Erosion of Stereochemical Control with Increasing Nucleophilicity: O-Glycosylation at the Diffusion Limit

Abstract

Nucleophilic substitution reactions of 2-deoxyglycosyl donors indicated that the reactivity of the oxygen nucleophile has a significant impact on stereoselectivity. Employing ethanol as the nucleophile resulted in a 1:1 (α:β) ratio of diastereomers under S_N1-like reaction conditions. Stereoselective formation of the 2-deoxy-α-O-glycoside was only observed when weaker nucleophiles, such as trifluoroethanol, were employed. The lack of stereoselectivity observed in reactions of common oxygen nucleophiles can be attributed to reaction rates of the stereochemistry-determining step that approach the diffusion limit. In this scenario, both faces of the prochiral oxocarbenium ion are subject to nucleophilic addition to afford a statistical mixture of diastereomeric products. Control experiments confirmed that all nucleophilic substitution reactions were performed under kinetic control.

Introduction

The development of new methods for the synthesis of carbohydrates has been particularly challenging because glycosylation reactions often proceed with low or unpredictable selectivity.¹ The problem of low selectivity has been especially difficult to surmount for the synthesis of 2-deoxysugars, which are common structures found in biologically active natural products.² Although the use of participating groups at C-2 and their later removal can lead to selective reactions, the direct synthesis of 2-deoxy-α-O-glycosides from 2-deoxyglycosyl donors is not generally stereoselective.³ We have observed that the corresponding reactions with carbon nucleophiles to form 2-deoxy-α-C-glycosides, however, occur with high selectivity under comparable S_N1-like conditions (Scheme 1).⁴ A similar situation holds for C-glycosylations of other glycosyl donors, such as glucose-,⁵ mannose-,⁶ and ribose-derived systems,⁷ where the C-glycosylation was selective, but the O-glycosylation was not.⁸ No explanation has been provided to reconcile the different selectivities observed with the two types of nucleophiles.

Scheme 1.

Nucleophilic Substitutions of 2-Deoxyglycoside 1

Our studies of the reactions of six-membered ring oxocarbenium ions with carbon nucleophiles of varying reactivity suggest a possible explanation.⁹ The stereoselectivities of these reactions are generally analyzed by considering stereoelectronic effects. In the absence of participating counterions,¹⁰ both faces of the prochiral oxocarbenium ion can be attacked by a nucleophile (Scheme 2). Nucleophilic addition along the stereoelectronically preferred trajectory would provide the α-product 4 in a chair conformation (Scheme 2, path a).^4b,11,12 As the nucleophile becomes more reactive, the rates of nucleophilic addition to the cationic intermediate increase and approach the diffusion limit.¹³ In this case, both paths a and b result in product formation, affording a statistical mixture of diastereomeric products. We recently provided evidence for this divergence between stereoelectronically controlled and diffusion-controlled diastereoselectivity in C-glycosylation reactions.⁹ Because of the similar nucleophilicity of alcohols¹⁴ and silyl enol ethers¹⁵ (C-nucleophiles that react with oxocarbenium ions at rates approaching the diffusion limit⁹), the reactions of alcohols should be comparably rapid.¹⁶ In this Article, we provide evidence that the low stereoselectivity of some O-glycosylation reactions are the result of reactions of oxocarbenium ion intermediates that approach the diffusion-controlled rate limit.

Scheme 2.

Modes of Addition to the 2-Deoxyglucose-Derived Oxocarbenium Ion 5

Results and Discussion

Details of the Experimental Approach

Details of the experimental approach deserve mention prior to discussing the results of nucleophilic substitution:

1. 2-Deoxythioglycosides and related monosubstituted model systems were chosen as substrates for this study. Our previous experience with these systems provided evidence that the reaction pathway (S_N1 versus S_N2) could be controlled with careful choice of leaving group and activation conditions.⁹

2. In all cases, anomeric sulfides were employed as the oxocarbenium ion precursors.¹⁷ N-Iodosuccinimide (NIS) was chosen as the thioglycoside activating agent. This combination of C-1 leaving group and activating agent provided results consistent with S_N1-like additions to intermediate oxocarbenium ions.^18,19 Where indicated, 2,6-di-tert-butyl-4-methylpyridine (DTBMP) was employed as an additive to prohibit the epimerization of the acid-labile O-glycosylation products. Rigorous control experiments were conducted to verify that product ratios were obtained under kinetic control (vide infra, eq 3, Table 2).

3. Ethanol served as a model nucleophile due to its small size, and because its nucleophilicity could be modified by incorporating electron-withdrawing halogen substituents.^14,20–23 Field inductive effect parameters (F) were used as a quantitative measurement of the electron-withdrawing ability of the halogen substituents on the alcohol nucleophiles.^24,25 As the F-value increased, the alcohol should be rendered less nucleophilic; competition experiments verified this hypothesis (vide infra, eq 4, Table 3).

4. Both CH₃CN and CH₂Cl₂ were employed as solvents. Comparable yields and stereochemical trends were observed in either solvent, but CH₃CN generally provided higher diastereoselectivities consistent with stereoelectronically controlled attack on an oxocarbenium ion intermediate.²⁶

5. Diastereomeric ratios were obtained by analysis of GC and ¹H NMR spectroscopy of the unpurified reaction mixtures. The product stereochemistry was determined by analysis of ¹H NMR coupling constants and NOE measurements of the purified products.

Table 2.

Effect of the Glycosyl Donor Protecting Group

entry	compound	R	R1	d.r. (α:β)a	yield (%)b
1	14	Bn	CF3	81:19	68
2	2	Bn	CH3	50:50	80
3	15	Ac	CF3	75:25	69
4	16	Ac	CH3	56:44	80

^aDetermined by ¹H NMR spectroscopy of the unpurified reaction mixture.

^bIsolated yield.

Table 3.

Competition Experiments Confirm the Relative Reactivities of the Alcohol Nucleophiles

entry	solvent	R1a	R2a	product ratio (R1:R2)
1	CH3CN	CH3	CF3	98:2 (11:6)
2	CH2Cl2	CH3	CF3	87:13 (11:6)
3	CH3CN	CH2F	CF3	97:3 (8:6)
4	CH3CN	CH3	CH2F	70:30 (11:8)

^a10 equiv of nucleophile.

^bDetermined by GC analysis of the unpurified reaction mixture.

Nucleophilic Substitution Reactions of 2-Deoxythioglycosides

Experiments using 2-deoxyglucosyl donor 1c and a range of oxygen nucleophiles demonstrated an erosion of stereoselectivity with increasing nucleophilicity (eq 1, Table 1). For example, substitution with the weakest nucleophile examined, trifluoroethanol,¹⁴ resulted in an 83:17 (α:β) mixture of products (Table 1, entry 1).²⁷ This stereochemical outcome is consistent with stereoelectronically controlled attack (Scheme 2, path a), and the selectivity compares to those observed for reactions of less reactive carbon nucleophiles (Scheme 1). Nucleophiles with fewer electron-withdrawing groups, which should be more nucleophilic,¹⁴ exhibit lower selectivity. The strongest nucleophile employed, ethanol,¹⁴ afforded the 2-deoxy-α-O-glycoside 11 in a 51:49 (α:β) mixture of diastereomers (Table 1, entry 6).²⁸ The same substitution reaction performed in CH₂Cl₂ resulted in a 52:48 (α:β) mixture of diastereomeric products, suggesting that both reactions proceed through a similar S_N1-like mechanism (vide infra). These results clearly indicate that the nucleophilicity of alcohols impacts the stereoselectivity of glycosylation reactions.²⁹

Table 1.

Effect of Nucleophile Strength on Substitution Reactions of 2-Deoxythioglycoside 1c

entry	compound	R	Fa	d.r. (α:β)b	yield (%)c
1	6	CF3	0.38	83:17	80
2	7	CF2H	0.29	67:33	78
3	8	CH2F	0.15	56:44	69
4	9	CH2Br	0.14	55:45	72
5	10	CH2Cl	0.13	56:44	72
6	11	CH3	0.00	51:49	82

^aField inductive effect parameter, see ref 24.

^bDetermined by GC and ¹H NMR spectroscopy of the unpurified reaction mixture.

^cIsolated yield.

(1)

Several factors were considered to explain the trend of decreasing selectivity with increasing reactivity. The mechanism for activation of thioglycoside 1c involves two types of intermediates. Activation of the sulfur atom occurs to form sulfonium ion A, followed by rate-determining ionization of A to form oxocarbenium ion B (Scheme 3).¹⁹ The low diastereoselectivities observed with strong nucleophiles could result from competitive S_N2-like pathways^9,10,30 involving displacement of the activated starting material A (Scheme 3)³¹ or analogous compounds, such as the glycosyl iodide.^30c,32 This explanation, however, does not explain the stereochemical data (eq 1, Table 1), because the β-substitution products expected from direct displacement reactions of thioglycoside 1c³⁰ are not the major products in any case observed. Direct displacement of an adduct with CH₃CN (a nitrilium ion), which has been invoked in other glycosylation reactions,³³ also does not satisfactorily explain the observed diastereoselectivities. First, the expected β-glycoside products arising from direct displacement of an α-nitrilium species³³ are not favored for any of the substrates examined. Second, invoking an intermediate nitrilium species does not account for the similar selectivity trends observed in CH₂Cl₂ as in CH₃CN. The loss of selectivity with increasing reactivity, however, is consistent with erosion of diastereoselectivity by an S_N1-like pathway involving oxocarbenium ion B (Scheme 3), which has been observed for C-nucleophiles.⁹

Scheme 3.

Reactive Intermediates Involved in Nucleophilic Substitutions

The stronger nucleophiles employed in the substitution reactions of 2-deoxyglycosyl donor 1c follow the level of stereocontrol observed in a common glycosylation reaction. Substitution using the glucose-derived nucleophile 13³⁴ afforded a 57:43 (α:β) mixture of products (12, eq 2), comparable to the diastereoselectivities observed for reactions of alcohols containing a single electron-withdrawing substituent (Table 1, entries 3–5).²³

(2)

Varying the protecting groups on the 2-deoxyglycosyl donor had a minimal effect on the stereoselectivity of nucleophilic substitution. In all cases, reactions of trifluoroethanol provided the highest level of stereocontrol favoring the stereoelectronically preferred α-product, while use of ethanol as the nucleophile resulted in a near statistical mixture of diastereomers (eq 3, Table 2). The relationship between nucleophilicity and stereoselectivity appears to be a general characteristic of O-glycosylation reactions under S_N1-like conditions.¹⁹

(3)

Competition experiments between select alcohol nucleophiles confirmed the relative reactivities of the ethanol derivatives. Nucleophilic substitution reactions of 2-deoxyglycosyl donor 1c were performed in the presence of an equimolar mixture of two nucleophiles of differing reactivity (eq 4, Table 3).³⁵ As expected, increasing the number of electron-withdrawing substituents on the alcohol resulted in a decrease of nucleophilicity. For example, a competition experiment performed in CH₃CN between ethanol and trifluoroethanol resulted in near complete incorporation of ethanol, reflecting the relative nucleophilicities of the two nucleophiles (Table 3, entry 1).^36,37 Similarly, a competition experiment between fluoroethanol and trifluoroethanol provided incorporation of the more nucleophilic alcohol with nearly complete chemoselectivity (Table 3, entry 3). These results confirm that the stereochemistry-determining step of the substitution reaction of trifluoroethanol with 2-deoxyglycosyl donor 1c occurs at a rate below the diffusion limit. Lastly, ethanol and fluoroethanol were subjected to a competition experiment in CH₃CN. This experiment afforded the ethanol adduct 11 as the major product, but with diminished chemoselectivity (Table 3, entry 4). This result is consistent with the hypothesis that both nucleophiles react at rates near the diffusion limit, in accord with the stereochemical data (eq 1, Table 1).

