate (35 mL). The resulting biphasic mixture was transferred to a separatory funnel and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (3 × 35 mL). The organic layers were combined and the combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was purified by flash-column chromatography (eluting with 10% ethyl acetate–hexanes initially, grading to 30% ethyl acetate–hexanes, three steps) to provide the acetal 7 as a white solid (337 mg, 77%, 2:1 mixture of α/β diastereomers).

The diastereomers were not separable by flash-column chromatography; consequently the optical rotation of the product 7 was not determined.

R_f = 0.54 (50% ethyl acetate–hexanes; UV, CAM). ¹H NMR (400 MHz, CDCl₃, α-diastereomer only): δ 7.45 (t, J = 8.6 Hz, 4H, Ar), 7.29 (t, J = 7.4 Hz, 2H, Ar), 7.25–7.18 (m, 1H, Ar), 6.90 (d, J = 8.8 Hz, 2H, Ar), 5.88 (d, J = 5.3 Hz, 1H, H₁), 5.59 (s, 1H, CHAr), 4.26–4.04 (m, 5H, H₃, H₄, H₅, H₆), 3.81 (s, 3H, OCH₃), 2.42 (td, J = 12.6, 5.5 Hz, 1H, H₂), 2.32 (d, J = 10.7 Hz, 1H, OH), 2.18 (dd, J = 13.2, 4.8 Hz, 1H, H₂). ¹³C{¹H} NMR (101 MHz, CDCl₃, α-diastereomer only): δ 160.4 (C), 135.2 (C), 130.3 (C, 2 × CH), 129.1 (2 × CH), 127.8 (2 × CH), 126.9 (CH), 113.7 (2 × CH), 101.3 (CH), 84.3 (CH), 74.8 (CH), 70.0 (CH₂), 65.4 (CH), 63.7 (CH), 55.4 (CH₃), 34.6 (CH₂).

IR (ATR-FTIR) (cm⁻¹): 3450 (br, m), 2910 (m), 1615 (m), 1518 (s), 1248 (s). HRMS-ESI (m/z): [M + H]⁺ calcd for [C₂₀H₂₃O₅S]⁺, 375.1266; found, 375.1261.

Synthesis of the Thioglycoside 8α.

Oxotrichloro-triphenylphosphine-dimethylsulfoxide-rhenium-(V) [ReOCl₃(PPh₃)(Me₂SO)] (13.0 mg, 20 μmol, 0.01 equiv) was added in one portion to a solution of (2S,3R,4S)-4-((4-methoxybenzyl)oxy)-2-methyl-3,4-dihydro-2H-pyran-3-ol (S3, 500 mg, 2.00 mmol, 1 equiv) and thiophenol (265 μL, 2.60 mmol, 1.30 equiv) in toluene (10 mL) at 23 °C. The reaction mixture was stirred for 12 h at 23 °C. The product mixture was transferred directly to a silica gel column and purified by flash-column chromatography (eluting with 5% ether–hexanes initially, grading to 20% ether–hexanes, three steps) to provide the thioglycoside 8α as a white solid [560 mg, 78%, α diastereomer only (¹H NMR analysis)].

R_f = 0.61 (50% ethyl acetate–hexanes; UV, CAM). ¹H NMR (400 MHz, CDCl₃): δ 7.44 (d, J = 7.2 Hz, 2H, Ar), 7.33–7.27 (m, 4H, Ar), 7.25–7.20 (m, 1H, Ar), 6.91 (d, J = 8.6 Hz, 2H, Ar), 5.71 (d, J = 5.8 Hz, 1H, H₁), 4.56 (s, 2H, CH₂Ar), 4.34 (q, J = 6.6 Hz, 1H, H₅), 3.93–3.74 (m, 5H, H₃, H₄, OCH₃), 2.36 (ddd, J = 13.4, 11.7, 5.8 Hz, 1H, H₂), 2.20 (s, 1H, OH), 2.09 (ddd, J = 13.6, 4.7, 1.3 Hz, 1H, H₂), 1.30 (d, J = 6.6 Hz, 3H, H₆). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 159.6 (C), 135.4 (C), 130.9 (2 × CH), 129.9 (C), 129.6 (2 × CH), 129.1 (2 × CH), 127.0 (CH), 114.1 (2 × CH), 84.1 (CH), 73.3 (CH), 70.0 (CH₂), 68.6 (CH), 67.0 (CH), 55.4 (CH₃), 30.9 (CH₂), 16.8 (CH₃). IR (ATR-FTIR) (cm⁻¹): 3497 (br, m), 2935 (m), 2358 (m), 1613 (m), 1513 (s). HRMS-ESI (m/z): [M + Na]⁺ calcd for [C₂₀H₂₄O₄SNa]⁺, 383.1293; found, 383.1288. ${\left[\alpha \right]}_{\text{D}}^{21}-173.1$ (c 1.0, CHCl₃).

Synthesis of the Alcohol 10α.

A solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 M, 990 μL, 991 mmol, 1.00 equiv) was added to a solution of tert-butyl(((3aR,4R,6R,7aR)-2,2-dimethyl-6-(phenylthio)-tetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-4-yl)methoxy)-diphenylsilane (S4, 530 mg, 991 mmol, 1 equiv) in tetrahydrofuran (2.0 mL) at 23 °C. The reaction mixture was stirred for 12 h at 23 °C. The product mixture was diluted sequentially with saturated aqueous ammonium chloride solution (35 mL) and ethyl acetate (35 mL). The resulting biphasic mixture was transferred to a separatory funnel and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (2 × 35 mL). The organic layers were combined and the combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was purified by flash-column chromatography (eluting with 10% ethyl acetate–hexanes initially, grading to 30% ethyl acetate–hexanes, three steps) to provide the alcohol 10α as clear, colorless oil [290 mg, 99%, α diastereomer only (¹H NMR analysis)].

R_f = 0.50 (50% ethyl acetate–hexanes; UV, CAM). ¹H NMR (600 MHz, C₆D₆): δ 7.57 (d, J = 7.8 Hz, 2H, Ar), 7.00 (t, J = 7.7 Hz, 2H, Ar), 6.94 (t, J = 7.4 Hz, 1H, Ar), 5.63 (dd, J = 9.1, 6.1 Hz, 1H, H₁), 3.94 (dt, J = 7.5, 3.8 Hz, 1H, H₃), 3.85 (dd, J = 11.0, 7.1 Hz, 1H, H₆), 3.77 (ddd, J = 6.9, 4.6, 1.9 Hz, 1H, H₅), 3.71 (dd, J = 11.1, 4.5 Hz, 1H, H₆), 3.60 (dd, J = 7.4, 2.0 Hz, 1H, H₄), 2.18 (ddd, J = 15.0, 6.1, 4.2 Hz, 1H, H₂), 1.69 (s, 1H, OH), 1.46–1.40 (m, 1H, H₂), 1.40 (s, 3H, CH₃), 1.14 (s, 3H, CH₃). ¹³C{¹H} NMR (151 MHz, C₆D₆): δ 135.4 (C), 132.3 (2 × CH), 129.2 (2 × CH), 127.5 (CH), 109.2 (C), 81.5 (CH), 73.2 (CH), 71.0 (CH), 70.4 (CH), 62.4 (CH₂), 30.5 (CH₂), 26.8 (CH₃), 25.2 (CH₃). IR (ATR-FTIR) (cm⁻¹): 3463 (br, m), 2935 (m), 1583 (m), 1214 (s), 1048 (s). HRMS-ESI (m/z): [M + H]⁺ calcd for [C₁₅H₂₁O₄S]⁺, 297.1161; found, 297.1155. ${\left[\alpha \right]}_{\text{D}}^{21}+233.3$ (c 1.0, CHCl₃).

Synthesis of the Disaccharide 13α.

A solution of methyllithium in diethyl ether (1.41 M, 43.0 μL, 60.1 μmol, 1.50 equiv) was added dropwise via a syringe to a solution of the alcohol 5 (20.7 mg, 60.1 μmol, 1.50 equiv) in tetrahydrofuran–pentane (1:1 v/v, 1.0 mL) in a 10 mL round-bottomed flask that had been fused to a Teflon-coated valve at −78 °C. The resulting mixture was stirred for 30 min at −78 °C. A solution of lithium di-tert-butylbiphenylide in tetrahydrofuran (nominally 0.4 M) was then added dropwise via a syringe. The addition of lithium di-tert-butylbiphenylide was continued until green color persisted (310 μL, nominally 124 μmol, 3.10 equiv). The resulting mixture was stirred for 10 min at −78 °C. A solution of the MTHP monoperoxy acetal 11 (15.0 mg, 40.1 μmol, 1 equiv) in tetrahydrofuran (300 μL) was then added dropwise via a syringe. The resulting mixture was stirred for 3 h at −78 °C. The cold product mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (3.0 mL). The diluted product mixture was allowed to warm to 23 °C over 15 min. The warmed product mixture was transferred to a 20 mL test tube and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (4 × 5.0 mL). The organic layers were combined and the combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated under a stream of nitrogen. The residue obtained was purified by flash-column chromatography (eluting with 5% ethyl acetate–dichloromethane, initially, grading to 20% ethyl acetate–dichloromethane, three steps) to provide the disaccharide 13α as colorless oil (14.0 mg, 71%).

The diastereoselectivity of the reaction was determined to be >50:1 α/β by ¹H NMR analysis of the unpurified product mixture.

R_f = 0.77 (50% ethyl acetate–dichloromethane; UV, CAM). ¹H NMR (600 MHz, CDCl₃): δ 7.51–7.48 (m, 2H, Ar), 7.41–7.34 (m, 3H, Ar), 5.57 (s, 1H, CHAr), 5.54 (d, J = 5.0 Hz, 1H, H_1′), 4.97 (d, J = 3.7 Hz, 1H, H₁), 4.63 (dd, J = 7.9, 2.4 Hz, 1H, H_3′), 4.33 (dd, J = 5.1, 2.4 Hz, 1H, H_2′), 4.26 (td, J = 4.8, 2.7 Hz, 2H, H₆, H_4′), 4.21 (dtd, J = 10.9, 6.4, 3.1 Hz, 1H, H₃), 3.97 (td, J = 6.6, 1.9 Hz, 1H, H_5′), 3.86 (td, J = 9.9, 4.9 Hz, 1H, H₅), 3.80–3.70 (m, 2H, H₆, H_6′), 3.66 (dd, J = 10.4, 6.8 Hz, 1H, H_6′), 3.48 (t, J = 9.3 Hz, 1H, H₄), 2.42 (s, 1H, OH), 2.27 (dd, J = 13.3, 5.3 Hz, 1H, H₂), 1.79 (ddd, J = 12.7, 11.1, 3.9 Hz, 1H, H₂), 1.56 (s, 3H, CH₃), 1.45 (s, 3H, CH₃), 1.35 (s, 3H, CH₃), 1.34 (s, 3H, CH₃). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 137.5 (C), 129.4 (CH), 128.5 (2 × CH), 126.4 (2 × CH), 109.5 (C), 108.8 (C), 102.1 (CH), 98.2 (CH), 96.5 (CH), 84.0 (CH), 71.1 (CH), 70.8 (CH), 70.7 (CH), 69.2 (CH₂), 66.2 (CH₂), 66.2 (CH), 66.0 (CH), 62.9 (CH), 37.4 (CH₂), 26.3 (CH₃), 26.1 (CH₃), 25.1 (CH₃), 24.7 (CH₃). IR (ATR-FTIR) (cm⁻¹): 3475 (br, w), 2937 (m), 2360 (w), 1382 (m), 1211 (m). HRMS-ESI (m/z): [M + H]⁺ calcd for C₂₅H₃₅O₁₀]⁺, 495.2230; found, 495.2225. ${\left[\alpha \right]}_{\text{D}}^{21}+6.8$ (c 0.6, CHCl₃).

Synthesis of the Disaccharide 13β.

A solution of methyllithium in diethyl ether (1.60 M, 75.0 μL, 120 μmol, 2.00 equiv) was added dropwise via a syringe to a solution of the alcohol 5 (41.4 mg, 120 μmol, 2.00 equiv) in tetrahydrofuran–pentane (1:1 v/v, 1.5 mL) in a 10 mL round-bottomed flask that had been fused to a Teflon-coated valve at −78 °C. The resulting mixture was stirred for 30 min at −78 °C. A solution of lithium di-tert-butylbiphenylide in tetrahydrofuran (nominally 0.4 M) was then added dropwise via a syringe. The addition of lithium di-tert-butylbiphenylide was continued until a green color persisted (616 μL, nominally 246 μmol, 4.10 equiv). The resulting mixture was stirred for 10 min at −78 °C. The reaction vessel was then placed in a bath that had been precooled to −20 °C. The reaction mixture was stirred for 1 h at −20 °C and then cooled to −78 °C over 10 min. A solution of the MTHP monoperoxy acetal 11 (22.5 mg, 60.1 μmol, 1 equiv) in tetrahydrofuran (300 μL) was then added dropwise via a syringe. The reaction vessel was then placed in a cryogenic bath that had been precooled to −65 °C. The mixture was stirred for 6 h at −65 °C. The cold product mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (3.0 mL). The diluted product mixture was allowed to warm to 23 °C over 15 min. The warmed product mixture was transferred to a 20 mL test tube and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (4 × 5.0 mL). The organic layers were combined and the combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated under a stream of nitrogen. The residue obtained was purified by flash-column chromatography (eluting with 10% ethyl acetate–dichloromethane, initially, grading to 30% ethyl acetate–dichloromethane, three steps) to provide the disaccharide 13β as colorless oil (14.9 mg, 50%).

The diastereoselectivity of the reaction was determined to be 3.8:1 β/α by ¹H NMR analysis of the unpurified product mixture.

R_f = 0.68 (50% ethyl acetate–dichloromethane; CAM). ¹H NMR (500 MHz, CDCl₃): δ 7.51–7.46 (m, 2H, Ar), 7.41–7.35 (m, 3H, Ar), 5.56–5.54 (m, 2H, CHAr, H_1′), 4.74 (dd, J = 9.8, 2.2 Hz, 1H, H₁), 4.60 (dd, J = 7.9, 2.4 Hz, 1H, H_3′), 4.34–4.30 (m, 2H, H₆, H_2′), 4.22 (d, J = 7.9 Hz, 1H, H_4′), 4.04–3.98 (m, 2H, H_5′, H_6′), 3.96–3.89 (m, 1H, H₃), 3.79 (t, J = 10.3 Hz, 1H, H₆), 3.73 (td, J = 10.2, 3.8 Hz, 1H, H_6′), 3.46 (t, J = 9.0 Hz, 1H, H₄), 3.37 (td, J = 9.6, 4.9 Hz, 1H, H₅), 2.42–2.35 (m, 2H, H₂, OH), 1.73 (ddd, J = 12.6, 11.5, 10.7 Hz, 1H, H₂), 1.54 (s, 3H, CH₃), 1.46 (s, 3H, CH₃), 1.33 (s, 6H, 2 × CH₃). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 137.3 (C), 129.4 (CH), 128.5 (2 × CH), 126.4 (2 × CH), 109.6 (C), 108.8 (C), 102.1 (CH), 101.0 (CH), 96.4 (CH), 83.4 (CH), 71.6 (CH), 70.9 (CH), 70.5 (CH), 69.2 (CH₂), 69.0 (CH₂), 68.5 (CH), 68.1 (CH), 66.4 (CH), 38.6 (CH₂), 26.2 (CH₃), 26.1 (CH₃), 25.1 (CH₃), 24.5 (CH₃). IR (ATR-FTIR) (cm⁻¹): 3469 (br, w), 2975 (w), 2364 (m), 1385 (m), 1216 (m). HRMS-ESI (m/z): [M + H]⁺ calcd for [C₂₅H₃₅O₁₀]⁺, 495.2230; found, 495.2225. ${\left[\alpha \right]}_{\text{D}}^{21}-67.4$ (c 0.4, CHCl₃).