Comparison of the relative rates of reaction (k_EtOH/k_TFE) to the rates of nucleophilic addition to analogous oxocarbenium ion intermediates supports the transition to diffusion-limited diastereoselectivity with more nucleophilic alcohols. Additions of water to a propionaldehyde-derived oxocarbenium ion occur at rates of approximately 4 × 10⁸ M⁻¹s⁻¹, a rate at which diffusional processes begin to be important.^16a,38 The 50-fold decrease in reactivity of trifluoroethanol (Table 3, entry 1) would suggest that the rate of addition to the oxocarbenium ion intermediate is approximately 8 × 10⁶ M⁻¹s⁻¹, which is about one thousand-fold slower than the diffusion rate limit.

The competition experiment between ethanol and trifluoroethanol in CH₂Cl₂ resulted in lower chemoselectivity than the identical reaction performed in CH₃CN (Table 3, entry 2). This result can be explained by considering that the rate of addition of trifluoroethanol to oxocarbenium ion 5 (Scheme 2) approaches the diffusion rate limit in CH₂Cl₂.¹³ The dependence of chemoselectivity on solvent choice is consistent with the stereochemical data, in which stereoselectivity was greater in CH₃CN than in CH₂Cl₂. Increasing the polarity of the solvent results in the stabilization of the cationic intermediate, and subsequently reduces the rate of nucleophilic addition.²⁶ As the rate of nucleophilic addition is decreased from the diffusion limit regime, greater facial selectivity for the stereoelectronically preferred product would be observed.

(4)

Control experiments confirmed that the products derived from nucleophilic substitution of 2-deoxythioglycoside 1c were formed under kinetic control.^39,40 The presence or absence of epimerization could be tested by re-subjecting the products of nucleophilic substitution to the reaction conditions (eq 5, Table 4). For example, acetal 6 and tri-O-ethylthioglycoside 17 were subjected to difluoroethanol and N-iodosuccinimide in CH₃CN at −42 °C. Of the four possible products, only acetal 6 (which did not undergo epimerization) and nucleophilic substitution product 18 were observed (Table 4, entry 1). Increasing the temperature to 0 °C resulted in neither epimerization nor incorporation of difluoroethanol into acetal 6. At 25 °C, however, small amounts of epimerization of the trifluoroethanol addition product 6 was observed.⁴¹ Therefore, it was deemed critical to perform all nucleophilic substitution reactions at or below 0 °C. Following this model, control experiments were performed for each pyran system investigated; those results are provided as supporting information.

Table 4.

Control Experiments Confirm Kinetic Product Formation

entry	Temp (°C)	6 (α:β)a	18 (α:β)a	Incorporation Products (7, 19)
1	−42	61:39	58:42	none
2	0	62:38	59:41	none
3	25	71:29	59:41	none

^aDetermined by GC analysis of the unpurified reaction mixture.

(5)

Nucleophilic Substitution Reactions of Monosubstituted Tetrahydropyran Acetals

The inverse relationship between nucleophilicity and selectivity was also observed for the nucleophilic substitution reactions of monosubstituted tetrahydropyran acetals.¹⁷ In all cases examined, reactions of trifluoroethanol provided the highest level of stereocontrol, favoring the stereoelectronically preferred product, while use of ethanol as the nucleophile resulted in a 1:1 mixture of diastereomers. The major products of addition to each model system matched those products previously obtained with allyltrimethylsilane,⁴² which has a nucleophilicity parameter comparable to trifluoroethanol.^14,15

A graphical summary of the nucleophilic substitution data for the monosubstituted tetrahydropyran acetals is presented in Figure 1. Data for the nucleophilic substitution of 2-deoxythioglycosides (eq 1, Table 1) are included for comparison purposes. Clearly, the nucleophilicity-selectivity relationship is not restricted to highly oxygenated carbohydrate systems, but must be considered for any substitution reactions of acetals that proceed through oxocarbenium ion intermediates. Specific details concerning the origin of stereoselectivity (or lack thereof) of these nucleophilic substitutions provide additional insight into the trends depicted in Figure 1.⁴³

Figure 1.

Stereoselectivity (d.r.) vs. Nucleophilicity (F)²⁴ in Pyran Systems

The stereochemical trend observed upon nucleophilic substitution of the C5-benzyloxymethyl-substituted acetal 20 with various nucleophiles was consistent with reaction rates that approach the diffusion limit (eq 6, Table 5). Activation of acetal 20 occurred readily at −78 °C in CH₂Cl₂, and control experiments indicated that these conditions provided kinetic product ratios.^39,44 Formation of the favored 1,5-trans product (21–26) is consistent with stereoelectronically controlled addition to the lowest energy oxocarbenium ion conformer 27 (Scheme 4, path a).^4b At reaction rates below the diffusion limit, the minor 1,5-cis product arises from stereoelectronically controlled addition to the higher energy half-chair conformer 28 in which the C-5 substituent resides in a pseudo-axial orientation (Scheme 4, path c).^4b The erosion of stereoselectivity observed upon substitution with more reactive alcohols can be explained by considering the diffusion-controlled addition to oxocarbenium ions 27 and 28 through paths b and d.

Table 5.

Effect of Nucleophile Strength on Substitution Reactions of 5-CH₂OBn-Substituted Acetal 20

entry	compound	X	Fa	d.r. (trans:cis)b	yield (%)c
1	21	CF3	0.38	83:17	65
2	22	CF2H	0.29	74:26	79
3	23	CH2F	0.15	62:38	91
4	24	CH2Br	0.14	62:38	85
5	25	CH2Cl	0.13	65:35	85
6	26	CH3	0.00	49:51	81

^aField inductive effect parameter, see ref 24.

^bDetermined by GC and ¹H NMR spectroscopy of the unpurified reaction mixture.

^cIsolated yield.

Scheme 4.

Modes of Addition to the 5-CH₂OBn-Substituted Oxocarbenium Ions 27 and 28

(6)

Nucleophilic substitution reactions of the C4-benzyloxy-substituted acetal 29 proceeded under identical conditions to provide the expected stereochemical trend (eq 7, Table 6). As with the C5-benzyloxymethyl-substituted acetal model system (20), CH₂Cl₂ was employed as the solvent because it reliably provided kinetically derived diastereomeric ratios.^39,44 The low-energy oxocarbenium ion 36, in which the C4-benzyloxy substituent resides in the pseudo-axial position to maximize electrostatic stabilization of the cationic center,⁴² is shown in Scheme 4. Upon addition of trifluoroethanol, the major product 1,4-trans-30 arises from addition to the stereoelectronically favored face (Scheme 5, path a). The minor product 1,4-cis-30 arises from addition to the higher energy oxocarbenium ion 37 (path c) at rates below the diffusion limit. As nucleophilicity increases, reaction rates for addition to oxocarbenium ion 36 approach the diffusion rate limit. In this scenario, path b becomes a viable pathway for the formation of the 1,4-cis product. Therefore, the substitution reaction of ethanol results in a statistical mixture of products (35, Table 6, entry 6) arising from competing pathways a–d (Scheme 5).

Table 6.

Effect of Nucleophile Strength on Substitution Reactions of 4-OBn-Substituted Acetal 29

entry	compound	X	Fa	d.r. (trans:cis)b	yield (%)c
1	30	CF3	0.38	88:12	81
2	31	CF2H	0.29	82:18	68
3	32	CH2F	0.15	71:29	72
4	33	CH2Br	0.14	61:39	83
5	34	CH2Cl	0.13	67:33	79
6	35	CH3	0.00	51:49	70

^aField inductive effect parameter, see ref 24.

^bDetermined by GC and ¹H NMR spectroscopy of the unpurified reaction mixture.

^cIsolated yield.

Scheme 5.

Modes of Addition to the 4-OBn-Substituted Oxocarbenium Ions 36 and 37

(7)

In stark contrast, the C3-benzyloxy-substituted acetal 38 displayed no stereoselectivity in CH₂Cl₂ for any of the nucleophiles examined (eq 8). Substitution reactions employing both ethanol and trifluoroethanol as the nucleophile resulted in a 49:51 (cis:trans) ratio of diastereomers under conditions optimized for the C4- and C5-substituted acetals (20 and 29).^45,46

(8)

Performing the nucleophilic substitution reactions of C3-benzyloxy-substituted acetal 38 in CH₃CN, however, resulted in the stereochemical trend observed for other substrates (eq 9, Table 7).⁴⁷ The more polar solvent is expected to stabilize the oxocarbenium ions 41 and 42 (Scheme 6), thus decreasing their electrophilicities and lowering rates of nucleophilic addition from the diffusion-limit regime.²⁶ Of note, the nucleophilic substitution reaction of bromoethanol resulted in a data point that did not fit the expected trend (Table 7, entry 4). Because the destabilizing steric interactions encountered in the favored transition state are sensitive to nucleophile size,⁴² the unexpected erosion of selectivity may be the result of the size of the bromine atom as compared to the other halogen substituents.⁴⁸

Table 7.

Effect of Nucleophile Strength on Substitution Reactions of 3-OBn-Substituted Acetal 38

entry	compound	X	Fa	d.r. (cis:trans)b	yield (%)c
1	39	CF3	0.38	86:14	69
2	43	CF2H	0.29	84:16	68
3	44	CH2F	0.15	74:26	63
4	45	CH2Br	0.14	60:40	46
5	46	CH2Cl	0.13	75:25	64
6	40	CH3	0.00	52:48	89

^aField inductive effect parameter, see ref 24.

^bDetermined by GC and ¹H NMR spectroscopy of the unpurified reaction mixture.

^cIsolated yield.

Scheme 6.