Synthesis of the Disaccharide 14α.

A solution of methyllithium in diethyl ether (1.30 M, 66.0 μL, 85.5 μmol, 1.60 equiv) was added dropwise via a syringe to a solution of the alcohol 6 (23.7 mg, 80.1 μmol, 1.50 equiv) in tetrahydrofuran–pentane (1:1 v/v, 1.4 mL) in a 10 mL round-bottomed flask that had been fused to a Teflon-coated valve at −78 °C. The resulting mixture was stirred for 30 min at −78 °C. A solution of lithium di-tert-butylbiphenylide in tetrahydrofuran (nominally 0.4 M) was then added dropwise via a syringe. The addition of lithium di-tert-butylbiphenylide was continued until a green color persisted (414 μL, nominally 166 μmol, 3.10 equiv). The resulting mixture was stirred for 10 min at −78 °C. A solution of the MTHP monoperoxy acetal 11 (20.0 mg, 53.4 μmol, 1 equiv) in tetrahydrofuran (300 μL) was then added dropwise via a syringe. The resulting mixture was stirred for 3 h at −78 °C. The cold product mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (3.0 mL). The diluted product mixture was allowed to warm to 23 °C over 15 min. The warmed product mixture was transferred to a 20 mL test tube and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (4 × 5.0 mL). The organic layers were combined and the combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated under a stream of nitrogen. The residue obtained was purified by flash-column chromatography (eluting with 10% ethyl acetate–dichloromethane, initially, grading to 30% ethyl acetate–dichloromethane, three steps) to provide the disaccharide 14α as colorless oil (17.7 mg, 74%).

The diastereoselectivity of the reaction was determined to be >50:1 α/β by ¹H NMR analysis of the unpurified product mixture.

R_f = 0.50 (60% ethyl acetate–dichloromethane; CAM). ¹H NMR (500 MHz, CDCl₃): δ 5.52 (d, J = 5.0 Hz, 1H, H_1′), 4.93 (d, J = 3.7 Hz, 1H, H₁), 4.61 (dd, J = 7.9, 2.4 Hz, 1H, H_3′), 4.31 (dd, J = 5.1, 2.4 Hz, 1H, H_2′), 4.24 (dd, J = 7.9, 1.9 Hz, 1H, H_4′), 4.04 (ddd, J = 11.2, 8.9, 5.1 Hz, 1H, H₃), 3.95 (td, J = 6.6, 1.9 Hz, 1H, H₅), 3.83 (dd, J = 10.3, 5.1 Hz, 1H, H₆), 3.73 (ddd, J = 10.4, 8.4, 2.1 Hz, 2H, H₆, H_6′), 3.69–3.60 (m, 2H, H₅, H_6′), 3.49 (t, J = 9.2 Hz, 1H, H₄), 2.31 (s, 1H, OH), 2.22 (dd, J = 13.2, 5.1 Hz, 1H, H₂), 1.73 (ddd, J = 13.3, 11.2, 3.9 Hz, 1H, H₂), 1.54 (s, 3H, CH₃), 1.51 (s, 3H, CH₃), 1.44 (s, 3H, CH₃), 1.42 (s, 3H, CH₃), 1.34 (s, 3H, CH₃), 1.33 (s, 3H, CH₃). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 109.3 (C), 108.6 (C), 99.8 (C), 98.0 (CH), 96.3 (CH), 76.3 (CH), 71.0 (CH), 70.6 (CH), 70.6 (CH), 66.3 (CH), 66.0 (CH), 65.9 (CH₂), 63.6 (CH), 62.3 (CH₂), 37.4 (CH₂), 29.2 (CH₃), 26.1 (CH₃), 26.0 (CH₃), 24.9 (CH₃), 24.5 (CH₃), 19.2 (CH₃). IR (ATR-FTIR) (cm⁻¹): 3494 (br, w), 2992 (m), 2028 (w), 1458 (m), 1309 (m). HRMS-ESI (m/z): [M + H]⁺ calcd for [C₂₁H₃₅O₁₀]⁺, 447.2230; found, 447.2225. ${\left[\alpha \right]}_{\text{D}}^{21}+1.7$ (c 0.8, CHCl₃).

Synthesis of the Disaccharide 14β.

A solution of methyllithium in diethyl ether (1.12 M, 72.0 μL, 80.2 μmol, 2.00 equiv) was added dropwise via a syringe to a solution of the alcohol 6 (23.8 mg, 80.2 μmol, 2.00 equiv) in tetrahydrofuran–pentane (1:1 v/v, 1.0 mL) in a 10 mL round-bottomed flask that had been fused to a Teflon-coated valve at −78 °C. The resulting mixture was stirred for 30 min at −78 °C. A solution of lithium di-tert-butylbiphenylide in tetrahydrofuran (nominally 0.4 M) was then added dropwise via a syringe. The addition of lithium di-tert-butylbiphenylide was continued until a green color persisted (411 μL, nominally 164 μmol, 4.10 equiv). The resulting mixture was stirred for 10 min at −78 °C. The reaction vessel was then placed in a bath that had been precooled to −20 °C. The reaction mixture was stirred for 1 h at −20 °C and then cooled to −78 °C over 10 min. A solution of the MTHP monoperoxy acetal 11 (15.0 mg, 40.1 μmol, 1 equiv) in tetrahydrofuran (300 μL) was then added dropwise via a syringe. The reaction vessel was then placed in a cryogenic bath that had been precooled to −65 °C. The mixture was stirred for 6 h at −65 °C. The cold product mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (3.0 mL). The diluted product mixture was allowed to warm to 23 °C over 15 min. The warmed product mixture was transferred to a 20 mL test tube and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (4 × 5.0 mL). The organic layers were combined and the combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated under a stream of nitrogen. The residue obtained was purified by flash-column chromatography (eluting with 10% acetone–hexanes, initially, grading to 30% acetone–hexanes, three steps) to provide the disaccharide 14β as colorless oil (10.1 mg, 56%).

The diastereoselectivity of the reaction was determined to be 4.8:1 β/α by ¹H NMR analysis of the unpurified product mixture.

R_f = 0.41 (30% acetone–hexanes; CAM). ¹H NMR (500 MHz, C₆D₆): δ 5.53 (d, J = 5.0 Hz, 1H, H_1′), 4.44 (dd, J = 8.0, 2.3 Hz, 1H, H_3′), 4.40 (dd, J = 9.7, 2.2 Hz, 1H, H₁), 4.25 (dd, J = 10.6, 4.6 Hz, 1H, H_6′), 4.19–4.14 (m, 2H, H_2′, H_5′), 3.96 (dd, J = 8.0, 1.8 Hz, 1H, H_4′), 3.90 (dd, J = 10.6, 6.9 Hz, 1H, H_6′), 3.79 (dd, J = 10.6, 5.3 Hz, 1H, H₆), 3.64 (t, J = 10.5 Hz, 1H, H₆), 3.54–3.42 (m, 1H, H₃), 3.35 (t, J = 9.1 Hz, 1H, H₄), 2.94 (td, J = 9.9, 5.3 Hz, 1H, H₅), 2.25 (ddd, J = 12.9, 5.1, 2.2 Hz, 1H, H₂), 1.91 (s, 1H, OH), 1.84 (ddd, J = 12.8, 11.4, 9.7 Hz, 1H, H₂), 1.45 (s, 3H, CH₃), 1.43 (s, 3H, CH₃), 1.42 (s, 3H, CH₃), 1.17 (s, 3H, CH₃), 1.11 (s, 3H, CH₃), 1.04 (s, 3H, CH₃). ¹³C{¹H} NMR (126 MHz, C₆D₆): δ 109.2 (C), 108.4 (C), 101.2 (CH), 99.7 (CH), 96.8 (CH), 76.5 (CH), 71.6 (CH), 71.2 (CH), 71.1 (CH), 69.1 (CH), 69.1 (CH₂), 68.2 (CH), 67.6 (CH), 62.6 (CH₂), 39.4 (CH₂), 29.5 (CH₃), 26.3 (CH₃), 26.3 (CH₃), 24.9 (CH₃), 24.3 (CH₃), 19.0 (CH₃). IR (ATR-FTIR) (cm⁻¹): 3482 (br, w), 2991 (m), 2358 (w), 1381 (m), 1258 (m), 1069 (s). HRMS-ESI (m/z): [m + H]⁺ calcd for [C₂₁H₃₅O₁₀]⁺, 447.2230; found, 447.2225. ${\left[\alpha \right]}_{\text{D}}^{21}-29.1$ (c 1.0, CHCl₃).

Synthesis of the Disaccharide 15α.

A solution of methyllithium in diethyl ether (1.30 M, 66.0 μL, 85.4 μmol, 1.60 equiv) was added dropwise via a syringe to a solution of the alcohol 7 (30.0 mg, 80.1 μmol, 1.50 equiv) in tetrahydrofuran–pentane (1:1 v/v, 1.4 mL) in a 10 mL round-bottomed flask that had been fused to a Teflon-coated valve at −78 °C. The resulting mixture was stirred for 30 min at −78 °C. A solution of lithium di-tert-butylbiphenylide in tetrahydrofuran (nominally 0.4 M) was then added dropwise via a syringe. The addition of lithium di-tert-butylbiphenylide was continued until a green color persisted (414 μL, nominally 166 μmol, 3.10 equiv). The resulting mixture was stirred for 10 min at −78 °C. A solution of the MTHP monoperoxy acetal 11 (20.0 mg, 53.4 μmol, 1 equiv) in tetrahydrofuran (300 μL) was then added dropwise via a syringe. The resulting mixture was stirred for 3 h at −78 °C. The cold product mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (3.0 mL). The diluted product mixture was allowed to warm to 23 °C over 15 min. The warmed product mixture was transferred to a 20 mL test tube and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (4 × 5.0 mL). The organic layers were combined and the combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated under a stream of nitrogen. The residue obtained was purified by flash-column chromatography (eluting with 10% ethyl acetate–dichloromethane, initially, grading to 30% ethyl acetate–dichloromethane, three steps) to provide the disaccharide 15α as colorless oil (23.4 mg, 84%).

The diastereoselectivity of the reaction was determined to be >50:1 α/β by ¹H NMR analysis of the unpurified product mixture.

R_f = 0.55 (60% ethyl acetate–dichloromethane; UV, CAM). ¹H NMR (400 MHz, CDCl₃): δ 7.44 (d, J = 8.7 Hz, 2H, Ar), 6.89 (d, J = 8.7 Hz, 2H, Ar), 5.55 (s, 1H, CHAr), 5.51 (d, J = 5.0 Hz, 1H, H_1′), 5.09 (t, J = 2.4 Hz, 1H, H₁), 4.61 (dd, J = 7.9, 2.4 Hz, 1H, H_3′), 4.31 (dd, J = 5.0, 2.4 Hz, 1H, H_2′), 4.27–4.21 (m, 2H, H₆, H_4′), 4.19–4.09 (m, 2H, H₃, H₄), 4.04 (dd, J = 12.5, 1.8 Hz, 1H, H₆), 3.94 (ddd, J = 7.2, 5.5, 1.9 Hz, 1H, H_5′), 3.80 (s, 3H, OCH₃), 3.79–3.73 (m, 2H, H₅, H_6′), 3.67 (dd, J = 10.6, 5.5 Hz, 1H, H_6′), 2.19 (d, J = 10.9 Hz, 1H, OH), 2.00–1.95 (m, 2H, H₂), 1.53 (s, 3H, CH₃), 1.44 (s, 3H, CH₃), 1.34 (s, 6H, 2 × CH₃). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 160.3 (C), 130.6 (C), 127.8 (2 × CH), 113.7 (2 × CH), 109.5 (C), 108.7 (C), 101.2 (CH), 98.1 (CH), 96.5 (CH), 75.0 (CH), 71.4 (CH), 70.8 (CH), 70.7 (CH), 70.1 (CH₂), 66.8 (CH), 66.3 (CH₂), 64.6 (CH), 62.8 (CH), 55.4 (CH₃), 33.8 (CH₂), 26.3 (CH₃), 26.1 (CH₃), 25.1 (CH₃), 24.6 (CH₃). IR (ATR-FTIR) (cm⁻¹): 3502 (br, w), 2935 (m), 1616 (m), 1589 (m), 1371 (m), 1250 (s). HRMS-ESI (m/z): [M + Na]⁺ calcd for [C₂₆H₃₆O₁₁Na]⁺, 547.2155; found, 547.2150. ${\left[\alpha \right]}_{\text{D}}^{21}+63.1$ (c 0.1, CHCl₃).

Synthesis of the Disaccharide 16α.

A solution of methyllithium in diethyl ether (1.30 M, 63.0 μL, 81.5 μmol, 1.50 equiv) was added dropwise via a syringe to a solution of the alcohol 5 (28.1 mg, 81.5 μmol, 1.50 equiv) in tetrahydrofuran–pentane (1:1 v/v, 1.4 mL) in a 10 mL round-bottomed flask that had been fused to a Teflon-coated valve at −78 °C. The resulting mixture was stirred for 30 min at −78 °C. A solution of lithium di-tert-butylbiphenylide in tetrahydrofuran (nominally 0.4 M) was then added dropwise via a syringe. The addition of lithium di-tert-butylbiphenylide was continued until a green color persisted (421 μL, nominally 168 μmol, 3.10 equiv). The resulting mixture was stirred for 10 min at −78 °C. A solution of the MTHP monoperoxy acetal 12α (20.0 mg, 54.3 μmol, 1 equiv) in tetrahydrofuran (300 μL) was then added dropwise via a syringe. The resulting mixture was stirred for 3 h at −78 °C. The cold product mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (3.0 mL). The diluted product mixture was allowed to warm to 23 °C over 15 min. The warmed product mixture was transferred to a 20 mL test tube and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (4 × 5.0 mL). The organic layers were combined and the combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated under a stream of nitrogen. The residue obtained was purified by flash-column chromatography (eluting with 5% ethyl acetate–dichloromethane, initially, grading to 15% ethyl acetate–dichloromethane, three steps) to provide the disaccharide 16α as colorless oil (10.4 mg, 39%).