Modes of Addition to the 3-OBn-Substituted Oxocarbenium Ion

(9)

Conclusion

The stereoselectivity of O-glycosylation reactions are significantly affected by the nucleophilicity of the glycosyl acceptor. Common oxygen nucleophiles, such as ethanol, result in diastereomeric mixtures of products, regardless of the glycosyl donor. Only upon the addition of weaker nucleophiles, such as trifluoroethanol, is stereoselectivity observed favoring the product of stereoelectronically controlled addition (Figure 1). In many cases, the complete lack of stereocontrol observed for nucleophilic substitution may be attributed to reaction rates of the stereochemistry-determining step at or near the diffusion limit.

Experimental Section

General Procedure for the Nucleophilic Substitution of Acetals 1c, 20, 29, 38

To a cooled (−78 °C or 0 °C) solution of the sulfide in CH₃CN or CH₂Cl₂ (0.10 M) was added a nucleophile (4.0 equiv) and then N-iodosuccinimide (2.0 equiv). 2,6-Di-tert-butyl-4-methylpyridine (2.0 equiv) was added, where indicated. After 1 h, the cooled solution was washed with 10% aqueous Na₂S₂O₃ (1 mL per mL of reaction volume), and the aqueous layer was extracted with two portions of Et₂O (2 mL per mL of reaction volume). The combined organic layers were dried over MgSO₄ and concentrated in vacuo. The unpurified product was analyzed by GC and ¹H NMR spectroscopy and then purified as indicated.

2-Deoxyglycoside trifluoroethanol substitution product α-6/β-6

The standard procedure for nucleophilic substitution of acetals was followed with thioglycoside 1c (0.050 g, 0.20 mmol), trifluoroethanol (0.058 mL, 0.80 mmol), and N-iodosuccinimide (0.090 g, 0.40 mmol) in CH₃CN at 0 °C. GC and ¹H NMR spectroscopic analysis of the unpurified product indicated a pair of diastereomers in a 83:17 (α:β) ratio. Purification by flash chromatography (3:1 pentane:Et₂O) afforded an inseparable mixture of diastereomers α-6/β-6 as a colorless oil (0.047 g, 81%): GC t_R(major) 8.4 min, t_R(minor) 8.7 min; [α]²²_D + 80.2 (c 1.12, CHCl₃); IR (thin film) 2934, 2830, 1468, 1267, 1067 cm⁻¹; HRMS (ESI) m/z calcd for C₁₁H₁₉F₃O₅Na (M + Na)⁺ 311.1082, found 311.1086. Anal. Calcd for C₁₁H₁₉F₃O₅: C, 45.83; H, 6.64. Found: C, 45.61; H, 6.66.

Major Isomer (α-6)

¹H NMR (500 MHz, CDCl₃) δ 5.01 (d, J = 3.4 Hz, 1H), 3.88 (m, 2H), 3.56–3.64 (m, 4H), 3.55 (s, 3H), 3.45 (s, 3H), 3.42 (s, 3H), 3.18 (t, J = 9.2 Hz, 1H), 2.31 (ddd, J = 13.3, 5.1, 1.2 Hz, 1H), 1.60 (ddd, J = 13.2, 11.4, 3.5 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 123.9 (q, J = 278.4 Hz), 98.1, 79.6, 78.1, 71.3, 71.1, 64.1 (q, J = 26.0 Hz), 60.57, 59.3, 57.5, 34.4.

Minor Isomer (β-6)

¹H NMR (500 MHz, CDCl₃, distinctive peaks) δ 4.55 (dd, J = 9.8, 1.8 Hz, 1H), 4.13 (dq, J = 12.6, 8.9 Hz, 2H), 3.54 (s, 3H), 3.43 (s, 3H), 3.30 (m, 2H), 3.13 (t, J = 9.2 Hz, 1H), 2.38 (dd, J = 12.7, 5.1, 2.1 Hz, 1H), 1.53 (td, J = 11.9, 9.7 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 123.8 (q, J = 278.4 Hz), 99.9, 80.6, 79.2, 75.2, 71.5, 65.5 (q, J = 34.7 Hz), 60.61, 59.4, 57.0, 35.5.

2-Deoxyglycoside difluoroethanol substitution product α-7/β-7

The standard procedure for nucleophilic substitution of acetals was followed with thioglycoside 1c (0.050 g, 0.20 mmol), difluoroethanol (0.050 mL, 0.80 mmol), and N-iodosuccinimide (0.090 g, 0.40 mmol) in CH₃CN at 0 °C. GC and ¹H NMR spectroscopic analysis of the unpurified product indicated a pair of diastereomers in a 66:34 (α:β) ratio. Purification by flash chromatography (3:1 pentane:Et₂O) afforded an inseparable mixture of diastereomers α-7/β-7 as a colorless oil (0.042 g, 78%): GC t_R(major) 9.7 min, t_R(minor) 9.9 min; [α]²²_D +58 (c 0.80, CHCl₃); IR (thin film) 2935, 2832, 1449, 1111 cm⁻¹; HRMS (ESI) m/z calcd for C₁₁H₂₀F₂O₅Na (M + Na)⁺ 293.1176, found 293.1169.

Major Isomer (α-7)

¹H NMR (500 MHz, CDCl₃) δ 5.89 (tt, J = 55.5, 4.1 Hz, 1H), 4.96 (d, J = 3.4 Hz, 1H), 3.76 (dtd, J = 15.0, 11.9, 3.7 Hz, 1H), 3.55–3.67 (m, 4H), 3.54 (s, 3H), 3.44 (s, 3H), 3.42 (s, 3H), 3.29 (m, 1H), 3.14 (m, 1H), 2.27 (ddd, J = 13.3, 5.1, 1.0 Hz, 1H), 1.58 (ddd, J = 13.3, 11.7, 3.7 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 114.2 (t, J = 241.1 Hz), 98.3, 79.7, 78.2, 71.2, 71.0, 66.5 (t, J = 28.0 Hz), 60.55, 59.3, 57.4, 34.6.

Minor Isomer (β-7)

¹H NMR (500 MHz, CDCl₃, distinctive peaks) δ 5.90 (m, 1H), 4.49 (dd, J = 9.7, 1.7 Hz, 1H), 3.99 (m, 1H), 3.53 (s, 3H), 3.43 (s, 3H), 3.41 (s, 3H), 2.35 (ddd, J = 12.7, 5.0, 1.8 Hz, 1H), 1.51 (td, J = 11.9, 9.7 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 114.4 (t, J = 240.7 Hz), 100.2, 80.8, 79.4, 75.1, 71.6, 68.1 (dd, J = 30.5, 26.4 Hz), 60.60, 59.4, 57.0, 35.7.

2-Deoxyglycoside fluoroethanol substitution product α-8/β-8

The standard procedure for nucleophilic substitution of acetals was followed with thioglycoside 1c (0.030 g, 0.12 mmol), fluoroethanol (0.028 mL, 0.48 mmol), and N-iodosuccinimide (0.054 g, 0.24 mmol) in CH₃CN at 0 °C. GC and ¹H NMR spectroscopic analysis of the unpurified product indicated a pair of diastereomers in a 56:44 (α:β) ratio. Purification by flash chromatography (3:1 pentane:Et₂O) afforded an inseparable mixture of diastereomers α-8/β-8 as a colorless oil (0.021 g, 69%): GC t_R(major) 10.4 min, t_R(minor) 10.6 min; [α]²²_D +41 (c 0.39, CHCl₃); IR (thin film) 2934, 2830, 1450, 1110 cm⁻¹; HRMS (ESI) m/z calcd for C₁₁H₂₁FO₅Na (M + Na)⁺ 275.1271, found 275.1266. Anal. Calcd for C₁₁H₂₁FO₅: C, 52.37; H, 8.39. Found: C, 52.38; H, 8.35.

Major Isomer (α-8)

¹H NMR (500 MHz, CDCl₃) δ 4.97 (d, J = 3.4 Hz, 1H), 4.49–4.61 (m, 2H), 3.81 (m, 2H), 3.56–3.66 (m, 4H), 3.55 (s, 3H), 3.45 (s, 3H), 3.41 (s, 3H), 3.17 (t, J = 9.2 Hz, 1H), 2.28 (dd, J = 12.8, 5.2 Hz, 1H), 1.58 (ddd, J = 13.1, 11.6, 3.7 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 97.7, 82.7 (d, J = 165.3 Hz), 79.9, 78.4, 71.4, 70.6, 66.3 (d, J = 19.9 Hz), 60.5, 59.2, 57.4, 34.8.

Minor Isomer (β-8)

¹H NMR (500 MHz, CDCl₃, distinctive peaks) δ 4.52–4.70 (m, 3H), 4.26 (m, 1H), 4.06 (dddd, J = 35.0, 12.1, 4.3, 2.6 Hz, 1H), 3.69 (m, 1H), 3.54 (s, 3H), 3.43 (s, 3H), 3.41 (s, 3H), 3.30 (m, 2H), 3.10 (t, J = 9.2 Hz, 1H), 2.81 (dtt, J = 21.0, 13.6, 7.5 Hz, 1H), 2.38 (ddd, J = 12.6, 5.1, 1.8 Hz, 1H), 1.52 (td, J = 12.0, 9.9 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 100.0, 82.9 (d, J = 165.8 Hz), 80.9, 79.6, 75.1, 71.7, 68.1 (d, J = 19.9 Hz), 60.6, 59.4, 56.9, 35.9.

2-Deoxyglycoside bromoethanol substitution product α-9/β-9

The standard procedure for nucleophilic substitution of acetals was followed with thioglycoside 1c (0.030 g, 0.12 mmol), bromoethanol (0.034 mL, 0.48 mmol), and N-iodosuccinimide (0.054 g, 0.24 mmol) in CH₃CN at 0 °C. GC and ¹H NMR spectroscopic analysis of the unpurified product indicated a pair of diastereomers in a 55:45 (α:β) ratio. Purification by flash chromatography (1:1 pentane:Et₂O) afforded an inseparable mixture of diastereomers α-9/β-9 as a colorless oil (0.028 g, 74%): GC t_R(major) 13.2 min, t_R(minor) 13.4 min; [α]²²_D +21.8 (c 0.805, CHCl₃); IR (thin film) 2932, 2830, 1459, 1113 cm⁻¹; HRMS (ESI) m/z calcd for C₁₁H₂₁BrO₅Na (M + Na)⁺ 335.0470, found 335.0464. Anal. Calcd for C₁₁H₂₁BrO₅: C, 42.19; H, 6.76. Found: C, 41.94; H, 6.60.