The diastereoselectivity of the reaction was determined to be >50:1 α/β by ¹H NMR analysis of the unpurified product mixture.

R_f = 0.89 (50% ethyl acetate–dichloromethane; UV, CAM). ¹H NMR (600 MHz, CDCl₃): δ 7.51 (d, J = 6.7 Hz, 2H, Ar), 7.46 (d, J = 7.6 Hz, 2H, Ar), 7.41–7.34 (m, 3H, Ar), 7.31 (t, J = 7.5 Hz, 2H, Ar), 7.25 (d, J = 7.5 Hz, 1H, Ar), 5.60 (d, J = 5.9 Hz, 1H, H_1′), 5.58 (s, 1H, CHAr), 5.43 (d, J = 4.0 Hz, 1H, H₁), 4.28–4.15 (m, 3H, H₃, H₆, H_5–), 3.89 (td, J = 9.9, 4.9 Hz, 1H, H₅), 3.74 (t, J = 10.4 Hz, 1H, H₆), 3.61 (ddd, J = 11.5, 8.6, 4.8 Hz, 1H, H_3′), 3.50 (t, J = 9.3 Hz, 1H, H₄), 3.39 (s, 3H, OCH₃), 3.27 (t, J = 9.0 Hz, 1H, H_4′), 2.48 (dd, J = 13.5, 4.9 Hz, 1H, H_2′), 2.30 (dd, J = 13.2, 5.2 Hz, 1H, H₂), 1.94 (ddd, J = 13.2, 11.6, 5.7 Hz, 1H, H_2′), 1.83 (ddd, J = 13.0, 11.5, 4.2 Hz, 1H, H₂), 1.32 (d, J = 6.2 Hz, 3H, H_6′). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 137.4 (C), 135.2 (C), 131.3 (2 × CH), 129.4 (CH), 129.1 (2 × CH), 128.5 (2 × CH), 127.3 (CH), 126.3 (2 × CH), 102.0 (CH), 99.3 (CH), 83.9 (CH), 83.9 (CH), 81.6 (CH), 79.9 (CH), 69.0 (CH₂), 67.6 (CH), 66.1 (CH), 63.5 (CH), 56.7 (CH₃), 37.8 (CH₂), 35.4 (CH₂), 18.6 (CH₃). IR (ATR-FTIR) (cm⁻¹): 3441 (br, m), 2932 (m), 1583 (w), 1440 (m), 1200 (s). HRMS-ESI (m/z): [M + H]⁺ calcd for [C₂₆H₃₃O₇S]⁺, 489.1947; found, 489.1942. ${\left[\alpha \right]}_{\text{D}}^{21}+170.7$ (c 0.6, CHCl₃).

Synthesis of the Disaccharide 17α.

A solution of methyllithium in diethyl ether (1.30 M, 84.0 μL, 109 μmol, 2.00 equiv) was added dropwise via a syringe to a solution of the alcohol 6 (32.2 mg, 109 μmol, 2.00 equiv) in tetrahydrofuran–pentane (1:1 v/v, 1.4 mL) in a 10 mL round-bottomed flask that had been fused to a Teflon-coated valve at −78 °C. The resulting mixture was stirred for 30 min at −78 °C. A solution of lithium di-tert-butylbiphenylide in tetrahydrofuran (nominally 0.4 M) was then added dropwise via a syringe. The addition of lithium di-tert-butylbiphenylide was continued until a green color persisted (557 μL, nominally 223 μmol, 4.10 equiv). The resulting mixture was stirred for 10 min at −78 °C. A solution of the MTHp monoperoxy acetal 12α (20.0 mg, 54.3 μmol, 1 equiv) in tetrahydrofuran (300 μL) was then added dropwise via a syringe. The resulting mixture was stirred for 3 h at −78 °C. The cold product mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (3.0 mL). The diluted product mixture was allowed to warm to 23 °C over 15 min. The warmed product mixture was transferred to a 20 mL test tube and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (4 × 5.0 mL). The organic layers were combined and the combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated under a stream of nitrogen. The residue obtained was purified by flash-column chromatography (eluting with 10% ethyl acetate–dichloromethane, initially, grading to 40% ethyl acetate–dichloromethane, four steps) to provide the disaccharide 17α as colorless oil (14.0 mg, 59%).

The diastereoselectivity of the reaction was determined to be >50:1 α/β by ¹H NMR analysis of the unpurified product mixture.

R_f = 0.73 (80% ethyl acetate–dichloromethane; UV, CAM). ¹H NMR (600 MHz, C₆D₆): δ 7.50 (d, J = 7.5 Hz, 2H, Ar), 7.05 (t, J = 7.7 Hz, 2H, Ar), 6.98 (t, J = 7.4 Hz, 1H, Ar), 5.49 (d, J = 4.0 Hz, 1H, H₁), 5.39 (d, J = 5.5 Hz, 1H, H_1′), 4.31 (dq, J = 9.4, 6.2 Hz, 1H, H_5′), 4.21 (ddd, J = 11.4, 8.8, 5.1 Hz, 1H, H₃), 3.98 (td, J = 10.2, 5.3 Hz, 1H, H₅), 3.89 (dd, J = 10.7, 5.3 Hz, 1H, H₆), 3.72 (t, J = 10.7 Hz, 1H, H₆), 3.63–3.51 (m, 2H, H₄, H_3′), 3.30 (t, J = 9.0 Hz, 1H, H_4′), 2.92 (s, 3H, OCH₃), 2.42 (dd, J = 13.3, 5.0 Hz, 1H, H₂), 2.18 (ddd, J = 13.4, 4.9, 1.4 Hz, 1H, H_2′), 1.85 (ddd, J = 13.2, 11.4, 4.2 Hz, 1H, H₂), 1.63 (ddd, J = 13.2, 11.9, 5.7 Hz, 1H, H_2′), 1.49 (s, 3H, CH₃), 1.31 (d, J = 6.2 Hz, 3H, H_6′), 1.28 (s, 3H, CH₃). ¹³C{¹H} NMR (151 MHz, C₆D₆): δ 136.1 (C), 131.4 (2 × CH), 129.2 (2 × CH), 127.2 (CH), 100.0 (CH), 99.9 (C), 84.0 (CH), 82.5 (CH), 80.1 (CH), 77.2 (CH), 68.0 (CH), 66.8 (CH), 64.9 (CH), 62.6 (CH₂), 56.1 (CH₃), 38.5 (CH₂), 35.6 (CH₂), 29.6 (CH₃), 19.2 (CH₃), 18.6 (CH₃). IR (ATR-FTIR) (cm⁻¹): 3422 (br, m), 2935 (m), 1583 (w), 1383 (m), 1120 (m), 1055 (s). HRMS-ESI (m/z): [M + H]⁺ calcd for [C₂₂H₃₃O₇S]⁺, 441.1947; found, 441.1942. ${\left[\alpha \right]}_{\text{D}}^{21}+197.4$ (c 0.7, CHCl₃).

Synthesis of the Disaccharide 17β.

A solution of methyllithium in diethyl ether (1.34 M, 81.0 μL, 109 μmol, 2.00 equiv) was added dropwise via a syringe to a solution of the alcohol 6 (32.2 mg, 109 μmol, 2.00 equiv) in tetrahydrofuran–pentane (1:1 v/v, 1.4 mL) in a 10 mL round-bottomed flask that had been fused to a Teflon-coated valve at −78 °C. The resulting mixture was stirred for 30 min at −78 °C. A solution of lithium di-tert-butylbiphenylide in tetrahydrofuran (nominally 0.4 M) was then added dropwise via a syringe. The addition of lithium di-tert-butylbiphenylide was continued until a green color persisted (557 μL, nominally 223 μmol, 4.10 equiv). The resulting mixture was stirred for 10 min at −78 °C. The reaction vessel was then placed in a bath that had been precooled to −20 °C. The reaction mixture was stirred for 1 h at −20 °C and then cooled to −78 °C over 10 min. A solution of the MTHP monoperoxy acetal 12α (20.0 mg, 54.3 μmol, 1 equiv) in tetrahydrofuran (300 μL) was then added dropwise via a syringe. The reaction vessel was then placed in a cryogenic bath that had been precooled to −65 °C. The mixture was stirred for 6 h at −65 °C. The cold product mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (3.0 mL). The diluted product mixture was allowed to warm to 23 °C over 15 min. The warmed product mixture was transferred to a 20 mL test tube and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (4 × 5.0 mL). The organic layers were combined and the combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated under a stream of nitrogen. The residue obtained was purified by flash-column chromatography (eluting with 10% ethyl acetate–dichloromethane, initially, grading to 30% ethyl acetate–dichloromethane, three steps) to provide the disaccharide 17β as colorless oil (10.2 mg, 43%).

The diastereoselectivity of the reaction was determined to be 4.7:1 β/α by ¹H NMR analysis of the unpurified product mixture.

R_f = 0.55 (60% ethyl acetate–dichloromethane; UV, CAM). ¹H NMR (600 MHz, C₆D₆): δ 7.49 (d, J = 7.5 Hz, 2H, Ar), 7.04 (t, J = 7.7 Hz, 2H, Ar), 6.96 (t, J = 7.7 Hz, 1H, Ar), 5.44 (dd, J = 5.8, 2.2 Hz, 1H, H_1′), 4.54 (dd, J = 9.7, 2.3 Hz, 1H, H₁), 4.34 (dq, J = 9.4, 6.3 Hz, 1H, H_5′), 3.90 (dd, J = 10.6, 5.3 Hz, 1H, H₆), 3.72 (t, J = 10.5 Hz, 1H, H₆), 3.69 (ddd, J = 10.9, 7.9, 4.3 Hz, 1H, H_3′), 3.53 (ddd, J = 11.4, 8.7, 5.1 Hz, 1H, H₃), 3.41 (t, J = 9.0 Hz, 1H, H₄), 3.31 (t, J = 8.4 Hz, 1H, H_4′), 3.22 (s, 3H, OCH₃), 3.06 (td, J = 9.9, 5.3 Hz, 1H, H₅), 2.25 (ddd, J = 13.6, 4.9, 2.2 Hz, 1H, H_2′), 2.17 (ddd, J = 12.9, 5.1, 2.3 Hz, 1H, H₂), 1.90–1.79 (m, 2H, H₂, H_2′), 1.46 (s, 3H, CH₃), 1.22–1.20 (m, 6H, CH₃, H_6′). ¹³C{¹H} NMR (151 MHz, C₆D₆): δ 136.3 (C), 131.2 (2 × CH), 129.1 (2 × CH), 127.0 (CH), 100.9 (CH), 99.8 (C), 83.9 (CH), 83.6 (CH), 77.8 (CH), 76.4 (CH), 69.2 (CH), 68.4 (CH), 67.8 (CH), 62.6 (CH₂), 57.6 (CH₃), 39.7 (CH₂), 36.1 (CH₂), 29.5 (CH₃), 19.1 (CH₃), 18.4 (CH₃). IR (ATR-FTIR) (cm⁻¹): 3433 (br, w), 2929 (m), 2368 (w), 1585 (w), 1381 (m), 1084 (s). HRMS-ESI (m/z): [M + H]⁺ calcd for [C₂₂H₃₃O₇S]⁺, 441.1947; found, 441.1942. ${\left[\alpha \right]}_{\text{D}}^{21}+129.2$ (c 0.2, CHCl₃).

Synthesis of the Disaccharide 18α.

A solution of methyllithium in diethyl ether (1.12 M, 57.0 μL, 64.1 μmol, 1.60 equiv) was added dropwise via a syringe to a solution of the alcohol 1 (21.7 mg, 60.1 μmol, 1.50 equiv) in tetrahydrofuran–pentane (1:1 v/v, 1.0 mL) in a 10 mL round-bottomed flask that had been fused to a Teflon-coated valve at −78 °C. The resulting mixture was stirred for 30 min at −78 °C. A solution of lithium di-tert-butylbiphenylide in tetrahydrofuran (nominally 0.4 M) was then added dropwise via a syringe. The addition of lithium di-tert-butylbiphenylide was continued until a green color persisted (331 μL, nominally 132 μmol, 3.10 equiv). The resulting mixture was stirred for 10 min at −78 °C. A solution of the MTHP monoperoxy acetal 11 (15.0 mg, 40.1 μmol, 1 equiv) in tetrahydrofuran (300 μL) was then added dropwise via a syringe. The resulting mixture was stirred for 3 h at −78 °C. The cold product mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (3.0 mL). The diluted product mixture was allowed to warm to 23 °C over 15 min. The warmed product mixture was transferred to a 20 mL test tube and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (4 × 5.0 mL). The organic layers were combined and the combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated under a stream of nitrogen. The residue obtained was purified by flash-column chromatography (eluting with 10% ethyl acetate–dichloromethane, initially, grading to 30% ethyl acetate–dichloromethane, three steps) to provide the disaccharide 18α as colorless oil (17.0 mg, 83%).

The diastereoselectivity of the reaction was determined to be >50:1 α/β by ¹H NMR analysis of the unpurified product mixture.

R_f = 0.82 (60% ethyl acetate–dichloromethane; UV, CAM). ¹H NMR (400 MHz, CDCl₃): δ 7.27–7.24 (m, 2H, Ar), 6.88 (d, J = 8.6 Hz, 2H, Ar), 5.54 (d, J = 5.0 Hz, 1H, H_1′), 4.94 (d, J = 3.5 Hz, 1H, H₁), 4.63–4.57 (m, 2H, H_3′, CH₂Ar), 4.39 (d, J = 11.1 Hz, 1H, CH₂Ar), 4.32 (dd, J = 5.0, 2.4 Hz, 1H, H_2′), 4.23 (dd, J = 7.9, 1.9 Hz, 1H, H_4′), 3.96 (ddd, J = 7.2, 5.6, 1.9 Hz, 1H, H_5′), 3.83–3.78 (m, 1H, H_6′), 3.80 (s, 3H, OCH₃), 3.75–3.66 (m, 2H, H₃, H₅), 3.55 (dd, J = 10.3, 6.9 Hz, 1H, H_6′), 3.20 (td, J = 9.2, 1.6 Hz, 1H, H₄), 2.37 (d, J = 1.8 Hz, 1H, OH), 2.33 (ddd, J = 12.8, 4.9, 1.3 Hz, 1H, H₂), 1.62–1.57 (m, 1H, H₂), 1.56 (s, 3H, CH₃), 1.44 (s, 3H, CH₃), 1.35 (s, 3H, CH₃), 1.33 (s, 3H, CH₃), 1.27 (d, J = 6.2 Hz, 3H, H₆). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 159.5 (C), 130.6 (C), 129.6 (2 × CH), 114.1 (2 × CH), 109.4 (C), 108.7 (C), 97.6 (CH), 96.4 (CH), 76.8 (CH), 76.2 (CH), 71.3 (CH), 70.8 (CH), 70.7 (CH), 70.7 (CH₂), 67.7 (CH), 67.2 (CH), 65.7 (CH₂), 55.4 (CH₃), 34.8 (CH₂), 26.3 (CH₃), 26.1 (CH₃), 25.1 (CH₃), 24.6 (CH₃), 17.9 (CH₃). IR (ATR-FTIR) (cm⁻¹): 3450 (br, w), 2935 (m), 1613 (w), 1514 (m), 1173 (s). HRMS-ESI (m/z): [M + H]⁺ calcd for [C₂₆H₃₉O₁₀]⁺, 511.2543; found, 511.2538. ${\left[\alpha \right]}_{\text{D}}^{21}-64.9$ (c 0.4, CHCl₃).

Synthesis of the Disaccharide 19α.

A solution of methyllithium in diethyl ether (1.60 M, 59.0 μL, 94.1 μmol, 1.60 equiv) was added dropwise via a syringe to a solution of the alcohol 2α (31.3 mg, 88.2 μmol, 1.50 equiv) in tetrahydrofuran–pentane (1:1 v/v, 1.4 mL) in a 10 mL round-bottomed flask that had been fused to a Teflon-coated valve at −78 °C. The resulting mixture was stirred for 30 min at −78 °C. A solution of lithium di-tert-butylbiphenylide in tetrahydrofuran (nominally 0.4 M) was then added dropwise via a syringe. The addition of lithium di-tert-butylbiphenylide was continued until a green color persisted (456 μL, nominally 182 μmol, 3.10 equiv). The resulting mixture was stirred for 10 min at −78 °C. A solution of the MTHP monoperoxy acetal 11 (22.0 mg, 58.8 μmol, 1 equiv) in tetrahydrofuran (300 μL) was then added dropwise via a syringe. The resulting mixture was stirred for 3 h at −78 °C. The cold product mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (3.0 mL). The diluted product mixture was allowed to warm to 23 °C over 15 min. The warmed product mixture was transferred to a 20 mL test tube and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (4 × 5.0 mL). The organic layers were combined and the combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated under a stream of nitrogen. The residue obtained was purified by flash-column chromatography (eluting with 5% methanol–dichloromethane, initially, grading to 30% ethyl acetate–dichloromethane, three steps) to provide the disaccharide 19α as colorless oil (27.7 mg, 47%).

The diastereoselectivity of the reaction was determined to be >50:1 α/β by ¹H NMR analysis of the unpurified product mixture.

R_f = 0.65 (5% methanol–dichloromethane; CAM). ¹H NMR (400 MHz, C₆D₆): δ 5.49 (d, J = 5.0 Hz, 1H, H_1′), 4.85 (d, J = 3.5 Hz, 1H, H₁), 4.48 (dd, J = 7.9, 2.3 Hz, 1H, H_3′), 4.23–4.00 (m, 6H, H₃, H₅, H_2′, H_4′, H_5′, H_6′), 3.79 (dd, J = 10.1, 6.7 Hz, 1H, H_6′), 3.15 (td, J = 9.0, 2.5 Hz, 1H, H₄), 2.05 (ddd, J = 12.9, 5.1, 1.3 Hz, 1H, H₂), 2.01 (d, J = 2.7 Hz, 1H, OH), 1.60 (ddd, J = 12.9, 11.3, 3.6 Hz, 1H, H₂), 1.48–1.42 (m, 9H, H₆, 2 × CH₃), 1.15 (s, 3H, CH₃), 1.04 (s, 3H, CH₃), 0.93 (s, 9H, 3 × CH₃), 0.06 (s, 3H, CH₃), 0.05 (s, 3H, CH₃). ¹³C{¹H} NMR (151 MHz, C₆D₆): δ 109.3 (C), 108.4 (C), 98.0 (CH), 96.8 (CH), 78.5 (CH), 71.6 (CH), 71.3 (CH), 71.2 (CH), 71.1 (CH), 68.2 (CH), 67.7 (CH), 66.3 (CH₂), 39.2 (CH₂), 26.3 (CH₃), 26.2 (CH₃), 26.0 (3 × CH₃), 24.9 (CH₃), 24.4 (CH₃), 18.3 (CH₃), 18.2 (C), −4.2 (CH₃), −4.5 (CH₃). IR (ATR-FTIR) (cm⁻¹): 3521 (br, w), 2858 (m), 2345 (w), 1463 (w), 1382 (m), 1256 (m). HRMS-ESI (m/z): [M + Na]⁺ calcd for [C₂₄H₄₄O₉SiNa]⁺, 527.2652; found, 527.2647. ${\left[\alpha \right]}_{\text{D}}^{21}-71.2$ (c 0.3, CHCl₃).

Synthesis of the Disaccharide 20α.

A solution of methyllithium in diethyl ether (1.40 M, 143 μL, 200 μmol, 2.00 equiv) was added dropwise via a syringe to a solution of the alcohol 4α (50.9 mg, 200 μmol, 2.00 equiv) in tetrahydrofuran–pentane (1:1 v/v, 2.6 mL) in a 10 mL round-bottomed flask that had been fused to a Teflon-coated valve at −78 °C. The resulting mixture was stirred for 30 min at −78 °C. A solution of lithium di-tert-butylbiphenylide in tetrahydrofuran (nominally 0.4 M) was then added dropwise via a syringe. The addition of lithium di-tert-butylbiphenylide was continued until a green color persisted (1.03 mL, nominally 410 μmol, 4.10 equiv). The resulting mixture was stirred for 10 min at −78 °C. A solution of the MTHP monoperoxy acetal 11 (37.4 mg, 100 μmol, 1 equiv) in tetrahydrofuran (300 μL) was then added dropwise via a syringe. The resulting mixture was stirred for 3 h at −78 °C. The cold product mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (3.0 mL). The diluted product mixture was allowed to warm to 23 °C over 15 min. The warmed product mixture was transferred to a 20 mL test tube and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (4 × 5.0 mL). The organic layers were combined and the combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated under a stream of nitrogen. The residue obtained was purified by flash-column chromatography (eluting with 15% ethyl acetate–hexanes, initially, grading to 45% ethyl acetate–hexanes, three steps) to provide the disaccharide 20α as colorless oil (31.3 mg, 77%).

The diastereoselectivity of the reaction was determined to be >50:1 α/β by ¹H NMR analysis of the unpurified product mixture.

R_f = 0.19 (50% ethyl acetate–hexanes; CAM). ¹H NMR (600 MHz, CDCl₃): δ 5.53 (d, J = 5.0 Hz, 1H, H_1′), 4.96 (d, J = 3.7 Hz, 1H, H₁), 4.61 (dd, J = 8.0, 2.4 Hz, 1H, H_3′), 4.31 (dd, J = 5.0, 2.4 Hz, 1H, H_2′), 4.22 (dd, J = 7.9, 1.9 Hz, 1H, H_4′), 3.96 (td, J = 6.5, 1.9 Hz, 1H, H_5′), 3.89 (q, J = 6.7 Hz, 1H, H₅), 3.77 (s, 1H, H₄), 3.73 (dd, J = 10.7, 6.9 Hz, 1H, H_6′), 3.67–3.62 (m, 2H, H₃, H_6′), 3.37 (s, 3H, OCH₃), 2.08 (d, J = 2.7 Hz, 1H, OH), 1.92 (dd, J = 13.0, 5.2 Hz, 1H, H₂), 1.82 (td, J = 12.4, 3.7 Hz, 1H, H₂), 1.53 (s, 3H, CH₃), 1.44 (s, 3H, CH₃), 1.33 (s, 6H, 2 × CH₃), 1.28 (d, J = 6.6 Hz, 3H, H₆). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 109.5 (C), 108.7 (C), 97.4 (CH), 96.5 (CH), 74.7 (CH), 71.3 (CH), 70.8 (CH), 70.7 (CH), 67.8 (CH), 66.2 (CH), 65.8 (CH₂), 65.7 (CH), 55.7 (CH₃), 29.6 (CH₂), 26.2 (CH₃), 26.1 (CH₃), 25.1 (CH₃), 24.7 (CH₃), 16.9 (CH₃). IR (ATR-FTIR) (cm⁻¹): 3520 (br, w), 2982 (m), 2357 (w), 1456 (w), 1382 (m). HRMS-ESI (m/z): [M + Na]⁺ calcd for [C₁₉H₃₂O₉Na]⁺, 427.1944; found, 427.1939. ${\left[\alpha \right]}_{\text{D}}^{21}+20.4$ (c 1.0, CHCl₃).

Synthesis of the Disaccharide 21α.

A solution of methyllithium in diethyl ether (1.41 M, 43.0 μL, 60.2 μmol, 1.50 equiv) was added dropwise via a syringe to a solution of the alcohol 3α (13.5 mg, 60.2 μmol, 1.50 equiv) in tetrahydrofuran–pentane (1:1 v/v, 1.0 mL) in a 10 mL round-bottomed flask that had been fused to a Teflon-coated valve at −78 °C. The resulting mixture was stirred for 30 min at −78 °C. A solution of lithium di-tert-butylbiphenylide in tetrahydrofuran (nominally 0.4 M) was then added dropwise via a syringe. The addition of lithium di-tert-butylbiphenylide was continued until a green color persisted (311 μL, nominally 124 μmol, 3.10 equiv). The resulting mixture was stirred for 10 min at −78 °C. A solution of the MTHP monoperoxy acetal 11 (15.0 mg, 40.1 μmol, 1 equiv) in tetrahydrofuran (300 μL) was then added dropwise via a syringe. The resulting mixture was stirred for 3 h at −78 °C. The cold product mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (3.0 mL). The diluted product mixture was allowed to warm to 23 °C over 15 min. The warmed product mixture was transferred to a 20 mL test tube and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (4 × 5.0 mL). The organic layers were combined and the combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated under a stream of nitrogen. The residue obtained was purified by flash-column chromatography (eluting with 15% ethyl acetate–dichloromethane, initially, grading to 60% ethyl acetate–dichloromethane, four steps) to provide the disaccharide 21α as colorless oil (12.0 mg, 80%).

The diastereoselectivity of the reaction was determined to be >50:1 α/β by ¹H NMR analysis of the unpurified product mixture.

R_f = 0.32 (60% ethyl acetate–dichloromethane; CAM). ¹H NMR (600 MHz, CDCl₃): δ 5.54 (dd, J = 5.0, 1.6 Hz, 1H, H_1′), 4.84 (d, J = 3.3 Hz, 1H, H₁), 4.61 (dd, J = 7.9, 2.5 Hz, 1H, H_3′), 4.32 (dd, J = 4.9, 2.4 Hz, 1H, H_2′), 4.25 (d, J = 8.0 Hz, 1H, H_4′), 4.05–3.95 (m, 2H, H₅, H_5′), 3.76 (dd, J = 10.6, 6.6 Hz, 1H, H_6′), 3.68 (dd, J = 10.7, 6.4 Hz, 1H, H_6′), 3.56 (d, J = 7.0 Hz, 1H, H₄), 2.02 (tdd, J = 13.5, 4.6, 2.7 Hz, 1H, H₃), 1.93 (tt, J = 13.9, 4.1 Hz, 1H, H₂), 1.80 (d, J = 7.9 Hz, 1H, OH), 1.76–1.68 (m, 1H, H₃), 1.61 (dd, J = 9.9, 2.0 Hz, 1H, H₂), 1.54 (s, 3H, CH₃), 1.45 (s, 3H, CH₃), 1.34 (s, 6H, 2 × CH₃), 1.17 (d, J = 6.6 Hz, 3H, H₆). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 109.5 (C), 108.7 (C), 97.1 (CH), 96.5 (CH), 71.3 (CH), 70.8 (CH), 70.8 (CH), 67.6 (CH), 66.4 (CH), 66.3 (CH), 65.6 (CH₂), 26.1 (CH₃), 25.9 (CH₃), 25.1 (CH₂), 24.7 (2 × CH₃), 23.5 (CH₂), 17.3 (CH₃). IR (ATR-FTIR) (cm⁻¹): 3469 (br, w), 2936 (m), 1455 (w), 1382 (m), 1372 (m), 1070 (s). HRMS-ESI (m/z): [M + Na]⁺ calcd for [C₁₈H₃₀O₈Na]⁺, 397.1838; found, 397.1833. ${\left[\alpha \right]}_{\text{D}}^{21}-3.9$ (c 0.5, CHCl₃).

Synthesis of the Disaccharide 22α.

A solution of methyllithium in diethyl ether (1.30 M, 75.0 μL, 97.6 μmol, 2.00 equiv) was added dropwise via a syringe to a solution of the alcohol 4α (24.8 mg, 97.6 μmol, 2.00 equiv) in tetrahydrofuran–pentane (1:1 v/v, 1.2 mL) in a 10 mL round-bottomed flask that had been fused to a Teflon-coated valve at −78 °C. The resulting mixture was stirred for 30 min at −78 °C. A solution of lithium di-tert-butylbiphenylide in tetrahydrofuran (nominally 0.4 M) was then added dropwise via a syringe. The addition of lithium di-tert-butylbiphenylide was continued until a green color persisted (500 μL, nominally 200 μmol, 4.10 equiv). The resulting mixture was stirred for 10 min at −78 °C. A solution of the MTHP monoperoxy acetal 12α (18.0 mg, 48.8 μmol, 1 equiv) in tetrahydrofuran (300 μL) was then added dropwise via a syringe. The resulting mixture was stirred for 3 h at −78 °C. The cold product mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (3.0 mL). The diluted product mixture was allowed to warm to 23 °C over 15 min. The warmed product mixture was transferred to a 20 mL test tube and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (4 × 5.0 mL). The organic layers were combined and the combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated under a stream of nitrogen. The residue obtained was purified by flash-column chromatography (eluting with 15% ethyl acetate–hexanes, initially, grading to 45% ethyl acetate–hexanes, three steps) to provide the disaccharide 22α as colorless oil (10.7 mg, 55%).

The diastereoselectivity of the reaction was determined to be >50:1 α/β by ¹H NMR analysis of the unpurified product mixture.