Major Isomer (α-9)

¹H NMR (500 MHz, CDCl₃) δ 4.98 (d, J = 3.4 Hz, 1H), 3.92 (dt, J = 11.6, 6.1 Hz, 1H), 3.76 (m, 2H), 3.55–3.70 (m, 3H), 3.55 (s, 3H), 3.48 (m, 2H), 3.45 (s, 3H), 3.42 (s, 3H), 3.17 (t, J = 9.4 Hz, 1H), 2.26 (ddd, J = 13.1, 5.1, 1.0 Hz, 1H), 1.57 (ddd, J = 13.1, 11.5, 3.7 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 97.8, 79.9, 78.4, 75.1, 70.9, 67.4, 60.5, 59.3, 57.4, 34.8, 30.6.

Minor Isomer (β-9)

¹H NMR (500 MHz, CDCl₃, distinctive peaks) δ 4.49 (dd, J = 9.7, 2.1 Hz, 1H), 4.33 (m, 1H), 4.17 (ddd, J = 11.6, 6.6, 5.3 Hz, 1H), 3.54 (s, 3H), 3.43 (s, 3H), 3.41 (s, 3H), 3.30 (m, 2H), 3.11 (t, J = 9.2 Hz, 1H), 2.82 (m, 1H), 2.35 (ddd, J = 12.6, 5.1, 2.0 Hz, 1H), 1.51 (td, J = 12.3, 9.9 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 100.1, 80.9, 79.5, 71.6, 71.3, 69.2, 60.6, 59.4, 57.0, 35.8, 30.4.

2-Deoxyglycoside chloroethanol substitution product α-10β-10

The standard procedure for nucleophilic substitution of acetals was followed with thioglycoside 1c (0.030 g, 0.12 mmol), chloroethanol (0.032 mL, 0.48 mmol), and N-iodosuccinimide (0.054 g, 0.24 mmol) in CH₃CN at 0 °C. GC and ¹H NMR spectroscopic analysis of the unpurified product indicated a pair of diastereomers in a 56:44 (α:β) ratio. Purification by flash chromatography (1:1 pentane:Et₂O) afforded an inseparable mixture of diastereomers α-10/β-10 as a colorless oil (0.023 g, 72%): GC t_R(major) 12.3 min, t_R(minor) 12.4 min; [α]²²_D +26.5 (c 0.900, CHCl₃); IR (thin film) 2933, 2831, 1448, 1112 cm⁻¹; HRMS (ESI) m/z calcd for C₁₁H₂₁ClO₅Na (M + Na)⁺ 291.0975, found 291.0975. Anal. Calcd for C₁₁H₂₁ClO₅: C, 49.16; H, 7.88. Found: C, 49.12; H, 7.77.

Major Isomer (α-10)

¹H NMR (500 MHz, CDCl₃) δ 4.97 (d, J = 3.4 Hz, 1H), 3.86 (m, 1H), 3.55–3.75 (m, 7H), 3.54 (s, 3H), 3.45 (s, 3H), 3.42 (s, 3H), 3.17 (t, J = 9.4 Hz, 1H), 2.26 (ddd, J = 13.1, 5.1, 1.1 Hz, 1H), 1.57 (ddd, J = 13.1, 11.5, 3.7 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 97.8, 79.9, 78.4, 71.4, 70.8, 67.5, 60.5, 59.3, 57.4, 43.0, 34.8.

Minor Isomer (β-10)

¹H NMR (500 MHz, CDCl₃, distinctive peaks) δ 4.49 (dd, J = 9.8, 1.8 Hz, 1H), 4.28 (m, 1H), 4.11 (dt, J = 10.8, 5.3 Hz, 1H), 3.54 (s, 3H), 3.43 (s, 3H), 3.41 (s, 3H), 3.30 (m, 2H), 3.10 (t, J = 9.0 Hz, 1H), 2.82 (m, 1H), 2.35 (ddd, J = 12.6, 5.1, 1.8 Hz, 1H), 1.51 (td, J = 12.5, 9.9 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 100.2, 80.9, 79.5, 75.1, 71.7, 69.3, 60.6, 59.4, 57.0, 42.8, 35.8.

2-Deoxyglycoside ethanol substitution product α-11/β-11

The standard procedure for nucleophilic substitution of acetals was followed with thioglycoside 1c (0.030 g, 0.12 mmol), ethanol (0.028 mL, 0.48 mmol), and N-iodosuccinimide (0.054 g, 0.24 mmol) in CH₃CN at 0 °C. GC and ¹H NMR spectroscopic analysis of the unpurified product indicated a pair of diastereomers in a 51:49 (α:β) ratio. Purification by flash chromatography (1:1 pentane:Et₂O) afforded an inseparable mixture of diastereomers α-11/β-11 as a colorless oil (0.023 g, 82%): GC t_R(major) 9.4 min, t_R(minor) 9.7 min; [α]²²_D +1.0 (c 0.43, CHCl₃); ¹H NMR (500 MHz, CDCl₃, mixture of anomers) δ 4.93 (d, J = 3.7 Hz, 1H), 4.44 (dd, J = 9.7, 1.8 Hz, 1H), 3.95 (dq, J = 9.3, 7.0 Hz, 1H), 3.55–3.70 (m, 9H), 3.55 (s, 3H), 3.54 (s, 3H), 3.45 (s, 3H), 3.42 (s, 3H), 3.41 (s, 6H), 3.30 (m, 2H), 3.16 (t, J = 9.2 Hz, 1H), 3.08 (t, J = 9.2 Hz, 1H), 2.30 (ddd, J = 12.5, 5.0, 1.8 Hz, 1H), 2.21 (dd, J = 12.8, 5.2 Hz, 1H), 1.52 (m, 2H), 1.21 (m, 6H); ¹³C NMR (125 MHz, CDCl₃, mixture of anomers) δ 99.6, 97.1, 81.1, 80.1, 79.7, 78.7, 75.1, 71.8, 71.5, 70.4, 64.7, 62.6, 60.6, 60.5, 59.4, 59.2, 57.3, 56.9, 36.1, 35.0, 15.13, 15.07; IR (thin film) 2932, 2830, 1446, 1113 cm⁻¹; HRMS (ESI) m/z calcd for C₁₁H₂₂O₅Na (M + Na)⁺ 257.1365, found 257.1361. Anal. Calcd for C₁₁H₂₂O₅: C, 56.39; H, 9.46. Found: C, 56.47; H, 9.56.

2-Deoxyglycoside 2,3,4-tri-O-benzyl-αα α-D-glucopyranoside substitution product α-12/β-12

The standard procedure for nucleophilic substitution of acetals was followed with thioglycoside 1c (0.010 g, 0.040 mmol), 2,3,4-tri-O-benzyl-α-D-glucopyranoside 13³⁴ (0.020 g, 0.044 mmol), N-iodosuccinimide (0.018 g, 0.080 mmol), and 2,6-di-tert-butyl-4-methylpyridine (0.017 g, 0.080 mmol) in CH₃CN at 0 °C. ¹H NMR spectroscopic analysis of the unpurified product indicated a pair of diastereomers in a 57:43 (α:β) ratio. Purification by flash chromatography (1:1 hexanes:EtOAc) afforded an inseparable mixture of diastereomers α-12/β-12 as a colorless oil (0.014 g, 52%): [α]²²_D +20 (c 0.47, CHCl₃); ¹³C NMR (125 MHz, CDCl₃, mixture of anomers) δ 138.8, 138.7, 138.5, 138.4, 138.21, 138.18, 128.54, 128.52, 128.51, 128.48, 128.47, 128.44, 128.2, 128.12, 128.07, 127.99, 127.98, 127.97, 127.8, 127.74, 127.70, 127.68, 127.66, 100.1, 98.03, 97.99, 97.9, 82.29, 82.26, 81.0, 80.1, 79.9, 79.8, 79.7, 78.6, 77.8, 77.4, 77.3, 75.9, 75.8, 75.2, 74.9, 74.8, 73.41, 73.37, 71.9, 71.2, 70.7, 69.8, 69.7, 67.6, 65.8, 60.6, 60.5, 59.4, 59.2, 57.3, 56.9, 55.2, 35.8, 34.8; IR (thin film) 3063, 3030, 2930, 2834, 1454, 1097 cm⁻¹; HRMS (ESI) m/z calcd for C₃₇H₄₈O₁₀Na (M + Na)⁺ 675.3145, found 675.3151. Anal. Calcd for C₃₇H₄₈O₁₀: C, 68.08; H, 7.41. Found: C, 68.09; H, 7.64.

Major Isomer (α-12)

¹H NMR (500 MHz, CDCl₃) δ 7.26–7.38 (m, 15H), 4.57–5.00 (m, 8H), 3.99 (m, 1H), 3.83 (dd, J = 11.4, 4.2 Hz, 1H), 3.74 (dd, J = 10.0, 3.1 Hz, 1H), 3.46–3.62 (m, 7H), 3.50 (s, 3H), 3.42 (s, 3H), 3.37 (s, 3H), 3.34 (s, 3H), 3.20 (m, 1H), 3.15 (t, J = 9.4 Hz, 1H), 2.24 (dd, J = 13.0, 5.0 Hz, 1H), 1.53 (ddd, J = 13.0, 11.6, 3.7 Hz, 1H).

Minor Isomer (β-12)

¹H NMR (500 MHz, CDCl₃) δ 7.26–7.38 (m, 15H), 4.57–5.00 (m, 8H), 4.18 (dd, J = 9.8, 1.2 Hz, 1H), 4.08 (dd, J = 11.0, 1.6 Hz, 1H), 3.99 (m, 1H), 3.46–3.62 (m, 7H), 3.51 (s, 3H), 3.40 (s, 3H), 3.37 (s, 3H), 3.35 (s, 3H), 3.20 (m, 1H), 2.99 (t, J = 9.1 Hz, 1H), 2.13 (dd, J = 12.5, 4.9 Hz, 1H), 1.47 (td, J = 12.2, 9.9 Hz, 1H)

C5-OBn Pyranoside trifluoroethanol substitution product trans-21/cis-21

The standard procedure for nucleophilic substitution of acetals was followed with thioglycoside 20 (0.050 g, 0.19 mmol), trifluoroethanol (0.050 mL, 0.75 mmol), and N-iodosuccinimide (0.084 g, 0.38 mmol) in CH₂Cl₂ at −78 °C. GC and ¹H NMR spectroscopic analysis of the unpurified product indicated a pair of diastereomers in a 83:17 (trans:cis) ratio. Purification by flash chromatography (3:1 hexane:EtOAc) afforded an inseparable mixture of diastereomers trans-21/cis-21 as a colorless oil (0.037 g, 65%): GC t_R(major) 12.9 min, t_R(minor) 13.2 min; IR (thin film) 3034, 2940, 1445, 1282, 1156 cm⁻¹; HRMS (ESI) m/z calcd for C₁₅H₁₉F₃O₃Na (M + Na)⁺ 327.1184, found 327.1174. Anal. Calcd for C₁₅H₁₉F₃O₃: C, 59.20; H, 6.29. Found: C, 59.50; H, 6.37.