R_f = 0.39 (60% ethyl acetate–hexanes; UV, CAM). ¹H NMR (500 MHz, CDCl₃): δ 7.45 (d, J = 7.4 Hz, 2H, Ar), 7.30 (t, J = 7.4 Hz, 2H, Ar), 7.26–7.22 (m, 1H, Ar), 5.59 (dd, J = 5.7, 1.6 Hz, 1H, H_1′), 5.40 (d, J = 3.9 Hz, 1H, H₁), 4.15 (dq, J = 9.3, 6.2 Hz, 1H, H_5′), 3.95 (q, J = 6.7 Hz, 1H, H₅), 3.80 (s, 1H, H₄), 3.65–3.54 (m, 2H, H₃, H_3′), 3.42 (s, 3H, OCH₃), 3.38 (s, 3H, OCH₃), 3.29 (t, J = 8.9 Hz, 1H, H_4′), 2.45 (ddd, J = 13.5, 4.8, 1.6 Hz, 1H, H_2′), 2.04 (d, J = 3.0 Hz, 1H, OH), 2.00–1.92 (m, 2H, H₂, H_2′), 1.87 (td, J = 12.4, 4.0 Hz, 1H, H₂), 1.31–1.25 (m, 6H, H₆, H_6′). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 135.3 (C), 131.2 (2 × CH), 129.1 (2 × CH), 127.2 (CH), 99.0 (CH), 83.8 (CH), 81.1 (CH), 79.9 (CH), 74.8 (CH), 67.9 (2 × CH), 66.3 (CH), 56.7 (CH₃), 55.7 (CH₃), 35.4 (CH₂), 30.0 (CH₂), 18.4 (CH₃), 16.9 (CH₃). IR (ATR-FTIR) (cm⁻¹): 3475 (br, m), 2935 (m), 2363 (w), 1585 (w), 1440 (m), 1195 (m). HRMS-ESI (m/z): [M + H]⁺ calcd for [C₂₀H₃₁O₆S]⁺, 399.1841; found, 399.1836. ${\left[\alpha \right]}_{\text{D}}^{21}+217.5$ (c 0.8, CHCl₃).

Synthesis of the Disaccharide 23α.

A solution of methyllithium in diethyl ether (1.30 M, 75.0 μL, 97.6 μmol, 2.00 equiv) was added dropwise via a syringe to a solution of the alcohol 3α (21.9 mg, 97.6 μmol, 2.00 equiv) in tetrahydrofuran–pentane (1:1 v/v, 1.2 mL) in a 10 mL round-bottomed flask that had been fused to a Teflon-coated valve at −78 °C. The resulting mixture was stirred for 30 min at −78 °C. A solution of lithium di-tert-butylbiphenylide in tetrahydrofuran (nominally 0.4 M) was then added dropwise via a syringe. The addition of lithium di-tert-butylbiphenylide was continued until a green color persisted (500 μL, nominally 200 μmol, 4.10 equiv). The resulting mixture was stirred for 10 min at −78 °C. A solution of the MTHP monoperoxy acetal 12α (18.0 mg, 48.8 μmol, 1 equiv) in tetrahydrofuran (300 μL) was then added dropwise via a syringe. The resulting mixture was stirred for 3 h at −78 °C. The cold product mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (3.0 mL). The diluted product mixture was allowed to warm to 23 °C over 15 min. The warmed product mixture was transferred to a 20 mL test tube and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (4 × 5.0 mL). The organic layers were combined and the combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated under a stream of nitrogen. The residue obtained was purified by flash-column chromatography (eluting with 10% ethyl acetate–hexanes, initially, grading to 30% ethyl acetate–hexanes, three steps) to provide the disaccharide 23α as colorless oil (13.0 mg, 72%).

The diastereoselectivity of the reaction was determined to be >50:1 α/β by ¹H NMR analysis of the unpurified product mixture.

R_f = 0.19 (30% ethyl acetate–hexanes; UV, CAM). ¹H NMR (400 MHz, C₆D₆): δ 7.54–7.50 (m, 2H, Ar), 7.05 (t, J = 7.5 Hz, 2H, Ar), 7.01–6.95 (m, 1H, Ar), 5.45 (dd, J = 5.7, 1.5 Hz, 1H, H_1′), 5.41 (d, J = 2.9 Hz, 1H, H₁), 4.41 (dq, J = 9.3, 6.2 Hz, 1H, H_5′), 3.94 (qd, J = 6.5, 1.4 Hz, 1H, H₅), 3.63 (ddd, J = 11.5, 8.5, 4.7 Hz, 1H, H_3′), 3.45 (t, J = 8.9 Hz, 1H, H_4′), 3.29 (s, 1H, H₄), 2.99 (s, 3H, OCH₃), 2.22 (ddd, J = 13.4, 4.8, 1.5 Hz, 1H, H_2′), 1.91–1.85 (m, 2H, H₂, H₃), 1.72 (ddd, J = 13.4, 11.5, 5.7 Hz, 1H, H_2′), 1.65–1.54 (m, 2H, H₂, H₃), 1.42 (d, J = 6.2 Hz, 3H, H_6′), 1.11 (d, J = 6.6 Hz, 3H, H₆). ¹³C{¹H} NMR (151 MHz, C₆D₆): δ 136.3 (C), 131.2 (2 × CH), 129.2 (2 × CH), 127.0 (CH), 98.6 (CH), 84.0 (CH), 81.2 (CH), 80.4 (CH), 68.5 (CH), 67.4 (CH), 67.1 (CH), 56.2 (CH₃), 35.7 (CH₂), 26.2 (CH₂), 24.1 (CH₂), 18.8 (CH₃), 17.3 (CH₃). IR (ATR-FTIR) (cm⁻¹): 3464 (br, m), 2933 (m), 2343 (w), 1585 (w), 1440 (m). HRMS-ESI (m/z): [M + Na]⁺ calcd for [C₁₉H₂₈O₅SNa]⁺, 391.1555; found, 391.1550. ${\left[\alpha \right]}_{\text{D}}^{21}+215.2$ (c 0.5, CHCl₃).

Synthesis of the Disaccharide 24α.

A solution of methyllithium in diethyl ether (1.30 M, 84.0 μL, 109 μmol, 2.00 equiv) was added dropwise via a syringe to a solution of the alcohol 8α (39.1 mg, 109 μmol, 2.00 equiv) in tetrahydrofuran–pentane (1:1 v/v, 1.4 mL) in a 10 mL round-bottomed flask that had been fused to a Teflon-coated valve at −78 °C. The resulting mixture was stirred for 30 min at −78 °C. A solution of lithium di-tert-butylbiphenylide in tetrahydrofuran (nominally 0.4 M) was then added dropwise via a syringe. The addition of lithium di-tert-butylbiphenylide was continued until a green color persisted (557 μL, nominally 223 μmol, 4.10 equiv). The resulting mixture was stirred for 10 min at −78 °C. A solution of the MTHP monoperoxy acetal 12α (20.0 mg, 54.3 μmol, 1 equiv) in tetrahydrofuran (300 μL) was then added dropwise via a syringe. The resulting mixture was stirred for 3 h at −78 °C. The cold product mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (3.0 mL). The diluted product mixture was allowed to warm to 23 °C over 15 min. The warmed product mixture was transferred to a 20 mL test tube and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (4 × 5.0 mL). The organic layers were combined and the combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated under a stream of nitrogen. The residue obtained was purified by flash-column chromatography (eluting with 10% ethyl acetate–hexanes, initially, grading to 30% ethyl acetate–hexanes, three steps) to provide the disaccharide 24α as colorless oil (15.0 mg, 55%).

The diastereoselectivity of the reaction was determined to be >50:1 α/β by ¹H NMR analysis of the unpurified product mixture.

R_f = 0.26 (40% ethyl acetate–hexanes; UV, CAM). ¹H NMR (400 MHz, CDCl₃): δ 7.49–7.40 (m, 2H, Ar), 7.32–7.27 (m, 4H, Ar), 7.23 (d, J = 7.5 Hz, 1H, Ar), 6.90 (d, J = 8.6 Hz, 2H, Ar), 5.60 (dd, J = 5.7, 1.6 Hz, 1H, H_1′), 5.04 (d, J = 3.3 Hz, 1H, H₁), 4.57 (d, J = 11.2 Hz, 1H, CH₂Ar), 4.52 (d, J = 11.2 Hz, 1H, CH₂Ar), 4.27–4.07 (m, 2H, H₅, H_5′), 3.87 (ddd, J = 10.7, 6.1, 2.9 Hz, 1H, H₃), 3.81 (s, 4H, H₄, OCH₃), 3.50 (ddd, J = 11.2, 8.5, 4.7 Hz, 1H, H_3′), 3.36 (s, 3H, OCH₃), 3.24 (t, J = 8.9 Hz, 1H, H_4′), 2.48 (ddd, J = 13.5, 4.8, 1.7 Hz, 1H, H_2′), 2.15 (s, 1H, OH), 2.03–1.89 (m, 3H, H₂, H_2′), 1.29 (d, J = 6.6 Hz, 3H, H₆), 1.25 (d, J = 6.3 Hz, 3H, H_6′). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 159.5 (C), 135.3 (C), 131.2 (2 × CH), 130.3 (C), 129.5 (2 × CH), 129.1 (2 × CH), 127.2 (CH), 114.1 (2 × CH), 98.8 (CH), 83.7 (CH), 81.8 (CH), 77.3 (CH), 73.1 (CH), 69.9 (CH₂), 68.7 (CH), 68.6 (CH), 66.0 (CH), 56.3 (CH₃), 55.5 (CH₃), 35.4 (CH₂), 30.4 (CH₂), 18.2 (CH₃), 16.8 (CH₃). IR (ATR-FTIR) (cm⁻¹): 3472 (br, w), 2935 (m), 1613 (m), 1515 (s), 1069 (s). HRMS-ESI (m/z): [M + H]⁺ calcd for [C₂₇H₃₇O₇S]⁺, 505.2260; found, 505.2255. ${\left[\alpha \right]}_{\text{D}}^{21}+81.4$ (c 0.4, CHCl₃).

Synthesis of the Disaccharide 26α.

A solution of methyllithium in diethyl ether (1.30 M, 63.0 μL, 81.4 μmol, 1.50 equiv) was added dropwise via a syringe to a solution of the alcohol 9 (30.2 mg, 81.4 μmol, 1.50 equiv) in tetrahydrofuran–pentane (1:1 v/v, 1.4 mL) in a 10 mL round-bottomed flask that had been fused to a Teflon-coated valve at −78 °C. The resulting mixture was stirred for 30 min at −78 °C. A solution of lithium di-tert-butylbiphenylide in tetrahydrofuran (nominally 0.4 M) was then added dropwise via a syringe. The addition of lithium di-tert-butylbiphenylide was continued until a green color persisted (421 μL, nominally 168 μmol, 3.10 equiv). The resulting mixture was stirred for 10 min at −78 °C. A solution of the MTHP monoperoxy acetal 12α (20.0 mg, 54.3 μmol, 1 equiv) in tetrahydrofuran (300 μL) was then added dropwise via a syringe. The resulting mixture was stirred for 3 h at −78 °C. The cold product mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (3.0 mL). The diluted product mixture was allowed to warm to 23 °C over 15 min. The warmed product mixture was transferred to a 20 mL test tube and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (4 × 5.0 mL). The organic layers were combined and the combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated under a stream of nitrogen. The residue obtained was purified by flash-column chromatography (eluting with 10% ethyl acetate–dichloromethane, initially, grading to 30% ethyl acetate–dichloromethane, three steps) to provide the disaccharide 26α as colorless oil (17.8 mg, 64%).

The diastereoselectivity of the reaction was determined to be >50:1 α/β by ¹H NMR analysis of the unpurified product mixture.

R_f = 0.56 (60% ethyl acetate–dichloromethane; UV, CAM). ¹H NMR (500 MHz, CDCl₃): δ 7.45 (d, J = 7.4 Hz, 2H, Ar), 7.30 (t, J = 7.4 Hz, 2H, Ar), 7.24 (d, J = 7.4 Hz, 1H, Ar), 5.58 (d, J = 5.5 Hz, 1H, H_1′), 5.43 (d, J = 3.8 Hz, 1H, H₁), 4.14 (dq, J = 8.9, 6.0 Hz, 1H, H_5′), 4.11–4.06 (m, 1H, H₃), 3.86 (dt, J = 9.9, 3.6 Hz, 1H, H₅), 3.78 (t, J = 3.9 Hz, 2H, H₆), 3.63 (t, J = 9.9 Hz, 1H, H₄), 3.58 (ddd, J = 11.5, 8.6, 4.8 Hz, 1H, H_3′), 3.38 (s, 3H, OCH₃), 3.32 (s, 3H, OCH₃), 3.28 (s, 3H, OCH₃), 3.27–3.22 (m, 1H, H_4′), 2.46 (ddd, J = 13.4, 4.8, 1.5 Hz, 1H, H_2′), 2.05 (dd, J = 12.5, 4.7 Hz, 1H, H₂), 1.97–1.87 (m, 2H, OH, H_2′), 1.81 (td, J = 12.5, 4.0 Hz, 1H, H₂), 1.31 (s, 6H, 2 × CH₃), 1.29 (d, J = 6.2 Hz, 3H, H_6′). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 135.0 (C), 131.1 (2 × CH), 128.9 (2 × CH), 127.1 (CH), 99.9 (C), 99.7 (C), 99.2 (CH), 83.8 (CH), 81.5 (CH), 79.8 (CH), 70.7 (CH), 68.6 (CH), 67.6 (CH), 64.7 (CH), 61.4 (CH₂), 56.6 (CH₃), 48.1 (CH₃), 47.9 (CH₃), 35.3 (CH₂), 35.2 (CH₂), 18.6 (CH₃), 17.9 (CH₃), 17.8 (CH₃). IR (ATR-FTIR) (cm⁻¹): 3500 (br, w), 2935 (m), 2358 (m), 1585 (w), 1197 (m), 1048 (s). HRMS-ESI (m/z): [M + Na]⁺ calcd for [C₂₅H₃₈O₉SNa]⁺, 537.2134; found, 537.2129. ${\left[\alpha \right]}_{\text{D}}^{21}+261.9$ (c 0.8, CHCl₃).

Synthesis of the Disaccharide 26β.

A solution of methyllithium in diethyl ether (1.34 M, 81.0 μL, 109 μmol, 2.00 equiv) was added dropwise via a syringe to a solution of the alcohol 9 (40.2 mg, 109 μmol, 2.00 equiv) in tetrahydrofuran–pentane (1:1 v/v, 1.4 mL) in a 10 mL round-bottomed flask that had been fused to a Teflon-coated valve at −78 °C. The resulting mixture was stirred for 30 min at −78 °C. A solution of lithium di-tert-butylbiphenylide in tetrahydrofuran (nominally 0.4 M) was then added dropwise via a syringe. The addition of lithium di-tert-butylbiphenylide was continued until a green color persisted (556 μL, nominally 223 μmol, 4.10 equiv). The resulting mixture was stirred for 10 min at −78 °C. The reaction vessel was then placed in a bath that had been precooled to −20 °C. The reaction mixture was stirred for 1 h at −20 °C and then cooled to −78 °C over 10 min. A solution of the MTHP monoperoxy acetal 12α (20.0 mg, 54.3 μmol, 1 equiv) in tetrahydrofuran (300 μL) was then added dropwise via a syringe. The reaction vessel was then placed in a cryogenic bath that had been precooled to −65 °C. The mixture was stirred for 6 h at −65 °C. The cold product mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (3.0 mL). The diluted product mixture was allowed to warm to 23 °C over 15 min. The warmed product mixture was transferred to a 20 mL test tube and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (4 × 5.0 mL). The organic layers were combined and the combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated under a stream of nitrogen. The residue obtained was purified by flash-column chromatography (eluting with 10% ethyl acetate–dichloromethane, initially, grading to 40% ethyl acetate–dichloromethane, four steps) to provide the disaccharide 26β as colorless oil (9.1 mg, 33%).

The diastereoselectivity of the reaction was determined to be 7:1 β/α by ¹H NMR analysis of the unpurified product mixture.

R_f = 0.34 (60% ethyl acetate–dichloromethane; UV, CAM). ¹H NMR (600 MHz, CDCl₃): δ 7.44 (d, J = 7.2 Hz, 2H, Ar), 7.29 (t, J = 7.8 Hz, 2H, Ar), 7.23 (t, J = 6.8 Hz, 1H, Ar), 5.57 (dd, J = 5.7, 1.8 Hz, 1H, H_1′), 4.78 (dd, J = 9.5, 2.1 Hz, 1H, H₁), 4.21 (dq, J = 9.3, 6.3 Hz, 1H, H_5′), 3.89 (dd, J = 11.6, 3.1 Hz, 1H, H₆), 3.79 (ddd, J = 12.1, 9.5, 4.4 Hz, 1H, H₃), 3.72 (dd, J = 11.6, 5.6 Hz, 1H, H₆), 3.62 (ddd, J = 11.0, 8.3, 4.8 Hz, 1H, H_3′), 3.57 (t, J = 9.6 Hz, 1H, H₄), 3.51–3.47 (m, 1H, H₅), 3.44 (s, 3H, OCH₃), 3.28 (s, 3H, OCH₃), 3.27–3.23 (m, 4H, H_4′, OCH₃), 2.42 (ddd, J = 13.6, 4.9, 1.8 Hz, 1H, H_2′), 2.14–2.09 (m, 1H, H₂), 1.97 (ddd, J = 13.5, 11.2, 5.7 Hz, 1H, H_2′), 1.73 (td, J = 12.3, 9.6 Hz, 1H, H₂), 1.31 (s, 3H, CH₃), 1.30 (s, 3H, CH₃), 1.26 (d, J = 6.3 Hz, 3H, H_6′). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 135.1 (C), 131.3 (2 × CH), 129.1 (2 × CH), 127.2 (CH), 101.0 (CH), 100.0 (2 × C), 84.0 (CH), 83.6 (CH), 77.5 (CH), 74.0 (CH), 68.7 (CH), 68.0 (CH), 67.2 (CH), 62.0 (CH₂), 57.8 (CH), 48.2 (CH₃), 48.0 (CH₃), 36.3 (CH₂), 35.8 (CH₂), 18.1 (CH₃), 17.9 (2 × CH₃). IR (ATR-FTIR) (cm⁻¹): 3469 (br, w), 2934 (m), 2364 (w), 1376 (m), 1094 (s). HRMS-ESI (m/z): [M + Na]⁺ calcd for [C₂₅H₃₈O₉SNa]⁺, 537.2134; found, 537.2129. ${\left[\alpha \right]}_{\text{D}}^{21}+128.9$ (c 0.5, CHCl₃).

Synthesis of the Disaccharide 27α.

A solution of methyllithium in diethyl ether (1.30 M, 84.0 μL, 109 μmol, 2.00 equiv) was added dropwise via a syringe to a solution of the alcohol 10α (32.2 mg, 109 μmol, 2.00 equiv) in tetrahydrofuran–pentane (1:1 v/v, 1.4 mL) in a 10 mL round-bottomed flask that had been fused to a Teflon-coated valve at −78 °C. The resulting mixture was stirred for 30 min at −78 °C. A solution of lithium di-tert-butylbiphenylide in tetrahydrofuran (nominally 0.4 M) was then added dropwise via a syringe. The addition of lithium di-tert-butylbiphenylide was continued until a green color persisted (559 μL, nominally 223 μmol, 4.10 equiv). The resulting mixture was stirred for 10 min at −78 °C. A solution of the MTHP monoperoxy acetal 12α (20.0 mg, 54.3 μmol, 1 equiv) in tetrahydrofuran (300 μL) was then added dropwise via a syringe. The resulting mixture was stirred for 3 h at −78 °C. The cold product mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (3.0 mL). The diluted product mixture was allowed to warm to 23 °C over 15 min. The warmed product mixture was transferred to a 20 mL test tube and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (4 × 5.0 mL). The organic layers were combined and the combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated under a stream of nitrogen. The residue obtained was purified by flash-column chromatography (eluting with 10% ethyl acetate–dichloromethane, initially, grading to 30% ethyl acetate–dichloromethane, three steps) to provide the disaccharide 27α as colorless oil (18.0 mg, 75%).

The diastereoselectivity of the reaction was determined to be >50:1 α/β by ¹H NMR analysis of the unpurified product mixture.

R_f = 0.60 (60% ethyl acetate–dichloromethane; UV, CAM). ¹H NMR (400 MHz, C₆D₆): δ 7.56–7.46 (m, 2H, Ar), 7.04 (t, J = 7.4 Hz, 2H, Ar), 7.00–6.92 (m, 1H, Ar), 5.72 (dd, J = 7.7, 5.7 Hz, 1H, H₁), 5.44 (d, J = 5.6 Hz, 1H, H_1′), 4.42 (dq, J = 9.4, 6.2 Hz, 1H, H_5′), 4.04 (dt, J = 7.7, 3.3 Hz, 1H, H₃), 3.89 (dd, J = 10.3, 7.4 Hz, 1H, H₆), 3.79 (dt, J = 11.6, 6.2 Hz, 1H, H₆), 3.73 (dd, J = 7.7, 1.9 Hz, 1H, H₄), 3.66 (ddd, J = 11.5, 8.7, 4.7 Hz, 1H, H_3′.), 3.61–3.52 (m, 2H, H₅, H_4′), 2.96 (s, 3H, OCH₃), 2.36 (ddd, J = 15.2, 5.7, 3.5 Hz, 1H, H₂), 2.22 (ddd, J = 13.4, 4.7, 1.4 Hz, 1H, H_2′), 1.70 (ddd, J = 13.4, 11.5, 5.7 Hz, 2H, OH, H_2′), 1.49 (d, J = 6.3 Hz, 4H, H₂, H_6′), 1.45 (s, 3H, CH₃), 1.18 (s, 3H, CH₃). ¹³C{¹H} NMR (151 MHz, C₆D₆): δ 136.4 (C), 131.1 (2 × CH), 129.2 (2 × CH), 127.0 (CH), 109.1 (C), 97.0 (CH), 84.2 (CH), 80.2 (CH), 79.9 (CH), 73.7 (CH), 71.0 (CH), 69.8 (CH), 68.6 (CH), 62.6 (CH₂), 56.2 (CH₃), 35.9 (CH₂), 30.7 (CH₂), 26.6 (CH₃), 25.1 (CH₃), 18.6 (CH₃). IR (ATR-FTIR) (cm⁻¹): 3469 (br, w), 2934 (m), 2368 (m), 1584 (w), 1379 (m), 1098 (s). HRMS-ESI (m/z): [M + H]⁺ calcd for [C₂₂H₃₃O₇S]⁺, 441.1947; found, 441.1942. ${\left[\alpha \right]}_{\text{D}}^{21}+144.0$ (c 0.4, CHCl₃).

Synthesis of the Ether 28.

Sodium hydride (39.7 mg, 992 mmol, 1.40 equiv) was added to a solution of the alcohol 6 (300 mg, 709 μmol, 1 equiv) in N,N-dimethylformamide (7.1 mL) at 0 °C. The resulting solution was stirred for 15 min at 0 °C. Methyl iodide (750 μL, 1.21 mmol, 1.70 equiv) was then added dropwise via a syringe. Upon completion of the addition, the cooling bath was removed and the reaction mixture was allowed to warm to 23 °C. The reaction mixture was stirred for 3 h at 23 °C. The product mixture was diluted sequentially with saturated aqueous ammonium chloride solution (30 mL) and ethyl acetate (20 mL). The resulting mixture was transferred to a separatory funnel and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (2 × 25 mL). The organic layers were combined and the combined organic layers were washed sequentially with saturated aqueous sodium chloride solution (10 mL) and saturated aqueous sodium thiosulfate solution (10 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was purified by flash-column chromatography (eluting with 2% ethyl acetate–hexanes initially, grading to 10% ethyl acetate–hexanes, 4 steps) to provide the ether 28 as a white solid (644 mg, 91%, 2:1 mixture of α/β diastereomers).

The diastereomers were not separable by flash-column chromatography; consequently, the optical rotation of the product 28 was not determined.

R_f = 0.52 (20% ethyl acetate–hexanes; UV, CAM). ¹H NMR (600 MHz, C₆D₆): δ 7.40 (d, J = 7.1 Hz, 2H, Ar), 7.00 (d, J = 7.8 Hz, 2H, Ar), 6.98–6.93 (m, 1H, Ar), 5.38 (d, J = 6.0 Hz, 1H, H₁), 4.43 (td, J = 9.9, 5.2 Hz, 1H, H₅), 3.81 (dd, J = 10.6, 5.2 Hz, 1H, H₆), 3.74–3.67 (m, 3H, H₃, H₄, H₆), 3.29 (s, 3H, OCH₃), 2.29 (ddd, J = 13.9, 4.8, 1.1 Hz, 1H, H₂), 1.89 (ddd, J = 13.8, 11.0, 6.1 Hz, 1H, H₂), 1.48 (s, 3H, CH₃), 1.27 (s, 3H, CH₃). ¹³C{¹H} NMR (151 MHz, C₆D₆): δ 135.6 (C), 131.6 (2 × CH), 129.2 (2 × CH), 127.3 (CH), 99.7 (CH), 84.8 (CH), 77.0 (CH), 75.7 (CH), 65.5 (cH), 62.5 (CH₂), 58.3 (CH₃), 37.1 (CH₂), 29.6 (CH₃), 19.1 (CH₃). IR (ATR-FTIR) (cm⁻¹): 2995 (m), 2359 (m), 1370 (m), 1171 (m), 1096 (s). HRMS-ESI (m/z): [M + H]⁺ calcd for [C₁₆H₂₃O₄S]⁺, 311.1317; found, 311.1312.

Synthesis of the Disaccharide 29β.

A solution of lithium di-tert-butylbiphenylide in tetrahydrofuran (nominally 0.4 M) was added dropwise via a syringe to a solution of the alcohol 28 (34.8 mg, 112 μmol, 2.00 equiv) in tetrahydrofuran–pentane (1:1 v/v, 1.40 mL) in a 10 mL round-bottomed flask that had been fused to a Teflon-coated valve at −78 °C. The addition of lithium di-tert-butylbiphenylide was continued until a green color persisted (575 μL, nominally 230 μmol, 4.10 equiv). The resulting mixture was stirred for 10 min at −78 °C. The reaction vessel was then placed in a bath that had been precooled to −20 °C. The reaction mixture was stirred for 1 h at −20 °C and then cooled to −78 °C over 10 min. A solution of the MTHP monoperoxy acetal 11 (21.0 mg, 56.1 μmol, 1 equiv) in tetrahydrofuran (300 μL) was then added dropwise via a syringe. The reaction vessel was then placed in a cryogenic bath that had been precooled to −65 °C. The mixture was stirred for 6 h at −65 °C. The cold product mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (3.0 mL). The diluted product mixture was allowed to warm to 23 °C over 15 min. The warmed product mixture was transferred to a 20 mL test tube and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (4 × 5.0 mL). The organic layers were combined and the combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated under a stream of nitrogen. The residue obtained was purified by flash-column chromatography (eluting with 10% ethyl acetate–dichloromethane, initially, grading to 30% ethyl acetate–dichloromethane, three steps) to provide the disaccharide 29β as colorless oil (17.0 mg, 66%).

The diastereoselectivity of the reaction was determined to be >50:1 β/α by ¹H NMR analysis of the unpurified product mixture.

R_f = 0.73 (50% ethyl acetate–dichloromethane; CAM). ¹H NMR (400 MHz, C₆D₆): δ 5.55 (d, J = 5.0 Hz, 1H, H_1′), 4.45 (dd, J = 8.0, 2.3 Hz, 1H, H_3′), 4.38 (dd, J = 9.8, 2.2 Hz, 1H, H₁), 4.27 (dd, J = 10.6, 4.2 Hz, 1H, H_6′), 4.22–4.15 (m, 2H, H_2′, H_5′), 3.97–3.89 (m, 2H, H_4′, H_6′), 3.85 (dd, J = 10.6, 5.3 Hz, 1H, H₆), 3.70 (t, J = 10.5 Hz, 1H, H₆), 3.60 (t, J = 9.1 Hz, 1H, H₄), 3.22 (s, 3H, OCH₃), 3.13 (ddd, J = 11.2, 8.7, 5.1 Hz, 1H, H₃), 3.03 (td, J = 9.9, 5.3 Hz, 1H, H₅), 2.25 (ddd, J = 12.8, 5.1, 2.2 Hz, 1H, H₂), 1.73 (ddd, J = 12.8, 11.2, 9.8 Hz, 1H, H₂), 1.46 (s, 3H, CH₃), 1.44 (s, 6H, 2 × CH₃), 1.22 (s, 3H, CH₃), 1.11 (s, 3H, CH₃), 1.04 (s, 3H, CH₃). ¹³C{¹H} NMR (101 MHz, C₆D₆): δ 109.2 (C), 108.4 (C), 101.3 (CH), 99.5 (C), 96.9 (CH), 77.5 (CH), 75.8 (CH), 71.7 (CH), 71.2 (CH), 71.0 (CH), 69.3 (CH₂), 68.2 (CH), 68.0 (CH), 62.8 (CH₂), 57.5 (CH₃), 37.6 (CH₂), 29.6 (CH₃), 26.3 (CH₃), 26.3 (CH₃), 24.9 (CH₃), 24.3 (CH₃), 19.0 (CH₃). IR (ATR-FTIR) (cm⁻¹): 2982 (m), 2365 (m), 1382 (m), 1261 (m), 1085 (s). HRMS-ESI (m/z): [M + Na]⁺ calcd for [C₂₂H₃₆O₁₀Na]⁺, 483.2206; found, 483.2201. ${\left[\alpha \right]}_{\text{D}}^{21}-84.2$ (c 0.9, CHCl₃).

Synthesis of the Disaccharide 37α.