Major Isomer (trans-21)

¹H NMR (500 MHz, CDCl₃) δ 7.25–7.37 (m, 5H), 4.96 (d, J = 2.6 Hz, 1H), 4.57 (m, 2H), 3.82–4.05 (m, 3H), 3.45 (m, 2H), 1.86 (m, 1H), 1.78 (m, 1H), 1.55–1.70 (m, 3H), 1.45 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 138.33, 128.4, 127.64, 127.59, 124.3 (q, J = 278.4 Hz), 97.8, 73.4, 73.2, 68.8, 63.7 (q, J = 25.8 Hz), 29.0, 27.19, 17.4.

Minor Isomer (cis-21)

¹H NMR (500 MHz, CDCl₃, distinctive peaks) δ 4.53 (dd, J = 8.8, 2.2 Hz, 1H), 4.14 (dq, J = 12.6, 9.2 Hz, 1H), 3.65 (dddd, J = 10.8, 6.2, 4.5, 2.0 Hz, 1H), 3.57 (dd, J = 10.1, 6.2 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃, distinctive peaks) δ 138.30, 128.5, 127.72, 127.69, 124.0 (q, J = 277.9 Hz), 102.1, 75.7, 73.5, 73.1, 65.0 (q, J = 34.7 Hz), 30.6, 27.15, 21.3.

C5-OBn Pyranoside difluoroethanol substitution product trans-22/cis-22

The standard procedure for nucleophilic substitution of acetals was followed with thioglycoside 20 (0.050 g, 0.19 mmol), difluoroethanol (0.048 mL, 0.75 mmol), and N-iodosuccinimide (0.084 g, 0.38 mmol) in CH₂Cl₂ at −78 °C. GC and ¹H NMR spectroscopic analysis of the unpurified product indicated a pair of diastereomers in an 74:26 (trans:cis) ratio. Purification by flash chromatography (5:1 hexane:EtOAc) afforded an inseparable mixture of diastereomers trans-22/cis-22 as a colorless oil (0.045 g, 79%): GC t_R(major) 14.1 min, t_R(minor) 14.3 min; IR (thin film) 3031, 2943, 2867, 1455, 1075 cm⁻¹; HRMS (ESI) m/z calcd for C₁₅H₂₀F₂O₃Na (M + Na)⁺ 309.1278, found 309.1281. Anal. Calcd for C₁₅H₂₀F₂O₃: C, 62.92; H, 7.04. Found: C, 63.20; H, 7.18.

Major Isomer (trans-22)

¹H NMR (500 MHz, CDCl₃) δ 7.25–7.38 (m, 5H), 5.97 (tt, J = 55.8, 8.4 Hz, 1H), 4.91 (d, J = 2.3 Hz, 1H), 4.57 (s, 2H), 3.95 (m, 1H), 3.84 (tdd, J = 15.8, 12.0, 3.9 Hz, 1H), 3.70 (m, 1H), 3.45 (m, 2H), 1.85 (m, 1H), 1.75 (m, 1H), 1.55–1.70 (m, 2H), 1.43 (m, 1H), 1.25 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 138.35, 128.4, 127.61, 127.58, 114.6 (t, J = 240.7 Hz), 98.3, 73.4, 68.5, 66.5 (t, J = 28.0 Hz), 29.3, 27.3, 17.5.

Minor Isomer (cis-22)

¹H NMR (500 MHz, CDCl₃, distinctive peaks) δ 5.95 (tdd, J = 56.0, 5.4, 3.1 Hz, 1H), 4.47 (dd, J = 9.4, 1.8 Hz, 1H), 3.56 (dd, J = 10.2, 6.1 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 138.29, 128.5, 127.72, 127.70, 114.7 (t, J = 240.9 Hz), 102.7, 75.6, 73.5, 73.2, 67.8 (dd, J = 29.6, 26.8 Hz), 30.7, 27.2, 21.5.

C5-OBn Pyranoside fluoroethanol substitution product trans-23/cis-23

The standard procedure for nucleophilic substitution of acetals was followed with thioglycoside 20 (0.050 g, 0.19 mmol), fluoroethanol (0.044 mL, 0.75 mmol), and N-iodosuccinimide (0.084 g, 0.38 mmol) in CH₂Cl₂ at −78 °C. GC and ¹H NMR spectroscopic analysis of the unpurified product indicated a pair of diastereomers in a 62:38 (trans:cis) ratio. Purification by flash chromatography (3:1 hexane:EtOAc) afforded an inseparable mixture of diastereomers trans-23/cis-23 as a colorless oil (0.046 g, 91%): GC t_R(major) 14.7 min, t_R(minor) 14.9 min; IR (thin film) 3030, 2946, 2865, 1453, 1041 cm⁻¹; HRMS (ESI) m/z calcd for C₁₅H₂₁FO₃Na (M + Na)⁺ 291.1372, found 291.1372. Anal. Calcd for C₁₅H₂₁FO₃: C, 67.14; H, 7.89. Found: C, 67.44; H, 7.95.

Major Isomer (trans-23)

¹H NMR (500 MHz, CDCl₃) δ 7.25–7.37 (m, 5H), 4.92 (d, J = 2.7 Hz, 1H), 4.50–4.68 (m, 4H), 3.98 (m, 1H), 3.92 (ddd, J = 32.3, 5.1, 2.7 Hz, 1H), 3.70 (m, 1H), 3.45 (m, 2H), 1.88 (m, 1H), 1.75 (m, 1H), 1.67 (m, 1H), 1.59 (m, 1H), 1.43 (m, 1H), 1.25 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 138.5, 128.43, 127.70, 127.60, 97.6, 83.02 (d, J = 168.8 Hz), 73.53, 73.3, 68.2, 66.0 (d, J = 19.9 Hz), 29.5, 27.5, 17.7.

Minor Isomer (cis-23)

¹H NMR (500 MHz, CDCl₃, distinctive peaks) δ 4.49 (dd, J = 9.4, 1.8 Hz, 1H), 4.07 (ddd, J = 33.8, 4.4, 2.7 Hz, 1H), 3.80 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 138.4, 128.33, 127.66, 127.57, 102.3, 83.04 (d, J = 168.8 Hz), 75.5, 73.50, 67.6 (d, J = 19.9), 31.0, 21.7.

C5-OBn Pyranoside bromoethanol substitution product trans-24/cis-24

The standard procedure for nucleophilic substitution of acetals was followed with thioglycoside 20 (0.050 g, 0.19 mmol), bromoethanol (0.053 mL, 0.75 mmol), and N-iodosuccinimide (0.084 g, 0.38 mmol) in CH₂Cl₂ at −78 °C. GC and ¹H NMR spectroscopic analysis of the unpurified product indicated a pair of diastereomers in a 62:38 (trans:cis) ratio. Purification by flash chromatography (3:1 hexane:EtOAc) afforded an inseparable mixture of diastereomers trans-24/cis-24 as a colorless oil (0.053 g, 85%): GC t_R(major) 17.2 min, t_R(minor) 17.4 min; IR (thin film) 3029, 2942, 2861, 1454, 1124 cm⁻¹; HRMS (ESI) m/z calcd for C₁₅H₂₁BrO₃Na (M + Na)⁺ 351.0572, found 351.0574. Anal. Calcd for C₁₅H₂₁BrO₃: C, 54.72; H, 6.43. Found: C, 54.95; H, 6.59.

Major Isomer (trans-24)

¹H NMR (500 MHz, CDCl₃) δ 7.26–7.35 (m, 5H), 4.93 (d, J = 2.3 Hz, 1H), 4.57 (m, 2H), 4.01 (dddd, J = 12.0, 6.1, 4.0, 2.6 Hz, 1H), 3.98 (m, 1H), 3.81 (m, 1H), 3.41–3.58 (m, 4H), 1.88 (m, 1H), 1.73 (m, 1H), 1.50–1.69 (m, 2H), 1.42 (m, 1H), 1.25 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 138.44, 128.4, 127.71, 127.59, 97.7, 73.5, 73.33, 68.5, 67.3, 31.2, 29.5, 27.5, 17.7.

Minor Isomer (cis-24)

¹H NMR (500 MHz, CDCl₃, distinctive peaks) δ 4.48 (dd, J = 9.5, 2.0 Hz, 1H), 4.14 (ddd, J = 11.3, 7.1, 5.4 Hz, 1H), 3.66 (dddd, J = 10.9, 6.4, 4.8, 2.0 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 138.37, 128.5, 127.67, 127.57, 102.6, 75.6, 73.28, 68.9, 30.9, 30.7, 27.4, 21.7.

C5-OBn pyranoside chloroethanol substitution product trans-25/cis-25

The standard procedure for nucleophilic substitution of acetals was followed with thioglycoside 20 (0.050 g, 0.19 mmol), chloroethanol (0.050 mL, 0.75 mmol), and N-iodosuccinimide (0.084 g, 0.38 mmol) in CH₂Cl₂ at −78 °C. GC and ¹H NMR spectroscopic analysis of the unpurified product indicated a pair of diastereomers in a 65:35 (trans:cis) ratio. Purification by flash chromatography (3:1 hexane:EtOAc) afforded an inseparable mixture of diastereomers trans-25/cis-25 as a colorless oil (0.046 g, 85%): GC t_R(major) 16.4 min, t_R(minor) 16.6 min; IR (thin film) 3030, 2944, 2864, 1353, 1035 cm⁻¹; HRMS (ESI) m/z calcd for C₁₅H₂₁ClO₃Na (M + Na)⁺ 307.1077, found 307.1074. Anal. Calcd for C₁₅H₂₁ClO₃: C, 63.26; H, 7.43. Found: C, 63.24; H, 7.53.

Major Isomer (trans-25)

¹H NMR (500 MHz, CDCl₃) δ 7.26–7.36 (m, 5H), 4.93 (d, J = 2.3 Hz, 1H), 4.57 (m, 2H), 4.01 (dddd, J = 12.0, 6.1, 4.5, 2.3 Hz, 1H), 3.94 (ddd, J = 10.9, 6.1, 5.3 Hz, 1H), 3.64–3.80 (m, 3H), 3.45 (m, 2H), 1.88 (m, 1H), 1.74 (m, 1H), 1.50–1.68 (m, 2H), 1.43 (m, 1H), 1.25 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 138.44, 128.4, 127.71, 127.59, 97.8, 73.5, 73.33, 68.4, 67.3, 43.4, 29.5, 27.5, 17.7.

Minor Isomer (cis-25)

¹H NMR (500 MHz, CDCl₃, distinctive peaks) δ 4.48 (dd, J = 9.4, 2.1 Hz, 1H), 4.10 (ddd, J = 11.0, 5.9, 5.3 Hz, 1H), 3.56 (dd, J = 10.0, 6.1 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 138.38, 128.5, 127.67, 127.57, 102.6, 75.6, 73.29, 68.9, 43.0, 30.9, 27.4, 21.7.