A solution of methyllithium in diethyl ether (1.34 M, 132 μL, 176 μmol, 3.00 equiv) was added dropwise via a syringe to a solution of the alcohol 33 (21.2 mg, 88.2 μmol, 1.50 equiv) in tetrahydrofuran (1.4 mL) in a 10 mL round-bottomed flask that had been fused to a Teflon-coated valve at −78 °C. The resulting mixture was stirred for 30 min at −78 °C. A solution of lithium di-tert-butylbiphenylide in tetrahydrofuran (nominally 0.4 M) was then added dropwise via a syringe. The addition of lithium di-tert-butylbiphenylide was continued until a green color persisted (456 μL, nominally 182 μmol, 3.10 equiv). The resulting mixture was stirred for 10 min at −78 °C. A solution of the MTHP monoperoxy acetal 11 (22.0 mg, 58.8 μmol, 1 equiv) in tetrahydrofuran (300 μL) was then added dropwise via a syringe. The resulting mixture was stirred for 3 h at −78 °C. The cold product mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (3.0 mL). The diluted product mixture was allowed to warm to 23 °C over 15 min. The warmed product mixture was transferred to a 20 mL test tube and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (4 × 5.0 mL). The organic layers were combined and the combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated under a stream of nitrogen. The residue obtained was purified by flash-column chromatography (eluting with 5% methanol–dichloromethane) to provide the disaccharide 37α as colorless oil (10.0 mg, 44%).

The diastereoselectivity of the reaction was determined to be >50:1 α/β by ¹H NMR analysis of the unpurified product mixture.

R_f = 0.24 (5% methanol–dichloromethane; CAM). ¹H NMR (600 MHz, CDCl₃): δ 5.54 (d, J = 5.0 Hz, 1H, H_1′), 4.91 (d, J = 3.5 Hz, 1H, H₁), 4.60 (dd, J = 7.9, 2.4 Hz, 1H, H_3′), 4.31 (dd, J = 5.0, 2.4 Hz, 1H, H_2′), 4.24 (dd, J = 7.9, 1.9 Hz, 1H, H_4′), 3.97–3.89 (m, 2H, H₃, H_5′), 3.81 (dd, J = 10.2, 5.8 Hz, 1H, H_6′), 3.72 (dq, J = 9.0, 6.2 Hz, 1H, H₅), 3.55 (dd, J = 10.2, 6.9 Hz, 1H, H_6′), 3.12 (t, J = 9.1 Hz, 1H, H₄), 2.19 (dd, J = 12.9, 5.2 Hz, 2H, H₂, OH), 2.02 (s, 1H, OH), 1.68 (td, J = 12.3, 3.7 Hz, 1H, H₂), 1.54 (s, 3H, CH₃), 1.44 (s, 3H, CH₃), 1.34 (s, 6H, 2 × CH₃), 1.28 (d, J = 6.3 Hz, 3H, H₆). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 109.4 (C), 108.7 (C), 97.5 (CH), 96.4 (CH), 78.2 (CH), 71.3 (CH), 70.8 (CH), 70.7 (CH), 69.5 (CH), 67.7 (CH), 67.1 (CH), 65.6 (CH₂), 37.8 (CH₂), 26.3 (CH₃), 26.1 (CH₃), 25.1 (CH₃), 24.6 (CH₃), 17.7 (CH₃). IR (ATR-FTIR) (cm⁻¹): 3441 (br, m), 2989 (m), 2936 (m), 2360 (m), 1372 (m), 1071 (s). HRMS-ESI (m/z): [M + H]⁺ calcd for [C₁₈H₃₁O₉]⁺, 391.1968; found, 391.1963. ${\left[\alpha \right]}_{\text{D}}^{21}-120.7$ (c 0.1, CHCl₃).

Synthesis of the Disaccharide 37β.

A solution of methyllithium in diethyl ether (1.34 M, 167 μL, 224 μmol, 4.00 equiv) was added dropwise via a syringe to a solution of the alcohol 33 (27.0 mg, 112 μmol, 2.00 equiv) in tetrahydrofuran (1.4 mL) in a 10 mL round-bottomed flask that had been fused to a Teflon-coated valve at −78 °C. The resulting mixture was stirred for 30 min at −78 °C. A solution of lithium di-tert-butylbiphenylide in tetrahydrofuran (nominally 0.4 M) was then added dropwise via a syringe. The addition of lithium di-tert-butylbiphenylide was continued until a green color persisted (575 μL, nominally 230 μmol, 4.10 equiv). The resulting mixture was stirred for 10 min at −78 °C. The reaction vessel was then placed in a bath that had been precooled to −20 °C. The reaction mixture was stirred for 1 h at −20 °C and then cooled to −78 °C over 10 min. A solution of the MTHP monoperoxy acetal 11 (21.0 mg, 56.1 μmol, 1 equiv) in tetrahydrofuran (300 μL) was then added dropwise via a syringe. The reaction vessel was then placed in a cryogenic bath that had been precooled to −65 °C. The mixture was stirred for 6 h at −65 °C. The cold product mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (3.0 mL). The diluted product mixture was allowed to warm to 23 °C over 15 min. The warmed product mixture was transferred to a 20 mL test tube and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (4 × 5.0 mL). The organic layers were combined and the combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated under a stream of nitrogen. The residue obtained was purified by flash-column chromatography (eluting with 5% methanol–dichloromethane) to provide the disaccharide 37β as colorless oil (1.7 mg, 8%).

The diastereoselectivity of the reaction was determined to be 7:1 β/α by ¹H NMR analysis of the unpurified product mixture.

R_f = 0.60 (10% methanol–dichloromethane; CAM). ¹H NMR (500 MHz, CDCl₃): δ 5.51 (d, J = 5.0 Hz, 1H, H_1′), 4.61 (dd, J = 8.0, 2.4 Hz, 1H, H_3′), 4.55 (dd, J = 9.6, 2.0 Hz, 1H, H₁), 4.33–4.29 (m, 2H, H_2′, H_4′), 4.03 (ddd, J = 8.1, 5.9, 1.9 Hz, 1H, H_5′), 3.88 (dd, J = 10.2, 5.9 Hz, 1H, H_6′), 3.77 (dd, J = 10.1, 8.2 Hz, 1H, H_6′), 3.60 (ddt, J = 12.6, 8.7, 4.3 Hz, 1H, H₃), 3.28 (dq, J = 9.0, 6.1 Hz, 1H, H₅), 3.10 (td, J = 8.9, 3.2 Hz, 1H, H₄), 2.26 (ddd, J = 12.5, 5.0, 2.0 Hz, 1H, H₂), 2.14 (s, 1H, OH), 2.4 (d, J = 4.4 Hz, 1H, OH), 1.64 (td, J = 12.3, 10.1 Hz, 1H, H₂), 1.53 (s, 3H, CH₃), 1.45 (s, 3H, CH₃), 1.35 (s, 3H, CH₃), 1.34–1.31 (m, 6H, H₆, CH₃). ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 109.3 (C), 108.7 (C), 100.3, (CH), 96.5 (CH), 77.8 (CH), 71.9 (CH), 71.8 (CH), 70.9 (2 × CH), 70.7 (CH), 67.8 (CH₂), 66.1 (CH), 39.1 (CH₂), 26.3 (CH₃), 26.1 (CH₃), 25.1 (CH₃), 24.7 (CH₃), 17.8 (CH₃). IR (ATR-FTIR) (cm⁻¹): 3370 (br, m), 2923 (m), 2360 (m), 1380 (m), 1212 (m), 1070 (s). HRMS-ESI (m/z): [M + H]⁺ calcd for [C₁₈H₃₁O₉]⁺, 391.1968; found, 391.1963. ${\left[\alpha \right]}_{\text{D}}^{21}-23.5$ (c 0.1, CHCl₃).

Synthesis of the Disaccharide 38α.

A solution of methyllithium in diethyl ether (1.30 M, 168 μL, 218 μmol, 4.00 equiv) was added dropwise via a syringe to a solution of the alcohol 33 (26.1 mg, 109 μmol, 2.00 equiv) in tetrahydrofuran (1.4 mL) in a 10 mL round-bottomed flask that had been fused to a Teflon-coated valve at −78 °C. The resulting mixture was stirred for 30 min at −78 °C. A solution of lithium di-tert-butylbiphenylide in tetrahydrofuran (nominally 0.4 M) was then added dropwise via a syringe. The addition of lithium di-tert-butylbiphenylide was continued until a green color persisted (557 μL, nominally 223 μmol, 4.10 equiv). The resulting mixture was stirred for 10 min at −78 °C. A solution of the MTHP monoperoxy acetal 12α (20.0 mg, 54.3 μmol, 1 equiv) in tetrahydrofuran (300 μL) was then added dropwise via a syringe. The resulting mixture was stirred for 3 h at −78 °C. The cold product mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (3.0 mL). The diluted product mixture was allowed to warm to 23 °C over 15 min. The warmed product mixture was transferred to a 20 mL test tube and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (4 × 5.0 mL). The organic layers were combined and the combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated under a stream of nitrogen. The residue obtained was purified by flash-column chromatography (eluting with 5% methanol–ethyl acetate) to provide the disaccharide 38α as a white solid (10.0 mg, 48%).

The diastereoselectivity of the reaction was determined to be >50:1 α/β by ¹H NMR analysis of the unpurified product mixture.

R_f = 0.56 (5% methanol–ethyl acetate; UV, CAM). ¹H NMR (400 MHz, CDCl₃): δ 7.48–7.41 (m, 2H, Ar), 7.30 (t, J = 7.4 Hz, 2H, Ar), 7.23 (d, J = 7.2 Hz, 1H, Ar), 5.59 (dd, J = 5.6, 1.6 Hz, 1H, H_1′), 4.97 (d, J = 3.7 Hz, 1H, H₁), 4.17 (dq, J = 9.1, 6.4 Hz, 1H, H_5′), 4.01–3.90 (m, 2H, H₃, H₅), 3.51 (ddd, J = 11.2, 8.5, 4.8 Hz, 1H, H_3′), 3.37 (s, 3H, OCH₃), 3.21 (t, J = 9.0 Hz, 1H, H_4′), 3.14 (t, J = 9.3 Hz, 1H, H₄), 2.50 (ddd, J = 13.6, 4.9, 1.7 Hz, 1H, H_2′), 2.24–2.12 (m, 3H, 2 × OH, H₂), 1.97 (ddd, J = 13.5, 11.2, 5.8 Hz, 1H, H_2′), 1.72 (td, J = 12.4, 4.0 Hz, 1H, H₂), 1.29 (d, J = 6.3 Hz, 3H, H₆), 1.25 (d, J = 6.3 Hz, 3H, H_6′). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 135.1 (C), 131.0 (2 × CH), 128.9 (2 × CH), 127.0 (CH), 98.5 (CH), 83.5 (CH), 82.3 (CH), 78.1 (CH), 77.1 (CH), 69.3 (CH), 68.4 (CH), 67.8 (CH), 56.3 (CH₃), 38.0 (CH₂), 35.2 (CH₂), 18.0 (CH₃), 17.3 (CH₃). IR (ATR-FTIR) (cm⁻¹): 3329 (br, m), 2974 (m), 2355 (w), 1479 (m), 1121 (m), 1071 (s). HRMS-ESI (m/z): [M + Na]⁺ calcd for [C₁₉H₂₈O₆SNa]⁺, 407.1504; found, 407.1499. ${\left[\alpha \right]}_{\text{D}}^{21}+124.9$ (c 0.3, CHCl₃).

Synthesis of the Disaccharide 39α.

A solution of methyllithium in diethyl ether (1.30 M, 247 μL, 320 μmol, 6.00 equiv) was added dropwise via a syringe to a solution of the alcohol 34 (27.4 mg, 107 μmol, 2.00 equiv) in tetrahydrofuran (1.4 mL) in a 10 mL round-bottomed flask that had been fused to a Teflon-coated valve at −78 °C. The resulting mixture was stirred for 30 min at −78 °C. A solution of lithium di-tert-butylbiphenylide in tetrahydrofuran (nominally 0.4 M) was then added dropwise via a syringe. The addition of lithium di-tert-butylbiphenylide was continued until a green color persisted (547 μL, nominally 219 μmol, 4.10 equiv). The resulting mixture was stirred for 10 min at −78 °C. A solution of the MTHP monoperoxy acetal 11 (20.0 mg, 53.4 μmol, 1 equiv) in tetrahydrofuran (300 μL) was then added dropwise via a syringe. The resulting mixture was stirred for 3 h at −78 °C. The cold product mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (3.0 mL). The diluted product mixture was allowed to warm to 23 °C over 15 min. The warmed product mixture was transferred to a 20 mL test tube and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (4 × 5.0 mL). The organic layers were combined and the combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated under a stream of nitrogen. The residue obtained was purified by flash-column chromatography (eluting with 5% methanol–ethyl acetate) to provide the disaccharide 39α as colorless oil (9.1 mg, 42%).

The diastereoselectivity of the reaction was determined to be >50:1 α/β by ¹H NMR analysis of the unpurified product mixture.

R_f = 0.23 (5% methanol–ethyl acetate; CAM). ¹H NMR (600 MHz, CDCl₃): δ 5.52 (d, J = 5.0 Hz, 1H, H_1′), 5.02 (d, J = 3.5 Hz, 1H, H₁), 4.61 (dd, J = 7.9, 2.5 Hz, 1H, H_3′), 4.31 (dd, J = 5.0, 2.5 Hz, 1H, H_2′), 4.23 (dd, J = 7.9, 2.0 Hz, 1H, H_4′), 4.04 (dq, J = 10.6, 4.8, 3.5 Hz, 1H, H₃), 3.98–3.86 (m, 5H, H₄, H₅, H₆, H_5′), 3.76 (dd, J = 10.7, 7.1 Hz, 1H, H_6′), 3.69 (dd, J = 10.8, 5.3 Hz, 1H, H_6′), 2.86 (d, J = 3.6 Hz, 1H, OH), 2.25 (d, J = 6.3 Hz, 1H, OH), 2.04 (d, J = 8.2 Hz, 1H, OH), 1.99–1.85 (m, 2H, H₂), 1.53 (s, 3H, CH₃), 1.44 (s, 3H, CH₃), 1.33 (s, 6H, 2 × CH₃). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 109.6 (C), 108.8 (C), 97.9 (CH), 96.5 (CH), 71.4 (CH), 70.8 (CH), 70.7 (CH), 70.2 (CH), 69.3 (CH), 66.8 (CH), 66.7 (CH₂), 65.7 (CH), 64.4 (CH₂), 33.2 (CH₂), 26.2 (CH₃), 26.1 (CH₃), 25.1 (CH₃), 24.6 (CH₃). IR (ATR-FTIR) (cm⁻¹): 3427 (br, m), 2925 (m), 2362 (m), 1382 (m), 1070 (s), 1001 (s). HRMS-ESI (m/z): [M + H]⁺ calcd for [C₁₈H₃₁O₁₀]⁺, 407.1917; found, 407.1912. ${\left[\alpha \right]}_{\text{D}}^{21}+6.7$ (c 0.3, CHCl₃).

Synthesis of the Trisaccharide 40.

A solution of methyllithium in diethyl ether (1.34 M, 81.0 μL, 109 μmol, 2.00 equiv) was added dropwise via a syringe to a solution of the alcohol 3α (24.4 mg, 109 μmol, 2.00 equiv) in tetrahydrofuran–pentane (1:1 v/v, 1.4 mL) in a 10 mL round-bottomed flask that had been fused to a Teflon-coated valve at −78 °C. The resulting mixture was stirred for 30 min at −78 °C. A solution of lithium di-tert-butylbiphenylide in tetrahydrofuran (nominally 0.4 M) was added dropwise via a syringe. The addition of lithium di-tert-butylbiphenylide was continued until a green color persisted (557 μL, nominally 223 μmol, 4.10 equiv). The resulting mixture was stirred for 10 min at −78 °C. A solution of the MTHP monoperoxy acetal 12α (20.0 mg, 54.3 μmol, 1 equiv) in tetrahydrofuran (300 μL) was then added dropwise via a syringe. The resulting mixture was stirred for 3 h at −78 °C. A solution of lithium di-tert-butylbiphenylide in tetrahydrofuran (nominally 0.4 M) was added dropwise via a syringe to the resulting mixture. The addition of lithium di-tert-butylbiphenylide was continued until a green color persisted (285 μL, nominally 114 μmol, 2.10 equiv). The resulting mixture was stirred for 10 min at −78 °C. A solution of the MTHP monoperoxy acetal 11 (40.7 mg, 109 μmol, 2.00 equiv) in tetrahydrofuran (300 μL) was then added dropwise via a syringe. The resulting mixture was stirred for 6 h at −78 °C. The cold product mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (3.0 mL). The diluted product mixture was allowed to warm to 23 °C over 15 min. The warmed product mixture was transferred to a 20 mL test tube and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (4 × 5.0 mL). The organic layers were combined and the combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated under a stream of nitrogen. The residue obtained was purified by flash-column chromatography (eluting with 15% ethyl acetate–dichloromethane initially, grading to 45% ethyl acetate–dichloromethane, three steps) to provide the trisaccharide 40 as colorless oil (10.2 mg, 36%).

The product of the reaction was determined to be a single diastereomer (α,α) by ¹H NMR analysis of the unpurified product mixture.

R_f = 0.17 (40% ethyl acetate–hexanes; CAM). ¹H NMR (600 MHz, CDCl₃): δ 5.53 (d, J = 5.0 Hz, 1H, H_1″), 5.28 (d, J = 2.9 Hz, 1H, H₁), 4.91 (d, J = 3.6 Hz, 1H, H_1′), 4.62 (dd, J = 7.9, 2.5 Hz, 1H, H_3″), 4.32 (dd, J = 5.0, 2.4 Hz, 1H, H_2″), 4.25 (dd, J = 7.9, 2.0 Hz, 1H, H_4″), 4.07–4.1 (m, 1H, H₅), 3.97 (td, J = 6.8, 2.0 Hz, 1H, H_5″), 3.75–3.63 (m, 3H, H_5′, H_6″), 3.61–3.55 (m, 2H, H₄, H_3′), 3.33 (s, 3H, OCH₃), 3.26 (t, J = 9.1 Hz, 1H, H_4′), 2.27 (ddd, J = 13.1, 5.0, 1.5 Hz, 1H, H_2′), 1.97–1.93 (m, 2H, H₂, H₃), 1.75 (dt, J = 9.8, 3.5 Hz, 1H, H₃), 1.60–1.57 (m, 1H, H₂), 1.55 (s, 4H, H_2′, CH₃), 1.44 (s, 3H, CH₃), 1.35 (s, 3H, CH₃), 1.34 (s, 3H, CH₃), 1.28 (d, J = 6.2 Hz, 3H, H_6′), 1.16 (d, J = 6.6 Hz, 3H, H₆). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 109.5 (C), 108.7 (C), 98.2 (CH), 97.1 (CH), 96.5 (CH), 80.5 (CH), 79.4 (CH), 71.2 (CH), 70.8 (2 × CH), 67.7 (CH), 67.0 (CH), 66.7 (CH), 65.8 (CH), 65.5 (CH₂), 56.6 (CH₃), 34.7 (CH₂), 26.3 (CH₃), 26.1 (CH₃), 25.9 (CH₂), 25.1 (CH₃), 24.7 (CH₃), 23.8 (CH₂), 18.6 (CH₃), 17.2 (CH₃). IR (ATR-FTIR) (cm⁻¹): 3479 (br, w), 2979 (m), 2360 (m), 1444 (w), 1382 (m), 1210 (m), 1070 (s). HRMS-ESI (m/z): [M + H]⁺ calcd for [C₃₁H₅₃O₁₅]⁺, 665.3384; found, 665.3379. ${\left[\alpha \right]}_{\text{D}}^{21}+30.8$ (c 0.7, CHCl₃).

Synthesis of the Trisaccharide 41.

A solution of methyllithium in diethyl ether (1.34 M, 81.0 μL, 109 μmol, 2.00 equiv) was added dropwise via a syringe to a solution of the alcohol 6 (32.2 mg, 109 μmol, 2.00 equiv) in tetrahydrofuran–pentane (1:1 v/v, 1.4 mL) in a 10 mL round-bottomed flask that had been fused to a Teflon-coated valve at −78 °C. The resulting mixture was stirred for 30 min at −78 °C. A solution of lithium di-tert-butylbiphenylide in tetrahydrofuran (nominally 0.4 M) was added dropwise via a syringe. The addition of lithium di-tert-butylbiphenylide was continued until a green color persisted (557 μL, nominally 223 μmol, 4.10 equiv). The resulting mixture was stirred for 10 min at −78 °C. A solution of the MTHP monoperoxy acetal 12α (20.0 mg, 54.3 μmol, 1 equiv) in tetrahydrofuran (300 μL) was then added dropwise via a syringe. The resulting mixture was stirred for 3 h at −78 °C. A solution of lithium di-tert-butylbiphenylide in tetrahydrofuran (nominally 0.4 M) was added dropwise via a syringe to the resulting mixture. The addition of lithium di-tert-butylbiphenylide was continued until a green color persisted (285 μL, nominally 114 μmol, 2.10 equiv). The resulting mixture was stirred for 10 min at −78 °C. A solution of the MTHP monoperoxy acetal 11 (40.7 mg, 109 μmol, 2.00 equiv) in tetrahydrofuran (300 μL) was then added dropwise via a syringe. The resulting mixture was stirred for 6 h at −78 °C. The cold product mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (3.0 mL). The diluted product mixture was allowed to warm to 23 °C over 15 min. The warmed product mixture was transferred to a 20 mL test tube and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (4 × 5.0 mL). The organic layers were combined and the combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated under a stream of nitrogen. The residue obtained was purified by flash-column chromatography (eluting with 15% ethyl acetate–hexanes initially, grading to 45% ethyl acetate–hexanes, three steps) to provide the trisaccharide 41 as colorless oil (16.6 mg, 52%).

The product of the reaction was determined to be a single diastereomer (α,α) by ¹H NMR analysis of the unpurified product mixture.

R_f = 0.36 (60% ethyl acetate–hexanes; CAM). ¹H NMR (600 MHz, C₆D₆): δ 5.56–5.50 (m, 2H, H₁, H_1″), 4.85 (d, J = 3.6 Hz, 1H, H_1′), 4.54 (dd, J = 7.9, 2.4 Hz, 1H, H_3″), 4.26 (td, J = 6.7, 2.0 Hz, 1H, H_5″), 4.22–4.15 (m, 3H, H₃, H_2″, H_4″), 4.05 (dd, J = 10.2, 6.4 Hz, 1H, H_6″), 3.98 (td, J = 10.1, 5.3 Hz, 1H, H₅), 3.93–3.88 (m, 2H, H₆, H_5′), 3.85 (dd, J = 10.2, 6.9 Hz, 1H, H_6″), 3.75–3.68 (m, 2H, H₆, H_3′), 3.52 (t, J = 9.3 Hz, 1H, H₄), 3.33 (t, J = 9.1 Hz, 1H, H_4′), 2.93 (s, 3H, OCH₃), 2.41 (dd, J = 13.2, 5.1 Hz, 1H, H₂), 2.17–2.12 (m, 2H, OH, H_2′), 1.83 (ddd, J = 13.0, 11.4, 4.2 Hz, 1H, H₂), 1.48 (s, 3H, CH₃), 1.47 (s, 3H, CH₃), 1.44 (s, 3H, CH₃), 1.33 (d, J = 6.4 Hz, 4H, H_2′, H_6′), 1.27 (s, 3H, CH₃), 1.17 (s, 3H, CH₃), 1.03 (s, 3H, CH₃). ¹³C{¹H} NMR (151 MHz, C₆D₆): δ 109.4 (C), 108.4 (C), 99.9 (C), 99.8 (CH), 97.7 (CH), 96.9 (CH), 82.4 (CH), 79.5 (CH), 77.2 (CH), 71.7 (CH), 71.4 (CH), 71.1 (CH), 67.1 (CH), 66.9 (CH), 66.6 (CH), 66.5 (CH₂), 64.8 (CH), 62.6 (CH₂), 55.9 (CH₃), 38.5 (CH₂), 34.9 (CH₂), 29.6 (CH₃), 26.3 (2 × CH₃), 24.8 (CH₃), 24.7 (CH₃), 19.2 (CH₃), 18.8 (CH₃). IR (ATR-FTIR) (cm⁻¹): 3459 (br, w), 2991 (m), 2362 (w), 1457 (w), 1382 (m), 1204 (s), 1071 (s). HRMS-ESI (m/z): [M + Na]⁺ calcd for [C₂₈H₄₆O₁₃Na]⁺, 613.2836; found, 613.2831. ${\left[\alpha \right]}_{\text{D}}^{21}+30.8$ (c 0.4, CHCl₃).

Synthesis of the Trisaccharide 42.

A solution of methyllithium in diethyl ether (1.30 M, 84.0 μL, 109 μmol, 2.00 equiv) was added dropwise via a syringe to a solution of the alcohol 9 (40.2 mg, 109 μmol, 2.00 equiv) in tetrahydrofuran–pentane (1:1 v/v, 1.4 mL) in a 10 mL round-bottomed flask that had been fused to a Teflon-coated valve at −78 °C. The resulting mixture was stirred for 30 min at −78 °C. A solution of lithium di-tert-butylbiphenylide in tetrahydrofuran (nominally 0.4 M) was added dropwise via a syringe. The addition of lithium di-tert-butylbiphenylide was continued until a green color persisted (557 μL, nominally 223 μmol, 4.10 equiv). The resulting mixture was stirred for 10 min at −78 °C. A solution of the MTHP monoperoxy acetal 12α (20.0 mg, 54.3 μmol, 1 equiv) in tetrahydrofuran (300 μL) was then added dropwise via a syringe. The resulting mixture was stirred for 3 h at −78 °C. A solution of lithium di-tert-butylbiphenylide in tetrahydrofuran (nominally 0.4 M) was added dropwise via a syringe to the resulting mixture. The addition of lithium di-tert-butylbiphenylide was continued until a green color persisted (285 μL, nominally 114 μmol, 2.10 equiv). The resulting mixture was stirred for 10 min at −78 °C. A solution of the MTHP monoperoxy acetal 11 (40.7 mg, 109 μmol, 2.00 equiv) in tetrahydrofuran (300 μL) was then added dropwise via a syringe. The resulting mixture was stirred for 6 h at −78 °C. The cold product mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (3.0 mL). The diluted product mixture was allowed to warm to 23 °C over 15 min. The warmed product mixture was transferred to a 20 mL test tube and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (4 × 5.0 mL). The organic layers were combined and the combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated under a stream of nitrogen. The residue obtained was purified by flash-column chromatography (eluting with 10% ethyl acetate–dichloromethane initially, grading to 30% ethyl acetate–dichloromethane, three steps) to provide the trisaccharide 42 as colorless oil (23.0 mg, 64%).

The product of the reaction was determined to be a single diastereomer (α,α) by ¹H NMR analysis of the unpurified product mixture.

R_f = 0.27 (30% ethyl acetate–dichloromethane; CAM). ¹H NMR (500 MHz, C₆D₆): δ 5.60 (d, J = 3.8 Hz, 1H, H₁), 5.51 (d, J = 5.1 Hz, 1H, H_1″), 4.88 (d, J = 3.5 Hz, 1H, H_1′), 4.53 (dd, J = 7.9, 2.4 Hz, 1H, H_3″), 4.43 (ddd, J = 12.2, 9.6, 4.6 Hz, 1H, H₃), 4.23 (td, J = 6.7, 1.9 Hz, 1H, H_5″), 4.19 (dd, J = 5.1, 2.4 Hz, 1H, H_2″), 4.14 (dd, J = 7.9, 2.0 Hz, 1H, H_4″), 4.07–3.97 (m, 2H, H₅, H_6″), 3.94–3.79 (m, 5H, H₄, H₆, H_5′, H_6″), 3.72 (ddd, J = 11.3, 8.8, 5.0 Hz, 1H, H_3′), 3.38 (t, J = 9.1 Hz, 1H, H_4′), 3.20 (s, 3H, OCH₃), 3.12 (s, 3H, OCH₃), 2.95 (s, 3H, OCH₃), 2.29 (dd, J = 12.5, 4.7 Hz, 1H, H₂), 2.16 (dd, J = 12.9, 5.0 Hz, 1H, H_2′), 2.00–1.89 (m, 2H, OH, H₂), 1.46 (s, 3H, CH₃), 1.43 (s, 3H, CH₃), 1.38 (s, 4H, H_2′, CH₃), 1.35 (s, 3H, CH₃), 1.30 (d, J = 6.2 Hz, 3H, H_6′), 1.16 (s, 3H, CH₃), 1.04 (s, 3H, CH₃). ¹³C{¹H} NMR (151 MHz, C₆D₆): δ 109.3 (C), 108.4 (C), 100.3 (C), 100.2 (C), 99.5 (CH), 97.7 (CH), 96.9 (CH), 81.8 (CH), 79.6 (CH), 71.7 (CH), 71.6 (CH), 71.3 (CH), 71.1 (CH), 68.9 (CH), 67.2 (CH), 66.5 (CH), 66.4 (CH₂), 65.3 (CH), 61.5 (CH₂), 55.9 (CH₃), 47.7 (2 × CH₃), 35.8 (CH₂), 35.0 (CH₂), 26.3 (CH₃), 26.3 (CH₃), 24.8 (CH₃), 24.6 (CH₃), 19.1 (CH₃), 18.2 (CH₃), 18.1 (CH₃). IR (ATR-FTIR) (cm⁻¹): 3508 (br, w), 2936 (m), 2362 (w), 1454 (w), 1382 (m). HRMS-ESI (m/z): [M + H]⁺ calcd for [C₃₁H₅₃O₁₅]⁺, 665.3384; found, 665.3379. ${\left[\alpha \right]}_{\text{D}}^{21}+127.0$ (c 1.0, CHCl₃).