C5-OBn Pyranoside ethanol substitution product trans-26/cis-26

The standard procedure for nucleophilic substitution of acetals was followed with thioglycoside 20 (0.050 g, 0.19 mmol), ethanol (0.043 mL, 0.75 mmol), and N-iodosuccinimide (0.084 g, 0.38 mmol) in CH₂Cl₂ at −78 °C. GC and ¹H NMR spectroscopic analysis of the unpurified product indicated a pair of diastereomers in a 49:51 (trans:cis) ratio. Purification by flash chromatography (3:1 hexane:EtOAc) afforded an inseparable mixture of diastereomers trans-26/cis-26 as a colorless oil (0.038 g, 81%): GC t_R(major) 13.8 min, t_R(minor) 14.1 min; ¹H NMR (500 MHz, CDCl₃, mixture of anomers) δ 7.25–7.36 (10H), 4.88 (s, 1H), 4.57 (m, 4H), 4.43 (dd, J = 9.4, 2.1 Hz, 1H), 3.97 (m, 2H), 3.76 (ddd, J = 14.3, 9.8, 7.3 Hz, 1H), 3.66 (m, 1H), 3.41–3.60 (m, 6H), 1.86 (m, 2H), 1.78 (m, 1H), 1.48–1.69 (m, 7H), 1.41 (m, 2H), 1.23 (m, 6H); ¹³C NMR (125 MHz, CDCl₃, mixture of anomers) δ 138.53, 138.49, 128.41, 128.37, 127.7, 127.6, 127.5, 102.0, 97.0, 75.5, 73.7, 73.51, 73.46, 73.3, 67.9, 64.2, 62.2, 31.3, 29.8, 27.7, 27.6, 21.9, 17.8, 15.3, 15.2; IR (thin film) 3029, 2933, 2870, 1450, 1111 cm⁻¹; HRMS (ESI) m/z calcd for C₁₅H₂₂O₃Na (M + Na)⁺ 273.1467, found 273.1465. Anal. Calcd for C₁₅H₂₂O₃: C, 71.97; H, 8.86. Found: C, 72.22; H, 9.00.

C4-OBn Pyranoside trifluoroethanol substitution product trans-30/cis-30

The standard procedure for nucleophilic substitution of acetals was followed with thioglycoside 29 (0.050 g, 0.20 mmol), trifluoroethanol (0.057 mL, 0.80 mmol), and N-iodosuccinimide (0.089 g, 0.40 mmol) in CH₂Cl₂ at −78 °C. ¹H NMR spectroscopic analysis of the unpurified product indicated a pair of diastereomers in an 88:12 (trans:cis) ratio. Purification by flash chromatography (3:1 hexane:EtOAc) afforded a inseparable mixture of diastereomers trans-30/cis-30 as a colorless oil (0.046 g, 81%): GC t_R(major and minor) 12.6 min; IR (thin film) 3033, 2928, 1445, 1282, 1156 cm⁻¹; HRMS (ESI) m/z calcd for C₁₄H₁₇F₃O₃Na (M + Na)⁺ 313.1028, found 313.1031. Anal. Calcd for C₁₄H₁₇F₃O₃: C, 57.93; H, 5.90. Found: C, 58.19; H, 6.02.

Major Isomer (trans-30)

¹H NMR (500 MHz, CDCl₃) δ 7.26–7.37 (m, 5H), 4.83 (t, J = 2.9 Hz, 1H), 4.57 (m, 2H), 4.00 (dq, J = 12.2, 8.9 Hz, 1H), 3.88 (dq, J = 12.2, 8.6 Hz, 1H), 3.84 (dd, J = 12.0, 2.2 Hz, 1H), 3.66 (dt, J = 12.4, 2.5 Hz, 1H), 3.49 (bs, 1H), 2.12 (tt, J = 12.6, 3.8 Hz, 1H), 2.00 (tt, J = 12.7, 3.7 Hz, 1H), 1.79 (m, 1H), 1.62 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 138.5, 128.5, 127.7, 127.6, 125.1 (q, J = 278.3 Hz), 98.1, 70.8, 70.4, 64.3 (q, J = 25.9 Hz), 62.8, 25.0, 22.3.

Minor Isomer (cis-30)

¹H NMR (500 MHz, CDCl₃, distinctive peaks) δ 4.76 (s, 1H), 3.71 (dd, J = 10.5, 4.4 Hz, 1H), 3.58 (t, J = 10.2 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃, distinctive peaks) δ 138.4, 96.9, 72.0, 70.6, 64.0 (q, J = 34.5 Hz), 63.1, 28.2, 24.6.

C4-OBn Pyranoside difluoroethanol substitution product trans-31/cis-31

The standard procedure for nucleophilic substitution of acetals was followed with thioglycoside 29 (0.050 g, 0.20 mmol), difluoroethanol (0.050 mL, 0.80 mmol), and N-iodosuccinimide (0.089 g, 0.40 mmol) in CH₂Cl₂ at −78 °C. ¹H NMR spectroscopic analysis of the unpurified product indicated a pair of diastereomers in a 82:18 (trans:cis) ratio. Purification by flash chromatography (3:1 pentane:Et₂O) afforded an inseparable mixture of diastereomers trans-31/cis-31 as a colorless oil (0.037 g, 68%): GC t_R(major and minor) 13.7 min; IR (thin film) 3029, 2935, 2867, 1062 cm⁻¹; HRMS (ESI) m/z calcd for C₁₄H₁₈F₂O₃Na (M + Na)⁺ 295.1122, found 295.1126. Anal. Calcd for C₁₄H₁₈F₂O₃: C, 61.75; H, 6.66. Found: C, 62.04; H, 6.76.

Major Isomer (trans-31)

¹H NMR (500 MHz, CDCl₃) δ 7.26–7.37 (m, 5H), 5.91 (tt, J = 55.7, 4.1 Hz, 1H), 4.75 (t, J = 3.1 Hz, 1H), 4.57 (m, 2H), 3.86 (m, 2H), 3.70 (m, 1H), 3.62 (ddd, J = 12.0, 3.8, 1.6 Hz, 1H), 3.48 (bs, 1H), 2.09 (tt, J = 12.3, 3.6 Hz, 1H), 2.00 (tt, J = 12.2, 3.7 Hz, 1H), 1.75 (m, 1H), 1.58 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 138.50, 128.47, 127.7, 127.6, 114.5 (t, J = 240.7 Hz), 98.7, 71.0, 70.4, 66.8 (t, J = 28.0 Hz), 63.1, 25.6, 22.9.

Minor Isomer (cis-31)

¹H NMR (500 MHz, CDCl₃, distinctive peaks) δ 4.70 (t, J = 2.7 Hz, 1H), 1.91 (m, 2H), 1.83 (m, 1H); ¹³C NMR (125 MHz, CDCl₃, distinctive peaks) δ 138.46, 128.49, 127.8, 127.7, 97.3, 72.1, 70.6, 66.4 (t, J = 28.6), 28.3, 24.8.

C4-OBn Pyranoside fluoroethanol substitution product trans-32/cis-32

The standard procedure for nucleophilic substitution of acetals was followed with thioglycoside 29 (0.10 g, 0.40 mmol), fluoroethanol (0.044 mL, 0.16 mmol), and N-iodosuccinimide (0.18 g, 0.79 mmol) in CH₂Cl₂ at −78 °C. ¹H NMR spectroscopic analysis of the unpurified product indicated a pair of diastereomers in a 71:29 (trans:cis) ratio. Purification by flash chromatography (5:1 hexane:EtOAc) afforded an inseparable mixture of diastereomers trans-32/cis-32 as a colorless oil (0.072 g, 72%): GC t_R(major and minor) 14.4 min; IR (thin film) 3031, 2952, 2970, 1454, 1041 cm⁻¹; HRMS (ESI) m/z calcd for C₁₄H₁₉FO₃Na (M + Na)⁺ 277.1216, found 277.1217. Anal. Calcd for C₁₄H₁₉FO₃: C, 66.12; H, 7.53. Found: C, 66.31; H, 7.59.

Major Isomer (trans-32)

¹H NMR (500 MHz, CDCl₃) δ 7.25–7.37 (m, 5H), 4.75 (t, J = 3.1 Hz, 1H), 4.51–4.64 (m, 4H), 3.90 (dd, J = 11.7, 2.4 Hz, 1H), 3.62–3.77 (m, 2H), 3.59 (ddd, J = 12.0, 4.3, 1.5 Hz, 1H), 3.48 (bs, 1H), 2.06 (m, 1H), 1.91 (m, 1H), 1.73 (m, 1H), 1.58 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 138.59, 128.45, 127.6, 98.4, 83.0 (d, J = 169.2 Hz), 71.3, 70.4, 66.7 (d, J = 19.9 Hz), 63.2, 26.1, 23.4.

Minor Isomer (cis-32)

¹H NMR (500 MHz, CDCl₃, distinctive peaks) δ 4.71 (t, J = 3.2 Hz, 1H), 3.97 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 138.56, 128.47, 127.7, 96.9, 82.9 (d, J = 169.2 Hz), 72.3, 70.5, 66.2 (d, J = 19.9 Hz), 62.9, 28.5, 24.9.

C4-OBn Pyranoside bromoethanol substitution product trans-33/cis-33

The standard procedure for nucleophilic substitution of acetals was followed with thioglycoside 29 (0.10 g, 0.40 mmol), bromoethanol (0.11 mL, 1.6 mmol), and N-iodosuccinimide (0.18 g, 0.80 mmol) in CH₂Cl₂ at −78 °C. GC and ¹H NMR spectroscopic analysis of the unpurified product indicated a pair of diastereomers in n 61:39 (trans:cis) ratio. Purification by flash chromatography (5:1 hexane:EtOAc) afforded an inseparable mixture of diastereomers trans-33/cis-33 as a colorless oil (0.10 g, 83%): GC t_R(major) 17.1 min, t_R(minor) 17.2 min; IR (thin film) 3030, 2935, 2868, 1456, 1027 cm⁻¹; HRMS (ESI) m/z calcd for C₁₄H₁₉BrO₃Na (M + Na)⁺ 337.0415, found 337.0415. Anal. Calcd for C₁₄H₁₉BrO₃: C, 53.35; H, 6.08. Found: C, 53.45; H, 6.11.

Major Isomer (trans-33)

¹H NMR (500 MHz, CDCl₃) δ 7.25 (m, 5H), 4.75 (t, J = 3.1 Hz, 1H), 4.57 (m, 2H), 3.99 (m, 1H), 3.93 (dd, J = 12.0, 2.3 Hz, 1H), 3.79 (m, 1H), 3.60 (ddd, J = 11.9, 4.0, 1.7 Hz, 1H), 3.50 (m, 3H), 2.06 (m, 1H), 1.91 (m, 1H), 1.75 (m, 1H), 1.57 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 138.6, 128.4, 127.653, 127.646, 98.4, 71.2, 70.4, 67.7, 63.4, 31.0, 26.0, 23.4.

Minor Isomer (cis-33)

¹H NMR (500 MHz, CDCl₃, distinctive peaks) δ 4.71 (t, J = 2.6 Hz, 1H), 4.57 (m, 2H), 3.74 (m, 1H), 3.66 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 138.5, 128.5, 127.7, 97.0, 72.2, 70.6, 67.3, 63.2, 30.7, 28.5, 24.9.

C4-OBn Pyranoside chloroethanol substitution product trans-34/cis-34

The standard procedure for nucleophilic substitution of acetals was followed with thioglycoside 29 (0.10 g, 0.40 mmol), chloroethanol (0.11 mL, 1.6 mmol), and N-iodosuccinimide (0.18 g, 0.80 mmol) in CH₂Cl₂ at −78 °C. ¹H NMR spectroscopic analysis of the unpurified product indicated a pair of diastereomers in a 67:33 (trans:cis) ratio. Purification by flash chromatography (5:1 hexane:EtOAc) afforded an inseparable mixture of diastereomers trans-34/cis-34 as a colorless oil (0.085 g, 79%): GC t_R(major) 16.2 min, t_R(minor) 16.3 min; IR (thin film) 3031, 2937, 2869, 1454, 1038 cm⁻¹; HRMS (ESI) m/z calcd for C₁₄H₁₉ClO₃Na (M + Na)⁺ 293.0920, found 293.0925. Anal. Calcd for C₁₄H₁₉ClO₃: C, 62.10; H, 7.07. Found: C, 61.86; H, 7.08.

Major Isomer (trans-34)

¹H NMR (500 MHz, CDCl₃) δ 7.25–7.37 (m, 5H), 4.75 (t, J = 3.1 Hz, 1H), 4.57 (m, 2H), 3.95 (m, 1H), 3.92 (m, 1H), 3.73 (m, 1H), 3.67 (m, 2H), 3.59 (ddd, J = 11.9, 4.0, 1.6 Hz, 1H), 3.48 (bs, 1H), 2.06 (m, 1H), 1.91 (m, 1H), 1.75 (m, 1H), 1.57 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 138.6, 128.45, 127.653, 127.646, 98.5, 71.2, 70.4, 67.9, 63.4, 43.2, 26.0, 23.4.

Minor Isomer (cis-34)

¹H NMR (500 MHz, CDCl₃, distinctive peaks) δ 4.71 (t, J = 2.6 Hz, 1H), 4.57 (m, 2H), 3.49 (m, 1H), 1.85 (m, 1H), 1.67 (m, 1H); ¹³C NMR (125 MHz, CDCl_3,) δ 138.5, 128.48, 127.7, 97.0, 72.2, 70.6, 67.4, 63.1, 43.0, 28.5, 24.9.

C4-OBn Pyranoside ethanol substitution product trans-35/cis-35

The standard procedure for nucleophilic substitution of acetals was followed with thioglycoside 29 (0.050 g, 0.20 mmol), ethanol (0.046 mL, 0.80 mmol), and N-iodosuccinimide (0.089 g, 0.40 mmol) in CH₂Cl₂ at −78 °C. GC and ¹H NMR spectroscopic analysis of the unpurified product indicated a pair of diastereomers in a 51:49 (trans:cis) ratio. Purification by flash chromatography (3:1 hexane:EtOAc) afforded an inseparable mixture of diastereomers trans-35/cis-35 as a colorless oil (0.033 g, 70%): GC t_R(major) 13.5 min, t_R(minor) 13.6 min; ¹H NMR (500 MHz, CDCl₃, mixture of anomers) δ 7.25–7.37 (m, 10H), 4.66 (bs, 2H), 4.57 (m, 4H), 3.91 (dd, J = 11.7, 2.4 Hz, 1H), 3.71–3.83 (m, 2H), 3.65 (m, 2H), 3.40–3.56 (m, 5H), 2.04 (m, 2H), 1.80–1.94 (m, 3H), 1.67 (m, 2H), 1.58 (m, 1H), 1.22 (m, 6H); ¹³C NMR (125 MHz, CDCl₃, mixture of anomers) δ 138.64, 138.63, 128.45, 128.44, 127.66, 127.65, 127.64, 127.63, 98.4, 96.4, 72.4, 71.6, 70.50, 70.47, 63.8, 63.3, 62.9, 62.6, 28.8, 26.9, 25.1, 24.2, 15.3, 15.2; IR (thin film) 3030, 2934, 2872, 1364, 1090 cm⁻¹; HRMS (ESI) m/z calcd for C₁₄H₂₀O₃Na (M + Na)⁺ 259.1310, found 259.1311. Anal. Calcd for C₁₄H₂₀O₃: C, 71.16; H, 8.53. Found: C, 71.35; H, 8.47.

C3-OBn Pyranoside trifluoroethanol substitution product cis-39/trans-39

The standard procedure for nucleophilic substitution of acetals was followed with thioglycoside 38 (0.030 g, 0.12 mmol), trifluoroethanol (0.034 mL, 0.48 mmol), 2,6-di-tert-butyl-4-methylpyridine (0.049 g, 0.24 mmol), and N-iodosuccinimide (0.054 g, 0.24 mmol) in CH₃CN at 0 °C. GC and ¹H NMR spectroscopic analysis of the unpurified product indicated a pair of diastereomers in an 86:14 (cis:trans) ratio. Purification by flash chromatography (3:1 pentane:Et₂O) afforded a separable mixture of diastereomers cis-39/trans-39 as a colorless oil (0.024 g, 69%). IR, mass spectrometry, and combustion analysis data was obtained for major isomer (cis-39) and minor isomer (trans-39) as a mixture of diastereomers: GC t_R(major) 12.5 min, t_R(minor) 12.1 min; IR (thin film) 3029.8, 2954, 2861, 1280, 1162 cm⁻¹; HRMS (ESI) m/z calcd for C₁₄H₁₇F₃O₃Na (M + Na)⁺ 313.1028, found 313.1027.

Major Isomer (cis-39)

¹H NMR (500 MHz, CDCl₃) δ 7.26–7.38 (m, 5H), 4.58 (m, 2H), 4.56 (dd, J = 7.5, 2.2 Hz, 1H), 4.10 (m, 2H), 3.92 (m, 1H), 3.64 (tt, J = 8.9, 4.2 Hz, 1H), 3.40 (ddd, J = 12.2, 9.9, 2.8 Hz, 1H), 2.23 (m, 1H), 1.94 (m, 1H), 1.61–1.73 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 138.4, 128.5, 127.7, 127.6, 124.0 (q, J = 278.4 Hz), 99.9, 71.9, 69.9, 65.0 (q, J = 25.9 Hz), 60.8, 36.3, 31.3.

Minor Isomer (trans-39)

¹H NMR (500 MHz, CDCl₃) δ 7.22–7.39 (m, 5H), 5.01 (t, J = 2.8 Hz, 1H), 4.55 (m, 2H), 3.80–4.00 (m, 3H), 3.76 (m, 2H), 2.19 (ddt, J = 13.1, 4.5, 2.3 Hz, 1H), 2.0 (d, J = 12.2 Hz, 1H), 1.69 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 138.5, 128.5, 127.7, 127.6, 124.0 (q, J = 278.4 Hz), 98.8, 70.4, 70.1, 64.1 (q, J = 34.2 Hz), 59.4, 36.3, 31.9.

C3-OBn Pyranoside difluoroethanol substitution product cis-43/trans-43

The standard procedure for nucleophilic substitution of acetals was followed with thioglycoside 38 (0.030 g, 0.12 mmol), difluoroethanol (0.030 mL, 0.48 mmol), 2,6-di-tert-butyl-4-methylpyridine (0.054 g, 0.24 mmol), and N-iodosuccinimide (0.049 g, 0.24 mmol) in CH₃CN at 0 °C. GC and ¹H NMR spectroscopic analysis of the unpurified product indicated a pair of diastereomers in a 84:16 (cis:trans) ratio. Purification by flash chromatography (3:1 pentane:Et₂O) afforded a separable mixture of diastereomers cis-43/trans-43 as a colorless oil (0.022 g, 68%). IR, mass spectrometry, and combustion analysis data was obtained for major isomer (cis-43) and minor isomer (trans-43) as a mixture of diastereomers: GC t_R(major) 13.7 min, t_R(minor) 13.3 min; IR (thin film) 3029, 2931, 2851, 1359, 1072 cm⁻¹; HRMS (ESI) m/z calcd for C₁₄H₁₈F₂O₃Na (M + Na)⁺ 295.1122, found 295.1120.

Major Isomer (cis-43)

¹H NMR (500 MHz, CDCl₃) δ 7.24–7.37 (m, 5H), 5.93 (tdd, J = 55.7, 5.4, 3.1 Hz, 1H), 4.58 (m, 2H), 4.47 (dd, J = 8.2, 2.6 Hz, 1H), 4.08 (dt, J = 12.4, 4.1 Hz, 1H), 3.95 (m, 1H), 3.75 (m, 1H), 3.61 (tt, J = 9.4, 4.3 Hz, 1H), 3.38 (ddd, J = 12.0, 10.9, 2.7 Hz, 1H), 2.24 (ddt, J = 12.7, 4.2, 2.1 Hz, 1H), 1.94 (m, 1H), 1.62 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 138.4, 128.5, 127.7, 127.6, 114.5 (t, J = 240.9 Hz), 100.5, 72.3, 69.8, 67.7 (t, J = 28.5 Hz), 61.1, 36.9, 31.4.

Minor Isomer (trans-43)

¹H NMR (500 MHz, CDCl₃) δ 7.24–7.36 (m, 5H), 5.90 (tdd, J = 55.6, 4.6, 3.7 Hz, 1H), 4.96 (t, J = 3.2 Hz, 1H), 4.55 (m, 2H), 3.88 (tt, J = 9.2, 4.2 Hz, 1H), 3.82 (m, 1H), 3.76 (m, 2H), 3.66 (m, 1H), 2.14 (dddd, J = 13.0, 4.5, 2.8, 2.0 Hz, 1H), 1.98 (m, 1H), 1.71 (ddd, J = 13.3, 10.0, 3.4 Hz, 1H), 1.64 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 138.8, 128.7, 127.81, 127.76, 114.6 (t, J = 241.0 Hz), 99.2, 70.8, 70.2, 66.8 (t, J = 28.0 Hz), 59.5, 36.7, 32.0.

C3-OBn Pyranoside fluoroethanol substitution product cis-44/trans-44

The standard procedure for nucleophilic substitution of acetals was followed with thioglycoside 38 (0.030 g, 0.12 mmol), fluoroethanol (0.028 mL, 0.48 mmol), 2,6-di-tert-butyl-4-methylpyridine (0.049 g, 0.24 mmol), and N-iodosuccinimide (0.054 g, 0.24 mmol) in CH₃CN at 0 °C. GC and ¹H NMR spectroscopic analysis of the unpurified product indicated a pair of diastereomers in a 74:26 (cis:trans) ratio. Purification by flash chromatography (3:1 pentane:Et₂O) afforded a separable mixture of diastereomers cis-44/trans-44 as a colorless oil (0.019 g, 63%). IR, mass spectrometry, and combustion analysis data was obtained for major isomer (cis-44) and minor isomer (trans-44) as a mixture of diastereomers: GC t_R(major) 14.3 min, t_R(minor) 14.0 min; IR (thin film) 3028, 2959, 2864, 1359, 1058 cm^-1; HRMS (ESI) m/z calcd for C₁₄H₁₉FO₃Na (M + Na)⁺ 277.1216, found 277.1215.

Major Isomer (cis-44)

¹H NMR (500 MHz, CDCl₃) δ 7.23–7.38 (m, 5H), 4.50–4.69 (m, 4H), 4.45 (dd, J = 8.7, 2.4 Hz, 1H), 4.07 (m, 1H), 3.71–3.85 (m, 2H), 3.60 (tt, J = 9.9, 4.3 Hz, 1H), 3.37 (td, J = 11.7, 2.5 Hz, 1H), 2.29 (ddt, J = 12.4, 4.2, 2.1 Hz, 1H), 1.94 (m, 1H), 1.60 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 138.5, 128.5, 127.7, 127.6, 100.4, 83.0 (d, J = 169.2 Hz), 72.8, 69.8, 67.7 (d, J = 19.4 Hz), 61.5, 37.4, 31.7.

Minor Isomer (trans-44)

¹H NMR (500 MHz, CDCl₃) δ 7.21–7.40 (m, 5H), 4.96 (t, J = 3.1 Hz, 1H), 4.56 (dt, J = 47.6, 4.3 Hz, 2H), 4.55 (m, 2H), 3.92 (m, 2H), 3.85 (m, 1H), 3.72 (m, 2H), 2.16 (ddd, J = 13.1, 4.6, 2.2 Hz, 1H), 1.99 (m, 1H), 1.56–1.75 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 138.7, 128.5, 127.7, 127.6, 98.5, 82.9 (d, J = 169.2 Hz), 70.9, 70.0, 66.4 (d, J = 19.9 Hz), 59.1, 36.7, 32.0.

C3-OBn Pyranoside bromoethanol substitution product cis-45/trans-45

The standard procedure for nucleophilic substitution of acetals was followed with thioglycoside 38 (0.030 g, 0.12 mmol), bromoethanol (0.033 mL, 0.48 mmol), 2,6-di-tert-butyl-4-methylpyridine (0.049 g, 0.24 mmol), and N-iodosuccinimide (0.054 g, 0.24 mmol) in CH₃CN at 0 °C. GC and ¹H NMR spectroscopic analysis of the unpurified product indicated a pair of diastereomers in a 60:40 (cis:trans) ratio. Purification by flash chromatography (3:1 pentane:Et₂O) afforded a separable mixture of diastereomers cis-45/trans-45 as a colorless oil (0.017 g, 46%). IR, mass spectrometry, and combustion analysis data was obtained for major isomer (cis-45) and minor isomer (trans-45) as a mixture of diastereomers: GC t_R(major) 17.1 min, t_R(minor) 16.8 min; IR (thin film) 3030, 2930, 2858, 1362, 1097 cm⁻¹; HRMS (ESI) m/z calcd for C₁₄H₁₉BrO₃Na (M + Na)⁺ 337.0415, found 337.0410.

Major Isomer (cis-45)

¹H NMR (500 MHz, CDCl₃) δ 7.22–7.40 (m, 5H), 4.55 (m, 2H), 4.44 (dd, J = 8.6, 2.4 Hz, 1H), 4.06 (m, 1H), 3.82 (m, 1H), 3.75 (m, 1H), 3.59 (tt, J = 9.6, 4.3 Hz, 1H), 3.51 (m, 2H), 3.36 (td, J = 11.6, 2.6 Hz, 1H), 2.25 (ddt, J = 12.5, 4.2, 2.0 Hz, 1H), 1.92 (m, 1H), 1.58–1.72 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 138.5, 128.5, 127.6, 127.6, 100.5, 72.7, 69.8, 68.9, 61.4, 37.3, 31.6, 30.6.

Minor Isomer (trans-45)

¹H NMR (500 MHz, CDCl₃) δ 7.22–7.40 (m, 5H), 4.97 (t, J = 3.1 Hz, 1H), 4.55 (m, 2H), 4.07 (m, 1H), 3.96 (m, 1H), 3.90 (tt, J = 9.4, 4.2 Hz, 1H), 3.82 (td, J = 11.2, 3.2 Hz, 1H), 3.74 (m, 1H), 3.49 (m, 2H), 2.12 (m, 1H), 1.98 (m, 1H), 1.70 (ddd, J = 13.0, 9.7, 3.1 Hz, 1H), 1.64 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 138.7, 128.5, 127.7, 127.6, 98.5, 70.9, 70.0, 67.5, 59.3, 36.7, 31.9, 30.8.

C3-OBn Pyranoside chloroethanol substitution product cis-46/trans-46

The standard procedure for nucleophilic substitution of acetals was followed with thioglycoside 38 (0.030 g, 0.12 mmol), chloroethanol (0.032 mL, 0.48 mmol), 2,6-di-tert-butyl-4-methylpyridine (0.049 g, 0.24 mmol), and N-iodosuccinimide (0.054 g, 0.24 mmol) in CH₃CN at 0 °C. GC and ¹H NMR spectroscopic analysis of the unpurified product indicated a pair of diastereomers in a 75:25 (cis:trans) ratio. Purification by flash chromatography (3:1 pentane:Et₂O) afforded a separable mixture of diastereomers cis-46/trans-46 as a colorless oil (0.021 g, 64%). IR, mass spectrometry, and combustion analysis data was obtained for major isomer (cis-46) and minor isomer (trans-46) as a mixture of diastereomers: GC t_R(major) 16.2 min, t_R(minor) 15.9 min; IR (thin film) 3030, 2929, 2856, 1454, 1065 cm⁻¹; HRMS (ESI) m/z calcd for C₁₄H₁₉ClO₃Na (M + Na)⁺ 293.0920, found 293.0919.

Major Isomer (cis-46)

¹H NMR (500 MHz, CDCl₃) δ 7.24–7.38 (m, 5H), 4.58 (m, 2H), 4.45 (dd, J = 8.4, 2.4 Hz, 1H), 4.07 (m, 2H), 3.75 (m, 1H), 3.67 (m, 2H), 3.60 (tt, J = 9.8, 4.4 Hz, 1H), 3.37 (td, J = 11.6, 2.6 Hz, 1H), 2.26 (ddt, J = 12.5, 4.2, 2.0 Hz, 1H), 1.93 (m, 1H), 1.60 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 138.5, 128.5, 127.7, 127.6, 100.5, 72.7, 69.8, 69.0, 61.4, 43.0, 37.3, 31.6.

Minor Isomer (trans-46)

¹H NMR (500 MHz, CDCl₃) δ 7.23–7.38 (m, 5H), 4.96 (t, J = 3.1 Hz, 1H), 4.57 (m, 2H), 3.90 (m, 2H), 3.81 (td, J = 11.1, 2.8 Hz 1H), 3.74 (m, 1H), 3.66 (m, 3H), 2.13 (m, 1H), 1.97 (m, 1H), 1.71 (ddd, J = 13.2, 10.2, 3.5 Hz, 1H), 1.59 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 138.7, 128.5, 127.7, 127.6, 98.6, 70.9, 70.0, 67.6, 59.3, 43.1, 37.7, 31.9.

C3-OBn Pyranoside ethanol substitution product cis-40/trans-40

The standard procedure for nucleophilic substitution of acetals was followed with thioglycoside 38 (0.030 g, 0.12 mmol), ethanol (0.028 mL, 0.48 mmol), 2,6-di-tert-butyl-4-methylpyridine (0.049 g, 0.24 mmol), and N-iodosuccinimide (0.054 g, 0.24 mmol) in CH₃CN at 0 °C. GC and ¹H NMR spectroscopic analysis of the unpurified product indicated a pair of diastereomers in a 52:48 (cis:trans) ratio. Purification by flash chromatography (3:1 pentane:Et₂O) afforded a separable mixture of diastereomers cis-40/trans-40 as a colorless oil (0.027 g, 89%). IR, mass spectrometry, and combustion analysis data was obtained for major isomer (cis-40) and minor isomer (trans-40) as a mixture of diastereomers: GC t_R(major) 13.6 min, t_R(minor) 13.2 min; ¹H NMR (500 MHz, CDCl₃, mixture of anomers) δ 7.25–7.37 (m, 10H), 4.92 (t, J = 3.2 Hz, 1H), 4.56 (m, 4H), 4.35 (dd, J = 9.0, 2.3 Hz, 1H), 4.05 (ddd, J = 12.1, 4.7, 2.6 Hz, 1H), 3.90 (m, 2H), 3.70–3.80 (m, 3H), 3.57 (ddd, J = 14.8, 9.8, 4.4 Hz, 1H), 3.52 (dq, J = 9.4, 7.0 Hz, 1H), 3.44 (dq, J = 9.9, 7.1 Hz, 1H), 3.35 (td, J = 11.9, 2.4 Hz, 1H), 2.24 (ddt, J = 12.2, 4.0, 2.0 Hz, 1H), 2.07 (m, 1H), 1.89–1.98 (m, 2H), 1.71 (ddd, J = 13.1, 9.8, 3.3 Hz, 1H), 1.61 (m, 2H), 1.53 (m, 1H), 1.22 (m, 6H); ¹³C NMR (125 MHz, CDCl₃, mixture of anomers) δ 138.8, 138.5, 128.5, 128.4, 127.66, 127.65, 127.59, 127.56, 100.2, 97.9, 73.2, 71.2, 70.0, 69.7, 64.4, 62.9, 61.7, 59.0, 38.0, 37.0, 32.0, 31.9, 15.3, 15.2; IR (thin film) 3030, 2930, 2871, 1361, 1070 cm⁻¹; HRMS (ESI) m/z calcd for C₁₄H₂₀O₃Na (M + Na)⁺ 259.1310, found 259.1317.